WO2002074742A2 - Derives d'indirubine inhibiteurs de cdk ayant une solubilite elevee - Google Patents

Derives d'indirubine inhibiteurs de cdk ayant une solubilite elevee Download PDF

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WO2002074742A2
WO2002074742A2 PCT/EP2002/002983 EP0202983W WO02074742A2 WO 2002074742 A2 WO2002074742 A2 WO 2002074742A2 EP 0202983 W EP0202983 W EP 0202983W WO 02074742 A2 WO02074742 A2 WO 02074742A2
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alkyl
alkoxy
cycloalkyl
substituted
alkenyl
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Rolf Jautelat
Thomas Brumby
Olaf Prien
Martina SCHÄFER
Gerhard Siemeister
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Schering Aktiengesellschaft
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    • 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
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Definitions

  • the invention relates to indirubin derivatives which obtain a radically increased solubility while establishing the biological activity by establishing a quaternary center in the R 1 position, processes for their preparation and their use as Cdk inhibitors for the treatment of various diseases.
  • 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).
  • Example cancer such as solid tumors and leukemia, autoimmune diseases such as psoriasis 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.
  • 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.
  • R 1 for unsubstituted or optionally one or more, identical or different with hydroxy, Ci- ⁇ -alkoxy, amino, halogen, phenyl or with the group or -N- di-Ci- ⁇ -alkyl substituted C ⁇ - 10 alkyl, C ⁇ -io-alkenyl, C 2 - 10 - alkynyl, C3- 7 cycloalkyl or C 3 -7-cycloalkyl-C ⁇ - 3 alkyl stands, and the phenyl itself optionally one or more times, identically or differently with halogen, hydroxy, C ⁇ alkyl or Ci- ⁇ -alkoxy or with the group -CF 3 , -OCF3, -SCi ⁇ alkyl or -SCF 3 may be substituted,
  • R 6 represents hydrogen or fluorine
  • R 7 , R 8 and R 9 independently of one another for hydrogen, halogen, hydroxy, nitro, -C-10-alkyl, C ⁇ -10-alkoxy, C ⁇ -10-alkylthio, C2- ⁇ o-alkenyl, C 2 - 1 0 -alkynyl , C 3 -7-Cycloalkyl, C 3 -7-Cycloalkyl-C ⁇ -3-alkyl, aryl, heteroaryl or for the group -NR 10 R 11 , -SO 3 H, -PO 3 H 2 , - S (O) R 12 , -SO 2 R 12 , -NR 10 SO 2 R 11 , -SO 2 NR 10 R 11 , -NR 12 SO 2 NR 10 R 11 , -NR 12 SO 2 NH 2 , -NR 10 COR 11 , - NR 10 COOR 11 ,
  • CONH 2 -CONHCi- ⁇ -alkyl, -CON (C ⁇ -6-alkyl) 2 , -COOH or - COOCi-e-alkyl, or for one or more, the same or different, with hydroxy, halogen, Halo-Ci-e-alkoxy, amino, or phenyl substituted C ⁇ -1 0 alkyl, C 2 - ⁇ o-alkenyl, C 2 - ⁇ 0 -alkynyl, Ci-e-alkoxy, C ⁇ - 6 -thioalkyl, C 3 .7- cyclo-alkyl or C 3 -7-cycloalkyl-C -3-AJkyl, benzyloxy , Aryl or heteroaryl, and the phenyl itself one or more times, identically or differently, with halogen, hydroxy, Ci- ⁇ -alkyl, Ci- ⁇ -alkoxy, or
  • Halo-Ci- ⁇ -alkoxy can be substituted, or for CMO-alkyl, C 2 - ⁇ o-alkenyl, C 2 . ⁇ o-alkynyl, Ci- ⁇ -alkoxy, Ci-e-alkylthio, C 3rd 7-cycloalkyl or C3-7-cycloalkyl-C ⁇ - 3 alkyl, which are with the group -NR 13 R 14 , -SO 3 H, -PO3H2, -S (O) R 12 , -SO 2 R 12 , - NR 13 SO 2 R 14 , -SO 2 NR 13 R 14 , -NR 12 SO 2 NR 13 R 14 , -NR 12 SO 2 NH 2 , -
  • NR 13 COR 14 , -NR 13 COOR 14 , -NR 13 CONHR 14 , -NR 12 CONH 2 , - PO (OR 13 ) (OR 14 ), -POR 13 (OR 14 ), -CONH 2 , -CONR 13 R 14 or - COOR 12 can be substituted, or R 10 and R 11 together form a C3- ⁇ o-cycloalkyl ring, optionally one or more times, identically or differently, with hydroxy, halogen, amino, Ci- ⁇ -alkoxy, Ci - ⁇ -alkylthio, C1- 6 - alkoxy-C ⁇ - 6 alkyl or phenyl, which itself one or more times with halogen, hydroxy, C ⁇ - 6 alkyl, Ci- ⁇ -alkoxy, halo- C ⁇ - 6 alkyl, Halo-C ⁇ - 6 -alkoxy or C3- ⁇ o-cycloalkyl can be substituted, or with the group -NHCi- ⁇ -
  • Ci- ⁇ -alkyl C 3-7 cycloalkyl, C 3 - 7 cycloalkyl-C ⁇ -3-alkyl, d- ⁇ -alkoxy, Ci ⁇ - alkylthio, Ci-e-alkoxy-Ci-e-alkyl, phenyl, or benzyloxy, or represents a or several times, identically or differently, with hydroxy, halogen, Ci- ⁇ -alkoxy, Ci- ⁇ -alkylthio, halo-Ci-e-alkoxy, Amino or phenyl-substituted Ci-io alkyl, C 2 - ⁇ o alkenyl, C 2 - 1 0 alkynyl, Ci-e-alkoxy, Ci- ⁇ -thioalkyl, C3-7-cyclo-alkyl or C 3 -7 Are benzyloxy, aryl or heteroaryl, and the phenyl itself one or more times, identically or differently, with halogen,
  • Halo-C 6 alkyl or halo Ci-e-alkoxy can be substituted, or represents C 10 alkyl, C 2 -o alkenyl, C 2 -0 0 -alkynyl, Ci- ⁇ -alkoxy, Ci-e-thioalkyl, C3-7-cycloalkyl or C3.7-cycloalkyl-C1.
  • 3 - alkyl which with the group -NR 10 R 1i , -SO3H, -PO 3 H 2 , -NR 13 SO 2 R 14 , - SO 2 NR 13 R 14 , -
  • NR 12 SO 2 NR 13 R 14 -NR 12 SO 2 NH 2 , -NR 13 COR 14 , -NR 13 COOR 14 , -NR 13 CONHR 14 , -NR 12 CONH 2 , -PO (OR 13 ) (OR 14 ), - POR 13 (OR 14 ), -CONH 2 , -CONR 13 R 14 or -COOR 12 may be substituted, R 13 and R 14 independently of one another for hydrogen, amino, phenyl, Ci-io-
  • R 13 and R 14 together form a C 3 - ⁇ o-cycloalkyl ring, optionally with hydroxy, halogen, amino, Ci- ⁇ -alkoxy, Ci- ⁇ -alkylthio, Ci- ⁇ -alkoxy-Ci- ⁇ -alkyl or with the group -NHC1-6- alkyl, -N (C ⁇ -6-alkyl) 2 , -SOC ⁇ alkyl, -SO 2 C ⁇ - ⁇ -alkyl, -CONH 2 , - CONH-Ci- ⁇ -alkyl, - CON (C ⁇ - ⁇ -alkyl) 2 , -COOH or -COOC1.6-
  • Alkyl is in each case a straight-chain or branched alkyl radical, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. Butyl, tert.
  • alkyl radical such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. Butyl, tert.
  • 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 each straight-chain or branched, which means, for example, the following radicals: vinyl, propen-1-yl, propen-2-yl, but-1-en-1-yi, 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, ethynyl, 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-methyl-glucamine, dimethyl-glucamine, ethyl-glucamine, 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.
  • R 7 , R 8 and R 9 independently of one another for hydrogen, halogen, hydroxy
  • POR 10 (OR "), -CONH 2 , -CONR ⁇ R 11 or -COOR 12 , or for one or more, identical or different with hydroxy, halogen, C- ⁇ -alkoxy, Ci- ⁇ -alkylthio, halo -Ct- ⁇ -alkoxy, amino or with the group -NR , 0 R 11 , -SO 3 H, -PO 3 H 2 , - S (O) R 12 , -SO 2 R 12 , -NR 10 SO 2 R 11 , -SO 2 NR 10 R 11 , --
  • Halo-Ci-e-alkoxy amino or phenyl substituted C ⁇ - 10 alkyl, C 2 - ⁇ o-alkenyl, C 2 . ⁇ 0 -alkynyl, Ci- ⁇ -alkoxy, Ci- ⁇ -thioalkyl, C 3 -7- Cyclo-alkyl or C3-7-cycloalkyl-C ⁇ - 3 alkyl, benzyloxy, aryl or heteroaryl, and that Phenyl itself can be substituted one or more times, identically or differently, with halogen, hydroxyl, Ci- ⁇ -alkyl, Ci- ⁇ -alkoxy, halo-C 6 alkyl or halo-Ci- ⁇ -alkoxy, or for C1-1 0 -alkyl, C 2 - ⁇ o-alkenyl, C 2 - ⁇ o-alkynyl, C- ⁇ -alkoxy, Ci- ⁇ -thioalkyl, C 3 -7-cycloalkyl or C3
  • R 12 is hydrogen, amino, C ⁇ -10 alkyl, C 2 . ⁇ 0 alkenyl, C 2-0 alkynyl,
  • C 3 -7-Cycloalkyl C 3 -7-CycloalkyI-C ⁇ . 3- alkyl, Ci-e-alkoxy, Ci- ⁇ -alkylthio, Ci-e-alkoxy-C-e-alkyl, phenyl or benzyloxy, or for one or more, the same or different with
  • Halo-Ci-e-alkyl or Halo-Ci- ⁇ -alkoxy may be substituted, or represents -C-10-alkyl, C 2 . ⁇ 0 -alkenyl, C 2 - ⁇ o-alkynyl, Ci-e-alkoxy, Ci- ⁇ -thioalkyl, C3-7 cycloalkyl or C 3 . 7- cycloalkyl-C 1 . 3 - alkyl is, which with the group -NR 13 R 14 , -SO 3 H, -PO 3 H 2 , - NR 13 SO 2 R 14 , - SO 2 NR 13 R 14 , -NR 12 S0 2 NR 13 R 14 -NR 12 SO 2 NH 2 ,
  • -NR 13 COR 14 , -NR 13 COOR 14 , -NR 13 CONHR 14 , -NR 12 CONH 2 , - PO (OR 13 ) (OR 14 ), -POR 13 (OR 14 ), -CONH 2 , -CONR 13 R 14 or - may be substituted COOR 12, R 13 and R 14 independently of one another represent hydrogen, amino, phenyl, C 1 - 10 - alkyl, C 2 . ⁇ o alkenyl, C 2 - ⁇ o-alkynyl, C3- 7 cycloalkyl , C3.7-
  • CycloaIkyl-C ⁇ - 3 alkyl, Ci- ⁇ -alkoxy, Ci- ⁇ -alkylthio, C ⁇ - ⁇ -alkoxy-C ⁇ . stand for e-alkyl or for the group -CONH 2 , -CONHC - ⁇ -alkyl, - CON (C ⁇ - ⁇ -alkyl) 2 , -COOH or -COOCi- ⁇ -alkyl, or for C ⁇ - 10 alkyl, C 2 . ⁇ 0 alkenyl, C 2 - ⁇ 0 alkynyl, Ci-e-alkoxy, Ci- ⁇ - thioalkyl, C 3 7 -cycloalkyl, C 3-7 cycloalkyl-C ⁇ -3-alkyl,
  • Alkoxy or amino may be substituted, or R 13 and R 14 together form a ring
  • R 1 for unsubstituiert.es or optionally one or more, identically or differently with hydroxy, Ci- ⁇ -alkoxy, amino, halogen or phenyl substituted -CC 10 alkyl, C2-alko-alkenyl, C 3 -7-cycloalkyl, C 2 . ⁇ o-alkynyl, and the phenyl itself optionally one or more times, identically or differently, with halogen, hydroxy, Ci-e-alkyl or Ci-e-alkoxy or with the group -CF 3 , -OCF 3 , - SCi-e-alkyl or -SCF 3 can be substituted, RR 66 stands for hydrogen or fluorine,
  • R 7 , R 8 and R 9 independently of one another for hydrogen, halogen, hydroxy, nitro, Ci-io-alkyl, C 2 . ⁇ o-alkenyl, C 2 - ⁇ o-alkynyl, Ci- ⁇ -alkoxy, Ci- ⁇ -thioalkyl .
  • Phenyl itself can be substituted one or more times, identically or differently, with halogen, hydroxyl, Ci- ⁇ -alkyl, Ci- ⁇ -alkoxy, halo-Ci- ⁇ -alkyl or halo-Ci- ⁇ -alkoxy, or for CMO-alkyl, C 2 - ⁇ o-alkenyl, C 2 - ⁇ o-alkynyl, Ci- ⁇ -alkoxy, Ci- ⁇ -thioalkyl, C3-7-cyclo-alkyl or stand with the group -NR 13 R 14 , -SO 3 H, -PO 3 H 2 , -S (O) R 12 , -SO 2 R 12 , - NR 13 SO 2 R 14 , -SO 2 NR 13 R 14 , -NR 12 SO 2 NR 13 R 14 , -NR 12 SO 2 NH 2 , - NR 13 COR 14 , -NR 13 COOR 14 , -NR 13 CONHR 14 , -NR
  • R 12 is hydrogen, amino, C ⁇ ⁇ -0 alkyl, C 2 . ⁇ 0 alkenyl, C 2 - ⁇ o alkynyl,
  • Ci-e-alkoxy Ci- ⁇ -alkylthio, Ci- ⁇ -alkoxy-Ci-e-alkyl, phenyl or benzyloxy or for one or more, the same or different with Hydroxy, halogen, Ci-e-alkoxy, Ci- ⁇ -alkylthio, halo-Ci- ⁇ -alkoxy, amino or phenyl substituted C ⁇ -10-alkyl, C 2 - ⁇ o-alkenyl, C 2 .
  • Ci- ⁇ -alkoxy Ci- ⁇ -thioalkyl, C ⁇ cycloalkyl or C3-7- Benzyloxy, aryl or heteroaryl, and the phenyl itself one or more times, identically or differently, with halogen, hydroxy, Ci- ⁇ -alkyl, Ci- ⁇ -alkoxy, halo-Ci- ⁇ -alkyl or halo-Ci- ⁇ - alkoxy may be substituted
  • ⁇ stands for C 10 alkyl, C 2 -o alkenyl, C 2 -0 0 -alkynyl, Ci- ⁇ -alkoxy, Ci- ⁇ -thioalkyl, C3-7-cycloalkyl or C3 .7-Cycloalkyl-C1.3- alkyl, which with the group
  • -NR 13 R 14 -SO 3 H, -PO 3 H 2 , -NR 13 SO 2 R 14 , - SO 2 NR 13 R 14 , - NR 12 SO 2 NR 13 R 14 , -NR 12 SO 2 NH 2 , -NR 13 COR 14 , -NR 13 COOR 14 , -NR 13 CONHR 14 , -NR 12 CONH 2 , -PO (OR 13 ) (OR 14 ), - POR 13 (OR 14 ), -CONH 2 , -CONR 13 R 14 or -COOR 12 can be substituted,
  • R 13 and R 14 independently of one another for hydrogen, amino, phenyl, C1-1 0 -
  • Alkyl C 2 - ⁇ o-alkenyl, C 2 - ⁇ o-alkynyl, C ⁇ -cycloalkyl, C ⁇ - cycloalkyl-C ⁇ - 3 alkyl, Ci-e-alkoxy, Ci-e-alkyfthio, C ⁇ - ⁇ -alkoxy- C ⁇ - e-alkyl or for the group -CONH 2 , -CONHCi-e-alkyl, - CON (C ⁇ - ⁇ -alkyl) 2 , -COOH or -COOCi-e-alkyl, or for
  • R 1 for unsubstituted or optionally mono- or polysubstituted, identically or differently, with hydroxyl, Ci-e-alkoxy, amino or halogen-substituted C 10 alkyl, C 2 -0 0 -atkenyl, C 3 - 7 cycloalkyl or C 2 - ⁇ o-alkynyl,
  • R 6 represents hydrogen or fluorine
  • R 7 , R 8 and R 9 independently of one another are hydrogen, halogen, hydroxy, nitro, Ci-io-alkyl, C 2 . ⁇ o-alkenyl, C 2 - ⁇ 0 -alkynyl, C ⁇ -cycloalkyl, Ci-e-alkoxy, Ci-e-alkylthio, benzyloxy, phenyl or for the group -NR 10 R 11 ,
  • -NR 10 COR 11 , -SO 2 NR 10 R 11 , -COOR 12 , -S (O) R 12 , -SO 2 R 12 or -CONR 10 R 1 , R 10 and R 11 independently of one another are hydrogen, C ⁇ -10-alkyl, C 2 - ⁇ o-
  • Halo-Ci-e-alkoxy can be substituted, or are C 1 - 1 0-alkyl, C 2 - ⁇ o-alkenyl, C 2 - ⁇ o-alkynyl, Ci- ⁇ -alkoxy, Ci-e-thioalkyl, C3 -7-Cycloalkyl or C3-7-Cycloalkyl-C ⁇ - 3 alkyl are, which with the group -NR 13 R 14 , -SO 3 H, -PO 3 H 2 , -S (O) R 12 , -SO 2 R 12 , - NR 13 SO 2 R 14 , -SO 2 NR 13 R 14 -NR 12 SO 2 NR 13 R 14 , -NR 12 SO 2 NH 2 , -
  • NR 13 COR 14 , -NR 13 COOR 14 , -NR 13 CONHR 14 , -NR 12 CONH 2 , - PO (OR 13 ) (OR 14 ), -POR 13 (OR 14 ), -CONH 2 , -CONR 13 R 14 or - COOR 12 can be substituted, R 12 is hydrogen, amino, C 10 alkyl, C 2. 0 alkenyl, C 2.
  • Ci- ⁇ -alkoxy Ci-e-alkylthio, C ⁇ - ⁇ -alkoxy-C ⁇ -6-alkyl, phenyl or benzyloxy, or for one or more, identical or different with hydroxy, halogen, Ci-e-alkoxy, Ci-e-alkylthio, halo-Ci- ⁇ -alkoxy,
  • Ci-io-alkyl C 2 - ⁇ o-alkenyl, C 2 . 10-alkynyl, Ci-e-alkoxy, Ci- ⁇ -thioalkyl, C3-7-cyclo-alkyl or C3.7- cycloalkyl-C ⁇ - 3 alkyl, benzyloxy, aryl or heteroaryl, and the phenyl itself or multiple, identical or different with halogen, hydroxy, Ci- ⁇ -alkyl, Ci- ⁇ -alkoxy,
  • Halo-Ci- ⁇ -alkyl or halo-Ci-e-alkoxy may be substituted, or represents C ⁇ - 1 0 alkyl, C 2 . ⁇ o alkenyl, C 2 . ⁇ 0 alkynyl, Ci- ⁇ - alkoxy , Ci- ⁇ -thioalkyl, C3-7 cycloalkyl or alkyl, which with the group -NR 13 R 14 -SO 3 H, -PO 3 H 2 , -NR 13 SO 2 R 14 , - SO 2 NR 13 R 14 , -
  • NR 12 SO 2 NR 13 R 14 -NR 12 SO 2 NH 2 , -NR 13 COR 14 , -NR 13 COOR 14 , -NR 13 CONHR 14 , -NR 12 CONH 2 , -PO (OR 13 ) (OR 14 ), - POR 13 (OR 14 ), -CONH 2 , -CONR 13 R 14 or -COOR 12 can be substituted, R 13 and R 14 independently of one another for hydrogen, amino, phenyl, C1- 1 0-
  • Alkyl C 2 - ⁇ o-alkenyl, C 2 - ⁇ o-alkynyl, C ⁇ -cycloalkyl, C ⁇ - cycloalkyl-Ci-s-alkyl, Ci- ⁇ -alkoxy, Ci- ⁇ -alkylthio, C ⁇ -e-alkoxy- C ⁇ .
  • ⁇ -alkyl or for the group -CONH 2 , -CONHCi- ⁇ -alkyl, - CON (C ⁇ - ⁇ -alkyl) 2 , -COOH or -COOCi- ⁇ -alkyl, or for C ⁇ -10-alkyl, C 2 - ⁇ o-alkenyl, C 2 . ⁇ 0 -alkynyl, Ci- ⁇ -alkoxy, Ci-e-
  • thioalkyl Benzyloxy, benzyloxy, naphthyl, biphenyl, phenyl.thiophenyl, furanyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, triazinyl, quinolinyl or isoquinolinyl, which are optionally one or more, identical or different with hydroxy, halogen, Ci- ⁇ - Alkoxy, Ci- ⁇ -alkylthio, halo-Ci-e-alkoxy or amino may be substituted, and their isomers and salts.
  • Such compounds of the general formula I in which
  • R 1 represents Ci-io-alkyl, C 2 -6-alkenyl or C3- 7 -cycloalkyl,
  • R 2 represents hydrogen, benzyloxy or hydroxy
  • R 3 represents hydrogen, hydroxy, halogen, benzyloxy or the
  • R 4 , R 5 , R 6 , R 8 and R 9 are hydrogen
  • R 7 for halogen, nitro, Ci- ⁇ -alkoxy, Ci- ⁇ -alkylthio or for the
  • 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
  • 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.
  • mitosis the replicated DNA is separated and the cells are divided.
  • CDKs The cyclin-dependent kinases
  • Cyc a family of Ser / Thr kinases, members who require the binding of a cyclin (Cyc) as a regulatory subunit to activate them, drive the cell through the cell cycle.
  • 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, for example, 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 through 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.
  • Rb binds and inactivates E2F-type transcription factors and forms transcriptional repressor complexes with histone deacetylases (HDAC) (Zhang HS et al. (2000).
  • HDAC histone deacetylases
  • Exit from G1 and S phase of the cell cycle is regulated by repressor complexes containing HDAC-Rb-hSWI / SNF and Rb-hSWI / SNF.
  • Cell 101, 79-89 Through the Phosphorylation of Rb by CDKs releases bound E2F transcription factors and leads to transcriptional activation of genes, the products of which are required for DNA synthesis and progression through the S phase.
  • Rb phosphorylation causes the Rb-HDAC complexes to dissolve, thereby activating additional genes.
  • 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 directly controlled by various mechanisms, such as synthesis and degradation of the cyclines, complexation of the CDKs with the corresponding cyclins, phosphorylation and dephosphorylation of regulatory Thr and Tyr residues, and the binding of natural inhibitory proteins. While the amount of protein in CDKs in a proliferating cell is relatively constant, the amount of individual cyclines oscillates as the cycle goes through. For example, the expression of CycD is stimulated by growth factors during the early G1 phase, and the expression of CycE is induced by the activation of the transcription factors of the E2F type after the "restriction point" has been exceeded. The cyclines themselves are broken down by ubiquitin-mediated proteolysis.
  • Activating and inactivating phosphorylations regulate the activity of the CDK's, for example phosphorylate CDK-activating kinases (CAKs) 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
  • 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.
  • p53 is activated after detection of changes in the metabolism or the genomic integrity of the cell and can either stop cell cycle progression or trigger apoptosis.
  • the transcriptional activation of the expression of the CDK inhibitor protein p21 by p53 plays a crucial role.
  • 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.
  • 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 overexpression of D and E cyclins by gene amplification or chromosomal transiocations, 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. 50%). In tumor cells that express p53 without a mutation, it is often inactivated due to a greatly increased protein degradation. Similarly, the genes of other proteins necessary for the function of the control points are affected by mutations, for example ATM (inactivating mutations) or cdc25 phosphatases (overexpression).
  • 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 by means of 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).
  • Inhibitors of cyclin-dependent kinases as therapeutic agents for the treatment of cancer Curr. Opin. Oncol. Endo. Metab Invest. Drugs 2, 40-59; Rosiania GR & Chang YT (2000). Targeting hyperproliferative disorders with cyclin dependent kinase inhibitors. Exp. Opin. Ther. Patents 10, 215-230; Meijer L. et al. (1999) Properties and potential applications of chemical inhibitors of cyclin-dependent kinases. Pharmacol. Ther. 82, 279-284; Senderowicz AM & Sausville EA (2000). Preclinical and clinical development of cyclin-dependent kinase modulators. J. Natl. Cancer Inst. 92, 376-387).
  • 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, and 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, cardiovascular diseases, chemotherapy-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 restenosis under cardiovascular diseases, diseases caused by unicellular parasites under infectious diseases, glomerulonephritis under nephrological diseases, under chronic neurodegenerative diseases with chronic neurodegenerative diseases Sclerosis, Parkinson's disease, AIDS dementia and Alzheimer's disease, among acute neurodegenerative diseases ischemia of the brain rns and neurotraumata, and viral infections are to be understood as cytomegalus infections, herpes, hepatitis B or C, and HIV diseases.
  • the present invention also relates to medicaments for the treatment of the diseases listed
  • 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 14 60 mg (0.185 mmol) of the compound from Example 4 are slurried in 5 ml of dichloromethane. 60 mg (0.2 mmol, -77%) m-CPBA are then added and the mixture is stirred for 24 hours at room temperature. The compound 12 precipitates out in crystalline form. 28 mg of compound 14 are suctioned off.
  • Example 14 The mother liquor from Example 14 is subjected to column chromatographic purification (DCM / EE 1: 1). 5 mg of compound 15 are obtained from the eluate as a yellow solid.
  • Example 18 500 mg (1, 399 mmol) of the compound from Example 1, 0.7 g of bis (triphenylphosphine) palladium dichloride, 0.8 ml of triethylamine and 2.2 ml of methanol in 10 ml of acetonitrile are at 100 ° under a carbon monoxide atmosphere (11 bar) C shaken in an autoclave. The reaction mixture is concentrated, taken up in acetone, filtered off and concentrated again. The residue is digested with dichloromethanol and suction filtered. 309 mg (66% of theory) of compound 18 are obtained.
  • Example 21 becomes analogous to Example 22. Yield: 40% of theory
  • Example 23 Example 2 Example 27 Example 23
  • Example 23 The compound from Example 23 is prepared analogously to Example 1, 140 mg (0.5 mmol) of the starting material from Example 8 being reacted with 0.6 ml (1.8 mmol) of a 3 M solution of ethyl magnesium bromide in ether. The yield after flash chromatography using DCM / EE 2: 1 as eluent gives 80 mg of a brown solid of compound 23 (-52% of theory).
  • Example 24 The compound to Example 24 is prepared analogously to Example 1, 140 mg (0.5 mmol) of the starting material from Example 3 being reacted with 0.9 ml (1.8 mmol) of a 2 M solution of allyl magnesium bromide in ether. The yield is 117 mg of a yellowish foam of compound 24 (73% of theory).
  • Example 25 The compound to Example 25 is prepared analogously to Example 1, 185 mg (0.5 mmol) of indirubin-5-sulfonic acid dimethylamide being reacted with 1.5 ml of a 2 M solution of allyl magnesium bromide in ether. The yield is 108 mg (52% of theory) of compound 25.
  • Example 26 The compound to Example 26 is prepared analogously to Example 1, 185 mg (0.5 mmol) of indirubin-5-sulfonic acid dimethylamide being reacted with 1.5 ml of a 2 M solution of hexylmagnesium bromide in ether. The yield is 153 mg (67% of theory) of compound 26.
  • Example 27 The compound to Example 27 is prepared analogously to Example 1, 185 mg (0.5 mmol) of indirubin-5-sulfonic acid dimethylamide with 1.5 ml of a 2 M solution of Cyclohexylmagnesiumchlorid be implemented in ether. The yield is 50 mg (22% of theory) of compound 27.
  • Enantiomers of the compounds according to the invention are separated by means of preparative HPLC. The separation is shown by way of example using the following connections.
  • Example 5 The enantiomer separation of Example 5 is carried out on a Chiralpack AD 10 ⁇ m column. A mixture of hexane: ethanol 1: 1 serves as the eluent.
  • Example 13 The enantiomer separation of Example 13 is carried out on a Chiralpack AD 10 ⁇ m column. A mixture of hexane-ethanol 7: 3 serves as the eluent
  • the enantiomers of the compounds according to the invention are also a subject of the invention.
  • inventive starting compounds which can preferably be used for the preparation of the compounds according to the invention, are prepared according to the following reaction schemes.
  • the compound of general formula II is commercially available.
  • Compound VI is prepared using the method known from the literature (dissertation Ralph Hössel, University of Kaiserslautern 1999).
  • connection Vlll The connection Vlll is produced in an analogous manner to that described under connection V. Yield: 53% of theory
  • the starting compounds can also be prepared according to the following reaction scheme:
  • R 3 represents halogen, benzoxy or the group -NH-COR 10 ,
  • R 7 for halogen or the group -SR 10 or -SO 2 NR 10 R 11 and
  • R 10 and R 11 are Ci-e-alkyl mean.
  • the isomer mixtures can by conventional methods such as
  • Crystallization, chromatography or salt formation can be separated into the enantiomers or E / Z isomers.
  • 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 different concentrations of test substances (0 ⁇ M, as well as within the range 0.01-100 ⁇ M). 10 mM MgCI 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 ⁇ 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 different concentrations of test substances (0 ⁇ M, as well as within the range 0.01-100 ⁇ M. 10 mM MgCI 2 , 0.1 mM Na ortho
  • 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 plated at a density of 5000 cells / measuring point in a 96-well multi-titer plate in 200 ⁇ l of the corresponding growth medium. After 24 hours, the cells of one plate (zero point plate) were stained with crystal violet (see below), while the medium of the other plates was mixed with fresh culture medium (200 ⁇ l) containing the test substances in various concentrations (0 ⁇ M and in the range 0.01 - 30 ⁇ M; the final concentration of the solvent dimethyl sulfoxide was 0.5%) were replaced. The cells were incubated for 4 days in the presence of the test substances.

Abstract

La présente invention concerne des dérivés d'indirubine qui, grâce à l'établissement d'un centre quaternaire en position R1, ont une solubilité radicalement accrue tout en conservant une activité biologique. Cette invention concerne également la préparation desdits dérivés et les produits intermédiaires intervenant dans leur préparation, ainsi que leur utilisation en tant que médicament pour traiter le cancer tels que les tumeurs solides et la leucémie, les maladies auto-immunes telles que le psoriasis, l'alopécie et la sclérose en plaques, l'alopécie induite par la chimiothérapie et la mucosite, les maladies cardio-vasculaires telles que les sténoses, les artérioscléroses et les resténoses, les maladies infectieuses telles que celles causées par les parasites unicellulaires tels que, Trypanosoma, Toxoplasma ou Plasmodium, ou par des champignons, les maladies néphrologiques telles que Glomerulonephritis, des maladies de neurodégénérescence chroniques telles que la maladie de Huntington, la sclérose amyotropique latérale, la maladie de Parkinson, la démence du SIDA et la maladie d'Alzheimer, les maladies de neurodégénérescence aiguës telles que les ischémies cérébrales et Neurotraumata, et les infections virales telles que les infections cytomégaliques, l'herpès, l'hépatite B et C, les maladies dues aux VIH.
PCT/EP2002/002983 2001-03-16 2002-03-18 Derives d'indirubine inhibiteurs de cdk ayant une solubilite elevee WO2002074742A2 (fr)

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US7582670B2 (en) 2001-12-13 2009-09-01 Natrogen Therapeutics, Inc. Methods of treating an inflammatory-related disease
US7855223B2 (en) 2004-01-12 2010-12-21 Natrogen Therapeutics International, Inc. Method of treating inflammatory arthritis
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EP1706112A4 (fr) * 2004-01-12 2008-12-10 Natrogen Therapeutics Inc Procedes permettant de traiter une maladie de type inflammatoire
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EP2351564A1 (fr) * 2004-01-12 2011-08-03 Natrogen Therapeutics, Inc. Méthode de traitement des maladies inflammatoires
US7973069B2 (en) 2004-07-14 2011-07-05 Ptc Therapeutics, Inc. Methods for treating hepatitis C
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
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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
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

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