# US 5,348,949 A · Method of preparing N-oxo-tetrahydro-.beta.-carbolines > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 5,348,949 A - Document ID: US5348949A - Status: Granted - Kind: A - Application number: 08/016,675 - Filed: 1993-02-12 - Granted: 1994-09-20 - Earliest claimed: 1989-06-08 - Assignees: Duphar International Research B.V. - Inventors: Peter H. H. Hermkens; Jan H. Van Maarseveen; Johan W. Scheeren; Cornelis G. Kruse - Web page: https://patentgrep.com/patent/US5348949A ## CPC - C07D 515/14: Ortho-condensed systems - A61P 31/12: Antivirals - A61P 35/00: Antineoplastic agents - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract The invention relates to a method of preparing N-oxo-tetrahydro-.beta.-carbolines having formula 1. ##STR1## by an intramolecular ringclosure reaction of compounds of formula 2. ##STR2## wherein Z is an aldehyde function or acetal function, or is a functional group which can be converted into such a function during the ringclosure reaction. The eudistomin derivatives within the group of compounds having formula 1 have strong antiviral and antitumour activity. ## Claims ### Claim 1 A method of preparing an N-oxo-tetrahydro-.beta.-carboline of formula (1): ##STR13## wherein R.sub.1 is a lower alkyl, lower alkoxy, halogen, trifluoromethyl, lower alkylthio, or hydroxy; n has the value 0, 1 or 2 and if n is 0, R.sub.1 is hydrogen; R.sub.2 is hydrogen, lower alkyl or acyl having 1-4 carbon atoms, said acyl being derived from carboxylic acid only; R.sub.3 is hydrogen, lower alkyl, alkoxycarbonyl having 1-4 carbon atoms or phenyl which is unsubstituted or substituted by a group R.sub.1 ; and A is --(CH.sub.2).sub.p --Y--CH.sub.2 -- which is unsubstituted or substituted by one or more of the substituents: alkyl having 1-4 carbon atoms, alkoxycarbonyl having 1-4 carbon atoms, alkanoyl having 1-4 carbon atoms, alkoxy having 1-4 carbon atoms, hydroxy, oxo, amino, mono- or dialkylamino having 1-4 carbon atoms, or alkanoyl- or alkoxycarbonylamino having 1-4 carbon atoms, wherein p is 1-3, --Y--CH.sub.2 -- is connected to the --O-- present in the compound of formula (1), and Y is --CH.sub.2 --; comprising intramolecular ring closing a compound of formula (2): ##STR14## wherein R.sub.1, n, R.sub.2, R.sub.3 and A are as defined above and Z is a group which is capable of performing a double electrophilic attack on both the aliphatic nitrogen atom and the carbon atom of the indole ring, said group being selected from an aldehyde function, an acetal function, an ester function and a group which can be converted to such a function during the ring closure reaction. ### Claim 2 (depends on 1) A method as claimed in claim 1, wherein Z is selected from an aldehyde function, an acetal function and a group which can be converted into such a function during the ring closure reaction. ### Claim 3 (depends on 1, 2) A method as claimed in claim 1 or 2, wherein Z is a dimethylacetal function. ### Claim 4 (depends on 3) A method as claimed in claim 3, wherein the reaction is carried out in the presence of an acid catalyst. ### Claim 5 (depends on 3) A method as claimed in claim 3, wherein Z is an alkoxycarbonyl group. ### Claim 6 (depends on 5) A method as claimed in claim 5, wherein the reaction is carried out in the presence of a reductor. ### Claim 7 (depends on 1, 14) A method as claimed in claim 1, wherein the production of the compound of formula (2) comprises selectively protecting the aliphatic nitrogen atom of a compound of formula (3): ##STR15## wherein R.sub.1, n, R.sub.2 and R.sub.3 are defined as in claim 14; converting the protected compound with a compound of formula (4): ##STR16## wherein Z and A are defined as in claim 14 and X is a leaving group selected from the group consisting of halogen and sulphonate, into a protected compound of formula (2); and disprotecting the resulting compound of formula (2). ### Claim 8 (depends on 7) A method as claimed in claim 7, wherein X is halogen or sulphonate. ### Claim 9 (depends on 4) A method as claimed in claim 4, wherein the acid catalyst is trifluoroacetic acid. ### Claim 10 (depends on 6) A method as claimed in claim 6, wherein the reductor is diisobutyl aluminum hydride. ### Claim 11 An N-oxo-tetrahydro-.beta.-carboline of formula (1): ##STR17## wherein R.sub.1 is a member selected from the group consisting of lower alkyl, lower alkoxy, halogen, trifluoromethyl, lower alkylthio and hydroxy; n has the value 0, 1 or 2 and if n is 0, R.sub.1 is hydrogen; R.sub.2 is hydrogen, lower alkyl or acyl having 1-4 carbon atoms, the acyl being derived from carboxylic acid only; R.sub.3 is hydrogen, lower alkyl, alkoxycarbonyl having 1-4 carbon atoms or phenyl which is unsubstituted or substituted by a group R.sub.1, and A is --(CH.sub.2).sub.p --Y--CH.sub.2 which is unsubstituted or substituted by one or more of the substituents: alkyl having 1-4 carbon atoms, alkoxycarbonyl having 1-4 carbon atoms, alkanoyl having 1-4 carbon atoms, alkoxy having 1-4 carbon atoms, hydroxy, oxo, amino, mono- or dialkylamino having 1-4 carbon atoms, or alkanoyl- or alkoxycarbonylamino having 1-4 carbon atoms, wherein p is 1-3, --Y--CH.sub.2 -- is connected to the --O--present in the compound of formula (1), and Y is --CH.sub.2 --; or a therapeutically acceptable salt thereof. ### Claim 12 (depends on 11) A pharmaceutical composition comprising a pharmaceutically effective amount of a compound as claimed in claim 11 as an active substance and a pharmaceutically acceptable carrier. ### Claim 13 An intermediate compound of formula (2) ##STR18## wherein R.sub.1 is a member selected from the group consisting of lower alkyl, lower alkoxy, halogen, trifluoromethyl, lower alkylthio hydroxy; n has the value 0, 1 or 2 and when n is 0, R.sub.1 is hydrogen; R.sub.2 is hydrogen, lower alkyl or acyl having 1-4 carbon atoms, the acyl being derived from carboxylic acid only; R.sub.3 is hydrogen, lower alkyl, alkoxycarbonyl having 1-4 carbon atoms or phenyl which is unsubstituted or substituted by a group R.sub.1 ; A is --(CH.sub.2).sub.p --Y--CH.sub.2 which is unsubstituted or substituted by one or more of the substituents: alkyl having 1-4 carbon atoms, alkoxycarbonyl having 1-4 carbon atoms, alkanoyl having 1-4 carbon atoms, alkoxy having 1-4 carbon atoms, hydroxy, oxo-, amino, mono- or dialkylamino having 1-4 carbon atoms, or alkanoyl- or alkoxycarbonylamino having 1-4 carbon atoms, wherein p is 1-3, --Y--CH.sub.2 -- is connected to the --O-- present in the compound of formula (2), and Y is --CH.sub.2 --; and Z is an aldehyde function, an acetal function or a group which can be converted into such function.