Azacyclic compounds
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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 administered to a patient in need of such treatment.
116 Citations
80 Claims
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1. A compound of formula (I)
- View Dependent Claims (2, 3, 4, 5, 6, 7, 13, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78)
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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;
orX1 is NH or N(lower alkyl) and X2 is methylene.
- or
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3. A compound according to claim 2, wherein
Z is and W is oxygen. -
4. A compound according to claim 3, wherein
Ar1 and Ar2 independently are mono- or disubstituted phenyl groups. -
5. A compound according to claim 4, 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.
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6. A compound according to claim 1, having a formula (II)
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7. The compound according to claim 1, wherein the compound is selected from the group consisting of:
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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; and
N-(1-(cyclohexylmethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-N′
-phenylmethylcarbamide.
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13. A compound according to claim 7, having a formula (II):
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15. 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.
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16. The method of claim 15 wherein the monoamine receptor is a serotonin receptor.
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17. The method of claim 16 wherein the serotonin receptor is the 5-HT2A subclass.
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18. The method of claim 16 wherein the serotonin receptor is in the central nervous system.
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19. The method of claim 16 wherein the serotonin receptor is in the peripheral nervous system.
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20. The method of claim 16 wherein the serotonin receptor is in blood cells or platelets.
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21. The method of claim 16 wherein the serotonin receptor is mutated or modified.
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22. The method of claim 15 wherein the activity is signaling activity.
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23. The method of claim 15 wherein the activity is constitutive.
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24. The method of claim 15 wherein the activity is associated with serotonin receptor activation.
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25. 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.
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26. The method of claim 25 wherein the activation is by an agonistic agent.
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27. The method of claim 26 wherein the agonistic agent is exogenous.
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28. The method of claim 26 wherein the agonistic agent is endogenous.
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29. The method of claim 25 wherein the activation is constitutive.
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30. The method of claim 25 wherein the monoamine receptor is a serotonin receptor.
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31. The method of claim 30 wherein the serotonin receptor is the 5-HT2A subclass.
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32. The method of claim 30 wherein the serotonin receptor is in the central nervous system.
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33. The method of claim 30 wherein the serotonin receptor is in the peripheral nervous system.
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34. The method of claim 30 wherein the serotonin receptor is in blood cells or platelets.
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35. The method of claim 30 wherein the serotonin receptor is mutated or modified.
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36. 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.
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37. The method of claim 36 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.
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38. The method of claim 36 wherein the disease condition is associated with dysfunction of a monoamine receptor.
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39. The method of claim 36 wherein the disease condition is associated with activation of a monoamine receptor.
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40. The method of claim 36 wherein the disease condition is associated with increased activity of monoamine receptor.
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41. The method of claim 36 wherein the monoamine receptor is a serotonin receptor
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42. The method of claim 41 wherein the serotonin receptor is the 5-HT2A subclass.
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43. The method of claim 41 wherein the serotonin receptor is in the central nervous system.
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44. The method of claim 41 wherein the serotonin receptor is in the peripheral nervous system.
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45. The method of claim 41 wherein the serotonin receptor is in blood cells or platelets.
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46. The method of claim 41 wherein the serotonin receptor is mutated or modified.
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47. 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.
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48. 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.
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49. A method of treating psychosis 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.
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50. A method for identifying a genetic polymorphism predisposing a subject to being responsive to one or more of the compounds of claim 1, comprising:
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administering to a subject a therapeutically effective amount of the compound;
measuring the response of said subject to said compound, thereby identifying a responsive subject having an ameliorated disease condition associated with a monoamine receptor; and
identifying a genetic polymorphism in the responsive subject, wherein the genetic polymorphism predisposes a subject to being responsive to the compound.
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51. The method of claim 50 wherein the ameliorated disease condition is associated with the 5-HT class or 5-HT2A subclass of monoaminergic receptors.
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52. A method for identifying a subject suitable for treatment with one or more of the compounds of claim 1, comprising detecting the presence of a polymorphism in a subject wherein the polymorphism predisposes the subject to being responsive to the compound, and wherein the presence of the polymorphism indicates that the subject is suitable for treatment with one or more of the compounds of claim 1.
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53. The compound according to claim 1, wherein the compound is selected from the group consisting of:
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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-methoxyphenylacetamide;
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-methylpropyl)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)-4-methoxyphenylacetamide;
N-((3,4-di-methoxyphenyl)methyl)-N-(piperidin-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; and
N-((3-methylphenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide.
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54. The compound according to claim 1, wherein the compound is selected from the group consisting of:
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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;
N-((4-methylphenyl)methyl)-N-(1-(phenylmethyl)pyrrolidin-3-yl)-N′
-phenylmethylcarbamide;
N-((4-methylphenyl)methyl)-N-(1-(phenylmethyl)pyrrolidin-3-yl)-4-methoxyphenylacetamide;
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-chlorbenzyl)-N-(1-ethylpiperidin-4-yl)acetamide. 2-(4-methoxyphenyl)-N-(4-chlorbenzyl)-N-(1-isopropylpiperidin-4-yl)acetamide;
2-(4-methoxyphenyl)-N-(4-chlorobenzyl)-N-(piperidin-4-yl)acetamide; and
2-(4-methoxyphenyl)-N-(4-chlorbenzyl)-N-(1-cyclopentylpiperidin-4-yl)acetamide.
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55. The compound according to claim 1, wherein the compound is selected from the group consisting of:
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2-(4-methoxyphenyl)-N-(4-chlorbenzyl)-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)-AT-(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)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-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-(l -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; and
2-(4-methoxyphenyl)-N-(2-4(fluorophenyl)ethyl)-N-(1-methylpiperidin-4-yl)acetamide.
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56. The compound according to claim 1, wherein the compound is selected from the group consisting of:
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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; and
2-Phenyl-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)-acetamide.
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57. The compound according to claim 1, wherein the compound is selected from the group consisting of:
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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;
N-(4-Methylbenzyl)-N-(1-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; and
2-(4-Methoxyphenyl)-N-alpha-methylbenzyl-N-(1-methylpiperidin-4-yl)acetamide.
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58. The compound according to claim 1, wherein the compound is selected from the group consisting of:
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2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-acetamide; and
2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-(8-methyl-8-aza-bicyclo[3.2.1]octen-3-yl)-acetamide.
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59. The compound according to claim 1, wherein the compound is selected from the group consisting of:
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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.
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60. A compound according to claim 5, wherein
R is a lower alkyl group; -
n=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.
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61. A compound according to claim 60, wherein
R is a lower alkyl group; -
n=1;
Y1 is methylene, Y2 is a bond;
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.
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62. A compound according to claim 61, wherein
Ar1 is a p-substituted phenyl group, wherein said phenyl group is substituted with a halogen; - and
Ar2 is a p-substituted phenyl group, wherein said phenyl group is substituted with a lower alkoxy.
- and
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63. A compound according to claim 62, wherein
the halogen of Ar1 is a fluoro atom; - and
the lower alkoxy of Ar2 is a C1-6 cyclic organyl group attached to Ar2 via an oxygen atom.
- and
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64. A compound according to claim 63, wherein the C1-6 cyclic organyl group is attached to the oxygen atom via a substituted or unsubstituted —
- (CH2)—
or —
(CH2CH2)—
.
- (CH2)—
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65. A compound according to claim 63, wherein the C1-6 cyclic organyl group is attached to the oxygen atom via one or more carbon atoms appended from the C1-6 cyclic organyl group.
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66. A method of alleviating a condition associated with non-selective antipsychotic compounds comprising administering a therapeutically effective amount of a one or more of the compounds of claim 1 to a subject suffering from said condition.
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67. The method according to claim 66, wherein the compound of claim 1 is a selective antagonist or inverse agonist of a 5-HT2A receptor.
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68. The method of according to claim 66, wherein the compound of claim 1 has little to no activity on other monamine receptors.
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69. The method according to claim 68, wherein one of the other monamine receptors is a dopamine D2 receptor.
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70. The method according to claim 66, wherein Z is
-
71. The method according to claim 66, 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 in the compound of claim 1.
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72. A method of alleviating a condition which is a side effect which can arise in an individual who takes an antipsychotic compound which possess broad activity at multiple monamine receptors subtypes, comprising administering a therapeutically effective amount of one or more of the compounds of claim 1 to subject suffering from said condition.
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73. The method according to claim 72, wherein the compound of claim 1 is a selective antagonist or inverse agonist of a 5-HT2A receptor.
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74. The method of according to claim 72, wherein the compound of claim 1 has little to no activity on other monamine receptors.
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75. The method according to claim 74, wherein one of the other monamine receptors is a dopamine D2 receptor.
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76. The method according to claim 72, wherein Z is
-
77. The method according to claim 72, 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 in the compound of claim 1
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78. The compound according to claim 1, wherein X1 is an NH or N(lower alkyl) group;
and W is oxygen.
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2. A compound according to claim 1, wherein
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8. A compound of formula (I)
- View Dependent Claims (9, 10, 11, 12, 79)
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9. A compound according to claim 8, 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;
orX1 is NH or N(lower alkyl) and X2 is a methylene.
- or
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10. A compound according to claim 9, wherein
Z is and W is oxygen. -
11. A compound according to claim 10, wherein
Ar1 and Ar2 independently are mono- or disubstituted phenyl groups. -
12. A compound according to claim 11, wherein
R is a hydrogen, a lower alkyl group, a cyclic organyl group, or an, optionally substituted, alalkyl 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 alkyl, lower alkoxy and halogen.
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79. The compound according to claim 8, wherein X1 is an NH or N(lower alkyl) group;
and W is oxygen.
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9. A compound according to claim 8, wherein
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14. A pharmaceutical composition comprising an effective amount of a compound of formula (I):
- View Dependent Claims (80)
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80. The compound according to claim 14, wherein X1 is an NH or N(lower alkyl) group;
and W is oxygen.
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80. The compound according to claim 14, wherein X1 is an NH or N(lower alkyl) group;
Specification
- Resources
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Current AssigneeAcadia Pharmaceuticals Inc.
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Original AssigneeAcadia Pharmaceuticals Inc.
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InventorsAndersson, Carl-Magnus A., Hansen, E. L., Uldam, Allan Kjaersgaard, Croston, Glenn
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Application NumberUS11/417,790Publication NumberTime in Patent OfficeDaysField of SearchUS Class Current514/210.01CPC Class CodesA61K 31/40 having five-membered rings ...A61K 31/445 Non condensed piperidines, ...A61K 31/55 having seven-membered rings...A61P 25/00 Drugs for disorders of the ...A61P 25/02 for peripheral neuropathiesA61P 25/06 Antimigraine agentsA61P 25/18 Antipsychotics, i.e. neurol...A61P 25/20 Hypnotics; SedativesA61P 25/22 AnxiolyticsA61P 25/24 AntidepressantsA61P 3/04 Anorexiants; Antiobesity ag...A61P 43/00 Drugs for specific purposes...A61P 7/02 Antithrombotic agents; Anti...A61P 9/00 Drugs for disorders of the ...A61P 9/08 Vasodilators for multiple i...A61P 9/10 for treating ischaemic or a...A61P 9/12 AntihypertensivesC07D 207/14 Nitrogen atoms not forming ...C07D 211/26 with hydrocarbon radicals, ...C07D 211/58 attached in position 4C07D 401/06 : linked by a carbon chain co...C07D 401/12 : linked by a chain containin...C07D 407/06 : linked by a carbon chain co...C07D 407/12 : linked by a chain containin...C07D 409/06 : linked by a carbon chain co...C07D 409/12 : linked by a chain containin...C07D 417/12 : linked by a chain containin...C07D 451/02 : containing not further cond...C07D 451/06 : Oxygen atomsC07D 487/08 : Bridged systems