EP1979352A2 - Pyridopyrimidonderivate, deren herstellung und therapeutische verwendung - Google Patents

Pyridopyrimidonderivate, deren herstellung und therapeutische verwendung

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Publication number
EP1979352A2
EP1979352A2 EP07717935A EP07717935A EP1979352A2 EP 1979352 A2 EP1979352 A2 EP 1979352A2 EP 07717935 A EP07717935 A EP 07717935A EP 07717935 A EP07717935 A EP 07717935A EP 1979352 A2 EP1979352 A2 EP 1979352A2
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European Patent Office
Prior art keywords
ppm
compound
formula
pyrido
dihydro
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EP07717935A
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English (en)
French (fr)
Inventor
Pierre Perreaut
Samir Jegham
Bernard Bourrie
Pierre Casellas
Jean-Robert Labrosse
Florence Durand
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Sanofi SA
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Sanofi Aventis France
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Publication of EP1979352A2 publication Critical patent/EP1979352A2/de
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    • 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
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    • 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
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    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A61P35/00—Antineoplastic agents
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
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Definitions

  • the present invention relates to pyrido [2,3-d] pyrimidone derivatives, their preparation and their therapeutic application.
  • the subject of the present invention is compounds corresponding to formula (I):
  • R1 is selected from the group consisting of: H, (C-
  • R2 and R3 are independently selected from the group consisting of: H, halogen, (C1-C4) alkyl, trifluoromethyl and (C1-C4) alkoxy;
  • Ar 1 represents a radical chosen from:
  • R 5 is selected from the group consisting of: H, cyano, hydroxy (C 1 -C 4) alkyl, (C 1 -C 6 ) alkoxy (C 1 -C 4 ) alkyl, - (CH 2 ) n NR 6 R 7, - ( CH 2 ) mCO 2 R 6, (CH 2 ) m CO NHNR 6 R 7, - (CH 2 ) m CONR 6 R 7, - (CH 2 ) m CONR 7 OR 8,
  • R4 is selected from the group consisting of: H, (C1-C4) alkyl and R5; it being understood that when Ar 1 takes the value a), then R4 and R5 are not two hydrogen atoms,
  • R6 and R7 are independently selected from the group consisting of: H, (C1-C4) alkyl, (C3-C7) cycloalkyl, (C3-C7) cycloalkyl (C1-C4) alkyl, R7 may also represent a group te / t-butoxycarbonyl or benzyloxycarbonyl; or R6 and R7 together with the nitrogen atom to which they are attached constitute an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl radical;
  • R8 is selected from the group consisting of: H and (C -] - C4) alkyl;
  • X is O or S
  • X 1 and X 2 are independently selected from the group consisting of: H and - (C 1 -C 6 ) alkyl-N ((C 1 -C 6 ) alkyl) 2 ; when one of X1 and X2 is other than H, then X3 is selected from the group consisting of hydroxy and (C-
  • R 9 is selected from the group consisting of: H, 3-butyloxycarbonyl, benzyloxycarbonyl and (C 1 -C 8) alkyl;
  • R 10 is selected from the group consisting of: hydroxy, (C 1 -C 6) alkoxy and -NR 11 R 12;
  • R11 and R12 are independently selected from the group consisting of: H and (C -] -Cg) alkyl; or R11 and R12 together with the nitrogen atom to which they are attached constitute an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl radical;
  • n 0, 1, 2 or 3;
  • n 1, 2 or 3, in the form of a base or an addition salt with an acid, as well as in the hydrate or solvate state.
  • the compounds of formula (I) may exist in the form of bases or addition salts with acids.
  • compounds of formula (I) have free acid functions, for example carboxylic, sulphonic or phosphonic, these acid functions may be salified with bases to form addition salts.
  • Such addition salts are part of the invention.
  • the addition salts with acids or bases are advantageously prepared with, respectively, pharmaceutically acceptable acids or bases, but the salts of other acids or bases which are useful, for example, for the purification or isolation of compounds of formula (I) are also part of the invention.
  • the compounds of formula (I) may also exist in the form of hydrates or solvates, namely in the form of associations or combinations with one or more molecules of water or with a solvent. Such hydrates and solvates are also part of the invention.
  • the compounds of formula (I) can comprise one or more asymmetric carbon atoms.
  • Non-chiral, or racemic, or stereoisomerically enriched or enantiomerically enriched forms are part of the invention.
  • halogen atom a fluorine, a chlorine, a bromine or an iodine
  • an alkyl group a saturated, linear or branched aliphatic group.
  • alkyl group a saturated, linear or branched aliphatic group.
  • alkenyl group a linear or branched, mono- or poly-unsaturated aliphatic group, comprising, for example, one or two ethylenic unsaturations;
  • an alkynyl group a linear or branched, mono- or poly-unsaturated aliphatic group, comprising, for example, one or two acetylenic unsaturations; a cycloalkyl group: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo [2.2.1] heptyl, cyclooctyl, bicyclo [2.2.2] octyl, bicyclo [3.2.1] octyl, adamantyl.
  • - R- is selected from a group consisting of H, (C 1 -C 6) alkyl, (C 3 -C 7 ) cycloalkyl, (C 1 -C 6 ) alkyl- (C 3 -C 7) cycloalkyl,
  • R2 and R3 are independently selected from a halogen atom, a (C ⁇ - C / jJalkyle, trifluoromethyl or (C-
  • Ar 1 represents a radical chosen from:
  • R 5 represents a hydrogen atom or a cyano, hydroxy (C 1 -C 4) alkyl, (C 1 -C 6 ) alkoxy (C 1 -C 4) alkyl group or a (CH 2 ) n NR 6 R 7 group, 2) H1 Ro CO 2, (CH 2) m CONHNR6R7, (CH 2) m CONR6R7, (CH 2) m C0NR70R8, (CH 2) n NR6COR7, (CH 2) n NR6COOR7; R 4 represents a hydrogen atom, a (C 1 -C 4) alkyl group or one of the values of R 5, it being understood that when Ar 1 takes the value a), then R 4 and R 5 are not two carbon atoms; R 6 and R 7 are each independently of the other a substituent selected from H, (C 1 -C 4 ) alkyl, (C 3 -C 7) cycloalkyl, - (C 1 -C 4 ) alkyl-
  • X 1 and X 2 are independently selected from the group consisting of H and - (C 1 -C 6 ) alkyl-N ((C 1 -C 6 ) alkyl) 2 ; when one of X1 and X2 is different from H, then X3 is selected from the group consisting of OH and O- (C 1 -C ⁇ ) alkyl; when X1 and X2 are H, then X3 is selected from the group consisting of: (CH 2) n -CH (NH R9) -CO-R10, -0- (CH 2) H -CH (NHRQ) -CO-RI O, and -NHSO 2 - (C 1 -C 6 ) alkyl;
  • R 9 is selected from H, t-butyloxycarbonyl, benzyloxycarbonyl, and - (C 1 -C 8) alkyl;
  • R10 is selected from OH, O- (C 1 -C e) alkyl and NR 11 R 12;
  • R11 and R12 are independently selected from the group consisting of H and
  • R11 and R12 together with the nitrogen atom to which they are attached constitute an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl radical;
  • n 0, 1, 2 or 3
  • Ar - represents a radical chosen from: in which R4, R5, X1, X2, X3 and X are as defined above, in the form of a base or of an addition salt with an acid, and in the hydrate or solvate state.
  • R 1 is preferably a methyl.
  • R 1 is preferably a cyclopentyl.
  • R 1 is preferably a -CH 2 -C ⁇ CH group.
  • R2 and R3 are preferably two chlorine atoms in position 2 and 6.
  • Another subject of the present invention relates to a process for preparing a compound of formula (I), characterized in that a compound of formula (II) is reacted with:
  • R 1 , R 2, and R 3 are as defined for (I), with an amine of formula Ar ' 1 NH 2 (III) wherein Ar 1 represents Ar 1 , as defined for (I) or a precursor of Ar 1 ; where appropriate, the Ar 1 group of the compound thus obtained is converted into a group Ar 1 .
  • the compounds of formula (II) are prepared following the procedure described in J. Med. Chem. 1998, Vol. 41, pp. 3276-3292.
  • the amine functions present in the Ar 1 group of the compound (III) are previously salified or protected by a protective group G.
  • the amines of formula (III) are known or commercially available or prepared by conventional methods in organic chemistry. Certain preparations of the amines of formula (III) are known: from the corresponding nitro derivatives Ar ' 1 NO 2 (IV), by reduction either (i) in an acid medium in the presence of a metal such as iron or zinc powder or (ii) with hydrogen in the presence of a catalyst such as Pd / C.
  • the compounds of formula (IV) are known or prepared by known methods.
  • the 5-nitro-1,3-benzodioxoles, gem-disubstituted at 2 can be prepared according to Pharmazie, 2003, 58 (1), 13-17 by the action of ethyl dibromomalonate on A-nitrocatechol (4-nitrobenzene-1 , 2-diol).
  • the 7-nitro-2,3-dihydro-1,4-benzodioxins substituted in 2 or 3 by R5 and R4 can be prepared according to the method described in the patent application WO 01/021 577 from 4-nitrocatechol or by known chemical transformations.
  • (1,3-Dihydro-5-isobenzofuranyl) amine is described in J. Med. Chem., 1978, 21, 965-978.
  • (CH 2) m allows -C ⁇ 2Me to prepare compounds of formula (IV) or (I) in which R5 represents a group - (CH 2 ) m --CO 2 R 6, - (CH 2 ) m -CONR 6 R 7 .- (CH 2 ) m -CONHNR 6 R 7, - (CH 2) ) m -CONR7OR8, - (CH 2 ) n -NR6R7, - (CH 2 ) n -NR6COR7, - (CH 2 ) n -NR6COOR7 by methods known to those skilled in the art.
  • the compounds according to the invention are obtained in racemic form; the optically pure isomers can then be prepared using resolution methods known to those skilled in the art, such as crystallization by salt formation with chiral agents.
  • Compounds according to the invention can also be prepared in optically pure form using asymmetric or stereospecific synthesis methods, or chromatographic techniques using a chiral phase.
  • the products of the invention can be separated via the formation of diastereoisomers, their separation, and then the decomposition of the pharmacologically useful diastereoisomer into its enantiomerically pure active product. Enzymatic techniques can also be employed. Additional known separative techniques can be used.
  • the compounds according to the invention can also be prepared in a stereoisomerically enriched form as soon as the synthetic intermediates are prepared.
  • the resolution of the enantiomers of the amines of formula (III) or of the nitro precursors (IV) can be achieved by one of the abovementioned methods.
  • the following examples describe the preparation of certain intermediates and compounds according to the invention. These examples are not limiting and only illustrate the present invention.
  • BOP benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate.
  • DIPEA diisopropylethylamine
  • Step 1 A mixture of 0.384 g of compound of formula (II), 6- (2,6-Dichlorophenyl) -8-methyl-2-methylsulfonyl-8H-pyrido [2,3-d] pyrimidin-7-one, and 0.266 g of compound of formula
  • Step 2 The amine function of Ar 1 is deprotected by stirring 0.240 g of the above product for 1 h in a mixture of 3.5 mL of dichloromethane and 3.5 mL of trifluoroacetic acid. After concentration in vacuo to dryness the residue is taken up in a mixture of water and dichloromethane and the pH brought to 9 by a 15% solution of Na 2 CO 3 ; the organic phase is decanted, washed with water and then with a saturated solution of NaCl, dried over Na 2 SO 4 then evaporated; the yellow solid residue is triturated in ether, filtered and dried.
  • M 0.121 g MH + : 470
  • Step 1 To 17.6 g of 60% NaH suspended in 300 ml of DMF, 31.0 g of 4-nitrocatechol was added over 1 hour with cooling to keep the temperature below 30 ° C. After stirring for a further 15 minutes, 104 ml of methyl dichloroacetate are then added over 1 hour and the mixture is then stirred for 4 hours at 90 ° C. The reaction medium is poured into a mixture of 2 liters of ice / water and then extracted 4 times with 400 ml. mL of AcOEt. The combined organic phases are washed once with a saturated NaCl solution and then dried and concentrated under vacuum (evaporation of DMF).
  • Step 5 To 1.7 g of the product obtained in the preceding step, dissolved in 20 ml of AcOEt, 3.41 g of triphenylphosphine are added in small portions and then, after 10 minutes, 2.34 ml of water and the mixture is heated to 80.degree. 60 ° C. After 1 hour, the reaction medium is evaporated to dryness and then taken up in Et 2 O. The insolubles are removed and then a solution of saturated HCl in ether is added in excess. The solid formed is filtered, washed with ether and then dried to obtain the expected product in hydrochloride form. The corresponding amine is obtained by liberation of the hydrochloride.
  • Step 6 To the product obtained in the preceding step, in 30 ml of DCM, 1.49 ml of triethylamine are added and then in small portions 2.53 g of Boc 2 O. After 1 hour, the reaction medium is washed with KHSO 4 / K 2 SO 4 5%, H 2 O, saturated NaCl. After drying, the organic phase is concentrated to dryness and the residue is then triturated in heptane; 2 g expected product is obtained in the form of a solid.
  • Step 7 The product of formula (III) is obtained from 0.52 g of its nitrated precursor of formula (IV) dissolved in 15 ml of THF, 1.72 g of powdered zinc are added and then at -5 ° C. min 2 mL of acetic acid. Stirring is continued for 3 h at room temperature and the reaction medium is filtered, the solid rinsed with a little THF and methanol; the filtrate is taken up in a mixture of water and ethyl acetate and brought to pH 9 with a solution of Na 2 CO 3 at 15%. After decantation, the organic phase is washed with saturated NaHCO 3 solution and then with water and then with saturated NaCl solution. After drying over Na 2 SO 4 the solvent is evaporated, a thick oil is obtained. 100% yield.
  • the compound of formula (III) is commercial.
  • reaction medium After cooling to room temperature, the reaction medium is concentrated under vacuum and chromatographed on silica (Gradient: Heptane 100 to Heptane / ethyl acetate 35:65) to give 2.39 g of the expected product as a yellow solid.
  • Step 2 To 1.50 g of the product obtained previously in solution in 16 mL of tetrahydrofuran and 4 mL of water are added at 0 ° C, 117 mg of LiOH. After 2 hours of contact at 0 ° C, the reaction is complete. The reaction medium is then hydrolyzed with water, diluted with ethyl acetate and acidified to pH 1 with 2N HCl. The organic phase is washed with water, with saturated NaCl solution, dried over sodium sulfate and concentrated in vacuo. The residue is chromatographed on silica (gradient: dichloromethane 100 to dichloromethane / methanol 80:20) to give 1.01 g of the expected product as a yellow solid.
  • Step 3 To 900 mg of the product obtained previously in solution in 20 ml of dimethylformamide are added successively at room temperature under nitrogen, 136 mg of dimethylamine hydrochloride, 729 mg of (benzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate and 1.12 mL of diisopropylethylamine. After 1 hour of contact, the reaction is complete. The reaction medium is then hydrolyzed with water and diluted with ethyl acetate. The organic phase is washed with water, with saturated NaCl solution, dried over sodium sulfate and concentrated in vacuo.
  • Step 4 To 800 mg of the product obtained previously in solution in 10 ml of dichloromethane, 10 ml of trifluoroacetic acid are added at ambient temperature.
  • Step 1 To 20.00 g of the derivative of the methyl ester of the (D) serine dissolved in 250 ml of dichloromethane are added, at room temperature under nitrogen, 36.82 ml of triethylamine. After cooling the reaction medium to 0 ° C., a solution of trityl chloride in 200 ml of dichloromethane is poured so as to maintain the temperature of the medium between 0 ° C. and 5 ° C. After contacting for 3 hours at 5 ° C., the reaction medium is washed with saturated NH 4 Cl solution, with water, with saturated NaCl solution, dried over sodium sulphate and concentrated in vacuo. The residue is taken up in diethyl ether. The precipitate obtained is filtered and 41.72 g of the expected product in the form of a white solid are isolated after drying.
  • Step 2 To 41.00 g of the product obtained previously in solution in 1250 mL of tetrahydrofuran are added, at room temperature under nitrogen, successively 37.19 g of triphenylphosphine, 20.13 g of p-nitrophenol and 23.02 mL of diethylazodicarboxylate. After 20 minutes of contact, the reaction medium is diluted with ethyl acetate. The organic phase is washed with a saturated solution of NaHCO 3 , with a saturated solution of NaCl, dried over sodium sulphate and concentrated in vacuo. The residue is chromatographed on silica (Gradient: Heptane 100 to Heptane / ethyl acetate 70:30) to give 36.12 g of expected product as a white solid.
  • Step 3 To 36.00 g of the product obtained previously in solution in 370 ml of dichloromethane, 360 ml of trifluoroacetic acid are added at ambient temperature. After 30 minutes of contact, the reaction is complete and the reaction medium is concentrated under vacuum. The residue is taken up in diethyl ether and then the precipitate is filtered and 12.027 g of expected product (product in the form of trifluoroacetic acid salt) are isolated after drying.
  • Step 4 At 11.80 g of the product obtained previously in the form of TFA salt dissolved in 200 ml of dichloromethane are added, at ambient temperature under nitrogen, successively 20.54 ml of triethylamine and 13.26 g of di-iron. -butyldicarbonate.
  • reaction medium is hydrolyzed with an aqueous 5% KHS solution (VK 2 SO 4)
  • organic phase is washed with water, with saturated NaCl solution, dried over sodium sulphate and concentrated.
  • the residue is chromatographed on silica (Gradient: Heptane 100 to Heptane / ethyl acetate 50:50) and 10.41 g of the expected product as a yellow solid are obtained.
  • Step 5 To a solution of 10.15 g of the nitro product obtained above and 29.25 g of zinc in 300 ml of tetrahydrofuran, 30.70 ml of acetic acid are poured while maintaining the temperature between 0 ° C. and -5 ° C. ° C.
  • reaction medium After returning to ambient temperature and 3 hours of contact, the reaction medium is diluted with ethyl acetate and filtered through Celite. The organic phase is basified by addition of NaHCO 3 and then washed with a saturated solution of NaHCO 3 , with a saturated solution of NaCl. After drying over sodium sulphate and concentrating under vacuum, 9.41 g of an orange oil are isolated.
  • a compound of formula (III) is obtained wherein Ar 'i is a precursor of Ar, which will be modified after the addition reaction with the compound of formula (II).
  • Example 6 (2S) -2-Amino-3-r4-rr6- (2,6-dichlorophenyl) -7,8-dihydro-8-methyl-7-oxopyrido [2,3-d] pyrimidin-2 yl] amino] phenoxy] -N, N-dimethyl-propanamide.
  • the product of Example 6 is synthesized in the same manner as that of Example 5, replacing (D) serine with (L) serine.
  • MH + 527
  • aqueous phase is extracted with ethyl acetate and the combined organic phases are then washed with water and then with a saturated solution of NaCl. After drying over sulphate of sodium and filtration, the residue is chromatographed on silica (Gradient: Heptane 100 to Heptane / ethyl acetate 60:40) and precipitated in diethyl ether to give 283 mg of expected product as a yellow solid.
  • the compound of formula (III) is commercial.
  • Example 7 (R / S) -N-Methylamide of 7- [6- (2,6-dichloro-phenyl) -8-methyl-7-oxo-7,8-dihydro-pyrido [2,3-d] d] pyrimidin-2-ylamino] -2,3-dihydro-benzo [1,4] dioxin-2-carboxylic acid 600 mg of compound of formula (III), described below, and 1.11 g of compound of formula (II), 6- (2,6-Dichlorophenyl) -8-methyl-2-methylsulfonyl-8H-pyrido [2,3-d] pyrimidin-7-one, are dissolved in 10 mL of THF.
  • Step 1 To a solution of 1 g of 7-nitro-2,3-dihydro-benzo [1,4] dioxin-2-carboxylic acid in racemic form (described in the Journal of Organic publication
  • Step 1 558 mg of compound of formula (II), 6- (2,6-Dichlorophenyl) -8-methyl-2-methylsulfonyl-8H-pyrido [2,3-d] pyrimidin-7-one, and 407 mg of compound of formula (III), described below, dissolved in 5 mL of THF, are heated to 110 ° C in a sealed tube in a microwave oven for 45 minutes. After concentration to dryness, the residue is chromatographed on silica (Gradient: Heptane 100 to Heptane / EtOAc 30:70) to give 400 mg of expected product as a solid.
  • Step 1 To a solution of 2 g of racemic methanesulfonic acid (6-nitro-2,3-dihydro-benzo [1,4] -dioxin-2-yl) methyl ester (described in application patent WO 01021577) in 14 ml of DMF are added 1,350 g of sodium azide under nitrogen. After 6 hours of contact at 65 ° C. and overnight at room temperature, the reaction medium is hydrolyzed on a water / ice mixture and extracted with ethyl acetate. The organic phase is washed with a saturated solution of NaCl, dried over sodium sulfate and concentrated to give 1.60 g of expected product.
  • racemic methanesulfonic acid (6-nitro-2,3-dihydro-benzo [1,4] -dioxin-2-yl) methyl ester (described in application patent WO 01021577)
  • 1,350 g of sodium azide under nitrogen. After 6 hours of contact at 65 ° C. and overnight at
  • Step 2 1.5 g of the azide obtained above are dissolved in 40 ml of ethyl acetate and 2 ml of water. After adding 2.83 g of triphenylphosphine, the reaction medium is heated at 60 ° C. for 2 h and then concentrated to dryness. The residue is taken up in toluene and reevaporated twice in succession. After addition of diethyl ether and filtration of an insoluble material, the organic phase is acidified with hydrochloric ether. The precipitate formed is filtered, washed with diethyl ether and dried to give 1.59 g of the expected product in hydrochloride form.
  • Step 3 To 1. 59 g of the amine obtained previously dissolved in 20 ml of dichloromethane are added at room temperature 1.80 ml of triethylamine and 1.83 g of di-tert-butylcarbonate. After 1 h at room temperature, the reaction medium is diluted with a dichloromethane / water mixture. The organic phase is washed with a solution
  • Step 4 On a solution of 1.45 g of the carbamate obtained above and 4.58 g of zinc in 18 ml of tetrahydrofuran, 4.81 ml of acetic acid are poured while maintaining the temperature between 0 ° C. and -5 ° C. ° C. After returning to ambient temperature, the reaction medium is diluted with ethyl acetate and filtered through Celite. After addition of water, the organic phase is basified by addition of NaHCO 3 to pH 8-9, then washed with water and with a saturated solution of NaCl. After drying over sodium sulphate and concentration in vacuo, 1.15 g of the expected compound of formula (III) are isolated.
  • Step 1 A suspension of 4.5 g of 2-hydroxy-4-nitrobenzaldehyde (described in patent application WO 2006007693), 6.76 g of diethyl bromomalonate and 3.72 g
  • Step 2 A suspension of 3.75 g of benzofuran derivative obtained above and 3.39 g of 10% palladium on charcoal in 55 ml of methanol is heated at 45 ° C. under 10 bar of hydrogen for 48 hours. at room temperature, the reaction mixture is filtered on celite and concentrated to dryness to give 3 g of the expected product which is engaged without further purification in the next step.
  • Step 3 1 g of the intermediate obtained in the preceding step dissolved in 2.5 mL of 2M ethylamine in THF are heated at 150 ° C. in a sealed tube in a microwave oven for 40 minutes. After concentration to dryness, the residue is chromatographed on silica (Gradient: Heptane 100 to Heptane / EtOAc 40:60) to give 200 mg of the expected compound of formula (III).
  • MH + 207
  • Step 2 1.08 g of the intermediate obtained in the preceding step dissolved in 2.5 mL of 2M ethylamine in THF are heated at 150 ° C. in a sealed tube in a microwave oven for 40 minutes. After concentration to dryness, the residue is chromatographed on silica (gradient: CH 2 Cl 2 100 to CH 2 Cl 2 / Me0H 95: 5) to give 630 mg of compound of formula (III) expected in racemic form.
  • Step 1 503 mg of compound of formula (NI), described below, and 731 mg of compound of formula (II), 6- (2,6-Dichlorophenyl) -8-methyl-2-methylsulfonyl-8H-pyrido [2,3-d] pyrimidin-7-one, are dissolved in 30 ml of THF.
  • the reaction medium is heated at 120 ° C. in a sealed tube for 24 h. After concentration to dryness, the residue is chromatographed on silica (gradient: heptane 100 to Heptane / ethyl acetate 50:50) to give 730 mg of expected product. .
  • Step 2 To 730 mg of N-Boc intermediate dissolved in 10 mL of CH 2 Cl 2 is added 4 mL of TFA at room temperature. After 1 hour of contact, the reaction mixture is diluted with a dichloromethane / water mixture and basified to pH 9 with NaHCO 3 . The organic phase is washed with water, with saturated NaCl solution, dried over sodium sulfate and concentrated to dryness. The residue is chromatographed on silica (Gradient: CH 2 Cl 2 100 to CH 2 Cl 2 / MeOH 90:10 then CH 2 Cl 2 / MeOH / NH 4 OH 90: 10: 0.01) to give 160 mg of product expected as a solid.
  • Step 3 To 1. 55 g of the above amine dissolved in 10 ml of dichloromethane are added at room temperature 1.31 ml of triethylamine and 1.03 g of di-tert-butylcarbonate. After 1 h at room temperature, the reaction medium is diluted with a dichloromethane / water mixture. The organic phase is washed with a 5% KHSO 4 ZK 2 SO 4 solution and then with a saturated solution of NaCl. After drying over sodium sulphate and concentration, the residue is chromatographed on silica (Gradient: Heptane 100 to Heptane / Ethyl acetate 30:70) to give 1 g of the expected compound of formula (III).
  • Step 1 To 180 mg of compound of formula (II), described below, 8- [3- (tert-butyldimethylsilyl) -prop-2-ynyl] -6- (2,6-dichlorophenyl) -2-methylsulfonyl-8H-pyrido [2,3-d] pyrimidin-7-one and 81 mg of the compound of formula (III), 2,1, 3-benzothiadiazol-5-ylamine, dissolved in 5 ml of DMSO 62 mg of potassium iron-butoxide are added at room temperature under argon in 3 times. After 75 minutes of contact, the reaction medium is diluted with a mixture of water and ethyl acetate.
  • the aqueous phase is brought to neutral pH and extracted with dichloromethane. After drying over sodium sulphate of the organic phase and filtration, the residue is chromatographed on silica (Gradient: CH 2 Cl 2 100 to CH 2 Cl 2 / MeOH 98: 2) to give 52 mg of expected product.
  • Step 1 To 5 g of propargylamine dissolved in 50 ml of dichloromethane, cooled with the aid of an ice bath, are added 22.02 g of di-tert-butylcarbonate. After 1:30 at room temperature, the reaction medium is concentrated to give 15.5 g of expected intermediate.
  • Step 2 To 8.5 g of the previous protected amine dissolved in 350 mL of THF and cooled to -70 ° C. under argon, 43.8 mL of 2.5 M n-butyllithium in THF are added while maintaining the temperature. between -60 ° C. and -70 ° C. After 30 minutes of contact at -70 ° C., 17.02 g of iron-butyldimethylsilyl dissolved in 50 ml of THF are added and the medium is stirred at -60 ° C. for 1 hour. After returning to ambient temperature, 120 ml 0.25M acetic acid are added and the stirring is maintained for 1H.
  • aqueous phase is then extracted with ethyl acetate, the combined organic phases are washed with a saturated solution of NH 4 Cl, with a solution of saturated with NaCl, dried over sodium sulfate and concentrated in vacuo to generate 15.02 g of expected product as a yellow solid.
  • Step 3 To 14.76 g of derivative obtained in the preceding step dissolved in 300 ml of dichloromethane are added 42 ml of TFA. After 2 hours at room temperature, the reaction medium is concentrated to give 15.73 g of 3- (t-butyl-dimethyl-silanyl) -prop-2-ynylamine.
  • Step 1 300 mg of compound of formula (III), described below, and 654 mg of compound of formula (II), 6- (2,6-Dichlorophenyl) -8-methyl-2-methylsulfonyl-8H-pyrido [2,3-d] pyrimidin-7-one, are dissolved in 5 mL of THF.
  • the reaction medium is heated at 120 ° C. in a sealed tube for 24 hours. After concentration to dryness, the residue is chromatographed on silica (Gradient: Heptane 100 to Heptane / ethyl acetate 50:50) to give 290 mg of expected product.
  • MH + 568
  • the compound (III) is prepared according to the protocol described for the preparation of the compound (III) of Example 12, starting from the compound (R / S) -6-Amino-2,3-dihydro-benzofuran-2-carboxylate of ethyl, described in step 2 of the preparation of compound (III) of Example 10.
  • Example 15 2- (2-Aminomethyl-benzoxazol-5-ylamino) -6- (2,6-dichloro-phenyl) -8-methyl-8H-pyrido [2,3-d] pyrimidin-7-one
  • Step 1 687 mg of compound of formula (III), described below, and 2.506 g of compound of formula (II), 6- (2,6-Dichlorophenyl) -8-methyl-2-methylsulfonyl-8H-pyrido [2, 3-d] pyrimidin-7-one, are dissolved in 25 mL of THF.
  • the reaction medium is heated to 110 ° C. in a tube sealed for 8 h. After concentration to dryness, the residue is chromatographed on silica (gradient: dichloromethane 100 to dichloromethane / ethyl acetate 50:50) and 500 mg of expected product are isolated in powder form.
  • Step 2 To 500 mg of intermediate obtained previously dissolved in 5 mL of CH 2 Cl 2 are added 5 mL of TFA at room temperature. After 2 hours of contact, the reaction medium is concentrated to dryness and then taken up in a mixture of water and ethyl acetate and basified to pH 9 with NaHCO 3 . The aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with a saturated solution of NaCl, dried over magnesium sulphate and concentrated to dryness. The residue is chromatographed on silica (gradient: CH 2 Cl 2 100 to CH 2 Cl 2 / MeOH 90:10) to give 244 mg of expected product as a solid.
  • Step 1 To a solution of 9 g of 2-amino-4-nitrophenol in 50 ml of ethanol is added 14.95 g of 2-chlorotriethoxyethane. After a night of contact at 60 ° C., the reaction medium is concentrated to dryness and then taken up in ethyl acetate. The organic phase is washed with a 2N HCl solution, with water, with a saturated solution of NaHCO 3 and finally with a saturated solution of NaCl. After drying over magnesium sulphate and concentration, the residue is taken up in diethyl ether and the precipitate formed is filtered, washed with diethyl ether and dried to give 8.95 g of expected product.
  • Step 2 To a solution of 8.93 g of chlorinated derivative obtained previously in 135 mL of DMF are added under nitrogen at room temperature 6.83 g of sodium azide. After 30 minutes of contact, the reaction medium is hydrolyzed on a mixture of water and ice and is then added ethyl acetate. After filtration to remove an insoluble material, the organic phase is washed with water and then with a saturated solution of NaCl. After drying over magnesium sulfate and concentration, 8.60 g of expected product are isolated.
  • Step 3 To a solution of 8.60 g of the compound obtained in the preceding step in 180 ml of ethyl acetate, 17.50 g of triphenylphosphine are slowly added. After 10 minutes of contact, 7.1 ml of water are added and the reaction medium is heated at 60 ° C. for 1 hour. After returning to ambient temperature, the medium is diluted with ethyl acetate and the organic phase is washed with a saturated solution of NaCl, dried over magnesium sulfate and concentrated.
  • Step 4 To a solution of 2.70 g of amine obtained in the preceding step in 30 ml of dichloromethane is added 3.77 ml of triethylamine and then slowly 3.34 g of di-tert-butylcarbonate. After 1 hour of contact at ambient temperature, the reaction medium is diluted with dichloromethane and hydrolyzed with water. The organic phase is washed with a saturated solution of NaHCO 3 , with water and finally with a saturated solution of NaCl. After drying over magnesium sulphate and concentration, the residue is taken up in heptane, filtered and taken up again in diethyl ether to give, after filtration and drying, 1.50 g of the expected product.
  • the compounds according to the invention have been the subject of pharmacological tests for determining their anticancer activity.
  • MDA-MB231 American type culture collection, Rockville, Maryland, USA, ATCC-HTB26
  • MDA-A1 or MDA-ADR known as MDR-resistant multi-drug line, and described by E.Collomb et al. in Cytometry, 12 (1): 15-25, 1991
  • MCF7 ATCC-HTB22
  • prostate cancer DU145 (ATCC-HTB81) and PC3 (ATCC-CRL 1435),
  • HCT116 ATCC-CCL247
  • HCT15 ATCC-CCL225
  • lung cancer H460 (described by Carmichael in Cancer Research 47 (4): 936-942, 1987 and issued by the National Cancer Institute, Frederick Cancer Research and Development Center, Frederick, Maryland, USA), glioblastoma (SF268 described by Westphal in Biochemical & Biophysical Research Communications 132 (1): 284-289, 1985 and issued by the National Cancer Institute, Frederick Cancer Research and Development Center, Frederick, Maryland, USA),
  • CLT1 leukemias
  • the concentrations of compound according to the invention which lead to 50% loss of proliferation and cell viability (IC50) are between 1 nM and 10 ⁇ M, preferably between 1 nM and 1 ⁇ M, depending on the tumor line and the test compound.
  • the product of Example 1 has a Cl 50 of 3 nM on K562 cells
  • the product of Example 2 has a Cl 50 of 10 nM on MDA-MB231 cells
  • the product of Example 8 has a Cl 50 of 183 nM on MDA-MB231 cells and a Cl 50 of 20.5 nM on K562 cells.
  • the compounds of formula (I) cause a loss of proliferation and viability of tumor cells. It therefore appears that the compounds according to the invention have an anticancer activity and an activity in the treatment of other proliferative and inflammatory diseases such as psoriasis, rheumatoid arthritis, rosteoarthritis, multiple sclerosis, myasthenia, diabetes, the disease Crohn's, organ transplantation, restenosis, atherosclerosis, AIDS for example, as well as in diseases caused by the proliferation of vascular smooth muscle cells.
  • proliferative and inflammatory diseases such as psoriasis, rheumatoid arthritis, rosteoarthritis, multiple sclerosis, myasthenia, diabetes, the disease Crohn's, organ transplantation, restenosis, atherosclerosis, AIDS for example, as well as in diseases caused by the proliferation of vascular smooth muscle cells.
  • the subject of the invention is medicaments which comprise a compound of formula (I), or an addition salt thereof to a pharmaceutically acceptable acid or a hydrate or a solvate of the compound of formula (I).
  • These drugs find their therapeutic use, especially in the treatment or prevention of diseases caused or exacerbated by the proliferation of cells and in particular tumor cells.
  • These compounds are useful in the prevention and treatment of leukemias, both primary and metastatic solid tumors, carcinomas and cancers.
  • these compounds are useful in the prevention and treatment of leukemias, in particular Acute Lymphocytic Leukemia (ALL), Acute Myeloid Leukemia (AML), Chronic Myeloid Leukemia (CML), Chronic Lymphocytic Leukemia (CLL). ), myelodysplastic syndromes (MDS), chloromas, plasmocytomas, T or B cell leukemias, non-Hodgkin's or Hodgkin's lymphomas, myeloma and other hematological malignancies.
  • ALL Acute Lymphocytic Leukemia
  • AML Acute Myeloid Leukemia
  • CML Chronic Myeloid Leukemia
  • CLL Chronic Lymphocytic Leukemia
  • MDS myelodysplastic syndromes
  • chloromas chloromas
  • plasmocytomas plasmocytomas
  • T or B cell leukemias non-Hodgkin's or Hodgkin's lymphomas
  • myeloma myel
  • these compounds are also useful in the prevention and treatment of both primary and metastatic solid tumors, carcinomas and cancers, in particular: breast cancer; lung cancer ; small bowel cancer, colon and rectal cancer; cancer of the respiratory tract, oropharynx and hypopharynx; esophageal cancer; liver cancer, stomach cancer, bile duct cancer, gall bladder cancer, pancreatic cancer; urinary tract cancers including kidney, urothelium and bladder; cancers of the female genital tract including cancer of the uterus, cervix, ovaries, chlorocarcinoma and trophoblastoma; cancers of the male genital tract including prostate cancer, seminal vesicles, testes, germ cell tumors; cancers of the endocrine glands including thyroid, pituitary, adrenal gland cancer; skin cancers including hemangiomas, melanomas, sarcomas, including Kaposi's sarcoma; tumors of the brain, nerves,
  • the present invention relates to pharmaceutical compositions comprising, as active principle, a compound according to the invention.
  • These pharmaceutical compositions contain an effective dose of at least one compound according to the invention, or a pharmaceutically acceptable salt, a hydrate or solvate of said compound, as well as at least one pharmaceutically acceptable excipient.
  • excipients are chosen according to the pharmaceutical form and the desired mode of administration, from the usual excipients which are known to those skilled in the art.
  • the active ingredient of formula (I) above, or its salt, solvate or hydrate may be administered in unit dosage form, in admixture with conventional pharmaceutical excipients, to animals and humans for the prophylaxis or treatment of the above disorders or diseases.
  • Suitable unit dosage forms include oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, oral, intratracheal, intraocular, intranasal forms of administration. by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms and implants.
  • the compounds according to the invention can be used in creams, gels, ointments or lotions.
  • a unitary form of administration of a compound according to the invention in tablet form may comprise the following components:
  • the present invention also relates to therapeutic compositions containing a compound according to the invention, in combination with a pharmaceutically acceptable excipient according to the chosen mode of administration.
  • the pharmaceutical composition may be in solid, liquid or liposome form.
  • solid compositions include powders, capsules, tablets.
  • Oral forms may also include solid forms protected from the acidic environment of the stomach.
  • the supports used for the solid forms consist in particular of mineral supports such as phosphates, carbonates or organic supports such as lactose, celluloses, starch or polymers.
  • the liquid forms consist of solutions of suspensions or dispersions. They contain as dispersive carrier is water, or an organic solvent (ethanol, NMP or others) or mixtures of surfactants and solvents or complexing agents and solvents.
  • the liquid forms will preferably be injectable and, therefore, will have an acceptable formulation for such use.
  • Acceptable injection routes of administration include intravenous, intraperitoneal, intramuscular, and subcutaneous routes, the intravenous route being preferred.
  • the compounds of formula (I) above may be used at daily doses of 0.002 to 2000 mg per kilogram of body weight of the mammal to be treated, preferably at daily doses of 0.1 to 300 mg / kg.
  • the dose may preferably vary from 0.02 to 10,000 mg per day, more particularly from 1 to 3000 mg depending on the age of the subject to be treated or the type of treatment: prophylactic or curative.
  • the dosage appropriate to each patient is determined by the physician according to the mode of administration, the weight and the response of said patient.
  • the present invention also relates to a method of treatment of the pathologies indicated above which comprises the administration to a patient of an effective dose of a compound according to the invention, or one of its pharmaceutically acceptable salts or hydrates or solvates.
  • the compound (s) of formula (I) may be administered in combination with one or more anti-cancer active principle (s), in particular antitumor compounds such as alkylating agents such as alkylsulfonates ( busulfan), dacarbazine, procarbazine, cloretazine, nitrogen mustards (chlormethine, melphalan, chlorambucil), cyclophosphamide, ifosfamide; nitrosoureas such as carmustine, lomustine, semustine, streptozocin; antineoplastic alkaloids such as vincristine, vinblastine; taxanes such as paclitaxel or taxotere; antineoplastic antibiotics such as actinomycin; intercalators, antineoplastic antimetabolites, folate antagonists, methotrexate; inhibitors of purine synthesis; purine analogues such as mercaptopurine, 6-thioguanine; inhibitors of pyrimidine
  • the compounds of formula (I) may also be administered in combination with one or more other active ingredients useful in one of the pathologies indicated above, for example an anti-emetic, anti-pain, anti-inflammatory, anti- cachexia. It is also possible to associate the compounds of the present invention with a radiation treatment. These treatments can be administered simultaneously, separately, sequentially. The treatment will be adapted by the practitioner according to the patient to be treated.

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EP07717935A 2006-01-13 2007-01-12 Pyridopyrimidonderivate, deren herstellung und therapeutische verwendung Withdrawn EP1979352A2 (de)

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FR0600298A FR2896246B1 (fr) 2006-01-13 2006-01-13 Derives de pyrido-pyrimidone, leur preparation, leur application en therapeutique.
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FR2873118B1 (fr) 2004-07-15 2007-11-23 Sanofi Synthelabo Derives de pyrido-pyrimidine, leur application en therapeutique
FR2887882B1 (fr) 2005-07-01 2007-09-07 Sanofi Aventis Sa Derives de pyrido[2,3-d] pyrimidine, leur preparation, leur application en therapeutique
FR2910813B1 (fr) 2006-12-28 2009-02-06 Sanofi Aventis Sa Nouvelle utilisation therapeutique pour le traitement des leucemies
WO2015019037A1 (en) * 2013-08-05 2015-02-12 Almac Discovery Limited Pharmaceutical compounds
GB201322602D0 (en) 2013-12-19 2014-02-05 Almac Discovery Ltd Pharmaceutical compounds
WO2016015597A1 (en) 2014-07-26 2016-02-04 Sunshine Lake Pharma Co., Ltd. Compounds as cdk small-molecule inhibitors and uses thereof
KR20170054408A (ko) * 2014-09-12 2017-05-17 바이오랩 세너스 팔마씨우티카 엘티디에이. 신규한 피리도피리미딘 유도체 화합물

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