EP0000126B1 - Glucofuranos-6-yl-nitroso urea derivatives, processes for their preparation and pharmaceuticals containing them - Google Patents

Description

worin R, und R₂ Wasserstoff, gegebenenfalls durch freie oder verätherte Hydroxygruppen oder Halogen substituiertes Alkyl oder gegebenenfalls durch Niederalkyl, freies oder veräthertes Hydroxy, Halogen oder Trifluormethyl substituiertes Aralkyl oder Acyl, R, und R₂ zusammen auch Alkyliden oder Cycloalkyliden darstellen, R₃ und R₅ gegebenenfalls durch freie oder verätherte Hydroxygruppen oder Halogen substituiertes Alkyl oder gegebenenfalls durch Niederalkyl, freies oder veräthertes Hydroxy, Halogen oder Trifluoromethyl substituiertes Aralkyl oder Acyl, R₃ und R₅ zusammen auch Alkyliden oder Cycloalkyliden bedeuten, und R₆ gegebenenfalls durch freie oder verätherte Hydroxygruppen oder Halogen substituiertes Alkyl bedeutet.The invention relates to new N ₁ -glucofuranosid-6-yJ-N ₂ nitrosoureas of the formula

wherein R, and R _{2 are} hydrogen, optionally substituted alkyl by free or etherified hydroxy or halogen or optionally substituted by lower alkyl, free or etherified hydroxy, halogen or trifluoromethyl aralkyl or acyl, R, and R ₂ together also represent alkylidene or cycloalkylidene, R ₃ and R ₅ optionally substituted by free or etherified hydroxy groups or halogen alkyl or optionally substituted by lower alkyl, free or etherified hydroxy, halogen or trifluoromethyl aralkyl or acyl, R ₃ and R ₅ together also mean alkylidene or cycloalkylidene, and R ₆ optionally by free or etherified hydroxy groups or halogen-substituted alkyl means.

In the following, radicals, radicals or compounds modified with the expression “lower” contain, unless stated otherwise, up to 7, primarily up to 4 carbon atoms.

Alkyl is especially lower alkyl, e.g. B. isopropyl, straight-chain or branched, butyl, pentyl, hexyl or heptyl bound in any position and especially methyl, ethyl or n-propyl.

Possible substituents of the optionally substituted alkyl group are primarily free or etherified hydroxy groups, e.g. B. lower alkoxy groups, or halogen atoms. The substituted alkyl radical, such as lower alkyl radical, can carry one, two or more identical or different substituents, in particular free hydroxyl groups or halogen atoms.

Aralkyl is, in particular, aryl-lower alkyl, the lower alkyl part above all corresponding to the above-mentioned lower alkyl, and being primarily methyl or ethyl. The aromatic part is in particular a monocyclic and bicyclic aryl radical, primarily phenyl, but also naphthyl. He can optionally, for. B. by lower alkyl groups, free or etherified hydroxy, for. B. lower alkoxy or lower alkylenedioxy, halogen atoms and / or trifluoromethyl be mono-, di- or poly-substituted. Particularly noteworthy are 2-phenylethyl, chlorobenzyl, methylbenzyl, hydroxybenzyl, methoxybenzyl or especially benzyl.

The alkylidene radical is, in particular, a lower alkylidene radical, such as the 2-butylidene, 3-pentylidene and primarily isopropylidene radical.

The cycloalkylidene radical preferably contains 5-7 ring carbon atoms and is primarily cyclopentylidene or cyclohexylidene.

Acyl is in particular an acyl residue of an organic acid, in particular an organic carboxylic acid. Acyl is especially alkanoyl, especially with 2-18 carbon atoms, such as acetyl or propionyl, or also aroyl, such as naphthoyl-1, naphthoyl-2 and especially benzoyl or benzoyl substituted by halogen, lower alkyl, lower alkoxy, trifluoromethyl, hydroxy or lower alkanoyloxy or naphthoyl. Acyl can also be an acyl residue of an organic sulfonic acid, e.g. B. an alkanesulfonic acid, especially a lower alkanesulfonic acid, such as methanesulfonic acid or ethanesulfonic acid, or an arylsulfonic acid, especially an optionally lower alkyl-substituted phenylsulfonic acid, such as benzenesulfonic acid or p-toluenesulfonic acid, and the rest of a carbamic acid, such as unsubstituted carbamoyl, lower alkyl-carbamoyl or aryl- carbamoyl, such as methylcarbamoyl or phenylcarbamoyl.

Lower alkyl, as a substituent of the abovementioned radicals, is primarily methyl or ethyl, but also n-propyl, isopropyl or straight-chain or branched butyl.

Lower alkoxy, as a substituent of the abovementioned radicals, is in particular methoxy or ethoxy, furthermore n-propoxy, isopropoxy, n-butoxy or isobutoxy.

Halogen is e.g. B. fluorine, chlorine or bromine.

The new compounds can be in the form of mixtures of anomers or of pure a- or β-anomers.

The new compounds have valuable pharmacological properties, in particular they have a very good effect in some different types of transplantable tumors and leukemias, as well as in part in virus-induced leukemia. In doses of 25-500 mg / kg i.p. a strong inhibition of tumor growth in mice with z. B. Ehrlich ascites carcinoma or solid Harding-Passey melanoma, and in rats with z. B. Yoshida Ascites Sarcom. Analog doses prolong life compared to controls in mice with e.g. B. Leukemia L 1210 or Rauscher leukemia.

How to reach z. B. with the ethyl-6-deoxy-3,5-di-O-methyl-6- (3-methyl-3-nitroso-ureido) -ß-D-glucofuranoside in doses of 50-250 mg / kg i.p. an 800-100% inhibition of the growth of the tumors mentioned and in the case of leukemia L 1210 a life extension of approximately 60%, and after oral administration in mice with Rauscher leukemia a life extension of approximately 150%. The tolerance is good. No side effects are evident even after prolonged treatment. Even in normal animals, no organ changes can be seen macroscopically after three weeks of oral treatment.

Sugar derivatives that contain the nitrosourea grouping are known from the literature. Thus, in Chemical Abstracts 85, 94652u (1976) alkyl-N-carbamyl-N-2-chloroethyl-N'-nitroso-D-glucopyranoside and in Chemical Abstracts 86,16911j (1977) 5-nitrosoureido-5-deoxy -D-ribofuranose derivatives proposed as anti-tumor agents.

Against this, the compounds according to the invention show a broad spectrum of activity not only against transplantable ascitic tumors (CrSa 180, Ehrlich carcinoma), but above all also against various solid, transplantable or chemically induced tumors.

The invention relates in particular to compounds of the formula I in which R and R _{2 are} hydrogen, lower alkyl optionally substituted by hydroxyl, lower alkoxy or halogen, optionally substituted by hydroxy, lower alkoxy, halogen or trifluoromethyl, primarily in the para position, substituted benzyl, R, and R ₂ also denotes lower alkylidene or cycloalkylidene with 5-6 carbon atoms, R ₃ and R ₅ optionally lower alkyl substituted by hydroxy, lower alkoxy or halogen, optionally substituted by hydroxy, lower alkoxy, halogen or trifluoromethyl, primarily in the p-position, substituted benzyl, or lower alkanoyl, e.g. B. acetyl or propionyl, or optionally substituted by halogen, lower alkoxy, hydroxy or lower alkanoyloxy benzoyl, e.g. B. p-chlorobenzoyl, p-bromobenzoyl, p-methoxybenzoyl or o- or p-hydroxybenzoyl, but together also mean lower alkylidene or cycloalkylidene having 5-6 carbon atoms and R ₆ is lower alkyl optionally substituted by halogen, hydroxy or lower alkoxy.

Compounds in which R ₃ and R _{5 represent the} same radical are particularly valuable.

Particularly noteworthy are compounds of formula I above, wherein R, lower alkyl and R _{2 are} hydrogen or R, and R ₂ together are lower alkylidene, R ₃ and R _{5 are} lower alkyl or optionally substituted by halogen, hydroxy, lower alkoxy or alkyl, especially in the p-position Benzyl or R ₆ optionally substituted with chlorine lower alkyl, e.g. B. represent methyl or chloroethyl.

Primarily compounds are to be mentioned in which R ₃ and R _{5 are} methyl, R _{6 is} methyl or chloroethyl and R, hydrogen, methyl, ethyl or propyl and R _{2 is} hydrogen or R, and R ₂ together is the isopropylidene radical.

in an sich bekannter Weise nitrosiert.The new compounds are obtained if a compound of the formula II

nitrosated in a manner known per se.

For this purpose, compound II is preferably reacted with nitrous acid, its salts or derivatives. A salt, such as an alkali or alkaline earth metal, in particular the sodium salt of nitrous acid, is preferably used for this purpose, and an acid, such as a mineral acid, for. As hydrochloric acid, sulfuric acid or nitric acid, an organic acid such as carbonic acid, acetic acid or a sulfonic acid, e.g. B. a lower alkanesulfonic acid, such as methane or ethanesulfonic acid or a sulfonic acid group containing ion exchanger, for. B. Amberlite IR 120, the nitrous acid free. But you can also an anhydride of nitrous acid, especially a mixed anhydride with z. As the nitric acid or a hydrohalic acid use.

If necessary, one works in the presence of a solvent, z. B. an existing organic acid can also be used as such. The reaction is preferably carried out at low temperature, e.g. B. -10 ° C to 30 ° C.

The starting materials used in this process method are new. They can be obtained in a manner known per se from a corresponding glucofuranose which is unsubstituted in the 6-position, e.g. B. by converting to a reactive ester, e.g. B. with an alkanesulfonic acid, arylsulfonic acid or hydrohalic acid, then to an azide and reduction of the azide thus obtained to 6-deoxy-6-amino-glucofuranose, which then with a suitable NR ₆ -carbamic acid derivative, such as a corresponding isocyanate for 6- Deoxy-6 - (- 3-R ₆ -ureido) -glucofuranose is condensed. As mentioned above, these reactions are carried out in a manner known per se.

mit einem reaktionsfähigen Derivat einer N-Nitroso-N-R_s-carbaminsäure (IV)
umsetzt.Another method for the preparation of the new nitrosoureas consists in that a compound of formula III

with a reactive derivative of an N-nitroso-NR _s -carbamic acid (IV)
implements.

The reactive derivative can be, for example, an acid anhydride, preferably a mixed acid anhydride, such as an acid azide or an activated ester. Activated esters include, in particular, cyanomethyl esters, carboxymethyl esters, paranitrophenyl thioesters, paranitrophenyl esters, 2,4,5-trichlorophenyl esters, pentachlorophenyl esters, N-hydroxy-succinimide esters, N-hydroxy-phalimide esters, 8-hydroxyquinoline esters or N-hydroxypiperidine esters.

This reaction is carried out in a manner known per se, preferably in a solvent such as water or a halogenated coal water serstoff, e.g. B. dichloro- or trichloroethane, an ether such as diethyl ether, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, or an optionally alkylated pyridine, such as pyridine, picoline, lutidine, or quinoline.

The starting materials used are known or can be prepared in a manner known per se. So you can the amine of formula 111 from a corresponding, in the 6-position unsubstituted glucofuranose, for. B. by converting to a reactive ester, e.g. B. with an alkane or arylsulfonic acid or a hydrohalic acid, and then to an azide and reduction of the azide thus obtained to 6-deoxy-6-amino-glucofuranose.

The methods described above are carried out according to methods known per se, in the absence or preferably in the presence of diluents or solvents, if necessary, with cooling or heating, under elevated pressure and / or in an inert atmosphere, e.g. B. under nitrogen.

The new compounds can be present as pure α or β anomers or as anomer mixtures. The latter can be separated into the two pure anomers in a known manner due to the physicochemical differences or constituents, e.g. By means of chromatographic separation, such as thin layer chromatography or any other suitable separation method. The more effective of the two anomers is preferably isolated.

The invention also relates to those embodiments of the process in which a starting material is formed under the reaction conditions or used in the form of a reactive derivative or salt. The starting materials used are preferably those which, according to the process, lead to the compounds described above as being particularly valuable.

The present invention also relates to pharmaceutical preparations which contain compounds of the formula. The pharmaceutical preparations according to the invention are those for enteral, such as oral and rectal and parenteral administration to warm-blooded animals, which contain the pharmacological active ingredient alone or together with a pharmaceutically usable carrier material. The dosage of the active ingredient depends on the warm-blooded species, the age and the individual condition as well as on the mode of administration.

The new pharmaceutical preparations contain from about 10% to about 95%, preferably from about 20% to about 90% of the active ingredient. Pharmaceutical preparations according to the invention can e.g. B. present in unit dosage forms such as coated tablets, tablets, capsules, suppositories or ampoules. The pharmaceutical preparations of the present invention are manufactured in a manner known per se, e.g. B. produced by means of conventional mixing, granulating, coating, solution or lyophilization processes.

Suitable carriers are in particular fillers such as sugar, e.g. B. lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, e.g. As tricalcium phosphate or calcium hydrogen phosphate, further binders, such as starch paste using z. B. of corn, wheat, rice or potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose and / or polyvinyl pyrrolidone, and / or, if desired, disintegrants, such as the above-mentioned starches, furthermore carboxymethyl starch, cross-linked polyvinyl pyrrolidone, agar, Alginic acid or a salt thereof, such as sodium alginate, auxiliaries are primarily flow regulators and lubricants, e.g. B. silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol. Dragee kernels are provided with suitable, optionally gastric juice-resistant coatings, u. a. Concentrated sugar solutions, which optionally contain arabic gum, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions in suitable organic solvents or solvent mixtures or, for the production of gastric juice-resistant coatings, solutions of suitable cellulose preparations, such as acetyl cellulose phthalate or hydroxypropylmethyl cellulose phthalate. The tablets or dragee coatings can contain dyes or pigments, e.g. B. for identification or labeling of different doses of active ingredient.

In the treatment of warm-blooded animals suffering from tumors or leukemia in order to achieve anti-tumor and / or leukemic effects by administration of a pharmaceutical preparation according to the invention, the daily dose for a warm-blooded animal weighing approximately 70 kg is approximately 10-500 mg per day, preferably 50-300 mg per day .

The following examples illustrate the invention described above; however, they are not intended to limit their scope in any way. Temperatures are given in degrees Celsius.

example 1

(Chloroform, c = 1,465).A solution of 60.7 g of ethyl-3,5-di-O-methyl-6-deoxy-6- (3-methylureido) -aD-glucofuranoside cooled to 0 ° C in 500 ml of water and 15 ml of glacial acetic acid is added within 15 min dropwise with a solution of 15.8 g of sodium nitrite in 80 ml of water, stirred for one hour at the same temperature and left for 16 h at room temperature. The product which has crystallized out is filtered off with suction, washed with a little ice water and dried. The mother liquor is extracted with chloroform, the organic phase is dried over magnesium sulfate and the solvent is distilled off. The residue is purified by column chromatography on silica gel with methylene chloride / ethyl acetate (85:15), the crystalline product is combined with the first crystals and recrystallized from ether / petroleum ether. The ethyl 3,5-di-O-methyl-6-deoxy-6- (3-methyi-3-nitrosoureido) -aD-giuco- furanoside melts at 90 ° C; R _r value 0.45 on silica gel thin-layer plates in the methylene chloride / methanol system (15: 1);

(Chloroform, c = 1.465).

• Eine Lösung von 207 g 3,5-Di-O-methyl-1,2-0-isopropyliden-a-D-glucofuranose in 600 ml absolutem Pyridin wird unter Rühren und Aussenkühlung tropfenweise innerhalb von 45 min mit 67 ml Methansulfonsäurechlorid versetzt und 4 h bei Raumtemperatur stehen gelassen. Man gibt nun 50 ml Wasser zu und dampft nach weiteren 15 min die Hauptmenge Pyridin ab. Der Rückstand wird in Äther aufgenommen, die ätherische Lösung mit Wasser, eiskalter 2-n-Salzsäure, Wasser, einer gesättigten Natriumhydrogencarbonatlösung und Wasser gewaschen, über Magnesiumsulfat getrocknet und das Lösungsmittel abdestilliert. Der ölige Rückstand stellt die 3,5-Di-O-methyl-1,2-O-isopropyliden-6-O-mesyl-a-D-glucofuranose vom R_f-Wert 0,35 auf Kieselgeldünnschichtplatten im System Methylenchlorid/Essigester (85:15) dar. 240 g dieses Produktes werden in 1700 ml N,N-Dimethylformamid gelöst, mit 142 g Natriumazid und 170 ml Wasser versetzt und 3 h bei 110°C gerührt. Man kühlt das Reaktionsgemisch, filtriert und dampft das Filtrat ein. Der Rückstand wird in Äther aufgenommen, mit Wasser gewaschen, über Magnesiumsulfat getrocknet und das Lösungsmittel abdestilliert. Man erhält so die 6-Azi- do-6-deoxy-3,5-di-O-methyl-1,2-0-isopropyliden- a-D-glucofuranose als gelbliches Öl vom Rf-Wert 0,61 auf Kieselgeldünnschichtplatten im System
  
  Methylenchlorid/Essigester (85:15) und der optischen Drehung ±1° (Chloroform, c = 1,915).

The starting material can be produced as follows:

• A solution of 207 g of 3,5-di-O-methyl-1,2-0-isopropylidene-aD-glucofuranose in 600 ml of absolute pyridine is added dropwise with stirring and external cooling over the course of 45 minutes with 67 ml of methanesulfonic acid chloride and for 4 hours Let room temperature stand. 50 ml of water are now added and the main amount of pyridine is evaporated off after a further 15 min. The residue is taken up in ether, the ethereal solution is washed with water, ice-cold 2N hydrochloric acid, water, a saturated sodium hydrogen carbonate solution and water, dried over magnesium sulfate and the solvent is distilled off. The oily residue places the 3,5-di-O-methyl-1,2-O-isopropylidene-6-O-mesyl-aD-glucofuranose with an R _f value of 0.35 on silica gel thin-layer plates in the methylene chloride / ethyl acetate system (85: 15). 240 g of this product are dissolved in 1700 ml of N, N-dimethylformamide, mixed with 142 g of sodium azide and 170 ml of water and stirred at 110 ° C. for 3 h. The reaction mixture is cooled, filtered and the filtrate is evaporated. The residue is taken up in ether, washed with water, dried over magnesium sulfate and the solvent is distilled off. The 6-azido-6-deoxy-3,5-di-O-methyl-1,2-0-isopropylidene-aD-glucofuranose is thus obtained as a yellowish oil with an Rf value of 0.61 on thin silica gel layer plates in the system
  
  Methylene chloride / ethyl acetate (85:15) and the optical rotation ± 1 ° (chloroform, c = 1.915).

Methylenchlorid/Essigester (85:15) und die optische Drehung (Chloroform, c= 0,89) auf. Das entsprechende β-Glucofuranosid zeigt im gleichen System den Rf-Wert 0,11.A solution of 193 g of this compound in 3500 ml of 1N alcoholic hydrochloric acid is left to stand at room temperature for 18 hours. The majority of the solvent is then evaporated off in a water jet vacuum, the residue is taken up in ether and this solution is washed with water, a saturated sodium bicarbonate solution and water, dried over magnesium sulfate and evaporated to dryness. The anomer mixture obtained is separated by column chromatography on silica gel with methylene chloride / ethyl acetate (85:15). The ethyl 6-azido-6-deoxy-3,5-di-O-methyl-aD-glucofuranoside has an R _r value of 0.32 on silica gel thin-layer plates in the system

Methylene chloride / ethyl acetate (85:15) and the optical rotation (chloroform, c = 0.89). The corresponding β-glucofuranoside shows the Rf value 0.11 in the same system.

21.9 g of ethyl 6-azido-6-deoxy-3,5-di-O-methyl-a-D-glucofuranoside in 200 ml of ethanol are reduced with hydrogen in the presence of 2 g of 5% palladium / carbon. After filtering off the catalyst and distilling off the alcohol, the ethyl 6-amino-6-deoxy-3,5-di-O-methyl-a-D-glucofuranoside is obtained as a yellowish oil.

±1° (Chloroform, c = 1,134) und R_f-Wert 0,22 auf Kieselgel im System Methylenchlorid/Methanol (15:1).A solution of 74.9 g of this oil in 550 ml of ethanol is treated dropwise with a solution of 18.5 ml of methyl isocyanate in 60 ml of methylene chloride within an hour and the reaction mixture is evaporated to dryness. The ethyl 6-deoxy-3,5-di-O-methyl-6- (3-methyl-ureido) -aD-glucofuranoside obtained is crystallized from ethyl acetate / ether; Mp 144 °,

± 1 ° (chloroform, c = 1.134) and R _f value 0.22 on silica gel in the methylene chloride / methanol system (15: 1).

Example 2

(Chloroform, c = 1,127).A solution of 33.4 g of 3,5-D-0-methyl-6-deoxy-1,2-0-isopropylidene-6- (3-methylureido) -aD-glucofuranose cooled to 0-5 ° C in A solution of 8.5 g of sodium nitrite in 40 ml of water is added dropwise to 280 ml of water and 8.0 ml of glacial acetic acid within 30 minutes. The mixture is stirred for one hour at 0.5 ° and 18 h at room temperature. The solution is then extracted with chloroform, the organic phase washed with water, dried over magnesium sulfate and evaporated to dryness. The residue is chromatographed on 1200 g of silica gel with methylene chloride / ethyl acetate (85:15). The fractions of R _f 0.41 with the 6-deoxy-3,5-di-0-methyl-1,2-0-isopropylidene-6- (3-methyl-3-nitrosoureido) -aD-glucofuranose are evaporated to dryness;

(Chloroform, c = 1.127).

• 60,0 g 6-Azido-6-deoxy-3,5-di-O-methyl-1,2-0-isopropyliden-a-D-glucofuranose werden in 600 ml Äthanol gelöst und in Gegenwart von 5%-Palladium/Kohle mit Wasserstoff reduziert. Nach dem Abtrennen des Katalysators und Abdestillieren des Lösungsmittels erhält man die 6-Amino-6-deoxy-3,5-di-O-methyl-1,2-O-isopropyliden-α-D-glucofuranose als farbloses Öl. 33,2 g dieses Produktes werden in 250 ml Äthanol gelöst und unter Rühren tropfenweise innerhalb 30 min mit einer Lösung von 8,4 ml Methylisocyanat in 25 ml Methylenchlorid versetzt. Nach weiteren 60 min Rühren wird das Reaktionsgemisch zur Trockne eingedampft und der Rückstand aus Aceton kristallisiert. Die so erhaltene 6-Deoxy-3,5-di-O-methyl-1,2-O-isopropyliden-6-(3-methylureido)-a-D-glucofuranose vom R_rWert 0,45 auf Kieselgel im System Aceton und
  
  (Chloroform, c = 1,987) schmilzt bei 66-69°.

The starting material used can be produced as follows:

• 60.0 g of 6-azido-6-deoxy-3,5-di-O-methyl-1,2-0-isopropylidene-aD-glucofuranose are dissolved in 600 ml of ethanol and in the presence of 5% palladium / carbon Reduced hydrogen. After removing the catalyst and distilling off the solvent, the 6-amino-6-deoxy-3,5-di-O-methyl-1,2-O-isopropylidene-α-D-glucofuranose is obtained as a colorless oil. 33.2 g of this product are dissolved in 250 ml of ethanol and, with stirring, a solution of 8.4 ml of methyl isocyanate in 25 ml of methylene chloride is added dropwise within 30 minutes. After stirring for a further 60 min, the reaction mixture is evaporated to dryness and the residue is crystallized from acetone. The 6-deoxy-3,5-di-O-methyl-1,2-O-isopropylidene-6- (3-methylureido) -aD-glucofuranose thus obtained, with an R _r value of 0.45 on silica gel in the acetone and system
  
  (Chloroform, c = 1.987) melts at 66-69 °.

Example 3

(Chloroform, c = 1,858).A solution of 52.4 g of ethyl-6-deoxy-3,5-di-O-methyl-6- (3-methyl-ureido) -ß-D _- glucofuranoside in 420 ml cooled to 0-5 ° C A solution of 25.4 g of sodium nitrite in 130 ml of water is added dropwise to the water and 24.5 ml of glacial acetic acid with stirring over a period of 45 minutes and the mixture is stirred at the same internal temperature for 18 hours. The mixture is then extracted with chloroform, the organic phase is washed with water, dried over magnesium sulfate and evaporated to dryness. The residue is chromatographed on silica gel with methylene chloride / ethyl acetate (85:15). The fractions with the ethyl 6-deoxy-3,5-di-O-methyl-6- (3-methyl-3-nitrosoureido) -ß-D-glucofuranoside of Rf 0.15 are combined and dried to dryness steams:

(Chloroform, c = 1.858).

• 24 g Äthyl-6-azido-6-deoxy-3,5-di-O-methyl-ß-D-glucofuranosid werden in 240 ml Methanol gelöst und in Gegenwart von 5%-Palladium/Kohle mit Wasserstoff reduziert. Der Katalysator wird abfiltriert und das Filtrat zur Trockne eingedampft. Das erhaltene 6-Amino-derivat wird direkt weiter umgesetzt.

The starting material used can be produced as follows:

• 24 g of ethyl 6-azido-6-deoxy-3,5-di-O-methyl-β-D-glucofuranoside are dissolved in 240 ml of methanol and reduced with hydrogen in the presence of 5% palladium / carbon. The catalyst is filtered off and the filtrate is evaporated to dryness. The 6-amino derivative obtained is directly reacted further.

A solution of 39.2 g thereof in 330 ml of ethanol is added dropwise with stirring with a solution of 10 ml of methyl isocyanate in 30 ml of methylene chloride within 40 minutes and left to stand at room temperature for 16 hours. The reaction mixture is then evaporated to dryness and the residue is taken up in ethyl acetate. This solution is filtered through activated carbon and evaporated to dryness. The oil obtained represents the ethyl 6-deoxy-3,5-di-O-methyl-6- (3-methyl-ureido) -ß-D-glucofuranoside with an R _f value of 0.10 on silica gel in the methylene chloride / system Methanol (15: 1).

Example 4

• a) Äthyl-2-O-acetyl-6-deoxy-3,5-O-methyl-6-(3-methyl-3-nitrosoureido)-a-D-glucofuranosid, Öl [α]²⁰ _D = +96° ±1° (Chloroform, c = 0,710)
• b) Äthyl-6-(3-äthyl-3-nitrosoureido)-6-deoxy-3,5-di-0-methyl-a-D-glucofuranosid, Öl, [α]²⁰ _D = +41° ±1° (Chloroform, c = 1,174)
• c) Äthyl-6-[3-(2-chloräthyl)-3-nitrosoureido]-6-deoxy-3,5-di-0-methyl-D-glucofuranosid, Öl, [α]²⁰ _D = +37° ±1° (Chloroform, c = 0,935)
• d) Äthyl-6-(3-n-butyl-3-nitrosoureido)-6-deoxy-3,5-di-0-methyl-a-D-glucofuranosid, Öl [α]²⁰ _D = +25° ±1° (Chloroform, c = 1,579)
• e) Äthyl-6-deoxy-5-O-methyl-6-(3-methyl-3-ni- trosoureido)-3-0-propyl-a-D-glucofuranosid, F. = 41°, [α]²⁰ _D = +37° ±1° (Chloroform, c = 0,926)
• f) Äthyl-5-0-äthyl-6-deoxy-6-(3-methyl-3-nitro- soureido)-3-O-propyl-a-D-glucofuranosid, F. = 60°, [α]²⁰ _D ⁼ -28° ±1° (Chloroform, c = 1,362) und
• g) Äthyl-3-O-benzyl-6-deoxy-5-O-methyl-6-(3-methyl-3-nitrosoureido)-a-D-glucofuranosid, F. = 92-93°, [α]²⁰ _D = +32° ±1° (Chloroform, c = 1,438)

The following compounds are obtained analogously, starting from the corresponding starting materials:

• a) Ethyl-2-O-acetyl-6-deoxy-3,5-O-methyl-6- (3-methyl-3-nitrosoureido) -aD-glucofuranoside, oil [α] ²⁰ _D = + 96 ° ± 1 ° (chloroform, c = 0.710)
• b) Ethyl-6- (3-ethyl-3-nitrosoureido) -6-deoxy-3,5-di-0-methyl-aD-glucofuranoside, oil, [α] ²⁰ _D = + 41 ° ± 1 ° (chloroform , c = 1.174)
• c) ethyl 6- [3- (2-chloroethyl) -3-nitrosoureido] -6-deoxy-3,5-di-0-methyl-D-glucofuranoside, oil, [α] ²⁰ _D = + 37 ° ± 1 ° (chloroform, c = 0.935)
• d) ethyl 6- (3-n-butyl-3-nitrosoureido) -6-deoxy-3,5-di-0-methyl-aD-glucofuranoside, oil [α] ²⁰ _D = + 25 ° ± 1 ° ( Chloroform, c = 1.579)
• e) Ethyl-6-deoxy-5-O-methyl-6- (3-methyl-3-nitrosoureido) -3-0-propyl-aD-glucofuranoside, mp = 41 °, [α] ²⁰ _D = + 37 ° ± 1 ° (chloroform, c = 0.926)
• f) ethyl 5-0-ethyl-6-deoxy-6- (3-methyl-3-nitro-soureido) -3-O-propyl-aD-glucofuranoside, mp = 60 °, [α] ²⁰ _D ⁼ -28 ° ± 1 ° (chloroform, c = 1.362) and
• g) ethyl-3-O-benzyl-6-deoxy-5-O-methyl-6- (3-methyl-3-nitrosoureido) -aD-glucofuranoside, mp = 92-93 °, [α] ²⁰ _D = + 32 ° ± 1 ° (chloroform, c = 1.438)

Example 5

A solution of 5.0 g of ethyl 6-amino-6-deoxy-3,5-di-O-methyl-α-D-glucofuranoside in 40 ml of chloroform, cooled to 0 ° C., is stirred with a solution of 2. 5 g of N-nitroso-methylcarbamylazide in 40 ml of ether are added dropwise over the course of 10 min and stirring is continued for 1 h in an ice bath and for 3 h at room temperature. The solution is now concentrated in half, washed with ice-cold 2N hydrochloric acid, water, a saturated sodium hydrogen carbonate solution and water, dried over magnesium sulfate and evaporated to dryness. The crystalline residue of ethyl 3,5-di-O-methyl-6-deoxy-6- (3-methyl-3-nitrosoureido) -α-D-glucofuranoside is recrystallized from ether / petroleum ether, mp. 90 ° C., [α] ²⁰ _D = + 43 ° ± 1 ° (chloroform, c = 1.102).

Claims (21)

1. N₁-Glucofuranosid-6-yl-N₃-nitroso-ureas of the formula I

wherein R₁ and R₂ are each hydrogen, alkyl which is unsubstituted or substituted by free or etherified hydroxyl groups or halogen, or they are each aralkyl or acyl which are each unsubstituted or substituted by lower alkyl, free or etherified hydroxyl, halogen or trifluoromethyl, or R, and R₂ together are also alkylidene or cycloalkylidene, R₃ and R₅ are each alkyl which is unsubstituted or substituted by free or etherified hydroxyl groups or halogen, or they are each aralkyl or acyl which are each unsubstituted or substituted by lower alkyl, free or etherified hydroxyl, halogen or trifluoromethyl, or R₃ and R₅ together are also alkylidene or cycloalkylidene, and R₆ is alkyl which is unsubstituted or substituted by free or etherified hydroxyl groups or halogen.

2. Compounds according to Claim 1, wherein R₁ and R₂ are each hydrogen, lower alkyl which is unsubstituted or substituted by hydroxyl, lower alkoxy or halogen, or they are each benzyl which is unsubstituted or substituted by hydroxyl, lower alkoxy, halogen or trifluoromethyl, or R, and R₂ together are also lower alkylidene or cycloalkylidene having 5-6 carbon atoms, R₃ and R₅ are each lower alkyl which is unsubstituted or substituted by hydroxyl, lower alkoxy or halogen, or they are each benzyl which is unsubstituted or substituted by hydroxyl, lower alkoxy, halogen or trifuoromethyl, or they are each lower alkanoyl, or benzoyl which is unsubstituted or substituted by halogen, lower alkoxy, hydroxyl or lower alkanoy- loxy, or together they are also lower alkylidene or cycloalkylidene having 5-6 carbon atoms, and R₆ is a lower alkyl group which is unsubstituted or substituted by halogen, hydroxyl or lower alkoxy.

3. Compounds according to Claim 2, wherein the substituted benzyl group is substituted in the para-position.

4. Compounds according to Claim 1, wherein R₁ is lower alkyl and R₂ is hydrogen, or R₁ and R₂ together are lower alkylidene, R₃ and R₅ are each lower alkyl, or benzyl which is unsubstituted or substituted by halogen, hydroxyl, lower alkoxy or alkyl, and R₆ is lower alkyl which is unsubstituted or substituted by chlorine.

5. Compounds according to Claim 1, wherein R₁ is hydrogen, methyl, ethyl or propyl, and R₂ is hydrogen, or R₁ and R₂ together are the isopropylidene group, and R₃ and R₅ are each methyl, and R₆ is methyl or chloroethyl.

6. The a- or β-anomers of the compounds stated in Claims 1-5.

7. Ethyl-3,5-di-O-methyl-6-deoxy-6-(3-methyl-3-nitrosoureido)-a-D-glucofuranoside or -ß-D-glucofuranoside.

8. 6-Deoxy-3,5-di-O-methyl-1,2-O-isopropylidene-6-(3-methyl-3-nitroureido)-a-D-glucofuranose.

9. Ethyl-2-O-acetyl-6-deoxy-3,5-di-O-methyl-6-(3-methyl-3-nitrosoureido)-D-glucofuranoside.

10. Ethyl-6-(3-ethyl-3-nitrosoureido)-6-deoxy-3,5-di-O-methyl-D-glucofuranoside.

11. Ethyl-6-[3-(2-chloroethyl)-3-nitrosoureido]-6-deoxy-3,5-di-O-methyl-D-glucofuranoside.

12. Ethyl-6-(3-n-butyl-3-nitrosoureido)-6-deoxy-3,5-di-O-methyl-D-glucofuranoside.

13. Ethyl-6-deoxy-5-0-methyl-6-(3-methyl-3-nit- rosoureido)-3-O-propyl-D-glucofuranoside.

14. Ethyl-5-O-ethyl-6-deoxy-6-(3-methyl-3-nit- rosoureido)-3-O-propyl-D-glucofuranoside.

15. Ethyl-3-0-benzyl-6-deoxy-5-0-methyl-6-(3-methyl-3-nitrosoureido)-D-glucofuranoside.

16. Pharmaceutical preparations containing one of the compounds given in Claims 1 to 15.

17. Compounds according to Claim 1 for application in a process for the therapeutic treatment of the human or animal body.

18. Compounds according to Claim 1 as active substances inhibiting tumors.

19. The use of compounds according to Claim 1 for the production of pharmaceutical preparations.

20. A process for producing N_i-glucofuranosid-6-yl-N₃-nitroso-ureas according to Claim 1, which process comprises

a) introducing the nitroso group, in a manner known per se, into a compound of the formula

b) condensing, in a manner known per se, an amine of the formula

with a reactive derivative of an N-nitroso-N-R₆- carbamic acid (IV).

21. The compounds obtainable by the process according to Claim 20.