BE879217A - NOVEL 7ALPHA-METHOXYCEPHALOSPORINS, THEIR PREPARATION PROCESS AND THEIR THERAPEUTIC APPLICATION - Google Patents

Description

       

  The present invention relates to novel amethoxycephalosporins and a process for preparing them.

  
compounds.

  
The compounds of the invention are characterized by the fact that they have a broad antibacterial spectrum with respect to Gram-positive and -negative bacteria, by showing in particular an excellent antibacterial activity with respect to

  
Gram-negative bacteria, such as, among others,

  
Escherichia coli, Klebsiella pneumoniae, Proteus species,

  
Serratia marcesens, Alkaligenes faecalis, and that they are

  
stable towards p-lactamase produced from bacteria. These compounds are therefore very useful for the treatment of various infectious diseases.

  
Whereas the classic 7a-methoxycephalosporins

  
are known for their antibacterial activity vis-à-vis Gram-positive bacteria, they have a relatively weak antibacterial activity vis-à-vis Gram-negative bacteria

  
as mentioned above, which cause infectious diseases with a serious clinical prognosis.

  
The applicant has carried out extensive research

  
with regard to 7a-methoxycephalosporins. In

  
consequence she found that the new compounds

  
represented by the general formula (I), described below,

  
in which the cephem nucleus carries an oxy- or thiomethyl group substituted by an organic group in position 3 and

  
a methoxy group in position 7a, and the amino group in position

  
  <EMI ID = 1.1>

  

  <EMI ID = 2.1>


  
in which R <3>, R4, R5, A and n are defined as specified below, as well as the salts of said compounds, have effective antibacterial activity, and low toxicity, and are well absorbed in the living body.

  
According to an objective of the invention, new 7a-methoxycephalosporins are proposed having in their molecules

  
  <EMI ID = 3.1>

  
group

  

  <EMI ID = 4.1>


  
According to another objective of the invention, it is proposed

  
  <EMI ID = 5.1>

  
antibacterial.

  
Another objective of the invention also consists in proposing new 7a-methoxycephosphalins having a high resistance to &-lactamase produced from bacteria.

  
Another objective of the invention is also to provide new 7a-methoxycephalosporins having effective antibacterial activity with respect to clinical isolates of bacteria.

  
According to yet another objective, of the invention, a method is proposed for preparing the new 7a-methoxycephalosporins.

  
Yet another objective of the invention is to prepare a pharmaceutical composition comprising the new 7a-methoxycephalosporin or its salt, as active ingredient.

  
Other objectives and advantages of the invention will appear in the following description.

  
In accordance with the invention, the

  
  <EMI ID = 6.1>

  
cephalosporins represented by the general formula (I), and their salts.

  

  <EMI ID = 7.1>
 

  
wherein R represents a hydrogen atom or a carboxyl protecting group; R <2> represents an organic group linked via an oxygen or sulfur atom; R <3> represents a lower alkyl group; n is a number equal to 0.1 or 2; A represents an alkyl group

  
  <EMI ID = 8.1>

  
  <EMI ID = 9.1>

  
hydroxyl protecting group.

  
The term "alkyl" used in the context of the invention denotes a straight or branched chain alkyl group having 1 to 14 carbon atoms, such as methyl, ethyl, propyl, isopropyl, methyl, pentyl, hexyl, heptyl, octyl, dodecyl or the like; the expression "lower alkyl" used in the context of the invention denotes a straight chain alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl or butyl; the expression "lower alkoxy" used in the context of the invention denotes a monovalent -0-lower alkyl group in which the lower alkyl group defined above is linked

  
an oxygen atom, namely a straight chain alkoxy group having 1 to 4 carbon atoms; the term "acyl" used in the context of the invention denotes an acyl group having 1 to 10 carbon atoms, such as formyl, acetyl, propionyl, butyryl, benzoyl, naphthoyl, pentanecarbonyl,

  
  <EMI ID = 10.1>

  
term "acyloxy" used within the framework of the invention, designates a monovalent -0-acyl group in which the acyl group defined above is linked to an oxygen atom, namely an acyloxy group having 1 to 10 atoms carbon. When the terms "acyl" and "acyloxy" refer to those formed at

  
  <EMI ID = 11.1>

  
any number and in any position of the nucleus, the hetero atom or the hetero atoms are calculated as the number of carbon atoms.

  
In the general formulas described in the context of the invention, R is a hydrogen atom or a carboxyl protecting group, the carboxyl protecting groups of the invention are those which are commonly used in the fields of penicillins and cephalosporins and include ester-forming groups, which can be removed by catalytic reduction, chemical reduction or other treatments under moderate conditions; ester-forming groups which can be readily eliminated from living bodies; and other known ester-forming groups which can be easily removed by treatment with water or an alcohol, such as silyl organic groups, organic groups containing phosphorus, organic groups containing tin, or the like.

  
Examples of suitable carboxyl protecting groups are:
(a) alkyl groups, in particular a straight or branched chain alkyl group having 1 to 14 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, nbutyl, sec-butyl, isobutyl, tert-butyl, pentyl and the like;
(b) substituted lower alkyl groups, at least one of the substituents of which is a chlorine, bromine, fluorine atom, a nitro, carbalkoxy, acyl, lower alkoxy, oxo, cyano, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl group , lower alkylcarbonyl, 1-indanyl, 2-indanyl, furyl, pyridyl, 4-imidazolyl, phthalimido, acetidino, aziridino, pyrrolidinyl, piperidino, morpholino, thiomorpholino, N-lower alkyl-piperazino, 2,5-dimethylpyrrolidinyl, 1,4 , 5,6-tetrahydropyrimidinyl, 4-methyl- <EMI ID = 12.1>

  
lower alkyl-amino, acyloxy, acylamino, di-lower alkylaminocarbonyl, lower alkoxy-carbonylamino, lower alkoxy-carbonyloxy or lower alkyl-anilino or lower alkyl-anilino substituted by a chlorine, bromine atom, a lower alkyl or alkoxy group inferior ;
(c) cycloalkyl groups containing 3 to 7 atoms <EMI ID = 13.1>

  
substituted, or [2,2-di (lower alkyl) -1,3dioxolan-4-yl] methyl groups;
(d) alkenyl groups containing a number of carbon atoms up to 10;
(e) alkynyl groups containing a number <EMI ID = 14.1>
(f) a phenyl group, substituted phenyl groups, at least one of the substituents of which is chosen from those which are given by way of examples in the above-mentioned passage (b); or aryl groups represented by the formula:

  

  <EMI ID = 15.1>


  
in which X represents -CH = CH-O-, -CH = CH-S-, -CH2CH2S-,
-CH = N-CH = N-, -CH = CH-CH = CH-, -CO-CH = CH-CO-, or -CO-CO-CH = CH-, or their substituted derivatives, the substituents of which are those chosen from the substituents given as an example in passage (b) above, or the formula:

  

  <EMI ID = 16.1>


  
in which Y is a lower alkylene group such that <EMI ID = 17.1> the substituents are chosen from those given as examples in passage (b) above;

  
(g) aralkyl groups such as a benzyl group or substituted benzyl groups, at least one of the substituents of which is chosen from those given by way of example in passage (b);

  
(h) heterocyclic groups, such as furyl, quinoleyl, methyl-substituted quinoleyl, phenazinyl, 1,3benzodioxolanyl, 3- (2-methyl-4-pyrrolinyl), 3- (4-pyrrolinyl), 3- (4-pyrrolinyl ) and N- (methylpyridyle)., or substituted heterocyclic groups, at least one of the substituents of which is chosen from those given as examples in the passage
(b) above;

  
(i) alicyclic indanyl or phthalidyl groups or their substituted derivatives, the substituent of which is a methyl, chloro, bromo or fluoro group; an alicyclic tetrahydronaphthyl group or one of its substituted derivatives, the substituent of which is a methyl, chloro, bromo or fluoro group, a trityl group, a cholesteryl group, a bicyclo [4,4,0] -decyl group.

  
The carboxyl protecting groups mentioned above are typical examples and any group selected from those described in US Pat. Nos. 3,499,909 can be used; 3,573,296 and
3,641,018, as well as in the requests for

  
patents of the German Federal Republic N [deg.] 2,301,014,
2.253.287 and 2.337.105, published before examination.

  
In the general formulas of the invention, R2 is "an organic group linked via a

  
  <EMI ID = 18.1>

  
lower alkoxy groups; lower alkylthio groups,

  
acyloxy groups; a carbamoyloxy group; and heterocyclic-thio groups, containing in the heterocyclic ring

  
0, S and N alone or in any combination and in any position, such as: oxazolylthio, thiazolylthio, isoxazolylthio, isothiazolylthio, imidazolylthio, pyrazolylthio, pyridylthio, pyrazinylthio, pyrimidinylthio, pyridazinylthio, pyrolazinylthylthio isololololthio, thiadiazolylthio, triazolylthio, tetrazolylthio, triazinylthio, benzimidazolylthip, benzoxalolylthio, benzthiazolylthio, triazolopyridylthio, purinylthio, pyridine1-oxide-2-ylthio, and the like.

  
In addition, the R2 groups mentioned above

  
may be substituted by a halogen atom or a group

  
  <EMI ID = 19.1>

  
lower alkoxy, lower alkylthio, nitro, .cyano, lower alkyl-amino, di-lower alkyl-amino, acylamino, acyl, acyloxy, acyl-lower alkyl, carboxyl, carbamoyl, lower aminoalkyl, N-lower alkyl-lower amino-alkyl , N, N-di-lower alkyl-amino-lower alkyl, hydroxy-lower alkyl, hydroxyimino-lower alkyl, lower alkoxy lower alkyl, carboxy-lower alkyl, sulfo-lower alkyl, sulfo, sulfamoyl-lower alkyl, sulfamoyl,

  
  <EMI ID = 20.1>

  
hydroxycarbamoyl-lower alkyl or the like.

  
In said general formulas, A is a substituted or unsubstituted alkyl group, examples of said alkyl groups can be taken from the examples already given in the above definition of the alkyl group. Examples of substituents of substituted alkyl groups, for group A are halogen atoms, lower alkoxy groups, cyano group, nitro group, carboxyl group, lower alkoxy-carbonyl groups, hydroxyl group, groups lower alkyl-thio, acyl groups, N, N-disubstituted amino groups and the like.

  
In said general formulas, R4 is a lower alkyl group. Examples of said lower alkyl groups can be chosen from the examples given in the definition of the alkyl group presented above.

  
In said general formulas, R5 is a hydrogen atom or a hydroxyl protecting group. The hydroxyl protecting group includes all the groups which can be commonly used as hydroxyl protecting groups, such as a lower alkyl, a-ethoxyethyl, benzyl, benzhydryl, trityl, tetrahydrofuryl, tetrahydropyranyl, trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl group. p-toluenesulfonyl, p-nitrobenzyloxycarbonyl, o-bromobenzyloxycarbonyl, o-nitrophenylsulfenyl, acetyl, chloroacetyl, trifluoroacetyl, formyl, tert-butoxycarbonyl, p-methoxybenzyloxycarbonyl, 3,4dimethoxybenzyloxycarbonyl (4-) benzyloxycarbonyl, pyridine-1-oxide-2yl-methoxycarbonyl, 2-pyridylmethoxycarbonyl, 2-furyloxycarbonyl, diphenylmethoxycarbonyl, 1,

  1-dimethylpropoxycarbonyl, isopropoxycarbonyl, 1-cyclopropylethoxycarbonyl, phthaloyl, succinyl, 1-adamantyloxycarbonyl, 8-quinoleyloxycarbonyl

  
and the like, and a silyl organic group, such as di- or tri-lower alkyl-silyl, di- or tri-lower alkoxy-silyl, diphenylmethylsilyl and the like.

  
  <EMI ID = 21.1>

  
represented by the general formula (I) includes those formed in the acid group and those formed in the basic group, which are well known in the fields of penicillin and cephalosporin. Among the salts, the pharmaceutically acceptable salts are preferred. The salts formed in the acid group include salts of alkali metals, such as sodium, potassium and the like, alkaline earth metals, such as calcium, magnesium and the like; ammonium; and organic bases containing nitrogen, such as

  
  <EMI ID = 22.1>

  
triethylamine, tributylamine, pyridine, dimethylaniline, Nmethylpiperidine, N-methylmorpholine, diethylamine and dicyclohexylamine.

  
The salts formed in the basic group include salts of mineral acids, such as hydrochloric acid, sulfuric acid and the like; organic carboxylic acid, such as oxalic acid, formic acid, trichloroacetic acid, trifluoroacetic acid and the like; and organic sulfonic acid, such as

  
methanesulfonic acid, toluenesulfonic acid, acid

  
  <EMI ID = 23.1>

  
All optical isomers and racemic compounds, as well as all crystalline forms and hydrates of

  
7a-methoxycephalosporin represented by the general formula
(I) and its salts are included within the scope of the invention.

  
Among the various 7a-methoxycephalosporins of the invention, those which are represented by the following formula (la) as well as their salts, are preferred:

  

  <EMI ID = 24.1>


  
wherein A represents a lower alkyl group; R4

  
  <EMI ID = 25.1>

  
as specified above. Among the 7a-methoxycephalosporins represented by the above formula (la) and their salts, those which are more preferred are those in which R5 is a

  
  <EMI ID = 26.1>

  
  <EMI ID = 27.1>

  
  <EMI ID = 28.1> thio.

  
As preferable compounds of the invention, the following compounds may be mentioned by way of examples, although the invention is in no way restricted thereto:

  
Acid 7 &#65533; - [D-a- (4-ethyl-2,3-dioxo-1-piperazine)

  
  <EMI ID = 29.1>

  
cephem-4-carboxylic or one of its pharmaceutically acceptable salts.

  
7S- {D-a- [4- (n- or iso-) butyl-2,3-dioxo-1- acid

  
  <EMI ID = 30.1>

  
cephem-4-carboxyl.ique or one of its pharmaceutically acceptable salts.

  
Acid 7 &#65533; - [D-a- (4-ethyl-2,3-dioxo-1-piperazine)

  
  <EMI ID = 31.1>

  
pharmaceutically acceptable.

  
Acid 7 - - [D-a- (4-methyl-2,3-dioxo-1-piperazine)

  
  <EMI ID = 32.1>

  
4-carboxylic or one of its pharmaceutically acceptable salts.

  
Acid 7 &#65533; - [D-a- (4-n-octyl-2,3-dioxo-1-pipérazine-

  
  <EMI ID = 33.1> or one of its pharmaceutically acceptable salts.

  
  <EMI ID = 34.1>

  
or one of its pharmaceutically acceptable salts.

  
Acid 7 &#65533; - [D-a- (4-ethyl-2,3-dioxo-1-pipérazinecar-

  
  <EMI ID = 35.1>

  
cephem-4-carboxylic or one of its pharmaceutically acceptable salts.

  
The compounds represented by the general formula (I) or their salts are prepared by known procedures, such as, for example, those described below.

  
Preparation procedure (1): a procedure by which a compound of general formula (II) is reacted:

  

  <EMI ID = 36.1>
 

  
  <EMI ID = 37.1>

  
organic silyl or an organic group containing phosphorus;

  
  <EMI ID = 38.1>

  
with a reactive derivative, in the carboxyl group, of a compound represented by the general formula (III):

  

  <EMI ID = 39.1>


  
  <EMI ID = 40.1>

  
Preparation procedure (2): a procedure in which a compound of general formula (IV) is reacted:

  

  <EMI ID = 41.1>


  
  <EMI ID = 42.1>

  
above, with a compound represented by the general formula
(V):

  

  <EMI ID = 43.1>


  
in which R <3>, R4, R5, n and A are defined as specified above, or with a reactive derivative, in the carboxyl group, of said compound (V).

  
Preparation procedure (3): a procedure in which a cephalosporin of general formula (VI) is reacted:

  

  <EMI ID = 44.1>


  
  <EMI ID = 45.1>

  
specified above, in the presence of methanol, with an alkali metal or alkaline earth metal methylate, represented by the general formula (VII):

  

  <EMI ID = 46.1>


  
  <EMI ID = 47.1>

  
  <EMI ID = 48.1>

  
a reaction with a halogenating agent.

  
Preparation procedure (4): a procedure in which a 7a-methoxycephalosporin of general formula (VIII) is reacted:

  
1

  

  <EMI ID = 49.1>


  
  <EMI ID = 50.1>

  
  <EMI ID = 51.1>

  
as specified above, with a compound represented by the general formula (IX):

  

  <EMI ID = 52.1>


  
  <EMI ID = 53.1>

  
alkaline or an alkaline earth metal; m2 is 1 or 2; and R2 is defined as specified above.

  
The organic silyl groups and the organic phosphorus-containing groups represented by R in the general formulas mentioned above, include the groups which are commonly used as amino- or carboxyl-protecting groups in the fields of penicillin and cephalosporin synthesis, such as

  

  <EMI ID = 54.1>


  
  <EMI ID = 55.1>

  
example, with water or alcohol.

  
  <EMI ID = 56.1>

  
replaceable with a nucleophilic reagent, include halogen atoms, such as chlorine, bromine and the like; lower alkanoyloxy groups, such as formyloxy, acetoxy, propionyloxy, butyryloxy, pivaloyloxy and the like; arylcarbonyloxy groups, such as benzoyloxy, naphthoyloxy

  
  <EMI ID = 57.1>

  
benzoyloxy, thionaphthoyloxy and the like; arylcarbonylthio groups, such as benzoylthio, naphthoylthio and the like; arylthiocarbonylthio groups, such as thiobenzoylthio, thionaphtoylthio and the like; a carbamoyloxy group; a thiocarbamoyloxy group; a pyridine-N-oxide-2-yl group; and a pyridazine-N-oxide-6-yl group. These groups

  
  <EMI ID = 58.1>

  
such as, for example, a halogen atom, a nitro group, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, an acyl group and the like.

  
The compound represented by the general formula (V) is easily obtained by the reaction between an alkali metal salt, an alkaline earth metal salt and an organic base salt of a compound represented by the general formula (X):

  

  <EMI ID = 59.1>


  
in which R4 and R5 are defined as specified above, and a reactive derivative, in the carboxyl group, of a compound represented by the general formula (III) in the presence of an acid-fixing agent, in a solvent inert.

  
The synthesis of the compounds represented by the general formulas (II) and (IV) can be carried out in a manner known per se, for example, as described

  
in Journal of Synthetic Organic Chemistry, Japan, Vol.
35, 568-574 (1977).

  
The protocols for implementing the preparation procedures (1) ,. (2), (3) and (4) are described below.

  
We can implement the procedures (1)

  
and (2) practically under the same conditions. The compound (II) or (IV) is dissolved or suspended in an inert solvent, such as, for example: water, acetone, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethylacetamide, methanol, ethanol, methoxyethanol, diethyl ether, ether diisopropyl, benzene, toluene, methylene chloride, chloroform, ethyl acetate or methyl isobutyl ketone, each alone or as a mixture of two or more of them.

  
To the resulting solution or suspension, a reactive derivative, in the carboxyl group, of the compound (III) or of the compound (V), or a reactive derivative, in the carboxyl group, of the compound (V) is added. The mixture is left to react in the presence or absence of a base at a temperature of - 60 [deg.] C to 80 [deg.] C, preferably from - 40 [deg.] C to 30 [deg. ]VS. A reaction time of 5 minutes to 5 hours is generally sufficient.

  
The bases used in the above reaction, include inorganic bases, such as alkali metal hydroxides, alkali metal bicarbonates, alkali metal carbonates and alkali metal acetates; tertiary amines, such as trimethylamine, triethylamine, tributylamine, pyridine, N-methylpiperidine, N-methylmorpholine, lutidine, collidine and the like; and secondary amines, such as dicyclohexylamine, diethylamine and the like.

  
When the compound (V) or one of its salts is used in procedure (2), as starting material, the reaction can be carried out in the presence of a dehydrating-condensing agent, such as, for example , N, N-dicyclo-

  
  <EMI ID = 60.1>

  
N, N'-diethylcarbodiimide, N, N'-carbonyl bis (2-methylimidazole), trialkylic phosphites, ethyl polyphosphate, phosphorus oxychloride, phosphorus trichloride, 2-chloro-1,3,2-dioxaphospholane, chloride d oxazolyl, dimethyl chloride-

  
  <EMI ID = 61.1>

  
The operating mode (3) is implemented in the following way: a cephalosporin of formula (VI) obtained in a known manner is dissolved or suspended (Japanese patent applications submitted for public inspection under Nos. 70.788 / 76 and 113.890 / 76], in an inert solvent such as, for example, tetrahydrofuran, dioxane, ether

  
  <EMI ID = 62.1>

  
chloroform, dimethylformamide, dimethylacetamide, acetonitrile, methanol or the like or a mixture of two or more of

  
these solvents. In the resulting solution or suspension,

  
adds an alkali metal or alkaline earth metal methylate (VII) together with methanol. The resulting mixture is subjected to the reaction, then the

  
reaction mixture with a halogenating agent. In this reaction, excess methanol is used and the amount of alkali metal or alkaline earth metal methylate
(VII) used is preferably two to six equivalents

  
per equivalent of the cephalosporin (VI) used. The expression "in excess" denotes an amount greater than one equivalent per equivalent of the cephalosporin (VI). All the above reactions are carried out at a temperature between - 120 [deg.] C and - 10 [deg.] C, preferably from - 100 [deg.] C to
- 50 [deg.] C. A reaction time of 5 to 30 minutes is sufficient and the reaction is terminated by acidification of the reaction system.

  
The halogenating agent used in this procedure is generally known as a source of supply for

  
  <EMI ID = 63.1>

  
examples of these halogenating agents include halogens such as chlorine, bromine and the like; N-haloimides, such as N-chlorosuccinimide, N-bromosuccinimide and the like; N-haloamides, such as N-chloroacetamide, N-bromoacetamide and the like; N-halo-sulfonamides, such as N-chlorobenzenesulfamide, N-chloro-p-toluenesulfamide and the like; 1-halo-benzotriazoles; 1-halotriazines; an organic hypohalogenite, such as tert-methyl hypochlorite, tert-methyl hypoiodide and the like; halo-hydantoines, such as N, Ndibromohydantoine, and the like. Among said halogenating agents, tert-butyl hypochlorite is preferred.

   The halogenating agent is used in an amount sufficient to ensure the presence of a positive halogen in an amount equivalent to that of the cephalosporin of general formula
(VI).

  
Acids suitable for completion of the reaction are those which, when added to a cold reaction mixture, do not cause solidification

  
said reaction mixture or freezing the reaction mixture to a viscous, heavy mixture. Examples of suitable acids are 98% formic acid, glacial acetic acid, trichloroacetic acid and methanesulfonic acid.

  
After completion of the reaction, the excess halogenating agent can be removed by treatment with a reducing agent, such as a trialkyl phosphite, sodium thiosulfate or the like.

  
In the implementation of the preparation procedure (IV), when a compound of formula is used

  
  <EMI ID = 64.1>

  
thio amine-N-heterocyclic aromatic oxide group having a thio group on the carbon atom adjacent to the Nooupe rump, said compound is reacted with a compound of formula (IX) in an inert solvent such as, for example,

  
water, methanol, ethanol, propanol, isopropanol, butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, tetrahydrofuran, dioxane, acetonitrile, ethyl acetate, 2 methoxyethanol, dimethoxyethane, dimethylformamide, dimethyl sulfide, dimethyl acetylchloride, dimethyl acetamide , alone or as a mixture of two or more of them.

  
The above reaction is carried out, preferably in a strongly polar solvent, such as water. It is advantageous to keep the pH of the reaction solvent at 2-10, preferably from 4 to 8. The reaction is carried out after the addition of a buffer, such as sodium phosphate, to bring the pH to a value. desired. Although the reaction conditions are not critical, the reaction is generally carried out at a temperature of 0 [deg.] C to 100 [deg.] C for several hours to several tens of hours.

  
When using a compound of general formula
(VIII) in which the group R is a heterocyclic aromatic amineN-oxide group comprising a thio group on the carbon atom adjacent to the N-oxide group, the compound of general formula (VIII) and a compound of general formula (IX) in the inert solvent indicated above, in the presence of a bivalent copper compound. This operating technique is particularly useful when the compound of general formula (IX) is an alcohol, such as methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, n-butyl alcohol, benzyl alcohol, ethylene glycol or the like. In this case, the reaction proceeds smoothly when an excess of the alcohol intended to serve as solvent is used.

   The bivalent copper compounds used in this operating technique are inorganic or organic bivalent copper compounds, such as, for example, cupric chloride, cupric bromide, cupric fluoride, cupric nitrate, cupric sulfate, cupric borate, cupric phosphate, cupric cyanide, cupric formate, cupric acetate, cupric propionate, cupric citrate, cupric tartrate, cupric benzoate and cupric salicilate. The amount of bivalent copper compound used is preferably 0.5 mole or more per mole of the compound represented by the general formula (VIII).

   Although they depend on the types of the compound of general formula (VIII), the bivalent copper compound and the compound of general formula
(IX) used, the reaction temperature is generally from 0 [deg.] C to 100 [deg.] C and the reaction time is several minutes

  
to several days.

  
The conversion of a compound of general formula (I) in which R is a carboxyl protecting group to a compound of general formula (I) in which R is a hydrogen atom or a salt can be carried out in a standard manner of the latter compound, the conversion of a compound of general formula (I) in which R is a hydrogen atom to a salt or to a compound of general formula (I)

  
  <EMI ID = 65.1>

  
  <EMI ID = 66.1>

  
its free acid.

  
When the starting substances contain active groups, said active groups can be protected, during the reaction, by a group which is commonly used as a protective group for a carboxyl, amino or hydroxyl group. After the completion of the reaction, the protective group can be removed by obtaining the compound of the invention, represented by formula (I).

   As protecting group of an amino group, the following may be mentioned by way of example: trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl, p-toluenesulfonyl, p-nitrobenzyloxycarbonyl, o-bromobenzyloxycarbonyl, o-nitrophenylsulfenyl, acetyl, chloroacetyl tertbutoxycarbonyl, p-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4- (phenylazo) benzyloxycarbonyl, 4- (4methoxyphenylazo) benzyloxycarbonyl, pyridine-1-oxide-2-ylmethoxycarbonyl, 2-pyridylmethoxyyloxycarbonyl

  
  <EMI ID = 67.1>

  
carbonyl, isopropoxycarbonyl, 1-cyclopropylethoxycarbonyl, phthaloyl, succinyl, 1-adamantyloxycarbonyl, 8-quinoleyloxycarbonyl and the like; and other easily removable aminoprotective groups, for example, trityl, 2nitrophenylthio, 2,4-dinitrophenylthio, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, 2-hydroxy-1-naphthylmethylene,

  
  <EMI ID = 68.1>

  
hexylidene, 2-ethoxycarbonylcyclopentylidene, 2-acetylcyclo-hexylidene, 3,3-dimethyl-5-oxocyclohexylidene, di- or trialkylsilyl, and the like.

  
As the protecting group for a hydroxyl group, the following may be mentioned by way of example: a-ethoxyethyl, benzyl, trityl, benzhydryl, tetrahydrofuryl, tetrahydropyranyl and the substituted or unsubstituted acyl, alkoxycarbonyl and aralkoxycarbonyl groups mentioned above. as amino protecting groups.

  
As the protecting group for the carboxyl group, the same protecting carboxyl groups can be used as for R.

  
The preparation conditions are not limited to those described above, but one can

  
on the contrary, modify them appropriately in accordance with the particular type of reagent used.

  
The isolation of a 7a-methoxycephalosporin (I) or one of its salts can be carried out from the reaction mixture, in a conventional manner.

  
The process for the preparation of 7a-methoxycephalosporin represented by the general formula (I) and its salt is not limited to that which is described above. Said compounds can also be prepared by other known methods.

  
The 7a-methoxycephalosporin represented by the general formula (I) and its salts, thus obtained, are very useful for the therapy of diseases of human beings and mammals, because of their broad antibacterial spectrum with respect to Gram- bacteria. positive and Gram-negative bacteria, for their excellent antibacterial activity against Gram-negative bacteria, such as among others,

  
  <EMI ID = 69.1>

  
Serratia marcescens, Alkaligenes faecalis, and their stability towards p-lactamase.

  
The pharmacological effect of typical compounds among those of the invention is shown below.

  
(1) Minimum inhibitory concentration (ICD in mcg / ml).

  
The figures given in Table I represent

  
  <EMI ID = 70.1> each compound, which is determined according to the method described in "Chemotherapy (Society of Chemotherapy, Japan), Vol. 16,
98-99 (1968) ": a culture obtained by cultivating is inoculated

  
the test bacteria in a heart infusion broth (marketed by the Japanese firm Eiken Kagaku Co.). In a heart agar-infusion medium (marketed by the firm Eikén Kagaku Co.). After an incubation for 20 hours at 37 [deg.] C, the growth of the bacteria is observed, to determine the minimum inhibitory concentration (MIC in mcg / ml). The inoculation rate of the bacteria is 104 cells / plate.

  

  <EMI ID = 71.1>


  

  <EMI ID = 72.1>
 

  

  <EMI ID = 73.1>


  

  <EMI ID = 74.1>
 

  

  <EMI ID = 75.1>


  

  <EMI ID = 76.1>
 

  

  <EMI ID = 77.1>


  

  <EMI ID = 78.1>
 

  
Note:

  
  <EMI ID = 79.1>

  

  <EMI ID = 80.1>


  
(2) Compound A: Sodium salt of acid 7p- [D-a- (4-ethyl-2,3-

  
  <EMI ID = 81.1>

  

  <EMI ID = 82.1>


  
(hereinafter referred to as T-1982)

  
  <EMI ID = 83.1>

  
formula :

  

  <EMI ID = 84.1>


  
(4) Compound C: Sodium salt of acid 7 - - [D-a- (4-ethyl-

  
  <EMI ID = 85.1> 26

  
&#65533; 3-cephem-4-carboxylic represented by the formula:

  

  <EMI ID = 86.1>


  
  <EMI ID = 87.1>

  
represented by the formula:

  

  <EMI ID = 88.1>


  
  <EMI ID = 89.1>

  
formula :

  

  <EMI ID = 90.1>


  
(7) Compound F: Sodium salt of acid 7p- [D-a- (4-ethyl-

  
  <EMI ID = 91.1>

  
formula :

  

  <EMI ID = 92.1>


  
  <EMI ID = 93.1>

  
formula :

  

  <EMI ID = 94.1>


  
  <EMI ID = 95.1>

  
formula :

  

  <EMI ID = 96.1>


  
  <EMI ID = 97.1>

  
[Perret, C.J., "Iodometric assay of penicillinase", Nature,
174, 1012-1013 (1954)], except that a 0.1 M phosphate buffer solution (pH 7.0) was used in place of the 0.2 M phosphate buffer solution (pH 6 , 5). The stability of each compound is represented in Table II by the relative degree of hydrolysis, taking as value
100 for the stability of Cephalosporidine (CER) with respect to cephalosporinase, and the value of 100 for the stability of Penicillin G (PC-G) with respect to penicillinase.

  

  <EMI ID = 98.1>


  

  <EMI ID = 99.1>


  

  <EMI ID = 100.1>
 

  
(3) Protective activity of infection

  
Injected intraperitoneally into mice
(males) of ICR strain, four weeks old, distributed

  
in groups each of which includes five mice, the prescribed amount of a pathogenic bacteria suspended in the mucin at 5%. One hour after inoculation, the mice are administered subcutaneously with the test preparation to determine the protective activity of infection. The results obtained are shown in Table III. The figures indicated in Table III represent the protective activity in terms of ED 50 *
  <EMI ID = 101.1>
  <EMI ID = 102.1>
  <EMI ID = 103.1>
   <EMI ID = 104.1>

  
  <EMI ID = 105.1>

  
5 g / kg or more (ICR strain mouse; intravenously).

  
The 7 & methoxycephalosporins of the invention, represented by the general formula (I) and their salts, are administered to humans and mammals in the form of the free acid or the pharmaceutically acceptable salt or ester. The formulation of the compound is carried out under

  
various forms of dosage presentations which are usual in the case of preparations of penicillins or cephalosporins, such as, for example, capsules, syrups and compositions for injections, the administration of which is by oral or parenteral route.

  
When the compound is intended for administration to humans, intravenous injection (including drip infusion) or intramuscular injection

  
is particularly suitable. In addition, one can use

  
the antibacterial compound of the invention, in admixture with a solid or liquid support or a diluent which is commonly used in the injection of known antibiotics, and the like.

  
The form of the composition for injection comprises a powder which is dissolved, before use, in a suitable vehicle, for example, sterilized water, saline solution or the like. When the antibacterial compound of the invention is used in the form of a composition for injection, it can be used in conjunction with a local anesthetic, for example, lidocaine hydrochloride, or other drugs.

  
The dose of administration of the antibacterial compound of the invention can be varied depending on whether it is a human being or a mammal, and when administered in a human being, one can choose the appropriate administration dose depending on the age, type of infectious disease and

  
the symptom of the disease. For example, in the case of an injection, an adult should be administered 0.5 g to 10 g, in terms of activity, of the compound per day, in several portions.

  
The invention will now be illustrated below in more detail with reference to examples of preparation which are given purely by way of illustration, but which in no way limit the invention in its scope and spirit. In the said examples, all the percentages are expressed by weight, unless otherwise stated.

  
EXAMPLE 1

  
(1) Suspended in 50 ml of methylene chloride, 2.0 g of D-threonine and 6.58 ml of trimethylchlorosilane is added to the resulting suspension, after which

  
7.01 ml of triethylamine is added dropwise to it at 0 [deg.] C-5 [deg.] C. The temperature of the suspension is gradually raised and the reaction is carried out at 20 ° C. for 1.5 hours, after which 5.9 g of a mixture of 4-ethyl-2 chloride are added to the reaction mixture, 3-dioxo-1-piperazinecarbonyl and triethylamine hydrochloride (the content of 4ethyl-2,3-dioxo-1-piperazinecarbonyl chloride is 58.55% by weight). The resulting mixture is subjected to a reaction at 20 ° C. for one hour, then it is distilled under reduced pressure to remove the solvent. 30 ml of water are added to the residue and the pH of the resulting solution is adjusted to 7.5 with sodium bicarbonate, after which the solution is washed with 50 ml of ethyl acetate, then 50 ml of water are added. acetonitrile in solution.

   The pH of the resulting mixture is adjusted to 1.5 with 2N hydrochloric acid. Sodium chloride is added to the mixture to saturate it, and the acetonitrile layer is then separated.

  
  <EMI ID = 106.1>

  
four 50 ml portions of acetonitrile and the four acetonitrile extraction layers are combined with the above-mentioned acetonitrile layer, then the combined acetonitrile layer is washed with saturated sodium chloride solution, after which the layer of acetonitrile over anhydrous magnesium sulfate, then distilled under reduced pressure to remove the solvent. The residue is recrystallized from n-butanol, obtaining 3.6 g (yield

  
  <EMI ID = 107.1>

  
166 [deg.] C.

  

  <EMI ID = 108.1>


  
(2) In 15 ml of methylene chloride, 1.0 g of D-a- (4-ethyl-2,3-dioxo-1-piperazine-) acid is suspended.

  
  <EMI ID = 109.1>

  
of 1 - methylmorpholine to transform the suspension into a solution. To said solution is added 0.35 ml of ethyl chlorocarbonate at a temperature of - 15 [deg.] C to -20 [deg.] C, and the solution is subjected to a reaction at the same temperature for a hour and a half. Then add to the mixture

  
  <EMI ID = 110.1>

  
and the resulting mixture is subjected to a reaction at the same temperature for one hour, and then at a temperature of <EMI ID = 111.1> reaction under reduced pressure to remove the solvent and 30 ml of water and -30 ml of ethyl acetate are added to the residue, after which the resulting solution is stirred. The white crystals which have thus precipitated are collected by filtration in

  
  <EMI ID = 112.1>

  
of diphenylmethyl having a melting point of 121 [deg.] C to 125 [deg.] C
(with decomposition).

  

  <EMI ID = 113.1>


  
(3) In a mixture of 30 ml of methylene chloride

  
  <EMI ID = 114.1>

  
  <EMI ID = 115.1> <EMI ID = 116.1>

  
cooled, 3.55 ml (1.66 mM / ml) of a methanolic solution of lithium methoxide is added at the same temperature,

  
and the resulting mixture is stirred for 3 minutes, after

  
to which 0.18 ml of tert-butyl hypochlorite is added. The resulting mixture is stirred at the same temperature for 15 minutes, after which 0.39 ml of acetic acid is added to the resulting solution, and the temperature of the solution is raised to room temperature. The solution is distilled under reduced pressure to remove the solvent, and 20 ml of ethyl acetate and 20 ml of water are added to the residue to dissolve the said residue, after which the pH of the resulting solution is adjusted to 6.5 with an aqueous solution of sodium bicarbonate. The organic layer is separated, washed with water, and dried over anhydrous magnesium sulfate, then distilled under reduced pressure to remove the solvent.

   The residue is purified by column chromatography [silica gel marketed under the name of Wako C-200; eluted with a mixture of benzene and ethyl acetate
(1: 2 by volume)] on which we obtain 0.6 g (40.8% yield)

  
  <EMI ID = 117.1>

  

  <EMI ID = 118.1>


  
(4) In 5 ml of anisole, 0.5 g of 7p- [D-a-

  
  <EMI ID = 119.1>

  
add 5 ml of trifluoroacetic acid to the resulting solution, cooling with ice, after which the resulting solution is stirred at the same temperature for 30 minutes. The reaction mixture is distilled under reduced pressure to remove the solvent, and 10 ml of ethyl acetate and 10 ml of water are added to the residue, after which a saturated solution of sodium bicarbonate is added thereto with stirring to bring its pH at 6.5, thereby dissolving the residue. The aqueous layer is separated, to which 10 ml of methyl acetate are then added. The pH of the resulting mixture is adjusted to 2.0 with

  
  <EMI ID = 120.1>

  
extract the aqueous layer with two 10 ml portions of methyl acetate, and combine the two extracts with the organic layer mentioned above, then wash the combined organic layer with a saturated aqueous solution of sodium chloride.

  
After drying over anhydrous magnesium sulphate, the organic layer is distilled under reduced pressure to remove the solvent, and the residue is treated with ether

  
  <EMI ID = 121.1>

  
  <EMI ID = 122.1>

  
118 [deg.] C to 120 [deg.] C (with decomposition).

  

  <EMI ID = 123.1>


  
In the same way as above, the following compounds are obtained:

  
  <EMI ID = 124.1>

  
108 [deg.] C to 112 [deg.] C (with, decomposition).

  

  <EMI ID = 125.1>


  
  <EMI ID = 126.1> <EMI ID = 127.1>

  
melting point 113 [deg.] C to 115 [deg.] C. (with decomposition).

  

  <EMI ID = 128.1>


  
  <EMI ID = 129.1>

  
melting point 125 [deg.] C-133 [deg.] C (with decomposition).

  

  <EMI ID = 130.1>


  
  <EMI ID = 131.1>

  
melting point 144 [deg.] C to 150 [deg.] C. (with decomposition).

  

  <EMI ID = 132.1>


  
EXAMPLE 2

  
(1) In 45 ml of methylene chloride, one suspends

  
  <EMI ID = 133.1>

  
&#65533;-( S) -hydroxybutyrique, and 1.60 g of N-methylmorpholine is added to the resulting suspension to transform the suspension into a solution. The solution is cooled to -20 [deg.] C, and 1.78 g of ethyl chlorocarbonate are added thereto, after which the resulting solution is subjected to a reaction at a temperature of between -13 [deg.] C and - 16 [deg.] C for an hour and a half. Subsequently, the reaction mixture is added to <EMI ID = 134.1> diphenylmethyl carboxylate. The reaction is carried out at a temperature of - 10 [deg.] C to - 15 [deg.] C. for 30 minutes, then at a temperature of - 10 [deg.] C to 0 [deg.] C for 30 minutes, after which

  
the reaction mixture is distilled under reduced pressure to remove the solvent. 50 ml of ethyl acetate, 50 ml of methyl acetate and 40 ml of water are added to the residue to dissolve the residue. The organic layer is separated, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue is purified by column chromatography [Wako C-200 silica gel; eluted with a mixture of chloroform and ethanol (60: 1 by volume)], obtaining 8.2 g (yield 78.2%)

  
  <EMI ID = 135.1>

  
diphenylmethyl, obtained in the above-mentioned phase (1), and

  
  <EMI ID = 136.1>

  
lithium methoxide (the lithium methoxide content is 1.51 mM / ml) at -70 [deg.] C. The solution is stirred at a temperature of - 65 [deg.] C. at -70 [deg.] C for 3 minutes, and then add to the

  
  <EMI ID = 137.1>

  
carry out the reaction at the same temperature for 15 minutes. 3 ml of acetic acid are added to the reaction mixture and the temperature of the mixture is gradually raised to 0 [deg.] C, after which the mixture is distilled under reduced pressure to remove the solvent. 100 ml of ethyl acetate and 50 ml of water are added to the residue to dissolve the residue, and the organic layer is separated, dried over anhydrous magnesium sulphate, then distilled under reduced pressure to remove the solvent. The residue is purified by column chromatography

  
  <EMI ID = 138.1>

  
obtaining 2.65 g (31.8% yield) of a white powder <EMI ID = 139.1>

  

  <EMI ID = 140.1>


  
  <EMI ID = 141.1>

  
in the above-mentioned phase (2), 26 ml of anisole and 26 ml of trifluoroacetic acid are added, while cooling with ice, and the resulting mixture is subjected to the reaction at the same temperature for 30 minutes, after which it is distilled the reaction mixture under reduced pressure to remove the solvent.

  
Diethyl ether is added to the residue to wash the latter, thereby obtaining 2.0 g (yield 97.6%) of a

  
  <EMI ID = 142.1>

  
acetoxymethyl-A-cephem-4-carboxylic having a melting point of 142 [deg.] C to 145 [deg.] C (with decomposition).

  

  <EMI ID = 143.1>


  
EXAMPLE 3

  
0.71 g is dissolved in 24 ml of nitromethane

  
  <EMI ID = 144.1>

  
4-carboxylic acid and 0.22 g of 1- (2-hydroxyethyl) -5-mercapto-1Htetrazole, and the resulting solution is subjected to a reaction at 80 [deg.] C for 5 hours, after which the reaction mixture is distilled under reduced pressure to remove the solvent. To the resulting residue, 20 ml of ethyl acetate are added and
20 ml of acetone to dissolve the residue. Then we add to

  
  <EMI ID = 145.1>

  
the purple-reddish color remains permanent, without disappearing, and the resulting mixture is then distilled under reduced pressure to remove the solvent. The resulting residue is purified by column chromatography [Wako C-200 silica gel, eluted with a mixture of chloroform and ethanol (20: 1 by volume)], obtaining a pale yellow powder. 3.5 ml of anisole and 3.5 ml of trifluoroacetic acid are added to the powder while cooling with ice, and the resulting mixture is subjected to a reaction at the same temperature for 30 minutes, after which the mixture is distilled. reaction under reduced pressure to remove the solvent. Ethyl acetate is added to the resulting residue to wash the latter, whereupon 0.28 g (34% yield) of a pale yellow powder is obtained.

  
  <EMI ID = 146.1>

  
having a melting point of 128 [deg.] C to 135 [deg.] C (with decomposition).

  

  <EMI ID = 147.1>


  
We repeat the same protocol as above, except

  
  <EMI ID = 148.1>

  
  <EMI ID = 149.1>

  
of this product are identical to those of the product of Example 1. EXAMPLE 4

  
In 7 ml of anhydrous methylene chloride,

  
  <EMI ID = 150.1>

  
carboxamido) - &#65533;-( S) -tert-butoxybutyrique, after which we add

  
  <EMI ID = 151.1>

  
drop of dimethylformamide, in the order thus indicated, while cooling with ice, and the resulting mixture is subjected to a reaction at room temperature for 30 minutes. The reaction mixture is distilled under reduced pressure to remove the solvent. The resulting residue is dissolved in 8 ml of anhydrous methylene chloride, and the solution is cooled. <EMI ID = 152.1>

  
  <EMI ID = 153.1>

  
dimethylaniline, in the order shown, after which

  
  <EMI ID = 154.1>

  
a night. The reaction mixture is distilled under reduced pressure to remove the solvent, and the residue is dissolved in a mixture of. 10 ml of water and 15 ml of ethyl acetate, after which the ethyl acetate layer is separated, washed abundantly with water, then distilled to remove the solvent. The resulting residue is purified by column chromatography [Wako C-200 silica gel; eluted with a mixture of benzene and ethyl acetate (2: 1 1 by volume), obtaining

  
  <EMI ID = 155.1>

  
diphenylmethyl cephem-4-carboxylate, having a melting point of 109 [deg.] C to 115 [deg.] C (with decomposition).

  

  <EMI ID = 156.1>


  
The above-mentioned product is dissolved in a mixture of

  
2 ml of anisole and 2 ml of trifluoroacetic acid, and the resulting solution is subjected to a reaction at room temperature for 30 minutes. The reaction mixture is dried under reduced pressure to dryness, after which 10 ml of ethyl acetate is added to the residue, and the resulting mixture is stirred for one hour. The crystals which have thus precipitated are collected by filtration and dried, obtaining

  
  <EMI ID = 157.1>

  
carboxylic. The melting point (with decomposition), the

  
  <EMI ID = 158.1> those of the product obtained in Example 1.

  
EXAMPLE 5

  
1 g of an acid is dissolved in a mixture of 40 ml of anhydrous methylene chloride and 20 ml of anhydrous methanol

  
  <EMI ID = 159.1>

  
3.7 ml of a lithium methoxide solution in methanol

  
  <EMI ID = 160.1>

  
subjects the solution to the reaction at a temperature of -75 [deg.] C to
- 70 [deg.] C for 3 minutes, after which 0.22 ml of tert-butyl hypochlorite is added thereto, and the resulting mixture is subjected to a reaction for 15 minutes. 0.28 ml of formic acid is added to the reaction mixture, and the temperature of the mixture is raised to the value of room temperature. The mixture is distilled under reduced pressure to remove the solvent, and 4 ml of water, 4 ml of a saturated aqueous solution of sodium chloride and 20 ml are added to the resulting residue. <EMI ID = 161.1>

  
resulting, 6N hydrochloric acid is added dropwise to adjust the pH of the solution to 1.2. The organic layer is separated, then dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. To the resulting residue is added 14 ml of acetone and the resulting mixture is stirred. The crystals which have thus precipitated are collected by filtration, obtaining

  
  <EMI ID = 162.1>

  
Said adduct is suspended in 4.3 ml of 20% hydrated acetone, and bicarbonate is added. of sodium in the suspension to adjust its pH to 5.0. 70 mg of active carbon are added to the suspension, and the mixture is stirred for 3 to 4 minutes, then filtered through celite to remove the active carbon. The pH of the filtrate is brought to 1.5 with 6N hydrochloric acid. The mixture is then stirred at room temperature for 30 minutes, then cooled with ice for 3 hours, after which

  
the crystals which have thus precipitated are collected by filtration and then dried, obtaining 0.5 g (yield

  
  <EMI ID = 163.1>

  
carboxylic, having a melting point of 173 [deg.] C to 175 [deg.] C (with decomposition).

  

  <EMI ID = 164.1>


  
  <EMI ID = 165.1>

  
product of Example 1.

  
EXAMPLE 6

  
In 20 ml of anhydrous methylene chloride, put

  
  <EMI ID = 166.1>

  
and to the suspension is added 0.8 ml of vinyl ethyl ether and
42 mg of pyridinium p-toluenesulfonate, then the resulting mixture is subjected to a reflux reaction for 50 minutes

  
  <EMI ID = 167.1>

  
0.5 ml of anhydrous methanol, after which 2.87 ml of a solution of lithium methoxide to methanol are introduced therein dropwise (7.52 mM of lithium methoxide are contained in said solution). The resulting mixture is subjected to the reaction at a temperature of - 75 [deg.] C to - 70 [deg.] C for 3 minutes, after which 30 ml of anhydrous methylene chloride are added dropwise for 10 minutes. containing 0.25 ml of tert-butyl hypochlorite. The resulting mixture is subjected to the reaction

  
at the same temperature for an additional 5 minutes, after which 0.34 ml of acetic acid is added thereto, and the

  
  <EMI ID = 168.1>

  
5 ml of water, and the resulting mixture is stirred, after which the organic layer is separated and distilled under reduced pressure to remove the solvent. We dissolve the residue <EMI ID = 169.1>

  
cephem-4-carboxylic in 15 ml of acetone, and 30 mg of p-toluenesulfonic acid monohydrate are added to the solution, then the solution is added at room temperature for

  
2 hours and then allowed to stand at 5 [deg.] C overnight. The precipitated crystals are collected by filtration and then washed with water, obtaining 0.85 g of the adduct of acetone with acid 7p- [D-

  
  <EMI ID = 170.1>

  
This adduct is suspended in 5 ml of 20% hydrated acetone, then its pH is adjusted to 5.0 in

  
  <EMI ID = 171.1>

  
of active carbon, and the resulting mixture is stirred for 3 to 4 minutes, and then filtered through celite to remove the active carbon. 6N hydrochloric acid is added to the filtrate to adjust the pH of the said filtrate to 1.5, after which the filtrate is stirred at room temperature for 30 minutes, then cooled in ice for 3 hours. The crystals which have thus precipitated are collected by filtration, obtaining 0.66 g (yield 60%)

  
  <EMI ID = 172.1>

  
carboxylic, having a melting point of 173 [deg.] C to 175 [deg.] C (with decomposition).

  

  <EMI ID = 173.1>


  
The NMR spectrum of the product is identical to that of

  
  <EMI ID = 174.1>

  
EXAMPLE 7

  
(1) In 50 ml of anhydrous methylene chloride,

  
  <EMI ID = 175.1>

  
diethyl ether (BF3 content. 47% by weight) and 50 ml of a diazomethane solution in diethyl ether (content

  
in diazomethane: approximately 1.4 g) in the order thus indicated.

  
The mixture is subjected to the reaction. The temperature of the reaction mixture is gradually raised to bring it to room temperature, and 20 ml of water are added to the mixture, after which the organic layer is separated, washed with a saturated aqueous chloride solution. sodium, dried over anhydrous magnesium sulfate, then distilled under reduced pressure to remove the solvent. The resulting residue is purified by column chromatography [Wako C-200 silica gel; eluted with a mixture of benzene and ethyl acetate (5: 1 by volume)], obtaining 0.68 g (yield 26.4%)

  
  <EMI ID = 176.1>

  
(2) 0.6 g of D-a- (4-ethyl-2,3-dioxo-) is dissolved in a mixture of 5 ml of anisole and 5 ml of trifluoroacetic acid

  
  <EMI ID = 177.1>

  
methyl, obtained in the above-mentioned phase (1), and the resulting solution is subjected to a reaction, while cooling it with ice, for 30 minutes. The reaction mixture is distilled under reduced pressure to remove the solvent, and 10 ml of diethyl ether and 10 ml of diisopropyl ether are added to the residue, then the resulting mixture is stirred for one hour. The crystals which have thus precipitated are collected, by

  
  <EMI ID = 178.1>

  
  <EMI ID = 179.1>

  
butyric.,. having a melting point of 132 [deg.] C to 133 [deg.] C.

  
(3) In 3 ml of anhydrous methylene chloride, put

  
  <EMI ID = 180.1>

  
phase (2) above, and 0.1 g of oxalyl chloride is added thereto. A drop of N, N-dimethylformamide is added to the suspension, and the temperature of the suspension is raised to the value of room temperature, after which the suspension is subjected

  
to a reaction for an hour. The reaction mixture is distilled under reduced pressure to remove the solvent, then the resulting residue is dissolved in 5 ml of anhydrous methylene chloride, after which it is added to the resulting solution <EMI ID = 181.1>

  
methyl at a temperature of - 30 [deg.] C. at -40 [deg.] C, and then 0.086 g of dimethylaniline. The resulting mixture is subjected to

  
  <EMI ID = 182.1>

  
12 hours, then it is distilled under reduced pressure to remove the solvent. The resulting residue is dissolved in a mixture of 5 ml of water and 10 ml of ethyl acetate. The organic layer is separated, washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The organic layer is distilled under reduced pressure to remove the solvent, and the resulting residue is purified by column chromatography [Wako C-200 silica gel; eluted with a mixture of benzene and ethyl acetate (1: 1 by volume)], obtaining 0.28 g

  
  <EMI ID = 183.1>

  
of diphenylmethyl.

  
(4) In a mixture of 2 ml of anisole and 2 ml of acid

  
  <EMI ID = 184.1>

  
diphenylmethyl cephem-4-carboxylate, and the solution is reacted for 30 minutes while ice-cooling. The reaction mixture is distilled under reduced pressure to remove the solvent, and 10 ml of ethyl acetate is added to the resulting residue, after which the mixture is stirred for 30 minutes. The crystals which have thus precipitated are collected by filtration, obtaining 0.1 g (yield

  
  <EMI ID = 185.1>

  

  <EMI ID = 186.1>
 

  

  <EMI ID = 187.1>


  
In the same way as above, the following compounds are obtained:

  
  <EMI ID = 188.1>

  
fusion 110 [deg.] C to 119 [deg.] C (with decomposition).

  

  <EMI ID = 189.1>


  
  <EMI ID = 190.1> of fusion, 110 [deg.] To 115 [deg.] C (with decomposition).

  

  <EMI ID = 191.1>


  
EXAMPLE 8

  
  <EMI ID = 192.1>

  
formic, and the resulting mixture is subjected to a reaction with
50 [deg.] C for two hours, after which the reaction mixture is distilled under reduced pressure to remove the solvent. 5 ml of ethyl acetate are added to the resulting residue, and the crystals which have thus precipitated are collected by filtration in

  
  <EMI ID = 193.1>
  <EMI ID = 194.1>
 
  <EMI ID = 195.1>
(2) In 5 ml of anhydrous methylene chloride,

  
  <EMI ID = 196.1>

  
suspension 0.14 g of oxalyl chloride, cooling it

  
to ice, after which a drop of dimethylformamide is added. The temperature of the suspension is raised to room temperature, and the suspension is subjected to reaction for 30 minutes. The reaction mixture thus obtained is distilled under reduced pressure to remove the solvent. The resulting residue is dissolved in 5 ml of anhydrous methylene chloride, and the solution is cooled to -40 [deg.] C. We

  
  <EMI ID = 197.1>

  
of diphenylmethyl, after which 0.12 ml of N, Ndimethylaniline is added thereto. The resulting mixture is subjected to a reaction at -20 [deg.] C. overnight. The reaction mixture is distilled under reduced pressure to remove the solvent, and added

  
10 ml of water and 20 ml of ethyl acetate to the resulting residue to dissolve the latter, after which the organic layer is separated, washed: washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate and then distilled under reduced pressure to remove the solvent. The resulting residue is purified by column chromatography [Wako silica gel

  
  <EMI ID = 198.1> diphenylmethyl cephem-4-carboxylate, and the resulting solution is subjected to a reaction for 15 minutes while cooling with ice. The reaction mixture is distilled under reduced pressure to remove the solvent, and added

  
10 ml of ethyl acetate to the resulting residue, after which the resulting mixture is stirred for 30 minutes. The crystals which have thus precipitated are collected by filtration, obtaining 0.15 g (yield 94%) of 7p- [D-a- (4-ethyl-2,3-dioxo-) acid.

  
  <EMI ID = 199.1>

  
carboxylic, having a melting point of 147 [deg.] C to 155 [deg.] C (with decomposition).

  

  <EMI ID = 200.1>


  
In the same way as above, we obtain the following compound

  
  <EMI ID = 201.1>

  
of fusion, 136 [deg.] C to 142 [deg.] C (with decomposition).

  

  <EMI ID = 202.1>


  
EXAMPLE 9

  
(1) In 20 ml of anhydrous methylene chloride, put

  
  <EMI ID = 203.1> after which 0.76 ml of 2,3-dihydro- is added to the suspension

  
  <EMI ID = 204.1>

  
brings the resulting mixture to reflux for two hours., After the end of the reaction, the mixture is cooled

  
  <EMI ID = 205.1>

  
lithium methoxide to methanol (this solution containing 3.725 mM lithium methoxide), after which the resulting mixture is subjected to a reaction for 3 minutes. To the reaction mixture is added 0.123 ml of tert-butyl hypochlorite, and the mixture is subjected to a reaction for 15 minutes. We

  
  <EMI ID = 206.1>

  
raises the temperature of the mixture to room temperature, after which the mixture is distilled under reduced pressure to remove the solvent. The resulting residue is dissolved in a mixture of 10 ml of water and 10 ml of ethyl acetate, after which the pH of the solution is adjusted to 7.5 with a dilute aqueous solution of sodium bicarbonate. The aqueous layer is separated and 10 ml of ethyl acetate are added thereto, after which its pH is adjusted to 1.5 with acid

  
  <EMI ID = 207.1>

  
the organic layer, which is washed with water and a saturated aqueous solution of sodium chloride, in the order thus indicated, and which is then dried over anhydrous sodium sulfate. The organic layer is distilled under pressure

  
reduced to remove the solvent, and to the residue is added diethyl ether, after which the crystals which have thus precipitated are collected, by filtration, obtaining 0.42 g (yield

  
  <EMI ID = 208.1>

  
cephem-4-carboxylic, having a melting point of 132 [deg.] C
(with decomposition).

  

  <EMI ID = 209.1>
 

  
(2) Dissolve in 10 ml of 20% hydrated acetone

  
  <EMI ID = 210.1>

  
carboxylic, after which the pH of the solution is adjusted to 0.5 with 6N hydrochloric acid. The solution is subjected to reaction at room temperature for two hours with stirring, after which the mixture is distilled under pressure. reduced to remove the solvent. The resulting residue is dissolved in a mixture of 8 ml of acetonitrile and 2 ml of a saturated aqueous solution of sodium chloride, and then separated

  
the organic layer. The aqueous layer is extracted with two 4 ml portions of acetonitrile, and the two layers extracted with acetonitrile are combined with the above-mentioned organic layer. The combined organic layer is dried over anhydrous sodium sulfate, then distilled under reduced pressure to remove the solvent. 7 ml of acetone are added to the resulting residue and the resulting mixture is sufficiently stirred, after which the crystals which have thus precipitated are collected by filtration, obtaining 0.4 g of the adduct of

  
  <EMI ID = 211.1>

  
This adduct is suspended in 2.4 ml

  
  <EMI ID = 212.1>

  
sodium bicarbonate, after which 40 mg of active carbon is added. The resulting mixture is stirred for 3 to 4 minutes, then filtered through celite to remove the active carbon. The pH of the filtrate is then adjusted to 1.5 with 6N hydrochloric acid, and the filtrate is stirred for
30 minutes at room temperature, then stirred for 3 hours while cooling with ice. The crystals are thus collected. precipitated, by filtration, obtaining

  
  <EMI ID = 213.1>

  
173 [deg.] C to 175 [deg.] C (with decomposition).

  

  <EMI ID = 214.1>


  
EXAMPLE 10

  
In 10 ml of tetrahydrofuran hydrated at 80%,

  
  <EMI ID = 215.1>

  
triethylamine in the suspension to adjust its pH to 7.0-7.5. 0.48 g of a chloride mixture is added to the resulting solution

  
  <EMI ID = 216.1>

  
amine to adjust the pH to 7.0-7.5. At the same temperature, the reaction is carried out for one hour, after which the pH is brought to 5.5 with 6N hydrochloric acid. The reaction mixture is distilled under reduced pressure to remove the solvent, and the residue is added to the residue. 4 ml of acetone hydrated to
20% to dissolve the residue, after which the pH of the solution is adjusted to 1.5 with 6 N hydrochloric acid at a temperature of 3 [deg.] C to 5 [deg.] C. The solution is then stirred for 5 hours and the crystals which have thus precipitated are collected,

  
  <EMI ID = 217.1>

  
  <EMI ID = 218.1>

  
having a melting point of 173 [deg.] C to 175 [deg.] C (with decomposition) ..

  

  <EMI ID = 219.1>


  
The NMR spectrum of the product is identical to that of the product of Example 1.

  
Example of pharmaceutical preparation 1

  
Add sodium bicarbonate to acid 7 - - [D-a-

  
  <EMI ID = 220.1> A-cephem-4-carboxylic, and the resulting mixture is treated in the conventional manner to obtain the sodium salt which is subjected to lyophilization and sterilization. In 20 ml of a saline solution, 1 g, in terms of activity, of said sodium salt is dissolved, obtaining a solution for injection. Example of pharmaceutical preparation 2

  
In 3 ml of an aqueous solution of hydrochloride

  
  <EMI ID = 221.1>

  
of activity, of the same compound as in Example of pharmaceutical preparation 1, obtaining a solute for injection. Example of pharmaceutical preparation 3

  
  <EMI ID = 222.1>

  
1 g is dissolved, in terms of activity, of the same compound as

  
  <EMI ID = 223.1>

  
solution for injection.

  
In the same way as in Pharmaceutical Preparation Example 1, the lyophilized sodium salts of other compounds can be obtained, just as compositions for injections can be obtained from said salts.

CLAIMS

  
  <EMI ID = 224.1>

  
said 7a-methoxycephalosporin being represented by the following general formula.

  

  <EMI ID = 225.1>


  
in which R represents a hydrogen atom or a

  
  <EMI ID = 226.1>

  
organic linked via an oxygen or sulfur atom; R3 represents a lower alkyl group; n is 0, 1 or 2; A represents a substituted or unsubstituted alkyl group; R4 represents a lower alkyl group; and

  
  <EMI ID = 227.1>

  
hydroxyl.

  
2. 7a-methoxycephalosporin or one of its salts


    

Claims (1)

<EMI ID = 228.1> represents a methyl group. 3. 7a-methoxycephalosporin or one of its salts <EMI ID = 229.1> represents a hydrogen atom. 4. 7a-methoxycephalosporin or one of its salts <EMI ID = 230.1> represents a hydroxyl protecting group. 5. 7a-methoxycephalosporin or one of its salts according to claim 3, characterized in that A represents a lower alkyl group. <EMI ID = 231.1> according to claim 5, characterized in that R <2> <EMI ID = 232.1> substituted or unsubstituted tetrazolyl) thio or 2- (1,3,4-thiadiazolyl) thio. <EMI ID = 233.1> <EMI ID = 234.1> or one of its pharmaceutically acceptable salts. <EMI ID = 235.1> cephalosporin represented by the following general formula <EMI ID = 236.1> in which R represents a hydrogen atom or a group <EMI ID = 237.1> linked via an oxygen or sulfur atom; <EMI ID = 238.1> or 2; A represents a substituted or unsubstituted alkyl group; R4 represents a lower alkyl group; and R5 represents a hydrogen atom or a hydroxyl protecting group, or one of its salts, characterized in that (A) a compound of the following general formula is reacted <EMI ID = 239.1> wherein R represents a hydrogen atom, a silyl organic group or an organic group containing <EMI ID = 240.1> above, with a reactive derivative of the carboxyl group, of a compound represented by the following general formula: <EMI ID = 241.1> i <EMI ID = 242.1> above, or (B) a compound of the following general formula is reacted: 1 <EMI ID = 243.1> <EMI ID = 244.1> above, with a compound represented by the following general formula: <EMI ID = 245.1> in which A, R <3>, R4, R5 and n are defined as specified above or a reactive derivative, in the carboxyl group, of the said compound, or (C) a compound of the following general formula is reacted: <EMI ID = 246.1> <EMI ID = 247.1> the following general formula: <EMI ID = 248.1> <EMI ID = 249.1> alkaline earth; m is 1 or 2; then the reaction product thus obtained is reacted with a halogenating agent, or (D) a 7a-methoxycephalosporin of the following general formula is reacted: <EMI ID = 250.1> <EMI ID = 251.1> <EMI ID = 252.1> defined as specified above, with a compound represented by the general formula: <EMI ID = 253.1> wherein M2 represents a hydrogen atom, an alkali metal or an alkaline earth metal; m2 is 1 or 2; and R2 is defined as specified above. 16. Pharmaceutical composition, particularly useful for treating bacterial infections in humans and mammals, characterized in that it comprises an antibacterial effective amount of a 7a-methoxycephalosporin or its pharmaceutically acceptable salt according to claim, 1, 2, 3 or 5, in combination with a pharmaceutically acceptable diluent or inert carrier. 17. Pharmaceutical composition according to <EMI ID = 254.1> cephalosporin or its pharmaceutically acceptable salt is acid 7 - - [D-a- (4-ethyl-2,3-dioxo-1-pipérazinecarboxamido) - <EMI ID = 255.1> of its pharmaceutically acceptable salts. New 7a-methoxycephalosporins, their preparation process and their therapeutic application.