JP2008120708A - Phlorizin derivative and method for producing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a water-soluble polymer-bound oral phlorizin derivative enabling diabetes to be prevented and treated, improved in solubility to water through binding phlorizin via a spacer to a water-soluble polymer having appropriate functional group, having high hypoglycemic activity, and in addition, owing to binding its phloretin moiety to the polymer chain, not hindering promotive diffusion-type saccharide transport carrier at all without absorption of the phloretin into enteric canals even when the phlorizin is hydrolyzed. <P>SOLUTION: The phlorizin derivative represented by general formula [1] (wherein, A is a spacer; -R-R'- denotes a water-soluble polymer, wherein R and R' each mean one unit of the polymer, and R' is bound, via the spacer A or without via the spacer A, to phlorizin, and the bound site of the water-soluble polymer to the phlorizin via the spacer A or without via the spacer A may be 4'-, 6'- or 4-site), or a pharmacologically acceptable salt thereof, is provided. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a phlorizin derivative useful as a therapeutic agent and preventive agent for oral diabetes.

So far, in addition to insulin administration, sulfonylurea preparations and biguanide preparations, which are oral diabetes treatment agents, have been used for the treatment of diabetes. Development of therapeutic agents is desired. On the other hand, it has been reported that hyperglycemia is involved in the development and development of diabetes, and it is possible to prevent and treat diabetes by excreting excess sugar directly into the urine while maintaining normal blood glucose levels. Has been considered.
Phloridin is a glycoside contained in the bark and root bark of rosaceae plants such as apples and pears. By inhibiting the sodium-glucose symporter present in the intestinal tract and kidney chorion, glucose in the intestinal tract As well as reabsorption of glucose in the kidneys and lower blood sugar. However, when phlorizin is administered orally, most of it is hydrolyzed into phloretin and glucose, and the ratio of acting as phlorizin is small and its hypoglycemic action is very weak. In addition, it is known that phloretin produced by hydrolysis of phlorizin strongly inhibits the accelerating diffusion type sugar transporter. For example, it is reported that phloretin intravenously administers phloretin to rats reduces the glucose concentration in the brain. (Non-patent Document 1), if it is used over a long period of time, it is considered to adversely affect various tissues. Therefore, there is no example using phlorizin as an oral diabetes drug.

  In order to reduce the side effect of phlorizin, a derivative has been studied (Patent Document 1), (Patent Document 2), (Patent Document 3), and (Patent Document 4). However, the development of a satisfactory phlorizin derivative has not yet been completed.

Stroke, 14, p. 388 (1983) J. Pharm. Pharmacol. 52, 303 (2000). JP-A-9-124684 Japanese Patent Laid-Open No. 9-124685 Special table 2003-238417 Japanese translation of PCT publication No. 2004-018376

  An object of the present invention is to provide means for maintaining the pharmacological effect of phlorizin and removing the side effects caused by the production of phloretin.

  The present invention improves the water solubility by binding phlorizin with a water-soluble polymer having an appropriate functional group, has an excellent hypoglycemic effect, and in addition, the phloretin moiety is bonded to a polymer chain. Thus, even when hydrolysis of phlorizin occurs, a phlorizin derivative is provided which has the characteristics that phloretin is not absorbed into the intestinal tract and does not inhibit the facilitated diffusion type sugar transporter at all. That is, the present invention provides a novel phlorizin derivative and provides a means for protecting against the side effects of phlorizin.

The present invention comprises:
1. General formula [1]
(In the formula, A is a spacer, -R-R'- is a water-soluble polymer, and R and R 'each represents one unit of the polymer. R' is bonded to phlorizin with or without spacer A. Or a pharmacologically acceptable salt thereof, wherein the binding site to the phlorizin may or may not be through the spacer A of the water-soluble polymer through the spacer A.
2.
Spacer is ethylene, oligoethylene, polyethylene, oligoethylene glycol, polyethylene glycol, oligoethyleneimine, polyethyleneimine, polyacrylic acid, polymethacrylic acid, polyglycolic acid, polylactic acid, poly (hydroxybutanoic acid), polycaprolactone, amino acid , A phlorizin derivative according to item 1 which is an oligopeptide, polypeptide, monosaccharide, oligosaccharide or polysaccharide, or a pharmaceutically acceptable salt thereof.
3.
Water-soluble polymers are aspartic acid, glutamic acid, serine, cysteine, lysine, vinyl alcohol, vinylamine, acrylic acid, methacrylic acid, N-vinylamide, N-vinylalkylamide, acrylamide, alkylacrylamide, 2-hydroxyethyl acrylate, methacrylamide , 2-hydroxyethyl methacrylate, 2-hydroxypropyl methacrylate, glucosyloxyethyl methacrylate polymer or copolymer thereof, alginic acid, pectin, hyaluronic acid, chitin, chitosan, amylose, polyglycerin, polyvinylpyrrolidone, or first to fifth 3. The phlorizin derivative or pharmacologically acceptable salt thereof according to item 1 or 2, which is a generation polyamidoamine type dendrimer.
4).
The phlorizin derivative according to any one of items 1 to 3, wherein the introduction rate of phlorizin unit (bonded phlorizin and spacer A) or phlorizin into the water-soluble polymer is 1 to 50%, or a pharmacologically acceptable product thereof. Salt.
5.
5. The phlorizin derivative or the pharmaceutically acceptable salt thereof according to any one of items 1 to 4, wherein the water-soluble polymer has a molecular weight of 1,000 to 1,000,000.
6).
A method for removing a side effect of phlorizin, characterized in that a phlorizin unit or phlorizine itself is bonded to a side chain of a water-soluble polymer.
7).
Water-soluble polymers are aspartic acid, glutamic acid, serine, cysteine, lysine, vinyl alcohol, vinylamine, acrylic acid, methacrylic acid, N-vinylamide, N-vinylalkylamide, acrylamide, alkylacrylamide, 2-hydroxyethyl acrylate, methacrylamide , 2-hydroxyethyl methacrylate, 2-hydroxypropyl methacrylate, glucosyloxyethyl methacrylate polymer or copolymer thereof, alginic acid, pectin, hyaluronic acid, chitin, chitosan, amylose, polyglycerin, polyvinylpyrrolidone, or first to fifth 7. The method according to item 6 above, which is a generation polyamidoamine type dendrimer.
8).
4-position, 4 'of phlorizin (1- [2'-(β-D-glucopyranosyloxy) -4 ', 6'-dihydroxyphenyl] -3- (4-hydroxyphenyl) propan-1-one) A fluoridine unit is constructed by introducing a spacer having an amino group or a carboxyl group at the terminal with respect to the hydroxyl group at the position or 6 ′ position, and this unit or phlorizine itself is substituted with a carboxyl group, an amino group, a hydroxyl group or a water-soluble polymer. A method for producing a phlorizin derivative or a pharmacologically acceptable salt thereof, which comprises bonding a plurality of thiol group sites.
9.
Water-soluble polymers are aspartic acid, glutamic acid, serine, cysteine, lysine, vinyl alcohol, vinylamine, acrylic acid, methacrylic acid, N-vinylamide, N-vinylalkylamide, acrylamide, alkylacrylamide, 2-hydroxyethyl acrylate, methacrylamide , 2-hydroxyethyl methacrylate, 2-hydroxypropyl methacrylate, glucosyloxyethyl methacrylate polymer or copolymer thereof, alginic acid, pectin, hyaluronic acid, chitin, chitosan, amylose, polyglycerin, polyvinylpyrrolidone, or first to fifth 9. The method according to item 8 above, which is a generation polyamidoamine type dendrimer.

  The novel phlorizin derivative of the present invention has an excellent hypoglycemic action, exhibits a hypoglycemic action superior to that of phlorizin, and in addition, even when phlorizin is hydrolyzed by oral administration, the phloretin moiety into the intestinal tract is also shown. Absorption does not occur and does not show an inhibitory effect on the facilitated diffusion type sugar transporter.

The novel phlorizin derivative of the present invention is represented by the general formula [1].
Formula [1]
In the formula, A represents a spacer, -R-R'- represents a water-soluble polymer, and R and R 'represent one unit of the polymer. R ′ is directly bonded to the phlorizin itself without the phlorizin unit or the spacer A, which is a combination of phlorizin and the binding spacer A. A unit including phlorizin and spacer A is referred to as a phlorizin unit. A plurality of these phlorizin units or phlorizin itself are bonded to the water-soluble polymer. This binding site is that of phlorizin (1- [2 '-(β-D-glucopyranosyloxy) -4', 6'-dihydroxyphenyl] -3- (4-hydroxyphenyl) propan-1-one) It can be 4 ', 6' or 4th position. The water-soluble polymer has a molecular weight of 1,000 to 1,000,000, particularly preferably 10,000 to 200,000, more preferably 30,000 to 100,000. 1 to 50%, preferably 5 to 30%, more preferably 10 to 20% of the structural unit of the water-soluble polymer (18% is the case where the phlorizin unit or phlorizin itself is introduced into 18 units of 100 structural units) The phlorizin unit or phlorizin is introduced at the introduction rate of). Examples of water-soluble polymers include aspartic acid, glutamic acid, serine, cysteine, lysine, vinyl alcohol, vinylamine, acrylic acid, methacrylic acid, N-vinylamide, N-vinylalkylamide, acrylamide, alkylacrylamide, 2-hydroxyethyl acrylate, Polymers of methacrylamide, 2-hydroxyethyl methacrylate, 2-hydroxypropyl methacrylate, glucosyloxyethyl methacrylate or copolymers thereof, alginic acid, pectin, hyaluronic acid, chitin, chitosan, amylose, polyglycerin, polyvinylpyrrolidone or first Examples are ˜5 generation polyamidoamine type dendrimers. Particularly preferably, a polymer of glutamic acid [Formula 2] is used.
Formula [2]

In the present invention, the bond between phlorizin and the water-soluble polymer may be directly bonded to phlorizin itself, but is more preferably used as a phlorizin unit having a spacer A therebetween. The spacer is not particularly limited, but a spacer having 2 to 50 carbon atoms, preferably 4 to 20 carbon atoms, more preferably 5 to 15 carbon atoms is used in order to maintain molecular flexibility. For example, ethylene, oligoethylene, polyethylene, oligoethylene glycol, polyethylene glycol, oligoethyleneimine, polyethyleneimine, polyacrylic acid, polymethacrylic acid, polyglycolic acid, polylactic acid, poly (hydroxybutanoic acid), polycaprolactone, amino acid, Examples include oligopeptides, polypeptides, monosaccharides, oligosaccharides, and polysaccharides. For convenience, oligoethylene glycol or polyethylene glycol is sufficient.
In the present invention, the bond between phlorizin and the water-soluble polymer or the bond between phlorizin and the spacer is fluoridine (1- [2 '-(β-D-glucopyranosyloxy) -4', 6'-dihydroxyphenyl] -3- (4-hydroxyphenyl) propan-1-one) can be in the 4 ′, 6 ′ or 4 position, but more preferably 4 ′.

  The derivatives of the present invention can be prepared into their pharmacologically acceptable salts. Examples of the salt include salts with nitrogen-containing organic bases of alkali metals, alkaline earth metals, ammonium, various amines, etc. with respect to acidic groups such as hydroxyl groups and carboxyl groups.

  In the derivative of the present invention, a carboxyl group, a hydroxyl group, an amino group, and a thiol group can have a protecting group for each group, as long as the water-soluble property is not changed. As each protecting group, those known as a protecting group for a carboxyl group, a protecting group for a hydroxyl group, a protecting group for an amino group, and a protecting group for a thiol group can be widely used.

  When the derivative of the present invention is used as a pharmaceutical, formulation adjuvants such as excipients, carriers, and diluents that can be used for normal formulation may be mixed as appropriate, and these may be mixed in a conventional manner by tablets, capsules, It is preferable to administer mainly orally mainly in the form of powders, syrups, granules, pills, suspensions, emulsions, liquids, powder formulations and the like. The dose, administration method, and number of administrations can be appropriately selected according to the age, weight, and symptoms of the patient, but usually 0.1 to 1000 mg / kg per day is administered orally to adults. The dose may be divided into several times.

  The target of application of the pharmaceutical comprising the derivative of the present invention as a main component is prevention and treatment of diabetes, which suppresses the transfer of sugar into the blood and is effective in suppressing a hyperglycemic state in the blood.

  The present invention also provides means for removing the side effects of phlorizin. The means is characterized in that the phlorizin unit or phlorizine itself is bonded to the side chain of the water-soluble polymer to stabilize the phlorizin. In the present invention, the phlorizin unit is as defined above. By introducing the phlorizin itself or the phlorizin unit into the water-soluble polymer defined above at a certain ratio, the side effect of phlorizin is eliminated. The introduction ratio is as described above. In addition, the phlorizin unit is (1- [2 '-(β-D-glucopyranosyloxy) -4', 6'-dihydroxyphenyl] -3- (4-hydroxyphenyl) propan-1-one) A phlorizin unit is constructed by introducing a spacer having an amino group or a carboxyl group at the end of the hydroxyl group at the 4th, 4 'or 6' position. The definition of the spacer is as described above. Or 4-position or 4 of (1- [2 ′-(β-D-glucopyranosyloxy) -4 ′, 6′-dihydroxyphenyl] -3- (4-hydroxyphenyl) propan-1-one) The side effects of phlorizin can also be eliminated by coupling a water-soluble polymer directly to the hydroxyl group at the 'position or 6' position.

In addition, the present invention relates to a method for producing a phlorizin derivative or a pharmacologically acceptable salt thereof, comprising phlorizin (1- [2 ′-(β-D-glucopyranosyloxy) -4 ′, 6 Introducing a spacer with an amino group or carboxyl group at the end of the hydroxyl group at the 4th, 4 'or 6' position of '-dihydroxyphenyl] -3- (4-hydroxyphenyl) propan-1-one) A method for producing a phlorizin derivative or a pharmacologically acceptable salt thereof comprising constructing a phlorizin unit and binding a plurality of such units to the carboxyl group, amino group, hydroxyl group or thiol group of the water-soluble polymer. is there.
The present invention also relates to phlorizin (1- [2 ′-(β-D-glucopyranosyloxy) -4 ′, 6′-dihydroxyphenyl] -3- (4-hydroxyphenyl) propan-1-one) A phlorizin derivative or a pharmacologically derivative thereof, which is bonded directly to the carboxyl group, amino group, hydroxyl group or thiol group of the water-soluble polymer directly to the hydroxyl group at the 4-position, 4'-position or 6'-position of An acceptable salt production method.

In the following, the preparation method of the phlorizin derivative of the present invention will be described with reference to examples.
Example 1
(Preparation of phlorizin unit)
The outline of the preparation of the phlorizin unit is shown in the reaction formula [1].
Reaction formula [1]

1) Synthesis of N- [2- (2-hydroxyethoxy) ethoxy] ethylphthalimide Triethylene glycol monochlorohydrin (2- [2- (2-chloroethoxy) ethoxy] ethanol) 9.0 mL (61.9 mmol), potassium phthalimide 12.5 g (67.5 mmol) and DMF 75 mL were mixed and stirred at 100 ° C. for 17 hours. After insoluble matter was filtered off, DMF was distilled off and extracted with 75 mL of dichloromethane and 75 mL of water. The dichloromethane layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain N- [2- (2-hydroxyethoxy) ethoxy] ethylphthalimide (yellow transparent oily liquid 14.7 g, yield 85%).
¹ H-NMR (CDCl ₃ ): δ 3.46-3.56 (m, 2H), 3.57-3.69 (m, 6H), 3.70-3.81 (m, 2H), 3.83-3.96 (m, 2H), 7.62-7.78 ( m, 2H), 7.78-7.91 (m, 2H).

2) Synthesis of 2- [2- (2-aminoethoxy) ethoxy] ethanol
N- [2- (2-hydroxyethoxy) ethoxy] ethylphthalimide (6.6 g, 23.6 mmol), hydrazine monohydrate (2.0 mL, 41.2 mmol), and ethanol (120 mL) were mixed and refluxed at 78 ° C. for 2 hours. After cooling to room temperature, the insoluble material was filtered off and the solvent was distilled off under reduced pressure. Then, 100 mL of dichloromethane was added to filter out the insoluble material, and the filtrate was concentrated under reduced pressure to give 2- [2- (2-aminoethoxy) ethoxy] ethanol (3.4 g of light yellow transparent liquid, yield). 96%).
¹ H-NMR (CDCl ₃ ): δ 2.39-2.76 (br, 4H), 2.83-2.92 (t, 2H, J = 5.0 Hz), 3.47-3.58 (t, 2H, J = 5.2 Hz), 3.57-3.68 (m, 5H), 3.68 -3.79 (t, 2H, J = 4.4 Hz)

3) Synthesis of 2- {2- [2- (benzyloxycarbonylamino) ethoxy] ethoxy} ethanol
2- [2- (2-aminoethoxy) ethoxy] ethanol 4.97 g (33.3 mmol) and sodium bicarbonate 2.94 g (35.0 mmol) were dissolved in 50 mL of deionized water under ice cooling. Thereto, 17.4 mL (concentration 33%) of a toluene solution of benzyloxycarbonyl chloride was added and stirred overnight at room temperature. Then, extraction was performed with 100 mL of ethyl acetate, and the ethyl acetate layer was washed with 80 mL of saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. 2- {2- [2- (benzyloxycarbonylamino) -ethoxy] ethoxy} ethanol (1.92 g of a colorless transparent oily liquid) was purified by silica gel column chromatography using an ethyl acetate-hexane mixed solution as an eluent. Yield 20%).
¹ H-NMR (CDCl ₃ ): δ 3.30-3.47 (q, 2H, J = 5.2 Hz), 3.52- 3.61 (q, 3H J = 5.2 Hz), 3.61-3.67 (br, 4H), 3.68-3.79 ( t, 2H, J = 4.4Hz), 5.10 (s, 2H), 7.27-7.45 (5H)
FAB-MS: 284.2 (M + 1) ⁺

4) Methanesulfonylation reaction of 2- {2- [2- (benzyloxycarbonylamino) -ethoxy] ethoxy} ethanol under a nitrogen atmosphere, 2- {2- [2- (benzyloxycarbonylamino) -ethoxy] ethoxy} Ethanol 0.67 g (2.36 mmol), triethylamine 1.65 mL (11.8 mmol), methanesulfonyl chloride 0.37 mL (4.72 mmol) and dichloromethane 10 mL were mixed, stirred for 1 hour under ice-cooling, and then stirred at room temperature overnight. The solvent was distilled off under reduced pressure at room temperature, 20 mL of dichloromethane was added, and the mixture was washed 3 times with 30 mL of saturated brine. The dichloromethane layer was dried over anhydrous magnesium sulfate, and then the solvent was concentrated under reduced pressure to obtain the target product, methanesulfonic acid ester (brown liquid 0.56 g, yield 66%).
¹ H-NMR (CD ₃ OD): δ 3.06 (s, 3H), 3.46-3.55 (t, 2H, J = 5.4 Hz), 3.55-3.67 (d, 4H, J = 6.4 Hz), 3.68-3.76 ( m, 2H), 4.22-4.41 (m, 2H), 5.06 (s, 2H), 7.18-7.44 (5H).

5) Reaction of phlorizin with methanesulfonate
Under a nitrogen atmosphere, 0.92 g (1.94 mmol) of phlorizin and 0.33 g (2.40 mmol) of potassium carbonate were dissolved in 25 mL of DMSO. Methanesulfonic acid ester 0.87 g (2.40 mmol) was added there, and it stirred at 50 degreeC overnight. After neutralization with a saturated aqueous ammonium chloride solution, extraction was performed twice with 80 mL of ethyl acetate. After drying the ethyl acetate layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. Purification by silica gel column chromatography using a chloroform-methanol mixed solvent as an eluent yielded the desired product, phlorizin derivative (Bn-PRZ) (yellow transparent viscous liquid 0.31 g, yield 25%).
¹ H-NMR (CD ₃ OD): δ 2.83-2.91 (t, 2H, J = 7.2 Hz), 3.32- 3.40 (m, 1H,), 3.42-3.50 (m, 5H), 3.50-3.56 (t, 2H, J = 5.4 Hz), 3.56 -3.64 (m, 2H), 3.64-3.71 (m, 3H), 3.77-3.84 (m, 2H), 3.85-3.91 (dd, 1H, J = 2.4, 2.4 Hz) , 4.03-4.22 (t, 2H, J = 4.6 Hz), 4.97-5.17 (m, 3H), 6.10-6.14 (d, 1H, J = 2.0 Hz), 6.22-6.41 (d, 1H, J = 2.4 Hz ), 6.56-6.76 (dt, 2H, J = 9.0, 2.4 Hz), 6.95-7.14 (dt, 2H, J = 9.0, 2.4 Hz), 7.17-7.45 (m, 5H).
FAB-MS: 702.3 (M + 1) ⁺
Anal.Calcd (%) for C ₃₅ H ₄₃ NO ₁₄・ 2H ₂ O: C, 56.98; H, 6.42; N, 1.90
Found: C, 57.39; H, 6.05; N, 1.82

6) Debenzyloxycarbonyl reaction of phlorizin derivative (Bn-PRZ) 157 mg (2.23 × 10 ^-1 mmol) of phlorizin derivative (Bn-PRZ) was dissolved in 5 mL of ethanol. 83.0 mg of palladium carbon (20%) was added thereto, and the mixture was stirred overnight under hydrogen pressure (5 atm). The palladium carbon was removed by filtration, and the solvent was distilled off under reduced pressure to obtain the target product, phlorizin unit (Am-PRZ) (light yellow transparent viscous liquid 101 mg, yield 80%).
¹ H-NMR (DMSO-d ₆ ): δ 2.69-2.84 (t, 2H, J = 7.4 Hz), 2.88-3.00 (t, 2H, J = 5.2 Hz), 3.06-3.20 (t, 1H, J = 8.4 Hz), 3.21 -3.51 (m, 15H), 3.53-3.65 (m, 6H), 3.66-3.78 (m, 3H), 4.07-4.21 (t, 2H, J = 4.8 Hz), 4.29-4.42 (br , 1H), 4.98-5.06 (d, 1H, J = 7.6 Hz), 5.07-5.25 (br, 1H), 6.05-6.19 (d, 1H, J = 2.0 Hz), 6.20-6.34 (d, 1H, J = 2.4 Hz), 6.54-6.76 (dt, 2H, J = 8.6, 2.4 Hz), 6.93-7.11 (dt, 2H, J = 8.6, 2.4 Hz).
FAB-MS: 568.2 (M + 1) ⁺
_{Anal.Calcd (%) for C 27 H} 37 NO 12 · 2H 2 O: C, 53.72; H, 6.85; N, 2.32
Found: C, 53.63; H, 6.42; N, 2.72

(Example 2)
(Introduction to water-soluble polymer)
The outline of introduction of the phlorizin unit into the water-soluble polymer is shown in the reaction formula [2].
Reaction formula [2]

Table 1 also shows that the introduction ratio of Am-PRZ into PGA-PRZ can be controlled by changing the mixing ratio of γ-PGA, EDC, and Am-PRZ. The introduction rate was based on the following formula. Proton was measured by NMR spectrum measurement.
Introduction rate =
(Number of protons in aromatic ring / 6 ÷ Number of methylene protons in γ-PGA / 4) x 100 (%)
Under ice-cooling, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC) 27.8 mg (1.45 × 10-1 mmol), γ-PGA (molecular weight: 60000) 18.7 mg (1.45 × 10 ^-1 mmol) Dissolved in 10 mL of deionized water and stirred for 30 minutes. Am-PRZ27.4 mg (4.83 * 10 ^<-2 > mmol) was added there, and it stirred at room temperature overnight. After dialysis for 3 days (molecular weight fraction: 10,000), PGA-PRZ (white solid 16.2 mg) was obtained by lyophilization.

Experimental example

A typical experiment using the phlorizin derivative of the present invention is shown below.
(Experimental example 1)
Using the in vitro intestinal tract method (Non-patent Document 2), the ability of the phlorizin derivative of the present invention to inhibit glucose absorption was examined. The in vitro intestinal tract method was prepared by cutting and inverting the small intestine of a rat (male, 7-8 weeks of age 200 grams) and setting the intestine in a test tube. For the extraintestinal fluid, 90 ml of glucose solution ( ³ H glucose and test compound added: glucose concentration 20 mM, test compound concentration 1 mM) was used. The intestinal fluid used was a pH 7.8 phosphate buffer (750 μl). During the test, a gas of oxygen: carbon dioxide = 95: 5 was vented to the external liquid. The reaction time was followed up to 60 minutes, 20 μl of the intestinal fluid was collected at each elapsed time, the radioactivity was measured, and the glucose permeation amount was calculated. The results are shown in FIG. Both PGA-PRZ with the introduction rate of the phlorizin unit (Am-PRZ) of 15% and 25% showed an inhibitory effect on glucose absorption. In particular, PGA-PRZ having a 15% introduction rate of phlorizin unit (Am-PRZ) showed a high glucose absorption inhibitory ability equivalent to phlorizin. In addition, the glucose absorption inhibitory ability of any PGA-PRZ significantly exceeded the inhibitory ability of the phlorizin unit (Am-PRZ). In this system, the passage of the PGA-PRZ-derived phlorizin portion through the intestine was not confirmed.

(Experimental example 2)
Using rats (6 males, 7-8 weeks old, 200g), the effect of oral administration of test compounds on blood glucose level was examined. A test compound (PGA-PRZ: 27 mg / 0.5 mL) (phlorizin: 24 mg / 0.5 mL) was orally administered to rats, and 0.5 mL of a 20% glucose aqueous solution was orally administered 10 minutes after the administration. After 15, 30, 60, 90, 120 minutes after oral administration of this aqueous glucose solution, 5 μL of blood was collected from the tail vein of the rat, and the blood glucose level (glucose) was measured using a glucose pilot system (manufactured by Aventir Biotech, LLC) for laboratory animals. Concentration). The results are shown in FIG. As a result, when an aqueous solution of PGA-PRZ was administered, the blood glucose level hardly increased throughout the measurement period even after glucose administration, and it was confirmed that the blood glucose level was superior to that of phlorizin. In addition, when the PGA-PRZ of the present invention was administered, no abnormality was observed in rats and there were no deaths.

  The novel phlorizin derivative of the present invention suppresses hyperglycemia and can be effectively used for the treatment and prevention of diabetes without side effects. The novel phlorizin derivative of the present invention can also be used as a health supplement, and in particular, can be used for assisting diet therapy for persons with diabetes reserve.

It is a figure which shows the result of a glucose absorption inhibition ability evaluation test. In the figure, control is additive-free, Am-PRZ is phlorizin unit (substance before binding to water-soluble polymer), PGA-PRZ25% is the compound of the present invention in which 25% phlorizin unit is introduced, PGA-PRZ15% is phlorizin The compound of the present invention in which 15% of the unit is introduced, Phloridzin is a system using phlorizin, and WithoutNa + is an intestinal solution without Na +. It is a figure which shows a time-dependent change of the blood glucose rise value after orally administering a test compound to a rat. In the figure, x represents water, ■ represents phlorizin, and ● represents the compound of the present invention.

Claims (9)

General formula [1]
(In the formula, A is a spacer, -R-R'- is a water-soluble polymer, and R and R 'each represents one unit of the polymer. R' is bonded to phlorizin with or without spacer A. Or a pharmacologically acceptable salt thereof, wherein the binding site to the phlorizin may or may not be through the spacer A of the water-soluble polymer through the spacer A.   Spacer is ethylene, oligoethylene, polyethylene, oligoethylene glycol, polyethylene glycol, oligoethyleneimine, polyethyleneimine, polyacrylic acid, polymethacrylic acid, polyglycolic acid, polylactic acid, poly (hydroxybutanoic acid), polycaprolactone, amino acid The phlorizin derivative or a pharmaceutically acceptable salt thereof according to claim 1, which is an oligopeptide, polypeptide, monosaccharide, oligosaccharide or polysaccharide.   Water-soluble polymers are aspartic acid, glutamic acid, serine, cysteine, lysine, vinyl alcohol, vinylamine, acrylic acid, methacrylic acid, N-vinylamide, N-vinylalkylamide, acrylamide, alkylacrylamide, 2-hydroxyethyl acrylate, methacrylamide , 2-hydroxyethyl methacrylate, 2-hydroxypropyl methacrylate, glucosyloxyethyl methacrylate polymer or copolymer thereof, alginic acid, pectin, hyaluronic acid, chitin, chitosan, amylose, polyglycerin, polyvinylpyrrolidone, or first to fifth The phlorizin derivative or a pharmacologically acceptable salt thereof according to claim 1 or 2, which is a generation polyamidoamine type dendrimer. The introduction rate of a phlorizin unit (a conjugate of phlorizin and spacer A) or phlorizin into the water-soluble polymer is 1 to 50%, or the phlorizin derivative according to any one of claims 1 to 3, or a pharmacologically thereof Acceptable salt. The molecular weight of the water-soluble polymer is 1,000 to 1,000,000. The phlorizin derivative or a pharmacologically acceptable salt thereof according to any one of claims 1 to 4.   A method for removing a side effect of phlorizin, characterized in that a phlorizin unit or phlorizine itself is bonded to a side chain of a water-soluble polymer.   Water-soluble polymers are aspartic acid, glutamic acid, serine, cysteine, lysine, vinyl alcohol, vinylamine, acrylic acid, methacrylic acid, N-vinylamide, N-vinylalkylamide, acrylamide, alkylacrylamide, 2-hydroxyethyl acrylate, methacrylamide , 2-hydroxyethyl methacrylate, 2-hydroxypropyl methacrylate, glucosyloxyethyl methacrylate polymer or copolymer thereof, alginic acid, pectin, hyaluronic acid, chitin, chitosan, amylose, polyglycerin, polyvinylpyrrolidone, or first to fifth The process of claim 6 which is a generation polyamidoamine type dendrimer. 4-position, 4 'of phlorizin (1- [2'-(β-D-glucopyranosyloxy) -4 ', 6'-dihydroxyphenyl] -3- (4-hydroxyphenyl) propan-1-one) A fluoridine unit is constructed by introducing a spacer having an amino group or a carboxyl group at the terminal with respect to the hydroxyl group at the position or 6 ′ position, and this unit or phlorizine itself is substituted with a carboxyl group, an amino group, a hydroxyl group or a water-soluble polymer. A method for producing a phlorizin derivative or a pharmacologically acceptable salt thereof, which comprises bonding a plurality of thiol group sites.   Water-soluble polymers are aspartic acid, glutamic acid, serine, cysteine, lysine, vinyl alcohol, vinylamine, acrylic acid, methacrylic acid, N-vinylamide, N-vinylalkylamide, acrylamide, alkylacrylamide, 2-hydroxyethyl acrylate, methacrylamide , 2-hydroxyethyl methacrylate, 2-hydroxypropyl methacrylate, glucosyloxyethyl methacrylate polymer or copolymer thereof, alginic acid, pectin, hyaluronic acid, chitin, chitosan, amylose, polyglycerin, polyvinylpyrrolidone, or first to fifth The process according to claim 8, which is a generation polyamidoamine type dendrimer.