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WO2006110119A1 - Produit antineoplasique (et variantes) - Google Patents

Produit antineoplasique (et variantes) Download PDF

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Publication number
WO2006110119A1
WO2006110119A1 PCT/UA2006/000020 UA2006000020W WO2006110119A1 WO 2006110119 A1 WO2006110119 A1 WO 2006110119A1 UA 2006000020 W UA2006000020 W UA 2006000020W WO 2006110119 A1 WO2006110119 A1 WO 2006110119A1
Authority
WO
WIPO (PCT)
Prior art keywords
gluconate
magnesium
acid
antineoplastic
calcium
Prior art date
Application number
PCT/UA2006/000020
Other languages
English (en)
Russian (ru)
Inventor
Victor Pavlovich Kutnyak
Vadym Alekseyevich Kozlovskiy
Yurii Iosifovich Kudryavets
Original Assignee
Victor Pavlovich Kutnyak
Vadym Alekseyevich Kozlovskiy
Yurii Iosifovich Kudryavets
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
Application filed by Victor Pavlovich Kutnyak, Vadym Alekseyevich Kozlovskiy, Yurii Iosifovich Kudryavets filed Critical Victor Pavlovich Kutnyak
Publication of WO2006110119A1 publication Critical patent/WO2006110119A1/fr

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19Carboxylic acids, e.g. valproic acid
    • A61K31/191Carboxylic acids, e.g. valproic acid having two or more hydroxy groups, e.g. gluconic acid
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19Carboxylic acids, e.g. valproic acid
    • A61K31/195Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents

Definitions

  • the invention relates to the composition of such antineoplastic preparations based on rluconic acid, which exhibit a proapoptotic and antiproliferative effect.
  • cytokines The main role in it is played by the immune system. After recognition of foreign (in particular, mutated) cells, its cells produce chemical agents called cytokines, which “shut down” the multi-stage apoptosis process.
  • antibiotics of the anthracycline group include (see CD Mosbu's, 2003) antibiotics of the anthracycline group: doxorubicin, otherwise referred to as adriamycin (A. SWadapowski & J. Kopora. Adriatus apditus pogroptochelpocillosophosompochem. 46, 375)), and similar to it bleomycin ⁇ dactinomycin, daunorubicin, idarubicin, etc.
  • doxorubicin and its analogues induce apoptosis by inhibiting topoisomerase (the enzyme responsible for malignant cells).
  • therapeutic agents of this kind can also induce apoptosis in healthy cells.
  • the cytotoxic effect of doxorubicin for the human body as a whole occurs with a cumulative dose of more than 20 mg / kg.
  • concomitant organic lesions develop (often with a fatal outcome).
  • the main ones are thrombocytopenia, neutropenia, anemia and cardiopathy, leading to the death of 5-20% of patients treated with doxorubicin (CD Mosbu's, 2003) and other well-known drugs of the same class (Ez-assess kur opsologogu. Corea UPHAR PHARM, 2004, p. 107).
  • apoptosis is caused by: betulinic acid (Betulipis acid ipodus aortosis ip humapulobell cellulitis: M.L.Schmidt, et al .; Eur. J.
  • cytosphatic antineoplastic drugs which slow down, and often completely suppress, the proliferation (growth) of cancerous tumors (or ⁇ z ⁇ z-assess kur opsologogu, p. Z).
  • platinum preparations cis-platinum, oxyplatinum, carboplatin
  • alkylating agents cyclophosphamide, busulfan, dacarbazine, thiotepa, etc.
  • antimetabolites cytarabine, fluorouracil, methotrexate, mercaptopurine, etc.
  • herbal preparations docetaxel, paclitaxel, vincristine, vinblastine, etc.
  • hormonal agents chlormadinone, diethylstilbestrol, flutamide, etc.
  • TNF tumor necrotic factor
  • the basis of the invention is the task of changing the composition to create a drug based on gluconic acid, which, when introduced into the human body, would exhibit a pronounced antineoplastic effect against the background of the preservation of healthy cells.
  • the antineoplastic preparation based on gluconic acid according to the invention is at least one such salt in which the salt-forming agent is selected from the group consisting of magnesium, sodium, potassium, ⁇ -aminobutyric acid (hereinafter GABA ), ethylenediamine or mixtures thereof.
  • GABA ⁇ -aminobutyric acid
  • the first and second additional differences, respectively, are that the antineoplastic preparation is magnesium gluconate, or potassium gluconate.
  • This drug is preferably used for oncological diseases of arbitrary etiology against a background of deficiency of potassium or magnesium ions in the body.
  • the antineoplastic preparation based on gluconic acid according to the invention is a coordination compound based on magnesium gluconate, in which the ligands are selected from the group consisting of GABA, 3-hydroxy-GAMK, ethylene diamine tetraacetic acid (hereinafter EDTA) ) and ethylene glycol tetraacetic acid (hereinafter referred to as EGTA).
  • GABA GABA
  • 3-hydroxy-GAMK ethylene diamine tetraacetic acid
  • EDTA ethylene diamine tetraacetic acid
  • EGTA ethylene glycol tetraacetic acid
  • antineoplastic preparation is the coordination compound diHAMK-Mg-gluconate. This prep It is preferred to use rats for oncological diseases of the respiratory organs, brain and intestines.
  • the antineoplastic preparation is a double salt selected from the group consisting of magnesium butyratogluconate, magnesium hydroxybutyrate gluconate, magnesium glucarate gluconate, calcium butyratogluconate, calcium hydroxybutyrate gluconate, calcium glucarate gluconate and their combination. These drugs are preferably used for neoplasty.
  • antineoplastic drug is magnesium glucaratogluconate, which is preferable for cancer of arbitrary etiology against the background of a deficiency of magnesium ions in the body.
  • Gluconic acid empirical formula C 6 H 12 O 7
  • magnesium gluconate empirical formula dihydrate C 12 H 22 MgO 11 ⁇ H 2 O
  • GABA empirical formula C 4 H 9 NO 2
  • 3-hydroxy-GAMK empirical formula C 4 H 9 NO 3
  • EDTA empirical formula C 10 H 2 o0 10 N 2
  • EGTA empirical formula Ci 4 H 24 N 2 Oi 0
  • glu- carboxylic acid empirical formula C 6 H 8 O 8
  • chemical reagents which for the implementation of the invention must have a quality of at least “xh” (chemically pure).
  • magnesium gluconate can be obtained by neutralizing gluconic acid (usually taken as an aqueous solution of the easily hydrolyzable d-gluconolactone) with an almost equimolar amount of magnesium oxide (or hydroxide).
  • Normal gluconic acid salts are prepared by a neutralization reaction, in particular by adding a calculated amount of a base (or amphoteric compound) to a (usually aqueous) acid solution.
  • the target products are isolated, as a rule, by evaporation of the solvent and drying the residue to constant weight (and, optionally, additional recrystallization).
  • Magnesium gluconate coordination compounds are prepared from magnesium gluconate and a source of selected ligand as follows. First in distilled When stirring and heating in a water bath, a certain amount (for example, 0.1 mole) of magnesium gluconate is slowly dissolved. The solution is cooled to. temperature 35-4O 0 C and gradually, with stirring, the calculated amount of the ligand is introduced in a molar ratio to magnesium r-jonate 2: 1. The finished product is isolated from the solution by spray drying.
  • DiHAMK-Mg-gluconate (empirical formula of dihydrate C 20 H 38 MgN 2 O 18 ⁇ H 2 O) is obtained by dissolving magnesium gluconate in water when heated in a water bath. After cooling the solution to 35-4O 0 C, the calculated amount of GABA in molar ratio to magnesium gluconate 2: 1 is added with stirring. The desired product is isolated by spray drying.
  • Coordination compounds of calcium gluconate are obtained from calcium gluconate and the corresponding ligand according to a scheme that is similar to the above.
  • Double magnesium salts are obtained in this way. Initially, an almost 50% aqueous solution of an equimolar (calculated as a cation) mixture of gluconic and one of the above (butyric, or hydroxybutyric, or glucaric) acids is prepared. Then, an equimolar amount of magnesium oxide (or hydroxide) is gradually introduced into such a solution with vigorous stirring. After assimilation of the magnesium source, the reaction mixture is cooled in an ice bath, the remaining water is separated on a Shot filter, and the precipitate dried to constant weight.
  • an equimolar (calculated as a cation) mixture of gluconic and one of the above (butyric, or hydroxybutyric, or glucaric) acids is prepared. Then, an equimolar amount of magnesium oxide (or hydroxide) is gradually introduced into such a solution with vigorous stirring. After assimilation of the magnesium source, the reaction mixture is cooled in an ice bath, the remaining water is
  • Double calcium gluconate salts are prepared in a similar manner.
  • Experimental dosage forms are prepared by dissolving said compounds in an isotonic aqueous solution of sodium chloride or glucose. 2) Experiments on laboratory models of cancer cultures.
  • A-549 cells obtained by biopsy of a large cell lung cancer of a person
  • A-549-R cells of the same type, resistant to interferon at a concentration of 10,000 IU / ml
  • U-937 cells sensitive to known apoptosis inducers.
  • the control was healthy cells of the same tissues, not exposed to antineoplastic drugs.
  • Cells of each indicated line and corresponding healthy cells were cultured at 37 ° C in complete nutrient medium RPMM 640 (SIGMA, USA) with the addition of 2 mM L-glutamine, 10% fetal serum, and 40 ⁇ g / ml gentamicin in a humidified atmosphere with volumetric concentration of CO 2 5%. The indicated medium was replaced every 2-3 days. After the formation of a dense monolayer of cells on a substrate (4-5 days of growth), cell suspensions were prepared and 24-well plates were seeded at a concentration of 3 * 10 4 cells per well.
  • control drug doxorubicin and preparations according to the invention were used as additives to liquid nutrient media at the same concentration of 10 "3 mM / L. During the experiments, the nutrient medium was replaced daily.
  • part of the preparations according to the invention exhibits either predominantly antiproliferative activity or predominantly proapoptotic activity and that the cumulative antineoplastic effect depends both on the type of tumor and on the composition and structure of the preparation and on its concentration and / or duration of action on tumor cells.
  • Example 1 Cell suspensions based on the A-549 line were obtained and seeded in four 24-well plates at a concentration of 3 ⁇ 10 4 cells per well, as described above. DiHAMK-Mg-gluconate was added to the culture media in dilutions of 10 ⁇ 1 , 10 "2 , 10 ⁇ , and 10 ⁇ mmol / L.
  • Example 2 Cell suspensions based on the line U-937 were obtained and seeded in four 24-well plates at a concentration of 3-10 4 cells per well, as described above. DiHAMK-Mg-gluconate was added to the culture media in dilutions from 10 ⁇ 1 to 10 "4 mM / L.
  • the antineoplastic preparations according to the invention can be easily manufactured industrially and used for the prevention and outpatient or clinical treatment of cancer. They are easily absorbed and practically harmless to the human body, even in such single doses, which significantly exceed the therapeutically necessary doses.
  • Control 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100
  • GABA-gluconate 50 50 60 50 50 60 50 50 60

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Le produit antinéoplasique à base d'acide gluconique est capable d'avoir un effet apoptosique et antiprolifératif sur un fond de préservation des cellules saines. Dans une première variante, il se présente comme au moins un gluconate dans lequel l'agent de formation de sel est sélectionné dans un groupe constitué de sodium, de potassium, de magnésium, d'acide aminogammabutyrique (GABA), d'éthylènediamine ou de leurs mélanges. Dans une deuxième variante, il se présente comme une composition coordonnée sur la base de gluconate de magnésium dans laquelle les ligands ont été sélectionnés dans un groupe constitué de GABA, de 3-hydroxy-GABA, d'acide éthylène-diamine-tétra-acétique et d'acide éthylène-glycol-tétra-acétique. Dans une troisième variante, il se présente comme un sel double sélectionné dans un groupe constitué de butyrate-gluconate de magnésium, d'oxybutyrate-gluconate de magnésium, de glucarate-gluconate de magnésium, d'oxybutyrate-gluconate de calcium, de glucarate-gluconate de calcium et de leurs combinaisons.
PCT/UA2006/000020 2005-04-15 2006-04-12 Produit antineoplasique (et variantes) WO2006110119A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
UAA200503576 2005-04-15
UA200503576 2005-04-15

Publications (1)

Publication Number Publication Date
WO2006110119A1 true WO2006110119A1 (fr) 2006-10-19

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PCT/UA2006/000020 WO2006110119A1 (fr) 2005-04-15 2006-04-12 Produit antineoplasique (et variantes)

Country Status (2)

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RU (1) RU2358721C1 (fr)
WO (1) WO2006110119A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MD4132C1 (ro) * 2010-12-13 2012-05-31 Государственный Университет Молд0 Di(µ-S)-bis{cloro-[fenil(piridin-2-il)metanon-tiosemicarbazonato(1-)]cupru} care manifestă proprietatea de inhibare a proliferării celulelor T-47D ale cancerului mamar
CN111281968A (zh) * 2020-02-14 2020-06-16 杭州憶盛医疗科技有限公司 一种抗神经组织肿瘤药及其制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2356347A (en) * 1999-10-04 2001-05-23 John Carter Pharmaceutical compositions for treating neoplastic disease
WO2001087265A2 (fr) * 2000-05-18 2001-11-22 Zentaris Ag Forme d'administration pharmaceutique pour des peptides, son procede de production et son utilisation
RU2223759C1 (ru) * 2002-09-18 2004-02-20 Виктор Павлович Кутняк Антиаритмический препарат

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2223756C1 (ru) * 2002-05-23 2004-02-20 Сотникова Лариса Федоровна Способ лечения рецидивирующего иридоциклохориоидита лошадей

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2356347A (en) * 1999-10-04 2001-05-23 John Carter Pharmaceutical compositions for treating neoplastic disease
WO2001087265A2 (fr) * 2000-05-18 2001-11-22 Zentaris Ag Forme d'administration pharmaceutique pour des peptides, son procede de production et son utilisation
RU2223759C1 (ru) * 2002-09-18 2004-02-20 Виктор Павлович Кутняк Антиаритмический препарат

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MD4132C1 (ro) * 2010-12-13 2012-05-31 Государственный Университет Молд0 Di(µ-S)-bis{cloro-[fenil(piridin-2-il)metanon-tiosemicarbazonato(1-)]cupru} care manifestă proprietatea de inhibare a proliferării celulelor T-47D ale cancerului mamar
CN111281968A (zh) * 2020-02-14 2020-06-16 杭州憶盛医疗科技有限公司 一种抗神经组织肿瘤药及其制备方法

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