WO2012058174A1 - Nouveaux dérivés thiazole-carboxamide en tant qu'inhibiteurs de pdk1 - Google Patents

Nouveaux dérivés thiazole-carboxamide en tant qu'inhibiteurs de pdk1 Download PDF

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Publication number
WO2012058174A1
WO2012058174A1 PCT/US2011/057558 US2011057558W WO2012058174A1 WO 2012058174 A1 WO2012058174 A1 WO 2012058174A1 US 2011057558 W US2011057558 W US 2011057558W WO 2012058174 A1 WO2012058174 A1 WO 2012058174A1
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amino
piperidinecarboxamide
carbonyl
methylamino
phenyl
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PCT/US2011/057558
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English (en)
Inventor
Hon-Chung Tsui
Sunil Paliwal
Xiaolei Gao
Hyunjin M. Kim
Ronald J. Doll
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Schering Corporation
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Priority to EP11836930.5A priority Critical patent/EP2632263A1/fr
Publication of WO2012058174A1 publication Critical patent/WO2012058174A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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

Definitions

  • This invention relates to certain thiazole carboxamide derivatives as inhibitors of 3-phosphoinositide-dependent protein kinase (PDK-1).
  • PDK-1 3-phosphoinositide-dependent protein kinase
  • PDK1 serine/threonine kinase
  • AGC kinase family cAMP-dependent, cGMP-dependent, and protein kinase C.
  • PIP3 phosphoinositide-3 kinase
  • PIP2 phosphoinositidylinositol-4,5-triphosphate
  • PIP3 phosphoinositidylinositol-3 ,4, 5 -triphosphate
  • PIP3 binds to both PDK1 and PKB/Akt, which are believed to co-localize at the cell membrane as a consequence.
  • PDK1 In addition to its interaction with PKB/Akt, PDK1 also phosphorylates and activates p70S6Kl, SGK, RSK and PKC, which influences cell growth, proliferation, and survival, and regulates metabolism. Bayascas, J.R., Cell Cycle, 7, 2978-2982 (2008).
  • Cancer cells of common human tumor types including breast, lung, gastric, prostate, haemotological and ovarian cancers, have gene mutations that result in abnormally high levels of PIP3.
  • High levels of PIP3 cause overstimulation of PDK1 which result in constitutive activation the members of the AGC kinase family.
  • tumor cell proliferation reduced apoptosis and angiogenesis occur.
  • cells lacking functioning PTEN, a lipid phosphatase that reduces cellular PIP3 are associated with a variety of human tumours including breast, prostate, endometrial cancers along with melanomas and glioblastomas. Steck et al., Nat. Genetics, 15, 356-362 (1997).
  • This invention relates to certain thiazole carboxamide derivatives and pharmaceutically acceptable salts thereof as inhibitors of 3-phosphoinositide-dependent protein kinase (PD -1):
  • the present invention provides Thiazole Carboxamide Compounds and pharmaceutical compositions comprising a Thiazole Carboxamide Compound.
  • the present invention provides methods of using the Thiazole Carboxamide Compounds in treating a disease or disorder characterized by excessive or pathologically elevated cell growth, e.g., cancer, in a patient in need of such treatment.
  • the present invention provides compounds of the instant invention:
  • the enantiomers can be resolved by methods known to those skilled in the art, such as formation of diastereoisomeric salts which may be separated, for example, by crystallization (see, CRC Handbook of Optical Resolutions via Diastereomeric Salt Formation by David Kozma (CRC Press, 2001)); formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic esterification; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent.
  • an active agent or "a pharmacologically active agent” includes a single active agent as well a two or more different active agents in combination
  • reference to "a carrier” includes mixtures of two or more carriers as well as a single carrier, and the like.
  • an active agent or "a pharmacologically active agent” includes a single active agent as well a two or more different active agents in combination
  • reference to "a carrier” includes mixtures of two or more carriers as well as a single carrier, and the like.
  • Carboxamide Compounds are useful in treating proliferative diseases such as cancer and other proliferative diseases because of their PDKl inhibitory activity.
  • cancers for which the Thiazole Carboxamide Compounds can be useful include lung cancer, bronchial cancer, prostate cancer, breast cancer, pancreatic cancer, colon cancer, rectal cancer, colorectal cancer, thyroid cancer, liver cancer, intrahepatic bile duct cancer, hepatocellular cancer, gastric cancer, glioma/glioblastoma, endometrial cancer, melanoma, kidney cancer, renal pelvic cancer, urinary bladder cancer, uterine corpus cancer, uterine cervical cancer, ovarian cancer, multiple myeloma, esophageal cancer, acute myelogenous leukemia, chronic myelogenous leukemia, lymphocytic leukemia, myeloid leukemia, brain cancer, oral cavity cancer, and pharyngeal cancer, laryngeal cancer, small intestinal cancer, non-Hodgkin's lymphoma, and villous colon adenom
  • Carboxamide Compounds can be useful include neuro-fibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis, proliferative diabetic retinopathy (PDR), hypertrophic scar formation, inflammatory bowel disease, transplantation rejection, angiogenesis, and endotoxic shock.
  • PDR proliferative diabetic retinopathy
  • the invention also provides the Thiazole Carboxamide Compounds for use in the treatment of cancer.
  • the term "therapeutically effective amount” means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • the therapeutic effect is dependent upon the disease or disorder being treated or the biological effect desired. As such, the therapeutic effect can be a decrease in the severity of symptoms associated with the disease or disorder and/or inhibition (partial or complete) of progression of the disease.
  • the amount needed to elicit the therapeutic response can be determined based on the age, health, size and sex of the subject. Optimal amounts can also be determined based on monitoring of the subject's response to treatment.
  • Subject refers to animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, pigs, dogs, cats, rabbits, guinea pigs, rats, mice or other bovine, ovine, equine, canine, feline, rodent or murine species.
  • administration in reference to a compound of the invention means introducing the compound or a prodrug of the compound into the system of the animal in need of treatment.
  • a compound of the invention or prodrug thereof is provided in combination with one or more other active agents (e.g., a cytotoxic agent, etc.)
  • “administration” and its variants are each understood to include concurrent and sequential introduction of the compound or prodrug thereof and other agents.
  • anticancer agents include, but are not limited to, the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic/cytostatic agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors and other angiogenesis inhibitors, inhibitors of cell proliferation and survival signaling, apoptosis inducing agents, agents that interfere with cell cycle checkpoints, agents that interfere with receptor tyrosine kinases (RTKs) and cancer vaccines.
  • the instant compounds are particularly useful when co-administered with radiation therapy.
  • the instant compounds are also useful in combination with known anti-cancer agents including the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors, and other angio genesis inhibitors.
  • known anti-cancer agents including the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors, and other angio genesis inhibitors.
  • Estrogen receptor modulators refers to compounds that interfere with or inhibit the binding of estrogen to the receptor, regardless of mechanism.
  • Examples of estrogen receptor modulators include, but are not limited to, diethylstibestral, tamoxifen, raloxifene, idoxifene, LY353381, LY117081, toremifene, fluoxymestero, lfulvestrant, 4-[7-(2,2-dimethyl-l- oxopropoxy-4-methyl-2- [4- [2-( 1 -piperidiny l)ethoxy]phenyl] -2H- 1 -benzopyran-3 -yl]-pheny 1- 2,2-dimethylpropanoate, 4,4'-dihydroxybenzophenone-2,4-dinitrophenyl-hydrazone, and SH646.
  • hormonal agents include: aromatase inhibitors (e.g., aminoglutethimide, anastrozole and tetrazole), luteinizing hormone release hormone (LHRH) analogues, ketoconazole, goserelin acetate, leuprolide, megestrol acetate and mifepristone.
  • aromatase inhibitors e.g., aminoglutethimide, anastrozole and tetrazole
  • LHRH luteinizing hormone release hormone
  • Cytotoxic/cytostatic agents refer to compounds which cause cell death or inhibit cell proliferation primarily by interfering directly with the cell's functioning or inhibit or interfere with cell mytosis, including alkylating agents, tumor necrosis factors, intercalators, hypoxia activatable compounds, microtubule inhibitors/microtubule-stabilizing agents, inhibitors of mitotic kinesins, inhibitors of histone deacetylase, inhibitors of kinases involved in mitotic progression, antimetabolites; biological response modifiers; hormonal/anti-hormonal therapeutic agents, haematopoietic growth factors, monoclonal antibody targeted therapeutic agents, topoisomerase inhibitors, proteasome inhibitors and ubiquitin ligase inhibitors.
  • cytotoxic agents include, but are not limited to, sertenef, cachectin, chlorambucil, cyclophosphamide, ifosfamide, mechlorethamine, melphalan, uracil mustard, thiotepa, busulfan, carmustine, lomustine, streptozocin, tasonermin, lonidamine, carboplatin, altretamine, dacarbazine, procarbazine, prednimustine, dibromodulcitol, ranimustine, fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin, estramustine, improsulfan tosilate, trofosfamide, nimustine, dibrospidium chloride, pumitepa, lobaplatin, satraplatin, profiromycin, cisplatin, irofulven, dexifos
  • proteasome inhibitors include but are not limited to lactacystin and bortezomib.
  • topoisomerase inhibitors are topotecan, hycaptamine, irinotecan, rubitecan, 6"ethoxypropionyl-3',4'-0-exo-benzylidene-chartreusin, 9-methoxy-N,N- dimethyl-5-nitropyrazolo[3,4,5-kl]acridine-2-(6H) propanamine, l-amino-9-ethyl-5-fluoro-2,3- dihydro-9-hydroxy-4-methyl- 1 H, 12H-benzo [de]pyrano[3 ' ,4 ' :b,7]-indoIizino [ 1 ,2b]quinoline- 10,13(9H,15H)dione, lurtotecan, 7-[2-(N-isopropylamino)ethyl]-(20S)camptothecin, BNP1350, BNPI1100, BN80915, BN80942,
  • inhibitors of mitotic kinesins are described in PCT Publications WO 01/30768, WO 01/98278, WO 03/050,064, WO 03/050,122, WO 03/049,527, WO 03/049,679, WO 03/049,678, WO 03/39460 and WO2003/079973, WO2003/099211, WO2004/039774, WO2003/105855, WO2003/106417.
  • Antiproliferative agents includes antisense RNA and DNA oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231, and INX3001, and antimetabolites such as enocitabine, carmofur, tegafur, pentostatin, doxifluridine, trimetrexate, fludarabine,
  • capecitabine galocitabine, cytarabine ocfosfate, fosteabine sodium hydrate, raltitrexed, paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed, nelzarabine, 2'-deoxy-2'- methylidenecytidine, 2'-fluoromethylene-2' -deoxycytidine, N-[5-(2,3-dihydro- benzofuryl)sulfonyl] ⁇ N ' -(3 ,4-dichlorophenyl)urea, N6-[4-deoxy-4- [N2- [2(E),4(E)- tetradecadienoyl]glycylamino]-L-glycero-B-L-manno-heptopyranosyl]adenine, aplidine, ecteinas
  • monoclonal antibody targeted therapeutic agents include those therapeutic agents which have cytotoxic agents or radioisotopes attached to a cancer cell specific or target cell specific monoclonal antibody. Examples include Bexxar.
  • HMG-CoA reductase inhibitors refers to inhibitors of 3-hydroxy-3- methylglutaryl-CoA reductase.
  • HMG-CoA reductase inhibitors include but are not limited to lovastatin (MEVACOR®; see U.S. Pat. Nos. 4,231,938, 4,294,926 and 4,319,039), simvastatin (ZOCOR®; see U.S. Pat. Nos. 4,444,784, 4,820,850 and
  • Prenyl -protein transferase inhibitor refers to a compound which inhibits any one or any combination of the prenyl-protein transferase enzymes, including farnesyl-protein transferase (FPTase), geranylgeranyl-protein transferase type I (GGPTase-I), and
  • GGPTase-II geranylgeranyl-protein transferase type-II (GGPTase-II, also called Rab GGPTase).
  • prenyl-protein transferase inhibitors can be found in the following publications and patents: WO 96/30343, WO 97/18813, WO 97/21701, WO 97/23478, WO 97/38665, WO 98/28980, WO 98/29119, WO 95/32987, U.S. Pat. No. 5,420,245, U.S. Pat. No. 5,523,430, U.S. Pat. No. 5,532,359, U.S. Pat. No. 5,510,510, U.S. Pat. No. 5,589,485, U.S. Pat. No. 5,602,098, European Patent Publ. 0 618 221, European Patent Publ.
  • Angiogenesis inhibitors refers to compounds that inhibit the formation of new blood vessels, regardless of mechanism.
  • angiogenesis inhibitors include, but are not limited to, tyrosine kinase inhibitors, such as inhibitors of the tyrosine kinase receptors Flt-1 (VEGFRl) and Flk-l KDR (VEGFR2), inhibitors of epidermal-derived, fibroblast-derived, or platelet derived growth factors, MMP (matrix metalloprotease) inhibitors, integrin blockers, interferon- , interleukin-12, erythropoietin (epoietin-a), granulocyte-CSF (filgrastin), granulocyte, macrophage-CSF (sargramostim), pentosan polysulfate, cyclooxygenase inhibitors, including nonsteroidal anti-inflammatories (NSAIDs) like aspirin and ibuprofen as well as selective cyclooxy
  • steroidal anti-inflammatories such as corticosteroids, mineralocorticoids, dexamethasone, prednisone, prednisolone, methylpred, betamethasone
  • carboxyamidotriazole combretastatin A-4, squalamine, 6-O-chloroacetyl- carbonyl)-rumagillol, thalidomide, angiostatin, troponin- 1, angiotensin II antagonists (see
  • agents that modulate or inhibit angiogenesis and may also be used in combination with the compounds of the instant invention include agents that modulate or inhibit the coagulation and fibrinolysis systems (see review in Clin, Chem. La. Med. 38:679-692 (2000)).
  • agents that modulate or inhibit the coagulation and fibrinolysis pathways include, but are not limited to, heparin (see Thromb. Haemost. 80: 10-23 (1998)), low molecular weight heparins and carboxypeptidase U inhibitors (also known as inhibitors of active thrombin activatable fibrinolysis inhibitor [TAFIa]) (see Thrombosis Res. 101 :329-354 (2001)).
  • TAFIa inhibitors have been described in PCT Publication WO 03/013,526 and U.S. Ser. No. 60/349,925 (filed January 18, 2002).
  • agents that interfere with receptor tyrosine kinases refer to compounds that inhibit RTKs and therefore mechanisms involved in oncogenesis and tumor progression.
  • agents include inhibitors of c-Kit, Eph, PDGF, Flt3 and c-Met.
  • Further agents include inhibitors of RTKs shown as described by Bume- Jensen and Hunter, Nature, 411 :355-365, 2001.
  • “Inhibitors of cell proliferation and survival signaling pathway” refer to pharmaceutical agents that inhibit cell surface receptors and signal transduction cascades downstream of those surface receptors.
  • Such agents include inhibitors of inhibitors of EGFR (for example gefitinib and erlotinib), inhibitors of ERB-2 (for example trastuzumab), inhibitors of 1GFR, inhibitors of CD20 (rituximab), inhibitors of cytokine receptors, inhibitors of MET, inhibitors of PI3K family kinase (for example LY294002), serine/threonine kinases (including but not limited to inhibitors of Akt such as described in (WO 03/086404, WO 03/086403, WO 03/086394, WO 03/086279, WO 02/083675, WO 02/083139, WO 02/083140 and WO
  • inhibitors of Raf kinase for example BAY-43-9006
  • inhibitors of MEK for example CI- 1040 and PD-098059
  • inhibitors of mTOR for example Wyeth CCI-779 and Ariad AP23573.
  • Such agents include small molecule inhibitor compounds and antibody antagonists.
  • mTOR inhibitors include ridaforolimus, temsirolimus, everolimus, a rapamycin-analog.
  • Ridaforolimus also known as AP 23573, MK-8669 and deforolimus, is a unique, non-prodrag analog of rapmycin that has antiproliferative activity in a broad range of human tumor cell lines in vitro and in murine tumor xenograft models utilizing human tumor cell lines. Ridaforolimus has been administered to patients with advanced cancer and is currently in clinical development for various advanced malignancies, including studies in patients with advanced soft tissue or bone sarcomas. Thus far, these trials have demonstrated that ridaforolimus is generally well-tolerated with a predictable and manageable adverse even profile, and possess anti-tumor activity in a broad range of cancers. A description and preparation of ridaforolimus is described in U.S. Patent No. 7,091,213 to Ariad Gene
  • Temsirolimus also known as Torisel®, is currently marketed for the treatment of renal cell carcinoma.
  • Torisel® Temsirolimus
  • a description and preparation of temsirolimus is described in U.S. Patent No.
  • Everolimus also known as Certican® or RADOOl , marketed by Novartis, has greater stability and enhanced solubility in organic solvents, as well as more favorable pharmokinetics with fewer side effects than rapamycin (sirolimus). Everolimus has been used in conjunction with microemulsion cyclosporin (Neoral®, Novartis) to increase the efficacy of the immunosuppressive regime.
  • Apoptosis inducing agents include activators of TNF receptor family members (including the TRAIL receptors).
  • NSAID's which are selective COX-2 inhibitors are defined as those which possess a specificity for inhibiting C X-2 over COX-1 of at least 100 fold as measured by the ratio of IC50 for COX-2 over IC50 for COX-1 evaluated by cell or microsomal assays.
  • Such compounds include, but are not limited to those disclosed in U.S. Pat. 5,474,995, U.S. Pat. 5,861,419, U.S. Pat. 6,001,843, U.S. Pat. 6,020,343, U.S. Pat. 5,409,944, U.S. Pat. 5,436,265, U.S. Pat.
  • angiogenesis inhibitors include, but are not limited to, endostatin, ukrain, ranpirnase, IM862, 5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]- l-oxaspiro[2,5]oct-6-yl(chloroacetyl)carbamate, acetyl dinanaline, 5-amino-l-[[3,5-dichloro-4- (4-chlorobenzoyl)phenyl]rnethyl]-lH-l J 2,3-triazole-4-carboxamide s CM101 > squalamine, combretastatin, RPI4610, NX31838, sulfated mannitol, 5-amino-l-[[3,5-dichloro-4- (4-chlorobenzoyl)phenyl]rnethyl]-lH-l J 2,3-triazole-4-carboxamide
  • integrated circuit blockers refers to compounds which selectively antagonize, inhibit or counteract binding of a physiological Hgand to the ⁇ 3 integrin, to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to the ⁇ 5 integrin, to compounds which antagonize, inhibit or counteract binding of a physiological ligand to both the ⁇ ⁇ ⁇ 3 integrin and the ⁇ ⁇ ⁇ 5 integrin, and to compounds which antagonize, inhibit or counteract the activity of the particular integrin(s) expressed on capillary endothelial cells.
  • the term also refers to antagonists of the ⁇ 6 > ⁇ * ⁇ 8 > ⁇ > ⁇ 2 ⁇ > ⁇ ⁇ , ⁇ 6 ⁇ 1 and ⁇ 3 ⁇ 4 ⁇ 4 integrins.
  • the term also refers to antagonists of any combination of ⁇ ⁇ ⁇ 3 , ⁇ ⁇ ⁇ 5, ⁇ ⁇ ⁇ 6> ⁇ ⁇ 8, ⁇ ⁇ , ⁇ 3 ⁇ 4 ⁇ , ⁇ 5 ⁇ , ⁇ *6 ⁇ and o ⁇ 4 integrins.
  • Combinations with compounds other than anti-cancer compounds are also encompassed in the instant methods.
  • combinations of the instantly claimed compounds with PPAR- ⁇ (i.e., PPAR-gamma) agonists and PPAR- ⁇ (i.e., PPAR-delta) agonists are useful in the treatment of certain malingnancies.
  • PPAR- ⁇ and PPAR- ⁇ are the nuclear peroxisome proliferator-activated receptors ⁇ and ⁇ .
  • the expression of PPAR- ⁇ on endothelial cells and its involvement in angiogenesis has been reported in the literature (see J. Cardiovasc. Pharmacol. 1998; 31 :909-913; J Biol. Chem. 1999; 274:91 16-9121 ; Invest.
  • PPAR- ⁇ agonists and PPAR- ⁇ / ⁇ agonists include, but are not limited to, thiazolidinediones (such as DRF2725, CS-011, troglitazone, rosiglitazone, and pioglitazone), fenofibrate, gemfibrozil, clofibrate, GW2570, SB219994, AR-H039242, JTT-501, MCC-555, GW2331, GW409544, NN2344, KRP297, NPOl 10, DRF4158, NN622, GI262570, PNU182716, DRF552926, 2- [(5 ,7-dipropyI-3-trifluoromethyl- 1 ,2-benzisoxazol-6-yl)oxy] -2-methylpropionic acid (disclosed in USSN 09/782,856), and 2(R)-7-(3-(2-chIoro-4-(4-fluorophen
  • Another embodiment of the instant invention is the use of the presently disclosed compounds in combination with gene therapy for the treatment of cancer.
  • Gene therapy can be used to deliver any tumor suppressing gene. Examples of such genes include, but are not limited to, p53, which can be delivered via recombinant virus-mediated gene transfer (see U.S. Pat. No.
  • Duc-4 NF-1, NF-2, RB, WT1, BRCA1, BRCA2, a uPA/uPAR antagonist
  • a uPA/uPAR antagonist adenovirus-Mediated Delivery of a uPA uPAR Antagonist Suppresses
  • the compounds of the instant invention may also be administered in combination with an inhibitor of inherent multidrug resistance (MDR), in particular MDR associated with high levels of expression of transporter proteins.
  • MDR inhibitors include inhibitors of p- glycoprotein (P-gp), such as LY335979, XR9576, OC144-093, R101922, VX853 and PSC833 (valspodar).
  • a compound of the present invention may be used in conjunction with other anti-emetic agents, especially neurokinin-1 receptor antagonists, 5HT3 receptor antagonists, such as ondansetron, granisetron, tropisetron, and zatisetron, GABAB receptor agonists, such as baclofen, a corticosteroid such as Decadron (dexamethasone), Kenalog, Aristocort, Nasalide, Preferid, Benecorten or others such as disclosed in U.S. Patent Nos.
  • neurokinin-1 receptor antagonists especially 5HT3 receptor antagonists, such as ondansetron, granisetron, tropisetron, and zatisetron, GABAB receptor agonists, such as baclofen, a corticosteroid such as Decadron (dexamethasone), Kenalog, Aristocort, Nasalide, Preferid, Benecorten or others such as disclosed in U.S. Patent Nos.
  • an antidopaminergic such as the phenothiazines (for example prochlorperazine, fluphenazine, thioridazine and mesoridazine), metoclopramide or dronabinol.
  • an anti-emesis agent selected from a neurokinin-1 receptor antagonist, a 5HT3 receptor antagonist and a corticosteroid is administered as an adjuvant for the treatment or prevention of emesis that may result upon administration of the instant compounds.
  • Neurokinin-1 receptor antagonists of use in conjunction with the compounds of the present invention are fully described, for example, in U.S. Pat. Nos. 5,162,339, 5,232,929, 5,242,930, 5,373,003, 5,387,595, 5,459,270, 5,494,926, 5,496,833, 5,637,699, 5,719,147;
  • the neurokinin- 1 receptor antagonist for use in conjunction with the compounds of the present invention is selected from: 2-(R)-(l-(R)-(3,5- bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-lH,4H-l,2,4- triazolo)methyI)morpholine, or a pharmaceutically acceptable salt thereof, which is described in U.S. Pat. No. 5,719,147.
  • a compound of the instant invention may also be administered with an agent useful in the treatment of anemia.
  • an anemia treatment agent is, for example, a continuous eythropoiesis receptor activator (such as epoetin alfa).
  • a compound of the instant invention may also be administered with an agent useful in the treatment of neutropenia.
  • a neutropenia treatment agent is, for example, a hematopoietic growth factor which regulates the production and function of neutrophils such as a human granulocyte colony stimulating factor, (G-CSF).
  • G-CSF human granulocyte colony stimulating factor
  • Examples of a G-CSF include filgrastim.
  • a compound of the instant invention may also be administered with an immunologic-enhancing drug, such as levamisole, bacillus Calmette-Guerin, octreotide, isoprinosine and Zadaxin.
  • an immunologic-enhancing drug such as levamisole, bacillus Calmette-Guerin, octreotide, isoprinosine and Zadaxin.
  • a compound of the instant invention may also be useful for treating or preventing cancer, including bone cancer, in combination with bisphosphonates (understood to include bisphosphonates, diphosphonates, bisphosphonic acids and diphosphonic acids).
  • bisphosphonates include but are not limited to: etidronate (Didronel), pamidronate (Aredia), alendronate (Fosamax), risedronate (Actonel), zoledronate (Zometa), ibandronate (Boniva), incadronate or cimadronate, clodronate, EB-1053, minodronate, neridronate, piridronate and tiludronate including any and all pharmaceutically acceptable salts, derivatives, hydrates and mixtures thereof.
  • a compound of the instant invention may also be useful for treating or preventing breast cancer in combination with aromatase inhibitors.
  • aromatase inhibitors include but are not limited to anastrozole, letrozole and exemestane.
  • a compound of the instant invention may also be useful for treating or preventing cancer in combination with siRNA therapeutics.
  • a compound of the instant invention may also be useful for treating or preventing cancer in combination withcompounds which induce terminal differentiation of the neoplastic cells.
  • Suitable differentiation agents include the compounds disclosed in any one or more of the following references.
  • a compound of the instant invention may also be useful for treating or preventing cancer in combination with ⁇ -secretase inhibitors.
  • a method of treating cancer comprises administering a therapeutically effective amount of a compound in combination with radiation therapy and/or in combination with a second compound selected from: an estrogen receptor modulator, an androgen receptor modulator, a retinoid receptor modulator, a
  • the compounds of the instant invention are useful in combination with the following therapeutic agents: abarelix (Plenaxis depot®); aldesleukin (Prokine®); Aldesleukin (Proleukin®); Alemtuzumabb (Campath®); alitretinoin (Panretin®); allopurinol (Zyloprim®); altretamine (Hexalen®); amifostine (Ethyol®); anastrozole (Arimidex®); arsenic trioxide (Trisenox®); asparaginase (Elspar®); azacitidine (Vidaza®); bendamustine hydrochloride (Treanda®); bevacuzimab (Avastin®); bexarotene capsules (Targretin®); bexarotene gel (Targretin®); bleomycin (Blenoxane®); bortezomib (Velcade®); busulfan intravenous
  • Rasburicase (Elitek®); raloxifene hydrochloride (Evista®); Rituximab (Rituxan®); romidepsin (Istodax®); romiplostim (Nplate®); sargramostim (Leukine®); Sargramostim (Prokine®); sorafenib (Nexavar®); streptozocin (Zanosar®); sunitinib maleate (Sutent®); talc (Sclerosol®); tamoxifen (Nolvadex®); temozolomide (Temodar®); temsirolimus (Torisel®); teniposide, VM- 26 (Vumon®); testolactone (Teslac®); thiogua ine, 6-TG (Thioguanine®); thiotepa
  • the Thiazole Carboxamide Compounds can be administered as a component of a composition that comprises a pharmaceutically acceptable carrier or vehicle.
  • the present invention provides pharmaceutical compositions comprising an effective amount of at least one Thiazole Carboxamide Compound and a pharmaceutically acceptable carrier.
  • the active ingredients will typically be administered in admixture with suitable carrier materials suitably selected with respect to the intended form of administration, i.e., oral tablets, capsules (either solid-filled, semi-solid filled or liquid filled), powders for constitution, oral gels, elixirs, dispersible granules, syrups, suspensions, and the like, and consistent with conventional pharmaceutical practices. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington 's
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted, and the active ingredient is dispersed homogeneously therein as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify.
  • the Thiazole Carboxamide Compounds of the present invention may also be delivered transdermally.
  • the transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
  • compositions of the present invention may be formulated in sustained release form to provide the rate controlled release of any one or more of the
  • compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the present compositions can contain, in one embodiment, from about 0.1% to about 99% of the Thiazole Carboxamide Compound(s) by weight or volume.
  • the quantity of Thiazole Carboxamide Compound in a unit dose of preparation may be varied or adjusted from about 0.1 mg to about 5000 mg. In various embodiments, the quantity is from about 10 mg to about 5000 mg, about 10 mg to about 1000 mg, 1 mg to about 500 mg, 1 mg to about 100 mg, and 1 mg to about 50 mg.
  • the dosage is from about 1 to about 200 mg/day, administered in a single dose or in 2-4 divided doses. In another embodiment, the dosage is from about 10 to about 5000 mg/day, administered in a single dose or in 2-4 divided doses. In another embodiment, the dosage is from about 100 to about 5000 mg/day, administered in a single dose or in 2-4 divided doses. In still another embodiment, the dosage is from about 500 to about 5000 mg/day, administered in a single dose or in 2-4 divided doses.
  • the present invention also provides methods of using the Thiazole Carboxamide compounds of the present invention for inducing terminal differentiation, cell growth arrest and/or apoptosis of neoplastic cells thereby inhibiting the proliferation of such cells.
  • the methods can be practiced in vivo or in vitro.
  • the present invention provides in vitro methods for selectively inducing terminal differentiation, cell growth arrest and/or apoptosis of neoplastic cells, thereby inhibiting proliferation of such cells, by contacting the cells with an effective amount of any one or more of the Thiazole Carboxamide compounds described herein.
  • the present invention relates to an in vitro method of selectively inducing terminal differentiation of neoplastic cells and thereby inhibiting proliferation of such cells.
  • the method comprises contacting the cells under suitable conditions with an effective amount of one or more of the Thiazole Carboxamide compounds described herein.
  • the invention in another embodiment, relates to an in vitro method of selectively inducing cell growth arrest of neoplastic cells and thereby inhibiting proliferation of such cells.
  • the invention in another embodiment, relates to an in vitro method of selectively inducing apoptosis of neoplastic cells and thereby inhibiting proliferation of such cells.
  • the method comprises contacting the cells under suitable conditions with an effective amount of one or more of the Thiazole Carboxamide compounds described herein.
  • the invention in another embodiment, relates to an in vitro method of inducing terminal differentiation of tumor cells in a tumor comprising contacting the cells with an effective amount of any one or more of the Thiazole Carboxamide compounds described herein.
  • the methods of the present invention can be practiced in vitro, it is contemplated that the preferred embodiment for the methods of selectively inducing terminal differentiation, cell growth arrest and/or apoptosis of neoplastic cells, and of inhibiting PD -1 will comprise contacting the cells in vivo, i.e., by administering the compounds to a subject harboring neoplastic cells or tumor cells in need of treatment.
  • the present invention provides in vivo methods for selectively inducing terminal differentiation, cell growth arrest and/or apoptosis of neoplastic cells in a subject, thereby inhibiting proliferation of such cells in the subject, by administering to the subject an effective amount of any one or more of the Thiazole Carboxamide compounds described herein.
  • the invention in another embodiment, relates to a method of selectively inducing cell growth arrest of neoplastic cells and thereby inhibiting proliferation of such cells in a subject.
  • the method comprises administering to the subject an effective amount of one or more of the Thiazole Carboxamide compounds described herein.
  • the invention in another embodiment, relates to a method of treating a patient having a tumor characterized by proliferation of neoplastic cells.
  • the method comprises administering to the patient one or more of the Thiazole Carboxamide compounds described herein.
  • the amount of compound is effective to selectively induce terminal differentiation, induce cell growth arrest and/or induce apoptosis of such neoplastic cells and thereby inhibit their proliferation.
  • kits comprising a therapeutically effective amount of at least one Thiazole Carboxamide Compound, or a pharmaceutically acceptable salt of said compound, and a pharmaceutically acceptable carrier, vehicle or diluent.
  • pH concentration of hydronium ions in a solution
  • IP A isopropanol
  • CDI ⁇ , ⁇ '-carbonyldiimidazole
  • LiHMDS Lithium bis(trimethylsilyl)amide
  • HMDS hexamethyldisilazane
  • Int-8h was prepared from Int-11 and 2-bromothiazole-4-carboxylic acid using similar procedures for the preparation of Int-8b.
  • Table 1 (List of Int-2)
  • Tetrakistriphenylphosphorous palladium 13 mg, 0.01 1 mmol was added. The mixture was heated in a sealed-tube at 90 °C for overnight. After being cooled to r.t, methanol and hydrochloric acid (4N in dioxane) were added. Silica gel was added to the mixture and solvents were removed in vacuum. The solid mixture was then purified by chromatographic separation [dichloromethane - methanol (7N ammonia)] to give compound 2 as white solid.
  • Int-45 was prepared from Int-2n and Int-1 using similar procedures for the preparation of Int-3 (step 1).
  • lnt-48 was prepared from Int-47 using similar procedures for the preparation of compound 2 from Int-3.
  • Int-68, Int-69 and Int-70 were prepared by following similar procedures for the syntfo
  • the reaction mixture was diluted with H 2 0 (300 mL) and EtOAc (150 mL). The layers were separated and the aqueous layer was washed with EtOAc (1 x 200 mL). The organic layers were discarded. Then the aqueous layer was acidified to pH ⁇ 4 by addition of 1 N HCl( a ) , and extracted with CH2CI2 (4 x 1 0 mL). All the CH 2 C1 2 layers were combined, dried over Na 2 S0 4 , filtered, concentrated, and dried in vacuum to yield lnt-30 as tan solid.
  • reaction mixture was diluted with EtOAc (100 r L), washed with sat. aHC0 3(aq) (3 x 100 mL), H 2 0 (3 x 100 mL), brine (1 x 100 mL), dried over Na 2 S0 4 , filtered, and concentrated.
  • the crude product was purified by column chromatography using EtOAc and hexanes as eluents to yield amide lnt-74 as white solid.
  • Table 5 lists representative compounds of the invention with activity data whereby the ICso values are rated “A”, “B,” “C “ or “D.”
  • the IC 50 values are rated “A” for IC 50 values in the range of 1 nM to 50 nM, "B” for IC S o values in the range from 51 nM to 250 nM, "C” for IC50 values in the range from 251 nM to 1 ⁇ , and “D” for IC50 values greater than 1 ⁇ .
  • IC 5 o values were obtained by testing the compounds in the assay described in Example 2.
  • the assay used to test the compounds' abilities to inhibit phosphorylation of a substrate by PDKl uses the IMAP® technology system available from Molecular Devices (Silicon Valley, CA, United States).
  • the technology enables the detection of the phosphorylation of protein substrates by PDKl and does not require the addition of antibodies to detect substrate phosphorylation.
  • the technology is based on the high-affinity interaction of trivalent metal containing nanoparticles (beads) with phospho-groups on the substrate of interest.
  • the readout for the assay was fluorescence polarization (FP) which increased once the fluorescently labeled substrate was phosphorylated and was bound to the beads as opposed to the unphosphorylated substrate which did not bind the beads and had relatively lower polarization.
  • FP fluorescence polarization
  • the fluorescently-labeled peptide substrate from glycogen synthase- 1 (5FAM-PLS TLSVSSLPGL-NH2 (SEQ ID NO: l) Molecular Devices part no RP7045). was phosphorylated in a kinase reaction. Addition of the IMAP® Binding System (available from Molecular Devices) stopped the kinase reaction and specifically bound the phosphorylated substrates. Phosphorylation and subsequent binding of the substrate to the beads was detected by FP.
  • RREPRILSEEEQEMFRDFDYIADWC SEQ ID NO:2.
  • PIFtide is a peptide sequence that interacts with PDK-1 and is derived from PRK2 kinase, a PDK-1 substrate. This sequence is present in the hydrophobic motif present in PDK-1 substrates and binds to the kinase domain of PDK-1. It is thought to act as a docking site for PDK-1 on the substrate and in vitro has been shown enhance PDK-1 phosphorylation of substrates by approximately 4-fold. See Biondi et al, EMBO 19, 979-988 (2000).
  • the detection beads were then added and allowed to incubate for 1 hour at room temperature and the fluorescence was then read.
  • Staurosporine a broad spectrum kinase inhibitor, was used as a positive control for the assay resulting in typical IC50S of 3 nM.
  • Test compounds in 100% DMSO at a range of concentrations were added at 0.5 ⁇ 1 minutes prior to ATP addition.
  • the fluorescence polarization units (mP) generated with 1 uM stauroporine is considered to be background mP and the mP units generated with DMSO is considered to be total mP for each assay.
  • the IC50 value is calculated based on fitting the mP units to the total and background mP and the concentration required to inhibit the mP units by 50% is reported to be

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Abstract

Cette invention concerne certains dérivés de thiazole carboxamide en tant qu'inhibiteurs de la protéine kinase dépendante du 3-phosphoinositide (PDK-1). Les composés peuvent être utiles dans l'inhibition de la prolifération de cellules cancéreuses et d'autres états aberrants où la voie de signalisation de PDK-1 est excessivement stimulée.
PCT/US2011/057558 2010-10-29 2011-10-25 Nouveaux dérivés thiazole-carboxamide en tant qu'inhibiteurs de pdk1 WO2012058174A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017015152A1 (fr) 2015-07-17 2017-01-26 Memorial Sloan-Kettering Cancer Center Thérapie combinée utilisant des inhibiteurs de pdk1 et de pi3k
EP3643310A1 (fr) * 2018-10-25 2020-04-29 Korea Advanced Institute Of Science And Technology Composition de contrôle inverse de la sénescence cellulaire comprenant un inhibiteur pdk1

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090286766A1 (en) * 2006-04-19 2009-11-19 Astellas Pharma Inc. Azolecarboxamide derivative
US20100216767A1 (en) * 2006-12-22 2010-08-26 Mina Aikawa Quinazolines for pdk1 inhibition

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090286766A1 (en) * 2006-04-19 2009-11-19 Astellas Pharma Inc. Azolecarboxamide derivative
US20100216767A1 (en) * 2006-12-22 2010-08-26 Mina Aikawa Quinazolines for pdk1 inhibition

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017015152A1 (fr) 2015-07-17 2017-01-26 Memorial Sloan-Kettering Cancer Center Thérapie combinée utilisant des inhibiteurs de pdk1 et de pi3k
US11696924B2 (en) 2015-07-17 2023-07-11 Memorial Sloan-Kettering Cancer Center Combination therapy using PDK1 and PI3K inhibitors
EP3643310A1 (fr) * 2018-10-25 2020-04-29 Korea Advanced Institute Of Science And Technology Composition de contrôle inverse de la sénescence cellulaire comprenant un inhibiteur pdk1

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