WO2002064607A1 - Nouveaux derives de macrolides a 16 elements modifies en 12 et 13 - Google Patents

Nouveaux derives de macrolides a 16 elements modifies en 12 et 13 Download PDF

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Publication number
WO2002064607A1
WO2002064607A1 PCT/JP2002/001241 JP0201241W WO02064607A1 WO 2002064607 A1 WO2002064607 A1 WO 2002064607A1 JP 0201241 W JP0201241 W JP 0201241W WO 02064607 A1 WO02064607 A1 WO 02064607A1
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group
propyl
represented
substituent
hydrogen atom
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PCT/JP2002/001241
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English (en)
Japanese (ja)
Inventor
Ken-Ichi Kurihara
Tomoaki Miura
Naoto Ohkura
Takuji Yoshida
Takeshi Furuuchi
Keiichi Ajito
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Meiji Seika Kaisha, Ltd.
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Priority to JP2002564537A priority Critical patent/JP4248244B2/ja
Publication of WO2002064607A1 publication Critical patent/WO2002064607A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
    • 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 novel 16-membered ring macrolide derivative effective against Gram-positive bacteria and Gram-negative bacteria.
  • Eris mouthmycin has long been used as a clinically useful antibiotic because of its distinctive antibacterial properties, good tissue transfer, and few side effects.
  • the drug is degraded by gastric acid during oral administration, so absorption is not constant and blood concentration is low.
  • new macrolides such as clarithromycin, which overcome these disadvantages of erythromycin, were launched one after another.
  • macrolides have been positioned as clinically important antibacterial agents due to their high efficacy, and their share in the antimicrobial market has increased significantly.
  • erythromycin-resistant bacteria are steadily increasing year by year with the increase in the frequency of their use, and it is easily expected that these resistant bacteria may become a major problem in the future.
  • the macrolide antibiotics used clinically include 14-membered macrolides derived mainly from erythromycin (however, azithromycin is a 15-membered macrolide obtained by introducing a nitrogen atom to erythromycin) and leucomyci.
  • 14-membered macrolides derived mainly from erythromycin (however, azithromycin is a 15-membered macrolide obtained by introducing a nitrogen atom to erythromycin) and leucomyci.
  • Leucomycin-based 16-membered macrolides are superior to 14-membered macrolides in terms of safety, such as side effects, and ease of administration, but are inferior to new macrolides in terms of efficacy. So far, many groups have conducted research aimed at improving their effectiveness.
  • leucomycin-based 16-membered The main purpose of improving the efficacy of E.
  • coli was to susceptible bacteria, and no improvement was made to erythromycin-resistant bacteria other than our invention described below.
  • conventional macrolide antibiotics are mainly effective against Gram-positive bacteria, there is still room for improvement in antibacterial activity against Gram-negative bacteria, and a 15-membered ring derived from erythromycin.
  • Azithromycin, a macrolide only ameliorated these problems for the first time, and few reports have shown that the antibacterial activity of leucomycin-based 16-membered macrolides against gram-negative bacteria has been improved.
  • the present inventors have synthesized a derivative in which the 3-position hydroxyl group of the leucomycin-based 16-membered ring-shaped macrolide is derivatized and an epi-type derivative in which the 3-position hydroxyl group is inverted, and as a result, certain derivatives are excellent.
  • terithromycin removes neutral sugars from clarithromycin, oxidizes the hydroxyl groups that appear, converts them to carbonyl groups, and converts the nitrogen atoms of the citral carbamates constructed at the lactone ring 11, 12 It has a structure in which a side chain that contributes to activity expression is extended (US Pat. No. 5,635,485).
  • ketolide ABT-773 which was converted to a carbonyl group by cycling, was also announced (International Publication W098 / 09978). These ketolides have greatly improved antibacterial activity against not only susceptible bacteria but also resistant bacteria. However, there remains a major problem in pharmacokinetics, such as the blood concentration does not increase.
  • erythromycin-resistant bacteria are known to have various mechanisms.
  • ribosome methylidase production type in clinical settings, there are ribosome methylidase production type and drug excretion type.
  • the activity of eumacrolide such as clarithromachine is greatly reduced against erythromycin resistant bacteria of drug excretion type.
  • the antimicrobial activity against drug excretion-resistant bacteria itself has been improved in ketolide, there is a large gap compared with the antimicrobial activity against susceptible bacteria, so it has already been affected by the gene of the excretion mechanism. I cannot deny the possibility of being.
  • the present invention relates to useful novel 16-membered macrolides derived mainly from leucomycin-based macrolides and pharmaceutically acceptable salts thereof.
  • the present inventors have conducted intensive studies to meet the above-mentioned expectations, and starting from a leucomycin-based macrolide as a starting material, after introducing a new functional group at the ratatone ring 12 and 13 positions, various new chemical modifications have been made. A 16-membered macrolide derivative was created.
  • certain derivatives of the compounds of the present invention can be used in erythromycin-resistant pneumococci, which have recently become a particular problem, in addition to drug efflux-resistant bacteria as well as methylase. It has been found that the antibacterial activity is improved even against production-type resistant bacteria. Furthermore, they have found that certain derivatives have strong antibacterial activity against Gram-negative bacteria, and have completed the present invention. There are no known reports of leukomycin-based 16-membered macrolides in which a new functional group was introduced at positions 12 and 13 for various modifications.
  • the first invention provides a compound represented by the following formula (I) or a pharmacologically acceptable salt thereof.
  • R represents a hydrogen atom, an alkylcarbonyl group, an alkyl group, or an arylalkyl group which may have a substituent
  • R 0 represents a hydrogen atom or an alkyl group which may have a substituent
  • R 1 and R 2 are the same or different and each represent a hydrogen atom or an alkylcarbonyl group
  • R 3 and R 4 may be the same or different and each independently represent a hydrogen atom, an alkyl group optionally having a substituent, an alkylcarbon group optionally having a substituent, or a substituent Aralkylcarbonyl group, aralkyl group optionally having substituent (s), arylalkyl group optionally having substituent (s), heterocyclic alkyl group optionally having substituent (s) Or a heterocyclic alkyl group which may have a substituent.
  • the present invention provides a compound represented by the following formula (II) or a pharmacologically acceptable salt thereof.
  • R represents a hydrogen atom, an alkylcarbonyl group which may have a substituent, an alkyl group which may have a substituent, or an arylamine group which may have a substituent,
  • R. Represents a hydrogen atom or an alkylcarbonyl group which may have a substituent
  • R 3 and R 3 are the same or different and each represent a hydrogen atom, an alkyl group which may have a substituent, or a substituent.
  • a heterocyclic alkyl group which may have a substituent or a heterocyclic alkenyl group which may have a substituent.
  • the present invention provides a compound represented by the following formula (III) or a pharmacologically acceptable salt thereof.
  • R represents a hydrogen atom, an alkylcarbonyl group which may have a substituent, an alkyl group which may have a substituent, or an arylanolekeninole group which may have a substituent;
  • R ° represents a hydrogen atom or an alkyl group which may have a substituent, and R 1 and R 2 may be the same or different and each represents a hydrogen atom or an alkylcarbonyl group; Indicates that
  • R 5 is a hydrogen atom, an alkyl group which may have a substituent, an alkyl group which may have a substituent V, an alkyl group which may have a substituent, an aralkylquinolecarponyl which may have a substituent Group, aralkyl group optionally having substituent (s), arylalkyl group optionally having substituent (s), heterocyclic alkyl group optionally having substituent (s), or even having substituent (s) Shows a good heterocyclic alkenyl group. ]
  • the fourth invention provides a compound represented by the following formula (IV) or a pharmacologically acceptable salt thereof.
  • R represents a hydrogen atom, an alkylcarbol group, an alkyl group, or a substituted or unsubstituted arylalkenyl group
  • R ° represents a hydrogen atom or an alkylcarbonyl group which may have a substituent
  • R 1 and R 2 are the same or different and each represent a hydrogen atom or an alkylcarbonyl group
  • R 5 is a hydrogen atom, an alkyl group which may have a substituent, an alkyl group which may have a substituent, an aralkylcarbonyl group which may have a substituent, An aralkyl group which may have a substituent, an arylalkyl group which may have a substituent, a heterocyclic alkyl group which may have a substituent, or a group which has a substituent. Represents a good heterocyclic alkenyl group. ]
  • the fifth invention provides a compound represented by the following formula (V) or a pharmacologically acceptable salt thereof.
  • R represents a hydrogen atom, a propioyl group, an alkylcarbonyl group, or a 3-phenyl-norpropene-2-yl group;
  • R Represents a hydrogen atom, an acetyl group, a chloroacetyl group, or an imidazolylacetyl group
  • R 2 , R 6 and R 8 are the same or different and each represent a hydrogen atom, an alkylcarbonyl group, or an alkyloxycarbol group;
  • R 7 represents a dimethoxymethyl group or a formyl group.
  • a compound represented by the above formula (1), formula (11), formula (111), formula (IV) or formula (V) or a pharmaceutically acceptable salt thereof is used as an active ingredient.
  • a medicament is provided. This medicament is useful for treating and preventing or preventing infectious diseases, and in a preferred form, is provided as a pharmaceutical composition comprising the above-mentioned active ingredient and one or more pharmaceutical additives.
  • a method for treating and preventing infectious diseases comprising the compound represented by the above formula (1), formula (11), formula (111), formula (IV), formula (V) or There is provided a method comprising the step of administering a therapeutically and / or prophylactically effective amount of a pharmaceutically acceptable salt thereof to a mammal, including a human.
  • BEST MODE FOR CARRYING OUT THE INVENTION a “lower alkyl group” or a “lower alkoxy group” as a group or a part of a group means a linear or branched alkyl group having 1 to 6, preferably 1 to 4 carbon atoms or an alkoxy group. Means a group.
  • alkyl or alkenyl as a group or a part of a group means an alkyl group having 1 to 10, preferably 1 to 8, and more preferably 1 to 6 carbon atoms in a straight or branched chain. . '
  • alkyl and alkenyl examples include methyl, ethyl, propyl, butyl, pentinole, hexinole, heptinole, octinole, noel, decanil, isopropinole, isopentinole, t-butyl, isopentyl, neopentinole, t-pentinole, t-pentynole, , Aryl, 1-propenyl, isopropyl, 1-butenyl, 2-butenyl and the like.
  • Alkyl or alkenyl as a group or part of a group may be substituted with a halogen atom or a hydroxyl group.
  • the aralkyl group and the arylalkenyl group may be substituted with 6 to: 14-membered (monocyclic to tricyclic, preferably monocyclic to bicyclic) alkyls having one or more aromatic rings. Or an alkenyl group.
  • Examples of an aralkyl group and an arylalkenyl group which may have a substituent include phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, and 3-methoxyphenyl. Toxifenil ', 4-methoxyphenyl, 2-hydroxyfenyl,
  • Examples of the substituent which the aralkyl group and the arylalkenyl group may have Represents an alkyl group of Cl-4, an alkoxy group of Cl-4, a nitrogen atom, an alkyl group of Cl-4, a nitro group, a hydroxyl group, a mono- or dialkylamino group, or an arylalkyloxy group.
  • a heterocyclic alkyl group or a heterocyclic alkenyl group refers to an optionally substituted 5- to 14-membered (monocyclic to tricyclic, preferably monocyclic to bicyclic) heterocyclic Cl Means up to 7 alkyl or alkenyl groups.
  • Specific examples of the heterocycle include pyridine, quinoline, isoquinoline, imidazole, imidazo [5,1-b] thiazol, pyrrolidine, piperidine, morpholine and the like.
  • Examples of the optionally substituted heterocyclic alkyl group and heterocyclic alkenyl group include 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolinyl, 3-quinolinyl, 4-quinolinyl, 5_ Quinolinyl, 6-quinolinyl, 7-quinolinyl, 8-quinolinyl, 2-isoquinolinyl, 3-isoquinolinyl, 4-isoquinolinyl, 5-isoquinolinyl, 6-isoquinolinyl, 7-isoquinolinyl, 8-isoquinolinyl, 2-imidazolyl, 3-imidazolyl, 4-imidazolyl, 2-imidazo [5,1-b] thiazolyl, 3-imidazo [5,1-b] thiazolyl, 6-imidazo [5,1-b] thiazolyl, 8 -Imidazo [5, 1-b] thiazolyl, 2-pyrrolidinyl
  • Examples of the substituent which the heterocyclic alkyl group and the heterocyclic alkenyl group may have include a hydroxyl group, a halogen atom, an alkyl group of Cl to 4, an aralkyl group, and a heterocyclic ring. Examples include a methyl group, an ethyl group, a fluorine atom, a chlorine atom, a hydroxyl group, a benzyl group, and a pyridyl group.
  • acyl group means a linear or branched Cl to C10 alkylcarbyl group, a C6 to C15 aralkylcarbonyl group, and the like.
  • Halogen atom means fluorine, chlorine, bromine, and iodine. Heteroatom means nitrogen, oxygen or sulfur.
  • R is preferably a hydrogen atom, an alkylcarbonyl group or a phenylalkenyl group, more preferably A propiohill group, an alkylcarbyl group, and a 3-phenylpropenyl-2-yl group.
  • R Q is preferably a hydrogen atom, an alkylcarbonyl group, or an alkyl optionally substituted with a heterocyclic ring.
  • R 1 is preferably a hydrogen atom.
  • R 2 is preferably an alkylcarbyl group.
  • R 3 and R 4 are preferably a hydrogen atom; an alkyl group which may be substituted with a hydroxyl group; an alkyl group; an aralkylcarbonyl group; Group, an alkoxy group of Cl-4, a halogen atom, a haloalkyl group of Cl-4, a nitro group, a hydroxyl group, a dialkylamino group, or an aralkyl which may be substituted with a group selected from an arylalkyloxy group An arylalkenyl group; a heterocyclic alkyl group which may be substituted with a heterocycle; or a heterocyclic alkenyl group, more preferably a hydrogen atom; an alkyl group; a phenylalkylcarbonyl group; , Methoxy, trifluoromethyl, hydroxyl, dimethylamino, fluorine, nitro, or benzyloxy Phenylalkyl groups;
  • R 5 is preferably a hydrogen atom; an alkyl group; an alkylcarbonyl group; an aralkylcarbonyl group; an alkyl group, an alkoxyl group, a hydroxyl group, a dialkylamino group, a nitro group, An aralkyl group which may be substituted with a group selected from a halogen atom, a halogenated alkyl group and an arylalkyloxy group; an arylalkenyl group; a heterocyclic alkyl group; and a heterocyclic alkenyl group.
  • R 6 is preferably an alkylcarbonyl group or an alkyloxycarbonyl group
  • R 8 is preferably an alkylcarbonyl group
  • R 7 is a dimethoxymethyl group or a formyl group. preferable.
  • R 1 and R 2 are the same or different and each is a hydrogen atom or an alkyl-propionyl group
  • R 3 and R 4 are the same or different and each have a hydrogen atom, an alkyl group, a phenylalkylcarbonyl group which may have a substituent, a phenylalkyl group which may have a substituent, and a substituent
  • a substituent optionally substituted phenylalkenyl group, optionally substituted naphthylalkyl group, optionally substituted diphenylalkyl group, optionally substituted biphenylylalkyl
  • a compound which is a quinolylalkyl group which may have a substituent is mentioned, and a more preferable compound group includes
  • R 1 and R 2 are the same or different and each is a hydrogen atom, an acetyl group, or a propionyl group;
  • R 4 is the same or different and each represents a hydrogen atom, a methyl group, a 2-phenylethylcarponyl group, a benzyl group, a 2-phenylenolethyl group, a 3-phenylpropyl group, a 3-phenylpropene-2-yl Group, 4-phenylbutyl group, 5-phenylpentyl group, 6-phenylenohexyl group, 7-phenylenoheptinol group, 3- (4-methylinophenyl) propynole group, 3- (4 -Methoxyphenyl) propyl group, 3- (4-hydroxyphenyl) propyl group, 3- (4-dimethylaminophenyl) propyl group, 3- (4-ditrophenyl) propyl group, 6 -(4--1
  • a preferred compound group is that R 3 and R 4 are the same or different and each is a hydrogen atom, an anoalkyl group, a phenylalkylcarbonyl group which may have a substituent, a substituent A phenylalkyl group which may have a substituent, a phenylalkenyl group which may have a substituent, a naphthylalkyl group which may have a substituent, and a group which may have a substituent.
  • Benzyloxyalkyl group diphenylalkyl group optionally having substituent (s), biphenylylalkyl group optionally having substituent (s), pyridylalkyl group optionally having substituent (s), substitution A benzylpiperidinoalkyl group which may have a group, or a quinolylalkyl group which may have a substituent.
  • R 4 are the same or different and each is hydrogen atom, methyl group, 2-phenylethyl Carbonyl group, benzyl group, 2-phenylethyl group, 3-phenylpropyl group, 3-phenylpropene-2-yl group, 4-phenylphenolinole group, 5-phenylpentyl group, 6-phenylhexyl group , 7-phenyl-heptyl, 3- (4-methylphenyl) propyl, 3- (4-methoxyphenyl) propyl, 3- (4-hydroxyphenyl) propyl, 3- (4-dimethylphenyl) Minophenyl) propyl, 3- (4-diphenyl) propyl, 6- (4-diphenyl) hexyl, 3- (4-fluorophenyl) propyl, 6- (4-fluoro Phenyl) hexyl group, 3-[(4-trifluoromethyl) phenyl] propyl group, 3- (1-naph
  • a preferred compound group is that R 1 and R 2 are the same or different and each is a hydrogen atom, an acetyl group or a propionyl group, and R 5 is a hydrogen atom, a methyl group, a 2 -Phenylethylcarponinole, benzyl, 2-phenyl-phenyl, 3-phenylpropyl, 3-phenylpropene-2-yl, 4-phenylbutyl, 5-phenylpentyl 6-phenylhexyl group, 7-phenylheptyl group, 3- (4-methylphenyl) propyl group, 3- (4-methoxyphenyl) propyl group, 3- (4-hydroxyphenyl) propyl Group, 3- (4-dimethylaminophenyl) propyl group, 3- (4-nitrophenyl) propyl group, 6- (4-nitrophenyl) hexyl group, 3- (4-phenolerophenyl) )
  • R 1 is a hydrogen atom
  • R 2 is a propioyl group
  • R 5 is a hydrogen atom, a benzyl group, a 2-phenylethylenol group, a 3-phenylpropyl group, a 4-phenylbutyl group, or a 3- (4-dimethylaminophenyl) propyl group Is raised.
  • R is an alkylcarbyl group or an arylalkyl group which may have a substituent
  • R is a hydrogen atom or an alkylcarbonyl group which may have a substituent;
  • R 1 and R 2 are the same or different and each is a hydrogen atom, an acetyl group, or a propionyl group;
  • R 5 is a hydrogen atom, a methyl group, a 2-phenylethylcarboxyl group, a benzyl group, a 2-phenylethyl group, a 3-phenylpropyl group, a 3-phenylpropene-2-yl group, the 4 -Phenylphenyl, 5-phenylpentyl, 6-phenylhexyl, 7-phenylheptyl, 3- (4-methylphenyl) propyl, 3- (4-methoxyphenyl) Propyl, 3- (4-hydroxyphenyl) 'propyl, 3- (4-dimethylaminophenyl) propyl, 3- (4-nitrophenyl) propyl, 6- (4-ditrophenyl) hexyl Sil, 3- (4-fluorophenyl) propyl, 6- (4-fluorophenyl) hexyl, 3-[(4-trifluoromethyl) phenyl] propyl, 3- (1-
  • R is a propioyl group, an alkylcarbonyl group, or a 3-phenylpropen-2-yl group
  • R ° is a hydrogen atom, an acetyl group, a chloroacetyl group, or an imidazolylacetyl group,
  • R 1 is a hydrogen atom
  • R 2 is a propionyl group
  • R 5 is a hydrogen atom, a benzyl group, a 2-phenylethyl group, a 3-phenylpropyl group, a 4-phenylbutyl group, or a 3- (4-dimethylaminophenyl) propyl group.
  • the compounds of the formulas (1), (11), (III), (IV) and (V) of the present invention are produced as follows through the six-step process shown in the process chart. These manufacturing methods will be described in detail for each of the first to sixth steps separately for each step.
  • the compound represented by the formula (VII) is synthesized by modifying the group. R below. The details are described for each structure.
  • R ° has a substituent in the formula (VI) of the compound as a starting material, only the operation of modifying the formyl group at the 18-position with an acetal-based protecting group may be performed.
  • Shinoreharai de (R ° 'COX ) Is preferably used in an amount of 1 to 5 equivalents, and as a base, in addition to pyridine, an organic base such as noretidine, collidine, triethylamine, diisopropylethylamine or the like is used in an amount of 1 to 20 equivalents.
  • nonprotonic solvents such as chloroform, benzene, toluene, and xylene may be used.
  • the reaction proceeds in a good yield in the range of 20 ° C to 60 ° C, and the reaction time is 1 hour to 24 hours.
  • the base to be used in addition to pyridine, 1 to 20 equivalents of an organic base such as norethidine, collidine, triethylamine, diisopropylethylamine or the like may be used.
  • the reaction solvent may be a non-protonic solvent such as chlorophonolem, benzene, toluene, and xylene, in addition to methylene chloride, and the reaction proceeds in a good yield in the range of 20 ° C to 60 ° C. 1 hour to 24 hours.
  • the subsequent modification of the formyl group at the 18-position with an acetal-based protecting group proceeds in a high yield by performing the modification in a mixed solvent of methyl orthoformate and methanol in the presence of an organic acid.
  • the acid used may be an organic acid such as paratoluenesulfonic acid or camphorsulfonic acid, and is preferably pyridinium paratoluenesulfonate (PPTS).
  • PPTS pyridinium paratoluenesulfonate
  • solvent a mixed solution of the same amount of methyl orthoformate and methanol, which also serves as a reagent, is used in an amount of 10 times (V / W) to 60 times (V / W).
  • the reaction proceeds at a high yield in the range of 20 ° C to 80 ° C, and the reaction time is 1 hour to 4 days.
  • the deprotection at the 9-position may be performed after modifying the formyl group at the 18-position with an acetal-type protecting group.
  • the reaction proceeds with ammonia water in a methanol solvent.
  • a mixed solution containing the same amount of aqueous ammonia as an alcoholic solvent such as methanol may be used in an amount of 5 times (VIW) to 50 times (VIW).
  • the reaction proceeds in a good yield in the range of 0 ° C to 60 ° C, and the reaction time is 1 hour to 12 hours.
  • the compound represented by the formula (VII) is oxidized at the same time after being subjected to epoxidation at 12 and 13 sites by reaction with 3-chloroperbenzoic acid (ni-CPBA) in chloroform.
  • the compound represented by the formula (VIII) is obtained by performing selective reduction of the dimethylamino group site with sodium dithionite.
  • the epoxidizing agent used in this reaction may be a peracid such as monoperoxyphthalic acid, tri- / leo-peracetic acid, or peracetic acid, or a peracid such as dioxysilane, preferably m-CPBA. It is recommended to use! To 10 equivalents.
  • a solvent used in this reaction a halogenated solvent such as chloroform and methylene chloride is preferable. The reaction proceeds in a temperature range of 0 ° C to 50 ° C with good yield, and the reaction time is 1 hour to 36 hours.
  • an aqueous solution in which a reducing agent such as sodium thiosulfate is dissolved may be added after adding a lower alcohol to the above reaction solvent, preferably after adding ethanol, and then dissolving sodium dithionite. It is preferable to use 1 to 4 equivalents of the prepared 1 to 10% aqueous solution. This reaction proceeds in a good yield in the range of -15 ° C to 20 ° C, and the reaction time is 5 minutes to 1 hour.
  • the compound represented by the formula (VI) (R is a hydrogen atom) is used as a starting material.
  • the epoxidation reaction is carried out in the same manner as above, and the compound is converted into a compound represented by the formula (VIII) (where R is a hydrogen atom) (see Example 144), and is appropriately selected depending on the structure of R.
  • the compound represented by the formula (VIII) (where R is a hydrogen atom)
  • RX alkyl halide
  • DMF dimethylformamide
  • the selective acetylation of the 2′-hydroxyl group proceeds quantitatively by reaction with acetic anhydride in acetonitrile.
  • the acetic anhydride used may be 1 to 5 equivalents, proceeds with good yield in the range of 20 ° C to 60 ° C, and the reaction time is 1 hour to 24 hours.
  • 1 to 10 equivalents of alkyl halide (RX) may be used, and the solvent may be an aprotic solvent used in a general alkyl reaction, but is preferably DMF.
  • the reaction proceeds with good yield in the range of 0 ° C to 50 ° C, and the reaction time is 1 hour to 24 hours.
  • the selective deacetylation reaction at the 2'-position carried out after the alkylation reaction may be carried out using a water-containing lower alcohol solvent, preferably a 1-10% water-containing methanol solvent.
  • the reaction proceeds with good yield in the range of 20 ° C to 60 ° C, and the reaction time is 12 hours to 48 hours.
  • the alkylich reaction to the 3-position hydroxyl group can be carried out according to the method described in International Publication (TO 0073317).
  • the third step that is, a method for producing the compound represented by the formula (V) will be described.
  • a compound of the formula (V) in which R 6 and R 8 are a hydrogen atom and R 7 is a dimethoxymethyl group is described.
  • the compound represented by the formula (VIII) is reacted with sodium azig in the presence of ammonium chloride (R 6 and R 8 are hydrogen atoms, and R 7 is a dimethoxymethyl group).
  • the compound represented by (V) was obtained.
  • the solvent used in this reaction is preferably a mixed solvent of a lower alcohol such as methanol or ethanol and water.
  • the additive used may be ammonium chloride, ammonium bromide, ammonium thiocyanate, etc., and 1 to 10 equivalents may be used.
  • Good. Sodium azide proceeds in good yield in the range of 20 ° C to 100 ° C using 1 to 15 equivalents, and the reaction time is 1 hour to 48 hours.
  • R 6 and R 8 obtained here are a hydrogen atom, and R 7 is a dimethoxymethyl group
  • the 2′-position of the compound A protected form obtained by selective acetylation of the hydroxyl group was also synthesized.
  • This protection step proceeds quantitatively by reaction with acetic anhydride in acetonitrile.
  • the acetic anhydride used may be 1 to 5 equivalents, proceeds with good yield in the range of 20 ° C to 60 ° C, and the reaction time is 1 hour to 24 hours.
  • R 7 is represented by a formyl group and R 6 is represented by an alkylcarbonyl group which may have a substituent
  • R 6 is a hydrogen atom
  • R 8 is an acetyl group
  • R 7 is a dimethoxymethyl group.
  • a base with respect to the compound of the formula (V)
  • R 6 'defined as, Ashiruno ⁇ ride (R 6' R 6 two C0R 6 C0X) or an acid anhydride ((R 6 'C0) 2 0)
  • Ashirui spoon agent after reaction to be described later It is provided by performing the sixth step.
  • the Ashiru agent used Oite in this reaction may R 6 'C0X or (R 6' C0) 2 0 in either 1 equivalent to 10 Using equivalents, other pyridine as base, lutidine, collidine, triethanolamine It is preferable to use 1 to 20 equivalents of an organic base such as tilamine and diisopropylethylamine, and the addition of 0.1 to 4 equivalents of 4-dimethylaminopyridine promotes the progress of the reaction.
  • the reaction solvent is preferably an aprotic solvent such as dichloroethane, chloroform, benzene, toluene, or xylene, in addition to methylene chloride.
  • the reaction proceeds with good yield in the range of 20 ° C to 70 ° C, and the reaction time is 1 hour to 4 days.
  • the fourth step of producing the compound represented by the formula (IX) will be described.
  • Triphenyl phosphine was used for a compound represented by the formula (V) or a compound obtained by acetylating the 2, hydroxyl group.
  • the solvent used in this reaction acetonitrile, THF, getyl ether and the like are preferable, and the triphenylphosphine used is preferably used in an amount of 1 to 2 equivalents.
  • the reaction proceeds with good yield in the range of 20 ° C to 100 ° C, and the reaction time is 1 hour to 48 hours.
  • R 3 and R 3 are an alkyl group, an optionally substituted aralkyl group, an optionally substituted arylaryl alkenyl group, Is represented by the formula (IX) when it is represented by any of a substituted or unsubstituted heterocyclic alkyl group and a substituted or unsubstituted heterocyclic alkyl group.
  • R 3 'CH0 and R 4 ' CH0 used in the present reductive alkyl 'reaction may be 1 to 5 equivalents
  • the solvent may be a lower alcohol such as methanol or ethanol, as well as acetonitrile or dimethylene chloride.
  • the acid catalyst to be added may be hydrochloric acid, trifluoroacetic acid, or the like in addition to acetic acid, and is preferably used in an amount of 1 to 15 equivalents.
  • the reducing agent may be sodium borohydride or the like, but preferably 1 to 5 equivalents of sodium cyanoborohydride or sodium triacetoxypolyhydride is used.
  • the reaction proceeds with good yield in the range of 20 ° C to 100 ° C, and the reaction time is 30 minutes to 24 hours.
  • R 3 is an aralkyl group which may have a substituent, an aryl alkenyl group which may have a substituent, or a heterocyclic group which may have a substituent.
  • the desired R 3 is added in the presence of a base.
  • R 4 'C0X or an acid anhydride ((R 4 ' C0) 20 )
  • an acyl reagent used in this reaction it is preferable to use 1 to 10 equivalents of either R 4 'C0X or (R 4 ' C0) 20 .
  • a base in addition to pyridine, lutidine, collidine, and triethylamine are used.
  • 1 equivalent of an organic base such as disopropylethylamine
  • the reaction solvent is preferably a non-protonic solvent such as dichloroethane, chlorophonolem, benzene, toluene, xylene and the like, in addition to methylene chloride.
  • the reaction proceeds with good yield in the range of 20 ° C to 70 ° C, and the reaction time is 1 hour to 4 days. '
  • the reductive alkylation reaction in this reaction may be carried out in the same manner as in the method described above.
  • an organic base such as triethylamine is used in an amount of 1 to 10 equivalents, and as a reagent to be used, it may be reacted with carbonyldiimidazole (PDI) in addition to triphosgene.
  • PDI carbonyldiimidazole
  • the reaction proceeds with good yield in the range of 0 ° C to 100 ° C, and the reaction time is 1 hour to 3 days.
  • the mixed solution of equal amounts of acetonitrile and water used as a solvent may be used in an amount of 10 times (g I ml) to 300 times (g I ml) .
  • difluoroacetic acid monofluoroacetic acid, trifluoroacetic acid, acetic acid, and the like may be used. ,:! ⁇ 30 equivalents should be used.
  • the reaction proceeds at a high yield in the range of 20 ° C to 50 ° C, and the reaction time is 12 hours to 4 days.
  • the reaction proceeds in good yield in the range of 20 ° C to 60 ° C, and the reaction time is 12 hours. ⁇ 48 hours.
  • the base it is preferable to use 1 to 5 equivalents of the acylating agent R 0 ′ C0X.As the base, it is preferable to use 1 to 20 equivalents of an organic base such as lutidine, collidine, triethylamine, diisopropylethylamine, etc. in addition to pyridine.
  • the reaction solvent is preferably an aprotic solvent such as dichloroethane, chloroform, benzene, toluene, xylene and the like, in addition to salted methylene.
  • the reaction proceeds with good yield in the range of 20 ° C to 70 ° C, and the reaction time is 1 hour to 24 hours.
  • Examples of the form of the pharmaceutically acceptable salt of the compound of the present invention include hydrohalides such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, and hydroiodic acid, sulfates, and nitrates. , Phosphates, perchlorates, carbonates, and other inorganic acid salts, acetic acid, trichloroacetic acid, trifluoroacetic acid, hydroxyacetic acid, lactic acid, citric acid, tartaric acid, oxalic acid, benzoic acid, mandelic acid, butyric acid, Examples thereof include carbonates such as maleic acid, propionic acid, formic acid and malic acid; amino acid salts such as alginic acid, aspartic acid and glutamate; and organic acid salts such as methanesulfonic acid and paratoluenesulfonic acid.
  • hydrohalides such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, and hydroiodic acid, sul
  • the compounds of the present invention may exist as hydrates or solvates.
  • the type of the solvent forming the solvate is not particularly limited, but examples thereof include alcohols such as methanol, ethanol, and isopropanol; and ethers such as tetrahydrofuran.
  • 12-position, 13-position - 0C0NR 5 - 5-membered ring containing has an asymmetric carbon
  • compounds of the present invention depending on the type of substituents
  • the compound of the present invention may have one or more asymmetric carbon atoms
  • the compound of the present invention may exist as a stereoisomer such as an optically active substance or a diastereoisomer. Pure stereoisomers, any mixtures of stereoisomers, racemates and the like are all included in the scope of the present invention.
  • the medicament of the present invention a substance selected from the group consisting of the above-mentioned compound of the present invention, a pharmacologically acceptable salt thereof, a hydrate thereof, and a solvate thereof is used as it is.
  • a pharmaceutical composition containing the above-mentioned substance as an active ingredient and one or more pharmaceutical additives is administered to humans and non-human animals by any of oral or parenteral (for example, intravenous, intramuscular, subcutaneous, intraperitoneal, rectal, transdermal) administration routes. be able to.
  • the medicament of the present invention can be prepared as a pharmaceutical composition in an appropriate form depending on the administration route. Specifically, injections, capsules, tablets, granules, powders, pills, fine granules, lozenges, etc., oral preparations, rectal preparations, oils and fats, mainly for intravenous or intramuscular administration It can be prepared as a pharmaceutical composition in any form such as a suppository, an aqueous suppository and the like. These medicines and compositions contain commonly used excipients, extenders, binders, wetting agents, disintegrants, surfactants, lubricants, dispersants, buffers, preservatives, solubilizing agents. It can be produced by a conventional method using pharmaceutical additives such as preservatives, flavoring agents, soothing agents, stabilizers and the like.
  • Excipients include, for example, lactose, fructose, pudose, corn starch, sonorebit, crystalline cellulose, and the like.
  • Disintegrants include, for example, starch, sodium alginate, gelatin, calcium carbonate, calcium citrate, dextrin, magnesium carbonate,
  • the binder include synthetic cellulose magnesium and the like, and binders such as methylcellulose or a salt thereof, ethylcellulose, arabia gum, gelatin, hydroxypropyl cellulose, polyvinylpyrrolidone, and the like.
  • Magnesium thearate, polyethylene glycol, hydrogenated vegetable oil, etc.Other additives include syrup, petrolatum, glycerin, ethanol, propylene glycol, cunic acid, sodium salt, sodium sulfite, sodium phosphate Beam, and the like, respectively.
  • the content of the active ingredient in the above-mentioned pharmaceutical composition is not particularly limited, and can usually be appropriately selected depending on the form of the pharmaceutical composition. Usually, 10 to 95% by weight, preferably 30 to 95% by weight of the whole composition. It is about 80% by weight.
  • the dose of the medicament of the present invention is not particularly limited, and is appropriately determined in consideration of the administration route and administration form, age of the patient, gender, difference in disease, degree of symptoms, and the like. About 1-3,000 mg, preferably about 100-2, OOOmg per active ingredient weight Yes, this dose can be administered once or several times a day.
  • R is represented by a propioyl group
  • R Q is represented by an acetyl group
  • R 1 is represented by a hydrogen atom
  • R Wherein 2 is a propionyl group
  • R is represented by a propionyl group
  • R ° is represented by an acetyl group
  • R 1 Wherein R is a hydrogen atom and R 2 is a propionyl group
  • the organic layer was washed successively with 100 ml of a saturated aqueous sodium hydrogen carbonate solution and 100 ml of a saturated saline solution, and the organic layer was dried over anhydrous sodium sulfate and then filtered.
  • the residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (chlorophonolem-methanol (70: 1)) to obtain 2.84 g of a compound.
  • R is represented by a propioyl group, and R ° is acetinole Wherein R 1 is a hydrogen atom and R 2 is a propionyl group
  • R is represented by a propioyl group
  • R is A compound represented by an acetyl group, R 1 by a hydrogen atom, and R 2 by a propioyl group
  • Example 5 9-0-Acetyl-12,13-dihydro-12-N, N-dimethylamino-13-hydroxymiddecamicin 18-dimethylacetal (Formula In (X), R is represented by a propionyl group, R 0 is represented by an acetyl group, R 1 is represented by a hydrogen atom, R 2 is represented by a propionyl group, R s is represented by a methyl group, R Method for producing compound represented by 4- methyl group)
  • Acetonitrile (1.4 ml) was added to and dissolved in 71 mg of the compound of Example 4, and 62 ml of 37% formaldehyde solution, 40 ml of acetic acid, and 14.3 mg of sodium cyanoborohydride were added, followed by stirring at room temperature for 1 hour.
  • 20 ml of saturated aqueous sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted with 30 ml of ethyl acetate.
  • the organic layer was washed successively with 15 ml of saturated aqueous sodium hydrogen carbonate and 15 ml of saturated saline, dried over anhydrous sodium sulfate, and filtered.
  • the residue obtained by concentrating the filtrate under reduced pressure was purified by preparative TLC (form-form-methanol-ammonia water (15: 1: 0.1)) to obtain 44 mg of the compound.
  • R is represented by a propionyl group
  • R Q is represented by an acetyl group
  • R 1 is represented by a hydrogen atom
  • R 2 is represented by a propionyl group
  • R 4 is represented by a benzyl group.
  • Example 4 To 100 mg of the compound of Example 4 was added 2 ml of methanol to dissolve, 13 ml of 4-pyridine aldehyde and 25 ml of acetic acid were added, and the mixture was stirred at room temperature for 2.5 hours. '13 .5 mg of sodium persulfonyl hydride was added to the reaction mixture, and the mixture was further stirred for 2 hours. To the reaction mixture was added 10 ml of saturated sodium bicarbonate solution, and the mixture was extracted twice with 20 ml of ethyl acetate.
  • the organic layer was washed sequentially with 20 ml of saturated aqueous sodium hydrogen carbonate and 20 ml of saturated saline, and the organic layer was dried over anhydrous sodium sulfate and filtered.
  • the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol / ammonia water (50: 1: 0.1)) to give 9-0-acetinole-12,13-dihydro-13-hydroxy 95 rag of 12- (pyridine-4-ylmethylamino) midecamycin 18-dimethylacetal was obtained.
  • R is expressed in flop port Pioniru group, R. is represented by Asechiru group, R 1 is represented by a hydrogen atom, R 2 is represented by propionic two Honoré group, R 3 is represented by a methyl group, R 4 is 2 -Compound represented by -phenylethyl group)
  • R is represented by propionyl group
  • R ° is represented by Asechiru group
  • R 1 is represented by a hydrogen atom
  • R 2 is represented by a propionyl group
  • R 3 is represented by a methyl group
  • R 4 is 3-Fuweerupu opening pill
  • R is represented by a propionyl group
  • R. is represented by an acetyl group
  • R 1 is represented by a hydrogen atom
  • R 2 is represented by a propioel group
  • R 3 is a methyl group.
  • R 4 is a 3- (4-methylphenyl) propyl group
  • Example 11 3-H), 5.39 (br s, 9—H), 5.71 (dd, 11-H), 5.78 (dd, 10-H), 7.05 (m, C 6 H 4 CH 3 ).
  • R is represented by a propionyl group
  • R D is represented by an acetyl group
  • R 1 is represented by a hydrogen atom
  • R 2 is represented by a propionyl group
  • R 3 is represented by a methyl group
  • R 4 is represented by Is a compound represented by 3- (4-methoxyphenyl) propyl group
  • R is represented by a propionyl group
  • R. is represented by an acetyl group
  • R 1 is represented by a hydrogen atom
  • R 2 is represented by a propionyl group
  • R 3 is represented by a methyl group
  • R 4 is a compound represented by a 3- (4-acetoxyphenyl) propyl group
  • R is represented by a propionyl group
  • R ° is represented by an acetyl group
  • R 1 is represented by a hydrogen atom
  • R 3 is represented by a methyl group, and is represented by a 3- (4-hydroxyphenyl) propyl group
  • Example 12 was added sodium hydrogen carbonate 1.7 m g, and stirred at room temperature for 5.5 hours. 15 ml of water was added to the reaction solution, which was extracted with 20 ml of chloroform. The organic layer was washed with 15 ml of a saturated saline solution, and the organic layer was dried over anhydrous sodium sulfate and then filtered. The residue obtained by concentrating the filtrate under reduced pressure was purified by preparative TLC (form-form-methanol-ammonia water (15: 1: 0.1)) to obtain 18.5 mg of the compound.
  • R is a propionyl group
  • Is represented by an acetyl group
  • R 1 is represented by a hydrogen atom
  • R 2 is represented by a propioyl group
  • R 3 is represented by a methyl group
  • R 4 is 3-(4-dimethylaminophenyl) propyl
  • R is represented by a propionyl group
  • R. is represented by an acetyl group
  • R 2 is represented by a propionyl group
  • R 3 is represented by a methyl group.
  • R 4 is a 3- (4-trifluoromethylphenyl) propyl group
  • 110 mg of the compound of Example 4 and 64 mg of the title compound were obtained from 3- (4-trifluoromethylphenyl) propionaldehyde (synthesized according to the method of Reference Example 1).
  • R is represented by a propionyl group
  • R Q is represented by an acetyl group
  • R 1 is represented by a hydrogen atom
  • R 2 is represented by a propionyl group
  • R 3 is represented by a methyl group
  • R 4 is a compound represented by a 3- (4-fluorophenyl) propyl group
  • R is represented by a propionyl group
  • R fl is represented by an acetyl group
  • R 1 is represented by a hydrogen atom
  • R 2 is represented by a propionyl group
  • R 3 is represented by a methyl group
  • R 4 is a compound represented by 3-(4-ditrophenyl) propyl group
  • R is represented by a propionyl group
  • R Q is represented by an acetyl group
  • R 1 is represented by a hydrogen atom
  • R 2 is represented by a pionyl group
  • R 3 is represented by a methyl group.
  • R 4 is a 3- (pyridine-4-yl) propyl group
  • Example 7 In the same manner as in Example 7, 130 mg of the compound of Example 4 and 3- (pyridine-4-yl) propionaldehyde (synthesized according to the method of Reference Example 5) were obtained. (36%) (97%) was obtained.
  • R is represented by a propionyl group
  • R Q is represented by an acetyl group
  • R 1 is represented by a hydrogen atom
  • R 2 is represented by a propionyl group
  • R s is represented by a methyl group.
  • R 4 is a 3-phenylpropene-2-yl group
  • R is a propionyl group.
  • R D is represented by an acetyl group
  • R 1 is represented by a hydrogen atom
  • R 2 is represented by a propionyl group
  • R s is represented by a methyl group
  • R 4 is a 3-phenylpropioyl ′ group
  • R is represented by a propioyl group
  • R ° is represented by an acetyl group
  • R 1 is represented by a hydrogen atom
  • R 2 is represented by a propionyl group
  • R 3 is a methyl group.
  • R 4 is a 3- (quinoline-4-yl) propyl group;
  • Example 7 In the same manner as in Example 7, 130 mg of the compound of Example 4 and 61 mg of the title compound were obtained from the aldehyde of Reference Example 5.
  • R is represented by a propionyl group
  • R Q is represented by an acetyl group
  • R 1 is represented by a hydrogen atom
  • R 2 is represented by a propionyl group
  • R 3 is represented by a methyl group.
  • R is represented by a propio- ⁇ group
  • R. is represented by an acetyl group
  • R 1 is represented by a hydrogen atom
  • R 2 is represented by a propionyl group
  • R 4 is a 3- (quinoline-7-yl) propyl group
  • R is represented by a propionyl group
  • R ° is represented by an acetyl group
  • R 1 is represented by a hydrogen atom
  • R 2 is represented by a propionyl group
  • R 3 is represented by a methyl group
  • R is represented by a propionyl group
  • R Q is represented by an acetyl group
  • R 1 is represented by a hydrogen atom
  • R 2 is propionol
  • R 3 is a methyl group
  • R 4 is 3- (imidazo [5,1-b] thiazol-2-yl) propene-2-y
  • Example 7 60 mg of the compound of Example 4 and 9-0-acetyl-12,13-dihydro were synthesized from 6- (4-fluorophenyl) hexanal (synthesized according to the method of Reference Example 3). 32 mg of 12- (N- (6- (4-fluorophenyl) hexyl) amino) -13-hydroxymidamicin 18-dimethyl acetal was obtained. Further, 72 mg of the title compound was obtained from 92 mg of this compound.
  • R is represented by a propionyl group
  • R ° is represented by an acetyl group
  • R 1 is represented by a hydrogen atom
  • R 2 is represented by a propionyl group
  • R s is represented by a methyl group.
  • R 4 is a 6- (4-nitropheninole) hexyl group
  • R is represented by a propionyl group
  • R ° is represented by an acetyl group
  • R 1 is represented by a hydrogen atom
  • R 2 is represented by a propionyl group
  • R 3 is 3-phenyl.
  • R is represented by a propionyl group
  • R. is represented by an acetyl group
  • R 2 is represented by a propionyl group
  • R 3 is represented by a methyl group, Represented by the formula 3-(2 benzyloxypropyl) propyl group)
  • R is represented by a propioninole group
  • R ° is represented by an acetyl group
  • R 1 is represented by a hydrogen atom
  • R 2 is represented by a propionyl group
  • R 3 is a methyl group.
  • R 4 is a 1-benzylpiperidine-4-ylmethyl group
  • R is a propioyl group.
  • R. is represented by an acetyl group
  • R 1 is represented by a hydrogen atom
  • R 2 is represented by a propionyl group
  • R 5 is represented by a hydrogen atom
  • Example 41 In the same manner as in Example 39, 68 mg of the title compound was obtained from 82 mg of the compound of Example 41.
  • R is represented by a propionyl group
  • R ° is represented by an acetyl group
  • R 1 is represented by a hydrogen atom
  • R 2 is represented by a propionyl group
  • R Wherein 5 is a 4- (4-dimethylaminophenol) propyl group
  • Example 4 In the same manner as in Example, 220 mg of the compound of Example 4 and 3- (4-dimethylaminophenyl) propionanolaldehyde (synthesized according to the method of Reference Example 4) were used to give 9-0-acetyl-12, 13-Dihydro-1 13-hydroxy-12- (3- (4-N ', N, -dimethylaminophenyl) propylamino) midecamycin 115. mg of 18-dimethylacetal was obtained. Further, 45 mg of the title compound was obtained from 50 mg of this compound. .
  • 9-0-acetyl-12,13-dihydro-13-hydrochloride was prepared from 250 mg of the compound of Example 4 and 4-phenylbutanal (synthesized according to the method of Reference Example 2). 167 mg of xy-12- (N- (4-phenylbutyl) amino) midecamycin 18-dimethylacetate / re was obtained. Further, 71 mg of the title compound was obtained from 77 mg of this compound.
  • R is a propioyl group and R Q is acetyl
  • R 1 is represented by an acetyl group and R 2 is represented by a propioninole group
  • R is a propionyl group; Is represented by an acetyl group, R 1 is represented by an acetyl group, and R 2 is represented by a propionyl group)
  • Example 448 mg of the compound of Example 48 was used to convert 9,3 ⁇ -di-0-acetyl-12-azido-12,13-dihydro-13 hydroxymidecamycin 18-dimethylacetal (
  • R is represented by a propioel group
  • R ° is represented by an acetyl group
  • R 1 is represented by an acetyl group
  • R 2 is a compound represented by a propionyl group
  • R is represented by a propionol group
  • R. is represented by an acetyl group
  • R 1 is represented by an acetyl group
  • R 2 is represented by a propionol group
  • R 3 is represented by a methyl group
  • R 4 is a compound represented by a 3-phenylpropyl group
  • R is represented by a propioninole group
  • R ° is represented by an acetyl group
  • R 1 is represented by a hydrogen atom
  • R 6 is represented by a hydrogen atom
  • R 7 is represented by a formyl group
  • R 8 is represented by a hydrogen atom
  • R is represented by a propionyl group
  • fl is represented by an acetyl group
  • R 1 is represented by a hydrogen atom
  • R 2 is represented by a propioyl group
  • R 6 is represented by an acetyl group
  • R 7 is represented by a dimethoxymethyl group
  • R 8 is represented by a dimethoxymethyl group.
  • R is a propioyl group
  • R Q is an acetyl group
  • R 2 is represented by a propionyl group
  • R 6 is represented by an acetinole group
  • R 7 is represented by a formyl group
  • R 8 is represented by a hydrogen atom.
  • R is a propionyl group Represented, R ° is represented by Asechiru group, R 1 is represented by a hydrogen atom, R 2 is represented by a propionyl group, R 6 is represented by a methoxycarbonyl group, R 7 is represented by dimethoxymethyl group Wherein R 8 is an acetyl group)
  • Example 37 To 50 mg of the compound of Example 37 was added and dissolved 1 ml of tetrahydrofuran, 40.4 mg of carbodiimidazole was added, and the mixture was stirred at room temperature for 4 hours. 24 mg of carbonyldiimidazole was added to the reaction solution, and the mixture was further stirred at room temperature for 1 hour, diluted with 25 ml of ethyl acetate, and added with 0.1 hydrochloric acid 10] 111. After separating the organic layer, the mixture was washed twice with 10 ml of 0.1N hydrochloric acid, 10 ml of water, 15 ml of saturated aqueous sodium hydrogen carbonate and 15 ml of saturated saline solution in that order.
  • R is a propionyl group and R 0 is an acetyl group
  • R 1 is represented by a hydrogen atom
  • R 2 is represented by a propionyl group
  • R 6 is represented by a methoxycarbonyl group
  • R 7 is represented by a dimethoxymethyl group
  • R 8 is represented by a hydrogen atom.
  • Example 40 In the same manner as in Example 40, 45 mg of the title compound was obtained from 67 mg of the compound of Example 55.
  • R is represented by a propionyl group
  • R. is represented by an acetyl group
  • R 1 is represented by a hydrogen atom
  • R 2 is represented by a propionyl group
  • R 4 is a compound represented by a methyl group
  • Example 51 In a similar manner to Example 51, 11 mg of the title compound was obtained from 33 mg of the compound of Example 5.
  • R is a propionyl group
  • R is an acetyl group
  • R 1 is represented by a hydrogen atom
  • R 2 is represented by a propioyl group
  • R 3 is represented by a methyl group
  • R 4 is represented by a benzyl group.
  • R is propiole
  • R a is represented by a acetyl group
  • R 1 is represented by a hydrogen atom
  • R 2 is represented by a propiol group
  • R 3 is represented by a methyl group
  • R is a propionyl group.
  • R 0 is represented by an acetyl group
  • R 1 is represented by a hydrogen atom
  • R 2 is represented by a pionyl group
  • R 3 is represented by a methyl group
  • R 4 is represented by a 2-phenylethyl group.
  • R is a propionyl group.
  • R 1 is represented by a hydrogen atom
  • R 2 is represented by a propionyl group
  • R 3 is represented by a methyl group
  • R 4 is represented by a 3-phenylphenol group.
  • R is propiomycin
  • R is represented by an acetyl group
  • R 1 is represented by a hydrogen atom
  • R 2 is represented by a propionyl group
  • R 3 is represented by a methyl group
  • R 4 is represented by 3- ( 4- (Methylphenyl) compound represented by propyl group)
  • R is propio expressed in two Le group
  • R Q is represented by Asechiru group
  • R 1 is represented by a hydrogen atom
  • R 2 is represented by propionic alkenyl group
  • R 3 is represented by a methyl group
  • R is represented by a propionyl group
  • R 0 is represented by an acetyl group
  • R 1 is represented by a hydrogen atom
  • R 2 is represented by a propionyl group
  • R 3 is a methyl group.
  • R 4 is a 3- (4- ⁇ , ⁇ -dimethylaminophenyl) propyl group)
  • R is represented by a propioyl group
  • R Q is represented by an acetyl group
  • R 1 is represented by a hydrogen atom
  • R 2 is represented by a propioyl group
  • R 3 is represented by a methyl group
  • R ′ 1 is represented by a 3- (4-trifluoromethylphenyl) propyl group
  • R is It is represented by a propionyl group
  • R ° is represented by an acetyl group
  • R 1 is represented by a hydrogen atom
  • R 2 is represented by a propionyl group
  • R 3 is represented by a methyl group
  • R 4 is represented by 3-( Method for producing 4-fluoropropyl) compound represented by propyl group
  • R 9-0-Acetyl-12,13-dihydro-13-Hydroxy-12- (N-methyl-N- (3- (4-ditrophenyl) propyl) amino) midemycin
  • R is expressed in two Le group, R. is represented by Asechiru group, R 1 is represented by a hydrogen atom, R 2 is represented by propionic alkenyl group, R 3 is represented by a methyl group, R 4 is 3- ( 4-Ditrophene-yl) a compound represented by the formula:
  • R is expressed in propionic two / Les radical
  • R ° is represented by Asechinore group
  • R 1 is represented by a hydrogen atom
  • R 2 is a propionate - expressed in Le group
  • R 3 is represented by a methyl group, but 3 (Compound represented by pyridine-4-yl) propyl group)
  • R is represented by a propioyl group
  • R ° is represented by an acetyl group
  • R 1 is represented by a hydrogen atom
  • R 2 is represented by a propionyl group
  • R 3 is represented by a methyl group
  • R is represented by a propionyl group; 0 is represented by an acetyl group, R 1 is represented by a hydrogen atom, R 2 is represented by a propionyl group, Wherein R 3 is represented by a methyl group and is represented by a 2-phenylethylcarboxyl group)
  • Example 51 In a similar manner to Example 51, 37 mg of the title compound was obtained from 60 mg of the compound of Example 20.
  • R is Is represented by a propionyl group
  • R Q is represented by an acetyl group
  • R 1 is represented by a hydrogen atom
  • R 2 is represented by a propioninole group
  • R 3 is represented by a methyl group
  • Example 51 In the same manner as in Example 51, 25 mg of the title compound was obtained from 93 mg of the compound of Example 22.
  • R is Represented by a propionyl group
  • R ° is represented by an acetyl group
  • R 1 is represented by a hydrogen atom
  • R 2 is represented by a propioel group
  • R 3 is represented by a methyl group
  • R 4 is represented by 3- (4- Method for producing biphenylyl) a compound represented by a pinole group
  • R is represented by a propionyl group
  • R ° is represented by an acetyl group
  • R 1 is a hydrogen atom
  • R 2 is represented by a propionyl group
  • R s is represented by a methyl group
  • R 4 is represented by 3-'(imidazo [5,1-b] thiazol-2-yl) propene-2- Of the compound represented by the aryl group)
  • R is a propioninole group
  • R D is represented by an acetyl group
  • R 1 is represented by a hydrogen atom
  • R 2 is represented by a propionyl group
  • R 3 is represented by a methyl group
  • R 4 is a 5-phenylpentyl group.
  • R is a propioyl group.
  • R is represented by an acetyl group
  • R 1 is represented by a hydrogen atom
  • R 2 is represented by a propionyl group
  • R 3 is represented by a methyl group
  • R 4 is represented by a 6-phenylhexyl group.
  • R is represented by a propionyl group
  • R ° is represented by an acetyl group
  • R 1 is represented by a hydrogen atom
  • R 2 is represented by a propionyl group
  • R 4 is represented by 6-( 4-Nitrophenyl) a compound represented by a hexyl group
  • R is represented by a propyl group
  • R Q is represented by an acetyl group
  • R 1 is represented by a hydrogen atom
  • R 2 is represented by a propionyl 'group
  • R 4 is a 6-phenylhexyl group
  • R is represented by a propionyl group
  • R Q is represented by an acetyl group
  • R 1 is represented by a hydrogen atom
  • R 2 is represented by a propionyl group
  • R 3 is represented by a methyl group
  • R 4 is represented by 7- 21 mg of the title compound was obtained from 41 mg of the compound of Example 34 in the same manner as in Example 51 of the compound represented by the following formula:
  • R is represented by a propionyl group
  • R Q is represented by an acetyl group
  • R 1 is represented by a hydrogen atom
  • R 2 is represented by a propionyl group
  • R 3 is represented by a methyl group
  • R 4 is represented by 3 -(2-benzyloxyphenyl) propyl group

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Abstract

L'invention concerne des nouveaux dérivés de macrolides à 16 éléments représentés par la formule générale (I) et efficaces contre les bactéries Gram-positives résistantes à l'érythromycine et analogues, ou des sels pharmaceutiquement acceptables desdits composés. Dans la formule (I), R est hydrogène, alkylcarbonyle, alkyle ou arylalcényle, R0 est hydrogène ou alkylcarbonyle, R1 et R2 sont chacun indépendamment hydrogène ou alkyle carbonyle, et R3 et R4 sont chacun indépendamment hydrogène, alkyle, alkylcarbonyle, aralkylcarbonyle, aralkyle, arylalcényle, hérétocycle-alkyle ou hétérocycle-alcényle.
PCT/JP2002/001241 2001-02-14 2002-02-14 Nouveaux derives de macrolides a 16 elements modifies en 12 et 13 WO2002064607A1 (fr)

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Cited By (7)

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Publication number Priority date Publication date Assignee Title
WO2006073172A1 (fr) * 2005-01-07 2006-07-13 Meiji Seika Kaisha, Ltd. Derive de macrolide cyclique a 16 membres contenant un groupe 12-oxy-13-amino- et procede pour le produire
JP2007502817A (ja) * 2003-08-20 2007-02-15 イーライ リリー アンド カンパニー グルカゴン様ペプチド（ｇｌｐ）−１化合物またはメラノコルチン４受容体（ｍｃ４）アゴニストペプチドの経口デリバリーのための化合物、方法および製剤
US7365174B2 (en) 2003-08-22 2008-04-29 Meiji Seika Kaisha, Ltd. Azalide and azalactam derivatives and method for producing the same
WO2012105563A1 (fr) * 2011-01-31 2012-08-09 Ｍｅｉｊｉ Ｓｅｉｋａファルマ株式会社 Médicament vétérinaire contenant un dérivé macrolide
WO2012105562A1 (fr) 2011-01-31 2012-08-09 Ｍｅｉｊｉ Ｓｅｉｋａファルマ株式会社 Nouveau dérivé macrolide
WO2012118048A1 (fr) 2011-02-28 2012-09-07 Ｍｅｉｊｉ Ｓｅｉｋａファルマ株式会社 Nouvel intermédiaire macrolide et nouveau procédé de production
US8552039B2 (en) 2003-08-20 2013-10-08 Emisphere Technologies, Inc. Compounds, methods and formulations for the oral delivery of a glucagon-like peptide (GLP-1) compound or a melanocortin-4 receptor (MC4) agonist peptide

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JPS5448779A (en) * 1977-02-07 1979-04-17 Toyo Jozo Co Ltd Derivative of hydrogenated macrolide antibiotic substance

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JPS5448779A (en) * 1977-02-07 1979-04-17 Toyo Jozo Co Ltd Derivative of hydrogenated macrolide antibiotic substance

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Title
MASAYUKI MUROI ET AL.: "Maridomycin, a new macrolide antibiotic. XI. The structures of maridomycin components", CHEM. PHARM. BULL., vol. 24, no. 3, 1976, pages 463 - 478, XP002951538 *

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8552039B2 (en) 2003-08-20 2013-10-08 Emisphere Technologies, Inc. Compounds, methods and formulations for the oral delivery of a glucagon-like peptide (GLP-1) compound or a melanocortin-4 receptor (MC4) agonist peptide
US8546581B2 (en) 2003-08-20 2013-10-01 Emisphere Technologies, Inc. Compounds, methods and formulations for the oral delivery of a glucagon-like peptide (Glp)-1 compound or a melanocortin-4 receptor (Mc4) agonist peptide
US8765796B2 (en) 2003-08-20 2014-07-01 Emisphere Technologies, Inc. Compounds, methods and formulations for the oral delivery of a glucagon-like peptide (GLP-1) compound or a melanocortin-4 receptor (MC4) agonist peptide
US7947841B2 (en) 2003-08-20 2011-05-24 Emisphere Technologies, Inc. Compounds, methods and formulations for the oral delivery of a glucagon-like peptide (GLP)-1 compound or a melanocortin-4 receptor (MC4) agonist peptide
JP4754487B2 (ja) * 2003-08-20 2011-08-24 エミスフィアー テクノロジーズ インコーポレイテッド グルカゴン様ペプチド（ｇｌｐ）−１化合物またはメラノコルチン４受容体（ｍｃ４）アゴニストペプチドの経口デリバリーのための化合物、方法および製剤
JP2007502817A (ja) * 2003-08-20 2007-02-15 イーライ リリー アンド カンパニー グルカゴン様ペプチド（ｇｌｐ）−１化合物またはメラノコルチン４受容体（ｍｃ４）アゴニストペプチドの経口デリバリーのための化合物、方法および製剤
US7365174B2 (en) 2003-08-22 2008-04-29 Meiji Seika Kaisha, Ltd. Azalide and azalactam derivatives and method for producing the same
WO2006073172A1 (fr) * 2005-01-07 2006-07-13 Meiji Seika Kaisha, Ltd. Derive de macrolide cyclique a 16 membres contenant un groupe 12-oxy-13-amino- et procede pour le produire
WO2012105563A1 (fr) * 2011-01-31 2012-08-09 Ｍｅｉｊｉ Ｓｅｉｋａファルマ株式会社 Médicament vétérinaire contenant un dérivé macrolide
WO2012105562A1 (fr) 2011-01-31 2012-08-09 Ｍｅｉｊｉ Ｓｅｉｋａファルマ株式会社 Nouveau dérivé macrolide
CN103380141A (zh) * 2011-01-31 2013-10-30 明治制果药业株式会社 新大环内酯衍生物
WO2012118048A1 (fr) 2011-02-28 2012-09-07 Ｍｅｉｊｉ Ｓｅｉｋａファルマ株式会社 Nouvel intermédiaire macrolide et nouveau procédé de production
CN103391944A (zh) * 2011-02-28 2013-11-13 明治制果药业株式会社 一种新大环内酯中间体和新的制备方法
US20140039171A1 (en) * 2011-02-28 2014-02-06 Meiji Seika Pharma Co., Ltd. Novel macrolide intermediate and novel production process

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