CS203946B2 - Method of producing n1-glucofuranosid-6-yl-n 3-nitrosoureas - Google Patents

Abstract

Die vorliegende Erfindung betrifft neue itrosoharnstoff-derivate, insbesondere N₁-Glucofuranosid-6-yl-N3-nitrosoharnstoffe der allgemeinen Formel I worin R₁, R₂ und R₅ Wasserstoff, gegebenenfalls substituiertes Alkyl oder Aralkyl oder Acyl, R₁ und R₂ zusammen auch Alkyliden oder Cycloalkyliden darstellen und R₆ gegebenenfalls substituiertes Alkyl bedeutet und Verfahren zu deren Herstellung.

Die neuen Verbindungen, zeigen eine sehr gute Wirkung bei einigen verschiedenartigen transplantablen Tumoren und Leukämien, wie auch zumTeil bei Virus-induzierter Leukämie.

Description

The invention relates to novel nitrosourea derivatives; in particular Ni-glycofuranosid-6-yl-Ns-nitrosoureas of formula (I).

in which

R 1, R 2 and R 5 are hydrogen, C 1 -C 5 alkyl, benzyl or alkanoyl. C 1 -C 5 group

R @ 1 and R @ 2 together are also C1 -C5 -alkylene

R 6 represents an optionally halogenated alkyl group having 1 to 5 carbon atoms.

Alkyl is especially isopropyl, straight or branched, butyl or pentyl bonded in any position, and especially methyl, ethyl or n-propyl.

C 1 -C 5 alkylidene is, for example, a 2-butylidene radical,

A 3-pentylidene residue and in particular an isopropylidene residue.

The alkanoyl radical is preferably acetyl or propionyl.

Halogen is, for example, fluorine, chlorine or bromine.

The novel compounds may exist in the form of mixtures of anomers or as pure d-anomers.

The novel compounds have valuable pharmacological properties, in particular they show a very good effect in some different types of transplantable tumors and leukemias. Thus, they cause at doses of 25 to 500 mg / kg

i. p. strong suppression of growth of tumors and mice such as Ehrlich's (ascites) carcinoma or rats such as Walker CaSa 256. Analogous doses cause a prolongation of life compared to control: in mice such as L 1210 leukemia.

Thus, for example, 80 to 100% growth inhibition is achieved by treatment with ethyl 6-deoxy-5-Q-methyl-6 - (: 3-methyl-3-nitrosoureido) - .alpha.-D-glucofuranoside in doses of from 50 to 250 mg / kg. these tumors, and in the L1210 leukemia an increase in life expectancy of more than 90%.

203948

Similar results were obtained with the post-application of the drug. Tolerance is good. Side effects were not found even after prolonged exposure. Even in normal animals, no changes in organs were observed macroscopically after three weeks of oral administration.

In particular, the invention relates to compounds of formula I wherein:

R 1 represents an alkyl group having 1 to 5 carbon atoms and

R2 is hydrogen or

R1 and Ra together represent an alkylidene group having 1 to 5 carbon atoms,

R 5 is hydrogen, C 1 -C 5 alkyl or benzyl;

R 6 represents an optionally chlorine substituted C 1 -C 5 alkyl radical, for example a methyl or chloroethyl radical.

In particular, compounds of formula I in which:

R 5 represents a methyl group,

Re represents a methyl or chloroethyl group and

R 1 represents hydrogen, methyl, ethyl or propyl and

R2 is hydrogen or

R1 and R2 together represent an isopropylidene group.

The novel compounds of the formula I are obtained by nitrosating a compound of the formula II in a known manner,

C 1-4 NH-CO-NM-phy

RSO-CHq in which

R 1, R 2, R 5 and R 6 are as defined above.

For this purpose, the compound of the formula II is preferably reacted with nitrous acid, a salt thereof or derivatives thereof. Preferably, salts such as alkali metal or alkaline earth metal nitrous acid salts, especially sodium salts, are used for this purpose, and nitrous acid is liberated therefrom by treatment with an acid, such as a mineral acid such as hydrochloric, sulfuric or nitric acid, organic acids, such as carbonic, acetic or sulfonic acids, for example lower alkanesulfonic acids, such as methanes or ethanesulfonic acids, or by treatment with sulfonate-containing ion exchangers such as Amberlite IR 20. However, it is also possible to use nitric anhydride, in particular mixed anhydride, e.g. or hydrohalic acids.

If necessary, the reaction is carried out in the presence of a solvent, for example the organic acid present can also be used as a solvent. The reaction is preferably carried out at a lower temperature, for example at -10 to 30 ° C.

The starting materials used in this production method are new. They can be obtained in a known manner from the corresponding glucofuranose which is not substituted at the 6-position, for example by reaction with a reactive ester, for example alkanesulfonic acid, arylsulfonic acid or hydrohalic acid, then conversion to azide and reduction of the azide thus obtained to 6-deoxy-6-aminoglucofuranose which is then condensed with a suitable N-R 6 -carbamic acid derivative, such as the corresponding isocyanate, to 6-deoxy-6- (3-R 6 -ureido) glucofuranose. As mentioned above, these reactions are carried out in a known manner.

The above process is carried out by known methods, in the absence or preferably in the presence of a diluent or solvent, if necessary, with cooling or heating, under increased pressure and / or under an inert atmosphere, for example under nitrogen.

The novel compounds can be present as pure α- or D-anomers or as mixtures of anomers. The latter mixtures can be separated into the two pure anomers in a known manner, for example by chromatographic separation, such as thin-layer chromatography or any other suitable separation procedure, based on the physicochemical differences of the components. Preferably, the more active is isolated from both anomers.

The invention also relates to those embodiments of the process in which the starting material is formed under the reaction conditions or used in the form of a reactive derivative or a salt. In this connection, it is advantageous to start with those starting materials which lead to the compounds which have been described as being particularly valuable.

The invention also relates to pharmaceutical compositions comprising compounds of the formula

I. The pharmaceutical preparations according to the invention are preparations for enteral, such as oral or rectal, as well as for parenteral administration to warm-blooded animals, which contain a pharmacologically active substance alone or together with a pharmaceutically acceptable carrier. The dose of the active ingredient is dependent on the species of warm-blooded individual, age and individual condition as well as the mode of administration.

The novel pharmaceutical preparations contain from about 10 to 95%, preferably from about 20 to 90%, of the active ingredient. For example, the pharmaceutical compositions of the invention may be presented in unit dose form, such as dragees, tablets, capsules, suppositories, or ampoules.

The pharmaceutical preparations according to the invention are prepared in a known manner, for example by means of conventional mixing, granulating, dra203946

With mowing, dissolving or lyophilizing processes.

Suitable carriers are, in particular, fillers, such as sugars, for example lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, for example calcium phosphate or calcium dihydrogen phosphate, binders such as greasy starch using, for example, corn, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, and / or optionally tablet disintegrants such as the aforementioned starches, further carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, alginic acid or its salt, such as sodium, excipients which are primarily flow regulators and lubricating agents, such as silicic acid, talc, stearic acid or its salts, such as magnesium or calcium stearic acid, and / or polyethylene glycol.

Dragee cores are provided with suitable coatings which are optionally resistant to gastric juice, using, inter alia, concentrated sugar solutions which optionally contain gum arabic, talc, polyvinylpyrrole, polyethylene glycol and / or titanium dioxide; solutions of lacquers in suitable organic solvents or solvent mixtures, or for the manufacture of coatings resistant to gastric juice, solutions of suitable cellulose derivatives such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. The tablets or dragee cores may contain the addition of dyes or pigments, for example to distinguish or identify different doses of the active ingredient.

The invention further relates to the treatment of warm-blooded animals infected with tumors or leukemias to achieve the effects of tumor suppression and / or leukemia using the pharmaceutical composition of the invention. The daily dose in a warm-blooded animal weighing about 70 kg is about 10 to 500 mg per day, preferably 50 to 300 mg per day.

The invention is illustrated by the following examples. However, these examples are not intended to limit the scope of the invention in any way. Temperatures are given in degrees Celsius.

Example 1

To a solution of 13.5 g of ethyl 6-deoxy-5-O-methyl-6- (3-methylureido) -α-D-glucofuranoside in 150 ml of distilled water and 6.2 ml of glacial acetic acid, cooled A solution of 3.6 g of sodium nitrite in 20 ml of distilled water is added dropwise over 2 hours. The reaction mixture was stirred for 16 hours in an ice bath, then saturated with sodium chloride and extracted five times with 200 ml of chloroform. The chloroform extracts were combined, dried over sodium sulfate and evaporated. The residue is taken up in 100 ml of distilled water and freeze-dried. Ethyl 6-deoxy-5-O-methyl-6- (3R, 4R, 4R, 4R, 4R, 4'-4'oureido) -α-D-glucofuranoside is obtained, m.p. ° C and [α] ²⁰ equals + 65 ° ± 1 ° (chloroform, c = 1.003).

The starting material can be prepared as follows:

To a solution of 52.6 g of 6-azido-3-O-benzyl-6-deoxy-1,2-O-isopropylidene-α-D-glucofuranose in 600 ml of Ν, Ν-dimethylformamide is added 8 g of sodium hydride (free of oil), the mixture was stirred at room temperature for 1 hour and then cooled to 0 ° C. 19.2 ml of methyl iodide are now added dropwise over 30 minutes and the mixture is stirred for a further hour. The reaction mixture was filtered and the filtrate was evaporated. Distilled water was added to the residue and extraction was performed with ether. The ethereal solution was washed with distilled water until neutral, dried over magnesium sulphate and evaporated. There was thus obtained 6-azido-3-O-benzyl-6-deoxy-1,2-O-isopropylidene-5-O-methyl-.alpha.-D-glucofuranose as a yellowish oil having a [.alpha.] D @ 20 = -59 DEG. + -. 1 ° (chloroform, c = 0.667).

A solution of 54.6 g of 6-azido-3-O-benzyl-6-deoxy-1,2,0-isopropylidene-5-O-methyl-α'-D-glucofuranose in 430 ml of absolute ethanol and 120 ml of The 4.6 N alcoholic hydrogen chloride was allowed to stand at room temperature for 18 hours and then evaporated in a water pump vacuum. The residue is taken up in ether, washed with a saturated sodium bicarbonate solution and evaporated. Column chromatography on 1.2 kg of silica gel using methylene chloride / ethyl acetate (19: 1) as the eluent gave ethyl 6-azido-3-O-benzyl-6-deoxy-5-O-methyl as a colorless oil. - α D -glucofuranoside of [α] d ²⁰ = + 35 ° ± 1 ° (chloroform, c = 0.834).

10.1 g of ethyl 6-azido-3-O-benzyl-6-deoxy-5-O-methyl-α-D-glucofuranoside in 100 ml of ethanol are reduced in the presence of 0.5 g of palladium on carbon (5%) catalyst as hydrogen for 90 minutes. After filtering off the catalyst, the filtrate is mixed, with stirring and external cooling, with 36.7 ml of methyl isocyanate which is added dropwise and then evaporated to dryness. The residue was recrystallized from ethyl acetate / ether. There was thus obtained ethyl 3-O-benzyl-6-deoxy-5-O-methyl-6- (3-methyl) -α-D-glukof uranosid m.p. 92 DEG-93.5 DEG C. [aji ^ ⁰ = + 42 ° ± 1 ° (chloroform, c = 0.973).

This product was dissolved in methanol and hydrogenated in the presence of 10% palladium on carbon. After treatment, ethyl 6-deoxy-5-O-methyl-6- (3-methylureido) -α-D-glucofuranoside is obtained as an oil, [α] D ²⁰ = + 73 ° ± 1 ° (chloroform, c) = 0.330).

Example 2

In an analogous manner, starting from 203948

The following compounds are obtained from the corresponding starting materials:

also ethyl 6- [3- (2-chloroethyl) -3-nitrosoureido] -1-6-deoxy-5-methyl-1,2,3-dihydro-trifluoromethanoside, [α] _D ²⁰ - = + 53.p ± Γ [-chloroform, c = 1.231]

(b) ethyl-6-deoxy-6- [3-methyl-3-nitrosoureido] -D-glucofuranoside, - []] _D ²⁰ - = + 31 ° ± Γ [water, c - = 1,124),

C)

6'-deoxy-1,2-O-isopropylthiazole-6- [3-methyl-3-nitrosulfonyl] -1H-f-iodo] -α-D-glucofuranose, [a] p ⁰ equals - 11 ° ± 1 ° (chloroform, c = 1.002), melting point = 45 ° C (decomposition),

d) Ethyl 5 · O-ethyl-6-defxy-6- [3-methyl-3-j-nlt'roso.uFeido - ADG] · .u.kGfuranosid - [a) ^ ⁰ is equal to + · 57 ° ± 1 ° (chloroform, c = 1,023),

e) ethyl-6-defxy [3-methyl-3-mitrosoureid. o) -5-O-propyl-D-glucofuranoside, [.alpha.] D @ 20 = + 45 DEG. + -. 1 DEG [chloroform, c = 1.045.] ,

f) ethyl-5-O-benzyl-6-deoxy-6- [3-methyl-3-nitrosureido + α-D-glucurofuranoside], [α] 20 D = + 41 ° ± -1 ° [chloroform, c = 1,217),

(g) methylyl-6-defxy-6- [3-methyl-3-nitrofuranoside-4-methyl-α-D-glucurofuranoside, [α] 20 D = + 76 ° ± 1 ° [chloroform, c =.

M.p. = -1.001), m.p. 82-83 ° C.

h) ethyl-6-diphenyl-2,5-di-O'methyl-6- [3-methyl-

-3 ° nitrosoureido) -al D-glucofuguanoside,. [.alpha.] D @ 20 = - + 97 DEG ± 1 DEG (chloroform, c = 1.049), - melting point = 9.3 DEG, 5 DEG to 95 DEG C.,

i) ethyl-2Ό-actyl-6-deox-γ-51Q-methyl-1-t

- [3'-Methyl-3'-nitro-phosphorido) -I-1'-trifluoro-furanoside, [α _D ²⁰ ] - = + 109 ° - ± 1 ° - [chloroform; mp 55-57 ° C, m.p.

6-Deoxy-1,2-di-O-acetyl-5-O-methyl-6- [3-methyl-1H-nitro (S) fureidyl] -Dluoro-glucose, [α] _d 20 - = ₊ 1 < 7 &gt; = 0.995)

(k) benzyl] 6-defxy-5-Olmethyl-6- [3-methyl-11'-nitro-sulfide] -Dluoro-fluorophenamide, [#) d ²⁰ = +69? ± Γ [chloroform, c = 1,318]

l) '

5-acetyl-6-deoxy-2-O-issprsp.y.lidenl6 -L3-l-methyl-3-nttτosoureido.) · D-R® glukoO'israno-SA [Al _D 20 = -26 ° ± 1 ° [chloroform, c = 1,107) -amethyl-6- (4-ethyl-4-nitro) -1,6-deoxy-5-O-methyl] -1-D-glucofuranoside, [α] D 20 = + 58? + 1 ° - [chloroform, m.p.

c = - 0.949) (

Claims (2)

1 (A process for the preparation of N1-Glucofuranfsid-6lyll -N3-nitrosoureas of formula I) CMNNWCO-N - R ± ^R s ° - ^{c 14} o ° · χ m in which R 1, R 2 and R 5 are hydrogen, - (C 1 -C 5) alkyl, benzyl, or (C 1 -C 5) alkanoyl - (C 1 -C 5) -alkyl; R 1 and R 2 together represent an alkylidene group having from 1 to 5 carbon atoms and R 5 represents an optionally halogen-substituted C 1 -C 5 alkyl group characterized in that it nitroses the compound of the formula II in which R 1, R 2, R 5 and R 5 are as defined above. 2. The process according to claim 1, wherein the compounds of the formula II are used as starting materials R 1 represents hydrogen, methyl, ethyl- or -s ^, phenyl-, and R2 is hydrogen or R 1 and R 2 together represent an isoprosylSden group, and R 5 represents a methyl group and R6 represents a methyl- or chloroethyl- group.