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Claims for Patent: 10,287,294

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Summary for Patent: 10,287,294
Title:Compounds for use in treating or preventing cancerous diseases
Abstract: The invention relates to new compounds of formula (I) that are useful in medicine, specifically in treating or preventing cancerous diseases in a mammal, to pharmaceutical compositions comprising such compounds, optionally together with other pharmaceutically active compounds, or to pharmaceutical formulations comprising such compounds or pharmaceutical compositions. The invention further relates to methods of making these compounds.
Inventor(s): Stellas; Dimitris (Athens, GR), Tamvakopoulos; Constantin (Athens, GR), Klinakis; Apostolos (Iraklio, GR), Efstratiadis; Argiris (Athens, GR), Cournia; Zoe (Kifissia, GR)
Assignee: BIOMEDICAL RESEARCH FOUNDATION OF THE ACADEMY OF ATHENS (GR)
Application Number:15/742,330
Patent Claims:1. A compound of formula (I) ##STR00023## or a tautomer, polymorph, metabolite, or a pharmaceutically acceptable salt thereof, wherein n is 0; X is N; CY.sub.3 is CF.sub.3, CF.sub.2Cl, or CFCl.sub.2; R.sub.1 is ##STR00024## R.sub.2 is 2-thiophenyl, 2-furanyl, 2-pyrrolyl, or 5-pyrazolyl; R.sub.3 is a group --R.sub.5--COOH group or a pharmaceutically acceptable salt thereof; wherein R.sub.5 is either a bond or a C.sub.1-alkyl group; and R.sub.4 is selected from any one of the following: substituted or unsubstituted cyclohexyl, substituted or unsubstituted tetrahydropyran, piperidine, thiacyclohexane, dioxane, piperazine, morpholine, pyran, oxazine, thiazine, substituted or unsubstituted phenyl, pyridine, or pyrimidine.

2. The compound of claim 1, wherein R.sub.2 is 2-furanyl; and R.sub.3 is a carboxyl group directly attached to the pyrazole ring, or a pharmaceutically acceptable salt thereof; and R.sub.4 is a phenyl group.

3. The compound of claim 1, having the following formula (II): ##STR00025## or a pharmaceutically acceptable salt thereof.

4. A pharmaceutical composition comprising the compound of claim 1, optionally further comprising one or more additional therapeutic agents.

5. The pharmaceutical composition of claim 4, wherein the one or more additional therapeutic agents are selected from the group consisting of: 10-Hydroxycamptothecin, 17-Allylamino-geldanamycin, 2-Methoxyanti-mycin A3, 3,4-Dichloroisocoumarin, 4-Hydroxyphenylretinamide, 9-cis Retinoic acid, Abiraterone, Ado-Trastuzumab Emtansine, Adriamycin, Afatinib, N-(3-chlorophenyl)-6,7-dimethoxyquinazolin-4-amine, 2-Amino-4-(1H-indol-5-yl)-1,1,3-tricyanobuta-1,3-diene, Aldesleukin, Alemtuzumab, Amifostine, Anastrozole, Anisomycin, Aphidicolin, Arsenic Trioxide, Asparaginase Erwinia chrysanthemi, Axitinib, N-[2(S)-(2(R)-2-Amino-3-mercaptopropylamino)-3-methylbutyl]-L-phenylalany- l-L-methionine trifluoroacetate salt, Bacillus Calmette-Guerin, bisphenol A diglycidyl ether, Bendamustine, Beta-lapachone, Betulinic acid, Bevacizumab, Bexarotene, Bicalutamide, BisBenzimide, Bleomycin, Bortezomib, Bosutinib, Buserelin, Busulfan, Cabazitaxel, Calpeptin, Camptothecin, Caffeic acid phenethyl ester, Capecitabine, Carboplatin, Carboplatin, Carfilzomib, Carmustine, Cetuximab, Chlorambucil, Ciglitazone, Cisplatin, Clodronate, Clofarabine, Crizotinib, Curcumin, Cyclo [Arg-Gly-Asp-D-Phe-Val], Cycloheximide, Cyclopamine, Cyclophosphamide, Cyclosporin A, Cyproterone, Cytarabine, D12-Prostaglandin J2, Dabrafenib, Dacarbazine, Dactinomycin, Dasatinib, Daunorubicin, Degarelix, Denosumab, Dexamethasone, Docetaxel, Doxorubicin, Ebselen, Ellipticine, Enzalutamide, Epirubicin, Erlotinib, Etoposide, Everolimus, Exemestane, Fludarabine, Fluorouracil, Flutamide, Folinic acid, Fulvestrant, Gefitinib, Geldanamycin, Gemcitabine, Genistein, Gingerol, Gliotoxin, Goserelin, 2-Chloro-5-nitrobenzanilide, 2-Amino-6-bromo-.alpha.-cyano-3-(ethoxycarbonyl)-4H-1-benzopyran-4-acetic acid ethyl ester, Hinokitiol, Sobuzoxane, Idarubicin, ifosfamide, Imatinib, Indomethacin, Ipilimumab, Irinotecan, Ixabepilone, Lanreotide, Lapatinib, Lenalidomide, Letrozole, Leucovorin, Leuprolide, Medroxyprogesterone, Megestrol, Melphalan, Mepesuccinate, Mercaptopurine, Mesna, Methotrexate, Methoxy verapamil, carbobenzoxy-L-leucyl-L-leucyl-L-leucinal, Mitomycin C, Mitoxantrone, N,N-Dimethylsphingosine, Nelarabine, Nilotinib, Octreotide, Ofatumumab, Oligomycin A, Omacetaxine, Oxaliplatin, Paclitaxel, Pamidronate, Panitumumab, Pazopanib, Pegaspargase, Pemetrexed, Pertuzumab, Pifithrin, plerixafor, Podophyllotoxin, Pomalidomide, Ponatinib, Prednisone, 2,2-Bis(hydroxymethyl)-1-azabicyclo[2.2.2]octan-3-one, Procarbazine, Radium 223 Dichloride, Raltitrexed, Rapamycin, Recombinant Human Papillomavirus (HPV) Bivalent Vaccine, Recombinant HPV Quadravalent Vaccine, Recombinant HPV Bivalent Vaccine, Recombinant HPV Quadravalent Vaccine, Recombinant Interferon Alfa-2b, Regorafenib, Resveratrol, all trans Retinoic acid, Rheumatrex, Rituximab, Rolipram, Roscovitine, Rottlerin, Shikonin, Sipuleucel-T, Sirolimus, Sorafenib, Sphingosine, Splitomycin, Staurosporine, Stilboestrol, Streptozocin, 3-(4-Dimethylaminobenzylidenyl)-2-indolinone, 3-[[(4-Dimethyl-amino)phenyl] methylene]-1,3-dihydro-2H-indol-2-one, Sulindac sulphide, Sunitinib, Tamoxifen, Temozolomide, Temsirolimus, Thalidomide, Topotecan, Toremifene, Trametinib, Trastuzumab, Trichostatin-A, Trifluoperazine, 4-[(E)-2-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propen- yl]benzoic acid, 3,4-Dihydroxy-.alpha.-cyanothiocinnam-amide, (3-Hydroxy-4-nitrobenzylidene)malononitrile, Valproic acid, Vemurafenib, Verapamil, Vinblastine, Vincristine, Vinorelbine, Wortmannin, 4-Chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid, Ziv-Aflibercept, Zoledronic Acid, salts thereof, and combinations thereof.

6. The pharmaceutical composition of claim 4, further comprising one or more additional therapeutic agents, which are selected from the group consisting of Acetylsalicylic acid, Diflunisal, Salsalate, Ibuprofen, Dexibuprofen, Naproxen, Fenoprofen, Ketoprofen, Dexketoprofen, Flurbiprofen, Oxaprozin, Loxoprofen, Indomethacin, Tolmetin, Sulindac, Etodolac, Ketorolac, Diclofenac, Nabumetone, Piroxicam, Meloxicam, Tenoxicam, Droxicam, Lornoxicam, Isoxicam, Mefenamic acid, Meclofenamic acid, Flufenamic acid, Tolfenamic acid, Celecoxib, Rofecoxib, Valdecosib, Parecoxib, Lumiracoxib, Etoricoxib, Firocoxib, Nimesulide, Licofelone, H-harpagide, Lysine clonixinate, pharmaceutically acceptable salts thereof, and combinations thereof.

7. The pharmaceutical composition of claim 4, further comprising one or more agents inducing unscheduled DNA repair synthesis (UDS) at a target oncogene, and, optionally, one or more antimetabolites.

8. The pharmaceutical composition of claim 7, wherein the agent inducing unscheduled DNA repair synthesis (UDS) is a triple helix forming oligonucleotide specifically binding to Myc; and/or wherein the antimetabolite is a purine or pyrimidine analog.

9. A method of treating a cancerous disease in a mammal, comprising the administration of a therapeutically effective amount to the mammal of the compound of claim 1.

10. The method of claim 9, wherein the mammal is human.

11. The method of claim 9, wherein the cancerous disease is susceptible to Myc overexpression and/or deregulation.

12. The method of claim 9, wherein the cancerous disease is selected from the group consisting of acute monocytic leukemia, acute myelogenous leukemia, acute myelomonocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, adult T-cell lymphoma, astrocytoma, atypical carcinoid lung cancer, basal cell carcinoma, B-acute lymphocytic leukemia, B-cell acute lymphoblastic leukemia/lymphoma, Bladder cancer, brain cancer, breast cancer, bronchial cancer, Burkitt's lymphoma, cancer of the bile duct, cancer of unknown primary origin, cervix cancer, chronic myeloproliferative disorder, colon cancer, diffuse large cell lymphoma, endometrial cancer, ependymoma, esophageal cancer, gastric cancer, glioma, glioblastoma, head and neck cancer, hemagiopericytoma, hepatocellular carcinoma, Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer, large cell neuroendocrine carcinoma, large granular lymphocytic leukemia, leukemia, liver cancer, lung cancer, lymphoma, medulloblastoma, melanoma, Multiple myeloma, myelodysplastic syndrome, nasopharygeal cancer, neuroblastoma, NK cell tumor, non-Hodgkin's lymphoma, oesophageal squamous cell carcinoma, osteosarcoma, ovarian cancer, pancreatic cancer, peripheral T-cell leukemia, primary plasma cell leukemia, prostate cancer, renal clear cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, small cell lung carcinoma, T-cell acute lymphoblastic leukemia, T-cell acute lymphoblastic lymphoma, testicular cancer, thymoma, urachal cancer, uterine cancer, vaginal cancer, and combinations thereof.

13. The method of claim 9, wherein the cancerous disease is selected from the group consisting of colon adenocarcinoma, lung adenocarcinoma, prostatic adenocarcinoma, urachal adenocarcinoma, vaginal adenocarcinoma, mammary adenocarcinoma, esophageal adenocarcinoma, bronchial adenocarcinoma, pancreatic adenocarcinoma, gastrointestinal adenocarcinoma; and combinations thereof.

14. A method for the manufacture of a compound of formula (I) ##STR00026## wherein the method comprises reacting a 2-carboxyl-substituted bicyclic moiety of formula (III): ##STR00027## wherein X, R.sub.2, CY.sub.3 and n are defined as in claim 1, with a moiety R.sub.1 as defined in claim 1 but with an additional amino-group to form the corresponding amide compound of formula (I) and, optionally, converting it to its corresponding pharmaceutically acceptable salt form.

15. The pharmaceutical composition of claim 5, wherein the one or more additional therapeutic agents are selected from the group consisting of: Abiraterone, Ado-Trastuzumab Emtansine, Afatinib, Anastrozole, Bevacizumab, Cabazitaxel, Capecitabine, Carboplatin, Cisplatin, Crizotinib, Cyclophosphamide, Degarelix, Denosumab, Docetaxel, Doxorubicin, Enzalutamide, Epirubicin, Erlotinib, Etoposide, Everolimus, Exemestane, Fluorouracil, Fulvestrant, Gefitinib, Gemcitabine, Ixabepilone, Lapatinib, Letrozole, Leuprolide, Megestrol, Methotrexate, Mitomycin C, Paclitaxel, Pamidronate, Pemetrexed, Pertuzumab, Prednisone, Radium 223 Dichloride, Sipuleucel-T, Sunitinib, Tamoxifen, Topotecan, Toremifene, Trastuzumab, salts thereof, and any combination thereof.

16. The pharmaceutical composition of claim 6, further comprising one or more additional therapeutic agents, which are selected from the group consisting of Celecoxib, Rofecoxib, Valdecosib, Parecoxib, Lumiracoxib, Etoricoxib, Firocoxib, pharmaceutically acceptable salts thereof, and combinations thereof.

17. The pharmaceutical composition of claim 8, wherein the triple helix forming oligonucleotide has the sequence 3'-TGGGTGGGTGGT TTGTTTTTGGG-5' (SEQ ID NO:1, "Myc2T"); and/or wherein the antimetabolite is selected from 5-fluorouracil, floxuridine, gemcitabine, cytarabine, 6-azauracil, and wherein the triple helix forming oligonucleotide has the sequence 3'-TGGGTGGGTGGT TTGTTTTTGGG-5', (SEQ ID NO:1, "Myc2T").

18. The method of claim 14, wherein the method is for preparing a compound of formula (II), or its pharmaceutically acceptable salt, by reacting a compound of formula (D1) ##STR00028## with a compound of formula (7) ##STR00029## to yield the compound of formula (II): ##STR00030## and, optionally, converting it to its corresponding pharmaceutically acceptable salt form.

Summary for Patent:   Start Trial

Foriegn Application Priority Data
Foreign Country Foreign Patent Number Foreign Patent Date
15175918Jul 8, 2015
PCT Information
PCT FiledJuly 08, 2016PCT Application Number:PCT/EP2016/066340
PCT Publication Date:January 12, 2017PCT Publication Number:WO2017/005919

Details for Patent 10,287,294

Applicant Tradename Biologic Ingredient Dosage Form BLA Number Approval Date Patent No. Assignee Estimated Patent Expiration Status Orphan Source
Merck ELSPAR asparaginase VIAL 101063 001 1978-01-10   Start Trial BIOMEDICAL RESEARCH FOUNDATION OF THE ACADEMY OF ATHENS (GR) 2035-07-08 RX search
Organon Usa Inc. TICE BCG bacillus calmette-guerin POWDER, FOR SUSPENSION 102821 1 1990-08-24   Start Trial BIOMEDICAL RESEARCH FOUNDATION OF THE ACADEMY OF ATHENS (GR) 2035-07-08 search
Schering INTRON A interferon alfa-2b VIAL 103132 001 1986-06-04   Start Trial BIOMEDICAL RESEARCH FOUNDATION OF THE ACADEMY OF ATHENS (GR) 2035-07-08 RX search
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Number >Approval Date >Patent No. >Assignee >Estimated Patent Expiration >Status >Orphan >Source

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