Indian Patents. 263383:3-ETHYLIDENEHYDRAZINO SUBSTITUTED HETEROCYCLIC COMPOUNDS AS THROMBOPOIETIN RECEPTOR ACTIVATORS

Title of Invention	3-ETHYLIDENEHYDRAZINO SUBSTITUTED HETEROCYCLIC COMPOUNDS AS THROMBOPOIETIN RECEPTOR ACTIVATORS
Abstract	A compound represented by the formula (1): wherein A, B, R1, L1, R2, L2, L3, Y, L4, R3 and X are the same as defined in the description, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.

Full Text	DESCRIPTION HETEROCYCLIC COMPOUNDS AND THROMBOPOIETIN RECEPTOR ACTIVATORS BACKGROUND OF THE INVENTION TECHNICAL FIELD The present invention relates to preventive, therapeutic and improving agents having affinity for and agonistic action on the thrombopoietin receptor for diseases against which activation of the thrombopoietin receptor is effective. Specifically, it relates to pharmaceutical compositions comprising compounds which increase platelets through stimulation of differentiation and proliferation of hematopoietic stem cells, megakaryocytic progenitor cells and megakaryocytes or compounds for therapeutic angiogenesis or with anti-arteriosclerosis action that stimulate differentiation and proliferation of vascular endothelial cells and endothelial progenitor cells. BACKGROUND ART Thrombopoietin is a cytokine consisting of 332 amino acids that increases platelet production by stimulating differentiation and proliferation of hematopoietic stem cells, megakaryocytic progenitor cells and megakaryocytes mediated by its receptor and therefore is promising as a drug for hematological disorders. Recent reports that it stimulates differentiation and proliferation of vascular endothelial cells and endothelial progenitor cells have raised expectations of therapeutic angiogenesis, anti-arteriosclerosis and prevention of cardiovascular events (for example, non-patent document 1, non-patent document 2 and non-patent document 3). Biologically active substances which have been known so far to regulate platelet production through the thrombopoietin receptor include, in addition to thrombopoietin itself, low molecular weight peptides having affinity for the thrombopoietin receptor (for example, patent document 1, patent document 2, patent document 3 and patent document 4). As a result of search for nonpeptidic low molecular weight compounds that increase platelet production mediated by the thrombopoietin receptor, low molecular weight compounds having affinity for the thrombopoietin receptor have been reported (for example, patent document 5 to patent document 26). 1) Applications filed by Hokuriku Seiyaku Co., Ltd. relating to 1,4-benzodiazepine derivatives (patent documents 5 and 6) 2) International Laid-open Patent Applications filed by Shionogi & Co., Ltd. (patent documents 7-10) 3) International Laid-open Patent Applications filed by SmithKline Beecham Corp (patent documents 11-19) 4) Japanese Laid-open Patent Application filed by Torii Pharmaceutical Co., Ltd. (patent document 20) 5) International Laid-open Patent Application filed by Roche Diagnostics GMBH (patent document 21) 6) International Laid-open Patent Application filed by Yamanouchi Pharmaceutical Co., Ltd. (patent document 22 and 23) 7) Japanese Laid-open Patent Application filed by Japan Tabacco Inc. (patent document 24) 8) Japanese Laid-open Patent Applications filed by Nissan Chemical Industries, Ltd. (patent documents 25 and 26) Patent document 1 JP-A-10-72492 Patent document 2 WO96/40750 Patent document 3 WO96/40189 Patent document 4 WO98/25965 Patent document 5 JP-A-11-1477 Patent document 6 JP-A-11-152276 Patent document 7 WO01/07423 Patent document 8 WO01/53267 Patent document 9 WO02/059099 Patent document 10 WO02/059100 Patent document 11 WO00/35446 Patent document 12 WO00/66112 Patent document 13 WO01/34585 Patent document 14 WO01/17349 Patent document 15 WO01/39773 Patent document 16 WO01/21180 Patent document 17 WO01/89457 Patent document 18 WO02/49413 Patent document 19 WO02/085343 Patent document 20 JP-A-2001-97948 Patent document 21 WO99/11262 Patent document 22 WO02/062775 Patent document 23 WO03/062233 Patent document 24 JP-A-2003-238565 Patent document 25 WO04/033433 Patent document 26 WO04/108683 Non-patent document 1 Microvasc. Res., 1999: 58, p.108-113 Non-patent document 2 Circ. Res., 1999: 84, p.785-796 Non-patent document 3 Blood 2001:98, p.71a-72a DISCLOSURE OF THE INVENTION Thrombopoietin and low molecular weight peptides having affinity for the thrombopoietin receptor are likely to be easily degraded in the gastrointestinal tract and are usually difficult to orally administer. As to thrombopoietin itself, the appearance of anti-thrombopoietin antibodies have been reported. Besides, though it is probably possible to orally administer nonpeptidic low molecular weight compounds, no practical drugs have been put on the market. Therefore, orally administrable low molecular weight compounds having excellent affinity for and agonistic action on the thrombopoietin receptor as preventive, therapeutic and improving agents for diseases against which activation of the thrombopoietin receptor is effective have been demanded. Specifically, low molecular weight compounds which can serve as platelet increasing agents or increasing agents for other blood cells by stimulating differentiation and proliferation of hematopoietic stem cells, megakaryocytic progenitor cells and megakaryocytes or low molecular weight compounds which can be used for therapeutic angiogenesis or as preventive and therapeutic agents for arteriosclerosis by stimulating endothelial cells and endothelial progenitor cells have been demanded. The present inventors conducted extensive research to find low molecular weight compounds having affinity for and agonistic action on the thrombopoietin receptor, and as a result, found that the compounds of the present invention have high affinity and agonistic action which enable them to show potent platelet increasing action by stimulating differentiation and proliferation of megakaryocytic progenitor cells and megakaryocytes. The present invention was accomplished on the basis of this discovery. Namely, the present invention relates to: 1. A compound represented by the formula (1) wherein A is a nitrogen atom or CR4 (wherein R4 is a hydrogen atom, a hydroxyl group (the hydroxyl group may be substituted with a C2?6 alkenyl group or a C2?6 alkynyl group), a thiol group (the thiol group may be substituted with a C1?10 alkyl group, a C2?6 alkenyl group, a C2?6 alkynyl group or a C1?10 alkylcarbonyl group), an amino group (the amino group may be substituted with one or two C2?6 alkenyl groups or one or two C2?6 alkynyl groups), a formyl group, a halogen atom, a nitro group, a cyano group, a C1?10 alkyl group, a C2?6 alkenyl group, a C2?6 alkynyl group, a C1?10 alkylcarbonylamino group, a mono- or di-C1?10 alkylamino group, a C1?10 alkoxy group (the C1?10 alkyl group, the C2?6 alkenyl group, the C2?6 alkynyl group, the C1?10 alkylcarbonylamino group, the mono- or di-C1?10 alkylamino group and the C1?10 alkoxy group may be optionally substituted with one or more substituents selected from the group consisting of carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups (the C2?14 aryl groups and the C2?14 aryloxy groups may be substituted with one or more C1?6 alkyl groups (the C1?6 alkyl groups may be substituted with one or more halogen atoms) or one or more halogen atoms)), a C2?14 aryl group (the C2?14 aryl group may be optionally substituted with one or more substituents selected from the group consisting of C1?10 alkyl groups (the C1?10 alkyl groups may be substituted with one or more halogen atoms), C2?6 alkenyl groups, C2?6 alkynyl groups, carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups), a C2?14 aryloxy group (the C2?14 aryloxy group may be optionally substituted with one or more substituents selected from the group consisting of C1?10 alkyl groups (the C1?10 alkyl groups may be substituted with one or more halogen atoms), C2?6 alkenyl groups, C2?6 alkynyl groups, carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups), SO2R5, SOR5 or COR5 (wherein R5 is a hydroxyl group, a C1?10 alkyl group, a C2?6 alkenyl group, a C2?6 alkynyl group, a C2-9 heterocyclic group, a C1?10 alkoxy group (the C1?10 alkyl group, the C2?6 alkenyl group, the C2?6 alkynyl group, the C2-9 heterocyclic group and the C1?10 alkoxy group may be optionally substituted with one or more substituents selected from the group consisting of carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups (the C2?14 aryl groups and the C2?14 aryloxy groups may be substituted with one or more C1?6 alkyl groups (the C1?6 alkyl groups may be substituted with one or more halogen atoms) or one or more halogen atoms)), a C2?14 aryl group (the C2?14 aryl group may be optionally substituted with one or more substituents selected from the group consisting of C1?10 alkyl groups (the C1?10 alkyl groups may be substituted with one or more halogen atoms), C2?6 alkenyl groups, C2?6 alkynyl groups, carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups), a C2?14 aryloxy group (the C2?14 aryloxy group may be optionally substituted with one or more substituents selected from the group consisting of C1?10 alkyl groups (the C1?10 alkyl groups may be substituted with one or more halogen atoms), C2?6 alkenyl groups, C2?6 alkynyl groups, carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups) or NR6R7 (wherein each of R6 and R7 is independently a hydrogen atom, a hydroxyl group, a formyl group, a C1?10 alkyl group, a C2?6 alkenyl group, a C2?6 alkynyl group, a C1?10 alkylcarbonyloxy group, a C1?10 alkoxycarbonyl group, a C1?10 alkylcarbonyl group (the C1?10 alkyl group, the C2?6 alkenyl group, the C2?6 alkynyl group, the C1?10 alkylcarbonyloxy group, the C1?10 alkoxycarbonyl group and the C1?10 alkylcarbonyl group may be optionally substituted with one or more substituents selected from the group consisting of carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups (the C2?14 aryl groups and the C2?14 aryloxy groups may be substituted with one or more C1?6 alkyl groups (the C1?6 alkyl groups may be substituted with one or more halogen atoms) or one or more halogen atoms)) or a C2?14 aryl group (the C2?14 aryl group may be optionally substituted with one or more substituents selected from the group consisting of C1?10 alkyl groups (the C1?10 alkyl groups may be substituted with one or more halogen atoms), C2?6 alkenyl groups, C2?6 alkynyl groups, carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups), or R6 and R7 mean, together with each other, ?(CH2)m1-E-(CH2)m2- (wherein E is an oxygen atom, a sulfur atom, CR26R27 (wherein each of R26 and R27 is independently a hydrogen atom, a C1?10 alkyl group, a C2?14 aryl group, a C1?10 alkoxy group, a C2?14 aryloxy group, a hydroxyl group or a protected hydroxyl group) or NR8 (wherein R8 is a hydrogen atom, a hydroxyl group, a formyl group, a C1?10 alkyl group, a C2?6 alkenyl group, a C2?6 alkynyl group, a C1?10 alkoxy group, a C1?10 alkylcarbonyloxy group, a C1?10 alkoxycarbonyl group, a C1?10 alkylcarbonyl group (the C1?10 alkyl group, the C2?6 alkenyl group, the C2?6 alkynyl group, the C1?10 alkoxy group, the C1?10 alkylcarbonyloxy group, the C1?10 alkoxycarbonyl group and the C1?10 alkylcarbonyl group may be optionally substituted with one or more substituents selected from the group consisting of carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups (the C2?14 aryl groups and the C2?14 aryloxy groups may be substituted with one or more C1?6 alkyl groups (the C1?6 alkyl groups may be substituted with one or more halogen atoms) or one or more halogen atoms)) or a C2?14 aryl group (the C2?14 aryl group may be optionally substituted with one or more substituents selected from the group consisting of C1?10 alkyl groups (the C1?10 alkyl groups may be substituted with one or more halogen atoms), C2?6 alkenyl groups, C2?6 alkynyl groups, carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups)), and each of m1 and m2 is independently an integer of from 0 to 5 provided that m1+m2 is 3, 4 or 5)))), B is an oxygen atom, a sulfur atom or NR9 (wherein R9 is a hydrogen atom, a hydroxyl group, a formyl group, a C1?10 alkyl group, a C2?6 alkenyl group, a C2?6 alkynyl group, a C1?10 alkoxy group, a C1?10 alkylcarbonyloxy group, a C1?10 alkoxycarbonyl group, a C1?10 alkylcarbonyl group (the C1?10 alkyl group, the C2?6 alkenyl group, the C2?6 alkynyl group, the C1?10 alkoxy group, the C1?10 alkylcarbonyloxy group, the C1?10 alkoxycarbonyl group and the C1?10 alkylcarbonyl group may be optionally substituted with one or more substituents selected from the group consisting of carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups (the C2?14 aryl groups and the C2?14 aryloxy groups may be substituted with one or more C1?6 alkyl groups (the C1?6 alkyl groups may be substituted with one or more halogen atoms) or one or more halogen atoms)), a C2?14 aryl group (the C2?14 aryl group may be optionally substituted with one or more substituents selected from the group consisting of C1?10 alkyl groups (the C1?10 alkyl groups may be substituted with one or more halogen atoms), C2?6 alkenyl groups, C2?6 alkynyl groups, carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups) or a C2?14 aryloxy group (the C2?14 aryloxy group may be optionally substituted with one or more substituents selected from the group consisting of C1?10 alkyl groups (the C1?10 alkyl groups may be substituted with one or more halogen atoms), C2?6 alkenyl groups, C2?6 alkynyl groups, carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups)) (provided that when A is a nitrogen atom, B is not NH), R1 is a C2?14 aryl group (the C2?14 aryl group may be substituted with one or more substituents selected from the group consisting of halogen atoms, carboxyl groups, nitro groups, formyl groups, cyano groups, hydroxyl groups, protected hydroxyl groups, C1?10 alkyl groups, C2?6 alkenyl groups, C2?6 alkynyl groups, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups (the C1?10 alkyl groups, the C2?6 alkenyl groups, the C2?6 alkynyl groups, the C1?10 alkoxy groups, the C1?10 alkylcarbonyl groups, the C1?10 alkylcarbonyloxy groups and the C1?10 alkoxycarbonyl groups may be optionally substituted with one or more substituents selected from the group consisting of carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups (the C2?14 aryl groups and the C2?14 aryloxy groups may be substituted with one or more C1?6 alkyl groups (the C1?6 alkyl groups may be substituted with one or more halogen atoms) or one or more halogen atoms)), C2?14 aryl groups (the C2?14 aryl groups may be optionally substituted with one or more substituents selected from the group consisting of C1?10 alkyl groups (the C1?10 alkyl groups may be substituted with one or more halogen atoms), C2?6 alkenyl groups, C2?6 alkynyl groups, carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups), thiol groups and amino groups (the thiol groups and the amino groups may be optionally substituted with one or two substituents selected from the group consisting of formyl groups, C1?10 alkyl groups, C2?6 alkenyl groups, C2?6 alkynyl groups and C1?10 alkylcarbonyl groups (the C1?10 alkyl groups, the C2?6 alkenyl groups, the C2?6 alkynyl groups and the C1?10 alkylcarbonyl groups may be optionally substituted with one or more substituents selected from the group consisting of carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups (the C2?14 aryl groups and the C2?14 aryloxy groups may be substituted with one or more C1?6 alkyl groups (the C1?6 alkyl groups may be substituted with one or more halogen atoms) or one or more halogen atoms)))), L1 is a bond, CR10R11 (wherein each of R10 and R11 is independently a hydrogen atom or a C1?6 alkyl group (the C1?6 alkyl group may be substituted with one or more halogen atoms)), an oxygen atom, a sulfur atom or NR12 (wherein R12 is a hydrogen atom, a hydroxyl group, a formyl group, a C1?10 alkyl group, a C2?6 alkenyl group, a C2?6 alkynyl group, a C1?10 alkoxy group, a C1?10 alkylcarbonyloxy group, a C1?10 alkoxycarbonyl group, a C1?10 alkylcarbonyl group (the C1?10 alkyl group, the C2?6 alkenyl group, the C2?6 alkynyl group, the C1?10 alkoxy group, the C1?10 alkylcarbonyloxy group, the C1?10 alkoxycarbonyl group and the C1?10 alkylcarbonyl group may be optionally substituted with one or more substituents selected from the group consisting of carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups (the C2?14 aryl groups and the C2?14 aryloxy groups may be substituted with one or more C1?6 alkyl groups (the C1?6 alkyl groups may be substituted with one or more halogen atoms) or one or more halogen atoms)) or a C2?14 aryl group (the C2?14 aryl group may be optionally substituted with one or more substituents selected from the group consisting of C1?10 alkyl groups (the C1?10 alkyl groups may be substituted with one or more halogen atoms), C2?6 alkenyl groups, C2?6 alkynyl groups, carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups)), X is OR13, SR13 or NR14R15 (wherein R13 is a hydrogen atom, a C1?10 alkyl group, a C2?6 alkenyl group, a C2?6 alkynyl group or a C1?10 alkylcarbonyl group (the C1?10 alkyl group, the C2?6 alkenyl group, the C2?6 alkynyl group and the C1?10 alkylcarbonyl group may be optionally substituted with one or more substituents selected from the group consisting of carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups (the C2?14 aryl groups and the C2?14 aryloxy groups may be substituted with one or more C1?6 alkyl groups (the C1?6 alkyl groups may be substituted with one or more halogen atoms) or one or more halogen atoms)), and each of R14 and R15 is independently a hydrogen atom, a formyl group, a C1?10 alkyl group, a C2?6 alkenyl group, a C2?6 alkynyl group, a C1?10 alkoxy group, a C1?10 alkylcarbonyl group (the C1?10 alkyl group, the C2?6 alkenyl group, the C2?6 alkynyl group, the C1?10 alkoxy group and the C1?10 alkylcarbonyl group may be optionally substituted with one or more substituents selected from the group consisting of carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups (the C2?14 aryl groups and the C2?14 aryloxy groups may be substituted with one or more C1?6 alkyl groups (the C1?6 alkyl groups may be substituted with one or more halogen atoms) or one or more halogen atoms)) or a C2?14 aryl group (the C2?14 aryl group may be optionally substituted with one or more substituents selected from the group consisting of C1?10 alkyl groups (the C1?10 alkyl groups may be substituted with one or more halogen atoms), C2?6 alkenyl groups, C2?6 alkynyl groups, carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups)), R2 is a hydrogen atom, a formyl group, a C1?10 alkyl group, a C2?6 alkenyl group, a C2?6 alkynyl group, a C1?10 alkoxy group, a C1?10 alkylcarbonyl group (the C1?10 alkyl group, the C2?6 alkenyl group, the C2?6 alkynyl group, the C1?10 alkoxy group and the C1?10 alkylcarbonyl group may be optionally substituted with one or more substituents selected from the group consisting of carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups (the C2?14 aryl groups and the C2?14 aryloxy groups may be substituted with one or more C1?6 alkyl groups (the C1?6 alkyl groups may be substituted with one or more halogen atoms) or one or more halogen atoms)) or a C2?14 aryl group (the C2?14 aryl group may be optionally substituted with one or more substituents selected from the group consisting of C1?10 alkyl groups (the C1?10 alkyl groups may be substituted with one or more halogen atoms), C2?6 alkenyl groups, C2?6 alkynyl groups, carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups), L2 is a bond, CR34R35 (wherein each of R34 and R35 is independently a hydrogen atom or a C1?6 alkyl group (the C1?6 alkyl group may be substituted with one or more halogen atoms)), an oxygen atom, a sulfur atom or NR16 (wherein R16 is a hydrogen atom, a hydroxyl group, a formyl group, a C1?10 alkyl group, a C2?6 alkenyl group, a C2?6 alkynyl group, a C1?10 alkoxy group, a C1?10 alkylcarbonyloxy group, a C1?10 alkoxycarbonyl group, a C1?10 alkylcarbonyl group (the C1?10 alkyl group, the C2?6 alkenyl group, the C2?6 alkynyl group, the C1?10 alkoxy group, the C1?10 alkylcarbonyloxy group, the C1?10 alkoxycarbonyl group and the C1?10 alkylcarbonyl group may be optionally substituted with one or more substituents selected from the group consisting of carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups (the C2?14 aryl groups and the C2?14 aryloxy groups may be substituted with one or more C1?6 alkyl groups (the C1?6 alkyl groups may be substituted with one or more halogen atoms) or one or more halogen atoms)) or a C2?14 aryl group (the C2?14 aryl group may be optionally substituted with one or more substituents selected from the group consisting of C1?10 alkyl groups (the C1?10 alkyl groups may be substituted with one or more halogen atoms), C2?6 alkenyl groups, C2?6 alkynyl groups, carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups)), L3 is a bond, CR17R18 (wherein each of R17 and R18 is independently a hydrogen atom, a C1?10 alkyl group, a C2?6 alkenyl group, a C2?6 alkynyl group, a C1?10 alkoxy group, a C1?10 alkylcarbonyl group (the C1?10 alkyl group, the C2?6 alkenyl group, the C2?6 alkynyl group, the C1?10 alkoxy group and the C1?10 alkylcarbonyl group may be optionally substituted with one or more substituents selected from the group consisting of carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups (the C2?14 aryl groups and the C2?14 aryloxy groups may be substituted with one or more C1?6 alkyl groups (the C1?6 alkyl groups may be substituted with one or more halogen atoms) or one or more halogen atoms)) or a C2?14 aryl group (the C2?14 aryl group may be optionally substituted with one or more substituents selected from the group consisting of C1?10 alkyl groups (the C1?10 alkyl groups may be substituted with one or more halogen atoms), C2?6 alkenyl groups, C2?6 alkynyl groups, carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups)), an oxygen atom, a sulfur atom or NR19 (wherein R19 is a hydrogen atom, a hydroxyl group, a formyl group, a C1?10 alkyl group, a C2?6 alkenyl group, a C2?6 alkynyl group, a C1?10 alkoxy group, a C1?10 alkylcarbonyloxy group, a C1?10 alkoxycarbonyl group, a C1?10 alkylcarbonyl group (the C1?10 alkyl group, the C2?6 alkenyl group, the C2?6 alkynyl group, the C1?10 alkylcarbonyloxy group, the C1?10 alkoxycarbonyl group, the C1?10 alkoxy group and the C1?10 alkylcarbonyl group may be optionally substituted with one or more substituents selected from the group consisting of carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups (the C2?14 aryl groups and the C2?14 aryloxy groups may be substituted with one or more C1?6 alkyl groups (the C1?6 alkyl groups may be substituted with one or more halogen atoms) or one or more halogen atoms)) or a C2?14 aryl group (the C2?14 aryl group may be optionally substituted with one or more substituents selected from the group consisting of C1?10 alkyl groups (the C1?10 alkyl groups may be substituted with one or more halogen atoms), C2?6 alkenyl groups, C2?6 alkynyl groups, carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups)), Y is an oxygen atom, a sulfur atom or NR23 (wherein R23 is a hydrogen atom, a hydroxyl group, a formyl group, a C1?10 alkyl group, a C2?6 alkenyl group, a C2?6 alkynyl group, a C1?10 alkoxy group, a C1?10 alkylcarbonyloxy group, a C1?10 alkoxycarbonyl group, a C1?10 alkylcarbonyl group (the C1?10 alkyl group, the C2?6 alkenyl group, the C2?6 alkynyl group, the C1?10 alkoxy group, the C1?10 alkylcarbonyloxy group, the C1?10 alkoxycarbonyl group and the C1?10 alkylcarbonyl group may be optionally substituted with one or more substituents selected from the group consisting of carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups (the C2?14 aryl groups and the C2?14 aryloxy groups may be substituted with one or more C1?6 alkyl groups (the C1?6 alkyl groups may be substituted with one or more halogen atoms) or one or more halogen atoms)) or a C2?14 aryl group (the C2?14 aryl group may be substituted with one or more substituents selected from the group consisting of C1?10 alkyl groups (the C1?10 alkyl groups may be substituted with one or more halogen atoms), C2?6 alkenyl groups, C2?6 alkynyl groups, carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups)), L4 is a bond, CR20R21 (wherein each of R20 and R21 is independently a hydrogen atom, a C1?10 alkyl group, a C2?6 alkenyl group, a C2?6 alkynyl group, a C1?10 alkoxy group, a C1?10 alkylcarbonyl group (the C1?10 alkyl group, the C2?6 alkenyl group, the C2?6 alkynyl group, the C1?10 alkoxy group and the C1?10 alkylcarbonyl group may be optionally substituted with one or more substituents selected from the group consisting of carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups (the C2?14 aryl groups and the C2?14 aryloxy groups may be substituted with one or more C1?6 alkyl groups (the C1?6 alkyl groups may be substituted with one or more halogen atoms) or one or more halogen atoms)) or a C2?14 aryl group (the C2?14 aryl group may be A compound represented by the formula (1): wherein A, B, R1, L1, R2, L2, L3, Y, L4, R3 and X are the same as defined in the description, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.

Full Text

DESCRIPTION

HETEROCYCLIC COMPOUNDS AND THROMBOPOIETIN RECEPTOR ACTIVATORS

BACKGROUND OF THE INVENTION
TECHNICAL FIELD
The present invention relates to preventive, therapeutic and improving agents having affinity for and agonistic action on the thrombopoietin receptor for diseases against which activation of the thrombopoietin receptor is effective. Specifically, it relates to pharmaceutical compositions comprising compounds which increase platelets through stimulation of differentiation and proliferation of hematopoietic stem cells, megakaryocytic progenitor cells and megakaryocytes or compounds for therapeutic angiogenesis or with anti-arteriosclerosis action that stimulate differentiation and proliferation of vascular endothelial cells and endothelial progenitor cells.

BACKGROUND ART
Thrombopoietin is a cytokine consisting of 332 amino acids that increases platelet production by stimulating differentiation and proliferation of hematopoietic stem cells, megakaryocytic progenitor cells and megakaryocytes mediated by its receptor and therefore is promising as a drug for hematological disorders. Recent reports that it stimulates differentiation and proliferation of vascular endothelial cells and endothelial progenitor cells have raised expectations of therapeutic angiogenesis, anti-arteriosclerosis and prevention of cardiovascular events (for example, non-patent document 1, non-patent document 2 and non-patent document 3).
Biologically active substances which have been known so far to regulate platelet production through the thrombopoietin receptor include, in addition to thrombopoietin itself, low molecular weight peptides having affinity for the thrombopoietin receptor (for example, patent document 1, patent document 2, patent document 3 and patent document 4).
As a result of search for nonpeptidic low molecular weight compounds that increase platelet production mediated by the thrombopoietin receptor, low molecular weight compounds having affinity for the thrombopoietin receptor have been reported (for example, patent document 5 to patent document 26).
1) Applications filed by Hokuriku Seiyaku Co., Ltd. relating to 1,4-benzodiazepine derivatives (patent documents 5 and 6)
2) International Laid-open Patent Applications filed by Shionogi & Co., Ltd. (patent documents 7-10)
3) International Laid-open Patent Applications filed by SmithKline Beecham Corp (patent documents 11-19)
4) Japanese Laid-open Patent Application filed by Torii Pharmaceutical Co., Ltd. (patent document 20)
5) International Laid-open Patent Application filed by Roche Diagnostics GMBH (patent document 21)
6) International Laid-open Patent Application filed by Yamanouchi Pharmaceutical Co., Ltd. (patent document 22 and 23)
7) Japanese Laid-open Patent Application filed by Japan Tabacco Inc. (patent document 24)
8) Japanese Laid-open Patent Applications filed by Nissan Chemical Industries, Ltd. (patent documents 25 and 26)
Patent document 1 JP-A-10-72492
Patent document 2 WO96/40750
Patent document 3 WO96/40189
Patent document 4 WO98/25965
Patent document 5 JP-A-11-1477
Patent document 6 JP-A-11-152276
Patent document 7 WO01/07423
Patent document 8 WO01/53267
Patent document 9 WO02/059099
Patent document 10 WO02/059100
Patent document 11 WO00/35446
Patent document 12 WO00/66112
Patent document 13 WO01/34585
Patent document 14 WO01/17349
Patent document 15 WO01/39773
Patent document 16 WO01/21180
Patent document 17 WO01/89457
Patent document 18 WO02/49413
Patent document 19 WO02/085343
Patent document 20 JP-A-2001-97948
Patent document 21 WO99/11262
Patent document 22 WO02/062775
Patent document 23 WO03/062233
Patent document 24 JP-A-2003-238565
Patent document 25 WO04/033433
Patent document 26 WO04/108683
Non-patent document 1 Microvasc. Res., 1999: 58, p.108-113
Non-patent document 2 Circ. Res., 1999: 84, p.785-796
Non-patent document 3 Blood 2001:98, p.71a-72a

DISCLOSURE OF THE INVENTION
Thrombopoietin and low molecular weight peptides having affinity for the thrombopoietin receptor are likely to be easily degraded in the gastrointestinal tract and are usually difficult to orally administer. As to thrombopoietin itself, the appearance of anti-thrombopoietin antibodies have been reported.
Besides, though it is probably possible to orally administer nonpeptidic low molecular weight compounds, no practical drugs have been put on the market.
Therefore, orally administrable low molecular weight compounds having excellent affinity for and agonistic action on the thrombopoietin receptor as preventive, therapeutic and improving agents for diseases against which activation of the thrombopoietin receptor is effective have been demanded. Specifically, low molecular weight compounds which can serve as platelet increasing agents or increasing agents for other blood cells by stimulating differentiation and proliferation of hematopoietic stem cells, megakaryocytic progenitor cells and megakaryocytes or low molecular weight compounds which can be used for therapeutic angiogenesis or as preventive and therapeutic agents for arteriosclerosis by stimulating endothelial cells and endothelial progenitor cells have been demanded.
The present inventors conducted extensive research to find low molecular weight compounds having affinity for and agonistic action on the thrombopoietin receptor, and as a result, found that the compounds of the present invention have high affinity and agonistic action which enable them to show potent platelet increasing action by stimulating differentiation and proliferation of megakaryocytic progenitor cells and megakaryocytes. The present invention was accomplished on the basis of this discovery.
Namely, the present invention relates to:
1. A compound represented by the formula (1)

wherein A is a nitrogen atom or CR4 (wherein R4 is a hydrogen atom, a hydroxyl group (the hydroxyl group may be substituted with a C2?6 alkenyl group or a C2?6 alkynyl group), a thiol group (the thiol group may be substituted with a C1?10 alkyl group, a C2?6 alkenyl group, a C2?6 alkynyl group or a C1?10 alkylcarbonyl group), an amino group (the amino group may be substituted with one or two C2?6 alkenyl groups or one or two C2?6 alkynyl groups), a formyl group, a halogen atom, a nitro group, a cyano group, a C1?10 alkyl group, a C2?6 alkenyl group, a C2?6 alkynyl group, a C1?10 alkylcarbonylamino group, a mono- or di-C1?10 alkylamino group, a C1?10 alkoxy group (the C1?10 alkyl group, the C2?6 alkenyl group, the C2?6 alkynyl group, the C1?10 alkylcarbonylamino group, the mono- or di-C1?10 alkylamino group and the C1?10 alkoxy group may be optionally substituted with one or more substituents selected from the group consisting of carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups (the C2?14 aryl groups and the C2?14 aryloxy groups may be substituted with one or more C1?6 alkyl groups (the C1?6 alkyl groups may be substituted with one or more halogen atoms) or one or more halogen atoms)), a C2?14 aryl group (the C2?14 aryl group may be optionally substituted with one or more substituents selected from the group consisting of C1?10 alkyl groups (the C1?10 alkyl groups may be substituted with one or more halogen atoms), C2?6 alkenyl groups, C2?6 alkynyl groups, carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups), a C2?14 aryloxy group (the C2?14 aryloxy group may be optionally substituted with one or more substituents selected from the group consisting of C1?10 alkyl groups (the C1?10 alkyl groups may be substituted with one or more halogen atoms), C2?6 alkenyl groups, C2?6 alkynyl groups, carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups), SO2R5, SOR5 or COR5 (wherein R5 is a hydroxyl group, a C1?10 alkyl group, a C2?6 alkenyl group, a C2?6 alkynyl group, a C2-9 heterocyclic group, a C1?10 alkoxy group (the C1?10 alkyl group, the C2?6 alkenyl group, the C2?6 alkynyl group, the C2-9 heterocyclic group and the C1?10 alkoxy group may be optionally substituted with one or more substituents selected from the group consisting of carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups (the C2?14 aryl groups and the C2?14 aryloxy groups may be substituted with one or more C1?6 alkyl groups (the C1?6 alkyl groups may be substituted with one or more halogen atoms) or one or more halogen atoms)), a C2?14 aryl group (the C2?14 aryl group may be optionally substituted with one or more substituents selected from the group consisting of C1?10 alkyl groups (the C1?10 alkyl groups may be substituted with one or more halogen atoms), C2?6 alkenyl groups, C2?6 alkynyl groups, carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups), a C2?14 aryloxy group (the C2?14 aryloxy group may be optionally substituted with one or more substituents selected from the group consisting of C1?10 alkyl groups (the C1?10 alkyl groups may be substituted with one or more halogen atoms), C2?6 alkenyl groups, C2?6 alkynyl groups, carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups) or NR6R7 (wherein each of R6 and R7 is independently a hydrogen atom, a hydroxyl group, a formyl group, a C1?10 alkyl group, a C2?6 alkenyl group, a C2?6 alkynyl group, a C1?10 alkylcarbonyloxy group, a C1?10 alkoxycarbonyl group, a C1?10 alkylcarbonyl group (the C1?10 alkyl group, the C2?6 alkenyl group, the C2?6 alkynyl group, the C1?10 alkylcarbonyloxy group, the C1?10 alkoxycarbonyl group and the C1?10 alkylcarbonyl group may be optionally substituted with one or more substituents selected from the group consisting of carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups (the C2?14 aryl groups and the C2?14 aryloxy groups may be substituted with one or more C1?6 alkyl groups (the C1?6 alkyl groups may be substituted with one or more halogen atoms) or one or more halogen atoms)) or a C2?14 aryl group (the C2?14 aryl group may be optionally substituted with one or more substituents selected from the group consisting of C1?10 alkyl groups (the C1?10 alkyl groups may be substituted with one or more halogen atoms), C2?6 alkenyl groups, C2?6 alkynyl groups, carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups), or R6 and R7 mean, together with each other, ?(CH2)m1-E-(CH2)m2- (wherein E is an oxygen atom, a sulfur atom, CR26R27 (wherein each of R26 and R27 is independently a hydrogen atom, a C1?10 alkyl group, a C2?14 aryl group, a C1?10 alkoxy group, a C2?14 aryloxy group, a hydroxyl group or a protected hydroxyl group) or NR8 (wherein R8 is a hydrogen atom, a hydroxyl group, a formyl group, a C1?10 alkyl group, a C2?6 alkenyl group, a C2?6 alkynyl group, a C1?10 alkoxy group, a C1?10 alkylcarbonyloxy group, a C1?10 alkoxycarbonyl group, a C1?10 alkylcarbonyl group (the C1?10 alkyl group, the C2?6 alkenyl group, the C2?6 alkynyl group, the C1?10 alkoxy group, the C1?10 alkylcarbonyloxy group, the C1?10 alkoxycarbonyl group and the C1?10 alkylcarbonyl group may be optionally substituted with one or more substituents selected from the group consisting of carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups (the C2?14 aryl groups and the C2?14 aryloxy groups may be substituted with one or more C1?6 alkyl groups (the C1?6 alkyl groups may be substituted with one or more halogen atoms) or one or more halogen atoms)) or a C2?14 aryl group (the C2?14 aryl group may be optionally substituted with one or more substituents selected from the group consisting of C1?10 alkyl groups (the C1?10 alkyl groups may be substituted with one or more halogen atoms), C2?6 alkenyl groups, C2?6 alkynyl groups, carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups)), and each of m1 and m2 is independently an integer of from 0 to 5 provided that m1+m2 is 3, 4 or 5)))),
B is an oxygen atom, a sulfur atom or NR9 (wherein R9 is a hydrogen atom, a hydroxyl group, a formyl group, a C1?10 alkyl group, a C2?6 alkenyl group, a C2?6 alkynyl group, a C1?10 alkoxy group, a C1?10 alkylcarbonyloxy group, a C1?10 alkoxycarbonyl group, a C1?10 alkylcarbonyl group (the C1?10 alkyl group, the C2?6 alkenyl group, the C2?6 alkynyl group, the C1?10 alkoxy group, the C1?10 alkylcarbonyloxy group, the C1?10 alkoxycarbonyl group and the C1?10 alkylcarbonyl group may be optionally substituted with one or more substituents selected from the group consisting of carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups (the C2?14 aryl groups and the C2?14 aryloxy groups may be substituted with one or more C1?6 alkyl groups (the C1?6 alkyl groups may be substituted with one or more halogen atoms) or one or more halogen atoms)), a C2?14 aryl group (the C2?14 aryl group may be optionally substituted with one or more substituents selected from the group consisting of C1?10 alkyl groups (the C1?10 alkyl groups may be substituted with one or more halogen atoms), C2?6 alkenyl groups, C2?6 alkynyl groups, carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups) or a C2?14 aryloxy group (the C2?14 aryloxy group may be optionally substituted with one or more substituents selected from the group consisting of C1?10 alkyl groups (the C1?10 alkyl groups may be substituted with one or more halogen atoms), C2?6 alkenyl groups, C2?6 alkynyl groups, carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups)) (provided that when A is a nitrogen atom, B is not NH),
R1 is a C2?14 aryl group (the C2?14 aryl group may be substituted with one or more substituents selected from the group consisting of halogen atoms, carboxyl groups, nitro groups, formyl groups, cyano groups, hydroxyl groups, protected hydroxyl groups, C1?10 alkyl groups, C2?6 alkenyl groups, C2?6 alkynyl groups, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups (the C1?10 alkyl groups, the C2?6 alkenyl groups, the C2?6 alkynyl groups, the C1?10 alkoxy groups, the C1?10 alkylcarbonyl groups, the C1?10 alkylcarbonyloxy groups and the C1?10 alkoxycarbonyl groups may be optionally substituted with one or more substituents selected from the group consisting of carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups (the C2?14 aryl groups and the C2?14 aryloxy groups may be substituted with one or more C1?6 alkyl groups (the C1?6 alkyl groups may be substituted with one or more halogen atoms) or one or more halogen atoms)), C2?14 aryl groups (the C2?14 aryl groups may be optionally substituted with one or more substituents selected from the group consisting of C1?10 alkyl groups (the C1?10 alkyl groups may be substituted with one or more halogen atoms), C2?6 alkenyl groups, C2?6 alkynyl groups, carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups), thiol groups and amino groups (the thiol groups and the amino groups may be optionally substituted with one or two substituents selected from the group consisting of formyl groups, C1?10 alkyl groups, C2?6 alkenyl groups, C2?6 alkynyl groups and C1?10 alkylcarbonyl groups (the C1?10 alkyl groups, the C2?6 alkenyl groups, the C2?6 alkynyl groups and the C1?10 alkylcarbonyl groups may be optionally substituted with one or more substituents selected from the group consisting of carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups (the C2?14 aryl groups and the C2?14 aryloxy groups may be substituted with one or more C1?6 alkyl groups (the C1?6 alkyl groups may be substituted with one or more halogen atoms) or one or more halogen atoms)))),
L1 is a bond, CR10R11 (wherein each of R10 and R11 is independently a hydrogen atom or a C1?6 alkyl group (the C1?6 alkyl group may be substituted with one or more halogen atoms)), an oxygen atom, a sulfur atom or NR12 (wherein R12 is a hydrogen atom, a hydroxyl group, a formyl group, a C1?10 alkyl group, a C2?6 alkenyl group, a C2?6 alkynyl group, a C1?10 alkoxy group, a C1?10 alkylcarbonyloxy group, a C1?10 alkoxycarbonyl group, a C1?10 alkylcarbonyl group (the C1?10 alkyl group, the C2?6 alkenyl group, the C2?6 alkynyl group, the C1?10 alkoxy group, the C1?10 alkylcarbonyloxy group, the C1?10 alkoxycarbonyl group and the C1?10 alkylcarbonyl group may be optionally substituted with one or more substituents selected from the group consisting of carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups (the C2?14 aryl groups and the C2?14 aryloxy groups may be substituted with one or more C1?6 alkyl groups (the C1?6 alkyl groups may be substituted with one or more halogen atoms) or one or more halogen atoms)) or a C2?14 aryl group (the C2?14 aryl group may be optionally substituted with one or more substituents selected from the group consisting of C1?10 alkyl groups (the C1?10 alkyl groups may be substituted with one or more halogen atoms), C2?6 alkenyl groups, C2?6 alkynyl groups, carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups)),
X is OR13, SR13 or NR14R15 (wherein R13 is a hydrogen atom, a C1?10 alkyl group, a C2?6 alkenyl group, a C2?6 alkynyl group or a C1?10 alkylcarbonyl group (the C1?10 alkyl group, the C2?6 alkenyl group, the C2?6 alkynyl group and the C1?10 alkylcarbonyl group may be optionally substituted with one or more substituents selected from the group consisting of carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups (the C2?14 aryl groups and the C2?14 aryloxy groups may be substituted with one or more C1?6 alkyl groups (the C1?6 alkyl groups may be substituted with one or more halogen atoms) or one or more halogen atoms)), and each of R14 and R15 is independently a hydrogen atom, a formyl group, a C1?10 alkyl group, a C2?6 alkenyl group, a C2?6 alkynyl group, a C1?10 alkoxy group, a C1?10 alkylcarbonyl group (the C1?10 alkyl group, the C2?6 alkenyl group, the C2?6 alkynyl group, the C1?10 alkoxy group and the C1?10 alkylcarbonyl group may be optionally substituted with one or more substituents selected from the group consisting of carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups (the C2?14 aryl groups and the C2?14 aryloxy groups may be substituted with one or more C1?6 alkyl groups (the C1?6 alkyl groups may be substituted with one or more halogen atoms) or one or more halogen atoms)) or a C2?14 aryl group (the C2?14 aryl group may be optionally substituted with one or more substituents selected from the group consisting of C1?10 alkyl groups (the C1?10 alkyl groups may be substituted with one or more halogen atoms), C2?6 alkenyl groups, C2?6 alkynyl groups, carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups)),
R2 is a hydrogen atom, a formyl group, a C1?10 alkyl group, a C2?6 alkenyl group, a C2?6 alkynyl group, a C1?10 alkoxy group, a C1?10 alkylcarbonyl group (the C1?10 alkyl group, the C2?6 alkenyl group, the C2?6 alkynyl group, the C1?10 alkoxy group and the C1?10 alkylcarbonyl group may be optionally substituted with one or more substituents selected from the group consisting of carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups (the C2?14 aryl groups and the C2?14 aryloxy groups may be substituted with one or more C1?6 alkyl groups (the C1?6 alkyl groups may be substituted with one or more halogen atoms) or one or more halogen atoms)) or a C2?14 aryl group (the C2?14 aryl group may be optionally substituted with one or more substituents selected from the group consisting of C1?10 alkyl groups (the C1?10 alkyl groups may be substituted with one or more halogen atoms), C2?6 alkenyl groups, C2?6 alkynyl groups, carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups),
L2 is a bond, CR34R35 (wherein each of R34 and R35 is independently a hydrogen atom or a C1?6 alkyl group (the C1?6 alkyl group may be substituted with one or more halogen atoms)), an oxygen atom, a sulfur atom or NR16 (wherein R16 is a hydrogen atom, a hydroxyl group, a formyl group, a C1?10 alkyl group, a C2?6 alkenyl group, a C2?6 alkynyl group, a C1?10 alkoxy group, a C1?10 alkylcarbonyloxy group, a C1?10 alkoxycarbonyl group, a C1?10 alkylcarbonyl group (the C1?10 alkyl group, the C2?6 alkenyl group, the C2?6 alkynyl group, the C1?10 alkoxy group, the C1?10 alkylcarbonyloxy group, the C1?10 alkoxycarbonyl group and the C1?10 alkylcarbonyl group may be optionally substituted with one or more substituents selected from the group consisting of carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups (the C2?14 aryl groups and the C2?14 aryloxy groups may be substituted with one or more C1?6 alkyl groups (the C1?6 alkyl groups may be substituted with one or more halogen atoms) or one or more halogen atoms)) or a C2?14 aryl group (the C2?14 aryl group may be optionally substituted with one or more substituents selected from the group consisting of C1?10 alkyl groups (the C1?10 alkyl groups may be substituted with one or more halogen atoms), C2?6 alkenyl groups, C2?6 alkynyl groups, carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups)),
L3 is a bond, CR17R18 (wherein each of R17 and R18 is independently a hydrogen atom, a C1?10 alkyl group, a C2?6 alkenyl group, a C2?6 alkynyl group, a C1?10 alkoxy group, a C1?10 alkylcarbonyl group (the C1?10 alkyl group, the C2?6 alkenyl group, the C2?6 alkynyl group, the C1?10 alkoxy group and the C1?10 alkylcarbonyl group may be optionally substituted with one or more substituents selected from the group consisting of carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups (the C2?14 aryl groups and the C2?14 aryloxy groups may be substituted with one or more C1?6 alkyl groups (the C1?6 alkyl groups may be substituted with one or more halogen atoms) or one or more halogen atoms)) or a C2?14 aryl group (the C2?14 aryl group may be optionally substituted with one or more substituents selected from the group consisting of C1?10 alkyl groups (the C1?10 alkyl groups may be substituted with one or more halogen atoms), C2?6 alkenyl groups, C2?6 alkynyl groups, carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups)), an oxygen atom, a sulfur atom or NR19 (wherein R19 is a hydrogen atom, a hydroxyl group, a formyl group, a C1?10 alkyl group, a C2?6 alkenyl group, a C2?6 alkynyl group, a C1?10 alkoxy group, a C1?10 alkylcarbonyloxy group, a C1?10 alkoxycarbonyl group, a C1?10 alkylcarbonyl group (the C1?10 alkyl group, the C2?6 alkenyl group, the C2?6 alkynyl group, the C1?10 alkylcarbonyloxy group, the C1?10 alkoxycarbonyl group, the C1?10 alkoxy group and the C1?10 alkylcarbonyl group may be optionally substituted with one or more substituents selected from the group consisting of carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups (the C2?14 aryl groups and the C2?14 aryloxy groups may be substituted with one or more C1?6 alkyl groups (the C1?6 alkyl groups may be substituted with one or more halogen atoms) or one or more halogen atoms)) or a C2?14 aryl group (the C2?14 aryl group may be optionally substituted with one or more substituents selected from the group consisting of C1?10 alkyl groups (the C1?10 alkyl groups may be substituted with one or more halogen atoms), C2?6 alkenyl groups, C2?6 alkynyl groups, carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups)),
Y is an oxygen atom, a sulfur atom or NR23 (wherein R23 is a hydrogen atom, a hydroxyl group, a formyl group, a C1?10 alkyl group, a C2?6 alkenyl group, a C2?6 alkynyl group, a C1?10 alkoxy group, a C1?10 alkylcarbonyloxy group, a C1?10 alkoxycarbonyl group, a C1?10 alkylcarbonyl group (the C1?10 alkyl group, the C2?6 alkenyl group, the C2?6 alkynyl group, the C1?10 alkoxy group, the C1?10 alkylcarbonyloxy group, the C1?10 alkoxycarbonyl group and the C1?10 alkylcarbonyl group may be optionally substituted with one or more substituents selected from the group consisting of carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups (the C2?14 aryl groups and the C2?14 aryloxy groups may be substituted with one or more C1?6 alkyl groups (the C1?6 alkyl groups may be substituted with one or more halogen atoms) or one or more halogen atoms)) or a C2?14 aryl group (the C2?14 aryl group may be substituted with one or more substituents selected from the group consisting of C1?10 alkyl groups (the C1?10 alkyl groups may be substituted with one or more halogen atoms), C2?6 alkenyl groups, C2?6 alkynyl groups, carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups)),
L4 is a bond, CR20R21 (wherein each of R20 and R21 is independently a hydrogen atom, a C1?10 alkyl group, a C2?6 alkenyl group, a C2?6 alkynyl group, a C1?10 alkoxy group, a C1?10 alkylcarbonyl group (the C1?10 alkyl group, the C2?6 alkenyl group, the C2?6 alkynyl group, the C1?10 alkoxy group and the C1?10 alkylcarbonyl group may be optionally substituted with one or more substituents selected from the group consisting of carboxyl groups, nitro groups, cyano groups, halogen atoms, C1?10 alkoxy groups, C1?10 alkylcarbonyl groups, C1?10 alkylcarbonyloxy groups, C1?10 alkoxycarbonyl groups, C1?10 alkylcarbonylamino groups, amino groups, mono- or di-C1?10 alkylamino groups, hydroxyl groups, protected hydroxyl groups, C2?14 aryl groups and C2?14 aryloxy groups (the C2?14 aryl groups and the C2?14 aryloxy groups may be substituted with one or more C1?6 alkyl groups (the C1?6 alkyl groups may be substituted with one or more halogen atoms) or one or more halogen atoms)) or a C2?14 aryl group (the C2?14 aryl group may be

A compound represented by the formula (1): wherein A, B, R1, L1, R2, L2, L3, Y, L4, R3 and X are the same as defined in the description, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.

3-ETHYLIDENEHYDRAZINO SUBSTITUTED HETEROCYCLIC COMPOUNDS AS THROMBOPOIETIN RECEPTOR ACTIVATORS

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