WO2009037512A1 - Therapeutic methods 013 - Google Patents
Therapeutic methods 013 Download PDFInfo
- Publication number
- WO2009037512A1 WO2009037512A1 PCT/GB2008/050846 GB2008050846W WO2009037512A1 WO 2009037512 A1 WO2009037512 A1 WO 2009037512A1 GB 2008050846 W GB2008050846 W GB 2008050846W WO 2009037512 A1 WO2009037512 A1 WO 2009037512A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- methyl
- propyl
- pyrimidin
- dihydro
- oxo
- Prior art date
Links
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
- A61K31/519—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 the use of an Eg5 inhibitor for the treatment of cancer.
- Homo sapiens Eg5 (HsEg5; Accession X85137; see Blangy, A., Lane H.A., d'Heron, P., Harper, M., Kress, M. and Nigg, 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.
- Monastrol treatment was shown to be specific for Eg5 over kinesin heavy chain, another closely related motor with different functions (Marcher et ah, 1999). Monastrol blocks the release of ADP (adenosine 5 '-diphosphate) from the Eg5 motor (Maliga, Z., Kapoor, T. M., and Mitchison, TJ.: 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, there are reports of over- expression in tumor cells (International Patent Application WO 01/31335; Carter B., Z., Mak D.H., Shi Y., Schoeber W.D., Wang R.Y., Konopleva M., Roller E. Dean N.M., Andreeff M.: Regulation and targeting of Eg5, a mitotic motor protein in blast crisis CML: overcoming imatinib resistance. Cell Cycle 2006, 5:2223-2229), 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-mi crotubule drugs.
- Eg5 is targeted to microtubules by phosphorylation at an early point in mitosis (Blangy et ah, 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).
- the present invention is directed, in part, to an Eg5 inhibitor for use in the treatment of bladder cancer.
- Bladder cancer refers to any of several types of malignant growths of the urinary bladder.
- bladder cancer include transitional cell carcinomas (TCC) that arise from the inner lining of the bladder called the urothelium, squamous cell carcinoma, adenocarcinoma, sarcoma, and small cell carcinoma.
- TCC transitional cell carcinomas
- the Eg5 inhibitor can be selected from an enantiomer of a compound of Formula (I):
- X is selected from -C(CHs)- 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 0 or 1 ;
- R 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 ;
- 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 0 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:
- the Eg5 inhibitor can be selected from an enantiomer of a compound of Formula (Ib):
- Ib 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 0 or 1 ;
- R 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 (R) enantiomer.
- Particular compounds of Formula (Ib) include: (S) N-(3-Amino-propyl)-N-[l-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-
- stereoisomers of Formula (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) or Formula (Ib), 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.
- 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.
- 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.
- the Eg5 inhibitor may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy.
- Such chemotherapy may include one or more of the following categories of anti -tumour agents: (i) antiproliferative/antineoplastic drags and combinations thereof, as used in medical oncology, such as alkylating agents (for example cisplatin, carboplatin, oxaliplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan and nitrosoureas); antimetabolites (for example antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, gemcitabine and hydroxyurea); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirub
- cytostatic agents such as antioestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene), oestrogen receptor down regulators (for example fulvestrant), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5 ⁇ -reductase such as finasteride; (iii) agents which inhibit cancer cell invasion (for example metalloproteinase inhibitors like marimastat and inhibitors of urokinase plasminogen activator receptor function
- antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, (for example the anti-vascular endothelial cell growth factor antibody bevacizumab [AvastinTM], compounds such as those disclosed in International Patent
- antisense therapies for example those which are directed to the targets listed above, such as
- gene therapy approaches including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and
- GDEPT gene-directed enzyme pro-drug therapy
- immunotherapy approaches including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine -transfected dendritic cells, approaches using cytokine -transfected tumour cell lines and approaches using anti-idiotypic antibodies.
- cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor
- a 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.
- 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, 10,11,12, 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
- the microtubule interfering agent is a destabilizing agent such as a vinca-alkaloid.
- Vinca alkaloids include vinblastine, vincristine, vindesine and vinorelbine.
- Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment.
- Such combination products employ the compounds of this invention within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.
- the present invention provides a method for the treatment of bladder cancer by administering an Eg5 inhibitor.
- a pharmaceutical combination that comprises an Eg5 inhibitor, or a pharmaceutically acceptable salt thereof, and an anti -tumour agent as described above, for use in the treatment of bladder cancer.
- the invention includes:
- the Eg5 inhibitor 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 100 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 100 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.
- kits comprising an Eg5 inhibitor, or a pharmaceutically acceptable salt thereof with instructions for use for the treatment of cancer.
- kits comprising: a) an Eg5 inhibitor, or a pharmaceutically acceptable salt thereof; b) a container means for containing said Eg5 inhibitor; and c) instructions for administering the Eg5 inhibitor.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to the use of an Eg5 inhibitor for the treatment of bladder cancer.
Description
THERAPEUTIC METHODS 013
FIELD OF THE INVENTION
The present invention relates to the use of an Eg5 inhibitor for the treatment of cancer.
BACKGROUND OF THE INVENTION
Homo sapiens Eg5 (HsEg5; Accession X85137; see Blangy, A., Lane H.A., d'Heron, P., Harper, M., Kress, M. and Nigg, 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. The first Eg5 inhibitor, called monastrol, was isolated in a cell-based screen for mitotic blockers (Mayer, T.U., Kapoor, T. M., Haggarty, SJ., King, R.W., Schreiber, S.L., and Mitchison, TJ.: 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 ah, 1999). Monastrol blocks the release of ADP (adenosine 5 '-diphosphate) from the Eg5 motor (Maliga, Z., Kapoor, T. M., and Mitchison, TJ.: 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
Sablin, 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, Eg5. 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 (DeBonis et ah, In vitro screening for inhibitors of the human mitotic kinesin Eg5 with antimitotic and antitumor activities. MoI Cancer Ther 2004, 3:1079-1090; Sakowicz et ah, Antitumor activity of a kinesin inhibitor. Cancer Res 2004, 64:3276-3280; Marcus et ah, Mitotic kinesin inhibitors induce mitotic arrest and cell death in taxol-resistant and -sensitive cancer cells. J Biol Chem 2005, 280: 11569-11577; Chin and Herbst. Induction of apoptosis by monastrol, an inhibitor of the mitotic kinesin Eg5, is independent of the spindle checkpoint. MoI Cancer Ther 2006, 5:2580-2591; Tao et ah, An inhibitor of the kinesin spindle protein activates the intrinsic apoptotic pathway independently of p53 and de novo protein synthesis. MoI Cell Biol 2007, 27:689-698; Vijapurkar et ah, Potentiation of kinesin spindle protein inhibitor- induced cell death by modulation of mitochondrial and death receptor apoptotic pathways. Cancer Res 2007, 67:237-245).
Although Eg5 is thought to be necessary for mitosis in all cells, there are reports of over- expression in tumor cells (International Patent Application WO 01/31335; Carter B., Z., Mak D.H., Shi Y., Schoeber W.D., Wang R.Y., Konopleva M., Roller E. Dean N.M., Andreeff M.: Regulation and targeting of Eg5, a mitotic motor protein in blast crisis CML: overcoming imatinib resistance. Cell Cycle 2006, 5:2223-2229), 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-mi crotubule drugs. Eg5 is targeted to microtubules by phosphorylation at an early point in mitosis (Blangy et ah, 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 an Eg5 inhibitor for use in the treatment of bladder cancer.
DETAILED DESCRIPTION
The present invention is based on the finding that an Eg5 inhibitor is useful for the treatment of bladder cancer. Bladder cancer refers to any of several types of malignant growths of the urinary bladder. Examples of bladder cancer include transitional cell carcinomas (TCC) that arise from the inner lining of the bladder called the urothelium, squamous cell carcinoma, adenocarcinoma, sarcoma, and small cell carcinoma.
The Eg5 inhibitor can be selected from an enantiomer of a compound of Formula (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 0 or 1 ;
R 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 (+).
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- { 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-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-[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- { l-[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-dihydro-isothiazolo[5,4- d]pyrimidin-6-yl)-2-methyl-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]-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]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]-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-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;
(+) 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- { 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;
(+) 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):
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 0 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- 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-isothiazolo[5,4- d]pyrimidin-6-yl]-propyl}-4-methyl-benzamide;
(R) 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;
(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-benzyl-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- isopropylamino-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-isothiazolo[5,4- d]pyrimidin-6-yl]-2-methyl-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)-2-methyl-propyl]-4-methyl-benzamide;
(R) N-(3-Amino-propyl)-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;
(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-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-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]-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-[I -(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;
(R) N-[I -(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;
(R) N-[I -(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;
(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-methyl-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 another aspect, the Eg5 inhibitor can be selected from an enantiomer of a compound of Formula (Ib):
Ib 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 0 or 1 ;
R 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 (R) enantiomer.
Particular compounds of Formula (Ib) include:
(S) N-(3-Amino-propyl)-N-[l-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-
<i]pyrimidin-6-yl)-propyl]-4-methyl-benzamide;
(S) 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;
(S) 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;
(S) 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;
(S) 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;
(S) 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;
(S) 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;
(S) 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;
(S) 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;
(S) 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;
(S) 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;
(S) 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;
(S) N-(3-Amino-propyl)-N- { l-[5-(4-fluoro-benzyl)-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4- d]pyrimidin-6-yl]-2-methyl-propyl}-4-methyl-benzamide;
(S) 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;
(S) N-(3-Amino-propyl)-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;
(S) 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;
(S) 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;
(S) 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-methyl-benzamide;
(S) 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;
(S) 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;
(S) 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;
(S) 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;
(S) 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;
(S) 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;
(S) 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;
(S) 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
(S) 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 (Ib) 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 Formula (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) or Formula (Ib), 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 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. 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.
The Eg5 inhibitor may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anti -tumour agents:
(i) antiproliferative/antineoplastic drags and combinations thereof, as used in medical oncology, such as alkylating agents (for example cisplatin, carboplatin, oxaliplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan and nitrosoureas); antimetabolites (for example antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, gemcitabine and hydroxyurea); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarabicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere, and epothilones like epothilone A, epothilone B and epothilone D); and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin);
(ii) cytostatic agents such as antioestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene), oestrogen receptor down regulators (for example fulvestrant), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5α-reductase such as finasteride; (iii) agents which inhibit cancer cell invasion (for example metalloproteinase inhibitors like marimastat and inhibitors of urokinase plasminogen activator receptor function); (iv) inhibitors of growth factor function, for example such inhibitors include growth factor antibodies, growth factor receptor antibodies (for example the anti-erbb2 antibody trastuzumab [Herceptin™] and the anti-erbbl antibody cetuximab [C225]) , famesyl transferase inhibitors, tyrosine kinase inhibitors and serine/threonine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N- (3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefϊtinib, AZD 1839), N-(3 -ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4- amine (CI 1033)), for example inhibitors of the platelet-derived growth factor family and for example inhibitors of the hepatocyte growth factor family;
(v) antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, (for example the anti-vascular endothelial cell growth factor antibody
bevacizumab [Avastin™], compounds such as those disclosed in International Patent
Applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) and compounds that work by other mechanisms (for example linomide, inhibitors of integrin αvβ3 function and angiostatin);
(vi) vascular damaging agents such as Combretastatin A4 and compounds disclosed in
International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224,
WO 02/04434 and WO 02/08213;
(vii) antisense therapies, for example those which are directed to the targets listed above, such as
ISIS 2503, an anti-ras antisense;
(viii) gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and
(ix) immunotherapy approaches, including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine -transfected dendritic cells, approaches using cytokine -transfected tumour cell lines and approaches using anti-idiotypic antibodies.
In one example, a 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, 10,11,12, 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); Taxoprexin; DJ-927; Docetaxel (Taxotere); XRP9881 (RPR- 109881 A); 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); Abraxane, 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.
Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products employ the compounds of this invention within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.
The present invention provides a method for the treatment of bladder cancer by administering an Eg5 inhibitor.
According to a further aspect of the invention there is provided a pharmaceutical combination that comprises an Eg5 inhibitor, or a pharmaceutically acceptable salt thereof, and an anti -tumour agent as described above, for use in the treatment of bladder cancer.
Moreover the invention includes:
Use of an Eg5 inhibitor, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating bladder cancer.
Use of pharmaceutical combination of an Eg5 inhibitor, or a pharmaceutically acceptable salt thereof, and an anti-tumour agent as described above, for the manufacture of a medicament for treating bladder cancer.
The Eg5 inhibitor, alone or in combination, 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 100 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 100 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.
According to a further aspect of the present invention there is provided a kit comprising an Eg5 inhibitor, or a pharmaceutically acceptable salt thereof with instructions for use for the treatment of cancer.
For example, there is provided a kit comprising: a) an Eg5 inhibitor, or a pharmaceutically acceptable salt thereof; b) a container means for containing said Eg5 inhibitor; and c) instructions for administering the Eg5 inhibitor.
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. All 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
Determination of cell viability of four bladder cell lines following exposure to an Eg5 inhibitor
The anti-proliferative activity of (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-methyl-benzamide was evaluated in four bladder cell lines using the MTS tetrazolium colorimetric assay (Promega Corporation). To perform the assay, 1500, 2500, 2000, 4500 cells from the bladder carcinoma cell lines J82, T24, HTl 197, and 5637, respectively, were plated per well of a 96 well plate, cultured overnight and then exposed to 3 fold serial dilutions of (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- methyl-benzamide, in triplicate. Following 72 hours of drug exposure, cell viability was determined using the MTS colorimetric assay (Promega Corporation).
*ND - not determined
**NE - not evaluable, GI50 not achieved
The results show that three of the cell lines displayed marked sensitivity to (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-methyl-benzamide, with GI50's in the 2-9 nM range. The HTl 197 cell line also showed growth inhibition in response to drug, however the GI50 was not evaluable, as 50% growth inhibition was not attained in the 72 hour assay.
Claims
1. A method of treating bladder cancer comprising administering a pharmaceutical composition comprising: an Eg5 inhibitor selected from an enantiomer of a compound of Formula (I):
I 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 0 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 (+).
2. The method of claim 1, wherein the 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-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-[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- { l-[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-dihydro-isothiazolo[5,4- d]pyrimidin-6-yl)-2-methyl-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]-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]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]-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-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;
(+) 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- { 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;
(+) 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; and 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. A method of treating bladder cancer comprising administering a pharmaceutical composition comprising: an Eg5 inhibitor 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(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 0 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.
4. The method of claim 3, wherein the compound of Formula (Ia) is selected from the group consisting of:
(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-methyl-benzamide;
(R) 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;
(R) 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;
(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-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-
6-yl)-propyl]-4-methyl-benzamide;
(R) N-[I -(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- isopropylamino-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-isothiazolo[5,4- d]pyrimidin-6-yl]-2-methyl-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)-2-methyl-propyl]-4-methyl-benzamide;
(R) N-(3-Amino-propyl)-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;
(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-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-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]-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-[I -(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;
(R) N-[I -(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;
(R) N-[I -(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;
(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-methyl-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.
5. A method of treating bladder cancer comprising administering a pharmaceutical composition comprising (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-methyl-benzamide, wherein the compound is substantially free of the corresponding S enantiomer.
6. The method of claims 1-5, wherein the bladder cancer is transitional cell carcinomas (TCC), squamous cell carcinoma, adenocarcinoma, sarcoma, or small cell carcinoma.
7. The method of claims 1-5, further comprising administering simultaneously, sequentially or separately another anti -tumor agent selected from the group consisting of an antiproliferative/antineoplastic drug, a cytostatic agent, an agent that inhibits cancer cell invasion, an inhibitor of growth factor function, an antiangiogenic agent, and a vascular damaging agent.
8. An Eg5 inhibitor for use in treating bladder cancer comprising the Eg5 inhibitor of claims 1-5.
9. A kit comprising a preparation of an Eg5 inhibitor as defined in any one of claims 1-5, and instructions for administration of the inhibitor to a patient having bladder cancer.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US97436207P | 2007-09-21 | 2007-09-21 | |
| US60/974,362 | 2007-09-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2009037512A1 true WO2009037512A1 (en) | 2009-03-26 |
Family
ID=39870162
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/GB2008/050846 WO2009037512A1 (en) | 2007-09-21 | 2008-09-19 | Therapeutic methods 013 |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2009037512A1 (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004106492A2 (en) * | 2003-05-22 | 2004-12-09 | Bristol-Myers Squibb Company | Bicyclicpyrimidones and their use to treat diseases |
| WO2006018628A1 (en) * | 2003-03-07 | 2006-02-23 | Astrazeneca Ab | Enantiomers of selected fused pyrimidones and uses in the treatment and preventi on of cancer |
-
2008
- 2008-09-19 WO PCT/GB2008/050846 patent/WO2009037512A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006018628A1 (en) * | 2003-03-07 | 2006-02-23 | Astrazeneca Ab | Enantiomers of selected fused pyrimidones and uses in the treatment and preventi on of cancer |
| WO2004106492A2 (en) * | 2003-05-22 | 2004-12-09 | Bristol-Myers Squibb Company | Bicyclicpyrimidones and their use to treat diseases |
Non-Patent Citations (4)
| Title |
|---|
| "The Merck Manual of Diagnosis And Therapy - Eighteenth Edition", 2006, MERCK RESEARCH LABORATORIES, XP002501862 * |
| COLQUHOUN A J ET AL: "Combination treatment with ionising radiation and gefitinib ('Iressa', ZD1839), an epidermal growth factor receptor (EGFR) inhibitor, significantly inhibits bladder cancer cell growth in vitro and in vivo.", JOURNAL OF RADIATION RESEARCH SEP 2007, vol. 48, no. 5, September 2007 (2007-09-01), pages 351 - 360, XP002501861, ISSN: 0449-3060 * |
| ESMO GUIDELINES WORKING GROUP ET AL: "Invasive bladder cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up.", ANNALS OF ONCOLOGY : OFFICIAL JOURNAL OF THE EUROPEAN SOCIETY FOR MEDICAL ONCOLOGY / ESMO APR 2007, vol. 18 Suppl 2, April 2007 (2007-04-01), pages ii38 - ii39, XP002501859, ISSN: 0923-7534 * |
| MÜLLER ARNDT-CHRISTIAN ET AL: "Organ-sparing treatment of advanced bladder cancer: paclitaxel as a radiosensitizer.", STRAHLENTHERAPIE UND ONKOLOGIE : ORGAN DER DEUTSCHEN RÖNTGENGESELLSCHAFT ... [ET AL] APR 2007, vol. 183, no. 4, April 2007 (2007-04-01), pages 177 - 183, XP002501860, ISSN: 0179-7158 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| ZA200701082B (en) | Enantiomers of selected fused pyrimidones and uses in the treatment and prevention of cancer | |
| El-Nassan | Advances in the discovery of kinesin spindle protein (Eg5) inhibitors as antitumor agents | |
| US7361691B2 (en) | Method of treating cancers using β-lapachone or analogs or derivatives thereof | |
| Schmidt et al. | Mitotic drug targets and the development of novel anti-mitotic anticancer drugs | |
| US20090221488A1 (en) | Certain Compositions and Methods of Treatment | |
| US20070060637A1 (en) | Anti-cancer combinations | |
| CN101023082A (en) | Fused pyrimidones useful in the treatment and the prevention of cancer | |
| JP2015506376A (en) | CDK8 / CDK19 selective inhibitors and their use in methods of anti-metastasis and chemoprotection for cancer | |
| JP2008514726A (en) | Combination therapy with hedgehog inhibitor, radiation and chemotherapy | |
| US6248752B1 (en) | Azabicyclooctane compositions and methods for enhancing chemotherapy | |
| KR20070046175A (en) | Selected fused heterocyclics and uses thereof | |
| US20160128988A1 (en) | Combinations for the treatment of cancer comprising a mps-1 kinase inhibitor and a mitotic inhibitor | |
| US20090048214A1 (en) | Methods for Treating Renal Tumors Using 2, 4-Pyrimidinediamine Drug and Prodrug Compounds | |
| US20130131156A1 (en) | Cancer Treatment with Wortmannin Analogs | |
| WO2007132220A1 (en) | Combination of a 2-substituted-4-heter0aryl-pyrimidine amine with a cytotoxic drug and use thereof in the treatment of a proliferative disorder | |
| WO2009037512A1 (en) | Therapeutic methods 013 | |
| WO2021058967A1 (en) | Combination of gold complexes with olaparib or other parp1/2 inhibitors for use in the treatment of cancer resistant to said parp1/2 inhibitors | |
| JP2007186511A (en) | Cancer chemotherapy | |
| KR19990082064A (en) | How to induce the death of neoplastic cells using piperazine oxirane derivatives | |
| KR20020008407A (en) | Use of 1,4-Benzothiazepine Derivatives as Drugs for Overcoming Resistance to Anticancer Drugs | |
| WO2008122798A2 (en) | Pharmaceutical composition of an eg5 inhibitor and a microtubule interfering agent for the treatment of cancer | |
| WO2024123297A2 (en) | Development of new docetaxel conjuged drug candidates to treat castration-resistant prostate cancer (crpc) | |
| Greco | Synthesis and biological evaluation of pyrazolo [3, 4-d] pyrimidine derivatives active as SGK1, Fyn and Src kinases inhibitors | |
| CN116251107A (en) | Application of Z-2-366 in preparation of medicines for inhibiting eEF2K expression | |
| CN111718328A (en) | Application of 4-methyl-1H-diaryl pyrazole derivatives in preparation of antitumor drugs |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 08806662 Country of ref document: EP Kind code of ref document: A1 |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 08806662 Country of ref document: EP Kind code of ref document: A1 |