CS203194B2 - Method of producing n1-glucofuranoside-6-yln3-nitrosoureas - Google Patents

Description

SUMMARY OF THE INVENTION The present invention relates to a process for the preparation of novel nitrosourea derivatives, in particular Na2-glucofuranosld-6-yl-N3-nitrosoureas of the formula

NO

I CN-NH-CO-NR ₆

O “^ ·) (I) in which

R 1 and R 2 are hydrogen or C 1 -C 5 alkyl, wherein R 1 is also C 1 -C 5 alkanoyl; or

R1 and R <2 together are also C1 -C5 alkylidene,

R 3 is hydrogen, C 1 -C 5 alkyl or benzyl,

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

R 6 represents an alkyl group having 1 to 5 carbon atoms or a haloalkyl group having 1 to 5 carbon atoms.

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

The alkylidene radical is in particular as a 2-butylidene, 3-pentylidene and in particular an isopropylidene radical.

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

The novel compounds can exist in the form of non-isomeric mixtures or of the pure α or β-anomers.

The novel compounds have valuable pharmacological properties, in particular they show a very good effect in some differently transplanted tumors and leukemias, as well as partly in virus-induced leukemia. For example, at doses of 25 to 500 mg / kg i.p., they cause a strong suppression of tumor growth in mice with Ehrlich's ascitic carcinoma or solid Harding-Passey melanoma, and in rats with, for example, Yoshida's ascitic sarcoma. Analogous doses cause prolongation of life compared to control in mice such as L 1210 leukemia or Rauscher leukemia.

This is achieved, for example, with ethyl 6-desoxy-3,5-di-O-methyl-6- (3-methyl-3-nitrosoureido) - (3-D-glucofuranoside) at doses of from 50 to 250 mg / kg ip 80 to 100 60% inhibition of growth of said tumors and, in L 1210 leukemia, a prolongation of life of about 60 why, and after ¹ oral administration in Rauscher leukemia mice, an extension of life of about 150%. no organ changes were macroscopically detected after three weeks of oral administration.

Particular mention should be made of the compounds of formula (I) above, in which R1 is lower alkyl and R2 is hydrogen or R1 and R2 together are lower alkylidene,

R 3 and R 5 are lower alkyl or optionally halogen, hydroxy, lower alkoxy or alkyl, especially in the β-position, substituted benzyl or R 6 is optionally chlorine substituted lower alkyl, for example methyl or chloroethyl.

In particular, compounds in which R 3 and R 5 are methyl, R 6 is methyl or chloroethyl and R 1 is hydrogen, methyl, ethyl or propyl and R 2 is hydrogen or R 1 and R 2 together represent an isopropylidene group.

The novel compounds are obtained by treating the compound of formula II

in which

R 1, R 2, R 3 and R 5 are as defined above, react with a reactive N-nitroso-N-R 6 -carbamic acid derivative of the general formula III

NO

R 5 —N — COOH (HI) wherein

Re has the meaning given above.

The reactive derivative may be, for example, an acid anhydride, preferably a mixed acid anhydride, such as an acid azide or an activated ester. Activated esters include, but are not limited to, cyanomethyl ester, carboxymethyl ester, p-nitrophenylthioester, p-nitrophenyl ester, 2,4,5-trichlorophenyl ester, pentachlorophenyl ester, N-hydroxysuccinimide ester, N-hydroxyphthalimide ester, 8-hydroxyquinolinester or N-hydroxypiperidinester.

This reaction is carried out in a manner known per se, preferably in a solvent such as water, in a halogenated hydrocarbon, for example in dichloro or trichloroethane, an ether such as diethyl ether, tetrahydrofuran, dimethylformamide, dimethylsulfoxide or 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. Thus, the amine of formula II can be obtained from the corresponding unsubstituted glucofuranose at the 6-position, for example by reaction to form a reactive ester, e.g.

The processes described above are carried out by methods known per se, 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 may exist as pure α- or β-anomers or as mixtures of anomers. The latter can be separated into the two pure anomers in a manner known per se by physico-chemical differences of the individual components, for example by chromatographic separation, such as by thin-layer chromatography or by any other suitable separation procedure. 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 after. reaction conditions or used in the form of a reactive derivative or salt. Preference is given here to starting materials which lead to the compounds described above as being particularly valuable according to the invention.

The invention also relates to pharmaceutical compositions comprising the compounds of formula I. The pharmaceutical compositions of the invention are enteral, such as oral and rectal, as well as parenteral by warm-blooded administration, and which contain the pharmacologically active substance alone or together with a pharmaceutically acceptable carrier material. . The dosage of the active ingredient depends on the type of warm-blooded animal, the age and the individual condition as well as the mode of administration.

The novel pharmaceutical preparations contain from about 10 to about 95% by weight, preferably from about 20 to about 90% by weight of active ingredient. The pharmaceutical compositions of the invention may be presented, for example, in unit dosage form, such as dragees, tablets, capsules, suppositories, or ampoules. The pharmaceutical preparations according to the invention are prepared in a manner known per se, for example by means of conventional mixing, granulating, coating, dissolving or lyophilizing processes.

Suitable carriers are, in particular, fillers, such as sugar, for example lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, for example tertiary or medium calcium phosphate, binders such as greasy starch using, for example, corn, wheat, rice or potato ^1, starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, and / njebo or disintegrants, such as the above mentioned starches, also carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar, alginic acid or a salt thereof such as sodium alginate . In particular, the auxiliaries are flow control agents and lubricating agents such as silica gel, talc, stearic acid or its salts, such as magnesium or calcium stearate, and / or polyethylene glycol. Dragee cores are provided with suitable coatings, optionally resistant to gastric juice, including, for example, concentrated sugar solutions which optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, or lacquer solutions in suitable organic solvents or solvent mixtures. or, in order to produce gastric juice-resistant coatings, solutions of suitable cellulosic preparations such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Tablets or dragee coatings may be used with the addition of dyes or pigments, for example for identification or identification. the indication of the different doses of active substances.

The invention further relates to the treatment of warm-blooded infected tumors or leukemias in order to achieve the effects of tumor suppression and / or leukemia with the use of a pharmaceutical composition according to the invention. Preferably, the daily dose for a warm-blooded weight of about 70 kg is about 10 to 500 mg / day, preferably 50 to 300 mg / day.

The following examples illustrate the invention described above. 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 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, a solution of 2.5 g of N-nitrosomethylcarbamoylazide was added dropwise with stirring. in 40 ml of ether over 10 minutes and further stirred for 1 hour in an ice bath and 3 hours at room temperature. The solution is now concentrated to half its original volume, washed with ice-cooled 2 N hydrochloric acid solution, void, saturated sodium bicarbonate solution and water, dried over magnesium sulfate and evaporated to dryness. Crystalline ethyl 6-deoxy-3,5-di-O-methyl-6-deoxy-6- (3-methyl-3-nitrosoureidoy-α-D-glucofuranoside) was recrystallized from ether / petroleum ether, m.p. 90 ° C. [ _.alpha. ] _D @ ²⁰ = + 43 DEG + 1 DEG (chloroform, c = 1.102).

Example 2

The following compounds were obtained in an analogous manner using the corresponding starting materials:

6-deoxy-3,5-di-O-methyl-1,2-O-isopropylidene-6- (13-methyl-3-nitrosoureido) -α-D-glucofuranoside, oil [α] _η ^2θ = - - 49 ^α + 1 ° (chloroform, c = 1.127), ethyl 6-deoxy-3,5-di-O-methyl-6- (3-methyl-3-nitrosoureido) - β-D-glucofuranoside, oil [cf. _D ²⁰ - 57 ° + 1 ° (chloroform, c = 1,858), ethyl-2-O-acetyl-6-deoxy-3,5-di-O-methyl-6- (3-methyl-3-nitrosoureido) -D-glucofuranoside, oil [α] D ²⁰ = + 96 ° + 1 ° (chloroform, c = 0.710), ethyl 6- (3-ethyl-3-nitrosoureido) -6-deoxy-3,5-di -O-methyl-α-D-glucofuranoside, oil [α] ²⁰ D + 41 ° + 1 ° (chloroform, c = 1.174), ethyl 6- [3- (2-chloroethyl) -3-nitrosoureido] -6-deoxy- 3,5-di-O-methyl, D-glucofuranoside, oil, [?] _D ²⁰ = J-37 ^O '+ 1 ° (chloroform · c - 0.935) ethyl 6- (3-n-butyl -3-nitrosourido) -6-deoxy-3,5-di-O-methyl-α-D-glucofuranoside, oil [α] _D ²⁰ = + 25 ° + 1 ° (chloroform, c = 1.579), ethyl-6-deoxy -5-O-methyl-6- (3-methyl-3-nitrosoureido) -α-D-glucofuranoside, m.p. = 54-55 [α] _D ²⁰ = + 65 ° + + 1 ° (chloroform, c = 1.003), ethyl 6-deoxy-5-O-methyl-6- (3-methyl-3-nitrosoureido) -3-O-propyl-α-D-glucofuranoside, m.p. - 41 ° [a] _D ²⁰ - = + 37 ° + 1 ° (chloroform, c = 0.93), ethyl-5-O-ethyl-6-deoxy-6- (3-methyl-3-nitrosouride) -3-O-propyl- αD-glucofuranoside, melting point = 60 ° [α] _D ²⁰ - + 28 ° + 1 ° (chloroform, c = 1,362), ethyl-3-O-benzyl-6-deoxy-5-O-methyl-6- (3-methyl-3-nitrosoureido) -α-D-glukof uranosid, mp = 92-93 ° [<x] _D ²⁰ = -) - 32 ° + L ⁰ (chloroform, c = 1.438).

Claims (3)

A process for the preparation of the N-glucolofuranosid-6-yl-N 3 -nitrosoureas of formula I NO AND CH-NH-CO-N-R I ^A ω in which R 1 and R 2 are hydrogen or C 1 -C 5 alkyl, wherein R 1 is also C 1 -C 5 alkanoyl; or R1 and Ra together represent an alkylidene group having 1 to 5 carbon atoms, R 3 is hydrogen, C 1 -C 5 alkyl or benzyl, R 5 represents an alkyl group having 1 to 5 carbon atoms, and R6 is alkyl of 1-5 carbon atoms or halogenoalkyl having 1 to 5 carbon atoms, wherein the compound of formula II _& ch _£ NH R10-ch A> ~ or in which R 1, R 2, R 3 and R 5 are as hereinbefore defined, condenses with the relative N-nitroso-N-Re-carbamic acid derivative of formula III NO AND Re — N — COOH (III) wherein R6 is as defined above. 2. Method according to claim 1, characterized in that the starting materials used are compounds of ^one of formulas II and III in which R 1 represents an alkyl group having 1 to 5 carbon atoms and R2 is hydrogen or R1 and R2 together represent an alkylidene group having 1 to 5 carbon atoms, R3 is C1 -C5 alkyl or benzyl, R 5 represents an alkyl group having 1 to 5 carbon atoms and R 6 represents an optionally chlorine substituted alkyl group having 1 to 5 carbon atoms. 3. The process according to claim 1, wherein the starting materials are compounds of formulas II and III in which: R 1 is hydrogen, methyl, ethyl or propyl R 2 is hydrogen, or R1 and R2 together represent an isopropylidene radical, R 3 and R 5 are methyl and Re represents a methyl or chloroethyl group.