DERIVES DE LA THALIDOMIDE, METHODE POUR LEUR FABRICATION ET LEUR UTILISATION DANS DES MEDICAMENTS

THALIDOMIDE DERIVATIVES, METHOD OF MANUFACTURE AND USE THEREOF IN MEDICAMENTS

Abrégé anglais

New thalidomide derivatives, pharmaceutical compositions
containing those compounds and a process for preparing
those compounds and compositions are disclosed.

Revendications

8
CLAIMS:
1. A thalidomide derivative of general formula I:
<IMG>
wherein: R1 and R2 independently represent a C1-6-alkyl
group, or R1 and R2 together represent -CH2CH2-X-CH2CH2-; R3
represents H or CH3; and X represents 0 or NH; or a salt
thereof; in racemic or optically active form.
2. A thalidomide derivative according to claim 1,
wherein R3 is H.
3. A thalidomide derivative according to claim 1 or
2, wherein R1 and R2 together represent -CH2CH2-X-CH2CH2-.
4. A thalidomide derivative according to claim 3,
wherein R1 and R2 together represent -CH2CH2-O-CH2CH2-.
5. A pharmaceutical composition, comprising: as
active ingredient, at least one thalidomide derivative or a
pharmaceutically acceptable salt thereof in racemic or
optically active form according to any one of claims 1 to 4;
and a pharmaceutically acceptable diluent or carrier.
6. A pharmaceutical composition according to claim 5,
in a dosage format adapted for parenteral administration.
7. A process for preparing a pharmaceutical
composition comprising admixing at least one thalidomide

9
derivative or a pharmaceutically acceptable salt thereof in
racemic or optically active form according to any one of
claims 1 to 4, and a pharmaceutically acceptable diluent or
carrier, optionally with one or more auxiliary agents and
preparing a dosage form from the resulting admixture.
8. A process for preparing a thalidomide derivative
of general formula I:
<IMG>
wherein R1, R2 and R3 are as defined in any one of claims 1
to 4, or a salt thereof in racemic or optically active form,
said process comprising: reacting a compound of general
formula II:
<IMG>
wherein R3 is as defined above in racemic or optically active
form with formaldehyde to form a N-hydroxymethyl compound of
general formula III:

10
<IMG>
wherein R3 is as defined above and reacting the resulting
N-hydroxymethyl compound with 4-chloromethylbenzoic acid in
the presence of dicyclohexylcarbodiimide to form an ester of
general formula IV:
<IMG>
wherein R3 is as defined above and transforming the resulting
ester into a thalidomide derivative of general formula I by
reaction with a di(C1-6-alkyl)amine, morpholine or piperazine
and, if desired, converting the resulting thalidomide
derivative with an acid into a corresponding salt.
9. A process according to claim 8, wherein said ester
of general formula IV is reacted with morpholine or
piperazine.
10. A process according to claim 9, wherein said ester
of general formula IV is reacted with morpholine.
11. Use of a thalidomide derivative or a
pharmaceutically acceptable salt thereof in racemic or

11
optically active form according to any one of claims 1 to 4,
for treating an immunological disorder.
12. Use of a thalidomide derivative or a
pharmaceutically acceptable salt thereof in racemic or
optically active form according to any one of claims 1 to 4,
for treating graft-versus-host disease.
13. Use of a pharmaceutical composition according to
claim 5 or 6, for treating an immunological disorder.
14. Use of a pharmaceutical composition according to
claim 5 or 6, for treating graft-versus-host disease.
15. A kit, comprising:
(a) a container containing therein a pharmaceutical
composition according to claim 5 or 6; and
(b) a written matter associated therewith, the written
matter describing indications of the pharmaceutical
composition for use in treating an immunological disorder.
16. A kit, comprising:
(a) a container containing therein a pharmaceutical
composition according to claim 5 or 6; and
(b) a written matter associated therewith, the written
matter describing indications of the pharmaceutical
composition for use in treating graft-versus-host disease.

Description

CA 02104776 2002-06-11
24272-50
New thalidomide derivatives,
process of preparing them
and use of these derivatives in medicaments
(G 2105)
The invention relates to new thalidomide derivatives of
formula I
0 3
R
N
o l o
0
CH2 R7
( O CH N ~
R2
medicaments containing at least one of these compounds and
a process for preparing -these compounds and medicaments.
It is known that thalidomide {3-phthalimido-piperidine-
2,6-dione) has immunosuppressive and immunomodulati.ng
properties. The poor water solubility of this compound,
however, is disadvantageous in respect to its therapeutic
use. The result is that up to now thalidomide can only be
orally administered which causes disturbances of resorp-
tion and considerable variations in plasma levels in case
of disorders which are associated with mucosa defects in
the gastrointestinal tract, e.g. the graft-versus-host
disease.
The invention provides water-soluble derivatives of
thalidomide which are suitable for parenteral
administration. Further the immunosuppressive and
immunomodulating properties of these derivatives

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2
are equal or better compared to the corresponding properties
of thalidomide.
Accordingly, the present invention relates to thalidomide
derivatives of formula I
0
R3
a
N
0 0 i 0
CH2
R~
0_ i - ~ CH2- N
0 ~R2
in which the residues R1 and R2 independently represent a
C1_6-alkyl group or R1 and R2 together represent
-CH2CH2-X-CH2CH2-, R3 represents H or C;H3 and X represents
O or NH, and/or the salts thereof in racemic or optically
active form.
Derivatives of thalidomide in which the residue R3 is H
are preferred. Derivatives of thalidomide wherein the
residues R1 and R2 together represent -CHZCH2C~H2CH2- or
-CH2CH2NHCH2CH2-, especially -CH2CH20C1H2CH2- are particu-
larly preferred.
Due to their solubility in water and their stability in
aqueous solutions or dispersions the compounds of the
invention are especially suitable for parenteral admini-
stration.
Accordingly the invention also relates to medicaments
containing as active ingredient at least one thalidomide

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3
derivative and/or at least one salt thereof in racemic or
optically active form.
Compositions for parenteral administration may be soluti-
ons, suspensions, dry formulations suitable for easy re-
constitution, ointments, pastes, gels, depots of an active
ingredient in diluted form or plasters.. All of the fore-
going general types of pharmaceutical compositions to
which the invention is applicable as well as the prepara-
tion of these compositions are known. The incorporation of
the thalidomide derivatives according to the invention
into these pharmaceutical compositions in the form and
dosage desired poses no problems for an ordinarily skilled
pharmacist. In the production of pharmaceutical compositi-
ons according to the invention the usual care must natu-
rally be taken in the selection of carriers and inorganic
or organic adjuvants such as diluents, solvents. stabili-
zers, dispersing agents, wetting agents, binders, coloring
agents and flavorings. In particular care should be taken
to achieve sterility and if the compositions are in liquid
form, isotonicity.
The medicaments acco-rding to the invention are suitable in
the treatment of immunological disorders such as leprosy,
Becet's syndrome, lupus erythematosus, pruri.go nodularis,
mundaphtene in AIDS-patients, colitis ulcerosa and especi-
ally in the treatment of the graft-versus-host disease.
The medicaments may be intravenously( intradermally, in-
tramusculary, intranasally and locally administered. The
local application is especially suitable in the treatment
of infections of the skin, mucosae and eyes.
Further, the invention provides a process for preparing
thalidomide derivatives of formula I

2~.~~~'~'~
4
0
R3 I
N
0 0 ~ 0
. IH2
0- i ~ CH2 N\
0 R
in which the residues R1 and R2 independently represent a
C1_6-alkyl group or R1 and R2 together represent
-CH2CH2-X-CH2CH2-, R3 represents H or CH3 and X represents
O or NH, and/or the salts thereof in racemic or optically
active form, said process comprising the steps of reacting
a compound of formula II
0
R3
N
2 0 N ~0
0
H
in racemic or optically active form with formaldehyde to
form a N-hydroxymethyl compound of formula III
o I
R3
~ N
i
N ~0
0 I
CH20H
reacting the resulting N-hydroxymethyl compound with
4-chloromethylbenzoic acid in the presence of di~cyclo
hexylcarbodiimide to form an ester of formula IV

5
0 I
R3
'.
0 0 N~0
CH2
0- i O CH2 C L
0
transforming the resulting ester into a thalidomide deri
vativ~ of formula I by reaction with a di(C1-6-al
kyl)amine, morpholine or piperazine, and optionally con
verting the resulting thalidomide derivative with an acid
into a corresponding salt.
To prepare thalidomide derivatives according to the in-
vention the preferably used starting compound thalidomide
is hydroxymethylated with formaldehyde at the glutarimide
nitrogen atom. After reaction with 9-chloromethylbenzoic
acid in the presence of dicyclohexylcarbodiimide in a
solvent or solvent mixture, followed by reaction pre-
ferably with morpholine or piperazine, especially with
morpholine in the presence of an alkali halide, e.g. so-
dium iodide, in an anhydrous solvent or solvent mixture a
thalidomide derivative according to the invention is ob-
tained which may be converted with an acid, e.g. hydro-
chloric acid, optionally in presence of a C1_3-alkyl alco-
hol into a corresponding salt.

i
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24272-50
5a
The invention also provides a kit, comprising:
(a) a container containing therein a pharmaceutical
composition according to the invention; and
(b) a written matter associated therewith, the written
matter describing indications of the pharmaceutical
composition for use in treating an immunological disorder or
graft-versus-host disease.

.. ~1~~~'l'~~i
6
Example
Preparation of N-(4-morpholinomethyl-benzoyloxymethyl)tha-
lidomide, hydrochloride salt
2.58 g of thalidomide in 30 ml of an aqueous solution
containing 35 ~ by weight of formaldehyde were heated
under reflux. After formation of a clear solution the
mixture was allowed to cool to 20° C. After 24 hours the
mixture was filtered and the resulting residue washed with
an aqueous solution containing 3 ~ by weight of formalde-
hyde. The N-hydroxymethyl-thalidomide obtained (yield:
70 ~) melted at 165° C.
1.1 g of N-hydroxymethyl-thalidomide, 0.68 g of 4-chloro-
methylbenzoic acid, 1.03 g of dicyclohexylcarbodiimide and
0.06 g of 4-pyrrolidinopyridin in 25 ml of dichloromethane
were stirred at 20° C for 24 hours. After removal of cy-
clohexylurea by filtration and dichloromethane by destil-
lation the resulting residue was recrystallized from etha-
nol to yield N-(4-chloromethyl-benzoyloxymethyl)thalidomi-
de (yield: 60 $) melting at 215 to 220° C.
880 mg of N-(4-chloromethyl-benzoyloxymethyl)thalidomide,
350 mg of morpholine and 20 mg of sodium iodide in anhy-
drous acetone were stirred at 20° C for- 24 hours. After
removal of acetone by destillation the resulting oily
residue was purified by column chromatography ("Kiesel-
gel 60" from E. Merck of Darmstadt, Germany) with ethyl
acetate. The resulting oil was dissolved in ethanolic
hydrochloric acid and precipitated by addition of diethyl
ether. After recrystallization from ethanol N-(4-morpholi-
nomethyl-benzoyloxymethyl)thalidomide, hydrochloride salt
was obtained (yield: 40 ~) melting at 236° C.

2~Ot~ d'~
z
1H-NMR (200 MHz, DMSO-d6):
2.08, 2.62 (m, m, 2H, CH2-CH):
2.84, 2.91 (m, m, 2H, CH2C0)~ .
3.10, 3.70 (m, m, 8H, -CH2-CH2);
9.41 (s, 2H, -CH2-N);
5.35, 5.43 (dd, 1H, CH-CH2);
5.92 (d, 2H, N-CH2-0)
7.72, 7.92 (m, m, 8H, aromat.): w
11.20 (s, 1H, H+)

Dessin représentatif