WO2008122798A2 - Pharmaceutical composition of an eg5 inhibitor and a microtubule interfering agent for the treatment of cancer - Google Patents

Pharmaceutical composition of an eg5 inhibitor and a microtubule interfering agent for the treatment of cancer Download PDF

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WO2008122798A2
WO2008122798A2 PCT/GB2008/001233 GB2008001233W WO2008122798A2 WO 2008122798 A2 WO2008122798 A2 WO 2008122798A2 GB 2008001233 W GB2008001233 W GB 2008001233W WO 2008122798 A2 WO2008122798 A2 WO 2008122798A2
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methyl
propyl
oxo
pyrimidin
benzyl
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PCT/GB2008/001233
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French (fr)
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WO2008122798A3 (en
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Jeffery Lester Brown
Dennis Huszar
Patricia Elizabeth Mccoon
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Astrazeneca Ab
Astrazeneca Uk Limited
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Publication of WO2008122798A3 publication Critical patent/WO2008122798A3/en

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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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles 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
    • A61K31/435—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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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 combinations of pharmaceutically active substances for use in the treatment of cancer.
  • Taxol® (paclitaxel), one of the most effective drugs of this class, is a microtubule stabilizer. It interferes with the normal growth and shrinkage of microtubules thus blocking the progression of cells through mitosis and resulting in cell death (Blagosklonny, M.V. and Fojo, T.: Molecular effects of paclitaxel: myths and reality (a critical review), hit J Cancer 1999, 83:151-156.).
  • Paclitaxel is known to cause abnormal bundling of microtubules in interphase cells.
  • some tumor types are refractory to treatment with paclitaxel, and other tumors become insensitive during treatment.
  • Paclitaxel is also a substrate for the multi-drug resistance pump, P-glycoprotein (see Chabner et al, 2001).
  • Kinesins are a large family of molecular motor proteins, which use the energy of adenosine 5 '-triphosphate (ATP) hydrolysis to move in a stepwise manner along microtubules.
  • ATP adenosine 5 '-triphosphate
  • Some members of this family transport molecular cargo along microtubules to the sites in the cell where they are needed. For example, some kinesins bind to vesicles and transport them along microtubules in axons.
  • mitotic kinesins as they play roles in the reorganization of microtubules that establishes a bipolar mitotic spindle.
  • the mitotic spindle lines up the chromosomes at metaphase of mitosis and coordinates their movement apart and into individual daughter cells at anaphase and telophase (cytokinesis). See Alberts, B., Bray, D., Lewis, J., Raff, M., Roberts, K., and Watson, J. D., Molecular Biology of the Cell, 3 rd edition, Chapter 18, The Mechanics of Cell Division, 1994, Garland Publishing, Inc. New York.
  • HsEg5 (homo sapiens Eg5) (Accession X85137; see Blangy, A., Lane H.A., d'Heron, P., Harper, M., Kress, M. andNigg, E.A.: Phosphorylation by p34cdc2 regulates spindle association of human Eg5, a kinesin-related motor essential for bipolar spindle formation in vivo. Cell 1995, 83(7): 1159-1169) or, KSP (kinesin spindle protein), is a mitotic kinesin whose homologs in many organisms have been shown to be required for centrosome separation in the prophase of mitosis, and for the assembly of a bipolar mitotic spindle.
  • KSP kinesin spindle protein
  • Monastrol treatment was shown to be specific for Eg5 over kinesin heavy chain, another closely related motor with different functions (Marcher et al., 1999). Monastrol blocks the release of ADP (adenosine 5 '-diphosphate) from the Eg5 motor (Maliga, Z., Kapoor, T. M., and Mitchison, T. J.: Evidence that monastrol is an allosteric inhibitor of the mitotic kinesin Eg5. Chem & Biol 2002, 9: 989-996 and DeBonis, S., Simorre, J.-P., Crevel, L, Lebeau, L, Skoufias,
  • Eg5 is thought to be necessary for mitosis in all cells, one report indicates that it is over-expressed in tumor cells (International Patent Application WO 01/31335), suggesting that they may be particularly sensitive to its inhibition.
  • Eg5 is not present on the microtubules of interphase cells, and monastrol has no detectable effect on microtubule arrays in interphase cells (Mayer et al, 1999), thus Eg5 inhibition may not produce the peripheral neuropathy associated with treatment with paclitaxel and other anti-microtubule drugs.
  • Eg5 is targeted to microtubules by phosphorylation at an early point in mitosis (Blangy et al., 1995). See also: Sawin, K. E. and Mitchison, TJ.
  • the present invention is directed, in part, to a pharmaceutical combination of an Eg5 inhibitor and a microtubule interfering agent for sequential use in therapy, and uses of the combination in methods of treatment of the human or animal body.
  • Figure 1 is a graph depicting the results obtained from the simultaneous exposure of (+) N-(3 -amino-propyl)-N-[ 1 -(5 -benzyl-3-methyl-4-oxo-4,5 -dihydro-isothiazolo[5 ,4-d]pyrimidin-6- yl)-2-methyl-propyl]-4-methyl-benzamide and paclitaxel.
  • Figure 2 is a graph depicting the results obtained from the sequential exposure of paclitaxel followed by (+) N-(3-amino-propyl)-N-[l-(5-benzyl-3-methyl-4-oxo-4,5-dihydro- isothiazolo[5,4-d]pyrimidin-6-yl)-2-memyl- ⁇ ropyl]-4-methyl-benzamide.
  • Figure 3 is a graph depicting the results obtained from the sequential exposure of : (+) N- (3 -amino-propyl)-N- [ 1 -(5 -benzyl-3 -methyl-4-oxo-4, 5 -dihydro-isothiazolo [5 ,4-d]pyrimidin-6-yl)- 2-methyl-propyl]-4-methyl-benzamide followed by paclitaxel.
  • the present invention is based on the finding that the sequential administration of an Eg5 inhibitor and a microtubule interfering agent such as taxane, in any order, is useful for inhibiting cell proliferation and is therefore useful in methods of treatment of the human or animal body.
  • the Eg5 inhibitor is selected from an enantiomer of a compound of Formula (D:
  • X is selected from -C(CH 3 )- or -S- provided that when X is -S- then Y is -C(CH 3 )-;
  • Y is selected from -C(CH 3 )- or -O- or -S- provided that when Y is -C(CH 3 )- then X is not -C(CH 3 )-; m is O or 1;
  • R 1 is F when m is 1 ;
  • R 2 and R 3 are independently selected from H or Ci_ 3 alkyl; wherein if both R 2 and R 3 are selected from Ci. 3 alkyl they are identical; n is 2 or 3;
  • R 4 and R 5 are independently selected from H or C ⁇ aUcyl
  • Z is optionally substituted phenyl, or optionally substituted benzothiophene wherein the number of optional substituents is 1 or 2 and each is independently selected from F, Cl, Br, CH 3 or CH 2 CH 3 ;
  • Examples of a compound of Formula (I) include:
  • the Eg5 inhibitor can be selected from an enantiomer of a compound of Formula (Ia):
  • Ia including a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, wherein:
  • X is selected from -C(CH 3 )- or -S- provided that when X is -S- then Y is -C(CH 3 )-;
  • Y is selected from -C(CH 3 )- or -O- or -S- provided that when Y is -C(CH 3 )- then X is not -C(CH 3 )-; m is O or 1;
  • R 1 is F when m is 1 ;
  • R 2 and R 3 are independently selected from H or Ci- 3 alkyl; wherein if both R 2 and R 3 are selected from Ci -3 alkyl they are identical; n is 2 or 3;
  • R 4 and R 5 are independently selected from H or Ci -3 alkyl
  • Z is optionally substituted phenyl, or optionally substituted benzothiophene wherein the number of optional substituents is 1 or 2 and each is independently selected from F, Cl, Br, CH 3 or CH 2 CH 3 ; wherein said enantiomer is substantially free of the (S) enantiomer.
  • Particular compounds of Formula (Ia) include:
  • stereoisomers of Fo ⁇ nula (I) are substantially free of all other stereoisomers.
  • substantially free refers to less than 10% of the other isomer, more particularly less than 5%, in particular less than 2%, more particularly less than 1%, particularly less then 0.5%, in particular less than 0.2%.
  • pharmaceutically acceptable salts refer to derivatives of the disclosed compounds, for example, compounds of Formula (I) or Formula (Ia), wherein the parent compound is modified by making acid or base salts thereof.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, phosphoric, and the like; and the salts prepared from organic acids such as lactic, maleic, citric, benzoic, methanesulfonic, and the like.
  • the pharmaceutically acceptable salts of the invention also include salts prepared with one of the following acids benzene sulfonic acid, fumaric acid, methanesulfonic acid, naphthalene- 1,5- disulfonic acid, naphthalene-2-sulfonic acid or L-tartaric acid.
  • a compound of the invention particularly one of the Eg5 inhibitors described herein, as a pharmaceutically acceptable salt, particularly a benzene sulfonic acid, fumaric acid, methanesulfonic acid, naphthalene- 1,5- disulfonic acid, naphthalene-2-sulfonic acid or L-tartaric acid salt.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • Microtubule interfering agents include both microtubule stabilizing agents and microtubule destabilizing agents.
  • a microtubule stabilizing agent can be a taxane or an epothilone.
  • Taxanes are known in the art and include (2aR,3aR,4aR,6R,9S,l lS,12S,12aR,12bS)-6,12b- diacetoxy-9-[3(S)-(tert-butoxycarbonylamino)-2(R)-hydroxy-3-phenylpropionyloxy]-12- benzoyloxy-l l-hydroxy-8,13,13-trimethyl-2a,3,3a,4,5,6,9,10,l l,12,12a,12b-dodecahydro-lH- 7,l l-methanocyclodeca[3,4]-cyclopropa[4,5]benz[l,2-b]oxet-5-one dihydrate; Paclitaxel (Taxol), BMS 184476 (7-methylthiomethylpaclitaxel); BMS 188797; BMS 275183
  • the microtubule interfering agent is a destabilizing agent such as a vinca-alkaloid.
  • Vinca-alkaloids include vinblastine, vincristine, vindesine and vinorelbine.
  • the pharmaceutical combination of the invention is for sequential administration and the combination includes a preparation of each active ingredient.
  • the preparation of an Eg5 inhibitor disclosed above are known in the art, for example, as described in WO2006/018628, the contents of which are incorporated herein by reference.
  • Preparation of microtubule interfering agents such as taxanes are also well known in the art.
  • sequential administration is meant that the Eg5 inhibitor and the microtubule interfering agent are administered separately, in any order, to achieve the desired therapeutic effect.
  • the Eg5 inhibitor is administered before the taxane.
  • the taxane is administered before the Eg5 inhibitor.
  • each agent may be at least 6 hours apart but no more than 80 hours apart.
  • the Eg5 inhibitor and taxane are administered at least 6 hours apart, 12 hours apart, 18 hours apart, 24 hours apart, 28 hours apart, 36 hours apart, 48 hours apart, 52 hours apart, 60 hours apart, 68 hours apart or 72 hours apart.
  • tumour stabilization can include tumour growth of no more than 25%, for example, measured from the longest diameter of a single tumour mass.
  • Objective shrinkage can include a reduction of tumour length or diameter, for example, of greater than 15%, 20% or more than 25%.
  • the present invention provides a method for the treatment of anti-cell proliferation such as cancer.
  • Cancers that can be treated include breast cancer, colorectal cancer, ovarian cancer, lung (non small cell) cancer, malignant brain tumors, sarcomas, melanoma and lymphoma.
  • the invention includes a method of treating a cancer comprising administering sequentially an Eg5 inhibitor, or a pharmaceutically acceptable salt thereof, and a microtubule interfering agent, to a human or animal patient in need thereof.
  • a pharmaceutical combination which is administered sequentially that comprises an Eg5 inhibitor, or a pharmaceutically acceptable salt thereof, and a microtubule interfering agent, for use hi the treatment of cancer.
  • the invention includes:
  • Eg5 inhibitor or a pharmaceutically acceptable salt thereof, and a microtubule interfering agent, for treating cancer, wherein the Eg5 inhibitor and the microtubule interfering agent are administered sequentially, in any order.
  • a pharmaceutical combination comprising an Eg5 inhibitor, or a pharmaceutically acceptable salt thereof, and a microtubule interfering agent, for use in treating cancer wherein the Eg5 inhibitor and the microtubule interfering agent are administered sequentially, in any order.
  • the Eg5 inhibitor and the microtubule interfering agent may be administered orally, sublingually, intramuscularly, subcutaneously, topically, intranasally, intraperitoneally, intrathoracially, intravenously, epidurally, intrathecally, intracerebroventricularly and by injection into the joints.
  • the Eg5 inhibitor and the microtubule interfering agent combinations may be administered by different routes but typically the compositions will be administered by oral or parenteral administration using conventional systemic dosage forms, such as tablets, capsules, pills, powders, aqueous or oily solutions or suspensions, emulsions and sterile injectable aqueous or oily solutions or suspensions.
  • These dosage forms will usually include one or more pharmaceutically acceptable ingredients which may be selected, for example, from adjuvants, carriers, binders, lubricants, diluents, stabilising agents, buffering agents, emulsifying agents, viscosity-regulating agents, surfactants, preservatives, flavourings and colorants.
  • Preferred routes of administration are orally, intravenously or intramuscularly.
  • the Eg5 inhibitor or a pharmaceutically acceptable salt thereof, will normally be administered to a warm-blooded animal at a unit dose of 300 mg or less daily and this would be expected to provide a therapeutically-effective dose.
  • the Eg5 inhibitor will be administered from about 5 mg to 500 mg of active ingredient.
  • the Eg5 inhibitor is a conventional tablet formulation for oral administration containing 5 mg, 10 mg, 20 mg, 40 mg, 100 mg, 250 mg or 300 mg of active ingredient.
  • the daily oral dose of an Eg5 inhibitor may be above 5 mg, for example, in the range 5 to 80 mg.
  • the active ingredients may be compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
  • Dosage unit forms will generally contain about 5 mg to about 300 mg of each active ingredient.
  • the daily dose may be varied depending upon the host treated, the particular 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.
  • the microtubule interfering agent will normally be administered to a warm-blooded animal at a unit dose, for example, from about 1 mg to 500 mg of active ingredient.
  • the dose usually administered weekly, may be varied depending upon the host treated, the particular 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.
  • the dosage of each of the two drugs and their proportions have to be composed so that the best possible treatment effects, as defined by national and international guidelines (which are periodically reviewed and re-defined), will be met.
  • kits comprising an Eg5 inhibitor, or a pharmaceutically acceptable salt thereof, and a microtubule interfering agent such as taxane; optionally with instructions for use.
  • a kit comprising: a) an Eg5 inhibitor, or a pharmaceutically acceptable salt thereof, in a first unit dosage form; b) a microtubule interfering agent; in a second unit dosage form; and c) container means for containing said first and second dosage forms; and optionally d) with instructions for administering the Eg5 inhibitor and the microtubule interfering agent sequentially.
  • NCI-H226 cells were seeded in 96 well plates on Day O and treated with either a single drug, or simultaneously with both drugs, for 24 hours on Day 1. For simultaneous exposure, medium and drug were removed after 24 hours of treatment on Day 2 and replaced with medium alone; cell viability was measured on day 4.
  • medium and drug were removed 24 hours after treatment with either (+) N- (3-amino-propyl)-N-[l-(5-benzyl-3-methyl-4-oxo-4,5-dihydiO-isothiazolo[5,4-d]pyrimidin-6-yl)- 2-methyl-propyl]-4-methyl-benzamide or paclitaxel, and the other drug was added for an additional 24 hours of exposure.
  • Medium and drug were removed on Day 3, replaced with medium alone, and cell viability was measured on Day 4.
  • (+) N-(3-amino-propyl)-N-[l-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4- d]pyrimidin-6-yl)-2-methyl-propyl]-4-methyl-benzamide and paclitaxel were combined at constant ratio of IC50[paclitaxel]:IC50[(+) N-(3-amino-propyl)-N-[l-(5-benzyl-3-methyl-4-oxo- 4,5-dmydro-isothiazolo[5,4-d]pyrimidin-6-yl)-2-metliyl-propyl]-4-methyl-benzamide] (see Table 1 for examples of drug concentrations used in each cell line) and a dose response curve was generated for each drug alone and in combination.
  • a Combination Index (CI; Chou and Talalay, Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul. 1984;22:27-55) was calculated from the dose response curve, and a Combination Index curve generated which indicates whether the drug combinations are antagonistic (CI values >1), additive (CI values ⁇ 1), or synergistic (CI values ⁇ 1).
  • Figures 1-3 are representative combination index curves for treatment of NCI-H460 cells with (+) N-(3-amino-propyl)-N-[l-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4- d] ⁇ yrimidin-6-yl)-2-methyl-propyl]-4-methyl-benzamide and paclitaxel.
  • Simultaneous treatment (Fig 1) resulted in synergy at lower inhibitory concentrations (ICs), but additivity and antagonism were observed at higher ICs.
  • NCI-H226 cells In NCI-H226 cells (CI curves not shown) simultaneous treatment resulted in antagonism and additivity at lower ICs, and synergy at higher drug concentrations. Simultaneous treatment of NCI-H460d/np53 cells (CI curves not shown) resulted primarily in antagonism. However, comparable to the observations in NCI-H460 cells, sequenced treatment of both NCI-H226 and NCI-H460d/np53 cell lines was primarily synergistic in either sequence tested.

Abstract

The invention is directed, in part, to a pharmaceutical combination for sequential use in therapy comprising an Eg5 inhibitor, and a microtubule interfering agent.

Description

THERAPEUTIC METHODS 711
FIELD OF THE INVENTION
The present invention relates to combinations of pharmaceutically active substances for use in the treatment of cancer.
BACKGROUND OF THE INVENTION
One sub-class of anti-cancer drugs (taxanes, vinca-alkaloids) now used extensively in the clinic is directed at microtubules and block the cell division cycle by interfering with normal assembly or disassembly of the mitotic spindle (see Chabner, B. A., Ryan, D. P., Paz-Ares, L, Garcia-Carbonero, R., and Calabresi, P: Antineoplastic agents. In Hardman, J. G., Limbird, L.E., and Gilman, A. G., eds. Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10fll edition, 2001, The MacGraw-Hill Companies, Inc). Taxol® (paclitaxel), one of the most effective drugs of this class, is a microtubule stabilizer. It interferes with the normal growth and shrinkage of microtubules thus blocking the progression of cells through mitosis and resulting in cell death (Blagosklonny, M.V. and Fojo, T.: Molecular effects of paclitaxel: myths and reality (a critical review), hit J Cancer 1999, 83:151-156.).
Some of the side effects of treatment with paclitaxel are neutropenia and peripheral neuropathy. Paclitaxel is known to cause abnormal bundling of microtubules in interphase cells. In addition, some tumor types are refractory to treatment with paclitaxel, and other tumors become insensitive during treatment. Paclitaxel is also a substrate for the multi-drug resistance pump, P-glycoprotein (see Chabner et al, 2001).
Thus, there is a need for effective anti-mitotic agents that have fewer side effects than anti-microtubule drugs, and also for agents that are effective against taxane-resistant tumors.
Kinesins are a large family of molecular motor proteins, which use the energy of adenosine 5 '-triphosphate (ATP) hydrolysis to move in a stepwise manner along microtubules. For a review, see Sablin, E.P.: Kinesins and microtubules: their structures and motor mechanisms. Curr Opin Cell Biol 2000, 12:35-41 and Schief, W. R. and Howard, J.: Conformational changes during kinesin motility. Curr Opin Cell Biol 2001, 13:19-28.
Some members of this family transport molecular cargo along microtubules to the sites in the cell where they are needed. For example, some kinesins bind to vesicles and transport them along microtubules in axons. Several family members are mitotic kinesins, as they play roles in the reorganization of microtubules that establishes a bipolar mitotic spindle.. The mitotic spindle lines up the chromosomes at metaphase of mitosis and coordinates their movement apart and into individual daughter cells at anaphase and telophase (cytokinesis). See Alberts, B., Bray, D., Lewis, J., Raff, M., Roberts, K., and Watson, J. D., Molecular Biology of the Cell, 3rd edition, Chapter 18, The Mechanics of Cell Division, 1994, Garland Publishing, Inc. New York.
HsEg5 (homo sapiens Eg5) (Accession X85137; see Blangy, A., Lane H.A., d'Heron, P., Harper, M., Kress, M. andNigg, E.A.: Phosphorylation by p34cdc2 regulates spindle association of human Eg5, a kinesin-related motor essential for bipolar spindle formation in vivo. Cell 1995, 83(7): 1159-1169) or, KSP (kinesin spindle protein), is a mitotic kinesin whose homologs in many organisms have been shown to be required for centrosome separation in the prophase of mitosis, and for the assembly of a bipolar mitotic spindle. For a review see Kashina, A.S., Rogers, G.C., and Scholey, J.M.: The bimC family of kinesins: essential bipolar mitotic motors driving centrosome separation. Biochem Biophys Acta 1997, 1357: 257-271. Eg5 forms a tetrameric motor, and it is thought to cross-link microtubules and slide them in an anti-parallel orientation, generating the force required to separate the spindle poles during mitosis (Walczak,
C. E., Vernos, L, Mitchison, T. J., Karsenti, E., and Heald, R.: A model for the proposed roles of different microtubule-based motor proteins in establishing spindle bipolarity. Curr Biol 1998, 8:903-913). Several reports have indicated that inhibition of Eg5 function leads to metaphase block and the appearance of monopolar, or monoastral, mitotic spindles. Recently an Eg5 inhibitor called monastrol was isolated in a cell-based screen for mitotic blockers (Mayer, T.U., Kapoor, T. M., Haggarty, S.J., King, R.W., Schreiber, S.L., and Mitchison, T.J.: Small molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen. Science 1999, 286: 971-974).
Monastrol treatment was shown to be specific for Eg5 over kinesin heavy chain, another closely related motor with different functions (Mayer et al., 1999). Monastrol blocks the release of ADP (adenosine 5 '-diphosphate) from the Eg5 motor (Maliga, Z., Kapoor, T. M., and Mitchison, T. J.: Evidence that monastrol is an allosteric inhibitor of the mitotic kinesin Eg5. Chem & Biol 2002, 9: 989-996 and DeBonis, S., Simorre, J.-P., Crevel, L, Lebeau, L, Skoufias,
D. A., Blangy, A., Ebel, C, Gans, P., Cross, R., Hackney, D. D., Wade, R. H., and Kozielski, F.: Interaction of the mitotic inhibitor monastrol with human kinesin Eg5. Biochemistry 2003, 42: 338-349) an important step in the catalytic cycle of kinesin motor proteins (for review, see Sab Hn, 2000; Schief and Howard, 2001). Treatment with monastrol was shown to be reversible and to activate the mitotic spindle checkpoint which stops the progress of the cell division cycle until the chromosomes are fully attached to a bipolar mitotic spindle (Kapoor, T.M., Mayer, T. U., Coughlin, M. L., and Mitchison, TJ.: Probing spindle assembly mechanisms with monastrol, a small molecule inhibitor of the mitotic kinesin, EgS. J Cell Biol 2000, 150(5): 975-988). Recent reports also indicate that inhibitors of Eg5 lead to apoptosis of treated cells and are effective against several tumor cell lines and tumor models (Mayer et ah, 1999).
Although Eg5 is thought to be necessary for mitosis in all cells, one report indicates that it is over-expressed in tumor cells (International Patent Application WO 01/31335), suggesting that they may be particularly sensitive to its inhibition. Eg5 is not present on the microtubules of interphase cells, and monastrol has no detectable effect on microtubule arrays in interphase cells (Mayer et al, 1999), thus Eg5 inhibition may not produce the peripheral neuropathy associated with treatment with paclitaxel and other anti-microtubule drugs. Eg5 is targeted to microtubules by phosphorylation at an early point in mitosis (Blangy et al., 1995). See also: Sawin, K. E. and Mitchison, TJ. : Mutations in the kinesin-like protein Eg5 disrupting localization to the mitotic spindle. Proc Natl Acad Sci USA 1995, 92(10): 4289-4293. Certain pyrimidones have recently been described as being inhibitors of KSP (WO 03/094839, WO 03/099211, WO 03/050122, WO 03/050064, WO 03/049679, WO 03/049527, WO 04/078758, WO 04/106492 and WO 04/111058).
SUMMARY OF THE INVENTION
The present invention is directed, in part, to a pharmaceutical combination of an Eg5 inhibitor and a microtubule interfering agent for sequential use in therapy, and uses of the combination in methods of treatment of the human or animal body. BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a graph depicting the results obtained from the simultaneous exposure of (+) N-(3 -amino-propyl)-N-[ 1 -(5 -benzyl-3-methyl-4-oxo-4,5 -dihydro-isothiazolo[5 ,4-d]pyrimidin-6- yl)-2-methyl-propyl]-4-methyl-benzamide and paclitaxel. (Fa = fraction affected and Ci = combination index).
Figure 2 is a graph depicting the results obtained from the sequential exposure of paclitaxel followed by (+) N-(3-amino-propyl)-N-[l-(5-benzyl-3-methyl-4-oxo-4,5-dihydro- isothiazolo[5,4-d]pyrimidin-6-yl)-2-memyl-ρropyl]-4-methyl-benzamide. (Fa = fraction affected and Ci = combination index).
Figure 3 is a graph depicting the results obtained from the sequential exposure of : (+) N- (3 -amino-propyl)-N- [ 1 -(5 -benzyl-3 -methyl-4-oxo-4, 5 -dihydro-isothiazolo [5 ,4-d]pyrimidin-6-yl)- 2-methyl-propyl]-4-methyl-benzamide followed by paclitaxel. (Fa = fraction affected and Ci = combination index).
DETAILED DESCRRIPTION
The present invention is based on the finding that the sequential administration of an Eg5 inhibitor and a microtubule interfering agent such as taxane, in any order, is useful for inhibiting cell proliferation and is therefore useful in methods of treatment of the human or animal body.
In one aspect, the Eg5 inhibitor is selected from an enantiomer of a compound of Formula (D:
Figure imgf000005_0001
including a pharmaceutically acceptable salt thereof, wherein:
X is selected from -C(CH3)- or -S- provided that when X is -S- then Y is -C(CH3)-;
Y is selected from -C(CH3)- or -O- or -S- provided that when Y is -C(CH3)- then X is not -C(CH3)-; m is O or 1;
R1 is F when m is 1 ;
R2 and R3 are independently selected from H or Ci_3alkyl; wherein if both R2 and R3 are selected from Ci.3alkyl they are identical; n is 2 or 3;
R4 and R5 are independently selected from H or C^aUcyl;
Z is optionally substituted phenyl, or optionally substituted benzothiophene wherein the number of optional substituents is 1 or 2 and each is independently selected from F, Cl, Br, CH3 or CH2CH3; and
"*" represents a chiral center; wherein said enantiomer is substantially free of the other enantiomer; and wherein the optical rotation of the enantiomer, when said enantiomer is dissolved at a concentration of lmg/ml in methanol, at 20.0 0C measured at 589 nM is (+).
Examples of a compound of Formula (I) include:
(+) N-(3-Amino-propyl)-N-[l-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4- d]pyrimidin-6-yl)-propyl]-4-methyl-benzamide;
(+) N-(3-Amino-propyl)-N-{l-[5-(4-fluoro-benzyl)-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4- d]pyrimidin-6-yl]-propyl}-4-methyl-benzamide;
(+) N-(3-Amino-propyl)-N- { 1 -[5-(3-fluoro-benzyl)-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4- d]pyrimidin-6-yl]-propyl}-4-methyl-benzamide;
(+) N-(3-Amino-propyl)-N-[l-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4- d]pyrimidin-6-yl)-propyl]-4-bromo-benzamide;
(+) N-(3-Amino-propyl)-N-[l-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4- d]pyrimidin-6-yl)-propyl]-4-chloro-benzamide; (+) N-(3-Amino-propyl)-N-[l-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4- d]pyrimidin-6-yl)-propyl] -3 -fluoro-4-methyl-benzamide;
(+) N-(3-Amino-propyl)-N-[] -(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4- d]pyrimidin-6-yl)-propyl]-2,3-dichloro-benzamide;
(+) Benzo[b]thiophene-2-carboxylic acid (3-ainino-propyl)-[l-(5-benzyl-3-niethyl-4-oxo-4,5- dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-propyl]amide;
(+) N-(2-Amino-ethyl)-N-[l-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-
6-yl)-propyl]-4-methyl-benzamide;
(+) N-[l-(5-Benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-propyl]-N-(3- dimethylamino-propyl)-4-methyl-benzamide;
(+) N-[l-(5-Benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-propyl]-N-(3- isopropylamino-propyl)-4-methyl-benzamide;
(+) N-(3-Aniino-propyl)-N-[l-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isoxazolo[5,4-d]pyrimidin-
6-yl)-propyl]-4-methyl-benzamide;
(+) N-(3-Arnino-propyl)-N- { 1 -[5-(4-fluoro-benzyl)-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4- d]ρyrimidin-6-yl]-2-methyl-propyl}-4-methyl-benzamide;
(+) N-(3-Amino-propyl)-N-[l-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4- d]pyrimidin-6-yl)-2-methyl-propyl]-4-methyl-benzamide;
(+) N-(3-Amino-propyl)-N- { 1 -[5-(3-fluoro-benzyl)-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4- d]pyrimidin-6-yl]-2-methyl-propyl}-4-methyl-benzamide;
(+) N-(2-Amino-ethyl)-N-[l-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-
6-yl)-2-methyl-propyl]-4-bromo-benzamide;
(+) N-(2-Amino-ethyl)-N-[l-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-
6-yl)-2-methyl-propyl]-4-methyl-benzamide;
(+) N-(2-Amino-ethyl)-N-[l-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyriniidin-
6-yl)-2-methyl-propyl]-3-fluoro-4-methyl-benzamide;
(+) N-(3-Amino-propyl)-N-[l-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4- d]pyrimidin-6-yl)-2-methyl-propyl]-3-fluoro-4-methyl-benzamide;
(+) N-(3-Amino-propyl)-N-[l-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4- d]pyrimidin-6-yl)-2-methyl-propyl]-4-bromo-benzamide; (+) N-[l-(5-Benzyl-3-metlαyl-4-oxo-4,5-diliydro-isothiazolo[5,4-d.]pyrimidin-6-yl)-2-methyl- propyl] -N-(3 -dimethylamino-propyl)-4-methyl-benzamide;
(+) N-[l-(5-Benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-2-methyl- propyl]-N-(3-dimethylamino-propyl)-4-bromo-benzamide;
(+) N-[l-(5-Benzyl-3-methyl-4-oxo-4,5-dihydiO-isothiazolo[5,4-d]pyrimidin-6-yl)-2-methyl- propyl]-N-(3-dimethylamino-propyl)-3-fluoro-4-methyl-benzamide;
(+) N-(3 -Amino-propyl)-N- [ 1 -(5 -benzyl-3 -methyl-4-oxo-4,5 -dihydro-isoxazolo [5 ,4-d]pyrimidin-
6-yl)-2-methyl-propyl]-4-methyl-benzamide;
(+) N-(3-Amino-propyl)-N-{l-[5-(4-fluoro-benzyl)-3-methyl-4-oxo-4,5-dihydro-isoxazolo[5,4- d]pyrimidin-6-yl]-2-methyl-propyl}-4-methyl-benzamide;
(+) N-(3 - Amino-propyl)-N- { 1 - [5 -(3 ~fiuoro-benzyl)-3 -methyl-4-oxo-4,5 -dihydro-isoxazolo [5 ,4- d]pyrimidin-6-yl]-2-methyl-ρropyl}-4-methyl-benzamide;
(+) N-(3-Amino-propyl)-N-[l-(6-benzyl-3-methyl-7-oxo-6,7-dihydro-isothiazolo[4,5- d]pyrimidin-5-yl)-propyl]-4-methyl-benzamide; or a pharmaceutically acceptable salt thereof; wherein the (+) optical rotation of the enantiomer is measured at a concentration of lmg/ml in methanol, at 20.0 0C at 589 nM.
In another aspect, the Eg5 inhibitor can be selected from an enantiomer of a compound of Formula (Ia):
Figure imgf000008_0001
Ia including a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, wherein:
X is selected from -C(CH3)- or -S- provided that when X is -S- then Y is -C(CH3)-;
Y is selected from -C(CH3)- or -O- or -S- provided that when Y is -C(CH3)- then X is not -C(CH3)-; m is O or 1;
R1 is F when m is 1 ;
R2 and R3 are independently selected from H or Ci-3alkyl; wherein if both R2 and R3 are selected from Ci-3alkyl they are identical; n is 2 or 3;
R4 and R5 are independently selected from H or Ci-3alkyl;
Z is optionally substituted phenyl, or optionally substituted benzothiophene wherein the number of optional substituents is 1 or 2 and each is independently selected from F, Cl, Br, CH3 or CH2CH3; wherein said enantiomer is substantially free of the (S) enantiomer.
Particular compounds of Formula (Ia) include:
(R) N-(3-Amino-propyl)-N-[l-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4- t/]pyrimidin-6-yl)-propyl]-4-methyl-benzamide;
(R) Ν-(3-Amino-propyl)-Ν-{l-[5-(4-fluoro-benzyl)-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4- d]pyrimidin-6-yl]-propyl}-4-methyl-benzamide;
(R) N-(3-Amino-propy I)-N- { l-[5-(3-fluoro-benzyl)-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4- d]pyrimidin-6-yl]-propyl}-4-methyl-benzamide;
(R) N-(3-Amino-propyl)-N-[l-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4- d]pyrimidin-6-yl)-propyl]-4-bromo-benzamide;
(R) N-(3-Amino-propyl)-N-[l-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4- d]pyrimidin-6-yl)-propyl]-4-chloro-benzamide;
(R) N-(3-Amino-propyl)-N-[l-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4- d]pyrimidin-6-yl)-propyl]-3-fluoro-4-methyl-benzamide;
(R) N-(3-Amino-propyl)-N-[l-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4- d]pyrimidin-6-yl)-propyl]-2,3-dichloro-benzamide; (R) Benzo[b]thiophene-2-carboxylic acid (3-amino-propyl)-[l-(5-benzyl-3-methyl-4-oxo-4,5- dihydro-isothiazolo [5 ,4-d]pyrimidin-6-yl)-propyl] amide;
(R) N-(2-Amino-ethyl)-N-[l-(5-ben2yl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-
6-yl)-propyl]-4-methyl-benzamide;
(R) N-[l-(5-Benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-propyl]-N-(3- dimethylamino-propyl)-4-methyl-benzamide;
(R) N-[l-(5-Benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-propyl]-N-(3- isoproρylamino-propyl)-4-methyl-benzamide;
(R) N-(3-Amino-propyl)-N-[l-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isoxazolo[5,4-d]pyrimidin-
6-yl)-propyl]-4-methyl-benzamide;
(R) N-(3-Amino-propyl)-N-{l-[5-(4-fluoro-benzyl)-3-methyl-4-oxo-4,5-dihydro-isotliiazolo[5,4- d]pyrimidin-6-yl]-2-methyl-propyl}-4-metiiyl-benzamide;
(R) N-(3-Amino-propyl)-N-[l-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4- d]pyrimidin-6-yl)-2-methyl-proρyl]-4-methyl-benzamide;
(R) N-(3-Amino-propyl)-N- { 1 -[5-(3-fluoro-benzyl)-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4- d]pyrimidin-6-yl]-2-methyl-propyl}-4-methyl-benzamide;
(R) N-(2-Amino-ethyl)-N-[l-(5-ben2yl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-
6-yl)-2-methyl-propyl]-4-bromo-benzamide;
(R) N-(2-Amino-ethyl)-N-[l-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-
6-yl)-2-methyl-propyl]-4-methyl-benzamide;
(R) N-(2-Amino-ethyl)-N-[l-(5-ben2yl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-
6-yl)-2-methyl-propyl]-3-fluoro-4-methyl-benzamide;
(R) N-(3-Amino-propyl)-N-[l-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4- d]pyrimidin-6-yl)-2-methyl-propyl]-3-fluoro-4-methyl-benzamide;
(R) N-(3-Amino-propyl)-N-[l-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4- d]pyrimidin-6-yl)-2-methyl-propyl]-4-bromo-benzamide;
(R) N-[l-(5-Benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-2-methyl- propyl]-N-(3-dimethylaiτιino-propyl)-4-methyl-benzamide;
(R) N-[l-(5-Benzyl-3-metliyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-2-methyl- ρropyl]-N-(3-dimethylamino-propyl)-4-bromo-benzamide; (R) N-[l-(5-Ben2yl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-2-methyl- propyl]-N-(3-dimethylamino-propyl)-3-fluoro-4-methyl-benzamide;
(R) N-(3-Amino-propyl)-N-[l-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isoxazolo[5,4-d]pyrimidin-
6-yl)-2-methyl-propyl]-4-methyl-benzamide;
(R) N-(3-Amino-propyl)-N-{l-[5-(4-fluoro-benzyl)-3-methyl-4-oxo-4,5-dihydro-isoxazolo[5,4- d]pyrimidin-6-yl]-2-memyl-propyl}-4-methyl-benzamide;
(R) N-(3-Amino-propyl)-N-{l-[5-(3-fluoro-benzyl)-3-methyl-4-oxo-4,5-dihydro-isoxazolo[5,4- d]pyrimidin-6-yl]-2-methyl-propyl} -4-methyl-benzamide; or
(R) N-(3-Amino-propyl)-N-[l-(6-benzyl-3-methyl-7-oxo-6,7-dihydro-isothiazolo[4,5- d]pyrimidin-5-yl)-propyl]-4-methyl-benzamide; or a pharmaceutically acceptable salt thereof.
Said compounds of formula (Ia) may be used, where appropriate, with any of the definitions, claims or embodiments defined hereinbefore or hereinafter, particularly where compounds of formula (I) are referred to.
In one embodiment, stereoisomers of Foπnula (I) are substantially free of all other stereoisomers.
The term "substantially free" refers to less than 10% of the other isomer, more particularly less than 5%, in particular less than 2%, more particularly less than 1%, particularly less then 0.5%, in particular less than 0.2%.
As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds, for example, compounds of Formula (I) or Formula (Ia), wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, phosphoric, and the like; and the salts prepared from organic acids such as lactic, maleic, citric, benzoic, methanesulfonic, and the like. The pharmaceutically acceptable salts of the invention also include salts prepared with one of the following acids benzene sulfonic acid, fumaric acid, methanesulfonic acid, naphthalene- 1,5- disulfonic acid, naphthalene-2-sulfonic acid or L-tartaric acid.
Thus in one aspect of the invention there is provided a compound of the invention, particularly one of the Eg5 inhibitors described herein, as a pharmaceutically acceptable salt, particularly a benzene sulfonic acid, fumaric acid, methanesulfonic acid, naphthalene- 1,5- disulfonic acid, naphthalene-2-sulfonic acid or L-tartaric acid salt.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
Any microtubule interfering agent can be used in the combination of the present invention. Microtubule interfering agents include both microtubule stabilizing agents and microtubule destabilizing agents.
In one example, a microtubule stabilizing agent can be a taxane or an epothilone. Taxanes are known in the art and include (2aR,3aR,4aR,6R,9S,l lS,12S,12aR,12bS)-6,12b- diacetoxy-9-[3(S)-(tert-butoxycarbonylamino)-2(R)-hydroxy-3-phenylpropionyloxy]-12- benzoyloxy-l l-hydroxy-8,13,13-trimethyl-2a,3,3a,4,5,6,9,10,l l,12,12a,12b-dodecahydro-lH- 7,l l-methanocyclodeca[3,4]-cyclopropa[4,5]benz[l,2-b]oxet-5-one dihydrate; Paclitaxel (Taxol), BMS 184476 (7-methylthiomethylpaclitaxel); BMS 188797; BMS 275183; CYC-3204 (a penetratin-paclitaxel conjugate); docosahexaenoic acid-paclitaxel conjugate (TaxoprexinTm); DJ- 927; Docetaxel (Taxotere); XRP9881 (RPR-109881A); XRP6258 (RPRl 12658); Milataxel; MST 997; MBT-206; NBT-287; ortataxel; Protax-3; PG-TXL; PNU-166945; 106258; BMS-188797; 109881; BAY 598862 (IDN 5109; semisynthetic taxane); paclitaxel protein-bound (AbraxaneTm), Protaxel and MAC-321 (Taxalog). Example of epothilones include epothilone A, B and D.
In yet another example, the microtubule interfering agent is a destabilizing agent such as a vinca-alkaloid. Vinca-alkaloids include vinblastine, vincristine, vindesine and vinorelbine. The pharmaceutical combination of the invention is for sequential administration and the combination includes a preparation of each active ingredient. The preparation of an Eg5 inhibitor disclosed above are known in the art, for example, as described in WO2006/018628, the contents of which are incorporated herein by reference. Preparation of microtubule interfering agents such as taxanes are also well known in the art.
By sequential administration is meant that the Eg5 inhibitor and the microtubule interfering agent are administered separately, in any order, to achieve the desired therapeutic effect. In one example, the Eg5 inhibitor is administered before the taxane. In another example, the taxane is administered before the Eg5 inhibitor.
To achieve the desired therapeutic effect, the sequential administration of each agent may be at least 6 hours apart but no more than 80 hours apart. In one example, the Eg5 inhibitor and taxane are administered at least 6 hours apart, 12 hours apart, 18 hours apart, 24 hours apart, 28 hours apart, 36 hours apart, 48 hours apart, 52 hours apart, 60 hours apart, 68 hours apart or 72 hours apart.
By therapeutic effect is meant a measurable objective clinical response. For example, the sequential administration of an Eg5 inhibitor and a microtubule interfering agent results in an objective stabilization of the tumour or objective shrinkage of the tumour. Objective stabilization can include tumour growth of no more than 25%, for example, measured from the longest diameter of a single tumour mass. Objective shrinkage can include a reduction of tumour length or diameter, for example, of greater than 15%, 20% or more than 25%.
The present invention provides a method for the treatment of anti-cell proliferation such as cancer. Cancers that can be treated include breast cancer, colorectal cancer, ovarian cancer, lung (non small cell) cancer, malignant brain tumors, sarcomas, melanoma and lymphoma.
Thus, according to the invention, the invention includes a method of treating a cancer comprising administering sequentially an Eg5 inhibitor, or a pharmaceutically acceptable salt thereof, and a microtubule interfering agent, to a human or animal patient in need thereof.
According to a further aspect of the invention there is provided a pharmaceutical combination which is administered sequentially that comprises an Eg5 inhibitor, or a pharmaceutically acceptable salt thereof, and a microtubule interfering agent, for use hi the treatment of cancer. Moreover the invention includes:
Use of pharmaceutical combination of an Eg5 inhibitor, or a pharmaceutically acceptable salt thereof, and a microtubule interfering agent, for the manufacture of a medicament for treating cancer, wherein for the treatment the Eg5 inhibitor and the microtubule interfering agent are administered sequentially, in any order.
Use of an Eg5 inhibitor, or a pharmaceutically acceptable salt thereof, and a microtubule interfering agent, for treating cancer, wherein the Eg5 inhibitor and the microtubule interfering agent are administered sequentially, in any order.
A pharmaceutical combination comprising an Eg5 inhibitor, or a pharmaceutically acceptable salt thereof, and a microtubule interfering agent, for use in treating cancer wherein the Eg5 inhibitor and the microtubule interfering agent are administered sequentially, in any order.
The Eg5 inhibitor and the microtubule interfering agent may be administered orally, sublingually, intramuscularly, subcutaneously, topically, intranasally, intraperitoneally, intrathoracially, intravenously, epidurally, intrathecally, intracerebroventricularly and by injection into the joints. The Eg5 inhibitor and the microtubule interfering agent combinations may be administered by different routes but typically the compositions will be administered by oral or parenteral administration using conventional systemic dosage forms, such as tablets, capsules, pills, powders, aqueous or oily solutions or suspensions, emulsions and sterile injectable aqueous or oily solutions or suspensions. These dosage forms will usually include one or more pharmaceutically acceptable ingredients which may be selected, for example, from adjuvants, carriers, binders, lubricants, diluents, stabilising agents, buffering agents, emulsifying agents, viscosity-regulating agents, surfactants, preservatives, flavourings and colorants. Preferred routes of administration are orally, intravenously or intramuscularly.
The Eg5 inhibitor, or a pharmaceutically acceptable salt thereof, will normally be administered to a warm-blooded animal at a unit dose of 300 mg or less daily and this would be expected to provide a therapeutically-effective dose. For example, the Eg5 inhibitor will be administered from about 5 mg to 500 mg of active ingredient. In one example the Eg5 inhibitor is a conventional tablet formulation for oral administration containing 5 mg, 10 mg, 20 mg, 40 mg, 100 mg, 250 mg or 300 mg of active ingredient. Conveniently the daily oral dose of an Eg5 inhibitor may be above 5 mg, for example, in the range 5 to 80 mg. For a single dosage form, the active ingredients may be compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition. Dosage unit forms will generally contain about 5 mg to about 300 mg of each active ingredient. However the daily dose may be varied depending upon the host treated, the particular 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.
The microtubule interfering agent will normally be administered to a warm-blooded animal at a unit dose, for example, from about 1 mg to 500 mg of active ingredient. The dose, usually administered weekly, may be varied depending upon the host treated, the particular 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.
The dosage of each of the two drugs and their proportions have to be composed so that the best possible treatment effects, as defined by national and international guidelines (which are periodically reviewed and re-defined), will be met.
According to a further aspect of the present invention there is provided a kit comprising an Eg5 inhibitor, or a pharmaceutically acceptable salt thereof, and a microtubule interfering agent such as taxane; optionally with instructions for use. For example, there is provided a kit comprising: a) an Eg5 inhibitor, or a pharmaceutically acceptable salt thereof, in a first unit dosage form; b) a microtubule interfering agent; in a second unit dosage form; and c) container means for containing said first and second dosage forms; and optionally d) with instructions for administering the Eg5 inhibitor and the microtubule interfering agent sequentially.
It is contemplated that the invention described herein is not limited to the particular methodology, protocols, and reagents described as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention in any way. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods, devices and materials are herein described. AU publications mentioned herein are incorporated by reference for the purpose of describing and disclosing the materials and methodologies that are reported in the publication which might be used in connection with the invention.
The present invention will now be further understood by reference to the following illustrative examples.
EXAMPLES
The anti-proliferative activity of (+) N-(3-amino-propyl)-N-[l-(5-benzyl-3-methyl-4-oxo- 4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-2-methyl-propyl]-4-methyl-benzamide was evaluated in combination with paclitaxel (Calbiochem, Ltd) in an MTS tetrazolium colorimetric assay (Promega Corporation). NCI-H460, NCI-H460d/np53 (NCI-H460 cells transfected with a dominant negative p53 construct as described in Shaulian, E. Zauberman, A. Milner, J. Davies, E A. Oren, M. EMBO Journal. 12:2789-97, 1993) and NCI-H226 cells were seeded in 96 well plates on Day O and treated with either a single drug, or simultaneously with both drugs, for 24 hours on Day 1. For simultaneous exposure, medium and drug were removed after 24 hours of treatment on Day 2 and replaced with medium alone; cell viability was measured on day 4. For sequential exposure, medium and drug were removed 24 hours after treatment with either (+) N- (3-amino-propyl)-N-[l-(5-benzyl-3-methyl-4-oxo-4,5-dihydiO-isothiazolo[5,4-d]pyrimidin-6-yl)- 2-methyl-propyl]-4-methyl-benzamide or paclitaxel, and the other drug was added for an additional 24 hours of exposure. Medium and drug were removed on Day 3, replaced with medium alone, and cell viability was measured on Day 4.
(+) N-(3-amino-propyl)-N-[l-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4- d]pyrimidin-6-yl)-2-methyl-propyl]-4-methyl-benzamide and paclitaxel were combined at constant ratio of IC50[paclitaxel]:IC50[(+) N-(3-amino-propyl)-N-[l-(5-benzyl-3-methyl-4-oxo- 4,5-dmydro-isothiazolo[5,4-d]pyrimidin-6-yl)-2-metliyl-propyl]-4-methyl-benzamide] (see Table 1 for examples of drug concentrations used in each cell line) and a dose response curve was generated for each drug alone and in combination. A Combination Index (CI; Chou and Talalay, Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul. 1984;22:27-55) was calculated from the dose response curve, and a Combination Index curve generated which indicates whether the drug combinations are antagonistic (CI values >1), additive (CI values ~1), or synergistic (CI values <1).
Table 1 IC50 Values Used to Determine paclitaxel: (+) N-(3-amino-propyl)-N-[l-(5- benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-2- methyl-propyl]-4-methyl-benzamide Ratio and Top Concentration Used in Combination (uM)
Drug H460 H460dnp53 H226 IC50 Top Cone. IC50 Top Cone. IC50 Top Cone.
Paclitaxel 0.009 1.0 0.0037 1.0 0.018 10.0 Eg5 Inhibit 0.010 1.11 0.004 1.11 0.023 12.83
Shown in Figures 1-3 are representative combination index curves for treatment of NCI-H460 cells with (+) N-(3-amino-propyl)-N-[l-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4- d]ρyrimidin-6-yl)-2-methyl-propyl]-4-methyl-benzamide and paclitaxel. Simultaneous treatment (Fig 1) resulted in synergy at lower inhibitory concentrations (ICs), but additivity and antagonism were observed at higher ICs. In contrast, sequential exposure of cells to (+) N-(3-amino-propyl)- N-[l-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-2-methyl-ρropyl]- 4-methyl-benzamide and paclitaxel, in either order, resulted in a synergistic enhancement of growth inhibition at all drug concentrations tested (Figs 2 and 3).
In NCI-H226 cells (CI curves not shown) simultaneous treatment resulted in antagonism and additivity at lower ICs, and synergy at higher drug concentrations. Simultaneous treatment of NCI-H460d/np53 cells (CI curves not shown) resulted primarily in antagonism. However, comparable to the observations in NCI-H460 cells, sequenced treatment of both NCI-H226 and NCI-H460d/np53 cell lines was primarily synergistic in either sequence tested.

Claims

What is claimed is:
1. A pharmaceutical combination for sequential use in therapy comprising: an Eg5 inhibitor selected from an enantiomer of a compound of Formula (I):
Figure imgf000018_0001
I including a pharmaceutically acceptable salt thereof, wherein:
X is selected from -C(CHs)- or -S- provided that when X is -S- then Y is -C(CH3)-;
Y is selected from -C(CH3)- or -O- or -S- provided that when Y is -C(CH3)- then X is not -C(CH3)-; m is O or 1;
R1 is F when m is 1;
R2 and R3 are independently selected from H or Ci_3alkyl; wherein if both R2 and R3 are selected from Ci-3alkyl they are identical; n is 2 or 3;
R4 and R5 are independently selected from H or Ci-3alkyl;
Z is optionally substituted phenyl, or optionally substituted benzothiophene wherein the number of optional substituents is 1 or 2 and each is independently selected from F, Cl, Br, CH3 or CH2CH3; and
"*" represents a chiral center; wherein said enantiomer is substantially free of the other enantiomer; and wherein the optical rotation of the enantiomer, when said enantiomer is dissolved at a concentration of lmg/ml in methanol, at 20.0 0C measured at 589 nM is (+), and; (ii) a microtubule interfering agent.
2. The combination of claim 1, wherein a compound of Formula (I) is selected from the group consisting of:
(+) N-(3-Amino-propyl)-N-[l-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4- d]pyrimidin-6-yl)-propyl]-4-methyl-benzamide;
(+) N-(3-Amino-propyl)-N-{l-[5-(4-fluoro-benzyl)-3-methyl-4-oxo-4,5-dihydro- isothiazolo[5,4-d]pyrimidin-6-yl]-propyl}-4-methyl-benzamide;
(+) N-(3-Amino-propyl)-N-{l-[5-(3-fluoro-benzyl)-3-methyl-4-oxo-4,5-dihydro- isothiazolo[5,4-d]pyrimidin-6-yl]-propyl}-4-methyl-benzamide;
(+) N-(3-Amino-proρyl)-N-[l-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4- d]pyrimidin-6-yl)-propyl]-4-bromo-benzamide;
(+) N-(3-Amino-propyl)-N-[l-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4- d]pyrimidin-6-yl)-propyl]-4-chloro-benzamide;
(+) N-(3-Amino-propyl)-N-[l-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4- d]pyrimidin-6-yl)-propyl]-3-fluoro-4-methyl-benzamide;
(+) N-(3-Amino-propyl)-N-[l-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4- d]pyrimidin-6-yl)-propyl]-2,3-dichloro-benzamide;
(+) Benzo[b]thiophene-2-carboxylic acid (3-amino-propyl)-[l-(5-benzyl-3-methyl-4-oxo-
4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-propyl]amide;
(+) N-(2-Amino-ethyl)-N-[l-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4- d]pyrimidin-6-yl)-propyl]-4-methyl-benzamide;
(+) N-[l-(5-Benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)- propyl]-N-(3-dimethylamino-propyl)-4-methyl-benzamide;
(+) N-[l-(5-Benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)- propyl]-N-(3-isopropylamino-propyl)-4-methyl-benzamide;
(+) N-(3-Amino-propyl)-N-[l-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isoxazolo[5,4- d]pyrimidin-6-yl)-propyl]-4-methyl-benzamide; (+) N-(3-Amino-propyl)-N- { 1 -[5-(4-fluoro-benzyl)-3-methyl-4-oxo-4,5-dihydro- isothiazolo[5,4-d]pyrimidin-6-yl]-2-methyl-propyl}-4-methyl-benzamide;
(+) N-(3-Amino-propyl)-N-[l-(5-benzyl-3-methyl-4-oxo-4,5-diliydro-isothiazolo[5,4- d]pyrimidin-6-yl)-2-methyl-propyl]-4-methyl-benzamide;
(+) N-(3-Amino-ρropyl)-N-{l-[5-(3-fluoro-benzyl)-3-methyl-4-oxo-4,5-dihydro- isothiazolo[5,4-d]pyrimidin-6-yl]-2-methyl-propyl}-4-methyl-benzamide;
(+) N-(2-Amino-ethyl)-N-[l-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4- d]pyrimidin-6-yl)-2-methyl-propyl]-4-bromo-benzamide;
(+) N-(2-Amino-ethyl)-N-[l-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4- d]pyrimidin-6-yl)-2-methyl-ρropyl]-4-methyl-benzamide;
(+) N-(2-Amino-ethyl)-N-[l-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4- d]pyrimidin-6-yl)-2-methyl-propyl]-3-fluoro-4-metiiyl-benzamide;
(+) N-(3-Amino-propyl)-N-[l-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4- d]pyrimidin-6-yl)-2-methyl-propyl]-3-fluoro-4-methyl-benzamide;
(+) N-(3-Amino-propyl)-N-[l-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4- d]pyrimidin-6-yl)-2-methyl-propyl]-4-bromo-benzamide;
(+) N-[l-(5-Benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-2- methyl-propyl]-N-(3-dimethylamino-propyl)-4-methyl-benzamide;
(+) N-[l-(5-Benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-2- methyl-propyl]-N-(3-dimethylamino-propyl)-4-bromo-benzamide;
(+) N-[l-(5-Benzyl-3-methyl-4-oxo-4,5~dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-2- methyl-propyl]-N-(3-dimethylamino-propyl)-3-fluoro-4-methyl-benzamide;
(+) N-(3-Amino-proρyl)-N-[l-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isoxazolo[5,4- d]pyrimidin-6-yl)-2-methyl-propyl]-4-methyl-benzamide;
(+) N-(3-Amino-propyl)-N-{l-[5-(4-fluoro-benzyl)-3-methyl-4-oxo-4,5-dihydro- isoxazolo[5,4-d]pyrimidin-6-yl]-2-methyl-propyl}-4-methyl-benzamide;
(+) N-(3-Amino-propyl)-N- { 1 -[5-(3-fluoro-benzyl)-3-methyl-4-oxo-4,5-dihydro- isoxazolo[5,4-d]pyrimidin-6-yl]-2-methyl-propyl}-4-methyl-benzamide;
(+) N-(3-Amino-ρropyl)-N-[l-(6-benzyl-3-methyl-7-oxo-6,7-diliydro-isothiazolo[4,5- d]pyrimidin-5-yl)-propyl]-4-methyl-benzamide; or a pharmaceutically acceptable salt thereof; wherein the (+) optical rotation of the enantiomer is measured at a concentration of lmg/ml in methanol, at 20.0 0C at 589 nM.
3. The combination of either claim 1 or claim 2, wherein the microtubule interfering agent is selected from the group consisting of a taxane, an epothilone and a vinca- alkaloid.
4. The combination of any one of claims 1-3, wherein the microtubule interfering agent is a taxane.
5. The combination of any one of claims 1-3 wherein the taxane is selected from the group consisting of docosahexaenoic acid-paclitaxel conjugate, taxoprexin, docetaxel, milataxel, protaxel, paclitaxel and paclitaxel protein-bound.
6. The combination of any one of claims 1-5, wherein the Eg5 inhibitor is administered prior to the microtubule interfering agent.
7. The combination of any one of claim 1-5, wherein the microtubule interfering agent is administered prior to the Eg5 inhibitor.
8. A method of treating cancer comprising administering sequentially a therapeutically effective amount of a pharmaceutical combination as defined in any one of claims 1-7 to a patient in need thereof.
9. The method of claim 8, wherein the cancer is breast cancer, colorectal cancer, ovarian cancer, lung (non small cell) cancer, malignant brain tumors, sarcomas, melanoma and lymphoma.
10. Use of the pharmaceutical combination as defined in any one of claims 1-7 in the treatment of cancer, wherein the Eg5 inhibitor and the microtubule interfering agent are administered sequentially, in any order.
11. The use of claim 10, wherein the cancer is breast cancer, colorectal cancer, ovarian cancer, lung (non small cell) cancer, malignant brain tumors, sarcomas, melanoma and lymphoma.
12. A pharmaceutical combination comprising an Eg5 inhibitor, or a pharmaceutically acceptable salt thereof, and a microtubule interfering agent, for use in treating cancer wherein the Eg5 inhibitor and the microtubule interfering agent are administered sequentially, in any order.
13. A kit comprising a preparation of a pharmaceutical composition as defined in any one of claims 1-7, and instructions for the sequential administration of the preparations to a patient in need thereof.
PCT/GB2008/001233 2007-04-10 2008-04-09 Pharmaceutical composition of an eg5 inhibitor and a microtubule interfering agent for the treatment of cancer WO2008122798A2 (en)

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