US20110118278A1 - Carbamoyl derivatives of bicyclic carbonylamino-pyrazoles as prodrugs - Google Patents

Carbamoyl derivatives of bicyclic carbonylamino-pyrazoles as prodrugs Download PDF

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US20110118278A1
US20110118278A1 US12/991,564 US99156409A US2011118278A1 US 20110118278 A1 US20110118278 A1 US 20110118278A1 US 99156409 A US99156409 A US 99156409A US 2011118278 A1 US2011118278 A1 US 2011118278A1
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methyl
benzoylamino
carboxylic acid
ester
pyrazole
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Maurizio Pulici
Paolo Polucci
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Nerviano Medical Sciences SRL
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D497/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D497/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D497/04—Ortho-condensed systems

Definitions

  • the present invention relates to carbamoyl derivatives of bicyclic carbonylamino-pyrazoles for use as medicament, in particular for the treatment of diseases due to the malfunctioning of protein kinases (PKs), such cancer and tumors, to the pharmaceutical compositions comprising such carbamoyl derivatives, and to their use as prodrugs of therapeutically active agents.
  • PKs protein kinases
  • the present invention also relates to a method of treating cancer and cell proliferation disorders using such prodrugs, and to some new carbamoyl derivatives.
  • PKs protein kinases
  • PKs A large share of the oncogenes and proto-oncogenes involved in human cancers code for PKs.
  • the enhanced activities of PKs are also implicated in many non-malignant diseases, such as benign prostate hyperplasia, familial adenomatosis, polyposis, neuro-fibromatosis, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis and post-surgical stenosis and restenosis.
  • PKs are also implicated in inflammatory conditions and in the multiplication of viruses and parasites. PKs may also play a major role in the pathogenesis and development of neurodegenerative disorders.
  • Aurora kinases in particular Aurora-2.
  • Aurora-2 was found to be over-expressed in a number of different tumor types. Its gene locus maps at 20q13, a chromosomal region frequently amplified in many cancers, including breast [Cancer Res. 1999, 59(9), 2041-4] and colon.
  • the insulin-like growth factor 1 receptor (IGF-1R, IGF1R) is a member of the insulin receptor subfamily of RTKs.
  • IGF-1R signaling can contribute to tumour genesis, and that interfering with IGF-1R function represents a valid therapeutic option in cancer.
  • Forced expression of the receptor leads to ligand-dependent transformed growth of murine and of rat fibroblasts (e.g. Kaleko M., Rutter W. J. and Miller A. D. Mol Cell Biol vol. 10, pages 464-73, 1990; Rubini M., Hongo A., D'Ambrosio C. and Baserga R. Exp Cell Res vol.
  • chemotherapeutic agents can be cytotoxic to normal tissues
  • the use of prodrugs is beneficial in terms of reduction of the side-effects.
  • PKs protein kinases
  • the prodrugs of this invention are useful in the treatment of a variety of cancers including, but not limited to: carcinoma such as bladder, breast, colon, kidney, liver, lung, including small cell lung cancer, esophagus, gall-bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma; hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma and Burkett's lymphoma; hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia; tumors of mesenchymal origin, including fibro
  • these prodrugs are also useful in the treatment of a variety of cell proliferative disorders such as, for instance, benign prostate hyperplasia, familial adenomatosis, polyposis, neuro-fibromatosis, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis and post-surgical stenosis and restenosis.
  • the present invention provides a compound of the formula (I):
  • R represents a straight or branched C 1 -C 12 alkyl, an aryl or heteroaryl group
  • R 1 represents a hydrogen atom or a substituent attached to any available atom of the A ring
  • R 2 represents an optionally substituted group selected from straight or branched C 1 -C 6 alkyl, aryl, heteroaryl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl or alkynyl, C 3 -C 6 cycloalkyl C 1 -C 6 alkyl, aryl C 1 -C 6 alkyl, heteroaryl C 1 -C 6 alkyl, a 5 or 6 membered heterocyclyl and heterocyclyl C 1 -C 6 alkyl with from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulphur
  • a ring represents a phenyl or a heterocycle and m is a value from 1 to 6, or a pharmaceutically acceptable salt thereof, for use as a
  • the present invention provide a compound of formula (I) as defined above for use as a prodrug. Even more preferably, the invention provides a compound of formula (I) as above defined for use as prodrug for treating cell proliferative disorders caused by and/or associated with an altered protein kinase activity, in particular cancer.
  • the invention further provides any therapeutic method of treatment using as prodrug a compound of the formula (I) as defined above.
  • the present invention also provides a method for treating cell proliferative disorders caused by and/or associated with an altered protein kinase activity, which comprises administering to a mammal in need thereof an effective amount of a compound of formula (I) as above defined.
  • the above method enables treatment of cell proliferative disorders caused by and/or associated with altered protein kinases, for example Aurora kinases or IGF-1R activity.
  • the cell proliferative disorder is cancer.
  • cancers that may be treated include carcinoma, squamous cell carcinoma, hematopoietic tumors of myeloid or lymphoid lineage, tumors of mesenchymal origin, tumors of the central and peripheral nervous system, melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoxanthoma, thyroid follicular cancer, and Kaposi's sarcoma.
  • the present invention also includes pharmaceutical compositions comprising a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable excipient, which may be a carrier or a diluent, and to a method for treating cell proliferative disorders caused by and/or associated with an altered protein kinase activity, which comprises administering to a mammal in need thereof an effective amount of a compound of formula (I) as above defined or a pharmaceutical composition as specified herein.
  • a pharmaceutically acceptable excipient which may be a carrier or a diluent
  • the compounds of formula (I) may have asymmetric carbons and may therefore exist either as racemic admixtures or as individual optical isomers.
  • the two isomers of formula (Ia) and (Ib) may be conveniently separated according to well-known methods, for instance under chromatographic conditions, and each isomer so isolated subsequently worked out.
  • the mixture of isomers can be treated as such in the subsequent steps of the process, without providing any separation.
  • C 1 -C 12 or C 1 -C 6 alkyl either as such or as aryl C 1 -C 6 alkyl or heteroaryl C 1 -C 6 alkyl
  • it is a C 1 -C 4 alkyl, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, sec-butyl.
  • aryl group we intend any aromatic carbocyclic ring system of 1 or 2 ring moieties, either fused or linked to each other through a single bond, for instance including phenyl, - or -naphthyl or biphenyl groups.
  • heteroaryl any aromatic heterocyclic ring which may comprise an optionally benzocondensed 5 or 6 membered heterocycle with from 1 to 3 heteroatoms selected among N, O or S.
  • Non limiting examples of heteroaryl groups according to the invention may thus include, for instance, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, imidazolyl, thiazolyl, isothiazolyl, pyrrolyl, phenyl-pyrrolyl, furyl, phenyl-furyl, oxazolyl, isoxazolyl, pyrazolyl, thienyl, benzothienyl, isoindolinyl, benzoimidazolyl, quinolinyl, isoquinolinyl, 1,2,3-triazolyl, 1-phenyl-1,2,3-triazolyl, and the like.
  • halogen atom we intend a fluorine, chlorine, bromine or iodine atom.
  • C 3 -C 6 cycloalkyl we intend any group such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • C 2 -C 6 alkenyl or C 2 -C 6 alkynyl group we intend any unsaturated straight or branched group such as, for instance, vinyl, allyl, 1-propenyl, isopropenyl, 1-, 2- or 3-butenyl, pentenyl, hexenyl, ethynyl, 1- or 2-propynyl, butynyl, pentynyl, hexynyl, and the like.
  • heterocyclyl or heterocyclic group we also intend an optionally benzocondensed 4 to 7 membered heterocycle, hence encompassing aromatic heterocyclic groups also known as heteroaryl groups, either saturated or partially unsaturated, with from 1 to 3 heteroatoms selected among N, O and S.
  • Examples of these 4 or 7 membered heterocyclic groups are, for instance, 1,3-dioxolane, pyran, pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazolidine, pyrazoline, piperidine, piperazine, morpholine, tetrahydrofuran, hexamethyleneimine, 1,4-hexahydrodiazepine, azetidine, and the like.
  • a ring in formula (I) above represents a phenyl or a heterocycle such as
  • n R 1 and m are as defined above.
  • R 1 represents a substituent attached to any available atom of the A ring, it is selected from: halogen, nitro, oxo groups ( ⁇ O), carboxy, cyano, alkyl, polyfluorinated alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl; aryl, heterocyclyl, alkyl-heterocyclyl, heterocyclyl-alkyl, amino groups and derivatives thereof such as, for instance, alkylamino, dialkylamino, arylamino, diarylamino, ureido, alkylureido or arylureido; carbonylamino groups and derivatives thereof such as, for instance, formylamino, alkylcarbonylamino, alkenylcarbonylamino, arylcarbonylamino, alkoxycarbonylamino; hydroxy groups and derivatives thereof such as, for instance, alkoxy, polyfluorinated al
  • the two or more substituents that R 1 represents may be the same, such as two methyl groups, or have different meanings, for example halogen atom and alkyl, on the same atom or on two or more different atoms of the A ring.
  • each of the above substituents may be further substituted by one or more of the aforementioned groups.
  • any of the groups in their definitions above may be optionally further substituted in any of their free positions by one or more groups, for instance 1 to 6 groups, such substituents being as defined above for R 1 .
  • pharmaceutically acceptable salts embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases.
  • the nature of the salt is not critical, provided that it is pharmaceutically acceptable.
  • Suitable pharmaceutically acceptable acid addition salts of the compounds of the present invention may be prepared from an inorganic or organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric, and phosphoric acid.
  • organic acids may be selected from aliphatic, cycloaliphatic, aromatic, arylaliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, trifluoroacetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, stearic, cyclohexylaminosulfonic, algenic, hydroxybutyric,
  • Suitable pharmaceutically acceptable base addition salts of the compounds of the present invention include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methyl-glucamine) and procaine. All of these salts may be prepared by conventional means from the corresponding compounds of the present invention, for instance by reacting them with the appropriate acid or base.
  • the present invention provides a compound of formula (I i ), (I ii ), (I iv ), (I iv ), (I v ), (I vi ), (I vii ) and
  • R is a group selected from
  • R 1 is a group selected from:
  • R 1 is a group selected from:
  • R 2 is a group selected from:
  • the present invention provides a compound of formula (I iv′ ):
  • R is as defined above, or a pharmaceutically acceptable salt thereof, for use as a medicament; more preferably as prodrug, even more preferably as anticancer produg.
  • the configuration of the asymmetric carbon atom is (R), and R is selected from methyl, ethyl, cyclopentyl, n-pentyl, t-butyl, 2-propynyl, allyl, benzyl, n-heptyl, neopentyl, n-butyl, iso-butyl, vinyl, 3-chloro-propyl, 3-fluoro-propyl, 2-methoxyethyl, 2-ethoxyethyl, iso-propyl, n-propyl, phenyl, n-hexyl, sec-butyl, isopropenyl or a group of formula:
  • the present invention provides a compound of formula (r) having (R) configuration and characterized in that R is a ethyl group for use as a medicament; more preferably as prodrug, even more preferably as anticancer produg.
  • the present invention provides the compound of the formula:
  • prodrug or a pharmaceutically acceptable salt thereof for use as a medicament, preferably as prodrug, even more preferably as prodrug for treating cell proliferative disorders caused by and/or associated with an altered protein kinase activity, in particular as prodrug for treating cancer.
  • the invention further provides any therapeutic method of treatment using as prodrug the compound coded A024 as defined above.
  • the present invention also includes pharmaceutical compositions comprising a compound coded A024 as defined above or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable excipient, which may be a carrier or a diluent, and to a method for treating cell proliferative disorders caused by and/or associated with an altered protein kinase activity, which comprises administering to a mammal in need thereof an effective amount of a compound coded A24 as defined above or a pharmaceutical composition as specified herein.
  • a pharmaceutically acceptable excipient which may be a carrier or a diluent
  • the compounds listed above “per se” are another object of the present invention as such their pharmaceutically acceptable salts, but for the compounds coded A02, A024 and C024, known as intermediates, that are object of the present invention for use as medicament as above described only.
  • A, R 1 , R 2 and m are as defined above, with any suitable agent for inserting the desired —C(O)OR group wherein R is as defined above on one of the pyrazole nitrogen atoms, such as a chloroformate derivative, followed by optional removal of the protecting group, if present; b) if necessary converting the resultant compound of formula (I):
  • A, R, R 1 , R 2 and m are as defined above, into another compound of formula (I) wherein one or more of R 1 , R 2 or m is different by known reactions; separating if necessary the obtained isomers of formula (Ia) and (Ib) as defined above according to well-known methods; converting a compound of formula (I) as defined above into a pharmaceutically acceptable salt or converting the salt thereof into the free compound of formula (I) as defined above.
  • the compounds of the formula (I) of present invention may also be obtained by means of well known method described in the patent literature cited above, wherein such compounds are described as useful intermediates.
  • step (a) of the process the fused-pyrazole derivative of formula (II) is reacted, according to well-known methods, with an agent for introducing the desired carbamoyl group (—COOR) on one of the pyrazole nitrogen atoms.
  • an agent for introducing the desired carbamoyl group (—COOR) on one of the pyrazole nitrogen atoms may occur with an alkyl chloroformate, also named chlorocarbonate, in a suitable solvent such as tetrahydrofuran, dichloromethane, chloroform, acetonitrile, toluene or mixtures thereof, at a temperature ranging from about ⁇ 5° C. to about 35° C. and for a time varying from about 30 minutes to about 72 hours, in the presence of an opportune proton scavenger such as triethylamine or diisopropylethylamine.
  • the compounds of formula (I) of the present invention can use as medicament, and in particular as prodrugs for releasing the active parent drug, according to formula (IA):
  • the released compounds of formula (IA) are active as protein kinase inhibitors, more particularly Aurora kinases inhibitors or IGF-R 1 inhibitors and are therefore useful, for instance, to restrict the unregulated proliferation of tumor cells.
  • the inhibiting activity and the potency of selected compounds is determined through a method of assay based on the use of the SPA technology (Amersham Pharmacia Biotech).
  • the assay consists of the transfer of radioactivity labelled phosphate moiety by the kinase to a biotinylated substrate.
  • the resulting 33P-labelled biotinylated product is allowed to bind to streptavidin-coated SPA beads (biotin capacity 130 pmol/mg), and light emitted was measured in a scintillation counter.
  • the buffers/components used in the assay were as follows.
  • Kinase Buffer (buffer KB) was composed of 50 mM HEPES, 3 mM MnCl2, 1 mM DTT, 3 microM Na3VO4, pH 7.9.
  • Enzyme Buffer (buffer EB) was composed of buffer KB containing 0.6 mg/ml BSA (bovine serum albumin).
  • SPA scintillation beads (Product Code Number RPNQ0007, Amersham Biosciences, Piscataway, N.J. USA) were prepared as a 10 mg/ml suspension in PBS containing 32 mM EDTA, 500 microM unlabeled ATP, and 0.1% Triton X-100.
  • This preparation is referred to below as “SPA bead suspension”.
  • IGF-1R was pre-phosphorylated in order to linearize reaction kinetics. To achieve this, the desired quantity of enzyme was incubated for 30 min at 28° C. at a concentration of 1050 nM enzyme in buffer EB containing 100 microM unlabeled ATP. After preincubation, and immediately before assay, this pre-phosphorylated IGF-1R kinase preparation was diluted to an enzyme concentration of 60 nM by addition of 16.5 volumes of buffer KB. This diluted prephosphorylated enzyme is referred to below as “enzyme mix”.
  • the substrate used in the assay was a carboxy-terminally biotinylated peptide of the following sequence: KKKSPGEYVNIEFGGGGGK-biotin.
  • the peptide was obtained in batches of >95% peptide purity from American Peptide Company, Inc. (Sunnyvale, Calif., USA).
  • “ATP Mix”, referred to below, consisted of buffer KB containing 6 nM 33Pg-ATP (gamma phosphate-labeled, RedivueTM Code Number AH9968, 1000-3000 Ci/mmole, Amersham Biosciences Piscataway, N.J. USA), 18 microM unlabeled ATP, and 30 microM biotinylated substrate peptide.
  • This solution contained these components at 3 ⁇ their final reaction concentrations.
  • Compounds to be tested were prepared in 100% DMSO at appropriate concentrations. These preparations were then diluted 33-fold using buffer KB, so as to obtain compound at 3 ⁇ the desired final assay concentration in buffer KB containing 3% DMSO. This 3 ⁇ preparation is referred to below as “compound working solution”.
  • a dilution curve of a known kinase inhibitor such as staurosporine can be routinely included as a positive control for IGF-1R inhibition.
  • results data were analysed using the “Assay Explorer” software package (Elsevier MDL, San Leandro, Calif. 94577). For single compound concentrations, inhibitory activity was typically expressed as expressed as % inhibition obtained in presence of compound, compared to total activity of enzyme obtained when inhibitor is omitted. Compounds showing desired inhibition can be further analysed in order to study the potency of the inhibitor through IC50 calculation. In this case, inhibition data obtained using serial dilutions of the inhibitor can be fitted by non-linear regression using the following equation:
  • MCF-7 cells (ATCC# HTB-22) were seeded in 12-well tissue culture plates at 2 ⁇ 10′′5 cells/well in E-MEM medium (MEM+ Earle's BSS+ 2 mM glutamine+0.1 mM non-essential amino acids)+10% FCS, and incubated overnight at 37° C., 5% CO2, 100% relative humidity. Cells were then starved by replacing E-MEM +10% FCS with E-MEM +0.1% BSA, and incubating overnight. After this incubation, wells were treated with desired concentrations of compound for 1 hour at 37° C., and were then stimulated with 10 nM recombinant human IGF-1 (Invitrogen, Carlsbad, Calif., USA) for 10 minutes at 37° C.
  • E-MEM medium MEM+ Earle's BSS+ 2 mM glutamine+0.1 mM non-essential amino acids
  • Filters bearing transferred protein were incubated for 1 hour in blocking buffer (TBS+5% BSA+0.15% Tween 20), and probed for 2 hours in the same buffer containing 1/1000 rabbit anti-phospho IGF-1R Tyr1131/InsR Tyr 1146 antibody (product #3021, Cell Signaling Technology, Beverly, Mass., USA) for the detection of phosphorylated IGF-1R, or 1/1000 dilution of rabbit IGF-1r ⁇ (H-60) antibody (product #sc-9038, Santa Cruz Biotechnology, Inc., Santa Cruz, Calif., USA) for detecting total IGF-1R ⁇ chain.
  • blocking buffer TBS+5% BSA+0.15% Tween 20
  • filters were then washed for 30 minutes with several changes of TBS+0.15% Tween 20, and incubated for 1 hour in washing buffer containing 1/5000 dilution of horseradish peroxidase conjugated anti-rabbit IgG (Amersham, product #NA934), then were washed again and developed using the ECL chemiluminescence system (Amersham) according to manufacturer's recommendations.
  • reagents used were from Sigma-Aldrich, St. Louis, Mo., USA.
  • NHDF normal human dermal fibroblasts
  • NHDF were seeded in 384-well tissue culture plates (clear- and flat-bottomed black plates; Matrix Technologies Inc., Hudson, N.H., USA) at a density of 5000 cells/well in serum-free medium containing 0.1% bovine serum albumin (BSA) and incubated for 5 days. Starved cells were treated for 1 hour with desired doses of compounds and then stimulated for a further 2 hours with either 10 nM IGF-1 (Invitrogen Corp., CA, USA), 10 nM EGF (Gibco BRL, USA) or 1 nM PDGF-B/B (Roche Diagnostics GmbH, Germany).
  • 10 nM IGF-1 Invitrogen Corp., CA, USA
  • 10 nM EGF Gabco BRL, USA
  • 1 nM PDGF-B/B Roche Diagnostics GmbH, Germany.
  • Fluorescence images in the DAPI and Cy5TM channels were automatically acquired, stored and analysed using a Cellomics ArrayScanTM IV instrument (Cellomics, Pittsburgh, USA); the Cellomics Cytotoxicity Algorithm was used to quantify cytoplasmic fluorescence associated with phospho-S6 (Cy5TM signal parameter: “Mean Lyso Mass-pH”) for each cell in 10 fields/well, and eventually expressed as a mean population value. Unless otherwise stated, reagents were obtained from Sigma-Aldrich, St. Louis, Mo., USA.
  • Biotinylated peptide 4 repeats of LRRWSLG
  • 10 ATP 0.5 uCi P 33 -ATP
  • 7.5 ng Aurora 2, inhibitor in a final volume of 30 l buffer (HEPES 50 mM pH 7.0, MgCl2 10 mM, 1 mM DTT, 0.2 mg/mL BSA, 3 M orthovanadate) were added to each well of a 96 U bottom well plate.
  • HEPS 50 mM pH 7.0, MgCl2 10 mM, 1 mM DTT, 0.2 mg/mL BSA, 3 M orthovanadate were added to each well of a 96 U bottom well plate. After 60 minutes at room temperature incubation, reaction was stopped and biotinylated peptide captured by adding 100 l of bead suspension.
  • IC50 determination inhibitors were tested at different concentrations ranging from 0.0015 to 10 M. Experimental data were analyzed by the computer program GraphPad Prizm using the four parameter logistic equation:
  • x is the logarithm of the inhibitor concentration
  • y is the response; y starts at bottom and goes to top with a sigmoid shape.
  • Kinetic parameter estimates were estimated by simultaneous nonlinear least-square regression using [Eq.1] (competitive inhibitor respect to ATP, random mechanism) using the complete data set (80 points):
  • the compounds of the invention were further tested, in vitro, to assess the anti-proliferative effect onto cell cultures.
  • the human colon cancer cell line HCT-116 was seeded at 5000 cells/cm 2 in 24 wells plate (Costar) using F12 medium (Gibco) supplemented with 10% FCS (EuroClone, Italy) 2 mM L-glutamine and 1% penicillin/streptomycin and maintained at 37° C., 5% CO2 and 96% relative humidity. The following day, plates were treated in duplicates with 5 ul of an appropriate dilution of compounds starting from a 10 mM stock in DMSO. Two untreated control wells were included in each plate.
  • IC 50 values were calculated by LSW/Data Analysis using Microsoft Excel sigmoidal curve fitting.
  • the compounds of formula (I) of the invention resulted to be very useful as medicament, preferably as prodrugs, even more preferably as prodrugs for the treatment of diseases due to the malfunctioning of protein kinases (PKs), such tumors.
  • PKs protein kinases
  • Oral bioavailability was calculated as percent ratio of average oral AUC value of parent compound after prodrug to average IV AUC value of parent compound after parent compound itself following parent compound dose normalization.
  • the tested compounds resulted to possess also a very remarkable cell antiproliferative effect.
  • the compounds of formula (I) of the invention appear to be endowed with a biological profile, considered as a whole, which is unexpectedly superior to that of the prior art and, hence, are particularly advantageous, in therapy, against proliferative disorders associated with an altered kinase activity, in particular altered Aurora-2 kinase activity.
  • the compounds of the present invention can be administered either as single agents or, alternatively, in combination with known anticancer treatments such as radiation therapy or chemotherapy regimen in combination with cytostatic or cytotoxic agents, antibiotic-type agents, alkylating agents, antimetabolite agents, hormonal agents, immunological agents, interferon-type agents, cyclooxygenase inhibitors (e.g. COX-2 inhibitors), matrixmetalloprotease inhibitors, telomerase inhibitors, tyrosine kinase inhibitors, anti-growth factor receptor agents, anti-HER agents, anti-EGFR agents, anti-angiogenesis agents (e.g.
  • cytostatic or cytotoxic agents antibiotic-type agents, alkylating agents, antimetabolite agents, hormonal agents, immunological agents, interferon-type agents, cyclooxygenase inhibitors (e.g. COX-2 inhibitors), matrixmetalloprotease inhibitors, telomerase inhibitors, tyrosine kinase inhibitors, anti-growth factor receptor agents, anti
  • angiogenesis inhibitors farnesyl transferase inhibitors, ras-raf signal transduction pathway inhibitors, cell cycle inhibitors, other cdks inhibitors, tubulin binding agents, topoisomerase I inhibitors, topoisomerase II inhibitors, and the like.
  • such combination products employ the compounds of this invention within the dosage range described below and the other pharmaceutically active agent within the approved dosage range.
  • the compounds of formula (I) of the present invention suitable for administration to a mammal, e.g., to humans, can be administered by the usual routes and the dosage level depends upon the age, weight, and conditions of the patient and administration route.
  • a suitable dosage adopted for oral administration of a compound of formula (I) may range from about 10 to about 500 mg per dose, from 1 to 5 times daily.
  • the compounds of the invention can be administered in a variety of dosage forms, e.g., orally, in the form tablets, capsules, sugar or film coated tablets, liquid solutions or suspensions; rectally in the form suppositories; parenterally, e.g., intramuscularly, or through intravenous and/or intrathecal and/or intraspinal injection or infusion.
  • the present invention also includes pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable excipient, which may be a carrier or a diluent.
  • a pharmaceutically acceptable excipient which may be a carrier or a diluent.
  • Another object is therefore the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above, in the manufacture of a medicament for treating a disease caused by and/or associated with a dysregulated protein kinase activity, in particular for treating a disease caused by and/or associated with a dysregulated IGF-1R or Aurora kinases activity, preferably with a dysregulated Aurora kinase activity.
  • a medicament for treating a disease caused by and/or associated with a dysregulated protein kinase activity, in particular for treating a disease caused by and/or associated with a dysregulated IGF-1R or Aurora kinases activity, preferably with a dysregulated Aurora kinase activity.
  • Such medicament also provides tumor angiogenesis and metastasis inhibition.
  • the treated disease is preferably selected from the group consisting of cancer, cell proliferative disorders, viral infections, retinopathies including diabetic and neonatal retinopathies and age related macular degeneration, atherosclerosis and conditions involving vascular smooth muscle proliferation or neointimal formation such as restenosis following angioplasty or surgery, graft vessel disease, such as can occur following vessel or organ transplantation, acromegaly and disorders secondary to acromegaly as well as other hypertrophic conditions in which IGF/IGF-1R signalling is implicated, such as benign prostatic hyperplasia, psoriasis, fibrotic lung disease, pulmonary fibrosis, pathologies related to chronic or acute oxidative stress or hyperoxia induced tissue damage, and metabolic disorders in which elevated IGF levels or IGF-1R activity are implicated, such as obesity.
  • Another object of the present invention is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above, in the manufacture of a medicament with antitumor activity.
  • the treated cancer is selected from the group consisting of carcinoma, squamous cell carcinoma, hematopoietic tumors of myeloid or lymphoid lineage, tumors of mesenchymal origin, tumors of the central and peripheral nervous system, melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratocanthomas, thyroid follicular cancer and Kaposi's sarcoma.
  • the treated cancer can be selected from the group consisting of breast cancer, lung cancer, colorectal cancer, prostate cancer, ovarian cancer, endometrial cancer, gastric cancer, clear cell renal cell carcinoma, uveal melanoma, multiple myeloma, rhabdomyosarcoma, Ewing's sarcoma, Kaposi′ sarcoma and medulloblastoma.
  • the treated cell proliferative disorder is selected from the group consisting of benign prostate hyperplasia, familial adenomatosis polyposis, neuro-fibromatosis, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis and post-surgical stenosis and restenosis.
  • compositions containing the compounds of the invention are usually prepared following conventional methods and are administered in a suitable pharmaceutical form.
  • the solid oral forms may contain, together with the active compound, diluents, e.g., lactose, dextrose saccharose, sucrose, cellulose, corn starch or potato starch; lubricants, e.g., silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents, e.g., starches, arabic gum, gelatine methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disintegrating agents, e.g., starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents such as lecithin, polysorbates, laurylsulphates; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations.
  • diluents e.g., lactose, dextrose saccharose, suc
  • liquid dispersions for oral administration may be, e.g., syrups, emulsions and suspensions.
  • the syrups may contain, as a carrier, saccharose or saccharose with glycerine and/or mannitol and sorbitol.
  • the suspensions and the emulsions may contain, as examples of carriers, natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.
  • the suspension or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g., sterile water, olive oil, ethyl oleate, glycols, e.g., propylene glycol and, if desired, a suitable amount of lidocaine hydrochloride.
  • a pharmaceutically acceptable carrier e.g., sterile water, olive oil, ethyl oleate, glycols, e.g., propylene glycol and, if desired, a suitable amount of lidocaine hydrochloride.
  • the solutions for intravenous injections or infusions may contain, as a carrier, sterile water or preferably they may be in the form of sterile, aqueous, isotonic, saline solutions or they may contain propylene glycol as a carrier.
  • the suppositories may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g., cocoa butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin.
  • a pharmaceutically acceptable carrier e.g., cocoa butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin.

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CN113072562A (zh) * 2021-04-06 2021-07-06 山东大学 一种GSK-3β抑制剂及其制备方法与应用
CN115073471A (zh) * 2021-03-11 2022-09-20 沈阳药科大学 吡唑并四氢吡咯类衍生物、其制备方法和在医药上的应用

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CA2835478C (en) * 2011-05-12 2019-02-05 Nerviano Medical Sciences S.R.L. Substituted indazole derivatives active as kinase inhibitors
WO2015110467A1 (en) * 2014-01-23 2015-07-30 Nerviano Medical Sciences S.R.L. Process for the preparation of substituted n-(5-benzenesulfonyl-1h-indazol-3-yl)-benzamides
JP6771464B2 (ja) 2014-11-27 2020-10-21 ジェネンテック， インコーポレイテッド Ｃｂｐおよび／またはｅｐ３００インヒビターとしての、４，５，６，７−テトラヒドロ−１ｈ−ピラゾロ［４，３−ｃ］ピリジン−３−アミン化合物
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CN113072562A (zh) * 2021-04-06 2021-07-06 山东大学 一种GSK-3β抑制剂及其制备方法与应用

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