EP1745044A2 - Derives de benzothiazoles capables de moduler l'activité des cdk et leur utilisation comme agents anticancereux - Google Patents

Derives de benzothiazoles capables de moduler l'activité des cdk et leur utilisation comme agents anticancereux

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Publication number
EP1745044A2
EP1745044A2 EP05744302A EP05744302A EP1745044A2 EP 1745044 A2 EP1745044 A2 EP 1745044A2 EP 05744302 A EP05744302 A EP 05744302A EP 05744302 A EP05744302 A EP 05744302A EP 1745044 A2 EP1745044 A2 EP 1745044A2
Authority
EP
European Patent Office
Prior art keywords
benzothiazol
ester
acid
amino
benzenesulfonic acid
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.)
Withdrawn
Application number
EP05744302A
Other languages
German (de)
English (en)
French (fr)
Inventor
Stéphanie Deprets
Anke Steinmetz
Odile Angouillant-Boniface
Daniel Bezard
Jidong Zhang
Yannick Benedetti
François CLERC
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Aventis Pharma SA
Original Assignee
Rhone Poulenc Rorer SA
Aventis Pharma SA
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Publication date
Application filed by Rhone Poulenc Rorer SA, Aventis Pharma SA filed Critical Rhone Poulenc Rorer SA
Publication of EP1745044A2 publication Critical patent/EP1745044A2/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D277/82—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates in particular to new chemical compounds, particularly new derivatives of benzothiazoles, the compositions containing them, and their use as medicaments.
  • the invention relates to new sulfonic esters of benzothiazoles exhibiting anticancer activity, via the modulation of the activity of proteins, in particular kinases.
  • Protein kinases are a family of enzymes that catalyze the phosphorylation of hydroxy groups of specific protein residues such as tyrosine, serine or threonine residues. Such phosphorylations can greatly modify the function of proteins; thus, protein kinases play an important role in the regulation of a wide variety of cellular processes, including in particular metabolism, cell proliferation, cell differentiation, cell migration or cell survival. Among the various cellular functions in which the activity of a protein kinase is involved, certain processes represent attractive targets for treating cancerous diseases as well as other diseases.
  • one of the objects of the present invention is to provide compositions having anti-cancer activity, by acting in particular with respect to kinases.
  • cyclin dependent kinases as well as Aurora-2 are preferred.
  • the progression of the cell cycle is often managed by cyclin dependent kinases (CDKs) which are activated by an interaction with proteins belonging to the cyclin family, activation which ends in the phosphorylation of substrates and finally by cell division.
  • CDKs cyclin dependent kinases
  • the endogenous CDK inhibitors that are activated (family of INK4 and KIP / CIP) negatively regulate the activity of CDKs.
  • normal cell growth is due to a balance between CDK activators (cyclins) and endogenous CDK inhibitors.
  • the expression or aberrant activity of several of these cell cycle regulators has been described.
  • Cyclin E activates the kinase Cdk2 which then acts to phosphorylate the protein pRb (retinoblastoma protein) resulting in an engagement in irreversible cell division and a transition to the S phase (PL Toogood, Medicinal Research Reviews (2001), 21 (6) ); 487-498.
  • the kinase CDK2 and may be CDK3 are necessary for progression into the G1 phase and entry into the S phase.
  • cyclin E they maintain the hyperphosphorylation of pRb to help progression from phase G1 to phase S.
  • CDK2 plays a role in the inactivation of E2F and is necessary for the realization of phase S (TD. Davies et al. (2001) Structure 9 , 389-3).
  • the CDK1 / cyclin B complex regulates the progression of the cell cycle between phase G2 and phase M.
  • the negative regulation of the CDK / Cyclin B complex prevents normal cells from entering the S phase before the G2 phase has been correctly and completely performed.
  • CAKs Cyclin-dependent kinase activators
  • This kinase named aurora2, STK15 or BTAK belongs to the family of serine / threonine kinases. Bischoff et al. have shown that Aurora2 is oncogenic, and is amplified in human colorectal cancers (EMBO J, 1998, 17, 3052-3065). This has also been exemplified in cancers involving epithelial tumors such as breast cancer.
  • the present invention relates to new benzothiazole derivatives. It thus relates to the use of benzothiazole derivatives as kinase inhibiting agents and more particularly as an anticancer agent. Among these, it preferably relates to the sulfonic esters of benzothiazoles. It also relates to the use of said derivatives for the preparation of a medicament intended for the treatment of humans.
  • Y1 can represent a sulfur atom
  • n can be zero
  • Z can be an acylamino group the groups X1, X2, X3, X4, are equal to H or can represent an alkylsulfonyoxy group.
  • • X represents a group chosen from a covalent bond, (Chbjn, with n equal to 1 or 2 • Ar represents an aryl or heteroaryl group; this group is optionally substituted by a group chosen from alkyl, halogen, NR- 1 R 2 (Ri and R 2 being chosen from hydrogen, alkyl or cycloalkyl groups or together may form a heterocyclic or heteroaryl radical, these groups being themselves optionally substituted), SOaalk, Salkyl, alkoxy, heteroaryl, or aryls • R represents a group chosen from hydrogen, an alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, cycloalkoxy, heterocycloalkoxy, amino group; R may be optionally substituted by one or more groups chosen from the same radicals as those defined for R.
  • R 1 and R 2 are chosen in particular from hydroxy, heteroaryl, cycloalkyl, aminoalkyl groups.
  • alkyl group means straight or branched chains containing 1 to 10 carbon atoms.
  • cycloalkyl group means cyclic alkyl chains containing 3 to 10 carbon atoms.
  • heterocycloalkyl group means cyclic alkyl chains containing 3 to 10 carbon atoms and containing at least one heteroatom chosen from O, N or S.
  • R 2 group is understood to mean amino groups, preferably secondary, ie groups for which at least one of the substituents is hydrogen.
  • aryl and heteroaryl radicals means monocyclic radicals optionally comprising one or more heteroatoms chosen from O, N and S or radicals fused to another cycle comprising 5 or 6 members and optionally one to three heteroatoms chosen from O, N and S.
  • aryl or heteroaryl radicals mention may be made of phenyl, pyridyl, pyrimidine, triazine, pyrrolyl, imidazolyl, thiazolyl, furyl, thienyl, indolyl, azaindazolyl, isobenzofuranyl, isobenzothienyl, benzoxazolyl, benzothiazole groups. , arylamido, arylcarboxamide, aralkylamine, quinoleyl, isoquinoleyl, cinnolyl, quinazolyl, naphthyridyl, triazolyl or tetrazolyl. It is preferred to choose from the aryl and heteroaryl groups the phenyl, thienyl, pyrazolyl, imidazolyl groups which may be substituted.
  • the amino groups and the halogens are preferred, in particular chlorine and fluorine, thus among the aryl groups, the di and trifluorophenyls and the monoalkylamino phenyls are particularly preferred, the alkyl chain optionally being substituted by a hydroxy group , dialkylamino.
  • the compounds of the present invention can be easily prepared from 5-methoxy-benzothiazol-2-ylamine (commercial compound).
  • the starting product is demethoxylated in an acid medium, preferably in an acetic acid / aqueous hydrobromic acid mixture.
  • the 5-hydroxy-benzothiazol-2-ylamides (4) are obtained by reaction between 5-hydroxy-benzothiazol-2-ylamine (2) and an acid of formula (3) (R as defined in the general formula (I)) in the presence of a coupling agent such as HATU or HBTU and a base such as diisopropylethylamine or triethylamine in an appropriate solvent.
  • the sulfono-esters of formula (6) are obtained by reaction between the 5-hydroxy-benzothiazol-2-ylamides (4) and a sulfonyl chloride of formula (5) (X and Ar as defined in the general formula (I)) in an inert solvent (acetone, THF, dichloromethane, toluene) in the presence of a base such as triethylamine or pyridine.
  • the nucleophilic substitution of F by amines of formula (7) (R1R2 as defined in the general formula (I)) to yield the derivatives of formula (8) is carried out in a aprotic solvent such as N-methylpyrrolidone or dimethylformamide at a temperature varying from 90 to 130 ° C in a sealed tube or in the microwave.
  • a aprotic solvent such as N-methylpyrrolidone or dimethylformamide
  • the compounds of the present invention can be easily prepared from 5-methoxy-benzothiazol-2-ylamine (commercial compound).
  • the starting product is demethoxylated in an acid medium, preferably in an acetic acid / aqueous hydrobromic acid mixture.
  • the sulfono-esters of formula (4) are obtained by reaction between 5-hydroxy-benzothiazol-2-ylamine (2) and a sulfonyl chloride of formula (3) (X and Ar as defined in the general formula (I)) in an inert solvent (acetone, THF, dichloromethane, toluene) in the presence of a base such as triethylamine or pyridine.
  • an inert solvent acetone, THF, dichloromethane, toluene
  • the nucleophilic substitution of F by amines of formula (6) (R1 R2 as defined in the general formula (I)) to yield the derivatives of formula (7) is carried out in an aprotic solvent such as N-methylpyrrolidone or dimethylformamide at a temperature varying from 90 to 130 ° C in a sealed tube or in the microwave.
  • an aprotic solvent such as N-methylpyrrolidone or dimethylformamide
  • the carbamates (8) are obtained by reaction between the amines of formulas (4 and 7) and a chloroformate of formula (5) (R3 as defined in general formula (I)) in the presence of an organic base such as pyridine, the triethylamine, diisopropylethylamine or inorganic such as potassium carbonate in an appropriate solvent.
  • an organic base such as pyridine
  • potassium carbonate such as potassium carbonate
  • solvents that can be used we can cite tetrahydrofuran, dichloromethane and dioxane.
  • the temperature of choice for carrying out this reaction is between 0 ° C. and reflux.
  • an aprotic solvent such as N-methylpyrrolidone or dimethylformamide
  • the compounds according to the invention can be used in human therapy and more particularly in the treatment of cancer, more particularly cancers sensitive to inhibitors of Aurora-2 and to those of Cdk2.
  • the present invention will be more fully described with the aid of the following examples which should not be considered as limiting the invention.
  • the DCI spectra were carried out in chemical desorbtion-ionization (reactant gas: ammonia, Finnigan SSQ7000 device).
  • the electrospray spectra (ES + ) were performed on a Platform II device (Micromass).
  • LC / MS analyzes were carried out on a Micromass model LCT device connected to an HP 1100 device.
  • the abundance of the products was measured using an HP G1315A diode array detector over a wave range of 200-600 nm and a Sedex 65 light scattering detector.
  • Mass spectra mass spectra were acquired over a range of 180 to 800. The data were analyzed using Micromass MassLynx software.
  • 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
  • Sedex 65 Mass spectra mass spectra were acquired over a range of 50 to 1500. The data were analyzed using Micromass MassLynx software. The separation was carried out on a 3.5 ⁇ m XTerral column (50 ⁇ 2.1 mm), eluting with a linear gradient of 5 to 95% acetonitrile in water containing 0.1% (v / v) of formic acid in 9 min at a flow rate of 0.7 mL / min. The total analysis time, including the column rebalancing period, is 9 min.
  • 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 was 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 an LC Packing Accurate, diluted with methyl alcohol at a flow rate of 0.5 ml / min and sent to the detectors, at a rate of 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] + .
  • the crude reaction product is purified by preparative LC / MS (basic medium (pH 9)) to lead, after lyophilization, to 21 mg of 4- (2-hydroxy-2-methyl-propylamino) - benzenesulfonic 2- (cyclopropanecarbonylamino) -benzothiazol-6 -yl ester (pale yellow solid).
  • the crude reaction product is purified by preparative LC / MS (basic medium (pH 9)) to lead, after lyophilization, to 63 mg of 4- (3-imidazol-1-yl-propylamino) -benzenesulfonic 2- (cyclopropanecarbonylamino) -benzothiazol- 6-yl ester (white solid).
  • the crude reaction product is purified by preparative LC / MS (basic medium (pH 9)) to lead, after lyophilization, to 61 mg of 4- (2-hydroxy-2-methyl-propylamino) -benzenesulfonic 2- (cyclopropane-carbonylamino) -benzothiazol-6-yl ester (beige solid).
  • reaction crude is purified by preparative LC / MS (basic medium (pH 9)) to lead after lyophilization to 66 mg of 4- (2-hydroxy-2-methyl-propylamino) - benzenesulfonic 2- (cyclopropane-carbonylamino) -benzothiazol-6-yl ester (beige solid).
  • the crude reaction product is purified by preparative LC / MS (basic medium (pH 9)) to lead, after lyophilization, to 36 mg of 4- (2-hydroxy-2-methyl-propylamino) - benzenesulfonic 2- (cyclo-propanecarbonylamino) -benzothiazol -6-yl ester (beige solid).
  • reaction medium is brought to dryness and the residue obtained is washed with dichloromethane and ethyl ether, resulting in 2.35 g of (6-Hydroxy-benzothiazol-2-yl) -carbamic acid tert-butyl ester (beige powder) with a yield of 77%.
  • 1 st step In a test tube with a stir bar, a solution of 4 - ⁇ [6- (4-Fluoro-benzenesulfonyloxy) -benzothiazol-2-ylcarbamoyl] -methyl ⁇ - piperidine-1-carboxylic acid tert-butyl ester (intermediate 17) (174 mg, 0.318 mmol), N-isopropylethylenediamine (97 mg, 0.954 mmol), cesium carbonate (103 mg, 0.318 mmol) in 3 ml of dimethyl sulfoxide is stirred overnight at 90 ° C. 100 ml of water are added to the reaction medium extracted with ethyl acetate.
  • Example 19 Using the same method as Example 18, the following examples are performed using 4 - ⁇ [6- (4-Fluoro-benzenesulfonyloxy) - benzothiazoI-2-ylcarbamoyl] -methyl ⁇ -piperidine-1 - carboxylic acid terf-butyl ester as a precursor (intermediate 17) combined with different amines.
  • the compound obtained after the first step is purified on a flash cartridge of 5 g of Interchim silica (15-35 ⁇ ) ⁇ ) by a gradient of 5 to 10% of methanol in dichloromethane with a flow rate of 10 ml / min.
  • 4-Fluoro-benzenesulfonic acid 2- (8- tert-buto ⁇ ycarbonylamino-octanoylaminp) -benzothiazol-6-yl ester is prepared by combining 4-Fluoro-benzenesulfonic acid 2-amino-benzothiazol -6-yl ester (intermediate 16) with Boc-8-aminocaprylic acid.
  • Example 22 Using the same method as Example 21, the following examples are carried out using 4-Fluoro-benzenesulfonic acid 2- (8-tert-butoxycarbonylamino-octanoylamino) -benzothiazol-6-yl ester (intermediate 20) as a precursor combined with different amines. These examples are presented in the following table:
  • Example 24 4- (2-isopropylamino-ethylamino) -benzenesulfonic acid 2- (3-piperidin-4-yl-propionylamino) -benzothiazol-6-yl ester hydrochloride
  • the compound resulting from the first step (4- (2- ⁇ 6- [4- (2- lsopropylamino-ethylamino) -benzenesulfonyloxy] -benzothiazol-2- ylcarbamoyl ⁇ -ethyl) -piperidine-1 -carboxylic acid tert-butyl ester) is purified on a flash cartridge of 5 g of silica with a porosity of 15-35 ⁇ by a gradient of 1% to 10% of methanol in dichloromethane.
  • Example 25 Using the same method as Example 24, the following examples are carried out using 4- ⁇ 2- [6- (4-Fluoro-benzenesulfonyloxy) - benzothiazol-2-ylcarbamoyl] -ethyl ⁇ -piperidine- 1 -carboxylic acid tert-butyl ester as a precursor (intermediate 23) combined with different amines. These examples are presented in the following table: Intermediate 26: Preparation of 4-isobutylamino-benzenesulfonic acid 2- tert-butoxycarbonylamino-benzothiazol-6-yl ester
  • reaction medium is concentrated to dryness and the residue is washed with ethyl ether leading to 700 mg of 4-isobutylamino-benzenesulfonic acid 2-amino-benzothiazol-6-yl ester in the form of the salt of trifluoroacetic acid (white solid ) with a yield of 52%.
  • the organic phase is washed with water, then with a saturated solution of sodium chloride, dried over magnesium sulfate and concentrated to dryness.
  • the residue obtained is purified by HPLC on a Dynamax C18 column, 60 ⁇ , 21 x 300 mm by a mixture of water / acetonitrile 95/5 for 5 minutes, by a gradient of 5 to 40% in water for 5 minutes, by a gradient of 40 to 80% of acetonitrile in water for 30 minutes, by a gradient from 80 to 95% acetonitrile in water for 5 minutes, then by a mixture of water / acetonitrile 5/95 for 5 minutes with a flow rate of 20 ml / min.
  • the solvents each contain 0.07% (v / v) of trifluoroacetic acid.
  • the fractions are collected every 30 seconds and are checked by analytical HPLC on a Hypersil C18 column, 4.6 x 50 mm. By a gradient from 0 to 100% acetonitrile in water in 10 minutes at a flow rate of 1 ml / min.
  • the solvents each contain 0.07% (v / v) of trifluoroacetic acid.
  • Example 29 Using the same method as Example 28, the following examples are carried out using 4-isobutylamino-benzenesulfonic acid 2-amino-benzothiazol-6-yl ester as precursor (intermediate 27) combined with different acids. These examples are presented in the following table:
  • Example 32 Preparation of Thiophene-2-sulfonic acid 2 - [(piperidine-4-carbonyl) -amino] -benzothiazol-6-yl ester; compound with trifluoro-acetic acid
  • Ee step 2 A solution of 4- [6-Thiophene-2-sulfonyloxy) benzothiazol-2-yl carbamoyl] -piperidine-1-carboxylic acid tert-butyl ester, trifluoroactéique acid (1.5 ml) in 1.5 ml of dichloromethane and 100 ⁇ l of water is stirred overnight at room temperature.
  • reaction medium is concentrated to dryness, taken up in 500 ⁇ l of DMSO and a sample is purified by preparative LC / MS (method B), leading to 3 mg of Thiophene-2-sulfonic acid 2 - [(piperidine-4-carbonyl) -amino] -benzothiazol- 6-yl ester; compound with trifluoro-acetic acid.
  • Example 33 Using the same method as Example 32, the following examples are carried out using Thiophene-2-sulfonic acid 2-amino-benzothiazol-6-yl ester as a precursor (intermediate 31) combined with different acids. These examples are presented in the following table, the LC / MS are produced according to the A1 method:
  • Example 39 Preparation of 4- (2-Diisopropylamino-ethylamino) -benzene-sulfonic acid 2 - [(azetidine-3-carbonyl) -amino] -benzothiazol-6-yl ester.
  • Example 40 Preparation of 4- (2-Diisopropylamino-ethylamino) -benzene-sulfonic acid 2- (8-amino-octanoylamino) -benzothiazol-6-yl ester.
  • Example 43 a Preparafondu4- (2-Diisopropylamino-ethylamino) -benzene-sulfonic acid 2-acetylamino-benzothiazol-6-yl ester hydrochloride:
  • Example 43 a is synthesized from 250 mg (0.557 mmol) of 4- (2-diisopropylamino-ethylamino) -benzenesulfonic acid 2-amino-benzo-thiazol-6-yl ester (intermediate 34) in solution with 57 mg (0.557 mmol) acetic anhydride, 216 mg (1.671 mmol) of N, N-diisopropylethylamine, in 10 ml of dichloromethane. The reaction medium is stirred overnight, then the same amounts of acetic anhydride and of N, N-diisopropylethylamine are added 2 times and the reaction is continued for 3 days at room temperature.
  • Example 44 4- (2-Diisopropylamino-ethylamino) -benzenesulfonic acid 2- (2- methoxy-acetylamino) -benzothiazol-6-yl ester
  • Example 44a Preparation of 4- (2-Diisopropylamino-ethylamino) -benzene-sulfonic acid 2- (2-methoxy-acetylamino) -benzothiazol-6-yl ester hydrochloride:
  • Example 44 a is synthesized according to the method of Example 44, starting from 750 mg (1.672 mmol) of 4- (2-diisopropylamino-ethylamino) -benzenesulfonic acid 2-amino-benzothiazol-6-yl ester (intermediate 34) to obtain the: 4- (2- Diisopropylamino-ethylamino) -benzenesulfonic acid 2- (2-methoxy-acetyl-amino) -benzothiazol-6-yl crude ester. This was dissolved in 1 ml of methanol, 3 ml of dioxane.
  • Example 45 4- (2-Diisopropylamino-ethylamino) -benzenesulfonic acid 2- (cyclopentanecarbonyl-amino) -benzothiazol-6-yl ester.
  • This oil is purified by LC / MS to give 55.2 mg of 4- (2-Diisopropylamino-ethylamino) -benzenesulfonic acid 2- (cyclopentane-carbonyl-amino) -benzothiazol-6-yl ester.
  • the reaction medium is extracted with ethyl acetate, washed with a hydrochloric acid N solution and then with water.
  • the organic phase is dried over sodium sulfate, filtered and then evaporated to dryness.
  • the residue is purified by chromatography using the Quad 12/25 on a Biotage type cartridge. (40 g of silica), eluting with a methylene chloride-isopropanol 97: 3 mixture. After evaporation of the solvent, 0.199 g of 4-Fluoro- benzenesulfonic acid 2- (6-tert-butoxycarbonylamino-hexanoylamino) -benzothiazol- 6-yl esters are recovered with a yield of 80%.
  • reaction medium is taken up in water and then brought to pH 8 with 28% ammonia. Extracted with AcOEt, washed with water and then dried the organic phase over sodium sulfate. After filtration, the filtrate is evaporated to dryness, leading to 0.1 g of white powder which is dissolved in 5 ml of methanol and then brought to pH 2 with hydrochloric acid in solution in AcOEt.
  • 4-Fluoro-benzenesulfonic acid 2- (7-tert-butoxycarbonylamino-heptanoylamino) -benzothiazol-6-yl ester is prepared by the action of 4-fluoro-benzenesulfonic acid 2-amino-benzothiazol -6- yl ester (intermediate 16, patent benzothiazole_V2) with BOC-7-aminoheptanoic acid leading to 0.164 g of product.
  • 4- (2-Diisopropylamino-ethylamino) - benzenesulfonic acid 2- (7-tert-butoxycarbonylamino-heptanoylamino) - benzothiazol-6-yl ester is prepared by the action of 4-Fluoro-benzenesulfonic acid 2- (7-tert-butoxycarbonylamino-heptanoylamino) -benzothiazol-6-yl ester with N, N-diisopropylethylenediamine.
  • the product is purified by chromatography on a Biotage type column (8 g of silica) eluting with a CHaC -MeOH 95: 5 mixture, leading to 86 mg of product, ie 44% yield.
  • Example 49 According to the method of Example 49, ie 4- (2-Diisopropylamino-ethylamino) - benzenesulfonic acid 2- (7-amino-heptanoylamino) -benzothiazol-6-yl ester hydrochloride is prepared by hydrolysis of 4- (2-Diisopropylamino -ethylamino) - benzenesulfonic acid 2- (7-tert-butoxycarbonylamino-heptanoylamino) - benzothiazol-6-yl in the presence of hydrochloric acid in solution in AcOEt, leading to 47 mg of hydrochloride, ie 77% yield.
  • the 4-Fluoro-benzenesulfonic acid 2-isobutyrylamino-benzothiazol-6-yl ester is prepared by the action of 4-fluoro- benzenesulfonic acid 2-amino-benzothiazol-6-yl ester (intermediate 16 , patentbenzothiazole_V2) with isobutyric acid.
  • the crude reaction product is crystallized with ethyl ether, after spinning, 0.17 g of colorless solid is isolated, ie 86% yield.
  • the 4-Fluoro-benzenesulfonic acid 2-propionylamino-benzothiazol-6-yl ester is prepared by the action of 4-fluoro- benzenesulfonic acid 2-amino-benzothiazol-6-yl ester (intermediate 16 , patentbenzothiazole_V2) with propionic acid.
  • the product, 0.397 g, is obtained with a yield of 93%.
  • 4-Fluoro-benzenesulfonic acid 2- (cyclobutanecarbonyl-amino) -benzothiazol-6-yl ester is prepared by the action of 4-fluoro-benzenesulfonic acid 2-amino-benzothiazol-6-yl ester with cyclobutanecarboxylic acid.
  • Example 53 4- (2-Diisopropylamino-ethylamino) - benzenesulfonic acid 2- (cyclobutanecarbonyl-amino) -benzothiazol-6-yl ester is prepared by the action of 4-Fluoro-benzenesulfonic acid 2-propionylamino - benzothiazol-6-yl ester with N, N-diisopropylethylenediamine by heating for 10 minutes in the microwave at 150 ° C.
  • the product, 0.054 g is obtained after purification with a yield of 18% in the form of the hydrochloride.
  • the 4 Fluo ⁇ benzenesuifonic acid 2- (3-pyridin-3-yl-propionylamino) -benzothiazol-6-yl ester is prepared by the action of 4-fluoro-benzenesulfonic acid 2-amino-benzothiazol -6-yl ester with 3- (3- pyridyl) -propionic acid.
  • the product is obtained with a quantitative yield.
  • Example 62 Preparation of 4- (2-Diisopropylamino-ethylamino) - benzenesulfonic acid 2- (3-pyridin-3-yl-propionylamino) -benzothiazol-6-yl ester hydrochloride.
  • Example 63 Preparation of 4- (2-Hydroxy-2-methyl-propylamino) - benzenesulfonic acid 2- (3-pyridin-3-yl-propionylamino) -benzothiazol-6-yl ester hydrochloride.
  • Example 67 Preparation of 4- (2-isopropylamino-ethylamino) - benzenesulfonic acid 2- (2-methoxy-acetylamino) -benzothiazol-6-yl ester.
  • the oil obtained is dissolved in 35 ml of dimethylsulfoxide, then purified in 7 times by preparative HPLC on a reverse phase column Nucleodur C18, 100 A, 10 ⁇ m by a gradient in 52 minutes from 5 to 95% acetonitrile added with 0.07% trifluoroacetic acid in water, added with 0.07% trifluoroacetic acid.
  • the flow rate is 70 ml / min.
  • the fractions containing the clean product are concentrated to obtain 300 mg of 4-Fluoro-benzenesulfonic acid 2-propionylamino-benzothiazol-6-yl ester with a yield of 69%.
  • intermediary 72 is synthesized using butyric acid. 80 mg of 4-Fluoro-benzenesulfonic acid 2-butyryl-amino-benzothiazol-6-yl ester are obtained with a yield of 18%.
  • Example 73 is obtained using intermediate 72 with N-isopropylethylenediamine. 37 mg of 4- (2- isopropylamino-ethylamino) -benzene-sulfonic acid 2-butyrylamino-benzothiazol-6-yl ester; compound with trifluoro-acetic acid with a yield of 36%.
  • intermediate 74 is synthesized using isobutyric acid. 75 mg of 4-Fluoro-benzenesulfonic acid 2- isobutyrylamino-benzothiazol-6-yl ester are obtained with a yield of
  • Example 75 is obtained using intermediate 74 with N-isopropylethylenediamine. 49 mg of 4- (2- isopropylamino-ethylamino) -benzenesulfonic acid 2-isobuty ⁇ ylamino-benzothiazol-6-yl ester; compound with trifluoro-acetic acid are obtained with a yield of 44%.
  • intermediate 76 is synthesized using cyclobutanecarboxylic acid. 185 mg of 4-Fluoro-benzenesulfonic acid 2- (cyclobutanecarbonyl-amino) -benzothiazol-6-yl ester are obtained with a yield of 40%.
  • Example 77 is obtained using intermediate 76 with N-isopropylethylenediamine. 41 mg of 4- (2- ls ⁇ propylarnino-ethylamino) -benzenesulfonic acid 2- (cyclobutanecarbonylamino) -benzothiazol-6-yl ester; compound with trifluoro-acetic acid are obtained with a yield of 37%.
  • Example 79 Preparation of 4- (2-Diisopropylamino-ethylamino) - benzenesulfonic acid 2-butyrylamino-benzothiazol-6-yl ester hydrochloride.
  • Example 80 Preparation of 4- (2-Hydroxy-2-methyl-propylamino) - benzenesulfonic acid 2-butyrylamino-benzothiazol-6-yl ester hydrochloride. o In a 5 ml vial for microwaves fitted with a magnetic bar, a solution of 4-Fluoro-benzenesulfonic acid 2-butyrylamino-benzothiazol-6-yl ester (intermediate 78) (135 mg, 0.34 mmol), 1-amino-2-methyl-propan- 2-ol (153 mg, 1,718 mmol) in 3 ml of N-methylpyrrolidone is heated
  • the organic phase is dried over magnesium sulfate, then concentrated to dryness.
  • the dry residue is purified by reverse phase chromatography on a C18 Dynamax 300 x 20 mm column, by a gradient in 5 minutes from 5 to 40% acetonitrile in water supplemented with 0.07% trifluoroacetic acid, then from 40 to 80% in 30 minutes.
  • the solution is then diluted with water, extracted with ethyl acetate, washed with a saturated solution of sodium chloride and dried over sodium sulfate, then evaporated to dryness, leading to 258 mg of crude product.
  • This is purified by flash chromatography on a cartridge of 5 g of silica.
  • the eluents used are respectively dichloromethane, then dichloromethane with 1% of 0.01% ammoniacal methanol at 7M.
  • the reaction medium is filtered and then concentrated.
  • the oil obtained is reacted with 278 mg of ammonium formate (4.41 mmol) and 300 mg of palladium on carbon at 10% in 15 ml of ethanol.
  • the reaction medium is stirred and heated to reflux for 1 hour 20 minutes.
  • the reaction medium is filtered and concentrated to dryness.
  • the residue obtained is purified by preparative LC / Ms (method B) leading to 6.2 mg of 4- (2-Methyl-2-phosphonooxy-propylamino) -benzenesulfonic acid 2- (cyclopropanecarbonyl- amino) -benzothiazol-6-yl ester with a yield of 3%.
  • CDK2 / cyclin E protocol Purification of the CDK2 / CyclineE- (His) 6 complex by IMAC (Immobilized Metal Affinity Chromatography): Two recombinant baculoviruses carrying the human sequences coding respectively for CDK2 and CyclineE (the latter containing a hexa-histidine tag at C terminal) are used to co-infect Sf21 insect cells. Two to three days after the start of co-infection, the cells are harvested by centrifugation, then stored at - ⁇ * 0 ° C until they are used. After thawing and mechanical lysis of the cells, the complex present in the lysis supernatant is purified by affinity chromatography on nickel (IMAC), and stored at -80 ° C.
  • IMAC affinity chromatography on nickel
  • a 96-well plate format coated with streptavidin is used to test the activity of the compounds on the kinase activity of CDK2 / Cyclin E.
  • the biotynilized peptide substrate, fragment of the pRb protein, (biotinyl-SACPLNLPLQNNHTAADMYLSPVRSPKKKGSTTR - OH) is dissolved at the concentration of 1 mM in kinase buffer (HEPES / NaOH 50 mM, NaCI 1 mM, MgCI 2 5 mM, pH 7.5) in order to constitute a stock solution stored at -20 ° C in the form of aliquots of 110 ⁇ l.
  • Dilutions are thus made to 1000 ⁇ M, 333.3 ⁇ M, 111.1 ⁇ M, 37.03 ⁇ M, 12.35 ⁇ M, 4.11 ⁇ M and 1.37 ⁇ M.
  • One ⁇ l of each of these solutions (or 1 ⁇ l of DMSO for the controls) is transferred to the wells of the test plate.
  • 19 ⁇ l of a solution of a mixture of adenosinetriphosphate (ATP) and ATPy 33 P in kinase buffer at the concentration of 5.26 ⁇ M of total ATP and 52.6 are then added to each well. ⁇ Ci / ml of 33 P.
  • the enzymatic reaction is triggered by the addition of 10 ⁇ l per well of a solution of CDK2 / Cyclin E at 200 nM in the kinase buffer containing 1 mM of dithiothreitol (or 10 ⁇ l of kinase buffer containing 1 mM dithiothreitol for reaction blanks).
  • the final volume of each well is 100 ⁇ l
  • the final substrate concentration is 10 ⁇ M
  • the final inhibitor concentrations are 10 ⁇ M, 3.33 ⁇ M, 1.11 ⁇ M, 0.37 ⁇ M , 0.123 ⁇ M, 0.041 ⁇ M and 0.014 ⁇ M (depending on the concentration of the intermediate dilution)
  • the final concentration of ATP is 1 ⁇ M
  • the final quantity of 33 P is 1 ⁇ Ci / well
  • the final concentration of CDK2 / Cyclin complex E is 20 nM.
  • Two recombinant baculoviruses carrying the human sequences respectively coding for CDK4-HA (C terminal fusion with the tag Hemaglufinine) and for Cycline D1- (His) 6 are used to co-infect insect cells S / 9. Sixty hours after the start of co-infection, the cells are harvested by centrifugation, then frozen at -20 ° C until they are used.
  • buffer A HEP 200 mM pH 7.0, NaCI 50 mM, MgCI 2 2 mM, imidazole 25 mM, TCEP 1 mM, glycerol 10% (w / v), 1 mM NaF, 1 mM Na 3 VO
  • IMAC affinity chromatography on nickel
  • Flashplate CDK4 / CvclinD1 assay in 96-well format A 96-well "flashplate” plate test coated with streptavidin is used to evaluate the inhibition of the CDK4 / cyclin D1 kinase complex by the products of the invention.
  • Dilutions are thus made to 1000 ⁇ M, 333.3 ⁇ M, 111.1 ⁇ M, 37.03 ⁇ M, 12.35 ⁇ M, 4.11 ⁇ M and 1.37 ⁇ M.
  • One ⁇ l of each of these solutions (or 1 ⁇ l of DMSO for the controls) is then transferred to the wells of the test plate.
  • 19 ⁇ l of a solution of a mixture of adenosinetriphosphate (ATP) and ATP ⁇ 33 P in the kinase buffer at the concentration of 5.26 ⁇ M of total ATP and 78.9 ⁇ Ci / are then added to each well.
  • the enzymatic reaction is triggered by the addition of 10 ⁇ l per well of a solution of CDK4 / Cycline D1 complex at 250 nM in the kinase buffer containing 1 mM of dithiothreitol (or 10 ⁇ l of kinase buffer containing 1 mM dithiothreitol for reaction blanks).
  • the final volume in each well is 100 ⁇ l
  • the final substrate concentration is 1.8 ⁇ M
  • the final inhibitor concentrations are 10 ⁇ M, 3.33 ⁇ M, 1.11 ⁇ M, 0, 37 ⁇ M, 0.123 ⁇ M, 0.041 ⁇ M and 0.014 ⁇ M (depending on the concentration of the intermediate dilution)
  • the final concentration of ATP is 1 ⁇ M
  • the final quantity 33 P is 1.5 ⁇ Ci / well
  • the final concentration of CDK4 / Cycline D1 complex is 25 nM.
  • the incorporation of 33 P into the substrate peptide is measured by scintillation counting with a Packard Topco ⁇ nt.NXT device.
  • the inhibitory activity of the products of the invention is evaluated by determining the concentration of inhibitor causing a reduction of 50% in the enzymatic activity (IC50).
  • the inhibitory effect of compounds against the Aurora2 kinase is determined by a radioactivity scintillation test.
  • NuMA Nuclear protein which associates with the Mitotic Apparatus
  • the kinase activity of Aurora2 is measured by scintillation in a microplate saturated with nickel chelate (New England Nuclear, model SMP107). Each well contains 100 ⁇ l of the following solution: 0.02 ⁇ M of Aurora2; 0.5 ⁇ M of NuMA substrate; 1 ⁇ M ATP plus 0.5 ⁇ Ci ATP- [ 33 P]. The solutions are incubated for 45 minutes at 37 ° C. The test buffer is then removed and the wells are rinsed twice with 300 ⁇ l of kinase buffer. Radioactivity is measured in each well using a Packard Model Top Count NXT device. The background noise is measured in duplicate in wells containing radioactive ATP alone containing buffered kinase treated in the same way as the other samples. The control activity is carried out by measuring in duplicate the radioactivity in the complete test mixture (ATP, Aurora2 and the NuMA substrate), in the absence of test compound.
  • the inhibition of the activity of Aurora2 with a compound of the invention is expressed as a percentage of inhibition of the control activity in the absence of test compound. Staurosporine is added to each plate as an inhibition control.

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EP05744302A 2004-04-01 2005-03-30 Derives de benzothiazoles capables de moduler l'activité des cdk et leur utilisation comme agents anticancereux Withdrawn EP1745044A2 (fr)

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US8236338B2 (en) 2004-07-13 2012-08-07 The University Of Tennessee Research Foundation Adhesive composition for carrying therapeutic agents as delivery vehicle on coatings applied to vascular grafts
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US8119655B2 (en) 2005-10-07 2012-02-21 Takeda Pharmaceutical Company Limited Kinase inhibitors
US20070112589A1 (en) * 2005-11-17 2007-05-17 Searete Llc, A Limited Liability Corporation Of The State Of Delaware User interface for providing assistance related to health
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US20100120717A1 (en) 2006-10-09 2010-05-13 Brown Jason W Kinase inhibitors
FR2922550B1 (fr) 2007-10-19 2009-11-27 Sanofi Aventis Nouveaux derives de 6-aryl/heteroalkyloxy benzothiazole et benzimidazole, application comme medicaments, compositions pharmaceutiques et nouvelle utilisation notamment comme inhibiteurs de cmet
CN102391207B (zh) * 2011-07-26 2014-04-09 贵州大学 N-(2-(取代苯并噻唑-2-氨基甲酰基)-苯基)-苯甲酰胺及其制备方法和用途
AU2013338051C1 (en) 2012-10-29 2017-08-10 Ariste Medical, Llc. Polymer coating compositions and coated products
CN106471074A (zh) 2014-04-22 2017-03-01 阿里斯特医疗公司 用于施加药物递送聚合物涂料的方法和工艺

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