U.S. patent application number 11/460677 was filed with the patent office on 2006-11-16 for 3-z-[1-(4-(n-((4-methyl-piperazin-1-yl)-methylcarbonyl)-n-methyl-amino)-an- ilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulpho- nate and the use thereof as a pharmaceutical composition.
Invention is credited to Thomas Bock, Frank Hilberg, Guenter Linz, Werner Rall, Gerald J. Roth, Peter Sieger.
Application Number | 20060258681 11/460677 |
Document ID | / |
Family ID | 30469050 |
Filed Date | 2006-11-16 |
United States Patent
Application |
20060258681 |
Kind Code |
A1 |
Roth; Gerald J. ; et
al. |
November 16, 2006 |
3-Z-[1-(4-(N-((4-Methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-an-
ilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulpho-
nate and the use thereof as a pharmaceutical composition
Abstract
The present invention relates to the compound
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulph-
onate of formula I and the use thereof as a pharmaceutical
composition. ##STR1##
Inventors: |
Roth; Gerald J.; (Biberach,
DE) ; Linz; Guenter; (Mittelbiberach, DE) ;
Sieger; Peter; (Mittelbiberach, DE) ; Rall;
Werner; (Mittelbiberach, DE) ; Hilberg; Frank;
(Vienna, AT) ; Bock; Thomas; (Dully, CH) |
Correspondence
Address: |
MICHAEL P. MORRIS;BOEHRINGER INGELHEIM CORPORATION
900 RIDGEBURY ROAD
P. O. BOX 368
RIDGEFIELD
CT
06877-0368
US
|
Family ID: |
30469050 |
Appl. No.: |
11/460677 |
Filed: |
July 28, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10623971 |
Jul 21, 2003 |
|
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11460677 |
Jul 28, 2006 |
|
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60404460 |
Aug 19, 2002 |
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Current U.S.
Class: |
514/254.09 ;
544/373 |
Current CPC
Class: |
A61P 35/04 20180101;
A61P 43/00 20180101; A61P 35/00 20180101; C07D 209/34 20130101 |
Class at
Publication: |
514/254.09 ;
544/373 |
International
Class: |
A61K 31/496 20060101
A61K031/496; C07D 403/02 20060101 C07D403/02 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 24, 2002 |
DE |
102 33 500 |
Claims
1.
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino-
)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesu-
lphonate.
2.
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino-
)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesu-
lphonate in crystalline form, having a melting point of
T.sub.m.p.=305.+-.5.degree. C. (determined by DSC; evaluation using
peak-maximum; heating rate: 10.degree. C./min).
3. Crystalline
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulph-
onate according to claim 2, the X-ray powder diagram of which
includes, inter alia, the characteristic values d=5.43 .ANG., 5.08
.ANG., 4.71 .ANG., 4.50 .ANG. and 4.43 .ANG. with an intensity of
more than 40%.
4. Crystalline
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulph-
onate according to claim 2, characterised by a unit cell determined
by X-ray powder diffractometric measurements having the following
dimensions: a=16.332 .ANG., b=19.199 .ANG., c=11.503 .ANG.,
.alpha.=95.27.degree., .beta.=90.13.degree., .gamma.=110.83.degree.
and V=3354.4 .ANG..sup.3
5. Crystalline
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulph-
onate according to one of claims 2 to 4, in the form of the
hemihydrate.
6. A pharmaceutical composition comprising
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulph-
onate and one or more inert carriers and/or diluents.
7. A metabolite of
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulph-
onate.
8. A prodrug of
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulph-
onate.
9. A method for treating excessive or abnormal cell proliferation
which comprises administering a therapeutically effective amount of
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulph-
onate.
Description
RELATED APPLICATIONS
[0001] This is a continuation of U.S. application Ser. No.
10/623,971 filed on Jul. 21, 2003, which claims, as does the
present application, priority benefit of U.S. Provisional
Application Ser. No. 60/404,460, filed on Aug. 19, 2002, and DE 102
33 500, filed on Jul. 24, 2002.
FIELD OF THE INVENTION
[0002] The present invention relates to the compound
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulph-
onate of formula I and the use thereof in a pharmaceutical
composition. ##STR2##
BACKGROUND TO THE INVENTION
[0003] A number of 2-indolinone derivatives are already known in
the prior art. Thus, for example, International Patent Application
WO 01/27081 discloses 2-indolinone derivatives which have valuable
pharmacological properties.
[0004] Like the 2-indolinone derivatives mentioned in the prior
art, the compound of formula I also has, in particular, an
inhibiting effect on various kinases, particularly receptor
tyrosine kinases such as VEGFR1, VEGFR2, VEGFR3, PDGFR.alpha.,
PDGFR.beta., FGFR1, FGFR3, EGFR, HER2, c-Kit, IGF1R, Flt-3 and
HGFR, and on the proliferation of cultivated human cells,
particularly endothelial cells, e.g. in angiogenesis, but also on
the proliferation of other cells, particularly tumour cells.
[0005] The pharmacologically valuable properties of the indolinone
derivatives disclosed in the art and mentioned above constitute the
basic prerequisite for effective use of the compounds as
pharmaceutical compositions. An active substance must in any case
satisfy additional requirements in order to be accepted for use as
a drug. These parameters are largely connected with the
physicochemical nature of the active substance.
[0006] Without being restrictive, examples of these parameters are
the stability of effect of the starting substance under various
environmental conditions, the stability during production of the
pharmaceutical formulation and stability in the final compositions
of the drug. The pharmaceutically active substance used to prepare
the pharmaceutical compositions should therefore have great
stability which is ensured even under all kinds of environmental
conditions. This is absolutely essential to prevent pharmaceutical
compositions being used which contain breakdown products, for
example, in addition to the active substance itself. In such a case
the content of active substance present in the pharmaceutical
formulation might be lower than specified.
[0007] The absorption of moisture reduces the content of
pharmaceutically active substance as a result of the increased
weight caused by the uptake of water. Pharmaceutical compositions
with a tendency to absorb moisture have to be protected from
moisture during storage, e.g. by the addition of suitable drying
agents or by storing the drug in an environment where it is
protected from moisture. In addition, the uptake of moisture may
reduce the content of pharmaceutically active substance during
manufacture if the pharmaceutical substance is exposed to the
environment without being protected from moisture in any way.
Preferably, therefore, a pharmaceutically active substance should
be only slightly hygroscopic.
[0008] As the crystal modification of an active substance is
important to the reproducible active substance content of a
preparation, there is a need to clarify as far as possible any
existing polymorphism of an active substance present in crystalline
form. If there are different polymorphic modifications of an active
substance care must be taken to ensure that the crystalline
modification of the substance does not change in the pharmaceutical
preparation later produced from it. Otherwise, this could have a
harmful effect on the reproducible potency of the drug. Against
this background, active substances characterised by only slight
polymorphism are preferred.
[0009] Another criterion which may be of exceptional importance
under certain circumstances depending on the choice of formulation
or the choice of manufacturing process is the solubility of the
active substance. If for example pharmaceutical solutions are
prepared (e.g. for infusions) it is essential that the active
substance should be sufficiently soluble in physiologically
acceptable solvents. It is also very important for drugs which are
to be taken orally that the active substance should be sufficiently
soluble.
[0010] The problem of the present invention is to provide a
pharmaceutically active substance which not only is characterised
by high pharmacological potency but also satisfies the
above-mentioned physicochemical requirements as far as
possible.
DETAILED DESCRIPTION OF THE INVENTION
[0011] Surprisingly, it has been found that the problem outlined
above is solved by the salt
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulph-
onate of formula I.
[0012] The monoethanesulphonate according to the invention is
characterised by good crystallinity and low amorphisation during
grinding and compression. In addition it is not hygroscopic and is
readily soluble in physiologically acceptable solvents.
[0013] The crystalline form of the monoethanesulphonate of the
compound
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone
according to the invention is characterised by a melting point of
T.sub.m.p.=305.+-.5.degree. C. (determined by DSC=Differential
Scanning Calorimetry; evaluated by the peak maximum; heating rate:
10.degree. C./min). The value given was determined using a DSC
821.sup.e made by Messrs Mettler Toledo.
[0014] Therefore a first object of the present invention is the
salt
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulph-
onate, preferably in crystalline form, characterised by a melting
point of T.sub.m.p.=305.+-.5.degree. C. (determined by DSC;
evaluation by peak maximum; heating rate: 10.degree. C./min).
[0015] The crystalline form of
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulph-
onate according to the invention was investigated in more detail by
x-ray powder diffraction. The diagram obtained is shown in FIG.
1.
[0016] Table 1 that follows contains the data obtained in this
analysis: TABLE-US-00001 TABLE 1 X-ray powder reflections and
intensities (standardised) of
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-
methyl-amino)-anilino)-1-phenyl-methylene]-6-
methoxycarbonyl-2-indolinone-monoethanesulphonate. h k l 2 .THETA.
[.degree.] d.sub.hkl Value [.ANG.] Intensity [%] 0 0 1 7.70 11.47
17.7 0 -1 0 8.78 10.07 19.2 -1 0 1 9.47 9.33 26.4 1 0 1 9.82 9.00
32.2 2 0 0 11.59 7.63 30.9 0 -2 1 11.93 7.41 26.3 1 2 0 13.15 6.73
29.6 -2 0 1 13.69 6.47 31.8 2 1 0 14.17 6.24 30.9 3 -1 0 16.32 5.43
41.7 0 1 2 16.72 5.30 29.0 -1 1 2 16.92 5.238 9.8 3 0 0 17.43 5.08
42.7 2 2 0 17.77 4.99 26.9 1 -4 0 18.58 4.77 31.1 -3 0 1 18.81 4.71
41.8 -2 0 2 19.03 4.66 39.2 3 -3 1 19.73 4.50 40.2 0 4 0 19.87 4.47
6.2 2 -4 1 20.03 4.43 100.0 0 -4 1 20.61 4.31 8.3 -3 -1 1 20.83
4.26 5.5 1 2 2 21.26 4.18 31.1 -1 3 2 21.76 4.08 19.8 0 4 1 22.05
4.03 32.4 3 -4 1 22.19 4.00 10.1 0 3 2 22.57 3.94 25.6 -3 4 1 23.10
3.85 32.3 -1 0 3 23.81 3.73 32.0 1 4 1 24.69 3.60 26.6 1 3 2 24.78
3.58 24.6 0 5 0 24.91 3.572 15.6 -1 5 1 25.42 3.50 23.7 -4 4 1
26.24 3.39 24.8 3 -2 2 26.91 3.31 22.9 -3 4 2 27.19 3.28 23.9 1 5 0
27.61 3.23 22.0 -1 -5 1 27.95 3.19 22.3 3 -1 3 28.71 3.11 22.1 5 0
0 29.25 3.05 20.2
[0017] In Table 1 above the value "2 .THETA. [.degree.]" denotes
the angle of diffraction in degrees and the value "d.sub.hkl
[.ANG.]" denotes the specified distances in .ANG. between the
lattice planes.
[0018] The x-ray powder diagram was recorded, within the scope of
the present invention, using a Bruker D8 Advanced-diffractometer
fitted with a location-sensitive detector (OED) and a Cu anode as
the x-ray source (CuK.sub..quadrature. radiation,
.quadrature.=1.54056 .ANG., 40 kV, 40 mA).
[0019] According to the findings shown in Table 1 the present
invention relates to crystalline
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulph-
onate, characterised in that in the x-ray powder diagram it has,
inter alia, the characteristic values d=5.43 .ANG., 5.08 .ANG.,
4.71 .ANG., 4.50 .ANG. and 4.43 .ANG. with an intensity of more
than 40%.
[0020] Evaluation of the x-ray powder data obtained yields the unit
cell of the compound according to the invention, the
crystallographic data of which are provided in Table 2 below:
TABLE-US-00002 Formula C.sub.66H.sub.78N.sub.10O.sub.15S.sub.2
Molecular weight 1315.52 Crystal system triclinic a 16.332 .ANG. b
19.199 .ANG. c 11.503 .ANG. .quadrature. 95.27.degree. .quadrature.
90.13.degree. .quadrature. 110.83.degree. V .sup. 3354.4
.ANG..sup.3
[0021] The unit cell is defined by the lengths of the side of this
cell a, b and c, by the relative angles .alpha., .beta. and .gamma.
of the cell sides to one another and by the cell volume V (see
Table 2). Methods of recording and evaluating x-ray powder diagrams
for determining unit cells and their dimensions are known in the
prior art and are recognised for characterising the crystalline
nature and structure of a product.
[0022] Thus, the present invention also relates to the crystalline
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulph-
onate according to the invention, characterised by a unit cell
determined by x-ray powder diffractometric measurements, having the
following dimensions:
a=16.332 .ANG.
b=19.199 .ANG.
c=11.503 .ANG.
.alpha.=95.27.degree.
.beta.=90.13.degree.
.gamma.=110.83.degree.
V=3354.4 .ANG..sup.3
[0023] Using a monocrystal it was also possible to determine the
space group of the compound according to the invention. The
corresponding data are shown in Table 3 below: TABLE-US-00003
Structural resolution From monocrystal data Space group P{overscore
(1)} (#2) Density (calculated) 2.605 g/cm.sup.3 Cell contents 2
molecules of different conformation 2 .times. EtSO.sub.4 1 .times.
H.sub.2O
[0024] Under standard conditions the monoethanesulphonate of the
compound
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone
according to the invention is present in the form of the
hemihydrate, from which water escapes at a temperature of about
130.degree. C. FIG. 2 shows the thermoanalysis.
[0025] The present invention also relates to the metabolites of the
compound
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-
-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoet-
hanesulphonate of formula I, to prodrugs of this compound or of
these metabolites obtained via, for example, chemical or
non-chemical derivatization of the entire molecule or of one or
more chemical groups on the molecule, and to the use thereof in a
pharmaceutical composition.
[0026] Hence, metabolites of the compound
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulph-
onate may occur via, for example, de-esterification of an ester
group on the molecule. This de-esterification may occur in-vivo
through the action of specific or a-specific esterases present in
the body of the patient to which the drug is administered.
[0027] Prodrugs of the compound
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulph-
onate or of metabolites thereof may be obtained via, for example,
any chemical substitution of a carboxy or amino group present on
the molecule or by substitution of the the N-1-atom of the
indolinone moiety by a group which may be cleaved in vivo.
[0028] By a group which may be cleaved in vivo and converted
in-vivo into a carboxy group is meant for example a hydroxymethyl
group, a carboxy group esterified with an alcohol wherein the
alcoholic moiety preferably denotes a C.sub.1-6-alkanol, a
phenyl-C.sub.1-3-alkanol, a C.sub.3-9-cycloalkanol, while a
C.sub.5-8-cycloalkanol may additionally be substituted by one or
two C.sub.1-3-alkyl groups, a C.sub.5-8-cycloalkanol, wherein a
methylene group is replaced in the 3 or 4 position by an oxygen
atom or by an imino group optionally substituted by a
C.sub.1-3-alkyl, phenyl-C.sub.1-3-alkyl,
phenyl-C.sub.1-3-alkoxy-carbonyl or C.sub.1-6-alkyl-carbonyl group
and the cycloalkanol moiety may additionally be substituted by one
or two C.sub.1-3-alkyl groups, a C.sub.4-7-cycloalkenol, a
C.sub.3-5-alkenol, a phenyl-C.sub.3-5-alkenol, a C.sub.3-5-alkynol
or phenyl-C.sub.3-5-alkynol, with the proviso that no bond to the
oxygen atom starts from a carbon atom which carries a double or
triple bond, a C.sub.3-8-cycloalkyl-C.sub.1-3-alkanol, a
bicycloalkanol with a total of 8 to 10 carbon atoms which may
additionally be substituted in the bicycloalkyl moiety by one or
two C.sub.1-3-alkyl groups, a 1,3-dihydro-3-oxo-1-isobenzofuranol
or an alcohol of formula R.sub.a--CO--O--(R.sub.bCR.sub.c)--OH,
[0029] wherein [0030] R.sub.a denotes a C.sub.1-8-alkyl,
C.sub.5-7-cycloalkyl, phenyl or phenyl-C.sub.1-3-alkyl group,
[0031] R.sub.b denotes a hydrogen atom, a C.sub.1-3-alkyl,
C.sub.5-7-cycloalkyl or phenyl group and [0032] R.sub.c denotes a
hydrogen atom or a C.sub.1-3-alkyl group, and by a group which may
be cleaved in vivo from an amino group or from the N-1 atom of the
indolinone moiety is meant for example a hydroxy group, an acyl
group such as the benzoyl or pyridinoyl group or a
C.sub.1-16-alkyl-carbonyl group such as the formyl, acetyl,
propionyl, butanoyl, pentanoyl or hexanoyl group, an
allyloxycarbonyl group, a C.sub.1-16-alkoxy-carbonyl group such as
the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
isopropoxycarbonyl, butoxycarbonyl, tert.butoxycarbonyl,
pentoxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl,
nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl,
dodecyloxycarbonyl or hexadecyloxycarbonyl group, a
phenyl-C.sub.1-6-alkoxy-carbonyl group such as the
benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonyl
group, a C.sub.1-3-alkylsulphonyl-C.sub.1-4-alkoxy-carbonyl,
C.sub.1-3-alkoxy-C.sub.2-4-alkoxy-C.sub.2-4-alkoxy-carbonyl or
R.sub.aCO--O--(R.sub.bCR.sub.c)--O--CO-group wherein [0033] R.sub.a
denotes a C.sub.1-8-alkyl, C.sub.5-7-cycloalkyl, phenyl or
phenyl-C.sub.1-3-alkyl group, [0034] R.sub.b denotes a hydrogen
atom, a C.sub.1-3-alkyl, C.sub.5-7-cycloalkyl or phenyl group and
[0035] R.sub.c denotes a hydrogen atom, a C.sub.1-3-alkyl or
R.sub.aCO--O--(R.sub.bCR.sub.c)--O-group wherein R.sub.a to R.sub.c
are as hereinbefore defined, and additionally the phthalimido
group, while the abovementioned ester groups may also be used as a
group which can be converted in vivo into a carboxy group.
[0036] Preferred prodrug groups for a carboxy group include a
C.sub.1-6-alkoxy-carbonyl group such as the methoxycarbonyl,
ethoxycarbonyl, n-propyloycarbonyl, isopropyloxycarbonyl,
n-butyloxy-carbonyl, n-pentyloxycarbonyl, n-hexyloxycarbonyl or
cyclohexyloxycarbonyl group or phenyl-C.sub.1-3-alkoxy-carbonyl
group such as the benzyloxycarbonyl group and
[0037] for an amino group or the N-1 group of the indolinone moiety
a C.sub.1-9-alkoxy-carbonyl group such as the methoxycarbonyl,
ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl,
n-butyloxycarbonyl, n-pentyloxycarbonyl, n-hexyloxycarbonyl,
cyclohexyloxycarbonyl, n-heptyloxycarbonyl, n-octyloxycarbonyl or
n-nonyloxycarbonyl group, a phenyl-C.sub.1-3-alkoxy-carbonyl group
such as the benzyloxycarbonyl group, a phenylcarbonyl group
optionally substituted by a C.sub.1-3-alkyl group such as the
benzoyl or 4-ethyl-benzoyl group, a pyridinoyl group such as the
nicotinoyl group, a
C.sub.1-3-alkylsulphonyl-n-C.sub.2-3-alkoxy-carbonyl or
C.sub.1-3-alkoxy-C.sub.2-3-alkoxy-C.sub.1-4-alkoxy-carbonyl group
such as the 2-methylsulphonylethoxycarbonyl or
2-(2-ethoxy)-ethoxycarbonyl group.
[0038] Moreover, the saturated alkyl and alkoxy moieties containing
more than 2 carbon atoms mentioned in the definitions above as well
as the alkanoyl and unsaturated alkyl moieties which contain more
than 3 carbon atoms also include the branched isomers thereof such
as the isopropyl, tert.butyl, isobutyl group, etc.
[0039] For the chemical synthesis of the above-mentioned
metabolites and prodrugs, reference is made to WO 01/27081.
[0040] Experimental studies have shown that a metabolite of the
compound
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulph-
onate is the de-esterified
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-carbonyl)-N-methyl-amino)-anilino-
)-1-phenyl-methylene]-6-carboxy-2-indolinone. The in-vitro
inhibitory activity of this metabolite on several kinases has been
evaluated, using standard known kinase inhibition assays as well as
a standard known cellular proliferation inhibition assay
(inhibition of the proliferation of Human Umbilical Cord
Endothelial Cells stimulated by the VEGF, the so-called "HUVEC
cellular assay"). These experimental results have shown that this
metabolite inhibits several kinases, such as VEGFR-2, VEGFR-3,
Her-2, FGFR-1, PDGFR-alpha or InsR, as well as the proliferation of
HUVEC VEGF stimulated cells.
[0041] Furthermore, the compounds in accordance with the present
invention may be administered to a patient in need thereof in any
type of galenical form such as tablets, capsules or in a liquid
formulation.
[0042] An especially suitable pharmaceutical formulation for the
compounds in accordance with the present invention is soft gelatine
capsules. Suitable soft gelatine capsules for the encapsulation of
pharmaceutical compounds and the process for their preparation are
described, for example, in GB patent No. 395546, U.S. Pat. No.
2,720,463, U.S. Pat. No. 2,870,062, U.S. Pat. No. 4,829,057, and in
the following publications: ANON (Verpack-Rundsch., Vol. 21, No. 1,
January 1970, pp. 136-138), Lachman et al. (The Theory and Practice
of Industrial Pharmacy, Chap. 13, published by Lea & Febiger,
1970), Ebert (Soft Gelatine Capsules: A Unique Dosage Form, reprint
from Pharmaceutical Technology, October 1977) and R. F. Jimerson
(Soft Gelatine Capsule Update, Drug Development and Industrial
Pharmacy, Vol. 12 (8 & 9), pp. 1133-1144, 1986).
EXPERIMENTAL SECTION
[0043] The HPLC data given below were measured using the parameters
listed hereinafter:
[0044] Column: Inertsil ODS-2, 5 .mu.m, 53.times.4.0 mm; solvent A:
0.2% aqueous KH.sub.2PO.sub.4 solution, adjusted to pH=6.0 with
dilute sodium hydroxide solution; solvent B: acetonitrile; column
temperature: 45.degree. C.; flow: 1 mL/min; gradient system: within
5 minutes, from 5% to 30% solvent B, then maintained for 1 minute
at 30% solvent B and then within 9 minutes increased to 55% solvent
B, then maintained for 4 minutes at 55% B; concentration of the
sample solution: 5 mg/mL in acetonitrile/water=3:7; injection
volume: 3 .mu.L; detection at 225 nm and 210 nm, respectively.
Example 1
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-an-
ilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone
[0045] 10.5 g (30.0 mmol) of
1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone
(for preparation see WO 01/27081 mentioned above) and 8.60 g (33.0
mmol)
N-[(4-methyl-piperazin-1-yl)-methylcarbonyl]-N-methyl-p-phenylenediamine
(for preparation see WO 01/27081 mentioned above) are dissolved in
80 mL of dimethylformamide and stirred for 1 hour at 80.degree. C.
After cooling 6.50 mL of piperidine are added and the mixture is
stirred for another two hours at ambient temperature. Water is
added, the precipitate formed is suction filtered and washed with a
little water. The residue is suspended in 200 mL of methanol,
suction filtered and washed with cold water and diethyl ether. The
substance is dried in vacuo at 110.degree. C.
[0046] Yield: 12.4 g (77% of theory),
[0047] IR spectrum: 1610, 1655, 1711 cm.sup.-1
[0048] T.sub.m.p.=253.degree. C.
[0049] Empirical formula: C.sub.31H.sub.33N.sub.5O.sub.4
[0050] ESI mass spectrum: m/z=540 [M+H].sup.+
[0051] Elemental analysis: calculated: C, 68.99; H, 6.16; N, 12.98.
found: C, 68.32; H, 6.29; N, 12.85.
Example 2
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-an-
ilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulpho-
nate
[0052] 605 g (1.12 mol) of
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone are
suspended in 9 litres of methanol and heated to 50.degree. C. 183.7
g (1.121 mol) of 70% aqueous ethanesulphonic acid are added. The
solution obtained is cooled to 40.degree. C. and 4.5 litres of
tert.-butylmethylether are added. After a few minutes
crystallisation sets in. To achieve total precipitation the mixture
is stirred for another 16 hours at ambient temperature. After
cooling to 10.degree. C. it is suction filtered, washed with 2
litres of tert.-butylmethylether and dried at 40.degree. C. in
vacuo.
[0053] Yield: 638 g (87.6% of theory)
[0054] T.sub.m.p.=305.+-.5.degree. C. (DSC 10K/min)
[0055] Purity according to HPLC: 99.4%
[0056] Water content: 1.0 to 2.0% (KF)
BRIEF DESCRIPTION OF THE FIGURES
[0057] FIG. 1 shows the X-ray powder diffractogram of crystalline
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulph-
onate.
[0058] FIG. 2 shows the thermoanalysis and determination of the
melting point (DSC) of crystalline
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulph-
onate.
* * * * *