FI70026C - FREQUENCY REFRIGERATION FOR AV 4-UREIDO-OXAZAFOSFORINER - Google Patents

Description

70026

A process for the preparation of 4-ureidooxazaphosphorines is known from DE-OS 2,231,311 and 2,552,135 by the introduction of the hydroperoxy group -OOH from the following known cytostatics: 2- [bis- (2-chloroethyl) -amino] -2-oxo-tetrahydro -2H-1,3,2-oxazophosphorine (cyclophosphamide), 3- (2-chloroethylamino) -2- [bis- (2'-chloroethyl) amino] -2-oxo-tetrahydro-2H -1,3,2-oxazaphosphorine (trophosphamide), 3- (2-chloroethylamino) -2- (2'-chloroethylamino) -2-oxo-tetrahydro-2H-1,3,2-oxaphaphosphorine (ifosfamide), 3- (2-chloroethylamino) -2- (2'-methanesulfonylethylamino) -2-oxo-tetrahydro-2H-1,3,2-oxazaphosphorine (sulfophamide), and other similar cyclophosphamides of structural formula 4 position, compounds with valuable cytostatic properties are obtained, but the stability of these compounds is so poor that it is not possible to process them further into pharmaceutical preparations, as is necessary in human medicine. It is therefore an object of the present invention to provide cyclophosphamides which have a modified hydroxy group as a substituent in the 4-position and which are particularly characterized by a strong cytostatic effect and greater stability.

The present invention relates to a process for the preparation of novel 4-ureidooxazaphosphorines of the general formula I

Oh X

I H / r6

n - c - n; T

V? 3 R4 yN s-1 <- h R2 'Sp 10 O-t ^ -R4 wherein 70026 X is oxygen or sulfur,

R 1, R 2 and R 3 /, which may be the same or different, represent hydrogen, methyl, ethyl, 2-chloroethyl or 2-methanesulfonyloxyethyl, the radicals R 1, which may be the same or different, represent hydrogen, methyl or ethyl,

R 8 is hydrogen, C 1-4 alkyl, hydroxy-C 1-4 alkyl or phenyl, and R 7 is hydrogen, carbamoyl or C 1-8 -OR, wherein R is hydrogen, C 1-4 alkyl, phenyl or benzyl, or straight-chain or branched alkyl having 1 to 18 carbon atoms, and the alkyl residue may have 1 to 3 identical or different substituents selected from the group consisting of -OH, -halogen, -COOH, -COOR 9, -CONH 2, phenyl, benzyloxycarbonyl residue, -N ( R 9) 7, - (R 9) -, -OR 9, -SR 9, -SO-R 9, 9 Δ J 9 -SO 2 -R, -SO 2 H or -PO 2 CH 2 - / wherein R represents methyl or ethyl, or is a phenyl-C 1-4 alkyl residue which may be optionally substituted by 1 or 2 carboxy groups in the phenyl and / or alkyl part of the residue, allyl or cycloalkyl having 3 to 8 carbon atoms or tetrahydrofuranyl, or tetrahydropyranyl or phenyl which may be substituted be unsubstituted or may have one or two substituents such as C 1-4 alkyl, C 1-4 alkoxy, nitro, halogen, trifluoromethyl, -SO 2 NH 2, carboxy, benzyloxycarbonyl and / or k arb-C 1-4 alkoxy, or benzyl or benzhydryl or naphthyl or fluorenyl or 370026 pyridyl or thienyl or benzoyl or C 1-4 alkanoyl or R 5 and R 8 or R 8 and together with the atoms to which they are attached are a saturated heterocyclic ring as part of a theme which may further contain an oxygen atom, a lower alkyl-substituted nitrogen atom or may have an -S, -SO- or -SO 2 sulfur atom, or R 9 and R 7 are unsubstituted or part of an aziridine ring in which the substituent is cyano or carbamoyl.

Due to their particularly advantageous properties and easy preparation, the 4-ureidooxazaphosphorines of the general formula I in which X is oxygen, R 1 is hydrogen, methyl or ethyl and R 7 is hydrogen or straight or branched alkyl having 1 to 18 a carbon atom, phenyl or benzyl.

Another preferred group of compounds of formula I are those wherein X is oxygen, R 1, R 2 and R 2, which are the same or different, represent hydrogen or a 2-chloroethyl residue, R 1, and R 8 represent hydrogen and R 7 is hydrogen, benzyl, phenyl which is unsubstituted or has one or two carboxy groups as substituents, C 1-4 alkyl optionally substituted by one carboxy group, or phenyl-C 1-4 alkyl, the residue of which in the phenyl and / or alkyl part is optionally substituted with 1 or 2 carboxy groups.

The process according to the invention for the preparation of novel 4-ureidooxazaphosphorines of the general formula I is characterized in that 4-hydroxy- or 4-methoxy- or 4-ethoxy-oxazaphosphorine of the general formula II is administered.

4,70026

Ro OY

N> —k-'i

, / Υ V

Ο Ο - / - R, R 4 wherein R 1, R 2, R 2, Da R 4 are as defined in formula I and Y is hydrogen, methyl or ethyl, react

with a hydroxycarbamate derivative of the general formula III

! i / r6

HO- NH - C - N III

R 7 wherein X is as defined in formula I, in an inert solvent, optionally with cooling or heating and / or optionally in the presence of an acid catalyst.

Suitable solvents include water, lower alkyl halides such as especially methylene chloride, lower alkyl ketones such as acetone, diethyl ether, dimethylformamide (DMF), hexamethylphosphoric triamide (HMPT) or the like, or the like. The reaction is carried out at a temperature between -35 ° C and + 50 ° C, i.e. possibly by cooling, at room temperature or by 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 2, ZnCl 2 or TiCl 2.

Another process for the preparation of compounds of formula I wherein = H is characterized in that an oxime of general formula en IV is administered.

70026

Rl \ f3 r2 y \

0 - ^ c - (j] H - C = N - OH IV

R4 \ R4 K

wherein R 1 - - R 2 is as defined in formula I, react in an inert solvent at a temperature in the range of -70 ° to + 50 ° C with a compound of general formula V

x = c = n-r7 V

wherein X and R 2 are as defined in formula I.

The progress of the reaction can be monitored according to the process of the invention by thin layer chromatography. The isolation of thin-layer chromatographically uniform substances is achieved by the working methods commonly used in connection with 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 1 H-NMR spectral analysis.

The compounds used as starting materials in the process according to the invention are widely known, can be used as crystals or crude products and can be prepared synthetically in the following known manner: 4-hydroxyoxazaphosphorines are obtained by reduction of 4-hydroperoxy derivatives / for example A. Takamizava et al., J. Med. Chem. 18, 376 (1975). 4-Methoxy- or 4-ethoxy-oxazaphosphorines are formed by naphtha catalysis from 4-hydroxy derivatives in methanol or ethanol or in inert solvents containing methanol or ethanol. Hydroxyurea derivatives are prepared by reacting correspondingly substituted isocyanates or uric acid chlorides with hydroxylamine or N-monosubstituted hydroxylamines. In a similar manner, N-hydroxycarbamic acid esters (hydroxycarbamates) can be obtained by reacting the corresponding chloro-carbonic acid esters with hydroxylamine or N-monosubstituted hydroxylamines, an amount of hydroxycarboxylic acid carboxylic acid or acid N-hydroxycarbamic acid esters. it is recommended to perform the synthesis with a protecting group.

The oximes of formula IV are obtained by various synthetic methods. They can be obtained, for example, by reacting the corresponding 4-hydroxyoxazaphosphorines with hydroxylamine or hydroxylamine salts. The pH should be between 2-7 if possible.

Racemic cis and trans isomers (cis = 2R, 4R / 2S, 4S; trans = 2R, 4S / 2S, 4R) can be prepared from the 4-ureidooxazaphosphorines of the invention. This order is consistent with the IUPAC nomenclature rules and the corresponding literature on branches-safosphorine derivatives. the cis and trans forms can also be intentionally prepared, depending on the choice of reaction conditions. There is no pharmacologically significant difference between the isomers.

The compounds of the invention have considerable chemotherapeutically valuable properties. Compared to the reference substance, the previously known cyclophosphamide, they have almost equal potent chemotherapeutic chemotherapeutic effects in rat experimental transplant tumors. They have a direct alkylating effect in aqueous solution and have a strong cytotoxicity in vitro, whereas cyclophosphamide requires enzymatic activation and has virtually no cytotoxic effect in vitro. The acute toxicity of the compounds according to the invention is about 4 times lower than that of the reference substance cyclophosphamide, so that the therapeutic range is considerably wider. The compounds of the invention also have clear advantages over the reference substance cyclophosphamide in terms of organotoxic side effects such as leukocyte depletion and immunosuppression.

The compounds of the invention are suitable for the treatment of malignancies and similar malignancies, such as leukemia, in humans. In this case, amounts of approximately 0.01-100 mg / kg are used. Pharmaceutical preparations made therefrom are prepared by conventional methods using customary additives and carriers.

The following examples are intended to further illustrate the present invention without limiting it.

Example 1 1-Hydroxy-1- [2- [hex- (2-chloroethyl) amino] -2-oxo-tetrahydro-2H-1,3,2-oxazaphosphorin-4-yl] urea 15 g ( 54 mmol) of 4-hydroxycyclophosphamide (i.e. 2- [bxs- (2-chloroethyl) -amino] -4-hydroxy-tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide) and 4.4 g ( 58 mmol) of hydroxy-urea was dissolved in 79 ml of DMF, acidified with trichloroacetic acid (pH 3-4) and allowed to stand at 0 ° C in a refrigerator for 20 h. It was then diluted with 7 ml of ethyl acetate and suction filtered after 2 h, washed, dried and recrystallized from methanol.

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

M.p .: 139-143 ° C (decomposed).

Example 2 1-Hydroxy-1- [2- (bis- (2-chloroethyl) -amino] -2-oxo-tetrahydro-2H-1,3,2-oxazaphosphorin-4-yl urea, cis- Form 1.1 g (4.0 mmol) of 4-hydroxycyclophosphamide were dissolved in methanol, a little trichloroacetic acid was added, allowed to stand overnight at -25 ° C, then the methanol was carefully distilled off, the residue was dissolved in a small amount of methylene chloride, dried and evaporated. , and 1.2 g of 8,70026 4-methoxycyclophosphamide (i.e., 2- [N- (2-chloroethyl) amine] -4- (4-methoxy-tetrahydro-2H, 1,3,2-oxazaphosphorine-2- oxide). 1.2 g of 4-methoxy-cyclophosphamide and 304 mg of hydroxyurea were then dissolved in 3 ml of DMF and stored for 20 h at -25 ° C in a refrigerator. The crystalline mass was diluted with 3 ml of ethyl acetate, filtered off with suction, washed, dried and recrystallized from methanol.

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

Example 3 1-Hydroxy-1- [2- (bis- (2-chloroethyl) amino] -2-oxo-tetrahydro-2H-1,3,2-oxazaphosphorin-4-yl] urea, trans form 16 g (59 mmol) of 4-hydroxycyclophosphamide and 5.2 g (68 mmol) of hydroxyurea were dissolved in 160 money of water, acidified with trichloroacetic acid (pH 3-4) and allowed to stand for 20 h at 0 ° C in a refrigerator. It was then filtered off with suction, washed with water, dried over P2O2 under high vacuum and recrystallized from methanol / chloroform.

Yield: 12.7 g (65% of theory) of the trans form of the compound of Example 1, m.p .: 148 ° C (decomposed).

Example 4 1-Hydroxy-1-N- (2-chloroethyl) -2- (bis- (21-chloroethyl) amino) -2-oxo-tetrahydro-2H-1,3,2-oxazaphosphorin-4-yl] urea 20 g (50 mmol) of 4-hydroxytrophosphamide (i.e. 3- (2-chloroethyl) -2- [bis- (2-chloroethyl) amino] -4-hydroxy-tetrahydro-2H-1,3, 2-Oxazaphosphorine-2-oxide and 5.3 g (70 mmol) of hydroxyurea were dissolved in 100 ml of DMF and cooled to -15 [deg.] C. It was then acidified with trichloroacetic acid (pH 3-4). and stirred for 5 h at -15 [deg.] C. Allow to stand overnight at 0 [deg.] C. and then dilute the reaction solution with 2 times the amount of water, then shake 4 times with 300 ml each of ethyl acetate / methanol (10: 1). ), the combined ethyl acetate phases were washed twice with water, dried over sodium sulfate and evaporated in vacuo to 22 g of an oil, dissolved in ethyl acetate / methanol to give 4.2 g of crystals (m.p. 106-110 ° C). off using life chloroform / methanol (10: 1) and recrystallized together with the first crystals from ethyl acetate / methanol.

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

Example 5 3-Benzyl-1-hydroxy-1- {2- [bis- (2-chloroethyl) amino] -2-oxo-tetrahydro-2H-1,3,2-oxazaphosphorin-4-yl} urea substance To 900 mg (3.25 mmol) of 4-hydroxycyclophosphamide in 1 ml of methylene chloride were added 540 mg (3.25 mmol) of 3-benzyl-1-hydroxyurea in 40 ml of acetone and a catalytic amount of trichloroacetic acid. The mixture was stored overnight at -25 ° C, then the crystals were filtered off with suction, washed with acetone and ether and recrystallized from ethyl acetate.

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

Example 6 3- (o-Bromophenyl) -1-hydroxy-1- {2-Zbis- (2-chloroethyl) amino] -2-oxo-tetrahydro-2H-1,3,2-oxazaphosphorin-4-yl} urine To 560 mg (2 mmol) of 4-hydroxycyclophosphamide in 10 ml of acetone were added 460 mg of 3-o-bromophenyl-1-hydroxy urea and a catalytic amount of trichloroacetic acid and allowed to stand at -25 ° C. The crystals were filtered off with suction after 2 days and recrystallized from acetone.

Yield: 320 mg (32% of theory), m.p .: 110-111 ° C (decomposed).

Example 7 N-Hydroxy-N- {2-, bis- (2-chloroethyl) -amino] -2-oxo-tetrahydro-2H-1,3,2-oxazaphosphorin-4-yl} -N-morpholinocarbonyl- amine 10 70026 To 1.2 g (4.3 mmol) of 4-hydroxycyclophosphamide in 15 mL of acetone was added 630 mg (4.3 mmol) of N-hydroxy-morpholinocarboxamide and a little trichloroacetic acid and stored at -25 ° C. After 4 days, the crystals were filtered off with suction and recrystallized from acetone.

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

n 70026

-P

-P

to I ϊ ^ c -p u u o

m O O OH

5 a) h r- o

in ro -P to rH

,> Op- rn to -HH U U U CJ I U I I u r ^ to (¾ O O O O o o X v; ΟΙΟ'ΌΗΟ'ιΟΟΗι.ηΟΓΟ

'72 -H> ooa \ LnHHtDOH

g P Η Η Ή ΗγΗ n <U rö 03

I a h I

CM 'P 3 I a) (/ 3 (¾ • H Ή G> "

•B

• H ö P a / 0 Ή

MP H

'S'-' onro (0] j [0 I] 'K ffi ffi ^ -v "^

S + J oj u U U I I

XJ CD m -. I I II ™ ~ "S ω tnroooLT) X X ^

S -H U K «- UUK

Ϊ ID I U «N« Ν 1 I U

nC «(Λ <N - XX fO> OJ CN ~ re χχχυυΐκ χχχ

A m *> u u u w w <v> · U u V

_ x (¾ I I i I I i I pe nx: \ ^ / xmxxxxxxg „o V '' \ / z z x x x Z z X i

II I I I I I I I R

V | n I I ooooooooy 1 ο ρΓ — ζ υ υυυυυουυΛ N -o '1111 1 Λ JL g ό <3 / \ SBSSS S δ e 5 g,? A ° ?????? ¥?

m ^ of1 qT1 p * i l I l l I I I I

U + j XXSXXXXXXX

P tP

<U -P

V 2 oo i i il I I I I I

.H-p xxxxxxxxxx in cn x aj

2 to I I I I I I I I

rt m OMCMCNfMCMCNCMCMCM

s, m XXXXXXXXX

m uuuuouuuu

I K CNCN (NfNr \ jrs) CNCNCN

Λ P cnXXXXXXXXX

m «UUUUUUUUU ·

rr) u I I I I I I I I

I I r-r I — I H rH rH rH rH r — I I l 1 I

in qj uuauauuuu H 03>

ία £ I I I I I I I I

(Mjjrn CNCNCNCNCMCMCNCNCN

to m 03 XXXXXXXXX

.mm uuuuuuuua

1 .T “1 CN ^ CNCNCNCNCNCMCM

00 H HXXXXXXXXX

• tan xuuuuuoouu .PHH lllllllll

Η Η Η Η Η i — I H H H

uuuuauuuu p S to - a »a> p

6 -P C

• H X -H I Λ M j n 03 (D ”OOC ^ OHCNOOHLnt £>

I — 1> —I I — I I — t t — I '—t rH

70026 Η rtf W υ υ υ υ υ ο ο ο ο ο υ (D Ο Ο Γ- Ο 00 CM Ο Ο CM CM rH «ί rH -Η 00 to-— cr> f- \ I — I CT» γη γη

ι-I «-I

U O I I U U U I I U I I

ΪΛΟΟΟ οοο ο

-η £> ο οο ι — ι cooom ·. — icx> eOrHr- ~ rHrH

£ SH CO <3> CT \ ι — Ir — lONOiHONOr — and — ιο> CC3 CT5 ι-I rH f — I t — I I — I I — C! —I I —- t

rH I 3 UH

uy PS

.2?

OM H V CM CM CO., LTD

“U ϋ * o § I &

T Ο ΟΟ O O Ox'10 O O O OW

QS U Oh X; / 'Xh x / X /' X / X> A Ox X / Xh ι ι ι iti r ι: r r \ cir r r i32 x k x m w k κ ^ w π w k κ χ z w £ x x x x x x x r, j x x x

ill ι ι ι ι ι ι ι ι ι X.

ooc ocoooooooR

111 1 1 1 1 1 1 1 1 1 i g g g sggggggggä? 7 f

^ 111 I I I I I I I I I

PS FAQ KKXKKWKffiKffi

cP I I I I I I I I I I I I

PS FAQ WffiWWWKWWWW

III I I I I I I I I I

CM CM CM CMCNCMCMCMCMCMCMCMCM

WWW WtdffiaKWKUlwtr: uuu uuuuuuuuuu

CM CM CM CM CM CM - so there is a free kick

cMEffiX ΚΕΚΚΕΚΧΚΚΚ PS uuu uuuuuuuuuu ill ι ι ι ι ι ι ι ι ι ι

ι — l t — I ι — I (—I ι — I ι — I X ι — 1 ι — I ι — I ι — I ι — I rH

uou uuuuuuuuuu

III I I I I I I I I I

CM CM CM CM CM CMMMM's Day Search

EKK KKKKKKKKffiffi uuu uuuuuuuuuu

CM CM CM CM CMCMCMCMCMCMCMCMCM

H X K K

PS uuu uuuuuuuuuu

III I I I I I I I I I

rH ι— (ι — I r — i rH ι — I f — I ι — I ι — C ι — I t — I rH rH

uuu uuuuuuuuuu c Ή Ι, Υ OHCMCOHLTlVOr'-COcTi

-H> H 0 P ~ 00 CTi CMCMCMCMCM CMCMCMCMCM

tfl d) ·· ι — I ι — I rH

wee 70026

•B

Π3 p u u U O O <->

CU O ro n O U

U O o .H Ή O

en —- OI rH r-t ^ 5

• H r-1 -H

D. U I U I IUU, n i ωοο o moo m 1 nu 1 • H> o »oo au oj n o m m« u m ° N in S E M o ^ σι o * r-ι o 04 v ^ ^ §03 ΓΗ —I O iH f— | .H o Zl o i — I I> -l ° a in en ei m K '^ 04

U CM V

oj m * H o K ro 2 ^ M U U O 2 m ~

ta i i i u u -F

r-, | O) - OI - 04, ΥΥ n

ri, _iai2oi200 λ f II H

, u - U 2 U Λ U f ^ N <5 ^ -11 „.

JL 7 m i a i i i ™ 1

Ä 04 ’04 04 04’ ivj Ύ. ^ "O

04 [U 2 2 2 2 2 Y ro JP Y. ^ 'iYY - uuuuu u = o 2 „~ ο4-ο Π K 33 K X X K K K - flHSd.

2 222222 2 2 k-J "" "

1 llllll I T F F F

0 o o o o o o o o Λ Λ Λ Λ V VVYVVV V γ ^ ννν ο o o o o o o g g g g g - f f φ ψ 2 ^ κ x i i s i i i i i '' i, r ° I llllll I | ,. . , 2 2 222222 2 2 JL i J. J.

1 I I I I I I I I. ...

04 OI 04 O) 04 04 04 04 04>, *,>, <

2 222222 2 2 ^ JF JF

u uuuuuu u. u F. F F F

<N (N (NCNCnJCNCNCM (N ΓΜ O U

2 2 222222 2 2 ™ ™ ™ ™

U UUUUUU U U F F F F

I llllll I I V V V V

Γ-H rH I-H * H I-H iH rH pH iH *,, I

u uuuuuu u u uuu 1, ......... . ,

04 010104040404 04 04 1 III

2 222222 2 2 S * S * S * S * U UUUUUU U U K 222

<—I OI 040104 040104 04 04 U UUU

2 2 222222 2 2 ™ »Y Y4

u uuuuuu u u F FFF

I llllll I I VVVV

r * "1« H »HT — I i — 1» H »H» H #H * II * U UUUUUU UU £ uuu e I A3 • H MO O 1-10401 ^ 1010 o- au σι ot— 04 W ( U ·· n 010101010101 oi oi oi ^

W E C

14 70026

•B

(0 »4- * LO 00 rs] U), —i ro | HM ^ ^ ^

w O u CJ U I I <j CJ I

H> 0 oj o 0 o · as M-r ^ O O

g ^ CO Γ "O · o · O · (O OJ 4D LO LO m as o

<TJ (Π Ή - CO ry M <* CO ^ - o · o M

1 — I I Ή o I r-ι I — I O O P — I O O I — I I-H M

P 4-1 u) «Q S» T (o) f 0 ^ [o) S _ ^

V u \ V U U

1 T CN OJ OJ CN OJ CN | 1 I f I I

Di K M 2 2 2 2 2 2 2 tC 2 k J 2 2 2 22222S2 2 2 2 2

I I i l i i i i i I i i

w 2 o o o o o o o w o o o U CJ CJ CJ CJ CJ CJ CJ CJ u u cj cj JL JL JL JL JL 1 1 'r 1' 1 '

§ S SSSlsiS § I I I

f? ? H H ^? f? f jr I I I I I I i 'n | ι ι i 'ro tn tn tn 2222222 2 tn 2 te cj cj

III (N I

CN (N OJ 2 OJ

te te te u te CJ CJ CJ cn u ro I I 01 n n Ξ oj 1 1 I | | ι en k 2 2220222 2 2 2 2 CJ CJ CJ I cj

III ro I

Γ-t rH 1 — I O r — I

o u u w u ro te il CJ 11 * 1111

OJ CN CN CN CN Os] OI CN

tn 2 2 2 2 2 2 2 u cj II cj cj ο υ u u

<N CN I (O CO I I (N CN OJ (N CN (N

OJ te 2 2222222 2 2 2 2 tn ucj u o cj cj cj cj cj u '' ι ι ι ι ι ι

Tl Ti M M M M M M

υ CJ U CJ CJ CJ- CJ CJ

, ι ι I I I I CN I CN | I I I,.

fN OI CN CN 2 fN 2 CN (N CN CN CN OJ

K 2 2 2 CJ 2 CJ 2 2 2 2 2 2

CJ CJ U U cn CJ cn CJ CJ CJ O CJ O

fN CN CNCN2CN2CNCN CN CN Oj O] Ή 2 2 2 2 CJ 2 CJ 2 2 2 2 2 2 en cjcjcjcjicjicjcjcjcjuu

ι, ι I 1 CO I ro ι I ι | ι Y

Tl Ή I — I M O Ή O r-1 r — I r-H M M M

U u CJ CJ 2 CJ 2 CJ CJ CJ CJ CJ CJ

CO CO., LTD

2 2

• H CJ CJ

M

sll 5? S S 5? S ° i; s s s s, 15 70026 cn ή 3 d

• H P O

ro <D 3 -μ U U 5¾ ^ O O U 4-i

CD n U oo O Ö CD

-P ή O O m O e 01 .—. , —T <T> d CO> \ • Hi — I i — I P d di I U U U d I I «5 e en o O O O I h

d> o d d- ro d ro d O

g p d ro d ro O 00 (X P

rt Γ0 '—I' —1' — I i — I (• '"P' / i i — I O

1— 'i ICy 3 ^ rt d -n o

CO On T -h iH

CM -P y

CN k -P

a / 7Λ / ih \ U, CD rt

Z (O) \ 0 / I «^ y -3 C

CN W / \ _Y «NOK! en CD

o / yoo \ d -h cd 0 = (cj UT CC · X Y_ V — lii ^ e -H: (0 / \ / _ \ cn nk yyg rt rt d K [OKO / (O / 1 * 13 [OI ^ '1 ^ «o xyz vy v_y uo -e -hiriii ix ide en

KKK aaa K CDd-P

Z Z Z Z Z Z Z (D 0 en lii lii I -p rt d OOO OOO O mdrt uuu uuu u -h mx III III I Τ3> 1 SSI §§ O S ^ id ¥? Ψ? F? V s s s

> PZ 01 3 -rt P C CD

• a- I i i lii i en -h -P

05 FAQ EKK K Ort'H

rt -h dx en en DX C: rt O (D C d 4-) ή 3 3 en d dx

ro II 1 I III I -H -H

oi aaa warn a; rt cvh e 3> id -P nDrt d en rt C CD ft en rt

III III I · d + J

CN CN CN CN CN CN CN 3d aaa aaa a -Prtd

UUU UUU U -Prt-P

CN (N (N CN CNCNCN CN li 5 C

a aaa aaa a -η end uuu uuu u p o o lii lii I o -P tn i — Idd ddd <—I DX rt d

UUU UUU U SP

H O CD CD P -P DX DX: rt to rt

III III -P> P

CNCNCN CNCNCN CN dCDrt aaa aaa a <dd dx UUU UUU U -P -P: rt d CNCNCN CNCNCN CN Cnrttn a aaa aaa adad uuu uuu u doa lii ill I en dddddi — I dd rt · UUU UUU U gd - rt i> —i rt d cd ··

d rt CD LO

I DX CO -P 'd P O vd r- ~ oo oio · - cn en <D ·· ίο lo lo 10 cd eo co WSC d 16 70026

Example 63 {3-Hydroxy-3- [2- (bis- (2-chloro-ethyl) -amino) -2-oxo-tetrahydro-2H-1,3,2-oxazaphosphorin-4-yl] -ureido} - acetic acid-cyclohexyl-amine 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 stirred with stirring, 17,70026 bath temperature at 140 ° C, for 2 h on dry phosgene gas suspension. The reaction mixture was then evaporated in vacuo to a smaller volume and the residue was distilled under high vacuum.

Yield: 51 g (95% of theory) of benzyl isocyanate acetate b.p. 0.05: 100-102 ° C- 28.7 g (0.15 mol) of benzyl isocyanate acetate in 50 ml of dioxane were added dropwise while stirring and occasionally cooling, 6.6 g (0.2 mol) of hydroxylamine in 200 ml of dioxane. After stirring for a further 1 h at room temperature and evaporating in vacuo to a smaller volume, the residue was crystallized from the special ester.

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

To 22.4 g (0.1 mol) of benzyl 3-hydroxy-ureido acetate in 300 ml of methanol was added 5 g of palladium on carbon and hydrogenated in a shaking vessel. After about 20 minutes, the hydrogen reception was complete. The catalyst was filtered off with suction, the filtrate was evaporated in vacuo and the solid residue was recrystallized from dioxane.

Yield: 9.8 g (73% ‘-.eor.) Of 3-hydroxy-ureido-acetic acid, m.p. 135 ° C.

b) To 2.4 g (18 mmol) of 3-hydroxy-ureidoacetic acid in a mixture of 10 ml of water and 25 ml of acetone were added 6.1 g (2 mmol) of 4-hydroxycyclophosphamide and allowed to stand overnight -25 ° C. Then 25 ml of acetone and 1.8 g of 818 mmol) of cyclohexylamine in 10 ml of acetone were added, allowed to stand for 2 h and suction filtered and recrystallized from acetone with a small amount of methanol.

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

18 70026

Example 64 (starting material for Examples 65-71) 3- {N, N- / bis- (2-chloroethyl) -diamino-phosphinyloxy) -propionaldehyde oxime (aldophosphamide oxime) 4.0 g (13, 7 mmol) of 4-hydroxyperoxycyclophosphamide was suspended in 50 ml of water under ice-cooling, and 500 mg of sodium thiosulfate x 5 moles of water were added. After stirring at 5-10 ° C and controlling the pH with a pH meter, the pH was maintained between 4.5-5.5 with 2N sulfuric acid and concentrated sodium thiosulfate solution was added dropwise until the pH no longer rose. After stirring for 1/2 h at about 10 ° C, an aqueous solution containing 950 mg of hydroxylamine hydrochloride was added dropwise, the pH was maintained at 5 with 2N sodium hydroxide solution, the reaction mixture was allowed to stand overnight in a refrigerator at 5 ° C, extracted four times. using in each case 50 ml of ethyl acetate and, after drying over sodium sulphate, the organic extracts were evaporated to dryness in vacuo at 30 ° C. The residue was dissolved in methylene chloride and the crystals were filtered off with suction after 1 day.

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

Example 65 3-p-Bromophenyl-1-hydroxy-1- {2- [bis- (2-chloroethyl) amino "-2-oxo-tetrahydro-2H-1,3,2-oxazaphosphorin-4-yl} urine To 5.8 g (20 mmol) of aldophosphamide oxime in 60 ml of acetone was added 4 g (20 mmol) of p-bromophenyl isocyanate in 40 ml of acetone, and stirred for 5 h with cooling. the precipitate was removed in vacuo on a rotary evaporator at 40 ° C and recrystallized from methanol.

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

Example 66 3-m-Trifluoromethylphenyl-1-hydroxy-1- {2- [bis- (2-chloroethyl) amino] -2-oxo-tetrahydro-2H-1,3,2-oxazaphosphorine-4,70026 yl} urea To 7.3 g (25 mmol) of aldophosphamide oxime in 80 ml of acetone was added 4.7 g (25 mmol) of m-trifluoromethylphenyl isocyanate in 40 ml of acetone. After stirring for 3 h at 0 ° C, it was left to stand overnight at -25 ° C, 150 ml of petroleum ether were added and the mixture was allowed to stand overnight in a refrigerator at -25 ° C. The crystalline mass was dried at 30 ° C and recrystallized from isopropanol.

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

Example 67 3-Cyclohexyl-1-hydroxy-1- {2- (bis- (2-chloroethyl) -amino] -2-oxo-tetrahydro-2H-1,3,2-oxazaphosphorin-4-yl} urinary 5 g (18 mmol) of aldophosphamide oxime and 2.2 g of cyclohexyl isocyanate were each dissolved in 10 ml of acetone, combined at 0 [deg.] C., and after 2 h the crystals were filtered off with suction and then washed with acetone / ether.

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

Example 68 3-Ethyl-1-hydroxy-1- {2- [bis- (2-chloroethyl) -amino] -2-oxo-tetrahydro-2H-1,3,2-oxazaphosphorin-4-yl) urine 5 g (18 mmol) of aldophosphamide oxime and 1.2 g of ethyl isocyanate were each dissolved in 15 ml of acetone and combined at about 0 ° C. After 5 h, the crystals were filtered and washed with acetone / ether.

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

Example 69 3- (Fluoren-2-yl) -1-hydroxy-1- {2- [bis- (2-chloroethyl) amino] -2-oxotetrahydro-2H-1,3,2-oxazaphosphorin-4- yl} urea To 2.9 g (10 mmol) of aldophosphamide oxime in 30 ml of acetone was added 2.1 g (10 mmol) of fluorenyl 2-isocyanate in 20 ml of acetone at 0 ° C. The next day, the precipitate was filtered off with suction, dried in vacuo at 60 ° C and recrystallized from isopropanol / methanol.

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

Example 70 3-Benzoyl-1-hydroxy-1- {2-Zbis- (2-chloroethyl) -amino] -2-oxo-tetrahydro-2H-1,3,2-oxazaphospin-4-yl} -urea 5.8 To g (20 mmol) of aldophosphamide oxime in 60 ml of acetone was added 2.9 g (20 mmol) of benzoyl isocyanate in 40 ml of acetone. After stirring for 5 h in an ice bath under nitrogen and after 2 h, the solid was filtered off, 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.

Example 71 3-p-Nitrophenyl-1-hydroxy-1- {2-Zbis- (2-chloroethyl) -amino] -2-oxo-tetrahydro-2H-1,3,2-oxazaphosphorin-4-yl} -urea substance To 5.8 g (20 mmol) of aldophosphamide oxime in 60 ml of acetone was added a solution of 3.3 g (20 mmol) of p-nitrophenyl isocyanate in 40 ml of acetone, after 2 h the solid was filtered off, dried on a rotary evaporator. At 40 ° C and recrystallized from dimethylformamide / ethanol.

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

Claims (3)

21 70026 A process for the preparation of pharmacologically active 4-ureidooxazaphosphorines of the general formula I OH X I II, p-6 R-v N C N * 1! I R X R7 R2 R4 _ O_____X_ „. R 4 0 4 R 4 in which X is oxygen or sulfur, R 1, R 2 and R 2, which may be the same or different, represent hydrogen, methyl, ethyl, 2-chloroethyl or 2-methanesulfonyloxyethyl, the radicals R, which may be the same or different, various, denote hydrogen, methyl or ethyl, R 9 is hydrogen, C 1-4 alkyl, hydroxy-C 1-4 alkyl or phenyl, and R 2 is hydrogen, carbamoyl or '8 -OR, where R is hydrogen, C 1-4 alkyl, phenyl or benzyl, or straight-chain or branched alkyl having 1 to 18 carbon atoms, and the alkyl residue may have 1 to 3 identical or different substituents selected from the group consisting of -OH, 9 -halogen, -COOH, -COOR, -CONH2, phenyl , benzyloxycarbonyl residue, -N (R9) 2, -S (R®) R, -OR9, -SR9, -SO-R9, -SO2-R9, -SO4H or -POtCH2- f where R9 is methyl , or ethyl, or R 1 is a phenyl-C 1-4 alkyl residue which may be optionally substituted by 1 or 2 carboxy groups in the phenyl and / or alkyl part of the residue, allyl or cycloalkyl of 3 to 8 carbon atoms or tetrahydrofuranyl, or tetrahydropyranyl or 70026 phenyl, which may be unsubstituted or may have one or two substituents such as N-alkyl, 2-alkoxy / nitro, halogen, trifluoromethyl, -SO 2 NH 2, carboxy, benzyloxycarbonyl and / or carb-C 1-4 alkoxy, or benzyl or benzhydryl or naphthyl or fluorenyl or pyridyl or thienyl or benzoyl or C 1-4 alkanoyl or R 9 and together with the atoms to which they are attached form part of a saturated heterocyclic ring system which may further contains an oxygen atom, a lower alkyl-substituted nitrogen atom, or may have an -S-, -SO- or -SO 2 sulfur atom, or R 9 and are part of an unsubstituted or aziridine ring substituted with cyano or carbamoyl and their pharmaceutically acceptable salts. characterized in that a) 4-hydroxy- or 4-methoxy- or 4-ethoxy-oxaza-phosphorin, which is generally The formula is II R. R, OY 1. r___ur4 \ / \ h II O o ______. Z-p R 4 / R 4 R 4 wherein R 1, R 2, R 2 and R 2 are as defined in formula I and Y is hydrogen, methyl or ethyl, react with a hydroxycarbamate derivative of general formula III X R 1. HO - NH - C - N III R7 23 70026 wherein X is as defined in formula I, in an inert solvent, optionally under cooling or heating and / or optionally in the presence of an acid catalyst, or b) an oxime of general formula IV R1 is administered R3 n / LR / P 2 / S \ 0 - C - CH C - N - OH IV / is VX = C = N - R? V wherein X and R 1 are as defined in formula I to form compounds of formula I wherein R 1 is O is hydrogen. Process according to Claim 1, characterized in that the starting materials are those compounds of the formula II and III or IV and V in which X is oxygen, R 9 is hydrogen, methyl or ethyl and R 1 is hydrogen or straight or branched alkyl having 1-18 carbon atoms, phenyl or benzyl. Process according to Claim 2, characterized in that the starting materials are compounds of the formula II in which the R 1 radicals are hydrogen atoms. 24 70026