NZ209397A - Nitrosourea-substituted pyranose derivatives and pharmaceutical compositions - Google Patents

Nitrosourea-substituted pyranose derivatives and pharmaceutical compositions

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Publication number
NZ209397A
NZ209397A NZ209397A NZ20939784A NZ209397A NZ 209397 A NZ209397 A NZ 209397A NZ 209397 A NZ209397 A NZ 209397A NZ 20939784 A NZ20939784 A NZ 20939784A NZ 209397 A NZ209397 A NZ 209397A
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New Zealand
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group
carbon atoms
hal
groups
halogen
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NZ209397A
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P Choay
C Monneret
P Roger
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Dropic
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/12—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by acids having the group -X-C(=X)-X-, or halides thereof, in which each X means nitrogen, oxygen, sulfur, selenium or tellurium, e.g. carbonic acid, carbamic acid

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  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)

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.

Description

New Zealand Paient Spedficaiion for Paient Number £09397 209397 Priority Date(s): . 7. ?. ~~ ^>3 i Complete Specification Filed: class: Celttl&iljMiM'faift ..... C?X£$$$./{?& r'-oi;:,ation D<>te- -" 0. Journal, .2 9 APR 1988 NO DRAWINGS N-7. PATENT OFFIPP 3 0 AUG 1984 Patents Form No. 5 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION "NITROSOUREA DERIVATIVES, PROCESS FOR THEIR PREPARATION AND MEDICAMENTS CONTAINING THEM" iy WE DROPIC : SOCIETE CIVILE DE GESTION DE DROIT DE PROPRIETE INDUSTRIELLE CHOAY, of 10, avenue Matignon 75008 Paris, France, of French nationality hereby declare the invention, for which -J-/we pray that a patent may be granted to -me-Zus, and the method by which it is to be performed, to be particularly described in and by the following statement (followed by page T A.) 2 0 93 9 1<* NITROSOUREA DERIVAflVES. PROCESS FUR THEIR PREPARATION AND AHDICAMEtfTS CONTAINING THEM BACKGROUND OF THE INVENTION The present invention relates to novel nitrosourea derivatives and, more specifically, to novel 2-des-oxy—su,~ar-nitrosoureas and 4-u esoxy-su^ar-ni urosoureas, to processes for their preparation and to their therapeutic uses.
It is known that various nitrosoureas have powerful cytostatic and oncostatic activity detected within the framework of pharmacological experiments and clinical treatment : this is the case, in particular, of ( 1, j-bis-2-chloroethyl)-1-nitrosourea [bgnu] marketed under the trademark "BICNU" (cf. Dictiormaire VI DAL 1984), of 1-( 2-chloro-ethyl)-j-cyclohexyl nitrosourea [CCNU] marketed under the trademark "BELUST1NE" (cf. Dictionnaire VIDAL 1984) and 1-( 2-chloro-ethyl)-j-(4-methyl-cy c'lohexyl)-nitrosourea [Me CCNUJ : cf. G. MATHE and Y. KENlb : Expansion Scientifique, 197b, 3rd Ed.. "La Chimiodherapie des cancers (leucemies, hematosarcomes et tumeurs solides)" and T.H. WASHERMAN, M. SLAVIK & S.K. CARTER, Cancer Treat. Rev., 1974, J., p. 131 > "Review of CCNU in clinical cancer therapy". G.P. WHEELER et al (Cancer Res., 1974, 34, 194) attribute their oncostatic action to an alkylation and a carbomoylation of proteins. It has also been suggested that their lipophilic character is essential in so far as it" conditions the passage through cell membranes in particular the blood-brain barrier. However, these compounds have the drawback of showing certain toxicity, particularly hematological, at the doses at which they are revealed to be active. Consequently, this- toxicity limits their use at doses less Chan 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 respect to the preceding ones, such as sugar-nitrosoureas, in which the sugar molecule is ribose, xylose or glucose : cf. J.L. IMBACH et al, Biomedicine, 1975, 23, p. 410-413, "The oncostatic and immunosuppressive action of new nitrosourea derivatives containing sugar radicals". Thus these authors have established the oncostatic action of the following four compounds on L 1210 leucemia ana their low toxicity: 1-(2-chloro-ethyl)3-(ribofuranosy1-2',3'-isopropyli-aene-5-paranitro benzoatc)-nitrocourea [li£Cr:lO ^3-^2-chloro-1-ethyl-2'-desoxy-glucopyranosyl-14,3' , 4", 6' -1 e trace tat e)-"-nitrosourea [GCHU] , 1-( 2-chloro-ethyl) 3-(ribopyranosyl-2',3'»4' — triacetate)-ni trosourea [KPCNu] and 1-(2-chloro ethyl) 3-(xylopyranosyl 2',3',4'-triacetate)-nitrosourea [xPCNll] . 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. x'his is why, within the scope of the experiments carried out on these products, recourse has preferably been had to their solidification by blocking the hydroxy groups.
In a subsequent work J.L. MOJNTEIiO et al (Eur. J. Med. Chem. Chimica i'herapeutica, raars/avril 1976, 11, n 2, p. 183-187 : "Synthese de nouvelles glycosylnitroso-urees a visees oncostatiques - les 1-nitrosoureido-1-desoxy-glucopyranoses"), described glycosyl-nitrosoureas in which the sugar-nitrogen bond is located in an anomeric position, which has oncostatic activity, namely 1- C3-(2-chloro-ethyl) 3-nitroso-ureido ]-1-beta-D-glucopyranose and 2,3,4»6-tetra-O-acetyl 1- [3-(2-chlor-ethyl) nitroso-3-ureido J -1-desoxy-beta-l)-glucopyranose, and which represents in addition the advantage of lower toxicity on the bone marrow and not being diabetogenic, whereas streptozo-tocine or 2-desoxy-2-(3-methyl-2-nitrosoureido)-D-gluco-pyranose, which is a compound of natural origin, presents antibiotic, antineoplasic properties, and also presents un desirable diabetogenic properties as well as a high renal and hematological toxicity (cf. Drugs of the future, vol. IV, n 2, 1979, p. 137-139).
One of the aspects of the invention is to provide novel nitrosourea derivatives, for which the profile of the activity curve ihowa its maximum at a dosage far below the threshold of the toxicity.
Another aspect of the invention is to provide novel nitrosourea derivatives havinq a aood therapeutic index.
It is another aspect of the invention to provide also novel nitrosourea derivatives having physical properties enabling their use in therapeutics.
Another aspect of the invention is to provide novel nitrosourea derivatives having a solid and stable form. (jEWEKAl DESCKIPTION 0*' 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 nitrosourea 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 carbon at the 2 position of the above-said sugar, when it relates to a 4-desoxy-sugar, novel nitrosourea, derivatives are obtained whose activity is considerably increased and whose toxicity is "low with respect to the compounds already known. One of the interests of these derivatives can be connected with the hypothesis accor^inc tc which the 2-desoxy-suaars and the 4-riesoxy-suqars have a certain lability at the level of the oside linkage ,which can result in tte for- 2093 9 4 mation of a free sugar in certain biological media and permit the provision of compounds firstly lipophilic, which then become hydrophilic, which would make easier the 'passage of cellular barriers and would account for an increase of antitumor activity.
An object of the invention is to provide novel nitrosourea derivatives, characterised in that they correspond to the following general formula (I) : V. in which : -R represents a hydrogen atom, an alkyl group trrml to 30, preferably 1 to 12 carbon atoms or an aralkyl group fran7 to 12, preferably 7 to 9 carbon atoms, optionally substituted by one or several, particularly up to 3, halogen atoms, CF^ groups or alkoxy groups of 1 to 4 carbon atoms, -X represents a hydroxy group or an NR^R^ group -Y represents a hydrogen atom R' a hydroxy group or an K 1 group R' 2 where R^ and/or R1 1 each represent a hydrogen atom or a -C-K-CHrjCIIyHal group, Hal being a halogen, preferably CI, II t C. C. 0 NO and R^ and/or R'g each represent a hydrogen atom, an alkyl group comprising from 1 to 6 carbon atoms, an aralkyl group comprising 7 to 12, preferably 7 to 9 carbon atoms, a cycloalkyl group comprising from 3 to b carbon atoms, an aryl group of 4 to 10 carbon atoms, the aryl and aralkyl groups being possibly substituted by one or several, particularly up to 3, halogen atoms, N02»NH2,CF-^ groups or alkoxy groups of 1 to 4 carbon atoms, w ' Q C ^ & - 7 </ c - R' and R" represent hydrogen, OM, M representing an alkyl group comprising from 1 to 30, preferably from 1 to 12 carbon atoms, an aryl-' group fixm 4 to 10 carbon atoms, an aralkyl group comprising from 7 to 12, pre-5 ferably from 7 to 9 carbon atoms, the aryl and aralkyl groups being possibly substituted by 1 or several, particularly up to 3, halogen atoms, groups or alkoxy groupsfran 1 to 4 carbon atoms, or M representing .an acyl group fran 2 to 8 carbon atoms, preferably 2 or 3, or 311 10 aroylgroup fran 5 to 12, preferably 5 to 9 carbon atoms, un-substituted or substituted by one or several, particularly up to 3, ^2* ^3 SrouPs»- halogen, alkoxy of 1 tc 4 carbon atoms, provided that either R' or R" represents hydrogen. P.' and R" being not simultaneously hydrogen and R1 provided that at least X represents ,with *2 \ 1 representing -C-N-CHgCHgHal, or Y represents with 0 NO - It 2 R'., representing -C-N-CHoCHoHal I i| | c. tL 0 NO In a preferred class of compounds of the invention, R' represents H and R" represents OH. in another preferred class of compounds of the invention R" represents H and R' represents OH.
In Formula I. and certain of the Formulas following, linkages have been shown between the groups R, R', R'^CH^Y and X on the one hand and the ring structure on the other hand, by the symbol . This representa tion means that each of the RjR'jR'^C^Y and X groups can be either at the ot position or at the p> position, according to the HAYWORTH representation, and in an arrangement compatible with the stereochemical requirements.
In the rest of the description, the term alkyl includes linear, branched or cyclic alkyl groups (cyclop alkyl).
A preferred class of compounds according to the invention is constituted by the compounds corresponding to the Formula II below : in which (II) - R represents a hydrogen atom, an alkyl group from l to 30, preferably 1 to 12 carbon atoms, or an aralkyl group from 7 to 12, preferably 7 vo 9 carbon atoms, option-nally substituted by one or severals. particularly up to 3, haloqen atoms. NO2.NH2.CF2 qroups or alkoxy qroups from 1 to 4 carbon atoms.
- X represents a hydroxy group or an NR^R^, group - Y represents a hydrogen atom, "1 a hydroxy group or an group R' 2 where R^ and/or R'^ each represent a hydrogen atom or a Hal group, Hal being a 1. 1 «• U i^O halogen, preferably 01, 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 y carbon atoms, a cycloalkyl group com- and R2 and/or R',, / 0 iJ o ij prising 1'rora 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 severs], b particularly up to 3 halogen atoms, group or alkoxy groups oi' 1 to 4 carbon atoms, R" represents Dreferably OH, but can be replaced by OM. M representing an alkyl group comprising from 1 to 10 30, preferably 1 to 12 carbon atoms, an aryl group from 4 to 10 carbon atoms, an aralkyl group comprising from 7 to 12, preferably 7 to 9 carbon atoms, the aryl and aralkyl groups being optionally substituted by one or several, particularly up to 3 halogen atoms, NC^.Nt^.CF^ groups or 15 alfvTxy groups of 1 to 4 carbon atoms, or M representing an acyl group from 2 to 8 carbon atoms, preferably 2 or 3, or an aroyl group from 5 to 12. preferably 5 to 9 carbon atoms, unsubstituted or substituted by one or several, particularly up to 3, NC^.NH^CF^ groups, haloqen, ?0 alkoxy from 1 to 4 carbon atoms. provided that at least X represents -h' , with representing -C-Ji-CH9CH5Hal, I £ c. t 0 INO K, or Y represents ^ with H*.. representing XK' ' -(J-N-CH, .<JH. ,11 al .
M I ^ '• U NO These compounds of Formula II represent the particular case of Formula I in which R' represents hydrogen.
Among "Che compounds oi formula II, a prelerrea class oi compounds according to the invention is constituted by those oi' Formula III below : CH-.Y °^lii) ' §N - A R" 1*29 FEB 1988 • 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 constituted by those of Formula IV below : meanings.
The compounds of Formula (IV) belong to the clas class of 4-desoxy,alpha-L-xylohexopyranoside compounds.
A particularly preferred class of compounds according to the invention is constituted by the compounds corresponding to the Formula V below : - R represents a hydrogen atom, an alkyl group from I to 30, preferably 1 to 12 carbon atoms or an aralkyl group from 7 to 12 , preferably 7 to 9 carbon atoms, optionally substituted by one or several. particularly up to 3, haloqen atoms. NC^.NK^.CF^ groups or alkoxy groups of 1 to carbon atoms, -X. represents a hydroxy group or an group -Y represents a hydrogen atom, a hydroxy group or an N^ ^group R'2 where and/or R'^ each represent a hydrogen atom or a -C-N-CH9CHyHal group, Hal being II « C. C.
U i\0 halogen, preferably CI, 9 2 093 9 a and a-nd/or R'^ each represent a hydrogen atom, an alkyl group comprising 1 to b carbon a-coms, an aralkyl group comprising 7 to 12, preferably 7 to 9 carbon atoms, a cyeloalkyl group comprising from 3 to b carbon atoms, an aryl group of 4 to 10 carbon atoms, the aryl and aralkyl groups being optionally substituted by one or several, particularly up to 3, halogen atoms, ,DH^,CF^ groups or alkoxy groups of 1 to 4 carbon atoms P.' represents preferably OH, but OH can be replaced bv OM , M representing an alkyl group comprising from 1 to 30, preferably from 1 to 12 carbon atoms, an aryl group of 4 to 10 carbon atoms, and aralkyl group comprising 7 to 12, —s preferably 7 to 9 carbon atoms, the aryl and aralkyl groups "—^ being optionally substituted by one or several, particularly up to 3, halogen atoms. NO2.NH2.CF2 groups or alkoxy groups from 1 to 4 carbon atoms. or M representina an acyl group of 2 to 8 carbon atoms, preferably 2 or 3. or an aroyl group from 5 to 12, preferably 5 to 9 carbon atoms, unsubstituted or substituted by one or several, particularly 20 up to 3, N02,NH2,CF3 groups, halogen, alkoxy of 1 to 4 carbon atoms n / 1 provided that at least x represents -N , with K1 x w 1 - representing -C-N-CH9CH5Hal, or Y represents -in ^ with " ' VK', 0 NO * u'- representing -C-N-CH CH, Hal and 1 11 « <- 0 NO These compounds of Formula V represent the particu-3C lar case of Formula I in which R" represents a hydrogen atom.
Among tne compounds of Formula V, a preferred class of compounds of the invention is constituted by thos those of Formula (VI) below : / . I 209397 (VI I in which K, R', X and Y have the previously indicated | 5 meanings. l • j The compounds of formula (VI) belong to the class of 2-desoxy, alpha-D-arabinohexopyranoside com-pounds.
"! Among the compounds of .formula (V), another \! ' 10 preferred class of compounds provided by the invention is constituted by those of the following Formula (VII) : 0 UR (VII) j in which R, R1, X and. Y have the previously indicated i meanings. j These compounds belong to the class oi 2-desoxy, alpha-L-arabinohexopyranoside compounds. | 20 A Preferred class of compounds according Co the invention is constituted by those of formulas (I), (II), ! (HI), (IV), (V), (VI), and (Vll) in which : ! - R represents an alkyl group from 1 to 12 carbon atoms, aralkyl from 7 to 12 carbon atoms ; 2>p - R' or R" represent an Um group, n'i being an alkyl group comprising from 1 to 12 carbon atoms, an aryl group comprising 4 to 10 carbon atoms ; - X represents an InR^k^ group , R^ representing -U-N-CH,,CH,,Hal, Hal being a halogen, particularly 01, ii t ^ e- 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), (ill), (IV), (V), (Vi), and (Vj.1) in which : - R represents an alkyl group from 1 to 12 carbon / 11 :ojoj atoms, halogenoaralkyj. firrn 7 to 12 carbon atoms ; - ]<• or h" represents an Uivi group, k being an acyl group of 2 to 6 carbon atoms; an aroyl group f nsn 5 to 12 carbon atoms ; - X represents an group, representing -C-N-CH,,CH.,Hal, Hal being a halogen, particularly Cl, II 1 ^ ^ 0 wo - Y represents a hydrogen atom or a hydroxy group.
Another preferred class of compouncs according to the invention is constituted by those of formulas (1), (11), (III), (IV), (V), (VI), and (Vll) ana in which : - H represents an alkyl group fruni to 12 carbon atoms, an aralkyl group frcm 7 to 12 carbon atoms ; - K' or K" represents OH ; - k represents an "inh1K2 group, representing -C-is-UH^CriyHal, Hal representing a halogen, particularly «t t 0 NO CI, - Y represents a hydrogen atom.
Another class ol preferred compounds according to the invention is constituted by those of Formula (l), (II), (III), (IV), (V), (VI) and (VII) in which : - R represents an alkyl group frcml to 12 carbon atoms, an aralkyl group fron7 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 arylajnino in which the aryl group has 4 to 10 carbon atoms, and - Y represents nr^r^ , K' ^representing -C-N-CHpCHyHal, Hal representing a halogen, particularly tl 1 ^ 0 m ci.
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 whiclj^s- " x- £/ p29 FEB 1988 V* , 12 2093 9 -R represents an alkyl group of 1 to 12 carbon atoms, an aralkyl group of 7 to 12 carbon atoms ; - R* or RH represents OH ; - X represents a hydroxy group, - Y represents NR'^R'^, R'1 representing -C-N-CH,,CH,.Hal, Hal representing halogen, particularly t» t d C. 0 NO CI.
Another class of preferred compounds according to the invention is constituted by those of Formula (I), (II), (III), (IV), (V), (VI) and (VII) in which : - R represents an alkyl group of 1 to 12 carbon atoms, an aralkyl group of 7 to 12 carbon atoms, - K' or R" represent OH, - X represents an KR^R^ group, representing —C—N-CH9CHoHal, Hal being a halogen, particularly CI, it i ^ *- 0 NO - Y represents an alkylamino group, in which the alkyl group has 1 to fa carbon atoms or arylamino in which the aryl group has 4 to 10 carbon atoms.
Another preferred class of compounds according to the invention is constituted by those of Formula (V), (VI) and (VII) in which : - R represents an alkyl group fran 1 to 12 carbon atoms, aralkyl frcm 7 to 12 carbon atoms ; - R' represents an 0M group, M being an alkyl group comprising 1 to 12 carbon atoms, an aryl group comprising 4 to 10 carbon atoms; - X represents a group NR^R^, R-j representing -C-N-CH9CH9Hal, Hal being a halogen, particularly CI, 11 I ^ ^ 0 NO - Y represents a hydrogen atom or a hydroxy group. dL* %*■ > 13 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 frcm 1 to 12 carbon atoms, a halogenoaralkyl of 4 to 10 carbon atoms ; - R' represents an OM group, M being an acyl group of 2 to H carbon atoms, an aroyl group fran 5 to 12 carbon atoms ; - X represents an iNRgroup, representing -C-N-CH^CH^Hal, Hal being a halogen, particularly CI, It f C. C. 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 fran 1 to 12 carbon atoms, an arylkyl group fran7 to 12 carbon atoms; - R* represents OH ; - X represents an -NR^R2 group, representing -C-N-CHp-CH,,Hal, Hal being a halogen, particularly CI, It f ^ ^ 0 NO - Y represents a hydrogen atom.
Another class of preferred compounds according to the invention is constituted by those of Formulas (V), (VI), and (VII) in which : - R represents an alkyl group 1 to 12 carbon atoms, an aralkyl group frcm 7 to 12 carbon atoms ; - R' represents OH ; - X represents an alkylamino group, in which the alkyl group has 1 to 6 carbon atoms, or arylamino in which the aryl group has 4 to 10 carbon atoms and - Y represents -NR'^R'g, R'^ representing -C-N-CH-CHpHal, Hal being a halogen, particularly CI.
(II d. d. 0 NO 14 • ~\ • ) Another class of preferred compounds according to the invention is constituted by those of Formula (V), (VI), and (VII) in which : - R represents an alkyl group of 1 to 12 carbon atoms, an aralkyl group of 7 to 12 carbon atoms ; -R' represents OH ; - X represents a hydroxy group, - X represents K1 ^ representing -C-.N—(Jri.jCh,..Hal, Hal being a halogen, particularly 01. it * ^ £- 0 WO Another class of preferred compounds according to the invention is constituted by those of Formula (V), (VI) and (VII) in which : - ri represents an alkyl group of 1 to 12 carbon atoms, an aralkyl group 7 to 12 carbon atoms ; k' represents Oh ; - X represents an group, representing -0—N-CH,,CH..Hal, Hal being a halogen atom, particularly 01, II t c. c. 0 no - 1 represents an alkylamino group, in which the alkyl group has 1 to 6 carbon atoms or arylamino in which the aryl group has 4 to 10 carbon atoms.
In accordance with the invention, the novel derivatives of nitrosoureas of the general Formula I are 2,3,b, -tridesoxy oC-JJ-arabinohexopyranosyl-nitrosoureas, 2,3- didesoxy-o(-D-arabinohexopyranosyl-nitrosoureas, 2,fa-did esoxy-c<-D- arabinohexopyranosyl-nitrosoureas, 2,3,6-tridesoxy^X- L-arabinohexopyranosyl-nitrosoureas, 2,3-did esoxy- c<-L-arabinohexopyr anosy'l-ni trosoureas, 2, b-aidesoxy -oC-L-arabinohexopyranosyl-nitrosoureas,* 3,4,b-tridesoxy cK -D-xylohexopyranosyl-nitrosoureas, 3,4-dides-fe oxy c\-D-xylohexopyranosyl-mtrosoureas, 4,b-aidesoxy <X -D-xylohexopyranosyl-nitrosoureas, 3,4,6-tridesoxy <X.-L-xylohexopyranosyl-nitrosoureas, 3,4-didesoxy cX, -L- 1 i> xylohexopyranosyl-nitrosoureas, 4,b-didesoxy c?<-L-xylo-hexopyranosyl-nitrosoureas.
A preferred class of compounds according to the invention is constituted by those of the following formula : 3 HC/i °v OCH.
W * l.'HCOi.'-CH-CH-CI I 2 2 I JO CII3 o IC 84 1530 IC 83 1183 *0 OCII3 C0-N-C1I -?CH ->C1 0 VO 11 1 nn- c-;:-ai-ni-ci O , .AOH , HO\i /OCM3 IC 83 1184 IC 83 13.50 O <0 0 • HO fTII- CH2CH2CI ~Ov !J" A. 110 \ / 3 CO-t:-CM,Cll,Cl I 2 * NO IC 83 1375 coi:-cii -,cii 2c 1 1.0 IC 8 3 13 74 ;X r * *29 FEB 1988 1b It is also an object of the present invention to provice a process for the prepara-cion of the novel derivatives of general Formula I according to the invention, which consists of reacting, in a first step, an oside group of general Formula (I bis) c„2y -o (I bis) X ' ' ^ R " - in which K, K* and R" have the meanings indicated above.
- X' represents a hydroxy or -riHR.^ group; - Y' represents a hydrogen atom, a hydroxy group or -NHk'^ - &2 and- identical or different, represent independently of one another, a hydrogen atom, an alkyl group from 1 to 6 carbon atoms, an aralkyl group fran 7 to 12 carbon atoms, aryl fran 4 to 10 carbon atoms, cyclo-alkyl fran 3 to b carbon atoms, the aryl ana aralkyl groups being optionally substituted by 1 or several particularly up to 3, halogen atoms, WO^WH^CF^ groups or alkoxy groups fran 1 co 4 carbon atoms, and in which one at least of the groups A' or Y' represent or on 2-halogeno-ethyl isocyanate to convert the -NHR^ or group of the compound of Formula I bis respectively into UK U ^HCH20H2Hal or C NHCH^II^Hal, 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 nitrite of an alkali metal, preferably sodium nitrite, to convert the -NR^U NH CH2CH2Hal or C NHOH^Cl^Hal 0 0 groups respectively into -NR,,C -N CH,,CH,,Hal or £lu f C. C. 0 NO 17 2 0VJ ^/ -WK' ,.C -isUH,JCh,)Hal, 2n i U iNU 2vli2 The process described above can be illustrated by the following diagram in the case where X' represents JNHRg. w -a R 0=C=N-CH2-CH2-Hal •OR \ NHR / \ R" R 1 .
NR-CNHCH0CH-Hal Zn It NR ~CNCII0CH_Hal 2 f: l 2 2 ONO In the case where Y' represents the process described above can be illustrated by the following diagrajn : V 1o & * 9 7 -3 CH2 NHR ' 0=C=N-CH2-CH2Hal 7 10 1b CHZ N R-2 C NH CH2CH2 Hal I) 0 X 1 R" ZNO.
Z = alkali metal R ' :h,n r0 c ^ 2 2 w o v /" O N CH2CH2Hal NO OR 2b \ / \ ^ x ' r" 2 093 9? rhe present invention relates also to a process for preparing novel compounds of the general formula VI according to the invention, which consists of reacting, in a first step, an oside group of the general formula VI bis : (VI bis) in which: - R and R' are such as defined above ; - X' represents an -WhR^ or hydroxy group ; - Y' represents a hydrogen atom, a hydroxy group or -NHR',, -R., and R'^, identical or different, represent independently of one another a hydrogen atom, an alkyl group from 1 to 6 carbon atoms, an aralkyl group of 7 to 12 carbon atoms, aryl from 4 to 1U carbon atoms, cycloalkylfrom 3 to b carbon atoms, the aryl ana aralkyl groups being optionally substituted by one or several, particularly up to 3, halogen atoms, groups NH2,CF^ or alkoxy groups from 1 to 4 carbon atoms, and in which, one at least of the.croups X' and Y' repre-*-sents -wHR^ or JNHR',, On a 2—halogeno—ethyl isocyanate to convert the or NHR'2 group of the compound of Formula VI bis respectively into JNH., U wH OH,, CH9Hal or NR» C NH CH9Ch' Hal, Hal being a ^ It d d d tl d d 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 convert the groups -NRr>0 NHCH^CHgHal or -NR'^ C NHCH^CH^Hal 0 0 respectively into c N CH2CH2Hal or NR 12 c N CH2CH2Hal, 0 NO O NO / fr / ^•10 rhe present invention relates also bo a process for preparing novel compounds oi' the general formula VII according to the invention, which consists of reacting, in a first step, an oside group of the general formula VII bis : O, OR in which: (VII bis) - R and R' are such as defined above ; - X' represents an or hydroxy group ; - Y' represents a hydrogen atom, a hydroxy 1b group or -NHK'.
-R2 and R'2, identical or different, represent independently of one another a hydrogen atom, an alkyl group froml to b carbon atoms, an aralkyl from 7 to 12 carbon atoms, aryl from 4 to 10 carbon atoms, cycloalkyl from 20 3 to b carbon atoms, the aryl and aralkyl groups being optionally substituted by one or several, particularly up to 3, halogen atoms, groups NH2,CF^ or alkoxy groups from 1 to 4 carbon atoms, and in which one at least of the.groups X' and Y' repre*-23 sents —WHR^ or NHR'^ On a 2-halogeno-ethyl isocyanate to convert the or NHR'2 group of the compound of Formula VII bis respectively into 0 NH CH2 CH2Hal or NR'r, C NH CH2CH2Hal, Hal being a 30 o o halogen atom, particularly chlorine, and in a second step to subject the compound obtained at the end of the preceding step to nitrosation, by means of - an alcali metal nitrite, preferably sodium nitrite to con- vert the groups -LviR~C NHCHyCH5Hal or — NR',. C NHCHyCH.,Hal £,i c. d. c u cL c. 0 0 respectively into -1NR,. C n CHyCH^Hal or -NR_ C n CH-CH.Hal d if I d d £, || | £ Z.
O NO O NO 21 To prepare the compounds of formula (I bis), which enter into the preparation of the compounds according to the invention, it is possible to resort to one of the processes described below.
I Preparation of' the compounds of formula L\\Ly' * \ NHR R CU^NH R\ )-o R AA\' C )i. M M R j OR R. aaa/ 0 R X' R.
NHR., K 1A first modification The compounds of formula %.
R ***"/ 0 & WH R( k, ]{f, H", and y* having the previously indicated meanings, which enter into the preparation of the compounds of lormu'la C'1,71 -Q. ft.' lAVtA ( ^)/VU OQ* t \ Hal = halogen C »>)«. of the invention, can oe obtained-from the compounds of formula 2093 97 22 tH,/' R AyV\'- .Od V which are subjected - in a first step to the action of an aldehyde Ry C H, to convert the amine into an inline tl II 0 - in a second step, to the action of a reducing agent, such as a hydride, for example sodium borohydride or sodium cyanoborohydride, to convert the imine into a secondary amine. rhe process which has just been described can also be applied to the obtaining of compounds of formula in which K, ft1, it", X' have the above-indicated meanings, and to obtaining compounds of formula and in which In the latter case, the amounts of aldehyde and reducing agent employed are doubled.
I.tJ oecond Modification cd i N H r2 i C II i. (Vj * I z.
The compounds of formula R, R', K", Y' and. R^ having the previously indicated meanings which enter into the preparation ol' the compounds according to the invention of formula ci^v' )——a (Va.u/ Hal = halogen \ S r" hl Hi Mai1 <_> ^ can also be prepared from the compounds of formula <"iV A 1-YA Naaa. O ^ X V which are subjected to the action of an alkyl halogeno-formate, of formula halCOR, , particularly an alkyl u chloroformate to give the compounds of formula cm, V' / C R' a. x \r/ yv*-- G R. \ a" these compounds being then subjected to a reducing agent, for example aluminium ana lithium hydride, to convert the group into WHR„. ii ^ *- u i'his process can also be applied to the obtaining of compounds of formula cu7N CH^n, HqJ' t 1 'j t\iz> ft a.A>\ Vi/u. O Q <> S YS, K'' ...■ST;*. .v •is VI 24 as well as to those of formula 2093 97 <f .V cutciij| jj? J Aio? ft AA/lv/ C / \ <v?,c a/cu ""t II Preparation of compounds of formula -J£t i 10 , I -0 > \ ; _.i ? S £(l aa\0R VAAOR RAAV/ WAOR. •^q The compounds of formula u<ty' I ° f2. \/jLn/ 6'(? ) hn„ in which k, h' and k" have the above-indicated meanings ana Y* represents a hydroxy group can be obtained from compounds of formula >-—CL JO R A/vvv/ \-^m. O Q \ \ " l< (Z N.i which are reduced, particularly by catalytic hyarogena-r 35 tion, for example hydrogenation in the presence of palla-dized carbon. / i ■ ,? 4 ^ ;>• .j x The compounds of formula C Mty' Ho oQ N>A, in which Ret R" have the above indicated meanings and Y* represents a hydroxy,group, can be obtained from compounds of formula CH,CM tic GC H i <1 /VII 7 O 1 in which one of the hydrogen atoms or -NH^ groups in the 3 position is protected, particularly by reacting the previously represented compounds with trif'luoroacetic anhydride to give the compounds of formula CD .CM II 0 -o OCH To" 'vi "CiKr. which are treated with an alcohol ROH, in an acid medium, to give the compounds of formula ( UiOH ft O VI/W 'UAO £ ,M I t the protective group -COCi?1^ being simultaneously hy-drolizea.
The compounds of formula CVy' fl 1A-V, O ^ NU . ■*> L v. , 26 in which R, R' and R" have the above-indicated meanings and Y' represents a hydrogen atom, can be obtained from compounds of formula > / X R iyvv\/ Q.
V in which R, R' and R" have the above-indicated meanings and Hal represents halogen, particularly bromine, these >' 10 compounds being reduced, particularly by catalytic hy-drogenation, for example in the presence of palladized carbon.
The compounds of formula C ii z5 13 \ / U ^)w 0(t i' ^ in which R, R* and R" have the above-indicated meanings 20 and X' represents a hydroxy group, can be obtained from the compounds of formula ■0 ft /\AAy\ * <J rt by reduction, particularly by catalytic hydrogen£tion, for example in the presence of palladized carbon. Compounds of formula C. (4 , (\J I' ' V in which R, R' and R" have the above-indicated meanings 35 can be obtained from compounds of formula V: i ^ ^ 10 V. it 27 CN^V / ° R ^>^aa. O 2. ?. ^r>'' which are subjected to reduction, particularly catalytic hydrogenation, for example in the presence of palladized carbon.
Ill Preparation of compounds of formula Hal=halogen, / ^ I particularly Br ilC.\vt\/ yvuvOR r'w/ y^s^oQ ft "15 \ni, N»z The compounds of formula «. u,o' -) HO -WAA/ >'VWC)R ■J njk« «! > c o" in which K, R' and R" have the above-indicated meanings 2^ can be obtained from the compounds of formula Vk ^°\h / C?v / \WC'C^ Ph=phenyl , x /\ / -J f h 0 \ \ ^ which are subjected to the action of acetyl chloride, then to neutralization with ammonia to give the compounds of formula O' H tV l+ 3b "i p" I ^ which, are reduced, particularly by catalytic hydrogena-tion, for example in the presence of palladized carbon, to give the compounds of formula cUto H y^ocrfT, which can be converted by the action of an alcohol ROH, in an acid medium, into compounds of formula t hUOH > o The compounds of formula t'V/" ay AAV in which R, R1 and R" have the above-indicated meanings and Y" represents a halogen atom, particularly bromine, can be obtained from compounds of formula CHi '4<r^ -0 Bz=benzoyl / ) s ' \ > which are subjected to an alcohol of formula ROH, in an acid medium to give the compounds of formula 29 CHillni >-^u\ 0 R Aj T, which are then converted into compounds of the formula by removal of the benzoyl group, for example by means of a base, particularly an alkali alcoholate, such as sodium methylate. ed with an alkylating agent, such as M^SO^ or MX, X representing halogen, M representing an alkyl group from 1 to 30, preferably 1 to 12 carbon atoms, an aryl group of b to 12 carbon atoms, an aralkyl group from 7 to 12 carbon atoms, preferably 7 to 9 carbon atoms, the aryl and aralkyl groups being optionally substituted by one or several, particularly up to 3 halogen atoms, N02, NH2, CF^ groups or alkoxy from 1 to 4 carbon atoms, or representing an acyl group from 2 to 8 carbon atoms, preferably 2 or 3, or an aroyl group from 5 to 12, preferably to 9 carbon atoms, un-substituted or substituted by one or several, particularly up to 3 ri02,NH2,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 I Vo" Nx The compounds obtained above can then be treat- with R' = MO M having the above-indicated meaning -r ft fV m ■5 < 10 IV Preparation of compounds of the formula in which R, R' and R" have the above—indicated meanings and X' represents an OH group, can be obtained from the compounds of formula in which the OH functions at the 4 and b positions are protected, by causing the above-described compounds to react, for example on acetic anhydride, in the presence of pyridine to protect the hydroxy group at the 3 posi- ,/ 2!? 31 2 093 97 which in the presence of K-halogeno succinimide, preferably N-bromosuccinimide, and barium carbonate give the compounds of formula ,UI, IV -Q biC^A,/ -uu-O'? Bz = benzoyl which are subjected to a azotide, particularly an alkali metal azotide, such as sodium, in the presence of dimethy1-formamide, to give the compounds of the formula c N, I— O ftnVwv/ O <\c which in the presence of a base, particularly an alkali alcoholate, such as sodium methylate give r m ? n ,, )—0 V < •j H which can be subjected to or M*. ( A = halogen) in the presence of a base such as NaOH to give the compounds 30 of the formula M0a- with MO = H' ivj having the above- indicated meaning 32 2 093 9 7 The compounds of formula ft 1AA in which R, it* and k" have the above-indicated, meanings, can be obtained from the ...compounds of the formula C'h.H&P "vu or a ^ in which Hal represents a halogen atom,particularly, bromine, which are subjected to the reaction of an azotide, particularly, of an alkali metal, such as sodium azotide, to give the compounds of formula CMiM I C ft ?.0 s 'VVV OC ( ( v vJ in which, the benzoyl group is removed, for example, by the addition of a base, particularly of an alkali alco-holate such as sodium methylate, to give the compounds of the formula X f * / <V' \ I If a \,\A o \ c.-c /■ i L- \ Q These compounds can be converted into compounds of the formula fl -v C'U M \ ,V. .L* Nl r 33 by protecting the hydroxy group at the 4 position, particularly by means of benzyl chloride to obtain compounds of formula V FS AA/vif V^uui^ then by adding an alcohol of the formula R OH, in an acid medium, to obtain the compounds of the formula 01. then by removing the protective group of the hydroxy function at the 4 position, particularly by means of a base, especially an alkali alcoholate such as sodium methylate, to obtain the compounds of the formula then oy alkylating the above compounds, especially by means of ii^SO^ or kiX, X representing a halogen iii representing an alkyl group from 1 to 30, preferably 1 to 12 carbon a corns, an aryl group of 4 to 10 carbon 30 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, N02,jNHr,,C.P^ groups or alkoxy of 1 to 4 carbon atoms, or representing an acyl group of 35 d to 8 carbon atoms, preferably 2 or 3> an aroyl group of 5 to 12, preferably 5 to 9 carbon atoms, unsubstituted or substituted by one or several, particularly up to 3 209397 Ci?'^ 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 The processes which have just been described above are advantageously applied to the preparation of the compounds usable for the synthesis of compounds of formula VI according to the invention. lViore precisely, the process described in the paragraph I, enables the preparation of compounds of the formula ttvy' ft'X) y or in which K, K1, X*, Y •, R2 and K'2 have the above-indi-& cated meanings. f • ■- &■_, W' V / l'he process described, in paragraph II enables the preparation of compounds of the formula — 0 J o. z- / oa in which K, R' and Hal have the above-indicated meanings l'he process described in paragraph III enables the synthesis of the compounds of the formula -- u J— 0 in which R, R' and Hal have the above-indicated meanings l'he process described in paragraph IV enables the preparation of compounds of the formula / OR- in which R, R' , X' have the above-indicated meanings.
According to a preferred embodiment of the pro^ cess according to the invention, the compounds of the general formula Vlbis.are prepared, to obtain the compounds of lormula VI according to the invention, by reacting an <si -L-arabinohexopyranoside of the general 36 formula Vlter below P "o VI Hr r )r in which K and. K' are as defined above, X" is an azide, hydroxy, group or an alkylamine group whose alkyl radical includes 1 to 6 carbon atoms, Y" can represent halogen,when X" represents an azide or hydroxy group, or Y" represents hydrogen, an azide group, an Mi^ group, hydroxy group or an WHK',, 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 one or several, particularly up to 3, halogen atoms, NC>2> NHgj CF^ groups or alkoxy groups from lto 4 carbon atoms, a) either with an alcohol in an acid medium, in the case where X" is an azide group and Y" a halogen atom, hydrogen or hydroxy group or in a case where X" is a hydroxy group and Y" is an azide group, it is an alkyl group from 1 to 12 carbon atoms, aralkyl from 7 to 12 carbon atoms or halogenoalkyl from 1 to 12 carbon atoms and R' represents UM, M being an acyl group of 2 to 8 caroon atoms or arylester from 6 to 12 carbon atoms and where q\ -D-arabinohexopyranoside is deoxylated at 2,3»6-, the compound..obtained then being reduced, particularly by catalytic hydrogenation, for example in the presence of palladized carbon to convert the azide group into 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 ana K is an alkyl group from 1 to 12 carbon atoms or aralkyl from 7to 12 carbon atoms and where ^(_ D-arabinohexopyranosiae is trideoxylated at if, 3,6-th e compound obtained being then reduced, particularly / 209397 37 by catalytic hydrogenation, for example in the presence of palladized carbon, to convert the azide group into an NH2 group, c) or with trilluoroacetic anhydride, in Che case where X" is an ImH^ group and Y" is a hydroxy group, a hydrogen atom or in the case where X" is a hydroxy group and Y" is an NH^ group, R is an alkyl group from 1 to 12 carbon atoms or aralkyl from 7 to 12 carbon atoms .and K' a hydroxy group, the trifluoro acetamide 3-cX-u-ara-binohexopyranoside obtained being treated with an alcohol in acid medium to obtain the J-amino compound of the corresponding general formula and where c^-D-arabinohexopyranoside is dideoxylated at 2,3» or tri— deoxylated at 2,3*b- ; d) or with an aldehyde in an alcoholic medium, in the case where X" is an group, Y" is a hydrogen atom, an NH^ group or NHR*., group or a hydroxy group or in a case where X" is a hydroxy group and Y" is JNH., or ishk'., group and K and R' are as defined above, to obtain respectively the 3-desoxy 3-imino compound and/or the corresponding b—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 Oi -D-arabinohexopyranoside 3-nitrosourea of the corresponding general formula VI, 2,3- or 2,6 - aideoxylatea or 2,3,6-trideoxylated.
To prepare the o(-u-arabinohexopyranosides-nitrosoureas according to the invention, procedure is preferably as follows : r/lodification a) of the process : To a solution of methyl 3-a.zido 4-U-acyl (or arylester) b-oromo 2,3»b-tridesoxy cK-K-srabinohexopyranoside, 0.01 mole, in 200 ml of hexane, are added 10 ml of alcohol (ethanol, benzyl or other alcohol) and 2 g of paratoluenesulfonic acid.
The solution is heated to reflux for 12 to 4& hours. After cooling, the reaction medium is poured onto a saturated sodium bicarbonate solution, then extracted / C*11 f*- A- ' . 4 / 38 with ether. The organic phase is evaporated to dryness and gives a crude residue which is chromato-graphed on silica to give Che ether of the general formula I corresponding to the alcohol.
Modification b of the process : An alkyl-or aralkyl-J-azido-b-bromo-2,3,b-tri-desoxy (X-D-arabinohexopyranoside, and preferably methyl-3-azido-6-bromo 2,3>b-tridesoxy CK-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 haliae, an aralkyl halide, for example. The suspension so-obtained is heated under reflux for 12 to 46 hours. After cooling and the slow addition of O 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 tetrahydrofuran. The organic phase, dried over sodium sulfate is evaporated to dryness. 60 to 90 c/o 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 -D-arabinohexopyranoside prepared by the method of J. BOIVIN et coll., Garb. Res. 65_ ( 1960) 223-42 to obtain methyl-trifluoro 3-acetamido-Q<.-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 £ of p-toluenesulfonic acid. 3y 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 2 0 9397 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 O.U5 ml of a suitable reducing agent such as sodium borohydride or cyanoborohydride, and it is shaken for 12 hours. After evaporation of the solvent, the residue is taken up again in 20 ml of water, the precipitate is drained, then dried under vacuum under P2 0^. The secondary amine obtained is recrystallized in alcohols.
The process is the same in the case where the 3-amino group is replaced, in the starting compound, by a 3-hydroxy group, the amino being in the 6 position. In the case where the desired compound must include a substitution by a secondary amine not only at the 3- position but also at the b- 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 - DI£GRAM_OF_THE_ MODIFICATION a) OF THE PROCESS : ETHERIFICATION / 40 2 093 9 II - DIAGRAM OF THE MODIFICATION b) OF THE PROCESS : J"MO=R 1 'Ranu JV1 = methyl, ethyl, benzyl, etc ..
■ Br and I r or (M )2SO40U M X '6r NaOH OR III - DIAGRAM OF THE MODIFICATION gl._0F _TIIE_PH0CES5 WITH BLOCKING OF THK AMINE AT THE 3 POSITION cn2y'I CJ3 tY ■O O(CCCF3)2 HO 'CCH3 0ck3 ho \VHcocFy CP. ho\^:;:2 IV - DIAGRAM OF THE MODIFICATION d) OF THE PROCESS CH2V" "Ov 0 iiC-R? 'V;H2 /OR NaEH4 if Y = NH, with R^ = R'2 CHONHT OHCP.'o BH4IJa CH2»HR'2 ~Ov • vI!HP-2/„n R •\__/0R 3b To prepare the cX-L-arabinohexopyranosides-nitrosoureas according to the invention, of formula VII and in which the nitroso group is on the 3 carbon, and E, Rf, X and Y have the above-indicated meanings procedure is advantageously as follows.
The compound of the following formula is treated with O-methylhydroxylamine hydrochloride and sodium acetate to obtain the compound of the following formula - A Q 0CH3 By treating the compound obtained previously by diborane and OH~ ions, the compound of formula is obtained. i'his compound is then treated with 2-chloro echyl isocyanate, to give the compound of formula nhconhch2ch2ci i'his compound is then dissolved, for example in formic acid, then treated with sodium nitrite, to give the compoundsof the formula j(ic-nch_ch_c1 II I 2 2 O NO i'o prepare the cX-D-xyl°hexopyranosides-nitrosoureas of the invention of formula I'll, particularly those including a nitrosourea group in 3 position, in particular the com y 9397 pound, of the following formula rH K :h 3 CrO I N-NO CH2CH2C1 it is possible to use the compound of the following for- which in a first step, is treated with 2-chloro ethyl isocyanate, to give the corresponding urea, that is to say methyl 3- C3-(2-chloro ethyl) ureidoj —3,4,b-tridesoxy cX-D-xylohexopyranoside of the formula l'he compound indicated above, by treatment with sodium nitrite in formic acid results in the corresponding nitrosourea, that is to say methyl 3- £ 3-(2-chloro ethyl) 3-nitroso ureidoj 3»4,b-tridesoxy (A-D-xylohexopyranoside of the tormula : mula P3 oh C.-0 ^HCM2CH2C1 ch3 n-no c112 c h 1 All the compounds which can be used in the preparation of the compounds of the formula I, particularly of formula VI, can be prepared by applying one or other of the reaction sequences described above, as well as suitr-able reaction sequences described in the examples given "belov/, by way of illustration. 44 EXAMPLES EXAMPLE 1 Preparation of benzyl 3-azido 4-0- benzoyl 6-broino 2 , 3, 6-tridesoxy cA-D-arabinohcxopyranoside °y resorting to the first modification of the process.
To a solution of methyl 3-az.ido 4-0-benzoy.l 6-bromo 2, 3 , 6-tr.idesoxy cX.-D-arabinchexopyrano.side (1.5 g> 4.0 5 ramol.) in 125 ml of n-hexane, are added 10 ml of benzyl alcohol andl g of p-toluenesulfonic acid. The suspension is heated to reflux for 20 hours v/ith azeo tropic removal of the methanol released,, After cooling, the reaction medium is poured into a saturated, solution of sodium "bicarbonate then extracted with ether. The excess benzyl alcohol is then removed by azeotropic extraction with water, then with toluene. The crude residue so-obtained (1,8 g) is chro-matographed on silica K with the mixture hexane/methylene chloride, 2:1 as eluant. 1.5 £ of benzyl 3-azido 4-0-benzoyl 6-brorno 2,3 » 6-tr.idesoxy tX-D-arabinohcxopyranos.ide (84«) are isolated .
MP l 77°0 (hexane) - [<4 ^°; -j. 20° (c ; l£jCIiCl3) lfinuj0ls' 2100 cm"' <"3) "v 1760, 1260, 1030 era (eater) \j 1600, 1585 cm~ (aromatic) In the same manner there is prepared, for example: - Ethyl 3-azido 4-0-benzoy.l 6-bronio 2,3 > 6-tr.idesoxy 2^-D-arab inohexopyrano.s j.de. - p -ch] orobonzyl 3-«*ziflo 4-0-be;izoyl 6-bromo 2,3,6-tridnsoxy C<-D-arabinohexopyranos.Lde. 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 uC-D-arabinohexopyranoside. / *09^97 45 - methyl 3-azido 6-bromo 2,3,6-tridesoxy 4-0- ethyl CX-D-arabinohexopyranoside . methyl 3-azido 6-bromo 2,3,6-tridesoxy 4-0- benzy1 (X-D-arahinohexopyranoside . ethyl 3-azido 6-bromo 2 , 3, 6-tr idesoxy 4-0- ethyl (X-D-arabi nohexopyranoside . ethyl 3-azido 6-bromo 2,3,6-tridr.soxy 4-0- benzyl <X-D-arabi nohexopyranoside . benzyl 3-azido 6-bromo 2,3,6-tridesoxy 4-0- ethyl cX -D-arabinohexopyranosi do . benzyl 3-azido 6-bromo 2 , 3 > 6-tr.idesoxy 4-0-bonzyl C\-D-arabitiohexopyranoside.
EXAMPLE 3 Use of the third modification of the process.
To a solution of 300 m# (1.16 mmole) methyl 3-f1uoroacetamido 2,3,6-tridesoxy CX-D-arabinohexopyranoside in 100 ml of n-hexane, are added 5 ml of benzyl alcohol and 300 mfr 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 (30^5) of pure product are isolated.
MP : 16 "j0 C - [<*] D : + 66 (c : 0.5%, CHCl^).
The amine is then liberated by the action of potassium carbonate in an aqueous methanol medium.
By proceeding in the manner which lias just been described, the following compounds, given by way of example, are prepared : . benzyl 3-amino 2 , 3 , 6-tride.soxy oi -D-arabinohexo-pyrarosido . ethyl 3-amino 2 , 3>6-tridesoxy <X-D-arabinohexo-pyranoside . benzyl 3-amino 2,3-didesoxy ex.-D-arabinohexopy-ranoside . ethyl 3-amino 2,3-didesoxy cK-D-arabinohexopyranoside . 46 EXAMPLE 4 Use of the fourth modification of the process. By proceeding in accordance with the fourth modification of the process it is possible to 5 prepare, among others, the following compounds, given by way of example: . methyl 3-ethylamino 2,3,6-tridesoxy CX-D-arabi-nohexopyranos ide ^ . methyl 3-benzylami no 2,3>6-tridesoxy C*-D-ara- —' 10 1) inohexopyranoside . methyl 3-ethylamino 2,3-didesoxy cA-D-arabino- hexopyranoside . methyl 3-benzy1 amino 2,3-didesoxy cX-D-arabino-—v hexopyranoside ^5 . benzyl 3-ethylamino 2, 3,6-tridesoxy cK-l)-ara- binohexopyranosido . benzyl 3-benzylami no 2,3»6-tirdesoxy cX-D-ara- b inohexopyranoside . methyl 6-ethylamino 2,6-didesoxy cX-D-arabino-20 hexopyranoside . methyl 6-benzylamino 2,6-didesoxy cX-D-arabino- hexopyranoside . henzyl 6-ethylamino 2,6-didesoxy Oi -D-arabino-hexopyranoside . benzyl 6-benzylamino 2,6-didesoxy -D-arabino- hexopyranoside.
By doubling the amount of aldehyde and of reducing agent employed, the following secondary aminos substituted at the 3,6 positions are prepared: . methyl 3,6-diethy1 amino 2 , 3,6-tridesoxy Oi-D- arabi nohexopyranos i de . methyl 3,6-dibenzylamino 2,3,6-tridesoxy CX-D-arabinohexopyranoside •~J • benzyl 3 , 6-diethyl amino 2 , 3 > 6-tridesoxy CX-D- arabinohexopyranoside . benzyl 3 , 6-d.ibenzy lamino 2 , 3 , 6-tr idesoxy (Pi-D-arabinohexopyranoside. 2 0^3 9 47 EXAMPLE 3 Methyl 3 - [.3-( 2-ch 1 oro ethyl) ureido] 2,3,6-tridesoxv -D-arabinohexopyranoside - Compound 1.
To a solution of 0.8 g (5 x 10~-^mole) of methyl 3—amino 2,3,6-tridesoxy CX-D-arabinohexopyranoside (prepared according to the method of J. BOIVIN et Coll. Carb. Res. &5_ (1980) 223-42) in 2ml of anhydrous DMF are added, drop by drop, at 0°C and with stirring, 0.4 ml (5.10~-^ mole) of 2-chloro ethyl isocyanate. After 5 hours stirring, the reaction mixture is evaporated to dryness under vacuum. The residue, after purification by chromatography on a silicate column, with CHCl-j : 95» MeOH : 5 eluant, gives a single spot product crystallizing in anhydrous ethyl ether. The crystals were drained and then dried. (0.8 g, yield 60^) ANALYSIS C^yH^gCl : 266.5 - Calculated °/o C:45.0, H: 7.1, N : 10.5 - Found Jo C : 44.9, H : 7.0, N : 10.5. MP: 125 - 127° NMR Spectrum Solvent : DMSO.dg : 1.14 (d CH^-b' J =6Hz) 1.46 (t(a) H-2'axJ = J» * 12 Hz, J" = 4Hz) 1.90 (dd H-2' J= 12Hz, J'= 4Hz) 2.78 (t H-4' J = J' = 9Hz) 3.19 (s 0CH3) 3.28 (m OH^-4) 3.42 (m H-5') 3.53 (m CH^-5) 3.61 (m H-3') 4.58 (d H-1' J = 3Hz) 5.99 (d NH J = 8Hz) 6.14 (t i*H J = J' = b riz).
EXAMPLE b Methyl 3-[3-(2-ch1oro ethyl) 3-nitroso ureido] 2 , 3>6-tridesoxy CK -D-arabino-hexopyranoside - Compound 2 (IC 8l. 1 183) _ "3 1.2 g (4.5.10 mole) of methyl 3-[3-(2-chloro ethyl ) uroi do] 2,3, 6-tri desoxy -D-arahinohexopyranoside were dissolved in 6 ml of formic acid. To the solution maintained at 0°C, were added in small portions and with stirring 2.5 g (0.03b 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 poured onto 100 ml of ethyl acetate and then dried over sodium sulfate and evaporated to dryness under vacuum. After purification on a chromatograph column, with silicate sup 48 port, an eluant CHCl^ : 9, MeOH : 1, colorless crystals were obtained (600 mg, Yield 45>).
ANALYSIS C^H^gOl N^O^: 295.71 - Calculated °/o c : 40,6, H : 6.1, ft : 14.2 - Found 7° u : 40.9, H : 6.0, N : 13.9. MP : 100°C • + 92.5° (c: O.b io CHC13) - [a]^ : 123.6° (c : 0.5 io CHCl^) ftMK Spectrum (l)MSO, dfe) 1.1b (d CHyb1 J = 6 Hz) 1.78 to 1.94 (m Cti2 -2') 3.04 (t H-4' J = J'=9Hz) 3.25 (s 0CH3) 3.51 (m H-b') 3.60 (t CH2-4 J = J» = 6Hz) 4.10 (m CH2-5, H-3') 4.bb (d H—1' J = 3Hz) 8.48 (d NH J = 9 Hz).
Mass Spectrum : (M + 1) : 296.
EXAMPLH 7 Methyl 3-azido 2, 3-didesoxy 0<^-D- arabinohoxopvranoside Compound 3 To 7 p (0.024 mole) of methyl 3-azido 4,6-benzyli-dene 2,3-didesoxy- 0^ -D-arabinohexopyranoside prepared according to RICHARDSON A.C., (Carbohyd. Res. 4 (1967),422-428), in solution in 400 ml of anhydrous methanol is added drop by drop and with stirring, 8 ml of acetyl chloride. After 6 hours stirring at ambient temperature, the solution is neutralized by bubbling gaseous ammonia through it. After evaporation under reduced pressure, the residue is taken up again with acetone under reflux.
The acetone solution is concentrated under reduced pressure. Ry the addition of hexane, and then by cooling, white crystals are obtained which are drained, washed with hexane, then dried under vacuum. 3*45 g (71$) is obta i ned.
ANALYSIS C7H13N^04 : 203-2 MP : 123°-124<>C 9 n [OQ D : + 183° (c : 1 %, MeOH) IR : OH 3340, 3280 cm"1; 2100 cm-1 EXAMPLE 8 Methyl 3-amino 2,3-didesoxy -D-arabino- hnxopyranoside Compound 4 A solution of 5 g (0.0225 mole;) of methyl 3~ azido 2,3-didesoxy -D-arabinohexopyranoside in 10 ml of methanol is stirred 12 hours und«r a hydrogen atmosphere, 2093 97 49 in the presence of triethy1 amine (1 ml) and 10% palladized carbon (l g) . The catalyst is removed by filtration.
The filtrate, evaporated to dryness under reduced pressure, gives 4*35 ff of compound 4 in the form of a colorless 5 oil .
This compound is crystal1ized in hydrochloride form.
ANALYSIS C7H15N04, HC1 : 213-67 MP : 120°C (dec.) [*.] : + 90° (c : 1%, "2°)« EXAMPLE 9 Methyl 3-C3~(2-chloro ethyl) 3-nitroso ureidoj 2,3-didesoxy CK-D-arabinohexo-pyranoside - Compound 6 (IC 81.1184) From compound 4, following the operational method already described, methyl 3-[ 3-( 2-chloro ethyl)ureido] 15 2 .3-didesoxy o( -D-arabinohexopyranoside, _5 is obtained by the action of 2-chloro ethyl isocyanate.
ANALYSIS C10H19C1N205: 282 - Calculated % C : 42.5, H:6.7, V : 9.Q Found t C : 42.3, H : 6.8, N : 10.0 MP : 12 5°C [a*3 n : + 1680 (c:0.25%, CJIC1 ) Then by nitrosation with sodium nitrite, in formic acid, Compound 6_ is obtained.
ANALYSIS C10HlgCl 311-71 - Calculated % : C:38.5, H 5.8, N 13-5 Found %: C: 38.4, H: 5-6, N: 13-6.
MP: 118°C 2 0 2 0 [«*] D : +96.2° (c: 0.5%, CHC1 ) - ^365 : ll8-°° <c : 0.5 %, CIIC1 3) NMR Spectrum (DMSO.d^J : 1.82 (t(d) II-2'^J = J 1 = 12 Hz, J" : 4Hz) 1.88 (d (d) II-2'eqJ=l2 IIz J1 = 4Hz) 3-28 (s 0CH3) 3-43 (r H-4' J=.J' = 9 Hz) 3.35 to 3. S3 (m H-5', »-3' ) 30 3-49 to 3. 67 5ab CI1„-61 J = 1211z) 3-61 (t CH -4 J = J' fL,& ill = 6Hz) 4.10 (m CH2-5) 4-73 (d 11-1 ' J = 4Hz) 8.53 (d NH J = 9Hz).
Mass Spectrum (chemical ionization) : m/e 312 (Cl^, M+l, Basic peak) and m/e 314 (d-37' 30%); m/e 280 (M+l-32, 30%) 35 and m/e 282 (10%). so EXAMPLE 10 Methyl 3-azido 6-bromo 2,3,6-tridesoxy Q(-D-arabinohexopyranoside-Compound 7 10 g (0,026 mole) of methyl 3-azido 4-0-benzoyl 6-bromo 2,3,6-tridesoy Gk -D-arabinohexopyranoside prepared according to Hanessian, J. Org. Chem. ^4 (1969)1045-1053, are dissolved in 100 ml of 1 M methanol ic 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 11-60 and gives 6 g (Yield 84^) of Compound _7_.
ANALYSIS Cy"j 2^r N3°3 : 266.22 M ^° : + 124° (c : 1%, CHCl ) IR Spectrum : 3420-3440 cm" (OH) 2100 cm-1 (N.j) EXAMPLE 11 Methyl 3-azido 6-bromo 2,3,6-tridesoxy■ 4-0-methyl <o( -D-arabinohexopyranoside - Compound 8 «5 g (0.021 mole) of compound 7_ are dissolved in 200 ml of anhydrous tetrahydrofuran. 20 g of soda are added an<^ then 20 ml of methyl sulfate. The reaction mixture is brought to reflux for 24 hours. After cooling, 100 ml of water were added. The organic phase is drawn off by decantation then the aqueous phase is again extracted with 100 ml of tetrahydrofuran. The organic phase, dried over sodium sulfate, is evaporated to dryness. 5-7 g (Yield 9S%) of compound 8_ is obtained. It is purified by chromatography on silica H (eluant hexane-methylene chloride 1:1).
ANALYSIS c8H14BrN3°3 : 28o>25 n r\ IbO n : + l88° (c : 1%> CHCl ) . -1 IRSpectrum : \i N^ 2 100 cm EXAMPLE 12 Methyl 3~amino 2, 3,6-tridesoxy 4- 0-methyl -D-arabinohexopyranoside -Compound 9 -15 £ (0.0l8 mole) of compound _8 in solution in 100 ml of anhydrous ethanol and 3 nil of redistilled 51 triethylamine are placed under hydrogenation in the presence of 2 g of palladium on carbon, at ordinary pressure, for 12 hours. After removal of the catalyst, the solution is passed over an IR 45 ion exchange resin, OH- form. The solution evaporated to dryness results in 3-5 g of crude product purified by chromatography on silica H, eluant CH2CI2 - MeOH 9:1 ANALYSIS C8H17N03 : !?5.22 [>] 20. + 109o (c . cue 1 ) EXAMPLE 13 Methyl 3-[3-(2-chloro ethyl) 3-nitroso ureido] 2,3,6-tridesoxy 4-0-methyl iCX-D-arabino hexopyranoside - Compound 10 (IC 83-1373) It is obtained by the usual method from compound 9.- ANALYSIS Cj 1H20C1N3°5 : 309-75 - Calculated % C-.42.6, H:6.5, N:13•6 - Found % C: 4-2. 3, H:6.2, K:13.6.
MP : 60°C M p° : + 68.8° (c : 0.5 % CHClj) - [<*] *[? : +113-0° (c : 0.5 %, CHCl^) NMR Spcctrum (DMSO-d^): 1.19 (d CIl^ J = 6Hz), I.87 (m CH^-2') 3-01 (t H-4'J=J'= 9Hz) 3-25 (s 0CH3-1) 3.35 (s OCH - 4) 3-53 (m II- 5) 3-63 (t CH2-4 J = J' = 6llz) 3-61 (m CH2> ) 4.18 (m H-3') 4.66 (d H — 1 ' J = 3Hz) 8.73 (d NH J=9Hz). Mass Spectrum (chemical ionisation) : m/e 310 (C13_,(M+1, Basic peak) and m/e 312 (CI^7' 30$)J m/e 278 (m+1-32, 90%) and m/e 280 (27%).
EXAMPLE 14 Methyl 3j6-diazido 4-0-benzyl 2,3j6- tridesoxy cK. -D-arabi nohexopyranoside Compound 11 6 g (0.092 mole) of sodium azotide were added to a solution of 6 g (0.016 mole) of methyl 3-azido 4 — 0—benzyl 6—bromo 2,3,6 — tridesoxy D — arabinohexopyranoside in 50 ml of anhydrous dimethylformamide . The reaction medium is brought to 80°C for 8 hours. After cooling and dilution with 150 ml of water, it is extracted several 209397 52 times with ethyl ether. The ether phase, after evaporation to dryness, under vacuum, gives a colorless oil : 5 g(98/£).
ANALYSIS c14h16N6°4 : 332.32 20 W D : + 51° (c: 2.2 %, CHCl^ IR Spectrum : 3450 cm * (Oil) 2115 cm * (N3) EXAMPLE 15 Methyl 3>6-diazido 2,3, 6-tridesoxy cK-D-arabinohexopyranoside - Compound 12 5 g (0.015 mole) of compound 11 were placed in solution in 50 ml of anhydrous methanol, then a molar solution of sodium methylate (50 ml) was added and it was stirred for 3 hours at ambient temperature. The solution was neutralized by filtration on Amberlite IR + 50 Fl 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 CI^C^K ANALYSIS CyH12N60 20 CcKl D : + 128° (c : 1.6 %, CHCl3) IR Spectrum£^m ' 3450 cm *(011) 2115 cm * ^3^ EXAMPLE 16 Methyl 3>6-diamino 2,3,6-tridesoxy (X-D-arabinohexopyranoside - Compound 13 3 g (0.013 mole) of compound 12 in solution in 100 ml of ethanol with \% triethylamine are hydroeenated 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 j ainmoniacal MeOH 80:20) enabled isolation of the pure product 1 3• ANALYSIS C7Hl6-N'20 : 176.25 [cC + 130° (c : 1.13??, MeOH) IR Spcctrum£^jm : 3700 cm * (OH), 3360 cm * (NH) EXAMPLE 17 Methyl bis 3,6-[3-(2-chloro ethyl) 3-nitroso ureido] 2,3, 6-tridesoxy C^-D-arabinohexopyranoside.
-Compound 14 (IC 83-1374) <£hn W 53 1 1 2 n 2 5 '-j usual method from com- c : 3 5 • 1 j It is obtained by the pound 13■ analysis c13h22ci2n6o7 H:5-0, N:l8.9 - Found MP : 102 °C M d°: '59-0° (c : 0.5 (c : 0.5 %, CHCl^) NMR Spectrum (DMS0-d6): 1.84 (m CH2~2') 3-15 (s 0CH ) : 445*267 - Calculated C : 35 • 3 > II: 5. 1 , N: 19-2.
S, CUC1 )- fcO 20 . +74.0° 3.17 to 3-77 (m CH2-6\ H-3', H-4' , H-5', 2CH2-4) (m 2ch2-5) 8.41 4.06 (t NH J=j1=6Uz) 447 449 37 37 EXAMPLE 18 4.66 (d 11-1 J = 3Hz) 8.50 (d NH J = Q H z ).
Mass Spectrum : (M + l) : 445 100 % Basic peak CI 35 37 Methyl 3-0-acetyl 4, 6-0-benzylidene 2-desoxy 0( -D-arabinohexopyranoside - Compound 15 40 ml of redesti1led acetic anhydride are added to 10 g (0.037 mole) of methyl 4,6-0—benzylidene 2-desoxy "D-arabinohexopyranoside in solution in 50 ml of anhydrous pyridine . After 48 at 50°C, the reaction mixture is cooled then poured onto cracked ice, extracted 3 times with 100 ml of dich I oramethane. The organic phase dried over sodium sulfate gave after evaporation, 11.5 P (99%) of a crystalline product that is purified by recrystalli-zation in the hexane-acetone mixture.
MP : 12 5° - 127 °C. n M - : + 74° (c IR SpcctrumNi| .ol if., chloroform) 1728, 1240 cm - 1 (c = 0 ester).
EXAMPLE 10 Methyl 3-0-acety] 4-0-benzoyl 6-bromo 2,6-didesoxy C(-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 J_5 in solution in 200 ml of carbon tetrachloride.were added. The reaction was brought to reflux for 3 hours. After cooling and removal of the insoluble by filtration, the organic phase was washed with a saturated solution of sodium bicarbonate.
After evaporation, 6.4 g (98%) of a single spot oily product in t.l.c. are obtained. [crt] 1° : +70 (c : 1.45 %, CHC13> IR Spectrum : 1730 cm-1, 1240 cm-1 (CO ester) 1600, 1585 cm-1 (aromatic) EXAMPLE 20 Methyl 3-0-acetyl 6-azido 4-0-benzoyl 2,6-didesoxy cX-D-arabinohexopyrano-side. - Compound 17 To a solution of 8 g (0.020 mole) of compound _1_6 in 50 ml of anhydrous dimethylformamide were added 8 g (0.12 mole) of sodium azotide. The reaction mixture was o brought to 80 C for 8 hours.
After cooling and dilution with water, the reaction mixture was extracted with ether. The solution washed several times with water, was dried over sodium sulfate. After evaporation under vacuum, the residue was purified by chromatography on silica (eluant hexane-ethyl acetate, 3-1). 6.5 g of pure product were isolated (95%). The product was recrystallized from hexane.
ANALYSIS C16HigN305 : 349.38 MP : 68cC H 1° ' + 90 (c : r/c, CHC13) IR : 2100 cm"1 (azide) 1725, 1280, 1050 cm"1 (ester) 1610, 1590 cm"1 (aromatic) EXAMPLE 21 Methyl 6-azido 2,6-didesoxy -D-ara binohexopyranoside - Compound 18 A methanolic solution of sodium methylate (20 ml) was added to a solution of 4.96 g (0.014 mole) of compound 17 in 50 ml of anhydrous methanol. 2 C v '3 9 7 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 on a silica column to remove the methyl benzoate. 2.76 g of compound 18 were obtained (96$).
ANALYSIS : CyH^N^ : 203.2 +104 (c : 1%, chloroform).
IR Spectrum : 3400 cm-1 (OH) 2120 cm-1 (azide).
EXAMPLE 22 Methyl 6-amino 2-desoxy oi-D—arabino- hexopyranoside - Compound 19 A solution of 2.40 g (0.011 mole) of compound in 25 ml of anhydrous ethanol was shaken under a hydrogen atmosphere in the presence of 10% palladium on carbon (500 mg) for 12 hours. After elimination of the catalyst, the evaporation of the filtrate led to an oily product 2 g (95 7°) • A sample was converted into the picrate.
ANALYSIS : c-|3Hi8N4°11 ; 406.35 MP : 156"c (ethanol) +75 (c : 1.2 chloroform).
EXAMPLE 23 Methyl 3- [3—(2-chloro ethyl) 3-nitroso ureido ] 2,b-didesoxy c< -D-arabinohexopyranoside -Compound 20 (IC83 1350) It is obtained by the usual method from compound 12- ANALYSIS C10Hl8Cltf30b : 311.728 - Calculated % : C:38.5, H:5.8, N:13.5 - Found % : C:38.5, H:5.5, N:13.4.
MP : 101 C (dea) P°: +26.2 (□ : 0.5 7°, CHCl^) Of) ^5: +51.0 (c : 0.5% , CHC13) NMR Spectrum (CMS0-dfo) : <3 1.45 (t(d) H-2'axJ = J» = 12Hz, J" = 4Hz), 1.85 (d(d) H-2'eq J= 12Hz J' = 4Hz), 2.95 (t H-4' J=J'=9Hz), 3.10 (s-0CH3), 3.30 (m H-3' )» 3.51 (m H-5 + a CH2-6«), 3-56 (t CH2-4 J=J'=bHz), 3.75 (dbCH2-6' m = 12Hz), 4.06 (m CH„-5), 4.15 (d H-1'J = 3Hz), 4.81 (OH), 5.10 (OH), 8.50 (t NH).
Mass Spectrum : (M+ 1) = 312 CI^ 314 01^ (Loss of MeOH -32) 280.
EXAMPLE 24 Methyl N methoxycarbonyl 3-amino 2,3,6- . tridesoxy c*-I)-arabinoh.exopyranoside - 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 c{_-D-arabinohexopyranoside in 200 ml of anhydrous methylen chloride. The reaction mixture was kept 2 hours at ordinary temperature, then 100 ml of 4N soda were added. After one night with stirring, the organic phase was separated by decantation, the aqueous phase extracted with 100 ml of methylene chloride. The organic phase washed with distilled water was dried over sodium sulfate.
After evaporation under vacuum, the residue obtained was recrystallized in a methanol-methylene chloride mixture, 1.7 g (80%).
ANALYSIS (JgH17N05 : 219.24 MP : 180°C [<*] : +157 (c : 1%, CHC13).
EXAMPLE 25 Methyl 3-methylamino 2, 3»6-tridesoxy (X -D-arabinohexopyranoside-C ompound 22 1.7 g (0.00 77 mole) of compound 21_ in 50 ml of anhydrous ethyl ether were added drop by drop, so as to maintain a slight reflux (30') to 1 g of lithim and aluminium hydride in 100 ml of anhydrous ethyl ether. The reflux was continued for 6 hours. After cooling, the excess of hydride was decomposed by the very slow addition of 1 ml of water, then 1 ml of 3N soda, then 3 ml of water. The precipitate was removed by filtration. After evaporation under vacuum and then recrystallization in a mixture acetone-hexane the organic phase dried over sodium sulfate gave , 1.U5 g of crystals (8<J%); MP : 105 C.
ANALYSIS CgH17W0s : 175.23 / 2 0 9 j 9 7 57 h b9 (c: >/>, chg13) EXAMPLE 26 Methyl 3-[3-(2-chloro ethyl) 1-methyl 3-nitroso ureido ] 2,3,6-tridesoxy o(-D-arabinohexopyranoside - Compound 23 (IC 83.1375) It was prepared according to the usual method from compound 22. l'he examples 5 to 25 above are illustrated by the following reaction diagrams : -••v o u Examples 5 and 6 "ch; / o NH .■ HO V 3 /OCH- Examples 7a 9 0 = c = n-ch2ch2c 1 : > NaNO.
HO\f"\" / OCH3 HCOOH conh-cil2ch2cl COMPOUND 1 pd/c hoy3 /och3 h2 compound 3 CII3 I\nh hq\f\ / och 3 nsvcon-cii2ch2ci no 0 = C = n-CH2CH ci h<knh* /och- U1 00 compound 4 oh 0 NaNO. 2 ho^L/0CH3 hcooh ^CO-W!- CU2-CII2C1 compound 5 COMPOUND 6 ocii3 co-n-cii2ch2ci mo tVii t .t i.j. .. . . i-i»..n »r«wra»ott!*^rg?^ o I ) •'% ■Br Examples j n loTljy w B zcN^3 /OCH3 c h 3 0 h a —> (CHjJgSO,, OCH, laOII COMPOUND " - CH30\T /OCH COMPOUND S Pd/C i) o=c=ii-ch2ch2gi CHnO\i 2 /OCH3 2) NaNO,,, HCOOH CHa° NaN /DMF compose 9 BzO OCH, C H 2 0IJ a COMPOUND 11 O CHn COMPOSE 10 'CON-CI^CH^CI' to pd/c c;i2nh2 HO V3 _./OCH3 COMPOUND 12 in \D /OCH3 COMPOUND 11 1) O=C=M=CH2CH2CI 2) NaNO^COOH •NO H„NHCO-Vj- COMPOUND 14 Cfl2Cl N-CH,CH_C1 I 2 2 NO % <4 i VI ■-VII.1 ■/! !.\ c () Examples 18 a 23 ( ) NBS 3 BaCO.
CH,Br d ^.\OAc BzO\i / OCH- i> a M.
DKF CH30Na <\OAc , BzO\ /OCH3 Pd/C nu HOV /OCH, COMPOUND 16 OCH- compound 1*7 compound 18 compound 19 cr» o 1) 0 = c = n-chgchgc1 2) fJaN02, HCOOH 0 NO ii i ■NH- C-N-CH2CH2CI o OH HOV / OCH- compooni) 20 >v n a. t /• / ~ \ o Examples 24 a 26 ClCOOCH.
. NH, /' hox' 2 och3 A L 1 i H, K NH h°\k _/och. COOCII- och3 COMPOUND 21 compound 22 / • 1) 0=c=n-ch2ch2c1 2) HaN02 i HCOOH CTi honK^'Voch, CON-CIl2CH2Cl NO compound 23 K) O t-i vO V) 62 < * EXAMPLE 27 : Methyl 3 [3-(2-chloro ethyl) 3- nitroso ureido] 2,3,6-tridesoxy ©t - L-arabinohexopyranoside Compound 26 - IC 841530 5 The preparation of methyl 3-amino 2,3,6-tridesoxy-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 chlo-10 rhydrate are added to 1.92g (0.012 mole) of methyl 2,6-didesoxy c(-L-erythrohexopyranoside 3-ulose in 25 ml of 50 % aquous ethanol. The reaction medium is brought to reflux 3 hours, then ethanol is evaporated. After extraction with dichloromethane and drying over sodium sulfate 15 sodium, a clear oil (2o) is obtained, the structure of which is confirmed by NMR and corresponds to 0-methvloxime of L-acosamine.
This oil is solubilized in 20 ml of anhydrous tetrahydrofurane and 30 milliequivalents of diborane are 20 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 % potash are added carefully. The reaction medium, brought to reflux 3 hours, then cooled, is extracted with ethyl 25 acetate. The organic phase gives, after evaporation, a residue, which, after purification, gives L-acosamine crystals.
M.P. 130°-133°C. [o(] 20 : - 140°C (c : 0,6 %, MeOH).
The preparation of methyl 3-[3(2-chloro ethyl)ureido] 2, 3, 6 -tridesoxy Of-L-arabinohexopyranoside (compound 2_5) 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 35 3-amino 2, 3, 6-tridesoxy O^-L-arabinohexopyranoside in 8 ml of redistillated dimethylformamide. After 2 hours of 20T3>cn 63 Stirring, the reaction mixture is evaporated to dryness under vacuum. The crystals are dried^then washed with ether : 781 m£ (98 %) NMft Spectrum: Solvent DMSO D& : 1,14 (d, CH3~6', J=6Hz) ; 1,46 (T(d), H-2' J=J'=12 Hz, J "= 4 Hz) ; 1,90 (dd.H-21 , ox ' ' eq' J=12 Hz, J '=4 Hz) ; 2,78 (T,H-4\ J=J'= 9 Hz) ; 3,19 (s,0CH3) ; 3,28 (m,CH2-4) ; 3,42 (m,H-5') ; 3,53 (m,CH2-5) ; 3,61 (in, 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 2_6) , i.e. methyl 3 [3-(2-chloroethyl)3-nitroso ureido] 2,3,6-tridesoxy 2,3,6 a-L-arabinohexopyranoside is obtained from the product which has been previously synthesized, as follows 0.66g (2.5 X 10"^ mole) of [3 ( 2-chloro ethyl) 15 ureido] 2 , 3 , 6-tridesoxy ct-L-arabinohexopyranoside are dissolved in 5 ml of formic acid. 1.4 (0.02 mole) of sodium nitrite are added by small portions and under stirring to the solution which is kept at 0°C . After 30 minutes, 5 ml of water are added and the stirring is maintained for one 20 hour. The reaction mixture is poured on to 100 ml of ethyl acetate then dried over sodium sulfate and evaporated to dryness under vacuum. After purification, on a silica support column, eluent CH2 Cl2 : 98, MeOH : 2 colorless crystals are obtained : 210 mg (30 %) MP : 100°C ANALYSIS C1oH18C1N305 : 295,71 .
Calculated % :*- '■ 40,6 ; H : 6,1 ; N : 14,2.
Found % : C : 40,9 ; H : 6,1 ; N : 13,90.
NMR 4Spectrum_ (OMSO.Dg) : .1 , J 5 (d,01^-6 ' J=6 II/.) ; I ,78 a 30 1,94 (m, CH2-2') ; 3,04 (t,H-4'f J= 9 IIz) ; 3,25 (s,0CH3) ; 3,51 (m, H-5 ' ) ; 3,60 (T,CH2~4, ,7=J,= 6 Hz) ; 4,1O (m,CH2-5, H-3') ; 4,65 (d,H-l',J=3 Hz) ; 8,48 (d,NH, J=9 Hz). (followed by pages 63a ^o 63o) /P \ fe-8ttW«8Sj 63a ftdcifcienal example 28 Preparation of methyl 3-/3-(2-chloroethyl) 3-nltroso ureido/ 2,3,6-trideoxy P-L -arabino-hexopyranoside (IC 85-1615) 0 ) ^/och3 NHCNCH-CH-C1 II 2 2 0N0 a) Preparation of methyl 3-azido 2,3,6-trideoxy p-L-arabinohexopyranoside . 3 g. (0.016 mole) of methyl 3-azido 2,3,6-trideoxy ot-L-arabino hexopyranoside and 1 g. of toluene sulfonic acid in 50 ml of anhydrous methanol are stirred for 48 hours at room temperature.
The reaction mixture is evaporated to dryness in a vacuum. The residue is taken up in methylene chloride. After being washed twice with water, the organic phase is dried over sodium sulfate, evaporated to dryness in a vacuum and chromatographed on a column of silica (eluant hexane-ethyl acetate 5:1).
Analysis: C? H N 0 = 187.20 m.p.: 72°-73° (hexane) /~C*7d = + 63.5° (c, 0.8 CHC13) IR (Nujol) 3370 cm"1 (OH) 2100 cm"1 (azide) b) Preparation of methyl 3-amino 2,3,6-trideoxy f -L-arabino-hexopyranoside This compound is prepared analogously to Example 8. patent application Ijirun.1 H"—72817.■ 63b Analysis: C7H15N03 = 161.20 Yield - 85% m.p.: 136° /."c<7d: + 75.8° (c, 0.5 CHC13) . c) Preparation of methyl 3-/3-(2-chloroethyl) 3-nitroso ureido/ 2,3,6-5 trideoxy p-L-arabino-hexopyranoside.
The procedure is analogous to that indicated for example 9 application—Iaracl M"—720171 in which 2-chloroethyl isocyanate is used and nitrosation is carried out, for example, with the aid of sodium nitrite to give the compound of the invention,the physical properties of which are 10 indicated below.
Analysis: C10H18C1N305 = 295.7 tn.p.: 109°-110° /©<L7d = + 22.8° (c, 0.5% CHC13) •A^ditifcno4- example 29 15 Preparation of methyl 3-/3-(2-chloroethyl) 3-nitroso ureidoT 2,3,6-trideoxy -L-arabino-hexopyranoside (IC. 85-1625) VH3 shcncr/ch,ci jlT1 2 This compound is prepared from methyl 3-amino 2,3,6-trideoxy p-D-arabino-hexopyranoside analogously to the preparation of the compound described in example 9 of the application Iaiail M? 72017 by using 2-chloroethyl isocyanate and by nitrosating with the aid, for example, of sodium nitrite.
The physical properties of the compound of the invention are as follows: Analysis: C10H18C1N3°5 = 295 *7 m.p. 103°-105° / OC/D = -25.0° (c, 0.3% CHC13) 63c 2.0=1391 • example 30 \ I J ; v i -*! J Preparation of methyl 3—/3—(2 chloroethyl) 3-nltroso ureido/ 2,3-dideoxy B-D-arabino-hexopyranoside (IC 85-1673) ch2oh Preparation of methyl 3-azido 2,3 dideoxy p-D-arabino-hexopyranoside. 19.2 g. (0.095 mole) of methyl 3-azido 2,3-dideoxyt(-D-arabiro-hexcpyranoside 15 and 1 g. of p-toluene sulfonic acid in 200 ml of methanol are stirred for 48 hours at room temperature. The 1 residue obtained after evaporation in a vacuum is taken up in 60 ml of anhydrous pyridine. g. of acetic anhydride are added drop-wise while the temperature is 20 maintained at 15°. After being stirred for 16 hours the reaction mixture is evaporated to dryness. The residue is taken up in methylene chloride; the organic phase is washed with a solution of 2N HC1, then with water, and finally with a solution of sodium bicarbonate. The organic phase is dried 25 over sodium sulfate, evaporated in a vacuum and chromatographed on silica using as eluant hexane: acetone 4:1 to give 19.5 g. of compound 3 in the o form of its diacetate and 2.5 g. of methyl 3-a2ido 2,3-dideoxy p -D-arabino-1 hexopyranoside in the form of its diacetate.
This latter compound is taken up in 45 ml of anhydrous methanol and 30 then 5 ml of sodium methoxide are added. After being stirred for 4 hours the solution is neutralized by the addition of Amberlite IRC50 resin.
After evaporation the filtrate yields methyl 3-azido 2,3-dideoxy £ -D-arabino-hexopyranoside in the form of crystals.
Analysis: C?H N^: 203.2.
Preparation of methyl-3-amino 2,3-dideoxy p-D-arabino-hexj^gWafio&Jc] - This compound is prepared analogously to that indicated rear example 85^. application—Isiael N* 72017.1 ji\ _ p Jfi 63d 0093=17 k O Analysis: C?H NO : 177 m.p.: 140°-142° Z"c<_7d: -61.8° (c, 0.55% MeOH).
Preparation of methyl 3-/3-(2-chloroethyl) 3-nitroso ureido/ 2,3-5 dideoxy f-D-arabino-hexopyranoside.
The procedure is analogous to that indicated for example, for the preparation of the compound described in example 9 of the application Israel -NJ—72017 in which 2-chloroethyl isocyanate is used and nitrosation is carried out, for example, by the aid of sodium nitrite to give the compound 10 of the invention with the following physical properties.
Analysis: C10H18C1N306: 311.72 Yield: 70% m.p.: 68°-70° ^o47d: -37.9°(c, 0.36% MeOH).
-ArHitiawal* example 31 15 Preparation of methyl 3-/3-(2-chloroethyl) 3-nitroso-ureido/ 3,4,6-trideoxy QC-D-xylo-hexopyranoside (IC 85-1590).
CNCH,CH,C1 l»« 2 2 0N0 a) Preparation of methyl 2-0-acetyl 3-azido 4,6-dichloro 3,4,6 trideoxy oC-D-galacto-hexopyranoside. 52 ml of sulfuryl chloride are added drop-wise to 44 g. (0.21 mole) of 3-azido 3-deoxy D-gluco-pyranose in 160 ml of anhydrous pyridine and 200 ml of chloroform cooled to -78°C. After being maintained for 2 hours at -78°C, the mixture is stirred for 5 hours at room temperature.
The reaction mixture is diluted with 400 ml of chloroform, then washed 35 with 2N hydrochloric acid, water, then with a solution of sodium and again with water. After drying over sodium sulfate and evai v*'- to dryness in a vacuum, the residue is taken up in 200 ml of methanol to which is then added a 10% solution of potassium iodide in a water-methanol mixture (1:1).
After being neutralized by potassium bicarbonate, the solution is 5 filtered and evaporated and then the residue is taken up in chloroform. The organic phase is washed with a solution of sodium thiosulfate, then '2. with water, dried over sodium sulfate and evaporated to dryness.
The residue is taken up in 100 ml of pyridine and the solution is cooled to 0°C 20 ml of acetic anhydride are added drop-wise at 0°C 10 and the solution is stirred for one day, then the reaction mixture is evaporated in a vacuum, the aqueous phase is extracted 2 or 3 times with > 200 ml of methylene chloride. The organic phase is then washed with water, evaporated to dryness in a vacuum and 36 g. of a mixture corresponding to the 2 anomers and p are obtained. The two anomers 15 are isolated in the pure state by chromatography on a column of silica (eluant: hexane-acetone 10:1). 0*. Anomer: 14.5 g.; m.p.: 74°-76° (hexane-ethyl acetate) /1<_7d = +171° (c, 1.17 CHC13) anomer: 16.0 g.; m.p.: 108°-110° (hexane-ethyl acetate) 20 l~oUD = -6,5° (c, 1.58 CHC13). b) Preparation of methyl 3-azido 4,6-dichloro 3,4,6,-trideoxy oC-D-galacto-hexopyranoside. g. (0.017 mole) of the preceding c^-anomer are dissolved in 50 ml of 25 anhydrous methanol in the presence of 1 g. of p-toluene sulfonic acid.
The reaction mixture is allowed to stand at room temperature for 18 hours and then is evaporated to dryness in a vacuum. The residue is taken up in methylene chloride and the organic phase is washed twice with water, dried, filtered and then evaporated.
The crystals obtained (4.2 g.) are recrystallized from a mixture of hexane-ethyl acetate.
Analysis: c7h11c12n303: 256 >• , „„o . ,, o m.p.: 139°-14r = +188° (c, 1.035 CH30H). c) Preparation of methyl 3-araino 3,4,6-trideoxy o(. -D-xylo-hexopyranoside. To 2 g. (0.0075 mole) of the preceding compound dissolve anhydrous toluene under nitrogen are added 0.5 g. of azo 2,2' 2C^3,°fl isobutyronitrile followed by 8 ml of tributyltin hydride added drop-wise. The reaction mixture is heated under reflux for 10 hours. After the mixture has been cooled and the precipitate has been removed from filtration, the filtrate is evaporated to dryness in a vacuum. 5 Chromatography on silica (eluant: Cl^Clj- aramoniacal MeOH 9:1) leads to the pure amino sugar in the form of white crystals.
Analysis: C^H1cN0_: 161 7 15 3 m.p.: 136°-139° (ether-methanol) /X7d: +172° (c, 1% CHC13). d) Preparation of methyl 3-/3-(2-chloroethyl) 3-nitroso ureido/ 3,4,6-3 trideoxy e>(.-D-xylo-hexopyranoside (IC 85-1591) .
^ The procedure is the same as that for the preparation of the previous compound.
Analysis: C^H^CIN^: 295.7 Yield: 65% 15 m.p.: 103°-105° /X7d: +138° (c, 1.41 CHC13).
•Addifcim'igrir example 32 Preparation of methyl 3-/3-(2-chloroethyl) 3-nitroso ureid£/ 3,4,6-trideoxy p-D-xylo-hexopyranoside (IC 85-1591). 20 CH^ 0 CNCH_CH,C1 III 2 2 ONO a) Preparation of methyl 2-0-acetyl 3-azido 4,6-dichloro 3,4,6-trideoxy -D-galacto-hexopyranoside. 52 ml of sulfuryl chloride are added drop-wise to 44 g. (0.21 mole) of 3-azido 3-deoxy D-gluco-pyranose in 160 ml of anydrous pyridine and u , 200 ml of chloroform cooled to -78°C. After being maintained for 2 hours at -78°C, the mixture is stirred for 5 hours at room temperature. > % £>&4 The reaction mixture is diluted with 400 ml of chloroform, then washed with 2N hydrochloric acid, water, then with a solution of sodium bicarbonate and again with water. After drying over sodium sulfate and evaporation to dryness in a vacuum, the residue is taken up in 200 ml of methanol 5 to which is then added a 10% solution of potassium iodide in a water-methanol mixture (1:1).
After being neutralized by potassium bicarbonate, the solution is filtered and evaporated and then the residue is taken up in chloroform. The organic phase is washed with a solution of sodium thiosulfate, then 10 with water, dried over sodium sulfate and evaporated to dryness.
The residue it taken up in 100 ml of pyridine and the solution is f ^ cooled to 0° C 20 ml of acetic anhydride are added drop-wise at 0°C and the solution is stirred for one day, then the reaction mixture is evaporated in a vacuum, the aqueous phase is extracted 2 or 3 times with 15 200 ml of methylene chloride. The organic phase is then washed with water, evaporated to dryness in a vacuum and 36 g. of a mixture corresponding to the 2 anomers»(. and £ are obtained. The two anomers are isolated in the pure state by chromatography on a column of silica (eluant: hexane-acetone 10:1). oC Anomer: 14.5 g.; m.p.: 74°-76° (hexane-ethyl acetate) A<_7d =+171° (c, 1.17 CHC13) anomer: 16.0 g.; m.p.: 108°-110^ (hexane-ethyl acetate) o / 0C_/D = -6.5° (c,1.58 CHC13). b) Preparation of methyl 3-azido 4,6-dichloro 3,4,6-trideoxy J5-D-galacto-hexopyranoside.
The procedure is the same as that described in part b of IC 85-1590. Analysis: C^^Cl^O.^: 256 Yield: 85% m.p.: 135° +10-°° <c, 0.97% CH30H). c) Preparation of methyl 3-amino 3,4,6-3 trideoxy ^-D-xylo-hexopyranoside. y The procedure is the same as that described in part c of IC 85-1590.
Analysis: C^H^,.N03: 161 m.p.: 148°-149° ? /c<7d: -52° (c, 1% CHC13). * d) Preparation of methyl 3-/3-(2-chloroethyl) 3-nitroso ureido^ trideoxy p -D-xylo-hexopyranoside. t 6$h ■2.0 93^ > 15 25 o O , The preparation procedure is the same as that for the preceding compound.
Analysis: C^H^CIN^: 295. 7 Yield: 90% m.p.: 84°-90° £pC7d: +11-5° (c, 1.25 CHC13).
Additional example 33 Preparation of methyl 3-/3-(2-chloroethyl) 3-nitroso ureido/ 3,4,6-trideoxy -L-xylo-hexopyranoside (IC 85-1626).
NHCNCH-CH-C1 HI 21 CNO The compound is prepared according to the usual method starting from methyl 3-amino 3,4,6-trideoxy oL -L-xylo-hexopyranoside prepared according to H. Baer, Canad. J. Chem., vol. 52, 1974, p. 122-124.
Analysis: c10hi8c1n3°5: 295'7 yleld: 65Z m.p.: 103°-105° /&C7d - -141.5 (c, 0.71 CHC13).
Additional example 34 Preparation of methyl 3- /3-(2-chloroethyl) 3-nitroso ureido/ 3,4,6-trideoxy £ -L-xylo-hexopyranoside (IC 85-1627).
ONO £3/ - X - ^.o<=i3q^ The compound is prepared starting from methyl 3-nitro 3,4,6-trideoxy -L-xylo-hexopyranoside described by H. Baer, Canad, J. Chem., 52, 1974, p. 122-124. 1) Preparation of methyl 3-nitro 3,4,6-trideoxy ^-L-xylo hexopyranos ide. 40 ml of IN hydrogen chloride in methanol are added to 1.8 g. of the above »<. anomer. After being refluxed for 2 hours the reaction mixture is evaporated to dryness and the residue is purified on a column of silica (eluant: CK^Cl^-MeOH 98:2). 500 mg of the pure p anomer are obtained. 2) Preparation of methyl 3-amino-3,4,6-trideoxy p-L-xylo-hexopyranoside. The preceding compound is dissolved in ethanol and hydrogenated at atmospheric pressure in the presence of platinum oxide.
Analysis: C^H^NC^: 161 Yield 80% m.p.: 146°-148° /H7d = + 36.0° (c, 0.96 CHC13). 3) Preparation of methyl 3-/3-(2-chloroethyl) 3-nitroso ureid£/ 3,4,6-trideoxy -L-xylo-hexopyranoside.
The procedure is the same as that previously described.
Analysis: C^HgClN^: 295.7 m.p.: 90°-92° (isopropyl ether) ' Z-c<7d: -9.0° (c, 0.6 CHC13) PROTOCOL FOR TREATMENT USING THE PRODUCTS OF THE INVENTION I. Materials and methods A - Tumors used. 2 murine tumors were used for the "in vivo" studies: leukemia L1210 and melanoma, B16. 1) Leukemia LI 210 . Animals The experiments were always carried out on female mice which were specific pathogen-free (S. P. F.), - either of the line DBA/2JIco - or of the line B6 D2 Fl/Jlco (first geiv6i%tIon // « hybrids between the lines C57BL/6 and DBA/2). .'m* m 6i i -yf-i ■2.QC13R1 r7* v -• o o The line used in each experiment is specified.
. Tumoral graft On the day of the graft (by convention day 0 = DO) an inoculum of 1 x 10^ tumor cells in a volume of 0.2 ml is 5 administered to each mouse by the intraperitoneal route (I.P.).
This inoculum is prepared by diluting ascites fluid taken from the peritoneum of a donor female nrpuse in NCTC 109 medium (Eurobio Laboratories, Paris, France), counting of the cells in a MALASSEZ cell under a microscope and adjustment of the concentration to 10 5 x 10 cells per liter by means of the same medium.
The tumor line is an American strain of the line L1210.
. Distribution in experimental groups After the tumor graft, the mice are 15 distributed at random in cages of 5 animals. Subsequently, these cages containing 5 mice are themselves distributed at random into a control group (control) and groups treated with the I.C. products. 2) Melanoma 16 . Animals The experiments are always carried out y on SPF female mice, B6 D2 Fl/JIco (first generation hybrids between the lines C57BL/6 and DBA/2).
. Tumoral graft On the day of the graft (day 0), an inoculum 25 of 2 x 10^ tumor cells in a volume of 0.5 ml is administered to each mouse by the intraperitoneal route (I.P.). This inoculum is prepared from a sub-cutaneous tumor excised from a donor female mouse. After excision the tumor is fragmented by means of a pair of scissors in the NCTC 109 medium. After filtration through sterile gauze in order to remove 30 large cellular fragments, the homogeneous cell suspension obtained is counted by means of a MALASSEZ cell and diluted to the desired concentration (4 x 10^ tumor cells per ml) by dilution with the NCTC 109 medium.
. Distribution in experimental groups This was performed in the manner descrl 35 for the leukemia L1210 (see above).
B - Protocol for treatment. } 6sic -x- 2033^ The doses of the products of the invention used in the different experiments are expressed in milligrams per kilogram of body weight.
In each experiment the animals of the control group received 1 or more injections, depending on the experimental protocol used, by the same route (I.P. or I.V.) of the same volume (0.2 ml/20 g) of the vehicle without the active principle (isotonic sodium chloride solution). II - Expression of results For each experiment a table specifies: the number and percentage of the total of the mice surviving to D60, the T/C x 100 for the treated groups. in the control group (controls).
III - Comment The strains of mice used, the experimental protocols and the mode of expression of the results are in accordance with directive 271 F of the "N.C.I. Division of Cancer Treatment" (November 1983).
IV - Pharmacological results IC. 1625 L1210 USA - DBA2 - I.P. treatment on Dl, D5, D9 . T representing the mean survival time of the mice in the treated group, . C representing the mean survival time of the mice T/C 190 3 x 10 mg/kg Number of survivors at D60 (0/10) IC. 1673 L1210 USA - B,D0F. - I.P. treatment on Dl, D5, D9 O * 1 3 x 1.25 mg/kg K ^ £3/ -y£- 2os2m kj, T/C Number of survivors 158 (0/10) L1210 USA - 6^2^ - I.P. treatment on Dl, D5, D9 T/C 626 Melanoma B16 - T/C 232 3x5 mg/kg Number of survivors (6/10) I.P. treatment on Dl, D5, D9 3 x 10 mg/kg Number of survivors (A/10) IC. 1591 L1210 strain USA - DBA2 - I.P. treatment on Dl 1 x 20 mg/kg T/C Number of survivors on D60 >600 (7/10) L1210 strain USA - DBA2 - I.P. treatment on Dl, D5, D9 3x5 mg/kg T/C Number of survivors on D60 y 600 (6/10) L1210 strain USA 3 x 1.25 3x5 3 x 10 T/C 116 f 217 600 Melanoma B16 - B^D2F^ - I.P.
T/C 194 IC. 1626 30 L1210 strain USA B,D_F, - I.P. treatment on Dl, D5, D9 D / 1 3 x 1.25 mg, 3 x 5 mg, 3 x 10 mg/kg Number of survivors on D60 (0/10) (2/10) (8/10) treatment of Dl, D5, D9 3 x 10 mg/kg Number of survivors on D60 (3/10) DBA2 - I.P. treatment on Dl Number of survivors on D60: 1 x 20 mg/kg 3/10 L1210 strain USA - DBAj - I.P. treatment on Dl, D5, D9 T/C 3 x 2.5 mg/kg, 3 x 10 mg/kg Number of survivors on D60 OJDS3>°l"T v 3 x 2.5 150 (0/10) 3 x 10 275 (3/10) IC. 1627 L1210 strain USA - DBA^ - I.P. treatment on Dl, 5 1 x 20 mg/kg Number of survivors on D60: 3/10 L1210 strain USA - DBA^ - I.P. treatment on Dl, D5, D9 3x2.5 mg/kg, 3 x 10 mg/kg T/C Number of survivors on D60 3 x 2.5 141 (0/10) 3 x 10 >600 (6/10) V - Toxicological results DLO, DL50, single I.P. dose administered to the aforementioned strains of mice.
For the compound in IC. 85-1625,the DLO is higher than or equal to 40 mg/kg.
For the compound in IC. 85-1590, the DLO is higher than or equal to 25 mg/kg.
For the compound in IC. 85-1591, the DLO is higher than or equal to 20 20 mg/kg.
For the compound in IC. 85-1626, the DLO is higher than or equal to 20 mg/kg.
For the 'compound in IC. 85-1627, the DLO is higher than or equal to 25 40 mg/kg.
For the compound in IC. 85-1673, the DL50 is approximately 20 mg/kg. For the compounds in IC. 85-1591 and IC. 85-1626, the DL50 is approximately 40 mg/kg.
O - '/ ISPISFIT- TABLE A ANTITUMOR ACTION OF THE COMPOUNDS OF THE INVENTION ON THE MELANOMA 1 (SC injection) Product Dose Average weight TC/X100 Number of mice mg/kg/inj• of tumor at having a tumor day 20 at day 20 IC 1184 A»t- o (£~?0 IC BCNU 10 5 10 5 34, 3 .3 23.4 0 203 97,7 124 2 1 2 0 15 7 1/5 2/7 4/7 0/6 3/7 4/7 2/6 Non treated controls 1297 14/14 •' - &3o *20^3^1 TABLE B ANTITUMOR ACTION OF DERIVATIVES IC 1184 AND IC 1530 ON MELANOMA B16 Products Doses Median survival T/C mg/kg/inj. (days) % IC 1184 20 35 112 46 148 36 116 i£?o ic ease- 20 29 93 36 116 43 138 BCNU 20 38 122 Controls - 31 100 ^ / 64 The reaction diagram hereafter summarizes the steps which have just been described : ho a o fxt'l b-h- a nh-och,, hc1 \/cw \ 3 2 6 2—21 ► K 3 ^ ^^ AcONa methyl 2,6 didesoxy a. -L-ery throhex opyranoside 3-ulose /1 O, 1 och.
NH, o=c=n-ch2ch2ci \ och.
OlP/1 H NaN02 hcooh NHCONHCH2CII2Cl compound 24 compound 25 0 och. no compound 26 h-c-n-ch-ch-Cl j!' 2 2 0X ✓ m _ y 65 97 Pharmacological study Tn order to test the antitumoral activity of the compounds described above, in the first place leucemia murin LI 210 was used. Among murin leucemias leucemia 5 L1210 is resistant and selective. A substance having a great activity on leucemia L1210 presents a potential of activity in the clinical field of humans (J.M. Venditti, Relevance of transplantable animal tumor systems to the Selection of new agents for clinical trial in Pharmaco- .) logical Basis of Cancer Chemotherapy, the University of Texas ed Williams and Wilkins Co, publ. 1975j Baltimore USA, p. 24 5-270).
Besides , the experimental tumor, leucemia LI 210 of the mouse is in fact currently used 15 for the evaluation of all antitumoral compounds at present used in human therapy, as described, for example by C.C. Zubrod in Proc. Nat. Acad. Sci. USA, 1972,p. 1042-1047- The tumoral system so-constitutod experimentally enables very accurate experimental evaluation of the 20 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., 3Ji,> 19^4, 25 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° Q, September 83.
In practice, the biological effects of the 30 novel nitrosourea derivatives according to the present invention have been tested as follows: 66 HOD The test used is that of W.J. DURKIN et Al.
Cancer Research 1979, .39, 402-407, modified.
All the nitrosoureas were dissolved in lOfc ethanol in the proportion of 10 mg/ml.
The test was carried out in two steps. 1 - Determination of the 20% cytotoxic index 100 pi of an L 1210 cell suspension (10^ cells per ml) in R P M I 1640 culture medium supplemented with 10?'o of fetal calf serum and 40 |ig/ml of gentamycin, contain-int various doses of the products to be tested (0 to 100 jig/ml) were incubated 24 hours at 37°C. At the end of this time, the cell viability is determined by the trypan blue exclusion test. The cytotoxic index is defined by the formula: Cytotoxic index : 100 °/q treated living cells fo control living cells.
The amount of ethanol is the same in the cultures containing the products to be tested and in the control cultures (this amount has no effect either on growth nor on cell viability).
For each product the dose which gives a cytotoxic index of 20y° is determined. 2 - Determination of the potential "in vivo" activity L 1210 cells, under conditions similar to the preceding protocol, were contacted for 1 hour with a dose of the various products tested corresponding to a cytotoxic index equal to 207°. 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.
W.J. DURKllN et Al...showed that, under these conditions, if the cytotoxic index was equal to or greater than 407°, the product concerned would be active ,kin vivo" in the mouse. 209397 n 67 RESULTS The results are collected, in the following tabled -'A o j<.',LiL- .\ o o o ^ _ TABLE I PRODUCT TESTED TEST H° 1 DOSE CORRESPONDING TO A ■ 20% CYTOTOXIC INDEX ug/ml TEST N° 2 CYTOTOXIC INDEX % POTENTIAL "IN VIVO" ACTION "IN VIVO" ACTIVITY COMP.2 > IC 1183 50 77 + + COMP.6 IC 1184 & 25 N.D.
N.D.
COMP.10 IC 1373 80 68 + N.D.
COMP.14 IC 13 74 5C 71 + N.D.
COMP.20 IC 1350 N.S.
N.S .
COMP.23 IC 1375 60 69 + N.D.
N.D. = undetermined A L- ■ U.S. = not significant Nl t / "r 69 3 - Determination of the effective "in vivo" activity in the mouse The experimentation which is reported below used the compound 2 prepared according to the above example 6 5 (Ref. IC 61 1163). 3.1. Protocol . The mice (female, average weight 20g) used were F 1/1>£A2/Cc)^/B1 (Animal selection and breeding center of the Laboratories of the CNK3, Orleans, La Source).
. . The mice distributed in cages by drawing lots were 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-15 jection : product 2 + neutralized and sterilized olive oil.
'. The mortality of the animals was observed regularly, the relative increase in the survival (l'/C x 100) was calculated from the average survival of the treated 20 animals (T) and that of the control animals (C).
. The doses used are in mg/kg of mouse : 1.25, 2.5, 5, 10, 20, 40, 50, 60, 60. 3.2. Results 1.25 mg-* T/C = 118 . ^.50 mg-» T/C = 158 mg-J> T/C = 170 10 mg-> T/C = 220 20 mgr> T/C = CD 40 mg* T/C = UU 30 .50 mg* T/C = 100 ^ bO mg-» Toxicity 3.3- Remarks a) T/C = CO : for definition : more than 5Cr/o of the treated animals were finally cured; now in the ex-35 periments carried, all the animals at doses of and 40 mg/kg were cured finally.
O 9 3 9 7 '^ 10 70 h) This curve of efficiency is as good as that obtained with RFCNU and RPCNU described by IMBACH et al (Loc. Cit) ami it is very distinctly higher than those obtained by CCNU and Me CCNU described by MATHE and KENIS (Loc. cit). c) A sudden drop of the T/C is observed after 40 mg/kg. This phenomenon is also observed with nitrosoureas used as comparison products : the rapid rise in toxicity cancelled the efficiency of the product. 3«4. The value of T/C ^ 125$ was sought in order to determine a minimum active dose which is situated between 1.25 mg/kg of body weight and 2.5 mg/kg ; in fact, at 1.2 5 mg/kg it is found to be slightly below the \ significant threshold of 125$ survival, which is not the case at the dose of 2.5 mg/kg. 4. Determination of the "in vivo" activity of the com pounds according to the invention on the three respective tumors leucemia L 1210 IGR, Lewis tumor and mela-noma Bl6.
The compounds tested were the compounds of examples referenced by IC 1183, IC 1i 84, IC 1350, JC 1373 and IC 1374. 4.1. Leucemia L1210 Female DBA2 mice were used, about 8 weeks old and 25 weighing about 20 g from the IFFA-CRED0 center (les Oncins, 60210 Arbresles) At day "0", each mouse received intraperi toneal ly 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 35 5 experimental series of 3 cages each, and of which the mice were intended to be treated by the compounds of the invention. 1 71 Melanoma Bl6 Female C57 B l/6 mice were used, about 8 weeks old and weighing about 20 g, from the IFFA-CREDO center.
At clay "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.
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.
Protocol and treatment The protocol was identical for the 3 tumors and the 5 compounds of the invention to be tested.
As regards the experimental series to be treated, each mouse received, at days 1, 5 and 9, intraperitoneally, a dose of 20 mg/kg of the compound to be tested, in the volume of 0.2 ml of neutralized and sterilized olive oil.
. As regards the control series, each mouse received, intraperitoneally, 0.2 ml of neutralized and sterilized olive oi1.
Results . Control series (comparison) The average survival of the comparison mice is expressed in days - 2 typical deviation of the mean /I 26 o m) : - L1210 : 8, 9 - °-26 - 3LL Lewis tumor : 12.87 + 0.79 - Melanoma B16 : 14.52 + 0.80. r •' '/ 97 72 . Treated series (see Table II below) - The results are expressed by the relative increase in surviva 1 (T/C x 100) cal culated from the average survival of the treated animals (T) and that of the control animals (C) - The mice surviving more than 60 days were considered as cured.
The figures between parentheses indicate the percentage of cured mice.
- The sign CO 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 15 (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 were Killed at the 60th day. No anomaly was observed in macroscopic examinations of the organs removed.
The other mice were preserved and kept alive to the 200th day; they did not manifest any apparent disturbance in their behavior.
The animals which died in the course of the e xperiment were autopsied and there was no death through toxicity. 0 o O G> TABLE II ^Qompounc ^vtested Tumor I.C. 1183.
I.C. 1184 I.C. 1350 I.C. 1373 I.C. 1374 • r Leucemia 1210 on '( 100) 556 (47) 362 (20) <-^0( 100) OO (67) Tumor LEWIS 3LL oo ( 75) OO (90) 325 (40) 316 • ( 30) OO (75) MELANOMA 234 235 225 165 246 B 16 ( 5) (15) ( 5) ( 0) (10) ® > y 9 Ji 9 / if.> ^ j 74 Determination of the "in vivo" activity of the compounds according to the invention on the tumors L1210 USA and L1210 IGR.
The tumor L1210 USA is more resistant than tumor L1210 IGR.
• The compounds tested were compounds IC 1183* IC ll84> IC 1350, IC 1373 and IC 1374.
The experiments were identical to those described in preceding paragraph 4 but lower dosos 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 15 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 L1 kr 1 (J 1GK, by inoculating 10 tumor cells of L1210 20 IGR intraperitoneally in the volume of 0.2 ml then, at days 1, 5 and 9, there were injected intraperitoneally 5mg/kg of each of the compounds to be tested. The results are shown in Tables III and IV below.
C;. O O W table: m L 1210 USA Tumor (Comparison) Controles IC 1350 IC 1373 IC 1374 IC 1183 IC 1184 Average survivaj + 2 a m + 8,6 + 0,22 ,5 + 0,74 lO,6 + 0,44 12,9 + 0,55 13,5 + 0,91 18 + 1,19 Variance (S2 ) 0,013 0,139 0,049 0,077 0,205 0,355 T/c x 100 126 123 150 157 209 Median survival 8,7 ,25 ,6 13,1 14,0 17,8 T/c x loo 118 1 122 151 161 205 TABLE IV L 1210 IGR TUMOR (Comparison) Controles I.C. 1350 I.C. 1373 I.C. 1374 I.C. 1183 I.C. 1184 Average survival - 9,05 + 0,18 14,3 + 1,23 12,9 + 0,55 17,1 + 2,10 18,7 *1,30" Variance (C2 ) m 0,008 0,379 0,077 1,10 0,423 » T/c x 100 158 142 189 207 378 Median survival 9 ,0 5 14,25 13,1 16,75 19 24 T/c x 100 157 145 185 210 265 / £0939? 77 6. Study of the toxicity ol the compounds according to the invention.
. Histological examinations were carried out on the organs of DBA2 mice inoculated by the tumor L1210 IGR 5 and treated for 60 days with products IG 11S3» IC 1184, 1350, IC 137 3 and 10 1374, as well as on organs of the comparison DBA^ mice, that is to say inoculated with the tumor L1210 IGK.
. The organs subjected to these histological exami— V • -|(j nations were the liver, the kidneys, the spleen, the adrenal glands and the lungs.
. Examination showed that the comparison animals inoculated by L1210 IGR presented a cellular disorganisa-— tion of the hepatocytes.
. On the contrary the hepatic structure of mice inoculated by L1210 IUK,then treated with the products according to the 20 invention, did not show as great a disturbance as that observed with the comparison mice inoculated with L1210 IGR, and the hepatic nuclear hypertrophy does not consequently seem to be connected with the toxicity itself of the products of the invention.
A hematological study has been carried out on some animals treated with the products according to the invention ; it is the case particularly of DBA2 mice inoculated with Ll2lO leucemia and C57/B16 mice which have been inoculated with Lewis tumor. 30 The study comprised. from a blood sampling by cardiac puncture t col lected 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 35 centers has been undertaken. 78 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 marrow aplasia and the marrows which have been observed are rich in cells of all kinds. The spleens seem to be substantially normal. 7. General conclusion 10 . The animal experiments carried out with the product according to the invention give interesting results when the model selected is melanoma 1316, and excellent results when the models selected are the Lewis tumor and the L1210 IGR tumor as well as the L1210 USA tumor, 15 more resistant than the L1210 IGR.
The compounds according to the invention are hence particularly suitable for the treatment of various human cancers, especially those which are sensitive to chimiothera-py. The compounds of the invention are particularly suit-20 able for the treatment of various forms of cancer meeting this condition and which are identified in the publications already mentioned. The compounds of the invention are also suitable for the treatment of primary and secondary cerebral tumors, broncho-pulmonary tumors, tumors of 25 the ORL sphere, digestive tumors (gastric, pancreatic, colic and rectal), tumors of the breast, of the genital organs in the woman, bone tumors ( osteosarcomas, reticulo-sarcomas), melanomas, hemato-sarcomas (Hodgkinian and non-Hodgkinian lymphomas), and multiple myelomas. 30 The invention relates also to pharmaceutical com positions comprising the above-said novel compounds in association with a pharmaceutical vehicle suitable for the selected mode of administration.
The invention relates particularly to sterile or 35 sterilizable solutions, injectable or suitable for use for mm- .'v.. * ; 79 the preparation, particularly extemporaneously, of injectable solutions suitable for administration by intravenous injection5or perfusions. They relate, in particular, to physiologically acceptable hydroalcoholic solutions.
The products according to the invention, may be for ins tance presented in the form of free?.e-dried powder , which, for administration, is prepared extemporaneously by solubilisation by means of a sterile alcoholic solvent. The solution so-obtained is then diluted with apyrogenic sterile water, then 10 before being administered by intravenous perfusion, the solution is again rediluted in 9%o isotonic salt serum or 57° isotonic glucose serum.
The doses administered daily must be sufficient so that an action can be manifested at least in a relatively 15 large proportion of patients afflicted with one or other of the various forms of cancer which are or will be accessible to chemotherapy, 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, 1934-1937, June 1977, PS SCHEIN.
- Cancer Chimiotherapy Reports, vol. 50, No. 4, May 19b6, 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 p of the lethal dose (LD10) expressed in mg/m of body sura-face. 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- ^ "J ^ 80 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 administration, especially, for the oral route (solid or liguid 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 or therapy, the doses administered must in each case be evaluated by the clinician taking into account the state of the patient and of his personal reactivity with respect to the medicaments.
An example of pharmaceutical composition of the products according to the invention comprises 100 mg of at least one of the products of the invention, presented in the form of a sterile freeze-dried powder, associated with an ampouia of physiologically acceptable solvent, particularly of alcohol, such as ethanol, at the dosage of about 5 ml per ampouia.
Because of their particularly important activity, the compounds of the invention are also useful as reference products in pharmalogical studies, particularly in order to carry out antitumor comparisons of the products which are studied with respect to a reference product.
'OOdu 81

Claims (26)

WHAT WE CLAIM IS:
1. Nitrosourea derivatives, corresponding to the following formula (I) : (I) 10 in which : - R represents a hydrogen atom, an alkyl group 15 having from 1 to 30, preferably 1 to 12 carbon atoms or an aralkyl group having from 7 to 12, preferably 7 to 9 carbon atoms, optionyfally substituted by one or several, halogen atoms, NO2, NH^ or CF^ groups or alkoxy groups having from 1 to 4 carbon atoms 20 x represents a hydroxy group or an NR.^2 group 25 Y represents a hydrogen atom, a hydroxy group or an N group where R1 and R'^ each represents a hydrogen atom or a -C-N-CH2~CH2Hal group, Hal being a halogen, 0 NO 30 preferably CI, and R2 and R^ each represents a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an aralkyl group having from 7 to 12, preferably from 7 to 9 carbon atoms, a cyclo«4*y4 group 35 having from 3 to 6 carbon atoms, an aryl group having 6 or 10 carbon atoms, the aryl and_____. 82 aralkyl groups being optionnally substituted by one or several, halogen atoms, NO^, NH^ or CF^ groups or alkoxy groups having from 1 to 4 carbon atoms, R' and R" represent hydrogen, OH, OM, M representing an alkyl group having from 1 to 30, preferably from 1 to 12 carbon atoms, an aryl group having 6 or 10 carbon atoms, an aralkyl group having from 7 to 12, preferably from 7 to 9 carbon atoms, the aryl and aralkyl groups being optionnally substituted by one or several, halogen atoms, N02, NH2 or CF^ groups or alkoxy groups having from 1 to 4 carbon atoms, or M representing an acyl group of 2 to 8 carbon atoms, preferably 2 or 3, or an aroyl group having 7 or 11 carbon atoms, unsubstituted or substituted by one or several, N02, NH2 or CF^ groups, halogen atoms or alkoxy groups having from 1 to 4 carbon atoms, provided that at least /R1 X represents - N with R. representing -C-N-CH„CH_Hal \ 1 " * II T ~2"'T R2 0 NO /R'1 or Y represents -N with R' representing XR' R 2 -C-N-CH_CH_Hal II I 2 2 0 NO and either R' represents hydrogen or R" represents hydrogen, and R' and R" cannot be simultaneously hydrogen atoms.
2. Nitrosourea derivatives according to claim 1, corresponding to the following formula (II) : JQOijfu 83 (II) 10 in which : - R represents a hydrogen atom, an alkyl group having from 1 to 30, preferably 1 to 12 carbon atoms or an aralkyl group having from 7 to 12, preferably 7 to 9 carbon atoms, optionnally substituted by one or several, 15 halogen atoms, NO^, or CF3 groups or alkoxy groups having from 1 to 4 carbon atoms, group X represents a hydroxy group or an NR^2 20 - Y represents a hydrogen atom, or an N \r group where R^ and R'^ each represents a hydrogen atom or a -C-N-Cf^-CI^Hal group, Hal being a halogen, 25 H Ao preferably Cl, and R2 and R^ each represents a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an aralkyl group having from 7 to 12, preferably _ a.' fcy I 30 from 7 to S carbon atoms, a cycloaJijiii. group having from 3 to 6 carbon atoms, an aryl group of 4 or 10 carbon atoms, the aryl and aralkyl groups being optionnally substituted by one or several, halogen atoms, N0_, NH_ or CF_ groups 35 or alkoxy groups^from 1 to 4 carbon atoms, R" represents preferably OH, but £gaa&i}$., .&''k £ •N f '~\ ft > /v 1, WN -u I'Z C'l 29 FEB 1988^ g \ y.V' 84 replaced by OM, M representing an alkyl group having from 1 to 30, preferably from 1 to 12 carbon atoms, an aryl group having 6 or 10 carbon atoms, an aralkyl group having from 7 to 12, preferably from 7 to 9 carbon atoms, the aryl and aralkyl groups being optionally substituted by one or several, halogen atoms, NO2, or CF^ groups or alkoxy groups having from 1 to 4 carbon atoms, or M representing an acyl group having from 2 to 8 carbon atoms, preferably 2 or 3, or an aroyl group having 7 or 11 carbon atoms, unsubstituted or substituted by one or several, NO2, NF^ or CF^ groups, halogen atoms or alkoxy groups having from 1 to 4 carbon atoms, provided that at least ./Rl ■ X represents - N with R1 representing -C-N-CH_CH_Hal \ ' II I ^ ^ R2 0 NO /R'l or Y represents - Nr 2 -C-N-CH_CH„Hal „ ii i 2 2 ; O NO N^ with R 1 ^ representing R2 and R*2 having the meanings mentioned in claim 1.
3. Nitrosourea derivatives according to claim 2, corresponding to the following formula (III) : (III) 85 in which R, R" and X have the meanings mentioned in 5 claim 2.
4. Nitrosourea derivatives according to claim 2, corresponding to the following formula (IV) : 10 (IV) 15 in which R, R", X and Y have the meanings mentioned in 20 claim 2.
5. Nitrosourea derivatives according to claim 1, corresponding to the following formula (IV) : 25 30 (IV) in which R, R" and X have the meanings above mentioned 35 in claim 1 and Y represents a hydroxy group.
6. Nitrosourea derivatives according to c^laim ., \ t N -lJUcj 10 86 1, corresponding to the following formula (V) : (V) in which : 15 - R represents a hydrogen atom, an alkyl group having from 1 to 30, preferably 1 to 12 carbon atoms or an aralkyl group having from 7 to 12, preferably from 7 to 9 carbon atoms, optionnally substituted by one or several, halogen atoms, N02, NH2 or CF^ groups or alkoxy 20 groups having from 1 to 4 carbon atoms, X represents a hydroxy group or an NR^R2 group Y represents a hydrogen atom, R 25 a hydroxy group or an N ^ group where R1 and R'^ each represents a hydrogen atom or a -j!-N-CH2-CI^Hal group, Hal being a halogen, 30 0 lio preferably CI, and R2 and R'2 each represents a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an aralkyl group having from 7 to 12, preferably 35 from 7 to 9 carbon atoms, a cycloiAj 1* group having from 3 to 6 carbon atoms, an aryl group *29 FEB 1988 +« *o./ € I SJt*' A 87 having 6 or 10 carbon atoms, the aryl and aralkyl groups being optiorfj?ally substituted by one or several, halogen atoms, N02, NH2 or 5 CF3 groups or alkoxy group having from 1 to 4 carbon atoms, - R' represents preferably OH, OH being ^ufrilacc^ by OM, M representing an alkyl group having from 1 to 30, preferably from 1 to 12 carbon atoms, an 10 aryl group having 6 or 10 carbon atoms, an aralkyl group having from 7 to 12, preferably from 7 to 9 carbon atoms, the aryl and aralkyl groups being optionj?ally substituted by one or several, halogen atoms, N02, NH2 or CF^ groups or alkoxy groups having from 1 to 4 carbon 15 atoms, or M representing an acyl group having from 2 to 8 carbon atoms, preferably 2 or 3, or an aroyl group having 7 or 11 carbon atoms, unsubstituted or substituted by one or several, N0_, NH_ or CF, groups, halogen atoms or alkoxy groups prom 1 to 4 carbon atoms, 20 provided that at least /R1 X represents - N with R„ representing -C-N-CH0CH_Hal V 1 II I 2 2 nR2 0 NO w 25 /R,1 or Y represents -N with R'^ representing -C-N-CH_CH0Hal ^'2 |l i 2 2 ; 0 NO R2 and R'2 having the meanings mentioned in claim 1. 30
7. Nitrosourea derivatives according to claim 1, 2 or 6 wherein when R represents an aralkyl group, or when R', R", R2 or R'2 represent an aryl or aralkyl group, the aryl and aralkyl groups are substituted by up to 3 halogen atoms, N02' NH2 or CF3 9rouPs or alkoxy 35 groups having from 1 to 4 carbon atoms.
8. Nitrosourea derivatives according to claim tL, /;' V '29 FEB 1988" /: •<C F? I >}.>* - 0 013 J 88 6, corresponding to the following formula (VI) : (VI) R' >1 f UK 10 in which R, R', X and Y have the meanings indicated in 15 claim 3.
9. Nitrosourea derivatives according to claim 6, corresponding to the following formula (VII) : in which R, R', X and Y have the meanings indicated in 30 claim 3.
10. Nitrosourea derivatives according to claims 1 and 6 to 9, wherein : - R represents an alkyl group having from 1 to 12 carbon atoms or an aralkyl group having from 7 to 12 35 carbon atoms ; R' and R" represent an 0M group, M beij en r X 'o, s v .A 29FEBI988 89 alkyl group having from 1 to 12 carbon atoms or an aryl group having 6 or 10 carbon atoms ; - X represents an NR^R2 group, R1 representing 5 -jj-N-C^C^Hal, Hal being a halogen, preferably Cl, 0 NO - R2 has the meaning mentioned in claim 1 and Y represents a hydrogen atom or a hydroxy group. 10
11. Nitrosourea derivatives according to claims 1 and 6 to 9, wherein : - R represents an alkyl group having from 1 to 12 carbon atoms or halogenoaralkyl having from 7 to 12 carbon atoms ; 15 - R' and R" represent an 0M group, M being an acyl group having from 2 to 8 carbon atoms or an aroyl group having 7 or 11 carbon atoms ; X represents an -NR1R2 group, R1 representing -C-N-CH2CH2Hal, Hal being a halogen, 20 0 NO preferably Cl, - R2 has the meaning mentioned in claim 1 and Y represents a hydrogen atom or a hydroxy group. 25
12. Nitrosourea derivatives according to claims 1 and 6 to 9, wherein : - R represents an alkyl group having from 1 to 12 carbon atoms or an aralkyl group having from 7 to 12 carbon atoms ; 30 - R1 and R" represent OH ; - X represents an NR^R2 group, R1 representing -C-N-CH-CH-Hal, Hal representing halogen, preferably Cl, II I z z 0 NO - R2 has the meaning according to claim 1 and 35 - Y represents a hydrogen atom.
13. Nitrosourea derivatives according to 90 claims 1 to 4 and 6 to 9, wherein : - R represents an alkyl group having from 1 to 12 carbon atoms or an aralkyl group having from 7 to 12 5 carbon atoms ; - R' and R" represent OH ; X represents an alkylamino group, in which the alkyl group has from 1 to 6 carbon atoms, or arylamino in which the aryl group has 6 or 10 carbon 10 atoms, - Y represents NR'^R'^i R'-j representing -C-N-CH2CH2Hal, Hal being a halogen, preferably Cl, and 0 NO - R'2 has the meaning mentioned in claim 1. 15
14. Nitrosourea derivatives according to claims 1 to 4 and 6 to 9, wherein : - R represents an alkyl group having from 1 to 12 carbon atoms or an aralkyl group having from 7 to 12 carbon atoms ; 20 - R' and R" represent OH ; - X represents a hydroxy group and, - Y represents NR' R'2 group, R'^ representing -C-N-CH2CH2Hal, Hal being a halogen atom, preferably Cl, 0 NO 25 and - R'2 has the meaning mentioned in claim 1.
15. Nitrosourea derivatives according to claims 2 to 4, wherein : - R represents an alkyl group having from 1 to 30 12 carbon atoms or aralkyl group having from 7 to 12 carbon atoms ; R' and R" represent an 0M group, M being an alkyl group having from 1 to 12 carbon atoms or an aryl group having 6 or 10 carbon atoms ; 35 - X represents an NR^2 group, R1 representing J.(j iicoj 91 -C-N-CH-CH-Hal, Hal being a halogen, preferably Cl, and li I ^ ^ 0 NO R2 has the meaning mentioned in to claim 1 5 and - Y represents a hydrogen atom.
16. Nitrosourea derivatives according to claims 2 to 4, wherein : - R represents an alkyl group having from 1 to 10 12 carbon atoms or halogenoaralkyl group having from 7 to 12 carbon atoms ; R' and R" represent an OM group, M being an acyl group having from 2 to 8 carbon atoms or an aroyl group having 7 or 11 carbon atoms ; 15 X represents an -NR^R2 group, R1 representing -C-N-CH2CH2Hal, Hal being a halogen, I) NO preferably Cl, - R2 has the meaning mentioned in claim 1 and 20 - y represents a hydrogen atom.
17. Nitrosourea derivatives according to claim 5, wherein : - R represents an alkyl group having from 1 to 12 carbon atoms or aralkyl group having from 7 to 12 25 carbon atoms ; R' and R" represent an OM group, M being an alkyl group having from 1 to 12 carbon atoms or an aryl group having 6 or 10 carbon atoms ; - X represents an NR^2 group, R^ representing 30 -C-IjI-CH2CH2Hal, Hal being a halogen, preferably Cl, and 0 NO - R2 has the meaning mentioned in claim 1 and - Y represents a hydroxy group.
18. Nitrosourea derivatives according to claim 35 5, wherein : R represents an alkyl group from 1 to 12 | 29FEBI988 // ' (J U ti j 92 carbon atoms or halogenoaralkyl group having from 7 to 12 carbon atoms ; R' and R" represent an OM group, M being an acyl group having from 2 to 8 carbon atoms or an aroyl group having 7 or 11 carbon atoms ; X represents an representing -C-N-CI^CI^Hal, Hal being a halogen NR^R2 group, R1 NO 10 preferably Cl, - R^ has the meaning mentioned in claim 1 and - Y represents a hydroxy group.
19. Compounds according to claim 1, of the formulae : 15 20 WHCOIf-CH2CH2Cl / NO ch3 0CH3 con-ch2ch2ci 1 NO 25 r oh 30 HO \ /0CH3 0 NO I' 1 co-kj-ch2ch2ci MO rNHQC~-N~CTI2a2Cl 3v!1_/och3 # 35 - 0 jo j 94 and in which one at least of the X' or Y' groups represents NHR2 or NHR'2 with a 2-halogeno-ethyl isocyanate to convert the NHR2 5 or NHR'2 group of the compound of formula I bis respectively into NR_C-NHCH_CH«Hal or NR' C-NHCH.CH_Hal, 2|| 22 21| 22 0 0 Hal being a halogen atom, particularly chlorine, and in a secon d 4 step, subjecting the compound obtained at the 10 end of the first step to nitrosation, by means of an alkali metal nitrite, preferably, sodium nitrite to convert the NR„CNHCH„CH„Hal or NR' CNHCH_CH_Hal groups 21| 2 2 2|| 2 2 15 respectively into NR_C-N-CH_CH0Hal or NR' 0C-N-CH_CH0Hal . 2|| | 2 2 21| 1 2
2 0 NO 0 NO
21. Process of the preparation according to claim 20, for compounds of formula (VI) : 20 (VI) 25 said process comprising reacting a compound of formula (VI bis) : sj 30 (VI bis) where R and R' are as defined in claim 8, 35 - X' represents an -NHR2 or hydroxy group ; Y' represents a hydrogen atom, a hydroxy or 'f 29 FEB my .0, \ :<> 95 o 15 -NHR'2 group, - R£ and R'2 identical or different, represent independently of one another a hydrogen atom, an alkyl 5 group having from 1 to 6 carbon atoms, an aralkyl group having from 7 to 12 carbon atoms, aryl group having 6 or 10 carbon atoms, cycloalkyl group having from 3 to 6 carbon atoms, the aryl and aralkyl groups being optionnally substituted by one or several, halogen 10 atoms, NOj, NH2 or CF^ groups or alkoxy groups from 1 to 4 carbon atoms and in which one at least of the X' or Y' groups represents NHR2 or NHR'2 with a 2-halogeno-ethyl isocyanate to convert the -NHR2 or -NHR'2 group of the compound of formula VI bis respectively into NR2C-NHCH2CH2Hal or NR'2C-NHCH2CH2Hal, <)reAe ra. b ( m Hal being a halogen atom, /particulaarLy chlorine, the compound obtained at the end of the preceding step being then subjected to nitrosation, by means of an alkali 20 metal nitrite, preferably sodium nitrite to convert the NR»CNHCH_CH_Hal or NR' CNHCH_CH0Hal groups 2H 2 2 2g 2 2 respectively into NR_C-N-CH.CH_Hal or NR' C-N-CH-CH-Hal. 21| | 2 2 2|j | 2 2 0 NO 0 NO 25
22. Process of the preparation according to claim 20, for compounds of formula (VII) : 30 e (VII) said process comprising reacting a compound of formula 35 (VII bis) : o 96 (VII bis) 15 20 where R and R' are as defined in claim 9, - X' represents -NHR_ or hydroxy group ; 10 2 '/y - Y' represents a hydrogen atom, a hydroxy or -NHR'2 group, - R2 and R^ identical or different, represent independently of one another a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an aralkyl group having from 7 to 12 carbon atoms, an aryl group having 6 or 10 carbon atoms, cycloalkyl group having from 3 to 6 carbon atoms, the aryl and aralkyl groups being optionally substituted by one or several, halogen atoms, NC^, NH2 or CF^ groups or alkoxy groups from 1 to 4 carbon atoms and in which one at least of the X' or Y' groups represents NHR2 or NHR'^ with a 2-halogeno-ethyl isocyanate to convert the -NHR2 or -NHR' group of the compound of formula (VII bis) -Hoi? respectively into NR2C-NHCH2CH2Hal or NR'2C-NHCH2CH2^iS7 0 £ » / 0 (Oretena-bW Hal being a halogen atom, fearti ithIibtI y- chlorine, the compound obtained at the end of the preceding step being then subjected to nitrosation, by means of an alkali metal nitrite, preferably, sodium nitrite to convert the NR0CNHCH_CH_Hal or NR' CNHCH^CH-Hal groups Z. 11 £ /. <£|i c. Z. 0 o respectively into NR_C-N-CH_CH_Hal or NR' C-N-CH„CH_Hal. 2II C 2 2 2,| | 2 2 0 NO 0 NO
23. Frocess according to claims 20 to 22, wherein when R represents an aralkyl group, or when* 25 30 35 I'M y « \ 29 FEB 1988 "•<> r ! 10 97 R", R2 or R'2 represent an aryl or aralkyl group, the aryl and aralkyl groups are substituted by up to 3 halogen atoms, NC^, NI^ or CF^ groups or alkoxy groups having from 1 to 4 carbon atoms.
24. Process of the preparation according to 2.0 claim for preparing compounds of the following formula : CH 15 CH2CH2C1 characterized by the fact compounds of formula : 20 och3 3-cM(ofa efajf- are reacted with / isocyanate o-f ehloro-3—ethyl a to 25 *"• transform the NH2 group into NHCONHCF^Cf^Cl, to give the compound of the following formula : o o 30 35 OCH. ^hch2CH2CI o!; r;7; ' 29 FEB 1988 © ,92' 'UUdiJ ^kic-k 'i 96 ferftw** r\tfr,/c '*> %c*tc fc,c/ Aoquol—oot-traity mi ri i f r \ fa (An aodium dans 1 ' eiiiJt: fur1 -ft> "h-crn f Tor*^ * / iftiquc.—pom; Lggncformar ib gsoupe. NHCONHCB^CI^Cl e«. /I'd NHC0NHCH_CH_C1. I 1 * NO 5 ...
25. Pharmaceutical composition, comprising, in association with a pharmaceutical vehicle, a compound according to any one of claims 1 to 19.
26. Pharmaceutical composition according to claim 24 comprising 100 mg of at least one of the 10 <^/ compounds according to claims 1 to 19, presented under the form of sterile freeze-dryed powder associated with an ampouia of a physiologically acceptable solvent, in an amount of 5 ml per ampouia. 20 25 tr-.-. . DROPIC By their Attorneys BAMWIN.SON & CAREY TL4i
NZ209397A 1983-08-30 1984-08-30 Nitrosourea-substituted pyranose derivatives and pharmaceutical compositions NZ209397A (en)

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FR2614303B1 (en) * 1987-04-22 1990-06-08 Sanofi Sa NITROSOURED DERIVATIVES, THEIR NEW PREPARATION PROCESS AND THEIR THERAPEUTIC APPLICATIONS.
FR2614304A1 (en) * 1987-04-22 1988-10-28 Sanofi Sa NITROSOUREES DERIVATIVES, THEIR NEW PREPARATION METHOD AND THERAPEUTIC APPLICATIONS THEREOF.
DE19524515A1 (en) * 1995-07-05 1997-01-09 Deutsches Krebsforsch Saccharide conjugates
WO1998043628A1 (en) * 1997-04-02 1998-10-08 Viktor Veniaminovich Tets Antitumoral drugs (chlonidan)

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US3940383A (en) * 1974-12-12 1976-02-24 Stanford Research Institute Streptozotocin analogs
JPS554324A (en) * 1978-06-26 1980-01-12 Kaken Pharmaceut Co Ltd Novel glycopyranosidoamine derivative, its preparation, and antitumor agent comprising it as active constituent
JPS5681596A (en) * 1979-12-07 1981-07-03 Tokyo Tanabe Co Ltd Glucopyranose-nitrosourea derivative, carcinostatic agent consisting of the same and preparation
JPS57200397A (en) * 1981-06-03 1982-12-08 Akira Kimura Novel aldohexopyranose-, aldopentopyranose-, or and medicament composition comprising it aldopentofuranose- nitrosourea compound, its preparation

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FR2551068B1 (en) 1986-03-21
PT79158A (en) 1984-09-01
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AU580009B2 (en) 1988-12-22
ES8602031A1 (en) 1985-12-01
IL72817A0 (en) 1984-11-30
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GR80249B (en) 1984-12-14
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ATE50264T1 (en) 1990-02-15
KR920001690B1 (en) 1992-02-22

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