CN104926742A - Compound with benzisoxazole and nitrobenzophenone structure and application thereof - Google Patents

Compound with benzisoxazole and nitrobenzophenone structure and application thereof Download PDF

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Publication number
CN104926742A
CN104926742A CN201510412033.1A CN201510412033A CN104926742A CN 104926742 A CN104926742 A CN 104926742A CN 201510412033 A CN201510412033 A CN 201510412033A CN 104926742 A CN104926742 A CN 104926742A
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compound
formula
diabetes
stirs
application
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蔡子洋
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Foshan Saiweisi Pharmaceutical Technology Co Ltd
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Foshan Saiweisi Pharmaceutical Technology Co Ltd
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Priority to CN201510412033.1A priority Critical patent/CN104926742A/en
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D261/00Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/20Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems

Abstract

The invention relates to the field of drugs relevant to 2-diabetes mellitus, in particular to an 11 beta -HSD1 inhibitor with a benzisoxazole and nitrobenzophenone structure, a preparation method thereof and application of the 11 beta-HSD1 inhibitor in preparing drugs for the 2-diabetes mellitus. The chemical formula is shown in the specification.

Description

One class contains compound of benzisoxa oxazole and nitrophenyl class formation and uses thereof
Technical field
The present invention relates to the pharmaceutical field of diabetes B treatment.Specifically, the present invention relates to the medicative class of diabetes B tool containing 11 beta-HSD 1 inhibitors of benzisoxa oxazole and nitrophenyl class formation, its preparation method and in purposes pharmaceutically.
Background technology
Diabetes are the lysis caused by multi-pathogenesis, have influence on the population of global 6%-7%.Expect 2025, number of patients can double again and reach 300,000,000.The most important clinical pathologic characteristic of diabetes is that plasma glucose (blood sugar) concentration increases.It is the major cause leading diabetogenic various clinical symptom that blood sugar concentration increases.Unsteered hyperglycemia causes many diabetic complications, comprises ephrosis, neuropathy, retinopathy, hypertension, cerebral ischemia and coronary heart disease etc.Therefore, the key that blood sugar is treatment and prevent diabetes and complication thereof is reduced.
11-beta-hydroxy steroid dehydrogenase type 1 (11 β-HSD1) is the Effective target site of the symptom relevant with improving other diabetes to glycemic control in the past few years confirmed.Research is determined, glucocorticoid activity does not control by means of only secretion hydrocortisone and hands over control in tissue mutually horizontally through in the cell of active Cortisol and nonactive cortisone, this mutual traffic is crossed through 11-beta-hydroxysteroid dehydrogenase, namely 11 β-HSD1 (it activates cortisone) and 11 β-HSD-2 (its deactivation hydrocortisone) complete (Sandeep TC & Walker BR, Trends Endocrinol & Metab., 2001,12,446-453).This mechanism may be important for people, several in carbenoxolone (the anti-stain of a kind of suppression 11 β-HSD1 and-2 is die young medicine) treatment at first, this treatment causes insulin sensitivity to improve, illustrate 11 β-HSD1 by reduce active glucocorticoid organize horizontal Effective Regulation insulin action (WalkerBR et al.J.Clin.Endocrinol.Metab., 1995,80,3155-3159).
Many have insulin resistance but the patient not developing into diabetes B also has development to be called the risk of the symptom of " syndrome X " or " metabolic syndrome ".Syndrome X or metabolic syndrome take insulin resistance as feature, and with abdominal obesity, hyperinsulinemia, hypertension, low high-density lipoprotein (HDL) (HDL) and high vldl (VLDL).No matter whether these patients, develop into obvious diabetes, all have the risk of the above-mentioned cardiovascular complication of the development of increase.11 beta-HSD 1 inhibitors, except having therapeutic action ten thousand to diabetes B, increase the cognition enhancing needed for lipid disorders, obesity, atherosclerosis, Alzheimer and associated conditions, hypertension, intraocular pressure, promote that wound healing and metabolic syndrome etc. all have certain treatment and prophylactic effect.
The invention discloses 11 beta-HSD 1 inhibitors that a class contains benzisoxa oxazole and nitrophenyl class formation, these compounds can be used for the medicine preparing treatment diabetes B and relative disease thereof.
Summary of the invention
An object of the present invention is to provide a kind of 11 beta-HSD 1 inhibitors with the excellent activity of general formula I.
Another object of the present invention is to provide the method that preparation has the compound of general formula I.
The compound that another object of the present invention is to provide containing general formula I is treating the application in diabetes B as effective constituent.
Now in conjunction with object of the present invention, content of the present invention is specifically described.
The compound that the present invention has general formula I has following structural formula:
The compound of preferred formula I has following structure,
Compound of Formula I of the present invention is synthesized by following route:
Compound II per and compound III be first reacting generating compound IV in the presence of a base, and the latter is at AlCl 3reset under catalysis and generate compound V; Compound V and azanol reaction generate compound VI; Compound VI first processes at low temperatures with n-BuLi, generates corresponding lithium aryl, and the latter is again at BF 3et 2react with (R)-polychlorinated dibenzo-furans under O catalysis and generate product VII; Compound VI I reacts with compound VI II in the presence of a base, obtains Compound I.
Compound of Formula I of the present invention has 11 β-HSD1 restraining effect, can be used as effective constituent for the preparation of diabetes B medicine.The activity of compound of Formula I of the present invention is verified by receptor binding assays.
Compound of Formula I of the present invention is effective in quite wide dosage range.The dosage that such as every day takes, within the scope of 1mg-500mg/ people, is divided into once or administration for several times.The actual dosage taking compound of Formula I of the present invention can be decided according to relevant situation by doctor.
Embodiment
Below in conjunction with embodiment, the present invention is further illustrated.It should be noted that, following embodiment be only for illustration of, and not for limiting the present invention.The various changes that those skilled in the art's training centre according to the present invention is made all should within the protection domain required by the application's claim.
the synthesis of embodiment 1 Compound I-1
A. the synthesis of compound V-1
1.73g (10mmol) Compound II per is dissolved in the methylene dichloride of 15mL drying, ice-water bath cooling is lower stirs, add 3.04g (30mmol) triethylamine, then slowly drip the solution prepared by the methylene dichloride of 2.02g (12mmol) compound III-1 and 2mL drying, after dropwising, reaction system at room temperature stirs spends the night, and TLC checks that reaction completes.Reaction mixture pours in 200mL frozen water, stirs, with 50mL × 3CH 2cl 2extraction, merges extraction phase, uses 1% dilute hydrochloric acid and salt water washing successively, anhydrous sodium sulfate drying.Suction filtration removing siccative, filtrate is evaporate to dryness on a rotary evaporator, and resistates is dissolved in 20mL Nitromethane 99Min., slowly drips 2.00g (15mmol) anhydrous AlCl under ice-water bath cooling 3, dropwise rear reaction mixture and be warming up to 50 DEG C of reactions 3 hours, TLC checks that reaction completes.Reaction mixture pours in 200mL frozen water, stirs, with 50mL × 3CH 2cl 2extraction, merges extraction phase, uses 1% dilute hydrochloric acid and salt water washing successively, anhydrous sodium sulfate drying.Suction filtration removing siccative, filtrate is evaporate to dryness on a rotary evaporator, and resistates uses purification by silica gel column chromatography, obtains compound V-1, white solid, ESI-MS, m/z=307 ([M+H] +).
The synthesis of B.VI-1
1.83g (6mmol) compound V-1 is dissolved in 15mL ethanol, stirred at ambient temperature, and add 0.69g (10mmol) oxammonium hydrochloride and 2.46g (30mmol) sodium-acetate, then temperature rising reflux spends the night under a nitrogen.TLC shows reaction to be completed.Reaction mixture pours in 200mL frozen water, stirs, with 50mL × 3CH 2cl 2extraction, merges extraction phase, uses salt water washing, anhydrous sodium sulfate drying.Suction filtration removing siccative, filtrate is evaporate to dryness on a rotary evaporator, and resistates uses purification by silica gel column chromatography, obtains compound VI-1, white solid, ESI-MS, m/z=302,304 ([M+H] +).
The synthesis of C.VII-1
1.21g (4mmol) compound VI-1 is dissolved in the THF of 15mL drying; be cooled to-78 DEG C under nitrogen protection; induction stirring; slowly drip the hexane solution of the n-BuLi of 2.5mL (4mmol) 1.6M with syringe, dropwise rear reaction mixture and continue stirring at such a temperature 1 hour.The solution of 0.57g (4mmol) boron trifluoride diethyl etherate and 1mL THF preparation is slowly dripped with syringe, after dropwising, the solution of the THF preparation of 0.46g (5mmol) (R)-polychlorinated dibenzo-furans and 1mL drying is slowly dripped again with syringe, after dropwising, compound of reaction is slowly warmed up to room temperature, and at room temperature stirring is spent the night, TLC detection reaction completes.Reaction mixture pours in 100mL frozen water, stirs, with 50mL × 3CH 2cl 2extraction, merges extraction phase, uses salt water washing, anhydrous sodium sulfate drying.Suction filtration removing siccative, filtrate is evaporate to dryness on a rotary evaporator, and resistates uses purification by silica gel column chromatography, obtains compound VI I-1, white solid, ESI-MS, m/z=316 ([M+H] +).
The synthesis of D.I-1
0.63g (2mmol) compound VI I-1,0.34g (2mmol) compound VI II-1 and 0.83g (6mmol) solid K 2cO 3add in 10mL DMF, room temperature for overnight, TLC shows reaction to be completed.Reaction mixture pours in 100mL frozen water, stirs, with 50mL × 3CH 2cl 2extraction, merges extraction phase, uses salt water washing, anhydrous sodium sulfate drying.Suction filtration removing siccative, filtrate is evaporate to dryness on a rotary evaporator, and resistates uses purification by silica gel column chromatography, obtains Compound I-1, white solid, ESI-MS, m/z=449 ([M+H] +).
embodiment 2-3
With reference to the method for embodiment 1, synthesize compound listed in Table.
the synthesis of embodiment 4 compound R-1
In order to further illustrate the beneficial effect of the compounds of this invention, this invention describes and be all the applicant's invention and not yet disclosed compound R-1:
Its synthetic method is as follows:
A. the synthesis of compound V-1
1.73g (10mmol) Compound II per is dissolved in the methylene dichloride of 15mL drying, ice-water bath cooling is lower stirs, add 3.04g (30mmol) triethylamine, then slowly drip the solution prepared by the methylene dichloride of 2.02g (12mmol) compound III-1 and 2mL drying, after dropwising, reaction system at room temperature stirs spends the night, and TLC checks that reaction completes.Reaction mixture pours in 200mL frozen water, stirs, with 50mL × 3CH 2cl 2extraction, merges extraction phase, uses 1% dilute hydrochloric acid and salt water washing successively, anhydrous sodium sulfate drying.Suction filtration removing siccative, filtrate is evaporate to dryness on a rotary evaporator, and resistates is dissolved in 20mL Nitromethane 99Min., slowly drips 2.00g (15mmol) anhydrous AlCl under ice-water bath cooling 3, dropwise rear reaction mixture and be warming up to 50 DEG C of reactions 3 hours, TLC checks that reaction completes.Reaction mixture pours in 200mL frozen water, stirs, with 50mL × 3CH 2cl 2extraction, merges extraction phase, uses 1% dilute hydrochloric acid and salt water washing successively, anhydrous sodium sulfate drying.Suction filtration removing siccative, filtrate is evaporate to dryness on a rotary evaporator, and resistates uses purification by silica gel column chromatography, obtains compound V-1, white solid, ESI-MS, m/z=307 ([M+H] +).
The synthesis of B.VI-1
1.83g (6mmol) compound V-1 is dissolved in 15mL ethanol, stirred at ambient temperature, and add 0.69g (10mmol) oxammonium hydrochloride and 2.46g (30mmol) sodium-acetate, then temperature rising reflux spends the night under a nitrogen.TLC shows reaction to be completed.Reaction mixture pours in 200mL frozen water, stirs, with 50mL × 3CH 2cl 2extraction, merges extraction phase, uses salt water washing, anhydrous sodium sulfate drying.Suction filtration removing siccative, filtrate is evaporate to dryness on a rotary evaporator, and resistates uses purification by silica gel column chromatography, obtains compound VI-1, white solid, ESI-MS, m/z=302,304 ([M+H] +).
The synthesis of C.VII-1
1.21g (4mmol) compound VI-1 is dissolved in the THF of 15mL drying; be cooled to-78 DEG C under nitrogen protection; induction stirring; slowly drip the hexane solution of the n-BuLi of 2.5mL (4mmol) 1.6M with syringe, dropwise rear reaction mixture and continue stirring at such a temperature 1 hour.The solution of 0.57g (4mmol) boron trifluoride diethyl etherate and 1mL THF preparation is slowly dripped with syringe, after dropwising, the solution of the THF preparation of 0.46g (5mmol) (R)-polychlorinated dibenzo-furans and 1mL drying is slowly dripped again with syringe, after dropwising, compound of reaction is slowly warmed up to room temperature, and at room temperature stirring is spent the night, TLC detection reaction completes.Reaction mixture pours in 100mL frozen water, stirs, with 50mL × 3CH 2cl 2extraction, merges extraction phase, uses salt water washing, anhydrous sodium sulfate drying.Suction filtration removing siccative, filtrate is evaporate to dryness on a rotary evaporator, and resistates uses purification by silica gel column chromatography, obtains compound VI I-1, white solid, ESI-MS, m/z=316 ([M+H] +).
The synthesis of D.R-1
0.63g (2mmol) compound VI I-1,0.25g (2mmol) compound VI II-4 and 0.83g (6mmol) solid K 2cO 3add in 10mL DMF, room temperature for overnight, TLC shows reaction to be completed.Reaction mixture pours in 100mL frozen water, stirs, with 50mL × 3CH 2cl 2extraction, merges extraction phase, uses salt water washing, anhydrous sodium sulfate drying.Suction filtration removing siccative, filtrate is evaporate to dryness on a rotary evaporator, and resistates uses purification by silica gel column chromatography, obtains compound R-1, white solid, ESI-MS, m/z=404 ([M+H] +).
embodiment 5 Compound ira vitro is to the restraining effect of 11 β-HSD1
The vitro enzyme activity of test compound is evaluated through scintillation proximity assay (SPA).The determined compound 11 β-HSD1 enzymes optimizing cortisone substrate, NADPH cofactor and structural formula (I) are made to carry out to the conversion of hydrocortisone 37 DEG C of cultivations.After incubation, the preparation of the SPA pearl applied by the a-protein with the pre-mixing of anti-hydrocortisone monoclonal antibody and nonspecific 11 β-HSD inhibitor such as 18 β-glycyrrhetinic acids adds in each hole.Mixture, 15 DEG C of vibrations, reads with the liquid scintillation counter being suitable for 96 orifice plates subsequently.Calculate relative to non-suppression control wells and suppress percentage ratio, obtain IC 50curve.Specifically, add in the hole of specifying on 96 orifice plates 40 μ L substrates (25nM in 50mM HEPES damping fluid [ 3h]-cortisone+1.25mM NADPH, pH 7.4).Compound is dissolved in DMSO with 10mM, 50 times of dilutions successively in DMSO.Material 4 times of titration subsequently of dilution 7 times.In substrate, add the titrated compound of 1 μ L respectively subsequently in duplicate.For starting reaction, in each hole, add 11 β-HSD1 microsomes that 10 μ L obtain by Chinese hamster ovary celI transfection thing with the feedstock conversion producing about 10% with suitable concentration.For finally calculating suppression percentage ratio, add in a series of holes of the minimum and maximum test of expression: the one group of material not having compound or enzyme (background) containing substrate, containing substrate and enzyme without any another group material (peak signal) of compound.Plate is centrifugal to collect reactant simply under the low speed in centrifuges, with adhesive tape sealing, slowly mixes, cultivates 2 hours at 37 DEG C.After incubation, in each hole, add SPA pearl and formula (I) compound that the anti-hydrocortisone monoclonal antibody of 45 μ L suspends in advance.Plate is resealed, 15 DEG C of gentle vibrations more than 1.5 hours.Data are collected in plate base liquid scintillation counter.For controlling the suppression that anti-hydrocortisone antibody/hydrocortisone combines, will with 1.25nM [ 3h-] hydrocortisone do in target substrate add in the single hole of specifying.In each such hole, add 200 μMs of compounds of 1 μ L, replace enzyme with 10 μ L damping fluids simultaneously.The suppression of any calculating is incorporated into the interference of the antibody on SPA pearl to hydrocortisone owing to compound.
Test result sees the following form.
Compound IC 50(nM)
Reference compound R-1 23.8
Compound I-1 12.4
Compound I-2 13.1
Compound I-3 14.0
As can be seen from upper table result, compound of the present invention has very strong restraining effect to 11 β-HSD1, can as preparation treatment diabetes B medicine.

Claims (4)

1. there is the compound of general formula I,
2. the compound of Formula I that defines of claim 1, is selected from:
3. synthesize the method for arbitrary the defined compound of Formula I of claim 1-2:
Compound II per and compound III be first reacting generating compound IV in the presence of a base, and the latter is at AlCl 3reset under catalysis and generate compound V; Compound V and azanol reaction generate compound VI; Compound VI first processes at low temperatures with n-BuLi, generates corresponding lithium aryl, and the latter is again at BF 3et 2react with (R)-polychlorinated dibenzo-furans under O catalysis and generate product VII; Compound VI I reacts with compound VI II in the presence of a base, obtains Compound I.
4. the compound of Formula I that one of claim 1-2 defines is preparing the application in treatment diabetes B medicine.
CN201510412033.1A 2015-07-14 2015-07-14 Compound with benzisoxazole and nitrobenzophenone structure and application thereof Pending CN104926742A (en)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1543451A (en) * 2001-06-07 2004-11-03 Receptor modulators activated by peroxizonal proliferators (ppar)
US20080021022A1 (en) * 2006-07-20 2008-01-24 Amgen Inc. Substituted azole aromatic heterocycles as inhibitors of 11beta-hsd-1
WO2010011917A1 (en) * 2008-07-25 2010-01-28 Glaxosmithkline Llc SEH AND 11β-HSD1 DUAL INHIBITORS
CN103360376A (en) * 2013-07-16 2013-10-23 临海市联盛化学有限公司 Method for preparing 17 beta-HSD1 inhibitor
WO2013157511A1 (en) * 2012-04-16 2013-10-24 大日本住友製薬株式会社 Arylaminopyrazole derivative
CN103709223A (en) * 2012-10-09 2014-04-09 中国科学院昆明植物研究所 Dammarane triterpene derivative, pharmaceutical composition thereof, and applications of dammarane triterpene derivative in pharmacy

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1543451A (en) * 2001-06-07 2004-11-03 Receptor modulators activated by peroxizonal proliferators (ppar)
US20080021022A1 (en) * 2006-07-20 2008-01-24 Amgen Inc. Substituted azole aromatic heterocycles as inhibitors of 11beta-hsd-1
WO2010011917A1 (en) * 2008-07-25 2010-01-28 Glaxosmithkline Llc SEH AND 11β-HSD1 DUAL INHIBITORS
WO2013157511A1 (en) * 2012-04-16 2013-10-24 大日本住友製薬株式会社 Arylaminopyrazole derivative
CN103709223A (en) * 2012-10-09 2014-04-09 中国科学院昆明植物研究所 Dammarane triterpene derivative, pharmaceutical composition thereof, and applications of dammarane triterpene derivative in pharmacy
CN103360376A (en) * 2013-07-16 2013-10-23 临海市联盛化学有限公司 Method for preparing 17 beta-HSD1 inhibitor

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HALE, CLARENCE ET AL.: "Development of 11β-HSD1 inhibitors for the treatment of type 2 diabetes", 《MINI-REVIEWS IN MEDICINAL CHEMISTRY》 *

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Application publication date: 20150923