AU580009C - Nitrosourea derivatives. - Google Patents

Description

NITROSOUREA DERIVATIVES, PROCESS FOR THEIR PREPARATION AND MEDICAMENTS CONTAINING THEM

BACKGROUND OF THE INVENTION

The present invention relates to novel nitrosourea derivatives and, more specifically, to novel 2-desoxy-sugar-nitrosoureas and 4-desoxy-sugar-nitrosoureas, to processes for their preparation and to their therapeutic uses.

It is known that various nitrosoureas have powerful cytostatic and oncostatic activity detected within the framework of pharmacological experiments and clinical treatment : this is the case, in particular, of (1,3bis-2-chloroethyl)-1-nitrosourea [BCNU] marketed under the trademark "BICNU" (cf. Dictionnaire VIDAL 1984), of 1-(2-chloro-ethyl)-3-cyclohexyl nitrosourea [CCNU] marketed under the trademark "BELUSTINE" (cf. Dictionnaire VIDAL 1984) and 1-(2-chloro-ethyl)-3-(4-methyl-cyclohexyl)nitrosourea [Me CCNU] : cf. G. MATHE and Y. KEN13 : Expansion Sciehtifique, 1975, 3rd Ed, îLA Chimiotherapie des cancers (leucemies, hematosarcomes et tumeurs solides)" and T.H. WASSERMAN, M. SLAVIK & S.K. CARTER, Cancer Treat. Rev., 1974, 1, p. 131, "Review of CCNU in clinical cancer therapy". G .P. WHEELER et al (Cancer Res., 1974, 34, 194) attribute their oncostatic action to an alkylation and a αarbomoylation of proteins. It has also been suggested that their Ijpophilic character is essential in so far as it conditions the passage through cell membranes in particular the blood-brain barrier. However, these compounds have the drawback of showing certain toxicity, particularly hematological, at the doses at which they are revealed to be active. Consequently, this toxicity limits their use at doses less than those which seem necessary for the removal of cancer cells and has incited a team of researchers to aim at obtaining medicaments more active and less toxic than the preceding ones, by synthesizing derivatives of nitros soureas whose hydrophilic character is increased with respect to the preceding ones, such as sugar-nitrosoureas, in which the sugar molecule is ribose, xylose or glucose : cf. J.L. IMBACH et al, Biomedicine, 1975, 23, p. 410-413, "The oncostatic and immunosuppressive action of new nitrosourea derivatives containing sugar radicals". Thus these authors have established the oncostatic action of the following four compounds on L 1210 leucemia anu their low toxicity: 1-(2-chloro-ethyl)3-(ribofuranosyl-2',3'-isopropylidene-5-paranitro benzoate)-nitrosourea [R FCNU] ,3-(2-chloro1-ethyl-2'-desoxy-glucopyranosyl-14,3',4",6'-tetracetate)nitrosourea [GCNU] , 1-(2-chloro-ethyl) 3-(ribopyranosyl2',3',4'-triacetate)-nitrosourea [RPCNU] and 1-(2-chloro ethyl) 3-(xylopyranosyl 2',3',4'-triacetate)-nitrosourea [XPCNU] . These compounds are prepared by reacting the appropriate amino-sugar with 2-chloro-ethyl isocyanate, then by proceding with nitrosation of the urea obtained.

These compounds are in oily form, a difficult physical state to handle in therapeutics. This is why, within the scope of the experiments carried out on these products, recourse has preferably been had to their solidification by blocking the hydroxy groups.

In a subsequent work J.L. MONTERO et al (Eur. J. Med. Chem. Chimica Therapeutica, mars/avril 1976, 11, n 2, p. 183-187 : "Synthese de nouvelles glycosylnitrosourees a visees oncostatiques - les 1-nitrosoureido-1desoxy-glucopyranoses"), described glycosyl-nitro soureas in which the sugar-nitrogen bond is located in an anomeric position, which has oncostatic activity, mamely 1- [3-(2chloro-ethyl) 3-nitroso-ureido]-1-beta-D-glucopyranose and 2,3,4,6-tetra-O-acetyl 1- [3-(2-chlor-ethyl) nitroso3-ureido]-1-desoxy-beta-D-glucopyranose, and which represents in addition the advantage of lower toxicity on the bone marrow and not being diabetogenic, whereas streptozotocine or 2-desoxy-2-(3-methyl-2-nitrosoureido)-D-glucopyranose, which is a compound of natural origin, presents antibiotic, antineoplasic properties, and also presents un desirable diabetogeni c properties as well as a high renal and hematological toxicity ( cf . Drugs of the future , vol .

IV , n 2 , 1979 , p . 137- 139) .

One of the aspects of the invention is to provide novel nitrosourea derivatives, for which the profile of the activity curve showό its maximum at a dosage far below the threshold of the toxicity.

Another aspect of the invention is to provide novel nitrosourea derivatives having a αood therapeutic index. It is another aspect of the invention to provide also novel nitrosourea derivatives having physical properties enabling their use in therapeutics.

Another aspect of the invention is to provide novel nitrosourea derivatives having a solid and stable form.

GENERAL DESCRIPTION OF THE INVENTION

According to the invention these various aspects are achieved by means of a novel series of derivatives of 2-desoxy-sugar-nitrosoureas and 4-desoxy-sugar-nitroso-r ureas, which are distinguished from known nitrosourea derivatives, particularly by the nature of the oside synthon, which is a 2-desoxy-sugar or a 4-desoxy-sugar.

It has been observed that by resorting to 2desoxy-sugar or a 4-desoxy-sugar, substituted on the 3 and/or at the 6 carbon of the above-said sugar, by a nitrosourea group, and which can carry different substituents on the carbon at the 4 position of the above-said sugar, when it relates to a 2-desoxy-sugar or on the carbon at the 2 position of the above-said sugar, when it relates to a 4-dssoxy-sugar, novel nitrosourea derivatives are obtained whose activity is considerably increased and whose toxicity is low with respect to the compounds already known. One of the interests- of these derivatives can be connected with the hvpothesi-s according tc which the 2-desoxy-suqars and she 4-desoxy-suqars have a certain lability at the level of the oside linkage which can result in the for mation of a free sugar in certain biological media and permit the provision of compounds firstly lipophilic, which then become hydrophilic, which would make easier the 'passage of cellular barriers and would account for an increase of antitumor activity.

An object of the invention is to provide novel nitrosourea derivatives, characterised in that they correspond to the following general formula (I) :

(I)

in which : -R represents a hydrogen atom, an alkyl group ιfrrm1 to 30, preferably 1 to 12 carbon atoms or an aralkyl group from 7 to 12, preferably 7 to 9 carbon atoms, optionally substituted by one or several, particularly up to 3, halogen atoms, NO₂, NH₂, CF₃ groups or alkoxy groups of 1 to 4 carbon atoms,

-X represents a hydroxy group or an NR₁R₂ group

-Y represents a hydrogen atom a hydroxy group or an N 1 group where R₁ and/or R'₁ each represent a hydrogen atom or a

-C-N-CH₂CH₂Hal group, Hal being a halogen, preferably Cl, O NO and R₂ and/or R'₂ each represent a hydrogen atom, an alkyl group comprising from 1 to 6 carbon atoms, an aralkyl group comprising 7 to 12, preferably 7 to 9 carbon atoms, a cycloalkyl group comprising from 3 to 6 carbon atoms, an aryl group of 4 to 10 carbon atoms, the aryl and aralkyl groups being possibly substituted by one or several, particularly up to 3, halogen atoms, NO₂,NH₂,CF₃ groups or alkoxy groups of 1 to 4 carbon atoms, - R' and R" represent hydrogen, OM, M repre¬

senting an alkyl group comprising from 1 to 30, preferably from 1 to 12 carbon atoms, an aryl group frαn 4 to 10 carbon atoms, an aralkyl group comprising from 7 to 12, preferably from 7 to 9 carbon atoms, the aryl and aralkyl groups being possibly substituted by 1 or several,, particularly up to 3, halogen atoms, NO₂,NH₂,CF₃ groups or alkoxy groupsfrαn 1 to 4 carbon atoms, or M representing an acyl group from 2 to 8 carbon atoms, preferably 2 or 3, or an aroylgroup frαn 5 to 12, preferably 5 to 9 carbon atoms, unsubstituted or substituted by one or several, particularly up to 3, NO₂, NH₂, CF₃ groups, halogen, alkoxy of 1 to 4 carbon atoms, provided that either R' or R" represents hydrogen, R' and'R" being not simultaneously hydrogen and

provided that at least X represents ,with R₁ representing C-N CH₂CH₂Hal, or Y represents N with O NO ^R ₂ R'₁ representing -C-N-CH₂CH₂Hal O NO

In a preferred class of compounds of the invention, R' represents H and R" represents OH.

In another preferred class of compounds of the invention R" represents H and R' represents OH. In Formula I and certain of the Formulas following, linkages have been shown between the groups R, R', R",CH₂Y and X on the one hand and the ring structure on the other hand, by the symbol . This representation means that each of the R,R',R",CH₂Y and X groups can be either at the α position or at the β position, according to the HAYWORTH representation, and in an arrangement compatible with the stereochemical requirements.

In the rest of the description, the term alkyl includes linear, branched or cyclic alkyl groups (cycloalkyl). A preferred class of compounds according to the invention is constituted by the compounds corresponding to the Formula II below :

(II) in which

- R represents a hydrogen atom, an alkyl group from 1 to 30, preferably 1 to 12 carbon atoms, or an aralkyl group from 7 to 12, preferably 7 to 9 carbon atoms, optionnally substituted by one or severals. particularly up to 3, halogen atoms. NO₂.NH₂.CF₃ qroups or alkoxy qroups from 1 to 4 carbon atoms. - X represents a hydroxy group or an NR₁R₂ group

- Y represents a hydrogen atom, _R a hydroxy group or an N 1 group where R₁ and/or R'₁ each represent a hydrogen atom or a -C-N-CH₂CH₂Hal group, Hal being a

O NO halogen, preferably Cl, and R₂ and/or R'₂ represent a hydrogen atom, an alkyl group comprising from 1 to 6 carbon atoms, an aralkyl group comprising from 7 to 12, preferably 7 to 9 carbon atoms, a cycloalkyl group com prising from 3 to 6 carbon atoms, an aryl group from 4 to 10 carbon atoms, the aryl and aralkyl groups being optionally substituted by one or several, particularly up to 3 halogen atoms, NO₂, NH₂, CF₃ group or alkoxy groups of 1 to 4 carbon atoms, - R" represents preferably OH, but can be replaced by OM , M representing an alkyl group comprising from 1 to 30, preferably 1 to 12 carbon atoms, an aryl group from 4 to 10 carbon atoms, an aralkyl group comprising from 7 to 12, preferably 7 to 9 carbon atoms, the aryl and aralkyl groups being optionally substituted by one or several, particularly up to 3 halogen atoms, NO₂, NH₂, CF₃ groups or alkoxy groups of 1 to 4 carbon atoms, or M representing an acyl group from 2 to 8 carbon atoms, preferably 2 or 3, or an aroyl group from 5 to 12, preferably 5 to 9 carbon atoms, unsubstituted or substituted by one or several, particularly up to 3, NO₂, NH₂, CF₃ groups, halogen, alkoxy from 1 to 4 carbon atoms, provided that at least X represents -N R₁ with R₁ re R₂ presenting C N CH₂,CH₂,Hal, O NO or Y represents -N R '₁ with R ' ₁ representing

-C-N CH ₂CH ₂ H al O NO

These compounds of formula (II) represent the particular case of formula (I) in which R' represents hydrogen.

Among the compounds of formula (II), a preferred class of compounds according to the invention is constituted by those of formula (III) below :

(III) in which R, R", X and Y have the above-indicated meanings.

The compounds according to the invention of Formula III belong to the class of 4-desoxy,alpha-D-xylohexopyranoside compounds. Among the compounds of Formula (II), a preferred class of compounds according to the invention is constituted by those of Formula IV below :

O OR

(IV) in which R, R", X and Y have the previously indicated meanings.

The compounds of Formula (IV) belong to the clas class of 4-desoxy,alpha-L-xylohexopyranoside compounds.

A particularly preferred class of compounds according to the invention is constituted by the compounds corresponding to the Formula V below : OR (V) in which

- R represents a hydrogen atom, an alkyl group from 1 to 30, preferably 1 to 12 carbon atoms or an aralkyl group from 7 to 12, preferably 7 to 9 carbon atoms, optionally substituted by one or several, particularly up to 3, halogen atoms. NO₂,NH₂,CF₃ groups or alkoxy groups of 1 to 4 carbon atoms -X represents a hydroxy group or an NR₁R₂ group

-Y represents a hydrogen atom, _R' ₁ a hydroxy group or anN group R'₂ where R₁ and/or R'₁ each represent a hydrogen atom or a -C-N CH₂CH₂Hal group, Hal being

O NO halogen, preferably Cl, and R₂ and/or R'₂ each represent a hydrogen atom, an alkyl group comprising 1 to 6 carbon atoms, an aralkyl group comprising 7 to 12, preferably 7 to 9 carbon atoms, a cycloalkyl group comprising from 3 to 6 carbon atoms, an aryl group of 4 to 10 carbon atoms, the aryl and aralkyl groups being optionally substituted by one or several, particularly up to 3, halogen atoms, NO₂,NH₂,CF₃ groups or alkoxy groups of 1 to 4 carbon atoms

R' represents preferably OH, but OH can be replaced by OM, M representing an alkyl group comprising from 1 to 30, preferably from 1 to 12 carbon atoms, an aryl group of 4 to 10 carbon atoms, and aralkyl group comprising 7 to 12, preferably 7 to 9 carbon atoms, the aryl and aralkyl groups being optionally substituted by one or several, particularly up to 3, halogen atoms, NO₂,NH₂,CF₃ groups or alkoxy groups from 1 to 4 carbon atoms, or M representinσ an acyl group of 2 to 8 carbon atoms, preferably 2 or 3, or an aroyl group from 5 to 12, preferably 5 to 9 carbon atoms, unsubstituted or substituted by one or several, particularly up to 3, NO₂,NH₂,CF₃ groups, halogen, alkoxy of 1 to 4 carbon atoms R provided that at least X represents -N , with R₁ R ^R1 R'₁ representing - C-N-CH₂CH₂Hal, or Y represents -N with O NO ²

R'₁ representing -C-N CH₂CH₂Hal

O NO

These compounds of Formula V represent the particular case of Formula I in which R" represents a hydrogen atom.

Among the compounds of Formula V, a preferred class of compounds of the invention is constituted by those of Formula (VI) below : ( VI) in which R, R', X and Y have the previously indicated meanings.

The compounds of formula (VI) belong to the class of 2-desoxy, alpha-D-arabinohexopyranoside compounds.

Among the compounds of formula (V), another preferred class of compounds provided by the invention is constituted by those of the following formula (VII) :

(VII) in which R, R', X and Y have the previously indicated meanings.

These compounds belong to the class of 2-desoxy, alpha-L-arabinohexopyranoside compounds. A preferred class of compounds according to the invention is constituted by those of formulae (I), (II), (III), (IV), (V), (VI), and (VII) in which :

- R represents an alkyl group from 1 to 12 carbon atoms, aralkyl from 7 to 12 carbon atoms ; - R' or R" represents an OM group, M being an alkyl group comprising from 1 to 12 carbon atoms, an aryl group comprising 4 to 10 carbon atoms ;

- X represents an NR.R, group, R, representing -C-N-CH₂CH₂Hal, Hal being a halogen, particularly Cl ; O NO

- Y represents a hydrogen atom or a hydroxy group. Another preferred class of compounds according to the invention is constituted by those of formulae (I), (II), (III), (IV), (V), (VI), and (VII) in which : - R represents an alkyl group from 1 to 12 carbon atoms, halogenoaralkyl from 4 to 10 carbon atoms ;

- R' or R" represents an OM group, M being an acyl group of 2 to 8 carbon atoms, an aroyl group from 5 to 12 carbon atoms ; - X represents an NR₁R₂ group, R₁ representing - C-N-CH₂CH₂Hal, Hal. being a halogen, particularly Cl,

O NO

- Y represents a hydrogen atom or a hydroxy group. Another preferred class of compounds according to the invention is constituted by those of Formulas (I), (II), (III), (IV), (V), (VI), and (VII) and in which :

- R represents an alkyl group frcmi to 12 carbon atoms, an aralkyl group from 7 to 12 carbon atoms ; - R' or R" represents OH ;

- X represents an NR₁R₂ group, R₁ representing C-N CH₂CH₂Hal, Hal representing a halogen, particularly

O NO Cl, - Y represents a hydrogen atom.

Another class of preferred compounds according to the invention is constituted by those of Formula (I), (II), (III), (IV), (V), (VI) and (VII) in which :

- R represents an alkyl group frcmi to 12 carbon atoms, an aralkyl group frαn7 to 12 carbon atoms ;

- R' or R" represent OH ;

- X represents an alkyl amino group, in which the alkyl group has 1 to b carbon atoms, or arylaraino in which the aryl group has 4 to 10 carbon atoms, and - Y represents NR'₁NR'₂, R'₁representing

-C-N-CH₂CH₂Hal, Hal representing a halogen, particularly

O NO Cl.

Another class of preferred compounds according t to the invention is constituted by those of Formula (I), (II), (III), (IV), (V), (VI) and (VII) in which : -R represents an alkyl group of 1 to 12 carbon atoms, an aralkyl group, of 7 to 12 carbon atoms ;

- R' or R" represents OH ;

- X represents a hydroxy group, - Y represents NR'₁R'₂, R'₁ representing

-C-N-CH₂CH₂Hal, Hal representing halogen, particularly

O NO Cl.

Another class of preferred compounds according to the invention is constituted by those of Formula (I),

(II), (III), (IV), (V), (VI) and (VII) in which : - R represents an alkyl group of 1 to 12 carbon atoms, an aralkyl group of 7 to 12 carbon atoms,

- R' or R" represent OH, - X represents an NR₁R₂ group, R₁ representing

-C-N-CH₂CH₂Hal, Hal being a halogen, particularly Cl,

O NO

- Y represents an alkylamino group, in which the alkyl group has 1 to 6 carbon atoms or arylamino in which the aryl group has 4 to 10 carbon atoms.

Another preferred class of compounds according to the invention is constituted by those of Formula (V), (VI) and (VII) in which :

- R represents an alkyl group from 1 to 12 carbon atoms, aralkyl from 7 to 12 carbon atoms ;

- R' represents an 0M group, M being an alkyl group comprising 1 to 12 carbon atoms, an aryl group comprising 4 to 10 carbon atoms;

- X represents a group NR₁R₂, R₁ representing -C-N-CH₂CH₂Hal, Hal being a halogen, particularly Cl,

O NO

- Y represents a hydrogen atom or a hydroxy group. Another preferred class of compounds according to the invention is constituted by those of Formulas (V), (VI) and (VII) in which :

- R represents an alkyl group frαn 1 to 12 carbon atoms, a halogenoaralkyl of 4 to 10 carbon atoms ;

- R' represents an OM group, M being an acyl group of 2 to 8 carbon atoms, an aroyl group from 5 to 12 carbon atoms ;

- X represents an NR₁R₂ group, R₁ representing -C-N-CH₂CH₂Hal, Hal being a halogen, particularly Cl,

O NO

- Y represents a hydrogen atom or a hydroxy group. Another preferred class of compounds according to the invention is constituted by the Formulas (V) , (VI) and (VII) and in which :

- R represents an alkyl group frαn 1 to 12 carbon atoms, an arylkyl group frαn 7 to 1-2 carbon atoms; - R' represents OH ;

- X represents an -NR₁R₂ group, R₁ representing -C-N-CH₂-CH₂Hal, Hal being a halogen, particularly Cl,

O NO

- Y represents a hydrogen atom. Another class of preferred compounds according to the invention is constituted by those of Formulas (V), (VI), and (VII) in which :

- R represents an alkyl group from 1 to 12 carbon atoms, an aralkyl group from 7 to 12 carbon atoms ; - R' represents OH ;

- X represents an alkylamino group, in which the alkyl group has 1 to 6 carbon atoms, or arylamino in which the aryl group has 4 to 10 carbon atoms and

- Y represents -NR'₁R'₂, R'₁ representing -C-N-CH₂CH₂Hal, Hal being a halogen, particularly Cl.

O NO Another class of preferred compounds according to the invention is constituted by those of Formula

(V), (VI), and (VII) in which :

- R represents an alkyl group of 1 to 12 carbon atoms, an aralkyl group of 7 to 12 carbon atoms ; -R' represents OH ;

- X represents a hydroxy group,

- Y represents -NR'₁R'₂, R'₁ representing -C-N-CH₂CH₂Hal, Hal being a halogen, particularly Cl. O NO

Another class of preferred compounds according to the invention is constituted by those of Formula

(V), (VI) and (VII) in which :

- R represents an alkyl group of 1 to 12 carbon atoms, an aralkyl group 7 to 12 carbon atoms ;

R' represents OH ;

- X represents an NR₁R₂ group, R₁ representing -C-N-CH₂CH₂Hal, Hal being a halogen atom, particularly Cl,

O NO - Y represents an alkylamino group, in which the alkyl group has 1 to 6 carbon atoms or arylamino in which the aryl group has 4 to 10 carbon atoms.

In accordance with the invention, the novel derivatives of nitrosoureas of the general Formula I are 2,3,6, -tridesoxy α-D-arabinohexopyranosyl-nitrosoureas, 2,3- didesoxy-α-D-arabinohexopyranosyl-nitrosoureas, 2,6didesoxy-α-D- arabinohexopyranosyl-nitrosoureas, 2,3,6tridesoxy α- L-arabinohexopyranosyl-nitrosoureas, 2,3didesoxy-α-L-arabinohexopyranosyl-nitrosoureas, 2,6didesoxy -α-L-arabinohexopyranosyl-nitrosoureas, 3,4,6tridesoxy α-D-xylohexopyranosyl-nitrosoureas, 3,4-didesoxy α-D-xylohexopyranosyl-nitrosoureas, 4,6-didesoxy α-D-xylohexopyranosyl-nitrosoureas, 3,4,6-tridesoxy α -L-xylohexopyranosyl-nitrosoureas, 3,4-didesoxy α-L xylohexopyranosyl-nitrosoureas, 4,6-didesoxy alpha-L-xylohexopyranosyl-nitrosoureas.

A preferred class of compounds according to the invention is constituted by those of the following formula :

It is also an object of the present invention to provide a process for the preparation of the novel derivatives of general Formula I according to the invention, which consists of reacting, in a first step, an oside group of general Formula (I bis)

(I bis)

- in which R, R' and R" have the meanings indicated above. - X' represents a hydroxy or -NHR₂ group;

- Y' represents a hydrogen atom, a hydroxy group or -NHR'₂

- R₂ and R'₂ identical or different, represent independently of one another, a hydrogen atom, an alkyl group from 1 to 6 carbon atoms, an aralkyl group from 7 to

12 carbon atoms, aryl from 4 to 10 carbon atoms, cycloalkyl frσn 3 to 6 carbon atoms, the aryl and aralkyl groups being optionally substituted by 1 or several particularly up to 3, halogen atoms, NO₂,NH₂CF₃ groups or alkoxy groups from 1 to 4 carbon atoms, and in which one at least of the groups X' or Y' represent NHR₂ or NHR'₂ on 2-halogeno-ethyl isocyanate to convert the -NHR₂ or NHK'₂ group of the compound of Formula I bis respectively into NR₂C NHCH₂CH₂Hal or NR'₂ C NHCH₂CH₂Hal,

O O Hal being a halogen atom, particularly chlorine, and in a second step, subjecting the compound obtained at the end of the first step to nitrosation, by means of a nitrite of an alkali metal, preferably sodium nitrite, ±0 convert the -NR₂C NH CH₂CH₂Hal or -NR'₂ C NHCH₂CH₂Hal O O groups respectively into -NR₂C -N CH₂CH₂Hal or '' ' O NO

The process described above can be illustrated by the following diagram in the case where X' represents NHR₂.

In the case where Y' represents -NHR'₂, the process described above can be illustrated by the following diagram : The present invention relates also to a process for preparing novel compounds of the general formula VI according to the invention, which consists of reacting, in a first step, an oside group of the general formula VI bis :

(VI bis) in which:

- R and R' are such as defined above ; - X' represents an -NHR₂ or hydroxy group ;

- Y' represents a hydrogen atom, a hydroxy group or -NHR'₂

-R₂ and R'₂, identical or different, represent independently of one another a hydrogen atom, an alkyl group from 1 to 6 carbon atoms, an aralkyl group of 7 to 12 carbon atoms, aryl from 4 to 10 carbon atoms, cycloalkyl from 3 to 6 carbon atoms, the aryl and aralkyl groups being optionally substituted by one or several, particularly up to 3, halogen atoms, groups NO₂, NH₂,CF₃, or alkoxy groups from 1 to 4 carbon atoms, and in which one at least of the groups X' and Y' repres sents -NHR₂ or NHR'₂

On a 2-halogeno-ethyl isocyanate to convert the -NHR₂ or NHR'₂ group of the compound of Formula VI bis respectively into

NR₂ C NH CH₂ CH₂Hal or NR'₂ C NH CH₂CH₂Hal, Hal being a O O halogen atom, particularly chlorine, and in a second step to subject the compound obtained at the end of the preceding step to nitrosation, by means of an alcali metal nitrite, preferably sodium nitrite to convert- the groups -NR₂C NHCH₂CH₂Hal or -NR'₂ C NHCH₂CH₂Hal

O O respectively into -NR₂ C N CH₂ CH₂Hal or NR'₂ C N CH₂CH₂Hal. O NO O NO The present invention relates also to a process for preparing novel compounds of the general formula VII according to the invention, which consists of reacting, in a first step, an oside group of the general formula vil bis :

(Vllbis) X' in which:

- R and R' are such as defined above ;

- X' represents an -NHR₂ or hydroxy group ;

- Y' represents a hydrogen atom, a hydroxy group or -NHR'₂

-R₂ and R'₂, identical or different, represent independently of one another a hydrogen atom, an alkyl group froml to 6 carbon atoms, an aralkyl from 7 to 12 carbon atoms, aryl from 4 to 10 carbon atoms, cycloalkyl from 3 to 6 carbon atoms, the aryl and aralkyl groups being optionally substituted by one or several, particularly up to 3, halogen atoms, groups NO₂, NH₂,CF₃ or alkoxy groups from 1 to 4 carbon atoms, and in which one at least of the groups X' and Y' repres sents -NHR₂ or NHR'₂

On a 2-halogeno-ethyl isocyanate to convert the -NHR₂ or NHR'₂ group of the compound of Formula VII bis respectively into NR₂ C NH CH₂ CH₂Hal or NR'₂ C NH CH₂CH₂Hal, Hal being a O O halogen atom, particularly chlorine, and in a second step to subject the compound obtained at the end of the preceding step to nitrosation, by means of an alcali metal nitrite, preferably sodium nitrite to con- vert the groups -NR₂C NHCH₂CH₂Hal or -NR'₂ C NHCH₂CH₂Hal

O O respectively into -NR₂ CN CH₂CH₂Hal or -NR₂ C N CH₂CH₂Hal ^ c.

O NO O NO To prepare the compounds of formula (Ibis), which enter into the preparation of the compounds according to the invention, it is possible to resort to one of the processes described below.

I Preparation of the compounds of formula

R, R', R", R₂ and Y' having the previously indicated meanings, which enter into the preparation of the compounds of formula :

Hal = halogen

NR₂ CNCH₂CH₂Hal ONO of the invention, can be obtained from the compounds of formula :

which are subjected :

- in a first step to the action of an aldehyde R₂CH, to

O convert the amine into an imine ;

- in a second step, to the action of a reducing agent, such as a hydride, for example sodium borohydride or sodium cyanoborohydride, to convert the imine into a secondary amine.

The process which has just been described can also be applied to the obtaining of compounds of formula :

CH₂NHR'₂

R OR in which R, R', R", R'₂, X' have the above indicated meanings ; and to obtaining compounds of formula : C

and in which R₂ = R'₂.

In the latter case, the amounts of aldehyde and reducing agent employed are doubled. IB Second modification

The compounds of formula :

R, R', R", Y' and R₂ having the previously indicated meanings which enter into the preparation of the compounds according to the invention of formula :

Hal = halogen

can also be prepared from the compounds of formula :

which are subjected to the action of an alkyl halogenoformate, of formula HaLCOR₂, particularly an alkyl chlorofor

O mate to give the compounds of formula :

these compounds being then subjected to a reducing agent, for example aluminium and lithium hydride, to convert the

NHCOR₂ group into NHR₂.

O

This process can also be applied to the obtaining of compounds of formula :

as well as to those of formula :

II Preparation of compounds of formula :

The compounds of formula :

in which R, R' and R" have the above indicated meanings and Y' represents a hydroxy group can be obtained from compounds of formula :

which are reduced, particularly by catalytic hydrogenation, for example hydrogenation in the presence of palladized carbon. The compounds of formula :

in which R and R" have the above indicated meanings and Y' represents a hydroxy group, can be obtained from compounds of formula :

in which one of the hydrogen atoms or -NH₂ groups in the 3 position is protected, particularly by reacting the previously represented compounds with trifluoroacetic anhydride to give the compounds of formula :

which are treated with an alcohol ROH in an acid medium to give the compounds of formula:

the protective group -COCF₃ being simultaneously hydrolized. The compounds of formula :

in which R, R' and R" have the above indicated meanings and Y' represents a hydrogen atom, can be obtained from compounds of formula :

in which R, R' and R" have the above indicated meanings and Hal represents halogen, particularly bromine, these compounds being reduced, particularly by catalytic hydrogenation, for example in the presence of palladized carbon. The compounds of formula :

X ' R " in which R, R' and R" have the above indicated meanings and

X' represents a hydroxy group, can be obtained from the compounds of formula :

by reduction, particularly by catalytic hydrogenation, for example in the presence of palladized carbon.

Compounds of formula :

in which R, R' and R" have the above indicated meanings can be obtained from compounds of formula : which are subjected to reduction, particularly catalytic hydrogenation, for example in the presence of palladized carbon.

Ill Preparation of compounds of formula :

Hal = halogen, particularly Br

The compounds of formula :

in which R, R' and R" have the above indicated meanings can be obtained from the compounds of formula :

Ph = phenyl which are subjected to the action of acetyl chloride, then to neutralization with ammonia to give the compounds of formula :

which are reduced, particularly by catalytic hydrogenation, for example in the presence of palladized carbon, to give the compounds of formula

which can be converted by the action of an alcohol ROH, in an acid medium, into compounds of formula

The compounds of formula

in which R, R' and R" have the above-indicated meanings and Y" represents a halogen atom, particularly bromine, can be obtained from compounds of formula

Bz=benzoyl which are subjected to an alcohol of formula ROH, in an acid medium to give the compounds of formula which are then converted into compounds of the formula

by removal of the benzoyl group, for example by means of a base, particularly an alkali alcoholate, such as sodium methylate. The compounds obtained above can then be treated with an alkylating agent, such as M₂SO₄ or MX, X representing halogen, M representing an alkyl group from 1 to 30, preferably 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, an aralkyl group from 7 to 12 carbon atoms, preferably 7 to 9 carbon atoms, the aryl and aralkyl groups being optionally substituted by one or several, particularly up to 3 halogen atoms, NO₂, NH₂, CF₃ groups or alkoxy from 1 to 4 carbon atoms, or representing an acyl group from 2 to 8 carbon atoms, preferably 2 or 3, or an aroyl group from 5 to 12, preferably to 9 carbon atoms, unsubstituted or substituted by one or several, particularly up to 3 NO₂,NH₂,CF₃ groups halogen, alkoxy from 1 to 4 carbon atoms, in the presence of a base such as NaOH, to result in the compound of formula

with R' = MO

M having the aboveindicated meaning IV Preparation of compounds of formula :

The compounds of the formula :

in which R, R' and R" have the above indicated meanings and X' represents an OH group, can be obtained from the compounds of formula :

in which the OH functions at the 4 and 6 positions are protected, by causing the above described compounds to react, for example on acetic anhydride, in the presence of pyridine to protect the hydroxy group at the 3 position, to give the compounds of the formula :

Ac = acetyl which, in the presence of N-halogeno succinimide, preferably N-brornosuccinimide, and barium carbonate give the compounds of formula : Bz = benzoyl which are subjected to an azotide, particularly an alkali metal azotide, such as sodium, in the presence of dimethylformamide, to give the compounds of the formula :

which, in the presence of a base, particularly an alkali alcoholate, such as sodium methylate, give :

which can be subjected to M₂SO₄ or MX (X = halogen) in the presence of a base such as NaOH to give the compounds of the formula :

with MO = R ', M having the above indicated meaning, The compounds of formula :

in which R, R' and R" have the above indicated meanings, can be obtained from the compounds of the formula :

in which Hal represents a halogen atom, particularly bromine, which are subjected to the reaction of an azotide, particularly, of an alkali metal, such as sodium azotide, to give the compounds of formula :

in which, the benzoyl group is removed, for example, by the addition of a base, particularly of an alkali alcoholate such as sodium methylate, to give the compounds of the formula :

These compounds can be converted into compounds of the formula :

by protecting the hydroxy group at the 4 position, particularly by means of benzyl chloride to obtain compounds of formula : then by adding an alcohol of the formula ROH , in an acid medium, to obtain the compounds of the formula :

then by removing the protective group of the hydroxy function at the 4 position, particularly by means of a base, especially an alkali alcoholate such as sodium methylate, to obtain the compounds of the formula :

then by alkylating the above compounds, especially by means of M₂SO₄ or MX, X representing a halogen, M representing an alkyl group from 1 to 30, preferably 1 to 12 carbon atoms, an aryl group of 4 to 10 carbon atoms, an aralkyl group from 7 to 12 carbon atoms, preferably 7 to 9 carbon atoms, the aryl and aralkyl groups being optionally substituted by one or several, particularly up to 3 halogen atoms, NO₂, NH₂, CF₃ groups or alkoxy of 1 to 4 carbon atoms, or representing an acyl group of 2 to 8 carbon atoms, preferably 2 or 3, an aroyl group of 5 to 12, preferably 5 to 9 carbon atoms, unsubstituted or substituted by one or several, particularly up to 3 NO₂ , NH₂, CF₃ groups, halogen, alkoxyde from 1 to 4 carbon atoms, in the presence of a base such as NaOH , to result in compounds of the formula :

with R' = MO, M having the above indicated meaning.

The processes which have just been described above are advantageously applied to the preparation of the compounds usable for the synthesis of compounds of formula (VI) according to the invention.

More precisely, the process described in the paragraph I, enables the preparation of compounds of the formul

in which R, R', X', Y', R₂ and R'₂ have the above indicated meanings.

The process described in paragraph II enables the preparation of compounds of the formula

in which R, R' and Hal have the above indicated meanings . The process described in paragraph III enables the synthesis of the compounds of the formula :

in which R, R' and Hal have the above indicated meanings.

The process described in paragraph IV enables the preparation of compounds of the formula :

in which R, R', X' have the above indicated meanings.

According to a preferred embodiment of the process according to the invention, the compounds of the general formula (Vlbis) are prepared, to obtain the compounds of formula (VI) according to the invention, by reacting an alpha-D-arabinohexopyranoside of the general formula (Vlter) below :

(Vlter)

in which R and R' are as defined above, X" is an azide, hydroxy, NH₂ group or an alkylamine group, whose alkyl radical includes 1 to 6 carbon atoms, Y" can represent halogen,when X" represents an azide or hydroxy group, or Y" represents hydrogen, an azide group, an NH₂ group, hydroxy group or an NHR'₂ group where R'₂ is a hydrogen atom or an alkyl group from 1 to 6 carbon atoms, aralkyl from 7 to 12 carbon atoms, aryl from 4 to 10 carbon atoms, or cycloalkyl from 3 to 6 carbon atoms, the aryl and aralkyl groups being optionally substituted by one or several, particularly up to 3_» halogen atoms, NO₂, NH₂, CF₃ groups or alkoxy groups from lto 4 carbon atoms, a) either with an alcohol in an acid medium, in the case where X" is an azide group and Y" a halogen atom, hydrogen or hydroxy group or in a case where "X" is a hydroxy group and Y" is an azide group, R is an alkyl group from 1 to 12 carbon atoms, aralkyl from 7 to 12 carbon atoms or halogenoalkyl from 1 to 12 carbon atoms and R' represents OM, M being an acyl group of 2 to 8 carbon atoms or arylester from 6 to 12 carbon atoms and where α -D-arabinohexopyranoside is deoxylated at

2,3,6-, the compound.,obtained then being reduced, particularly by catalytic hydrogenation, for example in the presence of palladized carbon to convert the azide group into NH₂, b) or with an alkylating agent in the case where X" is an azide group, Y" is a halogen atom or hydrogen, R' is an OH group and R is an alkyl group from 1 to 12 carbon atoms or aralkyl from 7to 12 carbon atoms and where α- D-arabinohexopyranoside is trideoxylated at 2,3,6the compound obtained being then reduced, particularly by catalytic hydrogenation, for example in the presence of palladized carbon, to convert the azide group into an NH₂ group, c) or with trifluoroacetic anhydride, in the case where X" is an NH₂ group and Y" is a hydroxy group, a hydrogen atom or in the case where X" is a hydroxy group and Y" is an NH₂ group, R is an alkyl group from 1 to 12 carbon atoms or aralkyl from 7 to 12 carbon atoms and R' a hydroxy group, the trifluoro acetamide 3-α -D-arabinohexopyranoside obtained being treated with an alcohol in acid medium to obtain the 3-amino compound of the corresponding general formula and where α-Darabinohexopyranoside is dideoxylated at 2,3, or trideoxylated at 2,3,6- ; d) or with an aldehyde in an alcoholic medium, in the case where X" is an NH₂ group, Y" is a hydrogen atom, an NH₂ group or NHR'₂ group or a hydroxy group or in a case where X" is a hydroxy group and Y" is NH₂ or NHR'₂ group and R and R' are as defined above, to obtain respectively the 3-desoxy 3-imino compound and/or the corresponding 6-desoxy 6-imino compound, which by reduction with a suitable reducing agent such as sodium borohydride or cyanoborohydride, gives the amine which then enables to obtain the α -D-arabinohexopyraneside 3-nitrosourea of the corresponding general formula VI, 2,3- or 2,6 - dideoxylated or 2,3,6-trideoxylated. To prepare the α -D-arabinohexopyranosides-nitrosoureas according to the invention, procedure is preferably as follows : Modification a) of the process :

To a solution of methyl 3-azido 4-0-acyl (or arylester) 6-bromo 2,3,6-tridesoxy α-D-arabinohexopyranoside, 0.01 mole, in 200 ml of hexane, are added 10 ml of alcohol (ethanol, benzyl or other alcohol) and 2 g of paratoluenesulfonic acid.

The solution is heated to reflux for 12 to 48 hours. After cooling, the reaction medium is poured onto a saturated sodium bicarbonate solution, then extracted with ether. The organic phase is evaporated to dryness and gives a crude residue which is chromatographed on silica to give the ether of the general formula I corresponding to the alcohol. Modification b of the process :

An alkyl-or aralkyl-3-azido-6-bromo-2,3,6-tridesoxy (α-D-arabinohexopyranoside, and preferably methyl-3-azido-6-bromo 2,3,6-tridesoxy α -D-arabinohexopyranoside, 0.01 mole, are placed in solution in a suitable solvent such as anhydrous tetrahydrofuran (100ml) or in another volvent such as dioxane, isopropyl ether, etc ... 5-10 g of NaOH are added, then 5-10 g of an alkylating agent such as an alkyl sulfate, an alkyl halide, an aralkyl halide, for example. The suspension so-obtained is heated under reflux for 12 to 48 hours. After cooling and the slow addition of water, it is stirred at 20ºC for 2 hours. The organic phase is withdrawn by decantation, then the aqueous phase is again extracted with 100 ml of tetrahydrofuran. The organic .phase, dried over sodium sulfate is evaporated to dryness. 60 to 90 % of the desired compound are obtained, which is purified by chromotography on silica. Modification c) of the process : Trifluoroacetic anhydride is reacted with methyl

3-amino 2,3,6-tridesoxy α -D-arabinohexopyranoside prepared by the method of J. BOIVIN et coll., Carb. Res. 85 (1980) 223-42 to obtain methyl-trifluoro 3acetamido-α -D-arabinohexopyranoside (the methyl group being replaceable by another alkyl group or an aralkyl group, as defined above).

To a solution of 0.01 mole of the trifluoro3-acetamido derivative so-obtained, in 200 ml of nhexane, is added 5 to 20 ml of alcohol and 1 to 3 g of p-toluenesulfonic acid. By continuing the treatment as described in the first modication of the process, the ether of the general formula I corresponding to the alcohol is obtained, after having liberated the pro tected amine, by means of potassium carbonate, in an aqueous alcoholic medium. Modification d) of the process :

An aldehyde is reacted with the corresponding amine (Cf. 3rd modification of the process) as follows, to obtain the corresponding imine : a solution of 0.01 mole of aldehyde in ethanol or the methanol is added drop by drop, at ambiant temperature, to a solution of 0.01 mole of the amine which constitutes the starting compound of the third modification of the process, in anhydrous ethanol or methanol. The solution is heated under reflux for 2 to 12 hours. After cooling, there is added, in small portions, from 0.01 to 0.05 ml of a suitable reducing agent such as sodium borohydride or cyanoborohydride, and it is shaken for 12 hours. After evaporation of the solvent, the residue is taken up again in 20 ml of water, the precipitate is drained, then dried under vacuum under P₂ O₅. The secondary amine obtained is recrystallized in alcohols.

The process is the same in the case where the 3-amino group is replaced, in the starting compound, by a 3-hydroxy group, the amino being in the 6 position. In the case where the desired compound must include a substitution by a secondary amine not only at the 3- position but also at the 6- position, the amounts of aldehyde and reducing agent employed are doubled.

The four modifications of the process described above are illustrated by the diagrams below :

I - DIAGRAM OF THE MODIFICATION a) OF THE PROCESS:

ETHERIFICATION

ll - DIAGRAM OF THE MODIFICATION b) OF THE PROCESS : - methyl , ethyl , benzyl , etc . .

III - DIAGRAM OF THE MODIFICATION c) OF THE PROCESS WITH BLOCKING OF THE AMINE AT THE 3 POSITION

IV - DIAGRAM OF THE MODIFICATION d) OF THE PROCESS

To prepare the α-L-arabinohexopyranosides-nitrosoureas according to the invention, of formula VII

and in which the nitroso group is on the 3 carbon, and R, R', X and Y have the above-indicated meanings procedure is advantageously as follows. The compound of the following formula

is treated with O-methylhydroxylamine hydrochloride and sodium acetate to obtain the compound of the following formula

By treating the compound obtained previously by diborane and 0H- ions, the compound of formula

is obtained.

This compound is then treated with 2-chloro ethyl isocyanate, to give the compound of formula

NHCONHCH₂CH₂Cl This compound is then dissolved, for example in formic acid, then treated with sodium nitrite, to give the compoundsof the formula

To prepare the α -D-xylohexopyranosides-nitrosoureas of the invention of formula III, particularly those including a nitrosourea group in 3 position, in particular the com pound of the following formula

it is possible to use the compound of the following formula :

which in a first step, is treated with 2-chloro ethyl isocyanate, to give the corresponding urea, that is to say methyl 3- [3-(2-chloro ethyl) ureido] -3,4,6-tridesoxy α -D-xylohexopyranoside of the formula

The compound indicated, above, by treatment with sodium nitrite in formic acid results in the corresponding nitrosourea, that is to say methyl 3- [ 3-( 2-chloro ethyl) 3nitroso ureidoj 3,4,6-tridesoxy α -D-xylohexopyranoside of the formula :

All the compounds which can be useα in the preparation of the compounds of the formula I, particularly of formula VI, can be prepared by applying one or other of the reaction sequences described above, as well as suitrable reaction sequences described in the examples given below, by way of illustration.

EXAMPLES EXAMPLE 1 Preparation of benzyl 3-azido 4-0benzoyl 6-bromo 2,3,6-tridesoxy αD-arabinohexopyranoside by resorting to the first modification of the process.

To a solution of methyl 3-azido 4-0-ber!zoyl 6bromo 2,3,6-tridesoxy α-D-arabinohexopyranoside (1.5 g, 4.05 mmol.) in 125 ml of n-hexane, are added 10 ml of benzyl alcohol andl g of p-toluenesulfonic acid. The suspension is heated to reflux for 20 hours with azeotropic removal of the methanol released.,

After cooling, the reaction medium is poured into a saturated solution of sodium bicarbonate then extracted with ether. The excess benzyl alcohol is then removed by azeotropic extraction with water, then with toluene. The crude residue so-obtained (1,8 g) is chromatographed on silica H with the mixture hexane/methylene chloride, 2:1 as eluant..

1.5 g of benzyl 3-azido 4-0-benzoyl 6-bromo 2,3 , 6-tridesoxy (α-D-arabinohexopyranoside (84%) are isolated.

MP : 77°C (hexane) - [α] 20 D : 20° (c : 1%;CHCl₃)

IR_nujol: v 2100 cm^-1 (N₃) v 1760, 1260, 1030 cm^-1 (ester) v 1600, 1585 cm^-1 (aromatic)

In the same mariner there is prepared, for sxample:

- Ethyl 3-azido 4-0-benzoyl 6-bromo 2,3,6-tridesoxy α-D-arabinohexopyranoside.

- p -chlorobenzyl 3-azido 4-0-benzoyl 6-bromo

2,3,6-tridesoxy α -D-arabinohc-xopyranoside. EXAMPLE 2 Use of the second modification of the process. The following compounds given by way of example, are prepared by alkylation of an alkyl or aralkyl-3-azido 6-bromo, 2,3,6tridesoxy α-D-arabinohexopyranoside. . methyl 3-azido 6-bromo 2,3,6-tridesoxy 4-0ethyl α-D-arabinohexopyranoside . methyl 3-azido 6-bromo 2,3,6-tridesoxy 4-0benzyl α-D-arabinohexopyranoside . ethyl 3-azido 6-bromo 2,3,6-tridesoxy 4-0ethyl α -D-arabinohexopyranoside . ethyl 3-azido 6-bromo 2 , 3 ,6-tridesoxy 4-0benzyl α(-D-arabiηohexopyranoside . benzyl 3-azido 6-bromo 2,3,6-tridesoxy 4-0ethyl α-D-arabinohexopyranoside

. benzyl 3-azido 6-bromo 2,3,6-tridesoxy 4-0benzyl α -D-arabinohexopyranoside. EXAMPLE 3 Use of the third modification of the process. To a solution of 300 mg (1.16 mmole) methyl

3-fluoroacetamido 2,3,6-tridesoxy α.-D-arabinohexopyranoside in 100 ml of n-hexane, are added 5 ml of benzyl alcohol and 300 mg of dry p-toluene sulfonic acid, and the treatment is as described in Example 1. After chromatography and crystallization in a hexane-acetone mixture, 100 mg (30%) of pure product are isolated. MP : 165°C - [α ] D : + 66 (c : 0.5%, CHCl₃).

The amine is then liberated by the action of potassium carbonate in an aqueous methanol medium.

By proceeding in the manner which has just been described, the following compounds, given, by way of example, are prepared :

. benzyl 3-amino 2 ,3,6-tridesoxy α -D-arabinohexopyranoside

. ethyl 3-amind 2,3,6-tridesoxy α-D-arabinohexopyranoside . benzyl 3-amino 2,3-didesoxy α -D-arabinohexopyranoside . ethyl 3-amino 2,3-didesoxy α-D-arabinohexopyranoside. EXAMPLE 4 Use of the fourth modification of the process. By proceeding in accordance with the fourth modification of the process it is possible to prepare, among others, the following compounds, given by way of example: . methyl 3-ethylamino 2,3,6-tridesoxy α -D-arabinohexopyranoside . methyl 3-benzylamino 2,3,6-tridesoxy α -D-arabinohexopyranoside

. methyl 3-ethylamino 2,3-didesoxy α -D-arabinohexopyranoside . methyl 3-benzylamino 2,3-didesoxy α-D-arabinohexopyranoside . benzyl 3-ethylamino 2,3,6-tridesoxy α -D-arabinohexopyranoside . benzyl 3-benzylamino 2 , 3.6-tirdesoxy α -D-arabinohexopyranoside . methyl 6-ethylamino 2,6-didesoxy α -D-arabinohexopyranoside

. methyl 6-benzylamino 2,6-didesoxy α -D-arabinohexopyranoside . benzyl 6-ethylamino 2,6-didesoxy α -D-arabinohexopyranoside . benzyl 6-benzylamino 2,6-didesoxy α -D-arabinohexopyranoside. By doubling the amount of aldehyde and of reducing agent employed, the following secondary amines substituted at the 3,6 positions are prepared: . methyl 3,6-diethylamino 2,3,6-tridesoxy α -Darabinohexopyranoside . methyl 3.6-dibenzyl amino 2,3,6-tridesoxy α -Darabinohexopyranoside . benzyl 3,6-diethylamino 2,3,6-tridesoxy α -Darabinohexopyranoside

. benzyl 3,6-dibenzylamino 2,3,6-tridesoxy α-Darabinohexopyranoside . EXAMPLE 5

Methyl 3-[3-(2-chloro ethyl) ureido] 2,3,6-tridesoxy alphaD-arabinohexopyranoside - Compound 1

To a solution of 0.8 g (5 x 10^-3 mole) of methyl 3-amino 2,3,6-tridesoxy alpha-D-arabinohexopyranoside (prepared according to the method of J. BOIVIN et coll. Carb. Res. 85 (1980) 223-42) in 2 ml of anhydrous DMF are added, drop by drop, at 0°C and with stirring, 0.4 ml (5.10^-3 mole) of 2-chloro ethyl isocyanate. After 5 hours stirring, the reaction mixture is evaporated to dryness under vacuum. The residue, after purification by chromatography on a silicate column, with CHCl₃ : 95, MeOH : 5 eluant, gives a single spot product crystallizing in anhydrous ethyl ether. The crystals were drained and then dried. (0.8 g, yield 60 %). ANALY SIS C₁₀H₁₉Cl N₂O₄ : 266.5 - Calculated %. 0:45.0, H: 7.1, N : 10.5 - Found % C : 44.9, H : 7.0, N : 10.5. MP: 125 - 127°

NMR Spectrum Solvent : DMSO. d₆ : 1.14 (d CH₃-6' J =6Hz), 1.46 (t(d) H-2'axJ = J' = 12 Hz, J" = 4Hz) 1.90 (dd H-2' eq J= 12Hz, J'= 4Hz) 2.78 (t -H-4' J = J' = 9Hz) 3.19 (s OCH₃) 3,28 (m CH₂-4) 3.42 (m H-5') 3.53 (m CH₂-5) 3.61 (m H-3') 4.58 (d H-1' J = 3Hz) 5.99 (d NH J = 8Hz) 6.14 (t NH J = J' = 6 Hz). ΕXAW[PLE 6 Methyl 3-[,3-(2-chloro ethyl) 3-nitroso ureido] 2,3,6-tridesoxy α -D-arabinohexopyranoside - Compound 2 (IC 81.

1183) 1.2 g (4.5.10^-3 mole) of methyl 3-[3-(2-chloro ethyl) ureido] 2,3,6-tridesoxy α(-D-arabinohexopyranoside were dissolved in 8 ml of formic acid. To the solution maintained at 0 0, were added in small portions and with stirring 2.5 g (0.036 mole) of sodium nitrite. After 30 minutes, 10 ml of water were added, the stirring was then maintained for one hour. The reaction mixture was poure onto 100 ml of ethyl acetate and then dried over sodium sulfate and evaporated to dryness under vacuum. After purification on a ohromatograph column, with silicate sup in the presence of triethylamine (1 ml) and 10% palladized carbon (1 g). The catalyst is removed by filtration.

The filtrate, evaporated to dryness under reduced pressure, gives 4_*35 g of compound 4 in the form of a colorless oil.

This compound is crystallized in hydrochloride form.

ANALYSIS C₇H₁₅NO₄, HCl : 213.67 MP : 120°C (dec.) [α] _D ²⁰ : + 90° (c : 1%, H₂O).

EXAMPLE 9 Methyl 3- [3-(2-chloro ethyl) 3-nitroso ureido] 2,3-didesoxy α -D-arabinohexopyranoside - Compound 6 ( IC 81.1184)

From compound 4, following the operational method already described, methyl 3-[3-(2-chloro ethyl)ureido] 2,3-didesoxy α -D-arabinohexopyranoside, 5 is obtained by the action of 2-chloro ethyl isocyanate.

ANALYSIS C₁₀H₁₉C1N₂O₅: 282 - Calculated % C : 42.5, H:6.7,

N : 9.9 Found % C : 42.3, H : 6.8, N : 10.0 20 MP : 125°C [α] _D : + 168° (c:0.25%, CHCl₃ ) Then by nitrosation with sodium nitrite, in formic acid, Compound 6 is obtained.

ANALYSIS C₁₀H₁₈Cl N₃O₆; 311-71 - Calculated % : C-38.5, H 5.8, N 13.5 Found % : C: 38.4, H: 5-6, N: 13-6. MP: 118°C 20 20 [α]_D : +96.2° (c: 0.5%, CHCl₃) - [α]₃₆₅ : 118.0° (c : 0.5 % , CHCl₃)

NMR Spectrum (DMSO.d₆) : 1-82 (t(d) H-2' _aχJ = J' = 12 Hz, J" : 4Hz) 1.88 (d(d) H-2'eqJ=12 Hz J' = 4Hz) 3-28 (s OCH₃) 3.43 (r H-4' J=J' = 9Hz) 3-35 to 3-53 (m H-5', H-3') 3-49 to 3.67 5ab CH₂-6' J = 12Hz) 3.61 (t CH₂-4 J = J' = 6Hz) 4-10 (m CH₂-5) 4-73 (d H-l' J=4Hz) 8.53 (d NH J = 9Hz).

Mass Spectrum (chemical ionization) : m/e 312 (Cl₃₅, M+1, Basic peak) and m/e 314 (Cl₃₇, 30%); m/e 280 (M+1-32, 30%) and m/e 282 (10%). EXAMPLE 10 Methyl 3-azido 6-bromo 2,3,6-tridesoxy α-D-arabinohexopyranoside-Compound 7 10 g (0.026 mole) of methyl 3-azido 4-0-benzoyl 6-bromo 2,3,6-tridesoy α-D-arabinohexopyranoside prepared according to Hanessian, J. Org. Chem. 34 (1969)1045-1053, are dissolved in 100 ml of 1 M methanolic sodium methanolate. After 4 hours stirring at 20°C, the solution is then neutralized by passage over Amberlite IRA 50 resin, form H+ . The filtrate, evaporated to dryness under vacuum, is purified by chromatography on silica H-60 and gives 6 g (Yield 84%) of Compound 7 . ANALYSIS C₇H₁₂Br N₃O₃ : 266.22 [α] _D ²⁰ : + 124º (c : 1%,CHCl₃)

IR Spectrum : 3420-3440 cm^-1 (OH) 2100 cm^-1 (N₃) EXAMPLE 11 Methyl 3-azido 6-bromo 2,3,6-tridesoxy

4-0-methyl α -D-arabinohexopyranoside

- Compound 8 5 .5 g (0.021 mole) of compound 7 ars dissolved in 200 ml of anhydrous tetrahydrofuran. 20 g of soda are added and then 20 ml of methyl sulfate. The reaction mixture is brought to reflux for 24 hours. After cooling, 100 ml of water were added. The organic phase is drawn off by decantation then the aqueous phase is again extracted with 100 ml of tetrahydrofuran. The organic phase, dried over sodium sulfate, is evaporated to dryness. 5.7 g (Yield 98%) of compound 8 is obtained. It is purified by chromatography on silica H (eluant hexane-methylene chloride 1:1). ANALYSIS C8H₁₄BrN₃O₃ : 280.25 [α] _D ²⁰ : + 188° (c : 1%, CHCl₃). IRSpectrum : v N₃ 2100 cm^-1

EXAMPLE 12 Methyl 3-amino 2,3,6-tridesoxy 4¬

O-methyl α -D-arabinohexopyranoside

-Compound 9 5 .15 g (0.018 mole) of compound 8 in solution in 100 ml of anhydrous ethanol and 3 ml of redistilled triethylamine are placed under hydrogenation in the presence of 2 g of palladium on carbon, at ordinary pressure, for 12 hours. After removal of the catalyst, the solution is passed over an IR 45 ion exchange resin, OH- form. The solution evaporated to dryness results in 3.5 g of crude product purified by chromatography on silica H, eluant CH₂C1₂ - MeOH 9:1 ANALYSIS C₈H₁₇NO₃ : 175.22

[α] _D : + 109º (c : 1%, CHCl₃)

EXAMPLE 13

Methyl 3-[3-(2-chloro ethyl) 3-nitroso ureido] 2,3,6-tridesoxy 4-O-methyl alpha-D-arabinohexopyranoside - Compound 10 (IC 83 1373) It is obtained by the usual method from compound 9.

ANALYSIS c_nH₂₀ClN₃O₅ : 309.75 - Calculated % C:42.6, H:6.5, N:13-6 - Found % C:42-3, H:6.2, N:13-6. MP : 60°C. [α] : + 68.8° (c : 0.5 % CHCl₃) - [α] : +113.0º (c : 0.5 %, CHC1₃)

NMR Spectrum (DMSO-dg): 1.19 (d CH₃ J = 6Hz), 1.87 (m CH₂2') 3.01 (t H-4'J=J^,= 9Hz) 3.25 (s OCH₃-1) 3-35 (s OCH₃4) 3-53 (m H-5) 3-63 (t CH₂-4 J = J' = 6Hz) 3.61 (m CH₂5) 4.18 (m H-3') 4.66 (d H-l' J = 3Hz) 8.73 (d NH J=9Hz). Mass Spectrum (chemical ionisation) : m/e 310 ( Cl_{3 5}, (M+1, Basic peak) and m/e 312 (Cl₃₇, 30%); m/e 278 (m+1-32, 90%) and m/e 280 (27%).

EXAMPLE 14 Methyl 3,6-diazido 4-0-benzyl 2,3,6tridesoxy α -D-arabinohexopyranoside Compound 11

6 g (0.092 mole) of sodium azotide were added to a solution of 6 g (0.016 mole) of methyl 3-azido 4-0-benzyl 6-bromo 2,3,6-tridesoxy α-D-arabinohexopyranoside in 50 ml of anhydrous dimethylformamide . The reaction medium is brought to 80°C for 8 hours. After cooling and dilution with 150 ml of water, it is extracted several times with ethyl ether. The ether phase, after evaporation to dryness, under vacuum, gives a colorless oil : 5 g(98%).

ANALYSIS C₁₄H₁6N₆O₄ : 332.32 [α] : + 51° (c: 2.2 %, CHCl₃) IR Spectrum : 3450 cm^-1 (OH) 2115 cm^-1 (N₃)

EXAMPLE 15 Methyl 3,6-diazido 2,3,6-tridesoxy α -D-arabinohexopyranoside - Compound 12

5 g (0.015 mole) of compound 11 were placed in solution in 50 ml of anhydrous methanol, then a molar solution, of sodium methylate (50 ml) was added and it was stirred for 3 hours at ambient temperature. The solution was neutralized by filtration on Amberlite IR 50 H⁺ resin, then evaporated to dryness under reduced pressure. A syrupy oil (3.4 g 100%) was obtained which was purified on a silica column H (eluant CH₂Cl₂). ANALYSIS C₇H₁₂N₆O₃

[α] : + 128° (c : 1.6 %, CHCl₃) IR Spectrum_film : 3450 cm ^-1 OH) 2115 cm^-1 (N₃) EXAMPLE 16 Methyl 3,6-diamino 2,3,6-tridesoxy α-D-arabinohexopyranoside - Compound 13

3 g (0.013 mole) of compound 12 in solution in 100 ml of ethanol with 1% triethylamine are hydrogenated at ordinary pressure for 12 hours in the presence of palladium on carbon as catalyst. After removal of the catalyst, the filtrate evaporated to dryness gives a syrupy residue (2.8 g). Chromatography on silica (eluant CH₂CI₂ , ammoniacal MeOH 80:20) enabled isolation of the pure product 13. ANALYSIS C₇H₁₆N₂O₃ : 176.25 [σfl : + 130° (c : 1.13%, MeOH)

IR Spectrum_gilm : 3700 cm^-1 (OH), 3360 cm^-1 (NH) EXAMPLE 17 Methyl bis 3,6-[3-(2-chloro ethyl)

3-nitroso ureido] 2,3,6-tridesoxy (-X-D-arabinohexopyranoside. -Compound 14 ( IC 83-1374) It is obtained by the usual method from compound 13. ANALYSIS C₁₃H₂₂C1₂N₆O₇ : 445-207 - Calculated % C:35.1,

H:5.0, N:18.9 - Found % C:35-3, H.5.1, N.19.2. MP : 102°C

[α] - -59.0° (c : 0.5 %, CHCl₃)- [α] : +74-0° (c : 0.5 %, CHCl₃)

NMR Spectrum (DMSO-d₆): 1.84 (m CH₂-2') 3.15 (s OCH₃) 3.17 to 3.77 (m CH₂-6', H-3', H-4', H-5', 2CH₂-4) 4.06 (m 2CH₂-5) 4.66 (d H-1 J=3Hz) 8.41 (t NH J=J'=6Hz)

8.50 (d NH J=9Hz).

Mass Spectrum : (M + 1 ) : 445 100 % Basic peak

447 - 35 449 37 37 37

EXAMPLE 18 Methyl 3-0-acetyl 4, 6-0-benzylidene 2-desoxy α -D-arabinohexopyranoside

- Compound 15

40 ml of redestilled acetic anhydride are addedto 10 g (0.037 mole) of methyl 4, 6-0-benzylidene 2-desoxy α -D-arabinohexopyranoside in solution in 50 ml of anhydrous pyridine . After 48 at 50°C, the reaction mixture is cooled then poured onto cracked ice, extracted 3 times with 100 ml of dichloramethane. The organic phase dried over sodium sulfate gave after evaporation, 11.5 g (99%) of a crystalline product that is purified by recrystallization in the hexane-acetone mixture. MP : 125° - 127°C.

[α] : + 74° (c : 1%, chloroform)

IR Spectrum_Nujol : 1728, 1240 cm^-1 (c = 0 ester).

EXAMPLE 19 Methyl 3-0-acetyl 4-0-benzoyl 6-bromo

2,6-didesoxy α -D-arabinohexopyranoside

-Compound 16 7.13 g (0.04 mole) of barium carbonate and 3.23 g (0.020 mole) of N-bromo-succinimide were added to 5.12 g (0.02 mole) of compound 15 in solution in 200 ml of carbon tetrachloride,were added. The reaction was brought to reflux for 3 hours. After cooling and removal of the insoluble by filtration, the organic phase was washed with a saturated solution of sodium bicarbonate.

After evaporation, 6.4 g (98%) of a single spot oily product in t.l.c. are obtained. M : +70 (c: 1.45%, CHCl₃)

IR Spectrum : 1730 cm^-1, 1240 cm^-1 (CO ester)

1600, 1585 cm^-1 (aromatic)

EXAMPLE 20 Methyl 3-0-acetyl 6-azido 4-0-benzoyl

2,6-didesoxy α-D-arabinohexopyranoside. - Compound 17

To a solution of 8 g (0.020 mole) of compound 16 in 50 ml of anhydrous dimethylformamide were added 8 g (0.12mole) of sodium azotide. The reaction mixture was brought to 80ºC for 8 hours. After cooling and dilution with water, the reaction mixture was extracted with ether. The solution washed several times with water, was dried over sodium sulfate. After evaporation under vacuum, the residue was purified by chromatography on silica (eluant hexane-ethyl acetate, 3-1). 6.5 g of pure product were isolated (95%). The product was recrystallized from hexane. ANALYSIS C_l6H₁₉N₃O₅ : 349.38 MP : 68°C

[α] : +90 (c : 1%; CHCl₃)

IR : 2100 cm^-1 (azide) 1725, 1280, 1050 cm^-1 (ester)

1610, 1590 cm^{- 1} (aromatic)

EXAMPLE 21 Methyl 6-azido 2,6-didesoxy α-D-arabinohexopyranoside - Compound 18 A methaaolic solution of sodium methylate (20 ml) was added to a solution of 4.96 g (0.014 mole) of compound 17 in 50 ml of anhydrous methanol. After 12 hours stirring at room temperature, the reaction medium was neutralized by filtration on Amberlite IR 50 resin (form H⁺). After removal of the solvent, the syrupy residue obtained was chromatographed on a silica column to remove the methyl benzoate. 2.76 g of compound 18 were obtained (96%). ANALYSIS : C₇H₁₃N₃O₄ : 203.2

[α] : + 104° (c : 1%, chloroform). IR Spectrum : 3400 cm^-1 (OH) 2120 cm^-1 (azide).

EXAMPLE 22 Methyl 6-amino 2-desoxy α-D-arabinohexopyranoside - Compound 19 A solution of 2.40 g (0.011 mole) of compound 18 in 25 ml of anhydrous ethanol was shaken under a hydrogen atmosphere in the presence of 10% palladium on carbon (500 mg) for 12 hours. After elimination of the catalyst, the evaporation of the filtrate led to an oily product 2 g (95 %). A sample was converted into the picrate. ANALYSIS : C₁₃H₁₈N₄O₁₁ : 406.35 MP : 156°C (ethanol) [α : +75° (c : 1.2 %, chloroform). EXAMPLE 23 Methyl 3- [3-(2-chloro ethyl) 3-nitroso ureido] 2,6-didesoxy α-D-arabinohexopyranoside -Compound 20 (IC83 1350)

It is obtained by the usual method from compound 19.

ANALYSIS C₁₀H₁₈ClN₃O₆ : 311.728 - Calculated % : C.38.5,

H:5.8, N:13.5 - Pound % : 0:38.5, H:5.5, N.13-4. MP : 101ºC (dec) : + 26.2 (c : 0.5 %, CHCl₃) : + 51.0 (c : 0.5% , CHCl₃) NMR Spectrum (CMSO-d ₆) : δ 1.45 (t(d) H-2'_ax J = J' = 12Hz, J" = 4Hz), 1.85 (d(d) H-2' J= 12Hz J' = 4Hz), 2.95 (t H-4' J=J'=9Hz), 3.10 (s-OCH₃), 3.30 (m H-3'), 3.51 (m H-5 + a CH₂-6'), 3.58 (t CH₂-4 J=J'=6Hz), 3.75 (d_bCH₂-6' J_gem = 12Hz), 4.06 (m CH₂-5), 4.15 (d H-l'J = 3Hz), 4.81 (OH), 5.10 (OH), 8.50 (t NH). Mass Spectrum : (M + 1) = 312 Cl₃₅ 314 Cl ₃₇ (Loss of MeOH -32) 280.

EXAMPLE 24 Methyl N methoxycarbonyl 3-amino 2,3,6tridesoxy α-D-arabinohexopyranoside

- Compound 21 6 ml of methyl chloroformate were added at 0°C and with stirring, in 10 minutes to 1.5 g (0.0093 mole) of methyl 3-amino 2,3,6-tridesoxy α-D-arabinohexopyranoside in 200 ml of anhydrous methylen chloride. The reaction mixture was kept 2 hours at ordinary temperature, then 100 ml of 4N soda were added. After one night with stirring, the organic phase was separated by decantation, the aqueous phase extracted with 100 ml of methylene chloride. The organic phase washed with distilled water was dried over sodium sulfate.

After evaporation under vacuum, the residue obtained was recrystallized in a methanol-methylene chloride mixture, 1.7 g (80%). ANALYSIS C₉H₁₇NO₅ : 219.24 MP : 180°C

[α] . + 157 (c : 1%, CHCl₃).

EXAMPLE 25 Methyl 3-methylamino 2,3,6-tridesoxy (X -D-arabinohexopyranoside-Compound 22

1.7 g (0.0077 mole) of compound 21 in 50 ml of anhydrous ethyl ether were added drop by drop, so as to maintain a slight reflux (30') to 1 g of lithim and aluminium hydride in 100 ml of anhydrous ethyl ether. The reflux was continued for 6 hours. After cooling, the excess of hydride was decomposed by the very slow addition of 1 ml of water, then 1 ml of 3N soda, then 3 ml of water. The precipitate was removed by filtration. After evaporation under vacuum and then recrystallization in a mixture acetonehexane the organic phase dried over sodium sulfate gave , 1.05 g of crystals (80%); MP : 105ºC ANALYSIS C₈H₁₇NO₅ : 175.23 [α] 89 (c: 1%, CHC1₃)

EXAMPLE 26 Methyl 3-[3-(2-chloro ethyl) 1-methyl

3-nitroso ureido] 2,3,6-tridesoxy α -D-arabinohexopyranoside - Compound 23

(IC 83.1375) It was prepared according to the usual method from compound 22.

The examples 5 to 25 above are illustrated by the following reaction diagrams :

EXAMPLE 27 : Methyl 3 [3- ( 2-chloro ethyl) 3nitrosc ureido] 2,3,6-tridesoxy α -L-arabinohexopyranoside

Compound 26 - IC 841530 The preparation of methyl 3-amino 2,3,6-tridesoxyα(-Larabinohepoxyranoside (L-acosamine) is first carried out, as mentioned hereafter.

3.1g (0.04 mole) of anhydrous sodium acetate and 2.1g (0.024 mole) of 0-methyl hydroxylamine chlorhydrate are added to 1.92g (0.012 mole) of methyl 2,6didesoxy α-L-erythrohexopyranoside 3-ulose in 25 ml of 50 % aquous ethanol. The reaction medium is brought to reflux 3 hours, then ethanol is evaporated. After extraction with dichloromethane and drying over sodium sulfate sodium, a clear oil ( 2g ) is obtained, the structure of which is confirmed by NMR and corresponds to O-methyloxime of L-acosamine.

This oil is solubilized in 20 ml of anhydrous tetrahydrofurane and 30 milliequivalents of diborane are added to the solution under nitrogen and at 0°C .

The reaction mixture is brought to reflux two hours then cooled at 0°C.5 ml of water, then 5 ml of 20 % pjptash are added carefully. The reaction medium, brought to reflux 3 hours, then cooled, is extracted with ethyl acetate. The organic phase gives, after evaporation, a residue, which, after purification, gives L-acosamine crystals. M.P. 130°-133°C. [ α] : - 140°C (c : 0,6 % , MeOH). The preparation of methyl 3-[3 (2-chloro ethyl) ureido] 2,

3, 6 -tridesoxy α-L-arabinohexopyranoside (compound 25) is carried out, as mentioned hereafter. 0.3 ml (4.10^-3 mole) of 2-chloro ethyl isocyanate are added to a solution of 0.48 g (3.10^-3 mole) of methyl 3-amino 2, 3, 6-tridesoxy α-L-arabinohexopyranoside in

8 ml of redistillated dimethylformamide. After 2 hours of Stirring, the reaction mixture is evaporated to dryness under vacuum. The crystals are dried then washed with ether : 781 mg (98 %)

NHR spectrum: Solvent DMSO D₆ : 1,14 (d, CH₃-6', J=6Hz) ;

1,46 (T(d), H-2 _ox J=J'= 12 Hz, J"=4 Hz) 1,90 (dd.H-2'_eq'

J=12 Hz, J'=4 Hz) ; 2,78 (T,H-4', J=J'= 9 Hz) ; 3,19 (s,OCH₃) ;

3,28 (m,CH₂-4) 3,42 (m,H-5') 3,53 (m.CH₂-5) ; 3,61 (m,

H-3') ; 4,58 (d,H-1', J=3Hz) ; 5,99 (d,NH, J= 8 Hz) ; 6,14 (t,NH, J-=J'= 6 Hz).

The final product which is desired (compound 26) , i.e. methyl 3 [3-(2-chloroethyl)3-nitroso ureido] 2,3,6tridesoxy 2,3,6 α-L-arabinohexopyranoside is obtained from the product which has been previously synthesized, as follows 0.66g (2.5 X 10^-3 mole) of [3 ( 2-chloro ethyl) ureido] 2,3,6-tridesoxy α-L-arabinohexopyranoside are dissolved in 5 ml of formic acid. 1.4 (0.02 mole) of sodium nitrite are added by small portions and under stirring to the solution which is kept at 0°C . After 30 minutes, 5 ml of water are added and the stirring is maintained for one hour. The reaction mixture is poured on to 100 ml of ethyl acetate then dried over sodium sulfate and evaporated to dryness under vacuum. After purification, on a silica support column, eluent CH₂ Cl₂ : 98, MeOH : 2 colorless crystals are obtained : 210 mg (30 %) MP : 100°C ANALYSIS C ₁₀H₁₈ClN₃O₅ : 295,71. Calculated % :C : 40,6 H : 6 ,1 N 14,2. Found % : C : 40,9 H : 6.1 N 13.90.

NMR. Spectrum ( DMSO, D₆ ) : 1,15 (d ,CH₃-6 J=6 Hz) 1,78 à

1,94 (m, CH₂-2') ; 3,04 (t,H-4', J=9 Hz 3,25 (s,OCH₃) ;

3,51 (m,H-5') ; 3,60 (T,CH₂-4, J=J'=6 Hz) ;

4,10 (m,CH₂-5, H-3') ; 4,65 (d,H-l',J=3 Hz) ; 8,48 (d,NH,

J=9 Hz). Pharmacological study

In order to test the antitumoral activity of the compounds described above, in the first place leucemia murin L1210 was used. Among murin leucemias, leucemia L1210 is resistant and selective. A substance having a great activity on leucemia L1210 presents a potential of activity in the clinical field of humans (J. M. Venditti, Relevance of transplantable animal tumor systems to the selection of new agents for clinical trial in pharmacological basis of cancer chemotherapy, the University of Texas ed Williams and Wilkins Co. publ. 1975, Baltimore USA, p. 245-270).

Besides, the experimental tumor, leucemia L1210 of the mouse is in fact currently used for the evaluation of all antitumoral compounds at present used in human therapy, as described, for example by C. C. Zubrod in Proc.

Nat. Acad. Sci. USA, 69, 1972, p. 1 042-1 047. The tumoral system so-constituted experimentally enables very accurate experimental evaluation of the activity of the compound tested and, consequently also, an objective comparison between the respective activities of the different compounds, for example according to the methods described by R . E. Skipper, F. M. Schapel Jr. and W. S. Wilcox in Cancer Chemother, Rep., 35, 1964, p. 1-111 and 45, 1965, p. 5-28. This has been confirmed by the results of recent work of Staquet et al. Cancer Treatment Reports, vol. 67, nº 9, September, 83.

In practice, the biological effects of the novel nitrosourea derivatives according to the present invention have been tested as follows. METHOD

The test used is that of W. J. Durkin et al. Cancer Research 1979, 39, 402-407, modified.

All the nitrosoureas were dissolved in 70 % ethanol in the proportion of 10 mg/ml. The test was carried out in two steps. 1 - Determination of the 20% cytotoxic index

100 μl of an L 1210 cell suspension (10⁶ cells per ml) in R P M I 1640 culture medium supplemented with 10% of fetal calf serum and 40 μg/ml of gentamycin, containint various doses of the products to be tested (0 to 100 ug/ml) were incubated 24 hours at 37°C. At the end of this time, the cell viability is determined by the trypan blue exclusion test. The cytotoxic index is defined by the formula:

Cytotoxic index : 100

% control living cells. The amount of ethanol is the same in the cultures containing the products to be tested and in the control cultures (this amount has no effect either on growth nor on cell viability).

For each product the dose which gives a cytotoxic index of 20% is determined. 2 - Determination of the potential "in vivo" activity

L 1210 cells, under conditions similar to the preceding protocol, were contacted for 1 hour with a dose of the various products tested corresponding to a cytotoxic index equal to 20%. After this time, the cells were placed in culture medium not containing nitrosoureas and incubated at 37ºC. After 48 hours, the cytotoxic index was determined.

W.J. DURKIN et Al...showed that, under these conditions, if the cytotoxic index was equal to or greater tha 40%, the product concerned would be active "in vivo" in the mouse. RESULTS

The results are collected in the following table I. N

3 - Determination of the effective "in vivo " activi ty in the mouse

The experimentation which is reported below used the compound 2 prepared according to the above example 6 (Ref. IC 81 1183).

3.1. Protocol

. The mice (female, average weight 20g) used were

F₁/DBA₂/C₅₇/Bl (Animal selection and breeding center of the Laboratories of the CNRS, Orleans, La Source). . The mice .distributed in cages by drawing lots were inoculated on day "0" with 10⁵ leucemia L1210 cells.

. The animals were treated with the compound IC 81 1183 intraperitoneally on days 1, 5 and 9.

. The suspensions were prepared just before the injection : product 2 + neutralized and sterilized olive oil. . The mortality of the animals was observed regularly, the relative increase in the survival (T/C x 100) was calculated from the average survival of the treated animals (T) and that of the control animals (C).

. The doses used are in mg/kg of mouse : 1.25, 2.5, 5,

10, 20, 40, 50, 60, 80.

3.2. Results . 1.25 mg→ T/C = 118 . 2.50 mg→ T/C = 158 . 5 mg→ T/C = 170 . 10 mg→ T/C = 220 . 20 mg→ T/C = 00 . 40 mg→ T/C = CO . 50 mg→ T/C = 100

≥60 mg→ Toxicity

3.3. Remarks a) T/C = 00 : for definition : more than 50% of the treated animals were finally cured; now in the experiments carried, all the animals at doses of

20 and 40 mg/kg were cured finally. b) This curve of efficiency is as good as that obtained with RFCNU and RPCNU described by IMBACH et al (Loc. Cit) and it is very distinctly higher than those obtained by CCNU . and Me CCNU described by MATHE and KENIS (Loc. cit). c) A sudden drop of the T/C is observed after 40 mg/kg. This phenomenon is also observed with nitrosoureas used as comparison products : the rapid rise in toxicity cancelled the efficiency of the product. 3.4. The value of T/C ≥ 125% was sought in order to determine a minimum active dose which is situated between 1.25 mg/kg of body weight and 2.5 mg/kg ; in fact, at 1.25 mg/kg it is found to be slightly below the significant threshold of 125% survival, which is not the case at the dose of 2.5 mg/kg.

4. Determination of the "in vivo" activity of the compounds according to the invention on the three respective tumors leucemia L 1210 IGR, Lewis tumor and melanoma B16. The compounds tested were the compounds of examples referenced by IC 1183, IC 1184, IC 1350, IC 1373 and IC 1374. 4.1. Leucemia L1210

Female DBA₂ mice were used, about 8 weeks old and weighing about 20 g from the IFFA-CREDO center (les

Oncins, 69210 Arbresles) . At day "0", each mouse received intraperitoneally an inoculum of 1 x 10 tumor cells in a volume of 0.2 ml. . After tumoral graft, the mice were distributed at random into 21 cages of 5 animals, themselves then distributed, by drawing lots, into 6 experimental series. Within these 6 experimental series, there were constituted a control series of 6 cages and 5 experimental series of 3 cages each, and of which the mice were intended to be treated by the compounds of the invention. 4. 2. Melanoma B16 . Female C57 B 1/6 mice were used , about 8 weeks old and weighing about 20 g, from the IFFA-CREDO center .

. At day "0", each mouse received intraperitoneally an inoculum, of 2 x 10 tumor cells in a volume of 0.5 ml. . After tumoral graft, distribution at random was carried out as indicated above, to obtain a control series of 8 cages and 5 experimental series of

4 cages each, and of which the mice were intended to be treated by the compounds of the invention.

4.3. Lewis tumor . Procedure was under the conditions which have just been described previously with regard to melanoma

Bl6, by injecting the tumor cells, in the proportion of 2 x 10 per mouse, in the volume of 0.2 ml.

4.4. Protocol and treatment . The protocol was identical for the 3 tumors and the 5 compounds of the invention to be tested. . As regards the experimental series to be treated, each mouse received, at days 1, 5 and 9, intraperitoneally, a dose of 20 mg/kg of the compound to be tested, in the volume of 0.2 ml of neutralized and sterilized olive oil.

. As regards the control series, each mouse received, intraperitoneally, 0.2 ml of neutralized and sterilized olive oil.

4.5. Results . Control series (comparison)

The average survival of the comparison mice is expressed in days ± 2 typical deviation of the mean

( ± 26 σ m) :

- L1210 : 8, 9 - 0.26 - 3LL Lewis tumor : 12.87 ± 0.79

- Melanoma B16 : 14-52 ± 0.80. . Treated series (see Table II below)

- The results are expressed by the relative increase in survival (T/C x 100) calculated from the average survival of the treated animals (T) and that of the control animals (C)

- The mice surviving more than 60 days were considered as cured.

The figures between parentheses indicate the percentage of cured mice. - The sign 00 indicates that 50% at least of the mice were cured.

- When the percentage of mice cured is less than 50%, the cured mice are considered as dead at

60 days for the calculation of the T/C x 100 (in this case the T/C x 100 is hence more or less underestimated).

- Among the mice which had lived at least 60 days, and hence considered as cured, certain we re killed at the 60th day. No anomaly was observed in macroscopic examinations of the organs removed.

- The other mice were preserved and kept alive to the 200th day; they did not manifest any apparent disturbance in their behavior. - The animals which died in the course of the experiment were autopsied and there was no death through toxicity.

5. Determination of the "in vivo" activity of the compounds according to the invention on the tumors L1210 USA and L1210 IGR.

. The tumor L1210 USA is more resistant than tumor L1210 IGR.

. The compounds tested were compounds IC 1183, IC,1184,

IC 1350, IC 1373 and IC 1374. . The experiments were identical to those described in preceding paragraph 4 but lower doses were used.

. There were inoculated into the mice, 10 tumor cells of L1210 USA intraperitoneally in a volume of 0.2 ml.

. At days 1, 5 and 9, the compounds of the invention under test were injected intraperitoneally, at a lower dose than that used in the experiment described at 4, that is to say in the proportion of 5mg/kg. . The same protocol was carried out with the tumor L1210 IGR, by inoculating 10⁵ tumor cells of L1210 IGR intraperitoneally in the volume of 6.2 ml then, at days 1, 5 and 9, there were injected intraperitoneally 5mg/kg of each of the compounds to be tested. The results are shown in Tables III and IV below.

6. Study of the toxicity of the compounds according to the invention . Histological examinations were carried out on the organs of DBA₂ mice inoculated by the tumor L1210 IGR and treated for 60 days with products IC 1183, IC 1184,

IC 1350, IC 1373 and IC 1374, as well as on organs of the comparison DBA₂ mice, that is to say inoculated with the tumor L1210 IGR.

. The organs subjected to these histological examinations were the liver, the kidneys, the spleen, the adrenal glands and the lungs.

. Examination showed that the comparison animals inoculated by L1210 IGR presented a cellular disorganisation of the hepatocytes. . On the contrary, the hepatic structure of mice inoculated by L1210 IGR, then treated with the products according to the invention, did not show as great a disturbance as that observed with the comparison mice inoculated with L1210 IGR, and the hepatic nuclear hypertrophy does not consequently seem to be connected with the toxicity itself of the products of the invention.

A hematological study has been carried out on some animals treated with the products according to the invention ; it is the case particularly of DBA₂ mice inoculated with L1210 leucemia and C57/B16 mice which have been inoculated with Lewis tumor. The study comprised, from a blood sampling by cardiac puncture, collected on heparin, a blood count ( erythrocytes and leukocytes), hematocrit, platelet count, differential blood count. From marrow smears of femoral origin and from a spleen print, a short study of hematopoietic centers has been undertaken.

A histological study has also been carried out on liver, spleen, kidneys, adrenal glands, lungs, which were sampled when the animals were killed. No important disturbances have been observed, either in the blood count or in the differential blood count ; there is no bone marrowaplasia and the marrows which have been observed are rich in cells of all kinds. The spleens seem to be substantially normal. 7. General conclusion

. The animal experiments carried out with the product according to the invention give interesting results when the model selected in melanoma B16, and excellent resuits when the models selected are the Lewis tumor and the L1210 IGR tumor as well as the L1210 USA tumor, more resistant than the L1210 IGR.

The compounds according to the invention are hence particularly suitable for the treatment of vari.ous human cancers, especially those which are sensitive to chimiotherapy. The compounds of the invention are particularly suitable for the treatment of various forms of cancer meeting this condition and which are identified in the publications already mentioned. The compounds of the invention are also suitable for the treatment of primary and secondary cerebral tumors, broncho-pulmόnary tumors, tumors of the ORL sphere, digestive tumors (gastric, pancreatic, colic and rectal), tumors of the breast, of the genital organs in the woman, bone tumors ( os teosarcomas, reticulosarcomas), melanomas, hemato-sarcomas (Hodgkinian and non Hodgkinian lymphomas), and multiple myelomas.

The invention relates also to pharmaceutical compositions comprising the above said novel compounds in association with a pharmaceutical vehicle suitable for the selected mode of administration.

The invention relates particularly to sterile or sterilizable solutions, injectable or suitable for use for the preparation, particularly extemporaneously, of injectable solutions suitable for administration by intravenous injections or perfusions. They relate, in particular, to physiologically acceptable hydroalcoholic solutions. The products according to the invention, may be for instance presented in the form of freeze-dried powder, which, for administration, is prepared extemporaneously by solubilisation by means of a sterile alcoholic solvent. The solution so-obtained is then diluted with apyrogenic sterile water, then before being administered by intravenous perfusion, the solution is again rediluted in 9 %. isαtonic salt serum or 5 % isotonic glucose serum.

The doses administered daily must be sufficient so that an action can be manifested at least in a relatively large proportion of patients afflicted with one or other of the various forms of cancer which are or will be accessible to chimiόtherapy, however without nonetheless exceeding those for which the compounds become too toxic. More particularly, the doses to be administered are determined according to models conventionally used in this field which are, for example, described in the two following articles :

- Cancer Research, 37, 1 934-1 937, June 1977, P. S. Schein ;

- Cancer Chimiotherapy Reports, vol. 50, n° 4, May 1966, E. J. Freireich.

The model for determining the suitable doses for a given compound, consist of determining the dose which is tolerated by the animal and which corresponds to about 1/10 of the lethal dose (LD10) expressed in mg/m2 of body surface. The doses which can be used in man correspond to 1 /3 to 1 /10 of the LD10 dose mentioned above ( cf . Cancer Research, 37, 1935, column 1, June 1977). By way of example, the daily doses administered by the general route, particularly by perfusion, and expressed in mg/kg can vary from about 1 to about 50 mg/kg, for example, about 3 mg/kg.

The invention also relates to other forms of administration, especially, for the oral route (solid or liquid compositions) or for the rectal route (glycerin compositions suitable for the latter route).

These dosage ranges are obviously only by way of indication. It is naturally understood that in this type of therapy, the doses administered must in each case be evaluated by the clinician taking into account the state of the patient and of his personal reactivity with respect to the medicaments.

An example of pharmaceutical composition of the products according to the invention comprises 100 mg of at least one of the products of the invention, presented in the form of a sterile freeze-dried powder, associated with an ampoula of physiologically acceptable solvent, particularly of alcohol, such as ethanol, at the dosage of about 5 ml per ampoula. Because of their particularly important activity, the compounds of the invention are also useful as reference products in pharmacological studies, particularly in order to carry out antitumor comparisons of the products which are studied with respect to a reference product.

Claims (1)

1. 1. Nitrosourea derivatives, corresponding to the following formula (I) :

   (l)

   in which

   - R represents a hyαrogen atom, an allcyl group from 1 to 30 , preferably 1 to 1 2 carbon atoms or an aralkyl group from 7 to 12 , preferably 7 to 9 carbon a corns , op tionally substituted by one or several , particularly up to 3, halogen atoms , NO₂ , N H₂ , CF ₃ groups or alkoxy groups from 1 to 4 carbon atoms

   - .X. represents a hydroxy group or an NR ₁R₂ group

   - Y represents a hyαrogen atom a hydroxy group or an group where R₁ and/or R '₁ each represent a hydrogen atom or a - C-N-CH₂-CH₂Halgroup, Hal being a halogen, preO NO ferably Cl, and R₂ and/or R'₂ each represent a hydrogen atom, an alkyl group comprising from 1 to b carbon atoms, an aralkyl group comprising from 7 to 12, preferably from 7 to 9 carbon atoms, a cycloalkyl group comprising from 3 to b carbon atoms, an aryl group from 4 to 10 carbon atoms, the aryl and aralkyl groups being optionally substituted by one or several, particularly up to 3 halogen atoms, NO₂,NH₂,CF₃ groups or alkoxy groups from 1 to 4 carbon atoms. -R' and R" represent hydrogen,OH,OM, M representing an alkyl group comprising from 1 to 30, preferably from 1 to 12 carbon atoms, an aryl group from 4 to 10 carbon atoms, an aralkyl group comprising from 7 to 12, preferably from 7 to 9 carbon atoms, the aryl and aralkyl groups being optionally substituted by one or several particularly up to 3, halogen atoms, W0₂,NH₂,CF₃ groups or alkoxy groups of 1 to 4 carbon atoms, or M representing an acyl group of 2 to 8 carbon atoms, preferably 2 or 3, an aroyl group from 5 to 12, preferably from 5 to 9 carbon atoms, unsubstituted or substituted by one or several, particularly up to 3, NO₂,NH₂, CF₃ groups, halogen, alkoxy from 1 to 4 carbon atoms, provided that at least

   X represents - N with R₁ representing - C-N OH₂CH₂Hal , O NO

   or Y represents 1 with R'₁ representing 2

   and either R' represents hydrogen or R" represents hydrogen, and R' and R" cannot be simultaneously hydrogen atoms.

   2. Nitrosourea derivatives according to Claim 1, corresponding to the following formula (II) :

   (II) in which

   - R represents a hydrogen atom, an alkyl group of 1 to 30, preferably from 1 to 12 carbon atoms or an aralkyl group from 7 to 12, preferably from 7 to 9 carbon atoms, optionally substituted by one or several, particularly up to 3, halogen atoms, NO₂,NH₂,CF₃ groups or alkoxy groups from 1 to 4 carbon atoms,

   - X represents a hydroxy group or an NR₁R₂ group

   - Y represents a hydrogen atom ' a hydroxy group or an 1 group ₂ where R₁ and/or R'₁ each represents a hydrogen atom or a

   -C-N CH₂CH₂Hal group, Hal being a halogen, pre

   O NO ferably Cl and R₂ and/or R'₂ each represent a hydrogen atom, an alkyl group comprising from 1 to 6 carbon atoms, an aralkyl group comprising from 7 to 12, preferably from 7 to 9 carbon atoms, a cycloalkyl group comprising from 3 to 6 carbon atoms, an aryl group of 4 to 10 carbon atoms, the aryl and aralkyl groups being optionally substituted by one or several, particularly up to 3, halogen atoms, NO₂,NH₂,CF₃ groups or alkoxy groups of 1 to 4 carbon atoms, R" represents preferably OH, but can be replaced by OM, M representing an alkyl group comprising from 1 to 30, preferably from 1 to 12 carbon atoms, an aryl group of 4 to 10 carbon atoms, an aralkyl group comprising from 7 to 12, preferably from 7 to 9 carbon atoms, the aryl and aralkyl groups being optionally substitut ed by one or several, particularly up to 3 halogen atoms, NO₂,NH₂,CF₃ groups or alkoxy groups from 1 to 4 carbon atoms, or M representing an acyl group from 2 to 8 carbon atoms, preferably 2 or 3, an aroyl group from 5 to 12, preferably from 5 to 9 carbon atoms, unsubstituted or substituted by one or several, particularly up to 3, NO₂ ,NH₂,CF₃ groups, halogen, alKoxy of 1 co 4 carbon atoms. provided that at least X represents .witn R₁ representing -C-N-CH₂CH₂Hal or Y represents

   R with R ₁ represen ting -C-N CH ₂ -CH ₂ Hal . .

   3. N i trosourea αerivatives according to Ciaim 1 , corresponding to the following formula (V ) :

   (v) in which

   - R represents a hyαrogen atom, an alkyl group of 1 to 30, preferably from 1 to 12 carbon atoms or an aralkyl group from 7 to 12, preierably from 7 to 9 carbon atoms, optionally substituted by one or several, particularly up to 3, halogen atoms, NO₂,NH₂,CH₃ groups or alkoxy groups from 1 to 4 carbon atoms,

   - X represents a hydroxy group or an NR₁R₂ group

   - Y represents a hydrogen atom a nyαroxy group or an ' group '₂ wnere _R. and/or R ' ₁ each repres ent a hydrogen atom or N H₂CH₂ Hal group , Hal being a halogen, preferably Cl , and R₂ and/or R ' ₂ each represent a hydrogen atom, an alkyl group comprising from 1 to 6 carbon atoms, an aralkyl group comprising from 7 to 12 , preferably from 7 to 9 carbon atoms, a cycloalkyl group comprising from 3 to 6 carbon atoms, an aryl group from 4 to 10 carbon atoms, the aryl and aralkyl groups being optionally substituted by one or several, particularly up to 3 halogen atoms, NO₂,NH₂,CF₃ groups or alκoxy σroup from 1 to 4 carbon atoms,

   R ' represents preferably OH, OH being replaceable by OM, M representing an alkyl group comprising from 1 to 30, preferably from 1 to 12 carbon atoms, an aryl group from 4 to 10 carbon atoms, an aralkyl group comprising from 7 to 12, preferably from 7 to 9 carbon atoms, the aryl and aralkyl groups being optionally substituted by one or several particularly up to 3 halogen atoms, NO₂, NE₂,CF₃ groups or alkoxy groups of 1 to 4 carbon atoms, or M representing an acyl group from 2 to 8 carbon atoms, preferably 2 or 3, an aroylgroup from 5 to 12, preferably from 5 to 9 carbon atoms, unsubstituted or substituted by one or several, particularly up to 3, NO₂,NH₂,CF₃ groups, halogen, alkoxy cf 1 to 4 carbon atoms. provided that at least X represents with R ₁ repres enting -C-N-CH₂CH₂Hal or Y represents with R ' ₁ representing -C-N -CH₂ CH₂Hal

   4. Nitrosourea derivatives according to Claim 3, corresponding to the following formula (VI) :

   (VI) in which R, R', X ana Y have the meanings indicated in

   Claim 3.

   5. Nitrosourea derivatives according to Claim 3, corresponding to the lollowing formula (VII) :

   (VII)

   in which R, R', X and Y have the meanings indicated in Claim 3.

   6. Nitrosourea derivatives according to Claims 1 to 5, wherein

   - R represents an alkyl group from 1 to 12 carbon atoms, aralkyl from 7 to 12 carbon atoms ;

   - R' or R" represent an OM group, M being an alkyl group comprising from 1 to 12 carbon atoms, an aryl group comprising from 4 to 10 carbon atoms ;

   - X represents an NR₁R₂ group, R₁ representing -C-N-CH₂CH₂Hal, Hal being a halogen, preferably Cl, <- --

   O NO

   -Y represents a hydrogen atom or a hydroxy group.

   7. Nitrosourea derivatives according to Claims 1 to 5, wherein

   - R represents an alkyl group from 1 to 12 carbon atoms, halogeno aralkyl of 7 to 12 carbon atoms ;

   -R' or R" represent an OM group, M being an acyl group from 2 to 8 carbon atoms, an aroylgroup from 5 to 12 carbon atoms ;

   - X represents an -NR₁R₂ group, R₁ representing -C-N-CH₂CH₂Hal, Hal being a halogen, particularly Cl

   O NO - Y represents a hydrogen atom or a hydroxy group.

   8 . Nitrosourea derivatives ac cording to Claims 1 to 5 , wherein

   - R repres ents an alkyl group from 1 to 12 carbon atoms , an aralkyl group of 7 to 1 2 carbon atoms ;

   - R ' or R " represent OH ;

   - X represents an NR ₁R₂ group , R ₁ representing CH₂CH₂Hal, Hal representing halogen, parti cularly Cl ^ O

   - Y represents a hydrogen atom.

   9. Nitrosourea derivatives according to Claims 1 to 5, wherein

   -R represents an alkyl group of 1 to 12 carbon atoms, an aralkyl group of 7 to 12 carbon atoms ;

   - R' and R" represent OH ;

   - X represents an alkylamino group, in which the alkyl group has from 1 to 6 carbon atoms, or arylamino in which the aryl group has from 4 to 10 carbon atoms, and

   - Y represents NR'₁.R'₂, R'₁ representing -CH₂CH₂Hal, Hal being a halogen, particularly Cl.

   10. Nitrosourea derivatives according to Claims 1 to 5, wherein

   - R represents an alkyl group of 1 to 12 carbon atoms, an aralkyl group of 7 to 12 carbon atoms ;

   - R' or R" represent OH ;

   - X represents a. hydroxy group,

   -Y represents NR'₁R'₂, R'₁ representing -CH₂CH₂Hal, Hal representing a halogen atom, particuO lariy Cl.

   11. Compounds according to Claim 1, of the formula

   12. Process for the preparation of compounds according to any one of Claims 1 to 11, said process consisting of reacting in a first step an oside group of t the general formula I bis below :

   (I bis

   in which :

   - R, R' and R"" have the meanings indicated in Claims 1 to 11

   - X' represents a hydroxy group or -NHR₂ ;

   - Y' represents a hydrogen atom, a hydroxy group or -NHR'₂

   - R₂ and R'₂ identical or different, represent an alkyl group from 1 to 12 carbon atoms, an aralkyl group from .7 to 12 carbon atoms, a cycloalkyl from 3 to 6 carbon atoms, the aryl and aralkyl groups being optionally substituted by one or several, particularly up to 3, halogen atoms, NO₂,NH₂,CF₃ groups or alkoxy groups of 1 to 4 carbon atoms, and in which one at least of the X' or Y' groups represents NHR₂ or NHR'₂ on an 2-halogeno-ethyl isocyanate to convert the NHR₂ or NHR'₂ group of the compound of Formula 1 bis respectively into N, NHCH₂ CH₂Hal or NH' NHCH₂CH₂Hal,

   O O

   Hal being a halogen atom, particularly chlorine, and in a second step, subjecting the compound Obtained at the end of the first step to nitrosation, by means of an alkali metal nitrite, preferably, sodium nitrite to convert the NR₂C NHCH.₂CH₂Hal or NR₂' C NHCH₂CH₂Hal groups respective

   O O tively into CH₂CH₂Hal or NR' CH₂ CH₂ Hal.

   13. Process of the preparation according to Claim 12, of compounds of formula (VI) ( VI)

   said process comprising reacting a compound of formula (VI bis)

   (VI bis) where R and R' are as defineα above,

   - X' represents an -NHR₂ or hydroxy group ;

   - Y' represents a hydrogen atom, a hydroxy or -NHR'₂ group and can represent a halogen atom when X' -represents a hydroxy group,

   - R₂ and R'₂, identical or difierent, represent independently of one another a hydrogen atom, an alkyl group of 1 to 30 carbon atoms, an aralkyl group of

   7 to 12 carbon atoms, aryl of 4 to 10 carbon atoms, cycloalKyl of 3 to 6 carbon atoms, the aryl and aralkyl groups being optionally substituted by one or several particularly up to 3, halogen atoms, NO₂ ,NH₂,CF₃ groups or alkoxy groups of 1 to 4 carbon atoms and in which 1 at least of the X' and Y" groups represent NHR ₂ or -NHR' ₂ on a 2-halogeno-ethyl isocyanate to convert the -NHR₂ or -NHR' ₂ group of the crompound of formula VI bis respectively into N H CH₂ CH₂,Hal or NH CH₂CH₂,Hal,

   Hal being a halogen atom, particularly chlorine, the compound obtained at the end of tne preceding step being then subjected to nitrosation, by means of an alkali metal nitrite, preferably sodium nitrite to convert the NH and groups respec¬ tively into -NR₂ CH₂CH₂Hal and -NR'₂ CH₂CH₂Hal . ^"

   14. Process of the preparation according to claim 12, of compounds of formula (VII)

   (VII)

   said process comprising reacting a compound of formula (VII bis)

   (VII bis)

   where R and R' are as defined above,

   - X' represents an -NHR₂ or hydroxy group ;

   - Y' represents a hydrogen atom, a hydroxy or -NHR'₂ group and can represent a halogen atom when X' represents a hydroxy group,

   - R₂ and R'₂, identical or different, represent independently of one another a hydrogen atom, an alkyl group of 1 to 30 carbon atoms, an aralkyl group of

   7 to 12 carbon atoms, aryl of 4 to 10 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, the aryl and aralkyl groups being optionally substituted by one or several particularly up to 3, halogen atoms, NO₂,NH₂,CF₃ groups or alkoxy groups of 1 to 4 carbon atoms and in which 1 at least of the X' and Y' groups represent NHR₂ or -NHR'₂ on a 2-halogeno-ethyl isocyanate to convert the -NHR₂ or -NHR' ₂ group of the compound of formulavil bis respectively into -NR₂ NH CH₂ CH₂Hal or -NR'₂ NH CH₂CH2Hal, Hal being a halogen atom, particularly chlorine, the compound obtained at the end of the preceding step being then subjected to nitrosation, by means of an alkali metal nitrite, preferably sodium nitrite to convert the NH NHR₂CNHCH₂CH₂Hal and ' groups respec¬ tively into -NR₂ CH₂CH₂Hal

   15. Pharmaceutical composition, comprising, in association with a pharmaceutical vehicle, a compound according to anyone of Claims 1 to 11.

   16. Pharmaceutical composition according to claim 15 comprising 100 mg of at least one of the products according to claims 1 to 11, presented under the form of sterile freeze-dryed powder associated with an ampoula of a physiologically acceptable solvent, particularly alcohol, such as ethanol at the dosage of 5 mg per ampoula.

   17, process for the preparation of nitrosourea derivatives of the following formula. 1 :

   ⁽ U

   in which :

   - R represents a hydrogen atom, an alkyl group from 1 to 30, preferably 1 to 12 carbon atoms or an aralkyl grouo from 7 to 12, preferably 7 to 9 carbon atoms, optionally substituted by one or several, particularly up to 3, halogen atoms, NO₂,NH₂,CF₃ groups or alkoxy groups from 1 to 4 carbon atoms

   - X represents a hyαroxy group or an NR₁R₂ group

   - Y represents a hydrogen atom a hydroxy group or an group where R₁ and/or R'₁ represent a hydrogen atom or a Hal group, Hal being halogen, pref er ably Cl, and R₂ and/or R'₂ each represent a hydrogen atom, an alkyl group comprising 1 to 6 carbon atoms, an aralkyl group comprising 7 to 12, preferably 7 to 9 carbon atoms, a cycloalkyl group comprising from 3 to 6 carbon atoms, an aryl group from 4 to 10 carbon atoms, the aryl and aralkyl groups being optionally substituted by one or several particularly up to 3, halogen atoms, NO₂,NH₂,

   CF₃ groups or alkoxy groups from 1 to 4 carbon atoms

   - R' and R" represent hydrogen, OH, OM, M representing an alkyl group comprising from 1 to 30, pre_¬ ferably from 1 to 12 carbon atoms, an aryl group from 4 to 10 carbon atoms, an aralkyl group comprising from 7 to 12, preferably from 7 to 9 caroon atoms, the aryl and aralkyl groups being optionally substituted by one or several particularly up to 3, halogen acorns, NO_2.NH₂,CF₃ groups or alκoxy groups from 1 to 4 carbon atoms, or M representing an acyl group from 2 to 8 carbon atoms, preleraoly 2 or 3, an aroylgroup from 5 to 12, preferably 5 to 9 carbon atoms, unsubstifuted or substituted by one or several, particularly up to 3, NO₂,NH₂,CF₃ groups, halogen, a.lkoxy from 1 to 4 caroon atoms, orovided that at least

   X represents - with R₁ representing ' ^"

   or Y represents - with R' ₁ representing and provided that either R' or R" represents hydrogen, and R' and R" cannot simultaneously represent hydrogen, said process consisting of reacting in a first step an oside group of the following Formula I Bis:

   I bis

   in which

   - R, R' and R" have the above-indicated meanmgs,

   - X' represents a hydroxy or -NHR₂ group ;

   - Y' represents a hydrogen atom, hydroxy group, or -NHR'₂ group ;

   - R₂ and R '₂ identical or different, represent, an alkyl group from 1 to 12. carbon atoms, an aralkyl group from 7 to 12 carbon atoms, cycloalkyl from 3 to 6 carbon atoms, the aryl and aralkyl groups being optionally substituted by one or several particularly up to 3, halogen atoms, NO₂,NH₂,CF₃ groups or alkoxy groups from 1 to 4 carcon atoms, and in which one at least of tne groups X' or Y' represents -NHR₂ or NHR'₂ on a 2-ethyl-halogeno isocyanate, to convert the NHR₂ or NHR'₂ group of the compound of formula I bis respectively into NHCH₂ CH₂Hal or NR' C NHCH₂CH₂Hal,

   Hal being a halogen atoms, particularly chlorine, and in the second step, subjecting the compound obtained in the preceding step to nitrosation, by means of a nitrite of an alkali metal, preferably, sodium nitrite to convert the NR₂CNHCH₂CH₂Hal or NR ' ₂CNHCH₂VH₂Hal groups respectively O O

   18, Process according to Claim 17, for preparing nitrosourea derivatives of the following formula II :

   (ui

   in which

   - R represents a hydrogen atom, an alkyl group of 1 to 30, preferably from 1 to 12 carbon atoms or an aralkyl group from 7 to 12, preferably from 7 to 9 carbonatoms, optionally substituted particularly by one or several, particularly up to 3, halogen atoms, NO₂,NH₂,

   CF₃ groups of alkoxy groups from 1 to 4 carbon atoms,

   - X represents a hydroxy group or an NR₁R₂ group

   - Y represents a hyαrogen atom, a hyαroxy group or an group vhere R₁ and/or R'₁ each represent a hydrogen atom or a

   -C-N-CH₂CH₂Hal group, Hal being a halogen, pre O NO ferably Cl. and R₂ and/or R'₂ each represent a hydrogen atom, an alkyl group comprising 1 to b carbon atoms, an aralkyl group comprising 7 to 12, preferably 7 to 9 carbon atoms, a cycloalkyl group comprising 3 to 6 carbon atoms, the aryl and aralkyl groups being optionally substituted by one or several particularly up to 3, halogen atoms, NO₂,NH₂, CF₃ groups or alkoxy groups of 1 to 4 carbon atoms, - R" represents preferably OH, but can represent OM, M representing an alkyl group comprising from 1 to 30, preferably 1 to -12 carbon atoms, an aryl group from 4 to 10 carbon atoms, an aralkyl group comprising 7 to 12, preferably 7 to 9 carbon atoms, the aryl and aralkyl groups being optionally substituted by one or several, particularly up to 3 halogen atoms, NO₂,NH₂,CF₃ groups or alkoxy groups from 1 to 4 carbon atoms, or M representing an acyl group from 2 to 8 carbon atoms, preferably 2 or 3, an aroyl group from 5 to 12, preferably 5 to 9 carbon atoms, unsusbstituted or substituted by one or several, particularly up to 3, NO₂,NH₂,CF₃ groups, halogen, alkoxy from 1 to 4 carbon atoms, provided that at least

   X represents - with R₁ representing

   or Y represents with R'₁ representing

   19. Process according to Claim 17, for preparing nitrosourea derivatives of the following formula III :

   (V) whi ch

   - R represents a hydrogen atom, an alkyl group of 1 to 30, preferably 1 to 12 carbon atoms or an aralkyl froup of 7 to 12, preferably 7 to 9 carbon atoms, optionally substituted particularly by one or several, particularly up to 3, halogen atoms, NO₂,NH₂,CF₃ groups or alkoxy groups of 1 to 4 carbon atoms,

   X represents a hydroxy group or an NR₁R₂ group

   - Y represents a hydrogen atom, a hydroxy group oorr an group where R ₁ and/or R ' ₁ ea ch repres ent a hydrogen atom or a group , Hal being a halogen, pre ferably Cl, and R₂ and/or R'₂ each represent a hydrogen atom, an alkyl group comprising 1 to 6 carbon atoms, an aralkyl group comprising 7 to 12, preferably 7 to 9 carbon atoms, a cycloalkyl group comprising 3 to 6 carbon atoms, an aryl group from 4 to 10 carbon atoms, the aryl and aralkyl groups being optionally substituted by one or several, particularly up to 3, halogen atoms, NO₂,NH₂,CF₃ groups or alkoxy groups from 1 to 4 carbon atoms,

   - R' represents preferably OH, but can represent OM, M representing an alkyl group comprising from 1 to 30, preferably 1 to 12 carbon atoms, an aryl group from 4 to

   10 carbon atoms, an aralkyl group comprising 7 to 12, preferably 7 to 9 carbon atoms, the aryl and aralkyl groups being optionally substituted by one or several, particularly up to 3 halogen atoms, NO₂,NH₂,CF₃ groups or alkoxy groups from 1 to 4 carbon atoms, or M representing an acyl group from 2 to 8 carbon atoms, preferably 2 or 3, an aroyl group from 5 to 12, preferably 5 to 9 carbon atoms, unsusbstituted or substituted by one or several, particularly up to 3, NO₂ , NH₂ ,CF₃ groups, halogen, alkoxy from 1 to 4 carbon atoms, provided that at least

   X represents - with R₁ representing

   or Y represents with R'₁ representing

   20. Process according to Claim 19, for preparing compounds of the following formula VI :

   (VI)

   in which R, R', X and Y have the meanings indicated in

   Claim 19.

   21. Process according to Claim 19, for preparing compounds of the following formula VII :

   (VII

   in wnich R, R', X and Y have the meaning indicated in Claim 19.

   22. Process according to Claims 17 to 21, for preparing compounds of formula I, II, V, VI or VII in which

   - it represents an alkyl group from 1 to 12 carbon εtoms, aralkyl from 7 to 12 carbon atoms ; - R' or R" represent an OM group, M being an alkyl group comprising from 1 to 12 carbon atoms, an aryl group comprising from 4 to 10 carbon atoms ; presents an NR₁R₂ group, R₁ representing Hal being halogen, preferably Cl,

   - Y represents a hydrogen atom or a hydroxy group.

   23. Process according to Claims 17 to 21, for the preparation of compounds l, II, V, Vl or vll in which - R represents an alkyl group from 1 to 12 caroon atoms , halogenoaralkyl from 7 to 12 carbon atoms ;

   - R' or R'' represent an OM group , M being an acyl group of 2 to 6 caroon atoms , an aroyl group from 5 to 12 carbon atoms ;

   - A represents an -N R ₁ R ₂ group , R ₁ repres enting Hal being halogen, particularly Cl

   - Y represents a hydrogen atom or a hydroxy group.

   24. rrocess according to Claims 17 to 21, for preparing compounds of formula l, ll, V, VI or VII in which

   - R represents an alkyl group from 1 to 12 carbon atoms, an aralkyl group from 7 to 12 carbon atoms ;

   - R' or R" represent OH ;

   - X represents an NR₁R₂ group, R₁ representing Hal representing halogen, particularly Cl - Y represents a hydrogen atom,

   25. Process according to Claims 17 to 21, for preparing compounds of formula I, II, V, VI or VII in which - R represents an alkyl group from 1 to 12 carbon atoms, an aralkyl group from 7 to 12 carbon atoms ; R' or R" represent OH ;

   - X represents an alkylamino group, in which the alkyl group has from 1 to 6 carbon atoms, or arylamino in which tne aryl group has 4 to 10 carbon atoms, and

   - Y represents NR'₁R'₂, R'₁ representing Hal being a halogen, particularly Cl.

   26. Process according to Claims 17 to 21, for preparing compounds of formula I, II, v, VI or VII in which

   - R represents an alicyl group from 1 to 12 carbon atoms, an aralkyl group from 7 to 12 carbon atoms ;

   - R' or R" represent OH ;

   - X represents an hydroxy group,

   - Y represents NR'₁R'₂, R'₁ representing

   Hal representing a halogen atoms, par¬ ticularly Cl.

   27. Process for the oreoaration according to

   Claim 17, of compounds of formula :

   28. Process for preparing a pharmaceutical composition, characterized by the fact that one at least of any of the compounds obtained according to claim 17 to 27 is associated with a pharmaceutically acceptable vehicle under conditions enabling to obtain said pharmaceutical composition.