WO2014106826A2 - Analogue d'anthracycline et utilisations associées - Google Patents

Analogue d'anthracycline et utilisations associées Download PDF

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Publication number
WO2014106826A2
WO2014106826A2 PCT/IB2014/058075 IB2014058075W WO2014106826A2 WO 2014106826 A2 WO2014106826 A2 WO 2014106826A2 IB 2014058075 W IB2014058075 W IB 2014058075W WO 2014106826 A2 WO2014106826 A2 WO 2014106826A2
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Prior art keywords
cancer
compound
formula
leukemia
pharmaceutically acceptable
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PCT/IB2014/058075
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English (en)
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WO2014106826A3 (fr
Inventor
Rajashri Ramakant PARAB
Rajan Mukund Panshikar
Prashant Venkatesh Shanbhag
Girish Badrinath Mahajan
Prabhu Dutt Mishra
Prafull Vasant Ranadive
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Piramal Enterprises Limited
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Publication of WO2014106826A2 publication Critical patent/WO2014106826A2/fr
Publication of WO2014106826A3 publication Critical patent/WO2014106826A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10—Oxygen atoms

Definitions

  • the present invention relates to a compound of Formula 1 (as described herein), or a pharmaceutically acceptable salt or a derivative thereof.
  • the present invention further relates to a process for the production of the compound of Formula 1 from an isolated microorganism belonging to Streptomycetes strain (PM1029477/MTCC 5709).
  • the present invention also relates to pharmaceutical compositions containing the compound of Formula 1, as an active ingredient and use of the compound of Formula I and the composition containing the compound for the treatment of cancer.
  • Cancer is a generic term for a large group of diseases caused by uncontrolled growth and spread of cells that can affect any part of the body.
  • numerous treatment options are available for cancer, including chemotherapy, surgery and radiation for localised disease or a combination of said treatments.
  • the choice of therapy depends upon the location of cancer and also the extent to which the cancer has spread at the time of diagnosis.
  • Chemotherapy is one of the most common forms of treatment for cancer, which involves use of anticancer drugs that can destroy cancer cells.
  • this disease still remains one of the leading causes of death in the world, most probably for the reason that the available treatment options are associated with undesirable side effects and limited efficacy.
  • novel anticancer agents/drugs having clinical benefits for treating cancer are needed.
  • target-based drugs These are the agents that are pre-designed to inhibit and/or modify a selected molecular marker deemed important in cancer prognosis, growth, and/or metastasis.
  • the examples of such drugs include imatinib mesylate (Gleevec, Novartis), gefitinib (Iressa, AstraZeneca & Teva) and bortezomib (Velcade, Millenium Pharmaceuticals).
  • anticancer agents obtained from natural resources.
  • the examples of such agents include paclitaxel, vincristine, torreyanic acid and camptothecin (Natural Product Communications, 2009, Vol. 4 (11), 1513).
  • the present invention relates to a compound of Formula 1 (as described herein).
  • the compound of Formula 1 is an anthracycline analogue.
  • the present invention particularly relates to a purified compound of Formula 1, isolated from the fermented broth of the Streptomycetes strain (PM1029477/MTCC 5709) or one of its variants or mutants. Accordingly, the compound of the present invention is an isolated compound of Formula 1.
  • the invention also relates to all isomeric forms and tautomeric forms of the compound of Formula 1 or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, or a derivative thereof.
  • the present invention also relates to a process for the production of the compound of Formula 1 or its isomers or tautomers from the Streptomycetes strain (PM1029477).
  • the present invention also relates to process for the isolation of the Streptomycetes strain (PM 1029477) which on cultivation produces the compound of Formula 1 or its isomer or tautomer.
  • the present invention relates to a process for the production of the compound of Formula 1 or its isomers or tautomers from the variant of the Streptomycetes strain (PM 1029477).
  • the present invention relates to a method for the treatment of cancer comprising administering to a subject in need thereof, a therapeutically effective amount of the compound of Formula 1 or its isomer or tautomer or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate or a derivative thereof.
  • the present invention relates to a method for the treatment of cancer comprising administering to a subject in need thereof, a therapeutically effective amount of the compound of Formula 1 or its isomer or tautomer or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate or a derivative thereof, in combination with a known therapeutically active agent.
  • the compound of Formula 1 its isomer, tautomer, or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate or a derivative thereof, for use in the treatment of cancer.
  • the present invention also relates to use of the compound of Formula 1 or its isomer, a tautomer, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate or a derivative thereof, for the manufacture of a medicament for the treatment of cancer.
  • the present invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of Formula 1 or its isomer or tautomer or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate or a derivative thereof, as an active ingredient and at least one pharmaceutically acceptable excipient, a carrier or a vehicle.
  • the present invention relates to use of the pharmaceutical composition comprising the compound of Formula 1 or its isomer or tautomer or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or a derivative thereof for the treatment of cancer.
  • Figure 1 illustrates 1H NMR (CDC1 3 ; 300 MHz; Instrument: Bruker) spectrum of the compound of Formula 1.
  • Figure 2 illustrates 13 C NMR (CDC1 3 ; 75 MHz; Instrument: Bruker) spectrum of the compound of Formula 1.
  • salt(s) may indicate a single salt or more than one salt of the compound of Formula 1.
  • the term “isomer” is a general term used for all the isomers of the compound of Formula 1 or of the derivative thereof that differ only in the orientation of their atoms in space.
  • the term isomer includes mirror image isomers (enantiomers), mixtures of mirror image isomers (racemates, racemic mixtures) and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereoisomers).
  • the compound of the present invention may have asymmetric centers and occur as racemates, racemic mixtures, individual diastereoisomers, or enantiomers, or may exist as geometric isomers, with all stereochemically isomeric forms of said compound being included in the present invention.
  • stereochemically isomeric forms defines the possible different isomeric as well as conformational forms which the compounds of Formula 1 may possess.
  • tautomer refers to the coexistence of two (or more) compounds that differ from each other only in the position of one (or more) mobile atoms and in electron distribution, for example, keto-enol tautomers.
  • solvate or “pharmaceutically acceptable solvate” as used herein refers to a compound formed by the interaction of a solute (in this invention, a compound of Formula 1 or a salt thereof) and a solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute.
  • the solvent used is a pharmaceutically acceptable solvent.
  • suitable pharmaceutically acceptable solvents include, without limitation, water, ethanol and acetic acid or mixtures thereof.
  • the solvent used is water and the solvates obtained are referred to as hydrates.
  • suitable solvates are the mono- or di-hydrates or alcoholates of the compounds of the present invention.
  • mutant refers to an organism or cell carrying a mutation, which is an alternative phenotype to the wild-type.
  • mutant refers to an organism or a cell in which one or more genes in the genome(s) has/have been modified, with the gene, or the genes, which is/are responsible for the ability of the organism to produce the compound according to the invention.
  • Such mutants can be produced, in a manner known per se, using physical means, for example irradiation, as with ultraviolet rays or X-rays, or chemical mutagens.
  • variant refers to an individual organism that is recognizably different from an arbitrary standard type in that species.
  • naturally variant refers to well isolated clone derived from the parent strain.
  • parent strain refers to the culture no. PM 1029477.
  • subject refers to an animal, preferably a mammal, and most preferably a human.
  • mammal refers to refers to warm-blooded vertebrate animals of the class 'mammalia', including humans, characterized by a covering of hair on the skin and, in the female, milk-producing mammary glands for nourishing the young. 1, and the term mammals include, but is not limited to, cows, horses, pigs, dogs, cats and humans. In the context of the present invention, the term “mammal” may be used interchangeably with the term "patient” or "subject”.
  • treat or “treatment” or “treating” as used herein includes prophylaxis, amelioration [i.e., reduction in the severity of the disease or accompanying symptoms], regression or curing of a disease or a disorder as described herein.
  • cancer refers to the physiological condition in a mammal that is characterized by unregulated cell growth or proliferation.
  • cancer includes but is not limited to: leukemia, lung cancer, brain tumor, non-Hodgkin's lymphoma, hodgkin's disease, liver cancer, kidney cancer, renal cancer, bladder cancer, cancer of urinary tract, stomach cancer, gastrointestinal (gastric, colorectal, and duodenal), breast cancer (e.g., triple negative breast cancer), head and neck cancer, endometrial cancer, lymphoma, melanoma, cervical cancer, thyroid cancer, bladder cancer, gastric cancer, germ cell tumor, cholangiocarcinoma, extracranial cancer, sarcoma, mesothelioma, malignant fibrous histiocytoma of bone, retinoblastoma, esophageal cancer, chronic or acute leukemia, multiple myelo
  • whole broth can be used interchangeably with the terms "nutrient broth”, “culture broth” or “fermented broth”.
  • active ingredient or “active compound” can be used interchangeably and as used herein, refers to the compound of Formula 1 or to an isomer or a tautomer or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate or a derivative thereof.
  • compound of Formula 1 includes the compound of Formula 1 itself and an isomer, a tautomer, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof.
  • compound of the present invention active ingredient or active compound
  • active compound can be used interchangeably with the term “compound of Formula 1".
  • substantially pure means that the compound of Formula 1 or an isomer thereof is sufficiently pure such that further purification would not detectably alter its physical and chemical properties, such as enzymatic and biological activities.
  • the compound of Formula 1 can be purified substantially by following the methods known to those skilled in the art.
  • the term "therapeutically effective amount" in reference to the treatment of cancer (as listed herein) using the compound of Formula 1, a pharmaceutically acceptable salt or a derivative thereof, refers to an amount capable of invoking one or more of the following effects in a subject receiving the compound of the present invention: (i) inhibition, to some extent, of tumor growth, including, slowing down and complete growth arrest; (ii) reduction in the number of tumor cells; (iii) reduction in tumor size; (iv) inhibition (i.e., reduction, slowing down or complete stopping) of tumor cell infiltration into peripheral organs; (v) inhibition (i.e., reduction, slowing down or complete stopping) of metastasis; (vi) enhancement of anti-tumor immune response, which can, but does not have to, result in the regression of the tumor; and/or (vii) relief, to some extent, of one or more symptoms associated with the cancer being treated.
  • pharmaceutically acceptable salt(s) means those salts of compound(s) of the invention i.e. the compound of formula 1, which retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects; and are prepared by treating the compound with suitable acids or bases, depending on the functional groups in the compound of Formula 1 available for forming salts.
  • Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, phosphate, acetate, lactate, salicylate, citrate, tartrate, ascorbate, succinate, maleate, fumarate, formate, benzoate, glutamate, methanesulfonate, benzensulfonate, or p- toluenesulfonate salts.
  • Suitable base addition salts include, but are not limited to, calcium, lithium, magnesium, potassium, sodium, or zinc salts.
  • Suitable pharmaceutically acceptable organic base addition salts of the compound of the present invention include those derived from organic bases such as lysine, arginine, guanidine, diethanolamine, choline, tromethamine and the like
  • the present invention relates to a compound of Formula 1 (as described herein), or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate or a derivative thereof.
  • the compound of Formula 1 has molecular formula C 4 oHsoOi 7 and molecular weight 802.3.
  • the compound of Formula 1 is structurally represented as follows:
  • the compound of Formula 1, obtained from purified Streptomycetes strain (PM1029477/MTCC 5709) is hereinafter referred to as culture no. PM 1029477, which was isolated from the soil sample, collected from Pochampally, in Nalgonda district of Andhra Pradesh, India.
  • the compound of Formula 1 is an anthracycline analogue.
  • the compound of Formula 1 can be characterized by any one or more physico-chemical and spectral properties, such as high performance liquid chromatography (HPLC), ultraviolet spectroscopy (UV), infra red spectroscopy (IR), high resolution mass spectrum (HR MS) and nuclear magnetic resonance (NMR) spectroscopic data.
  • HPLC high performance liquid chromatography
  • UV ultraviolet spectroscopy
  • IR infra red spectroscopy
  • HR MS high resolution mass spectrum
  • NMR nuclear magnetic resonance
  • An aspect of the present invention provides a process for the production of the compound of Formula 1 from the culture no. PM1029477, comprising the steps of:
  • the step (c) involving purification of the compound of Formula 1 is carried out by the purification procedures generally used in the related art. Typically, the compound of Formula 1 is purified by column chromatography.
  • the compound of Formula 1 produced according to the process of the present invention is a substantially pure compound.
  • the compound of Formula 1 is an isolated pure compound.
  • MTCC World Intellectual Property Organization
  • IDA International Depository Authority
  • mutants of culture no. PM1029477 such as those produced by the use of chemical or physical mutagens including X-rays, U.V. rays etc. and organisms whose genetic makeup has been modified by molecular biology techniques, may also be cultivated to produce the compound of Formula 1.
  • the compound of Formula 1 is produced using the variant of culture no. PM1029477.
  • the variant of culture no. PM1029477, from which the compound of Formula I is produced, is a naturally occurring variant isolated from the culture slant PM1029477 as described herein.
  • the present invention relates to a process for the production of the compound of Formula 1 as claimed in claim 1, comprising the steps of:
  • step c The process as described above further comprising the step of converting the compound of Formula 1 obtained in step c), to its pharmaceutically acceptable salt.
  • the screening of suitable mutants and variants including naturally occurring variants for producing the compound of the present invention is carried out and production of the compound can be confirmed by HPLC, NMR, IR, MS and/or determination of biological activity of the active compounds accumulated in the culture broth, for example by testing the compounds for anticancer activity.
  • the medium and/or nutrient medium used for isolation and cultivation of culture no. PM 1029477, which produces the compound of Formula 1, preferably contains sources of carbon, nitrogen and nutrient inorganic salts.
  • the carbon sources are, for example, one or more of soluble starch, glucose, sucrose, dextrin, fructose, molasses, glycerol, lactose, or galactose.
  • soluble starch, glycerol and glucose can be used as the carbon sources in the process involving isolation and cultivation of culture no. PM 1029477.
  • the sources of nitrogen are, for example, one or more of soyabean meal, peanut meal, soya flour, active dry yeast, yeast extract, beef extract, peptone, malt extract, corn steep liquor, gelatin, casein, sodium caseinate, L-Asparagine or casamino acids.
  • peptone, corn steep liquor, malt extract and yeast extract can be used as nitrogen sources in the process involving isolation and cultivation of culture no. PM 1029477.
  • the nutrient inorganic salts are, for example, one or more of sodium chloride, potassium chloride, calcium chloride, manganese chloride, magnesium chloride, strontium chloride, cobalt chloride, potassium bromide, sodium fluoride, sodium hydrogen phosphate, potassium hydrogen phosphate, dipotassium hydrogen phosphate, disodium phosphate, calcium carbonate, sodium bicarbonate, sodium silicate, sodium nitrate, ammonium nitrate, potassium nitrate, sodium sulphate, ammonium sulphate, ammonium heptamolybdate, ferric citrate, copper sulphate, magnesium sulphate, ferrous sulphate, zinc sulphate or boric acid.
  • sodium chloride, dipotassium hydrogen phosphate, potassium nitrate and calcium carbonate can be used as nutrient inorganic salts in the process involving isolation and cultivation of culture no. PM1029477.
  • culture no. PM1029477 can be carried out at a temperature ranging from 24°C to 32°C. Typically, culture no. PM 1029477 is maintained at 27°C to 29°C.
  • the well- grown cultures can be preserved on ISP2 (as described in experimental) slants in the refrigerator at 4°C to 8°C.
  • Seed culture cultivation of culture no. PM1029477 can be carried out at a temperature ranging from 27°C to 33°C and a pH of about 6.5 to 7.5, for 68 to 76 hours at 220 to 260 rpm.
  • culture no. PM1029477 seed is cultivated at 29°C to 31°C and a pH of about 6.8 to 7.2, for 71 to 73 hours at 230 to 250 rpm.
  • the production of the compound of Formula 1 can be carried out by cultivating culture no. PM1029477 in shake flasks at a temperature ranging from 27°C to 33°C and a pH of about 6.5 to 7.5 for 2 to 8 days at 220 to 260 rpm.
  • culture no. PM1029477 is cultivated at 29°C to 31°C and pH 6.8 to 7.2, for 3 to 5 days at 230 to 250 rpm.
  • the production of the compound of Formula 1 can also be carried out by cultivating culture no. PM 1029477 in a fermenter.
  • the production of the compound of Formula 1 can be carried out by cultivating culture no. PM 1029477 in a suitable nutrient broth under conditions described herein, preferably under submerged aerobic conditions in shake flasks or fermenters.
  • the progress of fermentation and production of the compound of Formula 1 can be detected by high performance liquid chromatography (HPLC) and by measuring the bioactivity of the culture broth by testing against the cancer cell lines.
  • HPLC high performance liquid chromatography
  • fermentation is a process of growing microorganisms for the production of various useful chemical or pharmaceutical compounds.
  • Microbes are normally incubated under specific conditions in the presence of nutrients.
  • Whole broth is obtained after completing the process of fermentation.
  • the whole broth is subjected to centrifugation which results in the formation of cell mass and culture filtrate, which can be processed further by processes, described herein.
  • the compound of Formula 1 present in the culture broth can be isolated using different extraction methods and chromatographic techniques known in the art.
  • the compound of Formula 1 can be recovered from the culture filtrate by extraction with a water immiscible solvent such as petroleum ether, dichloromethane, chloroform, ethyl acetate, diethyl ether or butanol, or by hydrophobic interaction chromatography using polymeric resins such as "Diaion HP-20 ® “ (Mitsubishi Chemical Industries Limited, Japan), “Amberlite XAD ® “ (Rohm and Haas Industries, USA) or adsorption on activated charcoal. These techniques can be used repeatedly, alone or in combination.
  • a water immiscible solvent such as petroleum ether, dichloromethane, chloroform, ethyl acetate, diethyl ether or butanol
  • polymeric resins such as "Diaion HP-20 ® " (Mitsubishi Chemical Industries Limited, Japan), “Amberlite XAD ® “ (Rohm and Haas Industries, USA) or adsorption on activated charcoal.
  • the compound of Formula 1 can be recovered from the cell mass by extraction with a water miscible solvent such as methanol, acetone, acetonitrile, n-propanol, or iso-propanol or with a water immiscible solvent such as petroleum ether, dichloromethane, chloroform, ethyl acetate or butanol.
  • a water miscible solvent such as methanol, acetone, acetonitrile, n-propanol, or iso-propanol
  • a water immiscible solvent such as petroleum ether, dichloromethane, chloroform, ethyl acetate or butanol.
  • the whole broth can be extracted with a solvent selected from petroleum ether, dichloromethane, chloroform, ethyl acetate, methanol, acetone, acetonitrile, n-propanol, iso-propanol, or butanol.
  • a solvent selected from petroleum ether, dichloromethane, chloroform, ethyl acetate, methanol, acetone, acetonitrile, n-propanol, iso-propanol, or butanol.
  • the compound of Formula 1 is extracted from the whole broth using ethyl acetate. Concentration of the extract gives the active crude material containing the compound of Formula 1.
  • the compound of Formula 1 of the present invention can be recovered from the crude material by fractionation using any of the following techniques: normal phase chromatography (using alumina or silica gel as stationary phase; eluents such as petroleum ether, ethyl acetate, chloroform, dichloromethane, acetone, methanol, or combinations thereof; and if required, additions of amines such as triethylamine); reverse phase chromatography (using reverse phase silica gel such as dimethyloctadecylsilylsilica gel, (RP-18) or dimethyloctylsilyl silica gel (RP-8) as stationary phase; and eluents such as water, buffers (for example, phosphate, acetate, citrate (pH 2-8)), and organic solvents (for example, methanol, acetonitrile, acetone, tetrahydrofuran, or combinations of these solvents)); gel permeation chromatography (using resins such as Sep
  • the present invention also provides solvates of the compound of Formula 1 as described herein.
  • the compound of Formula 1, an isomer or a tautomer thereof can be converted into their pharmaceutically acceptable salts and/or derivatives, which are all contemplated by the present invention.
  • salts of the compounds of Formula 1 can be prepared by standard procedures known to one skilled in the art, for example, salts like sodium and potassium salts, can be prepared by treating the compound of Formula 1, or an isomer, a tautomer or a derivative thereof, with a suitable base, for example sodium hydroxide or potassium hydroxide.
  • salts like hydrochloride and sulphate salts can be prepared by treating the compound of Formula 1, or its isomer, a tautomer, or a derivative thereof, with a suitable acid, for example hydrochloric acid or sulphuric acid.
  • the derivatives of the compound of Formula 1 of particular interest according to the present invention are those wherein one or more of the hydroxyl groups of the compound of Formula 1 are derivatised.
  • Such derivatives can be prepared by the methods known in the literature.
  • the esters and ethers of the compound of Formula 1 can be prepared by the methods given in the literature (Advanced Organic Chemistry, 1992, 4 th Edition, J. March, John Wiley and Sons) or other methods known to one skilled in the art.
  • the compound of Formula 1 or a pharmaceutically acceptable salt or a derivative thereof has anticancer activity.
  • the anti-cancer activity exhibited by the compound of Formula I or a pharmaceutically acceptable slat thereof, is demonstrated by biological testing of the compound against a wide range of cancer cells.
  • the compound of Formula 1 or its isomer or its tautomer or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate or a derivative thereof can be administered to a subject in need thereof in the form of a pharmaceutical composition.
  • the compound of Formula 1 or its isomer, a tautomer, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate or a derivative thereof can be administered to a subject who is diagnosed having cancer.
  • the present invention also relates to use of the compound of Formula 1 or its isomer or its tautomer or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate or a derivative thereof, for the manufacture of a medicament for the treatment of cancer.
  • the present invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the compound of Formula 1 or its isomer or a tautomer or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate or a derivative thereof and a pharmaceutically acceptable excipient or a carrier.
  • the pharmaceutical composition is provided for use in the treatment of cancer.
  • the therapeutically effective amount of the compound of Formula 1, or its isomer, or its tautomer or a pharmaceutically acceptable salt or a derivative thereof, as the active ingredient in the pharmaceutical composition can range from about 0.01 mg to 1000 mg or from about 0.5 mg to 750 mg or from about 1 mg to 500 mg or the therapeutically effective amount can be lower than or higher than the lower and the upper limit respectively.
  • the present invention provides a method for the treatment of cancer in a subject by administering to a subject in need thereof, a therapeutically effective amount of a compound of Formula 1 or its isomer or its tautomer or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate or a derivative thereof.
  • the present invention provides a method for the treatment of cancer in a subject comprising administering to a subject in need thereof, a therapeutically effective amount of the compound of Formula 1 or its isomer or its tautomer or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate or a derivative thereof in combination with a known therapeutically active agent.
  • the cancer is selected from acute lymphocytic leukemia, acute myeloid leukemia, adult acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, lymphoma, lung cancer (non-small-cell and small-cell), liver cancer, kidney cancer, brain tumor, brain stem glioma, glioblastoma, astrocytoma including cerebellar astrocytoma and cerebral astrocytoma, visual pathway glioma, hypothalamic glioma, supratentorial primitive neuroectodermal, pineal tumors, medulloblastoma, primary central nervous system lymphoma, mantle cell lymphoma, non-Hodgkin's lymphoma, hodgkin's disease, hepatocellular carcinoma, renal cell carcinoma, Wil
  • the cancer is selected from acute lymphoblastic leukemia, acute myeloid leukemia, acute lymphocytic leukemia, adult acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, non-Hodgkin's lymphoma, hodgkin's disease, lymphoproliferative disease, refractory multiple myeloma, resistant multiple myeloma or myeloproliferative disorder.
  • the cancer is selected from lung cancer, liver cancer, kidney cancer, bladder cancer, cancer of urinary tract, breast cancer, head and neck cancer, endometrial cancer, melanoma, cervical cancer, thyroid cancer, gastric cancer, germ cell tumor, cholangiocarcinoma, extracranial cancer, sarcoma, brain tumor, mesothelioma, malignant fibrous histiocytoma of bone, retinoblastoma, esophageal cancer, stomach cancer, pancreatic cancer, ependymoma, neuroblastoma, skin cancer, ovarian cancer, recurrent ovarian cancer, prostate cancer, testicular cancer and colorectal cancer.
  • the cancer is selected from pancreatic cancer, colorectal cancer, renal cell carcinoma, lung carcinoma, non-small cell lung cancer, breast cancer, colon cancer and melanoma.
  • the cancer is pancreatic cancer.
  • the cancer is colorectal cancer.
  • the cancer is renal cell carcinoma. In an embodiment, the cancer is lung carcinoma.
  • the cancer is non-small cell lung cancer.
  • the cancer is breast cancer.
  • the cancer is colon cancer.
  • the cancer is melanoma.
  • the compound of the present invention is used in a method for reducing the population of Renal cell carcinoma (ACHN) cells, Pancreatic cancer (Panel), Lung carcinoma (Calul), Non-small cell lung cancer (H460) and Colorectal cancer (HCT116) cell lines in vitro.
  • ACTN Renal cell carcinoma
  • Pancreatic cancer Pancreatic cancer
  • Lung carcinoma Calul
  • Non-small cell lung cancer H460
  • Colorectal cancer HCT116
  • the compound of the present invention is used to reduce proliferation of the human cell lines that comprise: Human triple negative breast cancer cell lines (MCF7, T47D, MDA-MB-468, MDA-MB 231, MDA-MB 453, BT549), colon cancer cell lines (HT29, SW480) and melanoma (A375).
  • human triple negative breast cancer cell lines MCF7, T47D, MDA-MB-468, MDA-MB 231, MDA-MB 453, BT549
  • colon cancer cell lines HT29, SW480
  • melanoma A375
  • the compound of Formula 1 or a pharmaceutically acceptable salt or a derivative thereof can be administered orally, nasally, topically, subcutaneously, intramuscularly, intravenously, or by other modes of administration.
  • the method of administration which is suitable in a specific case depends on the type of cancer to be treated and on the stage of the cancer. Further, the method of administration can be optimized by a medical practitioner using methods known in the art.
  • the dosage range which are suitable in a specific case depend on the type of cancer to be treated and on the state of the respective condition or disease (e.g. cancer), and can be optimized using methods known in the art. It is known that the selected dosage level will depend upon a variety of factors including the route of administration, the time of administration, the rate of excretion of the compound being administered, the duration of the treatment, other concurrently administered drugs, compounds and/or materials, the age, sex, weight, condition, general health and prior medical history of the patient (subject) being treated, and like factors well known in the medical arts.
  • the daily dose of active compound (the compound of Formula 1) in a patient is 0.05 mg to 200 mg per kg, or 0.1 mg to 150 mg per kg or 1 mg to 100 mg or the daily dose can be lower than or higher than the lower and the upper limit respectively.
  • compositions containing compound of Formula 1 or its isomer or a tautomer, a pharmaceutically acceptable salt or a derivative thereof can be prepared by mixing the compound of Formula 1 with one or more pharmacologically tolerated auxiliaries and/or excipients such as, wetting agents, solubilisers such as surfactants, vehicles, tonicity agents, fillers, colorants, masking flavors, lubricants, disintegrants, diluents, binders, plasticizers, emulsifiers, ointment bases, emollients, thickening agents, polymers, lipids, oils, cosolvents, complexation agents, or buffer substances, and converting the mixture into a suitable pharmaceutical form such as, for example, tablets, coated tablets, capsules, granules, powders, creams, ointments, gels, syrup, emulsions, suspensions, or solutions suitable for parenteral administration.
  • auxiliaries and/or excipients such as, wetting agents
  • auxiliaries and/or excipients that can be mentioned for use in preparation of pharmaceutical composition are cremophor, poloxamer, benzalkonium chloride, sodium lauryl sulphate, dextrose, glycerin, magnesium stearate, polyethylene glycol, starch, dextrin, lactose, cellulose, carboxymethylcellulose sodium, talc, agar-agar, mineral oil, animal oil, vegetable oil, organic and mineral waxes, paraffin, gels, propylene glycol, benzyl alcohol, dimethylacetamide, ethanol, polyglycols, Tween 80, solutol HS 15, and water. It is also possible to administer the compound of Formula 1 as such, without vehicles or diluents, in a suitable form, for example, in capsules.
  • the compound of Formula 1 or its isomer or its tautomer, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate or a derivative thereof; or the pharmaceutical composition containing the compound of Formula I, or an isomer or a tautomer, a pharmaceutically acceptable salt can be used in combination with one or more anticancer agents such as asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin, epirubicin, etoposide, fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitox
  • anticancer agents such as
  • PBS Phosphate buffered saline
  • IC50 50 %
  • Inhibitory concentration g mL Microgram per millilitre
  • ⁇ Micron
  • Starch lOg casein 0.3g, potassium nitrate 2g, sodium chloride 2g, dipotassium hydrogen phosphate 2g, magnesium sulphate 0.05g, calcium carbonate 0.02g, ferrous sulphate O.Olg, agar
  • the soil sample was collected from open land in Pochampally, in Nalgonda district of Andhra Pradesh, India.
  • the soil (lg) was taken in a sterile test tube in a laminar air flow.
  • distilled water (lOmL) was added and vortexed for 1 minute.
  • the soil debris was allowed to settle and lmL of the supernatant was serially diluted twice in 9mL of distilled water to get 1: 1000 dilution.
  • ⁇ of the diluted sample was spread on starch casein agar plates containing 50 ⁇ g/mL of amphotericin B using sterile spreader. The plates were allowed to dry in the laminar air flow and incubated at 28°C for 6 to 10 days.
  • Colony of PM 1029477 was circular, convex colony with regular margin, pink-red substrate mycelia with greenish-gray sporulation. Colonies were picked up with sterile needle under stereomicro scope and were transferred to ISP2 medium for purification. The culture was maintained on ISP2 slants. The well-grown cultures were stored in the refrigerator at 4°C to 8°C.
  • Glycerol 3g glucose 3g, yeast extract 2g, sodium chloride 3g, sodium nitrate lg, calcium carbonate 3g, peptone 3g, Trace salt solution (TSS) lmL/lL, dimineralized water lOOmL, pH 7.
  • TSS solution Copper sulphate 0.7%, ferrous sulphate 0.1%, manganese chloride 0.8%, zinc sulphate 0.2%, demineralized water lOOmL].
  • a loopful of the culture from a well sporulated slant (age 14-18 days) was inoculated into the seed medium 274(1) and was incubated at 30°C for 72hrs on the shaker 240rpm to obtain the seed inoculum. 2.5% of the inoculum from the seed medium was then inoculated into the production medium 1M and incubated at 30°C for 72-120 hrs on the shaker at 240rpm.
  • the crude extract was subjected to flash chromatography (silica gel, 76g, chloroform: methanol, Flow: 15mL/min).
  • the compound of Formula 1 was eluted with 1.5-2% methanol in chloroform, which was concentrated to obtain fraction containing enriched compound.
  • UV Detection (UV) 492 nm.
  • Solvent system Gradient (2 % acetonitrile to 100 % acetonitrile in 30 mins against water, followed by 100% acetonitrile for additional 5 mins)
  • UV Detection (UV) 234 nm.
  • the spore suspension was prepared from culture slant PM1029477, by adding 0.01% tween80 followed by scrapping and filtration through sterile cotton filter.
  • the spore suspension was diluted till 10 - " 8 and different dilutions were plated on the ISP2 agar plate containing 2% soft crude agar. After incubation at 30°C for seven days, the isolated colonies (referred to herein as natural variants or naturally occurring variants) were picked up and transferred to slants.
  • Glucose 15g corn steep liquor 5g, peptone 7.5g, yeast extract 7.5g, calcium carbonate 2g, sodium chloride 5g, demineralized water 1.0L, pH 6.5-7.5 (before sterilization).
  • the seed medium of step a) was distributed in 200mL amounts in lOOOmL Erlenmeyer flasks and autoclaved at 121°C for 20mins.
  • the flasks were cooled to room temperature and each flask was inoculated with a loopful of the well-grown natural variant isolated as per example 4 and shaken on a rotary shaker for 70-72 hrs at 230-250 rpm at 29-30°C to give the seed culture.
  • the production medium (50L) was sterilized with 0.04% of desmophen in a fermenter (20L) for 30 mins at 121°C, cooled to 29-30°C and seeded with the seed culture (600ml) as mentioned in example 6.
  • the yield based on HPLC in the harvested broth was lmg/L
  • MCF10 normal cell line
  • a non-tumourigenic cell line was cultured in Mammary Epithelial Basal Medium (MEBM) with all standard additions (Lonza, Catalog. No. CC-3150). All the cells were grown at 37°C with 5 % C0 2 incubator. Cells were passaged at 80 - 90 % confluency. Adherent cells were trypsinised using Trypsin-EDTA (Sigma) and maintained.
  • MEBM Mammary Epithelial Basal Medium
  • Test compounds (Example 3 (Crude) and Example 3 (Semi pure fraction) as obtained in Example 3) were dissolved in DMSO to give a required stock solution of 20 mg/mL.
  • the dose response analysis for test compounds was carried out at 10 ⁇ g/mL, 1 ⁇ g/mL, O. ⁇ g/mL and 0.0 ⁇ g/mL concentrations. Each concentration was evaluated in triplicate.
  • the percent inhibition was calculated in comparison with control values.
  • Example 3 compositions Example 3 (Crude) and Example 3 (Semi pure fraction) are active in cancer cell lines.
  • a propidium iodide (Pl)-based fluorescence assay was used to characterize the in vitro activity of test compounds [compound of Formula 1 (obtained in Example 3), doxorubicin, epirubicin and idarubicin] in cell growth inhibition assay as per the NCGC guidelines:
  • a total number of 3000 cells contained in 199 ⁇ of the cell growth medium were plated overnight in a 96 well white tissue culture plate. To obtain three fold final dilutions of the test compound, ⁇ of the appropriately diluted test compound was added to cells in 199 ⁇ medium in a 96-well plate.
  • Control wells included cells incubated with 0.5% DMSO in medium and blank included 0.5% DMSO in medium. Cells were incubated for desired period in a C0 2 incubator at 37°C in a humidified atmosphere of 5% C0 2 .
  • the assay was terminated by washing wells with PBS two times and cells in each well were incubated with 200 ⁇ of propidium iodide solution, (PI, Sigma-Aldrich, USA, 7 ⁇ g/mL, prepared in PBS). The plates were stored for 18 hrs at -70°C. Next day, plates were thawed to rupture the cells and stain the nucleic acid with PI. Fluorescence was measured at the excitation wavelength of 544 nm and emission wavelength of 620nm in a microplate fluorescence reader (POLARstar, BMG LABTECH GmbH, Germany).
  • Percent growth inhibition was calculated relative to DMSO treated cells using the following formula:
  • the anticancer activity of compound of Formula 1 is comparable with the activity of compounds doxorubicin, epirubicin and idarubicin in breast cancer cell lines, (MCF7, T47D, MDA-MB 468, MDA-MB 231, MDA-MB 453, BT549), colon cancer cell lines (HT29, SW480) and melanoma cell line (A375).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un composé purifié de formule 1. L'invention concerne toutes les formes isomères et les formes tautomères du composé de formule 1 et leurs sels et dérivés pharmaceutiquement acceptables. La présente invention concerne en outre les procédés d'isolement et de production du composé de formule 1 par fermentation de la souche PM1029477/MTCC 5709 de Streptomycetes. L'invention concerne également les compositions pharmaceutiques contenant composé de formule 1 sous la forme d'un ingrédient actif et leur utilisation dans le traitement du cancer.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108210935A (zh) * 2016-12-09 2018-06-29 凯惠科技发展(上海)有限公司 抗体药物偶联物、制备方法、中间体、药物组合物及应用
CN114761389A (zh) * 2019-10-10 2022-07-15 塞勒科塔生物科学公司 磷脂-flavagline缀合物和将其用于靶向癌症治疗的方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0022574A1 (fr) * 1979-07-13 1981-01-21 Sanraku-Ocean Co., Ltd. Antibiotiques appartenant au groupe rhodomycine et procédé pour leur préparation

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0022574A1 (fr) * 1979-07-13 1981-01-21 Sanraku-Ocean Co., Ltd. Antibiotiques appartenant au groupe rhodomycine et procédé pour leur préparation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
YOSHIMOTO, A. ET AL.: 'Structure-sensitivity relationship of anthracycline antibiotics to C7-reduction by redox enzymes' JAPANESE JOURNAL OF ANTIBIOTICS vol. 44, no. 3, 1991, pages 287 - 295 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108210935A (zh) * 2016-12-09 2018-06-29 凯惠科技发展(上海)有限公司 抗体药物偶联物、制备方法、中间体、药物组合物及应用
CN108210935B (zh) * 2016-12-09 2023-08-18 凯惠科技发展(上海)有限公司 抗体药物偶联物、制备方法、中间体、药物组合物及应用
CN114761389A (zh) * 2019-10-10 2022-07-15 塞勒科塔生物科学公司 磷脂-flavagline缀合物和将其用于靶向癌症治疗的方法

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