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WO2013001830A1 - Dérivé antibiotique nucléoside - Google Patents

Dérivé antibiotique nucléoside Download PDF

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Publication number
WO2013001830A1
WO2013001830A1 PCT/JP2012/004227 JP2012004227W WO2013001830A1 WO 2013001830 A1 WO2013001830 A1 WO 2013001830A1 JP 2012004227 W JP2012004227 W JP 2012004227W WO 2013001830 A1 WO2013001830 A1 WO 2013001830A1
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Prior art keywords
substituted
group
unsubstituted
alkyl
hydrogen atom
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PCT/JP2012/004227
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English (en)
Japanese (ja)
Inventor
聡 市川
松田　彰
岡本　和也
昌浩 阪上
Original Assignee
国立大学法人北海道大学
塩野義製薬株式会社
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Publication of WO2013001830A1 publication Critical patent/WO2013001830A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention relates to a substance having antibacterial activity.
  • Nucleosides are one of the most important biological substances. These are not only the components of DNA and RNA that control the storage and expression of genetic information, but also function as coenzymes and intracellular signaling substances, and are involved in intracellular metabolism and energy supply. Have a role to play. Nucleosides have long been recognized as a good lead for conducting drug discovery chemistry research, and various nucleoside compounds have been clinically used.
  • nucleoside natural products can be good leads for drug development.
  • nucleoside derivatives there are several problems to be overcome in the method for synthesizing nucleoside derivatives.
  • nucleobase which is a nitrogen-containing aromatic ring
  • the reagents that can be used are limited due to its high coordination ability, and aldehydes and ketone bodies that are used as raw materials for the carbon increase reaction to the sugar part
  • it is unstable under various reaction conditions.
  • the inventors have conducted synthetic studies on antibacterial nucleosides having a novel mechanism of action.
  • MraY intracellular membrane enzyme translocase I
  • MraY inhibitors that can be cell wall synthesis inhibitors have recently attracted attention as new targets for the development of antibacterial agents, and are expected to lead to the creation of drugs that are widely effective against bacteria including drug-resistant bacteria.
  • MraY inhibitors are resistant to drug-resistant bacteria such as MRSA and VRE. It is expected to lead to the creation of drugs that are broadly effective against bacteria containing them (see Non-Patent Document 1 and Non-Patent Document 2).
  • Patent Literatures 1 to 3 describe Pacidamycins (pacidamycins), and Patent Literatures 4 and 5 describe Mureidomycin C (mureidomycin C). Are all produced from fermentation.
  • the present invention relates to the following.
  • R 1 is a hydrogen atom or alkyl
  • R 2 is a hydrogen atom, alkyl, or a group shown below:
  • R a is hydroxy, alkyl, or halogen, and m is an integer of 0 to 3, provided that when there are a plurality of R a s , they may be the same or different.
  • R 3 is a hydrogen atom or alkyl;
  • R 4 is a hydrogen atom or alkyl, or R 3 and R 4 may together form a cyclopropane ring;
  • R 5 is a hydrogen atom or alkyl;
  • R 6 represents a hydrogen atom, alkyl, or a group shown below:
  • R b is hydroxy, alkyl, or halogen
  • n is an integer of 0 to 3, provided that when there are a plurality of R b s , they may be the same or different.
  • R 7 is a hydrogen atom, alkyl substituted with amino, or alkylcarbonyl substituted with amino) Or a pharmaceutically acceptable salt thereof, or the compound or a solvate of the salt.
  • R 6 is a hydrogen atom, methyl, or a group shown below:
  • R 7 is a hydrogen atom, or alkylcarbonyl substituted with amino, or a pharmaceutically acceptable salt thereof, or the compound Or a solvate of the salt.
  • R c is a hydrogen atom or alkyl
  • R 8 is a hydrogen atom, alkyl-substituted silyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted aromatic carbocyclic Group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic carbonyl Substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, or substituted or unsubstituted non-aromatic heterocyclic carbonyl, L 1 is a single bond, alkylene, alkenylene, or alkynylene; R 9 is a hydrogen atom or
  • R 12 is a hydrogen atom, or substituted or unsubstituted alkyl
  • R 13 is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted An unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group)) Or a salt thereof.
  • R 9 is —OL 2 —R 11
  • L 2 is a single bond
  • R 11 is a hydrogen atom or silyl substituted with alkyl.
  • a pharmaceutical composition comprising the compound according to any one of (1) to (4) above or a pharmaceutically acceptable salt thereof.
  • a method for treating or preventing various diseases caused by pathogenic bacteria comprising administering the compound according to any one of (1) to (4) above or a pharmaceutically acceptable salt thereof.
  • the compound according to the present invention has MraY inhibitory activity and anti-gram-negative bacterial activity, and is useful as a therapeutic and / or prophylactic agent for various diseases caused by pathogenic bacteria.
  • the present invention relates to Pacidamycin derivatives and synthetic intermediates thereof. According to the present invention, the total synthesis of the natural product Pacidamycin D and its derivatives has been achieved.
  • Halogen includes fluorine atom, chlorine atom, bromine atom, and iodine atom. In particular, a fluorine atom and a chlorine atom are preferable.
  • Alkyl includes straight or branched hydrocarbon groups having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and still more preferably 1 to 4 carbon atoms. To do. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl , Isooctyl, n-nonyl, n-decyl and the like.
  • alkyl examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and n-pentyl. Further preferred examples include methyl, ethyl, n-propyl, isopropyl and tert-butyl.
  • Alkenyl has 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and further preferably 2 to 4 carbon atoms, having one or more double bonds at any position. These linear or branched hydrocarbon groups are included.
  • alkenyl examples include vinyl, allyl, propenyl, isopropenyl, and butenyl.
  • Alkynyl has 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms, having one or more triple bonds at any position. Includes straight chain or branched hydrocarbon groups. Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like. These may further have a double bond at an arbitrary position.
  • alkynyl examples include ethynyl, propynyl, butynyl and pentynyl.
  • Alkylene is a straight or branched divalent hydrocarbon having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and still more preferably 1 to 4 carbon atoms. Includes groups. Examples include methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene and the like.
  • alkenylene refers to a carbon number of 2 to 15, preferably 2 to 10, more preferably 2 to 6 and even more preferably 2 to 4 having one or more double bonds at an arbitrary position. And a linear or branched divalent hydrocarbon group.
  • vinylene, propenylene, butenylene, pentenylene and the like can be mentioned.
  • Alkynylene refers to carbon atoms of 2 to 15, preferably 2 to 10, more preferably 2 to 6, more preferably 2 to 4 carbon atoms having one or more triple bonds at any position.
  • a linear or branched divalent hydrocarbon group is included. These may further have a double bond at an arbitrary position. For example, ethynylene, propynylene, butynylene, pentynylene, hexynylene and the like can be mentioned.
  • “Aromatic carbocyclic group” means a monocyclic or bicyclic or more cyclic aromatic hydrocarbon group. For example, phenyl, naphthyl, anthryl, phenanthryl and the like can be mentioned.
  • a preferred embodiment of the “aromatic carbocyclic group” includes phenyl.
  • Non-aromatic carbocyclic group means a monocyclic or bicyclic or more cyclic saturated hydrocarbon group or cyclic non-aromatic unsaturated hydrocarbon group.
  • the non-aromatic carbocyclic group having 2 or more rings also includes those in which the ring in the above “aromatic carbocyclic group” is condensed with a monocyclic or 2 or more non-aromatic carbocyclic groups.
  • non-aromatic carbocyclic group includes a group that forms a bridge or a spiro ring as described below.
  • the monocyclic non-aromatic carbocyclic group preferably has 3 to 16 carbon atoms, more preferably 3 to 12 carbon atoms, and still more preferably 4 to 8 carbon atoms.
  • Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclohexadienyl, and the like.
  • non-aromatic carbocyclic group having two or more rings examples include indanyl, indenyl, acenaphthyl, tetrahydronaphthyl, fluorenyl and the like.
  • “Aromatic heterocyclic group” means a monocyclic or bicyclic or more aromatic cyclic group having one or more heteroatoms arbitrarily selected from O, S and N in the ring To do.
  • the aromatic heterocyclic group having two or more rings includes a monocyclic or two or more aromatic heterocyclic group condensed with a ring in the above “aromatic carbocyclic group”.
  • the monocyclic aromatic heterocyclic group is preferably 5 to 8 members, more preferably 5 or 6 members.
  • Examples include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, and the like.
  • bicyclic aromatic heterocyclic group examples include indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzisoxazolyl, Oxazolyl, benzoxiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyr Dazinyl, oxazolopyridyl, thiazolopyridyl and the like can be mentioned.
  • aromatic heterocyclic group having 3 or more rings examples include carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, dibenzofuryl and the like.
  • Non-aromatic heterocyclic group means a monocyclic or bicyclic or more cyclic non-aromatic cyclic group having at least one hetero atom selected from O, S and N in the ring. Means group.
  • the non-aromatic heterocyclic group having 2 or more rings is a monocyclic or 2 or more non-aromatic heterocyclic group, the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group”, and Also included are those in which each ring in the “aromatic heterocyclic group” is condensed.
  • non-aromatic heterocyclic group includes a group that forms a bridge or a spiro ring as described below.
  • the monocyclic non-aromatic heterocyclic group is preferably 3 to 8 members, more preferably 5 or 6 members.
  • non-aromatic heterocyclic group having two or more rings examples include indolinyl, isoindolinyl, chromanyl, isochromanyl and the like.
  • Alkyloxy means a group in which the above “alkyl” is bonded to an oxygen atom. Examples thereof include methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, tert-butyloxy, isobutyloxy, sec-butyloxy, pentyloxy, isopentyloxy, hexyloxy and the like.
  • alkyloxy examples include methoxy, ethoxy, n-propyloxy, isopropyloxy, and tert-butyloxy.
  • Alkenyloxy means a group in which the above “alkenyl” is bonded to an oxygen atom. Examples thereof include vinyloxy, allyloxy, 1-propenyloxy, 2-butenyloxy, 2-pentenyloxy, 2-hexenyloxy, 2-heptenyloxy, 2-octenyloxy and the like.
  • Alkynyloxy means a group in which the above “alkynyl” is bonded to an oxygen atom. Examples include ethynyloxy, 1-propynyloxy, 2-propynyloxy, 2-butynyloxy, 2-pentynyloxy, 2-hexynyloxy, 2-heptynyloxy, 2-octynyloxy and the like.
  • Haloalkyl means a group in which one or more of the above “halogens” are bonded to the above “alkyl”. For example, monofluoromethyl, monofluoroethyl, monofluoropropyl, 2,2,3,3,3-pentafluoropropyl, monochloromethyl, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2, Examples include 2,2-trichloroethyl, 1,2-dibromoethyl, 1,1,1-trifluoropropan-2-yl and the like.
  • haloalkyl include trifluoromethyl and trichloromethyl.
  • Haloalkyloxy means a group in which the above “haloalkyl” is bonded to an oxygen atom. Examples thereof include monofluoromethoxy, monofluoroethoxy, trifluoromethoxy, trichloromethoxy, trifluoroethoxy, trichloroethoxy and the like.
  • haloalkyloxy examples include trifluoromethoxy and trichloromethoxy.
  • Alkyloxyalkyl means a group in which the above “alkyloxy” is bonded to the above “alkyl”. For example, methoxymethyl, methoxyethyl, ethoxymethyl and the like can be mentioned.
  • Alkyloxyalkyloxy means a group in which the “alkyloxy” is bonded to the “alkyloxy”. Examples thereof include methoxymethoxy, methoxyethoxy, ethoxymethoxy, ethoxyethoxy and the like.
  • Alkyloxyalkyloxyalkyl means a group in which the “alkyloxyalkyloxy” is bonded to the “alkyl”. Examples thereof include methoxymethoxymethyl, methoxyethoxymethyl, ethoxymethoxyethyl, ethoxyethoxymethyl and the like.
  • Alkylcarbonyl means a group in which the above “alkyl” is bonded to a carbonyl group. Examples thereof include methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, tert-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, pentylcarbonyl, isopentylcarbonyl, hexylcarbonyl and the like.
  • alkylcarbonyl examples include methylcarbonyl, ethylcarbonyl, and n-propylcarbonyl.
  • Alkenylcarbonyl means a group in which the above “alkenyl” is bonded to a carbonyl group.
  • alkenyl ethylenylcarbonyl, propenylcarbonyl and the like can be mentioned.
  • Alkynylcarbonyl means a group in which the above “alkynyl” is bonded to a carbonyl group. For example, ethynylcarbonyl, propynylcarbonyl and the like can be mentioned.
  • “Monoalkylamino” means a group in which the above “alkyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group. For example, methylamino, ethylamino, isopropylamino and the like can be mentioned.
  • Preferred examples of “monoalkylamino” include methylamino and ethylamino.
  • Dialkylamino means a group in which the above “alkyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the amino group. Two alkyl groups may be the same or different. Examples include dimethylamino, diethylamino, N, N-diisopropylamino, N-methyl-N-ethylamino, N-isopropyl-N-ethylamino and the like.
  • dialkylamino examples include dimethylamino and diethylamino.
  • Alkylsulfonyl means a group in which the above “alkyl” is bonded to a sulfonyl group.
  • methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl and the like can be mentioned.
  • alkylsulfonyl include methylsulfonyl and ethylsulfonyl.
  • Alkenylsulfonyl means a group in which the above “alkenyl” is bonded to a sulfonyl group.
  • alkenyl ethylenylsulfonyl, propenylsulfonyl and the like can be mentioned.
  • Alkynylsulfonyl means a group in which the above “alkynyl” is bonded to a sulfonyl group. For example, ethynylsulfonyl, propynylsulfonyl and the like can be mentioned.
  • “Monoalkylcarbonylamino” means a group in which the above “alkylcarbonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group.
  • methylcarbonylamino, ethylcarbonylamino, propylcarbonylamino, isopropylcarbonylamino, tert-butylcarbonylamino, isobutylcarbonylamino, sec-butylcarbonylamino and the like can be mentioned.
  • Preferred embodiments of “monoalkylcarbonylamino” include methylcarbonylamino and ethylcarbonylamino.
  • Dialkylcarbonylamino means a group in which the above “alkylcarbonyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • Two alkylcarbonyl groups may be the same or different.
  • dimethylcarbonylamino, diethylcarbonylamino, N, N-diisopropylcarbonylamino and the like can be mentioned.
  • dialkylcarbonylamino examples include dimethylcarbonylamino and diethylcarbonylamino.
  • “Monoalkylsulfonylamino” means a group in which the above “alkylsulfonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group.
  • methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino, tert-butylsulfonylamino, isobutylsulfonylamino, sec-butylsulfonylamino and the like can be mentioned.
  • Preferred embodiments of “monoalkylsulfonylamino” include methylsulfonylamino and ethylsulfonylamino.
  • Dialkylsulfonylamino means a group in which the above “alkylsulfonyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • Two alkylsulfonyl groups may be the same or different.
  • dimethylsulfonylamino, diethylsulfonylamino, N, N-diisopropylsulfonylamino and the like can be mentioned.
  • dialkylcarbonylamino examples include dimethylsulfonylamino and diethylsulfonylamino.
  • Alkylimino means a group in which the above “alkyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • methylimino, ethylimino, n-propylimino, isopropylimino and the like can be mentioned.
  • Alkenylimino means a group in which the above “alkenyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. Examples thereof include ethylenylimino and propenylimino.
  • Alkynylimino means a group in which the above “alkynyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • alkynylimino ethynylimino, propynylimino and the like can be mentioned.
  • Alkylcarbonylimino means a group in which the above “alkylcarbonyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • methylcarbonylimino, ethylcarbonylimino, n-propylcarbonylimino, isopropylcarbonylimino and the like can be mentioned.
  • Alkenylcarbonylimino means a group in which the above “alkenylcarbonyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • alkenylcarbonylimino ethylenylcarbonylimino, propenylcarbonylimino and the like can be mentioned.
  • Alkynylcarbonylimino means a group in which the above “alkynylcarbonyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • alkynylcarbonylimino ethynylcarbonylimino, propynylcarbonylimino and the like can be mentioned.
  • Alkyloxyimino means a group in which the above “alkyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. Examples thereof include methyloxyimino, ethyloxyimino, n-propyloxyimino, isopropyloxyimino and the like.
  • Alkenyloxyimino means a group in which the above “alkenyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • alkenyloxyimino ethylenyloxyimino, propenyloxyimino and the like can be mentioned.
  • Alkynyloxyimino means a group in which the above “alkynyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • alkynyloxyimino ethynyloxyimino, propynyloxyimino and the like can be mentioned.
  • Alkylcarbonyloxy means a group in which the above “alkylcarbonyl” is bonded to an oxygen atom. Examples thereof include methylcarbonyloxy, ethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy, tert-butylcarbonyloxy, isobutylcarbonyloxy, sec-butylcarbonyloxy and the like.
  • alkylcarbonyloxy examples include methylcarbonyloxy and ethylcarbonyloxy.
  • Alkenylcarbonyloxy means a group in which the above “alkenylcarbonyl” is bonded to an oxygen atom.
  • alkenylcarbonyl ethylenylcarbonyloxy, propenylcarbonyloxy and the like can be mentioned.
  • Alkynylcarbonyloxy means a group in which the above “alkynylcarbonyl” is bonded to an oxygen atom.
  • alkynylcarbonyloxy ethynylcarbonyloxy, propynylcarbonyloxy and the like can be mentioned.
  • Alkyloxycarbonyl means a group in which the above “alkyloxy” is bonded to a carbonyl group. For example, methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, tert-butyloxycarbonyl, isobutyloxycarbonyl, sec-butyloxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, hexyloxycarbonyl, etc. It is done.
  • alkyloxycarbonyl examples include methyloxycarbonyl, ethyloxycarbonyl, and propyloxycarbonyl.
  • Alkenyloxycarbonyl means a group in which the above “alkenyloxy” is bonded to a carbonyl group. For example, ethylenyloxycarbonyl, propenyloxycarbonyl and the like can be mentioned.
  • Alkynyloxycarbonyl means a group in which the above “alkynyloxy” is bonded to a carbonyl group. For example, ethynyloxycarbonyl, propynyloxycarbonyl and the like can be mentioned.
  • Alkylsulfanyl means a group in which the above “alkyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, isopropylsulfanyl and the like can be mentioned.
  • Alkenylsulfanyl means a group in which the above “alkenyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • alkenyl ethylenylsulfanyl, propenylsulfanyl and the like can be mentioned.
  • Alkynylsulfanyl means a group in which the above “alkynyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • alkynylsulfanyl ethynylsulfanyl, propynylsulfanyl and the like can be mentioned.
  • Alkylsulfinyl means a group in which the above “alkyl” is bonded to a sulfinyl group. Examples thereof include methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl and the like.
  • Alkenylsulfinyl means a group in which the above “alkenyl” is bonded to a sulfinyl group.
  • alkenyl ethylenylsulfinyl, propenylsulfinyl and the like can be mentioned.
  • Alkynylsulfinyl means a group in which the above “alkynyl” is bonded to a sulfinyl group. For example, ethynylsulfinyl, propynylsulfinyl and the like can be mentioned.
  • “Monoalkylcarbamoyl” means a group in which the above “alkyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the carbamoyl group. Examples thereof include methylcarbamoyl and ethylcarbamoyl.
  • Dialkylcarbamoyl means a group in which the above “alkyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the carbamoyl group.
  • Two alkyl groups may be the same or different. Examples thereof include dimethylcarbamoyl, diethylcarbamoyl and the like.
  • “Monoalkylsulfamoyl” means a group in which the above “alkyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the sulfamoyl group. For example, methylsulfamoyl, dimethylsulfamoylmoyl, etc. are mentioned.
  • Dialkylsulfamoyl means a group in which the above “alkyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the sulfamoyl group.
  • Two alkyl groups may be the same or different. Examples thereof include dimethylcarbamoyl, diethylcarbamoyl and the like.
  • Trialkylsilyl means a group in which three of the above “alkyl” are bonded to a silicon atom.
  • the three alkyls may be the same or different.
  • trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl and the like can be mentioned.
  • “Aromatic carbocyclic alkyl” means an alkyl substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyl, phenethyl, phenylpropynyl, benzhydryl, trityl, naphthylmethyl, groups shown below
  • aromatic carbocyclic alkyl examples include benzyl, phenethyl, and benzhydryl.
  • Non-aromatic carbocyclic alkyl means alkyl substituted with one or more of the above “non-aromatic carbocyclic groups”.
  • the “non-aromatic carbocyclic alkyl” also includes “non-aromatic carbocyclic alkyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group”. For example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, groups shown below
  • “Aromatic heterocyclic alkyl” means alkyl substituted with one or more of the above “aromatic heterocyclic groups”. “Aromatic heterocyclic alkyl” also includes “aromatic heterocyclic alkyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. .
  • pyridylmethyl furanylmethyl, imidazolylmethyl, indolylmethyl, benzothiophenylmethyl, oxazolylmethyl, isoxazolylmethyl, thiazolylmethyl, isothiazolylmethyl, pyrazolylmethyl, isopyrazolylmethyl, pyrrolidinylmethyl, benz Oxazolylmethyl, group shown below
  • Non-aromatic heterocyclic alkyl means alkyl substituted with one or more of the above “non-aromatic heterocyclic groups”.
  • the alkyl portion is substituted with the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic heterocyclic group”.
  • non-aromatic heterocyclic alkyl For example, tetrahydropyranylmethyl, morpholinylethyl, piperidinylmethyl, piperazinylmethyl, groups shown below
  • “Aromatic carbocyclic alkyloxy” means alkyloxy substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyloxy, phenethyloxy, phenylpropynyloxy, benzhydryloxy, trityloxy, naphthylmethyloxy, groups shown below
  • Non-aromatic carbocyclic alkyloxy means alkyloxy substituted with one or more of the above “non-aromatic carbocyclic groups”.
  • the “non-aromatic carbocyclic alkyloxy” also includes “non-aromatic carbocyclic alkyloxy” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group”. For example, cyclopropylmethyloxy, cyclobutylmethyloxy, cyclopentylmethyloxy, cyclohexylmethyloxy, groups shown below
  • “Aromatic heterocyclic alkyloxy” means alkyloxy substituted with one or more of the above “aromatic heterocyclic groups”. “Aromatic heterocyclic alkyloxy” also includes “aromatic heterocyclic alkyloxy” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. Include.
  • Non-aromatic heterocyclic alkyloxy means alkyloxy substituted with one or more of the above “non-aromatic heterocyclic groups”.
  • the alkyl moiety is substituted with the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic heterocyclic group”. It also includes “non-aromatic heterocyclic alkyloxy”. For example, tetrahydropyranylmethyloxy, morpholinylethyloxy, piperidinylmethyloxy, piperazinylmethyloxy, groups shown below
  • “Aromatic carbocyclic alkyloxycarbonyl” means alkyloxycarbonyl substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyloxycarbonyl, phenethyloxycarbonyl, phenylpropynyloxycarbonyl, benzhydryloxycarbonyl, trityloxycarbonyl, naphthylmethyloxycarbonyl, groups shown below
  • Non-aromatic carbocyclic alkyloxycarbonyl means alkyloxycarbonyl substituted with one or more of the above “non-aromatic carbocyclic groups”.
  • the “non-aromatic carbocyclic alkyloxycarbonyl” also includes “non-aromatic carbocyclic alkyloxycarbonyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group”. For example, cyclopropylmethyloxycarbonyl, cyclobutylmethyloxycarbonyl, cyclopentylmethyloxycarbonyl, cyclohexylmethyloxycarbonyl, groups shown below
  • “Aromatic heterocyclic alkyloxycarbonyl” means alkyloxycarbonyl substituted with one or more of the above “aromatic heterocyclic groups”.
  • the “aromatic heterocyclic alkyloxycarbonyl” is an “aromatic heterocyclic alkyloxycarbonyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. Is also included.
  • pyridylmethyloxycarbonyl furanylmethyloxycarbonyl, imidazolylmethyloxycarbonyl, indolylmethyloxycarbonyl, benzothiophenylmethyloxycarbonyl, oxazolylmethyloxycarbonyl, isoxazolylmethyloxycarbonyl, thiazolylmethyl Oxycarbonyl, isothiazolylmethyloxycarbonyl, pyrazolylmethyloxycarbonyl, isopyrazolylmethyloxycarbonyl, pyrrolidinylmethyloxycarbonyl, benzoxazolylmethyloxycarbonyl, groups shown below
  • Non-aromatic heterocyclic alkyloxycarbonyl means alkyloxycarbonyl substituted with one or more of the above “non-aromatic heterocyclic groups”.
  • the alkyl moiety is substituted with the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic heterocyclic group”.
  • non-aromatic heterocyclic alkyloxycarbonyl For example, tetrahydropyranylmethyloxy, morpholinylethyloxy, piperidinylmethyloxy, piperazinylmethyloxy, groups shown below
  • “Aromatic carbocyclic alkyloxyalkyl” means alkyloxyalkyl substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyloxymethyl, phenethyloxymethyl, phenylpropynyloxymethyl, benzhydryloxymethyl, trityloxymethyl, naphthylmethyloxymethyl, groups shown below
  • Non-aromatic carbocyclic alkyloxyalkyl means alkyloxyalkyl substituted with one or more of the above “non-aromatic carbocyclic groups”.
  • non-aromatic carbocyclic alkyloxyalkyl means “non-aromatic carbocyclic alkyloxyalkyl” in which the alkyl moiety to which the non-aromatic carbocycle is bonded is substituted with the above “aromatic carbocyclic group”. Is also included. For example, cyclopropylmethyloxymethyl, cyclobutylmethyloxymethyl, cyclopentylmethyloxymethyl, cyclohexylmethyloxymethyl, groups shown below
  • “Aromatic heterocyclic alkyloxyalkyl” means alkyloxyalkyl substituted with one or more of the above “aromatic heterocyclic groups”.
  • the “aromatic heterocyclic alkyloxyalkyl” is obtained by replacing the alkyl moiety to which the aromatic heterocyclic ring is bonded with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. Also included are “aromatic heterocyclic alkyloxyalkyl”.
  • pyridylmethyloxymethyl furanylmethyloxymethyl, imidazolylmethyloxymethyl, indolylmethyloxymethyl, benzothiophenylmethyloxymethyl, oxazolylmethyloxymethyl, isoxazolylmethyloxymethyl, thiazolylmethyl Oxymethyl, isothiazolylmethyloxymethyl, pyrazolylmethyloxymethyl, isopyrazolylmethyloxymethyl, pyrrolidinylmethyloxymethyl, benzoxazolylmethyloxymethyl, groups shown below
  • Non-aromatic heterocyclic alkyloxyalkyl means alkyloxyalkyl substituted with one or more of the above “non-aromatic heterocyclic groups”.
  • “non-aromatic heterocyclic alkyloxy” means that the alkyl moiety to which the non-aromatic heterocyclic ring is bonded is the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic”.
  • non-aromatic heterocyclic alkyloxyalkyl substituted with “aromatic heterocyclic group”. For example, tetrahydropyranylmethyloxymethyl, morpholinylethyloxymethyl, piperidinylmethyloxymethyl, piperazinylmethyloxymethyl, groups shown below
  • “Aromatic carbocyclic alkylamino” means a group in which the above “aromatic carbocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group. Examples include benzylamino, phenethylamino, phenylpropynylamino, benzhydrylamino, tritylamino, naphthylmethylamino, dibenzylamino and the like.
  • Non-aromatic carbocyclic alkylamino means a group in which the above “non-aromatic carbocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • cyclopropylmethylamino, cyclobutylmethylamino, cyclopentylmethylamino, cyclohexylmethylamino and the like can be mentioned.
  • “Aromatic heterocyclic alkylamino” means a group in which the above “aromatic heterocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • aromatic heterocyclic alkyl For example, pyridylmethylamino, furanylmethylamino, imidazolylmethylamino, indolylmethylamino, benzothiophenylmethylamino, oxazolylmethylamino, isoxazolylmethylamino, thiazolylmethylamino, isothiazolylmethylamino , Pyrazolylmethylamino, isopyrazolylmethylamino, pyrrolidinylmethylamino, benzoxazolylmethylamino and the like.
  • Non-aromatic heterocyclic alkylamino means a group in which the above “non-aromatic heterocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • tetrahydropyranylmethylamino, morpholinylethylamino, piperidinylmethylamino, piperazinylmethylamino and the like can be mentioned.
  • aromatic carbocyclic oxy also include The same as the above “aromatic carbocyclic group”.
  • “Aromatic carbocyclic oxy” means a group in which “aromatic carbocycle” is bonded to an oxygen atom.
  • aromatic carbocycle for example, phenyloxy, naphthyloxy and the like can be mentioned.
  • Aromatic carbocyclic carbonyl means a group in which “aromatic carbocycle” is bonded to a carbonyl group.
  • aromatic carbocycle for example, phenylcarbonyl, naphthylcarbonyl and the like can be mentioned.
  • “Aromatic carbocyclic oxycarbonyl” means a group in which the above “aromatic carbocyclic oxy” is bonded to a carbonyl group.
  • aromatic carbocyclic oxy for example, phenyloxycarbonyl, naphthyloxycarbonyl and the like can be mentioned.
  • “Aromatic carbocyclic sulfanyl” means a group in which an “aromatic carbocyclic ring” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. Examples thereof include phenylsulfanyl and naphthylsulfanyl.
  • “Aromatic carbocycle sulfonyl” means a group in which “aromatic carbocycle” is bonded to a sulfonyl group.
  • aromatic carbocycle for example, phenylsulfonyl, naphthylsulfonyl and the like can be mentioned.
  • Non-aromatic carbocyclic oxy “non-aromatic carbocyclic carbonyl”, “non-aromatic carbocyclic oxycarbonyl”, “non-aromatic carbocyclic sulfanyl”, and “non-aromatic carbocyclic sulfonyl”
  • the “aromatic carbocyclic” moiety is the same as the above “non-aromatic carbocyclic group”.
  • Non-aromatic carbocyclic oxy means a group in which “non-aromatic carbocycle” is bonded to an oxygen atom.
  • cyclopropyloxy, cyclohexyloxy, cyclohexenyloxy and the like can be mentioned.
  • Non-aromatic carbocyclic carbonyl means a group in which a “non-aromatic carbocycle” is bonded to a carbonyl group.
  • cyclopropylcarbonyl, cyclohexylcarbonyl, cyclohexenylcarbonyl and the like can be mentioned.
  • Non-aromatic carbocyclic oxycarbonyl means a group in which the above “non-aromatic carbocyclic oxy” is bonded to a carbonyl group.
  • cyclopropyloxycarbonyl, cyclohexyloxycarbonyl, cyclohexenyloxycarbonyl and the like can be mentioned.
  • Non-aromatic carbocyclic sulfanyl means a group in which a “non-aromatic carbocyclic ring” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. Examples include cyclopropylsulfanyl, cyclohexylsulfanyl, cyclohexenylsulfanyl and the like.
  • Non-aromatic carbocycle sulfonyl means a group in which “non-aromatic carbocycle” is bonded to a sulfonyl group.
  • cyclopropylsulfonyl, cyclohexylsulfonyl, cyclohexenylsulfonyl and the like can be mentioned.
  • aromatic heterocycle part of “aromatic heterocycle oxy”, “aromatic heterocycle carbonyl”, “aromatic heterocycle oxycarbonyl”, “aromatic heterocycle sulfanyl”, and “aromatic heterocycle sulfonyl” The same as the above “aromatic heterocyclic group”.
  • “Aromatic heterocycle oxy” means a group in which “aromatic heterocycle” is bonded to an oxygen atom.
  • aromatic heterocycle means a group in which “aromatic heterocycle” is bonded to an oxygen atom.
  • pyridyloxy, oxazolyloxy and the like can be mentioned.
  • “Aromatic heterocycle carbonyl” means a group in which “aromatic heterocycle” is bonded to a carbonyl group. For example, pyridylcarbonyl, oxazolylcarbonyl, etc. are mentioned.
  • “Aromatic heterocyclic oxycarbonyl” means a group in which the above “aromatic heterocyclic oxy” is bonded to a carbonyl group.
  • aromatic heterocyclic oxy means a group in which the above “aromatic heterocyclic oxy” is bonded to a carbonyl group.
  • pyridyloxycarbonyl, oxazolyloxycarbonyl and the like can be mentioned.
  • “Aromatic heterocycle sulfanyl” means a group in which “aromatic heterocycle” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • aromatic heterocycle means a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • pyridylsulfanyl, oxazolylsulfanyl and the like can be mentioned.
  • “Aromatic heterocycle sulfonyl” means a group in which “aromatic heterocycle” is bonded to a sulfonyl group.
  • aromatic heterocycle for example, pyridylsulfonyl, oxazolylsulfonyl and the like can be mentioned.
  • Non-aromatic heterocyclic oxy “non-aromatic heterocyclic carbonyl”, “non-aromatic heterocyclic oxycarbonyl”, “non-aromatic heterocyclic sulfanyl”, and “non-aromatic heterocyclic sulfonyl”
  • the “heterocyclic ring” moiety is the same as the above “non-aromatic heterocyclic group”.
  • Non-aromatic heterocyclic oxy means a group in which “non-aromatic heterocyclic” is bonded to an oxygen atom.
  • non-aromatic heterocyclic for example, piperidinyloxy, tetrahydrofuryloxy and the like can be mentioned.
  • Non-aromatic heterocyclic carbonyl means a group in which “non-aromatic heterocyclic” is bonded to a carbonyl group.
  • non-aromatic heterocyclic is bonded to a carbonyl group.
  • piperidinylcarbonyl, tetrahydrofurylcarbonyl and the like can be mentioned.
  • Non-aromatic heterocyclic oxycarbonyl means a group in which the above “non-aromatic heterocyclic oxy” is bonded to a carbonyl group.
  • piperidinyloxycarbonyl, tetrahydrofuryloxycarbonyl and the like can be mentioned.
  • Non-aromatic heterocyclic sulfanyl means a group in which a “non-aromatic heterocyclic ring” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • a “non-aromatic heterocyclic ring” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • piperidinylsulfanyl, tetrahydrofurylsulfanyl and the like can be mentioned.
  • Non-aromatic heterocyclic sulfonyl means a group in which “non-aromatic heterocyclic” is bonded to a sulfonyl group.
  • non-aromatic heterocyclic for example, piperidinylsulfonyl, tetrahydrofurylsulfonyl and the like can be mentioned.
  • substituents of “substituted or unsubstituted alkyl”, “substituted or unsubstituted alkyloxy”, “substituted or unsubstituted alkylcarbonyl”, and “substituted or unsubstituted alkyloxycarbonyl” include the following substituents: Is mentioned.
  • the carbon atom at any position may be bonded to one or more groups selected from the following substituents.
  • Substituents halogen, hydroxy, carboxy, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso , Azide, hydrazino, ureido, amidino, guanidino, trialkylsilyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, monoalkylamino, dialkylamino, alkylsulfonyl, alkenylsulfonyl, alkynyl Sulfonyl, monoalkyl
  • Substituents halogen, hydroxy, carboxy, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso , Azide, hydrazino, ureido, amidino, guanidino, trialkylsilyl, alkyl, alkenyl, alkynyl, haloalkyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, alkyloxyalkyl, alkylcarbonyl, alkenylcarbonyl, Alkynylcarbonyl, monoalkylamino, dialkylamin
  • substituted or unsubstituted non-aromatic carbocyclic group and “substituted or unsubstituted non-aromatic heterocyclic group” may be substituted with “oxo”. In this case, it means a group in which two hydrogen atoms on a carbon atom are substituted as follows.
  • non-aromatic carbocycle and the non-aromatic heterocyclic portion of the above-mentioned “substituted or unsubstituted non-aromatic carbocyclic carbonyl” and “substituted or unsubstituted non-aromatic heterocyclic carbonyl” It may be substituted with “oxo”.
  • Alkyl substituted with amino means a group in which one or more amino groups are replaced with a hydrogen atom bonded to a carbon atom of the above “alkyl”. Examples include aminomethyl, 1-aminoethyl, 2-aminomethyl, 1-aminopropyl, 2-aminopropyl, 1,2-diaminoethyl and the like.
  • alkyl substituted with amino includes 2-aminoethyl.
  • Alkylcarbonyl substituted with amino means a group in which one or more amino groups are replaced with a hydrogen atom bonded to a carbon atom of the above “alkylcarbonyl”. Examples include aminomethylcarbonyl, 1-aminoethylcarbonyl, 2-aminoethylcarbonyl, 1-aminopropylcarbonyl, 2-aminopropylcarbonyl, 1,2-diaminopropylcarbonyl, and the like.
  • alkylcarbonyl substituted with amino includes aminomethylcarbonyl.
  • ⁇ ⁇ ⁇ ⁇ yl substituted with alkyl ⁇ means a group in which one or more of the above ‘alkyl’ groups are replaced with a hydrogen atom bonded to a silicon atom of the silyl group. Examples thereof include methylsilyl, dimethylsilyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl and the like.
  • sil substituted with alkyl includes tert-butyldimethylsilyl.
  • amide protecting group means a group that can replace a hydrogen atom bonded to a nitrogen atom of an amide group and can be deprotected after a desired reaction.
  • Amide protecting groups include alkyloxy, alkyloxyalkyl, alkyloxyalkyloxyalkyl, benzyl, benzyloxy, benzyloxyalkyl and the like.
  • allyl methoxymethyl, benzyloxymethyl, tert-butyldimethylsiloxymethyl, pyrrolidinomethyl, methoxy, benzyloxy, methylthio, N-triphenylmethylthio, tert-butyldimethylsilyl, 4-methoxyphenyl 4- (methoxymethoxy) phenyl, benzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl, di (4-methoxyphenyl) methyl, di (4-methoxyphenyl) phenylmethyl, N-tert-butoxycarbonyl, etc.
  • Protective Groups in Organic Synthesis T. W. By Greene, John Wiley & Sons Inc. The thing described in is mentioned.
  • the compounds of formula (I) or formula (II) are not limited to specific isomers, but all possible isomers (eg keto-enol isomers, imine-enamine isomers, diastereoisomers) Isomers, optical isomers, rotational isomers, etc.), racemates or mixtures thereof.
  • One or more hydrogen, carbon and / or other atoms of the compound of formula (I) or formula (II) may be replaced with hydrogen, carbon and / or isotopes of other atoms, respectively.
  • Examples of such isotopes are 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 123 I and
  • hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine are included.
  • the compound represented by the formula (I) or the formula (II) includes a compound substituted with such an isotope.
  • the compound substituted with the isotope is also useful as a pharmaceutical, and includes all radiolabeled compounds of the compound represented by formula (I) or formula (II).
  • a “radiolabeling method” for producing the “radiolabeled product” is also encompassed in the present invention, and is useful as a metabolic pharmacokinetic study, a study in a binding assay, and / or a diagnostic tool.
  • the radiolabeled compound of the compound represented by formula (I) or formula (II) can be prepared by a method well known in the art.
  • a tritium-labeled compound represented by the formula (I) or the formula (II) can be converted into a tritium-containing compound represented by the formula (I) or the formula (II) by a catalytic dehalogenation reaction using tritium.
  • This method comprises a precursor and tritium in which a compound of formula (I) or formula (II) is appropriately halogen-substituted in the presence of a suitable catalyst such as Pd / C, in the presence or absence of a base. It includes reacting with a gas.
  • Suitable methods for preparing other tritium labeled compounds include the document Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987). 14 C-labeled compounds can be prepared by using raw materials having 14 C carbon.
  • Examples of the pharmaceutically acceptable salt of the compound represented by the formula (I) or the formula (II) or the salt of the compound represented by the formula (II) include, for example, a compound represented by the formula (I) or the formula (II) , Alkali metals (eg, lithium, sodium, potassium, etc.), alkaline earth metals (eg, calcium, barium, etc.), magnesium, transition metals (eg, zinc, iron, etc.), ammonia, organic bases (eg, trimethylamine, triethylamine) , Dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, diethanolamine, ethylenediamine, pyridine, picoline, quinoline, etc.) and salts with amino acids, or inorganic acids (eg hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid) , Phosphoric acid, hydroiodic acid, etc.) and organic (For example, formic acid,
  • the compound represented by the formula (I) or the formula (II) of the present invention or a pharmaceutically acceptable salt thereof or the salt of the compound represented by the formula (II) is a solvate (for example, hydrate etc.) and / or Alternatively, crystal polymorphs may be formed, and the present invention also includes such various solvates and crystal polymorphs.
  • the “solvate” may be coordinated with any number of solvent molecules (for example, water molecules) with respect to the compound represented by the formula (I) or the formula (II).
  • solvent molecules for example, water molecules
  • the compound represented by the formula (I) or the formula (II) or a pharmaceutically acceptable salt thereof or a salt of the compound represented by the formula (II) is left in the air, the water is absorbed, It may adhere or form a hydrate.
  • the compound represented by the formula (I) or the formula (II) or a pharmaceutically acceptable salt thereof or the salt of the compound represented by the formula (II) is recrystallized to form a crystalline
  • the compound represented by the formula (I) or the formula (II) of the present invention or a pharmaceutically acceptable salt thereof may form a prodrug, and the present invention includes such various prodrugs.
  • a prodrug is a derivative of a compound of the invention that has a group that can be chemically or metabolically degraded and is a compound that becomes a pharmaceutically active compound of the invention in vivo by solvolysis or under physiological conditions.
  • a prodrug is hydrolyzed by a compound that is enzymatically oxidized, reduced, hydrolyzed, etc. under physiological conditions in vivo to be converted into a compound represented by formula (I) or formula (II), gastric acid, etc.
  • the compound etc. which are converted into the compound shown by Formula (I) or Formula (II) are included.
  • the compound represented by formula (I) or formula (II) or a pharmaceutically acceptable salt thereof has a hydroxyl group
  • a compound having a hydroxyl group and a suitable acyl halide, a suitable acid anhydride, a suitable acid anhydride examples thereof include prodrugs such as acyloxy derivatives and sulfonyloxy derivatives produced by reacting sulfonyl chloride, a suitable sulfonyl anhydride and mixed anhydride, or reacting with a condensing agent.
  • the compound represented by the formula (I) or the formula (II) according to the present invention can be produced, for example, by the general synthesis method shown below. Extraction, purification, and the like may be performed in a normal organic chemistry experiment.
  • the synthesis of the compound of the present invention can be carried out in consideration of a technique known in the art.
  • the compound represented by the formula (I) or the formula (II) according to the present invention can be produced, for example, by a general synthesis method shown below.
  • Compound a3 can be obtained by reacting compound a1 with compound a2 in the presence of a condensing agent.
  • dicyclohexylcarbodiimide carbonyldiimidazole, dicyclohexylcarbodiimide-N-hydroxybenzotriazole, EDC, 4- (4,6-dimethoxy-1,3,5, -triazin-2-yl) -4- Examples thereof include methylmorpholinium chloride and HATU, and 1 to 5 molar equivalents can be used with respect to compound i1.
  • the reaction temperature is ⁇ 20 ° C. to 60 ° C., preferably 0 ° C. to 30 ° C.
  • the reaction time is 0.1 to 24 hours, preferably 1 to 12 hours.
  • reaction solvent examples include DMF, DMA, NMP, tetrahydrofuran, dioxane, dichloromethane, acetonitrile and the like, and these can be used alone or in combination.
  • First Step A halide can be obtained by reacting compound b1 with a halogenating agent.
  • halogenating agent examples include thionyl chloride, phosphorus oxychloride, carbon tetrabromide-triphenylphosphine, and the like, and 1 to 5 molar equivalents can be used with respect to compound j1.
  • a sulfonyl compound can be obtained by reacting compound b1 with a sulfonylating agent in the presence of a base such as triethylamine or pyridine.
  • sulfonylating agent examples include methanesulfonyl chloride, p-toluenesulfonyl chloride and the like, and 1 to 5 molar equivalents can be used with respect to compound b1.
  • the reaction temperature is ⁇ 80 ° C. to 50 ° C., preferably ⁇ 20 ° C. to 20 ° C.
  • the reaction time is 0.1 to 24 hours, preferably 0.5 to 12 hours.
  • reaction solvent acetonitrile, tetrahydrofuran, toluene, dichloromethane or the like can be used.
  • Second Step Compound b3 can be obtained by reacting the obtained halide or sulfonyl compound with compound b2 in the presence of a base.
  • Examples of the base include DIEA, potassium carbonate, sodium hydrogen carbonate, sodium hydride, sodium hydroxide and the like.
  • the reaction temperature is 0 ° C. to 150 ° C., preferably 20 ° C. to 100 ° C.
  • the reaction time is 0.5 to 120 hours, preferably 1 to 72 hours.
  • reaction solvent examples include acetonitrile, tetrahydrofuran, toluene, dichloromethane and the like.
  • Compound c2 can be obtained by reacting compound c1 with an acid or a Lewis acid.
  • Examples of the acid include hydrochloric acid-ethyl acetate, hydrochloric acid-methanol, hydrochloric acid-dioxane, sulfuric acid, formic acid, trifluoroacetic acid and the like.
  • Examples of the Lewis acid include trimethylsilyl iodide, BBr 3 , AlCl 3 , BF 3. (Et 2 O) and the like, and 1 to 10 molar equivalents can be used with respect to the compound c1.
  • the reaction temperature is 0 ° C to 60 ° C, preferably 0 ° C to 20 ° C.
  • the reaction time is 0.5 to 12 hours, preferably 1 to 6 hours.
  • reaction solvent examples include methanol, ethanol, water, acetone, acetonitrile, DMF and the like, and these can be used alone or in combination.
  • First Step Compound (A1) can be debocated to obtain compound (A2) by the general synthesis method 0-C.
  • Hydrogen pressure is 1 to 50 atmospheres.
  • a hydrogen source cyclohexene, 1,4-cyclohexadiene, formic acid, ammonium formate, or the like can also be used.
  • the reaction temperature is 0 ° C. to 40 ° C., preferably 10 ° C. to 30 ° C.
  • the reaction time is 0.5 to 24 hours, preferably 1 to 12 hours.
  • reaction solvent examples include methanol, ethanol, water, tetrahydrofuran, ethyl acetate and the like, and these can be used alone or in combination.
  • Compound (A7) is obtained by reacting compound (A5) with compound (A6) having an appropriate leaving group X 1 by the method of second step of general synthesis method 0-B. Can do.
  • compound (A8) can be obtained by reacting compound (A7) with ammonium chloride in the presence of a condensing agent.
  • Pg 2 is an amide protecting group such as a tert-butoxycarbonyl group, a benzyloxycarbonyl group, or a benzyloxymethyl group
  • Pg 3 and Pg 4 are trimethylsilyl (TMS) groups or t-butyldimethyl
  • TMS trimethylsilyl
  • X 2 and X 3 are halogens, and other symbols are as defined above.
  • Examples of the base include sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, calcium carbonate, cesium carbonate, pyridine, triethylamine, diisopropylethylamine, DBU, DBN and the like, and 1 to 5 mol relative to the compound (B1) An equivalent amount can be used.
  • the reaction temperature is ⁇ 10 ° C. to 80 ° C., preferably 10 ° C. to 60 ° C.
  • the reaction time is 0.5 to 48 hours, preferably 1 to 24 hours.
  • reaction solvent examples include tetrahydrofuran, dioxane, acetonitrile, water, DMF, dichloromethane and the like, and these can be used alone or in combination.
  • Second step compound (B2) by reacting the acid, only Pg 4 group is a protecting group for the primary hydroxyl group selectively deprotected, to give compound (B3).
  • Examples of the acid include trifluoroacetic acid, formic acid, hydrochloric acid, sulfuric acid, acetic acid, oxalic acid, and the like, and can be used at 0.1 to 10 molar equivalents relative to the compound (B2).
  • the reaction temperature is 0 ° C. to 90 ° C., preferably 20 ° C. to 60 ° C.
  • the reaction time is 0.5 to 12 hours, preferably 1 to 6 hours.
  • reaction solvent examples include THF, methanol, ethanol, water, acetone, acetonitrile, DMF, dichloromethane and the like, and these can be used alone or in combination.
  • Third Step Compound (B4) can be obtained by reacting compound (B3) with (X 2 ) 2 (for example, iodine or the like) or C (X 2 ) 4 and phosphine in the presence of a base.
  • (X 2 ) 2 for example, iodine or the like
  • C (X 2 ) 4 phosphine
  • Examples of (X 2 ) 2 include iodine, bromine and the like, and 1 to 10 molar equivalents can be used with respect to compound (B3).
  • C (X 2 ) 4 includes carbon tetrabromide, carbon tetrachloride and the like, and can be used at 1 to 10 molar equivalents relative to compound (B3).
  • phosphine examples include triphenylphosphine and tributylphosphine, and 1 to 10 molar equivalents can be used with respect to compound (B3).
  • Examples of the base include pyridine, triethylamine, diisopropylethylamine, imidazole and the like, and 1 to 5 molar equivalents can be used with respect to compound (B3).
  • the reaction temperature is 0 ° C. to 60 ° C., preferably 0 ° C. to 25 ° C.
  • the reaction time is 0.5 to 24 hours, preferably 0.5 to 16 hours.
  • reaction solvent examples include dioxane, dichloromethane, tetrahydrofuran, acetonitrile and the like, and they can be used alone or in combination.
  • the compound (B5) can be obtained by reacting the compound (B4) with a base.
  • Examples of the base include DBU, DBN, sodium ethoxide, sodium methoxide and the like, and 1 to 5 molar equivalents can be used with respect to the compound (B4).
  • the reaction temperature is 0 ° C. to 60 ° C., preferably 0 ° C. to 25 ° C.
  • the reaction time is 0.5 to 48 hours, preferably 0.5 to 24 hours.
  • reaction solvent examples include acetonitrile, tetrahydrofuran, DMF, dioxane and the like, and they can be used alone or in combination.
  • a vinyl halide compound (B6) can be obtained by reacting the compound (B5) with an oxidative halogenating agent.
  • oxidative halogenating agent examples include iodonium dicorydinium triflate (IDCT), iodonium dicorydinium perchlorate (IDCP) and the like, and 1 to 5 molar equivalents can be used with respect to compound (B5).
  • IDCT iodonium dicorydinium triflate
  • IDCP iodonium dicorydinium perchlorate
  • the reaction temperature is -78 ° C to 25 ° C, preferably -40 ° C to 25 ° C.
  • the reaction time is 0.5 hours to 5 hours, preferably 0.5 hours to 1 hour.
  • reaction solvent examples include acetonitrile, propionitrile, dichloromethane, THF, dioxane, diethyl ether, ethyl acetate and the like, and these can be used alone or in combination.
  • Pg 1 is a carboxy protecting group such as a methyl group, an ethyl group, or a tert-butyl (t-Bu) group
  • Pg 2 is a tert-butoxycarbonyl group, a benzyloxycarbonyl group, or a benzyloxy group.
  • First Step Compound (C1) can be obtained by reacting compound (A8) with vinyl halide compound (B6) in the presence of a copper catalyst, a ligand and a base.
  • the copper catalyst examples include copper iodide, bromide cylinder, copper chloride, copper acetate and the like, and it can be used at 0.1 to 1 molar equivalent relative to the compound (B6).
  • Examples of the base include cesium carbonate, potassium carbonate, sodium carbonate, calcium carbonate and the like, and 1 to 10 molar equivalents can be used with respect to the compound (B6).
  • the ligands include (1R, 2R) -N, N'-dimethyl-1,2-diphenylethane-1,2-diamine, (1S, 2S) -N, N'-dimethyl-1,2-diphenyl
  • Examples include ethane-1,2-diamine, N, N′-dimethylethane-1,2-diamine, 1,10-phenanthroline, and the like, and 0.1 to 2 molar equivalents are used relative to compound (B6). Can do.
  • the reaction temperature is 20 ° C. to the reflux temperature of the solvent, and in some cases, the temperature under microwave irradiation.
  • the reaction time is 0.1 to 48 hours, preferably 0.5 to 12 hours.
  • reaction solvent examples include tetrahydrofuran, dioxane, toluene, DMF, dichloromethane, water and the like, and these can be used alone or in combination.
  • the compound (C2) can be obtained by reacting the compound (C1) with an acid or a Lewis acid and deprotecting by the general synthesis method 0-C.
  • Examples of the acid include hydrochloric acid-ethyl acetate, hydrochloric acid-methanol, hydrochloric acid-dioxane, sulfuric acid, formic acid, trifluoroacetic acid and the like.
  • Examples of the Lewis acid include BCl 3 , PhBCl 2 , trimethylsilyl iodide, BBr 3 , AlCl 3 , BF 3. (Et 2 O), FeCl 3 , TiCl 4 , Ti (OEt) 4, and the like (C1). 1 to 30 molar equivalents can be used.
  • the compound (C3) can be obtained by reacting the compound (C2) with a fluorine reagent to deprotect the hydroxy protecting group Pg 3 .
  • Fluorine reagents include hydrogen fluoride triethylamine, hydrogen fluoride pyridine, tetrabutylammonium fluoride, cesium fluoride, and the like, and can be used at 1 to 50 molar equivalents relative to compound (C2).
  • the reaction temperature is -78 ° C to 60 ° C, preferably -78 ° C to 30 ° C.
  • the reaction time is 0.5 to 120 hours, preferably 1 to 96 hours.
  • reaction solvent examples include acetonitrile, dichloromethane, tetrahydrofuran, nitromethane and the like, and they can be used alone or in combination.
  • Pg 1 is a carboxy protecting group such as a methyl group, an ethyl group, or a tert-butyl (t-Bu) group
  • Pg 2 is a tert-butoxycarbonyl group, a benzyloxycarbonyl group, or a benzyloxy group.
  • First Step Compound (B7) can be obtained by cross-coupling using copper by adding formamide to compound (B6) in the presence of a copper catalyst, a ligand, and a base.
  • the copper catalyst examples include copper iodide, bromide cylinder, copper chloride, copper acetate and the like, and it can be used at 0.1 to 1 molar equivalent relative to the compound (B6).
  • Examples of the base include cesium carbonate, potassium carbonate, sodium carbonate, calcium carbonate and the like, and 1 to 10 molar equivalents can be used with respect to the compound (B6).
  • Examples of the ligand include N, N'-dimethylethane-1,2-diamine, (1R, 2R) -N, N'-dimethyl-1,2-diphenylethane-1,2-diamine, (1S, 2S ) -N, N′-dimethyl-1,2-diphenylethane-1,2-diamine, 1,10-phenanthroline, etc., and is used in an amount of 0.1 to 2 molar equivalents relative to compound (B6). be able to.
  • the reaction temperature is 20 ° C. to the reflux temperature of the solvent, and in some cases, the temperature under microwave irradiation.
  • the reaction time is 0.1 to 48 hours, preferably 0.5 to 12 hours.
  • reaction solvent examples include tetrahydrofuran, toluene, DMF, dioxane, dichloromethane, water and the like, and these can be used alone or in combination.
  • An isonitrile compound (B8) can be obtained by reacting compound (B7) with triphosgene in the presence of a base.
  • Examples of the base include triethylamine, diisopropylethylamine, potassium carbonate, sodium cesium carbonate, calcium carbonate and the like.
  • the reaction temperature is ⁇ 80 ° C. to 50 ° C., preferably ⁇ 78 ° C. to 0 ° C.
  • the reaction time is 0.1 to 24 hours, preferably 0.5 to 12 hours.
  • reaction solvent examples include toluene, chloroform, dichloromethane, tetrahydrofuran and the like.
  • Third Step A compound (D1) can be obtained by reacting the isonitrile compound (B8), the amine represented by H 2 N—Pg 4 and the aldehyde with the compound (A3 ′) (so-called Ugi reaction). it can.
  • the reaction temperature is 0 ° C. to 150 ° C., preferably 20 ° C. to 100 ° C.
  • the reaction time is 0.1 hour to 72 hours, preferably 0.5 hour to 48 hours.
  • reaction solvent examples include ethanol, methanol, toluene, chloroform, dichloromethane, tetrahydrofuran, dioxane and the like.
  • the compound (D2) can be obtained by debocating the compound (D1) by the general synthesis method 0-C.
  • compound (C1 ′) can be obtained by reacting compound (D2) with compound (A6 ′) in the presence of a condensing agent.
  • Sixth Step Compound (C2) can be obtained by deprotecting compound (C1 ′) by the method of the second step of general synthesis method 3.
  • Seventh Step Compound (C3) can be obtained by deprotecting compound (C2) by the method of third step of general synthesis method 3.
  • the compound of the present invention can be protected using a protecting group.
  • protecting groups include Protective Groups in Organic Synthesis, T., such as ethoxycarbonyl, t-butoxycarbonyl, acetyl, and benzyl. W. By Greene, John Wiley & Sons Inc. And the like. Methods for introducing and removing protecting groups are those commonly used in organic synthetic chemistry [for example, Protective Groups in Organic Synthesis, T. et al. W. By Greene, John Wiley & Sons Inc. Reference] etc., or can be obtained according to them.
  • the conversion of the functional group contained in each substituent can be performed by a known method other than the above production method [for example, Comprehensive Organic Transformations, R.C.
  • the intermediates and target compounds in each of the above production methods are isolated and purified by purification methods commonly used in synthetic organic chemistry such as neutralization, filtration, extraction, washing, drying, concentration, recrystallization, and various chromatography. can do.
  • the intermediate can be subjected to the next reaction without any particular purification.
  • R 1 is preferably a hydrogen atom or alkyl.
  • R 1 is more preferably a hydrogen atom, methyl, ethyl, n-propyl, isopropyl, or isobutyl.
  • R 1 is more preferably a hydrogen atom or methyl.
  • R 2 is preferably a hydrogen atom, alkyl, or a group shown below:
  • R 2 is more preferably a hydrogen atom, methyl, ethyl, n-propyl, isopropyl, isobutyl or a group shown below:
  • R 2 is more preferably a hydrogen atom or a group shown below:
  • R 2 is particularly preferably a group shown below:
  • R a is preferably hydroxy, alkyl, or halogen.
  • R a is more preferably a hydroxy, methyl, ethyl, chlorine atom, or fluorine atom.
  • R a is more preferably hydroxy.
  • n is preferably an integer of 0 to 3.
  • m is more preferably an integer of 0 to 2.
  • m is more preferably 0. However, When there are a plurality of R a s , they may be the same or different.
  • R 3 is preferably a hydrogen atom or alkyl.
  • R 3 is more preferably a hydrogen atom, methyl, ethyl, or isopropyl.
  • R 4 is preferably a hydrogen atom or alkyl, or R 3 and R 4 may together form a cyclopropane ring.
  • R 4 is more preferably a hydrogen atom, methyl, ethyl, or isopropyl.
  • R 5 is preferably a hydrogen atom or alkyl.
  • R 5 is more preferably a hydrogen atom, methyl, ethyl, or isopropyl.
  • R 6 is preferably a hydrogen atom, alkyl, or a group shown below:
  • R 6 is more preferably a hydrogen atom, methyl, or a group shown below:
  • R 6 is more preferably represented by the formula:
  • R b is preferably hydroxy, alkyl, or halogen. R b is more preferably hydroxy.
  • n is preferably an integer of 0 to 3.
  • n is more preferably an integer of 0 or 1.
  • Rb when there are a plurality of Rb , they may be the same or different.
  • R 7 is preferably a hydrogen atom, alkyl substituted with amino, or alkylcarbonyl substituted with amino.
  • R 7 is more preferably a hydrogen atom or an alkylcarbonyl substituted with amino.
  • R 7 is more preferably a hydrogen atom, aminomethylcarbonyl, or aminoethylcarbonyl.
  • R 7 is particularly preferably a hydrogen atom or aminomethylcarbonyl.
  • R c is preferably a hydrogen atom or alkyl.
  • R c is more preferably a hydrogen atom, methyl, or ethyl.
  • R c is more preferably a hydrogen atom or methyl.
  • R c is particularly preferably a hydrogen atom.
  • R 8 is preferably a hydrogen atom, silyl substituted with alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted aromatic Carbocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic A carbocyclic carbonyl, a substituted or unsubstituted non-aromatic carbocyclic carbonyl, a substituted or unsubstituted aromatic heterocyclic carbonyl, or a substituted or unsubstituted non-aromatic heterocyclic carbonyl.
  • R 8 is more preferably a hydrogen atom, silyl substituted with alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted phenylcarbonyl, alkylcarbonyl, or alkyloxy.
  • R 8 is more preferably a hydrogen atom, tert-butyldimethylsilyl, triisopropylsilyl, triethylsilyl, phenyl, p-methoxyphenyl, phenylcarbonyl, methylcarbonyl, tert-butylcarbonyl, methoxy, or ethoxy.
  • R 8 is particularly preferably a hydrogen atom, tert-butyldimethylsilyl, triisopropylsilyl, or triethylsilyl.
  • L 1 is preferably a single bond, alkylene, alkenylene, or alkynylene.
  • L 1 is more preferably a single bond, methylene or ethylene.
  • L 1 is a single bond and R 8 is silyl substituted with a hydrogen atom or alkyl.
  • R 9 is preferably a hydrogen atom or a group represented by —OL 2 —R 11 .
  • R 9 is more preferably a hydrogen atom or —OH.
  • L 2 is preferably a single bond, alkylene, alkenylene, or alkynylene.
  • L 2 is more preferably a single bond, methylene, or ethylene.
  • L 2 is particularly preferably a single bond.
  • R 11 is preferably a hydrogen atom, silyl substituted with alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted aromatic Carbocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic A carbocyclic carbonyl, a substituted or unsubstituted non-aromatic carbocyclic carbonyl, a substituted or unsubstituted aromatic heterocyclic carbonyl, or a substituted or unsubstituted non-aromatic heterocyclic carbonyl.
  • R 11 is more preferably a hydrogen atom, or silyl substituted with alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted phenylcarbonyl, alkylcarbonyl, or alkyloxy.
  • R 11 is more preferably a hydrogen atom, tert-butyldimethylsilyl, triisopropylsilyl, triethylsilyl, phenyl, p-methoxyphenyl, phenylcarbonyl, methylcarbonyl, tert-butylcarbonyl, methoxy, or ethoxy.
  • R 11 is particularly preferably a hydrogen atom, tert-butyldimethylsilyl, triisopropylsilyl, or triethylsilyl.
  • R 9 is —OL 2 —R 11 , L 2 is a single bond, and R 11 is a hydrogen atom or silyl substituted with alkyl.
  • R 10 is preferably a hydrogen atom or an amide protecting group.
  • R 10 is more preferably a hydrogen atom, alkyloxy, alkyloxyalkyl, alkyloxyalkyloxyalkyl, benzyl, benzyloxy, or benzyloxyalkyl.
  • R 10 is more preferably a hydrogen atom, methyloxymethyl, methyloxyethyloxymethyl, benzyl, or benzyloxymethyl.
  • R 10 is particularly preferably a hydrogen atom.
  • X is preferably halogen, —OS (O) 2 —R 14 , or isocyano.
  • X is more preferably a chlorine atom, a bromine atom, an iodine atom, or isocyano.
  • X is more preferably a bromine atom, an iodine atom, or isocyano.
  • R 14 is preferably alkyl, haloalkyl, or a substituted or unsubstituted aromatic carbocyclic group.
  • R 14 is more preferably methyl, trifluoromethyl, or p-methylphenyl.
  • R 12 is preferably a hydrogen atom or substituted or unsubstituted alkyl.
  • R 12 is more preferably methyl.
  • R 13 is preferably a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted nonaromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group.
  • R 13 is more preferably a hydrogen atom, a substituted or unsubstituted alkyl, or a substituted or unsubstituted aromatic carbocyclic group.
  • R 13 is more preferably a hydrogen atom, methyl, or phenyl.
  • Another feature of the compound according to the present invention is that by introducing an alkylcarbonyl group substituted by a hydrogen atom or amino in R 7 of formula (I), that is, by introducing an amino group at the terminal, It has MraY inhibitory activity and anti-gram-negative bacterial activity.
  • Another feature of the compound according to the present invention is that it has high MraY inhibitory activity and anti-gram-negative bacterial activity by introducing an m-hydroxybenzyl group in R 6 of formula (I).
  • Another feature of the compounds according to the present invention is that the 3′-position of the sugars of formula (I) and formula (II) (position corresponding to R 9 in formula (II)) is substituted with —OH. .
  • the 3 ′ position of the sugar of Pacidamycin D is unsubstituted.
  • the compound according to the present invention Since the compound according to the present invention has MraY inhibitory activity and anti-gram-negative bacterial activity, it is useful as a therapeutic and / or prophylactic agent for various diseases caused by pathogenic bacteria.
  • Oral administration may be carried out by preparing a commonly used dosage form such as tablets, granules, powders, capsules and the like according to conventional methods.
  • a commonly used dosage form such as tablets, granules, powders, capsules and the like according to conventional methods.
  • parenteral administration any commonly used dosage form such as an injection can be suitably administered. Since the compound according to the present invention has high oral absorbability, it can be suitably used as an oral preparation.
  • отное отное отное отное отное о ⁇ ное ком ⁇ онентs such as excipients, binders, disintegrants, lubricants and the like suitable for the dosage form can be mixed with the effective amount of the compound of the present invention as necessary to obtain a pharmaceutical composition.
  • the dosage of the pharmaceutical composition of the present invention is preferably set in consideration of the age, weight, type and degree of disease, route of administration, etc. of the patient. 100 mg / kg / day, preferably in the range of 0.1 to 10 mg / kg / day. In the case of parenteral administration, although it varies greatly depending on the administration route, it is usually 0.005 to 10 mg / kg / day, preferably 0.01 to 1 mg / kg / day. This may be administered once to several times a day.
  • the compound according to the present invention is a nucleic acid antibiotic.
  • the compounds of the present invention have a broad spectrum of antibacterial activity, and various diseases caused by pathogenic bacteria in various mammals including humans such as respiratory tract infections, urinary tract infections, respiratory infections, sepsis, nephritis, gallbladder It can be used for the prevention or treatment of inflammation, oral infection, endocarditis, pneumonia, osteomyelitis, otitis media, enteritis, empyema, wound infection, opportunistic infection and the like.
  • the compound of the present invention exhibits MraY inhibitory action and is therefore effective against various bacteria including Gram-positive bacteria and Gram-negative bacteria.
  • a compound having an inhibitory effect on MraY acts at a position upstream in the biosynthetic pathway relative to the target of ⁇ -lactam antibiotics, and therefore, bacteria having resistance to ⁇ -lactam antibiotics, such as ⁇ -lactam resistant Pseudomonas aeruginosa, are used. It is expected to be effective against bacteria.
  • the NMR analysis obtained in each example was performed at 300 MHz and measured using DMSO-d 6 and CDCl 3 .
  • the underline in the NMR data in the examples indicates that the peak is a part with an underline.
  • RT represents LC / MS: retention time in liquid chromatography / mass spectrometry and was measured under the following conditions.
  • Measurement conditions 1 Column: Gemini-NX (5 ⁇ m, id 4.6 ⁇ 50 mm) (Phenomenex) Flow rate: 3 mL / min UV detection wavelength: 254 nm
  • Measurement condition 2 Column: Gemini-NX (5 ⁇ m, id 4.6 ⁇ 50 mm) (Phenomenex) Flow rate: 3 mL / min UV detection wavelength: 254 nm
  • Measurement condition 3 Column: Shim-pack XR-ODS (2.2 ⁇ m, id 50 ⁇ 3.0 mm) (Shimadzu) Flow rate: 1.6 mL / min UV detection wavelength: 254 nm
  • reaction solution was partitioned between ethyl acetate and 0.2 mol / L hydrochloric acid, and the organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (15 ⁇ 2.6 cm, chloroform / methanol 100/0 to 80/20) to obtain compound (7) (754.4 mg, 69%) as a brown solid substance.
  • reaction solution was partitioned between ethyl acetate and water, and the organic phase was washed with 0.2 mol / L hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (13 ⁇ 4.6 cm, chloroform / methanol 100/0 to 91/9) to obtain compound (8) (1.96 g, 82%) as a white solid substance.
  • reaction solution was partitioned between ethyl acetate and water, and the organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (13 ⁇ 4.6 cm, hexane / ethyl acetate 90/10 to 83/17) to obtain compound (10) (1.80 g, 99%) as a colorless oily substance.
  • reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution, and the organic phase was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (17 ⁇ 4.8 cm, hexane / ethyl acetate 80/20 to 60/40) to obtain compound (11) (4.5 g, 83%) as a white solid substance.
  • reaction solution was partitioned between ethyl acetate and water, and the organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (10 ⁇ 2.6 cm, hexane / ethyl acetate 90/10 to 80/20) to obtain compound (13) (130 mg, 93%) as a colorless oily substance.
  • the reaction mixture was partitioned between ethyl acetate and 5% aqueous sodium thiosulfate solution, and the organic phase was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (7.5 ⁇ 2 cm, hexane / ethyl acetate 90/10 to 80/20) to obtain Compound (14) (53 mg, 79%) as a pale yellow oily substance.
  • reaction mixture was diluted with ethyl acetate, insoluble material was filtered off through celite, and the filtrate was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (10 ⁇ 2.6 cm, chloroform / methanol 100/0 to 91/9) to obtain compound (15) (144.7 mg, 86%) as a white solid substance.
  • Example 1 Synthesis of Compound (3'-OH-pacidamycin D) (15) To a solution of 30 mg, 0.024 mmol) in dichloromethane (2 mL), 1 mol / L boron trichloride-dichloromethane solution (0.243 ml, 0.243 mmol) was added at ⁇ 78 ° C. in a nitrogen atmosphere, treated at the same temperature for 1 hour, and then treated at ⁇ 40 ° C. for 1 hour.
  • the reaction mixture was concentrated under reduced pressure, and the residue was purified by octadecyl silica column chromatography (30 ⁇ 1.1 cm, 0.1% aqueous trifluoroacetic acid / acetonitrile 100/0 to 60/40).
  • the compound (3′-OH-pacidamycin D, 5.1 mg, 25% over 2 steps) was obtained as a white foam.
  • reaction solution was partitioned between ethyl acetate and water, and the organic phase was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (7.5 ⁇ 2 cm, hexane / ethyl acetate 50/50 to 20/80) to obtain compound (24) (10 mg, 79%) as a white foam.
  • reaction solution was partitioned between ethyl acetate and water, and the organic phase was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (15 ⁇ 2.6 cm, hexane / ethyl acetate 90/10 to 80/20) to obtain compound (26) (424.9 mg, 83%) as a colorless oily substance.
  • reaction mixture was partitioned between ethyl acetate and 5% aqueous sodium thiosulfate solution, and the organic phase was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (7.5 ⁇ 2 cm, hexane / ethyl acetate 85/15) to obtain compound (30) (35 mg, 53%) as a pale yellow oily substance.
  • reaction mixture was diluted with ethyl acetate, insoluble material was filtered off through celite, and the filtrate was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (7.5 ⁇ 2 cm, chloroform / methanol 100/0 to 95/5) to obtain compound (31) (42.4 mg, 69%) as a pale yellow solid substance.
  • Example 3 It was synthesized by the route using Ugi reaction.
  • the target product was obtained as a mixture of two diastereomers (1: 1) and separated and purified by preparative TLC, but the compound having a higher Rf value was used.
  • the absolute configuration of the asymmetric carbon indicated by an asterisk has not been determined.
  • Example 4 It was synthesized by the route using Ugi reaction.
  • the target product was obtained as a mixture of two diastereomers (1: 1) and separated and purified by preparative TLC, but the compound having a smaller Rf value was used.
  • the absolute configuration of the asymmetric carbon indicated by an asterisk has not been determined.
  • Test Example 1 In vitro measurement of antibacterial activity (Test method) The minimum growth inhibitory concentration (MIC: ⁇ g / ml) was determined by a micro liquid dilution method based on CLSI.
  • the bacterial species used are as follows. (1) P. aeruginosa ATCC 27853 (2) P. aeruginosa PAO1 (3) P. aeruginosa YY165 ( ⁇ mexB) (4) P. aeruginosa ATCC 25619 (5) P. aeruginosa SR 27156 Brain Heart Infusion Agar was used for pre-culture of the bacteria used for MIC measurement, and Mueller Hinton Broth was used for the MIC measurement medium. The amount of inoculum for MIC measurement was 5 ⁇ 10 5 CFU / ml, and was determined after culturing at 35 ° C. for 20 hours.
  • Test Example 2 MraY Inhibitory Activity Test Compound concentrations of various concentrations dissolved in 100% DMSO were added to a 384-well microplate at 0.5 ⁇ L / well (final compound concentration 25 ⁇ g / mL to 0.05 ng / mL, final DMSO concentration 2%).
  • a Staphylococcus aureus-derived MalaY enzyme solution diluted with assay buffer (50 mM Tris-HCl (pH 7.6), 50 mM KCl, 25 mM MgCl2, 0.2% Triton-X, 8% glycerol)
  • assay buffer 50 mM Tris-HCl (pH 7.6), 50 mM KCl, 25 mM MgCl2, 0.2% Triton-X, 8% glycerol
  • the substrate mixed solution was added at 20 ⁇ L / well (undecaprenyl phosphate final concentration 100 ⁇ M, dansyl-UDP-MurNAc-pentapeptide final concentration 20 ⁇ M).
  • the mixture was reacted at room temperature for 3 to 4 hours, and the fluorescence signal intensity was measured using a plate reader under conditions of an excitation wavelength of 355 nm and a fluorescence wavelength of 535 nm.
  • the inhibitory activity was calculated at the concentration of the compound exhibiting 50% inhibitory activity, assuming that the fluorescent signal value in the presence of the enzyme was 0% and the fluorescent signal value in the absence of the enzyme was 100% inhibitory activity.
  • Formulation Example 1 Tablet 15 mg of the present compound Lactose 15mg Calcium stearate 3mg Ingredients other than calcium stearate are uniformly mixed, crushed and granulated, and dried to obtain granules of an appropriate size. Next, calcium stearate is added and compressed to form tablets.
  • Formulation Example 2 Capsule Compound of the present invention 10 mg Magnesium stearate 10mg Lactose 80mg Are mixed uniformly to make a powder as a fine powder or powder. It is filled into a capsule container to form a capsule.
  • Formulation Example 3 Granules Compound of the present invention 30 g Lactose 265g Magnesium stearate 5g After mixing well, compression molding, pulverizing, sizing, and sieving to make granules of appropriate size.
  • the compound according to the present invention can be a pharmaceutical product such as an antibacterial agent.

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Abstract

L'invention concerne un nouveau composé ayant des effets antibactériens. Plus spécifiquement, l'invention concerne un composé présentant une activité antibactérienne, de préférence un composé nucléoside antibactérien avec une activité antibactérienne par inhibition de l'action de MraY, en particulier un nouveau dérivé de Pacidamycine, laquelle est un inhibiteur de MraY. Ce nouveau dérivé de Pacidamycine ou un sel pharmaceutiquement acceptable de celui-ci permettent d'obtenir un composé antibactérien. Le procédé de cette invention permet en outre de réaliser la synthèse complète de la Pacidamycine D naturelle et de ses dérivés.
PCT/JP2012/004227 2011-06-30 2012-06-29 Dérivé antibiotique nucléoside WO2013001830A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63211295A (ja) * 1986-05-20 1988-09-02 Sankyo Co Ltd 抗生物質ムレイドマイシンａおよびｃ
JPH01230568A (ja) * 1987-11-20 1989-09-14 Sankyo Co Ltd ムレイドマイシン誘導体
WO2000044335A2 (fr) * 1999-01-28 2000-08-03 Microcide Pharmaceuticals, Inc. Derives d'antibiotiques du peptide uridylique (upa), leurs syntheses et utilisation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63211295A (ja) * 1986-05-20 1988-09-02 Sankyo Co Ltd 抗生物質ムレイドマイシンａおよびｃ
JPH01230568A (ja) * 1987-11-20 1989-09-14 Sankyo Co Ltd ムレイドマイシン誘導体
WO2000044335A2 (fr) * 1999-01-28 2000-08-03 Microcide Pharmaceuticals, Inc. Derives d'antibiotiques du peptide uridylique (upa), leurs syntheses et utilisation

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CHIHIRO INAGAKI ET AL.: "Ugi Hanno o Mochiita 4'-(R)-dihydropacidamycin D no Shusokuteki Zen Gosei Kenkyu", ABSTRACTS OF ANNUAL MEETING OF PHARMACEUTICAL SOCIETY OF JAPAN, vol. 131ST, no. 2, 5 March 2011 (2011-03-05), pages 120 *
OKAMOTO KAZUYA. ET AL.: "Synthesis of pacidamyc in analogues via an Ugi-multicomponent reaction", BIOORGANIC AND MEDICINAL CHEMISTRY LETTERS, vol. 22, 2012, pages 4810 - 4815 *
SATOSHI ICHIKAWA ET AL.: "Development of Antibacterial Agents Active against Drug- resistant Bacterial Pathogens Based on Total Synthesis of Nucleoside Natural Products", JOURNAL OF SYNTHETIC ORGANIC CHEMISTRY, JAPAN, vol. 69, no. 9, 1 September 2011 (2011-09-01), pages 1020 - 1033 *
TETSUYA TANINO ET AL.: "Comprehensive Synthetic Study of Muraymycins toward the Development of Novel Antibacterial Agents", JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN, vol. 131, no. 3, 1 March 2011 (2011-03-01), pages 335 - 346 *

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