CN1253136A - Thiazolidine derivatives and medicinal application thereof - Google Patents
Thiazolidine derivatives and medicinal application thereof Download PDFInfo
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- CN1253136A CN1253136A CN 99120250 CN99120250A CN1253136A CN 1253136 A CN1253136 A CN 1253136A CN 99120250 CN99120250 CN 99120250 CN 99120250 A CN99120250 A CN 99120250A CN 1253136 A CN1253136 A CN 1253136A
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- thiazolidine
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Abstract
The present invention relates to thiazolidine derivatives, its chemical formula, its preparing process and the application of the medicinal composition containing said compound in the prevention and treatment of hyperglycemia.
Description
The present invention relates to thiazolidine salt derivative, its preparation method contains the pharmaceutical composition of these compounds and their hypoglycemic activity.
PCT patent WO9405659 has described some and has had general formula (II) the thiazolidine biology of hypoglycemic activity.
M wherein
-Represent pharmaceutically acceptable acid radical anion.
But the solubleness of the maleate of general formula (II) compound that discloses from the document, its solubleness in the aqueous solution is lower, is unfavorable for the preparation of oral preparations.
The objective of the invention is to seek and have good water miscible new thiazolidine salt derivative.
One group of compound in the discoverable type (I) has good solubleness in the aqueous solution now, demonstrates good hypoglycemic activity simultaneously.For example, in room temperature water solution and neutral physiological buffer solution, the solubleness 〉=45mg/ml of formula (I) compound.Moreover the compound in the formula (I) has also shown satisfactory stability under solid conditions.But character that these compounds are soluble in water and good Pickering provide the good biological availability, thereby can prepare various preparations in a large number and effectively.
Therefore, the invention provides the compound that a class has general formula (I):
M wherein
+Receivable metallic cation on the expression medicine, n is the integer of 1-4.
Preferred metallic cation is basic metal or alkaline earth metal cation.
Preferred alkali metal cation is sodium or potassium ion.
According to the present invention, preferred formula (I) compound is 5-(4-(2-(N-methyl-N-(2-pyridyl) amino) oxyethyl group) benzyl) thiazolidine-2,4-diketone sodium salt.
Should be appreciated that formula of the present invention (I) compound salt also comprises acceptable solvent thing and hydrate on its appropriate drug.
The invention still further relates to the pharmaceutical composition that is used to prevent or treat hyperglycemia, it comprises formula I compound and pharmaceutical carrier,
Wherein, M
+Represent pharmaceutically acceptable metallic cation, n is the integer of 1-4.
According to the present invention, formula I compound of the present invention can use separately or use with the form of pharmaceutical composition.Pharmaceutical composition of the present invention can pass through oral, non-enteron aisle or topical administration.Form of administration has for example: tablet, capsule, solution, injection liquid, suppository, patch, ointment etc.
According to the present invention, pharmaceutical composition of the present invention can prepare by means known in the art, for example formula I compound is mixed with pharmaceutical carrier.
According to the present invention, formula I compound of the present invention can pass through 5-(4-(2-(N-methyl-N-(2-pyridyl) amino) oxyethyl group) benzyl) thiazolidine-2, and (Cantello is seen in its preparation to the 4-diketone, B.C.C, Cawthorne, M.A., Cottam, G.P., Deng the people, pharmaceutical chemistry magazine (J.Med.chem.), 1994, described in the 37:3977-85) and basic metal or alkaline-earth alkoxides such as ethanol an alkali metal salt prepared in reaction.
According to the present invention, the solubleness of The compounds of this invention can be measured with the solubility test method of standard.For example in room temperature water solution and neutral physiological buffer solution, the solubleness 〉=45mg/ml of sodium salt in formula (I) compound, and in similarity condition following formula (II) compound solubleness of maleate less than 10mg/ml.Therefore formula (I) compound is compared in the aqueous solution and neutral physiological buffer solution with formula (II) compound and is had the solubleness that significantly improves, this character be formula (I) but the biology availability of compound, a large amount of use and effectively prepare preparation advantage is provided.
According to the present invention, formula I compound of the present invention has satisfactory stability and this stability can be used conventional determination of quantitative analysis.For example formula I compound stability can be tested with accelerated stability and be measured, as at 40 degrees centigrade, and 75% relative humidity; 40 degrees centigrade, 92.5% relative humidity; And 80 degrees centigrade, the stability of mensuration formula I compound.Analysis can be used thin-layer chromatography, dsc, and the isothermal experiment under thermo-gravimetric analysis and the intensification carries out.The quantitative analysis of experimental compound is that sampling is carried out before storage period, between storage period and after storage period.
The present invention also provides formula (I) compound and/or its pharmaceutically acceptable solvate or its hydrate that is used for the treatment of and/or prevents hyperglycemia.
Formula (I) compound can, purifying synthetic with the following example, crystallization and carry out thermostability and the water absorbability analysis, and embodiment is used to illustrate the present invention, but without any restriction.
Embodiment 1
5-(4-(2-(N-methyl-N-(2-pyridyl) amino) oxyethyl group) benzyl) thiazolidine-2,4-diketone sodium salt.
The sodium Metal 99.5 of 32mg is dissolved in the 5ml dehydrated alcohol, reflux to sodium disappears, then the above-mentioned sodium ethylate that makes is added drop-wise to 500mg5-(4-(2-(N-methyl-N-(2-pyridyl) amino) oxyethyl group) benzyl) thiazolidine-2 that is dissolved in the 25ml dehydrated alcohol, in the 4-diketone.Beginning to keep temperature of reaction is zero degree, dropwise reaction is warmed up to room temperature gradually, stirring is spent the night, and mother liquor is concentrated, and adds ether and stirs, filter, with the resulting solid of ether repetitive scrubbing, vacuum-drying obtains 5-(4-(2-(N-methyl-N-(2-pyridyl) amino) oxyethyl group) benzyl) thiazolidine-2,4-diketone sodium salt, 426mg (yield 84.7%), m.p.215 ℃ (decomposition).
1HNMR δ (ppm) (400MHZ, d
6-DMSO): 3.0-3.3 (2H, multiplet), 3.1 (3H, unimodal), 3.9 (2H, triplets), 4.1 (2H, triplet), 4.2 (1H, multiplets), 6.5-6.7 (2H, multiplet), 6.8 (2H, bimodal), (7.1 2H, bimodal), 7.5 (1H, triplets), 8.1 (1H, bimodal).
Embodiment 2
5-(4-(2-(N-methyl-N-(2-pyridyl) amino) oxyethyl group) benzyl) thiazolidine-2, the thermostability of 4-diketone sodium salt.
5-(4-(2-(N-methyl-N-(2-pyridyl) amino) oxyethyl group) benzyl) thiazolidine-2,4-diketone sodium salt sample are put into 80 ℃ of baking oven bakings, and respectively the 0th, 3, sampling in 8,15 days is used the HSGF-254 silica-gel plate, CHCl
3: CH
3OH=10: 0.3 developping agent, carry out thin-layer chromatographic analysis, under ultraviolet 254nm wavelength, the R of all samples
f=0.51, this shows that the sample composition does not have decomposition.
Embodiment 3
5-(4-(2-(N-methyl-N-(2-pyridyl) amino) oxyethyl group) benzyl) thiazolidine-2, the sucting wet stability of 4-diketone sodium salt.
5-(4-(2-(N-methyl-N-(2-pyridyl) amino) oxyethyl group) benzyl) thiazolidine-2,4-diketone sodium salt sample is put into 40 ℃ of constant temperature respectively, is equipped with in the moisture eliminator of saturated KNO3 solution (relative humidity 92.5%) and saturated NaCl solution (relative humidity 75%).Be placed on sample in 92.5% relative humidity respectively 0,8, sampling in 15 days: be placed on sample in 75% relative humidity respectively 0,8, sampling in 15,45 days is used the HSGF-254 silica-gel plate, CHCl
3: CH
3OH=10: 0.3 developping agent, carry out thin-layer chromatographic analysis, under ultraviolet 254nm wavelength, the R of all samples
f=0.51, this shows sample composition no change.
Claims (6)
1. formula (I) compound or its solvate or its hydrate:
Wherein: M
+Receivable metallic cation on the expression medicine, n is the integer of 1-4.
2. the compound of claim 1, wherein M
+Be basic metal or alkaline earth metal cation.
3. claim 1 or 2 compound, wherein M
+Be sodium ion or potassium ion.
4. the compound of claim 1, it is 5-(4-(2-(N-methyl-N-(2-pyridyl) amino) oxyethyl group) benzyl) thiazolidine-2,4-diketone sodium salt.
5. the pharmaceutical composition that contains formula (I) compound or its solvate or its hydrate and pharmaceutical carrier.
Formula (I) compound or contain formula (I) compound/or its medicinal solvent thing or its medicinal compound of hydrate be used for the treatment of and/or prevent application in the medicine of hyperglycemia in preparation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB991202503A CN1183130C (en) | 1999-09-24 | 1999-09-24 | Thiazolidine derivatives and medicinal application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB991202503A CN1183130C (en) | 1999-09-24 | 1999-09-24 | Thiazolidine derivatives and medicinal application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1253136A true CN1253136A (en) | 2000-05-17 |
| CN1183130C CN1183130C (en) | 2005-01-05 |
Family
ID=5281443
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB991202503A Expired - Lifetime CN1183130C (en) | 1999-09-24 | 1999-09-24 | Thiazolidine derivatives and medicinal application thereof |
Country Status (1)
| Country | Link |
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| CN (1) | CN1183130C (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001044240A1 (en) * | 1999-12-18 | 2001-06-21 | Richter Gedeon Vegyészeti Gyár Rt. | Antidiabetic thiazolidinediones and their preparation |
| WO2002026736A1 (en) * | 2000-09-29 | 2002-04-04 | Smithkline Beecham P.L.C. | A thiazolidinedione derivative and its use as antidiabetic |
| WO2002060899A1 (en) * | 2001-01-31 | 2002-08-08 | Laboratorios Vita, S.A. | New salt of thiazolidinedione and its polymorphs as antidiabetic agents and method for obtaining them |
| JP2004508369A (en) * | 2000-09-06 | 2004-03-18 | スミスクライン ビーチャム パブリック リミテッド カンパニー | Hydrochloride salt of 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione |
| JP2004509959A (en) * | 2000-09-29 | 2004-04-02 | スミスクライン ビーチャム パブリック リミテッド カンパニー | 5-'4-'2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione sodium salt |
-
1999
- 1999-09-24 CN CNB991202503A patent/CN1183130C/en not_active Expired - Lifetime
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001044240A1 (en) * | 1999-12-18 | 2001-06-21 | Richter Gedeon Vegyészeti Gyár Rt. | Antidiabetic thiazolidinediones and their preparation |
| EP1475378A1 (en) * | 1999-12-18 | 2004-11-10 | Richter Gedeon Vegyeszeti Gyar R.T. | Antidiabetic thiazolidinedione potassium salt |
| JP2004508369A (en) * | 2000-09-06 | 2004-03-18 | スミスクライン ビーチャム パブリック リミテッド カンパニー | Hydrochloride salt of 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione |
| WO2002026736A1 (en) * | 2000-09-29 | 2002-04-04 | Smithkline Beecham P.L.C. | A thiazolidinedione derivative and its use as antidiabetic |
| JP2004509960A (en) * | 2000-09-29 | 2004-04-02 | スミスクライン ビーチャム パブリック リミテッド カンパニー | Thiazolidinedione derivatives and their use as antidiabetic agents |
| JP2004509959A (en) * | 2000-09-29 | 2004-04-02 | スミスクライン ビーチャム パブリック リミテッド カンパニー | 5-'4-'2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione sodium salt |
| AU2001292034B2 (en) * | 2000-09-29 | 2005-04-21 | Smithkline Beecham P.L.C. | A thiazolidinedione derivative and its use as antidiabetic |
| EP1795531A1 (en) * | 2000-09-29 | 2007-06-13 | Smithkline Beecham Plc | A thiazolidinedione derivative and its use as antidiabetic |
| CN100345846C (en) * | 2000-09-29 | 2007-10-31 | 史密斯克莱·比奇曼公司 | Sodium sal ts of 5'-4'-2-(N-methyl-N-(2-pyridyl)amino) ethoxy [benzyl] thiazolidine-2,4-dione |
| CN1915992B (en) * | 2000-09-29 | 2010-05-12 | 史密斯克莱.比奇曼公司 | Sodium salts of 5-'4-'2-(n-methyl-n-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione |
| CN1620453B (en) * | 2000-09-29 | 2010-12-08 | 史密斯克莱·比奇曼公司 | Thiazolidinedione derivative and its use as antidiabetic |
| WO2002060899A1 (en) * | 2001-01-31 | 2002-08-08 | Laboratorios Vita, S.A. | New salt of thiazolidinedione and its polymorphs as antidiabetic agents and method for obtaining them |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1183130C (en) | 2005-01-05 |
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Owner name: TAIJI GROUP CO., LTD. Free format text: FORMER OWNER: INST OF TOXIC MEDICINAL MATERIALS, P.L.A. ACADEMY OF MILITARY MEDICAL SCIENCES Effective date: 20070202 |
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Effective date of registration: 20070202 Address after: 401147 No. 38 Huanglong Road, Chongqing, Yubei District Patentee after: Taiji Group Co., Ltd. Address before: 100850 No. 27 Taiping Road, Beijing Patentee before: Institute of Poisonous Substance and Medicine of Military of Military academy of medical sciences of |
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Granted publication date: 20050105 Termination date: 20130924 |
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Former decision: cessation of patent right due to non-payment of the annual fee Former decision publication date: 20141126 |
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| CX01 | Expiry of patent term |
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