DERIVES DU XYLITE A DEUX FONCTIONS TERMINALES

TERMINAL BIFUNKTIONAL XYLITE-DERIVATIVES

Abrégé anglais

ABSTRACT OF THE DISCLOSURE
The invention is novel compounds of the general formula I
<IMG > (I)
wherein
R1 and R5 are the same and stand for halogen, tosyloxy or mexyloxy, in
which case
R2 and R4 stand for hydroxy or
R1 and R2 as well as R4 and R5 together form an an oxygen bridge,
R3 is independently of the definition of Rl, R2, R4 and R5 stands for
hydrogen or or aralkanoyl or aroyl. The novel compounds display
useful cytostatic activity.

Revendications

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a compound of formula I
<IMG>
wherein R is a halogen atom and R is a hydroxyl group or R and R2
together form an oxygen bridge and, independently of the definitions of R
and R ; R is an alkanoyl group containing 2 to 4 carbon atoms, unsubstituted
or substituted by a phenyl group, or a benzoyl group, unsubstituted or sub-
stituted by a phenyl group, which process comprises reacting a compound of
formula IV
<IMG> IV
with an acylating agent containing the group R in the presence of an acid
binding agent, to obtain a compound of formula I in which R and R together
form an oxygen bridge and, if required, reacting the compound of formula I
with a hydrogen halide to obtain a compound of formula I in which R is a
halogen and R is a hydroxyl group.
2. A process according to claim 1 wherein the acid binding agent is
a trialkylamine.
3. A process according to claim 1 wherein the acylating agent is an
acid chloride.
4. A process according to claim 1 wherein the compound of formula IV
is obtained by reacting xylitol of formula II
<IMG>

with a compound of formula R6-R7, wherein R6 is mesyl or tosyl and R7 is
halogen, or R6 is halogen and R7 is hydrogen, followed by treatment with a
basic, acid-binding agent.
5. A process according to claim 4 wherein the reaction between the
compound of formula II and the compound R6-R7 is carried out in the presence
of an acid binding agent.
6. A process according to claim 4 wherein R6 is halogen and R7 is
hydrogen and the reaction is conducted in a concentrated aqueous solution,
with heating.
7. A process according to claim 6 wherein the reaction is conducted
at a temperature of about 85 C.
8. A process according to claim 4, 5 or 6 wherein the basic, acid-
binding agent is an anion exchanger in hydroxy form.
9. A compound of formula I as defined in claim 1 when prepared by a
process according to claim 1 or an obvious chemical equivalent thereof.
10. A process for the preparation of 3-(p-phenylbenzoyl)-1,2-4,5-
dianhydro-xylitol which comprises reacting 1,2-4,5-dianhydro-xylitol with p-
phenyl benzoyl chloride in the presence of an acid binding agent.
11. A process for the preparation of 3-(.gamma.-phenylbutyryl)-1,2-4,5-
dianhydro-xylitol which comprises reacting 1,2-4,5-dianhydro-xylitol with
.gamma.-phenylbutyryl chloride in the presence of an acid binding agent.
12. A process for the preparation of 3-acetyl-1,2-4,5-dianhydro-xylitol
which comprises reacting 1,2-4,5-dianhydro-xylitol with acetyl chloride in
the presence of an acid binding agent.
13. A process according to claim 10, 11 or 12 wherein the 1,2-4,5-
dianhydro-xylitol is prepared by reacting xylitol with hydrogen bromide to
form 1,5-dibromo-1,5-didesoxy sylitol which is reacted with an ion exchange
12

resin in hydroxyl form to obtain the 1,2-4,5-dianhydro-xylitol.
14. 3-(p-Phenylbenzoyl)-1,2-4,5-dianhydro-xylitol when prepared by a
process according to claim 10 or an obvious chemical equivalent thereof.
15. 3-(.gamma.-Phenylbutyryl)-1,2-4,5-dianhydro-xylitol when prepared by a
process according to claim 11 or an obvious chemical equivalent thereof.
16. 3-Acetyl-1,2-4,5-dianhydro-xylitol when prepared by a process
according to claim 12 or an obvious chemical equivalent thereof.
17. A process according to claim 10 to which comprises the further step
of reacting 3-(p-phenylbenzoyl)-1,2-4,5-dianhydro-xylitol with hydrogen
bromide solution to prepare 3-(p-phenylbenzoyl)-1,5-dibromo-1,5-didesoxy-
xylitol.
18. 3-(p-Phenylbenzoyl)-1,5-dibromo-1,5-didesoxy-xylitol when prepared
by a process according to claim 17 or an obvious chemical equivalent thereof.
19. A process for preparing 3-benzoyl-1,5-dibromo-1,5-didesoxy-xylitol
which comprises reacting 1,2-4,5-dianhydro-xylitol with benzoylchloride and
then reacting the obtained 3-benzoyl-1,2-4,5-dianhydro xylitol with hydrogen
bromide solution.
20. 3-Benzoyl-1,5-dibromo-1,5-didesoxy-xylitol when made by a process
according to claim 19 or an obvious chemical equivalent thereof.
13

Description

~5~
The present invention relates to new xylitol derivatives of t'ne
general formula
R -CH2-fH-fH fH 2
R
wherein R is a halogen atom and R is a hydroxyl group or R and R2
together form an oxygen bridge, and R independently of the definitions of
R and R stands for an alkanoyl group containing 2 to 4 carbon atoms,
unsubstituted or substituted by a phenyl group, or a benzoyl group, unsub-
stituted or substituted by a phenyl group.
The invention also provides a process for the preparation of the
compounds of the general formula I and pharmaceutical compositions of cyto-
static activity containing compounds of the general formula I as active
ingredients.
Certain compounds being derivatives derived from C4 or C6 sugar
alcohols were reported to have cytostatic activity (Neoplasma, 17, 15 (1970)).
These compounds are ~,~-dihalogeno- and dimesyloxy derivatives of tetrites
and hexites or diepoxy derivatives thereof. The secondary hydroxy groups of
these compounds are free, i.e. not blocked by acetal groups [Ar~neimittel-
Forschung (Drug. Res.) 14, 668-70 (1964) and Tetrahedron Letters, 20, 716
(1~61)].
We have now found that the compounds of the general formula I show
a strong cytostatic activity.
The compounds of the general formula I may be prepared by reacting
a dianhydro-xylitol of the general formula
CIH2~o
CH
H0-CH IV
Cl H " o
CH2
with an acylating agent containing the group R in the presence of an acid
binding agent, to obtain a compound of formula I in which R and R
L

1~45~4~
together form an oxygen bridge, and, if required, reacting the compound of
formula I with a hydrogen halide to obtain a compound of formula I in which
R is a halogen and R is a hydroxyl group.
The compound of formula IV can be obtained by reacting xylitol of
formula II
fH2H
CHOH
HO-CH II
CHOH
CH2H
with a compound of formula R -R , wherein one of R and R is mesyl or tosyl
and the other is halogen, or R is halogen and R is hydrogen, to form a
compound of formula III
fH2-R6
CHOH
HO-CH III
I
CHOHR6
followed by treatment with a basic, acid-binding agent.
Xylitol of the general formula II and the acylating agent of the
general formula R -R may be reacted by various methods. If a hydrogen
halogenic acid is employed as acylating agent then xylitol may be heated with
a concentrated aqueous solution of the hydrogen halogenlc acid optionally
under pressure. If mesyl or tosyl halides are used as acylating agents of
the forrnula R -R then the hydrogen halogenic acid formed in the course of
the reaction has to be bound by an acid binding agent. As acid binding
agents the usual acid binding agents may be employed, such as organic or
inorganic acid binding agents, for example tertiary amines, such as pyridine,
picolines, trialkyl amines or alkali metal, alkali earth metal carbonates,
hydroyen carbonates or phosphates.
It is preferred to use an acid binding agent or a salt thereof
formed in the course of the acid binding which may be readily removed from

3~
the reaction mixture.
As basic acid binding agent for use in conversion of a compound of
formula III to a dianhydro xylitol of formula IV any strong organic or in-
organic base may be used. As examples for organic bases alkali metal or
alkali earth metal alcoholates or organic nitrogen bases, for inorganic bases
alkali metal or alkali earth metal hydroxides, carbonates or hydrogen car-
bonates may preferably be used. The reaction may be however carried out with
anion exchangers in hydroxy form as well.
The reactions according to the invention for conversion of the
compounds of the general formula II to different types of the compounds of
the general formula I are illustrated in the enclosed reaction scheme showing
the most characetistic reactants necessary to the conversion.
Halogen as stands in the definition of R or R may be any halogen
preferably chlorine, bromine or iodine, particularly bromine.
Tosyloxy and mesyloxy in R and R may stand for various toluene-
sulfonyloxy, particularly p-toluene-sulfonyloxy resp. methyl sulfonyloxy
groups. The alkanoyl group in the definition of R may be straight or
branched chained and is preferably acetyl. If R stands for an alkanoyl
group substituted by phenyl then the y-phenylbutyryl group is preferred. If
R stands for benzoyl substituted by phenyl, then p-phenyl benzoyl is pre-
ferred.
Halogens in place of X, R or R may stand for chlorine, bromine,
or iodine, particularly chlorine.
Pharmacological activity oE the compounds of the general formula I
is illustrated by showing the pharmacological activity of 3-(p-phenyl
benzoyl)-1,2-4,5-dianhydroxylitol and 1,2-4,5-dianhydroxylitol:
~a) NK/Ly ascites -tumour in mice
Mice were transplanted with 10 cell number and treated intra-
peritoneally on the first day with 3-(p-phenylbenzoyl)-1,2-4,5-dianhydro-
xylitol at a dose of 600 mg/kg, 300 mg/kg, and 150 mg/kg. The untreated
animals were dead on the 17th to 23rd day after the transplantation. 70, 60
resp. 30~ of the treated animals however were alive on the 50th day after
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the transplantation (in the same order as the doses).
When having treated the animals at doses of 700 and 500 my/kg,
intraperitoneally, 100% resp. 60% of the animals were alive on the 40th day
after transplantation.
(b) L 1210 leukaemia in mice
Mice derived from DsA/2 strain were transplanted intraperitoneally
with 10 cell number. The animals were treated intraperitoneally with 3-
(p-phenylbenzoyl)-1,2-4,5-dianhydroxylitol at doses of 200 resp. 400 mg/kg,
on the 1st, 4th and 7th day after transplantation. Between the 9th and 11th
day after the transplantation the untreated animals were dead. The treated
animals however were dead only by the 13th day.
(c) S 180 solid tumour in mice
Mice belonging to CFLP strain were transplanted with tumour sub-
cutaneously. On the 1st, 4th and 10th day following the transplantation
the mice were treated intraperitoneally with 3-(p-phenylbenzoyl)-1,2-4,5-
dianhydroxylitol at a dose of 400 to 500 mg/kg. The average survival of
the untreated animals was 23 days and that of the treated animals 33 days.
(d) Yoshida solid sarcoma in rats
Rats belonging to CFY strain were transplanted subcutaneously
with the test-tumour in a cell number of 7 x 10 . The animals were treated
intraperitoneally with 3-(p-phenylbenzoyl)-1,2-4,5-dianhydro-xylitol on the
5th, 8th and 12th day following the transplantation at a dose of 200 mg/kg.
The size of the tumour in the treated animals decreased by 55% compared with
the control. 50% of the control animals were dead by the 20th day following
the transplantation, while 20% of the treated animals were s-till alive on
the 25th day following the death of the control animals.
(e) NK/Ly ascites tumour in mice
The test was carried out by the method given under (a) but as test-
compound 1,2-4,5-dianhydro-xylitol was used which was administered at a dose
of 20 mg/kg, 60% of the test-animals were alive on the 60th day following
the transplantation.

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(f) Toxicity tests
LD50 dose intraperitoneally in mice is 1000 mg/kg, in the case of
3-(p-phenylbenzoyl)-1,2-4,5-dianhydro-xylitol and 200 mg/kg, in the case of
1,2-4,5-dianhydro-xylitol. LD1o dose of latter compound: 160 mg/kg.
The test results show that compounds of the invention of the gen-
eral formula I exhibit valuable cytostatic activity and may be used as active
ingredients of cytostatic pharmaceutical compositions. Besides -the active
ingredient the pharmaceutical compositions may contain the conventionally
employed filling agents, diluents, flavouring agents, stabilizers and/or
formulating excipients. The pharmaceutical compositions containing the
compound of the invention, such as tablets may be prepared by compressing the
active ingredients into -tablets alone without any inert excipients.
When preparing pharmaceutical compositions non-toxic, solid, liquid,
semi liquid additives or gases liquidized under pressure may preferably be
used. The active ingredients may be formulated by adding the above mentioned
additives to tablets, dragees, granules, powders, capsulated powders, oint-
ments, cremes, solutions or spray. The solutions include injectable solu-
tions, infusions, perorally or topically employed compositions. The com-
pounds of the formula I of the invention may also be formulated to powder
ampoules too. The pharmaceutical compositions may, if necessary, contain,
mainly in ease of injections and infusion compositions, additives which in-
fluence the pH-value or the osmotic pressure of the solution or which
stabilizes the same. Various buffers and sodium chloride may be used for
this purpose.
The pharmaceutical composition containing the active ingredients
aceording to the invention may be administered at a dose of 1 to 30 mg/kg/
day depending upon the severity of the disease, on the tolerance of the
patient to be treated, preferably in divided dosage units for 1 to 10 days.
The treatment may be performed by using the pharmaceutical compo-
sitions containing as active ingredient only the compound of the invention
but also by using the pharmaceutical composition of the invention in combin-
ation with a pharmaceutical composition containing more, different aetive
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ingredients forming thus an up-to-date treatment system.
The further details of the invention are illustrated by the follow-
ing examples which serve merely as illustration and not for limitation.
Example 1
1.0 kg. of xylitol is dissolved in 2000 ml. of 65-70% hydrogen
bromic acid and the obtained solution is saturated below 0 C with hydrogen
bromide gas, whereafter the solution is maintained at 85 C for 4 hours in a
closed system. After cooling sodium hydrogen carbonate is added to the reac-
tion mixture under stirring until a pH value of 6 is obtained. The precipi-
tated crystals are filtered and recrystallized from ethyl acetate. 1,5-
Dibromo-1,5-didesoxy-xylitol is obtained. Yield: 1390 g. (76.5%); Rf =
0.85 (developing system: 62:62:30:23:20 mixture of benzene:methanol:n-amyl
alcohol:water:isopropanol); m.p.: 104-106 C.
Example 2
1600 ml. of VARION* AD ion exchanger resin in hydroxy form (poly-
styrene-based resin containing strong basic amino groups, manufactured by
Nitrokemia Ipartelepek, BalatonfUzfo, Hungary) 222.4 g. of 1,5-dibromo-1,5-
didesoxy-xylitol and 1600 ml. of distilled water are stirred for 15 minutes.
The ion exchanger resin is filtered off and washed with distilled water.
The aqueous solutions are evaporated to 1 litre at a reduced pressure and
added under stirring to a suspension prepared of 20 litre e-thyl acetate
layer is dried above anhydrous sodium sulfate and evaporated to dryness.
The obtained crude product is subjected to chromatography on silica gel.
54 g. of pure 1,2-4,5-dianhydro-xylitol are obtained. Xylitol-epoxide
content: 98-100~, Rf = 0.05 (developing system: 95:5 mixture of benzene
and ethyl acetate).
Example 3
2 g. of 1,2-4,5-dianhydro-xylitol are dissolved in 2 ml. of dis-
tilled water and the solution is added dropwise to 12 ml. of concentrated
hydrogen bromide solution under cooling. After ten minutes to the solution
sodium hydrogen carbonate is added to pH = 6 whereafter the precipitated
crude product is filtered off and recrys-tallized from ethyl acetate. 3.5 g.
*Trade ~ark
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''..,

S34~
of 1,5-dibromo-1,5-didesoxy-xylitol are obtained. M.p.: 104-106 C.
Example 4
2 g. of 1,2-4,5-dianhydro-xylitol are dissolved in 2 ml. of dis-
tilled water and the solution is added dropwise to 15 ml. of concentrated
hydrogen iodide solution under cooling. After 10 minutes the solution is
cooled to 0 C and the precipitated crude product is filtered off and re-
crystallized from ethyl acetate. 3.1 g. of 1,5-diiodo-1,5-didesoxy-xylitol
is obtained. M.p.: 115-118 C. Rf = 0.865 (developing system see Example 1).
Example 5
2 g. of 1,2-4,5-dianhydro-xylitol are dissolved in 2 ml. of dis-
tilled water and the solution is added dropwise under cooling to 10 ml. of
concentrated hydrochloric acid solution. After ten minutes the solution is
evaporated to dryness in vacuo. The residue is dissolved in 50 ml. of ethyl
acetate and shaken out with saturated aqueous sodium hydrogen carbonate
solution. The ethyl acetate layer is dried and evaporated in vacuo. 1.4 g.
of colourless 1,5-dichloro-1,5-didesoxy-xylitol is obtained. Rf = 0.805
(developing system see in Example 1).
Example 6
12 g. of crude 1,2-4,5-dianhydro-xylitol (purity of about 75%) are
dissolved in 250 ml. of anhydrous benzene and under stirring 14 ml. of
anhyarous triethylamine are added whereafter at 45 C 21.6 g. of p-phenyl-
benzoyl chloride are added within 3 hours under stirring. The mixture is
then stirred for 4 hours at 45 C and the precipitated product is then filter-
ed off and washed with benzene. The benzene solutions are evaporated in
vacuo. The syrup residue is chromatographed on silica gel with a mixture
of benzene and ethyl acetate. Fractions containing 3-(p-phenyl-benzoyl)-1,2-
4,5-dianhydro-xylitol are evaporated in vacuo. The residue is recrystallized
from ethanol. 12.5 g. of 3-(p-phenylbenzoyl)-1,2-4,5-dianhydro-xylitol are
obtained. M.p.: 86-88 C. Rf = 0.344 (developing system: see Example 2).
Example 7
1.16 g. of 1,2-4,5-dianhydro-xylitol is dissolved in 25 ml. of
anhydrous benzene and under stirring 1.4 ml. of anhydrous triethylamine is
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f,

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added whereafter at 45 C 1.82 g. of y-phenylbutyryl chloride in 3 ml. of
anhydrous benzene is added dropwise. The reaction mixture is then stirred
for 30 minutes whereafter the precipitated product is filtered and washed
with benzene. The combined benzene solutions are evaporated in vacuo. The
syrup residue is chromatographed on silica gel with a mixture of benzene
and ethyl acetate. The fractions containing 3-(~-phenylbutyryl)-1,2-4,5-
dianhydro-xylitol are evaporated to dryness. 1.4 g. of colourless oil is
obtained. Rf = 0.30 (developing system is as used in Example 2).
Exarnple 8
1.16 g. of 1,2-4,5-dianhydro-xylitol is dissolved in 25 ml. of
anhydrous benzene and 1.4 ml. of triethylamine is added to the solution. At
45 C a solution of 0.71 g. of anhydrous acetyl chloride in 3 ml. of anhydrous
benzene is added dropwise within 1 hour. The mixture is stirred for 30
minutes at 45 C, whereafter the mixture is worked up according to Example 7.
The product is crystallized from ethyl acetate. 0.88 g. of 3-acetyl-1,2-4,5-
dianhydro-xylitol is obtained. M.p.: 36-38 C, Rf = 0.25 (developing system
as given in Example 2).
Example 9
0.5 g. of 3-(p-phenylbenzoyl)-1,2-4,5 dianhydro-xylitol is dis-
solved in 1 ml. of acetone and the solution is cooled to 0 C, whereafter the
solution is dropped into 5 ml. of concentrated hydrogen bromide solution
cooled below 0 C. The mixture is diluted with 10 ml. of water after 30
minutes, whereafter it is allowed to stand at 0 C for 8 to 12 hours. The
reaction mixture is filtered and the crystals are washed wi-th water to
neutral. The reaction product is recrystallized from benzene. 0.3 g. of
3-(p-phenylbenzoyl)-1,5-dibromo-1,5-didesoxy-xylitol is obtained. M.p.:
122-125 C. Rf = 0.32 (developing system is the same as used in Example 2).
Example 10
3 g. of 1,2-4,5-dianhydro-xylitol are dissolved in 75 ml. of an-
hydrous benzene and 4.2 ml. of anhydrous triethylamine are added under stir-
ring. A solution of 3 ml. of benzoyl chloride in 5 ml. of anhydrous benzene
is added dropwise. The reaction mixture is s-tirred at 45 C for 30 minutes.

"
3~9
The reaction mixture is then worked up according to Example 8 and a mixture
of hexane and ethyl acetate is used for recrystallization. 2.8 g. of 3-
benzoyl-1,2-4,5-dianhydro-xylitol is obtained. Melting point: 39-40 C.
Rf = 0.28 (developing system as given in Example 2).
Thin layer chromatography was carried out in every case on "DC
Fertigplatten l~ieselgel" plates of size 20 x 20 cm. 1,2-4,5-dianhydro
derivatives were developed with a 5% methanolic nitrobenzyl-pyridine solution
followed by heating and the 1,5-dihalogeno-1,5-didesoxy derivatives were
developed by spraying the plates sprayed with nitrobenzyl-pyridine solution
after heating with a 50% methanolic triethylamine solution too.
Example 11
50 mg. powder ampoule.
Active ingredient of granule size 0.06 to 0.32 mm. is filled into
powder ampoules under aseptic conditions with a feeder adjusted to 50 mg.
It is packed together with a 10 ml. ampoule containing isotonic saline
solution.
Example 12
250 mg. tablets.
2500 g. of crystalline active ingredient, 450 g. of anhydrous
lactose and 170 g. of anhydrous crystalline cellulose are homogenized with a
mixture of 80 g. of paraffinic oil and 350 ml. of isopropanol. The mass is
granulated and dried. To the dry mixture 50 g. of talc is added, the mixture
is then homogenized and pressed to tablets weighing 325 mg. Each tablet
contains 250 mg. of active ingredient.
Example 13
100 mg. tablets.
1000 g. of crystalline active ingredient are homogenized with a
previously thoroughly mixed mixture of 50 g. of Carbowax* 6000 and 50 g. of
talc. The obtained powder mixture is filled into hard gelatine capsules by
using a filling device adjusted to 110 mg.
*Trade Mark
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Example 14
Enterosolvent tablets and capsules.
Compositions prepared according to Example 12 or 13 are provided
with a known intestionosolvent coating to get an enterosolvent composition.
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