CN103880844A - Novel quinolinone compound and preparation method and use thereof - Google Patents
Novel quinolinone compound and preparation method and use thereof Download PDFInfo
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- CN103880844A CN103880844A CN201410139594.4A CN201410139594A CN103880844A CN 103880844 A CN103880844 A CN 103880844A CN 201410139594 A CN201410139594 A CN 201410139594A CN 103880844 A CN103880844 A CN 103880844A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
The invention discloses a novel quinolinone compound and a preparation method and use thereof. The novel compound is a compound of which the structure formula is shown in (I). The structure formula is as shown in the specification. The invention also discloses a preparation method of the compound and use thereof.
Description
Technical field
The present invention relates to organic quinolinones compound, relate in particular to a kind of new compound and its production and use.
Background technology
Diabetes be one group because Regular Insulin is absolute or relative hyposecretion and target tissue cell reduce and cause a series of metabolism disorder syndrome such as protein, fatty power and water Xie Zhi insulin sensitivity, wherein taking hyperglycemia as item key.The main clinical manifestation of diabetes is many drinks, diuresis, eats and weight loss (" three-many-one-little ") more, and blood sugar is high, contain glucose etc. in urine.If diabetes can not get effective treatment, can cause the infringement of health multisystem.In recent years, in China's urban population, particularly youthful sickness rate shows a rising trend, and diabetes are lifelong disease, and complication is many, at present serious harm the mankind's quality of life, become one of three large disease killers of the mankind.
Nineteen sixty-eight French scientist Lynnet reports vanadium first syrup effect, but Regular Insulin comes out, rear vanadium does not just come into one's own again.In recent decades, along with scientific and technological development, people find that to the further investigation of vanadium compound vanadium has biological action widely, and from then on, the medical circle of countries in the world particularly science power has started research climax wave after wave.Treating in the market diabetes medicament has development rapidly in recent years, and from original sulfonylurea and biguanides, existing the 3rd class alpha-glucosidase inhibitor is for clinical application, and the 4th para-insulin sensitizer also will be introduced domestic soon.Still testing and a small amount of clinic trial stage as for the 5th class glucagon inhibitor and the 6th class glyconeogenesis inhibitor.In above-mentioned antidiabetic medicine, sulfonylurea medicine is antidiabetic drug, can cause hypoglycemic reaction, and biguanides and alpha-glucosidase inhibitor do not cause hypoglycemic reaction, are called as hyperglycemia medicine.
Medical circle is not yet very clear and definite to the pathogeny of diabetes at present, though there is the Remedies for diabetes of many not same-actions, can not really improve diabetic subject's quality of life.For this reason, countries in the world spend huge sums input research to seek really to control the newtype drug that improves diabetes.
Summary of the invention
The present invention aims to provide a kind of to promoting glucose in urine excretion, and can effectively reduce new quinolinones compound of the interior plasma glucose of body and plasma insulin mass action and preparation method thereof.
A first aspect of the present invention, provides a kind of structure suc as formula the compound shown in I,
A second aspect of the present invention, provides a kind of preparation method suc as formula the compound shown in I provided by the invention, and described method comprises step:
(a) by structural formula, the midbody compound as shown in (II) and boric acid ester carry out Suzuky palladium catalysed cross coupling reaction under alkaline condition, obtain compound as claimed in claim 1 after column chromatography purification
Catalysts can be selected 0.05 times of [two (diphenylphosphino) ferrocene of 1,1'-] palladium chloride, tetra-triphenylphosphine palladium and palladium to 0.5 times of equivalents, preferably [two (diphenylphosphino) ferrocene of 1,1'-] palladium chloride.Alkali can be selected 1 times of sodium carbonate to 5 times of equivalents, salt of wormwood, cesium carbonate and potassiumphosphate, preferably phosphoric acid potassium.Reaction solvent can be selected Isosorbide-5-Nitrae-dioxy ring six alkane, acetonitrile/water, ethanol/water, dimethyl sulfoxide (DMSO), toluene and dimethyl formamide, preferably dimethyl formamide.Temperature of reaction is from 40 degree to 120 degree, and preferably 80 degree are to 100 degree.
(b) by structural formula, the compound as shown in (III) and alkylating reagent carry out methyl under alkaline condition, obtain the midbody compound (II) as described in (a) after column chromatography after purifying,
Reaction methylating reagent can be selected 1 times of methylcarbonate to 3 times of equivalents, methyl-sulfate or methyl iodide, preferably methyl iodide.Alkali can be selected 1 times of salt of wormwood to 5 times of equivalents, sodium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide and sodium hydride, preferably sodium hydride.Solvent can be selected methylene dichloride, tetramethyleneimine, dimethyl formamide, dimethyl sulfoxide (DMSO) and glycol dimethyl ether, preferably dimethyl formamide.Temperature of reaction is from 25 degree to 120 degree, preferably 80 to 100 degree.
A third aspect of the present invention, provides a kind of purposes of compound as shown in the formula (I) provided by the invention, for the preparation of the medicine for the treatment of diabetes.
Accordingly, the invention provides one to the medicative compound of diabetes.
Embodiment
With specific embodiment, technical scheme of the present invention is described below, but protection scope of the present invention is not limited to this:
Embodiment 1, synthesising target compound (I)
Synthetic route:
Steps A: Compound I I (8-bromo-1,1,3-trimethylammonium-1,3-dihydro-pyrrolo-[2,3-c] quinoline-2-ketone)
Under ice bath, add successively III:8-bromo-1,1-dimethyl-1,3-dihydro-pyrrolo-[2; 3-c] quinoline-2-ketone (8.6g; 29.5mmol), dimethyl formamide (80ml) and sodium hydride (1.42g, 59mmol), under nitrogen protection, react 2 hours.Drip methyl iodide (6.28g, 44.3mmol), be slowly warming up to 80 degree, react 14 hours, thin-layer chromatography monitoring remains without raw material.System is cooled to room temperature, slowly drips successively ammoniacal liquor (10ml) and water (50ml), stir 1 hour.Add methylene dichloride (30ml*2) extracting twice, after organic phase merges, water (30ml) is washed rear concentrating under reduced pressure and is obtained thick product, thick product is by column chromatography (petrol ether/ethyl acetate=30/1, v/v) after purifying, obtain 8.2g off-white color intermediate 8-bromo-1,1,3-trimethylammonium-1,3-dihydro-pyrrolo-[2,3-c] quinoline-2-ketone, productive rate 92%(calculates by compound III).
1H?NMR(CDCl3-d6)?，δ：?8.32（s,1H）,?7.79-7.82（d,1H）,?7.76-7.83（s,1H）,?7.47-7.54（d,1H）,?2.64-2.73(s,1H),?1.62-1.56（s,6H）。MS-ESI(m/z):304.3,306.2(M+H
+)。
Step B: Compound I (8-[6-amino-5-(1-hydroxyl-1-methyl-ethyl)-pyridine-3-yl]-1,1,3-trimethylammonium-1,3-dihydro-pyrrolo-[2,3-c] quinoline-2-ketone)
Under room temperature, add successively intermediate II: 8-bromo-1,1,3-trimethylammonium-1; 3-dihydro-pyrrolo-[2; 3-c] quinoline-2-ketone (6.6g, 21.6mmol), boric acid ester (12.0g, 43.2mmol), [1; two (diphenylphosphino) ferrocene of 1'-] palladium chloride (0.14g; 0.2mmol), potassiumphosphate (11.2g, 64.8mmol) and dimethyl formamide (65ml), nitrogen protection; be warming up to 85 degree reaction 14 hours, thin-layer chromatography monitoring remains without raw material.System is cooled to room temperature, adds water (60ml), stir 0.5 hour.Add methylene dichloride (30ml*2) extracting twice, after organic phase merges, water (30ml) is washed rear concentrating under reduced pressure and is obtained thick product, thick product is by column chromatography (petrol ether/ethyl acetate=15/1, v/v) after purifying, obtain 7.06g off-white color target product I:8-[6-amino-5-(1-hydroxyl-1-methyl-ethyl)-pyridine-3-yl]-1,1,3-trimethylammonium-1,3-dihydro-pyrrolo-[2,3-c] quinoline-2-ketone, productive rate 87%(calculates by Compound I I).Ultimate analysis C
22h
24n
4o
2calculated value: C, 70.19; H, 6.43; N, 14.88, measured value: C, 70.23; H, 6.56; N, 14.91.MS-ESI(m/z):358.2(M-H
2O)，377.2(M+H
+)。
Embodiment 2, synthesising target compound (I)
Working method, with embodiment 1, is used methylcarbonate to replace methyl iodide in steps A, uses lithium hydroxide to replace sodium hydride, uses methylene dichloride to replace dimethyl formamide, and temperature of reaction maintains 25 degree reaction 48 hours, and thin-layer chromatography monitoring remains without raw material.Slowly drip successively ammoniacal liquor and water, stir 1 hour.Add dichloromethane extraction twice, organic phase washes rear concentrating under reduced pressure with water after merging and obtains thick product, and thick product obtains off-white color intermediate II by column chromatography (petrol ether/ethyl acetate=30/1, v/v) purifying, and productive rate 68%(calculates by compound III).MS-ESI(m/z):304.3,306.2(M+H
+)。
working method is with embodiment 1; in step B, use tetra-triphenylphosphine palladium to replace [1; two (diphenylphosphino) ferrocene of 1'-] palladium chloride; use salt of wormwood to replace potassiumphosphate; use Isosorbide-5-Nitrae-dioxy ring six alkane to replace dimethyl formamide, under nitrogen protection; temperature of reaction maintains 40 degree reaction 36 hours, and thin-layer chromatography monitoring remains without raw material.System is cooled to room temperature, adds water, stir 0.5 hour.Add dichloromethane extraction twice, organic phase washes rear concentrating under reduced pressure with water after merging and obtains thick product, and thick product obtains off-white color target product I by after column chromatography (petrol ether/ethyl acetate=15/1, v/v) purifying, and productive rate 65%(calculates by Compound I I).MS-ESI(m/z):358.2(M-H
2O)。
Embodiment 3, synthesising target compound (I)
Working method, with embodiment 1, is used methylcarbonate to replace methyl iodide in steps A, uses salt of wormwood to replace sodium hydride, uses dimethyl sulfoxide (DMSO) to replace dimethyl formamide, is slowly warming up to 120 degree reaction 8 hours, and thin-layer chromatography monitoring remains without raw material.Slowly drip successively ammoniacal liquor and water, stir 1 hour.Add dichloromethane extraction twice, organic phase washes rear concentrating under reduced pressure with water after merging and obtains thick product, and thick product obtains off-white color intermediate II by after column chromatography (petrol ether/ethyl acetate=30/1, v/v) purifying, and productive rate 76%(calculates by compound III).MS-ESI(m/z):304.3,306.2(M+H
+)。
working method is with embodiment 1; in step B, use palladium to replace [1; two (diphenylphosphino) ferrocene of 1'-] palladium chloride; use cesium carbonate to replace potassiumphosphate; use dimethyl sulfoxide (DMSO) to replace dimethyl formamide; under nitrogen protection, temperature of reaction maintains 120 degree reaction 6 hours, and thin-layer chromatography monitoring remains without raw material.System is cooled to room temperature, adds water, stir 0.5 hour.Add dichloromethane extraction twice, organic phase washes rear concentrating under reduced pressure with water after merging and obtains thick product, and thick product obtains off-white color target product I by after column chromatography (petrol ether/ethyl acetate=15/1, v/v) purifying, and productive rate 82%(calculates by Compound I I).MS-ESI(m/z):358.2(M-H
2O)?，377.2(M+H
+)。
Embodiment 4: pharmacological evaluation
Experimental program
Animal model: 6 week age ICR mouse, raise and enter test after 1 week.Before on-test, every mouse is measured plasma glucose levels, as starting point concentration.Mouse overnight fasting, abdominal injection niacinamide (1000 mg/kg), 90 minutes pneumoretroperitoneum injection U-9889 solution (150 mg/kg).Normal group mouse peritoneal injecting normal saline.After 1 week, all mouse are measured plasma glucose levels.All mouse give the commercial feed of standard, and feed according to conventional laboratory condition.
The mensuration of urine glucose: diabetic mice gavage gives compound (I) (0.01-10mg/kg), and is placed in metabolic cage, collects the urine of 24 hours, measures the glucose level (blood glucose meter) in urine amount and urine.
Oral glucose tolerance test (OGTT): the diabetic mice fasting plasma glucose of overnight fasting and insulin level are that baseline is determined at test previous crops.Diabetic mice gavage gives compound (I) (0.01-3mg/kg) latter 0.5 hour, and oral (2g/kg) gives glucose, and then tail vein blood is measured plasma glucose levels and the insulin level of each time point
The plasma glucose levels of non-fasting: the diabetic mice fasting plasma glucose of overnight fasting and insulin level are not that baseline is determined at test previous crops.Diabetic mice gavage gives compound (I) (0.01-3mg/kg) latter 0.5 hour, and oral (2g/kg) gives glucose, and then tail vein blood is measured plasma glucose levels and the insulin level of each time point
The long-term antidiabetic effect of compound (I): diabetic mice gavage gives compound (I) 4 weeks (0.01-3mg/kg/day), measures weekly body weight and food ration.The 23rd day, the diabetic mice of overnight fasting did oral glucose tolerance test.The 26th day, diabetic mice was placed in metabolic cage, collected the urine of 24 hours, measured the glucose level (blood glucose meter) in urine amount and urine.The last day before putting to death, the diabetic mice of overnight fasting is not collected determination of plasma plasma glucose and insulin level.Grind even pancreas islet under 4 ° of C conditions with hydrochloric acid-ethanolic soln (75% ethanol, 23.5% pure water and 1.5% hydrochloric acid) extracting 1 hour to obtain Regular Insulin.HbA1c adopts full-automatic DCA2000 system (Bayer Medical, Tokyo) to measure.
Experimental result and conclusion:
Every group of 4 animals, each test parameter has been analyzed the result of 24 hours, the impact of analysis of compounds (I) on glucose in urine: the excretion of the increase urine glucose of oral administration of compound (I) (0.01 – 10mg/kg) dose-dependently, this effect is 0.3mg/kg or performance is obviously when higher at dosage.In addition, compound (I) obviously lures and has changed osmotic diuresis.
Every group of 4 animals, diabetic mice is oral administration of compound (I) (0.01 – 3mg/kg) dosage under fasted conditions, blood glucose value in the carbohydrate tolerance test (OGTT) of 2 hours and the impact of plasma insulin value: dependently suppressed plasma glucose during oral glucose tolerance test and the increase of plasma insulin, this effect dosage be 0.03mg/kg or when higher on the impact of plasma glucose value obviously, dosage be 0.1mg/kg or when higher on the impact of plasma insulin value obviously.
Every group of 4 animals, diabetic mice the blood glucose value in oral administration of compound (I) 24 hours and impact of plasma insulin value under non-fasted conditions: the inhibition of oral administration of compound (I) (0.01 – 3mg/kg) dose-dependently the plasma glucose during oral glucose tolerance test, dosage be 0.03mg/kg or when higher on the plasma glucose AUC value impact of 8 hours obviously, be 0.1mg/kg or obvious on the plasma glucose AUC value impact of 24 hours when higher at dosage.
Every group of 6 animals, diabetic mice is the oral administration of compound (I) of the 4 weeks contrast to the plasma glucose value in diabetic mice oral glucose tolerance test and plasma insulin value under fasted conditions: compare with Normal group, diabetic mice has demonstrated the plasma glucose value, HbA1c, plasma insulin value of obvious increase and the excretion of urine glucose, and the content of Regular Insulin in pancreas islet is approximately reduced to 50% of normal mouse.Plasma glucose value, HbA1c, plasma insulin value that the oral administration of compound (I) (0.1 – 3mg/kg) of 4 weeks has significantly reduced have increased the content of Regular Insulin in pancreas islet simultaneously.In addition, the insulin secretion of sugar tolerance and damage is significantly improved.The excretion of glucose in urine shows as the increase of dose-dependently.
The foregoing is only preferred embodiments of the present invention, not in order to limit essence technical scope of the present invention, essence technology contents of the present invention is in the claim scope that is defined in application of broad sense, any technology entity or method that other people complete, if defined identical with the claim scope of application, also or a kind of change of equivalence, be all covered by among this claim scope being regarded as.
Claims (10)
- Structure as shown in the formula a compound,
。 - 2. the preparation method of compound as claimed in claim 1, is characterized in that, described method comprises step:Midbody compound by structural formula as shown in (II) and boric acid ester carry out Suzuky palladium catalysed cross coupling reaction under alkaline condition,
React thick product and after column chromatography purification, obtain compound as claimed in claim 1, catalysts can be selected [two (diphenylphosphino) ferrocene of 1,1'-] palladium chloride, tetra-triphenylphosphine palladium and palladium. - 3. preparation method as claimed in claim 2, is characterized in that, alkali can be selected sodium carbonate, salt of wormwood, cesium carbonate and potassiumphosphate.
- 4. preparation method as claimed in claim 2, is characterized in that, reaction solvent can be selected Isosorbide-5-Nitrae-dioxy ring six alkane, acetonitrile/water, ethanol/water, dimethyl sulfoxide (DMSO), toluene and dimethyl formamide.
- 5. preparation method as claimed in claim 2, is characterized in that, temperature of reaction is from 40 degree to 120 degree.
- 6. by structural formula, the compound as shown in (III) reacts with alkylating reagent and carries out methyl under alkaline condition, excessive alkylating reagent buck cancellation after reaction, thick product obtains described midbody compound (II) through column chromatography purification
Reaction methylating reagent can be selected methylcarbonate, methyl-sulfate or methyl iodide. - 7. preparation method as claimed in claim 6, is characterized in that, alkali can be selected salt of wormwood, sodium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide and sodium hydride.
- 8. preparation method as claimed in claim 6, is characterized in that, solvent can be selected methylene dichloride, tetramethyleneimine, dimethyl formamide, dimethyl sulfoxide (DMSO) and glycol dimethyl ether.
- 9. preparation method as claimed in claim 6, is characterized in that, temperature of reaction is from 25 degree to 120 degree.
- 10. a purposes for the compound of claim as described in 1, is characterized in that, for the preparation of the medicine for the treatment of diabetes.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105348284A (en) * | 2014-08-23 | 2016-02-24 | 南京海纳医药科技有限公司 | Novel synthesis method for Istradefylline |
| WO2019201283A1 (en) * | 2018-04-20 | 2019-10-24 | Xrad Therapeutics, Inc. | Dual atm and dna-pk inhibitors for use in anti-tumor therapy |
| CN112469720A (en) * | 2018-04-20 | 2021-03-09 | 艾科思莱德制药公司 | Dual ATM and DNA-PK inhibitors for use in antitumor therapy |
| WO2021098734A1 (en) * | 2019-11-19 | 2021-05-27 | 南京明德新药研发有限公司 | Substituted quinolinopyrrolidone compound as atm inhibitor and application thereof |
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2014
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105348284A (en) * | 2014-08-23 | 2016-02-24 | 南京海纳医药科技有限公司 | Novel synthesis method for Istradefylline |
| WO2019201283A1 (en) * | 2018-04-20 | 2019-10-24 | Xrad Therapeutics, Inc. | Dual atm and dna-pk inhibitors for use in anti-tumor therapy |
| CN112469720A (en) * | 2018-04-20 | 2021-03-09 | 艾科思莱德制药公司 | Dual ATM and DNA-PK inhibitors for use in antitumor therapy |
| JP2021522316A (en) * | 2018-04-20 | 2021-08-30 | エクスラッド セラピューティクス，インコーポレーテッド | Dual ATM and DNA-PK inhibitors for use in antitumor therapy |
| EP3784671A4 (en) * | 2018-04-20 | 2021-11-17 | XRad Therapeutics, Inc. | Dual atm and dna-pk inhibitors for use in anti-tumor therapy |
| JP7366996B2 (en) | 2018-04-20 | 2023-10-23 | エクスラッド セラピューティクス，インコーポレーテッド | Dual ATM and DNA-PK inhibitors for use in anti-tumor therapy |
| CN112469720B (en) * | 2018-04-20 | 2024-03-29 | 艾科思莱德制药公司 | Dual ATM and DNA-PK inhibitors for use in anti-tumor therapy |
| EP4327877A3 (en) * | 2018-04-20 | 2024-04-24 | XRad Therapeutics, Inc. | Dual atm and dna-pk inhibitors for use in anti-tumor therapy |
| WO2021098734A1 (en) * | 2019-11-19 | 2021-05-27 | 南京明德新药研发有限公司 | Substituted quinolinopyrrolidone compound as atm inhibitor and application thereof |
| CN114746421A (en) * | 2019-11-19 | 2022-07-12 | 南京明德新药研发有限公司 | Substituted quinolinopyrrolones as ATM inhibitors and uses thereof |
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