HK1078851B - 2-indolinone-monoethanesulphonate and the use thereof in preparing a pharmaceutical composition - Google Patents

Description

2-indolinone-monoethanesulfonate and application thereof in preparing pharmaceutical composition

Technical Field

The present invention relates to the compound 3-Z- [1- (4- (N- ((4-methyl-piperazin-1-yl) -methylcarbonyl) -N-methyl-amino) -phenylamino) -1-phenyl-methylene ] -6-methoxycarbonyl-2-indolinone-monoethanesulfonate salt of formula I and its use as a pharmaceutical composition

Formula I:

background

Many 2-indolinone derivatives are known in the prior art. Thus, for example, international patent application WO 01/27081 discloses 2-indolinone derivatives having valuable pharmacological properties.

Like the 2-indolinone derivatives mentioned in the prior art, the compounds of formula I are particularly inhibitory against various kinases, in particular against receptor tyrosine kinases such as VEGFR1, VEGFR2, VEGFR3, PDGFR α, PDGFR β, FGFR1, FGFR3, EGFR, HER2, c-Kit, IGF1R, Flt-3 and HGFR, and also against the proliferation of cultured human cells, in particular endothelial cells, such as in angiogenesis, and also against the proliferation of other cells, in particular tumour cells.

The pharmacologically valuable properties of the indolinone derivatives disclosed in the prior art and described above constitute essential prerequisites for the effective use of the compounds as pharmaceutical compositions. The active substance must in any case meet additional requirements in order to be accepted for pharmaceutical use. These parameters are mostly related to the physicochemical properties of the active substance.

Without limitation, examples of such parameters are the stability of the starting material to function under various environmental conditions, the stability in the manufacture of pharmaceutical formulations, and the stability in the final composition of the drug. Therefore, the pharmaceutically active substance used for preparing the pharmaceutical composition should have great stability, ensuring stability even under various environmental conditions. This is absolutely necessary in order to avoid the use of pharmaceutical compositions which, in addition to the active substance itself, contain breakdown products. In this case, the content of active substance present in the pharmaceutical preparation may be lower than indicated.

As a result of the increased weight caused by water absorption, water absorption reduces the content of the pharmaceutically active substance. Pharmaceutical compositions which tend to absorb water must be protected from moisture during storage, for example by the addition of suitable desiccants or by storage of the drug in a water-resistant environment. Furthermore, if the drug substance is exposed to an environment that is not in any way water-resistant, the water absorbed during manufacture may reduce the content of the pharmaceutically active substance. Preferably, the pharmaceutically active substance should be only slightly water-absorbent.

Since the crystal modifications of the active substance are important for reproducible active substance contents of the formulation, any existing polymorphic forms of the active substance in crystalline form need to be defined as far as possible. If the active substance has different polymorphic forms, care must be taken to ensure that the crystal modifications of the substance do not change later in the pharmaceutical formulation from which it is made. Otherwise, it may have a detrimental effect on the degree of reproducibility of the drug. Against this background, the preferred active material is characterized by only slight polymorphism.

An additional indicator that may be of exceptional importance in certain situations depending on the choice of formulation or the choice of manufacturing process is the solubility of the active substance. For example, if a pharmaceutical liquid formulation is to be prepared (e.g. for infusion), the active substance must be sufficiently soluble in a physiologically acceptable solvent. It is also important that the orally administered pharmaceutically active substance should be sufficiently soluble.

The problem of the present invention is to provide a pharmaceutically active substance which not only has a high pharmacological efficacy profile, but also meets the above-mentioned physicochemical requirements as far as possible.

Disclosure of Invention

Surprisingly, it has been found that the above problems can be solved by the salt of formula I3-Z- [1- (4- (N- ((4-methyl-piperazin-1-yl) -methylcarbonyl) -N-methyl-amino) -phenylamino) -1-phenyl-methylene ] -6-methoxycarbonyl-2-indolinone-monoethanesulfonate.

The monoethanesulfonate salt according to the present invention is characterized by good crystallinity and low amorphization during grinding and pressing. Furthermore, they are non-hygroscopic and readily soluble in physiologically acceptable solvents.

The compound 3-Z- [1- (4- (N- ((4-methyl-piperazin-1-yl) -methylcarbonyl) -N-methyl-amino) -phenylamino) -1-phenyl-methylene according to the invention]Crystalline form of (E) -6-methoxycarbonyl-2-indolinone-monoethanesulfonate salt characterized by T_m.p.Melting point 305 + -5 deg.C (determined by DSC ═ differential scanning calorimetry; estimated from the maximum peak; heatingRate: 10 deg.c/min). The values shown are DSC 821 using a Messrs MettlerToledo^eAnd (4) measuring.

The first subject of the invention is therefore the salt 3-Z- [1- (4- (N- ((4-methyl-piperazin-1-yl) -methylcarbonyl) -N-methyl-amino) -phenylamino) -1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulfonate, preferably in crystalline form, characterised by T_m.p.Melting point 305 ± 5 ℃ (measured by DSC; calculated from the maximum peak; heating rate 10 ℃/min).

3-Z- [1- (4- (N- ((4-methyl-piperazin-1-yl) -methylcarbonyl) -N-methyl-amino) -phenylamino) -1-phenyl-methylene ] -6-methoxycarbonyl-2-indolinone-monoethanesulfonate salt according to the present invention was studied in more detail by x-ray powder diffraction method. The resulting graph is shown in FIG. 1.

Table 1 contains the data obtained in the analysis:

table 1: 3-Z- [1- (4- (N- ((4-methyl-piperazin-1-yl) -methylcarbonyl) -N-methyl-amino) -phenylamino) -1-phenyl-methylene]X-ray powder reflectance and intensity (normalized) of-6-methoxycarbonyl-2-indolinone-monoethanesulfonate

h	k	l	2Θ[°]	dhklValue [ Å]	Strength [% ]]
						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

In Table 1 above, "2 Θ [ °]"value represents the diffraction angle in terms of a meter, and" d_hkl[Å]The "value represents the specified distance in Å between the facets.

In the context of the present invention, the x-ray powder maps were recorded using a Bruker D8 Advanced-diffractometer equipped with a position-sensitive detector (OED) and a Cu anode as x-ray source (CuK)_αRadiation, λ 1.54056 Å, 40kV, 40 mA).

According to the data shown in table 1, the present invention relates to crystalline 3-Z- [1- (4- (N- ((4-methyl-piperazin-1-yl) -methylcarbonyl) -N-methyl-amino) -phenylamino) -1-phenyl-methylene ] -6-methoxycarbonyl-2-indolinone-monoethanesulfonate characterized by having the characteristic values d ═ 5.43 Å, 5.08 Å, 4.71 Å, 4.50 Å and 4.43 Å in x-ray powder diagram and an intensity of more than 40%.

Calculation of the x-ray powder data obtained gives the unit cell of the compound according to the invention, the crystallization diagram data of which are shown in table 2 below:

chemical formula (II)	C66H78N10O15S2
		Molecular weight	1315.52
Crystal system	Triclinic system
		a	16.332Å
b	19.199Å
		c	11.503Å
α	95.27°
		β	90.13°
γ	110.83°
		V	3354.4Å3

The cell is defined by its side lengths a, b and c, the relative angles α, β and γ of the cell sides to each other, and the cell volume V (see Table 2). Methods for recording and evaluating x-ray powder maps for determining the unit cell and its dimensions are known from the prior art and are believed to characterize the crystalline properties and structure of the product.

The present invention therefore also relates to crystalline 3-Z- [1- (4- (N- ((4-methyl-piperazin-1-yl) -methylcarbonyl) -N-methyl-amino) -phenylamino) -1-phenyl-methylene ] -6-methoxycarbonyl-2-indolinone-monoethanesulfonate according to the invention, characterized by a unit cell, as determined by x-ray powder diffractometry, having the following dimensions:

a＝16.332Å

b＝19.199Å

c＝11.503Å

α＝95.27°

β＝90.13°

γ＝110.83°

V＝3354.4ų

using single crystals, it is also possible to determine the space group of the compounds according to the invention. The corresponding data are shown in table 3 below:

structural analysis	Data from single crystals
		Space group	P1(#2)
Density (estimated)	2.605 g/cm3
		Cell content	2 molecules > 2 × EtSO of different conformation4＞1×H2O

The monoethanesulfonate salt of the compound 3-Z- [1- (4- (N- ((4-methyl-piperazin-1-yl) -methylcarbonyl) -N-methyl-amino) -phenylamino) -1-phenyl-methylene ] -6-methoxycarbonyl-2-indolinone according to the invention, is present as a hemihydrate under standard conditions whereby water escapes at a temperature of about 130 ℃. Fig. 2 shows a thermal analysis.

The invention also relates to metabolites of the compound 3-Z- [1- (4- (N- ((4-methyl-piperazin-1-yl) -methylcarbonyl) -N-methyl-amino) -phenylamino) -1-phenyl-methylene ] -6-methoxycarbonyl-2-indolinone-monoethanesulfonate salt of formula I, to prodrugs of this compound or of these metabolites obtained by chemical or non-chemical derivatization of one or more chemical groups of the whole molecule or of molecules, and to the use thereof in pharmaceutical compositions.

Thus, the metabolite of the compound 3-Z- [1- (4- (N- ((4-methyl-piperazin-1-yl) -methylcarbonyl) -N-methyl-amino) -phenylamino) -1-phenyl-methylene ] -6-methoxycarbonyl-2-indolinone-monoethanesulfonate can be obtained, for example, by de-esterification of the ester group on the molecule. This de-esterification can occur in vivo by the action of specific or non-specific esterases present in the patient to whom the drug is administered.

The prodrug of the compound 3-Z- [1- (4- (N- ((4-methyl-piperazin-1-yl) -methylcarbonyl) -N-methyl-amino) -phenylamino) -1-phenyl-methylene ] -6-methoxycarbonyl-2-indolinone-monoethanesulfonate or a metabolite thereof can be obtained, for example, by any chemical substitution of a carboxyl group or an amino group present on the molecule, or by substituting the N-1-atom of the indolinone moiety with a group that can be dissociated in vivo.

Groups which are cleavable in vivo and are converted in vivo into carboxyl groups, meaning, for example, hydroxymethyl groups, carboxyl groups esterified with alcohols, the alcohol moiety of which is preferably represented byShow C_1-6-alkanol, phenyl-C_1-3-alkanol, C_3-9-cycloalkanol, and C_5-8The cycloalkanol may additionally be substituted by 1 or 2C_1-3-alkyl substituted, C_5-8Cycloalkanols in which the methylene group in the 3 or 4 position may be replaced by an oxygen atom or an imino group, which may optionally be substituted by C_1-3Alkyl, phenyl-C_1-3Alkyl, phenyl-C_1-3-alkoxy-carbonyl or C_1-6-alkyl-carbonyl, and the cycloalkanol moiety may additionally be substituted by 1 or 2C_1-3Substituted by alkyl radicals, C_4-7-Cycloalkenol, C_3-5Enol, phenyl-C_3-5Enol, C_3-5-alkynols or phenyl-C_3-5Alkynols, with the proviso that starting from a carbon atom with a double or triple bond to an oxygen atom there is no bond, C_3-8-cycloalkyl-C_1-3Alkanols, bicyclic alkanols having a total of from 8 to 10 carbon atoms, which may additionally be interrupted by 1 or 2C atoms in the bicycloalkyl moiety_1-3-alkyl-substituted, 1, 3-dihydro-3-oxo-1-isobenzofuranol or an alcohol of formula

R_a-CO-O-(R_bCR_c)-OH，

Wherein

R_aIs represented by C_1-8-alkyl radical, C_5-7-cycloalkyl, phenyl or phenyl-C_1-3-an alkyl group,

R_brepresents a hydrogen atom, C_1-3-alkyl radical, C_5-7-cycloalkyl or phenyl and

R_crepresents a hydrogen atom or C_1-3-an alkyl group,

and groups which are cleavable in vivo from the amino group or from the N-1 atom of the indolinone moiety are intended to mean, for example, a hydroxyl group, an acyl group such as a benzoyl or pyridinoyl group, or C_1-16Alkyl-carbonyl, such as formyl, acetyl, propionyl, butyryl, pentanoyl or hexanoyl, alkoxycarbonyl, C_1-16Alkoxy-carbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonylPhenyl, pentyloxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl or hexadecyloxycarbonyl, phenyl-C_1-6Alkoxycarbonyl, such as benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonyl, C_1-3-alkylsulfonyl-C_1-4-alkoxycarbonyl, C_1-3-alkoxy-C_2-4-alkoxy-C_2-4-alkoxy-carbonyl or R_aCO-O-(R_bCR_c) -O-CO-group, wherein

R_aIs represented by C_1-8-alkyl radical, C_5-7-cycloalkyl, phenyl or phenyl-C_1-3-an alkyl group,

R_brepresents a hydrogen atom, C_1-3-alkyl radical, C_5-7-cycloalkyl or phenyl, and

R_crepresents a hydrogen atom, C_1-3-alkyl or R_aCO-O-(R_bCR_c) -O-radical, wherein R_aTo R_cAs defined above, in the above-mentioned manner,

and, in addition, a phthalimido group, and the above-mentioned ester group may also be used as a group which may be converted into a carboxyl group in vivo.

Preferred prodrug groups for carboxyl groups include C_1-6Alkoxy-carbonyl, such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, n-pentyloxycarbonyl, n-hexyloxycarbonyl or cyclohexyloxycarbonyl or phenyl-C_1-3Alkoxy-carbonyl, such as benzyloxycarbonyl, and

prodrug groups to the N-1 group of amino or indolinone moieties, including C_1-9Alkoxy-carbonyl, such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, n-pentyloxycarbonyl, n-hexyloxycarbonyl, cyclohexyloxycarbonyl, n-heptyloxycarbonyl, n-octyloxycarbonyl or n-nonyloxycarbonyl, phenyl-C_1-3Alkoxy-carbonyl, e.g. benzyloxycarbonyl, phenylcarbonyl optionally substituted by C_1-3Alkyl substituted, e.g. benzoyl or 4-ethyl-benzoyl, pyridinoyl, e.g. nicotinoyl, C_1-3-alkylsulfonyl-n-C_2-3-alkoxy-carbonyl or C_1-3-alkoxy-C_2-3-alkoxy-C_1-4Alkoxy-carbonyl, such as 2-methylsulfonylethoxycarbonyl or 2- (2-ethoxy) -ethoxycarbonyl.

In addition, the saturated alkyl and alkoxy moieties containing 2 or more carbon atoms, and the alkanoyl and unsaturated alkyl moieties containing 3 or more carbon atoms referred to in the above definitions also include branched isomers thereof, such as isopropyl, tert-butyl, isobutyl, and the like.

Chemical synthesis of the above metabolites and prodrugs can be found in WO 01/27081.

Experimental studies have shown that the metabolite of the compound 3-Z- [1- (4- (N- ((4-methyl-piperazin-1-yl) -methylcarbonyl) -N-methyl-amino) -phenylamino) -1-phenyl-methylene ] -6-methoxycarbonyl-2-indolinone-monoethanesulfonate is de-esterified 3-Z- [1- (4- (N- ((4-methyl-piperazin-1-yl) -carbonyl) -N-methyl-amino) -phenylamino) -1-phenyl-methylene ] -6-carboxy-2-indolinone. The in vitro inhibitory activity of this metabolite against a variety of kinases has been evaluated using standard, known kinase inhibition assays, as well as standard, known cell proliferation inhibition assays (inhibition of human umbilical cord endothelial cell proliferation stimulated by VEGF, so-called "HUVEC cell assay"). These experimental results have shown that this metabolite inhibits the proliferation of many kinases, such as VEGFR-2, VEGFR-3, Her-2, FGER-1, PDGFR-alpha or InsR, and HUVEC VEGF stimulated cells.

Furthermore, the compounds according to the invention may also be administered to a patient in need thereof in any pharmaceutical dosage form, such as tablets, capsules or liquid preparations.

A particularly suitable pharmaceutical formulation for the compounds of the invention is a soft gelatin capsule. Suitable soft gelatin capsules for encapsulation of pharmaceutical compounds, and processes for their preparation are described, for example, in GB patent No.395546, US patent No.2,720,463, US patent No.2,870,062, US patent No.4,829,057, and the following publications: ANON (Verpack-Rundsch., Vol.21, No.1, Jan 1970, pp.136-138), Lachman et al (The Theory and Practice of Industrial Pharmacy, Chapter 13, published by Lea & Febiger, 1970), Ebert (Soft gelatin Capsules: A Unique document Form, print from Pharmaceutical Technology, Oct.1977) and R.F.Jimers (Soft gelatin Capsule, Drug Development and Industrial Pharmacy, Vol.12(8& 9), pp.1133-1144, 1986).

Experimental part

The HPLC data given below were measured using the parameters listed below: column: inertsil ODS-2, 5 μm, 53X 4.0 mm; solvent A: 0.2% KH₂PO₄Adjusting the pH of the aqueous solution to 6.0 by using dilute sodium hydroxide solution; solvent B: acetonitrile, column temperature: 45 ℃; flow rate: 1 ml/min; gradient system: from 5% to 30% solvent B over 5 minutes, then held at 30% solvent B for 1 minute, and then increased to 55% solvent B over 9 minutes, and then held at 55% B for 4 minutes; concentration of sample solution: 5 mg/ml in acetonitrile/water 3: 7; injection volume: 3 microliter; detection was carried out at 225 nm and 210 nm, respectively.

Example 1

3-Z- [1- (4- (N- ((4-methyl-piperazin-1-yl) -methylcarbonyl) -N-methyl-amino) -phenylamino) -1-phenyl-methylene ] -6-methoxycarbonyl-2-indolinone

10.5 g (30.0 mmol) of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone (preparation see WO 01/27081 above) and 8.60 g (33.0 mmol) of N- [ (4-methyl-piperazin-1-yl) -methylcarbonyl ] -N-methyl-p-phenylenediamine (preparation see WO 01/27081 above) were dissolved in 80 ml of dimethylformamide and stirred at 80 ℃ for 1 hour. After cooling, 6.50 ml of piperidine were added and the mixture was stirred at room temperature for a further 2 hours. Water was added and the precipitate formed was filtered off with suction and washed with a little water. The residue is resuspended in 200 ml of methanol, filtered off with suction and washed with cold water and diethyl ether. The material was dried under vacuum at 110 ℃.

Yield: 12.4 g (77% of theory)

IR spectrum: 1610, 1655, 1711 cm^-1

T_m.p.＝253℃

Empirical formula: c₃₁H₃₃N₅O₄

ESI Mass Spectrometry: m/z 540[ M + H ] +

Elemental analysis: calculated values: C68.99H 6.16N 12.98

Measured value: C68.32H 6.29N 12.85

Example 2

3-Z- [1- (4- (N- ((4-methyl-piperazin-1-yl) -methylcarbonyl) -N-methyl-amino) -phenylamino) -1-phenyl-methylene ] -6-methoxycarbonyl-2-indolinone-monoethanesulfonate

605 g (1.12 mol) 3-Z- [1- (4- (N- ((4-methyl-piperazin-1-yl) -methylcarbonyl) -N-methyl-amino) -phenylamino) -1-phenyl-methylene ] -6-methoxycarbonyl-2-indolinone are suspended in 9 l of methanol and heated to 50 ℃. 183.7 g (1.121 mol) of 70% aqueous ethanesulfonic acid solution were added. The resulting solution was cooled to 40 ℃ and 4.5 l of t-butyl methyl ether was added. After a few minutes, it crystallizes out. To achieve complete precipitation, the mixture was stirred at room temperature for a further 16 hours. After cooling to 10 ℃ it is filtered off with suction, washed with 2 l of tert-butyl methyl ether and dried under vacuum at 40 ℃.

Yield: 638 g (87.6% of theory)

T_m.p.305 ± 5 ℃ (DSC 10K/min)

Purity by HPLC: 99.4 percent

Water content: 1.0 to 2.0% (KF)

Brief Description of Drawings

Figure 1 shows an X-ray powder diffraction pattern of crystalline 3-Z- [1- (4- (N- ((4-methyl-piperazin-1-yl) -methylcarbonyl) -N-methyl-amino) -phenylamino) -1-phenyl-methylene ] -6-methoxycarbonyl-2-indolinone-monoethanesulfonate salt.

FIG. 2 shows the thermal analysis and melting point Determination (DSC) of crystalline 3-Z- [1- (4- (N- ((4-methyl-piperazin-1-yl) -methylcarbonyl) -N-methyl-amino) -phenylamino) -1-phenyl-methylene ] -6-methoxycarbonyl-2-indolinone-monoethanesulfonate.

Claims (9)

1. 3-Z- [1- (4- (N- ((4-methyl-piperazin-1-yl) -methylcarbonyl) -N-methyl-amino) -phenylamino) -1-phenyl-methylene ] -6-methoxycarbonyl-2-indolinone-monoethanesulfonate.
2. 2. 3-Z- [1- (4- (N- ((4-methyl-piperazin-1-yl) -methylcarbonyl) -N-methyl-amino) -phenylamino) -1-phenyl-methylene ] -6-methoxycarbonyl-2-indolinone-monoethanesulfonate according to claim 1, characterized in that it is in the hemihydrate crystalline form and in that it is characterized in that it is in the form of a hemihydrate

   (1) Melting Point T_m.p.305 ± 5 ℃, determined by DSC; evaluating by using the maximum peak value; heating rate is 10 ℃/min;

   (2) x-ray powder diffractogram showing characteristic values d of 5.43 Å, 5.08 Å, 4.71 Å, 4.50 Å and 4.43 Å, and intensity of over 40%;

   (3) the unit cell has the following dimensions as determined by X-ray powder diffractometry:

   a＝16.332Å

   b＝19.199Å

   c＝11.503Å

   α＝95.27°

   β＝90.13°

   y is 110.83 °, and

   V＝3354.4ų。
3. 3. a pharmaceutical composition comprising the salt 3-Z- [1- (4- (N- ((4-methyl-piperazin-1-yl) -methyl-carbonyl) -N-methyl-amino) -phenylamino ] -1-phenyl-methylene ] -6-methoxycarbonyl-2-indolinone-monoethanesulfonic acid salt according to any one of claims 1 to 2, and optionally one or more inert carriers and/or diluents.
4. A metabolite of 3-Z- [1- (4- (N- ((4-methyl-piperazin-1-yl) -methylcarbonyl) -N-methyl-amino) -phenylamino ] -1-phenyl-methylene ] -6-methoxycarbonyl-2-indolinone-monoethanesulfonate characterized in that the metabolite is 3-Z- [1- (4- (N- ((4-methyl-piperazin-1-yl) -methylcarbonyl) -N-methyl-amino) -phenylamino ] -1-phenyl-methylene ] -6-carboxy-2-indolinone-monoethanesulfonate.
5. 5. A pharmaceutical composition comprising a metabolite according to claim 4, and optionally one or more inert carriers and/or diluents.
6. 6. Use of 3-Z- [1- (4- (N- ((4-methyl-piperazin-1-yl) -methylcarbonyl) -N-methyl-amino) -phenylamino ] -1-phenyl-methylene ] -6-methoxycarbonyl-2-indolinone-monoethanesulfonate according to any one of claims 1 to 2 for the preparation of a pharmaceutical composition suitable for the treatment of excessive or abnormal cell proliferation.
7. 7. Use of a metabolite according to claim 4 for the preparation of a pharmaceutical composition suitable for the treatment of excessive or abnormal cell proliferation.
8. 8. A process for the preparation of a pharmaceutical composition according to claim 3, characterized in that the salt 3-Z- [1- (4- (N- ((4-methyl-piperazin-1-yl) -methylcarbonyl) -N-methyl-amino) -phenylamino) -1-phenyl-methylene ] -6-methoxycarbonyl-2-indolinone-monoethanesulfonate salt according to any one of claims 1 to 2 is incorporated non-chemically into one or more inert carriers and/or diluents.
9. 9. A process for the preparation of a pharmaceutical composition according to claim 5, characterized in that the metabolite according to claim 4 is incorporated by non-chemical means into one or more inert carriers and/or diluents.