JPS58135883A - Novel compounds of 3-amino-2-oxoazetidine-1- sulfonic acid derivatives, manufacture, use as drug, composition and intermediate product - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel compound derivatives of 3-amino-2-oxoazetidine-1-sulfonic acid, methods for their production, use as medicaments, compositions containing the same and the production of intermediates obtained. relating to things.

Therefore, one subject of the present invention is the following general formula (D [where,
R has a hydrogen atom or at most 12 vertical atoms;
An optionally substituted linear or branched alkyl, alkenyl or alkynyl group.

Rel, group -(oat) -x (where n is 1 to 4
represents an integer of , X is a halogen atom, a cyano group, a group 0-
1'1 (凰'1 represents a hydrogen atom or an alkyl group), or X represents a group 8-]l', (R'□ represents a hydrogen atom, an alkini group having 71 to 4 carbon atoms) ,
Or 1' and R' are the nitrogen atoms to which they are bonded,
1.,'1' together form a monovalent group, or
1B-trans mixture.

The compounds of formula (I) are in racemic or optically active form 11, the oxime is in the ayn form] as well as in the salts of the compounds of formula (I) or in the salts with acids.

The meanings of the group R include the following.

a) Methyl, ethyl, propyl, isopropyl, butyl, 8eC-butyl, t-butyl, pentyl, isohentyl% 5ec-pentyl, t-bear f k .

Neopentyl, hexyl, isohexyl, 8-C-hexyl, t-hexyl, heptyl, octyl.

Decyl, one/decyl, dodecyl group.

b) Vinyl, allyl, 1-7'lopenyl, butenyl.

pentenyl, hexenyl group.

C) Ethynyl 7g Algyl, phthynyl group.

The radicals a) to C) K above may themselves contain one or more radicals (1), for example carxyl groups, which may optionally be salt-substituted or esterified;
alkoxycarbonyl; carbamoyl; dimethylcarbamoyl; amino; dialkylamino such as dimethylazano, diethylamino; alkylamino such as methylethyl; base;
Halogens such as bromine, iodine or fluorine; alkoxys such as methoxy, ethoxy, purobyloxy; alkylthios such as methylthio, ethylthio; aryls such as phenyl; aryl-heterocycles such as tetrazolyl, pyridinyl Formula; optionally substituted arylthio such as phenylthio; tetrazolylthio optionally substituted with alkyl such as methyl;
It may be substituted with 5-aryl monocyclic thio such as thiadiazolylthio.

The meaning of the group 1 is %K, hydrogen, methyl, carboxyethyl which may be esterified or salted from 4rK, 1-carboxy-1-methylethyl which may optionally be esterified or salted. , 2-aminoethyl and difluoromethyl.

As radical IL, mention may be made, in particular, of the chloromethyl, chloroethyl, chloropropyl, 1-10-1-methylethyl and chlorobutyl radicals.

Also, corresponding bromine, iodine or fluorine groups,
Mention may especially be made of the bromomethyl and fluoromethyl groups.

Also included are cyanomethyl, cyanale and the corresponding alkyl groups. Examples of the "group" include alkynyl groups and 11-methyl groups mentioned above in a) K, preferably having 1 to 4 carbon atoms.

As radicals R11 there can also be mentioned alkyl groups, preferably having 1 to 4 carbon atoms, and also methyl groups.

Examples of rewards that are compatible with ε represented by R1 include pyridyl, 1(2,3-11,2,H-11,2,4- or 1.
3゜4-thiadiazolyl 1lH-tetrasily, b, l,
3-thiazolyl, 1,2.3-, 1,2,4- or 1
,3.4-triazolyl i 1.2.3-,1,2.4
-, 1, 2. -1- or 1.3.4-okinacyazolyl group. These groups may be unsubstituted or may be substituted, for example, by the group consisting of methyl, ethyl, progyl, isopropyl, methoxy, ethoxy, propyloxy, isopropyloxy, amino, hydroxycarbonylmethyl, dimethylaminoethyl and diethylaminoethyl groups. It may be substituted with one or more groups selected from.

In particular, 1-methyltetrazol, 2-methyl-1,3,
4-thiadiazolyl, 3-methyl-1,2,4-thiadiazolyl, 3-methoxy-1,2,4-thiadiazolyl, 1,3.4-thiadiazol-5-yl, and 41
Examples include 1-methyltetrazolyl group.

Ethylamino, ethylamino, diethylamino.

It can represent a piperidino or morpholino group.

The sulfo group at position 1 as well as the carboxyl group that the group R may contain can form a salt.

Salts that can be manufactured include sodium and potassium.

Mention may be made of lithium, calcium, magnesium and ammonium salts. Also, trimethylamine, diethylamine, triethylamine, methylamine, propylamine, N,N-dimethylethanolamine, tris(hydroxymethyl)a-densumethane, ethanolamine, pyridine, picolizo, dicyclohexylamine, N
', N'-dipensilyethylenediamine, morpholine,
Also mentioned are salts of organic bases such as benzylamine, flocaine, lysine, arginine, histidine, N-methylglucamine.

The compounds of formula (I) can be provided in the form of organic or inorganic acids, in view of the fact that they contain at least one salt-formable amino group.

Examples of acids that can form a salt with the amino group of the metal compound of formula (I) include acetic acid and trifluoroacetic acid.

Murray ye11. lr right elt, mep sulfonic acid,
Examples include benzenesulfone, p-)luenesulfonic acid, hydrobromic acid, sulfuric acid, and phosphorus. Moreover, the compound of formula (1) can be provided in the form of a pentamolecular inner salt.

Preferred compounds are cIB compounds.

More particularly, the subject matter of the present invention is represented by the general formula () of the first order () [where s RI is a hydrogen atom, or optionally one or more halogen atoms, carboxyl].

A bell-shaped or branched alkyl group that may be substituted with an amino or cyano group.

n' represents an integer of l or 2.

X' represents a fluorine atom, a 2-pyridinylthiomethyl group, or a thiocyanato group] and is a racemic or optically active C18 form syn isomer; Found in salts with bases and acids.

Further, the present invention particularly provides a metal compound of the general formula (I) in which n' represents the number 1 and X' represents a fluorine atom, and the substituent 凰- is a hydrogen atom, or a methyl or difluoromethyl group. , a carboxymethyl group, an aminoethyl or cyanomethyl group, which may optionally be esterified or salted, or a 1-methyl-1-cal & diethyl group, optionally esterified or salted. The subject is hardware.

More particularly, the present invention describes the compounds described in the Examples below, especially racemic or optically active cis
-4-fluoromethyl-3-[2-(2-amino-4
-thiazolyl)-2-methoxyiminoacetamide]-
2-oxoazotidine-1-sulfonic acid ayn isomer,
and its salts as the subject matter.

The compound of formula (I) described above can exist in the form shown by this formula (I)K, or in the form of a tautomeric imine (1).

The lactam nuclei are numbered as follows:

The compound designated cig is a compound having the formula:

A trans compound is a compound that has a linear formula.

The present invention also provides a method for producing the compound of formula (I) described above, using the following formula (II) [wherein the tag represents R* (R1 has the meaning shown above) or the reaction to mtv whose sexual functional group is protected
and M represents a bulky water atom or a sulfo group] A racemic or optically active compound of the following formula (ill) (JR'
b [Here, lLb represents a bulky water atom or a protecting group for an amino group, R' represents a protecting group for a hydroxyl group, or ml represents R (1 has the meaning shown above) or nl represents 1 凰 in which the reactive functional group is protected] and by the following formula ■) (where "
``b''``b'' lLa and M have the meanings given above) to obtain a racemic or optically active compound, and then subject this compound, if necessary and if desired, to the following reactions: a) Rb
and separation of the protective groups that IL/b may represent or that 8'5 and Ra may contain by hydrolysis, hydrogenolysis or by the action of thiourea.

b) Esterification or salt formation of a carboxyl group that may be contained and salt formation of a sulfo group; C) Salt formation of an amino group with an acid; d) Sulfonation of a compound in which the group represents a hydrogen atom.

e) Resolution of molecules to obtain optically active compounds.

A method for producing a compound of formula (1) K11, characterized by carrying out one or more of the following in any order.

In formula (TI), R may generally be a group R1.

However, if the group represents a -(C11m)n'' group, where X represents a nitroxyl or amino group, it may be advantageous to protect these groups with a separable protecting group.

Protecting groups for amino groups may be, for example, alkyl groups, preferably t-butyl or t-amyl groups, and acyl may also include aliphatic, aromatic or cyclic groups or carbamoyl groups. can.

Also, lower alkanoyl groups such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl,
Examples include isovaleryl, oxalyl, stacinyl, pivaloyl, and the like. In addition, 1Lb is a lower alkoxy or cycloalkoxycarbonyl group 1 such as methoxycarbonyl, ethoxycarbonyl, fluoroxycarbonyl, 1-cyclopropylethoxycarbonyl, isopropyloxycarbonyl, butyloxycarbonyl, t-
butyloxycarbonyl, pentyloxycarbonyl,
hexyloxycarbonyl, benzoyl, toluoyl,
Naphtoil, 7tazonoil, metal.

It can represent an alkoxycarbonyl group such as phenylacetyl, phenylpionyl group or hapendyloxycarbonyl.

Acyl groups may be substituted, for example, with chlorine, bromine, iodine or fluorine atoms. For example, bromoacetyl or trifluoroacetyl groups can be mentioned in chloroacetyl, dichloroacetyl, trichloroacetyl.

Also, lower aralkyl groups 1 such as benzyl.

4-methoxybenzyl, phenylethyl, trityl, 3
．． It is also possible to use 4-di,methoxybenzyl or diphenylmethyl.

Other haloacetyl compounds such as trichloroethyl can also be used.

mata, chlorbe/soil, p-nitrobenzoyl, p-
It is also possible to use t-butylbenzoyl, phenoxyacetyl, caprylyl, n-decanoyl, acryloyl or trichloroethoxycarbonyl groups.

Furthermore, methylcarbamoyl, phenylcarbamoyl,
Naphthylcarbamoyl crystals and their corresponding thiocarbamoyl groups can also be used.

It is clear that the above list is not limiting and that conventional amine protecting groups, especially those known in peptide chemistry, can be used as well.

The retention Sa of the hydroxyl group can be selected from the following list.

Examples include formyl, acetyl, chloroacetyl, bromoacetyl, dichloroacetyl.

It may be trichloroacetyl, trifluoroacetyl, methoxyethyl, phenoxyacetyl, benzoyl, penzoylhorn, p-nitrobenzoyl. Also,
゛Ethoxycarbonyl, methoxycarbonyl, floboxycarbonyl, β, β, β-) 9/lorethoxycarbonyl, pencyloxycarbonyl, t-butoxycarbonyl, 1-cyclopropylethoxycarbonyl, tetrahydropyranyl, tetrahuman crossthiopyranyl , methoxytetrahydrobiranyl, trityl, benzyl, 4-methoxybenzyl, diphenylmethyl, tricoolethyl,
Mention may also be made of the 1-methyl-1-methoxyethyl and 7taloyl groups.

Mention may also be made of other acyls such as fuhionyl, butyryl, imbutyryl, valeryl, isovaleryl, oxalyl, succinyl and pivaloyl.

8, phenylacetyl, phenylpropionyl, mesyl, tarbenzoyl, p-nitrobenzoyl, p-
Examples include 1-butylbenzoyl, caprylyl, ataritoyl, methylcarbamoyl, phenylcarbamoyl and hinaphthylcarpamoyl groups.

Although it is obvious, the meaning of the substituted 1-b (when these do not represent a hydrogen atom) and the motive group that R/ may represent or contain (when %KR'b contains an amine) are as follows: , can be selected from the above enumeration.

In a preferred embodiment of the method of the invention, formula (II
) is treated with a functional derivative of a compound of formula (I[). This functional derivative can be, for example, a halide,
It may be a symmetrical or mixed anhydride, amide or activated ester.

Examples of mixed anhydrides include, for example, those formed with isobutyl chloroformate, those formed with dusted pivaloyl, and the mixed carboxylic acid-sulfonic anhydrides formed, for example, with p-toluenesulfonic acid. It will be done. Examples of activated esters include the esters formed with 2,4-dinitrophenol and the esters formed with dibenzothiazole in the slurry.

Examples of halides include chloride or bromide.

Also included are acid azides and acid amides.

The anhydride is a N,N-disubstituted carbodiimide, such as Ll
It can be formed in situ by reacting with N-dicyclohexylcarboxylate.

The acrylation reaction is preferably carried out in an organic solvent such as methylene chloride. However, other f)illNj
Hydrofuran, chloroform or dimethylformamide can also be used.

When a hydroxide is used, and generally when a hydroxide molecule is liberated during the reaction, the reaction is carried out with a base such as hydroxide, potassium hydroxide,
Sodium carbonate and ditarate, carbonate and sodium ditarate,
Preferably, it is carried out in the presence of sodium acetate, triethylamine, pyridine, morpholine or N-methylcarboline.

The reaction temperature is generally at or below ambient temperature.

When Rb represents a hydrogen atom, it is preferable to use a carboxyl-sulfone ll'fIh anhydride.

The compound of formula (5) may or may not constitute a compound of formula (H) depending on the meanings of Rb, R'5 and Ra.

The compound of formula GV), when Rb represents a hydrogen atom, U
/, does not represent a protecting group for a hydroΦyl group or does not represent a group containing a protected functional group, when lLa does not represent a group in which a reactive functional group is protected, and when M does not represent a group in which a reactive functional group is protected; Compounds of formula (I) are constituted when no atoms are represented.

In other cases, the compound of formula (5) #/kJK for 1
The action of one or more hydrolyzing or hydrogenating agents or thiourea is as follows: 1. When represents a protecting group for an amino group, the group R' is removed; when R' represents a protective group for a human-xyl group, the R'5 group is removed;
'The purpose is to remove any other protecting groups that may be present.' The types of reagents that should be used in all of these cases are well known to the insect industry. Examples of such reactions are further shown in Sōken no Iku.

Listed below are the means that can be used to remove various groups. Of course, it is not limited to this.

Removal of the group Rb can be carried out by acid or base catalytic decomposition or by using hydrazide.

optionally substituted alkoxy and Schifftetraalkoxycarbonyl groups, such as tert-benthylodicarbonyl or t-butyloxycarbonyl; optionally substituted aralkoxycarbonyl groups, such as the benzyloxycarbonyl group; and trityl, diphenylmethyl, t
Advantageously, acid hydrolysis is used to remove the -butyl or 4-methoxybenzyl groups.

Preferred acids used are hydrochloric acid, benzenesulfone II
I or p-) Rue/sulfonic acid, formic acid or trifluoroacetic acid.

However, other inorganic or organic acids can also be used.

Preferably, K uses basic hydrolysis to remove acyl groups such as triple olacetyl.

The bases preferably used are inorganic bases such as sodium or potassium hydroxide. Also useful are magnesia, baryta or alkali metal carbonates, acidic carbonates such as carbonic acid and acidic carbonates), lithium or potassium or other bases.

Also, sodium or potassium acetate can be used.

Hydrolysis with hydrazine is preferably used to remove groups such as 417taloyl.

Also, the tag group can be removed by zinc-acetic acid system (for trichloroethyl group) K, and diphenylmethylbenzyloxycarbonyl Iii! It is preferably removed by hydrogen in the presence of a catalyst.

The chloroacetyl group is J, mu, o,
g.

According to the reaction described in 90.4508 (196B) K, thiourea is removed from K on the action of thiourea in a neutral or acidic medium.

It is also possible to use other methods already known in the literature, for example separation by -f fluorination (for the 4IK benzyl group), to remove the protecting group.

Preferred groups include phoryl, acetyl, ethoxycarbonyl, metal, trifluoroacetyl, polyacetyl, and trityl. Both trityl and chloroacetyl are preferred for IF#.

The acid used is preferably trifluoroacetic acid or formic acid.

Removal of the l'5 group or the protecting groups contained by R'b and Ra, if necessary, is carried out under conditions similar to those described above for the removal of Rb.

Acid hydrolysis, among other methods, can be used to remove optionally substituted aralkyl or aralkyl 1.

As acids, Hanishun, formic acid, trifluoroacetic acid and p-)
Preferably, one selected from the group consisting of luenesulfonic acid is used.

The protecting groups contained by I&lLb or others of 凰'5 or tag or Ra are removed, if desired, by methods well known to those skilled in the art. Mild conditions are ideal for this.

Of course, several agents included in the above list may be used, for example, when Rb or R'b or R1 is a group that can be removed but belongs to a different class 11 or contains such a group. A compound of formula GV) can be acted upon.

Ring formation of the compound can be performed by conventional methods.

For example, #1 formation occurs in the late form of the compound or in l! of this acid.
It can be obtained by reacting a complex, such as an ethanol solvate or an inorganic base, such as potassium hydroxide or potassium, carbonate or potassium bicarbonate. Salts of inorganic acids such as trisodium phosphate can also be used. moreover,
Organic acids can also be used.

A list of such salts of organic acids can be found, for example, in French Patent No. 2.476.087.

As the sodium salt, it is preferable to use acetic acid, 2-ethylhexanoic acid or diethyl acetic acid salt.

Formation can also be achieved by the action of organic bases or amino acids.

In addition, it is necessary for compounds whose wings contain acid functional groups! The esterification carried out on tea is also carried out in a standard manner.

The sulfonation of compounds in which the moiety represents a bulk water atom is carried out with sulfuric anhydride or with reactive derivatives of this sulfuric anhydride.

It is preferred to use a pyridine-sulfuric anhydride complex, but other complexes of sulfuric anhydride and dioxane or trimethyla2/ may also be used.

The reaction is carried out in one common solvent, such as ethyl acetate, chloroform or dimethylformand, and can be carried out at ambient temperature. When a pyridine-sulfuric anhydride complex is used, the product can be isolated in the form of pyridinium hydroxide.

Any division of formula (If) or side helical molecules can be carried out by a conventional method.

Optically active carboxylic or organic sulfonic acids 1 such as tartaric acid, dibenzoyltartaric acid, camphosulfonic acid or glutasic acid can be used, and the decomposition of the salts so obtained is carried out using an inorganic base such as acidic sodium carbonate. ,
or with a tertiary amine, for example an organic base such as triethylamine.

In the present invention, a compound of the formula (It) in which M represents a hydrogen atom and a compound of the formula (nD) in which M represents a protecting group for an amino group are used; The present invention relates to the above-mentioned production method, characterized in that it is carried out on a compound of formula (I%') representing a protecting group.

The protecting group represented by ILb is preferably a trityl group.

Preferably, the sulfonation is carried out with a pyridine-sulfuric anhydride complex.

The subject matter of the present invention is a method for producing a compound of formula 1 (ID), which is produced by the following formula (■ N\8゜ (where R has the meaning shown above, and In the compound of the following formula (representing a protecting group) (where Rε and R5 represent a hydrogen atom on one hand and an atom on the other hand), or the tag and RIp together represent a divalent group. (wherein R, L, Rp, RIp and RIp have the above-mentioned meanings) by reacting the metal compound of (where B represents a hydroxyl group or a halogen) The compound of formula 1 is obtained by the following reaction: a) separation of the group Rp by hydrolysis, hydrogenolysis or action of thiourea;

b) optional sulfonation of the amine in position 1; C) hydrolysis, hydrogenolysis or separation of the groups R'p and RIp by the action of thiourea; d) optional conversion of the molecule to give the optically active compound. It is characterized by performing division.

The protecting group l can be selected from the list of substituents given above for amines.

However, for the reasons shown below, benzyl group or 2.4-
Preferably, a dimethoxybenzyl group or an equivalent is used.

Furthermore, the protecting group Rp can contain an asymmetric atom, and the subject of the invention therefore provides that ifIK, Rp represents a protecting group for an imino group containing an asymmetric group, starting from a compound of the formula (■), , and the above-mentioned production method, characterized in that the compound of the formula (匍) is isolated in optically active form.

These optically active compounds of formula (to) lead to optically active compounds of formula (I) according to the methods described above.

As a protecting group, 1-phenylethyl group can be mentioned in 41.

An example of the preparation of an optically active compound of the formula (@) is further shown in the experimental section.

The groups R5 and l- can be chosen from the list of protecting groups given above. Preference is given to using phthaloyl groups.

Group 1 can represent a halogen atom. Acid chlorides are preferred.

When 1 represents a halogen atom, the action of the compound of formula (2) on the metal compound of formula (2) is carried out in the presence of a base such as triethylamine or a metal such as zinc.

When 1 represents a hydroxyl group, the operation is carried out in the presence of an anhydride, preferably a dehydrating catalyst such as trifluoroacetic anhydride.

When the compound of 2) acts on the compound of formula (VD), a preferential Kci-compound is obtained.1rsina compound is
It is obtained by isomerization in a neutral medium.

When it is necessary to sulfonate the resulting compound,
The purpose of the deprotection reaction is to selectively convert the group Rp to Kl! It is to maintain a film. Therefore, as mentioned above, K.

Preferably, a benzyl or dimethoxybenzyl group is used, which is deprotected by an oxidizing agent such as potassium beroxonisulfate.

Preferably it is carried out in a solvent such as a water-acetic acid mixture or acetonitrile.

The optional sulfonation of compounds in which the secondary amine in position 1 is free is carried out as described above.

The optional second theory protection reaction operation is based on the groups R/p and 8
The purpose is to liberate the 3-position amine by eliminating '9. When carried out with the phthalimide group, as described above, the elimination is carried out with hydrazine, preferably hydrazine hydrate, in a solvent such as dimethylformamide, as described above.

Of course, the groups Rp, 1' and 4 can be removed at once, especially if no sulfo/conversion of the metal compound of formula av) is carried out.

The splitting is done in one conventional manner as described above.

According to the present invention @, the following formula (-) [Here, M has the meaning shown above, n represents an integer of 1.4, and X' is X (x is a halogen atom (excluding the above or X' represents X in which one reactive functional group is protected]. Treatment with a reactive derivative of ゎ15oy or -NO8 to produce a compound of the following formula OX) □ - (where X', A, R'9 and R'q have the meanings indicated above) 4b, optionally and if desired, the following reaction: a) When R′q and R19 are different from a hydrogen atom, the group represented by k is separated by hydrolysis, hydrogenolysis or the action of thiourea. , b) Sulfonation of compounds in which the group represents a hydrogen atom.

C) They can also be produced by a process consisting of carrying out one or more of the following: resolution of the molecule to obtain an optically active compound.

The action of the reactive derivative of the group intended to replace the halogen atom on the compound of formula (■) is carried out under normal conditions.

For example, the exchange of a halogen atom with a mercaptan is preferably carried out with an alkali metal salt of this mercaptan, such as the sodium salt.

Exchange between a halogen atom and an alkali metal salt of acetate, such as sodium or potassium acetate, allows the introduction of a retained hydroxyl group, which can be liberated or
It can also be esterified if desired.

This makes it possible to introduce the following:

In order to introduce an azide group, K can be treated with an alkali metal azide, preferably sodium azide. Alternatively, a metal cyanide or an alkali metal thiocyanate may be reacted to obtain a metal oxide or an inthioanate in which X represents one of these groups.

Further, the subsequent reactions performed by deprotecting groups, sulfonation and conjugation performed using pigeonholes are performed by the methods shown above.

A particular subject of the invention is a process for the preparation of formula (I) as defined above, characterized in that Ra is also a fluoromethyl group.

The compound of general formula (I) is suitable for Gram-negative ■, especially Escherichia coli,
It has a non-11K good antibiotic agent against bacteria of the genera Talepsiella, Salmonella and Proteus.

These compounds can be used as agents for the treatment of %K, coliosis and related infections, bacterial infections of the genera P4D, Thalepsiella and Salmonella, and other disorders caused by Gram-negative bacteria.

The subject of the present invention is therefore also the compounds of formula (I) as defined above and their pharmaceutically acceptable forms as medicaments and C5% antibiotic medicaments.

Particularly, the present invention provides 41 as a drug, an antibiotic drug of the following formula (T [where R1 is a hydrogen atom, or optionally one or more halogen atoms, carboxyl].

A linear or scissor-like alkyl group that may be substituted with an amino or cyano group.

n' represents an integer of 1 or 2.

X' represents a fluorine atom, a 2-pyridinylthiomethyl group or a thiocyanato group], and is a racemic or optically active gyn isomer in the cl-form, as well as compounds having the formula (
The subject matter is the preparation of the compound of I') with an acceptable base or acid.

More particularly, the subject of the present invention is a compound of the above formula (1), in which 49 represents the number 1 as an antibiotic agent and X' represents a fluorine atom, and the pharmaceutical differences thereof. salts with acceptable bases or acids, and the substituent R1 is a hydrogen atom, or a methyl or difluoromethyl group, a carboxymethyl group, an adenoethyl or cyanomethyl group, which may optionally be esterified or salted; or compounds of the above formula (■') representing a 1-methyl-1-carboxyethyl group which may optionally be esterified or salt-formed, and their salts with pharmaceutically acceptable bases or acids.

The present invention also provides 1% of the compounds described in the examples, especially 4-fluoromethyl-3-[2-(2-amino-4-thiazolyl)-
2-Methoxyiminoacetamide]-2-oxoazetidine-1-sulfo/ml.

cis, syn isomers, racemic or optically active forms and pharmaceutically acceptable salts thereof, and 4-fluoromethyl-3-C2-(2-at)-4-thiazolyl)-2-difluoromethoxyi-denoacetamide] -2-Soazetidine-1-sulfonic acid, 01B
, syn isomers, racemic or optically active forms and pharmaceutically acceptable salts thereof.

The invention therefore extends to pharmaceutical compositions containing at least one of the above-mentioned agents as an active ingredient.

These compositions can be administered orally, rectally or parenterally, or topically as a topical application to the skin and mucous membranes.

These compositions may be homogeneous or liquid and may be in the pharmaceutical forms currently used in human medicine, such as sugar-coated or intact compressed tablets, gelatin capsules, granules, herbal medicines, injectable preparations, ointments, They can be provided as creams and gels, which are made according to conventional methods. One or more active ingredients may be combined with excipients conventionally used in these pharmaceutical compositions, such as Merck, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous. Bisha Tal,
Animal or vegetable fatty substances, paraffin derivatives, glycols, various wetting agents, dispersants or emulsifiers and/or
Or it can be incorporated into a preservative.

4! These compositions can be prepared using a suitable carrier when required.
For example, it can be provided in the form of a non-pyrogenic, water-soluble powder.

The dosage may vary depending on the disease, patient, route of administration, and compound of interest. For example, that.

For the compound described in Example 1, the dosage for men may be from 0.250 g to 4 g per day for oral administration, or from 0.5009 to 1 g three times per day for intramuscular administration.

The compounds of formula (I) and their salts can also be used as disinfectants for surgical instruments.

Finally, one subject of the present invention is a compound of the following general formula (5) (wherein Rb, R/b, M and F have the meanings given above) as a new industrialized metal product, and The following formula (n) (where M and ILa have the meanings shown above, and when M represents a hydrogen atom, the tag represents a methylthio, hydroxymethyl, azidomethyl, aminomethyl or alkoxymethyl group. (shall not be obtained).

The unknown metal compound of formula (v) is the compound of formula 'BpNu,
can be prepared by treating the obtained amine with an aldehyde of the formula 1La0HO in the form of the hydrate 1a-OH (OIi), depending on the platform.

Examples of such preparation are shown in the experimental section.

In addition to the compounds described in the Examples of the present invention.

The following metal compounds are also metal compounds that can be obtained within the scope of the present invention. Here, the substituents X%R, M and 1 are of the formula (I
) K is shown.

Example 1: 4-tal methyl-3-(2-(2-A building 87m 132f#)!-(!-)ditylamino-4-thiazol)-1-methionoacetoid acid-aynJI
1m body is reduced to 236 methylene chloride and cooled down to 11 waves,! Zircal I diindo was added to the dicyclo of II4"f and stirred in the same cold oven for 20 minutes.
- Ahno 2-O Life Soazetidine A wave of acid vipers and 64t
-Add Trieter Aan. Maichi temperature 1:26
Stir for 0 minutes, separate the Nakashir poison into the resulting dicyclo,
Wash with methylene chloride, add 10-mL acidic sodium carbonate solution, and add 20A of water. This is then stirred and the organic phase is re-extracted and dried.

After concentrating to dryness under reduced pressure, the residue was triturated with a small amount of ethyl acetate, the insoluble matter was filtered out, washed with ethyl acetate, and concentrated to dryness again under reduced pressure.

The residue C* is dissolved in 5 parts of ethanol and slowly diluted with 1@a= of ether. The crystallization was stirred for 2 hours, then the resulting crystals were separated into layers and added to ethanol.
Ether (1-2) was washed with Kaji hardware to obtain electrified hardware weighing 68 g''f.

Analysis: OmmHtsOaNsllO1==5110
8 stitch count: 0%62.16 HIG4.68 NlG1
5 fruit 1111: 62.4 4.8 1
2.51) Dry dimethylforma of sulfonated 17.2a'#)"Formation of 2,403f obtained in the above process in one wave of 1,72F pyridine sulfane (visazine/anhydrous pyridine sulfane) dissolved in Ell. Stir the mixture at one temperature for 66 hours, remove any insoluble matter, wash with dimethylformide, dilute with ether, stir, stir, stir, test with ether - ether again. The folds and gum that were washed while using the frame metal were dissolved in 20A-g of ethanol and dissolved in G11, and the electrified metal crystallized when the metal was heated.
Stir, strain, wash with ethanol, then wash with ether.

I obtained the 1III chemical compound of the first drop, which was converted into 4-coolmethylene (-3-C2-C2-to-9-thiazolyl)-2-methoxymethane-2-oxoazetidine-! -S★honsunbipujeta^ b)) Removal of lythyl residue★ Pyridine sulfonate obtained above 3.Oq and 14-1
．． When the t-acid containing 3s is brought to 0.degree. C. and dissolved, crystallization of the 97-ester carbinol occurs. This at 50℃
Incubate for 1 minute, cool, dilute with a %0.6C bottle, remove insoluble matter once, and wash with a bottle.Add a small amount of ethanol, and dry-fight this under reduced pressure'FJlc.Water and ethanol. and then vacuum TKIII! Let them fight dryly. To the residue K add 1.2 cc of acidic carbonic acid and 17 ml of saturated water. After applying light insoluble matter once and washing with water, -
I took a close look at the liquid KB drops and scratched them. Place 11111: Possible substances crystallized. Stir for 10 minutes, evaporate, wash with water, wash with ether, and dry bales ~ 113q of expected metals were isolated.

Minutes #: ()to]Its(bNsllol=x
3@y, sg calculation 20-30, 11H! jg 3J
4 ig: 2fj, 6 3.2 kiln) 2-Klelu IK-7 el methyl ethane Book - Otsu 4th season glue acetaldehyde 20m- genus plant water Ki
Cool a wave formed by dissolving L14f's Pe/Silua in water of Sumire Oa-, and introduce it while stirring. The bales were stirred for 5 minutes at 1-15°C to obtain gummy and cloudy II bales, which were heated to 30ω and then zoer.
Extract with a pen of 100 ml. 2
Add a solution of 1 ml of fresh methylene chloride K to 50'.
CK wears cold clothes.

While stirring and maintaining the concentration, a solution prepared by dissolving 4f of 7-taluid W#shun koulide in toaa of cyclized methylene kll was introduced at 20°C, and 1
Continue stirring and then de★cites carbon layer fras:
! El: Wash with 5 og of deionized water and 5 se of 14 liters of carbonic acid, then wash with 1 ml (2 ml) of water.
1130aF)"t' washing 5. Re-extract the washing water with methylene (20t), dry, separate, wash and dry in a concentrated state under vacuum. A crude resin material (6f) was obtained. To rinse with yq force with Kumadoguthufi L and methylene chloride containing 5% sulfuric ether.Both fractions of 凰f = 1145 were isolated, dried, triturated with 161-sulfuric ether, and separated. ■ and washed S times with 2o:! of sulfuric ether. After vacuum drying, 1.25f product was obtained. MP = 14'l
'C017? If the product obtained above, 31f of Beotasoe potassium sulfate, 116 ay of water and 1110 gll?
Heat the hot metal of acetic acid in a 120℃ bath for 2 seconds while stirring well.

Next, this was cooled to shoulder temperature and 5 s of phosphoric acid di★l was added.
? Neutralize the acidity by thinning the mu and expel IIIfII & under reduced pressure, g59el! of water and 150 g of ethyl acetate, stir, and then add acidic sodium carbonate little by little until the generation of moth XIo stops. The medium was filtered, washed with ethyl acetate, exposed to 7 ml of filtrate, and 50 ml of
aII) Re-extracted with W# acid ether, dried, filtered, washed and concentrated under reduced pressure. the residue i
k! Elute with 01lf of silica (eluent: 25-methylene chloride with ethyl acetate). Both enriched fractions were collected, concentrated and dried, disintegrated with a needle, separated, washed and dried to obtain a compound with a concentration of 5.4'.

Analysis: C ■ Bird M y O1 = 264.67 Calculation: Os5
4.416 M % 3.43 Yiwa: s4.7 3.
5 The product obtained above was diluted with 5.4ω methylene chloride. To the suspension, 12a-hydrazine water 1N dimethyl Dimethylformad (required for 26ay)
drip. Collected envy% 20 minutes in the device, then add enough amount to completely solve alto@(63・et 11 Hani Shun to make the state 3・Shoulder circumference concentration 18
After stirring from time to time, the resulting phthalate was coated with dotjide, washed with water, then washed with ethanol, then washed with ether, and after drying, a 2.844 t#) product was obtained. Dispense the water and water into dimethyl chloride, dissolve the residue in 2-ethanol, drive off the ethanol, and add 21&- ethanol to the resulting product. Stir for 45 minutes,
After separating the resulting crystals and washing with ethanol and ether, the final K 2.4 fi·f of the desired compound was obtained.

a) Warm metal product of 2-(2-)lylamino-4-thiazo9-enzyme)-2-methoxyisoacetic acid of ring metal 1251, syn member, methylene chloride of 21ω and dicita p-hexyl carmediimide of 5rsq Stir in a cold water bath for 20 minutes. 11
By removing 9 of I, 587F of 4-(1-methyl-5-mer*budo1.!, 3,4-tetotuzol)methyl-3-
Unknown meaning - One wave of oquinoazetidine Hanishunani dissolved in methylene chloride KII of 1 (jay) and triethyl chloride of Q, 311a - Stir for 20 minutes with 111N at interlayer concentration, reduced pressure TK concentrated concentration leakage % - After washing with methylene chloride, working up with ether and drying, 1.594
The product of f (containing dicitalohexy λ urea) is subjected to single b) sulfonation! ,! The product obtained above S meeting 4t and O, SST's Piscidins fan (Pidgin anhydrous sulfur complex) are mixed with 6.6C dimethic acid formalde Kjl. . Wash twice with dimethic hexyl axillary, wash with the minimum amount of dimethic acid, and dilute 1P with ether of Ih2@ejta. Mix thoroughly, wash the intestine once, wash with ether, convert the product to -Is, dissolve in methanol, and crystallize the organic product in places. Apply this once, wash with methanol, finish with ether, dry, @2
oq.

A product was obtained.

A mixture of the product obtained in the above step, 0.8 ffl of water and 1.62 m of t acid was heated to .O'C for 12 days, then triphenylcal Because Pinot-y crystallizes.

The expected product also crystallizes out on cooling and dilution with a small amount of water. Mix the medium for 10 minutes, strain, wash with water,
Then, grind it in a 3-hole aetekei (dissolve 0F III with water and add acidic carbonic acid to C)! ? The mixture is stirred in a thin stream of koji and water, and then the unmoat is passed through, water is poured, and 111 hydrochloric acid is mixed until the concentration is -2, and the product is crystallized. After stirring for 5 minutes, filtering, washing with water, working up with ether, and drying, the iw product 2114q was obtained.

Analysis: OB15aOaM・B, 172H Maro 0 = 48 Ei 51 Calculation: 0%2tj, 631111G3.31 f
lZ5J1 g'jil177夷It: 2m, S
&4 25. li 111.8 Kinetsu 1 7.6f 4-coolmethyl-3-phthalimide-2-
oxinoazetidine, cis (obtained in the preparation of Example 1f) c)), 1-methyl-5-mercapto-1 of 5.41F,
A suspension of 2,3,4-tetrazole (dihydrate), 4.3f sodium iodide, and 571L dimethylformad was heated to 100°C, and electrostatic molding was continued at this concentration for 3 hours. . This was then cooled, poured into 119 g of ethyl acetate A, 119 g of water, washed, stirred vigorously, decanted and washed with 75 t of water and 119 g of ethyl acetate.
*Re-extract with ethyl and filter the insoluble material which is the desired product. After washing with 15 Qa water, re-extracting, drying, and F treatment, this was concentrated to a small spring ear and filtered twice.
Wash with ethyl acetate. Combine the nonwoven products, dry,
Finally, the expected product of 5.1F was isolated.

Analysis: 01. ■,, o, w, s 1/4 mu colt =
36137 calculation: 0 whisper 49.1711% 3.851%
22.94i1: 49.2 3.7 2
3.05.845F The product obtained above was suspended in 1 & 5α dry dimethyl formand, and 1 m of dorazine hydrate was added dropwise to the suspension, and the mixture was heated at 20F for 20F. 19 (Added ILF's water and spirit 4cM IN Hani Shun.

For a reason. The final bale of 3 was sealed and the mixture was kept stirring at ambient temperature overnight, then the resulting 7-talhydrazide was filtered off, washed with water, and concentrated under reduced pressure. Add ethanol, triturate, concentrate to 1 liter, reduce to solution with hot methanol, concentrate to dry bales, and the product crystallizes out.

Add 20 g CF of methanol, grind, cool, separate, wash with cold methanol and finish with ether.
Therefore, 2.49 t of product III were obtained.

C) A sign no aceto ano do]-2-okino azechijino 1
-Sulfonic acid, cis, syn, racemate 6.3
t's 2-(!-)η Chiruaken no 4-chia yvru>-z
-<2-tritylamnoethoxy)4 t/acetic acid s
syn member with 40a-methylene chloride and 1. !
4 Solution Kl of a- dissolved in ethyl athane
Add IF tosyl chloride.

4. After stirring for frequency division, 15 g of 5r of 4-talmethyl-3-a-electron-2-oxoa (II wave obtained by dissolving 4-C of methylene chloride and 2.4a- of toethylamine) was prepared. Add all at once and continue stirring at shoulder temperature for 2 hours, then decantate the water while stirring vigorously, re-extract with methylene chloride, dry the filtrate, and add 1 concentrated filtrate. bales of which the residue was treated with Termadogutfi L (IFl agent: ether) with Shi9i1; 4.
If I got a new product from Tokoro. mf=&8゜〜〜1111.4-Rysylmethyl-3-(2-1-)-1
Shizuku--1H ■-■ -- Shizuku --- ■ --- Ken -- ■-■
■１－－■－、、、、、、□い、、、、、□１． Yu,
,,,1. ．． ．． ．． ．． ．． ．． Yu, 1. ．． 1.1. □Hibiki---
2. The product obtained in the above step of Tsuga□-□□Irimu 4.9f. , @t no bi! The mixture of dinsulfane and 2sa-dimethylformamide is stirred at ambient temperature for 4 days. Next, do this 5
ooa'' of ether in 1 t of water.

The residue was ground, filtered, washed with ether, and dried to give the intermediate product of @]f. 1s)).

53f that contains 33 arcs of water
The suspension wave of the above product is 125°C to 1155°C. Then, after cooling and diluting with %3·ω water, the resulting Tri7EelCarpineau* was passed through, washed with water, and concentrated to dryness in a 40°C water bath.The residue was dissolved in 2 ml of a water-ethanol mixture. Then, concentrate and dry to reduce 1 water and add 1 acid sodium carbonate to 1111 so that the saturated water solution becomes slightly alkaline.

Remove any impurities, wash with water, and add 21i chlorinated acid to make the volume 4 to 5. Crystallization was initiated, the bales were stirred for 1 hour, filtered, washed with water, and then washed with ether, γ...
The desired product of the cape was obtained / Analysis: C ■ 110 @ N @ I judgment C1 Calculation: 013185 M2S, 54 Yi II: 3G1 3.8 Gin, 5yn 1, 527 f of 2-(2-) lythyl Kenno 4-Thiazotsuru)! -) A mixture of the sodium salt of lythyloxytinycin and 419q1) in 15 ffl of methylene chloride was mixed for 40 minutes, and then 342
A concentrated solution prepared by adding q's 4-rimethyl-3-arno-2-oxazetedine hanishun to 15 ml of methylene chloride and 0 and sar of triethylanitone are added.

Stir Nadashayu for 2 hours, add books, then stir.
Re-extracted with decanted II-methylene chloride,
The rice is dried and then allowed to pass.

- The solution was concentrated to dryness under reduced pressure and chromatographed with 9iI''C (eluent: ether).

After evaporating the solvent, the bell tower of 73＠q was heated to 11jI! do.

Zin-1-sulfo/vidazinicum 1,241 The product obtained as in the process of 241F was exposed to 64. Dendo KIII
In order to prepare the wetted liquid in a 4-Oka apparatus at a temperature of 10%, it was ground, poured into 309at of ether, and the impurities were passed through, washed with ether, and ground in 10aF methanol to give a concentration of 15%. The mixture was shaken, filtered, washed with methanol and then ether, and dried to obtain IJ2F raw material.

9.1fflf) @
・Stew becomes thin ■ Wait for 1 s -・℃・
By carrying out as described in Example 3, 1.C.
Obtained 1lriI product from Cape 18.

Setoand]-2-oxoa(thidine-1-XkO0-
15f#)! -(2-)Methyl-acetic acid, gyn-membered form, acetone of 7am, and tosyl chloride of 1L311f are heated. 2
・After heating the mold with S・tH at ℃, pass through the hot metal, and 0.2
Add a solution containing 118F of 4-fluoromethyl)h, @-amino-2-oxinoazetidine, cll, methane chloride and L42ell of ethyl chloride, mix for 45 minutes, and then evaporate to dryness. Add 11% water, add 11% water, then divide into layers, grind with 1 ton and divide again into 1 layer. The product is purified by trituration in ethyl acetate. Oo・! ! An intermediate product of 4F was obtained.

Analysis: 0tsM+n0sNslF S4
L@2 calculation! 01@t07MIG4. ll2M Shu11
8111'ji5. ')01%B, 49夷濶: ・4.
・ 41 114 SJ & 4 Koshiki [Product obtained by the process of 1f 1・411F's bijinsuruaan and 4. IC dimethylformand hot metal at 20℃
``c8 Hatake Tokito or Denka fyi.

Freeze it and pour it on 2・OC's Ete★ to surprise 1 living creature.
Add methanol and stir, resulting in 4k
II & 0.473 by separating and drying
At F, S product was obtained.

b) ml) Ethyl, 47.V.
87 m 6 full HC ■ turbid, heated to 5 liters °C for 5 minutes,
Next, heat for 1Φ'CE for 13 minutes, and further heat for 1.2 my
f) Reduce the g acid and then add again 70'CK for 15 minutes.・After cooling to ℃ and heating, add ethanol to the P solution and then concentrate.Add water and ethanol to the IIIF product and concentrate and dry again.
I understand %1. 10-bicarbonate of exposureffi) 9? Add 12M hydrochloric acid through V to make -2, evaporate the water, grind the residue with water, filter, wash with water, then wash with ether and dry, then add 6.14.f A product was obtained at a temperature of 240°C (with decomposition).Analysis: C3/II 0@N, g? =
3811 @ calculation: 0S31.50f13.171
s11L31111101 mF%4jl夷濶：
SIJ 31 1ts 1@, 5 Ll
l) ■-Methyl-M-methokitafluoroacetoid 21.2f #) * Mix fluoride with oleacyl and 12.1 methylene chloride, cool to inert gas 'FK + S °C,
IOg of methoxymethyl acetate is slowly introduced while keeping the temperature below 20°C - the whole is then stirred at 20°C for 2 hours. - The mixture was then expelled under reduced pressure, and the residue was distilled under reduced pressure to obtain intermediate products of 11-30 and 30,000 ml.

1P*a=93℃02) The product obtained in the above step of fluoroacetaldehyde hydrate 7.8f is cooled to 133ω tetrohydride vm79ylc@understanding, 0~+2''CK,
74a! Slowly introduce the IM hequinane S value of diisobutylaluminum hydride of 100 ml. Slowly bring the temperature to ambient concentration and pour with cooling into a solution of 28 molar concentrated hydrochloric acid and 11 molar reactor. Stir, then 1iI to atmospheric pressure T
A product of 38C (diluted with water) was obtained (IP = 7!!-166, !1℃). 1-(1-phenylethyl)azetidi/% clg ..The cylindrical casing obtained by K as in step 11 above for ω is 1.
- Dilute with a book. This was cooled in a water bath for Is minutes,
Next, 1) Lσ-7 ethyl acene of tS- was reduced, stirred at 10 f, dried, washed with water, and then 13.
Add methylene chloride in the stirrup to the P solution.Heat and reflux the mixture until it is completely dissolved. Dry the livestock rack for 1 decantation, then cool to -50°C in an inert gas oven.◎60
Slowly add 154F acetyl trichloride dissolved in methylene chloride and 10.4a triethylamine dissolved in methylene chloride. While stirring, return the temperature to 20°C in 1 hour.25ayf) Add 10-sodium bicarbonate and 60% water, then stir, decant, and extract with methylene chloride to yield %IFIII.
137f. I got it.

%@: O*eMsyOaN*F = 3! ! 137
Calculation: 0168.17 H%4.811 f17Jj
s F'jG5.31 Yiyang: @L! 4.1
7.8! L64) 4-fluoromethi #-3-7
The product obtained in the above process (2) of 117t of racemic body of soaitidine, cis, and 2-O-2-O was added to the acetate of
) 9 #Dissolve 1ml of K and add 1sOR of water.

The waste was refluxed, and then the 212t long sulphurous moat Anne 4a
c? A solution prepared by dissolving 2W of water in s2W of water was introduced over a period of 15 minutes, and the whole was kept under reflux for 1 hour and 1125 minutes.

Next, it was cooled, saturated with sodium monochloride, decanted, washed with sodium chloride saturated water II solution,
Re-extract with ethyl acetate, bring phase III to -111, dry and evaporate solvent to 111. Remove the residue with silica!
Todara fish, methylene chloride and ethyl acetate) (7!-2
5) The obtained crystals were washed with ethyl ether to give 9.75@f of product II.

11 Subek) # (OIIOIm) 841 @ ai' (-) [H), 1790.177
0 and 1721! im-” (OxO/-9ri) A and 7
B) Absorption of 4-7Jkl #Methyl-3-Adeno-2-Oxoa (Tidine IMWII #1s cigl, 24tl) The product obtained in the above step was absorbed in 1. ! - To the dioquinane, add turbidity, then add S wave formed by decomposing hydrazine hydrate of t"lcc to dioquinane KfIII of 2.C. Add this to jIW
Hold at temperature for 4s. Then add 5C of INI [acid, open the canopy for 15 minutes and continue to heat. Then concentrate to dryness, add ice and INI acid of tSS, stir, then f pass Add ethanol to r#1 and then concentrate to dryness. Add methanol and then ethanol to the a substance and add 1
Concentrate and dry again. Recrystallize the crystals from methanol・1a at 0.391f! The product was obtained.

MP (decomposition) = 220°C.

(!ia s j17n s racemic form, 2-(2-)richyl-4-thiazolyl)-4-(1-1-butoxycarbunyl-1-methylethoxy)ionoacetic acid 5ynJl form of 611, 5a of Mix 7 tons and 6.17 m'' of triethylamine - then t
Add 12@r of tosyl chloride, stir vigorously for minutes, pass through SP, 0.158 f#) 4-fluoromethyl-3-
Arano 2-oxoa (tidine cleavage acid 111 ei #s
Add 11 liquid obtained by dissolving aF in methylene chloride and 6SK" triethylamine in one wave while stirring. 20
After stirring at ℃ for 5 s, medium II was mixed with vI
Add methylene II and water! #f) 1. Assault bicarbonate)
91) Slimming down while weighing down. After decanting and rinsing with methylene chloride, the mixture was rolled up into a bundle, dried, and the residue was washed with silica to dry it. Sprinkle with ethyl ether @IIL, 0. The expected product of 1113F was obtained. , The thiazole compound layered at #1M was manufactured by France.
! , 421. ...described in No. 6.

The product obtained in the 4-thiazolyl)-2-(1-cal I reaction system and the pyridine sulfane of ossr were combined at 31C
This dimethyl solution is mixed at 20°C for 62 hours and then poured into water.

Stir, separate, and dry the resulting simmering radish.
The desired product was obtained. b) The product obtained in the above step was dissolved in 1lffif)) dichloroacetic acid. O'CKIS is maintained, and then the second season's isopouvir ete is well-organized, and the whole thing is passed through. The product was triturated in ethyl acetate for 15 minutes, dried, and
11th time! The product is 1a-010-natobicarbonate9? Dissolve a small amount of water containing 11 liters of water, let it pass again, and then PillK!
Add summer hydrochloric acid until uniform and re-add.

The water mixture was immersed in water, then cooled, and the crystals were separated and washed with ether to obtain 0.0*4 f.

W (decomposition) Yu 230℃ 0 Shizubetatle (]*10: 90 dig) 1.5
ppH (CIIIB) s 178-4.84 p
pIII (Ha and Saiyuki 1), 522-5.2'! −
5,32 and 5.371) I) 11(~4), L81p
pml (IIs thiazo-+gyn), 121 and L l
1 ppm (WHOO) peak 3.1 f! −
(2-)Rythyl ano-4-thiazolyl)-2-methoxyiminoacetic acid, gyn-membered form, is suspended in 59810 methylene. of IC) while stirring, then add 1.38f tosyl chloride 0 Continue stirring the whole at ambient temperature for 400 minutes, then 1.1 @!
Add 4-thiacyanatomethyl-3-amino-2-oxoa (triethylamine prepared by dissolving thidine hydrochloride aim in 40C methylene chloride) over 5 minutes. Stir this mixture for 4 hours. Continue washing with water, then 4
Wash with water containing 1M hydrochloric acid, dry, and concentrate to dryness. The residue was purified with ethyl acetate (KIFIFL).

The cooled, S&sol; crystals were separated, washed with methanol, and dried to yield the desired product at 0.701F. The mother liquor was dried for ms, the residue was termatized with v1/lica, and a mixture of lyroform and methanol (83-7)C' was distilled off to give m product at 1.0@If. .

Turtle) Obtaining Viridinic Sulfonate A mixture of the product obtained in Step 1.7f, 12ω of dimethyl chloride, and 1.1·t of pyridine sulfur is stirred at 20°C for 10 hours. . This was then poured into ether with stirring.1 The resulting precipitate was dissolved with methanol, cooled, and the crystals were then separated to give the desired product of 6544f. Heat the barley to 60°C, then add the product obtained above and stir until the mixture reaches 100°C. After cooling to 20° C., 49 my of ethyl ether was added at 0 to +5° C. for 1 hour while stirring. Separate the precipitate, wash with ethyl ether, and triturate with 6.1 m bicarbonate of water. The C-filtered 1I%P solution was acidified to -2 with IM oil, cooled, and the resulting crystals were washed with water and dried to obtain 6.28'lt.
The desired product was obtained. MP (decomposition) z 2 @ S
I.C.

+11t: o, 1x1. w・O・1. (430,
54) Calculation: 0 attack! 11.4211-2.88 N%1
1199㇉-2288 actual measurement: 31.2 B, 2
19.7 22.64-Thiocyanatomethyl JIy-3
-Akino 2-Oxo 26.5F 4-I'm so jealous-
3-phthalide-2-oxoazetidine, eiJt
% 30f of sodium iodide and 80C of dimethyl chloride were mixed and brought to 120°C for 2 hours, then cooled and poured into a mixture of 800Ω of water and 10L of ethyl acetate. Pour while stirring, filter out the crystals that form, wash with water, then wash with ethyl ether until colorless with ethyl acetate. Dissolve the mother liquor and add one decant
/Then, dry the turmeric, concentrate to dryness, dissolve in ethyl acetate, filter, wash with ethyl acetate, and dry. Two desired products of 214 F were obtained from this K.

The mixture of the product obtained above and dimethylformamide in the Z button was brought to 15° C. with stirring, and then 1.5 t of potassium thiocyanate was added with stirring for 3:01 sse. Pour the mino into water, remove it, wash it with water, and dry it. This is then ground in a hot sieve, separated and dried. 1.2 SP of the expected product was obtained.

The product obtained from the above step at 1.41 F was warmed with l5se of hot dioxidant, then cooled and combined with 0.3 ml of dorazine hydrate at 20° C. for 50 minutes. Add slowly. Next, add 7.5-season 1M Hanishun, stir the whole thing for 15 hours, separate 1 drop, and rinse with water.

Take the P solution and evaporate it to dryness a6. The desired product of 14F was obtained.

Ormet d&'4<-Noaceto-Ado]-2-O! Noah (chijin, aim, ayn, racemic body 0.914ff
) 2-(2-t9fkli7-4-thiazolyl)difluorometho diiminoacetic acid Nayn JQ form, 7cr 7ryushin and 0. ．． Mix 25 L of ethyl chloride and then add 339 F of tosyl chloride with stirring for 50 minutes. Then add 0.23 F of 4-fluoromethyl-3-anno-2-oxychloride (Tejin hydrochloride) with stirring. 7a'' methylene chloride ecIF solution and (L
45111! While stirring the triethylamine in F.
It can be completed in 5 seconds SO.

Aim the solvent, add methylene chloride, then add 3
Add with stirring 101 m of sodium bipodate. Decant 2 L, extract the aqueous phase with methylene chloride and gradually remove 10% of the phase with -JI K L % of the solvent.
The fII product was dissolved in ethanol, cooled, and the crystals were separated and washed with ethanol and then with nityl to give a dry bale of %O, 5S7f product.

±! 3.75? Dissolved in dimethylformand. The droplets are stirred for 72 hours at 20 DEG C., poured into 150 ml of ether, filtered and washed with ether, and the product is dissolved in ethanol. After stirring, the resulting crystallization was filtered off, washed with ethyl ether, and dried to give the desired product with a weight of 6.504 f.

b) 11) Rityl 6, 76 To mix the product obtained above with 4 buttons of 33≦ water and mint acid. The mixture was stirred at 60'C for 15 minutes, diluted with water, filtered, diluted with ethanol to the P solution, dried and washed with IIIFL in a mixture of water and ethanol.
, I again! Mix, dissolve with water and add 2 m' of 10-sodium bicarbonate. Insoluble matter is filtered out, 2M citric acid is added to the wetted solution to obtain 14 (2), which is then filtered and crystallized. The crystals are filtered out, washed with water, washed with ethyl ether, and dried. , the desired product of 6.312f was obtained @ Analysis: 01・■8.0・N, g child 18 Calculation: 0%28.78 H%2A111%16.781
1137567%15J6夷jll: 28j
2j 16s134 15.4) Q [l shek)
#(DWO) I 6M1x4.39 and 4.941)
pEm (-on, -y) Nopeak, 5.21-5.
26-5.3 and 5.35 pp Otori (lI3cig) peaks, 6.38-7.15 and 7.1$3 pP! 1
1 (-0HF,) Nopeak 7.01pp Otori (IIs
thiazole) peak, 9.66 and il, 76pp Otori (-0ONN) beater.

11 spectrum (OHOI,) 1770al-” (0xOI-lactam), 1@7s
m-" (and), 1640gm5""1 (and1)
, 1585dll (conjugated system), 1530 am-” (
97 Sole), 12 @ 1-1276 am-'
(-10111), 1 e) 52cm-' (-0-
Absorption of X-O-
4-Fluoromethyl-3-C2-C2-&Ie@f#)
! -(2-)rich, v7t, 4-thiashilik) - one methyloxyisogin isomer, 1ge of acetate and 0.17a- of tosethylamine are warmed and then 0. Add 22@f tosyl chloride. This mixture was stirred for 1 hour, then 6,155F dissolved in methylene chloride of Sa was added to 4-toluomethyl-3-adenano! −
Add oxoa (Taejin Hanjuncho and 611!f)) and stir for 2 minutes. Add methylene chloride again, stir for 1 hour and 30 minutes to dryness, add methylene chloride and water, stir, decantate, dry the blind ridge, and remove the solvent. 1/Evening with deer! After mixing with Todarafi and breaking with ethyl ether%
o, 5ssr of intermediate product was obtained. Starting from the product obtained, an intermediate product was obtained.

b) Removal) Process of Littel 1114 was carried out as shown in Ii1, and starting from the product obtained in the above step, a raw material was obtained. Water 11 things S
・Continuously cast in C water. Stir the tube and add (a) (l-7 ether) eteramino to 28 at e~+5°C. After stirring for 6 minutes, the precipitate was separated and washed with water.

The precipitate was dissolved in a mixture of methylene chloride and pμform.
1. To dissolve and dry - II wave inert gas at -50"Cm
Cool 1 then 4. A solution of st 7-tallic acid chloride in 2s methylene chloride and 2,74al
- triethylamine to 20m methylene chloride K11l
Once you understand it, slowly add it to the hole. Increase the concentration and continue mixing for 2 hours and 30 minutes with 1 part water and 9 parts sodium bicarbonate.
Pour it into a warm room with a glass of water, extract it with cool form, dry it,
After evaporating the solvent, the residue was dissolved in 1 liter of ethanol.
lt,ta. Pass through the intestines, wash with a mixture of ethanol and methylene chloride, remove the C wave, and rinse with JIIIL.
Condensed - Crystallized - Obtained a degeneracy of 1.364t in two layers - Take the mother liquor and terminate it with silica, then recombine - Strain mixture of form and ethyl acetate (S-Z) Elute with A pongee crystal of 1.5 II F was obtained. Gold body “cLf14
4t of product III was obtained. It consists of a single diastereomer.

・Meet the product obtained from the 3 tons of engineering with the second season of Aryu Tojiru, and have a meeting with Kanakura at 0A-010 ◎010
A solution prepared by dissolving 2F of ammonium persulfate in 2C of water was slowly added, stirred for 1 hour and 4 seconds, then poured into water, extracted with ethyl acetate, and the organic phase was dissolved in sodium thiosulfate. Wash it with water, dry it, and soak it with one drop of detergent.
o, a stump product of Os@r was obtained. α, = +10.5@
±1@(aaolm), )[p-172℃0 For example, even i, 2s By continuing the synthesis as described in 4 or 5, equation (1) Ell! ! An optically activated metal article was obtained for i.

What 11:・L! ii! L8111- An injectable anti-brow agent having the following formulation was prepared.

4轡Tsururuormechi) Iy-3-[2-(2-Anno 4
-ThiazoVru)-2-methoxyiminoacetamide]-
2-oxoazetidine-1-sulfolic acid, C1#%
s7n s racemic body----500q-carbonaceous supplement----1----5m-1yu'': Koguj
Amount - Capsules were prepared corresponding to the following formulation.

4-fluoromethyl-3-(!-(!-amino-4-thiazolyl)-2-methoxyiminoacetamide]-2-
Oxoazetidine-1-sulfanoic acid, cis s gi
Prepare test tubes containing enough ns racemic 2504 supplement to make 1 capsule 400"F, and dispense the same amount of sterile nutrient medium into each tube. Dispense increasing amounts of the test compound into separate test tubes, then inoculate each test tube with the vcall strain.Incubate at 37°C for 24 hours or 48 hours. The suppression of aS proliferation will be evaluated by the following method.

If this option is 6cz, the minimum inhibitory concentration (M, 1.0.
) (reward with fit/yal).

The following results were obtained.

Compound of Example 1, Metal compound of Example 5, Compound 6, Chemical compound of Example 8 (C07D 417/14
-205100 7242-4
C2131007138-4C 277100) 7306-4C2
571007132-4C 277100) 7306-4CO
Inventor Alain Bonnet French Country Subri Gargan Allée Lucien Michal 9 Procedural amendment (method) % formula % Indication of the case / 1984 Patent Application No. 184814 Person making the amendment Relationship with the 1-property case Patent Applicant Name: Rousselle-Yutarah Agent Amendment Order Date: February 22, 1982
(Shioriki), ＼ Contents of subject amendment of supplementary IF Reprint of specification as attached (no change in content) 735

Claims (1)

[Scope of Claims] (1) The following general formula (I) [where 1 is a water bulk atom or an optionally substituted carbon atom having at most 12 carbon atoms] Represents an alkyl, alkenyl, or alkynyl group in the form of a chain or a branch, R, is a group -(on,)n-x (where n represents an integer of 1 to 4, and X is a halogen atom, a cyano atom, group, group 0-R
/, (B/ represents a hydrogen atom or an alkyl group), or X is a group 8-R', (B# is a hydrogen atom,
a or R' and R1 together with the nitrogen atom to which they are bonded form a complex m, or X represents an azide, thiocyanato or isothiocyanato group. The wavy line indicates that the compound is cis or trans or c
is-1rana in the form of a mixture.
, the compound of formula (I) is in racemic or optically active form, and the oxime is in the ayn form] as well as salts of the compound of formula (I) or salts with acids. (2) The following general formula (1') [Here, R6 is a water bulk atom, or a linear or branched atom which may optionally be substituted with one or more halogen atoms, carboxyl, amino or cyano groups. represents an alkyl group, and n' is! or an integer of 2;
A compound according to claim 1 which is an isomer, and a compound which is a salt of a compound of formula (I) with a base and an acid. f3) A patent claim in which n' represents the number 1 and xl represents a fluorine atom. Compounds of the formula (I) described in Item 2. ((Transition) Substituent R is a hydrogen atom, or a methyl or difluoromethyl group, or a carboxymethyl group which may optionally be esterified or salted. Claim 1 representing an aminoethyl-attached or cyanomethyl group, or an optionally esterified or salt-formed l-methyl-1-carboxyethyl group
or a compound of formula (1) according to item 2. (4) racemic or optically active cia-4-fluoromethyl-3-[2-(2-amino-4-thiazolyl)-2
-Methoxyiminoacetamide]-2-oxoazetidine-1-sulfonic acid, gyn isomer, and its salt; Per K for producing the compound of formula (I), the following formula (It) [where Ra is Rr (Ri is Claim 1II)]
or ILa represents R1 in which a reactive functional group is protected, and M represents a hydrogen atom or a sulfo]. [Here, I
Lb represents a hydrogen atom or a protecting group for an amino group, and R'
represents a protecting group for the hydroxyl group, or
(R represents the meaning given in claim 1) or Bl represents the group R whose reactive functional group is protected], the following formula (5
) (wherein Rb, R'b, Ra and M have the meanings given above) 1. This compound is then subjected to the following reactions, if necessary and if desired: a) R
b and R' can represent or R'. and separation by hydrolysis, hydrogenolysis or action of thioaxillary of the protective group that RlL may contain, b) esterification or salt formation of the carboxyl group that the group R'b may contain and salt formation of the sulfo group, C ) II of the amino group
Salt formation by IK. d) Sulfonation of compounds in which the group represents a hydrogen atom, e)
Resolution of molecules to obtain optically active compounds. A method for producing a metal compound of formula (I), characterized in that one or more of the following are carried out in any order. In carrying out the implementation, the formula (
n) and the formula (where Rb represents a protecting group for an amino group)
m) and the sulfonation is carried out on a compound of formula (Iv) in which the sulfonation represents a protecting group for the amino group.
Method for producing the compound of I). (2) The compound of formula (I[) used at the start of the process has the following formula (V) The following formula (representing a protecting group)
(to) (Here, R'p and lL'p are hydrogen atoms on the one hand,
On the other hand, R′p and R1 together represent a divalent protective group, and B represents a hydroxyl crystal or a hydroxyl group). A compound of the formula (where "awFL-"p and R1 have the meanings given above) is obtained, and the compound of the formula (4) is subjected to the following reaction: a) Hydrolysis, hydrogenolysis or separation by the action of thiourea; b) optional sulfonation of the amine in position 1; C) separation of the groups R' and R'p by hydrolysis, hydrogenolysis or action of thiourea; d) optional splitting of the molecule to obtain an optically active compound. The method described in scope item 6. (9) carried out starting from a compound of formula (V) representing a protective group of an imino group containing an asymmetric carbon atom, and characterized in that the metal compound of the formula The method according to claim 318. The method according to any one of claims 6 to 9, characterized in that the trout group lLa represents a fluoromethyl group. □ (b) The method according to claim 318 as a drug Range tp Metal compounds corresponding to the formula (I) K described in JI and pharmaceutically acceptable salts thereof.■ Formula (
Claim 11 consisting of a compound corresponding to I/)
Drugs listed in section. - The drug according to claim 11, comprising the compound according to claim 11j15. - A potato composition containing as an active ingredient at least one of the drugs described in any one of claims @911-13. B) A metal compound of the following general formula W) as a new industrial compound (where R, , R'b, M and H have the meanings given in Claim 6). (b) The following formula (n) as a new industrial compound (where,
Mu and R&! has the meaning set forth in claim 6,
When the group represents a hydrogen atom, the tag cannot represent a methylthio, hydroxymethyl, azidomethyl, aminomethyl or alkoxymethyl group).