Thienopyridine derivatives, their production and use

A process for producing a compound represented by the formula (I):

• wherein G represents a halogen atom, hydroxyl group, an optionally substituted amino group, an optionally substituted lower ailcyl group or an optionally substituted alkoxy group;
• alk represents an optionally substituted lower alkylene group;
• X represents oxygen atom, an optionally oxidized sulfur atom, or —(CH2)q—, wherein q represents an integer of 0 to 5;
• R represents an optionally substituted amino group or an optionally substituted heterocyclic group;
• ring B represents an optionally substituted Y-contaming 5- to 8-membered ring whose ring constituent atoms contain no nitrogen atom;
• Y represents oxygen atom, an optionally oxidized sulfur atom,
• wherein Ra and Rb are the same or different and, respectively, represent hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted acyl group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally esterified carboxyl group, or an optionally substituted heterocyclic group, or Ra and Rb may be combined to form a 5- to 7-membered ring;
• and Rc represents hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted acyl group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally esterified carboxyl group, or an optionally substituted heterocyclic group;
• and ring A represents an optionally substituted benzene ring, or a salt thereof which comprises reacting a compound represented by the formula (II-1):
• wherein Q represents a leaving group;
• and the other symbols are as defined above, or a salt thereof, with a compound represented by the formula (III):
• R—X1 (III)
• wherein R is as defined above;
• and X1 represents oxygen atom, or an optionally oxidized sulfur atom, or a salt thereof to obtain a compound represented by the formula (I-1):
• wherein each symbol is as defined above, or a salt thereof;
• or
• reacting a compound represented by the formula (II-2):
• wherein each symbol is as defined above, or a salt thereof, with a compound represented by the formula (IV):
• wherein R1 and R2, which may be the same or different, respectively, represent an optionally substituted hydrocarbon group, an optionally substituted acyl group, an optionally substituted sulfonyl group, or an optionally substituted heterocyclic group, or R1 and R2 may be combined to form an optionally substituted nitrogen-containing 5- to 7-membered ring, or a salt thereof to obtain a compound represented by the formula (I-2):
• wherein each symbol is as defined above, or a salt thereof;
• or
• subjecting a compound represented by the formula (I-3):
• wherein ring B1 represents an optionally substituted Y1-contaming 5- to 8-membered ring whose ring constituent atoms contain no nitrogen atom;
• Y1 represents sulfur atom or
• and the other symbols are as defined above, or a salt thereof to oxidation to obtain a compound represented by the formula (I-4):
• wherein ring B2 represents an optionally substituted Y2-containing 5- to 8-membered ring whose constituent ring atoms contain no nitrogen atom;
• Y2 represents an oxidized sulfur atom or
• and the other symbols are as defined above, or a salt thereof;
• or
• reacting a compound represented by the formula (II-3):
• wherein G′ represents a halogen atom;
• and the other symbols are as defined above, or a salt thereof, with
• (C6H5)3P
• in a solvent to obtain a compound represented by formula (VI):
• wherein each symbol is as defined above, then reacting the compound represented by the formula (VI) with a compound represented by the formula (VII):
• Z1-(CH2)q′CHO (VII)
• wherein Z1 represents an optionally substituted heterocyclic group;
• and q′ represents an integer of 0 to 4, or a salt thereof to obtain a compound represented by formula (VIII):
• wherein each symbol is as defined above, or a salt thereof, and further subjecting the compound represented by formula (VIII) or a salt thereof to reduction to obtain a compound represented by the formula (I-5):
• wherein each symbol is as defined above, or a salt thereof;
• or
• reacting a compound represented by the formula (II-1):
• wherein each symbol is as defined above, or a salt thereof, with a compound represented by formula (XII):
• R—H (XII)
• wherein R is as defined above, or a salt thereof to obtain a compound represented by the formula (I-9):
• wherein each symbols is as defined above, or a salt thereof.

A pharmaceutical composition comprising a compound represented by the formula (I):

• wherein G represents a halogen atom, hydroxyl group, an optionally substituted amino group, an optionally substituted lower alkyl group or an optionally substituted alkoxy group;
• alk represents an optionally substituted lower alkylene group;
• X represents oxygen atom, an optionally oxidized sulfur atom, or —(CH2)q—, wherein q represents an integer of 0 to 5;
• R represents an optionally substituted amino group or an optionally substituted heterocyclic group;
• ring B represents an optionally substituted Y-containing 5- to 8-membered ring whose ring constituent atoms contain no nitrogen atom;
• Y represents oxygen atom, an optionally oxidized sulfur atom,
• wherein Ra and Rb are the same or different and, respectively, represent hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted acyl group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally esterified carboxyl group, or an optionally substituted heterocyclic group, or Ra and Rb may be combined to form a 5- to 7-membered ring;
• and Rc represents hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted acyl group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally esterified carboxyl group, or an optionally substituted heterocyclic group;
• and ring A represents an optionally substituted benzene ring, a prodrug thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or diluent.

A method for making a pharmaceutical composition for treating inflammatory diseases comprising combining a compound represented by the formula (I):

• wherein G represents a halogen atom, hydroxyl group, an optionally substituted amino group, an optionally substituted lower alkyl group or an optionally substituted alkoxy group;
• alk represents an optionally substituted lower alkylene group;
• X represents oxygen atom, an optionally oxidized sulfur atom, or —(CH2)q—, wherein q represents an integer of 0 to 5;
• R represents an optionally substituted amino group or an optionally substituted heterocyclic group;
• ring B represents an optionally substituted Y-containing 5- to 8-membered ring whose ring constituent atoms contain no nitrogen atom;
• Y represents oxygen atom, an optionally oxidized sulfur atom,
• wherein Ra and Rb are the same or different and, respectively, represent hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted acyl group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally esterified carboxyl group, or an optionally substituted heterocyclic group, or Ra and Rb may be combined to form a 5- to 7-membered ring;
• and Rc represents hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted acyl group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally esterified carboxyl group, or an optionally substituted heterocyclic group;
• and ring A represents an optionally substituted benzene ring, a prodrug thereof, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier, excipient or diluent.