FR2474034A2 - NOVEL 0-SUBSTITUTED OXIMES DERIVED FROM 7-AMINOTHIAZOLYL ACETAMIDO CEPHALOSPORANIC ACID, PROCESS FOR PREPARING THEM AND THEIR APPLICATION AS MEDICAMENTS - Google Patents

Abstract

THIS DIVISION IS FOR SUBJECT TO PRODUCTS RELATED TO THE GENERAL FORMULA OF CLAIM 1 OF THE MAIN PATENT, SUCH AS IN PARTICULAR THE SYN-ISOMER OF ACIDIC ACETOXYMETHYL 7-2- (2-AMINO THIAZOL-4-YL-2) (IMIDAZOL-1-YL ETHOXY) IMINOACETYLAMINOCEPH-3-EME 4-CARBOXYLIC, PROCESS FOR PREPARING THEM AND THEIR USE AS MEDICAMENTS.

Description

- 2474034

  In his main patent application, filed in France,

  on March 31, 1978, under number 78-09617, the Corporation asks-

  has described and claimed novel products of the general formula I: NH 2 CO 2 A syn isomers in which R represents: either a radical -i-RI in which X represents an atom of X sulfur or oxygen and Rt represents: or a radical alkyl or alkoxyl having 1 to 4 carbon atoms, or a phenyl radical, R

  or a radical - (CH2) n-N in which n represents

R3

  an integer of 0 to 4 and R2 and R3, identical or different

  fers, represent an atom of hydrogen, an alkyl radical having from 1 to 4 carbon atoms, R2 and R3 form with

  the nitrogen atom a piperidino group, morpholino or phthalate

  limido, Y is a radical - -C0.It in which AI represents a hydrogen atom, an equivalent of alkali metal, alkaline earth metal, magnesium, ammonium or an organic amine base or AI represents a pharmacologically acceptable ester group ,

  R4 represents a phenyl, hydroxyethyl or nitro-

  the, R "represents a hydrogen atom or an alkyl radical having 1 to 4 carbon atoms, a lactone of formula: o

2 2474034

  or a radical - (CH2) nI-R5 in which nt represents an integer of 1 to 4 and R represents: () ns or an alkoxy or Alk-S- radical containing from 1 to 4 carbon atoms and ns represents an integer from 0 to 2, or a radical: -R6 / 36 N R. in which R6 and R7 represent: - a hydrogen atom, - an alkyl radical having 1 to 4 carbon atoms or

  R6 and R7 together with the nitrogen atom form a group

  phthalimido or 1-pyridinyl, or when nt is different from 1, R5 represents a nitrile radical, or a radical -q-NH2 in which Xt represents a sulfur atom or, when X ut is different from 1, an oxygen atom or a 4-methyl or 4-amino-1,3-thiazol-2-yl radical, or a 1,2,3,4-tetrazol-5-yl radical, or an azido radical, or a radical acyl having from 2 to 4 carbon atoms, R1 represents: either a chloro or methoxy radical, or an alkyl, cycloalkyl, alkylthio radical having at most 5 carbon atoms or a -CH2-SR12 radical in which R12 represents a heterocyclic radical containing nitrogen, an acyl radical having 2 to 4 carbon atoms, a 2oxo (3H) thiazolin-4-yl carbonyl or 3-methyl 1,2-oxazol-5-yl carbonyl radical, or a acetoxymethyl or carbamoyloxymethyl radical, or an -NH-9-Alka radical in which Alka has 1 to 4 carbon atoms, A represents a hydrogen atom or a equivalent of alkali metal, alkaline earth metal, magnesium, ammonium or an organic amine base or A represents an easily cleavable ester group and the salts of the products

  of formula I with mineral or organic acids.

  The main patent application also described and claimed a process for preparing the products of

3 2474034

  as well as the application, as medicaments, of the products of formula I and the pharmaceutical compositions

containing them.

  In an application for the first certificate of addition filed on August 24, 1978 under number 78-24563, the plaintiff Company described and claimed new products included in general formula I of the main patent, as well as

  related to this general formula.

  The present application for a second certificate of addition, which was attended by Messrs René HEiMES and Michel VIGNAU, is intended first of all to illustrate, by new examples, the general formula I of the

  claim 1 of the main patent.

  The present application thus relates to the following products of formula I:

  3-acetoxymethyl-7- (2- (2-amino thiazol-4-yl) -2- (2-

  pyridylethoxyimino) acetylamino / ceph-3-yl 4-carboxylic acid, syn isomer, in internal salt form or in salt form with mineral or organic acids, 3-acetoxymethyl 7- / 2-amino-2-amino acid thiazol-4-yl)

  2 - / (ethoxycarbonyloxy) imino / acetyl / amino / ceph-3-th 4-

  carboxylic acid, isomer sn. its salts with alkali metals, alkaline earth metals, magnesium, ammonium and aminated organic bases and its esters with easily cleavable groups, as well as its salts with acids

minerals or organic.

  Among the salts formed with the bases include those formed with an equivalent of sodium, potassium, calcium lithium, magnesium, ammonium. We can

  also mention, among organic bases, trimethyl-

  amine, diethylamine, triethylamine, methylamine,

  propylamine, N, N-dimethylethanolamine, tris (hydro-

  xymethyl) aminoethane, ethanolamine, pyridine,

  picoline, dicyclohexylamine, Nt, N-dibenzylethylene

  diamine, morpholine, benzylamine, procaine,

  lysine, ltarginine, histidine, N-methyl-glucamine.

  As easily cleavable esters, mention may be made of

  esters formed with the methoxy-methyl, ethoxy-

  methyl, ethyl, ethoxyethyl, methylthio methyl, ethylthiomethyl, isopropylthiomethyl, pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl, methylmethyl, ethylmethyl, isopropylthiomethyl, pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl,

  isobutyryloxymethyl, isovaleryloxymethyl, propionyloxy-

  ethyl, isovaleryloxyethyl, 1-acetoxyethyl, 1-acetoxy-

  propyl, 1-acetoxybutyl, 1-acetoxyhexyl, 1-acetoxyheptyl.

  The products of formula I, mentioned above, may be in the form of salts of organic or mineral acids since these products contain at least one salifiable amino group. Among the acids with which the amino or pyridinium groups of the products of formula I may be salified, mention may be made, inter alia, of acetic acid, propionic acid, trifluoroacetic acid, maleic acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or hydrochloric acid,

  hydrobromic, hydroiodic, sulfuric, phosphoric.

  The new products of formula I described above,

  can be prepared by the process described in the main patent.

  pal. Examples of such preparations are provided,

  after, in the experimental part.

  The present application for a second certificate of addition also relates to: products related to general formula I of the main patent, of general formula Itb: NH k. CONH s Ilb Ns / NeRb R1 CO2A syn isomer, in which Rb represents a radical - (CH2), - R b in which nt represents an integer of 1 to 4 and R5b represents a radical: R6b \ RTb in which R6b and Rb form, with the nitrogen atom to which

  they are bound, an imidazolyl, morpholinyl or N-

  alkyl piperazinyl, the alkyl radical having 1 to 4 carbon atoms, R1 represents:

2474034

  or a chloro or methoxy radical or an alkyl, cycloalkyl or alkylthio radical having at most 5 carbon atoms, or a radical -CH 2 -S-R 12 in which R 12 represents a nitrogen-containing heterocyclic radical, an acyl radical; having 2 to 4 carbon atoms,

  a 2-oxo (3H) thiazolin-4-yl carbonyl or 3-

  methyl 1,2-oxazol-5-yl carbonyl, or an acetoxymethyl or carbamoyloxymethyl radical, or an -NH-Alka radical in which Alka has 1 to 4 carbon atoms, A represents a hydrogen atom or a equivalent of alkali metal, alkaline earth metal, magnesium, ammonium or an organic amine base or A represents an easily cleavable ester group as well as salts of

  I'b formula with mineral or organic acids.

  Among the values of R1, mention may be made of methyl radicals

  ethyl, propyl, isopropyl, butyl, isobutyl, tert-

  butyl, pentyl, pentylsecondary, tert-pentyl, cyclopro-

pyl, cyclobutyl, cyclopentyl.

  It is also possible to mention methylthio and ethylthio values.

  propylthio, isopropylthio, butylthio, isobutylthio or tert-

  butylthio. We can also mention acetamido values,

  propionylamido, butyrylamido, isobutyrylamido, valerylamido.

  Among the values of R 1 there may also be mentioned the radicals -CH 2 -S-R 12, in which R 12 represents a 1,2,3-1,2,5-1,2,4 or 1,3,4-thiadiazolyl radical; 1H-tetrazolyl,

  1,3-thiazolyl; 1,2,3 - 1,2,4 or 1,3,4-triazolyl; 1,2,3

  1,2,4 or 1,2,5 or 1,3,4-oxadiazolyl, these radicals being unsubstituted or substituted by one or more radicals chosen from the group formed by the methyl, ethyl and

  propyl, isopropyl, methoxy, ethoxy, propyloxy, isopropyl

  oxy, amino, hydroxycarbonylmethyl, dimethylaminoethyl and diethylaminoethyl, or R12 represents an acyl group

  selected from the group consisting of acetyl, propionyl, butyryl.

  Among the values of A, there may be mentioned the equivalents of sodium, potassium, lithium, calcium, magnesium and ammonium. It is also possible, among the organic bases, trimethylamine, diethylamine,

  triethylamine, monomethylamine, propylamine, N, N-

6 -2474034

  dimethylethanolamine, tris (hydroxymethyl) aminomethane,

  Ethnolamine, pyridine, picoline, dicyclohexyl-

  amine, NN'-dibenzylethylenediamine, morpholine,

  benzylamine, procarne, lysine, arginine, lthisti-

dine, N-methylglucamine.

  The substituent R 5b can be an N-alkylpiperazine radical.

1-yl.

  ln-mi l 4ublort tituants, we can quote the radicals 4-

  ## STR1 ## wherein R is 1-piopyl, 1-isopropyl, -butyl, sec-butyl, and the like.

or 4-tert-butyl piperazin-1-yl.

  The easily cleavable ester groups may be methoxymethyl, ethoxymethyl, isoproxymethyl, methoxyethyl, ethoxyethyl, methylthio methyl, ethylthiomethyl, isopropylthiomethyl, pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl, isobutyryloxymethyl,

  isovaleryloxymethyl, propionyloxyethyl, isovaleryoxy-

  ethyl, 1-acetoxyethyl, 1-acetoxypropyl, 1-acetoxybutyl,

  1-acetoxyhexyl, 1-acetoxyheptyl.

  Like the products of formula 1, formula products

  They may be in the form of organic acid salts

  or minerals, since these products contain at least

minus a salifiable amino radical.

  Among the acids with which the groups can be salified

  Examples of the amino acids of the products of formula Itb are acetic acid, trifluoroacetic acid, maleic acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid, and the like.

  p -toluenesulphonic, hydrochloric, hydrobromic, iodhy-

  drique, sulfuric, phosphoric. The products of formula Itb can also be in the form of salts

3 internal.

  The main feature of the Corridor of Addition is the products of formula IIb in which R12 is selected from the group consisting of

  acetyl radicals, 1-methyl tetrazolyl, 2-methyl-1,3,4-

  thiadiazolyl, 3-methyl-1,2,4-thiadiazol-5-yl, 3-methoxy-1,2,4-thiadiazolyl, 1,3,4-thiadiazol-5-yl, 2-amino

  1,3,1-tliadinzol-5-yl, 3-hydroxycarbonylmethyl 1,2,4-

  thiadiazol-5-yl, 5-methoxy-1,2,4-thiadiazol-3-yl, 4-methyl-5-hydroxycarbonylmethyl-1,3-thiazol-2-yl,

  1-dimethylaminoethyl 1,2,3,4-tetrazol-5-yl.

1 '2474034

  The invention is more particularly directed to the following products: 3-acetoxymethyl-2-amino-2-amino thiazol-4-yl) - (2-imidazol-1-yl ethoxy) imino acid acetyl / amino / ceph-3-th isomer 4-carboxylic acid and its salts with alkali metals, alkaline earth metals, magnesium, ammonium and aminated organic bases and its esters with easily cleavable groups, as well as its salts with the inorganic and organic acids, - 3-acetoxymethyl 7 - [2- (2-amino thiazol-4-yl) 2 - [(2-methylpiperazin-1-yl) ethoxy] imino] acetate syn isomeric amino / ceph-3-th 4carboxylic acid and its salts with alkali metals, alkaline earth metals, magnesium, ammonium and aminated organic bases and its esters with easily cleavable groups and its salts with inorganic and organic acids,

  - 3-Acetoxymethyl 7 - / 2- (2-amino thiazol-4-

  yl) 2 - ((1-morpholinylethoxy) imino / acetyl / amino / ceph-3-th 4-carboxylic acid syn isomer and its salts with alkali metals, alkaline earth metals, magnesium, ammonium and

  amino organic bases and its esters with

  readily cleavable substances and its salts with

mineral and organic acids.

  It is understood that the products of formula I'b previously

  may be: - either in the form indicated by that formula I'b - or in the form of products of formula I'b

S Z-H

  > CONH S X It Zb IR1 The present also for formula Itb of formula Y:

24-74034

  application for a second certificate of addition to a product preparation process characterized in that a product is processed

NHR 16

Ns N

CONH ^ _ SN

  X in which R.16 represents a protective group of

  amino radical, A "represents a hydrogen atom or a group of

  In the present invention, Hal is a halogen atom and R1 is as defined above by ltimidazole, morpholine or N-alkyl piperazine to give a product of the formula: ## STR2 ## CONlm IIIL s

N 1C - N 'R

  where Rb has the meaning indicated above, which product is treated with one or more agents chosen from hydrolysis agents, hydrogenolysis agents, thiourea to obtain a product of formula I "bs NH2 I "CON0 R1 Co. i, i.

9 2474034

  wherein R 1 and b have the above meaning and corresponding to a product of formula Itb wherein A is a hydrogen atom product of formula I "b which is salified or esterified, if desired, by the usual methods.

  The protective group of the amino radical that can be

  R 16 can for example be an alkyl radical of 1 to 6 carbon atoms such as preferably tert-butyl or tert-amyl; R16 can also represent a group

  aliphatic acyl, an aromatic acyl group or heterocyclic

or a carbamoyl group.

  Lower alkanoyl groups such as

  for example, formyl, acetyl, propionyl, butyryl, isobutyl

  tyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, lower alkoxy or cycloalkoxycarbonyl groups such as, for example, methoxycarbonyl, ethoxycarbonyl,

  propoxycarbonyl, 1-cyclopropylethoxycarbonyl, isopropoxy

  carbonyl, butoxycarbonyl, tertbutoxycarbonyl, pentyloxy-

  carbonyl, tert-pentoxycarbonyl, hexyloxycarbonyl, benzoyl, toluolyl, naphthoyl, phthaloyl, mesyl,

  phenylacetyl, phenylpropionyl, arylalkoxy

  carbonyls such as benzyloxycarbonyl.

  The acyl groups may be substituted for example with a chlorine, iodine bromine or fluorine atom such that

  for example chloroacetyl, dichloroacetyl, trichloroacetyl

  tyl, trifluoroacetyl or bromoacetyl.

  The substituent R16 may also represent a lower aralkyl group such as benzyl, 4-methoxybenzyl or

  phenylethyl, trityl, 3,4-dimethoxybenzyl, benzhydryl.

  The substituent R16 may also represent a grouping

  haloalkyl such as trichloroethyl.

  The substituent R16 may also represent a chlorobenzoyl, paranitrobenzoyl, paratert-butylbenzoyl group,

  phenoxyacetyl, caprylyl, n-decanoyl, acryloyl, tri-

  chloroethoxycarbonyl. The substituent R16 can also be

  present a methylcarbamoyl, phenylcarbamoyl group,

  naphthylcarbamoyl and the corresponding thiocarbamoyls.

  The above list is not an exhaustive list.

  It is obvious that other amine protecting groups, groups known in peptide chemistry, may also

to be used.

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  Among the values of C02A ", mention may be made of groupings

  esters formed with easily removable radicals

  - esters formed with alkyl radicals such as butyl, isobutyl, tert-butyl, pentyl or hexyl esters. Acetoxymethyl esters may also be mentioned,

  propionyloxymethyl, butyryloxymethyl, valeryloxy

  methyl, pivaloyloxymethyl, 2-acetoxyethyl,

  2-propionyloxyethyl, 2-butyryloxyethyl.

  There may also be mentioned a 2-mesylethyl ester,

  2-iodoethyl, N, -trichloroethyl, vinylic, allyl

  ethynyl, propynyl, benzyl, 4-methoxybenzyl, 4-nitrobenzyl, phenylethyl, trityl,

  diphenylmethyl, 3,4-dimethoxy benzyl.

  Mention may also be made of phenyl esters, 4-chloro

  phenyl, tolyl or tert-butylphenyl.

  The reaction of a product of formula V with llimidazole, morpholine or N-alkyl piperazine is carried out

  preferably in the presence of a hydrohalic acid sensor.

  For example, an organic base such as triethylamine can be used. It is also possible to use a mineral base such as carbonate or acidic carbonate of

  sodium or other alkali metal.

  One can also operate with a salt of a product of

  Formula V such as diethylamine salt.

  The reaction may also be conducted in the presence of a quaternary ammonium salt such as methyl tricaprylammonium chloride. The purpose of converting the products of formula IIIL into products of formula I "b is to eliminate the group R16 and, possibly, when the latter is a grouping

  ester eliminable, the group A ".

  The elimination of the R16 group is carried out by

for example, by hydrolysis.

  The hydrolysis can be acidic or basic or use

of hydrazine.

  It is preferable to use acid hydrolysis for

  eliminate the alkoxycarbonyl or cycloalkoxy groups

  optionally substituted carbonyls such as t-pentyloxy-

  carbonyl or t-butyloxycarbonyl, optionally substituted arylalkoxycarbonyl groups such as benzyloxycarbonyl, trityl, tert-butyl groups

or 4-methoxy benzyl.

  The acid which is preferably used may be selected from the group consisting of hydrochloric, benzenesulphonic or para-toluenesulphonic, formic or trifluoroacetic acids. However, other mineral or organic acids can be used. The hydrolyserbasique is preferably used for

  eliminate acyl groups such as trifluoroacetyl.

  The base which is preferably used is a mineral base such as an alkali metal hydroxide such as

soda or potash.

  It is also possible to use magnesia or barite or an alkali metal carbonate or acidic carbonate, such as

  the carbonates and carbonates of sodium or potassium.

  It is also possible to use sodium acetate or

  potassium. Other bases may however be used.

  Hydrolysis using hydrazine is preferably used.

  to eliminate groups such as phthaloyl.

  The group R16 can also be eliminated by the system

  zinc-acetic acid (for example, the trichlo-

  roéthy e). The benzhydryl, benzyloxycarbonyl groups are preferably removed by hydrogen in the presence of a catalyst. The chloroacetyl group is removed by the action of thiourea in neutral or acidic medium depending on the type of reaction

  described by MASAKI (JAcs, 20, 4508, 1968).

  Other means of deprotection can also be used

  of the amine known from the literature.

  The invention more particularly relates to the method described above, characterized in that it implements products in which R16 is selected from the group

  constituted by the trityl radicals, chloroacetyl, tert-

  pentyloxycarbonyl, tert-butyloxycarbonyl, benzyloxy-

carbonyl.

  The elimination of radical A "when it is different

  The hydrogen atom is produced under conditions similar to those previously described for the removal of R16. It is possible to use, inter alia, acid or basic hydrolysis. It is preferable to use acid hydrolysis for

  eliminate radicals such as alkyl, which may be substituted

  killed or optionally substituted aralkyl. An acid selected from the group consisting of hydrochloric, formic, trifluoroacetic or p-toluenesulphonic acid is preferably used. The other radical values A "are removed according to the processes

known to those skilled in the art.

  It is preferably carried out under moderate conditions, that is to say, at room temperature or by slightly heating. Naturally one can, when, for example, R16 and A "are removable groups belonging to different types, to act on the products III'L several agents

  considered in the previous enumerations.

  During the reactions described above, a fraction of the products obtained can be constituted by

ceph-2 nd.

  In this case, the product fraction 2 is converted into A3 products. We then operate according to a scheme

  known in the literature for products with a cephem nucleus.

  The scheme is as follows: the product containing part of A2 is oxidized to obtain the corresponding sulfoxide. A peracid such as metachloroperbenzoic acid is preferably used. The passage of sulfoxide

  A3 sulfoxide is in the presence of a hydro-

xylated or water.

  The reduction of the sulfoxide A3 is carried out in the presence

  an acid halide or phosphorus trichloride.

  This type of transition from A2 products to products 3 has been

  described for example by Kaiser et al. J.Org. M, 2430 (1970) -

  SPRY and Coll.J.Org. 40, 2411 (1975) or in patents

  American 3,705,897 or German 1,937,016.

  Salification of formula IIb products can be

  performed according to the usual methods.

  Salification can, for example, be obtained by action on these acids or on a solvate (for example the ethanolic solvate) or a hydrate of this acid, a mineral base such as sodium or potassium hydroxide,

13 2474034

  sodium hydrogen carbonate potassium, sodium carbonate or potassium carbonate. It is also possible to use the salts of mineral acids such as tri-sodium phosphate. We

  can also use organic acid salts.

  As organic acid salts, there may be mentioned for example the sodium salts of aliphatic carboxylic acids, linear or branched, saturated or unsaturated from 1 to 18 and from

  preferably from 2 to 10 carbon atoms. These aliphatic radicals

  ticks can be interrupted by one or more hetero-

  atoms such as oxygen or sulfur, or substituted by aryl radicals such as phenyl, thienyl, furyl, by one or more hydroxyl radicals or by one or more

  halogen atoms such as chlorine or bromine fluors, preferably

  chlorine, by one or more carboxylic radicals

  14 or lower alkoxycarbonyls, preferably methoxycarbonyl

  ethoxycarbonyl or propyloxycarbonyl, by one or

  several aryloxy radicals, preferably phenoxy.

  In addition, sufficiently soluble aromatic acids such as, for example, substituted benzoic acids, preferably

lower allkyles radicals.

  Examples of such organic acids that may be mentioned are formic acid, acetic acid, acrylic acid, butyric acid, adipic acid, isobutyric acid, ncaproic acid and isocaproic acid.

  chloropropionic and crotonic, phenylacetic, 2-thienyl

  acetic acid, 3-thienylacetic acid, 4-ethylphenylacetic acid, glutary

* the monoethyl ester of adipic acid, hexanoic, heptanoic, decanoic, oleic and stearic acids,

  palmitic, 3-hydroxypropionic, 3-methoxypropionic, 3-

  methylthiobutyric, 4-chlorobutyric, 4-phenylbutyric,

  3-phenoxybutyric, 4-ethylbenzoic, 1-propylbenzoic.

  Sodium salts, sodium 2-ethyl hexanoate or sodium acetate are preferably used as sodium salts.

sodium diethyl acetate.

  Salification may also be obtained by the action of an organic base such as triethylamine, diethylamine, trimethylamine, propylamine, N, N-dimethylethanolamine or tris (hydroxymethyl) amino methane. It can also be obtained by the action of arginine, lysine, methylamino, ethanol amine, pyridine, picoline, dicyclohexylamine, procane, histidine, N-methyl

1.42474034

  glucamine, morpholine and benzylamine.

  This salification is preferably carried out in a solvent or a mixture of solvents, such as water, ether

  ethyl, methanol, ethanol or acetone.

  The salts are obtained in amorphous or crystallized form

  depending on the reaction conditions used.

  The crystallized salts are preferably prepared by reacting the free acids with one of the acid salts.

  aliphatic carboxylic acids mentioned above, preferably

with sodium acetate.

  The optional esterification of the products of formula I'b is carried out under standard conditions. The reaction is carried out in general by reacting the acid of formula IIb with a derivative of formula Z-R20, in which Z represents a hydroxyl radical or a halogen atom such as fluorine, chlorine, bromine, iodine and R20 denotes the ester group to be introduced. ,

  grouping of which a nonlimiting list appears above.

  The present application for the second certificate of addition also relates to a process for the preparation of the products of formula Ilb as defined above, characterized in that a product of formula VIII is treated: -N Co02H VIII N O- Wherein R represents a protecting group of the amino radical, nt represents an integer of 1 to 4 and Hal represents a halogen atom by imidazole, morpholine or N-alkyl piperazine to obtain a product. of VItL formula: NHR16

S N VINL

  ## STR1 ## wherein Rb has the meaning indicated above

  product of formula VI'L in the form of carboxylic acid

  lique, or in the form of a functional derivative of this acid that is made to act on a product of formula IX:

H2N S

lx

NOT

02A "1

  in which A "represents a hydrogen atom or an easily removable ester group and R1 has the meaning indicated above to obtain a product of formula II'L that, according to the process described above, is converted into

  corresponding products of formula I'b.

  The action on the products of formula VIII of imidazole, morpholine or an N-alkyl piperazine is carried out under the same conditions when adding these products to the products of formula V. In a preferred mode of the process, the product of formula IX is treated with a functional derivative

  a product of formula VItL cited above.

  The derivative may be a functional derivative such as a halide, a symmetrical or mixed anhydride, an amide or

an activated ester.

  As an example of a mixed anhydride, there may be mentioned, for example, that formed with isobutyl chloroformate. As an example of activated ester, there may be mentioned the ester formed

  with 2,4-dinitrophenol or that formed with 1-hydroxy

  benzo / 1 / triazole. As an example of a halide, mention may be made

chloride or bromide.

  There may also be mentioned acid azide or acid amide.

  The anhydride can be formed in situ by carbon action.

  N, N'-disubstituted diimides, for example N, N-dicyclohexyl carbodiimide. The acylation reaction is preferably carried out in an organic solvent such as methylene chloride. However, other solvents such as

  tetrahydrofuran, chloroform or dimethylformamide.

16 - 2474034

  When using a product of formula VIIL comprising

  salification, one operates preferably in the

  dimethylformamide in the presence of pyridinium iodide.

  When using an acid halide or an anhydrid

  mixture is formed by action of isobutyl chloroformate, the reaction of the acylation is carried out preferably in the presence of a base such as sodium hydroxide, potassium hydroxide, carbonates and acidic carbonates of sodium and potassium, sodium acetate, triethylaminep pyridine, morpholine or

N-methyl morpholine.

  The reaction temperature is generally lower or

equal to the ambient temperature.

  The products of formula IIItL are converted into corresponding products of formula I'b in the

conditions described above.

  The invention more particularly relates to the method described above, characterized in that it implements products in which the R16 substituent is chosen

  in the group consisting of trityl radicals, chloro

  acetyl, tert-pentyloxycarbonyl, tert-butyloxycarbonyl, benzyloxycarbonyl. The products of the formula I described in this application for the second certificate of addition and the products of

  general formula Ilb possess a very good anti-

  biotic on gram (+) bacteria such as - staphylococcal

  streptococci and in particular staphylococci

  penicillin-resistant shells. Their effectiveness on gram (-) bacteria, especially on coliform bacteria,

  Klebsiella, Salmonella and Proteus are particularly

remarkable.

  These properties make these products suitable for use in

  as drugs in the treatment of conditions

  with susceptible germs and in particular in that of staphylococci

  cocci, such as staphylococcal septicemia, staphylococcal

  malignant phylococcal or cutaneous, pyoderma,

  septic or suppurative wounds, anthrax, phlegmons,

  staphylococcal, acute or post-influenza

  bronchopneumonia, pulmonary suppuration.

  These products can also be used as drugs in the treatment of collibacillosis and

17 2474034

  associated infections in Proteus, IClebsiella and Salmonella infections and other conditions

  caused by gram (-) bacteria.

  The subject of the present invention is therefore also, at

  The main products of formula I of the main patent described above, as well as their salts with mineral or organic acids, are of particular medicinal and especially antibiotic medicinal products.

pharmaceutically acceptable.

  The subject of the invention is therefore, as medicaments and in particular antibiotic medicaments: 3-acetoxymethyl 7 - [2- (2-aminothiazol-4-yl) -2- (2-pyridylethoxyimino) acetyl] acid; amino / ceph-3-thcarboxylic acid, salt isomer, in the form of an internal salt or in the form of a salt with inorganic or organic acids, - 3-acetoxymethyl-2-amino-2-amino thiazol-4-yl )

  2 - / (ethoxycarbonyloxy) imino / acetyl / amino / ceph-3-th 4-

  carboxylic acid, isomer sn, its salts with alkaline earth metals, magnesium, ammonium and organic amine bases and its esters with easily cleavable groups and its salts with acids

  inorganic or organic, pharmaceutically acceptable.

  The subject of the invention is also, as medicaments and in particular antibiotic medicaments, the products of formula I'b as defined above, as well as the salts with the pharmaceutically acceptable inorganic or organic acids of these products and in particular: 3-acetoxymethyl-7- [2- (2-amino-thiazol-4-yl) -2 - [(2-imidazol-1-yl-ethoxy) -imino] -acetyl] amino] ceph-3-th -4-carboxylic acid syn isomer and its salts with alkali metals, alkaline earth metals, magnesium, ammonium and aminated organic bases and its esters with easily cleavable groups, as well as its salts with mineral and organic acids, - 3-acetoxymethyl acid 7- 2-amino-thiazol-4-yl) 3e 2H-2- (4-methylpiperazin-1-yl) ethoxy-imino-acetyl-amino-ceph-3-th -carboxylic acid isomer and its salts with alkali metals, alkaline earth metals, magnesium, ammonium

  and the amino organic bases and its esters with the groups

  easily cleavable substances and its salts with inorganic and organic acids, - 3-acetoxymethyl-7- (2- (2-amino-thiazol-4-yl) -2- (1-morpholinylethoxy) imino / acetyl / amino acid) ceph-3-th 4-carboxylic acid, isomer and its salts with alkali metals, alkaline earth metals, magnesium, ammonium and organic amine bases and its esters with easily cleavable groups and its salts

  with mineral and organic acids.

  The invention extends to pharmaceutical compositions containing

  closing as active ingredient at least one of the drugs

defined above.

  These compositions may be administered orally, rectally, parenterally, intramuscularly or by

  local route for topical application to the skin and

  queuses. They can be solid or liquid and be in the pharmaceutical forms commonly used in human medicine, for example, tablets,

  simple or coated tablets, capsules, granules,

  sitatories, injectables, ointments, creams, gels; they are prepared according to the usual methods. The active ingredient (s) can be incorporated into excipients usually employed in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non aqueous vehicles. fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers,

conservatives.

  These compositions may also be in the form of a powder intended to be dissolved extemporaneously in

  a suitable vehicle, for example, sterile apyreous water

gene.

  The dose administered varies according to the condition treated.

  the subject, the route of administration and the product under consideration. It may be, for example, between 0.250 and 4 g per day, orally, in humans with the product described in Example 2 or between 0.500 g and 1 g three times a day, intramuscularly. . Io The products of formula I and their salts may also

19 2474034

  Be used as disinfectants for surgical instruments

gicaux. -

  The invention also relates, as products

  new industrial products and especially as

  intermediates necessary for the preparation of the products of formula Ilb as defined above, the products of formula IIItL: NHR16 S, N IIItL

- CONH I

NOT

/ I

  NRb Rb Co2A "in which R1, Rb, R16 and A" have the meaning indicated above as well as the products of formula VIIL:

NER 16

  Wherein Rb and R16 have the meaning indicated above. The products of formula V used starting from the process can be prepared as follows: A product of formula VI is treated: NHR16

S N

  / Co2H VI AV with 2-methoxypropene to obtain a product of formula:

SC N

\ - C02H

  Wherein it is acted, for example, in the form of a derivative of this acid such as symmetrical anhydride, on a product of formula IX

0 N / R1

  C02A "to obtain a product of formula: NHR16 CONH

CHA N X

  CH3 which is treated with an aqueous mineral acid such as dilute hydrochloric acid to obtain a product of formula:

CONH S

OH

ORR

- / 02A.

  that is treated with a product of formula: Hal- (CH2) nt, -Hal 9n t

21.2474034

  to obtain a product of formula V. The products of formula VIII may be prepared by the action of a product of formula:

  Hal- (CH2) nt-Hal on a product of formula VI.

  The following examples illustrate the invention without

however, limit it.

22 2474034

  EXAMPLE 1 Trifluoroacetate of 3-acetoxymethyl-7- [27 (2-amino-thiazol-4-yl) 2 - [(2-pyridylethoxy) imino] -acetyl] -amino] ceph-3-th -carboxylic acid isomer syn made of

internal salt of pyridinium).

  Stage A: 2- (2-Tritazlamino) thiazol-4-: 1-x 2: L2 ylldl.imoactuesoe sXn Assets form of salt

internal deyZridinium).

  5 g of 2 (2-iodo ethoxy) imino-2 (2-tritylamino-thiazol-4-yl) acetic acid, syn isomerized with dichloroethane is heated at 600 ° C. for 24 hours, or in pure form of 4.27 g in 30 cm 3. pyridine then left 56 hours at room temperature. The precipitate formed is filtered off, rinsed with pyridine

  then with ether, dried and obtains 1.66 g of product.

F = 2500C (decomposition)

NMR (CD3COCD3, D20 = 1-1)

  6.8 p.p.m H5 thiazole, 7.5 to 8 p.p.m. pyridyl proton, 4.58 to 5.08 p.p. m = N-O-CE2-CC 2 U.V. (EtOH-HCl N / 10) Max. 260nm E1 c 324 1 cm I.R. (nujol) C02o 1639 cm-1 C = C 1583 cm1 C = N 1523 cm1 Stage B: Iodide of 3 acetoxLZmethyl 7-Zh2-i2-trit lamino

  thiazol-4-yl) 2-: 2-zitrothethoxzyimino2acetylamino / ceph-3-

  4-carboxazlate benzhtdrylel isomer syn.

  540 mg of the product obtained above, 210 mg of pyridine hydroiodide, 420 mg of dicyclohexylcarbodiimide 350 mg of benzhydryl 7-amino-3-acetoxymethyl ceph-3-th -carboxylate and cm3 of anhydrous dimethylformamide are stirred for 20 minutes at ambient temperature. The precipitate of dicyclohexylurea formed is filtered off, rinsed with dimethylformamide and

  Pour the filtrate into 60 cm3 of ether. It forms an eraser.

  Stir 5 minutes at room temperature, decanted, removes the supernatant. The gum is taken up and triturated in 60 cm3 of ether. The precipitate formed is filtered off and 754 mg of crude product is obtained. It is purified by stirring for 20 minutes

  with 1.6 g of magnesium silicate in 7.5 cc of dichloromethane

  ethane. The insoluble material is drained, washed with 095 cm3 of

23 2474034

  dichloroethane and then evaporated to dryness the filtrate. We obtain

368 mg of the expected product.

  Stage C: trifluoroacetate of 3-acetoxymethyl acid 368 mg of the product obtained previously in 3 cm3 of pure trifluoroacetic acid. The insoluble material is rapidly filtered off and the filtrate is precipitated with 40 cm 3 of ether, stirred for 5 minutes, drained and rinsed with ether. The hygroscopic product is taken up in 0.35 cm 3 of methanol and precipitated with 4 cm 3 of ether. We

  drain, rinse with ether and obtain 140 mg of expected product.

P = 2050C (decomposition).

PM (DMS0)

  2.06 ppm OAc 6.86 ppm H5 thiazole 8.9-9.1 ppm H2 and H6 8.55 to 8.78 ppm 4 N 8.03 to 8.26 ppm H3 and E UV (EtOH, HCl N / 10) tax. 260 nm E 318 I.R. (nujol) -1 / lactam: 1777 cm OAc: 1740 cm -1 C02: 1633 cm -1 -1 C = NOR: 1037 cm

  2- (2-iodoethoxyimino) 2- (2-tritylamino) thiazol-4- acid

  yl) acetic isomer syn used from Example 1 was prepared in the following manner:

  a) 2- (2-bromoethoxyimino) acid ethyl ester 2-

  (2-Tritylamino thiazol-4-yl) acetic acid isomer sn.

  A mixture of 4.94 g of syn-isomeric 2-hydroxyimino-2- (2-tritylamino-4-thiazolyl) acetic acid hydrochloride under argon is introduced into the

  10 cm3 of dimethyl formamide and add, at room temperature,

  biante, in 3 minutes, 4.14 g of potassium carbonate. We

  Stir 20 minutes at 20 ° C. and add 8.65 cm3 of 1,2-dibromo

  ethane. Stirred 30 hours and poured into a medium comprising cm3 of distilled water and 20 cm3 of methylene chloride,

-2474034

  decanted, re-extracted with methylene chloride, washed with distilled water, reextracted dry organic solutions drained rinsed and distilled to dryness. The crude product is obtained which is chromatographed on silica eluting with benzene at 5% ether. A first fraction is collected which is recrystallized from methanol after dissolution at 50-600 ° C and spinning at 0 ° -5 ° C. and gives 1.16 g of creamy white product F = 117 ° C.

  A homogeneous fraction of 1.258 g is then obtained.

  b) 2- (2-iodoethoxyimino) 2- (2-tritylamino thiazol-4-yl)

ethyl acetate isomer sm.

  6 g of 2- (2-bromoethoxyimino) 2- (2-tritylamine) are introduced.

  ethyl thiazol-4-yl) acetate isomer is in 60 cm3 of methyl ethyl ketone and 21-4 g of sodium iodide. Reflux one hour and 10 minutes. We evaporate under pressure

  scaled down. Take up the residue with 120 cm3 of methyl chloride

  and wash it five times with 40 cc of water. Each wash is re-extracted with 2 cm3 of methylene chloride, the organic phase is dried and evaporated to dryness. The resin obtained is supplemented with ether. Dry pressurized

  reduced and obtains 6.22 g of product. F = 110 C.

  c) 2- (2-iodoethoxyimino) 2- (2-tritylamino) thiazolic acid

4-yl) acetic isomer syn.

  6.7 g of ethyl ester are introduced under an inert atmosphere.

  lique prepared in stage a) in 5.5 cm3 of dioxane and 44 cm3 of absolute ethanol. 5 cm 3 of a 2N solution of sodium hydroxide are then added dropwise. Absolute ethanol (7 cc) is added, the mixture is stirred overnight at room temperature and the sodium salt formed is filtered off. Rinsed twice with 3 cm3 of a 4-1 ethanol-dioxane mixture, then impasted with ether. The product obtained is treated in a separating funnel with 100 cm 3 of water and 100 cm 3 of chloroform. It is adjusted to pH 2 with normal hydrochloric acid. The organic phase is decanted, washed with a saturated solution of sodium chloride, dried and evaporated under reduced pressure. The

  resin obtained is dissolved at 40 ° C. in 35 cm3 of dichloromethane

  ethane, the crystallization is initiated, left at ambient temperature for 72 hours, the precipitate formed is filtered off, rinsed, dried and 5.4 g of white solvate product is obtained.

  with dichloroethane (ie 4.61 g of pure product) mp = 161 ° C.

24740

  UV SPECTRUM (Ethanol N / 10 hydrochloric acid) 278 nm E1 = 235 SPECTRUM RP2 (CDCl3): proton at 5 thiazole: 6.58 ppm Example 2: Trifluoroacetate of 3-acetoxymethyl acid 7 - // 2- (2) -aminothiazol-4-yl) 2 - [(2-imidazol-1-1-ethoxvimino]]

  acetyl / amino / ceDH-3-th 4-carboxylic isomer syn.

  Step A: 2- (2-Tritylamino-thiazol-4-yl) - acid

  imidazol-1-1-ethoxyimino-acetic acid syn-isomer in the form of inner salt of imidazolium1 3 g of 2- (2-tritylamino-thiazol-4-yl) -2- (2-iodoethoxy) imino are stirred at room temperature for 3 hours. ) acetic isomer syn, solvated with dichloroethane,

  either pure: 2.56 g, 4.2 g of imidazole and 10 cm3 of

  thylacétamrnide. We add another 10 cm3 of it and

  stirring is continued for 40 hours at room temperature.

  It is poured into 200 cm3 of isopropyl ether, stirred for 30 minutes,

  decant, remove the supernatant and resume tritu-

  gum thus obtained, with 200 cm3 of isopropyl ether.

  pyline, renew this treatment with 300 cm3 of ethyl ether. Stirred 30 minutes, filtered, rinsed with ether, taken up with 30 cm3 of acetone, stirred for one hour, filtered, rinsed with acetone and then with ether, dried and obtains 1.243 g

  of product. F = 2800C (decomposition).

  RN. DMSO 4.35 p.p.m. N-O-CH-C N = -oc2_c = 2-6.8 p.p.m H5 thiazole 7.82 p.p.m H- / | U.V. (EtOH, HCl N / 10) Max. 277 nm E: 259 I.R. (nujol) Co2? 1614 cm-1 -1 aromatic 1492 cm -1 heterocycle 1527 cm 1 Step B: 3-acetylth-1 - [2-yl] -tritramino-thiazol-4 -) 2gZ (1-imidazol-1-ylethoxy) imino / acetyl / amino ceph-3-em

4-carboqx.late benzh dryle.

  780 mg of the product obtained above, 315 mg of pyridine hydroiodide, 630 mg of dicyclohexylcarbodiimide, 600 mg of toluene are stirred vigorously in an ice-water bath.

  Benzyl benzyl 7-amino-3-acetoxymethyl ceph-3-th-4-carboxylate

  dryle and 6 cm3 of anhydrous dimethylformamide. Dicyclohexyl

  urea precipitates. The mixture is brought to ambient temperature and the stirring is continued for 20 minutes. The insoluble material is filtered off and rinsed with dimethylformamide. The filtrate is precipitated with 120 cm3 of ether. Stir 20 minutes, allow to settle, remove the supernatant, resume and triturate the gum obtained in cm3 of ether. It is stirred for 10 minutes at room temperature, filtered, rinsed with ether, dried and gives 1.3 g of product which is chromatographed on silica. Eluted with a mixture of ethyl acetate-ethanol and water (8-1-0.5) and gives 332 mg

the expected product.

RMI (CDcl3) 2 p.p.m OAc

6.75 p.p.m H5 thiazole syn.

  I.R. (CHCl1 lactam 1788 cm -1 ester and OAc 1759 cm -1 -1 heterocycles 1525 cm1

  Stage C: Trifluoroacetate of 3-acetoxymethyl 7-

  2-amino-thiazol-4-yl12 = 12-imidazol-1-2-ethoxy)

  Imino / Acetyla Minolceph-2-th 4-carboxylic acid Isomer Yr.

  Stirred for 3 minutes at room temperature 230 mg of

  product obtained previously and 2 cm3 of trifluoro-

  pure acetic. The resulting solution is poured into a mixture of isopropyl ether-ethyl ether (1-1), stirred for 20 minutes at room temperature, the precipitate formed is wrung out, rinsed with ethyl ether, taken up in 0.4 cm3 of methanol and precipitated again. with 4 cm3 of ethyl ether, stirred for 10 minutes at room temperature, drained, rinsed with ether, dried and obtained 140 mg of expected product. Mp = 205 ° C (decomposition).

RIN (DMISO)

  2.03 p.p.m OAc 6.8 p.p.m H5 thiazole syn 7.66 and 7.71 p.p.m H4 and H5 t imidazole 8.95 p.p.m H2 U.V. (EtOH, HCl N / 10) * 1

Max. 260 nm E1 = 271.

  Example 3: Acetate 3-acetoxymethyl 7- / 2- (2-amino thiazol-4-)

  Example 3: 3-Acetoxymethyl-2-amino-2-amino thiazol-4- acid

  X1) 2 - ((ethoxycarbonyloxy) imino / acetyl / amino / ceph-3-th

  The 4-carboxylic acid isomer is in the form of trifluoroacetate.

  Step A: 3-Acetylamethyl-2- (2-tritiamethyl-thiazol-4-yl) -2- (ethoxycarbonyloxy) imino / acetyl / amino / ceph-3-yl 4-carboxylic acid diethylamine salt syn isomer 1.67 g of 3-acetoxymethyl-7- (2- (2-tritylamino-thiazol-4-yl) -2-hydroxyiminoacetyl / amino / ceph-3-th -4-carboxylic acid isomer are dissolved under stirring under an inert atmosphere. syn in 25 cm3 of methylene chloride and 0.37 cm3

  pyridine. The solution is reftoidie in an ice bath.

  2.7 cc of chloroformate are added in five minutes.

  diethyl in molar solution in methylene chloride.

  After 10 minutes and still at 0 ° C + 5 ° C, 20 cm3 of water and 2.7 cm3 of N hydrochloric acid are added. The mixture is stirred and decanted. The organic phase is washed with water until neutral and dried. The solvent is distilled under pressure

  reduced and the residue is taken up in 10 cm3 of diethyl acetate.

  0.23 cm3 of diethylamine is added. The diethylamine salt precipitates by addition of 10 cm3 of isopropyl ether. The mixture is filtered off with suction, rinsed with isopropyl ether-ethyl acetate 1-1 and then with isopropyl ether. 1.60 g of product are obtained which is dissolved in 5 cm3 of methylene chloride and 10 cm3 of ethyl acetate. Concentrated under reduced pressure to have a final volume of; 6 cm3 and diluted with 5 cm3 of isopropyl ether. We drain, rinse

  as before and obtains 1.47 g of product.

RN (CDC13)

  2.03 p.p.m OAc 6.95 p.p.m H5 Thiazole 7.66 p.p.m Trityl 4.13 - 4.25 4.36 - 4.48 p.p.m CH2 C02Et I.R. (CHCl3) lactam 1781 cm1

OAc 1740 cm-

  -1 amide 1694 cm1 CO2 1634 cm1 Stage B: 3-AcetoXmethylZ1 = ZZ: t2aino thiazol41 = ZX)

  2-Zethoxcarbonyloxylimino / acetyl / amino / ceph-4-

  carboxylic isomer syvin in the form of trifluoroacetate.

  Stirred for 20 minutes at room temperature, 1.43 g

-28 -2474034

  of the product obtained above and 5.7 cm3I of trifluorinated

  roacétique. 57 cm 3 of isopropyl ether are added rapidly.

  pyline, stirred for another 15 minutes, drained and rinsed with isopropyl ether. 1.04 g of crude product is obtained which is dissolved in 4 cm3 of 1% water-acetone. 12 cm3 of ether are added to precipitate 0.69 g of the expected product. We

  recover 0.11 g of identical product in the mother liquors.

  Example 4: Sodium salt of 3-acetoxymethyl 7 - [(2-amino thiazol-4-yl) 2 - [(ethoxycarbonyloxy) imino] acetyl]

  amino / ceph-3-th 4-carboxy isomer syn.

  0.8 g of the product obtained above are dissolved in 4 cm 3 of a methanolic solution of 1M sodium acetate and 2 cm 3 of methanol. The solution is treated with activated charcoal and diluted with 20 cm3 of anhydrous ethanol and then concentrated to a final volume of 10 cm3 by distillation under reduced pressure at 30 C maximum. The precipitate obtained is filtered off, rinsed with ethanol then with ether and 420 mg of product is obtained. 580 mg of product prepared as above, are taken up with 8 cm 3 of methanol and 1.2 cm 3 of ethanol are added slowly and with stirring. The precipitate formed is filtered off and the filtrate is diluted with ethanol (10 cc) and then concentrated by distillation under

  reduced pressure to 300C maximum, to a final volume of 5 cm3.

  It is filtered off, rinsed with ether and gives 460 mg of product which is treated again as before to obtain 420 mg.

expected product.

  RMf (nMso) 1.13 - 1.25 - 1.36 ppm C and 4.03 - 4.16 - 4.28 - 4.4 ppm 2 1.98 ppm: OAc 7.03 pep.m: H5 from Thiazole UV (EtOH / HCl N / 10) Max. 259 nm E1 = 324 ú 17,350 Inflex.278 an E1 = 252 I.R. (nujol) lactam: 1763 cm1 OAc: 1726 cm-1 CO: 1609 cm-1

-1 2

  C = N-OR: 1038 cm EXAMPLE 5 3-Acetoxy-methyl-7- [2- (2-amino-thiazol-4-yl) -2 - [(2-morpholino-ethoxy) imino] -acetyl] -amino] -3-thiophosphonate isomeric carboxylic acid in the form of internal salt

* (Trifluoroacetate).

  Stage A: 2- (2-Tritylamino thiazol-4mo) -

  linoethoxy) imino acetic acid isomeric in the form of internal salt. 2 g of the 2- (2-tritylamino-thiazol-4-yl) 2- (2-iodoethoxy) iminoacetic acid, syn-isomer, are dissolved

  dichloroethane in pure 1.71 g in 7 cm3 of morpholine.

  The solution is stirred for one hour at room temperature and then concentrated under a nitrogen stream. It is taken up in 30 cm3 of ethyl acetate, stirred for twenty minutes at room temperature, filtered, rinsed with ethyl acetate. The product is stirred fifteen minutes in 15 cm3 of dimethoxypropane and then drained and rinsed with the same solvent. It is taken up in 15 cm3 of ether, stirred for 15 minutes, drained, rinsed with ether and obtains 2.3 g of product. F. 1800C (decomposition), used as it is

for the next stage.

  100 mg of product are purified by recrystallization from 0.5 cm 3 of ethanol and 46 mg of recrystallized product are obtained. F 182-184 ° C. (decomposition) I (CDCl 3) 7.33 ppm trityl 6.75 ppm H 5 thiazole syn UV (EtOH, N / 10) Max. 276 nm E = 172 I.R. (CHCl3) CO29 and aromatics 1606 - 1529 and 1495 cm-1 -NH 3399 cm-1 Stage B * 2-acetoxymethylthihydrate

  ethoxy-benzoimidazoic-3-thiobenzoyl benzoate

hXdrXle isomer syn.

  1 g of the product obtained above, 0.38 g of pyridine hydroiodide, 0.63 g of dicyclohexylcarbodiimide and 0.60 g of benzhydryl 3-acetoxymethyl-7-amino-ceph-3-th-4-carboxylate are dissolved in 5 cm 3 of anhydrous dimethylformamide. The solution is stirred for 30 minutes at room temperature. The dicyclohexylurea formed is filtered off and 100 cm3 of ether are added to the filtrate. Stirred ten minutes, filtered, rinsed with ether and chromatography on silica eluting with ethyl acetate-ethanol (7 -1). 0.524 g is obtained

  of product. F 167 C (decomposition).

  MIN (CDCl3) 2.03 p.p.m OAc 3.72 p.p.m CH 20

6.75 p.p.m H5 thiazole syn.

2474034

  u.v. (EtOH, N / 10 HCl) Max. 268 nm E: 165 to 15,900

I.R. (CHC13)

  L: lactam 1791 cm ester and OAc 1740 cm -1 amide 1678 cm 1 Step C: 3-acetoxazlethl Z-: L2-2-amino thiazol-4-yl

  2-ZZ2-mo2rEho2leinodtoxyliminoZecét1Z2Lnaino / Ceph-3-th 4-

  carboxIILIL1is.mè --.--. ----..............-

  carbox lique syn isomer as internal salt

ltrifluoroacétate).

  The mixture is stirred for two minutes at room temperature, 0.42 g of product obtained in Stage B and 3 cm3 of trifluoroacetic acid, the insoluble material is filtered off and rinsed with trifluoroacetic acid. The filtrate is collected in 30 cm3 of ether and stirred for 15 minutes at room temperature. The precipitate formed is filtered off and rinsed with ether. It is dissolved in 0.5 cm3 of methanol and reprecipitated with 5 cm3 of ether. Stir 5 minutes, wring

  and gets 208 mg of product. F 212-214eC (decomposition).

  salified mainly with trifluoroacetic acid.

RIN (DISO)

  2.05 p.p.m OAc 3.17 to 4.66 p.p.m CH2 N and CH20 6.85 p.p.m H5 thiazole syn

U.V. (EtOH N / 10 HCl) -

  Max. 260 nm E = 253 I.R. (CHCl 3) lactam 1797 cm -1 COC 1634 cm -1

C2 -1

amide 1667 cm

  Example 6: 3-Acetoxymethyl Acid 7 - / 2- (2-Aminothiazol-4-)

  yl) 2 - [(4-methyl-1-piperazin-1-yl) ethoxy] -imino-acetyl-amino-ceph-3-th -carboxylic isomer syn as internal salt (trifluoroacetate). Step A: 2-22-Tritoxlamino-4-thiazol-yl2-: 2-: 4- Methylpyrazine: 1Zl2ethox. inino / acetic isomer syn

  ____ ____ _________ _-__ _ __ _ _-___ __ _ __ _ __ _

in the form of internal salt.

  2.22 g of N-methylpiperazine in 15 cm.sup.3 of dioxane and 3.325 g of 2- (2-tert-aminothiazol-4-yl) -2- (2-iodoethoxy) iminoacetic acid, syn-isomersized, are stirred vigorously for 16 hours at room temperature. dichloroethane, either pure 2.84 g prepared as in Example 1. The N-methyl piperazine hydroiodide is formed filtered and the filtrate concentrated under reduced pressure to about 5 cm3 and then 200 cm3 of isopropyl ether and stirred for 30 minutes. The product is filtered off with suction and taken up with dimethoxypropane (10 cc), stirred for thirty minutes, filtered, taken up with water (24 cc), stirred for ten minutes and then drained. The insoluble material is stirred for two hours in 100 cm 3 of an isopropyl ether / ethyl ether mixture: 1-1. We squeeze and recrystallize in ethanol

  100. 1.47 g of product are obtained. F 2200C (decomposition).

  MIN (CDCl3) 2.52 p.p.m -NCH3 3.0 p.p.m CU2N

6.7 p.p.m H5 thiazole.

  U.V. (EtOn HCl N / 10) Max. 277 nm E = 257 -14,300 I.R. (nujol) C0- 1602 cm-1 -1 heterocycle 1529 cm absence of C02E

  Stage B: 3-acetoxxmethylthyl 7: LL 2: 12-tritoxlamino thiazol-4

  _______________________________________ _________________-yl) 2-Z2- (4-methylpiperazin-1-yl) ethoxy / imino / acetylzMamio /

  ceph-3-th 4-benzyl benzoyl isomer sZn.

  560 mg of the product obtained above and 140 mg of triethylamine hydrochloride in 5 cm3 of chloroform and 5 cm3 of methanol are heated to 601 for ten minutes. The solvents are evaporated under reduced pressure. The residue is taken up by

  cm3 of methylene chloride and then cooled to -20 C.

  10 cm 3 of chloromethyl alcohol solution are added over 10 minutes.

  12.5% of pivaloyl chloride and stirred for one hour at room temperature. The solution is cooled to -10 ° C. and 350 mg of benzhydryl 7-amino-3-acetoxy methyl ceph-3-e-4-carboxylate are added in one go. Stirred three hours and then concentrated to dryness under reduced pressure at 30 C at most. The residue is taken up in 50 ml of a benzene-ethyl acetate mixture (8-2). The insoluble material is removed and the solution evaporated to dryness under reduced pressure. The residue is taken up in 25 cm3 of dichloroethane.

  1.5 g of activated magnesium silicate and stirred for 30 minutes.

  We drain, rinse with dichloroethane, evaporate the filtrate

32 2474034

  under reduced pressure at 30 C maximum and obtains 870 mg

of white resin.

MR. (Cdc13)

  2102 - 2.03 p.p.m OAc 6.87 - p.p.m H5 Thiazole 2.45 p.p.m N-CH3 U.V. (EtOH HCl N / 10) Max. 267-268 nm ú 14.700

  Stage C: 3-acetoxymethyl-2-I = L2: 2-aminothiazol-4XI 2Z-

  (4-methyl-1-ethylhexyl-1-ethyloxo)

  4-carboxylic isomer Sy = in the form of internal salt trifluoro-

  __S_ ___ __ -___ ___--- - - - - - - ------------

  Its yield 524 mg of the product obtained above, in 3 cm3 of pure trifluoroacetic acid and stirred the solution for one minute at room temperature. Is precipitated with 30 cm3 of isopropyl ether and stirred for another 5 minutes, filtered and obtained 320 mg of a hygroscopic product which is dissolved in 1 cm3 of methanol and precipitated with 10 cm3 of ethyl ether, stirred for 5 minutes, filtered, rinsed with water. ethyl ether, chloroform and then ether, and obtains

  220 mg of salified product (trifluoroacetate) F. 2450C.

  NMR (DMSo) 2.03 p.p.m OAc 2.75 to 3.67 p.p.m CH2N 6.78 p.p.m H5 thiazole u.V. (EtOH, N / 10 HCl) Max. 262 nm E14.200 IR (nujol) -1 lactam 1773 cm OAc 1726 cm -1 Co 2 1627 cm-1 -1 C = NOR 1035 cm Excomplete: Bis trifluoroacetate acid-acetoxnuth-I-2-t [- nmllxt thima:, - $ - v3l) 2- (2-Amino-10-oxymeric) acetamido / ceph-3-th 4-carboxylic syn isomer

  Stage A: 2- (2-Tritylaminoethyloxino) 2- 2-tritzl-

  amino thiazol-4-ilXacetic isomer sn.

  A mixture of 75 g of tritylamine is placed under argon,

  2- (2-bromoethoxyimino) 2- (2-tritylamino thiazol-4-)

  yl) ethyl acetate and 100 cm3 of dimethyl sulfoxide.

  The suspension is stirred for 82 hours at 600C. We bring back

33 2474034

  then at room temperature and precipitated with 10 volumes of water. We drain, wash with water. The precipitate obtained is dissolved in one liter of chloroform, washed with water and then with a saturated solution of sodium chloride. Dry, evaporate under reduced pressure at a temperature below 400C. The raw product is taken up by a mixture of 320 cm3

  dioxane, 2 liters of absolute ethanol and 200 cm3 of 2N sodium hydroxide.

  The mixture is stirred for 24 hours at room temperature and then evaporated to dryness under reduced pressure at a lower temperature or

equal to 400C.

  This product is impasted by 5 times 60 cm3 of a dioxane

  ethanol (1-7). We take the product by a mixture of one

  liter of chloroform and one liter of water.

  A sufficient amount of normal hydrochloric acid is added with stirring to obtain pH 2. The organic phase is decanted, washed with water and then with a saturated solution of sodium chloride. Dry and evaporated to dryness under reduced pressure at a temperature below 40 C. The product obtained is suspended in 300 cm3 of dichloroethane and heated for 15 minutes at 50 C. After cooling to room temperature under reduced vacuum. It is rinsed with dichloroethane and then with isopropyl ether and then with ethyl ether. We dry to

  constant weight and gets 40 g of powder. F = 1760C.

  Nm (CDCl 3) 6.68 ppm proton at 5 thiazole 2.95 ppm CL, -N Step B: 2- (2-tritoxlamino ethoxydimino) 2- (2-tritylamino thiazole = 4 = hydroxy acetate benzotriazole 6.97 g of acid obtained in stage A and 1.54 g

  of benzotriazole hydroxy in 35 cm3 of methylene chloride.

  It is stirred in an ice bath and a solution of 2.44 g of dicyclohexylcarbodiimide in

cm3 of methylene chloride.

  Allowed to warm to room temperature and stirred for three hours thirty. The dicyclohexylurea formed is filtered off and rinsed with methylene chloride. The filtrate is washed with sodium bicarbonate and then with water and then with a saturated solution of sodium chloride. Dry and evaporate to dryness under reduced pressure. The resin obtonue is taken up by t, I 1 ', i t. The mixture is heated at room temperature for one hour at room temperature. The precipitate obtained is filtered off, rinsed with isopropyl ether and dried to constant weight. 8,046 g of product are obtained. F 150-152 C (decomposition).

RI4N (CDC13)

  6.68 ppm: proton at 5 thiazole 2.36 ppm: -CH 2 -N Step C: 3-acetoxymethyl-7-LZ 2 -tetrazlamino ethoxy-imino-2- (1-Eitlamino thiazol-4-yl): cetamido / ceph-3 11.55 g of activated ester product prepared in Stage B and the equivalent of 7.65 g of 7-amino cephalosporanic acid diphenyl methyl ester in 75 cm3 are introduced 11.55 g of activated diphenyl methyl 4-carboxylate isomer of methylene chloride is stirred for 18 hours at room temperature, evaporated under reduced pressure and chromatography

  on silica and under pressure eluting with a benzene mixture

  ethyl acetate (85-15). 9.1 g of expected product are obtained.

  Stage D: Bis trifluoroacetate of 3-acetoxymethyl 7-Z: L 2 -: -. Ino thiazol-4-z12 2- (2-aminoethoxyimino) acetamido

  ceph-3-th 4-carboxylic syn isomer

  186 mg of 3-acetoxymethyl 7- (2-trityl)

  amino thiazol-4-yl) diphenylmethyl 2- (2-tritylamino ethoxyimino) acetamido ceph-3-th 4-carboxylate prepared in Step C in 1.8 cm3 of pure trifluoroacetic acid. The yellow solution obtained is stirred for 3 minutes at room temperature and then under an inert atmosphere in an ice-water bath and 18 cm3 of isopropyl ether are added rapidly. It is stirred for 10 minutes, drained, rinsed with isopropyl ether and then with ethyl ether, dried and gives 100 mg of a powder

  white. F = about 210C (decomposition).

  EXAMPLE 8 Injection preparations of formulas were prepared: A. 3-Acetoxymethyl-7- [2- (2-amino-thiazol-4-yl) -2 - [(2-imidazol-1-yl-ethoxy) imino] acid acetyl / amino / ceph-3-th 4-carboxylic isomer syn ........... .0 ........ 500 mg

  - Sterile aqueous excipient q.s.p ............. ea 5 cm3.

  B. - Sodium salt of 3-acetoxymethyl 7- / 2- acid

  (2-Amino thiazol-4-yl) 2 - [(ethoxycarbonyloxy) imino] acetyl] amino] ceph-3-yl 4-carboxylic acid isomer ...... 500 mg

  - Sterile aqueous excipient q.s.p .............. 5 cm3.

  EXAMPLE 9 Gelulos of the Formula were Made

  Sodium salt of 3-acetoxymethyl 7- / 2- (2-

  amino thiazol-4-yl) 2 - ((ethoxycarbonyloxy) imino / acetyl / amino / ceph-3-th -4-carboxylic acid isomer syn ... 250 mg

  Excipient q.s. one capsule completed at .............. l * 400 mg.

  PHARMACOLOGICAL STUDY OF THE PRODUCTS OF THE INVENTION

  In vitro activity. dilution method in a liquid medium. A series of tubes are prepared in which the same amount of sterile nutrient medium is distributed. We distribute

  in each tube increasing quantities of the product under study.

  then each tube is inoculated with a bacterial strain

  born. After incubation for twenty-four or forty-eight hours in the oven at 37 ° C., inhibition of growth is assessed by transillumination, which makes it possible to determine the minimum inhibitory concentrations (C.M.I.) expressed in g / cm.sup.3. The following results have been obtended:

LTEXEMPLE PRODUCT 1

tSOUCHES C.M.I. in pg / ml

: --------______-_-____

: 24 H: 48 H

  Staphylococcus aureus ATCO 6,538: Pen-Sensitive .....................,: 5: 5 t 'Staphylococcus aureus UC 1 128 :: Pen-Resistant ... ........... At 10: 10 Staphylococcus aureus exp.n = 54 146: 5: 5

t_s ...........

  Streptococcus pyogenic A 561 ......:, 02 0.02 Streptococcus faecalis 5 432 ..

  ..: 20> 40 Bacillus subtilis ATCC 6,633 ......: 1: 2 t. Sensitive Escherichia coli: DTD: Tetracycline ATCC 9,637 ...........

  t i 0:17 <O0: '' soeuoXo snDzoo: ode.Ias to o500o 'o * --L95 s eu2oL sooo &. da.z ú: z: 9itL t0u * dxe snane snoooooT [d S :: 98ZL L a, sneina snDooooTldS ::. ú- - z ------------- * - @ lFséSUa :: sú5 9 DorV snaezr suoooTXdS Z / 2 / uA '' W: L: LCEouCoXaeueO% = estseH TaexxS t '8: H.n. 8: osapoto -cil -s / pu * I *: a _Oiiiim ;. -i) tUW z zQ. to Iau Ot [: aO: '*' '' eozoTo Ieo, qozeuO (: L: - (- TOPUT): * TTq.e.m sne: .Oa :: eo na Tese 'I: I:' LZ 'dxS eo; uomneud vTToTSqBIX Z 40: * 1 'C- -H - u-oXUoe. xqo'eu; Tore% o

(=

  * U! IIm o. Bacillus subtilis ATCC 6,633 .....: 2 Escherichia coli Sensitive Tetracycline ATCC 9,637 .........: 1: 1

* =

  Escherichia Coli Resistant :: Tetracycline ATCC 11 303 ........: 0.05: 0.05 = Escherichia Coli Exp.T026B6 .....: 0.2 0.2 = Escherichia Coli Resistant: Gentamycin, Tobramycin R 55 123D .: 0.2 0.2 Klebsiella pneumoniae Exp. 52 145 * 0.2 * 0.2 :: Klebsiella pneumoniae 2 536 :: Resistant Gentamycineo ... o ......... o: 1: 1 Proteus mirabilis (indol-) A 235 .. 0, 1 0, 1 Salmonella typhimurium 420. * eo1..oo = Enterobacter cloacae 681 .......... .s 20: 20 Providencia Of 48 ............... .. 10 Serratia Resistant Gentamycin

  2,532 ............................. 1

38 2474034

  PRODUCT OF EXAMPLE 4: Malo in H / ml

STEPS: - --- e--

: 24 H: 48 H

  t> Staphylococcus aureus ATCC 6,538: Pen-Sensitive ......... ........: I: 1 - * Staphylococcus aureus UC I 128: Pen-Resistant ..... oo. ........: I TO 1

= J

  Staphylococcus aureus exp.n 54146: 1: 1 Streptococcus pyogenic A 561 .....: 0.05: 0.05

AT. T, '' =

  Streptococcus faecalis 5,432 .....: 5 Bacillus subtilis ATCC 6,633, ....: 2: 2 Escherichia coli Sensitive: Tetracycline ATCC 9,637 ..........: 0.5 1 Escherichia Coli Resistant Tetracycline ATCC 11 303 ........: 0.05: 0.05 Escherichia Coli Exp. T026B6 .... 0.2 0.2 Escherichia Coli Genta Resistant: Mycine, Tobramycin R 55 123 D .... 0.2 0.2 Klebsiella pneumoniae Exp. 52 145 .: 0.05 0.05 _ * Ilebsiella pneumoniae 2536 :: Resistant Gentamycin ............: 0.5: 0.5 Proteus mirabilis (indol-) A 235 .. : 0, 05: 0.05 Salmonella typhimurium 420 ....... 0.2 0.2 Enterobacter cloacae 681. ,,, ..... 15 20 ProvidenciaDu 48 .......... ......: 5 5 Serratia Resistant Gentamycin ::

2,532 ................... 2: 2

39 2474034

LIEXEMPLE PRODUCT 5

C.M.I. in ml

STEM: 24 H: 48 H

  Staphylococcus aureus ATCC 6,538 Pen-Sensitive ... e ...... e .......... 5: 5 * Staphylococcus aureus UC 1 128 :: Pen-Resistant ... e,., ..... eee .: 5: 10 Staphylococcus aureus exp.n 54 146 .: 5: 5 Streptococcus pyogenic A 56t ...

  ...: 0.05: 0.05 = Bacillus subtilis ATCC 6 633 * ........: 1: 2 Escherichia Coli Sensitive Tetra- :: cyclin ATCC 9,637 ......... .........: 3: 3 Escherichia Coli Resistant Tetracycline ATCC 11 303 ..........: 0.2: 0.5 Escherichia Coli Exp. T026B6 1 2.DTD: Escherichia Coli Resistant Gentle

  mycine, Tobramycin R 55 123 D., ...: 2: 3 Klebsiella pneumoniae Exp. 52 145 .. 0.5: 1 Klebsiella pneumoniae 2,536: Resistant Gentamycin ... e ... ***,

  : 10: 10 Proteus mirabilis (indol-) A 235 ...: I: 1 Salmonella typhimurium 420., ........: 1: 2 Providencia Of 48 ........... .......: 40: 40 Serratia Resistant Gentamnycine 2,532 .: 2: 2 4o 2474034..DTD:

Claims (7)

REVENDI CATIONS   1) Products related to the general formula I of the main patent, of the general formula I'b: k ^ N I'b COOA N   syn isomer, wherein Rb represents a radical - (CH2) n, -   R 5b wherein n 'is an integer of 1 to 4 and R 5b is a - / R6b -N R7b radical in which R6b and R7b together with the nitrogen atom to which they are attached form an imidazolyl radical, morpholinyl or N-alkyl piperazinyl, the alkyl radical having from 1 to 4 carbon atoms, R1 represents: either a chloro or methoxy radical or else an alkyl, cycloalkyl or alkylthio radical having at most 5 carbon atoms, or else a radical; -CH2-S-R12 wherein R12 represents a nitrogen-containing heterocyclic radical, an acyl radical having 2 to 4 carbon atoms, a 2-oxo (3H) thiazolin-4-yl carbonyl or 3-methyl-1 radical, 2-oxazol-5-yl carbonyl, or an acetoxymethyl or carbamoyloxymethyl radical, or a radical -NH-C-Alka in which Alka has II aa o of 1 to 4 carbon atoms, A represents: a hydrogen atom or an equivalent of alkali metal, alkaline earth metal, magnesium, ammonium or   aminated organic base or A represents an ester group easily   as well as the salts of the products of formula I'b   with mineral or organic acids.   2) 3-Acetoxymethyl 7 - [2- (2-amino thiazol-4-yl) 2 -] - (2-   imidazol-1-yl ethoxy.v) imino / acetyl / amino / ceph-3-th 4-carboxy-   isomer svn and its salts with alkali metals, alkali   no-earth, magnesium, ammonium and organic amine bases and its esters with easily cleavable groups,   as well as its salts with mineral and organic acids.   3) Acetoxymethyl 7 - [2- (2-amino thiazol-4-yl) 2 -] -2-   (4-methylpiperazin-1-yl) ethoylmino / acetyl / amino / ceph-3-   syn-4-carboxy isomer and its salts with alkali metals, alkaline earth metals, magnesium, ammonium and aminated organic bases and its esters with groups   cleavable salts and its salts with organic.   4) 3-Acetoxymethyl 7- [2- (2-amino thiazol-4-yl) 2 -] - (1-   morpholinylethoxy) imino / acetyl / amino / ceph-3-th 4-carboxylic acid   syn isomer and its salts with alkali metals, alkaline   earth, magnesium, ammonium and organic bases   and its esters with easily cleavable groups   as well as its salts with mineral and organic acids.   Process for the preparation of the products of the formula I'b as defined in claim 1, characterized in that a product of the formula V is treated: SN s <zCo HS V NZ \ o I NH) ,, - Hal CD Wherein R16 represents a protecting group of   amino radical, A "represents a hydrogen atom or a group of   easily halogenated ester, Hal represents a halogen atom and n 'and R' have the meaning indicated in   claim 1 with imidazole, morpholine or N-   alkyl piperazine to obtain a product of formula: ## STR5 ##   in which Rb has the meaning indicated in the claim   The product is treated with one or more agents selected from the hydrolysis, hydrogenolysis and thiourea agents to produce a product of the formula ## STR1 ## wherein R 1 and Rb are previous meaning and corresponding to a product of formula I'b wherein A represents a hydrogen atom, product of formula I "b that   salified or esterified if desired according to the usual methods   the. 6) Process for preparing the products of formula I'b as defined in claim 1, characterized in that a product of formula VIII: R is treated 4 * ....   in which R 16 represents a protecting group of the   amino radical, n 'represents an integer of 1 to 4 and Hal represents   a halogen atom with imidazole, morpholine or N-alkyl piperazine to give a product of formula VI'L: S 1 \ 5VI 'L KC2H NE O N Rb   in which Rb has the meaning indicated in the claim   1, product of formula VI'L is in the form of carboxylic acid, or in the form of a functional derivative of this acid, which is made to act on a product of formula IX: H2N Ix O R | 1 CO A "   in which A "represents a hydrogen atom or a group   easily removable ester and R1 has the meaning   indicated in claim 1 to obtain a product of   muleII'L that, according to the method described in claim 5,   they are converted into corresponding products of formula I'b.   Method according to the preceding claims 5 or 6,   in which products are used in which   the substituent R16 is selected from the group consisting of   trityl, chloroacetyl, test-pentyloxycarbonyl, test-   butyloxycarbonyl and benzyloxycarbonyl.   (8) As medicinal products, the products as defined in   l. claim 1, pharmaceutically acceptable.   9) As medicaments, the products of general formula I'b   as defined in any one of claims 2, 3 and 4 pharmaceutically acceptable.   ) Pharmaceutical compositions containing, as a principle   active ingredient, at least one drug according to one of claims 8   and 9. 11-) As new industrial products necessary for the preparation of the products of formula I'b as defined in   the claims, the products of formula III'L: C 2> CO C0 III 'L   Rb 0A in which R1, Rb, R16 and A "have the indicated meaning in claim 5.   (12) As new industrial products necessary for the preparation of products of formula I'b as defined in   claim 1, the products of formula VI'L:   In which Rb and R16 have the meaning indicated in claim 6.