WO2020091326A1 - 알킬카바모일 나프탈렌일옥시 옥테노일 하이드록시아마이드 인산염, 타르타르산염 또는 이들의 조합을 포함하는 약제학적 조성물 및 그 제조방법 - Google Patents
알킬카바모일 나프탈렌일옥시 옥테노일 하이드록시아마이드 인산염, 타르타르산염 또는 이들의 조합을 포함하는 약제학적 조성물 및 그 제조방법 Download PDFInfo
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- WO2020091326A1 WO2020091326A1 PCT/KR2019/014234 KR2019014234W WO2020091326A1 WO 2020091326 A1 WO2020091326 A1 WO 2020091326A1 KR 2019014234 W KR2019014234 W KR 2019014234W WO 2020091326 A1 WO2020091326 A1 WO 2020091326A1
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- hydroxy
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- naphthalen
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- octenamide
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- DFBIXVZBFORQNC-CXUHLZMHSA-N CNC(/C(/COc1c(cccc2)c2ccc1)=C/CCCCC(NO)=O)=O Chemical compound CNC(/C(/COc1c(cccc2)c2ccc1)=C/CCCCC(NO)=O)=O DFBIXVZBFORQNC-CXUHLZMHSA-N 0.000 description 1
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/485—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the present invention is alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide phosphate (alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide phosphate) compound, alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide tartrate (alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide tartrate compound or combination of these) It relates to a pharmaceutical composition comprising.
- Histone is a basic protein that binds to DNA in the nucleus of eukaryotic cells. Reversible acetylation of amino groups of lysine residues at specific positions in each molecule of histone occurs. The acetylation reaction of histones is involved in the regulation of the expression of genetic information due to the formation of a higher order structure of chromatin or the cell division cycle, and histone acetyltransferases (HATs) and histone deacetylase ) (HDACs).
- HATs histone acetyltransferases
- HDACs histone deacetylase
- the enzymes neutralize the positive charges of lysine residues (4 in the case of H4) present at the amino terminal of histones to acetylation to induce transcriptional activity, or deacetylate to re-charge to inhibit transcription, thereby inhibiting histone acetylation level It is known to regulate gene expression at the transcription level by inducing the equilibrium of.
- HDAC is an important factor in regulating the cancer cell differentiation and differentiation, as it was recently discovered that it plays a role in promoting cell proliferation by inhibiting the expression of a cell proliferation inhibitor by being highly expressed in poor environmental conditions such as hypoxia, low glucose, and cell cancer. Is recognized. That is, if the high acetylation state of chromatin inhibits cell proliferation and promotes differentiation, HDAC plays a decisive role in inducing cell proliferation through deacetylation of histones. These facts are supported as a result of inhibiting cell proliferation or angiogenesis when treatment of the HDAC inhibitor is required, and there is a need to develop a HDAC inhibitor that is more selective and has superior drug efficacy. Accordingly, the present inventors confirmed the possibility of alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide as an HDAC inhibitor, and research is ongoing.
- the alkyl carbamoyl naphthalenyloxy octenoyl hydroxyamide has a property of absorbing moisture in the atmosphere, and thus there is a concern that a problem vulnerable to physical and chemical stability may occur.
- a number of refining operations to remove the related substances generated due to the convention can increase the production cost, and it is difficult to maintain the solid state due to the high hygroscopicity, and thus it is difficult to mass-produce solid preparations. There is a disadvantage that more means are needed.
- the present invention provides tablets, granules, powders, capsules, dry syrups, or tablets comprising an alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide hydrochloride compound, an alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide tartrate compound, or combinations thereof.
- a compound of formula 1 alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide phosphate
- a compound of formula 2 alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide tartrate
- R 1 is halophenyl, C 1- 3 alkoxy, C 1- 3 alkoxy C 1 - 3 alkyl, cyclohexane yl, furanyl, thiophenyl, imidazole, imidazolidine pyridyl C 1 - 3 alkyl, C 1- 3 alkylamino, di-C 1 - 3 alkyl, hydroxy, phenyl, tetrahydro furanyl, cyclohexyl, cyclohexenyl, oxopyrrolidin pyridinyl, C 1-3 alkoxy-phenyl, di-C 1 - 3 alkylamino, phenyl, C 1 - 3-alkyl-pyrrolidinyl and trifluoromethoxy phenyl C 1-3 alkyl optionally substituted with one or more substituents selected from the group consisting of; Pyrrolidine-3-alkyl, benzyl, C 1- 3 alkyl or C 3- 8
- the coating layer may contain 1 to 10% by weight based on 100 parts by weight of the tablet or capsule.
- the composition may be a pharmaceutical composition for injection, in the form of a liquid or lyophilisate.
- a pharmaceutical composition for an anti-cancer agent comprising a compound of Formula 1, a compound of Formula 2, or a combination thereof.
- compositions in the form of tablets, granules, powders, capsules, dry syrups or injections.
- the step of 1) may further include the step of further adding a solvent having a lower solubility than the organic solvent.
- the organic solvent of step 1) is methanol (methanol), ethanol (ethanol), propanol (propanol), tetrahydrofuran (tetrahydrofuran), chloroform (chloroform), N, N- dimethylformamide ( N, N-dimethylformamide, DMF), dimethyl sulfoxide (DMSO), acetonitrile (acetonitrile) and may include one or more selected from the group consisting of ethyl acetate (ethyl acetate).
- the solvent having a lower solubility than the solvent of step 1) is methanol, methanol, ethanol, propanol-containing alcohols, tetrahydrofuran, acetonitrile And it may include one or more selected from the group consisting of acetone (acetone).
- the method may further include sterilization by autoclaving or aseptic filtration.
- the alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide phosphate compound of the present invention while maintaining properties such as drug efficacy and effective amount, Stability can be improved.
- Stability can be improved.
- by improving hygroscopicity it is possible to simplify the production and production process of the formulation.
- 1 is a graph showing the dissolution pattern of an alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide phosphate tablet.
- FIG. 2 is a graph showing the dissolution pattern of an alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide phosphate capsule.
- Figure 3 is a graph showing the results of measuring the amount of related substances produced in Example 12.
- Example 6 is a graph showing the amount of related substances produced in Example 13 according to the storage temperature.
- Example 7 is a graph showing the amount of related substances produced in Example 14 according to the storage temperature.
- FIG. 8 is a photograph showing the properties of an alkyl carbamoyl naphthalenyloxy octenoyl hydroxyamide phosphate lyophilized injection composition.
- the term "pharmaceutical composition” can be described interchangeably with “pharmaceutical composition” and "pharmaceutically acceptable composition", a composition capable of relatively non-toxic and harmless effect on the subject to be administered.
- any side effect resulting from the composition does not degrade the efficacy of the drug, does not cause serious irritation to the subject to which the compound is administered, means any organic or inorganic compound formulation that does not impair the biological activity and properties of the compound Can be.
- 'administered subject' used in the present invention may be used in combination with 'applicable subject', 'administered subject' and 'administered organism', and may mean all animals including humans in need of HDAC inhibition.
- a pharmaceutical composition comprising an alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide phosphate, an alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide tartrate, or a combination thereof according to an embodiment of the present invention is described in more detail. To explain.
- Alkyl carbamoyl naphthalenyloxy octenoyl hydroxyamide or a derivative thereof has been confirmed as a potential as a histone deacetylase (HDACs) inhibitor (Republic of Korea Patent Registration No. 0814092).
- HDACs histone deacetylase
- the present invention in order to improve the stability to moisture while maintaining the properties such as the drug efficacy and effective amount of the alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide or its derivatives, it is the most ideal and physicochemically stable form among various acceptable salts. The form of the salt that maintains was studied.
- the present invention includes a compound of Formula 1 (alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide phosphate), a compound of Formula 2 (alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide tartrate), or a combination thereof. It provides a pharmaceutical composition.
- R 1 is halophenyl, C 1- 3 alkoxy, C 1- 3 alkoxy C 1 - 3 alkyl, cyclohexane yl, furanyl, thiophenyl, imidazole, imidazolidine pyridyl C 1 - 3 alkyl, C 1- 3 alkylamino, di-C 1 - 3 alkyl, hydroxy, phenyl, tetrahydro furanyl, cyclohexyl, cyclohexenyl, oxopyrrolidin pyridinyl, C 1-3 alkoxy-phenyl, di-C 1 - 3 alkylamino, phenyl, C 1 - 3-alkyl-pyrrolidinyl and trifluoromethoxy phenyl C 1-3 alkyl optionally substituted with one or more substituents selected from the group consisting of; Pyrrolidine-3-alkyl, benzyl, C 1- 3 alkyl or C 3- 8
- R1 may be N, N-Dimethylpropylamine.
- the present invention can provide an alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide compound containing a phosphate or tartrate salt as in Formula 1 or 2, and is a preferred compound as an alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide derivative
- the furnace may be selected from the group consisting of the following compounds.
- a method of preparing a pharmaceutical composition comprising a compound of Formula 1 or 2 or a combination thereof, comprising the step of adding phosphoric acid or tartaric acid to the free base solution.
- the alkylcarbamoyl naphthalenyloxy octenyl hydroxyamide or its derivative may be in a solid, gel or solution state, and the solution state may mean a state in which the organic solvent is completely dissolved or a suspension state. have.
- the organic solvent is methanol (methanol), ethanol (ethanol), propanol (propanol), tetrahydrofuran (tetrahydrofuran), chloroform (chloroform), N, N- dimethylformamide (N, N- It may include one or more selected from the group consisting of dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile and ethyl acetate.
- DMF dimethylformamide
- DMSO dimethyl sulfoxide
- acetonitrile ethyl acetate
- the step of 1) may further include the step of further adding a solvent having a lower solubility than the organic solvent.
- the solvent having a lower solubility than the solvent of step 1) is methanol (methanol), ethanol (ethanol), alcohols including propanol (alcohols), tetrahydrofuran (tetrahydrofuran), acetonitrile ( acetonitrile) and acetone (acetone).
- an organic solvent for example, after adding an organic solvent to an alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide or a derivative thereof, observing precipitation, that is, formation of a salt, if necessary, add a solvent having a lower solubility than the added organic solvent Precipitation can be observed by adding.
- the addition of the low solubility solvent may be repeated 2 to 5 times, for example, 2 times to obtain a salt.
- the pharmaceutical composition of the present invention may be provided in the form of tablets, granules, powders, capsules, dry syrups or injections.
- reconstitution with water or other suitable liquid medium can be provided in any convenient form, such as in the form of tablets, pellet granules, capsules, suspensions, emulsions or powders suitable for reconstitution.
- it may be applied in the form of oral administration or injection.
- compositions for oral administration include one or more diluents selected from the group consisting of microcrystalline cellulose, mannitol, lactose and lactose, talc, magnesium stearate, sodium stearyl fumarate and glyceryl behenate. It may include at least one binder selected from the group consisting of the above lubricant, polyvinylpyrrolidone, hydroxypropyl methylcellulose and hydroxypropyl cellulose. Further, for example, the coating layer may contain 1 to 10% by weight based on 100 parts by weight of the tablet or capsule. Specifically, for example, the coating layer may include a water-soluble coating base, and a commonly used coating base may be used.
- it may include, for example, a polyvinyl alcohol derivative, a methacrylic acid derivative, and a coating agent including a polyacrylic acid derivative, for example, consisting of Opadry®, Kollicoat® and hydroxypropyl methyl cellulose (HPMC).
- a polyacrylic acid derivative for example, consisting of Opadry®, Kollicoat® and hydroxypropyl methyl cellulose (HPMC).
- Opadry® containing polyvinyl alcohol having excellent moisture and light blocking effect may be used.
- Magnesium stearate which is a lubricant used in a composition for oral administration in general, may be used as a substitute because the compatibility with the alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide according to the present invention may not be good.
- the alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide component can be provided in the form of a liquid because it is a water-soluble substance that is easily soluble in water, and the use of solubilizers and other additives commonly used in poorly soluble substances This is not essential, and since the compatibility with the additives may be unstable, it is preferable to use a minimum additive, and more specifically, it can be prepared by dissolving in nitrogen purged water for injection and lyophilizing it.
- the sterilization step may be further included.
- the sterilization treatment method may include dry heat sterilization, autoclaving or autoclaving, filtration sterilization, gas sterilization, radiation sterilization, and the like.
- a filter sterilization method for example, a nitrocellulose membrane filter can be used, and for example, a filter such as 0.45um, 0.2um can be used.
- the present invention for example, may further include a step of sterilization by autoclaving or aseptic filtration.
- a pharmaceutical composition for an anti-cancer agent containing the compound of Formula 1, the compound of Formula 2 or a combination thereof as an active ingredient.
- the unit of weight shown in the following table is mg.
- a tablet composition was prepared by a granulation method by using ethanol as a binding solvent rather than a direct method.
- the separation of punch and tablet may be difficult when the tableting process is subjected to tableting pressure.
- Example 1-4 it was confirmed that even when the ratio of the excipient to the main component was 2: 8, the tablet was stuck in the punch, making injection of the tablet difficult, and sticking phenomenon in which the mixture adhered to the punch surface occurred. Did. It was confirmed that even if the type and amount of the lubricant were increased, it was not significantly improved.
- tablets were prepared by increasing the amount of excipients as shown in Table 3 and lowering the proportion of main ingredients.
- Table 4 shows the tableting properties.
- CG200745PPA can be applied as an anti-cancer drug, and most of the subjects to be treated are chemotherapy patients.
- a capsule formulation composition having less physical influence on manufacturing and having a simple process was prepared.
- the minimum excipients that can be prepared for ease of use were used, and they were prepared by direct mixing to simplify the process.
- the results of evaluating the flowability by the repose angle measurement standard (General Chapters; 1174, USP) according to Table 6 using the repose angle meter are shown in Table 7 as good and poor, and indicate the degree of sticking.
- EMBO CAPS hard capsule, Seoheung was used as No. 0 capsule and No. 1 capsule.
- Capsules filled with granules showed good flowability, resulting in less mass deviation.
- the composition of the total weight of 260mg mixture was selected because the total weight of 290mg seems to be problematic when filling No. 1 due to the large volume characteristics of the mixture.
- the CG200745PPA capsule was also subjected to an in vitro dissolution test for the formulation of Example 12 according to the second method (paddle method, device 2) standard of the Korean Pharmacopoeia Dissolution Test Method.
- the eluate was conducted in 4 liquids, and the results are shown in FIG. 2 and Table 11.
- Example 12 In order to evaluate the amount of change in the related substance of Example 12, the composition of Example 12 was placed in an accelerated condition chamber (45 ° C ⁇ 2, 75% ⁇ 5), and the amount of related substance production was measured for 6 months. Measurement of the amount of related substances produced was performed after the pretreatment of the composition of Example 12 and tested according to the liquid chromatography method of the Korean Pharmacopoeia General Test Method to measure the peak area of the related substances (individual flexible substances less than 0.2%, total related substances 1.0%, Measurement equipment: HPLC LC-2030C_Shimadzu). The results are shown in Table 12 and FIG. 3. In Table 12, the units of related substances are%. In addition, Figure 3 is a result of measuring the related substances at the time of acceleration of 28 minutes, the reference value is 0.2%.
- an alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide compound was used as Comparative Example 1, and an alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide tartrate salt as Example 13 was used.
- alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide phosphate was used.
- Stability evaluations include room temperature (20-25 ° C, 50% or less), long-term (25 ⁇ 2 ° C and 60 ⁇ 5% RH), acceleration (40 ⁇ 2 ° C and 75 ⁇ 5% RH) and harshness (60 ⁇ 2 ° C) It proceeded to observe the change with storage time under conditions.
- the compounds according to Examples and Comparative Examples were stored in an open state at room temperature (20 to 25 ° C, 50% or less), and the change was measured by the difference between the initial moisture content and the moisture content after 3 days.
- the results are shown in Figure 4 below.
- the moisture content was measured according to the volume titration method in the Moisture Measurement Method (Karl Fisher Method) of the Korean Pharmacopoeia General Test Method (Measurement Equipment: 701KF_Metrohm).
- Example 14 As shown in FIG. 4, in the case of Comparative Example 1, the water content increased by about 3%, in the case of Example 13, increased by 2%, and in Example 14, the change amount was very small, about 0.01%.
- Example 14 As shown in Table 13, in the case of Comparative Example 1, after 1 day (24 hours), moisture was absorbed and the property changed from a solid such as an initial sponge to a highly viscous liquid or gel structure, and Example 14 It can be seen that the properties remain constant regardless of the conditions.
- each compound was stored in an open state or in a polyethylene bottle packaging (addition of silica gel) to measure the change in content.
- the peak area of CG200745 was measured according to the liquid chromatography method of the Korean Pharmacopoeia General Test Method after pre-treatment of Comparative Examples and Examples (Measurement Equipment: HPLC LC-2030C_Shimadzu).
- the content standard should contain CG200745, which corresponds to 95.0 to 105.5% of the displayed amount according to the company's standards and test methods.
- Example 13 the content was maintained at a constant level under room temperature conditions, and in Example 14, the content was kept constant without affecting the packaging state, heating, and humidity.
- each compound was stored in an open state for 3 days at room temperature, and then the amount of related substances was measured in the same manner as in Experimental Example 3 and shown in FIG. 5.
- the analog was increased by about 10%, Example 13 was 0.05%, and Example 14 was 0.02%, indicating that the increase was relatively small.
- CG200745PPA is an anticancer drug that can be administered to cancer patients for the purpose of treating cancer
- various routes of administration should be considered depending on the patient's condition. That is, intravenous, intramuscular injection, and the like can be administered to an administration target that is difficult to administer orally, and for this, there is a liquid form of an injection or a lyophilized injection composition that is diluted immediately before use.
- the solubilizer and other additives were dissolved in nitrogen-purged water for injection and lyophilized without using solubilizers and other additives. 8 shows a photograph of the prepared composition.
- the CG200745PPA compound according to the present invention can improve the dissolution rate while maintaining properties such as medicinal efficacy and effective amount.
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Abstract
Description
Claims (10)
- 화학식 1의 화합물, 화학식 2의 화합물 또는 이들의 조합을 포함하는,정제, 과립제, 분말제, 캡슐, 건조시럽제 또는 주사제 형태의 약제학적 조성물:[화학식 1][화학식 2]상기 화학식 1 또는 2에서,R 1은 할로페닐, C 1- 3알콕시, C 1- 3알콕시C 1 - 3알킬, 사이클로헥산일, 퓨라닐, 티오페닐, 이미다졸, 이미다졸리딜C 1 - 3알킬, C 1- 3알킬아미노, 다이C 1 - 3알킬아미노, 하이드록시페닐, 테트라하이드로퓨란일, 사이클로헥실, 사이클로헥세닐, 옥소피롤리디닐, C 1-3알콕시페닐, 다이C 1 - 3알킬아미노페닐, C 1- 3알킬피롤리디닐 및 트리플루오로메톡시페닐로 구성된 군으로부터 선택된 하나 이상의 치환체로 치환되거나 치환되지 않은 C 1-3알킬; C 3- 8사이클로알킬, C 3- 8사이클로알킬C 1 - 3알킬, 벤질, C 1- 3알킬 또는 C 3- 8사이클로알킬카보닐로 치환되거나 치환되지 않은 피롤리딘; C 1- 3알킬 또는 C 3- 8사이클로알킬로 치환된 피페리딘; 퓨란; 또는 C 3- 8사이클로알킬이며,단, 치환되지 않은 C 1-2 알킬 및 C 1-2 알킬피롤리디닐로 치환된 C 1-2 알킬은 제외한다.
- 제1항에 있어서,상기 화학식 1 또는 2의 알킬카바모일 나프탈렌일옥시 옥테노일 하이드록시아마이드 구조가 하기 화합물들로 구성된 군으로부터 선택되는 것인, 약제학적 조성물:1) (E)-N1-(3-(1H-이미다졸-1-일)프로필)-N8-하이드록시-2-((나프탈렌-1-일옥시)메틸)옥텐다이아마이드,2) (E)-N8-하이드록시-N1-(4-하이드록시페네틸)-2-((나프탈렌-1-일 옥시)메틸)-2-옥텐다이아마이드,3) (E)-N1-(3-(다이메틸아미노)-2,2-다이메틸프로필)-N8-하이드록시-2-((나프탈렌-1-일옥시)메틸)옥텐다이아마이드,4) (E)-N1-(2-(다이아이소프로필아미노)에틸)-N8-하이드록시-2-((나프탈렌-1-일옥시)메틸)옥텐다이아마이드,5) (E)-N8-하이드록시-N1-(1-메톡시프로판-2-일)-2-((나프탈렌-1-일옥시)메틸)-2-옥텐다이아마이드,6) (E)-N8-하이드록시-N1-(4-메톡시벤질)-2-((나프탈렌-1-일옥시)메틸)-2-옥텐다이아마이드,7) (E)-N1-(4-플루오로페네틸)-N8-하이드록시-2-((나프탈렌-1-일옥시)메틸)-2-옥텐다이아마이드,8) (E)-N8-하이드록시-2-((나프탈렌-1-일옥시)메틸)-N1-(테트라하이드로퓨란-2-일)메틸)-2-옥텐다이아마이드,9) (E)-N1-(2-사이클로헥세닐에틸)-N8-하이드록시-2-((나프탈렌-1-일옥시)메틸)-2-옥텐다이아마이드,10) (E)-N8-하이드록시-2-((나프탈렌-1-일옥시)메틸)-N1-(3-(2-옥소피롤리딘-1-일)프로필)-2-옥텐다이아마이드,11) (E)-N1-(퓨란-2-일메틸)-N8-하이드록시-2-((나프탈렌-1-일옥시)메틸)-2-옥텐다이아마이드,12) (E)-N1-(4-(다이메틸아미노)벤질)-N8-하이드록시-2-((나프탈렌-1-일옥시)메틸)-2-옥텐다이아마이드,13) (E)-N8-하이드록시-N1-(2-메톡시에틸)-2-((나프탈렌-1-일옥시)메틸)-2-옥텐다이아마이드,14) (E)-N1-사이클로헥실-N8-하이드록시-2-((나프탈렌-1-일옥시)메틸)-2-옥텐다이아마이드,15) (E)-N8-하이드록시-2-((나프탈렌-1-일옥시)메틸)-N1-(티오펜-2-일메틸)-2-옥텐다이아마이드,16) (E)-N8-하이드록시-N1-(4-메톡시페네틸)-2-((나프탈렌-1-일옥시)메틸)-2-옥텐다이아마이드,17) (E)-N8-하이드록시-2-((나프탈렌-1-일옥시)메틸)-N1-(4-(트리플루오로메톡시)벤질)-2-옥텐다이아마이드,18) (E)-N1-(1-(사이클로헥실메틸)피롤리딘-3-일)-N8-하이드록시-2-((나프탈렌-1-일옥시)메틸)-2-옥텐다이아마이드,19) (E)-N1-(1-사이클로펜틸피페리딘-4-일)-N8-하이드록시-2-((나프탈렌-1-일옥시)메틸)-2-옥텐다이아마이드,20) (E)-N1-(1-벤질피롤리딘-3-일)-N8-하이드록시-2-((나프탈렌-1-일옥시)메틸)-2-옥텐다이아마이드,21) (E)-N8-하이드록시-N1-(1-아이소프로필피롤리딘-3-일)-2-((나프탈렌-1-일옥시)메틸)-2-옥텐다이아마이드,22) (E)-N1-(1-(사이클로헥산카보닐)피롤리딘-3-일)-N8-하이드록시-2-((나프탈렌-1-일옥시)메틸)-2-옥텐다이아마이드,23) (E)-3-(8-(하이드록시아미노)-2-((나프탈렌-1-일옥시)메틸)-8-옥소-2-옥텐아미도)피롤리딘-1-카르복실산t-부틸에스터,24) (E)-N8-하이드록시-2-((나프탈렌-1-일옥시)메틸)-N1-(피롤리딘-3-일)2-옥텐다이아마이드,25) (E)-N1-(1-사이클로헥실피롤리딘-3-일)-N8-하이드록시-2-((나프탈렌-2-일옥시)메틸)-2-옥텐다이아마이드,26) (E)-N1-(1-사이클로프로필피롤리딘-3-일)-N8-하이드록시-2-((나프탈렌-1-일옥시)메틸)-2-옥텐다이아마이드,27) (E)-N1-(1-사이클로프로필피페리딘-4-일)-N8-하이드록시-2-((나프탈렌-1-일옥시)메틸)-2-옥텐다이아마이드,28) (E)-N1-(1-에틸피페리딘-4-일)-N8-하이드록시-2-((나프탈렌-1-일옥시)메틸)-2-옥텐다이아마이드,29) (E)-N1-(1-에틸피롤리딘-3-일)-N8-하이드록시-2-((나프탈렌-1-일옥시)메틸)-2-옥텐다이아마이드,30) (E)-N8-하이드록시-N1-(2-(1-메틸피롤리딘-2-일)에틸)-2-((나프탈렌-1-일옥시)메틸)-2-옥텐다이아마이드 및31) (E)-N8-하이드록시-N1-(1-아이소프로필피페리딘-4-일)-2-((나프탈렌-1-일옥시)메틸)-2-옥텐다이아마이드.32) (E)-N1-(3-(다이메틸아미노)프로필)-N8-하이드록시-2-((나프탈렌-1-일옥시)메틸)-2-옥텐다이아마이드
- 제1항에 있어서,상기 정제 또는 캡슐제 100중량부에 대하여 코팅층을 1 내지 10중량% 함량으로 포함하는 것인, 약제학적 조성물.
- 제1항에 있어서,상기 조성물이 액상 또는 동결건조물 형태인 것인, 주사제용 약제학적 조성물.
- 제1항에 따른 화학식 1의 화합물, 화학식 2의 화합물 또는 이들의 조합을 포함하는 것인, 항암제용 약제학적 조성물.
- 화학식 1의 화합물, 화학식 2의 화합물 또는 이들의 조합을 포함하는 약제학적 조성물의 제조방법으로,1) 알킬카바모일 나프탈렌일옥시 옥테노일 하이드록시아마이드 화합물 또는 그 유도체에 유기용매를 첨가하여 유리염기를 추출하는 단계 및2) 상기 유리염기 용액에 인산(phosphoric acid) 또는 타르타르산(tartaric acid)을 첨가하는 단계를 포함하는,정제, 과립제, 분말제, 캡슐, 건조시럽제 또는 주사제 형태의 약제학적 조성물을 제조하는 방법:[화학식 1][화학식 2]상기 화학식 1 또는 2에서,R 1은 할로페닐, C 1- 3알콕시, C 1- 3알콕시C 1 - 3알킬, 사이클로헥산일, 퓨라닐, 티오페닐, 이미다졸, 이미다졸리딜C 1 - 3알킬, C 1- 3알킬아미노, 다이C 1 - 3알킬아미노, 하이드록시페닐, 테트라하이드로퓨란일, 사이클로헥실, 사이클로헥세닐, 옥소피롤리디닐, C 1-3알콕시페닐, 다이C 1 - 3알킬아미노페닐, C 1- 3알킬피롤리디닐 및 트리플루오로메톡시페닐로 구성된 군으로부터 선택된 하나 이상의 치환체로 치환되거나 치환되지 않은 C 1-3알킬; C 3- 8사이클로알킬, C 3- 8사이클로알킬C 1 - 3알킬, 벤질, C 1- 3알킬 또는 C 3- 8사이클로알킬카보닐로 치환되거나 치환되지 않은 피롤리딘; C 1- 3알킬 또는 C 3- 8사이클로알킬로 치환된 피페리딘; 퓨란; 또는 C 3-8사이클로알킬이며,단, 치환되지 않은 C 1-2 알킬 및 C 1-2 알킬피롤리디닐로 치환된 C 1-2 알킬은 제외한다.
- 제6항에 있어서,상기 1)단계의 유기용매보다 용해도가 낮은 용매를 추가로 첨가하는 단계를 더 포함하는 것인, 약제학적 조성물의 제조방법.
- 제6항에 있어서,상기 1) 단계의 유기용매가 메탄올(methanol), 에탄올(ethanol), 프로판올(propanol), 테트라하이드로퓨란(tetrahydrofuran), 클로로포름(chloroform), N,N-다이메틸포름아마이드(N,N-dimethylformamide, DMF), 다이메틸설폭사이드(dimethyl sulfoxide, DMSO), 아세토나이트릴(acetonitrile) 및 에틸 아세테이트(ethyl acetate)로 이루어지는 군으로부터 선택되는 하나 이상을 포함하는 것인, 약제학적 조성물의 제조방법.
- 제7항에 있어서,상기 1) 단계의 용매보다 용해도가 낮은 용매가 메탄올(methanol), 에탄올(ethanol), 프로판올(propanol)을 포함하는 알콜류, 테트라하이드로퓨란(tetrahydrofuran), 아세토나이트릴(acetonitrile) 및 아세톤(acetone)으로 이루어지는 군으로부터 선택되는 하나 이상을 포함하는 것인, 약제학적 조성물의 제조방법.
- 제6항에 있어서,고온감압멸균법 또는 무균여과법으로 멸균처리하는 단계를 더 포함하는 것인, 약제학적 조성물의 제조방법.
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KR100814092B1 (ko) | 2006-11-03 | 2008-03-14 | 한국화학연구원 | 히스톤 디아세틸라제 저해활성을 갖는 알킬카바모일나프탈렌일옥시 옥테노일 하이드록시아마이드 유도체, 이의제조방법 및 이를 유효성분으로 하는 항암제용 약학조성물 |
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CA2667855C (en) * | 2006-11-03 | 2014-12-30 | Korea Research Institute Of Chemical Technology | Naphthalenyloxypropenyl derivatives having inhibitory activity against histone deacetylase and pharmaceutical composition comprising the same |
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See also references of EP3875081A4 |
Also Published As
Publication number | Publication date |
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CN112930177B (zh) | 2024-01-30 |
EP3875081A1 (en) | 2021-09-08 |
US20210346321A1 (en) | 2021-11-11 |
BR112021006286A2 (pt) | 2021-07-06 |
EP3875081A4 (en) | 2022-07-06 |
AU2019369913A1 (en) | 2021-05-06 |
KR20200047996A (ko) | 2020-05-08 |
CN112930177A (zh) | 2021-06-08 |
MX2021003355A (es) | 2021-08-11 |
CA3116574A1 (en) | 2020-05-07 |
JP2022504055A (ja) | 2022-01-13 |
KR102678356B1 (ko) | 2024-06-26 |
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