Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
  • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D495/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
  • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/4355—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having oxygen as a ring hetero atom
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/04—Ortho-condensed systems
  • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
  • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered

Definitions

• the present invention relates to novel tricyclic quinone derivatives useful as medicament or a pharmacologically acceptable salt thereof. More particularly, the invention relates to pharmaceutical compositions comprising a novel tricyclic quinone derivative or a pharmacologically acceptable salt thereof. The invention relates to therapeutic agents comprising a novel tricyclic quinone derivative comprising the compound, or a pharmacologically acceptable salt thereof.
• Cancer develops when abnormality in gene occurs by an action of radiation, ultra violet rays, carcinogen, virus, or the like. The number of deaths by cancer increases year by year, and cancer is currently the top cause of death in Japan.
• antitumor agents surgical operation, radiotherapy, immunotherapy, and the like are performed.
• Major antitumor agents act on any of metabolism, DNA synthesis, RNA synthesis, or protein synthesis of a nucleic acid precursor.
• such metabolic processes occur in not only cancer cells, but also normal cells. Therefore, many antitumor agents act on not only on cancer cells, but also on normal cells, and consequently any types of side effects develop.
• molecular targeting agent is a pharmaceutical agent designed to target a molecule specifically expressed in each cancer. Therefore, it is believed that a molecular targeting agent has higher specificity to cancer cells than conventional antitumor agents, and has fewer side effects.
• molecular targeting agents although previous side effects are reduced, there are problems that new side effects are exhibited and alternatives of pharmaceutical agents are limited.
• the aforementioned antitumor agents were clinically used for the purpose of cancer therapy and prolonging the life of a cancer patients, there are still a number of unsolved problems including problems of side effects and the like as described above. Accordingly, it is recognized that the development of a novel antitumor agent is an important topic in the future.
• CSC cancer stem cells
• Non Patent Literature 1 One of the characteristics of CSCs is to have replication competence. Reliable methods established as a method of measuring replication competence of a cell include measurement of cancer cell sphere-forming ability in non-adhesion state in the absence of serum (Non Patent Literature 2). A compound that inhibits not only the proliferation of a non-CSC cancer cell, but also cancer cell sphere-forming ability is possibly very useful as a novel antitumor agent.
• Non Patent Literature 2 describes the following compounds as quinone derivatives isolated from the extract of a plant of the Tabebuia genus in the Bignoniaceae family.
• R 1 , R 2 , and R 3 are hydrogen atoms; R 1 and R 3 are H, R 2 is a hydroxyl group; R 1 is a hydroxyl group, R 2 and R 3 and hydrogen atoms; R 1 and R 2 and hydrogen atoms, and R 3 is COCH 3 ; or R 1 and R 2 are hydrogen atoms, R 3 is COC(CF 3 )(OCH 3 )C 6 H 5 .] It also discloses that these compounds have antitumor activity.
• Patent Literature 1 describes the following compound having antitumor activity and cancer cell sphere-forming ability.
• R 1 is a hydrogen atom, a halogen atom, a cyano group, a nitro group, a trifluoromethyl group, a trifluoromethoxy group, an optionally substituted alkyl group, or the like
• R 3 is a hydrogen atom, a cyano group, an optionally substituted alkyl group, or the like
• R 7 is a hydrogen atom, a halogen atom, a cyano group, a nitro group, an optionally substituted alkyl group, or the like
• n is 1 to 4, with the proviso that when R 3 is not an amino group, R 7 is not a hydrogen atom and at least one of R 1 and R 7 is a halogen atom, or an optionally substituted aryl group.
• Patent Literature 2 describes the following compound having antitumor activity.
• R 1 , R 2 , R 3 , R 4 , and R 5 are the same as or different from one another, and are a hydrogen atom, an alkyl group, an alkenyl group, an aryl group, or a substituent having a nitrogen atom, an oxygen atom, a sulfur atom, a phosphorus atom, or a halogen atom.
• Patent Literature 3 describes the following compound having antifungal activity.
• R 1 is a nitro group, an amino group, a cyano group, an alkyl group, a halogen atom, or the like
• R 2 is a hydrogen atom, a halogen atom, a short-chain alkyl group, a substituted aryl group, a methacrylate group, or the like
• the ring A is pyridine, isoxazole, or aryl.
• Non Patent Literature 3 describes the following compounds having antitumor activity.
• Non Patent Literatures 5 and 6 and Patent Literatures 1-3 describes any specific compound represented by formula (1) of the present invention.
• the problem of the present invention is to provide significantly useful compound as a novel antitumor agent by providing a compound that is targeted to CSC, which is important in continuous proliferation of a malignant tumor, metastasis and recurrence of cancer, and its resistance to an antitumor agent, and the compound inhibits not only the proliferation of non-CSC cancer cell but also cancer cell sphere-forming ability.
• the present inventors focused on quinone derivatives, and intensively studied with regard to their antitumor activities to find that a compound represented by the following formula (1) or a pharmacologically acceptable salt thereof (hereinafter also referred to as “the present compound”) has excellent effects on the inhibition of the proliferation of a cancer cell and cancer cell sphere-forming ability, and is significantly useful as a novel antitumor agent.
• the present inventors finally reached the completion of the present invention.
• the present invention is as described below.
• Item 1 A compound represented by formula (1) or a pharmacologically acceptable salt thereof:
• A is O, S, or N—R 6 ;
• the ring G is a 5- or 6-membered aromatic ring that contains one to three heteroatoms consisting of O, S, and N as constituent atoms;
• R 1 is each independently a hydrogen atom, a halogen atom, a cyano group, an optionally substituted 3- to 8-membered cyclic amino group, an optionally substituted C 1-6 alkyl group (with the proviso that an unsubstituted methyl group, and a C 1-6 alkyl group substituted with one dimethyl amino group or one chlorine atom are excluded), an optionally substituted C 3-10 cycloalkyl group, an optionally substituted C 1-6 alkenyl group, an optionally substituted C 1-6 alkynyl group, an optionally substituted C 6-10 aryl group, an optionally substituted 5- to 12-membered monocyclic or polycyclic heterocyclic group, an optionally substituted C 1-6 alkylcarbonyl group, an optionally substituted C 3-10 cycloalkylcarbony
• Item 2 The compound according to item 1 or a pharmacologically acceptable salt thereof, wherein A is S.
• Item 3 The compound according to item 1 or a pharmacologically acceptable salt thereof, wherein A is O.
• Item 4 The compound according to item 1 or a pharmacologically acceptable salt thereof, wherein A is N—R 6 .
• Item 5 The compound according to any one of items 1-4 or a pharmacologically acceptable salt thereof, wherein the ring G is of any formula selected from the group consisting of the following formulas (a) to (l):
• Item 6 The compound according to item 5 or a pharmacologically acceptable salt thereof, wherein the ring G is of any formula selected from the group consisting of the following formulas (a) to (h):
• Item 7 The compound according to item 6 or a pharmacologically acceptable salt thereof, wherein the ring G is of any formula selected from the group consisting of the following formulas (a) to (f):
• Item 8 The compound according to item 7 or a pharmacologically acceptable salt thereof, wherein the ring G is of any formula selected from the group consisting of the following formulas (b) or (e):
• Item 9 The compound according to any one of items 1-8 or a pharmacologically acceptable salt thereof, wherein R 1 is a group selected from the group consisting of: 1: a hydrogen atom; 2: a cyano group; 3: a C 1-6 alkyl group (wherein the alkyl is optionally substituted with one to three groups selected from the group consisting of a fluorine atom, hydroxy, C 1-6 alkoxy, C 3-10 cycloalkyl, C 6-10 aryl, and 3- to 8-membered cyclic amino); 4: a C 1-6 alkylcarbonyl group (wherein the alkyl is optionally substituted with one to three groups selected from the group consisting of a halogen atom, hydroxy, amino (which is optionally substituted with one or two C 1-6 alkyl groups), C 1-6 alkoxy, C 3-10 cycloalkyl, C 6-10 aryl, and a 5- to 12-membered monocyclic or polycyclic heterocycle (which
• Item 10 The compound according to item 9 or a pharmacologically acceptable salt thereof, wherein R 1 is a hydrogen atom or a C 1-6 alkylcarbonyl group (wherein the alkyl is optionally substituted with 3- to 8-membered cyclic amino).
• Item 11 The compound according to any one of items 1-10 or a pharmacologically acceptable salt thereof, wherein R 2 is a group selected from the group consisting of: 1: a hydrogen atom; 2: a halogen atom; 3: a cyano group; 4: an amino group (wherein the amino is substituted with one or two groups selected from the group consisting of (a) C 1-6 alkyl (wherein the alkyl is optionally substituted with one to three groups selected from the group consisting of a halogen atom, hydroxy, C 1-4 alkoxy, C 6-10 aryl, and a 5- to 12-membered monocyclic or polycyclic heterocycle (which is optionally substituted with one to three C 1-6 alkyl)), (b) C 1-6 alkylcarbonyl (wherein the alkyl is optionally substituted with one to three groups selected from the group consisting of a halogen atom, hydroxy, C 1-4 alkoxy, C 6-10 aryl, and a 5- to
• Item 12 The compound according to any one of items 1-11 or a pharmacologically acceptable salt thereof, wherein R 2 is a group selected from the group consisting of: 1: a hydrogen atom; 2: a halogen atom; 3: a cyano group; 4: an amino group (wherein the amino is substituted with one or two groups selected from the group consisting of (a) C 1-6 alkyl (wherein the alkyl is optionally substituted with one to three groups selected from the group consisting of a halogen atom, hydroxy, C 1-4 alkoxy, C 6-10 aryl, and a 5- to 12-membered monocyclic or polycyclic heterocycle (which is optionally substituted with one to three C 1-6 alkyl)), (b) C 1-6 alkylcarbonyl (wherein the alkyl is optionally substituted with one to three groups selected from the group consisting of a halogen atom, hydroxy, C 1-4 alkoxy, C 6-10 aryl, and a 5- to
• Item 13 The compound according to any one of items 1-11 or a pharmacologically acceptable salt thereof, wherein R 2 is a group selected from the group consisting of: 1: a hydrogen atom; 2: a halogen atom; 3: a cyano group; 4: an amino group (wherein the amino is optionally substituted with one to three C 1-6 alkyl groups); 5: a 3- to 8-membered cyclic amino group (wherein the cyclic amino is optionally substituted with one to three C 1-6 alkyl); 6: a C 1-6 alkyl group (wherein the alkyl is optionally substituted with one to three groups selected from the group consisting of (a) a halogen atom, (b) hydroxy, (c) amino (wherein the amino is optionally substituted with one or two groups selected from the group consisting of (i) C 1-6 alkyl (wherein the alkyl is optionally substituted with one to three groups selected from the group consisting of a halogen atom,
• Item 14 The compound according to item 13 or a pharmacologically acceptable salt thereof, wherein R 2 is a group selected from the group consisting of: 1: a C 1-6 alkyl group (wherein the alkyl is optionally substituted with one to three groups selected from the group consisting of a halogen atom, hydroxy, amino (which is optionally substituted with one or two C 1-6 alkyl groups), C 1-4 alkoxy, C 3-8 cycloalkyl, phenyl, and a 5- to 6-membered monocyclic heterocycle); 2: a C 1-6 alkylcarbonyl group (wherein the alkyl is optionally substituted with one to three groups selected from the group consisting of a halogen atom, hydroxy, amino (which is optionally substituted with one or two C 1-6 alkyl groups), C 1-4 alkoxy, C 3-8 cycloalkyl, phenyl, and a 5- to 6-membered monocyclic heterocycle (which is optionally substituted with one
• Item 15 The compound according to any one of items 1-14 or a pharmacologically acceptable salt thereof, wherein R 3 , R 4 , or R 5 is each independently a group selected from the group consisting of: 1: a hydrogen atom; 2: a halogen atom; 3: a cyano group; 4: a hydroxyl group; 5: an amino group (wherein the amino is optionally substituted with one or two groups selected from the group consisting of (a) C 1-6 alkyl (wherein the alkyl is optionally substituted with one to three groups selected from the group consisting of a halogen atom, hydroxy, C 1-4 alkoxy, C 6-10 aryl, and a 5- to 12-membered monocyclic or polycyclic heterocycle (which is optionally substituted with one to three C 1-6 alkyl)), (b) C 1-6 alkylcarbonyl (wherein the alkyl is optionally substituted with one to three groups selected from the group consisting of a halogen atom,
• Item 16 The compound according to item 15 or a pharmacologically acceptable salt thereof, wherein R 3 , R 4 , or R 5 is each independently a group selected from the group consisting of: 1: a hydrogen atom; 2: a halogen atom; 3: a cyano group; 4: a hydroxyl group; 5: an amino group (wherein the amino is optionally substituted with one or two groups selected from the group consisting of (a) C 1-6 alkyl (wherein the alkyl is optionally substituted with one to three groups selected from the group consisting of a halogen atom, hydroxy, C 1-4 alkoxy, C 6-10 aryl, and a 5- to 12-membered monocyclic or polycyclic heterocycle (which is optionally substituted with one to three C 1-6 alkyl)), (b) C 1-6 alkylcarbonyl (wherein the alkyl is optionally substituted with one to three groups selected from the group consisting of a halogen atom, hydroxy, C
• Item 17 The compound according to item 16 or a pharmacologically acceptable salt thereof, wherein R 3 , R 4 , or R 5 is all hydrogen atoms.
• Item 18 The compound according to any one of item 1 or 4-17 or a pharmacologically acceptable salt thereof, wherein R 6 is a group selected from the group consisting of: 1: a hydrogen atom; 2: a C 1-6 alkyl group (wherein the alkyl is optionally substituted with one to three groups selected from the group consisting of a halogen atom, C 1-6 alkoxy, C 6-10 aryl, and a 5- to 6-membered monocyclic heterocycle (which is optionally substituted with one to three C 1-4 alkyl)); 3: a C 3-10 cycloalkyl group (wherein the cycloalkyl is optionally substituted with one to three groups selected from the group consisting of a halogen atom, hydroxy, C 1-6 alkyl, and C 1-6 alkoxy); 4:
• Item 19 The compound according to item 18 or a pharmacologically acceptable salt thereof, wherein R 6 is a group selected from the group consisting of: 1: a hydrogen atom; 2: a C 1-6 alkyl group (wherein the alkyl is optionally substituted with one to three groups selected from the group consisting of a halogen atom, C 1-6 alkoxy, C 6-10 aryl, and a 5- to 6-membered monocyclic heterocycle (which is optionally substituted with one to three C 1-4 alkyl)); 3: a C 1-6 alkylcarbonyl group (wherein the alkyl is optionally substituted with one to three groups selected from the group consisting of a halogen atom, C 1-6 alkoxy, C 6-10 aryl, and a 5- to 6-membered monocyclic heterocycle (which is optionally substituted with one to three C 1-4 alkyl)); and 4: a C 1-6 alkylsulfonyl group (wherein the alkyl is
• Item 20 The compound according to item 19 or a pharmacologically acceptable salt thereof, wherein R 6 is a hydrogen atom.
• Item 21 The compound according to items 1-20 or a pharmacologically acceptable salt thereof, wherein R 2 is a group selected from the group consisting of: 1: a C 1-6 alkyl group (wherein the alkyl is optionally substituted with one to three groups selected from the group consisting of a halogen atom, hydroxy, amino (which is optionally substituted with one or two C 1-6 alkyl groups), C 1-4 alkoxy, C 3-8 cycloalkyl, and a 5- to 6-membered monocyclic heterocycle); 2: a C 1-6 alkylcarbonyl group; 3: an aminocarbonyl group (wherein the amino is optionally substituted with one to three C 1-6 alkyl groups (wherein the alkyl is optionally substituted with one to three halogen atoms)); and 4: a 3- to 8-membered cyclic amino
• A is O or S
• the ring G is either one selected from the group consisting of the following formula (b) or (e):
• R 1 is a hydrogen atom
• R 2 is a group selected from the group consisting of: 1: a C 1-6 alkyl group (wherein the alkyl is optionally substituted with one to three groups selected from the group consisting of a halogen atom, hydroxy, amino (which is optionally substituted with one or two C 1-6 alkyl groups), C 1-4 alkoxy, C 3-8 cycloalkyl, and a 5- to 6-membered monocyclic heterocycle); 2: a C 1-6 alkylcarbonyl group; 3: an aminocarbonyl group (wherein the amino is optionally substituted with one to three C 1-6 alkyl groups (wherein the alkyl is optionally substituted with one to three halogen atoms)); and 4: a 3- to 8-membered cyclic aminocarbonyl group (wherein the cyclic amino is optionally substituted with one to three C 1-6 alkyl).
• R 3 , R 4 , and R 5 are hydrogen atoms. I
• R 1 , R 2 , R 3 , R 4 , and R 5 are defined as in above item 1, wherein the method is characterized by comprising a step of mixing a compound represented by formula (2) or a salt thereof:
• R 7 and R 8 are each C 1-6 alkyl (wherein the alkyl is optionally substituted with one to three groups selected from the group consisting of a halogen atom, hydroxy, C 1-4 alkoxy, C 6-10 aryl, and a 5- to 12-membered monocyclic or polycyclic heterocycle (which is optionally substituted with one to three C 1-6 alkyl)), with an oxidant.
• Item 34 A method of producing a compound represented by formula (1) or a pharmacologically acceptable salt thereof:
• R 1 , R 2 , R 3 , R 4 , and R 5 are defined as in above item 1, and wherein the method is characterized by comprising a step of mixing a compound represented by formula (2) or a salt thereof:
• R 1 , R 2 , R 3 , R 4 , and R 5 are defined as in above item 1, or R 1 and R 2 are optionally substituted alkoxycarbonyl groups, and R 7 and R 8 are each C 1-6 alkyl (wherein the alkyl is optionally substituted with one to three groups selected from the group consisting of a halogen atom, hydroxy, C 1-4 alkoxy, C 6-10 aryl, and a 5- to 12-membered monocyclic or polycyclic heterocycle (which is optionally substituted with one to three C 1-6 alkyl)), with an oxidant.
• Item 35 A compound represented by the following formula (2) or a salt thereof:
• R 7 and R 8 are each C 1-6 alkyl (wherein the alkyl is optionally substituted with one to three groups selected from the group consisting of a halogen atom, hydroxy, C 1-4 alkoxy, C 6-10 aryl, and a 5- to 12-membered monocyclic or polycyclic heterocycle (which is optionally substituted with one to three C 1-6 alkyl)).
• the compounds represented by the formula (1) or the pharmacologically acceptable salts thereof exhibit strong inhibitory effects on proliferation of a cancer cell and cancer cell sphere-forming ability, and these compounds are useful, for example, as medicament to be effective in prevention and/or treatment of cancer.
• the number of substituents of a group defined by “an optionally substituted” or “substituted” is not particularly limited if it is substitutable, and is one or plural.
• the description for each group is also applied when the group is one part of or a substituent on other groups.
• halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Preferably, it is a fluorine atom or a chlorine atom.
• a “C 1-6 alkyl group” means a linear or branched, saturated hydrocarbon group of which the carbon number is one to six. Preferably, it includes a “C 1-4 alkyl group” and the like. Specific examples of the “C 1-6 alkyl group” include, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 2-methylpropyl, 1-methylpropyl, 1,1-dimethylethyl, pentyl, 3-methylbutyl, 2-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, 1,1-dimethylpropyl, hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, and the like.
• C 1-4 alkyl group examples include those having a carbon number from 1 to 4 that are exemplified in the specific examples of “C 1-10 alkyl group”.
• C 1-6 represents that the carbon number is one to six
• C 1-4 represents that the carbon number is one to four
• C 6 represents that the carbon number is six. The same applies to cases of other numbers.
• C 2-6 alkenyl group means a linear or branched, unsaturated hydrocarbon group that has two to six carbons and contains one to three double bonds.
• Specific examples of “C 2-6 alkenyl group” include, for example, vinyl, propenyl, methylpropenyl, butenyl, methylbutenyl, pentenyl, hexenyl, and the like.
• C 2-6 alkynyl group means a linear or branched, unsaturated hydrocarbon group that has two to six carbons and contains one triple bond.
• Specific examples of “C 2-6 alkynyl group” include, for example, propynyl, methylpropynyl, butynyl, methylbutynyl, pentynyl, hexynyl, and the like.
• a “C 3-10 cycloalkyl group” means a cyclic saturated hydrocarbon group of which the carbon number is three to ten, and also includes those having a partially crosslinked structure. Preferably, it includes a “C 3-7 cycloalkyl group” and the like. Specific examples of “C 3-10 cycloalkyl group” include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantyl, and the like.
• C 3-7 cycloalkyl group examples include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
• the “C 3-10 cycloalkyl group” also encompasses a compound fused to an aromatic ring. Specific examples thereof include, for example, groups represented by the following:
• C 1-6 alkoxy group refers to a “C 1-6 alkyloxy group” and the “C 1-6 alkyl” moiety in a “C 1-6 alkoxy group” is defined the same as the above-described “C 1-6 alkyl”.
• the “C 1-6 alkoxy group” includes, preferably, a “C 1-4 alkoxy group” and the like.
• C 1-6 alkoxy group examples include, for example, methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 2-methylpropoxy, 1-methylpropoxy, 1,1-dimethylethoxy, pentyloxy, 3-methylbutoxy, 2-methylbutoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, 1,1-dimethylpropoxy, hexyloxy, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 1-methylpentyloxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, and the like.
• C 3-10 cycloalkyl moiety in a “C 3-10 cycloalkyloxy group” is defined the same as the above described “C 3-10 cycloalkyl group”. Preferably, it is a “C 3-7 cycloalkyloxy group” and the like.
• Examples of “C 3-10 cycloalkyloxy group” include, for example, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and the like.
• the “C 1-6 alkyl” moiety in a “C 1-6 alkylcarbonyl group” is defined the same as the above-described “C 1-6 alkyl group”.
• the “C 1-6 alkylcarbonyl group” includes, preferably, a “C 1-4 alkylcarbonyl group” and the like.
• Specific examples of “C 1-6 alkylcarbonyl group” include, for example, methylcarbonyl, ethylcarbonyl, propylcarbonyl, 1-methylethylcarbonyl, butylcarbonyl, 2-methylpropylcarbonyl, 1-methylpropylcarbonyl, 1,1-dimethylethylcarbonyl, and the like.
• C 3-10 cycloalkyl moiety in a “C 3-10 cycloalkylcarbonyl group” is defined the same as the above described “C 3-10 cycloalkyl group”. Preferably, it is a “C 3-7 cycloalkylcarbonyl group” and the like. Specific examples of “C 3-10 cycloalkylcarbonyl group” include, for example, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl, and the like.
• the “C 1-6 alkylcarbonyl” moiety in a “C 1-6 alkylcarbonyloxy group” is defined the same as the above-described “C 1-6 alkylcarbonyl group”.
• the “C 1-6 alkylcarbonyloxy group” includes, preferably, a “C 1-4 alkylcarbonyloxy group” and the like. Specific examples of “C 1-6 alkylcarbonyloxy group” include methylcarbonyloxy, ethylcarbonyloxy, propylcarbonyloxy, 1-methylethylcarbonyloxy, butylcarbonyloxy, 2-methylpropylcarbonyloxy, 1-methylpropylcarbonyloxy, 1,1-dimethylethylcarbonyloxy, and the like.
• C 1-6 alkylcarbonyl moiety in a “C 1-6 alkylcarbonylamino group” is defined the same as the above-described “C 1-6 alkylcarbonyl group”.
• Specific examples of “C 1-6 alkylcarbonylamino group” include, for example, methylcarbonylamino, ethylcarbonylamino, and the like.
• C 1-6 alkyl moiety in a “C 1-6 alkylthio group” is defined the same as the above-described “C 1-6 alkyl group”.
• the “C 1-6 alkylthio group” includes, preferably, “C 1-4 alkylthio group” and the like.
• Specific examples of “C 1-6 alkylthio group” include, for example, methylthio, ethylthio, propylthio, 1-methylethylthio, butylthio, 2-methylpropylthio, 1-methylpropylthio, 1,1-dimethylethylthio, and the like.
• C 3-10 cycloalkyl moiety in a “C 3-10 cycloalkylthio group” is defined the same as the above-described “C 3-10 cycloalkyl group”. Preferably, it is a “C 3-7 cycloalkylthio group” and the like. Specific examples of “C 3-10 cycloalkylthio group” include, for example, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, cycloheptylthio, and the like.
• C 1-6 alkyl moiety in a “C 1-6 alkylsulfinyl group” is defined the same as the above-described “C 1-6 alkyl group”.
• the “C 1-6 alkylsulfinyl group” includes, preferably, “C 1-4 alkylsulfinyl group” and the like.
• C 1-6 alkylsulfinyl group include, for example, methylsulfinyl, ethylsulfinyl, propylsulfinyl, 1-methylethylsulfinyl, butylsulfinyl, 2-methylpropylsulfinyl, 1-methylpropylsulfinyl, 1,1-dimethylethylsulfinyl, and the like.
• C 3-10 cycloalkyl moiety in a “C 3-10 cycloalkylsulfinyl group” is defined the same as the above-described “C 3-10 cycloalkyl group”. Preferably, it is a “C 3-7 cycloalkylsulfinyl group” and the like.
• Specific examples of “C 3-10 cycloalkylsulfinyl group” include, for example, cyclopropylsulfinyl, cyclobutylsulfinyl, cyclopentylsulfinyl, cyclohexylsulfinyl, cycloheptylsulfinyl, and the like.
• C 1-6 alkyl moiety in a “C 1-6 alkylsulfonyl group” is defined the same as the above-described “C 1-6 alkyl group”. Preferably, it includes a “C 1-4 alkylsulfonyl group” and the like. Specific examples of “C 1-6 alkylsulfonyl group” include, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, pentylsulfonyl, hexylsulfonyl, and the like.
• C 3-10 cycloalkyl moiety in a “C 3-10 cycloalkylsulfonyl group” is defined the same as the above-described “C 3-10 cycloalkyl group”. Preferably, it is a “C 3-7 cycloalkylsulfonyl group” and the like.
• Specific examples of “C 3-10 cycloalkylsulfonyl group” include, for example, cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl, cyclohexylsulfonyl, cycloheptylsulfonyl, and the like.
• C 1-6 alkoxy moiety in a “C 1-6 alkoxycarbonyl group” is defined the same as the above-described “C 1-6 alkoxy group”.
• Specific examples of “C 1-6 alkoxycarbonyl group” include, for example, methoxycarbonyl, ethoxycarbonyl, and the like.
• an “alkoxycarbonyl group” may be referred to as an “alkyloxycarbonyl group”, the two are synonymous.
• C 3-10 cycloalkyl moiety in a “C 3-10 cycloalkyloxycarbonyl group” is defined the same as the above-described “C 3-10 cycloalkyl group”. Preferably, it is a “C 3-7 cycloalkyloxycarbonyl group” and the like.
• Specific examples of “C 3-10 cycloalkyloxycarbonyl group” include, for example, cyclopropyloxycarbonyl, cyclobutyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, cycloheptyloxycarbonyl, and the like.
• C 6-10 aryl group means an aromatic hydrocarbon of which the carbon number is six to ten.
• Specific examples of “C 6-10 aryl group” include, for example, phenyl, 1-naphthyl, 2-naphthyl, and the like. Particularly preferably, it includes a phenyl group.
• the “C 6-10 aryl group” also encompasses a 8- to 14-membered polycyclic group in which an aromatic ring and a C 4-6 cycloalkyl are ring-fused, or 9- to 14-membered polycyclic group in which an aromatic ring is fused to, for example, 5- to 6-membered heterocyclic group having one to three atoms that are identical or different and are selected from a nitrogen atom, an oxygen atom, or a sulfur atom.
• Specific examples thereof include, for example, groups represented by the following:
• heterocyclic group examples include 3- to 10-membered heterocyclic group having one to three atoms that are identical or different and are selected from a nitrogen atom, an oxygen atom, or a sulfur atom, and the like. Preferably, it is a 4- to 7-membered group, more preferably, a 5- or 6-membered group. All the aforementioned nitrogen atom, oxygen atom, and sulfur atom are atoms constituting a ring.
• the heterocyclic group may be any of saturated, partially unsaturated, or unsaturated heterocyclic groups, and a saturated heterocyclic group is more preferred.
• heterocyclic group examples include epoxy, aziridine, azetidine, pyranyl, tetrahydrofuryl, pyrrolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, hexamethyleneiminyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, oxoimidazolidinyl, dioxoimidazolidinyl, oxooxazolidinyl, dioxooxazolidinyl, dioxothiazolidinyl, tetrahydrofuranyl, tetrahydropyridinyl, oxetanyl, tetrahydropyranyl, and the like.
• the group encompasses heterocyclic groups having a bridge structure.
• a bond on the “group” cannot be from a nitrogen atom constituting a ring. That is, the group does not encompass the concept of, for example, a 1-pyrrolidino group and the like.
• heterocyclic group may form a fused ring with a 6-membered aromatic hydrocarbon or a 6-membered heteroaryl.
• examples thereof include a bicyclic “heterocycle” having eleven or twelve ring-constituting atoms, wherein the foregoing 5- or 6-membered “heterocyclic ring” is fused to a 6-membered aromatic hydrocarbon or a 6-membered heteroaryl.
• the 6-membered aromatic hydrocarbon include benzene and the like.
• a 6-membered unsaturated heterocyclic group include pyridine, pyrimidine, pyridazine, and the like.
• fused ring examples include dihydroindolyl, dihydroisoindolyl, dihydropurinyl, dihydrothiazolopyrimidinyl, dihydrobenzodioxanyl, isoindolyl, indazolyl, pyrrolidinyl, tetrahydroquinolinyl, decahydroquinolinyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, tetrahydronaphthyridinyl, tetrahydropyridoazepinyl, and the like.
• Examples of a “saturated heterocyclic group” include a 5- to 10-membered monocyclic or polycyclic group and the like.
• the group contains one or more (e.g., one to four) heteroatoms that are identical or different and are selected from a nitrogen atom, a sulfur atom, or an oxygen atom.
• examples thereof include a 5- or 6-membered monocyclic heteroaryl group, and the like.
• heteroaryl group examples include, for example, pyrrolyl, thienyl, benzothienyl, benzofuranyl, benzoxazolyl, benzothiazolyl, furyl, oxazolyl, triazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, benzisoxazolyl, benzisothiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrazyl, pyrimidyl, pyridazyl, quinolyl, isoquinolyl, triazolyl, triazinyl, tetrazolyl, indolyl, imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, [1,2,4]triazolo[1,5-a]pyridyl, benzimidazolyl, quinoxalyl,
• heterocycle moiety in a “heterocyclyloxy group” is defined the same as the above-described “heterocyclic group”. It is preferably 4- to 7-membered, and more preferably 5- or 6-membered. Specific examples thereof include a 4-pyranyloxy group and the like.
• heterocycle moiety in a “heterocyclylthio group” is defined the same as the above-described “heterocyclic group”. It is preferably 4- to 7-membered, and more preferably 5- or 6-membered. Specific examples thereof include a 4-pyranylthio group and the like.
• heterocycle moiety in a “heterocyclyloxycarbonyl group” is defined the same as the above-described “heterocyclic group”. It is preferably 4- to 7-membered, and more preferably 5- or 6-membered. Specific examples thereof include a pyranyloxycarbonyl group and the like.
• heterocycle moiety in a “heterocyclylsulfinyl group” is defined the same as the above-described “heterocyclic group”.
• It is preferably 4- to 7-membered, and more preferably 5- or 6-membered. Specific examples thereof include a pyranylsulfinyl group and the like.
• heterocycle moiety in a “heterocyclylsulfonyl group” is defined the same as the above-described “heterocyclic group”. It is preferably 4- to 7-membered, and more preferably 5- or 6-membered. Specific examples thereof include a pyranylsulfonyl group and the like.
• C 6-10 aryl moiety in a “C 6-10 aryloxy group” is defined the same as the above-described “C 6-10 aryl group”. It preferably includes a “C 6 aryloxy group” (phenoxy group). Specific groups thereof include, for example, phenoxy, 1-naphthoxy, 2-naphthoxy, and the like.
• C 6-10 aryl moiety in a “C 6-10 arylthio group” is defined the same as the above-described “C 6-10 aryl group”. It includes preferably a “C 6 arylthio group”. Specific examples thereof include, for example, phenylthio, 1-naphthylthio, 2-naphthylthio, and the like.
• a “C 6-10 arylcarbonyl group” means a group having the above-described “C 6-10 aryl group” bound with a carbonyl group.
• the “C 6-10 aryl” moiety is defined the same as the above-described “C 6-10 aryl group”. It preferably includes a “C 6 arylcarbonyl group” (a phenylcarbonyl group).
• Specific examples of the “C 6-10 arylcarbonyl group” include, for example, benzoyl, 1-naphthoyl, 2-naphthoyl, and the like.
• C 6-10 aryl moiety in a “C 6-10 arylsulfinyl group” is defined the same as the above-described “C 6-10 aryl group”. It preferably includes a “C 6 arylsulfinyl group”. Specific examples thereof include, for example, phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl, and the like.
• C 6-10 aryl moiety in a “C 6-10 arylsulfonyl group” is defined the same as the above-described “C 6-10 aryl group”. It preferably includes a “C 6 arylsulfonyl group”. Specific examples thereof include, for example, phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl, and the like.
• a “C 6-10 aryloxycarbonyl group” means a group having the above-described “C 6-10 aryloxy group” bound to a carbonyl group. It preferably includes a “C 6 aryloxycarbonyl group” (a phenyloxycarbonyl group). Specific examples of the “C 6-10 aryloxycarbonyl group” include, for example, phenoxycarbonyl, 1-naphthoxycarbonyl, 2-naphthoxycarbonyl, and the like.
• an optionally substituted amino group examples include amino, mono- or di-substituted amino.
• Examples of the “mono- or di-substituted amino” include “C 1-6 alkyl”, “C 3-10 cycloalkyl”, “C 3-10 cycloalkyl C 1-4 alkyl”, “C 3-7 cycloalkyl C 1-4 alkoxycarbonyl”, “C 1-4 alkylcarbonyl”, “C 1-4 alkoxycarbonyl”, “a 4- to 7-membered saturated heterocycle”, “4- to 7-membered saturated heterocyclyl C 1-4 alkyl”, “4- to 7-membered saturated heterocyclyl carbonyl”, “4- to 7-membered saturated heterocyclyloxycarbonyl”, “4- to 7-membered saturated heterocyclyl C 1-4 alkylcarbonyl”, “C 6-10 aryl”, “C 7-14 aralkyl”, “C 6-10 arylcarbonyl”, “C 6-10 aryloxycarbonyl”, “5- or 6-membered monocyclic heteroaryl”, “5- or 6-membere
• “mono-substituted amino” include, for example, “mono-C 1-6 alkylamino” (e.g., methylamino, ethylamino, propylamino, 1-methylethylamino, butylamino, 2-methylpropylamino, 1-methylpropylamino, 1,1-dimethylethylamino, and the like);
• C 3-8 cycloalkylamino (e.g., cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, cycloheptylamino, and the like); “(C 3-8 cycloalkylC 1-4 alkyl)amino” (e.g., cyclopropylmethylamino, cyclobutylmethylamino, cyclopentylmethylamino, cyclohexylmethylamino, cycloheptylmethylamino, and the like); “(C 3-8 cycloalkylC 1-4 alkoxycarbonyl)amino” (e.g., cyclopropoxycarbonylamino, cyclobutoxycarbonylamino, cyclopentoxycarbonylamino, cyclohexyloxycarbonylamino, cycloheptyloxycarbonylamino, and the like);
• di-substituted amino examples include, for example,
• di-C 1-6 alkylamino e.g., dimethylamino, diethylamino, dipropylamino, di-1-methylethylamino, dibutylamino, di-2-methylpropylamino, di-1-methylpropylamino, di-1,1-dimethylethylamino, and the like
• N—(C 1-6 alkyl)-N—(C 3-10 cycloalkyl)amino e.g., methylcyclopropylamino, methylcyclobutylamino, methylcyclopentylamino, methylcyclohexylamino, methylcycloheptylamino, and the like
• N—(C 1-6 alkyl)-N-(4- to 7-membered saturated heterocyclyl)amino e.g., methyltetrahydropyranylamino, methyltetrahydropyridinylamino,
• Examples of the “3- to 8-membered cyclic amino” include 3- to 8-membered monocyclic cyclic amino having one to three heteroatoms that are identical or different and are selected from a nitrogen atom, an oxygen atom, or a sulfur atom. It is preferably a 5- to 6-membered monocyclic cyclic amino group. In the “3- to 8-membered cyclic amino”, a bond on the “group” will be from a nitrogen atom constituting a ring.
• the “3- to 8-membered cyclic amino” include, for example, azetidino, pyrrolidino, imidazolidino, oxazolidino, thiazolidino, piperazino, piperidino, morpholino, thiomorpholino, azepano, oxoazepano, and the like. It is noted that the group encompasses cyclic amino of which the ring contains a partially unsaturated bond.
• the “3- to 8-membered cyclic amino” or “5- or 6-membered cyclic amino” may form a fused ring with C 3-6 cycloalkyl, 6-membered aromatic hydrocarbon, or a 5- or 6-membered heterocycle.
• Specific examples of cyclic amino forming such a fused ring include “groups” represented by the following:
• aminocarbonyl group means a group having the above-described “amino group” bound to a carbonyl group.
• amino means an unsubstituted amino group, a mono-substituted amino group, a di-substituted amino group, or 3- to 8-membered cyclic amino.
• aminosulfinyl group means a group having the above-described “amino group” bound to a sulfinyl group.
• amino means an unsubstituted amino group, a mono-substituted amino group, a di-substituted amino group, or 3- to 8-membered cyclic amino.
• aminosulfonyl group means a group having the above-described “amino group” bound to a carbonyl group.
• amino is an unsubstituted amino group, a mono-substituted amino group, a di-substituted amino group, or 3- to 8-membered cyclic amino.
• aminocarbonyl moiety in an “aminocarbonyloxy group” is defined the same as the above-described “aminocarbonyl group”.
• C 1-6 alkylaminocarbonyl group means a group that is the above-described “mono- or di-substituted amino” in which the amino group substituted with one or two C 1-6 alkyl is bound to a carbonyl group.
• C 1-6 alkylaminocarbonyl moiety of a “C 1-6 alkylaminocarbonylamino group” is defined the same as the above-described “C 1-6 alkylaminocarbonyl group”.
• Examples of a substituent of “an optionally substituted C 1-6 alkyl group” include:
• formula (1) is an isomer having a relationship with the following formula (1′) between an oxidant and a reductant that can attain equilibrium. They can be considered as being synonymous.
• A is an oxygen atom or a sulfur atom.
• ring G is the following formulas (a) to (h):
• ring G is the following formulas (a) to (f):
• ring G is the following formulas (a) to (d):
• ring G is the following formula (e) or (f):
• R 1 is a hydrogen atom or a C 1-6 alkylcarbonyl group (wherein the alkyl is optionally substituted with 3- to 8-membered cyclic amino).
• R 2 is a hydrogen atom.
• R 6 is a hydrogen atom.
• Preferred embodiments of the present invention encompass compounds represented by the following formulas (1a) to (1p).
• a “pharmacologically acceptable salt” includes acid addition salts and base addition salts.
• acid addition salts include: inorganic acid salts such as hydrochlorides, hydrobromides, sulfates, hydroiodides, nitrates, phosphates, and the like; and organic acid salts such as citrate, oxalate, phthalate, fumarate, maleate, succinate, malate, acetate, formate, propionate, benzoate, trifluoroacetate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, and the like; and examples of base addition salts include inorganic base salts such as sodium, potassium, calcium, magnesium, barium, and aluminum salts, and the like, organic base salts such as trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine,
• Suitable salts and pharmaceutically acceptable salts of starting compounds and target compounds are conventional nontoxic salts. They include acid addition salts such as organic acid salts (e.g., acetate, trifluoroacetate, maleate, fumarate, citrate, tartrate, methanesulfonate, benzenesulfonate, formate, p-toluenesulfonate, or the like) and inorganic acid salts (e.g., hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, or the like), salts with an amino acid (e.g., arginine, aspartic acid, glutamic acid, or the like), metal salts such as alkali metal salts (e.g., sodium salt, potassium salt, or the like), alkali earth metal salts (e.g., calcium salt, magnesium salt, or the like), and the like, ammonium salts, organic base salts (e.g.,
• the present compound when it is desired to obtain a salt of the present compound, if the present compound is obtained in a salt form, it may be purified as it is, or if it is obtained in free form, it may be dissolved or suspended in a suitable organic solvent, and an acid or a base is added thereto to form a salt in accordance with a general method.
• present compounds and pharmacologically acceptable salts thereof may exist in an adduct form with water or any kind of solvent, these adducts are also encompassed by the present invention.
• the present invention encompasses compounds represented by formula (1) or prodrugs thereof, or pharmacologically acceptable salts thereof. It also encompasses hydrates or solvates (such as ethanol solvates and the like) thereof. Further, the present invention encompasses all tautomers and all present stereoisomers of the present compound (1) as well as those in all modes of crystal forms.
• a prodrug of a compound of formula (1) in the present specification means a compound that is converted to a compound of formula (1) by reaction with an enzyme, gastric acid, or the like under physiological condition in vivo, for example, a compound that is converted to a compound of formula (1) by enzymatic oxidation, reduction, hydrolysis, or the like.
• the present compounds (1) there are compounds that may exist as enantiomers based on an optically-active center, atropisomers based on axial or planar chirality caused by restriction of intramolecular rotation, other stereoisomers, tautomers, geometric isomer, and the like.
• all possible isomers and mixtures thereof, including these, are encompassed within the scope of the present invention.
• an enantiomer and an atropisomer can be obtained as a racemic body, or an optically-active substance when an optically-active starting material or intermediate is used, respectively.
• a corresponding starting material, intermediate, or racemic body as a final product can be physically or chemically resolved into their optical enantiomers by a known separation method, such as a method using an optically active column, a fractional crystallization method, or the like.
• a diastereomer method two types of diastereomers are formed from a racemic body by reaction using an optical active resolving agent. Since these different diastereomers generally have different physical properties, they can be separated by a known method such as fractional crystallization and the like.
• a compound of the present invention represented by formula (1) or a salt thereof can be produced from a known compound, for example, the following production methods: Methods 1 to 14, and methods in accordance therewith, or by appropriately combining synthesis methods well-known to those skilled in the art.
• a compound in a reaction includes the case where it forms a salt, for example, salts similar to salts in compound (1) and the like are used as such a salt.
• a compound obtained in each step can be used in a next reaction as a reaction solution or as a composition.
• it can be isolated from a reaction mixture in accordance with a routine method, and readily purified by a separation means such as recrystallization, distillation, chromatography, and the like.
• Compound (1-2) can be produced by reacting it, in solvent in the presence of an oxidant, with (1-1) obtained by a known synthesis method or the following production method.
• Organic solvent includes aprotic solvent (N,N-dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, acetonitrile, propionitrile, and the like), ether type solvent (tetrahydrofuran, 1,4-dioxane, and the like), halogenated hydrocarbons (dichloromethane, chloroform, 1,2-dichloroethane, chlorobenzene, and the like), hydrocarbons (toluene, benzene, and the like), water, mixed solvents thereof, and the like, and suitably a mixed solvent of acetonitrile and water.
• aprotic solvent N,N-dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, acetonitrile,
• oxidants metal type oxidants [osmium tetraoxide, potassium permanganate, silver(II) picolinate, ammonium hexanitratocerate(IV), benzeneseleninic acid, bis(4-methoxyphenyl) selenoxide, bis(tetrabutylammonium) dichromate, lead tetraacetate, phosphomolybdic acid hydrate, pyridinium chlorochromate, pyridinium dichromate, pyridinium fluorochromate, quinolinium dichromate, silver(II) pyridine-2-carboxylate, tetrapropylammonium perruthenate, and the like], hypervalent iodine oxidants [(2-iodoxybenzoic acid, Dess-Martin periodinane, 1-(tert-butylperoxy)-1,2-benziodoxol-3-(1H)-one, bis(pyridine)io
• the amount of an oxidant used is, generally, 2 to 10 mol, preferably, to 3 mol per mol of compound (1-1).
• a reaction time is, generally, about 0.5 to about 48 hours, preferably, about 0.5 to about 12 hours.
• a reaction temperature is, generally, about ⁇ 20 to about 180° C., preferably, about 0 to about 100° C.
• R 9 is C 1-6 alkyl.
• This step 1 can produce compound (2-3) from compound (2-1) in accordance with a similar method to methods and the like described in literature [for example, Heterocycles, 1913, vol. 75, (2008), Journal of Medicinal Chemistry, 1819, vol. 53, (2010), Journal of the Chilean Chemical Society, 14, vol. 54, (2009), Molecules, 1388, vol. 17, (2012), Bioorganic & Medicinal Chemistry Letters, 4961, vol. 15, (2005), Synlett, 670, vol. 5, (2001), and the like].
• a solvent used in this step 1 may be any solvent as long as it is inactive in the reaction, and although it is not particularly limited, for example, THF, 1,4-dioxane, DME, benzene, toluene, xylene, DMF, DMA, NMP, and the like can be used alone or after mixing them. Among others, THF or DMF is preferred.
• basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, sodium hydride, calcium hydride, and the like, aromatic amines such as pyridine, lutidine, and the like, tertiary amines such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-diisopropylethylamine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, and the like can be used.
• potassium carbonate or sodium hydride is preferred.
• a reaction is performed from at a temperature between room temperature and the boiling point of a solvent used, preferably, 0 to 80° C., generally, for 0.5 to 24 hours.
• This step 1 can produce compound (3-3) from compound (3-1) in accordance with a similar method to methods and the like described in literature [for example, Tetrahedron, 12227, vol. 55, (1999), Journal of Organic Chemistry, 4692, vol. 76, (2011), Journal of Heterocyclic Chemistry, 683, vol. 49, (2012), and the like].
• R 1 , R 2 , R 7 , R 8 , and A are defined the same as above.
• This step 1 can produce compound (4-2) and compound (4-3) from compound (4-1) in accordance with a similar method to methods and the like described in literature [for example, Organic Letters, 2157, vol. 7, (2005), Journal of Medicinal Chemistry, 7574, vol. 56, (2013), Bioorganic & Medicinal Chemistry Letters, 138, vol. 22, (2012), Khimiya Geterotsiklicheskikh Soedinenii, 27, vol. 1, (1980), and the like].
• R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , and A are defined the same as above.
• steps (1 to 3) can produce compound (5-4) from compound (4-2) in accordance with similar methods to methods and the like described in literature [for example, Bioorganic & Medicinal Chemistry Letters, 806, vol. 22, 2012 Journal of Medicinal Chemistry, 7574, vol. 56, (2013), Khimiya Geterotsiklicheskikh Soedinenii, 27, vol. 1, (1980), Synlett, 1781, vol. 11, (2009), Tetrahedron Letters, 5452, vol. 52, (2011), Bulletin of the Chemical Society of Japan, 891, vol. 70, (1997), Synlett, 116, vol. 1, (2011), Tetrahedron, 4612, vol. 69, (2013), Tetrahedron Letters, 5145, vol. 52, (2011), Chemistry Letters, 1422, vol. 36, (2007), European Journal of Organic Chemistry, 4039, vol. 19, (2004), Tetrahedron, 2755, vol. 64, (2008), and the like].
• literature for example, Bioorganic & Medicinal Chemistry Letters, 806, vol. 22,
• R 1 , R 2 , R 7 , R 8 , and A are defined the same as above.
• This step can produce compound (6-1) and compound (6-2) from compound (4-1) in accordance with a similar method to methods and the like described in literature [for example, Physiological Zoology, 312, vol. 36, (1963), European Journal of Medicinal Chemistry, 4827, vol. 46, (2011), Synthetic Metals, 2491, vol. 159, (2009), Journal of the American Chemical Society, 4466, vol. 132, (2010), Bulletin of the Chemical Society of Japan, 4464, vol. 61, (1988), and the like].
• R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 , and A are defined the same as above.
• R 10 is C 1-6 alkyl.
• steps (1 to 3) can produce compound (7-4) from compound (6-1) in accordance with similar methods to methods and the like described in literature [for example, Journal of Organic Chemistry, 5026, vol. 78, (2013), Tetrahedron, 5787, vol. 62, (2006), Tetrahedron Letters, 8527, vol. 38, (1997), Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 72, vol. 25B, (1986), and the like].
• R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , and A are defined the same as above.
• X represents a leaving group (e.g., a chlorine atom, a bromine atom, an iodine atom, methoxy, ethoxy, propoxy, butoxy, imidazole, pyrrole, optionally substituted phenoxy, and the like).
• steps (1 to 4) can produce compound (8-6) from compound (6-1) in accordance with similar methods to methods and the like described in literature [for example, Compt. Rend., 1265, vol. 120, (1895), Journal of Organic Chemistry, 1418, vol. 68, (2003), Journal of the American Chemical Society, 3554, vol. 77, (1955), Journal of Organic Chemistry, 2353, vol. 60, (1995), Journal of Organic Chemistry, 3742, vol. 46, (1981), Tetrahedron: Asymmetry, 1395, vol. 22, (2011), Journal of Medicinal Chemistry, 8287, vol. 53, (2010), Tetrahedron, 11020, vol. 64, (2008), Tetrahedron: Asymmetry, 2281, vol. 6, (1995), Journal of Organic Chemistry, 650, vol. 14, (1949), Polish Journal of Chemistry, 1317, vol. 75, (2001), and the like].
• R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , and A are defined the same as above.
• steps (1 to 2) can produce compound (9-3) from compound (4-3) in accordance with similar methods to methods and the like described in literature [for example, Bulletin of the Chemical Society of Japan, 891, vol. 70, (1997), Tetrahedron Letters, 1783, vol. 47, (2006), Tetrahedron, 1763, vol. 67, (2011), Tetrahedron Letters, 6869, vol. 50, (2009), Synlett, 449, vol. 3, (2004), Heterocycles, 2631, vol. 60, (2003), Tetrahedron, 3259, vol. 42, (1986), Journal of Medicinal Chemistry, 1832, vol. 28, (1985), and the like].
• R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , and A are defined the same as above.
• steps (1 to 3) can produce compound (10-4) from compound (4-1) in accordance with similar methods to methods and the like described in literature [for example, European Journal of Medicinal Chemistry, 611, vol. 24, (1989), Heterocycles, 1623, vol. 34, (1992), European Journal of Medicinal Chemistry, 611, vol. 24, (1989), Journal of Medicinal Chemistry, 614, vol. 33, (1990), Asian Journal of Chemistry, 5575, vol. 22, (2010), Journal of the American Chemical Society, 8227, vol. 135, (2013), Journal of Organic Chemistry, 2548, vol. 73, (2008), Journal of Organic Chemistry, 6599, vol. 72, (2007), Bioorganic & Medicinal Chemistry Letters, 3771, vol. 14, (2004), Russian Chemical Bulletin, 414, vol. 58, (2010), Collection of Czechoslovak Chemical Communications, 285, vol. 49, (1984), and the like].
• This step can produce compounds (11-2) and (11-3) from compound (11-1) in accordance with a similar method to methods and the like described in literature [for example, Physiological Zoology, 312, vol. 36, (1963), European Journal of Medicinal Chemistry, 4827, vol. 46, (2011), Synthetic Metals, 2491, vol. 159, (2009), Journal of the American Chemical Society, 4466, vol. 132, (2010), Bulletin of the Chemical Society of Japan, 4464, vol. 61, (1988), and the like].
• R 3 , R 4 , R 5 , R 7 , R 8 , R 9 , A, and G are defined the same as above.
• steps (1 to 2) can produce compound (12-3) from compound (11-2) in accordance with similar methods to methods and the like described in literature [for example, Organic Letters, 2157, vol. 7, (2005), Journal of Medicinal Chemistry, 7574, vol. 56, (2013), Bioorganic & Medicinal Chemistry Letters, 138, vol. 22, (2012), Khimiya Geterotsiklicheskikh Soedinenii, 27, vol. 1, (1980), Heterocycles, 1913, vol. 75, (2008), Journal of Medicinal Chemistry, 1819, vol. 53, (2010), Journal of the Chilean Chemical Society, 14, vol. 54, (2009), Molecules, 1388, vol. 17, (2012), Bioorganic & Medicinal Chemistry Letters, 4961, vol. 15, (2005), Synlett, 670, vol. 5, (2001), and the like].
• L 1 and L 2 represent hydrogen, a hydroxyl group, or a leaving group (e.g., a chlorine atom, a bromine atom, an iodine atom, methanesulfonyloxy, tri fluoromethanesulfonyloxy, p-toluenesulfonyloxy, or the like).
• a leaving group e.g., a chlorine atom, a bromine atom, an iodine atom, methanesulfonyloxy, tri fluoromethanesulfonyloxy, p-toluenesulfonyloxy, or the like.
• compound (10-3) can be produced by reacting, in an organic solvent in the presence of a base, (13-1) obtained as a commercially available product or in accordance with a known method [for example, Journal of Medicinal Chemistry, 1329, vol. 29, (1986), European Journal of Medicinal Chemistry, 3938, vol. 45, (2010), Bioorganic & Medicinal Chemistry Letters, 952, vol. 21, (2011), European Journal of Organic Chemistry, 4201, vol. 18, (2006), Journal of Organic Chemistry, 5026, vol. 78, (2013), and the like], with (13-2) obtained as a commercially available product or in accordance with a known synthesis method [for example, Bioorganic & Medicinal Chemistry, 5705, vol.
• Organic solvent includes aprotic solvent such as N,N-dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, and the like, ether type solvent such as tetrahydrofuran, 1,4-dioxane, and the like, halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, chlorobenzene, and the like, hydrocarbons such as toluene, benzene, and the like, mixed solvents thereof, and the like, and suitably N,N-dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, acetonitrile, and tetrahydrofuran.
• aprotic solvent such as N,N-dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, and the like
• ether type solvent such as tetrahydrofuran, 1,4-diox
• Organic bases include 1-hydroxybenzotriazole, N-methylmorpholine, triethylamine, diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[5.4.0]undec-7-ene, pyridine, dimethylaminopyridine, picoline, and the like.
• Inorganic bases include alkali halides such as potassium fluoride and the like, alkali hydroxide such as sodium hydroxide, potassium hydroxide, and the like, alkali carbonate such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, and the like, alkali alkoxide such as sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, and the like, alkali metal such as n-butyl lithium, methyl lithium, isopropylmagnesium bromide, and the like.
• the amount of compound (9-2) used is generally 1 to 5 mol, preferably, 1.2 to 3 mol per mol of compound (9-1).
• the amount of a base used is generally 2 to 10 mol, preferably, 2 to 3 mol per mol of compound (1-1).
• a reaction time is generally about 0.5 to about 48 hours, preferably, about 0.5 to about 12 hours.
• a reaction temperature is generally about ⁇ 20 to about 180° C., preferably, about 0 to about 150° C.
• R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , L 1 , L 2 , A, and G are defined the same as above.
• steps (1 to 3) can produce compound (14-6) from compound (13-1) in accordance with similar methods to methods and the like described in literature [for example, US2012/0077986A1 and the like].
• a target compound can be obtained by protecting any point other than the reaction point as necessary, and unprotecting after the reaction is finished or a series of reactions are performed.
• a protecting group a common protecting group such as those described in literature (e.g., Protective Groups in Organic Synthesis, 3 rd ed., T. W. Greene, John Wiley & Sons Inc. (1999), and the like) can be used.
• examples of a protecting group for an amino group can include benzyloxycarbonyl, tert-butoxycarbonyl, acetyl, benzyl, and the like
• examples of a protecting group for a hydroxyl group include trialkylsilyl groups such as trimethylsilyl, tert-butyldimethylsilyl, and the like, acetyl, benzyl, and the like, respectively.
• Introduction and removal of a protecting group can be performed by routine methods in synthetic organic chemistry (e.g., refer to Protective Groups in Organic Synthesis, described above) or methods in accordance therewith.
• intermediates or final products in the above-described production methods can be derived to other compounds encompassed by the present invention by appropriately converting a functional group thereof, and in particular, extend any kind of side chain using an amino group, a hydroxyl group, a carbonyl group, a halogen group, or the like as an aid, and at this time, as necessary, performing the above-described protection and deprotection.
• Conversion of a functional group and extension of a side chain can be performed by a routine, general method (refer to, e.g., Comprehensive Organic Transformations, R. C. Larock, John Wiley & Sons Inc. (1999), and the like).
• Intermediates and target compounds in the above-described respective production methods can be subjected to a routine purification method in synthetic organic chemistry, for example, neutralization, filtration, extraction, washing, drying, concentration, recrystallization, any kind of chromatography, and the like to isolate and purify it.
• the intermediates can be subjected to a next reaction without particular purification.
• the present compound is provided, for example, as an anticancer agent.
• the type of cancer to which it is applied is not limited, specific examples thereof include acute leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, polycythemia vera, malignant lymphoma, brain tumor, head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small-cell lung cancer, breast cancer, gastric cancer, gallbladder•bile duct cancer, hepatoma, pancreatic cancer, colon cancer, rectal cancer, chorioepithelioma, endometrial cancer, cervical cancer, urothelial cancer, renal cell cancer, testicular tumor, Wilms' tumor, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's sarcoma, and soft tissue sarcoma.
• Hematological cancer in the present invention is a concept encompassing lymphoma and leukemia, and has an effect to reduce or annihilate carcinoma or to inhibit the growth of carcinoma for the purposes of preventing/or treating cancer. It is noted that in the present invention, “prevention (preventing)” is an action to administer an active ingredient of the present invention to a healthy human that does not develop a disease, and a purpose thereof is, for example, to prevent the onset of a disease.
• Treatment (treating) is an action to administer an active ingredient of the present invention to a person (patient) diagnosed as developing a disease by a medical doctor, and a purpose thereof is, for example, to alleviate the disease and symptoms, to inhibit the growth of carcinoma, or to return it to a state prior to the onset of the disease.
• a purpose of administration is to prevent a disease or symptoms from deteriorating or carcinoma from growing, if it is administered to a patient, it is an action for therapy.
• the amount of the compound used varies depending on symptoms, age, administration method, and the like.
• oral administration it is desirable to administer to an adult 0.01 mg as the lower limit (preferably 1 mg) and 5000 mg as the upper limit (preferably 500 mg) once or in several batches daily depending on the symptoms.
• an effect is expected by administering to an adult 0.01 mg as the lower limit (preferably 0.1 mg) and 1000 mg as the upper limit (preferably 30 mg) once or in several batches daily depending on the symptoms.
• Examples of its administration schedule include single-dose administration, once a day administration for three days in a row, and the like. Further, each administration described above can be repeated at intervals of about 7 days to about 60 days.
• the present compound can be administered orally or parenterally (e.g., intravenous, subdermal, or intramuscular injection, ocular administration, transrectally, percutaneously, transnasally, or the like).
• parenterally e.g., intravenous, subdermal, or intramuscular injection, ocular administration, transrectally, percutaneously, transnasally, or the like.
• oral administration for example, tablets, capsules, pills, granules, powders, solutions, suspensions, and the like can be used.
• parenteral administration injections, eye drops, suppositories, patches, poultices, lotions, creams, and the like can be used.
• These preparations comprise the present compound and pharmacologically acceptable additives, and produced using conventional known techniques.
• the present compound can be formed into a preparation using a suitable dosage form, and administrated.
• suitable dosage form include, but are not limited to, tablets, capsules, powders, granules, solutions, suspensions, injections, patches, poultices, and the like.
• the preparation is produced by a known method using a pharmaceutically acceptable additive.
• excipients can be used in accordance with a purpose.
• specific examples thereof include lactose, mannitol, crystalline cellulose, low-substituted hydroxypropylcellulose, corn starch, partly pregelatinized starch, carmellose calcium, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, magnesium stearate, sodium stearyl fumarate, polyethylene glycol, propylene glycol, titanium oxide, talc, and the like.
• non-pharmacological therapy examples include surgery, radiotherapy, gene therapy, thermotherapy, cryotherapy, laser cauterization therapy, and the like. Two or more types of these also can be combined.
• the present compound can be used in combination with another drug for purpose of enhancing its effect.
• the present compound can be used in combination with a drug such as a hormonal therapeutic agent, a chemotherapeutic agent, an immunotherapeutic agent, or a cell growth factor, a pharmaceutical agent to inhibit its receptor activity, and the like.
• a drug that may be used in combination with the present compound is abbreviated to a combination drug.
• the present compound even when used as a single agent, exhibits excellent anticancer effect, and further the combination use with one or several of the above-described combination drugs (polypharmacy) can further enhance its effect or improve the QOL of a patient.
• hormoneal therapeutic agents include Fosfestrol, Diethylstilbestrol, Chlorotrianisene, Medroxyprogesterone acetate, Megestrol acetate, Chlormadinone acetate, Cyproterone acetate, Danazol, Dienogest, Asoprisnil, Allylestrenol, Gestrinone, Nomegestrol, Tadenan, Mepartricin, Raloxifene, Ormeloxifene, Levormeloxifene, antiestrogen (e.g., Tamoxifen citrate, Toremifene citrate, and the like), pill preparation, Mepitiostane, Testololactone, aminoglutethimide, LH-RH derivatives (LH-RH agonist (e.g., Goserelin acetate, Buserelin, Leuprorelin, and the like), LH-RH antagonist), Droloxifene, Epitiostanol,
• chemotherapeutic agents for example, alkylating agents, antimetabolites, anticancer antibiotics, plant-derived anticancer agents, other chemotherapeutic agents, and the like are used. Representative examples are described below.
• alkylating agents include Nitrogen mustard, Nitrogen mustard N-oxide hydrochloride, Chlorambucil, Cyclophosphamide, Ifosfamide, Thiotepa, Carboquone, Improsulfan tosylate, Busulfan, Nimustine hydrochloride, Mitobronitol, Melphalan, dacarbazine, Ranimustine, Estramustine phosphate sodium, Triethylenemelamine, Carmustine, Lomustine, Streptozocin, Pipobroman, Etoglucide, Carboplatin, Cisplatin, miriplatin, Nedaplatin, Oxaliplatin, Altretamine, Ambamustine, Dibrospidium chloride, Fotemustine, Prednimustine, Pumitepa, Ribomustin, Temozolomide, Treosulfan, Trofosfamide, Zinostatin stimalamer, Adozelesin, Cystemustine, Bizeles
• antimetabolites include Mercaptopurine, 6-Mercaptopurine riboside, Thioinosine, Methotrexate, Pemetrexed, Enocitabine, Cytarabine, Cytarabin ocfosfate, Ancitabine hydrochloride, 5-FU type pharmaceutical agent (e.g., Fluorouracil, Tegafur, UFT, Doxifluridine, Carmofur, Galocitabine, Emitefur, Capecitabine, and the like), Aminopterin, Nelarabine, Leucovorin calcium, tabloid, Butocin, calcium folinate, calcium levofolinate, Cladribine, Emitefur, Fludarabine, Gemcitabine, hydroxycarbamide, Pentostatin, Piritrexim, Idoxuridine, Mitoguazone, Tiazofurin, Ambamustine, Bendamustine, and DDS preparations thereof, and the like.
• 5-FU type pharmaceutical agent e.g., Fluorouracil, T
• anticancer antibiotics include Actinomycin D, Actinomycin C, Mitomycin C, Chromomycin A3, Bleomycin hydrochloride, Bleomycin sulfate, Peplomycin sulfate, Daunorubicin hydrochloride, Doxorubicin hydrochloride, Aclarubicin hydrochloride, Pirarubicin hydrochloride, Epirubicin hydrochloride, Neocarzinostatin, Mithramycin, Sarkomycin, Carzinophilin, Mitotane, Zorubicin hydrochloride, Mitoxantrone hydrochloride, Idarubicin hydrochloride, and DDS preparations thereof, and the like.
• plant-derived anticancer agents include Etoposide, Etoposide phosphate, Vinblastine sulfate, Vincristine sulfate, Vindesine sulfate, Teniposide, Paclitaxel, Docetaxel, DJ-927, Vinorelbine, Irinotecan, Topotecan, and DDS preparations thereof, and the like.
• immunotherapeutic agents include Picibanil, Krestin, Sizofiran, Lentinan, Ubenimex, interferon, interleukin, macrophage colony stimulating factor, granulocyte-colony stimulating factor, Erythropoietin, Lymphotoxin, BCG vaccine, Corynebacterium parvum , Levamisole, polysaccharide K, Procodazole, anti-CTLA4 antibody, PD-1 antibody, Toll-like Receptors agonist (e.g., TLR7 agonist, TLR8 agonist, TLR9 agonist, and the like).
• TLR7 agonist e.g., TLR7 agonist, TLR8 agonist, TLR9 agonist, and the like.
• a cell growth factor and a cell growth factor in a pharmaceutical agent to inhibit the activity of its receptor may be any substance as long as it promotes cell growth. Generally, they include a factor that is a peptide having a molecular weight of 20,000 or less and exhibits an effect at a low concentration by binding with a receptor.
• EGF epidermal growth factor
• IGF insulin-like growth factor-1, IGF-2, and the like
• FGF fibroblast growth factor
• CSF colony stimulating factor
• EPO erythropoietin
• IL-2 interleukin-2
• NGF nerve growth factor
• PDGF platelet-derived growth factor
• TGF-beta transforming growth factor beta
• HGF hepatocyte growth factor
• VEGF vascular endothelial growth factor
• the period of administration of the present compound and a combination pharmaceutical agent is not limited, and these may be administered concurrently or at intervals to a subject to be administered.
• a mixture of the present compound and a combination pharmaceutical agent may be made.
• the dosage of a combination pharmaceutical agent can be appropriately selected using clinically used dose as criteria.
• the mixing ratio of the present compound and a combination pharmaceutical agent can be appropriately selected depending on a subject to be administered, an administration route, target disease, symptoms, combinations, and the like. For example, when a subject to be administered is a human, 0.01 to 100 parts by weight of a combination pharmaceutical agent may be used relative to one part by weight of the present compound.
• a pharmaceutical agent a combination pharmaceutical agent
• they can be used in combination with a pharmaceutical agent (a combination pharmaceutical agent) such as an antiemetic agent, a sleep-inducing agent, an anticonvulsant, and the like.
• DMSO dimethyl sulfoxide
• HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate
• HOBt 1-hydroxybenzotriazole
• THF tetrahydrofuran
• WSC.HCl 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride s: singlet brs: broad singlet d: doublet dd: double doublet t: triplet q: quartet m: multiplet br: broad J: coupling constant

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