Patent EA-001360-B1 (EA)
Title: Alkylaminobenzothiazole and -benzoxazole derivatives
Inventor: KENNIS LUDO EDMOND JOSEPHINE
IPC: A61K31/421
Filed: 1997-05-02
Abstract: 1. A compound of the formula   its a N-oxide form, a pharmaceutically acceptable acid addition salt or a stereochemically isomeric form thereof, wherein  X is O or S; n is 2, 3, 4 or 5;  R<1> is hydrogen, C1-6 alkyl, C1-6 alkyloxy or halo; R<2> is hydrogen, C1-6 alkyl, phenyl, phenyl C1-6 alkyl or phenylcarbonyl; R<3> and R<4> each independently are selected from hydrogen, halo, nitro, C1-6 alkyl, C1-6 alkyloxy, halo C1-6 alkyl, aminosulfonyl, mono- or di(C1-4 alkyl)aminosulfonyl; or R<3> and R<4> may also be taken together to form a bivalent radical of formula -CH=CH-CH=CH-. 2. A compound according to claim 1 wherein n is 2, 3 or 4. 3. A compound according to claim 1 wherein X is S and R<2> is hydrogen, C1-6 alkyl, phenyl or phenyl C1-6 alkyl. 4. A compound according to claim 1 wherein R<2> and R<3> are hydrogen and R<4> is chloro. 5. A compound according to claim 1 wherein the compound is N-[2-[4-(3,4-dichlorophenyl)-1-piperazinyl]ethyl]-2-benzothiazolamine; N-[2-(4-phenyl-1-piperazinyl)ethyl]-2-benzothiazolamine;  N-[2-[4-(4-chlorophenyl)-1-piperazinyl]ethyl]-2-benzothiazolamine; N-[2-[4-(4-bromophenyl)-1-piperazinyl]ethyl]-2-benzothiazolamine; a N-oxide, a stereoisomeric form or a pharmaceutically acceptable acid addition salt thereof. 6. A compound according to claim 1 having at least one halo which is a radioactive isotope of iodine, bromine or fluorine, or having at least one <11>C-atom or tritium atom. 7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, an effective dopamine D4 receptor antagonizing amount of a compound as described in any one of the claims 1 to 5. 8. A process of preparing a pharmaceutical composition as defined in claim 7, characterized in that, a pharmaceutically acceptable carrier is intimately mixed with an effective dopamine D4 receptor antagonizing amount of a compound as described in any one of claims 1 to 5. 9. A compound as claimed in any one of claims 1 to 5 for use as a medicine. 10. A process of preparing a compound as described in claim 1, characterized by a) N-alkylating an intermediate of formula (III)   wherein n and R<2> to R<4> are defined as in claim 1, with an intermediate of formul a (II)   wherein W represents an appropriate reactive leaving group, and X and R<1> are defined as in claim 1, in a reaction-inert solvent, optionally in the presence of a suit able base, and optionally in the presence of a catalyst, 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 conversely, converting the acid addition salt form into the free base by treatment with alkali, and, if desired, preparing stereochemically isomeric forms or N-oxides t hereof. 11. A process of preparing a compound as described in claim 1, characterized by b) reacting an intermediate of formula (III)   wherein n and R<2> to R<4> are defined as in claim 1, with an intermediate of formul a (IV)   wherein R<1> is defined as in claim 1, in a reaction-inert solvent and in the presence of thionylchloride; thus forming a compound of formula (I-a)   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 conversely, converting the acid addition salt form into the free base by treatment with alkali; and, if desired, preparing stereochemically isomeric forms or N-oxides thereof. 12. A process of preparing a compound as described in claim 1, characterized by N-alkylating an interrnediate of formula (VI)   wherein R<3> and R<4> are defined as in claim 1, with an intermediate of formula (VII)   wherein R<1>, R<2>, n and X are defined as in claim 1 and W<2> is an appropriate leavi ng group, in a reaction-inert solvent in the presence of a suitable base 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 conversely, converting the acid addition salt form into the free base by treatment with alkali; and, if desired, preparing stereochemically isomeric forms or N-oxides thereof. 13. A process of preparing a compound as described in claim 1, characterized by N-alkylating an intermediate of formula (XV)   wherein X, R<1> and R<2> are defined as in claim 1, with an intermediate of formula (XVI)   wherein n, R<3> and R<4> are defined as in claim 1 and W<2> is an appropriate leaving group, in a reaction-inert solvent, in the presence of a suitable base 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 conversely, converting the acid addition salt form into the free base by treatment with alkali; and, if desired, preparing stereochemically isomeric forms or N-oxides t hereof. 14. A process of marking a dopamine D4 receptor comprising the steps of  a) radiolabelling a compound as claimed in claim 1; b) administering said radiolabelled compound to biological material, c) detecting the emissions from the radiolabelled compound. 15. A process of imaging an organ, characterized by administering a sufficient amount of a radiolabelled compound of formula (I) in an appropriate composition, whereby said compound binds to the dopamine D4 receptor sites; and detecting the emissions from the radioactive compound.