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WO2013132263A1 - Dérivés de picropodophylline pour utilisation en thérapie - Google Patents

Dérivés de picropodophylline pour utilisation en thérapie Download PDF

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Publication number
WO2013132263A1
WO2013132263A1 PCT/GB2013/050576 GB2013050576W WO2013132263A1 WO 2013132263 A1 WO2013132263 A1 WO 2013132263A1 GB 2013050576 W GB2013050576 W GB 2013050576W WO 2013132263 A1 WO2013132263 A1 WO 2013132263A1
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WIPO (PCT)
Prior art keywords
cancer
compound according
compound
formula
trimethoxyphenyl
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PCT/GB2013/050576
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English (en)
Inventor
Magnus Axelson
Ulf Bremberg
Original Assignee
Axelar Ab
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Publication of WO2013132263A1 publication Critical patent/WO2013132263A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems

Definitions

  • the present invention is directed to new compounds, to a pharmaceutical composition comprising said compounds, and to the use of said compounds in therapy.
  • Picropodophyllin is a compound belonging to the class of compounds denominated cyclolignans, having the chemical structure:
  • picropodophyllin For a long time, picropodophyllin attracted little interest, since it was believed to possess no or low biological activity. However, research has proven that picropodophyllin exhibits interesting biological properties and hence potential as a medicament.
  • WO 02/102804 discloses that picropodophyllin is a specific and potent inhibitor of insulinlike growth factor-1 receptor (IGF-1R) and may be useful in the treatment of IGF-1R dependent diseases such as various types of cancer, artheriosclerosis, psoriasis, and restenosis following coronary angioplasty.
  • IGF-1R insulinlike growth factor-1 receptor
  • WO 2007/097707 discloses the use of picropodophyllin in the prophylaxis or treatment of diabetes mellitus type 2, nephropathy, retinopathy, macular degeneration, retinopathy of prematurity, central retinal vein occlusion, branch retinal vein occlusion, rubeotic glaucoma, thyroid eye disease, corneal graft rejection and corneal chemical burns; and for contraception.
  • WO 2009/157858 discloses the use of picropodophyllin for the prophylaxis or treatment of diseases or conditions characterized by a hyperactive immune system such as
  • rheumatoid arthritis Crohn ' s disease, ulcerative colitis, multiple sclerosis, Alzheimer ' s disease, asthma, eczematous dermatitis, and graft rejection following transplantation.
  • An aspect of the present invention is a compound of formula (I)
  • R 1 is OH, H, D or -0-C(0)-d-C 6 alkyl
  • R 2 is H or D
  • R 3 and R 4 is each and independently H or D;
  • R 5 , R 6 and R 7 is each and independently H or D; with the exception of the compounds (5R,5aS,8aR,9R)-5,8,8a,9-Tetrahydro-9-hydroxy-5- (3,4,5-trimethoxyphenyl)-furo[3',4':6,7]naphtho[2,3-d]-1 ,3-dioxol-6(5aH)-one
  • An aspect of the present invention is a compound of formula , wherein R 1 is OH
  • An aspect of the present invention is a compound of formula , wherein R 1 is D.
  • An aspect of the present invention is a compound of formula , wherein R 1 is H.
  • An aspect of the present invention is a compound of formula , wherein R 1 is -0-C(0)-CH 2 CH 3 .
  • An aspect of the present invention is a compound of formula , wherein R 2 is H.
  • An aspect of the present invention is a compound of formula , wherein R 2 is D.
  • An aspect of the present invention is a compound of formula , wherein R 3 is H.
  • An aspect of the present invention is a compound of formula , wherein R 3 is D.
  • An aspect of the present invention is a compound of formula , wherein R 4 is H.
  • An aspect of the present invention is a compound of formula , wherein R 4 is D.
  • An aspect of the present invention is a compound of formula , wherein R 5 is H.
  • An aspect of the present invention is a compound of formula , wherein R 5 is D.
  • An aspect of the present invention is a compound of formula , wherein R 6 is H.
  • An aspect of the present invention is a compound of formula , wherein R 6 is D.
  • An aspect of the present invention is a compound of formula , wherein R 7 is H.
  • An aspect of the present invention is a compound of formula , wherein R 7 is D.
  • An aspect of the present invention is a compound of formula (I), wherein R is OH and R 2 is D.
  • An aspect of the present invention is a compound of formula (I), wherein R 1 is D and
  • R 2 is H.
  • An aspect of the present invention is a compound of formula (I), wherein R 1 is H and
  • R 2 is D.
  • An aspect of the present invention is a compound of formula (I), wherein R 1 is OH and R 2 is H.
  • An aspect of the present invention is a compound of formula (I), wherein
  • R 1 is -0-C(0)-CH 2 CH 3 and R 2 is D.
  • An aspect of the present invention is a compound of formula (I), wherein R 1 and R 2 are both D.
  • An aspect of the present invention is a compound of formula (I), wherein R 3 and R are both H.
  • An aspect of the present invention is a compound of formula (I), wherein R 3 and R 4 are both D.
  • An aspect of the present invention is a compound of formula (I), wherein R 5 , R 6 and R 7 are all H.
  • An aspect of the present invention is a compound of formula (I), wherein R 5 , R 6 and R 7 are all D
  • An aspect of the present invention is a compound of formula (I), selected from any one of:
  • Deuterium also named heavy hydrogen, is an isotope of hydrogen with atomic weight of approximately 2. Its nucleus consists of one proton and one neutron, and has the double mass of the nucleus of ordinary hydrogen. Deuterium is commonly denoted 2 H or D.
  • Picropodophyllin which also has the generic name picropodophyllotoxin, is a compound having the chemical name (5R,5aS,8af?,9f?)-5,8,8a,9-Tetrahydro-9-hydroxy-5-(3,4,5- trimethoxyphenyl)-furo[3',4':6,7]naphtho[2,3-d]-1 ,3-dioxol-6(5aH)-one
  • Deoxypicropodophyllin is a compound having the chemical name (5R)-5,8,8a,9- Tetrahydro-5-(3,4,5-trimethoxyphenyl)furo[3 , ,4':6,7]naphtho[2,3-d]-1 ,3-dioxol-6(5aH)-one, [5R-(5.alpha. ,5a. beta. ,8a. alpha.)] and the chemical structure of formula (B)
  • C ⁇ -C 6 alkyl is herein defined as a straight or branched alkyl group having from 1 to 6 carbon atoms, such as 1 , 2, 3, 4, 5 or 6 carbon atoms in said alkyl chain, e.g.
  • alkyl includes both straight and branched chain alkyl groups. Examples of such alkyl groups are without being limiting methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, i-pentyl, neo-pentyl, n-hexyl, or i-hexyl.
  • cancer indications where a compound of formula (I) as herein described may be useful, are lung cancer such as non-small cell lung cancer (NSCLC) or small cell lung cancer; breast cancer; head and neck cancer such as oral, sinusoidal or pharyngeal cancer; gastrointestinal cancer such as oesophageal cancer, stomach cancer, colon cancer, rectal cancer, gastrointestinal stromal tumor, liver cancer or pancreatic cancer; genitourinary cancer such as prostate cancer, bladder cancer or kidney cancer;
  • NSCLC non-small cell lung cancer
  • breast cancer breast cancer
  • head and neck cancer such as oral, sinusoidal or pharyngeal cancer
  • gastrointestinal cancer such as oesophageal cancer, stomach cancer, colon cancer, rectal cancer, gastrointestinal stromal tumor, liver cancer or pancreatic cancer
  • genitourinary cancer such as prostate cancer, bladder cancer or kidney cancer
  • gynecologic cancer such as ovarian cancer, cervical cancer, endometric cancer or uterine sarcoma; hematologic cancer such as myeloid leukemia, lymphocytic leukemia, lymphomas or multiple myeloma; musculoskeletal cancer such as Ewings sarcoma, osteosarcoma or soft tissue sarcoma; skin cancer such as malignant melanoma, basal cell cancer, squamous cell cancer or Kaposi's sarcoma; brain and neurologic cancer such as gliomas, glioblastoma, astrocytoma, medulloblastoma, craniopharyngeoma or neuroblastoma; endocrine cancer such as adrenocortical cancer, paraganglioma, pheochromocytoma or thyroid cancer; or eye cancer such as retinoblastoma or uveal melanoma.
  • hematologic cancer such
  • non-small cell lung cancer examples include adenocarcinoma, squameous carcinoma or large-cell carcinoma.
  • Yet an aspect of the invention is the use of a compound of formula (I) as herein defined, for the manufacture of a medicament for the treatment of psoriasis; restenosis after coronary angioplasty; diabetes mellitus type 2; nephropathy; eye diseases such as retinopathy or macular degeneration; rheumatoid arthritis; inflammatory bowel disease such as Crohns disease or ulcerative colitis; multiple sclerosis; Alzheimers disease; or graft rejection.
  • Still an aspect of the invention is a compound of formula (I) for use in the treatment of IGF-1 R dependent diseases such as cancer.
  • Yet an aspect of the invention is a compound of formula (I) for use in the treatment of psoriasis; restenosis after coronary angioplasty; diabetes mellitus type 2; nephropathy; eye diseases such as retinopathy or macular degeneration; rheumatoid arthritis;
  • inflammatory bowel disease such as Crohns disease or ulcerative colitis
  • multiple sclerosis Alzheimers disease
  • Alzheimers disease or graft rejection.
  • One aspect of the invention is a method for the treatment of IGF-1 R dependent diseases such as cancer and more particularly for the treatment of lung cancer such as non-small cell lung cancer (NSCLC) or small cell lung cancer; breast cancer; head and neck cancer such as oral, sinusoidal or pharyngeal cancer; gastrointestinal cancer such as oesophageal cancer, stomach cancer, colon cancer, rectal cancer, gastrointestinal stromal tumor, liver cancer or pancreatic cancer; genitourinary cancer such as prostate cancer, bladder cancer or kidney cancer; gynecologic cancer such as ovarian cancer, cervical cancer, endometric cancer or uterine sarcoma; hematologic cancer such as myeloid leukemia, lymphocytic leukemia, lymphomas or multiple myeloma;
  • NSCLC non-small cell lung cancer
  • breast cancer breast cancer
  • head and neck cancer such as oral, sinusoidal or pharyngeal cancer
  • gastrointestinal cancer such as oesophageal cancer, stomach cancer, colon cancer
  • musculoskeletal cancer such as Ewings sarcoma, osteosarcoma or soft tissue sarcoma
  • skin cancer such as malignant melanoma, basal cell cancer, squamous cell cancer or Kaposi's sarcoma
  • brain and neurologic cancer such as gliomas, glioblastoma, astrocytoma, medulloblastoma, craniopharyngeoma or neuroblastoma
  • endocrine cancer such as adrenocortical cancer, paraganglioma, pheochromocytoma or thyroid cancer
  • eye cancer such as retinoblastoma or uveal melanoma
  • Yet an aspect of the invention is a method for the treatment of psoriasis; restenosis after coronary angioplasty; diabetes mellitus type 2; nephropathy; eye diseases such as retinopathy or macular degeneration; rheumatoid arthritis; inflammatory bowel disease such as Crohns disease or ulcerative colitis; multiple sclerosis; Alzheimers disease; or graft rejection; whereby a therapeutically effective amount of a compound of formula (I) as herein described, is administered to a patient in need of such treatment.
  • a pharmaceutical composition comprising a compound of formula (I) as herein described, in admixture with a pharmaceutically acceptable adjuvant, diluent and/or carrier.
  • a pharmaceutical combination such as a kit of parts combination, comprising:
  • kit of parts combination as herein described, for use in therapy there is provided a kit of parts combination as herein described, for use in therapy.
  • an aspect of the invention is a pharmaceutical combination, such as kit of parts as combination as herein described, for the treatment of cancer such as lung cancer such as non-small cell lung cancer (NSCLC) or small cell lung cancer; breast cancer; head and neck cancer such as oral, sinusoidal or pharyngeal cancer; gastrointestinal cancer such as oesophageal cancer, stomach cancer, colon cancer, rectal cancer, gastrointestinal stromal tumor, liver cancer or pancreatic cancer; genitourinary cancer such as prostate cancer, bladder cancer or kidney cancer; gynecologic cancer such as ovarian cancer, cervical cancer, endometric cancer or uterine sarcoma; hematologic cancer such as myeloid leukemia, lymphocytic leukemia, lymphomas or multiple myeloma;
  • NSCLC non-small cell lung cancer
  • breast cancer breast cancer
  • head and neck cancer such as oral, sinusoidal or pharyngeal cancer
  • gastrointestinal cancer such as oesophageal cancer, stomach cancer, colon
  • musculoskeletal cancer such as Ewings sarcoma, osteosarcoma or soft tissue sarcoma
  • skin cancer such as malignant melanoma, basal cell cancer, squamous cell cancer or Kaposi's sarcoma
  • brain and neurologic cancer such as gliomas, glioblastoma, astrocytoma, medulloblastoma, craniopharyngeoma or neuroblastoma
  • endocrine cancer such as adrenocortical cancer, paraganglioma, pheochromocytoma or thyroid cancer
  • eye cancer such as retinoblastoma or uveal melanoma.
  • a compound of formula (I) as herein described may be administered via the oral, parenteral, intravenous, intramuscular, subcutaneous or by injectable administration routes, buccal, rectal, vaginal, transdermal, nasal or ophtalmic route, or via inhalation in the form of pharmaceutical compositions comprising a pharmaceutically acceptable dosage form.
  • the compositions may be administered at varying doses.
  • An aspect of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I as herein described, in admixture with a pharmaceutically and pharmacologically acceptable adjuvant and/or carrier.
  • the pharmaceutically and pharmacologically acceptable carrier suitable for a particular pharmaceutical composition will be apparent to a person skilled in the art of pharmaceutical compositions.
  • the pharmaceutical composition may be administered to a subject or patient by an administration route suitable for the type of cancer or medical indication to be treated.
  • a compound of formula I as herein described may be administered as an injectable dosage form, or by continous infusion of a solution, a suspension or an emulsion.
  • a compound of formula I as herein described may be any compound of formula I as herein described.
  • a compound of formula I as herein described may be 30 administered in the form of an unguent, cream, ointment, lotion, solution or a patch.
  • a compound of formula (I) as herein described may also be administered in the form of a depot injection or implant preparation, which may be formulated in such a manner as to permit a sustained release of the active ingredient.
  • Still an aspect of the invention is a combination of at least one anti-cancer drug and a compound of formula (I) as herein described.
  • anti-cancer drugs useful in combination with a compound of formula (I) as herein described, are cytostatics; targeted anticancer agents being monoclonal antibodies or selective small-molecule inhibitors; hormones; antihormones; or immunostimulating agents.
  • cytostatics useful in combination therapy with a compound of formula (I) as herein described are alkylating agents such as melphalan; antimetabolites such as methotrexate or gemcitabine; mitotic inhibitors such as taxanes or vinca alkaloids;
  • cytotoxic antibiotics such as doxorubicin; topoisomerase II inhibitors such as etoposide; or other cytostatics such as cisplatin or carboplatin.
  • Examples of monoclonal antibodies useful in combination therapy with a compound of formula (I), as herein described, are those targeting the epidermal growth factor receptor (EGFR), HER2, and vascular endothelial growth factor such as trastozumab or bevacizumab.
  • EGFR epidermal growth factor receptor
  • HER2 vascular endothelial growth factor
  • trastozumab trastozumab or bevacizumab.
  • Examples of selective small-molecule inhibitors useful in combination therapy with a compound of formula (I), as herein described, are those targeting epidermal growth factor receptor, histone deacetylase (HDAC), Raf, platelet-derived growth factor receptors, vascular endothelial growth factor receptor, or c-Kit, such as gefitinib and imatinib.
  • HDAC histone deacetylase
  • Raf platelet-derived growth factor receptors
  • vascular endothelial growth factor receptor vascular endothelial growth factor receptor
  • c-Kit such as gefitinib and imatinib.
  • hormones useful in combination therapy with a compound of formula (I), as herein described are estrogens or gestagens.
  • antihormones useful in combination therapy with a compound of formula (I), as herein described are antiestrogens, antiandrogens or enzyme inhibitors.
  • immunostimulating agents useful in combination therapy with a compound of formula (I) as herein described are interferons.
  • An aspect of the present invention provides a process for the preparation of a compound of formula (I).
  • Compounds of the present invention may be prepared by the methods described in e.g. Synthesis and Applications of Isotopically Labelled Compounds, Volume 7, Ulrich Pleiss (Editor), R. Voges (Editor), Wiley 2001.
  • room temperature and “ambient temperature” shall mean, unless otherwise specified, a temperature of from 16 to 25 °C.
  • Picropodophyllin (PPP) (381 mg, 0.92 mmol) was suspended in dichloromethane (25 mL) and pyridiniumchlorochromate (PCC) was added. The suspension was stirred for 1.5 hours. Then diethyl ether (100 mL) was added and the solution was decanted and the residue washed with diethyl ether (2x 50 mL). The ether solutions were combined filtered through silica gel with Celite plug on top. The silica/celite was washed with 50% ethyl acetate in n-hexane (100 mL).
  • the solid material was suspended in water: acetone: barium carbonate (1mL: 1ml_: 67 mg) and refluxed for an hour.
  • the precipitate was filtered off and the pH of the filtrate was adjusted to 2-3 by 1 M hydrochloric acid and extracted five times with ethyl acetate.
  • the combined organic layers were washed with brine until the pH was 6 again, dried over Na 2 S0 4 and evaporated to afford 16 mg of the crude product.
  • the crude product was used as such.
  • PPP-d ⁇ prepared according to Example 2 (33.6 mg, 0.08 mmol) was dissolved in methanol and palladium (10%) on activated charcoal (42.3 mg, 0.02 mmol) was added. After 1 hour of stirring, more Pd/C (0.6 equiv.) was added and the reaction stirred for additional 3 hours. The reaction mixture was filtered through celite, and washed with methanol and acetonitrile.
  • the human lung carcinoma cell line H-1299 (CRL-5803) was purchased from ATCC.
  • the human lung cancer cell line A-549 and the human breast carcinoma cell line MCF-7 were kind gifts from Dr. Klas Wiman, and the human prostate carcinoma cell line PC-3 was a kind gift from Dr. Sten Nilsson, both working at CCK, Karolinska Hospital, Sweden.
  • Cell culture conditions
  • Human lung cancer cells H-1299 and human prostate carcinoma cells (PC-3) were cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum and with 2 mM glutamine, 50 lU/mL benzyl-penicillin and 50 microgram/mL streptomycin.
  • Human lung cancer cells A-549) and human breast carcinoma cells (MCF-7) were cultured in Dulbecco ' s Modified Eagle's Medium (DMEM) supplemented with 10% fetal bovine serum and with 2 mM glutamine, 50 lU/mL benzyl-penicillin and 50 microgram/mL streptomycin.
  • DMEM Dulbecco ' s Modified Eagle's Medium
  • the cells were grown in 75 cm 2 tissue culture flasks maintained at 95 % air/5% C0 2 atmosphere at 37 °C in a humidified incubator. For the experiments 15,000 cells were seeded into each well of a 24-well tissue culture plate. The cells were allowed to attach/equilibrate for 24 h before addition of compounds dissolved in DMSO at a stock concentration of 10 mM. The concentration of DMSO in control and experiment wells was always 0.1 %, a concentration known not to affect growth or viability of the cells. The experiments were initiated under subconfluent growth conditions. After incubation for 48 hours the cell viability was determined by resazurin assay.
  • resazurin (Sigma, St Louis, MO). This assay included addition of 100 microL resazurin (dissolved in PBS at 440 microM) to wells containing cells in 1 mL medium followed by 1 h incubation at 37 °C in a humidified incubator. Analysis of fluorescence was performed by using a Wallac Victor Multilabel Counter (Wallac, Turku, Finland), in which the resazurin was excited at 550 nm and the emitted light was measured at 590 nm. The fluorescence of the experiment wells were subtracted from the fluorescence of blank wells (containing cell culture medium only) resulting in Afluorescence.
  • Resazurin is the active compound of the commercially available growth indicator dye Alamar Blue. In response to metabolically active cells, resazurin becomes increasingly fluorescent, and there is a linear correlation between the number of viable cells and the emitted light.
  • PPP picropodophyllin
  • Example 7 68 +/-6 60 +/-3 55 +/-4 53 +1-3
  • Example 8 56 +1-2 45 +1-2 43 +1-2 32 +/-1 The results show that compounds of the invention are general potent inhibitors of cancer cell viability.
  • PPP picropodophyllin

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention se rapporte à de nouveaux composés de formule (I) dans laquelle R1 est OH, H, D ou-o-C (0)-C1C6 alkyle ; R2 est H ou D ; R3 et R4 est chacun et indépendamment l'un de l'autre H ou D ; et R5, R6 et R7 est chacun et indépendamment l'un de l'autre H ou D ; à l'exception des composés (5R,5aS,8aR,9R) -5,8,8 a, 9-Tétrahydro -9-hydroxy -5- (3,4,5-triméthoxyphényl)-furo [3', 4': 6,7] naphto [2,3-d] -1,3-dioxol -6 (5 aH) un (la picropodophylline) et (5R) -5,8,8 a, 9-Tétrahydro -5 (3,4,5-triméthoxyphényl) furo [3', 4': 6,7] naphto 2,3-d] -1,3-dioxol -6 (5aH)-one, [5R- (5, alpha. 5a. bêta., 8A. alpha.)] (la désoxypicropodophylline) à une composition pharmaceutique comprenant lesdits composés et à l'utilisation de ces composés en thérapie.
PCT/GB2013/050576 2012-03-09 2013-03-08 Dérivés de picropodophylline pour utilisation en thérapie WO2013132263A1 (fr)

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Cited By (2)

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Publication number Priority date Publication date Assignee Title
WO2014183055A1 (fr) 2013-05-10 2014-11-13 M. Alphabet 2, L.L.C. Méthodes permettant de traiter des affections cutanées au moyen de composés de cyclolignans
WO2021164749A1 (fr) * 2020-02-20 2021-08-26 南京药石科技股份有限公司 Inhibiteur de la tyrosine kinase du récepteur du facteur 1 de croissance de type insuline et ses utilisations

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WO2014183055A1 (fr) 2013-05-10 2014-11-13 M. Alphabet 2, L.L.C. Méthodes permettant de traiter des affections cutanées au moyen de composés de cyclolignans
US9907783B2 (en) 2013-05-10 2018-03-06 m.Alphabet 2, LLC Methods of treating skin conditions using cyclolignan compounds
WO2021164749A1 (fr) * 2020-02-20 2021-08-26 南京药石科技股份有限公司 Inhibiteur de la tyrosine kinase du récepteur du facteur 1 de croissance de type insuline et ses utilisations

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