DD202166A5 - PROCESS FOR THE PREPARATION OF NEW 4-CARBAMOYLOXY-OXAZAPHOSPHORINES - Google Patents

Abstract

The present invention relates to processes for the preparation of novel 4-carbamoyloxyoxazaphosphorines of the general formula I.

Description

Process for the preparation of new 4-carbamoyloxy-oxazaphosphorines

Field of application of the invention

The invention relates to a process for the preparation of new oxazaphosphorines having improved cytostatic properties and reduced organotoxic side effects.

Characteristic of the Known Technical Solutions It is known from DE-OS 2 231 311 and 2 552 135 that 2- / bis- (2-chloroethyl) -amino7 can be obtained by introducing a hydroperoxy group -OOH into the 4-position of the molecule of the known cytostatics -2-oxo-tetrahydro-2H-1,3,2-oxazaphosphorin (Cyclophosphamide), 3- (2-chloroethylamino) -2 _/ {bis- (2 ^{<chloroethyl)} amino7-2-oxo-tetrahydro-2H- 1 _r 3,2-oxazaphosphorine (trofosfamide), 3- (2-chloroethylamino) -2- (2'-chloroethylamino) -2-oxo-tetrahydro-2H-1,3,2-oxazaphosphorine (ifosfamide), 3- ( 2-chloroethylamino) - 2- (2'-methanesulfonylethylamino) -2-oxo-tetrahydro-2H-1,3,2-oxazaphosphorine (sufosfamide) and other cyclophosphamides of similar structural formula can provide compounds having valuable cytostatic properties, but such compounds have low stability that their processing into pharmaceutical preparations, such as is necessary in human medicine, is not possible.

233132 5

Object of the invention

The aim of the present invention is to provide the preparation of substituted in the 4-position of the oxazaphosphorin ring with a further modified hydroxy group cyclophosphamide, which are characterized in particular by high cytostatic activity and improved stability.

Explanation of the essence of the invention

The present invention relates to processes for the preparation of the new 4-carbamoyloxy-oxazaphosphorines of general formula I.

wherein

Z is the group -N or the group -OR

^No. 7

X is oxygen or sulfur,

R, R ₂ and R ₃ , which may be identical or different, represent hydrogen, methyl, ethyl, 2-chloroethyl or 2-methanesulfonyloxyethyl,

233132 5

the Recte R., which are the same or different from each other

may represent hydrogen, methyl or ethyl, Rg and R- which may be the same or different from each other, hydrogen, C,. -alkyl, hydroxy-C-, -alkyl or

Phenyl, and R ~ is hydrogen, carbamoyl or

Is -OR, where R is hydrogen, C 1 -C 4 -alkyl, phenyl or

Benzyl is, or

a straight- or branched-chain alkyl is from I to 18

C-atom is,

where the alkyl radical has 1-3 identical or different substituents from the group -OH, -halogen, -COOH, -COOR ⁹ , -CONH ₂ , phenyl, the benzyloxycarbonyl radical, -N (R ⁹ ) ₂ , ~ $ (R ⁹ ) ₃ , -OR ⁹ , -SR ⁹ , "SO-R ⁹ , -SO ₂ -R ⁹ , -SO H, or -PO (CH ₃ J ₂ may be substituted, v or or R methyl or ethyl means, or

a phenyl-Cj ^ -alkyl radical, optionally with 1 or

'2 carboxy groups in the phenyl and / or alkyl portion of the radical is substituted,

Allyl or

Cycloalkyl having 3 to 8 carbon atoms or tetrahydrofuranyl or

Tetrahydropyranyl or phenyl which is unsubstituted or

one or two times with Cj-alkyl, C ^ _-2- alkoxy, nitro, halogen, trifluoromethyl, -SO ₂ NH ₂ , carboxy, benzyloxycarbonyl and / or carb-C. . Alkoxy may be substituted, or

Benzyl or ·

Benzhydryl or naphthyl or

2331 32 5 - * -

Fluorenyl or

Pyridyl or ·

^ Thienyl or

Benzoyl or C ₄ alkanoyl or R and R, or R, and R_ together with the atoms with

9 0 0 /

to which they are attached are part of a saturated heterocyclic ring system, which may additionally contain an oxygen atom, a lower alkyl-substituted nitrogen atom or an -S, -SO- or -SC ^ sulfur atom, or R _g and R _{7 are} part of an unsubstituted or with Cyano or carbamoyl substituted aziridine ring is.

Because of their particularly favorable properties and ready availability, the 4-carbamoyloxy ~ oxa7.aphosphorine of general formula I are preferred in which Z is the group-N ^, X is oxygen, R _r and R _r which is equal to

R ₇

may be hydrogen, methyl or ethyl and R _{7 is} hydrogen or straight or branched chain alkyl having 1 to 18 carbon atoms, phenyl or benzyl,

Another group of preferred compounds of formula I are those in which X is oxygen, R 1, R ₂ and R ₃ , which are the same or different, are hydrogen or a 2-chloroethyl radical, R, R ₅ and R _ß hydrogen, and R ₇ Vihydrogen, benzyl, phenyl which is unsubstituted or substituted by one or two carboxy groups, optionally substituted with 1 carboxy group C _1-4 alkyl or phenyl-C,. -alkyl, which is optionally with 1 or 2 carboxy groups in the phenyl and / or alkyl portion of the radical is substituted.

The process according to the invention for the preparation of the novel 4-carbamoyloxy-oxazaphosphorines of general formula I is characterized in that a 4-hydroxy- or 4-methoxy- or 4-ethoxy-o-azaphosphorine of general formula I is used

233132 5

v orin R ^, R _2, R ^ and R ₄ have the-same meaning as in formula I and Y is hydrogen and _R is methyl or ethyl,?

with a Hydrojcycarbamat-Derivcxt of the general formula III

I ⁵ Il

HO-N-C-Z III

wherein Z, R ₅ and X have the same meaning as in formula I,

in the presence of an inert solvent _f optionally with cooling or heating, and / or optionally in the presence

ti) ~

Essence of an acidic catalyst, is implemented.

Suitable solvents are water, Niederallcylhalogenide such as especially methylene chloride , lower alkyl ketones such as acetone in particular, diethyl ether, dimethylformamide (DMF), hexamethylphosphoric triamide (IMPT) or similar solvents or mixtures of several such solvents into consideration. The reaction is conducted at temperatures ranging from -35 ° C and +50 ⁰ C transit

233 132 5

guided, d, h. optionally with cooling> at room temperature or with heating. The reaction may 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 AlCl ₃ , ZnCl ₂ or TiCl ₄ .

Another method for the preparation of Verbin | HBEN of formula I wherein Z is -N ^ 6 with R _B = -H, and R _r VJawerstoff

eating _f is characterized in that an oxime ^c ^ ^cr general formula IV

o - c - cn - c == ν - oh iv

/ \ ι ι

«4 ^R 4 ^R 4 ^R 4

orin R, _{mm / have} the same meaning as in formula I, in an inert solvent at a temperature in the range of -70 to + 50 ° C with a compound of the general formula V? ^? "

X β C = N - R ₇ V

Yiorin X and R- have the same meaning as in formula I.

The Renktionsablauf let follow thin-layer chromatography according to the inventive method. The isolation of thin-layer chromatography uniform

233132 5

Substances succeed by conventional workup procedures for such products, in particular by crystallization or chromatographic purification. The structure is confirmed 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 widely known, can be used crystalline or as crude product and can be synthesized in a manner known per se as follows:

4-Hydroxy-oxazaphosphorines are obtained by reduction of the 4-memberediproperoxy derivatives (z ₍ B, A. Takamizawa et al., J. Med. Chem., 18, 376 (197S)). 4-methoxy- or 4-ethoxy- Oxazaphosphorines are formed under acidic catalysis from the 4-hydroxy derivatives in methanol or ethanol or in * inert solvents containing methanol or ethanol The hydroxyurea derivatives are by the reaction of appropriately substituted isocyanates or .. Carbamic acid chlorides with hydroxylamine Similarly, the N-hydroxycarbamic acid esters (hydroxycarbamates) can be obtained by reaction of the corresponding chlorocarbonic acid esters with hydroxylamine or N-methyl-substituted hydroxylamines, for the synthesis of hydroxyurea or N-hydroxybenzamines. Hydroxyccirbamidsüureestern with an additional hydroxy, carboxy or sulfonic acid group is a synthetic route with protective group is recommended.

The oximes of formula IV are accessible by various synthetic routes. Thus, they can be obtained by reacting the corresponding 4-hydroxy-oxazaphosphorine with hydroxylamine or with hydroxylamine salts. The pH should preferably be kept between 2 and 7,

2331 32 5

The racemic cis and trans isomers of the 4-carbamoyloxy-oxazaphosphorines according to the invention can be prepared (cis = 2R, 4R / 2S, 4S, trans = 2R, 4S / 2S, 4R). The assignment is in accordance with the IUPAC nomenclature rules and with the literature on corresponding oxazaphosphorine derivatives. The cis or trans form can also be selectively prepared according to the reaction conditions selected. Pharmacologically, the isomers show no. significant differences.

The erfindungsgomäßen compounds are distinguished by remarkable, chemotherapeutically valuable properties. In comparison with the previously known reference substance cyclophosphamide, they have an approximately equally strong carcinogenic chemotherapeutic efficacy on experimental transplantation tumors of the rat. They act directly alkylated in aqueous solution and have high cytotoxicity in vitro, while cyclophosphamide requires enzymatic activation and is virtually non-cytotoxic in vitro. The acute toxicity of the compounds of the invention is about 4 times lower than that of the reference substance cyclophosphamide _f 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.

The compounds according to the invention are suitable for the treatment of malignant tumors and similar malignant diseases such as leukemia in humans. Amounts in the range of 0.01 - 100 mg / kg are used. The pharmaceutical preparations used in this case are prepared by conventional methods using conventional additives and carriers. , ;

23 3 1 3 2 '5- · -

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

Exemplary embodiments Example 1

2 "(BiS"'(2-chloroethyl) amino) -2-oxo-tetrahydro-2H ~ 1 _> 3 _f 2-

oxazaphosphorin-A-yl-oxy-urea

15β (54 mmol) 4-hydroxycyclophospharaid (ie, 2- (bis (2-chloroethyl) amino) -4-hydroxy-tetrahydro-2H ~ 1,3,2-oxazaphosphorine 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 allowed to stand in the refrigerator at ⁰ ° C. for 20 h. Thereafter, the crystal pulp was diluted with 70 ml of ethyl acetate and filtered off with suction after 2 h, washed with water, dried and recrystallised from methanol. Yield: 11.3 g (62% of theory) of the cis-form, m.p .: 139-143 ⁰ C (dec.)

Example 2

2- (bis (2-chloroethyl ) amino) -2 -oxo- tetrahydro-2H-1,3 _? 2- oxazaphoGphorin-4-yl-oxy-cis-form harnsto.ff _t

1 »1 ß (4.0 mmol) 4-Hydroxycyclophosphamid vairden dissolved in methanol, treated with a trace of trichloroacetic acid, allowed to stand overnight at ~ 25 ° C, then carefully evaporated methanol, the residue taken up in a little methylene chloride, dried and to 1, 2 g of 4-methoxycyclophosphamide (ie 2 ~ (bis (2-chloroethyl) amino) -4-methoxy-tetrahydro-2H-1,3- _t 2-oxazaphosphorine-2-oxide). Subsequently

233132 5 - ¹⁰ -

1.2 g of 4-Methoxycyclophosphamid and 304 mg of hydroxyurea were dissolved in 3 ml of DMF, and kept for 20 hours at -25 ⁰ C in the refrigerator. The crystal slurry was diluted with 3 ml of ethyl acetate, filtered off, washed, dried and recrystallized from methanol.

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

Example 3 '.

2- (Bi s - (2 ~ chloroethyl ) ~ amino) -2 ~ oxo-tetrahydro ~ 2H-1,3 «? ~ Px azaph osphor .tn-4 ~ yl-oxy-urea _? trans-form *

16 g (58 mmol) of 4-hydroxycyclophosphamide and 5.2 g (68 mmol) of hydroxybam were dissolved in 160 ml of water, acidified with trir-chloroacetic acid (pH 3-4) and allowed to stand in the refrigerator at ⁰ ° C. for 20 h. Thereafter, the crystal pulp was filtered off with suction, washed with water, dried over Pp ^ 5 ^ ^m high vacuum and recrystallized from methanol / chloroform, yield: 12.7 g (65 % of theory) of the trans-forra of the product in Example 1 , F .: 148 ⁰ C (Zers.).

Example 4

.3- (2-Chloroethyl) -2- (bis (2- ^t- chloroethyl) amino) -2-oxo-tetra. hydro-2H-1 . 3,2-oxazaphosphorin-4-yl-oxy-urea

20 g (50 mmol) of 4-hydroxytrofosfamide (ie 3- (2-chloroethyl) .2- (bis (2-chloroethyl) amino) -4-hydroxy-tetrahydro-2H-1,3,2-oxazaphosphorin-2 Oxide and 5.3 g (70 mmol) of hydroxyurea were dissolved in 100 ml of DMF and cooled to -15 ° C. Then it was acidified with trichloroacetic acid (pH 3-4) and stirred for 5 h

233132 5

at -15 ⁰ C stirred. After standing overnight at ⁰ ° C, the reaction solution was diluted with 2 times the amount of water. The mixture was then shaken out 4 times with 300 ml of ethyl acetate / methanol (10: 1), the combined ethyl acetate phases were washed twice with water, dried over sodium sulphate and concentrated under reduced pressure to 22 g of oil. After uptake in ethyl acetate / methanol, 4.2 g (mp 106-110 C) crystallized out. The mother liquor was separated by column chromatography on silica gel with chloroform / methanol (10: 1) and recrystallized together with the first crystals of ethyl acetate / methanol. ,

Yield: 7.0 g (35 ^ d.Th .-) ι F .: 115-116 ⁰ C (dec.).

Example 5 _i 3 ~ Benzyl-1/ 2 "(bis- (2-chloroethyl) -amino) -2-o>: o-tetrahydro-

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

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

23 3 132 5 " ¹² "

Example 6. ,

^ ~ (o-bromophenyl) ~ 1 ~ Z2 ~ (bis (2 - chloroethvl) amino) -? - ~ oxotetrahydro-1 _f 3 _r 2-oxazaphosphorin-4-yl ~ oxy7-urea

560 mg (2 nunol) of 4-hydroxycyclophosphamide in 10 ml of acetone were treated with 460 mg of 3-o-bromophenyl-1-hydroxyharastoff and a catalytic amount of trichloroacetic acid and allowed to stand at -25 ⁰ C. After 2 days, the crystals were filtered off with suction and from acetone recrystallized. Yield: 320 mg (32% of theory), m.p .: 110-111 ⁰ C (dec.).

Example 7

N - Z 2 - ( bis (2-chloroethyl) amino) -2-oxo-tetrahydro- o-1,3> 2- oxazaphosphorin-4-yl-oxy-7-morpholinocarboxylate d

1.2 g (4.3 mmol) of 4-hydroxycyclophosphamide in 15 ml of acetone were treated with 63O mg (4.3 mmol) of N-hydroxy-morpholino-carboxamide and a trace of trichloroacetic acid and stored at -25 ⁰ C. After 4 days, the crystals were filtered off and recrystallized from acetone. Yield: 780 mg (45% of theory), m.p .: 123-124 ⁰ C (dec.).

Examples 8-70 .

Starting from the corresponding 4-hydroxy-tetrahydro-2H-1 j3j2-öxazaphosphorin-2-oxides, the | in the following list, further 4-ureidooxy derivatives of the general formula (

prepared analogously.

Example no. L »X ^w UxlrtUXlp"" R ₂ H- ^R 4 R Melting point _Λ % bzv ?. Rf "value " 8th Cl-CH ₂ CH ₂ - Cl-CH ₂ CH ₂ - H- ' H- -NH-CO-NH-CH ₃ 106 ⁰ C. 9 Cl-CK ₂ CH ₂ -Cl-CH ₂ CH ₂ -Cl-CH ₂ CH ₂ - OT ρττ pTJ w JL · ν- »η ^ ^ JQ f ^ "" KKK H- -NH-CO-NH-CH ₂ -CH ₃ 101 ⁰ C. 10 11 12 Cl-CH ₂ CH ₂ - Cl-CH ₂ CH _2. Cl-CH ₂ CH ₂ -Cl-CH ₂ CH ₂ - H- H, H, H -NH-CO-NH-CH (CH-) ₂ . -NH-CO-NH- (CH ₂ ) -CH ₃ -NH-CO-NH- (CH ₂ ) ^ - CH ₃ 99 ⁰ C 50 ⁰ C 70 - 71 ° C 13 Cl-CH ₂ CH ₂ - Cl-CH ₂ CH ₂ - H- H- . -NH-CO-NH-Zh ^ 14 rin ρττ ρττ V ^ JL wllp w lip - Cl-CH ₂ CH ₂ - H- • H- -NH-CO-NH-CH ₂ -CH = Ch ₂ 65 - 67 ° C ' 15 Cl-CH ₂ CH ₂ - Cl-CH ₂ CH ₂ - H- H- -NH-CO-NH-CH ₂ -CH ₂ - ^ - 100-101 ° C 16 Cl-CH ₂ CH ₂ - H- -NH-CO-NH-CH (CH ₃ ) - ^ ~ \ 113 ° C

Example no.

^R 3 ^R 4 H- H- H- H- H- H- H- · H- H- H- H- H- H- , H- H- H- H- • H- H- H-

Melting point ,, ν or Rf value ^i;

17 18 19

20 21 22

• 23 24

25

26

Cl-CH ₂ CH ₂ -Cl-CH ₂ CH ₂ -

Cl-CH ₂ CH ₂ -

Cl-CH ₂ CH ₂ -Cl-CH ₂ CH ₂ -Cl-CH ₂ CH ₂ -

Cl-CH ₂ CH ₂ -

Cl

Cl-CH ₂ CH ₂ -Cl-CH ₂ CH ₂ -

Cl-CH ₂ CH ₂ -Cl-CH ₂ CH ₂ -Cl-CH ₂ CH ₂ -

Cl-CH ₂ CH ₂ -Cl-CH ₂ CH ₂ -Cl-CH ₂ CH ₂ -

Cl-CH ₂ CH ₂ -Cl-CH ₂ CH ₂ -

Cl-CH ₂ CH ₂ -Cl-CH ₂ CH ₂ - -NH-CO-NH-CH

-NH-CO-NH- ^ f \

-NH-CO-NH- ^ V Br -NH-CO-NH- ^ Λ- Cl

-NH-CO-NH-C'-NH-CO-NH- ^

-NH-CO-NH-Z ^- VO-CH,

-NH-CO-NH-

13O ⁰ C

98 ° C

91 -

118-118 ⁰ C 120 ~ C I _ » 94 ⁰ C I 101 ⁰ C. 116 - 117 ⁰ C 93 - 94 ⁰ C 101 ⁰ C.

CH ₃

example

No,

R ₁

V ^R 4 H- H- H- · H- Ή- H-. H- Η- H- H- H- H- H- .H- H- H- H-' H- · H- H- H- H- H- H-

Melting point or Rf value

27 23

31 32 33-

34

35 36

37 38

Cl-CK ₂ CH ₂ - ^r

Cl-CH ₂ CH ₂ -

Cl-CH ₂ CH ₂ -

Cl-CH ₂ CH ₂ -

Cl-CH ₂ CH ₂ Cl-CH ₂ CH ₂

Cl-CH ₂ CH ₂ Cl-CH ₂ CH ₂ Cl-CH ₂ CH ₂

Cl-CH ₂ CH ₂

Cl-CH ₂ CH ₂ -

Cl-CH ₂ CH ₂ -

Cl-CH ₂ CH ₂ -

Cl-CH ₂ CH ₂ -

Cl-CH ₂ CH ₂ -H-

Cl-CH ₂ CH ₂ -H-

Cl-CH ₂ CH ₂ -

Cl-CH ₂ CH ₂ -

Cl-CH ₂ CH ₂ -

Cl-CH ₂ CH ₂ -

Cl-CH ₂ CH ₂ -

Cl-CH ₂ CH ₂ -H-

Cl-CH ₀ CH ₀ -H-NH-CO-NH-f 1 -NO,

-NH-CO-NH- ¹

NO,

NH-CO-NH- / y

-NH-CO-NH- ^) -Cl

-NH-CO-NH-

-NH-CO-NH-Ch ₂ -CH ₂ -CI -NH-CO-NH-CHC CH ₃ ) -CO ₂ C ₂ H ₅

-NH-CO-NH-CH ₂ -Ch ₂ -OH

-NH-CO-NH-CH ₂ -PO

-NH-CO-NH-CH ₂ -CO ₂ C ₂ H ₅

NH-CO-NH-C

117-118 ⁰ C

111 -

91 -

107 ⁰ C.

112 ° C

93 ° C

48 - 50 ^Q C ι

98 ° C 103 ° C 102 - 0.33 113 ⁰ C 110 - 106 ° C 125 ° C

0.65

Example no. R ₁ R ₂ ^R 3 ^R 4 R or Rf value ¹ ^ 39 Cl-CH ₂ CH ₂ - Cl-CH ₂ CH ₂ - H- H- -N- (CH ₃ ) -CO-NH- / 3 125 - 126 ⁰ C 40 Cl-CH ₂ CH ₂ - Cl-CH ₂ CH ₂ - H- H- -N- (CH-) -CO-N (CH ₃ ) - / - 0.57 41 Cl-CH ₂ CH ₂ - Cl-CH ₂ CH ₂ - H- H- -NH-CO-N S 119 - 121 ° C 42 Cl-CH ₂ CH ₂ - Cl-CH ₂ CH ₂ - H- H- -NH-CO-N (C ₅ H ₅ ) ₂ 92 ⁰ C 43 Cl-CH ₂ CH ₂ - Cl-CH ₂ CH ₂ - · H- - H- -NH-CO-N- (CKL) ₂ "·. 96 - 98 ° C 44. Cl-CH ₂ CH ₂ - Cl-CH ₂ CH ₂ - ' H- · H- -N (CH,) - CO-NH ₉ 115-117 ° C 45. 47. 47. 4S I I I I CM CM CM OJ KWWW O O O O eg Oj Oj cm O OO I I I HHHH O O O O Cl-CH ₂ CH ₂ -Cl-CH ₂ CH ₂ -Cl-CH ₂ CH ₂ -Cl-CH ₂ CH ₂ - H- H- H-. r H ^ V ,. ' WW WW ' -N (C ₂ H ₅ ) -CO-NH ₂ -N (CH ₃ ) -CO-NH-CH ₃ -NH-CO-N- (CH ₃ ) - (CHg) ₅ -CH ₃ -N (C ₂ H ₅ ) -CO-NH-CH ₃ 0.51 125 - 127 ° C 0.63 112 ⁰ C 49, 50 Cl-CH ₂ CH ₂ - 'Cl-CH ₂ CH ₂ - Cl-CH ₂ CH ₂ -Cl-CH ₂ CH ₂ - H-'';. ^: H H- -N (CH ₃ ) -CO-NH-C ₂ H ₅ -N (C ₂ H ₅ ) CO-N (C ₂ H ₅ ) ₂ 0.60 x 0.61 51 Cl-CH ₂ CH ₂ - Cl-CH ₂ CH ₂ - H- H- -NH-CS-NH-CH ₂ - / ⁷ "→ 118 ⁰ C 52 Cl-CH ₂ CH ₂ - Cl-CH ₂ CH ₂ - , K- H- -NH-CS-NH-zits 0.72 53 Cl-CH ₂ CH ₂ - H- Cl-CH ₂ CH ₂ - H- -NK-CO-NH ₂ 134 ° C

<E- sj

\ t

Wii

- 17 -

O O

co

CM V-O VO

υ υ υ Ο O ο O τ- "Τ" N vo "· O τ- T Ι O ο O Ι ν-

CM CM CM

O Ü

'4

ο υ

υ ι

ο ο ο υ ι ι

ρα κ m if «&

W K> β

W W

ΙΛ «

ι ι ι ι

duo

CM CM f \

ι I I ι I t M W ta W W tu

O I I

O O

O W

H U

CM

O O

HI

CJ CI Cl CnI

tu κ w w

cj υ cj ο

ei ci ei

ft ^ ΡΊ Γ ¹ ^

most of the time

ι ι ι ι

* - \ rl rl r-i

υ υ α u

ι ι

CI M

ta μ

U CJ

CI Cl

U CJ

CJ

III

CM CM CM CM

'δ δ δ

CM OsJ

W CM

H O O

υ ο cj υ

ι υ ο ο

to

CO

ι I I ι Cl N CJ Cl S δ W υ S CJ Cl CJ Cl -CH -CH HO -CH H H H CJ CJ υ O

CJ

8th.

CI

ir \ VO N (0

IPt ITv ΙΓ \ ΙΓ \

O VO

VO

CJ

VO

VO

VO

Example Kr.

Melting point ,, f> • .bzw. Rf value ^i; *

65 66

67

68 69 ··

70

Cl-CH ₂ CH ₂

Cl-CH ₂ CH ₂

Cl-CH ₂ CH ₂ -

Cl-CH ₂ CH ₂

Cl-CH ₂ CH ₂ -

Cl-CH ₂ CH ₂

Cl-CH ₂ CH ₂ -

Cl-CH ₂ CH ₂ -

Cl-CH ₂ CH ₂ -

Cl-CH ₂ CH ₂ -

Cl-CH ₂ CH ₂ -

Cl-CH ₂ CH ₂ -

H-H

XJ mm

H-H

H-

H-

H-

H-

E-

H-

-NH-CO-NH- <

-NH-CO-NH-CH ₂ -COOh

X NH ₂ - (H

-NH-CO-NH- (O ^

1) The peeling points have not been corrected. The oily compounds were characterized by the Rf value on thin-layer chromatography on silica gel in the laurin Chloroforai / methanol (5: 1). The further characterization was carried out as for the crystalline compounds.

131 ° C

114 ° C

133 ° C

119 ° C

106-108 ° C I

83-85 ° C

233132 5

·. 19 -

Example 71,

Ethyl ~ 2- (bis- (2-chloroethyl) -ainino-2 * -oxo-tetrahydro - 1,3,2-oxazaphosphorine-2H' ~ 4 - yl ~ oxy ~ carbaTnat

550 mg (2 mmol) of 4-hydroxycyclophosphamide and 210 mg (2 mmol) of ethylhydroxycarbamate (hydroxyurethane) were dissolved in 5 ml of dry / alcohol-free methylene chloride, treated with a catalytic amount of trichloroacetic acid, 4 A molecular sieve added and allowed to stand 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 dried over sodium sulfate methylene chloride phase i.V. concentrated and diluted with ether. After standing for 20 hours at -25 ° C, the crystals were filtered off with suction, washed and dried.

Yield: 290 mg (40% d, Tb.), Mp. 96 ° C.

Example 72

Benzyl 2- (bis- (2-chloroethyl) -amino-2-oxo-t- etrahydro-2I-1 -3, 2-oxa-2- phospho-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-free methylene chloride, mixed with a little trichloroacetic acid, allowed to stand at -25 ° C. in the refrigerator, filtered off after 3 days, the mother liquor diluted with 5 ml of chloroform, washed with water, with dilute sodium bicarbonate solution and washed again with water, dried over sodium sulfate 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

3 3 13 2 5 - ²⁰ -

Example 73

^ - /% - (bis- (2-chloroethyl) -amino) -2-oo-oo-α-α-αα-αι-αι-αι-αι-αι-α, β-α, α-α, α-α, α -α, α, β-α, α, β-α, α, β-α, α, β-α, α, ε-α, α, ε-α, α, ε-α, α, ε-α, ε -α, ε -α, ε -α, ε-α, ε-ω-ε-ε-ε-ω -cyclohexanone -

salt

^a ) 3 "hydroxyureidoacetic acid

56.5 g (0.28 mol) of glycine benzyl ester hydrochloride were suspended in 300 ml of toluene and introduced with stirring at a bath temperature of -140 ⁰ C for two hours dry phosgene gas. Thereafter, the Reaktionsgernisch was concentrated in vacuo and the residue was distilled under high vacuum.

Yield: 51 g (95 SD) of benzyl isocyanate acetate ^Kp * o, o5 ^{: 10} ° ** ¹⁰² ° ^C.

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

Yield: 28.1 g (83.6% of theory) of benzyl-3-hydroxyureido-aceta, m.p. 113-120 ° C. ^:

22.4 g (0.1 mol) of benzyl-3 ~ hydroxyureido acetate in 300 ml of methanol were mixed with 5 g of palladium-carbon and hydrogenated in a shaker. After about 20 minutes, the corresponding hydrogen uptake was completed. The catalyst was filtered off with suction, the filtrate i.V. concentrated and the solid residue recrystallized from dioxane.

Yield: 9.8 g (73% of theory) of 3-hydroxyureidoacetic acid, mp 135.degree.

233132

~ 21 -

b) 2/4 g (18 mmol) of 3-hydroxyureidoacetic acid in 10 ml of water and 25 ml of acetone were combined with 6.1 g (2 mmol) of 4-hydroxycyclophosphamide and allowed to stand at -25 ° C. overnight. Subsequently, 25 ml of acetone and 1.8 g (18 mmol) of cyclohexylamine in 10 ml of acetone was added, filtered off with suction after 2 hours standing and recrystallized from acetone with a little methanol.

Yield: 3.1 g (44% of theory..), F .: 107-108 ⁰ C.

Example 74

3- / N, N- (bis- (2-chloroethyl) -din-amino- phosphinyl- yy- n- propyl aldehyde-oxime (aldophospharaid oxime)

4.0 g (13.7 mmol) of 4-hydroperoxycyclophosphamide were suspended in 50 ml of water while cooling with ice, and 500 mg of sodium thiosulfate χ 5 mol of water were added. With stirring at 5-10 ⁰ C, the pH is controlled with a pH meter, maintained with 2 normal sulfuric acid between pH 4.5 and 5.5 and as long as a concentrated solution of sodium thiosulfate is added dropwise until the pH no longer increased , The mixture was stirred for half an hour at about 10 ⁰ C, added dropwise to an aqueous solution of 950 mg of hydroxylamine hydrochloride, the pH was maintained with 2 normal sodium hydroxide solution to 5, allowed overnight the reaction mixture 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 ⁰ C. The residue was taken up in methylene chloride and the crystals were filtered off with suction after 1 day.

Yield: 3.4 g (85.d. th. D.), Mp. 79 ~ 81 ° C.

23 3 132 5 - ²² -

Example 75

3-p ~ Bronvl / 2- (bis (2-chloroethyl) amino) -2-oxo-tetrahydro-1,3, 2-oxazaphosphorin-4-yl-oxy-7-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, the extracted crystals iV were dried on a rotary evaporator at 40 ⁰ C and recrystallized in methanol.

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

Example 76

m-Trif luormeth y phen yl-1 - / 5- (bis- (2-chloroethyl) amino) -2-0x0-tetrahydro-1, _3-f 2 oxa2a] phosphorin- "4-yl-urea oxy7

7.3 g (25 mmol) of aldophosphamidoxime in 80 ml of acetone were mixed with 4.7 g (25 mmol) of trifluoromethylphenyl isocyanate in 40 ml of acetone. Stirred at 0 ° C for 3 hours, allowed to stand overnight in the refrigerator at -25 ° C, treated with 150 ml of petroleum ether and filtered with suction after standing in the refrigerator at -25 ° C overnight. The crystals were; dried at 30 C and recrystallized from isopropanol.

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

Example 77

3 ~ Cyclohexyl-1- / 2- (bis (2-chloroethyl) amino) -2-oxotetrahydro-1,3-oxazaphosphorine ^ -yl-oxy-urea

5 g (18 mmol) of aldophosphamide oxime and 2.2 g of cyclohexyl isocyanate were dissolved in 10 ml of acetone, combined at 0 ⁰ C, after 2 hours, the crystals filtered off with suction and washed with acetone / ether.

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

233132 5

Example 78

3-Ethyl-1 - / 2- (bis- (2- chloroethyl) -amino) -2-oxo-tetrahydro-1/3 , 2-o>: azaphosphorin-4-yl-oxY7-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 hours, the crystals were filtered off with suction and washed with acetone / ether.

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

Example 79

2- (Fluorp.n-2-yl) -1 - £ 2- (bis- (2-chloroethyl ^ amino) -2-oxo-tetrahyd r o-1, 3 _e ~ o 2; iazaphosphorin-4 ~ yl --o>: y7-urea f

2.9 g (10 mmol) of aldophosphamide oxime in 30 ml of acetone were mixed with 2.1 g (10 mmol) of fluorenyl-2-isocyanate in 20 ml of acetone at 0 C. The next day, the precipitated product was suctioned off, dried previous year at 60 ⁰ C and recrystallized from Isopronal / methanol "

Yield: 2.5 g (40.1% of theory), P ₀ : 114 ° C.

Example 80

3-BeIiZQ yIM - £ 2 ~ (bis- ( 2-chloroethyl) amino) -2-oxo- tetrahydro-1 _f 3 ^ -oxa-z- aphpsphorin ^ -yl-ox ^ -har

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. Stirred for 5 hours in an ice bath under a nitrogen atmosphere, filtered off with suction after 2 hours, dried on a rotary evaporator at 30 ⁰ C and recrystallized from methanol.

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

2331 32 5

Example 81

3 ~ p -nitrophenyl ~ 1 / 2- (bis (2-chloroethyl) amino) -2-oxotetrahydro-1 . 3 . 2-oxazaphosphorin-4-yl-urea oxy7

To 5.8 g (20 mmol) of Aldophosphamid-oxime in 60 ml of acetone vjurde a solution of 3.3 g (20 mmol) of p-nitrophenyl isocyanate in 40 ml of acetone, after 2 hours the pest product was filtered off with suction, on a rotary evaporator at 40 ⁰ C. dried, and recrystallized from dimethylformamide / ethanol.

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

Claims (3)

3 3 132 5 invention claims 1. Process for the preparation of 4 ~ Carbarftoylo>: y-oxaza- phosphorin general formula I. I ⁵ Il 0 - N - C - Z where ~, Z is the group ~ li or the group -0R _? is ^R 7 X is oxygen or sulfur,
R ₁ , R ₀ and R, which may be the same or different from each other, hydrogen, methyl, ethyl, 2-Chlorethyi or 2 ~ methanesulfonyloxyethyl, the radicals R ₄ , which are the same or different from each other may be hydrogen, methyl or ethyl; R ₅ and R _c , which may be the same or different, are hydrogen, C 1-4 -alkyl, hydroxy-C 1-4 -alkyl; Phenyl, and R _{7 is} hydrogen, carbamoyl or -OR ⁸ wherein R ⁸ is hydrogen, C. , Alkyl, phenyl or benzyl, or 233132 5 a straight or branched chain alkyl of 1 to 18 C atoms is _r wherein the alkyl group with 1 ~ 3 same or different substituents from the group 9
-OH, -halogen, -COOH, -COOR, -CONH, phenyl, yours Benzyloxycarbonyl radical, -N (R ⁹ J ₂ , -IT (R ⁹ J ₃ , -OR ⁹ , -SR ⁹ , -SO-R ⁹ , -SO ₂ -R ⁹ , -SO ₃ II or -PO (CH ₃ J ₂ may be substituted, wherein R is methyl or ethyl, or a phenyl-C. _/ -alkyl ~ Hest which is optionally substituted with 1 or carboxy groups in the phenyl and / or alkyl part of the radical, ' Allyl or Cycloalkyl having 3 to 8 carbon atoms or tetrahydrofuranyl or Tetrahydro-pyranyl or phenyl which is unsubstituted or once or twice with C ₁ -C 4 alkyl, C ₂ alkoxy, nitro, halogen, trifluoromethyl, -SO ₀ NH ₀ , carboxy, benzyloxycarbonyl and / or carb-C. substituted alkoxy. can, or Benzyl or benzhydryl or naphthyl or fluorenyl or pyridyl or thienyl or benzoyl or C ^ alkanoyl or 233132 5 - ²⁷ Rc and R / - or Rg and R "together with the atoms to which they are attached are part of a saturated heterocyclic ring system which additionally has an oxygen atom, a lower alkyl-substituted nitrogen atom or an -S, -SO- or -SO 2 - Rg and R _{7 is} part of an unsubstituted or substituted with cyano or Car.bamoyl Aziridinringes, and their pharmaceutically acceptable salts, characterized in that a 4-hydroxy- or 4-methoxy- or 4-ethoxy-axazaphosphorin of the general formula II wherein R ₁ , Rp, 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 R _r ^ι 5 HO-NCZ wherein Z, R ₅ and X have the same meaning as in Pormel I, in the presence of an inert solvent, optionally with cooling or heating and / or optionally in the presence of an acidic catalyst, or -8 ^ 11982 * 021311 2 3 3 13 2 5 wherein in formula I according to item 1 Z -N ^ _a "with Rg = H and Rc is hydrogen, that is an oxime of the general formula RJ ₃ N MH C GH C = N OH IV R I. Π. _λ Β. _Λ R ₁ wherein R _1- / has the same meaning as in formula I half, in an inert solvent at a temperature in the range of -70 to + 50 ⁰ C with a compound of general formula JV wherein X and R _{7 have} the same meaning as in formula I reacted. 2. The method according to item 1, characterized in that starting from such a compound of formula II or IV, where Z is -β ^ β, X is oxygen, R _K and R _c , which may be the same or different from each other, "Hydrogen, methyl or ethyl and R" is hydrogen or straight or branched chain alkyl of 1 to 18 carbon atoms, phenyl or benzyl 3.The method according to item 2, characterized in that starting from such compounds of formula II * in which R, are hydrogen atoms · -aJUL.1982 * O2l3ii 233132 - 23 - If "'method according to item 1 .eafesssg-, characterized in that starting from such compounds of the formulas II and III or, IV and V, in which X is oxygen, R., R ₂ and R ₃ , the same or from each other are hydrogen, or the 2-chloroethyl radical, R., R ₁ . , and R _ß hydrogen and R ₇ V / on Hydrogen, benzyl, phenyl which is unsubstituted or substituted with one or two carboxy groups, optionally substituted with 1 carboxy group C, .- alkyl or phenyl-C. . -alkyl which is optionally substituted with 1 or 2 carboxy groups in the phenyl and / or alkyl portion of the radical.