CS203947B2 - Method of producing n 1-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 derivatives of urea, in particular; Ni-Glucofuranoside-G-yL Nsnitrosom., Including formula I, tfG '

OR _f ° ^R b () in which

Rt; . R- and -Rs- are hydrogen; an alkyl group. with; 1 to 5; carbon atoms, benzyl group or alkanoyl group st. 1 · to 5 ·. carbon atoms,

R @ 1 and R @ 2 together represent an alkyldene group; sl 'to. 5. carbon atoms and R 6 - means · optionally · halogen substituted; alkyl: st. 1 to 51 carbon atoms.

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

The alkylidene radical is especially a lower alkylidene radical, such as a 2-butylidene radical, a 3-pentyl radical, and in particular an isopropylideric radical. residue.

The alkanoyl radical is preferably an acetyl or propioryl radical.

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

The novel compounds may be present in the form of mixtures of anomers or as pure. and / or or Saniomers.

The new compounds have. Valuable pharmacological properties, in particular, show a very good effect u 'some different ways transplanto cotton Шуп! leukemia. Thus, at doses of from 25 to 500 mg / kg i.p., they cause a strong suppression of tumor growth in mice with, for example, Ehrlich (ascites) carcinoma or a mask with, for example, a Walker CaSa. 256. Analogous doses cause prolongation of life compared to control

in mice, for example with leukemia, D 1'2-10.

This is achieved, for example, by treatment with ethyl acetate-E-N, N-methyl-6- (3-methyl-1-yl) -3-nitro-uride. <tb> <sep> <tb> <sep> <tb> <sep> <tb> <sep> <tb> <sep> <tb> <tb> <tb> <tb> <tb> <tb> <tb> <tb> <tb> <tb> <tb> <tb> <tb> More than 390.When the results of the treatment were / were achieved in the post-treatment of the active substance, the compatibility was good, the side effects were not found even after prolonged action, even in normal animals, no macroscopic appearance of organs was apparent after three weeks of oral administration.

The invention relates in particular to compounds of the formula I in which:

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

R 2 is hydrogen or

R 1 and R 2 together represent an alkylidene group having 1 to 5 carbon atoms,

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

R 6 is an optionally 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

R 1 and R 2 together represent an isopropylidene group.

The novel compounds of formula (I) are obtained by reacting to a compound of formula (III), R10-CW _q % - ^ U77j in which:

R1 _; R 2 and R 5 are as defined above, react with a reactive N-mitroso-N-R 6 -carbamic acid derivative of the general formula IV, NO

R5-N-QOQH, wherein R6 is as defined above.

^ Reactive _derivative: may; be NSPR. 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-nitrophenyl ester, pithrophenyl ester, 4,5-trichlorophenyl ester, pentachlorophenyl ester, N-hydroxysuccinimide ester, N-hydroxy ifthalimide ester, bihydroxy ester ester, bishydroxy ester ester, bihydroxy ester ester, bishydroxy ester ester.

This reaction is carried out in a known manner by working preferably in a solvent such as water, a halogenated hydrocarbon such as dichloro- or trichloroethane, an ether such as diethyl ether, tetrahydrofuran, dimethylformamide, dimethylsulfoxide or in optionally alkylated pyridine such as pyridine , piperidine, lutidine, or dhinoline.

The starting materials used are known or can be prepared in a known manner. Thus, the amine of formula III can be obtained from the corresponding unsubstituted gluhofuranose, for example by reaction with a reactive ester, for example an alkane or aryl sulfonic acid or with a hydrohalic acid, and then converting it to the azide and reducing the obtained azide to e. -deoxy-4-aminoglucdfuranose.

The above described procedure 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 may occur as pure α- or β-anomers or as mixtures of anomers. The latter mixtures can be separated into the two pure anomers in known manner, for example by thin-layer chromatography or by any other suitable separation method, 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 use starting materials which lead to the compounds described above as particularly valuable.

The invention also relates to pharmaceutical compositions containing the compounds of formula (I). The pharmaceutical compositions according to the invention are those for enteral, such as oral or rectal, as well as for parenteral administration to warm-blooded animals, comprising a pharmacologically active substance alone or together with a pharmaceutically usable 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.

New .farmaceutické (preparations contains about .10 to -95 ° / o, specifically from about 20 to 90% ¹ useful in ameliorating the slaughterhouse. Pharmaceutical _(prepared, Posts .According to the invention can be present for example in unit dosage form such as dragees, tablets, capsules, suppositories or ampoules.

The pharmaceutical preparations of the invention are prepared in a manner known per se, for example by means of conventional mixing, granulating, coating, dissolving or lyophilizing processes.

20Г3947

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 above-mentioned starches, further carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, alginate or its salt 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, vinylpyrrolidone, polyethylene glycol and / or titanium dioxide, and lacquer solutions in suitable organic solvents or solvent mixtures, or to produce gastric juice-resistant coatings, 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 substance.

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 4.7 g of ethyl 6-amino-6-deoxy-5-O-methyl-α-D-glucofuranoside in 40 ml of chloroform cooled to 0 ° C, a solution of 2.5 g of N-nitrosomethylcarbamoylazide in 40 ml of ether was added dropwise. was stirred at room temperature for a further 3 hours. This solution was evaporated to dryness and the residue was dissolved in distilled water. Extraction with ether is then carried out once, the aqueous phase is separated and lyophilized. To give ethyl 6-deoxy-5-O-methyl-6- (3-methyl-3-nitrosoureido) -ad-glucofuranoside, m.p. 54-55 ^Q C and [?] _D ²⁰ = + 65 ° ± I ^е (chloroform, c = 0.914).

Example 2

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

a) Ethyl 6- [3- (2-chloroethyl) -3-nitrosoureido] -6-deoxy-5-0-methyl-D-glucofuranoside _{[a] D} 20 = 4-53 ° ± 1 ° (CHCl (c = 1.231)

(b) ethyl 6-deoxy-6- (3-methyl-3-nitrosoureido) -α-D-glucofuranoside, [α] _D 20 = 4-31 ° ± 1 ° (water, c = 1,124),

c) deoxy-1,2-O-isopropylidene-6- (3-methyl-S-nitrosoureidene) -D-glucofuranose, [α] _{D 20} = 11 ° ± 1 ° (chloroform, c = 1.002), m.p. 45 (decomposition),

d) ethyl 5-O-ethyl-6-deoxyl-6- (3-methyl-3-nitrosoureido) -α-D-glucofuranoside, [α] _D ²⁰ ₌ 4-57 ° ± 10 ° (chloroform, c) = 1,023),

e) methyl 4-deoxy- ¹ (3-methyl-3-nitrosouréido) -5-O-propyl-α-D-glucofuranOSide, [α] ²⁰ D = + 45 ° ± 1 ° ¹ (chloroform, c = 1; 045) ethyl-5-O-benzyl-6'deoxy-6- (3-methyl-3-mtrosoureido) -ad-glucofuranoside, [a] _D ²⁰ = 41 ^е ± 1 ° (chloroform, c = 1.217)

(g) methyl 6-deoxy-6- (3-methyl-3-nitrosoureido) -5-O-methyl-α-D-glucofuranoside, [α] ²⁰ D = + 76 ° ± 1 ° (chloroform, c - 1,001), m.p. 82 to 83 ° C,

(h) ethyl-6-deoxy-2,5-di-O-methyl-6- (3-methyl-

- 3-nitrosoureido) -ω-D-glukof uranosid, _{[?] D} 20 ₌ + ₇ ° 4_g! ° (chloroform, c = 1.049), mp 93.5 DEG-95 DEG C.

i) ethyl-2-O-acetyl-6-deoxy-5-O-methyl-6-

- (3-methyl-3-nitrosoureido) -α-D-glucofuranoside, [α] _D ²⁰ = + 109 ° + Г (chloroform, c = 1.011), m.p. 55-57 ° C,

Τ

0? 3s®4í77

ί)

6-Deoxy-1,2-di-O-acetyl-5-O-methyl-6-

- (3-methyl-3-nitrosoureido) -D-glucofurano se [Jo ²⁰ = + 17 ° ± 1 ° (chloroform, c = 0.995);

(k) benzyl-G-deoxy-5-O-methyl-6- (3-methyl-

3-nitrosoureido-D-glucofuranoside, [.alpha.] _D @ ²⁰ = + 59 DEG. 1?

(chloroform, c = 1.338),

1.)

5-acetyl ^; 6 deoxy-2-O-isopropylidene-6- (3: -methyb3.nitr.os.oureido) га.Ш glukofuranasa, [α] _υ = ²⁰ -26 ° ± Г (chloroform; c = 1; 1D7) am :):

ethyl 6 ^- (3-ethyl-3-mitrosoureldo) -6-dioxo-5-methyl-D-glucofuranoside;

[.alpha.] = ²⁰ _{b. 5} + 8 ^О ± 1 ° (chloroform, c = 0.949)

Claims (2)

OBJECT OF VYN-JA-UEZU 1. A process for the preparation of 6-yl-N3-nitrosoureas of the formula I, qo CHr NHr GQ ~ Nr R & R 1, R 2 and R 5 are hydrogen, alkyl of 1 to 5 carbon atoms, benzyl or alkanoyl. the radical having 1 to 5 carbon atoms, R 1 and R 2 together are also an alkylidene group having 1 to 5 carbon atoms, R 6 represents an optionally halogenated alkyl group having 1 to 5 carbon atoms; characterized by the fact that. an amine of formula (III), ^{Rf Q} '%. (ΉιΙ J in which Rh. Rz and Rs. it has meaning; defined under. formula I, acts; a reactive derivative. N, -nitroso-NrR @ 4 carhames. acids * general? him. of formula IV NO, AND Re — N — COOH.,. (IV) wherein R6 has the meaning defined below? formula Л. 2. Way, fallen point. 1, characterized in that. like, default! substances, uses compounds of general formulas, III. and IV wherein R 1 is hydrogen, methyl, ethyl or propyl and R 2 is! hydrogen, and R 1 and R 2. together are isopropylidene. and R 6 represents ¹ methyl and R 6 represents methyl or chloroethyl. fleverng ^ afta, n. p., xáffod 7 ,; Apple juice