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WO1999012914A1 - Derives de thiouree - Google Patents

Derives de thiouree Download PDF

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Publication number
WO1999012914A1
WO1999012914A1 PCT/JP1998/004074 JP9804074W WO9912914A1 WO 1999012914 A1 WO1999012914 A1 WO 1999012914A1 JP 9804074 W JP9804074 W JP 9804074W WO 9912914 A1 WO9912914 A1 WO 9912914A1
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WO
WIPO (PCT)
Prior art keywords
group
phenyl
methylthiourea
optionally substituted
substituted
Prior art date
Application number
PCT/JP1998/004074
Other languages
English (en)
Japanese (ja)
Inventor
Toshihiko Yoshida
Ryukou Tokuyama
Yayoi Tomita
Original Assignee
Hokuriku Seiyaku Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hokuriku Seiyaku Co., Ltd. filed Critical Hokuriku Seiyaku Co., Ltd.
Priority to AU90015/98A priority Critical patent/AU9001598A/en
Publication of WO1999012914A1 publication Critical patent/WO1999012914A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a novel thiourea derivative or a salt thereof useful as an antibacterial agent.
  • An object of the present invention is to provide a compound having excellent antibacterial activity against clinical isolates including not only standard bacteria but also multidrug-resistant bacteria.
  • the present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, a novel thiourea derivative represented by the following general formula or a salt thereof has been obtained from clinical isolates including not only standard bacteria but also other drug-resistant bacteria. The present inventors have also found that they have an excellent antibacterial activity against, and completed the present invention.
  • R 1 , R 2 and R 3 each independently represent a hydrogen atom, an alkyl group, a cycloalkyl group, a protecting group for a nitrogen atom, an alkoxycarbonylalkyl group, an optionally substituted amino group, Represents an optionally substituted aryl group or an optionally substituted benzyl group; R represents an optionally substituted phenyl group) or a thiourea derivative or a salt thereof. It is.
  • R 1 , R 2 and R 3 are each independently a hydrogen atom, an alkyl group, a cycloalkyl group, a protecting group for a nitrogen atom, an alkoxycarbonylalkyl group
  • R 4 , R 5 and R 6 each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, or a diamino group, an aryl group which may be substituted or a benzyl group which may be substituted
  • Mercapto group amino group, cyano group, nitro group, carboxyl group, carbamoyl group, alkyl group which may be substituted, alkyl group which may be substituted, alkyl group which may be substituted, alkenyl group which may be substituted Alkynyl group which may be substituted, alkoxy group which may be substituted, alkylthio group which may be substituted, alkylamino group which may be substituted, dialkylamino group which may be substituted,
  • the present invention provides a medicament comprising the above thiourea derivative or a salt thereof as an active ingredient.
  • the medicament provided by the present invention can be suitably used, for example, as an antibacterial agent.
  • the present invention provides a method for treating an infectious disease, comprising using the above thiourea derivative or a salt thereof for the manufacture of the above medicament.
  • a method comprising the step of administering to a mammal, including a human, is provided.
  • the compound of the above formula ( ⁇ ), which is a preferred embodiment of the thiourea derivative of the present invention, will be specifically described.
  • This compound is a thiourea of the present invention represented by the general formula (I)
  • the derivative is characterized by having a specific substituted phenyl group or an unsubstituted phenyl group as a scale.
  • the scope of the present invention is not limited to the compound of the general formula (II), and the compound represented by the general formula (I) (the compound having a substituted or unsubstituted furyl group as R) is Needless to say, both are included in the scope of the present invention.
  • alkyl group represented by R 1 , R 2 , R 3 , R 4 , R 5 and R 6 a linear or branched alkyl group having 1 to 6 carbon atoms, for example, a methyl group, an ethyl group , N-propyl group, isopropynole group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, n-hexyl group, etc.
  • a linear or branched alkyl group having 1 to 6 carbon atoms for example, a methyl group, an ethyl group , N-propyl group, isopropynole group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, neopen
  • cycloalkyl group examples include a cycloalkyl group having 3 to 6 carbon atoms, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.
  • cycloalkyl group is used as a concept including an alkyl group containing a cycloalkyl moiety (for example, a cyclopropylmethyl group).
  • aryl group examples include a phenyl group, a pyridine-12f group, a pyridine-3-yl group, a pyridine-14-yl group, a pyrazine-12-yl group, and a pyrazine-13-yl group.
  • the protecting groups for the nitrogen atoms represented by R 1 , R 2 and R 3 include those which are substantially inert in a system in which the nitrogen atoms should not participate in the reaction, and which have a specific deprotection reaction. Any material that can be easily cleaved under the conditions may be used.
  • a protecting group for example, an alkanoyl group, a halogenoalkanoyl group, an aryl group Examples thereof include a propyl group, an aryloxycarbonyl group, an aralkyloxycarbonyl group, and an alkoxycarbonyl group.
  • examples of the alkanol group include a formyl group, an acetyl group, a propionyl group, a butyryl group, a bivaloyl group and the like.
  • the halogenoalkanoyl group one or more of the same or different halogen atoms can be substituted for the above-mentioned alkynyl group, and the halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine. Any of the atoms may be used.
  • Examples thereof include a fluoroacetyl group, a difluoroacetyl group, a trifluoroacetyl group, a chloroacetyl group, a dichloroacetyl group, and a trichloroacetyl group.
  • Examples of the arylcarbonyl group include a benzoyl group, a 4-phenylbenzoyl group, a 4-methoxybenzoyl group, a 2-nitrobenzoyl group, and a 2- (benzoyloxymethyl) benzoyl group.
  • Examples of the aryloxycarbonyl group include a phenyloxycarbonyl group and a 2,4,6-tri-n-butylphenylenoleoxycarbonyl group. it can.
  • Examples of the aralkyloxycarbonyl group include a benzyloxycarbonyl group, a 4-methoxybenzyloxycarbonyl group, a 4-bromobenzyloxycanolebonyl group, and a 2,4,6-trimethycarbonyl group.
  • Examples of the alkoxycarbonyl group include a methoxycarbonyl group, an ethoxycarbinole group, an n-propoxy group, a carbonyl group, and a tert-butoxycarbonyl group. And the like.
  • alkoxycarbonylalkyl group represented by R ′, R 2 and R 3 examples include, for example, a methoxycarbonylethyl group, an ethoxycarbonylethyl group, an n-propoxycarbonylethyl group, an isopropoxycarbonylethyl group, and an n-propoxycarbonylethyl group.
  • any of a fluorine atom, a chlorine atom, a bromine atom and an iodine atom may be used.
  • the alkenyl group for example, an alkenyl group having 2 to 4 carbon atoms can be used, and more specifically, for example, a vinyl group, a propenyl group, a butenyl group and the like can be mentioned.
  • alkynyl group for example, an alkynyl group having 2 to 4 carbon atoms can be used, and more specifically, an ethynyl group, a propynyl group, a petynyl group and the like can be mentioned.
  • alkoxy group represented by R 4 , R 5 and R 6 include, for example, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group.
  • alkylthio group examples include methylthio group, ethylthio group, n -Propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butynolethio, tert-butynolethio, n-pentynolethio, isopentylthio, neopentylthio, n-hexylthio, etc.
  • alkylamino group or dialkylamino group represented by R 4 , R 5 and R 6 for example, an amino group substituted with a chain or cyclic alkyl group having 1 to 6 carbon atoms can be used. . More specifically, for example, a methylamino group, an ethylamino group, an II-propylamino group, an isopropylamino group, an n-butylamino group, an isobutylamino group, a sec-butylamino group, a tert-butylamino group, an n-pentinoamino group Group, isopentylamino group, neopentylamino group, n-hexylamino group, dimethylamino group, getylamino group, N-ethyl-N-methylamino group, N-methyl-1-N-n-propylamino group, N-isopropylamine Noley N-methylamin
  • alkylaminocarbonyl group or dialkylaminocarbonyl group represented by R 4 , R 5 and R 6 include, for example, aminoaminocarbonyl substituted with a linear or cyclic alkyl group having 1 to 6 carbon atoms.
  • a radical can be used.
  • Examples of the alkanoyl group represented by R 4 , R 5 and R 6 include, for example, acetyl group, propylionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, Examples thereof include a xanoyl group and a heptanyl group.
  • As the halogenoalkanoyl group for example, one obtained by substituting one or more same or different halogen atoms for the above alkanoyl group can be used.
  • As the halogen atom a fluorine atom, a chlorine atom, a bromine atom is used. Either an atom or an iodine atom may be used.
  • Examples thereof include a fluoroacetyl group, a difluoroacetyl group, a trifluoroacetyl group, a chloroacetyl group, a dichloroacetyl group, and a trichloroacetyl group.
  • the alkanesulfonyl group for example, a linear or branched alkyl group-substituted sulfonyl group having 1 to 6 carbon atoms can be used. More specifically, for example, a methanesulfonyl group, an ethanesulfonyl group Ninole group, n-prono.
  • Examples include a snolephoninole group, an isopropanesulfonyl group, and an n-butanesulfonyl group.
  • Examples of aryl groups include benzoyl, 4-phenylbenzoyl, 41-methoxybenzoyl, 2-nitrobenzoinole, 2- (benzoyloxymethyl) benzoyl and the like. be able to.
  • an alkyl group having 1 to 4 carbon atoms substituted with an aryl group can be used, and more specifically, for example, a benzyl group, a phenethyl group, a phenylpropyl group, a phenyl group Examples thereof include a butyl group, a (pyridine-2-yl) methyl group, a (pyridine-13-yl) methyl group, and a (pyridine-14-yl) methyl group.
  • aryloxy group examples include a phenyloxy group, a pyridinyloxy group, a pyrimidinyloxy group, a virazinyloxy group, a furyloxy group, and a chelyloxy group.
  • Examples of the cycloalkyloxy group containing a hetero atom as a ring-constituting atom include, for example, azetiduroxy group, pyrrolidinyloxy group, piperidyloxy group, homopyrazinyloxy group, oxetanyloxy group, and tetrahydroxy group.
  • saturated heterocyclic group examples include an azetidinyl group, a pyrrolidinyl group, an oxazolidinyl group, a thiazolidinyl group, a piperidyl group, a piperazinyl group, an oxetanyl group, a tetrahydrofuranyl group, a tetrahydrovinylil group, a cetanyl group, and a tetrahydrylthiol group.
  • Tetrahydrothiopyranyl group Tetrahydrothiopyranyl group, morpholinyl group, thiomorpholinyl group, 1-hydroxy 4-thiomorpholinyl group, 1,1-dioxido 4-thiomorpholinyl group, homopiperidyl group, homopiperazinyl group, 3-azabicyclo [3.3. 0] otatanyl group and 3,7-diazabicyclo [3. 3. 0] octanol group.
  • Examples of the case where any two groups of R 4 , R 5 and R 6 form a condensed hydrocarbon ring with a benzene ring include, for example, an indane-5-yl group, an 11-indanone-5- ⁇ f, indene-5-yl, indene-6-yl, 1-indanone-1-yl, 2-indanone-5-yl, 1,3-indandione-5 Yl group, naphthalene-1-yl group, 1 (2H) —naphthalenone 6-yl group, 1 (2H) —naphthalenone-17-yl group, 1,2,3,4-tetrahydronaphthalene-6 —Yl group, 1,2,3,4-tetrahydro-1--1-naphthalenone-6-yl group, 1,2,3,4-tetrahydro-1-naphthalenone-17-yl group, 1,2,3 1,4-tetrahydro-2-naphthalenone-1-yl, 1,2,3,4
  • a functional group when a functional group is "may have a substituent", the number and type of the substituent are not particularly limited, and two or more substituents are present. If so, they may be the same or different.
  • substituents include an alkyl group, a cycloalkyl group, a hydroxyl group, a mercapto group, an alkoxy group, an alkylthio group, a halogen atom, an amino group, an alkylamino group, a dialkylamino group, a cyano group, a nitro group, and an alkoxy group.
  • the substituted phenyl group represented by R includes, for example, a 4-methynolephenyl group, a 3-methynolephenyl group, a 2-methynolepheninole group, a 3,4-dimethynolepheninole group, a 3,5 —Dimethinolepheninole group, 4-Ethynolephenine group, 4-n-Propylphenyl group, 4-Isopropinolefeninole group, 4-n-Butylphenyl group, 4-Isobutynolephenine group, 4-n-pentylphene group 4-, 4-isopentynolepheninole, 4-n-hexynolepheninole, 4-cyclopropinolepheninole, 4-cyclopentinolephenine, 4-cyclopentylpheninole, 4 —Cyclohexylphenyl group,
  • the thiourea derivative of the present invention represented by the general formula (I) has one asymmetric carbon in the oxazolidine ring, and further has one or more asymmetric carbons depending on the type of the substituent.
  • the asymmetric carbons present in the compounds of the present invention can each independently have the (S) or (R) configuration, and are optical isomers 2diastereoisomers based on one or more asymmetric carbons.
  • Stereoisomers may exist. Pure forms of the stereoisomers, arbitrary mixtures of the stereoisomers, racemates and the like are all included in the scope of the present invention.
  • the thiourea derivative of the present invention represented by the general formula (I) can be converted into a salt, preferably a pharmacologically acceptable salt, if desired. It can also be converted.
  • a pharmacologically acceptable salt is preferable, and as the acid addition salt, for example, hydrochloride, hydrobromide, nitrate, sulfate, hydroiodide or phosphate Or mineral salts such as acetate, maleate, fumarate, citrate, oxalate, malate, methanesulfonate, p-toluenesulfonate, mandelicate, 10- Camphorsulfonate, tartrate, lactate, 5-oxotetrahydrofuran-12-caproluvate or Organic acid salts such as 2-hydroxydartartrate can be used.
  • alkali addition salts include, for example, an inorganic alkali salt such as a sodium salt, a potassium salt, a calcium salt, a magnesium salt or an ammonium salt, or an ethanolamine salt or N, N-dialkylethanolamine, triethanol.
  • Salts of organic bases such as amine, piperidine, piperazine, morpholine and thiomorpholine salts can be used.
  • the thiourea derivative of the present invention represented by the general formula (I) or a salt thereof can exist as an arbitrary crystal form depending on production conditions, and can also exist as an arbitrary hydrate or solvate. These crystalline forms, hydrates and solvates, and mixtures thereof, which may exist, are also included in the scope of the present invention.
  • Preferred compounds of the present invention represented by the general formula (I) include the following compounds, but the scope of the present invention is not limited to these examples.
  • the compound wherein R 2 is a hydrogen atom has the following general formula (III):
  • the compound can be produced by reacting the resulting isothiosinate derivative with or without a solvent in the presence or absence of a base and, if necessary, deprotecting.
  • the solvent used for the reaction between the compound represented by the general formula (III) and the compound represented by the general formula (IV) may be any solvent as long as the reaction is not inhibited.
  • methanol, ethanol, n- Alcohol solvents such as butanol, sec-butanol, tert-butanol, etc., acetone, acetonitrile, N, N-dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, tetramethylene sulfone, tetramethylene
  • Non-protonic polar solvents such as sulfoxide and hexamethylphosphoric triamide
  • ether solvents such as getyl ether, diisopropyl ether and tetrahydrofuran
  • ester solvents such as methyl acetate and ethyl benzoate
  • benzene Aromatic hydrocarbon solvents such as toluene, pyridine, picoline, Examples include organic
  • the deprotection reaction of this production method can be carried out by various methods depending on the types of the nitrogen-protecting groups R 1 and R 3 .
  • R 1 and R 3 are protecting groups that form an amide structure such as a lower alkanoyl group, a halogeno lower alkanoyl group, or an arylcarbonyl group
  • a hydrolysis reaction using an acid or an alcohol is used. Deprotected and can be manufactured.
  • the amide hydrolysis reaction is a method known per se, and acids such as hydrochloric acid and sulfuric acid can be used for acidic hydrolysis, and alkalis such as sodium hydroxide and potassium hydroxide can be used for alkaline hydrolysis. be able to.
  • the alkali can be used as an aqueous solution, but can also be used as an organic solvent such as methanol, ethanol, n-butanol, sec-butanol, tert-butanol, or a water-containing organic solvent.
  • the reaction is carried out at a temperature ranging from room temperature to the reflux temperature of the solvent.
  • the protecting groups R 1 and R 3 of the nitrogen atom are protecting groups which form a pentane structure such as aryloxycarbonyl group, aralkyloxycarbonyl group and lower alkyloxycarbonyl group
  • Deprotection and production by treatment with an acid such as hydrochloric acid, hydrobromic acid, trifluoroacetic acid or the like without solvent or in a solvent such as acetic acid, ethyl acetate, 1,4-dioxane, water, methanol, ethanol or a mixture thereof can do.
  • the reaction can be carried out in a temperature range from under ice-cooling to 200 ° C.
  • the compound represented by the general formula ( ⁇ ) wherein R 3 is a hydrogen atom has the following general formula (V):
  • R 1 -NH-R 2 (wherein R 1 and R 2 have the same meanings as described above) Can be produced in the absence of a solvent or in a solvent and, if necessary, by a deprotection reaction.
  • the solvent used for the reaction between the compound represented by the general formula (V) and the compound represented by the general formula (VI) may be any solvent as long as the reaction is not inhibited.
  • methanol, ethanol, n Alcohol solvents such as butanol, sec-butanol, tert-butanol, etc., acetone, acetonitrile, N, N-dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, tetramethylene sulfone, tetramethylene
  • Non-protonic polar solvents such as sulfoxide and hexamethylphosphoric triamide
  • ether solvents such as getyl ether, diisopropyl ether, and tetrahydrofuran
  • esterol solvents such as methyl acetate and ethyl acetate
  • Aromatic hydrocarbon solvents such as benzene and toluene
  • organic base solvents such as pyridine
  • the deprotection reaction of the production process depending on the type of the protecting group R 'and R 2 nitrogen atoms, according to the conditions of the deprotection reaction described in the first manufacturing fashion, by treatment with hydrolysis reaction or acid Deprotection can be easily performed.
  • the following method for example, the following method can be mentioned. That is, the general formula the substituents represented by compounds sac Chi 1 to R 6 represented by ([pi), or groups which can be replaced by a group represented by R 4 to R 6 is a protecting group, previously
  • the compound of the present invention can be produced by performing a deprotection reaction according to the first or second production mode described above. Further, in the compound represented by the general formula (II), a substituent represented by R 4 to R S or a group substituted by a group represented by R 4 to R 6 is oxidized or reduced according to a conventional method. By doing so, the compound of the present invention converted to a stable and suitable substituent can also be produced.
  • the oxidation reaction of the present production method includes, for example, using dimethyl sulfoxide and oxalyl chloride in the presence of bases such as triethylamine, potassium carbonate, sodium carbonate, and sodium hydrogencarbonate in the presence of tetrahydrofuran, toluene, N, N-dimethyl Oxidation reaction in a solvent such as norefonolemamide, dichloromethane, 1,2-dichloroethane, and chlorohonolem at a temperature ranging from 178 ° C to the reflux temperature of the solvent, 2,3-dichloro-5,6-dicyano-1, 4 Oxidation reactions using quinones such as benzoquinone in a solvent such as benzene, 1,4-dioxane or toluene in a range from ice-cooling to the reflux temperature of the solvent.
  • bases such as triethylamine, potassium carbonate, sodium carbonate, and sodium hydrogencarbonate in the
  • oxidation reaction is an oxidation reaction using chromic acids such as chromium oxide and pyridinium chromate, and reacting in a solvent in the presence of an acid or a base.
  • Acids used in the reaction include, for example, hydrochloric acid, sulfuric acid, drunk acid and the like, and bases include, for example, pyridine and collidine.
  • bases include, for example, pyridine and collidine.
  • any solvent can be used as long as it does not inhibit the reaction.
  • acetone acetate ditrinole, N, N-dimethylformamide, N-methyl-2-pyrrolidone, dimethylsulfoxide, tetramethylenesulfone, tetramethylenesulfoxide, hexamethylphosphoric triamide, etc.
  • Non-protonic polar solvents ether solvents such as getyl ether, diisopropyl ether, and tetrahydrofuran; ester solvents such as methyl acetate and ethyl acetate; aromatic hydrocarbon solvents such as benzene and toluene; pyridine; Organic base solvents such as picoline, lutidine, collidine, etc .; halogenated hydrocarbon solvents such as dichloromethane, 1,2-dichloroethane, chloroform; and mixed solvents thereof.
  • the reaction is carried out in the range from the temperature under ice cooling to the reflux temperature of the solvent.
  • Examples of the reduction reaction include a reduction reaction using a reducing agent such as lithium borohydride or sodium borohydride.
  • a reducing agent such as lithium borohydride or sodium borohydride.
  • a solvent methanol, ethanol, n-butanol, sec-butanol, etc.
  • a solvent such as phenol or tert-butanol can be used, and ether solvents such as getyl ether, diisopropyl ether, and tetrahydrofuran can be used.
  • the reaction can be carried out under ice cooling to the solvent reflux temperature. Done in a range.
  • Boc represents a tert-butoxycarbonyl group
  • Z represents a benzyloxycarbonyl group
  • Ms represents a methanesulfonyl group
  • Ph represents a phenyl group
  • R 3 , R 4 , R 5 and R 6 are as defined above.
  • the compound represented by the general formula (VII) is reduced by an appropriate reduction method, for example, a hydrogenation reduction method using a catalyst such as platinum oxide, Raney nickel, palladium carbon, or the like;
  • the nitro group is reduced by a method such as the reduction method used
  • step 2 the compound represented by the general formula (VIII) is urethanized with di-tert-butyl dicarbonate using an appropriate solvent such as methanol or tetrahydrofuran, or triethylamine, carbonated lime, or carbonated carbonate.
  • an appropriate solvent such as methanol or tetrahydrofuran, or triethylamine, carbonated lime, or carbonated carbonate.
  • bases such as sodium and sodium bicarbonate
  • the solvent is added at 178 ° C in a solvent such as tetrahydrofuran, N, N-dimethylformamide, etc. in the presence of a base such as n-butyllithium and glycidyl butyrate.
  • a base such as n-butyllithium and glycidyl butyrate.
  • step 3 the compound represented by the general formula (IX) is heated to reflux with methanesulfonyl chloride in a solvent such as tetrahydrofuran in the presence of a base such as triethylamine under ice cooling.
  • the compound represented by the general formula (X) can be obtained by reacting at a temperature up to the range.
  • step 4 the compound represented by the general formula (X) is reacted with the compound represented by the general formula (XI) in a solvent such as methanol in a range from under ice-cooling to the heating reflux temperature of the solvent.
  • a compound represented by the general formula (III) can be obtained.
  • an appropriate reduction method for example, is reduced by a hydrogenation reduction method using a catalyst such as platinum oxide or palladium on carbon, or a method using triphenylphosphine and water to obtain a compound represented by the general formula ( ⁇ ⁇ ).
  • a catalyst such as platinum oxide or palladium on carbon
  • triphenylphosphine and water to obtain a compound represented by the general formula ( ⁇ ⁇ ).
  • a compound in which 3 is a hydrogen atom can be obtained.
  • the isothiocyanate derivative represented by the general formula (V), which is a raw material in the method for producing the compound of the present invention, is also a novel compound and can be produced as follows.
  • the medicament of the present invention is characterized by containing a thiourea derivative represented by the general formula (I) or a salt thereof as an active ingredient.
  • a substance selected from the group consisting of the above-mentioned compound in a free form, a physiologically acceptable salt thereof, a solvate thereof and a hydrate thereof can be used. Alternatively, two or more substances may be used in combination.
  • the above-mentioned substance itself may be used as it is, but it is usually used in the form of a pharmaceutical composition containing the above-mentioned substance as an active ingredient and one or more kinds of pharmaceutical additives. Preferably provided.
  • a pharmaceutical composition for oral administration such as capsules, tablets, fine granules, granules, powders, syrups, or injections, suppositories, eye drops, eyes
  • a pharmaceutical composition for parenteral administration such as ointments, ear drops, transdermal absorbents, transmucosal absorbents, inhalants, or dermatological agents.
  • These preparations can be manufactured by a conventional method by adding pharmacologically and pharmaceutically acceptable additives for preparations.
  • excipients lactose, D-mannitol, corn starch, microcrystalline cellulose, etc.
  • disintegrants carboxymethylcellulose, carboxymethylcenorelose calcium, etc.
  • binders Hydroxypropinolylcellulose, hydroxypropylmethinolecellulose, polyvinylinopyrrolidone, etc.
  • lubricants magnesium stearate, talc, etc.
  • coating agents hydroxypropylmethylcellulose, sucrose, titanium oxide, etc.
  • Plasticizer Po Pharmaceutical additives such as polyethylene glycol, etc.
  • bases polyethylene glycol, hard fat, etc.
  • a solubilizer or solubilizing agent that can constitute an aqueous medium or a ready-to-use dosage form (distilled water for injection, physiological saline, propylene glycol, etc.), Ingredients such as pH regulators (inorganic or organic acids or bases), tonicity agents (salts, glucose, glycerin, etc.), stabilizers, etc. Can be used as ointments, creams, patches, and other suitable formulation components (white petrolatum, macrogol, glycerin, liquid paraffin, cotton cloth, etc.).
  • the medicament of the present invention can be administered, for example, as an antibacterial agent for treating or preventing infectious diseases in mammals including humans.
  • the dose of the medicament of the present invention is not particularly limited, and an appropriate dose can be selected according to the type of pathogenic bacteria, the age and weight of the patient, the severity of the disease, and the like. In general, for an adult, the daily dose can be about 10 to 200 mg by oral administration and about 1 to 100 mg by parenteral administration. It can be administered once or several times a day. However, it is desirable to increase or decrease as appropriate according to the purpose of treatment or prevention, the site of infection, the type of pathogenic bacteria, the age and symptoms of the patient, and the like.
  • a suspension of 0.25 g of 60% sodium hydride in 5 ml of anhydrous N, N-dimethylformamide was stirred at room temperature while stirring N-tert-butoxycarbonyl-3-azetidinol 1 ⁇ Og of anhydrous N, N -Add 3 ml of dimethylformamide solution, stir at room temperature for 30 minutes, and add 0.98 g of 2-methoxetinolemethanesulfonate in 2 ml of anhydrous N, N-dimethylformamide. The mixture was added dropwise and stirred at room temperature for 4 hours. The reaction solution was added to ice water and extracted with ethyl acetate.
  • the extract was washed successively with water and saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure.
  • N-tert-butoxycarbonyl-4-methoxypiperidine (43.9 g) was added to 22% of 9% hydrogen chloride in ethyl acetate under ice-cooling while stirring, and then cooled in ice. Stirred for 2.5 hours. The precipitated crystals were collected by filtration to obtain 29.1 g of colorless crystals.
  • Reference Yi 2 0 4- (Monorehorin one 4 Inore) Single 3-n-propoxy-nitrobenzene nature yellow prisms JoAkira (recrystallization solvent: E t 2 ⁇ )
  • N-benzyloxycarbonyl 4- (thiomorpholine-1-yl) aniline 25.0 g of anhydrous tetrahydrofuran 25 Oml was added to a solution of n-butyllithium (1.63 mol / l) in a nitrogen stream.
  • a 50 ml solution of n-hexane of 1) was added dropwise with stirring at 178 ° C, and after the addition, the mixture was stirred at the same temperature for 1 hour.
  • 11.5 ml of (R)-(-1) -glycidyl butyrate was added dropwise, and after the addition, the mixture was stirred at the same temperature for 1 hour and then at room temperature for 23 hours.
  • the extract was washed successively with diluted hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure.
  • the residue was crystallized from a mixed solution of isopropanol-diisopropyl ether, and the collected crystals were washed with diisopropyl ether to give pale yellow crystals (4.35 g). Recrystallization from ethanol gave pale yellow prisms with a melting point of 99-101 ° C.
  • a suspension of 00 ml of methanol in 300 ml was stirred at 60 ° C. and a hydrogen pressure of 70 kg m 2 for 12 hours.
  • the catalyst was removed by filtration and the solvent was distilled off under reduced pressure.
  • the residue was made alkaline by adding water and a 10% aqueous sodium hydroxide solution, and then extracted with a mixed solution of 1,2-dichloromethane-ethane-ethanol. After the extract was dried over sodium sulfate, the solvent was distilled off under reduced pressure. Isopropanol was added to the residue, and the precipitated crystals were collected by filtration and washed with diisopropyl ether to obtain 2.63 g of colorless crystals.
  • Example 36 (S) —N— [3- [4- (3- (3-propoxy) -13-phenoleolopheninole] -12-oxosoxa51-yl] methylthiourea Properties Colorless crystals (Recrystallization solvent: Me OH )
  • Example 41 1 (S) —N— [3- [3-Fluoro-41- (thiomorpholine-14-yl) phenyl] -12-oxooxoxolidine-5-yl] methylthiourea
  • the extract was washed with saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure.
  • the crystals were recrystallized from acetonitrile to obtain 1.0 g of colorless needles having a melting point of 174 to 175.5 ° C.

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Abstract

Dérivés antimicrobiens de thiourée représentés par la formule (I) ou leurs sels dans laquelle R?1, R2 et R3¿ représentent chacun hydrogène, alkyle, cycloalkyle, un groupe protecteur d'azote, alkoxycarbonylalkyle etc.; R représente phényle pouvant être substitué par halogéno, hydroxyle, mercapto, amino, cyano, nitro, carboxyle, carbamoyle, alkyle, cycloalkyle, alkoxyle, alkylamino, alkanoyle, arylcarbonyle, aryle, aralkyle, aryloxy, cycloalkyloxy contenant un hétéroatome en tant qu'atome de noyau, un groupe hétérocyclique saturé etc..
PCT/JP1998/004074 1997-09-11 1998-09-10 Derives de thiouree WO1999012914A1 (fr)

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AU90015/98A AU9001598A (en) 1997-09-11 1998-09-10 Thiourea derivatives

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JP9/265054 1997-09-11

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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000029396A1 (fr) * 1998-11-17 2000-05-25 Bayer Aktiengesellschaft Nouveaux derives de phenyloxazolidone substitues
WO2000032599A1 (fr) * 1998-11-27 2000-06-08 Pharmacia & Upjohn Company Agents antibacteriens oxazolidinone a fonction thiocarbonyle
WO2001009107A1 (fr) * 1999-07-28 2001-02-08 Pharmacia & Upjohn Company Oxazolidinones et leur utilisation comme anti-infectieux
WO2001042229A1 (fr) * 1999-08-12 2001-06-14 Ortho-Mcneil Pharmaceutical, Inc. Amidinomethyl- et guanidinomethyl-oxazolidinones antibacteriens
WO2001046164A1 (fr) * 1999-12-21 2001-06-28 Ortho-Mcneil Pharmaceutical, Inc. Piperidinyloxy et pyrrolidinyloxyphenyl oxazolidinones a activite antibacterienne
WO2001058885A1 (fr) * 2000-02-10 2001-08-16 Pharmacia & Upjohn Company Thioamides d'oxazolidinone a substituants amides de piperazine
WO2001041724A3 (fr) * 1999-12-08 2001-12-20 Oreal Compositions pour la teinture des fibres keratiniques contenant des derives de paraphenylenediamine a groupement azetidinyle
US6617339B1 (en) 1998-06-05 2003-09-09 Syngenta Limited Oxazolidinone derivatives, process for their preparation and pharmaceutical compositions containing them
US6642238B2 (en) 2000-02-10 2003-11-04 Pharmacia And Upjohn Company Oxazolidinone thioamides with piperazine amide substituents
WO2004018439A1 (fr) * 2002-08-22 2004-03-04 Orchid Chemicals & Pharmaceuticals Ltd Nouveaux agents antibacteriens
WO2005019214A1 (fr) * 2003-08-25 2005-03-03 Warner-Lambert Company Llc Nouveaux composes d'aryloxazolidinone antimicrobiens
US7081538B1 (en) 1999-12-03 2006-07-25 Astrazeneca Ab Substituted isoxazolines and their use as antibacterial agents
US7141583B2 (en) 2000-04-25 2006-11-28 Astrazeneca Ab Oxazolidinone derivatives with antibiotic activity
US8148362B2 (en) 2006-03-31 2012-04-03 Research Foundation Itsuu Laboratory Compound having heterocyclic ring
US8530646B2 (en) 2007-10-02 2013-09-10 Research Foundation Itsuu Laboratory Oxazolidinone derivative having 7-membered hetero ring

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0127902A2 (fr) * 1983-06-07 1984-12-12 E.I. Du Pont De Nemours And Company Dérivés de benzène aminométhyl-oxooxazolidinyliques utilisables comme agents antibactériels
EP0789025A1 (fr) * 1996-02-06 1997-08-13 Bayer Ag Oxazolidinones substituées et leur utilisation comme médicaments antibactériens
EP0789026A1 (fr) * 1996-02-06 1997-08-13 Bayer Ag Hetero-aryl oxazolidinones et leur utilisation comme médicaments antibactériens

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0127902A2 (fr) * 1983-06-07 1984-12-12 E.I. Du Pont De Nemours And Company Dérivés de benzène aminométhyl-oxooxazolidinyliques utilisables comme agents antibactériels
EP0789025A1 (fr) * 1996-02-06 1997-08-13 Bayer Ag Oxazolidinones substituées et leur utilisation comme médicaments antibactériens
EP0789026A1 (fr) * 1996-02-06 1997-08-13 Bayer Ag Hetero-aryl oxazolidinones et leur utilisation comme médicaments antibactériens

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6617339B1 (en) 1998-06-05 2003-09-09 Syngenta Limited Oxazolidinone derivatives, process for their preparation and pharmaceutical compositions containing them
WO2000029396A1 (fr) * 1998-11-17 2000-05-25 Bayer Aktiengesellschaft Nouveaux derives de phenyloxazolidone substitues
WO2000032599A1 (fr) * 1998-11-27 2000-06-08 Pharmacia & Upjohn Company Agents antibacteriens oxazolidinone a fonction thiocarbonyle
WO2001009107A1 (fr) * 1999-07-28 2001-02-08 Pharmacia & Upjohn Company Oxazolidinones et leur utilisation comme anti-infectieux
US6441005B1 (en) 1999-07-28 2002-08-27 Pharmacia & Upjohn Company Oxazolidinone compounds and compositions, and methods of using the same
US6743811B2 (en) 1999-07-28 2004-06-01 Pharmacia & Upjohn Company Oxazalidinone compounds and methods of preparation and use thereof
WO2001042229A1 (fr) * 1999-08-12 2001-06-14 Ortho-Mcneil Pharmaceutical, Inc. Amidinomethyl- et guanidinomethyl-oxazolidinones antibacteriens
US7081538B1 (en) 1999-12-03 2006-07-25 Astrazeneca Ab Substituted isoxazolines and their use as antibacterial agents
WO2001041724A3 (fr) * 1999-12-08 2001-12-20 Oreal Compositions pour la teinture des fibres keratiniques contenant des derives de paraphenylenediamine a groupement azetidinyle
WO2001046164A1 (fr) * 1999-12-21 2001-06-28 Ortho-Mcneil Pharmaceutical, Inc. Piperidinyloxy et pyrrolidinyloxyphenyl oxazolidinones a activite antibacterienne
US6518285B2 (en) 1999-12-21 2003-02-11 Ortho Mcneil Pharmaceutical, Inc. Piperidinyloxy and pyrrolidinyloxy oxazolidinone antibacterials
US6642238B2 (en) 2000-02-10 2003-11-04 Pharmacia And Upjohn Company Oxazolidinone thioamides with piperazine amide substituents
WO2001058885A1 (fr) * 2000-02-10 2001-08-16 Pharmacia & Upjohn Company Thioamides d'oxazolidinone a substituants amides de piperazine
US7141583B2 (en) 2000-04-25 2006-11-28 Astrazeneca Ab Oxazolidinone derivatives with antibiotic activity
WO2004018439A1 (fr) * 2002-08-22 2004-03-04 Orchid Chemicals & Pharmaceuticals Ltd Nouveaux agents antibacteriens
WO2005019214A1 (fr) * 2003-08-25 2005-03-03 Warner-Lambert Company Llc Nouveaux composes d'aryloxazolidinone antimicrobiens
US8148362B2 (en) 2006-03-31 2012-04-03 Research Foundation Itsuu Laboratory Compound having heterocyclic ring
US8785625B2 (en) 2006-03-31 2014-07-22 Research Foundation Itsuu Laboratory Compound having heterocyclic ring
US8530646B2 (en) 2007-10-02 2013-09-10 Research Foundation Itsuu Laboratory Oxazolidinone derivative having 7-membered hetero ring

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