Classifications

• • 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
  • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents

Definitions

• the present invention relates to a method for the production of an antiangiogenic and/or vascular permeability reducing effect in a warm-blooded animal such as a human, particularly a method for the treatment of a cancer, particularly a cancer involving a solid tumour, which comprises the administration of ZD6474 in combination with ionising radiation; and to the use of ZD6474 in the manufacture of a medicament for use in the production of an antiangiogenic and/or vascular permeability reducing effect in a warm-blooded animal such as a human which is being treated with ionising radiation.
• Normal angiogenesis plays an important role in a variety of processes including embryonic development, wound healing and several components of female reproductive function.
• Undesirable or pathological angiogenesis has been associated with disease states including diabetic retinopathy, psoriasis, cancer, rheumatoid arthritis, atheroma, Kaposi's sarcoma and haemangioma (Fan et al, 1995, Trends Pharmacol. Sci. 16: 57-66; Folkman, 1995, Nature Medicine 1: 27-31).
• vascular permeability is thought to play a role in both normal and pathological physiological processes (Cullinan-Bove et al, 1993, Endocrinology 133: 829-837; Senger et al, 1993, Cancer and Metastasis Reviews, 12: 303-324).
• Several polypeptides with in vitro endothelial cell growth promoting activity have been identified including, acidic and basic fibroblast growth factors (aFGF & bFGF) and vascular endothelial growth factor (NEGF).
• aFGF & bFGF acidic and basic fibroblast growth factors
• NEGF vascular endothelial growth factor
• NEGF is an important stimulator of both normal and pathological angiogenesis (Jakeman et al, 1993, Endocrinology, 133: 848-859; Kolch et al, 1995, Breast Cancer Research and Treatment, 36: 139-155) and vascular permeability (Connolly et al, 1989, J. Biol. Che 264: 20017-20024).
• Antagonism of NEGF action by sequestration of NEGF with antibody can result in inhibition of tumour growth (Kim et al, 1993, Nature 362: 841-844).
• Receptor tyrosine kinases are important in the transmission of biochemical signals across the plasma membrane of cells.
• transmembrane molecules characteristically consist of an extracellular ligand-binding domain connected through a segment in the plasma membrane to an intracellular tyrosine kinase domain. Binding of ligand to the receptor results in stimulation of the receptor-associated tyrosine kinase activity which leads to phosphorylation of tyrosine residues on both the receptor and other intracellular molecules. These changes in tyrosine phosphorylation initiate a signalling cascade leading to a variety of cellular responses. To date, at least nineteen distinct RTK subfamilies, defined by amino acid sequence homology, have been identified.
• Flt-1 the fms-like tyrosine kinase receptor Flt-1
• KDR the kinase insert domain-containing receptor
• Flt-4 another fms-like tyrosine kinase receptor
• Two of these related RTKs, Flt-1 and KDR have been shown to bind NEGF with high affinity (De Nries et al, 1992, Science 255: 989-991; Terman et al, 1992, Biochem. Biophys. Res. Comm 1992, 187: 1579-1586). Binding of NEGF to these receptors expressed in heterologous cells has been associated with changes in the tyrosine phosphorylation status of cellular proteins and calcium fluxes.
• NEGF is a key stimulus for vasculogenesis and angiogenesis.
• This cytokine induces a vascular sprouting phenotype by inducing endothelial cell proliferation, protease expression and migration, and subsequent organisation of cells to form a capillary tube (Keck, P.J., Hauser, S.D., Krivi, G., Sanzo, K., Warren, T., Feder, J., and Connolly, D.T., Science (Washington DC), 246: 1309-1312, 1989; Lamoreaux, W.J., Fitzgerald, M.E., Reiner, A., Hasty, K.A., and Charles, S.T., Microvasc.
• NEGF induces significant vascular permeability (Dvorak, H.F., Detmar, M., Claffey, K.P., ⁇ agy, J.A., van de Water, L., and Senger, D.R., (Int. Arch. Allergy Immunol., 107: 233- 235, 1995; Bates, D.O., Heald, R.I., Curry, F.E. and Williams, B. J. Physiol. (Lond.), 533: 263-272, 2001), promoting formation of a hyper-permeable, immature vascular network which is characteristic of pathological angiogenesis.
• WO 01/32651 then goes on to describe examples of such conjoint treatment including surgery, radiotherapy and various types of chemotherapeutic agent. Nowhere in WO 01/32651 does it state that use of any compound of the invention therein with other treatments will produce surprisingly beneficial effects.
• ZD6474 used in combination with ionising radiation produces significantly better anti-cancer effects than any one of ZD6474 and ionising radiation used alone.
• ZD6474 used in combination with ionising radiation produces significantly better effects against a solid tumour than any one of ZD6474 and ionising radiation used alone.
• Anti-cancer effects of a method of treatment of the present invention include, but are not limited to, anti- tumour effects, the response rate, the time to disease progression and the survival rate.
• Anti-tumour effects of a method of treatment of the present invention include, but are not limited to, inhibition of tumour growth, tumour growth delay, regression of tumour, shrinkage of tumour, increased time to regrowth of tumour on cessation of treatment, slowing of disease progression.
• a method of treatment of the present invention when administered to a warm-blooded animal such as a human, in need of treatment for cancer, with or without a solid tumour, said method of treatment will produce an effect, as measured by, for example, one or more of: the extent of the anti-tumour effect, the response rate, the time to disease progression and the survival rate.
• a method for the production of an antiangiogenic and/or vascular permeability reducing effect in a warm-blooded animal such as a human which comprises administering to said animal an effective amount of 4-(4-bromo-2- fluoroani_i_ ⁇ o)-6- ⁇ nethoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazo_ine, also known as ZD6474:
• ZD6474 or a pharmaceutically acceptable salt thereof before, after or simultaneously with an effective amount of ionising radiation.
• a method for the treatment of a cancer in a warm-blooded animal such as a human which comprises administering to said animal an effective amount of ZD6474 or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of ionising radiation.
• a method for the treatment of a cancer involving a solid tumour in a warm-blooded animal such as a human which comprises administering to said animal an effective amount of ZD6474 or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of ionising radiation.
• a warm-blooded animal such as a human which is being treated with ionising radiation means a warm-blooded animal such as a human which is treated with ionising radiation before, after or at the same time as the administration of a medicament comprising ZD6474.
• said ionising radiation may be given to said warm-blooded animal such as a human within the period of a week before to a week after the administration of a medicament comprising ZD6474.
• ZD6474 is administered to a warm-blooded animal after the animal has been treated with ionising radiation.
• the warm-blooded animal may experience the effect of each of ZD6474 and ionising radiation simultaneously.
• combination treatments of the present invention are of interest for their antiangiogenic and/or vascular permeability effects.
• Such combination treatments of the invention are expected to be useful in the prophylaxis and treatment of a wide range of disease states where inappropriate angiogenesis occurs including cancer and Kaposi's sarcoma.
• Cancer may affect any tissue and includes leukaemia, multiple myeloma and lymphoma.
• combination treatments of the invention are expected to slow advantageously the growth of primary and recurrent solid tumours of, for example, the colon, breast, prostate, lungs and skin.
• More especially combination treatments of the present invention are expected to slow advantageously the growth of tumours in lung cancer, particularly non-small cell lung cancer (NSCLC).
• NSCLC non-small cell lung cancer
• combination treatments of the invention are expected to inhibit any form of cancer associated with VEGF including leukaemia, mulitple myeloma and lymphoma and also, for example, to inhibit the growth of those primary and recurrent solid tumours which are associated with VEGF, especially those tumours which are significantly dependent on VEGF for their growth and spread, including for example, certain tumours of the colon, breast, prostate, lung, vulva and skin, particularly NSCLC.
• ZD6474 and ionising radiation are expected to inhibit the growth of those primary and recurrent solid tumours which are associated with EGF especially those tumours which are significantly dependent on EGF for their growth and spread.
• ZD6474 and ionising radiation are expected to inhibit the growth of those primary and recurrent solid tumours which are associated with both VEGF and EGF especially those tumours which are significantly dependent on NEGF and EGF for their growth and spread.
• the effect of a method of treatment of the present invention is expected to be at least equivalent to the addition of the effects of each of the components of said treatment used alone, that is, of each of ZD6474 and ionising radiation, used alone.
• the effect of a method of treatment of the present invention is expected to be greater than the addition of the effects of each of the components of said treatment used alone, that is, of each of ZD6474 and ionising radiation, used alone.
• the effect of a method of treatment of the present invention is expected to be a synergistic effect.
• a combination treatment is defined as affording a synergistic effect if the effect is therapeutically superior, as measured by, for example, the extent of the response, the response rate, the time to disease progression or the survival period, to that achievable on dosing one or other of the components of the combination treatment at its conventional dose.
• the effect of the combination treatment is synergistic if the effect is therapeutically superior to the effect achievable with ZD6474 or ionising radiation alone.
• the effect of the combination treatment is synergistic if a beneficial effect is obtained in a group of patients that does not respond (or responds poorly) to ZD6474 or ionising radiation alone.
• the effect of the combination treatment is defined as affording a synergistic effect if one of the components is dosed at its conventional dose and the other component is dosed at a reduced dose and the therapeutic effect, as measured by, for example, the extent of the response, the response rate, the time to disease progression or the survival period, is equivalent to that achievable on dosing conventional amounts of the components of the combination treatment.
• synergy is deemed to be present if the conventional dose of ZD6474 or ionising radiation may be reduced without detriment to one or more of the extent of the response, the response rate, the time to disease progression and survival data, in particular without detriment to the duration of the response, but with fewer and/or less troublesome side-effects than those that occur when conventional doses of each component are used.
• a combination method of treatment of the present invention as defined herein may be achieved by way of the simultaneous, sequential or separate administration of the individual components of said treatment.
• a combination treatment as defined herein may be applied as a sole therapy or may involve surgery, in addition to a combination method of treatment of the invention.
• Surgery may comprise the step of partial or complete tumour resection, prior to, during or after the administration of the combination treatment with ZD6474 described herein.
• compositions described herein may be in a form suitable for oral administration, for example as a tablet or capsule, for nasal administration or administration by inhalation, for example as a powder or solution, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) for example as a sterile solution, suspension or emulsion, for topical administration for example as an ointment or cream, for rectal administration for example as a suppository or the route of administration may be by direct injection into the tumour or by regional delivery or by local delivery.
• parenteral injection including intravenous, subcutaneous, intramuscular, intravascular or infusion
• sterile solution for example as a sterile solution, suspension or emulsion
• topical administration for example as an ointment or cream
• rectal administration for example as a suppository or the route of administration may be by direct injection into the tumour or by regional delivery or by local delivery.
• the ZD6474 of the combination treatment may be delivered endoscopically, intratracheally, intralesionally, percutaneously, intravenously, subcutaneously, intraperitoneally or intratumourally.
• ZD6474 is administered orally.
• the compositions described herein may be prepared in a conventional manner using conventional excipients.
• the compositions of the present invention are advantageously presented in unit dosage form
• ZD6474 will normally be administered to a warm-blooded aiiimal at a unit dose within the range 10-500mg per square metre body area of the animal, for example approximately 0.3- 15mg/kg in a human.
• 0.5-5mg kg is envisaged and this is normally a therapeutically-effective dose.
• a unit dosage form such as a tablet or capsule will usually contain, for example 25-500mg of active ingredient.
• the ionising radiation employed may be X-radiation, ⁇ -radiation or ⁇ -radiation.
• the dosages of ionising radiation will be those known for use in clinical radiotherapy.
• the radiation therapy used will include for example the use of ⁇ -rays, X-rays, and/or the directed delivery of radiation from radioisotopes.
• DNA damaging factors are also included in the present invention such as microwaves and UV-irradiation. It is most likely that all of these factors effect a broad range of damage on DNA, on the precursors of DNA, on the replication and repair of DNA and on the assembly and maintenance of chromosomes.
• X-rays may be dosed in daily doses of 1.8-2.0Gy, 5 days a week for 5-6 weeks. Normally a total fractionated dose will lie in the range 45-60Gy.
• Single larger doses, for example 5- lOGy may be administered as part of a course of radiotherapy.
• Single doses may be administered intraoperatively.
• Hyperfractionated radiotherapy may be used whereby small doses of X-rays are administered regularly over a period of time, for example 0. IGy per hour over a number of days.
• Dosage ranges for radioisotopes vary widely, and depend on the half- life of the isotope, the strength and type of radiation emitted, and on the uptake by cells.
• the size of the dose of each therapy which is required for the therapeutic or prophylactic treatment of a particular disease state will necessarily be varied depending on the host treated, the route of administration and the severity of the illness being treated. Accordingly the optimum dosage may be determined by the practitioner who is treating any particular patient. For example, it may be necessary or desirable to reduce the above-mentioned doses of the components of the combination treatments in order to reduce toxicity.
• the present invention relates to combinations of ionising radiation with ZD6474 or with a salt ofZD6474.
• Salts for use in pharmaceutical compositions will be pharmaceutically acceptable salts, but other salts may be useful in the production of ZD6474 and its pharmaceutically acceptable salts.
• Such salts may be formed with an inorganic or organic base which affords a pharmaceutically acceptable cation.
• Such salts with inorganic or organic bases include for example an alkali metal salt, such as a sodium or potassium salt, an alkaline earth metal salt such as a calcium or magnesium salt, an ammonium salt or for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2- hydroxyethyl)amine.
• ZD6474 may be made, for example, according to any of the following processes illustrated by examples (a) -(c) in which, unless otherwise stated: - (i) evaporations were carried out by rotary evaporation in vacuo and work-up procedures were carried out after removal of residual solids such as drying agents by filtration;
• the starting material was prepared as follows:
• 1,4-Diazabicyclo[2.2.2]octane (42.4g, 0.378mol) was added to a solution of l-(tert- butoxycarbonyl)-4-hydroxymethylpiperidine (52.5g, 0.244mol) in tert-butyl methyl ether (525ml). After stirring for 15 minutes at ambient temperature, the mixture was cooled to 5°C and a solution of toluene sulphonyl chloride (62.8g, 0.33mmol) in tert-butyl methyl ether (525ml) was added in portions over 2 hours while maintaining the temperature at 0°C. After stirring for 1 hour at ambient temperature, petroleum ether (11) was added. The precipitate was removed by filtration.
• Potassium carbonate (414mg, 3mmol) was added to a suspension of 4-(4-bromo-2- fluoroa ⁇ ___lino)-7-hydroxy-6-methoxyqu_nazoline (546mg, 1.5mmol) in DMF (5ml). After stirring for 10 minutes at ambient temperature, l-(tert-butoxycarbonyl)-4-(4- methylphenylsulphonyloxymethyl)piperidine (636mg, 1.72mmol) was added and the mixture was heated at 95 °C for 2 hours. After cooling, the mixture was poured onto cooled water (20ml).
• TFA (3ml) was added to a suspension of 4-(4-bromo-2-fluoroani_ino)-7-(l-(tert- butoxycarbonyl)piperidin-4-ylmethoxy)-6-methoxyquinazoline (673mg, 1.2mmol) in methylene chloride (10ml). After stirring for 1 hour at ambient temperature, the volatiles were removed under vacuu The residue was triturated with a mixture of water/ether. The organic layer was separated. The aqueous layer was washed again with ether. The aqueous layer was adjusted to pHIO with 2N aqueous sodium hydroxide. The aqueous layer was extracted with methylene chloride.
• the 6-methoxy-7-(l-methylpiperidin-4-ylmethoxy)-3,4- dfl ⁇ ydroquinazolin-4-one can be prepared as follows: Sodium hydride ( 1.44g of a 60% suspension in mineral oil, 36mmol) was added in portions over 20 minutes to a solution of 7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (8.46g, 30mmol), (prepared, for example, as described in WO 97/22596, Example 1), in DMF (70ml) and the mixture was stirred for 1.5 hours.
• Chloromethyl pivalate (5.65g, 37.5mmol) was added in portions and the mixture stirred for 2 hours at ambient temperature.
• the mixture was diluted with ethyl acetate (100ml) and poured onto ice/water (400ml) and 2N hydrochloric acid (4ml).
• the organic layer was separated and the aqueous layer extracted with ethyl acetate, the combined extracts were washed with brine, dried (MgSO 4 ) and the solvent removed by evaporation.
• Calu-6 (lung carcinoma) cells were obtained from the American Type Culture Collection (Manassas, VA). All cell culture reagents, where not specified, were obtained from Life Technologies, Paisley, UK. Cells were maintained as exponentially growing monolayers in Eagle's Minimal Essential Medium (EMEM) containing 10% FCS (Labtech International, Ringmer, UK), 2mM L-glutamine (Sigma Chemical Co., Poole, UK), 1% sodium pyruvate (lOOmM) and 1% non-essential amino acids. Cells were periodically screened for the presence of microplasma in culture, and analysed for 15 types of virus in a mouse antibody production test (AstraZeneca Central Toxicology Laboratories, Alderley Park, UK) prior to routine use in vivo.
• EMEM Eagle's Minimal Essential Medium
• Calu-6 cells (2 x 10 7 cells/ml) were prepared for implantation in a mixture of 50% (v/v) matrigel (Fred Baker, Liverpool, UK) in serum free Roswell Park Memorial Institute (RPMI)- 1640 media.
• Tumour xeno grafts were established by subcutaneously injecting 0.1ml of the cell suspension (i.e. 2 x 10 6 cells/mouse) into female Alderley Park nude mice (nu/nu genotype; 8- 10 weeks of age). Once a palpable tumour was evident, tumour volume was assessed daily by calliper measurement and calculated using the formula, length x width x height.
• mice were randomised into groups of eight, prior to treatment, when tumours measured 225-315 mm 3 .
• Ionising radiation where given, was administered at a dose rate of 2Gy per min to unanaesthetised mice restrained in polyvinyl jigs with lead shielding and a cut away section to allow local irradiation of the tumour by the unilateral beam (Pantac X-ray set).
• Jigs were turned through 180° halfway through the radiation exposure time to provide a uniform dosing. Radiation was administered either as a single dose (5Gy on day 1) or by multiple daily dosing (2Gy/day on days 1-3). Thirty minutes after the last dose of radiation, ZD6474 (25 mg kg), or vehicle, was administered by oral gavage (0.
• ZD6474 was prepared as a suspension in 1% polysorbate 80 (i.e. a 1% (v/v) solution of polyoxyethylene (20) sorbitan mono-oleate in deionised water). Mice were humanely killed when the relative volume of their tumour reached four times that at the initiation of therapy (RTV 4 ). A two-tailed two-sample t-test was used to evaluate the significance of the results obtained. Table 1 - RTV, in Davs
• mice bearing Calu-6 tumours (220-300 mm 3 ) were randomized into groups of eight, to receive either ZD6474 (50 mg/kg p.o. once daily) or vehicle only (1% polysorbate in deionized water) for the duration of the experiment.
• ZD6474, or vehicle was also administered with or without radiotherapy (3 x 2 Gy at 24-hour intervals during the first 3 days of treatment).
• radiotherapy 3 x 2 Gy at 24-hour intervals during the first 3 days of treatment.
• two treatment schedules were examined: a) Concurrent combination treatment: ZD6474 dosing given 2 hours prior to the first dose of radiation; and b) Sequential combination treatment: ZD6474 dosing given 30 minutes after the last dose of radiotherapy.
• mice bearing Calu-6 xenografts were treated with vehicle and 5 x 2 Gy of radiotherapy at 24-hour intervals. Treatment efficacy was assessed by measuring the time for tumours to quadruple in volume (RTV 4 ) from their pretreatment size and calculating the relative growth delay (i.e. comparing RTV 4 values from individual treated groups, with that of the control).
• the antitumour effect produced by sequential combination treatment with 3 x 2 Gy radiation and 50 mg/kg ZD6474 was greater than the sum of the growth delays induced by the individual therapies, and comparable to treatment with 5 x 2 Gy of radiation alone.

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