WO2003070725A2 - Process for preparing indolinone derivatives - Google Patents

Process for preparing indolinone derivatives Download PDF

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Publication number
WO2003070725A2
WO2003070725A2 PCT/US2003/004520 US0304520W WO03070725A2 WO 2003070725 A2 WO2003070725 A2 WO 2003070725A2 US 0304520 W US0304520 W US 0304520W WO 03070725 A2 WO03070725 A2 WO 03070725A2
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Prior art keywords
group
alkyl
hydrogen
process according
general formula
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PCT/US2003/004520
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French (fr)
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WO2003070725A3 (en
Inventor
Qingwu Jin
Michael A. Mauragis
Paul D. May
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Pharmacia & Upjohn Company
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Priority claimed from PCT/US2002/004407 external-priority patent/WO2002066463A1/en
Priority to CA002475455A priority Critical patent/CA2475455A1/en
Priority to MXPA04006992A priority patent/MXPA04006992A/en
Priority to AU2003216282A priority patent/AU2003216282A1/en
Priority to BR0307721-7A priority patent/BR0307721A/en
Priority to KR1020047012598A priority patent/KR100657110B1/en
Application filed by Pharmacia & Upjohn Company filed Critical Pharmacia & Upjohn Company
Priority to JP2003569632A priority patent/JP2005528344A/en
Priority to EP03742760A priority patent/EP1476443A2/en
Priority to YU70904A priority patent/RS70904A/en
Publication of WO2003070725A2 publication Critical patent/WO2003070725A2/en
Publication of WO2003070725A3 publication Critical patent/WO2003070725A3/en
Priority to HK05109991A priority patent/HK1078075A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention refers to a process for preparing indolinone derivatives and intermediates of that process.
  • indolinone derivatives have been found to exhibit pharmaceutical activity. Due to the ability to modulate the protein kinase activity, they have been suggested to treat an number of conditions such as various types of cancer, mastocytosis, allergy associated chronic rhinitis, diabetes, autoimmune disorders, restenosis, fibrosis, psoriasis, von Hippel-Lindau disease, osteoarthritis, rheumatoid arthritis, angiogensis, inflammatory disorders, immunological disorders, and cardiovascular disorders (WO 01/45689, WO 01/60814, WO 99/48868, US-A-6,316,429, US-A-6,316,635,6, 133,305, and US-A-6,248,771).
  • indolinone derivatives those having an amide group on a heterocyclic ring condensed with the indolinone have been of interest. These compounds modulate protein kinase activity and are thus useful in treating diseases relating to abnormal protein kinase activity.
  • a process for preparing the amide derivatives is disclosed in WO 01/60814. An appropriate pyrrole is formylated and subsequently condensed with a 2-indolinone to give a respective 5-(2-oxo-l,2-dihydroindole -3-ylidenemethyl) -lH-pyrrole. If an amide derivative of the pyrrole is desired, a pyrrole having a carboxylic acid group is selected.
  • the carboxylic acid group is reacted with the desired arriine in the presence of dimethyhbrmamide, l-ethyl-3-(3-dimethylamino- propyl)carbodiimide and 1-hydroxybenzotriazole.
  • dimethyhbrmamide dimethyhbrmamide
  • l-ethyl-3-(3-dimethylamino- propyl)carbodiimide and 1-hydroxybenzotriazole.
  • a scale-up procedure is disclosed in which the amidation is conducted in the presence of dimethytformamide, benzotriazole- 1 -yloxytris(dimethylamino)phos ⁇ honium hexafluorophosphate (BOP) and triethylamine.
  • the present invention provides a process for preparing an indolinone of the general formula (VI)
  • R 1 , R 2 , R 3 , R 4 are independently selected from the group consisting of hydrogen, C ⁇ _ 12 alkyl, C ⁇ _i2 alkoxy, C5-12 cycloalkyl, C ⁇ _i2 aryl, C5-.12 heterocyclic group containing 1 to 3 atoms selected fromN, S or O, provided that the heterocyclic group may be partially unsaturated, but not aromatic, C 6 _i2 aryloxy, C 6 -i2 alkaryl, C 6 -i2 alkaryloxy, halogen, trihalomethyl, hydroxy, -S(O)R', -SO 2 NR'R", -SO 3 R', -SR', -NO 2 , -NR'R", -OH, - CN, -C(O)R', -OC(O)R', -NHC(O)R', -(CH 2 ) n CO 2 R', and -CONR'R"; each R 5 is
  • R 9 is selected from the group consisting of-NR 10 R u , -OH, -C(O)R 12 , C 6 - 12 aryl, C 5 -n heterocyclic group containing 1 to 3 atoms selected fromN, S or O, -N ⁇ O ' jR 10 , and-
  • R 10 and R 11 are independently selected from the group consisting of hydrogen, C ⁇ _ 12 alkyl, C ⁇ _i2 cyanoalkyl, C5-12 cycloalkyl, C6- 12 aryl, and C5-12 heterocyclic group containing 1 to 3 atoms selected fromN, S or O; or R 10 and R n may be combined to form a five- or six-membered heterocyclic group optionally containing 1 to 3 atoms selected from N, O, or S in addition to the nitrogen atom to which R 10 and R 11 are bound, provided that the heterocyclic group formed by R 10 and R u may optionally be substituted by R'
  • R 12 is selected from the group consisting of hydrogen, -OH, C ⁇ _i 2 alkoxy and
  • R 13 is selected from the group consisting of C1-12 alkyl, C ⁇ _ ⁇ 2 haloalkyl, and C ⁇ - 12 aralkyl;
  • R' and R" are independently selected from the group consisting of hydrogen
  • halogen and “halo” refer to substituents selected from the group consisting of F, Cl, Br, and I J is selected from the group consisting of O, S, and NH; one of K, L and M is C and the group -C(O)R 6 is bound thereto, the others of the group of K, L and M are independently selected from the group consisting of CR 5 , n is 0, 1 or 2; mis 1, 2, 3, or 4; and p is 0, 1 or 2; comprising the steps of (i) reacting a compound of general formula (I)
  • one of X 1 and X 2 is chlorine, or bromine; and the other is selected from the group consisting of hydroxy, -O-C ⁇ _4 alkyl and -O-phenyl; and R is selected from the group consisting of-C(O)-C ⁇ _4 alkyl, -C(O)-O-(C M ) alkyl, -C(O)-O-phenyl, provided that the phenyl may optionally be substituted by 1 to 3 halogen atoms, -C(O)-O-CH 2 - phenyl., provided that the phenyl may optionally be substituted by 1 to 3 halogen atoms, or
  • X 1 is chlorine or bromine
  • X 2 is hydrogen
  • R is selected from the group consisting of
  • X is hydroxy, -O-C1- 4 alkyl and -O-phenyl, X is
  • R* is -O-R in case (a) of step (i) and -R in cases (b) and (c) of step (i); (ii) reacting the compound of general formula (III) with a compound of general formula (IN)
  • a further embodiment the present invention relates to a process for preparing a compound of the general formula (III)
  • R 5 , J, K, L, M, and p are as defined above; with a compound of general formula (II)
  • the present invention also refers to a process for preparing an indolinone of the general formula (VI)
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , J, K, L, M, and p are as defined above; comprising the steps of reacting a compound of the general formula (III)
  • R 5 , J, K, L, M, and p are as defined above; wherein R* is selected from the group consisting of-O-C(O)-C ⁇ _ 4 alkyl,
  • -O-C(O)-O-(C ⁇ _ 4 ) alkyl -O-C(O)-O-phenyl, provided that the phenyl may optionally be substituted by 1 to 3 halogen atoms, -O-C(O)-O-CH 2 -phenyl, provided that the phenyl may optionally be substituted by 1 to 3 halogen atoms,
  • R 1 , R 2 , R 3 , and R 4 are as defined above; and an amine of general formula (V)
  • R , J, K, L, M, and p are as defined above and R* is selected from the group consisting of-O-C(O)-C ⁇ - 4 alkyl, -O-C(O)-O-(C M ) alkyl,
  • -O-C(O)-O-phenyl provided that the phenyl may optionally be substituted by 1 to 3 halogen atoms, -O-C(O)-O-CH 2 -phenyl, provided that the phenyl may optionally be substituted by 1 to 3 halogen atoms,
  • R* is
  • the present invention provides a process for preparing indolinone derivatives of general formula (VI).
  • the compounds can modulate the activity of protein kinases and the compounds themselves, their pharmaceutically acceptable salts and derivatives are useful in a wide range of medical applications.
  • Preferred compounds having the formula (VI) pharmaceutical compositions containing such compounds and the medical utility of these compounds have been described, e.g. in WO 01/45689, WO 01/60814, WO 99/48868, US-A-6,316,429, US-A-6,316,635,6,133,305, and US-A-6,248,771, all of which are incorporated herein by reference in the entirety.
  • Particularly preferred compounds are described in WO 01/45689 (e.g. compounds 15 and 16) and WO 01/60814 (e.g. in the examples and in Table 1).
  • the indolinone compounds have the general formula (VI)
  • R 1 , R 2 , R 3 , R 4 are independently selected from the group consisting of hydrogen, C ⁇ _ ⁇ 2 alkyl, C ⁇ _ 12 alkoxy, C5-12 cycloalkyl, C ⁇ -n aryl, C5-12 heterocyclic group containing 1 to 3 atoms selected fromN, S or O, provided that the heterocyclic group may be partially unsaturated, but not aromatic, C ⁇ -n aryloxy, C6_i2 alkaryl, C ⁇ -n alkaryloxy, halogen, trihalomethyl, hydroxy, -S(O)R', -SO 2 NR'R", -SO 3 R ⁇ -SR', -NO 2 , -NR'R", -OH, - CN, -C(O)R', -OC(O)R', -NHC(O)R', -(CH2) n CO 2 R', and -CONR'R".
  • R 1 is hydrogen or alkyl; more preferably R 1 is hydrogen.
  • R 2 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, C1-4 alkyl, -O-C M alkyl, phenyl, -COOH, -CN, -C(O)CH 3 , -SO 2 NH 2 and- SO2N(CH 3 ) 2 ; more preferably R 2 is selected from the group consisting of hydrogen, fluorine, chlorine, C1- alkyl, -O-C1- alkyl, -CN, -SO 2 NH 2 and -SO 2 N(CH 3 ) 2 and even more preferably R 2 is hydrogen, fluorine, chlorine, and C 1 - alkyl. Most preferably R 2 is fluorine.
  • R 3 is selected from the group consisting of hydrogen, alkyl, phenyl, C ⁇ _ 4 alkoxy and -COOH; more preferably R 3 is hydrogen or C ⁇ - alkyl; most preferably R 3 is hydrogen.
  • R 4 is hydrogen
  • Each R 5 is independently selected from the group consisting of hydrogen, C ⁇ _ ⁇ 2 alkyl, C ⁇ _i2 alkoxy, C5-.12 cycloalkyl, C6-12 aryl, C5-12 heterocyclic group containing 1 to 3 atoms selected fromN, S or O, provided that the heterocyclic group may be partially unsaturated, but not aromatic, C ⁇ -i2 aryloxy, C ⁇ -n alkaryl, C ⁇ - alkaryloxy, halogen, trihalomethyl, hydroxy, -S(O)R', -SO 2 NR'R", -SO 3 R', -SR', -NO 2 , -NR'R", -OH, CN, -C(O)R', -OC(O)R', -NHC(O)R', -(CH 2 )nCO 2 R', and -CONR'R".
  • the heterocyclic group may be partially unsaturated, but not aromatic, C ⁇ -i2 aryl
  • R 5 is hydrogen or a alkyl.
  • R 6 is is selected from -NR 8 (CH ) m R 9 and-NR 10 R u , provided that optionally one to two of the CH 2 groups may be substituted by -OH or halogen.
  • R ⁇ is - NR 8 (CH2) m R 9 -
  • the CH 2 groups are unsubstituted or one of the CH 2 groups is substituted by -OH.
  • R 8 is hydrogen or C ⁇ _i2 alkyl.
  • R 8 is hydrogen or C 1 - alkyl, and more preferably R 8 is hydrogen.
  • R 9 is selected from the group consisting of-NR 10 R ⁇ , -OH, -C(O)R 12 , C 6 - ⁇ 2 aryl, C5- 12 heterocyclic group containing 1 to 3 atoms selected fromN, S or O, -N ⁇ O ⁇ R 10 , and -
  • R 9 is preferably -NR 10 R n In a second embodiment
  • R 9 is preferably a C5- 1 2 heterocyclic group containing 1 to 3 atoms selected fromN, S or O.
  • the heterocyclic group is a five- to seven-membered heterocyclic group bonded to the (CH 2 )ni group via a nitrogen atom and optionally containing a further heteroatom selected from N, O, and S. Examples of the heterocyclic group are, but are not limited to
  • heterocyclic group is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R r. 1 1 1 1 are independently selected from the group consisting of hydrogen, C ⁇ _ ⁇ 2 alkyl, C ⁇ _ ⁇ 2 cyanoalkyl, C5-12 cycloalkyl, C ⁇ -12 aryl, and Cs-n heterocyclic group containing 1 to 3 atoms selected fromN, S or O; or R 10 and R 11 may be combined to form a five- or six-membered heterocyclic group optionally containing 1 to 3 atoms selected fromN, O, or S in addition to the nitrogen atom to which R 10 and R 11 are bound, provided that the heterocyclic group formed by R 10 and R 11 may optionally be substituted by R'.
  • R 10 and R u are hydrogen or C1- 4 alkyl. More preferably R 10 and R 11 are H.
  • R 12 is selected from the group consisting of hydrogen, -OH, - E alkoxy and C6-12 aryloxy.
  • R 12 is a C1- alkyl.
  • R 13 is selected from the group consisting of C1-12 alkyl, C ⁇ _ 12 haloalkyl, and C ⁇ -n aralkyl.
  • R 13 is a C1- alkyl.
  • R' and R" are independently selected from the group consisting of hydrogen, C ⁇ _i2 alkyl, C ⁇ _ ⁇ 2 cyanoalkyl, C5-12 cycloalkyl, C ⁇ -i2 aryl, C5-12 heterocyclic group containing 1 to 3 atoms selected fromN, S or O, provided that the heterocyclic group may be partially unsaturated, but not aromatic, or in the group -NR'R" the R' and R" substituents may be combined to form a five- or six-membered heterocyclic group optionally containing 1 to 3 atoms selected fromN, O, or S in addition to the nitrogen atom to which R' and R" are bound.
  • R' and R" are independently a C 1 - 4 alkyl.
  • J is selected from the group consisting of O, S, and NH, preferably J is NH.
  • one of K, L and M is C and the group -C(O)R 6 is bound thereto, the others of the group of K, L and M are independently selected from the group consisting of CR 5 , CR 5 2, N, NR 5 , O and S.
  • Preferred heterocyclic groups
  • heterocyclic group is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • n 0, 1 or 2.
  • m is 1, 2, 3, or 4; preferably m is 2 or 3.
  • p is 0, 1 or 2. Preferred compounds are shown wherein X is a halogen
  • R* is -O-R in case (a) of step (1) and -R in cases (b) and (c) of first step.
  • option (c) is preferred.
  • the compounds of general formulae (I) and (II) are either commercially available or can be prepared by methods well known in the art.
  • heterocycles having a formyl group can be obtained by slowly adding POCl 3 to dimethylformamide followed by addition of the appropriate heterocycle, which is also dissolved in dimethytformamide. This reaction is described in more detail and exemplified e.g. in WO 01/60814, which is incorporated herein by reference.
  • the reaction is generally carried out in a polar aprotic solvent.
  • An aprotic solvent is any solvent that, under normal reaction conditions, does not donate a proton to a solute.
  • Polar solvents are those which have a non-uniform distribution of charge. Generally they include 1 to 3 atoms selected from heteroatom such as N, S or O.
  • polar aprotic solvents examples include ethers such as tetrahydrofuran, diethylether, methyl tert-butyl ether; nitrile solvents such as acetonitrile; and amide solvents such as dimethylfoirrjarnide.
  • the reaction solvent is an ether, more preferably the solvent is tetrahydrofuran. Mixtures of the solvents may also be employed.
  • the aprotic, polar solvent preferably has a boiling point from 30 °C to 130 °C, more preferably from 50 °C to 80 °C. Both components of the reaction are introduced into a reaction vessel together with the solvent.
  • the reactants may be added in any order, although it is preferred to add compound I to a stirred suspension of compound II in a suitable solvent, at room temperature (18 - 25 °C).
  • a reactant concentration of 0.3 to 0.5 moles / liter is preferred, although the person of skill in the art will appreciate that the reaction may be conducted at different concentrations.
  • the reaction may be conducted at a temperature of 0° C up to the reflux temperature of the solvent. However, it is preferred to conduct the reaction at a temperature of 25° C to 80° C with mechanical stirring.
  • the progress of the reaction may be monitored by a suitable analytical method, such as HPLC. Upon completion of the reaction the reaction mixture is cooled and the intermediate compound III crystallizes.
  • intermediate compound III may be separated from the reaction mixture by methods known to those skilled in the art, such as centrifuging, and filtration.
  • Intermediate III is a crystalline solid that is non- hygroscopic and is stable in air at room temperature.
  • R 6 is as defined above to form the indolinone of the general formula (VI).
  • the reaction can be carried out in solution, using the same solvents used in the first reaction step.
  • the reaction may be carried out sequentially by reacting compound III with either compound compound TV or compound V and then adding the other compound.
  • compounds II, IN and N are introduced into a reaction vessel together with the solvent.
  • the reactants may be added in any order, although it is preferred to add compound III to a stirred suspension of compound IV and the amine V in a suitable solvent, at room temperature (18 - 25 °C).
  • a reactant concentration of 0.3 to 0.5 moles / liter is preferred, although the person of skill in the art will appreciate that the reaction may be conducted at different concentrations.
  • the reaction may be conducted at a temperature of 50° C up to the reflux temperature of the solvent. However, it is preferred to conduct the reaction at a temperature of 50° C to 80° C with mechanical stirring. The progress of the reaction may be monitored by a suitable analytical method, such as HPLC. Upon completion of the reaction, the reaction mixture is cooled and compound VI crystallizes. It is preferred to cool the reaction mixture to a temperature below room temperature and 0° C is most preferred. Compound VI may be separated from the reaction mixture by methods known to those skilled in the art, such as centrifuging, and filtration. Although Compound VI obtained from the process above is often of sufficient purity for medical use, if desired, compound VI may be further purified by methods known to those skilled in the art, such as recrystallization.
  • indolinone compounds of general formula (VI) can be further reacted to their pharmaceutically acceptable salts or derivatives according to conventional processes.
  • the present invention provides a process for preparing indolinone derivatives, which is more convenient than the prior art processes. Generally the intermediates are easier to handle. Furthermore, product isolation is facilitated.
  • the following examples serve to illustrate the invention and should not be construed as limiting. Unless otherwise specified all percentages, parts, and amounts are based on weight.
  • Drying provided 3.7g (57.7%>) first crop of 5-[(Z)-(5-bromo-2-oxo-l,2-dihydro-3H-indol-3-ylidene)methyl]- N-[2-(diethylam o)ethyl]-2,4-dimethyl-lH-pyrrole-3-carboxamide.
  • the mother liquors are cooled to -10° C for 6h for an additional 1.9g (29.6%).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Indole Compounds (AREA)

Abstract

The present invention refers to a process for preparing indolinone derivatives of the general formula (VI) as defined in the specification and intermediates of that process.

Description

PROCESS FOR PREPARING INDOLINONE DERIVATIVES
FIELD OF THE INVENTION
The present invention refers to a process for preparing indolinone derivatives and intermediates of that process.
BACKGROUND OF THE INVENTION
A number of indolinone derivatives have been found to exhibit pharmaceutical activity. Due to the ability to modulate the protein kinase activity, they have been suggested to treat an number of conditions such as various types of cancer, mastocytosis, allergy associated chronic rhinitis, diabetes, autoimmune disorders, restenosis, fibrosis, psoriasis, von Hippel-Lindau disease, osteoarthritis, rheumatoid arthritis, angiogensis, inflammatory disorders, immunological disorders, and cardiovascular disorders (WO 01/45689, WO 01/60814, WO 99/48868, US-A-6,316,429, US-A-6,316,635,6, 133,305, and US-A-6,248,771).
Among the indolinone derivatives those having an amide group on a heterocyclic ring condensed with the indolinone have been of interest. These compounds modulate protein kinase activity and are thus useful in treating diseases relating to abnormal protein kinase activity. A process for preparing the amide derivatives is disclosed in WO 01/60814. An appropriate pyrrole is formylated and subsequently condensed with a 2-indolinone to give a respective 5-(2-oxo-l,2-dihydroindole -3-ylidenemethyl) -lH-pyrrole. If an amide derivative of the pyrrole is desired, a pyrrole having a carboxylic acid group is selected. The carboxylic acid group is reacted with the desired arriine in the presence of dimethyhbrmamide, l-ethyl-3-(3-dimethylamino- propyl)carbodiimide and 1-hydroxybenzotriazole. In example 129 a scale-up procedure is disclosed in which the amidation is conducted in the presence of dimethytformamide, benzotriazole- 1 -yloxytris(dimethylamino)phosρhonium hexafluorophosphate (BOP) and triethylamine.
It is an object of the present invention to provide an improved process for preparing indolinone derivatives which have an amide group on a heterocyclic ring condensed with the indolinone.
SUMMARY OF THE INVENTION
The present invention provides a process for preparing an indolinone of the general formula (VI)
Figure imgf000003_0001
wherein
R1, R2, R3, R4 are independently selected from the group consisting of hydrogen, Cι_12 alkyl, Cι_i2 alkoxy, C5-12 cycloalkyl, Cβ_i2 aryl, C5-.12 heterocyclic group containing 1 to 3 atoms selected fromN, S or O, provided that the heterocyclic group may be partially unsaturated, but not aromatic, C6_i2 aryloxy, C6-i2 alkaryl, C6-i2 alkaryloxy, halogen, trihalomethyl, hydroxy, -S(O)R', -SO2NR'R", -SO3R', -SR', -NO2, -NR'R", -OH, - CN, -C(O)R', -OC(O)R', -NHC(O)R', -(CH2)nCO2R', and -CONR'R"; each R5 is independently selected from the group consisting of hydrogen, Cι_ι2 alkyl, Cι_i2 alkoxy, C5-12 cycloalkyl, β-n aryl, C5--12 heterocyclic group containing 1 to 3 atoms selected from N, S or O, provided that the heterocyclic group may be partially unsaturated, but not aromatic, Cβ_i2 aryloxy, Cβ-12 alkaryl, Cβ-12 alkaryloxy, halogen, trihalomethyl, hydroxy, -S(O)R', -SO2NR'R", -SO3R', -SR', -NO2, -NR'R", -OH, - CN, -C(O)R', -OC(O)R', -NHC(O)R', -(CH2)nCO2R', and -CONR'R"; R6 is selected from -NR8(CH2)mR9 and -NR10RU, provided that optionally one to two of the CH2 groups may be substituted by -OH or halogen; R8 is hydrogen or Cι_ι2 alkyl;
R9 is selected from the group consisting of-NR10Ru, -OH, -C(O)R12, C6-12 aryl, C5-n heterocyclic group containing 1 to 3 atoms selected fromN, S or O, -N^O'jR10, and-
NHC(O)R13;
R10 and R11 are independently selected from the group consisting of hydrogen, Cι_12 alkyl, Cι_i2 cyanoalkyl, C5-12 cycloalkyl, C6-12 aryl, and C5-12 heterocyclic group containing 1 to 3 atoms selected fromN, S or O; or R10 and Rn may be combined to form a five- or six-membered heterocyclic group optionally containing 1 to 3 atoms selected from N, O, or S in addition to the nitrogen atom to which R10 and R11 are bound, provided that the heterocyclic group formed by R10 and Ru may optionally be substituted by R'
R12 is selected from the group consisting of hydrogen, -OH, Cι_i2 alkoxy and
C6-i2 aryloxy;
R13 is selected from the group consisting of C1-12 alkyl, Cι_ι2 haloalkyl, and Cβ-12 aralkyl;
R' and R" are independently selected from the group consisting of hydrogen,
Cι-12 alkyl, Cι_ι2 cyanoalkyl, s-n cycloalkyl, -n aryl, C5-12 heterocyclic group containing 1 to 3 atoms selected fromN, S or O, provided that the heterocyclic group may be partially unsaturated, but not aromatic, or in the group -NR'R"the R' and R" substituents may be combined to form a five- or six-membered heterocyclic group optionally containing 1 to 3 atoms selected fromN, O, or S in addition to the nitrogen atom to which R' and R" are bound;
The terms "halogen" and "halo" refer to substituents selected from the group consisting of F, Cl, Br, and I J is selected from the group consisting of O, S, and NH; one of K, L and M is C and the group -C(O)R6 is bound thereto, the others of the group of K, L and M are independently selected from the group consisting of CR5,
Figure imgf000004_0001
n is 0, 1 or 2; mis 1, 2, 3, or 4; and p is 0, 1 or 2; comprising the steps of (i) reacting a compound of general formula (I)
Figure imgf000005_0001
Formula I wherein R5, J, K, L, M and p are as defined above, Q is selected from the group consisting of
Figure imgf000005_0002
with a compound of general formula (II)
X2 R (II)
wherein: (a) one of X1 and X2 is chlorine, or bromine; and the other is selected from the group consisting of hydroxy, -O-Cι_4 alkyl and -O-phenyl; and R is selected from the group consisting of-C(O)-Cι_4 alkyl, -C(O)-O-(CM) alkyl, -C(O)-O-phenyl, provided that the phenyl may optionally be substituted by 1 to 3 halogen atoms, -C(O)-O-CH2- phenyl., provided that the phenyl may optionally be substituted by 1 to 3 halogen atoms, or
(b) X1 is chlorine or bromine, X2 is hydrogen and R is selected from the group consisting of
Figure imgf000005_0003
or (c) X is hydroxy, -O-C1-4 alkyl and -O-phenyl, X is
O
\=/
and R is
\=/
to form a compound of the general formula (III)
Figure imgf000006_0001
wherein R* is -O-R in case (a) of step (i) and -R in cases (b) and (c) of step (i); (ii) reacting the compound of general formula (III) with a compound of general formula (IN)
Figure imgf000006_0002
wherein R1, R2, R3, and R4 are as defined above, and an a ine of general formula (V)
HRϋ (V)
wherein R6 is as defined above, to form the indolinone of the general formula (VI). The dashed lines in the heterocyclic ring system mean that two double bonds are present but their position is not specified.
A further embodiment the present invention relates to a process for preparing a compound of the general formula (III)
Figure imgf000007_0001
wherein
R >5 , J, K, L, M, and p are as defined above; comprising the steps of
(i) reacting a compound of general formula (I)
Figure imgf000007_0002
R5, J, K, L, M, and p are as defined above; with a compound of general formula (II)
X2 R (II)
(a) wherein one of X1 and X2 is chlorine, or bromine; and the other is selected from the group consisting of hydroxy, -O-Cι_ alkyl and -O-phenyl; and R is selected from the group consisting of -C(O)-Cι_4 alkyl,
-C(O)-O-(Cι^)alkyL -C(O)-O-phenyl, -C(O)-O-CH2-phenyl, wherein the phenyl can optionally be substituted by 1 to 3 halogen atoms;
(b) wherein X1 is chlorine or bromine, X2 is hydrogen and R is selected from the group consisting of
Figure imgf000008_0001
or
(c) wherein X1 is hydroxy, -O-Cι_ alkyl and -O-phenyl, and X2 is
Figure imgf000008_0002
and R is
to form a compound of the general formula (III)
Figure imgf000008_0003
wherein R* is -O-R in case (a) of step (i) and -R in cases (b) and (c) of step (i). (ii) reacting the compound of general formula (III) with a compound of general formula (IV)
Figure imgf000009_0001
wherein R1, R2, R3, and R4 are as defined above, and an arnine of general formula (V)
HRd (V)
wherein R > 6 i •s as defined above, to form the indolinone of the general formula (VI).
The present invention also refers to a process for preparing an indolinone of the general formula (VI)
Figure imgf000009_0002
wherein
R1, R2, R3, R4, R5, R6, J, K, L, M, and p are as defined above; comprising the steps of reacting a compound of the general formula (III)
Figure imgf000010_0001
R5, J, K, L, M, and p are as defined above; wherein R* is selected from the group consisting of-O-C(O)-Cι_4 alkyl,
-O-C(O)-O-(Cι_4) alkyl, -O-C(O)-O-phenyl, provided that the phenyl may optionally be substituted by 1 to 3 halogen atoms, -O-C(O)-O-CH2-phenyl, provided that the phenyl may optionally be substituted by 1 to 3 halogen atoms,
Figure imgf000010_0002
with a compound of general formula (TV)
Figure imgf000010_0003
R1, R2, R3, and R4 are as defined above; and an amine of general formula (V)
HR6 (V)
wherein R6 is as defined above, to form the indolinone of the general formula (VI). In yet another embodiment compounds of the general formula (III):
Figure imgf000011_0001
wherein R , J, K, L, M, and p are as defined above and R* is selected from the group consisting of-O-C(O)-Cι-4 alkyl, -O-C(O)-O-(CM) alkyl,
-O-C(O)-O-phenyl, provided that the phenyl may optionally be substituted by 1 to 3 halogen atoms, -O-C(O)-O-CH2-phenyl, provided that the phenyl may optionally be substituted by 1 to 3 halogen atoms,
Figure imgf000011_0002
are disclosed. Preferably R* is
\=/
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for preparing indolinone derivatives of general formula (VI). The compounds can modulate the activity of protein kinases and the compounds themselves, their pharmaceutically acceptable salts and derivatives are useful in a wide range of medical applications. Preferred compounds having the formula (VI), pharmaceutical compositions containing such compounds and the medical utility of these compounds have been described, e.g. in WO 01/45689, WO 01/60814, WO 99/48868, US-A-6,316,429, US-A-6,316,635,6,133,305, and US-A-6,248,771, all of which are incorporated herein by reference in the entirety. Particularly preferred compounds are described in WO 01/45689 (e.g. compounds 15 and 16) and WO 01/60814 (e.g. in the examples and in Table 1). The indolinone compounds have the general formula (VI)
Figure imgf000012_0001
R1, R2, R3, R4 are independently selected from the group consisting of hydrogen, Cι_ι2 alkyl, Cι_12 alkoxy, C5-12 cycloalkyl, Cβ-n aryl, C5-12 heterocyclic group containing 1 to 3 atoms selected fromN, S or O, provided that the heterocyclic group may be partially unsaturated, but not aromatic, Cβ-n aryloxy, C6_i2 alkaryl, Cβ-n alkaryloxy, halogen, trihalomethyl, hydroxy, -S(O)R', -SO2NR'R", -SO3R\ -SR', -NO2, -NR'R", -OH, - CN, -C(O)R', -OC(O)R', -NHC(O)R', -(CH2)nCO2R', and -CONR'R". Preferably R1 is hydrogen or
Figure imgf000012_0002
alkyl; more preferably R1 is hydrogen. In a preferred embodiment R2 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, C1-4 alkyl, -O-CM alkyl, phenyl, -COOH, -CN, -C(O)CH3, -SO2NH2 and- SO2N(CH3)2; more preferably R2 is selected from the group consisting of hydrogen, fluorine, chlorine, C1- alkyl, -O-C1- alkyl, -CN, -SO2NH2 and -SO2N(CH3)2 and even more preferably R2 is hydrogen, fluorine, chlorine, and C1- alkyl. Most preferably R2 is fluorine.
In a preferred embodiment R3 is selected from the group consisting of hydrogen,
Figure imgf000012_0003
alkyl, phenyl, Cι_4 alkoxy and -COOH; more preferably R3 is hydrogen or Cχ- alkyl; most preferably R3 is hydrogen.
It is preferred that R4 is hydrogen.
Each R5 is independently selected from the group consisting of hydrogen, Cι_ι2 alkyl, Cι_i2 alkoxy, C5-.12 cycloalkyl, C6-12 aryl, C5-12 heterocyclic group containing 1 to 3 atoms selected fromN, S or O, provided that the heterocyclic group may be partially unsaturated, but not aromatic, Cβ-i2 aryloxy, Cβ-n alkaryl, Cβ- alkaryloxy, halogen, trihalomethyl, hydroxy, -S(O)R', -SO2NR'R", -SO3R', -SR', -NO2, -NR'R", -OH, CN, -C(O)R', -OC(O)R', -NHC(O)R', -(CH2)nCO2R', and -CONR'R". Preferably
R5 is hydrogen or a
Figure imgf000013_0001
alkyl.
R6 is is selected from -NR8(CH )mR9 and-NR10Ru, provided that optionally one to two of the CH2 groups may be substituted by -OH or halogen. Preferably Rδ is - NR8(CH2)mR9- In a preferred embodiment the CH2 groups are unsubstituted or one of the CH2 groups is substituted by -OH.
R8 is hydrogen or Cι_i2 alkyl. Preferably R8 is hydrogen or C1- alkyl, and more preferably R8 is hydrogen.
R9 is selected from the group consisting of-NR10Rπ, -OH, -C(O)R12, C6-ι2 aryl, C5-12 heterocyclic group containing 1 to 3 atoms selected fromN, S or O, -N^O^R10, and -
NHC(O)R13. In one embodiment R9 is preferably -NR10Rn In a second embodiment
R9 is preferably a C5-12 heterocyclic group containing 1 to 3 atoms selected fromN, S or O. Preferably the heterocyclic group is a five- to seven-membered heterocyclic group bonded to the (CH2)ni group via a nitrogen atom and optionally containing a further heteroatom selected from N, O, and S. Examples of the heterocyclic group are, but are not limited to
Figure imgf000013_0002
Figure imgf000013_0003
Preferably the heterocyclic group is
Figure imgf000013_0004
R > ιιυo a „n„dj R r.1111 are independently selected from the group consisting of hydrogen, Cι_ι2 alkyl, Cι_ι2 cyanoalkyl, C5-12 cycloalkyl, Cβ-12 aryl, and Cs-n heterocyclic group containing 1 to 3 atoms selected fromN, S or O; or R10 and R11 may be combined to form a five- or six-membered heterocyclic group optionally containing 1 to 3 atoms selected fromN, O, or S in addition to the nitrogen atom to which R10 and R11 are bound, provided that the heterocyclic group formed by R10 and R11 may optionally be substituted by R'. Preferably R10 and Ru are hydrogen or C1-4 alkyl. More preferably R10 and R11 are H.
R12 is selected from the group consisting of hydrogen, -OH, -E alkoxy and C6-12 aryloxy. Preferably R12 is a C1- alkyl. R13 is selected from the group consisting of C1-12 alkyl, Cι_12 haloalkyl, and Cβ-n aralkyl. Preferably R13 is a C1- alkyl.
R' and R" are independently selected from the group consisting of hydrogen, Cι_i2 alkyl, Cι_ι2 cyanoalkyl, C5-12 cycloalkyl, Cβ-i2 aryl, C5-12 heterocyclic group containing 1 to 3 atoms selected fromN, S or O, provided that the heterocyclic group may be partially unsaturated, but not aromatic, or in the group -NR'R" the R' and R" substituents may be combined to form a five- or six-membered heterocyclic group optionally containing 1 to 3 atoms selected fromN, O, or S in addition to the nitrogen atom to which R' and R" are bound. Preferably R' and R" are independently a C1-4 alkyl. J is selected from the group consisting of O, S, and NH, preferably J is NH. one of K, L and M is C and the group -C(O)R6 is bound thereto, the others of the group of K, L and M are independently selected from the group consisting of CR5, CR52, N, NR5, O and S. Preferred heterocyclic groups
Figure imgf000014_0001
are
Figure imgf000015_0001
Particularly preferred as the heterocyclic group is
Figure imgf000015_0002
n is 0, 1 or 2. m is 1, 2, 3, or 4; preferably m is 2 or 3. p is 0, 1 or 2. Preferred compounds are shown wherein X is a halogen
Figure imgf000016_0001
15
Figure imgf000017_0001
and
Figure imgf000017_0002
In the first step of the process of the present invention, a compound of general formula (I)
Figure imgf000018_0001
wherein R5, R6, J, K, L, M and p are as defined above, is reacted with a compound of general formula (II)
X'- -R (II)
(a) wherein one of X1 and X2 is chlorine, or bromine; and the other is selected from the group consisting of hydroxy, -O-C1- alkyl and -O-phenyl; and R is selected from the group consisting of-C(O)-Cι_ alkyl,
-C(O)-O-(Cι^ι.) alkyl, -C(O)-O-phenyl, provided that the phenyl may optionally be substituted by 1 to 3 halogen atoms, -C(O)-O-CH2-phenyl, provided that the phenyl may optionally be substituted by 1 to 3 halogen atoms,
(b) wherein X1 is chlorine or bromine, X2 is hydrogen and R is selected from the group consisting of
Figure imgf000018_0002
or
(c) wherein X1 is hydroxy, -O-C1- alkyl and -O-phenyl, and X2 is
Figure imgf000018_0003
and R is \=/
to form a compound of the general formula (III)
Figure imgf000019_0001
wherein R* is -O-R in case (a) of step (1) and -R in cases (b) and (c) of first step. In first step, option (c) is preferred.
The compounds of general formulae (I) and (II) are either commercially available or can be prepared by methods well known in the art. For example, heterocycles having a formyl group can be obtained by slowly adding POCl3 to dimethylformamide followed by addition of the appropriate heterocycle, which is also dissolved in dimethytformamide. This reaction is described in more detail and exemplified e.g. in WO 01/60814, which is incorporated herein by reference.
The reaction is generally carried out in a polar aprotic solvent. An aprotic solvent is any solvent that, under normal reaction conditions, does not donate a proton to a solute. Polar solvents are those which have a non-uniform distribution of charge. Generally they include 1 to 3 atoms selected from heteroatom such as N, S or O.
Examples of polar aprotic solvents that can be used in the invention are ethers such as tetrahydrofuran, diethylether, methyl tert-butyl ether; nitrile solvents such as acetonitrile; and amide solvents such as dimethylfoirrjarnide. Preferably the reaction solvent is an ether, more preferably the solvent is tetrahydrofuran. Mixtures of the solvents may also be employed. The aprotic, polar solvent preferably has a boiling point from 30 °C to 130 °C, more preferably from 50 °C to 80 °C. Both components of the reaction are introduced into a reaction vessel together with the solvent. The reactants may be added in any order, although it is preferred to add compound I to a stirred suspension of compound II in a suitable solvent, at room temperature (18 - 25 °C). A reactant concentration of 0.3 to 0.5 moles / liter is preferred, although the person of skill in the art will appreciate that the reaction may be conducted at different concentrations. The reaction may be conducted at a temperature of 0° C up to the reflux temperature of the solvent. However, it is preferred to conduct the reaction at a temperature of 25° C to 80° C with mechanical stirring. The progress of the reaction may be monitored by a suitable analytical method, such as HPLC. Upon completion of the reaction the reaction mixture is cooled and the intermediate compound III crystallizes. It is preferred to cool the reaction mixture to a temperature below room temperature and 0° C is most preferred. The intermediate compound III may be separated from the reaction mixture by methods known to those skilled in the art, such as centrifuging, and filtration. Intermediate III is a crystalline solid that is non- hygroscopic and is stable in air at room temperature.
The compound of general formula (III) is then reacted in a second step with a compound of general formula (IV)
Figure imgf000020_0001
wherein R1, R2, R3 R4 are as defined above and an amine of general formula (N)
HR6 (V)
wherein R6 is as defined above to form the indolinone of the general formula (VI). The reaction can be carried out in solution, using the same solvents used in the first reaction step. The reaction may be carried out sequentially by reacting compound III with either compound compound TV or compound V and then adding the other compound. However, it is preferred that compounds II, IN and N are introduced into a reaction vessel together with the solvent. The reactants may be added in any order, although it is preferred to add compound III to a stirred suspension of compound IV and the amine V in a suitable solvent, at room temperature (18 - 25 °C). A reactant concentration of 0.3 to 0.5 moles / liter is preferred, although the person of skill in the art will appreciate that the reaction may be conducted at different concentrations. The reaction may be conducted at a temperature of 50° C up to the reflux temperature of the solvent. However, it is preferred to conduct the reaction at a temperature of 50° C to 80° C with mechanical stirring. The progress of the reaction may be monitored by a suitable analytical method, such as HPLC. Upon completion of the reaction, the reaction mixture is cooled and compound VI crystallizes. It is preferred to cool the reaction mixture to a temperature below room temperature and 0° C is most preferred. Compound VI may be separated from the reaction mixture by methods known to those skilled in the art, such as centrifuging, and filtration. Although Compound VI obtained from the process above is often of sufficient purity for medical use, if desired, compound VI may be further purified by methods known to those skilled in the art, such as recrystallization.
If desired the indolinone compounds of general formula (VI) can be further reacted to their pharmaceutically acceptable salts or derivatives according to conventional processes.
The present invention provides a process for preparing indolinone derivatives, which is more convenient than the prior art processes. Generally the intermediates are easier to handle. Furthermore, product isolation is facilitated. The following examples serve to illustrate the invention and should not be construed as limiting. Unless otherwise specified all percentages, parts, and amounts are based on weight.
EXAMPLES
Example 1 N-[2-(άϊethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-l,2-di ydro-3H-indol-3-
Figure imgf000022_0001
ylidene)met yl]-2,4-dln ethyl-lH-pyrrole-3-carboxamide
4-(lH-imidazol-l-ylcarbonyl)-3,5-dimethyl-lH-pyrrole-2-carbaldehyde (14.0 g), N,N- diethylethylenediamine (15.0 g), 5-fluorooxindole (9.86 g), triethylamine (27 ml), and acetonitrile (250 ml) were mixed and heated to 60° C. The black slurry was stirred for 18 h at 60° C (needs mechanical stirrer). The resulting yellow slurry was cooled to room temperature, diluted with 100 ml acetonitrile, and filtered. The cake was washed with 3 x 100 ml acetonitrile and dried overnight at 50 °C under house vacuum. N-[2- (diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-l,2-dihydro-3H-indol-3-ylidene)methyl]- 2,4-dimethyl-lH-pyrrole-3-carboxamide (21.7 g) was obtained with 85% yield.
Example 2
5-[(Z)-(5-bromo-2-oxo-l,2-dihydro-3H-indol-3-ylidene)met yl]-N-[2- (diethylamino)ethyl]-2,4-djιιιethyl-lH-pyrrole-3-carboxamide
Figure imgf000023_0001
A 0.1L flask fitted with a thermometer, condenser, heating mantle, nitrogen inlet and magnetic stirring was charged with; 3.0g 5-Bromooxindole, 3.03g 4-(lH-imidazol-l- ylcarbonyl)-3,5-dimethyl-lH-pyrrole-2-carbaldehyde, 3.24g N,N-Diethylethylene diamine, 4.23g Triethylamine and 30ml Tetrahydrofuran. The mixture was heated to 60-65° C for 8 hours, then cooled to ambient temperature. 10ml Tetrahydrofuran was added to aid stirring and the reaction rnixture was filtered. Drying provided 3.7g (57.7%>) first crop of 5-[(Z)-(5-bromo-2-oxo-l,2-dihydro-3H-indol-3-ylidene)methyl]- N-[2-(diethylam o)ethyl]-2,4-dimethyl-lH-pyrrole-3-carboxamide. The mother liquors are cooled to -10° C for 6h for an additional 1.9g (29.6%). lHNMR (DMSO): δ 8.08 (lH,s); 7.75 (lH,s); 7.41 (lH,s); 7.24 (lH,d); 6.81 (lH,d); 3.31 (4H,bs); 2.46 (14H,bm); 0.96 (6H,t).
Example 3
5-[(Z)-(5-fluoro-2-oxo-l,2-dlhydro-3H-indol-3-y]idene)met yl]-N-[(2R)-2- yάroxy-3-morp olin-4-ylpropyl]-2,4-dinιethyl-lH-pyrrole-3-carboxamide
Figure imgf000024_0001
A 0.25L flask fitted with a thermometer, condenser, magnetic stirring, and nitrogen inlet was charged with 4.92g 5-Fluorooxindole, 7.0g 4-(lH-imidazol-l-ylcarbonyl)- 3,5-dimethyl-lH-pyrrole-2-carbaldehyde, 15.5g (R)-l-Amino-3-(4-morpholinyl)-2- propanol, 9.78g Triethylamine and 88ml Tetrahydrofuran. The mixture was heated to 60° C for 16.5 hours. The reaction was cooled to ambient temperature and filtered. The solids obtained were slurried (3) three successive times in acetonitrile at 1 lml/g, dried in vacuoto produce a yield of 3.6g (25.25%) of 5-[(Z)-(5-fluoro-2-oxo-l,2- dihydro-3H-indol-3-ylidene)methyl]-N-[(2R)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4- dimethyl- 1 H-pyrrole-3-carboxamide.
IHNMR (DMSO): δ 10.86 (lH,bs); 7.75 (lH,d); 7.70 (lH,s); 7.50 (lH,m); 6.88 (2H,m); 4.72 (lH/bs); 3.78 (lH,bs); 3.56 (4H,m); 3.32 (6H, m); 3.15 (lH,m); 2.43 (8H,bm). Example 4
5-[(Z)-(5-chloro-2-oxo-l,2-dihydro-3H-indol-3-yMene)methyl]-N-[(2S)-2- hyάroxy-3-ιnoι^holin-4-ylpropyl]-2,4-dtaιethyl-lH-pyrrole-3-carboxamide
Figure imgf000025_0001
4-(lH-imidazol-l-ylcarbonyl)-3,5-dimethyl-lH-pvrrole-2-carbaldehyde (6.8 g, 31.3 mmol), (2S)-l-amino-3-morpholin-4-ylpropan-2-ol (10.0 g, 62.5 mmol), 5- chlorooxindole (5.3 g, 31.6 mmol), and THF (100 ml) were mixed and heated to 60° C. After stirring for 68 h at 60° C, triethylamine (14ml) was added and stirred for 5 h at 60° C. Added 4.6 g of (2S)-l-amino-3-morpholin-4-ylpropan-2-ol, and stirred for 20 h at 60° C. The yellow slurry was cooled to room temperature and filtered. The cake was washed with 2 x 50 ml THF and dried overnight at 50° C under house vacuum. 5-[(Z)-(5-chloro-2-oxo-l,2-dihydro-3H-indol-3-ylidene)methyl]-N-[(2S)-2- hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-lH-pyrrole-3-carboxamide (5.48 g) was obtained with 38%) yield.
Example 5 5-[(Z)-(5-fluoro-2-oxo-l,2-(IΛyάro-3H-mdol-3-yHdene)methyl]-2,4-clmιethyl-N-
Figure imgf000026_0001
(2-pyrrolidin-l-ylethyl)-lH-pyrrole-3-carboxamide
Figure imgf000026_0002
A mixture of 4-( 1 H-imidazol- 1 -ylcarbonyι)-3 ,5-dimethyl- 1 H-pyrrole-2-carbaldehyde (4. lKg), THF (70.8 Kg), and water (4.7L) were heated at 40-50° C until the solids were dissolved. The resulting solution was filtered, and then distilled to 40-50. The mixture was subsequently cooled to 25-30° C. A solution ofl-(2-aminoethyl) pyrrolidine (2.8 Kg) in THF (2.1 L) was added. A solution of 5-Fluorooxindole (2.9 Kg) in THF (18.8 Kg) was also added. The mixture was then heated to 45-50° C for 17h. The mixture was cooled, filtered, washed with THF (28 Kg), and dried at 45-50 °C to afford 5.53 Kg (73%) of 5-[(Z)-(5-fluoro-2-oxo-l,2-dihydro-3H-indol-3- ylidene)methyl]-2,4-dimethyl-N-(2-pyrrolidin- 1 -ylethyl)- 1 H-pyrrole-3 -carboxamide. IH NMR (DMSO- d) δ 2.48 (d, J= 8 Hz, 6 H), 2.55 (m, 7 H), 2.62 (t, J= 8 Hz, 1 H), 3.37 (m, 6 H), 6.90 (m, 1 H), 7.00 (m, 1 H), 7.57 (t, J= 4 Hz, 1 H), 7.80 (m, 2 H).
Example 6
5-[(Z)-(5-chloro-2-oxo-l,2-dihydro-3H-indol-3-ylidene)methyl]-N-[(2R)-2- hyd^oxy-3-morpholm-4-ylpropyl]-2,4-dimethyl-lH-pyrrole-3-carboxamide
Figure imgf000028_0001
4-(lH-imidazol-l-ylcarbonyl)-3,5-dimethyl-lH-pyrrole-2-carbaldehyde (7.0 g, 32.3 mmol), (2R)-l-amino-3-morpholin-4-ylpiOpan-2-ol (15.5 g, 96.9 mmol), 5- chlorooxindole (5.48 g, 32.6 mmol), triethylamine (14 ml), and THF (88 ml) were mixed and heated to 60° C. A red solution formed. After stirring for 16 h at 60° C, the yellow slurry was cooled to room temperature and filtered. The cake was washed with 2 x 50 ml of THF and dried overnight at 50° C under house vacuum. 5-[(Z)-(5- chloro-2-oxo-l,2-dihydro-3H-indol-3-ylidene)methyl]-N-[(2R)-2-hydroxy-3- morpholin-4-ylpropyl]-2,4-dimethyl-lH-pyιτole-3-carboxamide (4.36 g) was obtained in 29 % yield.
Example 7
5-[(Z)-(5-fluoro-2-oxo-l,2-dihydro-3H-indol-3-yMene)methyl]-N-[(2S)-2- hydroxy-3-moι^holin-4-ylpropyl]-2,4-άmιethyl-lH-pyrrole-3-carboxamide
Figure imgf000029_0001
4-(lH-imidazol-l-ylcaι-bonyl)-3,5-dimethyl-lH-pyriOle-2-carbaldehyde (7.0 g, 32.3 mmol), (2S)-l-amino-3-morpholin-4-ylpropan-2-ol (15.0 g, 64.6 mmol), 5- fluorooxindole (4.93 g, 32.6 mmol), triethylamine (9.79 g, 96.9 mmol), and THF (88 ml) were mixed and heated to 60° C. After stirring for 24 h at 60° C, the mixture was cooled to rt and filtered. The cake was washed with 80 ml THF and dried overnight at 50° C under house vacuum. A brown solid (23.2 g) was obtained. The solid was slurried in 350 ml water for 5 h at room temperature and filtered. The cake was washed with 100 ml water and dried at 50° C under house vacuum overnight. 5-[(Z)- (5-fluoro-2-oxo-l,2-dihydro-3H-indol-3-ylidene)methyl]-N-[(2S)-2- hydroxy-3- morpholm-4-ylpropyl]-2,4-dimethyl-lH-pyιτole-3-carboxamide (8.31 g) was obtained in 56 % yield.
Example 8
5 (Z)-(5-fluoro-2-oxo-l,2-d y(bro-3H-indol-3-yMene)methyl]-2,4-dimethyl-N- (2-morpholm-4-ylethyl)-lH-pyrrole-3-carboxamide
Figure imgf000030_0001
4-(lH-iιmdazol-l-ylcarbonyl)-3,5-dmethyl-lH-pyrrole-2-caι-baldehyde (5.0 g, 23.0 mmol), 4-(2-aminoethyl)morpholine (4.5 g, 34.6 mmol), 5-fluorooxindole (3.47 g, 23.0 mmol), and THF (80 ml) were mixed and heated to 65° C. After stirring for 24 h at 65° C, the mixture was cooled to room temperature and filtered. The cake was washed with 40 ml THF and dried overnight at 50° C under house vacuum. 5-[(Z)-(5- fluoro-2-oxo-l,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-N-(2-morpholin-4- ylethyl)-lH-pyrrole-3-carboxamide (8.28g) was obtained in 87 % yield.
Example 9
(3Z)-3-({3,5-dmιethyl-4-[(4-moι^hoto-4-ylpiperidln-l-yl)carboιιyl]-lH-pyrrol-2- yl}methylene)-5-fluoro-l,3-dihydro-2H-Midol-2-one
Figure imgf000031_0001
4-( 1 H-imidazol- 1 -ylcarbonyl)-3 , 5-dimethyl- 1 H-pyrrole-2-carbaldehyde (11.3 g, 51.9 mmol), 4-morpholinopiperidine (15.0 g, 88.2 mmol), 5-fluorooxindole (7.84 g, 51.9 mmol), and THF (126 ml) were mixed and heated to 66° C. After stirring for 68 h at 66° C, the mixture was cooled to room temperature and filtered. The cake was washed with 4 x 20 ml THF and dried overnight at 70° C under house vacuum. (3Z)- 3 -( {3 , 5-dimethyl-4- [(4-morpholin-4-ylpiperidin- 1 -yl)carbonyl]- 1 H-pyrrol-2- yl}methylene)-5-fluoro-l,3-dihydro-2H-indol-2-one 16.09 g was obtained in 68 % yield.

Claims

What is claimed is:
1. A process for preparing an indolinone of the general formula (NI)
Figure imgf000032_0001
wherein
R1, R2, R3, R4 are independently selected from the group consisting of hydrogen, Cι_ι2 alkyl, Cι_12 alkoxy, C5_ι2 cycloalkyl, Cβ-n aryl, C5_ι2 heterocyclic group containing 1 to
3 atoms selected fromΝ, S or O, provided that the heterocyclic group may be partially unsaturated, but not aromatic, Cβ-n aryloxy, Cβ-n alkaryl, Cβ-i2 alkaryloxy, halogen, trihalomethyl, hydroxy, -S(O)R', -SO2ΝR'R",
-SO3R', -SR', -NO2, -NR'R", -OH, -CN, -C(O)R', -OC(O)R', -NHC(O)R', -
(CH2)nCO2R', and -CONR'R"; each R5 is independently selected from the group consisting of hydrogen, Cι_ι2 alkyl,
Cι_i2 alkoxy, C5-12 cycloalkyl, Cβ-i2 aryl, C5-12 heterocyclic group containing 1 to 3 atoms selected fromN, S or O, provided that the heterocyclic group may be partially unsaturated, but not aromatic, C - aryloxy, C6-12 alkaryl, C6_ι2 alkaryloxy, halogen, trihalomethyl, hydroxy, -S(O)R\ -SO2NR'R", -SO3R', -SR', -NO2, -NR'R", -OH, -
CN, -C(O)R', -OC(O)R', -NHC(O)R', -(CH2)nCO2R', and -CONR'R";
Rb is is selected from -NR (CH2)mR and -NR 10τ R» ll \ provided that optionally one to two of the CH2 groups may be substituted by -OH or halogen;
R8 is hydrogen or Cι_ι2 alkyl;
R9 is selected from the group consisting of-NR10Ru, -OH, -C(O)R12, C6-12 aryl, C5_ι2 heterocyclic group containing 1 to 3 atoms selected fromN, S or O, -N^O^R10, and-
NHC(O)R13;
R10 and R11 are independently selected from the group consisting of hydrogen, Cι_i2 alkyl, Cι_ι2 cyanoalkyl, C5-12 cycloalkyl, Cδ-12 aryl, and C5_12 heterocyclic group containing 1 to 3 atoms selected fromN, S or O; or R10 and R11 may be combined to form a five- or six-membered heterocyclic group optionally containing 1 to 3 atoms selected fromN, O, or S in addition to the nitrogen atom to which R10 and R11 are bound, provided that the heterocyclic group formed by R10 and R11 may optionally be substituted by R'
R12 is selected from the group consisting of hydrogen, -OH, Cι_ι2 alkoxy and
C6-n aryloxy;
R13 is selected from the group consisting of Cι_ι2 alkyl, Cι_i2 haloalkyl, and Cβ-n aralkyl; R' and R" are independently selected from the group consisting of hydrogen,
Cι-12 alkyl, Cι_ι2 cyanoalkyl, C5-12 cycloalkyl, C6-12 aryl, Cs-^ heterocyclic group containing 1 to 3 atoms selected fromN, S or O, provided that the heterocyclic group may be partially unsaturated, but not aromatic, or in the group -NR'R", R' and R" may be combined to form a five- or six-membered heterocyclic group optionally containing 1 to 3 atoms selected fromN, O, or S in addition to the nitrogen atom to which R' and R" are bound;
Halo is a substituent selected from the group consisting of F, Cl, Br, and I
I is selected from the group consisting of O, S, and NH; one of K, L and M is C and the group -C(O)R6 is bound thereto, the others of the group of K, L and M are independently selected from the group consisting of CR5,
CR5 2, N, NR5, O and S; n is 0, 1 or 2; mis 1, 2, 3, or 4; and p is 0, 1 or 2; comprising the steps of
(i) reacting a compound of general formula (I)
Figure imgf000033_0001
Formula I wherein R5, J, K, L, M and p are as defined above, Q is selected from the group consisting of
Figure imgf000034_0001
with a compound of general formula (II)
X2 R (II)
wherein:
(a) one of X1 and X2 is chlorine, or bromine; and the other is selected from the group consisting of hydroxy, -O-C1- alkyl and -O-phenyl; and R is selected from the group consisting of-C(O)-CM alkyl, -C(O)-O-(C1-4)alkyl, -C(O)-O-phenyl, provided that the phenyl may optionally be substituted by 1 to 3 halogen atoms, -C(O)-O-CH2- phenyl, provided that the phenyl may optionally be substituted by 1 to 3 halogen atoms, or
(b) X1 is chlorine or bromine, X2 is hydrogen and R is selected from the group consisting of
Figure imgf000034_0002
or
(c) X1 is hydroxy, -O-C1- alkyl and -O-phenyl, X2 is
Figure imgf000034_0003
and R is
Figure imgf000035_0001
to form a compound of the general formula (III)
Figure imgf000035_0002
wherein R* is -O-R in case (a) of step (i) and -R in cases (b) and (c) of step (i); (ii) reacting the compound of general formula (III) with a compound of general formula (IN)
Figure imgf000035_0003
wherein R ,ι , R , R , and R are as defined above, and an amine of general formula (V)
HRC (V)
wherein R6 is as defined above, to form the indolinone of the general formula (VI). 2. The process according to claim 1, wherein
Figure imgf000035_0004
is selected from the group consisting of
Figure imgf000036_0001
3. The process according to claim 1, wherein
Figure imgf000036_0002
is
Figure imgf000036_0003
4. The process according to claim 1, wherein R1 is hydrogen or Cι_4 alkyl.
5. The process according to claim 1, wherein R1 is hydrogen.
6. The process according to claim 1, wherein R2 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, C1-4 alkyl, -O-C1-4 alkyl, phenyl, -COOH, -CN, -C(O)CH3, -SO2NH2 and -SO2N(CH3)2.
7. The process according to claim 1, wherein R2 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, Cι_4 alkyl, -O-C1-4 alkyl, CN, -SO2NH2 and-SO2N(CH3)2.
8. The process according to claim 1, wherein R2 is selected from the group consisting of hydrogen, fluorine, chlorine, and bromine.
9. The process according to claim 1 , wherein R2 is fluorine.
10. The process according to claim 1 , wherein R3 is selected from the group consisting of hydrogen, C1- alkyl, phenyl,
Figure imgf000037_0001
alkyl and -COOH.
11. The process according to claim 1 , wherein R3 is hydrogen or Cχ_ alkyl.
12. The process according to claim 1, wherein R3 is hydrogen.
13. The process according to claim 1 , wherein R4 is hydrogen.
14. The process according to claim 1 , wherein R5 is selected from the group consisting of hydrogen, C1- alkyl, — C(O)-Cι_ alkyl, -C(O)-phenyl and phenyl.
15. The process according to claim 1, wherein R5 is hydrogen, or C^ alkyl.
16. The process according to claim 1, wherein R6 is -NR8(CH2)mR9, provided that one or two of the CH2 groups can optionally be substituted by -OH or halogen. 17. The process according to claim 1 , wherein R8 is hydrogen or C1- alkyl.
18. The process according to claim 1 , wherein m is 2 or 3.
19. The process according to claim 1, wherein R9 is -NR10R1:l.
20. The process according to claim 19, wherein R10 and R11 are hydrogen or
Figure imgf000037_0002
alkyl. 21. The process according to claim 1 , wherein R9 is a C5-ι2 heterocyclic group containing 1 to 3 atoms selected fromN, S or O. 22. The process according to claim 21, wherein the heterocyclic group is a five- to seven-membered heterocyclic group bonded to the (CH2)m group via a nitrogen atom and optionally containing a further heteroatom selected fromN, O, and S.
23. The process according to claim 22, wherein the heterocyclic group is selected from the group consisting of
Figure imgf000038_0001
Figure imgf000038_0002
24. The process of claim 23 , wherein the heterocyclic group is selected from the group consisting of
Figure imgf000038_0003
25. The process according to claim 16, wherein R8 is hydrogen or
Figure imgf000038_0004
alkyl.
26. The process according to claim 16, wherein m is 2 or 3.
27. The process according to claim 16, wherein R9 is -NR^R11. 28. The process according to claim 27, wherein R10 and R11 are hydrogen or C1-4 alkyl
29. The process according to claim 16, wherein R9 is a C5_ι2 heterocyclic group containing 1 to 3 atoms selected fromN, S or O.
30. The process according to claim 29, wherein the heterocyclic group is a five- or six-membered heterocyclic group bonded to the (CH2)m group via a nitrogen atom and optionally containing a further heteroatom selected fromN, O, and S.
31. The process according to claim 30, wherein the heterocyclic group is selected from the group consisting of
Figure imgf000039_0001
Figure imgf000039_0002
32. The process of claim 31 , wherein the heterocyclic group is selected from the group consisting of
Figure imgf000039_0003
33. The process according to claim 1, wherein the compounds of general formula (I) and general formula (II) are reacted in a polar, aprotic solvent.
34. The process according to claim 33, wherein the polar, aprotic solvent is an ether.
35. The process according to claim 33, wherein the compounds of general formula (I) and general formula (II) are reacted at a temperature in the range of from about 0 °C to about the temperature at which the reaction mixture refluxes.
36. The process according to claim 1, wherein the compounds of general formula (III), general formula (IN) and general formula (N) are reacted in a polar, aprotic solvent. 37. The process according to claim 36, wherein the polar, aprotic solvent is an ether.
38. The process according to claim 36, wherein the compounds of general formula (III), general formula (IV) and general formula (N) are reacted at a temperature in the range of from about +50° C to about the temperature at which the reaction mixture refluxes.
39. The process according to claim 1, wherein the compounds of general formula (Ill), general formula (IV) and general formula (N) are reacted in a one-pot reaction.
40. The process according to claim 1, wherein the compound of general formula
(NI) is selected from the group consisting of:
Figure imgf000040_0001
Figure imgf000040_0002
or wherein X is selected from the group consisting of hydrogen, fluorine, chlorine and bromine.
41. The process according to claim 40, wherein X is fluorine.
42. The process of claim 1, wherein the compound of the general formula (VI) is further converted into a pharmaceutically acceptable salt or derivative. 43. A process for preparing a compound of the general formula (III)
Figure imgf000041_0001
wherein each R5 is independently selected from the group consisting of hydrogen, Cι_ι2 alkyl, Cι_i2 alkoxy, C5_i2 cycloalkyl, Cβ-12 aryl, Cs-n heterocyclic group containing 1 to 3 atoms selected fromN, S or O, provided that the heterocyclic group may be partially unsaturated, but not aromatic, C6-12 aryloxy, Cδ-12 alkaryl, Cβ-ι2 alkaryloxy, halogen, trihalomethyl, hydroxy, -S(O)R', - SO2NR'R'\ -SO3R', -SR', -NO2, -NR'R", -OH, -CN, -C(O)R', -OC(O)R', -NHC(O)R\
Figure imgf000041_0002
R6 is -NR8(CH2)mR9 or -NR10Rn; R8 is hydrogen or Cι_ι2 alkyl;
R9 is selected from the group consisting of-NR10Ru, -OH, -C(O)R12, Cβ-n aryl, C5-12 heterocyclic group containing 1 to 3 atoms selected fromN, S or O, -N+(O-)R10, and-NHC(O)R13;
R10 and R11 are independently selected from the group consisting of hydrogen, Cι_i2 alkyl, Cι_ι2 cyanoalkyl, C5-12 cycloalkyl, Cβ-n aryl, and C5-12 heterocyclic group containing 1 to 3 atoms selected fromN, S or O; or R10 and R11 may be combined to form a five- or six-membered heterocyclic group optionally containing 1 to 3 atoms selected fromN, O, or S in addition to the nitrogen atom to which R10 and R11 are bound, provided that the heterocyclic group formed by R10 and R11 may optionally be substituted by R'; R12 is selected from the group consisting of hydrogen, -OH, Cι_i alkoxy and C6-i2 aryloxy; R13 is selected from the group consisting of C1-12 alkyl, Cm haloalkyl, and C6_ 12 aralkyl;
R' and R" are independently selected from the group consisting of hydrogen, Cι_i2 alkyl, Cι_ι2 cyanoalkyl, Cs-12 cycloalkyl, Cδ-12 aryl, C5-12 heterocyclic group containing 1 to 3 atoms selected fromN, S or O, provided that the heterocyclic group may be partially unsaturated, but not aromatic, or in the group —NR'R" the R' and R'substituents may be combined to form a five- or six-membered heterocyclic group optionally containing 1 to 3 atoms selected fromN, O, or S in addition to the nitrogen atom to which R' and R" are bound; J is selected from the group consisting of O, S, and NH; one of K, L and M is C and the group -C(O)R6 is bound thereto, the others of the group of K, L and M are independently selected from the group consisting of CR5, CR5 2, N, NR5, O and S; n is 0, 1 or 2; mis 1, 2, 3, or 4; p is 0, 1 or 2; comprising the steps of
(i) reacting a compound of general formula (I)
Figure imgf000042_0001
wherein R5, J, K, L, M, and p are as defined above, with a compound of general formula (II) χ2 R (II)
(a) wherein one of X1 and X2 is chlorine, or bromine; and the other is selected from the group consisting of hydroxy, -O-C1- alkyl and-O- phenyl; and R is selected from the group consisting of
-C(O)-C,_4 alkyl, -C(O)-O-(Cι-4)alkyl, -C(O)-O-phenyl, -C(O)-O-CH2-phenyl, wherein the phenyl can optionally be substituted by 1 to 3 halogen atoms; (b) wherein X1 is chlorine or bromine, X2 is hydrogen and R is selected from the group consisting of
Figure imgf000043_0001
or
(c) wherein X is hydroxy, -O-C1-4 alkyl and -O-phenyl, and X2 is
Figure imgf000043_0002
and R is
Figure imgf000043_0003
to form a compound of the general formula (III)
Figure imgf000043_0004
wherein R* is -O-R in case (a) of step (i) and — R in cases (b) and (c) of step
4. A process for preparing an indolinone of the general formula (VI)
Figure imgf000044_0001
wherein
R1, R2, R3, R4 are independently selected from the group consisting of hydrogen, Cι_ι2 alkyl, Cι_ι2 alkoxy, C5-12 cycloalkyl, C6-ι2 aryl, C5-12 heterocyclic group containing 1 to 3 atoms selected fromN, S or O, provided that the heterocyclic group may be partially unsaturated, but not aromatic, Cβ-π aryloxy, Cβ- alkaryl, Cβ-n alkaryloxy, halogen, trihalomethyl, hydroxy, - S(O)R', -SO2NR'R",
-SO3R', -SR', -NO2, -NR'R", -OH, -CN, -C(O)R', -OC(O)R', -NHC(O)R', -(ODaCOzR', and -CONR'R"; each R5 is independently selected from the group consisting of hydrogen, Cι_ι2 alkyl, Cι_ι2 alkoxy, C5-12 cycloalkyl, Cβ-n aryl, C5-12 heterocyclic group containing 1 to 3 atoms selected fromN, S or O, provided that the heterocyclic group may be partially unsaturated, but not aromatic, Cβ-n aryloxy, Cβ- alkaryl, Cβ-i2 alkaryloxy, halogen, trihalomethyl, hydroxy, -S(O)R', - SO2NR'R", -SO3R', -SR',-NO2, -NR'R", -OH, -CN, -C(O)R', -OC(O)R', - NHC(O)R',-(CH2)nCO2R', and -CONR'R"; R6 is -NR8(CH2)mR9 or -NR10RU; R8 is hydrogen or C1-.12 alkyl;
R9 is selected from the group consisting of-NR10Rn, -OH, -C(O)R12, C6_ι2 aryl, C5-12 heterocyclic group containing 1 to 3 atoms selected fromN, S or O, -N^O^R10, and-NHC(O)R13;
R10 and R11 are independently selected from the group consisting of hydrogen, Ci-12 alkyl, C1-12 cyanoalkyl, C5_i2 cycloalkyl, Cβ-π aryl, and C5-12 heterocyclic group containing 1 to 3 atoms selected fromN, S or O; or R10 and R11 may be combined to form a five- or six-membered heterocyclic group optionally containing 1 to 3 atoms selected fromN, O, or S in addition to the nitrogen atom to which R10 and R11 are bound, provided that the heterocyclic group formed by R10 and Ru may optionally be substituted by R';
R12 is selected from the group consisting of hydrogen, -OH, Cι_ι2 alkoxy and Cδ-12 aryloxy;
R13 is selected from the group consisting of Cι_i2 alkyl, Cι_ι2 haloalkyl, and Cβ- 12 aralkyl; R' and R" are independently selected from the group consisting of hydrogen,
Cι_i2 alkyl, Cι_ι2 cyanoalkyl, C5-12 cycloalkyl, Cδ_i2 aryl, C5--12 heterocyclic group containing 1 to 3 atoms selected fromN, S or O, provided that the heterocyclic group may be partially unsaturated, but not aromatic, or in the group -NR'R" the R' and R" substituents may be combined to form a five- or six-membered heterocyclic group optionally containing 1 to 3 atoms selected fromN, O, or S in addition to the nitrogen atom to which R' and R" are bound; J is selected from the group consisting of O, S, and H; one of K, L and M is C and the group -C(O)R6 is bound thereto, the others of the group of K, L and M are independently selected from the group consisting of CR5, CR52, N, NR5, O and S; n is 0, 1 or 2; mis 1, 2, 3, or 4; and p is 0, 1 or 2; comprising the steps of reacting a compound of the general formula (III)
Figure imgf000045_0001
wherein R5, T, K, L, M, and p are as defined above, and wherein R* is selected from the group consisting of -O-C(O)-Cι_ alkyl, -O- C(O)-O-(Cι^)a]kyl -O-C(O)-O-phenyl provided that the phenyl may optionally be substituted by 1 to 3 halogen atoms, -O-C(O)-O-CH2-phenyl, provided that the phenyl may optionally be substituted by 1 to 3 halogen atoms;
Figure imgf000046_0001
with a compound of general formula (IN)
Figure imgf000046_0002
wherein R1, R2, R3, and R4 are as defined above and an amine of general formula (V)
HR° (V)
wherein R > 6 i •s as defined above, to form the indolinone of the general formula
(VI).
45. A compound of the general formula (III):
Figure imgf000046_0003
wherein each R >5 i •s independently selected from the group consisting of hydrogen, C1-12 alkyl, Cι_12 alkoxy, C5-12 cycloalkyl, Cβ-12 aryl, C5-12 heterocyclic group containing 1 to 3 atoms selected fromN, S or O, provided that the heterocyclic group may be partially unsaturated, but not aromatic, Cβ-n aryloxy, -n alkaryl, Cβ-n alkaryloxy, halogen, trihalomethyl, hydroxy, -S(O)R', -
SO2NR'R", -SO3R', -SR',
-NO2, -NR'R", -OH, -CN, -C(O)R', -OC(O)R', -NHC(O)R',
-(CH2)nCO2R', and -CONR'R";
J is selected from the group consisting of O, S, andNH; one of K, L and M is C and the group -C(O)R6 is bound thereto, the others of the group of K, L and M are independently selected from the group consisting of CR5, CR5 2, N, NR5, O and S; p is 0, 1 or 2; and wherein R* is selected from the group consisting of-O-C(O)-Cι- alkyl, -O-
C(O)-O-(Cι^)alkyl -O-C(O)-O-phenyl provided that the phenyl may optionally be substituted by 1 to 3 halogen atoms, -O-C(O)-O-CH2-phenyl, provided that the phenyl may optionally be substituted by 1 to 3 halogen atoms,
Figure imgf000047_0001
46. The compound of claim 45, wherein R* is
— Λ
\=J
47. The compound of claim 45, wherein is
Figure imgf000048_0001
The process according to claim 1, wherein the compound of general formula (VI) is selected from the group consisting of:
Figure imgf000048_0002
Figure imgf000049_0001
Figure imgf000049_0002
Figure imgf000049_0003
Figure imgf000050_0001
Figure imgf000050_0002
Figure imgf000051_0001
Figure imgf000051_0002
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EP1599200A2 (en) * 2003-02-24 2005-11-30 PHARMACIA & UPJOHN COMPANY Polymorphs of pyrrole substituted 2-indolinone protein kinase inhibitors
EP1599200A4 (en) * 2003-02-24 2007-02-07 Pharmacia & Upjohn Co Llc Polymorphs of pyrrole substituted 2-indolinone protein kinase inhibitors
WO2005023765A1 (en) * 2003-09-11 2005-03-17 Pharmacia & Upjohn Company Llc Method for catalyzing amidation reactions by the presence of co2
JP2007507482A (en) * 2003-10-02 2007-03-29 ファルマシア・アンド・アップジョン・カンパニー・エルエルシー Salts and polymorphs of pyrrole-substituted indolinone compounds
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WO2009109388A1 (en) * 2008-03-06 2009-09-11 Ratiopharm Gmbh Crystal forms of n-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3h-indol-3-ylidene)methyl]-2,4-dimethyl-1h-pyrrole-3-carboxamide and methods for their preparation
EA020067B1 (en) * 2008-03-06 2014-08-29 Рациофарм Гмбх Polymorph form iiiof n-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3h-indol-3-ylidene)methyl]-2,4-dimethyl-1h-pyrrole-3-carboxamide and method for preparation thereof
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WO2009128083A1 (en) * 2008-04-16 2009-10-22 Natco Pharma Limited Novel polymorphic forms of sunitinib base
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WO2010023474A1 (en) * 2008-08-25 2010-03-04 Generics [Uk] Limited Novel polymorphs of sunitinib and processes for their preparation
CN102197035A (en) * 2008-08-25 2011-09-21 基因里克斯(英国)有限公司 Novel crystalline form and processes for its preparation
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WO2011104555A2 (en) 2010-02-25 2011-09-01 Generics [Uk] Limited Novel process
WO2011110199A1 (en) 2010-03-10 2011-09-15 Synthon B.V. A process for amidation of pyrrole carboxylate compounds
WO2011128699A3 (en) * 2010-04-16 2012-03-08 Generics [Uk] Limited Novel process for the preparation of sunitinib
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CN104744442A (en) * 2013-12-25 2015-07-01 江苏豪森药业股份有限公司 Sunitinib malate preparation method

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