WO2005089714A1 - エマルション安定化製剤 - Google Patents
エマルション安定化製剤 Download PDFInfo
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- WO2005089714A1 WO2005089714A1 PCT/JP2005/005238 JP2005005238W WO2005089714A1 WO 2005089714 A1 WO2005089714 A1 WO 2005089714A1 JP 2005005238 W JP2005005238 W JP 2005005238W WO 2005089714 A1 WO2005089714 A1 WO 2005089714A1
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- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
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Definitions
- the present invention relates to an oral semi-solid or liquid pharmaceutical composition for forming or maintaining a stable emulsion, and a preparation encapsulating the same.
- SMEDDS TM Self Micro—Emulsifying Drug Delivery systems
- This system is composed of three components, a surfactant, a cosa factor, and a lipid phase (Patent Document 1 below, etc.).
- the present system is a miscible mixture composed of these three components, and when water is added thereto as a fourth component, a microemulsion is spontaneously formed.
- Neoral TM a cyclosporine preparation of an immunosuppressive agent disclosed by Novartis, is famous.
- digestive juices unlike simple water, contain various ionic species. It also shows different pH values depending on the digestive tract site. For this reason, there are cases where microemulsions are formed with simple water but do not become microemulsions in the digestive tract with little force. Therefore, there has been a demand for a system capable of forming or maintaining a microemulsion with good reproducibility even in the digestive tract, which has many factors that adversely affect the stability of the emulsion.
- Patent Document 1 U.S. Patent No. 6054136
- An object of the present invention is to provide a pharmaceutical composition having a high bioavailability and capable of forming a stable microemulsion containing a medicinal ingredient, particularly a poorly water-soluble medicinal ingredient, in the digestive tract and a method for producing the same. .
- the present invention provides [I] a semi-solid or liquid oral pharmaceutical composition comprising a pharmaceutical compound and two or more surfactants having different molecular weights,
- composition according to the above [3], wherein the surfactant in the homologous series is a fatty acid glyceride having a polyoxyethylene chain in a hydrophilic group.
- composition according to the above [5] comprising a long-chain fatty acid glyceride having a long-chain polyoxyethylene in a hydrophilic group and a medium-chain fatty acid glyceride having a short-chain polyoxyethylene in a hydrophilic group.
- composition according to the above-mentioned [7], comprising polyoxyethylene hydrogenated castor oil, and polyethylene glycol mono-prillic acid and glyceride of pric acid.
- composition according to the above-mentioned [8], comprising polyoxyethylene (40) hydrogenated castor oil, and polyethylene glycol (8) -caprylic acid / capric acid glyceride;
- the pharmaceutical compound has the formula (I):
- R 1 represents a 5- or 6-membered ring which may be substituted
- X 1 represents a bond or a divalent group having 1 to 4 atoms constituting a straight chain portion, and ring A is substituted !, may be! /, 5 !, and 6-membered ring And ring B is substituted !, may be! /, Represents an 8- to 10-membered ring,
- E and E are each optionally substituted carbon atoms or optionally substituted
- E and E are each an optionally substituted carbon atom and an optionally substituted nitrogen
- a and b each represent a single bond or a double bond
- X 2 represents a divalent group having 1 to 4 atoms constituting a straight chain portion
- Z 1 represents a bond or a divalent cyclic group
- Z 2 represents a bond or a divalent group
- R 2 represents (1) an optionally substituted nitrogen-nuclear-grade ammodimated or oxidized amino group, and (2) a sulfur atom or an oxygen as an optionally substituted ring-constituting atom.
- a nitrogen-containing heterocyclic group which may contain an atom and which may be subjected to nitrogen-nuclear-grade ammoxidation or oxidization;
- R 5 and R 6 may each be an optionally substituted hydrocarbon group. May be substituted A hydroxyl group or a substituted or an amino group, and R 5 and R 6 may be bonded to each other to form a cyclic group together with an adjacent phosphorus atom; (4) Substituted! Represents an amidino group or (5) Substituted! Represents a gua-dino group.
- the composition according to the above [10] which is a compound represented by the formula: or a salt thereof,
- the pharmaceutical composition of the present invention has a function of forming or maintaining a stable microemulsion.
- a preparation encapsulating the pharmaceutical composition of the present invention is orally administered, a fine microparticle containing a pharmaceutically active ingredient is present in the digestive tract. Since a stable microemulsion in which the particles are dispersed is formed or the microemulsion is maintained, the absorbability of the medicinal component, particularly the poorly water-soluble medicinal component from the digestion tube is greatly improved, and its biological properties are improved. High utilization rate.
- FIG. 1 is a photograph showing a liquid comparison of the compositions obtained in Example 1 and Control Example 1.
- FIG. 2 is a graph showing the results of turbidity ratio evaluation (absorbance ratio at a wavelength of 550 nm) of the compositions obtained in Example 1 and Control Example 1.
- FIG. 3 is a photograph showing a comparison of the liquid properties of the compositions obtained in Example 6 and Control Example 2 after a dissolution test.
- FIG. 4 is a graph comparing changes in blood concentration of Compound A when orally administered with the compositions obtained in Example 1 and Control Example 1.
- the oral pharmaceutical composition of the present invention is a semisolid or liquid composition, contains two or more surfactants having different molecular weights, and uniformly disperses a pharmaceutically active ingredient in a microemulsion in the digestive tract. It has a function of dispersing.
- “microphone emulsion” refers to a state in which a dispersed phase (a medicinal ingredient-containing phase) is dissolved in a dispersion medium via a surfactant micelle, and its droplet diameter is OO nm or less, preferably 100 nm or less, more preferably 50 nm or less.
- Microemulsions are thermodynamically stable systems, which are fundamentally different from thermodynamically unstable general emulsions (macroemulsions).
- the droplet diameter of the microemulsion can be measured by using a method suitable for the deviation, such as a laser scattering method (Mie's theory) or a dynamic light scattering method (photon correlation method).
- a method suitable for the deviation such as a laser scattering method (Mie's theory) or a dynamic light scattering method (photon correlation method).
- it can be measured using LA-920 (manufactured by HORIBA, Ltd.) when using the laser scattering method
- LB-550 manufactured by HORIBA, Ltd.
- Liquid pharmaceutical compositions may or may not be clear.
- the fact that the pharmaceutical composition of the present invention forms an emulsion means that 0.3 g of the pharmaceutical composition is dispersed in 20 mL of a solvent (1 M aqueous sodium salt solution or second liquid of Japanese Pharmacopoeia) heated to 40 ° C.
- the turbidity of the resulting dispersion can be easily evaluated by measuring it with an absorbance meter (wavelength: 550 nm, cell length: lcm). At this time, the absorbance is 0.2 or less, preferably 0.1 or less, and more preferably 0.05 or less, regardless of which solvent is used.
- the oral pharmaceutical composition of the present invention contains two or more surfactants having different molecular weights.
- the difference in molecular weight between the surfactant having the minimum molecular weight and the surfactant having the maximum molecular weight is preferably 300 or more, more preferably 800 or more, and most preferably 1200 or more.
- the two or more surfactants having different molecular weights are preferably surfactants belonging to the same family.
- the "homologous series" in the “homologous series of surfactants” means, for example, a long-chain fatty acid glyceride having a long-chain polyoxyethylene as a hydrophilic group and a medium-chain fatty acid glyceride having a short-chain polyoxyethylene as a hydrophilic group.
- the surfactants to be compared are formed of the same type of structural unit, respectively, as in the relationship of As the surfactant, a nonionic surfactant, a surfactant derived from a natural product, and the like are used.
- nonionic surfactant examples include glycerin fatty acid ester, fatty acid ethylene oxide adduct, higher alcohol ethylene oxide adduct, alkylphenol ethylene oxide adduct, and polyhydric alcohol fatty acid ester ethylene oxide adduct. Higher alkylamine ethylene oxide adducts, fatty acid amide ethylene oxide adducts, oil and fat ethylenoxide adducts, fatty acid esters of pentaerythritol, alkyl ethers of polyhydric alcohols, fatty acid amides of alkanolamines, etc.
- fatty acid esters of sorbitol and sorbitan polyoxyethylene sorbitan fatty acid esters, polyethylene glycol fatty acid esters, sucrose fatty acid esters, polyoxyethylene glycerin fatty acid esters, polyoxyethylene castor oil (polyethoxylated castor oil) oil), polyoxyethylene hydrogenated castor oil, polyoxyethylene polypropylene glycol copolymer, glycerin fatty acid ester, polyglycerin fatty acid ester and the like are preferably used.
- Examples of naturally-derived surfactants include lecithin phospholipids such as egg yolk lecithin (trade name: PL-100H, Kewpie Co., Ltd.) and soybean lecithin (trade name: Resinol S-10, Nikko Chemicals Co., Ltd.) Used.
- lecithin phospholipids such as egg yolk lecithin (trade name: PL-100H, Kewpie Co., Ltd.) and soybean lecithin (trade name: Resinol S-10, Nikko Chemicals Co., Ltd.) Used.
- the two or more surfactants having different molecular weights in the present invention each have 12 or more HLBs, and preferably have 14 or more HLBs.
- fatty acid glycerides having a polyoxyethylene chain in a hydrophilic group are preferred, and specifically, a long chain fatty acid glyceride having a long chain polyoxyethylene in a hydrophilic group and a short chain are preferred.
- a combination with a medium-chain fatty acid glyceride having polyoxyethylene as a hydrophilic group is preferred.
- a long-chain fatty acid glyceride having a long-chain polyoxyethylene as a hydrophilic group is a C fatty acid having a polyoxyethylene chain having a repeating number of ethylene oxide units of 20 to 500 in the hydrophilic group.
- polyoxyethylene curing Examples include a combination of castor oil and polyethylene glycol monolithic prylic acid z-capric acid glyceride, a combination of polyoxyethylene (40) -hardened castor oil and polyethylene glycol (8) -pyrrolic acid Z capric acid glyceride, and the like.
- the content of the surfactant is 10% by weight or more based on the whole pharmaceutical composition, preferably 20 wt% or more.
- the two or more surfactants having different molecular weights are a long-chain fatty acid glyceride having a long-chain polyoxyethylene in a hydrophilic group and a medium-chain fatty acid glyceride having a short-chain polyoxyethylene in a hydrophilic group, respectively.
- the pharmaceutical composition Each compounding ratio in the product is 1: 1
- the ratio is 0-10: 1, preferably 1: 5-5: 1.
- the pharmaceutically active ingredient that can be contained in the pharmaceutical composition of the present invention is not particularly limited.
- the present invention is particularly applicable to a poorly water-soluble or water-insoluble pharmaceutically active ingredient in the gastrointestinal tract upon oral administration. It has an excellent effect in enhancing the absorbability of the drug and improving the bioavailability of the active ingredient.
- Water-insoluble '' means, for example, that the solubility in water at 25 ° C is less than 10 mgZmL, preferably less than 0.1 mgZmL. Show. The solubility can be measured according to a conventional method.
- the “5- to 6-membered ring” of the “optionally substituted 5- to 6-membered ring group” represented by R 1 is a 6-membered aromatic such as benzene.
- 5- to 6-membered aliphatic hydrocarbons such as hydrocarbons, cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentagen and cyclohexane, furan, thiophene, pyrrole, imidazole, pyrazole, thiazole, oxazole, 5- to 6-members containing 1 to 2 heteroatoms selected from nitrogen, sulfur and oxygen, such as isothiazole, isoxazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine and triazole Aromatic heterocycle, tetrahydrofuran, tetrahydrothiophene, dithiolane, oxathio
- Benzene is particularly preferable as the "5- to 6-membered ring".
- benzene furan, thiophene, pyridine, cyclopentane, cyclohexane, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, tetrahydropyran (preferably Benzene is particularly preferable.
- Examples of the “substituent” included in the “5- to 6-membered ring” of the “substituted or may be a 5- to 6-membered ring group” represented by R 1 include, for example, halogen Atom, nitro, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyl, substituted or unsubstituted thiol group (sulfur atom is oxidized !, May be substituted !, may be!
- / ⁇ may be substituted with a sulfiel group or a substituted or formed sulfol group), or An amino group, an optionally substituted acyl, an optionally esterified V, a carboxyl group, a substituted or unsubstituted aromatic group, and the like are used.
- alkyl in the optionally substituted alkyl as the substituent for R 1 examples include linear or branched alkyl having 1 to 10 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. —Butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.
- halogen eg, fluorine, chlorine, bromine, iodine, etc.
- nitro hydroxyl group, substituted !
- thiol group eg, thiol, C alkylthio
- 5-, 6-membered cyclic amino such as pyrrole, imidazole, etc.
- esterified or amidated or carboxyl group (eg, carboxyl, C alkoxycarbol,
- C alkoxy eg, methoxy, ethoxy, propoxy, butoxy
- C Anorecoxy eg, methoxymethoxy, methoxyethoxy, ethoxyethoxy,
- Noyl eg, acetyl, propiole, etc.
- C alkylsulfol eg, methanesulfur
- the cycloalkyl in the cycloalkyl which may be substituted as a substituent of R 1 includes, for example, C cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Can be Said optionally substituted
- substituent in the mouth alkyl examples include halogen (eg, fluorine, chlorine, bromine, iodine, etc.), nitro, shear hydroxyl group, and thiol group which may be substituted (eg, thiol, C
- 5- or 6-membered cyclic amino such as ruphorin, pyrrole, imidazole, etc.), esterified or amidated, or carboxyl group (eg, carboxyl, C alkoxycarbo)
- C butoxy, trifluoromethoxy, trifluoroethoxy, etc.
- optionally halogenated C alkoxy C alkoxy eg, methoxymethoxy, methoxyethoxy, ethoxy
- Tansulfol, ethanesulfol, etc.), and the number of substituents is preferably 113.
- substituent in the optionally substituted hydroxyl group as a substituent of R 1 include (1) optionally substituted alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl) C-alkyl such as tert-butyl, pentynole, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl and decyl, preferably low
- (2) may be substituted !, may contain a hetero atom, may be a cycloalkyl (for example, Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. (DC cycloalkyl; tetrahydrofuranyl, tetrahydrothenyl, pyrrolidinyl, villa
- a saturated 5- to 6-membered heterocyclic group containing 112 heteroatoms such as zolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydroviranyl, tetrahydrothiopyranyl and the like (preferably tetrahydroviral); And the like);
- aryl for example, aryl, crotyl, 2-pentyl, 3-hexyl, etc., having 2 to 10 carbon atoms, preferably lower (C) ) Alkenyl
- Cycloalkenyl which may be substituted (for example, cycloalkyl having 3 to 7 carbon atoms such as 2-cyclopentyl, 2-cyclohexyl, 2-cyclopentylmethyl, 2-cyclohexylmethyl, etc.) -And the like);
- (6) formyl or substituted ! may! /, Acyl (for example, alkanol having 2 to 4 carbon atoms (eg, acetyl, propionyl, butyryl, isobutyryl, etc.), alkylsulfo having 114 carbon atoms) (Eg, methanesulfol, ethanesulfol, etc.);
- substituents such as aryl which may be substituted (for example, phenyl, naphthyl, etc.);
- halogen eg, fluorine, chlorine, bromine, iodine, etc.
- nitro sialic hydroxyl group
- thiol group which may be substituted (eg, thiol, C alkylthio, etc.), substitution It has been!
- 5- to 6-membered cyclic amino such as azine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.
- carboxyl group which may be esterified or amidated (eg, carboxyl, C alkoxycarbol, Lubamoyl, mono-C alkyl force Luba Moyl, di-alkyl alkyl rubamoyl, etc.), optionally halogenated C alk
- alkoxy eg, methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoromouth ethoxy, etc .; preferably optionally halogenated c alkoxy), formyl, c
- Alkanoyl eg, acetyl, propiole, etc.
- C alkylsulfol eg, meta
- 5- or 6-membered aromatic heterocyclic ring eg, furan, thiophene, pyrrole, imidazole, pyrazole, thiazole, oxazole, isothiazole, isoxazole, tetrazole, etc.
- a nitrogen atom such as pyridine, pyrazine, pyrimidine, pyridazine and triazole, a sulfur atom and an oxygen atom, a 5- to 6-membered aromatic heterocycle containing 124 selected heteroatoms, etc .
- substituent which the ring may have include a halogen (eg, fluorine, chlorine, bromine, iodine, etc.), a thiol group, a hydroxyl group, a thiol group, an amino group, a carboxyl group, and a halogenated group.
- Yo! ⁇ C alkyl eg, trifluoromethyl, methyl, ethyl, etc.
- c alkoxy eg, methoxy, ethoxy, propoxy, butoxy, trifluorome
- C alkylsulfol eg, methanesulfol, ethanesulfol, etc.
- the number of substituents is preferably 113. And the like, and the number of substituents is preferably one to three.
- Examples of the substituent in the thiol group which may be substituted as the substituent of R 1 include the same as the above-mentioned ⁇ substituted as a substituent of, or a substituent in a hydroxyl group '' But especially
- alkyl for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentinole, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl
- alkyl for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentinole, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl
- C alkyl preferred
- cycloalkyl for example, C cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like
- aryls for example, phenol, naphthyl, etc. are preferred.
- Substituted or substituted alkyl (2) Substituted !, substituted or cycloalkyl, (3) optionally substituted aralkyl, and (4) substituted or unsubstituted
- Substituents that may be possessed by good aryl include halogen (eg, fluorine, chlorine, bromine, iodine, etc.), nitro, hydroxyl group, thiol group which may be substituted (eg, thiol, C
- 5- or 6-membered cyclic amino such as ruphorin, pyrrole, imidazole, etc.), esterified or amidated, or carboxyl group (eg, carboxyl, C alkoxycarbo)
- C butoxy, trifluoromethoxy, trifluoroethoxy, etc.
- optionally halogenated C alkoxy C alkoxy eg, methoxymethoxy, methoxyethoxy, ethoxy
- Tansulfol, ethanesulfol, etc.), and the number of substituents is preferably 113.
- Examples of the substituent of the amino group which may be substituted as the substituent of R 1 include the same substituents as those described above as the “substituted or substituted in the hydroxyl group”. Examples thereof include an amino group which may have two, among which (1) optionally substituted alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butynole, tert —C alkyl, preferably lower (C) alkyl, such as butinole, pentinole, isopentenole, neopentinole, hexinole, heptyl, octyl, nonyl, and decyl
- optionally substituted alkyl for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butynole, tert —C alkyl, preferably lower (C) alkyl,
- cycloalkyl for example, cyclopropyl, cyclobutyl, cycloalkyl, C cycloalkyl such as clopentyl, cyclohexyl and cycloheptyl
- aryl for example, aryl, crotyl, 2-pentenyl, 3-hexyl, etc., having 2 to 10 carbon atoms, preferably lower (C) Alkenyl
- Cycloalkenyl which may be substituted (for example, cycloalkyl having 3 to 7 carbon atoms such as 2-cyclopentyl, 2-cyclohexyl, 2-cyclopentylmethyl, 2-cyclohexylmethyl, etc.) -And the like);
- (5) formyl or substituted ! may! /, Acyl (for example, alkanol having 2 to 4 carbon atoms (eg, acetyl, propionyl, butyryl, isobutyryl, etc.), alkylsulfo having 114 carbon atoms) (Eg, methanesulfol, ethanesulfol, etc.);
- halogen eg, fluorine, chlorine, bromine, Iodine, etc.
- nitro hydroxyl group
- substituted or thiol group eg, thiol, C alkyl
- 5- or 6-membered cyclic amino such as ruphorin, pyrrole, imidazole, etc.), esterified or amidated, or carboxyl group (eg, carboxyl, C alkoxycarbo)
- C butoxy, trifluoromethoxy, trifluoroethoxy, etc.
- optionally halogenated C alkoxy C alkoxy eg, methoxymethoxy, methoxyethoxy, ethoxy
- C alkanol eg, acetyl, propiole, etc.
- C alkylsulfur eg, methyl Tansulfol, ethanesulfol, etc.
- the number of substituents is preferably 113.
- the amino group which may be substituted as a substituent of R 1 is a cyclic amino group (for example, tetrahydropyrrole, piperazine, piperidine, morpholine, 5 to 6-membered ring-forming nitrogen atom such as thiomorpholine, pyrrole, imidazole, etc. may be formed except for one hydrogen atom, and may form a cyclic amino group having a bond on the nitrogen atom) .
- a cyclic amino group for example, tetrahydropyrrole, piperazine, piperidine, morpholine, 5 to 6-membered ring-forming nitrogen atom such as thiomorpholine, pyrrole, imidazole, etc. may be formed except for one hydrogen atom, and may form a cyclic amino group having a bond on the nitrogen atom
- the cyclic amino group may have a substituent, and such a substituent may be, for example, halogen (eg, fluorine, chlorine, bromine, iodine, etc.), nitro, shear hydroxyl group, or a substituted or unsubstituted hydroxyl group. , Thiol groups (eg, thiol, C alkylthio, etc.), substituted
- Amino groups that may be substituted eg, mono-C-anolequinoleamino,
- 5- or 6-membered cyclic amino such as trahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.), esterified or amidated
- carboxyl group eg, carboxyl, C alkoxycarbol, carbamoyl
- V may, c alkoxy (eg, methoxy, ethoxy, propoxy, butoxy, trifluoro
- C alkylsulfol eg, methanesulfol, ethane
- R 1 is substituted as a substituent!
- alkyl eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentinole, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl
- alkyl eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentinole, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl
- C alkyl preferred
- cycloalkyl for example, C cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like
- aryl for example, aryl, crotyl, 2-pentenyl, 3-hexyl, etc., having 2 to 10 carbon atoms, preferably lower (C)
- Alkenyl for example, aryl, crotyl, 2-pentenyl, 3-hexyl, etc., having 2 to 10 carbon atoms, preferably lower (C)
- Cycloalkyls which may be substituted for example, cycloalkyls having 3 to 7 carbon atoms such as 2-cyclopentyl, 2-cyclohexyl, 2-cyclopentylmethyl, 2-cyclohexylmethyl, etc.
- An optionally substituted 5- to 6-membered monocyclic aromatic group eg, phenyl, pyridyl, etc.
- a carboxy group or a sulfonyl group eg, formyl , Acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, otatanyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl, crotonyl, 2-cyclohexenecarbonyl, benzoyl , Nicotinoyl, methanesulfonyl, ethanesulfonyl, etc.) and the above-mentioned (2) substituted or unsubstituted alkyl, (3) optionally substituted cycloalkyl, and
- V a cycloalkyl, and (6) a substituted! -Substituted or 5- or 6-membered monocyclic aromatic group which may have a halogen atom (eg, Fluorine, chlorine, bromine, iodine, etc.), nitro, hydroxyl group, thiol group which may be substituted (eg, thiol, C
- 5- or 6-membered cyclic amino such as thiomorpholine, pyrrole, imidazole, etc.), esterified or amidated, or carboxyl group (eg, carboxyl, C alkoxy)
- V may be a C alkoxy C alkoxy (eg, methoxymethoxy, methoxyethoxy,
- One to three is preferred.
- the carboxyl group which may be esterified as a substituent of R 1 includes (1) hydrogen
- alkyl eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentinole, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl
- alkyl eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentinole, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl
- C alkyl preferred
- cycloalkyl for example, C cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
- aryl for example, aryl, crotyl, 2-pentenyl, 3-hexyl, etc., having 2 to 10 carbon atoms, preferably lower (C) ) Alkenyl
- Cycloalkyls which may be substituted for example, cycloalkyls having 3 to 7 carbon atoms such as 2-cyclopentyl, 2-cyclohexyl, 2-cyclopentylmethyl, 2-cyclohexylmethyl, etc.
- aryl eg, phenyl, naphthyl, etc.
- carboxyloxy group preferably carboxyl, lower (C 2) alkoxycarbo-
- aryloxycarbonyl eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbol, phenoxycarbol, naphthoxycarbol, etc.
- substituents that may be possessed by halogen include halogen (eg, fluorine, chlorine, bromine, iodine, etc.), nitro, hydroxyl group, thiol group (eg, thiol, C alkylthio etc.), substituted! / ⁇
- Amino groups eg, mono-C-alkylamido-containing di-Calkylamido-containing tetrahydropyro-
- methoxymethoxy, methoxyethoxy, ethoxyethoxy, trifluoromethoxyethoxy, trifluoroethoxyethoxy, etc. formyl, C alkanols (eg, acetyl, propyl
- C alkylsulfol eg, methanesulfol, ethanesulfol, etc.
- the aromatic group in the aromatic group which may be substituted as a substituent of R 1 includes phenyl, pyridyl, furyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, and tetrazolyl.
- 5- to 6-membered homo- or heterocyclic aromatic groups such as benzofuran, pyrazil, pyrimidinyl, pyridazinyl, triazolyl, benzofuran, indone, benzothiophene, benzoxazole, benzthiazonole, indazonole, benzimidazole, quinoline, isoquinoline
- condensed heterocyclic aromatic groups such as quinoxaline, phthalazine, quinazoline, cinnoline, and imidazopyridine.
- substituents of these aromatic groups include halogen (eg, fluorine, chlorine, bromine, iodine, etc.), nitro, sialic hydroxyl, and substituted or unsubstituted thiol groups (eg, thiol, C alkylthio).
- Substituted amino groups eg, mono-C alkyl with diamine, di-C alkyl with amino
- 1-4 4-5-membered cyclic amino such as lamino, tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.), esterified or amidated
- carboxyl groups eg, carboxyl, C alkoxycarbol, carboxyl
- C alkylsulfol eg, methanesulfol
- Tansulfol and the like, and the number of substituents is preferably 113.
- the strong R 1 substituents may be 114 (preferably 112) identical or different and may be substituted at any position of the ring.
- R 1 When the “5-6 membered ring” of the “optionally substituted 5-6 membered ring” represented by R 1 has two or more substituents, two of these substituents Bond to, for example, lower (C) alkylene (eg, trimethylene, tetramethylene, etc.)
- Lower (C) alkyleneoxy eg, —CH 2 —O—CH 2 —O—CH 2 —CH 2 O—C
- Luquilenamino eg, -O-CH-NH-O-CH-CH-NH-, etc.
- lower oxy C
- Alkylenethio eg, -O-CH-S-, -O-CH-CH-S-, etc.
- the divalent group formed by bonding two substituents of R 1 to each other is a “5- to 6-membered ring” of the “substituted or 5- to 6-membered ring” represented by R 1 .
- '' May have the same substituents as the ⁇ substituents '' (eg, a nitrogen atom, nitro, an optionally substituted alkyl, an optionally substituted cycloalkyl, a substituted A hydroxyl group which may be substituted, a thiol group which may be substituted (a sulfur atom may be oxidized, may be substituted, may be substituted, may be a sulfiel group, or may be substituted or may form a sulfol group, ), Substituted !, may! / Amino group, optionally substituted carbyl, esterified or amidated carboxyl group, substituted Alternatively, it may have one to three aromatic groups).
- the “5-substituted or 5- or 6-membered ring group” represented by R 1 has a “5- to 6-membered ring” having! /
- “Substituents” include, inter alia, halogenated or lower (C) alkoxylated
- lower (C) alkyl eg, methyl, ethyl, t-butyl, trifluoromethyl, methoxy
- Si butoxy, t-butoxy, trifluoromethoxy, methoxymethoxy, ethoxymethoxy, propoxymethoxy, butoxymethoxy, methoxyethoxy, ethoxyethoxy, propoxyshethoxy, butoxyethoxy, methoxypropoxy, ethoxypropoxy, propoxypropoxy
- Good amino eg, amino, methinoleamino, honoleminoleamino with dimethylami, acetinoleamino, etc.
- 5- to 6-membered cyclic amino group eg, 1-pyrrolidyl, 1-piperazyl, 1-piberidyl, 4 morpholinyl
- Examples of the ⁇ divalent group having 1 to 4 atoms constituting the straight-chain portion '' represented by X 1 and X 2 include, for example, (CH 2) (a ′ is an integer of 1 to 4 (preferably 1 An integer of 2)],
- V a diamino group (e.g., lower (C) alkyl, lower (C) cycloalkyl, formyl,
- X 1 represents a bond, — (CH 2) —O— [b, is an integer of 0, 1 or 2 (preferably 0—1
- — (CH) — [a, represents an integer of 1 to 2]
- X 3 represents an optionally substituted imino group, carboyl group, oxygen atom or optionally oxidized sulfur atom]
- CH CH—CO—NH—SO—NH—
- the divalent groups represented by X 1 and X 2 may have a substituent at any position (preferably on a carbon atom). If it is possible to bond to the chain of this type, it may be shifted, for example, lower (C) alkyl (eg, methyl, ethyl
- lower alkyl having 16 carbon atoms preferably, C alkyl
- Examples of the phosphono group which may be esterified include P (0) (OR 7 ) (OR 8 ), wherein R 7 and R 8 are each hydrogen, an alkyl group having 16 carbon atoms or a carbon atom having 3 carbon atoms. —7 represents a cycloalkyl group, and R 7 and R 8 are bonded to each other to form a 5- to 7-membered ring;
- the alkyl group having 16 carbon atoms represented by R 7 and R 8 includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl , Neopentyl, hexyl, etc.
- the cycloalkyl having 3-7 carbon atoms includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Examples include lower alkyl having 16 carbon atoms, more preferably lower alkyl having 13 to 13 carbon atoms.
- R 7 and R 8 may be the same or different, but are preferably the same. When R 7 and R 8 are bonded to each other to form a 5- to 7-membered ring, R 7 and R 8 are bonded to each other to form (CH)
- the esterified carboxyl group of the carboxyl group may be a carboxyl group and a carboxyl group having 16 to 16 carbon atoms or a cycloalkyl group having 3 to 7 carbon atoms.
- the “5- to 6-membered ring” of the “substituted or 5- to 6-membered ring” represented by A includes C cycloalkane (eg, cyclopentane, cyclopentane, Hexane, etc.), C cycloalkene
- C cycloalkadiene eg, 2,4-cyclopentadiene, 2,4-cyclopentene
- 5- to 6-membered saturated or unsaturated alicyclic hydrocarbons such as chlorohexene and 2,5-cyclohexadiene); 6-membered aromatic hydrocarbons such as benzene; oxygen, sulfur, and nitrogen atoms 5-6 members containing at least one (preferably 1 to 4, more preferably 1 to 2) heteroatom 1 or 3 (preferably 1 or 2) of the same selected heteroatoms
- the “aromatic heterocyclic ring” is a 5- to 6-membered aromatic monocyclic ring Heterocycles (e.g., furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazonole, pyrazonole, 1,2,3 oxaziazonole, 1,2,4 oxadiazonole, 1,3,4 oxaziazonole , Frazan, 1,2,3-Cheer Azonole, 1,2,4-thiadiazonole, 1,3,4-thiadiazole, 1,2,3 triazole, 1,2,4 triazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, etc.)
- Examples of the “non-aromatic heterocyclic ring” include 5- to 6-membered groups such as pyrrolidine, tetrahydrofuran,
- non-aromatic in which the double bond is partially or entirely saturated, such as a saturated or unsaturated non-aromatic heterocycle (aliphatic heterocycle) or the above-mentioned aromatic monocyclic heterocycle. And heterocycles.
- the “5- to 6-membered ring” of “substituted !, may be! /, 5- to 6-membered ring” represented by A is a 5- to 6-membered ring.
- An aromatic ring is preferred, and benzene, furan, thiophene, pyrrole, pyridine (preferably a 6-membered ring) and the like are preferred, and benzene is particularly preferred.
- the “substituted ! may be! /, 5-6 membered ring” of “5-6 membered ring” represented by A! /, May be! / ⁇
- the same substituents as the “substituent” which “5-6 membered ring” of “substituted or 5-6 membered ring group” represented by R 1 may have may be mentioned.
- the substituents of A may be the same or different and may be substituted at any one of fourteen (preferably one and twelve) positions on the ring. Replace with any of
- Examples of the lower alkyl group of the “substituted or lower alkyl group” represented by R 3 include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, CA such as pentyl, isopentyl, neopentyl and hexyl
- Examples of the lower alkoxy group of the “substituted or lower alkoxy group” represented by R 3 include C alkoxy such as methoxy, ethoxy, propoxy and butoxy.
- substituents which the "substituted or lower alkyl group” and the “substituted or lower alkoxy group” may have include, for example, halogen (eg, fluorine, chlorine) , Bromine, iodine), hydroxyl groups, mono- (lower alkyl) amido-containing di (lower alkyl) amido-containing lower alkanols.
- halogen eg, fluorine, chlorine
- the lower alkyl in which the mono (lower alkyl) Amino and di (lower alkyl) Amino has, for example, those similar to the lower alkyl group of the "optionally substituted lower alkyl group" represented by the above R 3 Is raised.
- Examples of the lower alkanol include C alkanol such as acetyl, propiol, butyryl, isoptyryl and the like.
- halogen atom represented by the above R 3
- fluorine, chlorine, bromine, and iodine can be mentioned up.
- R 3 is substituted !, and may be a lower C alkyl group or a halogen atom.
- Y ′ represents a divalent group, and other symbols are as defined above), and may have a substituent at any substitutable position. And the like.
- the divalent group represented by Y ′ represents a divalent group forming an 8- to 10-membered ring in which ring B may be substituted, for example,
- -Alk -O-Alk-(Alk and Alk are each a bond or a divalent C1-C5 al a2 al a2
- Alk-(Alk and Alk are each a bond or a carbon number of 1 to 5 2 el e2 el e2
- Alk and Alk are each a bond or a divalent linear hydrocarbon group having 1 to 4 carbon atoms e6 e7
- the total number of carbon atoms of Alk and Alk is 4 or less).
- Ring B is preferably an 8-membered ring.
- the divalent group may have a substituent, and the substituent may be, for example, a “5-substituted or 5-substituted 5-membered ring group” represented by R 1 .
- a 6-membered ring may have a lower (C) alkyl (e.g., methyl), even though it may have the same substituents and oxo as the substituent.
- the substituents of such a divalent group may be substituted with 116 (preferably, 112) identical or different substituents.
- the substitution position may be any position as long as it can bind to the divalent group.
- Formula -N (R)-wherein represents a hydrogen atom or a substituent. And a group having a divalent group represented by the formula: In particular, in the main chain, the formula -N (R)-[wherein represents a hydrogen atom or a substituent. And a group having a divalent group represented by the formula:
- R is a hydrogen atom, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, a hydroxyl group which may be substituted, a thiol group which may be substituted (sulfur atoms are oxidized; , May be substituted, may be, a sulfier group or substituted! Or a substituted or unsubstituted amino group, an esterified or amidated group, a carboxyl group, or a substituted group!
- Preferred are a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted heterocyclic group, and an optionally substituted acyl group.
- Preferred embodiments include a hydrogen atom, a hydrocarbon group which may be substituted, a substituted or unsubstituted group, and an acyl group. Converted or hydroxylated, C alkyl, halogenated or hydroxylated
- R is more preferably C alkanoyl, which may be hydrogenated or hydroxylated
- C alkanols which may be hydroxylated, are even more preferred, especially propyl,
- Isobutyl, isobutur or 3-hydroxy-2-methylpropyl are preferred.
- a 5- to 6-membered monocyclic aromatic group for example, those similar to the “5- to 6-membered monocyclic aromatic group” exemplified in the section of Ring A
- 1-4 represents 1-4, which may be substituted with alkoxy and the like, respectively, and represents pyryl, pyridyl, pyrazolyl, thiazolyl, oxazolyl, tetrazolyl, etc.). And the like.
- hydrocarbon group of the “substituted or may be a hydrocarbon group” include, for example,
- alkyl for example, C alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butynole, tert-butynole, pentynole, isopentynole, neopentynole, hexinole, heptyl, octyl, noel, decyl, etc., preferably Is low (C) alkyl (for example, C alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butynole, tert-butynole, pentynole, isopentynole, neopentynole, hexinole, heptyl, octyl, noel, decyl, etc., preferably Is low (C) al
- cycloalkyl for example, C cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like;
- alkaryl for example, alkaryl having 2 to 10 carbon atoms, such as allyl, crotyl, 2-pentenyl, and 3-xenyl, preferably lower (C) alkalyl, etc.
- cycloalkyl for example, cycloalkyl having 3-7 carbon atoms such as 2-cyclopentyl, 2-cyclohexyl, 2-cyclopentylmethyl, 2-cyclohexylmethyl, etc.
- Alkyl for example, alkyl having 2 to 10 carbon atoms such as ethur, 1-propier, 2-probyl, 1-butchur, 2-pentyl, and 3-kisul, preferably lower (C
- aralkyl eg, phenyl C alkyl (eg, benzyl, phenethyl, etc.)
- cycloalkyl alkyl for example, C cycloalkyl such as cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, etc.
- substituent which the cycloalkylalkyl may have include halogen (eg, fluorine, chlorine, bromine, iodine, etc.), nitro, shear hydroxyl group, and optionally substituted thiol group (eg, thiol group). , C alkylthio, etc.), substituted !, or amino groups (eg, mono-C
- 5- or 6-membered cyclic amino such as holin, thiomorpholine, pyrrole, imidazole, etc.
- halogenated may be c-alkyl (eg, trifluoromethyl)
- V may be a sulfonamide [e.g., substituted, may be an amino group (e.g., mono-C
- C alkylsulfonyl eg, methanesulfonyl, ethanesulfonyl
- the number of substituents is preferably 113.
- the "substituted or heterocyclic group” and the substituted represented by R ° may be substituted!
- the “heterocyclic group” in the / ⁇ complex ring group a group formed by removing one hydrogen atom from an aromatic hetero ring or a non-aromatic hetero ring and the like can be mentioned.
- the aromatic heterocycle include nitrogen such as furan, thiophene, pyrrole, imidazole, pyrazole, thiazole, oxazole, isothiazole, isoxazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, triazole, oxaziazole, and thiadiazole.
- Atoms, sulfur atoms and oxygen and nuclear selected from 5- to 6-membered aromatic heterocycles containing 1 to 4 selected heteroatoms, and the non-aromatic heterocycles include, for example, Tetrahydran furan, tetrahydrothiophene, dioxolan, dithiolane, oxathiolane, pyrrolidine, pyrroline, imidazolidine, imidazoline, villazolidine, pyrazoline, piperidine, piperazine, oxazine, oxazine, thiazine, thiadiazine, morpholine, thiomoline 5- to 6-membered non-aromatic heterocycles containing 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen, such as ruphorin, pyran and tetrahydropyran, and the above aromatics
- Non-aromatic heterocycles in which some or all of the heterocyclic bonds are saturated bonds preferably, aromatic heterocycles such as pyrazole,
- Substituted or may be a hydroxyl group “substituted or may be a thiol group”, “optionally substituted amino group”, or “optionally esterified carboxyl group”
- the “substituted or may be an acyl group” includes the “5 to 6-membered ring group” of the “substituted or may be a 5- to 6-membered ring group” for R 1 Alternatively, as a substituent, “substituted or optionally substituted hydroxyl group”, “optionally substituted thiol group”, “optionally substituted amino group", “esterified Also, a carboxyl group may be mentioned, and the same as the "substituted or substituted alkoxy group” may be mentioned.
- “Amidated, may be a carboxyl group” Wherein the above-mentioned “substituted or may be an amino group” and the like are bonded to a carboxy group, preferably a carbamoyl group, a mono-C-alkyl group or a di-C-alkyl group.
- heterocyclic group the substituted or unsubstituted methyl or the substituted or unsubstituted imino group which may have a heterocyclic methyl are defined as those described in the parentheses (Y). Means what goes in. Of these, 1) C alkyl, 2) C alkyl
- the above 1) and 2) may be substituted with a halogen or a hydroxyl group.
- the above 3), 4), 5) and 6) may be substituted with a halogen, a halogen or a hydroxyl group, and may be a C alkyl or a halo.
- such a substituent of B may be substituted at any position (including E and E) of 117 (preferably, 112) identical or different ring (s). Is unsubstituted
- E and E are each optionally substituted carbon atoms (preferably
- the “divalent cyclic group” represented by Z 1 includes “5-6 membered ring” of “optionally substituted 5- to 6-membered ring group” represented by R 1 Similar or condensed aromatic heterocyclic compounds such as benzofuran, indole, benzothiophene, benzoxazole, benzthiazoline / indole, indazole, benzimidazole, quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline, imidazopyridine, etc.
- aromatic heterocyclic compounds such as benzofuran, indole, benzothiophene, benzoxazole, benzthiazoline / indole, indazole, benzimidazole, quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline, imidazopyridine, etc.
- Groups formed by removing two atoms among which benzene, furan, thiophene, pyridine, pyridazine, pyrimidine, benzimidazole, cyclopentane, cyclohexane, pyrrolidine, piperidine, piperazine, morpholine , Thiomorpholine, tetrahydropyran, etc. are formed by removing two hydrogen atoms.
- a divalent cyclic group formed by the above method is preferably used.
- the “divalent cyclic group” represented by Z 1 has the “5- to 6-membered ring” of the “substituted or 5- to 6-membered ring group” represented by R 1 , It may have the same substituent as the ⁇ substituent '', and among them, a halogen atom (e.g., fluorine, chlorine, bromine, etc.) or a halogen atom may be substituted as a substituent. /, C alkyl group (eg, methyl, ethyl, trifluoromethyl, trif
- Z 1 is a 6-membered When it is a divalent cyclic group (preferably phenylene), the substitution position of Z 2 is preferably the para position of X 2 .
- the substituent may be 1) halogen atom, 2) substituted with halogen atom, or C alkyl group or 3) substituted with halogen atom!
- phenylene is preferred, and methyl is particularly preferred as a substituent.
- the divalent group represented by Z 2 is, for example,
- the formula- ⁇ ⁇ - ⁇ - ⁇ 213- ⁇ 23 and Z 2b are each 0, S (0) m (m represents 0, 1 or 2), and may be substituted with a dimino group (one N (R a ) represents one) or a bond, and W 1 represents a substituted or unsubstituted alkylene group, a substituted alkenylene group or a bond. ), And the bonding position of Z 2 may be any position when Z 1 is, for example, a benzene ring, but is preferably a nora position.
- R a a hydrogen atom, a substituted or unsubstituted lower (C) alkyl [eg, methyl, ethyl, propyl ,
- C alkyl cyanates eg, cyanoethyl, cyanopropyl
- Esterified or amidated may be carboxy C alkyl, etc.],
- Formyl, lower (C) alkanol eg, acetyl, propionyl, butyryl, etc.
- Alkylene group” represented by W 1 examples include, for example, an alkylene chain represented by (CH) — (kl is an integer of 1-4). Can be By W 1
- alkenyl group of the “optionally substituted alkenyl group” examples include, for example,
- the alkylene group and alkenylene group represented by W 1 may have a substituent at any position (preferably on a carbon atom). Any of those which can be bonded to a chain or an alkenylene chain may be used.
- lower (C) alkyl eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sebutyl
- cycloalkyl eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentyl
- Lower alkyl having 1 to 6 primes (preferably C alkyl), hydroxyl, oxo, hydroxy
- Amino group (hydroxyl group, cyano group, carboxyl group which may be esterified or amidified (eg, carboxyl, C alkoxycarbol, carbamoyl, mono C alkyl)
- 1-4 is substituted with a polar group such as l-bamoyl or di-alkyl alkyl l-bamoyl! /
- V ⁇ lower (C) alkoxyimino groups and the like.
- P (0) (OR 9 ) (OR 1G ) [wherein, and R 1G are each hydrogen, an alkyl group having 1 to 16 carbon atoms or carbon number. And represents a cycloalkyl group of 3-7, and R 9 and R 1G are bonded to each other to form a 5- to 7-membered ring.
- the alkyl group having 16 carbon atoms represented by R 9 and R 1C> includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pen Butyl, isopentyl, neopentyl, hexyl, etc.
- the cycloalkyl having 3-7 carbon atoms includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.
- Lower alkyl having 11 to 16 carbon atoms more preferably lower alkyl having 13 to 13 carbon atoms.
- R 9 and R 1G may be the same or different, but are preferably the same.
- R 9 and R 1G are bonded to each other to form a 5- to 7-membered ring
- R 9 and R 1C> are bonded to each other to form (CH 2)
- the chain may have a substituent.
- the strong substituent include a hydroxyl group and a halogen.
- the esterified carboxyl group may be, for example, a carboxyl group bonded to a carboxyl group and an alkyl group having 16 to 16 carbon atoms or a cycloalkyl group having 3 to 7 carbon atoms, for example, methoxycarboxy group.
- the amide compound of the carboxyl group after being subjected to the amidation may be, for example, a carboxyl group and an alkylamino group having 1 to 16 carbon atoms, a cycloalkylamino group having 3 to 7 carbon atoms, or a 5- to 8-membered cyclic amine (eg, , Pyrrolidine, piperidine, morpholine, etc.), for example, rubamoyl, mono-C alkyl rubamoyl, di-C alkyl rubamoyl,
- Examples include ethylaminocarbonyl, cyclohexylaminocarbonyl, pyrrolidinocarbonyl, piperidinocarbon, morpholinocarbon, and thiomorpholinocarbon.
- Z 2 one of Z 2a and Z 2b is 0, S (0) m (m is 0, 1 or 2) or N (R a ) (R a is a hydrogen atom or substituted, (Indicates lower C alkyl group.)
- W is-(CH) (p is an integer of 1 to 3) or Z 2 is -C
- H (OH) is preferably a divalent group.
- Z 2a and Z 2b is 0, S (0) m (m is 0, 1 or 2), the other is a bond, and W is ⁇ (CH) — (p is an integer of 1 to 3 )
- Z 2 gar CH (OH) - Z 2 in the gesture et divalent group is more preferred is the CH C
- z 2a represents a bond, s, so or so, but among them
- so is preferred, and the configuration of so is (S).
- the "substituted, optionally substituted, nitrogen-atomic-grade ammodimated or oxidized, optionally an amino group" represented by R 2 is Examples thereof include a diamino group having two substituents, an amino group having three substituents, and being a nitrogen atom-grade ammodime.
- those substituents may be the same or different, and when there are three substituents on the nitrogen atom, N + R P R P R- N + R P R P R q and - N + R P R q Rr (, R q and R 1 are different from each other, showing a hydrogen or a substituent) may be any type of Amino groups.
- a nitrogen atom S4 quaternary ammodimated as a counter-ion of a lumino group, in addition to an anion of a halogen atom (eg, Cl—, Br—, ⁇ , etc.), etc.
- a halogen atom eg, Cl—, Br—, ⁇ , etc.
- Anions derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, Organic acid-induced anions such as malic acid, methanesulfonic acid, benzenesulfonic acid, and P-toluenesulfonic acid; acidic amino acids such as aspartic acid and glutamic acid; and induced anions.
- Cl—, Br— and I— are preferred.
- the substituent of the amino group includes
- alkyl for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentinole, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl
- alkyl for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentinole, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl
- C alkyl preferred
- cycloalkyl which may be substituted (for example, C cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyanooctyl);
- the cycloalkyl contains one heteroatom selected from a sulfur atom, an oxygen atom and a nitrogen atom, and is composed of oxysilane, thiolane, aziridine, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, tetrahydropyran, and tetrahydrothione.
- the position of the bond to the amino group which may form pyran, tetrahydrothioviran 1-oxide, piperidine, etc. is 3-position Or position 4 (preferably position 4) is preferred;
- the cycloalkyl is condensed with a benzene ring to form indane (eg, indane 1-yl, indane 2-yl, etc.), tetrahydronaphthalene (eg, tetrahydronaphthalene 5-yl, tetrahydronaphthalene) -Preferably, such as 6-yl) (preferably, indane).
- indane eg, indane 1-yl, indane 2-yl, etc.
- tetrahydronaphthalene eg, tetrahydronaphthalene 5-yl, tetrahydronaphthalene
- 6-yl preferably, indane
- the cycloalkyl is cross-linked via a straight-chain atomic chain having 112 carbon atoms, and bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, Bicyclo [3.2.1] octyl, bicyclo [3.2.2] nor, and the like (preferably, cyclohexyl having a bridge through a straight-chain atomic chain having 112 carbon atoms, and the like; Preferably, it may form a bridged cyclic hydrocarbon residue of bicyclo [2.2.1] heptyl or the like);
- alkenyl for example, alkenyl having 2 to 10 carbon atoms such as allyl, crotyl, 2-pentyl, 3-hexyl, and preferably lower
- C alkenyl
- Cycloalkenyl which may be substituted (for example, cycloalkyl having 3 to 7 carbon atoms such as 2-cyclopentyl, 2-cyclohexyl, 2-cyclopentylmethyl, 2-cyclohexylmethyl, etc.) -And the like);
- (6) formyl or substituted ! may! /, Acyl (for example, alkanol having 2 to 4 carbon atoms (eg, acetyl, propionyl, butyryl, isobutyryl, etc.), alkylsulfo having 114 carbon atoms) (Eg, methanesulfol, ethanesulfol, etc.), alkoxycarbonyl having 14 to 14 carbon atoms (eg, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbol, etc.), aralkyl with 7 to 10 carbon atoms Xicarbole (eg, benzyloxycarbo ) And the like);
- Acyl for example, alkanol having 2 to 4 carbon atoms (eg, acetyl, propionyl, butyryl, isobutyryl, etc.), alkylsulfo having 114 carbon atoms) (Eg, methan
- aryl which may be substituted eg, phenol, naphthyl, etc.
- an optionally substituted heterocyclic group e.g., furan, thiophene, pyrrole, imidazole, pyrazole, thiazole, oxazole, isothiazole, isoxazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, triazole, oxaziazole
- a group formed by removing one hydrogen atom also having a 5- to 6-membered non-aromatic heterocyclic ring; and more preferably a group such as tetrahydrofuran, piperidine, tetrahydropyran, tetrahydrothiopyran, etc.
- a 5- to 6-membered non-aromatic heterocyclic force containing one heteroatom is also formed except for one hydrogen atom And other substituents.
- the substituents of the amino group may be bonded to each other to form a 5- to 7-membered cyclic amino such as piperidine, piperazine, morpholine and thiomorpholine.
- Alkyl eg, hydroxy C alkyl, cyano C alkyl, carboxyl C alkyl
- Alkyl, etc.), halogenated may be c-alkoxy (eg, methoxy, ethoxy)
- Nitro group, hydroxyl group, thiol group which may be substituted eg, thiol, C
- -Oxo group (preferably halogen, halogenated, or lower (C) alkyl
- the “optionally substituted nitrogen-nuclear-class ammodimed or oxidized amino group” represented by R 2 is preferably
- Halogen, halogenated may be lower (C) alkyl or lower
- (C) is a sulfur atom, an oxygen atom and a nitrogen atom which may have one to three alkyls
- Coal containing one heteroatom or condensed with benzene ring C cycloalkyl which may be bridged through a linear atomic chain having a prime number of 1 to 2 (e.g.,
- Halogen, halogenated may be lower (C) alkyl or halogenated
- a 5- or 6-membered aromatic heterocyclic group (eg, a group formed by removing one hydrogen atom such as furan, thiophene, pyrrole, pyridine, etc.) It has three and is a diamino group.
- the nitrogen atom represented by R 2 which may contain a sulfur atom or an oxygen atom as a ring-constituting atom which may be substituted, is quaternized ammodimated or
- the "nitrogen-containing heterocyclic ring" of the "nitrogen-containing heterocyclic group which may be oxidized” include pyrrole, imidazole, pyrazole, thiazole, oxazole, isothiazole, isoxazole, tetrazole, pyridine, pyrazine, pyrimidine, and pyridazine.
- Nitrogen, sulfur and oxygen atoms such as triazole, oxaziazole, thiadiazole, etc.
- Octane preferably, pyridin, imidazole, triazole, imidazopyridine, pyrrolidine, piperidine, morpholine
- the nitrogen atom of the “nitrogen-containing heterocycle” may be quaternized or oxidized.
- the counter “on” of the "nitrogen-containing heterocyclic group is converted into a nitrogen-nitrogen-containing ammodimated
- anions of halogen atoms eg, C1 Br I
- anions derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid
- Anions derived from organic acids such as trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid,
- anions derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid,
- the “nitrogen-containing heterocyclic group” may be 2-pyridyl, 3-pyridyl, 2-piberidyl which may be bonded to a divalent group represented by Z 2 via a carbon atom or a nitrogen atom. Bonding on the ring-constituting carbon atom as in
- the "nitrogen-containing heterocycle” may have, and as a substituent, halogen (eg, fluorine, chlorine, bromine, iodine, etc.), substituted or lower (C) alkyl, substituted Been!
- halogen eg, fluorine, chlorine, bromine, iodine, etc.
- a nitro group, a hydroxyl group, an optionally substituted thiol group eg, thiol, C
- 5- or 6-membered cyclic amino such as ruphorin, pyrrole, imidazole, etc.), esterified or amidated, or carboxyl group (eg, carboxyl, C alkoxycarbo)
- nitrogen, sulfur and oxygen such as phen, pyrrole, imidazole, pyrazole, thiazole, oxazole, isothiazole, isoxazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, triazole, oxaziazole, thiadiazole, etc.
- a condensed aromatic heterocyclic group containing 124 selected heteroatoms.
- nitrogen-containing heterocyclic ring may have, as a substituent, "substituted or optionally, lower (C) alkyl", “optionally substituted lower (C) alkoxy", "Being replaced
- each "group” may have include, for example, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), a halogenated group, a lower (C) alkyl, a hydroxyl group
- a halogen atom eg, fluorine, chlorine, bromine, iodine, etc.
- a halogenated group eg, fluorine, chlorine, bromine, iodine, etc.
- a lower (C) alkyl eg, hydroxy C alkyl, cyano C
- a polar group such as a carboxyl group which may be a cyano group, an esterified or amidated group.
- Lubamoyl C-alkyl mono C-alkyl power Lubamoyl C-alkyl, di-C al
- C alkoxy eg, methoxy, ethoxy, trifluoromethoxy
- C alkylsulfol eg, methanesulfol, ethanesulfol, etc.
- C alkylsulfol eg, methanesulfol, ethanesulfol, etc.
- 1-4 1-4 alkylenedioxy eg, methylenedioxy, ethylenedioxy, etc.
- cyano, nitro, hydroxyl, substituted or unsubstituted thiol groups eg, thiol, C alkylthio, etc.
- amino group which may be substituted eg, mono-c-alkylamino, di-C-alkylamino
- 1-4 4-5-membered cyclic amino such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrol, imidazole, etc.), esterified or amidated V,
- a carboxyl group eg, carboxyl, C alkoxycarbol, carbamo
- the nitrogen-containing heterocyclic group of the “nitrogen-containing heterocyclic group” may have the following substituents: (1) halogen, (2) cyano, (3) hydroxyl, (4) carboxyl , (5) carbamoyl group, (6) lower (C) alkoxycarbol, (7) lower (C) alkyl carbamoyl or 5-6
- R 5 and R 6 may each be an optionally substituted hydrocarbon group.
- a substituted or unsubstituted hydroxyl group or a substituted or unsubstituted amino group preferably a substituted or unsubstituted hydrocarbon group or a substituted or unsubstituted amino group; more preferably R 5 and R 6 may be substituted with each other to form a cyclic group together with an adjacent phosphorus atom, and R 5 and R 6 may be a group represented by).
- R 5 and R 6 may be a group represented by.
- alkyl for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentinole, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl
- alkyl for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentinole, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl
- C alkyl preferred
- cycloalkyl for example, C cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like
- alkenyl for example, alkenyl having 2 to 10 carbon atoms such as allyl, crotyl, 2-pentenyl, 3-hexyl, and preferably lower (C) Arce-
- Cycloalkenyl which may be substituted (for example, cycloalkyl having 3 to 7 carbon atoms such as 2-cyclopentyl, 2-cyclohexyl, 2-cyclopentylmethyl, 2-cyclohexylmethyl, etc.) -And the like);
- Alkyl which may be substituted (for example, ethur, 1 propyl, 2 propyl) Alkenyl having 2 to 10 carbon atoms, preferably lower (C) alkynyl and the like, such as 1-butyl, 1-butyl, 2-pentyl and 3-hexyl);
- Aralkyl eg, phenyl C alkyl (eg, benzyl
- aryl which may be substituted (for example, phenyl, naphthyl, etc.) and the like, and the above-mentioned (1) optionally substituted alkyl, and (2) optionally substituted ⁇ cycloalkyl, (3) optionally substituted alkyl, (4) optionally substituted cycloalkyl, (5) optionally substituted alkyl, (6) optionally substituted Aralkyl, and (7) substituted !, which may be substituted or unsubstituted, and the substituent may be halogen (eg, fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, etc. Hydroxyl groups, substituted or substituted, thiol groups (eg, thiol, C alkylthio, etc.), substituted!
- amino group e.g., mono-C-alkylamido-containing diCalkylamido-containing tetrahydro
- 5- to 6-membered cyclic amino such as pyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.
- carboxyl group which may be esterified or amidated (eg, carboxyl, C Alkoxy carbole, Levalmoyl, Mono C
- c alkoxy eg, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy
- the “optionally substituted hydroxyl group” represented by R 5 and R 6 includes, for example, (1) optionally substituted alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl) C-alkyl, such as tert-butyl, pentynole, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, and decyl, preferably lower
- optionally substituted alkyl eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl
- C-alkyl such as tert-butyl, pentynole, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, and decyl,
- cycloalkyl for example, C cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like
- aryl for example, aryl, crotyl, 2-pentenyl, 3-hexyl, etc., having 2 to 10 carbon atoms, preferably lower (C) Arce-
- Cycloalkenyl which may be substituted (for example, cycloalkyl having 3 to 7 carbon atoms such as 2-cyclopentyl, 2-cyclohexyl, 2-cyclopentylmethyl, 2-cyclohexylmethyl, etc.) -And the like);
- (6) formyl or substituted ! may! /, Acyl (for example, alkanol having 2 to 4 carbon atoms (eg, acetyl, propionyl, butyryl, isobutyryl, etc.), alkylsulfo having 114 carbon atoms) (Eg, methanesulfol, ethanesulfol, etc.);
- It may have an aryl which may be substituted (for example, phenyl, naphthyl and the like), and may be a hydroxyl group.
- 5- to 6-membered cyclic amino such as azine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.
- carboxyl group which may be esterified or amidated (eg, carboxyl, C alkoxycarbol, Lubamoyl, mono-C alkyl force Luba
- alkoxy eg, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.
- formyl C alkanol (eg, acetyl, propiole, etc.)
- C alkyl sulfol For example, methanesulfol, ethanesulfol, etc.
- One to three is preferred.
- R 5 and R 6 may be bonded to each other to form a cyclic group (preferably a 5- to 7-membered ring) together with an adjacent phosphorus atom.
- a cyclic group may have a substituent, and the substituent may be a halogen (eg, fluorine, chlorine, bromine, iodine, etc.), a nitro, a hydroxy group, a substituted or unsubstituted Thiol groups (eg, thiol, C alkylthio
- Substituted amino groups eg, mono-C alkyl with diamine, di-C alkyl with amino
- 1-4 1-4 5- or 6-membered cyclic amino such as lumino, tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.), esterified or amidated,
- carboxyl groups eg, carboxyl, C alkoxycarbol, carboxyl
- C alkylsulfol eg, methanesulfol, ethanesulfol, etc.
- the counter ion when the phosphorus atom forms a phosphonium salt, the counter ion may be a halogen atom anion (eg, Cl—, Br—, ⁇ , etc.) and the like.
- Inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.Induced anions, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid,
- Anions derived from organic acids such as malic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid, and anions derived from acidic amino acids such as aspartic acid and glutamic acid.
- Cl—, Br— and I— are preferred.
- alkyl for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentinole, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl
- alkyl for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentinole, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl
- C alkyl preferred
- C or lower (C) alkyl.
- optionally substituted cycloalkyl for example, C cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
- aryl for example, aryl, crotyl, 2-pentyl, 3-hexyl, etc., having 2 to 10 carbon atoms, preferably lower (C) ) Alkenyl
- Cycloalkenyl which may be substituted (for example, cycloalkyl having 3 to 7 carbon atoms such as 2-cyclopentyl, 2-cyclohexyl, 2-cyclopentylmethyl, 2-cyclohexylmethyl, etc.) -And the like);
- (5) formyl or substituted ! may! /, Acyl (for example, alkanol having 2 to 4 carbon atoms (eg, acetyl, propionyl, butyryl, isobutyryl, etc.), alkylsulfo having 114 carbon atoms) (Eg, methanesulfol, ethanesulfol, etc.);
- optionally substituted alkyl (2) optionally substituted cycloalkyl, (3) optionally substituted alkyl, and (4) optionally substituted cycloalkyl
- optionally substituted aryl and (6) optionally substituted aryl include halogen (eg, fluorine, chlorine, bromine, iodine, etc.), Toro, hydroxyl group, substituted or thiol group (eg, thiol, C alkyl)
- 5- or 6-membered cyclic amino such as ruphorin, pyrrole, imidazole, etc.), esterified or amidated, or carboxyl group (eg, carboxyl, C alkoxycarbo)
- C alkylsulfol eg, methanesulfol, ethanesulfol
- the number of substituents is preferably 113.
- R 2 ' is substituted, even by an amidino group "and” substituted, even yo guaiacolsulfonate - Jinomoto "Examples of the substituent in the" substituted represented by R 2 described above And the quaternary ammodimated or oxidized nitrogen atom, which may be the same as the substituent in the ⁇ amino group ''.
- R 2 is: (1) an amino group in which a substituted or unsubstituted nitrogen atom may be quaternized or oxidized, or (2) a ring structure which may be substituted. It may contain a sulfur atom or an oxygen atom as an atom, or may be subjected to nitrogen-nuclear-grade ammodimation or oxidation, and may be substituted with a nitrogen-containing heterocyclic group, (3) R 2 is preferably an amidino group or (4) a guadino group which may be substituted, and R 2 may be a nitrogen-nitrogen-grade ammodide which may be substituted.
- An amino group which may be substituted, a nitrogen atom which may or may not contain a sulfur atom or an oxygen atom as a ring constituent atom which may be substituted, or a nitrogen-containing heterocyclic group, etc. Is more preferably substituted with a sulfur atom as an amino group or a ring atom which may be optionally substituted. Contain an atom or an oxygen atom! /, I also, such as the particularly preferred nitrogen-containing heterocyclic group,.
- R 2 is a group represented by the formula NRR "or N + RR'R" (wherein R, R 'and R "may each be substituted.
- An aliphatic hydrocarbon group (aliphatic chain) Or a substituted or unsubstituted or alicyclic (non-aromatic) heterocyclic group), and a substituted or unsubstituted nitrogen atom is an oxidized hydrocarbon group.
- a nitrogen-containing aromatic heterocyclic group which may be substituted is more preferred.
- the “optionally substituted aliphatic hydrocarbon group” and the “optionally substituted alicyclic heterocyclic group” represented by R, R ′ and R ′′ include a substituent R
- the ⁇ substituted or may be an amino group '' represented by 2 has an! / Or an ⁇ substituted or optionally substituted aliphatic hydrocarbon group exemplified as a substituent (e.g., An optionally substituted alkyl, cycloalkyl, aryl, cycloalkyl, etc.) "and an optionally substituted alicyclic group (eg, an optionally substituted 5- to 6-membered group) And the like)) and the like.
- R and R ' are optionally substituted chain hydrocarbon groups (e.g., Or an optionally substituted alkyl, aryl, etc.), and an optionally substituted alkyl group is more preferred, and an optionally substituted methyl group is particularly preferred.
- R is an optionally substituted alicyclic hydrocarbon group (preferably, an optionally substituted C cycloalkyl group; more preferably substituted !, or! /, Cyclohexyl )
- a substituted or unsubstituted alicyclic heterocyclic group preferably, a substituted or unsaturated alicyclic heterocyclic group (preferably a 6-membered ring group);
- tetrahydroviral substituted or may be substituted with tetrahydrothioviral or substituted with V or piperidyl; particularly preferably substituted or optionally substituted tetrahydrovilla- Is preferred.
- nitrogen-containing aromatic heterocyclic group of the "nitrogen-containing aromatic heterocyclic group in which a substituted or unsubstituted nitrogen atom may be oxidized” represented by R 2
- preferred examples include Among gin, imidazole, triazole and imidazopyridine, imidazole and triazole are particularly preferable.
- amino group which may be substituted may be substituted with a nitrogen atom, may be ammodimated or oxidized” represented by R 2 ′ and R 2 , etc.
- R 2 ′ and R 2 may be ammodimated or oxidized
- Substituted ! may, or hydrocarbon group”, “substituted, may, C alkyl” in the substituent represented by R 4 of the imino group of Y and the substituent of the imino group of Y, As for each
- a pharmacologically acceptable salt is preferred, for example, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, and a salt with an organic acid. And salts with basic or acidic amino acids.
- the salt with an inorganic base include, for example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; and aluminum salt, ammonium salt and the like.
- Preferable examples of the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, ⁇ , ⁇ '-dibenzylethylene. And salts with diamine and the like.
- Preferable examples of the salt with an inorganic acid include, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
- salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, ⁇ -sulfonic acid, and the like. Salts with toluenesulfonic acid and the like can be mentioned.
- Preferable examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, orditin and the like.
- Preferred examples of the salt with an acidic amino acid include, for example, aspartic acid, glutamic acid And the like.
- the compound represented by the above formula (I) or a salt thereof can be prepared by a method known per se, for example, a method described in JP-A-2003-335776 and JP-A-8-73476 or a method similar thereto. It can be manufactured by a method.
- the pharmaceutical composition of the present invention can be produced by a method known per se. That is, all components except the pharmaceutically active component are heated in a hot water bath or other methods, and the components are uniformly mixed. Thereafter, a pharmaceutically active ingredient is added to the homogeneous mixture, and the mixture is sufficiently mixed to obtain the pharmaceutical composition.
- the pharmaceutical composition can be filled in a capsule according to a conventional method.
- the preparation of the present invention is an oral preparation encapsulating a semi-solid or liquid pharmaceutical composition containing two or more surfactants having different molecular weights as described above, and is a soft capsule, a hard capsule, a stick packaging. , Drink preparations, liquid preparations for use at the time of use, and the like.
- semi-solid or liquid pharmaceutical compositions containing two or more surfactants having different molecular weights according to the present invention which can be produced by a method described in the general rules of pharmaceutical preparations of the 14th revision of the Japanese Pharmacopoeia.
- Roussillon greatly improves the absorption of the medicinal components, particularly poorly water-soluble medicinal components, into the gastrointestinal tract, and increases the bioavailability. It is not necessary that the entire amount of the pharmaceutical composition of the present invention forms or maintains a microemulsion.
- the compound represented by the above formula (I) or a salt thereof has excellent CCR antagonism, particularly CCR5 and Z or CCR2 antagonism, and particularly strong CCR5 antagonism, and therefore, the human infection with HIV. For example, it can be used for prevention and treatment of AIDS and for prevention and treatment of various other diseases. Further, the compound represented by the above formula (I) or a salt thereof can be safely used with low toxicity.
- a pharmaceutical composition containing the compound represented by the above formula (I) or a salt thereof can be used as a CCR5 antagonist, for example, an agent for preventing or treating AIDS and an agent for suppressing the progression of AIDS.
- a pharmaceutical composition containing the compound represented by the above formula (I) or a salt thereof is useful for the prevention and treatment of graft-versus-host disease and Z or rejection, rheumatoid arthritis, autoimmune disease, allergic disease, Ischemic brain cell injury, myocardial infarction, chronic nephritis, It can be used as a therapeutic agent for preventing arteriosclerosis and as a therapeutic agent for preventing various diseases.
- Examples of the disease targeted by the preventive agent of the present invention include, for example, transplant rejection (rejection after transplantation, erythrocytosis after transplantation, hypertension, organ damage, vascular hypertrophy, graft-versus-host disease, etc.) Bone diseases such as rheumatoid arthritis, osteoarthritis, rheumatoid myelitis, osteoporosis, abnormal proliferation of cells, fractures, refractures, osteomalacia, bone peyet's disease, rigidity Destruction of joint tissues in myelitis, knee osteoarthritis and similar disorders, etc.), autoimmune diseases (collagenous disease, systemic lupus erythematosus, scleroderma, polyarthritis, myasthenia gravis, multiple sclerosis) ), Allergic diseases (allergic rhinitis, conjunctivitis, gastrointestinal allergy, hay fever, anaphylaxis, atopic dermatitis, bronchial asthma, etc.), inflammatory
- Arteriosclerosis including atherosclerosis (aneurysm, coronary arteriosclerosis, cerebral arteriosclerosis, peripheral arteriosclerosis, etc.), vascular reocclusion and restenosis after bypass surgery, intervention (percutaneous coronary angioplasty) Surgery, stent placement, intracoronary Thickening or obstruction and organ damage after endoscopy, intravascular ultrasound, coronary thrombolysis, etc.)
- vasoactive substances and thrombogenic substances endothelin, thromboxane A2, etc.
- angiogenesis including abnormal angiogenesis in abnormal capillary network formation in the outer membrane of atherosclerotic lesions
- Thrombosis fat deposition promotion
- eye disease glaucoma, ocular hypertension, etc.
- hypertension hypertensive tinnitus, dialysis hypotension, endothelial cell and organ disorders
- endocrine disease Additionalson's disease, Cushing's syndrome, brown cell type, primary Aldosteronism, etc.
- nephritis renal diseases (nephritis, glomerulonephritis, glomerulosclerosis, renal failure, thrombotic microangiopathy, complications of dialysis, organ disorders including nephropathy due to radiation, diabetic kidney ), Diabetic diseases (such as insulin-dependent diabetes, diabetic complications, diabetic retinopathy, diabetic microang
- Edema chronic fatigue syndrome
- benign prostatic hyperplasia Behcet's disease
- Hodgkin's disease Hodgkin's disease
- rattan infarction impaired consciousness
- psoriasis environment ⁇
- Occupational factors radiation damage, ultraviolet rays, infrared rays, laser beam disorders, altitude sickness, etc.
- the dosage of the pharmaceutical composition containing the compound represented by the above formula (I) or a salt thereof according to the present invention is determined by the administration subject, age and weight of the administration subject, symptoms, administration time, administration method, dosage form, etc. Thus, it can be appropriately selected.
- the dosage for a particular patient may vary depending on age, weight, general health, sex, diet, time of administration, mode of administration, rate of excretion, and the extent of the condition the patient is treating at the time. Is determined in consideration of other factors.
- the dosage varies depending on the patient's condition, body weight, and method of administration.
- activity per adult (body weight 50 kg) per person The component [compound represented by formula (I)] is about 5 to 1000 mg, preferably about 10 to 600 mg, more preferably about 10 to 300 mg, and particularly preferably about 15 to 150 mg. It is administered once or twice or three times a day.
- a pharmaceutical composition containing the compound represented by the above formula (I) or a salt thereof into an organ such as heart, kidney, liver, or bone marrow When used as an agent, it is administered 3 days before transplantation and continuously after transplantation.
- the daily dose of the pharmaceutical composition of the present invention varies depending on the condition and weight of the patient and the method of administration.In the case of oral administration, the active ingredient per adult (body weight 50 kg) is expressed by the formula (I). About 5 to 1000 mg, preferably about 10 to 600 mg, more preferably about 10 to 300 mg, particularly preferably about 15 to 150 mg, once or two to three times a day. Administered separately.
- inhibitors of graft-versus-host disease and Z or rejection at the time of organ transplantation which are used in combination with the compound represented by the above formula (I) or a salt thereof.
- Specific examples include cyclosporine, tacrolimus, rapamycin, steroids, azathioprine, mofuethyl mycophenolate, mizoribine and the like.
- the daily dose depends on the target disease.
- oral administration of about 5 mg of active ingredient [compound of formula (I)] per adult (50 kg) is recommended for oral administration (50 kg). It is about 10-600 mg, more preferably about 10-300 mg, particularly preferably about 15-150 mg, and is administered once or twice or three times a day.
- the dose of the other drug is appropriately selected, for example, in a range of about 1Z200 to 1Z2 or more and about 2 to 3 times or less the usual dose.
- the dose of each drug is appropriately adjusted, but generally, the dose of each drug is adjusted. The dose at the time of single drug administration is used.
- the compound represented by the above formula (I) or a salt thereof can be contained in blood transfusion or a blood product or used in combination.
- Transfusion blood or blood products are usually manufactured by mixing multiple human-derived blood sources. Some of these cells may be mixed with cells infected with the HIV virus and others not. In this case, there is a risk that the cells are infected and the cells are infected.
- the compound represented by the formula (I) of the present invention is blended, infection and proliferation of these viruses can be prevented or suppressed.
- a blood product is stored, it is effective to add the compound represented by the formula (I) to prevent or suppress virus infection and proliferation.
- the compound represented by the formula (I) can be added to the blood to administer the blood transfusion or blood product. HIV can be prevented from transmitting and multiplying in the recipient's body.
- Oral administration to adults is usually about 0.02 to 50 mg / kg, preferably 0.05 to 0.05 mg / kg as a single dose of CCR blocker.
- the dose is about 30 mgZkg, more preferably about 0.1 to 10 mgZkg, and it is desirable to administer these doses about 1 to about 3 times a day.
- these dosage ranges may be adjusted on a unit basis as needed to divide the daily dose.
- the dose may vary depending on the nature and extent of the disease, the age of the patient, weight, general health, sex, , Diet, time of administration, method of administration, rate of excretion, and other factors.
- the administration method can also be appropriately selected, and the above-mentioned agent for preventing HIV infection of the present invention may be directly added to blood or blood products to be transfused before blood transfusion or before use of blood products. In this case, it is desirable to mix immediately before to 24 hours before, preferably immediately before to 12 hours before, and more preferably immediately before to 6 hours before.
- administering the preventive agent for HIV infection of the present invention separately from blood or blood products to be transfused at the time of blood transfusion or use of blood products it is desirable to administer the drug at least one hour before and at the same time as blood transfusion or use of blood products. More preferably, administration is continued once to three times a day for 4 weeks.
- the dose of the reverse transcriptase inhibitor or the protease inhibitor is appropriately selected in the range of about 1Z200 to 1Z2 or more, about 2 to 3 times or less of the usual dose.
- Typical dosages of typical reverse transcriptase inhibitors and protease inhibitors are, for example, as follows.
- An adult (body weight: 50 kg) is administered to the same subject in the form of a combination of about 10 to 300 mg of the compound represented by the formula (I) or a salt thereof together with about 50 to 200 mg of zidovudine per person.
- Each drug may be administered at the same time, or at different times within 12 hours.
- Compound Alg is dispersed in 2.4 g of polyoxyethylene (40) hydrogenated castor oil and polyethylene daricol (8)-4.8 g of glyceride of prillic acid Z capric acid and 1.8 g of medium-chain fatty acid triglyceride while heating at 60 ° C. did.
- Table 6 shows the theoretical composition ratio.
- Compound Alg is dispersed in 3.4 g of polyoxyethylene (40) hydrogenated castor oil and 3.4 g of polyethylene daricol (8) -force prylic acid Z capric glyceride and 2.2 g of medium-chain fatty acid triglyceride while heating to 60 ° C did.
- Table 7 shows the theoretical composition ratios.
- composition Composition (mg) Compound A 28.5 Polyoxyethylene (40) — hydrogenated castor oil 56.5 Polyethylene glycol (8) — Power prillic acid Z Power purine 56.5 acid glyceride
- Polyoxyethylene (40) hydrogenated castor oil 2 2 6
- Compound Alg was dispersed in polyethylene glycol (8) -force prillic acid Z capric glyceride 6.8 g and medium chain fatty acid triglyceride 1.7 g while heating to 60 ° C. Further, 0.5 g of purified water was added to the dispersion and heated to obtain a clear composition liquid. Table 11 shows the theoretical composition ratios.
- Example 1 0.3 g of the composition of Example 1 was added to various solvents at 20 ° C or 40 ° C (A: purified water, B: 1M
- NaCl aqueous solution, C Japanese Pharmacopoeia second liquid, pH 6.8 »After dispersing in 20 mL, the liquid for 30 minutes and the turbidity ratio determined by the following formula were evaluated. The same evaluation was performed for the composition of Comparative Example 1. As shown in FIGS. 1 and 2, it was confirmed that the composition of Example 1 formed a stable microemulsion that did not cause turbidity regardless of the type of the solvent to be dispersed and the temperature. Was. On the other hand, in the composition of Control Example 1, turbidity was observed, and macroscopic formation of emulsion droplets was recognized.
- Example 6 About 0.3 g of the composition of Example 6 or Control Example 2 was filled into an empty soft gelatin capsule. The capsules were subjected to a dissolution test (paddle method, 100 rpm) specified in the Japanese Pharmacopoeia using purified water (900 mL) heated to 37 ° C. As shown in FIG. 3, the composition of Example 6 was a clear test solution, and the composition of Force Control Example 2 in which stable microemulsion formation was observed was observed to be turbid.
- Example 1 About 0.284 g of the composition of Example 1 or Control Example 1 was filled into an empty hard gelatin capsule. The capsules were administered to fasted beagle dogs. Over time, plasma was collected and the concentration of Compound A therein was quantified by high performance liquid chromatography. Industrial applicability
- the pharmaceutical composition of the present invention has a function of forming or maintaining a stable microemulsion.
- a preparation encapsulating the pharmaceutical composition of the present invention is orally administered, fine particles containing a pharmaceutically active ingredient are dispersed in the digestive tract.
- the stable and stable microemulsion is formed, or the microemulsion is maintained, so that the absorption of the medicinal component, particularly the poorly water-soluble medicinal component from the digestion tube is greatly improved, and the bioavailability is improved. Get higher.
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Abstract
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
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CA002562388A CA2562388A1 (en) | 2004-03-24 | 2005-03-23 | Emulsion-stabilized preparation |
ES05727183T ES2425937T3 (es) | 2004-03-24 | 2005-03-23 | Estabilizante de emulsión |
EP05727183.5A EP1728504B1 (en) | 2004-03-24 | 2005-03-23 | Emulsion stabilizer |
US10/592,905 US20080249147A1 (en) | 2004-03-24 | 2005-03-23 | Emulsion-Stabilized Preparation |
JP2006511303A JP5057779B2 (ja) | 2004-03-24 | 2005-03-23 | エマルション安定化製剤 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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JP2004087023 | 2004-03-24 | ||
JP2004-087023 | 2004-03-24 |
Publications (1)
Publication Number | Publication Date |
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WO2005089714A1 true WO2005089714A1 (ja) | 2005-09-29 |
Family
ID=34993420
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PCT/JP2005/005238 WO2005089714A1 (ja) | 2004-03-24 | 2005-03-23 | エマルション安定化製剤 |
Country Status (6)
Country | Link |
---|---|
US (1) | US20080249147A1 (ja) |
EP (1) | EP1728504B1 (ja) |
JP (1) | JP5057779B2 (ja) |
CA (1) | CA2562388A1 (ja) |
ES (1) | ES2425937T3 (ja) |
WO (1) | WO2005089714A1 (ja) |
Cited By (1)
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US7635675B2 (en) | 2003-08-13 | 2009-12-22 | Biocon Limited | Micro-particle fatty acid salt solid dosage formulations for therapeutic agents |
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DK2206702T3 (da) * | 2001-08-08 | 2012-02-13 | Tobira Therapeutics Inc | Bicyklisk forbindelse, fremstilling og anvendelse deraf |
JPWO2006059716A1 (ja) * | 2004-12-03 | 2008-06-05 | 武田薬品工業株式会社 | 固形製剤 |
RU2725888C2 (ru) | 2014-12-23 | 2020-07-07 | Тобира Терапьютикс, Инк. | Способ получения ценикривирока и родственных аналогов |
KR20190039087A (ko) | 2016-06-21 | 2019-04-10 | 토비라 쎄라퓨틱스, 인크. | 정제된 세니크리비록 및 세니크리비록을 제조하기 위한 정제된 중간체 |
WO2018045043A1 (en) | 2016-08-31 | 2018-03-08 | Tobira Therapeutics, Inc. | Solid forms of cenicriviroc mesylate and processes of making solid forms of cenicriviroc mesylate |
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- 2005-03-23 EP EP05727183.5A patent/EP1728504B1/en active Active
- 2005-03-23 CA CA002562388A patent/CA2562388A1/en not_active Abandoned
- 2005-03-23 WO PCT/JP2005/005238 patent/WO2005089714A1/ja active Application Filing
- 2005-03-23 JP JP2006511303A patent/JP5057779B2/ja not_active Expired - Fee Related
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Also Published As
Publication number | Publication date |
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US20080249147A1 (en) | 2008-10-09 |
JP5057779B2 (ja) | 2012-10-24 |
JPWO2005089714A1 (ja) | 2008-01-31 |
EP1728504B1 (en) | 2013-07-31 |
ES2425937T3 (es) | 2013-10-18 |
CA2562388A1 (en) | 2005-09-29 |
EP1728504A4 (en) | 2010-02-24 |
EP1728504A1 (en) | 2006-12-06 |
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