MXPA96005415A - Derivative of propiophenone and procedures to prepare my - Google Patents

Abstract

A propiophenone derivative of the formula I: wherein R 'is a lower alkanoyl group and R "is a hydrogen atom, or R' is a hydrogen atom and R" is a lower alkoxycarbonyl group, or a pharmaceutically acceptable salt thereof. Said compounds have an excellent hypoglycemic activity, being then useful in the prophylaxis or treatment of diabetes.

Description

DERIVATIVE OF PRQPIQFENONñ AND PROCEDURES PORA PREPARAR EL ??? snoop TECHNICAL CRYPT The present invention relates to a novel propiophenone derivative which has a hypoglycemic acivity, and methods to prepare the same.

DESCRIPTION OF THE PREVIOUS TECHNIQUE Although dietary therapy is essential in the treatment of diabetes, when diet therapy does not sufficiently cope with the conditions of the conditions, insulin or an oral antidiabetic drug is additionally used. They have used biguanide compounds and sulphurea compounds as digests. However, these devices have several side effects. For example, the big-anide compounds cause Lac-tena acidosis, and the compounds of the form cause significant hypoglycemia. Under such circumstances, it has been desired to develop novel drugs for the treatment of diabetes that do not have such side effects. Recently, it has been reported that hyperglycemia participates in the outbreak and in the progressive deterioration of diabetes, that is, the theory of glucose toxicity. This is, that chronic hyperglossary leads to a decrease in the secretion of insulin and contributes to increase the resistance to insulin, and as a result, the concentration of glucose in the blood is increased, causing diabetes to self-aggravate fcf. Diabetology, Vol 28, p. 119 (1985); 5 Diabetes Care, Vol .. 13, p. ñlO (1990), etc.]. In this way, through the hyperglia, the aforementioned cycle of self-aggravation is interrupted so that prophylaxis or treatment of diabetes becomes possible. Co or one of the m all to treat ia ht per gl i cetina, It is considered to excrete an excessive amount of direct glucose in the urine so that the concentration of glucose in the blood normalizes. The floricma is a glycoside that exists in peels and stems of the rosaceas (vr.g., apple, pear, etc.).

-Ib. Recently, it has been discovered that tloricin is an inhibitor of the orthransorption of Na + -glucose, which exists only on the cononic membrane of the intestine and the kidney, by means of which the flopci inhibits the renal reabsorption of tubular glucose- and promotes glucose excretion even when blood glucose is controlled. Based on this action of the flor-icma, when the concentration of glucose in the blood of diabetic animals is controlled at a normal level for a long period of time by the daily subcutaneous administration of flopcin but without the use of insulin, the conditions of 2b diabetic animals are improved to be normal Tcf. l urnal of- "Olinical Inves ation, Vol. 79, p 1510 (1987), ibid. Vol. 30, μ. 1037 (1987), ibld. Vol. 87, p. 561 (1991), et c. ] However, when the flopcma is administered orally, a large part of it is hydrolysed in the glucose and floretin, which is the aglycone of the flopcma, and therefore, the amount of tlopcin to be absorbed is so small. that the effect of excretion of glucose in the urine of the Iloricina is very weak, fidernas, it is known that the floretma, which is the aglycone of the tlopcin, strongly inhibits a The diffuser-type facilitated glucose transporter, for example, when the drug is intravenously administered to rats, the concentration of glucose in the brain of the rats is decreased. "Cf" S + roke, Vol, 14, page 388 (1983) .From this time, when administered to a flopci for a long period of time, there may be negative effects on various tissues, and therefore, flopcin has not been used. <i> anno diabetic.

BRIEF DESCRIPTION OF THE INVENTION An object of the present invention is to provide a derivative of propi ofenone, which inhibits the renal reabsorption of tubular glucose by means of which it shows increased urinary glucose activity in the urine, and I show Or an excellent iconic hypoglyph activity, and also an anglicon of the same that has a very weak inhibitory activity or a facilitated diffuser-type glucose transporter. Another object of the present invention is to provide a polygenic agent consisting of a propiophenone derivative of the present invention and a pharmaceutically acceptable salt thereof as the active ingredient. Another object of the present invention is to provide a method for preparing a propiophenone derivative of the present invention.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a propiophenone derivative of the formula Lll. wherein R 'is a lower alkanoyl group-, and R "is a hydrogen atom, or R' is a hydrogen atom and R" is a lower alkoxycarbonyl group, or a pharmaceutically acceptable salt thereof. The derivatives of propi ofenone! T1 of the present invention can be used for the purposes of the present invention, either in its free form or in the form of a pharmaceutically acceptable salt thereof, The -, at Pharmaceutically acceptable may be a metal sai of the cli, et c The compounds m of the present invention or a pharmaceutically acceptable salt thereof, can be administered either orally or pa entirely, or can be formulated in a preparation Pharmaceuticals mixed with a pharmaceutically acceptable vehicle or a suitable diluent will entrust its oral or parenteral administration. The pharmaceutically acceptable or di? Erent vehicle may be, for example, Ifi linkers (vr.g., syrup, go to arica, gelatin, sorbet t.ol, tragacanth, pol i v my Ipa r rol idona, etc.); excipients (eg, lactose, sucrose, corn starch, potassium phosphate, sorbatol, glycine, etc.); lubricants (eg, magnesium stearate, talc, polyethylene glycol, silica, etc.); disintegrators (eg, potato starch, etc.); moisturizing agents (eg, 1 aurium, sodium isulfate, etc.), and the like. These pharmaceutical preparations can be in the form of a solid preparation, such as tablets, capsules, powders, granules, etc., or in the form of a liquid preparation. 2 (1 co or a solution, suspension, emulsion, etc., when administered orally.) When administered parenterally, the pharmaceutical preparations may be in the form of an injection preparation or an intravenous drip preparation. using distilled water for injection, a saline solution Biological, an aqueous glucose solution, ote The dose of the present compound CU varies depending of the age, weight and conditions of the patients, or the severity of the diseases to be cured, but may be within the range of 0.1 to 500 rng / kg / day, preferably on a scale of 1 to 50 mg / kg / day in the case of oral administration. In the case of parenteral starch, the dose of the present compound can be in the range of 0.01 to 50 mg / g / day, preferably in the range of 0.1 to 10 mg / kg / day. ., F: the Ti compound of the present invention, wherein K 'is a lower alkanoyl group, and R "is a hydrogen atom, ie, the compound of the CT-al formula: wherein R 'is a group of the lower canoe, or a pharmaceutically acceptable salt thereof, can be prepared by reacting a propiophenone derivative of the formula [II] wherein R 'is a lower alkanoyl group, with a sulfuric acid or a sulfuric acid and, if desired, the product can be converted to a pharmaceutically acceptable salt thereof. The above reaction can be carried out in a suitable organic solvent, from an ambient temperature to a temperature with heat, preferably at a temperature of room temperature at 50 ° C. The organic solvento can be any solvent that does not affect the reaction, for example, 1U methanol, ethanol, etc. The alkanesulfonic acids and aryl ionic acids may include phonic acid, ethersulonic acid, benzenesulfoic acid, p-toluensulphonic acid, etc., which are normally used in an amount of 0.0 mol to 0.2 mol, equivalent to 1 mol of the starting compound Ib- GJ ?. t: compound III] of the present invention, wherein \ i 'is an atom of h? < Jrogono, and R "is a group of the lower coxycarbonyl, that is, the compound of the formula Ci-b.1.

[I-b] wherein R "is a lower alkoxycarbonyl group, or a latent acceptable salt thereof, and can be prepared by reacting a propiophenone derivative of the formula IT 1 T] :: with a lower alkanol and an alcansulphone acid or a polyalphaulic acid, and if it is damaged, converting the product into a pharmaceutically acceptable salt thereof. The lower alkanol used in the above reaction may be a branched chain or straight chain alkanol < It has 1 affix * - carbon, for example, methanol, ethanol, propanol, isopropanol, n-butanol, tert-1, etc., and can be used in an equimolar or a very little excessive amount to 1 mol of the starting compound GTTTI. The same alkanesulfonyl and apulsulonic acids described above can be used in the reaction. In this reaction, a lower alkanol, which is used as a rodent, can also serve as a solvent, and the other organic solvent, which does not affect the reaction, can also be used. This reaction can usually be carried out at a temperature which is at room temperature to one with heat. The starting compound r Til used in the present invention can be prepared according to the following steps: (1) First, the acetophenone compound of the formula FTVl, wherein R "'is a hydrogen atom or a protecting group for a hydroxy group, and is condensed with an aldehyde compound of the formula [VI: followed by the removal of the protecting groups to give the acp lofenone derivative of the formula [VI]: OH (2) The above acplofenone derivative- [VE] is reduced to give the compound of the formula [VII]: (3) The groups of 4- and & -h? Drox? from the group of ß-D- 10 gl ucopi ranosil or from the previous compound TVTI] are pro-dides to give the compound of the formula TVIITl: where R "" is the protective group for a hydroxy group, and the groups of 2- and 3-hydrox? of the group of 3-D-gluccopiranosi are acylated with lower alkanoyl groups, followed by the removal of the protective groups. The condensation reaction of the depot "Jo of acetophenone [TV] with the aldehyde compound [V], in step 1 described above, can be carried out by conventional methods, for example, in a solvent (a solvent organic or me o1, ethanol, etc. or a mixture of these organic solvents and water), in the presence of a base (alkalimetai hydroxy, etc.), from a low temperature cooled to a warm temperature, (especially at a temperature between I0 ° C and pn ° C). The protecting groups for the hydroxy groups in the acetophenone derivative [IV] can be any conventional "protecting group", for example, alkanoyl groups such as the acetyl group, etc., aralkyl groups as the group of bencí lo, etc. The reductive reaction of the acryophenone derivative [VJ], in step (2) described above, can be carried out by means of-) a conventional method such as reduction with a metal hydride, catalytic reduction, etc. For example, the removal with a metal hydride can be carried out using a metal hydride in a solvent, and the catalytic reduction can be carried out using a catalyst under atmospheric pressure of hydrogen gas in a solvent. In the catalytic reduction, the catalyst can be any conventional catalyst, for example, palladium carbon, pl + to non-carbon, platinum oxide, etc. In the reduction with a metal hydride, the metal hydride can be any way that can reduce a double bond. Without ernbar-go, you can < It is preferable to use metal hydrides which do not reduce a ketone, for example, tellurium hydroxide. J? Co (Malel-I), which is prepared in accordance with the method described in Synthesis, p. 545 (1978). Sodium tellurium fugue is normally used "in an amount of .1 a ') EciuLvalen is molars, preferably in an amount of 1 to 1.5 molar equivalents, to 1 molar equivalent of the compound rv?.?. In the above-mentioned reducing reaction, the solvent can be any solvent that does not affect the reaction, for example, an organic solvent such as methanol, ethanol, tet rahydrofuran, ethyl acetate, acetic acid, etc., or a mixture of these solvents. organic and water. The reductive reaction can be carried out at a low temperature or cooling to a temperature with heat, preferably at a temperature of 10 ° C to 30 ° C. The protecting groups of the 4- and 6-hydroxy groups of the group of ß-D-glycosylsilicate of the compound FVrrTl in step (3) can be any conventional group. (However, it is preferable to use the benzylidene group or alkylidene groups or the i-propyl idene group, etc., which are formed by combining these two protecting groups together for the 4- and 6-hydroxyl groups. The acylation of the compound [HIV] with a lower alkanoyl group in step (3) can be carried out by reacting an acid to the lucarcarboxylic corresponding to the desired alkanoyl group, a salt thereof, or a reactive derivative of the same (hereinafter these groups will be referred to as an alkanoylating agent), with the compound [VTTel.The reaction of an ajujuyl carboxyl eo acid compound or a salt thereof with the compound [HIV], it can be carried out in the presence or absence of a condensing agent - in a suitable solvent. The reaction of a reactive derivative of the compound of alkoxar boxyl ico acid with the compound [HIV] can be carried out in the presence or absence of an acid receptor in a suitable solvent or without a solvent. The salt of an alkylcarboxylic acid can be, for example, an alkali metal salt or alkaline earth metal salt such as sodium salt, potassium salt, calcium sai, etc. When a salt of an alkylcarboxylic acid is used in the condensation reaction, the salt is preferably used in the reaction after the conversion thereof into an acid. The alkylcarboxylic acid may be, for example, an acid halide, an acid anhydride or an ester-active of the acids to which the carboxylic acids correspond. The agen + e capacitor can be which < conventional agent, for example, di ci ciohe 11 earbodi, diethyl cyanophosphate, earboni idiimidazole, N, N-b? yes? -oxo-3 -oxazole d) phosphine chloride, etc. The acid receptor can be any conventional receptor, for example, an inorganic base co or a metal hydroxide of lcali (v. G., Sodium hydroxide, potassium hydroxide, etc.); a metallic carbonate of alkali fvr.g., sodium carbonate, potassium carbonate, etc.); a Alkali metal hydrogen carbonate (eg, sodium hydrogen carbonate, carbonate, hydrogen potassium, etc.); an alkali metal hydride (eg, sodium hydride, potassium hydride, etc.), or an organic base such as tri-lower aikylanin (eg, tilane, diisopropylethylamine, etc); pyridm; dimef i lam opí p di na; aniline; dimet i lanili na, etc. The solvent can be any conventional solvent < ] that it does not affect the reaction, for example, di chloromethane, di et? l fopnanu da, + et fna dro was ano, acet oni t rila, pin dina, et c. The reaction can be carried out at a temperature or cooling at a temperature with heat, preferably at a temperature of -10 ° C to 100 ° C, especially at a temperature of 0 ° C to 50 ° C. Removal of the lower alkoyl groups from the hydroxy phenolic groups < The lower alkanoylate can be carried out by treating the compound with a lyase in a suitable solvent. The base may be a conventional base, for example, a hydrogen carbonate or alkali metal, or sodium hydrogen carbonate, potassium hydrogen carbonate, e + .c. The solvent can be any conventional solvent that does not affect the reaction, for example, totrahydro-urane, methanol, water, etc. The reaction can be carried out by heating, preferably < ? a temperature of 25 ° C to f) 0 ° C, especially at a temperature of 25 ° C to 40 ° C. Removal of protective groups for groups of 4- and 6-h drox? The group of β-D-glucopyranosyl can be carried out in aqueous acetic acid in the presence of an alkaline acid or apleulonic acid. Cellulose acid and apulsic acid can be those described above. The reaction can be carried out preferably at room temperature. The other starting compound TTT is prepared by reacting the non-form of aryl or the chloro form of p-or trophenyl, etc., or carboruldiirnidazoia, etc., with the in e-rne io ante VTI .. The above reaction is carried out in a suitable organic solvent such as 2, 4, ñ-col i di na, 2, h-1 ut ia na, p L id i na, tetrahydrofuran, < + c, of a + ernperat u? under low cooling to ambient temperature in e. The derivative < The acetophenone TV used for the preparation of the above starting compound TT can be prepared as follows (1) according to a method described in .nalnal of Medicinal and Phar-maceut cal Chemist ry, Vol.%, P " 1054 (1962), for example, by reacting ', 6'- dihadroxy acetophenone with 2, 3, 4, 6-tetra-0-acet ii -of-D-glucopyranosyl bromide in the presence of potassium hydroxide in acetone aqueous, or di) for example, leading to reflux 2 ', F > '-dihi droxiacetophenone and bromide of 2, 3, 4, 6 - tetra ~ 0-acet i i - -D Ib Lucopyranosyl in the presence of cadmium carbonate in toluene. In the present invention, the lower alkanoalo group means a branched chain or straight chain alkanoalo group which has from 2 to 7 carbon atoms, for example, a group of acetyl, a group of propionyl, a group of butyl, a group of 2-mef to 1 propane, a group of valeryl, etc., preferably those with 2 to 5 volumes of car-bono. The lower alkoxycarbonyl group means a group of alkoxycarbonones in which the alkoxy portion is a branched chain or straight chain alkoxy group having 1 carbon atoms, preferably those having less than 1 carbon atom. to 4 carbon atoms, for example, a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbon group, an isopropoxycarbonyl group, a butoxycarbonyl group, an isobutoxycarbonyl group, a tert-buto and carbolic group, etc. .

EXAMPLES The following examples and reference examples are the specific explanation of the present invention, but the present invention should not be limited thereto.

EXAMPLE 1 2 '- (2,3-DT-0-Acetyl-ß-ü-gl-copyranosyloxy) h'-hi «JI? XI -3- (5-benzoCbl-f rani I) propiophenone (1000 mg) is dissolve in methanol (10 ml), and p-toluensul foni co (36 g) is added to it. The mixture is stirred at 40 ° C for 22.5 hours. After cooling, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution are added to the reaction solution, and the organic layer is obtained by separation, dried, and evaporated to remove the solvent. The resulting residue is purified by column chromatography of silica gel (solvent, chloroform-methanol) to give 2 '- (2-0-acetyl-ß-D-gl-ucopir-non-yl) -6' -hydroxy-4 - (5-ben oCb) furam 1) propiophenone (373 mg). p.f. 152-156 ° C FST ~ M (m / z): 509 [(M * Na) +] IR (nujol) cm-i;: 3450, 3350, 1750, 1630 NMR (DMSO-dβ) d: 1.98 (3H , s), 2.8- .1 (4H,? n), 3.26 (lH, rn), 3.4 -3.6 (3H, m), 3.72 (1.H, dd, 3--5.3, 10.2Hz), k. 67 (1H, t, J-5.6H2), 4 -76 (1H, "J d, J = 8.2, 9.5Hz), 5.12 (IH, d, J-- 8.1Hz), 5.27 (1H, d, J = 5.4Hz), 5.36 (1M, d, J 5.5Hz), 6.55 (1H, d, 3 ^ 8.1 Hz), 6.66 (1H, d, 3 = 8, .4Hz), 6.88 (1 H, dd, 3 ~ -ii .9, 2.2HZ), 7.17 (1H, t, J.-8.5Hz), 7.19 (LH, dd, 3 - 2.0, 8.5Hz), 7.48 (1H, d, 3-8.5Hz), 7.51 (lH, < i ,: l.6Hz), 7.93 (1H, d, 3 = 2.2Hz), 10.24 (ll-l, s) EXAMPLE 2 '- (, 6 -0-Oxomet ilen-ß-D-giucopirano iio) 6' -hydrox i -3- (5 ~ benzo [b] furaml)? Rop? of enone (? 794 mg) is dissolved in methanol (20 mg), and p-tol uensul foni co acid (32 mg) is added thereto. The mixture is stirred at temperature environment for 2 hours. To the reaction solution is added ethyl acetate and saturated aqueous sodium hydrogen carbonate solution, and the organic layer is obtained by separation, dried and evaporated to remove the solvent. The resulting residue is purified by colurnar chromatography on silica gel (solvent, chloroformnemphenol) to give 2 '- (4-0-rnetho-icarbona l-f3-I) -glucopran? A? Lox? ) -6 '-hydroxa-3- (5-benzo [b] furanyl-propylphenone (391 mg) as a yellow foam, ESI ~ MS (m / z): 525 [(M »Na) + ] IR (nu ol) crn-l .3420, 1750.1625 NMR (DMSO- <J6) d: 3.00 (2H, t, J = 7.5Hz), 3.2-3.6 (6H, rn), 3.66 (lll, rn), 3.72 (3H, s), 4.51 (1H, t, 3-.g .5Hz), 4.79 (1H, t, 3-5.5Hz), 5.06 (IH, d, 3 ^ 8, 1Hz), 5.5 i (1H, d, 3 = 5.9H), 5.57 (IH, d, 3 = 5.9Hz9, 6.56 (1H, < 1, J- 8.1 l-lz), 6.69 (1H,, 3 = 8.1 Hz), 6.09 (HI, "Id, 3 = 0.7.2.2Hz), 7.21 (1H, dd, 3 = 1.8, 8.4H z), 7.24 (LH, t, 3 = 8.4Hz), 7.47 (IH, d , 3 ~ 8.41-l) 7.53 (IH,, 3 --- 1.5Hz), 7.93 (lH, d, 302.2Hz), 10.89 (lH, s) REFERENCE EXAMPLE 1 (1) To a mixture of 2'- (2, 3, 4, 6-tetra-0-acet? 1-fi-D gl ucopyrosiloxy) -ñ'hydroxyacetophenone (965 mg), benzob is added. After carbaldehyde (350 mg) and ethanol (10 ml), a solution of 50% aqueous potassium hydroxide (2 ml) was added dropwise, and the mixture was stirred at room temperature overnight. The mixture evaporates to remove the solvent under reduced pressure, and water and dusopropyl ether are added to the residue. The mixture is stirred, and the aqueous layer is obtained by separation. The aqueous layer is neutralized using 10% hydrochloric acid under ice-cooling, and extracted with ethyl acetate. The resulting organic layer is washed with water, dried, and evaporated to remove the solvent for "Jar 2 '- (ß-D-glucopyranos? L-ox?) -6' - hydrox i -3- ( 5 - I> enzo [b] fu ram 1) acri 1 ot enona c ruda (?) The product of this form obtained is added to a solution of hydride «Je tellurium sodium in ethanol (15 ml), which it is prepared previously of tellurium (383 ing) and sodium borohydride (270 rng), and the mixture is reacted at room temperature for 2.5 hours. The insoluble materials are re-ovulated by filtration, and water and ethyl acetate are added to the filtrate. The mixture is stirred and the organic layer is obtained by separation washed with water, dried and evaporated to remove the solvent. The residue is purified by silica gel column chromatography to give 2 '(ß-D-gl ucopy anosiioxy) -6'-h? Drox? -3- (5-benzoCb 3-furaniJ) propiophenone (480 mg). (3) To a mixture of the product obtained in example 2 above (444 mg) and di chloro-methane (8 ml) is added dimethyl acetal of benzaldehyde (304 mg) and pt oluenesulphonic acid (19 mg), and the mixture is stirred at room temperature for 2 hours. The mixture is evaporated to remove the solvent under re fl uxed pressure, and the resulting residue is dissolved < ? n acetate? eti lo. The organic layer is washed with water, dried, and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent, chloroform-methanol) to give 2 '(4,6-0 ~ benzyl iden ~ f -D ~ glucoprans? Lox?) - 6' -hydro i- 3- (5-L> enzo [blfuran? 1) own phenone (584 mg). (4) The product obtained in Example 3 above (578 g) is dissolved in pyridine (5 ml), and to the ism is added acetic anhydride (665 mg). The mixture is stirred at room temperature for four hours. Ethyl acetate is added to the reaction solution, and the mixture is poured into a mixture of ice and 10% hydrochloric acid. The mixture is stirred, and the organic layer is obtained by separation, washed with water, dried, evaporated to remove the solvent to give 2 '- (2,3-d? -0-acet? -4-6. ~ 0 ~ ben? L iden-ß-D- gl ucopí ranos i lo xi) - 6 '- acetoxi -3- (5-benzo-Cblfuran? L) own phenone (724 ing) raw, (5) The product ob + enu1o in example 4 above (720 ing) is dissolved in a mixture of tetrahydrofuran-me anol (10 mi -10 rni), and sodium hydrogen carbonate (428 mg) and water (0.1 ml) are added thereto, and the mixture is stirred at 50 ° for 6.5 hours. The residual sodium hydrogen carbonate is removed by filtration, and the filtrate is concentrated under reduced pressure. The resulting residue is dissolved in ethyl acetate, and the solution is washed with water, dried and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform-ethyl acetate) couple to give '2' - (2, 3-d? -0-acet? l ~ 4,6-ü-benziliden-β-D-glucopyranosyl i) -6'-h? drox ? - 3- (5-benzoCbl furaml) propiophenone (520 mg). (ñ) The product obtained in the previous example 5 (121 mg) is dissolved in acetic acid (5 ml), and water (0.5 ml) and p-toluensulfomer acid (5 mg) are added thereto. The mixture is stirred at room temperature for 4.5 hours, and water and acetate are added thereto < 1e ethyl. The mixture s-? stir, and the organic layer is obtained by separation, washed with water, dried, and evaporated to remove the solvent. The resulting residue is purified by silica gel column chromatography (solvent, chloroform-methane I) to give 2 '- (2, 3- "i? -0-acetyl-β-D-glucopyranosyloxy) -6' -hydrox? -3- (5-benzo [b] f uraml) pro ?? ofenone (91.5 mg). mp "127-129 ° C TABM (/): 55 L [(M» Na +] NMR (DMS0- < J6) G: 1.92 (31-1,), 2.00 (3H, s), 2.85-3.05 ( 4H, m), 3.45- 3.75 (4H, in), 4.75 (LH,, 3 --5.4H), 4.87 (IH, «Id, 3 ^ -8.0.9.8Hz), 5.09 (1H, *, 3 = 9.7Hz), 5.36 (1H, d, 3- = 7"9Hz), 5.55 (1H, d, 3--5.6Hz), 6.57 (IH, d, 3 -.7.0 Hz), 5.68 (LH, d , 3 = 8.iHz), 6..88 and 1H, d, 3 ^ 2.2Hz), 7.17 (IH, d, H --- 9.6Hz), 7. 19 (1H, t, 3 ^ 8.3HZ), 7.48 (IH, d, H 9.3Hz), 7.49 (IH, «J, 3 = 1" 0Hz), 7.93 (1H, d, 3 = 2.2Hz), 10.28 (lH, s) REFERENCE EXAMPLE 2 2 '(ß-T) -Glucop? years? loxi) -6 '-ha droxi - 3- (5-benzo [bl furanyl) -propio-phenone (1.333 g) is dissolved in 2, 4, 6-col? di na (15 i). The solution is cooled to -40 ° C with dry ice-acetone, and a solution of p-nitrophenyl cloi ofor-mato (78b rng) in methylene chloride (3 rnl) ba or stirring is added thereto by dropping. The solution is stirred at -40 ° C for 1 hour and 45 minutes, subsequently stirred at room temperature for one hour, and then stirred at 50 ° C for 6.5 hours. After cooling, the reaction solution is poured into cold 10% hydrochloric acid, and extracted with ethyl acetate. The organic layer is washed with water, dried, and evaporated to remove the solvent. The residue is purified by chromatography on a column of silica gel (solvent, chloroform-acetone) to give-? '- (4, 6-0-oxomet i len-ß-D-gl ucopi r-anosiloxy) -6'-h? Drox? -3- (5-benzoC 1 furam 1) own phenone (994 rng) .. mp 70 ° C: - (slowly decomposed) F Al) - MS (m / z): 493 C (M • Na) +] [R (nuj? l) c? n-? : 3400, 1750, lb2Q NMR (DM O-d6) 6: 2, 98 (2H, t, 3 = 7.5Hz), 3.2 (2H,), 3.33 (1H, m), .63 (lH, rn), 4.13 (lH, m), 4. I 7 (IH, dd, 3 = 8.9, 9.5Hz), 4.25 (1H, dd, 3 ^ 9.5, 9. BH z), 4.47 (1 H, dd, 3 = 5.5, .2Hz), 5.21 (1H, d, 3 ~ - 7. gHz), 5.77 (IH, d, 3 = 5.9Hz), 5.84 (lH, d, J-5.5Hz), b .58 (LH, d, 3 = .1Hz), 6.68 ( LH, "J, 308.1Hz), 6.88 (lH, dd, J-- 0.9, 2.2Hz), 7.19 (1H, dd, 3 = 1.8, 8.5Hz), 7, 24 (LH, t, 3 = 8. JHz), 7.48 (LH, d, J-8.5H2),? .50 (1H, d, ^ 1. BHz), 7.93 (1H, d, 3- = 2.2Hz), 10.73 (1 H, s ) EFFECTS OF THE INVENTION The compounds [13 of the present invention and the pharmaceutically acceptable salts thereof have excellent hapoglycemic activity. For example, when administered orally to rats, the present compounds described in the examples increased the amount of glucose in the urine more than 50 times as increased by flonzine. In addition, the compounds [T] have low toxicity. In addition, the agli ices of the compounds [T] and the hydrolysates of the same, show extremely weak inhibitory activity against the facilitated diffuser-type glucose transporter. Therefore, the compounds [1] of the present invention can treat hyperglymia, by which the cycle of self-aggravation of glucose toxicity is interrupted, so that the compounds [1] are useful in the prophylaxis or treatment of diabetes (eg, diabetes mellitus, insulin-dependent diabetes (type T diabetes) and insulin-dependent diabetes m (type TT diabetes).

Claims (2)

1. NOVELTY OF THE INVENTION CLAIMS A derivative «le propioferona of formula 1 wherein R 'is a lower alkanoyl group, and R "is a hydrogen atom, or R" is a lower akoxycarbonyl group, or a pharmaceutically acceptable salt thereof.
2. 2. The compound in accordance with the rei indication 1, is furthermorereferred because R 'is a lower alkanoyl group, and R "is a hydrogen atom 3.- The compound according to the present invention, characterized in addition because R 'is a hydrogen atom, and R "is a lower alkoxycarbonyl group. 4.- A procedure to prepare a propiophenone derivative of the formula (T a) OFV or wherein R 'is a lower alkanoyl group-, or a pharmaceutically acceptable salt thereof, which is to react a proper phenone compound of the formula wherein R 'is the same as defined above, with an alcansulonic acid or an apulsulphonic acid, and if desired, converting the product into a pharmaceutically acceptable salt thereof. 5. A process for preparing a propiophenone derivative of the formula (T-b): wherein R "is a lower alkoxycarbonyl group, or a pharmaceutically acceptable salt thereof, which is to react a propiophenone compound of the formula (pr): with a lower alkanol and an alcansulonic acid or an arylsul acid. phonic, and if desired, the product is converted to a pharmaceutically acceptable salt thereof. 6. A pharmaceutical composition consisting of a therapeutically effective amount of the compound mentioned in claim 1, mixed with a pharmaceutically acceptable carrier or diluent. 7. ~ A use of a compound in accordance with the claim 1, in the production of a drug for the prophylaxis or treatment of diabetes. 8. 2 '- (2-O-Acetyl-β-D-glucopyranosyloxy) -6' -hydroxy-3- (5-benzo [b] -furanyl) propiophenone.