WO2008017465A1 - Dérivés de lactame bicycliques, leur fabrication et utilisation en tant qu'agents pharmaceutiques - Google Patents

Dérivés de lactame bicycliques, leur fabrication et utilisation en tant qu'agents pharmaceutiques Download PDF

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WO2008017465A1
WO2008017465A1 PCT/EP2007/007006 EP2007007006W WO2008017465A1 WO 2008017465 A1 WO2008017465 A1 WO 2008017465A1 EP 2007007006 W EP2007007006 W EP 2007007006W WO 2008017465 A1 WO2008017465 A1 WO 2008017465A1
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formula
dihydro
alkyl
compounds
oxo
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PCT/EP2007/007006
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Guy Georges
Bernhard Goller
Anja Limberg
Petra Rueger
Matthias Rueth
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F. Hoffmann-La Roche Ag
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to novel bicyclic lactam 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 overexpression 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.
  • the present invention relates to bicyclic lactam derivatives of the general formula I,
  • R 1 is hydrogen or alkyl
  • R 2 is a) phenyl optionally substituted one or several times by alkyl, halogen, cyano, -NO 2 , -NRR', -NR-C(O)alkyl, -OH, -OR, -CF 3 or -OCF 3 ; b) heteroaryl optionally substituted one or several times by alkyl; or c) alkyl;
  • R 3 and R 4 independently are alkyl;
  • X is -NH-, -O- or alkylene;
  • R and R' independently are 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 Aurora family kinase inhibitors, especially as Aurora A kinase inhibitors, and may therefore be useful for the treatment of diseases mediated by said kinase.
  • 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.
  • Treatment of acute- myelogenous leukemia (AML, acute lymphocytic leukemia (ALL) and gastrointestinal stromal tumor (GIST) is included.
  • 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 Aurora kinase inhibitors, 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. colorectal, breast, lung, prostate, pancreatic, gastric, bladder, ovarian, melanoma, neuroblastoma, cervical, kidney or renal cancers, leukemias or lymphomas) or in the manufacture of corresponding medicaments or pharmaceutical compositions.
  • tumors or cancer e.g. colorectal, breast, lung, prostate, pancreatic, gastric, bladder, ovarian, melanoma, neuroblastoma, cervical, kidney or renal cancers, leukemias or lymphomas
  • 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 as used herein means fluorine, chlorine or bromine, preferably fluorine or chlorine.
  • heteroaryl as used herein means a mono- or bicyclic aromatic ring with
  • 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, triazolyl, tetrazolyl, thienyl, pyridy
  • 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
  • N-protecting group means a blocking group for the amino functional group (which is introduced before a reaction and) which prevents the amino group to react in side reaction e.g. during acylation reactions. Such N- protecting group can be cleaved after the reaction to give the free amine again.
  • t-butyloxycarbonyl BOC
  • benzyloxycarbonyl Z
  • allyloxycarbonyl ethyloxycarbonyl
  • PG 1 a preferred group is ethyloxycarbonyl
  • PG 2 a preferred group is t- butyloxycarbonyl (BOC).
  • 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 is hydrogen or alkyl.
  • R 2 is a) phenyl optionally substituted one or several times, preferably once or twice, by alkyl, halogen, cyano, -NO 2 , -NRR', -NR-C(O)alkyl, -OH, -OR, -CF 3 or -OCF 3 , preferably by alkyl ; b) heteroaryl optionally substituted one or several times by alkyl, said heteroaryl being preferably unsubstituted and if substituted, being preferably substituted once or twice by alkyl; or c) alkyl.
  • R 3 and R 4 independently are alkyl, preferably methyl.
  • X is -NH-, -O- or alkylene.
  • R and R' independently are hydrogen or alkyl.
  • X is -NH-.
  • R 2 is phenyl optionally substituted one or several times, preferably once or twice, by alkyl, halogen, cyano, -NO 2 , -NRR', -NR-C(O)alkyl, -OH, -OR, -CF 3 or -OCF 3 , preferably by alkyl.
  • X is -NH-
  • R 2 is phenyl optionally substituted one or several times, preferably once or twice, by alkyl, halogen, cyano, -NO 2 , -NRR', -NR-C(O)alkyl, -OH, -OR, -CF 3 or -OCF 3 , preferably by alkyl.
  • Such compounds may be selected from the group consisting of: l-Isopropyl-3,3-dimethyl-2-oxo-2,3-dihydro-lH-indole-6-carboxylic acid [5-(2,6- diethyl-phenylcarbamoyl)-l,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl] -amide;
  • X is alkylene
  • R 2 is heteroaryl optionally substituted one or several times by alkyl, said heteroaryl being preferably unsubstituted and if substituted, being preferably substituted once or twice by alkyl.
  • X is alkylene
  • R 2 is heteroaryl optionally substituted one or several times by alkyl, said heteroaryl being preferably unsubstituted and if substituted, being preferably substituted once or twice by alkyl.
  • Such compounds may be selected from the group consisting of: l-Ethyl-3,3-dimethyl-2-oxo-2,3-dihydro-lH-indole-6-carboxylic acid [5-(2- thiophen-2-yl-acetyl)-l,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl] -amide; and
  • X is -O-.
  • R 2 is alkyl
  • X is -O-; and R 2 is alkyl.
  • Such a compound is for example:
  • Another embodiment of the invention is a process for the preparation of the compounds of formula I comprising the steps of
  • R 1 , R 2 , R 3 , R 4 and X have the significance given above for formula I and PG 1 is a N-protecting group, b) cleaving the N-protecting group PG 1 of the compounds of formula III to give the corresponding derivatives of formula I,
  • the bicyclic 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, R 1 , R 2 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.
  • R 1 , R 3 and R 4 have the significance as given above for formula I and
  • PG 1 and PG 2 are two different N-protecting groups, which are cleavable independently from each other.
  • N-protecting groups are e.g. t-butyloxycarbonyl (BOC), benzyloxycarbonyl (Z), allyloxycarbonyl, ethyloxycarbonyl and the like.
  • BOC t-butyloxycarbonyl
  • Z benzyloxycarbonyl
  • allyloxycarbonyl ethyloxycarbonyl and the like.
  • N-protecting groups are described e.g. in Greene, T.W. and Wuts, P.G.M., Protective Groups in Organic Synthesis, third edition, Wiley, New York (1999) or Kocienski, P., Protecting Groups, third edition, Georg Thieme Verlag, Stuttgart (2004).
  • the carboxylic acids of formula IV can be prepared by standard procedures of organic chemistry and are described in DE 39 32 953 and EP 0 344 634 (one method for the alleviation of such compounds is described in scheme 2, step 3).
  • the synthesis of compounds of formula V wherein PG 1 and PG 2 are two different oxycarbonyl groups e.g. as in a preferred embodiment, PG 1 is ethyloxycarbonyl and PG 2 is t- butyloxycarbonyl
  • Fancelli D. et al., J.
  • the carboxylic acids of formula IV are either converted into their acid chlorides using standard reagents well known to someone skilled in the art, such as thionyl chloride, oxalyl chloride, phosphoryl chloride and the like.
  • Those reagents can be used in presence of bases such as N.N-diisopropylethylamine, triethylamine or pyridine in inert solvent such as dichloromethane or dimethylformamide.
  • the resulting acid chloride is then reacted with the amines of formula V to give the compounds of formula VI in an inert solvent such as dimethylformamide (DMF), dichloromethane tetrahydrofuran and the like at temperatures between 0 0 C and 60 0 C eventually in the presence of a base such as N,N-diisopropylethylamine, triethylamine or pyridine and the like.
  • DMF dimethylformamide
  • dichloromethane tetrahydrofuran and the like at temperatures between 0 0 C and 60 0 C eventually in the presence of a base such as N,N-diisopropylethylamine, triethylamine or pyridine and the like.
  • the carboxylic acids of formula IV are converted in situ into activated acids by different peptide coupling procedures known to those skilled in the art. These activated acids were reacted directly with the amines of formula V to give the compounds of formula VI. Said activation with those peptide coupling procedures can involve the use of an activating agent like l-(3-dimethylaminopropyl)-3- ethylcarbodiimide (EDC) (or dicyclohexylcarbodiimide (DCC)), hydroxybenzotriazole (HOBt) with or without di-isopropylethylamine (DIPEA) in an inert solvent such as dimethylformamide (DMF) or dichloromethane at temperatures between 0 0 C and 60 0 C.
  • an activating agent like l-(3-dimethylaminopropyl)-3- ethylcarbodiimide (EDC) (or dicyclohexylcarbodiimide (DCC
  • reaction may alternatively be carried out in presence of O-(7-azabenzotriazol-l-yl)-N,JV,N',N'-tetramethyluronium hexafluorophosphate (HATU) or l-hydroxy-7-azabenzotriazole (HOAt) and triethylamine or di-isopropylethylamine in dimethylformamide or tetrahydrofuran.
  • HATU O-(7-azabenzotriazol-l-yl)-N,JV,N',N'-tetramethyluronium hexafluorophosphate
  • HOAt l-hydroxy-7-azabenzotriazole
  • triethylamine or di-isopropylethylamine in dimethylformamide or tetrahydrofuran.
  • R 1 , R 2 , R 3 and R 4 have the significance as given above for formula I, X is alkylene for Methods A, B and C, X is NH or O for Methods E and F and X' is N for Method D.
  • Removal of the Boc protecting group PG 2 (step 1) can be achieved by standard methods well know to someone skilled the art. For example acids like HCl or trifluoro acetic acid in solvents like ethyl acetate or methanol at ambient temperature can be used in this reaction.
  • scheme 2 can be used: IfX is alkylene, Methods A, B and C can be used:
  • Acid anhydrides (Method A) and acid chlorides(Method B) used in the formation of compounds of formula IHa are either commercially available or can be prepared using standard methods well known to someone skilled in the art. Those reagents can be used in presence of bases such as N,N-diisopropylethylamine, triethylamine or pyridine in inert solvent such as dichloromethane or dimethylformamide.
  • activated acids can be prepared by different peptide coupling procedures known to those skilled in the art. Activation with those procedures can involve the use of an activating agents like l-(3- dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (or dicyclohexylcarbodiimide
  • DCC hydroxybenzotriazole
  • DIPEA di-isopropylethylamine
  • DMF dimethylformamide
  • the reaction may alternatively be carried out in presence of O-(7-azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (HATU) or l-hydroxy-7- azabenzotriazole (HOAt) and triethylamine or di-isopropylethylamine in dimethylformamide or tetrahydrofuran.
  • HATU O-(7-azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate
  • HOAt l-hydroxy-7- azabenzotriazole
  • triethylamine or di-isopropylethylamine in dimethylformamide or tetrahydrofuran.
  • ureas of formula I can be synthesized by addition of amines of formula Ha to isocyanates of formula R 2 -X'CO (Method D, X' is N, scheme 2, step
  • a base such as N,N-diisopropylethylamine, pyridine, triethylamine and the like in an inert solvent like dichloromethane, dimethylformamide (DMF), tetrahydrofuran (THF) and the like.
  • a base such as N,N-diisopropylethylamine, pyridine, triethylamine and the like in an inert solvent like dichloromethane, dimethylformamide (DMF), tetrahydrofuran (THF) and the like.
  • DMF dimethylformamide
  • THF tetrahydrofuran
  • Ureas or carbamates can be obtained by reaction of the corresponding carbamoyl chlorides (X is NH) or chloroformates (X is O) of formula R 2 -X-C(O)C1 with amines of formula Ha (Method E, scheme 2, step 2) in the presence of a base such as N,N-diisopropylethylamine, pyridine, triethyl amine and the like in an inert solvent like dichloromethane, dimethylformamide (DMF), tetrahydrofuran (THF) and the like.
  • a base such as N,N-diisopropylethylamine, pyridine, triethyl amine and the like
  • an inert solvent like dichloromethane, dimethylformamide (DMF), tetrahydrofuran (THF) and the like.
  • Compounds of formula I wherein R 1 is alkyl can be obtained by alkylation of the corresponding amides of formula IHa by methods well known to someone skilled in the art (scheme 2, step 3).
  • alkyl chlorides or alkyl bromides can be used as alkylating reagents after deprotonation with bases like NaH or LiHMDS and the like in solvents like dimethylformamide (DMF), tetrahydrofuran (THF) and the like.
  • This alkylation can alternatively be performed at any stage before step 1 (scheme 2).
  • 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. Based on their 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 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. Bastin, RJ. 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 CellTiter-GloTM assay in HCT 116 cells The CellTiter- GIoTM 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), 2,5 %
  • 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
  • - Medium 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
  • 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, drag ⁇ es, 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 acceptable, 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, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
  • compositions comprise e.g. the following:

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Abstract

La présente invention a pour objet des composés de formule (I), leurs sels pharmaceutiquement acceptables, formes énantiomères, diastéréoisomères et mélanges racémiques, la préparation desdits composés, de médicaments qui les contiennent et leur fabrication, ainsi que l'utilisation desdits composés pour contrôler ou prévenir des maladies telles que le cancer.
PCT/EP2007/007006 2006-08-10 2007-08-08 Dérivés de lactame bicycliques, leur fabrication et utilisation en tant qu'agents pharmaceutiques WO2008017465A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102134243A (zh) * 2011-03-04 2011-07-27 中国医学科学院医药生物技术研究所 具有抗肿瘤活性的双环氨基吡唑类衍生物

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WO2002012242A2 (fr) * 2000-08-10 2002-02-14 Pharmacia Italia S.P.A. Bicyclo-pyrazoles actifs en tant qu'inhibiteurs de kinase, leur procede de preparation et compositions pharmaceutiques les contenant
WO2004080457A1 (fr) * 2003-03-11 2004-09-23 Pharmacia Italia S.P.A. Derives de bicyclo-pyrazol ayant une action inhibitrice contre la kinase, procedes de preparation de ceux-ci et compositions pharmaceutiques les contenant
WO2005005427A1 (fr) * 2003-07-09 2005-01-20 Pharmacia Italia S.P.A. Derives du pyrrolo[3,4-c]pyrazole actifs comme inhibiteurs des kinases

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002012242A2 (fr) * 2000-08-10 2002-02-14 Pharmacia Italia S.P.A. Bicyclo-pyrazoles actifs en tant qu'inhibiteurs de kinase, leur procede de preparation et compositions pharmaceutiques les contenant
WO2004080457A1 (fr) * 2003-03-11 2004-09-23 Pharmacia Italia S.P.A. Derives de bicyclo-pyrazol ayant une action inhibitrice contre la kinase, procedes de preparation de ceux-ci et compositions pharmaceutiques les contenant
WO2005005427A1 (fr) * 2003-07-09 2005-01-20 Pharmacia Italia S.P.A. Derives du pyrrolo[3,4-c]pyrazole actifs comme inhibiteurs des kinases

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102134243A (zh) * 2011-03-04 2011-07-27 中国医学科学院医药生物技术研究所 具有抗肿瘤活性的双环氨基吡唑类衍生物

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