Fused heterocyclic derivatives, their production and use

A pharmaceutical composition which comprises a compound represented by the general formula (I):

• 700
• wherein R1 represents an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted sulfinyl group, an optionally substituted sulfonyl group, an optionally substituted hydroxyl group, an optionally substituted thiol group or an optionally substituted amino group;
• R2 represents cyano group, formyl group, thioformyl group, or a group represented by the formula:
• -Z1-Z2 (wherein Z1 represents —CO—, —CS—, —SO— or —SO2—;
• and Z2 represents an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxyl group or an optionally substituted amino group);
• ring A represents an aromatic 5-membered heterocyclic ring represented by any of
• 701
• (wherein R3 represents hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted sulfonyl group or an optionally substituted acyl group;
• R14 represents hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted sulfonyl group or an optionally substituted acyl group);
• and ring B represents an optionally substituted 5- to 7-membered hydrocarbon ring;
• provided that the compound is other than, when ring A is
• 702
• Z1 of -Z1-Z2 is —CO— and Z2 thereof is optionally substituted amino group, or a pharmaceutically acceptable salt thereof or a prodrug thereof.

A cell differentiation inducing drug which comprises a compound represented by the general formula

• 703
• wherein R1 represents an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted sulfinyl group, an optionally substituted sulfonyl group, an optionally substituted hydroxyl group, an optionally substituted thiol group or an optionally substituted amino group;
• R2 represents cyano group, formyl group, thioformyl group, or a group represented by the formula:
• -Z1-Z2 (wherein Z1 represents —CO—, —CS—, —SO— or —SO2—;
• and Z2 represents an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxyl group or an optionally substituted amino group);
• ring A represents an aromatic 5-membered heterocyclic ring represented by any of
• 704
• (wherein R3 represents hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted sulfonyl group or an optionally substituted acyl group;
• R14 represents hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted sulfonyl group or an optionally substituted acyl group);
• and ring B represents an optionally substituted 5- to 7-membered hydrocarbon ring;
• provided that the compound is other than that represented by the formula:
• 705
• or a pharmaceutically acceptable salt thereof or a prodrug thereof.

A a prophylactic or therapeutic drug for bone or articular diseases which comprises a compound represented by the general formula (I):

• 706
• wherein R1 represents an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted sulfinyl group, an optionally substituted sulfonyl group, an optionally substituted hydroxyl group, an optionally substituted thiol group or an optionally substituted amino group;
• R2 represents cyano group, formyl group, thioformyl group, or a group represented by the formula:
• -Z1-Z2 (wherein Z1 represents —CO—, —CS—, —SO— or —SO2—;
• and Z2 represents an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxyl group or an optionally substituted amino group);
• ring A represents an aromatic 5-membered heterocyclic ring represented by any of
• 707
• (wherein R3 represents hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted sulfonyl group or an optionally substituted acyl group;
• R14 represents hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted sulfonyl group or an optionally substituted acyl group);
• and ring B represents an optionally substituted 5- to 7-membered hydrocarbon ring;
• provided that the compound is other than that represented by the formula:
• 708
• or a pharmaceutically acceptable salt thereof or a prodrug thereof.

A compound represented by general formula (II):

• 709
• wherein R1 represents an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted sulfinyl group, an optionally substituted sulfonyl group, an optionally substituted hydroxyl group, an optionally substituted thiol group, or an optionally substituted amino group;
• R2 represents cyano group, formyl group, thioformyl group or a group represented by the formula:
• -Z1-Z2 (wherein Z1 represents —CO—, —CS—, —SO—, or —SO2—;
• and Z2 represents an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxyl group or an optionally substituted amino group);
• R4 represents a substituted hydroxyl group;
• and ring C represents an optionally substituted 5- to 7-membered hydrocarbon ring, or a salt thereof.

A compound represented by the general formula (IX):

• 710
• wherein R1 represents an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted sulfinyl group, an optionally substituted sulfonyl group, an optionally substituted hydroxyl group, an optionally substituted thiol group, or an optionally substituted amino group;
• R2 represents cyano group, formyl group, thioformyl group, or a group represented by the formula:
• -Z1-Z2 (wherein Z1 represents —CO—, —CS—, —SO—, or —SO2—;
• and Z2 represents an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxyl group, or an optionally substituted amino group);
• R13 represents an optionally substituted amino group or an optionally substituted hydroxyl group;
• and ring D′ represents an optionally substituted 5- to 7-membered hydrocarbon ring, or a salt thereof.

A process for producing a compound represented by the general formula (IX-1):

• 711
• wherein R1 represents an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted sulfinyl group, an optionally substituted sulfonyl group, an optionally substituted hydroxyl group, an optionally substituted thiol group, or an optionally substituted amino group;
• R2 represents cyano group, formyl group, thioformyl group or a group represented by the formula:
• -Z1-Z2 (wherein Z1 represents —CO—, —CS—, —SO—, or —SO2—;
• and Z2 represents an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxyl group or an optionally substituted amino group);
• R” represents an optionally substituted amino group;
• ring D′-1 represents an optionally substituted 5- to 7-membered hydrocarbon, or a salt thereof, which comprises reacting a compound of the general formula (IV)
• 712
• wherein ring D represents an optionally substituted 5- to 7-membered hydrocarbon ring;
• and R1 and R2 are as defined above, with an amide acetal.

A process for producing a compound of the general formula (IX-2):

• 713
• wherein R1 represents an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted sulfinyl group, an optionally substituted sulfonyl group, an optionally substituted hydroxyl group, an optionally substituted thiol group, or an optionally substituted amino group;
• R2 represents cyano group, formyl group, thioformyl group or a group represented by the formula:
• -Z1-Z2 (wherein Z1 represents —CO—, —CS—, —SO—, or —SO2—;
• and Z2 represents an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxyl group or an optionally substituted amino group);
• R4 represents an optionally substituted hydroxyl group;
• ring D′-2 represents an optionally substituted 5- to 7-membered hydrocarbon ring, or a salt thereof, which comprises subjecting a compound of the general formula (II):
• 714
• wherein ring C represents an optionally substituted 5- to 7-membered hydrocarbon ring;
• and R1, R2 and R4 are as defined above, to a de-alcoholization reaction.

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

• 715
• wherein R1 represents an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted sulfinyl group, an optionally substituted sulfonyl group, an optionally substituted hydroxyl group, an optionally substituted thiol group or an optionally substituted amino group;
• R2 represents cyano group, formyl group, thioformyl group, or a group represented by the formula:
• -Z1-Z2 (wherein Z1 represents —CO—, —CS—, —SO— or —SO2—;
• and Z2 represents an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxyl group or an optionally substituted amino group);
• ring A represents an aromatic 5-membered heterocyclic ring represented by any of
• 716
• (wherein R3 represents hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted sulfonyl group or an optionally substituted acyl group;
• R14 represents hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted sulfonyl group or an optionally substituted acyl group);
• and ring B represents an optionally substituted 5- to 7-membered hydrocarbon ring, or a salt thereof, which comprises subjecting a compound represented by the general formula (IX)
• 717
• wherein R13 represents an optionally substituted amino group or an optionally substituted hydroxyl group;
• ring D′ represents an optionally substituted 5- to 7-membered hydrocarbon ring;
• and R1 and R2 are as defined above, or a salt thereof, and hydroxylamine or its salt, or a compound represented by the formula:
• R3′NHNH2 (wherein R3′ represents hydrogen atom or an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted sulfonyl group, or an optionally substituted acyl group), or a salt thereof to a cyclization reaction, if desired, followed by conversion into an optionally substituted hydroxyl group or an optionally substituted amino group.

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

• 718
• wherein R1′ represents, among an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted sulfinyl group, an optionally substituted sulfonyl group, an optionally substituted hydroxyl group, an optionally substituted thiol group, or an optionally substituted amino group, a group represented by the formula:
• —X′—W′ (wherein X′ represents a bond, an optionally substituted carbon atom, an optionally substituted nitrogen atom, oxygen atom or an optionally oxidized sulfur atom;
• R3″ represents an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted sulfonyl group or an optionally substituted acyl group;
• and W′ represents an optionally substituted cyclic group or carbon or nitrogen atom having 2 or more substituents);
• R2 represents cyano group, formyl group, thioformyl group, or a group represented by the formula:
• -Z1-Z2 (wherein Z1 represents —CO—, —CS—, —SO—, or —SO2—;
• and Z2 represents an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxyl group or an optionally substituted amino group);
• ring B-1 represents an optionally substituted 5- to 7-membered hydrocarbon ring, or a salt thereof, which comprises subjecting a compound represented by the general formula (IX-3):
• 719
• wherein R13′ represents an optionally substituted amino group or an optionally substituted hydroxyl group;
• ring D′-3 represents an optionally substituted 5- to 7-membered hydrocarbon ring;
• and R1′ and R2 are as defined above, or a salt thereof, and a compound resented by formula:
• R3″NHNH2 (wherein R3″ is as defined above), or a salt thereof to a cyclization reaction in the presence of an acid under substantially anhydrous conditions.

A method for inducing cell differentiation in a mammal in need thereof which comprises administering an effective amount of a compound represented by the general formula (I):

• 720
• wherein R1 represents an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted sulfinyl group, an optionally substituted sulfonyl group, an optionally substituted hydroxyl group, an optionally substituted thiol group or an optionally substituted amino group;
• R2 represents cyano group, formyl group, thioformyl group, or a group represented by the formula:
• -Z1-Z2 (wherein Z1 represents —CO—, —CS—, —SO— or —SO2—;
• and Z2 represents an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxyl group or an optionally substituted amino group);
• ring A represents an aromatic 5-membered heterocyclic ring represented by any of
• 721
• (wherein R3 represents hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted sulfonyl group or an optionally substituted acyl group;
• R14 represents hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted sulfonyl group or an optionally substituted acyl group);
• and ring B represents an optionally substituted 5- to 7-membered hydrocarbon ring;
• provided that the compound is other than that represented by the formula:
• 722
• or a pharmaceutically acceptable salt thereof or a prodrug thereof, to the mammal.

A method for preventing or treating bone or articular diseases in a mammal in need thereof which comprises administering an effective amount of a compound represented by the general formula (I):

• 723
• wherein R1 represents an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted sulfinyl group, an optionally substituted sulfonyl group, an optionally substituted hydroxyl group, an optionally substituted thiol group or an optionally substituted amino group;
• R2 represents cyano group, formyl group, thioformyl group, or a group represented by the formula:
• -Z1-Z2 (wherein Z1 represents —CO—, —CS—, —SO— or —SO2—;
• and Z2 represents an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxyl group or an optionally substituted amino group);
• ring A represents an aromatic 5-membered heterocyclic ring represented by any of
• 724
• (wherein R3 represents hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted sulfonyl group or an optionally substituted acyl group;
• R14 represents hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted sulfonyl group or an optionally substituted acyl group);
• and ring B represents an optionally substituted 5- to 7-membered hydrocarbon ring;
• provided that the compound is other than that represented by the formula:
• 725
• or a pharmaceutically acceptable salt thereof or a prodrug thereof, to the mammal.

Use of a compound represented by the general formula (I):

• 726
• wherein R1 represents an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted sulfinyl group, an optionally substituted sulfonyl group, an optionally substituted hydroxyl group, an optionally substituted thiol group or an optionally substituted amino group;
• R2 represents cyano group, formyl group, thioformyl group, or a group represented by the formula:
• -Z1-Z2 (wherein Z1 represents —CO—, —CS—, —SO— or —SO2—;
• and Z2 represents an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxyl group or an optionally substituted amino group);
• ring A represents an aromatic 5-membered heterocyclic ring represented by any of
• 727
• (wherein R3 represents hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted sulfonyl group or an optionally substituted acyl group;
• R14 represents hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted sulfonyl group or an optionally substituted acyl group);
• and ring B represents an optionally substituted 5- to 7-membered hydrocarbon ring;
• provided that the compound is other than that represented by the formula:
• 728
• or a pharmaceutically acceptable salt thereof or a prodrug thereof, for manufacturing a cell defferentiation inducing drug.

Use of a compound represented by the general formula (I):

• 729
• wherein R1 represents an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted sulfinyl group, an optionally substituted sulfonyl group, an optionally substituted hydroxyl group, an optionally substituted thiol group or an optionally substituted amino group;
• R2 represents cyano group, formyl group, thioformyl group, or a group represented by the formula:
• -Z1-Z2 (wherein Z1 represents —CO—, —CS—, —SO— or —SO2—;
• and Z2 represents an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxyl group or an optionally substituted amino group);
• ring A represents an aromatic 5-membered heterocyclic ring represented by any of
• 730
• (wherein R3 represents hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted sulfonyl group or an optionally substituted acyl group;
• R14 represents hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted sulfonyl group or an optionally substituted acyl group);
• and ring B represents an optionally substituted 5- to 7-membered hydrocarbon ring;
• provided that the compound is other than that represented by the formula:
• 731
• or a pharmaceutically acceptable salt thereof or a prodrug thereof, for manufacturing a prophylactic or therapeutic drug for bone or articular diseases which comprises.