BE835898A - PSEUDOTRISACCHARIDES AND THEIR PREPARATION METHODS - Google Patents

Description

       

   <EMI ID = 1.1>

  
, methods for their production, pharmaceutical formulations, as well as methods for their use.

  
 <EMI ID = 2.1>

  
More specifically, the present invention relates to

  
 <EMI ID = 3.1>

  
Antibiotics G-418, 66-40B, 66-40D, JI-20A, JI-20B and G-52, as well as the 1-N-alkyl derivatives thereof. ,

  
Broad spectrum anti-bacterial agents are known in the art which can be chemically classified.

  
 <EMI ID = 4.1>

  
which are particularly interesting are those in which the aminoglycosyl group in position 6- is a

  
 <EMI ID = 5.1>

  
JI-20A and Antibiotic JI-20B.

  
Also known in the prior art are

  
 <EMI ID = 6.1>

  
broad-spectrum anti-bacterial activity and possess increased activity against compounds resistant to the bacterial 1-N-unsubstituted agent.

  
The new pseudotrisaccharides of this

  
 <EMI ID = 7.1>

  
 <EMI ID = 8.1> <EMI ID = 9.1> Antibiotic 66-40D, Antibiotic G-418, Antibiotic

  
 <EMI ID = 10.1> a 1.3-diaminocyclitol of the formula

  

 <EMI ID = 11.1>


  
 <EMI ID = 12.1>

  
minohydroxyalkyl, phenyl, benzyl, or a tolyl, said aliphatic radicals having up to seven carbon atoms and carrying the substituents, in the case of substitution by amino and bydroxy groups, on different carbon atoms and X is hydroxy, azido or amino; with the condition that, in the case of derivatives

  
 <EMI ID = 13.1>

  
Antibacterial agents of the present invention

  
 <EMI ID = 14.1>

  
(aminoglycosyl) -2-deoxystreptamines in which the aminoglycoside radical in position 6- is garosaminyl.

  
 <EMI ID = 15.1>

  
 <EMI ID = 16.1> <EMI ID = 17.1>

  
Biotic JI-20B and Antibiotic G-52, which compounds are defined by the following structural formula X:

  

 <EMI ID = 18.1>


  
<1>

  
where X and R have the meanings given plus

  
 <EMI ID = 19.1>

  
aminoglycosyl group chosen from the group formed by:

  

 <EMI ID = 20.1>
 

  

 <EMI ID = 21.1>
 

  

 <EMI ID = 22.1>


  
Other useful derivatives of 4,6-di-0- (aminoglyeosyl) - 2-deoxystreptamines of the present invention include the derivatives of tobramycin, kanamycin A,

  
 <EMI ID = 23.1>

  

 <EMI ID = 24.1>


  
in which formula X and R have the given meanings

  
 <EMI ID = 25.1>

  
aminoglycosyl group chosen from the group formed by:

  

 <EMI ID = 26.1>


  
 <EMI ID = 27.1>

  

 <EMI ID = 28.1>


  
where X and R have the meanings given plus

  
 <EMI ID = 29.1>

  

 <EMI ID = 30.1>


  
in which X and R have the meanings given above for formula 1 and in which AG3 is a group

  
 <EMI ID = 31.1>

  

 <EMI ID = 32.1>


  
 <EMI ID = 33.1>

  
ized in that they are in the form of white amorphous powders.

  
. The present invention also relates, in its <EMI ID = 34.1>

  
salts are made according to known processes such as by neutralization of the free base with acid

  
 <EMI ID = 35.1>

  
suitable for this purpose include acids such as 2. * hydrochloric acid; sulfuric acid, phosphoric acid,

  
 <EMI ID = 36.1>

  
have the following physical properties: solid, blame ,. soluble in water and insoluble in most polar and non-polar organic solvents.

  
The compounds of the present invention, as defined by the formulas X - XIII, particularly those

  
 <EMI ID = 37.1>

  
and their non-toxic, pharmaceutically acceptable acid addition salts, in general, exhibit broad spectrum antibacterial activity and possess a high spectrum

  
 <EMI ID = 38.1>

  
parent ticks, that is, the antibiotics from which they are derived.

  
 <EMI ID = 39.1>

  
 <EMI ID = 40.1>

  
glycosyl) -2-deoxystreptamines mentioned above in which the 2-deoxystreptamine group is replaced by a 1,3-diaminocyclitol of formula

  

 <EMI ID = 41.1>


  
wherein X is either azido or amino, or (excluding sisomycin) hydroxy; or in which the 2-deoxystreptamine group is replaced by a 1,3-

  
 <EMI ID = 42.1>
-CH2Y 'with Y having the above meaning and X being either azido or amino, or (excluding sisomycin) hydroxy; as well as the addition salts. of pharmaceutically acceptable acid of these derivatives.

  
not.

  
 <EMI ID = 43.1>

  
most preferred, although propyl is also preferred.

  
A particularly preferred group of compounds

  
 <EMI ID = 44.1>

  
 <EMI ID = 45.1>

  
 <EMI ID = 46.1>

  
as well as the pharmaceutically acceptable acid addition salts of these derivatives.

  
Another particularly preferred group of compounds

  
 <EMI ID = 47.1>

  
G-418, wherein R is, in formula I, ethyl or hydrogen, while X is hydroxy; as well as the pharmaceutically acceptable acid addition salts of. these.

  
In another of its "product" aspects, the present invention relates to derivatives of 4,6-di-O- (aminoglycosyl) -

  
 <EMI ID = 48.1>

  
dideoxykanamycin B, Antibiotic G-52, Antibiotic
66-40B, Antibiotic 66-40D, Antibiotic G-418, Antibiotic JI-20A, Antibiotic JI-20B and sisomycin, in which the 2-deoxystreptamine moiety is replaced by a '1,3 -diaminocyclitol of formula:

  

 <EMI ID = 49.1>


  
he

  
 <EMI ID = 50.1>

  
hydrogen, alkyl, alkenyl, cycloalkyl,

  
 <EMI ID = 51.1>

  
nohydroxyalkyl, phenyl, benzyl, or a tolyl,

  
 <EMI ID = 52.1>

  
provided that, in the case of sisomycin derivatives ,. the X substituent is azido or amino; and acid addition salts thereof.

  
 <EMI ID = 53.1>

  
 <EMI ID = 54.1>

  
amino group at position 1- is acylated. In addition to the fact that they are intermediaries in the preparation

  
 <EMI ID = 55.1>

  
they are also interesting or valuable by the fact

  
that they present in themselves an anti-bacterial activity

  
 <EMI ID = 56.1>

  
being particularly useful compounds. Pharmaceutically acceptable acid addition salts of the compounds

  
 <EMI ID = 57.1>

  
sulfuric acid, phosphoric acid, propionic acid, maleic acid, and phenylacetic acid are also

  
included within the scope of the invention.

  
These salts can be prepared by dissolving the

  
free nitrogenous base in water, adjusting the pH to <EMI ID = 58.1>

  
solution of the antibacterial agent at 4.0 and lyophilizing the resulting solution.

  
In one of the methods of the present invention,

  
 <EMI ID = 59.1>

  
what are gentamycin A, gentamycin B, gentamycin

  
 <EMI ID = 60.1>

  
 <EMI ID = 61.1>

  
1,3-diaminocyclitol of the form

  

 <EMI ID = 62.1>


  
 <EMI ID = 63.1>

  
an N-alkylaminoalkyl, an aminohydroxyalkyl, an N-alkylaminohydroxyalkyl, phenyl, benzyl or a tolyl, said aliphatic radicals having up to seven carbon atoms, and, in the case of substitution by amino and hydroxy, bearing the substituents on different carbon atoms; and X is hydroxy, azido or amino; with the proviso that in the case of sisomycin derivatives, the substituent X is an azido or an amino when R is the group CH2Y; and the pharmaceutically acceptable acid addition salts thereof, are prepared

  
 <EMI ID = 64.1>

  
formula
 <EMI ID = 65.1>
 wherein formula R has the above meaning and XI is hydroxy or azido; and which derivative is per-Nprotected and O.-protected in all positions other than the 5- position; the removal of protecting groups and, if

  
 <EMI ID = 66.1>

  
wherein the substituent X is amino is desired, reducing the azido group to the 5- position either before or after removal of the protecting groups and, if desired, alkylating a compound wherein R is hydrogen, to

  
 <EMI ID = 67.1>

  
being defined as above; and isolating the derivative as or in the form of a pharmaceutically acceptable acid addition salt.

  
 <EMI ID = 68.1>

  
 <EMI ID = 69.1>

  
methods known in the prior art.

  
Obviously, when a final compound having a 5-epi-azido group is desired, the protecting groups should be such that the reaction conditions employed for the removal thereof do not interfere with the reaction.

  
 <EMI ID = 70.1>

  
in general, be susceptible to cleavage or scission by moderate acid hydrolysis or basic hydrolysis if the azido group is desired in the final compound. In such a case, the removal of the protecting groups can be effected by treating a compound, wherein the 1,3-diaminocyclitol moiety is of formula II with X 'being an azido, at elevated temperatures with an aqueous base and , when acetals or ketals are present, also by treatment with a moderate aqueous acid.

  
 <EMI ID = 71.1>

  
is hydroxy or amino, starting compounds are used

  
 <EMI ID = 72.1>

  
In such cases also, the protecting groups may be present, the removal thereof being advantageously carried out by reductive cleavage.

  
For example, in a 5-epi-azido-5deoxy intermediate in which the 1,3-diaminocyclitol group is of formula II and in which all the 0- and Nprotective groups are capable of cleavage by a base (for

  
 <EMI ID = 73.1>

  
cine), the treatment of this intermediate at 100 [deg.] C with aqueous sodium hydroxide will produce a 5-epi-azido-5deoxyaminoglycoside according to the invention, of antibacterial activity (for example 5-epi-azido -5-deoxysisomycin).

  
 <EMI ID = 74.1>

  
Antibiotic JI-20A), after treatment with a base as described above, the resulting product is treated with a moderate aqueous acid followed by the neutralization of said aqueous acid mixture with a moderate base (for example aqueous ammonium hydroxide). Purification of the resulting product

  
by known techniques, usually by chromatography gives an agent endowed with anti-bacterial activity according to the present invention of the form 5-epi-azido-5-deoxyaminogly-

  
 <EMI ID = 75.1>

  
a 5-epi-azido group is subjected to the removal of protecting groups and the azido group is transformed into amino. The conversion of the azido group is usually carried out either with hydrogen in the presence of a catalyst or with an alkali metal in liquid ammonia.

  
 <EMI ID = 76.1>

  
reduction by means of an alkali metal in ammonia:
liquid is preferable in order to avoid reduction of the double bond.

  
 <EMI ID = 77.1>

  
deoxy with hydrogen in the presence of a catalyst, the catalysts most frequently used are platinum and palladium and preferably palladium on charcoal.

  
The hydrogenation is usually carried out at room temperatures in lower alkanoic acids, preferably acetic acid, although other solvents, such as lower alkanols, can be used. The hydrogenation is continued until there is no more discernible drop in hydrogen pressure and the derivative

  
 <EMI ID = 78.1>

  
removing the solvent, for example by distillation, and then treating, if necessary, with a base and an acid

  
 <EMI ID = 79.1>

  
all N-protecting groups and 0 residual protectors. When the process is carried out with 5-epi-azido- intermediates

  
 <EMI ID = 80.1>

  
benzyloxycarbonyl protecting groups are advantageously removed during the hydrogenation process and the derivative

  
1 <EMI ID = 81.1>

  
 <EMI ID = 82.1>

  
base (eg by 2N sodium hydroxide) for

  
 <EMI ID = 83.1>

  
isolated and purified using known techniques. Thus, in a typical embodiment of the hydrogenation of a

  
 <EMI ID = 84.1>

  
dissolved in acetic acid, is hydrogenated at room temperature under an initial hydrogen pressure of

  
4 atmospheres in the presence of 30% palladium catalyst on charcoal. When no more drop in hydrogen pressure is detected, the catalyst is removed by filtration and the solvent is removed by distillation under

  
 <EMI ID = 85.1>

  
by treatment with 2N sodium hydroxide at high temperatures (for example at 100 [deg.] C), then neutralization with acetic acid, removal of all insolubles by filtration, concentration of the reaction solution

  
 <EMI ID = 86.1>

  
resin known under the trade name "Amberlite IRC-50" (H + form), followed by elution. by ammonium hydroxide, with a concentration and lyophilization of

  
 <EMI ID = 87.1>

  
which is a novel anti-bacterial agent according to the present invention.

  
Any acetal or ketal protecting groups of 5-epi-

  
 <EMI ID = 88.1>

  
starting materials can be removed after hydrogenation and treatment of the product thus formed with the base, by treatment with a moderate aqueous acid, for example with dilute mineral acids, or with trifluoroacetic acid, or usually with dilute alkanoic acids such as 'acetic acid.

  
 <EMI ID = 89.1>

  
by reaction thereof with an alkali metal (eg potassium, lithium and, preferably, sodium) in

  
 <EMI ID = 90.1>

  
such as tetrahydrofuran and liquid ammonia to which the alkali metal (eg sodium) is added slowly, and the reaction mixture is stirred for a few hours.

  
 <EMI ID = 91.1>

  
residual protectors are removed by adding water to the reaction mixture to give sodium hydroxide

  
 <EMI ID = 92.1> 5-deoxysisomycin.

  
 <EMI ID = 93.1>

  
 <EMI ID = 94.1>

  
final corresponding, having a 5-epi-azido group, removing all protecting groups and then converting the 5-epi-azido group to the 5-epi-amino group using essentially the same conditions as described above.

  
When a final compound is desired in which, in

  
 <EMI ID = 95.1>

  
 <EMI ID = 96.1>

  
removal of the protecting groups present in the molecule. Protecting groups are removed by reaction with an aqueous base or, when susceptible, reductive cleavage protecting groups are present, by reaction with a reducing agent (such as hydrogen in the presence of a catalyst or an alkali metal in it. liquid ammonia) following which treatment with an aqueous base is carried out; when des, acetals or ketals are present, <EMI ID = 97.1>

  
 <EMI ID = 98.1>

  
for the case where a 5-epi-amino derivative is obtained.

  
The starting compounds, in the above process, in which the 1,3-diaminocyclitol group is of formula II, and which contain protecting groups, are new compounds and they can be described as follows.

  
 <EMI ID = 99.1>

  
 <EMI ID = 100.1>

  
Although any amino protecting group can be used, particularly amino protecting groups.

  
 <EMI ID = 101.1>

  
below) for the starting compounds of the process of

  
present invention include (lower alkoxy) carbonyls (preferably having up to eight carbon atoms

  
 <EMI ID = 102.1>

  
analogues) and, preferably, benzyloxycarbonyl. The

  
lower alkanoyl preferably having up to 8 atoms

  
carbon (eg acetyl, propionyl, valeryl, caprylyl) are also. useful amino (Z) protecting groups, particularly for compounds derived

  
 <EMI ID = 103.1>

  
gentamycin A and kanamycins).

  
The above amino protecting groups can be removed by treatment with a base (eg with sodium hydroxide) or, in the case of benzyloxycarbonyl by reductive cleavage methods known in the art. Byloxycarbonyl is a preferred amino protecting group since it is removed under reaction conditions such as a 5-epi- intermediate.

  
 <EMI ID = 104.1> <EMI ID = 105.1> hydrogen in the presence of a catalyst (preferably

  
palladium) or with an alkali metal (eg sodium or potassium) in liquid ammonia to give a 5-epi-amino-5-deoxyaminoglycoside according to the present invention. In addition to the above, benzyloxycarbonyl is a preferred amino protecting group for the starting compounds of this process since, in aminoglycosides having a hydroxyl function adjacent to the amino function,

  
 <EMI ID = 106.1>

  
garosaminyl of the aminoglycosides of formula X, the derivative

  
 <EMI ID = 107.1>

  
benzyloxycarbonyl compounds of formula X), when subjected to basic conditions (for example with

  
 <EMI ID = 108.1>

  
benzyl. Similarly, the N-alkoxycarbonyl derivatives will form oxazolidinones with an adjacent hydroxyl function. In addition, when a starting compound

  
 <EMI ID = 109.1>

  
respectively.

  
The hydroxyl functions in the starting compounds of this process are suitably protected by the 2-acyl radicals of the hydrocarbylcarboxylic acids preferably having up to 8 carbon atoms (these

  
 <EMI ID = 110.1>

  
 <EMI ID = 111.1>

  
ketones and aldehydes preferably having up to 8 carbon atoms to form ketals and acetals, respectively, including cyclic acetals and ketals
(said hydrocarbonylidene radicals being designated by

  
 <EMI ID = 112.1> <EMI ID = 113.1>

  
used to protect the hydroxyl functions.

  
In general, the neighboring hydroxyl groups in the aminoglycoside precursors of the starting compounds of this process are suitably protected by cyclic acetals or ketals. By "neighboring hydroxyl groups" is meant neighboring hydroxyl groups and non-neighboring hydroxyl groups which are located so as to form together a cyclic ketal or cyclic acetal function with ketones and aldehydes, or their derivatives, respectively. As examples of neighboring hydroxyl groups, mention may be made of the 2 <1>, 3 <1> -hydroxyl groups in gentamycins B and Blet in kanamycin A (which form

  
 <EMI ID = 114.1>

  
dene), 3 ', 4 * -hydroxyl groups in Antibiotic? JI-20A and JI-20B and in kanamycin B (which form

  
 <EMI ID = 115.1>

  
Cyclic ketal and cyclic acetal derivatives of said neighboring hydroxyl groups include

  
 <EMI ID = 116.1>

  
being removable by treatment with a moderate aqueous acid

  
 <EMI ID = 117.1>

  
nature of the hydrocarbon radicals or of the substituted "ylidene" hydrocarbon radicals of the cyclic ketals and acetals

  
 <EMI ID = 118.1>

  
"blocking groups", do not enter into the method of the invention and are therefore removed so that

  
the free hydroxyls are regenerated in their initial form.

  
In the starting compounds of the processes of the present invention, the isolated hydroxyl groups other than the 5-hydroxyl group, such as 211-hydroxy present

  
in all of the aminoglycoside precursors of this invention,

  
 <EMI ID = 119.1>

  
Antibiotic 66-40B and in gentamycin A, as well as other hydroxyl groups which are not protected by cyclic ketal or cyclic acetal functions

  
 <EMI ID = 120.1>

  
 <EMI ID = 121.1>

  
said hydrocarbyl preferably having up to 8 carbon atoms. Useful hydrocarbylcarbonyl radicals are

  
 <EMI ID = 122.1>

  
arylcarboxylics such as o, m and p-toluayl, mesitoyl and, preferably, benzoyl.

  
 <EMI ID = 123.1> <EMI ID = 124.1>
 <EMI ID = 125.1>
  <EMI ID = 126.1>

  
for R, but in which any amino function is substituted

  
 <EMI ID = 127.1>

  
 <EMI ID = 128.1>

  
hydroxyl is alpha or beta to the amino protecting group Z, which is benzyloxycarbonyl or alkoxycarbonyl, the hydroxyl group together with said protecting group Z is transformed into an oxazolidinone or a

  
 <EMI ID = 129.1>

  
'as defined below; and <EMI ID = 130.1> mines of the following formula XV

  

 <EMI ID = 131.1>


  
 <EMI ID = 132.1>

  
chosen from the group formed by benzyloxycarbonyls,

  
 <EMI ID = 133.1>

  
by :
 <EMI ID = 134.1>
  <EMI ID = 135.1>

  
formula XVI:

  

 <EMI ID = 136.1>


  
 <EMI ID = 137.1>

  
W is a hydrocarbureylidene having up to 8 carbon atoms, which is selected from the group consisting of

  
 <EMI ID = 138.1>

  
 <EMI ID = 139.1>

  
 <EMI ID = 140.1>

  
 <EMI ID = 141.1>

  
chosen from the group formed by:

  

 <EMI ID = 142.1>


  
 <EMI ID = 143.1>

  
 <EMI ID = 144.1>
 <EMI ID = 145.1>
 <EMI ID = 146.1>

  
above and AG6 is an aminoglycosyl function chosen from the group formed by:

  

 <EMI ID = 147.1>


  
 <EMI ID = 148.1>

  
 <EMI ID = 149.1>

  
and 1 "Antibiotic G-418 of the following formula XVIII
 <EMI ID = 150.1>
 <EMI ID = 151.1>

  
trained by :

  

 <EMI ID = 152.1>


  
 <EMI ID = 153.1>

  
 <EMI ID = 154.1>
 <EMI ID = 155.1>
 <EMI ID = 156.1>

  
 <EMI ID = 157.1>

  

 <EMI ID = 158.1>


  
 <EMI ID = 159.1>

  
 <EMI ID = 160.1>

  

 <EMI ID = 161.1>


  
 <EMI ID = 162.1>

  
trained by

  

 <EMI ID = 163.1>


  
 <EMI ID = 164.1>

  
The new starting compounds which are necessary for the process of the present invention, that is to say the

  
 <EMI ID = 165.1>

  
 <EMI ID = 166.1>

  
 <EMI ID = 167.1> alkaline in organic solvent. ;

  
Organic solvents suitable for this process

  
 <EMI ID = 168.1>

  
streptamine and the alkali metal azide reagent are soluble, these solvents not having to react with the reagent so that the possibility of side reactions constraining the main reaction is minimized. Suitable organic solvents most useful in this process are solvents such as <EMI ID = 169.1>

  
used in an appropriate manner.

  
Sodium azide is commonly used in

  
 <EMI ID = 170.1>

  
of the present invention in the intermediate 5-epi-azido-

  
 <EMI ID = 171.1>

  
other alkali metal azides can be used, such as potassium azide and lithiasis azide.

  
 <EMI ID = 172.1>

  
The present process and also useful as starting materials in another process of the present invention are those derived from hydrocarbon sulfonic acids having up to 8 carbon atoms and including ethanesulfonic acid,

  
 <EMI ID = 173.1> <EMI ID = 174.1>

  
 <EMI ID = 175.1>

  
and had a 5-hydroxyl function, which compounds are used as starting materials in yet another process according to the present invention) by treatment

  
 <EMI ID = 176.1>
-methanesulfonyl chloride) in a tertiary amine
(usually triethylamine).

  
 <EMI ID = 177.1>

  
syl) -2-deoxystreptamine (having the amino functions and all the other hydroxyl functions protected by groups capable of reductive cleavage and / or moderate or basic acid hydrolysis) in the corresponding 5-epi-azido5-deoxy intermediate (as defined by formulas

  
 <EMI ID = 178.1> of) sodium azide. The reaction mixture is heated

  
 <EMI ID = 179.1>

  
proven by thin layer chromatographic analysis. The resulting product is usually isolated by concentrating the reaction mixture, dissolving the residue in an organic solvent free of acid, washing the organic solution with water, then evaporating the solution <EMI ID = 180.1>

  
which are precursors of the corresponding 5-epi-azido5-deoxy intermediates and also starting substances for a further process according to the present invention, are derived

  
 <EMI ID = 181.1>

  
all most easily converted to the preferred compounds of the present invention, i.e. to the 5-epi-azido-5-deoxy and 5-epi-amino-5- derivatives.

  
 <EMI ID = 182.1>

  
under the name of gentamycin X. The starting compound referenced

  
 <EMI ID = 183.1>

  
given here, is called gentamycin C2a in certain documents of the prior art.

K

  
 <EMI ID = 184.1>

  
firstly by formation of amides capable of

  
reductive cleavage or basic hydrolysis. For the methods of this invention, it is preferred to protect the amino groups.

  
 <EMI ID = 185.1>

  
The per-N-protected aminoglycosides thus formed

  
 <EMI ID = 186.1>

  
treated with an alkali metal hydride, usually sodium hydride in dimethylformamide, whereby

  
 <EMI ID = 187.1>

  
In aminoglycosides where other amino groups are

  
 <EMI ID = 188.1>

  
B with sodium hydride in dimethylformamide, oxazolidinone derivatives are formed, in this case the

  
 <EMI ID = 189.1>

  
In another embodiment, when protecting <EMI ID = 190.1>

  
amino groups are suitably protected by lower alkanoyl groups such as acetyl and

  
 <EMI ID = 191.1>

  
corresponding glycoside. So, for example, the processing

  
 <EMI ID = 192.1>

  
Adjacent hydroxyl groups which will form a ketal or acetal group are then usually protected by treatment with a ketone or aldehyde or derivative thereof in dimethylformamide in the presence of catalytic amounts of a strong acid such as p- acid. toluenesulphonic using known techniques. Thus, the intermediate of gentamycin E which was named above,

  
 <EMI ID = 193.1>

  
protected are transformed into the corresponding hydrocarbon-carbonyl derivatives by treatment of these derivatives with

  
 <EMI ID = 194.1>

  
in a tertiary amine (preferably pyridine), the molar amount of reacting acid halide being based on the number of hydroxy groups to be esterified. If only one hydroxy group other than 5-hydroxy remains in the molecule (for example the 2 "-hydro: cy group), an amount of acid halide equivalent to the amount

  
 <EMI ID = 195.1> molars of acid halide per mole of aminoglycoside.

  
Acyl halides of hydrocarbon carboxylic acids having up to 8 carbon atoms are preferably used.

  
carbon, including acid chlorides such as lower alkanoic acids such as acetic, propionic, valeric and caprylic acids: aralkanoic acids such as phenylacetic acid and arylcarboxylic acids

  
such as toluic acids and, preferably, benzoic acid. Thus, each of the aforementioned intermediaries of

  
 <EMI ID = 196.1>

  
equimolar of benzoyl chloride in pyridine, gives the corresponding 2 <1> <1> -0-benzoyl derivative, i.e.

  
 <EMI ID = 197.1>

  
streptamines) which are per-N-protected. and 0-protected in all positions other than the 5- position, are also used as starting substances in a process according to

  
: The present invention.

  
In another embodiment, after protection

  
 <EMI ID = 198.1>

  
Hydroxy groups except the 5-hydroxy group can be protected by converting them to a hydrocarbon-carbonyl group without having to first protect the neighboring hydroxy groups with acetal or ketal groups. So the

  
 <EMI ID = 199.1>

  
gentamycin B, by reaction with three molar equivalents

  
of benzoyl chloride in pyridine, gives the

  
 <EMI ID = 200.1>

  
reaction with mefhanesulfonyl chloride in pyridine, is converted into a compound useful in this <EMI ID = 201.1>

  
The other thing necessary, the new starting compounds for this process of the invention, that is to say the

  
 <EMI ID = 202.1>

  
which compounds are per-N-protected: and O-protected in all positions other than the 5- position, are prepared by the methods described below.

  
The compounds of this invention can be prepared by methods known in the art and, moreover, by methods which are original in themselves. A method

  
 <EMI ID = 203.1>

  
in which the 2-deoxystreptanine group is replaced by a 1,3-diaminocyclitol of formula

  

 <EMI ID = 204.1>


  
wherein R is hydrogen or a -CH2Y group with Y being hydrogen, alkyl, alkenyl, <EMI ID = 205.1>

  
benzyl or tolyl, said aliphatic radicals having up to 7 carbon atoms and, in the case of substitution by amino and hydroxy, bearing the substituents on

  
 <EMI ID = 206.1>

  
as well as pharmaceutically acceptable acid addition salts thereof: comprises treatment of a derivative

  
 <EMI ID = 207.1>

  
above, in which the 2-deoxystreptamine group is replaced by a 1, 3-diaminocyclitol of formula

  

 <EMI ID = 208.1>


  
in which formula R has the meaning above and

  
 <EMI ID = 209.1>

  
 <EMI ID = 210.1>

  
at 155 [deg.] C; removing protecting groups in the resulting product and, if desired, alkylating a compound wherein R is hydrogen to obtain a

  
 <EMI ID = 211.1>

  
or in the form of a pharmaceutical acid addition salt.

  
 <EMI ID = 212.1>

  
alone or preferably also in the presence of a tetraalkyl ammonium alkanoate. Processing an intermediary <EMI ID = 213.1>

  
 <EMI ID = 214.1>

  
say about 155 [deg.] C) since the reaction rate is usually greater than when the reaction is

  
 <EMI ID = 215.1>

  
 <EMI ID = 216.1>

  
 <EMI ID = 217.1>

  
 <EMI ID = 218.1>

  
yields a purer product. Acetate

  
,

  
 <EMI ID = 219.1>

  
 <EMI ID = 220.1>

  
tetramethylammonium acetate. tetraethyl formate

  
 <EMI ID = 221.1>

  
per mole of aminoglycoside is usually between about 1.5 and about 5 moles.

  
Intermediates produced by the reaction of

  
 <EMI ID = 222.1>

  
substituted buresulfonyl) -4, 6-di-O- (aminoglycosyl) -2deoxystreptamine with dimethylformamide, by hydrolysis, give a 5-epi compound according to the present invention. When

  
 <EMI ID = 223.1>

  
which, on hydrolysis, gives a 5-epi compound according to the present invention.

  
Protecting groups susceptible to reductive cleavage are frequently preferentially used to carry out the process since they can be easily removed by reduction techniques after epimerization at the 5- position. However, other protecting groups will remain after the reduction step, for example

  
 <EMI ID = 224.1>

  
an aqueous base at elevated temperatures. Also, to remove acetals or ketals, it is necessary to perform acid hydrolysis.

  
 <EMI ID = 225.1>

  
of reductive cleavage from the intermediates produced in this process, reduction with hydrogen in the presence of a catalyst is preferred when the intermediates

  
 <EMI ID = 226.1>

  
protected-0-protected products are devoid of unsaturation, such as processing-derived intermediates, by the

  
 <EMI ID = 227.1>

  
kanamycin B and Antibiotics G-418r JI-20A and JI-20B.

  
On the other hand, when the protective groups susceptible of reductive cleavage are removed from the intermediates

  
 <EMI ID = 228.1>

  
present, such as those derived from sisomycin, verdamycin, Antibiotic G-52, Antibiotics
66-40B and 65-40D, reduction by means of an alkali metal in liquid ammonia is preferable in order to avoid reduction of the double bond.

  
When removing the protecting groups from an intermediate with hydrogen in the presence of a catalyst, the most frequently employed catalyst is palladium, preferably the palladium star of charcoal.

  
 <EMI ID = 229.1>

  
This is done at room temperature in lower alkanoic acids, preferably acetic acid, although other solvents such as lower alkanols can be used. Hydrogenation is

  
 <EMI ID = 230.1>

  
 <EMI ID = 231.1>

  
then usually isolated by removing the solvent, for example by distillation, and then by treating the intermediate <EMI ID = 232.1> formed with a base and, when acetals or ketals are also present, with aqueous acid to remove residual protecting groups.

  
t In a typical mode of implementation of this method,

  
 <EMI ID = 233.1>

  

 <EMI ID = 234.1>


  
rather than an epi-azido group

  

 <EMI ID = 235.1>


  
 <EMI ID = 236.1>

  
 <EMI ID = 237.1>

  
reflux temperature for 18 hours, after which the solution is evaporated to give a residue of intermediate

  
 <EMI ID = 238.1>

  
2-Deoxystreptamine which is dissolved in acetic acid and hydrogenated at room temperature under an initial hydrogen pressure of 4 atmospheres in the presence of a 30% palladium catalyst on charcoal. When no more drop in hydrogen pressure is discernible, the catalyst is removed by filtration and the solvent is removed by vacuum distillation to give a residue which, on treatment with 2N sodium hydroxide

  
 <EMI ID = 239.1>

  
lization with acetic acid and then isolation and purification using known techniques, gives

  
 <EMI ID = 240.1>

  
bacterial according to the present invention.

  
In another preferred embodiment of this method. , a 5-0-hydrocarbon intermediate

  
 <EMI ID = 241.1> was added, and heated at 120 [deg.] C for 16 hours and the solution was evaporated to give the 5-epiacetyl derivative

  
 <EMI ID = 242.1>

  
mycin and the corresponding 1-N-ethyl derivative which ', by treatment with aqueous potassium hydroxide followed by neutralization, then isolation and purification by

  
 <EMI ID = 243.1>

  
Any acetal or ketal protecting groups from the intermediates are removed after removal of the N-protecting groups by treatment with dilute aqueous acid, e.g. dilute mineral acids, dilute trifluoroacetic acid, or usually with dilute alkanoic acids such as acid. acetic.

  
When removing carbobenzyloxy protecting groups from a per-N-protected-per-Oprotected aminoglycoside intermediate having a double bond (e.g.

  
 <EMI ID = 244.1>

  
intermediate with an alkali metal (e.g. potassium, lithium and, preferably, sodium), in liquid ammonia, the intermediate is usually dissolved in

  
 <EMI ID = 245.1>

  
tetrahydrofuran, to which a mixture is added the metal alkalia (eg sodium), after which the reaction mixture is stirred for a few hours. After allowing the ammonia to evaporate, all groups

  
 <EMI ID = 246.1>

  
carbonyl and the 211-O-benzoyl group) are removed by adding water to the reaction mixture to give sodium 1-hydroxide, and heating to high temperatures (eg 100 [deg.] C). The purification of the resulting product is carried out by chronatographic techniques to obtain a 5-epi-aminoglycoside according to the present invention, endowed with anti-bacterial activity, for example 5-epiverdamycin.

  
 <EMI ID = 247.1>

  
In another embodiment. protecting groups can be removed from the intermediate

  
 <EMI ID = 248.1>

  
by reaction thereof with a base at elevated temperatures and, when acetals or ketals are present, by treatment with an aqueous acid.

  
 <EMI ID = 249.1>

  
sisomycin, in which the 2-deoxystreptamine group is replaced by a 1,3-diaminocyclitol of the formula

  

 <EMI ID = 250.1>


  
 <EMI ID = 251.1>

  
or tolyl, said aliphatic radicals having up to 7 carbon atoms and, in the case of substitution by

  
 <EMI ID = 252.1>

  
i <EMI ID = 253.1> above, in which the 2-deoxystreptamine group is replaced by a 1,3-diaminocyclitol of formula

  

 <EMI ID = 254.1>


  
 <EMI ID = 255.1>

  
given above and in which the amino and hydroxy groups, other than the 5-hydroxy group, in the derivative

  
 <EMI ID = 256.1>

  
by groups susceptible to reductive cleavage or moderate or basic acid hydrolysis: with an agent

  
 <EMI ID = 257.1>

  
with an alkali metal borohydride, removing protective groups in the resulting product and, if desired, alkylating a compound in which R is

  
 <EMI ID = 258.1>

  
 <EMI ID = 259.1>

  
isolating the derivative as or in the form of a pharmaceutically acceptable acid addition salt.

  
In this process, starting compounds are used which are per-N-protected and per-O-protected with the exception of the hydroxy group at the 5- position which is extremely hindered, which starting compounds are obtained by introducing protective groups. or blockers as described above.

  
In the first step of this reaction, the oxidizing agent preferably employed is chosen from ruthenium tetroxide, chromic acid in acetone <EMI ID = 260.1>

  
and the chromium trioxide-pyridine complex in methylene chloride. The compound 5-dehydro differs from the compounds of the formulas XIV - XXI only in that a group

  

 <EMI ID = 261.1>


  
replaces the 5-epi-azido group '

  

 <EMI ID = 262.1>


  
The oxidation step of this process is usually carried out in an organic solvent such as acetone when chromic acid is used, or a halogenated hydrocarbon, preferably methylene chloride, when the trioxide complex is used. chromium-pyridine or ruthenium tetroxide as an oxidizing agent, at temperatures

  
 <EMI ID = 263.1>

  
 <EMI ID = 264.1>

  
(aminoglycosyl) is reduced to give the corresponding 5-epi intermediate, hindered alkali borohydrides are preferred reagents, e.g.

  
 <EMI ID = 265.1>. Alkali borohydride can be used, for example sodium or potassium borohydride. The reaction is usually carried out in a lower alkanol (eg methanol) or in an ether (eg dioxane or, preferably, tetrahydrofuran) at temperatures- <EMI ID = 266.1>

  
 <EMI ID = 267.1>

  
in the prior art to carry out reduction using alkali borohydrides.

  
In a typical mode of implementation of the invention

  
 <EMI ID = 268.1>

  
approximately 28 hours of reaction time). The intermediary

  
Vv <EMI ID = 269.1>

  
appropriate, by extraction with ether, evaporation of the solvent, and purification of the residue by chromatographic techniques. The 5-keto intermediate is then dissolved in an ether or lower alkanol, preferably tetrahydrofuran, and an alkali metal hydride (e.g.

  
 <EMI ID = 270.1>

  
(usually 2-4 moles of metal borohydride are used per mole of aminoglycoside intermediate), after which the reaction mixture is stirred at room temperature.

  
 <EMI ID = 271.1>

  
protected-5-epi-aminoglycoside so formed is usually isolated by adding saline to the reaction mixture, extracting with ethyl acetate, then evaporating

  
solvent. The N- and-protecting groups in the 5-epi-aminoglycoside intermediate are then removed as described above, for example by treatment with Le.

  
sodium in liquid ammonia, to remove benzyloxycarbonyl groups, following which treatment with sodium hydroxide is carried out at elevated temperatures.

  
Any compound (5-epi-azido-, 5-epi-amino or 5-epimers) obtainable by the methods of the invention

  
 <EMI ID = 272.1>

  
diaminocyclitol, the amino group in position 1- is unsubstituted, can be alkylated according to methods known in the prior art in order to introduce the group
-CH2Y with Y being as defined above, in position 1 of the molecule.

  
An alkylation process comprises treating the compound, which may have amino protecting groups at any position other than the 1- position, with an aldehyde of the formula

  
 <EMI ID = 273.1>

  
with Y 'being a group as defined for Y above,

  
 <EMI ID = 274.1>

  
where any amino or hydroxy group present can be protected,

  
 <EMI ID = 275.1>

  
 <EMI ID = 276.1>

  
in the molecule.

  
This process, by which the 1-amino function in a

  
 <EMI ID = 277.1>

  
diaminocyclitol, constituting an anti-bacterial agent, is selectively condensed with an aldehyde and, conco-

  
 <EMI ID = 278.1>

  
is usually carried out at room temperature in the presence of air, although it can advantageously be carried out under an inert atmosphere (eg argon or nitrogen).

  
Hydride-donor reducing agents include

  
 <EMI ID = 279.1>

  
tetrabutylammonium cyanoborohydride), alkali borohydrides (e.g. sodium borohydride) and,

  
 <EMI ID = 280.1>

  
lithium cyanoborohydride and sodium cyanoborohydride).

  
This process is advantageously carried out in an inert solvent. Although anhydrous aprotic solvents can sometimes be advantageously employed in this process (such as tetrahydrofuran when morpholinoboran is used as a hydride donor reducing agent), this process is usually carried out in solvents.

  
 <EMI ID = 281.1>

  
preferably in water or an aqueous lower alkanol
(eg aqueous methanol, aqueous ethanol), although other water-miscible co-solvent systems may

  
 <EMI ID = 282.1>

  
and aqueous ethylene glycol dimethyl ether.

  
The process is suitably carried out at a pH in the range of 1 to 11, preferably <EMI ID = 283.1>

  
 <EMI ID = 284.1>

  
 <EMI ID = 285.1>

  
 <EMI ID = 286.1>

  
or an inorganic acid such as hydrochloric acid,

  
 <EMI ID = 287.1>

  
 <EMI ID = 288.1>

  
addition salts and it is usually most suitable to use the addition salts derived from sulfuric acid. Optimal results are obtained when all amino groups present in the molecule are completely neutralized.

  
It is usually convenient to prepare the required starting compound which is the addition salt. acid in situ, by adding the desired acid (e.g. sulfuric acid) to a solution or a suspension,

  
 <EMI ID = 289.1>

  
in a protic solvent (eg water) until the pH of the solution is adjusted to the desired value.

  
 <EMI ID = 290.1>

  
tives when an aminoaldehyde is used as a reagent, it is preferable to protect the amino function in the aldehyde, for example with an acyl protecting group such as

  
 <EMI ID = 291.1>

  
carrying out the process, and then removing the N-protecting group in the resulting product. It can be too

  
It is advantageous to protect the hydroxyl group in hydroxyl-based aldehydes when performing this process, however, this is generally not necessary.

  
In another embodiment, partially N-protected intermediates can be used. Thus, by

  
 <EMI ID = 292.1>

  
 <EMI ID = 293.1>

  
is N-protected, for example the sulfur acid addition salt

  
 <EMI ID = 294.1>

  
cine, or a 1-N-unsubstituted derivative in which the

  
 <EMI ID = 295.1> 3- are N-protected (e.g. the acid addition salt

  
 <EMI ID = 296.1>

  
 <EMI ID = 297.1>

  
In addition, the 1-N-CH2Y derivatives of 4,6-di-O-

  
 <EMI ID = 298.1>

  
(eg benzaldehyde, phenylacetaldehyde or acetaldehyde) is transformed into Schiff's base

  
 <EMI ID = 299.1>

  
respectively).

  
In these methods, the AE-protecting groups which are suitable are those groups known in the art to be easily removable after preparation of the.

  
 <EMI ID = 300.1>

  
acyl groups such as acetyl, propionyl and benzoyl; alkoxycarbonyl groups such as -

  
 <EMI ID = 301.1> <EMI ID = 302.1>

  
loxycarbonyl.

  
Another alkylation process for the preparation of a compound wherein in formula r, R is a straight chain alkyl having up to 5 carbon atoms,

  
 <EMI ID = 303.1>

  
contains amino protecting groups at any position

  
 <EMI ID = 304.1>

  
may be in an activated state, with an alkylating agent containing the straight chain alkyl group having up to

  
5 carbon atoms and a leaving or mobile group, and the removal of protecting groups and, if necessary, the activating group or groups present in the molecule.

  
As examples of advantageous alkylating agents

  
ment used in the present process, there may be mentioned the alkyl iodides, the alkyl bromides, the sulphates of

  
 <EMI ID = 305.1>

  
the required straight chain alkyl group, having up to

  
5 carbon atoms.

  
Other alkylating agents, in which the

  
alkyl group preferably has one or two atoms of

  
 <EMI ID = 306.1>

  
or dialkyl ether.

  
The amino group at position 1- of the derivative of 4, 6-

  
 <EMI ID = 307.1>

  
amino protecting groups at any position other than the 1- position, with a compound providing the group <EMI ID = 308.1>

  
The 1-amino group can also be alkylated by means of the corresponding di- (2-cyanoethyl) derivative which is derived, by

  
 <EMI ID = 309.1>

  
amino protectors at any position other than position 1-. The 1-N-di- (2-cyanbethyl) derivative thus prepared is then alkylated with one of the alkylating agents listed above, whereupon the cyanoethyl groups are removed.

  
The process of the present invention is carried out under conditions similar to those used in well known processes for direct alkylation of amines.

  
Yet another alkylation process for the preparation of a compound wherein X is, in formula I, hydroxy or amino, comprises treating the compound, which may have amino protecting groups at any position other than position 1-, by an acylating agent chosen from an acid of formula

  

 <EMI ID = 310.1>


  
wherein Y 'is a group as defined above for Y, in which any amino or hydroxy group present can be protected; in the presence of a carbodiimide, and a reactive derivative of the above acid; removing all protective groups present in the molecule and processing the

  
 <EMI ID = 311.1>

  
amide reducing hydride.

  
The reduction of the 1-N-acyl compound is usually carried out in a non-reactive organic solvent in which the 1-N-acyl derivative and the amide reducing reagent are soluble and which will not react with the reagent so that it becomes soluble. produces minimal competitive side reactions. The non-reactive organic solvents which are most useful in this reduction process are the ethers

  
 <EMI ID = 312.1>

  
than diethylene glycol, etc.

  
 <EMI ID = 313.1>

  
 <EMI ID = 314.1>

  
isoamylborane, and 9-BBN (i.e. 9-borabicyclo <EMI ID = 315.1>
In general, diborane is preferably used as an amide reducing agent, except when the starting compound has a double bond, the compounds in question then being reduced, in a suitable manner, by means of lithium hydride. aluminum.

  
The preparation of 1-N-acyl intermediates is

  
 <EMI ID = 316.1>

  
part of the invention and they can be isolated such as. Accordingly, according to another of the method aspects of the invention, it relates to a method for the preparation.

  
 <EMI ID = 317.1>

  
Antibiotic G-52, Antibiotic 66-40B, Antibiotic
66-40D, Antibiotic G-418, Antibiotic JI-20A, Antibiotic JI-20B and sisotnycin, in which '

  
the 2-deoxystreptamine group is replaced by a 1,3diaminocyclitol of formula
 <EMI ID = 318.1>
  <EMI ID = 319.1>

  
 <EMI ID = 320.1>

  
hydrogen, alkyl, alkenyl, cyc3.oalkyl,

  
 <EMI ID = 321.1>

  
tolyl, said aliphatic radicals having up to 7 carbon atoms and, in the case of substitution by amino and hydroxy, bearing the substituents on different carbon atoms; and X is hydroxy, azido, or amino with the proviso that, in the case of sisomycin derivatives, the substituent X is azido or amino r and acid addition salts thereof which process

  
 <EMI ID = 322.1>

  
2-deoxystreptamine is replaced by a 1.3-diaminocyclitol of formula

  

 <EMI ID = 323.1>


  
in which formula X is as defined above, this derivative possibly having amino protecting groups at any position other than the 1- position; with an acylating agent chosen from an acid of formula

  

 <EMI ID = 324.1>


  
 <EMI ID = 325.1>

  
in which acid any amino or hydroxy group present can be protected, in the presence of a carbodiimide, such as

  
 <EMI ID = 326.1>

  
and, if necessary, removing any protecting groups present in the molecule, this last step of

  
&#65533;

  
process being followed by isolation of the derivative such as or

  
in the form of an acid addition salt.

  
The amino protecting groups useful in this process should be removable under conditions which

  
 <EMI ID = 327.1>

  
and benzyloxycarbonyl.

  
The starting compounds of this process may have

  
 <EMI ID = 328.1>

  
amino groups are protected in the starting compounds i

  
 <EMI ID = 329.1>

  
is usually protected. The derivatives of gentamyciae C.

  
 <EMI ID = 330.1>

  
can be used in the basic form

  
nitrogenous free (with or without N-protecting groups) or in the form of compounds partially neutralized by formation of acid addition salts.

  
In the present description, the expression "partial-

  
 <EMI ID = 331.1>

  
 <EMI ID = 332.1>

  
diaminocyclitol is associated with an amount of acid which. is less than the stoichiometric number of moles of acid which is required to form the per acid addition salt. In addition, this expression means that each mole of 4.6- <EMI ID = 333.1>

  
having five amino groups would require five acid equivalents to form the per acid addition salt. This process is carried out on an acid addition salt of 5-epi-

  
 <EMI ID = 334.1>

  
 <EMI ID = 335.1>

  
start is neutralized with (n-1) equivalents of acid, n being

  
 <EMI ID = 336.1>

  
amino groups are neutralized by forming an acid addition salt. However, it is understood that the process can also be advantageously carried out on partially neutralized starting compounds in which more or less than (n-1) equivalents of acid give rise to the formation of the addition salt of acid within the limits indicated above. The process is carried out in a pH range of 5.0 to 9.0, preferably 5.0 to 8.0. The most preferred range for the pH of the reaction medium is 6.5 to 7.5, particularly

  
6.8 to 7.2.

  
The term "acid addition salt" embraces salts such as those which may be formed between the basic antibiotic and an acid regardless of whether the acid may be considered inorganic or organic. As examples of acids encompassed by the above expression, there may be mentioned sulfuric acid, hydrochloric acid, phosphoric acid, nitric acid, trifluoroacetic acid or the like.

  
If you want to use as a starting substance

  
an acid addition salt in which (n-1) amino groups are protonized, this compound is advantageously produced

  
 <EMI ID = 337.1>

  
In general, the use of reactive derivatives of

  
HO-C-Y 'acid, as acylating agents, is preferred. Reactive derivatives of the acid include esters,

  
 <EMI ID = 338.1>

  
Y 'is not substituted, one of the preferred reactive derivatives is the required acid anhydride. In other cases, it

  
 <EMI ID = 339.1>

  
succinimidyl acid.

  
When carrying out the method by which a reactive derivative of an acid containing an amino function is used, it is preferable to protect the amino function.

  
 <EMI ID = 340.1>

  
 <EMI ID = 341.1>

  
It may also be advantageous to protect a hydroxy group present in the acylating agent, although this is not generally necessary, however. '

  
The following examples are given, without limitation, to illustrate the present invention.

Example 1

  
Per-N-benzyloxycarbonylaminoglycosides

  
 <EMI ID = 342.1>

  
 <EMI ID = 343.1>

  
 <EMI ID = 344.1>

  
methanol and 20 ml of a saturated solution of sodium bicarbonate and oa cools the solution to 0 "Ci. While stirring the solution, is added dropwise, over a period of

  
 <EMI ID = 345.1>

  
stir the mixture overnight while allowing

  
 <EMI ID = 346.1>

  
ambient temperature. 500 ml of chloroform are added to the mixture

  
 <EMI ID = 347.1>

  
the organic phase with four times 100 ml of water and dried over 100 g of sodium sulfate. We evaporate the phase

  
 <EMI ID = 348.1>

  
 <EMI ID = 349.1>

  
chloroform and added dropwise to 250 ml of a

  
 <EMI ID = 350.1>

  
resultant and washed with 100 ml of hexane, following

  
 <EMI ID = 351.1>

  
 <EMI ID = 352.1>

  
25 g of sisomycin and 13 g of carbonate are dissolved

  
 <EMI ID = 353.1>

  
 <EMI ID = 354.1>

  
 <EMI ID = 355.1>

  
solid by filtration, washing thoroughly with water. The solid is dried in vacuo and then washed with

  
of 1 Texan, then air-dried to obtain 62 g

  
 <EMI ID = 356.1>

  
.

  
 <EMI ID = 357.1>

  
mide dry for 1/2 hour, at room temperature and under nitrogen. The reaction mixture is stirred for 2 hours and then the insolubles are filtered off. We

  
 <EMI ID = 358.1>

  
organic with three times 50 ml of water. The organic phase is dried over 25 g of sodium sulfate and then evaporated under reduced pressure. The resulting residue is dissolved

  
 <EMI ID = 359.1>

  
a hexane-ether mixture containing 75% hexane (15 ml). The precipitate is filtered off and washed with 25 ml of hexane to obtain

  
 <EMI ID = 360.1> <EMI ID = 361.1>

  
To a stirred solution of 5 g of the product of Example 1B in 50 ml of dimethylformamide, 250 mg of sodium hydride are added. The reaction mixture is stirred under argon for 2 hours at room temperature. It is filtered and 2 ml of glacial acetic acid are added to the filtrate. The filtrate is concentrated in vacuo and the residue is extracted with
200 ml of chloroform (purified by passage through basic alumina). The chloroform extracts are washed with water and dried over sodium sulfate,

  
 <EMI ID = 362.1>

  
 <EMI ID = 363.1>

  
a period of 10 to 15 minutes and under a nitrogen atmosphere,

  
2 ml of benzoyl chloride. The reaction mixture is stirred

  
 <EMI ID = 364.1>

  
using a rotary evaporator while maintaining the temperature <EMI ID = 365.1> of the bath below 30 [deg.] C. The pale yellow oil is dissolved

  
 <EMI ID = 366.1>

  
organic with three times 50 ml of water and then dried

  
on 25 g of sodium sulfate. The chloroform is evaporated off in vacuo. The residual yellow foam is triturated with a small volume of ether to obtain 11.0 g (higher yield

  
 <EMI ID = 367.1>

  
 <EMI ID = 368.1>

  
2B in 20 ml of dry pyridine at 25 [deg.] C and under an argon atmosphere, 1.7 ml of benzoyl chloride are added over a period of 10 minutes. Stir at room temperature until all the starting material reacts

  
(control by thin layer chromatography). We evaporate

  
mixing at room temperature under high vacuum: the solid residue is extracted with 100 ml of chloroform (having previously passed through basic alumina). We wash them

  
 <EMI ID = 369.1>

  
5% aqueous, then with water, followed by drying over sodium sulfate. The solvent is evaporated to

  
 <EMI ID = 370.1> <EMI ID = 371.1>

  
 <EMI ID = 372.1>

  
dry, dropwise added over a period of

  
 <EMI ID = 373.1>

  
acetic. The reaction mixture is stirred for 1/2 hour and then remove the pyridine using a rotary evaporator, keeping the bath temperature below

  
 <EMI ID = 374.1>

  
acid-free chloroform. This organic solution is washed with three times 50 ml of water, then dried over sodium sulphate and evaporated in vacuo. The resulting residue is purified by trituration with small volumes of ether.

  
 <EMI ID = 375.1>

  
dry, with sodium hydride. The resulting product is isolated and purified in a manner similar to that described.

  
 <EMI ID = 376.1>

  
in pyridine. The resulting product is isolated and purified in a manner similar to that described in Example

  
 <EMI ID = 377.1>

  
in dimethylformamide. The product is isolated and purified in a manner similar to that described in

  
 <EMI ID = 378.1>

  
Cla mycin in 5 ml of triethylamine and 15 ml of tetrahydrofuran below 0 [deg.] C. The solution is stirred and to it is added, over a period of 15 minutes, a solution of

  
1 ml of methanesulfonyl chloride in 5 ml of tetrahydrofuran. The reaction mixture is stirred for.

  
 <EMI ID = 379.1>

  
of water and 25 ml of chloroform. The organic phase is washed with twice 15 ml of water and the said organic phase is then dried over sodium sulfate. The chloroforma was evaporated and the resulting yellow foam was triturated with small amounts of ether to obtain 1.2 g (yield, higher

  
 <EMI ID = 380.1> <EMI ID = 381.1>

  
2.5 g of the product of Example 3B are dissolved in

  
 <EMI ID = 382.1>

  
and 4 ml of methanesulfonyl chloride are added over a 10 minute period, after which the reaction mixture is allowed to stand overnight, then

  
 <EMI ID = 383.1>

  

 <EMI ID = 384.1>


  
 <EMI ID = 385.1>

Example 5

  
 <EMI ID = 386.1>

  
sealed flask at 110 [deg.] C for 4 hours, the solution is cooled, then the cooled solution is treated with 6 ml of resin known under the trade name

  
 <EMI ID = 387.1>

  
1 <EMI ID = 388.1>

  
of benzoyl chloride in pyridine and the resulting product is isolated and purified in a manner similar to

  
 <EMI ID = 389.1>

  
cyclohexane and 300 mg of dry para-toluenesulfonic acid.

  
 <EMI ID = 390.1>

  
The solution is cooled and then the solution is treated

  
 <EMI ID = 391.1>

  
hydroxide form. the resin is separated by filtration and the filtrate is evaporated in vacuo to obtain a residue of

  
 <EMI ID = 392.1>

  
with one equivalent of benzoyl chloride in pyridine and the resulting product is isolated and purified in a manner similar to that described in Example 3A, to obtain

  
 <EMI ID = 393.1>

  
In a manner similar to that described in

  
 <EMI ID = 394.1>

  
 <EMI ID = 395.1>

  
each of the resulting products in a manner similar to that described in Example 4A to obtain 1,3-di-N-

  
 <EMI ID = 396.1>

  
mycin.

  
 <EMI ID = 397.1>

  
mamide, at 120 [deg.] C for 24 hours. The mixture is cooled

  
 <EMI ID = 398.1>

  
dissolves the residue in 50 ml of water and 100 ml of chloroform.

  
The organic phase is washed with twice 50 ml of water and

  
it is dried over 25 g of sodium sulfate. The solvent is evaporated to obtain a white solid. The solid is dissolved in a small volume of chloroform and chromatographed on 200 g of silica gel. The column is eluted with CHCl

  
 <EMI ID = 399.1>

  
(1) 2 g of the product of Example 4B are dissolved in

  
15 ml of dry dimethylformamide. The mixture is stirred and 1.5 g of sodium azide are added. The reaction mixture is kept under argon at 120 [deg.] C overnight. The solution is concentrated under a high vacuum. The residue is extracted with 200 µl of acid-free chloroform. We wash

  
 <EMI ID = 400.1>

  
(2) In a similar manner, an equivalent quantity of a corresponding product is subjected to the preceding process <EMI ID = 401.1>

  
Example 5, with sodium azide in dimethylformamide. Each of the resulting products is isolated and purified in a manner similar to that described in Example 6A to obtain, respectively.

  
 <EMI ID = 402.1>

  
 <EMI ID = 403.1>

  
4 atmospheres, at room temperature, a solution of 6 g

  
 <EMI ID = 404.1>

  
than. The solvent and catalyst were removed (to obtain a gummy residue), then the resulting residue was heated in 25 ml of hydrogen.

  
 <EMI ID = 405.1>

  
mixture and neutralized with acetic acid. The resulting precipitate is filtered off and the filtrate is concentrated to 10 if the concentrated filtrate is passed through a column of resin known under the tradename "IRC-50" (H + form). The column is washed with 200 ml of water and the column is then eluted.

  
 <EMI ID = 406.1>

  

 <EMI ID = 407.1>
 

  

 <EMI ID = 408.1>


  
B. In a similar manner, one proceeds as described in

  
 <EMI ID = 409.1>

  
obtain, respectively ,: ';

  
 <EMI ID = 410.1>

  
liquid. Slowly added 2 g of sodium to the stirred mixture and stirring is continued at -400C for 2 hours. The ammonia is allowed to evaporate at room temperature overnight. The resulting residue is dissolved in 25 ml.

  
 <EMI ID = 411.1>

  
 <EMI ID = 412.1>

  
which gives an oily product. This substance is chromatographed on 50 g of silica gel, using the mixture

  
 <EMI ID = 413.1>

  
 <EMI ID = 414.1>

  
above process, we obtain respectively:

  
5-epi-amino-5-deoxy-Antibiotic G-52,

  
 <EMI ID = 415.1>

  
1-N-propyl-5-epi-amino-5-deoxysisotnycine,

  
 <EMI ID = 416.1>

  
 <EMI ID = 417.1>

  
 <EMI ID = 418.1>

  
Example 6C and similar compounds. In addition, the compounds are treated with 2N sodium hydroxide, as described, and additionally, these compounds are treated with the mixture.

  
 <EMI ID = 419.1>

  
to remove any acetal or ketal protecting groups.

  
Each of the resulting products is isolated and purified in a manner similar to that described in Example 7A to obtain, respectively, the following compounds:

  
 <EMI ID = 420.1>

L

  
 <EMI ID = 421.1>

  
 <EMI ID = 422.1>

  
1: 1 mixture of dioxane / water and 25 ml of sodium hydroxide

  
 <EMI ID = 423.1>

  
until dry, the residue is dissolved in 10 ml of water and neutralized with acetic acid. The solution is evaporated, the residue is taken up in 5 ml of water and the mixture is passed through

  
 <EMI ID = 424.1>

  
residue. The residue is lyophilized (to produce a pale brown solid), followed by chromatography on a column of

  
 <EMI ID = 425.1> <EMI ID = 426.1>

  
Bo Similarly, by proceeding as described in Example SA, the following resulting products are isolated, respectively: <EMI ID = 427.1>

  
 <EMI ID = 428.1> <EMI ID = 429.1>

  
In a similar manner, one operates according to the method

  
 <EMI ID = 430.1>

  
following results: <EMI ID = 431.1>

  
 <EMI ID = 432.1>

  
 <EMI ID = 433.1>

  

 <EMI ID = 434.1>


  
 <EMI ID = 435.1> <EMI ID = 436.1>

  
D. In a manner similar to that described in the example

  
 <EMI ID = 437.1>

  
24 hours, each of the per-N-protected-per-O-protected aminoglycosides prepared in Example 6C and similar compounds.

  
 <EMI ID = 438.1>

  
80% acetic / water for 1 hour, in a steam bath, to remove any acetal or ketal protecting groups.

  
Each of the resulting products is isolated and purified to obtain, respectively, the following derivatives: <EMI ID = 439.1> <EMI ID = 440.1>

Example 9

  
 <EMI ID = 441.1>

  
 <EMI ID = 442.1>

  
reflux temperature for 18 hours, then the solution is evaporated to obtain a residue consisting of

  
 <EMI ID = 443.1>

  
B. This residue is dissolved in acetic acid, then added

  
 <EMI ID = 444.1>

  
hydrogen at room temperature using <EMI ID = 445.1> pressure

  
 <EMI ID = 446.1>

  
sor by filtration and the filtrate evaporated to obtain a residue. This residue was dissolved in 25 ml of 5% sodium hydroxide and heated at 100 ° C for 4 hours. The solution is cooled and passed through a

  
 <EMI ID = 447.1>

  
well the resin column with water, then the

  
 <EMI ID = 448.1>

  
produced by chromatography on a column of silica gel eluting with the lower phase of a solvent system

  
 <EMI ID = 449.1>

  
Similar eluates were pooled as determined by thin layer chromatography and lyophilized to

  
 <EMI ID = 450.1>

  
solid white. ; melting point: 115-120 [deg.] C;

  

 <EMI ID = 451.1>
 

  

 <EMI ID = 452.1>


  
C. In another embodiment, the N-protecting and O-protecting groups in the intermediates prepared in Example 9 are removed by heating the intermediate with 1 to 2N sodium hydroxide to 100 [ deg.] C, until thin-layer chromatographic analysis of aliquots of the reaction mixture indicates that the protecting groups have been removed (usually 24 to
48 hours). The resulting product is isolated and purified in a manner similar to that described in Example 9B.

  
 <EMI ID = 453.1>

  
protectors and O-protectors can be removed from the intermediate prepared as described in Example 9, II. of the ' . following way. The product of Example 9A is dissolved

  
in a mixture of 10 ml of tetrahydrofuran and 50 ml of liquid ammonia. 2 g of sodium was slowly added to the stirred mixture and stirring continued for 2 hours.

  
The ammonia is allowed to evaporate by warming to room temperature overnight. The resulting residue is dissolved in 10 ml of 5% sodium hydroxide and

  
heated to 100 [deg.] C for 4 hours. We cool down and we pass

  
 <EMI ID = 454.1>

  
The resin is washed well with water and the product is eluted

  
 <EMI ID = 455.1>

  
of ammonium hydroxide to obtain a residue and purify this residue therefrom in a manner similar to that described in Example 93 to obtain 5-epigentamycin C.

Example 10

  
 <EMI ID = 456.1> A. <1>. In a similar manner to that described in Examples 9A and 9B, each of the following aminoglycoside derivatives is treated with dimethylformamide at reflux temperature,

  
 <EMI ID = 457.1>

  
protected results thus formed in acetic acid in the presence of palladium on charcoal, and treated

  
 <EMI ID = 458.1>

  
Each of the resulting products is isolated and purified in a manner similar to that described in Example 9B.

  
 <EMI ID = 459.1>

  
 <EMI ID = 460.1>

  
 <EMI ID = 461.1>

  
2. In another embodiment, after treatment

  
 <EMI ID = 462.1>

  
 <EMI ID = 463.1>

  
protectors of each of the intermediates thus formed can be removed by treatment with sodium hydroxide according to

  
 <EMI ID = 464.1>

  
in ammonia followed by treatment with sodium hydroxide as given in Example 9D.

  
In a similar manner to that described in Examples 9A and 9D, each of the following aminoglycoside derivatives is treated with dimethylformamide at a temperature of

  
 <EMI ID = 465.1> <EMI ID = 466.1>

  
Each of the resulting products is isolated and purified in a manner similar to that described in Example 9D to obtain, respectively, the following derivatives: <EMI ID = 467.1>

  
2. In another embodiment, after treatment with dimethylformamide at reflux temperature, the protecting groups of each of the intermediates thus formed can be removed by treatment with sodium hydroxide in the manner of Example 9C to obtain the corresponding 5-epiaminoglycoside.

  
C. <1>. In a manner similar to that described in the

  
 <EMI ID = 468.1>

  
side by dimethylformamide, at reflux temperature, after which each of the resulting intermediates is hydrogenated in acetic acid in the presence of palladium on charcoal and the product is treated,

  
 <EMI ID = 469.1>

  
 <EMI ID = 470.1>

  
 <EMI ID = 471.1>

  
obtained as described in Example 10C (1) above in

  
 <EMI ID = 472.1>

  
in the steam bath for 1 hour. The reaction mixture is evaporated in vacuo to obtain a residue consisting of the respective 5-epiaminoglycosides.

  
Each of these compounds is purified by chromatographic techniques similar to those described in Example 9B to obtain, respectively, the following derivatives:
- 5-epigentamycin A,
- 5-epigentamycin B, <EMI ID = 473.1>
- 5-epigentamycin X2.

  
5-epi-Antibiotic G-418,
- 5-epi-Antibiotic JI-20A,
- 5-epi-Antibiotic JI-20B:
 <EMI ID = 474.1>
- 5-epikanamycin B,
- 5-epitobramycin,
- 5-epikanamycin A, <EMI ID = 475.1>

  
and 1.0 g of tetra-n-butylammonium acetate to 10 ml of dimethylformamide. Heated to 120 ° C. for 16 hours, evaporated to obtain a residue and this residue is extracted with chloroform. The chloroform solution is washed with water, dried over sodium sulfate and evaporated <EMI ID = 476.1>

  
 <EMI ID = 477.1>

  
a solution of 2 g of potassium hydroxide in 4 ml of water and the mixture is heated to 100 [deg.] C for 24 hours.

  
 <EMI ID = 478.1>

  
IRC-SO "(H + form), the mixture is stirred for 1 hour, then the resin is separated, washed with water and then eluted with ammonium hydroxide ION. After combining the eluates in 1. ammonium hydroxide, these are concentrated in vacuo and the resulting residue chromatographed on 20 g of silica gel eluting with the lower phase of a chloroform / methanol / ammonium hydroxide solvent system ION (2 Similar eluates containing 5-episisomycin, as determined by thin layer chromatography, were pooled and the eluates evaporated.

  
 <EMI ID = 479.1>

  

 <EMI ID = 480.1>
 

  

 <EMI ID = 481.1>


  
 <EMI ID = 482.1>

  
reacting 1-N-ethylsisomycin according to the procedures of Examples 1 to 4.

  
In a manner similar to that described in the example

  
 <EMI ID = 483.1>

  
described in Example 11-A (1), then this derivative is treated with aqueous potassium hydroxide in the same manner as

  
 <EMI ID = 484.1>

  
purification by chromatographic techniques such as

  
 <EMI ID = 485.1>

  
melting point: 118-122 [deg.] C (decomposition);

  

 <EMI ID = 486.1>
 

  

 <EMI ID = 487.1>


  
 <EMI ID = 488.1> <EMI ID = 489.1>

  
(2) According to the manner of Example II-A (1), an equivalent amount of 1-N-ethyl derivative of the intermediates is treated.

  
 <EMI ID = 490.1>

  
 <EMI ID = 491.1>

  
to that described in Example 10-C, to obtain,

  
 <EMI ID = 492.1> <EMI ID = 493.1>

  
 <EMI ID = 494.1>

  
chromium trioxide in 1 ml of concentrated sulfuric acid and 1 ml of water. Stirring of the solution is continued at room temperature for 16 hours, then extracted with chloroform, the chloroform extract is washed with water, dried over sodium sulfate and evaporated.

  
 <EMI ID = 495.1> <EMI ID = 496.1>

  
 <EMI ID = 497.1>

  
add 100 mg of sodium borohydride and heat the

  
 <EMI ID = 498.1>

  
 <EMI ID = 499.1>

  
resulting with chloroform. After combining the chloroform extracts, they are washed with water, dried over sodium sulfate and the solvent is evaporated off to obtain

  
 <EMI ID = 500.1>

  
 <EMI ID = 501.1>

  
15 ml of acetic acid and hydrogenated in the presence of 200 mg of 30% palladium charcoal at room temperature for 18 hours under an initial pressure of

  
4 atmospheres. Filtered and the filtrate evaporated in vacuo

  
 <EMI ID = 502.1>

  
The product of Example 12-C is dissolved in 10 ml

  
 <EMI ID = 503.1>

  
wash the resin well with water, then the product is eluted

  
 <EMI ID = 504.1>

  
in ammonium hydroxide to obtain a residue comprising

  
 <EMI ID = 505.1>

  
silica gel column eluting with the lower phase

  
 <EMI ID = 506.1>
 <EMI ID = 507.1>
  <EMI ID = 508.1>

  
of methylene chloride under an argon atmosphere, one adds
11.2 g of chrcme trioxide-pyridine complex. The resulting slurry is heated to reflux temperature. An additional 12.1 g of the aforementioned complex is added after 22 hours and a further 11.2 g of said complex after 25 hours. When the reaction is complete, as indicated by thin layer chromatography (usually after about 28 hours), about 500 ml is evaporated.

  
 <EMI ID = 509.1>

  
resulting solution, the ethereal solution is separated by decantation from the resulting tarry precipitate and washed.

  
 <EMI ID = 510.1>

  
ethereal compounds combined with a solution of bicarbonate of

  
 <EMI ID = 511.1>

  
then water (twice). Dry over sodium sulfate and evaporate in vacuo to obtain a residue (8.2 g)

  
 <EMI ID = 512.1>

  
chromatography on a "dry" column containing 700 g of silica gel. The column was developed with a mixture of 60% ...: 1 ethyl acetate and 40% chloroform, then the product was eluted with ethyl acetate and the combined eluates were evaporated to give a residue (4 , 6 g) of

  
 <EMI ID = 513.1>

  
chromium-pyridine trioxide. The resulting product is isolated and purified in a manner similar to that described <EMI ID = 514.1>
40 ml of dry tetrahydrofuran under an argon atmosphere, 8 ml of the product known under the trade name are added.

  
 <EMI ID = 515.1>

  
nitrogen atmosphere at room temperature for 20 hours, poured into 400 ml of aqueous sodium chloride and extracted three times with 80 ml portions of ethyl acetate. The ethyl acetate extracts are washed, after combining, three times with water.

  
 <EMI ID = 516.1>

  
without further purification in the procedure of Example 12-G. In another embodiment, the

  
 <EMI ID = 517.1>

  
The product (2.2 g) obtained is dissolved in the first

  
 <EMI ID = 518.1> reaction. 2.2 g of metallic sodium are added and the reaction mixture is stirred vigorously for 2.5

  
 <EMI ID = 519.1>

  
allow the ammonia to evaporate on warming to room temperature. The residual solution is absorbed on the cation exchange resin known under the trade name

  
 <EMI ID = 520.1> <EMI ID = 521.1> Similar eluates in ammonium hydroxide, as determined by thin layer chromatography and evaporated

  
 <EMI ID = 522.1>

  
 <EMI ID = 523.1>

  
complementary in the process of Example 12-H.

  
 <EMI ID = 524.1>

  
 <EMI ID = 525.1>

  
in 20 ml of 2N sodium hydroxide. The solution is heated at reflux temperature for 4 hours, then cooled to room temperature and placed in.

  
 <EMI ID = 526.1>

  
 <EMI ID = 527.1>

  
 <EMI ID = 528.1>

  
 <EMI ID = 529.1>

  
ammonium, these are concentrated in vacuo to obtain a residue of 5-epigentamycin Cla (yield: 139 mg). Purification is carried out by chromatography on a column of 33 g of silica gel, eluting with the lower phase of a. chloroform / methanol / concentrated ammonium hydroxide solvent system (1: 1: 1). Similar fractions were pooled as determined by thin layer chromatography and

  
 <EMI ID = 530.1>

  
 <EMI ID = 531.1>

  
322; 304-he 160; 129.

Example 13

  
 <EMI ID = 532.1>

  
 <EMI ID = 533.1>

  
 <EMI ID = 534.1>

  
reflux for 6 hours under a nitrogen atmosphere. Carefully add 2 ml of water to decompose any excess diborane and evaporate. The resulting residue is dissolved in hydrazine hydrate and heated at reflux temperature under a nitrogen atmosphere for 16 hours. The solution is evaporated and the residue is extracted with very hot aqueous ethanol. The extracts are evaporated in ethanol, after their combination, and the resulting residue is chromatographed

  
on 10 ml of silica gel, eluting with the lower phase of a chloroform / methanol / hydroxide solvent system

  
 <EMI ID = 535.1>

  
epigentamycin Ci *

  
 <EMI ID = 536.1> <EMI ID = 537.1> <EMI ID = 538.1>

  
the resulting product in a manner similar to that

  
 <EMI ID = 539.1>

  
 <EMI ID = 540.1>

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

  
1 g of lithium aluminum hydrare is added, then the resulting suspension is stirred at reflux temperature for

  
 <EMI ID = 543.1>

  
 <EMI ID = 544.1>

  
small volume and diluted with water. Insoluble solids are separated by filtration and washed well with acetic acid. The combined filtrate is evaporated with washing liquid and the resulting residue is dissolved in water.

  
The pH of the aqueous solution is adjusted to about 7 by

  
 <EMI ID = 545.1>

  
on 20 g of silica gel, eluting with the lower phase of a chloroform / methanol / hydroxide solvent system <EMI ID = 546.1>

  
similar fractions as determined by chromatography in

  
 <EMI ID = 547.1>

  
deoxysisomycin.

  
(4) As described in the example process

  
 <EMI ID = 548.1>

  
ethyl-5-epi-Antibiotic 66-40D, 1-N-ethyl-5-epi-Antibioti-. than G-52.

Example 14

  
 <EMI ID = 549.1>

  
 <EMI ID = 550.1>

  
pH of the solution is adjusted to approximately 5. In the solution

  
5-epiverdamycin sulfuric acid addition salt

  
 <EMI ID = 551.1>

  
room temperature for 15 minutes, then concentrate

  
 <EMI ID = 552.1>

  
after which the solution is treated with a resin

  
 <EMI ID = 553.1>

  
 <EMI ID = 554.1>

  
Purification is carried out by chromatography on 200 g of silica gel, eluting with the lower phase of a chloroform / methanol / 7% aqueous ammonium hydroxide system.

  
 <EMI ID = 555.1>

  
by thin layer chromatography and the combined eluates of the main component are concentrated in vacuo to obtain

  
 <EMI ID = 556.1> purification by chromatographing again on 100 g of silica gel and eluting with a chloroform system /

  
 <EMI ID = 557.1>

  
similar eluates (as determined by thin layer chromatography) and passed through a column of basic ion exchange resin, following which

  
 <EMI ID = 558.1>

  
epiverdamycin.

  
B. In the process of 1? Example 14-A, neutral equivalent amounts of 5-epi-aminoglycosides and 5-epi-azido (and 5-epi-amino) -5-deoxy are now used

  
 <EMI ID = 559.1> <EMI ID = 560.1> <EMI ID = 561.1>

  
sodium carbonate. in 625 ml of distilled water.
100 µl of carbobenzoxy chloride in the stirred solution

  
 <EMI ID = 562.1>

  
the solid by filtration, washed completely with water, one. dried in vacuo and then washed with hexane to afford penta-N-carbobenzoxy-5-epiverdamycin as a colorless amorphous solid. We

  
 <EMI ID = 563.1>

  
250 mg of sodium hydride are added to the stirred solution and the reaction mixture is stirred under argon at room temperature.

  
 <EMI ID = 564.1>

  
glacial acetic acid (2 ml) to the filtrate which is then concentrated in vacuo. The residue is extracted with chloroform
(200 ml) after passing through basic alumina),

  
the extract is washed with water and dried over sodium sulfate. The solution is evaporated to give the tetra-

  
 <EMI ID = 565.1>

  
tetrahydrofuran (200 µl), 1 liter of liquid ammonia (redistilled from sodium) is added. To the stirred solution is added 6 g of sodium in small pieces. After stirring for 3 hours, the excess sodium is destroyed by the addition of ammonium chloride. The solvent is allowed to evaporate under a stream of nitrogen. The residue is dissolved in water and passed through a. resin medium <EMI ID = 566.1>

  
drop, with stirring, of t-butoxycarbonyl azide

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

  
The homogeneous fractions containing the title substance are combined and the solvent is removed by evaporation in vacuo.

  
 <EMI ID = 569.1>

  
of excess ether. The solid product is isolated by filtration and dried.

  
 <EMI ID = 570.1>

  
tick. After five minutes at room temperature, the trifluoroacetic acid is removed in vacuo and the residue is treated with 10% potassium hydroxide solution at 100 [deg.] C for 5 hours.

  
The refxoidized solution is lowered through a

  
 <EMI ID = 571.1>

  
 <EMI ID = 572.1>

  
The eluate is concentrated and lyophilized to obtain the title product, in the crude state.

  
 <EMI ID = 573.1> for 18 hours. The solution is brought to dryness and the residue is dissolved in dimethylformamide (10 ml), followed by stirring with ethyl iodide (330 mg).

  
and potassium carbonate (130 mg) for a further
18 hours. The solvent is removed by evaporation and the residue is treated with 10% aqueous potassium hydroxide.

  
 <EMI ID = 574.1>

  
 <EMI ID = 575.1>

  
are reduced to dryness in vacuo and the residue is

  
 <EMI ID = 576.1>

  
bottom of a chloroform / methanol / 7% ammonium hydroxide (2: 1: 1) solvent system to give 1-N-ethyl5-epiverdamycin.

  
 <EMI ID = 577.1>

  
 <EMI ID = 578.1>

  
leaves at room temperature for 24 hours. The solvent is removed in vacuo to give a residue which is then dissolved in dimethylformamide and treated with

  
 <EMI ID = 579.1>

  
 <EMI ID = 580.1>

  
descend the cooled solution through a column of

  
 <EMI ID = 581.1>

  
and eluting the crude product with 2N aqueous ammonium hydroxide. The combined eluates are reduced to dryness in vacuo and the residue is chromatographed on silica gel (200 g) in the lower phase of a chloroform / methanol / 7% ammonium hydroxide solvent system (2: 1: 1). ),

  
 <EMI ID = 582.1>

Example 16

Acid addition salts

  
A. Sulphates (sulfuric acid addition salts)

  
 <EMI ID = 583.1> <EMI ID = 584.1>

  
adjust the pH of the solution to 4.5 with sulfuric acid

  
 <EMI ID = 585.1>

  
vigorous, continue stirring for about 10-20 minutes and filter. The precipitate is washed with methanol and dried at about 60 [deg.] C under vacuum to obtain the

  
 <EMI ID = 586.1>

  
B. Hydrochlorides

  
 <EMI ID = 587.1>

  
 <EMI ID = 588.1>

  
by volume) and the mixture is suddenly cooled. We add

  
 <EMI ID = 589.1>

  
 <EMI ID = 590.1>

  
10 ml of methanol for a period of 15 minutes. The reaction mixture is allowed to warm to room temperature for a period of 2 hours, then evaporated.

  
the solvent under vacuum. The residue is dissolved in water and

  
the product is transformed into the free base by passing a

  
 <EMI ID = 591.1>

  
eluate from the column and the residue is chromatographed on
50 g of silica gel using the lower phase

  
 <EMI ID = 592.1>

  
similar, as determined by thin layer chromatography, and evaporated to give a residue of 1-N-acetyl-

  
 <EMI ID = 593.1>

  
Ni <EMI ID = 594.1>

  
 <EMI ID = 595.1>

  
 <EMI ID = 596.1>

  
acetyl-5-epitobramycin.

  
C. In the procedures of Examples 17-A and B, and ^ used other acid anhydrides, for example the anhydride

  
 <EMI ID = 597.1> the antibiotic solution. The mixture is stirred at room temperature for 16 hours. The reaction mixture is concentrated in vacuo to obtain a residue which

  
 <EMI ID = 598.1>

  
 <EMI ID = 599.1> silica in the lower phase 3 [deg.] A chloroform / methanol / 7% ammonium hydroxide (2: 1: 1) solvent system, this

  
 <EMI ID = 600.1>

  
deoxysisomycin. In the same way, we get the 1-N-

  
 <EMI ID = 601.1> <EMI ID = 602.1>

  
5% ethanolic under reflux for 4 hours. Concentrate the solution and add tetrahydrofuran to precipitate

  
 <EMI ID = 603.1>

  
(2) In a similar manner, an equivalent amount of the acid addition salt of each 5-epi-

  
 <EMI ID = 604.1>

  
starting compound aminoglycoside as used

  
in Example 17-B according to the method of Example 17-D (1). Each of the resulting products is isolated and purified in a manner similar to that described, to obtain the derivatives.

  
 <EMI ID = 605.1>

  
corresponding to each of the starting compounds 5-epiazido- and 5-epi-amirc-deoxy.

  
(3) In a similar manner, an equivalent amount of the acid addition salt of the following 5-epiaminoglycosides was subjected to the process of Example 17-D (1):

  
 <EMI ID = 606.1>

  
5-epitobramycin.

  
the resulting products are isolated in a

  
 <EMI ID = 607.1>

  
&#65533; t <EMI ID = 608.1>

  
in 250 ml of water and 100 ml of methanol are added. 0.35 g of triethylamine is added and the mixture is stirred for 15 minutes. we

  
 <EMI ID = 609.1>

  
and stirred at room temperature for 16 hours. The solution is evaporated in vacuo to obtain a solid residue. This residue is dissolved in 5 ml of a solution

  
 <EMI ID = 610.1>

  
reflux for 15 minutes. The solution is concentrated in vacuo to give an oily residue which is chromatographed on 200 g of silica gel in the lower phase of a solvent system consisting of chloroform / methanol / 7% ammonium hydroxide (2: 1 : 1), to obtain lN- (5-hydroxy-

  
 <EMI ID = 611.1>

  
 <EMI ID = 612.1>

  
(2) In a similar manner, an equivalent amount of the addition salt of those of 5-epi-azido- is treated.

  
 <EMI ID = 613.1>

  
resulting in a manner similar to that described, to obtain the following compounds:

  
 <EMI ID = 614.1> <EMI ID = 615.1>

  
l \ <EMI ID = 616.1>

  
 <EMI ID = 617.1>

  
 <EMI ID = 618.1>

  
 <EMI ID = 619.1>

  
 <EMI ID = 620.1>

  
for 10 minutes. A solution of 2.0 g of

  
 <EMI ID = 621.1>

  
drop by drop, with stirring. The reaction mixture is stirred at room temperature for 16 hours. The reaction mixture is concentrated in vacuo to obtain

  
 <EMI ID = 622.1>

  
(2) In a similar manner, an equivalent amount of the acid addition salt of 5-epi-azido- and

  
 <EMI ID = 623.1>

  
starting from Example 17-D (3), according to the process described in Example 17-F (1). The resulting product is isolated and purified in a manner similar to that described, to

  
 <EMI ID = 624.1> 5-epi-azido-5-deoxygentamycin C-

  
2.8 g (4 millimoles) of sulphate of

  
 <EMI ID = 625.1>

  
add 15 ml of methanol. Add 0.56 ml (4 millimoles} <EMI ID = 626.1>

  
of dry dimethylformamide, drop by drop and with stirring, to the antibiotic solution. The mixture is stirred overnight (16 hours) at room temperature. We

  
 <EMI ID = 627.1>

  
ammonium hydroxide (1: 1: 1), showing the presence of a plurality of minor constituents and a major constituent. The reaction mixture is concentrated under vacuum to give a residue which is triturated with methanol, this

  
 <EMI ID = 628.1>

  
 <EMI ID = 629.1>

  
 <EMI ID = 630.1>

  
The product of Example 17-G (la) is dissolved in

  
a mixture consisting of 12 ml of methanol and 3 ml of water, 20 mg of carbon containing 10% palladium are added and the mixture is hydrogenated under 4 atmospheres at room temperature. At the end of

  
3 hours, the reaction is substantially complete. The catalyst is removed by filtration and the lyophilized.

  
 <EMI ID = 631.1> <EMI ID = 632.1>

  
tion dropwise and with stirring. antibiotic solution. The resulting solution was stirred at room temperature for 18 hours, then concentrated in vacuo to obtain a residue. The residue is dissolved in water and treated with a dilute solution of barium hydroxide, with stirring, until the pH reaches about 8.0. The barium sulfate precipitate is removed by filtration using a filter aid. The precipitate is washed with water, the filtrate and the washings are combined and concentrated in vacuo to dryness. The residue is chromatographed on a column containing 600 g of silica gel using the lower phase of a solvent system consisting of chloroform / methanol / ammonium hydroxide (1: 1: 1). as an eluent. Similar fractions containing 1-N- (S-4-

  
 <EMI ID = 633.1>

  
deoxygentamycin B, as determined by chromatography

  
 <EMI ID = 634.1>

  
 <EMI ID = 635.1>

  
The product of Example 17-G (2a) above is dissolved in a mixture consisting of 20 ml of water and 8 ml of methanol. The product is hydrogenated in the presence of
60 mg of carbon at 5% palladium, under 3.5 atmospheres, at room temperature for 3 hours. The catalyst is removed by filtration using an adjuvant of <EMI ID = 636.1>

  
the filtrate and the washing waters. The liquid thus obtained is concentrated in vacuo to dryness. Chromatography

  
the residue on a silica gel column containing 100 g

  
 <EMI ID = 637.1>

  
collect the fractions containing the more polar constituent, concentrate and lyophilize, to obtain the

  
 <EMI ID = 638.1>

  
 <EMI ID = 639.1>

  
tion. The mixture is stirred overnight at room temperature, then concentrated "or" vacuum to obtain

  
 <EMI ID = 640.1>

  
silica: elution is carried out with the lower phase of a solvent mixture chloroform / methanol / concentrated ammonium hydroxide
(1: 1: 1). The fractions containing the major constituent of the reaction are combined and evaporated (determination by thin layer chromatography on gel platelets of

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

  
The product of Example 17-G (3a) is dissolved in

  
 <EMI ID = 643.1>

  
Refluxed for 3 hours, then evaporated to dryness in vacuo. The residue is chromatographed on.
160 g of silica gel, eluted with the lower phase of a solvent mixture chloroform / methanol / concentrated ammonium hydroxide (1: 1: 1). The fractions containing the major constituent of the reaction are combined and evaporated.
(determination by thin layer chromatography on silica gel platelets) and thus the

  
 <EMI ID = 644.1>

  
The present invention also relates to pharmaceutical compositions comprising the derivatives of

  
 <EMI ID = 645.1>

  
Antibiotic 66-40B, Antibiotic 66-40D, Antibiotic G-418, Antibiotic JI-20A, Antibiotic JI-20B and

  
 <EMI ID = 646.1>

  
wool is replaced by a 1,3-diaminocyclitol of formula

  

 <EMI ID = 647.1>


  
 <EMI ID = 648.1> <EMI ID = 649.1>

  
 <EMI ID = 650.1>

  
carbon atoms and, in the case of substitution by amino and hydroxy, carrying the substituents on atoms

  
different carbon; and X is hydroxy, azido or amino; with the proviso that, in the case of sisomycin derivatives, the substituent X is an azido or an amine: or the pharmaceutically acceptable acid addition salts of said derivatives, with a pharmaceutically acceptable carrier or coating. The invention further relates to a method of obtaining an anti-bacterial response in an animal.

  
warm blooded having a bacterial infection susceptible to treatment, which method comprises administering to said animal a non-toxic and effective amount of the point

  
 <EMI ID = 651.1>

  
The compounds of the present invention and the non-toxic pharmaceutically acceptable acid addition salts thereof are broad spectrum anti-bacterial agents which advantageously. exhibit activity against many organisms which are resistant to their 5-hydroxy precursors. Thus, the compounds of the present invention can be used alone or in combination with other antibiotic agents to prevent growth.

  
or reduce the number of bacteria in various environments. They can be used, for example, to disinfect laboratory glassware, dental and medical accessories and equipment contaminated with Staphvlococcus aureus

  
or other bacteria inhibited by aminoglycosides

  
of the invention. The activity of the compounds of this invention against Gram-negative bacteria makes them useful for

  
 <EMI ID = 652.1>

  
Gram negative, for example Proteus and Pseudomonas species. Compounds, for example, 5-epi-azido-

  
 <EMI ID = 653.1>

  
 <EMI ID = 654.1>

  
naires, especially in the treatment of mastitis

  
the <EMI ID = 655.1>

  
of cattle and diarrhea induced by. Salmonella ^ in domestic animals such as dogs and cats.

  
 <EMI ID = 656.1>

  
invention resides in increased power vis-à-vis

  
 <EMI ID = 657.1>

  
Thus, for example, the compounds of the present invention,

  
 <EMI ID = 658.1>

  
 <EMI ID = 659.1>

  
 <EMI ID = 660.1>

  
adenylylation of the 2 "-hydroxy group. Among these compounds,

  
 <EMI ID = 661.1>

  
Antibiotic G-52 and Antibiotic 66-40D. These compounds are broad spectrum anti-bacterial agents, active against

  
 <EMI ID = 662.1>

  
by conventional dilution tests, including &#65533;

  
bacteria resistant to parent compounds. In addition, the

  
 <EMI ID = 663.1>

  
improved potency against Pseudomonas.

  
 <EMI ID = 664.1>

  
 <EMI ID = 665.1>

  
the age and weight of the animal species to be treated, the method of administration, and the type and degree of severity

  
bacterial infection that we want to prevent or reduce.

  
In general, the determination of the derivatives of 4,6-di-O-.

  
 <EMI ID = 666.1>

  
a given bacterial infection is similar to the dosage

  
 <EMI ID = 667.1>

  
streptamines and pharmaceutical acid addition salts.

  
 <EMI ID = 668.1>

  
orally. They can also be applied topically in the form of ointments both of hydrophilic character and of

  
 <EMI ID = 669.1>

  
 <EMI ID = 670.1>

  
or in the form of creams. Pharmaceutical carriers useful for the preparation of such formulations include!

  
 <EMI ID = 671.1>

  
fats, polyesters, polyols and the like.

  
For oral administration, the compounds of the present invention can be formulated as

  
 <EMI ID = 672.1>

  
of the present invention are most effective for the treatment of bacterial infections of the gastrointestinal tract, the infections of which cause diarrhea.

  
In general, topical preparations will contain from about 0.1 to about 3.0 g of active ingredient per 100 g of ointment, creams or lotion. Topical preparations are usually used sparingly or gently

  
on lesions about two to about five times per <NDE ID = 673.1>

  
The anti-bacterial agents of the present invention can be used in liquid form as solutions, suspensions and the like for otic use and optical use and they can also be administered patentably by intramuscular injection. The solution or suspension for injection will usually be given

  
at a rate of from about 1 mg to about 10 mg of anti-bacterial agent per kg of body weight per day, this overall dose being divided into about two to about four unit doses. The exact dose depends on the stage and severity of the infection, the susceptibility of the infecting organism to the anti-bacterial agent, and the individual characteristics of the animal species being treated.

  
The following formulations are given as examples of some dosage forms in which the anti-bacterial agents of the present invention can be employed:

  
Formulation 1

  

 <EMI ID = 674.1>


  
* Excess of 5%

  
 <EMI ID = 675.1>

  
 <EMI ID = 676.1>

  
 <EMI ID = 677.1>

  
Process

  
 <EMI ID = 678.1>

  
&#65533; <EMI ID = 679.1> the porridge. corn starch and magnesium stearate are added. Mix and compress into tablets.

  
 <EMI ID = 680.1>

  
Ointment

  

 <EMI ID = 681.1>


  
Process

  
(1) The petroleum jelly is melted.

  
(2) 5-epigentamycin Cla, methylparaben and propylparaben are mixed with about 10% molten petroleum jelly.

  
 <EMI ID = 682.1>

  
colloids. :

  
(4) The remainder of petroleum jelly is added with stirring and the

  
 <EMI ID = 683.1>

  
At this stage, the product can be placed in suitable containers.

  
Ointments of other compounds of the

  
 <EMI ID = 684.1>

  
 <EMI ID = 685.1>

  
of this example.

Formulation. 3

  
Solution for injection For vial For 50 liters

  
from 2Q ml
 <EMI ID = 686.1>
 
 <EMI ID = 687.1>
 * Includes an additional 5% crafting amount

  
 <EMI ID = 688.1>

  
Approximately 35 liters of water for injection are placed in a suitable stainless steel container, surrounded by a jacket, and heated to approximately.

  
 <EMI ID = 689.1>

  
in heated water for injection and dissolved with stirring. When the parabens are completely dissolved,

  
 <EMI ID = 690.1>

  
tion of cold water in the jacket of said container. Nitrogen gas is passed through the solution for at least

  
 <EMI ID = 691.1>

  
during the rest of the process. Disodium ethylenediaminetetraacetate and sodium bisulfite are introduced and dissolved. Introduce and dissolve 5-

  
 <EMI ID = 692.1>

  
50.0 liters with water for injection and stirred until the mass is homogeneous.

  
Under sterile conditions, the solution is filtered through an appropriate bacteria retention filter

  
and collecting the filtrate in a filling tank.

  
Sterile, pyrogen-free, multi-dose vials are aseptically filled with said filtrate, closed and sealed.

  
In an analogous manner, injectable solutions of other compounds of the present invention, and in particular acid addition salts, can be prepared.

  
 <EMI ID = 693.1> <EMI ID = 694.1> <EMI ID = 695.1>

  
Of course, the invention is in no way limited

  
to the embodiments described which have been given only by way of example. In particular, it comprises all the means constituting technical equivalents of the means described as well as their combinations, if these are executed according to its spirit and implemented within the framework of the following claims.


    

Claims (1)

<EMI ID = 696.1> 1. Process for preparing 4,6-di-O- derivatives <EMI ID = 697.1> is replaced by a 1,3-diaminocyclitol of formula <EMI ID = 698.1> <EMI ID = 699.1> said aliphatic radicals having up to 7 carbon atoms and, in the case of substitution by amino and hydroxy, carrying the substituents on different carbon atoms; and X is hydroxy, azido or amino; with the proviso that, in the case of derivatives of the <EMI ID = 700.1> <EMI ID = 701.1> <EMI ID = 702.1> <EMI ID = 703.1> <EMI ID = 704.1> reduction of the azido group in the 5- position either before or after removal of the protecting groups and, if desired, <EMI ID = 705.1> with Y being as defined above; and isolate the derivative as or in the form of a pharmaceutical acid addition salt <EMI ID = 706.1> according to claim 1. <EMI ID = 707.1> <EMI ID = 708.1> and in that the reduction of the azido group in position 5 is effected by hydrogen in the presence of catalyst ion. <EMI ID = 709.1> <EMI ID = 710.1> <EMI ID = 711.1> position 5- is carried out by means of an alkali metal in liquid ammonia. 5. Method according to any one of claims <2> to 4, characterized in that the removal of the 'groups <EMI ID = 712.1> protectors is carried out by means of an aqueous base and then,; when acetals or ketals are present, using a moderate aqueous acid. 6. Process for the preparation of derivatives of 4, 6-di-0- <EMI ID = 713.1> 66-40B, Antibiotic 66-40D, Antibiotic G-418, Antibiotic JI-20A, Antibiotic JI-20B, and <EMI ID = 714.1> is replaced by 1,3-diaminocyclitol of formula <EMI ID = 715.1> where R is hydrogen or a -CH2Y group with Y being <EMI ID = 716.1> cycloalkylalkyl, hydroxyalkyl, aminoalkyl, N-alkylaminoalkyl, aminohydroxyalkyl, N-alkyl- <EMI ID = 717.1> said aliphatic radicals having up to 7 carbon atoms and, in the case of substitution by amino and <EMI ID = 718.1> <EMI ID = 719.1> pharmaceutically acceptable acids of these derivatives; characterized in that it consists in treating a derivative of <EMI ID = 720.1> <EMI ID = 721.1> in which formula R has the above meaning and :: ' <EMI ID = 722.1> while the hydroxy and amino groups of said derivative 4,6- <EMI ID = 723.1> groups susceptible to reductive cleavage or moderate or basic acid hydrolysis by dimethylformamide at <EMI ID = 724.1> <EMI ID = 725.1> <EMI ID = 726.1> <EMI ID = 727.1> upper ; and isolating the derivative as or in the form of a pharmaceutically acceptable acid addition salt. 7. Method according to claim 6, characterized in that the reaction with dimethylformamide is carried out. <EMI ID = 728.1> 9. A method according to any one of claims <EMI ID = 729.1> <EMI ID = 730.1> <EMI ID = 731.1> He. Process according to any one of Claims 6 to 10, characterized in that the removal of the protecting groups is carried out by means of an aqueous base or, when protecting groups capable of reductive cleavage are present, by reaction with hydrogen in the presence of a catalyst or with an alkali metal in liquid ammonia, then by treatment with an aqueous base and then, when all the protecting groups are acetals or ketals, with an aqueous acid. 12. Method according to any one of claims 6 to 11, characterized in that a derivative of sisomycin is used and in that R, in the 1,3-diamino- group <EMI ID = 732.1> 13. Method according to any one of claims 6 to 11, characterized in that a derivative of sisomycin is used and in that R, in the 1,3-diaminocyclitol group of formula III, is -CH2Y with Y being as defined in claim 6. 14. The method of claim 13, characterized <EMI ID = 733.1> tobramycin, verdamycin, kanamycin A, kanamycin <EMI ID = 734.1> Antibiotic 66-40B. Antibiotic 66-40D, Antibiotic G-418, Antibiotic JI-20A, Antibiotic JI-20B and sisomycin, in which the 2-deoxystreptamine group is replaced by a 1,3-diaminocyclitol of formula <EMI ID = 735.1> <EMI ID = 736.1> tolyl, said aliphatic radicals having up to 7 carbon atoms and, in the case of substitution by amino and hydroxy, bearing the substituents on atoms of <EMI ID = 737.1> <EMI ID = 738.1> <EMI ID = 739.1> <EMI ID = 740.1> <EMI ID = 741.1> 2-deoxystreptamine are protected by groups susceptible to reductive cleavage or moderate acid hydrolysis or <EMI ID = 742.1> alkaline, to remove the protective group in the product <EMI ID = 743.1> which R is hydrogen, to obtain a compound in <EMI ID = 744.1> .... <EMI ID = 745.1> <EMI ID = 746.1> in that the oxidizing agent is selected from the group formed by ruthenium tetroxide, the chronic acid in <EMI ID = 747.1> methylene chloride. 17. The method of claim 15 or 16, characterized in that the alkali metal diborohydride is <EMI ID = 748.1> 18. A method according to any one of claims 15. to 17, characterized in that the removal of protecting groups is carried out by means of a base aqueous or, when protecting groups capable of reductive cleavage are present, by reaction with hydrogen in the presence of a catalyst or with an alkali metal in <EMI ID = 749.1> <EMI ID = 750.1> acetals or ketals, with aqueous acid. <EMI ID = 751.1> tions 15 to 18, characterized in that a derivative <EMI ID = 752.1> 20. A method according to any one of claims 15 to 18, characterized in that a derivative is used. <EMI ID = 753.1> <EMI ID = 754.1> <EMI ID = 755.1> in that the -CH2Y group is ethyl. 22. A method according to any one of the claims <EMI ID = 756.1> resulting compound, in which R is hydrogen, is carried out by treating the compound, which may have amino protecting groups at any position, other than position <EMI ID = 757.1> <EMI ID = 758.1> <EMI ID = 759.1> any one of claims 1, 6 and 15, in which any amino or hydroxy group present can be protected; in the presence of a hydride reducing agent-donor and, if desired, removing any protecting groups present in the molecule. 23. The method of claim 22, characterized <EMI ID = 760.1> free, is treated with aldehyde, in which any amino group is protected and any hydroxy group is in free form. 24. The method of claim 22 or 23, characterized in that the reaction is carried out in a pH range from 1 to 11. 25. A method according to any one of claims 22 to 24, characterized in that the reaction is carried out in a pH range of from 2.5 to 3.5. 26. Process according to any one of claims 22 to 25, characterized in that the reducing agent <EMI ID = 761.1> alkali metal or a borohydride of an alkali metal. 27. Method according to any one of claims 22 to 26, characterized in that the compound is treated with at least one equivalent of aldehyde in the presence of one equivalent of reducing agent-hydride donor. <EMI ID = 762.1> . 1, 6 and 15, characterized in that the alkylation of a resulting compound, in which R is hydrogen, to obtain a compound in which R is a straight chain alkyl having up to 5 carbon atoms , is carried out by treating the compound, in which amino protecting groups at any position other than the 1- position have been introduced and in which the 1-amino group may be in <EMI ID = 763.1> carbon and a leaving group; and removing the protecting groups and, if desired, the group or groups <EMI ID = 764.1> activators present in the molecule. 29. The method of claim. 28, characterized <EMI ID = 765.1> 30. The method of claim 28, characterized in that the 1-amino group is alkylated in the form of the trifluoromethylsulfonyl derivative. 31. The method of claim 28, characterized in that the 1-amino group is alkylated in the form of the derivative di- (2-cyanoethyl). 32. A method according to any one of claims 28 to 31, characterized in that the alkylating agent is an alkylfluorosulfonate, a dialkylsulfate or an alkyl iodide. 33. A method according to any one of claims 1, 6 and 15, characterized in that the alkylation of a resulting compound, in which R is hydrogen, for <EMI ID = 766.1> Y being as defined in any one of the claims <EMI ID = 767.1> Claim 1 is hydroxy or amino, is effected by treating the compound, which may have amino protecting groups at any position other than the 1- position, with an acylating agent selected from an acid of the formula <EMI ID = 768.1> <EMI ID = 769.1> any one of claims 1, 6 and 15, wherein any amino or hydroxy group present may be protected; in the presence of a carbodiimide, and a reactive derivative of said acid; removing all protecting groups present in the molecule and treating the resulting 1-N-acyl derivative with an amide reducing hydride reagent. 34. The method of claim 33, characterized in that a reactive derivative of the acid is used as acylating agent. <EMI ID = 770.1> in that the reactive derivative of the acid is an ester, a <EMI ID = 771.1> 36. Method according to any one of the claims 33 to 35, characterized in. what the compound to be treated by <EMI ID = 772.1> tion of an acid addition salt. 37. Method according to any one of the claims 33 to 36, characterized in that the compound to be treated with the acylating agent is neutralized with (n - 1) equivalents of acid, n being the number of amino groups in the molecule. <EMI ID = 773.1> <EMI ID = 774.1> <EMI ID = 775.1> <EMI ID = 776.1> <EMI ID = 777.1> <EMI ID = 778.1> 0 11 <EMI ID = 779.1> <EMI ID = 780.1> <EMI ID = 781.1> phenyl, benzyl or va tolyl, said aliphatic radicals having up to 7 carbon atoms and, in the case of substitution by amine and hydroxy, bearing the substituents on different carbon atoms; and X is a <EMI ID = 782.1> in the case of sisomycin derivatives, the substituent X is a <EMI ID = 783.1> <EMI ID = 784.1> in which formula X is as defined above, while <EMI ID = 785.1> <EMI ID = 786.1> acylation selected from an acid of formula <EMI ID = 787.1> <EMI ID = 788.1> <EMI ID = 789.1> protectors present in the molecule, the last step of the process being followed by the isolation of the derivative such as or in the form of an acid addition salt. <EMI ID = 790.1> <EMI ID = 791.1> <EMI ID = 792.1> 41. The method of claim 39 or 40, characterized o in that the reactive derivative of 1.'acid EO-C-Y 'is an ester, <EMI ID = 793.1> 42. Method according to any one of the claims 39 to 41, characterized in that the derivative of 4,6-di- <EMI ID = 794.1> acylation is partially neutralized by formation of an acid addition salt. 43. Method according to any one of the claims 39 to 42, characterized in that the derivative of 4, 6-di- <EMI ID = 795.1> acylation. is neutralized by (n - 1) equivalents of acid, <EMI ID = 796.1> 44. A method according to any one of claims 1 to 43, substantially as described in the present description. 45. Method according to any one of the claims <EMI ID = 797.1> of the present description. <EMI ID = 798.1> biotic G-52, Antibiotic 66-40B, antibiotic 6S-40D, Antibiotic G-418, Antibiotic JI-20A, Antibiotic <EMI ID = 799.1> <EMI ID = 800.1> by a 1,3-diaminocyclitol of formula <EMI ID = 801.1> <EMI ID = 802.1> where R is hydrogen or a -CE group with Y being hydrogen, alkyl, alkenyl, un. cycloalkyl, a <EMI ID = 803.1> aliphatic radicals having up to 7 carbon atoms and, in the case of substitution by amino and hydroxy, bearing the substituents on different carbon atoms; and X is cyclroxy, azido or amino; with the proviso that, in the case of sisomycin derivatives, the X substituent is azido or amino &#65533; and acid addition salts <EMI ID = 804.1> Antibiotic G-418, Antibiotic JI-20A, Antibiotic JI-203 and sisomycin, in which the group 2- <EMI ID = 805.1> formula <EMI ID = 806.1> <EMI ID = 807.1> <EMI ID = 808.1> <EMI ID = 809.1> Antibiotic G-52, Antibiotic 66-40B, Antibiotic 66-40D, Antibiotic G-418, Antibiotic JI-20A and <EMI ID = 810.1> formula <EMI ID = 811.1> <EMI ID = 812.1> mines that are gentamycin A, gentamycin B, <EMI ID = 813.1> <EMI ID = 814.1> <EMI ID = 815.1> biotic G-52, Antibiotic 66-40B, Antibiotic 66-40D, <EMI ID = 816.1> JI-20B and sisomycin, in which the 2deoxystreptamine group is replaced by a diaminocyclitol of formula <EMI ID = 817.1> wherein formula R is a -CH2Y group with Y being hydrogen, alkyl, alkenyl, cycloalkyl, <EMI ID = 818.1> <EMI ID = 819.1> tolyl: Said aliphatic radicals having up to 7 atoms carbon and, in the case of substitution by amino and hydroxy, bearing the substituents on different carbon atoms and X is azido or amino; and the pharmaceutically acceptable acid addition salts of these derivatives. <EMI ID = 820.1> 66-40D, Antibiotic G-418, Antibiotic JI-20A and 1 "Antibiotic JI-20B, in which the group 2- <EMI ID = 821.1> formula <EMI ID = 822.1> <EMI ID = 823.1> <EMI ID = 824.1> tolyl, said aliphatic radicals having up to 7 carbon atoms and, in the case of substitution, by amino <EMI ID = 825.1> different carbon; and X is hydroxy; as well as <EMI ID = 826.1> these derivatives. 51. Compounds according to claim 46, characterized in that R is hydrogen or an alkyl having up to <EMI ID = 827.1> <EMI ID = 828.1> 52. Compounds according to claim 46, characterized in that R is hydrogen or ethyl, and addition salts <EMI ID = 829.1> 53. compounds according to any one of the claims 46, 51 and 52, characterized in that said derivatives of <EMI ID = 830.1> <EMI ID = 831.1> verdamycin, Antibiotic G-52, Antibiotic G-418, Antibiotic JI-20A, Antibiotic JI-20B and sisomycin, wherein in formula I, R is as defined in any one of claims 46, 51 and 52 and X is as defined in claim 46 and the addition salts <EMI ID = 832.1> which, in formula I, R is hydrogen and X is a <EMI ID = 833.1> <EMI ID = 834.1> <EMI ID = 835.1> R is hydrogen or 3 'ethyl and X is hydroxy; and the <EMI ID = 836.1> these derivatives. 56. Compounds according to claim 55, characterized in that R is hydrogen, and acid addition salts <EMI ID = 837.1> 63. 5-epigentamycin C2b and pharmaceutically acceptable acid addition salts thereof. <EMI ID = 838.1> 66. 5-epi-Aatibiotic G-52 and pharmaceutically acceptable diacid addition salts thereof. <EMI ID = 839.1> <EMI ID = 840.1> pharmaceutically acceptable acid addition of this compound. 79. 5-epi-amino-5-deoxy-Antibiotic 66-40D and salts <EMI ID = 841.1> compound. 88. 5-epi-azido-5-deoxy-Antibiotic 66-40D and salts <EMI ID = 842.1> compound.. 89. A compound according to any one of the claims 46 to 88, as far as it is prepared by the process according to the Orne of any one of claims 1 to 38, 44 and 45. <EMI ID = 843.1> 90. 5-episiscmycin, as far as prepared <EMI ID = 844.1> 1, 44 and 45. <EMI ID = 845.1> <EMI ID = 846.1> 6 to 12, 15 to 19, 44 and 45. <EMI ID = 847.1> <EMI ID = 848.1> <EMI ID = 849.1> claim 6, as far as they are prepared by the method according to any one of claims 6 to 13, <EMI ID = 850.1> <EMI ID = 851.1> prepared by the process according to any one of claims 6 to 38, 44 and 45. <EMI ID = 852.1> Antibiotic G-52, Antibiotic 66-40B, Antibiotic 66-40D, Antibiotic G-418, Antibiotic JI-20A, <EMI ID = 853.1> <EMI ID = 854.1> o He <EMI ID = 855.1> <EMI ID = 856.1> <EMI ID = 857.1> <EMI ID = 858.1> carbon and, in the case of substitution by amino and hydroxy, carrying the substituents on different carbon atoms; and X is hydroxy, azido or amino with the proviso that in the case of sisomy- derivatives. ci.ne. the substituent X is an azido or an amino as well as the acid addition salts of these derivatives. 95. Compounds according to claim 95, characterized in that X is as defined in claim 94 and <EMI ID = 859.1> compounds. 96. Compounds according to claim 94, characterized in that X is as defined in claim 94 and <EMI ID = 860.1> acid of these compounds. <EMI ID = 861.1> in that X is as defined in claim 94 and <EMI ID = 862.1> acid of these compounds. 98. A compound according to any one of the claims 94 to 97, provided that it is prepared by the process according to <EMI ID = 863.1> 99. Pharmaceutical compositions, characterized in that they comprise as active ingredient at least one compound according to claim 46, in association with a pharmaceutical excipient or carrier. 100. Composition according to claim 99, characterized in that it is in the form of dosage units. 101. Composition according to claim 99 or 100, characterized in that the aforementioned active ingredient is a compound according to any one of claims 57 to 88. 102. Pharmaceutical composition according to claim 99, substantially as described in the description with specific reference to examples thereof. Y <EMI ID = 864.1> Tick according to any one of claims 99 to 102, characterized in that the aforementioned active ingredient is supplied in a form suitable for therapeutic administration. 104. The method of claim 103, characterized in that the aforementioned active ingredient is mixed with a pharmaceutical carrier or excipient. <EMI ID = 865.1> is obtained by the process according to claim 103 or 104. <EMI ID = 866.1> bacterial in a warm-blooded animal having a bacterial infection susceptible to treatment, characterized in that it consists in administering to said animal a non-toxic and antibacterial effective amount of the compounds according to any one of claims 46 to 88 Referring to the above request, our principals wish to draw the attention of the reader of the patent to the two omissions noted below: - page 3, formula X must be correctly worded as follows: (see part underlined in red) <EMI ID = 867.1> <EMI ID = 868.1> <EMI ID = 869.1> <EMI ID = 870.1> The undersigned is aware that no document attached to the file of a patent for invention can be of a nature to make either the description or the drawings, substantive modifications and declares that the content of this note does not ap- <EMI ID = 871.1> to report one or more material errors. He acknowledges that the content of this note cannot have the effect of making the patent valid in whole or in part if it was not fully or partially valid under the legislation currently in force. He authorizes the Administration to attach this note to the patent file and to issue a photocopy of it. Enclosed, Frs 100.- in a fiscal stamp, amount of the official tax. Please accept. Gentlemen, our best regards. &#65533;