WO2011095050A1 - C-glycoside derivatives containing saturated 6-member rings, preparation methods and uses thereof - Google Patents
C-glycoside derivatives containing saturated 6-member rings, preparation methods and uses thereof Download PDFInfo
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- WO2011095050A1 WO2011095050A1 PCT/CN2011/000147 CN2011000147W WO2011095050A1 WO 2011095050 A1 WO2011095050 A1 WO 2011095050A1 CN 2011000147 W CN2011000147 W CN 2011000147W WO 2011095050 A1 WO2011095050 A1 WO 2011095050A1
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- pharmaceutically acceptable
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- prodrug
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- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 229920006395 saturated elastomer Polymers 0.000 title abstract description 8
- 229930182476 C-glycoside Natural products 0.000 title abstract 2
- 150000000700 C-glycosides Chemical class 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 58
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 19
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 13
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 13
- 239000003814 drug Substances 0.000 claims abstract description 12
- 239000003112 inhibitor Substances 0.000 claims abstract description 9
- 125000004430 oxygen atom Chemical group O* 0.000 claims abstract description 7
- 238000004519 manufacturing process Methods 0.000 claims abstract 2
- -1 cyclodecyl group Chemical group 0.000 claims description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
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- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
- 229910052799 carbon Inorganic materials 0.000 claims description 15
- 229940002612 prodrug Drugs 0.000 claims description 15
- 239000000651 prodrug Substances 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 13
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 12
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- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 9
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 9
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- QNLQKURWPIJSJS-UHFFFAOYSA-N trimethylsilylphosphane Chemical group C[Si](C)(C)P QNLQKURWPIJSJS-UHFFFAOYSA-N 0.000 claims 1
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Classifications
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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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4433—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
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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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing aromatic rings
Definitions
- the present invention relates to the field of medicines associated with diabetes.
- the present invention relates to a type 2 glucosinolate co-transporter (SGLT2) inhibitor containing a saturated six-membered ring C-glucoside structure which has a therapeutic effect on diabetes, a preparation method thereof, and a pharmaceutical composition containing the same.
- SGLT2 type 2 glucosinolate co-transporter
- the antidiabetic drugs currently in clinical use are mainly metformin, sulfonylureas, insulins, thiazolidinediones, (X-glucosidase inhibitors and dipeptidyl peptidase-IV inhibitors, these The drug has a good therapeutic effect, 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 glucosamine 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 blood glucose concentration. This method reduces blood sugar through different and previous ways. Level. When SGLT2 is blocked, more glucose will be secreted in the urine, which will help diabetics maintain the correct blood sugar levels. Since SGLT2 inhibitors are not involved in glucose metabolism, they can be used as a supplement to mainstream blood glucose control methods.
- x is a covalent bond or a lower order fluorenylene group.
- An object of the present invention is to overcome the shortcomings and deficiencies of the prior art and to provide a SGLT2 inhibitor having good activity, which is a saturated six-membered ring-containing C-glucoside having the structure of Formula I and a pharmaceutical thereof Acceptable salts and prodrug esters.
- Another object of the present invention is to provide a process for the preparation of a saturated six-membered ring-containing C-glucoside having the structure of the formula I of the present invention.
- a further object of the present invention is to provide a compound of formula I, and pharmaceutically acceptable salts and prodrugs thereof, as active ingredient, together with one or more pharmaceutically acceptable carriers, excipients and/or diluents Pharmaceutical composition, and its use in inhibiting type 2 glucosamine co-transporters, For example, in the treatment of diabetes.
- the C-glucoside derivatives containing a saturated six-membered ring provided by the present invention are novel SGLT2 inhibitors, and these inhibitors lay the foundation for the preparation of a medicament which can be further used for the treatment of diabetes, particularly non-insulin dependent diabetes.
- the present invention provides a compound of the I structure:
- R 1 is selected from the group consisting of H, F, Br, I, OR 3 , SR 4 , OCF 3 , CF 3 , CHF 2 , CH 2 F, a decyl group of dC 3 , a cyclodecyl group having 3 to 5 carbon atoms, wherein R 3 and R 4 are independently selected from the indenyl group of C r C 3 , which is optionally substituted by one or more atoms selected from the group consisting of F and C 1 ;
- R 2 is selected from the group consisting of H and C r C 5 ;
- R 1 is selected from the group consisting of H, F, OMe, SMe, OCF 3 , CF 3 , CHF 2 , CH 2 F, CH 3 , a cyclodecyl group having 3 to 5 carbon atoms, optionally having a fluorenyl group and a cyclodecyl group.
- the ground is replaced by one or more atoms selected from F and C1;
- R 2 is selected from the group consisting of H and ( ⁇ -(3 ⁇ 4);
- the base A may be selected from the group consisting of N-methylmorpholine, triethylamine, pyridine and 4-dimethylaminopyridine
- the base B may be selected from the group consisting of anhydrous sodium acetate, pyridine and 4-dimethylaminopyridine
- the base C may be selected from the group consisting of sodium methoxide, NaOH and KOH.
- the trimethylsilylating agent may be trimethylsilyl silane; the fluorenyl lithium reagent may be n-butyllithium; the acid may be selected from methanesulfonic acid, trifluoromethyl Sulfonic acid and p-toluenesulfonic acid; the Lewis acid may be selected from the group consisting of BF 3 .Et 2 0, BF 3 .MeCN and trifluoroacetic acid; the reducing agent may be selected from the group consisting of triethylsilyl and triisopropylsilyl The acetylating agent may be selected from the group consisting of acetic anhydride and acetyl chloride.
- Compound II is treated with a trimethylsilylating agent in the presence of a base A to obtain a compound III, and a base A such as N-methylmorpholine, triethylamine, pyridine, 4-dimethylaminopyridine or the like; A methylsilylation reagent such as trimethylsilyl silane or the like.
- Compound IV is treated with a mercaptolithium reagent such as n-butyllithium to give compound V.
- Compound V is directly reacted with compound III in the reaction system without isolation to give compound VI.
- Compound VI is treated with methanol under the catalysis of an acid such as methanesulfonic acid, trifluoromethanesulfonic acid or p-toluenesulfonic acid to obtain a compound.
- Compound VII is reduced with a reducing agent such as triethylsilyl, triisopropylsilyl or the like in the presence of a Lewis acid such as BF 3 .Et 2 0, BF 3 .MeCN or trifluoroacetic acid to give compound VIII.
- a reducing agent such as triethylsilyl, triisopropylsilyl or the like in the presence of a Lewis acid such as BF 3 .Et 2 0, BF 3 .MeCN or trifluoroacetic acid to give compound VIII.
- Compound VIII is acetylated with a reagent such as acetic anhydride or acetyl chloride in the presence of a base such as anhydrous sodium acetate, pyridine or 4-dimethylaminopyridine to give IX.
- Compound IX is treated by column chromatography or recrystallization to give compound X.
- Compound X is treated with a base such as sodium meth
- Compound IV can be prepared by the following method depending on the difference between X and Y.
- IV-1 Compound IV-1 can be synthesized by the following route:
- B such as triethylsilylphosphonium, triisopropylsilyl, or the like, is reduced in the presence of an acid such as boron trifluoride diethyl ether or trifluoroacetic acid to obtain a compound IV-1.
- Compound IV-2 can be synthesized by the following route:
- Compound IV-3 can be synthesized using the following route:
- Compound IV-4 can be synthesized by the following route
- 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, carbamoyl groups, fluorenyl groups, and the like. Ester.
- the compounds of formula I according to the invention may be combined with one or more pharmaceutically acceptable carriers, excipients or diluents to form a pharmaceutical composition.
- the pharmaceutical composition can be formulated into a solid oral preparation, a liquid oral preparation, an injection or the like.
- the solid and liquid oral preparations include: tablets, dispersible tablets, dragees, granules, dry powders, capsules, and solutions.
- the injection includes: a small needle, a large infusion, a lyophilized powder, and the like.
- the pharmaceutically or foodly acceptable adjuvant is selected from the group consisting of: a filler, a disintegrant, a lubricant, a glidant, an effervescent agent, a flavoring agent, a preservative, a coating material, or Other excipients.
- the filler is a filler comprising one or more of lactose, sucrose, dextrin, starch, pregelatinized starch, mannitol, sorbitol, calcium hydrogen phosphate, calcium sulfate, calcium carbonate, microcrystalline cellulose;
- the binder comprises sucrose, starch, povidone, sodium carboxymethylcellulose, hypromellose, hydroxypropylcellulose, methylcellulose, polyethylene glycol, medicinal ethanol, water.
- the disintegrant comprises starch, cross-linked poly-microketone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, carboxymethylcellulose, effervescent disintegration
- the disintegrant comprises starch, cross-linked poly-microketone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, carboxymethylcellulose, effervescent disintegration
- 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 doses.
- the dosage of the compound of formula I of the present invention may be determined by the physician in light of 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 sodium hydride solution and the saturated brine were washed, dried over anhydrous sodium sulfate, and evaporated to dryness on a rotary evaporator to obtain a colorless oil of 2,3,4,6-tetra-[-trimethylsilyl gluconic acid. Lactone, on a vacuum pump at room temperature Dry for two hours, spare.
- a 100 mL round bottom flask was charged with 2.22 g of 1-bromo-3-(cyclohexylmethyl)-4-fluorobenzene prepared above, 10 mL of dry tetrahydrofuran and a magnet, and then sealed with a thin rubber stopper. It was cooled to -78 ° C in an acetone-dry ice system. Under stirring, slowly add 8 mL (1.0 M) of n-BuLi hexamethylene solution to the reaction vessel with a syringe. After the addition, the system was stirred at -78 ° C for an additional hour, and then transferred to the reaction vessel with a syringe.
- aqueous solution was dried over sodium sulfate, and evaporated to dryness on a rotary evaporator to give an off-white solid, which was purified by silica gel column chromatography to give a colorless crystal, 2,3,4,6-tetra-O-acetyl-1- ⁇ 3- [(4-Ethylpiperazin-1-yl)methyl]-4-fluorophenyl ⁇ small deoxy- ⁇ -D-glucopyranose,
- the active ingredient, the portion and the microcrystalline cellulose are sieved, thoroughly mixed, added to a solution of polyvinylpyrrolidone, mixed, made into a soft material, sieved, wet-dried, dried at 50-60 ° C, and carboxymethyl starch
- the sodium salt, stearic acid and talc are pre-screened and then added to the above granules for tableting.
- the active ingredient, the portion and the microcrystalline cellulose are sieved, thoroughly mixed, added to a solution of polyvinylpyrrolidone, mixed, made into a soft material, sieved, wet-dried, dried at 50-60 ° C, and carboxymethyl starch
- the sodium salt, stearic acid and talc are pre-screened and then added to the above granules for tableting.
- the active ingredient, powder and microcrystalline cellulose are sieved, thoroughly mixed, and added to polyethylene Acetyl ketone solution, mixed, soft material, sifted, wet granules, dried at 50-60 ° C, pre-sintered the hard fat per magnesium and talc, and then added to the above granules, capsules, ie Got it.
- Example 22
- the active ingredient, powder and microcrystalline cellulose are sieved, thoroughly mixed, added to a solution of polyvinylpyrrolidone, mixed, softened, sieved, wet granules, dried at 50-60 ° C, magnesium stearate Pre-screened with talcum powder, then added to the above granules, capsuled, Example 23
- Example 24 In distilled water, first add distilled water and citric acid, stir and dissolve, then add the sample, slightly heat to dissolve, adjust the pH value to 4. ⁇ .0, add 0.2 g of activated carbon, stir at room temperature for 20 minutes, filter , filtrate, medium control solution concentration of 5 liters per amp bottle, high temperature sterilization for 30 minutes, that is, the injection, Example 24
- Preparation process The main drug and the auxiliary material are respectively passed through a 100 mesh sieve, thoroughly mixed, and then the prescription auxiliary material is sufficiently mixed with the main drug. Adding adhesive to soft material, 14 mesh sieve granules, drying at 55 ° C, 12 The sieve is sifted and the bag is repackaged.
- Example 27 A sample prepared in the examples of the present invention was formulated into a suspension of 5 mg/mL in a concentration of 1% carboxymethylcellulose, and the dosage was 0.2 mL/20 g body weight, which was equivalent to a dose of 10 mg/kg. .
- Healthy ICR mice half male and half female, weighing 20-24 g, meet the first grade standard.
- the animals were fasted for 16 hours, and 2 g/kg of gluconate solution was injected intraperitoneally 2 hours after the drug (dpagliflozin drug 1.5 h after glucose injection).
- Capillary from the mouse ball was taken at 0.5 h, lh, 2 h, 3 h and 4 h after modeling.
- Blood was taken from the posterior venous plexus, serum was separated by centrifugation, and serum glucose content was measured by glucose oxidase method at each time point.
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Abstract
Disclosed are C-glycoside sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors containing saturated 6-member rings shown as following general formula I, preparation methods, compositions containing such compounds and uses thereof in the manufacture of diabetes drugs, in which X and Y are selected from: (1) X=Y=C atom; (2) X=Y=N atom; (3) X=N atom, Y=O atom; (4) X=N atom, Y=C atom, and the definitions of other groups are as those defined in the description.
Description
含饱和六元环的 C-葡萄糖苷衍生物、 其制备方法和用途 技术领域 C-glucoside derivative containing saturated six-membered ring, preparation method and use thereof
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 有治疗作用的含饱和六元环的 C-葡萄糖苷结构的 2 型纳葡萄糖共转运子 ( 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 glucosinolate co-transporter (SGLT2) inhibitor containing a saturated six-membered ring C-glucoside structure which has a therapeutic effect on diabetes, a preparation method thereof, and a pharmaceutical composition containing the same. Background technique
全球糖尿病患者目前大约有 1.7亿左右, 其中约绝大多数为 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甲双 胍类、 磺酰脲类、 胰岛素类、 噻唑垸二酮类、 (X-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, and most of them are type II (ie, non-insulin dependent) diabetic patients. The antidiabetic drugs currently in clinical use are mainly metformin, sulfonylureas, insulins, thiazolidinediones, (X-glucosidase inhibitors and dipeptidyl peptidase-IV inhibitors, these The drug has a good therapeutic effect, but there are safety problems in long-term treatment, such as: liver toxicity, some drugs still have weight gain and many other problems.
2型纳葡萄糖共转运子(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 的就能够降低血液中葡萄糖浓度, 这种方法通 过不同与以往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 glucosamine 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 blood glucose concentration. This method reduces blood sugar through different and previous ways. Level. When SGLT2 is blocked, more glucose will be secreted in the urine, which will help diabetics maintain the correct blood sugar levels. Since SGLT2 inhibitors are not involved in glucose metabolism, they can be used as a supplement to mainstream blood glucose control methods.
中国专利申请 CN 200610093189.9公开了下列结构的化合物作为 SGLT2 抑制剂: Chinese patent application CN 200610093189.9 discloses compounds of the following structure as SGLT2 inhibitors:
其中, A为 0、 S、 NH、 (CH2)n, n = 0-3。 抑制剂:
其中, A为共价键、 0、 S、 NH、 (CH2)n, n = l-3。 抑制剂:、 S ' 、 Where A is 0, S, NH, (CH 2 ) n and n = 0-3. Inhibitor: Wherein A is a covalent bond, 0, S, NH, (CH 2 ) n , n = l-3. Inhibitor:, S ',
WO 2005/012326 GLT2抑制剂: WO 2005/012326 GLT2 inhibitor:
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结构的含饱和六元环的 C-葡萄糖苷及其药学上可以接受的盐和前药酯。 An object of the present invention is to overcome the shortcomings and deficiencies of the prior art and to provide a SGLT2 inhibitor having good activity, which is a saturated six-membered ring-containing C-glucoside having the structure of Formula I and a pharmaceutical thereof Acceptable salts and prodrug esters.
本发明的另一个目的是提供本发明具有通式 I结构的含饱和六元环的 C- 葡萄糖苷的制备方法。 Another object of the present invention is to provide a process for the preparation of a saturated six-membered ring-containing C-glucoside having the structure of the formula I of the present invention.
本发明的再一个目的是提供含有通式 I化合物及其药学上可以接受的盐 和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, 及其在抑制 2型纳葡萄糖共转运子方面的应用, 例
如, 在治疗糖尿病方面的应用。 A further object of the present invention is to provide a compound of formula I, and pharmaceutically acceptable salts and prodrugs thereof, as active ingredient, together with one or more pharmaceutically acceptable carriers, excipients and/or diluents Pharmaceutical composition, and its use in inhibiting type 2 glucosamine co-transporters, For example, in the treatment of diabetes.
本发明提供的含饱和六元环的 C-葡萄糖苷类衍生物是一种新型的 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。
The C-glucoside derivatives containing a saturated six-membered ring provided by the present invention are novel SGLT2 inhibitors, and these inhibitors lay the foundation for the preparation of a medicament which can be further used for the treatment of diabetes, particularly non-insulin dependent diabetes.
现结合本发明的目的对本发明内容进行具体描述。 The present invention will now be described in detail with reference to the purpose of the invention.
本发明提供了一种 I结构的化合物: The present invention provides a compound of the I structure:
R1选自 H、 F、 Br、 I、 OR3、 SR4、 OCF3、 CF3、 CHF2、 CH2F、 d-C3的 垸基、 含 3-5个碳原子的环垸基, 其中 R3和 R4独立选自 CrC3的垸基, 所述垸 基和环垸基任选地被一个或多个选自 F和 C1的原子所取代; R 1 is selected from the group consisting of H, F, Br, I, OR 3 , SR 4 , OCF 3 , CF 3 , CHF 2 , CH 2 F, a decyl group of dC 3 , a cyclodecyl group having 3 to 5 carbon atoms, wherein R 3 and R 4 are independently selected from the indenyl group of C r C 3 , which is optionally substituted by one or more atoms selected from the group consisting of F and C 1 ;
R2选自 H和 CrC5的垸基; R 2 is selected from the group consisting of H and C r C 5 ;
X和 Y的定义选自如下几种情况: The definitions of X and Y are selected from the following cases:
(1) X = Y =碳原子; (1) X = Y = carbon atom;
(2) Χ = Υ = 氮原子; (2) Χ = Υ = nitrogen atom;
(3) Χ = 氮原子, Υ = 氧原子; (3) Χ = nitrogen atom, Υ = oxygen atom;
(4) Χ = 氮原子, Υ =碳原子。 优选的具有通式 I结构的化合物为: (4) Χ = nitrogen atom, Υ = carbon atom. Preferred compounds having the structure of formula I are:
其中, among them,
R1选自 H、 F、 OMe、 SMe、 OCF3、 CF3、 CHF2、 CH2F、 CH3、 含 3-5个 碳原子的环垸基, 所述垸基和环垸基任选地被一个或多个选自 F和 C1的原子 所取代; R 1 is selected from the group consisting of H, F, OMe, SMe, OCF 3 , CF 3 , CHF 2 , CH 2 F, CH 3 , a cyclodecyl group having 3 to 5 carbon atoms, optionally having a fluorenyl group and a cyclodecyl group. The ground is replaced by one or more atoms selected from F and C1;
R2选自 H和 (^-(¾的垸基; R 2 is selected from the group consisting of H and (^-(3⁄4);
X和 Y的定义选自如下几种情况: The definitions of X and Y are selected from the following cases:
(1) X = Y =碳原子;
(2) X = Y= 氮原子; (1) X = Y = carbon atom; (2) X = Y = nitrogen atom;
(3) Χ= 氮原子, Υ= 氧原子; (3) Χ = nitrogen atom, Υ = oxygen atom;
(4) Χ= 氮原子, Υ=碳原子。 最优选的通式 I化合物具有以下结构: (4) Χ = nitrogen atom, Υ = carbon atom. The most preferred compounds of formula I have the following structure:
本发明所述通式 I化合物可以通过以下步驟合成:
The compounds of formula I according to the invention can be synthesized by the following steps:
其中, 所述碱 A可以选自 N-甲基吗啉、 三乙胺、 吡啶和 4-二甲氨基吡 啶, 所述碱 B可以选自无水醋酸纳、 吡啶和 4-二甲氨基吡啶, 所述碱 C可 以选自甲醇纳、 NaOH和 KOH。 Wherein, the base A may be selected from the group consisting of N-methylmorpholine, triethylamine, pyridine and 4-dimethylaminopyridine, and the base B may be selected from the group consisting of anhydrous sodium acetate, pyridine and 4-dimethylaminopyridine. The base C may be selected from the group consisting of sodium methoxide, NaOH and KOH.
在上述合成步骤中, 所述三甲基硅基化试剂可以为三甲基氯硅垸; 所述 垸基锂试剂可以为正丁基锂; 所述酸可以选自甲磺酸、 三氟甲磺酸和对甲苯 磺酸; 所述路易斯酸可以选自 BF3.Et20、 BF3.MeCN和三氟乙酸; 所述还原 剂可以选自三乙基硅垸和三异丙基硅垸; 所述乙酰化试剂可以选自醋酸酐和 乙酰氯。 In the above synthetic step, the trimethylsilylating agent may be trimethylsilyl silane; the fluorenyl lithium reagent may be n-butyllithium; the acid may be selected from methanesulfonic acid, trifluoromethyl Sulfonic acid and p-toluenesulfonic acid; the Lewis acid may be selected from the group consisting of BF 3 .Et 2 0, BF 3 .MeCN and trifluoroacetic acid; the reducing agent may be selected from the group consisting of triethylsilyl and triisopropylsilyl The acetylating agent may be selected from the group consisting of acetic anhydride and acetyl chloride.
化合物 II在碱 A的存在下用三甲基硅基化试剂进行处理, 得到化合物 III, 所用的碱 A如 N-甲基吗啉、 三乙胺、 吡啶、 4-二甲氨基吡啶等; 三甲 基硅基化试剂如三甲基氯硅垸等。
化合物 IV用垸基锂试剂如正丁基锂处理, 得到化合物 V, 化合物 V不 加分离在反应体系中直接与化合物 III反应, 得到化合物 VI。 化合物 VI在 酸如甲磺酸、 三氟甲磺酸、 对甲苯磺酸等催化下用甲醇处理, 得到化合物Compound II is treated with a trimethylsilylating agent in the presence of a base A to obtain a compound III, and a base A such as N-methylmorpholine, triethylamine, pyridine, 4-dimethylaminopyridine or the like; A methylsilylation reagent such as trimethylsilyl silane or the like. Compound IV is treated with a mercaptolithium reagent such as n-butyllithium to give compound V. Compound V is directly reacted with compound III in the reaction system without isolation to give compound VI. Compound VI is treated with methanol under the catalysis of an acid such as methanesulfonic acid, trifluoromethanesulfonic acid or p-toluenesulfonic acid to obtain a compound.
VII。 化合物 VII在路易斯酸如 BF3.Et20、 BF3.MeCN或者三氟乙酸等存在下 用还原剂如三乙基硅垸、 三异丙基硅垸等还原得到化合物 VIII。 化合物 VIII 用在碱如无水醋酸纳、 吡啶、 4-二甲氨基吡啶等存在下用醋酸酐、 乙酰氯等 试剂乙酰化得到 IX。 化合物 IX用柱层析或者重结晶等方法处理, 得到化合 物 X。 化合物 X用碱如甲醇纳、 NaOH、 KOH等处理, 脱掉乙酰基得到化合 VII. Compound VII is reduced with a reducing agent such as triethylsilyl, triisopropylsilyl or the like in the presence of a Lewis acid such as BF 3 .Et 2 0, BF 3 .MeCN or trifluoroacetic acid to give compound VIII. Compound VIII is acetylated with a reagent such as acetic anhydride or acetyl chloride in the presence of a base such as anhydrous sodium acetate, pyridine or 4-dimethylaminopyridine to give IX. Compound IX is treated by column chromatography or recrystallization to give compound X. Compound X is treated with a base such as sodium methoxide, NaOH, KOH, etc., and the acetyl group is removed to obtain a compound.
更具体地, 本发明所述通式 I化合物通过以下步骤合成: More specifically, the compound of the formula I of the present invention is synthesized by the following steps:
化合物 IV因 X和 Y的不同可以釆用下列方法制备。 Compound IV can be prepared by the following method depending on the difference between X and Y.
(1) Χ = Υ =碳原子, (1) Χ = Υ = carbon atoms,
IV-1 化合物 IV-1可以釆用下列路线合成: IV-1 Compound IV-1 can be synthesized by the following route:
XV 化合物 XI与 Mg反应得到化合物 XII, 其中 Hal选自 Cl、 Br和 I。 化合 物 XII与化合物 XIII反应得到化合物 XIV。 化合物 XIV用卤化剂如 PBr3、 P0C13等处理, 得到化合物 XV, 其中 Hal选自 Cl、 Br和 I。 化合物 XV用 还原剂 A如 LiAlH4等还原, 得到化合物 IV-1。 或者, 化合物 XIV用还原剂XV Compound XI is reacted with Mg to give compound XII wherein Hal is selected from the group consisting of Cl, Br and I. Compound XII is reacted with compound XIII to give compound XIV. Compound XIV is treated with a halogenating agent such as PBr 3 , P0C1 3 or the like to give compound XV wherein Hal is selected from the group consisting of Cl, Br and I. Compound XV is reduced with a reducing agent A such as LiAlH 4 or the like to give compound IV-1. Alternatively, the reducing agent for compound XIV
B如三乙基硅垸、 三异丙基硅垸等在酸如三氟化硼乙醚、 三氟乙酸等存在下 还原, 可以得到化合物 IV-1。 B, such as triethylsilylphosphonium, triisopropylsilyl, or the like, is reduced in the presence of an acid such as boron trifluoride diethyl ether or trifluoroacetic acid to obtain a compound IV-1.
(2) X = Y = 氮原子, (2) X = Y = nitrogen atom,
XVI XVII IV-2 化合物 XVI与化合物 XVII反应得到化合物 IV-2, 其中 Hal选自 Cl、 Br XVI XVII IV-2 Compound XVI is reacted with compound XVII to give compound IV-2, wherein Hal is selected from Cl, Br
I I
(3)X= 氮原子, Y= 氧原子, (3) X = nitrogen atom, Y = oxygen atom,
IV-3 IV-3
XVI XVIII IV-3 XVI XVIII IV-3
化合物 XVI与化合物 XVIII反应得到化合物 IV-3, 其中 Hal选自 Cl、 Compound XVI is reacted with compound XVIII to give compound IV-3, wherein Hal is selected from Cl,
Br和 I。 Br and I.
(4)X= 氮原子, Y=碳原子, (4) X = nitrogen atom, Y = carbon atom,
IV-3 IV-3
XVI XIX IV-4 化合物 XVI与化合物 XIV反应得到化合物 IV-4, 其中 Hal选自 Cl、 Br
和 I。 XVI XIX IV-4 Compound XVI is reacted with compound XIV to give compound IV-4, wherein Hal is selected from Cl, Br And I.
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、 氨基甲酰基、 垸氧甲酰基 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, carbamoyl groups, fluorenyl groups, and the like. Ester.
本发明所述式 I化合物, 可以与一种或多种药学上可接受的载体、 赋形 剂或稀释剂共同制成药物组合物。 该药物组合物可以制成固体口服制剂、 液 体口服制剂、 注射剂等剂型。 所述固体及液体口服制剂包括: 片剂、分散片、 糖衣剂、 颗粒剂、 干粉剂、 胶囊剂和溶液剂。 所述的注射剂包括: 小针、 大 输液、 冻干粉针等。 The compounds of formula I according to the invention may be combined with one or more pharmaceutically acceptable carriers, excipients or diluents to form a pharmaceutical composition. The pharmaceutical composition can be formulated into a solid oral preparation, a liquid oral preparation, an injection or the like. The solid and liquid oral preparations include: tablets, dispersible tablets, dragees, granules, dry powders, capsules, and solutions. The injection includes: a small needle, a large infusion, a lyophilized powder, and the like.
本发明的组合物, 所述的药学或食品学上可接受辅料选自: 填充剂、 崩 解剂、 润滑剂、 助流剂、 泡腾剂、 矫味剂、 防腐剂、 包衣材料、 或其它赋形 剂。 In the composition of the present invention, the pharmaceutically or foodly acceptable adjuvant is selected from the group consisting of: a filler, a disintegrant, a lubricant, a glidant, an effervescent agent, a flavoring agent, a preservative, a coating material, or Other excipients.
本发明的组合物, 所述的药学或食品学上可接受辅料。 填充剂为填充剂 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、 硫酸钙、 碳酸钙、 微晶纤维素的一种或几种的组合物; 所述的粘合剂包括蔗 糖、 淀粉、 聚维酮、 羧甲基纤维素纳、 羟丙甲纤维素、 羟丙纤维素、 甲基纤 维素、 聚乙二醇、 药用乙醇、 水的一种或几种的组合物; 所述的崩解剂包括 淀粉、 交联聚微酮、 交联羧甲基纤维素纳、 低取代羟丙基纤维素、 羧甲纤维 素纳、 泡腾崩解剂的一种或几种的组合物。 A composition of the invention, said pharmaceutically or foodly acceptable adjuvant. The filler is a filler comprising one or more of lactose, sucrose, dextrin, starch, pregelatinized starch, mannitol, sorbitol, calcium hydrogen phosphate, calcium sulfate, calcium carbonate, microcrystalline cellulose; The binder comprises sucrose, starch, povidone, sodium carboxymethylcellulose, hypromellose, hydroxypropylcellulose, methylcellulose, polyethylene glycol, medicinal ethanol, water. Or a combination of several; the disintegrant comprises starch, cross-linked poly-microketone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, carboxymethylcellulose, effervescent disintegration One or several compositions of the agents.
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 l 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。 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 doses. The dosage of the compound of formula I of the present invention may be determined by the physician in light of 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.
实施发明的最佳方式 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 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. Those skilled in the art in accordance with the teachings of the present invention All changes made should be within the scope of protection required by the claims of the present application.
卜 [3- (环己基甲基 )-4- -1-脱氧 -P-D-吡喃葡; [3-(cyclohexylmethyl)-4- -1-deoxy-P-D-glucopyran;
A. 1-溴 -3- (环己基甲基 )-4-氟苯 A. 1-bromo-3-(cyclohexylmethyl)-4-fluorobenzene
一只 100 mL的圆底烧瓶中加入 2.03 g 5-溴 -2-氟苯甲醛和 10 mL无水四 氢呋喃,所得溶液用冰水洛冷却电磁搅拌,用恒压滴液漏斗滴加 11 mL (1.0 M) 环己基溴化镁的 THF溶液, 滴加完毕后, 反应混合物在室温下搅拌一小时 后小心倾倒入 200 mL冰水中,用浓盐酸调节 pH = 3-4。所得酸性体系用 100 mL二氯甲垸分两次萃取, 合并萃取液体用饱和食盐水洗涤一次, 无水硫酸 纳干燥, 在旋转蒸发仪上蒸干, 得到一无色油状物, 为 (5-溴 -2-氟苯基) (环己 基)甲醇。 ESI-MS, m/z = 287.2 ([M(79Br)+l]), 289.2 ([M(81Br)+l])。 2.03 g of 5-bromo-2-fluorobenzaldehyde and 10 mL of anhydrous tetrahydrofuran were added to a 100 mL round bottom flask. The solution was stirred and cooled with ice water, and 11 mL (1.0 mL) was added dropwise with a constant pressure dropping funnel. M) A solution of cyclohexylmagnesium bromide in THF. After the dropwise addition, the reaction mixture was stirred at room temperature for one hour, then poured into 200 mL of ice water and adjusted to pH 3-4 with concentrated hydrochloric acid. The obtained acidic system was extracted twice with 100 mL of dichloromethane, and the combined extracts were washed once with saturated brine, dried over anhydrous sodium sulfate, and evaporated on a rotary evaporator to give a colorless oil (5- Bromo-2-fluorophenyl) (cyclohexyl)methanol. ESI-MS, m/z = 287.2 ([M ( 79 Br) + 1]), 289.2 ([M ( 81 Br) + l]).
上述得到的 (5-溴 -2-氟苯基) (环己基)甲醇油状物 2.58 g溶解到 3 mL干燥 二氯甲垸中, 冰水洛冷却下搅拌, 先后加入三乙基硅垸 2 mL和三氟化硼乙 醚 l mL。 所得反应体系在室温下搅拌过夜, 小心倾倒到 100 mL冰水中, 以 饱和碳酸氢纳溶液调节到 pH = 8, 用 100 mL二氯甲垸分两次萃取, 合并萃 取液体用饱和食盐水洗涤一次, 无水硫酸纳干燥, 在旋转蒸发仪上蒸干, 得 到一无色油状物, 即为 1-溴 -3- (环己基甲基 )-4-氟苯, ESI-MS, m/z = 271.1 ([M(79Br)+l]), 273.2 ([M(81Br)+l])„ 2.58 g of the above-obtained (5-bromo-2-fluorophenyl)(cyclohexyl)methanol oil was dissolved in 3 mL of dry dichloromethane, and the mixture was stirred under ice cooling, followed by the addition of triethylsilyl ruthenium 2 mL. And 1 mL of boron trifluoride etherate. The resulting reaction system was stirred at room temperature overnight, carefully poured into 100 mL of ice water, adjusted to pH = 8 with saturated sodium bicarbonate solution, extracted twice with 100 mL of dichloromethane, and the combined extracts were washed once with saturated brine. Drying in anhydrous sodium sulfate, evaporation to dryness on a rotary evaporator to give a colorless oil, 1-bromo-3-(cyclohexylmethyl)-4-fluorobenzene, ESI-MS, m/z = 271.1 ([M( 79 Br)+l]), 273.2 ([M( 81 Br)+l])„
B. 2,3,4,6-四 -O-三甲基硅基葡萄糖酸内酯 B. 2,3,4,6-tetra-O-trimethylsilyl gluconolactone
一只 250 mL的圆底烧瓶中加入 1.78 g葡萄糖酸内酯、 8.09 g N-甲基吗 啉和干燥四氢呋喃 20 mL, 体系在冰水洛冷却下电磁搅拌, 慢慢滴加 6.52 g 的三甲基氯硅垸溶解到 10 mL干燥 THF中得到的溶液。 滴加完毕后, 体系 在室温下搅拌过夜,用 100 mL甲苯稀释,冰水冷却下往其中慢慢滴加 10 mL 水, 而后把所得混合物转移到分液漏斗中, 依次用 lOO mL饱和磷酸二氢纳 溶液和饱和食盐水洗涤, 无水硫酸纳干燥, 在旋转蒸发仪上蒸干, 得到一无 色油状物, 为 2,3,4,6-四 -0-三甲基硅基葡萄糖酸内酯, 在真空油泵上室温下
干燥两小时, 备用。 A 250 mL round bottom flask was charged with 1.78 g of gluconolactone, 8.09 g of N-methylmorpholine and 20 mL of dry tetrahydrofuran. The system was stirred under ice cooling, and 6.52 g of the top three was slowly added dropwise. A solution obtained by dissolving chlorosilane in 10 mL of dry THF. After the completion of the dropwise addition, the system was stirred at room temperature overnight, diluted with 100 mL of toluene, and 10 mL of water was slowly added dropwise thereto while cooling with ice water, and then the resulting mixture was transferred to a separatory funnel, followed by 100 mL of saturated phosphoric acid. The sodium hydride solution and the saturated brine were washed, dried over anhydrous sodium sulfate, and evaporated to dryness on a rotary evaporator to obtain a colorless oil of 2,3,4,6-tetra-[-trimethylsilyl gluconic acid. Lactone, on a vacuum pump at room temperature Dry for two hours, spare.
C. 1-[3- (环己基甲基 )-4-氟苯基 ]-1-脱氧 -β-D-吡喃葡萄糖 C. 1-[3-(cyclohexylmethyl)-4-fluorophenyl]-1-deoxy-β-D-glucopyranose
一只 100 mL的圆底烧瓶中加入上述制备的 2.22 g 1-溴 -3- (环己基甲 基) -4-氟苯, 10 mL干燥的四氢呋喃和一个磁子, 而后以薄橡胶塞封口, 置 于丙酮 -干冰体系中冷却到 -78°C。 搅拌下, 用注射器往此反应容器中慢慢加 入 8 mL (1.0 M) n-BuLi的正己垸溶液, 加完后体系在 -78°C下再搅拌一小时, 而后用注射器再往该反应容器中慢慢加入上述制备的 2,3,4,6-四 -0-三甲基硅 基葡萄糖酸内酯溶解到 10 mL干燥甲苯中形成的溶液。 加完后,体系再搅拌 一小时,而后用注射器加入 1.92 g的甲磺酸溶解到 10 mL无水甲醇中形成的 溶液, 而后体系慢慢升温到室温, 室温下搅拌过夜。 反应混合物倾倒到饱和 食盐水中, 用 100 mL二氯甲垸分两次萃取, 合并萃取液体用饱和食盐水洗 涤一次, 无水硫酸纳干燥, 在旋转蒸发仪上蒸干, 得到一无色油状物, 即为 1-[3- (环己基甲基 )-4-氟苯基 ]-a/p-D-甲基吡喃葡萄糖苷, ESI-MS, m/z = 385.3 ([M+l])。 A 100 mL round bottom flask was charged with 2.22 g of 1-bromo-3-(cyclohexylmethyl)-4-fluorobenzene prepared above, 10 mL of dry tetrahydrofuran and a magnet, and then sealed with a thin rubber stopper. It was cooled to -78 ° C in an acetone-dry ice system. Under stirring, slowly add 8 mL (1.0 M) of n-BuLi hexamethylene solution to the reaction vessel with a syringe. After the addition, the system was stirred at -78 ° C for an additional hour, and then transferred to the reaction vessel with a syringe. A solution of the above prepared 2,3,4,6-tetra-O-trimethylsilylgluconolactone dissolved in 10 mL of dry toluene was slowly added. After the addition, the system was further stirred for one hour, and then a solution of 1.92 g of methanesulfonic acid dissolved in 10 mL of anhydrous methanol was added by a syringe, and then the system was slowly warmed to room temperature and stirred at room temperature overnight. The reaction mixture was poured into a saturated aqueous solution of sodium chloride, and extracted twice with 100 mL of dichloromethane. The combined extracts were washed once with brine, dried over anhydrous sodium sulfate and evaporated to dryness , that is, 1-[3-(cyclohexylmethyl)-4-fluorophenyl]-a/pD-methylpyranoside, ESI-MS, m/z = 385.3 ([M+l]).
上述得到的 1-[3- (环己基甲基 )-4-氟苯基 ]-α/β-ϋ-甲基吡喃葡萄糖苷油状 物 2.08 g溶解到 3 mL干燥二氯甲垸中, 冰水洛冷却下搅拌, 先后加入三乙 基硅垸 2 mL和三氟化硼乙醚 l mL。 所得反应体系在室温下搅拌过夜, 小心 倾倒到 100 mL冰水中, 以饱和碳酸氢纳溶液调节到 pH = 8, 用 100 mL二 氯甲垸分两次萃取,合并萃取液体用饱和食盐水洗涤一次,无水硫酸纳干燥, 在旋转蒸发仪上蒸干, 得到一无色油状物, 即为 1-[3- (环己基甲基 )-4-氟苯 基 ]-a/p-D-吡喃葡萄糖, ESI-MS, m/z = 355.1 ([M+l])„ The above-obtained 1-[3-(cyclohexylmethyl)-4-fluorophenyl]-α/β-ϋ-methylpyranoside oil 2.08 g was dissolved in 3 mL of dry dichloromethane, ice The water was stirred under cooling, and then 2 mL of triethylsilane and 1 mL of boron trifluoride diethyl ether were successively added. The resulting reaction system was stirred at room temperature overnight, carefully poured into 100 mL of ice water, adjusted to pH = 8 with saturated sodium bicarbonate solution, extracted twice with 100 mL of dichloromethane, and the combined extracts were washed once with saturated brine. Drying in anhydrous sodium sulfate, evaporation to dryness on a rotary evaporator to give a colorless oil, 1-[3-(cyclohexylmethyl)-4-fluorophenyl]-a/pD-glucopyranose , ESI-MS, m/z = 355.1 ([M+l])„
上述得到的 1-[3- (环己基甲基 )-4-氟苯基 ]-a/p-D-吡喃葡萄糖无色油状物 1.78 g溶解到 20 mL醋酸酐中, 加入 0.5 g无水醋酸纳, 电磁搅拌升温回流 1 小时。 冷却后, 体系倾倒到 lOO mL水中, 室温下搅拌过夜, 用 lOO mL二氯 甲垸分两次萃取, 合并萃取液体用饱和食盐水洗涤一次, 无水硫酸纳干燥, 在旋转蒸发仪上蒸干, 得到类白色固体, 经过硅胶柱层析纯化得到一无色晶 体, 2,3,4,6-四 -0-乙酰基 -1-[3- (环己基甲基 )-4-氟苯基 ]-1-脱氧 -β-D-吡喃葡萄 糖, ESI-MS, m/z = 523.2 ([M+l])„ 1.78 g of the 1-[3-(cyclohexylmethyl)-4-fluorophenyl]-a/pD-glucopyranose colorless oil obtained above was dissolved in 20 mL of acetic anhydride, and 0.5 g of anhydrous sodium acetate was added. , Electromagnetic stirring was heated and refluxed for 1 hour. After cooling, the system was poured into 100 mL of water, stirred at room temperature overnight, extracted twice with 100 mL of dichloromethane, and the combined extracts were washed once with saturated brine, dried over anhydrous sodium sulfate, and evaporated on a rotary evaporator. An off-white solid was obtained, which was purified by silica gel column chromatography to afford crystals of crystals of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of ]-1-deoxy-β-D-glucopyranose, ESI-MS, m/z = 523.2 ([M+l]) „
上述 2,3,4,6-四 -0-乙酰基 -1-[3- (环己基甲基 )-4-氟苯基 ]-1-脱氧 -β-D-吡喃 葡萄糖 1.98 g溶解到含有 0.11 g甲醇纳的 7 mL无水甲醇中, 室温下搅拌 5 小时, 而后加入 l g干燥的强酸性阳离子交换树脂, 室温下搅拌过夜。 过滤
除去树脂, 所得滤液在旋转蒸发仪上蒸干, 得到一白色固体, 即为 1-[3- (环 己基甲基) -4-氟苯基 ]-1-脱氧 -β-D-吡喃葡萄糖, ESI-MS, m/z = 355.2 ([M+l])。 实施例 2-12 The above 2,3,4,6-tetra-O-acetyl-1-[3-(cyclohexylmethyl)-4-fluorophenyl]-1-deoxy-β-D-glucopyranose 1.98 g was dissolved in The mixture was stirred at room temperature for 5 hours in 7 mL of anhydrous methanol containing 0.11 g of sodium methoxide, and then lg dried strong acid cation exchange resin was added thereto, and stirred at room temperature overnight. Filter The resin was removed and the filtrate obtained was evaporated to dryness on a rotary evaporator to give a white solid: 1-[3-(cyclohexylmethyl)-4-fluorophenyl]-1-deoxy-β-D-glucopyranose , ESI-MS, m/z = 355.2 ([M+l]). Example 2-12
可以理解的是, 使用实施例 1的方法和流程, 改变 R R2可以得到下表 所列的化合物。 It will be appreciated that using the method and scheme of Example 1, the RR 2 can be varied to provide the compounds listed in the table below.
l-{3-[(4-乙基哌嗪 -1-基) -4-氟-苯基}-1-脱氧 -P-D-吡喃葡萄糖 L-{3-[(4-ethylpiperazin-1-yl)-4-fluoro-phenyl}-1-deoxy-P-D-glucopyranose
A. 溴2—[(4乙基哌嗪 -1-基)甲基]小氟苯 A. bromo-2 - [(4-ethyl-piperazin-1-yl) methyl] Small-fluorophenyl
一只 100 mL的圆底烧瓶中加入 2.84 g 5-溴 -2-氟苄基溴, 1.14 g 1-乙基哌 嗪, 1.01 g三乙胺和 20 mL无水四氢呋喃, 所得反应混合物在室温下搅拌过 夜后倾倒到 200 mL水中,用 100 mL二氯甲垸分两次萃取,合并萃取液体用 饱和食盐水洗涤一次, 无水硫酸纳干燥, 在旋转蒸发仪上蒸干, 得到类白色 固体, 为 4-溴 -2-[(4-乙基哌嗪 -1-基)甲基] -1-氟苯。 ESI-MS, m/z = 301.2 ([M(79Br)+l]), 303.1 ([M(81Br)+l])。 A 100 mL round bottom flask was charged with 2.84 g of 5-bromo-2-fluorobenzyl bromide, 1.14 g of 1-ethylpiperazine, 1.01 g of triethylamine and 20 mL of anhydrous tetrahydrofuran. After stirring overnight, the mixture was poured into 200 mL of water, extracted twice with 100 mL of dichloromethane, and the combined extracts were washed once with saturated brine, dried over anhydrous sodium sulfate and evaporated to dryness Is 4-bromo-2-[(4-ethylpiperazin-1-yl)methyl]-1-fluorobenzene. ESI-MS, m/z = 301.2 ([M ( 79 Br) + 1]), 303.1 ([M ( 81 Br) + l]).
B. l-{3-[(4-乙基哌嗪 -1-基)甲基] -4-氟苯基 }小脱氧 -β-D-吡喃葡萄糖 一只 100 mL的圆底烧瓶中加入上述制备的 2.56 84-溴-2-[(4-乙基哌嗪
-1-基)甲基] -1-氟苯, 10 mL干燥的四氢呋喃和一个磁子, 而后以薄橡胶塞封 口, 置于丙酮 -干冰体系中冷却到 -78°C。 搅拌下, 用注射器往此反应容器中 慢慢加入 10 mL (1.0 M) n-BuLi的正己垸溶液, 加完后体系在 -78°C下再搅拌 一小时, 而后用注射器再往该反应容器中慢慢加入按照实施例 1中的方法制 备的 2,3,4,6-四 -0-三甲基硅基葡萄糖酸内酯溶解到 10 mL干燥甲苯中形成的 溶液。 加完后, 体系再搅拌一小时, 而后用注射器加入 1.92 g的甲磺酸溶解 到 10 mL无水甲醇中形成的溶液, 而后体系慢慢升温到室温, 室温下搅拌过 夜。 反应混合物倾倒到饱和食盐水中, 以饱和碳酸氢纳溶液调节到 pH = 8, 用 100 mL二氯甲垸分两次萃取, 合并萃取液体用饱和食盐水洗涤一次, 无 水硫酸纳干燥, 在旋转蒸发仪上蒸干, 得到一无色油状物, 即为 1-{3-[(4-乙 基哌嗪 -1-基)甲基] -4-氟苯基 }-α/β·0-甲基吡喃葡萄糖苷, ESI-MS, m/z = 415.1 ([M+l])。 B. l-{3-[(4-Ethylpiperazin-1-yl)methyl]-4-fluorophenyl}small deoxy-β-D-glucopyranose was added to a 100 mL round bottom flask 2.56 8 4-bromo-2-[(4-ethylpiperazine) prepared above 1-yl)methyl]-1-fluorobenzene, 10 mL of dry tetrahydrofuran and a magnet, then sealed with a thin rubber stopper and placed in an acetone-dry ice system to cool to -78 °C. While stirring, 10 mL (1.0 M) of n-BuLi n-hexane solution was slowly added to the reaction vessel with a syringe. After the addition, the system was further stirred at -78 ° C for one hour, and then transferred to the reaction vessel with a syringe. A solution of 2,3,4,6-tetra-O-trimethylsilylgluconolactone prepared according to the method of Example 1 dissolved in 10 mL of dry toluene was slowly added thereto. After the addition was completed, the system was further stirred for one hour, and then a solution of 1.92 g of methanesulfonic acid dissolved in 10 mL of anhydrous methanol was added by a syringe, and then the system was slowly warmed to room temperature and stirred at room temperature overnight. The reaction mixture was poured into a saturated saline solution, adjusted to pH = 8 with a saturated sodium hydrogencarbonate solution, extracted twice with 100 mL of dichloromethane, and the combined extracts were washed once with saturated brine, dried over anhydrous sodium sulfate Evaporation on an evaporator to give a colorless oil that is 1-{3-[(4-ethylpiperazin-1-yl)methyl]-4-fluorophenyl}-α/β·0- Methylpyranoside, ESI-MS, m/z = 415.1 ([M+l]).
上述得到的 1-{3-[(4-乙基哌嗪 -1-基)甲基] -4-氟苯基 }-a/p-D-甲基吡喃葡 萄糖苷油状物 2.50 g溶解到 3 mL干燥二氯甲垸中, 冰水洛冷却下搅拌, 先 后加入三乙基硅垸 2 mL和三氟化硼乙醚 l mL。所得反应体系在室温下搅拌 过夜, 小心倾倒到 100 mL冰水中, 以饱和碳酸氢纳溶液调节到 pH = 8, 用 lOO mL二氯甲垸分两次萃取, 合并萃取液体用饱和食盐水洗涤一次, 无水 硫酸纳干燥, 在旋转蒸发仪上蒸干, 得到一无色油状物, 即为 1-{3-[(4-乙基 哌嗪 -1-基)甲基] -4-氟苯基 }-a/p-D-吡喃葡萄糖, ESI-MS, m/z = 385.1 ([M+l])。 The 1-{3-[(4-ethylpiperazin-1-yl)methyl]-4-fluorophenyl}-a/pD-methylpyranoside oil obtained above was dissolved in 2. 5 g to 3 mL In the dry dichloromethane, the ice water was stirred under cooling, and then 2 mL of triethylsilane and 1 mL of boron trifluoride diethyl ether were successively added. The resulting reaction system was stirred at room temperature overnight, carefully poured into 100 mL of ice water, adjusted to pH = 8 with saturated sodium bicarbonate solution, extracted twice with 100 mL of dichloromethane, and the combined extracts were washed once with saturated brine. Drying in anhydrous sodium sulfate, evaporation to dryness on a rotary evaporator to give a colorless oil, 1-{3-[(4-ethylpiperazin-1-yl)methyl]-4-fluorobenzene }--/pD-glucopyranose, ESI-MS, m/z = 385.1 ([M+l]).
上述得到的 1-{3-[(4-乙基哌嗪 -1-基)甲基] -4-氟苯基 }-a/p-D-吡喃葡萄糖 无色油状物 2.21 g溶解到 20 mL醋酸酐中, 加入 0.5 g无水醋酸纳, 电磁搅 拌升温回流 1小时。 冷却后, 体系倾倒到 lOO mL水中, 室温下搅拌过夜, 以饱和碳酸氢纳溶液调节到 pH = 8, 用 lOO mL二氯甲垸分两次萃取, 合并 萃取液体用饱和食盐水洗涤一次, 无水硫酸纳干燥, 在旋转蒸发仪上蒸干, 得到类白色固体, 经过硅胶柱层析纯化得到一无色晶体, 2,3,4,6-四 -0-乙酰 基 -1-{3-[(4-乙基哌嗪 -1-基)甲基] -4-氟苯基 }小脱氧 -β-D-吡喃葡萄糖, 2-{3-[(4-Ethylpiperazin-1-yl)methyl]-4-fluorophenyl}-a/pD-glucopyranose obtained as a colorless oil 2.21 g dissolved in 20 mL of acetic acid To the anhydride, 0.5 g of anhydrous sodium acetate was added, and the mixture was heated under reflux with electromagnetic stirring for 1 hour. After cooling, the system was poured into 100 mL of water, stirred at room temperature overnight, adjusted to pH = 8 with saturated sodium bicarbonate solution, extracted twice with 100 mL of dichloromethane, and the combined extracts were washed once with saturated brine. The aqueous solution was dried over sodium sulfate, and evaporated to dryness on a rotary evaporator to give an off-white solid, which was purified by silica gel column chromatography to give a colorless crystal, 2,3,4,6-tetra-O-acetyl-1-{3- [(4-Ethylpiperazin-1-yl)methyl]-4-fluorophenyl}small deoxy-β-D-glucopyranose,
ESI-MS, m/z = 553.1 ([M+l])„ ESI-MS, m/z = 553.1 ([M+l])„
上述 2,3,4,6-四 -0-乙酰基 -1-{3-[(4-乙基哌嗪 -1-基)甲基] -4-氟苯基 }小脱 氧 -β-D-吡喃葡萄糖 2.34 g溶解到含有 0.11 g甲醇纳的 7 mL无水甲醇中, 室 温下搅拌 5小时, 而后加入 l g干燥的强酸性阳离子交换树脂, 室温下搅拌 过夜。 过滤除去树脂, 所得滤液在旋转蒸发仪上蒸干, 得到一白色固体, 即 为 1-{3-[(4-乙基哌嗪 -1-基)甲基] -4-氟苯基 }小脱氧 -β-D-吡喃葡萄糖,
ESI-MS, m/z = 384.3 ([M+l])。 The above 2,3,4,6-tetra-0-acetyl-1-{3-[(4-ethylpiperazin-1-yl)methyl]-4-fluorophenyl}small deoxy-β-D 2-2.3 g of glucopyranose was dissolved in 7 mL of anhydrous methanol containing 0.11 g of sodium methoxide, stirred at room temperature for 5 hours, and then lg dried strong acid cation exchange resin was added, and stirred at room temperature overnight. The resin was removed by filtration, and the obtained filtrate was evaporated to dryness on a rotary evaporator to give a white solid, which was 1-{3-[(4-ethylpiperazin-1-yl)methyl]-4-fluorophenyl} Deoxy-β-D-glucopyranose, ESI-MS, m/z = 384.3 ([M+l]).
实施例 14-18 Example 14-18
可以理解的是, 使用实施例 13的方法和流程, 改变 Rl、 R2和 Y, 可 以得到下表所列的化合物。 It will be appreciated that the compounds listed in the table below can be obtained by varying the R1, R2 and Y using the method and scheme of Example 13.
用量 /片 Dosage / film
10 mg
:晶纤维: 80 mg 10 mg :crystalline fiber: 80 mg
70 mg 70 mg
聚乙烯吡咯垸酮 6 mg Polyvinylpyrrolidone 6 mg
羧甲基淀粉纳盐 5 mg Carboxymethyl starch sodium salt 5 mg
硬脂酸镁 2 mg Magnesium stearate 2 mg
滑石粉 2 mg Talc powder 2 mg
将活性成分、 份和微晶纤维素过筛, 充分混合, 加入聚乙烯吡 咯垸酮溶液, 混合, 制软材, 过筛, 制湿颗粒, 于 50-60°C干燥, 将羧甲基 淀粉纳盐, 硬脂酸 和滑石粉预先过筛, 然后加入到上述的颗粒中压片。 实施例 20 The active ingredient, the portion and the microcrystalline cellulose are sieved, thoroughly mixed, added to a solution of polyvinylpyrrolidone, mixed, made into a soft material, sieved, wet-dried, dried at 50-60 ° C, and carboxymethyl starch The sodium salt, stearic acid and talc are pre-screened and then added to the above granules for tableting. Example 20
用量 /片 Dosage / film
实施例 4样品 10 mg Example 4 Sample 10 mg
:晶纤维: 80 mg :crystalline fiber: 80 mg
70 mg 70 mg
聚乙烯吡咯垸酮 6 mg Polyvinylpyrrolidone 6 mg
羧甲基淀粉纳盐 5 mg Carboxymethyl starch sodium salt 5 mg
硬脂酸镁 2 mg Magnesium stearate 2 mg
滑石粉 2 mg Talc powder 2 mg
将活性成分、 份和微晶纤维素过筛, 充分混合, 加入聚乙烯吡 咯垸酮溶液, 混合, 制软材, 过筛, 制湿颗粒, 于 50-60°C干燥, 将羧甲基 淀粉纳盐, 硬脂酸 和滑石粉预先过筛, 然后加入到上述的颗粒中压片。 实施例 21 The active ingredient, the portion and the microcrystalline cellulose are sieved, thoroughly mixed, added to a solution of polyvinylpyrrolidone, mixed, made into a soft material, sieved, wet-dried, dried at 50-60 ° C, and carboxymethyl starch The sodium salt, stearic acid and talc are pre-screened and then added to the above granules for tableting. Example 21
用量 /粒 Dosage / grain
实施例 5样品 10 mg Example 5 Sample 10 mg
20 mg 20 mg
聚乙烯吡咯垸酮 3 mg Polyvinylpyrrolidone 3 mg
硬脂酸镁 2 mg Magnesium stearate 2 mg
滑石粉 1 mg Talc powder 1 mg
将活性成分、 粉和微晶纤维素过筛, 充分混合, 加入聚乙
咯垸酮溶液, 混合, 制软材, 过筛, 制湿颗粒, 于 50-60°C干燥, 将硬脂每 镁和滑石粉预先过筛, 然后加入到上述的颗粒中, 装胶囊, 即得。 实施例 22 The active ingredient, powder and microcrystalline cellulose are sieved, thoroughly mixed, and added to polyethylene Acetyl ketone solution, mixed, soft material, sifted, wet granules, dried at 50-60 ° C, pre-sintered the hard fat per magnesium and talc, and then added to the above granules, capsules, ie Got it. Example 22
用量 /粒 Dosage / grain
实施例 10样品 10 mg Example 10 Sample 10 mg
:晶纤维: 30 mg : Crystal Fiber: 30 mg
20 mg 20 mg
聚乙: 比咯垸酮 3 mg Polyethylene: Bile ketone 3 mg
硬脂 i 2 mg Stearin i 2 mg
滑石粉 1 mg Talc powder 1 mg
将活性成分、 粉和微晶纤维素过筛, 充分混合, 加入聚乙烯 吡咯垸酮溶液, 混合, 制软材, 过筛, 制湿颗粒, 于 50-60°C干燥, 将硬脂 酸镁和滑石粉预先过筛, 然后加入到上述的颗粒中, 装胶囊,
实施例 23 The active ingredient, powder and microcrystalline cellulose are sieved, thoroughly mixed, added to a solution of polyvinylpyrrolidone, mixed, softened, sieved, wet granules, dried at 50-60 ° C, magnesium stearate Pre-screened with talcum powder, then added to the above granules, capsuled, Example 23
用量 /50mL Dosage /50mL
实施例 11样品 10 mg Example 11 Sample 10 mg
NaOH 适量 (调 ρΗ 4·0-5·0) NaOH amount (adjust ρΗ 4·0-5·0)
蒸馏水 50 mL Distilled water 50 mL
在蒸馏水中, 先加入. 馏水和柠檬酸, 搅拌溶解和后, 再加入样品, 微 热使溶解, 调 pH值为 4.α .0, 加 0.2克活性碳, 室温下搅拌 20分钟, 过滤, 滤液, 中控测定溶液浓度 按每安瓶 5亳升分装, 高温灭菌 30分钟, 即得 注射液, 实施例 24 In distilled water, first add distilled water and citric acid, stir and dissolve, then add the sample, slightly heat to dissolve, adjust the pH value to 4.α.0, add 0.2 g of activated carbon, stir at room temperature for 20 minutes, filter , filtrate, medium control solution concentration of 5 liters per amp bottle, high temperature sterilization for 30 minutes, that is, the injection, Example 24
用量 /50mL Dosage /50mL
实施例 12样品 10 mg Example 12 Sample 10 mg
柠檬酸 100 mg Citric acid 100 mg
NaOH 适量 (调 pH 4.0-5.0) NaOH amount (pH 4.0-5.0)
蒸馏水 50 mL
在蒸馏水中, 先加入蒸馏水和柠檬酸, 搅拌溶解和后, 再加入样品, 微 热使溶解, 调 pH值为 4.0-5.0, 加 0.2克活性碳, 室温下搅拌 20分钟, 过滤, 滤液, 中控测定溶液浓度, 按每安瓶 5亳升分装, 高温灭菌 30分钟, 即得 注射液。 Distilled water 50 mL In distilled water, first add distilled water and citric acid, stir and dissolve, then add the sample, slightly heat to dissolve, adjust the pH value to 4.0-5.0, add 0.2 g of activated carbon, stir at room temperature for 20 minutes, filter, filtrate, medium Control the concentration of the solution, add 5 liters per amp bottle, and sterilize for 30 minutes at high temperature to obtain the injection.
实施例 25 实施例 13样品 3.0g Example 25 Example 13 Sample 3.0g
泊洛沙姆 l.Og Polosham l.Og
氢氧化纳 0.2g Sodium hydroxide 0.2g
枸橼酸 QS Tannic acid QS
甘露醇 26.0g Mannitol 26.0g
乳糖 23.0g Lactose 23.0g
注射用水 100ml 制备工艺: 取注射用水 80ml, 加主药、 甘露醇、 乳糖、 泊洛沙姆搅拌 使溶解后, 力口 lmol/L的枸櫞酸调节 PH至 7.0-9.0, 补加水至 100ml。 加入 0.5g活性炭, 在 30°C下搅拌 20分钟, 脱炭, 釆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。 Water for injection 100ml Preparation process: Take 80ml of water for injection, add the main drug, mannitol, lactose, poloxamer to stir. After dissolving, adjust the pH of lmol/L citrate to 7.0-9.0, add water to 100ml. 0.5 g of activated carbon was added, and the mixture was stirred at 30 ° C for 20 minutes, decarburized, and sterilized by filtration through a microporous membrane. The filtrate was dispensed in 1 ml each, and after pre-freezing for 2 hours, it was dried under reduced pressure for 12 hours under refrigeration. 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.
实施例 26 颗粒剂 100袋 Example 26 Granules 100 bags
实施例 14样品 30.0g Example 14 Sample 30.0g
乳糖 55.0g Lactose 55.0g
甘露醇 14.0g Mannitol 14.0g
阿司巴甜 0.05g Aspartame 0.05g
香精 0.05g Fragrance 0.05g
2%羟丙甲纤维素 (纯水配制) QS 2% hypromellose (prepared in pure water) QS
制备工艺: 将主药与辅料分别过 100目筛, 充分混合, 然后称取处方量 辅料与主药充分混合。 再加入粘合剂制软材, 14目筛制粒, 55°C干燥, 12
目筛整粒, 测定袋重包装。 Preparation process: The main drug and the auxiliary material are respectively passed through a 100 mesh sieve, thoroughly mixed, and then the prescription auxiliary material is sufficiently mixed with the main drug. Adding adhesive to soft material, 14 mesh sieve granules, drying at 55 ° C, 12 The sieve is sifted and the bag is repackaged.
实施例 27 将本发明实施例制得的样品以 1%羧甲基纤维素纳配制成 5 mg/mL浓度 的混悬液, 给药容量为 0.2 mL/20g体重, 相当于 10 mg/kg剂量。 Example 27 A sample prepared in the examples of the present invention was formulated into a suspension of 5 mg/mL in a concentration of 1% carboxymethylcellulose, and the dosage was 0.2 mL/20 g body weight, which was equivalent to a dose of 10 mg/kg. .
健康 ICR小鼠, 雌雄各半, 体重 20-24 g, 符合一级标准。 动物禁食 16 小时, 药后 2h腹腔注射 2g/kg的葡萄糖盐水溶液(Dapagliflozin药后 1.5h 注射葡萄糖), 于造模后 0.5h、 lh、 2h、 3h和 4h定时取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。 Healthy ICR mice, half male and half female, weighing 20-24 g, meet the first grade standard. The animals were fasted for 16 hours, and 2 g/kg of gluconate solution was injected intraperitoneally 2 hours after the drug (dpagliflozin drug 1.5 h after glucose injection). Capillary from the mouse ball was taken at 0.5 h, lh, 2 h, 3 h and 4 h after modeling. Blood was taken from the posterior venous plexus, serum was separated by centrifugation, and serum glucose content was measured by glucose oxidase method at each time point.
部分样品的测定结果见如下表格: The results of the determination of some samples are shown in the following table:
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。 证 明本发明的具有通式 I结构的化合物可以作为 SGLT2抑制剂,并可以进一步用 于治疗糖尿病, 特别是非胰岛素依赖型糖尿病。
The above results indicate that each administration can significantly reduce glucose tolerance in mice induced by glucose. It is demonstrated that the compound of the present invention having the structure of the general formula I can be used as an inhibitor of SGLT2 and can be further used for the treatment of diabetes, particularly non-insulin dependent diabetes.
Claims
1. 具有通式 I结构的化合物或其药学上可以接受的盐或前药酯, A compound having the structure of formula I or a pharmaceutically acceptable salt or prodrug ester thereof,
R1选自 H、 F、 Br、 I、 OR3、 SR4、 OCF3、 CF3、 CHF2、 CH2F、 d-C3的 基以及含 3-5个碳原子的环垸基, 其中 R3和 R4独立选 CrC3的垸基, 所述 基和环垸基任选地被一个或多个选自 F和 C1的原子所取代; R 1 is selected from the group consisting of H, F, Br, I, OR 3 , SR 4 , OCF 3 , CF 3 , CHF 2 , CH 2 F, dC 3 and a cyclic fluorenyl group having 3 to 5 carbon atoms, wherein R 3 and R 4 independently independently selected a fluorenyl group of C r C 3 , which is optionally substituted by one or more atoms selected from F and C1;
R2选自 H和 CrC5的垸基; R 2 is selected from the group consisting of H and C r C 5 ;
X和 Y的定义选自如下几种情况: The definitions of X and Y are selected from the following cases:
(1) X = Y =碳原子; (1) X = Y = carbon atom;
(2) Χ = Υ = 氮原子; (2) Χ = Υ = nitrogen atom;
(3) Χ = 氮原子, Υ = 氧原子; (3) Χ = nitrogen atom, Υ = oxygen atom;
(4) X = 氮原子, Υ = 碳原子。 (4) X = nitrogen atom, Υ = carbon atom.
2. 根据权利要求 1所述的具有通式 I结构的化合物或其药学上可以接受 的盐或前药酯, 2. A compound of the formula I according to claim 1 or a pharmaceutically acceptable salt or prodrug thereof,
其中, among them,
R1选自 H、 F、 OMe、 SMe、 OCF3、 CF3、 CHF2、 CH2F、 CH3以及含有 3-5 个碳原子的环垸基, 所述垸基和环垸基任选地被一个或多个选自 F和 C1的原 子所取代; R 1 is selected from the group consisting of H, F, OMe, SMe, OCF 3 , CF 3 , CHF 2 , CH 2 F, CH 3 and a cyclic fluorenyl group having 3 to 5 carbon atoms, optionally having a fluorenyl group and a cyclodecyl group. The ground is replaced by one or more atoms selected from F and C1;
R2选自 H和 CrC3的垸基; R 2 is selected from the group consisting of H and C r C 3 ;
X和 Y的定义选自如下几种情况: The definitions of X and Y are selected from the following cases:
(4) Χ 氮原子, Υ = 碳原子。 (4) 氮 Nitrogen atom, Υ = carbon atom.
3. 根据权利要求 1或 2所述的具有通式 I结构的化合物或其药学上 接受的盐或前药酯, 其中, 该化合物的结构选自如下结构中的一种: The compound of the formula I or the pharmaceutically acceptable salt or prodrug ester thereof according to claim 1 or 2, wherein the structure of the compound is selected from one of the following structures:
4. 根据权利要求 1至 3中任一项所述的通式 I化合物或其药学上可以 受的盐或前药酯, 其中, 所述药学上可接受的前药酯包括分子中的任一 多个羟基与乙酰基、 特戊酰基、 磷酰基、 氨基甲酰基、 烷氧甲酰基中的 或多种所形成的酯。 The compound of formula I, or a pharmaceutically acceptable salt or prodrug thereof, according to any one of claims 1 to 3, wherein the pharmaceutically acceptable prodrug ester comprises any of the molecules An ester formed by a plurality of hydroxyl groups and one or more of an acetyl group, a pivaloyl group, a phosphoryl group, a carbamoyl group, and an alkoxycarbonyl group.
5. 权利要求 1至 4中任一项所述的通式 I化合物或其药学上可以接 盐或前药酯的制备方法, 该方法包括如下合成步骤: 5. A process for the preparation of a compound of formula I, or a pharmaceutically acceptable salt or prodrug thereof, according to any one of claims 1 to 4, which comprises the following synthetic steps:
其中, 所述碱 A选自 N-甲基吗啉、 三乙胺、 吡啶和 4-二甲氨基吡啶, 所述碱 B选自无水醋酸纳、 吡啶和 4-二甲氨基吡啶, 所述碱 C选自甲醇纳、 NaOH和 KOH。 Wherein the base A is selected from the group consisting of N-methylmorpholine, triethylamine, pyridine, and 4-dimethylaminopyridine, and the base B is selected from the group consisting of anhydrous sodium acetate, pyridine, and 4-dimethylaminopyridine. Base C is selected from the group consisting of sodium methoxide, NaOH and KOH.
6. 根据权利要求 5所述的制备方法,其中,所述三甲基硅基化试剂为三 甲基氯硅垸; 所述垸基锂试剂为正丁基锂; 所述酸选自甲磺酸、 三氟甲磺酸 和对甲苯磺酸; 所述路易斯酸选自 BF3.Et20、 BF3.MeCN和三氟乙酸; 所述 还原剂选自三乙基硅垸和三异丙基硅垸; 所述乙酰化试剂选自醋酸酐和乙酰 The method according to claim 5, wherein the trimethylsilylating agent is trimethylsilylphosphonium; the mercaptolithium reagent is n-butyllithium; and the acid is selected from methanesulfonate. Acid, trifluoromethanesulfonic acid and p-toluenesulfonic acid; the Lewis acid is selected from the group consisting of BF 3 .Et 2 0, BF 3 .MeCN and trifluoroacetic acid; the reducing agent is selected from the group consisting of triethylsilyl and triisopropyl Silicon oxime; the acetylating agent is selected from the group consisting of acetic anhydride and acetyl
7. 根据权利要求 5或 6所述的制备方法, 其中, 所述 = ¥ =碳原子, 化合物 IV为 IV-1 : The preparation method according to claim 5 or 6, wherein Said = ¥ = carbon atom, compound IV is IV-1:
IV-1 化合物 IV- 1釆用如下两种路线中的任一种合成: IV-1 Compound IV-1 is synthesized using either of the following two routes:
所述卤化剂为 PBr3和 /或 P0C13; 所述还原剂 A为 LiAlH4; 所述还原剂 B为三乙基硅垸和 /或三异丙基硅垸; 所述酸为三氟化硼乙醚和 /或三氟乙酸; 其中, Hal选自 Cl、 Br和 I; The halogenating agent is PBr 3 and/or P0C1 3 ; the reducing agent A is LiAlH 4 ; the reducing agent B is triethylsilane and/or triisopropylsilyl; the acid is trifluoride Boron ether and / or trifluoroacetic acid; wherein, Hal is selected from the group consisting of Cl, Br and I;
(2) 所述 X = Y = 氮原子, IV为 IV-2: (2) The X = Y = nitrogen atom and IV is IV-2:
XVI XVII IV-2 其中, Hal选自 Cl、 Br和 I; XVI XVII IV-2 wherein Hal is selected from the group consisting of Cl, Br and I;
(3) 所述 X = 氮原子, Y = 氧原子, 化合物 IV为 IV-3: (3) The X = nitrogen atom, Y = oxygen atom, and the compound IV is IV-3:
IV-3 IV-3
XVI XVIII IV-3 XVI XVIII IV-3
其中, Hal选自 Cl、 Br和 I; Wherein Hal is selected from the group consisting of Cl, Br and I;
(4) 所述 X= 氮原子, Y=碳原子, 化合物 IV为 IV-4: (4) The X = nitrogen atom, Y = carbon atom, and the compound IV is IV-4:
IV-3 IV-3
XVI XIX IV-4 其中, Hal选自 Cl、 Br和 I。 XVI XIX IV-4 wherein Hal is selected from the group consisting of Cl, Br and I.
8. 根据权利要求 5至 7中任一项所述的制备方法,该制备方法包括如下 合成步骤: The preparation method according to any one of claims 5 to 7, which comprises the following synthesis steps:
9. 权利要求 1至 4中任一项所述的通式 I化合物或其药学上可以接 盐或前药酯在抑制 2型纳葡萄糖共转运子中的应用。 9. Use of a compound of formula I according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or prodrug thereof, for inhibiting a type 2 glucosamine co-transporter.
10. 权利要求 1至 4中任一项所述的通式 I化合物或其药学上可以 的盐或前药酯在治疗糖尿病中的应用。 10. Use of a compound of formula I according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or prodrug thereof, for the treatment of diabetes.
11. 权利要求 1至 4中任一项所述的通式 I化合物或其药学上可以 ^ 的盐或前药酯在制备 2型纳半乳糖转运子抑制剂中的应用。 11. Use of a compound of formula I according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or prodrug thereof, for the preparation of a type 2 galactose transporter inhibitor.
12. 权利要求 1至 4中任一项所述的通式 I化合物或其药学上可以 的盐或前药酯在制备治疗糖尿病的药物中的应用。 12. Use of a compound of formula I according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or prodrug thereof, for the manufacture of a medicament for the treatment of diabetes.
13. 一种治疗糖尿病的方法, 该方法包括向患者给药有效剂量的权利 求 1至 4中任一项所述的通式 I化合物或其药学上可以接受的盐或前药酯。 13. A method of treating diabetes, the method comprising the right to administer an effective dose to a patient The compound of formula I according to any one of 1 to 4, or a pharmaceutically acceptable salt or prodrug ester thereof.
14. 一种药物组合物, 该药物组合物包含权利要求 1至 4中任一项所述 的通式 I化合物或其药学上可以接受的盐或前药酯, 以及药学上可以接受的 载体和 /或赋形剂。 14. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier and / or excipients.
15. 根据权利要求 14所述的药物组合物,其中,该药物组合物为固体口 服制剂、 液体口服制剂或注射制剂。 The pharmaceutical composition according to claim 14, wherein the pharmaceutical composition is a solid oral preparation, a liquid oral preparation or an injection preparation.
16. 根据权利要求 15所述的药物组合物,其中,所述固体口服制剂和液 体口服制剂包括: 分散片、 肠溶片、 咀嚼片、 口崩片、 胶囊、 颗粒剂和口服 溶液剂, 所述注射剂制剂包括注射用水针、 注射用冻干粉针、 大输液和小输 液。 16. The pharmaceutical composition according to claim 15, wherein the solid oral preparation and the liquid oral preparation comprise: a dispersible tablet, an enteric coated tablet, a chewable tablet, an orally disintegrating tablet, a capsule, a granule, and an oral solution, The preparation for injection includes a water injection needle, a lyophilized powder for injection, a large infusion, and a small infusion.
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CN102516215B (en) * | 2011-12-12 | 2014-04-09 | 天津药物研究院 | Preparation method of C-glucoside containing saturated cyclohexane structure |
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CN103058972B (en) * | 2013-01-17 | 2014-12-10 | 天津药物研究院 | Phenyl C-glucoside derivatives containing cyclohexane structure as well as preparation method and application thereof |
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US20060035841A1 (en) * | 2004-08-11 | 2006-02-16 | Boehringer Ingelheim International Gmbh | D-xylopyranosyl-phenyl-substituted cycles, medicaments containing such compounds, their use and process for their manufacture |
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US20060035841A1 (en) * | 2004-08-11 | 2006-02-16 | Boehringer Ingelheim International Gmbh | D-xylopyranosyl-phenyl-substituted cycles, medicaments containing such compounds, their use and process for their manufacture |
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