EP1786817A1 - Pteridinone als plk (polo like kinase) inhibitoren - Google Patents

Pteridinone als plk (polo like kinase) inhibitoren

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Publication number
EP1786817A1
EP1786817A1 EP05784644A EP05784644A EP1786817A1 EP 1786817 A1 EP1786817 A1 EP 1786817A1 EP 05784644 A EP05784644 A EP 05784644A EP 05784644 A EP05784644 A EP 05784644A EP 1786817 A1 EP1786817 A1 EP 1786817A1
Authority
EP
European Patent Office
Prior art keywords
group
pseudohalogen
halogen
sor
radical selected
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Withdrawn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
EP05784644A
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German (de)
English (en)
French (fr)
Inventor
Heinz Stadtmueller
Harald Engelhardt
Andreas Schoop
Martin Steegmaier
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.)
Boehringer Ingelheim International GmbH
Original Assignee
Boehringer Ingelheim International GmbH
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Application filed by Boehringer Ingelheim International GmbH filed Critical Boehringer Ingelheim International GmbH
Priority to EP05784644A priority Critical patent/EP1786817A1/de
Publication of EP1786817A1 publication Critical patent/EP1786817A1/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Withdrawn legal-status Critical Current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
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel pteridinones of the general formula (1)
  • Tumor cells partially or completely elude regulation and control by the organism and are characterized by uncontrolled growth. This is due, on the one hand, to the loss of control proteins, e.g. Rb, pl6, p21 and p53 as well as the activation of so-called cell cycle accelerators, the cyclin-dependent kinases (CDK's).
  • CDK's cyclin-dependent kinases
  • Aurora B is described as having an essential function in entering mitosis.
  • Aurora B phosphorylates histone H3 on SerlO and thus initiates chromosome condensation (Hsu et al., 2000, Cell 102: 279-91).
  • a specific cell cycle arrest in the G2 / M phase can also be triggered, for example, by inhibition of specific phosphatases such as Cdc25C (Russell and Nurse 1986, Cell 45: 145-53).
  • Cdc25C specific phosphatases
  • an arrest in the G2 / M phase also by inhibition of certain motor proteins, the so-called kinesins such as Eg5 (Mayer et al., 1999, Science 286: 971-4), or microtubule stabilizing or destabilizing agents (eg, colchicine, taxol, etoposide, vinblastine, vincristine) (Schiff and Horwitz 1980, Proc Natl. Acad. USA 77: 1561-5).
  • kinesins such as Eg5 (Mayer et al., 1999, Science 286: 971-4)
  • microtubule stabilizing or destabilizing agents eg, colchicine, taxol, etoposide, vinblastine, vincristine
  • polo-like kinases In addition to cyclin-dependent and Aurora kinases, the so-called polo-like kinases, a small family of serine / threonine kinases, play an important role in the regulation of the eukaryotic cell cycle. So far, the polo-like kinases PLK-I, PLK-2, PLK-3 and PLK-4 have been described in the literature. Especially for PLK-I a central role in the regulation of the mitosis phase has been shown. PLK-I is responsible for the maturation of the centrosomes, for the activation of the phosphatase Cdc25C, and for the activation of the anaphase Promoting Complex (Glover et al., 1998, Genes Dev.
  • Pteridinone derivatives are known as agents with antiproliferative action from the prior art.
  • WO 01/019825 and WO 03/020722 describe the use of pteridinone derivatives for the treatment of tumor diseases.
  • compounds of general formula (I) wherein the radicals L, Q 1 , Q 2 , X, Y, Z, R a , R b , R c , R 1 , R 2 , R 3 and R 4 have the meanings mentioned below, act as inhibitors of specific cell cycle kinases.
  • the compounds of the present invention can be used to treat diseases related to the activity of specific cell cycle kinases and characterized by excessive or abnormal cell proliferation.
  • the present invention relates to compounds of the general formula (1)
  • Y is N or CH
  • R 2 is hydrogen or an optionally monosubstituted or polysubstituted radical selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, aryl, heterocyclyl and heteroaryl, where the / the substituents may be the same or different and are selected from the group consisting of halogen, -NO 2 , -OR 5 , -C (O) R 5 , -C (O) OR 5 , -C (O) NR 5 R 6 .
  • Q 1 and Q 2 are each independently a bond or a radical selected from the group consisting of optionally mono- or polysubstituted
  • R 4 is hydrogen or a radical selected from the group consisting of optionally singly or multiply substituted C 1-16 alkyl, C 2-16 alkenyl, C 2-16 alkynyl, C 3- 10 cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the / the substituent (s) may be the same or different and are selected from the group consisting of -NO 2 , R 5 , -OR 5 , -C (O) R 5 , -C (O) OR 5 , -C (O) NR 5 R 6 , -NR 5 R 6 , -NR 5 C (O) R 6 , -NR 5 C (O) OR 6 , -NR 5 C (O) NR 6 R 7 , -NR 5 SO 2 R 6 , -NOR 5 R 6 , -SR 5 , -SOR 5 , -SO 2 R 5 , -SO 2 NR 5 R 6 , -NR 5 SO 2 NR 6 R 7
  • R a , R b , R c each independently a radical selected from the group consisting of hydrogen, halogen, -NO 2 , -OR 5 , -C (O) R 5 , -C (O) OR 5 , -C (O) NR 5 R 6 , -NR 5 R 6 , -NR 5 C (O) R 6 , -NR 5 C (O) OR 6 , -NR 5 C (O) NR 6 R 7 , -NR 5 SO 2 R 6 , -NOR 5 R 6 , -SR 5 , -SOR 5 , -SO 2 R 5 , -SO 2 NR 5 R 6 , -NR 5 SO 2 NR 6 R 7 , -OSO 2 NR 5 R 6 and pseudohalogen; or an optionally monosubstituted or polysubstituted radical selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6
  • R e is a radical selected from the group consisting of hydrogen, halogen, pseudohalogen or a radical selected from the group consisting of optionally monosubstituted or polysubstituted C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the / the
  • R 8 , R 9 and R 10 are each independently hydrogen or a radical selected from the group consisting of optionally substituted C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-10 cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the substituent (s) may be the same or different and are selected from the group consisting of halogen, -NH 2 , -OH and pseudohalogen;
  • One aspect of the invention are compounds of the general formula (1) wherein
  • R c is a radical selected from the group consisting of hydrogen, -F, -Cl, methyl and
  • R a and R b are each independently hydrogen or fluorine; or an optionally mono- or polysubstituted radical selected from the group consisting of C 1-2 alkyl, C 2 alkenyl, C 2 alkynyl, C 3-6 cycloalkyl, aryl, heterocyclyl and heteroaryl, where the substituent (s) may be identical or different and are selected from the group consisting of hydrogen,
  • R a and R b independently of one another denote hydrogen or fluorine and the other radicals are defined as mentioned above.
  • R 2 is isopropyl or cyclopentyl and the remaining radicals are as defined above.
  • One aspect of the invention is the use of compounds of general formula (1) as pharmaceuticals.
  • Another aspect of the invention is the use of compounds of general formula (1) as medicaments with antiproliferative activity.
  • An essential aspect of the invention is the use of compounds of general formula (1) for the manufacture of a medicament for the treatment and / or prevention of diseases selected from the group consisting of cancer, bacterial and viral infections, inflammatory and autoimmune diseases, chemotherapeutic induced alopecia and Mucositis, cardiovascular diseases, nephrological diseases, as well as chronic and acute neurodegenerative diseases.
  • Another aspect of the invention is the use of a compound of formula (I) for the manufacture of a medicament for inhibiting polo-like kinases.
  • An additional aspect of the invention is the use of a compound of general formula (1) for the preparation of a medicament for inhibiting the polo-like kinase PLK1.
  • One aspect of the invention is the use of compounds of general formula (1) for the manufacture of a medicament for the treatment and / or prevention of tumors based on overexpression of polo-like kinases.
  • Another aspect of the invention is a method for the treatment and / or prevention of diseases selected from the group consisting of cancer, bacterial and viral infections, inflammatory and autoimmune diseases, chemotherapeutic induced alopecia and mucositis, cardiovascular diseases, nephrological diseases, as well as chronic and acute neurodegenerative diseases, characterized in that an effective amount of a compound of formula (I) according to any one of claims 1 to 6 administered to a patient.
  • diseases selected from the group consisting of cancer, bacterial and viral infections, inflammatory and autoimmune diseases, chemotherapeutic induced alopecia and mucositis, cardiovascular diseases, nephrological diseases, as well as chronic and acute neurodegenerative diseases, characterized in that an effective amount of a compound of formula (I) according to any one of claims 1 to 6 administered to a patient.
  • An additional aspect of the invention are pharmaceutical preparations comprising as active ingredient one or more compounds of general formula (I) according to one of claims 1 to 6, optionally in combination with customary excipients and / or carriers.
  • alkyl substituents are meant in each case saturated, straight-chain or branched aliphatic hydrocarbon radicals (alkyl radical).
  • alkenyl substituents are each straight-chain or branched, unsaturated alkyl radicals which have at least one double bond.
  • Alkynyl substituents are to be understood as meaning in each case straight-chain or branched, unsaturated alkyl radicals which have at least one triple bond.
  • Haloalkyl refers to alkyl radicals in which one or more hydrogen atoms are replaced by halogen atoms.
  • Halogen refers to fluorine, chlorine, bromine and / or iodine atoms.
  • Pseudohalogens are understood as meaning the following radicals: -OCN, -SCN, -CF 3 and -CN.
  • Cycloalkyl is a monocyclic or bicyclic ring, it being possible for the ring system to be a saturated ring but also an unsaturated, nonaromatic ring which may optionally also contain double bonds, for example cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, Cyclohexyl, cyclohexenyl, norbornyl, norbornenyl, spiro [5.5] undecane, spiro [5.4] decane and spiro [4.4] nonane.
  • Aryl refers to monocyclic or bicyclic rings of 6-12 carbon atoms such as phenyl and naphthyl.
  • Heteroaryl is to be understood as meaning monocyclic or bicyclic rings which, instead of one or more carbon atoms, contain one or more identical or different heteroatoms, for example nitrogen, sulfur or oxygen atoms.
  • Examples which may be mentioned are furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl and triazinyl.
  • bicyclic heteroaryl radicals are indolyl, isoindolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, Benzisoxazolyl, benzisothiazolyl, benzimidazolyl, indazolyl, isoquinolinyl, quinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl and benzotriazinyl, indolizinyl, oxazolopyridinyl, imidazopyridinyl, naphthyridinyl, indolinyl, isochromanyl, chromanyl, tetrahydroisoquinolinyl, isoindolinyl, Isobenzotetrahydrofuranyl, Isobenzotetrahydrothienyl, isobenzothienyl, benzoxazo
  • Heterocyclyl refers to saturated or unsaturated, mono-, bicyclic, bridged or spirocyclic bicyclic rings containing 5 to 12 carbon atoms which carry heteroatoms such as nitrogen, oxygen or sulfur instead of one or more carbon atoms.
  • heterocyclyl radicals are tetrahydrofuranyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, indolinyl, isoindoliny, morpholinyl, thiomorpholinyl, homomorpholinyl, homopiperidyl, homopiperazinyl, thiomorpholinyl-S'-oxide, thiomethylholinyl-5 ', 1 S'-dioxide, tetrahydropyranyl, piperidinyl, tetrahydrothienyl, homopiperidinyl, homothiomorpholinyl- ⁇ S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridinyl, di
  • the compounds according to the invention can be prepared by the synthesis processes A to C described below, where the substituents of the general formulas (I) to (XVI) have the abovementioned meanings. These methods are to be understood as an explanation of the invention without limiting the same to their subject matter.
  • MLC medium-pressure chromatography
  • Millipore name: Granula Silica Si-60A 35-70 ⁇ m
  • C-18 RP silica gel from the company
  • Macherey nail (name: Polygoprep 100-50 Cl 8) used.
  • the measurement is carried out in deuterated dimethyl sulfoxide-d6. Be different
  • Solvents used are those explicitly noted in the examples or in the methods.
  • the measured values are given on a delta scale in the unit ppm.
  • tetramethylsilane is used.
  • the measurement is carried out on an Avance 400
  • the system is constructed in such a way that, subsequent to the chromatography (column: Zorbax SB-C8, 3.5 ⁇ m, 2, 1 * 50, from Agilent), a diode array detector (Gl 315B from Agilent) and a mass detector ( 1100 LS-MSD SL; G1946D; Agilent) are connected in series.
  • the plant is operated with a flow of 0.6 ml / min.
  • a gradient is run through within 3.5 minutes (initial gradient: 95% water and 5% acetonitrile; gradient end: 5% water and 95% acetonitrile, both solvents are admixed with 0.1% formic acid).
  • the radical R f corresponds to either NH-LQ 1 -Q 2 -R 4 or it represents benzyloxy, methoxy or hydroxy.
  • the compound III is dissolved in a solvent, for example, methanol, ethanol, N, N-dimethylformamide, ethyl acetate, tetrahydrofuran or acetone.
  • a catalyst for example palladium on carbon, palladium hydroxide or Raney nickel to.
  • This suspension is transferred into an autoclave. This is subjected to a hydrogen pressure of 2 to 10 bar. The mixture is stirred for 1 to 5 days at 20 to 60 ° C. Subsequently, the catalyst is filtered off and the solvent removed in vacuo.
  • a coupling reagent for example N, N-dicyclohexylcarbodiimide, N, N-diisopropylcarbodiimide, O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate or 1- (3-N, N-dimethylaminopropyl) -3-ethylcarbodiimide.
  • the reaction mixture is stirred for 4 to 24 hours at a temperature of 15 to 25 ° C. Thereafter, the solvent is distilled off and the residue is purified by chromatography.
  • Intermediate III is prepared by substitution of a leaving group LG, for example halogen, SCN, methoxy, methanesulfonyl, preferably methanesulfinyl or chlorine, on a heteroaromatic system I by a nucleophile II.
  • LG for example halogen, SCN, methoxy, methanesulfonyl, preferably methanesulfinyl or chlorine
  • a base for example potassium carbonate, sodium carbonate, cesium carbonate, N-ethyl-N, N-diisopropylamine or triethylamine are added.
  • the reaction mixture is further stirred at a temperature of 15 to 25 ° C for 12 to 72 h.
  • the insoluble constituents are filtered off and washed with one of the abovementioned solvents. Subsequently, the solvent is distilled off and the residue is purified by chromatography.
  • Step 2B The preparation of the intermediate compound VI is effected by condensation of an oxalic acid derivative with an intermediate compound IV.
  • a base for example potassium carbonate, sodium carbonate, cesium carbonate, N-ethyl ⁇ -N, N-diisopropylamine or triethylamine in a solvent, for example 1,4-dioxane, toluene, tetrahydrofuran , Ethyl acetate, N, N-dimethylformamide, acetonitrile or N, N-dimethylacetamide.
  • a solvent for example 1,4-dioxane, toluene, tetrahydrofuran
  • Ethyl acetate N, N-dimethylformamide, acetonitrile or N, N-dimethylacetamide.
  • 1 to 1.5 equivalents of a compound V are added.
  • the reaction mixture is further stirred at a temperature of -70 to -30 ° C for 3 to 6 hours. Then allowed to warm to 20 ° C within 5 to 12 h and then stirred for 6 to 12 h
  • Compound VIII is prepared by substitution of a leaving group LG, for example halogen, SCN, methoxy, methanesulfonyl, preferably methanesulfinyl or chlorine, on a heteroaromatic system VI by means of a nucleophile VII.
  • LG for example halogen, SCN, methoxy, methanesulfonyl, preferably methanesulfinyl or chlorine
  • Step 4B Compounds VIII whose radical R f represents hydroxy can be used directly for the preparation of
  • Terminals X are used, wherein a compound VIII is reacted with a compound IVX.
  • a coupling reagent for example N, N-dicyclohexylcarbodiimide, N, N-diisopropylcarbodiimide, O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate or 1 - (3-N, N-dimethylaminopropyl) -3-ethylcarbodiimide.
  • the reaction mixture is further stirred for 4 to 24 h at a temperature of 15 to 25 ° C. Thereafter, the solvent is distilled off and the residue is purified by chromatography.
  • Stage IC Compound I is prepared as described in WO19 / 19825.
  • the preparation of the compound III is carried out by substitution of a leaving group LG, for example halogen, SCN, methoxy, methanesulfonyl, preferably methanesulfinyl or chlorine, on a heteroaromatic system I by a nucleophile II.
  • LG for example halogen, SCN, methoxy, methanesulfonyl, preferably methanesulfinyl or chlorine
  • m IV V There are 1 equivalent of compound III, 1 to 1.5 equivalents of compound IV and 1 to 3 equivalents of a base, for example triethylamine or ethyldiisopropylamine in a solvent, for example 1,4-dioxane, N, N-dimethylformamide, N, N- Dimethylacetamide or N-methyl-2-pyrrolidinone stirred.
  • a base for example triethylamine or ethyldiisopropylamine in a solvent, for example 1,4-dioxane, N, N-dimethylformamide, N, N- Dimethylacetamide or N-methyl-2-pyrrolidinone stirred.
  • a coupling reagent for example N, N-dicyclohexylcarbodiimide, N, N-diisopropylcarbodiimide, O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate or 1- (3-N, N-dimethylaminopropyl) -3-ethylcarbodiimide.
  • the reaction mixture is further stirred at a temperature of 15 to 25 ° C for 4 to 24 hours. Thereafter, the solvent is distilled off and the residue is purified by chromatography.
  • Compound I is prepared as described in WOO 170741.
  • the preparation of the compound III is carried out by substitution of a leaving group LG, for example halogen, SCN, methoxy, methanesulfonyl, preferably methanesulfinyl or chlorine, on a heteroaromatic system I by a nucleophile II.
  • LG for example halogen, SCN, methoxy, methanesulfonyl, preferably methanesulfinyl or chlorine
  • a coupling reagent for example N, N-dicyclohexylcarbodiimide, N, N-diisopropylcarbodiimide, O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate or 1- (3-N, N-dimethylaminopropyl) -3-ethylcarbodiimide.
  • the reaction mixture is further stirred at a temperature of 15 to 25 ° C for 4 to 24 hours. Thereafter, the solvent is distilled off and the residue is purified by chromatography.
  • the carrier material used is Cl 8-RP silica gel and a gradient is run through which consists of 95% water and 5% acetonitrile at the starting point and 2% water and 98% acetonitrile at the end point. Both solvents are admixed with 0.1% formic acid. Yield: 80 mg (0.17 mmol, 24%) MS (ESI): 486 (M + H) +
  • Precipitate is filtered off and dried.
  • the solvent is removed in vacuo.
  • the crude product is purified by column chromatography.
  • the carrier material used is C18-RP silica gel and a gradient is passed through which consists of 95% water and 5% acetonitrile at the starting point and 2% water and 98% acetonitrile at the end point. Both solvents are admixed with 0.1% formic acid. The compound is obtained as a formate.
  • Examples 2-10 The following compounds are prepared by an analogous procedure as described in Example 1.
  • the amine used for the preparation of the amide is commercially available or prepared by the method described in Method 2 or Method 4.
  • the carrier material used is C18-RP silica gel and a gradient is passed through which consists of 95% water and 5% acetonitrile at the starting point and 2% water and 98% acetonitrile at the end point. Both solvents are admixed with 0.1% formic acid. The compound is obtained as a formate.
  • the aniline used for the preparation of the compounds is prepared by methods known from the literature (J Pharm Sci. 1989, 78 (10): 829-32; BioorgMed Chem Lett. 2003 13 (3): 369-373 or J Med Chem. 1990, 33 (II): 3072-78).
  • the crude product is purified by column chromatography.
  • the carrier material used is C18-RP silica gel and a gradient is passed through which consists of 95% water and 5% acetonitrile at the starting point and 2% water and 98% acetonitrile at the end point. Both solvents are admixed with 0.1% formic acid.
  • the compound is obtained as a formate. Yield: 12 mg (mmol; 14%) UV max: 363 nm MS (ESI): 492 (M + H) + 1 H-NMR: 1.53-1.68 (m, 4H), 1.74-1 , 91 (m, 6H), 1.96-2.04 (m, 2H), 2.14-2.25 (m,
  • Example 14 The following compound is prepared analogously to Example 14.
  • the amine used for the preparation of the amide is commercially available or is prepared by the method described in Method 2.
  • Examples 17-25 The following compounds are prepared by an analogous procedure as described in Example 14.
  • the preparation of the benzoic acid derivative is described in Method 5.
  • the amine used for the preparation of the amide is available commercially.
  • Examples 26-40 The following compounds are prepared by an analogous procedure as described in Example 14.
  • the preparation of the benzoic acid derivative is described in Method 5.
  • the amine used for the preparation of the amide is commercially available or described in Method 6.
  • proliferation inhibition caused by the compounds of the present invention is mediated primarily by arrest of the cells in the G2 / M phase of the cell cycle.
  • the cells arrest for a certain period of time in this cell cycle phase, depending on the cell type used, before the programmed cell death is initiated.
  • Arrest in the G2 / M phase of the cell cycle may e.g. by inhibiting specific
  • Cell cycle kinases are triggered. Due to their biological properties, the compounds of the general formula I according to the invention, their isomers and their physiologically tolerable salts are suitable for the treatment of diseases which are characterized by excessive or abnormal cell proliferation.
  • Such diseases include, for example: viral infections (eg HIV and Kaposi sarcoma); Inflammation and autoimmune diseases (eg, colitis, arthritis, Alzheimer's disease, glomerulonephritis and wound healing); bacterial, fungal and / or parasitic infections; Leukemias, lymphomas and solid tumors; Skin disorders (eg psoriasis); Bone diseases; cardiovascular diseases (eg restenosis and hypertrophy). Further, they are useful as protection of proliferating cells (eg, hair, intestinal, blood and progenitor cells) against DNA damage by radiation, UV treatment and / or cytostatic treatment (Davis et al., 2001).
  • the novel compounds can be used for the prevention, short-term or long-term treatment of the abovementioned diseases, also in combination with other active compounds which are used for the same indications, for example cytostatics, steroids or antibodies.
  • Recombinant human and at its N-terminal end linked to GST PLK1 enzyme is isolated from baculovirus-infected insect cells (Sf21). The purification is carried out by affinity chromatography on glutathione Sepharose columns.
  • Insect cell medium (Life Technologies) are seeded in a spinner bottle. After 72 hours incubation at 27 ° C. and 70 rpm, IxIO 8 Sf21 cells are seeded in a total of 180 ml of medium in a new spinner flask. After a further 24 hours, 20 ml of recombinant baculovirus stock suspension are added and the cells are cultured for 72 hours at 27 ° C. at 70 rpm. Okadaic acid is added 3 hours before harvesting
  • MgCl 2 1mM DTT, 5 ⁇ g / ml leupeptin, 5 ⁇ g / ml aprotinin, 100 ⁇ M NaF, 100 ⁇ M PMSF, 10mM ⁇ -glycerol phosphate, 0.1mM Na 3 VO 4 , 30mM 4-nitrophenyl phosphates) to IxIO 8 cells / 17.5 ml resuspended. The cells are lysed for 30 minutes on ice.
  • the clear supernatant is mixed with glutathione sepharose beads (1 ml of resuspended and washed beads for 50 ml of supernatant) and incubated for 30 minutes at 4 ° C. on a rotary board.
  • the protein concentration is determined by Bradford assay.
  • the reaction is started and carried out for 45 minutes at 30 ° C with gentle shaking (650 rpm on IKA shaker MTS2).
  • the reaction is stopped by addition of 125 ⁇ l of ice-cold 5% TCA per well and incubated on ice for at least 30 minutes.
  • the preciptitate is transferred by harvesting to filter plates (96-well microtiter filter plate: UniFilter-96, GF / B, Packard, No. 6005177), then washed four times with 1% TCA and dried at 60 ° C.
  • the slab is sealed with sealing tape and the precipitated amount of P33 is measured with the Wallac Betacounter.
  • the measured data are evaluated with the standard Graphpad software (Levenburg-Marquard Algorithm).
  • the effect of the compounds of the invention is in the cytotoxicity test on cultured human tumor cells and / or in a FACS analysis, for example HeLa S3 cells, determined.
  • the compounds show good to very good activity in both test methods, ie, for example, an EC50 value in the HeLa S3 cytotoxicity test of less than 5 ⁇ mol / L, generally less than 1 ⁇ mol / L.
  • HeLa S3 obtained from American Type Culture Collection (ATCC)
  • Ham's F12 medium Life Technologies
  • 10% fetal bovine serum Life Technologies
  • the HeLa S3 cells are then introduced into 96-well plates (Costar) with a density of 1000 cells per well and incubated overnight in an incubator (at 37 ° C. and 5% CO 2), with 6 wells on each plate only with medium (3 wells for medium control, 3 wells for incubation with reduced AlamarBlue reagent).
  • the active substances are added to the cells in different concentrations (dissolved in DMSO; final DMSO concentration: 0.1%) (each in triplicate).
  • AlamarBlue reagent (AccuMed International) are added to each well, and the cells are incubated for a further 5-7 hours.
  • AlamarBlue Reagent 20 ⁇ l of reduced AlamarBlue reagent to 3 wells (AlamarBlue Reagent, which is autoclaved for 30 min).
  • the color conversion of the AlamarBlue reagent in the individual wells is determined in a Perkin Elmer fluorescence spectrophotometer (Exitation 530 nm, emission 590 nm, Slits 15, Integrate time 0.1).
  • the amount of reacted AlamarBlue reagent represents the metabolic activity of the cells.
  • the relative cell activity is calculated as a percentage of the control (HeLa S3 cells without inhibitor) and the drug concentration, which inhibits cell activity by 50% (IC50), is derived.
  • the values are calculated from the average value of three individual determinations - with correction of the blank value (medium control). FACS analysis
  • Propidium iodide (PI) stoichiometrically binds to double-stranded DNA, and is thus capable of determining the proportion of cells in the Gl, S, and G2 / M phase of the cell cycle based on the cellular DNA content.
  • Cells in the GO and Gl phases have a diploid DNA content (2N), while cells in G2 or mitosis have a 4N DNA content.
  • IxIO 6 HeLa S3 cells are seeded on a 75 cm 2 cell culture flask, after 24 h either 0.1% DMSO is added as a control, or the substance in various concentrations (in 0.1% DMSO).
  • the cells are incubated with the substance or with DMSO for 24 h before the cells are washed twice with PBS and then with trypsin / EDTA.
  • the cells are centrifuged (1000 rpm, 5 min, 4 ° C) and the cell pellet washed twice with PBS before the cells are resuspended in 0.1 ml PBS.
  • the cells are fixed for 16 hours at 4 ° C or alternatively for 2 hours at -20 ° C with 80% ethanol.
  • the fixed cells are centrifuged (1000 rpm, 5 min, 4 ° C), washed with PBS and then centrifuged again.
  • the cell pellet is resuspended in 2 ml of 0.25% Triton X-100 in PBS and incubated on ice for 5 min before 5 ml of PBS are added and centrifuged again.
  • the cell pellet is resuspended in 350 ⁇ l PI staining solution (0.1 mg / ml RNase A (Sigma, No.
  • the compounds of the invention are also tested on other tumor cells.
  • these compounds are based on carcinomas of various tissues (eg breast (MCF7), colon (HCT16), head and neck (FaDu), Liver (HepG2), lung (NCI-H460), stomach (NCI-N87), pancreas (BxPC-3), prostate (DU145)), sarcomas (eg SK-UT-IB, Saos-2), leukemias and lymphomas (e.g., HL-60, THP-I, Raji, Jurkat, GRANTA-519) and other tumors (e.g., melanomas (BRO), gliomas (U-87MG)), and could be used in such indications become.
  • MCF7 breast
  • HCT16 colon
  • FaDu Liver
  • HepG2 liver
  • NCI-N87 lung
  • pancreas BxPC-3
  • prostate DU145
  • sarcomas eg SK-UT-I
  • the compounds of the general formula (I) can be used alone or in combination with other active compounds according to the invention, if appropriate also in combination with other pharmacologically active substances.
  • Suitable application forms are, for example, tablets, capsules, suppositories, solutions, in particular solutions for injection (s.c., i.V., i.m.) and infusion, juices, emulsions or dispersible powders.
  • the proportion of the pharmaceutically active compound (s) in each case in the range of 0.1 to 90 wt .-%, preferably 0.5 to 50 wt .-% of the total composition, i. in amounts sufficient to reach the dosage range given below.
  • the said doses may, if necessary, be given several times a day.
  • Corresponding tablets can be prepared, for example, by mixing the active substance (s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc, and / or agents to obtain the depot effect, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate.
  • excipients for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc, and / or agents to obtain the depot effect, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate.
  • excipients for example iner
  • Coated tablets can accordingly be produced by coating cores produced analogously to the tablets with agents customarily used in tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar.
  • the core can also consist of several layers.
  • the Drageum cover to achieve a depot effect consist of several layers, wherein the above mentioned in the tablets excipients can be used.
  • Juices of the active compounds or active compound combinations according to the invention may additionally contain a sweetener, such as saccharin, cyclamate, glycerol or sugar, as well as a taste-improving agent, e.g. Flavorings such as vanillin or orange extract. They may also contain suspending aids or thickening agents, such as sodium carboxymethylcellulose, wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or protective agents, such as p-hydroxybenzoates.
  • a sweetener such as saccharin, cyclamate, glycerol or sugar
  • a taste-improving agent e.g. Flavorings such as vanillin or orange extract.
  • suspending aids or thickening agents such as sodium carboxymethylcellulose, wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or protective agents, such as p-hydroxybenzoates.
  • Injection and infusion solutions are prepared in a conventional manner, e.g. with the addition of isotonic agents, preservatives, such as p-hydroxybenzoates, or stabilizers, such as alkali metal salts of ethylenediaminetetraacetic acid, optionally with the use of emulsifiers and / or dispersants, wherein, for example, when using water as a diluent organic solvents may optionally be used as solubilizers or auxiliary solvents , manufactured and filled into injection vials or ampoules or infusion bottles.
  • isotonic agents e.g. with the addition of isotonic agents, preservatives, such as p-hydroxybenzoates, or stabilizers, such as alkali metal salts of ethylenediaminetetraacetic acid, optionally with the use of emulsifiers and / or dispersants, wherein, for example, when using water as a diluent organic solvents may optionally be used as
  • the capsules containing one or more active ingredients or combinations of active substances can be prepared, for example, by mixing the active ingredients with inert carriers, such as lactose or sorbitol, and encapsulating them in gelatine capsules.
  • suitable suppositories can be prepared, for example, by mixing with suitable carriers, such as neutral fats or polyethylene glycol or its derivatives.
  • adjuvants there may be mentioned, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g., petroleum fractions), oils of vegetable origin (e.g., peanut or sesame oil), mono- or polyfunctional alcohols (e.g., ethanol or glycerin), excipients such as e.g. ground natural minerals (e.g., kaolins, clays,
  • paraffins e.g., petroleum fractions
  • oils of vegetable origin e.g., peanut or sesame oil
  • mono- or polyfunctional alcohols e.g., ethanol or glycerin
  • excipients such as e.g. ground natural minerals (e.g., kaolins, clays,
  • Talc ground synthetic minerals (eg fumed silica and silicates), Emulsifiers (eg, lignin, liquors, methyl cellulose, starch and polyvinylpyrrolidone) and lubricants (eg, magnesium stearate, talc, stearic acid and sodium lauryl sulfate) mentioned.
  • Emulsifiers eg, lignin, liquors, methyl cellulose, starch and polyvinylpyrrolidone
  • lubricants eg, magnesium stearate, talc, stearic acid and sodium lauryl sulfate
  • the application is carried out in a customary manner, preferably orally or transdermally, particularly preferably orally.
  • the tablets may also contain additives other than those mentioned.
  • Sodium citrate, calcium carbonate and dicalcium phosphate together with various adjuvants such as starch, preferably potato starch, gelatin and the like.
  • lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used for tableting.
  • the active ingredients may be added to the abovementioned excipients with various flavor enhancers or dyes.
  • solutions of the active ingredients may be employed using suitable liquid carrier materials.
  • the dosage for intravenous use is 1 - 1000 mg per hour, preferably between 5 - 500 mg per hour.
  • the finely ground active ingredient, lactose and part of the corn starch are mixed together.
  • the mixture is sieved, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet granulated and dried.
  • the granules, the remainder of the corn starch and the magnesium stearate are sieved and mixed together.
  • the mixture is compressed into tablets of suitable shape and size.
  • the active ingredient is dissolved in water at its own pH or optionally at pH 5.5-6.5 and treated with sodium chloride as isotonan.
  • the resulting solution is filtered pyrogen-free and the filtrate filled under aseptic conditions in ampoules, which are then sterilized and sealed.
  • the vials contain 5 mg, 25 mg and 50 mg active ingredient.

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EP05784644A 2004-08-26 2005-08-19 Pteridinone als plk (polo like kinase) inhibitoren Withdrawn EP1786817A1 (de)

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