Triazine derivative and pharmaceutical composition having an analgesic activity comprising the same

A compound of the formula (IX):

• wherein
• Z1 and Z2 are each independently an oxygen atom, a sulfur atom or ═N—Rx;
• Rx is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
• Rc is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
• R4a and R4b are each independently a hydrogen atom or substituted or unsubstituted alkyl, or R4a and R4b attached to the same carbon atom are taken together to form oxo or thioxo;
• n is an integer of 1 to 4;
• R2 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
• —X— is —O—, —S—, —N(R5)— or —(CR5aR5b)—;
• R5 is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted acyl;
• R5a and R5b are each independently a hydrogen atom, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkynyloxy, or substituted or unsubstituted alkenyloxy;
• ring D is a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring or a pyridazine ring;
• carbon atom a and carbon atom b are carbon atoms which constitute ring D;
• R13a and R13b are each independently a hydrogen atom, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkynyloxy, or substituted or unsubstituted alkenyloxy, or R13a and R13b attached to the same carbon atom are taken together to form oxo or thioxo;
• ring E is a cycloalkane ring or a cycloalkene ring;
• s and s′ are each independently an integer of 0 to 3;
• and
• R9 and R9′ are each independently halogen, hydroxy, carboxy, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, substituted or unsubstituted sulfamoyl, substituted sulfonyl, substituted sulfinyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted non-aromatic heterocyclyloxy, substituted or unsubstituted aryloxy or substituted or unsubstituted heteroaryloxy,
• or its pharmaceutically acceptable salt or a solvate thereof.

A compound of the formula (VII):

• wherein
• Z1 and Z2 are each independently an oxygen atom, a sulfur atom or ═N—Rx;
• Rx is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
• Rc is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
• R4a and R4b are each independently a hydrogen atom or substituted or unsubstituted alkyl, or R4a and R4b attached to the same carbon atom are taken together to form oxo or thioxo;
• n is an integer of 1 to 4;
• R2 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
• —X— is —O—, —S—, —N(R5)— or —(CR5aR5b)—;
• R5 is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted acyl;
• R5a and R5b are each independently a hydrogen atom, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkynyloxy, or substituted or unsubstituted alkenyloxy;
• s is an integer of 0 to 3;
• and
• R9 is each independently halogen, hydroxy, carboxy, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, substituted or unsubstituted sulfamoyl, substituted sulfonyl, substituted sulfinyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted non-aromatic heterocyclyloxy, substituted or unsubstituted aryloxy or substituted or unsubstituted heteroaryloxy, or its pharmaceutically acceptable salt or a solvate thereof.

A compound of the formula (IV):

• wherein
• Z1, Z2 and Z3 are each independently an oxygen atom or a sulfur atom;
• Rc1 is unsubstituted alkyl, unsubstituted alkynyl, alkyl substituted with one or more substituents selected from Substituent Group B (Substituent Group B:
• halogen, cyano, hydroxy, carboxy, sulfo, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amino, substituted or unsubstituted imino, substituted or unsubstituted guanidyl, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, and nitro), alkenyl substituted with one or more substituents selected from Substituent Group B, alkynyl substituted with one or more substituents selected from Substituent Group B;
• R4a is a hydrogen atom or substituted or unsubstituted alkyl;
• R4b is a hydrogen atom;
• R6 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
• R4a′ is a hydrogen atom or substituted or unsubstituted alkyl;
• R4b′ is a hydrogen atom;
• and
• R6′ is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
• provided that
• 1) a compound wherein Rc1 is ethyl substituted with substituted or unsubstituted amino, or propyl substituted with substituted or unsubstituted amino, and R6 and R6′ are both substituted or unsubstituted phenyl, and
• 2) a compound wherein Rc1 is unsubstituted oxirane, substituted or unsubstituted phenyl, or alkyl substituted with unsubstituted acetyl,
• are excluded,
• or its pharmaceutically acceptable salt or a solvate thereof.

A pharmaceutical composition having an analgesic effect or an improving effect of urination disorder comprising a compound of the formula (I):

• wherein
• (i)
• Rh and Rj are taken together to form a bond;
• Ra and Rb and/or Rd and Re are taken together to form oxo, thioxo or ═N—Rx;
• Rx is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
• Rc is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
• —Rf is —(CR4aR4b)n-R2;
• R4a and R4b are each independently a hydrogen atom or substituted or unsubstituted alkyl, or R4a and R4b attached to the same carbon atom are taken together to form oxo or thioxo;
• n is an integer of 1 to 4;
• R2 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
• —Rg is —X—R3;
• —X— is —O—, —S—, —N(R5)— or —(CR5aR5b)—;
• R3 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
• R5 is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted acyl;
• and
• R5a and R5b are each independently a hydrogen atom, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkynyloxy, or substituted or unsubstituted alkenyloxy;
• or
• (ii)
• Rh and Rj are taken together to form a bond;
• Ra is a group of —Y—R1a;
• R1a is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
• —Y— is —O—, —S—, —N(R7)— or —C(R8aR8b)—;
• R7 is a hydrogen atom, substituted or unsubstituted alkyl, or substituted or unsubstituted acyl;
• R8a and R8b are each independently a hydrogen atom, halogen or substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
• Rb and Rc are taken together to form a bond;
• Rd and Re are taken together to form oxo or thioxo;
• and
• Rf and Rg are as defined above (i);
• or
• (iii)
• Ra and Rb, Rd and Re, and/or Rg and Rh are taken together to form oxo or thioxo;
• Rc is unsubstituted alkyl, unsubstituted alkynyl, alkyl substituted with one or more substituents selected from Substituent Group B (Substituent Group B:
• halogen, cyano, hydroxy, carboxy, sulfo, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amino, substituted or unsubstituted imino, substituted or unsubstituted guanidyl, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, and nitro), alkenyl substituted with one or more substituents selected from Substituent Group B, or alkynyl substituted with one or more substituents selected from Substituent Group B;
• Rf is —(CR4aR4b)—R6;
• Rj is —(CR4a′R4b′)—R6′;
• R6 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
• R6′ is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
• and
• R4a, R4b, R4a′ and R4b′ are each independently a hydrogen atom, or substituted or unsubstituted alkyl;
• or
• (iv)
• Rj and Rb are taken together to form a bond;
• Ra is a group of —Y—R1a;
• —Y— is —O—, —S—, —N(R7)— or —C(R8aR8b)—;
• R1a is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
• Rc is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
• Rd and Re are taken together to form oxo, thioxo or ═N—Rx;
• Rx is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
• —Rf is —(CR4aR4b)n-R2;
• R4a and R4b are each independently a hydrogen atom or substituted or unsubstituted alkyl, or R4a and R4b attached to the same carbon atom are taken together to form oxo or thioxo;
• n is an integer of 1 to 4;
• R2 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
• Rg and Rh are taken together to form ═N—R3;
• and
• R3 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, provided that
• 1) a compound wherein, in (i), —X— is —NH—, and R3 is cyclohexyl substituted with guanidyl, and
• 2) a compound wherein, in (ii), Ra is substituted phenyl, Rd and Re are taken together to form thioxo, R4a and R4b are taken together to form oxo, and R3 is unsubstituted cyclohexyl,
• are excluded,
• or its pharmaceutically acceptable salt, or a solvate thereof.

A method of producing a compound of the formula (XI):

• wherein Z1 and Z2 are each independently an oxygen atom or a sulfur atom,
• Rf1 is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
• Rc1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
• R3 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
• X is —N(R5)—;
• R5 is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl or substituted or unsubstituted acyl, or its pharmaceutically acceptable salt or a solvate thereof, characterized by reacting a compound of the formula (X):
• wherein Z1, Z2, Rf1 and Rc1 are as defined above;
• R27 is substituted or unsubstituted alkyl;
• and
• n′ is an integer of 0 to 3, or its salt,
• with a compound of the formula:
• R3—X′
• wherein R3 is as defined above;
• —X′ is —NH(R5);
• and
• R5 is as defined above.

A compound of the formula (XII):

• wherein Z1 and Z2 are each independently an oxygen atom or a sulfur atom;
• Rf1 is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
• Rc1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
• provided that Rc1 is not unsubstituted alkyl, unsubstituted alkenyl or unsubstituted cycloalkyl when Rf1 is a hydrogen atom;
• R27 is substituted or unsubstituted alkyl;
• and
• n′ is an integer of 0 to 3, or its pharmaceutically acceptable salt or a solvate thereof.