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WO2015099362A1 - Promédicament de d-pinitol et son procédé de préparation - Google Patents

Promédicament de d-pinitol et son procédé de préparation Download PDF

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Publication number
WO2015099362A1
WO2015099362A1 PCT/KR2014/012593 KR2014012593W WO2015099362A1 WO 2015099362 A1 WO2015099362 A1 WO 2015099362A1 KR 2014012593 W KR2014012593 W KR 2014012593W WO 2015099362 A1 WO2015099362 A1 WO 2015099362A1
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Prior art keywords
methyl
inositol
formula
chiro
compound
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Korean (ko)
Inventor
김정민
박준호
남준우
박지선
이현호
김경훈
김강전
김영하
김미정
김종엽
예인해
조보영
김장현
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Jeil Pharmaceutical Co Ltd
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Jeil Pharmaceutical Co Ltd
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    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
    • A—HUMAN NECESSITIES
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    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
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Definitions

  • the present invention relates to a D -pinitol prodrug, and more particularly, to a D -pinitol prodrug, a method for preparing the same, a pharmaceutical composition containing the same as an active ingredient, a use thereof, and a method for preventing or treating diabetes using the same.
  • Finitol is a sugar component present in pine, alfalfa and legumes. It is a methyl ether type compound having methyl group on D- chiro-inositol, which has a number of stereo isomers and optical isomers.
  • finitol is required to take a large amount (1.4 g / day) to be used as a diabetes treatment because high cost and low oral absorption rate is required to extract as a natural product.
  • the patent provides a form of prodrug in order to increase oral absorption, thereby lowering the dose, improving patient compliance, and increasing the low bioavailability of pinitol, and thus staying in the current dietary supplement. It is expected to be developed as a new diabetic drug using finitol.
  • the present invention aims to provide a prodrug compound of D -finitol or a pharmaceutically acceptable salt thereof.
  • an object of the present invention is to provide a pharmaceutical composition containing a prodrug compound of D -pinitol or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Another object of the present invention is to provide a method for preventing or treating diabetes by administering a composition containing a prodrug compound of D -pinitol or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides prodrug compounds of D -finitol or pharmaceutically acceptable salts thereof.
  • the present invention also provides a method for preparing a prodrug compound of D -finitol or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a pharmaceutical composition containing a prodrug compound of D -pinitol or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention also provides the use of the prodrug compound of D -pinitol or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for the prevention or treatment of diabetes.
  • the present invention also provides a method for preventing or treating diabetes by administering a composition containing a prodrug compound of D -pinitol or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
  • Y 1 , Y 2 , Y 3 , Y 4 And Y 5 are each independently H; ; ; ; ; ; or ego,
  • G 1 is C 1 -C 8 alkyl; C 1 -C 8 hydroxyalkyl; C 1 -C 8 aminoalkyl; C 1 -C 12 amidoalkyl; C 3 -C 10 cycloalkyl; C 5 -C 10 aryl; C 4 -C 10 heterocycle comprising at least one heteroatom selected from the group consisting of N, O and S in the ring; or ego,
  • G 2 is C 1 -C 8 alkyl; Or C 5 -C 10 aryl,
  • G 3 and G 4 are each independently C 1 -C 8 alkyl; C 3 -C 10 cycloalkyl; C 5 -C 10 aryl; Or a C 4 to C 10 heterocycle comprising at least one heteroatom selected from the group consisting of N, O and S in the ring,
  • R 1 and R 1 ′ are each independently H; C 1 -C 8 alkyl; C 1 -C 8 aminoalkyl; Or R 1 and R 1 ′ combine with each other to form a ring of C 3 to C 12 ,
  • R 2 and R 2 ′ are each independently H; C 1 -C 8 alkyl; Or R 2 and R 2 ′ combine with each other to form a ring of C 3 to C 12 ,
  • R 3 is C 1 -C 8 alkyl
  • R 4 and R 5 are each independently H; C 1 -C 8 alkyl; or ego,
  • R 6 is C 1 -C 8 alkyl
  • n 1-6.
  • Y 1 , Y 2 , Y 3 , Y 4 And Y 5 are each independently H; ; or Can be.
  • Y 1 and Y 5 are identical to Y 1 and Y 5 .
  • the salts acid addition salts formed by pharmaceutically acceptable free acid are useful.
  • the free acid as may be used an organic acid and an inorganic acid, inorganic acids can be hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc.
  • organic acid is methanesulfonic acid, p - toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid (maleic acid), succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid (gluconic acid), galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanic acid, hydroiodic acid, and the like can be used. It is not limited.
  • Bases can also be used to make pharmaceutically acceptable metal salts.
  • the metal salt it is particularly suitable to prepare sodium, potassium or calcium salt, but is not limited thereto.
  • Pharmaceutically acceptable salts of the compounds of Formula 1 include salts of acidic or basic groups which may be present in the Formula 1 compound unless otherwise indicated.
  • pharmaceutically acceptable salts may include sodium, calcium and potassium salts of the hydroxy group
  • other pharmaceutically acceptable salts of the amino group include hydrobromide, sulfate, hydrogen sulphate, phosphate, hydrogen phosphate, Hydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p -toluenesulfonate (tosylate) salts and the like.
  • the D -pinitol prodrug of the present invention may be selected from the group consisting of the following compounds.
  • the D -pinitol prodrug of the present invention is preferably selected from the group consisting of the following compounds.
  • the D -pinitol prodrug of the present invention is remarkably superior in oral absorption compared to D -pinitol.
  • the D -pinitol prodrug of the present invention has an excellent anti-diabetic effect when the dosage is the same as D -finitol, and the dosage is reduced, so the medication compliance is excellent.
  • the present invention also provides a method for preparing the compound of Formula 1 or a pharmaceutically acceptable salt thereof.
  • the compound of Formula 1 of the present invention or a pharmaceutically acceptable salt thereof may be prepared by Preparation Methods 1 to 5 described below.
  • the present invention is not limited thereto, and a person skilled in the art will fully understand that the compound of Chemical Formula 1 of the present invention may be prepared by various methods using well-known techniques well known in the art. In particular, it can be prepared by a change or modification such as changing the reagents, solvents and reaction sequences used in the production method 1 to production method 5. Detailed preparation of the compounds of the invention is described in detail in each of these examples.
  • (S1) reacting a compound of formula (3) with D -finitol of formula (2) to prepare a compound of formula (4) into which a cyclic acetal protecting group is introduced; (S2) preparing a compound of Chemical Formula 5 by reacting a compound of Chemical Formula 4 with Y 3 -X; And (S3) removing the acetal protecting group of the compound of Formula 5 to prepare a compound of Formula 1a, thereby preparing a compound of Formula 1a or a pharmaceutically acceptable salt thereof.
  • Y 3 is as defined in Formula 1 (but not H),
  • X may be selected a leaving group commonly used in nucleophilic acyl substitution reaction, for example halogen (F, Br, Cl, I), hydroxy, -OCOR 9 , -OR 10 , or -NR 11 ,
  • R 7 , R 7 ′, R 8 , R 8 ′, R 9 , R 10 , and R 11 are each independently H, C 1 -C 8 alkyl, C 1 -C 8 alkoxyalkyl, or C 5 -C 10 aryl or R 8 and R 8 ′ bonded to each other are C 5 to C 7 cycloalkyl.
  • the compound of Formula 1a prepared by Method 1 of the present invention is included in the compound of Formula 1 of the present invention.
  • step (S1) the hydroxy group in the 1-, 2-, 5- and 6- position by introducing a protection group to D -pinitol (Formula 2) that can be easily obtained commercially cyclic acetal form Synthesized D -pinitol intermediate product (Formula 4).
  • a protection group to D -pinitol (Formula 2) that can be easily obtained commercially cyclic acetal form Synthesized D -pinitol intermediate product (Formula 4).
  • Methylene, isopropylidene, cyclohexylidene, benzylidene acetal and / or ketal or cyclic carbonate may be introduced as the protection group.
  • the reaction is performed using sodium hydride, potassium t-butoxide, sodium hydroxide, potassium carbonate, etc., and the solvent does not adversely affect the reaction of tetrahydrofuran, N, N-dimethylformamide
  • the reaction may be performed using acetonitrile, dichloromethane, toluene and the like, and water as a cosolvent, depending on the base used.
  • the reaction temperature is not particularly limited, but can generally be carried out from cold to warm, and preferably at cold.
  • step (S2) the general pro-drug formation reaction (pro-drug formation reaction) for producing a compound, such as ester, carbonate, phosphate, carbamate, ether form from the compound of formula (4) prepared in the step (S1)
  • a compound such as ester, carbonate, phosphate, carbamate, ether form
  • D -pinitol prodrug (Formula 5) protected in cyclic acetal form.
  • This reaction is generally carried out in the presence of bases and / or coupling reagents which can be used for prodrug production from alcoholic compounds.
  • bases examples include organic bases such as triethylamine, diisopropylethylamine, pyridine, or inorganic bases such as sodium hydride, potassium carbonate, sodium carbonate, cesium carbonate, sodium or potassium alkoxides Etc. can be used.
  • Coupling reagents are generally commercially available 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 1,3-dicyclohexyl carbodiimide (DCC) , 1,1-carbonyl diimidazole and the like.
  • reaction can be carried out without using a solvent, but preferably in the presence of a solvent that does not adversely affect the reaction, dichloromethane, chloroform, tetrahydrofuran, diethyl ether, toluene, N,
  • a solvent such as N-dimethylformamide or acetonitrile.
  • the reaction temperature is not particularly limited, but in general, the reaction can be carried out under cold to warm, preferably at room temperature to warm.
  • step (S3) the D -pinitol prodrug (Formula 5) protected in the cyclic acetal form prepared in the step (S2) is deprotected by a method known in general organic synthesis to 4-O-substituted D -finitol prodrug (Formula 1a) is prepared.
  • step (S2) may further include extending the chain of Y 3 of the prepared compound of formula (5).
  • the form of the 4-O-substituted D -pinitol prodrug (Formula 1a) can be variously modified.
  • the chain extension reaction can be carried out according to a general organic synthesis method.
  • (S1) preparing a compound of formula 1a according to the method of Preparation Method 1; And (S2) reacting a compound of Formula 1a with Y-X to prepare a compound of Formula 1b, to prepare a compound of Formula 1b or a pharmaceutically acceptable salt thereof.
  • Y is Y 1 , Y 2 , Y 4 or Y 5 ,
  • Y 1 , Y 2 , Y 3 , Y 4 and Y 5 are each independently the same as defined in Formula 1, provided that Y 3 is not H, and is not the same as Y 1 , Y 2 , Y 4 and Y 5 Not),
  • the compound of Formula 1b prepared by Method 2 of the present invention is included in the compound of Formula 1 of the present invention.
  • step (S2) at least one of the hydroxyl groups in the 1-, 2-, 5- and 6- position of the 4-O-substituted D -pinitol prodrug (Formula 1a) prepared in the step (S1)
  • a compound of Formula 1b is prepared in the form of ester, carbonate, phosphate, carbamate, ether, and the like.
  • the details of the base, coupling reagent, solvent, and reaction temperature used in this reaction are the same as described in step (S2) of Preparation Method 1.
  • a compound of Formula 1c or a pharmaceutically acceptable salt thereof may be prepared by reacting D -pinitol of Formula 2 with YX.
  • Y is the same as Y 1 defined in Formula 1 (but not H),
  • the compound of Formula 1c prepared by Method 3 of the present invention is included in the compound of Formula 1 of the present invention.
  • Reaction in Preparation Method 3 for preparing the compound of Formula 1c is a general pro-drug formation reaction of D -pinitol (Formula 2), which can be easily obtained commercially, with ester, carbonate, phosphate, and carba
  • D -pinitol Forma 2
  • ester, carbonate, phosphate, and carba To prepare a compound of formula (1c) substituted in the form of mate, ether and the like.
  • the details of the base, coupling reagent, solvent, and reaction temperature used in this reaction are the same as described in step (S2) of Preparation Method 1.
  • (S1) to D of the formula (2) - to the cyclic acetal protecting group is introduced to react the compound of formula (3) and pinitol to prepare a compound of formula (4); (S2) preparing a compound of formula 6 wherein a hydroxy group protecting group is introduced through a hydroxy protection reaction of a compound of formula 4; (S3) selectively removing only the acetal protecting group of the compound of formula 6 to produce a compound of formula 7; (S4) preparing a compound of Formula 8 by reacting YX with a compound of Formula 7; And (S5) removing the hydroxy protecting group of the compound of Formula 8 to prepare a compound of Formula 1d, to prepare a compound of Formula 1d or a pharmaceutically acceptable salt thereof.
  • Y is Y 1 , Y 2 , Y 4 or Y 5 ,
  • Y 1 , Y 2 , Y 4 and Y 5 are each independently the same as defined in Formula 1,
  • Pro is a protecting group of a hydroxyl group.
  • Pro may be allyl, benzyl, or p-methoxybenzyl, with benzyl or p-methoxybenzyl being preferred.
  • the compound of Formula 1d prepared by Method 4 of the present invention is included in the compound of Formula 1 of the present invention.
  • the step (S1) is the same as the step (S1) of the manufacturing method 1.
  • the base used in this reaction is sodium hydride, potassium t-butoxide, sodium hydroxide, potassium carbonate, etc., and the solvent is tetrahydrofuran, N, N -dimethylform, which does not adversely affect the reaction.
  • the reaction can be carried out using amide, acetonitrile, dichloromethane, toluene and the like, and water as a cosolvent, depending on the base used.
  • the reaction temperature is not particularly limited, but generally can be carried out under cold to warm, preferably from cold to room temperature.
  • step (S3) selectively protects only the protecting group of the cyclic acetal form by the method known in general organic synthesis of the 4-O-protected cyclic acetal compound (Formula 6) prepared in the step (S2) Reaction produces 4-O-protected D -pinitol (Formula 7).
  • step (S4) one or more of the hydroxyl groups in the 1-, 2-, 5-, and 6-position of the 4-O-protected D -pinitol (Formula 7) prepared in the step (S3) may be used.
  • Pro-drug formation reaction to prepare a compound of formula (8) substituted in the form of ester, carbonate, phosphate, carbamate, ether and the like.
  • the details of the base, coupling reagent, solvent, and reaction temperature used in this reaction are the same as described in step (S2) of Preparation Method 1.
  • the 4-O-protected D -pinitol prodrug (Formula 8) prepared in the step (S4) is deprotected by a method known in general organic synthesis to give D -pinitol pro of Formula 1d. Make a drug.
  • (S1) preparing a compound of formula 1d according to the method of Preparation 4; And (S2) reacting a compound of Formula 1d with Y 3 -X to prepare a compound of Formula 1e, to prepare a compound of Formula 1e or a pharmaceutically acceptable salt thereof.
  • Y 1 , Y 2 , Y 3 , Y 4 and Y 5 are each independently the same as defined in Formula 1, provided that Y 3 is not H, and is not the same as Y 1 , Y 2 , Y 4 and Y 5 Not),
  • step (S2) the hydroxy group in the 4-position of the D -pinitol prodrug (Formula 1d) prepared in the step (S1) in the form of ester, carbonate, phosphate, carbamate, ether, etc. in general
  • the pro-drug formation reaction produces a compound of Formula 1e.
  • the details of the base, coupling reagent, solvent, and reaction temperature used in this reaction are the same as described in step (S2) of Preparation Method 1.
  • the compounds of Formulas 1a to 1e of the present invention may be prepared as pharmaceutically acceptable salts and solvates according to methods conventional in the art as needed.
  • Acid addition salts formed by pharmaceutically acceptable free acid are useful.
  • Acid addition salts are prepared by conventional methods, for example by dissolving a compound in an excess of aqueous acid solution and precipitating the salt using a water miscible organic solvent such as methanol, ethanol, acetone or acetonitrile and the like. Equivalent molar amounts of the compound and acid or alcohol in water can be heated and the mixture can then be evaporated to dryness or the precipitated salts can be suction filtered.
  • inorganic acids can be hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc. and organic acid is methanesulfonic acid, p - toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid (maleic acid), succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid (gluconic acid), galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanic acid, hydroiodic acid, and the like can be used. It is not limited.
  • 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 alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and then evaporating and drying the filtrate.
  • the metal salt it is particularly suitable to prepare sodium, potassium or calcium salt, but is not limited thereto.
  • Corresponding silver salts can also be obtained by reacting an alkali or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).
  • pharmaceutically acceptable salts of the compounds of Formula 1 include salts of acidic or basic groups which may be present in the Formula 1 compound unless otherwise indicated.
  • pharmaceutically acceptable salts may include sodium, calcium and potassium salts of the hydroxy group
  • other pharmaceutically acceptable salts of the amino group include hydrobromide, sulfate, hydrogen sulphate, phosphate, hydrogen phosphate, Hydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p -toluenesulfonate (tosylate) salts; and the like through the methods for preparing salts known in the art. Can be prepared.
  • composition comprising finitol prodrug as an active ingredient
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising D -pinitol prodrug represented by Formula 1 and a pharmaceutically acceptable salt thereof as an active ingredient.
  • the pharmaceutical composition of the present invention comprising the same as an active ingredient may be used for preventing or It can be used for therapeutic purposes.
  • the pharmaceutical composition of the present invention may contain one or more active ingredients exhibiting the same or similar functions in addition to the compound of the formula (1) of the present invention or a pharmaceutically acceptable salt thereof.
  • the present invention is prepared in addition to the above-described active ingredient for administration in addition to one or more pharmaceutically acceptable carriers are prepared
  • the pharmaceutically acceptable carrier is saline, sterile water, Ringer's solution, buffered saline, dex Rose solution, maltodextrin solution, glycerol, ethanol and one or more of these components may be mixed and used, and other conventional additives such as antioxidants, buffers and bacteriostatic agents may be added as necessary.
  • diluents, dispersants, surfactants, binders and lubricants may be additionally added to formulate into injectable formulations, pills, capsules, granules or tablets such as aqueous solutions, suspensions, emulsions and the like.
  • it may be preferably formulated according to each disease or component by a suitable method in the art or using a method disclosed in Remington's Pharmaceutical Science, Merck Publishing Company, Easton PA.
  • the pharmaceutical composition of the present invention when the pharmaceutical composition of the present invention is for oral administration, the compound of formula 1 or a pharmaceutically acceptable salt thereof of the present invention may be contained in the formulation of 1 to 95% by weight, preferably 1 to 70% by weight. % May be contained.
  • the pharmaceutical composition may be administered orally or parenterally in the form of injection, suppository, transdermal, inhalant, or intra-bladder injection.
  • the pharmaceutical composition of the present invention may be used alone or in combination with methods using surgery, hormonal therapy, drug therapy and biological response modifiers for the prevention or treatment of diabetes.
  • the present invention also provides the use of a D -finitol prodrug compound represented by Formula 1 or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for the prevention or treatment of diabetes.
  • the present invention provides a method for preventing or treating diabetes, comprising administering to a subject in need thereof a composition containing the D -pinitol prodrug represented by Formula 1 and a pharmaceutically acceptable salt thereof as an active ingredient.
  • a method for preventing or treating diabetes comprising administering to a subject in need thereof a composition containing the D -pinitol prodrug represented by Formula 1 and a pharmaceutically acceptable salt thereof as an active ingredient.
  • composition used in the prophylactic or therapeutic method of the present invention includes the pharmaceutical composition described herein.
  • the subject in need of the prophylactic or therapeutic method of the present invention includes a mammal, particularly a human.
  • the D -pinitol prodrug of the present invention exhibits a remarkably excellent effect of oral absorption compared to D -pinitol (equivalent ratio).
  • the D -pinitol prodrug of the present invention can significantly increase the antidiabetic effect while significantly lowering the daily dose than D -pinitol.
  • 1 is a graph showing the change over time of the concentration of blood pinitol after oral administration of a compound according to an embodiment of the present invention.
  • Step 1 5,6-bis-O- (1-methylethylidene) -3-O-methyl- D Synthesis of -Kiro-inositol
  • step 1 The compound prepared in step 1 (100 mg, 0.36 mmol) was dissolved in dichloromethane (5 ml), and triethylamine (0.3 ml, 2.19 mmol) and ethylchloroformate (157 ⁇ l, 1.64 mmol) at 0 ° C. And 4- (dimethylamino) pyridine (27 mg, 0.07 mmol) was added sequentially and stirred at room temperature for 3 days. The reaction was terminated with cold ice water, extracted with dichloromethane, and the organic solvent layer was washed with saturated aqueous sodium chloride solution.
  • Step 1 5,6-bis-O- (1-methylethylidene) -4-O- (4-ethoxy-4-oxobutanoyl) -3-O-methyl- D Synthesis of -Kiro-inositol
  • Example 11 In the same manner as in Example 10, the compound of Example 11 was synthesized.
  • Step 1 5,6-bis-O- (1-methylethylidene) -4-O- (2-aminoethylcarbamoyl) -3-O-methyl- D Synthesis of -Kiro- Inositol
  • step 1 of Example 1 The compound prepared in step 1 of Example 1 (100 mg, 0.36 mmol) was dissolved in dichloromethane (1.5 ml), and then 1,1′-carbonyldiimidazole (71 mg, 0.44 mmol) was added at room temperature. Stir for 30 minutes. Triethylamine (0.06 ml, 0.44 mmol) and ethylenediamine (0.04 ml, 0.55 mmol) were added at room temperature and stirred for 5 hours.
  • step 1 The compound prepared in step 1 (35 mg, 0.097 mmol) was dissolved in a solution of trifluoroacetic acid / water (1 ml / 1 ml) at 0 ° C. and stirred overnight at room temperature. After concentration under reduced pressure, the mixture was washed with ethyl acetate and the residue was concentrated under reduced pressure and dried to obtain the title compound (29 mg, reaction yield: 74%, white solid).
  • Step 1 5,6-Bis-O- (1-methylethylidene) -4-O- (Boc-Val) -3-O-methyl- D Synthesis of -Kiro-inositol
  • step 1 The compound prepared in step 1 (118 mg, 0.25 mmol) was dissolved in ethanol (5 ml), 12 N hydrochloric acid aqueous solution (1.0 ml) was added thereto, and the mixture was stirred at room temperature for one day. The solvent was concentrated under reduced pressure, and a small amount of methanol and ethyl acetate were added to the residue, followed by stirring for 30 minutes. After that, the reaction solution was filtered, washed with ethyl acetate and dried to obtain the title compound (81.0 mg, reaction yield: 99%, white solid).
  • Step 1 5,6-bis-O- (1-methylethylidene) -4-O- (Cbz-Val) -3-O-methyl- D Synthesis of -Kiro-inositol
  • Step 3 1,2: 5,6-Bis-O- (1-Methylethylidene) -4-O- ⁇ [2- (dimethylamino) acetamido] -Val ⁇ -3-O-methyl- D Synthesis of -Kiro-inositol
  • step 3 The compound prepared in step 3 (45 mg, 0.01 mmol) was dissolved in ethanol (3 ml), 12 N hydrochloric acid aqueous solution (0.5 ml) was added thereto, and the mixture was stirred at room temperature for one day. The solvent was concentrated under reduced pressure, and a small amount of methanol and ethyl acetate were added to the residue, followed by stirring for 30 minutes. After that, the reaction solution was filtered, washed with ethyl acetate and dried to obtain the title compound (40 mg, reaction yield: 98%, white solid).
  • Step 1 5,6-Bis-O- (1-methylethylidene) -4-O- (2-benzamidoacetyl) -3-O-methyl- D Synthesis of -Kiro-inositol
  • Step 1 5,6-bis-O- (1-methylethylidene) -4-O-[(2,2-dimethylpropionyloxy) methyl] -3-O-methyl- D Synthesis of -Kiro-inositol
  • step 1 The compound (360 mg, 0.67 mmol) prepared in step 1 was dissolved in ethyl acetate / ethanol (7 ml / 7 ml), 10% -palladium (72 mg) was added at room temperature, and the mixture was stirred overnight under hydrogen gas. After completion of the reaction, the reaction product was filtered under reduced pressure and concentrated using Celite to give the title compound (230 mg, reaction rate: 97%, colorless oil).
  • Step 1 5,6-bis-O- (1-methylethylidene) -4-O-[(dipivaloyloxymethoxy) phosphoryl] -3-O-methyl- D Synthesis of -Kiro-inositol
  • step 2 The compound prepared in step 2 (46 mg, 0.079 mmol) was dissolved in acetonitrile (2.0 ml), and then perchloric acid-silica gel (9 mg, Tetrahedron Lett., 2006, 47, 3653 ⁇ 3658) was added and stirred at room temperature for one day. It was. The reaction solution was filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane: methanol 15: 1) to obtain the title compound (6.6 mg, reaction yield: 17%, colorless oil).
  • Example 29 The compound of Example 29 was synthesized in the same manner as in Example 28.
  • N- Boc-Gly (900 mg, 5.15 mmol) and 1,1'-carbonyldiimidazole (910 mg, 5.61 mmol) were dissolved in acetonitrile (10 ml) and stirred at room temperature for 10 minutes, followed by D -pinitol (100 mg, 0.51 mmol) and triethylamine (4.3 ml, 30.85 mmol) were added sequentially and stirred at 60 ° C. for 3 days. The solvent was concentrated under reduced pressure, and the residue was extracted with ethyl acetate and saturated aqueous sodium bicarbonate solution, and the organic layer was washed with saturated aqueous sodium chloride solution.
  • step 1 The compound prepared in step 1 (130 mg, 0.13 mmol) was dissolved in 1,4-dioxane (4 ml), and 4 M HCl 1,4-dioxane solution (0.7 ml) was added dropwise and stirred at room temperature for 2 days. The solvent was concentrated under reduced pressure, ethyl acetate was added to the residue, followed by stirring for 30 minutes. After that, the reaction solution was filtered, washed with ethyl acetate and dried to obtain the title compound (90 mg, reaction yield: 100%, white solid).
  • Step 1 5,6-bis-O- (1-methylethylidene) -4-O-benzyl-3-O-methyl- D Synthesis of -Kiro-inositol
  • step 1 The compound prepared in step 1 (10.29 g, 28.24 mmol) was dissolved in 1,4-dioxane (500 ml), and then 4M hydrochloric acid 1,4-dioxane solution (75 ml) was added and stirred at room temperature for 2 days. It was. The solvent was concentrated under reduced pressure, ethyl acetate was added to the residue, followed by stirring for 30 minutes. The reaction solution was filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate) to obtain the title compound (6.3 g, reaction yield: 78%, white solid).
  • step 3 The compound prepared in step 3 (47 mg, 0.08 mmol) was dissolved in ethanol (1 ml), 10% -palladium (15 mg) was added at room temperature, and stirred for one day under hydrogen gas. After completion of the reaction, the reaction product was filtered under reduced pressure using celite and concentrated to give the title compound (34 mg, reaction yield: 83%, white solid).
  • Step 1 1-O- (Boc-Gly) -2,5,6-tris-O-ethoxycarbonyl-4-O-benzyl-3-O-methyl-D-chiro-inositol and / or 6- Synthesis of O- (Boc-Gly) -1,2,5-tris-O-ethoxycarbonyl-4-O-benzyl-3-O-methyl-D-chiro-inositol
  • 1,2,5-tris-O-ethoxycarbonyl-4-O-benzyl-3-O-methyl- D -chiro-inositol prepared in the same manner as the compound synthesized in step 3 of Example 31; And / or 2,5,6-tris-O-ethoxycarbonyl-4-O-benzyl-3-O-methyl- D -chiro-inositol (100 mg, 0.20 mmol) and 1-ethyl-3- (3 -Dimethylaminopropyl) -carbodiimide hydrochloride (76 mg, 0.40 mmol), and Boc-Gly-OH (70 mg, 0.40 mmol) in dichloromethane (2 ml), followed by 4- (dimethylamino) pyridine (12 mg, 0.10 mmol) was added at room temperature and stirred overnight.
  • Step 2 1-O- (Boc-Gly) -2,5,6-tris-O-ethoxycarbonyl-3-O-methyl-D-kiro-inositol and / or 6-O- (Boc-Gly Synthesis of) -1,2,5-tris-O-ethoxycarbonyl-3-O-methyl-D-kiro-inositol
  • Step 3 2,5,6-Tris-O-ethoxycarbonyl-1-O-Gly-3-O-methyl- D -Kiro-inositol hydrochloride and / or 1,2,5-tris-O-ethoxycarbonyl-6-O-Gly-3-O-methyl- D -Synthesis of Chiro-inositol Hydrochloride
  • step 2 The compound prepared in step 2 (74 mg, 0.13 mmol) was dissolved in ethanol (3 ml), and then 12 N HCl aqueous solution (1 ml) was added thereto, and the mixture was stirred at room temperature overnight. The solvent was concentrated under reduced pressure, and a small amount of methanol and ethyl acetate were added to the residue, followed by stirring for 30 minutes. The reaction solution was filtered, washed with ethyl acetate and dried to give the title compound (61 mg, reaction yield: 92%, white solid).
  • Example 41 In the same manner as in Example 41, the compound of Example 42 was synthesized.
  • Step 2 3-O-methyl-1,6-bis-O- ⁇ [(isopropyloxy) carbonyl] oxy ⁇ methyl- D Sum of -Kiro-Inositol castle
  • Step 2 4-O- (Cbz-Val) -3-O-methyl-1-O- (pivaloyloxy) methyl- D -Kiro-inositol and / or 4-O- (Cbz-Val) -3-O-methyl-6-O- (pivaloyloxy) methyl- D Synthesis of -Kiro-inositol
  • step 1 The compound prepared in step 1 (300 mg, 0.70 mmol) was dissolved in N, N -dimethylformamide (10 ml), followed by cesium carbonate (230 mg, 0.70 mmol) and chloromethyl pivalate (101 ⁇ l, 0.70 mmol). It was added sequentially at room temperature and stirred overnight. The reaction was terminated with cold ice water, extracted with ethyl acetate, and the organic solvent layer was washed with saturated aqueous sodium chloride solution.
  • Step 3 3-O-Methyl-4-O-Val-1-O- (pivaloyloxy) methyl- D -Kiro-inositol and / or 3-O-methyl-4-O-Val-6-O- (pivaloyloxy) methyl- D Synthesis of -Kiro-inositol
  • step 2 The compound (140 mg, 0.26 mmol) prepared in step 2 was dissolved in ethyl acetate / ethanol (6 ml / 3 ml), and then 10% -palladium (56 mg) was added at room temperature, followed by stirring for 4 hours under hydrogen gas. It was. After completion of the reaction, the reaction product was filtered under reduced pressure using celite and concentrated to give the title compound (100 mg, reaction yield: 91%, white solid).
  • mice 250-310 g of male rats (Sprague-Dawely), purchased from Orient, were purified for approximately one week before being used for the experiment.
  • rats were anesthetized by intraperitoneal injection of diluted ketamine / lump solution, and a cannulation was performed in which the left jugular vein was filled with 50 IU / ml of heparin-filled catheter. Used for. Finitol was dissolved in water and injected intravenously into the catheter at a dose of 10 mg / kg, and in the case of oral administration, an oral zoned was administered at a dose of 30 mg / kg.
  • the column used Xbridge Amide (2.1x50 mm, 3.5 ⁇ m) and Xterra MS C18 (2.1x50 mm, 3.5 ⁇ m), the mobile phase was acetonitrile and water containing 0.1% formic acid and the mobile phase flow rate was 0.3 ml / min.
  • the sample injection amount was 10 ⁇ l.
  • Mass ion source was used by turbo ion spray (350 °C) and analyzed by electrospray ionization in negative MRM mode. Finitol was quantified by Analyst 1.5.2 (Applied Biosystems, Concord, Canada) program. PK parameters were calculated using the PK solution 2.0 (Summit PK, Montrose, Co., USA) program using the quantified concentration.
  • the compounds of the present invention were found to have an excellent oral absorption rate compared to finitol, and in particular, the ether-type compounds of Examples 44 to 66 increased the oral absorption rate by up to 8.7 times. It can be seen that the excellent compared to. Therefore, the compound according to the present invention can be effectively used to prevent and treat new diabetes by reducing the anti-diabetic effect while reducing the conventional intake of pinitol, which has an anti-diabetic effect, and also dramatically reduces various side effects of existing drugs. It is expected to be possible.
  • the compound according to the present invention that is, D -pinitol prodrug is superior to the oral absorption rate than D -pinitol, and thus can be usefully used for preventing or treating diabetes due to its excellent anti-diabetic effect and medication compliance.

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Abstract

La présente invention concerne un promédicament de D-pinitol, son procédé de préparation, et une composition pharmaceutique comprenant le promédicament de D-pinitol en tant que substance active. Le promédicament de D-pinitol de la présente invention a une capacité d'absorption orale supérieure au D-pinitol, de manière à présenter un effet antidiabétique et un effet d'excellente observance d'administration.
PCT/KR2014/012593 2013-12-23 2014-12-19 Promédicament de d-pinitol et son procédé de préparation Ceased WO2015099362A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022065895A1 (fr) * 2020-09-24 2022-03-31 동아에스티 주식회사 Nouveau sel d'un dérivé d'empagliflozine, en tant qu'inhibiteur de sglt-2, et hydrate de sel
CN119462443A (zh) * 2024-10-18 2025-02-18 河南中医药大学 布美他尼衍生物及其制备和用途

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5550166A (en) * 1995-03-17 1996-08-27 Ostlund; Richard E. Pinitol and derivatives thereof for the treatment of metabolic disorders

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5550166A (en) * 1995-03-17 1996-08-27 Ostlund; Richard E. Pinitol and derivatives thereof for the treatment of metabolic disorders

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KHURSHID A. BHAT ET AL., BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 19, 2009, pages 1939 - 1943 *
LUKAC, M. ET AL., ACTA FACULT. PHARM. UNIV. COMENIANCE, vol. 52, 2005, pages 31 - 45 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022065895A1 (fr) * 2020-09-24 2022-03-31 동아에스티 주식회사 Nouveau sel d'un dérivé d'empagliflozine, en tant qu'inhibiteur de sglt-2, et hydrate de sel
CN119462443A (zh) * 2024-10-18 2025-02-18 河南中医药大学 布美他尼衍生物及其制备和用途

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