Azacyclic compounds

• US 6,815,458 B2
• Filed: 03/06/2001
• Issued: 11/09/2004
• Est. Priority Date: 03/06/2000
• Status: Expired due to Term

• Current Assignee: Acadia Pharmaceuticals Inc.
• Original Assignee: Acadia Pharmaceuticals Inc.
• Inventors: Hansen, Eva Louise, Andersson, Carl-Magnus A., Croston, Glenn, Uldam, Allan Kjaersgaard
• Primary Examiner(s): Raymond, Richard L.
• Assistant Examiner(s): PATEL, SUDHAKER B
• Application Number:
  US09/800,096
• Publication Number:
  US 20020004513A1
• Time in Patent Office: 1,344 Days
• Field of Search: 514/183, 514/352, 514/357, 514/358, 546/244, 546/246, 546/248
• US Class Current: 514/352
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07D 207/14 Nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 211/26 with hydrocarbon radicals, substituted by nitrogen atoms
• CPC Class Codes: C07D 211/58 attached in position 4
• CPC Class Codes: C07D 401/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 407/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 407/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 451/02 : containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
• CPC Class Codes: C07D 451/06 : Oxygen atoms
• CPC Class Codes: C07D 487/08 : Bridged systems

Abstract

Compounds and methods are provided for the treatment of disease conditions in which modification of serotonergic receptor activity has a beneficial effect. In the method, an effective amount of a compound is adminstered to a patient in need of such treatment.

Claims

1. A compound of formula (I)

wherein

Z is

in which

R is a hydrogen, a cyclic or straight-chained or branched acyclic organyl group, a lower hydroxyalkyl group, a lower aminoalkyl group, or an aralkyl or heteroaralkyl up;

n is 1;

X₁ is methylene, vinylene, or an NH or N(lower alkyl) group; and

X₂ is methylene, or, when X₁ is methylene or vinylene, X₂ is methylene or a bond;

or when X₁ is methylene, X₂ is O, S, NH, or N(lower alkyl) or a bond;

Y₁ is methylene and Y₂ is methylene, vinylene, ethylene, propylene, or bond;

or

Y₁ is a bond and Y₂ is vinylene;

or

Y₁ is ethylene and Y₂ is O, S, NH, or N(lower alkyl);

Ar₁ and Ar₂ independently are unsubstituted or substituted aryl or heteroaryl groups, provided that Ar₁ and Ar₂ are not simultaneously unsubstituted phenyl; and

W is oxygen;

or

a pharmaceutically acceptable salt or prodrug thereof.

2. A compound according to claim 1, wherein

Y₁ is methylene and Y₂ is a bond, methylene, ethylene, or vinylene; or

Y₁ is ethylene and Y₂ is O or S; and

X₁ is methylene and X₂ is a bond, methylene, O, or S;

or

X₁ is NH or N(lower alkyl) and X₂ is methylene.

3. A compound according to claim 2, wherein Ar₁ and Ar₂ independently are mono- or disubstituted phenyl groups.

4. A compound according to claim 3, wherein

R is a hydrogen, a lower alkyl group, a cyclic organyl group, or a substituted or unsubstituted aralkyl or heteroaralkyl group;

n is 1;

Y₁ is methylene, Y₂ is a bond, methylene, ethylene, or vinylene;

X₁ is methylene and X₂ is a bond, or,

X₁ is NH or N(lower alkyl) and X₂ is methylene; and

Ar₁ and Ar₂ are phenyl groups, independently p-substituted with groups selected from lower alkyl, lower alkoxy and halogen.

5. A compound according to claim 1, having a formula (II)

wherein

R^N is hydrogen, lower alkyl, aralkyl, or heteroaralkyl;

Ar^L is selected from lower alkyl, lower alkoxy and halogen

Ar^R is selected from lower alkyl, lower alkoxy and halogen;

k is 1 or 2

and K is a suitable anion.

13. A method of inhibiting an activity of a monoamine receptor comprising contacting the monoamine receptor or a system containing the monoamine receptor with an amount of one or more of the compounds of claim 1 that is effective in inhibiting the activity of the monoamine receptor.

14. The method of claim 13 wherein the monoamine receptor is a serotonin receptor.

15. The method of claim 14 wherein the serotonin receptor is the 5-HT2A subclass.

16. The method of claim 14 wherein the serotonin receptor is in the central nervous system.

17. The method of claim 14 wherein the serotonin receptor is in the peripheral nervous system.

18. The method of claim 14 wherein the serotonin receptor is in blood cells or platelets.

19. The method of claim 14 wherein the serotonin receptor is mutated or modified.

20. The method of claim 13 wherein the activity is signaling activity.

21. The method of claim 13 wherein the activity is constitutive.

22. The method of claim 13 wherein the activity is associated with serotonin receptor activation.

23. A method of inhibiting an activation of a monoamine receptor comprising contacting the monoamine receptor or a system containing the monoamine receptor with an amount of a compound of one or more of the compounds of claim 1 that is effective in inhibiting the activation of the monoamine receptor.

24. The method of claim 23 wherein the activation is by an agonistic agent.

25. The method of claim 24 wherein the agonistic agent is exogenous.

26. The method of claim 24 wherein the agonistic agent is endogenous.

27. The method of claim 23 wherein the activation is constitutive.

28. The method of claim 23 wherein the monoamine receptor is a serotonin receptor.

29. The method of claim 28 wherein the serotonin receptor is the 5-HT2A subclass.

30. The method of claim 28 wherein the serotonin receptor is in the central nervous system.

31. The method of claim 28 wherein the serotonin receptor is in the peripheral nervous system.

32. The method of claim 28 wherein the serotonin receptor is in blood cells or platelets.

33. The method of claim 28 wherein the serotonin receptor is mutated or modified.

34. A method of treating a disease condition associated with a monoamine receptor comprising administering to a subject in need of such treatment a therapeutically effective amount of one or more of the compounds of claim 1.

35. The method of claim 34 wherein the disease condition is selected from the group consisting of schizophrenia, psychosis, migraine, hypertension, thrombosis, vasospasm, ischemia, depression, anxiety, sleep disorders and appetite disorders.

36. The method of claim 34 wherein the disease condition is associated with dysfunction of a monoamine receptor.

37. The method of claim 34 wherein the disease condition is associated with activation of a monoamine receptor.

38. The method of claim 34 wherein the disease condition is associated with increased activity of monoamine receptor.

39. The method of claim 34 wherein the monoamine receptor is a serotonin receptor.

40. The method of claim 39 wherein the serotonin receptor is the 5- HT2A subclass.

41. The method of claim 39 wherein the serotonin receptor is in the central nervous system.

42. The method of claim 39 wherein the serotonin receptor is in the peripheral nervous system.

43. The method of claim 39 wherein the serotonin receptor is in blood cells or platelets.

44. The method of claim 39 wherein the serotonin receptor is mutated or modified.

45. A method of treating schizophrenia comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of one or more of the compounds of claim 1.

46. A method of treating migraine comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of one or more of the compounds of claim 1.

47. A method of treating psychosis comprising administering to subject in need of such treatment a therapeutically effective amount of a compound of one more of the compounds of claim 1.

48. A method according to claim 47 wherein the psychosis is a drug-induced psychosis.

6. A compound is selected from the group consisting of:

N-(1-(1-methylethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;

N-(1-(2,2-dimethylethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;

N-(1-pentylpiperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;

N-(1-hexylpiperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;

N-(1-cyclohexylpiperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;

N-(1-cyclopentylpiperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;

N-(1-cyclobutylpiperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;

N-(1-cyclopropylpiperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;

N-(1-(cyclopentylmethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;

N-(1-(cyclobutylmethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;

N-(1-(cyclopropylmethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;

N-(1-(2-hydroxyethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;

N-(1-(3-hydroxypropyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;

N-((4-methylphenyl)methyl)-N-(piperidin-4-yl)-N′

-phenylmethylcarbamide;

N-((4-methylphenyl)methyl)-N-(1-(2-methylpropyl)piperidin-4-yl)-N′

-phenylmethylcarbamide;

N-(1-((2-bromophenyl)methyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-N′

-phenylmethylcarbamide;

N-(1-((4-hydroxy-3-methoxyphenyl)methyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-N′

-phenylmethylcarbamide;

N-(1-((5-ethylthien-2-yl)methyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-N′

-phenylmethylcarbamide;

N-(1-(imidazol-2-ylmethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-N′

-phenylmethylcarbamide;

N-(1-(cyclohexylmethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-N′

-phenylmethylcarbamide;

N-(1-((4-fluorophenyl)methyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-N′

-phenylmethylcarbamide;

N-((4-methylphenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide;

N-((4-methylphenyl)methyl)-N-(1-methylpiperidin-4-yl)-4-methoxyphenylacetamide;

N-(1-ethylpiperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;

N-((4-methylphenyl)methyl)-N-(1-propylpiperidin-4-yl)-4-methoxypheylacetamide;

N-(1-butylpiperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;

N-(1-(3,3-dimethylbutyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;

N-(1-(cyclohexylmethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;

N-((4-methylphenyl)methyl)-N-(1-(2-methytpropyl)piperidin-4-yl)-4-methoxyphenylacetamide;

N-((4-methylphenyl)methyl)-N-(1-((4-methylphenyl)methyl)piperidin-4-yl)-4-methoxyphenylacetamide;

N-(1-((4-hydroxyphenyl)methyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;

N-(1-((2-hydroxyphenyl)methyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;

N-(3-phenylpropyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide;

N-(2-phenylethyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide;

N-((2-methoxyphenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide;

N-((2-chlorophenyl)methyl)-N-(piperidin-4-yl)-4methoxyphenylacetamide;

N-((3,4-di-methoxyphenyl)methyl)-N-(piperdin-4-yl)-4-methoxyphenylacetamide;

N-((4-fluorophenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide;

N-((2,4-di-chlorophenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide;

N-((3-methylphenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide;

N-((3-bromophenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide;

N-(1-(phenylmethyl)piperidin-4-yl)-N-(3-phenyl-2-propen-1-yl)-4-methoxyphenylacetamide;

N-((4-methylphenyl)methyl)-N-(1-piperidin-4-yl)-phenylacetamide;

N-((4-methylphenyl)methyl)-N-(1-piperidin-4-yl)-3-phenylpropionamide;

N-((4-methylphenyl)methyl)-N-(1-piperidin-4-yl)-(phenylthio)acetamide;

N-((4-methylphenyl)methyl)-N-(1-piperidin-4-yl)-phenoxyacetamide;

N-((4-methylphenyl)methyl)-N-(1-piperidin-4-yl)-(4-chlorophenoxy)acetamide;

N-((4-methylphenyl)methyl)-N-(1-piperidin-4-yl)-3-methoxyphenylacetamide;

N-((4-methylphenyl)methyl)-N-(1-piperidin-4-yl)-4-fluorophenylacetamide;

N-((4-methylphenyl)methyl)-N-(1-piperidin-4-yl)-2,5-di-methoxyphenylacetamide;

N-((4-methylphenyl)methyl)-N-(1-piperidin-4-yl)-4-chlorophenylacetamide;

2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(piperidin-4-yl)acetamide;

2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N(1-methylpiperidin-4-yl) acetamide;

2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(1-ethylpiperidin-4-yl) acetamide;

2-(4-methoxyphenyl)-N-(4-chlorobenzyl)-N-(1-ethylpiperidin-4-yl)acetamide;

2-(4-methoxyphenyl)-N-(4-chlorobenzyl)-N-(1-isopropylpiperidin-4-yl) acetamide;

2-(4-methoxyphenyl)-N-(4-chlorobenzyl)-N-(piperidin-4-yl)acetamide;

2-(4-methoxyphenyl)-N-(4-chlorobenzyl)-N-(1-cyclopentylpiperidin-4-y) acetamide;

2-(4-methoxyphenyl)-N-(4-chlorobenzyl)-N-(1-isopropylpiperidin-4-yl) acetamide;

2-(phenyl)-N-(4-trifluoromethylbenzyl)-N-(1-methylpiperidin-4-yl) acetamide;

2-(4-fluorophenyl)-N-(4-trifluoromethylbenzyl)-N-(1-methylpiperidin-4-yl) acetamide;

2-(4-Methoxyphenyl)-N-(4-trifluoromethylbenzyl)-N-(1-methylpiperidin-4-yl) acetamide;

2-(4-Trifluoromethylphenyl)-N-(4-trifluoromethylbenzyl)N-(1-methylpiperidin-4-yl acetamide;

2-(4-Fluorophenyl)-N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl) acetamide;

2-(4-Methoxyphenyl)-N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl) acetamide;

2-(phenyl)-N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl) acetamide;

2-(4-Trifluoromethylphenyl)-N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl) acetamide;

2-(4-trifluoromethylphenyl)-N-[4-(methoxycarbonyl)benzyly]-N-(1-methylpiperidin-4-yl) acetamide;

2-Phenyl-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperidin-4-yl) acetamide;

2-(4-Chlorophenyl)-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperidin-4-yl) acetamide;

2-(4-Methoxyphenyl)-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperdin-4-yl) acetamide;

2-(4-trifluoromethylphenyl)-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperidin-4-yl) acetamide;

2-Phenyl-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperidin-4-yl) acetamide;

2-(4-Chlorophenyl)-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperidin-4-yl) acetamide;

2-(4-Methoxyphenyl)-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperidin-4-yl) acetamide;

2-(4 methoxyphenyl)-N-(4-methylbenzyl)-N-[1-(4-chloromethyl-2-thiazolylmethyl) piperidin-4-yl]acetamide;

2-(4 methoxyphenyl)-N-(4-methylbenzyl)-N-{(1-[3(1,3-dihydro-2H-benzimidazol-2-on-1-yl)propyl]piperidin-4-yl}acetamide;

2-(4-methoxyphenyl)-N-(2-4(fluorophenyl)ethyl)-N-(1-methylpiperidin-4-yl) acetamide;

2-(4-methoxyphenyl)-N-[2-(2,5-dimethoxyphenyl)ethyl]-N-(1-methylpiperidin-4-yl) acetamide;

2-(4-methoxyphenyl)-N-[2-(2,4-dichlorophenyl)ethyl]-N-(1-methylpiperidin-4-yl) acetamide;

2-(4-methoxyphenyl)-N-[2-(3-chlorophenyl)ethyl]-N-(1-methylpiperidin-4-yl) acetamide;

2-(4-methoxyphenyl)-N-[2-(4-methoxyphenyl)ethyl]-N-(1-methylpiperidin-4-yl) acetamide;

2-(4-methoxyphenyl)-N-[2-(3-fluorophenyl)ethyl]-N-(1-methylpiperidin-4-yl) acetamide;

2-(4-ethoxyphenyl)-N-[2-(4-fluorophenethyl]-N-(1-methylpiperidin-4-yl) acetamide;

2-(4-ethoxyphenyl)-N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl) acetamide;

2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-{1-[2-(2-hydroxyethoxy)ethyl]piperidin-4-yl}acetamide;

2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-[1-((2-chloro-5-thienyl)methyl)piperidin-4-yl]acetamide;

2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-[1-(2-(imidazolidinon-1-yl)ethyl)piperidin-4-yl]acetamide;

2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-{1-[2-(2,4(1H,3H)quinazolinedion-3-yl)ethyl]piperidin-4-yl}acetamide;

2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-{1-[2-(1,3-dioxolan-2-yl)ethyl]piperidin-4-yl}acetamide;

2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-{1-[2-(3-indolyl)ethyl]piperidin-4-yl}acetamide;

2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-{1-[3-(1,2,4-triazol-1-yl)propyl]piperidin-4-yl}acetamide;

2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-[1-(5-benzofurazanylmethyl)piperidin-4-yl]acetamide;

2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-[1-(5-chlorobenzo[b]thien-3-ylmethyl) piperidin-4-yl]acetamide;

2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-[1-(5-phenyl-1,2,4-oxadiazol-3-ylmethyl)piperidin-4-yl]acetamide;

2-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(1-isopropylpiperidin-4-yl) acetamide;

2-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(1-ethylpiperidin-4-yl)-acetamide;

2-Phenyl-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)-acetamide[,2(4-(Chlorophenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)-acetamide];

2-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)-acetamide;

2-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(1-cyclopentylpiperidin-4-yl)-acetamide;

2-(4-Fluorophenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)-acetamide;

2-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(1-(2-hydroxyethyl)-piperidin-4-yl)-acetamide;

2-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(1-cyclobutylpiperidin-4-yl)-acetamide;

2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-(1-cyclobutylpiperidin-4-yl)-acetamide(,2(4-Methoxyphenyl)-N-(methylbenzyl)-N-(tropin-4-yl)-acetamide];

N-(4-Methylbenzyl)-N-(4-methylpiperidin-4-yl)-N′

-benzyl-carbamide;

N-(4-Methylbenzyl)-N-(1-methylpiperidin-4-yl)-N′

-phenyl-carbamide;

N-Phenethyl-N-(1-methylpiperidin-4-yl)-N′

-benzyl-carbamide;

2-Phenyl-N-(4-methoxybenzyl)-N-(1-methylpiperidin-4-yl)-acetamide;

2-(4-Trifluoromethylphenyl)-N-(4-methoxybenzyl)-N-(1-methylpiperidin-4-yl)-acetamide;

2-(4-Fluorophenyl)-N-(4-methoxybenzyl)-N-(1-methylpiperidin-4-yl)-acetamide;

2-(4-Methoxyphenyl)-N-(4-methoxybenzyl)-N-(1-methylpiperidin-4-yl)-acetamide;

2-(4-Methylphenyl)-N-(4-chlorobenzyl)-N-(1-methylpiperidin-4-yl)-acetamide;

2-(4-Hydroxyphenyl)-N-(4-methylbenzyl)-N(1-methylpiperidin-4-yl)-acetamide;

N-Phenethyl-N-(1-methylpiperidin-4-yl)-N′

-phenyl-carbamide;

N-(3-Phenylpropyl)-N-(1-methylpiperidin-4-yl)-N′

-benzyl-carbamide;

N-(3-Phenylpropyl)-N-(1-methylpiperidin-4-yl)-N′

-phenyl-carbamide;

2-(4-Methoxyphenyl)-2,2-ethylene-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl) acetamide;

2-(4-Methoxyphenyl)-N-alpha-methylbenzyl-N-(1-methylpiperidin-4-yl) acetamide;

[2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-(3-tropen-4-yl) acetamide;

]

2-Phenyl-2-ethyl-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl) acetamide;

N-Phenethyl-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)-amine;

2-(4-Methoxyphenyl)-N-(1-indanyl)-N-(1-methylpiperidin-4-yl) acetamide;

N-(4-Methylbenzyl)-N-(1-methylpiperidin-4-yl)-N′

-(4-methoxybenzyl)-carbamide;

2-(3,4-dimethoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl) acetamide;

2-(3,4-Methylenedioxyphenyl)-N-(4-methylbenzyl)N(1-methylpiperidin-4-yl) acetamide;

2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-(1-t-butylpiperidin-4-yl)-acetamide;

N-(4-Methylbenzyl)-N-(1-methylpiperidin-4-yl)-N′

-phenethyl-carbamide;

N-Phenethyl-N-(1-methylpiperidin-4-yl)-N′

-phenethyl-carbamide;

N-(4-Methylbenzyl)-N-(1-t-butylpiperidin-4-yl)-N-(4-methoxybenzyl) carbamide;

2-(4-Ethoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl) acetamide;

2-(4-Butoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl) acetamide;

2-(4-i-Propoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl) acetamide;

2-(4-t-Butoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl) acetamide;

2-(4-Butoxyphenyl)-N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl) acetamide;

2-(4-Propoxyphenyl)-N-(4-flourobenzyl)-N-(1-methylpiperidin-4-yl) acetamide;

2-(4-i-Propoxyphenyl)-N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl) acetamide; and

2-(4-t-Butoxyphenyl)-N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl) acetamide.

7. A compound of formula (I)

wherein

Z is

in which

R is a hydrogen, a cyclic or straight-chained or branched acyclic organyl group, a lower hydroxyalkyl group, a lower aminoalkyl group, or an aralkyl or heteroaralkyl group;

and

n is 1;

X₁ is methylene, vinylene, or an NH or N(lower alkyl) group; and

X₂ is methylene, or, when X₁ is methylene or vinylene, X₂ is methylene or a bond;

or when X₁ is methylene, X₂ is O, S, NH, or N(lower alkyl) or a bond;

Y₁ is methylene and Y₂ is methylene, vinylene, ethylene, propylene, or bond;

or

Y₁ is a bond and Y₂ is vinylene;

or

Y₁ is ethylene and Y₂ is O, S, NH, or N(lower alkyl);

Ar₁ and Ar₂ are different unsubstituted or substituted aryl or heteroaryl groups; and

W is oxygen;

or

a pharmaceutically acceptable salt or prodrug thereof.

8. A compound according to claim 7, wherein

Y₁ is methylene and Y₂ is a bond, methylene, ethylene, or vinylene; or

Y₁ is ethylene and Y₂ is O or S; and

X₁ is methylene and X₂ is a bond, methylene, O, or S;

or

X₁ is NH or N(lower alkyl) and X₂ is a methylene.

9. A compound according to claim 8, wherein Ar₁ and Ar₂ independently are mono- or disubstituted phenyl groups.

10. A compound according to claim 9, wherein

R is a hydrogen, a lower alkyl group, a cyclic organyl group, or an, optionally substituted, alalkyl or heteroaralkyl group;

Y₁ is methylene, Y₂ is a bond, methylene, ethylene, or vinylene;

X₁ is methylene and X₂ is a bond, or

X₁ is NH or N(lower alkyl) and X₂ is methylene; and

Ar₁ and Ar₂ are phenyl groups, independently p-substituted with groups selected from alkyl, lower alkoxy and halogen.

11. A compound according to claim 7, having a formula (II):

wherein

RN is hydrogen, lower alkyl, aralkyl, or heteroaralkyl;

Ar^L is selected from lower alkyl, lower alkoxy and halogen

Ar^R is selected from lower alkyl, lower alkoxy and halogen;

k is 1 or 2

and N is a suitable anion.

12. A pharmaceutical composition comprising an effective amount of a compound of formula (I):

wherein

Z is

in which

R is a hydrogen, a cyclic or straight-chained or branched acyclic organyl group, a lower hydroxyalkyl group, a lower aminoalkyl group, or an aralkyl or heteroaralkyl group; and

n is 1;

X₁ is methylene, vinylene, or an NH or N(lower alkyl) group; and

X₂ is methylene, or, when X₁ is methylene or vinylene, X₂ is methylene or a bond;

or when X₁ is methylene, X₂ is O, S, Nil, or N(lower alkyl) or a bond;

Y₁ is methylene and Y₂ is methylene, vinylene, ethylene, propylene, or bond;

or

Y₁ is a bond and Y₂ is vinylene;

or

Y₁ is ethylene and Y₂ is O, S, NH, or N(lower alkyl);

Ar₁ and Ar₂ independently are unsubstituted or substituted aryl or heteroaryl groups, provided that Ar₁ and Ar₂ are not simultaneously phenyl; and

W is oxygen;

or a pharmaceutically acceptable salt or prodrug thereof, and

a pharmaceutically acceptable diluent or excipient.