Thiazolo[5,4,3-ij]quinolines, preparation and medicines containing the same

A process for the preparation of a compound of formula (I):

• or a racemate, an enantiomer, a diastereoisomer or an inorganic or organic acid salt thereof,
• wherein:
• R1 is a sulphur atom;
• R2 is a hydrogen atom;
• —R3—R4—R5— is a chain having formula —CH2—CH2—CH2—, —CH(R7)—CH2—CH2—, —CH2—CH2—CH(R8)—, —CH2—CH(R,)—CH2—, —CH2—CH2—CO—, —CH2—CF2—CH2—, or —CH2—CF2—CH(OH)—;
• R6 is a polyfluoroalkyl, polyfluoroalkoxy or polyfluoroalkylthio radical;
• R7 is an alkyl, —CH2OH, —CH2—SO2-alk or —CH2—NR11R12 radical;
• R8 is an alkyl radical, —CH2OH, —NR11R12, —CH2—NR11R12, —S-alk, —SO-alk, —SO2-alk, thienyl, furyl, or phenyl radical or a phenyl radical substituted with a substituent chosen from:
• halogen atoms, alkyl radicals and alkoxy radicals;
• R9 is an alkyl or —CH2OH radical;
• R11 is a hydrogen atom, an alkyl, a —CO-alk or —CO—CF3 radical;
• R12 is a hydrogen atom or an alkyl radical;
• or R11 and R12 form, with the nitrogen atom to which they are attached, a saturated or unsaturated 5- or 6-membered heterocycle which may or may not contain another heteroatom chosen from:
• nitrogen, oxygen and sulphur;
• wherein said heterocycle is unsubstituted or substituted with at least one substituent chosen from:
• alkyl radicals, phenyl radicals, halophenyl radicals and phenylalkyl radicals;
• alk is an alkyl radical;
• wherein, unless otherwise indicated, said alkyl and alkoxy radicals and portions thereof have from 1 to 6 straight- or branched-chain carbon atoms;
• said process comprising:
• reacting an alkali metal thiocyanate with a compound of formula (II):
• wherein:
• —R3—R4—R5— is a chain having formula —CH2—CH2—CH2—, —CH(R7)—CH2—CH2—, —CH2—CH2—CH(R8)—, —CH2—CH(R9)—CH2—, —CH2—CH2—CO—, —CH2—CF2—CH2—, or —CH2—CF2—CH(OH)—;
• R6 is a polyfluoroalkyl, polyfluoroalkoxy or polyfluoroalkylthio radical;
• R7 is an alkyl, —CH2OH, —CH2—SO2-alk or —CH2—NR11R12 radical;
• R8 is a —CH2—OH, —NR11R12, —CH2—NR11R12, —S-alk, SO-alk, SO2-alk, thienyl, or furyl, or phenyl radical or a phenyl substituted with a substituent chosen from:
• halogen atoms, and alkyl and alkoxy radicals;
• R9 is an alkyl or —CH2OH radical;
• R11 is a hydrogen atom, an alkyl, a —CO-alk or —CO—CF3 radical;
• R12 is a hydrogen atom or an alkyl radical;
• or R11 and R12 form, with the nitrogen atom to which they are attached, a saturated or unsaturated 5- or 6-membered heterocycle which may or may not contain another heteroatom chosen from:
• nitrogen, oxygen and sulphur;
• wherein said heterocycle is unsubstituted or substituted with at least one substituent chosen from:
• alkyl radicals, phenyl radicals, halophenyl radicals and phenylalkyl radicals;
• alk is an alkyl radical;
• wherein, unless otherwise indicated, said alkyl and alkoxy radicals and portions thereof have from 1 to 6 straight- or branched-cha carbon atoms.

A process for the preparation of a compound of formula (I):

• or a racemate, an enantiomer, a diastereoisomer or an inorganic or organic acid salt thereof,
• wherein:
• R1 is a sulphur atom;
• R2 is an alkyl radical;
• —R3—R4—R5— is a chain having formula —CH2—CH2—CH2—, —CH(R7)—CH2—CH2—, —CH2—CH2—CH(R8)—, —CH2—CH(R9)—CH2—, —CH2—CH2—CO—, —CH2—CF2—CH2—, or —CH2—CF2—CH(OH)—;
• R6 is a polyfluoroalkyl, polyfluoroalkoxy or polyfluoroalkylthio radical;
• R7 is an alkyl, —CH2OH, —CH2—SO2-alk or —CH2—NR11R12 radical;
• R8 is an alkyl radical, a hydroxyl, or a —CH2OH, —NR11R12, —CH2—NR11R12, —S-alk, —SO-alk, —SO2-alk, thienyl, furyl, or phenyl radical or a phenyl radical substituted with a substituent chosen from:
• halogen atoms, alkyl radicals and alkoxy radicals;
• R9 is an alkyl or —CH2OH radical;
• R11 is a hydrogen atom, an alkyl, a —CO-alk or —CO—CF3 radical;
• R12 is a hydrogen atom or an alkyl radical;
• or R1, and R12 form, with the nitrogen atom to which they are attached, a saturated or unsaturated 5- or 6-membered heterocycle which may or may not contain another heteroatom chosen from:
• nitrogen, oxygen and sulphur;
• wherein said heterocycle is unsubstituted or substituted with at least one substituent chosen from:
• alkyl radicals, phenyl radicals, halophenyl radicals and phenylalkyl radicals;
• alk is an alkyl radical;
• wherein, unless otherwise indicated, said alkyl and alkoxy radicals and portions thereof have from 1 to 6 straight- or branched-chain carbon atoms;
• said process comprising:
• alkylating a compound of formula (I)
• wherein:
• R1 is a sulphur atom;
• R2 is a hydrogen atom;
• —R3—R4—R5— is a chain having formula —CH2—CH2—CH2—, —CH(R7)—CH2—CH2—, —CH2—CH2—CH(R8)—, —CH2—CH(R,)—CH2—, —CH2—CH2—CO—, —CH2—CF2—CH2—, or —CH2—CF2—CH(OH)—;
• R6 is a polyfluoroalkyl, polyfluoroalkoxy or polyfluoroalkylthio radical;
• R7 is an alkyl, —CH2OH, —CH2—SO2-alk or —CH2—NR11R12 radical;
• R8 is an alkyl radical, a hydroxyl, or a —CH2OH, —NR11R12, —CH2—NR1,R12, —S-alk, —SO-alk, —SO2-alk, thienyl, furyl, or phenyl radical or a phenyl radical substituted with a substituent chosen from:
• halogen atoms, alkyl radicals and alkoxy radicals;
• R9 is an alkyl or —CH2OH radical;
• R11 is a hydrogen atom, an alkyl, a —CO-alk or —CO—CF3 radical;
• R12 is a hydrogen atom or an alkyl radical;
• or R11 and R12 form, with the nitrogen atom to which they are attached, a saturated or unsaturated 5- or 6-membered heterocycle which may or may not contain another heteroatom chosen from:
• nitrogen, oxygen and sulphur;
• wherein said heterocycle is unsubstituted or substituted with at least one substituent chosen from:
• alkyl radicals, phenyl radicals, halophenyl radicals and phenylalkyl radicals;
• alk is an alkyl radical;
• wherein, unless otherwise indicated, said alkyl and alkoxy radicals and portions thereof have from 1 to 6 straight- or branched-chain carbon atoms.

A process for the preparation of a compound of formula (I):

• or a racemate, an enantiomer, a diastereoisomer or an inorganic or organic acid salt thereof,
• wherein:
• R1 is a sulphur atom;
• R2 is a hydrogen atom or an alkyl radical;
• —R3—R4—R5— below is a chain having formula —CH2—CH2—CH(R8)—;
• R6 is a polyfluoroalkyl, polyfluoroalkoxy or polyfluoroalkylthio radical;
• and
• R8 is a hydroxyl radical;
• wherein, unless otherwise indicated, said alkyl and alkoxy radicals and portions thereof have from 1 to 6 straight- or branched-chain carbon atoms;
• said process comprising:
• reducing a compound of formula (I) in which:
• R1 is a sulphur atom;
• R2 is a hydrogen atom or an alkyl radical;
• —R3—R4—R5— is a chain having formula —CH2—CH2—CO—;
• R6 is a polyfluoroalkyl, polyfluoroalkoxy or polyfluoroalkylthio radical;
• and
• wherein, unless otherwise indicated, said alkyl and alkoxy radicals and portions thereof have from 1 to 6 straight- or branched-chain carbon atoms.

A process for the preparation of a compound of formula (I):

• or an isomer, a racemate, an enantiomer or an inorganic or organic acid salt thereof, wherein:
• R1 is a sulphur or selenium atom;
• R2 is a hydrogen atom or an alkyl radical;
• —R3—R4—R5— is a chain having formula —CH2—CH2—SO—, —CH2—CH2—SO2—, —CH2—CH(R13)—SO— or —CH2—CH(R13)—SO2—;
• R6 is a polyfluoroalkyl, polyfluoroalkoxy or polyfluoroalkylthio radical;
• R13 is an alkyl or —CH2OH radical;
• and
• wherein, unless otherwise indicated, said alkyl and alkoxy radicals and portions thereof have from 1 to 6 straight- or branched-chain carbon atoms;
• said process comprising:
• oxidizing a compound of general formula (I) in which
• R1 is a sulphur or selenium atom;
• R2 is a hydrogen atom or an alkyl radical;
• —R3—R4—R5— is a chain having formula —CH2—CH2—S—, or —CH2—CH(R13)—S—;
• R6 is a polyfluoroalkyl, polyfluoroalkoxy or polyfluoroalkylthio radical;
• R13 is an alkyl or —CH2OH radical;
• and
• wherein, unless otherwise indicated, said alkyl and alkoxy radicals and portions thereof have from 1 to 6 straight- or branched-chain carbon atoms.

A process for the preparation of a compound of formula (I):

• or a racemate, an enantiomer, a diastereoisomer or an inorganic or organic acid salt thereof,
• wherein:
• R1 is a sulphur atom;
• R2 is a hydrogen atom;
• —R3—R4—R5— is a chain having formula —CH(R7)—CH2—CH2—;
• R6 is a polyfluoroalkyl, polyfluoroalkoxy or polyfluoroalkylthio radical;
• R7 is a —CH2—NR11R12 radical;
• R11 is a hydrogen atom, an alkyl, a —CO-alk or —CO—CF3 radical;
• R12 is a hydrogen atom or an alkyl radical;
• or R11 and R12 form, with the nitrogen atom to which they are attached, a saturated or unsaturated 5- or 6-membered heterocycle which may or may not contain another heteroatom chosen from:
• nitrogen, oxygen and sulphur;
• wherein said heterocycle is unsubstituted or substituted with at least one substituent chosen from:
• alkyl radicals, phenyl radicals, halophenyl radicals and phenylalkyl radicals;
• alk is an alkyl radical;
• wherein, unless otherwise indicated, said alkyl and alkoxy radicals and portions thereof have from 1 to 6 straight- or branched-chain carbon atoms;
• and
• said process comprising:
• reacting an amine HNR11R12 wherein:
• R11 is a hydrogen atom, an alkyl, a —CO-alk or —CO—CF3 radical;
• R12 is a hydrogen atom or an alkyl radical;
• or R11 and R12 form, with the nitrogen atom to which they are attached, a saturated or unsaturated 5- or 6-membered heterocycle which may or may not contain another heteroatom chosen from:
• nitrogen, oxygen and sulphur;
• wherein said heterocycle is unsubstituted or substituted with at least one substituent chosen from:
• alkyl radicals, phenyl radicals, halophenyl radicals and phenylalkyl radicals;
• alk is an alkyl radical;
• wherein, unless otherwise indicated, said alkyl and alkoxy radicals and portions thereof have from 1 to 6 straight- or branched-chain carbon atoms;
• with a compound of formula (Ill) to form an intermediate;
• wherein said compound of formula (III) has the formula:
• in which:
• R1 is a sulphur atom;
• and
• R6 is a polyfluoroalkyl, polyfluoroalkoxy or polyfluoroalkylthio radical;
• and
• hydrolyzing said intermediate to release an imine.

A pharmaceutical composition, said composition comprising a pharmaceutically effective amount of a compound of formula (I):

• or a racemate, an enantiomer, a diastereoisomer or pharmaceutically acceptable inorganic or organic acid salt thereof,
• in which:
• R1 is a sulphur atom;
• R2 is a hydrogen atom or an alkyl radical;
• —R3—R4—R5— is a chain having formula —CH2—CH2—CH2—, —CH(R7)—CH2—CH2—, —CH2—CH2—CH(R8)—, —CH2—CH(R9)—CH2—, —CH2—CH2—CO—, —CH2—CF2—CH2—, or —CH2—CF2—CH(OH);
• R6 is a polyfluoroalkyl, polyfluoroalkoxy or polyfluoroalkylthio radical;
• R7 is an alkyl, —CH2OH, —CH2—SO2-alk or —CH2—NR11R12 radical;
• R8 is an alkyl radical, a hydroxyl atom, an —CH2OH, —NR1,R12, —CH2—NR11R12, —S-alk, —SO-alk, —SO2-alk, thienyl, furyl, or phenyl radical or a phenyl radical substituted with a substituent chosen from:
• halogen atoms, alkyl radicals and alkoxy radicals;
• R9 is an alkyl or —CH2OH radical;
• R11 is a hydrogen atom, an alkyl, a —CO-alk or —CO—CF3 radical;
• R12 is a hydrogen atom or an alkyl radical;
• or R11 and R12 form, with the nitrogen atom to which they are attached, a saturated or unsaturated 5- or 6-membered heterocycle which may or may not contain another heteroatom chosen from:
• nitrogen, oxygen and sulphur;
• wherein said heterocycle is unsubstituted or substituted with at least one substituent chosen from:
• alkyl radicals, phenyl radicals, halophenyl radicals and phenylalkyl radicals;
• alk is an alkyl radical;
• wherein, unless otherwise indicated, said alkyl and alkoxy radicals and portions thereof have from 1 to 6 straight- or branched-chain carbon atoms;
• and
• a pharmaceutically compatible diluent.