WO2003099813A1 - Nouvelles substances physiologiquement actives - Google Patents
Nouvelles substances physiologiquement actives Download PDFInfo
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- WO2003099813A1 WO2003099813A1 PCT/JP2003/006779 JP0306779W WO03099813A1 WO 2003099813 A1 WO2003099813 A1 WO 2003099813A1 JP 0306779 W JP0306779 W JP 0306779W WO 03099813 A1 WO03099813 A1 WO 03099813A1
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- 239000013543 active substance Substances 0.000 title description 8
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Classifications
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- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/336—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having three-membered rings, e.g. oxirane, fumagillin
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
-
- 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
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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Definitions
- the present invention relates to a 12-membered ring macrolide compound useful as a medicament, a method for producing the compound, and use thereof.
- cytotoxic compounds have been used as anticancer agents, and many screenings have been carried out using cytotoxicity as an index.
- most of the existing anticancer drugs also affect normal tissues with active cell proliferation at the same time as cancer cells, such as bone marrow and intestinal epithelium. Therefore, Q0L of patients has not been sufficiently improved.
- Fermentation products of microorganisms have also been screened for use as anticancer agents, mainly using in vitro cytotoxicity as an index.
- a number of compounds having cytotoxicity have been found, but most of them have only cytotoxicity in vitro, and compounds with anticancer effects in vivo have been found. Few compounds have been shown to be effective against solid tumors. Disclosure of the invention
- An object of the present invention is to find a compound that is effective not only in vitro but also in vivo and has an antitumor effect against a solid tumor, from a fermentation product of a microorganism or a derivative thereof.
- canceration of a normal cell is caused by mutation of a gene in the cell and expression of a gene different from normal. Therefore, the present inventors have proposed that cancer cells That the change in gene expression can lead to suppression of the growth of cancer cells, for example, by altering the expression of the cancer gene 'tumor suppressor gene, or the expression of genes involved in the cell cycle (cell cycle).
- the present inventors have proposed a compound that causes a change in gene expression, and in particular, a compound that suppresses VEGF (Vascular Endothelial Growth Factor) production under hypoxic conditions.
- VEGF Vascular Endothelial Growth Factor
- 11107D is stable even in an aqueous solution, and a compound obtained by chemically modifying 11107D (hereinafter referred to as 11107D derivative) is In addition to inheriting the stable properties of the above, the present inventors have found that in vivo experiments further suppress the growth of solid tumor cells, and thus completed the present invention.
- FD-895 Japanese Patent Application Laid-Open Publication No. Hei 4-1352783
- This publication discloses in vitro cytotoxic activity of FD-895 on P388 mouse leukemia cells, L-1210 mouse leukemia cells and HL-60 human leukemia cells in RPM-1640 medium (Japanese Patent Application Publication No. Column 6, Table 2).
- FD-895 had no effective antitumor activity in in vivo experiments using P388 mouse leukemia cells (Seki-Asano M. et al, J. Antibiotics, 47). , 1395-1401, 1994).
- FD-895 is unstable in aqueous solution, as described later, However, since it is expected that it will be difficult to mix it with an infusion solution, it cannot be said that it has sufficient qualities as an antitumor agent.
- R 3 , R 6 , R 7 and R 21 are the same or different,
- i) may have a substituent unsaturated C 2 - 22 alkoxy group
- R N 1 and R N2 are the same or different
- f may have a substituent group C 6 _ 14 Ariru group
- k a 3- to 14-membered non-aromatic heterocyclic group which may have a substituent formed together with a nitrogen atom to which R N1 and R N2 are bonded together (the non-aromatic heterocyclic group is May have a substituent), 1) optionally substituted 5- to 14-membered heteroaralkyl group, m) optionally substituted C 3 _ 14 cycloalkyl group or
- n represents a 3- to 14-membered non-aromatic heterocyclic group which may have a substituent
- a) may have a substituent group C physician 22 alkyl group
- b) may have a substituent group C 6 _ 14 Ariru group
- h represents a 5- to 14-membered heteroalkyloxy group which may have a substituent
- b) may have a substituent unsaturated C 2 _ 22 alkyl group
- d) may have a substituent group 5 to Teroariru group to 14-membered ring, e) which may have a substituent C 22 Ararukiru group or
- f represents a 5- to 14-membered heteroaralkyl group which may have a substituent
- R 3a , R 6a , R 7a and R 21a are the same or different,
- d) may have a substituent group C 6 14 Ariru group
- e) may have a substituent group 5 to Teroariru group to 14-membered ring
- f) may have a substituent group C 7 - 22 Ararukiru group
- k represents a 5- to 14-membered heteroaryloxy group which may have a substituent
- R aN1 and R aN2 are the same or different
- b) may have a substituent group C physician 22 alkyl group
- g) may have a substituent group 5 to Teroariru group to 14-membered ring, h) which may have a substituent C 7 _ 22 Ararukiru group,
- k a 3- to 14-membered non-aromatic heterocyclic group which may have a substituent formed together with the nitrogen atom to which R N1 and R N2 are bonded together (the non-aromatic heterocyclic group may be substituted May have a group),
- n represents a 3- to 14-membered non-aromatic heterocyclic group which may have a substituent], or a pharmacologically acceptable salt or a salt thereof, Their hydrates,
- R 3b , R 6b , R 7b and R 2lb are the same or different,
- e) may have a substituent group 5 to Teroariru group to 14-membered ring
- f) may have a substituent group C 7 _ 22 Ararukiru group
- k represents a 5- to 14-membered heteroaryloxy group which may have a substituent
- R bN1 and R bN2 are the same or different
- b) may have a substituent group C, _ 22 alkyl group,
- f may have a substituent group C 6 _ 14 Ariru group
- g) may have a substituent group 5 to Teroariru group to 14-membered ring, h) which may have a substituent C 7 _ 22 Ararukiru group,
- i) may have a substituent group C, _ 22 alkylsulfonyl group,
- n) represents a 3- to 14-membered non-aromatic heterocyclic group which may have a substituent]], the compound according to 1, or a pharmaceutically acceptable salt thereof, or Hydrates of them,
- R 3c , R 6c , R and R 2le are the same or different, 1) hydroxyl group or oxo group formed together with the bonding carbon atom
- a) may have a substituent group C 22 alkyl group
- c) may have a substituent group C 7 _ 22 Ararukiru group or
- d) represents a C 6-14 aryloxy group which may have a substituent
- b) represents a C 6-14 aryl group
- R cN1 and R cN2 are the same or different
- b) may have a substituent,? Alkyl group,
- An optionally substituted 5- to 14-membered heteroaralkyl group an optionally substituted C- 22 alkoxy group,
- R 6d , R 7 d and R 21 d are the same or different
- C 6 _ 14 aryloxy group optionally having substituent (s) f) may be substituted 5 to terrorist ⁇ reel O alkoxy group to 14-membered ring, g) may have a substituent group C 7 _ 22 Ararukiruokishi group or
- h represents a 5- to 14-membered heteroalkyloxy group which may have a substituent
- b) may have a substituent unsaturated C 2 _ 22 alkyl group
- d) may have a substituent group 5 to Teroariru group to 14-membered ring, e) which may have a substituent C 7 _ 22 Ararukiru group or
- f represents a 5- to 14-membered heteroaralkyl group which may have a substituent
- R 6 and R or R 7 are R N1 R N2 N— R M — [where R M is a) — CO— ⁇ one or
- R N1 and R N2 are the same as defined above (however, a) and b) represent the compound at the left end bonded to a nitrogen atom). Acceptable salts or hydrates thereof.
- R 21 is an oxo group formed together with the carbon atom to which it is bonded, or a pharmaceutically acceptable salt thereof, or a hydrate thereof.
- R 3e and R 21e are the same or different
- B) represents a C 1-6 alkyl group which may have a substituent
- R 6e and R 7e are the same or different
- R 6e is limited to a hydroxyl group
- n is an integer from 0 to 4,
- R eN1 is
- R eN3 and R eN4 are the same or different
- V a 5- to 14-membered heteroaryl group which may have a substituent
- V a C 7 _aralkyl group which may have a substituent
- vii) may have a substituent group C 3 - 8 Siglo alkyl group, viii) a C 4-9 cycloalkylalkyl group which may have a substituent, ix) a 5- to 14-membered heteroaralkyl group which may have a substituent,
- X a 5- to 14-membered non-aromatic heterocyclic group optionally having substituent (s), xi) —NR eN6 R eN7 (where R eN6 and R eN7 are the same or different and are each a hydrogen atom Or a C 1-6 alkyl group which may have a substituent) or
- iv) may have a substituent group C 14 Ariru group
- a 5- to 14-membered non-aromatic heterocyclic group which may have a substituent or 'xi) a substituent which is formed together with the nitrogen atom to which R eN3 and R eN5 are bonded together; Good 5- to 14-membered non-aromatic heterocyclic group (the non-aromatic heterocyclic group may have a substituent),
- X e, n, R eN3, R e 4 and R EN5 represent the definition of the group, R eN 'and R EN2 are 5 to may have a substituent together such connection formed 14-membered Ring non-aromatic compound
- X e , n, R eN2 , R eN4 and R eNn5 represent a group as defined above, and R eN1 and R e 3 are a 5- to 14-membered ring which may have a substituent formed together.
- X e , n, R eN R eN and R eN5 represent a group as defined above, and R eN2 and R eN3 may have a substituent formed together and may have a 5- to 14-membered non-aromatic ring. Represents a heterocyclic group] or
- R eN8 and R eN9 are the same or different,
- ii) may have a substituent group CI_ 6 alkyl group
- d 2 is an oxygen atom or a sulfur atom
- R d2 is a formula ( ⁇ ) dN5
- n is an integer from 0 to 4,
- R dN and R dN5 are the same or different
- R dN and R dN7 are the same or different
- RdN are the same or different Connexion, represent a hydrogen atom, a C 1-6 alkyl group which may have a substituent) or 12
- R d 6 and to R DN7 5 which may have a substituent together form A 14-membered non-aromatic heterocyclic group (the non-aromatic heterocyclic group may have a substituent)
- a 5- to 14-membered non-aromatic heterocyclic group which may have a substituent formed by a nitrogen atom to be bonded and R dM , R dN5 or R dN6 together (the non-aromatic The heterocyclic group may have a substituent) or
- R 12 It may have a nitrogen atom to be bonded and a substituent formed together with two types of substituents selected from the group consisting of R dN 4 , R dN5 and R dN6 .
- R dN 4 Represents a 14-membered non-aromatic heterocyclic group (the non-aromatic heterocyclic group may have a substituent)])
- n is an integer from 0 to 4,
- R fN2 is
- R 6d and Z or R 7d are R d3 C ⁇ — ⁇ (where R d3 is of the formula (VI)
- n and n 2 are the same or different and are each an integer of 0 to 4,
- R dN is
- R 7g is represented by R g C ⁇ 1-1 ⁇ (where R s is represented by the formula (VII) (VII)
- n 3 is 1 or 2
- R dN ' 7 is
- R 6d and / or R 7d is CO— ⁇ — [where R d4 is a compound of formula (VIII)
- n and n 2 are the same or different and are each an integer of 0 to 4,
- Rd "3 and RdN" are the same or different and each represent a hydrogen atom or a C ⁇ alkyl group which may have a substituent) or
- n 4 is an integer of 1 to 3
- n 4 is an integer of 1 to 3
- ⁇ 4 is an integer of 1 to 3
- n 4 is an integer from 1 to 3
- R m CO- 0- wherein, R n is the formula (XIII) m i - r ( Xiii)
- n 5 represents an integer of 1 to 3
- n 5 represents 2 or 3
- R 7n is R n C ⁇ — O— (where R n is the formula (XIV) Or a pharmacologically acceptable salt thereof, or a hydrate thereof,
- a medicament comprising, as an active ingredient, the compound according to any of 1. to 23., or a pharmacologically acceptable salt thereof, or a hydrate thereof.
- a pharmaceutical composition comprising an acceptable salt or a hydrate thereof as an active ingredient
- the medicament according to 24 as a prophylactic / therapeutic agent against a disease for which gene expression control is effective.
- the medicament according to 22. as a therapeutic agent for retinal angiogenesis or a therapeutic agent for diabetic retinopathy.
- the solid tumor is a lung cancer, a brain tumor cell, a breast cancer, a prostate cancer, an ovarian cancer cell, a colon cancer or a melanoma.
- a method for preventing and treating a disease for which gene expression control is effective by administering to a patient a pharmacologically effective amount of the medicine described in 24.
- a prophylactic / therapeutic agent against a disease for which angiogenesis inhibitory effect is effective using the compound according to any of 1 to 2 or a pharmacologically acceptable salt thereof or a hydrate thereof.
- the chemical formula of the compound according to the present invention is described as a planar chemical formula for convenience, but may include certain isomers derived from the chemical formula.
- the present invention includes all geometric isomers, optical isomers based on asymmetric carbon, rotamers, stereoisomers, tautomers, etc., and isomer mixtures existing in the structure of the compound
- the present invention is not limited to the description of the chemical formula for convenience, and may include any one of the above isomers and a mixture thereof. Therefore, when the compound of the present invention has an asymmetric carbon atom in the molecule, there are an optically active compound and a racemic compound, and both of them are included in the present invention.
- polymorphism may exist, but is not limited to one kind of crystal form in the same manner.Either one crystal form or a mixture of plural crystal forms may be used. Good.
- the compound of the formula (I) of the present invention or a salt thereof may be an anhydride or a hydrate, and both are included in the present invention.
- the metabolites formed by decomposing the compound of the formula (I) of the present invention in vivo and the prodrugs of the compound of the formula U) or a salt thereof of the present invention are also encompassed by the present invention.
- halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, and is preferably, for example, a fluorine atom, a chlorine atom, a bromine atom, etc., and particularly preferably, for example, a fluorine atom, a chlorine atom, etc. .
- C Medicine 2 2 alkyl group refers to a C 2 two linear or branched alkyl group having 1 carbon atoms, such as methyl group, Echiru group, n- propyl group, iso- Propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethyl Propyl, 1-ethylpropyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1-propylpropyl, 1-methylbutyl, 2-methylbutyl, 1 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl
- unsaturated C 2 _ 2 2 alkyl group was Chokukusarima to 2 2 of 2 to number 2 to 2 two linear or branched alkenyl group or the number of carbon atoms, carbon atoms Represents a branched alkynyl group, for example, a vinyl group, an aryl group, a 1-propenyl group, an isopropyl group, a 2-methyl-1-propenyl group, a 2-methyl-2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-pentenyl group, 1-hexenyl group, 1,3-hexanexenyl group, 1,5-hexanexenyl group, ethynyl group, 1-propynyl Group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, 1-ethynyl-2-propynyl group,
- 6-talctagenyl group ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, 3-methyl-11-propynyl group and the like.
- C 14 aryl group means an aromatic hydrocarbon cyclic group composed of 6 to 14 carbon atoms, and is a monocyclic group, a bicyclic group, a tricyclic group, Also included are condensed rings such as cyclic groups. Examples include phenyl, indenyl, 1-naphthyl, 2-naphthyl, azulenyl, heptanylenyl, indacenyl, acenaphthyl, fluorenyl, phenenyl, phenanthrenyl, anthracenyl, and the like.
- a phenyl group for example, a phenyl group, a 1-naphthyl group, a 2-naphthyl group or the like.
- the term "5- to 14-membered heteroaryl group” refers to a monocyclic, bicyclic or heterocyclic group containing at least one heteroatom selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom. Refers to a tricyclic 5- to 14-membered aromatic heterocyclic group.
- Preferable examples include nitrogen-containing aromatic heterocyclic groups such as pyrrolyl, pyridyl, pyridazinyl, pyrimidinyl, virazinyl, triazolyl, tetrazolyl, benzotriazolyl, pyrazolyl, Imidazolyl group, benzimidazolyl group, indolyl group, isoindolyl group, indolizinyl group, purinyl group, indazolyl group, quinolyl group, isoquinolyl group, quinolizyl group, phthalazyl group, naphthyridinyl group, quinoxalyl group, quinazolinyl group, cinnolinidyl group Zotriazinyl group, birazinopyridazinyl group, acridinyl group, phenanthridinyl group, carbazolyl group, carbazolinyl group, perimidinyl group,
- 3- to 14-membered non-aromatic heterocyclic group refers to a monocyclic ring which may contain one or more hetero atoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom.
- Preferred examples include aziridinyl group, azetidyl group, pyrrolidinyl group, pyrrolyl group, piperidinyl group, piperazinyl group, homopiperidinyl group, homopiperazinyl group, imidazolyl group, birazolidyl group, imidazolidyl group, morpholinyl group, thiomorpholyl group, and thiomorpholyl group.
- Imidazolinyl group oxazolinyl group, 2,5_diazabicyclo [2.2.1] heptyl group, 2,5-diazabicyclo [2.2.2] octyl group, 3,8-diazabicyclo [3.2.1] octyl Group, 1,4-diazabicyclo [4.3.0] nonyl group, quinuclidyl group, tetrahydrofuranyl group, tetrahydrothiophenyl group and the like.
- the non-aromatic heterocyclic group also includes a group derived from a pyridone ring and a non-aromatic condensed ring (for example, a group derived from a phthalimide ring, a succinimide ring, and the like).
- Cj_ 22 alkyl group refers to a substituted moiety is substituted with a "C 6 _ Ariru group” defined groups Specific examples include a benzyl group, a phenyl group, a 3-phenylpropyl group, a 4-phenylphenyl group, a 1-naphthylmethyl group, and a 2-naphthylmethyl group.
- An aralkyl group such as a benzyl group and a phenethyl group.
- the term "5- to 14-membered heteroaralkyl group” refers to a "C alkyl group” as defined above, in which a substitutable moiety is defined as "5 to 1"
- a group substituted with ⁇ 4-membered heteroaryl group '' means, for example, chenylmethyl group, furylmethyl group, pyridylmethyl group, pyridazylmethyl group, pyrimidylmethyl group, virazylmethyl group, and the like. Examples include a phenylmethyl group, a furylmethyl group, and a pyridylmethyl group.
- C 3 14 cycloalkyl group 3 to a cycloalkyl group composed of 14 carbon atoms, suitable groups, such as cyclopropyl group, cyclobutyl group, cyclopentyl group And cyclohexyl, cycloheptyl, cyclooctyl and the like, and preferably, for example, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
- suitable groups such as cyclopropyl group, cyclobutyl group, cyclopentyl group And cyclohexyl, cycloheptyl, cyclooctyl and the like, and preferably, for example, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
- C 4-9 cycloalkyl group used herein as a "C 4-9 cycloalkyl group" in the "CI_ 22 alkyl group” defined above, replaceable parts of the definitions - substituted by "C 3 14 cycloalkyl group”
- C, _ 22 alkoxy group Used herein as a "C, _ 22 alkoxy group", the "C l-22 alkyl group” defined above, it means a group having an oxygen atom attached to its end, is a suitable group, for example Methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, iso-pentyloxy, sec— Pentyloxy group, n-hexoxy group, iso-hexoxy group, 1,1-dimethylpropyloxy group, 1,2-dimethylpropoxy group, 2,2-dimethylpropyloxy group, 1-methyl-2-ene Tylpropoxy, 1-ethyl-2-methylpropoxy, 1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy Group, 2,2-dimethylbutoxy group, 2,3-dimethyl
- unsaturated C 2 _ 2 2 alkoxy group used herein "unsaturated C 2 _ 2 2 alkoxy group", “unsaturated C 2 - 2 2 alkyl group” defined above in, it means a group having an oxygen atom attached to its end.
- Suitable groups include, for example, vinyloxy group, aryloxy group, 1-propenyloxy group, 2-propenyloxy group, isopropyloxy group, 2-methyl-1-propenyloxy group, 2-methyl-2-propoxy group.
- Nyloxy group 1-butenyloxy group, 2-butenyloxy group, 3-butenyloxy group, 11-pentenyloxy group, 1-hexenyloxy group, 1,3-hexanenyloxy group, 1,5-hexanenyloxy group
- Examples thereof include a silyl group, a propargyloxy group, and a 2-butynyloxy group, and preferred examples include an aryloxy group, a propargyloxy group, and a 2-butynyloxy group.
- C to M aryloxy group refers to a group in which an oxygen atom is bonded to the terminal in the above-defined “C 6 -I 4 aryl group”.
- a phenyloxy group Indenyloxy, 1-naphthyloxy, 2-naphthyloxy, azulenyloxy, heptanylenyl, indacenyloxy, acenaphthyloxy, fluorenyloxy, phenalenyloxy, phenyl
- Examples thereof include a anthrenyloxy group and an anthracenyloxy group, and preferred examples include a phenyloxy group, a 1-naphthyloxy group, and a 2-naphthyloxy group.
- C 7 _ 2 2 Ararukiruokishi group used herein as a "C 7 _ 2 2 Ararukiruokishi group", the "C 7 _ 2 2 Ararukiru group” defined above, means a group having an oxygen atom attached to its end, specifically, for example, Benzyloxy group, phenethyloxy group, 3-phenylpropyloxy group, 4-phenylbutyloxy group, 1-naphthylmethyloxy group, 2-naphthylmethyloxy group and the like, preferably benzyloxy group and the like. It is.
- the term "5- to 14-membered heteroalkyloxy group” refers to a group in which an oxygen atom is bonded to the terminal of the "5- to 14-membered heteroalkyl group" defined above. It means, specifically, for example, a chenylmethyloxy group, a furylmethyloxy group, a pyridylmethyloxy group, a pyridazylmethyloxy group, a pyrimidylmethyloxy group, a virazylmethyloxy group, and the like.
- Is Cheni for example A methyloxy group, a furylmethyloxy group and a pyridylmethyloxy group.
- the term "5- to 14-membered heteroaryloxy group” means a group in which an oxygen atom is bonded to the terminal in the above-defined "5- to 14-membered heteroaryl group”.
- a pyrrolyloxy group a pyridyloxy group, a pyridazinyloxy group, a pyrimidinyloxy group, a virazinyloxy group, a triazolyloxy group, a tetrazolyloxy group, a benzotriazolyloxy group, a vilazolyloxy group, imidazolyl Oxy group, benzimidazolyloxy group, indolyloxy group, isoindolyloxy group, indolizinyloxy group, plinyloxy group, indazolyloxy group, quinolyloxy group, isoquinolyloxy group, quinolidyloxy group, phthalaziroxy group, naphth
- aliphatic C 2 - 2 2 Ashiru group refers to the definitions "-" alkyl group "," unsaturated C 2 - "the alkyl group” bonded carbonyl group in the terminal group Means acetyl group, propionyl group, butyryl group, iso- Ptyryl, valeryl, iso-valeryl, bivaloyl, propyl, decanoyl, lauroyl, myristoyl, palmitoyl, stearoyl, arachidoyl, acryloyl, propioyl, crotonyl, iso-crotol Nyl, oleynol, and linolenoyl groups.
- acetyl groups for example, an acetyl group, a propionyl group, a butyryl group, an iso-butyryl group, an acryloyl group and the like.
- Aromatic C 7 _ 15 Ashiru group used herein in the definition "C 6 _H Ariru group” or “5 to Teroariru group to 1 4-membered ring” is a carbonyl group bound to the end
- ⁇ I 22 alkylsulfonyl group means a sulfonyl Le group wherein the definition of "C, _ 22 alkyl group” is bonded, specifically, for example, methylstyrene Ruhoniru group, Echiru Examples thereof include a sulfonyl group, an n-propylsulfonyl group, and an iso-propylsulfonyl group, and a preferable example is a methylsulfonyl group.
- C 6 _ 14 ⁇ Li one Rusuruhoniru group means a sulfonyl Le group wherein the above “C 6- 14 Ariru group” defined bound, specifically, for example, benzene sulfonyl And benzenesulfonyl, 2-naphthylenesulfonyl and the like, and preferably benzenesulfonyl and the like.
- aliphatic c 2 _ 22 Ashirokishi group used herein, prior to his own definition "cycloaliphatic aliphatic C 2 - 22 Ashiru group” in means a group in which an oxygen atom is bound to its end, even if Examples include an acetoxy group, a propionyloxy group, an acryloxy group and the like, and preferably, for example, an acetoxy group, a propionyloxy group and the like.
- “. Les 22 alkoxy group” means a group Karuponiru group at its terminus is bonded, for example, methoxycarbonyl group, ethoxycarbonyl Cal Poni Le group, n- propoxy Cal Poni Le group, iso- propoxy carboxymethyl sulfonyl group, n- butoxycarbonyl two Group, iso-but Kishikarubo alkenyl group, s e c - butoxide deer Lupo sulfonyl group, tert- Butokishikarupo two Le group and the like, preferably such as ethoxy carbonyl group, iso- propoxy group, tert - a butoxycarbonyl group.
- unsaturated C 3 _ 2 2 alkoxy Cal Poni Le group in “unsaturated 0 DOO 2 2 alkoxy group” defined above, means a group Karuponiru group is bonded to the ends, e.g. A vinyloxycarbonyl group, an aryloxycarbonyl group, a 1-propenyloxycarbonyl group, an isopropenyloxycarbonyl group, a propargyloxycarbonyl group, a 2-butynyloxycarbonyl group, and the like. Is, for example, an aryloxycarbonyl group.
- C used herein as a "C" alkylthio group ", the" ⁇ 2 2 alkyl group "defined above, means a group in which a sulfur atom is bonded to its terminal, such as methyl Chiomoto, Echiruchio group, n- propylthio And an iso-propylthio group and the like, preferably, for example, a methylthio group, an ethylthio group and the like.
- C 1 2 2 alkyl group means a group sulfinyl group is bonded to its terminal, for example, methylsulfinyl group, Edji Luz sulfide El group, n- propyl sulfide El group, such as iso- propyl sulfinyl group .
- examples thereof include a methylsulfinyl group and an ethylsulfinyl group.
- C Bok 2 2 alkylsulfonyl O alkoxy group used herein, the in the definition of alkylsulfonyl group "means a group having an oxygen atom attached to its end, for example, methylsulfonyl O alkoxy group, E Examples include a tylsulfonyloxy group, an n-propylpyrusulfonyloxy group, an iso-propylsulfonyloxy group and the like, and preferably, a methylsulfonyloxy group and the like.
- C 3 _ 14 cycloalkyl group e.g. cyclopropyl group, cyclobutyl group, shea Kuropenchiru group, hexyl group, heptyl group cycloheteroalkyl, Shikurookuchiru group
- C 2 - 22 alkoxycarbonyl group (For example, methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, iso-propoxycarbonyl group, 11-butoxycarbonyl group, iso-butoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group etc)
- (33) one or more groups selected from formyl group and the like, preferably for example ⁇ amino group, Cj- 22 alkyl group, unsaturated C 2 _ 22 alkyl, C 6 - 14 Ariru group, stone five 14-membered ring to Teroariru group, 3 to 14-membered non-aromatic heterocyclic group, C 3 - 14 is a cycloalkyl group, etc., among them for example an amino group, C 1-22 alkyl group, from 3 1 4-membered non-aromatic heterocyclic group, C 3 _ 14 cycloalkyl group, and the like are preferable.
- the above-mentioned (9) amino group and (31) carbamoyl group as the substituents in “may have a substituent” further include one or two C 22 alkyl groups. And may be substituted with an unsaturated C 2-22 alkyl group or a C 6 -aryl group.
- the compound of the formula (I) inhibits VEGF production under hypoxic conditions and further has an inhibitory action on the growth of solid tumor cells in vivo, but the compound of the formula (I-a)
- a compound of the formula (I-b) is more preferable, and a compound of the formula (I-c) is particularly preferable.
- the compounds of formula (I) are structurally characterized by a side chain at position 6 and a Z or 7 side chain, a more preferred group of compounds can be defined as compounds of formula (Id) it can.
- the compounds of the formula (I-d) as well as the compounds of the formula (I) which form an oxo group together with the carbon atom to which R 21 is bonded have a good activity. It is.
- the compounds of the formula U-d more preferred embodiments of the compounds can be exemplified by the compounds of the invention of the above-mentioned "5.” to "19.”
- Preferred examples of the compound of the formula (I) will be described below.
- Preferred examples of the compound group include, for example, compound 6, compound 9, compound 12, compound 15, compound 16, compound 20, compound 21, compound 22, compound 25, compound 26, compound 27, compound 31, compound 34, compound 36, compound 38, compound 39, compound 40, compound 41, compound 43, compound 44, Compound 45, Compound 48, Compound 51, Compound 53, Compound 54, Compound 55, Compound 57, Compound 58, Compound 62, Compound 63, Compound 64, Compound 65, Compound 69, Compound 70, Compound 72, Compound 74, Compound 75, compound 77, compound 79, compound 85, compound 88, compound 105, compound 106, compound 108, compound 109, and compound 131.
- preferred compounds are compound 6, compound 9, compound 12, compound 16, compound 21, compound 25, compound 26, compound 27, compound 31, compound 36, compound 38, compound 44, compound 45, Compound 54, Compound 63, Compound 64, Compound 69, Compound 75, Compound 85, Compound 109, Compound 131, etc.
- compound 9, compound 12, compound 26, compound 44, compound 45, compound 75 and the like can be mentioned.
- the compound of the formula (I) is a Streptomyces genus having the ability to produce a biologically active substance 111107D [a compound of the formula (I) wherein R 3 , R 6 and R 21 are a hydroxyl group and R 7 is an acetoxy group].
- the following deposited strains can be exemplified as microorganisms used for producing 1107D.
- the strain has been deposited internationally with the National Institute of Advanced Industrial Science and Technology, Patent Organism Depositary (IP0D) at 1-1 1-1 Higashi, Tsukuba, Ibaraki, 305-8566, Japan.
- Streptomyces sp. Mer-11107 was deposited as FERM P-18144 at the Institute of Life Science and Industrial Technology, 1-3-1 Higashi, Tsukuba, Ibaraki, 305-8566, Japan.
- the strain for producing 1 1 107D is not particularly limited, including mutants of these strains, as long as it belongs to the genus Streptomyces and has the ability to produce 11 107 D.
- Other examples include Streptomyces sp. A-1532, Streptomyces sp. A-1533, and Streptomyces sp. A-1534.
- FERMBP-7849 and FERM BP-7850 respectively, at the National Institute of Advanced Industrial Science and Technology (AIST) and the Patent Organism Depositary Center (IP0D), 1-chome, 1-chome, Chuo No. 6, 305-8566, Ibaraki, Japan And has been deposited internationally as FERM BP-7851.
- the strain used in the present invention belongs to the genus Streptomyces and produces 1101D Although it is expected that any of the strains having the ability to carry out the method can be used, typical strains include the strain numbered by the present inventors as the Mer-11107 strain.
- the bacteriological properties of this strain are as follows.
- This strain elongates Spirales aerial mycelium from the base hypha. It forms a spore chain consisting of about 10 to 20 cylindrical spores at the tip of a mature aerial hypha. The size of the spores is about 0.7X1.0; uni. The surface of the spores is smooth, and there are no special organs such as spores, sclerotium, and flagella.
- the following shows the culture characteristics of this strain after cultivation on various media for 28 ⁇ for 2 weeks.
- the description of the color tone is displayed in accordance with Container, Corporation, Ob''Color of America, Harmony, Mani Yuarire (Color Harmony Manual of Container Corporation of America), and is indicated by the color name and the code shown in parentheses.
- This strain grows well and forms aerial hyphae on its surface to form light gray (d) spores.
- the back of the culture is Light melon yellow (3ea). No production of soluble dye is observed.
- This strain is moderately growing and forms a slight spore of aerial hyphae on its surface to form gray spores (Gray; g).
- the reverse side of the culture is Nude tan (4 gc) or Putty (1 1/2 ec). No soluble dye is produced.
- This strain grows well and forms aerial hyphae on its surface to form gray spores (Gray; e).
- the back of the culture is Fawn (4ig) or Gray (g). No production of soluble dye is observed.
- the strain is poorly grown and does not form aerial hyphae on its surface.
- the back of the culture is Light melon yellow (3ea). No production of soluble dye is observed.
- the following shows the growth status of this strain after 2 weeks of culturing on a medium containing various carbon sources added to a pred ham Gottling agar medium.
- this strain is considered to be a bacterium belonging to the genus Streptomyces. Therefore, the present inventors named this strain Streptomyces sp. EMI11.1 (St reptomyces sp. Mer- 11 107), and received the accession number FERM P- Deposited as 18144.
- the physiologically active substance 11107D of the present invention can be produced by inoculating the above strain into a nutrient medium and cultivating aerobically.
- the strain producing the bioactive substance 111107D belongs to the genus Streptomyces and has the ability to produce 11107D.
- the strain is not limited to the above strain, and can be used in the present invention.
- the method for culturing the above-mentioned microorganisms is basically the same as the method for culturing general microorganisms. However, it is usually preferable to carry out the culture under aerobic conditions such as shaking culture by liquid culture and aeration-agitation culture.
- the medium used for the culture may contain a nutrient source that can be used by microorganisms belonging to the genus Streptomyces, and any of various synthetic, semi-synthetic media, natural media, and the like can be used.
- a carbon source for example, glucose, sucrose, fructose, glycerin, dextrin, starch, molasses, soybean oil and the like can be used alone or in combination.
- an organic nitrogen source such as pharma media, peptone, meat extract, soybean powder, casein, amino acid, yeast extract, urea, etc., or an inorganic nitrogen source such as sodium nitrate, ammonium sulfate, etc. is used alone or in combination. be able to.
- Others such as sodium chloride, potassium chloride, carbonated calcium sulfate, magnesium sulfate, sodium phosphate, potassium phosphate, cobalt chloride Salts, heavy metal salts, and vitamins such as vitamin B and biotin can be added and used as necessary. If foaming during culturing is remarkable, various antifoaming agents can be appropriately added to the medium. When adding an antifoaming agent, it is necessary to have a concentration that does not adversely affect the production of the target substance. For example, a use concentration of 0.05% or less is desirable.
- Culture conditions can be appropriately selected within a range in which the strain can grow well and produce the substance.
- the pH of the medium is preferably, for example, about 5 to 9, usually around neutral.
- the culture temperature is usually kept at 20 to 40, preferably at 28 to 35.
- the culture period is about 2 to 8 days, usually about 3 to 5 days.
- the physiologically active substance 11107D of the present invention accumulated in the culture solution can be recovered by ordinary separation means utilizing its properties, such as a solvent extraction method and an adsorption resin method.
- the physiologically active substance 11107D is a microorganism belonging to the genus Streptomyces (eg, Streptomyces sp. AB-1704 strain (FERM P. -18999), etc.) can be used as a starting material for the substance 111 B (the compound of Example 84). 3. Purification of active substance
- the separation and purification methods generally used to isolate microbial metabolites from the culture can be used.
- organic solvent extraction using methanol, ethanol, butanol, ethyl acetate, orifice, etc. various ion exchange chromatography, gel filtration chromatography using Sephadex LH-20, etc., adsorption with activated carbon, silica gel, etc.
- All known methods such as adsorption / desorption treatment by chromatography or thin-layer chromatography, or high-performance liquid chromatography using a reversed-phase column or the like are applicable thereto.
- the purification method is not particularly limited to the method shown here.
- the compound of the formula (I) can be obtained by converting an isolated and purified 11107D as a starting compound and converting a hydroxyl group and / or an acetoxyl group on the compound using a common organic synthesis means. Can be synthesized.
- Typical synthetic methods include, for example, A. a method for producing a urethane derivative, B. a method for producing a thiourethane derivative, C. a method for producing an ether derivative, D. a method for producing an ester derivative, E. a phosphate ester or an amide phosphate Method for producing ester derivatives, F. Method for producing sulfate or amide sulfate derivatives, G. Method for producing halogen derivatives, H.
- Method for producing sulfonic acid ester derivatives I. Method for producing amine derivatives
- J. Method for producing hydroxyl groups A method for producing an oxo form by oxidation can be mentioned. The introduction and removal of a hydroxyl-protecting group as necessary depends on the type and stability of the compound involved in the production. For example, the method described in the literature [Protective 'Groups'in' Organic Synthesis (Protective) Growing sin Organic Synthesis, TW Greene, John Wiley & Sons, Inc., 3rd Edition (3rd Ed. Init.)] Or a method equivalent thereto. it can.
- the compound of the formula (I) can be produced by appropriately combining a reaction for introducing / removing a hydroxyl-protecting group and the above-mentioned production method.
- R 3 , R 6 , R 7 and R 2i are the compounds of the substituents listed in the above 9)
- a method for producing a urethane derivative, a method for producing a thiourethane derivative Using the method for producing an amidosulfate ester or the method for producing an amamine derivative, the compounds having the substituents listed in the above 2) to 5) are listed in the above 6) using the method for producing an ether derivative.
- the compounds of the substituents described above were prepared using the method for producing an ester derivative, and the compounds of the substituents listed in the above 11) to 13) were produced using the method for producing a phosphate ester or amide phosphate derivative.
- the compound of the substituent listed in the above 10) is prepared by using a method for producing a sulfate ester or a sulfonic acid ester derivative, and the compound of the substituent described in the above 8) is produced using a method for producing a halogen derivative.
- R 3A , R 6A , R 16A and R 2IA are a hydrogen atom or a protecting group (provided that R 3A , And and do not represent a hydrogen atom at the same time),,, and are a hydrogen atom, a protecting group or a group represented by the formula — (where, represents an aryl group which may have a substituent group). Shown) (However,
- R 3 B and do not simultaneously represent a hydrogen atom.
- the first step is a step for producing a compound of the formula (IA). This step is achieved by protecting the hydroxyl group of 1107D.
- the reaction for protecting the hydroxyl group depends on the type of the protecting group, but is carried out by a method well known in synthetic organic chemistry.
- Examples of the protecting group include 1-ethoxyhexyl, tetrahydropyranyl, 1-methyl-1-methoxyethyl, 1_ (2-chloroethoxy) ethyl, 1-methoxycyclohexyl, 4-methoxytetrahydroviranyl, and 4-methoxytetrahydro.
- protected derivatives of each hydroxyl group such as 1-ethoxyxetil, tetrahydropyrael, 1-methoxycyclohexyl, 4-methoxytetrahydroviranyl, 4-methoxytetrahydrothioviranyl, 4-methoxytetrahydrothiopyranyl-S, S-dioxide
- a corresponding vinyl ether such as ethyl vinyl ether or dihydropyran
- acid Organic acids such as pyridinium p-toluenesulfonic acid (PPTS), p-toluenesulfonic acid, camphorsulfonic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, etc., for example, hydrogen chloride, nitric acid, hydrochloric acid, sulfuric acid, etc.
- PPTS pyridinium p-toluenesulfonic acid
- camphorsulfonic acid acetic acid, trifluoroacetic acid, methanesulfonic acid, etc.
- acetic acid trifluoroacetic acid
- methanesulfonic acid etc.
- hydrogen chloride hydrogen chloride
- nitric acid hydrochloric acid
- sulfuric acid etc.
- It is an inorganic acid and preferably, for example, pyridinium p-toluenesulfonic acid (PPTS), p-toluenes
- the solvent used in the reaction is not particularly limited, but is preferably an inert solvent that does not easily react with the raw materials, for example, ethers such as tetrahydrofuran, ethyl ether, diisopropyl ether, dioxane, and dimethoxyethane, for example, dichloromethane, and chloroform.
- ethers such as tetrahydrofuran, ethyl ether, diisopropyl ether, dioxane, and dimethoxyethane, for example, dichloromethane, and chloroform.
- Halogenated hydrocarbons such as carbon tetrachloride and 1,2-dichloroethane; hydrocarbons such as hexane, benzene and toluene; ketones such as acetone and methyl ethyl ketone; such as acetonitrile Nitriles, for example, amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyridone, hexamethylphosphorylamide, and sulfoxides such as dimethylsulfoxide, are preferred. Is, for example, dichloromethane, black Holm, tetrahydrofuran or the like is used.
- the reaction time is 10 minutes to 5 days, preferably 1 day to 2 days.
- the reaction temperature is from ⁇ 78 to the reflux temperature, preferably room temperature.
- the vinyl ether and the acid used in the reaction are 1 to 200 equivalents and 0.05 to 2 equivalents, preferably 30 to 50 equivalents and 0.1 equivalent, respectively, based on 1 1 1 107 D. ⁇ 0.3 equivalents.
- protective groups include, for example, methoxymethyl, methylthiomethyl, methoxyethoxymethyl, trichloroethoxymethyl, trimethylsilylethyl, trimethylsilylethoxymethyl, tert-butyldimethylsilyl, triedilsilyl, trimethylsilyl, getylisopropylsilyl, and triisopropyl Virsilyl, di-tert-butylmethylsilyl, diphenylmethylsilyl, benzyl, P-methoxybenzyl, p-methylbenzyl, p-nitrobenzyl, p-cyclobenzyl, and driphenylmethyl.
- hydroxyl-protected derivatives can be synthesized by reacting each protected group in the presence of a chloro, bromo or trifluoromethanesulfonyl base.
- the base include general organic bases and inorganic bases.
- the organic base include imidazole, 4- (N, N-dimethylamino) pyridine (The terms 4-dimethylaminopyridine, N, N-dimethylaminopyridine and dimethylaminopyridine used herein are synonymous), aromatic bases such as pyridine, 2,6-lutidine and collidine, for example, N-methylbiperidine N-methylpyrrolidine, triditylamine, trimethylamine, di-is0-propylethylamine, cyclohexyldimethylamine, N-methylmorpholine, 1,8-bis (dimethylamino) naphthalene, etc.
- Secondary amines such as di-iso-butylamine and dicyclohexylamine; alkyllithiums such as methyllithium and butyllithium; and metal alkoxides such as sodium methoxide and sodium ethoxide.
- alkali metal hydrides such as calcium hydride; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkalis such as sodium carbonate, potassium carbonate and cesium carbonate
- Metal carbonates for example, alkali metal bicarbonate such as sodium bicarbonate and the like.
- Preferred bases used in protecting the hydroxyl group with a silyl protecting group include, for example, aromatic bases such as imidazole and 4-dimethylaminopyridine, and tertiary amines such as triethylamine.
- the solvent used in the reaction is not particularly limited, but is preferably one that does not easily react with the starting materials. Examples of the inert solvent include, for example, tetrahydrofuran, dichloromethane, N, N-dimethylformamide and the like.
- the reaction time is 10 minutes to 3 days, preferably 1 to 2 days.
- the reaction temperature is from ⁇ 78 ° C. to the temperature of heating to reflux, preferably from ⁇ 10 to 50.
- the chloro form, bromide form or trifluoromethanesulfonyl form and the base used in the reaction are 1 to 20 equivalents and 0.5 to 30 equivalents, respectively, preferably 1 to 1 equivalent to 111 D. 5 equivalents and 0.5 to 20 equivalents.
- reagent used for protecting the hydroxyl group and its equivalent selective protection of the hydroxyl group of 1107 D can be achieved.
- selective protection of the hydroxyl group of 1107 D can be achieved.
- 3- and 21-position hydroxyl groups are selective To obtain a protected compound.
- Step A2 is a step for producing a compound of the formula (IIA). This step is accomplished by treating the acetoxyl group of the compound of formula (IA) with a base in an inert solvent to convert it to a hydroxyl group.
- Examples of the base used include inorganic bases such as sodium hydride, potassium hydride and the like, and alkali metal hydrides such as calcium hydride and the like, for example, lithium hydroxide and sodium hydroxide.
- Hydroxide of an alkali metal such as potassium hydroxide, etc. for example, carbonate of an alkali metal such as lithium carbonate, sodium carbonate, and potassium carbonate, for example, hydrogen carbonate of an alkali metal such as sodium hydrogen carbonate, for example, lithium methoxide, sodium methoxide And alkoxides of metals such as sodium ethoxide and potassium tert-butoxide, and bases such as guanidine and ammonia.
- Preferred bases include potassium carbonate, guanidine and the like.
- the inert solvent used is, besides the above-mentioned inert solvent, an alcoholic solvent such as methanol, ethanol, isopropanol, tert-butanol, or water, or a mixture of these solvents. it can. Preferred solvents include alcoholic solvents and mixtures of alcohols and halogenated solvents.
- the reaction time is 10 minutes to 5 days, preferably 30 minutes to 1 day.
- the reaction temperature is from 1 78 X: to the temperature of heating to reflux, preferably room temperature.
- the base used in the reaction is 1 to 10 equivalents, preferably 2 to 5 equivalents, based on the compound of the formula (IA).
- Step A3 is a step for producing a compound of the formula (IIIA). This step is achieved by treating the hydroxyl group of the compound of the formula (IIA) with a formaldehyde derivative or liponyldiimidazole in the presence of a base.
- a formaldehyde derivative or liponyldiimidazole in the presence of a base.
- the black-mouthed formate derivatives include, for example, 4-12 trophenyl-formated mate, phenyl-formed-formate, Examples include lorophenyl chromate formate, 4-bromophenylchromate formate, and 2,4-dinitrophenylchromate formate.
- the base include the above-mentioned organic bases and inorganic bases.
- diisopropylethylamine, 4-dimethylaminopyridine, triethylamine, pyridine, 2,6-lutidine, sodium hydride and the like are used.
- the solvent used in the reaction is not particularly limited, but is preferably one that does not easily react with the raw materials, and includes the above-mentioned inert solvent, and preferably, for example, tetrahydrofuran, dichloromethane, N, N-dimethylformamide and the like are used.
- the formaldehyde derivative and base used in the reaction are 1 to 10 equivalents and 1 to 20 equivalents, preferably 1 to 5 equivalents and 1 to 10 equivalents, respectively, relative to the compound of the formula (IIA). is there.
- the reaction time is 10 minutes to 30 hours, preferably 1 to 4 hours.
- the reaction temperature is from 78 to the temperature of heating to reflux, preferably from 110 to 50.
- the hydroxyl group is converted to a carbonate ester in the step A3. It is also possible to convert to a group. That is, by treating with an equivalent amount of a base corresponding to the number of hydroxyl groups to be converted into a carbonate group and a chromate formate derivative, the other hydroxyl groups of compound (IA) can be converted to carbonate groups in the same manner as the hydroxyl group at the 7-position. Can be converted to
- Step A4 is a step for producing a compound of the formula (I VA).
- the carbonate of the formula (IIIA) is treated with an amine (R N1 R N2 H) capable of forming a desired compound of the formula (I) or an amine alone in an inert solvent in the presence of a base. This is achieved by:
- the amines used are, for example, methylamine, ethylamine, propylamine, butylamine, octylamine, decylamine, cyclopropylamine, cyclopentylamine, cyclohexylamine, dimethylamine, getylamine, ethylmethylamine, ethylenediamine, 1,3-propanediamine.
- the base examples include the above-mentioned organic bases and inorganic bases, and preferably, for example, diisopropylethylamine, dimethylaminopyridine, triethylamine, pyridine, 2,6-lutidine, sodium hydride and the like are used.
- the solvent used in the reaction is not particularly limited, but is preferably one that does not easily react with the raw materials, and examples thereof include the above-mentioned inert solvents, and preferably, for example, tetrahydrofuran, dichloromethane, N, N-dimethylformamide and the like are used. .
- the amine and base used in the reaction are 1 to 10 equivalents and 2 to 20 equivalents, preferably 1.5 to 5 equivalents and 2 to 10 equivalents, respectively, based on the compound of the formula (IIIA).
- the reaction time is 10 minutes to 30 hours, preferably 1 to 2 hours.
- the reaction temperature is from ⁇ 78 to the reflux temperature, preferably from 1 to 10 to 50.
- the compound of formula (IVA) can also be achieved by treating the compound of formula (IIA) with an isocyanate in an inert solvent in the presence of a base and / or cuprous chloride.
- the isocyanate includes, but is not limited to, for example, ethyl isocyanate, methyl isocyanate, phenyl isocyanate and the like.
- the base examples include the aforementioned organic bases and inorganic bases, and preferably, for example, diisopropylethylamine, dimethylaminopyridine, triethylamine, pyridine, 2,6-lutidine, sodium hydride and the like are used.
- the solvent used in the reaction is not particularly limited, but is preferably one that does not easily react with the raw materials.
- the inert solvent include, for example, tetrahydrofuran, dichloromethane, N, N-dimethylformamide and the like.
- the base and the isocyanate used in the reaction are 3 to 100 equivalents, 1 to 20 equivalents, preferably 5 to 20 equivalents, and 3 to 10 equivalents, respectively, relative to the compound of the formula (IIIA).
- cuprous chloride When cuprous chloride is used, the amount is 1 to 10 equivalents, preferably 2 to 6 equivalents.
- the reaction time is 10 minutes to 30 hours, preferably 1 to 2 hours.
- the reaction temperature is from 178 to the reflux temperature, preferably from -10 to 50.
- the OR 3 A, ⁇ _R 6 A, 1 connected to three of the compounds of the hydroxyl group unprotected OR 1 6 A and OR 2 IA in the A 1 step, the A 3 step with carbonate group and their hydroxyl groups
- the compound can be converted to a derivative having a plurality of urethane structures by converting the compound into a rubamoyloxy group in the fourth step.
- Step A5 is a step of producing a compound of the formula (VA). This step is achieved by subjecting a urethane derivative of the compound of the formula (IVA) to deprotection treatment as described below in an inert solvent. The reaction of deprotecting the hydroxyl-protecting group depends on the type of the protecting group, but is carried out by a method well known in synthetic organic chemistry.
- each hydroxyl group such as 11-ethoxyhexyl, tetrahydropyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydroviranyl, 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S, S-dioxide
- the acid include the above-mentioned organic acids and inorganic acids, and preferably, for example, pyridinium p-toluenesulfonate, Examples include paratoluenesulfonic acid and camphorsulfonic acid.
- the solvent used in the reaction is not particularly limited, but is preferably one that does not easily react with the starting materials, and is preferably an alcoholic solvent such as methanol, ethanol, isopropanol, tert-butanol, and the like. An inert solvent may be used as a mixture.
- the acid used in the reaction is 0.5 to 5 equivalents, preferably 1 to 3 equivalents, relative to the compound of the formula (IVA).
- the reaction time is 10 minutes to 10 days, preferably 1 day to 4 days.
- the reaction temperature is from 178 to the reflux temperature, preferably from 10 to 50.
- protecting groups when other protecting groups are protected by, for example, tert-butyldimethylsilyl, triethylsilyl, getylisopropylsilyl, trimethylsilyl, triisopropylsilyl, di-tert-butylmethylsilyl, diphenylmethylsilyl, etc. Protection is possible, for example, by treatment with fluorine or acid.
- fluorine or acid examples include tetrabutylammonium fluoride, hydrogen fluoride, potassium fluoride, pyridinium hydrogen fluoride, and the like.
- the acid include the above-mentioned organic acids and inorganic acids.
- the solvent used in the reaction is not particularly limited, but is preferably one that does not easily react with the raw material.
- the inert solvent include the above-mentioned inert solvents.
- tetrahydrofuran, getyl ether, water and the like are used.
- the fluorine anion and the acid used in the reaction are 1 to 5 equivalents and 0.5 to 5 equivalents, preferably 1 to 4 equivalents and 0.5 to 3 equivalents, respectively, relative to the compound of the formula (IVA). It is.
- the reaction time is 10 minutes to 30 hours, preferably 1 to 2 hours.
- the reaction temperature is from 178 to the reflux temperature, preferably from 110 to 50.
- the hydroxyl groups at the 3-, 6-, and 21-positions can be selectively converted to urethane derivatives.
- R 3 A the 6-position of the hydroxyl group of R '6A and "Gato Riechirushiriru group, Compound (IA)
- the third step a fourth step, by sequentially performing the fifth step, the 6-position hydroxyl group Derivatives of urethane structure Can be synthesized.
- the method for selectively modifying the hydroxyl group at the 3-, 6-, or 21-position performed by variously combining protection and deprotection can be used for the other modification methods described below.
- R 3A, R 6A, R l 6A and R 2LA represents the same groups as previously defined
- R 3E, R 6E, R 16E and R 2 l E is a hydrogen atom, a protecting group or the formula R Nl A group represented by R N2 N—CS— (where R N1 and R N2 represent the same group as defined above) (provided that R 3E , R 6E , R I6E and R 21E simultaneously have a hydrogen atom
- R 3F , R 6F , R 16F and R 21F are a hydrogen atom or a group represented by the formula R Nl R N2 N—CS— (where R Nl and R N2 are as defined above) Represents the same group as)
- Step B1 is a step of synthesizing a compound of the formula (IB) by using thioisocyanate or thiocarbamoyl chloride instead of isocyanate. This step is accomplished by treating a compound of formula (IIA) with isothiocynate or thiocarbamoyl chloride in an inert solvent in the presence of a base or bis (triptyltin) oxide.
- the isothiosocyanate to be used is not limited.
- ethyl isothiosinate methyl isothiosinate, phenyl isothiosinate, benzyl isothiosinate, aryl isothiosinate, 2- (N, N-dimethylamino) ethyl isothiocyanate, 2- (N, N-ethylamino) ethyl isothiocyanate, 3- (N, N-dimethylamino) propyl isothiocyanate, 3- (N, N-ethylamino) ) Propylisothiocyanate, 2- (morpholine-41-yl) ethyl isothiocyanate, 2- (piperidine-1-1-yl) ethylisothiocyanate, 2- (pyrrolidine-11-yl) F) ethyl isothiosinate.
- the thiocarbamoyl chloride used is not limited, but for example, N, N-dimethylthiocarbamoyl chloride, N-phenyl-2-methylthiodicarbamoyl chloride, (morpholine-14-yl) thiocarbamoyl chloride, (4-1) Methyl piperazine (11-yl) thiocarbamoyl chloride, (4-methylhomopirazine-11-yl) thiocarbamoyl chloride and the like.
- the base examples include the above-mentioned organic bases and inorganic bases, and preferably, for example, diisopropylethylamine, 4-dimethylaminopyridine, triethylamine, pyridine, 2,6-lutidine, sodium hydride and the like are used.
- the solvent used in the reaction is not particularly limited, but is preferably a solvent that does not easily react with the raw materials.
- the inert solvent include, for example, tetrahydrofuran, dichloromethane, N, N-dimethylformamide, toluene, and the like.
- Can be The base or bis (tributyltin) oxide and isothiocyanate or thiocarbamoyl chloride used in the reaction are used in an amount of 1 to 5 equivalents and 1 to 10 equivalents, preferably, respectively, based on the compound of the formula (IIA). 1-3 equivalents and 2-5 equivalents.
- the reaction time is 10 minutes to 72 hours, preferably 1 to 24 hours.
- the reaction temperature is from 170 to 70 ° C., preferably from 110 ° C. to 70 ° C.
- the hydroxyl group of the compound represented by the formula (IIA) in which one or three of OR 3 A, ⁇ R 6 A , OR and ⁇ R 21 A are not protected is converted to a thiocarbamoyloxy group in the first step.
- conversion to it is also possible to synthesize a compound represented by the formula (IB) having a plurality of thiocarbamoyl groups.
- step A5 the protecting group for the hydroxyl group is removed in step A5, and the thiourene derivative of the formula (IIB) can be synthesized.
- R 3G , R 6G , R , 6G and R 2lG represent a hydrogen atom or a protecting group (R 3G , R 6G , R , 6G and R 2lG do not simultaneously represent a hydrogen atom, and at least one is represents a hydrogen atom), R 3H, R 6H, R, 6H and R 21H show a C Bok 22 alkyl group which may have a protecting group or a substituent]
- Step C1 is a step of synthesizing a compound of the formula (IC). This step is performed in the same manner as the reaction corresponding to Method A and Step A1. However, one to three hydroxyl groups are protected.
- the 3-position, 6-position or A compound in which one of the 21-positions is a hydroxyl group and the other hydroxyl group is protected can be synthesized.
- Step C2 is a step of synthesizing a compound of the formula (IIC). This step is achieved by alkylating a hydroxyl group which is not protected by the compound of (IC).
- Alkylation can be achieved by treatment with an alkylating agent of the formula R m —X in the presence of a base.
- R n represents a Cl -22 alkyl group which may have a substituent, and examples thereof include a methyl group, an ethyl group, and a benzyl group.
- X represents a leaving group, and the leaving group is, for example, a chloro group, a bromo group, an odo group, a trifluoromethane And a sulfonyl group.
- the base include the above-mentioned organic bases and inorganic bases.
- the solvent used in the reaction is not particularly limited, but is preferably one that does not easily react with the starting materials.
- the inert solvent include, for example, dimethyl ether, tetrahydrofuran, dimethoxyethane, and toluene.
- the alkylating agent and the base used in the reaction are 3 to 20 equivalents and 5 to 30 equivalents, preferably 3 to 5 equivalents and 5 to 1 equivalent, respectively, relative to the compound of the formula (IC).
- the reaction time is 10 minutes to 48 hours, preferably 1 to 24 hours.
- the reaction temperature is from 1 to 78 to the temperature of heating to reflux, preferably from 10 to
- R 3 R 6 ], R , 6 J and R represent an alkyl group or a protecting group
- R 3 K , R 6 K , R , 6 K and R 21 K represent an alkyl group or hydrogen
- R 7 K represents an optionally substituted rubamoyl or thiocarbamoyl group on the nitrogen atom.
- the compound of the formula (IIC) may be optionally substituted with A2, A3, A4 and the like.
- Step A5 to obtain a derivative in which a hydroxyl group is introduced into the 7-position hydroxyl group and an alkyl group is introduced into one or two of the 3-, 6-, and 21-position hydroxyl groups. Can be.
- the compound of the formula (IIIC) is subjected to the first step B1 and then the fifth step A5, whereby a thiocarbamoyl group is introduced into the hydroxyl group at the 7-position, A derivative having an alkyl group introduced into one or two of the hydroxyl groups at the 21st and 21st positions can also be obtained.
- R 3A, R 6A, R l6A and R 2LA represents the same group as defined above, R, R, R u, R I 6L and R 2LL represents a hydrogen atom or an alkyl group]
- step C2 the compound of formula (IIA) is subjected to step C2 in the same manner as described above, and then to step A5, wherein the hydroxyl group at the 7-position is alkylated.
- An ether derivative can be obtained.
- an unsaturated alkylating agent an aralkylating agent, or a heteroaralkylating agent, which can produce a desired compound of the formula (I), in place of the above-mentioned alkylating agent, the corresponding ether can be prepared. Derivatives can be produced.
- R 3G, R. 6G, R 16G and R 2 IG indicates the same groups as defined above, R 3M, R 6M, R I 6M and R 2 IM is a hydrogen atom, a protecting group or the formula R c .
- a group represented by CO here, R e ° represents a hydrogen atom, a C 1-22 alkyl group which may have a substituent, an unsaturated C 2 22 group which may have a substituent, alkyl group, which may have a substituent group C Ariru group, 5 which may have a substituent to Teroariru group to 14-membered ring, which may have a substituent C 7 _ 22 Ararukiru group or Represents a 5- or 14-membered heteroalkyl group which may have a substituent) (however, R 3M , R 6M , RI 6M and R 21M do not simultaneously represent a hydrogen atom)
- the step D1 is a step of converting an unprotected hydroxyl group into an ester group using the compound of the formula (I C) synthesized in the step C1 as a raw material.
- the esterification reaction is carried out by, for example, an acid anhydride and a base, an acid octalogenate and a base, a carboxylic acid and a condensing agent, or a Mitsunobu reaction.
- the acid anhydride various carboxylic anhydrides are used.
- a mixed acid anhydride composed of acetic acid, propionic acid, butyric acid, valeric acid, benzoic acid, etc.
- Cyclic acid anhydrides such as dartaric anhydride and adipic anhydride
- acetic anhydride, propionic anhydride, butyric anhydride, and benzoic anhydride preferably acetic anhydride, propionic anhydride, butyric anhydride, and benzoic anhydride.
- Acid halides include, for example, various acid chlorides And acid bromide, and preferably, for example, acetyl chloride, propionyl chloride, benzoyl chloride, benzoyl bromide and the like.
- the base include the above-mentioned organic bases and inorganic bases, and preferably, for example, imidazole, 4-dimethylaminopyridine, pyridine, sodium hydride and the like.
- carboxylic acid various carboxylic acids are used, and preferably, for example, acetic acid, propionic acid, etc., and as the condensing agent, preferably, for example, dicyclohexylcarbodiimide, trifluoroacetic anhydride, carbonyldiimidazole, N , N-diisopropylcarboimide, and 1-ethyl-3- (3-dimethylaminopropyl) carboimide.
- various carboxylic acids can be replaced in the presence of triphenylphosphine and getyl azodicarboxylate or diisopropyl azodicarboxylate.
- the solvent used in each reaction is not particularly limited, but is preferably one that does not easily react with the starting materials.
- the inert solvent include, for example, dichloromethane, chloroform, tetrahydrofuran and the like.
- the acid anhydride and base, the acid octalogenate and base, and the carboxylic acid and condensing agent used in the reaction are 1 to 10 equivalents, 3 to 20 equivalents, and 1 to 10 equivalents to the compound of the formula (IC). 0 equivalents and 3 to 20 equivalents, 1 to 20 equivalents and 1 to 20 equivalents, preferably 1 to 5 equivalents and 2 to 10 equivalents, 1 to 5 equivalents and 2 to 10 equivalents, 1 to 5 equivalents And 1 to 5 equivalents.
- the progress of the reaction can be promoted by adding 0.2 to 2 equivalents of 4-dimethylaminopyridine as needed.
- the reaction time is 10 minutes to 30 hours, preferably 1 to 2 hours.
- the reaction temperature is from 178 to the reflux temperature, preferably from 10 to 50.
- the ester derivative thus synthesized is subjected to the same reaction as in the step A5 to remove the protecting group for the hydroxyl group, whereby the compound of the formula (ID) can be produced.
- Step Dl it is also possible to esterify one to four hydroxyl groups by performing the same esterification reaction as in Step D1 using 11107D as a raw material.
- R 3A , R 6A , R 16A and R 21 A represent the same group as defined above, and R 3N , R 6N , R, R , 6 or R 21 N represents a hydrogen atom or a formula R c .
- R tQ represents the same group as defined above
- step D1 the compound of formula (IIA) is subjected to step D1 in the same manner as described above, and then to step A5, whereby the compound represented by formula (ID ′) in which the hydroxyl group at the 7-position is esterified A dielectric can be synthesized.
- R 3A , R 6A , R 16A and R A represent the same group as defined above, and R 3P , R 6P, R 7P, R, 6P and R 2iP is a hydrogen atom, the formula (R N3 0) 2 P_ ⁇ one, the formula (R N 'R N2 N) 2 P_ ⁇ one or formula (R N1 R N2 N) ( R N3 ⁇ ) PO— represents a group represented by the formula (where R N1 , R 2 and R N3 represent the same groups as defined above)]
- the E1 step is a step of subjecting a hydroxyl group to phosphoric acid esterification and amide phosphoric acid esterification using the compound of the formula (IIA) as a raw material.
- the phosphoric esterification reaction is performed, for example, using a phosphoric acid halide and a base.
- Various types of phosphoric acid halides can be used, such as dialkoxyphosphoryl chloride, diphenyloxyphosphoryl chloride, alkoxy (N, N-disubstituted amino) phosphoryl chloride, and aryloxy (N, N-diol).
- the base include the above-mentioned organic bases and inorganic bases.
- pyridine 4-dimethylaminopyridine, triethylamine, ethyldiisopropylamine, sodium hydride, n-butyllithium, potassium carbonate, carbonate Sodium and the like.
- the solvent used in each reaction is not particularly limited, but is preferably one that does not easily react with the raw material, and includes the above-mentioned inert solvents.
- dichloromethane, chloroform, tetrahydrofuran, N, N-dimethylformamide Are used.
- the reaction time is 10 minutes to 72 hours, preferably 1 to 24 hours.
- the amount of the phosphate halide and the base used in the reaction is 1 to 10 equivalents and 2 to 20 equivalents, preferably 1 to 5 equivalents and 2 to 10 equivalents, respectively, based on the compound of the formula (IIA).
- the reaction temperature is from 178 to the reflux temperature, preferably from -1O) to 5O :.
- the thus-prepared phosphoric ester derivative is subjected to the same reaction as in Step A5 to remove the protecting group for the hydroxyl group, whereby the compound of the formula (IE) can be produced.
- R 3A , R 6A , R 16A and R 21A represent the same group as defined above, and R 3Q , R
- R 6 Q, R 7 Q ⁇ R1 6 Q and R'2 l Q are hydrogen atoms, RN 1 RN 2 N — S 0 2 — or R N 3 ⁇ —
- S0 2 — represents a group represented by the formula (where R 2 and R N3 represent the same groups as defined above)]
- Step F1 is a step of subjecting a hydroxyl group to sulfate esterification using the compound of the formula (IIA) as a raw material.
- the sulfuric acid esterification reaction is carried out using a sulfuric acid halide and a base.
- Various sulfate halides are used, and examples thereof include alkoxysulfonyl chloride and N, N-disubstituted sulfamoyl chloride.
- the base include the above-mentioned organic bases and inorganic bases, and preferably, for example, pyridine, 4-dimethylaminopyridine, triethylamine, ethyldiisopropylamine, sodium hydride, n-butyllithium, potassium carbonate, And sodium carbonate.
- the solvent used in each reaction is not particularly limited, but is preferably one that does not easily react with the starting materials.
- the inert solvent examples include the above-mentioned inert solvents.
- the inert solvent Preferably, for example, dichloromethane, chloroform, tetrahydrofuran, N, N-dimethyl Formamide and the like are used.
- the sulfate halide and base used in the reaction are 1 to 10 equivalents and 2 to 20 equivalents, preferably 1 to 5 equivalents and 2 to 10 equivalents, respectively, based on the compound of the formula (IIA).
- the reaction time is 10 minutes to 72 hours, preferably 1 to 24 hours.
- the reaction temperature is 1 The temperature is preferably between 10 and 50.
- the sulfate ester derivative thus synthesized is subjected to the same reaction as in the step A5 to remove the protecting group for the hydroxyl group, whereby the compound of the formula (IF) can be synthesized.
- R 3A , R 6A , R 16A and R 2IA represent the same groups as defined above, and R 3R , R
- R 16R and R 21 R represent a hydroxyl group or a halogen atom
- Step G1 is a step of converting a hydroxyl group to a halogen using the compound of the formula (IA) as a raw material.
- This halogenation reaction is carried out, for example, by treating with carbon tetrabromide, bromine, phosphorus tribromide, iodine, carbon tetrachloride, etc. in the presence of getylaminosulfur trifluoride (DAST) or triphenylphosphine and a base.
- DAST getylaminosulfur trifluoride
- Examples of the base include common organic bases and inorganic bases such as diisopropylethylamine, dimethylaminopyridine, triethylamine, pyridine, 2,6-lutidine, sodium hydride and the like.
- the solvent used for the reaction is not particularly limited, but a solvent that does not easily react with the raw material is desired.
- tetrahydrofuran More preferably, for example, tetrahydrofuran, dichloromethane, N-dimethylformamide and the like can be mentioned.
- a fluorination reaction with getylaminosulfur trifluoride is preferred, and getylaminosulfur trifluoride (DAST) used in the reaction is 1 to 5 equivalents, preferably 1 to 5 equivalents to the compound of the formula (IIA), respectively. ⁇ 3 equivalents.
- the reaction time is between 10 minutes and 10 hours. Reaction temperature is from -78 to room temperature.
- R 3A , R 6A , R 16A and R 2IA represent the same group as defined above, and R 3S , R 6S , R 7S , R 16S and R 2IS represent a hydrogen atom or R N 3S Represents a group represented by ⁇ 2 — (wherein, R N3 represents the same group as defined above)]
- the HI step is a step of sulfonylating a hydroxyl group using the compound of the formula (IIA) as a raw material.
- the sulfonylation reaction can be performed by treating a sulfonyl chloride such as p-toluenesulfonyl chloride, methanesulfonyl chloride, and benzenesulfonyl chloride in the presence of a base.
- Bases include common organic bases and inorganic bases such as diisopropylethylamine, dimethylaminopyridine, triethylamine, pyriamine. Gin, 2,6-lutidine, sodium hydride and the like.
- the solvent used in the reaction is not particularly limited, but is preferably one that does not easily react with the raw material, and examples thereof include tetrahydrofuran, dichloromethane, ⁇ , ⁇ -dimethylformamide and the like.
- the amount of the sulfonyl chloride and the base used in the reaction are 1 to 5 equivalents and 2 to 10 equivalents, preferably 1 to 3 equivalents and 2 to 6 equivalents, respectively, based on the compound of the formula (I ⁇ ).
- the reaction time is between 10 minutes and 30 hours.
- the reaction temperature is from 78 to the temperature of heating to reflux.
- Step A5 the protecting group for the hydroxyl group is removed from the sulfonic acid ester derivative thus synthesized in Step A5, whereby a derivative represented by the formula UH) in which the 7-hydroxyl group is sulfonylated can be synthesized.
- R 3A, R 6A, R I 6A and R 21A represents the same groups as previously defined
- R 3T, R 6T, R 7T, R I 6T and R 2 represents a hydroxyl group or the formula R NI R N2 N— (wherein R 1 and R N2 represent the same groups as defined above)]
- the first step is a step of converting a hydroxyl group directly to an amine or a group having good elimination property by using the compound of (IIA) as a raw material, then converting to an azide, and then converting to an amine by reduction. .
- DPPA diphenylphosphoryl azide
- DBU 1,8-diazabicyclo [5.4] [0] Pendecar 7-ene
- TMAD tetramethyl azodicarboxamide
- tributylphosphine 5
- a base sodium azide or the like can be used.
- the base examples include the aforementioned organic bases and inorganic bases, and preferably, for example, diisopropylethylamine, dimethylaminoviridine, triethylamine, pyridine, 2,6-lutidine, sodium hydride and the like are used. It is also possible to convert to azide by treating with sodium azide in the presence of a palladium catalyst.
- the palladium catalyst examples include Pd (PPh 3 ) 4 and the like.
- the solvent used in the reaction is not particularly limited, and it is desirable that the solvent does not easily react with the raw material. Examples thereof include tetrahydrofuran, dichloromethane, ⁇ , ⁇ -dimethylformamide, toluene, benzene and the like.
- the reaction time ranges from 10 minutes to 30 hours.
- the reaction temperature is from ⁇ 78 to the reflux temperature.
- the reduction of azide to amine can be carried out, for example, by using triphenylphosphine, lithium aluminum hydride or the like. Further, reduction to amine can be carried out in a hydrogen atmosphere by using a catalyst such as palladium carbon or Lindlar catalyst.
- the solvent used for the reaction is not particularly limited, but it is preferable that the solvent does not easily react with the raw material, and examples thereof include tetrahydrofuran, getyl ether, and ethanol.
- the reaction time is between 10 minutes and 30 hours.
- the reaction temperature is from -78 to the temperature of the heat return.
- the conversion of the hydroxyl group to a group having a good elimination property can be carried out according to the above-mentioned step G1 (halogenation) or step H1 (sulfonylation).
- the group having a good leaving property include a chloro group, a bromo group, an aldehyde group, a methanesulfonyl group and a p-toluenesulfonyl group.
- Examples of the amine to be used include methylamine, ethylamine, dimethylamine, and diethylamine.
- Examples of the base include the above-mentioned organic bases and inorganic bases, and preferably, for example, diisopropylethylamine, dimethylaminopyridine, triethylamine, pyridine, 2,6-lutidine, sodium hydride and the like are used.
- the solvent used in the reaction is not particularly limited, but is preferably one that does not easily react with the raw material, and examples thereof include the inert solvent. Preferably, for example, tetrahydrofuran, dichloromethane, N, N-dimethylformamide and the like are used.
- the reaction time is 10 minutes to 30 hours, preferably 1 to 2 hours.
- the reaction temperature is from 178 to the reflux temperature, preferably from 110 to 50.
- the amide derivative thus synthesized is subjected to the same reaction as in Step A5 to remove the protecting group for the hydroxyl group, whereby the compound of the formula (I ⁇ ) can be produced.
- one or two hydroxyl groups can be aminated by amination using 111107D as a raw material in the same manner as in Step I1.
- amino group of the compound of the formula (I ⁇ ) is subjected to alkylation, acylation, sulfamoylation or sulfonylation by a method well-known in organic synthetic chemistry and the above-mentioned method, respectively.
- the compound of (I) can be produced.
- the J1 step is a step of synthesizing a ketone compound represented by the formula (IIJ) by performing a hydroxyl group oxidation reaction using 11107D as a raw material.
- the oxidizing agent used in this step is, for example, manganese dioxide, pyridinium chromate, pyridinium dichromate, a Dess-Martin reagent, or a reagent under Swern oxidation conditions.
- the solvent used in the reaction is not particularly limited, but preferably does not easily react with the starting compound, and examples thereof include tetrahydrofuran, dichloromethane, chloroform, toluene and the like.
- the reaction is carried out at a temperature of from 1 to 78 under reflux with heating. Reaction times range from 10 minutes to 78 hours.
- a reaction with a Dess-Martin reagent, manganese dioxide or a reagent under Swern oxidation conditions is preferable, and a reaction using a Dess-Martin reagent is particularly preferable.
- a solvent for the oxidation reaction using the Dess-Martin reagent dichloromethane and chloroform are particularly preferable.
- the oxidizing agent to be used is 1 to 20 equivalents, preferably 1 to 10 equivalents to the compound (11107D). 5 equivalents.
- the reaction temperature is preferably from 0 to room temperature, and the reaction time is from 30 minutes to 24 hours, preferably from 1 to 8 hours.
- a compound derivatized in advance into a urethane derivative, a thiourethane derivative, an ester derivative, an alkyl derivative, or the like by the above-described method in place of 11107D is used, so that the third position of these derivatives or It is possible to synthesize a compound in which the hydroxyl group at position 21 has been converted to an oxo structure. Furthermore, it is also possible to obtain a 7-oxo compound by oxidizing the 7-hydroxyl group of the compound represented by the formula UIA).
- each of the hydroxyl groups at the 3-, 7- and / or 21-positions can be selectively converted to an oxo structure. It is possible to Further, the compound previously converted to an oxo structure is subjected to urea derivatization, thiourethane derivatization, ester derivatization, or alkyl derivation according to the above-described method, thereby modifying both the corresponding modification and the oxo conversion. Each of the compounds obtained can also be synthesized.
- the compound represented by the formula (I) can be synthesized by appropriately combining the reactions A to J described above with the protection and deprotection of a hydroxyl group.
- the target substance of each reaction is collected from the reaction mixture according to a conventional method.
- a conventional method for example, if insolubles are present, they are filtered off as appropriate and the solvent is distilled off under reduced pressure, or the reaction mixture is diluted with an organic solvent such as ethyl acetate and washed with water. After drying over magnesium sulfate or the like, it can be obtained by evaporating the solvent, and if necessary, can be further purified by a conventional method, for example, column chromatography, thin-layer chromatography, high-performance liquid chromatography and the like.
- a representative compound of the compound of the formula (I) of the present invention was used for inhibiting VEGF transcription, inhibiting the growth of WiDr human colon cancer cells, inhibiting the growth of solid tumors.
- the effects and weight loss (acute toxicity) and stability in aqueous solution were measured.
- VEGF promoter-sequence sequence To construct a repo overnight system that reflects transcription from the VEGF promoter, we cloned the VEGF promoter-sequence sequence and inserted it into a secreted alkaline phosphatase (PLAP) vector to construct a repo overnight system.
- PLAP secreted alkaline phosphatase
- VEGF genome was cloned from a phage library.
- VEGF cDNA GenBank access ion mraber: X625678
- a PCR primer having the sequence shown in SEQ ID NO: 1 and SEQ ID NO: 2 was designed, and PCR was carried out to obtain a fragment of about 340 b.
- a human genome phage library human genomic library, Clontech
- PUC18-VEGFA containing a VEGF 5 ′ flanking region of about 5.4 kb.
- This PUC 18-VEGFA was digested with Kpn I / Nhe I, and the obtained 2.3 kb VEGF promoter region was secreted by the allelic phosphatase (PLAP) repo overnight vector (Goto et al., Mol. Pharmacol. , 49, 860-873, 1996) to construct a VEGF-PLAP vector by insertion between KpnI / NheI.
- PLAP allelic phosphatase
- VEGF-PLAP vector was introduced into U251 cells cultured in Dulbecco's modified Eagle's medium (DMEM, manufactured by SIGMA) containing 103 ⁇ 4 fetal serum, and cultured in the presence of 1 mg / mL G418 (Merck). G418-resistant stable clones (U251 / cell 8 cells) were established.
- DMEM Dulbecco's modified Eagle's medium
- U251 / 1-8 cells were reported by Minchenko et al. (Cel. Mol. Biol. Res., 40, 35-39, 1994). Secrete PLAP into the medium in the same hypoxia (2% 0 2 incubator I) and, it was confirmed that the repo Isseki system reflecting the transcription from VEGF pro motor.
- a compound that suppresses VEGF production induced by hypoxic stimulation was screened.
- the U251 cells were washed twice with a sufficient amount of PBS (Phosphate buf fered saline) and treated with 65 for 20 minutes to lose alkaline phosphatase in the serum.
- the activated serum was diluted in a DMEM medium containing 10% and seeded on a 96-well plate at 4 ⁇ 10 4 cels / 180 xl.
- the 11107D derivative showed strong VEGF transcription inhibitory activity.
- the compounds of formula (I), the growth of WiDr human colon cancer cells was determined 50 suppresses concentration (IC 5Q values).
- Table 2 shows IC 5D values of representative compounds.
- the compound of the formula (I) exhibited a strong WiDr human colon cancer cell growth inhibitory action.
- WiDr human colorectal cancer cells were implanted subcutaneously in the body of nude mice, and when the tumor volume reached about 100 ⁇ 3 , The groups were divided so that the average of the tumor volumes of the groups was uniform, and the control group was 10 animals and the 11107D derivative-administered group was 5 animals.
- the administration group was intravenously injected for 5 days at any of 0.625 mg, 1.25 mg, 2.5 mg, 5 mg, and lOmg / kg / day, and the control group received vehicle.
- the tumor volume on the 15th day was measured, and the relative tumor weight ratio (T / C%) was determined with the tumor weight of the control group taken as 100%.
- Table 3 shows the T / C% of representative compounds of the formula (I).
- the body weight was measured on the first day of administration, the fifth day, the eighth day, the 12th day, and the 15th (or 16th) day, and the relative weight change was examined with the body weight on the first day of administration being 100%.
- Table 3 shows the relative body ratio on the day when the body weight decreased most as the minimum relative body weight ratio.
- the compound of formula (I) also showed an inhibitory effect on WiDr human colorectal cancer cells in vivo at doses without significant weight loss.
- the compound of formula (I) was dissolved in DMS0 at a concentration of 10-20 ⁇ , and this was diluted about 500-fold with Britton-Robinson buffer of ⁇ 7. This solution was used as a sample solution and incubated at 25T: for 24 hours.
- the compound of the formula (I) of the present invention can be used for, for example, a therapeutic agent for cancer, particularly a therapeutic agent for solid cancer, because it alters gene expression, and particularly suppresses VEGF production. It is expected to be used as a cancer metastasis inhibitor, a therapeutic agent for diabetic retinopathy, a therapeutic agent for rheumatoid arthritis, and a therapeutic agent for hematomas. Furthermore, as is clear from the toxicity test of Test Example 4, the compound of the formula (I) has the effect of inhibiting the growth of WiDr human colorectal cancer cells at a dose not accompanied by significant weight loss of the test mice. It is a highly safe compound.
- prevention / treatment refers to prevention or treatment or both.
- the compound of the formula (I) of the present invention is more specifically effective as an anticancer agent, particularly as an anticancer agent / cancer metastasis inhibitor for solid tumors.
- Solid tumors include, for example, knee cancer, stomach cancer, colon cancer, breast cancer, prostate cancer, lung cancer, kidney cancer, brain tumor, head and neck cancer, esophageal cancer, skin cancer, liver cancer, uterine cancer, cervical cancer, bladder cancer, Examples include thyroid cancer, testicular tumor, choriocarcinoma, osteosarcoma, soft tissue sarcoma, and ovarian cancer, and particularly preferred are cancers such as colon cancer, breast cancer, prostate cancer, lung cancer, head and neck cancer, and ovarian cancer. It is also effective as an anticancer drug against leukemia. Furthermore, it is also effective as a therapeutic agent for hemangiomas.
- VEGF vascular endothelial growth factor
- it is effective as a therapeutic agent for diabetic retinopathy, a therapeutic agent for rheumatoid arthritis, and a therapeutic agent for hemangioma based on the inhibitory action of VEGF production. It is also effective as a therapeutic agent for osteoarthritis, psoriasis, inflammatory diseases composed of delayed hypersensitivity reactions, and atherosclerosis.
- a pH adjuster, buffer, stabilizer, solubilizing agent, etc. may be added to the main drug as necessary, and subcutaneous, intramuscular, intraarticular, or intravenous injection is performed by a conventional method Agent.
- the compound When the compound is administered as a therapeutic or prophylactic agent for various diseases, it may be administered orally as tablets, powders, granules, capsules, syrups, etc., or as sprays, suppositories, injections, Parenteral administration as topical preparations or infusions is acceptable. Depending on the age, type of liver disease, etc., the usual adult dosage is about 1 mg to 100 mg per day, divided into one or several doses.
- formulation it is manufactured by a usual method using an ordinary formulation carrier. That is, when preparing a solid dosage form for oral use, an excipient and, if necessary, a binder, a disintegrant, a lubricant, a coloring agent, a flavoring agent, etc. are added to the active ingredient, and the tablet is prepared in a conventional manner. , Coated tablets, granules, powders, capsules, etc. Of course, these tablets and granules may be sugar-coated, gelatin-coated and appropriately coated as necessary.
- the compound of the formula (I) of the present invention by altering gene expression, particularly suppresses VEGF production and exhibits excellent antitumor effects in an in vivo solid tumor model.
- the compound of the formula (I) of the present invention is stable in an aqueous solution, for example, a therapeutic agent for cancer, particularly a therapeutic agent for solid cancer, a cancer metastasis inhibitor, a therapeutic agent for diabetic retinopathy, a therapeutic agent for rheumatoid arthritis , A therapeutic agent for hematoma, and the like.
- 0.6 mL of this seed culture was mixed with 60 mL of main culture medium (5% soluble starch, 0.5% corn stapler, 0.5% dried yeast, 0.5% dartene meal, 0.1% calcium carbonate) in a 500 mL triangular volume.
- main culture medium 5% soluble starch, 0.5% corn stapler, 0.5% dried yeast, 0.5% dartene meal, 0.1% calcium carbonate
- the column was eluted with a mixture (2 liters) of n-hexane and ethyl acetate (1: 9; v / v). The fractions eluted from 1440 mL to 1566 mL were collected, concentrated under reduced pressure and concentrated. 15 mg of an active fraction was obtained.
- the obtained crude active fraction was subjected to preparative high performance liquid chromatography (HPLC) under the following preparative conditions (A) to collect fractions eluted at a retention time of 17 minutes, and after distilling off acetonitrile, Each fraction was desalted by HPLC under the condition (B) to obtain 11107D (retention time: 36 minutes, 1.8 mg).
- HPLC high performance liquid chromatography
- 11107D was determined to be a structure represented by the following formula.
- Solubility soluble in dimethylsulfoxide, pyridine, methanol, acetone, poorly soluble in water
- Example 3-1 (8E, 12E, 14E) 1-7-acetoxy-3,6,16,21-tetrakis (1-ethoxyethoxy) -1,6,10,12,16,20-pentamethyl- 18, 19-Epoxytricoser 8, 12, 14-Triene 1 1-Oride (Formula XV) and (8E, 12E, 14E) -17-Acetoxy 3, 16, 21-Tris (1-ethoxyethoxy) 1 6-Hydroxy — 6, 10, 12, 16, 20 —Pennomethyl-18,19—Epoxytricosa-1,8,12,14—Trien-11-1—Oride (Formula XVI)
- Example 3-2 (8 E, 12 E, 14 E) — 3, 6, 16, 21-tetrakis (1-ethoxyethoxy) — 7-hydroxy-6, 10, 12, 16, 20-pentyl methyl — 18, 19—Epoxytricosa—8, 12, 14—Triene—1 1 _orido
- the reaction solution was diluted with ethyl acetate, and washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated saline solution.
- the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.
- Example 3-5 (8 E, 12 E, 14 E) -3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-1 7-((4- (pyrrolidine-1 1-yl) piperidine-1-yl) caprolponyl) oxy-18,19-epoxytricors 8,12,14-triene-1 11-olid (compound 3)
- Example 5 (8 E, 12 E, 14 E) — 3, 6, 16, 21-tetrahydroxy-1-610, 12, 16, 20-pentamethyl-7- (N- (3 -— (morpholine-4- 1), 19-epoxytricoser 8, 12, 14-triene-11-olide (compound 5)
- the title compound (colorless oil) was synthesized in the same manner as in Example 3.
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Description
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Priority Applications (15)
Application Number | Priority Date | Filing Date | Title |
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IL16538803A IL165388A0 (en) | 2002-05-29 | 2003-05-29 | Macrolide compounds and pharmaceutical compositions containing the same |
EP03733172A EP1508570A4 (en) | 2002-05-29 | 2003-05-29 | NEW PHYSIOLOGICAL ACTIVE SUBSTANCES |
BR0311331-0A BR0311331A (pt) | 2002-05-29 | 2003-05-29 | Composto, seu uso, medicamento, composição farmacêutica, método para prevenir ou tratar uma doença contra a qual um controle da expressão do gene é eficaz, método para prevenir ou tratar uma doença contra a qual a supressão da produção de vegf é eficaz, e método para prevenir ou tratar uma doença contra a qual uma inibição da angiogênese é eficaz |
CN038155966A CN1665807B (zh) | 2002-05-29 | 2003-05-29 | 生理活性物质 |
CA2486728A CA2486728C (en) | 2002-05-29 | 2003-05-29 | Novel physiologically active substances useful for suppressing vegf production |
MXPA04011885A MXPA04011885A (es) | 2002-05-29 | 2003-05-29 | Nuevas sustancias fisiologicamente activas. |
US10/515,647 US20060009439A1 (en) | 2002-05-29 | 2003-05-29 | Novel physiologically active substances |
AU2003241927A AU2003241927C1 (en) | 2002-05-29 | 2003-05-29 | Novel physiolgically active substances |
JP2004507470A JP4491341B2 (ja) | 2002-05-29 | 2003-05-29 | 新規生理活性物質 |
NZ536778A NZ536778A (en) | 2002-05-29 | 2003-05-29 | Novel physiologically active substances |
IL165388A IL165388A (en) | 2002-05-29 | 2004-11-24 | Macrolide compounds and pharmaceutical preparations containing them |
IS7571A IS7571A (is) | 2002-05-29 | 2004-11-29 | Ný lífeðlisfræðilega virk efni |
NO20045679A NO20045679L (no) | 2002-05-29 | 2004-12-28 | Nye fysiologik aktive substanser |
US11/473,201 US7550503B2 (en) | 2002-05-29 | 2006-06-23 | Physiologically active substances |
US11/927,542 US7619100B2 (en) | 2002-05-29 | 2007-10-29 | Physiologically active substances |
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JP2003063176 | 2003-03-10 | ||
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US (4) | US20060009439A1 (ja) |
EP (3) | EP2927228B1 (ja) |
JP (2) | JP4491341B2 (ja) |
KR (1) | KR100954401B1 (ja) |
CN (2) | CN1665807A (ja) |
AU (1) | AU2003241927C1 (ja) |
BR (1) | BR0311331A (ja) |
CA (1) | CA2486728C (ja) |
ES (1) | ES2603803T3 (ja) |
IL (2) | IL165388A0 (ja) |
IS (1) | IS7571A (ja) |
MX (1) | MXPA04011885A (ja) |
NO (1) | NO20045679L (ja) |
NZ (1) | NZ536778A (ja) |
PL (1) | PL373806A1 (ja) |
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WO (1) | WO2003099813A1 (ja) |
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