Patent EA-003698-B1 (EA)
Title: Halogen substituted tetracyclic tetrahydrofuran derivatives
Inventor: ANDRES-GIL JOSE IGNACIO
IPC: C07D493/04
Filed: 1998-10-06
Abstract: 1. A compound of formula a N-oxide form, a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof, wherein: n is zero, 1, 2, 3, 4, 5 or 6; X is CH2 or O; R<1> and R<2> each independently are hydrogen, C1-6alkyl, C1-6alkylcarbonyl, halomethylcarbonyl or C1-6alkyl substituted with hydroxy, C1-6alkyloxy, carboxyl, C1-6alkylcarbonyloxy, C1-6 alkyloxycarbonyl or aryl; or R<1> and R<2> taken together with the nitrogen atom to which they are attached may form a morpholinyl ring or a radical of formula: wherein m is zero, 1, 2, or 3; R<13> and R<14> are each independently are hydrogen, C1-6alkyl, aryl or arylcarbonyl; R<17> is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, halomethylcarbonyl, C1-6alkyloxycarbonyl, aryl, di(aryl)methyl or C1-6alkyl substituted with hydroxy, C1-6alkyloxy, carboxyl, C1-6alkylcarbonyloxy, C1-6alkyloxycarbonyl or aryl; R<3> and R<4> are both halogen; or R<3> is halogen and R<4> is hydrogen; or R<3> is hydrogen and R<4> is halogen; and aryl is phenyl or phenyl substituted with 1, 2 or 3 substituents selected from halo, hydroxy, C1-6 alkyl and halomethyl. 2. A compound as claimed in claim 1 wherein X is CH2. 3. A compound as claimed in claim 1 or 2 wherein the hydrogen atoms on carbon atoms 3a and 12b are on opposite sides of the mean plane determined by the tetracyclic ring system. 4. A compound as claimed in any one of claims 1 to 3 wherein R<3> is halogen and R<4> is hydrogen. 5. A compound as claimed in any one of claims 1 to 4 wherein n is 1. 6. A compound as claimed in any one of claims 1 to 5 wherein both R<1> and R<2> are each independently selected from hydrogen or C1-6alkyl or when taken together with the nitrogen atom to which they are attached form a morpholinyl ring or radical of formula (c) or (e). 7. A compound as claimed in claim 1 wherein the compound is 11-fluoro-3, 3a, 8, 12b-tetrahydro-N,N-dimethyl-2H-dibenzo-[3, 4:6, 7]cyclohepta[1, 2-b]furan-2-methanamine; a stereochemically isomeric form or a pharmaceutically acceptable addition salt thereof, or a N-oxide form thereof. 8. A composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound as claimed in any one of claims 1 to 7. 9. A compound according to any one of claims 1 to 7 for use as a medicament. 10. Use of a compound according to any one of claims 1 to 7 for manufacturing of a medicament for treating of anxiety, psychosis, schizophrenia, depression, migraine, sleep disorders and drug addiction. 11. A process of preparing a compound according to claim 7 wherein a). an intermediate of formula (II) is N-alkylated with an intermediate of formula (III) wherein in the intermediates (II) and (III) R<1> to R<4>, n and X are as defined in claim 1 and W is a suitable leaving group; in a reaction-inert solvent and, optionally, in the presence of a suitable base; b). converting compounds of formula (I) into other following art-known transformations, and further, if desired, converting the compounds of formula (I) into a therapeutically active non-toxic acid addition salt by treatment with an acid, or into a therapeutically active non-toxic base addition salt by treatment with a base, or conversely, converting the acid addition salt form into the free base by treatment with alkali, or converting the base addition salt into the free acid by treatment with acid; and, if desired, preparing stereochemically isometric forms or N-oxide forms thereof.