WO2007132221A1 - Inhibiteurs de la kinase aurora à base de pyrimidine-thiazole, anticancéreux, combinés - Google Patents

Inhibiteurs de la kinase aurora à base de pyrimidine-thiazole, anticancéreux, combinés Download PDF

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Publication number
WO2007132221A1
WO2007132221A1 PCT/GB2007/001763 GB2007001763W WO2007132221A1 WO 2007132221 A1 WO2007132221 A1 WO 2007132221A1 GB 2007001763 W GB2007001763 W GB 2007001763W WO 2007132221 A1 WO2007132221 A1 WO 2007132221A1
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Prior art keywords
compound
formula
cancer
pharmaceutically acceptable
cisplatin
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PCT/GB2007/001763
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English (en)
Inventor
David Maccallum
Simon Green
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Cyclacel Limited
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Priority claimed from GB0609533A external-priority patent/GB0609533D0/en
Priority claimed from GB0609531A external-priority patent/GB0609531D0/en
Application filed by Cyclacel Limited filed Critical Cyclacel Limited
Publication of WO2007132221A1 publication Critical patent/WO2007132221A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • 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
    • A61K31/28—Compounds containing heavy metals
    • A61K31/282—Platinum compounds
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to a pharmaceutical combination suitable for the treatment of cancer and other proliferative disorders.
  • Cell cycle inhibitors represent a key approach to the treatment of cancer.
  • Therapeutic agents have traditionally targeted early stages of the cell cycle (for example, the Gl /S phase checkpoint or the S phase) or mitotic spindle formation as exemplified by the alkaloids. More recently, a new approach to cell cycle regulation has emerged with the identification of the aurora kinase family.
  • Aurora kinases are a family of related serine/threonine kinases that are involved in mitotic progression.
  • a variety of cellular proteins are substrates for phosphorylation by aurora kinase enzymes, including p53, CENP-A, myosin II regulatory light chain, protein phosphatase- 1, histone H3, TPX-2, INCENP, survivin, topoisomerase II alpha, vimentin, MBD-3, MgcRacGAP, desmin, Ajuba, XIEg5 (in Xenopus), NdclOp
  • Aurora kinase enzymes also are themselves substrates for autophosphorylation, e.g., at Thr288.
  • aurora kinases play an important part in cellular events that become defective in cancer (for example, cell cycling) and manipulations that increase aurora kinase activity have been shown to promote various cellular events consistent with tumorigenesis. Specifically, the role of aurora kinases is particularly significant in the later stages of the cell cycle from the G2/M check point through to the mitotic checkpoint and late mitosis.
  • Mitosis is the stage of the cell cycle during which chromosome separation takes place.
  • Several current cancer therapies including those based on the alkaloids, are known to operate by inhibiting the mitotic machinery. Mitotic progression is largely regulated by mitotic kinases that modulate proteolysis and various phosphorylation events.
  • Aurora kinases are known to regulate mitotic progression through modulation of centrosome separation, spindle dynamics, spindle assembly checkpoint, chromosome alignment and cytokinesis (Dutertre et al., Oncogene, 21: 6175 (2002); Berdnik et al.,
  • aurora kinase inhibitors are have potential therapeutic applications in the treatment of a wide range of human tumours.
  • the present invention seeks to provide a new combination of known pharmaceutical agents that is particularly suitable for the treatment of proliferative disorders, especially cancer. More specifically, the invention centres on the surprising and unexpected effects associated with using certain aurora kinase inhibitors in combination with known anticancer drugs.
  • the invention provides a combination comprising cisplatin and a compound of formula I, or a pharmaceutically acceptable salt thereof,
  • R 1 is alkyl
  • R 2 and R 3 are each independently selected from H and alkyl
  • R 4 is a heteroalicyclic group optionally substituted by one or more substituents selected from alkyl, CO-alkyl and aralkyl.
  • a second aspect relates to a pharmaceutical product comprising a compound of formula I and cisplatin as a combined preparation for simultaneous, sequential or separate use in therapy
  • a third aspect relates to a method of treating a proliferative disorder, said method comprising simultaneously, sequentially or separately administering a compound of formula I and cisplatin to a subject.
  • a fourth aspect relates to the use of a compound of formula I in the preparation of a medicament for the treatment of a proliferative disorder, wherein said treatment comprises simultaneously, sequentially or separately administering a compound of formula I and cisplatin to a subject.
  • a fifth aspect relates to the use of a compound of formula I and cisplatin in the preparation of a medicament for treating a proliferative disorder.
  • a sixth aspect relates to the use of a compound of formula I in the preparation of a medicament for the treatment of a proliferative disorder, wherein said medicament is for use in combination therapy with cisplatin.
  • a seventh aspect relates to the use of cisplatin in the preparation of a medicament for the treatment of a proliferative disorder, wherein said medicament is for use in combination therapy with a compound of formula I.
  • An eighth aspect relates to a kit of parts comprising:
  • the invention provides a combination comprising 5 -FU, or a prodrug thereof, and a compound of formula I, or a pharmaceutically acceptable salt thereof,
  • R 1 is alkyl
  • R 2 and R 3 are each independently selected from H and alkyl; and R is a heteroalicyclic group optionally substituted by one or more substituents selected from alkyl, CO-alkyl and aralkyl.
  • a tenth aspect relates to a pharmaceutical product comprising a compound of formula I and 5-FU, or a prodrug thereof, as a combined preparation for simultaneous, sequential or separate use in therapy
  • An eleventh aspect relates to a method of treating a proliferative disorder, said method comprising simultaneously, sequentially or separately administering a compound of formula I and 5-FU, or a prodrug thereof, to a subject.
  • a twelfth aspect relates to the use of a compound of formula I in the preparation of a medicament for the treatment of a proliferative disorder, wherein said treatment comprises simultaneously, sequentially or separately administering a compound of formula I and 5 -FU, or a prodrug thereof, to a subject.
  • a thirteenth aspect relates to the use of a compound of formula I and 5 -FU, or a prodrug thereof, in the preparation of a medicament for treating a proliferative disorder.
  • a fourteenth aspect relates to the use of a compound of formula I in the preparation of a medicament for the treatment of a proliferative disorder, wherein said medicament is for use in combination therapy with 5 -FU, or a prodrug thereof.
  • a fifteenth aspect relates to the use of 5 -FU, or a prodrug thereof, in the preparation of a medicament for the treatment of a proliferative disorder, wherein said medicament is for use in combination therapy with a compound of formula I.
  • a sixteenth aspect relates to a kit of parts comprising:
  • a seventeenth aspect relates to pharmaceutical compositions comprising combinations according to the invention admixed with a pharmaceutically acceptable carrier, diluent or excipient.
  • An eighteenth aspect relates to the use of combinations according to the invention in the preparation of a medicament for treating a proliferative disorder.
  • one aspect of the present invention relates to a combination comprising a compound of formula I and cisplatin.
  • the compound cis-diaminedichloroplatinum (II), commonly referred to as cisplatin or cis-DDP, is a known anticancer agent which is widely used in the clinic, particularly in the treatment of testicular cancer.
  • the molecular structure is relatively simple and consists of two chlorine ligands and two NH 3 ligands situated in the cis position, forming a tetragonal (square) planar structure around a central platinum atom.
  • Cisplatin exists as an electroneutral, four-coordinate platinum complex. However, studies have shown that the dihydrated (active) form promotes binding to DNA.
  • Cisplatin is generally administered into the bloodstream intravenously as a sterile saline solution. Due to the high chloride concentration in the bloodstream, the drug remains intact in its neutral form. It then enters the cell by diffusion where it undergoes hydrolysis as a result of the much lower intracellular chloride concentration. Hydrolysis converts the neutral molecule into the active hydrated complex in which both chloride ligands are replaced by water molecules to generate a positively charged species.
  • the active form is a bifunctional electrophilic agent which is able to undergo nucleophilic substitution with DNA base pairs.
  • Cisplatin has biochemical properties similar to that of bifunctional alkylating agents, producing interstrand, intrastrand and monofunctional adduct cross-linking in DNA.
  • the most prevalent form is the 1,2-intrastrand crosslink.
  • the platinum is covalently bound to the N7 position of adjacent purine bases. As a consequence, the DNA is unwound and bent towards the major groove.
  • Other platinum-DNA adducts include monoftmctional and 1,3- and longer range intrastrand, interstrand and protein- DNA crosslinks.
  • adducts involve guanine residues as these offer three sites for hydrogen bonding with cytosine, thereby leading to greater stability compared to the two hydrogen bonds which are possible between adenine and thymine.
  • the formation of a cisplatin-DNA adduct distorts the DNA structure which in turn leads to disruption of replication and transcription.
  • the formation of a cisplatin-DNA adduct disrupts the ability of the cells to repair themselves, either by blocking and slowing down repair proteins, or negatively altering the function of nucleotide excision repair (NER) proteins, specifically XPA.
  • NER nucleotide excision repair
  • Cisplatin has antitumour activity either as a single agent or in combination chemotherapy. Cisplatin is approved for use in metastatic, non-seminomatous germ cell carcinoma, advanced stage and refractory ovarian carcinoma, advanced stages and refractory bladder carcinoma, squamous cell carcinoma of head and neck, cervical tumours, testicular carcinoma (palliative and curative poly-chemotherapy) and lung carcinoma. Cisplatin is indicated in combination with other antineoplastic agents for the treatment of metastatic testicular tumours. The combination of cisplatin, vinblastine and bleomycin is reported to be highly effective.
  • the combination of the invention is a synergistic combination comprising a compound of formula I and cisplatin, i.e. the combination has a synergistic effect.
  • the combination of cisplatin and the compound of formula I produces an enhanced effect as compared to either drug administered alone.
  • the surprising nature of this observation is in contrast to that expected on the basis of the prior art.
  • one aspect of the invention relates to a pharmaceutical product comprising a compound of formula I and cisplatin as a combined preparation for simultaneous, sequential or separate use in therapy.
  • the compound of formula I and cisplatin may be administered simultaneously, in combination, sequentially or separately (as part of a dosing regime).
  • “simultaneously” is used to mean that the two agents are administered concurrently, whereas the term “in combination” is used to mean they are administered, if not simultaneously, then “sequentially” within a timeframe that they both are available to act therapeutically within the same time-frame.
  • administration “sequentially” may permit one agent to be administered within 5 minutes, 10 minutes or a matter of hours after the other provided the circulatory half- life of the first administered agent is such that they are both concurrently present in therapeutically effective amounts.
  • the time delay between administration of the components will vary depending on the exact nature of the components, the interaction therebetween, and their respective half-lives.
  • the second agent is administered at least 2 hours, more prefereably at least 4 hours, even more preferably at least 8 hours, even more preferably still at least 12 or 24 or 48 hours after the first agent. In one particularly preferred embodiment, the second agent is administered at least 24 hours after the first agent.
  • One aspect of the present invention relates to the use of a compound of formula I in the preparation of a medicament for the treatment of a proliferative disorder, wherein said treatment comprises administering to a subject simultaneously, sequentially or separately cisplatin and a compound of formula I.
  • the compound of formula I and cisplatin are administered simultaneously or sequentially.
  • the cisplatin and compound of formula I are administered simultaneously.
  • the compound of formula I is administered to the subject prior to sequentially or separately administering the cisplatin, i.e. the dosing involves pretreatment with a compound of formula I.
  • the cisplatin is administered at least 2 hours, more preferably at least 4 hours, even more preferably at least 8 hours, even more preferably still at least 12 or 24 or 48 hours after the compound of formula I. In one particularly preferred embodiment, the cisplatin is administered at least 24 hours after the compound of formula I.
  • Another aspect of the invention relates to a method of treating a proliferative disorder in a subject, said method comprising the sequential administration of a therapeutically effective amount of a compound of formula I followed by a therapeutically effective amount of cisplatin.
  • the subject is a mammal, more preferably a human.
  • Another aspect of the invention relates to the use of a compound of formula I in the manufacture of a medicament for use in the treatment of proliferative disorders comprising the sequential administration of a therapeutically effective amount of a compound of formula I followed by a therapeutically effective amount of cisplatin.
  • cisplatin is administered to the subject prior to sequentially or separately administering the compound of formula I to said subject.
  • Another aspect of the invention relates to a method of treating a proliferative disorder in a subject, said method comprising the sequential administration of a therapeutically effective amount of cisplatin followed by a therapeutically effective amount of a compound of formula I.
  • Another aspect of the invention relates to the use of a compound of formula I in the manufacture of a medicament for use in the treatment of proliferative disorders comprising the sequential administration of a therapeutically effective amount of cisplatin followed by a therapeutically effective amount of a compound of formula I.
  • the compound of formula I and cisplatin are administered sequentially.
  • the compound of formula I and cisplatin are each administered in a therapeutically effective amount with respect to the individual components. In another preferred embodiment of the invention, the compound of formula I and cisplatin are each administered in a subtherapeutic amount with respect to the individual components.
  • the compound of formula I is administered in an amount of about 50-2000 mg dose per person per day, preferably as a once a day dose.
  • the compound of formula I is administered in an amount of about 50-1200 mg dose per person per day.
  • the compound of formula I is administered orally.
  • the cisplatin is administered intravenously.
  • Another aspect of the invention relates to the use of a compound of formula I and cisplatin in the preparation of a medicament for treating a proliferative disorder.
  • Yet another aspect of the invention relates to the use of a compound of formula I in the preparation of a medicament for the treatment of a proliferative disorder, wherein said medicament is for use in combination therapy with cisplatin.
  • a further aspect of the invention relates to the use of cisplatin in the preparation of a medicament for the treatment of a proliferative disorder, wherein said medicament is for use in combination therapy with a compound of formula I.
  • combination therapy refers to therapy in which the cisplatin and aurora kinase inhibitor of formula I are administered, if not simultaneously, then sequentially within a timeframe that they both are available to act therapeutically within the same time-frame.
  • preparation of a medicament includes the use of the components of the invention directly as the medicament in addition to their use in any stage of the preparation of such a medicament.
  • proliferative disorder is used herein in a broad sense to include any disorder that requires control of the cell cycle, for example cardiovascular disorders such as restenosis and cardiomyopathy, auto-immune disorders such as glomerulonephritis and rheumatoid arthritis, dermatological disorders such as psoriasis, anti-inflammatory, anti-fungal, antiparasitic disorders such as malaria, emphysema and alopecia.
  • cardiovascular disorders such as restenosis and cardiomyopathy
  • auto-immune disorders such as glomerulonephritis and rheumatoid arthritis
  • dermatological disorders such as psoriasis, anti-inflammatory, anti-fungal, antiparasitic disorders such as malaria, emphysema and alopecia.
  • the components of the present invention may induce apoptosis or maintain stasis within the desired cells as required.
  • the proliferative disorder is a cancer or leukaemia, most preferably cancer.
  • the cancer is testicular, ovarian, bladder, lung, head and neck, gastric, oesophagus or uterine cancer, or lymphoma, sarcoma, melanoma, mesothelioma or prostate cancer.
  • the cancer is selected from advanced bladder cancer, metastatic ovarian cancer, testicular cancer, germ cell carcinoma, squamous cell carcinoma of the head and neck, brain tumours, cervical cancer, neuroblastoma, oesophageal carncinoma and advanced prostatic carcinoma.
  • the cancer is lung cancer.
  • the cancer is non-small cell lung cancer (NSCLC). More preferably still, the cancer is stage IIIB/IV non-small cell lung cancer.
  • the compound of formula I is an aurora kinase inhibitor.
  • the invention relates to the use of the combination described herein in the treatment of an aurora kinase dependent or sensitive disorder.
  • Aurora kinase dependent disorders are associated with an above normal level of activity of one or more aurora enzymes. Such disorders preferably associated with an abnormal level of activity of aurora kinase A or B.
  • An aurora sensitive disorder is a disorder in which an aberration in the aurora kinase level is not the primary cause, but is downstream of the primary metabolic aberration. In such scenarios, aurora A and/or aurora B can be said to be part of the sensitive metabolic pathway and aurora inhibitors may therefore be active in treating such disorders.
  • Such disorders are preferably cancer or leukaemic disorders.
  • aurora kinase encompasses any aurora kinase protein from any species, including, aurora A, aurora B, and aurora C.
  • aurora kinase is aurora A or B.
  • aurora kinase is a human aurora kinase.
  • aurora kinase inhibitor or “inhibitor of aurora kinase” refers to a compound having a structure as defined herein, which is capable of interacting with an aurora kinase and inhibiting its en2ymatic activity. Inhibiting aurora kinase enzymatic activity means reducing the ability of an aurora kinase to phosphorylate a substrate peptide or protein.
  • the aurora kinase inhibitor is capable of reducing aurora kinase activity by at least about 10%, more preferably at least about 25 %, more preferably at least 50%, more preferably at least about 75%, more preferably still at least about 90%, at least about 95%, or at least about 99%.
  • the concentration of aurora kinase inhibitor required to reduce an aurora kinase enzymatic activity is less than about 10 ⁇ M, more preferably, less than about 5 ⁇ M, more preferably, less than about 1 ⁇ M, more preferably less than about 500 nM, less than about 100 nM, or less than about 50 nM.
  • the aurora kinase inhibitor also reduces the enzymatic activity of another kinase, preferably one that is implicated in cancer.
  • the aurora kinase inhibitor is selective, i.e., the aurora kinase inhibitor reduces the ability of an aurora kinase to phosphorylate a substrate peptide or protein at a concentration that is lower than the concentration of the inhibitor that is required to produce a similar effect on the activity of a different kinase.
  • the term "selective" means that the inhibitor is selective for aurora kinase over other protein kinases.
  • the inhibitor exhibits a selectivity ratio for aurora kinase over other protein kinases of greater than 2-fold, more preferably greater than 5-fold, more preferably greater than 10-fold, even more preferably greater than 25-fold, more preferably still, greater than 50-fold or 100-fold.
  • the compound of formula I is an inhibitor of aurora kinase A.
  • the compound of formula I is an inhibitor of aurora kinase B.
  • the aurora kinase inhibitor is selective for aurora A kinase.
  • the term "selective for aurora kinase A” means that the inhibitor is selective for aurora kinase A over other protein kinases, and more preferably, over aurora kinase B.
  • the inhibitor exhibits a selectivity ratio for aurora kinase A over other protein kinases of greater than 2-fold, more preferably greater than 5 -fold, more preferably greater than 10-fold, even more preferably greater than 25-fold, more preferably still, greater than 50-fold or 100-fold.
  • the aurora kinase inhibitor is selective for aurora kinase B.
  • the term "selective for aurora kinase B” means that the inhibitor is selective for aurora kinase B over other protein kinases, and more preferably, over aurora kinase A.
  • the inhibitor exhibits a selectivity ratio for aurora kinase B over other protein kinases of greater than 2-fold, more preferably greater than 5-fold, more preferably greater than 10-fold, even more preferably greater than 25-fold, more preferably still, greater than 50-fold or 100-fold.
  • the presently claimed combination comprises a compound of formula I as described above.
  • Compounds of formula I are known in the art and have been previously described in WO 01/72745 WO 04/043953 and WO 05/116025 (all in the name of Cyclacel Ltd).
  • alkyl includes both saturated straight chain and branched alkyl groups which may be substituted (mono- or poly-) or unsubstituted.
  • the alkyl group is a C 1-20 alkyl group, more preferably a C 1-15 , more preferably still a Ci -12 alkyl group, more preferably still, a C 1-6 alkyl group, more preferably a Ci -3 alkyl group.
  • Particularly preferred alkyl groups include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl.
  • Suitable substituents include, for example, one or more substituents selected from OH, CN, CF 3 , halo, alkoxy, nitro, NH 2 , COOH and COOMe.
  • the alkyl group is unsubstituted.
  • aryl refers to a substituted (mono- or poly-) or unsubstituted monoaromatic or polyaromatic system, wherein said polyaromatic system may be fused or unfused.
  • aryl includes groups having from 6 to 10 carbon atoms, e.g. phenyl, naphthyl etc. Suitable substituents include alkyl and those listed above for alkyl.
  • aralkyl is used as a conjunction of the terms alkyl and aryl as given above. Preferred aralkyl groups include CH 2 Ph and CH 2 CH 2 Ph and the like. Preferably, the aralkyl group is unsubstituted.
  • alicyclic refers to a cyclic aliphatic group.
  • heteroalicylic refers to an alicylic group containing one or more heteroatoms selected from O, S and N.
  • Preferred alicyclic groups include piperidinyl, pyrrolidinyl, piperazinyl and morpholinyl. More preferably, the alicyclic group is selected from N- piperidinyl, N-pyrrolidinyl, N-piperazinyl and N-morpholinyl
  • R is H and R is H or alkyl.
  • R is H and R is Me or Et.
  • R is methyl
  • R 4 is a morpholinyl, piperidinyl or piperazinyl group, each of which may be optionally substituted by one or more substituents selected from alkyl, CO-alkyl and aralkyl.
  • R 4 is a morpholinyl, piperidinyl or piperazinyl group, each of which may be optionally substituted by one or more substituents selected from Me, CO-Me and CH 2 Ph.
  • R 4 is N-piperidinyl optionally substituted by Me or COMe; or N-morpholinyl.
  • the compound of formula I is selected from the following:
  • the compound of formula I is selected from compounds [1], [2] and [3], the structures of which are shown below:
  • the compound of formula I is compound [I].
  • kits of parts comprising: (i) a compound of formula I, or a pharmaceutically acceptable salt thereof; (ii) cisplatin; and
  • the kit of parts further comprises instructions to administer said compound of formula I, or pharmaceutically acceptable salt thereof, and cisplatin in accordance with a dosing regimen.
  • said dosing regimen comprises administering the cisplatin sequentially or consecutively after administering said compound of formula I, or pharmaceutically acceptable salt thereof.
  • Another aspect of the present invention relates to a combination comprising a compound of formula I and 5-FU, or a prodrug thereof.
  • the preferred aspects set forth above for cisplatin combinations apply equally to those with 5-FU.
  • 5-Fluorouracil is an antitumour antimetabolite, extensively used in chemotherapeutic regimes against solid tumours, particularly those of gastric or colonic origin. 5-Fluorouracil was developed in 1957 based on the observation that tumour cells utilized the base pair uracil for DNA synthesis more efficiently than normal cells of the intestinal mucosa.
  • 5-FU is a fluorinated pyrimidine that is metabolized intracellularly to its active form, fluorodeoxyuridine monophophate (FdUMP). The active form inhibits DNA synthesis by inhibiting the normal production of thymidine.
  • 5-FU is cell cycle phase-specific (S-phase), i.e. it blocks cell progression from the S-phase of the cell cycle.
  • 5-FU may be used alone or in combination, for its palliative action in the management of common malignancies particularly cancer of the colon and breast, either as single agent or in combination with other cytotoxic agents. To date, however, there has been no suggestion of administering 5-FU in combination with a compound of formula I.
  • the present invention is based on the surprising observation that administering 5-FU and a compound of formula I in combination, either simultaneously, separately or sequentially, does not lead to any significant or dramatic adverse interaction between the two agents.
  • the unexpected absence of any such antagonistic interaction is critical for clinical applications.
  • the combination of the invention is a synergistic combination comprising a compound of formula I and 5-FU, or a prodrug thereof, i.e. the combination has a synergistic effect.
  • the combination of 5-FU, or prodrug thereof, and the compound of formula I produces an enhanced effect as compared to either drug administered alone.
  • the surprising nature of this observation is in contrast to that expected on the basis of the prior art.
  • the 5-FU is in the form of a prodrug or oral precursor.
  • the prodrug is capacitabine, an oral precursor of 5-FU.
  • one aspect of the invention relates to a pharmaceutical product comprising a compound of formula I and 5-FU, or prodrug thereof, as a combined preparation for simultaneous, sequential or separate use in therapy.
  • the compound of formula I and 5-FU, or prodrug thereof may be administered simultaneously, in combination, sequentially or separately (as part of a dosing regime).
  • One aspect of the present invention relates to the use of a compound of formula I in the preparation of a medicament for the treatment of a proliferative disorder, wherein said treatment comprises administering to a subject simultaneously, sequentially or separately 5-FU, or a prodrug thereof, and a compound of formula I.
  • the compound of formula I and 5-FU, or prodrug thereof are administered simultaneously or sequentially.
  • the 5-FU, or prodrug thereof, and compound of formula I are administered simultaneously.
  • the compound of formula I is administered to the subject prior to sequentially or separately administering the 5-FU, or prodrug thereof, i.e. the dosing involves pretreatment with the compound of formula I.
  • the 5-FU, or prodrug thereof is administered at least 2 hours, more preferably at least 4 hours, even more preferably at least 8 hours, even more preferably still at least 12 or 24 or 48 hours after the compound of formula I.
  • the 5-FU, or prodrug thereof is administered at least 24 hours after the compound of formula I.
  • Another aspect of the invention relates to a method of treating a proliferative disorder in a subject, said method comprising the sequential administration of a therapeutically effective amount of a compound of formula I followed by a therapeutically effective amount of 5-FU, or a prodrug thereof.
  • the subject is a mammal, more preferably a human.
  • Another aspect of the invention relates to the use of a compound of formula I in the manufacture of a medicament for use in the treatment of proliferative disorders comprising the sequential administration of a therapeutically effective amount of a compound of formula I followed by a therapeutically effective amount of 5 -FU, or a prodrug thereof.
  • 5-FU or a prodrug thereof, is administered to the subject prior to sequentially or separately administering the compound of formula I to said subject.
  • Another aspect of the invention relates to a method of treating a proliferative disorder in a subject, said method comprising the sequential administration of a therapeutically effective amount of 5-FU, or a prodrug thereof, followed by a therapeutically effective amount of a compound of formula I.
  • Another aspect of the invention relates to the use of a compound of formula I in the manufacture of a medicament for use in the treatment of proliferative disorders comprising the sequential administration of a therapeutically effective amount of 5- FU, or a prodrug thereof, followed by a therapeutically effective amount of a compound of formula I.
  • the compound of formula I and 5-FU, or prodrug thereof are administered sequentially.
  • the compound of formula I and 5-FU, or prodrug thereof are each administered in a therapeutically effective amount with respect to the individual components.
  • the compound of formula I and 5- FU, or prodrug thereof are each administered in a subtherapeutic amount with respect to the individual components.
  • the 5-FU is administered in an amount of about 5 to about 70 mg/kg/day, preferably about 5 to about 50 mg/kg/day, more preferably about 25 to about 45 mg/kg/day, more preferably still, about 30 to about 40 mg/kg/day, even more preferably about 40 mg/kg/day.
  • the 5-FU is administered in an amount of about 5-10 mg/kg up to a maximum dosing of 1 g per person daily.
  • the 5-FU is administered intravenously.
  • the capecitabine is administered in an amount of about 625-1250 mg/kg twice daily. In one highly preferred embodiment, the capecitabine is administered in an amount of about 1250 mg/m 2 twice daily for 14 days followed by 7 days off.
  • Another aspect of the invention relates to the use of a compound of formula I and 5- FU, or a prodrug thereof, in the preparation of a medicament for treating a proliferative disorder.
  • Yet another aspect of the invention relates to the use of a compound of formula I in the preparation of a medicament for the treatment of a proliferative disorder, wherein said medicament is for use in combination therapy with 5-FU, or a prodrug thereof.
  • a further aspect of the invention relates to the use of 5-FU, or a prodrug thereof, in the preparation of a medicament for the treatment of a proliferative disorder, wherein said medicament is for use in combination therapy with a compound of formula I.
  • the proliferative disorder is a cancer or leukaemia, most preferably cancer.
  • the cancer is selected from colon, breast, colorectal, head and neck cancer, cervical, stomach and pancreatic cancer. In one preferred embodiment, the cancer is selected from colon, colorectal and breast.
  • the invention relates to the use of the combination described herein in the treatment of an aurora kinase dependent or sensitive disorder.
  • kits of parts comprising:
  • the kit of parts further comprises instructions to administer said compound of formula I, or pharmaceutically acceptable salt thereof, and 5 -FU, or prodrug thereof, in accordance with a dosing regimen.
  • said dosing regimen comprises administering the 5-FU or prodrug thereof, sequentially or consecutively after administering said compound of formula I, or pharmaceutically acceptable salt thereof.
  • components of the present invention can be administered alone, for human therapy they will generally be administered in admixture with a pharmaceutical carrier, excipient or diluent.
  • a preferred embodiment of the invention therefore relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a combination according to the invention admixed with a pharmaceutically acceptable excipient, diluent or carrier.
  • suitable excipients for the various different forms of pharmaceutical compositions described herein may be found in the "Handbook of Pharmaceutical Excipients, 2 nd Edition, (1994), Edited by A Wade and PJ Weller.
  • Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985).
  • suitable carriers include lactose, starch, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol and the like.
  • suitable diluents include ethanol, glycerol and water.
  • compositions may comprise as, or in addition to, the carrier, excipient or diluent any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), solubilising agent(s).
  • Suitable binders include starch, gelatin, natural sugars such as glucose, anhydrous lactose, free-flow lactose, beta-lactose, corn sweeteners, natural and synthetic gums, such as acacia, tragacanth or sodium alginate, carboxymethyl cellulose and polyethylene glycol.
  • Suitable lubricants include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Preservatives, stabilizers, dyes and even flavoring agents may be provided in the pharmaceutical composition.
  • preservatives include sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid.
  • Antioxidants and suspending agents may be also used.
  • SALTS/ESTERS sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid.
  • Antioxidants and suspending agents may be also used.
  • the agents of the present invention can be present as salts or esters, in particular pharmaceutically acceptable salts or esters.
  • compositions of the agents of the invention include suitable acid addition or base salts thereof.
  • suitable pharmaceutical salts may be found in Berge et al, J Pharm Sci, 66, 1-19 (1977). Salts are formed, for example with strong inorganic acids such as mineral acids, e.g.
  • sulphuric acid, phosphoric acid or hydrohalic acids with strong organic carboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted (e.g., by halogen), such as acetic acid; with saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or tetraphthalic; with hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid; with aminoacids, for example aspartic or glutamic acid; with benzoic acid; or with organic sulfonic acids, such as (Ci-C 4 )-alkyl- or aryl-sulfonic acids which are unsubstituted or substituted (for example, by a halogen) such as methane- or p-toluene sulfonic acid.
  • Esters are formed either using organic acids or alcohols/hydroxides, depending on the functional group being esterified.
  • Organic acids include carboxylic acids, such as alkanecarboxylic acids of 1 to 12 carbon atoms which are unsubstituted or substituted (e.g., by halogen), such as acetic acid; with saturated or unsaturated dicarboxylic acid, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or tetraphthalic; with hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid; with aminoacids, for example aspartic or glutamic acid; with benzoic acid; or with organic sulfonic acids, such as (Ci-C 4 )-alkyl- or aryl-sulfonic acids which are unsubstituted or substituted (for example, by a halogen) such as methane- or p-tol
  • Suitable hydroxides include inorganic hydroxides, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminium hydroxide.
  • Alcohols include alkanealcohols of 1-12 carbon atoms which may be unsubstituted or substituted, e.g. by a halogen).
  • the invention also includes where appropriate all enantiomers and tautomers of the agents.
  • the man skilled in the art will recognise compounds that possess optical properties (one or more chiral carbon atoms) or tautomeric characteristics.
  • the corresponding enantiomers and/or tautomers may be isolated/prepared by methods known in the art.
  • agents of the invention may exist as stereoisomers and/or geometric isomers, e.g. they may possess one or more asymmetric and/or geometric centres and so may exist in two or more stereoisomeric and/or geometric forms.
  • the present invention contemplates the use of all the individual stereoisomers and geometric isomers of those agents, and mixtures thereof.
  • the terms used in the claims encompass these forms, provided said forms retain the appropriate functional activity (though not necessarily to the same degree).
  • the present invention also includes all suitable isotopic variations of the agents or pharmaceutically acceptable salts thereof.
  • An isotopic variation of an agent of the present invention or a pharmaceutically acceptable salt thereof is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.
  • isotopes that can be incorporated into the agent and pharmaceutically acceptable salts thereof include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 0, 18 0, 31 P, 32 P, 35 S, 18 F and 36 Cl, respectively.
  • isotopic variations of the agent and pharmaceutically acceptable salts thereof are useful in drug and/or substrate tissue distribution studies. Tritiated, i.e., 3 H, and carbon-14, i.e., * C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium, i.e., 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances. Isotopic variations of the agents of the present invention and pharmaceutically acceptable salts thereof can generally be prepared by conventional procedures using appropriate isotopic variations of suitable reagents.
  • the present invention also includes solvate forms of the agents of the present invention.
  • the terms used in the claims encompass these forms.
  • the invention furthermore relates to agents of the present invention in their various crystalline forms, polymorphic forms and (an)hydrous forms. It is well established within the pharmaceutical industry that chemical compounds may be isolated in any of such forms by slightly varying the method of purification and or isolation form the solvents used in the synthetic preparation of such compounds.
  • the invention also relates to combinations which comprise derivatives of the agents.
  • derivatives as used herein includes chemical modification of an agent. Illustrative of such chemical modifications would be replacement of hydrogen by a halo group, an alkyl group, an acyl group or an amino group.
  • the invention further includes agents of the present invention in prodrug form.
  • prodrugs are generally compounds wherein one or more appropriate groups have been modified such that the modification may be reversed upon administration to a human or mammalian subject.
  • Such reversion is usually performed by an enzyme naturally present in such subject, though it is possible for a second agent to be administered together with such a prodrug in order to perform the reversion in vivo.
  • esters for example, any of those described above
  • the reversion may be carried out be an esterase etc.
  • Other such systems will be well known to those skilled in the art.
  • compositions of the present invention may be adapted for oral, rectal, vaginal, parenteral, intramuscular, intraperitoneal, intraarterial, intrathecal, intrabronchial, subcutaneous, intradermal, intravenous, nasal, buccal or sublingual routes of administration.
  • compositions For oral administration, particular use is made of compressed tablets, pills, tablets, gellules, drops, and capsules. Preferably, these compositions contain from 1 to 2000 mg and more preferably from 50-1000 mg, of active ingredient per dose.
  • compositions of the present invention may also be in form of suppositories, pessaries, suspensions, emulsions, lotions, ointments, creams, gels, sprays, solutions or dusting powders.
  • transdermal administration is by use of a skin patch.
  • the active ingredients can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin.
  • the active ingredients can also be incorporated, at a concentration of between 1 and 10% by weight, into an ointment consisting of a white wax or white soft paraffin base together with such stabilisers and preservatives as may be required.
  • Injectable forms may contain between 10 - 1000 mg, preferably between 10 - 500 mg, of active ingredient per dose.
  • Compositions may be formulated in unit dosage form, i.e., in the form of discrete portions containing a unit dose, or a multiple or sub-unit of a unit dose.
  • the combination or pharmaceutical composition of the invention is administered intravenously.
  • the combination or pharmaceutical composition of the invention is administered orally.
  • a person of ordinary skill in the art can easily determine an appropriate dose of one of the instant compositions to administer to a subject without undue experimentation.
  • a physician will determine the actual dosage which will be most suitable for an individual patient and it will depend on a variety of factors including the activity of the specific agents employed, the metabolic stability and length of action of that agent, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual undergoing therapy.
  • the dosages disclosed herein are exemplary of the average case. There can of course be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
  • the agent may be administered at a dose of from 0.1 to 30 mg/kg body weight, or from 2 to 20 mg/kg, more preferably from 0.1 to 1 mg/kg body weight.
  • the compound of formula I and cytotoxic agent (5 -FU, cisplatin) are each administered in a therapeutically effective amount, preferably in the form of a pharmaceutically acceptable composition.
  • cytotoxic agent e.g., cisplatin
  • 5-FU is typically administered in accordance with a physician's direction at by intravenous injection or, intravenous or intra-arterial infusion.
  • the dosage is about 15mg/kg bodyweight but not more than Ig per infusion, diluted in 300 - 500ml of 5% glucose or 0.9% NaCl injection and given over 4 hours.
  • the daily dose may be infused over 30 - 60 minutes or may be given as a continuous infusion over 24 hours.
  • the infusion may be repeated daily until there is evidence of toxicity or a total dose of 12 - 15g has been reached.
  • a dose of 12mg/kg bodyweight may be given daily for 3 days and then, if there is no evidence of toxicity, 6mg/kg on alternate days for 3 further doses.
  • An alternative regimen is 15mg/kg as a single intravenous injection once a week throughout the course.
  • 5/7.5mg/kg bodyweight daily may be given by 24 hour continuous intra-arterial infusion.
  • an initial intensive course may be followed by maintenance therapy providing there are no significant toxic effects.
  • the initial course of fluorouracil can be repeated after an interval of 4 to 6 weeks from the last dose or, alternatively, treatment can be continued with intravenous injections of 5-15mg/kg bodyweight at weekly intervals.
  • a more recent alternative method is to give 15mg/kg IV once a week throughout the course of treatment. This obviates the need for an initial period of daily administration.
  • cisplatin is typically administered by intravenous infusion over a 6-8 hour period.
  • cisplatin is dissolved in water for injections such that the reconstituted solution contains 1 mg/ml of cisplatin.
  • This solution is preferably then diluted in 2 litres of 0.9% saline or a dextrose/saline solution (to which mannitol may be added).
  • cisplatin is administered in a dosage of 50 to 100 mg/m 2 as a single IV dose every 3 to 4 weeks, or 15 to 20 mg/m 2 intravenously daily for 5 days every 3 to 4 weeks.
  • cisplatin can be administered in a dosage of about 20 mg/m 2 or more once every 3 to 4 weeks. Dosages and frequency of application are typically adapted to the general medical condition of the patient and to the severity of the adverse effects caused, in particular to those caused to the hematopoietic, hepatic and to the renal system.
  • the compound of formula I is administered orally or intravenously.
  • 5-FU and cisplatin are administered in the manner deemed most suitable at an appropriate dosage as discussed above.
  • the cytotoxic agent (5-FU, cisplatin) is administered at least 4, more preferably at least 8, more preferably at least 12, more preferably at least 16, more preferably at least 20, and even more preferably, at least 24 hours after the administration of the compound of formula I.
  • the compound of formula I is administered for 24 hours, followed by 72 hour treatment with the cytotoxic agent. This cycle may be repeated one or more times.
  • the compound of formula I is typically administered orally or intravenously at a dosage of from about 0.05 to about 5g/day, preferably from about 0.5 to about 5 g/day or 1 to about 5 g/day, and even more preferably from about 1 to about 3 g/day.
  • the compound of formula I is preferably administered at a dosage of about 0.4 to about 3 g/day.
  • the compound of formula I is preferably administered orally in tablets or capsules.
  • the total daily dose of the compound of formula I can be administered as a single dose or divided into separate dosages administered two, three or four time a day.
  • Figure 1 shows the effect of different scheduling of compound [1] and 5-FU in H460 cells. Combination experiments were carried out in H460 cells as described in the accompanying examples. Three different treatment regimes were tested: 24h 5-FU followed by 72h compound [1] (A); 24h of compound [1] followed by 72h 5-FU (B); 72h concomitant treatment (C). After drug treatments, cell viability was determined using the Alamar blue assay and the C.I values calculated using the Calcusyn software and median effect graphs plotted. Data shown are from a representative experiment.
  • Figure 2 shows the effect of different scheduling of compound [1] and 5-FU in Hl 299 cells. Combination experiments were carried out in Hl 299 cells as described in the accompanying examples. Three different treatment regimes were tested: 24h 5-FU followed by 72h compound [1] (A); 24h compound [1] followed by 72h 5-FU (B); 72h concomitant treatment (C). After drug treatments, cell viability was determined using the Alamar blue assay and the C.I values calculated using the Calcusyn software and median effect graphs plotted. Data shown are from a representative experiment.
  • Figure 3 shows the effect of different scheduling of compound [1] and cisplatin in H460 cells. Combination experiments were carried out in H460 cells as described in the accompanying examples. Three different treatment regimes were tested: 24h cisplatin followed by 72h compound [1] (A); 24h of compound [1] followed by 72h cisplatin (B); 72h concomitant treatment (C). After drug treatments, cell viability was determined using the Alamar blue assay and the C.I values calculated using the Calcusyn software and median effect graphs plotted. Data shown are from a representative experiment.
  • Figure 4 shows the effect of different scheduling of compound [1] and cisplatin in H1299 cells. Combination experiments were carried out in H1299 cells as described in the accompanying examples. Three different treatment regimes were tested: 24h cisplatin followed by 72h compound [1] (A); 24h compound [1] followed by 72h cisplatin (B); 72h concomitant treatment (C). After drug treatments, cell viability was determined using the Alamar blue assay and the C.I values calculated using the Calcusyn software and median effect graphs plotted. Data shown are from a representative experiment. EXAMPLES
  • Drugs 5-FU was obtained from Sicor Pharmaceuticals.
  • Capecitabine was obtained from Roche Pharmaceuticals.
  • Cisplatin was obtained from Bristol-Myers Squibb.
  • NCI-H460 and H1299 cells were purchased from ATCC. Cells were cultured at 37 0 C with 5% CO 2 in Dulbecco's Modified Eagles Media (DMEM) containing 10% fetal calf serum. Stock solutions of compounds were prepared in dimethyl sulphoxide (DMSO). Cytotoxicity assays

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Abstract

Un premier aspect de l'invention concerne une combinaison comprenant (a) un médicament cytotoxique choisi parmi (i) la cisplatine et (ii) 5-FU, ou un promédicament de celui-ci; et (b) un composé de formule I ou son sel acceptable pharmaceutiquement. Dans cette formule, R1 représente alkyle; R2 et R3 sont indépendamment et respectivement choisis parmi H et alkyle, et R4 désigne un groupe hétéroalicyclique éventuellement substitué par un ou plusieurs substituants choisis parmi alkyle, CO-alkyle et aralkyle. D'autres aspects ont pour objet des produits pharmaceutiques contenant la combinaison de cette invention, et des méthodes de traitement de troubles prolifératifs au moyen desdits produits.
PCT/GB2007/001763 2006-05-12 2007-05-14 Inhibiteurs de la kinase aurora à base de pyrimidine-thiazole, anticancéreux, combinés WO2007132221A1 (fr)

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WO2010074724A1 (fr) 2008-12-22 2010-07-01 Millennium Pharmaceuticals, Inc. Inhibiteurs d'aurora kinases associés avec des anticorps anti-cd20
US8309566B2 (en) 2008-02-15 2012-11-13 Rigel Pharmaceuticals, Inc. Pyrimidine-2-amine compounds and their use as inhibitors of JAK kinases
WO2015085289A1 (fr) 2013-12-06 2015-06-11 Millennium Pharmaceuticals, Inc. Combinaison d'inhibiteurs de kinase aurora et d'anticorps anti-cd30
WO2021041532A1 (fr) 2019-08-26 2021-03-04 Dana-Farber Cancer Institute, Inc. Utilisation d'héparine pour favoriser la signalisation de l'interféron de type 1
US11874276B2 (en) 2018-04-05 2024-01-16 Dana-Farber Cancer Institute, Inc. STING levels as a biomarker for cancer immunotherapy

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WO2005113550A1 (fr) * 2004-05-20 2005-12-01 Mitsubishi Pharma Corporation Dérivé d'aminopyrimidine et utilisation médicinale de celui-ci
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WO2001072745A1 (fr) * 2000-03-29 2001-10-04 Cyclacel Limited 4-heteroaryle-pyrimidines substituees en 2 et leur utilisation dans le traitement de troubles proliferants
WO2002096905A1 (fr) * 2001-06-01 2002-12-05 Vertex Pharmaceuticals Incorporated Composes de thiazole inhibiteurs des proteines kinases
WO2004043953A1 (fr) * 2002-11-14 2004-05-27 Cyclacel Limited Composes de pyrimidine
WO2005094830A1 (fr) * 2004-03-30 2005-10-13 Pfizer Products Inc. Combinaisons d'inhibiteurs de transduction de signaux
WO2005113550A1 (fr) * 2004-05-20 2005-12-01 Mitsubishi Pharma Corporation Dérivé d'aminopyrimidine et utilisation médicinale de celui-ci
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US8309566B2 (en) 2008-02-15 2012-11-13 Rigel Pharmaceuticals, Inc. Pyrimidine-2-amine compounds and their use as inhibitors of JAK kinases
US8735418B2 (en) 2008-02-15 2014-05-27 Rigel Pharmaceuticals, Inc. Pyrimidine-2-amine compounds and their use as inhibitors of JAK kinases
US9624229B2 (en) 2008-02-15 2017-04-18 Rigel Pharmaceuticals, Inc. Pyrimidine-2-amine compounds and their use as inhibitors of JAK kinases
WO2010074724A1 (fr) 2008-12-22 2010-07-01 Millennium Pharmaceuticals, Inc. Inhibiteurs d'aurora kinases associés avec des anticorps anti-cd20
WO2015085289A1 (fr) 2013-12-06 2015-06-11 Millennium Pharmaceuticals, Inc. Combinaison d'inhibiteurs de kinase aurora et d'anticorps anti-cd30
US11874276B2 (en) 2018-04-05 2024-01-16 Dana-Farber Cancer Institute, Inc. STING levels as a biomarker for cancer immunotherapy
WO2021041532A1 (fr) 2019-08-26 2021-03-04 Dana-Farber Cancer Institute, Inc. Utilisation d'héparine pour favoriser la signalisation de l'interféron de type 1

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