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Title:
NITROSOUREA DERIVATIVES, PROCESS FOR THEIR PREPARATION AND MEDICAMENTS CONTAINING THEM
Document Type and Number:
WIPO Patent Application WO/1985/001050
Kind Code:
A1
Abstract:
Nitrosourea derivatives, process for their preparation and pharmaceutical compositions containing them. The nitrosourea derivatives of the invention correspond to the formula (I), in which: R can represent a hydrogen atom or an alkyl group from 1 to 30 carbon atoms, X represents a hydroxy group or an -NR1R2 group, Y represents a hydrogen atom, a hydroxy group or an -NR'1R'2 group, where R1 and/or R'1 each represent a hydrogen atom or formula (II), Hal being a halogen, and R2 and/or R'2 can each represent a hydrogen atom or an alkyl group comprising from 1 to 6 carbon atoms, R' and R'' can represent hydrogen or OH, provided that at least, X represents formula (III), with R1 representing formula (IV) or Y represents formula (V) with R'1 representing formula (VI) and provided that, either R' represents hydrogen or R'' represents hydrogen, and R' and R'' cannot be simultaneously hydrogen atoms. These compounds present an antitumor activity.

Inventors:
Roger
Pierre, Choay
Patrick, Monneret
Claude, Fournier
Jean-paul
Application Number:
PCT/EP1984/000260
Publication Date:
March 14, 1985
Filing Date:
August 29, 1984
Export Citation:
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Assignee:
DROPIC SOCIETE CIVILE DE GESTION DE DROITS DE PROPRIETE INDUSTRIELLE CHOAY ROGER
Pierre, Choay
Patrick, Monneret
Claude, Fournier
Jean-paul
International Classes:
A61K31/70; C07H13/12; C07H15/00; C07H15/04; (IPC1-7): C07H13/12; C07H15/00; A61K31/70
Foreign References:
EP0067019A11982-12-15
US3940383A1976-02-24
Download PDF:
Claims:
CLAIMS
1. Nitrosourea derivatives, corresponding to the following formula (I) : in which R represents a hyαrogen atom, an all yl 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 tion¬ ally substituted by one or several , parti¬ cularly up to j, halogen atoms , NO , I H,, , O . ' groups or al¬ koxy groups from 1 to 4 carbon atoms .X. represents a hydroxy group or an NR .R group Y represents a hyαrogen atom • , a hydroxy group or an group '._ where κ1 and/or IV 1 each represent a hydrogen atom or a CNCH_CH?Halgroup, Hal being a halogen, pre O NO ferably UI, and R„ and/or ϊV 2 each represent a hydrogen atom, an alkyl group comprising from 1 to b carbon atoms, an aralkyl group comprising from 7 to 12, pre¬ ferably from 7 to 9 carbon atoms, a cycloalkyl group comprising from j to b carbon atoms, an aryl group from 4' to 10 carbon atoms, the aryl and aralkyl groups being optionally substi¬ tuted by one or several, particularly up to j halogen atoms, iO^^H ^C , 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 jϋ, 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 ,0*'^ groups or alkoxy groups of 1 to 4 carbonatoms, or M representing an acyl group of 2 to 8 carbon atoms, preferably 2 or 3. an aroyl group fxcm 5 to 12, preferably from 5 to 9 carbon atoms, unsubstituted or sub¬ stituted by one or several, particularly up to 3, NO^ ,NHp, Cl.". groups, halogen, alkoxy from 1 to 4 carbon atoms, provided that at least X represents rr with . representing C OHpCHpHal XK.2 , 0 NO or Y represents W /R'ι with K' . representing Xβ,2 σιιCh.,cκ.Jhai and either R' represents hydrogen or R" represents hydrogen, and R' and R" cannot be simultaneously hydrogen atoms.
2. Nitrosourea derivatives accorαing to Claim 3, corresponding to the following formula (VI) : 35 in whi ch R , R ' , X ana Y have the meanings indi ca ted in Claim 3.
3. I.itrosoures* derivatives according to Claim 3, corresponding to the lollowing formula (VII) : in which R, R', X and Y have the meanings indicated in Claim 3.
4. 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 ; ?_' or R" represent an OM group, I.I being an alkyl group comprising from 1 to 12 carbon atoms, an aryl group comprising from 4 to 10 carbon atoms ; X represents an ^R2 group, R., representing CNCHpCHyHal, Hal being a halogen, preferably Cl, II I < 0 NO Y represents a hydrogen atom or a hydroxy group .
5. 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 f or R" represent an 0M group , M being an acyl" group from 2 to 8 carbon atoms , an aroyl group from 5 to 12 carbon atoms ; X represents an NR Rp group , R .. representing CNCHCH^Hal , Hal being a halogen, parti cularly Cl II I * ""** o NO Y represents a hydrogen atom or a hydroxy group. __ " 1. (f> δ . Nitrosourea derivatives ac cording to Claims 1 to 5 , wherein R repres ents an alkyl group from i to 12 carbon atoms , an aralkyl group of 7 to 1 2 carbon atoms ; R * or 11" represent OH ; X represents an NR.
6. R2 group , R_| representing _CNCHpCHpHal, Hal representing halogen, parti cularly Cl II l ^ * 0 NO Y represents a hydrogen atom.
7. 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 grouphas from.l to 6 carbon atoms, or arylamino in which the aryl group has from 4 to10 carbon atoms, and Y represents lxR'.R'p, R' _, representing CNCHpCHpHal, Hal being a halogen,. particularly Cl. II I * " 0 NO .
8. 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 R'.R'g, R' representing CNCH,,CHpHal, Hal representing a halogen atom, particu II t ^ ^ 0 NO lariy Cl. 01050 87' .
9. Compounds according to Claim 1, of the formula 2C 1 .
10. Process for the preparation of compounds according to any one of Claims 1 to 11, said process con¬ sisting of reacting in a first step an oside group of he general formula I bis below : in which : R, R1 and R"" have the meanings indicated in Claims 1 to 11 X' represents a hydroxy group or NHRp ; Y' represents a hydrogen atom, a hydroxy group or NHR' p 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 sub¬ stituted by one or several, particularly up to 3, halogen atoms, N02,NH ,CF, groups or alkoxy groups of 1 to 4 carbon atoms, and in which one at least of the X' or Y' groups repre¬ sents NKRp or INH '2 on an. 2halogenoethyl isocyanate to convert the HHRp or NriR'p group of the compound of Formula I bis respectively into M,C NHOrip CHpiial or NH' C WKCHyOϋ^Hal, u 0 Hal being a halogen atom, particularly chlorine, and in a second step, subjecting the compound ODtained at the end of the first step to nitrosation, by means of an alkali metal nitrite, preferably, sodium nitrite to convert the Mfi2C WHOH.2CH Hal or lR^C r.HCH20ii2Hal groups respective 0 U tively into UK.01N CHyCHprial or Nri' ci OH.. OH.. Hal. 0 JNO 0 υ .
11. Process of the preparation according to Claim 12, of compounds of formula (VI) said process comprising reacting a compound of formula where R and R' are as defineα above, X' represents an iHR,, or hydroxy group ; Y ' represents a hydrogen atom, a hydroxy or i.HR' group and can represent a halogen atom when X' represents a hydroxy group, R, and R'p, identical or difierent, repre¬ sent 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, cyclo alKyl of 3 to b carbon atoms, the aryl and aralkyl groups being optionally substituted by one or several particularly up to 3, halogen atoms, N0.ι,NHp,CF . groups or alkoxy groups of 1 to 4 carbon atoms and in which 1 at least of the X' and Y" groups represent r.Hin., or NHR', on a 2halogenoethyl isocyanate to convert the rιHR or KR' p grou oi' ^n.e crompound of formulaVI bis respectively into MR 0 ϊ.i Cri. CH,,hal or i.R' C NH ϋH..CH,,Hal, υ υ Hal being a halogen atom, particularly chlorine, the com¬ pound obtained at the end of tne preceding step being then subjected to nitrosation, by means of an alkali metal ni¬ trite, preferably sodium nitrite to convert the NH ilHR,CNHCH..CH,,hal and Wr.' , CNHCHpCHprial groups respec 0 0 tively into NR?C N CH CH _Hal and NR ' ?C N CH.CH..Hal. "θ NO "O NO .
12. Process of the preparation according to claim 12, of compounds of formula (VII) said process comprising reacting a compound of formula (VII bis) where R and R' are as defined above, — X' represents an NHRp or hydroxy group ; — Yr represents a hydrogen atom, a hydroxy or NHR'p roup and can represent a halogen atom when X' represents a hydroxy group, — p and R'p, identical or different, repre¬ sent 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, ar3rl of 4 to 10 carbon atoms, cyclo¬ alkyl of 3 to 6 carbon atoms, the aryl and aralkyl groups being optionally substituted ~oy one or several particularly up to 3, halogen atoms, N0 ,NH2,C , groups or alkoxy groups of 1 to 4 carbon atoms and in which 1 at least of the X' and Y' groups represent NH p or NHR'p on a 2halogenoethyl isocyanate to convert the NHRp or NHR' p group of the compound of formulavil bis respectively into R9 C,, NH CH<p_. CHp_Hal or NR'p_ C,, NH CHp_CH__.Hal, 0 0 Hal being a halogen atom, particularly chlorine, the com¬ pound obtained at the end of the preceding step being then subjected to nitrosation, by means of an alkali metal ni¬ trite, preferably sodium nitrite to convert the NH KHR„CNHCH CH«Hal and NR« 9CNHCH CH Hal groups respec 0 o tively into NR Δ_ C ,ι N , Ch'__CH 2Hal and NR ' 2 Cii Ni CH 2.CH 2.Hal O NO 0 NO .
13. Pharmaceutical composition, comprising, in asso¬ ciation with a pharmaceutical vehicle, a compound according to anyone of Claims 1 to 11.
14. 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 freezedryed powder associated with an ampoula of a physio¬ logically acceptable solvent, particularly alcohol, such as ethanol at the dosage of 5 mg per ampoula.
15. process for the preparation oi nitroso¬ urea αerivatives of the following formula. I : in which : ϊi 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, option¬ ally substituted by one or several, particularly up to 3, halogen atoms, ι;θp,l Hp,CF. groups or alkoxy groups om 1 to 4 carbon atoms X represents a hyαroxy group or an NR_.Rp group Y represents a hydrogen atom V a hydroxy group or an N 1 R' group w ere R, and/or K' Λ represent a hydrogen atom or a _Ci\CK. H Hal group, Hal being halogen, pref er II I ^ 0 uv ably Cl, and R, and/or R' each represent a hydrogen atom, an alkyl group comprising 1 to b carbon atoms, an aral¬ kyl group comprising 7 to 12, preferably 7 to 9 carbon atoms, a cycloalkyl group comprising from 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, iθ ,i'iH , C . groups or alkoxy groups from 1 to 4 carbon atoms R' and R" represent hydrogen, OH, OM , M re¬ presenting 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 irom 7 to 12, preferably from 7 to 9 caroon atoms, he aryl and aralkyl groups being optionally substituted by one or several particularly up to 3, halogen acorns, 02.MH2,CF> 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, unεubs ifuted or substituted by one or' several, parti¬ cularly up to 3, N0 ,i\H2,CF^ groups, halogen, a.lkoxy from 1 to 4 caroon atoms, orovided that at least D X represents II. 1 wich R. reoresentinr CN'Jrt, CH.Hal \ ' " 11 t ^ 2 0 NO or Y represents I /R'ι with R' representing X*', CiCHpCH..Hal it i <. <_: 0 NU and provided that either R' or R" represents hydrogen, and R1 and R" cannot simultaneously represent hydrogen, said process consisting of reacting in a first step an oside group of the following Formula I Bis: in wmcn K, K' and R" have the aboveindicated mean mgs, Λ1 represents a hydroxy or HR group ; "ϊ ' represents a hydrogen atom, hydroxy group, or NH ' group ; Kp and Jri'p 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 sub¬ stituted by one or several particularly up to 3, halogen atoms, groups or alkoxy groups from l to 4 car con atoms, and in which one at least of tne groups X' or Y' repre¬ sents iHR,. or I EIK' on a 2ethylhalogeno isocyanate, to convert the i.HRp or i'lH 'p group of the compound of formula I bis respectively into NH _.HCH CH Hal, Hal being a halogen atoms, particularly chlorine, and in the second step, subjecting the compound obtained in the preceding step to nitrosation, by mea.ns of a nitrite of an alkali metal, preferably, sodium nitrite to convert the NR2CNKCK2CH2Hal or NR' 2CNHCH CH Hai groups respectively 0 0 into NRCN CH„CH Hal or NR' CNCH_CH_Hal. £,, , __ .: 2 , 2 2 0 NO 0 NO.
16. Process "_cor ing to Claim 17, for preparing 5 nitrosourea derivatives of the following formula II : in which R represents a hydrogen atom, an alkyl group 15. 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 particularly by one or several, particularly up to 3, halogen' atoms, ϊ*.0.rNH.,, C j groups ■ of alkoxy groups from 1 to 4 carbon atoms, 20 X represents a hydroxy group or an NR..Rp group Y represents a hyαrogen atom, a hyαroxy group or an group v ere R1 and/or '. each represent a hydrogen atom or a 5 CNCHpCHpHal group, Hal being a halogen, pre II t ^ < 0 O ferably Cl. and Rp and/or R'2 each represent a hydrogen atom, an alkyl group comprising 1 to b carbon atoms, an aralkyl 0 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, N0 ,NK2, 5 CF, groups or alkoxy groups of 1 to 4 carbon atoms, 95 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 f om 4 to 10 carbon atoms, an aralkyl group comprising 7 to 12, prefer ably 7 to 9 carbon atoms, the aryl and aralkyl groups being optionally substituted by one or several, particularly up to 3 halogen atoms, NO ,NH_ ,CF. 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 subs¬ tituted by one or several, particularly up to 3, N02, H2,CF3 groups , halogen, alkoxy from 1 to 4 carbon atoms, provided that at least X represents N ^Rl with R, representing CNCHCHHal ""*"• p n i ^ ^ 2 0 NO or Y represents M ^^ R'l with R ' , representing CNCHCHHal. O NO .
17. Process according to Claim 17, for preparing r.itrosourea derivatives of the following formula III : which 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, option¬ ally substituted particularly by one or several, parti¬ cularly up to 3, halogen atoms, N02,NH2,CF, groups or alkoxy groups of 1 to 4 carbon atoms, X represents a hydroxy group or an NR.R2 group Y represents a hydrogen atom, a hydroxy group oorr aann grouo OMPI where R 1 and/or R ' .. ea ch repres ent a hydrogen atom or a CIΪCHpCHpHal group , Hal being a halogen, pre II » ' ' 0 NO ferably Cl, and R. and/or κ'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, particu* larly up to 3, halogen atoms, N02,NH2,CF. groups or al^ koxy 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, prefer¬ ably 7 to 9 carbon atoms, the aryl and aralkyl groups being optionally substituted by one or several , particularly up to 3 halogen atoms, N02,NH2,CF, groups or alkoxy groups from 1 to 4 carbon atoms , or M representing an acyl group f om 2 to 8 carbon atoms, preferably 2 or 3 , an aroyl group from 5 to 12, preferably 5 to 9 carbon atoms, unsusbstituted or subs¬ tituted by one or several, particularly up to 3, NO_ ,NH_ ,CF. groups, halogen, alkoxy from 1 to 4 carbon atoms, provided that at least X represents N '•Rl with R, representing CNCHCHHal """" R " ' 2 O NO or Y represents N "R,ι with R' representing CNCHCHHal, ' I 1 tl I ___ ___ O NO 97 .
18. Pro cess according to Claim 19^ f or preparing compounds of the following formula VI : in which R, K', X and Y have the meanings indicated in Claim 19.
19. irToc ess ac cording to Claim 19 , for preparing compounds of the following formula VII : in wnich R, R', X and Y have the meaning indicated in Claim 19.
20. Process according to Claims 17 to21, for pre¬ paring 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 ; K' or R" represent an OM group, ... being a alkyl group comprising from 1 to 12 carbon atoms, an aryl group comprising from 4 to 10 carbon atoms ; X represents an R 2 group, R.. representing σr('CH..CH.Ha.l, Hal being halogen, preferably Cl, II 1 . . O NO Y represents a hydrogen atom or a hydroxy group.
21. Process according to Claims 17 to 21, for the preparation of compounds 1, II, v, V'i or ll in which OMPI R represents an alkyl group from 1 to 12 caroon atoms , alogenoaralkyl from 7 to 12 carbon atoms ; R' or R,! represent an OM group , ivi being an acyl group of 2 to 6 caroon atoms , an aroyl group from 5 to 5 12 carbon atoms ; A represents an I.R ..R., group , R .. repres enting CNCH .CH^Hal , Hal being halogen, particularly Cl II t ^ < 0 NO Y represents a hydrogen atom or a hydroxy !0 ∑rroup .
22. rrocess accorαing to Claims 17 to 21, for preparing compounds of formula 1, il, V, VI or VII in which R represents an alkyl group from 1 to 12 carbon 15 atoms, an aralkyl group from 7 to 12 carbon atoms ; R* or R" represent OH ; X represents an ιsi_., group, . representing ,,CKpKal, Hal representing halogen, particularly Cl 0 Y represents a hydrogen atom, .
23. • Process accorαing to Claims 17 o 21, for preparing compounds of formula I, II, V, VI or VII in which 5 , R represents an alkyl group from 1 to 12 carbon atoms, an aralkyl group fm 7 to 12 carbon atoms ; R1 or R" represent OH ; X represents an alkylamino group, in which the alkyl group has from 1 to b carbon atoms, or arylamino in 0 which tne aryl group has 4 to 10 carbon atoms, and Y represents i'.R'..R' , R'.. representing Hal being a halogen, particularly Cl.
24. Process according to Claims 1 to 21, for 5 preparing compounds of formula I, II, v, VI or VII in w i ch '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, . ϊ represents i.K'R'^, R' ~ representing CNCH.^CH^nal, Hal representing a halogen atoms, par¬ n . υ ϊ.υ ticularly 01.
25. rocess for the oreoaration according to laim ^f. of compounαs of formula ?CHoCI .
26. 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.
Description:
NITROSOUREA DERIVATIVES, PROCESS FOR THEIR PREPARATION AND MEDICAMENTbi CONTAINING THEM

BACKGROUND OF THE INVENTION

The present invention relates to novel nitroso- urea derivatives and, more specifically, to novel 2-des- oxy-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 with¬ in the framework of pharmacological experiments and clini¬ cal treatment : this is the case, in particular, of (1,3- bis-2-chloroethyl)-l-nitrosourea [BCNU] marketed unde-- the trademark "BICNU" (cf. Dictionnaire VIDAL 1984), of 1-(2-chloro-ethyl)-3-cyclohexyl nitrosourea [CCNU] market¬ ed under the trademark "BELUSTINK" (cf. Dictionnaire VIDAL 1984) and 1-(2-chloro-ethyl)-i-(4-me * chyL-cyclohexyl)- nitrosourea fide CCNUj : cf. G-. MATHE and Y. KEN13 : Ex¬ pansion Sciehtifique, 1975, 3rd Ed., _1LH c.himiotherapie des cancers (leucemies, hematosarcomes et tumeurs solides)" and T.H. WASSERMAN, M. SLAVIK & S.K. CARTER, Cancer Treat. Rev., 1974, ±, p. 131, "Review of CCNU in clinical cancer therapy". ' Cr.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 th'-: doses at which they are revealed to be active. Con ¬ sequently, 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 nitron

soureas whose hydrophilic character is increased with re¬ spect 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, 5 "The oncostatic and immunosuppressive action of new nitro- sourea derivatives containing sugar radicals". Thus these authors have established the oncostatic action of the fol¬ lowing four compounds on L 1210 leucemia anu their low toxi ¬ city: 1-(2-chloro-ethyl)3-(ribofuranosyl-2' , 3'-isopropyli-

- jQ dene-5-paranitro benzoate)-nitrosourea [R_.'CNU] , 3-(2-chloro- 1-ethyl-2 , -desoxy-glucopyranosyl-14, 3 1 ,4",6 » -tetracetate)- nitrosourea GCNU] , 1-(2-chloro-ethyl) 3-(ribopyranosyl- 2' ,3' ,4'-triacetate)-nitrosourea [RPCNU] and 1-(2-chloro ethyl) 3~(xylopyranosyl 2' , 3' ,4'-triacetate)-nitrosourea

15 [XPCNUJ . 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,. 0 within the scope of the experiments carried out on these products, recourse has preferably been had to their soli¬ dification by blocking the hydroxy groups.

In a subsequent work J.L. MONTERO et al (Eur. J. Med. Chem. Chimica Therapeutica, mars/avril 1976, 1 , 5 n 2, p. 183-187 : "Synthese de nouvelles glycosylnitroso- urees a visees oncostatiques - les 1-nitrosoureido-1- desoxy-glucopyranoses") , described glycosyl-ni ro soureas in which the sugar-nitrogen bond is located in an anomeric position, which has oncostatic activity, namely 1- C3-(2-

30 chloro-ethyl) 3-nitroso-ureido ] -1-beta-D-glucopyranose and 2, 3,4,6-tetra-O-acetyl 1- [3-(2-chlor-e h l) nitroso- 3-ureido ] -1-desoxy-beta-D-glucopyranose, and which repre¬ sents in addition the advantage of lower toxicity on the bone marrow and not being diabetogenic, whereas streptozo-

35 tocine or 2-deso:_y-2-( 3-methyl-2-nitrosoureido)-D-gluco- pyranose, 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 pro- vide novel nitrosourea derivatives, for which the profile of the activity curve sho ό its maximum at a. dosage far below the threshold of the toxicity.

Another aspect of the invention is to provide no¬ vel nitrosourea derivatives having a αood therapeutic index. It is another aspect of the invention to pro¬ vide 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 syn- thon, which is a 2-desoxy-sugar or a 4-desoxy-sugar.

It has been observed that by resorting to 2- desoxy-sugar or a 4-desoxy-sugar, substituted on the 3 and/or at the 6 carbon of the above-said sugar, by a ni¬ trosourea group, and which can carry different substitu¬ ents on the carbon at the 4 position of the above-said sugar, when it relates to a 2-desoxy-sugar or on the car¬ bon at the 2 position of the above-said sugar, when it relates to a 4-dssoxy-su ar, novel nitrosourea derivatives are obtained whose activity is considerably increased and whose toxicity is low with respect to the compounds al¬ ready known. One of the interests- of these derivatives can b e connected with the hvpothesi-s accor d in g tc w h ic h t h e 2- d esox y - su q ars a n d she 4- esoxy-suqars have a certain la b ility at the level of the oside linkage ,w h ic h can resu l t in th e for-

ation 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 cor¬ respond to the following general formula (I) :

in which : ~ -R represents a hydrogen atom, an alkyl group ιfrrm1 to 30, preferably 1 to 12 carbon atoms or an aralkyl group * rm7 to 12, preferably 7 to 9 carbon atoms, option¬ ally substituted by one or several, particularly up to 3, halogen atoms, NO p , NH p , CF^ groups or. alkoxy groups of 0 1 to 4 carbon atoms,

-X represents a hydroxy group or an NR.R group

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

-C-N-CH p CE p Hal group, Hal being a halogen, preferably Cl,

0 NO and and/or R' each represent a hydrogen atom, an alkyl 0 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, par- 5 ticularly up to 3, halogen atoms, NO j H p jCF. 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 car¬ bon atoms, an aralkyl group comprising from 7 to 12 , pre- ferably from 7 to 9 carbon atoms , the aryl and aralkyl groups being possibly substituted by 1 or several,, parti¬ cularly up to 3, halogen atoms , N0 2 ,NH 2 ,CF^ groups or al¬ koxy groups frαn 1 to 4 carbon atoms , or " . , representing an acyL group frαπ 2 to 8 carbon atoms, preferably 2 or 3, or an aroylgroup frαn 5 to 12, preferably 5 to 9 carbon atoms , un— substituted or substituted by one or several, particularly up to 3, NO , NH CF , groups, halogen, alkoxy- of 1 to 4 carbon atoms, provided that either R * or R" represents hydrogen , R ' and ' R" - being not simul taneously hydrogen and

provided that R ή

representing w th R' - representing -C-N-CH p CH p Hal

0 NO

In a preferred class of compounds of the invention, R 1 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",CH p Y and X on the one hand and the ring structure on the other hand, by the symbol v- ^ — . This representa¬ tion means that each of the R,R' ? R",CH p Y and X groups can be either at the oi position or at t e 3 position, accor- ding to the HAYWORTH representation, and in an arrange¬ ment compatible with the stereochemical requirements.

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

in which

- R represents a hydrogen atom, an alkyl group rom 1 to 30 , preferably 1 to 12 carbon atoms, or an aralkyl group from 7 to 12, preferably 7 to 9 carbon atoms, option- nally substituted by one or severals. particularly up to 3, halogen atoms. NO-.NH-.CF., qroups or alkoxy qroups from 1 to 4 carbon atoms. - X represents a hydroxy group or an NR..R p group

- Y represents- a hydrogen atom, Rl a hydroxy group or an 1 * .-" ' 1group

where R_. and/or R'.. each represent a hydrogen atom or a -C-W-CH 9 CH 9 Hal group, Hal being a

0 NO halogen, preferably Cl, and p and/or ' p 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 car¬ bon atoms, a cycloalkyl group co -

prising from 3 to 6 carbon atoms, an aryl group from 4 to 10 carbon atoms, the aryl and aralkyl groups being optionally substi¬ tuted by one or several, particularly up to 3 halogen atoms, NO-, NH, , CF, group or al¬ koxy 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, par¬ ticularly up to 3 halogen atoms, NO, , NH, , CF, groups or al¬ koxy 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, particular¬ ly up to 3, NO,, NH, , CF.. groups, halogen, alkoxy from 1 to 4 carbon atoms, provided that at least X represents -N— R. with R- re- R. presenting -CII-Ni-CH2,CH2,Hal

O NO or Y represents -N- R with R ' representing

-C-N-CH ,CH , H al I i I 2 2

O NO

These compounds of formula (II) represent the par¬ ticular 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 :

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-xylo- hexopyranoside .compounds. Among the compounds of Formula (II), a preferred class of compounds according to the invention is consti¬ tuted by those of Formula IV below :

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

The compounds of Formula (IV) belong to the clas class of 4-des.oxy,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 :

- 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, option¬ ally substituted by one or several, particularly up to 3, halogen atoms. NO, .NH,,CF, groups or alkoxy groups of 1 to 4 carbon atoms . -X represents a hydroxy group or an NR.Rp group

-Y represents a hydrogen atom, a hydroxy group or an group - where R. and/or R' . each represent a hydrogen atom or a -C-N-CH p CH p Hal group, Hal being υ no halogen, preferably Cl,

and p and/or R* p 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 aral¬ kyl groups being optionally substituted by one or several, particularly up to 3, halogen atoms, N0 p , H p ,C ^ groups or alkoxy groups of 1 to 4 carbon atoms

R' represents preferably OH, but OH can be replaced by O . 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, NO,,NH,,CF 3 groups or alkoxy groups from 1 to 4 carbon atoms, or M representinσ an acyl group of 2 to 8 carbon atoms, prefe__ably 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, N0 2 ,NH 2 ,CF 3 groups, halogen, alkoxy of 1 to 4 carbon atoms provided that at least X represents - , with R.

\ H

Λ' 1 R' -, representing -C-N-CH p CH p Hal, or Y represents -N with 0 NO

H' -, representing -C-N-CH p CH p Hal

0 NO

These compounds of Formula V represent the particu- lar 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 :

,u dD/ u_.U5u PCT/EP84/00260

10

5 in which R, R', X and Y have the previously indicated mea¬ nings.

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

Among the compounds of formula (V) , another pre- 10 ferred class of compounds provided by the invention is cons¬ tituted by those of the following formula (VII) :

in which R, R', X and Y have the previously indicated mea¬ nings.

These compounds belong to the class of 2-desoxy, alpha-L-arabinohexopyranoside compounds. 20 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 ;

25 - R ' or R" represents an OM group, M being an al¬ kyl 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- -CH„CH,Hal , Hal being a halogen, particularly Cl ;

30 0 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 : 35 - R represents an alkyl group from 1 to 12 carbon

atoms, halogenoaralkyl f^" 1 4 to 10 carbon atoms ;

- K* or R" represents an O group, M being an acyl group of 2 to 3 carbon atoms, an aroyl group <f ^>5 to 12 carbon atoms ; - X represents an NR_,R p group, R_. represen¬ ting -C-N-CH p CH p Hal, Hal.being a halσgen, particularly Cl,

0 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 c i to 12 carbon atoms, an aralkyl group ft™ 7 to 12 carbon atoms ; - R' or R" represents OH ;

- X represents an R.R p group, R 1 representing -C-N-CH p CH p Hal, Hal representing a halogen, particularly

0 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' ..NR' p , R' representing

-C-N-CHpCHpHal, Hal representing a halogen, particularly .

0 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,

5 - Y represents NR'.-R' p , R'.. representing

-C-N-CH p CH p Hal, Hal representing halogen, particularly t l 1 c. .

0 NO Cl.

Another class of preferred compounds according 0 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, 5 - X represents an NR..R p group, R_, representing

-C-N-CH CH p Hal, Hal being a halogen, particularly Cl,

0 NO

-. Y represents an alkylamino group, in which the alkyl group has 1 to 6 carbon atoms or arylamino in 0 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 ro 1 to 12 carbon 5 atoms, aralkyl frσπ7 to 12 carbon atoms ;

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

- X represents a group NR.R p , R- | representing 0 -C-N-CH CHpHal, Hal being a halogen, particularly Cl,

0 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 1 represents an 0M group, M being- an acyl group of 2 to 8 carbon atoms, an aroyl group frαn5 to 12 carbon atoms ;

- X represents an NR^ p group, R_. representing -C-N-CH CH p Hal, Hal being a halogen, particularly Cl,

0 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 frαn7 to 1-2 carbon atoms; ' - R f represents OH ;

- X represents an -NR.R p group, R_. representing -C-N-CH p -CH p Hal, Hal being a halogen, particularly Cl,

0 NO

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

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

- X represents an alkylamino group , in whi ch 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' .R' p , R * - representing -C-N-CHpCHpHal , Hal being a halogen, parti cularly Cl .

H I *- ^

0 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 car-

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

- X represents a hydroxy group,

- Y represents -NRV.-k' p , R * - I representing -C-N-CH p CH p Hal, Hal being a halogen, particularly Cl.

H I C. . 0 0 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 NR_,R group, R-, representing -C-N-CH p CH. ial, Hal being a halogen atom, particularly Cl, ii t -£ -£

0 NO 0 - 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 5 2,3,6, -ifcridesoxy cX-U-arabinohexopyranosyl-nitrosoureas, 2,3- didesoxy-c-D-arabinohexopyranosyl-nitrosoureas, 2,6- didesoxy- -D- arabinohexopyranosyl-nitrosoureas, 2,3,6- tridesoxy c - -arabinohexopyranosyl-nitrosoureas, 2,3- didesoxy-c-L-arabinohexopyranosyl-nitrosoureas, 2,6- 0 d i d esoxy -^-L-ara b inohexopyranosyl-nitrosoureas, 3-4 > 6_ tridesoxy cX -D-xylohexopyranosyl-nitrosoureas, 3 . 4-dides-fe * oxy <Λ-D-xylohexopyranosyl-nitrosoureas, 4,6-didesoxy < -D-xylohexopyranosyl-nitrosoureas, 3 . 4, - ridesoxy σ< ^ -L-xylohexopyranosyl-nitrosoureas, 3 . 4-didesoxy ( -L-

xylohexopyranosyl-nitrosoureas, 4,6-didesoxy alpha- -xylo- hexopyranosyl-nitrosoureas.

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

IC 84 1530 IC 83 1183

IC 83 1184 IC 83 1350

IC 83 13 75 IC 83 13 74

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 inven¬ tion, which consists of reacting, in a first step, an 5 oside group of general Formula (I bis)

- in which R, R' and R" have the meanings indi¬ cated above.

-■- - X 1 represents a hydroxy or -NHR p group;

- Y' represents a hydrogen atom, a hydroxy group 5 or -NHR » 2

- p and R' p identical or different, represent independently of one another, a hydrogen atom, an alkyl group frOmi to 6 carbon atoms, an aralkyl group frσn 7 to

12 carbon atoms, aryl fraj * 4 to 10 carbon atoms, cyclo- 0 alkyl frσn 3 to 6 carbon atoms, the aryl and aralkyl groups being optionally substituted by 1 or several particularly up to 3 > halogen atoms, NO p ,iNHpCF, groups or alkoxy groups frcm 1 to 4 carbon atoms, and in which one at least of the groups X' or ϊ' repre- 5 sent HR 2 or 1NHK' 2 on 2-halogeno-ethyl isocyanate to convert the - HR p or NHK' p group of the compound of Formula I bis respectively into N 2 C NHCH 2 CH 2 Hal or HK' 2 C NHCH p CHgHal, 0 ' 0 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 ni¬ trite of an alkali metal, preferably sodium nitrite, ±0 convert the - R 2 C NH CH 2 CH 2 H l or -NR' C NHCHgCHgHal 5 groups respectively into -NR C -N CH y CH p Hal or

^11 I ^ *-

0. NO

-NR' 2 C -JNCHgCHgHal. 0 NO

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

In the case where Y' represents - HR' , the process described above can be illustrated by the fol¬ lowing diagram :

25

ι " he 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

in which:

- R and R' are such as defined above ;

- - - X' represents an -NHR 2 or hydroxy group ;

- Y' represents a hydrogen atom, a hydroxy 5 group or -NHR' p

-R 2 and R' p , 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 to 10 carbon atoms, cycloalkyl from 0 3 to 6 carbon atoms, the aryl and aralkyl groups being optionally substituted by one or several, particularly up to 3, halogen atoms, groups Op, NH p ,CF-, or alkoxy groups from 1 to 4 carbon atoms, and in which one at least of the.. groups X' and Y* repre^ 5 sents -NHR 2 or NHR' 2

On a 2-halogeno- eth l isocyanate to convert the - riRp °^ NHR'p group of the compound of Formula VI bis respec¬ tively into

NR 2 C „ NH CH 0 2 0H o 2Hal or NR' 0 2 C „ NH 0H 2CH2Hal,' Hal being a

30 0 0 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-

35 vert- the groups - R 2 C NHCHgCHgHal or -NR' 2 C NHCH 2 Cri 2 Hal δ δ respectively into -NR y C N CH CH~Hal or NR C N CH CH_Hal .

i'he 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

(Vllbis)

in which:

- R and R' are such as defined above ;

- X' represents an -NHR or hydroxy group ;

- Y' represents a hydrogen atom, a hydroxy 15 group or -NHR'

-R and R' p , identical or different, represent independently of one another a hydrogen atom, an alkyl group fro l to 6 carbon atoms, an aralkyl from 7 to 12 carbon atoms, aryl from 4 to 1U carbon atoms, cycloalkylfrom 0 3 to 6 carbon atoms, the aryl and aralkyl groups being optionally substituted by one or several, particularly up to 3, halogen atoms, groups NO,-,, NH 2 ,CF-, or alkoxy groups from 1 to 4 carbon atoms, and in which one at least of the_.groups X 1 and Y' repre-=-

-.'5 sents -NHR or NHR'

On a 2-halogeno- eth l isocyanate to convert the -Nril or NHR ' p group of the compound of Formul VII bis resp ec¬ tively into N 2 0 1NH CH 2 CH 2 Hal or NR ' 2 C NH CHgCH p Hal , Hal being a

30 δ 0 halogen atom, particularly chlorine, and in a second step to subj ect the comp ound obtained at the end of the preceding step to nitrosation, by means of an alcali metal nitrite , pref erably sodium nitri te to con-

35 vert the groups - R 2 C NHCH^CHgHal or -NR ' C NHCH^Cri^Hal δ δ respectively into -NR.. C N CH,.CH Hal or -NR, C N CH,CH,Hal

-. - , 1 ' ^ . 2. „ i __ __

O NO 0 NO

7. '-. ' ' " - "' ••

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 pro¬ cesses described below.

I Preparation of the compounds of formula

IA First modification The compounds of formula

R, R' , R", R, and Y 1 having the previously indicated mea¬ nings , which enter into the preparation of the compounds of formula :

R Hal = halogen

NR„CNCH,CH,Hal ONO Z of the invention, can be obtained from the compounds of formula :

OMPI

^,

which are subjected :

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

0 convert the amine into an imine ;

- in a second step, to the action of a reducing agent, such as a hy ' .dride, for example sodium borohydride or sodium cya- noborohydride, 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 :

in which R, R' , R", R ', , X'. have the above indicated mea¬ nings ; and to obtaining- compounds of formula :

and in which R, = R ' , .

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

The compounds of formula

R, R 1 , R", Y' and R_ having the previously indicated mea¬ nings which enter into the preparation of the compounds according to the invention of formula :

Hal = halogen

NR,CNCH,CH~Hal ^ONO can also be prepared from the compounds of formula

which are subjected to the action of an alkyl halogenofor- mate, of formula HalCOR, , 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

NHC | |OR2, group into NHR,2.

O

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

as well as to those of formula :

NR 2 CNCH 2 CH 2 Hal

ONO

II Preparation of compounds of formula

The compounds of formula

in which R, R' and R" have the above indicated meanings and Y 1 represents a hydroxy group can be obtained from com¬ pounds of formula :

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

u

. * •r

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 -NH, group ' s in the 3 position is protected, particularly by reacting the pre¬ viously represented compounds with trifluoroacetic anhydri¬ de 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 -COCF-. being simultaneously hydrolized. The compounds of formula : -

OMPI

in which R, R' and R" have the above indicated meanings and Y 1 represents a hydrogen atom, can be obtained from com¬ pounds of formula :

in which R, R' and R" have the above indicated meanings and Hal represents halogen, particularly bromine, these com¬ pounds being reduced, particularly by catalytic hydrogena¬ tion, 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 com¬ pounds 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 hy¬ drogenation, for example in the presence of palladized car¬ bon.

Ill Preparation of compounds of formula :

Hal = halogen, parti¬ cularly Br

The compounds of formula

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

phenyl

N. R' 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 hydrogena¬ tion, 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 1 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 sub ected to an a Vlcohol of formula ROH, in an acid medium to give the compounds of formula

which 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 treat¬ ed with an alkylating agent, such as.lV SO, or MX, X re¬ presenting halogen, M representing an alkyl group from l 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 aral¬ kyl groups being optionally substituted by one or several, particularly up to 3 halogen atoms, N0 p , NH p , C -, groups or alkoxy from 1 to 4 carbon atoms, or representing an acyl groupfrom 2 to 8 carbon atoms, preferably 2 or 3, or an aroyl group from 5 ' to 12, preferably to 9 carbon atoms, un- substituted or substituted by one or several, particularly up to 3 N0 2 ,NH p ,CF-, 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

M having the above- indicated meaning

IV Preparation of compounds of formula

T e compoun s o t e ormu a

in which R, R' and R" have the above indicated meanings and X 1 represents an OH group, can be obtained from the com¬ pounds of formula :

in which the OH functions at the 4 and 6 positions are pro¬ tected, by causing the above described compounds to react, for example on acetic anhydride, in the presence of pyri¬ dine to protect the hydroxy group at the 3 position, to gi¬ ve the compounds of the formula :

Ac = acetyl

which, in the presence of N-halogeno succinimide, prefera¬ bly N-brornosuccinimide, and barium carbonate give the com¬ pounds of formula :

BzO Bz = benzoyl

OAc R" which ' are subjected to an azotide, particularly an alkali metal azotide, such as sodium, in the presence of dimethyl¬ formamide, to give the compounds of the formula :

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

OH R" which can be subjected to M,SO. or MX (X = halogen) in the presence of a base such as NaOH to give the compounds of the formula :

OH R 1 with MO = R ' , M having the above indicated meaning, The compounds of formula :

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

"« tr

. .. .. * ..=-«•- - '■ > • ' - -

can be. obtained from the compounds of the formula :

in which Hal represents a alogen atom, particularly bromi¬ ne, which are subjected to the reaction of an azotide, par¬ ticularly, of an alkali metal, such as sodium azotide, to give the compounds of formula :

3 3 R" in which, the benzoyl group is removed, for example, by the addition of a base, particularly of an alkali alcohola- te 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, particu¬ larly by means of benzyl chloride to obtain compounds of formula :

O FI

then by adding an alcohol of the formu a ROH , in an acid medium, to obtain the compounds of the formula :

then by removing the protective group of the hydroxy func¬ tion 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 M,SO. 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 , NO, , NH, , CF.. groups or alkoxy of 1 to 4 carbon atoms, or repre¬ senting 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, par¬ ticularly up to 3 0 2 , NH-,, CF 3 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 1 = MO, M having the above indicated meaning.

The processes which have just been described abo¬ ve are advantageously applied to the preparation of the compounds usable for the synthesis of compounds of formu¬ 0 la (VI) according to the invention.

More precisely, the process described in the para¬ graph I, enables the preparation of compounds of the formu¬ la :

in which R, R' , X' , Y' , R_ and R' have the above indica¬ ' 0 ted 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 0 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 1 , X' have the above indicated meanings.

According to a preferred embodiment of the pro¬ cess according to the invention, the compounds of the ge¬ neral 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 1 are as defined above,

OlvTPI

X" is an azide, hydroxy, NH 2 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, 5 an H 2 group, hydroxy group or an NHR' 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 cycloalkylfrom 3 to 6 carbon atoms, the aryl and aralkyl groups being optionally substituted by Q one or several, particularly up to 3 » halogen atoms, NO p , NH p , C ^ 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, hy¬ drogen or hydroxy group or in a case where "X" is a 5 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 from1 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 Q where * -D-arabinohexopyranoside is deoxylated at

2,3j6-, the compound..obtained then being reduced, par¬ ticularly by catalytic hydrogenation, for example in the presence of palladized carbon to convert the azide group into NH p , 5 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 car¬ bon atoms or aralkyl from 7to 12 carbon atoms and where ^X.- D-arabinohexopyranoside is trideoxylated at 2,3,6-* Q the compound obtained being then reduced, particularly

by catalytic hydrogenation, for example in the presence ' of palladized carbon, to convert the azide group into an H 2 group, c) or with trifluoroacetic anhydride, in the case where 5 X" is an NH p group and Y" is a hydroxy group, a hydro¬ gen atom or in the case where X" is a hydroxy group and ϊ" is an NH 2 group, R is an alkyl group from 1 to 12 carbon atoms or aralkylfrom 7 to 12 carbon atoms .and R* a hydroxy group, the trifluoro acetamide 3- -D-ara- 0 binohexopyranoside obtained being treated with an al¬ cohol in acid medium to obtain the 3-ajain-o compound of the corresponding general formula and where o^—D— "' •' arabinohexopyranoside is dideoxylated at 2,3, or tri- deoxylated at 2,3 » 6- ; d) or with an aldehyde in an alcoholic medium, " in the case * where X" is an H 2 group, Y" is a hydrogen atom, an H 2 group or NHR' 2 group or a hydroxy group or in a case -where X" is a hydroxy group and Y" is NH p or NHR' p group and R and R » ' are as defined above, to ob- 0 tain respectively the 3-desoxy 3-iπιino 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 -D-arabinohexopyraneside 3-nitrosourea of the corresponding general formula VI, 2,3- or 2,6 - dideoxylated or 2, 3,6-trideoxylated. To prepare the c -D-arabinohexopyranosides-nitrosoureas according to the invention, procedure is preferably as follows : 0 Modification a) of the process :

To a s.olution of methyl 3-azido 4-ϋ-acyl (or arylester) 6-bromo 2,3,6-tridesoxy cχ-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 5 paratoluenesulfonic acid.

The solution is heated to reflux for 12 to 8 hours. After cooling, the reaction medium is poured onto a saturated sodium bicarbonate solution, then extracted

with ether. The organic phase is evaporated to dry¬ ness and gives a crude residue which is chromato- graphed on silica to give the ether of the general formula I corresponding to the alcohol. Modification b of the process -.

An alk l-or aralkyl-3-azido-β-bromo-2,3,6- ri¬ desoxy ( -D-arabinohexopyranoside, and preferably methyl-3-azido-6-bromo 2,3, -tridesoxy ύ -D-arabino- hexopyranoside, 0.01 mole, are placed in solution in a suitable solvent such as anhydrous tetrahydrofuran (100 ml) or in another volvent such as dioxane, iso- propyl 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 8 hours. After cooling and the slow addition of water, it is stirred at 20 C for 2 hours. The organic phase is withdrawn by decantation, then the aqueous phase is again extracted with 100 ml of tetrahydro- furan. The organic .phase, dried over sodium sulfate is evaporated to dryness. 60 to 90 ft of the desired compound are obtained, which is purified by chromo- tography on silica. •Modification c) * of the process : Trifluoroacetic anhydride is reacted with methyl

3-amino 2,3,6-tridesoxy c -D-arabinohexopyranoside prepared by the method of J. BOIVIN et coll., Carb. Res. 85 , (1980) 223-42 to obtain methyl-trifluoro 3- acetamido-CX-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 trifluoro- 3-acetamido derivative so-obtained, in 200 ml of n- hexane, 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-

39

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 P p 0,-. The secondary amine obtained is recrystallized in alcohols.

The process is the same in the case where th ' e 3-amino group is replaced, in the starting compound, " by a 3-hydroxy group, the amino being in the 6 posi¬ tion. 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 :

1 - 2ϊ .ι5-^._.2 2_ M2^

ETHERIFI CATION

R = Ethyl , benzyl , etc .

11 - 2I 25- _2_ Ϊ-S_-^ :

_[MO= R ' a - Ran M - methyl, ethyl, benzyl , etc ..

III - 2IAG M^F_TPffi_MODIF^ATION_c2_OF_THE_PROCESS WITH BLOCKING OF THE AMINE AT THE 3 POSITION

IV - D^Gg^_OT- Iffi^lODIPIC 0^d2-CJP_ra^MOCESS

with R = R 1

To prepare the c -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-meth lhydroxylamine hydrochloride and sodium acetate to obtain the compound of the following formula

j_>y treating the compound obtained previously by diborane and 0H~ " ions, the compound of formula

is obtained. rhis compound is then "created with 2-chloro ethyl isocy- anate, to give the compound of formula

2 CM 2 C1 This compound is then dissolved, for example in formic acid, then treated with sodium nitrite, to give the compoundsof the formula

To prepare the ^-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 for¬

which in a first step, is treated with 2-chloro ethyl iso- cyanate, to give the corresponding urea, that is to say methyl 3- C3-( -chloro ethyl) ureido] -3,4,6-tridesoxy ^-D-xylohexopyranoside of the formula

The compound indicated, above, by treatment with sodium nitrite in formic acid results in the corresponding nitro¬ sourea, that is to say methyl 3- j~ 3-(2-chloro ethyl) 3- u nitroso ureidoj 3 > 4, - ridesoxy c -D-xylohexopyranosiαe of the ior ula :

All the compounds which can be useα in the pre¬ paration 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 sui r¬ able reaction sequences described in the examples given below, by way of illustration.

EXAMPLES EXATPLE 1 Preparation of benzyl 3-azido 4-0- benzoyl 6-bromo 2, . 6-tridesoxy cλ- D-arabinohexop ranoside by resorting to the first modification of the process.

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

After cooling, the reaction medium is poured in¬ to a saturated solution of sodium bicarbonate then ex¬ tracted 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 chro- matograp ed on silica H with the mixture hexane/me ylene chloride, 2:1 as eluant..

1.5 g of benzyl 3-azido 4-0-benzoyl 6-bromo 2,3 . 6-tridesoxy (^-D-arabinohexopyranoside (84 ) are iso¬ lated.

MP ϊ 77 °C (hexane) - [<*] ^°; 20 ° ( c j 1# j CIICl , )

IB nuj ol : v 2 100 c " ' (W ) I 1760 , 1260 , 1030 cπf 1 ( ester) v 1600, 1585 * cm "1 (aromatic)

In the same mariner there is prepared, for sxample:

- Ethyl 3-azido 4-0-benzoy.l 6-I.ronιo 2,3,6-tr.i- desoxy (X-D-arabinohexopyrano__ide.

- p -chlorobenzyl 3-azido 4-0~be;ιzoyl 6-bromo

2 , , 6-tridesoxy c< -D-arabinohc-xopyranosido . 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 ,6- tridesoxy c -D-arabinohexopyranos ide .

* , * . j• * -π. c ~ Λ^

. methyl -azido 6-bromo 2, , 6-tridesoxy 4-0- ethyl O -D-arabinohexopyranoside . methyl 3-azido 6-bromo 2 , 3 , 6-tridesoxy 4-0- benzyl cX-D-arabinohexopyranoside . ethyl 3-azido 6-bromo 2, 3 , 6-tridesoxy 4-0- ethyl cX-D-arabinohexopyranoside . ethyl 3-azido 6-bromo 2 , 3 > 6-tridesoxy 4-0- benzyl C " -D-arabiηohexopyranoside . benzyl 3-azido 6-bromo 2, 3, 6-tridesoxy 4-0- ethyl £X-D-arabinohexopyranoside

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

3-fluoroacetamido 2, 3 , 6-tridesoxy CX.-D-arabinohexopyranoside in 100 ml of n-hexane, are added 5 nil 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 - [<*] D : + 66 (c : 0.556, CHC1 ) .

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 ζj( -D-arabinohexo- pyranoside

. ethyl 3-amind 2, 3 . 6-tridesoxy <_X_-D-arabinohexo- pyranoside . benzyl 3-amino 2,3-didesoxy CX-D-arabinohexopy- ranoside . ethyl 3-amino 2,3-didesoxy c * \ -D-arabinohexopy- ranoside.

EXAMPLE 4 Use of the fourth modification o * f the process. By proceeding in accor¬ dance with the fourth modification of the process it is possible to 5 prepare, among others, the following compounds, given by way of example: . methyl 3-ethylamino 2, 3.6-tridesoxy cX-D-arabi- nohexopyranoside . methyl 3-benzylamino 2, 3 ,6-tridesoxy CX-D-ara- 0 binohexopyranoside

. methyl 3-ethylamino 2,3-didesoxy c?\-D-arabino- hexopyranoside " ' " . methyl 3-benzylamino 2,3-didesoxy <_X-D-arabino- hexopyranoside . benzyl 3-ethylamino , 3.6-tridesoxy cK-D-ara- binohexopyranoside . benzyl 3-benzylamino 2, 3.6-tirdesoxy cX-D-ara- binohexopyranoside . methyl 6-ethylamino 2,6-didesoxy ( ~ -D-arabino- hexopyranoside

. methyl 6-benzylamino 2,6-didesoxy cΛ-D-arabino- hexopyranoside . benzyl 6-ethylamino 2,6-didesoxy Oi -D-arabino¬ hexopyranoside . benzyl 6-benzylamino 2,6-didesoxy Λ -D-arabino¬ hexopyranoside. 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 CX -D- arabinohexopyranoside . methyl 3.6-dibenzyl amino 2 , 3 , 6-tridesoxy C--D- arabinohexopyranoside . benzyl 3 , 6-diethylamino 2 , 3 ,6-tridesoxy CX-D- arabinohexopyranoside

. benzyl 3, 6-dibenzylamino 2, 3 , 6-tridesoxy <_ -D- arabinohexopyranoside.

8501050 PCTEP«4/ υ υ oυ

47 EXAMPLE 5

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

To a solution of 0.8 g (5 x 10 " mole) of methyl 3-amino 5 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,

3 0.4 ml (5.10 mole) of 2-chloro ethyl isocyanate. After 5 hours stir ring, the reaction mixture is evaporated to dryness under vacuum. The

10 residue, after purification by chromatography on a silicate column, with CHC1- : 95, MeOH : 5 eluant, gives a single spot product crystal lizing in anhydrous ethyl ether. The crystals were drained and then dried. (0.8 g, yield 60 ) . ANAIiϊSIS C 10 H ιg Cl NgO^ : 266.5 - Calculated °/. 0:45.0,

15 H: 7.1, N : 10.5 - Found C : 44.9, H : 7.0, N : 10.5. MP: 125 - 127°

KMR Spectrum Solvent : DM30. d g : 1.14 ( CH.-6' J =6Hz 1.46 (t(ά) H-2'axJ = ' 12 Hz, J" = 4Hz) 1.90 (dd H-2 « J= 12Hz, J'= 4Hz) 2.78 (t -H-4' J = J' = 9Hz) 3.19 (s 0GH 3

20 3, 8 ( 0H 2 -4) 3.42 (m H-5') 3.53 (m CH 2 ~5) 3.61 (ι H-3 1 ) 4.58 (d H-1* J = 3Hz) 5.99 (d NH J = δHz) 6.14 (t IxH J = J' = 6 Hz). * ΕXA [PLE 6 Methyl 3- [,3-(2-chloro ethyl) 3-nitros ureido " } 2 , 3 , 6-tridesoxy &\ -D-arabino- 5 hexopyranoside - Compound 2 (IC 81.

1183) 1.2 g (4.5.10 mole) of methyl 3- l3-( 2-chloro ethyl) ureido] 2 , 3 , 6-tridesoxy ( -D-arabinohexopyranoside were dissolved in 8 ml of formic acid. To the solution

30 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

35 sulfate and evaporated to dryness under vacuum. After purification on a ohromatograph column, with silicate su

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

5 oil.

This compound is crystallized in hydrochloride form.

ANALYSIS C 7 H 15 0 4 , HCl : 213.67 MP : 120°C (dec.) (XI ° : + ' 90° (c : 1$, H..0) .

EXAMPLE 9 Methyl 3- C3~( 2-chloro ethyl) 3-nitroso ureido] 2,3-didesoxy -D-arabinohexo-

"' " pyranoside - Compound 6 (IC 81.1184)

From compound 4, following the operational method already described, methyl 3-C3-( 2-chloro' ethyl)ureido] 2 ,3-didesoxy o< -D-arabinohexopyranoside, _5 is obtained by the action of 2-chloro ethyl isocyanate.

ANALYSIS C 10 H 19 C1N 2 0 5 : 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 Q I D - : + l6 8° (c:0.25$, CHC1 ) Then by nitrosation with sodium nitrite, in formic acid, Compound 6_ is obtained.

ANALYSIS C 10 H l8 Cl 0^; 311-71 - Calculated $ : C-38.5, H * 5.8, N 13.5 Found % : C: 38.4, H: 5-6, N: 13-6.

: 118.0° (c :

χ J = J' = 12 Hz, J" : 4Hz) 1.88 (d(d) H-2'eqJ=12 Hz J' = 4Hz) 3-28 (s 0CH 3 ) 3.43 (r H-4 * J=J' = 9Hz) 3-35 to 3-53 (m H-5', H-3 ) 3-49 to 3.67 5ab CH -6' J = 12Hz) 3.61 (t CH -4 J = J' = 6Hz) 4-10 (m CH 2 -5) 4-73 (d H-l' J=4Hz) 8.53 (d NH J = 9Hz).

Mass Spectrum (chemical ionization) : m/e 31 (Cl--, M + l, Basic peak) and m/e 314 (Cl--, 30%); m/e 280 (M+l-32, 30$) and m/e 282 (10$) .

EXAMPLE 10 Methyl 3-azido 6-bromo 2, 3 ,6-tridesoxy

(-X-D-arabinohexopyranoside-Compound 7 10 g (0.026 mole) of methyl 3-azido 4-0-benzoyl 6-bromo 2,3,6-tridesoy c -D-arabinohexopyranoside prepared according to Hanessian, J. Org. Chem. _J4 (1969)1045-1053, are dissolved in 100 ml of 1 M methanolic sodium metha- nolate. 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-6θ and gives 6 g (Yield 84$) of Compound J , -

(OH) 2100 cm "1 (N-) EXAMPLE 11 Methyl 3-azido 6-bromo 2, 3 , 6-tridesoxy

4-0-methyl X. -D-arabinohexopyranoside

- Compound 8 5 *5 g (0.021 mole) of compound J7 ars dissolved in 200 ml of anhydrous tetrahydrofuran. 20 g of soda are added anc \ 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 of: 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$) of compound 8_ is obtained. It is purified by chromatography on silica H (eluant hexane-methylene chloride 1:1). ANALYSIS CgH BrN 0 : 280.25 M J 0 : + 188° (c : 1$, CHC1 ).

-1 IRSpectrum : "vi N- 2100 cm

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

0-methyl CX 7 -D-arabinohexopyranoside

-Compound 9 5 ' 15 g (0.0l8 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 forrr The solution evaporated to dryness results in 3.5 g of crude product purified by chromatography on silica H, eluant CH 2 C1 2 - MeOH 9:1 ANALYSIS CgH 17 0 3 : 175.22 i ] 20 . + 109 o ( c . χ c 0 ) CHCl

EXAMPLE 13

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

ANALYSIS c n H 20 ClN 3 0 5 : 309.75 - Calculated $ C:42.6, H:6.5, N:13-6 - Found $ C:42-3, H:6.2, N:13-6. MP : 6θ°C. M J 0 : + 68.8° (c : 0.5 56 CHC1 3 ) - [oQ 2 ^ r : +-113.0 0 (c : 0.5 % , CHC1 3 ) MR Spectrum (DMSO-dg): 1.19 (d CH 3 J = 6Hz), 1.87 (m CH 2 ~ 2') 3.01 (t H-4'J=J , = 9Hz) 3-25 (s 0CH 3 -1) 3-35 (s OCH - 4 )> 3-53 (m H-5) 3-63 (t CH 2 ~4 J = J' = 6Hz) 3.61 (m CH 2 ~ 5) 4.18 (m H-3') 4.66 (d H-l « J = 3Hz) 8.73 Id NH J=9Hz). Mass Spectrum (chemical ionisation) : m/e 310 (Cl,. ,., (M+l , Basic peak) and m/e 312 (Cl^, 30$); m/e 278 (m+1-32, 90$) and m/e 280 (27$) .

EXAMPLE 14 Methyl 3,6-diazido 4-0-benzyl 2,3,6- tridesoxy c -D-arabinohexopyranoside Compound 1

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-tridesoxyσ<-D-arabinohexopyranoside in 50 ml of anhydrous dimethylformamide . The reaction medium is brought to 8θ°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 C 14 H 1 6 N : 332.32

20 [Λj D : + 51° (c: 2.2 % , CHC1 ) IR Spectrum : 3450 cm "1 (OH) 2115 cm "1 (N )

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

5 g (0.015 mole) .of compound J_l_ 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 CH 2 C1 2 ). ANALYSIS C 7 H 12 N 6°3

[cKl p°: + 128° (c : 1.6 $, CHC1 ) IR Spectrum film : 3450 crrT^OH) 2115 cm "1 (N ) EXAMPLE 16 Methyl 3,6-diamino 2, 3, 6-tridesoxy C -D-arabinohexopyranoside - Compound 13

3 g (0.013 mole) of compound Vl_ in solution in 100 ml of ethanol with 1$ triethylamine a re hy""drogenated 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 C 7 H l6 N £ 0 : 176.25 [σfl p°: + 130° (c : 1.13$, MeOH)

IR Spectrum gilm : 3700 cm "1 (OH), 336O cm "1 ( NH) EXAMPLE 17 Methyl bis 3,6- [3-( 2-chloro ethyl)

3-nitroso ureido] 2,3, 6-tridesoxy (- -D-arabinohexopyranoside . -Compound 14 ( IC 83-1374)

53 It is obtained by the usual method from com¬ pound 13 • ANALYSIS C 13 H 22 C1 2 N 6 0 7 : 445-207 - Calculated $ C:35-l,

H-5.0- N:l8.9 - Found $ C:35-3, H.5.1, N.19-2. MP : 102°C

D l °- -59.0° (c : 0.5 $, CHC1 )- &τ<3 3 ° 5 : +74-0° (c : 0.5 $, CHC1 3 )

NMR Spectrum (DMS0-d 6 ): I.84 (m CH 2 -2 ) 3- 15 (s 0CH 3 ) 3.17 to 3-77 (m CH 2 -6', H-3', H-4', H-5', 2CH 2 ~4) 4-06 ( m 2CH 9 -5) 4.66 (d H-l J=3Hz) 8.41 (t NH J=J'=6Hz)

8.50 (d NH J=9Hz).

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

447 J.J- 35 449 Z 37 L1 37 37

EXAMPLE l8 Methyl 3-0-acetyl 4,6-0-benzylidene 2-desoxy (_X -D-arabinohexopyranoside

- Compound 15

40 ml of redestilled acetic anhydride are added to 10 g (0.037 mole) of methyl 4 ,6-0-benzylidene 2-desoxy θ -D-arabinohexopyranoside in solution in 50 ml of anhy- drous 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$) of a crystalline product that is purified by recrystalli- zation in the hexane-acetone ' ixture. MP : 125° - 127°C r - 20 l° D : + 74° (c : 1$, chloroform)

IR Sp'ectrum.N,uj.o.l : 1728, 1240 cm "1 (c = 0 ester).

EXAMPLE 1Q Methyl 3-0-acetyl 4-0-benzoyl 6-bromo

2 ,6-didesoxy CX-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 _1_5 in solution in 200 ml of carbon tetrachloride,were added. The reaction was brought to re- flux for 3 hours. After cooling and removal of the in¬ soluble 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 D° : +7 ° ( ° 1 " 45 » CHC1 )

IE Spectrum : 1730 cm , 1240 cm (CO ester)

1600, 1585 cm ""1 (aromatic)

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

2,6-didesoxy <-X-D-arabinohexopyrano- side. - Compound 17

To a solution of 8 g (0.020 mole) of compound J_6 in 50 ml of anhydrous dimethylformamide were added 8 g (0.12 mole) of sodium azotide. The reaction mixture was brought to 80 C for 8 hours. After cooling and dilution with water, the re¬ action 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 l6 H ιg N 0 5 : 349.38 MP : 68 ° C

[<] ^° : +90 (c : τ?°j CHC1 3 )

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

1610, 1590 cm ""1 (aromatic)

EXAMPLE 21 Methyl 6-azido 2,6-didesoxy < τC-D-ara¬ binohexopyranoside - Compound 18 A methaaolic solution of sodium methylate (20 ml) was added to a solution of 4.96 g (0.014 mole) of compound 1_7 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 che solvent, the syrupy residue obtained was chromatographed 5 on a silica column to remove the methyl benzoate. 2.76 g of compound j3 were obtained (96%). : 203.2

: 1 , chloroform). 0 IR Spectrum : 3400 cm "*1 (OH) 2120 cm ""1 (azide).

EXAMPLE 22 Methyl 6-amino 2-desoxy < _ -D-arabino¬ hexopyranoside - Compound 19

„,- A solution of 2.40 g (0.011 mole) of compound _8 in 25 ml of anhydrous ethanol was shaken under a hydrogen 5 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 : C^H^N^^ : 406.35 0 MP : 156°C (ethanol)

M D° ! +75 ° (° : 1 « 2 » chloroform). EXAMPLE 23 Methyl 3- [ 3-(2-chloro ethyl) 3-nitroso ureido] 2,6-didesoxy c -D-arabinohexo- 5 pyranoside -Compound 20 (IC83 1350)

It is obtained by the usual method from compound

_1_2-

ANALYSIS C 1Q H 18 C1 3 0 6 : 311.728 - Calculated : C.38.5,

H:5.8, N:13.5 - Pound : 0:38.5, H:5.5, N.13-4.

30 MP : 101 * 0 (dec.)

20 : + 26.2 (c : 0.5 %, CHC1 3 ) 36 + 51 *° (c * 0.5$ , CHC1 3 ) NMR Spectrum (C SO-cL-) : ' <* 1.45 (t(d) H-2' J = J' = 12Hz, 35 J" = 4Hz), 1.85 (d(d) H-2 » J= 12Hz J' = 4Hz), 2.95 (t H-4' J= '=9Hz) f 3.10 (s-0CH 3 ), 3.30 (m H-3* ) , 3.51 ( H-5 + a CH 2 -6 » ).» 3.58 (t CH 2 -4 J=J'=6Hz), 3.75 (d b CH 2 - « J = 12Hz), 4.06 ( 0H 2 -5), 4.15 (d H-1'J = 3Hz), 4.81

f ? : ■ ■* ?-

(OH), 5.10 (OH), 8.50 (t NH). Mass Spectrum : (M + 1) = 312 Cl 35 314 Cl γ j (Loss of MeOH -32) 280.

EXAMPLE 24 Methyl N methoxycarbonyl 3-amino 2,3,6- 5 tridesoxy c -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 σ(.-D-arabinohexopyranoside i 'n 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 ethylene chloride. The organic phase washed with distilled water was dried over sodium sulfate.

After evaporation under vacuum, the residue ob¬ tained was recrystallized in a methanol-methylene chloride mixture, Ϊ.7 g (80%). ANALYSIS G g H 17 N0 5 : 219.24 MP : 180°C

[d] 20 . + 1 7 (c : 1%, CHC1 3 ).

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

1.7 g (0.0077 mole) of compound 2_L 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. e 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 acetone- hexane the organic phase dried over sodium sulfate gave , 1.05 g of crystals (80%); MP : 105 * C ANALYSIS CgH ιγ 0 5 : 175.23

M 20

D 89 (c: 1%, CHC1 3 )

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

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

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

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

Examples 7 a 9

COMPOUND 15 COMPOUND 16

cn

COMPOUND 17 COMPOUND 18 COMPOUND 19 o

Ex a ples 24 a 26

COMPOUND 22

COMPOUND 21

COMPOUND 23

•N \

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

Compound 26 - IC 841530 The preparation of methyl 3-amino 2 ,3 ,6-tridesoxy α(-L- arabinohepoxyranoside (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 chlσ- rhydrate are added to 1.92g (0.012 mole) of methyl 2,6- didesoxy o{ -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 extrac¬ tion with dichloromethane and drying over sodium sulfate sodium, a clear oil (2 ) is obtained, the structure of which is confirmed by NMR and corresponds to 0- 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. [c<] 2° : - 140°C (c : 0,6 % , MeOH). The preparation of methyl 3-C3 (2-chloro ethyl)ureido] 2,

3, 6 -tridesoxy O^-L-arabinohexopyranoside (compound 25) is carried out,as mentioned hereafter.

-3 0.3 ml (4.10 mole) of 2-chloro ethyl isocyanate

_3 are added to a solution of 0.48 g (3.10 mole) of methyl 3-amino 2, 3, 6-tridesoxy X'-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 D c : 1,14 (d, CH 3 -6' f 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,CCH 3 )

3,28 (m,CH 2 -4) 3,42 (m,H-5') 3,53 (m.CH-,-5) 3,61 (m_

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

The final product which is desired (compound 2j6_) , i.e. methyl 3 [3-(2-chloroethyl) 3-nitroso ureido] 2,3,6- tridesoxy 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 ad'ded 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 puri ication, on a silica support column, eluent CH- Cl_ : 98, MeOH : 2 colorless crystals are obtained : 210 mg (30 %) MP : 100°C

1 ! C 10 H 18 C1N 3°5 295,71. Calculated % ;C : 40,6 H : 6 ,1 N 14,2. Found % : C : 40,9 H : 6.1 N 13.90.

NM ^R._ ( Spectrum_ (DMSO ,D, ) : 1,15 ,CH 3 -6 J=6 Hz) 1,78 a

1,94 (m, CH-,-2 1 ) ; 3,04 (t,H-4' J=9 Hz 3,25 (s,0CH 3 )

3,51 ( m,H-5' ) ; 3,60 (T,CH 2 -4, J=J'=6 Hz) ;

4,10 ( m,CH 2 -5, H-3') ; 4,65 (d,H-l' ,J=3 Hz) ; 8,48 (d,NH,

J=9 Hz) .

64

The reaction diagram hereaft er summarizes the steps which have just been described :

N

Methyl 2,6 didesoxy . CH . alpha-L-erythrohexo- pyranoside 3-ulose

Compound 24 Compound 25

Compound 26

Pharmacological study

In order to test the antitumoral activity of the compounds described above, in the first place leucemia mu- rin L1210 was used. Among murin leucemias, leucemia L1210 is resistant and selective. A substance having a great acti¬ vity 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 the- rapy, as described, for example by C. C. Zubrod in Proc.

Nat. Acad. Sci. USA, 6_9, 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, n β 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 % etha¬ nol in the proportion of 10 mg/ l. The test was carried out in two steps.

1 - Determination of the 20 cytotoxic index

100- ul of an L 12iϋ cell suspension (10 cells per ml) in R P M I 1640 culture medium supplemented with 10ό of fetal- calf serum and 40 ug ml of genta ycin, contain int various doses of the products to be tested (0 to 100 ug/ l) were incubated 24 hours at 37°C. At the end of this time, the cell viability is determined by the tr pan blue exclusion test. The cytotoxic index is defined by the formula:

Cytotoxic index : 100 ["_, fό treated living cells io control living cells. The amount of ethanol is the same in the cultures containing the products to be tested and in the control cul tures (this amount has no effect either on growth nor on cell viability).

For each product the dose which gives a cyto¬ toxic index of 20yό 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 cyto¬ toxic index equal to 20 . After this time, the cells were placed in culture medium not containing nitrosoureas and incubated at 37 C. After 48 hours, the cytotoxic index was determined. .J. DURKIN et Al...showed that, under these con¬ ditions, if the cytotoxic index was equal to or greater tha 40ό, the product concerned would be active "in vivo" in .the mouse. RESULTS

The results are collected in the following table I

TABLE I

.i 1

N.D. = undetermined U.S. = not significant-

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 B /C c r/BI (Animal selection and breeding center of the Laboratories of the CNRS, Orleans, La Source). . The mice .distributed in cages by drawing lots were

5 inoculated on day "0" with 10 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 in- jection : product 2 + neutralized and sterilized olive oil.

' . The mortality of the animals was observed regularly, the relative increase in the survival (τ/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 g/ g 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

10 m * 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 0ό of the treated animals were finally cured; now in the ex- periments 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 5 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 nitroso¬ ureas 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 deter¬ mine a minimum active dose which is situated between 1.25 mg/kg of body weight and 2.5 mg/kg j in f ct, 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. . Determination of the "in vivo" activity of the com¬ pounds according to the invention on the three respec¬ tive tumors leucemia L 1210 IGR, Lewis tumor and mela- noma Bl6. 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 DBA- mice were used, about 8 weeks old and weighing about 20 g from the IFFA-CRED0 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 B ό

Female C57 B l/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, intraperi-

* toneally, 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. Resul s • 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 Bl6 : 14-52 + 0.80.

71 . 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 con¬ sidered 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 6θth 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 e xperiment were autopsied and there was no death through toxicity.

T A B L E II

N>

A

5. Determination of the "in vivo" activity of the com¬ pounds 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 1183j IC ll84,

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 LI210 IGR, by inoculating 10 5 tumor cells of L1210 IGR intra eritoneally in the volume of 6.2 ml then, at days 1, 5 and 9, there were injected intraperito¬ neally 5mg kg of each of the compounds to be tested. -The results are shown in Tables III and IV below.

PCT/EP84/00260

T A B L E IV

L 1210 IGR TUMOR

6. Study of the toxicity of the compounds according to the invention

. Histological examinations were carried out on the organs of DBA- 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 DBA- mice, that is to say inoculated with the tumor L1210 IGR.

. The organs subjected to these histological exa- minations were the liver, the kidneys, the spleen, the adre¬ nal glands and the lungs.

. Examination showed that the comparison animals inoculated by L1210 IGR presented a cellular disorganisa¬ tion 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 distur¬ bance 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 it¬ self of the products of the invention.

A hematological study has been carried out on some animals treated with the products according to the in- vention ; it is the case particularly of DBA- mice inocula- ted 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 pro¬ duct according to the invention give interesting results when the model selected in melanoma B16 , and excellent re- suits when the models selected are the Lewis tumor and the L1210 IGR tumor as well as the L1210 USA tumor, more resis¬ tant 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 chimiothe- rapy. The compounds of the invention are particularly sui¬ table for the treatment of various forms of cancer meeting this condition and which are identified in the publica¬ tions 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 (osteosarcomas , reticulosarcomas) , melanomas, hemato-sarcomas (Hodgkinian and non Hodgkinian lymphomas) , and multiple myelomas.

The invention relates also to pharmaceutical com¬ positions comprising the above said novel compounds in as¬ sociation 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 injecta¬ ble 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 ste¬ rile water, then before being administered by intravenous perfusion, the solution is again rediluted in 9 % a isαto- nic 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 relati¬ vely large proportion of patients afflicted with one or other of the various forms of cancer which are or will be accessible to chimiόtherap , 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 surfa¬ ce. 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 ex¬ pressed 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 ad- ministration, especially, for the oral route (solid or li¬ quid 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 evalua- ted by the clinician taking into account the state of the patient and of his personal reactivity with respect to the medicaments.

An example ofpharmaceutical 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 referen¬ ce products in pharmacological studies, particularly in or¬ der to carry out antitumor comparisons ' of the products which are studied- with respect to a reference product.