LU83613A1 - 4-CARBAMOYLOXY-OXAZAPHOSPORINE, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL PREPARATIONS CONTAINING THE SAME - Google Patents

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Title: 4-carbamoyloxy-oxazaphosphorine, process for their preparation and pharmaceutical preparations containing them

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From DE-OS 2 231 311 and 2 552 135 it is known that by introducing a hydroperoxy group -00H into the 4-position of the molecule of the known cytostatics 2- ^ bis- (2-chloroethyl) -amino7 “2-oxo- tetrahydro-2H-1,3,2-oxaza-phosphorine (cyclophosphamide), 3- (2-chloroethylamino) -2- / bis- (2 * -chloroethyl) amino / -2-oxo-tetrahydro-2H-1, 3,2-oxaza-; Phosphorin (trofosfamide), 3- (2-chloroethylamino) -2- (2'-; chloroethylamino) -2-oxo-tetrahydro-2H-1,3,2-oxazaphosphorine (ifosfamide), 3- (2-chloroethylamino) - 2- (2'-methanesulfonylethyl-! Amino) -2-oxo-tetrahydro-2H-1,3,2-oxazaphosphorine (Sufosfamid) and other cyclophosphamides of a similar structural formula, Verbin-j fertilize with valuable cytostatic properties, but these compounds can create one have such a low stability that their processing into pharmaceutical preparations, as is necessary in human medicine, is not possible. It is therefore an object of the present invention to provide cyclophosphamides which are substituted in the 4-position with a further modified hydroxyl group and which are distinguished in particular by high cystatic activity and improved stability.

I. 'I The present invention relates to the new 4-carbamoyloxy

oxazaphosphorines of the general formula I

! . R- X

i 15 II

! 0 - N - C - Z

V * 3 R4! y! / * 4 R4 Ï

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i * i! 'v | - 2 -! in which n! Z is the group -N or the group -or_, I> ^ R7 X is oxygen or sulfur, I, Rg and R ^, which may be the same or different, hydrogen, methyl, ethyl, 2-chloroethyl or j 2- Represent methanesulfonyloxyethyl, the radicals R ^, which may be the same or different from each other, represent hydrogen, methyl or ethyl,! Rg and Rg, which may be the same or different from one another, is hydrogen, C ^^ - alkyl, hydroxy-C ^^ - alkyl or j phenyl, and R_ is hydrogen, carbamoyl or t '8 8 -0R, where R is hydrogen, C ^^ - is alkyl, phenyl or benzyl, or i is a straight or branched chain alkyl having 1 to 18 * C atoms, I wherein the alkyl radical with 1-3 identical or different substituents from group I - OH, -halogen, -COOH, -COOR9, -CONHg, phenyl, the! Benzyloxycarbonyl radical, -N (R9) 2, -9 (R9) 3, -OR9, -SR9, -SO-R9, -S02-R9, "S03H or -PO (CH3) 2 may be substituted, in which R9 is methyl or ethyl, or I is a phenyl-C1-4-alkyl radical which is optionally substituted by 1 or 2 carboxy groups in the phenyl and / or alkyl part of the radical,

Allyl or

Cycloalkyl with 3 to 8 carbon atoms or tetrahydrofuranyl or

Tetrahydro-pyranyl or phenyl, which is unsubstituted or mono- or disubstituted with C1-4 ~ alkyl, C.j_2-alkoxy, nitro, halogen, trifluoromethyl, -so2nh2, carboxy, benzyloxy-carbonyl and / or carb-C ^ _4 ~ alkoxy may be substituted, or benzyl or benzhydryl or naphthyl or! * V, I i 3 *

Fluorenyl or pyridyl or thienyl or

Is benzoyl or C -alkanoy 1 or

Rg and Rg or Rg and R? together with the atoms with which they are connected, part of a saturated | are heterocyclic ring system, which may additionally contain Ί an oxygen atom, a lower alkyl-substituted nitrogen atom or an -S, -SO or -SO ^ sulfur atom, or Rg and R ^ form part of a j. unsubstituted or with cyano or carbamoyl | substituted aziridine ring.

i i - j Due to their particularly favorable properties and easy accessibility, the 4-carbamoyloxy-oxaza- | preferred phosphorines of the general formula I in which j Z is the group —N x 6, X is oxygen, Rg and Rg, which are i -ίϊ7 | or can be different from one another, hydrogen, j methyl or ethyl and R "hydrogen or straight or branched chain I alkyl with 1 to 18 carbon atoms, i! Are phenyl or benzyl.

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Another group of preferred compounds of formula I are those in which X is oxygen and,: the same or different, are hydrogen or a 2-chloroethyl radical, R ^, Rg and Rg are hydrogen and R? Hydrogen, benzyl, phenyl, the un i. is substituted or substituted with one or two carboxy groups, is optionally substituted with 1 carboxy group C1-4-alkyl or phenyl-C ^ alkyl, which is optionally substituted with 1 or 2 carboxy groups in the phenyl and / or alkyl part of the rest.

The 4-carbamoyloxy-oxazaphosphorines according to the invention of the general formula I are obtained according to the invention by a 4-hydroxy- or 4-methoxy- or

4-ethoxy-oxazaphosphorin of the general formula II

I> • * - * - 4 -

R R, OY

\ 13 I r4

A H

"/ Y h 2 ^ \ / \ r4" o 'o- ~ / -R4 r4 wherein, R2, R ^ and R ^ have the same meaning as in formula I and Y is hydrogen, methyl or ethyl,

with a hydroxycarbamate derivative of the general formula III

Rc X

I5 II

HO - N - C - Z III

wherein Z, R ,. and X has the same meaning as in formula I, in the presence of an inert solvent, if appropriate with cooling or heating and / or if appropriate in the presence of an acidic catalyst, '; Suitable solvents are water, lower alkyl halides such as in particular methylene chloride, lower alkyl ketones such as in particular acetone, diethyl ether, dimethylformamide (DMF), hexamethylphosphoric acid triamide (HMPT) or similar solvents or mixtures of several such solvents. The reaction is carried out at temperatures in the range of -35 ° C and + 50 ° C by “5” * '. » The reaction can be carried out in the presence of an acid catalyst such as an inorganic acid, trichloroacetic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid or a Lewis acid such as A1C1 ,,

i J

1 ZnCl2 or TiCl ^ can be performed.

| Another method of making connections! of the formula I, in which Z -N ^ R6 with Rc = H and R- hydrogen! R7 is 1, is characterized in that an oxime or all

| general formula IV

; * \ Î3? n m / \ / * 2

l er \) - C - CH - C tsssz N --- OH IV

/ \ \ I

! * 4 * 4 * 4 * 4

wherein R ^ _ ^ have the same meaning as in formula I, in an inert solvent at a temperature in the range from -70 ° to + 50 ° C with a compound of general formula V.

X = C = N-R? V

where X and Ry have the same meaning as in formula I.

The course of the reaction can be followed by thin-layer chromatography in accordance with the methods of the invention. The isolation of thin layer chromatographically uniform - 6 - ν »-

J V

Substances can be obtained by customary processing methods for such products, in particular by crystallization or chromatographic purification. The structure is secured by melting point, thin layer chromatography, elemental analysis and / or IR and ^ H NMR spectral analysis,

The compounds used as starting material in the process according to the invention are largely known, can be used in crystalline form or as a crude product and can be synthesized as follows in a manner known per se; 4-Hydroxy-oxazaphosphorines are obtained by reducing the 4-hydroperoxy derivatives (e.g. A. Takamizawa et al., J.Med.Chem. 18, 376 (1975)). 4-methoxy- or 4-ethoxy-oxazaphosphorines are formed under acidic catalysis from the 4-hydroxy derivatives in methanol or ethanol or in inert solvents which contain methanol or ethanol. The hydroxyurea derivatives are prepared by reacting appropriately substituted isocyanates or carbamic acid chlorides with hydroxylamine or N-monosubstituted hydroxylamines. The N-hydroxycarbamic acid esters (hydroxy carbamates) can be obtained in a similar manner by reacting the corresponding chlorocarbonic acid esters with hydroxylamine or N-monosubstituted hydroxylamines. For the synthesis of hydroxyurea or N-hydroxycarbamic acid esters with an additional hydroxy, carboxy or sulfonic acid group, a synthetic route with a protective group is recommended.

The oximes of the formula IV can be obtained by various synthetic routes. They can be obtained by reacting the corresponding 4-hydroxyoxazaphosphorines with hydroxylamine or with hydroxylamine salts.

’The pH should be kept between 2 and 7 if possible.

i t V »- 7 -

The racemic cis and trans isomers can be prepared from the 4-carbamoyloxyoxazaphosphorines according to the invention (cis 2R, 4R / 2S, 4S; trans = 2R, 4S / 2S, 4R).

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The assignment is in accordance with the IUPAC noun rules and with the literature on corresponding oxazaphosphorin derivatives. The cis or trans form can also be made in a targeted manner, depending on the reaction conditions selected. Pharmacologically, the isomers show no significant differences.

The compounds according to the invention are notable for their remarkable chemotherapeutic properties. In comparison with the previously known reference substance cyclophosphamide, they have approximately the same level of cancer-toxic chemotherapeutic activity on experimental transplantation tumors of the rat. They act directly alkylated in aqueous solution and have a high cytotoxicity in vitro, while 'cyclophosphamide requires enzymatic activation and has practically no cytotoxicity in vitro. The acute toxicity of the compounds according to the invention is about 4 times less than that of the reference substance cyclophosphamide, the therapeutic range is thus significantly increased. Also with regard to organotoxic side effects, such as leukocyte depression and immunosuppression, the compounds according to the invention have clear advantages over the reference substance cyclophosphamide.

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The compounds according to the invention are suitable for the treatment of malignant tumors and similar malignant diseases such as leukemia in humans. Quantities in the range of 0.01 - 100 mg / kg are used. The pharmaceutical preparations used here are produced by customary methods using customary additives and carriers.

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The following examples serve to further illustrate the present invention without restricting it thereto.

Example 1 2- (bis- (2-chloroethyl) amino) -2-oxo-tetrahydro-2H-1,3.2-oxazaphosphorin-4-yl-oxv-urea 15 g (54 mmol) 4-hydroxycyclophosphamide (ie 2- (Bis- (2-chloroethyl) amino) -4-hydroxy-tetrahydro-2H-1,3,2-oxaza-phosphorin-2-oxide) and 4.4 g (58 mmol) of hydroxyurea were dissolved in 70 ml of DMF , acidified with trichloroacetic acid (pH 3-4) and left in the refrigerator at 0 ° C for 20 h. The crystal slurry was then diluted with 70 ml of ethyl acetate and, after 2 h, filtered off, washed, dried and recrystallized from methanol.

Yield: 11.3 g (62% of theory) of the cis form, m .: 139-143 ° C (dec.)

Example 2 2- (bis (2-chloroethyl) amino) -2-oxo-tetrahydr0-2H-1,5.2-oxazaphosphorin-4-yl-oxv-urea ♦ cis form 1.1 g (4.0 mmol ) 4-Hydroxycyclophosphamide were dissolved in methanol, a trace of trichloroacetic acid was added, left to stand overnight at -25 ° C., then methanol was carefully removed, the residue was taken up in a little methylene chloride, dried and made into 1.2 g of 4-methoxycyclophosphamide ( (Bis- (2-chloroethyl) amino) -4-methoxy-tetrahydro-2H-1,3,2-oxazaphosphorin-2-oxide) concentrated. Subsequently, 1.2 g of 4-methoxycyclophosphamide and 304 mg of hydroxy-urea were dissolved in 3 ml of DMF and stored in the refrigerator for 20 hours at -25 ° C. The crystal slurry was with 3 ml of vinegar! ester diluted, suction filtered, washed, dried and out

Recrystallized methanol.

Yield: 670 mg (50% of theory) of the same product as in Example 1.

Example 5 2- (bis- (2-chloroethyl) amino) -2 ~ oxo-tetrahydro-2H-1 "3" 2- i oxazaphosphorinn-4-yl-oxy-urea, trans-form 'i * s | I 16 g (58 mmol) 4-hydroxycyclophosphamide and 5.2 g (68 mmol) j hydroxyurea were dissolved in 160 ml water, acidified with tri-] chloroacetic acid (pH 3-4) and 20 h at 0 ° C in the Refrigerator left. Then the crystal slurry i was suctioned off, washed with water, over ^ 2% in a high vacuum | dried and recrystallized from methanol / chloroform.

I Yield: 12.7 g (65% of theory) of the trans form of the product I Λ | in Example 1, F .: 148 C (dec.).

§ | ? Example 4 *. . .

i I’’s 3- (2-chloroethyl) -2- (bis- (2 * chloroethyl) amino) -2-oxotetra- 1 * | hydro-2H ~ 1,3,2-oxazaphosphorin-4-yl-oxy-urea! ] j 20 g (50 mmol) 4-hydroxytrofosfamide (ie 3- (2-chloroethyl) - j 2- (bis- (2-chloroethyl) amino) -4-hydroxy-tetrahydro-2H ~ 1,3,2- j oxazaphosphorin-2-oxide and 5.3 g (70 mmol) hydroxyurea | were dissolved in 100 ml DMF and cooled to -15 ° C. Then I was acidified with trichloroacetic acid (pH 3-4) and 5 ht * la ij ' V k} '- 10 - Îi 1 », * \\, stirred at ~ 15 ° C * After standing overnight at 0 ° C, the reaction solution was diluted with twice the amount of water.

The mixture was then shaken 4 times with 300 ml of ethyl acetate / methanol (10j1), the combined ethyl acetate phases were washed twice with water, dried over sodium sulfate and concentrated in vacuo to 22 g of oil. After shooting in

Ethyl acetate / methanol crystallized out 4.2 g (mp. 106-110 ° C). The mother liquor was separated by column chromatography on silica gel with chloroform / methanol (10: 1) and recrystallized from ethyl acetate / methanol together with the 1st crystallizate.

Yield: 7.0 g (35% of theory), m .: 115-116 ° C (dec.),

Example 5 3 ~ benzyl ~ 1- / 2- (bis ~ (2-chloroethyl) -arino) -2-oxc-tetrahTdro-1,3.2-oxazaphosphorin-4-yl ~ oxv7 ~ urea -

540 mg (3.25 mmol) -3-benzyl-1-hydroxyurea in 40 ml acetone and a catalytic amount of trichloroacetic acid were added to 900 mg (3.25 mmol) 4-hydroxycyclophosphamide in 1 ml methylene chloride. The mixture was stored at -25 ° C. overnight, the crystals were then filtered off with suction, washed with acetone and ether and recrystallized from ethyl acetate.

Yield: 500 mg (40% of theory), m .: 122-123 ° C (dec.).

I. * f - i 1 *, • t

Example 6% • t 5- (o-bromophenyl) -1- / 2- (bis- (2-chloroethyl) amino) -2-oxo-tetrahyàro-1 ♦ 3.2-oxazaphosphorin-4-yl-oxy7-urea 560 mg (2 mmol) of 4-hydroxycyclophosphamide in 10 ml of acetone were mixed with 460 mg of 3-o-bromophenyl-1-hydroxy haras toff and a catalytic amount of trichloroacetic acid and left at -25 ° C. After 2 days, the crystals were filtered off and recrystallized from acetone. Yield: 320 mg (32% of theory), m .: 110-111 ° C (dec.).

Example 7 NZ £ - (bis- (2-chloroethyl) amino) -2-oxo-tetrahydro-1,3.2-oxazaphosphorin-4-yl-oxv7 “4-morpholihocarboxamide 1.2 g (4.3 mmol) 4- Hydroxycyclophosphamide in 15 ml acetone were mixed with 630 mg (4.3 mmol) N-hydroxy-morpholino-carboxamide and a trace of trichloroacetic acid and stored at -25 ° C. After 4 days, the crystals were filtered off and recrystallized from acetone.

Yield: 780 mg (45% of theory), m .: 123-124 ° C (dec.).

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Ethyl 2- (bis- (2-chloroethyl) amino-2-oxo-tetrahydro-2H “1> 3,2-oxazaphosphorlen-4-yl-oxy-carbamate

Example 71-18% 550% (2 mmol) 4-hydroxycyclophosphamide and 210 mg (2 mmol) ethyl hydroxycarbamate (hydroxyurethane) were dissolved in 5 ml dry, alcohol-free methylene chloride, mixed with a catalytic amount of trichloroacetic acid, molecular sieve 4 A. added and left at -25 ° C for 3 days. It was then separated from the molecular sieve, washed once in a separating funnel with dilute sodium bicarbonate solution, the methylene chloride phase dried over sodium sulfate i.V. concentrated and diluted with ether. After standing at ~ 25 ° C for 20 hours, the crystals were suction filtered, washed and dried.

Yield: 290 mg (40% of theory), mp. 96 ° C.

Example 72

Benzyl-2- (bis- (2-chloroethyl) amino-2-oxo-tetrahydro-2H ~ 1,3,2-oxazaphosphorin-4-yl-oxy-carbamate 750 mg (2.7 mmol) 4-hydroxycyclophosphamide and 450 mg (2.7 mmol) of benzylhydroxycarbamate were dissolved in 6 ml of alcohol-free methylene chloride, a little trichloroacetic acid was added, left to stand in the refrigerator at -25 ° C, filtered off after 3 days, the mother liquor diluted with 5 ml of chloroform, with water, ' washed out with dilute sodium bicarbonate solution and again with water, dried over sodium sulfate and concentrated in vacuo, the oily residue was removed

Recrystallized ethyl acetate / a little methanol,

Yield: 680 mg (59% of theory), mp 112-114 ° C

{3 - /% - (bis- (2-chloroethyl) amino) -2-oxo-tetrahydro-2H-1, 3,2-oxazaphosphorin-4 "yl-oxy7 ,,,, ureido ^ -esslic acid-cyclohexylamine-

Salt - 19 -

EXAMPLE 73 V *% · a) 3-Hydroxy-ureido-Acetic Acid 56.5 g (0.28 mol) of glycine benzyl ester hydrochloride were suspended in 300 ml of toluene and dry phosgene was stirred for two hours at a bath temperature of 140 ° C. Gas introduced. The reaction mixture was then concentrated in vacuo and the residue was distilled in a high vacuum.

Yield: 51 g (95% of theory) benzyl isocyanato acetate Κρ.Λ 100 - 102 ° C.

6.6 g (0.2 mol) of hydroxylamine in 200 ml of dioxane were added dropwise to 28.7 g (0.15 mol) of benzyl isocyanato acetate in 50 ml of dioxane with stirring and temporary cooling. After stirring for 1 hour at room temperature, i.V. concentrated and the residue recrystallized from ethyl acetate,

Yield: 28.1 g (83.6% of theory) of benzyl-3-hydroxy-ureido acetate, mp 113-120 ° C.

22.4 g (0.1 mol) of benzyl-3-hydroxy-ureido acetate in 300 ml - methanol were mixed with 5 g of palladium-carbon and in a

Shake duck hydrogenated. The corresponding hydrogen uptake ended after about 20 minutes. The catalyst was suctioned off, the filtrate i.V. concentrated and the solid residue recrystallized from dioxane.

Yield: 9.8 g (73% of theory) of 3-hydroxy-ureido-acetic acid,

Mp 135 ° C.

- 20 - “*” b) 6.1 g (2 mmol) of 4-hydroxycyclophosphamide were added to 2.4 g (18 mmol) of 3-hydroxy-ureido-acetic acid in 10 ml of water and 25 ml of acetone and overnight at - Let stand at 25 ° C. 25 ml of acetone and 1.8 g (18 mmol) of cyclohexylamine in 10 ml of acetone were then added, suction filtered after standing for 2 hours and recrystallized from acetone with a little methanol.

Yield: 3.1 g (44% of theory), p .: 107-108 ° C.

Example 74.

3- / N, N- (bis- (2-chloroethyl) -diamino-phosphf ny.l-oxy7 ~ proplonaldehyde-oxime (aldophosphamide-oxime) 4.0 g (13.7 mmol) of 4-hydroperoxycyclophosphamide were dissolved in 50 ml Water suspended under ice cooling and 500 mg of sodium thiosulfate x 5 mol of water were added, the pH was checked with a pH meter while stirring at 5-10 ° C., maintained between pH 4.5 and 5.5 with 2 normal sulfuric acid and for as long as possible a concentrated solution of sodium thiosulfate was added dropwise until the pH no longer rose. "The mixture was stirred for a further half hour at approx. 10 ° C, an aqueous solution of 950 mg hydroxylamine hydrochloride was added dropwise, and the pH was maintained using 2 normal sodium hydroxide solution to 5, left the reaction mixture in the refrigerator overnight at 5 ° C., extracted four times with 50 ml of ethyl acetate each time and concentrated the organic extracts after drying over sodium sulfate in vacuo at 30 ° C. The residue was taken up in methylene chloride and the crystals aspirated after 1 day.

Yield: 3.4 g (85% of theory), m.p .: 79 -81 ° C.

* * 3-p-bromo-1-Z2 ~ (bis- (2-chloroethyl) amino) -2-oxo-tetrahydro-1,3,2-oxazaphosphorin-4-yl-oxy7-urea - 21 -

Example 75 4 g (20 mmol) of p-bromophenyl isocyanate in 40 ml of acetone were added to 5.8 g (20 mmol) of aldophosphamide oxime in 60 ml of acetone, and the mixture was stirred for 5 hours with cooling. After 2 hours, the suctioned crystals i.V. dried on a rotary evaporator at 40 ° C and recrystallized in methanol.

Yield: 8.1 g (82.8% of theory), m .: 118-120 ° C.

Example 76 m-Trifluoromethylphenyl-1-Z2- (bis- (2-chloroethyl) amino) -2-oxo-tetrahydro-1,3,2-oxazaphosphorin-4-yl-oxy7-urea 7.3 g (25 mmol ) 4.7 g (25 mmol) of m-trifluoromethylphenyl isocyanate in 40 ml of acetone were added to aldophosphamide oxime in 80 ml of acetone. The mixture was stirred at 0.degree. C. for 3 hours, left to stand in the refrigerator at -25.degree. C. overnight, 150 ml of petroleum ether were added and, after standing for a further time in the refrigerator, suction filtered overnight at -25.degree. The crystals were dried at 30 ° C. and recrystallized from isopropanol.

Yield: 9.2 g (76.8% of theory), m.p .: 91-93 ° C.

Example 77 3-Cyclohexyl-1- / 2- (bis- (2-chloroethyl) amino) -2-oxo-tetrahydro-1,3,2 “oxazaphosphorin-4-yl-oxy7-urea 5 g (18 mmol) Aldophosphamide oxime and 2.2 g of cyclohexyl isocyanate were dissolved in 10 ml of acetone, combined at 0 ° C., the crystals were filtered off after 2 hours and washed with acetone / ether.

Yield: 4.2 g (56% of theory), m .: 113 ° C.

'i 3-Ethyl-1 - / 2- (bis- (2-chloroethyl) amino) -2-oxo-tetrahydro-1,3,2-oxazaphQsphorin-4-yl-oxy7, “urea f 1 *» - 22 -

Example 78 * 5 g (18 mmol) of aldophosphamide oxime and 1.2 g of ethyl isocyanate "were dissolved in 15 ml of acetone and added together at about 0 ° C. After 5 hours, the crystals were filtered off with suction and with acetone / ether washed.

Yield 3.5 g (54% of theory), m .: 101 ° C.

Example 79 2- (Fluoren-2-yl) -1- / 2- (bis- (2-chloroethyl) amino) -2-oxo-tetrahydro-1,3,2-oxazaphosphorin-4-yl-oxy7-urine 2.1 g (10 mmol) of fluorenyl-2-isocyanate in 20 ml of acetone were added at 0 ° C. to 2.9 g (10 mmol) of aldophosphamide oxime in 30 ml of acetone. The next day, the precipitated product was filtered off, i.v., dried at 6 ° C. and recrystallized from isopronal / methanol.

Yield: 2.5 g (40.1% of theory), m .: 114 ° C.

Example 80 3-Benzoyl ~ l- / 2- (bis- (2-chloroethyl) amino) -2-oxo-tetrahydgo-1,3,2-oxazaphosphorus in-4-yl-oxy7-urea 5.8 2.9 g (20 mmol) of benzoyl isocyanate in 40 ml of acetone were added to g (20 mmol) of aldophosphamide oxime in 60 ml of acetone. The mixture was stirred for 5 hours in an ice bath under a nitrogenate atmosphere, after 2 hours the solid was filtered off with suction, dried on a rotary evaporator at 30 ° C. and recrystallized from methanol.

Yield: 2.4 g (27.3% of theory), m.p .: 124-125 ° C.

A

Example 81 - 23 - Λ 'ri χ «3-P-nitrophenyl-l- / 2- (bis- (2-chloroethyl) amino) -2-oxo-tetrahydro-1,3,2-oxazaphosphorin-4-yl -oxy7-urea

A solution of 3.3 g (20 mmol) of p-nitrophenyl isocyanate in 40 ml of acetone was added to 5.8 g (20 mmol) of aldophosphamide oxime in 60 ml of acetone, and after 2 hours the solid product was suctioned off on a rotary evaporator at 40 ° C dried, and recrystallized from dimethylformamide / ethanol.

Yield: 6.7 g (73.5% of theory), P.s 117-118 ° C.

Pharmaceutical application examples

Example 82 (enteric film tablets) 100 g of the compound according to Example No. 5 are passed through a sieve with 7.0 g of Aerosil and mixed. 76.0 g of Avicel PH 105, 10 g of corn starch and 7.0 g of stearic acid are added to this mixture and mixed until all the components have been homogeneously distributed. This mass is pressed in a known manner to 200 mg cores with 100 mg of active ingredient.

These cores are coated with an enteric film, e.g. coated from suitable cellulose derivatives or a fully synthetic film former in organic solution or aqueous dispersion, which may contain additives such as plasticizers, colorants, flavorings or defoamers.

Example 83 (enteric-coated gelatin capsules) * 24 * * * ** T * 250 g of the compound according to Example No. 5 are passed through a sieve with 7.5 g of Aerosil and mixed. 40 g of lactose and 2.5 g of magnesium stearate are added to this mixture and the mixture is mixed until homogeneous distribution of all V1 constituents.

This mass is filled in single doses of 300 mg in gelatin capsules.

One capsule contains 250 mg of active ingredient.

According to Example 1, the gelatin capsules are provided with an enteric film coating.

Claims (7)

4 »» V- · * Title 4-car bamoyloxy-oxazaphosphorin derivatives, process for their preparation and pharmaceutical preparations containing them Claims s * »1. 4-carbamoyloxy-oxazaphosphorin ~ derivatives of the general formula I. ? Rc X 15 h 0. N - C - Z K 13 RA / K4; V i where / Rg i Z is the group ~ N or the group -0R-,: n * 7 X is oxygen or sulfur, R2 and R3, which may be the same or different, hydrogen, methyl, ethyl, 2- Chloroethyl or Represent 2-methanesulfonyloxyethyl, the radicals R ^, which may be the same or different from each other, represent hydrogen, methyl or ethyl, R_ and R,., Which may be the same or different from one another; - Ο O can be hydrogen, alkyl, hydroxy-C.j ^ alkyl or phenyl, and R ^ is hydrogen, carbaraoyl or; Is -0R8, where R8 is hydrogen, C 1-4 alkyl, phenyl or benzyl, or '4 ♦ •, - 2 - ψ; '»\ - £' is a straight-chain or branched-chain alkyl having 1 to 18 carbon atoms, the alkyl radical having 1 to 3 identical or different substituents from the group -OH, -halogen, -COOH, -COOR9, -CONH -,; Q * -phenyl, the benzyloxycarbonyl radical, -N (R) 2, -N (R9) 3, -or9, -SR9, -SO-R9, -S02-R9, -SO, H or “-PO (CH ^) 2 can be substituted, in which R ° is methyl or ethyl, or a phenyl-C1-4 ~ alkyl radical, which optionally with 1 or 2 carboxy groups in the phenyl ”and / or alkyl part of. ; The rest is substituted, allyl or cyeloalkyl having 3 to 8 carbon atoms or tetrahydrofuranyl or tetrahydro-pyranyl or phenyl, which is unsubstituted or; can be mono- or disubstituted with C ^ alkyl, C ^ alkoxy, nitro, halogen, trifluoromethyl, -S02NH2r carboxy, benzyloxy-carbonyl and / or carb-C ^^ - alkoxy, or benzyl or benzhydryl or naphthyl or fluorenyl or pyridyl or thienyl or V is benzoyl or Cj_4-alkanoy 1 or Rg and Rg or Rg and Ry together with the atoms to which they are attached form part of a saturated heterocyclic ring system which additionally contains an oxygenator, a lower alkyl substituent tuiert nitrogen atom or an -S-, -SO- or -S02-sulfur atom, or Rg and R ^ is- <part of an unsubstituted or substituted with cyano or carbamoyl substituted aziridine ring, and their pharmaceutically acceptable salts. ψ - 3 ~ η \ ι 2. 4 -C ar bamoyloxy-oxaz aphos phor in-Der Ivate according to claim 1, characterized in that Z is -N ^ R7 and X Sauer- - substance, and Rg, the same or can be different from one another, is hydrogen, methyl or ethyl and Ry is hydrogen or straight or branched chain alkyl having 1 to 18 carbon atoms, phenyl or benzyl. 3. 4-carbamoyloxy-oxazaphosphorin derivatives according to claim 2, characterized in that R ^ hydrogen atoms. : are. 4. 4-carbamoyloxy-oxazaphosphorine according to claim 1, characterized in that X is oxygen, R2 and R2 »which are the same or different, are hydrogen or the 2-chloroethyl radical, R ^ and Rg are hydrogen and R ^ Hydrogen, benzyl, phenyl, which is unsubstituted or substituted with one or two carboxy groups, is optionally substituted with 1 carb, oxy group C-j _ ^ - alkyl or phenyl-C ^ _ ^ - alkyl, which is optionally with 1 or 2 carboxy groups in the phenyl 'and / or alkyl part of the rest is substituted. 5. A process for the preparation of the 4-carbamoyloxy-oxaza-phosphorine derivatives according to claims 1 to 4, characterized in that a 4-hydroxy or 4-methoxy or 4-ethoxy-oxazaphosphorin of the general formula II R. OY V I3 I r4 NN U- HR '> y II 2 ^ \ / \ R4 4 \ <ψ »4 ** where R ^, R2, R3 and R ^ are the same Meaning as in formula '' I and Y is hydrogen, methyl or ethyl, with an hydroxycarbamate derivative of the general formula - III Rc X I5 II HO - N - C - Z III wherein Z, Rj. And X have the same meaning as in formula I, in the presence of an inert solvent, if appropriate with cooling or heating and / or if appropriate in the presence of an acidic catalyst, 6. A process for the preparation of compounds of formula I according to claim 1, wherein Z with Rg = H and R,. Hydrogen is characterized in that an oxime of the general formula IV R1 * 3 Ά / “H> N • er N0 - C - CH - c ===== N- OH IV / \ II R4 R4 R4 R4 in which have the same meaning as in formula I, in an inert solvent at a temperature in the range from -70 to + 50 ° C. with a compound of the general formula VX = C = N - R? V in which X and R ^ have the same meaning as in formula I, is implemented. vie V. 4 - 5 " 7. Pharmaceutical preparations containing as active ingredient a compound according to claims 1 to 4 in addition to the usual physiologically compatible carriers and / or diluents. * ·. A