WO2007132228A1 - Combinaison de cndac avec une 4-hétéroaryl-pyrimidine amine 2-substituée et utilisation de celle-ci dans le traitement d'un trouble prolifératif - Google Patents

Combinaison de cndac avec une 4-hétéroaryl-pyrimidine amine 2-substituée et utilisation de celle-ci dans le traitement d'un trouble prolifératif Download PDF

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Publication number
WO2007132228A1
WO2007132228A1 PCT/GB2007/001780 GB2007001780W WO2007132228A1 WO 2007132228 A1 WO2007132228 A1 WO 2007132228A1 GB 2007001780 W GB2007001780 W GB 2007001780W WO 2007132228 A1 WO2007132228 A1 WO 2007132228A1
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compound
formula
cndac
prodrug
pharmaceutically acceptable
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PCT/GB2007/001780
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English (en)
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David Maccallum
Simon Green
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Cyclacel Limited
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Publication of WO2007132228A1 publication Critical patent/WO2007132228A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • 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
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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 5 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 0 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 5 mitotic progression.
  • a variety of cellular proteins are substrates for phosphorylation by aurora kinase enzymes, including p53, CENP-A 5 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 0 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 5 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. 0
  • 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 CNDAC, 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
  • R 4 is a heteroalicyclic group optionally substituted by one or more substituents selected from alkyl, CO-alkyl and aralkyl.
  • a second aspect provides a pharmaceutical composition
  • a pharmaceutical composition comprising a combination according to the invention admixed with a pharmaceutically acceptable carrier, diluent or excipient.
  • a third aspect relates to the use of a combination according to the invention in the preparation of a medicament for treating a proliferative disorder.
  • a fourth aspect relates to a pharmaceutical product comprising a compound of formula I and CNDAC, or a prodrug thereof, as a combined preparation for simultaneous, sequential or separate use in therapy
  • a fifth aspect relates to a method of treating a proliferative disorder, said method comprising simultaneously, sequentially or separately administering a compound of formula I and CNDAC, or a prodrug thereof, to a subject.
  • 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 treatment comprises simultaneously, sequentially or separately administering a compound of formula I and CNDAC, or a prodrug thereof, to a subject.
  • a seventh aspect relates to the use of a compound of formula I and CNDAC 5 or a prodrug thereof, in the preparation of a medicament for treating a proliferative disorder.
  • An eighth 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 CNDAC, or a prodrug thereof.
  • a ninth aspect relates to the use of CNDAC, 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 tenth aspect relates to a kit of parts comprising:
  • the present invention relates to a combination comprising a compound of formula I and CNDAC, or a prodrug thereof.
  • CNDAC is the compound known as 2'-C'-cyano-2'-dioxy-l- ⁇ -D-arabino- pentofuranosyl cytosine, also known as l-(2'-cyano- ⁇ -D-2'-deoxyarabino- furanosyl)cytosine, which has the structure shown below.
  • the present invention is based on the surprising observation that administering CNDAC 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 CNDAC, i.e. the combination has a synergistic effect.
  • the combination of CNDAC, 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 invention further includes agents of the present invention in prodrug form.
  • Such 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. Examples of such modifications include esters, wherein the reversion may be carried out be an esterase etc. Other such systems will be well known to those skilled in the art.
  • the CNDAC is in the form of a prodrug.
  • the prodrug is l-(2-C-cyano-2-dioxy- ⁇ -D-arabino-pentofuranosyl)-N 4 - palmitoyl cytosine ("CYC-682" or "CS-682"), also known as 2'-cyano-2-deoxy-N 4 - palimotoyl-1- ⁇ -D-arabinofuranosylcytosine (Hanaoka, K., et al, Int. J. Cancer, 1999:82:226-236 ; Donehower R, et al, Proc Am Soc CHn Oncol, 2000: abstract 764; Burch, PA, et al, Proc Am Soc Clin Oncol, 2001: abstract 364).
  • the preparation of CYC-682 is described in EP0536936B (Sankyo Company Limited).
  • CYC-682 is an orally administered novel 2'-deoxycytidine antimetabolite prodrug of CNDAC.
  • CYC-682 CNDAC CYC-682 has a unique mode of action over other nucleoside metabolites such as gemcitabine in that it has a spontaneous DNA strand breaking action, resulting in potent anti-tumour activity in a variety of cell lines, xenograft and metastatic cancer model.
  • CYC-682 has been the focus of a number of studies in view of its oral bioavailability and its improved activity over gemcitabine (the leading marketed nucleoside analogue) and 5-FU (a widely-used antimetabolite drug) based on preclinical data in solid tumours. Recently, investigators reported that CYC-682 exhibited strong anticancer activity in a model of colon cancer. In the same model, CYC-682 was found to be superior to either gemcitabine or 5-FU in terms of increasing survival and also preventing the spread of colon cancer metastases to the liver (Wu M, et al, Cancer Research, 2003:63:2477-2482).
  • CYC-682 has also been reported to be useful in a model for pancreatic cancer (Katz MH, Bouvet M, Takimoto S, Spivack D, Moossa AR, Hoffman RM., Cancer Res. 2003 Sep l;63(17):5521-5; Katz MH, Bouvet M, Takimoto S, Spivack D, Moossa AR, Hoffman RMCancer Res. 2004 Mar 1;64(5): 1828-33).
  • phase I data from patients with a variety of cancers suggest that CYC-682 is well tolerated in humans, with myelosuppression as the dose limiting toxicity.
  • one aspect of the invention relates to a pharmaceutical product comprising a compound of formula I and CNDAC, or a prodrug thereof, as a combined preparation for simultaneous, sequential or separate use in therapy.
  • the compound of formula I and CNDAC, or prodrug thereof 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 CNDAC, or a prodrug thereof, and a compound of formula I.
  • the compound of formula I and CNDAC, or prodrug thereof are administered simultaneously or sequentially.
  • the CNDAC, 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 CNDAC, or prodrug thereof, i.e. the dosing involves pretreatment with a compound of formula I.
  • the CNDAC, or prodrug thereof 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 compound of formula I. In one particularly preferred embodiment, the CNDAC, 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 CNDAC, or a prodrug thereof.
  • the subject is a mammal, more preferably a human.
  • the components of the combination are administered in accordance with a treatment regimen which comprises administering CNDAC (or prodrug thereof) orally for five days each week for two weeks and administering a compound of formula I orally on days 1, 3, 5, 8, 10 and 12.
  • a treatment regimen which comprises administering CNDAC (or prodrug thereof) orally for five days each week for two weeks and administering a compound of formula I orally on days 1, 3, 5, 8, 10 and 12.
  • the CNDAC (or prodrug thereof) is dosed about 12 hours after the compound of formula I. More preferably, the treatment regimen is repeated two or more times.
  • 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 CNDAC, or a prodrug thereof.
  • CNDAC, or 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 CNDAC, 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 CNDAC, or a prodrug thereof, followed by a therapeutically effective amount of a compound of formula I.
  • the compound of formula I and CNDAC, or a prodrug thereof are administered sequentially.
  • the compound of formula I and CNDAC, or prodrug thereof are each administered in a therapeutically effective amount with respect to the individual components.
  • the compound of formula I and CNDAC, or prodrug thereof 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 CNDAC, or prodrug thereof is administered in an amount of about 0.5 to about 2.5 mg/kg/day, preferably about 0.75 mg/kg/day to about 2.25 mg/kg/day, even more preferably about 1 mg/kg/day to about 2 mg/kg.
  • the CNDAC, or prodrug thereof is administered in an amount of about 100 mg a day per person or around 1.5 mg/kg/day 14 days every 21 days or about 150 mg a day or about 2.1 mg/kg/day seven days every 21 days.
  • the CNDAC, or prodrug thereof is administered orally.
  • Another aspect of the invention relates to the use of a compound of formula I and CNDAC, 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 CNDAC, or a prodrug thereof.
  • a further aspect of the invention relates to the use of CNDAC, 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 term “combination therapy” refers to therapy in which the CNDAC, or a prodrug thereof, 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 selected from lung, prostate, bladder, head and neck colon, breast, pancreatic, sarcoma and lymphoma.
  • the cancer is selected from lung, breast, prostate, bladder and pancreatic 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 which is capable of interacting with an aurora kinase and inhibiting its enzymatic 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 of formula I.
  • 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 Ci -15 , more preferably still a
  • Ci- 12 alkyl group more preferably still, a Ci -6 alkyl group, more preferably a C 1-3 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,
  • 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 2 is H and R 3 is H or alkyl.
  • R 2 is H and R 3 is H or Me or Et.
  • R 1 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: [4-(2-amino-4-methyl-thiazol-5-yl)-pyrimidin-2-yl] -(4-morpholin-4-yl-phenyl)-amine
  • the compound is selected from [1], [2] and [3].
  • the structures of compounds [1], [2] and [3] are shown below:
  • the compound of formula I is compound [I].
  • 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 compound of formula I and CNDAC, or a prodrug thereof, admixed with a pharmaceutically acceptable excipient, diluent or carrier.
  • 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.
  • 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 (Q-C ⁇ -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
  • 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 (CrC 4 )-alkyl- or aryl-sulfonic acids which are unsubstituted or substituted (for example, by a halogen) such as methane- or p-toluene sulfonic acid.
  • dicarboxylic acid for example oxalic, malonic, succinic, maleic, fumaric, phthalic or tetraphthalic
  • hydroxycarboxylic acids for example ascorbic, glycolic, lactic, malic, tart
  • 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., 14 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 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.
  • 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.
  • 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 CNDAC, or a prodrug thereof are each administered in a therapeutically effective amount preferably in the form of a pharmaceutically acceptable composition. These amounts will be familiar to those skilled in the art.
  • CNDAC is typically administered in accordance to a physicians direction at dosages of 40 mg twice daily for 14 days every 21 days, or 65 mg twice a day for 7 days every 21 days. 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.
  • CNDAC is administered in the manner deemed most suitable at an appropriate dosage as discussed above.
  • the CNDAC 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 CNDAC. This cycle may be repeated one or more times.
  • the compound of formula I is administered orally or intravenously.
  • 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 5g/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 I 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.
  • kits of parts comprising: (i) a compound of formula I, or a pharmaceutically acceptable salt thereof; (ii) CNDAC, or a prodrug thereof; and (iii) optionally a pharmaceutically acceptable diluent, excipient or carrier.
  • the kit of parts further comprises instructions to administer said compound of formula I, or pharmaceutically acceptable salt thereof, and CNDAC, or prodrug thereof, in accordance with a dosing regimen.
  • said dosing regimen comprises administering the CNDAC or prodrug thereof sequentially or consecutively after administering said compound of formula I, or pharmaceutically acceptable salt thereof.
  • Figure 1 shows the effect of different scheduling of compound [1] and CNDAC in H460 cells. Combination experiments were carried out in H460 cells as described in the accompanying examples. Three different treatment regimes were tested: 24h
  • FIG. 1 shows the effect of different scheduling of compound [1] and CNDAC in H 1299 cells. Combination experiments were carried out in H 1299 cells as described in the accompanying examples. Three different treatment regimes were tested: 24h CNDAC followed by 72h compound [1] (A); 24h compound [1] followed by 72h CNDAC (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 effects of compound [1] and sapacitabine (CYC682) alone and in combination in a DLD-I xenograft model.
  • Figure 4 shows the effects of compound [2] and CNDAC in H 1299 cells.
  • CNDAC may be prepared in accordance with the method described in EP0535231B (Sankyo Company Limited).
  • CYC-682 may be prepared in accordance with the method described in EP0536936B (Sankyo Company Limited).
  • CNDAC was obtained from Cyclacel.
  • Compounds of formula I were prepared in accordance with the methodology set forth in WO 01/72745, WO 04/043953 and WO 05/116025 (all in the name of Cyclacel Ltd).
  • 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).
  • DMEM Dulbecco's Modified Eagles Media
  • IC 50 a dilution series of each drug in media was added two hours after seeding. After a further 24 hours, media containing drug was removed and cells were re-fed with growth media only and incubated for 72h.
  • 72h ICs 0 after seeding, cells were incubated overnight and treated the following day with a dilution series of each drug in media and incubated for 72h.
  • a 20% stock of Alamar blue (Roche, Lewes, UK) was prepared in media and added to each well and incubated for two hours. Fluorescence was read at 488-595 nm and data was analysed (Excel Fit v4.0) to determine the IC 5 O (concentration of compound that inhibited cell growth by 50%) for each compound.
  • the IC 5O values after 24h treatment and 72h treatment were determined for the compound of formula I and CNDAC in both cell lines using the Alamar blue assay.
  • the compound of formula I was then tested in combination with CNDAC using three different treatment regimes: concomitant, compound of formula I pre-treatment followed by CNDAC and CNDAC pretreatment followed by the compound of formula I.
  • DLD-I human colon xenografts were grown in athymic nude mice (MCr-nu/nu). Tumour fragments (30-40 mg) were implanted in the flank and grown. Tumours with a weight range of 80-160 mg were randomly assigned to four groups of ten mice per group. Group 1; vehicle treated control. Group 2; sapacitabine dosed orally at 20 mg for five days each week for two weeks. Group 3; compound [1] dosed orally on day 1, 3, 5, 8, 10 and day 12. Group 4; a combination compound [1] dosed orally on day 1, 3, 5, 8, 10 and day 12 and sapacitabine dosed orally at 20 mg for five days each week for two weeks. Sapacitabine was dosed 12 hours after compound [I]. Tumour weight was recorded twice weekly and presented in a graph as mean tumour volume with standard error mean (Figure 3).
  • Table 4 showing sequential and concomitant treatments in H1299 cells with compound [1] and CNDAC

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Abstract

Un premier aspect de l'invention concerne une combinaison comprenant CNDAC ou un promédicament de celui-ci, et un composé de formule (I) ou un sel pharmaceutiquement acceptable de celui-ci, formule dans laquelle R1 est alkyle ; R2 et R3 sont chacun indépendamment choisis parmi H et alkyle ; et R4 est un groupe hétéroalicyclique facultativement substitué par un ou plusieurs substituants choisis parmi alkyle, CO-alkyle et aralkyle. Un second aspect de l'invention concerne un promédicament pharmaceutique comprenant un composé de formule (I) ou un sel pharmaceutiquement acceptable de celui-ci, et CNDAC ou un promédicament de celui-ci, en tant que préparation combinée pour utilisation simultanée, séquentielle ou séparée en thérapie. Un troisième aspect de l'invention concerne un procédé de traitement d'un trouble prolifératif, le procédé comprenant l'administration simultanée, séquentielle ou séparée à un sujet d'un composé de formule I ou d'un promédicament de celui-ci, et de CNDAC ou d'un promédicament de celui-ci.
PCT/GB2007/001780 2006-05-12 2007-05-14 Combinaison de cndac avec une 4-hétéroaryl-pyrimidine amine 2-substituée et utilisation de celle-ci dans le traitement d'un trouble prolifératif WO2007132228A1 (fr)

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WO2008132443A1 (fr) * 2007-04-25 2008-11-06 Cyclacel Limited Utilisation de la sapacitabine dans le traitement d'une maladie proliférative
WO2009133963A1 (fr) * 2008-04-29 2009-11-05 Taiho Pharmaceutical Co., Ltd. Procédés d'administration d'un agent anticancéreux comportant un dérivé de désoxycytidine
WO2009150405A1 (fr) * 2008-06-09 2009-12-17 Cyclacel Limited Combinaison de sapacitabine (cndac) et d’inhibiteurs d’adn méthyltransférase tels que la décitabine et la procaïne
WO2010074724A1 (fr) 2008-12-22 2010-07-01 Millennium Pharmaceuticals, Inc. Inhibiteurs d'aurora kinases associés avec des anticorps anti-cd20
CN101638808B (zh) * 2008-07-31 2012-10-17 复旦大学 筛选加强型抗肿瘤化合物的方法
WO2015085289A1 (fr) 2013-12-06 2015-06-11 Millennium Pharmaceuticals, Inc. Combinaison d'inhibiteurs de kinase aurora et d'anticorps anti-cd30
US10226478B2 (en) 2011-04-14 2019-03-12 Cyclacel Limited Dosage regimen for sapacitabine and decitabine in combination for treating acute myeloid leukemia
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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WO2005053699A1 (fr) * 2003-12-04 2005-06-16 Cyclacel Limited Combinaison d'un inhibiteur des cdk et du cs-682, ou de l'un de ses metabolites
WO2005116025A2 (fr) * 2004-05-26 2005-12-08 Cyclacel Limited Composes

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WO2005053699A1 (fr) * 2003-12-04 2005-06-16 Cyclacel Limited Combinaison d'un inhibiteur des cdk et du cs-682, ou de l'un de ses metabolites
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Cited By (20)

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US8536188B2 (en) 2007-04-25 2013-09-17 Cyclacel Limited Dosing regimens for treatment of proliferative disorders comprising administration of sapacitabine
US9675631B2 (en) 2007-04-25 2017-06-13 Cyclacel Limited Dosing regimens for treatment of proliferative disorders comprising administration of sapacitabine
WO2008132443A1 (fr) * 2007-04-25 2008-11-06 Cyclacel Limited Utilisation de la sapacitabine dans le traitement d'une maladie proliférative
AU2009240908B2 (en) * 2008-04-29 2013-10-03 Delta-Fly Pharma, Inc. Methods of administering antitumor agent comprising deoxycytidine derivative
WO2009133963A1 (fr) * 2008-04-29 2009-11-05 Taiho Pharmaceutical Co., Ltd. Procédés d'administration d'un agent anticancéreux comportant un dérivé de désoxycytidine
JP2011518761A (ja) * 2008-04-29 2011-06-30 佐々木 琢磨 デオキシシチジン誘導体を含有する抗腫瘍剤を投与する方法
US8530445B2 (en) 2008-06-09 2013-09-10 Cyclacel Limited Combinations of sapacitabine or CNDAC with DNA methyltransferase inhibitors such as decitabine and procaine
JP2015071637A (ja) * 2008-06-09 2015-04-16 サイクラセル リミテッド スパシタビン（ｃｎｄａｃ）と、デシタビン及びプロカイン等のｄｎａメチルトランスフェラーゼ阻害剤との組合せ
KR20110036547A (ko) * 2008-06-09 2011-04-07 싸이클라셀 리미티드 데시타빈 및 프로카인과 같은 ｄｎａ 메틸전이효소 저해제와 사팍시타빈 또는 ｃｎｄａｃ의 조합
JP2011522814A (ja) * 2008-06-09 2011-08-04 サイクラセル リミテッド スパシタビン（ｃｎｄａｃ）と、デシタビン及びプロカイン等のｄｎａメチルトランスフェラーゼ阻害剤との組合せ
WO2009150405A1 (fr) * 2008-06-09 2009-12-17 Cyclacel Limited Combinaison de sapacitabine (cndac) et d’inhibiteurs d’adn méthyltransférase tels que la décitabine et la procaïne
AU2009259136B2 (en) * 2008-06-09 2014-09-25 Cyclacel Limited Combinations of sapacitabine or CNDAC with DNA methyltransferase inhibitors such as decitabine and procaine
US8975239B2 (en) 2008-06-09 2015-03-10 Cyclacel Limited Combinations of sapacitabine or CNDAC with DNA methyltransferase inhibitors such as decitabine and procaine
KR101667641B1 (ko) 2008-06-09 2016-10-20 싸이클라셀 리미티드 데시타빈 및 프로카인과 같은 ｄｎａ 메틸전이효소 저해제와 사팍시타빈 또는 ｃｎｄａｃ의 조합
CN101638808B (zh) * 2008-07-31 2012-10-17 复旦大学 筛选加强型抗肿瘤化合物的方法
WO2010074724A1 (fr) 2008-12-22 2010-07-01 Millennium Pharmaceuticals, Inc. Inhibiteurs d'aurora kinases associés avec des anticorps anti-cd20
US10226478B2 (en) 2011-04-14 2019-03-12 Cyclacel Limited Dosage regimen for sapacitabine and decitabine in combination for treating acute myeloid leukemia
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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