Use of nicotinic acetylcholine receptor alpha 7 activators

Abstract

The present invention relates to the use of nicotinic acetylcholine receptor alpha 7 activators, in particular to the use of nicotinic acetylcholine receptor alpha 7 agonists for the treatment, prevention or delay of progression of dyskinesia associated with dopamine agonist therapy in Parkinson's disease.

Description

Uses of nicotinic acetylcholine receptor α7 activators

[0001] This application is a divisional application of PCT application PCT / EP2010 / 063946, filed on September 22, 2010, entitled "Use of nicotinic acetylcholine receptor α7 activator". The date of entry into the Chinese national phase of the PCT application was March 22, 2012, and the application number was 201080042255.4. Technical Field

[0002] This invention relates to the pharmaceutical use of nicotinic acetylcholine receptor α7 (α7-nAChR) activators, i.e., α7-nAChR agonists or positive allosteric modulators. Background Technology

[0003] Parkinson's disease (PD) is a chronic and progressive degenerative disorder of the central nervous system that typically impairs motor skills and language abilities. PD is characterized by a variety of features, including one or more of the following: tremor, rigidity, bradykinesia, akinesia, gait and postural disturbances, postural instability, speech and swallowing difficulties, and cognitive impairment (such as memory loss, dementia, and slowed reaction time). PD is believed to be directly caused by the loss of dopamine-producing cells in the substantia nigra. More than 60,000 new cases of PD are diagnosed annually in the United States alone.

[0004] The most common treatment for Parkinson's disease is dopamine agonist therapy, such as the combination of L-DOPA (levodopa) and decarboxylase inhibitors (e.g., carbidopa). However, for many patients, long-term dopamine agonist therapy causes involuntary movements (movement disorders), a significant side effect (Reviews: Fabbrini et al., Movement Disorders, 2007, 22(10), 1379-1389; Konitsiotis, Expert Opin Investig Drugs, 2005, 14(4), 377-392; Brown et al., IDrugs, 2002, 5(5), 454-468). Therefore, there is a need for an effective regimen to suppress or treat movement disorders without adversely affecting the treatment of Parkinson's disease.

[0005] Compounds described as α7-nAChR agonists or α7-nAChR positive allosteric modulators have been described, for example, in WO2001 / 85727, WO2004 / 022556, WO2005 / 118535, WO2005 / 123732, WO2006 / 005608, WO2007 / 045478, WO2007 / 068476, WO2007 / 068475 and Haydar et al. (Current Topics in Medicinal Chemistry, 2010, 10, 144-152). Summary of the Invention

[0006] α7-nAChR agonists or α7-nAChR-positive allosteric modulators have been found to be useful for treating, preventing, or delaying the development of motor disorders associated with dopamine agonist treatment for Parkinson's disease. In particular, α7-nAChR agonists or α7-nAChR-positive allosteric modulators have been found to be useful for treating, preventing, or delaying the development of said motor disorders, wherein said treatment includes administration of levodopa.

[0007] Therefore, a first aspect of the present invention relates to the use of an α7-nAChR agonist or an α7-nAChR positive allosteric modulator for the treatment (therapeutic or prophylactic), prevention of motor disorders associated with dopamine agonist treatment of Parkinson's disease, or delay of its progression.

[0008] One embodiment of the first aspect relates to the use of an α7-nAChR agonist for the treatment (therapeutic or prophylactic), prevention of motor disorders associated with dopamine agonist treatment of Parkinson's disease, or delay of its progression.

[0009] Another embodiment of the first aspect relates to the use of an α7-nAChR positive allosteric modulator for the treatment (therapeutic or prophylactic), prevention of motor disorders associated with dopamine agonist treatment of Parkinson's disease, or delay of its progression.

[0010] Another aspect of the present invention relates to a method for treating, preventing, or delaying the progression of motor disorders associated with dopamine agonist treatment for Parkinson's disease in subjects requiring such treatment, including administering a therapeutically effective amount of an α7-nAChR agonist or an α7-nAChR positive allosteric modulator to the subject.

[0011] One embodiment of the other aspect relates to a method for treating, preventing, or delaying the progression of motor disorders associated with dopamine agonist treatment for Parkinson's disease in subjects requiring such treatment, including administering a therapeutically effective amount of an α7-nAChR agonist to the subject.

[0012] Another embodiment of the other aspect relates to a method for treating, preventing, or delaying the progression of motor disorders associated with dopamine agonist treatment for Parkinson's disease in subjects requiring such treatment, including administering a therapeutically effective amount of an α7-nAChR-positive allosteric modulator to the subject.

[0013] Another aspect of the present invention relates to a method for treating, preventing, or delaying the progression of motor disorders associated with dopamine agonist treatment for Parkinson's disease in subjects requiring such treatment, comprising (i) diagnosing the subject with motor disorders associated with dopamine agonist treatment for Parkinson's disease; and (ii) administering to the subject a therapeutically effective amount of an α7-nAChR agonist or an α7-nAChR positive allosteric modulator.

[0014] One embodiment of the other aspect relates to a method for treating, preventing, or delaying the progression of motor disorders associated with dopamine agonist treatment for Parkinson's disease in subjects requiring such treatment, comprising (i) diagnosing the subject with motor disorders associated with dopamine agonist treatment for Parkinson's disease; and (ii) administering a therapeutically effective amount of an α7-nAChR agonist to the subject.

[0015] Another embodiment of the other aspect relates to a method for treating, preventing, or delaying the progression of dopamine agonist-related motor disorders in subjects requiring such treatment, including (i) diagnosing the subject with dopamine agonist-related motor disorders in the subject; and (ii) administering a therapeutically effective amount of an α7-nAChR-positive allosteric modulator to the subject.

[0016] Another aspect of the present invention relates to pharmaceutical compositions comprising an α7-nAChR agonist or an α7-nAChR positive allosteric modulator for the treatment, prevention, or delay of motor disorders associated with dopamine agonist treatment of Parkinson's disease.

[0017] One embodiment of the other aspect relates to a pharmaceutical composition comprising an α7-nAChR agonist or an α7-nAChR-positive allosteric modulator for the treatment, prevention, or delay of motor dysfunction associated with dopamine agonist treatment of Parkinson's disease.

[0018] Another embodiment of the other aspect relates to a pharmaceutical composition comprising an α7-nAChR agonist or an α7-nAChR-positive allosteric modulator for the treatment, prevention, or delay of motor dysfunction associated with dopamine agonist treatment of Parkinson's disease.

[0019] Another aspect of the present invention relates to the use of α7-nAChR agonists or α7-nAChR positive allosteric modulators in the preparation of medicaments for treating, preventing, or delaying the progression of motor disorders associated with dopamine agonist treatment of Parkinson's disease.

[0020] One embodiment of the other aspect relates to the use of an α7-nAChR agonist in the preparation of a medicament for treating, preventing, or delaying the progression of movement disorders associated with dopamine agonist treatment of Parkinson's disease.

[0021] Another embodiment of the other aspect relates to the use of an α7-nAChR positive allosteric modulator in the preparation of a medicament for treating, preventing, or delaying the progression of movement disorders associated with dopamine agonist treatment of Parkinson's disease.

[0022] Nicotinic acetylcholine receptor α7 agonists:

[0023] The “α7-nAChR agonist” used herein is a compound that binds to and activates a receptor containing an α7-nAChR subunit in vitro and in vivo to exert its physiological function. Activation can be determined by the method disclosed in WO2001 / 85727, i.e., a functional affinity assay of the isomeric α7 nicotinic acetylcholine receptor (α7 nAChR) using a rat pituitary cell line stably expressing α7 nAChR. As a reading, calcium influx upon receptor stimulation is compared with that scutellarin. According to the present invention, the “α7-nAChR agonist” typically induces at least 50% of the maximum influx induced by scutellarin, EC 100%. 50 The value is at least 1 µM; the preferred agonist induces calcium influx of at least 75% of the maximum influx induced by scutellarin, EC 50 The value is at least 400 nM; more preferably, the calcium influx induced by the agonist is at least 85% of the maximum influx induced by scutellarin, EC 50 The value is at least 50 nM.

[0024] In particular, preferred α7-nAChR agonists should be well absorbed in the gastrointestinal tract, be adequately and stably metabolized, and have good pharmacokinetic properties.

[0025] Further preferred α7-nAChR agonists bind effectively to α7-nAChR in vivo, while also binding to other receptors, especially other nAChRs, such as α4. 2 nAChR, muscarinic acetylcholine receptors such as M1 and / or 5-HT3 receptors show almost no affinity.

[0026] Further optimized α7-nAChR agonists can effectively cross the blood-brain barrier.

[0027] Preferred α7-nAChR agonists should be non-toxic and have virtually no side effects.

[0028] Furthermore, the preferred α7-nAChR agonist can exist in a stable, non-hygroscopic, and easily formulated form.

[0029] In one implementation, the α7-nAChR agonist is selective for receptors containing the α7-nAChR subunit, and therefore such agonists are expected to cause fewer side effects in patients compared to non-selective agonists. Agonists selective for receptors containing the α7-nAChR subunit exhibit a much higher functional affinity for that receptor compared to other nicotinic acetylcholine receptors, such as EC50. 50 The affinity difference is at least 10-fold, preferably at least 20-fold, and more preferably at least 50-fold. To assess the affinity of the α7-nAChR agonist of the present invention for other nicotinic acetylcholine receptors, the method disclosed in WO2001 / 85727 can be used, i.e., to assess the affinity for human neuronal α4... 2. Affinity of nAChR, using stable expression of human α4 Similar functional analyses were performed on two subtypes of human embryonic kidney cell lines. To evaluate the activity of the compounds of the present invention on the nicotinic receptor "ganglionic subtype" and "muscular subtype", similar functional analyses were performed using human embryonic kidney cell lines that stably express the human "ganglionic subtype" or cell lines that endogenously express the human nicotinic receptor "muscular subtype".

[0030] Over the past 15 years, numerous attempts have focused on developing selective α7 nAChR agonists, resulting in the discovery of many different chemotypes exhibiting the aforementioned selective activity. These attempts are outlined in the review by Horenstein et al. (Mol Pharmacol, 2008, 74, 1496-1511), which describes at least nine different families of α7 nAChR agonists, most of which have been found to be selective agonists. All compounds shown in Figure 1 of the review are again introduced for reference. Indeed, several drug candidates with α7 nAChR agonist modes of action have entered preclinical or even clinical trial stages (reviews: Broad et al., Drugs of the Future, 2007, 32(2), 161-170; Romanelli et al., Expert Opin Ther Patents, 2007, 17(11), 1365-1377). Examples of these compounds—also belonging to multiple chemotypes—are MEM3454, MEM63908, SSR180711, GTS21, EVP6124, ABT107, ABT126, TC-5619, AZD-6319, and SAR-130479. Other α7 nAChR agonists and their uses as pharmaceuticals are known, for example, from WO2001 / 85727, WO2004 / 022556, WO2005 / 118535, WO2005 / 123732, WO2006 / 005608, WO2007 / 045478, WO2007 / 068476, and WO2007 / 068475.

[0031] In one implementation, the α7-nAChR agonist is a compound of formula (I) in either a free base form or an acid addition salt form:

[0032]

[0033] in

[0034] L1 is –CH2-; L2 is –CH2- or –CH2-CH2-; and L3 is –CH2- or –CH(CH3)-; or

[0035] L1 is –CH2-CH2-; L2 is –CH2-; and L3 is –CH2-CH2-;

[0036] L4 is selected from

[0037]

[0038] The bonds marked with an asterisk are connected to the azabicycloalkyl group;

[0039] R1 is hydrogen or C. 1-4 alkyl;

[0040] X1 is –O- or –NH-;

[0041] A2 is selected from

[0042]

[0043] The key marked with an asterisk is connected to X1;

[0044] A1 is a five- to ten-membered monocyclic or fused polycyclic aromatic ring system, which may contain 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain no more than 2 oxygen atoms and no more than 2 sulfur atoms, and wherein the ring system may be substituted by R2 once or more, and wherein the substituent on the nitrogen of the heterocyclic ring system may not be a halogen.

[0045] R2 is C independently. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 A haloalkoxy, halogen, cyano, or tri- to hexa-membered monocyclic ring system, wherein the monocyclic ring system may be aromatic, saturated or partially saturated, and may contain 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, wherein each ring system may contain no more than 2 oxygen atoms and no more than 2 sulfur atoms, and wherein each ring system may be further divided by C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 The alkyl halogen, halogen, or cyano group is substituted once or more, and the substituent on the nitrogen of the heterocyclic ring cannot be halogen.

[0046] Or two R2 atoms at adjacent ring atoms form C 3-4 Alkylene, wherein 1-2 carbon atoms can be replaced by X2, and wherein C 3-4 Alkylenes may be substituted by R3 once or more;

[0047] X2 is independently –O- or -N(R4)-;

[0048] R4 is either hydrogen or C independently. 1-6 Alkyl; and

[0049] R3 is either halogen or C. 1-6 alkyl.

[0050] In one embodiment, the α7-nAChR agonist is a compound of formula (II) in either a free base form or an acid addition salt form.

[0051] (II),

[0052] in

[0053] A3 is a five- to ten-membered monocyclic or fused and polycyclic aromatic ring system, which may contain 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain no more than 2 oxygen atoms and no more than 2 sulfur atoms, and wherein the ring system may be substituted by R5 once or more, and wherein the substituent on nitrogen in the heterocyclic ring system may not be a halogen.

[0054] R5 is C independently. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 A haloalkoxy, halogen, cyano, amino, or tri- to hexa-membered monocyclic ring system, wherein the ring may be aromatic and saturated or partially saturated, and may contain 1 to 4 heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each ring system may contain no more than 2 oxygen atoms and no more than 2 sulfur atoms, and wherein each ring system may be further divided by C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 The alkyl halide, halogen, or cyano group is substituted once or more, and the substituent on the nitrogen in the heterocyclic ring system cannot be halogen.

[0055] Or two R5 atoms at adjacent ring atoms form C 3-4 Alkylene, wherein 1-2 carbon atoms can be replaced by X3, and wherein C 3-4 Alkylenes may be substituted by R6 once or more;

[0056] X3 is independently –O- or -N(R7)-;

[0057] R7 is either hydrogen or C. 1-6 Alkyl; and

[0058] R6 is either halogen or C. 1-6 alkyl.

[0059] Unless otherwise stated, the expressions used in this invention have the following meanings:

[0060] "alkyl" refers to a straight-chain or branched alkyl group, such as methyl, ethyl, n- or isopropyl, n-, iso-, secondary or tert-butyl, n-pentyl, n-hexyl; C 1-6 Alkyl groups preferably refer to straight-chain or branched C-chains. 1-4 Alkyl groups, particularly methyl, ethyl, n-propyl, isopropyl and tert-butyl.

[0061] Each "alkoxy", "halogenated alkyl", etc., alkyl moiety has the same meaning as the alkyl group defined above, especially regarding linearity and preferred size.

[0062] Substituents that are replaced "once or more than once," for example, as defined for A1, are preferably replaced by one to three substituents.

[0063] Halogens generally refer to fluorine, chlorine, bromine, or iodine; fluorine, chlorine, or bromine are preferred. The haloalkyl group preferably has a chain length of 1 to 4 carbon atoms, such as fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2-fluoroethyl, 2-chloroethyl, pentafluoroethyl, 1,1-difluoro-2,2,2-trichloroethyl, 2,2,2-trichloroethyl, 1,1,2,2-tetrafluoroethyl, 2,2,3,3-tetrafluoropropyl, 2,2,3,3,3-pentafluoropropyl, or 2,2,3,4,4,4-hexafluorobutyl; preferably -CF3, -CHF2, -CH2F, -CHF-CH3, –CF2CH3, or –CH2CF3.

[0064] In the context of this invention, "two R2 atoms at adjacent ring atoms form C" 3-4 Alkylene, wherein 1-2 carbon atoms can be replaced by X2" or "two R5 atoms at adjacent ring atoms form C". 3-4 The definition of "alkylene group, wherein 1-2 carbon atoms may be replaced by X3" includes -CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-, -O-CH2-O-, -O-CH2-CH2-O-, and -CH2-CH2-NH-. An example of a substituent is -CH2-CH2-N(CH3)-.

[0065] In the context of this invention, the definition of "penta- to deca-membered monocyclic or fused and polycyclic aromatic ring system" in A1 or A3 includes C6- or C 10 -Aromatic hydrocarbon group or five- to ten-membered heterocyclic aromatic ring system. "Polycyclic" preferably refers to bicyclic.

[0066] In the context of this invention, the definition of "tri- to hexa-membered monocyclic ring system" for R2 includes C6-aromatic groups, five- to six-membered heterocyclic aromatic ring systems, and tri- to six-membered monocyclic aliphatic or heterocyclic ring systems.

[0067] C6- or C 10 - The aromatic hydrocarbon group is usually phenyl or naphthyl, especially phenyl.

[0068] Preferably, but also depending on the definition of the substituent, a "penta-to-deca-membered heterocyclic aromatic ring system" consists of 5 to 10 ring atoms, of which 1 to 3 ring atoms are heteroatoms. Such heterocyclic aromatic ring systems can be monocyclic, bicyclic, or tricyclic; monocyclic or benzo-annelated ring systems are preferred. Bicyclic or tricyclic ring systems can be formed by the ring-annealing reaction of two or more rings, or by bridging atoms such as oxygen, sulfur, and nitrogen. Examples of heterocyclic ring systems include: imidazo[2,1-b]thiazole, pyrrole, pyrrolin, pyrrolidinyl, pyrazole, pyrazoline, pyrazolidine, imidazoline, imidazoline, triazole, triazolidine, triazolidine, tetraazole, furan, dihydrofuran, tetrahydrofuran, furazolidone (oxadiazole), dioxopentane, thiophene, dihydrothiophene, tetrahydrothiophene, oxazole, oxazolidine, oxazolidine, isoxazole, isoxazolidine Isoxazolidine, thiazole, thiazoline, thiazoline, isothiazole, isothiazolline, isothiazolidine, thiadiazole, thiadiazoleline, thiadiazole, pyridine, piperidine, pyridazine, pyrazine, piperazine, triazine, pyran, tetrahydropyran, thiaran, tetrahydrothiaran, oxazine, thiazine, dioxene, morpholine, purine, pteridine, and corresponding benzo[2,1-b]thiazolium heterocycles, such as indole, isoyindole, coumarin, isoquinoline, quinoline, etc. Preferred heterocycles include: imidazo[2,1-b]thiazole, oxazole, isoxazole, thiazole, isothiazole, triazole, pyrrole, furan, tetrahydrofuran, pyridine, pyrimidine, imidazolium, or pyrazole.

[0069] In the context of this invention, tri- to hexa-membered monocyclic aliphatic ring systems are typically cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0070] Because compounds of formula (I) and formula (II) may contain asymmetric carbon atoms, the compounds may exist in an optically active form or a mixture of optical isomers, such as racemic mixtures or diastereomer mixtures. All optical isomers and mixtures thereof, including racemic mixtures, are part of this invention.

[0071] In one implementation, the α7-nAChR agonist is a compound of formula (I):

[0072] (I),

[0073] in

[0074] L1 is –CH2-; L2 is –CH2-CH2-; and L3 is –CH2- or –CH(CH3)-;

[0075] L4 is selected from the following groups:

[0076]

[0077] The asterisked bonds are connected to the aziridine alkyl group;

[0078] R1 is hydrogen or C. 1-4 alkyl;

[0079] X1 is –O- or –NH-;

[0080] A2 is selected from

[0081]

[0082] The key marked with an asterisk is connected to X1;

[0083] A1 is a pentaneous to decacyclic monocyclic or fused polycyclic aromatic ring system, which may contain 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the ring system may contain no more than 2 oxygen atoms and no more than 2 sulfur atoms, and wherein the ring system may be substituted by R2 once or more, and wherein the substituent on nitrogen in the heterocyclic ring system may not be a halogen; and

[0084] R2 is C independently. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or halogen.

[0085] In one implementation, the α7-nAChR agonist is a compound of formula (I):

[0086] (I),

[0087] in

[0088] L1 is –CH2-; L2 is –CH2-CH2-; L3 is –CH2-;

[0089] L4 is

[0090]

[0091] The asterisked bonds are connected to the aziridine alkyl group;

[0092] R1 is hydrogen or C. 1-4 alkyl;

[0093] A1 is a pentaneous to decacyclic monocyclic or fused polycyclic aromatic ring system, which may contain 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the ring system may contain no more than 2 oxygen atoms and no more than 2 sulfur atoms, and wherein the ring system may be substituted by R2 once or more, and wherein the substituent on nitrogen in the heterocyclic ring system may not be a halogen; and

[0094] R2 is C independently. 1-6 Alkyl, C1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or halogen.

[0095] In one implementation, the α7-nAChR agonist is a compound of formula (I):

[0096] (I),

[0097] in

[0098] L1 is –CH2-; L2 is –CH2-CH2-; and L3 is –CH2- or –CH(CH3)-;

[0099] L4 is

[0100]

[0101] The asterisked bonds are connected to the aziridine alkyl group;

[0102] X1 is –O- or –NH-;

[0103] A2 is selected from

[0104]

[0105] The key marked with an asterisk is connected to X1;

[0106] A1 is a pentaneous to decacyclic monocyclic or fused polycyclic aromatic ring system, which may contain 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the ring system may contain no more than 2 oxygen atoms and no more than 2 sulfur atoms, and wherein the ring system may be substituted by R2 once or more, and wherein the substituent on nitrogen in the heterocyclic ring system may not be a halogen; and

[0107] R2 is C independently. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or halogen.

[0108] In one embodiment, the α7-nAChR agonist is a compound of formula (I).

[0109] (I),

[0110] in

[0111] L1 is –CH2-CH2-; L2 is –CH2-; and L3 is –CH2-CH2-;

[0112] L4 is

[0113]

[0114] The asterisked bonds are connected to the aziridine alkyl group;

[0115] X1 is –O- or –NH-;

[0116] A2 is selected from

[0117]

[0118] The key marked with an asterisk is connected to X1;

[0119] A1 is a pentaneous to decacyclic monocyclic or fused polycyclic aromatic ring system, which may contain 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the ring system may contain no more than 2 oxygen atoms and no more than 2 sulfur atoms, and wherein the ring system may be substituted by R2 once or more, and wherein the substituent on nitrogen in the heterocyclic ring system may not be a halogen; and

[0120] R2 is C independently. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or halogen.

[0121] In one embodiment, the α7-nAChR agonist is a compound of formula (II):

[0122] (II),

[0123] in

[0124] A3 is a pentaneous to decacyclic monocyclic or fused polycyclic aromatic ring system, which may contain 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the ring system may contain no more than 2 oxygen atoms and no more than 2 sulfur atoms, and wherein the ring system may be substituted by R5 once or more, and wherein the substituent on nitrogen in the heterocyclic ring system may not be a halogen; and

[0125] R5 is C independently. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, amino, or halogen.

[0126] In one embodiment, the α7-nAChR agonist is a compound selected from group P1; group P1 consists of the following:

[0127] A-1: (S)-(1-aza-bicyclo[2.2.2]oct-3-yl)-carbamic acid (S)-1-(2-fluoro-phenyl)-ethyl ester;

[0128] A-2: (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)-carbamic acid (R)-1-(2-chloro-phenyl)-ethyl ester;

[0129] A-3: (S)-(1-aza-bicyclo[2.2.2]oct-3-yl)-carbamic acid (S)-1-phenyl-ethyl ester;

[0130] B-1: (R)-3-(5-phenyl-pyrimidin-2-yloxy)-1-aza-bicyclo[2.2.2]octane;

[0131] B-2: (R)-3-(5-p-tolyl-pyrimidin-2-yloxy)-1-aza-bicyclo[2.2.2]octane;

[0132] B-3: (R)-3-(5-(2-fluoro-4-methyl-phenyl)-pyrimidin-2-yloxy)-1-aza-bicyclo[2.2.2]octane;

[0133] B-4: (R)-3-(5-(3,4-dimethyl-phenyl)-pyrimidin-2-yloxy)-1-aza-bicyclo[2.2.2]octane;

[0134] B-5: (R)-3-(6-p-tolylpyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane;

[0135] B-6: (R)-3-(6-phenyl-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane;

[0136] B-7: (R)-3-(6-(3,4-dimethyl-phenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane;

[0137] B-8: (R)-3-[6-(2-fluoro-4-methyl-phenyl)-pyridazin-3-yloxy]-1-aza-bicyclo[2.2.2]octane;

[0138] B-9: (R)-3-[6-(4,5-dimethyl-2-fluoro-phenyl)-pyridazin-3-yloxy]-1-aza-bicyclo[2.2.2]octane;

[0139] B-10: (R)-3-[6-(3,4-dimethyl-phenyl)-pyridazin-3-yloxy]-1-aza-bicyclo[2.2.2]octane;

[0140] B-11: (R)-3-[6-(4-methyl-phenyl)-pyridazin-3-yloxy]-1-aza-bicyclo[2.2.2]octane;

[0141] B-12: (R)-3-[6-(2,5-difluoro-4-methyl-phenyl)-pyridazin-3-yloxy]-1-aza-bicyclo[2.2.2]octane;

[0142] B-13: (2S,3R)-3-[6-(1H-indol-5-yl)-pyridazin-3-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane;

[0143] B-14: (2R,3S)-3-[6-(1H-indol-5-yl)-pyridazin-3-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane;

[0144] B-15: (2S,3R)-3-[5-(1H-indol-5-yl)pyrimidin-2-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane;

[0145] B-16: (2R,3S)-3-[5-(1H-indol-5-yl)pyrimidin-2-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane;

[0146] B-17: 3-[6-(1H-indol-5-yl)-pyridin-3-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane;

[0147] B-18: (2S,3R)-2-methyl-3-[6-(5-methyl-thiophen-2-yl)-pyridazin-3-yloxy]-1-aza-bicyclo[2.2.2]octane;

[0148] B-19: 3-[6-(2,3-dimethyl-1H-indol-5-yl)-pyridazin-3-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane;

[0149] B-20: trans-2-methyl-1-aza-bicyclo[2.2.2]oct-3-yl)-(6-phenyl-pyridin-3-yl)-amine;

[0150] B-21: trans-[6-(1H-indol-5-yl)-pyridin-3-yl]-(2-methyl-1-aza-bicyclo[2.2.2]oct-3-yl)-amine;

[0151] C-1: (4S,5R)-4-[5-(1H-indol-5-yl)-pyrimidin-2-yloxy]-1-aza-bicyclo[3.3.1]nonane;

[0152] C-2: 5-{2-[(4S,5R)-(1-aza-bicyclo[3.3.1]non-4-yl)oxy]-pyrimidin-5-yl}-1,3-dihydro-indole-2-one;

[0153] C-3: (4S,5R)-4-[6-(1H-indol-5-yl)-pyridin-3-yloxy]-1-aza-bicyclo[3.3.1]nonane;

[0154] C-4: (4S,5R)-4-[5-(1H-indol-5-yl)-pyridin-2-yloxy]-1-aza-bicyclo[3.3.1]nonane;

[0155] C-5: (4S,5R)-4-[6-(1H-indol-5-yl)-pyridazin-3-yloxy]-1-aza-bicyclo[3.3.1]nonane;

[0156] C-6: 5-{6-[(4S,5R)-(1-aza-bicyclo[3.3.1]non-4-yl)oxy]-pyridazin-3-yl}-1,3-dihydro-indole-2-one;

[0157] C-7: (1-aza-bicyclo[3.3.1]non-4-yl)-[5-(1H-indol-5-yl)-pyridin-2-yl]-amine;

[0158] C-8: (1-aza-bicyclo[3.3.1]non-4-yl)-[5-(1H-indol-5-yl)pyrimidin-2-yl]-amine;

[0159] C-9: (1-aza-bicyclo[3.3.1]non-4-yl)-[6-(1H-indol-5-yl)-pyridin-3-yl]-amine;

[0160] C-10: (1-aza-bicyclo[3.3.1]non-4-yl)-[6-(1H-indol-5-yl)-pyridin-3-yl]-amine;

[0161] C-11: (1-aza-bicyclo[3.3.1]non-4-yl)-[5-(1H-indol-4-yl)-pyrimidin-2-yl]-amine;

[0162] C-12: (1-aza-bicyclo[3.3.1]non-4-yl)-[6-(1H-indol-5-yl)-pyridazin-3-yl]-amine;

[0163] D-1: 5-Benzofuran-5-ylethynyl-1-methyl-3-piperidin-1-ylmethyl-pyrrolidine-2-one;

[0164] D-2: 1-Methyl-5-phenylethynyl-3-piperidin-1-ylmethyl-pyrrolidone-2-one;

[0165] D-3: 1-Methyl-5-(1-Methyl-1H-indol-5-ylethynyl)-3-piperidin-1-ylmethyl-pyrrolidone-2-one;

[0166] D-4: 5-(3-amino-phenylethynyl)-1-methyl-3-piperidin-1-ylmethyl-pyrrolidone-2-one;

[0167] E-1: 4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)-1-azatricyclic [3.3.1.1] 3,7 Decane:

[0168] ;

[0169] E-1a: (4S)-4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)-1-azatricyclic [3.3.1.1] 3,7 ] Decane;

[0170] E-1b: 4-(6-(1H-indol-5-yl)-pyridazin-3-yloxy)-1-azatricyclic [3.3.1.1] 3,7 ] Decane;

[0171] E-1c: 4-(6-(1H-indol-5-yl)-pyridin-3-yloxy)-1-azatricyclic [3.3.1.1] 3,7 ] Decane;

[0172] E-1d: 4-(5-(1H-indol-5-yl)-pyrimidin-2-yloxy)-1-azatricyclic [3.3.1.1] 3,7 ] Decane;

[0173] E-2: 2-(6-phenylpyridazin-3-yl)octahydropyrrolo[3,4-c]pyrrole of the following formula:

[0174] ;

[0175] E-3: 5-[6-(5-methyl-hexahydro-pyrrolo[3,4-c]pyrrolo-2-yl-pyridazin-3-yl-1H-indole]

[0176] ;

[0177] E-3a: 5-[6-(cis-5-methyl-hexahydro-pyrrolo[3,4-c]pyrrolo-2-yl-pyridazin-3-yl-1H-indole;]

[0178] E-4: 5-[5-{6-methyl-3,6-diazabicyclo[3.2.0]hept-3-yl}-pyridin-2-yl]-1H-indole:

[0179] ;

[0180] E-4a: 5-[5-{(1R,5R)-6-methyl-3,6-diazabicyclo[3.2.0]hept-3-yl}-pyridin-2-yl]-1H-indole;

[0181] E-5: 2-Methyl-5-(6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole of the following formula

[0182] ;

[0183] E-6: 5-{6-[1-azabicyclo[2.2.2]oct-3-yloxy]pyridazin-3-yl}-1H-indole;

[0184] E-6a: 5-{6-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]pyridazin-3-yl}-1H-indole;

[0185] E-7: 5-{6-[1-azabicyclo[2.2.2]oct-3-yloxy]pyridazin-3-yl}-1,3-dihydro-indole-2-one;

[0186] E-7a: 5-{6-[(3R)1-azabicyclo[2.2.2]oct-3-yloxy]pyridazin-3-yl}-1,3-dihydro-indole-2-one;

[0187] E-8: N-(1-azabicyclo[2.2.2]oct-3-yl)-1H-indazole-3-carboxamide;

[0188] E-8a: N-((3R)-1-azabicyclo[2.2.2]oct-3-yl)-1H-indazole-3-carboxamide;

[0189] E-8b: N-((3S)-1-azabicyclo[2.2.2]oct-3-yl)-1H-indazole-3-carboxamide;

[0190] E-9: N-(1-azabicyclo[2.2.2]oct-3-yl)-5-(trifluoromethoxy)-1H-indazole-3-carboxamide;

[0191] E-9a: N-((3R)-1-azabicyclo[2.2.2]oct-3-yl)-5-(trifluoromethoxy)-1H-indazole-3-carboxamide;

[0192] E-9b: N-((3S)-1-azabicyclo[2.2.2]oct-3-yl)-5-(trifluoromethoxy)-1H-indazole-3-carboxamide;

[0193] E-10: N-(2-((3-pyridyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide;

[0194] E-10a: (2S,3R)-N-(2-((3-pyridyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide;

[0195] E-11: N-(2-((3-pyridyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3,5-difluorobenzamide;

[0196] E-11a: (2S,3R)-N-(2-((3-pyridyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3,5-difluorobenzamide;

[0197] E-11b: N-(2-((3-pyridyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-5-methylthiophene-2-carboxamide;

[0198] E-11c: (2S,3R)-N-(2-((3-pyridyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-5-methylthiophene-2-carboxamide;

[0199] E-11d: N-(2-((3-pyridyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-5-(2-pyridyl)thiophene-2-carboxamide;

[0200] E-11e: (2S,3R)-N-(2-((3-pyridyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-5-(2-pyridyl)thiophene-2-carboxamide;

[0201] E-12: 4-(5-methyloxazolo[4,5-b]pyridin-2-yl)-1,4-diazabicyclo[3.2.2]nonane;

[0202] E-13: [N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-chlorobenzamide;

[0203] E-14: Furano[2,3-c]pyridine-5-carboxylic acid (1-aza-bicyclo[2.2.2]oct-3-yl)-amide;

[0204] E-15: 2,3-Dihydro-benzo[1,4]dioxen-6-carboxylic acid (1-azabicyclo[2.2.2]oct-3-yl)-amide;

[0205] E-16: 5-morpholino-4-yl-valeric acid (4-pyridin-3-yl-phenyl)-amide;

[0206] E-17: N-{4-[4-(2,4-dimethoxy-phenyl)-piperazin-1-yl]-butyl}-4-pyridin-2-yl-benzamide;

[0207] E-18: 1-[6-(4-fluorophenyl)pyridin-3-yl]-3-(4-piperidin-1-ylbutyl)-urea;

[0208] E-19: 7,8,9,10-tetrahydro-6,10-methylene-6H-pyrazino-(2,3-h)(3)-benzozazepine ;

[0209] E-20: (2'R)-spiro-[1-azabicyclo[2.2.2]octane-3,2'(3'H)-furano[2,3-b]pyridine];

[0210] E-21: 1,4-diaza-bicyclo[3.2.2]nonane-4-carboxylic acid 4-bromo-phenyl ester;

[0211] E-22: 3-[1-(2,4-dimethoxy-phenyl)-methyl-(E)-ylidene]-3,4,5,6-tetrahydro-[2,3']bipyridine;

[0212] E-23: 7-(2-methoxy-phenyl)-benzofuran-2-carboxylic acid (1-azabicyclo[2.2.2]oct-3-yl)-amide;

[0213] E-24: N-methyl-1-{5-[3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furano[2,3-b]pyridin]-5'-yl]-2-thienyl}methylamine of the following formula:

[0214] ;

[0215] E-24a: N-methyl-1-{5-[(2R)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furano[2,3-b]pyridin]-5'-yl]-2-thienyl}methylamine;

[0216] E-24b: N-methyl-1-{5-[(2S)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furano[2,3-b]pyridin]-5'-yl]-2-thienyl}methylamine;

[0217] E-25a: 6-[(aniline carbonyl)amino]-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide;

[0218] E-25b: N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-({[(4-chlorophenyl)amino]carbonyl}amino)-1-benzothiophene-2-carboxamide;

[0219] E-25c: N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-({[(2-methoxyphenyl)amino]carbonyl}-amino)-1-benzothiophene-2-carboxamide;

[0220] E-25d: N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-({[(4-methoxyphenyl)amino]carbonyl}-amino)-1-benzothiophene-2-carboxamide;

[0221] E-25e: N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-({[(2-phenylethyl)amino]carbonyl}amino)-1-benzothiophene-2-carboxamide;

[0222] E-25f: N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-({[(3-cyanophenyl)amino]carbonyl}amino)-1-benzothiophene-2-carboxamide;

[0223] E-25g: N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-({[(3-bromophenyl)amino]carbonyl}amino)-1-benzothiophene-2-carboxamide;

[0224] E-25h: N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-({[(2-ethoxyphenyl)amino]carbonyl)amino)-1-benzothiophene-2-carboxamide;

[0225] E-25i: N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-({[(4-(dimethylamino)phenyl)amino]-carbonyl)amino)-1-benzothiophene-2-carboxamide;

[0226] E-25j: N-(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-({[(2-nitrophenyl)amino]carbonyl}amino)-1-benzothiophene-2-carboxamide;

[0227] E-25k: N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-({[(2,6-difluorophenyl)amino]carbonyl}-amino)-1-benzothiophene-2-carboxamide;

[0228] E-25l: N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-({[(2,4-dichlorophenyl)amino]carbonyl}-amino)-1-benzothiophene-2-carboxamide;

[0229] E-25m: N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-[({[3-(trifluoromethyl)phenyl]amino]-carbonyl)amino]-1-benzothiophene-2-carboxamide;

[0230] E-25n: N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-({[(3,4,5-trimethoxyphenyl)amino]-carbonyl}amino)-1-benzothiophene-2-carboxamide;

[0231] E-25o: N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-[({[4-methoxy-3-(trifluoromethyl)phenyl]-amino}carbonyl)amino]-1-benzothiophene-2-carboxamide;

[0232] E-25p: N-{(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-[({[3-methoxyphenyl]amino}carbonyl)-amino]-1-benzothiophene-2-carboxamide;

[0233] E-25q: N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-[({[3-trifluoromethoxyphenyl]amino}-carbonyl)-amino]-1-benzothiophene-2-carboxamide;

[0234] E-25r: N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-{[(tert-butylamino)carbonyl]amino}-1-benzothiophene-2-carboxamide;

[0235] E-25s: N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-{[(cyclohexylamino)carbonyl]amino}-1-benzothiophene-2-carboxamide;

[0236] E-25t: N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-[({[(1S)-1-phenylethyl]amino}carbonyl-amino]-1-benzothiophene-2-carboxamide;

[0237] E-25u: 7-[(aniline carbonyl)amino]-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide;

[0238] E-25v: ​​N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-({[(4-methoxyphenyl)amino]carbonyl}-amino)-1-benzofuran-2-carboxamide;

[0239] E-26a: N-[4-(2-thienyl)phenyl]-1-azabicyclo[2.2.2]octane-3-carboxamide;

[0240] E-26b: N-[4'-(hydroxymethyl)-1,1'-biphenyl-4-yl]-1-azabicyclo[2.2.2]octane-3-carboxamide;

[0241] E-26c: N-(4'-fluoro-1,1'-biphenyl-4-yl)-1-azabicyclo[2.2.2]octane-3-carboxamide;

[0242] E-26d: N-(4'-methylthio-1,1'-biphenyl-4-yl)-1-azabicyclo[2.2.2]octane-3-carboxamide;

[0243] E-26e: 2-(1-azabicyclo[2.2.2]oct-3-yl)-N-(4'-fluoro-1,1'-biphenyl-4-yl)acetamide;

[0244] E-26f: 2-(1-azabicyclo[2.2.2]oct-3-yl)-N-(4'-methoxy-1,1'-biphenyl-4-yl)acetamide;

[0245] E-26g: 2-(1-azabicyclo[2.2.2]oct-3-yl)-N-(4'-fluoro-1,1'-biphenyl-3-yl)acetamide;

[0246] E-26h: 2-(1-azabicyclo[2.2.2]oct-3-yl)-N-(3'-nitro-1,1'-biphenyl-4-yl)acetamide;

[0247] E-26i: 2-(1-azabicyclo[2.2.2]oct-3-yl)-N-[4'-(hydroxymethyl)-1,1'-biphenyl-3-yl]acetamide;

[0248] E-26j: 2-(1-azabicyclo[2.2.2]oct-3-yl)-N-[4'-(bromomethyl)-1,1'-biphenyl-4-yl]acetamide;

[0249] E-26k: 2-(1-azabicyclo[2.2.2]oct-3-yl)-N-[2'-(hydroxymethyl)-1,1'-biphenyl-3-yl]acetamide;

[0250] E-26l: N-[3'(acetylamino)-1,1'-biphenyl-4-yl]-2-(1-azabicyclo[2.2.2]oct-3-yl)acetamide;

[0251] E-26m: (3R)-N-[2'-(hydroxymethyl)-1,1'-biphenyl-4-yl]-1-azabicyclo[2.2.2]octane-3-carboxamide;

[0252] E-26n: (3R)-N-[4'-(hydroxymethyl)-1,1'-biphenyl-4-yl]-1-azabicyclo[2.2.2]octane-3-carboxamide;

[0253] E-26o: (3S)-N-[4'(hydroxymethyl)-1,1'-biphenyl-4-yl]-1-azabicyclo[2.2.2]octane-3-carboxamide;

[0254] E-26p: (3R)-N-[4'-(4-morpholinyl)-1,1'-biphenyl-4-yl]-1-azabicyclo[2.2.2]octane-3-carboxamide;

[0255] E-26q: (3R)-N-[4'-(hydroxymethyl)-3'-(methoxy)-1,1'-biphenyl-4-yl]-1-azabicyclo[2.2.2]-octane-3-carboxamide;

[0256] E-26r: 4'-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylcarbonyl]amino}-1,1'-biphenyl-4-carboxylic acid methyl ester;

[0257] E-26s: 4'-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylcarbonyl]amino}-1,1'-biphenyl-4-carboxylic acid;

[0258] E-26t: (3R)-N-[4'-(hydroxy-1-methylethyl)-1,1'-biphenyl-4-yl]-1-azabicyclo[2.2.2]-octane-3-carboxamide;

[0259] E-26u: (3R)-N-[4'-(aminocarbonyl)-1,1'-biphenyl-4-yl]-1-azabicyclo[2.2.2]octane-3-carboxamide;

[0260] E-26v: (3R)-N-[4'-(hydroxymethyl)-3-fluoro-1,1'-biphenyl-4-yl]-1-azabicyclo[2.2.2]octane-3-carboxamide;

[0261] E-26w: Methylcarbamate (4'-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylcarbonyl]amino}-1,1'-biphenyl-4-yl)methyl ester;

[0262] E-26x: Isopropylcarbamate (4'-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylcarbonyl]amino}-1,1'-biphenyl-4-yl)methyl ester;

[0263] E-26y: Ethylcarbamate (4'-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylcarbonyl]amino}-1,1'-biphenyl-4-yl)methyl ester;

[0264] E-26z: The free base form of compounds selected from Examples 26, 27, 28, 29, 30, 31, 32, 33, 34 and 35 of WO2003 / 078431;

[0265] E-27a: 2-(1-azabicyclo[2.2.2]oct-3-yl)-N-(7-bromo-1-benzothiophen-2-yl)acetamide;

[0266] E-27b: 2-(1-azabicyclo[2.2.2]oct-3-yl)-N-(6-bromo-1-benzothiophen-2-yl)acetamide;

[0267] E-27c: 2-(1-azabicyclo[2.2.2]oct-3-yl)-N-(7-quinolinyl)acetamide;

[0268] E-27d: 2-(1-azabicyclo[2.2.2]oct-3-yl)-N-(2-naphthyl)acetamide;

[0269] E-27e: 2-(1-azabicyclo[2.2.2]oct-3-yl)-N-(8-nitro-2-naphthyl)acetamide;

[0270] E-28a: N-(1-azabicyclo[2.2.2]oct-3-yl)-6-quinoline carboxamide;

[0271] E-28b: N-(1-azabicyclo[2.2.2]oct-3-yl)-2-phenazine carboxamide;

[0272] E-28c: N-(1-azabicyclo[2.2.2]oct-3-yl)-7-quinoline carboxamide;

[0273] E-28d: N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-quinoline carboxamide;

[0274] E-28e: N-(1-azabicyclo[2.2.2]oct-3-yl)-2-ethyl-7-quinoline carboxamide;

[0275] E-28f: N-(1-azabicyclo[2.2.2]oct-3-yl)-2-ethyl-6-quinoline carboxamide;

[0276] E-28g: N-(1-azabicyclo[2.2.2]oct-3-yl)-2-methyl-7-quinoline carboxamide;

[0277] E-28h: N-(1-azabicyclo[2.2.2]oct-3-yl)-2-methyl-6-quinoline carboxamide;

[0278] E-28i: N-(1-azabicyclo[2.2.2]oct-3-yl)-4-methyl-6-quinoline carboxamide;

[0279] E-28j: N-(1-azabicyclo[2.2.2]oct-3-yl)-2-propyl-6-quinoline carboxamide;

[0280] E-28k: N-(1-azabicyclo[2.2.2]oct-3-yl)-2-ethyl-4-methyl-6-quinoline carboxamide;

[0281] E-28l: N-(1-azabicyclo[2.2.2]oct-3-yl)-2-propyl-7-quinoline carboxamide;

[0282] E-28m: N-(1-azabicyclo[2.2.2]oct-3-yl)-2-ethyl-4-methyl-7-quinoline carboxamide;

[0283] E-28n: N-(1-azabicyclo[2.2.2]oct-3-yl)-4-(tetrahydro-2H-pyran-2-yl)-6-quinoline-carboxamide;

[0284] E-28o: N-(1-azabicyclo[2.2.2]oct-3-yl)-4-(tetrahydro-2H-pyran-2-yl)-7-quinoline-formamide;

[0285] E-28p: N-(1-azabicyclo[2.2.2]oct-3-yl)-2-phenyl-6-quinoline carboxamide; and

[0286] E-28q: N-(1-azabicyclo[2.2.2]oct-3-yl)-2-phenyl-7-quinoline carboxamide;

[0287] Each of the compounds is in the form of a free base or an acid addition salt.

[0288] In one embodiment, the α7-nAChR agonist is a compound selected from compounds A-1, A-2, and A-3; wherein each of the compounds is in a free base form or an acid addition salt form.

[0289] In one embodiment, the α7-nAChR agonist is a compound selected from compounds B-1, B-2, B-3, B-4, B-5, B-6, B-7, B-8, B-9, B-10, B-11, B-12, B-13, B-14, B-15, B-16, B-17, B-18, B-19, B-20, and B-21; wherein each of the compounds is in a free base form or an acid addition salt form.

[0290] In one embodiment, the α7-nAChR agonist is a compound selected from compounds C-1, C-2, C-3, C-4, C-5, C-6, C-7, C-8, C-9, C-10, C-11, and C-12; wherein each of the compounds is in a free base form or an acid addition salt form.

[0291] In one embodiment, the α7-nAChR agonist is a compound selected from compounds D-1, D-2, D-3, and D-4; wherein each of the compounds is in a free base form or an acid addition salt form.

[0292] In one embodiment, the α7-nAChR agonist is a compound selected from group P2; group P2 consists of compounds A-1, A-2, A-3, B-1, B-2, B-3, B-4, B-5, B-6, B-7, B-8, B-9, B-10, B-11, B-12, B-13, B-14, B-15, B-16, B-17, B-18, B-19, B-20, B-21, C-1, C -2, C-3, C-4, C-5, C-6, C-7, C-8, C-9, C-10, C-11, C-12, E-1, E-1a, E-1b, E-1c, E-1d, E-2, E- 3. E-3a, E-4, E-4a, E-8, E-8a, E-8b, E-9, E-9a, E-9b, E-10, E-10a, E-11, E-11a, E-11b, E-11 c, E-11d, E-11e, E-12, E-19, E-22, E-24, E-24a, E-24b, E-25a, E-25b, E-25c, E-25d, E-25e, E-25f, E-25g, E-25h, E-25i, E-25j, E-25k, E-25l, E-25m, E-25n, E-25o, E-25p, E-25q, E-25 The compound comprises r, E-25s, E-25t, E-25u, E-25v, E-28a, E-28b, E-28c, E-28d, E-28e, E-28f, E-28g, E-28h, E-28i, E-28j, E-28k, E-28l, E-28m, E-28n, E-28o, E-28p, and E-28q; wherein each of the compounds is in the form of a free base or an acid addition salt.

[0293] In one embodiment, the α7-nAChR agonist is a compound selected from group P3; group P3 consists of compounds A-1, A-2, A-3, B-1, B-2, B-3, B-4, B-5, B-6, B-7, B-8, B-9, B-10, B-11, B-12, B-13, B-14, B-15, B-16, B-17, B-18, B-19, B-20, B-21, C-1, C-2, C-3, C-4, C-5, C-6, C-7. The compound comprises C-8, C-9, C-10, C-11, C-12, E-1, E-1a, E-1b, E-1c, E-1d, E-2, E-3, E-3a, E-4, E-4a, E-8, E-8a, E-8b, E-9, E-9a, E-9b, E-10, E-10a, E-11, E-11a, E-12, E-19, E-22, E-24, E-24a, and E-24b; wherein each of the compounds is in the form of a free base or an acid addition salt.

[0294] Compounds of formula (I) (such as compounds A-1 to A-3, B-1 to B-21 and C-1 to C-12) or compounds of formula (II) (such as compounds D-1 to D-4) and their preparation are known from WO2001 / 85727, WO2004 / 022556, WO2005 / 118535, WO2005 / 12373, WO2006 / 005608, WO2007 / 045478, WO2007 / 068476 and WO2007 / 068475, or can be prepared in a similar manner to those described in the literature.

[0295] Compounds E-1 and E-1a can be prepared according to WO2008 / 058096.

[0296] Compounds E-2, E-3, E-3a, E-4, E-4a and E-5 (A-582941) can be prepared according to WO2005 / 028477.

[0297] Compounds E-6, E-6a, E-7 and E7a can be prepared according to WO2006 / 065233 and / or WO2007 / 018738.

[0298] Compounds E-8, E-8a, E-8b, E-9, E-9a and E-9b can be prepared according to WO2004 / 029050 and / or WO2010 / 043515.

[0299] Compounds E-10 and E-10a can be prepared according to WO2004 / 076449 and / or WO2009 / 018505;

[0300] Compounds E-11, E-11a to E-11e can be prepared according to WO2004 / 076449 and / or WO2010 / 085724 and / or WO2010 / 056622;

[0301] Compounds E-12 (CP-810123) and E-19 (varenicline) are described in O'Donnell et al., J Med Chem, 2010, 53, 1222-1237.

[0302] Compounds E-13 (PNU-282987), E-14 (PHA543613), E-21 (SSR-180771) and E-23 (ABBF) are described in Horenstein et al., Mol Pharmacol, 2008, 74, 1496-1511.

[0303] Compounds E-15 (PHA568487), E-16 (WAY-317538), E-17 (WAY-264620), E-20 (AZD-0328), and E-22 (GTS-21) are described in Haydar et al., Current Topics in Medicinal Chemistry, 2010, 10, 144-152.

[0304] Compound E-18 (WYE-103914) is described in Ghiron et al., J Med Chem, 2010, 53, 4379-4389.

[0305] Compounds E-24, E-24a and E-24b are described in WO2007 / 133155 and / or WO2009 / 066107.

[0306] Compounds E-25a to E-25v are described in WO2004 / 013136.

[0307] Compounds E-26a to E-26z are described in WO2003 / 078431.

[0308] Compounds E-27a to E-27e are described in WO2003 / 078430.

[0309] Compounds E-28a to E-28q are described in WO2003 / 043991.

[0310] Another aspect of the present invention relates to the use of an α7-nAChR agonist for the treatment (therapeutic or prophylactic), prevention of motor disorders associated with dopamine agonist treatment of Parkinson's disease, or delay of its progression; wherein the α7-nAChR agonist is a compound of formula (I).

[0311] Another aspect of the present invention relates to the use of an α7-nAChR agonist for the treatment (therapeutic or prophylactic), prevention of motor disorders associated with dopamine agonist treatment of Parkinson's disease, or delay of its progression; wherein the α7-nAChR agonist is a compound selected from group P1.

[0312] Another aspect of the present invention relates to the use of an α7-nAChR agonist for the treatment (therapeutic or prophylactic), prevention of motor disorders associated with dopamine agonist treatment of Parkinson's disease, or delay of its progression; wherein the α7-nAChR agonist is a compound selected from group P2.

[0313] Another aspect of the present invention relates to the use of an α7-nAChR agonist for the treatment (therapeutic or prophylactic), prevention of motor disorders associated with dopamine agonist treatment of Parkinson's disease, or delay of its progression; wherein the α7-nAChR agonist is a compound selected from group P3.

[0314] Another aspect of the present invention relates to a method for treating, preventing, or delaying the progression of motor disorders associated with dopamine agonist treatment for Parkinson's disease in subjects requiring such treatment, comprising administering to the subject a therapeutically effective amount of an α7-nAChR agonist; wherein the α7-nAChR agonist is a compound of formula (I).

[0315] Another aspect of the present invention relates to a method for treating, preventing, or delaying the progression of motor disorders associated with dopamine agonist treatment for Parkinson's disease in subjects requiring such treatment, comprising administering to the subject a therapeutically effective amount of an α7-nAChR agonist; wherein the α7-nAChR agonist is a compound selected from group P1.

[0316] Another aspect of the present invention relates to a method for treating, preventing, or delaying the progression of motor disorders associated with dopamine agonist treatment for Parkinson's disease in subjects requiring such treatment, comprising administering to the subject a therapeutically effective amount of an α7-nAChR agonist; wherein the α7-nAChR agonist is a compound selected from group P2.

[0317] Another aspect of the present invention relates to a method for treating, preventing, or delaying the progression of motor disorders associated with dopamine agonist treatment for Parkinson's disease in subjects requiring such treatment, comprising administering to the subject a therapeutically effective amount of an α7-nAChR agonist; wherein the α7-nAChR agonist is a compound selected from group P3.

[0318] Another aspect of the present invention relates to a method for treating, preventing, or delaying the progression of motor disorders associated with dopamine agonist treatment for Parkinson's disease in subjects requiring such treatment, comprising (i) diagnosing the subject with motor disorders associated with dopamine agonist treatment for Parkinson's disease; and (ii) administering to the subject a therapeutically effective amount of an α7-nAChR agonist; wherein the α7-nAChR agonist is a compound of formula (I).

[0319] Another aspect of the present invention relates to a method for treating, preventing, or delaying the progression of motor disorders associated with dopamine agonist treatment for Parkinson's disease in subjects requiring such treatment, comprising (i) diagnosing the subject with motor disorders associated with dopamine agonist treatment for Parkinson's disease; and (ii) administering to the subject a therapeutically effective amount of an α7-nAChR agonist; wherein the α7-nAChR agonist is a compound selected from group P1.

[0320] Another aspect of the present invention relates to a method for treating, preventing, or delaying the progression of motor disorders associated with dopamine agonist treatment for Parkinson's disease in subjects requiring such treatment, comprising (i) diagnosing the subject with motor disorders associated with dopamine agonist treatment for Parkinson's disease; and (ii) administering to the subject a therapeutically effective amount of an α7-nAChR agonist; wherein the α7-nAChR agonist is a compound selected from group P2.

[0321] Another aspect of the present invention relates to a method for treating, preventing, or delaying the progression of motor disorders associated with dopamine agonist treatment for Parkinson's disease in subjects requiring such treatment, comprising (i) diagnosing the subject with motor disorders associated with dopamine agonist treatment for Parkinson's disease; and (ii) administering to the subject a therapeutically effective amount of an α7-nAChR agonist; wherein the α7-nAChR agonist is a compound selected from group P3.

[0322] Another aspect of the present invention relates to a pharmaceutical composition comprising an α7-nAChR agonist for treating, preventing or delaying motor dysfunction associated with dopamine agonist treatment of Parkinson's disease; wherein the α7-nAChR agonist is a compound of formula (I).

[0323] Another aspect of the present invention relates to a pharmaceutical composition comprising an α7-nAChR agonist for treating, preventing, or delaying the progression of motor disorders associated with dopamine agonist treatment for Parkinson's disease; wherein the α7-nAChR agonist is a compound selected from group P1.

[0324] Another aspect of the present invention relates to a pharmaceutical composition comprising an α7-nAChR agonist for treating, preventing, or delaying the progression of motor disorders associated with dopamine agonist treatment for Parkinson's disease; wherein the α7-nAChR agonist is a compound selected from group P2.

[0325] Another aspect of the present invention relates to a pharmaceutical composition comprising an α7-nAChR agonist for treating, preventing, or delaying the progression of motor disorders associated with dopamine agonist treatment of Parkinson's disease; wherein the α7-nAChR agonist is a compound selected from group P3.

[0326] Another aspect of the present invention relates to the use of an α7-nAChR agonist in the preparation of a medicament for treating, preventing, or delaying the progression of motor disorders associated with dopamine agonist treatment of Parkinson's disease; wherein the α7-nAChR agonist is a compound of formula (I).

[0327] Another aspect of the present invention relates to the use of an α7-nAChR agonist in the preparation of a medicament for treating, preventing, or delaying the progression of motor disorders associated with dopamine agonist treatment of Parkinson's disease; wherein the α7-nAChR agonist is a compound selected from group P1.

[0328] Another aspect of the present invention relates to the use of an α7-nAChR agonist in the preparation of a medicament for treating, preventing, or delaying the progression of motor disorders associated with dopamine agonist treatment of Parkinson's disease; wherein the α7-nAChR agonist is a compound selected from group P2.

[0329] Another aspect of the present invention relates to the use of an α7-nAChR agonist in the preparation of a medicament for treating, preventing, or delaying the progression of motor disorders associated with dopamine agonist treatment of Parkinson's disease; wherein the α7-nAChR agonist is a compound selected from group P3.

[0330] Nicotinic acetylcholine receptor α7 positive allosteric modulator

[0331] The “α7-nAChR positive allosteric modulator” used herein is a compound that binds to receptors containing α7-nAChR subunits in vitro and in vivo and enhances receptor activation when its physiological ligand (i.e., acetylcholine) is bound. The enhancing effect can be determined using the method disclosed in WO2001 / 85727, i.e., a functional affinity assay of the homopolymer α7-nicotinic acetylcholine receptor (α7 nAChR) using a rat pituitary cell line stably expressing α7nAChR. As a reading, calcium influx upon receptor stimulation is used compared to acetylcholine binding alone. According to the invention, the calcium influx typically induced by the “α7-nAChR positive allosteric modulator” is at least 200% of the maximum influx induced by acetylcholine, EC50. 50 The value is at least 5000 nM; the preferred agonist induces calcium influx of at least 300% of the maximum influx induced by acetylcholine, EC 50 The value is at least 1000 nM; more preferably, the calcium influx induced by the agonist is at least 400% of the maximum influx induced by acetylcholine, EC 50 The value is at least 500 nM.

[0332] In particular, preferred α7-nAChR positive allosteric modulators should be well absorbed from the gastrointestinal tract, be adequately and stably metabolized, and have good pharmacokinetic properties.

[0333] Further optimized α7-nAChR-positive allosteric modulators effectively bind to α7-nAChR in vivo while exhibiting almost no affinity for other receptors, especially other nAChRs such as α4. 2 nAChR, muscarinic acetylcholine receptors such as M1 and / or 5-HT3 receptors.

[0334] Further preferred α7-nAChR positive allosteric modulators can effectively cross the blood-brain barrier.

[0335] Preferred α7-nAChR positive allosteric modulators should be non-toxic and have virtually no side effects.

[0336] Furthermore, the preferred α7-nAChR positive allosteric modifier can exist in a stable, non-hygroscopic and easily formulated form.

[0337] In one implementation, the α7-nAChR positive allosteric modulator is selective for receptors containing the α7-nAChR subunit, and therefore such positive allosteric modulators are expected to cause fewer side effects in patients than non-selective positive allosteric modulators. Positive allosteric modulators selective for receptors containing the α7-nAChR subunit have a much higher functional affinity for these receptors than for any other nicotinic acetylcholine receptor, such as EC50. 50 The affinity difference is at least 10-fold, preferably at least 20-fold, and more preferably at least 50-fold. To assess the affinity of the α7-nAChR-positive allosteric modulator of the present invention for other nicotinic acetylcholine receptors, the method disclosed in WO2001 / 85727 can be used, i.e., to assess the affinity for human neuronal α4... The affinity of 2nAChR was assessed using stable expression of human α4. Similar functional analyses were performed on two subtypes of human embryonic kidney cell lines. To evaluate the activity of the compounds of the present invention on the nicotinic receptor "ganglionic subtype" and "muscular subtype", similar functional analyses were performed using human embryonic kidney cell lines that stably express the human "ganglionic subtype" or cell lines that endogenously express the human nicotinic receptor "muscular subtype".

[0338] Over the past 12 years, numerous attempts have focused on developing selective α7-nAChR positive allosteric modulators, leading to the discovery of many different chemotypes exhibiting the aforementioned selective activity. These attempts are summarized in the review by Haydar et al. (Current Topics in Medicinal Chemistry, 2010, 10, 144-152), which describes 11 compounds belonging to seven different chemical families as α7-nAChR positive allosteric modulators: XY-4083; PNU-120596, PHA-758454, and NS-1738; PHA-709829; SB-206553; LY-2087101, LY-1078733, and LY-2087133; compound 26; and A-867744 (compound name taken from Haydar et al.). All 11 compounds described by Haydar et al. are incorporated herein by reference. In fact, at least one candidate drug with an α7 nAChR-positive allosteric modulator mode of action has been approved by the U.S. Food and Drug Administration for clinical trials (i.e., XY-4083).

[0339] In one embodiment, the α7 nAChR positive allosteric modulator is a compound selected from group P4; group P4 consists of the following compounds:

[0340] F-1: (Z)-N-(4-chloro-phenyl)-3-(4-chloro-phenylamino)-2-(3-methyl-isoxazol-5-yl)-acrylamide (XY-4083);

[0341] F-2: 1-(5-chloro-2,4-dimethoxy-phenyl)-3-(5-methyl-isoxazol-3-yl)-urea (PNU-120596);

[0342] F-3: 1-(5-fluoro-2,4-dimethoxy-phenyl)-3-(5-trifluoromethyl-isoxazol-3-yl)-urea (PHA-758454);

[0343] F-4: 1-(5-chloro-2-hydroxy-phenyl)-3-(2-chloro-5-trifluoromethyl-phenyl)-urea (NS-1738);

[0344] F-5: 4-(4-chloro-phenyl)-2-(4-methoxy-phenyl)-5-methyl-2H-pyrazol-3-ylamine (PHA-709829);

[0345] F-6: 5-Methyl-3,5-dihydro-2H-pyrrolo[2,3-f]indol-1-carboxylic acid pyridin-3-ylamide (SB-206553);

[0346] F-7: [2-(4-fluoro-phenylamino)-4-methyl-thiazolyl-5-yl]-thiophene-3-yl-methyl ketone (LY-2087101);

[0347] F-8: [2-(4-fluoro-phenylamino)-4-methyl-thiazolyl-5-yl]-p-tolyl-methyl ketone (LY-1078733);

[0348] F-9: Benzo[1,3]m-dioxacyclopenten-5-yl-[2-(4-fluoro-phenylamino)-4-methyl-thiazo-5-yl]-methyl ketone (LY-2087133);

[0349] F-10: 4-naphth-1-yl-3a,4,5,9b-tetrahydro-3H-cyclopentadieno[c]quinoline-8-sulfonamide; and

[0350] F-11: 4-[5-(4-chloro-phenyl)-2-methyl-3-propionyl-pyrrolo-1-yl]-benzenesulfonamide (A-867744);

[0351] The compound is either a free base or an acid addition salt.

[0352] Another aspect of the present invention relates to the use of an α7-nAChR positive allosteric modulator for the treatment, prevention or delay of motor dysfunction associated with dopamine agonist treatment of Parkinson's disease; wherein the α7-nAChR positive allosteric modulator is a compound selected from group P4.

[0353] Another aspect of the present invention relates to a method for treating, preventing, or delaying the progression of motor disorders associated with dopamine agonist treatment for Parkinson's disease in subjects requiring such treatment, comprising administering to the subject a therapeutically effective amount of an α7-nAChR-positive allosteric modulator; wherein the α7-nAChR-positive allosteric modulator is a compound selected from group P4.

[0354] Another aspect of the present invention relates to a method for treating, preventing, or delaying the progression of motor disorders associated with dopamine agonist treatment for Parkinson's disease in subjects requiring such treatment, comprising (i) diagnosing the subject with motor disorders associated with dopamine agonist treatment for Parkinson's disease; and (ii) administering to the subject a therapeutically effective amount of an α7-nAChR-positive allosteric modulator; wherein the α7-nAChR-positive allosteric modulator is a compound selected from group P4.

[0355] Another aspect of the present invention relates to a pharmaceutical composition comprising an α7-nAChR positive allosteric modulator for treating, preventing, or delaying the progression of motor disorders associated with dopamine agonist treatment of Parkinson's disease; wherein the α7-nAChR positive allosteric modulator is a compound selected from group P4.

[0356] Another aspect of the present invention relates to the use of an α7-nAChR positive allosteric modulator in the preparation of a medicament for treating, preventing, or delaying the progression of motor disorders associated with dopamine agonist treatment of Parkinson's disease; wherein the α7-nAChR positive allosteric modulator is a compound selected from group P4.

[0357] Acid addition salts of α7-nAChR agonists or α7-nAChR positive allosteric modulators are preferably pharmaceutically acceptable salts. Such salts are well known in the field (e.g., SM Berge et al., “Pharmaceutical Salts”, J. Pharm. Sd., 1977, 66:1-19; and “Handbook of Pharmaceutical Salts, Properties, Selection, and Use”, Stahl, RH., Wermuth, CG, Eds.; Wiley-VCH and VHCA: Zurich, 2002). “Pharmaceutical acceptable salt” refers to a salt of the free base of an α7-nAChR agonist or α7-nAChR positive allosteric modulator that is non-toxic, not biologically intolerable, or otherwise not biologically undesirable. Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with patient tissues without causing undue toxicity, irritation, or allergic reactions.

[0358] Dopamine agonist treatment for related movement disorders

[0359] "Dopamine agonist therapy" is generally used to treat Parkinson's disease. As used herein, "dopamine agonist therapy" means, unless otherwise stated, any treatment that enhances the stimulation of dopamine receptors, including but not limited to treatment that directly stimulates dopamine receptors (such as administration of bromocriptine) and treatment that increases dopamine levels (such as the use of levodopa or drugs that inhibit dopamine metabolism).

[0360] Dopamine agonist therapy includes, but is not limited to, treatment involving the administration of one or more of the following active agents:

[0361] L-DOPA (or L-DOPA, a precursor to dopamine);

[0362] Levodopa combined with levodopa decarboxylase inhibitors, such as carbidopa or benserazide;

[0363] Levodopa combined with catechol-O-methyltransferase inhibitors, such as tocapone or entacapone;

[0364] Monoamine oxidase B inhibitors, such as selegiline or rasagiline;

[0365] Dopamine receptor agonists, such as bromocriptine, mercapto-ergoline, pramipexole, repirilol, cabergoline, apomorphine, or cyclohexane.

[0366] As used herein, the term "dopamine agonist" means any active agent that enhances the stimulation of dopamine receptors, unless otherwise stated. Preferred dopamine agonists include levodopa; levodopa combined with a levodopa decarboxylase inhibitor; levodopa combined with a catechol-O-methyltransferase inhibitor; monoamine oxidase B inhibitors; and dopamine receptor agonists.

[0367] In one embodiment of the invention, treatment includes administration of levodopa. Due to the prevalence of associated motor disorders, the daily dose of dopamine for effective dopamine agonist treatment of Parkinson's disease needs to be determined individually for each patient, typically ranging from 250 to 1500 mg. The total daily dose is divided into 2-6 administrations per day, or 3-6 administrations of 50-100 mg each. Generally, the daily dose of levodopa required for effective treatment increases with the duration of treatment.

[0368] In one embodiment of the invention, the treatment comprises the combined administration of levodopa and a levodopa decarboxylase inhibitor, such as carbidopa or benserazide.

[0369] As used herein, "dopamine agonist-related movement disorder" means, unless otherwise stated, any movement disorder that occurs, arises, is related to, or is exacerbated by dopamine agonist treatment, either concurrently with or after treatment with dopamine agonists, where the movement disorder and dopamine agonist are as defined above. Although not absolute, such movement disorder often occurs as a side effect of the aforementioned dopamine agonist treatment for Parkinson's disease.

[0370] This movement disorder is characterized by movement impairments, such as slow and uncoordinated involuntary movements, tremors, stiffness, and gait disturbances.

[0371] For example, patients treated with levodopa often experience a reduction in Parkinson's disease symptoms, but they experience increased difficulty maintaining a standing or even sitting position. With prolonged levodopa use, most patients develop motor disorders. Motor disorders can occur at any time during a levodopa treatment cycle.

[0372] In one embodiment, an α7-nAChR agonist or an α7-nAChR-positive allosteric modulator is used to treat movement disorders, wherein the treatment includes administration of levodopa, and the movement disorder occurs at the peak of the patient's levodopa plasma concentration.

[0373] In one implementation, an α7-nAChR agonist or an α7-nAChR-positive allosteric modulator is used to treat a movement disorder, wherein the treatment includes administration of levodopa, and the movement disorder occurs when the patient’s levodopa plasma concentration increases or decreases (biphasic dyskinesia).

[0374] Surprisingly, it was found that α7-nAChR agonists and / or α7-nAChR-positive allosteric modulators can prolong the effect of dopamine agonists such as levodopa. Therefore, compared to treatment with these dopamine agonists, the interval between doses of the dopamine agonists can be prolonged, resulting in a lower daily dose required to achieve the same Parkinson's disease control.

[0375] Another aspect of the invention relates to a method for treating or delaying the progression of Parkinson's disease in subjects requiring such treatment, comprising administering to the subject a therapeutically effective amount of (i) a dopamine agonist and (ii) an α7-nAChR agonist or an α7-nAChR-positive allosteric modulator, wherein the daily dose of the dopamine agonist is reduced compared to the daily dose of the dopamine agonist required to achieve the same Parkinson's disease control in the subject without the combined administration of the α7-nAChR agonist or the α7-nAChR-positive allosteric modulator.

[0376] In a preferred embodiment, the dopamine agonist comprises levodopa.

[0377] In a further preferred embodiment, the reduced daily dose refers to a dose reduction of at least 10%.

[0378] In a further preferred embodiment, the reduced daily dose refers to a dose reduction of at least 20%.

[0379] In a further preferred embodiment, the reduced daily dose is achieved by administering the dopamine agonist at longer intervals.

[0380] Treatment may include a reduction in characteristics associated with the movement disorder, such as, but not limited to, a reduction in the degree of involuntary movements, a reduction in the number of involuntary movements, an improvement in the ability to perform routine tasks, an improvement in walking ability, and a prolonged period between movement disorder episodes.

[0381] One aspect of treating movement disorders associated with dopamine agonist therapy for Parkinson's disease is that the treatment should have minimal side effects on the treatment of Parkinson's disease itself, which is achieved through dopamine agonists. For example, neuroleptics, used to treat movement disorders, have side effects on the efficacy of dopamine agonist therapy, such as parameters related to cognition, depression, and sleep behavior in Parkinson's patients. Highly relevant are anti-movement disorder agents, which have a positive effect on the treatment of Parkinson's disease itself, such as improving cognitive parameters.

[0382] In the case of preventative treatment, α7-nAChR agonists or α7-nAChR positive allosteric modulators can be used to delay or prevent the onset of movement disorders.

[0383] The term “object” as used here preferably refers to humans, especially patients diagnosed with Parkinson’s disease.

[0384] The term “therapeutic effective dose” as used herein generally refers to a dose of medication that, when administered to a subject, is sufficient to provide therapeutic benefit, such as sufficient to treat, prevent, or delay the progression of dopamine agonist-related movement disorders (e.g., the dose improves symptoms, such as reducing the degree of involuntary movements).

[0385] For the aforementioned indications (conditions and disorders), the appropriate dosage will depend, for example, on the compound used, the host, the route of administration, and the nature and severity of the condition being treated. However, generally, satisfactory results in animals are obtained at daily doses of about 0.01 to about 100 mg / kg body weight, preferably about 0.1 to about 10 mg / kg body weight, for example, 1 mg / kg body weight. For large mammals such as humans, the recommended daily dose is about 0.1 to about 1000 mg, preferably about 1 to about 400 mg, and most preferably about 3 to about 100 mg of α7-nAChR agonists or α7-nAChR positive allosteric modulators, conveniently administered in divided doses, for example, no more than four times a day.

[0386] Pharmaceutical Composition

[0387] For the purposes of this invention, α7-nAChR agonists or α7-nAChR positive allosteric modulators may be administered as a single active agent or in combination with other active agents in any conventional manner, such as orally, as in tablets or capsules, parenterally, as in injections or suspensions, or transdermally, as in patches.

[0388] In one implementation, the administration method is oral, such as in the form of tablets or capsules.

[0389] In one implementation, the method of application is transdermal, for example, in the form of a patch.

[0390] Furthermore, the present invention provides pharmaceutical compositions comprising an α7-nAChR agonist or an α7-nAChR-positive allosteric modulator and at least one drug carrier or diluent for treating, preventing, or delaying the progression of dopamine agonist-related motor disorders in Parkinson's disease. Such compositions can be prepared in a conventional manner. Unit doses may contain, for example, about 2.5 to about 25 mg of one or more α7-nAChR agonists or α7-nAChR-positive allosteric modulators.

[0391] The pharmaceutical compositions according to the invention are compositions administered enterically, such as via the nose, rectum, or orally, parenterically, such as intramuscularly or intravenously, or transdermally (e.g., via a patch) to warm-blooded animals (humans and animals), comprising an effective dose of a single pharmacologically active ingredient or together with a useful amount of a pharmaceutically acceptable carrier. The dose of the active ingredient depends on the species, weight, age and condition of the warm-blooded animal, its respective pharmacokinetic data, the disease to be treated, and the route of administration.

[0392] The pharmaceutical composition comprises about 1% to about 95%, preferably about 20% to about 90%, of the active ingredient. The pharmaceutical composition according to the invention may be in, for example, unit dosage form, such as ampoules, vials, suppositories, sugar-coated pills, tablets, or capsules.

[0393] The pharmaceutical compositions of the present invention are prepared in a manner known per se, for example by conventional dissolution, lyophilization, mixing, granulation, or molding processes. Examples of such processes are found in WO 2005 / 079802, WO 2003 / 047581, WO 2004 / 000316, WO 2005 / 044265, WO 2005 / 044266, WO 2005 / 044267, WO 2006 / 114262, and WO 2007 / 071358.

[0394] For a description of the transdermal composition, see Remington's Pharmaceutical Sciences, page 16. th ed., Mack; Sucker, Fuchs and Spieser, Pharmazeutische Technologie, 1 st Version, Springer.

[0395] combination

[0396] The present invention also provides a combination comprising (A) an α7-nAChR agonist or an α7-nAChR positive allosteric modulator; and (B) at least one of levodopa, a levodopa decarboxylase inhibitor, a catechol-O-methyltransferase inhibitor, a monoamine oxidase B inhibitor, or a dopamine receptor agonist.

[0397] Another aspect of the present invention relates to a combination comprising (A) an α7-nAChR agonist; and (B) at least one of levodopa, a levodopa decarboxylase inhibitor, a catechol-O-methyltransferase inhibitor, a monoamine oxidase B inhibitor, or a dopamine receptor agonist; wherein the α7-nAChR agonist is a compound of formula (I).

[0398] Another aspect of the present invention relates to a combination comprising (A) an α7-nAChR agonist; and (B) at least one of levodopa, a levodopa decarboxylase inhibitor, a catechol-O-methyltransferase inhibitor, a monoamine oxidase B inhibitor, or a dopamine receptor agonist; wherein the α7-nAChR agonist is a compound selected from group P1.

[0399] Another aspect of the present invention relates to a combination comprising (A) an α7-nAChR agonist; and (B) at least one of levodopa, a levodopa decarboxylase inhibitor, a catechol-O-methyltransferase inhibitor, a monoamine oxidase B inhibitor, or a dopamine receptor agonist; wherein the α7-nAChR agonist is a compound selected from group P2.

[0400] Another aspect of the present invention relates to a combination comprising (A) an α7-nAChR agonist; and (B) at least one of levodopa, a levodopa decarboxylase inhibitor, a catechol-O-methyltransferase inhibitor, a monoamine oxidase B inhibitor, or a dopamine receptor agonist; wherein the α7-nAChR agonist is a compound selected from group P3.

[0401] Preferably, the combination is a pharmaceutical composition or a combination pharmaceutical preparation.

[0402] In this pharmaceutical composition, the combination partner is...

[0403] (A) α7-nAChR agonists or α7-nAChR positive allosteric modulators, and

[0404] (B) At least one of the following:

[0405] i) Levodopa, or

[0406] ii) Dopa decarboxylase inhibitors, or

[0407] iii) Catechol-O-methyltransferase inhibitors, or

[0408] iv) Monoamine oxidase B inhibitors, or

[0409] iv) Dopamine agonists

[0410] They can be administered together, one after another, or separately, in the same combined unit dose or in two separate unit doses. The unit doses can also be a fixed combination.

[0411] The term “combination” as used herein should be defined as one or more substances that may be administered together, one after another, or separately, in the form of the same combined unit dose or in the form of two separate unit doses.

[0412] Dosage form administration can be co-cominant, simultaneous, partially simultaneous, separate, or sequential. The combined dosage forms do not need to be the same and may include one or more of the following:

[0413] via the stomach: oral (capsules, tablets, solution), rectal (suppositories)

[0414] Parenteral administration: intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, intramammary injection

[0415] Respiratory system: inhalation, intranasal, tracheal

[0416] Topical application: mucosal application, skin application.

[0417] In addition, the release patterns of drugs also differ; for example, one or more components in a combination may have a prolonged release profile.

[0418] In one embodiment of the invention, a specific combination is used. The combination includes:

[0419] (A) α7-nAChR agonists or α7-nAChR positive allosteric modulators; and

[0420] (B) At least one active agent selected from levodopa, carbidopa, benserazide, tocapone, entacapone, bromocriptine, mercapto-ergoline, pramipexole, repirilol, cabergoline, apomorphine, and cyclohexane.

[0421] Another aspect of the present invention relates to a combination comprising: (A) an α7-nAChR agonist; and (B) at least one active agent selected from levodopa, carbidopa, benserazide, tocapone, entacapone, bromocriptine, mercapto-ergoline, pramipexole, repirilol, cabergoline, apomorphine, and cyclohexane; wherein the α7-nAChR agonist is a compound of formula (I).

[0422] Another aspect of the present invention relates to a combination comprising: (A) an α7-nAChR agonist; and (B) at least one active agent selected from levodopa, carbidopa, benserazide, tocapone, entacapone, bromocriptine, mercapto-ergoline, pramipexole, repirilol, cabergoline, apomorphine, and cyclohexane; wherein the α7-nAChR agonist is a compound selected from group P1.

[0423] Another aspect of the present invention relates to a combination comprising: (A) an α7-nAChR agonist; and (B) at least one active agent selected from levodopa, carbidopa, benserazide, tocapone, entacapone, bromocriptine, mercapto-ergoline, pramipexole, repirilol, cabergoline, apomorphine, and cyclohexane; wherein the α7-nAChR agonist is a compound selected from group P2.

[0424] Another aspect of the present invention relates to a combination comprising: (A) an α7-nAChR agonist; and (B) at least one active agent selected from levodopa, carbidopa, benserazide, tocapone, entacapone, bromocriptine, mercapto-ergoline, pramipexole, repirilol, cabergoline, apomorphine, and cyclohexane; wherein the α7-nAChR agonist is a compound selected from group P3.

[0425] In one embodiment of the invention, a specific combination is used. The combination includes:

[0426] (A) α7-nAChR agonists or α7-nAChR positive allosteric modulators; and

[0427] (B) Levodopa and at least one active agent selected from carbidopa, benserazide, tocapone, entacapone, bromocriptine, mercapto-ergoline, pramipexole, repirilol, cabergoline, apomorphine or cyclohexane.

[0428] An example of the described implementation is a combination of an α7-nAChR agonist or an α7-nAChR positive allosteric modulator with levodopa, which may further include a levodopa decarboxylase inhibitor such as carbidopa or benserazide.

[0429] An example of the implementation scheme is a combination of an α7-nAChR agonist selected from group P3 with levodopa, the combination also containing a levodopa decarboxylase inhibitor such as carbidopa.

[0430] An example of the described implementation is a combination of an α7-nAChR agonist selected from group P3 with levodopa, the combination also containing a levodopa decarboxylase inhibitor such as benserazide.

[0431] In one embodiment of the invention, a specific combination is used. The combination includes:

[0432] (A) α7-nAChR agonists or α7-nAChR positive allosteric modulators; and

[0433] (B) Levodopa, carbidopa and entacapone.

[0434] An example of the implementation scheme is a combination of an α7-nAChR agonist or an α7-nAChR positive allosteric modulator with Stalevo®.

[0435] An example of the implementation scheme is a combination of an α7-nAChR agonist selected from group P3 with Stalevo®.

[0436] The present invention also provides a product, such as a kit, comprising an α7-nAChR agonist or an α7-nAChR-positive allosteric modulator and levodopa as a combination formulation for simultaneous, separate, or sequential treatment. The product may further comprise a levodopa decarboxylase inhibitor, such as carbidopa or benserazide. Detailed Implementation

[0437] The usefulness of α7-nAChR agonists or α7-nAChR positive allosteric modulators in treating the above-mentioned disorders can be confirmed by a series of standard tests including those shown below.

[0438] 1. In vitro experiments

[0439] 1.1. Selectivity of the selected α7-nAChR agonist for α4β2-nAChR

[0440] Based on the activity / selectivity data shown below, it is concluded that the compound is a selective agonist of α7-nAChR.

[0441]

[0442] DetectionTo assess α7-nAChR activity, a functional assay was performed using GH3 cells expressing recombinant human α7-nAChR. 72 hours prior to the experiment, 50,000 cells / well were seeded in black 96-well (Costar) plates and incubated at 37°C in a humidified atmosphere (5% CO2 / 95% air). On the day of the experiment, the culture medium was discarded by gently tapping the plate and replaced with 100 µl of growth medium containing 2 mM Fluo-4 (Molecular Probes) and 2.5 mM probenecid (Sigma). The cells were then incubated at 37°C in a humidified atmosphere (5% CO2 / 95% air) for 1 hour. Discard excess Fluo-4 by gently tapping the culture plate. Wash twice with Hepes buffered saline (mM: NaCl 130, KCl 5.4, CaCl2 2, MgSO4 0.8, NaH2PO4 0.9, glucose 25, Hepes 20, pH 7.4; HBS), and add 100 µl of HBS containing the antagonist as needed. Incubate with the antagonist for 3-5 minutes. Place the culture plate on the cell plate stage of a FLIPR device (Molecular Devices, Sunnyvale, CA, USA). After recording the baseline (laser: excitation 488 nm, 1 W, CCD camera exposure time 0.4 s), add the agonist (50 µl) to the cell plate using a FLIPR 96-tip pipette, while recording the fluorescence value. Normalize the calcium kinetic data to the maximum fitted response value induced by hygroscopic scutellarin, a complete agonist of α7-nAChR. The concentration-response value was fitted to the four-parameter Hill equation. The Emax (maximum effect in % compared to the response value of scutellarin) and EC50 (concentration in µM at which the half-maximum effect is produced) values ​​were generated from this fit.

[0443] For a description of the test, see: D Feuerbach et al., Neuropharmacology (2005), 48, 215-227.

[0444] To evaluate the activity of the compounds of this invention against human neuronal nAChR α4β2, similar functional tests were performed using human epithelial cell lines that stably express the human α4β2 isotype (Michelmore et al., Naunyn-Schmiedeberg's Arch. Pharmacol. (2002) 366, 235).

[0445] 2. In vivo preclinical experiments

[0446] 2.1. Oral bioavailability and brain penetration in mice

[0447] Based on the pharmacokinetic data shown below, it can be concluded that, at least 4 hours after rapid oral administration of a 30 µmol / kg dose, the brain concentration of the compound in mice exceeded (or was at least equal to) the EC50 of the compound against α7-nAChR. 50 .

[0448] Compound A-1:

[0449]

[0450] Compound B-13:

[0451]

[0452] Compound C-1:

[0453]

[0454] Detection The compound was administered orally (30 µmol / kg). Male mice (30–35 g, OF1 / IC strain) were sacrificed at the indicated time point following oral administration. Blood was collected from the trunk in tubes containing EDTA, the brain was removed, and the mice were immediately frozen with dry ice.

[0455] Add 10 µl of internal standard (1.0 pmol of a compound with similar solubility and ionization properties to the analyte) to 100 µl of plasma and extract three times with 500 µl of dichloromethane. Dry the combined extracts under a nitrogen stream and redissolve in 100 µl of acetonitrile / water (70% acetonitrile). Weigh brain and homogenize with water (1:5 w / v). Extract three times with 500 µl of dichloromethane in two 100 µl aliquots each, adding 10 µl of internal standard (consistent with the internal standard used for the plasma sample), as with further processing of the plasma sample. Separate the samples using a Beckmann high-performance liquid chromatography system (Gilson 233XL) with an autosampler. Elute the compound from a Nucleosil CC-125 / 2C18 reversed-phase (Machery & Nagel) column using a 10-min linear gradient (10-70%) of acetonitrile containing 0.5% (v / v) formic acid.

[0456] The limit of detection (LOD) is defined as the lowest concentration of the extracted standard, with a signal-to-noise ratio of approximately 3.

[0457] 2.2. Mouse functional readouts (social cognition experiment)

[0458] Based on the in vivo functional data shown below, it is concluded that oral administration of appropriate concentrations of the compound induces specific effects associated with α7-nAChR (i.e., improved cognition in mice during social cognition tests).

[0459]

[0460] Detection The social interaction between two experimental animals is influenced by their intimacy: the more familiar they are with each other, the less time they spend examining each other at each encounter. Consistent with published rat data (Mondadori et al., 1993), we have observed that (i) when two mice are arranged to meet again within a short period (e.g., 1 hour), adult mice show a shorter examination time for the same type of younger mouse; (ii) this shortening is attributed to memory processes: if the familiar younger partner is replaced by a strange (unfamiliar) younger mouse at the second meeting, no shortening occurs; and (iii) the adult mouse's memory of the previously examined younger partner fades over time, for example, after 24 hours, the examination time is as long as the first encounter. Memory enhancers (i.e., piracetam) promote the degree to which previously encountered (familiar) partners are remembered up to 24 hours later, while in excipient-treated control animals, memory typically fades in less than 1 hour (Thor and Holloway, 1982) or 2–3 hours.

[0461] Baseline testing: Several pairs of mice, consisting of one adult and one juvenile mouse, were randomly assigned to the experimental and control groups. In each pair, only the adult mouse was orally administered the excipient or test compound 1 hour prior to the test. The duration of active contact between the adult and juvenile mice within 3 minutes was manually recorded, including the following approach-related behaviors: sniffing, nasal touching, grooming, licking, pawing and playing, genital exploration, and orientation towards the juvenile mouse; here, orientation was defined as the distance between the tip of the adult mouse's nose and the body of the juvenile mouse being less than approximately 1 cm.

[0462] Repeat Experiment: 24 hours after baseline testing, adult mice in each treatment group were again exposed to their previously encountered (familiar) partners. Half of the adult animals were placed with their previously encountered (familiar) partners, while the other half were placed with other (unfamiliar) young mice. The duration of the active approach-behavior within 3 minutes was recorded again. No oral injection was given before the repeat experiment. The table shows the reduction in the time spent with familiar partners at 24 hours compared to the time spent with familiar partners at 0 minutes (zero indicates no reduction).

[0463] 2.3. Evaluation of anti-movement disorder efficacy in primates with Parkinson's disease

[0464] Based on the in vivo data of Parkinson's disease primates shown below, it can be concluded that compound A-1 does not delay the onset of levodopa's action, does not reduce the anti-Parkinsonian activity of levodopa, significantly reduces levodopa-induced motor dysfunction, and significantly increases the duration of levodopa's anti-Parkinsonian activity.

[0465] 2.3.1 Method

[0466] Evaluation was conducted using female ovariectomized rhesus monkeys (Macaca fascicularis). Animals were continuously perfused with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) until they developed stable Parkinson's disease symptoms, thus diagnosing Parkinson's disease. After recovery, the animals were treated daily with levodopa until well-defined and reproducible motor impairments developed.

[0467] 2.3.2 Assessment

[0468] Monkeys in cages were observed through a one-way screen window. Their condition was repeatedly observed and recorded at baseline and after subcutaneous injection of a standard dose of levodopa. Motor activity was assessed and tracked using an electronic monitoring system. Anti-Parkinsonian response was evaluated by measuring motor activity and the Parkinson's Disease Energy Exhaustion Scale (see Hadj Tahar A et al., Clin Neuropharmacol 2000; 23:195-202; and Samadi P et al., Neuropharmacology 2003; 45:954-963). Motor dysfunction was closely monitored and scored every 15 minutes according to the Motor Dysfunction Rating Scale (see Hadj Tahar A et al.; and Samadi P et al.) until the effect wore off. The selected dose of levodopa induced motor activation and reproducible motor dysfunction without excessive excitation.

[0469] 2.3.3 Scheme

[0470] Monkeys were observed for at least 2 hours after oral administration of the excipient. A subsequent day, a trial was conducted with the selected levodopa dose. Animals were observed for the entire duration of the levodopa effect (measured by the Parkinson's Disease and Movement Disorder Scale) and motor activity was monitored. This provides excipient control values ​​and data on levodopa's anti-Parkinsonian and movement disorder responses for comparison with combinations of α7-nAChR agonists / positive allosteric modulators and levodopa. Monkeys were subsequently tested with a fixed dose of levodopa in combination with an α7-nAChR agonist / positive allosteric modulator. An α7-nAChR agonist / positive allosteric modulator suspension for oral administration was administered prior to levodopa. After each administration, animals were observed for the entire duration of the effect (measured by the Parkinson's Disease and Movement Disorder Scale) and motor activity or any behavioral changes (e.g., circling, agitation, lethargy, and drowsiness) were monitored.

[0471] Using this protocol, compound A-1 at a dose of 20 mg / kg was tested. Results based on five monkeys (levodopa / benserazide doses: 22.5 / 50 mg, 65 / 50 mg, 30 / 50 mg, 35 / 50 mg, and 25 / 50 mg) are shown in Figures 1-4. In the experiment, compound A-1 reduced the mean motor impairment score (total period) from 2.8 to 2.1; moreover, compound A-1 prolonged the duration of the levodopa-response from 230 minutes to 265 minutes. The addition of compound A-1 did not significantly alter the elapsed time after levodopa administration or the degree of anti-Parkinsonian activity as determined by the anti-Parkinson's disease score.

[0472] 2. Clinical trials: Improved trials

[0473] Clinical trials of α7-nAChR agonists / positive allosteric modulators can be conducted, for example, in one of the following study designs. A skilled physician can examine multiple aspects of the patient's behavior and abilities. He will be aware that this type of study serves as a guiding principle, and certain aspects of the study can be modified and redefined, for example, depending on the circumstances and environment.

[0474] 2.1 Trial A: Standard Patient Population

[0475] In a standard control group, administer the medication once daily for one week or longer and test the patient. Design the trial to allow for improvement, i.e., an increase in a measurable parameter indicating impaired function. Test patients at the beginning and end of the dosing period, compare and analyze the results.

[0476] 2.2 Experiment B: Defective Group

[0477] For patients with Parkinson's disease-related deficits and associated conditions, such as Parkinsonian dyskinesia or Parkinsonian dyskinesia caused by levodopa, administer once daily for one week or longer and test. Design trials to allow for improvement, i.e., an increase in measurable parameters of impaired function. Test patients at the beginning and end of the dosing period, compare and analyze the results.

[0478] 2.3 Considerations for Experimental Design

[0479] When designing experiments, technicians will understand the need to protect against floor and ceiling effects. In other words, the study design should allow for measurable increases or decreases in perception.

[0480] Artificial impairment of function, such as cognitive impairment, is one way to test for enhancement of that function. Examples of such impairments include sleep deprivation and drug attacks.

[0481] A placebo control is required in any trial.

[0482] When evaluating data, the potential for the learning and practice effects of repeated assessments must be assessed. The possibility of this effect contaminating the data and causing false positives should be considered when designing trials; for example, trials should not be identical (e.g., performing the same list of words to memorize), but should be designed to study the same mechanism. Other countermeasures may include conducting a single trial only at the end of the trial.

[0483] The data description is shown in Figure 1-4. Attached Figure Description

[0484] Figure 1: Time to disappearance of behavioral response in Parkinson's disease primates after levodopa administration.

[0485] Figure 2: Average Parkinson's disease score (total period) in primates after levodopa administration.

[0486] Figure 3: Mean motor impairment score (total period) in primates with Parkinson's disease after levodopa administration.

[0487] Figure 4: Duration of levodopa response in Parkinson's disease primates after levodopa administration.

Claims

1. Selective nicotinic acetylcholine receptor α7 (α7-nAChR) agonists of formula (I) in free base or acid addition salt form: (I) Where L1 is –CH2-; L2 is –CH2- or –CH2-CH2-; L3 is –CH2-; and L4 is group L4b. The bonds marked with an asterisk are connected to the aziridine bicycloalkyl moiety; X1 is –O- or –NH-; A2 is… , or The bonds marked with an asterisk are connected to X1; A1 is a pentaneous to decacyclic monocyclic or fused polycyclic aromatic ring system, which may contain 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the ring system may contain no more than 2 oxygen atoms and no more than 2 sulfur atoms, and wherein the ring system may be substituted by R2 once or more, and wherein the substituent on the nitrogen of the heterocyclic ring system may not be a halogen; R2 is independently C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 A haloalkoxy, halogen, cyano, or tri- to hexa-membered monocyclic ring system, wherein the monocyclic ring system may be aromatic, saturated or partially saturated, and may contain 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, wherein each ring system may contain no more than 2 oxygen atoms and no more than 2 sulfur atoms, and wherein each ring system may be further divided by C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 The alkyl halogen, halogen, or cyano group is substituted once or more, and the substituent on the nitrogen atom of the heterocyclic ring cannot be halogen; or two R2 atoms at adjacent ring atoms form a C2 group. 3-4 Alkylene, wherein 1-2 carbon atoms can be replaced by X2, and wherein C 3-4 The alkylene group can be substituted once or more by R3; X2 is independently –O- or -N(R4)-; R4 is independently hydrogen or C. 1-6 Alkyl group; and each of R3 is independently a halogen or C. 1-6 Alkyl group; use in the preparation of medicaments for treating, preventing, or delaying the progression of levodopa-induced motor disorders in Parkinson's disease, and for increasing the duration of the anti-Parkinsonian activity of levodopa in Parkinson's disease.

2. The use according to claim 1, wherein the drug is used to treat levodopa-induced motor disorders in Parkinson's disease.

3. The use according to claim 1, wherein the drug is used to prevent levodopa-induced motor dysfunction in Parkinson's disease.

4. The use according to claim 1, wherein the drug is used to delay the progression of levodopa-induced motor dysfunction in Parkinson's disease.

5. The use according to any one of claims 1-4, wherein the compound of formula (I) is (R)-3-(6-p-tolyl-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in the form of a free base or an acid addition salt.

6. The use according to any one of claims 1-4, wherein the treatment comprises administration of levodopa.

7. The use according to claim 5, wherein the treatment comprises administration of levodopa.

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