Patent EA-001002-B1 (EA)
Title: Substituted tetracyclic tetrahydrofuran derivatives
Inventor: GIL-LOPETEGUI PILAR
IPC: C07D495/04
Filed: 1997-04-09
Abstract: 1. A compound of formula   a N-oxide form thereof, a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof, wherein: n is zero, 1, 2, 3, 4, 5, or 6; p is zero, 1, 2, 3 or 4; q is zero, 1, 2, 3 or 4; r is zero, 1, 2, 3, 4 or 5; R<1> and R<2> each independently are hydrogen; C1-6 alkyl; C1-6 alkylcarbonyl; halomethylcarbonyl; C1-6 alkyl substituted with hydroxy, C1-6 alkyloxy group, carboxyl, C1-6 alkylcarbonyloxy, 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: R<9>, R<10>, R<11> and R<12> each independently are hydrogen, halo, halomethyl, or C1-6 alkyl; m is zero, 1, 2, or 3; R<13>, R<14>, R<15> and R<16> each independently are hydrogen, C1-6alkyl, aryl or arylcarbonyl; or R<15> and R<16> taken together may form a bivalent radical C4-5alkanediyl; R<17> is hydrogen; C1-6 alkyl; C1-6 alkylcarbonyl; halomethylcarbonyl; C1-6 alkyloxycarbonyl; aryl; di(aryl)methyl; C1-6 alkyl substituted with hydroxy, C1-6 alkyloxy, carboxyl, C1-6 alkylcarbonyloxy, C1-6 alkyloxycarbonyl or aryl; each R<3> independently is halo, cyano, hydroxy, halomethyl, halomethoxy, carboxyl, nitro, amino, mono- or di(C1-6 alkyl)amino group, C1-6 alkylcarbonylamino group, aminosulfonyl, mono- or di(C1-6 alkyl)aminosulfonyl, C1-6 alkyl, C1-6 alkyloxy, C1-6 alkylcarbonyl, C1-6 alkyloxycarbonyl; each R<4> independently is halo, cyano, hydroxy, halomethyl, halomethoxy, carboxyl, nitro, amino, mono- or di(C1-6 alkyl)amino group, C1-6 alkylcarbonylamino group, aminosulfonyl, mono- or di(C1-6 alkyl)aminosulfonyl, C1-6 alkyl, C1-6 alkyloxy, C1-6 alkylcarbonyl, C1-6 alkyloxycarbonyl; each R<5> independently is C1-6 alkyl, cyano or halomethyl; X is CR<6>R<7>, NR<8>, O, S, S(=O) or S(=O)2; wherein R<6> and R<7> each independently are hydrogen, hydroxy, C1-6 alkyl, halomethyl, C1-6 alkyloxy, or R<6> and R<7> taken together may form methylene; mono- or di(cyano)methylene; a bivalent radical of formula -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -O-(CH2)2-O-, -O-(CH2)3-O-; or, together with the carbon atom to which they are attached, they form carbonyl; R<8> is hydrogen, C1-6 alkyl, C1-6 alkylcarbonyl, arylcarbonyl, aryl C1-6 alkylcarbonyl, C1-6 alkylsulfonyl, arylsulfonyl or aryl C1-6 alkylsulfonyl; aryl is phenyl; or phenyl substituted with 1, 2, or 3 substituents selected from halo, hydroxy, C1-6 alkyl or halomethyl;provided that the compound is other than (a)3, 3a, 8, 12b-tetrahydro-N-methyl-2H-dibenzo[3,4:6,7]-cyclohepta[1,2-b]furan-2-methanamine and (b) (+-)-3, 3a,8,12b-tetrahydro-N-methyl-2H-dibenzo[3,4:6,7]-cyclohepta[1,2-b]furan-2-methanamine oxalic acid. 2. A compound as claimed in claim 1, wherein R<13>, R<14>, R<15> and R<16> each independently are hydrogen or C1-6 alkyl. 3. A compound as claimed in any of claims 1-2, wherein X is CR<6>R<7> or O. 4. A compound as claimed in any of claims 1-3, wherein R<1> and R<2> both are C1-6 alkyl or R<1> and R<2> taken together with the nitrogen atom to which they are attached, form a morpholinyl ring; a radical of formula (c) or a radical of formula (e). 5. A compound as claimed in any of claims 1-4, wherein the substituents on carbon atoms 3a and 12b have the trans-configuration. 6. A compound as claimed in any of claims 1-5, wherein r, p and q are zero. 7. A compound as claimed in any of claims 1-6, wherein p is 1, R<3> is halo, C1-6 alkyl or C1-6 alkyloxy. 8. A compound as claimed in any of claims 1-6, wherein q is 1, R<4> is halo, C1-6 alkyl or C1-6 alkyloxy. 9. A compound as claimed in claim 1, wherein 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 thereof or a pharmaceutically acceptable addition salt thereof, or an N-oxide form thereof. 10. A composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound as claimed in any of claims 1-9. 11. The use of a compound as claimed in any of claims 1-9 for treatment or prevention of central nerve system disorders. 12. A process of preparing a compound as described in claim 1, characterized in that: an intermediate of formula (II) is N-alkylated with an intermediate of formula (III):   wherein in the intermediates (II) and (III) radicals from R<1> to R<5>, n, p, q, r and X are defined as in claim 1, and W is a suitable leaving group; in a reaction-inert solvent and, optionally, in the presence of a suitable base; 13. A method as claimed in claim 12, characterised in that one prepared compound is converted into another using art-known transformations, and further, if desired, converting the compounds of formula (I), into a therapeutically active non-toxic acid addition salts 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 isomeric forms thereof or N-oxide forms thereof.