WO1999053911A1 - Agents antifongiques - Google Patents

Agents antifongiques Download PDF

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Publication number
WO1999053911A1
WO1999053911A1 PCT/JP1999/001998 JP9901998W WO9953911A1 WO 1999053911 A1 WO1999053911 A1 WO 1999053911A1 JP 9901998 W JP9901998 W JP 9901998W WO 9953911 A1 WO9953911 A1 WO 9953911A1
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Prior art keywords
group
ethyl acetate
added
silica gel
solution
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PCT/JP1999/001998
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English (en)
Japanese (ja)
Inventor
Shigeo Nozoe
Jun-Ichi Masuda
Akira Takahashi
Muneaki Kanou
Ken-Ichi Tanaka
Toshiyuki Wakayama
Nobuaki Koike
Takayoshi Uchida
Toshiyuki Nagata
Toshiaki Segawa
Sanae Tanaka
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Toa Gosei Co., Ltd.
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Publication of WO1999053911A1 publication Critical patent/WO1999053911A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/075—Ethers or acetals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/223—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of alpha-aminoacids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/225—Polycarboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/336—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having three-membered rings, e.g. oxirane, fumagillin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/417—Imidazole-alkylamines, e.g. histamine, phentolamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4453—Non condensed piperidines, e.g. piperocaine only substituted in position 1, e.g. propipocaine, diperodon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/695—Silicon compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • 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 an antifungal agent containing a compound having a hydronaphthene ring structure as an active ingredient, and belongs to a pharmaceutical production technique.
  • antimicrobial drugs mainly antibiotics
  • antifungal drugs are not always in a satisfactory state, judging from their type and effectiveness.
  • Deep fungal infections to humans include candidiasis, aspergillosis, cryptococcosis, and mucormycosis, and include other imported mycosis, including actinomycosis, nocardiosis, chromoblast mycolysis, and hiss Toplasosis, coccidioidomycosis, geotrichum disease, penicillium disease, etc. are known. There are also superficial mycosis such as athlete's foot and bugs.
  • chemotherapeutic agents such as amphotericin B, fluconazole, itraconazole, miconazole, and 5-fluorocytosine are used as therapeutic agents for these fungal infections.
  • Cryptopollic acid derivatives are a group of compounds represented by the following structural formula and the like.
  • R 11, R 12, and R 13 are the same or different and may be a hydrogen atom, an alkyl group, particularly a lower alkyl group, and more specifically, a methyl group R 14 is a methyl group, a hydroxymethyl group or an acetyloxymethyl group, and R 15 is an alkylidene group such as a methylidene.
  • examples of the cryptoporic acid derivative also include a dimer including a ring of the compound represented by Structural Formula 2 or the like. Disclosure of the invention
  • the present inventors have paid attention to the fact that cryptoporic acid derivatives are excellent as antifungal agents, studied the mechanism of action of the cryptoporic acid derivatives, and further studied the function and structure. of Accordingly, the present inventors have conducted intensive studies to find compounds that have a strong antibacterial activity against the above-mentioned fungi that cause opportunistic infections, that is, can be effectively used as antifungal agents. That is, the present invention seeks to provide a novel antifungal agent.
  • the hydronaphthylene ring structure has a great effect on the antifungal activity, that is, the hydronaphthalene Albicanol having a ring structure and sclareol, sclareolide, manol, labdanolic acid, etc. having a similar structure, and those obtained by adding various substituents thereto, as well as derivatives thereof and two rings obtained from copearl resin
  • the inventors have found that all of the sex diterpenes and their derivatives have antifungal activity, and have completed the present invention.
  • the present invention may have an unsaturated bond represented by the following structural formula: ⁇ a hydronaphthene ring structure, and the structure derived from isosquenic acid may be formed through an ether bond.
  • the present invention relates to an antifungal agent comprising, as an active ingredient, a compound that is not bonded to the methyloxy group at the 9-position of a ren ring.
  • R 1, R 2, and R 3 may be the same or different from each other, and may be an alkyl group which may have a substituent, and R 4 may have a carbon atom which may have a substituent.
  • the hydroxy group and the hydroxy group A carboxyl group at the head of a straight-chain hydrocarbon having 0 to 3 carbon atoms, which may have an organic group or a substituent group having an ether, ester or urethane bond derived from a droxy group, and an ester derived from the carboxyl group; Alternatively, it is an organic group having an amide bond.
  • the carboxyl group at the head of a straight-chain hydrocarbon having 0 carbon atoms means that the carboxyl group is directly added to the hydronaphthalene ring.
  • the center of the structure is a hydronaphthylene ring, and more specifically, as shown in the structural formula, R 4 and R 3 are substituted at the 4-position, and R 1 is substituted at the 10-position.
  • Alkyl groups which may have a group, especially hydronaphthylene to which a methyl group is added, or R 1 and R 2 are alkyl groups, especially a methyl group, and R 3 is a hydroxyalkyl group or a substituent or a protecting group.
  • a carboxyl group having a carboxyl group or a carboxyl group having a substituent or a protecting group, and the hydronaphthylene ring may partially have an unsaturated bond.
  • R 4 is a straight-chain hydrocarbon having 1 to 4 carbon atoms, which may have a substituent, and a hydroxy group and an organic group having an ether, ester or urethane bond originating from the hydroxy group. Or an organic group having a carboxyl group and an ester or amide bond derived from the carboxyl group at the tip of a linear hydrocarbon having 0 to 3 carbon atoms which may have a substituent.
  • the present invention is also characterized in that an organic group defined by R 4 is further added to the 8-position to the hydronaphthylene ring, which can be actively synthesized from a commercially available drug. Is preferred.
  • Examples of the substituent of R 4 include the following, which have an antifungal effect and side effects. It can be appropriately selected in consideration of the specific examples. Specific examples thereof include a hydroxy group and a group having a substituent or a protecting group attached thereto, a carbonyl group and a group having the group protected by a protecting group, for example, ethylene glycol or the like. Protected, straight-chain or branched alkyl, alkenyl or cycloalkyl groups having up to 10 and preferably up to 8 carbon atoms, such as alkylidene groups having up to 6 and preferably up to 4 carbon atoms, preferably methylidene, etc.
  • An alkyl or alkenyl group having one or more hydroxy groups such as a hydroxy-3-methyl-4,5-epoxypentyl group and having up to 12 and preferably up to 10 carbon atoms, preferably a hydroxymethyl group , 2-hydroxyl, 4-hydroxyl, 3-hydroxy-3-methylpentyl, 3-hydroxy-3-methyl-4-pentenyl, 3,4,5-trihydroxy -3-methylpentyl group, 3,4-bishydroxymethyl-6-hydroxyhexyl group, etc., in which these hydroxy groups have a substituent ⁇ methoxymethyl group ⁇ methylthiomethyl group ⁇ It is protected by a hydroxyl-protecting group such as a tetrahydroviranyl group.
  • a salt may be formed with a salt, for example, an alkali metal, an earth metal, an amine, or the like.
  • alkylamino group or an alkenylamino group having up to 8 carbon atoms, preferably up to 4 carbon atoms, preferably an aminomethyl group and the like, which are non-toxic salts such as hydrochloride, hydrobromide, Hydroiodide, sulfate, bisulfate, phosphate, hydrogen phosphate, acetate, maleate, fumarate, lactate, benzoate, citrate, glucuronate, methanesulfone
  • Non-toxic salts such as acid salts, p-toluenesulfonic acid salts and the like may be formed.
  • substituents are further bonded to these hydroxy groups, carboxyl groups, amino groups, etc. by esterno, amidoether, tether, urethane, etc. May be.
  • substituents include an alkyl group having one or more hydroxy groups and having up to 18 carbon atoms, preferably up to 14 carbon atoms, an alkenyl group having 10 or preferably up to 6 carbon atoms, or an aryl group.
  • cycloalkyl groups having up to 10 and preferably up to 8 carbon atoms, such as methanol, ethanol, hexanol, dodecanol, cyclohexanol, aryl alcohol, benzyl alcohol, ethylene glycol and the like.
  • substituents derived from compounds such as glycerin are preferred.
  • it is an alkyl group, an alkenyl group or an aryl group having up to 18 and preferably up to 14 carbon atoms having one or more hydroxyl groups, such as acetic acid, trifluoroacetic acid, caproic acid, dodecanoic acid, and succinic acid.
  • the carboxyl group may form a non-toxic salt.
  • it is a hydroxy acid having up to 10 and preferably up to 8 carbon atoms containing one or more hydroxy groups and carboxyl groups, for example.
  • a compound such as glycolic acid disodecanoic acid may be used as a substituent, except that isoquinic acid is ether-bonded to methyloxy at the 9-position.
  • the carboxyl group may form a non-toxic salt.
  • alkyl group or an alkenyl group having an epoxy and a hydroxy group and having up to 8 carbon atoms, preferably up to 6 carbon atoms, preferably, for example, a 2,3-epoxypropyloxy group and the like.
  • a preferred example of a 5- or 6-membered saturated monocyclic ring containing one is piperidine and the like, a preferred substituent is a 3- (1-piperidinyl) -2-hydroxypropyloxy group and the like, and two or more nitrogens are used.
  • 5 members including 3 Preferred examples of the aromatic monocyclic ring include triazoledimidazole and the like.
  • Preferred substituents include 2-hydroxy-3- (1-triazolyl) propyloxy group and the like, and oxygen or nitrogen and nitrogen.
  • a preferred example of a 6-membered saturated monocyclic ring containing 6 is morpholine or the like, and a preferred substituent is a 5- or 6-membered saturated monocyclic ring containing 2 nitrogen atoms, such as a 3-morpholino-2-hydroxypropyloxy group.
  • Preferred examples of the compound include piperazine and the like.
  • Preferred examples of the substituent include a 3- (1- (4-methyl) piperazinyl) -2-hydroxypropyloxy group and a 3- (1- (4-hydridyl) group.
  • Xyethyl) piperazinyl) -2-hydroxypropyloxy group, 3- (topiperazinyl) -2-hydroxypropyloxy group, etc. which may form a non-toxic salt .
  • Aliphatic amines having one or more hydroxy groups and having up to 10, preferably up to 8 carbon atoms are preferably 3- (tris (hydroxymethyl) methyl) amino-2-hydroxypropyl.
  • Oxy group, 3-(bishydroxylethyl) amino-2-hydroxypropyloxy group, 3-glucosamyl-2-hydroxypropyloxy group, etc., and these amino groups may form non-toxic salts.
  • Aliphatic amines having up to 10 and preferably up to 8 carbon atoms, preferably cyclohexylamino groups and the like; these amino groups may form non-toxic salts and may be heterocyclic
  • a 5-membered heteroaromatic ring containing 2 or 3 nitrogens such as an aliphatic amine having a compound and an alkyl group having up to 8 carbon atoms, preferably up to 4 carbon atoms; And a 3- (1-imidazolyl) propylamino group or a 3-morpholinopropylamino group.
  • aromatic amines aromatic amines.
  • Preferred examples thereof include compounds such as aniline as a substituent, which may form a non-toxic salt, and further include an aliphatic azide.
  • Preferred examples include an azidomethyl group, etc., and amino acids or amino acids with a protective group, and preferred examples include lysine, aspartic acid, proline, and alanine, which are non-toxic salts. May be further formed, and these substituents may be further bonded to these substituents by ester amide ether, urethane or the like.
  • Preferred substituents for the present invention include, as examples of the substituent R 4 at the 9-position, a hydroxy group, a hydroxy group protected or substituted with a protecting group, an epoxy group, a hydroxy group and an epoxy group.
  • Alkyl groups or alkenyl groups having up to 10 and preferably up to 8 carbon atoms such as alkyl groups or alkenyl groups having one or more hydroxy groups and having up to 10 and preferably up to 8 carbon atoms
  • This hydroxy group may have a substituent or may be protected by a protecting group such as a methoxymethyl group, a methylthiomethyl group, or a tetrahydrobiranyl group, and one or more hydroxy groups and one hetero group.
  • the amine may form a non-toxic salt, and these substituents may be further substituted with esters, amides, ethers, ethers, urethanes and the like as follows.
  • One or more substituents may be bonded.
  • Examples of the substituent attached to the ester, amide-ether-thioether, urethane, or the like include an alkyl group having up to 18 carbon atoms, and a group having up to 18 carbon atoms having one or more hydroxy groups, and preferably having up to 18 carbon atoms.
  • This carboxyl group may form a non-toxic salt, and is a hydroxy acid having up to 10 carbon atoms containing one or more hydroxyl groups and one or more carboxyl groups.
  • the carboxyl group may form a non-toxic salt, and preferably has up to 10 carbon atoms having an epoxy and a hydroxy group.
  • One or more hydroxy groups and one heterocyclic compound such as an alkyl group or alkenyl group having up to 6 and an alkyl group or alkenyl group having up to 8 and preferably up to 6 carbon atoms.
  • Cyclic compounds are 5- or 6-membered saturated monocyclic rings containing one nitrogen, 5-membered heteroaromatic rings containing 2 or 3 nitrogens, 6-membered saturated monocyclic rings containing oxygen or iodine and one nitrogen, nitrogen It is a 5- or 6-membered saturated monocyclic ring containing two or more, which may form a non-toxic salt.
  • These amino groups may be in the form of a non-toxic salt, may be a non-toxic salt, may be an aromatic amine, may be in the form of a non-toxic salt, and may be an aliphatic group.
  • Azides, amino acids or amino acids with protecting groups which may form non-toxic salts, or which are further substituted with ester substituents or urea. They may be combined in the evening or the like.
  • Examples of the substituent at the 8-position include a carbonyl group, a carbonyl group protected with a protecting group, an alkylidene group, an alkyl group, a hydroxy group or a group having a protecting group attached thereto, an alkyloxy group, or an alkyl group attached via a urethane.
  • Salt a 6-membered heterocyclic monocyclic alkyl group containing one oxygen and nitrogen, which may form a non-toxic salt, in which an amino acid or a protected amino acid is ester-bonded. It may form a non-toxic salt, and is preferably an epoxy group or an alkyl group having an epoxy group. These may be used alone or in a hydroxy group. Or a hydroxy group such as a methoxymethyloxy group with a protecting group and a 6-membered saturated monocyclic ring containing an alkyl group, a hydroxymethyl group and a hydroxy group, and one oxygen atom and one nitrogen atom. Combinations of an alkyl group and a hydroxy group having a 5-membered heteroaromatic ring containing two or three nitrogen atoms and a hydroxy group are also preferable.
  • R 2 at position 4 is an alkyl group
  • R 3 is an alkyl group
  • Preferred are a hydroxyalkyl group, a hydroxyalkyl group having a substituent or a protecting group, an aldehyde group, a carboxyl group, and a carboxyl group having a protecting group.
  • Preferred as a combination of the substituent at the 8-position and R 4 are an alkyl group or an alkenyl group to which an alkylidene group at the 8-position and a hydroxy group which may have a substituent at R 4 are bonded, or a substituent.
  • these hydroxy groups and carboxyl groups may have a substituent or a protecting group.
  • the number of carbon atoms containing an alkyl group and a hydroxy group at the 8-position, an alkyl group or an alkenyl group in which the hydroxy group is bonded to R4, and a hydroxy group and an epoxy group are up to 10 and preferably up to 8.
  • An alkyl or alkenyl group an alkyloxy group having an alkyl group having a carboxyl group attached through an ester bond, an alkyl group or an alkenyl group having a carboxyl group, a hydroxy group and one or more and one nitrogen
  • An alkyl or alkenyl group having up to 10, preferably up to 8 carbon atoms containing a 5-membered heteroaromatic monocyclic ring containing 2 or 3 and an alkyl group containing a hydroxy group through an ether bond.
  • a nitrogen-containing compound is bonded by a hydroxyalkyl group, and these alkyl or alkenyl groups have a substituent.
  • R 3 be bonded to a hydroxyalkyl group, an aldehyde group, a carboxyl group, or the like, and the above-mentioned hydroxy group, carboxyl group, etc. have a substituent or a protecting group. It may be.
  • a carbonyl group at position 8 or a compound protected by a protecting group is represented by R 4
  • An alkyl or alkenyl group having a carbonyl group or a carbonyl group, which may have a protecting group or a substituent, an alkyl or alkenyl group having a hydroxy group, which may have a protecting group or a substituent, for example, hydroxy Preferred examples include combinations in which an amino acid is ester-bonded to a group and an alkyl group is bonded to the 4-position, and these substituents may form a non-toxic salt.
  • a methoxymethyl group (MOM), a methylthiomethyl (MTM), a tetrahydrodrobilanyl (THP), a t-butyl (t-Bu), a trityl (Trt), a benzyl ( Bzl or Bn), ether-type protecting groups such as p-methoxybenzyl (MP), acyl-type protecting groups such as acetyl, silyl-type protecting groups such as trimethylsilyl (TMS) and t-butyldimethylsilyl (TBDMS)
  • ester-type protecting groups such as methyl and benzyl groups
  • silyl ester-type protecting groups such as trimethylsilyl groups
  • carbonyl groups dimethyl ketones such as ethylene acetal.
  • Substituents include alkyl or alkenyl bonded by a carbon bond, an epoxy or hydroxy group, a carboxylic acid having a hydroxy group, one having one or more carboxylic acids, and nitrogen as a complex.
  • 5- or 6-membered heterocyclic monocyclic ring containing 1 or 3 nitrogens 5- or 6-membered heterocyclic saturated monocyclic ring containing 1 nitrogen, 5- or 6-membered heterocyclic saturated monocyclic ring containing 2 nitrogens, oxygen or iodine and nitrogen
  • alkyl or alkenyl or epoxy or hydroxy groups examples are alkyl or alkenyl or epoxy or hydroxy groups, carboxylic acids with hydroxy groups, those with one or more carboxylic acids, amines, alkyl groups with heterocycles and up to two nitrogens as heterocycles.
  • 5- or 6-membered heteroaromatic monocyclic ring containing 1 or 3 nitrogens 5- or 6-membered saturated monocyclic ring containing 1 nitrogen, 5- or 6-membered saturated monocyclic ring containing 2 nitrogens, 1 oxygen and 1 nitrogen
  • glycerin, ethylene glycol, and the like, polyethylene glycol, terminal-blocked polyethylene glycol, sugar, and the like can also be used as a substituent.
  • the compound in the present invention for example, commercially available products such as sclareoyl, sclareolide, manol, and rapdanolic acid are applied, and furthermore, those obtained by employing conventional methods for these commercially available products. Derivatives apply. In addition, those obtained by cyclizing naturally occurring chain-like linalool and the like, bicyclic diterpenes obtained from copearl resin, and the like are also applicable without any problem.
  • the antifungal agent containing the compound of the present invention as an active ingredient is particularly useful as a therapeutic agent for mycosis involving fungi such as molds and yeasts included in humans.
  • fungi such as molds and yeasts included in humans.
  • oral administration tablets and capsules
  • parenteral administration it can be used as a solution, suspension, ointment and the like.
  • the dosage varies depending on the severity of the disease, the weight of the patient, etc., but it is generally preferable to be about 1 to 500 mg, and it is better to administer the dosage once to several times a day. .
  • an injection solution it can be administered by drip.
  • FIG. 1 is a 1 H-NMR chart of AT-5.
  • FIG. 2 is an NMR chart of AT-24.
  • FIG. 3 is a 1 H-NMR chart of AT-25.
  • FIG. 4 is a NMR chart of HAL-1.
  • FIG. 5 is a 13 C-NMR chart of HAL-1.
  • FIG. 6 is a 1 H-NMR chart of HAL-2.
  • FIG. 7 is a 13 C-NMR chart of HA L-2.
  • FIG. 8 is an NMR chart of HA L-3.
  • FIG. 9 is a 13 C-NMR chart of HA L-3.
  • FIG. 10 is a 1 H-NMR chart of HAL_4.
  • FIG. 11 is a 1 H-NMR chart of HAL-5.
  • FIG. 12 is a 1 H-NMR chart of Manol G.
  • FIG. 13 is an NMR chart of labudanolic acid.
  • FIG. 14 is a tH-NMR chart of C ⁇ P—e.
  • FIG. 15 is a 1 H-NMR chart of C 0 P—a—0 H.
  • FIG. 16 is an NMR chart of COP—c.
  • FIG. 17 is an NMR chart of BC-2.
  • FIG. 18 is a 1 H-NMR chart of BC-3.
  • Figure 19 shows a 13C- MR chart of BC-3.
  • antifungal activity measurement method and infection treatment test method in each example are as follows. It is as follows.
  • Candida albicans (Candida albicans) was used as a test bacterium, and the susceptibility to the fungus was tested at in r 0 to confirm its activity.
  • the antifungal susceptibility test was performed according to the method proposed in the Journal of the Japanese Society for Medical Mycology, Vol. 36 (1), 62-64 (1995).
  • the strains used in the experiments used were T IMM 1768 and T IMM33 18 which were provided by Teikyo University Medical Fungus Research Center Yuichi.
  • the TIMM3318 strain has resistance to azolic antifungal agents.
  • the culture medium for sensitivity measurement was prepared by dissolving 10.4 RPMI1640 (Irvine Scientific Cat. # 9512) and 2.0 g of sodium bicarbonate in 900 ml of sterile distilled water, adding 34.53 g of MOPS as a buffer, and stirring well until dissolved. Next, the pH was adjusted to 7.0 with sodium hydroxide, the volume was adjusted to 1 liter by adding sterile distilled water, and the solution was sterilized by filtration and stored at 4 ° C.
  • test strains were obtained by culturing at least twice at 35 ° C and 24 to 48 hours in YM agar medium (Difco), and then suspended in 5 ml of sterile physiological saline. The absorbance of this suspension was measured at 600 nm, the bacterial amount was determined from a calibration curve prepared in advance, and diluted with a culture medium for sensitivity measurement to a bacterial count of 2 ⁇ 10 3 cells / ml to obtain a test bacterial solution.
  • test sample was dissolved using a 20 mM SO-added methanol solution, and a test assay solution was prepared by 2-fold serial dilution.
  • dispense 901 medium for sensitivity measurement into a 96-well flat-bottom microplate To test for antifungal susceptibility, dispense 901 medium for sensitivity measurement into a 96-well flat-bottom microplate, add 10/1 test assay solution and 100/1 test bacterial solution to each well, and add Concentrations were made. Place the microplate in a container kept at humidity, incubate at 35 ° C for a maximum of 72 hours, observe every 24 hours, and when the turbidity of the growth control reaches 0.2, ⁇ The turbidity of El It was measured.
  • test drug was weighed and a drug dilution step was made with 20% DMSO-added methanol.
  • RPMI1640 (Irvine Scientific Cat. # 9512 ) 10.4g, was dissolved in sterile distilled water 900ml and NaHCO 3 2.0, a MOPS 34.53G added and stirred as buffer capacity adjusted to 1 liter after correcting the pH 7.0 with NaOH And used after sterilization by filtration.
  • test bacteria were cultured on a potato dextrose agar medium (Difco) at 30 ° C. for 1 week, and sterile physiological saline containing 0.05% Tween80 was added to obtain a conidia suspension. The number of conidia was counted under a microscope using a hemocytometer, and adjusted to 2.5 ⁇ 10 5 cells / ml in the measurement medium.
  • mice Healthy growing mice (ICR, 4-week-old, female, 19-22g, Nippon Charles River) were tested against Aspergillus fumigatus (1.0%) suspended in saline containing 0.1% Tween80. (xl0 fi CFU / mouse) was inoculated through the tail vein (0.2 ml) to establish infection.
  • the treatment was performed by dissolving or suspending the sample in a gum arabic solution, and orally administering a 0.2 ml volume each time using a gastric probe (50 mg / kg and 10 mg / kg or 10 mg / kg and 2 mg / kg) o
  • a gastric probe 50 mg / kg and 10 mg / kg or 10 mg / kg and 2 mg / kg
  • the first time One hour after inoculation, and once a day thereafter, 6 doses were given every 24 hours (once / day, for a total of 7 days).
  • the control group received the vehicle alone in an amount of 0.2 ml.
  • the efficacy was determined as follows from the number of surviving mice in the sample administration group at the time when all the control animal groups died.
  • sclareolide (1.25 g, 5.00 mmoK Aldrich reagent) is dissolved in a mixture of tetrahydrofuran (hereinafter referred to as THF) (10 ml) and ether (10 ml), and lithium aluminum hydride (10 ml) is stirred under ice-cooling. 190 mg, 5.00 mmol) were added in small portions. After stirring at the same temperature for 1 hour, add ethyl acetate little by little and add excess Was decomposed.
  • THF tetrahydrofuran
  • ether 10 ml
  • lithium aluminum hydride 10 ml
  • Acetic anhydride (1 ml) was added to a solution of AT-1 (1.20 g, 4.72 mol) in pyridine (1.5 ml) under ice cooling, and the mixture was allowed to stand at room temperature overnight. Ice water (40 ml) was added to the reaction solution, and the mixture was extracted twice with ethyl acetate (30 ml). The extract was washed successively with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and saturated saline. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off.
  • the residue obtained was subjected to silica gel column chromatography [13 g, 1.5 cm IDxl6.5, eluting solvent: porcine form-ethyl acetate 100 / 0 7 0/3 0], and 1.35 g of hydronaphthylene (hereinafter referred to as AT-2) having a methyl group and a hydroxy group at the 8-position and a 2-acetoxityl group at the 9-position were obtained as a colorless candy. Obtained as a solid.
  • the NMR spectrum 400 MHz was as follows.
  • the combined extracts are 1N hydrochloric acid, saturated carbonated water
  • Tables 1 and 2 show the results of the antifungal activity and infection treatment test of each prepared compound.
  • Coloring reagent positive for anisaldehyde reagent (purple).
  • AT-16-1 (900 mg, 1.89 mmol) obtained in Example 2 was dissolved in dichloromethane (15 ml), and m-perbenzoic acid (hereinafter referred to as m-CPBA) (932 mg) was stirred with ice cooling. , 5.40 mmol), and the mixture was stirred at room temperature for 5 hours and then left for 15 hours. After the reaction solution was extracted with chloroform, it was washed with a 10% aqueous sodium thiosulfate solution, a saturated aqueous sodium hydrogen carbonate solution and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off.
  • m-CPBA m-perbenzoic acid
  • DMF dimethylformamide
  • 1H-1,2,4-triazole 140 mg, 0.81 mmol
  • AT-16-2 400 mg, 0.81 mmol
  • the reaction solution was extracted with ethyl acetate, and then saturated brine was added. And dried over anhydrous magnesium sulfate, and the solvent was distilled off.
  • AT-16-3 (195 mg, 0.35 mmol) was dissolved in methanol (15 ml), pyridinium p-toluenesulfonate (68 mg, 0.28 mmol) was added, and the mixture was allowed to stand at room temperature for 15 hours.
  • the characteristics were as follows.
  • Coloring reagent positive for anisaldehyde reagent (purple).
  • Tables 3 and 4 show the results of the antifungal activity and infection treatment test of each prepared compound.
  • Hexane / ethyl acetate 90 / 10-80 5.5 g of the eluted fraction was transferred to a 200 ml eggplant-shaped flask and dissolved in 50 ml of ethanol. After adding 50 ml of 1N sodium hydroxide water while stirring under ice cooling, the reaction solution was returned to room temperature and stirred for 2 hours. After 2 hours, the reaction mixture was concentrated under reduced pressure to remove the ethanol, and extracted twice with 50 ml of ethyl acetate. Went out. The extract was washed successively with 20 ml of distilled water and 20 ml of saturated saline, and dried over anhydrous magnesium sulfate.
  • HAL-1 colorless columnar crystals of a compound represented by the following structural formula (hereinafter referred to as HAL-1) were obtained. Its characteristics are as follows, ' ⁇ - ⁇ spectrum (400MHz: CDC1 3) Chiya one preparative FIG 4, 13 C-NMR spectrum (400MHz: CDC1 3) Chiya 5 an bets As shown.
  • HAL-2 a colorless oily product of a compound represented by the following structural formula
  • HAL-3 a colorless oil of a compound represented by the following structural formula
  • HAL-4A a compound represented by the following structural formula (hereinafter referred to as HAL-4A). This was placed in a 50 ml flask, and 4 ml of acetate and 1.7 mmol (636 ml) of a dione's reagent (2.67 fflmol / ml) were added under ice-cooling, followed by stirring for 1 hour. After 1 hour, add isopropyl alcohol until the reaction solution turns green, add an appropriate amount of celite, further add 30 ml of getyl ether, filter the cerate, and filter the filtrate in distilled water and saturated saline. And then dried over anhydrous magnesium sulfate.
  • HAL-4A a compound represented by the following structural formula
  • Tables 5 and 6 show the results of the antifungal activity and infection treatment test of each prepared compound.
  • manol E hydronaphthylene
  • Coloring reagent positive for anisaldehyde reagent (purple).
  • Tables 7 and 8 show the results of the antifungal activity and infection treatment test of each prepared compound.
  • a suspension obtained by adding 120 ml of anhydrous DMF to 15 g of ALB003 and 48.1 g of lithium iodide was heated and refluxed for 4 hours under a nitrogen stream.
  • the reaction solution was transferred to a chloroform solution and a dilute aqueous hydrochloric acid solution, and separated.
  • the chloroform layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • ALB 909 hydronaphthylene linked by the bond, and its isomer, hydronaphthylene (hereinafter referred to as ALB 0 1), which is bonded by a double bond at the 8- and 9-positions 6.2 g).
  • ALB 0 1 hydronaphthylene
  • the obtained white solid is washed with a small amount of ethyl acetate, and the solid is dried to obtain a compound represented by the following structural formula (hereinafter referred to as AL B 0 13) 3 lg (82% yield).
  • the iH-NMl 400MHz) spectrum data is as follows.
  • pyridine 600 mg of AL B 08, 590 mg of benzoic anhydride, and N, N-dimethylamino 29 mg of pyridine (hereinafter abbreviated as DMAP) was dissolved in 12 ml of pyridine and stirred at room temperature for 4 days. After a small amount of water was added to the reaction solution, pyridine was distilled off under reduced pressure, and the residue was partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was washed with an aqueous sodium hydrogen carbonate solution and saturated saline, and then dried by adding anhydrous sodium sulfate. After drying, filtration was performed, and the filtrate was concentrated under reduced pressure to obtain 900 mg of a residue.
  • DMAP N, N-dimethylamino 29 mg of pyridine
  • hydronaphthylene having a methylthiomethyloxy group at the 8-position and a methoxycarbonyl group at the 9-position (hereinafter referred to as ALB020) was also obtained.
  • the NMR (400 MHz) spectrum is as follows.
  • ALB 011 700 mg was dissolved in 15 ml of ethyl acetate, and 20 mg of 5% palladium carbon (Pd / C) was added.
  • the inside of the reaction vessel was set to a hydrogen atmosphere, and vigorously stirred at room temperature for ⁇ days.
  • Its ⁇ -NMR ⁇ OOMHz) spectrum data is as follows.
  • Hydronaphine having a methoxy group at the 8-position and a carboxyl group at the 9-position 150 mg (40%) was obtained.
  • the 'H-NMR ⁇ OOMHz) spectrum is as follows.
  • Tables 9 and 10 show the results of the antifungal activity and infection treatment tests of the prepared compounds.
  • ALB030 5 g was dissolved in a mixed solvent of 80 ml of acetate and 20 ml of water, 8.8 g of bis (trifluoroacetoxoxy) chloride was added, and the mixture was stirred at room temperature for 15 hours.
  • ALB031 hydronaphthylene having an aminomethyl group
  • reaction product 15 g was dissolved in 50 ml of pyridine, cooled with ice, and 6.74 ml of mesyl chloride was added. After removing the ice bath, the mixture was stirred at room temperature for 15 hours. After adding a small amount of water, pyridine was distilled off, the residue was partitioned between ethyl acetate and 2N hydrochloric acid, and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The aqueous layer was re-extracted with ethyl acetate, and the organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. Dried.
  • ALB086 326 mg was dissolved in 4 ml of THF, 0.4 ml of a 0% aqueous sodium perchlorate solution was added, and the mixture was stirred at room temperature for 15 hours.
  • the reaction solution was partitioned between ethyl acetate and water, and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate.
  • the aqueous layer was re-extracted with ethyl acetate, and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate.
  • Tables 11 and 12 show the antifungal activity and the results of infection treatment tests of the prepared compounds.
  • Table 11 Antifungal activity (IC 80 g / ⁇ )
  • Table 12 Infection treatment test results
  • ALB049 300 mg was dissolved in 10 ml of dehydrated black hole form and stirred. Thereto was added 50 mg of palladium carbon, and the mixture was stirred at room temperature for 3 days under a hydrogen atmosphere. The reaction solution was diluted by addition of chloroform, and the organic layer was washed twice with a saturated saline solution, and dried by adding anhydrous sodium sulfate.
  • Hydronaphthalene having a hydroxy group and a hydroxymethyl group at the 9-position (hereinafter referred to as ALB059) is a yellow solid. 254 mg (yield: 45%) was obtained.
  • the NMR (400 MHz) spectrum is as follows.
  • ALB062 100 mg was added to 1 ml of trifluoroacetic acid, cooled in an ice bath and stirred. After 5 minutes, the trifluoroacetic acid was removed under reduced pressure, and the residue was subjected to gel chromatography (silica gel gel: 90: 10) to obtain a compound represented by the following structural formula (hereinafter referred to as ALB0). 77 mg (1003 ⁇ 4) was obtained.
  • the 1-NMR (400 MHz) spectrum data is as follows.
  • Tables 13 and 14 show the results of the antifungal activity and infection treatment test of each prepared compound.
  • ALB204 was dissolved in 100 ml of ethyl acetate, and about 200 mg of 5% Pd / C was added.
  • the reaction vessel was placed under a hydrogen gas atmosphere, and vigorously stirred at room temperature for 5 days.
  • A 540mg related to hydronaphthylene (hereinafter referred to as ALB208) having a 3,4-bishydroxymethyl-6-hydroxyhexyl group at the 9-position.
  • Fr.B 310 mg).
  • ALB2111 (mixture of A and B) obtained by hydrolyzing ALB204 was dissolved in 5 ml of THF, 20 ml of an 80% aqueous acetic acid solution and 400 ⁇ 1 of 2N hydrochloric acid were added, and the mixture was stirred at room temperature for 5 days. . After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate 2.8: 2-6: 4), and a methyl group, a hydroxyl group and a ninth position were placed at the 8th and 8th positions, respectively.
  • ALB214 -Hydronaphtherene having a carboxypropyl group (hereinafter referred to as ALB214) was obtained as white crystals.
  • the ⁇ -NMR (400 MHz) spectrum is as follows, and the Rf is 0.4 for Fr.A (hereinafter referred to as ALB 215—A) (Silica gel thin-layer chromatography, Chloroform: The average is 8: 2), and Fr.B (hereinafter referred to as ALB2 15 -B) is 0.3 (same as above).
  • the NMR (400 MHz) spectrum is as follows, and the Rf was 0.38 for Fr.A (hereinafter referred to as ALB216-A). 8: 2, 1% acetic acid added), Fr.B (hereinafter referred to as ALB2 16-B) 0.28 (as above), Fr.C (hereinafter as ALB2 16-C) as 0.25 (as above) ).
  • ALB216-A and ALB216-B contain a small amount of a compound from which the 8-position hydroxyl group has been eliminated.
  • N, N £ -Di-1-butoxycarbonyl-L-lysine 3.1 lg of dicyclohexylammonium salt and 1.57 g of pentachlorophenol were dissolved in 12 ml of dehydrated DMF and adjusted to 2M.
  • 40 ml of a DMF solution of -dicyclohexylcarbodiimide (hereinafter abbreviated as DCC) was added, and the mixture was stirred at room temperature for 4 hours.
  • Lg of AT-1 and 40 mg of DMAP were added, and the mixture was further stirred for 2 hours.
  • the reaction solution was separated with ethyl acetate and water, and the organic layer was washed with an aqueous solution of sodium hydrogen carbonate and a saturated saline solution in that order, and dried over anhydrous sodium sulfate.
  • ALB234 is hydrolyzed in a 2N aqueous solution of sodium hydroxide, and has a methyl group at the 8-position and a hydroxethyl group at the 9-position, and a double bond between the 8- and 9-positions. Len (hereinafter ALB 083) was obtained.
  • the ' ⁇ -NMR (400MHz) spectrum is as follows.
  • ALB237 Lg of ALB237 was dissolved in 30 ml of methanol, and 50% of 5% Pd / C was added. The reaction vessel was placed under a hydrogen atmosphere and stirred vigorously at room temperature for 15 hours. After evaporating the solvent under reduced pressure, the residue was subjected to column chromatography (Cosmo Seal 140-C180PN, 703 ⁇ 4 methanol) to obtain 0.4 g of a compound represented by the following structural formula (hereinafter, referred to as ALB238). That The following is the Stokkulde evening.
  • ALB072 160 mg of ALB240 and 1001 of pyridine were added to 5 ml of dehydrated DMF, and 120 ml of cyclohexyl isocyanate was added, followed by stirring at room temperature for 6 hours.
  • the reaction solution was diluted by addition of chloroform, and the organic layer was washed twice with saturated saline and dried over anhydrous sodium sulfate. After drying, filtration and concentration of the filtrate, the residue is purified by silica gel column chromatography (n-hexane: ethyl acetate-70: 30) to give a compound represented by the following structural formula (hereinafter referred to as ALB072). ) 200 mg (88%) were obtained. That The spectrum data is as follows.
  • Tables 15 and 16 show the results of the antifungal activity and infection treatment test of each prepared compound.
  • ALB 005 330 mg was dissolved in 10 ml of pyridine, 250 ⁇ 1 of hexanoyl chloride was added, and the mixture was stirred at room temperature for 14 hours.
  • the reaction solution was concentrated to about half the volume, diluted with ethyl acetate, washed once with 2N hydrochloric acid and twice with saturated brine, and dried over anhydrous sodium sulfate. After drying The mixture is filtered and the filtrate is concentrated.
  • reaction mixture 350 mg of ALB 005 and 20 mg of MAP were added to 20 ml of pyridine, and the mixture was stirred for 30 minutes in an ice bath. After adding 730 mg of lauric anhydride, 3 Stirred for days. After concentrating the reaction solution to about half the volume, the reaction mixture was diluted with ethyl acetate, washed once with 2N hydrochloric acid and twice with saturated saline, and dried by adding sodium sulfate anhydride.
  • Lonaf Yuren hereinafter ALB 303 2.28 g (yield: 50%) was obtained as an oil.
  • the ⁇ - ⁇ 400MHz) spectrum is as follows.
  • Tables 17 and 18 show the results of the antifungal activity and infection treatment tests of the prepared compounds.
  • ALB322 hydronaphthylene having a (2,3-dihydroxypropyl) oxhetyl group at the ninth position was obtained as an oily substance.
  • the spectrum data ( ⁇ - ⁇ 400MHz) is as follows.
  • ALB322 Using 5.17 g (7.17 mmol) of ALB322, the same operation as that of ALB307 was performed. The obtained residue was purified by silica gel column chromatography (SiO 2: 400 ml, ethyl acetate / hexane 2 16/8 4), and 1.33 g of a compound represented by the following structural formula (hereinafter, referred to as ALB 325) was obtained (yield). : 50%) as a white solid.
  • the 1 H-NMR (400 MHz) spectrum is as follows.
  • ALB328 hydronaphthylene having a (droxityl) oxhetyl group was obtained as an oily substance.
  • the -NMiU 400MHz) spectrum data is as follows.
  • ALB330 The same operation as that of ALB330 was carried out using 250 mg (0.705 mniol) of ALB321 and 0.12 ml (0.821 mmol) of 4- (3-aminopropyl) morpholine.
  • the 1 H-NMR (400 MHz) spectrum is as follows.
  • ALB330 The same operation as that of ALB330 was carried out using 250 mg (0.705 mmol) of ALB332 and 0.1 ml (0.90 mmol) of N-methylbiverazine.
  • the resulting residue by silica gel column chromatography (Si0 2: 60 ml, methanol / black port Holm 4/9 6-1 6/8 4) to obtain the compound represented by the following structural formula (hereinafter ALB 3 3 248 mg (yield: 77%) was obtained as an oil.
  • the 1 H-NMR (400 MHz) spectrum is as follows.
  • ALB330 The same operation as that of ALB330 was performed using 250 mg (0.705 mmol) of ALB321 and 0.1 ml (0.82 orchidol) of l- (2-hydroxyxetyl) piperazine.
  • the ⁇ -NMIU 400MHz) spectrum is as follows.
  • ALB329 177 mg (0.418 mmol) of ALB329 was dissolved in a mixed solvent of 0.5 ml of THF and 3 ml of an 80% aqueous acetic acid solution, 0.2 ml of 2N hydrochloric acid was added, and the mixture was stirred at 80 ° C for 5 hours.
  • the solvent was distilled off from the reaction solution under reduced pressure, and the obtained residue was dissolved in chloroform.
  • the solution was washed three times with a saturated aqueous solution of sodium hydrogencarbonate and once with a saturated saline solution.
  • ALB330 Almost the same operation as ALB330 was performed using 250 mg (0.705 mmol) of ALB332 and 69 mg (1.06 mmol) of sodium azide.
  • the resulting residue by silica gel column chromatography (Si0 2: 50 ml, acetic acid Echiru / n - hexane; 1 6/84) to give the methyl group at the 8-position, main Tokishimechiruoki sheet group, the 9-position 3- 209 mg (yield: 75) of hydronaphthylene (hereinafter referred to as ALB339) having an azide-2-hydroxyproviroxilethyl group was obtained as an oily substance. That The following is the Stokkulde evening.
  • ALB330 The same operation as ALB330 was performed using 250 mg (0.705 mmol) of ALB321 and 0.1 ml (1.04 mmol) of diethanolamine.
  • the obtained residue was purified by silica gel column chromatography (Si 2 : 50 ml, methanol / chloroform: 4/96 to 24/76), and the compound represented by the following structural formula (hereinafter referred to as ALB) was obtained. 247 mg (yield: 76%) was obtained as an oil. Its ⁇ -NMR ⁇ OOMHz) spectrum is as follows.
  • Table 19 and Table 20 show the antifungal activity and the results of infection treatment tests of the prepared compounds.
  • the reactions were positive for Ehrlich's reagent (purple), positive for anisaldehyde's reagent (purplish red), and positive for 50% sulfuric acid reagent (brown).
  • Table 21 and Table 2 show the results of the antifungal activity of ravudanolic acid and the results of treatment tests for infection. See Figure 2.
  • Table 21 Antifungal activity (IC 80 g / ml)
  • Table 22 Infection treatment test results
  • Scan Bae click Toruchiya one bets of the ' ⁇ - NMR (400MHz, CDC1 3 ) is as in Figure 1 5, 13 C- NMR (100MHz , CDC1 3) spectrum Torude Isseki 15.2, 17.8, 19.0, 24.4, 27.1, 27.6, 35.4, 38.6, 38.8, 39.0, 39.7, 41.3, 56.3, 57.3, 65.0, 73.5, 106.8, 111.6, 145.2, 148.1.
  • C 0 P—c was hydrolyzed to remove the acetyl group, and C 0 P—c, (Agatholic acid) was obtained.
  • Table 23 and Table 2 show the results of the antifungal activity and infection treatment tests of the prepared compounds. See Figure 4.
  • Table 2 3 antifungal activity (IC 8:. ⁇ G / ml)
  • Bacillus cereus IF03132 strain was inoculated into a medium having the composition shown in Table 25 below (aliquots of 100 ml each in 500 ml Erlenmeyer flasks, and sterilized by high-pressure steam at 121 ° C for 15 minutes). After heating 1.2 liters of the culture at 27 ° C for 4 days, heating at 65 ° C for 20 minutes, adding the mixture to 40 liters of medium of the same composition, and heating at 27 ° C for 24 hours Time shaking culture was performed. After 24 hours, it was confirmed that Bacillus cereus had grown sufficiently, and then 8 g of sclareol (10% ethanol solution) was added, followed by further culturing for 14 days. Table 25
  • the resulting culture was centrifuged at 3000 rpm for 20 minutes to separate the cells from the culture.
  • the culture solution was extracted with 40 liters of ethyl acetate, and the cells were extracted with 4 liters of ethyl acetate to obtain 8.64 g of extract.
  • Ethyl acetate / hexane 7/3 (fraction 1: 0.15 g)
  • ethyl acetate / hexane 8/2
  • fraction 2: 0.46 g
  • ethyl acetate / hexane 10/0 (fraction 3: 0.10 g).
  • fraction 1 was fractionated by reverse phase chromatography (2 cm ID x 16 cm, elution solvent: 40 to 100% methanol), and 31.6 mg of a compound (hereinafter referred to as BC-1) was obtained from the 50 ° elution fraction. .
  • fraction 2 was recrystallized from hexane to obtain 69.5 mg of a compound represented by the following structural formula (yidani 92, hereinafter referred to as BC-2) as white powdery crystals ( the thin gel layer thereof).
  • CD 3 0D) of the scan Bae click Toruchiya The figures are as shown in Figure 17.
  • fraction 3 was fractionated by reverse-layer chromatography (2 cm ID x 6 cm, elution solvent: 50 to 100% methanol), and a compound represented by the following structural formula was obtained from the 70 to 80% elution fraction. 3, hereinafter referred to as BC-3).
  • NMR 400MHz, scan Bae click Toruchiya one bets CD 3 0D
  • 13 C- NMR 100MHz : CDCl 3 + CD 3 0D
  • spectrum Toruchiya one metropolitan Figure 19 shows the results.
  • Tables 26 and 27 show the results of the antifungal activity and infection treatment tests of the prepared compounds.
  • Table 26 Antifungal activity (IC 80 g / ml)
  • Coloring reagent positive for anisaldehyde reagent (purple).
  • C0P-a (cupressic acid) isolated from Copearl resin is converted into a methyl ester with diazomethane, and this methyl ester (300 mg, 0.9 mmol) is dissolved in dichloromethane (5 ml), and metachloroperbenzoic acid ( 234 mg, 1.4 mmol) under ice-cooling and stirring, and the mixture was stirred with water-cooling for 1 hour and at room temperature for 1.5 hours.
  • the reaction solution was extracted with a chloroform solution, washed successively with a 10% aqueous sodium thiosulfate solution, a saturated aqueous sodium hydrogen carbonate solution, and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off.
  • Coloring reagent positive for anisaldehyde reagent (purple).
  • Coloring reagent positive for anisaldehyde reagent (purple).
  • BC-3 (18-hydroxysclareoK 100mg, 0.31mmol) is dissolved in pyridine (2ml), and stirred under ice-cooling with 4-dimethylaminopyridine (llmg, 0.09 marl ol) and succinic anhydride (100mg, 1.0 ol). ) And stirred at room temperature for 24 hours.
  • the reaction solution was extracted with ethyl acetate, washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography (5 g (lcmlDx 16 cm, developing solvent: chloroform / methanol 100/0 to 9/1)) to give MK-22 (42 mg, yield 32%). Obtained.
  • Coloring reagent positive for anisaldehyde reagent (purple).
  • Boc-5-alanine (88 mg, 0.46 mmol) is dissolved in dichloromethane (1 ml), and ⁇ , ⁇ '-dicyclohexylcarpoimide (128 mg, 0.62 mmol) is added under ice-cooling with stirring. Stirred for minutes. Then, 4-dimethylaminopyridine (12 mg, 0.1 mmol) and BC-3 (100 mg, 0.31 mmol) were added under ice-cooling, and the mixture was stirred at room temperature for 4 hours.
  • Coloring reagent positive for anisaldehyde reagent (purple).
  • BC-3 (100 mg, 0.31 mmol) was dissolved in pyridine (1 ml), and 4-dimethylaminopyridine (19 mg, 0.17 mmol) and diglycolic acid anhydride (116 mg, 1.0 mmol) were added under ice-cooling and stirring. The mixture was stirred at room temperature for 4 hours. After the reaction solution was extracted with ethyl acetate, the ethyl acetate layer was extracted with a saturated aqueous solution of sodium hydrogen carbonate, the aqueous layer was acidified with IN hydrochloric acid, and then extracted again with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off to obtain MK-26 (79 mg, yield 585).
  • Coloring reagent positive for anisaldehyde reagent (purple).
  • Coloring reagent positive for anisaldehyde reagent (purple).
  • Coloring reagent positive for anisaldehyde reagent (purple).
  • Tables 29 and 30 show the antifungal activity and the results of infection treatment tests of the prepared MK-1, 2, and 12, respectively.
  • ALB203 and Z-proline were condensed by DCC, and then the Z group was removed.
  • AT-24 was dissolved in dehydrated acetonitrile, 2,6-dimethylmorpholine or tetrazol and anhydrous lithium perchlorate were added, and the mixture was stirred at room temperature for 1 day. Additional lithium oxide was added, and the mixture was stirred for 15 hours while heating to 60 ° C.
  • the reaction solution was separated into chloroform and aqueous ammonium chloride solution, and the chloroform layer was washed with saturated saline and dehydrated by adding anhydrous sodium sulfate. The aqueous layer was extracted with black hole form and subjected to the same treatment as above.
  • AT-1 (3 g) and 1-bromo-2,3,4,6-tetraacetylglucose (7.28 g) were dissolved in dehydrated chloroform (50 ml) and cooled in an ice bath. Silver re-flat
  • the obtained compound was dissolved in methanol, sodium methoxide was added little by little, and the point at which spots with low Rf values became one on TLC was defined as the end point of the reaction.
  • the solvent of the reaction solution is distilled off, and the residue is purified by silica gel column chromatography. Filtration yielded 800 mg of the title compound in 16.3% yield.
  • This product was dissolved in methanol (10 ml), 2N hydrochloric acid (0.5 ml) was added, and the mixture was stirred at room temperature for 15 hours. After evaporating the solvent, the residue was purified by recrystallization from acetone / ethanol, and 67 mg of ALB246 was added.
  • ⁇ 3.7 (3H, m, CH-0- and 0- CH 2) 3.45 (1H, m, CH-0-) 2.6 (2H, t, CH 2 -CN) 1.9-0.75 (26H, m, cyclic CH And Mex4).
  • a solution of ALB030 (3.0 g) in dehydrated THF (40 ml) was added dropwise to a suspension of LAH (300 mg) in dehydrated THF (10 ml), and the mixture was stirred at 60 ° C for 15 hours.
  • LAH (300 mg) and dehydrated THF (30 ml) were further added, and the mixture was refluxed for 8 hours.
  • a small amount of water was added to the reaction solution to inactivate the excess reagent, and then chloroform and 2N hydrochloric acid were added to separate the solution.
  • the ethyl acetate layer was washed with saturated saline and dehydrated by adding anhydrous sodium sulfate.
  • the aqueous layer was extracted with ethyl acetate (twice), and the combined ethyl acetate layers were treated as above.
  • the aqueous layer was extracted with ethyl acetate (twice) and the combined ethyl acetate layers were treated as above. Was.
  • the combined filtrate is concentrated, and the residue is purified by silica gel column chromatography.
  • the aqueous layer was extracted with ethyl acetate, and the ethyl acetate layer was dried over anhydrous sodium sulfate. After filtration, the filtrate is concentrated. The residue was dissolved in methanol (100 ml), potassium carbonate (1.5 g) was added, and the mixture was vigorously stirred at room temperature for 1 hour. The reaction solution was separated into a black hole form and an aqueous solution of ammonium chloride. The aqueous layer was extracted with chloroform, and the combined chloroform layer was washed with saturated saline and dried over anhydrous sodium sulfate.
  • the aqueous layer was extracted with ethyl acetate, and anhydrous sodium sulfate was added to the ethyl acetate layer and dried. Combine these ethyl acetates After concentration, the residue was subjected to silylation gel column chromatography (n-hexane: ethyl acetate 75:25), ALB 260 (285 mg, 20%), ALB 261 (468 mg, 39%), AL B262 (324 mg, 27%) was obtained, respectively.
  • Disopropylethylamine (7 ml) was added to a solution of sclareoyl (3.08 g) in dehydrated chloroform (50 ml), and the mixture was cooled in an ice bath.
  • An equimolar amount of a reaction mixture (5.5 ml) of 1,3-dioxane and acetyl chloride or separately synthesized 3-acetoxypropyl chloromethyl ether was added dropwise to the solution, and the mixture was stirred at room temperature for 24 hours. .
  • the reaction solution was separated into ethyl acetate and an aqueous solution of ammonium chloride, and the ethyl acetate layer was washed with an aqueous solution of ammonium chloride and a saturated saline solution in that order, and dried by adding anhydrous sodium sulfate.
  • the aqueous layer was extracted with ethyl acetate, and anhydrous sodium sulfate was added to the ethyl acetate layer and dried.

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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Epoxy Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
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Abstract

Agents antifongiques contenant en tant qu'ingrédient actif des composés possédant une structure de noyau d'hydronaphtalène, en particulier, albicanol dans la fraction de la structure de noyau d'hydronaphtalène et sclareol, sclareolide, manool, acide labdanolique, leur structure étant semblable et chacun possédant différents substituants. Ces agents antifongiques sont efficaces contre des champignons provoquant des infections opportunistes.
PCT/JP1999/001998 1998-04-14 1999-04-14 Agents antifongiques WO1999053911A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102643167A (zh) * 2012-03-05 2012-08-22 中国科学院烟台海岸带研究所 一种海藻内生真菌倍半萜类化合物及其制备和应用
WO2013013178A1 (fr) * 2011-07-21 2013-01-24 Kansas State University Research Foundation Sesquiterpènes pour applications antifongiques
JP2018135335A (ja) * 2013-01-09 2018-08-30 アクイノックス ファーマシューティカルズ （カナダ） インコーポレイテッド Ｓｈｉｐ１モジュレーターおよびそれに関連する方法
CN116808055A (zh) * 2022-03-22 2023-09-29 新疆大学 一种香紫苏内酯和两性霉素b联合抗新型隐球菌的方法

Citations (4)

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WO1996025385A1 (fr) * 1995-02-15 1996-08-22 Toa Gosei Co., Ltd. Composes de sesquiterpene
JPH09323986A (ja) * 1996-06-04 1997-12-16 Toagosei Co Ltd セスキテルペン系化合物及び抗真菌剤
WO1998006388A1 (fr) * 1996-08-13 1998-02-19 Toa Gosei Co., Ltd. Agent antifongique
JPH10298070A (ja) * 1997-04-22 1998-11-10 Toagosei Co Ltd 抗真菌剤

Patent Citations (4)

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Publication number Priority date Publication date Assignee Title
WO1996025385A1 (fr) * 1995-02-15 1996-08-22 Toa Gosei Co., Ltd. Composes de sesquiterpene
JPH09323986A (ja) * 1996-06-04 1997-12-16 Toagosei Co Ltd セスキテルペン系化合物及び抗真菌剤
WO1998006388A1 (fr) * 1996-08-13 1998-02-19 Toa Gosei Co., Ltd. Agent antifongique
JPH10298070A (ja) * 1997-04-22 1998-11-10 Toagosei Co Ltd 抗真菌剤

Non-Patent Citations (2)

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Title
BAILEY J. A., VINCENT G. G., BURDEN R. S.: "DITERPENES FROM NICOTIANA GLUTINOSA AND THEIR EFFECT ON FUNGAL GROWTH.", JOURNAL OF GENERAL MICROBIOLOGY, SOCIETY FOR MICROBIOLOGY, READING, GB, vol. 85., 1 January 1974 (1974-01-01), GB, pages 57 - 64., XP000648063, ISSN: 0022-1287 *
MELA P., ET AL.: "EPOXYDATION DIASTEREOSELECTIVE DU SCLAREOL.", RIVISTA ITALIANA ESSENZE PROFUMI PIANTE OFFICINALI, XX, XX, vol. 08., 1 January 1997 (1997-01-01), XX, pages 807 - 811., XP002921286 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013013178A1 (fr) * 2011-07-21 2013-01-24 Kansas State University Research Foundation Sesquiterpènes pour applications antifongiques
US8980951B2 (en) 2011-07-21 2015-03-17 Kansas State University Research Foundation Sesquiterpenes for antifungal applications
CN102643167A (zh) * 2012-03-05 2012-08-22 中国科学院烟台海岸带研究所 一种海藻内生真菌倍半萜类化合物及其制备和应用
CN102643167B (zh) * 2012-03-05 2014-05-14 中国科学院烟台海岸带研究所 一种海藻内生真菌倍半萜类化合物及其制备和应用
JP2018135335A (ja) * 2013-01-09 2018-08-30 アクイノックス ファーマシューティカルズ （カナダ） インコーポレイテッド Ｓｈｉｐ１モジュレーターおよびそれに関連する方法
US10272081B2 (en) 2013-01-09 2019-04-30 Aquinox Pharmaceuticals (Canada) Inc. SHIP1 modulators and methods related thereto
CN116808055A (zh) * 2022-03-22 2023-09-29 新疆大学 一种香紫苏内酯和两性霉素b联合抗新型隐球菌的方法

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