US20030073692A1 - Amino-phthalazinone derivatives active as kinase inhibitors, process for their preparation and pharmaceutical compositions containing them - Google Patents

Amino-phthalazinone derivatives active as kinase inhibitors, process for their preparation and pharmaceutical compositions containing them Download PDF

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US20030073692A1
US20030073692A1 US09/922,729 US92272901A US2003073692A1 US 20030073692 A1 US20030073692 A1 US 20030073692A1 US 92272901 A US92272901 A US 92272901A US 2003073692 A1 US2003073692 A1 US 2003073692A1
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Prior art keywords
phthalazin
dihydro
oxo
benzyl
phenyl
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Maurizio Pulici
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Pfizer Italia SRL
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Pharmacia and Upjohn SpA
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Priority to US09/922,729 priority Critical patent/US20030073692A1/en
Assigned to PHARMACIA & UPJOHN S.P.A. reassignment PHARMACIA & UPJOHN S.P.A. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: PULICI, MAURIZIO
Assigned to PHARMACIA ITALIA S.P.A. reassignment PHARMACIA ITALIA S.P.A. MERGER (SEE DOCUMENT FOR DETAILS). Assignors: PHARMACIA & UPJOHN S.P.A.
Priority to JP2003519040A priority patent/JP2005501085A/ja
Priority to EA200400283A priority patent/EA006645B1/ru
Priority to PCT/EP2002/008544 priority patent/WO2003014090A1/fr
Priority to AT02758416T priority patent/ATE407928T1/de
Priority to IL15984302A priority patent/IL159843A0/xx
Priority to DK02758416T priority patent/DK1427708T3/da
Priority to CA002455759A priority patent/CA2455759A1/fr
Priority to SI200230738T priority patent/SI1427708T1/sl
Priority to NZ531310A priority patent/NZ531310A/en
Priority to MXPA04000905A priority patent/MXPA04000905A/es
Priority to US10/486,463 priority patent/US7432263B2/en
Priority to CNA2007101101264A priority patent/CN101085759A/zh
Priority to ES02758416T priority patent/ES2315385T3/es
Priority to CNA028154193A priority patent/CN1538960A/zh
Priority to CZ2004305A priority patent/CZ2004305A3/cs
Priority to BR0211807-6A priority patent/BR0211807A/pt
Priority to DE60228857T priority patent/DE60228857D1/de
Priority to EP02758416A priority patent/EP1427708B1/fr
Priority to PT02758416T priority patent/PT1427708E/pt
Priority to KR10-2004-7001814A priority patent/KR20040029400A/ko
Priority to PL02368440A priority patent/PL368440A1/xx
Publication of US20030073692A1 publication Critical patent/US20030073692A1/en
Priority to NO20040547A priority patent/NO20040547L/no
Priority to ZA200401316A priority patent/ZA200401316B/en
Priority to CO04019499A priority patent/CO5560573A2/es
Abandoned legal-status Critical Current

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Definitions

  • the present invention relates to amino-phthalazinone derivatives active as kinase inhibitors and, more in particular, it relates to 7-amino-phthalazin-1-one derivatives, to a process for their preparation, to pharmaceutical compositions comprising them and to their use as therapeutic agents, particularly in the treatment of diseases linked to disregulated protein kinases.
  • PKs protein kinases
  • 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.
  • PKs malfunctioning or disregulation see, for instance, Current Opinion in Chemical Biology 1999, 3, 459-465. It is an object of the invention to provide compounds which are useful in therapy as agents against a host of diseases caused by and/or associated to a disregulated protein kinase activity. It is another object to provide compounds which are endowed with multiple protein kinase inhibiting activity.
  • amino-phthalazinone derivatives 7-amino-phthalazin-1-one derivatives, hereinafter shortly referred to as amino-phthalazinone derivatives or amino-phthalazinones, are endowed with multiple protein kinase inhibiting activity and are thus useful in therapy in the treatment of diseases associated with disregulated protein kinases.
  • the amino-phthalazinones 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 lymphocitic 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
  • these amino-phthalazinones 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 compounds of the invention can be useful in the treatment of Alzheimer's disease, as suggested by the fact that cdk5 is involved in the phosphorylation of tau protein ( J. Biochem., 117, 741-749, 1995).
  • the compounds of this invention may also be useful in the treatment of cancer, viral infections, prevention of AIDS development in HIV-infected individuals, autoimmune diseases and neurodegenerative disorders.
  • the compounds of this invention may be useful in inhibiting tumor angiogenesis and metastasis.
  • the compounds of the invention are useful as cyclin dependent kinase (cdk) inhibitors and also as inhibitors of other protein kinases such as, for instance, protein kinase C in different isoforms, Met, PAK-4, PAK-5, ZC-1, STLK-2, DDR-2, Aurora 1, Aurora 2, Bub-1, PLK, Chk1, Chk2, HER2, raf1, MEK1, MAPK, EGF-R, PDGF-R, FGF-R, IGF-R, VEGF-R, PI3K, weel kinase, Src, Abl, Akt, ILK, MK-2, IKK-2, Cdc7, Nek, and thus be effective in the treatment of diseases associated with other protein kinases.
  • cdk cyclin dependent kinase
  • amino-phthalazinone and amino-phthalazinedione derivatives are known in the art, as chemical intermediates, as therapeutic agents and even as protein kinase inhibitors.
  • the compounds N-[3-[2,4-bis(1,1-dimethylpropyl)phenoxy]propyl]-N′-(3,4-dihydro-4-oxo-6-phthalazinyl)-urea and 2-[2,4-bis(1,1-dimethylpropyl)phenoxy]-N-(3,4-dihydro-4-oxo-6-phthalazinyl)-butanamide are disclosed as heat development image forming agents, in JP-A-09061961 by Heisei.
  • N-[3,4-dihydro-4-oxo-1-(4-pyridinylmethyl)-6-phthalazinyl]-acetamide and N-[3,4-dihydro-4-oxo-1-(4-pyridinylmethyl)-6-phthalazinyl]-2,2,2-trifluoro-acetamide are disclosed in WO 98/35958 by Novartis, as synthetic intermediates for the preparation of anilino-phthalazines, as VEGF receptor tyrosine kinase inhibitors.
  • phthalazinedione or phthalazinone derivatives bearing substituted amino groups in both positions 6 and 7 of the ring such as, for instance, 7-(cyclohexylamino)-6-phenylamino-1(2H)-phthalazinone and 6,7-bis(phenylamino)-1(2H)-phthalazinone, are disclosed in EP-A-600831 by Ciba-Geigy as protein kinase inhibitors.
  • the present invention provides a method for treating diseases caused by and/or associated with an altered protein kinase activity, by administering to a mammal in need thereof an effective amount of an amino-phthalazinone derivative represented by formula (I):
  • Ra and Rb are, each independently, a hydrogen atom or a group, optionally further substituted, selected from straight or branched C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or cycloalkyl C 1 -C 6 alkyl, aryl, aryl C 1 -C 6 alkyl, 5 to 7 membered heterocyclyl or heterocyclyl C 1 -C 6 alkyl with from 1 to 3 heteroatoms selected among nitrogen, oxygen or sulfur; or one of Ra or Rb is hydrogen or an optionally substituted straight or branched C 1 -C 6 alkyl group, and the other is a group selected from —COR′, —CONHR′, —COOR′ or —SO 2 R′, wherein R′ is hydrogen or an optionally substituted group selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalky
  • R 1 is a group of formula —CHR 4 R 5 wherein R 4 and R 5 are, each independently, hydrogen or an optionally substituted group selected from straight or branched C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or cycloalkyl C 1 -C 6 alkyl, aryl, aryl C 1 -C 6 alkyl, 5 to 7 membered heterocyclyl or heterocyclyl C 1 -C 6 alkyl with from 1 to 3 heteroatoms selected among nitrogen, oxygen or sulfur; or R 1 is a group of formula —NHR′, —NR′COR′′, —NR′CONHR′′ or —NR′SO 2 R′′, wherein R′ has the above reported meanings other than hydrogen, and R′′ is hydrogen or has the meanings set forth above for R′;
  • R 2 is a hydrogen atom or it is a group, optionally further substituted, selected from straight or branched C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or cycloalkyl C 1 -C 6 alkyl, aryl, aryl C 1 -C 6 alkyl, 5 to 7 membered heterocyclyl or heterocyclyl C 1 -C 6 alkyl with from 1 to 3 heteroatoms selected among nitrogen, oxygen or sulfur;
  • any R 3 being placed in one or more of the free positions 5, 6 and 8 of the phthalazinone ring are, independently from each other, halogen, nitro, carboxy, cyano or a group optionally further substituted selected from straight or branched C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or cycloalkyl C 1 -C 6 alkyl, aryl, aryl C 1 -C 6 alkyl, 5 to 7 membered heterocyclyl or heterocyclyl C 1 -C 6 alkyl with from 1 to 3 heteroatoms selected among nitrogen, oxygen or sulfur; or R 3 is a group selected from —COR′, —CONHR′, —SO 2 R′, —NR′R′′, —NR′COR′′, —NR′CONHR′ or —NR′SO 2 R′′, wherein R′ and R′′ are, the same or different, hydrogen or a group as set forth above;
  • m is 0 or an integer from 1 to 3;
  • the disease caused by and/or associated with an altered protein kinase activity is selected from the group consisting of cancer, cell proliferative disorders, Alzheimer's disease, viral infections, auto-immune diseases and neurodegenerative disorders.
  • Specific types of cancer 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, keratocanthoma, thyroid follicular cancer and Kaposi's sarcoma.
  • the 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.
  • the method object of the present invention also provides tumor angiogenesis and metastasis inhibition.
  • the present invention further provides an amino-phthalazinone derivative represented by formula (I)
  • Ra and Rb are, each independently, a hydrogen atom or a group, optionally further substituted, selected from straight or branched C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or cycloalkyl C 1 -C 6 alkyl, aryl, aryl C 1 -C 6 alkyl, 5 to 7 membered heterocyclyl or heterocyclyl C 1 -C 6 alkyl with from 1 to 3 heteroatoms selected among nitrogen, oxygen or sulfur; or one of Ra or Rb is hydrogen or an optionally substituted straight or branched C 1 -C 6 alkyl group, and the other is a group selected from —COR′, —CONHR′, —COOR′ or —SO 2 R′, wherein R′ is hydrogen or an optionally substituted group selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalky
  • R 1 is a group of formula —CHR 4 R 5 wherein R 4 and R 5 are, each independently, hydrogen or an optionally substituted group selected from straight or branched C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or cycloalkyl C 1 -C 6 alkyl, aryl, aryl C 1 -C 6 alkyl, 5 to 7 membered heterocyclyl or heterocyclyl C 1 -C 6 alkyl with from 1 to 3 heteroatoms selected among nitrogen, oxygen or sulfur; or R 1 is a group of formula —NHR′, —NR′COR′′, —NR′CONHR′′ or —NR′SO 2 R′′, wherein R′ has the above reported meanings other than hydrogen, and R′′ is hydrogen or has the meanings set forth above for R′;
  • R 2 is a hydrogen atom or it is a group, optionally further substituted, selected from straight or branched C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or cycloalkyl C 1 -C 6 alkyl, aryl, aryl C 1 -C 6 alkyl, 5 to 7 membered heterocyclyl or heterocyclyl C 1 -C 6 alkyl with from 1 to 3 heteroatoms selected among nitrogen, oxygen or sulfur;
  • any R 3 being placed in one or more of the free positions 5, 6 and 8 of the phthalazinone ring are, independently from each other, halogen, nitro, carboxy, cyano or a group optionally further substituted selected from straight or branched C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or cycloalkyl C 1 -C 6 alkyl, aryl, aryl C 1 -C 6 alkyl, 5 to 7 membered heterocyclyl or heterocyclyl C 1 -C 6 alkyl with from 1 to 3 heteroatoms selected among nitrogen, oxygen or sulfur; or R 3 is a group selected from —COR′, —CONHR′, —SO 2 R′, —NR′R′′, —NR′COR′′, —NR′CONHR′ or —NR′SO 2 R′′, wherein R′ and R′′ are, the same or different, hydrogen or a group as set forth above;
  • m is 0 or an integer from 1 to 3;
  • the compounds of formula (I), object of the present invention may have asymmetric carbon atoms and may therefore exist either as racemic admixtures or as individual optical isomers. Accordingly, all the possible isomers and their admixtures and of both the metabolites and the pharmaceutically acceptable bio-precursors (otherwise referred to as pro-drugs) of the compounds of formula (I), as well as any therapeutic method of treatment comprising them, are also within the scope of the present invention.
  • halogen atom we intend a chlorine, bromine, fluorine or iodine atom.
  • straight or branched C 1 -C 6 alkyl we intend a group such as, for instance, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and the like.
  • C 3 -C 6 cycloalkyl we intend a group such as, for instance, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • aryl we intend a mono-, bi- or poly- either carbocyclic as well as heterocyclic hydrocarbon with from 1 to 4 ring moieties, either fused or linked to each other by single bonds, wherein at least one of the carbocyclic or heterocyclic rings is aromatic.
  • Non limiting examples of aryl groups are, for instance, phenyl, indanyl, biphenyl, ⁇ - or ⁇ -naphthyl, fluorenyl, 9,10-dihydroanthracenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, imidazolyl, imidazopyridyl, 1,2-methylenedioxyphenyl, thiazolyl, isothiazolyl, pyrrolyl, pyrrolyl-phenyl, furyl, phenyl-furyl, benzotetrahydrofuranyl, oxazolyl, isoxazolyl, pyrazolyl, chromenyl, thienyl, benzothienyl, isoindolinyl, benzoimidazolyl, isoindolinyl-phenyl, quinolinyl, isoquinolin
  • heterocyclyl hence encompassing aromatic heterocyclyc groups also referred to as aryl groups, we further intend a saturated or partially unsaturated 5 to 7 membered carbocycle wherein one or more carbon atoms are replaced by 1 to 3 heteroatoms such as nitrogen, oxygen and sulfur.
  • heteroaryl groups additional examples of 5 to 7 membered heterocyclyl groups, optionally benzocondensed or further substituted, are 1,3-dioxolane, pyran, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazoline, piperidine, piperazine, morpholine, tetrahydrofuran, azepine, diazepine and the like.
  • any of the above groups may be further optionally substituted in any of the free positions by one or more groups, for instance 1 to 6 groups, selected from: halogen, nitro, oxo groups ( ⁇ O), carboxy, cyano, alkyl, perfluorinated alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, 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
  • each of the above substituents may be further substituted by one or more of the aforementioned groups.
  • perfluorinated alkyl we intend a straight or branched C 1 -C 6 alkyl group as above defined, wherein more than one hydrogen atom are replaced by fluorine atoms.
  • perfluorinated alkyl groups are, for instance, trifluoromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 1,1,1,3,3,3-hexafluoropropyl-2-yl and the like.
  • alkenyl or alkynyl we intend a straight or branched C 2 -C 6 alkenyl or alkynyl group such as, for instance, vinyl, allyl, isopropenyl, 1-, 2- or 3-butenyl, isobutylenyl, hexenyl, ethynyl, 1- or 2-propynyl, butynyl and the like.
  • any group which name has been identified as a composite name such as, for instance, cycloalkylalkyl, arylalkyl, heterocyclylalkyl, alkoxy, alkylthio, aryloxy, arylalkoxy, heterocyclyloxy, heterocyclylalkoxy, alkylcarbonyloxy and the like, have to be intended as conventionally construed from the parts to which derive.
  • heterocyclyl-alkoxy stands for an alkoxy (e.g. alkyl-oxy) group further substituted by a heterocyclyl group.
  • salts of the compounds of formula (I) are the acid addition salts with inorganic or organic, e.g. nitric, hydrochloric, hydrobromic, sulfuric, perchloric, phosphoric, acetic, trifluoroacetic, propionic, glycolic, lactic, oxalic, malonic, malic, maleic, tartaric, citric, benzoic, cinnamic, mandelic, methanesulfonic, isethionic and salicylic acid, as well as the salts with inorganic or organic bases, e.g.
  • alkali or alkaline-earth metals especially sodium, potassium, calcium or magnesium hydroxides, carbonates or bicarbonates, acyclic or cyclic amines, preferably methylamine, ethylamine, diethylamine, triethylamine or piperidine.
  • a first class of preferred compounds of the invention is represented by the compounds of formula (I) wherein one of Ra or Rb is a hydrogen atom or an optionally substituted straight or branched C 1 -C 6 alkyl group and the other is a group —COR′ wherein R′ is an optionally substituted group selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl, as set forth above, and R 1 , R 2 , R 3 and m are as above defined. More preferred, within this class, are the compounds of formula (I) wherein R 1 is a group —CHR 4 R 5 wherein R 4 and R 5 are as above defined, R 2 is hydrogen and m is 0.
  • Another class of preferred compounds of the invention is represented by the compounds of formula (I) wherein one of Ra or Rb is a hydrogen atom or an optionally substituted straight or branched C 1 -C 6 alkyl group and the other is a group —CONHR′ wherein R′ is a hydrogen atom or an optionally substituted group selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl, as set forth above, and R 1 , R 2 , R 3 and m are as above defined. More preferred, within this class, are the compounds of formula (I) wherein R 1 is a group —CHR 4 R 5 wherein R 4 and R 5 are as above defined, R 2 is hydrogen and m is 0.
  • Another class of preferred compounds of the invention is represented by the compounds of formula (I) wherein one of Ra or Rb is a hydrogen atom or an optionally substituted straight or branched C 1 -C 6 alkyl group and the other is a group —COOR′ wherein R′ is a hydrogen atom or an optionally substituted group selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl, as set forth above, and R 1 , R 2 , R 3 and m are as above defined. More preferred, within this class, are the compounds of formula (I) wherein R 1 is a group —CHR 4 R 5 wherein R 4 and R 5 are as above defined, R 2 is hydrogen and m is 0.
  • Another class of preferred compounds of the invention is represented by the compounds of formula (I) wherein one of Ra or Rb is a hydrogen atom or an optionally substituted straight or branched C 1 -C 6 alkyl group and the other is a group —SO 2 R′ wherein R′ is an optionally substituted group selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl, as set forth above, and R 1 , R 2 , R 3 and m are as above defined. More preferred, within this class, are the compounds of formula (I) wherein R 1 is a group —CHR 4 R 5 wherein R 4 and R 5 are as above defined, R 2 is hydrogen and m is 0.
  • Another class of preferred compounds of the invention is represented by the compounds of formula (I) wherein Ra and Rb are both hydrogen atoms and R 1 , R 2 , R 3 and m are as above defined. More preferred, within this class, are the compounds of formula (I) wherein R 1 is a group —CHR 4 R 5 wherein R 4 and R 5 are as above defined, R 2 is hydrogen and m is 0.
  • Another class of preferred compounds of the invention is represented by the compounds of formula (I) wherein one of Ra or Rb is a hydrogen atom or an optionally substituted straight or branched C 1 -C 6 alkyl and the other is a group, optionally further substituted, selected from alkyl, cycloalkylalkyl, arylalkyl or heterocyclylalkyl as set forth above, and R 1 , R 2 , R 3 and m are as above defined. More preferred, within this class, are the compounds of formula (I) wherein R 1 is a group —CHR 4 R 5 wherein R 4 and R 5 are as above defined, R 2 is hydrogen and m is 0.
  • Furan-2-carboxylic acid [1-(4-chloro-3-fluoro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-amide;
  • the process for preparing the amino-phthalazinone derivatives of formula (I) represents a further object of the present invention.
  • the compounds of formula (I) and the pharmaceutically acceptable salts thereof, may be thus obtained by a process comprising:
  • R 3 and m have the above reported meanings and Hal represents a halogen atom, with a suitable phosphine derivative (PL 3 ), under optional reductive conditions, so as to obtain a compound of formula (III)
  • P is a phosphorous atom and L are the phosphine ligands
  • A is a group ⁇ CR 4 R 5 or ⁇ NR′, respectively; and optionally reacting the compound of formula (VII) according to any one of the alternative steps d.1) or d.2) below
  • Rb is —COR′, —CONHR′, —COOR′ or —SO 2 R′, respectively;
  • Z is a halogen atom and Rb is alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl as above defined, so as to obtain the corresponding compound of the above formula (XII);
  • Rb, R 2 , R 3 , m and the Resin are as above defined and R 1 is a group of formula —CHR 4 R 5 or —NHR′ wherein R 4 , R 5 and R′ are as above defined;
  • a compound of formula (II) wherein Hal represents a halogen atom, preferably bromine is reacted with a suitable phosphine derivative PL 3 such as, for instance, triphenylphosphine, tri-n-butylphoshine, tri-t-butylphosphine or 1,4-bis(diphenylphosphino)butane.
  • a suitable phosphine derivative PL 3 such as, for instance, triphenylphosphine, tri-n-butylphoshine, tri-t-butylphosphine or 1,4-bis(diphenylphosphino)butane.
  • the phosphine derivative is triphenylphosphine PPh 3 .
  • the reaction may be carried out in a variety of solvents for instance comprising ethyl acetate, ethyl propionate and the like, dimethylformammide, dimethylacetammide and the like, dichloromethane chloroform and the like, acetone, or acetonitrile; preferred is the use of ethyl propionate.
  • the temperature may vary from about 20° C. to about 100° C.
  • the reaction may be performed by adding the phosphine to a solution of the compound of formula (II) or by adding a solution of (II) to the phosphine.
  • the compound of formula (II) is directly converted into the corresponding derivative of formula (III) bearing the amino group in place of the original nitro group.
  • the compound of formula (II) may be first converted into an intermediate derivative of formula (IIa)
  • R 3 , m, P and L are as above defined, which has to be properly reduced to the compound of formula (III).
  • the reductive conditions to be employed are those conventionally used for reducing aromatic nitro derivatives to amino derivatives and comprise, for instance, the use of chemical reducing agents such as, for instance, tin dichloride, iron and acetic acid, zinc and hydrochloric acid, or titanium trichloride.
  • the reductive step may occur under catalytic hydrogenation conditions in the presence of suitable catalysts, typically platinum, palladium or palladium on charcoal.
  • the compound of formula (II) is conveniently converted into the compound of formula (III) by using triphenylphosphine.
  • step b) of the process the compound of formula (III) is reacted, in the presence of a reducing agent such as, for instance, a pyridine-borane complex, sodium cyanoboron hydride, sodium triacetoxy boron hydride, dimethylsufide borane and the like, with a suitable aldehydic RCHO resin, for instance a polystirene or polyethyleneglycol resin.
  • a suitable aldehydic RCHO resin for instance a polystirene or polyethyleneglycol resin.
  • the resin is a 4-(4-formyl-3-methoxyphenoxy)butyryl aminomethylated resin or 4-(4-formyl-3-methoxyphenoxy)butyryl (NOVAGELTM).
  • the reaction is carried out in the presence of a suitable solvent, preferably dichloromethane, 2,2,2-trifluoroethanol and acetic acid, by adding an excess of the reducing agent, optionally dissolved into the same solvent, directly to the mixture of resin and of the compound of formula (III), and by stirring at a temperature ranging from about 0° C. to about 40° C. for a suitable time.
  • a suitable solvent preferably dichloromethane, 2,2,2-trifluoroethanol and acetic acid
  • step c) of the process the compound of formula (IV) is then reacted with a compound of formula (V) or, alternatively, of formula (VI), so as to obtain the corresponding derivative of formula (VII).
  • the reaction is carried out in the presence of a suitable base, for instance triethylamine, diisopropylethylamine, piperidine, sodium carbonate, cesium carbonate, potassium t-butoxide, sodium methoxide, diazabicycloundecene, potassium hydroxide and the like, optionally in the presence of a suitable phase-transfer catalyst.
  • a suitable base for instance triethylamine, diisopropylethylamine, piperidine, sodium carbonate, cesium carbonate, potassium t-butoxide, sodium methoxide, diazabicycloundecene, potassium hydroxide and the like, optionally in the presence of a suitable phase-transfer catalyst.
  • the compound of formula (V) or, alternatively, of formula (VI), is added to a suspension of the compound of formula (IV) in a suitable solvent such as dichloromethane, dimethyl formammide, tetrahydrofuran or the like.
  • a suitable solvent such as dichloromethane, dimethyl formammide, tetrahydrofuran or the like.
  • the temperature is then brought to a suitable value, for instance from about ⁇ 70° C. to about 40° C. according to the electrophile (V) or (VI), and the base is added. Stirring is carried on for a suitable time, for instance from about 2 to about 15 hours.
  • step d.1) of the process in particular, the compound of formula (VII) is reacted with a carboxylic acid derivative of formula (VIII), with an isocyanate of formula (IX), with a chloroformate derivative of formula (X) or with a sulphonyl derivative of formula (XI), so as to obtain the corresponding compound of formula (XII) wherein Rb is a group of formula —COR′, —CONHR′, —COOR′ or —SO 2 R′, respectively.
  • Z is preferably a halogen atom and, even more preferably, a chlorine atom.
  • the compound of formula (VII) is suspended into a suitable solvent such as dichloromethane, dimethylformammide, tetrahydrofurane, dioxane or the like, and a suitable base is then added, for instance triethylamine, diisopropylethylamine, sodium carbonate or the like.
  • the electrophile of general formula (VIII), (X), or (XI) is then added and the mixture stirred for about 2 to about 15 hours, at a temperature ranging from about 20° C. to about 80° C.
  • an isocyanate of general formula (IX) the reaction conditions are the same as above reported except that the base may not be required. In the latter case a catalyst such as dimethylamino pyridine may be optionally used.
  • the compound of formula (VII) may be reacted with a derivative of formula (XIII) wherein Z is halogen, for instance bromine, and Rb is an arylalkyl group such as, for instance, the benzyl group, by working according to conventional methods.
  • step e) of the process the compound of formula (VII) obtained from step c) or, alternatively, the compound of formula (XII) obtained from any one of steps d.1) or d.2), is reacted with hydrazine or a hydrazine derivative of formula (XIV) so as to obtain the corresponding compounds of formula (XV) or (XVI).
  • the compound of formula (XII) is suspended in a suitable solvent, preferably dimethylformammide, in the presence of hydrazine hydrate or another hydrazine of general formula (XIV) and stirred at a suitable temperature, for instance at 20° C., for about 2 to about 20 hours.
  • step f) of the process the compounds of formula (XV) or (XVI) are reacted under acidic conditions, preferably in the presence of trifluoroacetic acid, so as to yield the desired compound of formula (I).
  • Compounds of formula (XV) or (XVI) may be thus suspended in a solution of 5-95% trifluoroacetic acid in dichloromethane and the mixture stirred at a temperture ranging from about 20° C. to refluxing temperature, for a time varying from about 5 minutes to about 3 hours.
  • the compounds of formula (I) wherein both Ra and Rb are other than hydrogen atoms may be prepared according to well-known methods by reacting any compound of formula (I) having one of Ra or Rb as a hydrogen atom, into another compound of formula (I) having this same hydrogen atom being replaced by a suitable group.
  • optional functional groups within both the starting materials or the intermediates thereof, which could give rise to unwanted side reactions, need to be properly protected according to conventional techniques.
  • the conversion of these latter into the free deprotected compounds may be carried out according to known procedures.
  • the compounds of formula (II) are known or easily prepared according to known methods [see, for a reference, J. Org. Chem. (1985), 50, 4120-4125; J. Chem. Soc. (1961), 5275-5284].
  • the compounds of formula (II) wherein Hal represents a bromine atom may be prepared as reported in the working examples, that is by reacting commercially available 6-nitro-phthalide under brominating conditions, for instance with bromine in the presence of aqueous hydrogen peroxide, in a suitable solvent such as dichloromethane, dichloromethane/water or hexane/water admixtures, at a temperature varying from about 20° C. to reflux.
  • the compounds of formula (V), (VI), (VIII), (IX), (X), (XI), (XIII) and (XIV) are known or easily prepared according to well-known methods.
  • the aldehydic resin R—CHO, the phosphine derivative PL 3 and any other suitable reagent of the process are known compounds which are commercially available or easily prepared according to known methods.
  • 2-butyl-4-formylimidazole 25 5-benzyloxy-1h-pyrrolo[2,3-c]pyridine-3- carboxaldehyde 26. 6-methyl-2-pyridinecarboxaldehyde 27. 4-[4-(tert-butyl)thiazol-2-yl]benzaldehyde 28. 5-formyl-2,4-dimethoxy-pyrimidine 29. 2-[(4-chlorobenzyl)thio]pyrimidine-4- carbaldehyde 30. 3-fluoro-2-hydroxybenzaldehyde 31. 3-hydroxybenzaldehyde 32. 3-carboxybenzaldehyde 33. 4-vinylbenzaldehyde 34.
  • 4-(trifluoromethyl)benzoyl chloride 30 4-tert-butylbenzoyl chloride 31. p-toluoyl chloride 32. 4-ethylbenzoyl chloride 33. 4-n-propylbenzoyl chloride 34. 4-n-butylbenzoyl chloride 35. pivaloyl chloride 36. isobutyryl chloride 37. 2-ethylhexanoyl chloride 38. acetyl chloride 39. phenoxyacetyl chloride 40. 4-chlorophenoxyacetyl chloride 41. methoxyacetyl chloride 42. phenylacetyl chloride 43. tert-butylacetyl chloride 44.
  • thiophene-2-acetyl chloride 61 (3,4-dimethoxyphenyl)acetyl chloride 62. 3,5-dichlorobenzoyl chloride 63. 2,5-difluorobenzoyl chloride 64. 3,4-difluorobenzoyl chloride 65. 9-fluorenone-4-carbonyl chloride 66. 3,5-difluorobenzoyl chloride 67. benzyloxyacetyl chloride 68. 3-cyanobenzoyl chloride 69. (2,5-dimethoxyphenyl)acetyl chloride 70. 3-methoxyphenylacetyl chloride 71. nicotinoyl chloride hydrochloride 72.
  • 3-(methylthio)phenyl isocyanate 53 3-acetylphenyl isocyanate 54. 3,4-dimethylphenyl isocyanate 55. 3,5-dimethylphenyl isocyanate 56. 2-methoxy-5-methylphenyl isocyanate 57. 3-ethylphenyl isocyanate 58.
  • 4-ethoxyphenyl isocyanate 64 4-acetylphenyl isocyanate 65. 4-isopropylphenyl isocyanate 66. 4-ethylphenyl isocyanate 67. 4-n-butylphenyl isocyanate 68. 2,4,6-trimethylphenyl isocyanate 69. 2-isopropyl-6-methylphenyl isocyanate 70. 2,6-diethylphenyl isocyanate 71. 5-chloro-2-methylphenyl isocyanate 72. 4-chloro-2-methylphenyl isocyanate 73. 4-(trifluoromethoxy)phenyl isocyanate 74.
  • 2-chloro-5-(trifluoromethyl)phenyl isocyanate 75 2-chloro-6-methylphenyl isocyanate 76. 2,4,5-trimethylphenyl isocyanate 77. 3-chloro-2-methoxyphenyl isocyanate 78. 3-chloro-2-methylphenyl isocyanate 79. 3-chloro-4-fluorophenyl isocyanate 80. 4-bromo-2-methylphenyl isocyanate 81. 4-bromo-2,6-dimethylphenyl isocyanate 82. 2,6-dibromo-4-fluorophenyl isocyanate 83. 4-butoxyphenyl isocyanate 84.
  • 3-fluoro-4-methylphenyl isocyanate 85 5-fluoro-2-methylphenyl isocyanate 86.
  • 2-(trifluoromethoxy)phenyl isocyanate 94 4-benzyloxyphenyl isocyanate 95. 4-bromo-2-chlorophenyl isocyanate 96. 4-bromo-2-fluorophenyl isocyanate 97. 2-fluoro-5-methylphenyl isocyanate 98. 2,3,4-trifluorophenyl isocyanate 99. 2-(difluoromethoxy)phenyl isocyanate 100. 4-(difluoromethoxy)phenyl isocyanate 101. 2-methylbenzyl isocyanate 102. 2-chlorobenzyl isocyanate 103. 4-fluorobenzyl isocyanate 104.
  • 4-methoxybenzyl isocyanate 105 2,6-difluorobenzoyl isocyanate 106. 4-fluorobenzoyl isocyanate 107. 2-fluoro-3-(trifluoromethyl)phenyl isocyanate 108. 2-fluoro-5-(trifluoromethyl)phenyl isocyanate 109. 2-fluoro-6-(trifluoromethyl)phenyl isocyanate 110. 4-fluoro-2-(trifluoromethyl)phenyl isocyanate 111. 2-(tert-butyl)phenyl isocyanate 112. 3-pyridyl isocyanate
  • Ra and Rb are, each independently, a hydrogen atom or a group, optionally further substituted, selected from straight or branched C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or cycloalkyl C 1 -C 6 alkyl, aryl, aryl C 1 -C 6 alkyl, 5 to 7 membered heterocyclyl or heterocyclyl C 1 -C 6 alkyl with from 1 to 3 heteroatoms selected among nitrogen, oxygen or sulfur; or one of Ra or Rb is hydrogen or an optionally substituted straight or branched C 1 -C 6 alkyl group, and the other is a group selected from —COR′, —CONHR′, —COOR′ or —SO 2 R′, wherein R′ is hydrogen or an optionally substituted group selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalky
  • R 1 is a group of formula —CHR 4 R 5 wherein R 4 and R 5 are, each independently, hydrogen or an optionally substituted group selected from straight or branched C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or cycloalkyl C 1 -C 6 alkyl, aryl, aryl C 1 -C 6 alkyl, 5 to 7 membered heterocyclyl or heterocyclyl C 1 -C 6 alkyl with from 1 to 3 heteroatoms selected among nitrogen, oxygen or sulfur; or R 1 is a group of formula —NHR′, —NR′COR′′, —NR′CONHR′′ or —NR′SO 2 R′′, wherein R′ has the above reported meanings other than hydrogen, and R′′ is hydrogen or has the meanings set forth above for R′;
  • R 2 is a hydrogen atom or it is a group, optionally further substituted, selected from straight or branched C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or cycloalkyl C 1 -C 6 alkyl, aryl, aryl C 1 -C 6 alkyl, 5 to 7 membered heterocyclyl or heterocyclyl C 1 -C 6 alkyl with from 1 to 3 heteroatoms selected among nitrogen, oxygen or sulfur;
  • any R 3 being placed in one or more of the free positions 5, 6 and 8 of the phthalazinone ring are, independently from each other, halogen, nitro, carboxy, cyano or a group optionally further substituted selected from straight or branched C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or cycloalkyl C 1 -C 6 alkyl, aryl, aryl C 1 -C 6 alkyl, 5 to 7 membered heterocyclyl or heterocyclyl C 1 -C 6 alkyl with from 1 to 3 heteroatoms selected among nitrogen, oxygen or sulfur; or R 3 is a group selected from —COR′, —CONHR′, —SO 2 R′, —NR′R′′, —NR′COR′′, —NR′CONHR′ or —NR′SO 2 R′′, wherein R′ and R′′ are, the same or different, hydrogen or a group as set forth above;
  • m is 0 or an integer from 1 to 3;
  • the compounds of formula (I) are active as protein kinase inhibitors and are therefore useful, for instance, to restrict the unregulated proliferation of tumor cells.
  • they may be used in the treatment of various tumors such as, for instance, carcinomas, e.g. mammary carcinoma, lung carcinoma, bladder carcinoma, colon carcinoma, ovary and endometrial tumors, sarcomas, e.g. soft tissue and bone sarcomas, and the hematological malignancies such as, e.g., leukemias.
  • the compounds of formula (I) are also useful in the treatment of other cell proliferative disorders such as psoriasis, vascular smooth cell proliferation associated with atherosclerosis and post-surgical stenosis and restenosis and in the treatment of Alzheimer's disease.
  • the inhibiting activity of putative protein kinase inhibitors and the potency of selected compounds was determined through a method of assay based on the use of the MultiScreen-PH 96 well plate (Millipore), in which a phosphocellulose filter paper was placed at each well bottom allowing binding of positive charged substrate after a washing/filtration step. When a radioactivity labeled phosphate moiety was transferred by the ser/threo kinase to the filter-bound histone, light emitted was measured in a scintillation counter.
  • x is the logarithm of the inhibitor concentration
  • y is the response; y starts at bottom and goes to top with a sigmoid shape.
  • Ki calculation either the concentration of ATP and histone H1 substrate were varied: 4, 8, 12, 24, 48 ⁇ M for ATP (containing proportionally diluted P 33 ⁇ -ATP) and 0.4, 0.8, 1.2, 2.4, 4.8 ⁇ M for histone were used in absence and presence of two different, properly chosen inhibitor concentrations.
  • the selected compounds have been characterized on a panel of ser/threo kinases strictly related to cell cycle (cdk2/cyclin E, cdk1/cyclin B1, cdk4/Cyclin D1), and also for specificity on MAPK, PKA, EGFR, IGF1-R, Cdc7/dbf4 and aurora-2.
  • Kinase reaction 0,4 uM ⁇ M mouse GST-Rb(769-921) (#sc-4112 from Santa Cruz) substrate, 10 ⁇ M ATP (0.5 ⁇ Ci P 33 ⁇ -ATP), 100 ng of baculovirus expressed GST-cdk4/GST-Cyclin D1, suitable concentrations of inhibitor in a final volume of 50 ⁇ l buffer (TRIS HCl 10 mM pH 7.5, MgCl 2 10 mM, 7.5 mM DTT+0.2 mg/ml BSA) were added to each well of a 96 U bottom well plate. After 40 min at 37° C. incubation, reaction was stopped by 20 ⁇ l EDTA 120 mM.
  • Capture 60 ⁇ l were transferred from each well to MultiScreen plate, to allow substrate binding to phosphocellulose filter. Plates were then washed 3 times with 150 ⁇ l/well PBS Ca ++ /Mg ++ free and filtered by MultiScreen filtration system. Detection: filters were allowed to dry at 37° C., then 100 ⁇ l/well scintillant were added and 33 P labeled Rb fragment was detected by radioactivity counting in the Top-Count instrument.
  • Kinase reaction 25 nM in house biotinylated PolyGluTyr (Sigma #0275) substrate, 2,5 ⁇ M ATP (0.3 ⁇ Ci P 33 ⁇ -ATP), 80 ng baculovirus expressed GST-EGFR, suitable concentrations of inhibitor in a final volume of 100 ⁇ l buffer (Hepes 50 mM pH 7,5, MnCl 2 -MgCl 2 3 mM, 1 mM DTT+3 ⁇ M NaVO3, 0.1 mg/ml BSA) were added to each well of a 96 U bottom well plate. After 5 min. at 37° C. incubation, reaction was stopped by 20 ⁇ l EDTA 120 mM.
  • the inhibition assay of IGF1-R activity was performed according to the following protocol.
  • Kinase reaction 10 ⁇ M biotinylated MBP (Sigma cat. #M-1891) substrate, 0-20 ⁇ M inhibitor, 6 ⁇ M cold ATP, 2 nM 33 P-ATP, and 22.5 ng IGF1-R (pre-incubated for 30 min at room temperature with cold 60 ⁇ M cold ATP) in a final volume of 30 ⁇ l buffer (50 mM HEPES pH 7.9, 3 mM MnCl 2 , 1 mM DTT, 3 ⁇ M NaVO 3 ) were added to each well of a 96 U bottom well plate.
  • the inhibiting activity of putative protein kinase inhibitors and the potency of selected compounds was also determined through a method of assay based on the use of a SPA (Scintillation Proximity Assay) 96 well plate assay.
  • the assay is based on the ability of streptavidin coated SPA beads to capture a biotinylated peptide derived from a phosphorylation site of histone.
  • a radioactivity labeled phosphate moiety was transferred by the ser/threo kinase to the biotinylated histone peptide, light emitted was measured in a scintillation counter.
  • the inhibition assay of cdk5/p25 activity was performed according to the following protocol.
  • Kinase reaction 1.0 ⁇ M biotinylated histone peptide substrate, 0.25 uCi P33g-ATP, 4 nM cdk5/p25 complex, 0-100 ⁇ M inhibitor in a final volume of 100 ⁇ l buffer (Hepes 20 mM pH 7.5, MgCl2 15 mM, 1 mM DTT) were added to each well of a 96 U bottom well plate. After 20 min at 37° C.
  • the inhibition assay of Cdc7/dbf4 activity was performed according to the following protocol.
  • the Biotin-MCM2 substrate is trans-phosphorylated by the Cdc7/Dbf4 complex in the presence of ATP traced with ⁇ 33 -ATP.
  • the phosphorylated Biotin-MCM2 substrate is then captured by Streptavidin-coated SPA beads and the extent of phosphorylation evaluated by ⁇ counting.
  • the inhibition assay of Cdc7/dbf4 activity was performed in 96 wells plate according to the following protocol. To each well of the plate were added:
  • Substrate, enzyme and ATP were diluted in 50 mM HEPES pH 7.9 containing 15 mM MgCl 2 , 2 mM DTT, 3 ⁇ M NaVO 3 , 2 mM glycerophosphate and 0.2 mg/ml BSA.
  • the solvent for test compounds also contained 10% DMSO. After incubation for 20 minutes, the reaction was stopped by adding to each well 100 ⁇ l of PBS pH 7.4 containing 50 mM EDTA, 1 mM cold ATP, 0.1% Triton X100 and 10 mg/ml streptavidin coated SPA beads.
  • the inhibiting activity and the potency of selected compounds was determined through a method of assay based on the use of the streptavidin scintillation proximity assay beads (amershampharmacia biotech) run in a 96 well plates. At the end of the reaction, the biotinylated peptide substrate was captured with the beads and subsequently allowed to stratify using CsCl 2 . When a radioactivity labeled phosphate moiety was transferred by the kinase to the beads-bound peptide, light emitted was measured in a scintillation counter. The inhibition assay of Aurora-2 activity was performed in 96 wells plate according to the following protocol.
  • 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, conditions of the patient and the administration route.
  • a suitable dosage adopted for oral administration of a compound of formula (I) may range from about 10 to about 500 mg pro 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 of tablets, capsules, sugar or film coated tablets, liquid solutions or suspensions; rectally in the form of suppositories; parenterally, e.g. intramuscularly, or by intravenous and/or intrathecal and/or intraspinal injection or infusion.
  • the compounds of the 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 COX-2 inhibitors
  • metallomatrixprotease inhibitors telomerase inhibitors
  • tyrosine kinase inhibitors anti-growth factor receptor agents
  • anti-HER agents anti-EGFR agents
  • anti-angiogenesis agents 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.
  • the compounds of the invention can be administered in combination with one or more chemotherapeutic agents such as, for instance, exemestane, formestane, anastrozole, letrozole, fadrozole, taxane, taxane derivatives, encapsulated taxanes, CPT-11, camptothecin derivatives, anthracycline glycosides, e.g., doxorubicin, idarubicin, epirubicin, etoposide, navelbine, vinblastine, carboplatin, cisplatin, estramustine, celecoxib, tamoxifen, raloxifen, Sugen SU-5416, Sugen SU-6668, Herceptin, and the like, optionally within liposomal formulations thereof.
  • chemotherapeutic agents such as, for instance, exemestane, formestane, anastrozole, letrozole, fadrozole, taxane, taxane derivatives,
  • Such combination products employ the compounds of this invention within the dosage range described above and the other pharmaceutically active agent within the approved dosage range.
  • Compounds of formula (I) may be used sequentially with known anticancer agents when a combination formulation is inappropriate.
  • 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 can be a carrier or a diluent).
  • a pharmaceutically acceptable excipient which can be a carrier or a diluent.
  • the pharmaceutical compositions containing the compounds of the invention are usually prepared following conventional methods and are administered in a pharmaceutically suitable 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, magnesium or calcium stearate, and/or polyethylene glycols; binding agents, e.g.
  • starches arabic gum, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents, e.g. a starch, alginic, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents such as lecithin, polysorbates, laurylsulfates; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations.
  • Said pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tabletting, sugar-coating, or film-coating processes.
  • the liquid dispersions for oral administration may be e.g. syrups, emulsions and suspensions.
  • the syrups may contain as carrier, for example, saccharose or saccharose with glycerin and/or mannitol and/or sorbitol.
  • the suspensions and the emulsions may contain as carrier, for example, a 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.
  • the solutions for intravenous injections or infusions may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions or they may contain as a carrier propylene glycol.
  • the suppositories may contain together with the active compound a pharmaceutically acceptable carrier, e.g. cocoa butter, polyethylene glycol, a polyoxyethylene sorbitan fatty ester surfactant or lecithin.
  • N- ⁇ 2-Methoxy-4-[3-(4-resin-benzylcarbamoyl)-propoxy]-benzyl ⁇ -N- ⁇ 3-oxo-1-[1-pyridin-3-yl-methylidene]-1,3-dihydro-isobenzofuran-5-yl ⁇ -benzamide of example 5 was suspended in dimethylformammide (3 ml) and aqueous hydrazine (approximately 25% solution) was added (400 ⁇ l, about 40 eq.). After stirring at room temperature for 20 hours, the resin was filtered, washed with dimethylformammide, methanol and dichloromethane before drying under vacuum. (IR: disappearance of lactone stretching band).
  • Furan-2-carboxylic acid [1-(4-chloro-3-fluoro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-amide; [M+H]+398; HPLC r.t. 4.58.

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US09/922,729 2001-08-07 2001-08-07 Amino-phthalazinone derivatives active as kinase inhibitors, process for their preparation and pharmaceutical compositions containing them Abandoned US20030073692A1 (en)

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US09/922,729 US20030073692A1 (en) 2001-08-07 2001-08-07 Amino-phthalazinone derivatives active as kinase inhibitors, process for their preparation and pharmaceutical compositions containing them
KR10-2004-7001814A KR20040029400A (ko) 2001-08-07 2002-07-30 키나제 억제제로서 작용하는 아미노-프탈라지논 유도체,이의 제조방법 및 이를 함유하는 약제학적 조성물
PL02368440A PL368440A1 (en) 2001-08-07 2002-07-30 Amino-phthalazinone derivatives active as kinase inhibitors, process for their preparation and pharmaceutical compositions containing them
US10/486,463 US7432263B2 (en) 2001-08-07 2002-07-30 Amino-phthalazinone derivatives active as kinase inhibitors, process for their preparation and pharmaceutical compositions containing them
CNA028154193A CN1538960A (zh) 2001-08-07 2002-07-30 作为激酶抑制剂的氨基-2,3-二氮杂萘酮衍生物,它们的制备方法和含有它们的药物组合物
PCT/EP2002/008544 WO2003014090A1 (fr) 2001-08-07 2002-07-30 Derives d'amino-phtalazinone actifs comme inhibiteurs de kinase, processus de preparation et compositions pharmaceutiques contenant ces derives
AT02758416T ATE407928T1 (de) 2001-08-07 2002-07-30 Amino-phtalazinon derivate, anwendung als kinase inhibitoren, herstellung und pharmazeutische zusammensetzung
IL15984302A IL159843A0 (en) 2001-08-07 2002-07-30 Amino-phthalazinone derivatives active as kinase inhibitors, process for their preparation and pharmaceutical compositions containing them
DK02758416T DK1427708T3 (da) 2001-08-07 2002-07-30 Amino-phthalazinon-derivater som kinase-inhibitorer, fremgangsmåde til deres fremstilling og farmaceutiske sammensætninger der indeholder det samme
CA002455759A CA2455759A1 (fr) 2001-08-07 2002-07-30 Derives d'amino-phtalazinone actifs comme inhibiteurs de kinase, processus de preparation et compositions pharmaceutiques contenant ces derives
SI200230738T SI1427708T1 (sl) 2001-08-07 2002-07-30 Derivati amino-ftalazinona kot zaviralci kinaze, postopek za njihovo pripravo in farmacevtski sestavki, ki jih vsebujejo
NZ531310A NZ531310A (en) 2001-08-07 2002-07-30 Amino-phthalazinone derivatives active as kinase inhibitors, process for their preparation and pharmaceutical compositions containing them
MXPA04000905A MXPA04000905A (es) 2001-08-07 2002-07-30 Derivados de amino-ftalazinona activos como inhibidores de cinasa, procedimiento para su preparacion y composiciones farmaceuticas que los contienen.
JP2003519040A JP2005501085A (ja) 2001-08-07 2002-07-30 キナーゼ阻害剤として活性なアミノフタラジノン誘導体、それらを調製する方法およびそれらを含有する薬剤組成物
CNA2007101101264A CN101085759A (zh) 2001-08-07 2002-07-30 作为激酶抑制剂的氨基－2,3－二氮杂萘酮衍生物,它们的制备方法和含有它们的药物组合物
ES02758416T ES2315385T3 (es) 2001-08-07 2002-07-30 Derivados de amino-ftalazinona como inhibidores de quinasa, procedimiento para su preparacion y composiciones farmaceuticas que los contienen.
EA200400283A EA006645B1 (ru) 2001-08-07 2002-07-30 Производные аминофталазинона, активные как ингибиторы киназ, способ их получения и содержащие их фармацевтические композиции
CZ2004305A CZ2004305A3 (cs) 2001-08-07 2002-07-30 Aminoftalazinonové derivátyŹ účinné jako kinázové inhibitoryŹ způsob jejich přípravy a farmaceutické prostředkyŹ které je obsahují
BR0211807-6A BR0211807A (pt) 2001-08-07 2002-07-30 Derivados ativos amino-ftalazinona como inibidores de cinase, processo para sua preparação e composições farmacêuticas para os mesmos
DE60228857T DE60228857D1 (de) 2001-08-07 2002-07-30 Amino-phtalazinon derivate, anwendung als kinase inhibitoren, herstellung und pharmazeutische zusammensetzung
EP02758416A EP1427708B1 (fr) 2001-08-07 2002-07-30 Derives d'amino-phtalazinone comme inhibiteurs de kinase, procede de preparation et compositions pharmaceutiques contenant ces derives
PT02758416T PT1427708E (pt) 2001-08-07 2002-07-30 Derivados amino-ftalazinona activos como inibidors de cinase, processo para a sua preparação e composições farmacêuticas contendo-os
NO20040547A NO20040547L (no) 2001-08-07 2004-02-06 Amino-ftalazinonderivater aktive som kinaseinhibitorer, fremgangsmate for deres fremstilling og farmasoytiske sammensetninger inneholdende disse.
ZA200401316A ZA200401316B (en) 2001-08-07 2004-02-18 Amino-phthalazinone derivatives active as kinase inhibitors, process for their preparation and pharmaceutical compositions containing them.
CO04019499A CO5560573A2 (es) 2001-08-07 2004-03-03 Derivados activos de amino-ftalazinona como inhibidores de quinasa, proceso para su preparacion y composiciones farmaceuticas que los contienen

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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050153966A1 (en) * 2003-12-19 2005-07-14 Syrrx, Inc. Kinase inhibitors
US20050250829A1 (en) * 2004-04-23 2005-11-10 Takeda San Diego, Inc. Kinase inhibitors
US20060041137A1 (en) * 2004-08-18 2006-02-23 Takeda San Diego, Inc. Kinase inhibitors
WO2006036981A2 (fr) * 2004-09-28 2006-04-06 Angion Biomedica Corp. Petits modulateurs moleculaires de l'activite de cytokines
US20060084650A1 (en) * 2004-10-15 2006-04-20 Qing Dong Kinase inhibitors
US20060199817A1 (en) * 2005-03-03 2006-09-07 Amgen Inc. Phthalazine, aza- and diaza-phthalazine compounds and methods of use
US20070117816A1 (en) * 2005-10-07 2007-05-24 Brown Jason W Kinase inhibitors
US20090156557A1 (en) * 2007-04-18 2009-06-18 Takeda San Diego, Inc. Kinase inhibitors
US20110098304A1 (en) * 2008-10-22 2011-04-28 Bijoy Panicker Small molecule inhibitors of PARP activity
US20110184038A1 (en) * 2008-07-10 2011-07-28 Angion Biomedica Corp. Methods and compositions of small molecule modulators of hepatocyte growth factor (scatter factor) activity
US8278450B2 (en) 2007-04-18 2012-10-02 Takeda Pharmaceutical Company Limited Kinase inhibitors
US8497269B2 (en) 2008-10-10 2013-07-30 Amgen Inc. Phthalazine compounds as p38 map kinase modulators and methods of use thereof
US8772481B2 (en) 2008-10-10 2014-07-08 Amgen Inc. Aza- and diaza-phthalazine compounds as P38 map kinase modulators and methods of use thereof
US10875849B2 (en) 2019-04-11 2020-12-29 Angion Biomedica Corp. Solid forms of (E)-3-[2-(2-thienyl)vinyl]-1H-pyrazole
CN114728912A (zh) * 2019-09-12 2022-07-08 米拉蒂医疗股份有限公司 Mta-协同prmt5抑制剂

Families Citing this family (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7151102B2 (en) * 2000-10-30 2006-12-19 Kudos Pharmaceuticals Limited Phthalazinone derivatives
GB0305681D0 (en) 2003-03-12 2003-04-16 Kudos Pharm Ltd Phthalazinone derivatives
GB0317466D0 (en) 2003-07-25 2003-08-27 Univ Sheffield Use
DE602004031037D1 (de) * 2003-11-19 2011-02-24 Array Biopharma Inc Heterocyclische inhibitoren von mek
DK2305221T3 (en) 2003-12-01 2015-08-24 Kudos Pharm Ltd DNA damage repair inhibitors for the treatment of cancer
GB0419072D0 (en) * 2004-08-26 2004-09-29 Kudos Pharm Ltd Phthalazinone derivatives
GB0428111D0 (en) * 2004-12-22 2005-01-26 Kudos Pharm Ltd Pthalazinone derivatives
KR101292598B1 (ko) * 2005-01-14 2013-08-05 질레드 코네티컷 인코포레이티드 키나아제 활성 조절제로서의 １，３-디아릴 치환된 우레아
DE102005011822A1 (de) * 2005-03-15 2006-09-21 Merck Patent Gmbh Phthalazinone
US20080318960A1 (en) * 2005-05-26 2008-12-25 Ethan Burstein PAR2-modulating compounds and their use
GB0521373D0 (en) * 2005-10-20 2005-11-30 Kudos Pharm Ltd Pthalazinone derivatives
US7618982B2 (en) 2005-12-19 2009-11-17 Nerviano Medical Sciences S.R.L. Heteroarylpyrrolopyridinones active as kinase inhibitors
KR20080095912A (ko) * 2006-03-20 2008-10-29 에프. 호프만-라 로슈 아게 프탈라지논 피라졸 유도체, 그의 제조 및 약학적 제제로서의 용도
EP2041087A1 (fr) * 2006-06-15 2009-04-01 Kudos Pharmaceuticals Limited Dérivés d'oxybenzamide 2 en tant qu'inhibiteurs d'activité parp
WO2007144652A2 (fr) * 2006-06-15 2007-12-21 Kudos Pharmaceuticals Limited Inhibiteurs de parp
JP2009539962A (ja) * 2006-06-15 2009-11-19 クドス ファーマシューティカルズ リミテッド Ｐａｒｐ阻害剤としての２−オキシヘテロアリールアミド誘導体
UY30639A1 (es) * 2006-10-17 2008-05-31 Kudos Pharm Ltd Derivados sustituidos de 2h-ftalazin-1-ona, sus formas cristalinas, proceso de preparacion y aplicaciones
WO2008061108A2 (fr) 2006-11-15 2008-05-22 Forest Laboratories Holdings Limited Dérivés de phtalazine
JP5337717B2 (ja) 2007-02-27 2013-11-06 ネルビアーノ・メデイカル・サイエンシーズ・エツセ・エルレ・エルレ キナーゼ阻害剤として活性なイソキノリノピロロピリジノン
US20080280910A1 (en) * 2007-03-22 2008-11-13 Keith Allan Menear Phthalazinone derivatives
TW200900396A (en) * 2007-04-10 2009-01-01 Kudos Pharm Ltd Phthalazinone derivatives
EP2003129B1 (fr) 2007-06-11 2017-08-09 Nerviano Medical Sciences S.r.l. Dérivés de 1H-pyrido[3,4-B]indol-1-one et de 2,3,4,9-tétrahydro-1H-bêta-carbolin-1-one
EP2215082B1 (fr) * 2007-10-11 2011-09-21 Glaxo Group Limited Phthalazine et composés pyrido[3,4-d]pyridazine comme antagonistes du récepteur h1
KR101598231B1 (ko) * 2007-10-17 2016-02-26 쿠도스 파마슈티칼스 리미티드 4-[3-(4-시클로프로판카르보닐-피페라진-1-카르보닐)-4-플루오로-벤질]-2ｈ-프탈라진-1-온
EP2346495B2 (fr) * 2008-10-07 2023-05-24 Kudos Pharmaceuticals Limited Formulation pharmaceutique 514
AR079774A1 (es) * 2009-07-15 2012-02-22 Astrazeneca Ab Compuesto de ftalazinona como forma cristalina c , composicion farmaceutica y usos del mismo
CN102933571A (zh) * 2010-04-16 2013-02-13 Abbvie公司 激酶的酞嗪-(2h)-酮抑制剂
CN103058927B (zh) * 2011-10-21 2015-04-22 华国媛 一种喹啉衍生物及其应用
MX365950B (es) 2013-03-13 2019-06-19 Flatley Discovery Lab Llc Compuestos de piridazinona y metodos para el tratamiento de la fibrosis quistica.
CN107298640B (zh) * 2017-07-19 2020-08-04 曲阜师范大学 一种亚甲基酮化合物的制备方法及其应用
WO2023125540A1 (fr) * 2021-12-27 2023-07-06 南京明德新药研发有限公司 Composé pyrazole-1(2h)-phtalazinone et application associée
CN116903611A (zh) * 2022-01-26 2023-10-20 上海优理惠生医药有限公司 一种酞嗪酮类化合物、其制备方法、包含其药物组合物及其应用

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE567431A (fr) * 1957-05-07
EP0600831A1 (fr) * 1992-11-27 1994-06-08 Ciba-Geigy Ag Dérivés de phtalazinone
EP0634404A1 (fr) * 1993-07-13 1995-01-18 Rhone Poulenc Agriculture Ltd. Dérivés de phtalazine et leur utilisation comme pesticides
JPH0961961A (ja) * 1995-08-21 1997-03-07 Fuji Photo Film Co Ltd 熱現像感光材料
CO4950519A1 (es) * 1997-02-13 2000-09-01 Novartis Ag Ftalazinas, preparaciones farmaceuticas que las comprenden y proceso para su preparacion
EP0875512A3 (fr) 1997-04-16 1999-04-07 Fabrica Espanola De Productos Quimicos Y Farmaceuticos, S.A. (Faes) Dérivés de la naphthylpipérazine avec une activité antipsychotique
BR0009650A (pt) * 1999-04-09 2002-01-02 Meiji Seika Kaisha Composto, composição farmacêutica, processos para inibir a secreção de uma lipoproteìna contendo apolipoproteìna b, para inibir a biossìntese de triglicerìdeos e para prevenir ou tratar hiperlipidemia, doenças arterioscleróticas e pancreatite, e, uso do composto

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Publication number Priority date Publication date Assignee Title
US7572914B2 (en) 2003-12-19 2009-08-11 Takeda Pharmaceutical Company Limited Kinase inhibitors
US20050153966A1 (en) * 2003-12-19 2005-07-14 Syrrx, Inc. Kinase inhibitors
US20050250829A1 (en) * 2004-04-23 2005-11-10 Takeda San Diego, Inc. Kinase inhibitors
US20060041137A1 (en) * 2004-08-18 2006-02-23 Takeda San Diego, Inc. Kinase inhibitors
US7550598B2 (en) 2004-08-18 2009-06-23 Takeda Pharmaceutical Company Limited Kinase inhibitors
WO2006036981A3 (fr) * 2004-09-28 2006-07-27 Angion Biomedica Corp Petits modulateurs moleculaires de l'activite de cytokines
US20060116365A1 (en) * 2004-09-28 2006-06-01 Zembower David E Small molecule modulators of cytokine activity
US20100137285A1 (en) * 2004-09-28 2010-06-03 Angion Biomedica Corp. Small molecule modulators of cytokine activity
US7648978B2 (en) 2004-09-28 2010-01-19 Angion Biomedica Corp. Small molecule modulators of cytokine activity
WO2006036981A2 (fr) * 2004-09-28 2006-04-06 Angion Biomedica Corp. Petits modulateurs moleculaires de l'activite de cytokines
US20060084650A1 (en) * 2004-10-15 2006-04-20 Qing Dong Kinase inhibitors
US8288536B2 (en) 2004-10-15 2012-10-16 Takeda Pharmaceutical Company Limited Kinase inhibitors
US7713973B2 (en) 2004-10-15 2010-05-11 Takeda Pharmaceutical Company Limited Kinase inhibitors
US20060199817A1 (en) * 2005-03-03 2006-09-07 Amgen Inc. Phthalazine, aza- and diaza-phthalazine compounds and methods of use
WO2006094187A3 (fr) * 2005-03-03 2008-03-20 Amgen Inc Composes de phthalazine, aza- et diaza-phthalazine et procedes d'utilisation de ceux-ci
US7759337B2 (en) 2005-03-03 2010-07-20 Amgen Inc. Phthalazine compounds and methods of use
WO2006094187A2 (fr) 2005-03-03 2006-09-08 Amgen Inc Composes de phthalazine, aza- et diaza-phthalazine et procedes d'utilisation de ceux-ci
US20070117816A1 (en) * 2005-10-07 2007-05-24 Brown Jason W Kinase inhibitors
US8119655B2 (en) 2005-10-07 2012-02-21 Takeda Pharmaceutical Company Limited Kinase inhibitors
US20090156557A1 (en) * 2007-04-18 2009-06-18 Takeda San Diego, Inc. Kinase inhibitors
US8278450B2 (en) 2007-04-18 2012-10-02 Takeda Pharmaceutical Company Limited Kinase inhibitors
US10899750B2 (en) 2008-07-10 2021-01-26 Angion Biomedica Corp. Methods and compositions of small molecule modulators of hepatocyte growth factor (scatter factor) activity
US20110184038A1 (en) * 2008-07-10 2011-07-28 Angion Biomedica Corp. Methods and compositions of small molecule modulators of hepatocyte growth factor (scatter factor) activity
US8772326B2 (en) 2008-07-10 2014-07-08 Anigion Biomedica Corp. Methods and compositions of small molecule modulators of hepatocyte growth factor (scatter factor) activity
US8497269B2 (en) 2008-10-10 2013-07-30 Amgen Inc. Phthalazine compounds as p38 map kinase modulators and methods of use thereof
US8772481B2 (en) 2008-10-10 2014-07-08 Amgen Inc. Aza- and diaza-phthalazine compounds as P38 map kinase modulators and methods of use thereof
US20110098304A1 (en) * 2008-10-22 2011-04-28 Bijoy Panicker Small molecule inhibitors of PARP activity
US10875849B2 (en) 2019-04-11 2020-12-29 Angion Biomedica Corp. Solid forms of (E)-3-[2-(2-thienyl)vinyl]-1H-pyrazole
US11370783B2 (en) 2019-04-11 2022-06-28 Angion Biomedica Corp. Solid forms of (E)-3-[2-(2-thienyl)vinyl]-1H-pyrazole
CN114728912A (zh) * 2019-09-12 2022-07-08 米拉蒂医疗股份有限公司 Mta-协同prmt5抑制剂

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IL159843A0 (en) 2004-06-20
ES2315385T3 (es) 2009-04-01
CO5560573A2 (es) 2005-09-30
ZA200401316B (en) 2005-03-10
EP1427708A1 (fr) 2004-06-16
JP2005501085A (ja) 2005-01-13
NZ531310A (en) 2006-02-24
MXPA04000905A (es) 2004-04-02
EA006645B1 (ru) 2006-02-24
DE60228857D1 (de) 2008-10-23
WO2003014090A1 (fr) 2003-02-20
US7432263B2 (en) 2008-10-07
CN101085759A (zh) 2007-12-12
CA2455759A1 (fr) 2003-02-20
NO20040547L (no) 2004-03-03
EA200400283A1 (ru) 2004-08-26
DK1427708T3 (da) 2008-11-24
SI1427708T1 (sl) 2008-12-31
CZ2004305A3 (cs) 2004-08-18
ATE407928T1 (de) 2008-09-15
US20050020583A1 (en) 2005-01-27
PL368440A1 (en) 2005-03-21
PT1427708E (pt) 2008-11-20
CN1538960A (zh) 2004-10-20
EP1427708B1 (fr) 2008-09-10

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