JPS5865284A - Cephalosporin derivative - 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 describes a unique cephalosporin barrier, that is, in the general formula, A is a group 2 (α) (b) represents gold, R
1 is hydrogen, methyl or carxy (lower alkyl)
, and X is zeC yellow.

-17- represents a modification or a group -8O- or -δ°O-,
Y represents the group -C1l- or all silkworms.

Z represents sulfur or selenium, R2 is hydrogen or optionally carboxy, hydroxy, acyloxy, dimethylamino and/or phenyl which can be easily decomposed by water;
i) Even if it is *, it is a low algyl, or a lower alkenyl or a phenyl,
and Rst, aqueous, lower argyl, phenyl-(CI
-4-alkyl) or (R4-phenyl)-(lower alkyl), where A'4 represents halogen, lower alkyl, or lower "f-alkoxy", which can be easily hydrolyzed in the compound. The present invention relates to esters, hydrates of the esters, and hydrates of the esters or salts.

B for “lower alkyl”? ! is alone or in combination-1
8 - straight-chain or branched lower alkyl groups containing up to 7 carbon atoms, preferably 4 carbon atoms (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, Isobutyl% represents 5ea-butyl, n-pentyl and n-hebutyl).

The term "lower alkoxy" has a similar prefix.

11 (in the substituted 18-alkyl group, a direct group (1
For example, 1-cal is xyethyl, 2-carboxyethyl, 1-carboxy-1-
Methyl-ethyl, 2-carboxy-1-7'thyl-ethyl, 1-lupoxy-1-methyl-n-propyl, /fluboxymethyl and α-carboxypentyl. 1
-Caldexy-1-methyl-ethyl is a preferred carboxy-(lower alkyl) group. Alkyl directly substituted with acyloxy which can be easily hydrolyzed is, for example, hivaloyloxymethyl, acetoxymethyl, 1-(pivaloyloxy)-ethyl, -(ethoxycarbonyloxy)
-ethyl i;;'t''.

"Lower alkenyl" has a total of 7 carbon atoms,
Preferably, a linear or split-chain olefinic hydrocarbon having 4 or more polymers (for example, vinyl, 2-propenyl, 1-nia'lopenyl, 2-methyl-2-7'lopenyl, 2-guthynyl) , 3-Gutenir Ministry;) wo represents. 1if:t for "Halloween" is a good place to wear υJ weir wood, threads or threads.

h! covers hydrogen [combination, group ((It) and (b)r
mesomeric equilibrium as first order
It's on qtbilibriwt)! As readily hydrolyzable esters of compounds of formula I,
At least one cal-oxy group is easily hydrolyzed s, fL
It is to be understood that the compound of formula I is present in the form of an ester group. t13 of such esters are lower alkanoyloxyalkyl esters (e.g. acetoxymethyl, pivaloyloxymethyl, 1-acetoxyethyl and 1-pivaloyloxyethyl esters), lower alkoxycarbonyloxyalkyl esters (e.g. methoxycarbonyloxymethyl, 1 -ethoxycal 7I?nyloxyethyl and 1-isopropoxycarbonyloxyethyl esters), lactonyl esters (e.g. phthalidyl and thiophthalidyl esters).

(lower alkoxy)-(lower alkyl)esters (e.g. methoxymethyl ester), phenyl esters optionally optionally substituted directly with halogen, lower alkyl or lower alkoxy; acetamidomethyl ester). Other esters (eg evabenzyl and cyanomethyl esters) can also be used. The ester is a monoester.

It can be a diester, triester or detraester. Ester formation t 4-cal is xy group or cal is xy-(1 substitution bearkyl) group R1 car? It occurs in compounds having an xy group R8 and a carboxylic (lower alkyl) group R1.

Easily hydrolyzed esters of compounds of formula I yield the salts of 11 upon conversion or modification.

Examples of such salts include halogenated water salts (such as halogenated water salts, bromide water salts and hydroiodide salts), as well as other non-sulfuric salts such as sulfur salts, nitric salts, Phosphate, etc., alkyl sulfone and monoaryl sulfone W salt vlJ
f flytanesulfone Wbni, ) ruenesulfone ha salt, benzenesulfone enemy salt, and also other -22- anti-salts such as t(rba salt, tartaric acid salt, maleic acid ring, citrate , apricot fermentation salt, salicylate, and ascorbic acid.

Easily hydrolyzable esters of compounds of formula I as well as acid addition salts thereof can be hydrated.

This hydration may occur during the production process or may occur gradually as a result of the hygroscopic nature of the anhydrous product initially.

In the present invention, the product is in the syn-isomeric form or in the anti-isomeric form.
Existing as an isomeric form or a mixture of these two forms - 2
3- I can do it. syn-isomer form′ or syn-isomer
A mixture in which the main component is a mold is preferred.

In accordance with the present invention, the above-mentioned cephalosporin derivatives are subjected to esterification of the corresponding carvone, i.e., a compound of formula I or a salt of the compound, and optionally the resulting product. Converting things to S-+'+J 1~. And if necessary, I will visit the 1 or C proboscis that will be used. 1., r; It can be manufactured by converting the proboscis (・ko, or ko) into a proboscis using water from Yowaka's old profit.

Calvin 1 6l-yIJ of formula 1 used in the above method
Eld'(CL) In order to leave a compound of formula I in which RI covers 7 with a radical or methyl and Y covers a group -CM-, the general formula % formula % where A and has the above meaning, 7t11 represents hydrogen or methyl, fiaL represents a halodane atom, and Cal/oxy group may be present in a preserved state, is reacted with selenourea and, if necessary, cleaved off any carboxy-carrying groups present, or (b) in the general formula, R1, A and The protective group R and optionally, from the salt of the compound or formula compound, where Cal may be present in a protected state, the protective group R and optionally, Cal may be present in a protected state. -25- (C) General formula In the formula, RmiX%Y and Z have the above meanings.

Q represents a leaving group, and the carboxy group can be protected by salt formation with a basic base or a third bulk national base; The salt is added to the general formula % in the presence of a glass of water, where A has the above meaning.

It reacts with thiol! and, if necessary, cleave any carboxy anchoring groups that may be present.

(d) A compound of the general formula % HH in which X and A have the above meanings and the carboxy group and/or amino group may be present in a retained state, R, Y and Z have the same meanings as above.

(g) If X is a group -5o- or -8O1-, A compound of formula I can be prepared by converting a salt of a compound of formula I or a compound in which %X represents a group -8O- or a compound of formula I to 1v.

If necessary, Cal 1N? exists at the 3-position of the base substance of Formula 1 and ■. An ester that can be esterified and easily cleaved can be preserved by forming a silyl ester (Iyll is a trimethylsilyl ester). 2. If a base is used as a base or a tertiary base, it can also be used by forming K with triethylamine.

The halide of TakeU used in the above method ((1) is H11
When represents methyl 1 For example, the compound 'k of formula (1) General formula 〇fl, 0N=C-Cool-1a1 In the formula, Ha16 represents a halodane atom.

It can be prepared by reacting with a halogenated carboxylic acid or a reactive isomer of the wire plate. The halogenated carboxylic version of formula Carbonylsoimidazole or IV'
, N'-thionylsoimidazole) in the free form, in the halide form such as chlorides or modified products, and in the anhydride form in the presence of anhydrides such as carbonic monoesters (e.g. monomethyl carbonate or monoisopropyl carbonate). The type of product, or (arch-activated ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, 8-hydroxysuccinimide ester, <t
It is used either in the form of riN-hydroxyphthalimide ester. This reaction is generally carried out in a 29-inert, unobtrusive solvent such as a halogenated hydrocarbon (e.g. chloroform, dichloromethane or carbon tetrachloride),
The reaction is carried out in ether (for example, tetrahydrofuran or sooxane), dimethylformamide, trimethylacetamide, water, or a mixture of these. Reaction gamma 1
．． D, t is a yoke IH of about -50°C to 140°C, preferably about -111°C to +10''C.

R1 represents an aqueous compound of 2H halide (t, 1, 2) is a compound of total diketene and the corresponding halodane (Gusujitsu or Hanwamoto), in the general formula 6, X, A and NoJal are the above South of Kei 1 tree.

-30- can be prepared by converting it into a 4-haloacetoacetamide barrier and treating this product with nitration.

Reaction of a halide of the formula (■) or its halides with thiourine* or selenourea according to method (α) of F4e above 1d Preferably, an aliphatic bath medium such as a lower alkanol (e.g. ethanol), a lower ketone ('+7!l) (geacetone),
It is carried out in ether (for example, tetrahydrone or chloride), trimethylformamide, trimethylacetamide, water, or mixtures thereof.

The reaction temperature generally ranges from about 0°C to 60°C, preferably room temperature. As the halide of formula (2), chloride, bromide, fluoride or iodide can be used, preferably chloride or bromide. The compound of formula (1) or a salt thereof may be used, thereby providing the same salt as the compound salt of formula I above.

After carrying out method (1), 1 reaction product contains molasses, ÷
The carboxy group that is present can be cleaved at your convenience. The body and eye base is Shirilno I! , (silyl ester), this group can be easily cleaved by treating the reaction mineral with water.

When the carboxyl group is protected by one-temperature formation (triethylamine is used), cleavage of this protecting group
You can process it with -i modification. It is used for this purpose.
It can be 4% acid, phosphoric acid or citric acid.

The protective group R in the proboscis 14j of formula 111 used in method (b) of dUi above is, for example, the protective group R in the proboscis 14j, which is carbonyl (i1 it ij) lythyl) or cleaved by basic hydrolysis.

A protective group (e.g. trifluoroacetyl).

Preferred R-protection groups are chloroacetyl, phyromoacetyl and iodoacetyl, such as chloroacetyl. The protective group of the protectant can be opened by treatment with thiourea.

The starting material in Part 2 is, for example, the corresponding 7-amino compound with N
- acylated, i.e. the compound τ of the above formula (2) - in the general formula R, R'', Y and Z have the meanings given above, is reacted with a reactive functional 1 conductor of an acid or nuclear enemy, and with confidence Depending on the situation, they can be produced by cleaving any carboxy anchoring groups that may be present.

If desired, the carboxy group present in the 7-ainocompound of 2) can be transferred in the manner described above to the starting materials of formulas 1 and 2 to be prepared. The amino group of the compound 2) can be protected, for example, with a silyl protecting group such as trino-33-tylsilyl.

For example, halides (i.e. chloride, bromide and fluoride),
When azides and anhydrides are mixed with strong anhydrides, reactive esters (such as N-hydroxysuccinimide esters) and amides (such as imidazolides) are present.

The reaction of the 7-amino compound tm of the formula (1) with the 1°λ compound of the formula (2) or its reactive functional compound can be carried out by any known method. Thus, it is possible to convert the free radical of the formula (■) into an inert solvent such as ethyl, acetonitrile, sooxane, chloroform, dichloromethane, benzene, or dimethylformamide by a carbosimide such as soimide of the socyclohexyl carbohydrate of the formula (■). can be condensed with one of the above-mentioned esters corresponding to 34-, followed by cleavage of the Nisder. Further, as a compounding agent, an oxacillium salt (for example, A-methyl-5-phenyl-isoxazolium-31-sulfonate) can be used in place of carbodiimide.

According to another embodiment, the cough salt of II. react with the reactive sensual fat conductor.

Furthermore, according to a preferred embodiment, a modified compound of formula (2), preferably a chloride, is reacted with an amine of formula (2).

This reaction is preferably carried out in the presence of a binder, e.g. , or in the presence of a low profile alkylated amine such as triethylamine. As solvent, water is preferably used, optionally in a mixture with an inert, unobtrusive solvent such as tetrahydrofuran dioxoxane. - The reaction can also be carried out in aprotic swimming solvents such as trimethylformamide, trimethylsulfoxide or hexamethylphosphoric triamide. When using the silylated starting material 2), the reaction is carried out in an anhydrous medium.

Which reaction between the 7-amino compound of formula (2) and the reactive compound of formula (2) occurs between about -40'C and room temperature, e.g., about 0 to 10°C? What can you do with 41 interest with I+A degree?

R is monohalogenated (e.g. bromoacetyl).

The starting material of 2) which is not (chloroacetyl or iodoacetyl) is converted by thiolation, i.e. in the general formula, R'', X, Y and Z have the above-mentioned taste, Ro
is similar to R, but cannot be monohalogenated, QFi, # & leaving group
In the presence of water, a compound of formula V
It can be produced by reacting with a thiol and, if necessary, cleaving the cal, hp, and protective gold that is present.

Examples of leaving-off compounds include halogens (e.g. basic, odorous or iodine), acyloxy groups (e.g. lower alkanoyloxy groups such as acetoxy), low M alkylsulfonyloxy or esters such as mesyloxy or Tosyloxy, azudo or azudo groups are possible.

The reaction of a compound of the formula (II) with a thiol of the formula (II) is carried out in a manner known per se, for example in water or a buffer bath having p li (iii) of about 6 to 7, preferably 6.5.
0℃~80℃ songs,'! -+: If'J to V about 60℃
It can be carried out at a temperature of The carboxy group in the resulting compound IIIII can be preserved if desired (for example by dove formation or esterification).

The 7-amino compound of No. 2 is a formula in which X has the above meaning, Q represents a leaving group,
Calcium compounds can be protected by forming a chemical compound with a base or a tertiary organic base.

can be prepared by reaction with a thiol of formula V in the presence of water, starting from a compound of This reaction can be carried out under the same conditions as already mentioned for the reaction of a compound of formula (1) with a thiol of formula (2). Also, is the compound of formula (■) a compound of (2) and (2)? Under the same conditions as already mentioned for the reaction, it can be prepared starting from a compound of 2X and a reactive functional conductor of the formula 2 or Q;1.

The carboxyl group and/or llJ amino group of the resulting compound 2) can be protected, depending on the required VC, for example by esterification of the carboxy group or by silylation.

The compound of the formula (2) in which Y represents a group -CH,= and Z represents selenium can be prepared by the general formula NOBIE ON, ,=
C-COOR6 a1 In the formula, R1 and l1at have the above-mentioned M taste, and R6 represents lower argyl, ethyl, which is a mixture of bamboo and methyl.

It is possible to make a bond by reacting the compound with selenourea. Thus, in the formula, Nobi1 and R6 have the above meanings.

followed by an amino group, preferably a compound of formula 7<-1
ial can be protected by reaction with the corresponding halide and resulting in a compound of the formula % formula % in which R, Rs and R. have the meanings given above, in order to cleave the ester group R6, Saponify by coughing or alkali. The reactive Pvj compound of formula (1) thus obtained is produced by a method known per se.

The acid in the formula ■ where Y represents a phoneme is Yorotsu-zo Patent No. 27,
No. 599 or (in the case of Z-selenium) analogously to that patent.

The thiols of formula V are in tautomeric equilibrium with the corresponding thiones and in a manner known per se.

For example l-R”-thiosemic pad or 4-R”-
It can be prepared from thiosemic pads by boiling with alkali gold λ4 lower alcoholates (e.g. sodium methylate) in lower alkanols (e.g. methanol) and oxalic acid. Optionally, the 1-RL thiosemicarpad or 4-RL thiosemicarbazide is prepared from the corresponding sulfur [monoRs-ester halide (
For example, heat with "stem chloride", then Tsumugi raw hSt
Alkali gold lA in lower alkanols like Geroki
Cyclization with primary alcoholate. resulting 1, 2-
dihydro-RL5-thioquine-5B-1,2,4-)riasol-3-cargane (By RL ester or 4
゜5-ㅅhydro4-)? L5-thioxo 111-1
゜2.4-) Riazole-3-karoo? The phosphoric acid RL ester can be saponified and re-esterified if necessary.

According to the above method (b), the starting material for the first product is h.
42- Cleave the amine-protected R. Low-number alkanes, which can be cleaved by water decomposition overnight and can be converted into ηmano\location 9n, are removed by the enemy. Especially, Gi 1
Use a small amount of trifluoroacetic acid. This cleavage is generally carried out at room temperature, but at slightly higher or lower temperatures (1
It can be carried out at a temperature range of about θ°C to +40°C). Holding groups that can be cleaved under alkaline conditions are generally hydrolyzed with diluted aqueous caustic at 0°C to 30°C. Chloroacetyl, bromoacetyl and iodoacetyl compounds can be cleaved by thiourea in a neutral, neutral or alkaline host at about 0 to 30°C.

Hydrogenolytic cleavage (also known as pendyl cleavage) is undesirable because the oxime functionality is reduced to an amino group during hydrogenolysis.

The carboxy retaining groups that may be present are as described above (with respect to process (a)).
It can be cleaved by the method described above.

This carboxylic acid can be cleaved in the same manner as the method already described for the cleavage of the carboxy group R.

6 compounds of the formula (1) used in the above method (C) -0J: The compound of the above formula (1) can be prepared by cleaving the amino-holding group 0 to ij:4. If this cleavage is performed, something can be done from the starting point of formula 11 in the same manner as the upper-mount UR cleavage of the amino group N'Ji group.

117It in the compound of formula ■ (as J, '
171J, for example, halogen (e.g. ring system, bromine or iodine,
i≦).

Examples include acylsoxy groups (eg, acetoxy, lower alkanoyloxy groups), lower alkylsulfonyloxy or arylsulfonyloxy, such as mesyloxy or hatosyloxy, -ma or azudo.

The reaction of the compound 2 with the thiol of the formula V is carried out in a manner known per se, for example by diluting water or at a pH value of 16.
~7. About 40°C in a trowel bath, preferably 6.5
It can be carried out at temperatures between 80°C and 60°C. Intervening radicals can be cleaved in a similar manner as linked above with respect to method (Z).

If necessary, in the reaction of compounds of formulas 1 and V or 2 and 2 or X and 2, easily hydrolysable esters thereof can be used in place of the compound of formula V,
-t8. In the formula, R" An intermediate is obtained.

These compounds are considered active metabolites after oral administration of the ester provided by the present invention.

Using the method described above, activated esters of formula (1) can be prepared from triphenylphosphine or triphenylphosphite (triphosphite) from carboxylate (which may be preserved as described above) of formula (2). In the presence of lower alkyl), inactive 1) 16
The solvent can be prepared by reaction with 2,2'-sothiobispenzothiazole in acetonitrile at room temperature. The subsequent reaction of compounds 2 and 2 is preferably 6.4 non-tj''i (in a mixture with d medium or water (e.g. in salt ichmethylene or 1, ethyl ethyl)
, preferably in the presence of a radical such as triethylamine, at about room temperature.

Next is Cal S4, which still exists? Kishiho rijl! L'
UM can be cleaved as described above for method (α)-46-.

In the above method (4), X is
Of course, the compounding of formula I, which is a change in form, or the transformation of the fence, can be dealt with by stopping a certain tradition or by removing one wave of one precept and one wave. Individual compounds that easily give the system as ``1 scissorized oki'' 1 course, e.g.
1 to C4 alkyl or alkanoyl hydroperoxides (e.g. t-butyl hydroperoxide, peroxide and peracetic acid) and phenyl-substituted derivatives of these hydroperoxytonomy oxides such as cumene hydroperoxide and It is possible to use kanjosai mt. Depending on the comfort, the phenyl substituent can be further substituted with a lower group (e.g. C1
~C4 alkyl or alkoxy), halogen or cal has an xyl group (e.g. 4-methyl peroxy, 4-methoxy perdef, 3-chloro perphthalate and monoperphthalic acid) be able to. As an oxidizing agent, there are various non-competent cough suppressants, such as 1γ1, 1, hydrogenated water, ozone, permanganates, such as potassium permanganate, and 1γ1.
, sodium, hypobase rl! ! ! Salt e.g. -111
i Hanwam PJI sodium, potassium or ammonium.

It can also be produced using peroxymono-acid and peroxyiso-111c acid. It is preferred to use 3-chlorothoracic acid r1. For this conversion, one inert solvent, such as a non-7'-rotonic inert solvent, is used. , H (hymethylene, chloroborum, ethyl acetate or acetone, or 11): a protic solvent such as water, a lower alkanol (one molecule is methanol or ethanol) or a lower alkanol that can be halodanized. It is carried out at a particular time during a change (for example, an awakening, an awakening, or a trifluoro□口trR*).

Konoba 61. It is preferably carried out at a temperature range of -20°C to +50°C.

When the molar amount of oxidized M or a slight excess thereof is used in relation to the starting material of formula I or a salt thereof in which X represents a fluorine, the corresponding sulfoxide of formula Mainly obtained. If the power in front of [Kiwaoki] is doubled or more than the chemical child theory ratio, then X is the group -8O1
- yields the corresponding sulfone of formula I. Similarly 1
It is possible to prepare the sulfones of formula I from the corresponding sulfoxides by treatment with equimolar amounts of liquefiers or multiple liquefiers. is the same as

Cal 7 of formula I attached]? The compound I'J can subsequently be converted into a salt, such as an addition salt or a salt with a base, as described above. Examples of salts with bases are alkali metal salts such as sodium and potassium salts, ammonium salts, alkaline earth metal salts such as calcium salts.

Fences made of organic tA tubs, e.g. fencing made of amines (e.g. -4
9-N-Ethyl-piperidine, propylene, dipensolamine, #, N''-dipendylethylenediamine.

salts with alkyl amines or dialkyl amines) as well as salts with amino acids such as arginine or lysine. This salt is mono-, g-,
It can be a tree spanning tetra-t. This salt can be prepared in a manner known per se, for example with the formula ! of a carboxylic acid, preferably in a hexagonal solvent such as water or an organic solvent such as ethanol, methanol, acetone, etc., with an equivalent amount of the desired monomer ti group. The temperature for clay formation is not critical. In general, the polarization is warmer, but also slightly warmer than room temperature or 1J-(Yllllll(
One temperature range can be from 0° C. to +50° C.).

According to the present specifications, easily hydrolyzed mL of carboxylic acid of formula I
In order to prepare a monoester, soester, triester or tetraester, one of the salts of Carpone N*' is preferably combined with the corresponding halide containing an ester group, preferably a reaction with iodide.This reaction can be accelerated by cyclic groups, such as alkaline fluorophores or charcoal salts.1 Depending on the esterifying agent used, monoesters, diesters, triesters, etc. The ester or natraester is obtained.For the preemptive esterification of the acid of formula 1, an excess of the corresponding halide is preferably used.The esterification is preferably carried out in an inert solvent. Examples of such inert, unobtrusive solvents are trimethylacetamide, hexamethylphosphoric triamide, trimethylsulfoxide or preferably dimethylformamide. Preferably it is in the range of about θ to 40°C.

The resulting ester can be converted to s-H if necessary, and the sulfur atom covered by X can be converted into a radical -8O- or -8O8-. This oxidation can be carried out as described above.

The hydration of the ester of the compound 1m of the formula I and the hydration of the anti-addition salt can be carried out in a manner known per se; rαα Addition salt - L analogy is advantageously d
/lG': It is produced by reacting with the desired acid in water or a Ca-containing medium (e.g., ethanol, methanol, acetone, etc.). Do clay generation? 1', degree A is not critical. The temperature is generally room temperature, but slightly above or below room temperature (l/l).
temperature ranges from 0°C to +50°C).

Hydrate production usually occurs automatically 71 during the manufacturing process or as a result of the hygroscopic properties of the hydrothermal products at the outset. water λ″] to apply for and manufacture one product.

The pre-metal or partially anhydrous product can be exposed to a humid atmosphere (eg, at about +10°C to +40°C).

The resulting syn/anti complex can be subsequently separated into the corresponding syn and anti forms by recrystallization or by chromatographic methods using suitable solvents or solvent mixtures.

However, one ester provided by the present invention is
Departure of 2) in Shin-type) Using Mu'R, Shin-
Preferably, it is obtained in a mold.

The esters of compounds of formula I and the corresponding salts or aqueous compounds of formulas I and X provided by the present invention have antimicrobial activity of 1 to 1:3 and monocutillary activity. These compounds are found in Gram-positive bacteria (:
If fit, m ij 4 bulbs - genus (Streptococcus
i)], and A's
iαcoli) and Klgbsiella
pntnbrrtoniag)fz praise.

Broad-spectrum -53 against Gram-positive bacteria
- Has activity.

Esters of compounds of formula l provided by the present invention as well as formula! The compounds of and X and their corresponding salts or hydrates can be used for the treatment and prevention of infectious diseases. r, l for adults: about 0.11 to about 4E1
．． A daily dose of about 0.25 # to about 2 g per hour is considered. Easily hydrolyzable esters and corresponding acid addition salts of each compound of formula I which are enteral or lli dt4 myenteral re-administration surface, For example, it has the advantage of having a long life and being cooler.

One-fourth of the above-mentioned fused proboscis activity can be controlled based on in vivo tests in mice.

Horror, Ji4j;e Throwing Rat (L Dio' RO-+
〃i / kg) l'j', 50% of the test mice survive i''E ILI yakuban (yo).

Test compound; Product A: Methylene C6N,'IR)-'I<CZ)-
54- -2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamide]-3-[[5-(methoxycarbonyl)-4-nonal-4jj-1,2,4-triazole-3- yl]thio]methyl]-8-oxo-5-
Thia-1-azabicyclo[4,2,0)oct-2-ene-2-carboxy 1/-tovino9ate.

Product B: methylene (6)j,7R)-7-[(Z)-
2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamide]-3-(((5-(methoxycarbonyl)-1-[(DL)-α-[[(piparoyloxy)methoxy]carbonyl [Penzl]-xli-1
t 2 + 4-triazol-3-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4
40] Oct-2-ene-2=carboxylate pivalate.

Product C: Methylene (6R,TR)-T-CCZ)-2
-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamide]-3-([5-(methoxycarbonyl)-1-phenyl-17:/-1,2,4-1lyazole-3- [yl]thio]methyl]-8-oxo-5-
Cheer l-azabicyclo(4,2,0,]]octoh2
-en-2-carboxylate hybarate product 1): methylene (6A + 7) r) -7-[(
1-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamide J -3-[[:(5-(methoxycarbonyl)-4-(2-propenyl)-4#-1,
2,4-)lyazol-3-yl]≠o]methyl]-8
-Oxo-5-thi f-1-azabishic CI (4,zo
] Oct-2-ene-2-carboxylate bivalate.

Raw & product g + methylene (6#, '1L4(Z)-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamide] -3-[((4-(n-f thyl)-S- (
methoxycarbonyl)-4B-1,2,4-triazol-3-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[:440]oct-2-ene-2
-Carboxylate bivalate.

Cephalexin (a recognized widely active cephalosporin known from CgphαIgxin-5).

-57- 58- Products A, C and D are at least as harmless as cephalexin (241 Ginma, LD5 in mice).
Op, o,! For generation qmA, C and D)s
o o oη/1600 for cephalexin
-4500+9/yu).

The products provided by the invention may be used as a cross-linking agent, such as pregnant women; non-monopolytic carriers such as water, gelatin, arabic, with or without a cross-linking agent suitable for lifting or parenteral administration. Rubber, lactose, starch, magnesium stearate,
Taruri, ↑l1rononde, polyalkylene glycol,
It can be used in the form of a preparation containing the product as a mixture with petrolatum or the like. Pharmaceutical style!
Product A can be in solid form (for example, tablets, sugar pills, and capsules for Zasukuma Trap) or liquid form (for example, bath liquid, evil 8Ii).
It can be made into liquid or milky lotion. as needed,
The preparation may be made sterile or may contain additives such as preservation agents, stabilizing agents, wetting agents or emulsifying agents.
Osmotic pressure 'f: salts, anesthetic mail or slow laxative HL] can be included to change the osmotic pressure. The strained preparation may further contain other therapeutically valuable substances.

The following examples further illustrate that the present invention +t;
-amino-4-thiazolyl)-2-(methoxyimino)
acetamido)-3-(:[(5-(methoxycaryl)-4-methyl-4M-1,2,4-triazole-
3-yl]thio]methyl]-8-oxo-5-thia-1
-Azabicyclo[4,2,Oloct-2-en-2-
Preparation of carboxylate biparate: (sR,7R)-ri (Z)-2-(2-amino-4
-thiazolyl)-2-(methoxyimino)acetamide)-3-[[5-(methquinecarbonyl)-4-methyl-4H-1,2,41riazol-3-yl]thio]methyl]-8-oxo -5-thia-1-azabicyclo[4
, 2,03 Sodium salt of oct-2-ene-2-carboxylic acid (5.91) was dissolved in dimethylformamide (100), and this solution was dissolved at 0 to 5°C to dissolve piparoyloxymethyl iodide (4.91). 499. The mixture was stirred at 0-5°C for 30 minutes while bubbling with total nitrogen, then 50°C with water.
The mixture was poured into 0+d and extracted twice with 300ml of ethyl acetate. The combined organic phase is sequentially poured with 250 rn water! , twice with 5% sodium carbonate solution, twice with 250 ml of water and 250 ml of water.
ml, dried over sodium sulfate, and dried under vacuum for 4 hours.
It was sufficiently concentrated at 0°C. After treatment with low-boiling petroleum ether, the precipitated material was suctioned off, washed with low-boiling petroleum ether, and dried overnight at 40°C under Makabe. A pale brown crude product was obtained, which was purified by chromatography on a silica column using ethyl acetate as eluent.

[α] = -70,15° (c = 0.949, in acetone)? A white amorphous pure title substance was obtained. Trace analysis and nuclear magnetic resonance absorption spectrum were consistent with the structural formula shown in -62-.

(6R,7R)-7-((Z)- used as starting material
2-(2-amino-4-thiazolyl)-2-methoxyimino)acetamide] -3-[[5-(methoxycarbonyl)-4-methyl-4H-1,2,4-)riazol-3-yl] thio]methyl]-8-oxo-5-thia-1-azabicyclo[4,2,Oloct-2-ene-
2-Carboxylic acid could be produced as follows =
(a) Methyl 4,5-dihydro-4-methyl-5-
Preparation of thioxo-IM-1,2,4-triazole-3-carboxylate: 4-methylthiosemical pad 176i and shuuki dimethyl 199fi were dissolved in methanol L6tVC with heating, and the solution was cooled (crystals precipitated). ). This suspension was introduced in portions with shaking over a period of 3 hours into a stirred bath of 392 grams of sodium in 500 grams of total methanol. After the introduction was complete, the mixture was stirred at room temperature for 1 hour and then boiled under reflux for 4 hours. This mixture was left at room temperature overnight. The next day, the mixture was evaporated to dryness under reduced pressure at 45°C. The solid residue was dissolved in 2 tVC of water and adjusted to a pH value of 5 with concentrated acid, and the product crystallized. After cooling in a water bath for 4 hours, the product was vacuumed and recrystallized from 1 t of moist vacuum filtered water. The title pure 9-terminus was obtained as white crystals with a contact point of 146-148°C.

(b) (6R,7R)-7-amino-3-[[5
-(methoxycarbonyl)-4-mef-ru4H-1
,2,4-triazol-3-yl]thio]methyl]-
8-oxo-5-thia-1-azabicyclo[4,2,O
] Production of oct-2-ene-2-carganic acid.

7-Aminocephalosporan l'1t27.2fi, methyl 4,5-dihydro-4-methyl-5-thioxo-I
42.
The mixture was stirred together with 61 in 250° C. of acetonitrile at 50 to 55° C. for 30 minutes while bubbling with nitrogen and excluding moisture. Cool this mixture to 20°C and add 500ml of water to it.
Then, the pH value was adjusted to 3.5 with concentrated ammonia. 0
After stirring for 30 minutes at ~5°C, the precipitated material was vacuumed and mixed with 500ml of water, 500ml of methanol, and 50ml of acetone.
Washed with 0- and low boiling petroleum ether and dried at 45° C. under significant vacuum overnight. The title compound was obtained, and its nuclear magnetic resonance absorption spectrum was consistent with the structural formula shown.

(c) (eR,rR)-r-amino-3-[[[5
-(methoxycarbonyl)-4-methyl-4H-1,2
,4-triacy/l/-3-yl]thio]methy-65
-8-oxo5-thia1-azabicyclo(4,
Preparation of silyl ester of 2,03 oct-2-ene-2-carboxylic acid: (67i!, 7R)-7-amino-3-(:[[5-
methoxycarbonyl)-4-methyl-4H-1.

2.41-riazol-3-yl]thio]methyl]-8
-Oxo-5-thia-1-azabinclo[4,2,O]
Oct-2-ene-2-carboxylic acid 23.12F in vinegar
Suspend in 480 ml of β-ethyl, add 2N of this suspension,
O-bis-(trimethylsilyl)-acetamide 60m
[treated with e]. This mixture was stirred at room temperature for 30 minutes to form an orange solution. This bath liquid was cooled to 10°C,
It was stored at this temperature until needed for acylation.

(d) 4-promo 2-(Z)-methoxyimino-
Production of 3-oxo-butyryl chloride = 4-promo 2-(Z)-methquinimino-3-66- -oxo-butyryl [13,44? krA-methydimethylene 1
80-, and this bath solution total θ~5℃ phosphorus pentachloride 1448
1'. Mix this for 15 minutes at ~5°C.
The mixture was stirred for 45 minutes without cooling.

(g) (6R,7R)-7-[4-promo 2-C
Z)-methoxyimino-3-oxo-butyramide]-
3-[[[5-(methoxycaryl)-4-methyl-
4B-1,2,4-trizol-3-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4
, 2,0] Production of oct-2-ene-2-carboxylic acid:
It was added dropwise to the silyl ester solution prepared in section (c) over a period of 5 minutes. This mixture was heated at θ~5°C for 1 hour and then 20
℃ for 1 hour by pressing .r'/. The VC mixture was then treated with 50° of ethyl acetate and 25° of water with stirring. The aqueous phase was separated by suction, washed three times with 500 ml of M Kisoiboku Mizutani, dried over sulfuric acid, and thoroughly concentrated at 40° C. under reduced pressure. Trowel treated with ether, precipitated fC,
All the material was vacuumed off, washed with ether and low boiling petroleum needles, and dried under reduced pressure at 40°C. [α]”=-7
1° (c-1, in acetone) was obtained as a white amorphous title compound. The nuclear magnetic resonance absorption spectrum was consistent with the structural formula shown.

1, Q (6R,7/iri-7-11Z)-2-(2
-amino-4-thiazolyl)-2(methoxyimino)acetamide]-3-[[[5-(methoxycarvinyl)
-4-methyl-4H-1,2,4-triazole-3-
Preparation of sodium salt of yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo(4,2゜0)oct-2-en-2-cal,3e/acid: (6A', 7R) -7-(4-promo 2- (Z)-
Methoxyimino-3-oxo-butyramide]-3-[
(:5-(methoxycaryl)-4-methyl-4H-
1,2,4-triazol-3-yl]thio]methyl]
-8-oxo-5-thia-1-azabicyclo[4,2,
O] oct-2-ene-2-carganic acid 14.8 S'
was dissolved in a mixture of 200 grams of ethanol and 200 grams of methanol, and the total thiourea in this bath solution was 3. 20℃ with T5f
The mixture was stirred for 1 hour. This mixture was treated with 30 m of a 2N solution of sodium 2-ethylcaproate in ethyl acetate,
Translated into lt volume with methanol. 5 tons of activated carbon was added to this solution, and the mixture was stirred at 20° C. for 30 minutes.

After filtering through the entire surface of grained P paper, the P solution was treated with 500% ethanol and thoroughly concentrated under vacuum at 40°C. The precipitated substance is vacuumed and separated, l1lfi! then washed with ethanol, ether and low boiling petroleum ether;
Dry at 40° C.-69° C. under vacuum. A beige crude product was obtained, which for purification was first dissolved in 300 methanol. This solution was treated with 250 ml of ethanol and thoroughly concentrated under vacuum at 40'C. Ethanol was added again and the mixture was again thoroughly concentrated. The precipitated material was suctioned off, washed with ethanol, ether and low boiling petroleum ether, and dried in VC at 45°C under vacuum. [α]
25=-518 DEG C. (c=1 in water) A beige pure title material was obtained. Micropupil analysis and nuclear magnetic resonance absorption spectrum are consistent with the structural formula shown (7).

Example 2 Methylene (6/i!, 77i-7-[” (Z)~2
-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamide)-3-[[[1-ethyl 5-(
methoxycaryl)-17-1,2,4-triazol-3-yl]thio]methyl]70- -8-oxo-5-thea-1-azabicyclo[4,2,
Preparation of Ol oct-2-ene-2-carboxylate bivalate: (6R,?R)-7-((Z)-2-(2-amino-4
-thiazolyl)-2-(methoxyimino)acetamide]-3-1: [I[x-ethyl-5-(methoxycarbonyl)-1#-1,2,4-triazol-3-yl]
Sodium thio]methyl]-8-okyne-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carganic acid m3 fk trimethylformamide 100r
neVC was dissolved and this solution was treated with piparoyloxymethyl iodide 4.489 at -5'C.

The mixture was stirred at 0-5°C for 1 hour while bubbling with nitrogen, poured with 500 ml of water, and poured with 1 ml of water. rl: ethyl acid 30
Extracted twice with 01rLl. Add 250% water to the combined organic phase.
- twice, 5% sodium bicarbonate water bath solution 250 - twice
Washed twice and again with 250° C. of water, dried over IJ sulfuric acid and thoroughly concentrated under vacuum at 40° C. After adding low boiling petroleum ether, the crude product precipitated in amorphous form. The product was suctioned off, washed with low boiling petroleum ether and dried under vacuum at 25°C. A beso colored crude product was obtained which was purified by flash column chromatography on silica gel using ethyl acetate as eluent. After precipitation from ethyl acetate with low boiling petroleum ether, [α]”=−92
A white pure title material was obtained with a c=1.056 in acetone. The nuclear magnetic co-11(2) absorption spectrum and trace analysis were consistent with the structural formula shown.

The starting material could be prepared as follows: 1-ethylthiosemical pad 752 and sodium bicarbonate 106f' were suspended in acetonitrile 100d. This suspension was warmed to 35-40°C and added dropwise over a period of 1 hour to a solution of monomethyloxalyl chloride 852 in 50°C of acetonitrile. The mixture was then stirred at this temperature for 2 hours and then filtered. 40% of F solution under vacuum
Evaporated at °C. The solid residue was treated with ethanol and filtered with suction. Pure methyl N-(
1-Ethyl-3-thiosemicarbazido) oxamate was obtained.

29.3 of methyl #(1-ethyl-3-thiosemicalpad)oxame-) was added to a bath solution of 3.32% of IJum in 200% of methanol, and the mixture was simmered under total reflux for 30 minutes. Boiled. This solution was heated at 40°C under vacuum.
It was evaporated. The oily residue was dissolved in 200 mL of ethanol. The chemical compound that crystallized in a short time was separated by suction filtration.

The mother liquor was acidified with hydrochloric acid and evaporated under vacuum at 40'C. The residue was taken up in ethyl acetate and diluted with Nato chloride 73
- The Rium meeting was held separately. The ethyl acetate solution was heated at 40°C under vacuum.
evaporated with. The entire residue was chromatographed on silica using ethyl acetate as eluent. After recrystallization from isozolopanol, methyl l-
Ethyl-3-mercapto-IH-1,2,4-triazole-5-carxylate was obtained.

Methyl 1- to 7-aminocephalosporanic acid 2.7f'
Ethyl-3-mercapto-IH-1,2,4-triazole-5-cal was dissolved in water 50 along with xylate 21. 1.74 f of aqueous sodium carbonate was carefully added and the mixture was stirred at 55° C. for 4 hours with nitrogen bubbling. (There was a clear solution at the beginning of the reaction, then some of the product started to precipitate). This mixture was cooled to 20°C,
The precipitated substance was vacuumed up, washed with water, acetone, and low-grade petroleum ether, and heated overnight at 5℃-7
I searched for dry at 4-. Beige pure (6R,yR)-7-
Amino-3-[[[1-ethyl-5-(methoxykalkagnyl)-1H-1,2,4-)lyazol-3-yl]thio]methyl]-8-oxo-5-thia-1 -Azabicyclo[4,2,0)oct-2-ene-2-carvone was obtained, and the quantitative analysis and nuclear magnetic resonance absorption spectrum of this product were consistent with the structural formula shown. Aqueous mother liquor rO~5
A pH value of a5 was adjusted at 0.degree. C. with 3N hydrochloric acid. The material thus precipitated was suctioned off, washed with water, acetone and low-point petroleum ether, and dried at 45° C. under high vacuum. In this way additional pure substances were obtained.

(6R,tR)-'I-amino-3-[[[x-xthyl-5-(methoxycaryl)-tH-t, 2.4-)
Riazol-3-yl]thio]methyl]-8-oxo-
5-thia-1-azabinculo[4,2,O]octo-2
-ene-2-carvone 1!1126F in methanol 75
m/, and this suspension wotriethylamine 2.1
Treated with ml. The mixture was stirred for 15 minutes and virtually no material became liquid. Therefore, an additional 2.1 units of triethylamine and 75 units of dichloromethane were obtained. After stirring for about 10 minutes, the mixture turned into m liquid. 2
-penzthiazolylthi(2-amino-thiazol-4-yl)-2-(Z)-meth41diimino-acetate) 5.76 F was added and this mixture heated to 20°C.
The mixture was stirred for 2 hours. After 30 minutes, a solution formed.

To this were added 25 liters of a 2N solution of sodium 2-ethyl chloride/acid in ethyl acetate, 200 ml of ethanol, 100 ml of methanol and 2 f of activated carbon.

After stirring for 15 minutes at 20°C, the mixture ? The entire solution was filtered through F paper with vertical texture. Yellow-orange p liquid total ethanol 2
50° and concentrated under vacuum at 40° C. to a trough weight of about 100°. All precipitated material was aspirated, washed with ethanol and low-boiling petroleum ether, and dried under high vacuum for 45 nights.
Dry at °C.

[α] knee 35.9° (c = 0.7, beige pure (eR,7R)-7-[(Z)
-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamide]-3-[[[1-ethyl-5
-(methoxycarbonyl)-1#-1,2,4-)lyazol-3-yl]thio]methyl]-8-oxo-5-
The sodium salt of thia-1-azabicyclo[4,2,0)oct-2-ene-2-carbone was obtained. The nuclear magnetic resonance absorption spectrum was consistent with the structural formula shown.

2-penzthiazolylthi-2-(2-amino-thiazol-4-yl)-2-(Z)-methoxyimino-acetate could be prepared as follows.

77- 2-(2-amino-4-thiazolyl)-2-(Z)-methoxyimino-acetic acid (anhydride, containing about 5% methanol)
64. J1M' and 2', 2-sothiobis-benzothiazole 112.5P' were suspended in 1.8 tK acetonitrile, and the suspension was treated with N-methyl-morpholine 40.4- while stirring.

The resulting suspension was warmed to 30°C and treated within 60 minutes with 64.8-triethyl phosphite. This suspension Ke30
Stirred at 0°C for 60 minutes and then at 0°C for 60 minutes. The product was suctioned off, washed with acetonitrile and ether, and dried under vacuum at 35°C.

The title substance was obtained with a melting point of 140°C.

Example 3 Analogously to Example 1, the following compound was obtained: methylene(6R9)R)-(1)-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamide)-a −
[[:5-(Methoxycar-78-bonyl)-4-(2-gropenyl)-4H-1゜2.4
-) lyazol-3-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4,2,Ol oct-2-ene-2-carboxylate bivalate, white amorphous powder, [α ]2G=-72,1' (c=0.8
488 in acetone).

Methylene(6,/-1', rR)-C(Z)-(2-
Amino-4-thiazolyl)-2-(methoxyimino)acetamide)-3-[[[4-(n-butyl)-5-(
(methoxycaryl)-4#-1,2゜4-triazol-3-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[42,0]oct-2-ene-2
-Cal xylate bivalate, white amorphous powder, [α
] Gover-9° (C=0.9326, in acetone).

Methylene(6R,TR)-7-El)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamide]-a-[Is-(methoxymino)-1-
((DL)-α-[[[hyvaloyloxy)methoxy]
carbonyl]penzyl]-1H-t, 2,4-t'riazol-3-yl]thio]methyl]-8-oxo-5-
Thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylate bivalate powder, [α]”-181.37° (c=o, g61
s in acetone).

Methylene(6R,r)<)-7-[(Z)-2-(2-
Amino-4-thiazolyl)-2-methoxyimino)acetamide]-3-[[5-(methoxycaryl)-1
-7 enyl IH-1,2,4-to IJ azole-3-
[yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylate bivalate, white amorphous powder, [α]20
= f) −103,27° (C=0.917 in acetone).

The nuclear magnetic resonance absorption spectrum and trace analysis of the compound were consistent with the structural formula shown.

Example 4 Conjugated gelatin capsules containing the following ingredients were prepared in the following manner: Chia 1-Azavincro[I4.2.0]Octo-2-
En-2-carboxylate bivalate
500#v/l/
Lwviskol (water-bath polyvinylpyrrolidone) 2omg mannitol 20a%ll talc 15 #9 stearin version magnenium 2q575v 81 - Example 5 Tablets of the following composition All prepared in a conventional manner: en-2-cal xylate Vivalate 250aF Lactose 70#v Corn Starch 65# Polyvinylpyrrolidone 10η Stearin Magnesium 5119400η Granules were prepared in a conventional manner with the active substance, lactose, polyvinylpyrrolidone and 40 parts by weight of corn starch. The granules were mixed with the remaining 25 parts by weight of Tumoco 7 starch and 5 parts by weight of magnesium stearate,
This mixture was completely compressed into tablets.

=83-

Claims (1)

[Claims] 1. In the general formula, A represents a group, R1 is hydrogen, methyl or carboxy (lower alkyl), and X is 51 fluoride. represents oxygen or a group -80- or -5O8-, Y
represents the group -CH=-J or nitrogen. Z represents sulfur or selenium; 111 is hydrogen or lower alkyl optionally substituted with carboxy, hydroxy, easily hydrolyzable acyloxy, trimethylamino and /f or phenyl; M7<1 follows lower alkenyl or phenyl, and
-1" U water, (1 alkyl, phenyl-(C2
4-alkyl) or (phenyl)-(lower alkyl), where li' is halogeno, lower alkyl or lower alkoxy, is an easily hydrolyzed cephalosporin conductor of The ester obtained and the amount of the ester 7Jllt, 4 and the ester or the aqueous salt 111'l of course. Z R" is aqueous or optionally carboxy, hydroxy,
An ester according to claim 1, which coats a lower alkyl which may be directly substituted with an acyloxy or dimethylamino which is easily hydrolysable. 3. Aesthetic A' according to paragraph 2 of the patent claim in the form of a syn-isomer type or a mixture mainly consisting of a syn-isomer type. t An ester according to claim 2 or 3, wherein R2 represents hydrogen, carboxymethyl, hydroxymethyl, dimethylaminomethyl or pivaloyloxymethyl. 5. The ester according to claim 2 or 3, wherein R2 is methyl, ethyl or n-butyl. 6. Claims 1 to 3 in which R2 is phenyl
The ester described in any of the paragraphs. 7.8! The ester according to any one of claims 1 to 3, wherein .alpha.-cal and .alpha. 8. R2 is 2-zorobenyl f: 轡♂Fii-
The ester according to any one of Items 1 to 3 of Box I&Q of Rice. 9. Ranges 2 to 5 of patent WNj where X represents sulfur
Nisdel of ii and ii & of the section. 10. Scope 2 of Qv-approval application where X is a group -5O-
- Ester of Y1 celebration in any of the 5 items. Le. 136 Z wears the individual C
An ester based on Nl2 in any of items 5 and 9 to 12. 14, R' is a water-based sign, i-may search range 2nd ~
5 and 9 to 13: the ester described in h for any one of IJj. The ester according to any one of claims 2 to 5 and 9 to 13, wherein lad' is methyl violet. 1s, R'' is carboxymethyl e=&was the ester described in any one of claims 2 to 5 and 9 to 13. 1r, R' is 1-carboxy-1-methyl-ethyl; The ester according to any one of claims 2 to 5 and 9 to 13, wherein IIILp represents methyl.
-5 and 9-17 ester. 19. Claims 2 to 19 in which R” is ethyl
5 and 9 to 17. The ester according to any one of claims 2 to 5 and 9 to 17, wherein 2o, R'' is aqueous. 5-2, the ester according to any one of claims 2 to 5 and 9 to 20. Piparoyloxymethyl ester as described in 22, methylene C61i, TR)-T-CCZ)-
2-(2-amino-4-thiazolyl)-2-methoxyimino)acetamide)-3-(((s-(methoxycarbonyl)-4-me/-4H-1+2.4-triazol-3-yl [thio]methyl]-8-oxo-
5-thia-1-azabicyclo[4゜zO]octo-2-
En-2-carbogysylate biparate and the acidifying power of the compound (i) and the compound (ii) when the compound is also a hydrate of salt (ti); +i+
Esther on page 2. 23, f-v7c6R,'IR)-'1-CCZ)
-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamide]-3-[[[1-ethyl-5
-methoxycaryl)-1#-1゜6- 2,4-triazol-3-yl]thio]methyl]-8
-Oxo-5-thia-1-azabicyclo [4°2,. 0
``Oct-2-ene-2-carboxylate bivalate,'' is the acidity of this compound, and the hydration of the compound's acidity or its salt. Ester of the last postal box No. 1 entry 1/, f5. 24, methylene (6A, '1I-7-C(1-2-
(2-amino-4-thiazolyl)-2-(methoxyimino)acetamide) -3-[[[5-(methoxycarbonyl)-1-[(DL)-α-[((piparoyloxy)methoxy]carbonyl]benzyl , 1-1#-1,
2,4-1 riazol-3-yl]thio]methyl]-8
-oxo-5-thia-1-azabicyclo[4,2,0]
The esters of claim 1 which are oct-2-nin-2-carboxylate bivalate and acidic/IO salts of said compound and hydrates of said compound or rib addition salts. 25, methylene (6R,'r)l-7-C(Z)-
2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamide] -3-(((5-(methoxycalcinyl)-1-fuconinyl-tl:I-
1,2,4-)lyazol-3-yl]thio]methyl]
-8-oxo-5-thia-1-azabicyclo[=i,
2.0 ] ] Octo-2-en-2-ka is a xylate bivalate and cough compound C proboscis r r r ca 11'', ~K and the compound #L1e4 which is a hydrate of the oral proboscis. '
n' F 26, MethiV7(6R,q)i-7-[(,?)-
(2-amino-4-thiazolyl)-2-(methoxyimino)acetamide]-3-[([5-[methoxycarbonyl)-4-(2-propenyl)-4H-1,2,4-
triazol-3-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4,2,01oct-
2-en-2-cal is a xylate bivalate and a hydrate of a compound or a ridge addition salt of the same. . 27, methine y(67<,7R)-C1;)-(2
-amino-4-thiazolyl)-2-(methoxyimino)
acetocaramide)-3-01m4-(n-butyl)-
S-(methoxycarbonyl)-4#-1,2,4-triazol-3-yl]thio]methyl]-8-oxo-5
-thia-1-azabishik o[4,LO]octo-2-4
7-2-Cal 1]? The ester according to claim 1, which is a xylate pivalate, a ribbed addition salt of said compound, and a hydrate of said compound's proboscis or ribbed addition salt. 2& In the general formula, A, R'', X, Y and Z refer to the footwear described in the scope of patent M+j, item 1. Salt water 1st + proboscis. 29. In the general formula, #lJ, Y, and Z have the meanings described in the first paragraph of the range of patent music, and A' is the range of special d'to mountain 1 &31
It is the same as A in the description above, except that C0OR" is a hemiester of easily hydrolyzed ester-10-. 30. In the general formula, A and A compound having the meaning as described in item 1, R11 represents a water atom or methyl, Ha L represents a halogen atom, and the carboxy group may be present in a preserved state, and R3 is an aqueous compound. An easily scalable ester of the compound of the formula (1) and a salt of the Iwao compound, which coats the compound.31.In the general formula, %RA and ,i< Ester which can be easily hydrolyzed and salt of the compound. 32, tautomer formula % formula % In the formula, Novi 2 and R3 are l Yugen h11 Water d button!i4 Described in Item 1 The formulas Va' and Va2 in which the compound and 7tB coat the aqueous system set the body of
easily hydrolyzable esters of compounds of 33, tautomeric form % formula % In the formula, R20 and R'' are 8 of the watch claim paragraph 1
The same Jimikai night as 2 and R3 will be held. However, Bv represents methyl, and R'' is phenyl-CC
2'4-alkyl) or (R4-phenyl)-(Buddhist alkyl)=S. R4 here represents halo r, lower alkyl or lower alkoxy. 34. Easily water-repellable esters of compounds of formulas Vb1 and vbz in which R'' is an aqueous system. ), and the carboxyl group and/or amino group can be compressed with 44-pressure in a state in which the amino group is preserved. 35. In the general formula, 4X and A have the meaning of 4- as described in Section 1, Section 1, Section 1 of the clock claim, and Mal represents a halogen atom. Easily hydrolyzable esters of compounds of the formula hself1jZ for any of
Compound C1 of course. 37. FD of infectious diseases, intestine (・l tarie is miro) part 1
Patent Lti as a substance active in cross-agent [1' in addition to prevention and prevention]
1 sword combination 9 course. 38. Any one of claims 1 to 29 of Claims 1 to 29 of Claims 38. 39. A Sakaehata preparation for the oral administration (for example, oral administration) and prevention of an infectious disease consisting of a compound according to any one of Items 1 to 27, indicated by sN*. 40, Zj-corresponding carvone, i.e., the compound of formula l or the salt of said compound, is subjected to a corresponding esterification, and if necessary, the corresponding product is converted into S-version, and if necessary, Patent i "J" for converting the water of 11 salts with Cv into crystals or hydrates, or the water of 11 salts with Cv. 41. How to use a compound of any one of the 1st to 17th sections of the Shiki Shiki, 1eIII.
, llN;i<40:! , L-4'% method. 42. The method according to item 41, wherein the halide is iodide. 43. I'm here for the first time. Jj Fj
Claims 1 to 29: The length of ljJ is V, UI2, and ItlS. 44. Infectious Diseases (ψ′0ehashaguchi) Department 1
11 or Prevention 2.
Renewal. Saitama f+ produced by the method described in any of 45 and 45 and i4M water by the method described in any of 40 to 42) or clearly chemically equivalent thereto. Fj Ice Po “J Items 1-27
A compound containing d self in any of the terms! ! Of course.