WO2008025526A1 - Dérivés d'indole, fabrication de ceux-ci et utilisation comme agents pharmaceutiques - Google Patents

Dérivés d'indole, fabrication de ceux-ci et utilisation comme agents pharmaceutiques Download PDF

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WO2008025526A1
WO2008025526A1 PCT/EP2007/007538 EP2007007538W WO2008025526A1 WO 2008025526 A1 WO2008025526 A1 WO 2008025526A1 EP 2007007538 W EP2007007538 W EP 2007007538W WO 2008025526 A1 WO2008025526 A1 WO 2008025526A1
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pyridin
indol
methoxy
alkyl
formula
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PCT/EP2007/007538
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English (en)
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Guy Georges
Eike Hoffmann
Matthias Koerner
Wolfgang Jenni
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F. Hoffmann-La Roche Ag
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the present invention relates to novel indole derivatives, to a process for their manufacture, pharmaceutical compositions containing them, and their manufacture as well as the use of these compounds as pharmaceutically active agents.
  • the serine/threonine kinase family includes members that control cell growth, migration, differentiation, gene expression, muscle contraction, glucose metabolism, cellular protein synthesis, and regulation of the cell cycle.
  • Aurora kinases are a family of serine/ threonine kinases that are believed to play a key role in the protein phosphorylation events that are essential for the completion of essential mitotic events.
  • the Aurora kinase family is made up of three key members: Aurora A, B and C (also known as Aurora-2, Aurora- 1 and
  • Aurora-3 respectively.
  • Aurora-1 and Aurora-2 are described in US 6,207,401 of Sugen and in related patents and patent applications, e.g. EP 0 868 519 and EP 1 051 500.
  • Aurora A there is increasing evidence that it is a novel proto-oncogene.
  • Aurora A gene is amplified and transcript/protein is highly expressed in a majority of human tumor cell lines and primary colorectal, breast and other tumors. It has been shown that Aurora A overexpression leads to genetic instability shown by amplified centrosomes and significant increase in aneuploidy and transforms Ratl fibroblasts and mouse NIH3T3 cells in vitro. Aurora A-transformed NIH3T3 cells grow as tumors in nude mice (Bischoff, J. R. and Plowman, G. D., Trends Cell Biol. 9
  • Aurora A contributes to cancer phenotype by being involved in chromosome segregation and mitotic checkpoint control.
  • Low molecular weight inhibitors for protein kinases are widely known in the state of the art.
  • Aurora inhibition such inhibitors are based on i.e. pyrazole or quinazoline derivatives as claimed in the following patents and patent applications: WO 00/44728 or WO 02/22601.
  • WO 02/079192, WO 2004/031401, WO 2004/063151 and WO 2005/021510 relate to benzimidazole pyridone derived kinase inhibitors.
  • the present invention relates to indole derivatives of the general formula I,
  • R'and R 2 independently represent hydrogen, alkyl, halogen, -CF 3 , -OCF 3 , -CN, -NO 2 , -NRR', -C(O)OR, -C(O)alkyl, -OR, -NR-C(O)alkyl or -C(O)NRR';
  • R 3 is a) phenyl optionally substituted one or several times by alkyl, halogen, -CF 3 , -OCF 3 , -CN, -NO 2 , -NRR', -OR, -NR-S(O) 2 -alkyl,
  • -S(O) 2 -alkyl -S(O) 2 -alkyl, -S(O) 2 -NRR', -alkylene-NRR', -C(O)OR, -NR- C(O)alkyl or -C(O)NRR'; b) heteroaryl optionally substituted one or several times by alkyl, halogen, -OR, -NRRVCN, -CF 3 or -OCF 3 ; or c) heterocyclyl optionally substituted one or several times by alkyl, -C(O)-alkyl or -S(O) 2 -alkyl; Y is -NR-, -NR-S(O) 2 - or -O-;
  • L is a single bond or alkylene optionally substituted one or several times by -OR;
  • R and R' independently represent hydrogen or alkyl; and all pharmaceutically acceptable salts thereof.
  • the compounds according to this invention show activity as protein kinase inhibitors.
  • Many diseases are associated with abnormal cellular responses triggered by protein kinase mediated events. These diseases include autoimmune diseases, inflammatory diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease or hormone-related diseases. Accordingly, there has been a substantial effort in medicinal chemistry to find protein kinase inhibitors that are effective as therapeutic agents.
  • the compounds according to this invention in particular show activity as kinase inhibitors, especially as Aurora A kinase inhibitor, and may therefore be useful for the treatment of diseases mediated by said kinases.
  • Aurora A inhibition leads to cell cycle arrest in the G2 phase of the cell cycle and exerts an antiproliferative effect in tumor cell lines.
  • Aurora A inhibitors may be useful in the treatment of i.e. hyperproliferative diseases such as cancer and in particular colorectal, breast, lung, prostate, pancreatic, gastric, bladder, ovarian, melanoma, neuroblastoma, cervical, kidney or renal cancers, leukemias or lymphomas.
  • AML acute-myelogenous leukemia
  • ALL acute lymphocytic leukemia
  • GIST gastrointestinal stromal tumor
  • Objects of the present invention are the compounds of formula I and their tautomers, pharmaceutically acceptable salts, enantiomeric forms, diastereoisomers and racemates, their use as protein kinase inhibitors, in particular as Aurora A kinase inhibitor, the preparation of the above-mentioned compounds, medicaments or pharmaceutical compositions containing them and their manufacture as well as the use of the above-mentioned compounds in treatment, control or prevention of illnesses, especially of illnesses and disorders as mentioned above like tumors or cancer (e.g.
  • alkyl as used herein means a saturated, straight-chain or branched-chain hydrocarbon containing from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, t-butyl, n- pentyl, n-hexyl.
  • halogen means fluorine, chlorine or bromine, preferably fluorine or chlorine and more preferably chlorine.
  • alkylene as used herein means a saturated, straight-chain or branched- chain, preferably straight-chain, hydrocarbon containing from 1 to 5 carbon atoms, preferably from 1 to 3 carbon atoms, such as methylene, ethylene, trimethylene (1,3-propylene); tetramethylene (butylene), pentamethylene, methyl -methylene, ethyl-methylene, methyl-ethylene (1,2-propylene), ethyl-ethylene, propyl-ethylene,
  • heterocyclyl as used herein means a saturated, monocyclic ring with 5 to 6 ring atoms which contains up to 3 heteroatoms, preferably 1 or 2 heteroatoms, selected independently from N, O or S and the remaining ring atoms being carbon atoms.
  • heteroatoms preferably 1 or 2 heteroatoms, selected independently from N, O or S and the remaining ring atoms being carbon atoms.
  • at least one heteroatom of the ring is N and the remaining heteroatoms are selected independently from N, O or S and such heterocyclyl group is preferably attached via the ring N atom.
  • saturated heterocyclic groups pyrrolidinyl, morpholinyl, piperazinyl, piperidyl, oxazolidinyl, thiazolidinyl, and the like, preferably morpholinyl, piperazinyl, piperidyl or pyrrolidinyl.
  • heteroaryl as used herein means a mono- or bicyclic aromatic ring with 5 to 10 ring atoms, preferably with 5 to 6 ring atoms, which contains up to 3 heteroatoms, preferably 1 or 2 heteroatoms, selected independently from N, O or S and the remaining ring atoms being carbon atoms.
  • heteroaryl groups include pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, indolyl, indazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl and the like, preferably pyrazolyl, imidazolyl, triazolyl, thienyl, pyridyl or pyrimidyl and more preferably pyridyl or imidazolyl.
  • a "pharmaceutically acceptable carrier” is intended to include any and all material compatible with pharmaceutical administration including solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and other materials and compounds compatible with pharmaceutical administration. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions of the invention are contemplated. Supplementary active compounds can also be incorporated into the compositions.
  • a therapeutically effective amount of a compound means an amount of compound that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is within the skill in the art.
  • the therapeutically effective amount or dosage of a compound according to this invention can vary within wide limits and may be determined in a manner known in the art. Such dosage will be adjusted to the individual requirements in each particular case including the specific compound(s) being administered, the route of administration, the condition being treated, as well as the patient being treated. In general, in the case of oral or parenteral administration to adult humans weighing approximately 70 Kg, a daily dosage of about 10 mg to about 10,000 mg, preferably from about 200 mg to about 1,000 mg, should be appropriate, although the upper limit may be exceeded when indicated. The daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, it may be given as continuous infusion.
  • R 1 and R 2 independently represent hydrogen, alkyl, halogen, -CF 3 , -OCF 3 , -CN, -NO 2 , -NRR', -C(O)OR, -C(O)alkyl, -OR, -NR-C(O)alkyl or -C(O)NRR'; preferably hydrogen alkyl, -CF 3 , -NRR', -C(O)OR or -OR.
  • R 3 is a) phenyl optionally substituted one or several times , preferably once or twice, by alkyl, halogen, -CF 3 , -OCF 3 , -CN, -NO 2 , -NRR', -OR, -NR-S(O) 2 -alkyl, -S(O) 2 - alkyl, -S(O) 2 -NRR', -alkylene-NRR', -C(O)OR, -NR-C(O)alkyl or -C(O)NRR'; preferably the phenyl being optionally substituted by alkyl, halogen, -OR, -NR- S(O) 2 -alkyl or -S(O) 2 -alkyl; b) heteroaryl optionally substituted one or several times, preferably once or twice, by alkyl, halogen, -OR, -NRR',-CN, -CF 3 or -OCF
  • heterocyclyl optionally substituted one or several times, preferably once or twice, by alkyl, -C(O)-alkyl or -S(O) 2 -alkyl, preferably the heterocyclyl being optionally substituted by alkyl.
  • Y is -NR-, -NR-S(O) 2 - or -O-, preferably -NR- or -O- and more preferably -NH-.
  • L is a single bond or alkylene optionally substituted one or several times, preferably once or twice, by -OR, preferably the alkylene being optionally substituted by -OH.
  • L is alkylene optionally substituted by -OH.
  • R and R' independently represent hydrogen or alkyl.
  • one of Rl and R2 represents hydrogen and the other of Rl and R2 represents hydrogen, alkyl, halogen, -CF3, -0CF3, -CN, -NO2, -NRR', - C(O)OR, -C(O)alkyl, -OR, -NR-C(O)alkyl or -C(O)NRR'; preferably hydrogen alkyl, -CF3, -NRR', -C(O)OR or -OR.
  • R'and R 2 independently represent hydrogen, alkyl, -CF 3 , -NRR', -C(O)OR or -OR.
  • Y is -NR-.
  • R'and R 2 independently represent hydrogen, alkyl, -CF 3 , -NRR', -C(O)OR or-OR;
  • Y is -NR-.
  • R 3 is phenyl optionally substituted once or twice by alkyl, halogen,
  • R 3 is phenyl optionally substituted once or twice by alkyl, halogen,
  • L is alkylene optionally substituted once or twice by -OR.
  • R'and R 2 independently represent hydrogen, alkyl, -CF 3 , -NRR', -C(O)OR or -OR;
  • R 3 is phenyl optionally substituted once or twice by alkyl, halogen,
  • L is alkylene optionally substituted once or twice by -OR.
  • Such compounds may be selected from the group consisting of:
  • R 3 is heteroaryl optionally substituted once or twice by alkyl
  • L is alkylene
  • R 3 is heteroaryl optionally substituted once or twice by alkyl
  • Y is -NR-; and L is alkylene.
  • R 1 and R 2 independently represent hydrogen, alkyl, -CF 3 , -NRR', -C(O)OR or-OR, preferably hydrogen or -OR;
  • R 3 is heteroaryl optionally substituted once or twice by alkyl;
  • Y is -NR-; and L is alkylene.
  • Such compounds may be selected from the group consisting of: 3-(5-Methoxy-lH-indol-2-yl)-4-(2-pyridin-2-yl-ethylamino)-lH-pyridin-2-one; 3-(5-Methoxy-lH-indol-2-yl)-4-[(pyridin-2-ylmethyl)-amino]-lH-pyridin-2-one; 3-(5-Methoxy-lH-indol-2-yl)-4-[(pyridin-3-ylmethyl)-arnino]-lH-pyridin-2-one;
  • R 3 is heterocyclyl optionally substituted once or twice by alkyl; and L is alkylene.
  • R 3 is heterocyclyl optionally substituted once or twice by alkyl
  • Y is -NR-; and L is alkylene.
  • R'and R 2 independently represent hydrogen, alkyl, -CF 3 , -NRR', -C(O)OR or-OR, preferably hydrogen;
  • R 3 is heterocyclyl optionally substituted once or twice by alkyl;
  • Y is -NR-; and L is alkylene.
  • Such compounds may be selected from the group consisting of: 3-(lH-Indol-2-yl)-4-(2-pyrrolidin-l-yl-ethylamino)-]H-pyridin-2-one; 3-(lH-Indol-2-yl)-4-(3-morpholin-4-yl-propylamino)-lH-pyridin-2-one;
  • Y is -NR-S(O) 2 -.
  • Another embodiment of the invention are the compounds according to formula I, wherein
  • R 3 is phenyl
  • L is a single bond or alkylene.
  • R 3 is phenyl
  • Y is -NR-S(O) 2 -
  • L is a single bond or alkylene.
  • R'and R 2 independently represent hydrogen, alkyl, -CF 3 , -NRR', -C(O)OR or-OR, preferably hydrogen or -OR;
  • R 3 is phenyl;
  • Y is -NR-S(O) 2 -;
  • L is a single bond or alkylene.
  • Such compounds may be selected from the group consisting of:
  • R 3 is phenyl optionally substituted once or twice by alkyl or -OR; and L is alkylene.
  • Another embodiment of the invention are the compounds according to formula I, wherein
  • R 3 is phenyl optionally substituted once or twice by alkyl or -OR;
  • Another embodiment of the invention are the compounds according to formula I, wherein
  • R 1 and R 2 independently represent hydrogen, alkyl, -CF 3 , -NRR', -C(O)OR or-OR, preferably hydrogen or -OR;
  • R 3 is phenyl optionally substituted once or twice by alkyl or -OR;
  • Y is -O-; and L is alkylene.
  • Such compounds may be selected from the group consisting of: 3-(lH-Indol-2-yl)-4-(2-m-tolyl-ethoxy)-lH-pyridin-2-one; 3-(5-Methoxy-lH-indol-2-yl)-4-(2-m-tolyl-ethoxy)-lH-pyridin-2-one;
  • R 3 is heteroaryl
  • L is alkylene
  • R 3 is heteroaryl
  • Y is -O-; and L is alkylene.
  • R 1 and R 2 independently represent hydrogen, alkyl, -CF 3 , -NRR', -C(O)OR or-OR, preferably hydrogen; R is heteroaryl;
  • Y is -O-; and L is alkylene.
  • Such a compound is for example: 3-(5-Methoxy-lH-indol-2-yl)-4-(pyridin-2-ylmethoxy)-lH-pyridin-2-one.
  • Another embodiment of the invention is a process for the preparation of the compounds of formula I comprising the steps of a) reacting a compound of formula V,
  • R 1 and R 2 have the meaning as defined for formula I above, and X is a halogen selected from chlorine, bromine or iodine, preferably chlorine or iodine, with a compound of formula Villa,
  • the indole compounds of formula I, or a pharmaceutically acceptable salt thereof, which are subject of the present invention may be prepared by any process known to be applicable to the preparation of chemically-related compounds. Such processes, when used to prepare a compound of the formula I, or a pharmaceutically-acceptable salt thereof, are illustrated by the following representative schemes 1 to 2 and examples in which, unless otherwise stated, Rl, R2 and X have the significance given herein before for formula I.
  • Necessary starting materials are either commercially available or they may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described within the accompanying examples or in the literature cited below with respect to schemes 1 to 2. Alternatively necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist.
  • pyridinone-substituted indoles of the general formula I bearing substituted amino- or alcohol-side chains can be prepared on a straightforward synthesis route starting from methoxypyridine-substituted indoles of the general formula VII.
  • Aryl-substituted indoles of formula VII can in general be prepared similar to synthesis strategies described in the literature (Kuethe, J.T., et al., Org. Lett. 5
  • Nitrobenzenes of formula II with R 1 and R 2 have the meaning described herein before are converted into ortho-substituted TMS-methylene nitrobenzenes III by treatment with trimethylsilyl-magnesium chloride and subsequent oxidation with suitable oxidation agents as e.g. DDQ or iodine. After desilylation, the resulting ort/i ⁇ -methylene substituted nitrobenzene intermediate undergoes an Aldol-type condensation reaction with e.g. a pyridine aldehyde of formula IV (A is H and X represents a halogen selected from chlorine, bromine and iodine) to form an alcohol of the general formula V (scheme 1).
  • a pyridine aldehyde of formula IV A is H and X represents a halogen selected from chlorine, bromine and iodine
  • the condensation product of formula V is dehydrated by activation of the alcohol and subsequent reduction to olef ⁇ nes of formula VI.
  • Appropriate dehydrating agents include e.g. trifluoroacetic acid anhydride for the transformation of the hydroxy group into a good leaving group and subsequent treatment with DBU to form the olefine.
  • the intermediate indole of formula VII is formed by ring closure of the intermediate orf/io-nitro olefine with e.g. triethyl phosphite (scheme 1).
  • ring closure can be achieved by Pd-catalyzed reductive cyclization (using for instance the following conditions: Pd(OAc) 2 , PPh 3 , CO).
  • Pyridine aldehydes of formula IV (A is H and X represents a halogen selected from chlorine, bromine and iodine) can for example be prepared according to procedures described in WO 95/29917 or Gabarda, A.E., et al., Tetrahedron 58 (2002) 6329-6341.
  • Pyridine carboxylates of formula IV (A is OH and X represents a halogen selected from chlorine, bromine and iodine) can for example be prepared according to procedures described in WO 2004/063151.
  • Alkyl pyridine carboxylates of formula IV (A is e.g. OMe and X represents a halogen selected from chlorine, bromine and iodine) can for example be prepared according to procedures described in WO 2004/063151.
  • substituents on the groups Y, L, R 1 , R 2 , and R 3 may not be inert to the conditions of the synthesis sequences described above and may require protection by standard protecting groups known in the art. For instance, an amino or hydroxyl group may be protected as an acetyl or tert.-butoxycarbonyl derivative. Alternatively, some substituents may be derived from others at the end of the reaction sequence. For instance, a compound of formula I may be synthesized bearing a nitro-, an ethoxycarbonyl, an ether, a sulfonic acid substituent on the groups Y, L, R 1 , R 2 , and R 3 , which substituents are finally converted to an amino-
  • alkylamino- e.g. by reductive amination of an amino group
  • dialkylamino- e.g. by alkylation of an amino group, reduction of an appropriate acylamino group with lithium aluminum hydride or Eschweiler- Clarke reaction with an appropriate amino or alkylamino group
  • acylamino- by amide formation from an amino group e.g. with appropriate acyl halides or with appropriate carboxylic acids after their activation with CDI, EDC etc.
  • alkylsulfonylamino e.g.
  • compositions containing a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier are an object of the present invention, as is a process for their production, which comprises bringing one or more compounds of the present invention and/or pharmaceutically acceptable salts and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more pharmaceutically acceptable carriers.
  • the compounds of the present invention as well as their pharmaceutically acceptable salts are useful in the control or prevention of illnesses.
  • said compounds Based on their protein kinase activity, e.g. Aurora tyrosine kinase inhibition and their antiproliferative activity, said compounds are useful for the treatment of diseases such as cancer in humans or animals and for the production of corresponding pharmaceutical compositions.
  • the dosage depends on various factors such as manner of administration, species, age and/or individual state of health.
  • An embodiment of the invention is a pharmaceutical composition, containing one or more compounds according to formula I as active ingredients, together with pharmaceutically acceptable carriers.
  • Another embodiment of the invention is a pharmaceutical composition containing one or more compounds of formula I as active ingredients together with pharmaceutically acceptable carriers for the treatment of diseases mediated by an inappropriate activation of Aurora family tyrosine kinases.
  • Another embodiment of the invention is a pharmaceutical composition, containing one or more compounds according to formula I as active ingredients, for the inhibition of tumor growth.
  • Another embodiment of the invention is a pharmaceutical composition, containing one or more compounds according to formula I as active ingredients, for the treatment of cancer.
  • Another embodiment of the invention is a pharmaceutical composition containing one or more compounds of formula I as active ingredients together with pharmaceutically acceptable carriers for the treatment of colorectal, breast, lung, prostate, pancreatic, gastric, bladder, ovarian, melanoma, neuroblastoma, cervical, kidney or renal cancers, leukemias or lymphomas.
  • Another embodiment of the invention is a pharmaceutical composition containing one or more compounds of formula I as active ingredients together with pharmaceutically acceptable carriers for the treatment of acute-myelogenous leukemia (AML), acute lymphocytic leukemia (ALL) and gastrointestinal stromal tumor (GIST).
  • AML acute-myelogenous leukemia
  • ALL acute lymphocytic leukemia
  • GIST gastrointestinal stromal tumor
  • Another embodiment of the invention is the use of one or more compounds of formula I for the manufacture of pharmaceutical compositions for the treatment of diseases mediated by an inappropriate activation of Aurora family tyrosine kinases.
  • Another embodiment of the invention is the use of a compound according to formula I, for the manufacture of corresponding pharmaceutical compositions for the inhibition of tumor growth.
  • Another embodiment of the invention is the use of a compound according to formula I, for the manufacture of corresponding pharmaceutical compositions for the treatment of colorectal, breast, lung, prostate, pancreatic, gastric, bladder, ovarian, melanoma, neuroblastoma, cervical, kidney or renal cancers, leukemias or lymphomas.
  • Another embodiment of the invention is the use of a compound according to formula I, for the manufacture of pharmaceutical compositions for the treatment of acute-myelogenous leukemia (AML), acute lymphocytic leukemia (ALL) and gastrointestinal stromal tumor (GIST).
  • AML acute-myelogenous leukemia
  • ALL acute lymphocytic leukemia
  • GIST gastrointestinal stromal tumor
  • Another embodiment of the invention is the use of the compounds of formula I as Aurora A tyrosine kinase inhibitors.
  • Another embodiment of the invention is the use of the compounds of formula I as anti-proliferating agents.
  • Another embodiment of the invention is the use of one or more compounds of formula I for the treatment of cancer.
  • Another embodiment of the invention is a method of treating cancer comprising administering to a person in need thereof a therapeutically effective amount of a compound of formula I.
  • Another embodiment of the invention is a method of treating cancer comprising administering to a person in need thereof a therapeutically effective amount of a compound of formula I, wherein the cancer is colorectal cancer, breast cancer, lung cancer, prostate cancer, pancreatic cancer, gastric cancer, bladder cancer, ovarian cancer, melanoma, neuroblastoma, cervical cancer, kidney cancer or renal cancer, leukemia, or lymphoma.
  • the cancer is colorectal cancer, breast cancer, lung cancer, prostate cancer, pancreatic cancer, gastric cancer, bladder cancer, ovarian cancer, melanoma, neuroblastoma, cervical cancer, kidney cancer or renal cancer, leukemia, or lymphoma.
  • the compounds according to the present invention may exist in the form of their pharmaceutically acceptable salts.
  • pharmaceutically acceptable salt refers to conventional acid-addition salts that retain the biological effectiveness and properties of the compounds of formula I and are formed from suitable non-toxic organic or inorganic acids.
  • Sample acid-addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, methanesulfonic acid, ethanesulfonic acid, citric acid, ascorbic acid and the like.
  • the chemical modification of a pharmaceutical compound i.e.
  • a drug) into a salt is a technique well known to pharmaceutical chemists to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds (see, e.g., Stahl, P. H. and Wermuth, G. (editors), Handbook of Pharmaceutical Salts, Verlag Helvetica Chimica Acta (VHCA), Zurich (2002), or Bastin, R.J., et al., Organic Proc. Res. Dev. 4 (2000) 427- 435).
  • the compounds of formula I can contain one or several chiral centers and can then be present in a racemic or in an optically active form.
  • the racemates can be separated according to known methods into the enantiomers. For instance, diastereomeric salts which can be separated by crystallization are formed from the racemic mixtures by reaction with an optically active acid such as e.g. D- or L- camphorsulfonic acid.
  • separation of the enantiomers can also be achieved by using chromatography on chiral HPLC-phases (HPLC: High Performance Liquid Chromatography) which are commercially available.
  • the compounds of formula I and their pharmaceutically acceptable salts possess valuable pharmacological properties. It has been found that said compounds show activity as inhibitors of the Aurora kinase family and also show anti-proliferative activity. Consequently the compounds of the present invention are useful in the therapy and/or prevention of illnesses with known over-expression of kinases of the Aurora family preferably Aurora A, especially in the therapy and / or prevention of illnesses mentioned above.
  • the activity of the present compounds as inhibitors of the Aurora kinase family is demonstrated by the following biological assay:
  • Aurora A is a serine threonine kinase involved in spindle assembly and chromosome segregation.
  • the assay is a typically ELISA-type assay where substrate (GST-Histone H3) is coupled to the assay-plate and is phosphorylated by the kinase. Phosphorylation is detected by a mouse anti-Phosphopeptid mAb and an HRP-labeled anti-mouse pAb. The assay is validated for IC 50 -determination.
  • ELISA Enzyme-Linked Immunosorbent Assay
  • the reaction buffer was 1OX Kinase Buffer (Cell Signaling cat # 9802) supplemented with 1 ⁇ g/mL I-block. Reactions were stopped after 40 minutes by addition of 25 mM EDTA. After washing, substrate phosphorylation was detected by addition of anti-phospho-Histone H3 (Ser 10) 6G3 mAb (Cell Signaling cat #9706) and sheep anti-mouse pAb-HRP (Amersham cat# NA931V), followed by colorimetric development with TMB (3,3',5,5'-tetramethylbenzidine from Kirkegaard & Perry Laboratories). After readout of the adsorbance, IC 50 values were calculated using a non-linear curve fit (XLfit software (ID Business Solution Ltd.,
  • the CellTiter-GloTM Luminescent Cell Viability Assay (Promega) is a homogeneous method of determining the number of viable cells in culture based on quantitation of the ATP present, which signals the presence of metabolically active cells.
  • HCT 116 cells human colon carcinoma, ATCC-No. CCl-247 were cultivated in RPMI 1640 medium with GlutaMAXTM I (Invitrogen, Cat-No. 61870-010), 5 %
  • FCS Fetal Calf Serum
  • FBS Fetal Calf Serum
  • lOOUnits/ml penicillin/lOO ⁇ g/ml streptomycin Pen/Strep from Invitrogen Cat. No. 15140.
  • the cells were seeded in 384 well plates, 1000 cells per well, in the same medium. The next day the test compounds were added in various concentrations ranging from 30 ⁇ M to 0.0015 ⁇ M (10 concentrations, 1:3 diluted). After 5 days the
  • CellTiter-GloTM Luminescent Cell Viability Assay from Promega.
  • the cell-plate was equilibrated to room temperature for approximately 30 minutes and than the CellTiter-Glo reagent was added. The contents were carefully mixed for 15 minutes to induce cell lysis. After 45 minutes the luminescent signal was measured in Victor 2, (scanning multiwell spectrophotometer, Wallac).
  • RPMI 1640 with GlutaMAXTM I Invitrogen, Cat-Nr. 61870
  • 5 % FCS Sigma Cat.-No. F4135
  • Pen/Strep Invitrogen, Cat No. 15140.
  • HCTl 16 (ATCC-No. CCl-247): 1000 cells in 60 ⁇ l per well of 384 well plate (Greiner 781098, ⁇ Clear-plate white)
  • step e) of the dilution procedure described below was followed.
  • a serial dilution with dilution steps of 1:3 was followed according to the procedure (a -e) as described here below:
  • a) for the second highest concentration add 10 ⁇ l of 10 mM stock solution of compound to 20 ⁇ l dimethylsulfoxide (DMSO) b) dilute 8x 1:3 (always 10 ⁇ l to 20 ⁇ l DMSO) in this DMSO dilution row (results in 9 wells with concentrations from 3333,3 ⁇ M to 0.51 ⁇ M) c) dilute each concentration 1: 47,6 (3,5 ⁇ l compound dilution to 163 ⁇ l media) d) add 10 ⁇ l of every concentration to 60 ⁇ l media in the cell plate resulting in final concentration of DMSO : 0.3 % in every well and resulting in 10 final concentration of compounds ranging from 30 ⁇ M to 0.0015 ⁇ M.
  • DMSO dimethylsulfoxide
  • the compounds according to this invention and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical compositions.
  • the pharmaceutical compositions can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions.
  • the administration can, however, also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
  • compositions can be obtained by processing the compounds according to this invention with pharmaceutically inert, inorganic or organic carriers.
  • Lactose, corn starch or derivatives thereof, talc, stearic acids or it's salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatine capsules.
  • Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatine capsules.
  • Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like.
  • Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
  • compositions can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsif ⁇ ers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
  • a pharmaceutical compositions comprise e.g. the following: a) Tablet Formulation (Wet Granulation):
  • Example 4 N-f3-(5-Methoxy-lH-indol-2-yl)-2-oxo-L2-dihydro-pyridin-4-yll- benzenesulfonamide a) N-[2-Methoxy-3-(5-methoxy-lH-indol-2-yl)-pyridin-4-yl]-benzenesulfonamide
  • the indole building block 2-(4-Iodo-2-methoxy-pyridin-3-yl)-5-methoxy-lH- indole is synthesized according to example 1 steps a)-d) in 31 % overall yield from 4-methoxy-nitrobenzene as starting material (yields for reaction steps: 75 %, 80 %,

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne des composés représentés par la formule (I),des sels pharmaceutiquement acceptables de ceux-ci, leur formes énantiomères, des diastéréoisomères et des racémates, la préparation des composés susmentionnés, les médicaments les contenant ainsi que leur fabrication, et l'utilisation des composés susmentionnés dans la lutte contre une maladie telle que le cancer ou la prévention de celle-ci.
PCT/EP2007/007538 2006-08-31 2007-08-29 Dérivés d'indole, fabrication de ceux-ci et utilisation comme agents pharmaceutiques WO2008025526A1 (fr)

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Publication number Priority date Publication date Assignee Title
WO2009093012A1 (fr) * 2008-01-22 2009-07-30 Vernalis (R & D) Ltd Dérivés d'indolyl-pyridone
WO2011010083A1 (fr) * 2009-07-18 2011-01-27 Vernalis (R & D) Ltd Dérivés d'indolylpyridone
WO2012052954A1 (fr) * 2010-10-20 2012-04-26 Universite Bordeaux Segalen Profil de l'issue clinique associée à des tumeurs stromales gastro-intestinales et méthode de traitement de tumeurs stromales gastro-intestinales
US8410144B2 (en) 2009-03-31 2013-04-02 Arqule, Inc. Substituted indolo-pyridinone compounds
CN111004220A (zh) * 2019-12-11 2020-04-14 徐州医科大学 3-（4-苯基-1h-2-咪唑基）-1h-吡唑类化合物、制备方法及其应用
CN111039940A (zh) * 2019-12-31 2020-04-21 北京鑫开元医药科技有限公司 一种Aurora A激酶抑制剂、制备方法、药物组合物及其用途
CN115028655A (zh) * 2022-05-20 2022-09-09 上海大学 一种2-三氟甲基-3-碘-吲哚类化合物及其制备方法

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WO2002079192A1 (fr) * 2001-03-28 2002-10-10 Bristol-Myers Squibb Company Nouveaux inhibiteurs de la tyrosine kinase
WO2005000804A2 (fr) * 2003-06-05 2005-01-06 Merck & Co., Inc. Indoles substitues et procede de preparation d'indoles substitues

Patent Citations (2)

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WO2002079192A1 (fr) * 2001-03-28 2002-10-10 Bristol-Myers Squibb Company Nouveaux inhibiteurs de la tyrosine kinase
WO2005000804A2 (fr) * 2003-06-05 2005-01-06 Merck & Co., Inc. Indoles substitues et procede de preparation d'indoles substitues

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8916591B2 (en) 2008-01-22 2014-12-23 Vernalis (R&D) Ltd Indolyl-pyridone derivatives having checkpoint kinase 1 inhibitory activity
US10696652B2 (en) 2008-01-22 2020-06-30 Vernalis (R&D) Ltd. Indolyl-pyridone derivatives having checkpoint kinase 1 inhibitory activity
US9604975B2 (en) 2008-01-22 2017-03-28 Vernalis (R&D) Ltd Indolyl-pyridone derivatives having checkpoint kinase 1 inhibitory activity
WO2009093012A1 (fr) * 2008-01-22 2009-07-30 Vernalis (R & D) Ltd Dérivés d'indolyl-pyridone
EA021464B1 (ru) * 2008-01-22 2015-06-30 Вернэлис (Р&Д) Лтд. Производные индол-пиридона, обладающие ингибиторной активностью в отношении киназы 1, содержащая их фармацевтическая композиция и их применение
US8410144B2 (en) 2009-03-31 2013-04-02 Arqule, Inc. Substituted indolo-pyridinone compounds
WO2011010083A1 (fr) * 2009-07-18 2011-01-27 Vernalis (R & D) Ltd Dérivés d'indolylpyridone
JP2014501496A (ja) * 2010-10-20 2014-01-23 ユニヴェルシテ ボルドー セガラン 消化管間質腫瘍における臨床転帰のシグネチャーおよび消化管間質腫瘍の治療の方法
WO2012052954A1 (fr) * 2010-10-20 2012-04-26 Universite Bordeaux Segalen Profil de l'issue clinique associée à des tumeurs stromales gastro-intestinales et méthode de traitement de tumeurs stromales gastro-intestinales
CN111004220A (zh) * 2019-12-11 2020-04-14 徐州医科大学 3-（4-苯基-1h-2-咪唑基）-1h-吡唑类化合物、制备方法及其应用
CN111039940A (zh) * 2019-12-31 2020-04-21 北京鑫开元医药科技有限公司 一种Aurora A激酶抑制剂、制备方法、药物组合物及其用途
CN111039940B (zh) * 2019-12-31 2022-10-21 北京鑫开元医药科技有限公司 一种Aurora A激酶抑制剂、制备方法、药物组合物及其用途
CN115028655A (zh) * 2022-05-20 2022-09-09 上海大学 一种2-三氟甲基-3-碘-吲哚类化合物及其制备方法
CN115028655B (zh) * 2022-05-20 2024-01-16 上海大学 一种2-三氟甲基-3-碘-吲哚类化合物及其制备方法

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