Method of preparing N-oxo-tetrahydro-.beta.-carbolines
AssigneeDuphar International Research B.V.
InventorsPeter H. H. Hermkens, Jan H. Van Maarseveen, Johan W. Scheeren, Cornelis G. Kruse
Life of this patent
Estimating the term…
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.
Claims13
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.
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).
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.
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.
Dependencies are inferred from the claim text.