BE890499A - NOVEL CEPHALOSPORINS, THEIR PREPARATION PROCESS AND THEIR THERAPEUTIC APPLICATION - Google Patents

Description

       

    <EMI ID = 1.1>

  
and a chairman of the making of these. intermediate products.

  
The authors of the present invention have sought to discover

  
  <EMI ID = 2.1>

  
  <EMI ID = 3.1>

  
stable to the action of ase-lactase ’produced by bacteria, not very toxic, administered both orally and parenterally and giving excellent results in human therapy

  
  <EMI ID = 4.1>

  
or tetrazolyl is attached to the exomethylene group in position 3 of the cephem ring, said aromatic heterocycle group being

  
  <EMI ID = 5.1>

  
or tetrazolyl being attached by a carbon-nitrogen bond, and that a group of the following formula is attached to the amino group in position 7:

  

  <EMI ID = 6.1>


  
  <EMI ID = 7.1>

  
The subject of the present invention is new cephalosporins having this structure, endowed with bactericidal properties,

  
  <EMI ID = 8.1>

  
toxic and well tolerated during oral or parenteral administration and giving excellent results in human and animal therapy.

  
Another object of the invention is to provide a process for the manufacture of these new cephalosporins, as well as intermediate products used for this manufacture and a process for the manufacture of these intermediates.

  
Other objects and advantages relating to the invention will become apparent in the light of the description which follows.

  
The new cephalosporins in accordance with the invention are represented by the compounds and their salts corresponding to the following formula (I):

  

  <EMI ID = 9.1>


  
  <EMI ID = 10.1>

  
  <EMI ID = 11.1>

  
can be protected or substituted; A represents a group according to the formula <EMI ID = 12.1>
  <EMI ID = 13.1>
 the formula:

  
  <EMI ID = 14.1>

  
and the like; the term "alkoxy" denotes -0- alkyl in which the alkyl group has the above meanings; the term "lower alkyl" <1> means

  
  <EMI ID = 15.1>

  
  <EMI ID = 16.1>

  
means -0- lower alkyl, the alkyl group of which is as defined above. above ; the term acyl includes

  
  <EMI ID = 17.1> <EMI ID = 18.1>

  
logues; the term cycloalkadiènyle includes cycloalkadiènyles en

  
  <EMI ID = 19.1>

  
the term "aryl" means, for example, phenyl, naphthyl, indanyl and the like; the term "aralkyl" includes ar-lower alkyls, for example benzyl, phenethyl, 4-methylbenzyl, naphthylmethyl and the like; the term "heterocyclic group" includes groups having at least one heteroatom selected from the group consisting of oxygen, nitrogen and sulfur, for example

  
example furyle, thienyle, pyrrolyle, pyrazolyle, imidazolylejbhia-

  
  <EMI ID = 20.1>

  
denotes a group containing a heterocycle group as defined above

  
  <EMI ID = 21.1>

  
gene "includes the fluorine, chlorine, bromine and iodine atoms.

  
  <EMI ID = 22.1>

  
In the formulas shown above, R is a hydrogen atom or a carboxyl protecting group. The latter groups, which are commonly used in the fields of penicillin and cephalosporin, are available and include ester groups, which can be removed by catalytic reduction, chemical reduction or other treatments under moderate conditions, groups forming esters, which can be easily removed by living organisms and other ester-forming groups which can be removed by treatment with water or alcohol, such as organic groups containing silicon, phosphorus, tin or the like.

  
Typical examples of protecting carboxyl groups are:
(a) alkyl groups
(b) substituted lower alkyl groups, at least one of the substituents being halogen, nitro, carboalkoxy, acyl, alkoxy, oxo, cya- <EMI ID = 23.1>

  
tidino, aziridino, pyrrolidino, pipéridino, norpholino, thiomorpho- <EMI ID = 24.1>

  
amino, dialkylamino, acyloxy, acylamino, acylthio, dialkylaminocar- -, bonyle,. alkoxycarbonylamino, alkenyloxy, aryloxy, aralkyloxy,. ali-

  
  <EMI ID = 25.1>

  
cyclo-oxycarbonyloxy, alkenyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, alicyclo-oxycarbonyl, heterocyclo-oxycarbonyl, alkylanilino

  
and halogen, lower alkyl or lower alkoxy substituted alkylanilino.

  
  <EMI ID = 26.1>
(d) alkenyl groups
(e) alkynyl groups
(f) phenyl or substituted phenyl groups, at least one of the substituents being chosen from the group illustrated in (b), or an aryla group corresponding to the formula:

  

  <EMI ID = 27.1>


  
  <EMI ID = 28.1> their substituted derivatives, the substituents being chosen from those set out under (b), or corresponding to the formula:

  

  <EMI ID = 29.1>


  
in which Y is a lower alkylene group, such as - (CE 2) 3

  
  <EMI ID = 30.1>

  
chosen from those listed under (b).

  
  <EMI ID = 31.1>

  
substituting at least is chosen from the group stated in (b)

  
(h) heterocyclic groups, optionally substituted, at least one of the substituents being chosen from those listed in (b)

  
  <EMI ID = 32.1>

  
titrated, the substituent being halogen or methyl; alicyclic tetrahydronaphthyl groups or their substituted derivatives, the substituent being halogen or methyl; trityl, cholesteryl or bicy-

  
  <EMI ID = 33.1>

  
  <EMI ID = 34.1>

  
substituted derivatives, the substituent being halogen or lower alkoxy.

  
The carboxyl protecting groups listed above are cited as examples, but any other group may be used from those cited in U.S. Patents 3,499,909. 3,573,296 and

  
  <EMI ID = 35.1>

  
and 2,337,105.

  
Among them we will preferably choose those who are easily eliminated

  
  <EMI ID = 36.1>

  
1,3-dioxol-4-yl., Acyloxyalkyl, acylthioalkyl, phthalidyl, indanyl, phenyl groups, substituted or unsubstituted groups

  
  <EMI ID = 37.1>

  
formulas:

  

  <EMI ID = 38.1>


  
  <EMI ID = 39.1>

  
  <EMI ID = 40.1>

  
  <EMI ID = 41.1>

  
alkyl group, R8 represents a hydrogen or halogen atom or a substituted alkyl, cycloalkyl, aryl or heterocyclic group

  
  <EMI ID = 42.1>

  
n being 0, 1 or 2 and m being 0, 1 or 2.

  
These carboxyl protecting groups include in particular the

  
  <EMI ID = 43.1>

  
  <EMI ID = 44.1>

  
nylalkyl such as methoxycarbonylmethyl, ethoxycarbonylmethyl

  
and the like; phthalidyl, indanyl, phenyl and groups.

  
  <EMI ID = 45.1>

  
carbon and said triazolyl or tetrazolyl group being attached to the 3-exomethylene group by a carbon-nitrogen bond. The group

  
  <EMI ID = 46.1>

  
is for example an alkyl, alkenyl, alkadienyl, cycloalkyl, cycloalkenyl, cycloalkadienyl, aryl, aralkyl, heterocyclic or heterocycloalkyl group. The aromatic heterocyclic group includes, for example, furyl, thienyl, pyridyl, benzofuryl, benzothienyl,

  
  <EMI ID = 47.1>

  
Since these triazolyl and tetrazolyl groups have isomers, any nitrogen atom present in the ring can be attached to 3-exomethylene. The present invention includes all of them. Special examples

  
  <EMI ID = 48.1>

  
In addition, the aryl, acylamino, aromatic heterocycles, triazolyl and tetrazolyl groups represented by may be substituted by. at least one substituent such as halogen, alkyl, aral-

  
  <EMI ID = 49.1> <EMI ID = 50.1>

  
usually one can use for. protect the hydroxyl group,

  
  <EMI ID = 51.1>

  
all the groups known for this use *, in particular the easily eliminated acyl groups such as trichloroethoxycarbonyl,

  
  <EMI ID = 52.1>

  
carbonyl, phthaloyl, succinyl, 1-adamantyloxycarbonyl, 8-quinolyloxycarbonyl, and the like, as well as groups which are eliminated

  
  <EMI ID = 53.1>

  
alkylsilyles and the like. As group protection group <EMI ID = 54.1> usually in the areas of penicillin and

  
  <EMI ID = 55.1>

  
killed by one or more substituents. These protecting groups and these substituents can in addition be substituted by one or more substituents such as halogen, alkyl, nitro, hydroxyl,

  
  <EMI ID = 56.1>

  
cyclic such as furyl, thienyl or others. The hydroxyl, amino..and carboxyl groups used as substituents can be additionally protected by a usual suitable group comprising, for example, protective groups for hydroxyl, amino and carboxyl groups.

  
  <EMI ID = 57.1>

  
  <EMI ID = 58.1>

  

  <EMI ID = 59.1>


  
  <EMI ID = 60.1>

  
  <EMI ID = 61.1>

  

  <EMI ID = 62.1>


  
also includes its syn and anti isomers, as well as their "praise.

  
  <EMI ID = 63.1>

  

  <EMI ID = 64.1>


  
  <EMI ID = 65.1>

  
also included in the invention:

  

  <EMI ID = 66.1>


  
  <EMI ID = 67.1>

  
represents an imino group which can be protected or substituted. As

  
  <EMI ID = 68.1>

  
protection group for the imino group represented by R can be used groups usually used in the fields. penicillin and cephalosporin, comprising in particular the same groups as the monovalent groups among the

  
  <EMI ID = 69.1>

  
As a substituent for said imino group, the

  
  <EMI ID = 70.1>

  
Among the salts of the compound represented by the: formula (I), mention may be made of the basic or acid salts known in the field of penicillin and cephalosporin, comprising in particular

  
  <EMI ID = 71.1>

  
  <EMI ID = 72.1>

  

  <EMI ID = 73.1>


  
  <EMI ID = 74.1>

  
both on the standard compounds according to the invention.

  
(1) Bactericidal activity.

  
  <EMI ID = 75.1>

  
  <EMI ID = 76.1>

  
visually undermined the growth of bacteria. the minimum concentration, at which growth was inhibited, is taken as

  
  <EMI ID = 77.1>

  
cells per tray (10 6 cells / ml) -

  
Compounds used for the test: <EMI ID = 78.1>

  
  <EMI ID = 79.1>

  
acidic.

  
Compounds (A) and (L) designated by the asterisk were prepared according to Example 21, etc., the position of the 1,2,4-triazole bond is not specified, because this group has been attached to the exomethylene group in position 3 of the cephem ring by a carbon-nitrogen bond, but it has not been detected which of the nitrogen atoms has been attached

  
to the exomethylene group in position 3 of the cephem cycle. In addition, the position of the substituent on the group 1, 2,4-triazolyl is specified by reference to the position of the substituent in the starting compound used. This also applies when it has not been confirmed which of the nitrogen atoms in 1,2,4-triazole is attached to the exomethylene group in position 3 of the cephem ring. For example,

  
  <EMI ID = 80.1>

  
similar to that set out above.

  

  <EMI ID = 81.1>


  

  <EMI ID = 82.1>
 

  

  <EMI ID = 83.1>


  

  <EMI ID = 84.1>
 

  
  <EMI ID = 85.1>

  
the corresponding free carboxylic acids. These free acids were dosed after their recovery from the urine.

  
Administration mode:

  
  <EMI ID = 86.1>

  
the bacteria tested listed in Table 2.

  
(3) Acute toxicity test

  
Three test compounds were administered intravenously

  
  <EMI ID = 87.1>

  

  <EMI ID = 88.1>


  

  <EMI ID = 89.1>
 

  

  <EMI ID = 90.1>


  

  <EMI ID = 91.1>


  

  <EMI ID = 92.1>
 

  
  <EMI ID = 93.1>

  

  <EMI ID = 94.1>
 

  
the compounds represented by formula (I) and their salts can be administered to. humans and animals as free acid, non-toxic salt or physiologically tolerated ester to treat and prevent infectious conditions of bacterial origin.

  
It is preferable to administer them parenterally as free acid or non-toxic salt or orally as a physiologically tolerated ester.

  
In these cases, they can be packaged in a form usually used in the field of cephalosporin-based medicines, such as cachet, capsule, powder, granule, fine granule, syrup, injectable (including by drop). , suppository and the like. Can be used for such preparations, if necessary. diluents and / or additives comprising. excipients such as starch, lactose, sucrose, calcium phosphate, calcium carbonate and the like, binders such as gum arabic, starch, crystalline cellulose, carboxymethyl cellulose, hydroxypropyl cellulose and the like, lubricants such as talc, magnesium stearate and the like and dividing agents such as calcium carboxymethyl, talc and the like.

  
  <EMI ID = 95.1>

  
According to the invention, the dose and the frequency of administration are chosen according to the degree of the affection and the other factors. The preparation is usually administered either by

  
  <EMI ID = 96.1>

  
of the cephalosporin compound according to the invention in 1 to 4 times a day for an adult.

  
The invention not only relates to the compounds represented. by formula (I) and their salts, described above, and processes for their manufacture, which will be described below, also arise from intermediate compounds represented by the formulas
(IIIb), (IV) and (V) and their salts, the description of which follows, as well as a process for the manufacture of the intermediate compound represented by the formula (IIIa) and its salts, which process will be described below.

  

  <EMI ID = 97.1>


  
or their salts

  

  <EMI ID = 98.1>


  
or their salts

  

  <EMI ID = 99.1>


  
or their salts

  

  <EMI ID = 100.1>


  
or their salts In the above formulas of intermediate compounds, the

  
  <EMI ID = 101.1>

  
  <EMI ID = 102.1>

  
retort below.

  
The process for the preparation of these compounds according to the invention is described below. By way of example, these compounds can be prepared by said method.

  
Although the intermediate compounds according to the invention and their salts have per se bactericidal properties, it is advantageous to convert them into new cephalosporins represented by formula (I), as will be explained by the diagrams which follow.

  

  <EMI ID = 103.1>


  

  <EMI ID = 104.1>
 

  

  <EMI ID = 105.1>


  

  <EMI ID = 106.1>
 

  

  <EMI ID = 107.1>
 

  

  <EMI ID = 108.1>
 

  

  <EMI ID = 109.1>
 

  
  <EMI ID = 110.1>

  
lower as defined for B, Y represents

  

  <EMI ID = 111.1>


  
  <EMI ID = 112.1>

  
  <EMI ID = 113.1>

  
a formula group

  

  <EMI ID = 114.1>


  
  <EMI ID = 115.1>

  
rents, represent a hydrogen atom or an organic residue which does not participate in the reaction, or a group of formula

  

  <EMI ID = 116.1>


  
  <EMI ID = 117.1>

  
represent hydrogen atoms or organic residues which do not take part in the reaction, R 17 represents an acyloxy or carbamoyloxy group, substituted or not.

  
For the compounds represented by formulas (II) and (III) and

  
  <EMI ID = 118.1>

  
by the formula

  

  <EMI ID = 119.1>


  
a group represented by the formula

  

  <EMI ID = 120.1>


  
and a group represented by the formula
  <EMI ID = 121.1>
  <EMI ID = 122.1>

  
from the previous group:

  

  <EMI ID = 123.1>


  
One can use, as. that organic remains. participating in the

  
  <EMI ID = 124.1>

  
(2) alicyclic remains:. cycloalkyl and cycloalkenyl groups

  
(3) aromatic residues: aryl groups <EMI ID = 125.1> <EMI ID = 126.1>

  
(6) acyl groups: those derived from organic carboxylic acids.

  
lics, such as aliphatic, alicyclic carboxylic acids,

  
alicycloaliphatics, substituted aliphatics

  
  <EMI ID = 127.1>

  
organic carboxyls in which an aromatic ring, an aliphatic or alicyclic group is attached to the carbonyl group by an oxygen, nitrogen or sulfur atom, aromatic carboxylic acids, heterocyclic carboxylic acids and the like.

  
  <EMI ID = 128.1>

  
ncique, methoxyacetic, methylthioacetic, acrylic, crotonic and the like. As aliphatic carboxylic acids there may be mentioned

  
  <EMI ID = 129.1>

  
cite for alicycloaliphatic carboxylic acids, cyclopentane-acetic acids, cyclohexane acetic, cyclohexadiene acetic

  
^ 7 and others.

  
Aryl groups already mentioned above and r can be used as aromatic residues in the acids mentioned above.

  
  <EMI ID = 130.1>

  
previously.

  
The individual groups constituting these carboxylic acids can be substituted by substituents such as halogen, hydroxyl,

  
  <EMI ID = 131.1>

  
teged, carboxyl, protected carboxyl or the like.

  
As protecting group for asino, hydroxyl and

  
  <EMI ID = 132.1>

  
  <EMI ID = 133.1>

  
xyle, include, for example, the following compounds:
(a) esters: those applied in the fields of penicillin and cephalosporin can be used, comprising specifically

  
  <EMI ID = 134.1>
(b) anhydrides of the carboxyl group with N-hydroxysuccinimide, N-hy- <EMI ID = 135.1> zole substituted in position 4, triazolopyridone and the like.

  
  <EMI ID = 136.1>

  
  <EMI ID = 137.1>

  
yloxy, naphthoyloxy and the like and carbamoyloxy groups. They can be substituted by one or more substituents such as halogen, .nitro, alkyl, alkoxy, alkylthio, acyloxy, acylamino, hydroxyl, carboxyl, sulfamoyl, carbamoyl, carboalkoxycarbamoyl, aroyl-

  
  <EMI ID = 138.1>

  
  <EMI ID = 139.1>

  
yours for R 17 can be protected by means of usual protection groups, as mentioned in connection with R <2>.

  
  <EMI ID = 140.1>

  
mule (I) can be used.

  
The invention also extends to all isomers of intermediate compounds (eg syn and anti isomers, tautomers, optical isomers and the like), as well as to mixtures thereof, their crystalline forms and their hydrates. The following is a description of the process for the preparation of.

  
  <EMI ID = 141.1>

  
on the previous reaction scheme.

  
(1) As a result of the conversion reaction in position 3 according to

  
  <EMI ID = 142.1>

  
reacting the cephalosporanic acid represented by the formula (II) or its derivative on the carboxyl group or its salt with a substituted or non-substituted aromatic hydrocarbon, a substituted or unsubstituted nitrile compound, a substituted or unsubstituted aromatic heterocyclic compound, or a triazole or tetrazole which may be substituted at the carbon atones of the ring, in an organic solvent in the presence of an acid or an acidic complex compound and then by removing, if desirable, the protecting group and by adding a protecting the carboxyl group or by transforming the carboxyl group into a salt. It is possible, if necessary, to remove the substituent on the 7-amino group by a conventional method in order to obtain a compound

  
  <EMI ID = 143.1>

  
According to this preparation process, the compound represented by formula (II), its derivative of the carboxyl group or its salt can react with an aromatic hydrocarbon, substituted or not, to give a

  
  <EMI ID = 144.1>

  
corresponding aromatic hydrocarbon group, or similarly, it can react with a nitrile compound, substituted or not, to give a compound of formula (III) or its salt, in which R <2> is the corresponding acylamino group, either it can react with a heterocyclic aromatic compound, substituted or not, to give <EMI ID = 145.1>

  
substituted or not, and more particularly a compound of. formula

  
  <EMI ID = 146.1>

  
ment on an industrial scale and a high purity product with a high yield is obtained.

  
It is possible to use, as a substituted or non-substituted aromatic hydrocarbon which is one of the reactants in this reaction,

  
  <EMI ID = 147.1>

  
  <EMI ID = 148.1>

  
nitrile, substituted or not, we can use the one that corresponds -

  
  <EMI ID = 149.1>

  
substituted or not, we can use the one that corresponds to the group

  
  <EMI ID = 150.1>

  
  <EMI ID = 151.1>

  
As triazole or tetrazole which can be substituted at the carbon atones of the ring, those which correspond to the group can be used

  
  <EMI ID = 152.1>

  
  <EMI ID = 153.1>

  
lange can be used as reagents.

  

  <EMI ID = 154.1>
 

  
  <EMI ID = 155.1>

  
identical or different.

  
  <EMI ID = 156.1>

  
sic or acid. Their shape can be the mine than that mentioned

  
  <EMI ID = 157.1>

  
posed represented by formula (1). The salt of the compound represented by formula (II) can be isolated beforehand and used in

  
  <EMI ID = 158.1>

  
As acid compounds or acid complexes suitable acids

  
  <EMI ID = 159.1>

  
  <EMI ID = 160.1>

  
  <EMI ID = 161.1>

  
  <EMI ID = 162.1>

  
  <EMI ID = 163.1>

  
  <EMI ID = 164.1>

  
boron trifluoride with dialkyl ethers such as diethyl ether di-n-propyl ether, di-n-butyl ether and the like; mixtures with carboxylic esters such as ethyl formate, ethyl acetate

  
  <EMI ID = 165.1>

  
  <EMI ID = 166.1>

  
organic xylics such as formic, acetic, trifluoroacetic, dichloroacetic, propionic, and the like; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; ethers such as diethyl ether, diisopropyl ether,

  
  <EMI ID = 167.1>

  
  <EMI ID = 168.1> <EMI ID = 169.1>

  
logues. These solvents can be used Ball or in mixtures.

  
  <EMI ID = 170.1>

  
these "acids and Lads acids. The amount of acid or complex compound used is one mole per mole of the compound represented by

  
  <EMI ID = 171.1>

  
may vary depending. conditions. It is recommended to use. acid or complex acid compound in proportion of 2-10 moles per mole of the compound. When using the complex acid compound,

  
  <EMI ID = 172.1>

  
ser, a mixture of two or more complex compounds.

  
  <EMI ID = 173.1>

  
posed heterocyclic aromatic or triasole or tetrazole to be used as reagent is 1 mole or more per mole of the compound represented. smells by the formula (II) or its derivative or its salt. It is recommended

  
  <EMI ID = 174.1>

  
  <EMI ID = 175.1>

  
and the duration of the reaction is from several minutes to dozens of hours. In the presence of water in the reaction medium, it is feared that undesirable side reactions, such as the lactonization of the starting product and the breaking of the cycle.

  
  <EMI ID = 176.1>

  
anhydrous. To achieve this condition, or .. can add to the reaction medium a dehydrating agent such as a phospho- compound

  
  <EMI ID = 177.1>

  
phosphorus chloride, phosphorus trichloride, oxychloride

  
  <EMI ID = 178.1>

  
similar; an acid anhydride, eg acetic anhydride, tri-fluvroac ethical anhydride or the like; an inorganic desiccant, eg anhydrous magnesium sulfate, anhydrous calcium chloride; molecular sieve, calcium carbide or the like; and others.

  
If we use as a starting compound a derivative of the living room compound

  
  <EMI ID = 179.1>

  
times, depending on the treatment applied after the reaction, obtain a <EMI ID = 180.1>

  
  <EMI ID = 181.1>

  
  <EMI ID = 182.1> <EMI ID = 183.1> <EMI ID = 184.1>

  
  <EMI ID = 185.1>

  
xyle, the desired compound can be obtained by first protecting

  
these groups using the protective group mentioned above before

  
  <EMI ID = 186.1>

  
attached to the exomethylene group in position 3 of the cephem ring via a carbon-carbon bond, we can set

  
work, in application of the position 3 conversion reaction

  
mentioned above, a known method by which a penicillin,

  
  <EMI ID = 187.1>

  
to cause the opening of the cycle and finally to a series of reactions to form the dihydrothiadin cycle (namely * the cephaloskeleton-

  
  <EMI ID = 188.1>

  
J.M.C., 20, 1081 (1977). ; ibid., 20, 1086 (1977)].

  
When a compound of formula (III) is obtained, where B is a hydrogen atom, it may be converted into a compound of formula (III)

  
  <EMI ID = 189.1>

  
Journal of Synthetic Organic Chemistry, Japan, vol. 35, 568-574-
1977)).

  
(2) The acylation reactions according to schemes 1 to 4 can all be carried out in the same way. The compound represented by the formula- (III) or its salt is reacted with a compound represented by the formula (VI), - (VII), (IX), (XIIi or (XIII) or a reactive derivative. get a compound represented by the formula

  
  <EMI ID = 190.1>

  
As reactive derivatives of compounds represented by the formulas- (VI),. (VII), (IX) ,. (XII) and (XIII), there may be mentioned acid halides, acid anhydrides, mixed acid anhydride, reactive acid amides, reactive esters and reactive derivatives formed between the Vilsmeier reagent and the compound represented by the

  
  <EMI ID = 191.1>

  
mixed acid, mixed acid anhydrides can be used

  
  <EMI ID = 192.1>

  
butyl.carbonate and the like; acid anhydrides mixed with

  
lower alkanoic acids, optionally substituted with

  
halogen such as pivalic acid, trichloroacetic or the like.

  
As reactive acid amide, there can be used, eg N-acylsaccharide, N-acylimidazole, N-acylsulfonamide, N-acylbenzoylamide, N, N'-

  
  <EMI ID = 193.1>

  
use cyanomethyl esters; substituted phenyl, substituted benzyl, substituted thienyl and the like.

  
  <EMI ID = 194.1>

  
ser a reaction product of an acid amide such as dimethylformamide, N, N-dimethylacetamide or the like with a halogenating agent such as phosgene, thionyl chloride, phosphorus trichloride, phosphorus tribromide, phosphorus oxychloride, phosphorus oxybromide, phosphorus pentachloride, trichloromethyl chloroformate, oxalyl chloride and the like.

  
When. the compound of formula (VI), (VII), (IX), (XII) or (XIII)

  
is used in the form of free acid or salt, an appropriate condensing agent is used. As such, .carbodi-

  
  <EMI ID = 195.1>

  
acetylene and the like, 2-halopyridinium (salt of) such as

  
methyl 2-chloropyridinium iodide, 2-fluoropyridinium iodide

  
methyl and the like.

  
These acylation reactions are usually carried out in a

  
suitable solvent in the presence or absence of a base. As ground-

  
Beforehand, halogenated hydrocarbons such as chloroform, methylene dichloride and the like are often used, ethers such as

  
  <EMI ID = 196.1>

  
acetamide, acetone, water and their mixtures. The base used comprises inorganic bases such as alkali hydroxides, alkali carbonates or alkali bicarbonates, alkali acetates and the like,

  
  <EMI ID = 197.1>

  
  <EMI ID = 198.1>

  
^ 2.

  
lutidine, collidine and the like. secondary amines such as dicyclohexylamine, diethylamine and the like.

  
The amount of the compound represented by formula (VI), (VII), (IX), ([pound] II) or (XIII) or its reactive derivative used in the acylation reaction according to Schemes 1 to 4 is usually from 1 mole to several moles per mole of compound according to formula (III) or its salt.

  
  <EMI ID = 199.1>

  
lasts from 10 minutes to 48 hours.

  
During the acylation reaction according to scheme 3, where A is

  
  <EMI ID = 200.1>

  
  <EMI ID = 201.1>

  
duiketene and a halogen according to the method published in the Journal, of the Chemical Society, 97, 1987, (1910) and then in. reacting the reaction product with a compound of formula (III) or its salt.

  
  <EMI ID = 202.1>

  
  <EMI ID = 203.1>

  
a carboxyl protecting group, this compound can be converted in the usual way to the corresponding compound or its salt, in which

  
  <EMI ID = 204.1>

  
R is a hydrogen atom; when it is a compound of formula

  
  <EMI ID = 205.1>

  
compound can be converted in the usual way into the corresponding compound or its salt, in which R is a carboxyl protecting group; when it is a salt of formula (I), (IV), (V), (VIII) or ( X), this compound

  
can be converted into the corresponding free compound in the usual way.

  
When, during these acylation reactions, there are among the

  
  <EMI ID = 206.1>

  
  <EMI ID = 207.1>

  
and it can be removed at the end of the reaction.

  
  <EMI ID = 208.1>

  
salts thus obtained can be separated in a conventional manner.

  
  <EMI ID = 209.1>

  
  <EMI ID = 210.1>

  
it can undergo a nitrosation reaction described below (and possibly a subsequent alkylation reaction)

  
to convert A to

  

  <EMI ID = 211.1>


  
and then proceed to the reaction of &#65533; v

  
  <EMI ID = 212.1>

  
The nitrosation reaction can be carried out as follows:

  
  <EMI ID = 213.1>

  
his. salt with a nitrosating agent to convert it to the compound represented by formula (VII) or its salt is usually carried out in a solvent medium. Solvents which do not harm the course of the reaction are used, such as water, acetic acid, benzene, methanol, ethanol, tetrahydrofuran and the like. As a nitrosating agent; preferably nitric acid and its derivatives such as nitrosyl halides (chloride, bromide, for example), alkali metal nitrites (of sodium, potassium, for example), nitrites of 'alkyl (butyl, pentyl for example). When a nitrous acid salt is used as the nitrosating agent, the reaction is preferably carried out in the presence of an inorganic or organic acid such as hydrochloric, sulfuric, fornic, acetic acid or the like.

   When a nitrous acid ester is used as the nitrosating agent, it is possible to carry out the reaction in the presence of a strong base such as alkali metal alcoholate. Although the reaction temperature is not critical, it is preferable to carry out the reaction while cooling or at room temperature. Salts of the compounds represented by the formula (X), in which R5 is a hydrogen atom, can be obtained by a conventional method. These salts can be the same as those mentioned with regard to the salts of compounds according to formula (I). One can separate by the usual method, as well as purify, the compounds thus obtained conform

  
  <EMI ID = 214.1>

  
their salts. They can also be used as a starting compound for the next reaction, without separating them.

  
(4) After the nitrosation reaction described above, we

  
  <EMI ID = 215.1>

  
  <EMI ID = 216.1>

  
The alkylation reaction is carried out according to a normal method. For example, it can be completed in an interval of several minutes to several hours in most cases, if

  
  <EMI ID = 217.1>

  
temperature approaching room temperature. You can use any solvent that does not delay the. reaction, e.g.

  
  <EMI ID = 218.1> <EMI ID = 219.1>

  
  <EMI ID = 220.1>

  
Salts of the compound represented can be readily obtained by the form

  
  <EMI ID = 221.1>

  
These salts are the same as the salts mentioned with regard to the salts of the compound represented by the formula CI). The compounds thus obtained can be separated and purified from

  
  <EMI ID = 222.1>

  
also possible to use them as starting materials for

  
the next reaction, without separating them.

  
  <EMI ID = 223.1>

  
is obtained. by reacting the compound according to formula (X) or

  
its salt with a halogenating agent according to scheme 2. As

  
halogenating agent,. halogens such as chlorine,

  
  <EMI ID = 224.1>

  
nimide or the like; halogen-pyridine complexes such as pyridinium hydrobromide perbromide or the like. The amount of ha-

  
  <EMI ID = 225.1>

  
minium, boron trifluoride, titanium tetrachloride or the like. As a solvent, any Drink can be used as long as it does not harm

  
  <EMI ID = 226.1>

  
methylene chloride, benzene or the like, alone or as a mixture of two or more. The reaction is carried out either by cooling, or at elevated temperature in an interval ranging from 10 minutes to 24 hours.

  
  <EMI ID = 227.1>

  
react a compound represented by formula (V) or its with <EMI ID = 228.1>

  
  <EMI ID = 229.1>

  
as previously mentioned. The reaction is normally carried out in a solvent such as water, an alcohol or the like. or in.

  
  <EMI ID = 230.1>

  
according to the, formula (XIV), the reaction is preferably carried out

  
in the presence of a base. comprising an inorganic base such as hydro-

  
  <EMI ID = 231.1>

  
calcium, for example), alkaline earth metal phosphate (magnesium or calcium, for example) and acidic alkali metal phosphate such as phos-

  
  <EMI ID = 232.1>

  
such as alkali metal, sodium, or potassium acetate for example, a. ,

  
  <EMI ID = 233.1>

  
(7) The closing of the cycle according to diagrams 2 and 3 can in principle be carried out in the same way. So a compound represented by

  
formula (IV), which comprises (IVa), or its salt reacts with a thioformamide or thiourea represented by formula (XI) to obtain a compound represented by formula (la) or (Ib) respectively or its salt. The reaction is carried out in a solvent medium which does not delay

  
  <EMI ID = 234.1>

  
  <EMI ID = 235.1>

  
such addition sometimes regulates the course of the reaction without

  
  <EMI ID = 236.1>

  
nics or organic such as alkali metal hydroxides, car-

  
  <EMI ID = 237.1>

  
dimethylaniline and the like. The reaction is carried out normally

  
  <EMI ID = 238.1>

  
  <EMI ID = 239.1>

  
represented by formula (XI) per equivalent of the compound of the form

  
  <EMI ID = 240.1>

  
1 to 48 hours, preferably 1 to 10 hours. In addition,

  
  <EMI ID = 241.1>

  
  <EMI ID = 242.1> <EMI ID = 243.1>

  
  <EMI ID = 244.1>

  
mined after the reaction. We can separate and purify the compounds

  
  <EMI ID = 245.1>

  
  <EMI ID = 246.1>

  
  <EMI ID = 247.1>

  
  <EMI ID = 248.1>

  
compound represented by formula (Id) in an inert solvent such

  
  <EMI ID = 249.1>

  
acetamide, acetonitrile, methanol, ethanol they are mixed -

  
A composite represented by la is added to the resulting solution.

  
  <EMI ID = 250.1>

  
reaction and then. a halogenating agent is reacted. Lower alcohol is used in excess and the amount of compound (XV) is

  
  <EMI ID = 251.1>

  
  <EMI ID = 252.1>

  
  <EMI ID = 253.1>

  
acidifying the reaction medium.

  
The halogenating agent used is known to be a source of positive atoms

  
  <EMI ID = 254.1>

  
  <EMI ID = 255.1>

  
the amount used must be sufficient to provide an amount of positive halogen equivalent to that of the compound (Id).

  
  <EMI ID = 256.1>

  
  <EMI ID = 257.1>

  
The invention will be explained in more detail in the. In light of the reference examples and those of preparation, given by way of illustration and which do not limit the scope of the invention.

  
Reference example 1.

  
  <EMI ID = 258.1>

  
boron-diethyl ether to form a solution, after which the solution was reacted at room temperature for .5 -, hours. At the end of the. reaction, the solvent was removed by distillation at reduced pressure

  
  <EMI ID = 259.1>

  
  <EMI ID = 260.1>

  
medium ammonia at 28% by weight with ice cooling. The deposited crystals were collected by filtration, washed successively-

  
  <EMI ID = 261.1>

  
  <EMI ID = 262.1>

  
  <EMI ID = 263.1>

  

  <EMI ID = 264.1>


  
(2) 2.71 g of acid was suspended in 30 ml of methanol.

  
  <EMI ID = 265.1>

  
(1) and the suspension was added with 1.90 g of p-toluenesulfonic monohydrate to form a. solution. Then, 4 g of diphenol were slowly added to the solution at room temperature.

  
  <EMI ID = 266.1>

  
cross off for 30 minutes. At the end of the reaction, the solvent has

  
was removed by distillation at reduced pressure and the residue thus

  
  <EMI ID = 267.1>

  
ethyl acetate, while the pH was adjusted using sodium hydrogen carbonate to the value of 7.0. The crystals deposited were filtered, washed thoroughly with water and dried to obtain 2.84 g (65% yield) of diphenylmethyl 7-amino-3-acetamido-

  
  <EMI ID = 268.1>

  

  <EMI ID = 269.1>


  
Reference example 2.

  
Reactions and treatments were carried out as in the example

  
  <EMI ID = 270.1>

  
acetic as a solvent. The products listed in Table 4 were obtained.

  

  <EMI ID = 271.1>


  

  <EMI ID = 272.1>
 

  

  <EMI ID = 273.1>


  

  <EMI ID = 274.1>
 

  

  <EMI ID = 275.1>


  

  <EMI ID = 276.1>


  

  <EMI ID = 277.1>
 

  
  <EMI ID = 278.1>

  

  <EMI ID = 279.1>


  
Table .5

  

  <EMI ID = 280.1>


  
Exespicl

  
  <EMI ID = 281.1>

  
tetrazole. The mixture was left for 17 hours at room temperature. At the end of the reaction, the reaction mixture

  
  <EMI ID = 282.1>

  
  <EMI ID = 283.1>

  
  <EMI ID = 284.1>

  
  <EMI ID = 285.1>

  
  <EMI ID = 286.1> <EMI ID = 287.1>

  
  <EMI ID = 288.1>

  

  <EMI ID = 289.1>


  

  <EMI ID = 290.1>
 

  
  <EMI ID = 291.1>

  

  <EMI ID = 292.1>

FI "

  
  <EMI ID = 293.1>

  

  <EMI ID = 294.1>

Example 2.

  
  <EMI ID = 295.1>

  
and 7.1 of boron trifluoride-diethyl ether complex and we added

  
  <EMI ID = 296.1>

  
swaddle for 7 hours at room temperature. At the end of the reaction, the solvent was removed by. reduced pressure distillation <EMI ID = 297.1>

  

  <EMI ID = 298.1>


  
  <EMI ID = 299.1>

  
results are shown in Table 6. Thereafter, the

  
  <EMI ID = 300.1>

  
  <EMI ID = 301.1>

  
obtain the esters and carboxylic acids listed in Table 7.

  

  <EMI ID = 302.1>


  

  <EMI ID = 303.1>
 

  

  <EMI ID = 304.1>


  

  <EMI ID = 305.1>
 

  

  <EMI ID = 306.1>


  

  <EMI ID = 307.1>


  

  <EMI ID = 308.1>
 

  

  <EMI ID = 309.1>


  

  <EMI ID = 310.1>
 

  

  <EMI ID = 311.1>


  

  <EMI ID = 312.1>
 

  

  <EMI ID = 313.1>


  

  <EMI ID = 314.1>
 

  

  <EMI ID = 315.1>


  

  <EMI ID = 316.1>
 

  

  <EMI ID = 317.1>


  

  <EMI ID = 318.1>
 

  

  <EMI ID = 319.1>


  

  <EMI ID = 320.1>
 

  

  <EMI ID = 321.1>


  

  <EMI ID = 322.1>
 

  

  <EMI ID = 323.1>


  

  <EMI ID = 324.1>
 

  

  <EMI ID = 325.1>


  

  <EMI ID = 326.1>
 

  

  <EMI ID = 327.1>


  

  <EMI ID = 328.1>


  

  <EMI ID = 329.1>
 

  
  <EMI ID = 330.1>

  

  <EMI ID = 331.1>


  

  <EMI ID = 332.1>
 

  

  <EMI ID = 333.1>


  

  <EMI ID = 334.1>
 

  

  <EMI ID = 335.1>


  

  <EMI ID = 336.1>
 

  

  <EMI ID = 337.1>


  

  <EMI ID = 338.1>
 

  

  <EMI ID = 339.1>


  

  <EMI ID = 340.1>
 

  

  <EMI ID = 341.1>


  

  <EMI ID = 342.1>
 

  

  <EMI ID = 343.1>


  

  <EMI ID = 344.1>


  

  <EMI ID = 345.1>
 

  
  <EMI ID = 346.1> table 10.
  <EMI ID = 347.1>
  <EMI ID = 348.1>
 
  <EMI ID = 349.1>
  <EMI ID = 350.1>
  <EMI ID = 351.1>
   <EMI ID = 352.1>

  
  <EMI ID = 353.1>

  
^ conditions specified in Table 11 to obtain results also shown in this table.

  

  <EMI ID = 354.1>


  

  <EMI ID = 355.1>
 

  

  <EMI ID = 356.1>


  

  <EMI ID = 357.1>


  

  <EMI ID = 358.1>
 

  
  <EMI ID = 359.1>

  
The same reaction and the same treatment as in Example 2 were repeated, except that 7-ACA was' replaced by the starting compounds specified in Table 12 to obtain products listed in the same Table.

  
Table 12

  

  <EMI ID = 360.1>


  
  <EMI ID = 361.1>

  
(1) Was dissolved in 40 ml of anhydrous methylene chloride

  
  <EMI ID = 362.1>

  
tick, then 1.06 g of N-methylmorpholine was added to the solution, after which the mixture was cooled to -35 [deg.] C. Then.,

  
1.12 g of ethyl chlorocarbonate was added and allowed to react

  
  <EMI ID = 363.1>

  
  <EMI ID = 364.1>

  
  <EMI ID = 365.1>

  
  <EMI ID = 366.1>

  
sidu obtained was dissolved in a mixture of 40 μl of ethyl acetate <EMI ID = 367.1> <EMI ID = 368.1>

  
  <EMI ID = 369.1>

  

  <EMI ID = 370.1>


  
  <EMI ID = 371.1>

  
  <EMI ID = 372.1>

  
re by distillation at reduced pressure and the residue has been dissolved

  
  <EMI ID = 373.1>

  
  <EMI ID = 374.1> for 30 minutes. Then the solvent was dilated by distillation.

  
  <EMI ID = 375.1>

  
  <EMI ID = 376.1>

  
  <EMI ID = 377.1>

  
  <EMI ID = 378.1>

  
ice cooling. The organize layer has been separated ,. then

  
  <EMI ID = 379.1>

  
removed by distillation under reduced pressure. Diethyl ether was added to the residue and the precipitated crystals were collected by filtration, washed well with diethyl ether and then dried, which

  
  <EMI ID = 380.1>

  
  <EMI ID = 381.1>

  
The physical properties (IR and NMR) of this compound were identical

  
to those of the compound obtained above.

  
  <EMI ID = 382.1>

  

  <EMI ID = 383.1>


  
  <EMI ID = 384.1>
  <EMI ID = 385.1>
 
  <EMI ID = 386.1>
  <EMI ID = 387.1>

  

  <EMI ID = 388.1>


  
  <EMI ID = 389.1> <EMI ID = 390.1>

  
We cool. let the mixture react for 40 minutes at 5-10 [deg.] C until a homogeneous solution is obtained. The solution has been poured

  
  <EMI ID = 391.1>

  
  <EMI ID = 392.1> distillation at reduced pressure, the residue for

  
  <EMI ID = 393.1>

  
was adjusted to 7.5 by addition of the acid carbonate '. sodium with cooling. The aqueous layer was separated and mixed with 40 ml of ethyl acetate, while the pH was adjusted to 2.0. addition of 2N hydrochloric acid while cooling.

  
  <EMI ID = 394.1>

  
and dried with anhydrous magnesium sulfate. The solvent has been dried

  
  <EMI ID = 395.1>

  
  <EMI ID = 396.1>

  
xylic, with a melting point of 138-142 [deg.] C (decomp.)

  
  <EMI ID = 397.1>

  

  <EMI ID = 398.1>


  
(2) Was dissolved in 25 ml of trifluoroacetic acid and 8 ml

  
  <EMI ID = 399.1>

  
gir the solution for 30 minutes at room temperature.

  
At the end of the reaction, the solvent was separated by distillation at reduced pressure and diethyl ether was added to the residue, the crystals formed were filtered, washed with diethyl ether and dried.

  
  <EMI ID = 400.1>

  
  <EMI ID = 401.1> <EMI ID = 402.1>

  
  <EMI ID = 403.1>

  
The physical properties (IR and NMR) of this product are identical with those of the product obtained according to the example. 8 - (2).

Example 10.

  
  <EMI ID = 404.1>

  
  <EMI ID = 405.1>

  
  <EMI ID = 406.1>

  
the resulting mixture was allowed to react for 30 minutes between <EMI ID = 407.1> <EMI ID = 408.1>

  
  <EMI ID = 409.1>

  
silyDacetamide, cooling. The reaction was carried out at room temperature for 1 hour, after which the mixture was

  
  <EMI ID = 410.1>

  
acid chloride prepared previously in the suspension mixture. Towards the end of the addition, the temperature rose slowly and. the reaction went.

  
  <EMI ID = 411.1>

  
solvent was separated by distillation at reduced pressure and the residue was dissolved in 30 ml of ethyl acetate and 20 ml of water, after that the organic layer was separated, washed with 20 ml of water, then 20 ml saturated sodium chloride solution and dried using anhydrous magnesium sulfate. The solvent was removed by distillation at reduced pressure. The diethyl ether residue was added and the crystals formed were filtered, which were washed.

  
  <EMI ID = 412.1>

  
  <EMI ID = 413.1>

  
  <EMI ID = 414.1>

  
  <EMI ID = 415.1>

  
  <EMI ID = 416.1>

  
2 hours at room temperature. At the end of the reaction,

  
  <EMI ID = 417.1>

  
by adding sodium bicarbonate while cooling. The resulting precipitate was filtered, washed successively with water, with acetone

  
  <EMI ID = 418.1>

  
  <EMI ID = 419.1>

  
  <EMI ID = 420.1>

  
  <EMI ID = 421.1>

  

  <EMI ID = 422.1>


  
  <EMI ID = 423.1>

  
thiourea place:

  
  <EMI ID = 424.1>

  
  <EMI ID = 425.1>

  
  <EMI ID = 426.1>

Example 11.

  
By reacting starting compounds presented in Table 13

  
  <EMI ID = 427.1>

  
  <EMI ID = 428.1>

  

  <EMI ID = 429.1>


  

  <EMI ID = 430.1>
 

  

  <EMI ID = 431.1>


  

  <EMI ID = 432.1>
 

  

  <EMI ID = 433.1>


  

  <EMI ID = 434.1>
 

  

  <EMI ID = 435.1>


  

  <EMI ID = 436.1>
 

  

  <EMI ID = 437.1>


  

  <EMI ID = 438.1>
 

  

  <EMI ID = 439.1>


  

  <EMI ID = 440.1>
 

  

  <EMI ID = 441.1>


  

  <EMI ID = 442.1>
 

  

  <EMI ID = 443.1>


  

  <EMI ID = 444.1>
 

  

  <EMI ID = 445.1>


  

  <EMI ID = 446.1>
 

  

  <EMI ID = 447.1>


  

  <EMI ID = 448.1>
 

  

  <EMI ID = 449.1>


  

  <EMI ID = 450.1>
 

  

  <EMI ID = 451.1>


  

  <EMI ID = 452.1>
 

  

  <EMI ID = 453.1>


  

  <EMI ID = 454.1>
 

  

  <EMI ID = 455.1>


  

  <EMI ID = 456.1>
 

  

  <EMI ID = 457.1>


  

  <EMI ID = 458.1>
 

  

  <EMI ID = 459.1>


  

  <EMI ID = 460.1>
 

  
  <EMI ID = 461.1>

  
  <EMI ID = 462.1>

  
  <EMI ID = 463.1>

  
of diketene in 20 ml of anhydrous methylene chloride and effected

  
  <EMI ID = 464.1>

  
drop by drop the mixture in a solution of 4.62 g of diphenyl-methyl

  
  <EMI ID = 465.1>

  
  <EMI ID = 466.1>

  
The mixture was allowed to react at -30 [deg.] C to -20 [deg.] C for 30 minutes.

  
  <EMI ID = 467.1>

  
reaction, the solvent is separated off by distillation at reduced pressure, the residue is dissolved in 60 ml of ethyl acetate and 60 ml of water, the organic layer is separated, it is washed successively with

  
30 ml of water and 30 ml of solution. saturated with sodium chloride, drying is carried out using anhydrous magnesium sulfate and the solvent is separated off by distillation at reduced pressure. The residue of diethyl ether is added and the crystals formed are filtered to

  
  <EMI ID = 468.1>

  

  <EMI ID = 469.1>


  
  <EMI ID = 470.1>

  
room temperature for 2 hours. At the end of the reaction, the solvent was distilled off at reduced pressure, the residue was washed with diethyl ether, then mixed with 100 ml of acetate

  
  <EMI ID = 471.1> edition of a saturated sodium bicarbonate solution with cooling, then the organic layer is separated and dried using anhydrous magnesium sulfate. The solvent was separated by distillation at reduced pressure to obtain 5.9 g of

  
  <EMI ID = 472.1>

  
  <EMI ID = 473.1>

  
  <EMI ID = 474.1>

  
trifluoroacetic, then the mixture was allowed to react at room temperature for 30 minutes. At the end of the reaction, we

  
  <EMI ID = 475.1>

  
  <EMI ID = 476.1>

  

  <EMI ID = 477.1>

Example 13.

  
  <EMI ID = 478.1>

  
according to example 9- (1). Then the solution was added in

  
cooling it with 1 g of triethylamine and 2.9 g of pivaloyloxymethyl iodide and the mixture was allowed to react for 30 minutes. At the end of the reaction the mixture was poured into a solvent

  
  <EMI ID = 479.1> <EMI ID = 480.1> <EMI ID = 481.1>

  
  <EMI ID = 482.1>

  
  <EMI ID = 483.1>

  
the solvent by distillation at reduced pressure, the

  
  <EMI ID = 484.1>

  
addition of sodium bicarbonate with cooling. Layer

  
  <EMI ID = 485.1>

  
  <EMI ID = 486.1>

  
ether, stirring with cooling using ice,. after which a precipitate of white powder is obtained. It is filtered, washed with diethyl ether and recrystallized from ethyl acetate

  
  <EMI ID = 487.1>

  

  <EMI ID = 488.1>

-CONH-).

  
  <EMI ID = 489.1>

  
By reacting the starting compounds listed in the tables

  
  <EMI ID = 490.1>

  
corresponding compounds which appear in Tables 11 and 15.

  

  <EMI ID = 491.1>


  

  <EMI ID = 492.1>
 

  

  <EMI ID = 493.1>


  

  <EMI ID = 494.1>
 

  

  <EMI ID = 495.1>


  

  <EMI ID = 496.1>
 

  

  <EMI ID = 497.1>


  

  <EMI ID = 498.1>


  

  <EMI ID = 499.1>
 

  

  <EMI ID = 500.1>


  

  <EMI ID = 501.1>
 

  

  <EMI ID = 502.1>


  

  <EMI ID = 503.1>
 

  
  <EMI ID = 504.1>

  
and the mixture was allowed to react at room temperature for

  
  <EMI ID = 505.1>

  
The mixture was allowed to react for 20 minutes. At the end of the

  
  <EMI ID = 506.1>

  
  <EMI ID = 507.1>

  
using sodium bicarbonate, the organic layer was separated,

  
  <EMI ID = 508.1>

  
  <EMI ID = 509.1>

  
  <EMI ID = 510.1>

  
  <EMI ID = 511.1>

  

  <EMI ID = 512.1>


  
  <EMI ID = 513.1>

  
two 30 ml portions of diethyl ether, 100 ml of diethyl ether

  
  <EMI ID = 514.1>

  
  <EMI ID = 515.1> <EMI ID = 516.1>

  
  <EMI ID = 517.1>

  
  <EMI ID = 518.1>

  

  <EMI ID = 519.1>


  
  <EMI ID = 520.1>

  
  <EMI ID = 521.1>

  
  <EMI ID = 522.1>

  
  <EMI ID = 523.1>

  
  <EMI ID = 524.1>

  
  <EMI ID = 525.1>

  
2.43 g of N, N-dimethylaniline in 50 ml of anhydrous methylene chloride. After the addition, the temperature was raised slightly and the mixture was reacted at 0-5 [deg.] C for 1 hour. AT

  
  <EMI ID = 526.1>

  
  <EMI ID = 527.1>

  
ethyl and 50 ml of water. The organic layer was separated, washed successively with water and with a saturated solution of sodium chloride, then dried with anhydrous magnesium sulfate, after which the solvent "was removed by distillation at reduced pressure to obtain a viscous product. viscous product was dissolved in 15 ml of N, N-dimethylformamide The solution was added <EMI ID = 528.1> ambient temperature for 2 hours. At the end of the reaction the

  
  <EMI ID = 529.1>

  
  <EMI ID = 530.1>

  
  <EMI ID = 531.1>

  
  <EMI ID = 532.1>

  
in diethyl ether, which led to the deposition of a powder

  
white. it was filtered, washed carefully with diethyl ether and

  
  <EMI ID = 533.1>

  
identical to those of the product according to Example 13.

Example 16.

  
  <EMI ID = 534.1>

  
that in Example 9- (1), obtained the following compound:

  
  <EMI ID = 535.1>

  
  <EMI ID = 536.1>

  
  <EMI ID = 537.1>

  

  <EMI ID = 538.1>


  
  <EMI ID = 539.1>

  
  <EMI ID = 540.1>

  
  <EMI ID = 541.1> <EMI ID = 542.1>

  
anhydrous magnesium and the solvent was removed by distillation at reduced pressure. The residue was added with diethyl ether and the

  
  <EMI ID = 543.1>

  

  <EMI ID = 544.1>


  
  <EMI ID = 545.1>

  
  <EMI ID = 546.1>

  
  <EMI ID = 547.1>

  
  <EMI ID = 548.1>

  
  <EMI ID = 549.1>

  
  <EMI ID = 550.1>

  
  <EMI ID = 551.1>

  
  <EMI ID = 552.1>

  
NMR (dg-DMSO) ppm:

  

  <EMI ID = 553.1>

Example 17.

  
(1) 3.15 g were dissolved in 16 ml of N, N-dimethylacetamide

  
  <EMI ID = 554.1>

  
iminoacetic and 1.69 g of oxychloride of drip was added to the solution.

  
  <EMI ID = 555.1>

  
for 1.5 hours and poured dropwise into the solution of 3.16 g of acid

  
  <EMI ID = 556.1>

  
of methylene anhydride chloride at a temperature of -30 to -20 [deg.] C.

  
  <EMI ID = 557.1>

  
for 30 minutes and finally at the frenzied temperature for
30 minutes. At the end of the reaction, the methylene chloride was removed by distillation at reduced pressure and the residue introduced into a mixed solvent of 80 ml of water and 100 ml of ethyl acetate. The organic layer was separated, 80 ml of water was added thereto and the pH was adjusted to 7.0 with sodium bicarbonate. The aqueous layer was separated, 80 ml of ethyl acetate was added thereto and the pH was adjusted to 1.5 with 2N hydrochloric acid with cooling. The organic layer was separated, washed successively with 50 ml of water and 50 ml of saturated sodium chloride solution and dried with anhydrous magnesium sulphate, after which the solvent was removed by. pressure distillation

  
  <EMI ID = 558.1>

  
  <EMI ID = 559.1> <EMI ID = 560.1>

  
  <EMI ID = 561.1>

  
(decomp.).

  
  <EMI ID = 562.1>
  <EMI ID = 563.1>
  <EMI ID = 564.1>
(2) 5.62 g was dissolved in 30 ml of trifluoroacetic acid

  
  <EMI ID = 565.1>

  
performed at room temperature after 30 minutes. At the end of

  
the reaction the solvent was removed by pressure distillation

  
  <EMI ID = 566.1>

  
NMR (d6-DMSO) ppm:

  
  <EMI ID = 567.1>
  <EMI ID = 568.1>
   <EMI ID = 569.1>

Example 18.

  
(1) Was dissolved in 40 ml of anhydrous methylene chloride

  
  <EMI ID = 570.1>

  
pholine, after which the mixture was cooled to -35 [deg.] C. Then, the mixture of 1.12 g of ethyl chlorocarbonate was added and reacted at -35 [deg.] C to -25 [deg.] C for 1.5 hours. After

  
  <EMI ID = 571.1>

  
we warmed up slowly. and reacted at room temperature for 3 hours. At the end of the reaction, the solvent was

  
removed by distillation at reduced pressure. We added the

  
residue of 50 ml of ethyl acetate and 40 ml of water to dissolve

  
the residue. The organic layer was separated, it was added with

  
40 ml water and the pH was adjusted to 1.5 using chlorhy-

  
  <EMI ID = 572.1>

  
  <EMI ID = 573.1>

  
tion of sodium bicarbonate with application of cooling. The organic layer was separated and dried with anhydrous magnesium sulfate, after which the solvent was removed by distillation at

  
reduced pressure. Diethyl ether was added to the residue and the molten crystals were filtered to obtain 7.06 g (93.0% yield)

  
  <EMI ID = 574.1>
  <EMI ID = 575.1>
 
  <EMI ID = 576.1>
  <EMI ID = 577.1>

-CONH-).

  
(2) The compound obtained previously was subjected to the same reaction

  
  <EMI ID = 578.1>

  
before:

  
  <EMI ID = 579.1>

  
Melting point: 123-125 [deg.] C (decomp.)

  
  <EMI ID = 580.1>

  
NMR (CD30D) ppm:

  

  <EMI ID = 581.1>


  
  <EMI ID = 582.1>

  

  <EMI ID = 583.1>


  
  <EMI ID = 584.1>

  
sodium.

  
  <EMI ID = 585.1>

  
  <EMI ID = 586.1>

  
  <EMI ID = 587.1>
  <EMI ID = 588.1>
   <EMI ID = 589.1>

  

  <EMI ID = 590.1>


  
  <EMI ID = 591.1>

  
  <EMI ID = 592.1>

  
  <EMI ID = 593.1>

  
  <EMI ID = 594.1>

  
crystals appeared were filtered, washed with water, then with acetone

  
  <EMI ID = 595.1>

  
  <EMI ID = 596.1>

  

  <EMI ID = 597.1>


  
  <EMI ID = 598.1>

  
The compound was obtained in the same way as above.

  
  <EMI ID = 599.1> <EMI ID = 600.1>

  
  <EMI ID = 601.1>

  
  <EMI ID = 602.1>

  
  <EMI ID = 603.1>

  

  <EMI ID = 604.1>


  

  <EMI ID = 605.1>
 

  

  <EMI ID = 606.1>


  

  <EMI ID = 607.1>
 

  

  <EMI ID = 608.1>


  

  <EMI ID = 609.1>
 

  

  <EMI ID = 610.1>


  

  <EMI ID = 611.1>
 

  

  <EMI ID = 612.1>


  

  <EMI ID = 613.1>
 

  

  <EMI ID = 614.1>


  

  <EMI ID = 615.1>
 

  

  <EMI ID = 616.1>


  

  <EMI ID = 617.1>
 

  

  <EMI ID = 618.1>


  

  <EMI ID = 619.1>
 

  

  <EMI ID = 620.1>


  

  <EMI ID = 621.1>
 

  

  <EMI ID = 622.1>


  

  <EMI ID = 623.1>
 

  

  <EMI ID = 624.1>


  

  <EMI ID = 625.1>
 

  
Table 18
  <EMI ID = 626.1>
 Table 18 (continued)
  <EMI ID = 627.1>
   <EMI ID = 628.1>

  
of methylene, then the mixture was reacted between -30 and
-20 [deg.] C for 30 minutes and at O-10 [deg.] C for one hour. At the end of the reaction, the solvent was removed by distillation at reduced pressure and the residue obtained was dissolved in 100 ml of ethyl acetate and 80 ml of water. The organic layer has been separated, washed

  
  <EMI ID = 629.1>

  
sodium chloride, then dried with anhydrous magnesium sulfate.

  
  <EMI ID = 630.1>

  
  <EMI ID = 631.1>

  
  <EMI ID = 632.1>

  

  <EMI ID = 633.1>


  
  <EMI ID = 634.1>

  
  <EMI ID = 635.1> <EMI ID = 636.1>

  

  <EMI ID = 637.1>


  
  <EMI ID = 638.1>

  
  <EMI ID = 639.1>

  
  <EMI ID = 640.1>

  
crystals, which have been filtered and purified by chromatography
(Wako silica gel C-200; development by benzene solvent:

  
  <EMI ID = 641.1> <EMI ID = 642.1>

  
  <EMI ID = 643.1> <EMI ID = 644.1>

  

  <EMI ID = 645.1>


  
  <EMI ID = 646.1>

  
let the solution react at room temperature for two hours. At the end of the reaction, the mixture was poured into a

  
  <EMI ID = 647.1>

  
  <EMI ID = 648.1>

  
separated the organic layer. The aqueous layer was further extracted using two 300 ml portions of ethyl acetate, the organic layer was combined, washed with two portions

  
  <EMI ID = 649.1>

  
diethyl ether was added to the residue and the resulting crystals

  
  <EMI ID = 650.1>

  
  <EMI ID = 651.1>

  

  <EMI ID = 652.1>


  
  <EMI ID = 653.1>

  
  <EMI ID = 654.1>

  
  <EMI ID = 655.1>

  
  <EMI ID = 656.1> <EMI ID = 657.1>

  

  <EMI ID = 658.1>


  
  <EMI ID = 659.1>
  <EMI ID = 660.1>
   <EMI ID = 661.1>

  

  <EMI ID = 662.1>

Example 24.

  
  <EMI ID = 663.1>

  
acid methoxyiminobutyric acid, 2.0 g of L-oxybenzotriazole and 4.62 g of diphenylmethyl

  
  <EMI ID = 664.1>

  
react the mixture at the same temperature for 30 minutes, then

  
at room temperature for 5 hours. At the end of the reaction, the insolubles were filtered and the solvent was evaporated by distillation at reduced pressure. To the residue was added 40 ml of ethyl acetate, the insolubles were filtered; the filtrate was washed successively with a sodium bicarbonate solution

  
at 5% by weight and with water, then dried with anhydrous magnesium sulfate. The solvent was evaporated by distillation at reduced pressure. The residue was purified on a chromatographic column (Wàko

  
silica gel C-200, benzene developing agent: ethyl acetate

  
  <EMI ID = 665.1>
  <EMI ID = 666.1>
  <EMI ID = 667.1>

  

  <EMI ID = 668.1>

-CONH -) -.

  
In the same way as above "" the following compound was obtained:

  
  <EMI ID = 669.1>

  

  <EMI ID = 670.1>


  
  <EMI ID = 671.1>

  

  <EMI ID = 672.1>


  
  <EMI ID = 673.1>

  
  <EMI ID = 674.1>

  
  <EMI ID = 675.1>

  
and to the suspension, 2.02 g of tri-

  
  <EMI ID = 676.1>

  
  <EMI ID = 677.1>

  
100 µl of water was added and the aqueous layer was separated. Then, the aqueous layer was added to 100 ml of ethyl acetate. <EMI ID = 678.1>

  
After separation of small amounts of the insolubles, the organic layer was separated and dried over anhydrous magnesium sulfate.

  
  <EMI ID = 679.1>

  
diazomethane and the mixture was reacted for 30 minutes.

  
At the end of the reaction, the solvent was evaporated by distillation at reduced pressure; the residue of isopropyl ether was added

  
  <EMI ID = 680.1>

  
  <EMI ID = 681.1> <EMI ID = 682.1>
  <EMI ID = 683.1>
  <EMI ID = 684.1>

  

  <EMI ID = 685.1>


  
  <EMI ID = 686.1>

-CONH-).

  
In the same way as above, the following compound was obtained:

  
  <EMI ID = 687.1>

  
  <EMI ID = 688.1>

  
  <EMI ID = 689.1>

  
  <EMI ID = 690.1>

  

  <EMI ID = 691.1>


  
  <EMI ID = 692.1>
  <EMI ID = 693.1>
  <EMI ID = 694.1>

  
  <EMI ID = 695.1>

  

  <EMI ID = 696.1>


  
  <EMI ID = 697.1>

  

  <EMI ID = 698.1>


  
  <EMI ID = 699.1>

  
= N-og).

  
By proceeding in the same manner as above, the following compound was obtained

  
  <EMI ID = 700.1>

  
  <EMI ID = 701.1> <EMI ID = 702.1>
  <EMI ID = 703.1>
  <EMI ID = 704.1>

  

  <EMI ID = 705.1>


  
  <EMI ID = 706.1>

  
previously obtained In (2)

  
in the same way as according to example 22- (3) to obtain the

  
  <EMI ID = 707.1>

  
  <EMI ID = 708.1>

  
  <EMI ID = 709.1>

  
ticks to those of the compounds obtained in Example 24.

Example 26.

  
  <EMI ID = 710.1> <EMI ID = 711.1>

  
  <EMI ID = 712.1>

  
  <EMI ID = 713.1>

Example 28.

  
  <EMI ID = 714.1>

  
  <EMI ID = 715.1>

  
a solution of 1 g of sodium nitrite in 6 ml of water, in re-

  
  <EMI ID = 716.1>

  
react at room temperature for 2 hours. At the end of the

  
  <EMI ID = 717.1>

  
crystals which have been filtered, washed with water and dried to obtain

  
  <EMI ID = 718.1>

  
  <EMI ID = 719.1>

  
  <EMI ID = 720.1>

  

  <EMI ID = 721.1>


  
  <EMI ID = 722.1>

  

  <EMI ID = 723.1>


  
  <EMI ID = 724.1>

  
and 1 g of thburea, then allowed to react at room temperature for 2 hours. At the end of the reaction, the mixture was

  
  <EMI ID = 725.1>

  
  <EMI ID = 726.1> the organic layer has been separated. the aqueous layer was also extracted in. using two 200 ml portions of ethyl acetate. The organic layers were combined and dried using anhydrous magnesium sulfate, after which the solvent was evaporated by distillation at reduced pressure. The residue has been purified

  
on a chromatographic column (Wako, silica gel C-200, chloroform developing agent: methanol = 20: 1) to obtain 3.2 g (

  
  <EMI ID = 727.1>

  

  <EMI ID = 728.1>


  
  <EMI ID = 729.1>

  
oroacetic and 10 ml of anisole 6,319 of

  
  <EMI ID = 730.1>

  
  <EMI ID = 731.1>

  
  <EMI ID = 732.1>

  
  <EMI ID = 733.1>

  
  <EMI ID = 734.1>

  
7-C2- (2-aminothiazol-4-yl) -2- trifluoroacetic acid <EMI ID = 735.1>

  

  <EMI ID = 736.1>


  
d, J = 8Hz, -CONH-).

  
In the same way as previously, the following compounds were obtained:

  
  <EMI ID = 737.1>

  
  <EMI ID = 738.1>

  
  <EMI ID = 739.1>

  
  <EMI ID = 740.1>

  

  <EMI ID = 741.1>


  
  <EMI ID = 742.1>

  
t
  <EMI ID = 743.1>
   <EMI ID = 744.1>

  

  <EMI ID = 745.1>


  
  <EMI ID = 746.1>

  

  <EMI ID = 747.1>


  

  <EMI ID = 748.1>

Example 29.

  
  <EMI ID = 749.1>

  
  <EMI ID = 750.1>

  
  <EMI ID = 751.1>

  

  <EMI ID = 752.1>


  
  <EMI ID = 753.1>

  

  <EMI ID = 754.1>


  
  <EMI ID = 755.1>

  
carboxylate

  
  <EMI ID = 756.1>

  
rature room for 3 hours. At the end of the reaction, the solvent was evaporated by distillation at reduced pressure and the

  
  <EMI ID = 757.1>

  
The organic layer was separated, washed with 20 ml of water and dried with anhydrous magnesium sulfate. The solvent was evaporated by distillation at reduced pressure. Diethyl was added to the residue

  
  <EMI ID = 758.1>

  
  <EMI ID = 759.1>

  

  <EMI ID = 760.1>


  
  <EMI ID = 761.1>

  

  <EMI ID = 762.1>


  
  <EMI ID = 763.1> <EMI ID = 764.1>

  

  <EMI ID = 765.1>


  
  <EMI ID = 766.1> <EMI ID = 767.1>

  

  <EMI ID = 768.1>

-CONH-).

  
(4) The compound was treated and reacted. obtained in (3) above in the same manner as in Example 17- (2) to obtain the compounds appearing in Table 20.

  
Table 20
  <EMI ID = 769.1>
 Table 21
  <EMI ID = 770.1>
   <EMI ID = 771.1>

  

  <EMI ID = 772.1>
 

Example 30.

  
By proceeding as in Example 29, the compounds shown in Table 21 are obtained.

  
The physical properties of these compounds were identical to those

  
  <EMI ID = 773.1>

Example 31.

  
(1) Was dissolved in 50 ml of anhydrous methylene chloride

  
  <EMI ID = 774.1> was added to the solution, after which the mixture was cooled to -35 [deg.] C.

  
Then, 1.12 g of ethyl chlorocarbonate were added and the mixture was allowed to react between -30 [deg.] C and -20 [deg.] C for 2 hours and

  
  <EMI ID = 775.1>

  
  <EMI ID = 776.1>

  
in 50 ml of anhydrous chloroform. We let the mixture react

  
  <EMI ID = 777.1>

  
room for 3 hours. At the end of the reaction, the solvent was evaporated by distillation at reduced pressure and the residue

  
  <EMI ID = 778.1>

  
after which the organic layer was separated. Again, we added

  
  <EMI ID = 779.1>

  
1.5 by addition of 2N hydrochloric acid while cooling. The organic layer was separated and dried with anhydrous magnesium sulfate. The solvent was evaporated by distillation at reduced pressure and the residue was added with diethyl ether. Crystals

  
  <EMI ID = 780.1>

  
  <EMI ID = 781.1>

  
  <EMI ID = 782.1>

  
  <EMI ID = 783.1>

  
ppm

  

  <EMI ID = 784.1>


  
  <EMI ID = 785.1>

  
  <EMI ID = 786.1>

  
  <EMI ID = 787.1>

  
sodium bicarbonate and insolubles were filtered. The filtrate was washed with 30 ml of ethyl acetate and then added

  
  <EMI ID = 788.1>

  
  <EMI ID = 789.1>

  
vee with 30 ml of solution. saturated with sodium chloride and dried

  
with anhydrous magnesium sulfate. the solvent was separated by distillation at reduced pressure and diethyl ether was added to the residue.

  
  <EMI ID = 790.1> <EMI ID = 791.1>

  

  <EMI ID = 792.1>


  
  <EMI ID = 793.1>

  
  <EMI ID = 794.1>

  

  <EMI ID = 795.1>


  

  <EMI ID = 796.1>
 

  

  <EMI ID = 797.1>


  

  <EMI ID = 798.1>
 

  

  <EMI ID = 799.1>


  

  <EMI ID = 800.1>
 

  

  <EMI ID = 801.1>


  

  <EMI ID = 802.1>
 

Example 33.

  
  <EMI ID = 803.1>

  
and 1 g of triethylamine and 2.9 g of pivaloyloxymethyl iodide were added to the solution while cooling, then the mixture was allowed to react for 30 minutes. At the end of the reaction, the mixture was poured into 300 ml of water and 300 ml of ethyl acetate and

  
  <EMI ID = 804.1>

  
the organic layer was separated, washed successively with 100 ml of water and 100 ml of saturated sodium chloride solution and dried with anhydrous magnesium sulfate, after which the solvent was evaporated by distillation at reduced pressure. The residue was

  
  <EMI ID = 805.1>

  
  <EMI ID = 806.1>

  
90.8%) of

  
pivaloyloxymethyl 7- [2- (2-tert.-amyloxy- <EMI ID = 807.1>

  
carboxylate.

  
  <EMI ID = 808.1>

  
  <EMI ID = 809.1>

  

  <EMI ID = 810.1>
 

  

  <EMI ID = 811.1>


  
  <EMI ID = 812.1>

  
carboxylate ..

  
and the solution was allowed to react at room temperature for 30 minutes. At the end of the reaction, the solvent was removed by distillation at reduced pressure and the residue was added.

  
  <EMI ID = 813.1>

  
  <EMI ID = 814.1>

  
dissant. The organic layer was separated and. dried. over anhydrous magnesium sulfate and a solution of dry HCl in diethyl ether was added thereto with cooling and stirring to obtain a deposit of white powder. The powder was filtered, washed

  
  <EMI ID = 815.1>

  
hydrochloride

  
pivaloyloxy-

  
  <EMI ID = 816.1>
  <EMI ID = 817.1>
  <EMI ID = 818.1>

  
  <EMI ID = 819.1>

  
let the mixture react at 0-5 [deg.] C for 1 hour. At the end of the

  
  <EMI ID = 820.1>

  
  <EMI ID = 821.1>

  
  <EMI ID = 822.1>

  
Read, the organic layer was separated and dried with anhydrous magnesium sulfate and the solvent was evaporated by distillation at reduced pressure. The residue was washed with diethyl ether and

  
  <EMI ID = 823.1>

  
  <EMI ID = 824.1>

  
while cooling. The crystals formed were. filtered, washed with diethyl ether and recrystallized from chloroform for. get 2,? 2g

  
(yield of 60.9%) of hydrochloride: from.

  
  <EMI ID = 825.1>
  <EMI ID = 826.1>
   <EMI ID = 827.1>

  

  <EMI ID = 828.1>


  

  <EMI ID = 829.1>
 

  

  <EMI ID = 830.1>


  

  <EMI ID = 831.1>
 

  

  <EMI ID = 832.1>


  

  <EMI ID = 833.1>
 

  

  <EMI ID = 834.1>


  

  <EMI ID = 835.1>
 

  

  <EMI ID = 836.1>


  

  <EMI ID = 837.1>
 

  

  <EMI ID = 838.1>


  

  <EMI ID = 839.1>
 

  

  <EMI ID = 840.1>


  

  <EMI ID = 841.1>
 

  

  <EMI ID = 842.1>


  

  <EMI ID = 843.1>


  

  <EMI ID = 844.1>
 

  

  <EMI ID = 845.1>


  

  <EMI ID = 846.1>
 

  

  <EMI ID = 847.1>


  

  <EMI ID = 848.1>
 

  

  <EMI ID = 849.1>


  

  <EMI ID = 850.1>
 

  

  <EMI ID = 851.1>


  

  <EMI ID = 852.1>


  

  <EMI ID = 853.1>
 

Example 35.

  
Was introduced into a mixed solvent of 8 ml of anhydrous chloride

  
  <EMI ID = 854.1>

  
phosphorus chloride at 0-5 [deg.] C and the mixture was allowed to react

  
at this temperature for 30 minutes .: Then we cooled

  
the mixture between -15 [deg.] C to -10 [deg.] C and 2.4 g of acid were added

  
  <EMI ID = 855.1>

  
let the mixture react at this temperature for 20 minutes.

  
Then, a solution of 4.47 g of pivaloyl hydrochloride was poured dropwise into the mixture.

  
  <EMI ID = 856.1>

  
  <EMI ID = 857.1>

  
during 30 minutes. At the end of the reaction, the solvent was evaporated off under reduced pressure and the residue was added with 50 ml of water and 50 ml of ethyl acetate, after which the pH was adjusted to 7 .0 using sodium bicarbonate. The organic layer was separated, washed with 30 ml of water and 30 ml of saturated sodium chloride solution and dried with magnesium sulfate. The solvent was evaporated by distillation at reduced pressure and the residue was added with diethyl ether. Crystals

  
  <EMI ID = 858.1>

  
pivaloyloxymethyl 7- [2-

  
  <EMI ID = 859.1>

  
carboxylate

  
  <EMI ID = 860.1>

  
  <EMI ID = 861.1>

Example 36.

  
By proceeding with. various starting compounds as in examples 33 or 35, corresponding compounds are obtained as follows

  
  <EMI ID = 862.1>

  
  <EMI ID = 863.1>

  

  <EMI ID = 864.1>


  

  <EMI ID = 865.1>
 

  

  <EMI ID = 866.1>


  

  <EMI ID = 867.1>
 

  

  <EMI ID = 868.1>


  

  <EMI ID = 869.1>
 

  

  <EMI ID = 870.1>


  

  <EMI ID = 871.1>
 

  

  <EMI ID = 872.1>


  

  <EMI ID = 873.1>
 

  

  <EMI ID = 874.1>


  

  <EMI ID = 875.1>
 

  

  <EMI ID = 876.1>


  

  <EMI ID = 877.1>
 

  

  <EMI ID = 878.1>


  

  <EMI ID = 879.1>
 

  

  <EMI ID = 880.1>


  

  <EMI ID = 881.1>
 

  

  <EMI ID = 882.1>


  

  <EMI ID = 883.1>
 

  

  <EMI ID = 884.1>


  

  <EMI ID = 885.1>
 

  

  <EMI ID = 886.1>


  

  <EMI ID = 887.1>
 

  

  <EMI ID = 888.1>


  

  <EMI ID = 889.1>
 

  

  <EMI ID = 890.1>


  

  <EMI ID = 891.1>
 

  

  <EMI ID = 892.1>


  

  <EMI ID = 893.1>


  

  <EMI ID = 894.1>
 

Example 37.

  
The procedure was as in Example 33- (D to obtain the compounds appearing in Table 29.

  

  <EMI ID = 895.1>


  

  <EMI ID = 896.1>
 

  

  <EMI ID = 897.1>


  

  <EMI ID = 898.1>
 

  
  <EMI ID = 899.1>

  

  <EMI ID = 900.1>


  
  <EMI ID = 901.1>

  

  <EMI ID = 902.1>


  
  <EMI ID = 903.1>

  

  <EMI ID = 904.1>


  
  <EMI ID = 905.1>

  
  <EMI ID = 906.1>

  
The procedure was as in examples 12- (l) and 28- (l) and (2)

  
  <EMI ID = 907.1>

  
to get the <EMI ID = 908.1>
  <EMI ID = 909.1>
  <EMI ID = 910.1>
  <EMI ID = 911.1>

  
  <EMI ID = 912.1>

  
  <EMI ID = 913.1>

  
laundered triturated with starch, then the mixture was packaged in the form of tablets.

  
  <EMI ID = 914.1>

  

  <EMI ID = 915.1>


  
  <EMI ID = 916.1>

  
Formulation

  
  <EMI ID = 917.1>

  

  <EMI ID = 918.1>


  
Similar capsules can be obtained using other compounds than those listed above.

  
  <EMI ID = 919.1>

  
According to the formulation shown below, the main component has been mixed and kneaded beforehand with lactose. The mixture

  
was added with an aqueous solution of hydroxypropyl cellulose. The resulting mixture was kneaded, dried and powdered. The powder was mixed with magnesium stearate kneaded beforehand with starch, then the final mixture was tableted.

  
Formulation

  
Acid salt

  
  <EMI ID = 920.1>

  
  <EMI ID = 921.1>

  
aminothiazol-4-yl) -2- (syn) -

  
  <EMI ID = 922.1>

  
r:

  

  <EMI ID = 923.1>


  
Using other compounds, analogous tablets are obtained. Preparation example 4.

  
  <EMI ID = 924.1>

  
magnesium spleen were mixed and kneaded, then the mixture was mixed with the remaining starch, hydroxypropyl cellulose and the main component. The final mixture was packaged in capsule form according to a conventional process.

  
Formulation

  
  <EMI ID = 925.1>

  
  <EMI ID = 926.1>

  

  <EMI ID = 927.1>


  
Using other compounds, analogous capsule formulations are obtained.

  
Preparation example 5 ..

  
A mixture of sodium bicarbonate and d. acid

  
  <EMI ID = 928.1>

  
4-carboxylic

  
to obtain a sterilized and lyophilized sodium salt. One gram of sodium salt (activity) has been dissolved in physiological solution

  
saline to obtain an injectable dose.

  
Preparation example 6.

  
One gram (activity) of the lyophilized product obtained according to the example

  
of preparation 5 was dissolved in 4 ml of a chlorine solution

  
  <EMI ID = 929.1>

  
  <EMI ID = 930.1>

  
Preparation example 7.

  
One gram (activity) of the lyophilized product obtained. according to preparation example 5 was dissolved in 20 ml of glucose solution

  
  <EMI ID = 931.1>

  
  <EMI ID = 932.1>

  
  <EMI ID = 933.1>

  
formed into freeze-dried products (sodium salts) or injectable products using the preparation examples 5-7.

  
  <EMI ID = 934.1>

  

  <EMI ID = 935.1>


  
  <EMI ID = 936.1>

  
  <EMI ID = 937.1>

  
tetrazolyl being attached to the exomethylene group in position 3

  
  <EMI ID = 938.1>

  
  <EMI ID = 939.1>

  
hydrogen or an amino group which can optionally be

  
  <EMI ID = 940.1>

  
  <EMI ID = 941.1>

  

  <EMI ID = 942.1>


  
  <EMI ID = 943.1>

  
  <EMI ID = 944.1>

  
syn or anti isomer or a mixture of both; B represents a

  
hydrogen atom or a lower alkoxy group .., '


    

Claims (1)

 <EMI ID = 945.1> that B is a hydrogen atom "  <EMI ID = 946.1> that A is a group -CE  <EMI ID = 947.1> A is a group represented by the formula:  <EMI ID = 948.1>  <EMI ID = 949.1> <EMI ID = 950.1>  <EMI ID = 951.1>  <EMI ID = 952.1>  <EMI ID = 953.1>  <EMI ID = 954.1>  <EMI ID = 955.1> that A represents a group of formula:  <EMI ID = 956.1>  <EMI ID = 957.1>  <EMI ID = 958.1>  <EMI ID = 959.1> that A is represented by one; formula group:  <EMI ID = 960.1>  <EMI ID = 961.1>  <EMI ID = 962.1> that A is represented by the formula:  <EMI ID = 963.1>  <EMI ID = 964.1>  <EMI ID = 965.1> carbon-nitrogen .. <EMI ID = 966.1> that A is a group of formula:  <EMI ID = 967.1> HHH »Hrap  <EMI ID = 968.1>  <EMI ID = 969.1>  <EMI ID = 970.1>  <EMI ID = 971.1> <EMI ID = 972.1>  <EMI ID = 973.1>  <EMI ID = 974.1> minus one compound chosen from the group comprising halogen, <EMI ID = 975.1> forming ester easily eliminated in living organisms. and its salts ..  <EMI ID = 976.1> ester easily eliminated in living organisms and its salts.  <EMI ID = 977.1> its esters comprising an ester group easily eliminated in living organisms and its salts.  <EMI ID = 978.1> its esters comprising an ester group easily eliminated in living organisms and its salts.  <EMI ID = 979.1> an ester-forming group easily eliminated in living organisms, and its salts.  <EMI ID = 980.1> forming an aster easily eliminated in living organelles, and its salts. <EMI ID = 981.1> forming -ester easily eliminated in living organisms, and its salts.  <EMI ID = 982.1> un.group ester easily eliminated in living organisms, and its salts.  <EMI ID = 983.1> a. ester group easily eliminated in living organisms, and its salts.  <EMI ID = 984.1>  <EMI ID = 985.1> and its salts.  <EMI ID = 986.1> salts. <EMI ID = 987.1> its esters comprising an ester group easily eliminated in living organisms, and its salts. 47. Process for preparing cephalosporins corresponding to the form following mule, and their salts:  <EMI ID = 988.1>  <EMI ID = 989.1>  <EMI ID = 990.1> no, aryl, acylamino, aromatic heterocyclic, triazolyl or tetrazolyl;; said aromatic heterocyclic group being attached to the exomethylene group in position 3 of the cephem ring by a carbon-carbon bond and said triazolyl or tetrazolyl group being attached to the exomethylene group in position  <EMI ID = 991.1>  <EMI ID = 992.1> me of hydrogen or an amino group, possibly protected or  <EMI ID = 993.1>  <EMI ID = 994.1>   <EMI ID = 995.1> a syn or anti isomer or the mixture of the two; B represents  <EMI ID = 996.1>  <EMI ID = 997.1>  <EMI ID = 998.1>  <EMI ID = 999.1>  <EMI ID = 1000.1> formula  <EMI ID = 1001.1>  <EMI ID = 1002.1> different, represent hydrogen atoms or remainders  <EMI ID = 1003.1> R15  <EMI ID = 1004.1> organic residues not participating in the reaction, and  <EMI ID = 1005.1>  <EMI ID = 1006.1>  <EMI ID = 1007.1>  <EMI ID = 1008.1> a reactive derivative at the carboxyl group level of the same compound, or (B) by reacting a compound of the following formula, or its salt:  <EMI ID = 1009.1>  <EMI ID = 1010.1>  <EMI ID = 1011.1>  <EMI ID = 1012.1>  <EMI ID = 1013.1>  <EMI ID = 1014.1>  <EMI ID = 1015.1>  <EMI ID = 1016.1> react a compound corresponding to the following formula, or its salt:  <EMI ID = 1017.1>  <EMI ID = 1018.1>  <EMI ID = 1019.1> of an alkali or alkaline earth metal represented by the form  <EMI ID = 1020.1>  <EMI ID = 1021.1>  <EMI ID = 1022.1> and then, by reacting the reaction product obtained <EMI ID = 1023.1>  <EMI ID = 1024.1>  <EMI ID = 1025.1>  <EMI ID = 1026.1>  <EMI ID = 1027.1> a reactive derivative at the carboxyl group of this compound, then optionally, by eliminating the protective group, by protecting  <EMI ID = 1028.1>  <EMI ID = 1029.1>  <EMI ID = 1030.1>  <EMI ID = 1031.1>  <EMI ID = 1032.1> presents a group of formula  <EMI ID = 1033.1>  <EMI ID = 1034.1>  <EMI ID = 1035.1>  <EMI ID = 1036.1>  <EMI ID = 1037.1>  <EMI ID = 1038.1> <EMI ID = 1039.1>  <EMI ID = 1040.1>  <EMI ID = 1041.1> adorns the compound corresponding to the formula:  <EMI ID = 1042.1>  <EMI ID = 1043.1>  <EMI ID = 1044.1>  <EMI ID = 1045.1> optionally, by eliminating the protective group, by protecting the carboxyl group or by transforming the product into a salt.  <EMI ID = 1046.1>  <EMI ID = 1047.1>  <EMI ID = 1048.1> presents a group of formula  <EMI ID = 1049.1>  <EMI ID = 1050.1>  <EMI ID = 1051.1>  <EMI ID = 1052.1>  <EMI ID = 1053.1> 58. Method according to claim 47, characterized in that prepares the compound corresponding to the formula, or its salt:,,,.  <EMI ID = 1054.1>   <EMI ID = 1055.1>  <EMI ID = 1056.1>  <EMI ID = 1057.1>  <EMI ID = 1058.1>  <EMI ID = 1059.1>  <EMI ID = 1060.1>  <EMI ID = 1061.1>  <EMI ID = 1062.1> claim-47, in the presence of a lower alcohol, with a lower alcoholate of an alkali or alkaline earth metal  <EMI ID = 1063.1>  <EMI ID = 1064.1> gir the reaction product with a halogenating agent and removing the protective group, protecting the carboxyl group or converting the product to salt. 62. Method according to claim 61, characterized in that A  <EMI ID = 1065.1>  <EMI ID = 1066.1> meets the formula  <EMI ID = 1067.1>  <EMI ID = 1068.1> are defined as in claim 47.  <EMI ID = 1069.1>  <EMI ID = 1070.1> 65. Method according to one of claims 61 to 64, characterized in  <EMI ID = 1071.1> <EMI ID = 1072.1> 66. Cephalosporins corresponding to the following formula and their salts:  <EMI ID = 1073.1> -> in which R &#65533; represents a hydrogen atom or a group  <EMI ID = 1074.1>  <EMI ID = 1075.1> or tetrazolyl. said aromatic heterocyclic group being  <EMI ID = 1076.1> tetrazolyl being attached to the exomethylene group in position 3 of the cephèae ring by a carbon-nitrogen bond, A represents the group -CE 2- or a group of formula  <EMI ID = 1077.1> in which  <EMI ID = 1078.1> or a mixture of. two, R represents a halogen atom, B represents a hydrogen atom or a lower alkoxy group. 67. Cephalosporins and their salts according to claim 66, charac-  <EMI ID = 1079.1> amino, or a triazolyl or tetrazolyl group, substituted or not, attached to the exomethylene group in position 3 of the cephem ring by a carbon-nitrogen bond. 68. Cephalosporins and their salts according to claim 67, characterized in that B is a hydrogen atom. 69. Cephalosporins and their salts according to claim 68, charac- that A represents the group -CE 70. Cephalosporins and their salts according to claim 69, ca-  <EMI ID = 1080.1> methylene in position 3 of the cephem ring by a carbon-nitrogen bond. 71. Cephalosporins and their salts according to claim 68. because characterized in that A represents a group of formula -C- v  <EMI ID = 1081.1>  <EMI ID = 1082.1> claim 66. 72. Cephalosporins and their salts according to claim 71, characterized in that R is a group, substituted or unsubstituted, 1,2,  <EMI ID = 1083.1> bone-nitrogen. 73- Cephalosporins corresponding to the following formula and their salts:  <EMI ID = 1084.1>  <EMI ID = 1085.1> protector of carboxyl, R <2> represents a group, substituted or  <EMI ID = 1086.1> tetrazolyl, said aromatic heterocyclic group being attached to the exomethylene group in position 3 of the cephem ring by a carbon-carbon bond and said triazclyl group or tetrazolyl being attached to the exomethylene group in po-  <EMI ID = 1087.1>  <EMI ID = 1088.1> a hydrogen atom or an amino group which may optionally be protected or substituted, B represents a hydrogen atom or a lower alkoxy group. 74. Cephalosporins and their salts according to claim 73, characterized in that B is a hydrogen atom.  <EMI ID = 1089.1> characterized in that R is a group, substituted or unsubstituted, 1,2,4-triazolyl or 2- (1,2,3,4-tetrazolyl) attached to the exomethylene group in position 3 of the cephem ring by a carbon- nitrogen.  <EMI ID = 1090.1> characterized in that R <3> is a hydrogen atom. 77. Cephalosporins and their salts according to claim 76,  <EMI ID = 1091.1>  <EMI ID = 1092.1>  <EMI ID = 1093.1> corresponding to the following formula, and its salts, ::.  <EMI ID = 1094.1> in which R represents a hydrogen atom or a group  <EMI ID = 1095.1>  <EMI ID = 1096.1> attached to the exomethylene group in position 3 of the cephem cycle  <EMI ID = 1097.1> a formula group  <EMI ID = 1098.1>   <EMI ID = 1099.1> represent hydrogen atoms or organic residues not participating in the reaction, or, a group of formula  <EMI ID = 1100.1>  <EMI ID = 1101.1>  <EMI ID = 1102.1> refer to hydrogen atoms or organic residues not participating in the reaction, B represents a hydrogen atom or a lower alkoxy group.  <EMI ID = 1103.1> cephème-4-carboxylic and its salts according to claim 78,  <EMI ID = 1104.1>  <EMI ID = 1105.1> cephème-4-carboxylic and its salts according to claim 80,  <EMI ID = 1106.1> substituent selected from the group consisting of halogen, alkyl hydrox, hydroxyl, protected hydroxyl, aralkyl, alkoxy, alkythio, cyano, amino, protected amino, carboxyl, protected carboxyl, alko-  <EMI ID = 1107.1>  <EMI ID = 1108.1> carboxylic acid and its salts according to claim 81, charac-  <EMI ID = 1109.1> <EMI ID = 1110.1> 4-carboxylic acid and its salts according to claim 82, charac-  <EMI ID = 1111.1>  <EMI ID = 1112.1>  <EMI ID = 1113.1> following formula, and its salts;  <EMI ID = 1114.1>  <EMI ID = 1115.1> carboxyl protector, R2a represents a group, substituted or not, triazolyl or tetrazolyl attached to the exomethylene group in position 3 of the cephem ring by a car-  <EMI ID = 1116.1>  <EMI ID = 1117.1>   <EMI ID = 1118.1>  <EMI ID = 1119.1>  <EMI ID = 1120.1>  <EMI ID = 1121.1>  <EMI ID = 1122.1> ferent, represent hydrogen atoms or organic residues not participating in the reaction, B represents a  <EMI ID = 1123.1> by reacting a responding cephalosporanic acid  <EMI ID = 1124.1>  <EMI ID = 1125.1>  <EMI ID = 1126.1>  <EMI ID = 1127.1> represents a group, substituted or not, acyloxy or carbamoyloxy, Y represents> S or;: - 50 + 0, or its derivative at group level  <EMI ID = 1128.1> no, in an organic solvent in the presence of an acid or an acid complex compound, and then optionally, the protective group is removed, the carboxyl group is protected or the product is transformed into a salt.  <EMI ID = 1129.1> according to claim 85, characterized in that B is a hydrogen atom. 87. Process for the preparation of acid 7- (substituted or unsubstituted amino) -  <EMI ID = 1130.1> according to claim 86, characterized in that said acid or complex acid compound is a protonic acid, a Lewis acid or a complex Lewis acid compound. 88. Process for the preparation of acid 7- (substituted or unsubstituted amino) -  <EMI ID = 1131.1> according to claim 87, characterized in that the protonic acid is sulfuric, sulfonic acid or a super-acid. 89. Process for the preparation of acid 7- (substituted or unsubstituted amine) -  <EMI ID = 1132.1> <EMI ID = 1133.1>  <EMI ID = 1134.1> boron rure or a complex of this compound.  <EMI ID = 1135.1>  <EMI ID = 1136.1> that said organic solvent is a carboxylic acid. organic, a ketone, an ether, an ester, a nitrile, an aitroalkane or a sulfolane.  <EMI ID = 1137.1> according to one of claims 85 to 90, characterized in that R is an acetoxy group. 92. Process for the preparation of acid 7- (substituted or unsubstituted amino) -  <EMI ID = 1138.1> according to one of claims 85 to 92, characterized in that  <EMI ID = 1139.1> 94. Pharmaceutical composition for the treatment of ailments  <EMI ID = 1140.1> main and animal, characterized by the presence of an appropriate amount of a cephalosporin or its acceptable salt of  <EMI ID = 1141.1>  <EMI ID = 1142.1> inert acceptable. Brussels, 25 September 1981  <EMI ID = 1143.1>