US 2006/0135573 A1 · Benzothiazole-4,7-diones and benzoxazole-4,7-diones with substituents in position 5 or 6 and method for production thereof

Abstract

A subject of the invention is a selective process for the preparation of derivatives of benzothiazole-4,7-diones and benzoxazole-4,7-diones monosubstituted in position 5 or in position 6 by an amino group itself optionally substituted. Said derivatives are inhibitors of the Cdc25 phosphatases and can be used for preparing medicaments intended to treat cancer. The invention also offers synthesis intermediates which are useful in implementing the process of the invention. The invention also relates in particular to the following derivatives of benzothiazole-4,7-diones: 2-(2-chloro-6-fluorophenyl)-5-{[2-(dimethylamino)ethyl]amino}-1,3-benzothiazole-4,7-dione; 2-(2-chloro-6-fluorophenyl)-5-[(2-pyrrolidin-1-ylethyl)amino]-1,3-benzothiazole-4,7-dione.

A process for the preparation of a compound of the formula

or of a compound of the formula
wherein W is sulfur in formula (III)1 and oxygen in formula (III)2,
R1 is selected from the group consisting of hydrogen, alkyl, alkoxyalkyl, cycloalkyl, —(CH2)—X—Y, —(CH2)—Z—NR5R6 and —CHR35R36 in which R35 and R36 form together with the carbon atom which carries them indanyl or tetralinyl, or R35 and R36 form together with the carbon atom which carries them a saturated heterocycle of 5 to 7 ring members and 1 to 2 heteroatoms selected from the group consisting of O, N and S, the nitrogen atoms of said heterocycle being optionally substituted by alkyl or benzyl,
R1 also being able, when W is O, to be carbocyclic aryl optionally substituted 1 to 3 times by substituents independently selected from the group consisting of halogen, alkyl, haloalkyl and alkoxy, X is a saturated carbon-containing cyclic system of 1 to 3 condensed rings selected independently from rings with 3 to 7 ring members, or Y is saturated heterocycle containing 1 to 2 heteroatoms independently selected from the group consisting of O, N and S and attached to X by an N or CH member, said saturated heterocycle containing moreover 2 to 6 additional members independently selected from the group consisting of —CO—, —NR8—, —O— and —S—, R7 is hydrogen or alkyl and R8 is selected from the group consisting of hydrogen alkyl and aralkyl, or Y is carbocyclic or heterocyclic aryl optionally substituted 1 to 3 times by substituents independently selected from the group consisting of halogen, alkyl, halaoalkyl, alkoxy, haloalkoxy, hydroxy, nitro, cyano, phenyl, SO2NHR9 and —NR10R11, R9 is selected from the group consisting of hydrogen, alkyl and phenyl radical, and R10 and R11 are independently alkyl,
Z is a bond or alkylene of 1 to 5 carbon atoms,
R5 and R6 are independently selected from the group consisting of hydrogen, alkyl, aralkyl and —CH2)n—OH in which n is an integer from 1 to 6,
or R5 is selected from the group consisting of alkoxycarbonyl, haloalkoxycarbonyl and aralkoxycarbonyl and R6 is hydrogen or a methyl,
or R5 and R6 form together with the nitrogen atom a heterocycle with 4 to 7 ring members comprising 1 to 2 heteroatoms, the members necessary to complete the heterocycle being independently selected from the group consisting of —CR12R13—, —O—, —S— and —NR14—, R12 and R13 independently are each time that they occur hydrogen or alkyl, and R14 is selected from the group consisting of hydrogen, alkyl and aralkyl, or R14 is phenyl optionally substituted 1 to 3 times by substituents independently selected from the group consisting of halogen, alkyl and alkoxy,
R2 is selected from the group consisting of hydrogen, alkyl and aralkyl;
or R1 and R2 form together with the nitrogen atom a heterocycle with 4 to 8 ring members comprising 1 to 2 heteroatoms, the members necessary to complete the heterocycle being independently selected from the group consisting of —CR15R16—, —O—, —S— and —NR7—, R15 and R16 independently are each time that they occur hydrogen or alkyl, and R17 is selected from the group consisting of hydrogen, or alkyl;
and
R4 is selected from the group consisting of alkyl, cycloalkyl, cycloalkyl, cycloalkylalkyl, cyano, amino, —CH2—COOR18, —CH2—CO—NR19R20 and —CH2—NR21R22, or R4 is carbocyclic or heterocyclic aryl optionally substituted 1 to 4 times substituents independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy and —NR37R38, or R4 is phenyl possessing two substituents which form together methylenedioxy or ethylenedioxy,
R18 is hydrogen or alkyl,
R19 is selected from the group consisting of hydrogen, alkyl aralkyl, and the aryl group of which is optionally substituted 1 to 3 times by substituents independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy hydroxy, nitro, cyano, phenyl, —SO2NHR23 and —NR24R25, R23 is selected from the group consisting of hydrogen, alkyl and phenyl, and R24 and R25 independently are alkyl,
R20 is hydrogen or alkyl,
or R19 and R20 form together with the nitrogen atom a heterocycle with 4 to 7 ring members comprising 1 to 2 heteroatoms, the members necessary to complete the heterocycle being independently selected from the group consisting of —CR26R27—, —O—, —S— and —NR28—, R26 and R27 independently are each time that they occur hydrogen or alkyl, and R28 is selected from the group consisting of hydrogen, alkyl and aralkyl, or R28 is phenyl optionally substituted 1 to 3 times by substituents independently selected from the group consisting of halogen, alkyl and alkoxy,
R21 is selected from the group consisting of hydrogen, alkyl and aralkyl, the aryl group of which is optionally substituted 1 to 3 times by substituents independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, nitro, cyano, phenyl, —SO2NHR29 and —NR30R31, R29 is selected from the group consisting of hydrogen, alkyl and phenyl, and R30 and R31 independently are alkyl,
R22 is hydrogen or alkyl,
or R21 and R22 form together with the nitrogen atom a heterocycle with 4 to 7 ring members comprising 1 to 2 heteroatoms, the members necessary to complete the heterocycle being independently selected from the group consisting of —CR32R33—, —O—, —S— and —NR34—, R32 and R33 independently are each time that they occur hydrogen or alkyl, and R34 is selected from the group consisting of hydrogen, alkyl and aralkyl, or R34 is phenyl optionally substituted 1 to 3 times by substituents independently selected from the group consisting of halogen, alkyl and alkoxy,
R37 and R38 being independently from hydrogen, or alkyl or R37 and R38 form together with the nitrogen atom a heterocycle with 4 to 7 ring members comprising 1 to 2 heteroatoms, the members necessary to complete the heterocycle being independently selected from the group consisting of —CR39R40—, —O—, —S— and —NR41—, R39 and R40 independently are each time that they occur hydrogen or alkyl, and R41 is hydrogen or alkyl, or R4 is —CH2—Ar in which Ar aryl optionally substituted 1 to 4 times by substituents independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy and —NR42R43, or R4 is biphenyl,
R42 and R43 being independently from hydrogen, or alkyl or R42 and R43 form together with the nitrogen atom a heterocycle with 4 to 7 ring members comprising 1 to 2 heteroatoms, the members necessary to complete the heterocycle being independently selected from the group consisting of —CR44R45—, —O—, —S— and —NR46—, R44 and R45 independently are each time that they occur hydrogen or alkyl, and R46 is hydrogen or alkyl;
said process comprising reacting a compound of the formula
wherein W is sulfur or oxygen and R4 has the same meaning as in formula (III)1 or (III)2 with an amine of the formula R1R2NH in a protic solvent.

20 more elements

Benzothiazole-4,7-diones and benzoxazole-4,7-diones with substituents in position 5 or 6 and method for production thereof

Life of this patent

Benzothiazole-4,7-diones and benzoxazole-4,7-diones with substituents in position 5 or 6 and method for production thereof

Life of this patent

Abstract

Claims11