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WO1991011451A1 - Analogue de l'acide griseolique et inhibiteur de lak le contenant - Google Patents

Analogue de l'acide griseolique et inhibiteur de lak le contenant Download PDF

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Publication number
WO1991011451A1
WO1991011451A1 PCT/JP1991/000072 JP9100072W WO9111451A1 WO 1991011451 A1 WO1991011451 A1 WO 1991011451A1 JP 9100072 W JP9100072 W JP 9100072W WO 9111451 A1 WO9111451 A1 WO 9111451A1
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WIPO (PCT)
Prior art keywords
group
formula
acid
compound
griseoic
Prior art date
Application number
PCT/JP1991/000072
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English (en)
Japanese (ja)
Inventor
Isao Kaneko
Masahiko Ohtsuki
Masakatsu Kaneko
Makoto Kamokari
Takashi Yasumoto
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Sankyo Company, Limited
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Publication of WO1991011451A1 publication Critical patent/WO1991011451A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals

Definitions

  • the present invention relates to a firewood parental griseoic acid analog having an excellent lyiiiphokine aq3 ⁇ 4va ed killer cell (LAK) or killer T cell (CTL) activity inhibitory activity, and a LAK or C'TL activity inhibitor containing the same. . ⁇
  • Griseol acid itself is disclosed in JP-A-56-6SB95. Further, derivatives in which the hydroxyl group or Z and amino groups of griseol acid are modified with a lower aliphatic acyl group are disclosed in JP-A-60-94992. These are described in Japanese Unexamined Patent Publication No. 62-309, Japanese Unexamined Patent Publication No. 63-304426, and Chemical, Pharm Bulltin, Volume, 1036 (1987). It is not known that these compounds have an inhibitory effect on LAK or CTL activity.
  • Organ transplant rejection viral hepatitis and certain autoimmune diseases mainly occur when killer cells such as CTLLAK, NK (natural killer) 'cells destroy target cells (cytotoxic activity).
  • killer cells such as CTLLAK, NK (natural killer) 'cells destroy target cells (cytotoxic activity).
  • cyclosporin A is used as a major preventive measure against such organ transplant rejection and autoimmune ft disease./ / ⁇ ⁇
  • the mechanism of action is to induce (activate) the killer cell group. It does not inhibit the cytotoxic activity of the already induced mature killer cell population, and therefore cannot suppress the progressive rejection and viral hepatitis induced by the killer cell population.
  • cyclosporin A is often used as a prophylactic (organ transplantation agent) rather than as a rejection treatment.
  • the progressive rejection virus Fiber autologous cell is a killer T cell. In the case of fulminant ffF inflammation that is rapidly destroyed by such factors, it is essential to directly suppress the cytotoxic activity of the killer cell group.
  • immunosuppressants Although several immunosuppressants have been found for the purpose of power, they have been found to be suitable for experimental rejection, etc., but none of them have been identified as ⁇ I immunosuppressants.
  • the present inventors have conducted intensive studies on the synthesis and activity of griseoic acid analogs over many years using an in vitro experimental system using LAK and CTL, and as a result, the structure differs from that of known derivatives.
  • New derivatives that have good LAK and The present inventors have found that it can be an excellent immunosuppressant or the like which has an activity inhibitor and has a low toxicity which acts directly on the killer cell group in the effector phase, and completed the present invention.
  • R 1 and R 2 are a group having a “ ⁇ formula-C0-BR 3 ( ⁇ ) (where B is interrupted by a group selected from the following group A) Good, straight or branched chain alkylene having 1 to 25 carbon atoms, straight or branched chain alkylene having 2 to 25 carbon atoms or straight or branched chain alkylene having 2 to 25 carbon atoms
  • R 3 represents a hydrogen atom, a halogen atom, a halogenomethyl group, an optionally protected amino group, an optionally protected hydroxyl group, an optionally protected mercapto group or an aryl group.
  • the other is a hydrogen atom or a group having the above formula (II)], a physiologically hydrolyzed ester or amide thereof, or a pharmaceutically acceptable compound Salt,
  • the novel LA K of the present invention is a hydrogen atom or a group having the above formula (II)], a physiologically hydrolyzed ester or amide thereof, or a pharmaceutically acceptable compound Salt
  • R 1 and R 2 are the same or different and are each a hydrogen atom or a group having an “IS formula —CO—B—R 3 (II) (where B is a group selected from the following group A) Linear or branched alkylene having 1 to 25 carbon atoms, straight or branched chain alkylene diene having 2 to 25 carbon atoms, or linear chain having 2 to 25 carbon atoms Or a branched-chain alkynylene group; R 3 is a hydrogen atom, a halogen atom, an octogenomethyl group, an optionally protected amino group, an optionally protected hydroxyl group, an optionally protected mercapto group Or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.
  • a group having the formula -0C00-, a group having the formula -0C0-, a group having the formula-(, a group having the formula -S-, a group having the formula -SS-, a group having the formula -SCO-, a formula -NHC0 - group having the formula - NHC00- group and the formula has a - R 4 - (wherein, R 4 represents a lower alkyl group.) groups of.
  • a linear or branched 25 alkylene group of the formula 1 means, for example, methylene, methylmethylene, ethylene, propylene, trimethylene, 1-methylethylene, tetramethylene, 1-methyltrimethylene, 2-methyltrimethylene, 3-methyltrimethylene, 1-methylpropylene, 1,1-dimethylethylene, pentamethylene, 1-methyltetramethylene, 2-methyltetramethylene, 3-methyltetramethylene, 4-methyltetramethylene , 1, 1-dimethyltrimethylene, 2,2-dimethyl Tiltrimethylene, 3,3-dimethyltrimethylene, hexamethylene, methylpentamethylene, 2-methylpentamethylene, 3-methylpentamethylene, 4-methylpentamethylene, 5-methylpentamethylene, 1: 1-dimethyltetramethylene, 2,2-dimethyltetramethylene, 3,3-dimethyltetramethylene, 4,4-dimethyltetramethylene, heptamethylene, 1-methylhexamethylene, methyl
  • straight or branched chain alkenylene having 2 to 2 carbon atoms includes 2-propylenylene, 1-methyl-2-propylenylene, 2-methyl-2-prodylene Nylene, 2-ethyl-2-propenylene, 2-butenylene, 1-methyl-2-butenylene, 2-methyl-2-butenylene, 1-ethyl-2-butenylene, 3-butenylene, 1-methyl- 3-butenylene, 2-methyl-3-butenylene, 1-ethyl-3-butenylene, 2-pentenylene, 1-methyl-2-pentenylene, 2-methyl-2-pentenylene, 3-pentenylene Len, 1-methyl-3-pentenylene, 2-methyl-3-pentenylene, 4-pentenylene, 1-methyl-4-pentenylene, 2-methyl-4-pentenylene, 2 -Hexenylene, 3-hexenylene, 4-hexenylene, 5-hexenylene, 9-hexadecen
  • straight or branched chain alkynylene having 2 to 25 carbon atoms includes 2-brovinylene, 1-methyl-2-propynylene, 2-methyl-2-propynylene, 2-ethyl- 2-propynylene, 2-butynylene, 1-methyl-2-butynylene, 2-methyl-2-butynylene, 1-ethyl-2-butynylene, 3-butynylene, 1-methyl-3-butynylene, 2-methyl- 3-butynylene, 1-ethyl-3-butynylene, 2-pentynylene, 1-methyl-2-pentynylene, 2-methyl-2-pentynylene, 3-pentynylene, 1-methyl-3-pentyne Nylene, 2-methyl-3-pentynylene, 4-pentynylene, 1-methyl-4-pentynylene, 2-methyl-4-pentynylene, 2-hexynylene, 3-hexynylene
  • halogen atom can include hydrogen, chlorine, bromine or iodine, and ⁇ ? ⁇ includes zero fluorine; chlorine and ft3 ⁇ 4.
  • ⁇ means chloromethyl, difluoromethyl, trifluoromethyl, kuguchi ⁇ 3 ⁇ 4 «tyl, dichloromethyl, trichloromethyl, bromomethyl, dibutylmethyl, tribromo.
  • Methyl groups substituted with a logen atom such as methyl, oxymethyl, jodmethyl, and trimethyl, can be cited as a methyl group substituted with a fluorine atom, a nitrogen atom or a bromine atom. Is a methyl group substituted by a fluorine atom or an element atom.
  • the term “protected ⁇ amino acid” refers to one or two of the following protecting groups, ttr that protects the amino group, and the protecting group is usually the protection of an amino group. It is preferred, but not limited, to use as a group, for example, formyl, acetyl, propionyl, butyryl 'isobutyryl, pentanoyl, viva mouth, valeryl, isovaleryl, octanoyl, lauroyl, myristoyl, tridecanol, Alkylcarbonyl groups such as palmitolyl and stearoyl; halogenated aliphatic acyl groups such as chloroacetyl, dichloroacetyl, trichloroacetyl, and trifluoroacetyl; lower alkoxy groups such as methoxyacetyl; (E) Unsaturated fatty acids of unsaturated fatty acids such as 2-methyl-2-buten
  • the protecting group of “optionally protected hydroxyl group” in the definition of R 3 includes And a protecting group for forming a prodrug when administered to a living body, for example, the above-mentioned “lipacyl group”, “aromatic acyl group”;
  • a protecting group in a reaction such as the above-mentioned “alkenyloxydicarboxy group”; a protecting group in a reaction such as an “aralkyloxycarbonyl group”;
  • Protecting groups which are easily hydrolyzed in vivo for the purpose of carboxylation are more preferable, and are more preferably an aliphatic acyl group and an aromatic acyl group, and most preferably have 23 ⁇ 43 ⁇ 4 ⁇ carbon atoms;
  • the protecting group of the “optionally protected mercapto group” in the definition of R 3 is not particularly limited as long as it is generally used for protecting mercapto.
  • acyl group examples of the above-mentioned “aromatic silyl group J” and the above-mentioned “aralkyl group J”; more preferred are an aliphatic flaxyl group and 0 ⁇ aromatic acyl group; most preferred An alkyl carbonyl group having 2 to 6 carbon atoms and an arylcarbonyl group having 7 to 15 carbon atoms.
  • aryl in the definition of R 3 includes, for example, an aromatic hydrocarbon group having 6 to 14 carbon atoms such as phenyl and naphthyl, and is a phenyl group. The group may have 1 to 4 substituents on the ring of the aryl group.
  • Examples of such a substituent include an aryl group; an amino group; a nitro group; a cyano group; A carboxylic acid residue which may be substituted with a “lower alkyl group” or the above-mentioned aralkyl group to form an ester; a carpamoyl group; methylcarbamoyl, ethylcarbamoyl, ⁇ -propyl-lubamoyl, isopropyl-lubamoyl, -Butylcarbamoyl, isobutylcarbamoyl, s-butylcarbamoyl, t-butylcarbamoyl, n-pentylcarbamoyl, isopentylcarbamoyl, 2-methylbutylcarbamoyl, neopentylcarbamoyl, n-hexylcarbamoyl, 4-methylpentylcarbam
  • the depressions are a phenyl group, a ⁇ alkyl group-substituted phenyl group and a halogen atom-substituted phenyl group, more preferably a phenyl group, a methylphenyl group and a bromphenyl group, most preferably.
  • phenyl 4-methylphenyl JUS and 2-bromophenyl.
  • the “lower alkyl group” in the definition of IT includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl , 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylbentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1 Straight-chain or branched-chain alkyl groups having 1 to 6 carbon atoms, such as, 3-dimethylbutyl, 2, 3-dimethylbutyl, and 2-ethylbutyl; A chain or branched alkyl group.
  • the compound (I) of the present invention can be converted into a salt when the carboxylic acid group is free ⁇ , and such a salt is preferably a sodium salt, a potassium salt, a magnesium salt or a calcium salt.
  • Salts of alkali metals or alkaline earth metals such as; salts of organic bases such as methylamine, ethylamine, morpholine, piperidine; hydrofluoride, hydrochloride, hydrobromide, iodide
  • Inorganic acid salts such as hydrohalides, nitrates, perchlorates, sulfates, and phosphates such as citrate; methanesulfonate, trifluoromethanesulfonate, and ethanesulfonate Lower alkyl sulfonate, benzene sulfonate, aryl sulfonate such as P-toluene sulfonate, fumarate, succinate, citrate, tartrate
  • the compound (I) of the present invention has an asymmetric carbon in the liver, and there are stereoisomers each having S-coordination and R-coordination. Included in the invention.
  • examples of the compound include:
  • (3) is a group having the formula ( ⁇ ), and R 2 is a hydrogen atom or a group having the formula (II).
  • R 3 is a hydrogen atom, a halogen atom, a halogenomethyl group, an amino group, a hydroxyl group, a mercapto group or an aryl group.
  • R 3 is a hydrogen atom, a halogen atom, an amino group, a hydroxyl group or an aryl group
  • (7) B may be interrupted by a group selected from the following group A, a linear or branched alkylene having 1 to 25 carbon atoms or a linear or branched alkylene having 2 to 25 carbon atoms.
  • examples of the following compounds are 2, 3, 5, 7, 9, 101, 12, 13, 14, 15, 16, 17, 24, 26, 28, 29, 324, 38, 43, 45, 46, 47, 48, 51, 53, 56, 59, 604, 65, 66, 67, 72, 74, 75, 77, 80, 84, 85, 86 7, 88, 96, 100, 104, 107 , 1 10, 1 12, 1 15, 16, 1 17, 1 18, 120, 126, 127, 128, 130, 13132, 133, 135, 139, 141, 148, 149, 150, 15152, 153, 154, 158, 160, 162, 163, 165, 166 67, 168, 172, 173, 177, 180, 185, 193, 19495, 198, 199, .200, 206, 207, 209, 210, 21 1 213 and 215 compounds can be mentioned.
  • preferred compounds include 10, 11, 12, 13, 14, 15, 16, 59, 60, 74, 75, 84, 96, 107, 115, 116, 117, 118, 126, 127, 128, 130, 131, 132, 139, 141, 151, 172, 173, 177, 180, 185, 206, 213 and 215 compounds.
  • the most preferred compounds include the compounds of 10, 11, 12, 13, 14, 15, 16, 59, 115, 117, 130, 141, 151, 177 and 215.
  • the glyceolic acid derivative of the present invention can be produced by the method described below.
  • R 1 and R 2 have the same meanings as described above, and R 5 is a lower alkylidene group such as methylidene, ethylidene and isopropylidene; an aralkylidene group such as benzylidene or methoxylethylidene;
  • the protective group for the dihydroxy group of the alkoxyethylidene such as can be modified, and is a lower alkylidene group, more preferably an isopropylidene group.
  • R 6 represents a protecting group for a carboxy group, and examples thereof include a protecting group for a ruboxyl group in a reaction such as the “lower alkyl group”; the “halogeno lower alkyl group”; and the “aralkyl group”.
  • halogeno lower alkyl groups and aralkyl groups and more preferably, 2,2,2 trichloroethyl, 2-bromoethyl and benzhydryl.
  • the 7'-position hydroxyl group and the 9'-position carboxy group of the raw material compound griseol acid (1) were This is a process for producing a compound (2) by protecting a xyl group with a protecting group under the same conditions as that of a solvent except for ⁇ in a solvent according to a conventional method.
  • a dehydrating agent such as copper sulfate, sodium sulfate, calcium carbonate, or molecular sieve, or to remove water using azeotropic distillation.
  • r is a lower alkylcarbonyl compound such as formaldehyde, acetate aldehyde or acetone; an arylcarbonyl compound such as benzaldehyde or a trimethyl orthoformate or triethyl orthoformate;
  • a lower alkyl orthoformate can be obtained, preferably a lower alkylcarbonyl compound, and more preferably acetone.
  • the solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • the solvent include aromatic hydrocarbons such as benzene, toluene and xylene; methylene chloride Halogenated hydrocarbons such as ethyl form; esters such as ethyl acetate; ethers such as ether, tetrahydrofuran, dioxane, dimethoxyethane; methanol, ethanol, n-propanol, isopropanol, ⁇ Alcohols such as butanol, isobutanol and isoamyl alcohol; amides such as dimethylformamide, dimethylacetamide and hexamethylphosphorotriamide; sulfoxides such as dimethylsulfoxide; ketones such as acetone.
  • the acid catalyst to be used is not particularly limited as long as it is usually used as an acid catalyst in the reaction.
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid or the like is used.
  • Blenstead acids such as organic acids such as paratoluenesulfonic acid, trifluoroacetic acid, and trifluoromethanesulfonic acid; or zinc chloride, tin tetrachloride, polon tricyclide, polontriff, and polontripromide.
  • Lewis acids can be mentioned, preferably Bronsted acids, more preferably organic acids, and most preferably strong organic acids.
  • the reaction temperature is from ⁇ if to loo, preferably from ⁇ to room temperature, and the reaction time varies depending mainly on the reaction temperature, the starting compound or the solvent used, and the type of acid catalyst. Usually 10 minutes to 3 days.
  • the target compound (2) of this reaction can be collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to the reaction mixture, washing with water and distilling off the solvent.
  • the obtained target compound can be further purified by a conventional method, for example, recrystallization, recrystallization or chromatography, etc., but includes: alkali metal charcoals such as sodium carbonate and calcium carbonate; sodium hydrogencarbonate, hydrogencarbonate Alkali metal carbonate such as lithium hydride; lithium hydride, sodium hydride, aluminum hydride such as hydrogen hydride; sodium hydroxide, calcium hydroxide, barium hydroxide Neutralization with a base insoluble in organic solvents such as alkali metal hydroxides, and filtration of the unpromoted compounds, followed by distilling off the solvent. Attached to
  • the second step is a step of esterifying the carboxy group at the 8′-position of the compound (2) according to a conventional method to produce the compound (3).
  • the reaction is preferably carried out in a ketone solvent such as acetone, preferably at -10 to 100 ° C., for 2 to 17 hours. Will be implemented.
  • the product can be isolated or used without isolation in the second step, but without isolation, this step is carried out following the first step, Good results can be obtained by using the solvent used in the step as it is.
  • the 2′-hydroxyl group of the compound (3) is replaced with “ ⁇ a compound having the formula R 3 -B-C0-X
  • R 3 and B have the same meanings as described above, and X is, for example, the aforementioned “halogen atom”; a lower alkanesulfonyloxy group such as methanesulfonyloxy and ethanesulfonyloxy; trifluoromethanesulfonyloxy) And a leaving group such as a halogeno lower alkane sulfonyloxy group such as pentafluorofluorosulfonyloxy; an arylsulfonyloxy group such as benzene sulfonyloxy and P-toluenesulfonyloxy.
  • R 3 - B- compounds with C0-0-C0-BR 3 wherein In 2: 7, R 3 and B represent the same fiber as above; or react with
  • a condensing agent preferably, carboxymethyl imide dicyclohexyl (DCC), ⁇ , ⁇ '-Carbo diimidazole (CDI), diphenyl holidine
  • the solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent.
  • it is preferably a halogenated hydrocarbon such as dichloromethane or dichloroethane or benzene.
  • aromatic hydrocarbons such as toluene.
  • the reaction temperature is not particularly limited from ⁇ 10 to 100 ° C., but the reaction is preferably carried out at room temperature, and the reaction time is different depending on the reaction temperature or the like.For example, when the reaction is carried out in a room, it is 1 hour. ⁇ 17 hours.
  • the step of removing ⁇ S of the 7'-hydroxyl group and the 9'-hydroxyl group is carried out in the presence or absence of a solvent in the presence of an acid catalyst.
  • the solvent used is not particularly limited as long as it does not detract from the reaction and dissolves the starting material to some extent.
  • aromatic hydrocarbons such as benzene, toluene, and xylene
  • Halogenated carbons such as methylene chloride and black form
  • d such as ethyl acetate and propyl acetate :
  • Alcohols; ethers such as ether, tetrahydrofuran, dioxane, dimethyloxetane !; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, isomayl alcohol
  • Amides such as dimethylboramide, dimethylacetamide, hexamethylphospho fttriamide; Examples include sulfoxides such as rufoxide and ketones such as acetone.
  • the acid catalyst to be used is not particularly limited as long as it is used as an acid catalyst in a usual reaction, but is preferably an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, or perchloric acid, or paraacid.
  • An aqueous solution of Brnsted acid such as an organic acid such as toluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, or citric acid, can be cited as an aqueous solution of Br ⁇ nsted acid.
  • An aqueous solution of an acid most preferably an aqueous solution of trifluoroacetic acid.
  • the reaction temperature is carried out at -10 to 100 hands, preferably, 0 e Ri c to room temperature der, the reaction time varies mainly on the reaction temperature, solvent raw material compound or using, by the type of acid catalyst Force Usually 10 minutes to 1 day.
  • reaction temperature is not particularly limited, but is preferably the boiling point of the solvent used, and the reaction time is, for example, 1 to 20 hours when methanol is used as the solvent.
  • the removal of the protecting group for the carboxy group at the 8'-position varies depending on the type, but is generally carried out as follows by a method well known in the art.
  • an alkyl group or aryl group When an alkyl group or aryl group is used as a protecting group for a carboxy group, it can be removed by treating with an acid or a base.
  • Acids that can be used include hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid.
  • the base that can be used as long as it does not affect the other parts of the compound. Is carried out using alkali metal carbonates such as sodium carbonate and potassium carbonate, sodium hydroxide, alkaline metal hydroxides such as hydroxylated realm or concentrated ammonia methanol !. It should be noted that hydrolysis with a base has the power to cause isomerization.
  • Solvents used are those used in normal hydrolysis reactions There is no particular limitation as long as it is mixed with water or an organic solvent such as alcohols such as methanol, ethanol and n-propanol, or ethers such as furan and dioxane. it.? is not particularly limited depends on the reaction ⁇ g and the reaction time Departure material and base used and the like, in order was suppress side reactions, suitably at 0 to 150, rows 1 to 10 hours Will be
  • the protecting group for the carboxy group is a dial-substituted methyl group such as benzhydryl
  • it is usually removed with ⁇ tt ⁇ ftT.
  • ffil is preferably an aromatic hydrocarbon such as anisol, and the most commonly used is a sulfur or sulphated organic acid such as trifluoroacetic acid.
  • the reaction temperature is not particularly limited from ⁇ 10 to 100 ° C., but is preferably room temperature, and the reaction time for 5 hours is 30 minutes to 17 hours.
  • the protecting group for the carboxy group is an aralkyl group or a halogeno lower alkyl group
  • the protecting group can usually be obtained by contacting with a reducing agent.
  • the carboxy group is a halogeno-igit alkyl group
  • the reducing agent used is zinc monoacetic acid.
  • a catalyst such as palladium carbon or platinum is used.
  • the catalytic reduction is performed by using an alkaline metal sulfide such as potassium sulfate or sodium sulfide.
  • the reaction is carried out in the presence of a solvent, and the solvent used is not particularly limited as long as it does not participate in the process.
  • Alcohols such as methanol and ethanol; tetra, hydrofuran, and dioxane
  • a mixed solvent of these organic solvents and water is preferred.
  • the reaction temperature and reaction time vary depending on the starting material, the reducing agent used, and the like, but are preferably around 0 ° C. and 5 minutes to 12 hours.
  • the protecting group for the carboxy group is an alkylmethyl group, it can be usually removed by treating with an acid. Examples of the acid used include hydrochloric acid, acetic acid, sulfuric acid and P-toluenesulfonic acid.
  • the reaction is carried out in the presence of a solvent, and the solvent used is not particularly limited as long as it does not participate in the reaction, but alcohols such as methanol and ethanol; and alcohols such as tetrahydrofuran and dioxane Preferred are ethers or a mixed solvent of these organic solvents and water.
  • the reaction temperature and the reaction time vary depending on the starting material and the kind of the acid to be used, etc., but for SK, it is 0 to 5 ( ⁇ , 10 minutes to 18 hours)
  • amidation can be carried out by ammonia treatment according to a conventional method to remove a protecting group for a carboxy group.
  • the above-described carboxylation ⁇ ! Is dissolved in a mixed solvent of water and an organic solvent immiscible with water, such as ethyl acetate, and an aqueous solution of an alkali metal carbonate or bicarbonate such as an aqueous sodium hydrogen carbonate solution or an aqueous carbonated water solution. Is added to the solution at the temperature of (TC-M) to adjust the pH to around 7, and the deposited precipitate is collected by filtration to form an alkyl metal salt.
  • the salt or the carboxylic acid compound produced in this manner is converted into an ether such as tetrahydrofuran or N, N-dimethylfosolemamide, dimethylsulfoxide, hexamethylphosphorotriamide, triethylphosphene.
  • a polar solvent such as ethanol
  • organic bases such as triethylamine and dicyclohexylamine
  • metal hydrides such as sodium hydride or sodium bicarbonate
  • sodium carbonate and salts formed by the reaction of alkali metal carbon or bicarbonate, such as potassium carbonate, with aliphatic acyloxy, such as acetomethyl chloride and propionyloxymethyl bromide.
  • Methyl halides 1-methoxycarbonyloxylethyl chloride, 1-ethoxycarboxyloxoche 1-lower alkoxycarbonyloxyshetyl halides such as tyl iodide; phthalidyl halides, (2-oxo-5-methyl-1,3-dioxolen-4-yl) methyl halides and 4-acetoxy
  • benzyl halides an ester form protected with a carboxy-protecting group which is easily hydrolyzed in vivo can be produced.
  • the reaction solvent is not particularly limited as long as it does not inhibit the reaction, but is preferably a polar solvent such as ⁇ , ⁇ -dimethylformamide, dimethyl sulfoxide, hexamethyl phosphorotriamide, or triethyl phosphite.
  • the reaction temperature and the reaction time are different depending on the type of the starting material, the reaction solvent and the reaction reagent.
  • the reaction is preferably performed at 0 to 100 ° C. for 0.5 to 10 hours.
  • the protecting group for the 8'-position carboxy group and the protecting group for the 7'-position hydroxyl group and the 9'-position there is no particular limitation on the reagent used in the case where the protecting group is used to remove both protecting groups.
  • the protecting group at the 8′-carboxy group is a benzhydryl group.
  • the protecting groups for the 7'-hydroxyl group and the 9'-ruboxy group are alkylidene groups such as isopropylidene, this can be achieved by leaving the compound in water-containing trifluoroacetic acid.
  • the reaction temperature is not particularly limited, but is preferably room temperature and the reaction time is 2 to 30 hours.
  • the desired step, removal of the protecting group is carried out as in example tfJiTF.
  • a silyl group When a silyl group is used as a protecting group for an amino group or Z and a hydroxyl group, it is usually removed by treating with a compound that generates a fluorine anion such as tetrabutylammonium fluoride.
  • the reaction solvent is not particularly limited as long as it does not inhibit the reaction, but ethers such as tetrahydrofuran and dioxane are preferable.
  • the reaction temperature and reaction time are not particularly limited, but the reaction is preferably performed at room temperature for 10 to 18 hours.
  • the battle used is not particularly limited as long as it is usually used as an acid, but preferably, hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid is used, and the base used is There is no particular limitation as long as it does not affect the other parts of the arsenic compound, but preferably, alkali metal carbonates such as sodium carbonate and potassium carbonate, sodium hydroxide: such as potassium hydroxide This is performed using an alkali metal hydroxide or concentrated ammonia-methanol.
  • the solvent to be used is not particularly limited as long as it is used in a usual hydrolysis reaction, and is preferably water or water and alcohols such as methanol, ethanol and n-propanol, or tetrahydrofuran or dioxane.
  • a mixed solvent with an organic solvent such as ethers is used.
  • the reaction temperature and the reaction time are different depending on the starting material, the base used and the like, and are not particularly limited. However, in order to suppress a side reaction, the reaction is preferably performed at 0 to 150 ° C and 1 to 10 hours.
  • the protecting group is a trichloroethyl group
  • the protecting group for amino group, hydroxyl group or Z and mercapto group is aralkyl group or aralkyloxycarbonyl group
  • catalytic reduction at room temperature is carried out using a catalyst such as platinum or palladium carbon.
  • the method is to remove by using an oxidizing agent.
  • the solvent used in the removal by catalytic reduction is not particularly limited as long as it does not participate in the reaction, but alcohols such as methanol, ethanol, and isopropanol, dimethyl ether, tetrahydrofuran, Ethers such as dioxane, aromatic hydrocarbons such as toluene, benzene and xylene, lipophilic hydrocarbons such as hexane and cyclohexane, esters such as ethyl acetate and propyl acetate, and acetic acid Or a mixed solvent of these organic solvents and water.
  • the catalyst to be used is not particularly limited as long as it is usually used in a catalytic reduction reaction.
  • Preferable is palladium carbon, Raney nickel, platinum oxide, platinum black, rhodium aluminum monoxide, triphenyl. Phosphine rhodium monochloride and palladium monosulfate barrier are used.
  • the pressure is not particularly limited, but is preferably 1 to 10 atm.
  • the reaction temperature and the reaction time vary depending on the starting material and the type of the catalyst. The reaction is performed at 0 to 100 for 5 minutes to 24 hours.
  • the solvent used in the removal by oxidation is not particularly limited as long as it does not participate in the present reaction. Examples of the solvent include a water-containing organic solvent. Examples of such an organic solvent include ketones such as acetone.
  • Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, nitriles such as acetate ditriol, ethers such as getyl ether, tetrahydrofuran, and dioxane Amides, such as dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide, and sulfoxides, such as dimethylsulfoxide.
  • the oxidizing agent to be used is not particularly limited as long as it is a compound usually used for oxidation, but is preferably, for example, potassium persulfate, sodium persulfate or ammonium cerium nitrate (CAN).
  • nitriles such as acetonitrile, methylene chloride, and methyl chloride
  • Halogen hydrogen such as form or a mixed solvent thereof is used.
  • the reaction temperature is different depending on the starting material and the like. ⁇ It is preferably 0 to 50.
  • the removal reaction is usually carried out in the same manner as in the case of the removal reaction when the protecting group is an aliphatic group or an aromatic acyl group. It can be eliminated by treating with a base.
  • ⁇ Lil O alkoxycarbonyl in particular, a convenient way force be removed using palladium and triphenyl phosphinite down or nickel tetracarbonyl, it can be carried out side reactions power s less.
  • the acid is usually dissolved in a solvent with an acid. It can be removed by treatment.
  • the acid used is preferably hydrochloric acid, acetic acid, sulfuric acid, P-toluenesulfonic acid or the like, but a strongly acidic cation exchange resin such as Dowex 50W can also be used.
  • the solvent used is not particularly limited as long as it does not participate in the reaction.
  • the solvent examples include alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane; or a mixed solvent of these organic solvents and water. It is suitable.
  • the reaction temperature and the reaction time vary depending on the starting material, the kind of the acid used, and the like, but are preferably 0 to 5 (in 10 minutes to 18 hours in ⁇ ).
  • the removal of the protecting group of the amino group, the removal of the protecting group of the hydroxyl group, and the removal of the protecting group of the mercapto group can be performed in any order, and the desired removal reaction can be performed in any order.
  • the target compound of each of the above steps is collected from the reaction mixture according to a conventional method.
  • it can be obtained by adding an organic solvent immiscible with water to the reaction mixture, washing with water, and distilling off the solvent.
  • the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.
  • Griseoic acid which is a raw material compound of the present invention, is a known compound, for example, Japanese Patent Publication No. 56-68695, Japanese Patent Application Laid-Open No. 60-94992, Japanese Patent Application Laid-Open No. 60-149394, It can be produced by the methods described in Japanese Unexamined Patent Publication Nos. 60-246396 and 61-100593.
  • a compound having the general formula R3-B-C0-X (wherein R 3 , X and B have the same meanings as described above) or the formula R 3 -B-C0, which is the esterification reagent of the present invention.
  • URN compounds have a -0-C0-BR 3, R 3 and B are as defined above.
  • R 3 and B are as defined above.
  • human lymphocytes are obtained by culturing them under ⁇ E of interleukin 2 (IL-2). the resulting LAK as the effector, using 51 Cr-labeled K562 cells as targets Bok.
  • IL-2 interleukin 2
  • LAK to various Gurizeoru acid derivatives concentration-dependent manner was added, after 24 hours at 37 ° C, 51 Cr-labeled K562 cells was added, it was further reacted for 4 hours at 37 ° C.
  • the cytotoxic activity of LAK was calculated according to the following equation by measuring the amount of 51 CrS released into the supernatant using a counter.
  • Cytotoxic activity (A-B) / (C-B) 100
  • Cyclosbolin A> 10 As described above, the cytotoxic activity of LAK was also strongly inhibited by chemical imaging (IC S0 0.002 / ml), followed by the compound 13, 12, 6, 9, 15, and 8 Inhibited in order. The lignin compounds 1, 4 and griseoic acid also showed sufficiently strong inhibitory effects.
  • cyclosporin A was capable of inhibiting cytotoxic activity by 503 ⁇ 4 even at a concentration of 10 wg / ml.
  • griseoic acid derivatives did not show a cytotoxic effect on LAK and had no effect on the sensitivity of the target to LAK.
  • the compounds of the present invention significantly inhibited the cytotoxic activity of CTL in the concentration range of 0.01 to 10 itg / ml.
  • inactivated Daudi cells are used as stimulator cells, and human peripheral lymphocytes are reacted.
  • the cells were cultured at 37 ° C for 7 days in the presence of various test samples to induce CTLs specific to Daudi cells.
  • Daudi cells (target) labeled with 51 Cr were added to the washed CTL (Effecta) after removing the sample, and reacted for 4 hours.
  • the reaction as in Test Example 1, the cytotoxic activity was measured from 51 Cr »released into the supernatant, and the amount of CTLs induced was examined.
  • the cytotoxic activity (induction activity) of CTL induced without addition of the sample was defined as 100%, and the concentration (IC 5 ) of the sample that inhibited the inducing activity by 50% was determined.
  • the results are shown in Table 4.
  • Griseoic acid 1.6 As described above, Compounds 3, 9 and griseoic acid significantly inhibited CTL induction at concentrations of 1 ixg / ml or more. The strength of the inhibition is compound 9> 3 ⁇ griseo The order of oleic acid.
  • IL-2 Glyzeol ⁇ conductor interleukin 2 (IL-2) induced lymphocyte blastogenesis
  • the potency of inhibition was in the order of compound 3> cyclosbolin A.
  • mice 5-week-old ddy male mice, 5 mice a group, 0. 53 ⁇ 4 carboxymethyl 0 for each dose was suspended in methyl cellulose solution 2 '- palmitoyl glyceride Rize ol acid (compound of Example 3) was administered once intraperitoneally The number of deaths up to 7 days after administration was counted. The results are shown in Table 6.
  • Symptoms of death include respiratory depression, gait ataxia, and stomach crawling. [Table 6]. Dose (mg / kg) Number of animals
  • the griseoic acid analog which is the active ingredient of the present invention has excellent 1 ⁇ 1 ⁇ or (: 1: 1 activity inhibitory activity and low activity). When used in combination, it has the following advantages.
  • Examples of the dosage form of the compound (I) of the present invention or a textile include oral administration or eye drops such as »Ij, capsule, microcapsule, granule, intestinal tablet, powder or syrup, and the like.
  • Injectable preparations include parenteral administration using suppositories and the like. These preparations use additives such as excipients, binders, disintegrating lubricants, stabilizers, and flavoring agents. It is made by a well-known method ⁇ .
  • the dose varies depending on symptoms, body weight, age, etc., but usually 0.001-100 rag / kg body weight per day is 0.010 mg / kg body weight per day for adults, once or daily for adults. It can be administered in several divided doses. [Best Mode for Carrying Out the Invention]
  • the compound was suspended in 40 ml of a mixture of methanol and water (7: 3) and heated under reflux for 5 hours. After returning to room temperature and left at 5 for 2 hours, the precipitate was collected by filtration and dried using phosphorus pentoxide. This was added to a mixture of 2 ml of trifluoroacetic acid and 2 ml of anisol, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off, a saturated aqueous sodium hydrogen carbonate solution was added to dissolve the residue, and the mixture was washed with ethyl acetate. The pH was adjusted to 2.0 with concentrated hydrochloric acid under ice-cooling, and the reaction was continued for 2 hours. The precipitate was centrifuged and the supernatant was separated and washed twice with water. The precipitate was suspended in water and freeze-dried to obtain the target compound 200.
  • Example 1 0 8 '- benzhydryl - 0 7', 0 9 '- iso blow pyridinium Dengue Rize O - Le ester (compound of Reference Example) 585 mg, n-Kaburiru acid 288 mg, DCC454 rag, 4- pylori using Jinopirijin 15 mg, pyridine 20 ml, 0 8 '- benzhydryl - 0 7 ,, 0 3' - Isoburopiriden -0 2 '- O Kuta noisy Legris peptidase Saiichi Le acid: to obtain a t ester 395 mg.
  • the aqueous layer was washed twice with 50 ml of ethyl acetate, transferred to a beaker and adjusted to pH 2 with concentrated hydrochloric acid while cooling with ice, and an insoluble white precipitate was formed. Allow to stand, filter out the precipitate, wash twice with 100 ml of water, dry in the presence of phosphorus pentoxide at room temperature overnight and 60 ° C for 7 hours to obtain the target compound as a white powdery substance 6.33 g (84%).
  • Example 3 1 g of the white powder was treated in the same manner as in Example 3 to obtain 403 mg of the target compound as a white powder.
  • This compound was dissolved in acetone, 50 ml of a 1 mol aqueous solution of sodium phosphate sodium and 5 g of zinc dust were added with stirring, and the solvent was distilled off for 17 hours and 30 minutes. The residue was dissolved in ethyl acetate and aqueous sodium hydrogen carbonate, and the zinc dust was filtered off. After liquid separation, the ethyl acetate layer was dried over anhydrous magnesium sulfate and filtered, and the solvent was distilled off. The residue was dissolved in 5% methanol-methylene chloride, subjected to silica gel chromatography, and eluted with the same solution.
  • the aqueous solution was adjusted to pH 2.0 with concentrated hydrochloric acid under water cooling, the precipitate was centrifuged, the supernatant was separated, and the precipitate was washed twice with water. The mixture was turbidized and freeze-dried to obtain 285 mg of the desired compound.
  • This compound 367 was suspended in 15 ml of a mixture of methanol and water (7: 3), and the mixture was refluxed for 12 hours. After returning to room temperature, the precipitate was collected and subjected to EESi using phosphorus pentoxide. 5 ral of anisol and 5 ml of trifluoroacetic acid were added to the resulting precipitate (300 mg), and the mixture was allowed to stand at room temperature for 2 hours and a half. The solvent was distilled off, a 5% aqueous sodium hydrogen carbonate solution was added for dissolution, and the mixture was washed with ethyl acetate.
  • the pH was adjusted to 2.0 with concentrated hydrochloric acid under ice-cooling, and the mixture was allowed to stand in a refrigerator for 2 hours to precipitate the precipitate by centrifugation. The supernatant was separated and washed twice with water. The precipitate was suspended in water and freeze-dried to obtain 170 mg of the desired product.
  • the solvent was distilled off under reduced pressure, the residue was dissolved in methylene chloride (50 ml), washed successively with 0.1 N hydrochloric acid (50 ml), saturated saline (50 ml) and sodium hydrogencarbonate (50 ml), and dried over magnesium sulfate. The solvent was distilled off under reduced pressure.
  • Example 1 the compound 1.17 g of Reference Example, pi-decanoate 689 mg, DCC 908 rag, 4 - with pyrrolidinopyridine 30'mg and pyridine 40 ml, 0 8 '- benzhydryl -
  • Embodiment according to Example 1 using the compound of Reference Example 1.17 g, .pi. dodecanoic acid 801 mg, DCC 908 mg, a 40 ml 4-pyrrolidinopyridine 30 mg and pyridine, 0 beta '- benzhydryl -0 7, .0 9 '- isopropylidene - 0 2' - to give dodecamethylene noisy Legris peptidase ol ester 0.84 g.
  • Example 1 the compound of Reference Example '1. ⁇ g, n- tetradecanoate 913 mg, using DCC 906 mg, 4-pyrrolidinopyridine 29.6 mg beauty pyridine 30 ml, Omicron beta' - Bentsuhi Drill - 0 7 ', 0 9' - isopropylidene -0 2 '- to give the tetradecanoyl noisy Legris peptidase ol acid ester ether 1.51 g.
  • the Example 1 ⁇ same way, 0 2 '- to give the tetradecanoyl noisy Legris peptidase ol acid 940 mg. ,
  • Example 1 the compound 1.17 g of Reference Example, .pi. down evening with decanoic acid 969 mg, DCC 906 mg, 4-pyrrolidine Ginobili Jin 29.6 mg 3 ⁇ 4 beauty pyrid 3 ⁇ 4D ml, 0 8 '- Bentsuhi Drill - 0 7 ', 0 9' - isopropylidene pen evening give the Kano I Legris peptidase ol acid ester ether I. 29 g.
  • 0 2 '- was obtained mg shed pentadecapeptide noisy Legris peptidase all acid 65.
  • Example 1 the compound 1.75 g of Reference Example, n- heptane evening with decanoic acid 1.62 g, DCC 1.36 g, a 30 ml 4-pyrrolidinopyridine 44 ra and pyridine, 0 8 '- Benz hydryl - 0 7' , 0 9 '- isopropylidene -0 2' - heptene evening was obtained deca noisy Legris peptidase ol Sane ester 2.35 g. Using this compound 500 mg, in the same manner as in Example 1, 0 2 '- heptene evening was obtained deca noisy Legris peptidase ol acid 300 mg.
  • Example 1 using compound 1-75 g of Reference Example, .pi. Okutadekan acid 1.7 g, DCC 1.36 g, a 45 ml 4-pyrrolidinopyridine 44 rag and pyridine, 0 8 '- Bentsuhido Lil - 0 7' , 0 9 '- isopropylidene - 0 2' - to give the O Kuta dec noisy Legris peptidase ol acid ester le 2.02 g.
  • 0 2 '- O was obtained Kuta dec noisy Legris peptidase ol acid 120 mg.
  • Tablets of the above formulation were coated with cellulose dihydrofluorate to give enteric tablets according to a conventional method.
  • 0 2 '- prepared palmitoyl glyceride Rize ol acid 100 mg to pH 7, construed soluble in saline 20ml, and filtered sterilized according to a conventional method, then aseptically enclosed in 20ml ampoules and an injection .

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Abstract

Sont décrits des composés représentés par la formule générale (I), ainsi que des compositions les contenant. Dans cette formule, un élément parmi R1 et R2 représente -CO-B-R3 (où B représente alkylène C¿1? à C25, alkénylène C1 à C25 ou alkynylène C1 à C25 qui peuvent comporter un groupe d'intervention choisi parmi -OCOO-, -OCO-, -O-, -S-, -SS-, -SCO-, -NHCO-, -NHCOO- et -NR?4 où R4¿ représente alkyle inférieur; et R3 représente hydrogène, halogène, halogénométhyle, éventuellement amino protégé, éventuellement hydroxyle protégé, éventuellement mercapto protégé, ou aryle) et l'autre représente hydrogène ou bien -CO-B-R3 (où B et R3 ont la notation précitée). Ces composés et les compositions les renfermant sont faiblement toxiques et possèdent une excellente action pour inhiber l'activité LAK ou CTL.
PCT/JP1991/000072 1990-01-26 1991-01-24 Analogue de l'acide griseolique et inhibiteur de lak le contenant WO1991011451A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006008556A1 (fr) * 2004-07-22 2006-01-26 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa Derives imidazole et thiazole utilises comme agents antiviraux

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0319316A2 (fr) * 1987-12-02 1989-06-07 Sankyo Company Limited Monoesters de l'acide griséolique, leur préparation et application
JPH01146895A (ja) * 1987-12-02 1989-06-08 Sankyo Co Ltd グリゼオール酸ジエステル誘導体

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0319316A2 (fr) * 1987-12-02 1989-06-07 Sankyo Company Limited Monoesters de l'acide griséolique, leur préparation et application
JPH01146895A (ja) * 1987-12-02 1989-06-08 Sankyo Co Ltd グリゼオール酸ジエステル誘導体

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL & PHARMACEUTICAL BULLETIN, Vol. 36, No. 4, pages 1309-29 (1988); & CHEMICAL ABSTRACTS, Vol. 109, No. 13, page 292, 106906J. *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006008556A1 (fr) * 2004-07-22 2006-01-26 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa Derives imidazole et thiazole utilises comme agents antiviraux

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