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WO1997031896A1 - Derives de thiazolidine - Google Patents

Derives de thiazolidine Download PDF

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Publication number
WO1997031896A1
WO1997031896A1 PCT/JP1997/000581 JP9700581W WO9731896A1 WO 1997031896 A1 WO1997031896 A1 WO 1997031896A1 JP 9700581 W JP9700581 W JP 9700581W WO 9731896 A1 WO9731896 A1 WO 9731896A1
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group
prn
chxln
sac
compound
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PCT/JP1997/000581
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English (en)
Japanese (ja)
Inventor
Sadao Ishihara
Fujio Saito
Hidekazu Masuko
Yasuo Ohhata
Shigeki Miyake
Ryosuke Yorikane
Norio Fukuda
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Sankyo Company, Limited
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Priority to AU22308/97A priority Critical patent/AU2230897A/en
Publication of WO1997031896A1 publication Critical patent/WO1997031896A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D277/06—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members 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

Definitions

  • the present invention relates to a thiazolidine or a pharmacologically acceptable salt thereof having an excellent collateral vasodilating action and an antianginal action, and a & ⁇ for preventing or treating angina pectoris containing them as an active ingredient.
  • nitroglycerin is most frequently used clinically as a therapeutic agent for cardiovascular diseases, particularly angina pectoris.
  • This drug has the disadvantage of being susceptible to the first-pass effect and its duration of action is short.
  • headache, dizziness and tachycardia due to a decrease in blood pressure appear.
  • it has been clinically ineffective as a first-pass effect and has been used as a persistent angina treatment drug.
  • ⁇ — CONH— Q— ⁇ ⁇ ⁇ 2 (wherein, ⁇ represents a piperidine ring, a pyrrolidinone ring, a thiazolidine ⁇ , a thiazolidinone ring, etc .; . which are shown) compounds heart having a circulatory system diseases, for example, the prevention of angina, it is known that force s is 3 ⁇ 4 to treatment such as (e.g., JP-a-2 - 1 6 9 5 7 0 No. Gazette, Japanese Patent Application Laid-Open No. 5-504304, Japanese Patent Application Laid-Open No. 6-503018, Japanese Patent Application Laid-Open No. 5-213910, etc.).
  • the present inventors have a long history of synthesizing a series of thiazolidines and their pharmacological actions.
  • thiazolidines such as pyrrolidine, oxazolidine, and thiazolidine, having a specific substituent on the nitrogen atom on the ring have excellent collateral vasodilator action, and the action is sustained.
  • * ⁇ ! 1 The action was also small and found to be useful as a therapeutic or preventive agent for angina pectoris (preferably, a therapeutic agent), thereby completing the present invention.
  • the present invention relates to a thiazolidine or a pharmacologically acceptable salt thereof having an excellent collateral vasodilator action and an antianginal action, and a composition for preventing or treating angina pectoris, which contains them as a component.
  • a method for preventing or treating angina pectoris in which a pharmacologically effective amount thereof is administered to a warm-blooded animal, or a method for producing the same I do.
  • the thiazolidine of the present invention has a general formula
  • X represents a methylene group, an oxygen atom or a sulfur atom
  • R 1 is a C 2 -Ce alkyl group having a substituent
  • the substituent is required to be of the formula: S—R 2 (where R 2 is a hydrogen atom; C-Ce date) Aliphatic acyl group; C2-C7 alkoxycarbonyl group; Ci-Ce alkyl, d-Cs alkoxy or C 7 -CH arylcarbonyl group optionally substituted with halogen; or CC e alkyl, C Ce alkoxy or 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, which may be substituted by halogen It represents a 5- or 6-membered aromatic heterocyclic carbonyl group containing a hetero atom. ), And as desired, an amino group, a mono- or di-d-C 6 alkylamino group, a protected amino group or a protected mono-C,-(36 alkylamino group) is shown. Indicates that
  • A is C e alkylene group or the formula one B- D-E- (wherein the C, B and E are the same or different and each represents a single bond or a C t-Cs alkylene group, D is, d-C Represents a C 3 -C 6 cycloalkylene group which may be substituted with 6 alkyl.) Represents a group having the above formula.
  • the alkanoyl part of the “mail group” is a d-C 7 alkyl group (showing a linear or branched alkyl group having 1 to 7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, 2-methylpropyl, butyl, isobutyl) , S-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, netylpentyl, 1-ethylpropyl, hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethyl Butyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-eth
  • d—C 6 aliphatic acetyl group in the definition of R 2 is a carbonyl group bonded to a hydrogen atom or a saturated or unsaturated d-C 5 chain hydrocarbon group. represents a group such as formyl, Asechiru, Burobi old alkenyl, butyryl, Isobuchiri Le, Kisanoiru valeryl, isovaleryl, pivaloyl to, Akuriroiru, meta acryloyl be a Kurotomeiru group, preferably, C, one C 6 Arukanoiru group And more preferably a d—C 4 alkanoyl group, still more preferably an acetyl or propionyl group, and particularly preferably an acetyl group.
  • the “C 2 —C 7 alkoxycarbonyl group” in the definition of R 2 is a C 6 -C 6 alkoxy group (a straight-chain having 1 to 6 carbon atoms among the above C and -CT alkyl groups). Or a group in which an alkyl group which is a branched chain is bonded to an oxygen atom.) Represents a group in which a carbonyl group is bonded to, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isobroboxycarbonyl, butoxy.
  • the arylcarbonyl portion of the “optionally substituted C 7 —CHarylcarbonyl group” in the definition of R 2 is C 6 -C ,.
  • An aryl hydrocarbon group (indicating an aromatic hydrocarbon having 6 to 10 carbon atoms, such as phenyl, indenyl and naphthyl, and preferably a phenyl group), and a carbonyl group bonded thereto.
  • it may be benzoyl, indanecarbonyl, naphthyl, preferably a benzoyl group.
  • the substituent (preferably 1 to 3, particularly preferably 1.) is, for example, an unsubstituted C, —C 6 alkyl group, a C, 1 C 6 alkoxy group (the aforementioned C 2 -Cr represents a group obtained by removing a carbonyl group from an alkoxycarbonyl group.) Or a halogen atom (for example, fluorine, chlorine, bromine or iodine), preferably C, —C 2 alkyl, d—C 2 alkoxy, fluorine or chlorine, wherein “in the definition of R 2 , it may be substituted and is selected from a heteroatom group consisting of nitrogen, oxygen and sulfur atoms.
  • a halogen atom for example, fluorine, chlorine, bromine or iodine
  • a 5- or 6-membered aromatic heterocyclic carbonyl group containing 1 to 3 heteroatoms refers to a group in which a carbonyl group is bonded to a 5- or 6-membered aromatic heterocyclic ring.
  • substituents are, for example, the C, -C 6 alkyl group, the C, -C 6 alkoxy group, It may be a halogen atom, preferably methyl, methoxy, fluorine or chlorine, particularly preferably methyl or chlorine.
  • the desired substituent of the C 2 -Ce alkanoyl group in the definition of R 2 B is "mono- or di one CC 6 alkylamino group", one or two of the the Amino group C, - C s represents an alkyl group force attached group, for example, Mechiruamino, E Chiruamino, Puropiruamino, Buchiruamino, t Buchiruamino, Penchiruami Roh to, Kishiruamino, Jimechiruamino, Jechiruamino, methyl E chill ⁇ Mino, jib port Biruamino, Jibuchiruamino, dipentyl ⁇ Mino, be a Kishiruamino group to di, preferably, a mono- or di-d -C 4 alkylamino group And more preferably a methylamino, ethylamino, dimethylamino or methylethylamino group
  • protecting groups of “protected amino group” and “protected mono-d-C 6 alkylamino group” in the definition of R ′ are well known in the field of synthetic organic chemistry. Is not particularly limited, for example, the C, one C 6 aliphatic acyl group, the C 2 -C 7 alkoxycarbonyl group, the formula S i R 3 a R 3 b R 3 c (wherein R 3 a, R and R 3 C may be the same or different, wherein the C, -C 6 alkyl group or a
  • C six one C Shows an aryl group. And 1 to 3 of the above C 6 —.
  • It is a main Bok alkoxycarbonyl group substituted by Ariru group, preferably one C 4 Arukanoiru group, C, -C 4 alkoxides aryloxycarbonyl group, tri d - C 2 alkyl silyl group, t chromatography butyldimethyl Shi Lil group, phenylene Le dimethylsilyl group, optionally substituted benzyl group (the substituent be in the case of more than one, same or different, d - C 2 alkyl, d - C 2 alkoxy, fluorine or chlorine Or a benzyloxycarbonyl group which may be substituted (in the case of plural, the same or different, d—C 2 alkyl, C.-Cz alkoxide, fluorine or chlorine) And more preferably a
  • An alkenyl group even more preferably more, C, -C 4 Arukanoiru group or Is C, - a C 4 alkoxycarbonyl group, still more preferably also, d - a C 2 Arukanoiru group or t one-but pheasant carbonyl group, particularly preferably at Asechiru or t-flop Bok alkoxycarbonyl group is there.
  • C 2 -C 8 alkanoyl group having a substituent” in the definition of R ′ include, for example, mercaptoacetyl, 2-mercapto-1-methylacetyl, and 3-mercaptobro Pionyl, 3-mercapto-1-methylbrobiyl, 3-mercapto-3-methylpropionyl, 3-merbut-1-ethylpropionyl, 4-mercaptobutyryl, 4-mercapto-2-methylbutyryl, 4-1-1 Mercapto-3-methylbutyryl, 4-merbutyr-4-methylbutyryl, 5-mercaptovaleryl, 5-mercapto-1-methylvaleryl, 6-mercaptohexanoyl, 2-amino-3-mercaptopropionyl, 2-amino-4- Mercaptobutyryl, 3-amino-4-mercaptobutyryl, 2-amino-5-mercaptovaleryl, 2-amino-6-methyl L-butahexameyl,
  • d-C 8 alkylene group in the definition of A represents a linear or branched alkylene group having 1 to 8 carbon atoms, for example, methylene, methylmethylene, ethylene, propylene, Trimethylene, methylethylene, ethylethylene, tetramethylene, 1-methyltrimethylene, 2-methyltrimethylene, 3-methyltrimethylene, 1-methylpropylene, 1,1-dimethylethylene, pentamethylene, 1-methyltetramethylene, 2 —Methyltetramethylene, 3-methyltetramethylene, 4-methyltetramethylene, propylethylene, 1,1-dimethyltrimethylene, 2,2-dimethyltrimethylene, 3,3-dimethyltrimethylene, hexamethylene, 1-methylpentane Methylene, 2-methylpentamethylene, 3-methylpentamethylene, 4 —Methylpentamethylene, 5-methylpentamethylene, 1,1-dimethyltetramethylene, 2,2-dimethylte
  • the “ ⁇ -C 6 alkylene group” in the definition of B and E is a straight-chain or branched-chain alkylene group having 1 to 6 carbon atoms in the C, -C 8 alkylene group.
  • B it is preferably a C, —C 4 alkylene group, more preferably a methylene or ethylene group, particularly preferably a methylene group
  • E it is preferably a methylene group.
  • the cycloalkylene moiety of the “optionally substituted C 3 -Cs cycloalkylene group” in the definition of D represents a divalent group of a linear hydrocarbon having 3 to 6 carbon atoms, for example, be a cyclopropylene, cyclobutylene, cyclopentylene, Kijiren group cycloheteroalkyl, preferably, C s - a C 6 cycloalkylene group, more preferably a cyclohexylene group, a particularly preferred A 1,4-cyclohexylene group.
  • the substituent (preferably 1 to 3, particularly preferably 1) is the CC 6 alkyl group, preferably a C, -alkyl group, and Preferably, it is a CC 2 alkyl group, and particularly preferably, a methyl group.
  • a compound having a basic group such as an amino group can be converted into a pharmacologically acceptable salt by treating it with an acid, if necessary.
  • Such salts include hydrofluorides, hydrochlorides, hydrobromides, hydrohalides such as hydroiodates, nitrates, perchlorates, sulfates, phosphates, etc.
  • 10 aryl sulfonic acid Sulfonates such as salts; carboxylates such as fumarate, succinate, citrate, tartrate, oxalate, and maleate; or amino acids such as glutamate, aspartate. Can be mentioned.
  • the compound (I) or a salt thereof of the present invention may absorb water when left in the air or recrystallize, and may absorb water or form a hydrate. Such water-containing compound salts are also included in the present invention.
  • the compound (I) or a salt thereof of the present invention may have an asymmetric carbon atom in the molecule and may have an R-coordinate or S-coordinate stereoisomer.
  • any of the compounds in any proportions thereof is included in the present invention.
  • the compound is an X-methylene group
  • the steric configuration at the 2-position on the pyrrolidine ring is the S-configuration.
  • Such stereoisomers can be obtained by synthesizing compound (I) using the optically resolved starting compound or by subjecting the synthesized compound (I) to optical resolution using an ordinary optical resolution or separation method as desired. it can.
  • the compound (I) or a salt thereof of the present invention is a group having the formula —B—D—E—, a geometric isomer exists, and the present invention relates to such a geometric isomer. And preferably a trans isomer.
  • preferred compounds include
  • R 2 -C 2 -C 6 alkanoyl group having a substituent is, as an essential, a compound represented by the formula: SR 2 wherein R 2 is a hydrogen atom; d—C 6 alkanol groups; C 2 - C 5 alkoxycarbonyl group; C, one C 2 alkyl, C, - C 2 ⁇ alkoxy, optionally Benzoiru group optionally substituted by fluorine or chlorine; or methyl, main butoxy, substituted with fluorine or chlorine
  • the protecting group is a C> -CH alkanoyl group, C, alkoxycarbonyl Group, tri - C i - C 2 alkyl silyl group, t chromatography butyldimethylsilyl group, phenylene Le dimethylsilyl group, C, -C 2 alkyl, C, -C 2 alkoxy, fluorine Wakashi Ku is substituted with chlorine which may benzyl or C, one C 2 alkyl, C, one C 2 alkoxy, Ru good benzyl old alkoxycarbonyl group der be substituted by fluorine or chlorine. ).
  • R 1 force C 2 —C 6 alkanoyl group having a substituent
  • the substituent is essentially a compound of the formula —S—R 2 (wherein, R 2 is a hydrogen atom; C, —C A alkenyl group; a C 2 -C 3 alkoxycarbonyl group; a t-butoxycarbonyl group; a benzoyl group; or a thienylcarbonyl, furylcarbonyl or pyridylcarbonyl group which may be substituted by methyl or chlorine.
  • R 1 force C 2 -C 6 alkanoyl group having a substituent
  • the substituent is an essential one represented by the formula: S—R 2 (wherein R 2 is a hydrogen atom; d alkanol group A C 2 -C 3 alkoxycarbonyl group; a t-butoxycarbonyl group; a benzoyl group; or a thienylcarbonyl, furylcarbonyl or pyridylcarbonyl group which may be substituted with methyl or chlorine.
  • the desired one is an amino, methylamino, dimethylamino, acetylamino, N-acetyl-N-methylamino, t-butoxycarbonylamino or Nt-butoxycarbonyl-N-methylamino group.
  • R 1 is a C 2 —C 4 alkanoyl group having a substituent.
  • the substituent is essentially a compound of the formula —S—R 2 (wherein R 2 is a hydrogen atom or C, — Alkanol groups), and are preferably an amino, methylamino, dimethylamino, acetylamino or N-acetyl-N-methylamino group. is there.
  • R 1 force substituted S gamma one [pi 4 alkanol I le has a 't [D substitutions S, as the indispensable wherein one S- R 2 (wherein, in R 2 forces a hydrogen atom or a Asechiru 3 ⁇ 4 is there.
  • Desirable ones are an amino group and an acetylamino group.
  • a C 5 -C 6 cycloalkylene group which may be a group having a single bond, methylene, ethylene, trimethylene or tetramethylene group.
  • a compound obtained by combining arbitrarily selected from the group consisting of (1) (1) (7) and (8)-(12) above is also a suitable compound.
  • R 1 is a substituted C 2 -C 6 alkanoyl group
  • the substituent is essentially a compound represented by the formula: S—R 2 (wherein, R 2 is a hydrogen atom; 6 alkanol group; C 2 -C 5 alkoxycarbonyl group; C, -Cz alkyl, — C 2 alkoxy, benzoyl group optionally substituted with fluorine or chlorine; or substituted with methyl, methoxy, fluorine or chlorine may be, Choi alkenyl carbonyl, furyl carbonyl or pyridylcarbonyl group.) is a group having, as a desired one, amino group, mono eleven C 4 alkylamino group, di-C, alkylamino group, or protected Amino or mono one C, -C 4 alkylamino amino group (said protecting group is, d - C 4 Al force mail group, d -C 4 alkoxycarbonyl two group, tree C, -
  • R 1 -forced C 2 -C e -mail group having a substituent is essentially a compound of the formula —S—R 2 (wherein R 2 is a hydrogen atom; C one C 4 alkanol I le radical; C 2 - C 3 alkoxycarbonyl group; t one-butoxycarbonyl group; Ben Zoiru group; may be substituted by, or methyl or chlorine, Choi alkenyl carbonyl, furyl carbonyl or pyridylcarbonyl group .
  • a cycloalkylene group which is a group having an E-force single bond, a methylene, ethylene, trimethylene or tetramethylene group.
  • a desired group is an amino, methylamino, dimethylamino, acetylamino, N-acetyl-N-methylamino, t-butoxycarbonylamino or Nt-butoxycarbonyl N-methylamino group. . ]
  • R 1 force C 2 -C 4 alkanoyl group having a substituent
  • the substituent is essentially a group represented by the formula —S—R 2 (wherein R 2 is a hydrogen atom or C, And a desired group is an amino, methylamino, dimethylamino, acetylamino or N-acetyl-N-methylamino group. ]
  • R 1 is a C 3 -C 4 alkanol group having a substituent
  • the substituent is essentially a group represented by the formula —S—R 2 (wherein, R 2 is a hydrogen atom or an acetyl group; )), And a desirable group is an amino group or an acetylamino group. ]
  • R 1 force 3-mercaptobution, 3-mercapto-2-methylpropionyl, 3-mercapto-3-methylpropionyl, 4-mercaptobutyryl, 3-mercaptobutyryl, 2-merethylbutionion Le, 2-amino-3-merkabutov Mouth pionyl, 2-Acetylamino-3-mercapto alpha, 3-Acetyl thiob Mouth pionyl, 3-Acetylthio-1-methylpropionyl, 3-Acetylthio-3-methylpropionyl, 4-Acetylthiobuti Ryl or 2-acetylamino-3-oncetylthioobionyl group;
  • Ethylene methylethylene, propylethylene, butylethylene or isobutylethylene or a formula —B—D—E— (where B is a methylene group, D is a cyclohexyl group, and E is A compound having the following formula:
  • R 1 force 3-mercapto-2-methylpropionyl, 2-amino-3-mercaptopropionyl, 2-acetylamino 3-mercaptopropionyl, 3-acetylthio-12-methylpropionyl or 2 —Acetylamino-3 is an acetylthiopropionyl group,
  • A is a compound wherein A is a methylethylene group.
  • Representative compounds of the present invention include, for example, compounds listed in Table 1, Table 2 and Table 3. The present invention is not limited to these compounds.
  • the compounds in Table 1, Table 2 and Table 3 have structural formulas (la), (Ib) and (Ic), respectively.
  • Compound No. 3-284 It is a compound of 3- (2-acetylamino-3-acetylthiopropionyl) monothiazolidine-14-yl-N- (1-methyl-2-dioxochetyl) amide.
  • the compound having the general formula (I) of the present invention can be easily produced according to the following method.
  • R ', A and X are the same meanings as described above
  • R l a is Merukabuto groups contained in R 1
  • a protected mercapto group, a protected amino group and a protected mono-C, —C 6 alkylamino group are the same as R ′
  • R 4 is the amino group.
  • a protecting group (having the same meaning as described above).
  • Protecting groups Merukabuto group is, for example, the d -C 3 Abura ⁇ Ashiru group, the C 2 -CT alkoxycarbonyl group, previous remarks yourself optionally substituted C 7 - Arirukaru Boniru group, 5 to the may be substituted It may be a 6-membered aromatic heterocyclic carbonyl group, preferably an acetyl, t-butoxycarbonyl or benzoyl group.
  • Method A is a method for producing compound (I).
  • Step A1 is a step of producing a compound having the general formula (I), and in an inert solvent, a compound having the general formula (II) or a reactive derivative thereof (acid halides, mixed acid anhydride or active ester). ) And a compound having the general formula (III) or a caro salt with an acid thereof (for example, a mineral salt such as a hydrochloride, a nitrate, or a sulfate).
  • a mineral salt such as a hydrochloride, a nitrate, or a sulfate.
  • the reaction between the compound (II) and the compound (III) is carried out, for example, by an acid halide method, a mixed acid anhydride method, an active ester method or a condensation method.
  • compound (II) is reacted with a halogenating agent (for example, thionyl chloride, oxalic acid chloride, phosphorus pentachloride, etc.) in an inert solvent to produce an acid halide, and the acid octide and the compound ( III) or an acid addition salt thereof is reacted in an inert solvent in the presence or absence (preferably in the presence) of a base.
  • a halogenating agent for example, thionyl chloride, oxalic acid chloride, phosphorus pentachloride, etc.
  • Bases used are, for example, organic amines such as triethylamine, N-methylmorpholine, pyridine, 4-dimethylaminopyridine, alkali metal bicarbonates such as sodium bicarbonate and bicarbonate, sodium carbonate, It can be an alkali metal carbonate such as potassium carbonate, and is preferably an organic amine (particularly preferably, triethylamine).
  • the inert solvent used is not particularly limited as long as it does not participate in the reaction, and examples thereof include hydrocarbons such as hexane, cyclohexane, benzene, toluene, and xylene, dichloromethane, 1,2-dichloroethane, and tetrachloromethane.
  • Halogenated carbon such as carbon chloride Hydrides, ethers, ethers such as tetrahydrofuran, dioxane, ketones such as acetone, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, hexamethylphospho Amides such as amides and sulfoxides such as dimethyl sulfoxide, preferably hydrocarbons, halogenated hydrocarbons or ethers, more preferably ethers (particularly preferred Is tetrahydrofuran).
  • the reaction temperature depends on the type of the starting compounds (11) and (III) and the solvent.
  • the reaction temperature of the reaction between the halogenating agent and the compound (II) and the reaction between the acid halide and the compound (III) is usually -20 °. C to 150 ° C., preferably, the reaction between the halogenating agent and the compound (II) is 110 ° C. to 5 CTC, and the reaction between the acid halide and the compound (III) is CTC. To 100 ° C.
  • both reactions are usually 15 minutes to 24 hours (preferably 30 minutes to 16 hours).
  • the reaction for preparing the mixed acid anhydride include methyl chlorocarbonate, chlorocarbonate Echiru, black Le carbonate Isopuchiru, halogeno carbonate C, such as hexyl chlorocarbonate, -C 6 alkyl Le (preferably chlorocarbonate Echiru or chlorocarbonate Di-C, -C 6 alkyl cyanophosphoric acid or diphenylphosphoric acid azide such as isoptyl), dimethylcyanophosphoric acid, getylcyanophosphoric acid, dihexylcyanophosphoric acid
  • the reaction is carried out by reacting a di-C 6 -C 10 aryl phosphate azide such as dinaphthyl phosphate azide (3 ⁇ 4F ⁇ is diphenyl phosphate azide) with the compound (II), preferably in an inert solvent, Performed in the presence of a base.
  • the base and inert solvent used are the same as those used in the acid halide method described above. It is
  • the reaction temperature varies depending on the starting compound (II), the type of the solvent, and the like, but is usually from 20 ° C to 50 ° C (preferably from 0 ° C to 30 ° C).
  • the reaction time varies depending on the reaction temperature and the like, but is usually 15 minutes to 24 hours (preferably 30 minutes to 16 hours).
  • the reaction between the mixed acid anhydride and the compound (III) or an acid salt thereof is carried out in an inert solvent in the presence or absence (preferably in the presence) of a base.
  • the inert solvent is the same as that used in the above-mentioned acid halide method.
  • the reaction temperature varies depending on the starting compound (III), the type of the solvent, and the like, but is usually from 20 ° C to 100 ° C (preferably from 10 ° C to 50 ° C).
  • the reaction time varies depending on the reaction temperature and the like, but is usually 15 minutes to 24 hours (preferably 30 minutes to 16 hours).
  • di-C> -C 6 alkyl cyanophosphoric acid or
  • compound (II) can be directly reacted with compound (III) in the presence of a base.
  • compound (II) is converted into an active esterifying agent (for example, N-hydroxysuccinimide, N-hydroxybenzotriazole) in the presence of a condensing agent (for example, dicyclohexylcarbodiimide, carbonyldiimidazole, etc.).
  • an N-hydroxy compound such as the following
  • the active ester is reacted with the compound (III) or an acid addition salt thereof to produce an active ester.
  • the reaction is carried out in an inert solvent, and the inert solvent used is the same as that used in the above-mentioned acid halide method.
  • the reaction temperature varies depending on the starting compounds (11) and (III), the type of the solvent, and the like. In the reaction between the active ester compound and the compound (III), ⁇ 20 ° C. to 50 ° C. (preferably, 10 ° C. to 30 ° C.).
  • both reactions are usually 15 minutes to 24 hours (preferably 30 minutes to 16 hours).
  • the condensation method is carried out in the presence of a compound (II) in the presence of a condensing agent [for example, dicyclohexylcarbodiimide, carbonyldiimidazole, 11- (N, N-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, etc.] And the compound (III) or an acid addition salt thereof.
  • a condensing agent for example, dicyclohexylcarbodiimide, carbonyldiimidazole, 11- (N, N-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, etc.
  • the desired (a) reaction for removing the protecting group for the amino group or imino group is generally carried out as follows by a method well known in the art. Is done.
  • the protecting group of amino group or imino group is C 1, 1 C 6 aliphatic acyl group or C 2 -C 7 alkoxycarbonyl group
  • the corresponding compound is reacted with an acid or a base in the presence of an aqueous solvent. As a result, the substituent is removed.
  • the acid used is not particularly limited, as long as it does not inhibit the reaction, and it is preferably used as an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, or hydrobromic acid.
  • the acid is particularly preferably hydrochloric acid
  • the base used is not particularly limited as long as it does not affect the other parts of the compound.
  • sodium methoxide and sodium ethoxide are used.
  • isomerization may occur in hydrolysis with a base.
  • the inert solvent used in the above reaction is not particularly limited as long as it is used in a usual hydrolysis reaction.
  • alcohols such as methanol and ethanol are used.
  • It can be an organic solvent such as ethers such as tetrahydrofuran and dioxane, or a mixed solvent of water and the above organic solvent, and is preferably a hydrated alcohol or a hydrated ether.
  • the reaction temperature and reaction time vary depending on the starting material, the solvent, and the acid or base used, and are not particularly limited.In order to suppress a side reaction, the reaction temperature is usually from 10 ° C to 150 ° C. C (preferably 0 ° C. to 100 ° C.), and the reaction time is usually 30 minutes to 20 hours (preferably 1 hour to 10 hours).
  • Protecting group of the amino or imino group (wherein, R 3 a, R 3 Wa, and R 3 C is,. Showing the same meanings as defined above) wherein -S i R 3 a R 3 bR 3 c the In the case of a group having a substituent, the substituent is removed by reacting the corresponding compound with a compound which generates fluorine anneal such as tetrabutylammonium fluoride in an inert solvent. .
  • the inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction.Ethers such as tetrahydrofuran and dioxane are suitable.
  • the reaction temperature and reaction time are not particularly limited, but are not particularly limited.
  • the reaction temperature is usually 1 to 50 ° C (preferably 0 to 30 ° C), and the reaction time is usually 2 to 24 hours (preferably 10 to 18 hours). It is.
  • the inert solvent used in the removal by catalytic reduction is not particularly limited as long as it does not participate in the present reaction.
  • alcohols such as methanol and ethanol, getyl ether,
  • ethers aromatic hydrocarbons such as toluene, benzene, and xylene; aliphatic hydrocarbons such as hexane, cyclohexane; and ethers such as ethyl acetate and propyl acetate.
  • It may be a fatty acid such as ters or acetic acid, or a mixed solvent of these organic solvents and water, and is preferably an alcohol.
  • the catalyst to be used is not particularly limited as long as it is usually used for a catalytic reduction reaction.
  • Examples thereof include palladium monocarbon, Raney nickel, platinum oxide, platinum black, dimethyl-aluminum oxide and triphenylphenylphosphine.
  • the pressure of hydrogen is not particularly limited, but is usually 1 to 10 atm (preferably 1 to 3 atm).
  • reaction temperature and reaction time vary depending on the starting material, solvent, type of catalyst, etc., but the reaction temperature is usually from 12 CTC to 10 CTC (preferably from 0 ° to 50 CTC). Is usually 30 minutes to 10 hours (preferably 1 hour to 5 hours).
  • the inert solvent used is not particularly limited as long as it does not participate in the reaction.
  • ketones such as acetone, methylene chloride, chloroform, tetrachloride
  • Halogenated hydrocarbons such as carbon, nitriles such as acetonitrile, ethers such as getyl ether, tetrahydrofuran, and dioxane
  • Amides and sulfoxides such as dimethyl sulfoxide or a mixed solvent of these organic solvents, preferably amides or sulfoxides.
  • the oxidizing agent to be used is not particularly limited as long as it is a compound used for acidification.
  • alkali metal persulfates such as potassium persulfate and sodium persulfate, ammonium cerium nitrate ( CAN), 2,3-dichloro-5,6-dicyano-1) -benzoquinone (DDQ), preferably ammonium cerium nitrate (CAN) or 2,3-dichloro-5,6 -Diciano-P-benzoquinone (DDQ).
  • the reaction temperature and reaction time vary depending on the starting material, solvent, type of catalyst, etc.
  • the reaction temperature is usually from 11 CTC to 15 CTC (preferably from 0 ° C. to 5 TC), and the reaction time is usually from 10 minutes to 24 hours (preferably from 30 minutes to 24 hours). 10 hours).
  • the protecting group for the amino or imino group is t-butyl, t-butoxycarbonyl, methoxybenzyl or methoxybenzyloxycarbonyl
  • the corresponding compound is usually converted to an acid in an inert solvent. The reaction removes the substituent.
  • the inert solvent used in the above reaction is not particularly limited as long as it is inert to this reaction.
  • examples thereof include ethers such as ether, tetrahydrofuran, dioxane, dichloromethane, 1,1, and the like. It may be a halogenated hydrocarbon such as 2-dichloroethane, or an aromatic hydrocarbon such as benzene, toluene, or xylene, and is preferably an ether.
  • the acid used is not particularly limited as long as it does not inhibit the reaction, and is not particularly limited.
  • examples include inorganic acids such as hydrochloric acid, sulfuric acid, and nitric acid, acetic acid, trifluoroacetic acid, and methane. It is an organic acid such as sulfonic acid or p-toluenesulfonic acid, and is preferably an inorganic acid (particularly preferably, hydrochloric acid).
  • reaction temperature and reaction time are not particularly limited, but the reaction temperature is usually -10 ° C to 50 ° C (preferably 0 ° C to 30 ° C), and the reaction time is Usually, it is 30 minutes to 50 hours (preferably 1 hour to 2 hours).
  • the desired (b) reaction for removing the protecting group for the mercapto group is generally carried out by a method well known in the art, and for example, the obtained compound is hydrolyzed in an inert solvent. It is done by doing.
  • the alkali used in the above reaction is, for example, an alkali metal hydroxide such as sodium hydroxide or hydroxide hydroxide, or an alkali metal carbonate such as sodium carbonate or potassium carbonate. It is a metal hydroxide.
  • the inert solvent used in the above reaction is not particularly limited as long as it does not participate in this reaction.
  • ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethyloxetane, diethylene glycol, dimethyl ether, alcohols such as methanol, ethanol, and propanol
  • amides such as formamide, dimethylformamide, dimethylacetamide and hexamethylenephosphate triamide, and preferably ethers or alcohols.
  • the reaction temperature and the reaction time are not particularly limited, but the reaction temperature is usually from ⁇ 10 ° C. to 100 ° C. (preferably from 0 to 30 ° C., and the reaction time is usually 5 minutes to 10 hours (preferably 30 minutes to 5 hours).
  • the desired (c) reaction of protecting the amino or imino group which depends on the type of protecting group, is generally carried out by methods well known in the art, and is carried out in an inert solvent in the presence of a base. In the presence or absence (preferably in the presence), the obtained compound is represented by the general formula
  • R 4 has the same meaning as described above, and Y represents a halogen atom (preferably, a chlorine atom, a bromine atom or an iodine atom). ]
  • the reaction is performed by reacting with a compound having
  • the base used is not particularly limited as long as it does not affect the other parts of the compound.
  • examples include alkali metal alkoxides such as sodium methoxide and sodium ethoxide, lithium carbonate, sodium carbonate, and the like.
  • Alkali metal carbonates such as potassium carbonate, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide or amines such as triethylamine, N, N-dimethylaniline, pyridine And preferably amines.
  • the inert solvent used in the above reaction is not particularly limited as long as it does not participate in the reaction.
  • inert solvent examples include halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, and Jetille.
  • halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, and Jetille.
  • Tel diisopropyl ether, tetrahydride Mouth furan, dioxane, dimethoxetane, diethylene glycol, ethers such as dimethyl ether, alcohols such as methanol, ethanol, propanol, and the like, preferably ethers or alcohols.
  • the reaction temperature and the reaction time are not particularly limited, but the reaction temperature is usually from 1 ° C. to 10 CTC (preferably from 0 ° C. to 30 ° C.). Usually, it takes 30 minutes to 10 hours (preferably 1 hour to 5 hours).
  • the reaction for acylating the desired (d) &] core mercapto group is generally carried out by a method well known in the art, and the obtained compound is converted to a compound represented by the general formula
  • R 2 a is. Of the same meanings as defined except for the force et hydrogen atom) compound and the presence of a base having carried out Te cowpea to be.
  • the inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction, and examples thereof include hydrocarbons such as hexane, cyclohexane, benzene, toluene, and xylene.
  • Dichloromethane 1,2-dichloroethane, hydrogen halides such as tetrachloride, ethers such as ether, tetrahydrofuran, dioxane, ketones such as acetone, N, N-dimethylform Amides, N, N-dimethylacetamide, N-methyl-1-pyrrolidone, amides such as hexmethylphosphoramide, and sulfoxides such as dimethylsulfoxide, preferably halogenated And hydrogen (particularly preferably, dichloromethane).
  • ethers such as ether, tetrahydrofuran, dioxane
  • ketones such as acetone
  • N, N-dimethylform Amides N, N-dimethylacetamide, N-methyl-1-pyrrolidone
  • amides such as hexmethylphosphoramide
  • sulfoxides such as dimethylsulfoxide, preferably halogenated And hydrogen (particularly preferably, dichloromethane
  • Bases used in the above are, for example, alkali metal alkoxides such as sodium methoxide and sodium ethoxide, alkali ⁇ carbonate i ⁇ l such as lithium carbonate, sodium carbonate and potassium carbonate, lithium hydroxide, water Sodium hydroxide, alkaline metal hydroxides such as lithium hydroxide or triethylamine, N, N-dimethylaniline, pyridine, 4-N, N- (dimethylamino) pyridyl It is a tertiary amine such as I 01, preferably a tertiary amine, and particularly preferably a combination of pyridine and 4-N, N- (dimethylamino) pyridine.
  • alkali metal alkoxides such as sodium methoxide and sodium ethoxide
  • alkali ⁇ carbonate i ⁇ l such as lithium carbonate, sodium carbonate and potassium carbonate
  • lithium hydroxide water Sodium hydroxide
  • the target compound (I) of each reaction is collected from the reaction mixture according to a conventional method.
  • the precipitated crystals are filtered, or insoluble matter is appropriately discriminated, neutralized as appropriate, the solvent is distilled off, water is added, and acetate is added. It can be obtained by extracting with a water-immiscible organic solvent such as chilled ethyl acetate and drying, and then distilling off the extraction solvent. If necessary, use a conventional method, for example, recrystallization, column chromatography, etc. It can be further purified.
  • Method B is a method for separately producing compound (I).
  • Step B1 is a step for producing a compound having the general formula (V), wherein the compound (II) or a reactive derivative thereof (acid halides, mixed acid anhydrides or active esters) is synthesized in an inert solvent. This is achieved by reacting a compound having the formula (IV) or an acid addition salt thereof.
  • an acid halide method, a mixed acid anhydride method, an active ester method or a condensation method can be used.
  • Step B2 is a step of producing a compound having the general formula (I), wherein the compound having the general formula (V) is reacted with a nitrating agent in a solvent-free or inert solvent, and
  • Nitroi dangling agents used are, for example, fuming nitric acid, nitrocollidium tetrafluoride. Boron, thiocyanyl chloride nitric acid, thiocyanyl nitric acid, nitronitrate nitrafluorate, or nitrosulfuric acid, preferably fuming nitric acid, nitrocollidium tetraflurochlorinic nitrate or thionyl chloride nitric acid.
  • the inert solvent used is not particularly limited as long as it does not participate in the reaction.
  • examples thereof include hydrocarbons such as hexane, cyclohexane, benzene, toluene, and xylene, dichloromethane, 1,2-dichloroethane, and tetrachloromethane.
  • Halogenated hydrocarbons such as carbon chloride; ethers such as ether, tetrahydrofuran and dioxane; ketones such as acetone; ditriles such as acetate nitrile; N, N Amides such as dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, and hexamethylphosphoramide; and sulfoxides such as dimethylsulfoxide.
  • They are hydrocarbons, ethers, nitriles or amides, particularly preferably nitriles.
  • the reaction temperature varies depending on the type of the starting compound (II), the nitrating agent and the like, and is usually from ⁇ 2 CTC to 50 ° C. (preferably around room temperature).
  • the reaction time varies depending on the reaction temperature and the like, but is usually 30 minutes to 24 hours (preferably 1 hour to 10 hours).
  • the target compound of each reaction is collected from the reaction mixture according to a conventional method.
  • the precipitated crystals are filtered or neutralized as appropriate, the solvent is distilled off, water is added, the mixture is extracted with a water-immiscible organic solvent such as ethyl acetate, dried, and then dried. It can be obtained by evaporating the extraction solvent, and if necessary, can be further purified by a conventional method, for example, recrystallization, column chromatography or the like.
  • Method C is a method for separately producing compound (I).
  • Step C1 is a step of producing a compound having the general formula (VII), in which a compound having the general formula (VI) or a reactive derivative thereof and a compound (III) or an acid addition salt thereof are mixed in an inert solvent. It is achieved by reacting. For example, a mixed acid anhydride method, an active ester method or a condensation method can be used. It is performed in the same way as the I 03 process.
  • Step C2 is a step of producing a compound having the general formula (VIII), which is achieved by removing the protecting group of the amino group of compound (VII) in an inert solvent.
  • the reaction is carried out in the same manner as in the reaction (a) for removing the protecting group for the amino group or imino group in the first step A1.
  • Step C3 is a process for producing a compound having the general formula (I), wherein the compound (VIII) or an acid addition salt thereof (for example, a mineral acid salt such as hydrochloride, nitrate or sulfate) is prepared in an inert solvent. And a compound having the general formula (IX), if desired,
  • the method is carried out in the same manner as in the method A, step A1.
  • the starting compounds (II) and (VI) are known or are easily produced according to known methods or methods similar thereto.
  • the starting compound (III) was prepared by a known method, a known method or a method similar thereto. Therefore, it is easily manufactured.
  • Chemical 'Abstract, Vol. 88, 7376, 1978: 01611 Organic Abstr., 88, 7376 (1978)
  • the starting compound (IV) is known or is easily produced according to a known method or a method similar thereto.
  • Chemical 'Abstract, 61, 9415, 1964: Chem. Abstr., 61, 9415 (1964), Tetrahedron, 47, 8177, 1999 Tetrahedron, 47, 8177 (1991), Tetrahedron Letters, Vol. 28, p. 6069, 1987: Tetrahedron Letters, 28, 6069 (1987), Tetrahedron Letters, Vol. 29, p. 1265, 1988: Tetrahedron Letters , 29, 1265 (1988), The Journal of the American Society of Chemicals, Vol. 113, pp. 8980, 1999: Am. Chem. So, 113, 8980 (1991), The Journal 'Science', 'Organic' Chemistry, Vol. 47, p. 3016, 1998: ⁇ Org. Chem., 47, 3016 (1982) etc.].
  • the starting compound (IX) is known or is easily produced according to a known method or a method similar thereto.
  • A represents the same meaning as described above, and Aa represents a C, —C 7 alkylene group (methylene is removed from the C, —C a alkylene group, and has 1 to 7 carbon atoms). Or a linear or branched alkylene group) or a formula —B—D—Ea— wherein B and D have the same meanings as described above, and Ea is a single bond or a C 5 -C 5 alkylene group ( A methylene is removed from the C, —C 6 alkylene group, and represents a linear or branched alkylene group having 1 to 5 carbon atoms.
  • Ab represents the above-mentioned C, -Ce alkylene group or a formula B a—D—E a— (where D and Ea have the same meanings as described above, and Ba represents , A single bond or the above-mentioned C, -C 3 alkylene group.)
  • Ac is the above-mentioned C, -C 6 alkylene group or a formula B-D-Eb- wherein B and D Represents the same meaning as described above, and Eb represents a single bond or an alkylene group (the above C, 1 C 6 alkylene group obtained by removing ethylene, and a straight or branched chain having 1 to 4 carbon atoms) Alkylene group).
  • Ad is the aforementioned C, -C 7 alkylene group or a formula —Ba—D—E—
  • Ae represents the d alkylene group or a formula —B—D—Ec— (wherein B and D Represents the same meaning as described above, and Ec represents a single bond or a group having the C, -C 2 alkylene group.)
  • R 5 represents a hydrogen atom
  • the C, 1 Cs alkyl group R 6 and R 7 are the same or different, and the above-mentioned C, 1 C 6 aliphatic acetyl group (preferably acetyl, propionyl, butyryl or isoptyryl group, particularly preferably an isoptyryl group) is preferred.
  • R s a represents an Shiano group or force Rubamoiru group
  • R 8 is , Shiano group or the formula one CH (C0 2 R s a) 2
  • R 9 is a hydroxyl protecting group (e.g., 2-Te Bok Rahidorofuriru, 2-tetrahydropyran Vila two Le, 4 5- or 6-membered cyclic ether groups such as 2-methoxy-2-tetrahydrobiranyl, 2-tetrahydrothiopyranyl, trimethylsilyl, triethylsilyl, t Bokuri d, such as single heptyl dimethylsilyl - c 4 alkyl silyl group, benzyl, methylbenzyl, main Bok Kishibenjiru, full old Robenjiru, d -C 6 alkyl, such as black hole base Njiru, d-c 6 alkoxy or halogen Benzyl group which may be substituted with benzyloxycarbonyl, methylbenzyloxycarbony
  • a benzyloxycarbonyl group which may be substituted with C, ⁇ Cs alkyl, d-Cealkoxy or halogen such as benzyloxycarbonyl, preferably 2-tetrahydroviranyl. And t-butyldimethylsilyl or P-methoxybenzyl.
  • R l ° represents a cyano group or an azide group
  • Ya is the halogen atom (preferably, a chlorine or bromine atom);
  • a C 6 alkylsulfonyloxy group preferably a methanesulfonyloxy or ethanesulfonyloxy group
  • C e a methanesulfonyloxy or ethanesulfonyloxy group
  • arylsulfonyloxy group preferably a benzenesulfonyloxy group or a toluenesulfonyloxy group
  • P represents an integer of 0 to 1
  • q represents an integer of 2 to 3.
  • Method D is a method for producing the compound (III).
  • Step D1 is a step for producing a compound having the general formula (I Va), which is carried out in an inert solvent (preferably, ethers such as ether and tetrahydrofuran).
  • an inert solvent preferably, ethers such as ether and tetrahydrofuran.
  • An aminocarboxylic acid having the formula (XII) is combined with a reducing agent (preferably, a borohydride compound such as sodium borohydride or sodium cyanoborohydride) at 0 ° C to 50 ° C.
  • a reducing agent preferably, a borohydride compound such as sodium borohydride or sodium cyanoborohydride
  • the reaction is carried out at C (preferably around room temperature) for 30 minutes to 10 hours (preferably 1 hour to 5 hours).
  • inert solvent preferably, a borohydride compound such as sodium borohydride or sodium cyanoborohydride
  • ethers such as ether and tetrahydrofuran, alcohols such as methanol and ethanol), and bases (preferably amines such as triethylamine and pyridine).
  • the amino group can be protected by reacting with the compound (X) in the presence, and the reaction is carried out in the same manner as in the reaction (c) for protecting the amino group or imino group in Step A1 of Method A described above.
  • the step D2 is a step of producing the compound (III), which is carried out by subjecting the compound (I Va) to double-dropping and, if desired, removing a protecting group for an amino group. The process is performed in the same manner as in the first step of Step 2 of Method B.
  • the desired reaction of removing the protecting group for the amino group is carried out in the same manner as the reaction (a) for removing the protecting group for the amino group or imino group in Step A1 of Method A after the above reaction.
  • Method E is a compound (IVa) wherein a group having the formula R 6 R 7 N— (wherein R 6 and R 7 have the same meanings as described above) is an amino group, and Aa is This is a method for separately producing a compound (IVb), which is a group having the formula: CH 2 —Ab- (wherein, Ab has the same meaning as described above).
  • Step E1 is a step for producing a compound (IVb).
  • an inert solvent preferably, ethers such as ether and tetrahydrofuran
  • a compound having the general formula (XIII) is reduced with a reducing agent (for example, Preferably, sodium borohydride, borohydride compound such as sodium cyanoborohydride, aluminum hydride compound such as lithium aluminum hydride, preferably lithium hydride aluminum
  • a reducing agent for example, Preferably, sodium borohydride, borohydride compound such as sodium cyanoborohydride, aluminum hydride compound such as lithium aluminum hydride, preferably lithium hydride aluminum
  • the reaction is carried out at 0 ° C. to 150 ° C. (preferably 30 ° C. to 10 CTC) for 15 minutes to 10 hours (preferably 30 minutes to 5 hours).
  • the compound (IVb) is produced by the catalytic reduction in the first step A of the above-mentioned Method A.
  • Step F1 is a process for producing a compound having the general formula (XIV), and a compound having the general formula (IVc) is dissolved in an inert solvent (preferably an ether such as ether or tetrahydrofuran).
  • an inert solvent preferably an ether such as ether or tetrahydrofuran.
  • Chloride phosphorus trichloride, phosphorus tribromide, phosphorus oxychloride, methanesulfonyl chloride, ethanesulfonyl chloride, benzenesulfonyl chloride, benzenesulfonyl bromide in the presence or absence of A halide such as p-toluenefonyl chloride or sulfonic anhydride such as methanesulfonic anhydride,
  • the obtained sulfonyloxy compound is dissolved in an inert solvent (preferably, ketones such as acetone, amides such as dimethylformamide and dimethylacetamide), sodium bromide and sodium iodide.
  • an inert solvent preferably, ketones such as acetone, amides such as dimethylformamide and dimethylacetamide
  • sodium bromide and sodium iodide By reacting with such an alkali metal halide at 0 ° C to 50 ° C (preferably around room temperature) for 30 minutes to 20 hours (preferably 1 hour to 10 hours), Can be manufactured.
  • Step F2 is a step of producing a compound having the general formula (XV).
  • Compound (XIV) is dissolved in an inert solvent (preferably, ethers such as ether and tetrahydrofuran, dimethylformamide, dimethylacetate).
  • Amides such as triamide), cyanolithium, sodium cyanide, potassium cyanide, or the like, or a compound of the formula M + — CH (COz R 5 a) 2 (where R 5 a Has the same meaning as described above, and M represents an alkali metal atom.)
  • a malonic acid derivative having a temperature of 0 ° C to 50 ° C (preferably around room temperature) for 30 minutes to 10 hours ( Preferably, the reaction is carried out for 1 hour to 5 hours.
  • This step is also preferably performed in the presence of sodium iodide.
  • the F 3 step is a step for preparing a compound (XII a), compound Te (XV) odor, compounds where R e Ca Nano group, in an aqueous solution, acid (preferably, hydrochloric acid, nitric acid, a sulfuric acid Reaction at 0 ° C to 150 ° C (preferably 30 ° C to 120 ° C) for 30 minutes to 10 hours (preferably 1 hour to 5 hours)
  • acid preferably, hydrochloric acid, nitric acid, a sulfuric acid Reaction at 0 ° C to 150 ° C (preferably 30 ° C to 120 ° C) for 30 minutes to 10 hours (preferably 1 hour to 5 hours
  • a compound in which R 5 is a hydrogen atom and P is 0 is produced.
  • 1 I 3 are granulated, and in Ihigo product (XV), R e is wherein one CH- (C0 2 5 a) 2
  • R 5 a is. Showing the same meanings as defined above
  • a group having a compound, by Nozomu Tokoro the following reaction conditions, i.e., in an inert solvent (preferably, water E one ether , Hydrated ethers such as tetrahydrofuran, hydrated alcohols such as hydrated methanol and hydrated ethanol, and bases (preferably, alkali metal waters such as dimethyl lithium hydroxide, sodium hydroxide, and potassium hydroxide).
  • an inert solvent preferably, water E one ether , Hydrated ethers such as tetrahydrofuran, hydrated alcohols such as hydrated methanol and hydrated ethanol, and bases (preferably, alkali metal waters such as dimethyl lithium hydroxide, sodium hydroxide, and potassium hydroxide).
  • the obtained carboxylic acid compound is dissolved in an inert solvent (preferably, ethers such as ether and tetrahydrofuran) in a diazomethane such as diazomethane, diazoethane, or diazohexane. 6 alkyl at 0 ° C. to 50 ° C.
  • an inert solvent preferably, ethers such as ether and tetrahydrofuran
  • a diazomethane such as diazomethane, diazoethane, or diazohexane. 6 alkyl at 0 ° C. to 50 ° C.
  • a reaction such as methanol, ethanol or hexanol wherein the C Ji 6 alcohol, the more reacted similarly to the active ester method a Act a 1 step, it is possible to produce the corresponding esters, carboxylic acid compounds, halogeno carbonate C, and -Ce alkyl
  • the corresponding acyl compound can be produced by carrying out the reaction in the same manner as in the reaction for producing the mixed acid anhydride in Step A1 of Method A.
  • Method G is a method for separately producing compound (XIlb) in which P is 1 in compound (XIlia).
  • Step G1 is a step of producing a compound having the general formula (XVI), and a compound having the general formula (XIIc) is reacted with an inert solvent (preferably, ether or tetrahydrofuran).
  • an inert solvent preferably, ether or tetrahydrofuran.
  • Halo such as ethers, methylene chloride, Hydrogenated hydrocarbons) and bases (preferably amines such as triethylamine, pyridine and N-methylmorpholine) in the presence or absence of methyl chlorocarbonate, ethyl chlorocarbonate, isobutyl chlorocarbonate, chlorocarbonate
  • Step G2 is the step of producing compound (XI lb).
  • Compound (XVI) is converted to silver acetate, silver carboxylate such as silver benzoate, silver methanesulfonate, silver benzenesulfonate, and p-toluene.
  • An organic amine in the presence of silver sulfonate such as silver sulfonate, silver powder, silver compound such as silver oxide (preferably silver benzoate or silver oxide)
  • Method H is for compounds (I Va) in which R 6 is a hydrogen atom.
  • Step H1 is a step of producing a compound having the general formula (XVIII), which is achieved by protecting the hydroxyl group of the compound having the general formula (XVII).
  • XVIII general formula (XVIII)
  • XVII hydroxyl group of the compound having the general formula (XVII)
  • the reaction is performed according to 1 IB.
  • the solvent is preferably used in an inert solvent (preferably, ethers such as ether and tetrahydrofuran, and halogenated hydrocarbons such as methylene chloride and chloroform).
  • an acid for example, a mineral acid such as hydrochloric acid, sulfuric acid, or nitric acid, an organic acid such as acetic acid, trifluroacetic acid, methanesulfonic acid, or P-toluenesulfonic acid, preferably hydrochloric acid).
  • the compound to be reacted with an unsaturated cyclic ether such as dihydrofuran, dihydropyran, 4-methoxydihydropyran or dihydrothiopyran at 0 ° C to 50 ° C (preferably around room temperature) for 30 minutes to By reacting for 5 hours (preferably 1 hour to 2 hours), the hydroxyl group can be protected.
  • an unsaturated cyclic ether such as dihydrofuran, dihydropyran, 4-methoxydihydropyran or dihydrothiopyran
  • the protecting group is a tri-C] -C ⁇ alkylsilyl group, an optionally substituted benzyl group or an optionally substituted benzyloxycarbonyl group
  • the protecting group is preferably used in an inert solvent (preferably Are ethers, such as ether, tetrahydrofuran, halogenated hydrocarbons, such as methylene chloride and chloroform, amides, such as dimethylformamide and dimethylacetamide, and sulfoxides, such as dimethylsulfoxide.
  • a base preferably, an alkali metal hydride such as lithium hydride, sodium hydride, or potassium hydride, or an amine such as triethylamine, pyridin, or N-methylmorpholine.
  • a base preferably, an alkali metal hydride such as lithium hydride, sodium hydride, or potassium hydride, or an amine such as triethylamine, pyridin, or N-methylmorpholine.
  • Trimethylsilyl chloride triethylsilyl chloride, t-butyldimethylsilyl chloride , T-butyldimethylsilyl bromide, benzyl chloride, benzyl bromide, methyl benzyl chloride, methoxy benzyl chloride, fluorobenzyl chloride, benzobenzyl chloride, benzyloxycarbonyl chloride, methylbenzyloxycarbonyl Halides such as chloride, methoxybenzyloxycarbonyl chloride, chlorobenzyloxycarbonyl chloride, and benzyloxycarbonyl chloride; and 0 ° C to 50 ° C.
  • C preferably around room temperature
  • the second step is a step of producing a compound having the general formula (XIX), which is achieved by halogenation or sulfonylation, and this step is performed in the same manner as in the above-mentioned Method F, Step F1.
  • the third step is a step for producing a compound having the general formula (XX) in an inert solvent (preferably, an ether such as ether or tetrahydrofuran, or an amide such as dimethylformamide or dimethylacetamide).
  • an inert solvent preferably, an ether such as ether or tetrahydrofuran, or an amide such as dimethylformamide or dimethylacetamide.
  • Sulfoxides such as dimethyl sulfoxide
  • compound (XIX) lithium metal cyanide, lithium cyanide, lithium cyanide, lithium metal cyanide or lithium azide, sodium azide
  • Reaction with alkali gold azide such as potassium azide at 0 ° C to 20CTC (preferably 50 ° C to 15CTC) for 15 minutes to 20 hours (preferably 30 minutes to 10 hours) It is performed by
  • the step H4 is a step of producing a compound having the general formula (XXI), which is achieved by reducing the compound (XX) .
  • This step is carried out in the same manner as the above-mentioned Method E, step E1; a compound R l ° is azido, a is compound force is Ad, from compounds R l ° is Shiano, a is Ah Ru compound group having the formula -CH 2 -Ad- is produced .
  • Step H5 is a step of producing compound (IVd), wherein the hydroxyl-protecting group achieved by removing the hydroxyl-protecting group of compound (XXI) and, if desired, protecting the amino group is It is removed by a method usually used in the field of synthetic organic chemistry.
  • the substituent is removed by reacting the corresponding compound with an acid.
  • the removal reaction is carried out in the same manner as the removal reaction in the case where the protecting group such as an amino group in the reaction (a) in Step A1 of Method A is a t-butyl group or the like.
  • the protecting group is a tri-substituted silyl group
  • the corresponding compound is treated in an inert solvent (preferably ethers such as tetrahydrofuran and dioxane) with a compound such as fluorotetrabutylammonium.
  • the protecting group is an optionally substituted benzyl group or an optionally substituted benzyloxycarbonyl group
  • the corresponding compound is catalytically reduced to remove the substituent
  • This reaction is carried out in the same manner as the removal reaction in the case where the protecting group such as an amino group in the reaction (a) in Step A1 of Method A is an optionally substituted benzyl group or the like.
  • the reaction for protecting the amino group is carried out in the same manner as in the reaction (c) in Step A1 of Method A.
  • Method I is a method for producing a compound having the general formula (IVe) included in compound (IV).
  • the first step is a step of producing a compound having the general formula (XXIII), wherein the compound having the general formula (XXIII) is concentrated ammonia at 0 ° C to 50 ° C.
  • the reaction is carried out at C (preferably around room temperature) for 30 minutes to 20 hours (preferably 1 hour to 10 hours).
  • the step I2 is a step of producing the compound (IVe), which is achieved by reducing the compound (XXIII). This step is carried out in the same manner as in the above-mentioned Method E, step E1.
  • Method J is a method for producing a compound having the general formula (IVf) contained in compound (IV).
  • Step J1 is a step of producing a compound having the general formula (XXV), which is achieved by reacting a compound having the general formula (XXIV) with concentrated ammonia in the same manner as in the above-mentioned Method I step I1.
  • Step J2 is a step of producing compound (IVf), which is performed by reducing compound (XXV). This step is performed in the same manner as in the above-mentioned Method E, step E1.
  • Method K is a method for producing a compound having the general formula (IVg) contained in the compound (IV).
  • the K1 step is a step of producing a compound having the general formula (XXV II) in an inert solvent (preferably, a halogenated hydrocarbon such as dichloromethane or chloroform, dimethylformamide, dimethylformamide).
  • an amide such as acetoamide, a sulfoxide such as dimethyl sulfoxide) or a compound having the general formula (XXVI); an oxidizing agent (for example, monopyridine chromate, dimethyl sulfoxide silicyl chloride, dimethyl sulfoxide); —Chlorine gas, dimethyl sulfoxide—trifluoroacetic anhydride, succiniimide dimethyl sulfonium chloride, etc., preferably dimethyl sulfoxide oxalic acid chloride) and 0 ° C. to 50 ° C. (preferably room temperature) Around 15 minutes to 20 hours (preferably 30 minutes to 10 hours),
  • the K2 step is a step of producing a compound having the general formula (XXV III), and the compound (XXV II) is prepared in an inert solvent (preferably, ethers such as ether and tetrahydrofuran) in the presence of a base.
  • an inert solvent preferably, ethers such as ether and tetrahydrofuran
  • strong base amines such as 1,5-diazabicyclo [4.3.0] nonane 5-ene, 1,8-diazabicyclo [5.4.0] pendes-1-ene, butyl
  • An alkyllithium such as lithium
  • R 1 ') 3 P + (CH 2 ) qOH Y- wherein ⁇ and q have the same meanings as described above, and R 11 is a C 6 — d
  • a compound having the aryl group C to 150.
  • the reaction is carried out at C (preferably CTC to 100 ° C) for 1 hour to 10 days (preferably 5 hours to 7 days).
  • Step K3 is a step of producing compound (IVg).
  • Compound (XXVIII) is reacted with compound (XXVIII) in the same manner as in the reaction (a) for removing the amino group or imino group protecting group in step A1 of method A described above. It is carried out by catalytic reduction.
  • Method L is a method for producing a compound having the general formula (IVh) contained in compound (IV).
  • the first step is a step of producing a compound having the general formula (XXVIa), which is achieved by reducing a compound having the general formula (XIId). It is performed in the same manner as the process.
  • Step L2 is a step of producing a compound (XXIVIA), and
  • This step is achieved by oxidizing (XXVIa), and this step is performed in the same manner as the K method, the first K step.
  • Step L3 is a step of producing compound (IVh), which is carried out in an inert solvent (preferably, ethers such as ether and tetrahydrofuran).
  • an inert solvent preferably, ethers such as ether and tetrahydrofuran.
  • the target compound of each reaction is collected from the reaction mixture according to a conventional method.
  • a conventional method for example, when there may or insolubles to collected precipitated from crystals were filtered off as appropriate, in the case of the reaction solution strength s acidic or alkaline, suitably neutralized, water was added, acetic acid Echiru Extraction with a water-immiscible organic solvent such as described above, drying, and then distilling off the extraction solvent can be obtained.If necessary, it can be further purified by a conventional method, for example, recrystallization, column chromatography, etc. can do.
  • the compound of the present invention having the general formula (I) or a pharmacologically acceptable salt thereof has an excellent collateral vasodilatory effect, and has an effect on headache, dizziness, tachycardia or digestive organs, liver, bone and the like. Since it has no side effects such as adverse effects and does not receive the first-pass effect, it is useful as a therapeutic or preventive agent (preferably, a therapeutic agent) for angina pectoris.
  • the compound (I) of the present invention and a pharmacologically acceptable salt thereof are used as a therapeutic or prophylactic agent for angina pectoris
  • the compound (I) itself or an appropriate pharmacologically acceptable excipient or diluent may be used.
  • These preparations may contain excipients (eg, sugar derivatives such as lactose, sucrose, glucose, mannitol, sorbite; starch derivatives such as corn starch, potato starch, ⁇ -starch, dextrin, carboxymethyl starch).
  • excipients eg, sugar derivatives such as lactose, sucrose, glucose, mannitol, sorbite
  • starch derivatives such as corn starch, potato starch, ⁇ -starch, dextrin, carboxymethyl starch.
  • Cellulose derivatives such as crystalline cellulose, low-substituted hydroxybutyl cellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, and internal carboxymethylcellulose cellulose; Gum arabic; Dextran; Bullane; Light anhydrous silicic acid, Synthetic aluminum silicate, Silicate derivatives such as magnesium metasilicate aluminate; Phosphate derivatives such as calcium phosphate; Carbonic acid such as calcium carbonate Salt derivatives; sulfate derivatives such as calcium sulfate; binders (eg, the above-mentioned excipients; gelatin; polyvinylpyrrolidone; magrogol, etc.); disintegrants (eg, the above-mentioned excipients; Chemically modified such as scarmellose sodium, sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone, starch, cellulose derivatives, etc., lubricants (eg, talc; stea
  • stabilizers eg, methyl paraben, propi Paraoxybenzoic
  • the dosage varies depending on symptoms, age, etc., but in the case of oral administration, the lower limit lmg (preferably 5mg) and the upper limit lOOOmg (preferably 300mg) should be administered intravenously. In this case, a lower limit of 0.1 mg (preferably 0.5 mg) and an upper limit of 100 mg (preferably 50 mg) are administered to an adult 1 to 6 times per day depending on the symptoms. That power. [Best mode for carrying out the invention]
  • Example 5 of 1-[(2S) —3-mercapto-2-methylpropynyl] -l-broline-N — [(1R) 1-1-methyl-2-nitroxicetyl] amide, 0
  • the reaction was carried out in the same manner as in Example 4 using acetic anhydride (23 ml) and pyridine (0.2 Om1) to obtain 566 mg of the title compound as colorless crystals.
  • Example 7 (a) 1-t-butoxycarbonyl L-broline—N — [(1S) —1-methyl-2-nitroxequityl] amide 0.50 g of 5 ml of 4N hydrochloric acid The mixture was dissolved in a solution of oxane and stirred at room temperature for 40 minutes. The solvent was distilled off under reduced pressure, and toluene was added to the obtained residue, which was azeotropically dried.
  • Example (11a) of Example 1 [(2R) —2-Acetylamino-3-mercaptoprobinyl] 1-L-proline-t-butyl ester was dissolved in 75 ml of pyridine, Under ice-cooling and stirring, 4.5 ml of acetic anhydride was added, and the mixture was stirred at room temperature overnight.
  • the reaction solution was poured into ice water and extracted with dichloromethane. The extract was washed with aqueous citric acid and saturated saline, and dried over anhydrous magnesium sulfate.
  • Example of Og 1-t-butoxycarbone-L-proline-N-[(1S) -1-methyl-2-ditroxicetyl] amide of (7a) was converted to 1 Om 1 of 4N hydrochloric acid. It was dissolved in a dioxane solution and stirred at room temperature for 40 minutes. The solvent was distilled off under reduced pressure, and toluene was further added to the residue, followed by azeotropic drying. To the residue was added 1.02 g of 2-acetyl thioacetic acid and 4 Oml of anhydrous tetrahydrofuran, and the mixture was updated.
  • Example (14a) 1 — [(2 S) — 3— “t-butoxycarbonylthio-2-methylpropionyl] — L-proline-N- (trans-one-4-2 (Oxymethylcyclohexylmethyl) carboxamide was dissolved by adding 1 Om 1 of 4N hydrochloric acid in dioxane, and the mixture was stirred at room temperature for 3 hours and 10 minutes. The solvent was distilled off under reduced pressure, and the residue was separated and purified by silica gel column chromatography (elution solvent: cyclohexane ethyl acetate -2: 1). This gave 147 mg of the title compound as a colorless oil.

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Abstract

Cette invention concerne des dérivés de thiazolidine, ou leurs sels acceptables sur le plan pharmacologique, lesquels correspondent à la formule générale (I) où X représente méthylène, oxygène ou soufre, et R1 représente un groupe alcanoyle possédant un ou plusieurs substituants. Les substituants essentiels comprennent des groupes correspondant à la formule -S-R2 où R2 représente hydrogène, acyle aliphatique, alcoxycarbonyle ou arylcarbonyle éventuellement substitué par alkyle, alcoxy ou halogéno, ou encore, un carbonyle hétérocyclique aromatique qui contient un hétéroatome choisi dans le groupe azote, oxygène et soufre et qui peut éventuellement être substitué par alkyle, alcoxy ou halogéno. Les substituants souhaitables sont amino, mono ou dialkylamino, amino protégé ou monoalkylamino protégé. 'A' représente quant à lui un groupe correspondant à la formule -B-D-E- où B et E peuvent être identiques ou différents et représentent chacun une liaison unique ou alcylène, tandis que D représente cycloalcylène éventuellement substitué par alkyle. Ces composés ont une excellente action anti-angineuse et de vasodilatation collatérale, et peuvent être utilisés dans le traitement ou la prévention des angines de poitrine.
PCT/JP1997/000581 1996-03-01 1997-02-27 Derives de thiazolidine WO1997031896A1 (fr)

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Application Number Priority Date Filing Date Title
AU22308/97A AU2230897A (en) 1996-03-01 1997-02-27 Thiazolidine derivatives

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JP8/44829 1996-03-01
JP4482996 1996-03-01

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998021193A1 (fr) * 1996-11-14 1998-05-22 Nicox S.A. Nitrates organiques a activite antithrombotique
EP0984928A1 (fr) * 1997-03-26 2000-03-15 Yissum Research Development Company Of The Hebrew University Of Jerusalem Derives de nitrate aromatiques et heterocycliques
WO2007043615A1 (fr) * 2005-10-14 2007-04-19 Osaka University Réactif ester de peptide et son utilisation pour la ligature ou la production d’un composé thio-ester

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06500318A (ja) * 1990-09-05 1994-01-13 セドナ　ファルマス―ティカルズ　ベスローテン　フェンノートシャップ 新規チアゾリジン誘導体
JPH07258212A (ja) * 1991-02-25 1995-10-09 Sankyo Co Ltd ピロリジノン誘導体
JPH08217765A (ja) * 1994-12-15 1996-08-27 Sankyo Co Ltd チアゾリジノン化合物

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06500318A (ja) * 1990-09-05 1994-01-13 セドナ　ファルマス―ティカルズ　ベスローテン　フェンノートシャップ 新規チアゾリジン誘導体
JPH07258212A (ja) * 1991-02-25 1995-10-09 Sankyo Co Ltd ピロリジノン誘導体
JPH08217765A (ja) * 1994-12-15 1996-08-27 Sankyo Co Ltd チアゾリジノン化合物

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998021193A1 (fr) * 1996-11-14 1998-05-22 Nicox S.A. Nitrates organiques a activite antithrombotique
EP0984928A1 (fr) * 1997-03-26 2000-03-15 Yissum Research Development Company Of The Hebrew University Of Jerusalem Derives de nitrate aromatiques et heterocycliques
EP0984928A4 (fr) * 1997-03-26 2004-08-18 Yissum Res Dev Co Derives de nitrate aromatiques et heterocycliques
WO2007043615A1 (fr) * 2005-10-14 2007-04-19 Osaka University Réactif ester de peptide et son utilisation pour la ligature ou la production d’un composé thio-ester

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AU2230897A (en) 1997-09-16

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