CN105001171A - Nitrobenzene triazole sulphoxides 11[beta]-HSD1 inhibitor and application of same - Google Patents
Nitrobenzene triazole sulphoxides 11[beta]-HSD1 inhibitor and application of same Download PDFInfo
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- CN105001171A CN105001171A CN201510409665.2A CN201510409665A CN105001171A CN 105001171 A CN105001171 A CN 105001171A CN 201510409665 A CN201510409665 A CN 201510409665A CN 105001171 A CN105001171 A CN 105001171A
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- diabetes
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles 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
- C07D249/14—Nitrogen atoms
Abstract
The present invention relates to the field of medicines for type 2 diabetes. Specifically, the present invention relates to a nitrobenzene triazole sulphoxides 11[beta]-HSD1 inhibitor, a preparation method of the same, and an application of the same in preparing medicines for type 2 diabetes.
Description
Technical field
The present invention relates to the pharmaceutical field of diabetes B treatment.Specifically, the present invention relates to medicative class oil of mirbane triazole sulfoxide type 11 beta-HSD 1 inhibitors of diabetes B tool, its preparation method, and the purposes in pharmacy.
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 of a class nitrobenzene-containing triazole sulfoxide structure, 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.
Another object of the present invention is to provide compound containing general formula I as effective constituent, and the application in treatment diabetes B.
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 IV is according to document route synthesis (US20130345271).
Compound II per is at low temperatures first through n-BuLi process, and the phenyl lithium obtained is again at BF
3et
2with (S)-polychlorinated dibenzo-furans generation substitution reaction under O catalysis, obtain compound III; Compound III and compound IV are reacted, and obtain compound V; Compound V obtains Compound I through oxidizing.
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 III-1
Compound II per-1 (1.71g; 10mmol) be dissolved in the THF of 20mL drying; be cooled to-78 DEG C under nitrogen protection; induction stirring; hexane solution (the 6.25mL of the n-BuLi of 1.6M is slowly dripped with syringe; 10mmol), dropwise rear reaction mixture and continue stirring at such a temperature 1 hour.Boron trifluoride diethyl etherate (1.42g is slowly dripped with syringe, solution 10mmol) prepared with 1mL THF, after dropwising, (1.11g is slowly dripped again with syringe, 12mmol) the solution of the THF preparation of (S)-polychlorinated dibenzo-furans and 1mL drying, 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 200mL frozen water, stirs, uses CH
2cl
2(60mL × 3) extract, and merge extraction phase, use 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 III-1, white solid, ESI-MS, m/z=185 ([M+H]
+).
B. the synthesis of compound V-1
Compound III-1 (1.29g, 7mmol), compound IV-1 (1.66g, 7mmol) and solid K
2cO
3(2.90g, 21mmol) adds in 20mL DMF, room temperature for overnight, and TLC shows reaction to be completed.Reaction mixture pours in 200mL frozen water, stirs, uses CH
2cl
2(60mL × 3) extract, and merge extraction phase, use 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 V-1, white solid, ESI-MS, m/z=386 ([M+H]
+).
C. the synthesis of Compound I-1
Compound V-1 (1.93g, 5mmol) is dissolved in 20mL CH
2cl
2in, ice-water bath cooling is lower stirs, and slowly adds metachloroperbenzoic acid (mCPBA, 1.04g, 6mmol), and after adding, stirred at ambient temperature 1 hour, TLC shows reaction to be completed.Reaction mixture pours in 200mL frozen water, stirs, uses CH
2cl
2(60mL × 3) extract, and merge extraction phase, use saturated NaHCO successively
3with 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=402 ([M+H]
+).
embodiment 2-3
With reference to the method for embodiment 1, synthesize following compounds.
the synthesis of embodiment 4 reference compound R-1
In order to further illustrate the pharmacological effect of the compounds of this invention, this invention describes and be all applicant's invention and not yet disclosed novel compounds R-1, its structure is as follows:
Its synthetic method is as follows:
A. the synthesis of compound III-1
Compound II per-1 (1.71g; 10mmol) be dissolved in the THF of 20mL drying; be cooled to-78 DEG C under nitrogen protection; induction stirring; hexane solution (the 6.25mL of the n-BuLi of 1.6M is slowly dripped with syringe; 10mmol), dropwise rear reaction mixture and continue stirring at such a temperature 1 hour.Boron trifluoride diethyl etherate (1.42g is slowly dripped with syringe, solution 10mmol) prepared with 1mL THF, after dropwising, (1.11g is slowly dripped again with syringe, 12mmol) the solution of the THF preparation of (S)-polychlorinated dibenzo-furans and 1mL drying, 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 200mL frozen water, stirs, uses CH
2cl
2(60mL × 3) extract, and merge extraction phase, use 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 III-1, white solid, ESI-MS, m/z=185 ([M+H]
+).
B. the synthesis of compound V-4
Compound III-1 (1.29g, 7mmol), compound IV-4 (1.35g, 7mmol) and solid K
2cO
3(2.90g, 21mmol) adds in 20mL DMF, room temperature for overnight, and TLC shows reaction to be completed.Reaction mixture pours in 200mL frozen water, stirs, uses CH
2cl
2(60mL × 3) extract, and merge extraction phase, use 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 V-4, white solid, ESI-MS, m/z=341 ([M+H]
+).
C. the synthesis of compound R-1
Compound V-4 (1.70g, 5mmol) is dissolved in 20mL CH
2cl
2in, ice-water bath cooling is lower stirs, and slowly adds metachloroperbenzoic acid (mCPBA, 1.04g, 6mmol), and after adding, stirred at ambient temperature 1 hour, TLC shows reaction to be completed.Reaction mixture pours in 200mL frozen water, stirs, uses CH
2cl
2(60mL × 3) extract, and merge extraction phase, use saturated NaHCO successively
3with 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=357 ([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) |
| Compound R-1 (embodiment 4) | 16.3 |
| Compound I-1 | 7.2 |
| Compound I-2 | 8.7 |
| Compound I-3 | 10.6 |
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 arbitrary the defined method belonging to the compound of general formula I of claim 1-2:
Compound II per is at low temperatures first through n-BuLi process, and the phenyl lithium obtained is again at BF
3et
2with (S)-polychlorinated dibenzo-furans generation substitution reaction under O catalysis, obtain compound III; Compound III and compound IV are reacted, and obtain compound V; Compound V obtains Compound I through oxidizing.
4. the compound of Formula I that one of claim 1-2 defines is preparing the application in treatment diabetes B medicine.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010009210A2 (en) * | 2008-07-17 | 2010-01-21 | Schering Corporation | Acetylsalicyclic acid derivatives useful to treat metabolic syndromes |
| CN102395567A (en) * | 2009-02-12 | 2012-03-28 | 埃克塞利希斯股份有限公司 | Triazole and imidazole derivatives for use as tgr5 agonists in the treatment of diabetes and obesity |
| CN103724335A (en) * | 2005-10-20 | 2014-04-16 | 默沙东公司 | Triazole derivatives as inhibitors of 11-beta-hydroxysteroid dehydrogenase-1 |
-
2015
- 2015-07-13 CN CN201510409665.2A patent/CN105001171A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103724335A (en) * | 2005-10-20 | 2014-04-16 | 默沙东公司 | Triazole derivatives as inhibitors of 11-beta-hydroxysteroid dehydrogenase-1 |
| WO2010009210A2 (en) * | 2008-07-17 | 2010-01-21 | Schering Corporation | Acetylsalicyclic acid derivatives useful to treat metabolic syndromes |
| CN102395567A (en) * | 2009-02-12 | 2012-03-28 | 埃克塞利希斯股份有限公司 | Triazole and imidazole derivatives for use as tgr5 agonists in the treatment of diabetes and obesity |
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Application publication date: 20151028 |
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