WO2015073072A1 - 7-benzyl-4-(2-méthylbenzyl)-2,4,6,7,8,9-hexahydroimidazo[1,2-a]pyrido[3,4-e]pyrimidin-5(1h)-one - Google Patents

7-benzyl-4-(2-méthylbenzyl)-2,4,6,7,8,9-hexahydroimidazo[1,2-a]pyrido[3,4-e]pyrimidin-5(1h)-one Download PDF

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Publication number
WO2015073072A1
WO2015073072A1 PCT/US2014/048241 US2014048241W WO2015073072A1 WO 2015073072 A1 WO2015073072 A1 WO 2015073072A1 US 2014048241 W US2014048241 W US 2014048241W WO 2015073072 A1 WO2015073072 A1 WO 2015073072A1
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WO
WIPO (PCT)
Prior art keywords
cancer
compound
therapeutic agent
inhibitors
treatment
Prior art date
Application number
PCT/US2014/048241
Other languages
English (en)
Inventor
Martin Stogniew
Joshua E. ALLEN
Original Assignee
Oncoceutics, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US14/208,657 external-priority patent/US9265765B2/en
Application filed by Oncoceutics, Inc. filed Critical Oncoceutics, Inc.
Priority to CN201910972122.XA priority Critical patent/CN110669047A/zh
Priority to EA201691008A priority patent/EA033744B1/ru
Priority to EA201991877A priority patent/EA201991877A3/ru
Priority to TR2019/06711T priority patent/TR201906711T4/tr
Priority to MX2020002814A priority patent/MX2020002814A/es
Priority to ES19158371T priority patent/ES2895600T3/es
Priority to PL19158371T priority patent/PL3546461T3/pl
Priority to PT14861931T priority patent/PT3068401T/pt
Priority to DK14861931.5T priority patent/DK3068401T3/da
Priority to MX2016006318A priority patent/MX2016006318A/es
Priority to KR1020237045471A priority patent/KR20240006008A/ko
Priority to SI201431203T priority patent/SI3068401T1/sl
Priority to KR1020227034791A priority patent/KR20220140042A/ko
Priority to EP14861931.5A priority patent/EP3068401B1/fr
Priority to HUE14861931A priority patent/HUE043291T2/hu
Priority to EP19158371.5A priority patent/EP3546461B1/fr
Priority to PL14861931T priority patent/PL3068401T3/pl
Priority to BR112016011072-2A priority patent/BR112016011072B1/pt
Priority to HUE19158371A priority patent/HUE056389T2/hu
Priority to CA2930535A priority patent/CA2930535C/fr
Priority to PT191583715T priority patent/PT3546461T/pt
Priority to US15/036,210 priority patent/US9688679B2/en
Priority to IL311202A priority patent/IL311202A/en
Priority to AU2014349150A priority patent/AU2014349150B2/en
Priority to HRP20211653TT priority patent/HRP20211653T8/hr
Priority to ES14861931T priority patent/ES2724331T3/es
Priority to SI201431890T priority patent/SI3546461T1/sl
Priority to RS20190518A priority patent/RS58745B1/sr
Priority to SG10201809189UA priority patent/SG10201809189UA/en
Priority to LTEP19158371.5T priority patent/LT3546461T/lt
Priority to NZ721055A priority patent/NZ721055B2/en
Priority to PCT/US2014/055373 priority patent/WO2015073109A1/fr
Priority to KR1020217034110A priority patent/KR102453679B1/ko
Priority to KR1020167015829A priority patent/KR102318238B1/ko
Priority to DK19158371.5T priority patent/DK3546461T3/da
Priority to IL296386A priority patent/IL296386B2/en
Priority to JP2016554306A priority patent/JP6670751B2/ja
Priority to CA3204925A priority patent/CA3204925A1/fr
Priority to EP21183202.7A priority patent/EP3939594A1/fr
Priority to RS20211310A priority patent/RS62572B1/sr
Priority to MEP-2019-129A priority patent/ME03387B/fr
Priority to CN201480070502.XA priority patent/CN106163524B/zh
Publication of WO2015073072A1 publication Critical patent/WO2015073072A1/fr
Priority to IL245603A priority patent/IL245603B/en
Priority to MX2022001966A priority patent/MX2022001966A/es
Priority to US15/626,518 priority patent/US10045992B2/en
Priority to US16/100,045 priority patent/US10456402B2/en
Priority to HRP20190814TT priority patent/HRP20190814T1/hr
Priority to CY20191100520T priority patent/CY1121628T1/el
Priority to IL268248A priority patent/IL268248B/en
Priority to US16/654,889 priority patent/US10953014B2/en
Priority to JP2019233099A priority patent/JP2020097577A/ja
Priority to AU2020200875A priority patent/AU2020200875B2/en
Priority to US17/166,560 priority patent/US20210154200A1/en
Priority to IL281785A priority patent/IL281785B/en
Priority to CY20211100939T priority patent/CY1124832T1/el
Priority to IL288674A priority patent/IL288674B2/en
Priority to JP2022076459A priority patent/JP2022105170A/ja
Priority to AU2022203043A priority patent/AU2022203043B2/en
Priority to JP2024027134A priority patent/JP2024059840A/ja

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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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems

Definitions

  • the pharmaceutical composition comprises compound (1) in the form of a pharmaceutically acceptable salt selected from the group consisting of p-toluene-sulfonate, benzenesulfonate, methanesulfonate, oxalate, succinate, tartrate, citrate, fumarate, glucuronate, ascorbate and maleate.
  • the pharmaceutical composition comprises compound (1) in the form of a pharmaceutically acceptable salt selected from the group consisting of ammonium, sodium, potassium, calcium, magnesium, zinc, lithium, and/or with other counter-ions such as methylamino, dimethylamino, diethylamino and triethylamino counter-ions.
  • the pharmaceutical composition comprises compound (1) in the form of a hydrochloride di-salt or hydrobromide di-salt.
  • the method of treatment comprises administering to the subject a pharmaceutical composition comprising a pharmaceutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof. In one embodiment, the method of treatment comprises administering to the subject a pharmaceutical composition comprising a pharmaceutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • compositions and various dosage forms, as well as modes of administration are well-known in the art, for example as detailed in Pharmaceutical Dosage Forms: Tablets, edited by Larry L. Augsburger and Stephen W. Hoag., London: Informa Healthcare, 2008; and in L. V. Allen, Jr. et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems, 8th Ed., Philadelphia, Pa.: Lippincott, Williams & Wilkins, 2004; A. R. Gennaro, Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 21st ed., 2005, particularly chapter 89; and J. G. Hardman et al., Goodman & Gilman's The Pharmacological Basis of Therapeutics, McGraw-Hill Professional, 10th ed., 2001.
  • the pharmaceutical composition includes compound (1) or a pharmaceutically acceptable salt thereof and at least one other therapeutic agent.
  • the at least one other therapeutic agent is selected from the group consisting of hormone analogues and antihormones, aromatase inhibitors, LHRH agonists and antagonists, inhibitors of growth factors, growth factor antibodies, growth factor receptor antibodies, tyrosine kinase inhibitors; antimetabolites; antitumour antibiotics; platinum derivatives; alkylation agents; antimitotic agents; tubuline inhibitors; PARP inhibitors, topoisomerase inhibitors, serine/threonine kinase inhibitors, tyrosine kinase inhibitors, protein protein interaction inhibitors, RAF inhibitors, MEK inhibitors, ERK inhibitors, IGF-1R inhibitors, ErbB receptor inhibitors, rapamycin analogs, BTK inhibitors, CRM1 inhibitors (e.g., KPT185), P53 modulators (e.g., Nutlin
  • the at least one other therapeutic agent comprises one or more LHRH agonists and/or antagonists selected from the group consisting of goserelin acetate, luprolide acetate, triptorelin pamoate and combinations thereof and wherein the LHRH antagonists are selected from the group consisting of Degarelix, Cetrorelix, Abarelix, Ozarelix, Degarelix
  • the at least one other therapeutic agent comprises one or more growth factor inhibitors selected from the group consisting of inhibitors of: platelet derived growth factor (PDGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), insuline-like growth factors (IGF), human epidermal growth factor (HER) and hepatocyte growth factor (HGF).
  • the at least one other therapeutic agent comprises one or more inhibitors of the human epidermal growth factor selected from the group consisting of HER2, HER3, and HER4.
  • Anthracyclines examples include, but are not limited to, Daunorubicin
  • Nucleotide synthesis inhibitors include, but are not limited to, methotrexate, pralatrexate, hydroxyurea, and 5-fluorodeoxyuridine, 3 ,4-dihydroxybenzy lam ine .
  • SAHA Romidepsin
  • Istodax Panobinostat
  • LH589 Valproic acid (as Mg valproate)
  • Belinostat PXD101
  • Mocetinostat MCD0103
  • Abexinostat PCI-24781
  • Entinostat MS-275
  • SB939 Resminostat (4SC-201)
  • Givinostat Quisinostat (JNJ-26481585)
  • CUDC-101 AR-42, CHR-2845, CHR-3996, 4SC-202, CG200745, ACY-1215, ME-344, sulforaphane, Kevetrin, and ATRA.
  • a pharmaceutical composition according to the invention comprises compound (1) or a pharmaceutically acceptable salt thereof in a dose ranging from about 100 mg to about 2000 mg, where the weight can, in certain embodiments be based on compound (1) in its free base form. In one embodiment, a pharmaceutical composition according to the invention comprises compound (1) or a pharmaceutically acceptable salt thereof in a dose ranging from about 40 mg to about 2000 mg, where the weight can, in certain embodiments be based on compound (1) in its free base form. In one embodiment, a pharmaceutical composition according to the invention comprises compound (1) or a pharmaceutically acceptable salt thereof in a dose ranging from about 50 mg to about 2000 mg, where the weight can, in certain embodiments be based on compound (1) in its free base form.
  • the method of treatment of the present invention is useful for treating cancer, wherein the cancer is selected from the group consisting of Oral Cancer, Lip and Oral Cavity Cancer, Oropharyngeal Cancer, Osteosarcoma and Malignant Fibrous Histiocytoma of Bone, Ovarian Cancer, Ovarian Germ Cell Tumor, Ovarian Epithelial Cancer, and Ovarian Low Malignant Potential Tumor.
  • the cancer is selected from the group consisting of Oral Cancer, Lip and Oral Cavity Cancer, Oropharyngeal Cancer, Osteosarcoma and Malignant Fibrous Histiocytoma of Bone, Ovarian Cancer, Ovarian Germ Cell Tumor, Ovarian Epithelial Cancer, and Ovarian Low Malignant Potential Tumor.
  • the method of treatment of the present invention is useful for treating cancer, wherein the cancer is selected from the group consisting of Carcinoma of Unknown Primary Site, Cancer of Unknown Primary Site, Unusual Cancers of Childhood, Transitional Cell Cancer Of the Renal Pelvis and Ureter, Urethral Cancer, and Uterine Sarcoma.
  • the second therapeutic agent is selected from the group consisting of tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproterone acetate, finasteride, buserelin acetate, fludrocortisone, fluoxymesterone, medroxy-progesterone, octreotide, and combinations thereof.
  • the second therapeutic agent is selected, without limitation, from the group consisting of LHRH agonists and LHRH antagonists.
  • FOLFOX4, FOLFIRI formestane, fotemustine, galarubicin, gallium maltolate, gefinitib, gemtuzumab, gimatecan, glufosfamide, GCS-100, GDC-0623, GDC-0941 (pictrelisib), GDC-0980, GDC-0032, GDC-0068, GDC-0349, GDC-0879, G17DT immunogen, GMK, GPX-lOO, gplOO-peptide vaccines, GSK-5126766, GSK-690693, GSK-1120212 (trametinib), GSK-2118436 (dabrafenib), GSK-2126458, GSK-2132231A, GSK-2334470, GSK-2110183, GSK-2141795, GW2016, granisetron, herceptine, hexamethylmelamine, histamine, homoharringtonine, hyaluronic acid, hydroxy
  • maximum concentration of the first therapeutic agent in blood (whole blood, plasma, or serum) ("Cmax") of the subject following its administration to the subject is selected from about 85 ng/dl to about 1500 ng/dl, from about 95 ng/dl to about 1500 ng/dl, from about 105 ng/dl to about 1500 ng/dl, from about 1 15 ng/dl to about 1500 ng/dl, from about 125 ng/dl to about 1500 ng/dl, from about 135 ng/dl to about 1500 ng/dl, from about 145 ng/dl to about 1500 ng/dl, from about 155 ng/dl to about 1500 ng/dl, from about 165 ng/dl to about 1500 ng/dl, from about 175 ng/dl to about 1500 ng/dl, from about 185 ng/dl to about 1500 ng/dl, from about 195 ng/dl to about 1500 ng/dl, from about 85 ng/
  • the multimodal therapeutic method comprises administering to a subject a pharmaceutical composition comprising compound (1) or a pharmaceutically acceptable salt thereof in conjunction with radiation therapy in a sequential arrangement. In one embodiment, the multimodal therapeutic method comprises administering to a subject in need of such treatment a pharmaceutical composition comprising compound (1) or a pharmaceutically acceptable salt thereof concurrently with radiation therapy. In one embodiment, the multimodal therapeutic method of the present invention is used for the treatment of cancer. In one embodiment, the multimodal therapeutic method includes administering to a cancer subject in need of such treatment a pharmaceutical composition comprising compound (1) or a pharmaceutically acceptable salt thereof and irradiating cancer cells with a radiation beam.
  • the synthetic process includes neutralizing the intermediary compound of (3) with a base (Step 1) to produce the compound of (4), a free base.
  • the synthetic process includes neutralizing the intermediary compound of (3) with an inorganic base to produce the compound of (4).
  • the synthetic process includes neutralizing the intermediary compound of (3) with an organic base to produce the compound of (4).
  • the intermediary compound of (3) is neutralized in the presence of an alcohol.
  • the intermediary compound of (3) is neutralized in the presence of n-butanol.
  • the intermediary compound of (3) is neutralized in the presence of at least one organic solvent.
  • compound (10) can be synthesized starting either with methyl l-R 4-oxo-3-piperidinecarboxylate (6) or by reacting compound (12) with compound (6).
  • Scheme 3 illustrates the synthesis of compound (10) starting from compound (6).
  • compound (6) was converted into
  • Ci -4 alkylphenyl, and Cj- 4 benzyl-piperazine are optionally substituted with Ci_ 4 alkyl, hydroxyl, or halo.
  • the analogs have the structure of compound (25), wherein Ri, R 2 , R 3 , and R4 are independently selected from the group consisting of H, CH 3 , CH 2 Ph, CH 2 -((2-Cl)-Ph), CH 2 -(2-thienyl), CH 2 CH 2 Ph,
  • analogs have the structure of compound (29):
  • reaction mixture from EXAMPLE 8 was washed with 500 mL of water and diluted with methyl tert-butyl ether (MTBE) (800 mL).
  • MTBE methyl tert-butyl ether
  • the organic phase was washed with water (500 mL ⁇ 2) and transferred to a 3 L three-neck round bottom flask equipped with mechanical stirring, N2 inlet, a thermocouple, a condenser and a Dean-Stark trap.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne, au moins en partie, une méthode de traitement qui consiste à administrer, à un sujet nécessitant un tel traitement, un premier agent thérapeutique contenant la 7-benzyl-4-(2-methylbenzyl)-2,4,6,7,8,9-hexahydroimidazo[1,2-a]pyrido[3,4-e]pyrimidin-5(1H)-one, ou un sel pharmaceutiquement acceptable de celle-ci en association avec un second agent thérapeutique, le premier agent thérapeutique et le second agent thérapeutique étant administrés soit simultanément, soit successivement.
PCT/US2014/048241 2013-03-13 2014-07-25 7-benzyl-4-(2-méthylbenzyl)-2,4,6,7,8,9-hexahydroimidazo[1,2-a]pyrido[3,4-e]pyrimidin-5(1h)-one WO2015073072A1 (fr)

Priority Applications (59)

Application Number Priority Date Filing Date Title
CN201910972122.XA CN110669047A (zh) 2013-11-15 2014-09-12 用于治疗癌症的化合物、其组合物及应用方法
EA201691008A EA033744B1 (ru) 2013-11-15 2014-09-12 7-бензил-4-(2-метилбензил)-2,4,6,7,8,9-гексагидроимидазо[1,2-a]пиридо[3,4-e]пиримидин-5(1h)-он, его соли и способы применения
EA201991877A EA201991877A3 (ru) 2013-11-15 2014-09-12 7-бензил-4-(2-метилбензил)-2,4,6,7,8,9-гексагидроимидазо[1,2- a]пиридо[3,4-e]пиримидин-5(1h)-он, его соли и способы применения
TR2019/06711T TR201906711T4 (tr) 2013-11-15 2014-09-12 7-benzil-4-(2-metilbenzil)-2,4,6,7,8,9-hekzahidroimidazo[1,2-a]pirido[3,4-e]pirimidin-5(1h)-on, bunun tuzları ve kullanım metotları.
MX2020002814A MX2020002814A (es) 2013-11-15 2014-09-12 7-bencil-4-(2-metilbencil)-2,4,6,7,8,9-hexahidroimidazo[1,2-a]pir ido[3,4-e]pirimidin-5(1h)-ona, sales de la misma y metodos de uso.
ES19158371T ES2895600T3 (es) 2013-11-15 2014-09-12 7-Bencil-4-(2-metilbencil)-2,4,6,7,8,9-hexahidroimidazo[1,2-a]pirido[3,4-e]pirimidin-5(1H)-ona, sales de la misma y procedimientos de uso de la misma en terapia de combinación
PL19158371T PL3546461T3 (pl) 2013-11-15 2014-09-12 7-benzylo-4-(2-metylobenzylo)-2,4,6,7,8,9- heksahydroimidazo[1,2-a]pirydo[3,4-e]pirymidyn-5(1h)-on, jego sole i sposoby jego stosowania w terapii skojarzonej
PT14861931T PT3068401T (pt) 2013-11-15 2014-09-12 7-benzil-4-(2-metilbenzil)-2,4,6,7,7,8,9-hexaidroimidazo[1,2- a]pirido[3,4-e]pirimidin-5(1h)-ona, seus sais e métodos de uso
DK14861931.5T DK3068401T3 (da) 2013-11-15 2014-09-12 7-benzyl-4-(2-methylbenzyl)-2,4,6,7,8,9-hexahydroimidazo[1,2-a]pyrido[3,4-e]pyrimidin-5(1h)-on, salte deraf og fremgangsmåder til anvendelse
MX2016006318A MX2016006318A (es) 2013-11-15 2014-09-12 7-bencil-4-(2-metilbencil)-2,4,6,7,8,9-hexahidroimidazo[1,2-a]pir ido[3,4-e]pirimidin-5(1h)-ona, sales de la misma y metodos de uso.
KR1020237045471A KR20240006008A (ko) 2013-11-15 2014-09-12 7-벤질-4-(2-메틸벤질)-2,4,6,7,8,9-헥사하이드로이미다조[1,2-a]피리도[3,4-e]피리미딘-5(1H)-온,이의 염 및 이의 용도
SI201431203T SI3068401T1 (sl) 2013-11-15 2014-09-12 7-benzil-4-(-2-metilbenzil)-2,4,6,7,8,9-heksahidroimidazo(1,2-a) pirido(3,4-e)pirimidin-5(1h)-on, njegove soli in postopki uporabe
KR1020227034791A KR20220140042A (ko) 2013-11-15 2014-09-12 7-벤질-4-(2-메틸벤질)-2,4,6,7,8,9-헥사하이드로이미다조[1,2-a]피리도[3,4-e]피리미딘-5(1H)-온, 이의 염 및 이의 용도
EP14861931.5A EP3068401B1 (fr) 2013-11-15 2014-09-12 7-benzyl-4-(2-méthylbenzyl)-2,4,6,7,8,9-hexahydroimidazo[1,2-a]pyrido[3,4-e]pyrimidin-5(1h)-one, ses sels et procédés d'utilisation
HUE14861931A HUE043291T2 (hu) 2013-11-15 2014-09-12 7-benzil-4-(2-metilbenzil)-2,4,6,7,8,9-hexahidroimidazo[1,2-a] pirido[3,4-e]pirimidin-5(lH)-on, sói és alkalmazási eljárások
EP19158371.5A EP3546461B1 (fr) 2013-11-15 2014-09-12 7-benzyl-4-(2-méthylbenzyle)-2,4,6,7,8,9-hexahydroimidazo[1,2-a]pyrido[3,4-e]pyrimidine-5(1h)-one, sels associés et leurs procédés d'utilisation en thérapie de combinaison
PL14861931T PL3068401T3 (pl) 2013-11-15 2014-09-12 7-Benzylo-4-(2-metylobenzylo)-2,4,6,7,8,9-heksahydroimidazo[1,2-a]pirydo[3,4-e]pirymidyn- 5(1H)-on, jego sole i sposoby zastosowania
BR112016011072-2A BR112016011072B1 (pt) 2013-11-15 2014-09-12 Composto 7-benzil-4-(2-metilbenzil)-2,4,6,7,8,9- hexahidroimidazo[1,2-a]pirido[3,4-e]pirimidin-5(1h) -ona e composição farmacêutica contendo o referido composto
HUE19158371A HUE056389T2 (hu) 2013-11-15 2014-09-12 7-Benzil-4-(2-metilbenzil)-2,4,6,7,8,9-hexahidroimidazo[1,2-a]pirido[3,4-e]pirimidin-5(1H)-on, sói és eljárások kombinációs terápiában való alkalmazására
CA2930535A CA2930535C (fr) 2013-11-15 2014-09-12 7-benzyl-4-(2,4-difluorobenzyl)-2,4,6,7,8,9-hexahydroimidazo[1,2-a]pyrido[3,4-e] pyrimidin-5(1h)-one, sels connexes et compositions pharmaceutiques connexes
PT191583715T PT3546461T (pt) 2013-11-15 2014-09-12 7-benzil-4-(2-metilbenzil)-2,4,6,7,8,9-hexahidroimidazo[ 1,2-a]pirido[3,4-e]pirimidin-5(1h)-ona, seus sais e métodos de utilização dos mesmos em terapia de combinação
US15/036,210 US9688679B2 (en) 2013-03-13 2014-09-12 7-benzyl-4-(methylbenzyl)-2,4,6,7,8,9-hexahydroimidazo[1,2-A]pyrido[3,4-E]pyrimidin-5 (1H)-one, salts thereof and methods of using the same in combination therapy
IL311202A IL311202A (en) 2013-11-15 2014-09-12 7-Benzyl-4-(2-methylbenzyl)-2, 4, 6, 7, 8, 9-hexahydroimidazo [1,2-A] pyrido[3,4-E] pyrimidine-5(1H)one, its salts and methods Use
AU2014349150A AU2014349150B2 (en) 2013-11-15 2014-09-12 7-benzyl-4-(2-methylbenzyl)-2,4,6,7,8,9-hexahydroimidazo[1,2-a]pyrido[3,4-e]pyrimidin-5(1h)-one, salts thereof and methods of use
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US11040027B2 (en) 2017-01-17 2021-06-22 Heparegenix Gmbh Protein kinase inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death
US10946022B2 (en) 2017-01-30 2021-03-16 Oncoceutics, Inc. Imipridones for gliomas
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CN111153891A (zh) * 2020-01-10 2020-05-15 贵州医科大学 一种取代苯并咪唑类PI3Kα/mTOR双靶点抑制剂及其药物组合物和应用
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