EP1981879A1 - Dérivés d'aminoindazole - Google Patents

Dérivés d'aminoindazole

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Publication number
EP1981879A1
EP1981879A1 EP07702672A EP07702672A EP1981879A1 EP 1981879 A1 EP1981879 A1 EP 1981879A1 EP 07702672 A EP07702672 A EP 07702672A EP 07702672 A EP07702672 A EP 07702672A EP 1981879 A1 EP1981879 A1 EP 1981879A1
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EP
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Prior art keywords
het
compounds
salts
solvates
stereoisomers
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.)
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Application number
EP07702672A
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German (de)
English (en)
Inventor
Markus Klein
Rolf Gericke
Werner Mederski
Norbert Beier
Florian Lang
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Merck Patent GmbH
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Merck Patent GmbH
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Publication of EP1981879A1 publication Critical patent/EP1981879A1/fr
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    • C07D405/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to compounds and to the use of compounds in which the inhibition, regulation and / or modulation of the signal transduction of kinases, in particular the tyrosine kinases and / or serine / threonine kinases, also pharmaceutical compositions containing these compounds, and the use of the compounds to treat kinase-related diseases.
  • the present invention relates to compounds in which the inhibition
  • CHK1 and CHK2 - kinase as well as the cell volume-regulated human kinase h-sgk (human serum and glucocorticoid dependent kinase or SGK) plays a role, also pharmaceutical compositions containing these compounds, as well as the use of the compounds for the treatment of CHK1-, CHK2- and SGK-related diseases.
  • Cell cycle control points are regulatory pathways that control the order and timing of cell cycle transitions. They ensure that important events, such as DNA replication and chromosomal segregation, are completed with high reliability. The control of this
  • CHK1 Ser / Thr kinase checkpoint kinase 1
  • CHK2 Another essential checkpoint kinase that plays a critical role in p53-dependent apoptosis is CHK2. Inhibition of CHK2 can protect normal sensitive tissue against chemotherapeutic agents (B.B.S. Zhou et al., Progress in Cell Cycle Research, 35 Vol. 5, 413-421, 2003).
  • Compounds of formula I can be shown to inhibit checkpoint kinase activity.
  • Checkpoint kinase inhibitors can be shown to allow cells to inappropriately advance to the metaphase of mitosis, resulting in apoptosis of affected cells, and therefore possess antiproliferative effects.
  • the compounds of formula I can be used for the treatment of neoplastic disease.
  • neoplastic diseases such as carcinoma of the brain, breast, ovary, lung, colon, prostate, skin or other tissues as well as leukemias and lymphomas, tumors of the central and peripheral neoplastic diseases.
  • neoplastic diseases such as carcinoma of the brain, breast, ovary, lung, colon, prostate, skin or other tissues as well as leukemias and lymphomas, tumors of the central and peripheral neoplastic diseases.
  • ⁇ c nervous system and other tumor types, such as melanoma, sarcoma,
  • Fibrosarcoma and osteosarcoma are used.
  • the compounds of the formula I are also suitable for the treatment of other proliferative disorders.
  • the compounds of formula I can also be used in combination with a wide range of DNA damaging agents
  • the present invention therefore relates to the use of the compounds of the formula I for the treatment of diseases or conditions in which an inhibition of CHK1 and / or CHK2 activity is advantageous.
  • SGK belongs to the serine / threonine kinases.
  • the present invention further relates to the use of
  • SGK plays a role in the treatment of SGK-related diseases. 35 - A -
  • the SGK with the isoforms SGK-1, SGK-2 and SGK-3 are one
  • the compounds according to the invention are inhibitors of SGK-1. Further, they may be inhibitors of SGK-2 and / or SGK-3.
  • the present invention thus relates to the use of the compounds of the formula I 1 which inhibit, regulate and / or modulate the signal transduction of SGK, compositions containing these compounds
  • diabetes e.g., diabetes mellitus, diabetic nephropathy, diabetic neuropathy, diabetic angiopathy and microangiopathy
  • obesity e.g., obesity, metabolic syndrome
  • .J 5 dislipidemia
  • cardiovascular diseases eg cardiac fibrosis after myocardial infarction, cardiac hypertrophy and heart failure, arteriosclerosis
  • kidney diseases eg glomerulosclerosis, nephrosclerosis, nephritis, nephropathy,
  • Fibrosis and inflammatory processes e.g., cirrhosis, pulmonary fibrosis, fibrosing pancreatitis, rheumatism and arthrosis, Crohn's disease, chronic bronchitis, radiation fibrosis, sclerodermitis, cystic fibrosis, scarring, Alzheimer's disease).
  • the compounds according to the invention can also inhibit the growth of tumor cells and tumor metastases and are therefore suitable for tumor therapy.
  • the compounds according to the invention continue to be used
  • coagulopathies such as dysfibrinogenemia, hypoproducinemia, hemophilia B, Stuart-Prower defect, prothrombin complex deficiency, consumption coagulopathy, hyperfibrinolysis, immuno-coagulopathy or complex coagulopathies, as well as neuronal coagulopathies, such as dysfibrinogenemia, hypoproducinemia, hemophilia B, Stuart-Prower defect, prothrombin complex deficiency, consumption coagulopathy, hyperfibrinolysis, immuno-coagulopathy or complex coagulopathies, as well as neuronal
  • the compounds of the invention may also be used therapeutically in the treatment of glaucoma or cataract.
  • the compounds of the invention are also used in the treatment of bacterial infections and in an anti-infective therapy.
  • the compounds of the invention may also be used therapeutically to increase learning and attention.
  • the compounds of the invention counter cell aging and stress and thus increase life expectancy and fitness in old age.
  • the compounds according to the invention are also used in the treatment of tinitus.
  • the present invention therefore relates to compounds according to the invention as medicaments and / or active pharmaceutical ingredients in the treatment and / or prophylaxis of said diseases and the
  • the host or patient may be of any mammalian species, e.g. B. a 5
  • EMBO, 1997, 16, 2783-93 models of transgenic animals (e.g., White et al., Oncogene, 2001, 20, 7064-7072).
  • interacting compounds can be used to modulate the signal (e.g., Stephens et al., Biochemical J., 2000, 351, 95-105).
  • the compounds according to the invention can also be used as reagents for testing kinase-dependent signal transduction pathways in animals and / or cell culture models or in the clinical diseases mentioned in this application.
  • kinase activity is a technique well known to those skilled in the art.
  • Generic Assay Systems for Determining Kinase Activity with Substrates e.g. Histone (eg Alessi et al., FEBS Lett. 1996, 399, 3, pages 333-338) or the myelin basic protein are described in the literature (eg Campos-Gonzalez, R. and Glenney, Jr., JR 1992, J. Biol. Chem. 267, page 14535).
  • Inhibitors are available in various assay systems.
  • Scintillation Proximity Assay Sorg et al., J. of Biomolecular Screening, 2002, 7, 11-19
  • FlashPlate assay radioactive phosphorylation of a protein or peptide is described as
  • Non-radioactive ELISA assay methods use specific phospho-antibodies (Phospho-AK).
  • Phospho-AK binds only the phosphorylated substrate. This binding is detectable with a second peroxidase-conjugated anti-sheep antibody by chemiluminescence
  • indazole derivatives are as protein kinase inhibitors in WO
  • indazole derivatives are described as kinase inhibitors in WO2003097610.
  • indazole derivatives are disclosed as GSK-3 inhibitors in WO2003051847.
  • WO 00/62781 the use of medicaments containing inhibitors of the cell volume-regulated human kinase H-SGK is described.
  • the use of kinase inhibitors in anti-infective therapy is described by C.Doerig in Cell. Biol. Lett. Vol.8, No. 2A 1 2003, 524-525.
  • the invention relates to compounds of the formula
  • R 1 , R 2 are each independently H, A,
  • R 3 is H or A
  • Y is H, A, Ar, Het, -C (R 5 ) 2 Ar or C (R 5 ) 2 Het,
  • Ar is unsubstituted or mono-, di-, tri-, tetra- or quintuple by Hal, A, OR 5 , SR 5 , N (R 5 ) 2> NO 2 , CN, COOR 5 , CON (R 5 ) 2 , NO 5 COA, NR 5 CON (R 5 ) 2 1 NR 5 SO 2 A, COR 5 , SO 2 N (R 5 ) 2 , S (O) 1n A, - [C (R 5 ) 2 ] n -COOR 5 and /or -O [C (R 5 ) 2 ] o-COOR 5 substituted phenyl, naphthyl or biphenyl, Het a mono- or binuclear saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and / or S
  • Carbonyl oxygen may be substituted
  • Het 1 is a mono- or binuclear saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and / or S atoms which is mono-, di- or trisubstituted by A, OA, OH 1 SH,
  • Carbonyl oxygen may be substituted
  • R 5 is H or A
  • F and / or chlorine may be replaced, Hal, F, Cl, Br or I 1 m is 0, 1 or 2, n is O, 1, 2, 3, 4 or 5, o is 0, 1 or 2, and their pharmaceutically acceptable Derivatives, solvates, salts,
  • the invention also relates to the optically active forms
  • Solvates are e.g. Mono- or dihydrate or
  • compositions of the invention are understood, for example, as the salts of the compounds of the invention as well as so-called prodrug compounds.
  • biodegradable polymer derivatives of the compounds of the invention include biodegradable polymer derivatives of the compounds of the invention, as z. In Int. J. Pharm. 115, 61-67 (1995).
  • the term "effective amount” means the amount of a drug or pharmaceutical agent which elicits a biological or medical response in a tissue, system, animal or human, e.g. sought or desired by a researcher or physician.
  • the term "therapeutically effective amount” means an amount which, compared to a corresponding subject who has not received this amount, results in: improved curative treatment, cure, prevention or elimination of a disease, a disease, a disease state, a disease Suffering, a disorder or side effects or even the reduction of the progression of a disease, a disease or a disorder.
  • therapeutically effective amount also includes the amounts effective to increase normal physiological function.
  • the invention also provides the use of mixtures of
  • the invention relates to the compounds of the formula I and their salts and to a process for the preparation of compounds of the formula I and their pharmaceutically usable derivatives, salts, solvates, tautomers and stereoisomers, characterized in that a) for the preparation of compounds of the formula I. in which R 1 and R 2 are H,
  • L is F, Cl, Br, I or a free or reactive functionally modified OH group
  • A is alkyl, is unbranched (linear) or branched, and has 1, 2, 3, 4,
  • A is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1, 1-, 1,2- or 2,2-dimethylpropyl,
  • ⁇ 5 A very particularly preferably denotes alkyl having 1, 2, 3, 4, 5 or 6 C atoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl , Trifluoromethyl, pentafluoroethyl or 1,1,1-trifluoroethyl.
  • R 1 is preferably H.
  • R 2 is preferably H;
  • A such as methyl, ethyl or propyl;
  • n is preferably 0, 1 or 2 and Het is preferably piperidin-4-yl, morpholin-4-yl, 1-methylpiperidin-4-yl, 2Q piperazin-4-yl Pyrrolidin-2-yl or pyrrolidin-1-yl;
  • -COAr such as benzoyl
  • Het is preferably a mononuclear aromatic
  • -COA such as e.g. Acetyl or propionyl; CHO;
  • -SOAr such as -SO-phenyl
  • Het is preferably a mononuclear aromatic
  • Heterocycle having 1 to 3 N, O and / or S atoms, which may be mono-, di- or trisubstituted by A, and / or Hal means; -SOA, such as SOCH 3 ; -SO 2 Ar, such as -SO 2 phenyl; -SO 2 HeI, wherein Het preferably a mononuclear aromatic heterocycle having 1 to 3 N, O and / or S atoms, which may be mono-, di- or trisubstituted by A, and / or Hal; -SO 2 A, such as -SO 2 methyl; -SO 2 N (R 5 ) 2 such as -SO 2 NH 2 , -SO 2 NH (CH 3 ) or -SO 2 N (CH 3 ):. -SO 2 NHAr, such as -SO 2 NHPhenyl;
  • Het is preferably a mononuclear aromatic heterocycle having 1 to 3 N, O and / or S atoms, which may be mono-, di- or trisubstituted by A, and / or Hal;
  • -SO 2 NAAr such as -SO 2 (CH 3 ) phenyl
  • -SO 2 NAHet such as -SO 2 (CH 3 ) Het, wherein Het preferably a mononuclear aromatic heterocycle having 1 to 3 N, O and / or S
  • Atoms which may be mono-, di- or trisubstituted by A, and / or Hal are;
  • -CON (R 5 ) 2 such as -CONH 2 or -CONHCH 3 ;
  • -CONHAr such as -CONHPhenyl
  • Het is preferably a mononuclear aromatic heterocycle having 1 to 3 N, O and / or S atoms, which may be mono-, di- or trisubstituted by A, and / or Hal;
  • -CONAAr such as -CON (CH 3 ) phenyl or
  • -CONAHet such as -CON (CH 3 ) Het, wherein Het preferably a mononuclear aromatic heterocycle having 1 to 3 N, O and / or S
  • R 2 particularly preferably denotes H 1 -COAr 1 -COHet, -COA, -SO 2 Ar, 5 -SO 2 Het, -SO 2 A, -SO 2 N (R S ) 2 , -SO 2 NHAr or -SO 2 NHHet.
  • R 2 most preferably means H, -COAr 1 , -COHet, -COA, -SO 2 Ar 1 , -SO 2 Het or -SO 2 A, wherein
  • Ar 1 phenyl which is unsubstituted or mono-, di-, tri- or tetra-substituted by 10 Hal and / or A,
  • R 3 is preferably H.
  • R 4 is preferably H or A.
  • R 5 is H or A 1 is preferably H or CH 3 , more preferably H.
  • X is preferably Ar-diyl or Het 1 -diyl.
  • X particularly preferably denotes Het 1 -diyl, where Het 1 is a monocyclic aromatic heterocycle having 1 to 3 N, O and / or S atoms, which may be monosubstituted or disubstituted by A and / or Hal.
  • Y is preferably Ar, furthermore H.
  • Y is particularly preferably Ar 2 , where Ar 2 is phenyl which is unsubstituted or mono-, di-, tri-, tetra- or trisubstituted by Hal, OH 1 OA and / or A, and also H.
  • O Q Ar is, for example, phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p-aminophenyl, o-, m- or p- (N Methylamino) -phenyl, o-, m- or p- (N Methylamino) -phenyl, o-, m- or p- (N Methylamino) -phenyl, o-, m- or p- (N Methylamino)
  • Ar is preferably unsubstituted or mono-, di-, tri-, tetra- or quintuple phenyl substituted by A, Hal, OA and / or OH.
  • Het, unge partyet further substitutions, for example, 2- or 3-furyl, 2- or 3-thienyl 30, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3- , 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2- , 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, more preferably 1, 2,3-triazole-1, -4- or -5-yl, 1, 2,4-tri azole-1, -3- or 5-yl, 1- or 5-tetrazolyl, 1, 2,3-oxadiazol-4 or 5-yl,
  • heterocyclic radicals may also be partially or completely hydrogenated. Het can so z. B. also mean 2,3-dihydro-2-, -3-, -4- or -5-furyl,
  • Het is preferably a mono- or binuclear saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and / or S atoms which is mono-, di- or trisubstituted by A, OA, Hal and / or OO
  • ⁇ c Het particularly preferably denotes a mononuclear aromatic
  • Heterocycle having 1 to 3 N, O and / or S atoms e.g. Thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyrimidinyl, triazolyl or tetrazolyl, which may be mono-, di- or trisubstituted by A and / or Hal, where A is preferably methyl, ethyl,
  • Het 1 is preferably a mononuclear aromatic heterocycle having 1 to 3 N, O and / or S atoms, such as thienyl or furyl, which may be mono-, 25- or trisubstituted by A and / or Hal, wherein A is preferably methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl or trifluoromethyl.
  • the compounds of formula I may contain one or more chiral centers
  • R 2 represents H, -COAr 1 -COHet, -COA, -SO 2 Ar, -SO 2 Het, -SO 2 A, -SO 2 N (R 5 ) 2 , -SO 2 NHAr or -SO 2 NHHet ; in Ie R 2 is H, -COAr, -CO-Het, -COA, -SO 2 Ar, -SO 2 Het or -SO 2 A;
  • Het is a mononuclear aromatic heterocycle having 1 to 3 N, O and / or S atoms, which may be mono-, di- or trisubstituted by A, and / or Hal;
  • Ij X is ar-diyl or Het 1 -diyl
  • Het 1 is a mononuclear aromatic heterocycle having 1 to 3 N, O and / or S atoms, which may be mono- or disubstituted by A and / or Hal;
  • Il Y means H or Ar
  • Ar 2 is phenyl which is unsubstituted or mono-, di-, tri-, tetra- or trisubstituted by Hal, OH, OA and / or A;
  • Het 1 is a mononuclear aromatic heterocycle containing 1 to 3 N-,
  • Ar is unsubstituted or mono-, di-, tri-, tetra- or quintuplet of Hal, A 1 OR 5 , SR 5 , N (R 5 ) 2 , NO 2 , CN, COOR 5 , CON (R 5 ) 2 , NR 5 COA, NR 5 CON (R 5 ) 2 , NR 5 SO 2 A, COR 5 , SO 2 N (R 5 ) 2 , S (O) 1n A, - [C (R 5 ) 2 ] n -COOR 5 and / or -O [C (R 5) 2] 0 -COOR 5 substituted phenyl, naphthyl or biphenyl, Het denotes a mono- or bicyclic saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and / or S Atoms which are mono-, di- or trisubstituted by A, OA 1 OH, SH,
  • R 5 is H or A, A alkyl having 1 to 10 carbon atoms, wherein also 1-7 H atoms
  • F and / or chlorine may be replaced, Hal F, Cl, Br or I, m is 0, 1 or 2, n is 0, 1, 2, 3, 4 or 5, o is O 1 1 or 2;
  • R 2 is H, -COHet or -SO 2 Het
  • Het 1 is a mononuclear aromatic heterocycle having 1 to 3 N-,
  • O and / or S atoms which may be monosubstituted or disubstituted by A and / or Hal, Y is H or Ar 2 ,
  • Ar 2 is phenyl which is unsubstituted or monosubstituted, disubstituted, trisubstituted, trisubstituted or pentane-substituted by Hal 1 OH, OA and / or A;
  • the starting materials may, if desired, also be formed in situ, so that they are not isolated from the reaction mixture, but immediately further reacted to the compounds of formula I.
  • L preferably denotes F 1 Cl, Br, I or a freely modified or reactively modified OH group, for example an activated ester, an imidazolide or alkylsulfonyloxy having 1-6 C atoms (preferably methylsulfonyloxy or trifluoromethylsulfonyloxy) or Arylsulfonyloxy having 6-10 C atoms (preferably phenyl or p-Tolylsulfonyl- oxy).
  • L is preferably F.
  • the compounds of formula II are usually new.
  • the reaction is usually carried out in an inert solvent.
  • the reaction time is between a few minutes and 14 days, depending on the conditions used, the reaction temperature between about 0 ° and 150 °, usually between 15 ° and 120 °, more preferably between 50 and 100 0 C.
  • Suitable inert solvents are e.g. Hydrocarbons such as hexane,
  • Tetrahydrofuran (THF) or dioxane Tetrahydrofuran (THF) or dioxane
  • Glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Amides such as acetamide, dimethylacetamide or dimethylformamide (DMF);
  • Nitriles such as acetonitrile; Sulfoxides such as dimethylsulfoxide (DMSO); Sulfuric 5 carbon; Carboxylic acids such as formic acid or acetic acid; Nitro compounds such as nitromethane or nitrobenzene; Esters such as ethyl acetate or mixtures of said solvents, particularly preferred is butanol.
  • Sulfoxides such as dimethylsulfoxide (DMSO); Sulfuric 5 carbon
  • Carboxylic acids such as formic acid or acetic acid
  • Nitro compounds such as nitromethane or nitrobenzene
  • Esters such as ethyl acetate or mixtures of said solvents, particularly preferred is butanol.
  • Compounds of the formula I can furthermore be obtained by reacting compounds of the formula III with compounds of the formula IV.
  • L is preferably F, Cl, Br, I ⁇ g, or a free or reactively modified OH group, e.g. an activated ester, an imidazolide or alkylsulfonyloxy having 1-6 C atoms (preferably methylsulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxy having 6-10 C atoms (preferably phenyl- or p-tolylsulfonyl-oxy).
  • L is preferably OH. 20
  • Activated esters are conveniently formed in situ, e.g. By addition of HOBt, N-hydroxysuccinimide or DAPECI ( ⁇ / - (3-dimethylaminopropyl) -W-ethylcarbodiimide hydrochloride).
  • the reaction is usually carried out in an inert solvent.
  • Reaction time is between a few minutes and 14 days depending on the conditions used, the reaction temperature between about 0 ° and 150 °, normally between 15 ° and 120 °, particularly preferably between 20 and 100 0 C.
  • Suitable solvents are those mentioned above, DMF is preferred.
  • the reaction is optionally carried out in the presence of an acid-binding agent, preferably an alkali or alkaline earth metal hydroxide, carbonate or bicarbonate or another salt of a weak acid of the alkali or alkaline earth metals, preferably of potassium, sodium, calcium or cesium.
  • an organic base such as triethylamine, dimethylaniline, pyridine or quinoline or an excess of the amine component of formula IV may be beneficial.
  • the reaction time is between a few minutes and 14 days, depending on the conditions used, and the reaction temperature is between about 0 ° and 150 °, normally between 20 ° and 130 °. Suitable inert solvents are those mentioned above.
  • the invention further relates to intermediate compounds of
  • L is F, Cl, Br, I or a freely or reactively functionally modified OH group
  • R 3 is H or A 1
  • Het 1 is a mono- or binuclear saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and / or S atoms, which is mono-, di- or trisubstituted by A, OA 1 OH, SH, SA, Hal, NO 2 , CN 1 (CHz) n COOH 1 (CH 2 ) n COOA, CHO, COA 1 SO 2 A, CON (R 5 ) 2 , SO 2 N (R 5 ) 2 L N (R 5 ) 2 , OCON ( R 5 ) 2L NHCOA 1 NHCOOA 1 NACOOA 1
  • a alkyl having 1 to 10 C atoms, wherein also 1-7 H atoms may be replaced by F and / or chlorine,
  • Hal is F, Cl, Br or I
  • m is 0, 1 or 2
  • n is O 1 1, 2, 3, 4 or 5
  • o is O 1 1 or 2
  • L is preferably F, Cl, Br, I or a free or a reactively modified OH group such as an activated ester, an imidazolide or alkylsulfonyloxy having 1-6 C atoms (preferred
  • compositions according to the invention can be used in their final non-salt form.
  • present invention also encompasses the use of these compounds in the form of their pharmaceutically acceptable salts, which are known in the art from various organic and inorganic acids and bases
  • Example alkali metal hydroxides including potassium hydroxide, sodium hydroxide and lithium hydroxide; Alkaline earth metal hydroxides such as barium hydroxide and calcium hydroxide; Alkali metal alcoholates, e.g. Potassium ethanolate and
  • Hydrogen bromide or hydrogen iodide other mineral acids and their corresponding salts such as sulphate, nitrate or phosphate and the like, and also alkyl and monoaryl sulphonates such as ethanesulphonate, toluenesulphonate and benzenesulphonate, and also other organic acids and their corresponding salts such as acetate, trifluoroacetate, tartrate, maleate, succinate,
  • pharmaceutically acceptable acid addition salts of the compounds of formula I include the following: acetate, adipate, alginate, arginate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate , Cyclopentane propionate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, fumarate, galacterate (from mucic acid), galacturonate, glucoheptanoate, gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate,
  • Phenylpropionate, phosphate, phosphonate, phthalate but this is not limiting.
  • base salts of the invention include
  • Derive bases include salts of primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted ones
  • Amines, cyclic amines and basic ion exchange resins eg Arginine, betaine, caffeine, chloroprocaine, choline, N, N'-dibenzylethylenediamine (benzathine), dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-
  • Tromethamine Hydrabamine, iso-propylamine, lidocaine, lysine, meglumine, N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethanolamine, triethylamine, trimethylamine, tripropylamine and tris- (hydroxymethyl) -methylamine ( Tromethamine), but this is not intended to be limiting.
  • Compounds of the present invention containing basic nitrogen-containing groups can be reacted with agents such as (C r C 4 ) alkyl halides,. j 5, for example, methyl, ethyl, isopropyl and tert-butyl chloride, bromide and iodide; Di (C 1 -C 4 ) alkyl sulfates, for example dimethyl, diethyl and diamyl sulfate; (Ci 0 - Ci 8 ) alkyl halides, eg decyl, dodecyl, lauryl, myristyl and stearyl chloride, bromide and iodide; and aryl (Ci-C 4 ) alkyl halides, eg
  • compositions which are preferred include acetate, trifluoroacetate, besylate, citrate, fumarate, gluconate,
  • the amount of the desired acid brings into contact, whereby one on usual
  • the free base can be prepared by contacting the salt form with a base and isolating the free base in the usual way Regenerate way.
  • the free base forms in some sense differ from their corresponding salt forms in terms of certain physical properties such as solubility in polar solvents; in the
  • the pharmaceutically acceptable base addition salts of the compounds of the formula I are formed with metals or amines such as alkali metals and alkaline earth metals or organic amines.
  • Preferred metals are sodium, potassium, magnesium and calcium.
  • Preferred organic amines are N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.
  • the base addition salts of acidic compounds of the invention are prepared by contacting the free acid form with a sufficient amount of the desired base to form the salt in a conventional manner.
  • the free acid can be passed through
  • a compound according to the invention contains more than one group which can form such pharmaceutically acceptable salts
  • the invention also encompasses multiple salts.
  • Typical multiple salt forms include, for example, bitartrate, diacetate, difumarate, dimeglumine, diphosphate, disodium and trihydrochloride, but this is not intended to be limiting.
  • the term "pharmaceutically acceptable salt” in the present context means an active ingredient which contains a compound of the formula I in the form of one of its salts, especially if this salt form is the active ingredient in the Imparts improved pharmacokinetic properties to the free form of the active ingredient or any other salt form of the active ingredient which has previously been used.
  • the pharmaceutically acceptable salt form of the active substance may also first impart a desired pharmacokinetic property to this active ingredient which it has not previously possessed, and may even positively influence the pharmacodynamics of this active ingredient in terms of its therapeutic activity in the body.
  • the invention furthermore relates to medicaments comprising at least one compound of the formula I and / or pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and optionally excipients and / or adjuvants.
  • compositions may be presented in the form of dosage units containing a predetermined amount of active ingredient per unit dose.
  • a moiety may contain, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, more preferably 5 mg to 100 mg of a compound of the invention, depending on the condition being treated, the route of administration and the age, weight and condition of the patient, or pharmaceutical formulations may be presented in the form of dosage units containing a predetermined amount of active ingredient per unit dose.
  • Preferred dosage unit formulations are those containing a daily or partial dose as indicated above or a corresponding fraction thereof
  • compositions may be administered by any suitable route, for example, oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) Ways, adapt.
  • Such formulations can be prepared by any method known in the pharmaceutical art, for example, by bringing the active ingredient together with the carrier (s) or excipient (s).
  • compositions adapted for oral administration may be administered as separate units, e.g. Capsules or tablets; Powder or granules; Solutions or suspensions in aqueous or non-aqueous liquids; edible foams or foam foods; or
  • Oil-in-water liquid emulsions or water-in-oil liquid emulsions Oil-in-water liquid emulsions or water-in-oil liquid emulsions.
  • the active ingredient component when administered orally in the form of a tablet or capsule, may be admixed with an oral, non-toxic and pharmaceutically acceptable inert carrier, e.g. Ethanol, glycerin, water and the like. combine.
  • an oral, non-toxic and pharmaceutically acceptable inert carrier e.g. Ethanol, glycerin, water and the like.
  • Powders are prepared by comminuting the compound to a suitable fine size and mixing it with a similarly comminuted pharmaceutical excipient, e.g. an edible carbohydrate such as
  • Starch or mannitol is mixed.
  • a flavor, preservative, dispersant and dye may also be present.
  • Capsules are made by preparing a powder mix as described above and filling shaped gelatin casings therewith.
  • Lubricants and lubricants such as highly disperse silica, talc, Magnesium stearate, calcium stearate or polyethylene glycol in solid form can be added to the powder mixture before the filling process.
  • An explosive or solubilizer such as agar-agar, calcium carbonate or sodium carbonate may also be added to improve the availability of the drug after ingestion of the capsule.
  • suitable bonding, lubricating and disintegrating agents and dyes may also be included in the mixture
  • Suitable binders include starch, gelatin, natural sugars, e.g. Glucose or beta-lactose, corn sweeteners, natural and synthetic gums, e.g. Acacia, tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol,
  • E waxes and used in these dosage forms lubricants include sodium, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and Among the explosives, without limitation, starch, methylcellulose, agar,
  • a powder mixture is prepared, granulated or dry pressed, a lubricant and disintegrant are added, and the whole is compressed into tablets.
  • a powder mixture is prepared by mixing the appropriately comminuted compound with
  • a diluent or a base as described above and optionally with a binder, e.g. Carboxymethylcellulose, an alginate, gelatin or polyvinylpyrrolidone, a dissolution reducer, such as e.g. Paraffin, a resorption accelerator, such as one
  • a binder e.g. Carboxymethylcellulose, an alginate, gelatin or polyvinylpyrrolidone
  • a dissolution reducer such as e.g. Paraffin
  • a resorption accelerator such as one
  • the powder mixture can be granulated by wetting it with a binder such as syrup, starch paste, Acadia slime or solutions of cellulose or polymer materials and pressing it through a sieve.
  • a binder such as syrup, starch paste, Acadia slime or solutions of cellulose or polymer materials
  • Granulation can be run through the powder mixture through a tabletting machine, resulting in irregularly shaped lumps in Granules are broken up.
  • the granules may be greased by the addition of stearic acid, a stearate salt, talc or mineral oil to prevent sticking to the tablet molds.
  • the greased mixture is then compressed into tablets.
  • the compounds according to the invention can also be reacted with a free-flowing inert
  • a transparent or opaque protective layer consisting of a shellac sealant, a layer of sugar or polymeric material, and a glossy layer of wax may be present. Dyes can be added to these coatings in order to differentiate between different dosage units.
  • Oral fluids e.g. Solution, syrups and elixirs may be prepared in unit dosage form such that a given quantity contains a predetermined amount of the compound.
  • Syrups can be prepared by dissolving the compound in an appropriate taste aqueous solution while preparing elixirs using a non-toxic alcoholic vehicle.
  • Suspensions can be formulated by dispersing the compound in a non-toxic vehicle.
  • Solubilizers and emulsifiers e.g. ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavoring additives such as e.g. Peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, i.a. can also be added.
  • the unit dosage formulations for oral administration may optionally be encapsulated in microcapsules.
  • the formulation can also be prepared so that the release is prolonged or retarded, such as by coating or embedding particulate material in polymers, wax and others.
  • the compounds of the formula I and salts, solvates and physiologically functional derivatives thereof can also be administered in the form of liposome delivery systems, such as, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be prepared from various phospholipids, such as e.g.
  • Cholesterol, stearylamine or phosphatidylcholines Cholesterol, stearylamine or phosphatidylcholines.
  • the compounds of formula I as well as the salts, solvates and physiologically functional derivatives thereof can also be delivered using monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds can also be coupled with soluble polymers as targeted drug carriers.
  • Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidophenol or polyethyleneoxidepolylysine substituted with palmitoyl radicals.
  • the compounds may be linked to a class of biodegradable polymers which are capable of controlled release of a
  • Drugs suitable e.g. Polylactic acid, polyepsilon-caprolactone,
  • Polyhydroxybutyric acid Polyorthoesters, polyacetals, polydihydroxy-pyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • compositions adapted for transdermal administration may be presented as discrete patches for prolonged, intimate contact with the epidermis of the recipient.
  • the drug may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3 (6), 318 (1986).
  • compositions adapted for topical administration may be used as ointments, creams, suspensions, lotions, powders, solutions,
  • the formulations are preferably applied as a topical ointment or cream.
  • the active ingredient may be either paraffinic or water-miscible
  • Cream base can be used.
  • the active ingredient can be formulated into a cream with an oil-in-water cream base or a water-in-oil base.
  • the pharmaceutical formulations adapted for topical application to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.
  • compositions adapted for topical application in the mouth include lozenges, troches and mouthwashes.
  • compositions adapted for rectal administration may be presented in the form of suppositories or enemas.
  • compositions adapted for nasal administration in which the vehicle is a solid contain a coarse powder having a particle size, for example, in the range of 20-500 microns, which is administered in the manner in which snuff is received, i. by rapid inhalation via the nasal passages from a container held close to the nose with the powder.
  • Suitable formulations for administration as a nasal spray or nasal drops with a liquid carrier include drug solutions in water or oil.
  • Formulations include fine particulate dusts or mists, which by means of various types of pressurized dispensers with aerosols, nebulizers or insufflators can be produced.
  • Formulations can be used as pessaries, tampons, creams, gels, pastes,
  • Foams or spray formulations are presented.
  • compositions adapted for parenteral administration include aqueous and nonaqueous sterile injection solutions containing antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the recipient to be treated; and aqueous and non-aqueous sterile suspensions which may contain suspending agents and thickeners.
  • the formulations may be administered in single or multiple dose containers, e.g. sealed vials and vials, and stored in the freeze-dried (lyophilized) state so that only the addition of the sterile carrier liquid, e.g. Water for
  • Injection solutions and suspensions prepared by formulation can be prepared from sterile powders, granules and tablets.
  • formulations may include other means conventional in the art with respect to the particular type of formulation; for example, formulations suitable for oral administration may contain flavorings.
  • a therapeutically effective amount of a compound of formula I depends on a number of factors, including e.g. the age and
  • an effective amount of a compound of the invention for the treatment of neoplastic growth is generally in the range of 0.1 to 100 mg / kg body weight of the recipient (mammal) per day, and more typically in the range of 1 to 10 mg / kg body weight per
  • the actual amount per day would usually be between 70 and 700 mg, this amount as a single dose per day or more commonly in a number of divided doses (such as two, three, four, five or six) per Day can be given so that the total daily dose is the same.
  • An effective amount of a salt or solvate or a physiologically functional derivative thereof can be determined as a proportion of the effective amount of the compound of the invention per se. It can be assumed that similar dosages are suitable for the treatment of the other, above-mentioned disease states.
  • the invention furthermore relates to medicaments comprising at least one compound of the formula I and / or pharmaceutically usable compounds thereof
  • the invention is also a set (kit), consisting of separate packages of
  • the kit contains suitable containers, such as boxes or boxes, individual bottles, bags or ampoules.
  • suitable containers such as boxes or boxes, individual bottles, bags or ampoules.
  • the set may e.g. separate
  • Contain ampoules each containing an effective amount of one Compound of formula I and / or its pharmaceutically acceptable derivatives, solvates and stereoisomers, including mixtures thereof in all ratios, and an effective amount of another active pharmaceutical ingredient dissolved or in lyophilized form.
  • CHK1-mediated disorder includes any disorder, disease or condition caused or characterized by an increase in CHK1 expression or activity or which requires CHK1 activity.
  • CHK1-mediated disorder further includes any disorder, disease or condition in which inhibition of CHK1 activity is beneficial.
  • CHK1 inhibition can be used to achieve a beneficial therapeutic or prophylactic effect, for example in patients with a proliferative disorder.
  • proliferative disorders include i.a. chronic inflammatory proliferative disorders, e.g. Psoriasis and rheumatoid arthritis, proliferative eye disorders, e.g. diabetic retinopathy, benign proliferative disorders, e.g. Hemangiomas, as well as cancer.
  • the term refers to
  • Cancer means a cellular disorder characterized by uncontrolled or misregulated cell proliferation, decreased cell differentiation, inadequate ability to invade surrounding tissue, and / or the ability to establish new growth at ectopic sites.
  • the term “cancer” includes, but is not limited to, solid tumors and blood-borne tumors.
  • the term “cancer” includes diseases of the skin, tissues, organs, bones, cartilage, blood and vessels.
  • the term “cancer” further includes primary and metastatic cancers.
  • CHK1 inhibitors can be treated, i.a. Pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, including metastatic breast cancer, prostate cancer, including androgen-dependent and
  • kidney cancer including e.g. metastatic renal cell carcinoma, hepatocellular carcinoma
  • lung cancer including e.g. non-small cell lung cancer (NSCLC), bronchioloalveolar carcinoma (BAC) and adenocarcinoma of the lung,
  • NSCLC non-small cell lung cancer
  • BAC bronchioloalveolar carcinoma
  • ⁇ c Ovarian cancer, including, for example, progressive epithelial or primary
  • Peritoneal, cervical, gastric, esophageal, head and neck including e.g. Scalp cell carcinoma of the head and neck, melanoma, neuroendocrine cancer, including metastatic neuroendocrine tumors, brain tumors, including
  • Glioma e.g. Glioma, anaplastic oligodendroglioma, glioblastoma multiforme in adults and anaplastic astrocytoma in adults, bone cancer and soft tissue sarcoma.
  • Non-limiting examples of hematological malignancies that may be treated with the disclosed CHK1 inhibitors include: acute myeloid leukemia (AML), chronic myeologenic leukemia (CML), including accelerated CML and CML blast phase (CML)
  • AML acute myeloid leukemia
  • CML chronic myeologenic leukemia
  • CML blast phase CML
  • O Q BP acute lymphoblastic leukemia
  • CLL chronic lymphocytic leukemia
  • HD Hodgkin's disease
  • NHL non-Hodgkin's lymphoma
  • MM multiple myeloma
  • Macroglobulinemia myelodysplastic syndromes (MDS), including
  • RA Refractory anemia
  • RARS refractory anemia with ringsideroblasts
  • RAEB refractory anemia with blast excess
  • RAEB-T RAEB in transformation
  • the disclosed compounds of formula I are particularly useful in the treatment of cancers or cell types in which CHK1 protein or activity is upregulated, including, without limitation, rapidly proliferating cells and drug resistant cells (Shyjan et al., US Pat. No. 6,723,498 (2004 ) as well as retinoblastomas, such as Rb-negative or inactivated cells (Gottifredi et al., Mol. Cell Biol., 21: 1066 (2001)), or in which the ARF p14 / p19 locus is inactivated or misregulated.
  • the disclosed CHK1 inhibitors are also particularly useful for the treatment of cancers or cell types in which another checkpoint pathway is mutated or abolished, including, without limitation,
  • the disclosed compounds of Formula I can be administered in conjunction with other therapeutic agents, including anticancer agents.
  • anticancer agent refers to any agent that is administered to a patient with cancer for the purpose of treating the cancer.
  • the anticancer treatment as defined herein may be used as a sole therapy or may include conventional surgery or radiation therapy or chemotherapy in addition to the compound of the present invention.
  • Such chemotherapy may include one or more of the following categories of antitumor agents: (i) antiproliferative / antineoplastic / DNA damaging agents and combinations thereof, as used in medical oncology, such as
  • Alkylating agents for example cisplatin, carboplatin, cyclophosphamide,
  • Antifolates such as fluoropyrimidines, such as Fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea and gemcitabine
  • Antitumour antibiotics eg anthracycline such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin,
  • Agents for example, vinca alkaloids such as vincristine, vinblastine, vindesine and vinorelbine, and taxoids such as taxol and taxotere); Topoisomerase inhibitors (for example, epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan, irinotecan and camptothecin) and cell-differentiating agents (for example all-trans retinoic acid, 13-cis retinoic acid and fenretinide);
  • Topoisomerase inhibitors for example, epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan, irinotecan and camptothecin
  • cell-differentiating agents for example all-trans retinoic acid, 13-cis retinoic acid and fenretinide
  • cytostatic agents such as anti-estrogens (eg tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfen), the estrogen receptor downregulating agents (eg fulvestrant), anti-androgens (eg bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH Antagonists or LHRH agonists (for example, goserelin, leuprorelin and buserelin), progesterone (for example megestrol acetate), aromatase
  • anti-estrogens eg tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfen
  • the estrogen receptor downregulating agents eg fulvestrant
  • anti-androgens eg bicalutamide, flutamide, nilutamide and cyproterone
  • Inhibitors for example anastrozole, letrozole, vorazole and exemestane
  • inhibitors of 5 ⁇ -reductase such as finasteride
  • agents that inhibit the invasion of cancer cells for example, metalloproteinase inhibitors such as marimastat and inhibitors of urokinase plasminogen activator receptor function);
  • inhibitors of growth factor function for example, such inhibitors include growth factor antibodies, growth factor receptor antibodies (for example, the anti-erbb2 antibody trastuzumab [Herceptin TM] and the anti-erbb1 antibody cetuximab [C225]), Famesyltransferase inhibitors, tyrosine kinase inhibitors and serine / threonine
  • Kinase inhibitors for example, epidermal growth factor family inhibitors (for example, EGFR family tyrosine kinase inhibitors, such as N- (3-chloro-4-fluorophenyl) -7-methoxy-6- (3-morpholinopropoxy) quinazoline).
  • epidermal growth factor family inhibitors for example, EGFR family tyrosine kinase inhibitors, such as N- (3-chloro-4-fluorophenyl) -7-methoxy-6- (3-morpholinopropoxy) quinazoline.
  • antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor (for example, the vascular endothelial cell growth factor bevacizumab antibody [Avastin TM], compounds such as those disclosed in published international patent applications WO 97/22596, WO 97 No.
  • vascular endothelial growth factor for example, the vascular endothelial cell growth factor bevacizumab antibody [Avastin TM]
  • compounds such as those disclosed in published international patent applications WO 97/22596, WO 97 No.
  • vascular damaging agents such as combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;
  • antisense therapies for example, those directed against the targets listed above, such as ISIS 2503, an anti-Ras
  • GDEPT gene-directed enzyme pro-drug therapy
  • immunotherapy approaches including, for example, ex vivo and in vivo approaches to increase the immunogenicity of patient tumor cells such as transfection with cytokines such as interleukin 2, interleukin 4 or
  • Granulocyte-macrophage colony-stimulating factor approaches to
  • T-cell anergy Reduction of T-cell anergy, approaches using transfected Immune cells, such as cytokine-transfected dendritic cells, assays using cytokine-transfected tumor cell lines, and anti-idiotypic antibody approaches.
  • transfected Immune cells such as cytokine-transfected dendritic cells
  • assays using cytokine-transfected tumor cell lines and anti-idiotypic antibody approaches.
  • the medicaments of Table 1 below are combined with the compounds of the formula I.
  • Mitoxantrone diflomotecan (Beaufourrinotecan (CPT-11) Ipsen)
  • Rhizoxin (Fujisawa) LU 223651 (BASF)
  • Epothilone B Novartis
  • ZD 6126 AstraZeneca
  • T 900607 Tularik
  • PEG paclitaxel Enzon
  • Auristatin PE (Teikoku NeuroPharma)
  • Taxoprexin (Protarga) CA-4 (OXiGENE)
  • Thymidylate pemetrexed (EIi Lilly) Nolatrexed (Eximias) synthase ZD-9331 (BTG) CoFactor TM (BioKeys)
  • Histone acetyl trans-Tacedinalin Pfizer pivaloyloxymethyl butyrate ferase inhibitors SAHA (Aton Pharma) (titanium)
  • TNF-alpha-virulizine (Lorus Revimid (Celgene)
  • CapCell TM CYP450-N-acetylcysteine
  • Antagonist kappaB inhibitor, Encore
  • Efaproxiral oxygenator, receptor agonist, Leo
  • PI-88 heparanase antagonist
  • PBM 402 PMN stimulant, (immunotoxin, KS
  • SRL-172 T-cell doranidazole (apoptosis
  • TLK-286 glutthione-S-CHS-828 (cytotoxic)
  • PT-100 growth factor (differentiator, NIH)
  • Point MX6 apoptosis promoter
  • CDA-II apoptosis-Ro-31-7453 (apoptosis
  • SDX-101 apoptosis-brostallicin (apoptosis)
  • Rhizoxin (Fujisawa) LU 223651 (BASF)
  • Epothilone B Novartis.
  • ZD 6126 AstraZeneca
  • Auristatin PE (Teikoku NeuroPharma)
  • BMS azaepothilone B
  • Metalloproteinase neovastate (Aeterna CMT -3 (CollaGenex)
  • TNF-alpha-virulizine (Lorus Revimid (Celgene)
  • CapCell TM CYP450-R flurbiprofen (NF-1)
  • GCS-IOO gal3 inhibitor, Active Biotech
  • SR-31747 (IL-1 PG2 (hematopoietic)
  • SRL-172 T-cell (differentiator, NIH)
  • TLK-286 (glutathione-S-MAXIA)
  • PLC-brostallicin apoptosis
  • Such joint treatment can be achieved by simultaneously, sequentially or separately dosing the individual components of the treatment.
  • Such combination products employ the compounds of the invention.
  • the present compounds of the formula I are furthermore suitable as pharmaceutical active ingredients for mammals, in particular for humans, in the treatment of SGK-related diseases.
  • the invention thus relates to the use of compounds according to claim 1, as well as their pharmaceutically usable derivatives, solvates and stereoisomers, including mixtures thereof in all proportions, for the preparation of a medicament for the treatment of diseases in which the inhibition, regulation and / or modulation of Signal transduction of kinases plays a role.
  • Preferred is the use of compounds according to claim 1, as well as their pharmaceutically usable derivatives, solvates and stereoisomers, including mixtures thereof in all proportions, for the manufacture of a medicament for the treatment of diseases which are affected by inhibition of SGK by the compounds of claim 1.
  • the present invention comprises the use of the compounds of the invention according to claim 1 and / or their physiologically acceptable salts and solvates for the manufacture of a medicament for the treatment or prevention of diabetes (eg diabetes mellitus, diabetic nephropathy, diabetic neuropathy, diabetic angiopathy and microangiopathy), obesity, metabolic syndrome (dyslipidaemia), systemic and pulmonary hypertension, cardiovascular diseases (eg cardiac fibrosis after myocardial infarction, cardiac hypertrophy and cardiac insufficiency, atherosclerosis) and renal diseases (eg glomerulosclerosis, nephrosclerosis, nephritis, nephropathy, disturbance of excretion of electrolytes), in general for all types of fibrosis and inflammatory processes (eg liver cirrhosis,
  • the compounds of the invention can also increase the growth of
  • tumor cells and tumor metastases inhibit and are therefore suitable for tumor therapy.
  • the compounds of the invention are also used for the treatment of coagulopathies, e.g. Dysfibrinogenemia, hypoproducinergia, hemophilia B, Stuart-Prower defect, prothrombin complex deficiency, consumption coagulopathy, hyperfibrinolysis, immunocagulopathy or complex coagulopathies, as well as in neuronal excitability, e.g. Epilepsy.
  • coagulopathies e.g. Dysfibrinogenemia, hypoproducinergia, hemophilia B, Stuart-Prower defect, prothrombin complex deficiency, consumption coagulopathy, hyperfibrinolysis, immunocagulopathy or complex coagulopathies, as well as in neuronal excitability, e.g. Epilepsy.
  • the compounds of the invention may also be used therapeutically in the treatment of glaucoma or cataract.
  • the compounds according to the invention are furthermore used in the
  • the compounds of the invention may also be used therapeutically to increase learning and attention.
  • Diabetes obesity, metabolic syndrome (dyslipidemia), systemic and pulmonary hypertension, cardiovascular and renal diseases, in general for any type of fibrosis and inflammatory processes, cancer, tumor cells, tumor metastases, coagulopathies,
  • Diabetes is preferably diabetes mellitus, diabetic nephropathy, diabetic neuropathy, diabetic angiopathy and microangiopathy.
  • Cardiovascular diseases are primarily cardiac fibrosis after myocardial infarction, cardiac hypertrophy, heart failure and atherosclerosis.
  • Kidney disease is preferably glomerulo-sclerosis, nephrosclerosis, nephritis, nephropathy, and electrolyte clearance disorder.
  • Fibrosis and inflammatory processes are preferably liver cirrhosis, pulmonary fibrosis, fibrosing pancreatitis, 35
  • the compounds of the formula I described in the examples can be tested for a kinase-inhibiting action in the assays described below.
  • Other assays are known in the literature and can be readily performed by those skilled in the art (see, eg, Dhanabal et al., Cancer Res. 59: 189-197; Xin et al., J. Biol. Chem. 274: 9116-9121; Sheu et Biol. 38: 237-248; Gimbrone et al., J. Natl. Cancer Inst. 52: 413-427; Nicosia et 5 a ⁇ , In Vitro 18: 538-549).
  • CHK1 kinase is used for protein production in insect cells
  • Phospho-antibodies Phospho-AK.
  • the phospho-antibody binds only the phosphorylated substrate. This bond is with a second
  • Peroxidase-conjugated antibodies can be detected by chemiluminescence (Ross et al., 2002, Biochem. J.).
  • test plates used are 384-well streptavidin-coated flashplates Plus R from Perkin Elmer (Cat.No. SMP410A001PK).
  • the assay plate is equilibrated 30 minutes before the start of the experiment with 75 ⁇ l of assay buffer per well.
  • the buffer is aspirated before starting the experiment and the components of the kinase reaction described below are pipetted onto the plate.
  • CHK1 kinase a biotinylated substrate peptide (eg CHKtide: KKKVSRSGLYRSPSMPENLNRPR), is incubated with radioactively labeled ATP in the presence and absence of test substances at 30 ° Celsius and a
  • the inhibitor-free kinase reaction is used. This should be approximately in the range of 3000-4000 cpm.
  • the pharmacological zero value used is staurosporine in a final concentration of 0.1 ⁇ M.
  • a determination of the inhibition values (IC50) is carried out using the program RS1_MTS ().
  • Kinase reaction conditions per well 5-20 mU CHK1 kinase
  • bovine serum albumin (final concentration 0.1%) takes place shortly before use.
  • Phosphoric acid stopped and filtered through P81 filter plates. After repeated washing of the filter plates, the determination of the bound radioactivity takes place in the scintillation counter.
  • the inhibition of SGK1 protein kinase may occur in the filter binding process
  • “usual workup” means adding water if necessary, adjusting to pH values between 2 and 10, if necessary, depending on the constitution of the final product, extracting with ethyl acetate or dichloromethane, separating, drying organic phase over sodium sulfate, evaporated and purified by chromatography Silica gel and / or by crystallization. Rf values on silica gel; Eluent:
  • APCI-MS atmospheric pressure chemical ionization - mass spectrometry (M + H) + .
  • Hewlett Packard HP 1100 series system with the following features: Ion source: electrospray (positive mode); Scan: 100-1000 m / z; Fragrnentierschreib: 60 V; Gas temperature: 300 ° C, DAD: 220 nm.
  • Pillar Flow rate: 2.4 ml / min.
  • the splitter used after DAD reduces the flow rate for the MS to 0.75 ml / min. Pillar:
  • Solvent LiChrosolv grade from Merck KGaA Solvent A: H 2 O (0.01% TFA) Solvent B: acetonitrile (0.008% TFA)
  • Example A Injection glasses
  • a solution of 100 g of an active compound of the formula I and 5 g of disodium hydrogen phosphate is adjusted to pH 6.5 in 3 l of bidistilled water with 2N hydrochloric acid, filtered sterile, filled into injection jars, lyophilized under sterile conditions and sealed under sterile conditions , Each injection jar contains 5 mg of active ingredient.
  • a mixture of 20 g of an active compound of the formula I is melted with 100 g of soya lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.
  • a solution of 1 g of an active compound of the formula I, 9.38 g of NaH 2 PO 4 .2H 2 O, 28.48 g of Na 2 HPO 4 .12H 2 O and 0.1 g of benzalkonium chloride in 940 is prepared ml of double distilled water. Adjust to pH 6.8, make up to 1 liter and sterilize by irradiation. This solution can be used in the form of eye drops.
  • a mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose, 1, 2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is in the usual
  • Tablets are pressed analogously to Example E, which are then coated in the usual way with a coating of sucrose, potato starch, talc, tragacanth and dye.
  • Example G capsules
  • a solution of 1 kg of active compound of the formula I in 60 l of bidistilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed sterile. Each vial contains 10 mg of active ingredient.

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Abstract

La présente invention concerne des composés de formule (I) dans laquelle X, Y, R1, R2, R3 et R4 ont les significations énoncées dans la revendication 1. Ces composés sont des inhibiteurs des kinases CHK1, CHK2 et SGK et peuvent, entre autres, être utilisés pour le traitement du cancer.
EP07702672A 2006-02-06 2007-01-10 Dérivés d'aminoindazole Withdrawn EP1981879A1 (fr)

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DE102006005179A DE102006005179A1 (de) 2006-02-06 2006-02-06 Aminoindazolderivate
PCT/EP2007/000172 WO2007090494A1 (fr) 2006-02-06 2007-01-10 Dérivés d'aminoindazole

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CA (1) CA2641350A1 (fr)
DE (1) DE102006005179A1 (fr)
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EP2242755B1 (fr) 2008-01-08 2012-09-12 Array Biopharma, Inc. Pyrrolopyridines en tant qu'inhibiteurs de kinase
WO2009089359A1 (fr) 2008-01-09 2009-07-16 Array Biopharma Inc. Pyrrolopyridines en tant qu'inhibiteurs de kinase
US7956051B2 (en) 2008-01-24 2011-06-07 Allergan, Inc. Therapeutic amides and related compounds
CL2009001152A1 (es) 2008-05-13 2009-10-16 Array Biopharma Inc Compuestos derivados de n-(4-(cicloalquilo nitrogenado-1-il)-1h-pirrolo[2,3-b]piridin-3-il)amida, inhibidores de cinasa; proceso de preparacion; composicion farmaceutica; y su uso para el tratamiento de una enfermedad proliferativa.
DE102008029072A1 (de) * 2008-06-10 2009-12-17 Lang, Florian, Prof. Dr.med. Sgk3 als therapeutisches und diagnostisches Target für Alterserkrankungen
DE102008038222A1 (de) * 2008-08-18 2010-02-25 Merck Patent Gmbh Indazol-5-carbonsäurehydrazid-derivate
US8481557B2 (en) 2009-04-11 2013-07-09 Array Biopharma Inc. Method of treatment using checkpoint kinase 1 inhibitors
AT509045B1 (de) 2010-01-29 2011-06-15 Planta Naturstoffe Vertriebsges M B H Verbindungen zur behandlung von asthma bronchiale
KR101125334B1 (ko) 2010-04-09 2012-03-27 엘지이노텍 주식회사 발광 소자, 발광 소자 제조방법 및 발광 소자 패키지
RU2017127088A (ru) 2010-11-16 2019-02-04 Эррэй Биофарма Инк. Комбинация ингибиторов чекпойнт-киназы 1 и ингибиторов киназы wee 1
EP3461480A1 (fr) 2017-09-27 2019-04-03 Onxeo Combinaison d'inhibiteurs de point de contrôle du cycle cellulaire de réponse à un dommage à l'adn et de belinostat pour traiter le cancer

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DE1280878B (de) * 1961-11-30 1968-10-24 Smith Kline French Lab 3-Aminoindazole
WO2003051847A1 (fr) * 2001-12-19 2003-06-26 Smithkline Beecham P.L.C. Derives de (1-h-indazol-3-yl) -amide comme inhibiteurs de gsk-3
MXPA04011417A (es) * 2002-05-17 2005-02-14 Pharmacia Italia Spa Derivados de aminoindazol activos como inhibidores de cinasa, procedimiento para su preparacion y composiciones farmaceuticas que los comprenden.
NZ539193A (en) * 2002-09-05 2008-04-30 Aventis Pharma Sa Novel aminoindazole derivatives as medicines and pharmaceutical compositions containing same
BR0316606A (pt) * 2002-12-12 2005-10-11 Aventis Pharma Sa Derivados de aminoindazóis e sua utilização como inibidores de quinases
FR2871158A1 (fr) * 2004-06-04 2005-12-09 Aventis Pharma Sa Indazoles substitues, compositions les contenant, procede de fabrication et utilisation
DE102004028862A1 (de) * 2004-06-15 2005-12-29 Merck Patent Gmbh 3-Aminoindazole

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US20090036508A1 (en) 2009-02-05
CA2641350A1 (fr) 2007-08-16
IL193210A0 (en) 2009-02-11
AU2007214086A1 (en) 2007-08-16
WO2007090494A1 (fr) 2007-08-16
AR059293A1 (es) 2008-03-26

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