4-CARBAMOYLOXY-OXAZAPHOSPHORINES, METHODE DE PREPARATION ET COMPOSITIONS PHARMACEUTIQUES QUI EN RENFERMENT

4-CARBAMOYLOXY-OXAZAPHOSPHORINS, METHOD OF PRODUCING THEM AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM

Abrégé anglais

- 1 -
Abstract
The present invention relates to new 4-carbamoyloxy-
oxazaphosphorins of the general Formula I
<IMG>
and provides a method of producing them as well as pharma-
ceutical preparations containing them as active substances.

Revendications

Claims:
1. A method of producing the 4-carbamoyloxy-oxaza-
phosphorins of the general formula I
<IMG> I
in which Z is the group <IMG> or the group -OR7; X is
oxygen or sulphur; R1, R2 and R3, are the same or
different and represent hydrogen, methyl, ethyl, 2-chloro-
ethyl or 2-methanesulphonyloxyethyl; the groups R4 are the
same or different and represent hydrogen, methyl or ethyl; R5
and R6 are the same or different and represent hydrogen, C1-4
-alkyl, hydroxy-C1-4-alkyl or phenyl; R7 is hydrogen, the
carbamoyl group, -OR8 (in which R8 is hydrogen, C1-4-
alkyl, phenyl or benzyl), straight or branched chain C1-18-
alkyl (or such alkyl substituted by 1 to 3 substituents
selected from the group consisting of hydroxy, halogen,
-COOH, -COOR9, -CONH2, -phenyl, benzyloxycarbonyl, -N(R9)2,
-?(R9)3, -OR9, -SR9, -SO-R9, -SO2-R9, -SO3H or -PO(CH3)2,
in which R9 represents methyl or ethyl), phenyl- C1-4-alkyl
or such group substituted by 1 or 2 carboxy groups in the phenyl
and/or alkyl part, allyl, C3-8-cycloalkyl, tetrahydrofur-
anyl, tetrahydropyranyl, phenyl or phenyl substituted by one or
two C1-4-alkyl, C1-2-alkoxy, nitro, halogen, trifluormethyl,
-SO2NH2, carboxy, benzyloxycarbonyl and/or carb-C1-4-
alkoxy, benzyl, benzhydryl, naphthyl, fluorenyl, pyridyl,
thienyl, benzoyl or C1-4- alkanoyl; or R5 and R6 or R6 and
R7 together with the atoms to which they are connected form
a saturated heterocyclic ring or such ring containing an
oxygen atom, a C1-4-alkyl substituted nitrogen atom or
an -S-, -SO- or -SO2- group; or R6 and R7 together

with the adjacent nitrogen form an aziridin ring or such
ring substituted by a cyano or carbamoyl group, and the
pharmaceutically useful salts thereof, characterized in that
a compound of formula II
<IMG> II
in which R1, R2, R3 and R4 have the above meanings and Y is
hydrogen, methyl or ethyl, is subjected to reaction with a
compound of formula III
<IMG> III
in which Z, R5 and X have the above meanings; and when a
pharmaceutical salt is required, reacting the free base with
a corresponding salt forming reagent.
2. A method of producing 4-Carbamoyloxy-oxazaphosphorins
of the general formula I
<IMG> I
in which Z is the group <IMG>; X is oxygen or sulphur;
R1, R2 and R3, are the same or different and
represent hydrogen, methyl, ethyl, 2-chloro-ethyl or
2-methanesulphonyloxyethyl; the groups R4 are the same
or different and represent hydrogen, methyl or ethyl; R5
31

and R6 each represents hydrogen; R7 is hydrogen, the
carbamoyl group, -OR8 (in which R8 is hydrogen, C1-4-
alkyl, phenyl or benzyl), straight or branched chain C1-18-
alkyl (or such alkyl substituted by 1 to 3 substituents
selected from the group consisting of hydroxy, halogen,
-COOH, -COOR9, -CONH2, -phenyl, benzyloxycarbonyl, -N(R9)2,
-?(R9)3, -OR9, -SR9, -SO-R9, -SO2-R9, -SO3H or -PO(CH3)2,
in which R9 represents methyl or ethyl), phenyl-C1-4-alkyl
or such group substituted by 1 or 2 carboxy groups in the
phenyl and/or alkyl part, allyl, C3-8-cyclo-alkyl, tetra-
hydrofuranyl, tetrahydropyranyl, phenyl or phenyl sub-
stituted by one or two C1-4-alkyl, C1-2-alkoxy, nitro,
halogen, trifluormethyl, -SO2NH2, carboxy, benzyloxy-
carbonyl and/or carb-C1-4-alkoxy, benzyl, benzhydryl,
naphthyl, fluorenyl, pyridyl, thienyl, benzoyl or C1-4-
alkanoyl; or R5 and R6 or R6 and R7 together with the
atoms to which they are connected form a saturated hetero-
cyclic ring or such ring containing an oxygen atom, a C1-4-
alkyl substituted nitrogen atom or an -S-, -SO- or -SO2-
group; or R6 and R7 together with the adjacent nitrogen
form an aziridin ring or such ring substituted by a cyano
or carbamoyl group, and the pharmaceutically useful salts
thereof, characterized in that an oxime of formula IV
<IMG> IV
wherein R1 to R4 have the above meanings, is subjected to
reaction with a compound of formula V
X = C = N - R7 V
wherein X and R7 have the above meanings.
32

3. A method according to claim 1 conducted in the presence
of an inert solvent.
4. A method according to claim 3 conducted in the presence
of an acid catalyst.
5. A method according to claim 2 conducted in an inert
solvent at a temperature ranging from -70°C to +50°C.
6. 4-Carbamoyloxy-oxazaphosphorins of the general formula I
<IMG> I
in which Z is the group <IMG> or the group -OR7; X is
oxygen or sulphur; R1, R2 and R3, are the same or
different and represent hydrogen, methyl, ethyl, 2-chloro-
ethyl or 2-methanesulphonyloxyethyl; the groups R4 are the
same or different and represent hydrogen, methyl or ethyl;
R5 and R6 are the same or different and represent hydrogen,
C1-4-alkyl, hydroxy-C1-4-alkyl or phenyl; R7 is hydrogen,
the carbamoyl group, -OR8 (in which R8 is hydrogen, C1-4-
alkyl, phenyl or benzyl), straight or branched chain C1-18-
alkyl (or such alkyl substituted by 1 to 3 substituents
selected from the group consisting of hydroxy, halogen,
-COOH, -COOR9, -CONH2, -phenyl, benzyloxycarbonyl, -N(R9)2,
-?(R9)3, -OR9, -SR9, -SO-R9, -SO2-R9, -SO3H or -PO(CH3)2,
in which R9 represents methyl or ethyl), phenyl-C1-4-alkyl
or such group substituted by 1 or 2 carboxy groups in the
phenyl and/or alkyl part, allyl, C3-8-cycloalkyl, tetra-
hydrofuranyl, tetrahydropyranyl, phenyl or phenyl sub-
stituted by one or two C1-4-alkyl, C1-2-alkoxy, nitro,
halogen, trifluormethyl, -SO2NH2, carboxy, benzyloxy-
carbonyl and/or carb-C1-4-alkoxy, benzyl, benzhydryl,
33

naphthyl, fluorenyl, pyridyl, thienyl, benzoyl or C1-4-
alkanoyl; or R5 and R6 or R6 and R7 together with the
atoms to which they are connected form a saturated hetero-
cyclic ring or such ring containing an oxygen atom, a C1-4-
alkyl substituted nitrogen atom or an -S-, -SO- or -SO2-
group; or R6 and R7 together with the adjacent nitrogen
form an aziridin ring or such ring substituted by a cyano
or carbamoyl group, and the pharmaceutically useful salts
thereof, whenever produced by the process of claim 1 or an
obvious chemical equivalent.
7. 4-Carbamoyloxy-oxazaphosphorins of the general formula
I as defined in claim 6 wherein: Z is <IMG> and R5 and
R6 are each hydrogen, whenever produced by the process
of claim 2 or an obvious chemical equivalent.
8. A method as claimed in claim 1, characterized in that
reactants of formula II and formula III are used in which Z
is <IMG>; X is oxygen; R5 and R6 are the same or dif-
ferent and represent hydrogen, methyl or ethyl; and
R7 is hydrogen, straight or branch chained C1-18- alkyl,
phenyl or benzyl.
9. A method as claimed in claim 1 or claim 2, character-
ized in that all R4 groups in the reactants are hydrogen
atoms.
10. A method as claimed in claim 1, characterized in that
reactants of formula II and formula III are used in which
X is oxygen; R1, R2 and R3, are the same or different and
represent hydrogen or the 2-chloroethyl group; R4, R5 and
R6 represent hydrogen; and R7 is hydrogen, benzyl, phenyl
or such phenyl substituted by one or two carboxy groups,
C1-4-alkyl or such alkyl substituted by one carboxy group
or phenyl-C1-4-alkyl or such phenyl alkyl substituted by
one or two carboxy groups in the phenyl and/or alkyl part
of the group.
34

Description

i~61453
4-Carbamoyloxy-oxazaphosphorins, method_of producing them
and pharmaceutical preparations containing them
It is known from German Offenlegungsschriften
2,231,311 and 2,552,135 that the introduction of a hydro-
peroxy group -OOH into the 4-position of the known cyto-
statics 2-[bis-(2-chloroethyl)-amino]-2-oxo-tetrahydro-2H-l,
3,2-oxazaphosphorin t~yclophosphamide), 3-(2-chloroethyl-
amino)-2-[bis-(2'-chloroethyl)-amino]-2-oxo-tetrahydro-2H-l,
3,2-oxazaphosphorin (trofosfamid), 3-(2-chloroethylamino)-2-
(2'-chlororethylamino)-2-oxo-tetrahydro-2H-1,3,2-oxaza-
phosphorin (ifosfamid), 3-(2-chloroethylamino)-2-(2'-methane-
sulfonylamino)-2-oxo-tetrahydro-2H-1,3,2-oxazaphosphorin
(sufosfamid) and other similar cyclophosphamides yields into
compounds having valuable cytostatic properties. These
compounds however have only so low a stability that it is
not possible to convert them into pharmaceutical preparations
as is necessary for their use in human therapy. It is
therefore an object of the present invention to provide new
cyclophosphamide compounds substituted in the 4-position
by a further converted hydroxy group which are characterized
in particular by a high cytostatic activity and an improved
stability.
The new compounds of the present invention represent
4-carbamoyloxy-oxazaphosphorins of the formula
-~jJ ;

-- 2 --
R X
15 11
O - N --C -- Z
Rl ~ 3~R4
~ R6
in which Z is the group -N or the group -OR7; X is oxygen
R7
or sulphur; Rl, R2 and R3, which may be the same or
different, represent hydrogen, methyl, ethyl, 2-chloroethyl
or 2-methanesulphonyloxyethyl; the groups R4, which may be
the same or different, represent hydrogen, methyl or ethyl;
R5 and R6, which may be the same or different, represent
hydrogen, Cl_4-alkyl, hydroxy-Cl 4-alkyl or phenyl; R7 is .
hydrogen, the carbamoyl group, -OR8 (in which R8 is hydrogen,
Cl 4-alkyl, phenyl or benzyl), straight or branched chain
Cl_l8-alkyl (optionally substituted by 1 to 3 substituents
which may be the same or different and are selected from
the group consisting of hydroxy, halogen, -COOH, -COORg,
-CONH2, -phenyl, benzyloxycarbonyl, -N(r9)2, -~(Rg)3, -ORg,
SR SO-R, -S02-Rg, -S03H or -PO(CH3)2, 9
15 represents methyl or ethyl), phenyl-Cl 4-alkyl (optionally
substituted by 1 or 2 carboxy groups in the phenyl and/or
alkyl part), allyl, C3 8-cycloalkyl, tetrahydrofuranyl,
tetrahydropyranyl, phenyl (optionally substituted by one or
two Cl 4-alkyl, Cl 2-alkoxy, nitro, halogen, trifluormethyl,
-S02NH2, carboxy, benzyloxycarbonyl and/or carb-Cl 4-alkoxy),
benzyl, benzhydryl, naphthyl, fluorenyl, pyridyl, thienyl,
benzoyl or Cl 4-alkanoyl; or R5 and R6 or R6 and R7 together
with the atoms to which they are connected form a saturated
heterocyclic ring optionally containing an oxygen atom, a
Cl_4-alkyl substituted nitrogen atom or an -S-, -SO- or
-S02- group; or R6 and R7 together with the adjacent nitrogen
form an aziridin ring optionally substituted by a cyano or
carbamoyl group,

453
-- 3 --
and the parmaceutically useful salts thereof.
Due to their particularly favourable properties and ease
of manufacture, the preferred compounds of formula I are
hose in which Z is -N 6; x is oxygen; R5 and R6, which
R7
may be the same or different, are hydrogen, methyl or ethyl;
and R7 is hydrogen, straight or branched chain Cl l8-alkyl,
phenyl or benzyl.
Particularly preferred compounds are those of the
above preferred ccmpounds in which all R4 groups in formula
I represent hydrogen atoms.
Another group of preferred compounds are those of
formula I in which X is oxygen, Rl, R2 and R3 which may be
the same or different, represent hydrogen or the 2-chloro-
ethyl group, R4, R5 and R6 represent hydrogen and R7 is
hydrogen, benzyl, phenyl (optionally substituted by one or
two carboxy groups), Cl 4-alkyl (Qptionally substituted by
one carboxy group) or phenyl-Cl 4-alkyl (optionally sub-
stituted by one or two carboxy groups in the phenyl and/or
alkyl part of the group).
The 4-carbamoyloxy-oxazaphosphorins of formula I
are obtained, according to the invention, by reacting a
compound of formula II
R3 OY
/ \ ~ ~ R4H II
0~ \ 0 ~ 4R4
R4
in which Rl, R2, R3 and R4 are as defined in formula I and Y
is hydrogen, methyl or ethyl, with a compound of formula III
R X
ll
~- N - C - Z III

53
4 --
in which Z, R5 and X are as defined in formula I, in the
presence of an inert solvent, optionally with heating or
cooling and/or in the presence of an acid catalyst.
Water, lower alkyl halides such as methylene chloride,
lower alkyl ketones such as acetone, diethyl ether, dimethyl-
formamide (DMF), hexamethylphosphoric acid triamide (HMPT)
or similar solvents or mixtures of such solvents are suitable
inert solvents for use in the above process. The reaction
may be carried out at temperatures in the range from -35C
to +50C, that is to say possibly with cooling, at room
temperature or with heating. The reaction can be carried
out in the presence of an acid catalyst such as an inorganic
acid, trichloroacetic acid, trifluoromethanesulphonic acid
or a Lewis acid such as AICI3, ZnC12 or TiC14.
Another embodiment of the process to produce compounds
--R6
of formula I wherein Z is -N (with R6 being hydrogen)
and R5 is hydrogen, is characterized in that an oxime of for-
mula IV
Rl\ l3
N NH
/\ /
2 O~ \ O C - CH- -C ,N - OH IV
R / R l l
4 4 R4 R4
wherein Rl to R4 are as defined in formula I, is subjected
to reaction with a compound of formula V
X = C = N - R V
wherein X and R7 are as defined in formula I, in an inert
solvent at a temperature ranging from -70C to +50C.
The course of the reaction in both embodiments can
be followed by thin layer chromatography. The isolation of
thin layer chromatographically uniform substances is
achieved by conventional preparation processes for such
products, particularly by crystallisation or chromatographic

53
purification.
Confirmation of structure may be effected by
melting point, thin layer chromatography, elementary
analysis, infra red and/or lH-NMR spectral analysis.
The compounds of formulae II and III used as raw
materials in the method according to the invention are
largely known and may be used in crystalline form or as a
crude product. They can be synthesized in known manner, for
example as follows:
4-Hydroxy-oxazaphosphorins are obtained by reduction of the
4-hydroperoxy-derivatives (see for example A. TAKAMIæAWA
et al., J.MED.CHEM. 18, 376 (1975). The 4-methoxy- or
4-ethoxy-oxazaphosphorins may be formed under acid catalysis
from the 4-hydroxy derivatives in methanol or ethanol or in
inert solvents which contain methanol or ethanol. The
hydroxy urea derivatives are produced by the conversion of
suitably substituted isocyanates or carbamic acid chlorides
with hydroxylamine or N-monosubstituted hydroxylamines.
Racemic cis- and trans-isomers can be produced from
the 4-carbamoyloxy-oxazaphosphorins according to the
invention. The cis configuration is 2R, 4R/2S, 4S whilst
the trans configuration is 2R, 4S/2S, 4R which correlation
is in accordance with the IUPAC nomenclature rules and with
the literature concerning corresponding oxazaphosphorin deri-
vatives. The cis- or trans-form can be produced deliberately
by selection of the reaction conditions. Pharmacologically
the isomers do not display any significant differences.
The compounds according to the invention possess
particularly valuable chemotherapeutic properties. In
comparison with the previously known cyclic phosphamides such
as cyclophosphamide, trofosfamide, ifosfamide and sufosfamide,
they display substantially equal carcinotoxic chemothera-
peutic effectiveness on experimental transplant tumours in
rats. They have a direct alkylating effect in aqueous
solution and have a high cytotoxicity in vitro, unlike the
cyclic phosphamides where, for example, cyclophosphamide
requires an enzymatic activation and has practically no

~161453
cytotoxic effect in vitro. The acute toxicity of the
compounds according to the invention is considerably lower
than that of the known cyclic phosphamides, for example it
i-s about 4 times less than that of the reference substance
cyclophosphamide, and thus the therapeutic ratio of the
compounds of the invention is considerably improved. The
compounds according to the invention also have clear
advantages over the prior art cyclic phosphamides with regard
to organotoxic side effects such as leukocyte depression and
10 immunosuppressiOn.
The 4-carbamoyloxy-oxazaphosphorins according to
the present invention are useful in the treatment of maiign
tumors and similar malign diseases in humans such as leukemia.
They are administered in daily dosages in the range of 0.01
to 100 mg per kg of body weight. The pharmaceutical prepa-
rations used in such therapy are those usual for cyclo-
phosphamide and the other known cytostatic oxazaphosphorins.
They may be produced in a usual manner using usual addi-
tives, diluents and/or carrier materials.
The compounds of the present invention may be
administered to animals, including humans, in the same manner
and against the same disease conditions as those known in
connection with the above mentioned cyclic phosphamides.
However, in view of the lower toxicity of the compounds of
the invention they can be used at higher dosage rates and
therefore possess a significantly expanded effective thera-
peutic dosage range. Normally, the compounds of the
invention are administered in conventional formulations
produced by mixing the compounds with physiologically
acceptable vehicles and/or diluents and by conventional
routes for example orally or by in]ection. The production
of such formulations and the methods by which they are
administered are well known to those skilled in the art.
The compounds according to the present application
are useful in the preparation of pharmaceutical products or
drugs containing as active agent one or several of such
compounds, possibly together with other pharmacologically
or pharmaceutically active agents. The production of the

53
pharmaceutical preparation is effected in manners known per
se using known and usual pharmaceutical auxiliary agents or
usual carrier materials or diluents.
Useful as carrier and auxiliary materials are for
instance compounds which are described in ULLMANNS ENCYKLO-
PAEDIE DER TECHNISCHEN CHEMIE (1953) vol. 4, pgs. 1 to 39;
JOURNAL OF PHARMACEUTICAL SCIENCES, (1963), vol. 52, pgs.
918 and following; H. v CZETSCH-LINDENWALD, Hilfsstoffe
fur Pharmazie und angrenzende Gebiete, Pharm. Ind. (1961),
vol. 2, pgs. 72 and following; Dr. H. P. FIEDLER, Lexikon
der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende
Gebiete, Cantor KG. Aulendorf (Wurttemberg) 1971.
Examples are gelatine, natural sugars such as cane
sugar or lactose, lecithine, pectin, starch (such as corn
starch), alginic acid, tylose, talkum, lycopodium, silicic
acid (for instance colloidal silicic acid), cellulose, cellulose
derivatives (for instance cellulose ethers, the hydroxy group
whereof being partly etherized with lower aliphatic saturated
alcohols and/or lower aliphatic saturated
oxyalcohols, such as methyloxypropylcellulose), stearates,
magnesium and calcium salts of fatty acids having from 12 to
22 C-atoms, in particular of saturated fatty acids (such as
stearates), emulgators, oils and fats, in particular plant
fats (such as peanut oil, castor oil, olive oil, sesame oil,
cottonseed oil, corn oil, wheatgrain oil, sunflower oil,
codfish leaver oil, mono-, di- and triglycerides of saturated
Y C12H242 to ClgH36O2 and mixtures thereof),
pharmaceutically compatible mono- or polyols and polyglycols
such as polyethyleneglycol and derivatives thereof, esters
of aliphatic saturated or unsaturated fatty acids (having
from 2 to 22, in particular from 10 to 18 carbon atoms) with
aliphatic monoalcohols (having from 1 to 20 carbon atoms) or
of polyols such as glycols, glycerol, diethyleneglycol, pen-
taerythritol, sorbitol, mannitol and the like which possibly
are etherized; benzylbenzoate, dioxolanes, glycerol formales,
tetrahydrofurfuryl alcohol, polyglycol ether with Cl-C12-
alcohols, dimethylacetamide, lactamides, lactates, ethyl-
carbonates, silicones (in particular dimethylpolysiloxanes
..
~.

-- 8 --
having a medium range viscosity3, magnesiumcarbonate and
the like.
For preparing solutions there are used for instance
water or physiologically compatible organic solvents such
as ethanol, 1.2-propyleneglycole, polyglycoles and
derivatives thereof, dimethylsulfoxide, fatty alcohols,
triglycerides, partial esters of glycerol, paraffines and
the like.
In the preparation of the pharmaceutical products
there may be used usual and known solubilizers or emulgators,
for instance: polyvinylpyrrolidone, sorbitane fatty acid
esters such as so'rbitane trioleate, lecithine, acacia,
tragacanth, po]yoxyethyl sorbitane monooleate, polyoxy-
ethylized fats, polyoxyethylized oleotriglycerides, lino-
lized oleotriglycerides, polyethyleneoxide-condensation
products of fatty alcohols, alkylphenols or'fatty acids
or l-methyl-3-(2-hydroxyethyl)-imidazolidon-(2). As above
used, polyoxyethylized means that the respective compound
contains polyoxyethylene chains with a polymerisation
degree generally between 2 to 40 and in particular 10 to 20.
Such polyoxyethylized products may for instance be
produced by subjecting the corresponding hydroxy compound
(for instance a mono- or diglyceride or unsaturated compound
such as containing the unsaturated oleyl group) with ethylene
oxide (for instance with 40 moles of ethylene oxide per mole
of glyceride).
Examples for oleotriglycerides are olive oil, peanut
oil, castor oil, sesame oil, cottonseed oil, corn oil (see
for instance Dr. H.P. FIEDLER "Lexikon der Holfsstoffe fur
Pharmazier Kosmetik und angrenzende Gebiete (1971),
pgs. 191 to 195~.
Furthermore, the pharmaceutical preparations
according to the present invention may contain preservatives,
stabilysing agents, buffering agents, such as CaHPO4,
colloidal aluminum hydroxide, flavoring agents, antioxidants
and complex forming agents (such as ethylenediaminotetra-
acetic acid) and the like. Possibly, the pH is rendered,

53
g
to about 3 to 7 by means of physiologically compatible
acids or buffers in order to stabilize the active agent.
An almost neutra] or weakly acid pH (up to pH 5) is
generally preferred. Useful antioxidants are for instance
sodium metabisulfite, ascorbic acid, gallic acid, gallic
acid alkylesters, butylhydroxyanisol, nordihydroguajaric
acid, tocopheroles as well as combinations of tocopheroles
and synergistically active agents (agents binding heavy
metal cations by complex formation, such as lecithine,
ascorbic acid, phosphoric acid). The addition of synergisti-
cally active agents considerably increases the antioxidizing
activity of tocopheroles.
Useful preservatives are for instance sorbic acid,
p-hydroxybenzoic acid esters (such as lower alkyl esters),
benzoic a~id, sodium benzoate, trichloroisobutyl alcohol,
phenol, cresol, benzethonium chloride and formaldehyde
derivatives.
The conversion of the compounds according to the
present invention into pharmaceutical products occurs with
the application of usual galenic principals and usual
methods. For instance, the active agent or agents and
auxiliary and/or carrier materials are thoroughly mixed (for
instance by means of usual mixers), applying generally
temperatures between 20 and 80C, preferably between 20 and
50C, in particular at room temperature. For further
details see: SUCKER, FUCHS, SPEISER, Pharmazeutische
Technologie, Stuttgart (1978).
The compounds according to the present invention
and, respectively, the pharmaceutical preparations
containing the same are administered on the skin or on mucous
membranes or for instance orally, enterally, pulmonally,
rectally, by way of the nose, vagina or tongue, intra-
venously, intra-arterially, intra-cardially, intra-
muscularly, intraperitoneally, intracutanously, subcuta-
nously, intrapleurally, intrathecally and generally intra-
caviterally.
In view of its very favourable results it is

,3
-- 10 --
preferred to combine the active compounds according to the
present invention with other active compounds usual in drugs,
in particular with uroprotecting agents (for instance and
preferably sodium-2-mercapto-ethane sulfonate or the di-
sodium salt of 2.2'-dithiodi-(ethane sulfonic acid), but
also with other systemically or regionally detoxifying
agents.
The compounds according to the present invention show a
good cytostatic and curative activity upon intravenous,
intraperitoneal or oral application to rats and mice
suffering from various experimental tumors.
Eor instance, depending upon the dose, a curative
activity is achieved with the compounds according to the
present invention after administering them intravenously,
intraperitoneally or orally in varying dosages one day after
intraperitonial implantation of cells of Yoshida-ascites-
sarkoma AH 13. For instance, tumor ascites is collected
under steril conditions (verified by bacteriological control)
from rats having a Yoshida-ascites-sarkoma 5 to 7 days old.
The average cell count of the ascites was 2 times 105 cells
per ~1. The cell count is brought to 108 cells/ml by the
addition of tyrode solution. 0.4 ml thereof (= 4 x 107 cells)
are implanted intraperitoneally to the test animals.
In the untreated control animals the rate at which
these tumors start to grow is 95%, the mean mortality time is
8 days (e ~ + 0.5 d). The compounds to be tested are
administered, also intraperitoneally, 3 hours after implan-
tation of the tumors. 6 animals are used in each test group.
The criterion of curative activity is the cure defined
as freedom from relapse and metastasis, for 90 days after
treatment. After determination of the per cent rate of cure
the dose which produces cure in 50% of the animals is cal-
culated from the dose activity line by means of probit
analysis according to R. FISCHER. This DC 50 is thP dose
at whic~ 50% of the tumor infected animals are cured. This
dose for the ~ompounds of the present invention in the above
test method upon intraperitoneal administration, is for

S3
instance between 0.05 and 30 mg/kg in rats. For instance,
with the dose DC 50 the mean survival time against leukemia
L121O in mice can be prolonged for 100%.
For determining the cytotoxic activity in vitro,
freshly collected cells of Yoshida ascites sarkoma are
incubated for 2 hours at 37C with increased concentrations
of the compounds to be tested in Ringer solution, as
described by SCHMAHL AND DRUCKREY, Naturwissenschaften, vol.
43 (1956) p. 199. After washing out of the test compound,
the transplantability of the tumor cells to untreated test
animals is determined. A quantitative value of the cytotoxic
activity in vitro can be obtained by determining the con-
centration EC 50 at which the survival of the transplanted
tumor cells in half of the animals is suppressed. With the
compounds of the present invention, the above test shows
for instance in vitro cytotoxic activity in concentrations
ranging from 1 to 100 ~g/ml.
For testing the activity of the compounds of the
present invention against leukemia L5222 in rats, the blood
of the donar rats of the strain BD IX was withdrawn by cardio-
puncture in pentobarbital narcosis (intraperitoneal appli-
cation). The leukocyte number in the blood varied between
50,000 and 150,000 cells per ~1. The blood is diluted with
sterile sodium chloride solution to a leukocyte number of
5 x 103 cell/~l. 1 ml )= 5 x 106 cells) are implanted intra-
peritoneally to test animals of the same strain. The rate
at which this tumor starts to grow is 100%, the time until
death of the test animals varies between 8 and 10 days.
6 animals are used for each test group. The test compounds
were administered 5 days after implantation of the leukemia.
The criterion of curative effectiveness is the freedom from
relapse for 90 days after treatment. After determination of
the per cent rate of cure, the DC 50 dose can be determined
from the dose activity line by means of a probit analysis
according to R. RISCHER. This is the dose producing cure
in 50% of the test animals. This DC 50 for leukemia L5222
in rats with the compounds according to the present
.,~

53
invention upon intraperitoneal administration is for
instance in the range of 0.5 to 20 mg/kg of rats.
Furthermore, the compounds according to the present
invention have been administered one or several times (4
times) during subsequent days after intraperitoneal
implantation of 106 cells of leukemia Ll210 of mice at
varying dosages and a cytostatic activity was achieved.
The cytostatic activity is the prolongation of the
mean survival time of tumor animals, i.e. the dose dependant
per cent prolongation of the survival time over an unin-
fested control group. This test method is described for
instance by N. sROCK, Pharmakologische Grundlagen der Krebs-
Chemotherapie in A. GEORGII, Verhandlungen der Deutschen
Krebsgesellschaft, vol. 1 (1978) pgs. 15 to 42.
This curative and cytostatic activity is comparable
with that of the known cytostatics cyclophosphamide and ifos-
famide.
The compounds according to the present invention
furthermore show a good therapeutic breadth. Furthermore,
they have definite advantages over the known cytostatic
cyclophosphamide in view of the lower organotoxic side
effects such as decrease of the number o leucocytes and
immunosuppression. Furthermore, the urotoxicity of the
compounds according to the present invention is considerably
lower. It can be further avoided by prophylactic
administration of a uroprotector, for instance and preferably
of sodium-2-mercapto-ethane sulfonate.
The lowest, already curative or cytostatic dose in
the above animal tests is for instance
0.01 mg/kg upon oral administration,
0.01 mg/kg upon intraperitoneal administration,
0.01 mg/kg upon intravenous administration.
The general dose range for the curative and cyto-
static activity (animal tests as above) is for instance:
0.01-100 mg/kg orally, in particular 0.1-10.0 mg/kg,
0.01-100 mg/kg intraperitoneally, in particular
0.1-10.0 mg/kg,

- 13 -
0.01-100 mg/kg intravenously, in particular 0.1-
10.0 mg/~g.
The compounds according to the present invention
are useful for the treatment of malign diseases in humans
and animals.
The pharmaceutical preparations in general contain
bet~een 1 mg and 1 g, preferably between 10 and 300 mg of
the active compound or compounds according to the present
invention.
The administration may be effected for instance
by means of tablets, capsules~ pills, dragees, suppositories,
ointments, gelees, cremes or in liquid form. Liquid forms
of application are for instance oily solutions or solutions
in alcohol or water as well as suspensions and emulsions.
The preferred form of administration are tablets, con-
taining between 10 and 200 mg of the active compound or
solutions containing between 0.1 and 5 % of the active
compound.
The single dose at which the compounds according
to the present invention are administered may be for instance:
a) between 1 and 100 mg/kg, preferably between 10 and 60
mg/kg for pharmaceutical preparations to be administered
orally;
b) between 1 and 100 mg/kg, preferably between 10 and 60
mg/kg for pharmaceutical preparations for parenteral
administration (for instance for intravenous or intra-
muscular administration);
c) between 1 and 100 mg/kg, preferably between 10 and 60
mg/kg for pharmaceutical preparations for rectal or
vaginal application;
d) between 1 and 100 mg/kg, preferably between 10 and 60
mg/kg for pharmaceutical preparations for local applica-
tion upon the skin or upon mucous membrances (for in~
stance in the form of solutions, lotions, emulsions,
ointments or the likel.
(The above single dosages refer to the free base the active
compound).

S3
- 14 -
For instance there may be administered 1 to 10
tablets 1 to 3 times per day, each tablet containing 10
to 300 mg of the active compound. Or there may be administered
one or several ampoules containing 1 to 10 ml with 10 to 50
mg of the active compound 1 or 2 times per day for intra-
venous injection. The minimal daily dose for oral
administration may be for instance 200 mg; the maximum daily
dose for oral administration should not be higher than 5000
mg. The compounds may also be administered by continuous
intravenous drip over 12 or more hours in particular cases.
For the treatment of dogs and cats the oral single
dose in general is between about 10 and 60 mg/kg of body
weight. The parenteral dose is approximately between 10 and
60 mg/kg of body weight.
For the treatment of horses and cattle the oral
single dose in general is between about 10 and 60 mg/kg. The
parenteral single dose is between about 10 and 60 mg/kg of
body weight.
The acute toxicity of the compounds of the present
application in mice (expressed by LD 50 mg~kg; test method
according to Miller and Tainter, Proc. Soc. Exper. Biol.
a. Med., vol. 57 (1944) p. 261) is for instance upon oral
administration between 100 and 1000 mg/kg or, respectively
above 1000 mg/kg.
The pharmaceutical preparations according to the
present invention may be used in human therapy, in veteri-
nary therapy or in agriculture alone or admixed with other
pharmacologically active agents.
The following examples will further illustrate the
preparations of the new compounds of the present invention
without however limiting the same thereto.
EXAMPLE 1
2-[bis-t2-chloroethyl)-amino]-2-oxo-tetrahydro-2-H-1,3,2-
oxazaphosphorin-4-yl-oxy-urea
15 g (54 mmol) of 4-hydroxycyclophosphamide (that is to say
2-[bis-(2-chloroethyl)-amino]-4-hydroxytetrahydro-2H-1,3,2-
oxazaphosphorin-2-oxide) and 4.4 g (58 mmol) of hydroxy-
urea were dissolved in 70 ml of DME, acidified with tri-
.

11~14~j3
- 15 -
chloroacetic acid (pH 3-4) and left for 20 hours at 0C in
a refrigerator. The resultant crystal sludge was diluted
with 70 ml of ethyl acetate and after 2 hours was drawn off
by suction, washed, dried and recrystallized from methanol.
Yield: 11.3 g (62% of the theoretical) in the cis form,
m.p. 139-143C (decomposition).
EXAMPLE 2
2-[bis-(2-chloroethyl)-amino]-2-oxo-tetrahydro-2H-1,3,2-ox-
azaphosphorin-4-yl-oxy-urea, cis form
1.1 g (4mmol) of 4-hydroxycyclophosphamide were dissolved in
methanol, treated with a trace of trichloroacetic acid, left
to stand overnight at -25C, then methanol was gently drawn
off, the residue dissolved in a little methylenechloride,
dried and concentrated to 1.2 g of 4-r.lethoxy-cyclophosphamide
(that is to say 2-[bis-(2-chloroethyl)-amino]-4-methoxy-
tetrahydro-2H-1,3,2-oxazaphosphorin-2-oxide). The 1.2 g of
4-methoxycyclophosphamide and 304 mg of hydroxyurea were
dissolved in 3 ml of DMF and kept in a refrigerator at -25C
for 20 hours. The crystal sludge was diluted with 3 ml of
ethyl acetate, drawn off by suction, washed, dried and re-
crystallized from methanol.
Yield: 670 mg (50~ of the theoretical) of the same product
as in Example 1.
EXAMPLE 3
2-[bis-(2-chloroethyl)-amino]-2-oxo-tetrahydro-2H-l~3~2
oxazaphosphorin-4-yl-oxy-urea, trans form
16 g (58 mmol) of 4-hydroxycyclophosphamide and 5.2 g (68 mmol)
of hydroxyurea were dissolved in 160 ml of water, acidified
with trichloracetic acid (pH 3-4) and left to stand for 20
hours at 0C in a refrigerator. The crystal sludge was then
drawn off by suction, washed with water, dried over P205
under high vacuum and recrystallized from methanol/chloroform.
Yield: 12.7 g (65~ of the theoretical) of the trans form
of the product in Example 1, m.p. 148C (decomposition).
.

116~S3
- 16 -
EXAMPLE 4
3-(2-chloroethyl)-2- [bis- (2'-chloroethyl)-amino]-2-oxo-
tetrahydro-2H 1,3,2-oxazaphosphorin-4-yl-oxy-urea
20 g (50 mmol) of 4-hydroxytrofosfamide (that is to say
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 DME
and cooled to -15C. Then acidification was effected with
trichloroacetic acid (pH 3-4) and agitation effected for 5
hours at -15C. After standing overnight at 0C, the
reaction solution was diluted with twice the amount of water.
Then extraction by shaking was effected 4 times each with
300 ml of acetic ester/methanol (10:1), the combined acetic
ester phase was washed twice with water, dried over sodium
sulphate and concentrated to 22 g of oil under vacuum. After
absorption in ethyl acetate/methanol, 4.2 g (Schmp. 106-110C)
crystallized out. The mother liquor was fractionated by
column chromatography on silica gel with chloroform/methanol
(10:1) and recrystallized together with the 1st crystallisate
from ethyl acetate/methanol.
Yield: 7.0 g (35% of the theoretical), m.p. 115-116C
(decomposition).
EXAMPLE 5
3-benzyl-1-[2-(bis-(2-chloroethyl)-amino)-2-oxo-tetrahydro-
2H-1,3,2-oxazaphosphorin-4-yl-oxy]-urea
540 mg (3.25 mmol) of 3-benzyl-1-hydroxyurea in 40 ml of
acetone and a catalytic amount of trichloroacetic acid were
added to 900 mg (3.25 mmol) of 4-hydroxycyclophosphamide in
1 ml of methylenechloride. The mixture was stored overnight
at -25C, the crystals were then drawn off by suction, washed
with acetone and ether and recrystallized from ethyl acetate.
Yield: 500 mg (40% of the theoretical), m.p. 122-123C
(decomposition).
_AMPLE 6
3-(0-bromophe;yl)-1-[2-(bis-(2-chloroethyl)-amino)-2-oxo-
tetrahydro-2H-1,3,2-oxazaphosphorin-4-yl-oxy]-urea

~i61~3
560 mg (2mmol) of 4-hydroxycyclophosphamide in 10 ml of
acetone were treated with 460 mg of 3-0-bromophenyl-1-
hydroxyurea and a catalytic amount of trichloroacetic acid
and let to stand at -25C. After 2 days, the crystals were
drawn off by suction and recrystallized from acetone.
Yield: 320 mg (32% of the theoretical), m.p. 110-111C
(decomposition).
EXAMPLE 7
.
N-[2-(bis-(2-chloroethyl)-amino)-2-oxo-tetrahydro-2H-1,3,2-
oxazaphosphorin-4-yl-oxy]-4-morpholinocarboxamide
1.2 g (4.3 mmol) of 4-hydroxycyclophosphamide in 15 ml of
acetone were treated with 630 mg (4.3 mmol) of N-hydroxy-
morpholineo-carboxamide and a trace of trichloroacetic acid
and stored at -25C. After 4 days the crystals were drawn
off by suction and recrystallized from acetone.
Yield: 780 mg (45% of the theoretical), m.p. 123-124C.
(decomposition).
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- 24 -
EXAMPLE 71
Ethyl-2-[bis-(2-chloroethyl)-amino]-2-oxo-tetrahydro-2H-1,3,
2-oxazaphosphorin-4-yl-oxy-carbamate
550 mg (2 mmol) of 4-hydroxycyclophosphamide and 210 mg (2 mmol)
of ethylhydroxycarbamate (hydroxyurethane) are dissolved in
5 ml of dry methylenechloride free of alcohol. A catalytic
amount of trichloroacetic acid and molecular sieve 4 A are
added thereto. The reaction mixture is allowed to stand at
-25C for 3 days. Thereafter, the molecular sieve is separated
and washed once with a diluted solution of NaHCO3. The
methylenechloride phase is dried over sodium sulfate and
part of the solvent is evaporated in a vacuum and thereafter
diluted with ether. After standing for 20 hours at -25C,
the separated crystals are filtered off, washed and dried.
Yield: 290 mg (40% of the theoretical) m.p. 96C~
EXAMPLE 72
Benzyl-2-[bis-(2-chloroethyl)-amino]-2-oxo-tetrahydro-2H-l,
3~2-oxazaphosphorin-4-yl-oxy-carbamate
750 mg (2.7 mmol) of 4-hydroxycyclophosphamide and 450 mg
(2.7 mmol) of benzyl-hydroxycarbamate are dissolved in 6 ml
of methylene chloride free of alcohol. A small amount of
trichloroacetic acid is added thereto and the solution is
allowed to stand at -25C in a refrigerator for 3 days. The
resulting solution is filtered off, the mother liquor is
diluted with 5 ml of chloroform, then is diluted with water
and thereafter is washed with a dilute solution of NaHCO3
and with water. The washed solution is dried over sodium
sulfate and is evaporated in a vacuum. The oily residue
thereafter is recrystallized from acetic acid ethyl ester
containing a small amount of methanol.
Yield: 680 mg (59~ of the theoretical) m.p. 112-114C.
,~
~ ,

1~61453
- 25 -
EXAMPLE 73
~3-[2-(bis-(2-chloroethyl)-amino)-2-oxo-tetrahydro-2H-1,3,2-
oxazaphosphorin-4-yl-oxy]-ureido~-acetic acid, cyclohexylamine
salt
a) 3-hydroxy-ureido-acetic acid
56.5 g (0.28 mole) of glycine benzylester-hydrochloride
are suspended in 300 ml of toluene. Dry gaseous phosgene
are introduced for 2 hours with stirring while the
reaction mixture is heated on an oil bath heated to 140C.
The reaction mixture thereafter is evaporated in a
vacuum and the residue of crude benzyl-isocyanato-
acetate is distilled in a high vacuum.
Yield: 51 g (95% of the theoretical) B.p. 0.05:100-102C.
A solution of 6.6 g (0.2 mole) of hydroxylamine in 200 ml
of dioxane is added to a solution of 28.7 g (o.15 mole)
of benzyl-isocyanato-acetate in 50 ml of dioxane dropwise
with stirring and temporary cooling. Stirring is con-
tinued for another hour at room temperature. A reaction
mixture thereafter is evaporated in a vacuum. The resul-
ting residue of crude benzyl-3-hydroxy-ureido-acetate is
recrystallized from ethyl acetate.
Yield: 28.1 g (83.6~ of the theoretical) m.p.: 113-120C.
5 g of palladium on activated charcoal are added to a
solution of 22.4 g (0.1 mole) of benzyl-3-hydroxy-ureido-
acetate in 300 ml of methanol. Hydrogen is introduced
with shaking. After about 20 minutes the hydrogen
uptake is finished. The catalyst is filtered off with
suction and the filtrate is evaporated in a vacuum. The
solid residue of crude 3-hydroxy-ureido-acetic acid is
recrystallized from dioxane.
Yield: 9.8 g (73% of the theoretical) m.p. 135C.
b) 6.1 g (2 mmol) of 4-hydroxycyclophosphamide are added to
a solution of 2.4 g (18 mmol) of 3-hydroxy-ureido-acetic
acid in 10 ml of water and 25 ml of acetone. The reac-
tion mixture is allowed to stand overnight at -25C.
Thereafter, 25 ml of acetone and a solution of 1.8 g
~18 mmol) of cyclohexylamine in 10 ml of acetone are

- 26 -
added thereto. After standing for 2 hours, the precip-
itate is filtered off with suction and is recrystallized
from acetone containing a small amount of methanol.
Yield: 3.1 g (44% of the theoretical) m.p. 107-108C.
5 EXAMPLE 74
3-[N,N-(bis-(2-chloroethyl)-diamino)-phosphinyl-oxy]-
propionaldehyde-oxime (aldophosphamide-oxime)
4.0 g (13.7 mmol) of 4-hydroperoxycyclophosphamide are
suspended in 50 ml of water with ice-cooling. 500 mg Na2S2
03 x 5 H20 are added thereto. During the stirring at 5 to
10C the pH is controlled with a pH-measuring device and is
k-ept between pH 4.5 and 5.5 by the addition of 2nH2SO4. A
concentrated solution of sodium thiosulfate is added drop-
wise thereto until there is no longer observed a continued
increase of the pH of the reaction mixture. Stirring is
continued for half an hour about 10C and an aqueous solution
of 950 mg of hydroxylamine-hydrochloride is added dropwise
keeping the pH at 5 by the addition of 2n-NaOH. The
resulting reaction mixture is allowed to stand overnight in
a cooling box at 5C. Thereafter, the reaction mixture is
extracted four times with 50 ml ethyl acetate each and the
organic extracts are dried over sodium sulphate and evapo-
rated in a vacuum at 30C. The residue is dissolved in
methylene chloride and the separated crystals are filtered
off after one day.
Yield: 3.4 g (85% of the theoretical) m.p.: 79-81C.
EXAMPI,E 75
3-p-bromophenyl-1-[2-(bis-t2-chloroethyl)-amino)-2-oxo-
tetrahydro-2H-1,3,2-oxazaphosphorin-4-yl-oxy]-urea
4 g (20 mmole) of p-bromophenylisocyanate in 40 ml of acetone
are added to 5.8 g (20 mmole) of aldophosphamide-oxime in
60 ml of acetone. The reaction mixture is stirred with
cooling for 5 hours. After standing for 2 hours, the
separated crystals are filtered off and dried in a vacuum
in a rotation evaporator at 40C and are recrystallized in
methanol.
-

L4~3
- 27 -
Yield: 8.1 g (82.8% of the theoretical) m.p.: 118-120C.
EXAMPLE 76
m-trifluoromethylphenyl-l-[2-(bls-(2-chloroethyl)-amino)-
2-oxo-tetrahydro-2H-1,3,2-oxazaphosphorin-4-yl-oxy]-urea
4.7 g (25 mmole) of m-trifluoromethyl phenylisocyanate
dissolved in 40 ml of acetone are added to 7.3 g (25 mmole)
of aldophosphamide-oxime in 80 ml of acetone. The reaction
mixture is stirred for 3 hours at 0C and is allowed to
stand overnight in a cooling box at -25C. Thereafter,
150 ml of petrolether are added thereto and the mixture is
allowed to stand for another night in the cooling box at
-25C. The resulting crystals are filtered off, dried at
30C and are recrystallized from isopropanol.
Yield: 9.2 g (76.8% of the theoretical) m.p.: 91-93C.
EXAMPLE 77
3-cyclohexyl-1-[2-(bis(2-chloroethyl)-amino)-2-oxo-tetra-
hydro-2H-1,3,2-oxazaphosphorin-4-yl-oxy]-urea
5 g (18 mmole) of aldophosphamide-oxime and 2.2 g cyclo-
hexylisocyanate are separately dissolved in 10 ml of acetone
and the solutions are admixed at 0C. After standing for
2 hours, the resulting crystals are filtered off with suction
and are recrystallized from acetone/ether.
Yield: 4.2 g (56~ of the theoretical) m.p.: 113C.
EXAMPLE 78
3-ethyl-1-[2-(bis-(2-chloroethyl)-amino)-2-oxo-tetrahydro-2H
1,3,2-oxazaphosphorin-4-yl-oxy]-urea
5 g (18 mmole) of aldophosphamide-oxime and 1.2 g ethyl-
isocyanate are separately dissolved in 15 ml of acetone
each. The solutions are admixed at about 0C. After
standing for 5 hours the separated crystals are filtered off
with suction and washed with acetone/ether.
Yield: 3.5 g (54~ of the theoretical) m.p.: 101C.

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EXAMPLE 79
3-(fluorene-2-yl)-1-[2-(bis-(2-chloroethyl?-amino)-2-oxo-
tetrahydro-2H-1,3,2-oxazaphosphorin-4-yl-oxy]-urea
2.1 g (10 mmole) of fluorenyl-2-isocyanate dissolved in
20 ml of acetone are added to 2.9 g (10 mmole) of aldo-
phosphamide-oxime in 30 ml of acetone at 0C. The sepa-
rated crystals were filtered off on the next day, are dried
in a vacuum at 60C and are recrystallized from isopropanol/
methanol.
Yield: 2.5 g (50.1% of the theoretical) m.p.: 114C.
EXAMPLE 80
3-benzoyl-1-[2-_(bis-(2-chloroethyl)-amino)-2-oxo-tetrahydro-
2H-1,3,2-oxazaphosphorin-4-yl-oxy]-urea
2.9 g (20 mmole) of benzoylisocyanate dissolved in 40 ml
of acetone are added to 5.8 g (20 mmole) of aldophosphamide-
oxime in 60 ml of acetone. A reaction mixture is stirred
for 5 hours under a nitrogen atmosphere with cooling in an
ice bath. The separated solid material is filtered off
with suction, is dried in a rotating evaporator at 30C and
is recrystallized from methanol.
Yield: 2.4 g (27.3% of the theoretical) m.p.: 124-125C.
EXAMPLE 81
3-p-nitrophenyl-1-[2-(bis-(2-chloroethyl)-amino)-2-oxo-
tetrahydro-2H-1,3,2-oxazaphosphorin-4-yl-oxy]-urea
3.3 g (20 mmole) of p-nitrophenylisocyanate dissolved in
40 ml of acetone are added to 5.8 g (20 mmole) of aldophos-
phamide-oxime in 60 ml of acetone. After standing for 2
hours the separated solid material is filtered off with
suction, is dried in a rotating evaporator at 40C and
is recrystallized from DMF/ethanol.
Yield: 6.7 g (73.5% of the theoretical) m.p.: 117-118C.
EXAMPLE 82
Tablet coated with a coating resistant against stomach juices
100 g of the compound of Example 5 together with 7.0 g

i3
- 29 -
of Aerosil (i.e. finely divided amorphous silicic acid) are
passed through a sieve and are thoroughly mixed. To this
mixture there are added 76.0 g of Avicel ~ pH 105 (i.e. micro
crystalline cellulose product of FMC), 10 g of corn starch
and 7.0 g of stearic acid. This mixture is mixed until
reaching a homogenous distribution of all components. The
mixture is pressed in usual manner to kernels each weighing
200 mg containing 100 mg of the active compound.
The kernels are coated with a usual stomach juice
resistant coating, for instance from suitable cellulose
derivatives or from a fully synthetic coating fro~ an organic
solution or aqueous dispersion which may contain usual
plasticizers, dyestuffs, sweeteners or defoamers.
EXAMPLE 83
Gelatine capsule coated with a stomach resistant coating
250 g of the compound of Example 5 together with 7.5 g
of Aerosil ~ are passed through a sieve and thoroughly
mixed. 40 g of lactose and 2.5 g of magnesium stearate are
added to this mixture which is mixed until reaching a
homogenous distribution of its components.
This product is filled into gelatine capsules each
capsule containing a single dose of 300 mg of the active
compound.
The capsules are closed and are coated as described
in Example 82.