EP1646632A2 - Substituierte tetrahydro-1h-pyrazolo[3,4-c] pyridine, zusammensetzungen, die diese enthalten, und anwendung - Google Patents

Substituierte tetrahydro-1h-pyrazolo[3,4-c] pyridine, zusammensetzungen, die diese enthalten, und anwendung

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Publication number
EP1646632A2
EP1646632A2 EP04767613A EP04767613A EP1646632A2 EP 1646632 A2 EP1646632 A2 EP 1646632A2 EP 04767613 A EP04767613 A EP 04767613A EP 04767613 A EP04767613 A EP 04767613A EP 1646632 A2 EP1646632 A2 EP 1646632A2
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EP
European Patent Office
Prior art keywords
chosen
product according
aryl
heteroaryl
alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP04767613A
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English (en)
French (fr)
Inventor
Fabienne Thompson
Patrick Mailliet
Teresa Damiano
Marie-Pierre Cherrier
François CLERC
Frank Halley
Hervé Bouchard
Laurence Gauzy-Lazo
Bernard Baudoin
Catherine Souaille
Fabrice Viviani
Michel Tabart
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Aventis Pharma SA
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Aventis Pharma SA
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Priority claimed from FR0308442A external-priority patent/FR2857363B1/fr
Priority claimed from FR0308441A external-priority patent/FR2857362B1/fr
Application filed by Aventis Pharma SA filed Critical Aventis Pharma SA
Priority to EP10173683A priority Critical patent/EP2251340A1/de
Publication of EP1646632A2 publication Critical patent/EP1646632A2/de
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to new chemical compounds, particularly new tetrahydro-1H-pyrazolo [3,4-c] pyridines, compositions containing them, and their use as medicaments.
  • the invention relates to new tetrahydro-1H-pyrazolo [3,4-c] pyridines having an anticancer activity, and in particular an activity inhibiting inases, in particular Tie2.
  • WO 02/012442 discloses tetrahydro-1H-pyrazolo [3,4-c] pyridines substituted in position 5 by an amino group, optionally substituted. These products are useful for the treatment of cancer and other diseases linked to cell proliferation.
  • WO 96/12720 claims tetrahydro-1H-pyrazolo [3,4-c] pyridines substituted in position 3 by substituents chosen from H, alkyl, alkylene, cycloalkyl, and methylenecycloalkyl, and in positions 1 and 6 by various substituents. These products are described as inhibitors (i) of phosphodiesterase type IV (PDE-IV), and (ii) of tumor necrosis factor (TNF), and are therefore considered useful in the treatment of inflammatory diseases. No example of a compound according to the invention is disclosed.
  • L is chosen from bond, CH 2 . CO, SO 2l CONH, COO, NHCO, NH, NHSO 2 , SO 2 NH, NHCONH, CH 2 NH, NHCH 2l
  • X is chosen from bond, CH 2 , CO, SO 2 , CONH, COO;
  • R1 is chosen from OH, H, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, optionally substituted, and, when X is bond, then R1 can also be halogen;
  • R2 is H or chosen from alkyl, alkylene, cycloalkyl, heterocyclyl, aryl, heteroaryl, optionally substituted; the substituents being independently chosen from R3, 0-R3, halogen, NO 2 , SO 2 -R3, CO-R3, SO2NH-R3, CONH-R3, N- (R3) 2 , NHCO-R3, NHSO 2 - R3, NHCONH-R3, NHSO 2 NH-R3, OCO-R3, COO-R3, OSO 2 -R3, SO 2 O-R3, OCONH-R3, OSO 2 NH-R3, where each R3 is independently selected from H, alkyl, cycloalkyl, alkenyl, aryl, heteroaryl, heterocyclyl, optionally substituted by halogen, aryl, heteroaryl, R4, OR4, N (R4) 2 , each R4 being independently chosen from H, C1-C4 alkyl, and C1-C4 halogenated alkyl
  • Products in accordance with the invention according to its first aspect are more particularly chosen from products of general formula (II) below:
  • R1 is chosen from alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, optionally substituted;
  • R2 is H or chosen from alkyl, alkylene, cycloalkyl, heterocyclyl, aryl, heteroaryl, optionally substituted; the substituents being independently chosen from R3, O-R3, halogen, NO 2 , SO 2 -R3, CO-R3, SO2NH-R3, CONH-R3, N- (R3) 2 , NHCO-R3, NHS0 2 - R3, NHCONH-R3, NHSO 2 NH-R3, OCO-R3, COO-R3, OSO 2 -R3, SO 2 O-R3, OCONH-R3, OSO 2 NH-R3, where each R3 is independently selected from H, alkyl, cycloalkyl, alkenyl, aryl, heteroaryl, heterocyclyl, optionally substituted by halogen, aryl, heteroaryl, OR4, N (R4) 2 , where each R4 is independently selected from H, C1-C4 alkyl.
  • Products in accordance with the invention according to its first aspect are more particularly chosen from products of general formula (III) below:
  • X is chosen from bond, CH 2 , CO, SO 2 , CONH, COO;
  • R1 is chosen from alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, optionally substituted;
  • R2 is H or chosen from alkyl, alkylene, cycloalkyl, heterocyclyl, aryl, heteroaryl, optionally substituted; in which the substituents are independently chosen from R3, O-R3, halogen, NO 2 , SO 2 -R3, CO-R3, SO2NH-R3, CONH-R3, N- (R3) 2 , NHCO-R3, NHSO 2 - R3, NHCONH-R3, NHSO 2 NH-R3, OCO-R3, COO-R3, OSO 2 -R3, SO 2 O-R3, OCONH-R3, OSO 2 NH-R3, in which each R3 is independently selected from H , alkyl, cycloalkyl, alkenyl, aryl, heteroaryl, heterocyclyl, optionally substituted by halogen, aryl, heteroaryl, OR4, N (R4) 2, and wherein each R4 is independently selected from H, C1-C4 alkyl.
  • a product in accordance with the invention is advantageously chosen from products according to its first aspect, in which R1 is heretoaryl, optionally substituted, in which a preferred heteroaryl is chosen from benzimidazolyl, indolyl, pyrrolyl, optionally substituted by halogen, R4, O- R4.
  • a preferred heteroaryl is chosen from benzimidazol-2-yl, indol-2-yl, pyrrol-2-yl, optionally substituted with halogen, R4, O-R4.
  • a product according to the invention according to its first aspect advantageously has an R2 substituent chosen from phenyl, pyridyl, thienyl, C1-C4 alkyl, and C3-C7 cycloalkyl, optionally substituted.
  • X can advantageously be chosen from CO and SO 2 .
  • a product according to the invention according to its first aspect is advantageously chosen from the products of formula (I), in which R1 is H.
  • a preferred product is advantageously chosen from the products of formula (I) in which R1 is substituted aryl.
  • a preferred product is advantageously chosen from the products of general formula (I) in which R1-L is R1-NH-CO, and more preferentially in the cases where Rlest H.
  • a preferred product is advantageously chosen from (i) the products of general formula (I) or (ii) preferably the products according to the first preferred embodiment, in which X is a bond, and in which R2 is selected from substituted aryl and substituted heteroaryl.
  • a more preferred product is chosen from the products according to the invention according to its second embodiment, in which R2 is chosen from - aryl substituted by NHSO 2 -R3 or NHCONH-R3, and - heteroaryl substituted by NHSO 2 -R3, or NHCONH-R3.
  • Products according to the third preferred embodiment are advantageously chosen from - aryl substituted by NHSO 2 -R3 or NHCONH-R3, and - heteroaryl substituted by NHSO 2 -R3, or NHCONH-R3, in which aryl is phenyl, and in which heteroaryl is selected from pyridyl and pyrimidyl.
  • products according to the third preferred embodiment are advantageously chosen from - aryl substituted by NHSO 2 -R3 or NHCONH-R3, and - heteroaryl substituted by NHSO 2 -R3, or NHCONH-R3, in which R3 is chosen from substituted aryl and substituted heteroaryl, in which R3 is advantageously substituted by a substituent selected from the group consisting of halogen, R4, OR4, N (R4) 2 , in which each R4 is independently chosen from H, C1-C4 alkyl, and C1-C4 halogenated alkyl.
  • products according to the fourth preferred embodiment are advantageously chosen from:
  • a product according to the invention according to its first aspect, can be in the form: 1) racemic, or 2) enriched in a stereoisomer, or 3) enriched in an enantiomer; and possibly be salified.
  • the invention relates to pharmaceutical compositions comprising a product as defined above, in combination with a pharmaceutically acceptable excipient.
  • the invention relates to the use of a product as defined above, as an agent modulating the activity of a kinase.
  • a preferred kinase will advantageously be chosen from Tie2 and KDR. Tie2 is more preferred.
  • the invention relates to the use of a product as defined above, for the manufacture of a medicament useful for treating a pathological condition, in particular cancer.
  • Products in accordance with the invention can be obtained by methods well known to those skilled in the art, in particular as regards coupling techniques between an acid and an amino. See, for example, J. March, Advanced organic chemistry, (J. Wiley & Sons, ed.), Fourth edition, 1992.
  • the products of the invention are useful as inhibitors of a kinase catalyzed reaction.
  • Tie2 is a kinase for which the products of the invention will be particularly useful as inhibitors.
  • These products may also be useful as inhibitors of other kinases such as KDR. Reasons why these kinases are chosen are given below:
  • Tie-2 is a member of a family of tyrosine kinase receptors, specific for endothelial cells.
  • Tie2 is the first receptor with tyrosine kinase activity, the agonist of which (angiopoietin 1 or Ang1) is known, which stimulates receptor autophosphorylation and cell signaling [S. Davis et al (1996) Cell 87, 1161-1169] and the antagonist (angiopoietin 2 or Ang2) [PC Maisonpier ⁇ et al. (1997) Science 277, 55-60].
  • Angiopoietin 1 can synergize with VEGF in the later stages of neo- angiogenesis [AsaharaT. Wax. Res.
  • Tie2 inhibitors can be used in situations where neovascularization is done inappropriately (i.e. in diabetic retinopathy, chronic inflammation, psoriasis, Kaposi's sarcoma, chronic neovascularization due to macular degeneration, rheumatoid arthritis, childhood hemoangioma and cancer).
  • KDR Keratinase insert Domain Receptor
  • VEGF-R2 Vascular Endothelial Growth Factor Receptor 2
  • VEGF-R2 Vascular Endothelial Growth Factor Receptor 2
  • VEGF-R2 Vascular Endothelial Growth Factor Receptor 2
  • VEGF-R2 mutants have been demonstrated in particular using VEGF-R2 mutants (Millauer et al., Cancer Research, 1996, vol. 56, pJ615-1620).
  • the VEGF-R2 receptor seems to have no other function in adults than that linked to the angiogenic activity of VEGF. Therefore, a selective inhibitor of VEGF-R2 kinase activity should demonstrate little toxicity.
  • recent results suggest that expression of VEGF contributes to the survival of tumor cells after chemotherapy and radiotherapy, highlighting the potential synergy of KDR inhibitors with other agents (Lee et al. Cancer Research, 2000, vol. 60, p.5565-5570).
  • the separation was carried out on a Hypersil BDS C18 column, 3 ⁇ m (50 ⁇ 4.6 mm), eluting with a linear gradient of 5 to 90% acetonitrile containing 0.05% (v / v) of trifluoroacetic acid ( TFA) in water containing 0.05% (v / v) TFA in 3.5 min at a flow rate of 1 mL / min.
  • TFA trifluoroacetic acid
  • Method B Purification by LC / MS: The products were purified by LC / MS using a Waters FractionsLynx system composed of a Waters model 600 gradient pump, a Waters model 515 regeneration pump, a Waters Reagent Manager dilution, Waters model 2700 auto-injector, two Rheodyne valves LabPro, Waters model 996 diode array detector, Waters model ZMD mass spectrometer and fraction collector Gilson model 204. The system is controlled by Waters FractionLynx software.
  • the separation was carried out alternately on two Waters Symmetry columns (Cis, 5 ⁇ M, 19x50 mm, catalog reference 186000210), one column being regenerated by a water / acetonitrile 95/5 (v / v) mixture containing 0.07% (v / v) trifluoroacetic acid, while the other column is being separated. Elution from the columns was carried out using a linear gradient of 5 to 95% acetonitrile containing 0.07% (v / v) of trifluoroacetic acid in water containing 0.07% (v / v) d trifluoroacetic acid, at a flow rate of 10 ml / min.
  • one thousandth of the effluent is separated by a LC Packing Accurate, diluted in methyl alcohol at a flow rate of 0.5 mL / min and sent to the detectors, 75% to the diode array detector, and the remaining 25% to the mass spectrometer.
  • the rest of the effluent (999/1000) is sent to the fraction collector where the flow is eliminated until the mass of the expected product is detected by the FractionLynx software.
  • the molecular formulas of the expected products are provided to the FractionLynx software which triggers the collection of the product when the detected mass signal corresponds to the [M + H] + ion and / or to the [M + Na] + .
  • Method C El analysis The mass spectra were carried out using electronic impact (70eV) on a Finnigan SSQ 7000 spectrometer.
  • BRUKER Avance DRX 400 4- (Diazo-ethoxycarbonyl-methyl) -4-hydroxy-piperidine-1-tert-butyl carboxylate
  • a freshly prepared solution of LDA (prepared by dropwise addition under an inert atmosphere at -78 ° C of 50.19 mL of 1.6M BuLi in hexane on a solution of 11.29 mL of diisopropylamine in 200 mL of THF dry) is added dropwise under an inert atmosphere at -78 ° C onto 10.0 g of N-Boc-piperidinone in suspension and 5.54 ml of ethyl diazoacetate in 300 ml of dry THF. The mixture is stirred at -78 ° C for 4 hours then is decomposed at -78 ° C with 14.35 ml of concentrated AcOH.
  • Diagram A In order to simplify the representation of the products in table 3 which follows, the pyrazolopiperidine nucleus presented in diagram A is symbolized by the letter H, the amines R1-NH 2 which are linked to H are symbolized by the letter B followed by '' a number ranging from 1 to 15, corresponding to the products listed in table 1, the R2-COOH acids which are linked to H are symbolized by the letter A followed by a number from 1 to 70, corresponding to the products listed in the table 2.
  • a product marked A1-H-B1 corresponds to the following structure:
  • 3- (5,6-dimethyl-1 H-benzoimidazol-2-yl) -6-methanesulfonyl-4,5,6,7-tetrahydro-2H-pyrazolo [3,4-c] pyridine can be prepared from as follows: 10 mg of 3- (5,6-dimethyl-1 H-benzimidazol-2-yl) -4,5,6,7-tetrahydro-2H- pyrazolo [3,4-c] pyridine are suspended in 0.3 mL dichloromethane. 15.8 ⁇ L of triethylamine are added as well as 4.5 ⁇ L of methanesulfonyl chloride. The reaction mixture is stirred at room temperature for 20 hours and then concentrated under reduced pressure.
  • the evaporation residue is purified by LC / MS (Method B). After purification by LC / MS, the fractions containing 3- (5,6-dimethyl-1 H-benzoimidazol-2-yl) - 6-methanesulfonyl-4,5,6,7-tetrahydro-2H-pyrazolo [3, 4-c] pyridine are combined and deposited on SCX phase (500 mg of CUBCX1-HL phase). The SCX phase is then washed with methanol and then extracted with a solution of 2M ammonia in methanol. The extraction solution obtained is then concentrated under reduced pressure.
  • [3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -2,4,5,7-tetrahydro-pyrazolo [3,4- c] pyridin-6-yl] -3-pyridinyl-methanone can be prepared as follows: 10 mg of 3- (5,6-dimethyl-1 H-benzimidazol-2-yl) -4,5,6,7-tetrahydro-2H- pyrazolo [3,4-c] pyridine are suspended in 0.3 mL of DMF. 6.9 mg of nicotinic acid are added, followed by 7.6 mg of HOBT and 8.7 ⁇ L of diisopropylcarbodiim.de.
  • 6- (3-chloro-benzyl) -3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -4,5,6,7- tetrahydro-2H-pyrazolo [3,4-c] pyridine can be prepared as follows: 10 mg of 3- (5,6-dimethyl-1H-benzimidazol-2-yl) -4,5,6,7-tetrahydro-2H- pyrazolo [3,4-c] pyridine are suspended in 0.3 mL of methanol. 12.7 ⁇ L of 3-chlorobenzaldehyde are added, followed by 4.7 mg of NaBH 3 CN. The reaction mixture is stirred at room temperature for 20 hours and then concentrated under reduced pressure.
  • the evaporation residue is purified by LC / MS (Method B). After purification by LC / MS, the fractions containing 6- (3-chloro-benzyl) -3- (5,6-dimethyl-1 H-benzoimidazol-2-yl) -4,5,6,7-tetrahydro- 2H-pyrazolo [3,4-c] pyridine are combined and deposited on the SCX phase (500 mg of CUBCX1-HL phase). The SCX phase is then washed with methanol and then extracted with a solution of 2M ammonia in methanol. The extraction solution obtained is then concentrated under reduced pressure.
  • the evaporation residue is purified by LC / MS (Method B). After purification by LC / MS, the fractions containing [3- (1 H-benzoimidazol-2-yl) -2,4,5,7- tetrahydro-pyrazolo [3,4-c] pyridin-6-yl] - 3-pyridinyl-methanone are combined and deposited on the SCX phase (500 mg of CUBCX1-HL phase). The SCX phase is then washed with methanol and then extracted with a solution of 2M ammonia in methanol. The extraction solution obtained is then concentrated under reduced pressure.
  • 6- (3-chloro-benzyl) -3- (1 H-benzoimidazol-2-yl) -4,5,6,7-tetrahydro-2H- pyrazolo [3,4-c] pyridine can be prepared from as follows: 15 mg of hydrochloride 3- (1H-benzimidazol-2-yl) -4,5,6,7-tetrahydro-2H- pyrazolo [3,4-c] pyridine are suspended in 0.5 ml of methanol. 26.5 mg of 3-chlorobenzaldehyde are added, followed by 7.9 mg of NaBH 3 CN. The reaction mixture is stirred at room temperature for 20 hours and then concentrated under reduced pressure.
  • the evaporation residue is purified by LC / MS (Method B). After purification by LC / MS, the fractions containing 6- (3-chloro-benzyl) -3- (1 H- benzoimidazol-2-yl) -4,5,6,7-tetrahydro-2H-pyrazolo [3, 4-c] pyridine are combined and deposited on SCX phase (500 mg of CUBCX1-HL phase). The SCX phase is then washed with methanol and then extracted with a solution of 2M ammonia in methanol. The extraction solution obtained is then concentrated under reduced pressure.
  • the amides library can be prepared as follows:
  • the 19 acids (Table 4) are weighed and placed in 19 individual test tubes.
  • 152 mg of HOBT and 142 mg of diisopropylcarbodiimide are placed in solution in 12 ml of DMF and the solution obtained is distributed in each of the 19 test tubes, at the rate of 600 ⁇ L per tube.
  • 200 mg of 3- (5,6-dimethyl-1 H-benzimidazol-2-yl) -4,5,6,7-tetrahydro-2H-pyrazolo [3,4-c] pyridine hydrochloride are suspended in 4 mL of DMF in the presence of 290 mg of N, N-diisopropylethylamine and the suspension obtained is distributed in each of the 19 test tubes, at a rate of 200 ⁇ L per tube.
  • the 19 reaction mixtures are stirred by orbital shaking at room temperature for 20 hours.
  • a sample of 10 ⁇ L is taken and diluted in 40 ⁇ L of DMSO (Gilson Liquid Handier Quad-Z 215). Each sample in solution in DMSO thus obtained is analyzed by LC / MS (Method A). The 19 reaction mixtures are then evaporated to dryness and the evaporation residues are placed in solution in 500 ⁇ L of DMSO each, then the solutions obtained are purified by LC / MS (Method B). After purification by LC / MS, the fractions containing the sought compounds are (optionally combined) deposited on the SCX phase (500 mg of CUBCX1-HL phase).
  • the SCX phases are then washed with methanol and then extracted with a solution of 2M ammonia in methanol.
  • the extraction solutions are collected in tared glass tubes, evaporated to dryness (Savant AES 2000 or Genevac HT8 centrifugal evaporator), weighed (Mettler Toledo Automated Workstation LA200) and diluted to 10 mM in DMSO (Gilson Liquid Handier Quad-Z 215). Each solution obtained is analyzed by LC / MS (Method A).
  • the sulfonamide library can be prepared as follows: 190 mg of 3- (5,6-dimethyl-1 H-benzimidazol-2-yl) -4,5,6,7- tetrahydro-2H-pyrazolo hydrochloride [3,4-c] pyridine are suspended in 2 ml of dichloromethane in the presence of 150 ⁇ L of triethylamine and the suspension obtained is distributed in 17 test tubes, at a rate of 500 ⁇ L per tube. The 17 sulfonyl chloride (Table 6) are weighed and added to each of the 17 test tubes. Table 6: Sulfonyl chloride used
  • the 17 reaction mixtures are stirred by orbital agitation at room temperature for 20 h.
  • a sample of 10 ⁇ L is taken and diluted in 40 ⁇ L of DMSO (Gilson Liquid Handier Quad-Z 215). Each sample in solution in DMSO thus obtained is analyzed by LC / MS (Method A).
  • the 17 reaction mixtures are then evaporated to dryness and the evaporation residues are placed in solution in 1 ml of DMSO each in the presence of a drop of an aqueous solution of 5N hydrochloric acid and the solutions obtained are purified by LC / MS (Method B). After purification by LC / MS, the fractions containing the sought compounds are (optionally combined) deposited on the SCX phase (500 mg of CUBCX1-HL phase). The SCX phases are then washed with methanol and then extracted with a solution of 2M ammonia in methanol.
  • the amine library can be prepared as follows: 180 mg of 3- (5,6-dimethyl-1H-benzimidazol-2-yl) -4,5,6,7- tetrahydro-2H-pyrazolo hydrochloride [3,4-c] pyridine are suspended in 2.7 ml of methanol and the suspension obtained is distributed in 16 test tubes, at a rate of 150 ⁇ L per tube. The 16 aldehydes (Table 8) are weighed and added to each of the 16 test tubes. Table 8: Aldehydes used
  • a solution of 85 mg of NaBH 3 CN in 2.7 mL of methanol is then also distributed in the 16 test tubes, at a rate of 150 ⁇ L per tube.
  • the 16 reaction mixtures are stirred by orbital agitation at room temperature for 20 h. 100 ⁇ L of methanol are then added to each of the 16 tubes.
  • a sample of 10 ⁇ L is taken and diluted in 40 ⁇ L of DMSO (Gilson Liquid Handier Quad-Z 215). Each sample in solution in DMSO thus obtained is analyzed by LC / MS (Method A).
  • the 16 reaction mixtures are then evaporated to dryness and the evaporation residues are placed in solution in 500 ⁇ L of DMSO each, filtered on a frit, then the residual solutions are purified by LC / MS (Method B). After purification by LC / MS, the fractions containing the sought compounds are (optionally combined) deposited on the SCX phase (500 mg of phase CUBCX1-HL). The SCX phases are then washed with methanol and then extracted with a solution of 2M ammonia in methanol.
  • the urea library can be prepared as follows:
  • the 9 isocyanates (Table 10) are weighed and added to each of the 9 test tubes.
  • the aqueous phase obtained is then extracted with dichloromethane, then the organic phase is dried over magnesium sulfate and concentrated under reduced pressure.
  • the residue obtained and the precipitate are combined and then dissolved in methanol with a few drops of DMF.
  • This solution is then deposited on the MEGA BE-SCX phase.
  • the SCX phase is then washed with methanol and then extracted with a solution of 2M ammonia in methanol.
  • the extraction solution obtained is then concentrated under reduced pressure.
  • the aqueous phase is extracted three times with 1 L of ethyl acetate, then the combined organic phases are dried over magnesium sulfate and concentrated under reduced pressure.
  • the crude residue obtained is taken up in 150 ml of dichloromethane and the insoluble material is removed by filtration on a frit.
  • the filtrate is then concentrated under reduced pressure and purified by chromatography on silica (20-45 ⁇ m Amicon) with a gradient of 50 to 100% ethyl acetate in cyclohexane. The fractions containing the desired product are combined and concentrated under reduced pressure.
  • Tert-butyl 3- (2-amino-phenylcarbamoyl) -2,4,5,7-tetrahydro-pyrazolo [3,4-c] pyridine-6-carboxylate can be prepared as follows: 150 mg of 2,4,5,7-tetrahydro-pyrazolo [3,4-c] pyridine-6-tert-butyl-3-carboxylic carboxylate in 1 ml of anhydrous DMF, are added, at room temperature , 425 mg of HBTU as well as 145 mg of diisopropylethylamine. After twenty minutes of stirring at room temperature, 121 mg of orthophenylenediamine are added.
  • the reaction medium is diluted in 100 ml of water and 50 ml of ethyl acetate.
  • the aqueous phase is extracted three times with 50 ml of ethyl acetate, then the combined organic phases are dried over magnesium sulfate and concentrated under reduced pressure.
  • the crude residue obtained is purified by HPLC (reverse phase C18 Lichroprep 12 ⁇ m) with a linear gradient of 5 to 95% acetonitrile containing 0.07% (v / v) of trifluoroacetic acid in water containing 0.07 % (v / v) of trifluoroacetic acid, at a flow rate of 10 mL / min.
  • the sulfonamide library can be prepared as follows: 40 mg of 6- [3- (5,6-dimethyl-1 H-benzimidazol-2-yl) -2,4,5,7-tetrahydro-pyrazolo [3 , 4-c] pyridin-6-yl] -pyridin-3-ylamine are suspended in 2 ml of dichloromethane and the solution obtained is distributed in 4 test tubes, at a rate of 500 ⁇ L per tube. The 4 sulfonyl chlorides (Table 12) are weighed and added to each of the 4 test tubes, followed by 15.6 ⁇ L of triethylamine. Table 12: Sulfonyl chloride used
  • the 4 reaction mixtures are then evaporated to dryness and the evaporation residues are placed in solution in 500 ⁇ L of DMSO each and the solutions obtained are purified by LC / MS (Method B). After purification by LC / MS, the fractions containing the sought compounds are (optionally combined) deposited on the SCX phase (500 mg of CUBCX1-HL phase). The SCX phases are then washed with methanol and then extracted with a solution of 2M ammonia in methanol.
  • the extraction solutions are collected in tared glass tubes, evaporated to dryness (Savant AES 2000 or Genevac HT8 centrifugal evaporator), weighed (Mettler Toledo Automated Workstation LA200) and diluted to 10 mM in DMSO (Gilson Liquid Handier Quad-Z 215). Each solution obtained is analyzed by LC / MS (Method A).
  • La 6- [3- (5,6-dimethy-1 H-benzimidazol-2-yl) -2,4,5,7-tetrahydro-pyrazolo [3,4- c] pyridin-6-yl] -pyridin- 3-ylamine can be prepared as follows:
  • 3- (5,6-dimethyl-1 H-benzimidazol-2-yl) -6- (5-nitro-pyridin-2-yl) -4,5,6,7- tetrahydro-2H-pyrazolo [3, 4-c] pyridine can be prepared as follows: To a solution of 500 mg of 3- (5,6-dimethyl-1 H-benzimidazol-2-yl) -4,5,6,7-tetrahydro-2H-pyrazoio [3,4-c] pyridine hydrochloride 287 mg of 2-chloro-5-nitropyridine and 500 mg of potassium carbonate are added to 5 ml of dimethylformamide. After 20 hours of stirring at room temperature, the reaction medium is added to 50 ml of water.
  • 6- ⁇ 5- [3- (2-Fluoro-5-trifluoromethyl-phenyl) -ureido] -pyridin-2-yl ⁇ -4,5,6,7- tetrahydro-2H-pyrazolo [3,4-cjpyridine -3-carboxamide can be prepared as follows from 6- (5-tert-butoxycarbonylamino-pyridin-2-yl) -4,5,6,7- tetrahydro-2H-pyrazolo [3,4-c] ethyl pyridine-3-carboxylate:
  • ethyl ester of ethyl 6- (5-tert-butoxycarbonylamino-pyridin-2-yl) -4,5,6,7- tetrahydro-2H-pyrazolo [3,4-c] pyridine-3-carboxylate is transformed into carboxamide by amidification with an ammonia solution and leads to obtaining 6- (5-tert-butoxycarbonylamino-pyridin-2-yl) -4,5,6,7-tetrahydro-2H-pyrazolo [3,4-c] pyridine-3-carboxamide.
  • the urea function is introduced on 6- (5-amino-pyridin-2-yl) -4,5,6,7- tetrahydro-2H-pyrazolo [3,4-c] pyridine-3-carboxamide according to the method described in Example 1 using 2-fluoro-5- (trifluoromethyl) phenyl-isocyanate, and leads to obtaining 6- ⁇ 5- [3- (2-fluoro-5-trifluoromethyl-phenyl) -ureido] -pyridin-2-yl ⁇ -4,5,6,7-tetrahydro-2H-pyrazolo [3,4-c] pyridine-3-carboxamide.
  • Ethyl 6- (5-tert-Butoxycarbonylamino-pyridin-2-yl) -4,5,6,7-tetrahydro-2H-pyrazolo [3,4-c] pyridine-3-carboxylate can be prepared from as follows:
  • Ethyl 6- (5-Nitro-pyridin-2-yl) -4,5,6,7-tetrahydro-2H-pyrazolo [3,4-c] pyridine-3-carboxylate can be prepared as follows :
  • 4,5,6,7-tetrahydro-2H-pyrazolo [3,4-c] pyridine-3-carboxylate trifluoroacetate can be prepared in the following manner:
  • the coding sequence of human Tie2 corresponding to the amino acids of the intracellular domain 776-1124 was generated by PCR using cDNA isolated from human placenta as a model. This sequence was introduced into a baculovirus expression vector pFastBacGT in the form of a GST fusion protein.
  • the inhibitory effect of the molecules is determined in a PLC phosphorylation test with Tie2 in the presence of GST-Tie2 purified to around 80% homogeneity.
  • the substrate is composed of the SH2-SH3 fragments of the PLC expressed in the form of GST fusion protein.
  • the kinase activity of Tie2 is measured in a 20 mM MOPS buffer, pH 7.2, containing 10 mM MgCl 2 , 10 mM MnCl 2 , 1 mM DTT, 10 mM glycerophosphate.
  • a reaction mixture composed of 70 ⁇ l of kinase buffer containing 100 ng of GST-Tie2 enzyme per well is placed in a 96-well FlashPIate plate kept on ice. Then 10 ⁇ l of the test molecule diluted in DMSO to a concentration of 10% maximum are added. For a given concentration, each measurement is carried out in four copies.
  • the reaction is initiated by adding 20 ⁇ l of solution containing 2 ⁇ g of GST-PLC, 2 ⁇ M of cold ATP and 1 ⁇ Ci of 33 P [ATP]. After 1 hour of incubation at 37 ° C, the reaction is stopped by adding 1 volume (100 ⁇ l) of EDTA at 200 mM. After elimination of the incubation buffer, the wells are washed three times with 300 ⁇ l of PBS. Radioactivity is measured on a MicroBeta1450 Wallac. The inhibition of Tie2 activity is calculated and expressed as a percentage of inhibition relative to the control activity determined in the absence of compound.
  • the inhibitory effect of the compounds is determined in a substrate phosphorylation test with the enzyme KDR in vitro by a scintillation technique (96-well plate, NEN).
  • the cytoplasmic domain of the human KDR enzyme was cloned as a GST fusion into the baculovirus expression vector pFastBac.
  • the protein was expressed in SF21 cells and purified to approximately 60% homogeneity.
  • KDR kinase activity is measured in 20 mM MOPS, 10 mM MgCI2,
  • 10 mM MnCI2, 1 mM DTT, 2.5 mM EGTA, 10 mM b-glycerophosphate, pH 7.2, in the presence of 10 mM MgC_2, 100 ⁇ M Na 3 V0 4 , 1 mM NaF.
  • 10 ⁇ l of the compound are added to 70 ⁇ l of kinase buffer containing 100 ng of KDR enzyme at 4 ° C.
  • the reaction is started by adding 20 ⁇ l of solution containing 2 ⁇ g of substrate (fragment SH2-SH3 of the PLCD expressed in the form of GST fusion protein), 2 ⁇ Ci y 33 P [ATP] and 2 ⁇ M cold ATP.
  • the reaction is stopped by adding 1 volume (100 ⁇ l) of 200 mM EDTA.
  • the incubation buffer is removed, and the wells are washed three times with 300 ⁇ l of PBS.
  • Radioactivity is measured in each well using a Top Count NXT radioactivity counter (Packard).
  • the background noise is determined by measuring the radioactivity in four different wells containing the radioactive ATP and the substrate alone.
  • a total activity control is measured in four different wells containing all the reagents ( ⁇ 33 P- [ATP], KDR and PLCy substrate) but in the absence of compound.
  • the inhibition of KDR activity with the compound of the invention is expressed as a percentage of inhibition of the control activity determined in the absence of compound.
  • Compound SU5614 (Calbiochem) (1 ⁇ M) is included in each plate as an inhibition control.

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EP04767613A 2003-07-10 2004-07-08 Substituierte tetrahydro-1h-pyrazolo[3,4-c] pyridine, zusammensetzungen, die diese enthalten, und anwendung Withdrawn EP1646632A2 (de)

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FR0308441A FR2857362B1 (fr) 2003-07-10 2003-07-10 Tetrahydro-1h-pyrazolo[3,4-c] pyridines substituees, compositions les contenant et utilisation
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