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WO2002100401A1 - Derives d'indirubine inhibiteurs de cdk solubles - Google Patents

Derives d'indirubine inhibiteurs de cdk solubles Download PDF

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Publication number
WO2002100401A1
WO2002100401A1 PCT/EP2002/006132 EP0206132W WO02100401A1 WO 2002100401 A1 WO2002100401 A1 WO 2002100401A1 EP 0206132 W EP0206132 W EP 0206132W WO 02100401 A1 WO02100401 A1 WO 02100401A1
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Prior art keywords
alkyl
alkoxy
cycloalkyl
group
hydroxy
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German (de)
English (en)
Inventor
Rolf Jautelat
Thomas Brumby
Olaf Prien
Martina SCHÄFER
Gerd Siemeister
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Bayer Pharma AG
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Schering AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention relates to indirubin derivatives which, by establishing a basic side chain in the 5-position, have a radically increased solubility at the same time
  • Indirubin and some Indirubin derivatives are effective against certain forms of cancer.
  • indirubin-3'-oxime methyl ether and indirubin-3'-oxime ethyl ether also show an in vitro inhibitory effect on various leukemia cell lines from patients with acute lymphatic, acute myeloid and chronic granulocytic leukemia (Li et al., 1996, Bull. Chem. Soc. Japan, 69, 1621-1627 and Tian et al., 1995, Chemical Research in Chinese Universities, 11, 75-78).
  • cancer such as solid tumors and leukemia
  • autoimmune diseases such as psoriasis, alopecia and multiple sclerosis
  • chemotherapy-induced alopecia and mucositis cardiovascular diseases such as stenoses, arteriosclerosis and restenosis
  • infectious diseases such as B. caused by unicellular parasites such as Trypanosoma, Toxoplasma or Plasmodium, or by fungi, nephrological diseases, such as. B.
  • glomerulonephritis chronic neurodegenerative diseases, such as Huntington's disease, amyotropic lateral sclerosis, Parkinson's disease, AIDS dementia and Alzheimer's disease, acute neurodegenerative diseases such as brain ischemia and neurotrauma, viral infections, such as. B. cytomegalus infections, herpes, hepatitis B and C, and HIV diseases.
  • chronic neurodegenerative diseases such as Huntington's disease, amyotropic lateral sclerosis, Parkinson's disease, AIDS dementia and Alzheimer's disease
  • acute neurodegenerative diseases such as brain ischemia and neurotrauma
  • viral infections such as. B. cytomegalus infections, herpes, hepatitis B and C, and HIV diseases.
  • Indirubin derivatives are very poorly soluble and are therefore less selective and in particular less effective. They are therefore only used in practice to a limited extent.
  • n -R 7 optionally also a ring of the structure
  • NR 10 R 11 in the meaning of R 7 is also a further hetero atom in the ring, and the ring can optionally be substituted by hydroxy-Ci-io-alkyl, n is 0, 1, 2, 3, 4, 5 or 6 , D for the group
  • R 1 for hydrogen or for the group or for unsubstituted or optionally one or more, identical or different with hydroxy, Ci- ⁇ -alkoxy,
  • R 6 , R 8 and R 9 independently of one another for hydrogen, halogen, hydroxy
  • CONR 10 R 11 or -COOR 12 substituted C ⁇ -1 0 alkyl, C 2-10 - alkenyl, C 2 - ⁇ o alkynyl, de-alkoxy, d -6 thioalkyl, C ⁇ -cycloalkyl or C 3 - 7-Cycloalkyl-C ⁇ - 3 alkyl, benzyloxy, aryl or heteroaryl, and Ci-io-alkyl, C 2- ⁇ 0 -alkenyl, C 2- ⁇ 0 -alkynyl, C 3 - 7 -cycloalkyl or C 3 - 7- cycloalkyl-d.
  • R 10 and R 11 independently of one another represent hydrogen, amino, hydroxy, C 1 . 10 -alkyl, C 2- ⁇ o-alkenyl, C 2- ⁇ 0 -alkynyl, C 3-7 -cycloalkyl, C 3-7 -
  • Alkyl) 2 , -COOH, -COOC ⁇ -6- alkyl can be substituted, R 12 for hydrogen, amino, Ci-io-alkyl, C 2 . ⁇ 0 -alkenyl, C 2 . 10 alkynyl,
  • COOCi- ⁇ -alkyl or represents optionally mono- or polysubstituted, identically or differently with hydroxy, halo, C ⁇ -6 alkoxy, d- ⁇ -alkylthio, halo-d- ⁇ -alkoxy, amino or the group -SO 3 H , -P0 3 H 2 -NHC 1-6 alkyl, -N-di-C ⁇ -6 alkyl, -CONH 2 , substituted C ⁇ - 10 alkyl, C 2 - ⁇ o-alkenyl, C 2 . ⁇ 0 -alkynyl , C 1 - 6 -
  • Ci- ⁇ -alkylthio Ci- ⁇ -Alkcxy-Ci- ⁇ -alkyl or the group - NHd- ⁇ -alkyl, -N (-C ⁇ -6- alkyl) 2 , -SOd-e-alkyl, -SO ⁇ d- 6 -alkyl, - CONH 2 , -CONH-C 1-6 -alkyl, -CON (C 1-6 -alkyl) 2 , -COOH or - COOCi- ⁇ -alkyl or may be substituted with phenyl, where appropriate the phenyl one or more times with halogen,
  • R 15 represents hydrogen or Ci-C ⁇ -alkyl, mean, and their
  • Alkyl is in each case a straight-chain or branched alkyl radical, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. Butyl, part.
  • alkyl radical such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. Butyl, part.
  • Cycloalkyl is understood to mean cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • the ring systems in which one or more possible double bonds may be present in the ring include, for example, cycloalkenyls such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl, with the linkage both to the double bond and to the single bonds can be done.
  • cycloalkenyls such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl
  • Halogen is to be understood as fluorine, chlorine, bromine or iodine.
  • alkenyl substituents are in each case straight-chain or branched, which means, for example, the following radicals: vinyl, propen-1-yl, propen-2-yl, but-1-en-1-yl, but-1-en-2-yl , But-2-en-1-yl, But-2-en-2-yl, 2-methyl-prop-2-en-1-yl, 2- Methyl-prop-1-en-1-yl, but-1-en-3-yl, ethinyl, prop-1-in-1-yl, but-1-in-1-yl, but-2-in 1-yl, but-3-en-1-yl, allyl.
  • the aryl radical has 6 to 12 carbon atoms such as naphthyl, biphenyl and especially phenyl.
  • the heteroaryl radical can be benzo-condensed in each case.
  • Examples include 5-ring heteroaromatics: thiophene, furan, oxazole, thiazole, imidazole and benzo derivatives thereof, and 6-ring heteroaromatics pyridine, pyrimidine, triazine, quinoline, isoquinoline and benzo derivatives thereof.
  • the physiologically compatible salts of organic and inorganic bases are suitable as salts, such as the readily soluble alkali and alkaline earth metal salts and N-methylglucamine, dimethylglucamine, ethylglucamine, lysine, 1,6-hexadiamine , Ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxymethylamino-methane, aminopropanediol, sovak base, 1-amino-2,3,4-butanetriol.
  • physiologically compatible salts of organic and inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid and others are suitable.
  • n 0, 1, 2, 3, 4, 5 or 6
  • R 1 stands for hydrogen or for the group C ⁇ -6 alkyl-CO-NR 10 R 11, or unsubstituted or optionally substituted one or more times, identically or differently, with hydroxy, C ⁇ . 6 -alkoxy, amino, halogen or the group -NHd- 6 -alkyl or -N-di-Ci. 6 alkyl substituted Ci-io alkyl, C 2- ⁇ o alkenyl, C 2- ⁇ 0 alkynyl, C 3- 7 cycloalkyl or C 3-7 cycloalkyl-d- C3 alkyl substituted by one or more heteroatoms interrupted C 3-7 cycloalkyl or C. 3
  • R 6 , R 8 and R 9 independently of one another for hydrogen, halogen, hydroxy
  • Heteroaryl is, and Ci-io-alkyl, C 2 . ⁇ 0 -alkenyl, C 2- ⁇ 0 -alkynyl, C 3 - 7 cycloalkyl or C 3 - 7 cycloalkyl-C ⁇ .
  • R 12 is hydrogen, amino, C 10 alkyl, C 2 0 alkenyl, C 2 alkynyl,
  • 3 -alkyl or phenyl which is unsubstituted or mono- or polysubstituted by halogen, hydroxyl, C 6 alkyl, C 6 alkoxy, halo 6 alkyl or halo C 1 -boxy, R 13 and R. 14 independently of one another for hydrogen, amino, Ci-io-alkyl, C 2 . ⁇ o-alkenyl, C 2 . ⁇ o-alkynyl, C 3 - 7 cycloalkyl, C 3 - 7 cycloalkyl-C ⁇ -
  • Z represents hydrogen or C 10 alkyl, or the group -N- (CH 2 ) n -R 7 optionally also a ring of the structure
  • Hetero atom in the ring, and the ring can optionally be substituted with hydroxy-Ci-io-alkyl, n stands for 0, 1, 2, 3, 4, 5 or 6,
  • R 1 for hydrogen or for the group -C 6 alkyl-CO-NR 10 R 11 , or for unsubstituted or optionally one or Ci.io-alkyl substituted several times, identically or differently with hydroxy, C ⁇ - 6- alkoxy, amino, halogen or the group -NHCi- ⁇ -alkyl or -N-di-Ci- 6 -alkyl.
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 8 and R 9 independently of one another represent hydrogen, halogen, hydroxy, hydroxy-d.C ⁇ -alkyl or the group -COOR 12 , R 7 represents hydrogen, Hydroxy, pyridyl or for the group -NR 10 R 11 , -CONR 10 R 11 or
  • R 10 and R 11 independently of one another for hydrogen, hydroxy, Ci-C ⁇ -alkoxy, C 3 .C 6 -cycloalkyl, - (CH 2 ) nCOO-dC 6 -alkyl, -CH (CH 3 ) - phenyl or for optionally with Hydroxy substituted Ciio-alkyl or for the group -NR 13 R 1 ,
  • R 12 represents Ci-Ce-alkyl
  • R 13 and R 14 independently of one another are hydrogen or C 6 alkyl
  • R 15 is hydrogen or C 6 alkyl, as well as their
  • the compounds according to the invention essentially inhibit cyclin-dependent kinases, followed by their action, for example, against cancer, such as solid tumors and leukemia, autoimmune diseases such as psoriasis, alopecia, and multiple sclerosis, chemotherapeutic-induced alopecia and mucositis, cardiovascular diseases, such as stenoses, arterioscleroses and restenosis, infectious diseases such as B. caused by unicellular parasites such as Trypanosoma, Toxoplasma or Plasmodium, or by fungi, nephrological diseases, such as. B.
  • cancer such as solid tumors and leukemia
  • autoimmune diseases such as psoriasis, alopecia, and multiple sclerosis
  • chemotherapeutic-induced alopecia and mucositis chemotherapeutic-induced alopecia and mucositis
  • cardiovascular diseases such as stenoses, arterioscleroses and restenosis
  • infectious diseases such as
  • glomerulonephritis chronic neurodegenerative diseases, such as Huntington's disease, amyotropic lateral sclerosis, Parkinson's disease, AIDS dementia and Alzheimer's disease, acute neurodegenerative diseases, such as brain ischemia and neurotrauma, viral infections, such as.
  • the eukaryotic cell division cycle ensures the duplication of the genome and its distribution to the daughter cells by going through a coordinated and regulated sequence of events.
  • the cell cycle is divided into four successive phases:
  • the G1 phase represents the time before DNA replication in which the cell grows and is susceptible to external stimuli.
  • S phase the cell replicates its DNA
  • G2 phase it prepares to enter mitosis.
  • M phase the mitosis (M phase)
  • the replicated DNA is separated and the cells are divided.
  • CDKs The cyclin-dependent kinases
  • Cyc cyclin-dependent kinases
  • Different CDK / Cyc pairs are active in the different phases of the cell cycle.
  • CDK / Cyc pairs that are important for the basic function of the cell cycle are such as CDK4 (6) / CycD, CDK2 / CycE, CDK2 / CycA, CDK1 / CycA and CDK1 / CycB.
  • CDK5 Some members of the CDK enzyme family have a regulatory function by influencing the activity of the aforementioned cell cycle CDKs, while other members of the CDK enzyme family have not yet been assigned a specific function.
  • CDK5 is characterized by the fact that it has an atypical regulatory subunit that differs from the cyclin (p35) and that its activity is highest in the brain.
  • the entry into the cell cycle and the passage of the "restriction point", which marks the independence of a cell from further growth signals for the completion of the started cell division, are controlled by the activity of the CDK4 (6) / CycD and CDK2 / CycE complexes.
  • the main substrate of these CDK complexes is the retinoblastoma protein (Rb), the product of the retinoblastoma tumor suppressor gene.
  • Rb is a transcriptional co-repressor protein.
  • HDAC histone deacety lase
  • the phosphorylation of Rb by CDK's is equivalent to the exceeding of the "restriction point".
  • the activity of the CDK2 / CycE and CDK2 / CycA complexes is necessary, e.g. B. the activity of the transcription factors of the E2F type is switched off by means of phosphorylation by CDK2 / CycA as soon as the cells have entered the S phase.
  • the CDK1 in complex with CycA or CycB controls the entry and the passage through phases G2 and M (Fig. 1). In accordance with the extraordinary importance of the cell division cycle, the cycle is strictly regulated and controlled.
  • the enzymes that are necessary for progression through the cycle must be activated at the right time and also switched off again as soon as the corresponding phase has been completed.
  • Corresponding control points arrest the progression through the cell cycle if DNA damage is detected, or DNA replication, or the construction of the spindle apparatus has not yet ended.
  • the activity of the CDKs is determined by various mechanisms, such as synthesis and degradation of the cyclin, complexation of the CDKs with the corresponding ones
  • Activating and inactivating phosphorylations regulate the activity of the CDKs, for example CDK-activating kinases (CAKs) phosphorylate Thr160 / 161 of CDK1, whereas the family of Wee1 / Myt1 kinases inactivate CDK1 by phosphorylation of Thr14 and Tyr15. These inactivating phosphorylations can be canceled by cdc25 phosphatases.
  • the regulation of the activity of the CDK / Cyc complexes by two families of natural CDK inhibitor proteins (CKIs), the protein products of the p21 gene family (p21, p27, p57) and the p16 gene family (p15, p16, p18, p19) is very important.
  • CKIs CDK inhibitor proteins
  • Members of the p21 family bind to cyclin complexes of CDKs 1,2,4,6, but only inhibit complexes that contain CDK1 or CDK2.
  • Members of the p16 family are specific inhibitor
  • the level of the control point regulation lies above this complex direct regulation of the activity of the CDKs.
  • Control points allow the cell to follow the orderly progress of the individual phases during the cell cycle. The most important control points are at the transition from G1 to S and from G2 to M.
  • the G1 control point ensures that the cell does not start DNA synthesis if it is not properly nourished, interacts correctly with other cells or the substrate, and their DNA is intact.
  • the G2 / M control point ensures the complete replication of the DNA and the build-up of the mitotic spindle before the cell enters mitosis.
  • the G1 control point is activated by the gene product of the p53 tumor suppressor gene.
  • a second branch of the G1 control point comprises the activation of the ATM and Chk1 kinases after DNA damage by UV light or ionizing radiation and finally the phosphorylation and subsequent proteolytic degradation of the cdc25A phosphatase (Milan N. et al. (2000). Rapid destruction of human cdc25A in response to DNA damage. Science 288, 1425-1429). This results in a locking of the cell cycle, since the inhibitory phosphorylation of the CDKs is not removed. After activating the G2 / M control point by damaging the DNA, both mechanisms are similarly involved in stopping the progression through the cell cycle.
  • the loss of regulation of the cell cycle and the loss of the function of the control points are characteristics of tumor cells.
  • the CDK-Rb signaling pathway is affected by mutations in over 90% of human tumor cells. These mutations, which ultimately lead to inactivating phosphorylation of the RB, include the overexpression of D and E cyclins by gene amplification or chromosomal translocations, inactivating mutations or deletions of CDK inhibitors of the p16 type, and increased (p27) or reduced (CycD ) Protein breakdown.
  • the second group of genes, which are affected by mutations in tumor cells code for components of the control points.
  • p53 which is essential for the G1 and G2 / M control points, is the most frequently mutated gene in human tumors (approx.
  • CDK2 / Cyc complexes occupy a crucial position during cell cycle progression: (1) Both dominant-negative forms of CDK2, as well as the transcriptional repression of CDK2 expression by anti-sense oligonucleotides, stop cell cycle progression. (2) Inactivation of the CycA gene in mice is lethal. (3) Disruption of the function of the CDK2 / CycA complex in cells using cell-permeable peptides led to tumor cell-selective apoptosis (Chen YNP et al. (1999). Selective killing of transformed cells by cyclin / cyclin-dependent kinase 2 antagonists. Proc. Natl. Acad. Sci. USA 96, 4325-4329).
  • Changes in cell cycle control do not only play a role in cancer.
  • the cell cycle is activated by a number of viruses, both transforming and non-transforming, in order to allow the multiplication of the viruses in the host cell.
  • the incorrect entry into the cell cycle of normally post-mitotic cells has been associated with various neurodegenerative diseases.
  • a pharmaceutical preparation which, in addition to the active ingredient for enteral or parenteral administration, has suitable pharmaceutical, organic or inorganic inert carrier materials, such as, for example, water, gelatin, gum arabic, lactose, starch , Magnesium stearate, talc, vegetable oils, polyalkylene glycols etc. contains.
  • the pharmaceutical preparations can be in solid form, for example as tablets, dragees, suppositories, capsules or in liquid form, for example as solutions, suspensions or emulsions. If necessary, they also contain auxiliary substances such as preservatives, stabilizers, wetting agents or emulsifiers; Salts to change the osmotic pressure or buffer.
  • Injection solutions or suspensions in particular aqueous solutions of the active compounds in polyhydroxyethoxylated castor oil, are particularly suitable for parenteral use.
  • Surfactant auxiliaries such as salts of bile acids or animal or vegetable phospholipids, but also mixtures thereof and liposomes or their components can also be used as carrier systems.
  • Tablets, coated tablets or capsules with talc and / or hydrocarbon carriers or binders, such as lactose, corn or potato starch, are particularly suitable for oral use. It can also be used in liquid form, for example as juice, to which a sweetener may be added.
  • enteral, parenteral and oral applications are also the subject of the present invention.
  • the dosage of the active ingredients can vary depending on the route of administration, age and weight of the patient, type and severity of the disease to be treated and similar factors.
  • the daily dose is 0.5-1000 mg, preferably 50-200 mg, whereby the dose can be given as a single dose to be administered once or divided into 2 or more daily doses.
  • the present invention also relates to the use of the compounds of the general formula I for the manufacture of a medicament for the treatment of cancer, autoimmune diseases and cardiovascular
  • chemotherapeutic-induced alopecia and mucositis infectious diseases, nephrological diseases, chronic and acute neurodegenerative diseases and viral infections, with solid tumors and leukemia under cancer, psoriasis, alopecia and multiple sclerosis under autoimmune diseases, stenoses, arteriosclerosis and cardiovascular diseases among infectious diseases caused by unicellular parasites, under nephrological diseases glomerulonephritis, under chronic neurodegenerative diseases Huntington's disease, amyotropic lateral sclerosis, Parkinson's disease, AIDS dementia and Alzheimer's disease, under acute neurodegenerative diseases ischemia of the brain and neurotrauma, neurotrauma Cytomegalus infections, herpes, hepatitis B or C, and HIV diseases are to be understood.
  • the present invention also relates to medicaments for the treatment of the diseases listed above, which contain at least one compound of the general formula I, and to medicaments with suitable formulations and carriers.
  • the compounds of general formula I according to the invention include excellent inhibitors of cyclin-dependent kinases, such as CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 and CDK9, and glycogen synthase kinase (GSK-3ß).
  • cyclin-dependent kinases such as CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 and CDK9
  • GSK-3ß glycogen synthase kinase
  • Example 30 Example 1.0
  • Tetramethylguanidine (0.04 ml) in ethanol (2 ml) and 70 mg of the intermediate compound (v) known from the literature from Scheme 1 are added to a solution of 38 mg of the compound from Example 2.0 and kept under reflux for 6 hours. It was then concentrated. After purification by column chromatography, 16 mg of compound 3.0 were obtained.
  • the united org. Phases are dried with magnesium sulfate, filtered off and concentrated.
  • intermediate products are produced in accordance with the procedure described under intermediate product iv) in accordance with the following process scheme:
  • a NaH suspension (55%, 44 mg, 1 eq) is added to a solution of imidazole (82 mg, 1.2 eq) in DMF (3 ml) at room temperature. After 15 minutes, 200 mg (0.55 eq) of the intermediate (ii) and DMAP (20 mg) are added. The reaction mixture is stirred at 80 ° C. for 5 hours. It is then cooled, poured onto water (100 ml) and suction filtered. The blue-violet solid is washed with water and, after drying in vacuo, gives 140 mg of compound 7.0 (64% of theory).
  • Bromine compound 300 mg bistriphenylphosphine palladium dichloride, 0.34 ml triethylamine, 10 ml acetonitrile and 2.1 ml methanol.
  • the reaction is carried out for 7 hours at + 100 ° C. under a carbon monoxide atmosphere of ⁇ 5 bar.
  • the reaction mixture is concentrated and chromatographed on silica gel.
  • racemates formed in the preparation of the compounds according to the invention are separated by means of chiral HPLC.
  • R 6 , R 8 , R 9 , A, D, Z and n are those given in the general formula I.
  • R 7 stands for the group -NR 10 R 11 , and R 10 and R 1 independently of one another for Ci.Cio-alkyl or for
  • Group -COO-C ⁇ .C ⁇ 0 alkyl is mean.
  • the isomer mixtures can be separated into the enantiomers or E / Z isomers by conventional methods such as, for example, crystallization, chromatography or salt formation.
  • the salts are prepared in the customary manner by adding a solution of the compound of the formula I with the equivalent amount or an excess of a base or acid, which is optionally in solution, and separating off the precipitate or working up the solution in the customary manner.
  • Fig. 1 shows the simplified scheme of cell cycle regulation in vertebrates.
  • CDK2 and CycE-GST fusion proteins purified from baculovirus-infected insect cells were developed by Dr. Dieter Marme, Clinic for Tumor Biology Dortmund. Histone IIIS, which was used as the kinase substrate, was purchased from Sigma.
  • CDK2 / CycE (50 ng / measuring point) was in assay buffer [50 mM Tris / HCl pH 8.0, 15 min at 22 ° C. in the presence of various concentrations of test substances (0 ⁇ M, as well as within the range 0.01-100 ⁇ M). 10 mM MgCl 2 , 0.1 mM Na ortho-vanadate, 1.0 mM dithiothreitol, 0.5 ⁇ M adenosine trisphosphate (ATP), 10 ⁇ g / measuring point histone IIIS, 0.2 ⁇ Ci / measuring point 33 P-gamma ATP, 0. 05% NP40, 12.5% dimethyl sulfoxide].
  • assay buffer 50 mM Tris / HCl pH 8.0, 15 min at 22 ° C. in the presence of various concentrations of test substances (0 ⁇ M, as well as within the range 0.01-100 ⁇ M. 10 mM MgCl 2 , 0.1 mM Na
  • the reaction was stopped by adding EDTA solution (250 mM, pH 8.0, 14 ⁇ l / measuring point). 10 ⁇ l of each reaction mixture were applied to P30 filter strips (Wallac), and 33 P-ATP which had not been incorporated was removed by washing the filter strips three times for 10 min in 0.5% strength phosphoric acid. After the filter strips had dried for 1 hour at 70 ° C., the filter strips were covered with scintillator strips (MeltiLex TM A, Wallac) and baked at 90 ° C. for 1 hour. The amount of 33 P incorporated (substrate phosphorylation) was determined by scintillation measurement in a gamma radiation measuring device (Wallac).
  • EDTA solution 250 mM, pH 8.0, 14 ⁇ l / measuring point
  • Cultivated human MCF7 tumor cells were at a density of 5000
  • the plates were dried at room temperature.
  • the cells were stained by adding 100 .mu.l / measuring point of a 0.1% crystal violet solution (pH adjusted to pH 3 by adding acetic acid).
  • the plates were dried at room temperature.
  • the dye was dissolved by adding 100 ⁇ l / measuring point of a 10% acetic acid solution.

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Abstract

L'invention concerne des dérivés d'indirubine qui, par établissement d'une chaîne latérale de base en position 5, permet d'obtenir une solubilité radicalement élevée, avec une amélioration simultanée de l'efficacité biologique, ainsi que des produits intermédiaires et des procédés permettant de les produire et leur utilisation comme inhibiteurs de Cdk pour traiter des cancers, comme des tumeurs et la leucémie, des maladies auto-immunes telles que le psoriasis, l'alopécie et la sclérose en plaques, l'alopécie induite par agents chimiothérapeutiques et la mucosite, les affections cardio-vasculaires telles que les sténoses, les artérioscléroses et les resténoses, des maladies infectieuses, telles que par ex. des affections neurodégénératives induites par des parasites unicellulaires, tels que le trypanosoma, le toxoplasme ou le plasmodium ou par des moisissures, ces affections neurodégénératives pouvant être la glomérulonéphrite, des maladies neurodégénératives chroniques telles que la maladie d'Huntington, la sclérose latérale amyotrophique, la maladie de Parkinson, la démence du SIDA et la maladie d'Alzheimer, des maladies neurodégénératives aiguës, telles que des ischémies cérébrales et des traumatismes neurologiques, des infections virales, telles que par ex. des infections cytomégaliques, l'herpès, l'hépatite B et C et des affections VIH.
PCT/EP2002/006132 2001-06-11 2002-06-05 Derives d'indirubine inhibiteurs de cdk solubles Ceased WO2002100401A1 (fr)

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DE10129028A DE10129028A1 (de) 2001-06-11 2001-06-11 Lösliche Cdk-inhibitorische Indirubinderivate
DE10129028.4 2001-06-11

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WO2002100401A1 true WO2002100401A1 (fr) 2002-12-19

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WO2005107466A1 (fr) * 2004-05-12 2005-11-17 Bayer Cropscience Gmbh Regulation de la croissance des plantes
WO2006117212A2 (fr) 2005-05-04 2006-11-09 Develogen Aktiengesellschaft Utilisation des inhibiteurs gsk-3 dans la prevention et le traitement des maladies auto-immunes pancreatiques
WO2007089445A2 (fr) 2006-01-27 2007-08-09 Amgen Inc. Combinaisons d'inhibiteurs d'ang2 et de vegf
EP1706112A4 (fr) * 2004-01-12 2008-12-10 Natrogen Therapeutics Inc Procedes permettant de traiter une maladie de type inflammatoire
US7582670B2 (en) 2001-12-13 2009-09-01 Natrogen Therapeutics, Inc. Methods of treating an inflammatory-related disease
US7863242B2 (en) 2003-05-16 2011-01-04 University Of Maryland, Baltimore Compositions for down-regulation of CCR5 expression and methods of use thereof
WO2011077171A1 (fr) 2009-12-21 2011-06-30 Vichem Chemie Kutató Kft. Dérivés de 4-phénylamino-pyrimidine ayant une activité d'inhibition d'une protéine kinase
WO2011110612A1 (fr) 2010-03-10 2011-09-15 Ingenium Pharmaceuticals Gmbh Inhibiteurs de protéine kinases
WO2012044577A1 (fr) 2010-09-27 2012-04-05 Exelixis, Inc. Doubles inhibiteurs de met et vegf pour le traitement du cancer de la prostate résistant à la castration et des métastases osseuses ostéoblastiques
WO2013011841A1 (fr) * 2011-07-15 2013-01-24 学校法人日本大学 Dérivé d'indirubine ayant une cytotoxicité hautement sélective pour les tumeurs malignes
US8563525B2 (en) 2004-01-12 2013-10-22 Natrogen Therapeutics International, Inc. Methods of treating an inflammatory-related disease
WO2013192493A1 (fr) * 2012-06-21 2013-12-27 Phosphorex, Inc. Nanoparticules d'indirubine, leurs dérivés et leurs procédés de fabrication et d'utilisation
EP2708556A1 (fr) 2012-09-12 2014-03-19 Samsung Electronics Co., Ltd Composition pharmaceutique à utiliser dans une thérapie combinée pour la prévention ou le traitement des maladies induites par C-Met ou le facteur dýangiogénèse
US8716296B2 (en) 2007-10-12 2014-05-06 Ingenium Pharmaceuticals Gmbh Inhibitors of protein kinases
JP2016519167A (ja) * 2013-05-28 2016-06-30 ▲チュウ▼洲市洛▲達▼生物科技有限公司 ベンゾフラノン−インドール／アザインドール複合体およびその調製と応用
WO2016112111A1 (fr) 2015-01-08 2016-07-14 The Board Of Trustees Of The Leland Stanford Junior University Facteurs et cellules pour l'induction d'os, de moelle osseuse et de cartilage
CN110590640A (zh) * 2019-06-28 2019-12-20 贵州医科大学 一种靛玉红衍生物及其作为cdk/hdac双靶标抑制剂的应用
WO2021112626A1 (fr) * 2019-12-06 2021-06-10 주식회사 펠레메드 Nouveau dérivé d'indirubine et son utilisation
CN113072540A (zh) * 2021-03-29 2021-07-06 贵州医科大学 一种靛玉红衍生的降解剂及其制备与应用

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Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7582670B2 (en) 2001-12-13 2009-09-01 Natrogen Therapeutics, Inc. Methods of treating an inflammatory-related disease
US7863242B2 (en) 2003-05-16 2011-01-04 University Of Maryland, Baltimore Compositions for down-regulation of CCR5 expression and methods of use thereof
US8563525B2 (en) 2004-01-12 2013-10-22 Natrogen Therapeutics International, Inc. Methods of treating an inflammatory-related disease
EP2351564A1 (fr) * 2004-01-12 2011-08-03 Natrogen Therapeutics, Inc. Méthode de traitement des maladies inflammatoires
EP1706112A4 (fr) * 2004-01-12 2008-12-10 Natrogen Therapeutics Inc Procedes permettant de traiter une maladie de type inflammatoire
US7855223B2 (en) 2004-01-12 2010-12-21 Natrogen Therapeutics International, Inc. Method of treating inflammatory arthritis
EA012602B1 (ru) * 2004-05-12 2009-10-30 Байер Кропсайенс Аг Регулирование роста растений
WO2005107466A1 (fr) * 2004-05-12 2005-11-17 Bayer Cropscience Gmbh Regulation de la croissance des plantes
WO2006117212A2 (fr) 2005-05-04 2006-11-09 Develogen Aktiengesellschaft Utilisation des inhibiteurs gsk-3 dans la prevention et le traitement des maladies auto-immunes pancreatiques
WO2007089445A2 (fr) 2006-01-27 2007-08-09 Amgen Inc. Combinaisons d'inhibiteurs d'ang2 et de vegf
US8716296B2 (en) 2007-10-12 2014-05-06 Ingenium Pharmaceuticals Gmbh Inhibitors of protein kinases
WO2011077171A1 (fr) 2009-12-21 2011-06-30 Vichem Chemie Kutató Kft. Dérivés de 4-phénylamino-pyrimidine ayant une activité d'inhibition d'une protéine kinase
US8518948B2 (en) 2010-03-10 2013-08-27 Ingenium Pharmaceuticals Gmbh Inhibitors of protein kinases
WO2011110612A1 (fr) 2010-03-10 2011-09-15 Ingenium Pharmaceuticals Gmbh Inhibiteurs de protéine kinases
US9067888B2 (en) 2010-03-10 2015-06-30 Astrazeneca Ab Inhibitors of protein kinases
WO2012044577A1 (fr) 2010-09-27 2012-04-05 Exelixis, Inc. Doubles inhibiteurs de met et vegf pour le traitement du cancer de la prostate résistant à la castration et des métastases osseuses ostéoblastiques
JPWO2013011841A1 (ja) * 2011-07-15 2015-02-23 学校法人日本大学 悪性腫瘍に対する高選択的細胞毒性を有するインディルビン誘導体
US9051306B2 (en) 2011-07-15 2015-06-09 Nihon University Indirubin derivative having highly selective cytotoxicity for malignant tumors
WO2013011841A1 (fr) * 2011-07-15 2013-01-24 学校法人日本大学 Dérivé d'indirubine ayant une cytotoxicité hautement sélective pour les tumeurs malignes
WO2013192493A1 (fr) * 2012-06-21 2013-12-27 Phosphorex, Inc. Nanoparticules d'indirubine, leurs dérivés et leurs procédés de fabrication et d'utilisation
US10039829B2 (en) 2012-06-21 2018-08-07 Phosphorex, Inc. Nanoparticles of indirubin, derivatives thereof and methods of making and using same
US10675350B2 (en) 2012-06-21 2020-06-09 Phosphorex, Inc. Nanoparticles of indirubin, derivatives thereof and methods of making and using same
EP2708556A1 (fr) 2012-09-12 2014-03-19 Samsung Electronics Co., Ltd Composition pharmaceutique à utiliser dans une thérapie combinée pour la prévention ou le traitement des maladies induites par C-Met ou le facteur dýangiogénèse
JP2016519167A (ja) * 2013-05-28 2016-06-30 ▲チュウ▼洲市洛▲達▼生物科技有限公司 ベンゾフラノン−インドール／アザインドール複合体およびその調製と応用
WO2016112111A1 (fr) 2015-01-08 2016-07-14 The Board Of Trustees Of The Leland Stanford Junior University Facteurs et cellules pour l'induction d'os, de moelle osseuse et de cartilage
CN110590640A (zh) * 2019-06-28 2019-12-20 贵州医科大学 一种靛玉红衍生物及其作为cdk/hdac双靶标抑制剂的应用
WO2021112626A1 (fr) * 2019-12-06 2021-06-10 주식회사 펠레메드 Nouveau dérivé d'indirubine et son utilisation
CN113072540A (zh) * 2021-03-29 2021-07-06 贵州医科大学 一种靛玉红衍生的降解剂及其制备与应用
CN113072540B (zh) * 2021-03-29 2023-07-14 贵州医科大学 一种靛玉红衍生的降解剂及其制备与应用

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