Patent EA-002621-B1 (EA)
Title: Piperidinylaminomethyltrifluoromethyl cyclic ether compounds as substance p antagonists
Inventor: SATAKE KUNIO
IPC: A61K31/452
Filed: 1998-10-26
Abstract: 1. A compound of formula (I):   or a pharmaceutically acceptable salt thereof, wherein R<1> is (C1-C6)alkyl; R<2> is hydrogen, C1-C6alkyl, halo C1-C6alkyl, or phenyl; R<3> is hydrogen or halo; R<4> and R<5> are independently hydrogen, C1-C6alkyl, or halo C1-C6alkyl; and n is 1, 2, or 3. 2. A compound according to Claim 1, wherein R<1> is C1-C3 alkyl; R<2> is hydrogen, C1-C3alkyl, halo C1-C3alkyl, or phenyl; R<3> is hydrogen or fluoro; R<4> and R<5> are independently hydrogen, C1-C3alkyl, or halo C1-C3alkyl; and n is 1 or 2. 3. A compound according to Claim 2, wherein R<1> is methyl; R<2> is hydrogen, methyl, trifluoromethyl, or phenyl; R<3> is hydrogen; and R<4> and R<5 >are hydrogen. 4. A compound according to Claim 3 selected from: (2S,3S)-3-(6-methoxy-3-trifluoromethyl-1,3-dihydroisobenzofuran-5-yl)methylamino-2-phenylpiperidine or its salts; (2S,3S)-3-(6-methoxy-1-methyl-1-trifluoromethylisochroman-7-yl)methylamino-2-phenylpiperidine or its salts; (2S,3S)-3-(6-methoxy-3-methyl-3-trifluoromethyl-1,3-dihydroisobenzofuran-5-yl)methylamino-2-phenylpiperidine or its salts; (2S,3S)-3-(6-methoxy-3-phenyl-3-trifluoromethyl-1,3-dihydroisobenzofuran-5-yl)methylamino-2-phenylpiperidine or its salts; and (2S,3S)-3-[1-(6-methoxy-3-methyl-3-trifluoromethyl-1,3-dihydroisobenzofuran-5-yl)ethylamino]-2-phenylpiperidine or its salts. 5. A compound according to Claim 4 wherein said compound is (2S,3S)-3-[(1R)-6-methoxy-1-methyl-1-trifluoromethylisochroman-7-yl]methylamino-2-phenylpiperidine or its salts; or (2S,3S)-3-[(3R)-(6-methoxy-3-methyl-3-trifluoromethyl-1,3-dihydroisobenzofuran-5-yl)]methylamino-2-phenylpiperidine or its salts. 6. A compound of the formula (III):   wherein W is hydrogen or Q(O=)C- wherein Q is H, C1-C6alkyl or halo C1-C6 alkyl; R<1> is C1-C6alkyl; R<2> is hydrogen, C1-C6alkyl, haloC1-C6 alkyl or phenyl; and n is one, two or three. 7. A compound according to Claim 6 wherein said compound is selected from: 5-methoxy-1-trifluoromethyl-1,3-dihydroisobenzofuran; 6-methoxy-3-trifluoromethyl-1,3-dihydrobenzofuran-5-carbaldehyde; 5-methoxy-1,1-bistrifluoromethyl-1,3-dihydroisobenzofuran; 6-methoxy-3,3-bis(trifluoromethyl)-1,3-dihydroisobenzofuran-5-carbaldehyde; 6-methoxy-1-methyl-1-trifluoromethylisochroman; 6-methoxy-1-methyl-1-trifluoromethylisochroman-7-carbaldehyde; 5-methoxy-1-methyl-1-trifluoromethyl-1,3-dihydroisobenzofuran; 6-methoxy-3-methyl-3-trifluoromethy-1,3-dihydroisobenzofuran-5-carbaldehyde; 1-trifluoromethyl-5-methoxy-1-phenyl-1,3-dihydroisobenzofuran; 3-trifluoromethyl-6-methoxy-3-phenyl-1,3-dihydroisobenzofuran-5-carbaldehyde; 5-acetyl-3-methyl-6-methoxy-3-trifluoromethyl-1,3-dihydroisobenzofuran; (1R)-6-methoxy-1-methyl-1-trifluoromethylisochroman; and (1R)-6-methoxy-1-methyl-1-trifluoromethylisochroman-7-carbaldehyde. 8. A pharmaceutical composition for treating a disorder or condition, for which antagonist activity toward substance P is needed, in a mammal, which comprises a pharmaceutically effective amount of the compound of Claim 1, or a salt thereof. 9. A pharmaceutical composition for treating a disorder or condition selected from cardiovascular diseases, allergic disorders, angiogenesis, gastrointestinal disorders, central nervous system disorders, inflammatory diseases, emesis, urinary incontinence, pain, migraine, severe anxiety disorders, stress disorders, anxiety, major depressive disorders, major depressive disorders with anxiety, depression, sunburn, sexual dysfunction, bipolar disorders, substance use disorders, schizophrenic disorders, movement disorders, cognitive disorders, and diseases, disorders and adverse conditions caused by Helicobacter pylori, in a mammal, comprising a pharmaceutically effective amount of the compound of Claim 1, or a salt thereof. 10. A method of treating a disorder or condition for which antagonist activity toward substance P is needed, in a mammal in need of such prevention or treatment, which comprises administering a pharmaceutically effective amount of a compound of Claim 1, or a salt thereof. 11. A method of treating a disorder or condition selected from cardiovascular diseases, allergic disorders, angiogenesis, gastrointestinal disorders, central nervous system disorders, inflammatory diseases, emesis, urinary incontinence, pain, migraine, severe anxiety disorders, stress disorders, anxiety, major depressive disorders, major depressive disorders with anxiety, depression, sunburn, sexual dysfunction, bipolar disorders, substance use disorders, schizophrenic disorders, movement disorders, cognitive disorders, and diseases, disorders and adverse conditions caused by Helicobacter pylori, in a mammal, comprising administering to a mammal in need of such prevention or treatment a pharmaceutically effective amount of a compound of Claim 1, or a salt thereof.