JPS62215585A - Cyclocanaline derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (R<1> represents amino or organic residue via N atom; R<2> represents COOH or group derivable therefrom; R<3>-R<6> represent H or organic residue, including a case where both R<3> or R<4> and R<5> or R<6> may form chemical bond) or salt thereof. EXAMPLE:4-Nitrobenzyl 2-[(4S)-4-benzyloxycarbonylamino-3-oxo-2-tetrahydro-1,2- oxazinyl]-5-oxo-2-tetrahydrofurancarboxylate. USE:A remedy for microbism and antimicrobial agent. PREPARATION:A compound expressed by formula II (R<1>' represents organic residue via N atom) is reacted with a compound expressed by formula III (R<2>' represents group derivable from COOH) or reactive derivative thereof and, if necessary, further subjected to converting reaction of the groups R<1>' and/or R<2>' of the resultant compound.

Description

Detailed Description of the Invention The present invention relates to novel cyclocanalin derivatives (cyclohomoserine derivatives), more specifically 2-(4-substituted amino-
3-oxo-2-tetrahydro-! .

The present invention relates to a 2-oxazinyl)-5-oxo-2-tetrahydrofurancarboxylic acid derivative and a method for producing the same.

Conventional technology A new antibiotic that exhibits antibacterial activity against Durham-positive bacteria and Gram-negative bacteria was recently isolated from soil and was developed from new bacterial species belonging to the genus Enbetobacter and Rhizobacter.
'AN-588 (hereinafter sometimes abbreviated as rTAN-588J) was discovered.

The antibiotic TAN-588 has a completely new, hitherto unknown skeleton in which 5-oxo-2-tetrahydrofurancarboxylic acid is bonded to the nitrogen atom of the 3-oxoisoxazolidine ring. Therefore, we synthesized a derivative of TAN-588, and found that the derivative had excellent antibacterial activity.
It has been found that it can be used as an antibacterial agent.

Conventionally, l- was added to the nitrogen atom of the 3-oxoisoxazolidine ring.
The synthesis of a compound into which a methyl acetate group has been introduced has been reported [Tsuji, both, Heterocycle
cs), Vol. 8, p. 153, 1977].

However, it has been reported that the antibacterial activity of the compound into which the l-methylacetic acid group has been introduced is not observed.

The present invention provides novel 2-(4-
Substituted amino-3-oxo-2-tetrahydro-1,2-
An object of the present invention is to produce carboxylic acid derivatives (oxazinyl)-5-oxo-2=tetrahydrofuran.

The present invention is directed to (1) the general formula [wherein R1 does not represent an amino group or an organic residue via nitrogen; R1 represents a carboxyl group or a group derived therefrom. It', l', IN' and R11 are the same or different and represent hydrogen or an organic residue, including the case where R'' or R4 and R' or R8 form a chemical bond. compound or its salt.

(2), general formula [wherein R'' represents an organic residue via nitrogen; A compound represented by the formula [wherein R'' does not represent a group that can be derived from a carboxyl group, and n 3 , n 4 , RI! and R8 have the same meanings as above]; or A method for producing a compound represented by general formula (1), which comprises reacting the compound with a reactive derivative thereof, and further subjecting the compound to a conversion reaction of R'' and/or R'', if necessary.

(3) Compound (Ill) and the general formula [wherein Y indicates an elimination method. R″', It3.rt'
, n' and R@ have the same meanings as above. This is a method for producing compound (1), which is characterized by reacting a compound represented by the formula (1) with a compound represented by the following formula, and further subjecting the compound to a conversion reaction of R1' and/or R8', if necessary.

In the above general formula, examples of organic residues via nitrogen represented by 1 or It'' include acylamino, amino substituted via carbon, alkenylamino, thioamino, silylamino, phosphate amino, formula -〇 〇 −
Examples include a group represented by G O-N II-.

Examples of the acyl in the above acylamino include the acyl group substituted at the 6-position amino group of conventionally known penicillin derivatives, the acyl group substituted at the 7-position amino group of cephalosporin derivatives, and the like.

Examples of the anruamino group include, for example, the formula +1''-G
O-N- R'' [In the formula, R1 is hydrogen or alkyl'' (In the description of each group in this specification, a group with '' indicates that any substituent may be substituted.) , alkenyl", cycloalkyl0
．． Aryl “Afi*8”, alkoxy 1 or aryloxy”, l” represents hydrogen or alkyl 8, R
11 includes cases in which R12 forms a ring with R12. ; or formula 1'l '5(C1-1t)
n C(=Z)-(in the formula, 1115 is a multi-chain ring "6 alkoxy" or amino 0, n is 0, 1 or 2,
Z represents 0 or S, respectively. ), R'4 represents alkyl, aryl, cycloalkenyl, or polycyclic ring, respectively. The group represented by ko.

Formula % Formula % [In the formula, R"JfFormula R" -C- (In the formula, ■R1I' haal n19 kyl", polychord ring" or aryl 0, rl19 is hydrogen, alkyl 0. alkenyl 1. cycloalkyl 1° complex ['' or the formula -rt! Ou Q l (where Rl
Q represents "alkylene", cycloalkylene or alkenylene, and R21 represents "aryl", carboxy or its ester or mono- or dialkylamide, respectively. ), R17 is a chemical bond or a group represented by the formula -co-
A group represented by N 1-1- Cl-t - (wherein rtt'' represents at1-kyl, 9-aryl-1 or a multi-chain ring).

Formula % Formula % 1 In the formula, R" is aryl", m*i" or cycloalkenyl", R24 is hydroxy, sulfamoyl,
Indicates sulfo, sulfooxy or acyloxy0, respectively. ] brackets.

formula %formula% [In the formula, R25 is "alkyl", cyano, aryl".

Aryloxy ", alkenylene 1 heterocycle", amino 0
or a group represented by 2rt"'-C(=S)- (in the formula, R"' represents an alkokene), and R" represents a chemical bond or -S-, respectively.] Base.

The expression [in the expression, nt? and Rls are the same or different,
hydrogen, alkyl, aryl, heterocycle, or cycloalkyl, Z represents 0 or S, respectively.

Also, the formula rtla c- in "I't" is the formula OR
111 represents the syn isomer represented by the formula % RlI C- and the anti-isomer I r represented by the formula % RlI C- (+·-8/ or a mixture thereof.

As an example of an amino substituted via carbon as an example of the organic residue via nitrogen represented by R1 or R1', for example, the formula % formula % 1 In the formula, rt'' is alkyl 7, aryl 0. alkenyl “Or indicates a compound ring 1. ”.

Formula [wherein R30 and R31 are the same or different and are alkyl7. aryl7 or alkenyl, respectively, including the case where 1130 and n31 form a multi-chain ring together with the adjacent nitrogen atom.

The formula [in the formula, n3? , +i 33 and rL'' are the same or different and represent alkyl 1. aryl 1. alkenyl, respectively, and n3? and l't'' or R'' together with the adjacent nitrogen atom to form a complex rAI''.

As an example of alkenylamino as an example of the nitrogen-mediated organic residue represented by R' or R'' above, examples of alkenylamino include the formula [wherein R35 and R'' are the same or different, hydrogen, alkyl'', aryl 1 ．． It represents a cycloalkyl, an amino group or a multi-stranded ring 1, including the case where IN 36 and R36 together with adjacent carbon atoms form a cycloalkyl'' or a multi-stranded ring 7.

An example of thioamino as an example of the nitrogen-mediated organic residue represented by R1 or R'' is the formula % [wherein R'' is alkyl 1 or aryl'', and n is O
9l or 2 respectively. Examples include groups represented by .

An example of silylamino as an example of an organic residue via nitrogen represented by 1' (l or R1') is, for example, the formula [where rt"4t" and rt" are the same or different, alkyl 1 or R'' represents hydrogen or silyl 1, including the case where these form a cyclic group.

An example of an amino phosphoric acid as an example of the nitrogen-linked organic residue represented by R1 or Ft'' is, for example, the formula [wherein R'' and R43 are the same or different, alkyl 1.7 ryl 0. Indicates "alkoxy" or "aryloxy", including the case where R42 and R43 form a heterocycle 0. Examples include groups represented by .

The formula -CO-G O-N H as an example of the nitrogen-mediated organic residue represented by AtE IN' or l't'' above.
Examples of the group represented by - include the formula 1. In the heterocycle "amino" in the above formula, the organic residue represented by R1 or R1' via nitrogen is preferably one having a molecular weight of up to 500, for example.

Examples of groups that can be derived from the carboxyl group represented by R' or R'' in the above formula include, for example, the formula % formula % [wherein R45 is alkyl", alkenyl 1. Aryl 1. Cycloalkyl", heterocycle" or silyl 1. In the group represented by formula 1, R4@ and R47 are the same or clearly,
Hydrogen, alkyl, aryl, cycloalkyl.

Indicates alkenyl 1 or polycyclic ring 1, R48 and n4
? includes the case in which the compound forms a polycyclic ring with adjacent nitrogen atoms.

In the above formula, n! The group derivable from a carboxyl group represented by , or IN'' preferably has a molecular weight of up to 500, for example.

The alkyl group in the above formula is preferably one having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 5ec-butyl, [-butyl . 1.1
-dimethylpropyl, n-pentyl.

Examples include isopentyl, n-hexyl, isohexyl, and the like.

Examples of the substituent that the alkyl group may have include balogen, oxo, deoxo, and nitro.

Amino (which may have alkyl, alkenyl, cycloalkyl, aryl, acyl, carbamoyl, N-sulfocarbamoyl as a substituent), sulfo, cyano, hydroxy, carboxy (which may be esterified with alkyl). ), cycloalkyl, cycloalkenyl, alkoxy (which may have amino, hydroxy, carboxy, halogen, aryl, cycloalkyl, alkoxy as a substituent), aryl (halogen, alkyl, alkoxy).

It may have alkylamino, amino, carbamoyl, sulfo, alkylsulfonyl, cyano, hydroxy, carboxy, nitro, acyloxy, aralkyloxy, or sulfoxy as a substituent. ), arylcarbonyl which may have the same substituent as the above aryl, aryloxy which may have the same substituent as the above aryl, tro, oxo, aryl, alkenylene, ha aGenoalkyl, alkylsulfonyl, alkyl, alkoxy, alkylamino, amino, halogen, carbamoyl, hydroxy, cyano, carboxy,
It may have sulfo as a substituent. ), acyl (
It may have arylcarbonylhydrazino as a substituent, which may have hydroxy, halogen, amino, or nitro as a substituent. ) Acyloxy, alkoxycarbonyl, alkoxycarbonyloxy (optionally substituted with halogen), acyloxy-ethoxy, aralkyl (alkyl, alkoxy, halogen, amino, hydroxy, nitro).

It may have cyano, carbamoyl, or sulfamoyl as a substituent. ), aralkyloxy (which may have acyloxy, alkyl, alkoxy, halogen, amino, hydroxy, nitro, cyano, carbamoyl, or sulfamoyl as a substituent).

hydroxysulfonyloxy, alkylsulfonyloxy, arylsulfonyloxy, alkylsulfonyl,
Aminosulfonyl, alkylsulfinyl, arylsulfonyl, alkylsulfinyl.

Alkylthio (which may have cyano, halogen, carboxy, alkylamino, imino, carbamoyl, or acylamino as a substituent), heteroruthio. Heterocyclic group - thio (cyano, hydroxy, amino, alkylamino, alkyl, halogen, oxo may be substituted as a substituent), heterocyclic group (cyano, hydroxy, amino, alkylamino, alkyl).

It may have halogen or oxo as a substituent. )
-alkylucio. Iminomethylamino, iminoethylamino. Silyl (alkyl, aryl may be substituted with Fl or U as a substituent), alkyloxycarbonyl,
Ori-rucarbonyl (acyloxy).

I\PI ^〆・) Ma 5117 may have 'I-I''-S noma -L 1A : Nof I+--7゜moyl as a substituent. ), phthalimide,
Succinimide, dialkylamino, dialkylaminocarbonyl, arylcarbonylamino, carbamoyl, carbamoyloxy, N-sulfocarbamoyloxy, alkylcarbonylcarbamoyloxy (optionally substituted with halogen), alkoxyimino, formula 1 % >=<>- (wherein It'' and R''n''ocs are the same or different and represent a hydroxyl group or an amino group), and the like.

In the above formula, the alkylene represented by Rlo preferably has 1 to 6 carbon atoms, and examples thereof include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, and hexamethylene.

Examples of substituents that the alkylene group may have include halogen, amino, hydroxy, alkoxy, carboxy, carbamoyl, cyano, and nitro.

The cycloalkyl in the group in the above formula, the cycloalkyl in cycloalkyloxy, or the cycloalkyl forming a ring is preferably one having 3 to B carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, Examples include cyclohexyl, cycloheptyl, and cyclooctyl.

Examples of the substituents that the cycloalkyl substituent may have include halogen, nitro, amino, hydroxy, sulfo, cyano, carboxy, oxo, and thioxo.

Examples of the cycloalkylene in the group in the above formula include those in which the above cycloalkyl has another bond.

Aryl in the group in the above formula, arylcarbonyl, aryloxycarbonyl, aryloxy or arylthio is, for example, phenyl, naphthyl, biphenyl.

Examples include anthryl and indenyl.

Examples of substituents that the aryl group may have include halogen, nitro, cyano, amino (which may have alkyl, alkenyl, cycloalkyl, and aryl as a substituent), sulfo, mercapto, Hydroxy, carboxy, acyl, sulfoxy, sulfamoyl, carbamoyl, alkyl (which may have amino, halogen, hydroxy, cyano, or carboxy as a substituent), alkoxy, aralkyloxy, alkylsulfonamide.

Examples include methylenedioxy, alkylsulfonyl, and alkylsulfonylamino. Also, cycloalkyl and fused rings (e.g., tetrahydronaphthyl).

indanyl, acenaphthyl, etc.).

The alkoxy in the group in the above formula has 1 to 1 carbon atoms.
6 is preferred, examples include methoxy, ethoxy, n-propoxy, l-propoxy, n-
Examples include butoxy, i-butoxy, t-butoxy, n-pentyloxy, n-hexyloxy and the like.

Examples of substituents that the alkoxy group may have include halogen, nitro, amino, hydroxy, sulfo, cyano, carboxy, aryl, tho, amino, hydroxy, alkyl, and alkoxy as substituents. good. ), silyl (which may have alkyl, aryl, or aralkyl as a substituent), and the like.

As the alkylthio in the group in the above formula, the number of carbon atoms is 1
-6 is preferred, and examples thereof include methylthio, ethylthio, n-propylthio, i-propyldio, n-butylthio, i-butylthio, n-pentylthio, n-hexylthio and the like. Examples of the substituent which may have the alkylthio group include the same substituents as the alkoxy substituents described above.

The alkenyl in the group in the above formula is preferably one having from i to 6 carbon atoms, such as methylene, vinyl, and allyl.

Isopropenyl, l-propenyl, 2-butenyl.

3-methyl-3-butenyl, 1,3-butadienyl.

1.3-pentagenyl, 4-pentaenyl, 1.3-
Examples include hexagenyl, ethylidene, propylidene, isopropylidene, and butylidene.

Examples of the substituents that the alkenyl group may have include halogen, nitro, amino (which may have acyl as a substituent), sulfo, cyano, hydroxy, carboxy, carbamoyl, sulfamoyl, aryl ( aryl), acyl, etc. - The alkenylene in the group in the above formula preferably has 2 to 6 carbon atoms, examples of which include vinylene, -propenylene, 2-butenylene, 2-
Examples include pentenylene, 1,3-hexadienylene, and the like.

The substituents that the alkenylene group may have include:
Examples include halogen, cyano, carbamoyl, and the like.

In the above formula, RI4. The cycloalkenyl represented by R1'' is preferably one having 3 to 8 carbon atoms,
For example, for example! -cyclopropenyl, 1-
Cyclobutenyl, l-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, l-cyclohexenyl, 2-cyclohexenyl.

3-cyclohexenyl, l-cyclohebutenyl, 1゜4
-cyclohexadienyl and the like.

Examples of the substituents that the cycloalkenyl group may have include halogen, nitro, and amino.

Examples include sulfo, cyano, hydroxy, carboxy, carbamoyl, and sulfamoyl.

The polychord ring in the group in the above formula or the heterocycle formed by these groups includes, for example, a 5- to 7-membered heterocyclic group containing one sulfur atom, nitrogen atom, or oxygen atom, and a 2- to 4-membered heterocyclic group.
a 5-6 membered hydrogen ring group containing 1-2 nitrogen atoms and 1-2 nitrogen atoms and 1 sulfur or oxygen atom;
Examples include membered heterocyclic groups, which may be fused with a 6-membered ring group containing up to two nitrogen atoms, a benzene ring, or a 5-membered ring group containing one sulfur atom.

Specific examples of the above heterocyclic groups include 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, piperinol,
Pyrazolyl, pyranyl, thiopyranyl, imidazolyl.

Thiazolyl, isothiazolyl.

Oxazolyl, isoxazolyl, pyrido [2,3-d]
Pyrimidyl, benzopyranyl, [,8-naphthyridyl,
1.5-naphthyridyl, 1.6-naphthyridyl.

1.7-naphthyridyl, 2.7-naphthyridyl, 2゜6
-naphthyridyl, quinolyl, cheno[2,3-b]pyridyl, tetrazolyl, thiadiazolyl, oxadiazolyl. triazinyl, triazolyl, chenyl, pyrrolyl, furyl, pyrrolidinyl, imidazolidinyl, dichetane, tetrahydropyranyl, tetrahydrofuranyl, benzothenyl, hexahydro-11-1-azepinyl,
Examples include indolyl, isointridinyl, and chromanyl.

Examples of the substituents that the polycyclic group may have include amino (which may have acyl, halogen-substituted alkylacyl, phenyl, or alkyl as a substituent);
Halogen, nitro, sulfo, cyano. Hydroxy, carboxy, oxo, deoxo, Ct-10 alkyl [aryl, halogen, amino, hydroxy.

It may have carboxy, alkoxy, alkylsulfonyl, dialkylamino, or phosphoric acid (which may have alkyl as a substituent) as a substituent. ], cycloalkyl, alkoxy (halogen.

It may have hydroxy as a substituent. ).

Acyl, aryl having 1 to 4 carbon atoms (halogen, nitro,
Alkyl, alkoxy, amino, sulfo, human hepoxy,
It may have cyano as a substituent. ).

oxo, thioxo, amino acid residue-thio (examples of amino acid residues include those mentioned below), Ct-8o alkyludio[aryl.

Halogen, amino, hydroxy, carboxy, alkoxy, alkylsulfonyl, dialkylamino.

It may have phosphoric acid (which may have alkyl as a ', !j, or substituent) as a substituent. Co, heterocycle (alkyl, alkoxy, halogen, nitro, cyano,
May have carboxy, formyl, alkylsulfonyl as a substituent, ), 2rt''-CH=N
-C formula, I month is a compound ring (alkyl, alkoxy,
Halogen, nitro, cyano, hydroxy.

It may have carboxy, formyl, or alkylsulfonyl as a substituent. ) is shown. ] and the like.

In the above formula, examples of the ring formed by R12 together with R'' include phthaloyl, succinyl, and maleoyl.

Cytotheconoyl. Examples of the ring formed with glutaryl, adipoyl, etc. include 2,2-dimethyl-5-oxo-4-phenyl-imidazolidine.

Examples of substituents that the cyclic group may have include halogen, nitro, amino, hydroxy, sulfo, cyano, and carboxy.

The acyl in acyloxy and the acyl in R3-6, 8, and 8 in the above formula preferably have 1 to 4 carbon atoms, and examples include formyl, acedel, propionyl, butyryl, isobutyryl, and the like. Examples of the substituent include alkyl (which may have amino, halogen, cyano, alkoxy, carboxy, or hydroxy as a substituent).

In the above formula, the amino acid residue represented by +t+3 is:
Examples include glyzul, alanyl, valyl, leucyl, isoloinyl, seryl, threonyl, cysteinyl, cisdel, methionyl, α- or β-asparagyl, α- or γ-glutamyl, lysyl, arginyl, phenylalanyl, phenylglycyl, tyrosyl, Examples include hisdecyl, tryptophanyl, prolyl, and the like.

Examples of substituents that the amino acid residue may have include halogen, hydroxy, sulfo, carboxy, cyano, alkylamino, aralkyloxycarbonyl,
Examples include aralkyloxy and guanidino.

In the above formula, as the amino group ff1JJ represented by R1'', those used for this purpose in the field of β-lactam and peptide synthesis are conveniently employed. For example, phthaloyl, 4-nitrobenzoyl, 4- t
ert-butylbenzoyl, 4-jerk-butylbenzenesulfonyl, benzenesulfonyl.

Aromatic anru groups such as toluenesulfonyl, such as formyl, acedel, propionyl, monochloroacetyl,
Dichloroacetyl, trichloroacedel.

Aliphatic acyl groups such as methanesulfonyl, ethanesulfonyl, trifluoroacedel, malonyl, succinyl, e.g. methoxycarbonyl, ethoxycarbonyl, t
-butoxycarbonyl, isopropoxycarbonyl, 2
-cyanoethoxycarbonyl, 2゜2.2-trichloroethoxycarbonyl, benzyloxycarbonyl, 4-
Nitrobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, diphenylmethyloxycarbonyl, methoxymethyloxycarbonyl, acetylmethyloxycarbonyl, isobornyloxycarbonyl,
Esterified carboxyl groups such as phenyloxycarbonyl, (hexahydro-11-1-azepine-1-
yl) methylene group such as methylene. Sulfonyl groups such as 2-amino-2-carboxyethylsulfonyl.

Furthermore, for example, trityl, 2-nitrophenylthio,
Protecting groups for amino groups other than acyl groups include benzylidene, 4-nitrobenzylidene, trialkylsilyl, benzyl, and 4-nitrobenzyl. The selection of the protecting group is not particularly limited in the present invention, but monochloroacedel, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, and 4-nitrobenzyloxycarbonyl are particularly preferred.

Examples of the substituent in the carboxy group which may have a substituent in the group in the above formula include, for example, alkyl (
It may have halogen, cyano, or hydroxy as a substituent. ), aryl (which may have alkyl, alkoxy, halogen, hydroxy, acyloxy, sulfo, cyano, or sulfamoyl as a substituent), silyl (which may have alkyl, aryl, or aralkyl as a substituent). ), compound ring (may have amino, alkylamino, sulfamoyl, carbamoyl, halogen, cyano, nitro as a substituent), amino (alkyl, aryl, cycloalkyl, sulfo or aralkyl as a 1ξ substituent) It may have.Also,
Together with the nitrogen in the amino group, a 5- to 6-membered central ring may be formed. ), etc.

In the above formula, examples of the ester of carboxy represented by R'' include alkyl esters having 1 to 6 carbon atoms, and specific examples thereof include methyl ester, ethyl ethyl, propyl ester, n-
Examples include butyl ester, isobutyl ester, tert-butyl ester, and the like.

Examples of the substituent for amino which has a substituent in the group in the above formula include amidine and iminomethyl. imino (aryl-substituted) methyl, guanidylcarbonyl, heterocycle (which may have the same substituents as the above-mentioned heterocycle), imino (optionally substituted with a heterocycle) methyl, Examples include alkylcarbonyl, arylcarbonyl, hydroxyalkyl, alkyl, and the like.

Examples of substituents on the silyl group in the above formula, which may be substituted, include alkyl, aryl, aralkyl, and the like.

The above R", R", It40 may form a cyclic group with R'1, such as 2,5-disilylazacyclopendyl, which is alkyl, aryl, etc. It may have substituents such as.

Examples of the halogen in the above description of the substituents include chlorine, bromine, fluorine, and iodine.

In the explanation of the above substituent, alkyl has 1 carbon number
~10, further 1~6. Furthermore, those having 1 to 4 are preferable, such as methyl, ethyl, n-
Propyl, l-propyl, n-butyl, i-butyl, t
-butyl, 5ec-butyl, n-pentyl, isopendel, n-hexyl, isohexyl.

Examples include heptyl, octyl, nonyl, and decyl.

The cycloalkyl as the above substituent has 3 carbon atoms.
-6 are preferred, examples of which are cyclopropyl, cyclobutyl, and cyclopentyl.

Examples include cyclohexyl.

The alkoxy as the above substituent has a carbon number of 1 to 4
Norano is preferred, examples include methoxy,
Examples include ethoxy, n-propoquine, i-propoxy, n-butoxy, i-butoxy, and thi-butoxy.

Examples of the aryl as the above-mentioned substituent include phenyl, naphthyl, and the like.

Examples of the heterocycle as the above-mentioned substituent include those similar to the above-mentioned heterocycles.

The above-mentioned acyl as a substituent preferably has 1 to 6 carbon atoms, and preferably 1 to 4 carbon atoms, such as formyl, acedel, propionyl, and butyryl. Examples include isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl and the like.

Examples of aralkyl as the above-mentioned substituent include benzyl, phenethyl, phenyl-propyl, and the like.

Examples of the alkenyl as the above-mentioned substituent include the same alkenyls as described above.

The amino acid residues as the above-mentioned substituents include the above-mentioned R
Examples include amino acid residues similar to those shown by 15.

Examples of the 5- to 6-membered heterocycle formed with the nitrogen in the amino group as the substituent include piperidine, pyrrolidine, imidazolidine, morpholine, piperazine, and the like.

The number of substituents in the above six brackets is preferably 1 to 3.

In the above acyl group, specific examples of the acylamino group represented by ``-GO-N-R'' include 3-(2,6-dichlorophenyl)-5-methylisoxazol-4-ylcarbonylamino , 4-ethyl-283-dioxo-1-piperazinocarponylamino, 3-phenyl-5-methylisoxazol-4-yl-carbonylamino.

3-(2-di[10phenyl)-5-methylisoxazol-4-yl-carbonylamino, 3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-ylcarbonylamino , nicotinylamino. Benzoylamino, 4-bromobe, nzoylamino,
2,6-Simethoxybenzoylamino, formylamino, acedelamino, propionylamino, butyrylamino, isobutyrylamino.

pivaloylamino, methoxycarbonylamino, benzyloxycarbonylamino, 1-amino-cyclohexylcarbonylamino, 2-amino-cyclohexylcarbonylamino, 3-ethoxynaphthoylamino, 2-(
2-amino-4-deazolyl)-2-edylidene-acedylamino, 2-(2-amino-4-thiazolyl)-2
-Chloromethylene-acetylamino, phthalimide, succinimide, 1,2-cyclohexanedicarboximide.

2-(trimethylsilyl)ethoxycarbonylamino,
2.2-Dimethyl-5-oxo-4-phenylimigzolidine, 4-(carbamoylcarboxymethylene)-
Examples include 1,3-dicetan-2-yl-carbonylamino.

Specific examples of the acylamino group represented by I4 include, for example, D-
Alanylamino, benzyl N7 carbobenzoxy γ-
〇-Glucumyl〇-alanylamino, D-phenylglycyl-D-alanylamino, N-carbobenzoxy-
D-alanylamino.

N-carbobenzoxy-D-phenylglycylamino,
D-alanyl-D-phenylglycylamino, γ-D-
Glutamyl-alanylamino, 2-(4-ethyl-
2,3-dioxo-1-piperazinocarboxamide)-
2-phenylacetylamino, 2-(4-cyclohexyl-2,3-dioxo-t-piperazinocarboxamide)-2-phenylacetylamino, 2-(4-ethyl-
2,3-dioxo-1-piperazinocarboxamide)-
2-(4-sulfoxyphenyl)acetylamino, N-
(4-ethyl-2,3-1oxo-1-piperazinocarbonyl)-D-alanylamino, N-(4-ethyl-2
, 3-dioxo-1-piperazinocarbonyl)-D-phenylglycylamino, 2-(2-amino-4-thiazolyl)-2-(4-edi-2゜3-dioxo-1-piperazinocarboxamide ) Acedelamino, 2-(4-
Hydroxo-6-methylnicotinamide)-2-phenylacetylamino, 2-(4-hydroxy-6-methylnicotinamide)-2-(4-hydroxyphenyl)acetylamino, 2-(5,8-dihydro- 2-(4-formyl-1-piperazinyl)-5-oxopyrido[2°3-d]pyrimidine-6-carboxamide)-2-phenylacetylamino, 2-(3,5-dioxo-1,2
,4-triazine-6-carboxamide)-2-(4-
hydroxyphenyl) acetylamino.

2-(3-furfrideneamino-2-oxoimidazolidine-1-carboxamide)-2-phenylacederamino, 2-(coumarin-3-carboxamide)-2-phenylacetylamino, 2-(4-hydroxy- 7-methyl-1,8-naphthylidene-3-carboxamide)-
2-phenylacederamino, 2-(4-hydroxy-
7-Dolifluoromethylquinoline-3-carboxamide)-2-phenylacetylamino, N-[2-(2-amine-4-thiazolyl)acetyl]-D-phenylglycylamino, 2-(6-bromo-1 -Ethyl-1゜4-
Dihydro-4-oxocheno[2,3-b]pyridine-
3-carboxamide)-2-phenylacederamino,
2-(4-ethyl-2,3-dioxo-1-piperazinocarboxamide)-2-chenylacedelamino, 2-
(4-n-pentyl-2,3-dioxo-1-piperazinocarboxamide)-2-chenylacedelamino, 2
-(4-n-octyl-2,3-diogysole-l-piperazinocarboxamide)-2-chenylacetylamino,
2-(4-Cyclohequin-2,3-dioxo-I-piperazinocarboxamide)-2-chenylacetylamino, 2-[4-(2-phenylethyl)-2,3-dioxo-1-pipe radinocarboxamide]-2-dienylacetylamino, 2-(3-methylsulfonyl-2-oxoimidazolidine-1-carbogizamide)-2-phenylacetylamino, 2-(3-furfrideneamino-
2-oxoimidazo II, zu -/I
J+ +1. , Jr-1aJ+-: L'S
l'l /J If -+xyphenyl)acetylamino, 2-(4-ethyl-2,3-dioxo-1-piperazinocarboxamide)-2-(4-
benzyloxyphenyl)acetylamino, 2-(4-
Ethyl-2,3-dioxo! -biperazinolupoxamide)-2-(4-methoxyphenyl)acetylamino, 2-(8-hydroxy-!, 5-naphdyridine-7-
carpoxamide)-2-phenylacetylamino, 2-
(2-amino-4-thiazolyl)-2-formamide acederamino, 2-(2-amino-4-thiazolyl)-
2-acetamidoacedelamino, 2-phenyl-2-
ureidoacedelamino, 2-phenyl-2-sulfouridoamino, 2-thenyl-2-ureidoacetylamino, 2-amino-3-sulfamoylpropionylamino, 2-amino-2-(tt[-indole-3 -yl) acetylamino, 2-amino-2-(3-benzo[
b] chenyl) ayadylamino, 2-amino-2-(2
-naphthyl) acetylamino, D-phenylglycyl,
D-2-amino-(4-hydroquinphenyl)acetylamino, D-2-amino-2-(1,4-cyclohexanoenyl)acetylamino, D-2-amino-2-(1
-cyclohexanyl)acetylamino, D-2-amino-2-(゛3-chloro-4-hydroxyphenyl)acedelamino, 2-hydroxymethylamino-2-phenylacetylamino, 2-(1-cyclohexanyl) -2
-(4-ethyl-2,3-dioxo-1-piperazinocarboxamide)acetylamino, N-[2-(4-ethyl-2,3-dioxo-1-piperazinocarbonyl)]
-]D-threonylamino 2-guanylcarboxamide-2-phenylacederamino, 2-(4-ethyl-2
,3-thioxole l-piperazinocarboxamide-2-
(3,4-dihydroquinphenyl)acetylamino.

2-(4-carboxy-5-imidazolylcarboxamide)-2-phenylacederamino, 2-amino-2-
(3-methylsulfonamidophenyl)acetylamino and the like.

Specific examples of the acylamino group represented by the formula IE18-R"-Co-Nll- include, for example, N-[2-(2
-amino-4-thiazolyl)-2-methoxyiminoacedel]-D-alanylamino, N-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetyl]-
D-phenylglycylamino.

2-(2-amino-4-deazolyl)-2-[2-(2
-amino-4-thiazolyl)-2-methquiniminoacetamidocoacetylamino, 2-(2-chloroacetamido-4-deazolyl)-2-methoxyiminoacetylamino, 2-(2-amino-4-diazolyl)- 2-methoxyiminoacedelamino, 2-(2-amino-4-
deazolyl)-2-ethoxyiminoacetylamino, 2
-(2-Amino-4-deazolyl)-2-isopropoxyiminoacetylamino, 2-(2-amino-4-deazolyl)-2-butoxyiminoacetylamino, 2-(
2-amino-4-thiazolyl)-2-cyclopropylmethyloxyiminoacedylamino, 2-(2-amino-
4-thiazolyl)-2-benzyloxyiminoacetylamino, 2-(2-amino-4-deazolyl)-2-allyloxyiminoacetylamino, 1-(2-amino-
4-thiazolyl)-2-[(1-methyl-1-carboxyethyl)oxyiminoacetylamino, 2-(2-amino-4-thiazolyl)-2-[(1-methyl-1-methoxylpoethyl)oxy iminocoacetylamino, 2-(2-amino-4-deazolyl)-2-carboxymethyloxyiminoacetylamino, 2-(2-amino-4-thiazolyl)-2-carboxyvinyloxyiminoacetylamino, 2-( 2-Amino-4-diazolyl)-2-carboxymethyloxyiminoacetylamino, 2-(2-amino-4-thiazolyl)-2-methoxycarbonylethyloxyiminoacetylamino, 2
-(2-amino-5-rio [1-4-thiazolyl)-
2-Methoxyiminoacetylamino, 2-(2-amino-5-but[l-4-thiazolyl)-2-methoxyiminoacetylamino, 2-(2-amino-11-deazolyl)-2-oxidiiminoacetyl Amino, 2-thenyl-2-methoxyiminoacetylamino, 2-furyl-2
-Methoxyiminoacetylamino, 2-(+, 2゜4-
deadiazol-3-yl)-2-methoxyiminoacetylamino, 2-(+,2,4-thiadiazole-5-
yl)-2-methoxyiminoacetylamino, 2-(1
, 3,4-deadiazolyl)-2-methoxyiminoacetylamino, 2-(4-hydroquinphenyl)-2-methoxyiminoacetylamino, 2-phenyl-2-methoxyiminoacetylamino, 2-phenyl-2- Oxyiminoacetylamino, 2-[4-(γ-D-glutamyloxy)phenyl]-2-oxyiminoacetylamino, 2-[4-(3-amino-3-carboxypropoxy)phenyl-2-oxyiminoacetyl Amino, 2
-thenyl-2-oxyiminoacedelamino, 2-(
5-amino-1,2,4-deadiazol-3-yl)
-2-methoxyiminoacetylamino, 2-(5-amino-1,2,4-deadiazol-3-yl)-2-ethoxyiminoacetylamino, 2-(5-amino-!,
2.4-thiadiazol-3-yl)-2-carboxymethyloxyiminoacetylamino, 2-(5-amino-1,2°4-deadiazol-3-yl)-2-[(
1-Methyl-1-carboxyethyl)oquinimino]acedelamino, 2-(2-amino-4-thiazolyl)-
2-(2-amino-2-carboxy)ethyloxyiminoacetylamino, 2-(2-amino-4-deazolyl)-2-(dimedylamidomethyloxyimino)acedelamino, 2-(2-amino-4- deazolyl)-2-
(3,4-diacetoxy-benzoyloxyimino)acetylamino, 2-(2-amino-4-deazolyl)-
2-(1-carboxy-sifurob[1-pyroxyimino)acedelamino, 2-(2-amino-4-thiazolyl)-2-(1-carboxycyclobutyloquinimino)acetylamino, 2-(2-amino -4-thiazolyl)-2-(2-imidazolylmethyloxyimino)acetylamino, 2-(2-amino-4-deazolyl)-2
-(2-methyl-4-nitro-1-imidazolyldyloxyimino)acetylamino, 2-(2-amino-4
-thiazolyl)-2-(3-birazolylmethyloxyimino)acetylamino, 2-(2-amino-4-deazolyl)-2-(Ill-tetrazol-5-ylmethyloquinimino)acetylamino, 2 -(2-amino-
4-thiazolyl)-2-(2-oxo-3-pyrrolidinyl-oquinimino)acetylamino, 2-[2-(2-amino-2-carboxyethyldio)]-]4-deazolyl-2-methoxyimino Examples include acetylamino 2-(2-thioxo-4-diazolidinyl)-2-methoquinoiminoacetylamino.

Specific examples of the acylamino group represented by the formula R" CHCo N1 (-) include 2-phenyl-2-sulfoacetylamino, 2-hydroxy-2-phenylacetylamino, 2-phenyl-2-sulfamoylacedel Amino, 2-carboxy-2-phenylacetylamino, 2-(4-hydroxyphenyl)-2-
Carboxyacetylamino, 2-phenoxycarbonyl-2-phenylacetylamino, 2-phenyl-2-tolyloxycarbonylacederamino, 2-(5-indanyloxycarbonyl)-2-phenylacetylamino, 2-formyloxy- 2-phenylacederamino, 2-alanyloxy-2-phenylacederamino,
2-carboxy-2-chenylacederamino, 2-(
2-methylphenoxycarponyl)-2-chenylacederamino, 2-(2=amino-4-thiazolyl)-2
-hydroxyacetylamino, 2-[4-(2-amino-2-carboxyethoxycarboxamide)phenyl-2-hydroquinoacetylamino, and the like.

Specific examples of the anrulamino group represented by the formula 1"-1"-C11, -Co-Nl-1-"i? include cyanoacedelamino and phenylacetylamino.

Phenoquinacetylamino, trifluoromethylthioacetylamino, cyanomethylthioacetylamino, difluoro[l-methylthioacetylamino, lI[-tetrazolyl-1-acetylamino, chenylacetylamino,
2-(2-amino-4-deazolyl)acetylamino,
ll-Pyridylthioacetyl-dichloro-1,4-dihydro-11-xopyridine-! -acetylamino, β
-carboxyvinylthioacetylamino, 2-(2-aminomethylphenyl)acedelamino, 2-chloroacedelamino.

3-aminopropionylamino, (2-amino-2-carboxy)ethylthioacedylamino, 4-amino-3
-Hydroxybutyrylamino. 2-Carboxyedylthioacetylamino, 2-benzyloxycarbonylamino-acetylamino, β-carbamoyl-β-fluorovinylthioacetylamino, 2-(1-isopropylamino-1-isopropyliminomethylthio)acedelamino, 2-[1 -(2-dimethylaminoethyl)-11
-1-tetrazol-5-yl-thiocoacetylamino, 2-(I-methyl-1,3,5-triazole-2-
yl)acedelamino, 2-(4-noano3-hydroquine-5-isodiazolylthio)acedelamino, and the like.

Specific examples include carbamoylamino.

Methylaminocarbonylamino. Ethylaminocarbonylamino, t-butylaminocarbonylamino, isobutylaminocarbonylamino, dimethylaminocarbonylamino, 2-methylphenylaminocarbonylamino, phenylaminocarbonylamino, 3-chlorophenylaminocarbonylamino, 4-nitrophenylaminocarbonyl Amino, 4-bromophenylaminocarbonylamino, diocarbamoylamino, methylaminodiocarbonylamino, ethylaminothiocarbonylamino, phenylaminothiocarbonylamino.

Examples include dimethylaminocarbonylamino, 3-fluorophenylaminocarbonylamino, and the like.

Expression+? Specific examples of the group represented by “-Nll-” include:
For example, methylamino, ethylamino, allylamino,
Cyclohexylamino, cyclohexylmethylamino.

Benzylamino, 4-chlorobenzylamino, phenylamino, 2-imidazolylamino.

l-Methyl-2-imidazolylamino, 2-C27amino-4-deazolyl)-2-methoxyimino-thioacetylamino,! -benzy-4-pyridinium amino,
Examples include 2-acedel-1-methylvinylamino.

Specific examples include dimethylamino, diethylamino, dipropylamino, dibenzylamino, dicyclohexylamino, N-benzyl-N-methylamino,
Examples include diallylamino, N-phenyl-N-methylamino, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and the like.

Specific examples include trimethylammonium, triethylammonium, tribenzylammonium, benzyldimethylammonium, and methylpyrrolidinium.

Examples include methylpiperidinium.

Specific examples of the mino group include dimethylaminomethyleneamino, l-dimethylaminoethylideneamino, hexahydro-11-1-azepin-1-ylmethyleneamino, 1-(N-benzyl-N-ethylamino)ethylideneamino, 4-dimethylaminobenzylidene amino,
(p-nitro)benzylidene amino, benzylidene amino, and the like.

Specific examples of the thioamino group represented by the formula [1''-3on-NH- include benzenesulfonylamino,
4-Methylbenzenesulfonylamino, 4-methoxybenzenesulfonylamino, 2°4.6-trimethylbenzenesulfonylamino.

Benzylsulfonylamino, 4-methylbenzylsulfonylamino, trifluoromethylsulfonylamino, phenacylsulfonylamino, methylsulfonylamino.

Ethylsulfonylamino, 4-fluorobenzenesulfonylamino, benzenesulfinylamino, 2-nitrobenzenesulfinylamino, 2,4-dimethylbenzenesulfinylamino, 4-chlorobenzenesulfinylamino.

4-Methoxybenzenesulfinylamino, phenylthioamino. Examples include 2,4-dinitrophenylthioamino, triphenylmethylthioamino, and 2-nitro-4-methoxyphenyldioamino.

) groups include, for example, trimedelsilylamino, triethylsilylamino 1. t-Butyldimedylsilylamino, [-butyldiphenylsilylamino. Isopropyldimethylsilylamino, triphenylsilylamino, triisopropylsilylamino, tribenzylsilylamino, (triphenylmethyl)dimethylsilylamino, 2,2,5,5-tetramethyl-2,5-disilylazacyclobencune Examples include.

Examples include amino diethyl phosphate, amino diethyl phosphate, amino diphenyl phosphate, amino dibenzyl phosphate, amino di-4-chlorophenyl phosphate, and the like.

A specific example of the group represented by the formula 1''-Co-Co-Nl-1- is methoxarylamino.

Ethoxarylamino, phenoxarylamino, benzyloxarylamino, pyruvoylamino, ethyloxarylamino, oxamoylamino, benzylaminooxarylamino, thenyloxarylamino, 2-amino-
Examples include 4-deazolyl-oxarylamino and ethylaminooxarylamino.

Specific examples of the group represented by the formula -coon" include methyl ester, ethyl ester, n-propyl ester, isopropyl ester, [-butyl ester,
t-amyl ester, benzyl ester, 4-bromobenzyl ester, 4-nitrobenzyl ester, 2-nitrobenzyl ester.

3.5-Dinitrobenzyl ester, 4-methoxybenzyl ester, benzhydryl ester, phenacyl ester, 4-bromo-phenacyl ester 8 phenyl ester, 4-nitrophenyl ester, methoxymethyl ester, methoxyethoxymethyl ester. Ethoxymethyl ester, benzyloxymethyl ester, acetoxymethyl ester, pivaloyloxymethyl ester, 2-methylsulfonyl ethyl ester, 2-trimethylsilylethyl ester, methylthiomethyl ester, trityl ester, 2,2.2-trichloroethyl ester, 2-iodoethyl ester, cyclohexyl ester, cyclopentyl ester, allyl ester, cinnamyl ester, 4-picolyl ester.

2-tetrahydropyranyl ester, 2-tetrahydrofuranyl ester, trimedelsilyl ester, t-butyldimethylsilyl ester, t-butyldiphenylsilyl ester, acetylmethyl ester. 4-nitrobenzoyl methyl ester, 4-mesylbenzoyl methyl ester, phthalimido methyl ester 8 propionyloxymethyl ester, 1. I-dimethylpropyl ester, 3-medy-3-butenyl ester, succinimide methyl ester, 3,5-di-butyl-4-hydroxybenzyl ester, mesyl methyl ester, benzenesulfonyl methyl ester, phenylthiomethyl ester, iminomedyl Aminoethyl ester, ■-iminoethylaminoethyl ester, dimethylaminoethyl ester, pyridine-1-oxyto-2-methyl ester, methylsulfinylmethyl ester, bis-(4
-methoxyphenyl) methyl ester. 2-cyano-1
, 1-dimethylethyl ester, [-butyloxycarbonylmethyl ester, benzoylaminomethyl ester.

l-acetoxyethyl ester, 1-isobutyryloxyethyl ester, l-ethoxycarbonyloxyethyl ester, phthalide ester, 4*--/:r-+
To I8・-yt +1. 'y +y 2+1. e
-11Δkl-+l-ster, 5-methyl-2-oxo-1,3-dioxolen-4-yl methyl ester,
5-1-butyl-2-oxo-1,3-dioxolene-
Examples include 4-ylmethyl ester.

Formula -Co-N<, 14. Specific examples of the group represented by are dimethylamide, diethylamide, dipropylamide, dibenzylamide, dicyclohexylamide, N-benzyl-N-methylamide, diallylamide, and N-phenyl-N-methylamide. Pyrrolidine amide, piperidine amide.

Examples include piperazinamide, morpholinamide, carboxymethylamide, l-carboxymethylamide, and the like.

In the above formula, the organic residues represented by R', IN', IN' and R@ include organic residues bonded at a carbon atom; organic residues bonded via an oxygen atom, nitrogen atom or sulfur atom: Or Haugen.

Examples of the organic residue bonded via the carbon atom include alkyl "cycloalkyl, alkenyl", aryl, acyl, cyano, and carbamoyl.

Heterocycle 1. Or, for esterification, carboxyl which may be amidated is preferable.

The organic residue bonded via the oxygen atom has the formula -
〇-r17 [wherein R7 is hydrogen, alkyl, aryl,
Indicates acyl and carbamoyl. A group represented by , or an oxo group is preferred.

Examples of the organic residue bonded via the nitrogen atom include hydrogen, alkyl, and aryl having the same or different formulas.

Indicates acyl. A group represented by is preferred.

The organic residue bonded via the sulfur atom is the formula-5
(O)n-IN'° [wherein R'' is hydrogen, alkyl 1.
Aryl 1. Heterocycle 1. or amino 1, n is Q, l
Or not showing 2. A group represented by is preferred.

Examples of the groups which may be substituted on the alkyl groups in 32R3, R', rt' and R6 above include hydroquine, acyloxy, carbamoyloxy, amino, dialkylamino, acylamino and alkylthio. Heterocycle thio, carboquine, alkoxycarbonyl, carbamoyl, cyano. Examples include azide, aryl, and halogen.

Examples of the groups that may be substituted on the aryl groups in It'', rt', It5 and R6 include halogen, alkoxy, and alkyl.

Examples of the group that may be substituted on alkenyl in n 3 , R4, n 5 and R8 include aryl.

Above n3. Examples of the group which may be substituted on the heterocycle in rt', n' and R8 include alkyl.

Examples of groups that may be substituted with amino in R1° include monoalkyl and dialkyl.

Examples include monoaryl.

The above rt3. Examples of the optionally esterified carboxyl in rt', n' and R6 include carboxy, alkyloxycarbonyl, and the like.

Examples of the optionally amidated carboxyl in R3, R', R5 and R6 include those of the formula [wherein R4@' and R47' are the same or different and represent hydrogen or alkyl, and the adjacent nitrogen It may form a heterocycle together with the atoms. ] Name the group represented by.

The above alkyl (including the case of alkyl in a group) is preferably one having 1 to 6 carbon atoms.

The above cycloalkyl is preferably one having 3 to 6 carbon atoms.

The above alkenyl is preferably 6 having 1 to 4 carbon atoms.

The above-mentioned acyl (including the case of acyl in a group) is preferably arylrubonyl having from X to 6 carbon atoms.

The above alkoxy (including the case of alkoxy in a group).

) preferably has 1 to 6 carbon atoms.

Alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, alkenyl having 1 to 4 carbon atoms, acyl having 1 to 6 carbon atoms, alkoxy having 1 to 6 carbon atoms, aryl, heterocycle (
Except when formed together with adjacent nitrogen atoms. ) and halogens include those represented by R1 and the like described above.

The heterocycle formed together with the adjacent nitrogen atoms is preferably a 5- to 6-membered ring, and specific examples thereof include pyrrolyl, pyrrolidinyl, piperidinyl, piperazinyl, and the like.

Preferred examples of the groups represented by R3Jt', R5 and R8 above include methyl, ethyl, cyclopropyl, cyclopendel, cyclohexyl, vinyl, allyl, phenyl, parachlorophenyl, paramethoxyphenyl, acetyl, propionyl, benzoyl. , cyano, carbamoyl, methoxycarbonyl, ethoxycarbonyl, dimethylaminocarbonyl, acetomethyl,
Methylthiomethyl, acetamitomedel, hydroquine,
Methoxy, ethoxy.

Acetoxy, phenyloxy, benzoyloxy.

Carbamoyloxy, methylamino, dimethylamino,
Phenylamino, acetylamino, methylthio.

Ethylthio. 2-acetamidoethyldio, 2-N.

N-dimethylaminoethylthio. 2-aminoethyldio, 2-hydroxyethylthio, carboxymethylthio,
Methoxycarbonylmethoxythio, carbamoylmethylthio, phenylthio, 3-pyridazinylthio, 2-pyrimidinylthio, 4-pyridylthio, l-methyl-111
-5-tetrazolylthio, benzylthio, 4-pyridyltyldis, sulfamoyl, phenylaminosulfonyl, chloro, pro-7 and the like.

In the above formula, the leaving group represented by Y is a compound ([)
Any hydrogen may be used as long as it can replace the hydrogen at the 2nd position. Examples include halogen (e.g., bromo, chloro), sulfonyloxy having a substituent (e.g., alkyl, aryl) (alkyl and aryl include the same substituents as above) Examples include, for example, p-toluenesulfonyloxy, p-
Examples include nitrophenylsulfonyloxy, methanesulfonyloquine), di-substituted phosphoryloxy (eg, diphenylphosphoryloxy, diethylphosphoryloxy), and the like.

Next, a method for producing the target compound of the present invention will be explained.

Compound (I[[) and compound (■) or a reactive derivative thereof are reacted to form the general formula, where RI', R1', R3, a4,
R% and R8 have the same meanings as above. Compound (1-2) represented by
By subjecting 111' and/or R'' of 1-2) to a conversion reaction, the general formula [where RI represents an amino group or an organic residue via nitrogen; IN'' is a carboxyl group or may be derived therefrom Indicates the group. R', 11', R', and na are the same or different and represent hydrogen or an organic residue;
Alternatively, a compound (+) represented by R4 and R5 or 11'' may form a chemical bond.

The reaction between compound (II) and compound (III) is carried out in a solvent in the presence of a condensing agent or a Lewis acid.

The reaction between the reactive derivative of compound (11) and compound (l[[) is carried out in a solvent.

Specifically, the condensing agent used here is, for example, N,N'-dicyclohexylcarbodiimide (D
CC), D CC with N-hydroxysuccinimide or l-hydroxybenzotriazole added: N-ethyN'-[3-(dimethylamino)propyl]carbodiimide: carbonyldiimidazole; N
-Ethyl-5-isoxazolium-3'-sulfonate: 2-ethyl-7-hydroxybenzisoxazolium trifluoroborate: l-ethoxycarbonyl-2-
Ethoxy-1,2-dihydroquinoline, a combination of 2,2'-dipyridyldisulfide and triphenylphosphine; a combination of carbon tetrachloride and triphenylphosphine; e.g. 2-chloro-1-methyl-pyridinium iodide, 2-fluoro- 2-halogenopyridinium salts such as 1-medyrupyridinium tosylate, e.g.
-pyrimidinium salts such as chloro-1-methylpyrimidinium fluorosulfate, 2-chloro-3-ethylbenzoxazolium tetrafluoroborate, 2-
Onium salts of azaarenes such as fluoro-3-methyl-penzothiazolium fluorosulfate and Angewante Hemi-International 6-edicilin (A
ngewandle Chemie.

International Edition),
18, 707 (1979).

Examples of the Lewis acid used in this reaction include boron trifluoride etherate, zinc chloride, tin tetrachloride, aluminum chloride, titanium tetrachloride, and boron trichloride.

As the reactive derivative of compound (II), reactive derivatives used in the C-end activation method during peptide synthesis can be used. The reactive derivative used here can be prepared in a solvent without being isolated and used as it is in the condensation reaction. Specific examples of reactive derivatives of carboxylic acids used here include acid halides such as acid chlorides and acid bromides; acid azides: mixed acid anhydrides with carbonic acid monoalkyl esters, such as acetic acid, pivalic acid, valeric acid, Mixed acid anhydrides consisting of aliphatic carboxylic acids such as valeric acid and trichloroacetic acid, for example mixed acid anhydrides consisting of phosphoric acids such as diphenyl phosphoric acid and diethyl phosphoric acid, and acids such as sulfuric acid, such as benzoic acid, etc. Mixed acid anhydrides, symmetrical acid anhydrides; e.g. pyrazole, imidazole, 4
- Amide compounds in which an acyl group is bonded to the nitrogen in the ring, such as substituted imidazole, dimethylpyrazole, benzotriazole, thiazolidine-2-thione; for example, 4-nitrophenyl, 2°4-dinitrophenyl, trichlorophenyl, pentachlorophenyl, pentachlorophenyl, etc. Fluorophenyl, cyanomethyl, N-hydroxysuccinimide, N-
Active esters with hydroxyphthalimide and the like; for example, active thioesters with heterocyclic thiols such as 2-pyridylthiol and 2-penzthiazolyldiol.

This reaction is based on the reactivity of compound (I[ This is done by reacting a derivative with a derivative in a solvent. Any solvent C) that does not affect the reaction may be used, such as dichloromethane, chloroform, tetrahydrofuran,
Dioxane, diethyl ether, ethyl acetate, benzene, toluene, n-hexane. Acetonitrile, N, N-
Common solvents such as dimethylformamide are used.

This reaction may be carried out in the presence of a base (e.g., 2-chloro-1-methylpyridinium iodide, 2,2'-dipyridyldisulfide-]-liphenylphosphine, carbon tetrachloride-triphenyl as a condensing agent). In some cases, phosphine, etc. are used), and the base used here is, for example, triethylamine. Diisopropylethylamine, N-methylmorpholine. 3
．． Examples include 4-nohydro211-pyrido[1,2-alpyrimidin-2-one, among which 63,4-dihydro211-pyrido[1,2-a]pyrimidin-2
-on is preferred.

There are also cases where silver chloride, silver tetrafluoroborate, for example 2,2'-dipyridyldisulfide-triphenylphosphine are used as condensing agents.

The reaction temperature is not particularly limited as long as the reaction proceeds, but is usually -50°C to 150°C, preferably about -1
It is carried out at 0°C to 100°C. Reaction time depends on the types of raw materials, reagents, and solvents used.

Although it varies depending on the reaction temperature etc., it is usually about 5 minutes to 30 minutes.
It takes about an hour. When condensation is carried out using a Lewis acid as a catalyst, a dehydrating agent such as molecular sieves may be present in the reaction system.

Further, compound (U[) and compound (IV) are reacted to form compound (1-2), and further, if necessary, compound (I-2
Compound (+) can also be produced by subjecting R1' and/or l'' of ) to a conversion reaction.

The reaction between compound (1[) and compound (IV) is carried out by reacting both in a solvent in the presence of a base.

As the @ group, for example, triethylami'/k
II -f r-I 1-' +lr? :
'i k II n-go R-117?
:'/diisopropylethylamine, triethylenediamine (DAI3CO), l,8-diazabicyclo[5°4.0-7-undecene (DBU),
N-methylphorphorine, N-methylpiperidine, N-methylpyrrolidine. 3. Organic amines such as 4-dihydro-21-[-pyrido[1,2-a]pyrimidin-2-one, 4-dimethylaminopyridine, pyridine, lutidine, γ-collidine, such as lithium, sodium, potassium, Alkali metals such as cesium, alkaline earth metals such as magnesium and calcium, and their hydrides, hydroxides, carbonates, and alcoholades are used. Examples of solvents include dichloromethane and chloroform.

Tetrahydrofuran, dioxane, benzene, toluene, acetonitrile, N,N-dimethylacetamide, N
, N-dimethylformamide and the like are used. Furthermore, among the bases mentioned above, liquid radish can also be used as a solvent.

In this reaction, compound (■) is added to compound (III).
and the base are usually used in approximately equivalent amounts, but may be used in excess as long as the reaction is not adversely affected. The reaction temperature is usually -
The reaction is carried out at a temperature of 20°C to 100°C, and the reaction time is usually about 5 minutes to 30 hours.

Compound (1) can be produced by subjecting compound (1-2) thus obtained to a conversion reaction of tt" and l", if necessary.

Examples of the conversion reaction include deprotection reaction, acylation reaction, ureidation (thioureidation) reaction, alkylation reaction, alkenylation reaction, thiolation reaction, silylation reaction,
Examples include phosphorylation reaction, esterification reaction, and amidation reaction.

The above deprotection reaction can be carried out by appropriately selecting a commonly used method such as an acid method, a base method, a hydrazine method, or a reduction method depending on the type of the protecting group. In the case of a method using an acid, the acid may be an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, etc., or an organic acid such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, etc., depending on the type of protecting group and other conditions. In addition, acidic ion exchange resins and the like are used. In the case of the base method,
Although it varies depending on the type of protecting group and other conditions, examples of bases include hydroxides of alkali metals such as sodium and potassium, or alkaline earth metals such as calcium and magnesium, inorganic bases such as carbonates, metal alkoxides,
In addition to organic bases such as organic amines and quaternary ammonium salts,
A basic ion exchange resin or the like is used. When a solvent is used in the above acid or base method, a hydrophilic organic solvent, water or a mixed solvent is often used.

In the case of the reduction method, it depends on the type of protecting group and other conditions, but for example, a metal such as tin or zinc or a metal compound such as chromium dichloride or chromium acetate, and acetic acid,
Methods using acids such as organic and inorganic acids such as propionic acid and hydrochloric acid, methods of reduction in the presence of a metal catalyst for catalytic reduction, etc. are used, and the catalysts used in the method by catalytic reduction include, for example. Platinum wire, platinum sponge, platinum black, platinum oxide.

Platinum catalysts such as colloidal platinum, palladium sponge, palladium black, palladium oxide, palladium barium sulfate, palladium barium carbonate, palladium carbon.

Examples include palladium catalysts such as palladium silica gel and colloidal palladium, reduced nickel, nickel oxide, Raney nickel, and urushihara nickel. Also, iron in the case of reduction methods using metals and acids.

Metals such as chromium and inorganic acids such as hydrochloric acid or organic acids such as formic acid, acetic acid, and propionic acid are used. Reduction methods are usually carried out in a solvent; for example, in catalytic reduction methods, methanol, ethanol, propyl alcohol,
Alcohols such as isopropyl alcohol, ethyl acetate, etc. are frequently used.

Furthermore, in the method using a metal and an acid, water, acetone, etc. are often used, but when the acid is liquid, the acid itself can also be used as a solvent.

In the acid-based method, base-based method, and reduction method, the reaction temperature is usually cooled or heated.

Furthermore, the protective groups in each group of the obtained compound can be removed by the same method as above.

By subjecting compound (I-2) to a deprotection reaction, compound (I-3) in which rtl is an amino group and nt is a group that can be derived from a carfoquinol group in compound (1),
Or a compound (1-4) in which R2 is a calhoquinol group and rtl is an organic residue via nitrogen in compound (1)
) can be produced, and by further subjecting these compounds to a deprotection reaction, n in compound (1) can be produced.
Is it possible to produce a compound (1-5) in which l is an amino group and R1 is a carfoquinol group?

Alternatively, compound (+-2) can be subjected to a deprotection reaction to form compound (1-5).

Furthermore, in compound (1), R3 or R4 and R5
Alternatively, if a compound in which rto forms a chemical bond is obtained, the compound (5-oxo-2,5
-dihydro-2-furancarboxylic acid derivatives), double bonds can be hydrogenated if necessary. For the hydrogenation, for example, a method similar to the reduction method used for removing the protective group described above can be employed. Note that by carrying out the reduction reaction, hydrogenation of the double bond and removal of the protecting group can be carried out simultaneously.

Alternatively, the compound ([-3) may be acylated, for example.

It can be converted to the compound ([-2) by subjecting it to reactions such as ureidation (thioureidation), alkylation, alkenylation, thiolation, silylation, and phosphorylation. Next, the reaction will be explained in detail.

Acylation of the acylated amino group is carried out in a solvent using the starting compound and the group R1.
This can be accomplished by reacting an acylating agent containing an acyl group, such as a reactive derivative of a carboxylic acid. Examples of reactive derivatives of carboxylic acids that can be used include acid halides, acid anhydrides, amide compounds, active esters, and active thioesters.Specific examples of such reactive derivatives are as follows.

(2) Acid halide: As the acid halide, for example, acid chloride, acid bromide, etc. are used.

2) Acid anhydride: Examples of acid anhydrides include monoalkyl carbonic acid mixed acid anhydrides, mixed acids consisting of aliphatic carboxylic acids (for example, acetic acid, pivalic acid, valeric acid, isovaleric acid, trichloroacetic acid, etc.) Anhydrides, mixed acid anhydrides made of aromatic carboxylic acids (eg, benzoic acid, etc.), symmetrical acid anhydrides, and the like are used.

3) Amide compound: Here, as the amide compound, a compound in which an acyl group is bonded to the nitrogen in the ring, such as pyrazole, imidazole, 4-substituted imidazole, dimethylpyrazole, benzotriazole, etc., is used.

4) Active ester; Examples of the active ester include methyl ester, ethyl ester, metquin methyl ester, propargyl ester, 4-nitrophenyl ester, 2.4-
In addition to dinitrophenyl ester, trichlorophenyl ester, and pentachlorophenyl, l-hydroxy-11
4-2-pyridone, N-hydroxysuccinimide, N
-Esters with hydroxyphthalimide etc. are used.

5) Active thioester: As the active thioester, for example, a thioester with a heterocyclic thiol such as 2-pyridylthiol or 2-benzthiazolylthiol is used.

The various reactive derivatives described above are appropriately selected depending on the type a of the carboxylic acid.

This reaction may be carried out in the presence of a base, and the bases used include, for example, aliphatic tertiary amines (e.g., trimedelamine, triethylamine, tripropylamine, tri-1-butylamine, etc.), N-methylpiperidine, Tertiary amines such as N-methylpyrrolidine, cyclohex'sildimethylamine, N-methylmorpholine, dialkylamines such as di-n-butylamine, diisobutylamine, dicyclohexylamine, aromatic amines such as pyridine, lutidine, γ-collidine, etc. For example, hydroxides or carbonates of alkali metals such as lithium, sodium, and potassium, and alkaline earth metals such as calcium and magnesium are used.

In this method, the reactive derivative of carboxylic acid is usually used in an amount equivalent to that of compound (1-3), but it can be used in excess as long as it does not interfere with the reaction. When using a base, the amount of the base used depends on the raw material compound (1-3) used.
The amount varies depending on the type of reactive derivative of carboxylic acid and other reaction conditions, but it is usually about equivalents to 30 equivalents, preferably about equivalents to 10 equivalents, relative to compound (+-3). This reaction is usually carried out in a solvent. Examples of the solvent include dioxane, tetrahydrofuran, and diethyl ether. Ethers such as diisopropyl ether, propylene oxide, butylene oxide, esters such as ethyl acetate, ethyl formate, eg chloro71; shim. dichloromethane, l.

2-dichloroethane, 1.1. halogenated hydrocarbons such as l-trichloroethane, hydrocarbons such as benzene, toluene, rhohexane, e.g. N, N-
Common organic solvents such as amides such as tumedelformamide, N,N-dimethylacetamide, and nitriles such as acetonitrile can be used alone or in combination. Moreover, among the above-mentioned bases, liquid ones can also be used as a solvent. The reaction temperature is not particularly limited as long as the reaction proceeds, but is usually between -50'C and 1
It is carried out at 50°C, preferably about -30°C to 80'C. The reaction usually completes in several tens of minutes to several tens of hours, although it varies depending on the raw materials, base, reaction temperature, and type of solvent used, but it may sometimes take several tens of days.

Ureidation (Thioureidation) The conversion reaction of an amino group into a ureido group or a thioureido group is carried out in the presence of a solvent, and Z has the same meaning as above. ) is carried out by reacting a substituted isocyanate or a substituted isothiocyanate containing a group represented by the following. Examples of the substituted isocyanate include methyl isocyanate, ethyl isocyanate, phenyl isocyanate, p-bromophenyl isocyanate, and examples of the substituted isothiocyanate include methyl isothiocyanate and phenyl isodiocyanate. In this reaction,
The substituted isocyanate or substituted isodiocyanate is usually used in an amount equivalent to that of the compound (1-3), but it can be used in excess as long as it does not interfere with the reaction. Examples of the solvent used include tetrahydrofuran and diethyl ether. Ethyl acetate, chloroform, dichloromethane, toluene, etc. are used. The reaction temperature is about -20'
The reaction time is usually about 10 minutes to about 5 hours.

The reaction of bonding a group bonding via carbon to the amino group of the alkylated compound (1-3) will be described below as alkylation.

Alkylation of compound (1-3) can be produced by reacting compound (+-3) with an alkylating agent containing a group bonded to the nitrogen of group R1 via carbon. Examples of alkylating agents include propyl chloride and butyl chloride. Halogenated alkyl compounds such as benzyl chloride, butyl bromide, benzyl bromide, allyl bromide, methyl iodide, ethyl iodide, propyl iodide, etc. Dialkyl sulfate compounds such as dimethyl sulfate, diethyl sulfate, etc., such as methyl mesylate, ethyl mesylate , substituted sulfonic acid ester compounds such as methyl tosylate and ethyl tosylate, nohalogenated alkyl compounds (
For example, 1,5-dichloropenkune, 1,4-dichlorobutane, etc.) are used. This reaction is usually carried out in a solvent, and the solvents used are water, methanol, ethanol, and benzyl alcohol.

Examples include benzene, N,N-dimethylformamide, tetrahydrofuran, and acetonitrile.

The temperature of this reaction is about 20°C to 200'C, and the reaction time is about 30 minutes to 50 hours. In this reaction, a secondary amine compound, a tertiary amine compound, or a quaternary amine compound can be selectively produced by changing reaction conditions 1, for example, the molar ratio of the compound (1-3) and the alkylating agent. It is also possible to introduce different substituents to nitrogen by performing the reaction stepwise. The reaction for introducing a group bonding through a carbon other than alkyl can also be carried out in the same manner as above.

Further, the alkylation can be carried out by combining compound (1-3) and a carbonyl compound in the presence of a reducing agent. Examples of the reducing agent used in this reaction include lithium aluminum hydride, sodium cyanoborohydride, sodium borohydride, sulfur/lium, sodium amalgam, and a combination of zinc and acid. Also palladium and platinum.

It can also be carried out by catalytic reduction using a catalyst such as rhodium.

Conversion of amino group to a compound represented by IN''-NH- (imino group-substituted alkylamino group, alkylimino group-substituted alkylamino group, or substituted guanidino group) Conversion reactions to amino groups include dioxane, tetrahydrofuran, N,N-dimethylformamide, chloroform, and acetone.

This is carried out, for example, by reaction with imidoesters in a solvent such as acetonitrile or water. Suitable imidoesters include, for example, methylformimidate and ethylformimidate. Benzylformimidate, methylacetimidate, ethyl acetimidate, methylphenylacetimidate, ethyl N
-Methylformimidate. Methyl N-ethylformimidate, methyl N-isopropylformimidate, etc. are used. The reaction temperature is around 0℃ to 25℃,
The reaction time is usually about 1 to 6 hours. The conversion reaction of an amino group to a guanidino group uses water.

For example, reacting with O-alkyl or O-aryl pseudoureas or S-alkyl or S-aryl pseudothioureas in a solvent such as N,N-dimethylformamide or hexamethylene phosphoramide. It is carried out by The above pseudoureas include:
0-methylpseudourea, S-methylpseudourea, O
-2,4-dichlorophenyl pseudourea, 0-N, N
As the pseudothioureas such as -trimedel pseudourea, 5-p-nitrophenyl pseudothiourea and the like are used. The reaction temperature is around 0°C to 40°C, and the reaction time is usually about 1 hour to 24 hours.

Alkenylation (Imination) The alkenylation (imimination) of the compound (+-3) can be carried out by dehydration condensation of the compound (1-3) and a carbonyl compound. Although this reaction proceeds without a solvent, it can also be carried out in a solvent. Acids or bases may be used as catalysts. It is also possible to produce the compound (1-3) and the carbonyl compound by heating and refluxing the compound in the presence of a dehydrating agent or using a dehydrating apparatus such as Dean-Stark.

-JjHfuv--/- wo city In :V jl X
? M kV si 21. ) Force I-i
Lrd ・t4-1, toluene, dichloromethane,
The reaction temperature is about θ°C to 200°C, and the reaction time is about 1 hour to 20 hours. Examples of acids used as catalysts include benzenesulfonic acid, methanesulfonic acid, sulfuric acid, boron trifluoride, and zinc chloride; examples of bases include potassium hydroxide and sodium carbonate. The dehydrating agents used in this reaction include molecular sieves, silica gel, anhydrous magnesium sulfate, anhydrous &lJ! Examples include sodium.

The thiolation reaction of thiolated compound (1-3) is usually carried out with compound (I-
3) and a halogenated thio compound containing a group represented by the formula n"-3on- (wherein rt" and n have the same meanings as above) (e.g., sulfonyl halide, sulfinyl halide, halogenated thio compound sulfenyl) in a solvent in the presence of a base. Examples of solvents used in this reaction include water, acetone,
Examples include diogyzan, N,N-dimethylformamide, benzene, tetrahydrofuran, dichloromethane, and a mixed solvent thereof. As the base, organic bases such as pyridine, picoline, triethylamine, diisopropylethylamine, and N-methylmorpholine, or inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, and potassium carbonate are used. In this reaction, approximately 1 equivalent of the halogenated thio compound is usually used for compound (+-3).

About 1 equim to 10 equim of base is used, and the reaction temperature is about -
The temperature is 20°C to 80°C, and the reaction time is 15 minutes to 10 hours.

This reaction may also be carried out using a thioic anhydride (eg, toluenesulfonic anhydride, trifluoromethanesulfonic anhydride, etc.) instead of the halogenated thio compound. Also, for example, N-sulfonyl-N-methylpyrrolidinium, N
-Sulfonylimidazolide or N-sulfonyl-1
It can also be carried out by reacting with a thiolating reagent such as 11-1,2,4-triazolide.

The silylation reaction of the silylated compound (+-3) usually involves R
"" has the same meaning as above. This can be carried out by reacting a halogenated silyl compound (eg, silyl chloride compound, silyl bromide compound) containing a group represented by () in the presence of a base. As the base,
For example, pyridine.

Examples include organic bases such as picoline, triethylamine, diisopropylethylamine, and N-methylmorpholine. - The reaction is preferably carried out in a solvent, such as acetone, dioxane, N,N-dimethylformamide, benzene, tetrahydrofuran, dichloromethane and the like. The reaction temperature is about -20°C to the boiling point of the solvent, or about -20°C to 80°C, and the reaction time is about 15 minutes to 20 hours.

In the phosphorylation reaction of phosphorylated compound (1-3), compound R43 usually has the same meaning as above. ) containing a group represented by (e.g., diethyl phosphoryl chloride, diethyl phosphoryl chloride, diphenyl phosphoryl chloride, dibenzyl phosphoryl chloride, etc.) and about an equivalent to an excess amount of a base in a solvent. It is done. As the base, organic bases such as pyridine, picoline, triethylamine, and N-methylmorpholine, or inorganic bases such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, and sodium carbonate are used. Examples of solvents include water, acetone, and acetonitrile.

Dioxane, N,N-dimethylformamide, tetrahydrofuran, dichloromethane, etc., or a mixed solvent thereof may be used. The reaction temperature is about -20℃ to 80℃
℃, and the reaction time is 15 minutes to 15 hours.

Compound (1-5) can be acylated, ureidated (
thioureidation), alkylation, alkenylation.

It can be converted to compound (1-4) by subjecting it to reactions such as thiolation, silylation, and phosphorylation. The conversion reaction converts the above-mentioned compound (+-3) to compound (1-
It can be carried out in the same manner as the conversion reaction to 2).

Compound ('l-4) can also be converted to compound (1-2), for example, by subjecting it to a carboxylic acid esterification reaction or a carboxylic acid amidation reaction. Next, the reaction will be explained.

Esterification of carboxylic acid Esterification of carboxylic acid is carried out, for example, by the following method.

1) A raw material compound is mixed with a diazoalkane such as diazomethane, phenyldiazomethane, diphenyldiazomethane, etc. and a solvent such as tetrahydrofuran, dioxane, etc.
Ethyl acetate. React for about 2 minutes to 2 hours at about 0°C to reflux temperature in acetonitrile or the like.

2) Activate the alkali metal salt of the raw material compound with an alkyl halide, such as methyl iodide, benzyl bromide, p-
React with nitro-benzyl bromide, m-phenoquine benzyl bromide, pt-butylbenzyl bromide, pivaloyloxymethyl chloride, etc. Appropriate reaction conditions include using a solvent such as N,N-dimethylformamide, N,N-dimethylacetamide or hexamethylphosphoramide, and reacting at about 0°C to 60°C for about 2 minutes to 4 hours. let Even if triethylamine or the like is present in this reaction solution, it will not interfere with the progress of the reaction.

3) Avoid reacting the raw material compound with alcohol, for example, methanol, ethanol, benzyl alcohol, etc. This reaction is carried out in the presence of a carbodiimide condensing agent, such as DCC. At about 0°C to reflux temperature, about 15
The reaction is carried out for a period of 1 minute to 18 hours, and chloroform, dichloromethane, dichloroethane, etc. are used as the solvent.

4) When the acid anhydride of the raw material compound obtained by reacting the raw material compound with an acid chloride such as ethyl chlorocarbonate or benzyl carbonate is used as an alcohol, such as the one described in 3), React under reaction conditions. This anhydride combines the starting compound with an acid chloride and a solvent, e.g.
Tetrahydrofuran.

It is obtained by reacting in dichloromethane, etc. at 25° C. to S1 temperature for about 15 minutes to 10 hours.

5) The raw material compound is coexisted with a silylating agent such as trimethylsilyl chloride, t-butyl-trimethylsilyl chloride, and triethylamine, etc., in a solvent such as dichloromethane, chloroform, tetrahydrofuran, etc. at a temperature of about 0°C to reflux for about 15 minutes. Allow to react for 16 hours.

Amidation of carboxylic acids Amidation of carboxylic acids involves converting the starting compound into an acid chloride, such as ethyl chlorocarbonate, benzyl chlorocarbonate, pivalic acid chloride, or an acid anhydride, such as acetic anhydride, trifluoroacetic anhydride, etc. This is carried out by synthesizing the anhydride and reacting it with ammonia or the selected amine, such as the alkyl-, dialkyl-, aralkyl- or heterocyclic amines mentioned above. Alternatively, the reaction can also be carried out by reacting a carboxylic acid and the above-mentioned amine in the presence of a condensing agent such as DCC or N-3-dimethylaminopropyl-N-ethylcarbodiimide.

The above reaction is carried out in a solvent such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide, etc. at a temperature of about 0.degree. C. to reflux for about 15 minutes to 16 hours.

The target compound (1) thus obtained can be isolated and purified by means known per se, such as concentration, liquid conversion, dissolution, solvent extraction, freeze-drying, crystallization, recrystallization, fractional distillation, chromatography, etc. I can do it.

Since the target compound (1) has two or more asymmetric carbon atoms in its basic skeleton, there are theoretically four or more types of stereoisomers, and each of these isomers and mixtures thereof are included in the present invention. Also, It', I'L', It3. I't'.

ITiIk'A r-,'r Ik 1.1.
+h+・Ik9ha: -4' 1A/g JM
, w-th 1u forms, and mixtures thereof are included in the present invention.

Furthermore, when the groups represented by rt', R', n', n' and R@ have an asymmetric carbon, open-frame stereoisomers occur, and the present invention also includes each of these isomers and mixtures thereof. include. If a mixture of these isomers is produced in the above reaction, each isomer can be isolated by conventional methods such as various chromatography and recrystallization, if necessary.

Compound (1) of the present invention may react with a base to form a salt. Examples of the base include sodium,
Inorganic bases such as potassium, lithium, carunium, magnesium, ammonia, e.g. pyridine, collidine,
Triethylamine. Examples include organic bases such as triethanolamine.

When the compound ([) of the present invention is obtained in a free form, it may be formed into a salt using a conventional method, or the compound obtained as a salt may be converted into a free form using a conventional method. .

Further, compound (1) may form an inner salt, and such cases are also included in the present invention.

The stereoisomers of compound (1) can be used as medicines either singly or as a mixture.

Compound (II/) used as a raw material compound in the method of the present invention can be produced, for example, by the following method. In addition, R", It', It', R5, R8, and Y in the formula have the same meanings as in V.

Compound (U) - Compound (■): This step is a step of converting compound (II) to compound (IV). This reaction is usually carried out by reacting with an activator in a solvent or without a solvent. Examples of the activator used here include thionyl chloride, thionyl bromide, sulfuryl chloride, phosphorus oxychloride,
Oxalyl chloride, chlorine.

Halogenating agents such as bromine or carbon tetrachloride and triphenylphosphine, such as p-toluenesulfonic anhydride, p-nitrobenzenesulfonic anhydride, anhydride 2.4.
Sulfonylating agents such as 6-dolyisobrobylphenyl sulfonic acid, methanesulfonic anhydride, p-toluenesulfonyl chloride, p-chlorobenzenesulfonyl chloride, phosphoryls such as diphenyl phosphoryl chloride, dimethyl phosphoryl chloride, diethyl phosphoryl chloride, etc. For example, a curing agent may be used. This reaction is carried out by reacting the compound (U) with about an equivalent to an excess amount of the activator listed in n in a solvent or without a solvent. Also, as long as it does not interfere with the reaction, for example, triethylamine, diisopropylethylamine, pyridine.

Bases such as 4-dimethylaminopyridine may also be used. The solvent is cyclomethane.

Chloroform, carbon tetrachloride, 1,2-dichloroethane,
N,N-dimethylpolamide, N,N-dimethylacetamide, acetonitrile, tetrahydrofuran, benzene, toluene, etc. are used. The reaction temperature is usually about -20°C to 100°C, and the reaction time is about 30 minutes to 50 hours.

Compound (Vl) → Compound (■): In this step, the compound represented by the formula is reacted with a halogenating agent to form the compound (
IVX Here, the case where Jt' and R8 form a chemical bond in the general formula (IV) and the case where Y represents halogen will be explained. ). In the starting compound (Vl), R2'=methyl, 1N'=r
The case where t'=hydrogen is known (see Japanese Patent Publication No. 35-9031), but other compounds can also be produced according to the method described in this document. This reaction is carried out by reacting compound (Vl) with an equivalent to a small excess of a halogenating agent in a solvent. As the halogenating agent, chlorine, bromine, etc. are suitable. As a solvent, chloro71;lum, carbon tetrachloride, dichloromethane,
l, 2-dichloroethane, benzene, acetonitrile, etc. are used. The reaction temperature is approximately 00C to 80C, and the reaction time is approximately 10 minutes to 10 hours.

Compound (IV) can be obtained through a carboxylic acid esterification reaction in which a raw material compound in which R8' of the compound (R/) corresponds to a carboxyl group is converted from, for example, the above-mentioned compound (1-4) to compound ([-2). It can also be produced by subjecting it to a reaction similar to the amidation reaction of carboxylic acid.

Compound (I[) used as a raw material compound in the method of the present invention can be produced, for example, by the following method. In addition, R'', II3.IN', II5 and na in the formula have the same meanings as above.

In this step, one of the two carboxyl groups of the compound represented by the formula
This step selectively esterifies only the carboxyl group at the position to produce compound (n), which is a Hafester compound. This reaction is carried out by reacting compound (V) with about the same amount to a small excess of the esterifying agent in a solvent under the presence of an equivalent amount of base.

Examples of the esterifying agent used here include methyl iodide, benzyl bromide, p-nitrobenzyl bromide, and ff1-phenoxybenzyl bromide.

Examples include halides such as pt-butylbenzyl bromide, diphenylmethyl bromide, pivaloyloxymethyl chloride, and dialkyl sulfates such as dimethyl sulfate and diethyl sulfate.

As the base, for example, diisopropylamine.

Dicyclohexylamine, cyclohexylisobu[I pyramine, triethylamine, tripropylamine, tri-n-butylamine, diisopropylethylamine,
0AI3CO, DnU, N-methylmorpholine, N-methylpiperidine, N-methylpyrrolisif, 3.4-)hydro-211-pyrido[1,2-a]pyrimidine-2-
organic amines such as ion, 4-dimethylaminopyridine, pyridine, lutidine, and γ-collidine; hydrides with alkali metals such as lithium, sodium, potassium, and cesium;

Hydroxides, carbonates, etc. are used.

As a solvent, N,N-dimethylpolamide.

N,N-dimethylacetamide, hexamethylphosphoramide, dimethylsulfoxide, dichloromethane, acetonitrile, tetrahydrofuran, etc. are used. The reaction temperature is usually about -20°C to 100°C,
The reaction time is approximately 5 minutes to 30 hours.

Compound (V) → Compound (■) → Compound (■') → Compound number 1: In this step, compound (V) is reacted with benzyl carbamate to produce a compound (■) represented by the formula, and then this is reacted with benzyl carbamate. This is a step of converting the compound (■') represented by the formula by subjecting it to an esterification reaction, and then producing the compound ([) by subjecting it to acid treatment.

This reaction is performed for compound (V) with pendylcarbame-1.
The dehydration condensation is usually carried out by heating under reduced pressure in the absence of a solvent, using about the same amount to a small excess of . The degree of decompression is approximately 0
．． It is about 1 mm 1 g to 50 mmHg. The reaction temperature is usually about 50°C to 120°C, and the reaction time is about 30 minutes to 20 hours. Compound (■
) is then subjected to an esterification reaction to convert it into compound (■'). The esterification reaction is carried out by applying the same conditions as for the esterification of compound (V)→compound (I). / Noue A tr 'J with azoalkanes or, for example, methanol.

Ethanol, benzyl alcohol, etc. and DC
Esterification may also be carried out in the presence of a carbodiimide condensing agent such as C. The esterification method is appropriately selected depending on the desired ester, and the ester used here is selected from one that is relatively stable to acids since an acid is used in the next reaction. Compound (■') is converted to compound (U) by acid treatment. Examples of acids used here include hydrochloric acid, sulfuric acid+'A hydrohydric acid, perchloric acid, and periodic acid.

Formic acid, acetic acid, trifluoroacetic acid, p-1-luenesulfonic acid, and the like may be used alone or in combination.

Among them, a combination of hydrobromic acid and acetic acid is preferred. The reaction temperature is approximately θ°C to 50°C, and the reaction time is approximately 15 minutes to 5 hours.

Compound (V) - Compound (■) → Compound (■); In this step, compound (V) is reacted with a halogenocarbonic acid ester to form a compound (■) represented by the formula, and then decarboxylated to form compound (11). This is the process of manufacturing.

2-oxoglutaric acid (a 3 in compound (V)
An example in which l-ethyl ester of 2-oxoglutaric acid was synthesized by reacting =11'=11'=r ("=II compound) with ethyl chlorocarbonate and then decarboxylating it is known in the literature. [ J. M. Domagala, Tetrahedron Letters ('I' etrahedro
n L etters) Volume 21, Page 4997, 198
Year 0]. In this reaction, Compound (■) is produced by reacting Compound (V) with a halogenocarbonic acid ester in a solvent in the presence of a base, followed by decarboxylation. Specific examples of halogenocarbonate include methyl chlorocarbonate.

Ethyl chlorocarbonate. Benzyl chlorocarbonate, chlorocarbonate
Examples include 2,2,2-trichloroethyl. The base and solvent used here are compound (IV)
- In the process of compound (1-2), those described in the production method can be mentioned. In this reaction, about an equivalent amount of base and about an equivalent amount of halogenocarbonate are used with respect to compound (V). The reaction temperature is usually -30°C to 60°C, and the reaction time is about 1 minute to 2 hours. Compound (■) does not need to be particularly isolated, and the decarboxylation reaction proceeds under the above-mentioned reaction conditions to yield compound (U) all at once.

Compound (V) - Compound (IX) - Compound (II)': In this step, compound (V) is treated with a dehydrating agent to produce compound (IK) represented by the formula, which is acid 111 hydrate, and then alcohol This is a step of reacting to produce compound (■). Examples of the dehydrating agent used in this reaction include halogen compounds such as phosphorus oxychloride, thionyl chloride, and chlorosulfonic acid, such as acetic anhydride.

Acid anhydrides of lower fatty acids such as trifluoroacetic anhydride, acid halides such as acedel chloride, e.g.
, N'-carbonyldiimidazole, imidazole derivatives such as N-trifluoroacetylimidazole, DC
Examples include C. When using the above acid halides, for example, pyridine.

An organic base such as triethylamine may also be used in combination. This reaction is carried out using a dehydrating agent in an amount of approximately equivalent to m excess relative to compound (V), and is carried out in a solvent, or if the dehydrating agent is liquid, it is carried out also as a solvent. As a solvent,
For example, dichloromethane.

Benzene, toluene, acetonitrile, etc. are used. The reaction temperature is usually about 0°C to 100°C,
The reaction time is approximately 15 minutes to 30 hours. Compound (IK) is then reacted with about an equivalent to an excess amount of alcohol to obtain compound (IT). Specific examples of alcohol include methyl alcohol, ethyl alcohol, benzyl alcohol, p-nitrobenzyl alcohol, and t-butyl alcohol. In this reaction, for example, sulfuric acid, p-toluenesulfonic acid, zinc chloride, sodium acetate, pyridine, 4-dimethylaminopyridine, 4-pyrrolidinopyridine, triethylamine.

Catalysts such as calcium carbide may also be used.

The reaction temperature is approximately θ°C to 100°C, and the reaction time is approximately 10 minutes to 4 days.

In this step, compound (V) is diesterified to produce compound (X) represented by the formula, and then only the 1-position ester group is selectively hydrolyzed to form compound (XI) represented by formula.
After conversion, an ester group different from the 5-position ester group is introduced into the 1-position carboxyl group to obtain the compound (■) represented by the formula, and finally only the 5-position ester group is selectively converted to a carboxyl group. and the compound (I
I) is a manufacturing process. The above formula (x).

n48 in (XI) and (■) is an alkyl group such as methyl, ethyl, etc., such as benzyl, p-
Examples include aralkyl groups such as benzyl and p-nitrobenzyl.

In the reaction of compound (V)-compound (X), the reaction of compound (V)-compound (
V) - The method described in the method for producing compound (II) is carried out by using an esterifying agent and a base in an amount of about 2 to 100% of the amount of compound (V), respectively. Hydrolysis of compound (X)-compound (Kari) is usually carried out by
For example, lithium and sodium.

It is carried out in a solvent with a base such as an alkali metal hydroxide such as potassium or cesium, a carbonate, or an alcoholade. As the solvent, water, methanol, ethanol, tetrahydrofuran, dimethyl sulfoxide, etc. can be used alone or as a mixed solvent. This hydrolysis reaction is
This is carried out using about an equivalent amount of base to compound (X). The reaction temperature is usually about 0°C to 80°C, and the reaction time is about 10 minutes to 20 hours. The esterification reaction of compound (kari)-compound (■) can be produced according to the method described above in the production method of compound (V)-compound (n). Furthermore, t-butyl ester may be produced by reacting compound (XI) with isobutyne in the presence of an acid catalyst. Compound (XI [) → Compound (II
) conversion reaction is possible when the ester group at position 1 is stable to base and the ester group at position 5 is not (for example, rt'' = t-butyloxycarbonyl, R48
-methyl, etc.) is achieved by applying the above-mentioned method of alkaline hydrolysis of compound (X)-compound (Kari). In addition, if the ester group at position 1 is stable under reducing conditions and the ester group at position 5 is not (for example,
rt'' = t-butyloxycarbonyl, R'' = benzyl, etc.), the Hafester form [compound (■)] can be selectively obtained by a reduction method. Reduction methods include, for example, catalytic reduction methods using metal catalysts such as palladium carbon, palladium black, palladium barium carbonate, Iv2 platinum gold black, and Raney nickel; , reduction methods using acids such as formic acid and acetic acid are applied. Reductive methods are usually carried out in a solvent, eg water, methanol, ethanol, ethyl acetate.

Acetone or the acids listed below are used. The reaction temperature is usually about 0°C to 60°C, and the reaction time is about 10 minutes to 20 hours.

In this step, the compound (XI[I) represented by the formula is esterified to lead to the compound (XIV) represented by the formula, and then subjected to a hydrolysis reaction to form the compound (XV ), this was esterified again to convert it into the compound (XVI) represented by the formula, and the hydroxyl group was further oxidized to form the compound (XIIX supra), which was converted into the above compound (Xl[)-compound (II) ) to produce compound (n).

In the raw material compound (Xllll), R'=rt'=1N'
Compounds in which =rt''= 1-1 are known in the literature and can be easily synthesized from glutamic acid [M.

'l'aniguchi at al, , tetrahedron ('l'etrahedron), 30.35
47 (1974)].

Compounds having substituents on R3 to IN'' can be synthesized according to this method.Esterification of compound (XIII)-compound (XIV) is performed first in the production of compound (V)-compound (II). In addition, when compound (XIII) is added with an alkene such as isobutyne as a catalyst, such as sulfuric acid, boron trifluoride, etc., to produce a t-alkyl ester. This reaction is usually carried out in a solvent.Solvents include dichloromethane, chloroform, dioxane, and diethyl ether.

Tetrahydrofuran, benzene, etc. are used, and after introducing an excess amount of isobutyne, the reaction is carried out by sealing and reacting at about 0° C. to 50° C. for about 5 hours to several days. Compound (XIV) - Compound (XV) is hydrolyzed with alkali to form compound (X) - compound (XI)
The method described in the manufacturing method can be applied. In addition, in order to carry out this reaction, the ester group of the compound (Xl'l/) must be relatively stable against alkali (for example, n '' =
t-butyloxycarbonyl). Esterification of compound (XV)-compound (XV[) is
It is carried out according to the method for compound (■)-compound (■') described above. The oxidation reaction between compound (XVI) and compound (■) is carried out by treating compound (XVI) with an oxidizing agent in a solvent. Examples of the oxidizing agent include potassium permanganate, manganese dioxide, dimethyl sulfoxide (DMSO)-DCC, DMSO-acetic anhydride, DMS
O-oxalyl chloride, DMSO-phosphorus pentoxide, etc. may be used. As the solvent, dichloromethane, chloroform, acetonitrile, ethyl acetate, benzene, toluene, DMSO, N, N-dimethylformamide, acetone, ether, etc. are used. This reaction is usually carried out using a compound (
XVI) is used in an amount of about an equivalent to an excess m of oxidizing agent. The reaction temperature is approximately -80°C to 60°C, and the reaction time is approximately 10 minutes to 30 hours.

The production of a compound in which IN" is an amidated carboxyl group in compound (11) can be carried out using the above-mentioned compound (xl).
It can be carried out by applying the method for producing amidation of carboxylic acid described above, and then following the method described in the method for producing compound (II) from compound (XI[).

Compound (V), which is a raw material compound used in the present invention, is
It can be produced by various methods that have already been reported. For example, the compound itself is known from the documents listed below, or the compound (V) can be obtained according to the methods described in these documents.

(1), Organic Synthesis (OrganicS
Synthesis), Co11active vol.
, 3.510(2), M, E, E, Blai
se ei al, , Bulletin du Société Simique du France (I3ulletin)
de la 5ocicLe Chimiqu
e de France), 9,458 (1911) (
3), W, Il, Perkin eL al.
, , Journal of the Chemical Society (
J o [the Chemical
Society) 79, 729(4), J
, C. Bardhan, Journal of the Chemical Society, 1928.2591(5), W.
N., I. Iaworth eL at, Journal of the Chemical Society, 105゜(
6), F. C. Hartman, Biochemistry (13iochemistry) 20. 894 (1
981) (7), G, l1esse et a.
L, Annalen Deer Hemi
dar Chesie), 697.

62(196G) Compound (V) can be produced according to the following reaction formula, for example, when It 3 = tl.

(X■) (X■) (XIX)
(V) In the above formula, ■E2', n4. nS
, n 11 is the same% as above! It has r, a.

The conversion of compound (X■)-compound (XIX) is the so-called C
This reaction is well known as 1aisen condensation, and is a step in which compound (X) and compound (X) are condensed in a solvent in the presence of a base. Examples of the base used in this reaction include alkali metals such as lithium, sodium, and potassium, alkaline earth metals such as magnesium and calcium, hydrides, alcoholades, amides, and alkyl metals thereof, and quaternary ammonium salts. (eg, tetra-n-butylammonium hydroxide, etc.). Examples of solvents include alcohols such as methanol and ethanol (if Alcolade is used, the same alcohol as the alkoxyl group of the ester), ether, tetrahydrofuran, dioxane, N,N-dimethylpolamide, 1,2-dimethoxyethane, dichloromethane. , benzene, toluene, etc.

The reaction temperature is usually about 0° C. to about 80° C., and the reaction time is about 10 minutes to about 1 hour.

The conversion of compound (XIX) to compound (V) is a process of producing compound (V) by acid, alkali or reductive treatment. This reaction is carried out using the above-mentioned compounds (
It can be carried out according to the method for producing X)-compound (Kari) or compound (XI[)→compound (II).

The compound (I
II) can be produced by various known methods. For example, the compound itself is known from the following documents, or compound (1) can be obtained according to the methods described therein.

(1), M. Franket et al.
, Tetrahedron Letters ('rrahedr
on Letters) 19 G 0.

28゜(2), M, Franket at al,
, Journal of the Chemical Society (C)
(Journal (3), n,, M, Khomot
ov et at, Chemical Abstracts 5B.

3944b For example, compound ([II) (when RI' is benzyloxycarbonylamino group) can be produced according to the method shown in Reference Example 2.

Each of the intermediate compounds thus obtained can be isolated by methods known per se, such as concentration, liquid conversion, dissolution, solvent extraction, freeze-drying, crystallization, recrystallization, fractional distillation, chromatography, and the like.

Compounds (■), (III) and (J) thus obtained are useful as raw material compounds for producing, for example, compound (1).

Compound (1) obtained as described above is useful as a medicine, such as certain Gram-positive bacteria.

It has antibacterial activity against Gram-negative bacteria.

Compound (1) has low toxicity.

In this way, the compound (1) of the present invention or a salt thereof +1-
It shows antibacterial activity of 1° against the antibacterial agent Gelamu Mushi Zeto Gelamu ■sujinkan, so it is effective against mammals (e.g. mice, rats, dogs, pigs, cows, etc.) that have been infected by bacteria. Bacterial infections (e.g., respiratory infections, urinary tract infections, purulent infections,
It can be used as a therapeutic agent for bacterial infections or as an antibacterial agent for the treatment of biliary tract infections, intestinal infections, obstetric and gynecological infections, surgical infections, etc.

The daily dosage of compound (I) or its salt is
The amount is about 10 to 5005 g/Kg, more preferably about 25 to 200 mg/Kg.

To administer compound (+), compound (1) or a pharmacologically acceptable salt thereof is added to an appropriate pharmaceutically acceptable carrier or excipient by conventional means.

It can be mixed with a diluent and administered orally in the form of a tablet, capsule, etc., or it can be formed into an injection by conventional means and incorporated into a sterile carrier prepared by conventional means. It can be administered parenterally.

When manufacturing the above oral preparations, such as tablets, a binder (
(e.g., hydroxypropylcellulose, hydroxypropylmethylcellulose, macrogol, etc.), disintegrants (e.g., starch, carboxymethylcellulose, etc.), excipients (e.g., lactose, starch, etc.), lubricants (e.g., magnesium stearate) , talc, etc.) can be appropriately blended.

In addition, when manufacturing parenteral preparations, such as injections,
Isotonic agents (eg, glucose, D-sorbitol, D-mannitol, sodium chloride, etc.), preservatives (eg, benzyl alcohol, chlorobutanol).

Methyl paraoxybenzoate, propyl paraoxybenzoate, etc.), buffers (eg, phosphate buffer, sodium acetate buffer, etc.), etc. can be appropriately blended.

EXAMPLES Next, the present invention will be explained in more detail with reference to Reference Examples and Examples, but the present invention is not limited thereto.

Example 1 2-[(4S)-4-benzyloxycarbonylamino-3-oxo-2-tetrahydro-! , 2-oxaxal]-5-oxo-2-tetrahydrofuranurubonic acid 4-nitrobenzyl ester [compound (1)]: (4S)-4-benzyloxycarbonylaminotetrahydro-1, obtained in Reference Example 2 143 mg of 2-oxazin-3-one and 177 mg of 2-oxoglutaric acid 1-(4-nitrobenzyl) ester obtained in Reference Example I were dissolved in 1.5 kl of dichloromethane, and dicyclohexylcarbodiimide 130D was added thereto for 30 minutes at 0°C. The mixture was then stirred at room temperature for 30 minutes. After removing the precipitated crystals by filtration, the filtrate was concentrated and the resulting residue was subjected to flash column chromatography (silica gel) and mixed with hexane-ethyl acetate (1:
1), 273 mg (1:1) of compound (1) was obtained.
A mixture of diastereomers) was obtained.

Ire νK"c+n-': 3320.1800.1
770.1?20,1710゜aX 1700, 1605.1525 NMR (90MHz, CI) C1s CD30D) δ
:1.65-2, to(lIl,m), 2.33-3
．． to (511, I++), 4.00-4.35 (2
11, m).

4.40-4.75(lit, m), 5.12(
2+1. s), 5.33(211,s), 5
．． 65-5.90 (111, m), 7, 35 (5
11,s), 7.52(211,d, J =
911z).

8.20 (211,d, J=911z) Example 2 2-[(4S)-3-oxo-4-(2-chenylacetamido)-2-tetrahydro-1,2-oxazinyl]-5-oxo 2-tetrahydrofurancarboxylic acid
Production of sodium salt [compound (2)] Compound (1) 15
0mg was dissolved in a mixture of 3d ethyl acetate and 3d PTT 7 phosphate buffer, and 5% palladium-carbon IQOmg
was added and stirred for 30 minutes at 0°C in a hydrogen stream. The catalyst was removed by filtration, and the filtrate was washed with ethyl acetate (twice). Add 7 h4 of tetrahydrofuran and 76 mg of 2-thiophene acetic acid chloride to the aqueous layer under cooling with water.
The solution was added and stirred for 30 minutes while maintaining the pll at 7 with a 4% aqueous sodium hydrogen carbonate solution. Tetrahydrofuran was distilled off under reduced pressure, and the aqueous layer was washed with ethyl acetate (twice).

After concentrating the aqueous layer under reduced pressure, the concentrated solution was subjected to XAD-2 column chromatography, and both fractions eluted with 10% methanol were lyophilized to give 48 mg of compound (2) as colorless crystals.

IRν ” B rcm-': 3420.1775.
1700.1650118X NMIN (90MIIZ, D20) δ: 1.90-3
．． 15 (611, m).

3,96(2[1,s), 4.20-4.60(2
11, m), 4.70-5.00 (ill, m)
.

7.05-7.15 (211, m), 7.38-7.4
8(ill,m) Example 3 2-((4S)-4-[2-(2-amino-4-thiazolyl)-(Z)-2-(methoxyimino)acetamide]-3-oxo-2-tetrahydro Production of -1,2-oxazinyl)-5-oxo-2-tetrahydrofurancarboxylic acid sodium salt [Compound (3)].

Compound (78 mg IN to 37.1 ethyl acetate and pH
7. Dissolved in 3 ml of phosphate buffer, 5% palladium on carbon 1
00 mg was added and stirred for 30 minutes at θ°C in a hydrogen stream. The catalyst was filtered off, and the filtrate was washed with ethyl acetate (twice). 18 d of tetrahydrofuran was added to the aqueous layer, and 2- Chloroacetamido-4-thiazolyl)-(Z)
-2-Methoxyiminoacetic acid chloride hydrochloride 173mg
was added and incubated for 30 minutes while keeping the po at 7 with a 4% aqueous sodium hydrogen carbonate solution. Tetrahydrofuran was distilled off under reduced pressure, and the aqueous layer was washed with ethyl acetate (twice). Next, tetrahydrofuran By4 and 90 mg of sodium N-methyldithiocarbamate were added to the aqueous layer, and the mixture was stirred at room temperature for 30 min.
Stir for a minute. Tetrahydrofuran was distilled off under pressure, and the aqueous layer was washed with ethyl acetate (twice) and then concentrated under reduced pressure.

The concentrated solution was subjected to XAD-2 column chromatography,
The fraction eluted with 10% ethanol was freeze-dried to obtain 72 mg of compound (3) as colorless crystals.

I Rv K"cn+-': 3250, 1?75,
1700.1650ax N M R (90 MHz, D t O) δ: 1.
95-3.20 (611, m).

4, 06 (311, s), 4.30-4, 60 (
211, m), 4.85-5.15 (111.

m) Reference example! Preparation of 2-oxoglutaric acid 1-(4-nitrobenzyl) ester: (a) Add 3.63 g of dicyclohexylamine to a 20 ml solution of 2.93 g of 2-oxoglutaric acid in dimethylformamide.
g was added and heated to 50°C. Then, 4.75 g of 4-nitrobenzyl bromide was added and stirred at 70°C for 5 minutes. After cooling, 100% of ethyl acetate was added and the precipitated crystals were filtered off and washed with ethyl acetate. Filtrate and washing liquid Combine,
After washing with water and saturated saline, drying (MgSO,)
did. The solvent was concentrated under reduced pressure, and the residue was subjected to column chromatography using silica gel and eluted with hexane-ethyl acetate-acetic acid (50:50:I) to give 5.2 g of the compound (1) as crystals. obtained as.

Melting point: 100-102°C 11'L v KI3rcm-': 1735.170
? , +530.1345°aX 1275, 1085 NMI (91085N, CD C1s do DM
S O) δ: 2, 5-2.8 (211, m), 2.
9-:C3 (211, m), 5.40 (211, s)
.

7.62 (211, d, J=911z) 4.28 (21
1, d, J=91tz) Elemental analysis value: C+ t l-
1, Calculated value of NO C, SL, 2S: H, a, 94
; N, 4.98 actual value 0.5LL7.1-1. :(
, 92; N, 4.96(b), To a solution of 2.93 g of 2-oxoglutaric acid in dimethylformamide 20) n11, 2.79 ml of triethylamine and 4.53 g of 4-nitrobenzyl bromide were added, and the mixture was stirred at room temperature for 5 hours. . The reaction solution was pressurized into ice water and extracted with ethyl acetate (twice).
did.

Then, in the same manner as in Reference Example 1(a), 3.6 g of the compound mentioned above was obtained as crystals.

(C), 2-oxoglutaric acid monosodium salt 3.3
6g of dimethylformamide 30%! 4 to B1B11 liquid
-4 Add 4.53 g of trobenzyl bromide and 50°C
Stirred at ~60°C for 2 hours. Pressure the reaction solution into ice water,
Extracted with ethyl acetate (twice). Next, reference example 1 (a
), 3.92 g of the compound listed above was obtained as crystals.

Reference Example 2 Production of (4S)-4-penzyloxycarbonylaminotetrahydro-1,2-oxazin-3-one: 900 mg of carbobenzoquin-L-aspartic acid 4-methyl ester, 681 mg of dicyclohexylcarbodiimide, and dimethyl aminopyridine 30mg t
ert-butanol 51n1. The solution was stirred at room temperature for 1 hour. After evaporating the solvent under reduced pressure, 5 hours of ethyl acetate was added, and the precipitated insoluble matter was filtered off. The filtrate was washed sequentially with an IN-potassium hydrogen sulfate aqueous solution, saturated saline, 4% sodium hydrogen carbonate, and saturated saline, and dried (N at SO4).
,Ta. When the solvent is distilled off under reduced pressure, carbobenzoxy-
1.03gh of 4-methyl aspartate 1-Lert-butyl diester (obtained).

I Rv NoaLcm-': 3330,2940.
175G-1700, 1505ax NMR (90MI[z, CDC1a) δ: 1.44 (
911, S) Main island 950 mg methanol 5-solution 1
Sodium borohydride at 00-20°C 1. Og was added little by little over about 1 hour, and the mixture was further stirred for 30 minutes. Add 20 turns of ether under water cooling and adjust the pH to 2 with 2N hydrochloric acid! After conditioning, the mixture was extracted with ether (3 times). The extract was washed with saturated brine and dried (MgSO,).

The solvent was distilled off under reduced pressure, the residue was subjected to column chromatography (silica gel), and hexane-ethyl acetate (3:
Elution with step 2) yielded 335 mg of (2S)-2-benzyloxycarbonylamino-4-hydroxylbutyric acid 1crt-butyl ester.

I n siN0aLcm-': 3360,2980
, 1730.1700.15+5ax N MIL (90MHz, CD C13) δ:
1.40 (911,S), 1.9Q-2,35 (21
1, m), 2.93 (111, bs), 3.53-:(
,80(21+,m).

4, 25-4.53 (llI, m), 5.10 (
211, s), 5.43-5.66 (ill, m)
.

7.33 (511, s) To a solution of 426 mg of Honjima in pyridine 2>J was added 205 mg of methanesulfonyl chloride at 0°C, and after stirring for 45 minutes, the pyridine was distilled off under reduced pressure. 30% ether to the residue
The ether layer was diluted with a saturated copper sulfate aqueous solution (twice),
% sodium bicarbonate aqueous solution (3 times) and saturated brine, and dried (Na, SQ, )t.

Ta. When the solvent was distilled off under reduced pressure, (2S)-2-benzyloxycarbonylamino-4-mesyloxybutyric acid tert-
546 mg of butyl ester was obtained. Then N −t
ert-butyloxycarbonylhydroxylamine 5
A solution of 57 mg of sodium methoxide and 168 mg of sodium methoxide in dimethylformamide 10d was stirred at room temperature for 10 minutes, and then the previously obtained 3d solution of mezilad in dimethylformamide was added and stirred for 5 hours. Three pI7 phosphate buffer solutions were added to the reaction mixture, followed by ether extraction (three times), and the ether layer was washed with water and then saturated saline. Dry the organic layer (MgSO
), the solvent was distilled off, and the residue was subjected to flash column chromatography (silica gel) using silica gel, eluting with hexane-ether (2: I') and (
2S)-2-benzyloxycarbonylamino-4-t
ert-butyloxyalponylaminooxyacetic acid t
435 mg of ert-butyl ester was obtained.

I N0'ILcm-': 3300,174
0.1730-1700ax N M IN (90M H7,, CI) Cl 3)
δ: 1.40 (911, S), 1.46 (911, S
), 1.93-2.25 (21+, m), 3.
92 (211, d, J = 611z).

4, 35 (111, Q, J= 611z), 5.
10 (211, s), 5.92 (lft, d, J
=7.511z), 7.30(511,s), 7.6
0 (ill, s) main island 435mg trifluoroacetic acid l
Add ad and 0.5 d of anisole and heat at 0°C for 1 hour.
Stirred at room temperature for 1.5 hours. The solvent was distilled off under reduced pressure, 22 g of water was added to the residue, and while maintaining the PTT at 3.2, 1-(
383 mg of 3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was added in 5 portions at 10 minute intervals. After the addition was completed, the mixture was further stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture for extraction (3 times), and the organic layer was washed with an aqueous IN-potassium hydrogen sulfate solution, then with saturated brine, and then dried (
Na, SO,). The solvent was distilled off, and the residue was subjected to flash column chromatography (silica gel) and eluted with hexane-ethyl acetate (1:1) to obtain 145 mg of the above compound as colorless crystals.

In νK"cm-': 330G, 1695.167
5.1545ax N M II (90M IIz, CD Cl 3)
δ: 1.60-1.95 (ill, m).

2,6O-LO3(1!I, m), 3.60-4
．． 30 (211, m), 4.30-4.70 (Ill
, m), 5. l:1 (211, s), 5.8
3(lIl, d, J = 611z), 7.
33 (511°S), 9.45 (ill, s) Effects of the Invention The compound of the general formula (+) of the present invention or its salt has an antibacterial effect and can be used as an antibacterial agent or a therapeutic agent for bacterial infections. obtain.

Claims (8)

[Claims] (1), General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1 represents an amino group or an organic residue via nitrogen. R^2 represents a carboxyl group or a group derived therefrom. R^3, R^4, R^5 and R^6
are the same or different and represent hydrogen or organic residues,
This includes the case where R^3 or R^4 and R^5 or R^6 form a chemical bond. ] or its salt. (2), R^3, R^4, R^5 or (and) R^
an organic residue in which 6 is bonded at a hydrogen or carbon atom;
The compound according to claim 1, which is an organic residue bonded via an oxygen atom, nitrogen atom or sulfur atom; or a halogen. (3), the organic residue bonded at the carbon atom is an alkyl which may have a substituent, a cycloalkyl, an alkenyl which may have a substituent, an aryl which may have a substituent, 3. The compound according to claim 2, which is acyl, cyano, carbamoyl, a heterocycle which may have a substituent, or carboxyl which may be esterified or amidated. (4), the organic residue bonded via the oxygen atom has the formula -O
-R^7 [wherein R^7 is hydrogen, alkyl, aryl,
Indicates acyl and carbamoyl. ] or an oxo group. (5), the organic residue bonded via the nitrogen atom has the formula ▲ mathematical formula, chemical formula, table, etc. ▼ [In the formula, R^8 and R
^9 are the same or different and represent hydrogen, alkyl, aryl, or acyl. ] The compound according to claim 2, which is a group represented by the following. (6), the organic residue bonded via the sulfur atom has the formula -S
(O)n-R^1^0 [wherein R^1^0 is hydrogen, alkyl which may have a substituent, aryl which may have a substituent, n represents 0, 1 or 2; ] The compound according to claim 2, which is a group represented by the following. (7), General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1' indicates an organic residue via nitrogen. ] and the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^2' represents a group that can be derived from a carboxyl group. R^3, R^4, R^5 and R^6 are the same or different and represent hydrogen or an organic residue, and R^3 or R^4 and R^5 or R^6 form a chemical bond. Including cases where it is formed. ] or a reactive derivative thereof, and if necessary, subjecting the compound to a conversion reaction of R^1' and/or R^2' ▲Mathematical formula, chemical formula, table etc.▼ [In the formula, R^1 represents an amino group or an organic residue via nitrogen, and R^2 represents a carboxyl group or a group that can be derived therefrom. R^3, R^4, R^5 and R
^6 has the same meaning as above. ] A method for producing a compound represented by. (8), General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1' indicates an organic residue via nitrogen. ] and the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^2' represents a group that can be derived from a carboxyl group. R^3, R^4, R^5 and R^6 are the same or different and represent hydrogen or an organic residue, and R^3 or R^4 and R^5 or R^6 form a chemical bond. Including cases where it is formed. Y represents a leaving group. ] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [ In the formula, R^1 represents an amino group or an organic residue via nitrogen, and R^2 represents a carboxyl group or a group derived therefrom. R^3, R^4, R^5 and R
^6 has the same meaning as above. ] A method for producing a compound represented by.