WO2011014009A2 - Nouveau composé à base de phénoxyacétyle disubstitué ou son sel pharmaceutiquement acceptable, son procédé de fabrication, et composition pharmaceutique de suppression de multirésistance aux médicaments qui contient ce composé en tant que principe actif - Google Patents

Nouveau composé à base de phénoxyacétyle disubstitué ou son sel pharmaceutiquement acceptable, son procédé de fabrication, et composition pharmaceutique de suppression de multirésistance aux médicaments qui contient ce composé en tant que principe actif Download PDF

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WO2011014009A2
WO2011014009A2 PCT/KR2010/004967 KR2010004967W WO2011014009A2 WO 2011014009 A2 WO2011014009 A2 WO 2011014009A2 KR 2010004967 W KR2010004967 W KR 2010004967W WO 2011014009 A2 WO2011014009 A2 WO 2011014009A2
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compound
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phenoxy
preparing
prepared
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WO2011014009A3 (fr
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이경
민경훈
이기호
하연
김영란
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한국생명공학연구원
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/38—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/40—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
    • C07C255/60—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton at least one of the singly-bound nitrogen atoms being acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/06—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes

Definitions

  • the present invention relates to a novel disubstituted phenoxyacetyl compound or a pharmaceutically acceptable salt thereof, a preparation method thereof, and a pharmaceutical composition for inhibiting multi-drug resistance containing the same as an active ingredient.
  • Surgical and radiation therapy is a useful method in the early stages of cancer development, so the dependence on chemotherapy is gradually increasing in cancers that are difficult to detect early, and the chemotherapy has a history of more than 50 years.
  • Hundreds of anticancer drugs have been developed and used in the clinic until now, but there are not many cases of obtaining clinically satisfactory effects.
  • MDR multidrug resistance
  • P-glycoprotein inhibitors can be searched and discovered.
  • the P-glycoprotein is a membrane protein encoded by 170 kDa by human ABCB-1 (MDR1) gene, which is divided into six membranes and one. It belongs to the superfamily of ATP binding cassette (ABP) transport proteins consisting of 1,280 amino acids formed of two homologous hydrophobic sites having an ATP-binding site of
  • ABCB-1 ABCB-1
  • the expression of multidrug resistance is indicated by multidrug resistance through a mechanism of lowering drug concentration in cells by releasing the drug out of the cell by an energy dependent mechanism in which P-glycoprotein directly binds to the drug and consumes ATP.
  • most human tumors such as colon or kidney cancer, express P-glycoprotein and increase the expression rate, thereby exacerbating tumor deterioration.
  • Anticancer agents affected by P-glycoprotein include vinblastine, vincristine and navelbine of the vinca alkaloids family; Paclitaxel (TAX) of the taxanes family, taxotere; Anthracyclines family of doxorubicin, daunorubicin, epirubicin and idarubicin; Epipodophyllotoxins family drugs etoposide and teniposide; Other drugs include colchicine, mitoxantrone, dactinomycin, topotecan, trimetrexate, mitramycin, mitomycin C Various drugs are known.
  • First-generation drugs which are used for other therapeutic purposes, such as calcium channel inhibitors verapamil, calmodulin antagonists, steroidal drugs, immunosuppressants (cyclosporins), and antimalarial drugs (quinine) Among these are drugs that inhibit P-glycoprotein.
  • first-generation drugs have not been sufficiently inhibited, and their original pharmacological action has been a side effect and failed to be used in clinical practice.
  • Second-generation drugs compensate for the shortcomings of the first generation, but many second-generation drugs not only inhibit other types of transporters but also inhibit metabolism-related enzymes, which increases the blood concentration of anticancer drugs for a long time. Showed a problem of increasing.
  • Third-generation drugs are highly selective for other transporters, have a very high inhibitory effect on P-glycoproteins, and are not metabolized by CYP450 3A4, which does not change the pharmacokinetic characteristics of anticancer drugs administered in combination, resulting in side effects from anticancer drugs. I never do that. Despite these characteristics, many of the third generation drugs that have been developed so far (Tariquidar, Zosuquidar, VX-710, Laniquidar, ONT-093, etc.), except for those in clinical trials, are cells that are caused by P-glycoprotein inhibitors themselves. Unexpected side effects from toxicity are a problem.
  • the present inventors have studied to search for compounds without self-cytotoxicity while inhibiting overexpression of P-glycoprotein, which is a major cause of multi-drug resistance, while increasing the therapeutic efficiency of existing anticancer drugs, and thus, a novel disubstituted phenoxy.
  • the acetyl compounds were synthesized, and it was confirmed that some of these compounds exhibited superior inhibitory activity in the expression of P-glycoprotein, thus completing the present invention.
  • An object of the present invention is to provide a novel disubstituted phenoxyacetyl compound.
  • Another object of the present invention is to provide a method for preparing the novel disubstituted phenoxyacetyl compound.
  • Still another object of the present invention is to provide a pharmaceutical composition for inhibiting multi-drug resistance, which contains the novel disubstituted phenoxyacetyl-based compound as an active ingredient.
  • the present invention provides a novel di-substituted phenoxyacetyl compound represented by the following formula (1).
  • the present invention also provides a method for preparing the novel disubstituted phenoxyacetyl compound.
  • the present invention provides a pharmaceutical composition for inhibiting multi-drug resistance, containing the novel disubstituted phenoxyacetyl-based compound as an active ingredient.
  • novel disubstituted phenoxyacetyl compound according to the present invention exhibits an inhibitory activity against overexpression of P-glycoprotein, which is a major cause of multidrug resistance, and an increase in anticancer activity upon co-administration with anticancer drugs, thereby overcoming multidrug resistance against anticancer drugs. It can be used as an agent, therapeutic agent or modulator, improve the effectiveness of anticancer drugs, increase the survival rate of cancer patients, reduce the dose of anticancer drugs administered in combination, reduce side effects on normal cells and provide economic benefits. It can be useful for chemotherapy.
  • FIG. 1 is a diagram showing the P-glycoprotein inhibitory activity of the compound according to an embodiment of the present invention
  • (A) is a control group
  • (B) a comparison group (add verapamil)
  • (C) is an experimental group (in the present invention) According to the compound)).
  • the present invention provides a novel disubstituted phenoxyacetyl compound represented by Formula 1 below or a pharmaceutically acceptable salt thereof.
  • R 1 and R 2 are XYZ, XZ or Z,
  • n is an integer from 1 to 5
  • Z is amino, phenyl, quinolinyl or isoquinolinyl, wherein the amino, phenyl, quinolinyl or isoquinolinyl is unsubstituted or at least one C 1 -C 4 straight or branched chain alkyl, C 1- C 4 alkoxy, C 1 -C 4 straight or branched chain alkyl carboxy, trifluoromethyl, halogen, aminocarbonyl, cyano, or furano C 1 -C 4 alkyl aminocarbonyl.
  • R 1 and R 2 are XYZ, XZ or Z,
  • n is an integer from 1 to 2
  • Z is amino, phenyl, quinolinyl or isoquinolinyl, wherein the amino, phenyl, quinolinyl or isoquinolinyl is unsubstituted or one or more methyl, ethyl, propyl, butyl, t-butyl, methoxy , Ethoxy, fluoro, trifluoromethyl, methylcarboxy, aminocarbonyl, cyano, or furanomethylaminocarbonyl.
  • R 1 is N, N -dimethylamino-ethylamino, amino, 4- t -butyl-phenylamino, 3,4-dimethoxybenzylamino, 6,7-dimethoxy-1,2,3,4-tetrahydro Isoquinolinyl, 1- (4-fluorobenzyl) piperazinyl, 1- (4-trifluoromethylbenzyl) piperazinyl, 1- (4-methoxybenzyl) piperazinyl or 1- (3 -Methoxybenzyl) piperazinyl,
  • R 2 is 2-methylcarboxyphenyl, 4-methylcarboxyphenyl, 3-aminocarbonylphenyl, N -furan-2-ylmethylaminocarbonylphenyl, 3-cyanophenyl, 3-trifluoromethylphenyl or 8- Quinolinyl.
  • Table 1 shows the structures of specific examples of the novel disubstituted phenoxyacetyl compounds of Formula 1 according to the present invention.
  • the present invention includes not only the novel disubstituted phenoxyacetyl-based compound represented by Formula 1 or a pharmaceutically acceptable salt thereof, but also all possible solvates, hydrates or prodrugs that can be prepared therefrom.
  • the derivative of formula 1 of the present invention may be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful.
  • Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. Obtained from non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids.
  • Such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and iodide.
  • the acid addition salts according to the invention are dissolved in conventional methods, for example, by dissolving a compound of formula 1 in an excess of aqueous acid solution and using the water miscible organic solvent, such as methanol, ethanol, acetone or acetonitrile. It can be prepared by precipitation. Equivalent amounts of the compound of formula 1 and the acid or alcohol in water may be heated and then the mixture is evaporated to dryness or prepared by suction filtration of the precipitated salt.
  • Bases can also be used to make pharmaceutically acceptable metal salts.
  • Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving a compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt.
  • Corresponding silver salts are also obtained by reacting alkali or alkaline earth metal salts with a suitable silver salt (eg, silver nitrate).
  • the present invention provides a method for preparing a new disubstituted phenoxyacetyl compound of formula (1).
  • step a Preparing a compound of formula 3 by bromination of the 1-adamantane carboxylic acid compound of formula 2 (step a);
  • step b Preparing a compound of formula 4 by alkylating the compound of formula 3 prepared in step a with an anisole and Friedel-Crafts (step b);
  • step c Preparing a compound of formula 5 by removing the methyl ester group of the compound of formula 4 prepared in step b under Lewis acid conditions (step c);
  • step d Preparing a compound of formula 6, wherein the protecting group is selectively introduced into the compound of formula 5 prepared in step c using benzyl bromide under basic conditions (step d);
  • step e Preparing a compound of formula 7 by alkylating the compound of formula 6 prepared in step d with ethyl chloroacetate (step e);
  • step g Coupling the compound of Formula 8 prepared in step f with methyl 3-aminobenzoate to prepare a compound of Formula 9 (step g);
  • step i Reacting the compound of formula 10 prepared in step h with a coupling agent in the presence of an organic base to prepare a compound of formula 1a (step i).
  • step g ′ Coupling the compound of Formula 11 prepared in step f ′ with 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline to prepare a compound of Formula 12 (step g ′);
  • step i' Coupling the compound of Formula 13 prepared in step h 'with various amine compounds to prepare a compound of Formula 1b (step i').
  • step a is a step of preparing a compound of Formula 3 by bromination of the 1-adamantane carboxylic acid compound of Formula 2.
  • Br 2 may be used as the reaction solvent or the reaction solute, and the reaction temperature is preferably performed at -10 to 25 ° C.
  • step b is a step of preparing a compound of formula 4 by alkylation of the compound of formula 3 prepared in step a with anisole and Friedel-Crafts.
  • anisole may be used as the reaction solvent and the reaction solute, and the reaction temperature is preferably performed at 160 to 180 ° C.
  • step c is a step of preparing a compound of formula 5 by removing the methyl ester group of the compound of formula 4 prepared in step b under acidic conditions.
  • BBr 3 AlCl 3 , HBr and the like may be used as the acid.
  • step d is a step of preparing a compound of formula 6, wherein a protecting group is selectively introduced into the compound of formula 5 prepared in step c using benzyl bromide under basic conditions.
  • reaction solvent may be acetone, DMF, or the like, and the reaction temperature is preferably performed at 40 ° C. to 60 ° C.
  • step e is a step of preparing a compound of formula 7 by alkylation of the compound of formula 6 prepared in step d with ethyl chloroacetate.
  • reaction solvent conventional inorganic salts such as K 2 CO 3 , Cs 2 CO 3 , and NaOH may be used, and the reaction temperature is preferably performed at 25 to 60 ° C.
  • step f is a step of preparing a compound of formula 8 by reacting the compound of formula 7 prepared in step e with LiOH.
  • reaction temperature is preferably carried out at 25 ⁇ 60 °C.
  • step g is a step of preparing the compound of formula 9 by coupling the compound of formula 8 prepared in step f with methyl 3-aminobenzoate.
  • reaction temperature is preferably carried out at 25 ⁇ 60 °C.
  • step h is a step of preparing a compound of formula 10 by hydrogenating the compound of formula 9 prepared in step g under a palladium / carbon catalyst.
  • step i is a step of preparing a compound of formula 1a by reacting the compound of formula 10 prepared in step h with a coupling agent in the presence of an organic base.
  • DIPEA, TEA, etc. may be used as the base, and EDC, PPAA, etc. may be used as the coupling agent.
  • DMF, CH 3 CN and the like can be used as the reaction solvent, the reaction temperature is preferably carried out at 25 ⁇ 60 °C.
  • the steps a to e of the production method 2 may be carried out in the same manner as the steps a to e of the production method 1.
  • step f ' is a step of preparing a compound of formula 11 by hydrogenation of the benzyl group of the compound of formula 7.
  • the hydrogenation reaction may use a method commonly used in the art.
  • step g ' is a compound of formula 12 by coupling the compound of formula 11 prepared in step f' with 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline To prepare.
  • reaction solvent CH 3 CN, CH 2 Cl 2, etc. may be used, and the reaction is preferably performed at room temperature.
  • step h ' is a step of preparing a compound of formula 13 by reacting the compound of formula 12 prepared in step g' with LiOH.
  • reaction temperature is preferably carried out at 25 ⁇ 60 °C.
  • step i ' is a step of preparing the compound of formula 1b by coupling the compound of formula 13 prepared in step h' with various amine compounds.
  • reaction solvent CH 3 CN, CH 2 Cl 2, etc. may be used, and the reaction is preferably performed at room temperature.
  • the new disubstituted phenoxyacetyl compound according to the present invention is not limited to the above production method, and may be used as long as it is a method capable of synthesizing the novel disubstituted phenoxyacetyl compound as well as a known method as well. Can be.
  • novel disubstituted phenoxyacetyl-based compound prepared according to the present invention may be separated and purified by high performance liquid chromatography after preparation, and the molecular structure may be confirmed by nuclear magnetic resonance.
  • the present invention provides a pharmaceutical composition for inhibiting multi-drug resistance, which contains a disubstituted phenoxyacetyl compound of Formula 1 as an active ingredient.
  • the present invention comprises administering a novel disubstituted phenoxyacetyl-based compound represented by Formula 1 or a pharmaceutically acceptable salt thereof to a patient in need thereof in a therapeutically effective amount.
  • a treatment method for treating a patient in need thereof.
  • the present invention provides the use of a novel disubstituted phenoxyacetyl compound represented by Formula 1 or a pharmaceutically acceptable salt thereof in the preparation of a multi-drug resistant inhibitor for treating cancer.
  • Compounds of Formula 1 of the present invention can control or treat multi-drug resistance by inhibiting overexpression of a protein that induces multi-drug resistance to anticancer drugs, wherein the protein that induces multi-drug resistance is a P-glycoprotein expressed in cancer cells To be the target.
  • the pharmaceutical composition containing the disubstituted phenoxyacetyl-based compound of the present invention as an active ingredient inhibits the induction of multi-drug resistance by coadministration with an anticancer agent, thereby enhancing the anticancer effect of the anticancer agent, and also reducing the dose of the anticancer agent coadministered. This reduces the side effects on normal cells caused by administration of anticancer drugs alone.
  • Multidrug resistance is mainly due to overexpression of P-glycoprotein by MDR1 in the cell membrane of cancer cells, which directly binds to anticancer drugs, resulting in the release of the drug out of the cell and reducing intracellular drug accumulation. As the drug concentration inside the cancer cells is reduced. Therefore, compounds that inhibit the overexpression of P-glycoprotein have the effect of inhibiting multi-drug resistance.
  • the phenoxyacetyl compound according to the present invention exhibits the same cytotoxicity as that of verapamil used as a multi-drug inhibitor in MES-SA / DX5 cancer cell line, which is a P-glycoprotein-expressing cell line, and its efficacy is about 3 to 14 more than that of verapamil. It was found to be twice as high (see Table 2).
  • the phenoxyacetyl compound according to the present invention enhances the cytotoxicity of paclitaxel against MES-SA / DX5 cancer cell line, which is a P-glycoprotein expressing cell line treated with paclitaxel, thereby inhibiting the expression of P-glycoprotein.
  • MES-SA / DX5 cancer cell line which is a P-glycoprotein expressing cell line treated with paclitaxel
  • the IC 50 value was highest for the MES-SA / DX5 cell line. It has been shown to lower by more than 1000 times (see Table 3).
  • the phenoxyacetyl compounds according to the present invention can be seen to inhibit the activity of the P-glycoprotein by inhibiting the release of DiOC 2 which is a substrate of the P-glycoprotein (see Fig. 1), metabolism of most anticancer drugs Because it rarely interacts with CYP3A4, a human metabolizing enzyme associated with, it does not change the pharmacokinetic characteristics of anticancer drugs administered in combination, and is expected to not cause side effects due to drug-drug interactions with anticancer drugs (Table 4). Reference).
  • the compounds of the present invention effectively inhibit P-glycoprotein that causes multi-drug resistance, and thus can be usefully used to treat or modulate multi-drug resistance.
  • the compounds of the present invention such as colon cancer, colorectal cancer, bladder cancer, ovarian cancer, breast cancer, lung cancer, etc., acute myeloid leukemia (AML) that is not normally expressed high P-glycoprotein, as well as cancers that normally express a lot of P-glycoprotein ), And can be used to treat or regulate multi-drug resistance by anticancer agents in malignant lymphomas and the like.
  • AML acute myeloid leukemia
  • the compounds of the present invention include vinblastine, vincristine and navelbine of the vinca alkaloids family; Paclitaxel (TAX), taxotere of the taxanes family; Anthracyclines family of doxorubicin, daunorubicin, epirubicin and idarubicin; Epipodophyllotoxins family drugs etoposide and teniposide; Other drugs include colchicine, mitoxantrone, dactinomycin, topotecan, trimetrexate, mitramycin, mitomycin C It can be used to treat or control multi-drug resistance to anticancer agents.
  • Paclitaxel TAX
  • Anthracyclines family of doxorubicin, daunorubicin, epirubicin and idarubicin Epipodophyllotoxins family drugs etoposide and teniposide
  • Other drugs include colchicine, mitoxantrone, dactinomycin, topotecan, tri
  • the pharmaceutical composition containing the disubstituted phenoxyacetyl-based compound represented by Chemical Formula 1 as an active ingredient is formulated in various oral or parenteral dosage forms as described below. It may be administered, but is not limited thereto.
  • Formulations for oral administration include, for example, tablets, pills, hard / soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, etc. These formulations may contain, in addition to the active ingredients, diluents (e.g., lactose, dextrose). Rose, sucrose, mannitol, sorbitol, cellulose and / or glycine), lubricants such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols.
  • diluents e.g., lactose, dextrose
  • Rose sucrose, mannitol, sorbitol, cellulose and / or glycine
  • lubricants such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols.
  • Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine, and optionally such as starch, agar, alginic acid or its sodium salt. Disintegrant or boiling mixtures and / or absorbents, colorants, flavors, and sweeteners.
  • binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine, and optionally such as starch, agar, alginic acid or its sodium salt.
  • compositions comprising the compound represented by Formula 1 as an active ingredient may be administered parenterally, and parenteral administration may be by injecting subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.
  • the disubstituted phenoxyacetyl-based compound of Formula 1 or a pharmaceutically acceptable salt thereof is mixed with water with a stabilizer or a buffer to prepare a solution or suspension, and the ampoule or It may be prepared in a vial unit dosage form.
  • the compositions may contain sterile and / or preservatives, stabilizers, hydrating or emulsifying accelerators, auxiliaries such as salts and / or buffers for the control of osmotic pressure, and other therapeutically useful substances, and conventional methods of mixing, granulating It may be formulated according to the formulation or coating method.
  • the dosage of the compound of the present invention to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and generally based on an adult patient having a weight of 70 kg. It is 30-120 mg / day, Preferably it is 40-80 mg / day, It can also divide and administer once a day to several times at regular time intervals according to a decision of a doctor or a pharmacist.
  • Step b Preparation of 3- (4-methoxyphenyl) -adamantane-1-carboxylic acid (4)
  • Step c Preparation of 3- (4-hydroxyphenyl) -adamantane-1-carboxylic acid (5)
  • Step d Preparation of 3- (4-hydroxyphenyl) -adamantane-1-carboxylic acid benzyl ester (6)
  • Step e Preparation of 3- (4-ethoxycarbonylmethoxyphenyl) -adamantane-1-carboxylic acid benzyl ester (7)
  • Step f Preparation of 3- (4-carboxymethoxyphenyl) -adamantane-1-carboxylic acid benzyl ester (8)
  • Step g Preparation of 3- ⁇ 4-[(3-methoxycarbonylphenylcarbamoyl) -methoxy] -phenyl ⁇ -adamantane-1-carboxylic acid benzyl ester (9)
  • Step h Preparation of 3- ⁇ 4-[(3-methoxycarbonylphenylcarbamoyl) -methoxy] -phenyl ⁇ -adamantane-1-carboxylic acid (10)
  • Step i Preparation of 3- (2- ⁇ 4- [3- (2-dimethylamino-ethylcarbamoyl) -adamantan-1-yl] -phenoxy ⁇ -acetylamino) -benzoic acid methyl ester
  • Step i Preparation of 3- ⁇ 2- [4- (3-carbamoyl-adamantan-1-yl) -phenoxy] -acetylamino ⁇ -benzoic acid methyl ester
  • Step i Preparation of 3- (2- ⁇ 4- [3- (4-t-butyl-phenylcarbamoyl) -adamantan-1-yl] -phenoxy ⁇ -acetylamino) -benzoic acid methyl ester
  • Example 3 The procedure of Example 3 was repeated except that 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (30 mg, 0.13 mmol) was used instead of 4- t -butylaniline. 19 mg (yield 28%) of the title compound were obtained.
  • Step f ' Preparation of 3- (4-ethoxycarbonylmethoxyphenyl) -adamantane-1-carboxylic acid (11)
  • Step h ' ⁇ 4- [3- (6,7-Dimethoxy-3,4-dihydro-1 H-isoquinolin-2-carbonyl) -adamantan-1-yl] -phenoxy ⁇ -acetic acid
  • Step i ' 2- (2- ⁇ 4- [3- (6,7-Dimethoxy-3,4-dihydro-1 H-isoquinolin-2-carbonyl) -adamantan-1-yl]- Preparation of phenoxy ⁇ -acetylamino) -benzoic acid methyl ester
  • MES-SA / DX5 (ATCC Number: CRL-1977) cell line was purchased from ATCC (American Type Culture Collection, Rockville, Maryland, U.S.A.) and cultured based on the culture method described by ATCC.
  • MES-SA / DX5 cell lines were cultured in DMEM (or RPMI-1640) containing 10% FBS and passaged from 1: 6 to 1:10 every 2-3 days.
  • MES-SA / DX5 cell lines were aliquoted into 96-well plates to be 1.2 ⁇ 10 4 cells / well in 100 ⁇ l of carrier and pre-incubated at 37 ° C. for 24 hours to allow cells to adhere to the plate bottom face. Attached cells were incubated for 60 hours in the presence or absence of 100 nM of paclitaxel (Taxol) with a control (without multidrug resistance inhibitor), the compound prepared in Examples 1-16, and Verapamil as a comparative group, respectively, for 60 hours. It was.
  • EC 50 is the concentration of the compound that inhibits the growth of 50% cancer cells in the presence of 100 nM anti-cancer agent paclitaxel (Taxol), GI 50 is 50%, showing the original cytotoxicity in the absence of the anti-cancer agent paclitaxel (Taxol) Is the concentration of a compound whose cancer cells are inhibited from growing.
  • the phenoxyacetyl-based compound and verapamil according to the present invention can be seen to enhance the cytotoxicity against MES-SA / DX5 cancer cell line, a P-glycoprotein expressing cell line.
  • the self-cytotoxicity is 12.1-20 ⁇ M or more, indicating self-toxicity equivalent to verapamil used as a conventional multi-drug resistance inhibitor, and in combination with 100 nM of paclitaxel, 50% of cancer cells are inhibited from growth.
  • concentration of the compound was lowered to 0.71-15 ⁇ M, it was confirmed that the drug-resistant inhibitory activity was exhibited.
  • the compounds prepared in Examples 4 to 11, 14 to 16 were found to have about 3 to 14 times higher potency than Verapamil.
  • the phenoxyacetyl-based compound of the present invention exhibits the same cytotoxicity as that of verapamil used as a conventional multi-drug resistance inhibitor, and shows superior multi-drug resistance inhibitory activity than verapamil.
  • the phenoxyacetyl-based compound and verapamil according to the present invention can be seen to enhance the cytotoxicity of paclitaxel against MES-SA / DX5 cancer cell line P-glycoprotein expressing cell line. That is, the experimental group in which 5 ⁇ M of the phenoxyacetyl compound according to the present invention was combined with paclitaxel was compared with the paclitaxel alone treatment group for the MES-SA / DX5 cell line. 50 Value It is lowered by 200 ⁇ 1000 times. In addition, the experimental group in which 1 ⁇ M of the phenoxyacetyl compound according to the present invention was co-treated with paclitaxel was also compared with the paclitaxel alone treatment group.
  • MES-SA / DX5 cancer cell line a P-glycoprotein expressing cell line
  • DiOC 2 a P-glycoprotein substrate of the fluorescent substance, which interacts with P-glycoprotein and is released out of cells.
  • no compound was added as a control, or 1 ⁇ M of the compound prepared in Example 8 or 5 ⁇ M of verapamil as a comparison group was added thereto, followed by incubation for 1 hour, followed by washing three times using PBS.
  • the MES-SA / DX5 cells were observed using (microscope), and the results are shown in FIG. 1.
  • FIG. 1 (A) is a control group, (B) is a comparative group (add verapamil), (C) shows an experimental group (addition of a compound according to the invention).
  • the control group exhibits no fluorescence due to the release of DiOC 2 by P-glycoprotein, but verapamil and the compound according to the present invention inhibit the activity of P-glycoprotein to inhibit the release of DiOC 2 . Therefore, it can be seen that fluorescence appears in the cells.
  • the disubstituted phenoxyacetyl compound according to the present invention can be usefully used as a multi-drug resistance inhibitor because it exhibits inhibitory activity against over-expression of P-glycoprotein, which is the main cause of multi-drug resistance.
  • CYP3A4 a human metabolizing enzyme involved in the metabolism of most anticancer drugs, was tested for CYP3A4 inhibitory activity against the compounds of Examples 7-10 and 14-16 using the CYP3A4 / BFC High Performance Inhibitor Screening Kit from BD Test. Measured. As a comparison group, ketoconazole used as a conventional CYP3A4 inhibitor was used.
  • the compound of Example 15 according to the present invention showed no interaction with CYP3A4, and other compounds according to the present invention showed weak inhibitory activity against CYP3A4.
  • the compounds of Examples 8 and 9 showed slightly stronger inhibitory activity of 0.89 ⁇ M and 0.82 ⁇ M, respectively, they were 200 times weaker than the inhibitory activity (0.004 ⁇ M) of ketoconazole used as a conventional CYP3A4 inhibitor. Able to know. Therefore, the compounds according to the present invention are expected to cause no side effects due to drug-drug interactions with anticancer agents because they rarely interact with CYP3A4 and thus do not change the pharmacokinetic characteristics of the anticancer agents administered in combination.
  • the disubstituted phenoxyacetyl compound of Formula 1 according to the present invention can be formulated in various forms according to the purpose.
  • the following are some examples of formulation methods containing the compound represented by Formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.
  • the above ingredients were added to the indicated contents, uniformly mixed, stirred and granulated. After drying, tablets were prepared using a tablet press.
  • the desired components were prepared by adding the above components in the amounts shown in the present invention, mixing them uniformly, and filling the gelatine capsules with an appropriate size.
  • the above components are dissolved in boiling water with a given content, stirred, filled, cooled, and filled into a 2 ml sterile vial, and supplemented with an appropriate amount of injectable purified water to 2 ml. Prepared.

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Abstract

L'invention concerne un nouveau composé à base de phénoxyacétyle disubstitué, son procédé de fabrication, et une composition pharmaceutique pour supprimer une multirésistance aux médicaments, qui contient ce composé en tant que principe actif. Le nouveau composé à base de phénoxyacétyle disubstitué selon l'invention présente une activité de suppression de la surexpression de la glycoprotéine P (Pgp), qui est une cause majeure de multirésistance aux médicaments, et présente une activité anticancéreuse accrue lorsqu'il est administré conjointement avec un agent anticancéreux de manière à être employé utilement dans une thérapie anticancéreuse, puisqu'il peut être utilisé en tant que préparation servant à vaincre une multirésistance aux médicaments par rapport à des agents anticancéreux, et en tant que préparation thérapeutique ou régulatrice, il peut présenter les effets de préparations anticancéreuses et augmenter les taux de survie de patients cancéreux, et permet également de diminuer les effets secondaires sur des cellules normales, la dose ou les doses de préparation(s) anticancéreuse(s) pouvant être réduite(s) car elles sont utilisées conjointement.
PCT/KR2010/004967 2009-07-29 2010-07-28 Nouveau composé à base de phénoxyacétyle disubstitué ou son sel pharmaceutiquement acceptable, son procédé de fabrication, et composition pharmaceutique de suppression de multirésistance aux médicaments qui contient ce composé en tant que principe actif WO2011014009A2 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103827080A (zh) * 2011-09-27 2014-05-28 东国大学校产学协力团 新的HIF-1α抑制剂化合物及其制备方法
WO2014084494A1 (fr) * 2012-11-30 2014-06-05 한국생명공학연구원 Nouveau dérivé adamantyle disubstitué ou sel pharmaceutiquement acceptable de celui-ci, procédé pour le produire et composition pharmaceutique pour supprimer une métastase de cancer le comprenant comme ingrédient actif
US11548893B2 (en) 2017-07-15 2023-01-10 Arisan Therapeutics Inc. Enantiomerically pure adamantane carboxamides for the treatment of filovirus infection
EP4098647A4 (fr) * 2020-01-23 2024-04-17 Onecuregen Co Ltd Dérivé d'adamantyle disubstitué ou son sel pharmaceutiquement acceptable, et composition pharmaceutique pour empêcher la croissance du cancer le contenant comme principe actif

Non-Patent Citations (1)

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Title
TARA LOVEKAMP ET AL.: 'Inhibition of human multidrug resistance P-glycoprotein 1 by analogues of a potent 8-opioid antagonist' BRAIN RESEARCH vol. 902, 2001, pages 131 - 134 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103827080A (zh) * 2011-09-27 2014-05-28 东国大学校产学协力团 新的HIF-1α抑制剂化合物及其制备方法
EP2760823A4 (fr) * 2011-09-27 2015-05-20 Univ Dongguk Ind Acad Coop Nouveaux composés en tant qu'inhibiteurs du hif-1alpha , et leur procédé de fabrication
AU2012316941B2 (en) * 2011-09-27 2016-02-25 Dongguk University Industry-Academic Cooperation Foundation Novel compounds as HIF-1alphainhibitors and manufacturing process thereof
US9315507B2 (en) 2011-09-27 2016-04-19 Dongguk University Industry-Academic Cooperation Foundation Compounds as HIF-1alphainhibitors and manufacturing process thereof
WO2014084494A1 (fr) * 2012-11-30 2014-06-05 한국생명공학연구원 Nouveau dérivé adamantyle disubstitué ou sel pharmaceutiquement acceptable de celui-ci, procédé pour le produire et composition pharmaceutique pour supprimer une métastase de cancer le comprenant comme ingrédient actif
KR101576235B1 (ko) * 2012-11-30 2015-12-11 한국생명공학연구원 신규한 이치환 아다만틸 유도체 또는 이의 약학적으로 허용가능한 염, 이의 제조방법 및 이를 유효성분으로 함유하는 암 전이 억제용 약학적 조성물
US9447063B2 (en) 2012-11-30 2016-09-20 Korea Research Institute Of Bioscience And Biotechnology Disubstituted adamantyl derivative or pharmaceutically acceptable salt thereof, production method for same, and pharmaceutical composition for suppressing cancer metastasis comprising same as active ingredient
US11548893B2 (en) 2017-07-15 2023-01-10 Arisan Therapeutics Inc. Enantiomerically pure adamantane carboxamides for the treatment of filovirus infection
EP4098647A4 (fr) * 2020-01-23 2024-04-17 Onecuregen Co Ltd Dérivé d'adamantyle disubstitué ou son sel pharmaceutiquement acceptable, et composition pharmaceutique pour empêcher la croissance du cancer le contenant comme principe actif

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