WO2013044608A1 - Anomeric alkyl-containing phenyl c-glucoside derivative, preparation method therefor and use thereof - Google Patents
Anomeric alkyl-containing phenyl c-glucoside derivative, preparation method therefor and use thereof Download PDFInfo
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- WO2013044608A1 WO2013044608A1 PCT/CN2012/071451 CN2012071451W WO2013044608A1 WO 2013044608 A1 WO2013044608 A1 WO 2013044608A1 CN 2012071451 W CN2012071451 W CN 2012071451W WO 2013044608 A1 WO2013044608 A1 WO 2013044608A1
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- 0 *C(*)[C@@]([C@]([C@@]1O)O)(c2cncc(*(*)c3ccccc3)c2)O[C@](CO)[C@]1O Chemical compound *C(*)[C@@]([C@]([C@@]1O)O)(c2cncc(*(*)c3ccccc3)c2)O[C@](CO)[C@]1O 0.000 description 2
- XTNGUQKDFGDXSJ-ZXGKGEBGSA-N Cc1ccc([C@@H]([C@@H]([C@H]2O)O)O[C@H](CO)[C@H]2O)cc1Cc1ccc(-c(cc2)ccc2F)[s]1 Chemical compound Cc1ccc([C@@H]([C@@H]([C@H]2O)O)O[C@H](CO)[C@H]2O)cc1Cc1ccc(-c(cc2)ccc2F)[s]1 XTNGUQKDFGDXSJ-ZXGKGEBGSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/10—Oxygen atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Definitions
- Phenyl C-glucoside derivative containing anomeric alkyl group preparation method and use thereof
- the present invention relates to the field of medicines associated with diabetes.
- the present invention relates to a type 2 sodium glucose co-transporter (SGLT2) inhibitor having an alkyl group-containing phenyl C-glucoside structure in an anomeric position, and a method for preparing the same, and a method for preparing the same Pharmaceutical composition.
- SGLT2 type 2 sodium glucose co-transporter
- the antidiabetic drugs currently used in clinical practice mainly include diterpenoids, sulfonylureas, insulins, thiazolidinediones, ⁇ -glucosidase inhibitors and dipeptidyl peptidase-IV inhibitors. These drugs have good therapeutic effects, but there are safety problems in long-term treatment, such as: liver toxicity, some drugs still have weight gain and many other problems.
- Type 2 sodium glucose co-transporter is a new target for the treatment of diabetes found in recent years.
- SGLT2 is mainly distributed in the proximal tubules of the kidney. Its function is to absorb the glucose in the urine and return it to the blood. Therefore, inhibition of SGLT2 can reduce the concentration of glucose in the blood. This method reduces blood sugar levels by different ways from the past. . When SGLT2 is blocked, more glucose is secreted in the urine, which will help diabetics maintain the correct blood sugar levels. Since the SGLT2 inhibitor does not interfere with glucose metabolism, it can be used as a supplement to mainstream blood glucose control methods.
- Chinese Patent CN200610093189.9 discloses a compound of the following structure as an SGLT2 inhibitor:
- Chinese Patent CN200480006761.2 discloses compounds of the following structure as SGLT2 inhibitors:
- Another object of the invention is to provide a process for the preparation of a compound of formula I or a pharmaceutically acceptable salt or prodrug ester thereof.
- a further object of the present invention is to provide a compound containing Formula I, or a pharmaceutically acceptable salt or prodrug ester thereof, as an active ingredient, together with one or more pharmaceutically acceptable carriers, excipients and/or Or a pharmaceutical composition of a diluent, and its use in the treatment of diabetes.
- the anomeric alkyl-containing phenyl C-glucoside derivatives provided by the present invention are novel SGLT2 inhibitors, and these inhibitors lay the foundation for the preparation of drugs which can be further used for the treatment of diabetes, especially non-insulin dependent diabetes. . invention
- the present invention provides a compound represented by (I)
- R 1 is selected from the group consisting of alkyl of dC 5 , which is optionally substituted with one or more groups selected from F, Cl, Br, I and OH;
- R 2 and R 3 are independently selected
- R 4 and R 5 are independently selected from H, C r C 5 alkyl group containing 3-5 carbon atoms and a cycloalkyl group OR 8, wherein R 8 is selected from C r C 5 alkyl group or an 3-5 a cycloalkyl group of a carbon atom, the alkyl group or a cycloalkyl group being optionally substituted by one or more atoms selected from the group consisting of F and C1;
- R 6 and R 7 are independently selected from the alkyl group of H and C r C 5 , or R 6 and R 7 together with the carbon atom to which they are attached form a cycloalkyl group having 3 to 5 carbon atoms.
- R 1 is selected from alkyl of dC 3 , which is optionally substituted with one or more groups selected from the group consisting of F and OH;
- R 2 and R 3 are independently selected from H, OH, dC 3 alkyl, F, Cl, CN, N0 2, CF 3, OR 8, SMe and cyclopropyl, wherein R 8 is selected from a C r C 3 alkyl
- the alkyl or cyclopropyl group is optionally substituted with one or more F atoms;
- R 4 and R 5 are independently selected from H, dC 3 alkyl, cyclopropyl and OR 8 , wherein R 8 is dC 3 alkyl or cyclopropyl, said alkyl or cyclopropyl optionally being one or Multiple F atoms substituted; R 6 and R 7 are independently selected from the group consisting of 11 and i-C 3 alkyl groups, or R 6 and R 7 and the carbon atom to which they are attached form a cyclopropyl group.
- the compound represented by (I) is selected from
- R 9 R 1G CH R 1 in the above route;
- Compound V is treated with a strong base and then reacted with Tf 2 0 to obtain Compound X, preferably the strong base is lithium diisopropylamide (LDA);
- compound XII 1 2 processing occurs cyclized compound XIII; compound XIII with «-Bu 3 SnH and azobisisobutyronitrile (AIBN) treatment to remove iodine to obtain compound XIV;
- compound XIV is treated with DDQ to remove the PMB protecting group to obtain compound I;
- -R 7 is as defined above, R 9 and R 1G is independently selected from the group consisting of H and C r C 4 alkyl groups.
- a pharmaceutically acceptable prodrug ester of a compound of formula I according to the invention comprising any one or more of the hydroxyl groups in the molecule formed with an acetyl group, a pivaloyl group, various phosphoryl groups, aminodecanoyl groups, alkanoyl groups, and the like Ester.
- the compounds of formula I of the present invention may be formulated into pharmaceutical compositions by mixing with one or more pharmaceutically acceptable carriers, excipients and/or diluents.
- the pharmaceutical composition can be formulated into a solid oral preparation, a liquid oral preparation, and an injection.
- the solid and liquid oral preparations include: Tablets, dispersible tablets, chewable tablets, coated tablets, granules, dry powders, capsules and solutions.
- the injection includes: a small needle, a large infusion, and a lyophilized powder needle.
- the pharmaceutical composition according to the present invention comprises a pharmaceutically acceptable excipient selected from the group consisting of: a filler, a binder, a disintegrant, a lubricant, a glidant, an effervescent, and a flavor.
- a pharmaceutically acceptable excipient selected from the group consisting of: a filler, a binder, a disintegrant, a lubricant, a glidant, an effervescent, and a flavor.
- Agents, preservatives, coating materials, surfactants, pH adjusters and stabilizers are examples of a pharmaceutically acceptable excipient selected from the group consisting of: a filler, a binder, a disintegrant, a lubricant, a glidant, an effervescent, and a flavor.
- Agents, preservatives, coating materials, surfactants, pH adjusters and stabilizers selected from the group consisting of: a filler, a binder,
- the filler comprises one of lactose, sucrose, dextrin, starch, pregelatinized starch, mannitol, sorbitol, dibasic calcium phosphate, sulfuric acid 4 bow, carbonic acid 4 bow and microcrystalline cellulose or
- binders include sugar, starch, povidone, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl cellulose, mercapto cellulose, polyethylene glycol, medicinal ethanol and One or more of the water;
- the disintegrant comprises starch, cross-linked poly-microketone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, effervescent
- the lubricant comprises magnesium stearate;
- the glidant comprises talc;
- the flavoring agent comprises a flavor and aspartame;
- the surfactant comprises a polka Sham, sodium lauryl sulfate, Twe
- the compound of the formula I of the present invention has an inhibitory action on the SGLT2 enzyme and can be used as an active ingredient for the preparation of a therapeutic drug for diabetes.
- the activity of the compounds of formula I according to the invention is verified by an in vivo hypoglycemic model.
- the compounds of formula I of the present invention are effective over a relatively wide dosage range.
- the daily dose is about 1 mg - 1000 mg / person, divided into one or several times.
- the dosage of the compound of formula I of the present invention may be determined by the physician in accordance with the circumstances. These conditions include: the physical condition of the subject, the route of administration, age, weight, individual response to the drug, severity of symptoms, and the like. The best way to implement the invention
- the compounds 1 to 1 and ⁇ -1 to: IX-1 in the above synthetic route are each one of the compounds represented by the corresponding I and III to IX.
- the THF was dissolved, and the flask was purged with nitrogen and then quickly sealed with a rubber stopper.
- the flask was cooled in an ice bath at -10 °C, and 25 mL of a 1.0 M compound ⁇ -1 in THF was slowly added dropwise with a syringe. After the completion of the dropwise addition, the resulting reaction mixture was stirred at room temperature overnight.
- the flask was again cooled in an ice water bath, and a solution prepared by dissolving 2.75 g of TBDPSC1 (tert-butyldiphenylchlorosilane) in 2 mL of dry THF was slowly added dropwise by a syringe, and the resulting solution was stirred at room temperature for 2 hours.
- TBDPSC1 tert-butyldiphenylchlorosilane
- reaction mixture was stirred at -78 ° C for 1 hour, and then heated to -20 ° C, and then slowly added dropwise with a syringe to the above-prepared V-1 (6.95 g) dissolved in 5 mL of dry THF. After the dropwise addition, the resulting mixture was stirred at room temperature for 1 hour.
- the compound IX-1 (3.85 g) prepared above was added to a 100 mL round bottom flask, dissolved in 40 mL of dichloromethane, stirred at room temperature, and then 9.00 g of DDQ and 4 mL of water were added in sequence, and the mixture was obtained. After stirring at room temperature overnight, the temperature was refluxed for 3 hours. At this point TLC showed the reaction was complete.
- a 100 mL dry round bottom flask was charged with 1.01 g of dry-Pr 2 NH and 10 mL of dry THF.
- the flask was purged with nitrogen and quickly sealed with a rubber stopper, and then cooled in liquid nitrogen-ethanol at -78 °C to start electromagnetic stirring.
- 6.2 mL of a 1.6 M solution of w-BuLi in n-hexane was slowly added dropwise with a syringe, and the resulting solution was stirred at the temperature for 1 hour.
- a solution of 9.13 g of dry V-1 dissolved in 10 mL of dry THF was added dropwise with a syringe.
- the resulting reaction mixture was further stirred at -78 ° C for 1 hour, and then a solution prepared by dissolving 2.82 g of Tf 2 0 in 2 mL of dry THF was slowly added dropwise with a syringe. After completion of the dropwise addition, the resulting reaction mixture was slowly warmed to room temperature and stirring was continued for 1 hour.
- Example 1 was passed through an 80 mesh sieve.
- Example 2 was passed through an 80 mesh sieve.
- Example 4 The sample of Example 4 was passed through an 80 mesh sieve and the auxiliary material was passed through a 60 mesh sieve.
- the sample of Example 4 was weighed according to the prescription, the povidone, aspartame and the essence were firstly mixed uniformly, and then mixed with mannitol, microcrystalline cellulose and lactose in order, and then uniformly mixed with magnesium stearate. Intermediate content, tableting, packaging.
- Example 22 Capsule
- Example 5 The sample of Example 5 was passed through an 80 mesh sieve, and the other auxiliary materials were passed through a 60 mesh sieve.
- the sample of Example 5 the calcium hydrogen phosphate, the croscarmellose sodium and the lactose were weighed uniformly according to the prescription amount, and mixed with a 2% (w/v) aqueous solution of hydroxypropylcellulose to prepare a soft material and sieved.
- the wet granules were dried at 55 °C.
- Magnesium stearate and talc powder were externally added to the above granules, and the content of the intermediate was measured, and the No. 3 capsule was placed and packaged.
- Example 24 Injection of citric acid to 40 ml of water for injection, stir and dissolve, then add the sample of Example 8, dissolve it by heat, adjust the pH to 4.0-6.0, add 1% activated carbon based on the weight of the whole injection, at room temperature. Stir for 20 minutes and measure the pH. Filter, decarbonize, add water for injection to the full amount. Packed in 5 ml per ampere, nitrogen filled, sealed. The mixture was sterilized at 121 ° C for 30 minutes to obtain an injection.
- Example 24 Injection 50 ml of water for injection.
- citric acid to 40 ml of water for injection, stir and dissolve, then add the sample of Example 8, dissolve it by heat, adjust the pH to 4.0-6.0, add 1% activated carbon based on the weight of the whole injection, at room temperature. Stir for 20 minutes and measure the pH. Filter, decarbonize, add water for injection to the full amount. Packed in 5 ml per ampere, nitrogen filled, sealed. The mixture was sterilized at 121 ° C
- Preparation process Take 80 mL of water for injection, add the sample of Example 10, mannitol, lactose and poloxamer to dissolve according to the prescription amount, and then adjust the pH to 6.0 - 8.0 by adding citric acid or sodium hydroxide, and add water for injection to 100mL. Add 0.5g of activated carbon, stir at 30 ° C for 20 minutes, decarbonize, filter and sterilize by microfiltration membrane, the filtrate is divided into 1 mL each, after pre-freezing for 2 hours, freeze under vacuum for 12 hours, until After the temperature of the sample reached room temperature, it was dried for another 5 hours to obtain a white loose mass, which was obtained by sealing.
- Example 26 Granules
- Example 11 The sample of Example 11 was passed through an 80 mesh sieve, and the auxiliary material was passed through a 60 mesh sieve. Weigh the prescribed amount of lactose, mannitol, aspartame, essence and sample mixed well with Example 11, add 2% (w/v) hydroxypropionate aqueous solution to soft material, 16 mesh sieve, 55° C dry, 14 mesh sieve granules, determination of intermediate content and moisture, packaging, a total of 100 bags of granules were prepared.
- Example 27 The sample of Example 11 was passed through an 80 mesh sieve, and the auxiliary material was passed through a 60 mesh sieve. Weigh the prescribed amount of lactose, mannitol, aspartame, essence and sample mixed well with Example 11, add 2% (w/v) hydroxypropionate aqueous solution to soft material, 16 mesh sieve, 55° C dry, 14 mesh sieve granules, determination of intermediate content and moisture, packaging, a total of 100 bags of granules were
- Example 1-2, 4-5, 8-12, 14 and 16-18 listed in Table 1 below were formulated at a concentration of 5 mg/mL with 1% (w/v) sodium carboxymethyl cellulose.
- the suspension was administered at a dose of 0.2 mL/20 g body weight, equivalent to a 10 mg/kg dose.
- Healthy ICR mice half male and half female, weigh 20-24 g, in line with the first grade standard.
- the animals were fasted for 16 h, 2 g/kg of dextrose solution was injected intraperitoneally 2 h after administration (glucose was injected 1.5 h after Dapagliflozin administration), and capillary was used at 0.5 h, 1.0 h, 1.5 h, 2.5 h and 3 h after modeling.
- the blood was taken from the posterior venous plexus of the mouse, and the serum was separated by centrifugation. The serum glucose content at each time point was measured by the glucose oxidase method (the results are shown in Table 1).
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Abstract
The present invention relates to the field of drugs associated with diabetes. Specifically, the present invention relates an inhibitor of sodium-dependent glucose transporter-2 having an anomeric alkyl-containing phenyl C-glucoside structure represented by Formula I, and a preparation method for same, a pharmaceutical composition containing same and a use of same in the preparation of drugs for treating diabetes. In Formula I, R1 is selected from C1-C5 alkyl groups; R2 and R3 are each independently selected from H, OH, C1-C5 alkyl groups, F, Cl, Br, I, CN, NO2, CF3, CHF2, CH2F, OR8, SMe and cycloalkyl groups containing 3 to 5 carbon atoms, wherein R8 is selected from C1-C5 alkyl groups; R4 and R5 are each independently selected from H, C1-C5 alkyl groups and OR8, wherein R8 is selected from C1-C5 alkyl groups or cycloalkyl groups containing 3 to 5 carbon atoms; and R6 and R7 are each independently selected from H and C1-C5 alkyl groups, or R6 and R7, together with a carbon atom connected thereto, form a cycloalkyl group containing 3 to 5 carbon atoms.
Description
含异头位烷基的苯基 C-葡萄糖苷衍生物、 其制法和用途 Phenyl C-glucoside derivative containing anomeric alkyl group, preparation method and use thereof
技术领域 Technical field
本发明涉及与糖尿病相关的药物领域。 具体而言, 本发明涉及对糖尿病 有治疗作用的在异头位含有烷基的苯基 C-葡萄糖苷结构的 2型钠葡萄糖共 转运子 (SGLT2)抑制剂及其制备方法, 以及含有它们的药物组合物。 背景技术 The present invention relates to the field of medicines associated with diabetes. In particular, the present invention relates to a type 2 sodium glucose co-transporter (SGLT2) inhibitor having an alkyl group-containing phenyl C-glucoside structure in an anomeric position, and a method for preparing the same, and a method for preparing the same Pharmaceutical composition. Background technique
全球糖尿病患者目前大约有 1.7亿左右, 其中绝大多数为 II型 (即非胰岛 素依赖型)糖尿病患者。 目前在临床使用的抗糖尿病药物主要有二曱双胍类、 磺酰脲类、 胰岛素类、噻唑烷二酮类、 α-葡糖苷酶抑制剂类和二肽基肽酶 -IV 抑制剂类药物,这些药物具有良好的治疗效果,但长期治疗存在安全性问题, 如: 肝毒性, 部分药物尚有体重增加等诸多问题。 There are currently about 170 million people with diabetes worldwide, the vast majority of whom are type II (ie, non-insulin dependent) diabetics. Currently, the antidiabetic drugs currently used in clinical practice mainly include diterpenoids, sulfonylureas, insulins, thiazolidinediones, α-glucosidase inhibitors and dipeptidyl peptidase-IV inhibitors. These drugs have good therapeutic effects, but there are safety problems in long-term treatment, such as: liver toxicity, some drugs still have weight gain and many other problems.
2型钠葡萄糖共转运子 (SGLT2)是近年来发现的治疗糖尿病的新靶点。 SGLT2主要分布在肾脏近端小管, 其作用是吸收尿中的葡萄糖, 并将其返回 到血液中, 因此抑制 SGLT2就能够降低血液中葡萄糖的浓度, 这个方法通过 与以往不同的途径降低了血糖水平。 当 SGLT2功能受阻时, 尿液中将分泌更 多的葡萄糖, 这将有助于糖尿病患者保持正确的血糖水平。 由于 SGLT2抑制 剂不介入葡萄糖代谢, 它可以作为血糖控制主流方法的补充手段。 Type 2 sodium glucose co-transporter (SGLT2) is a new target for the treatment of diabetes found in recent years. SGLT2 is mainly distributed in the proximal tubules of the kidney. Its function is to absorb the glucose in the urine and return it to the blood. Therefore, inhibition of SGLT2 can reduce the concentration of glucose in the blood. This method reduces blood sugar levels by different ways from the past. . When SGLT2 is blocked, more glucose is secreted in the urine, which will help diabetics maintain the correct blood sugar levels. Since the SGLT2 inhibitor does not interfere with glucose metabolism, it can be used as a supplement to mainstream blood glucose control methods.
中国专利 CN200610093189.9公开了下列结构的化合物作为 SGLT2抑制 剂: Chinese Patent CN200610093189.9 discloses a compound of the following structure as an SGLT2 inhibitor:
中国专利 CN200380110040.1公开了下列结构的化合物作为 SGLT2抑制 剂:
其中, A为共价键, O, S, NH, (CH2)n, n = l-3。 Chinese patent CN200380110040.1 discloses compounds of the following structure as SGLT2 inhibitors: Wherein A is a covalent bond, O, S, NH, (CH 2 ) n , n = l-3.
中国专利 CN200480006761.2公开了下列结构的化合物作为 SGLT2抑制 剂: Chinese Patent CN200480006761.2 discloses compounds of the following structure as SGLT2 inhibitors:
发明概述 Summary of invention
本发明的一个目的是克服现有技术的缺点和不足,提供一种具有良好活 性的 SGLT2抑制剂, 该 SGLT2抑制剂为具有通式 I的化合物或其药学上可 接受的盐或前药酯。 It is an object of the present invention to overcome the shortcomings and deficiencies of the prior art and to provide a SGLT2 inhibitor having good activity, the SGLT2 inhibitor being a compound of formula I or a pharmaceutically acceptable salt or prodrug ester thereof.
本发明的另一个目的是提供制备具有通式 I的化合物或其药学上可接受 的盐或前药酯的方法。 Another object of the invention is to provide a process for the preparation of a compound of formula I or a pharmaceutically acceptable salt or prodrug ester thereof.
本发明的再一个目的是提供含有通式 I的化合物或其药学上可接受的盐 或前药酯作为有效成分, 以及一种或多种药学上可接受的载体、 赋形剂和 /
或稀释剂的药用组合物, 及其在治疗糖尿病中的用途。 A further object of the present invention is to provide a compound containing Formula I, or a pharmaceutically acceptable salt or prodrug ester thereof, as an active ingredient, together with one or more pharmaceutically acceptable carriers, excipients and/or Or a pharmaceutical composition of a diluent, and its use in the treatment of diabetes.
本发明提供的异头位含烷基的苯基 C-葡萄糖苷类衍生物是新型的 SGLT2抑制剂,这些抑制剂为制备进一步可以用于治疗糖尿病,特别是非胰 岛素依赖型糖尿病的药物打下了基础。 发明 The anomeric alkyl-containing phenyl C-glucoside derivatives provided by the present invention are novel SGLT2 inhibitors, and these inhibitors lay the foundation for the preparation of drugs which can be further used for the treatment of diabetes, especially non-insulin dependent diabetes. . invention
本发明提供了一种 (I)所示的化合物 The present invention provides a compound represented by (I)
其中, among them,
R1选自 d-C5的烷基, 所述烷基任选地被一个或者多个选 F、 Cl、 Br、 I 和 OH的基团取代; R 1 is selected from the group consisting of alkyl of dC 5 , which is optionally substituted with one or more groups selected from F, Cl, Br, I and OH;
R2和 R3独立选 |] H、 OH、 d-C5的烷基、 F、 Cl、 Br、 I、 CN、 N02、 CF3、 CHF2、 CH2F、 OR8、 SMe和含 3-5个碳原子的环烷基, 其中 R8选自 d-C5的烷 基, 所述烷基或者环烷基任选地被一个或多个选自 F和 C1的原子取代; R 2 and R 3 are independently selected |] H, OH, dC 5 alkyl, F, Cl, Br, I, CN, N0 2 , CF 3 , CHF 2 , CH 2 F, OR 8 , SMe and 3- a cycloalkyl group of 5 carbon atoms, wherein R 8 is selected from an alkyl group of dC 5 , which is optionally substituted by one or more atoms selected from the group consisting of F and C 1 ;
R4和 R5独立选 H、 CrC5的烷基、 含 3-5个碳原子的环烷基和 OR8, 其 中 R8选自 CrC5的烷基或含 3-5个碳原子的环烷基,所述烷基或者环烷基任选 地被一个或多个选自 F和 C1的原子取代; R 4 and R 5 are independently selected from H, C r C 5 alkyl group containing 3-5 carbon atoms and a cycloalkyl group OR 8, wherein R 8 is selected from C r C 5 alkyl group or an 3-5 a cycloalkyl group of a carbon atom, the alkyl group or a cycloalkyl group being optionally substituted by one or more atoms selected from the group consisting of F and C1;
R6和 R7独立选自 H和 CrC5的烷基, 或者 R6和 R7与它们连接的碳原子一起 形成含 3-5个碳原子的环烷基。 R 6 and R 7 are independently selected from the alkyl group of H and C r C 5 , or R 6 and R 7 together with the carbon atom to which they are attached form a cycloalkyl group having 3 to 5 carbon atoms.
优选地, 在通式 (I)所示的化合物中, Preferably, among the compounds represented by the formula (I),
R1选自 d-C3的烷基,所述烷基任选地被一个或者多个选自 F和 OH的基团 取代; R 1 is selected from alkyl of dC 3 , which is optionally substituted with one or more groups selected from the group consisting of F and OH;
R2和 R3独立选 H、 OH、 d-C3的烷基、 F、 Cl、 CN、 N02、 CF3、 OR8、 SMe和环丙基, 其中 R8选自 CrC3的烷基, 所述烷基或者环丙基任选地被一个 或多个 F原子取代; R 2 and R 3 are independently selected from H, OH, dC 3 alkyl, F, Cl, CN, N0 2, CF 3, OR 8, SMe and cyclopropyl, wherein R 8 is selected from a C r C 3 alkyl The alkyl or cyclopropyl group is optionally substituted with one or more F atoms;
R4和 R5独立选 H、 d-C3的烷基、 环丙基和 OR8, 其中 R8为 d-C3的烷基 或环丙基, 所述烷基或者环丙基任选地被一个或多个 F原子取代;
R6和 R7独立选自 11和 i -C3的烷基, 或者 R6和 R7与它们连接的碳原子 形成环丙基。 R 4 and R 5 are independently selected from H, dC 3 alkyl, cyclopropyl and OR 8 , wherein R 8 is dC 3 alkyl or cyclopropyl, said alkyl or cyclopropyl optionally being one or Multiple F atoms substituted; R 6 and R 7 are independently selected from the group consisting of 11 and i-C 3 alkyl groups, or R 6 and R 7 and the carbon atom to which they are attached form a cyclopropyl group.
更优选地, 通 (I)所示的化合物选自以 More preferably, the compound represented by (I) is selected from
上述路线
ttig试剂) III 反应后再与 TBDPSCl反应, 最终转化为 IV; 化合物 IV经过 Wacker氧化转化 为 V; 化合物 V与芳基锂化合物 VI反应得到化合物 VII; 化合物 VII中的叔丁 基二曱基硅烷基(TBDPS)保护基用四丁基氟化铵(TBAF)处理除去得到 化合物 VIII; 化合物 VIII经过酸催化环化得到化合物 IX, 优选地所述酸为三 氟乙酸、 曱磺酸、 三氟曱橫酸、 硫酸、 HC1等; 化合物 IX用二氯二氰对苯醌 (DDQ)脱去其中的对曱氧基苄基(PMB)保护基, 得到目标化合物 I; 其 中 -R7的定义如以上所述, R9和 R1G独立选自 H和 CrC4的烷基。
Above route TTig reagent) III reacts with TBDPSCl and finally converts to IV; compound IV is converted to V by Wacker oxidation; compound V reacts with aryllithium compound VI to give compound VII; tert-butyldimercaptosilane group in compound VII (TBDPS) protecting group is removed by treatment with tetrabutylammonium fluoride (TBAF) to obtain compound VIII; compound VIII is subjected to acid-catalyzed cyclization to obtain compound IX, preferably the acid is trifluoroacetic acid, sulfonic acid, trifluoroanthracene Acid, sulfuric acid, HCl, etc.; Compound IX is deprotected with p-methoxybenzyl (PMB) protecting group with dichlorodicyanidine p-benzoquinone (DDQ) to obtain the target compound I; wherein -R 7 is as defined above R 9 and R 1G are independently selected from the group consisting of H and C r C 4 alkyl groups.
n-Bu3SnH/ n-Bu 3 SnH/
AIBN/ AIBN/
上述路线中的 R9R1GCH = R1; 化合物 V用强碱处理后再与 Tf20反应, 得 到化合物 X, 优选地所述强碱为二异丙基氨基锂(LDA ) ; 化合物 X与芳基 硼酸 XI在 Pd催化剂催化下偶合得到化合物 XII , 优选地所述 Pd催化剂为 Pd(PPh3)4; 化合物 XII用 12处理而发生环化得到化合物 XIII; 化合物 XIII用 «-Bu3SnH和偶氮二异丁腈(AIBN ) 处理脱去碘, 得到化合物 XIV; 化合物 XIV用 DDQ处理脱去 PMB保护基, 得到化合物 I; 其中的 -R7的定义如以上 所述, R9和 R1G独立选自 H和 CrC4的烷基。 R 9 R 1G CH = R 1 in the above route; Compound V is treated with a strong base and then reacted with Tf 2 0 to obtain Compound X, preferably the strong base is lithium diisopropylamide (LDA); Compound X XI with an aryl boronic acid under the Pd catalyzed coupling to give compound XII, preferably the Pd catalyst is Pd (PPh 3) 4; compound XII 1 2 processing occurs cyclized compound XIII; compound XIII with «-Bu 3 SnH and azobisisobutyronitrile (AIBN) treatment to remove iodine to obtain compound XIV; compound XIV is treated with DDQ to remove the PMB protecting group to obtain compound I; wherein -R 7 is as defined above, R 9 and R 1G is independently selected from the group consisting of H and C r C 4 alkyl groups.
本发明所述式 I化合物的药学上可接受的前药酯, 包括分子中的任意一 个或多个羟基与乙酰基、 特戊酰基、 各种磷酰基、 氨基曱酰基、 烷氧曱酰基 等形成的酯。 A pharmaceutically acceptable prodrug ester of a compound of formula I according to the invention, comprising any one or more of the hydroxyl groups in the molecule formed with an acetyl group, a pivaloyl group, various phosphoryl groups, aminodecanoyl groups, alkanoyl groups, and the like Ester.
本发明所述式 I的化合物,可以通过与一种或多种药学上可接受的载体、 赋形剂和 /或稀释剂混合来制成药物组合物。该药物组合物可以制成固体口服 制剂、 液体口服制剂和注射剂等剂型。 所述固体及液体口服制剂包括: 普通
片剂、 分散片、 咀嚼片、 包衣片、 颗粒剂、 干粉剂、 胶嚢剂和溶液剂。 所述 的注射剂包括: 小针、 大输液和冻干粉针等。 The compounds of formula I of the present invention may be formulated into pharmaceutical compositions by mixing with one or more pharmaceutically acceptable carriers, excipients and/or diluents. The pharmaceutical composition can be formulated into a solid oral preparation, a liquid oral preparation, and an injection. The solid and liquid oral preparations include: Tablets, dispersible tablets, chewable tablets, coated tablets, granules, dry powders, capsules and solutions. The injection includes: a small needle, a large infusion, and a lyophilized powder needle.
根据本发明的药物组合物包含药学上可接受的辅料, 所述药学上可接受 的辅料选自: 填充剂、 粘合剂、 崩解剂、 润滑剂、 助流剂、 泡腾剂、 矫味剂、 防腐剂、 包衣材料、 表面活性剂、 pH调节剂和稳定剂等。 The pharmaceutical composition according to the present invention comprises a pharmaceutically acceptable excipient selected from the group consisting of: a filler, a binder, a disintegrant, a lubricant, a glidant, an effervescent, and a flavor. Agents, preservatives, coating materials, surfactants, pH adjusters and stabilizers.
优选地, 所述的填充剂包括乳糖、 蔗糖、 糊精、 淀粉、 预胶化淀粉、 甘 露醇、 山梨醇、 磷酸氢钙、 硫酸 4弓、 碳酸 4弓和微晶纤维素中的一种或几种; 所述的粘合剂包括 糖、 淀粉、 聚维酮、 羧曱基纤维素钠、 羟丙曱纤维素、 羟丙纤维素、 曱基纤维素、 聚乙二醇、 药用乙醇和水中的一种或几种; 所述 的崩解剂包括淀粉、 交联聚微酮、 交联羧曱基纤维素钠、 低取代羟丙基纤维 素、 羧曱基纤维素钠、 泡腾崩解剂中的一种或几种; 所述润滑剂包括硬脂酸 镁; 所述助流剂包括滑石粉; 所述矫味剂包括香精和阿司帕坦; 所述表面活 性剂包括泊洛沙姆、 十二烷基硫酸钠、 吐温 80; 所述 pH调节剂包括枸橼酸 和氢氧化钠和所述稳定剂包括枸橼酸等。 Preferably, the filler comprises one of lactose, sucrose, dextrin, starch, pregelatinized starch, mannitol, sorbitol, dibasic calcium phosphate, sulfuric acid 4 bow, carbonic acid 4 bow and microcrystalline cellulose or Several kinds of binders include sugar, starch, povidone, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl cellulose, mercapto cellulose, polyethylene glycol, medicinal ethanol and One or more of the water; the disintegrant comprises starch, cross-linked poly-microketone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, effervescent One or more of the decomposers; the lubricant comprises magnesium stearate; the glidant comprises talc; the flavoring agent comprises a flavor and aspartame; the surfactant comprises a polka Sham, sodium lauryl sulfate, Tween 80; the pH adjusting agent includes citric acid and sodium hydroxide, and the stabilizer includes citric acid or the like.
本发明所述通式 I化合物具有 SGLT2酶的抑制作用, 可作为有效成分 用于制备糖尿病方面的治疗药物。 本发明所述通式 I化合物的活性是通过体 内降糖模型验证的。 The compound of the formula I of the present invention has an inhibitory action on the SGLT2 enzyme and can be used as an active ingredient for the preparation of a therapeutic drug for diabetes. The activity of the compounds of formula I according to the invention is verified by an in vivo hypoglycemic model.
本发明的通式 I化合物在相当宽的剂量范围内是有效的。 例如 每天服用的剂量约在 1 mg- 1000 mg/人范围内, 分为一次或数次给 药。 实际服用本发明通式 I化合物的剂量可由医生根据有关的情况 来决定。 这些情况包括: 被治疗者的身体状态、 给药途径、 年龄、 体重、 对药物的个体反应, 症状的严重程度等。 实施发明的最佳方式 The compounds of formula I of the present invention are effective over a relatively wide dosage range. For example, the daily dose is about 1 mg - 1000 mg / person, divided into one or several times. The dosage of the compound of formula I of the present invention may be determined by the physician in accordance with the circumstances. These conditions include: the physical condition of the subject, the route of administration, age, weight, individual response to the drug, severity of symptoms, and the like. The best way to implement the invention
下面结合实施例对本发明作进一步的说明。 需要说明的是, 下述实施例 仅是用于说明, 而并非用于限制本发明。 本领域技术人员根据本发明的教导 所做出的各种变化均应在本申请权利要求所要求的保护范围之内。 实施例 1 The present invention will be further described below in conjunction with the embodiments. It should be noted that the following examples are for illustrative purposes only and are not intended to limit the invention. Various changes made by those skilled in the art in light of the teachings of the present invention are intended to be included within the scope of the appended claims. Example 1
(2S,3R, ,5S,6R)-2-[4-氯 -3-(4-乙氧基苄基)苯基] -6-羟曱基 -2-曱基 -2,3,5,6-四 氢 -2H-吡喃 -3,4,5-三醇 (1-1) (2S,3R, ,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-hydroxydecyl-2-mercapto-2,3,5, 6-tetrahydro-2H-pyran-3,4,5-triol (1-1)
合成方法 A:
Synthesis Method A:
上述合成路线中的化合物 1- 1和 ΙΠ-1〜: IX-1均是相应的 I和 III~IX所代 表的化合物中的一个。 The compounds 1 to 1 and ΙΠ-1 to: IX-1 in the above synthetic route are each one of the compounds represented by the corresponding I and III to IX.
1. 化合物 IV- 1的合成 1. Synthesis of compound IV-1
一只 100 mL的干燥圓底烧瓶中加入 6.61 g化合物 II , 以 20 mL干燥的 6.61 g of compound II was added to a 100 mL dry round bottom flask and dried in 20 mL.
THF 溶解, 烧瓶用氮气吹扫后迅速用橡皮塞密封。 烧瓶在 -10 °C的冰盐浴中 冷却, 用注射器慢慢滴加 25 mL 1.0 M的化合物 ΠΙ-1的 THF溶液。 滴加完 毕后, 所得反应混合物在室温下搅拌过夜。 烧瓶再次用冰水浴冷却, 用注射 器慢慢滴加 2.75 g TBDPSC1 (叔丁基二苯基氯硅烷)溶于 2 mL干燥 THF制 成的溶液, 滴加完毕后所得溶液在室温下搅拌 2小时。 The THF was dissolved, and the flask was purged with nitrogen and then quickly sealed with a rubber stopper. The flask was cooled in an ice bath at -10 °C, and 25 mL of a 1.0 M compound ΠΙ-1 in THF was slowly added dropwise with a syringe. After the completion of the dropwise addition, the resulting reaction mixture was stirred at room temperature overnight. The flask was again cooled in an ice water bath, and a solution prepared by dissolving 2.75 g of TBDPSC1 (tert-butyldiphenylchlorosilane) in 2 mL of dry THF was slowly added dropwise by a syringe, and the resulting solution was stirred at room temperature for 2 hours.
反应混合物小心倾倒到 300 mL含有冰块的饱和 NH4C1溶液中, 搅拌, 用 50 mL X 3的二氯曱烷萃取。 合并萃取液, 用饱和食盐水洗涤, 无水硫酸钠 干燥, 而后在旋转蒸发仪上蒸去溶剂。 所得残余物用柱层析纯化, 得到化合 物 IV- 1的纯品, 无色油状物, ESI-MS, m/z = 897 ([M+H]+)。 The reaction mixture was carefully poured into 300 mL of a saturated NH 4 C1 solution containing ice, stirred, and extracted with 50 mL of X 3 dichloromethane. The combined extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated. The resulting residue was purified by column chromatography, to give pure Compound IV- 1, a colorless oil, ESI-MS, m / z = 897 ([M + H] +).
2. 化合物 V- 1的合成 2. Synthesis of compound V-1
一只 100 mL的圓底烧瓶中加入上述制备的化合物 IV-1 (7.27 g) , 以 50
mL N,N-二曱基曱酰胺(DMF )溶解, 室温下搅拌, 而后加入 5 mL水、 0.10 g CuCl2和 0.15 g PdCl2, 所得混合物在 02的气氛下(气球)搅拌 24小时, 此 时薄层色语 ( TLC )显示反应完成。 A 100 mL round bottom flask was charged with the compound IV-1 (7.27 g) prepared above to 50 Dissolve mL N,N-dimercaptoamide (DMF), stir at room temperature, then add 5 mL water, 0.10 g CuCl 2 and 0.15 g PdCl 2 , and the resulting mixture was stirred under a 0 2 atmosphere (balloon) for 24 hours. At this time, the thin layer color term (TLC) showed that the reaction was completed.
反应混合物抽滤, 滤液倾倒到 300 mL食盐水中, 而后用 50 mL X 3的二 氯曱烷萃取。 合并萃取液, 用饱和食盐水洗涤, 无水硫酸钠干燥, 而后在旋 转蒸发仪上蒸去溶剂。 所得残余物用柱层析纯化, 得到化合物 V-1的纯品, 无色油状物, ESI-MS, m/z = 913 ([M+H]+)。 The reaction mixture was suction filtered, and the filtrate was poured into 300 mL brine, and then extracted with 50 The combined extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated. The resulting residue was purified by column chromatography, to give pure Compound V-1, a colorless oil, ESI-MS, m / z = 913 ([M + H] +).
3. 化合物 IX- 1的合成 3. Synthesis of Compound IX-1
一只 100 mL的干燥圓底烧瓶中加入 3.26 g (2-氯 -5-溴苯基 )(4-乙氧基苯 基)曱烷, 以 20 mL干燥的四氢呋喃 (THF )溶解, 氮气吹扫后用橡皮塞封 口。 烧瓶用 -78 °C的液氮 -乙醇冷却, 开动电磁搅拌, 而后用注射器慢慢滴加 10 mL 1.0 M的《-BuLi正己烷溶液。 滴加完毕后反应混合物在 -78 °C搅拌 1 小时, 而后升温至 -20°C , 再用注射器慢慢滴加上述合成的 V-1 (6.95 g)溶解 到 5 mL干燥的 THF中制成的溶液, 滴加完毕后, 所得混合物在室温下搅拌 1小时。 Add a 3. 6 g (2-chloro-5-bromophenyl)(4-ethoxyphenyl)decane to a 100 mL dry round bottom flask, dissolve in 20 mL of dry tetrahydrofuran (THF), purge with nitrogen. After sealing with a rubber stopper. The flask was cooled with liquid nitrogen-ethanol at -78 °C, and electromagnetic stirring was started, and then 10 mL of 1.0 M "-BuLi n-hexane solution was slowly added dropwise by a syringe. After the completion of the dropwise addition, the reaction mixture was stirred at -78 ° C for 1 hour, and then heated to -20 ° C, and then slowly added dropwise with a syringe to the above-prepared V-1 (6.95 g) dissolved in 5 mL of dry THF. After the dropwise addition, the resulting mixture was stirred at room temperature for 1 hour.
室温下用注射器往上述反应混合物中慢慢加入 10 mL 1.0 M的 TBAF的 THF溶液, 加完后室温下搅拌 5小时。 而后在冰水冷却下用注射器往烧瓶中 慢慢加入 9.6 g MsOH (曱磺酸) 。 所得混合物在室温下搅拌过夜。 10 mL of a 1.0 M solution of TBAF in THF was slowly added to the above reaction mixture with a syringe at room temperature, and the mixture was stirred at room temperature for 5 hours. Then, 9.6 g of MsOH (anthracenesulfonic acid) was slowly added to the flask with a syringe under cooling with ice water. The resulting mixture was stirred at room temperature overnight.
反应混合物倾倒到 300 mL食盐水中,而后用 50 mL X 3的二氯曱烷萃取。 合并萃取液, 用饱和食盐水洗涤, 无水硫酸钠干燥, 而后在旋转蒸发仪上蒸 去溶剂。 所得残余物用柱层析纯化, 得到化合物 IX-1 的纯品, 白色固体, ESI-MS, m/z = 903 ([M+H]+)。 The reaction mixture was poured into 300 mL of brine and then extracted with 50 mL of EtOAc. The combined extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated. The resulting residue was purified by column chromatography to give compound IX-1 pure product, a white solid, ESI-MS, m / z = 903 ([M + H] +).
4. 化合物 1-1的合成 4. Synthesis of Compound 1-1
在一只 100 mL的圓底烧瓶中加入上述制备的化合物 IX-1 (3.85 g),以 40 mL二氯曱烷溶解, 室温下搅拌, 而后依次加入 9.00 g DDQ和 4 mL水, 所 得混合物在室温下搅拌过夜后再升温回流 3小时。 此时 TLC显示反应完成。 The compound IX-1 (3.85 g) prepared above was added to a 100 mL round bottom flask, dissolved in 40 mL of dichloromethane, stirred at room temperature, and then 9.00 g of DDQ and 4 mL of water were added in sequence, and the mixture was obtained. After stirring at room temperature overnight, the temperature was refluxed for 3 hours. At this point TLC showed the reaction was complete.
反应混合物用 200 mL二氯曱烷稀释, 而后用 100 mL 2的碳酸氢钠饱 和溶液洗涤, 再用饱和食盐水洗涤, 无水硫酸钠干燥, 而后在旋转蒸发仪上 蒸去溶剂。 所得残余物用柱层析纯化, 得到化合物 1-1 的纯品, 白色泡沫状 固体, ESI-MS, m/¾ = 423 ([M+H]+)。 合成方法 B:
The reaction mixture was diluted with 200 mL of dichloromethane, and then washed with a saturated aqueous solution of 100 mL of sodium hydrogencarbonate, and then washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) Synthesis Method B:
上述合成路线中的化合物 X-1~XIV-1均是相应的 X和 XIV所代表的化 合物中的一个。 Compounds X-1 to XIV-1 in the above synthetic route are each one of the compounds represented by the corresponding X and XIV.
1. 化合物 X- 1的合成 1. Synthesis of compound X-1
一只 100 mL的干燥圓底烧瓶中加入 1.01 g干燥的 -Pr2NH和 10 mL干燥 的 THF。 烧瓶用氮气吹扫后迅速用橡皮塞封口, 而后置于 -78 °C的液氮 -乙醇 中冷却, 开动电磁搅拌。 用注射器慢慢往烧瓶中逐滴加入 6.2 mL 1.6 M的 w-BuLi的正己烷溶液, 滴加完毕后所得溶液在该温度下搅拌 1小时。 而后再 用注射器逐滴加入 9.13 g 干燥的 V- 1溶于 10 mL干燥的 THF制成的溶液。 滴 加完毕后, 所得反应混合物在 -78 °C下继续搅拌 1 小时, 而后再用注射器慢 慢滴加 2.82 g Tf20溶于 2 mL干燥的 THF中制得的溶液。滴加完毕后,所得反 应混合物慢慢升温至室温, 继续搅拌 1小时。 A 100 mL dry round bottom flask was charged with 1.01 g of dry-Pr 2 NH and 10 mL of dry THF. The flask was purged with nitrogen and quickly sealed with a rubber stopper, and then cooled in liquid nitrogen-ethanol at -78 °C to start electromagnetic stirring. To the flask, 6.2 mL of a 1.6 M solution of w-BuLi in n-hexane was slowly added dropwise with a syringe, and the resulting solution was stirred at the temperature for 1 hour. Then, a solution of 9.13 g of dry V-1 dissolved in 10 mL of dry THF was added dropwise with a syringe. After the completion of the dropwise addition, the resulting reaction mixture was further stirred at -78 ° C for 1 hour, and then a solution prepared by dissolving 2.82 g of Tf 2 0 in 2 mL of dry THF was slowly added dropwise with a syringe. After completion of the dropwise addition, the resulting reaction mixture was slowly warmed to room temperature and stirring was continued for 1 hour.
反应混合物倾倒到冷却的 300 mL食盐水中,而后用 50 mL 3的二氯曱 烷萃取。 合并萃取液, 用饱和食盐水洗涤, 无水硫酸钠干燥, 而后在旋转蒸 发仪上蒸去溶剂。 所得残余物用柱层析纯化, 得到化合物 X-1的纯品, 无色 油状物, ESI-MS, m/z = 1045 ([M+H]+)„ The reaction mixture was poured into cooled 300 mL of brine and extracted with 50 mL of dichloromethane. The combined extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue obtained was purified by column chromatography to yield purified crystals of Compound 1-1, ESI-MS, m/z = 1045 ([M+H] + )
2. 化合物 XII- 1的合成 2. Synthesis of compound XII-1
一只 100 mL的圓底烧瓶中加入上步制备的化合物 X- 1 (9.09 g)、 2.81 g 4- 氯 -3-(4-氯苄基)苯基硼酸、 2.12 g碳酸钠、 0.23 g Pd(PPh3)4、 40 mL曱苯、 20
mL水和 10 mL乙醇, 所得混合物在氮气气氛中回流过夜, 此时 TLC显示反应 完成。 A 100 mL round bottom flask was charged with the compound X-1 (9.09 g) prepared in the previous step, 2.81 g of 4-chloro-3-(4-chlorobenzyl)phenylboronic acid, 2.12 g of sodium carbonate, and 0.23 g of Pd. (PPh 3 ) 4 , 40 mL of benzene, 20 The mixture was refluxed under nitrogen overnight at rt.
反应混合物冷却后, 倾倒到 300 mL饱和食盐水中, 用 100 mL 3的二 氯曱烷萃取。 合并萃取液, 用饱和食盐水洗涤, 无水硫酸钠干燥, 而后在旋 转蒸发仪上蒸去溶剂。 所得残余物用柱层析纯化, 得到化合物 XII-1的纯品, 白色固体, ESI-MS, m/z = 1 141 ([M+H]+)。 After the reaction mixture was cooled, it was poured into 300 mL of saturated brine and extracted with 100 mL of 3 dichloromethane. The combined extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)
3. 化合物 ΧΠΙ- 1的合成 3. Synthesis of the compound ΧΠΙ-1
一只 100 mL的干燥圓底烧瓶中加入上步制备的 XII- 1 (7.25 g) , 以 30 mL 干燥的二氯曱烷溶解, 室温下搅拌, 而后加入 2.00 g l2 , 室温下继续搅拌过 夜。 A 100 mL dry round bottom flask was charged with XII-1 (7.25 g) prepared in the previous step, dissolved in 30 mL of dry dichloromethane, stirred at room temperature, then 2.00 gl 2 and stirred at room temperature overnight.
反应混合物倾倒到 300 mL饱和食盐水中,用 50 mL X 3的二氯曱烷萃取。 合并萃取液, 依次用 10%的 Na2S203和饱和食盐水洗涤, 无水硫酸钠干燥, 而后在旋转蒸发仪上蒸去溶剂。所得残余物用柱层析纯化,得到化合物 XIII- 1 的纯品, 白色固体, ESI-MS, m々= 1029 ([M+H]+)。 The reaction mixture was poured into 300 mL of brine and extracted with 50 mL of EtOAc. The extracts were combined, washed successively with 10% Na 2 S 2 3 and brine, dried over anhydrous sodium sulfate, and evaporated. The residue obtained was purified by EtOAc EtOAc (EtOAc)
4. 化合物 XIV- 1的合成 4. Synthesis of compound XIV-1
一只 100 mL的干燥圓底烧瓶中加入上一步制备的化合物 XIII-1 (3.86 g)、 3.0 g «-Bu3SnH、 0.10 g AIBN (偶氮二异丁腈 )和 50 mL干燥的曱苯, 所 得混合物在氮气气氛中緩' f曼回流 3小时, 再加入 0.10 g AIBN, 继续回流 3 消失。 此时 TLC显示反应完成。 A 100 mL dry round bottom flask was charged with the compound XIII-1 (3.86 g) prepared in the previous step, 3.0 g «-Bu 3 SnH, 0.10 g AIBN (azobisisobutyronitrile) and 50 mL of dry benzene. The resulting mixture was refluxed for 3 hours under a nitrogen atmosphere, then 0.10 g of AIBN was added, and reflux 3 was continued. At this point TLC showed the reaction was complete.
反应混合物冷却后, 用 200 mL二氯曱烷稀释, 用饱和食盐水洗涤, 无水 硫酸钠干燥, 而后在旋转蒸发仪上蒸去溶剂。 所得残余物用柱层析纯化, 得 到化合物 XI V- 1的纯品, 白色固体, ESI-MS, m/z = 903 ([M+H]+)。 After the reaction mixture was cooled, it was diluted with 200 mL of dichloromethane, washed with brine, dried over anhydrous sodium sulfate, and evaporated. The resulting residue was purified by column chromatography to give compound XI V- pure 1, as a white solid, ESI-MS, m / z = 903 ([M + H] +).
5. 化合物 1-1的合成 5. Synthesis of Compound 1-1
按照方法 A中第 4步的操作合成 1-1。白色泡沫状固体, ESI-MS, m/z = 423 ([M+H]+)。 实施例 2-18 The 1-1 was synthesized in accordance with the operation of the fourth step in the method A. White foamy solid, ESI-MS, m/z = 423 ([M+H] + ). Example 2-18
可以理解的是, 使用实施例 1 中的方法 A和方法 B , 改变 -R7 , 可以得 到下表所列的化合物。
- - It will be appreciated that the use of methods A and B in Example 1, changing -R 7, the compounds in the table below can be obtained. - -
IS UO/ZlOZ lD/lDd 809W0/£I0Z OAV
- - IS UO/ZlOZ lD/lDd 809W0/£I0Z OAV - -
IS UO/ZlOZ lD/lDd 809 /£I0Z OAV
实施例 19 普通片剂 IS UO/ZlOZ lD/lDd 809 /£I0Z OAV Example 19 Ordinary tablet
用量 /片 Dosage / film
实施例 1样品 10 mg Example 1 Sample 10 mg
微晶纤维素 80 mg Microcrystalline cellulose 80 mg
预胶化淀粉 70 mg Pregelatinized starch 70 mg
聚维酮 6 mg Povidone 6 mg
羧曱基淀粉钠 5 mg Carboxymethyl starch sodium 5 mg
硬脂酸镁 2 mg Magnesium stearate 2 mg
滑石粉 2 mg Talc powder 2 mg
将实施例 1样 ^过 80目筛, Example 1 was passed through an 80 mesh sieve.
品、 预胶化淀粉和微晶纤维素充分混合均匀, 加入 10% (重量 /体积) 聚维 酮水溶液混合, 制软材, 过筛, 制湿颗粒, 于 55°C干燥。 将羧曱基淀粉钠, 硬脂酸镁和滑石粉加到上述的颗粒中, 测定中间体含量, 压片, 包装。 实施例 20 錄片 The product, pregelatinized starch and microcrystalline cellulose are well mixed, mixed with a 10% (w/v) aqueous solution of povidone, softened, sieved, wet granules, and dried at 55 °C. Sodium carboxymethyl starch, magnesium stearate and talc are added to the above granules to determine the intermediate content, tableting, and packaging. Example 20 Recording
用量 /片 Dosage / film
实施例 2样品 10 mg Example 2 Sample 10 mg
乳糖 80 mg Lactose 80 mg
预胶化淀粉 70 mg Pregelatinized starch 70 mg
羟丙曱纤维素 6 mg Hydroxypropyl cellulose 6 mg
交联聚维酮 5 mg Cross-linked povidone 5 mg
硬脂酸镁 4 mg Magnesium stearate 4 mg
将实施例 2样 ^过 80目筛, Example 2 was passed through an 80 mesh sieve.
品、 预胶化淀粉和乳糖充分混合均匀, 加入 1% (重量 /体积)羟丙曱纤维素 水溶液混合, 制软材, 过筛, 制湿颗粒, 于 55°C干燥。 将交联聚维酮和硬脂 酸镁加到上述的颗粒中, 测定中间体含量, 压片, 包装。 实施例 21 咀嚼片 The product, pregelatinized starch and lactose are well mixed, mixed with a 1% (w/v) aqueous solution of hydroxypropionate, made into a soft material, sieved, and wetted, and dried at 55 °C. The crospovidone and magnesium stearate are added to the above granules, and the intermediate content is determined, tableted, and packaged. Example 21 Chewable Tablets
用量 /片 Dosage / film
实施例 4样品 10 mg Example 4 Sample 10 mg
甘露醇 100 mg Mannitol 100 mg
微晶纤维素 30 mg
乳糖 50 mg Microcrystalline cellulose 30 mg Lactose 50 mg
聚维嗣 6m g 聚维嗣 6m g
阿司帕坦 5 mg Aspartame 5 mg
香精 2mg Fragrance 2mg
硬脂酸镁 1 mg Magnesium stearate 1 mg
将实施例 4样品过 80目筛, 辅料过 60目筛。 按处方量称取实施例 4样 品、 聚维酮、 阿司帕坦和香精先混合均匀, 再依次与甘露醇、 微晶纤维素和 乳糖充分混合均匀, 最后加入硬脂酸镁混合均匀, 测定中间体含量, 压片, 包装。 实施例 22 胶嚢 The sample of Example 4 was passed through an 80 mesh sieve and the auxiliary material was passed through a 60 mesh sieve. The sample of Example 4 was weighed according to the prescription, the povidone, aspartame and the essence were firstly mixed uniformly, and then mixed with mannitol, microcrystalline cellulose and lactose in order, and then uniformly mixed with magnesium stearate. Intermediate content, tableting, packaging. Example 22 Capsule
用量 /粒 Dosage / grain
实施例 5样品 10 mg Example 5 Sample 10 mg
乳糖 80 mg Lactose 80 mg
磷酸氢钙 20 mg Calcium hydrogen phosphate 20 mg
羟丙纤维素 3 mg Hydroxypropyl cellulose 3 mg
交联象曱纤维素钠 6mg Crosslinked like cellulose sodium 6mg
硬脂酸镁 2mg Magnesium stearate 2mg
滑石粉 1 mg Talc powder 1 mg
将实施例 5样品过 80目筛, 其它辅料过 60目筛。 按处方量称取实施例 5样品、 磷酸氢钙、 交联羧曱纤维素钠和乳糖充分混合均匀, 加入 2% (重 量 /体积)羟丙纤维素水溶液混合, 制软材, 过筛, 制湿颗粒, 于 55°C干燥。 将硬脂酸镁和滑石粉外加到上述的颗粒中,测定中间体含量,装入 3号胶嚢, 包装。 实施例 23 注射液 The sample of Example 5 was passed through an 80 mesh sieve, and the other auxiliary materials were passed through a 60 mesh sieve. The sample of Example 5, the calcium hydrogen phosphate, the croscarmellose sodium and the lactose were weighed uniformly according to the prescription amount, and mixed with a 2% (w/v) aqueous solution of hydroxypropylcellulose to prepare a soft material and sieved. The wet granules were dried at 55 °C. Magnesium stearate and talc powder were externally added to the above granules, and the content of the intermediate was measured, and the No. 3 capsule was placed and packaged. Example 23 Injection
用量 /50mL Dosage /50mL
实施例 8样品 10 mg Example 8 Sample 10 mg
枸橼酸 100 mg Citrate 100 mg
NaOH 适量(调 pH 4.0-6.0 ) NaOH amount (pH 4.0-6.0)
活性炭 适量 Activated carbon
注射用水 50 mL
将枸橼酸加入 40ml注射用水中, 搅拌溶解后, 再加入实施例 8样品, 微热使溶解, 调 pH值为 4.0-6.0, 加入基于整个注射液的重量计 1%的活性 碳, 室温下搅拌 20分钟, 测定 pH值。 滤过, 脱碳, 补加注射用水至全量。 按每安瓿 5毫升分装, 充氮, 封口。 于 121 °C灭菌 30分钟, 即得注射液。 实施例 24 注射液 50 ml of water for injection Add citric acid to 40 ml of water for injection, stir and dissolve, then add the sample of Example 8, dissolve it by heat, adjust the pH to 4.0-6.0, add 1% activated carbon based on the weight of the whole injection, at room temperature. Stir for 20 minutes and measure the pH. Filter, decarbonize, add water for injection to the full amount. Packed in 5 ml per ampere, nitrogen filled, sealed. The mixture was sterilized at 121 ° C for 30 minutes to obtain an injection. Example 24 Injection
用量 /50mL Dosage /50mL
实施例 9 10 mg Example 9 10 mg
枸橼酸 100 mg Citrate 100 mg
磷酸二氢钠 30mg Sodium dihydrogen phosphate 30mg
注射用水 50 mL Water for injection 50 mL
将枸橼酸加入 40ml注射用水中, 搅拌溶解后, 再加入实施例 8样品和 磷酸二氢钠, 微热使溶解, 调 pH值为 3.0-5.0, 加入基于整个注射液的重量 计 1%的活性碳, 室温下搅拌 20分钟, 测定 pH值。 滤过, 脱碳, 补加注射 用水至全量。 按每安瓿 2毫升分装, 充氮, 封口。 于 121 °C灭菌 30分钟, 即 得注射液。 实施例 25 冻干制剂 Add citric acid to 40 ml of water for injection, stir and dissolve, then add the sample of Example 8 and sodium dihydrogen phosphate, dissolve it by heat, adjust the pH to 3.0-5.0, and add 1% based on the weight of the whole injection. The activated carbon was stirred at room temperature for 20 minutes, and the pH was measured. Filter, decarbonize, add water to the full amount. Packed in 2 ml per ampere, nitrogen filled, sealed. Sterilize at 121 °C for 30 minutes to obtain an injection. Example 25 Lyophilized formulation
用量 /lOOmL Dosage /lOOmL
实施例 10 3-0g Example 10 3-0g
泊洛沙姆 l.Og Polosham l.Og
氢氧化钠 0.2g Sodium hydroxide 0.2g
枸橼酸 适量( QS ) 枸橼 acid amount (QS)
甘露醇 26.0g Mannitol 26.0g
乳糖 23.0g Lactose 23.0g
注射用水 lOOmL Water for injection lOOmL
制备工艺: 取注射用水 80mL, 按处方量加实施例 10样品、 甘露醇、 乳 糖和泊洛沙姆搅拌使溶解后, 加枸橼酸或氢氧化钠调节 pH至 6.0 - 8.0, 补 加注射用水至 100mL。 加入 0.5g活性炭, 在 30°C下搅拌 20分钟, 脱炭, 采 用微孔滤膜过滤除菌, 滤液按每支 lmL进行分装, 预冻 2小时后, 冷冻下 减压干燥 12小时, 至样品温度到室温后, 再干燥 5小时, 制得白色疏松块 状物, 封口即得。
实施例 26 颗粒剂 Preparation process: Take 80 mL of water for injection, add the sample of Example 10, mannitol, lactose and poloxamer to dissolve according to the prescription amount, and then adjust the pH to 6.0 - 8.0 by adding citric acid or sodium hydroxide, and add water for injection to 100mL. Add 0.5g of activated carbon, stir at 30 ° C for 20 minutes, decarbonize, filter and sterilize by microfiltration membrane, the filtrate is divided into 1 mL each, after pre-freezing for 2 hours, freeze under vacuum for 12 hours, until After the temperature of the sample reached room temperature, it was dried for another 5 hours to obtain a white loose mass, which was obtained by sealing. Example 26 Granules
用量 /100袋 Dosage / 100 bags
实施例 11样品 30.0g Example 11 Sample 30.0g
乳糖 55.0g Lactose 55.0g
甘露醇 14.0g Mannitol 14.0g
阿司帕坦 0.05g Aspartame 0.05g
香精 0.05g Fragrance 0.05g
2 %羟丙曱纤维素 2% hydroxypropyl cellulose
(纯水配制 ) QS (prepared in pure water) QS
制备工艺: 将实施例 11样品过 80目筛, 辅料过 60目筛。 称取处方量 乳糖、 甘露醇、 阿司帕坦、 香精与实施例 11样品充分混合, 再加入 2 % (重 量 /体积)羟丙曱纤维素水溶液制软材, 16目筛制粒, 55°C干燥, 14目筛整 粒, 测定中间体含量及水分, 包装, 共制得 100袋颗粒剂。 实施例 27 Preparation process: The sample of Example 11 was passed through an 80 mesh sieve, and the auxiliary material was passed through a 60 mesh sieve. Weigh the prescribed amount of lactose, mannitol, aspartame, essence and sample mixed well with Example 11, add 2% (w/v) hydroxypropionate aqueous solution to soft material, 16 mesh sieve, 55° C dry, 14 mesh sieve granules, determination of intermediate content and moisture, packaging, a total of 100 bags of granules were prepared. Example 27
下表 1 中列出的实施例 1-2、 4-5、 8-12、 14和 16-18的样品以 1% (重 量 /体积)羧曱基纤维素钠配制成 5 mg/mL浓度的混悬液, 给药剂量为 0.2 mL/20g体重, 相当于 10 mg/kg剂量。 The samples of Examples 1-2, 4-5, 8-12, 14 and 16-18 listed in Table 1 below were formulated at a concentration of 5 mg/mL with 1% (w/v) sodium carboxymethyl cellulose. The suspension was administered at a dose of 0.2 mL/20 g body weight, equivalent to a 10 mg/kg dose.
健康 ICR小鼠,雌雄各半,体重 20-24 g,符合一级标准。动物禁食 16h, 给药后 2h腹腔注射 2g/kg的葡萄糖盐水溶液( Dapagliflozin给药后 1.5h注射 葡萄糖) , 于造模后 0.5h、 1.0h、 1.5h、 2.5h和 3h定时使用毛细管自小鼠球 后静脉丛取血, 离心分离血清, 用葡萄糖氧化酶法测定各时间点血清葡萄糖 含量(结果见表 1 ) 。 Healthy ICR mice, half male and half female, weigh 20-24 g, in line with the first grade standard. The animals were fasted for 16 h, 2 g/kg of dextrose solution was injected intraperitoneally 2 h after administration (glucose was injected 1.5 h after Dapagliflozin administration), and capillary was used at 0.5 h, 1.0 h, 1.5 h, 2.5 h and 3 h after modeling. The blood was taken from the posterior venous plexus of the mouse, and the serum was separated by centrifugation. The serum glucose content at each time point was measured by the glucose oxidase method (the results are shown in Table 1).
表 1 葡萄糖氧化酶法测定各时间点血清葡萄糖含量结果 Table 1 Determination of serum glucose content at various time points by glucose oxidase method
3h血糖 剂量 0.5h血糖值 1.5h血糖值 2h血糖值 2.5h血糖值 组别 3h blood glucose dose 0.5h blood glucose value 1.5h blood glucose value 2h blood glucose value 2.5h blood glucose value
(mg/kg) (mg/dl) (mg/dl) (mg/dl) (mg/dl) 值 模型 - 441.1±51.5 291.1±42.6 189.2±24.3 130.6±12.6 (mg/kg) (mg/dl) (mg/dl) (mg/dl) (mg/dl) Value Model - 441.1±51.5 291.1±42.6 189.2±24.3 130.6±12.6
Dapagliflozin 10 243.2±32.1 132.4±25.5 96.3±26.2 81.4±22.3 实施例 1样品 10 241.2±42.5 143.3±14.3 94.2±21.6 76.2±12.8 实施例 2样品 10 290.2±43.5 171.2±37.2 107.2±21.6 72.2±24.2
实施例 4样品 10 297.2±31.4 167.2±22.5 112.3±15.2 82.2±12.3 73.5±12.1 实施例 5样品 10 159.2±41.0 130.2±14.2 103.1±10.1 70.1±11.1 65.1±11.4 实施例 8样品 10 292.3±34.2 201.4±23.0 140.2±21.1 103.1±12.4 80.1±12.3 实施例 9样品 10 220.2±32.4 165.1±22.1 113.4±15.5 91.1±14.5 70.2±21.0 实施例 10样品 10 201.1±33.2 155.2±24.1 138.4±21.3 91.0±11.8 70.1±14.1 实施例 11样品 10 210.3±31.3 181.1±34.5 120.1±22.7 96.0±12.7 67.0±15.2 实施例 12样品 10 295.1±29.2 190.1±24.1 107.3±21.3 79.8±21.8 65.1±12.7 实施例 14样品 10 152.2±22.5 147.2±28.2 92.2±11.3 69.1±20.7 65.1±12.3 实施例 16样品 10 199.3±23.2 160.1±11.5 133.4±12.7 73.4±22.2 63.1±13.4 实施例 17样品 10 248.4±43.4 181.1±21.7 140.1±22.3 103.1±11.7 77.1±12.1 实施例 18样品 10 252.1±34.5 151.3±24.6 125.2±33.3 121.1±11.3 71.2±11.5 以上结果表明,各给药均能显著降低葡萄糖引起的小鼠血糖耐 受量。
Dapagliflozin 10 243.2±32.1 132.4±25.5 96.3±26.2 81.4±22.3 Example 1 Sample 10 241.2±42.5 143.3±14.3 94.2±21.6 76.2±12.8 Example 2 Sample 10 290.2±43.5 171.2±37.2 107.2±21.6 72.2±24.2 Example 4 Sample 10 297.2 ± 31.4 167.2 ± 22.5 112.3 ± 15.2 82.2 ± 12.3 73.5 ± 12.1 Example 5 Sample 10 159.2 ± 41.0 130.2 ± 14.2 103.1 ± 10.1 70.1 ± 11.1 65.1 ± 11.4 Example 8 Sample 10 292.3 ± 34.2 201.4 ± 23.0 140.2±21.1 103.1±12.4 80.1±12.3 Example 9 Sample 10 220.2±32.4 165.1±22.1 113.4±15.5 91.1±14.5 70.2±21.0 Example 10 Sample 10 201.1±33.2 155.2±24.1 138.4±21.3 91.0±11.8 70.1±14.1 Example 11 Sample 10 210.3 ± 31.3 181.1 ± 34.5 120.1 ± 22.7 96.0 ± 12.7 67.0 ± 15.2 Example 12 Sample 10 295.1 ± 29.2 190.1 ± 24.1 107.3 ± 21.3 79.8 ± 21.8 65.1 ± 12.7 Example 14 Sample 10 152.2 ± 22.5 147.2 ± 28.2 92.2±11.3 69.1±20.7 65.1±12.3 Example 16 Sample 10 199.3±23.2 160.1±11.5 133.4±12.7 73.4±22.2 63.1±13.4 Example 17 Sample 10 248.4±43.4 181.1±21.7 140.1±22.3 103.1±11.7 77.1±12.1 Example 18 Sample 10 252.1 ± 34.5 151.3 ± 24.6 125.2 ± 33.3 121.1 ± 11.3 71.2 ± 11.5 The above results indicate that each administration can significantly reduce glucose-induced glucose tolerance in mice.
Claims
权 利 要 求 Rights request
其中, among them,
R1选自 d-C5的烷基, 所述烷基任选地被一个或者多个选 F、 Cl、 Br、 I 和 OH的基团取代; R 1 is selected from the group consisting of alkyl of dC 5 , which is optionally substituted with one or more groups selected from F, Cl, Br, I and OH;
R2和 R3独立选 |] H、 OH、 d-C5的烷基、 F、 Cl、 Br、 I、 CN、 N02、 CF3、 CHF2、 CH2F、 OR8、 SMe和含 3-5个碳原子的环烷基, 其中 R8选自 d-C5的烷 基, 所述烷基或者环烷基任选地被一个或多个选自 F和 C1的原子取代; R 2 and R 3 are independently selected |] H, OH, dC 5 alkyl, F, Cl, Br, I, CN, N0 2 , CF 3 , CHF 2 , CH 2 F, OR 8 , SMe and 3- a cycloalkyl group of 5 carbon atoms, wherein R 8 is selected from an alkyl group of dC 5 , which is optionally substituted by one or more atoms selected from the group consisting of F and C 1 ;
R4和 R5独立选 H、 CrC5的烷基、 含 3-5个碳原子的环烷基和 OR8, 其 中 R8选自 d-C5的烷基或含 3-5个碳原子的环烷基,所述烷基或者环烷基任选 地被一个或多个选自 F和 C1的原子取代; R 4 and R 5 are independently selected from H, C r C 5 alkyl group containing 3-5 carbon atoms and a cycloalkyl group OR 8, wherein R 8 is selected from 5 or dC alkyl having 3-5 carbon atoms a cycloalkyl group, optionally substituted by one or more atoms selected from the group consisting of F and C1;
R6和 R7独立选自 H和 d-C5的烷基, 或者 R6和 R7与它们连接的碳原子一起 形成含 3-5个碳原子的环烷基。 R 6 and R 7 are independently selected from the alkyl group of H and dC 5 , or R 6 and R 7 together with the carbon atom to which they are attached form a cycloalkyl group having 3 to 5 carbon atoms.
2. 根据权利要求 1所述的化合物或其药学上可接受的盐或前药酯, 其中, The compound according to claim 1 or a pharmaceutically acceptable salt or prodrug ester thereof, wherein
R1选自 CrC 々烷基,所述烷基任选地被一个或者多个选自 F和 OH的基团 取代; R 1 is selected from C r C decyl, and the alkyl group is optionally substituted with one or more groups selected from the group consisting of F and OH;
R2和 R3独立选 H、 OH、 d-C3的烷基、 F、 Cl、 CN、 N02、 CF3、 OR8、 SMe和环丙基, 其中 R8选自 CrC3的烷基, 所述烷基或者环丙基任选地被一个 或多个 F原子取代; R 2 and R 3 are independently selected from H, OH, dC 3 alkyl, F, Cl, CN, N0 2, CF 3, OR 8, SMe and cyclopropyl, wherein R 8 is selected from a C r C 3 alkyl The alkyl or cyclopropyl group is optionally substituted with one or more F atoms;
R4和 R5独立选 H、 CrC3的烷基、 环丙基和 OR8, 其中 R8选自 CrC3的烷 基或环丙基, 所述烷基或者环丙基任选地被一个或多个 F原子取代; R 4 and R 5 are independently selected from H, C r C 3 alkyl, cyclopropyl and OR 8, wherein R 8 is selected from C r C 3 alkyl or cyclopropyl, and any of said alkyl or cyclopropyl The ground is replaced by one or more F atoms;
R6和 R7独立选自 H和 d-C3的烷基, 或者 R6和 R7与它们连接的碳原子一起 形成环丙基。 R 6 and R 7 are independently selected from the alkyl group of H and dC 3 , or R 6 and R 7 together with the carbon atom to which they are attached form a cyclopropyl group.
3. 根据权利要求 2 所述的化合物或其药学上可接受的盐或前药酯, 其 中, 所述化合物选自下列化合物: 3. A compound according to claim 2, or a pharmaceutically acceptable or prodrug ester thereof, Wherein the compound is selected from the group consisting of:
4. 根据权利要求 1-3 中任一项所述的化合物或其药学上可接受的盐或 前药酯, 其中, 所述药学上可接受的前药酯包括所述化合物分子中的任意一 个或多个羟基与乙酰基、 特戊酰基、 磷酰基、 氨基曱酰基、 烷氧曱酰基中的 一种或多种所形成的酯。 The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or prodrug thereof, wherein the pharmaceutically acceptable prodrug ester comprises any one of the compound molecules Or an ester formed by one or more of a plurality of hydroxyl groups and an acetyl group, a pivaloyl group, a phosphoryl group, an aminodecanoyl group, or an alkoxycarbonyl group.
5. 一种制备权利要求 1-4 中任一项所述的化合物或其药学上可接受的 盐或前药酯的方法, 所述方法包括以下步骤: 5. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable compound thereof A method of salt or prodrug ester, the method comprising the steps of:
上述路线中的 RSR ^CH : !^; 化合物 II与 R9R1()C=PPh3 ( Wittig试剂) III 反应后再与 TBDPSCl反应, 最终转化为 IV; 化合物 IV经过 Wacker氧化转化 为 V;化合物 V与芳基锂化合物 VI反应得到化合物 VII;化合物 VII中的 TBDPS 保护基用 TBAF (四丁基氟化铵) 处理除去得到化合物 VIII; 化合物 VIII经 过酸催化环化得到化合物 IX, 优选地所述酸为三氟乙酸、 曱蹟酸、 三氟曱蹟 酸、硫酸或 HC1; 化合物 IX用 DDQ脱去其中的 PMB (对曱氧基苄基)保护基, 得到目标化合物 I; 其中 -R7的定义如权利要求 1-3中任一项所述, R9和 R1 G 独立选自 H和 CrC4的烷基。 RSR ^CH in the above route: !^; Compound II reacts with R 9 R 1 () C = PPh 3 (Wittig reagent) III and then reacts with TBDPSCl to be finally converted to IV; Compound IV is converted to V by Wacker oxidation; Compound V is reacted with aryllithium compound VI to give compound VII; the TBDPS protecting group in compound VII is removed by treatment with TBAF (tetrabutylammonium fluoride) to give compound VIII; compound VIII is subjected to acid-catalyzed cyclization to give compound IX, preferably The acid is trifluoroacetic acid, trace acid, trifluoroantimonic acid, sulfuric acid or HCl; Compound IX is removed from the PMB (p-methoxybenzyl) protecting group with DDQ to obtain the target compound I; wherein -R 7 Definitions As defined in any one of claims 1 to 3, R 9 and R 1 G are independently selected from the group consisting of H and C r C 4 alkyl.
6. 一种制备权利要求 1-4 中任一项所述的化合物或其药学上可接受的 盐或前药酯的方法, 所述方法包括以下步骤: 6. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable compound thereof A method of salt or prodrug ester, the method comprising the steps of:
上述路线中的 R9R1GCH = R1; 化合物 V用强碱处理后再与 Tf20反应, 得 到化合物 X,优选地所述强碱为 LDA; 化合物 X与芳基硼酸 XI在 Pd催化剂催 化下偶合得到化合物 XII,优选地所述 Pd催化剂为 Pd(PPh3)4;化合物 XII用 12处 理而发生环化得到化合物 XIII; 化合物 XIII用《-Bu3SnH和 AIBN处理脱去碘, 得到化合物 XIV; 化合物 XIV用 DDQ处理脱去 PMB保护基, 得到化合物 I; 其中 -R7的定义如权利要求 1-3 中任一所述, R9和 R1G独立选自 H和 CrC4的 烷基。 R 9 R 1G CH = R 1 in the above route; compound V is treated with a strong base and then reacted with Tf 20 to obtain compound X, preferably the strong base is LDA; compound X and aryl boronic acid XI in Pd catalyst catalyzed coupling to give the compound XII, preferably the Pd catalyst is Pd (PPh 3) 4; compound XII 1 2 processing occurs cyclized compound XIII; compound XIII with "-Bu 3 SnH and AIBN iodine off process, Compound XIV is obtained; compound XIV is treated with DDQ to remove the PMB protecting group to give compound I; wherein -R 7 is as defined in any one of claims 1-3, and R 9 and R 1G are independently selected from H and C r C 4 alkyl groups.
7. 根据权利要求 1-4 中任一项所述的化合物或其药学上可接受的盐或 前药酯在制备治疗糖尿病药物中的用途; 优选地, 所述糖尿病为非胰岛素依 赖型糖尿病。 The use of a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or prodrug thereof, for the preparation of a medicament for treating diabetes; preferably, the diabetes is non-insulin dependent diabetes.
8 一种药物组合物, 所述药物组合物包含权利要求 1-4中任一项所述的 化合物或其药学上可接受的盐或前药酯。 A pharmaceutical composition comprising the compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or prodrug ester thereof.
9 根据权利要求 8所述的药物组合物, 其中, 所述药物组合物还包含一 种或多种药学上可接受的载体、 赋形剂和 /或稀释剂。 The pharmaceutical composition according to claim 8, wherein the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers, excipients and/or diluents.
10. 根据权利要求 8或 9所述的药物组合物, 其中, 所述药物组合物为 固体口服制剂、 液体口服制剂或注射剂。 The pharmaceutical composition according to claim 8 or 9, wherein the pharmaceutical composition is a solid oral preparation, a liquid oral preparation or an injection.
1 1 根据权利要求 10所述的药物组合物, 其中, 所述固体及液 体口服制剂包括: 分散片、 肠溶片、 咀嚼片、 口崩片、 胶嚢、 颗粒 剂和口服溶液剂, 所述注射剂包括注射用水针、 注射用冻干粉针、 大输液和小输液。 The pharmaceutical composition according to claim 10, wherein the solid and liquid oral preparations comprise: a dispersible tablet, an enteric coated tablet, a chewable tablet, an orally disintegrating tablet, a capsule, a granule, and an oral solution, Injections include water for injection, lyophilized powder for injection, large infusion and small infusion.
12. 一种治疗糖尿病的方法, 该方法包括向患者给药治疗有效 量的权利要求 1至 4中任一项所述的化合物或其药学上可接受的盐 或前药酯; 优选地, 所述化合物或其药学上可接受的盐或前药酯的 治疗剂量范围为 l mg~ 1000mg/人 /日。 12. A method of treating diabetes, the method comprising administering to a patient a therapeutically effective amount of a compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt or prodrug thereof; The therapeutic dose of the compound or a pharmaceutically acceptable salt or prodrug ester thereof ranges from 1 mg to 1000 mg per person per day.
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