CH650787A5 - OXAZAPHOSPHORINE, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM. - Google Patents

Description

The present invention relates to oxazaphosphorines of the general formula I.

25th

30th

40

(XV)

45

55

wherein R] to R4 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 50

X = C = N-R7 (V)

wherein X and R7 have the same meaning as in formula I 'is implemented.

9. The method according to claim 7 or 8 for the preparation of compounds of formula I 'according to claim 2, wherein X = oxygen, R (, = hydrogen, methyl or ethyl and R7 = hydrogen or straight or branched chain alkyl having 1 to 18 C- Atoms, phenyl or benzyl.

10. The method according to claim 9 for the preparation of compounds of formula I ', wherein R4 is hydrogen.

11. The method according to claim 7 or 8 for the preparation of compounds of formula I 'according to claim 2, wherein X = oxygen; R), R2, R ;, = hydrogen or 2-chloroethyl, where Ri-Rj are the same or different, R4 = hydrogen, R6 = hydrogen and R7 = hydrogen, phenyl, optionally substituted by -COOH-Cr to C4- alkyl or phenyl Cr to C4 alkali.

C1)

in which mean:

R

oh x i ii

: Group - n - c - n

/

R,

\ r.

60

or

65

r,

x

-o-n-c-z

650 787

4th

Z is a group -OR7 or N

/ 6

According to this, the radical R in the compounds of the formula I either has the structure S '

V

r-

r '=

X oxygen or sulfur,

oh x i ii - n - c - or.

(N-substituted hydroxamic acid) or

10th

Ri, R2, R;, hydrogen, methyl, ethyl, 2-chloroethyl or 2-methanesulfonyloxyethyl, where R], R2, R3 are identical or different from one another,

R4 is hydrogen, methyl or ethyl, the individual R4

are the same or different,

R5 Cr to C4 alkyl, Cr to C4 hydroxyalkyl or phenyl.

where R5 can additionally be hydrogen if Z is -OR7, 15 Rf, hydrogen, Crbis C4-alkyl, Cr to C4-hydroxyalkyl or phenyl,

R7 (a) hydrogen, carbamoyl or -OR8, where R8 = water (N-hydroxyurea) substance, Cr to C4-alkyl, phenyl or benzyl,

(b) 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, -CONH2, -phenyl,

oh x i n r1 = - n- c- n

/ 6

r-

20th

or else the structure S "bound via oxygen:

30th

the benzyloxycarbonyl radical, -N (R9) 2, -N (R9) 3, -OR9, -SR9, -S02-R9, -SO3H or -PO (CH3) 2, where R9 is methyl or ethyl, or

(c) a phenyl-Cw-alkyl radical which is optionally substituted by 1 or 2 carboxy groups in the phenyl and / or alkyl part of the radical,

(d) allyl,

(e) cycloalkyl having 3 to 8 carbon atoms or tetrahydrofuranyl,

(f) tetrahydropyranyl, 35

(g) phenyl which can be unsubstituted or mono- or disubstituted by Ci_4-alkyl, C 1-4 alkoxy, nitro, halogen, trifluoromethyl, -S02NH2, carboxy, benzyloxycarbonyl and / or carb-Ci ^ alkoxy,

(h) benzhydryl,

(i) naphthyl,

(k) fluorenyl,

(1) pyridyl,

(m) thienyl,

(n) Benzoyl or C, 4-alkanoyl, or R (, and R7 together with the atoms to which they are attached form part of a saturated heterocyclic ring system which additionally contains an oxygen atom, a lower alkyl-substituted nitrogen atom or a - S-, -SO- or -S02-sulfur atom can contain, or Rfl and R7 are part of an unsubstituted or cyano or carbamoyl substituted aziridine ring,

and their pharmaceutically acceptable salts.

The compounds of formula I are new. Depending on the meaning of R, the compounds according to the invention correspond to one of the following formulas I 'and I ":

40

45

50

55

rc o l5 \\

r "= - o - n - c - or-

(O- and N-substituted hydroxamic acid).

Because of their particularly favorable properties and easy accessibility, the oxazaphosphorines of the general formula I in which Z is the group are preferred

_N / R6

\

r? '

X is oxygen, R6 is hydrogen, methyl or ethyl and R7 is hydrogen or straight or branched chain alkyl having 1 to 18 carbon atoms, phenyl or benzyl. These are compounds of the formula I '.

Another group of preferred compounds of the formula I 'are those in which X is oxygen, R 1, R 2 and R 3, which are identical or different from one another, are hydrogen or a 2-chloroethyl radical, R 4 and R 6 are hydrogen and R 7 is hydrogen, Benzyl, phenyl which is unsubstituted or substituted by one or two carboxy groups, optionally Q_4-alkyl or phenyl-Ci_4-alkyl which is substituted by 1 carboxy group, optionally by 1 or 2 carboxy groups in the phenyl and / or alkyl part of the remainder is substituted.

The oxazaphosphorines of the general formula I are obtained according to the invention in that a 4-hydroxy- or 4-methoxy- or 4-ethoxy-oxazaphosphorin of the general formula II

ho x

Ri \ R3 N-c-n ^ N '

i u p / -VH

'V ^ Xr ^

tD

R7 (I ')

R R Î5 «60

1\ . 3 O-N-C-Z 1

R.

0

65

(ii)

where the Svmbole have the meanings already given.

wherein R ,, R2, R3 and R4 have the same meaning as in formula I and Y is hydrogen, Methvl or Ethvl, with a

5,650,787

Hydroxycarbamate derivative (hydroxamic acid derivative) the general- The course of the reaction can be followed by thin-layer chromatography according to the formula III method according to the invention. The

Isolation of thin-layer chromatographic uniform r x substances is achieved by conventional processing methods for

1 5 II 5 such products, in particular by crystallization or high - n - c - z (iii) chromatographic purification. The structure is secured by melting point, thin-layer chromatography, elemental analysis and / or IR and 'H-NMR spectral analysis, in which Z, R5 and X have the same meaning as in formula I, in general, also allow assignment to formula I' or I " , and R5 additionally represents hydrogen, in the presence of a 0, optionally together with an X-ray structure analysis, of inert solvent, if appropriate with cooling or

Heating and / or, if appropriate, in the presence of an acid which is reacted as the starting material in the process according to the invention. Compounds used are largely known, can

If both R5 for hydrogen crystalline or as a crude product are used in the above formula III and Z for 5 can be synthesized as follows in a manner known per se:

4-Hydroxy-oxazaphosphorines are obtained by reducing the 4-5 hydroperoxy derivatives [e.g. B. A. Takamizawau. a., J.

Rg Med. Chem. 18,376 (1975)]. 4-methoxy- or 4-ethoxy-oxaza-

'' Phosphorines are formed from the 4-hydro-

v 20 x derivatives in methanol or ethanol or in inert solution

Ry mittein that contain methanol or ethanol. The hydroxy

Urea derivatives are obtained by the reaction of appropriately substituted isocyanates or carbamic acid chlorides, surprisingly, compounds of the formula I 'are obtained, probably as a result of rearrangement with hydroxylamine or N-monosubstituted hydroxylamines. ' produced. In a similar way, the N-hydroxy-carb

Suitable solvents are water, lower alkylamate esters (hydroxycarbamates) by reacting the logenides such as, in particular, methylene chloride, lower alkylke corresponding chlorocarbonic acid esters with hydroxylamine or tones, such as in particular acetone, diethyl ether, dimethylforma- N-monosubstituted hydroxylamines. For the Syn-mid (DMF), Hexamethylphosphorsäuretriamid (HMPT) or these of hydroxyurea- or N-hydroxycarbamic acid-like solvents or mixtures of several such esters with an additional hydroxy, carboxy or sulfone solvent. The reaction is generally carried out when the acid group is a synthetic route with protective group recommended temperatures in the range of -35 and + 50 ° C.

d. H. optionally with cooling, at room temperature or The oximes of the formula IV are based on various synthetic

with warming. The implementation can be accessed in the presence of a gene. For example, they can be obtained by reacting the correspondingly acidic catalyst, such as an inorganic acid, trichlorose-containing 4-hydroxyoxazaphosphorines with hydroxylamine or acetic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid or with hydroxylamine salts. The pH value of a Lewis acid such as A1C13, ZnCl2 or TiCl4 should be kept between 2 and 7 if possible.

will. Of the 4-carbamoyloxy-oxazaphos according to the invention

A further process for the preparation of compounds of the phorins can be the racemic eis and trans isomers of formula I ', in which 40 are prepared (eis = 2R, 4R / 2S, 4S; trans = 2R, 4S / 2S, 4R). The

Allocation is in accordance with the IUPAC nomenclature rules and with the literature on corresponding oxazaphos-

Z —N 6 phorin derivatives. The ice cream or trans-form can be chosen as you choose

R also produce the reaction conditions in a targeted manner. Pharmacological

7 43 nically, the isomers show no significant differences.

The compounds according to the invention are characterized by R6 = hydrogen, which is characterized in that an oxime of the general formula IV is distinguished by remarkable, chemotherapeutically valuable properties. In comparison with the known reference substance cyclo-

phosphamide, they have approximately the same level of cancer-toxic chemotherapeutic activity on experimental transplantation tumors in rats. They have a direct alkylating effect in aqueous | 3 solution and have a high cytoto-H WH xicity in vitro, while cyclophosphamide requires enzymatic activation / Np 'tion and is practically non-cytotoxic in vitro. The 2 <p \ 0 c ch c N OH 55 a'cute toxicity of the compounds according to the invention is approx.

~ / \ II * - \ 4 times less than that of the reference substance cyclophosphamide, the k4 r4 R4 R4 (iv / therapeutic range is thus significantly increased. Also with regard to organotoxic side effects such as leukocyte depression and immunosuppression, the 60 compounds according to the invention have clear advantages compared to the reference substance in which R 1 to R 4 have the same meaning as in formula I ', in cyclophosphamide.

an inert solvent at a temperature in the range The compounds of the invention are for the treatment of -70 to + 50 ° C with a compound of general malignant tumors and similar malignant diseases, such as

Formula V leukemia in humans. Amounts come in

X = C = N-R7 (V) 65 range from 0.01-100 mg / kg for use. The pharmaceutical preparations used here are implemented according to the usual methods in which X and R7 have the same meaning as in formula I, methods using customary additives and carriers. produced.

650 787 6

The following examples serve to explain the 20 g (50 mmol) 4-hydroxytrofosfamide (ie 3- (2-chloroethyl) present invention without further limitation. 2- (bis- (2-chloroethyl) amino) - 4-hydroxy-tetrahydro-2H-l, 3.2-

oxazaphosphorin-2-oxide) and 5.3 g (70 mmol) of hydroxyurea Example 1 were dissolved in 100 ml of DMF and cooled to -15 ° C. Then l-hydroxy-l- [2- (bis- (2-chloroethyl) -amin0) -2-oxo-tetrahydro-5 was acidified with trichloroacetic acid (pH 3-4) and added for 5 hours

2H-1,3,2-Oxazaphosphorin-4-yl] urea -15 C. After standing overnight at 0 C, the r r -j / j u o / r »- / <-> reaction solution was diluted with twice the amount of water.

15 g (54 mmol) of 4-hydroxycyclophosphamide (ie 2- (bis- (- Then 4 times with 300 ml of ethyl acetate / methanol were chloroethyl) amino) -4-hydroxy-tetrahydro-2H-l, 3,2-oxazap os- qq: 1) shaken out, the combined ethyl acetate phases twice with phorin-2-oxide) and 4.4 g (58 mmol) of hydroxyurea were washed in water, dried over sodium sulfate and in

70 ml of DMF dissolved, acidified with trichloroacetic acid (pH -4), vacuum concentrated to 22 g of oil. After pickling in vinegar

and left in the refrigerator at 0 ° C for 20 hours. Thereafter, ester / methanol crystallized 4.2 g (mp. 106-110 ° C). The crystal slurry was diluted with 70 ml of ethyl acetate and, after 2 h of mother liquor, was also filtered off by column chromatography on silica gel, washed, dried and separated from methanol-chloroform / methanol (10: 1) and together with the first crystals of ethyl acetate / Recrystallized from methanol.

Yield: 11.3 g (62% of theory) of the cis form, yield: 7.0 g (35% of theory)

F: 139-143 ° C (dec.). _ p. H5_H6 ° C (dec.).

Example 2 Example 5

1-hydroxy-l- [2- (bis- (2-chloroethyl) amino) -2-oxo-tetrahydro-20 3-benzyl-l-hydroxy-l- [2- (bis- (2-chloroethyl) - amino) -2-oxotetra-2H-1,3,2-oxazaphosphorin-4-yl] urea, cis-form hydro-2H-l, 3,2-oxazaphosphorin-4-yl] urea

1 * 1 g (4.0 mmol) of 4-hydroxycyclophosphamide was added to 900 mg (3.25 mmol) of 4-hydroxycyclophosphamide in 1 ml

Dissolved methanol, mixed with a trace of trichloroacetic acid, 540 mg (3.25 mmol) of 3-benzyl-1-hydro overnight at -25 C were left over methylene chloride, then gentle methanol 2s xyourea in 40 ml acetone and a catalytic amount of tri- deducted, the residue taken up in a little methylene chloride-chloroacetic acid. The mixture was dried overnight and dried to 1, 2g4-methoxycyclophosphamide (i.e. -25 ° C, the crystals were subsequently suction filtered) with

Washed 2- (bis- (2-chloroethyl) amino) -4-methoxy-tetrahydro-2H-l, 3,2-acetone and ether and recrystallized from ethyl acetate. oxazaphosphorin-2-oxide). Then 1.2 g yield: 500 mg (40% of theory)

4-methoxycyclophosphamide and 304 mg hydroxyurea in, n p. io9_m ° r / "vPrc \

3 ml of DMF dissolved and stored in the refrigerator for 20 h at -25 ° C () "

maintains. The crystal slurry was diluted with 3 ml of ethyl acetate, example 6

suction filtered, washed, dried and recrystallized from methanol

3- (o-bromophenyl) -l-hydroxy-l- [2- (bis- (2-chloroethyl) amino) -2-

Yield: 670 mg (50% of theory) of the same product as in 35 oxo-tetrahydro-2H-l, 3,2-oxazaphosphorin-4-yl] urea Example 1. 560 mg (2 mmol) of 4-hydroxycyclophosphamide in 10 ml of acetone were mixed with 460 mg of 3-o-bromophenyl-l-hydroxyurea and Example 3 of a catalytic amount of trichloroacetic acid and at

TT, r- N "j» TT -25 ° C. After 2 days, the crystals l-hydroxy-l- [2- (bis-2-chloroethyl) -amm0) -2-oxo-tetrahydro-2H- were recrystallized from acetone. 1 , 3,2-oxazaphosphonn-4-yl] urea, trans form «^ yield; 32 {) mg (32% d Th}

16 g (58 mmol) of 4-hydroxycyclophosphamide and 5.2 g (68 p. No_nioc (dec.).

mmol) of hydroxyurea were dissolved in 160 ml of water, with

Acidified trichloroacetic acid (pH 3-4) and left for 20 h at 0 ° C in Example 7 refrigerator. The crystal slurry was then filtered off with suction, washed with water and 45 N-hydroxy-N- [2- (bis (2-chloroethyl) amino) -2-oxo-tetrahydro- over P2Os under high vacuum.

dried and recrystallized from methanol / chloroform. 2H-l, 3,2-oxazaphosphorin-4-yl] -4-morpholinocarbonylamine

Yield: 12.7 g (65% of theory) of the trans form of the product. 1.2 g (4.3 mmol) of 4-hydroxycyclophosphamide in 15 ml of acetone in Example 1 were mixed with 630 mg (4.3 mmol). N-hydroxy-morpholino-carbox-

F: 148 ° C (dec.). amide and a trace of trichloroacetic acid and at-25 ° C.

50 stored. After 4 days the crystals were vacuumed and

Example 4 recrystallized from acetone.

l-Hydroxy-l- [3- (2-chloroethyl) -2-bis- (2'-chloroethyl) amino) -2- yield: 780 mg (45% of theory)

oxo-tetrahydro-2H-l, 3,2-oxazaphosphorin-4-yl] urea F: 123-124 ° C (dec.).

55

Examples 8-70

Starting from corresponding 4-hydroxy-tetrahydro-2H-l, 3,2-oxazaphosphorin-2-oxides, the further compounds of the general formula given in the following list

R1 ^? 3

2 P •> •

'0 ^ ~ <

made analog.

H

7

650 787

At r,

r:

rl game no.

8th

c1-ch, ch, -

c1-ch, ch, -

H-

9

c1-ch, ch, -

c1-ch, ch> -

H-

10th

c1-ch-.ch-1-

ci-ch2ch2-

H-

11

cl-chichi-

c1-ch-> ch> -

H-

12

c1-ch2ch2-

c1-ch2ch2-

H-

13

ci-ch2ch2-

c1-ch2ch2-

H-

14

ci-ch2ch2-

ci-ch2ch2-

H-

15

ci-ch2ch2-

ci-ch2ch2-

H-

16

ci-ch2ch2-

ci-ch2ch2-

H-

17th

ci-ch2ch2-

ci-ch2ch2-

H-

18th

ci-ch2ch2-

ci-ch2ch2-

H-

19th

ci-ch2ch2-

ci-ch2ch2-

H-

R, O

20th

21st

23

24th

25th

26

C1-CH-.CH, -

Cl-CHoCH, -

22 C1-CH-.CH, -

C1-CH2CH2-C1-CH2CH2-

C1-CH2CH2-C1-CH-.CH-I-

27 Cl-CFLiCH -> -

28 C1-CH-.CH -, -

29 C1-CH-.CH -.-

C1-CH2CH2-C1-CH2CH2-Cl-CH, CHo-

H-

H-

H-

C1-CH-> CH> - H-

CI-CHICHT H-

C1-CH-, CH> - H-

Cl-CH.CH, - H-

Cl-CH.CH, - H-

Cl-CHiCHi- H-

C1-CH, CH, - H-

H-H-H-H-H-

H-

H-

H-

H-

H-

H-

H-

H-

H-

H-

H-

H-

H-

H-

H-

-CO-NH-CH3 -CO-NH-CH, -CH3 -CO-NH-CH (CH3> -CO-NH- (CH,) 3-CH3 -CO-NH- (CH2) 5-CH3

-C0 ~ NH ~ <^ t)

-CO-NH-CH, -CH = CH,

~ c0 ~ nh ~ ch? -ch2- ^ -co-nh-ck (ch-) - ((_

-co-nh-ch r \

Melting point or Rf value "

106 ° C

îorc

99 ° C 50 ° C 70-71 ° C

111 ° C

65-67 ° C

100-101 ° C

a

-co-nh - <^ y. cl

-co-nh- ^ 3

\ ci

-co-nh - <^ V- f

-co-nh - ^

113 ° C 130 ° C 98 ° C 91-92 ° C

118-120 ° C 118 ° C 94 ° C 101 ° C 116-117 ° C

• F ^

• CO-NH - ^^ - O-CHj 93-94 ° C

-co-ira- <Q) -no.

H-co-mWv no,

H- -CO-NÎÏ- /

lorc

117-118 ° C

111-112 ° C

91-93 ° C

650

For example

30th

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

r.

Cl-ch-ichi-

R-.

c1-ch, ch, -

R,

H-

r-i h-

^ c1

Cl-CH, CH -> -

c1-ch2ch2-

ci-ch-> cht Cl-ch-ich-i-c1-ch2ch2-

C1 layer

C1-CH-ICH -> -

Cl-chich-.

H-

Cl-chich -.- h-

c1-ch, ch, -cl-chichi-c1-ch, ch, -

h-h-h-

Cl-CH-) CH -> - H-

C1-CHICHT H-

H-

H-

h-h-h-

H-

H-

<ch3) -0

-co-n '-co ~ n

-co-n (c, h,),

-co-n (ch, '),

-co-n- (ch3) - (ch,), - ch3

c1-ch2ch2-c1-ch2ch2-

ci-ch2ch2-

ci-ch2ch2-

ci-ch2ch2-ci-ch2ch2-ci-ch2ch2-

ci-ch2ch2-

ci-chiCH-i-

c1-ch2ch2- h-

ci-ch2ch2- h-

ci-ch2ch2- h-

ci-ch2ch2- h-

ci-ch2ch2- h-

ci-ch2ch2- h-

ci-ch2ch2- h-

ci-ch2ch2- h-

Cl-CH, CH -> - H-

h-h-h-

ch3-

H-

h-h-

-CS ~ NH- \

-co-nh-co-nh2 -CO -O

-CO-NH-CH2-

-co-nh-oh

-C0-NH ~ <O> -S02NH2

-CO-NH-

H- "C0-NH-CK2-C02-CK2-

H-

~ CO-NK-CH2-COOK

x ™ 2-0

Melting point or Rf value "

107 ° c

Cl-CH-.CH -> -

Cl-CHiCH, -

H-

H-

-CO-NH- (CH2) 3-Br

48-50 ° C

C1-CH-.CH, -

C1-CH, CH, -

H-

H-

-CO-NH-CH, -CH, -C1

98 ° C

Cl-CH, CH -> -

Cl-CH, CH -> -

H-

H-

-CO-NH-CH (CH,) - CO, C, H,

102-103 ° C

C1-CH2CHo-

Cl-CHiCHi-

H-

H-

-CO-NH-CH, -CH, -OH

0.33

ci-ch2ch> -

C1-CHOCH2-

H-

H-

-CO-NH-CH, -PO (CH3),

110-113 ° C

ci-ch2ch2-

ci-ch2ch2-

H-

H-

-co-nh-ch2-co, c2h5

106 ° C

ci-ch2ch2-

ci-ch2ch2-

H-

H-

-CO-NE-C-V ^)

125 ° C

U v = /

0.65

119-121 ° c

92 ° c 96-98 ° c 0.63

118 ° c

0.72

c1-ch, ch, -

H-

c1-ch, ch, -

H-

-co-nh,

134 ° c c1-ch, ch, -

chr cl-ch2ch, -

H-

-co-nh,

144 ° c ch3só3-ch, -ch, -

ch, -

cl-chichn-

H-

-co-nh,

114-115 ° c c1-ch, ch, -

H-

ch3-sö3-ch, -ch, -

H-

-co-nh,

0.34

ch3-sò, -ch, ch, -

H-

c1-ch, ch, -

H-

-co-nh,

0.29

c1-ch, ch, -

c1-ch2ch, -

H-

ch3-

-co-nh,

136-138 ° c c1-ch, ch, -

c1-ch, ch, -

H-

H-

-co-nh-c14h, 9n

0.64

0.67 141 ° c 109 ° c

110-112 ° c

110-113 ° c

131 ° c

114 ° c

119 ° c 106-108 ° c

9

650 787

Example No.

r.

R:

R,

rj q

Melting point or Rf value "

61

c1-ch2ch2-

c1-ch2ch2-

H-

H-

-c0-nh - <^ o ^

83-85 ° c

"The melting points were not corrected. The oily compounds were characterized by the Rf value in thin layer chromatography on silica gel in the eluent chloroform / methanol (5: 1). The further characterization was carried out as for the crystalline compounds.

Example 62

• j3-Hydroxy-3- [2- (bis (2-chloroethyl) amino) -2-oxo-tetrahydro-2H-1,3,2-oxazaphosphorin-4-yl] -ureido} - acetic acid cyclo -hexylamine salt 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, while stirring at a bath temperature of 140 ° C., dry phosgene gas was introduced for two hours . The reaction mixture was then concentrated in vacuo and the residue was distilled in a high vacuum.

Yield: 51 g (95% of theory) of benzyl isocyanato acetate Kp.o.os: 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 of methanol were mixed with 5 g of palladium-carbon and hydrogenated in a shaking plane. 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.

b) 2.4 g (18 mmol) of 3-hydroxy-ureido-acetic acid in 10 ml of water and 25 ml of acetone were mixed with 6.1 g (2 mmol) of 4-hydroxycyclophosphamide and left overnight 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)

F: 107-108 ° C.

Preparation A: starting product for Examples 63 to 77

3- [N, N- (bis- (2-chloroethyl) -diamino-phosphinyl-oxy] -propional-dehyd-oxime (aldophosphamide-oxime)

4.0 g (13.7 mmol) of 4-hydroperoxycyclophosphamide were suspended in 50 ml of water with ice cooling, and 500 mg of sodium thiosulfate x 5 mol of water were added. With stirring at 5-10 ° C, the pH is checked with a pH meter, kept between pH 4.5 and 5.5 with 2 normal sulfuric acid and a concentrated solution of sodium thiosulfate is added dropwise until the pH no longer increases . The mixture was stirred for half an hour at approx. 10 ° C., an aqueous solution of 950 mg of hydroxylamine hydrochloride was added dropwise, the pH was kept at 5 with 2 normal sodium hydroxide solution, and the reaction mixture was left overnight.

15 mixed in the refrigerator at 5 ° C, extracted four times with 50 ml of ethyl acetate 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 were filtered off with suction after 1 day.

20 Yield: 3.4 g (85% of theory)

F: 79-81 ° C.

Example 63

25 3-p-Bromophenyl-l-hydroxy-l- [2- (bis (2-chloroethyl) amino) -2-oxo-tetrahydro-2H-l, 3,2-oxazaphosphorin-4-yl] urea 5.8 g (20 mmol) of aldophosphamide oxime in 60 ml of acetone were mixed with 4 g (20 mmol) of p-bromophenyl isocyanate in 40 ml of acetone, stirred for 5 hours with cooling. After 2 hours it was

30 extracted crystals i.V. dried on a rotary evaporator at 40 ° C and recrystallized in methanol.

Yield: 8.1 g (82.8% of theory)

F: 118-120 ° C.

35

Example 64

3-m-trifluoromethylphenyl-l-hydroxy-l- [2- (bis- (2-chloroethyl) amino) -2-oxo-tetrahydro-2H-l, 3,2-oxazaphosphorin-4-yl] urine-

material

7.3 g (25 mmol) of aldophosphamide oxime in 80 ml of acetone 40 were mixed with 4.7 g (25 mmol) of m-trifluoromethylphenyl isocyanate in 40 ml of acetone. The mixture was stirred at 0.degree. C. for 3 h, 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. 45 and recrystallized from isopropanol.

Yield: 9.2 g (76.8% of theory)

F: 91-93 ° C.

50

Example 65

3-Cyclohexyl-l-hydroxy-l- [2- (bis- (2-chloroethyl) amino) -2-oxo-tetrahydro-2H-l, 3,2-oxazaphosphorin-4-yl] urea 5 g ( 18 mmol) of aldophosphamide oxime and 2.2 g of cyclohexyl isocyanate were dissolved in 10 ml of acetone, mixed together at 0 ° C., the crystals were filtered off after 2 h and washed with acetone / ether.

Yield: 4.2 g (56% of theory)

F: 113 ° C.

60

Example 66

3-ethyl-l-hydroxy-l- [2- (bis- (2-chloroethyl) amino) -2-oxotetra-hydro-2H-l, 3,2-oxazaphosphorin-4-yl] urea 5 g (18 mmol) of aldophosphamide oxime and 1.2 g of ethyl isocyanate were dissolved in 15 ml of acetone, and combined at about 0 ° C. After 5 h the crystals were filtered off and washed with acetone / ether.

Yield: 3.5 g (54% of theory)

F: 101 ° C.

650 787

10th

Example 67

'3- (Fluoren-2-yl) -l-hydroxy-l- [2- (bis- (2-chloroethyl) amino) -2-oxo-tetrahydro-2H-l, 3,2-oxazaphosphorin-4- yl] urea 2.9 g (10 mmol) of aldophosphamide oxime in 30 ml of acetone were mixed with 2.1 g (10 mmol) of fuorenyl-2-isocyanate in 20 ml of acetone at 0 ° C. The next day, the precipitated product was suctioned off, i.V. Dried at 60 ° C and recrystallized from isopropanol / methanol.

Yield: 2.5 g (40.1% of theory)

F: 114 ° C.

Example 68

3-Benzoyl-l-hydroxy-l- [2- (bis- (2-chloroethyl) amino) -2-oxotetrahydro-2H-1,3,2-oxazaphosphorin-4-yl] urea 5 , 8 g (20 mmol) of aldophosphamide oxime in 60 ml of acetone were mixed with 2.9 g (20 mmol) of benzoyl isocyanate in 40 ml of acetone. The mixture was stirred for 5 hours in an ice bath under a nitrogen 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)

5 F: 124-125 ° C.

Example 69

3-p-nitrophenyl-l-hydroxy-l- [2- (bis- (2-chloroethyl) amino) -2-oxo-l-tetrahydro-2H-l, 3,2-oxazaphosphorin-4-yl] - 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, the solid product was filtered off with suction on a rotary evaporator at 40 ° after 2 h C dried, and recrystallized from Dime-15 thylformamide / ethanol.

Yield: 6.7 g (73.5% of theory)

F: 117-118 ° C.

10th

Examples 70-77

Starting from corresponding 4-hydroxy-tetrahydro-2H-l, 3,2-oxazaphosphorin-2-oxides and N-substituted compounds of the formula III, compounds of the formula I "were obtained in accordance with the following list:

S

R,

N-

\ / "A ,.

Example No.

R,

R2

Ri

R,

R

Melting point Rf value "

70

c1-ch2ch2-

c1-ch2ch2-

H-

H-

-n (ch3) -co-nh - <^ j ^

125-126 ° c

71

ci-ch2ch2-

c1-ch2ch2-

H-

Al \

H-

-n (ch3) -c0n (ch3) - <^)

0.57

72

c1-CHich -> -

c1-CH-> cht h-

H-

-n (ch,) - co-nh,

115-117 ° c

73

ci-CH-not c1-CHich -> -

H-

H-

-n (c, h,) - co-nh,

0.51

74

ci-CHich -.-

Cl-CH, CHo-

H-

H-

^ (ch ^ -co-nh-ch,

125-127 ° c

75

Cl-chich> -

cl-ctlch, -

H-

H-

-n (c, h <0-co-nh-ch,

112 ° c

76

cl-ctlctl-

Cl-CH-> CH -> -

H-

H-

-n (ch, ") - co-nh-c, h, -

0.60

77

cl-ch-ichi-

ci-CH high h-

H-

-n (c, h, -) co-n (c, h, -),

0.61

50

Example 78

Ethyl 2- (bis- (2-chloroethyl) amino-2-oxo-tetrahydro-2H-l, 3,2-oxazaphosphorin-4-yl-oxy-carbamate 550 mg (2 mmol) 4-hydroxycyclophosphamide and 210 mg (2 mmol) of ethyl hydroxycarbamate (hydroxyurethane) were dissolved in 5 ml of dry, alcohol-free methylene chloride, a catalytic amount of trichloroacetic acid was added, molecular sieve 4 A was added and the mixture was left to stand at -25 ° C. for 3 days The methylene chloride phase, which was dried over sodium sulfate, was evaporated down and diluted with ether, and after standing for 20 hours at -25 ° C. the crystals were filtered off with suction, washed and dried.

Yield: 290 mg (40% of theory)

Mp: 96 ° C.

Example 79

Benzyl 2- (bis- (2-chloroethyl) amino-2-oxo-tetrahydro-2H-l, 3.2-55 oxazaphosphorin-4-yl-oxy-carbamate

750 mg (2.7 mmol) of 4-hydroxycyclophosphamide and 450 mg (2.7 mmol) of benzylhydroxycarbamate were dissolved in 6 ml of alcohol-60-free methylene chloride, mixed with a little trichloroacetic acid, left to stand in the refrigerator at -25 ° C., and filtered off after 3 days , the mother liquor diluted with 5 ml of chloroform, washed with water, with dilute sodium hydrogen carbonate solution and again with water, dried over sodium sulfate 65 and concentrated in vacuo. The oily residue was recrystallized from ethyl acetate / a little methanol.

Yield: 680 mg (59% of theory)

Mp: 112-114 ° C.

Pharmaceutical application examples

Example 80 (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 the mixture is mixed until all the components are homogeneously distributed. This mass is pressed in a known manner into cores of 200 mg with 100 mg of active ingredient.

These cores are coated with an enteric film, e.g. B. from suitable cellulose derivatives or a fully synthetic film former in organic solution or what ger dispersion, the additives such as plasticizers, dyes,

11 650 787

May contain flavorings or defoamers.

Example 81 (enteric-coated gelatin capsules) 5 250 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 mixed until all components are homogeneously distributed. This mass is filled in individual doses of 300 mg in gelatin plug capsules.

One capsule contains 250 mg of active ingredient.

The gelatin capsules are provided with an enteric film coating in accordance with Example 80.

M

Claims (8)

650 787 *1 > \ / (1) pyridyl, (m) thienyl, (n) Benzoyl or Ci_j-alkanoyl, or R6 and R7 together with the atoms to which they are attached form part of a saturated heterocyclic ring system which additionally contains an oxygen atom, a lower alkyl-substituted nitrogen atom or an -S-, - SO- or -SOrSchfelatom can contain, or R6 and R7 are part of an unsubstituted or cyano or carbamoyl substituted aziridine ring, and their pharmaceutically acceptable salts. 2. oxazaphosphorine derivatives of the formula ho x 20th 25th 30th (I *) X oxygen or sulfur, Z is a group -OR7 or -n r, \ r. 35 according to claim 1, wherein the symbols have the meanings given, and their pharmaceutically acceptable salts. 3. Oxazaphosphorine derivatives of the formula r4 r? rfi R7 Ri, R2, R3 are hydrogen, methyl, ethyl, 2-chloroethyl or 2-methanesulfonyloxyethyl, where Ri, R2, R3 are identical or different from one another, Hydrogen, methyl or ethyl, where the individual R4 are the same or different, Cr to C4-alkyl, Cr to C4-hydroxyalkyl or phenyl, where R5 can additionally be hydrogen if Z is -OR7, hydrogen, Q- to C4-alkyl, Cr to C4-hydroxyalkyl or phenyl, (a) hydrogen, carbamoyl or -OR8, where R8 = hydrogen, Cp to C4-alkyl, phenyl or benzyl, (b) 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., -Phenyl, the ® Benzyloxycarbonyl radical, -N (R9) 2, -N (R9) 3, -OR9, -SR9, -SO-R9, -S02-R9, -SO3H or -PO (CH-î) 2 may be substituted, wherein R9 denotes methyl or ethyl, or (c) a phenyl-C | _4-alkyl radical which is optionally substituted by 1 or 2 carboxy groups in the phenyl and / or alkyl part of the radical, (d) allyl, (e) cycloalkyl having 3 to 8 carbon atoms or tetrahydrofuran-anyl, (f) tetrahydropyranyl, (g) Phenyl, which can be unsubstituted or mono- or disubstituted by G, 4-alkyl, C | _2-alkoxy, nitro, halogen, trifluoromethyl, -S02NH2, carboxy, benzyloxycarbonyl and / or carb-Ci _ (- alkoxy. 40 45 50 rc x r i "3 o-n-c z (I ") according to claim 1, wherein the symbols have the meanings given, and their pharmaceutically acceptable salts. 1. oxazaphosphorine derivatives of the general formula in which: R is a group —N— C— N ^ r, r- or rc x I 5 II -0-N-C-Z, 10th (I) 15 (h) benzhydryl, (i) naphthyl, (k) fluorenyl, 2nd PATENT CLAIMS 3rd SB - c - / \ CH OH 12. The method according to claim 7, characterized in that the reaction is carried out with cooling or with heating. 13. The method according to claim 7 or 9, characterized in that the reaction is carried out in the presence of an acid catalyst. 14. Pharmaceutical preparation containing as active ingredient a compound according to one of claims 1 to 4 in addition to physiologically compatible carriers and / or diluents. wherein Z, Rs and X have the same meaning as in formula I and Rj is additionally hydrogen, is reacted in the presence of an inert solvent, compounds of the formula I 'according to claim 2 being obtained when in formula III R5 is hydrogen and Z is -N (R6) (R7). 3rd 650 787 4. oxazaphosphorine derivatives according to claim 2, characterized 55 characterized in that X is oxygen, R6 is hydrogen, methyl or ethyl and R7 is hydrogen or straight or branched chain alkyl having 1 to 18 carbon atoms, phenyl or benzyl. 5. oxazaphosphorine derivatives according to claim 4, characterized in that R4 are hydrogen atoms. 60 6. oxazaphosphorines according to claim 2, characterized in that X is oxygen, R], R2 and R3, which are identical or different from each other, signify hydrogen or the 2-chloro-ethyl-Ret, R4 and Rò represent hydrogen and R7 represent hydrogen, Benzyl, phenyl which is unsubstituted or substituted by one 65 or two carboxy groups is optionally substituted by Q.j-alkyl or phenyl-C 1-4 alkyl which is optionally substituted by one or two carboxy groups in the phenyl and / or alkyl part of the remainder. Process for the preparation of the oxazaphosphorine derivatives according to claim 2 or 3, characterized in that a 4-hydroxy- or 4-methoxy- or 4-ethoxy-oxazaphosphorin of the general formula II 10th (II) wherein R], R2, R3 and R4 have the same meaning as in formula I 'or I "and Y is hydrogen, methyl or ethyl, with a hydroxycarbamate derivative of the general formula III Rr x ii ho - n - c - z (III) 8. Process for the preparation of compounds of formula I ' H according to claim 2, wherein Z is -N-R7, characterized in that an oxime of the general formula IV From DE-OS 2231311 and 2552135 it is known that by introducing a hydroperoxy group -OOH into the 4-15 position of the molecule of the known cytostatics 2- [bis- (2-chloroethyl) amino] -2-oxo-tetrahydro- 2H-l, 3,2-oxazaphosphorine (cyciophosphamide), 3- (2-chloroethylamino) -2- [bis- (2'-chloroethyl) amino] -2-oxo-tetrahydro-2H-1,3, 2-oxazaphosphorin (trofosfamide), 3- (2-chloroethylamino) -2- (2'-chloroethyl-20 amino) -2-oxo-tetrahydro-2H-l, 3,2-oxazaphosphorine (Ifosfa-mid), 3- (2-Chloroethylamino) -2- (2'-methanesulfonylethylamino) -2-oxo-tetrahydro-2H-l, 3,2-oxazaphosphorine (Sufosfamide) and other cyciophosphamides of similar structural formula can create compounds with valuable cytostatic properties, this V However, compounds 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 cyciophosphamides 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.