CN104974080A - 11beta-HSD1 (11-beta-hydroxysteroid dehydrogenase 1) inhibitor containing bipyridine tertiary alcohol structure as well as preparation method and application thereof - Google Patents
11beta-HSD1 (11-beta-hydroxysteroid dehydrogenase 1) inhibitor containing bipyridine tertiary alcohol structure as well as preparation method and application thereof Download PDFInfo
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- CN104974080A CN104974080A CN201510423473.7A CN201510423473A CN104974080A CN 104974080 A CN104974080 A CN 104974080A CN 201510423473 A CN201510423473 A CN 201510423473A CN 104974080 A CN104974080 A CN 104974080A
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- IMRWILPUOVGIMU-UHFFFAOYSA-N Brc1ccccn1 Chemical compound Brc1ccccn1 IMRWILPUOVGIMU-UHFFFAOYSA-N 0.000 description 1
- 0 C=*c1ccccn1 Chemical compound C=*c1ccccn1 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
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Abstract
The invention relates to the field of medicines related to type II diabetes mellitus and in particular relates to a 11beta-HSD1 (11-beta-hydroxysteroid dehydrogenase 1) inhibitor containing a bipyridine tertiary alcohol structure, a preparation method of the inhibitor and an application of the inhibitor to preparation of medicines related to type II diabetes mellitus. A structure of the inhibitor is shown in a general formula I in the specification, wherein in the general formula I, R is selected from H and C1-C8 alkyl.
Description
Technical field
The present invention relates to the pharmaceutical field of diabetes B treatment.Specifically, the present invention relates to 11 beta-HSD 1 inhibitors, its preparation method of the medicative class of diabetes B tool containing two pyridine tertiary alcohol structures, 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 containing two pyridine tertiary alcohol structures, 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 the application of compound in treatment diabetes B containing general formula I.
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:
Wherein, R is selected from H, C
1-C
8alkyl.
Further, R is preferably from H, C
1-C
3alkyl.
More preferably the compound of general 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 reacting generating compound IV in case of heating; Compound V n-Butyl Lithium processes at low temperatures, obtains corresponding lithium aryl VI; The compound VI of compound IV and twice equivalent is reacted, and obtains Compound I; The definition of R as previously mentioned.
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-700mg/ 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
The synthesis of step 1. compound IV
Compound II per (0.80g, 10mmol) and compound III (0.86g, 10mmol) are dissolved in 10mL benzene, reflux 1 hour under nitrogen protection, and TLC checks and finds that reaction completes.Evaporate to dryness on a rotary evaporator after reaction mixture is slightly cold, resistates column chromatography purification, obtains compound IV, white solid, ESI-MS, m/z=167 ([M+H]
+).
The synthesis of step 2. Compound I-1
2-bromopyridine V-1 (1.90g; 12mmol) be dissolved in the THF of 20mL drying;-78 DEG C are cooled under nitrogen protection; 7.5mL (12mmol) n-BuLi is slowly dripped with syringe under stirring; after dropwising; reaction mixture continues stirring 1 hour at such a temperature; then slowly drip compound IV (0.83g with syringe again; the solution that THF 5mmol) being dissolved in 1mL drying makes; after dropwising; reaction mixture at room temperature stirs and spends the night, and 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 I-1, white solid, ESI-MS, m/z=293 ([M+H]
+).
the synthesis of embodiment 2 Compound I-2
The synthesis of step 1. compound IV
Compound II per (0.80g, 10mmol) and compound III (0.86g, 10mmol) are dissolved in 10mL benzene, reflux 1 hour under nitrogen protection, and TLC checks and finds that reaction completes.Evaporate to dryness on a rotary evaporator after reaction mixture is slightly cold, resistates column chromatography purification, obtains compound IV, white solid, ESI-MS, m/z=167 ([M+H]
+).
The synthesis of step 2. Compound I-2
Compound V-2 (2.04g; 12mmol) be dissolved in the THF of 20mL drying;-78 DEG C are cooled under nitrogen protection; 7.5mL (12mmol) n-BuLi is slowly dripped with syringe under stirring; after dropwising; reaction mixture continues stirring 1 hour at such a temperature; then slowly drip compound IV (0.83g with syringe again; the solution that THF 5mmol) being dissolved in 1mL drying makes; after dropwising; reaction mixture at room temperature stirs and spends the night, and 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 I-2, white solid, ESI-MS, m/z=321 ([M+H]
+).
embodiment 3-9
With reference to the method for embodiment 1,2, synthesize compound listed in Table:
embodiment 10 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 I-1 | 18.3 |
| Compound I-2 | 8.9 |
| Compound I-3 | 9.6 |
| Compound I-4 | 11.5 |
| Compound I-5 | 13.0 |
| Compound I-6 | 10.4 |
| Compound I-7 | 16.4 |
| Compound I-8 | 24.7 |
| Compound I-9 | 20.4 |
The display of 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 (5)
1. there is the compound of general formula I,
Wherein, R is selected from H, C
1-C
8alkyl.
2. the compound with general formula I that claim 1 defines,
Wherein, R is selected from H, C
1-C
3alkyl.
3. the compound of Formula I that defines of claim 2, is selected from:
4. synthesize arbitrary the defined method belonging to the compound of general formula I of claim 1-3:
Compound II per and compound III be reacting generating compound IV in case of heating; Compound V n-Butyl Lithium processes at low temperatures, obtains corresponding lithium aryl VI; The compound VI of compound IV and twice equivalent is reacted, and obtains Compound I; As described in the definition of R is as arbitrary in claim 1-3.
5. the compound of Formula I that one of claim 1-3 defines is preparing the application in treatment diabetes B medicine.
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|---|---|---|---|
| CN201510423473.7A CN104974080A (en) | 2015-07-19 | 2015-07-19 | 11beta-HSD1 (11-beta-hydroxysteroid dehydrogenase 1) inhibitor containing bipyridine tertiary alcohol structure as well as preparation method and application thereof |
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| CN201510423473.7A CN104974080A (en) | 2015-07-19 | 2015-07-19 | 11beta-HSD1 (11-beta-hydroxysteroid dehydrogenase 1) inhibitor containing bipyridine tertiary alcohol structure as well as preparation method and application thereof |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1897944A (en) * | 2003-12-19 | 2007-01-17 | 辉瑞有限公司 | Benzenesulfonylamino-pyridin-2-yl derivatives and related compounds as inhibitors of 11-beta-hydroxysteroid dehydrogenase type 1 (11-beta-hsd-1) for the treatment of diabetes and obesity |
| US20110039853A1 (en) * | 2007-02-23 | 2011-02-17 | High Point Pharmaceuticals, Llc | N-adamantyl benzamides as inhibitors of 11-beta-hydroxysteroid dehydrogenase |
| CN102933558A (en) * | 2010-01-22 | 2013-02-13 | 埃斯泰隆制药公司 | Reverse amide compounds as protein deacetylase inhibitor and methods of use thereof |
| CN102947295A (en) * | 2010-04-29 | 2013-02-27 | 爱丁堡大学 | 3,3-disubstituted-(8-aza-bicyclo [3.2.1]oct-8-y)-[5-(1 -pyrazol-4-yl)-thiophe-3-yl] methanones as inhibitors of 11[beta]-HSD1 |
| CN103025721A (en) * | 2010-05-07 | 2013-04-03 | Sk化学公司 | Picolinamide and pyrimidine-4-carboxamide compounds, process for preparing and pharmaceutical composition comprising the same |
-
2015
- 2015-07-19 CN CN201510423473.7A patent/CN104974080A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1897944A (en) * | 2003-12-19 | 2007-01-17 | 辉瑞有限公司 | Benzenesulfonylamino-pyridin-2-yl derivatives and related compounds as inhibitors of 11-beta-hydroxysteroid dehydrogenase type 1 (11-beta-hsd-1) for the treatment of diabetes and obesity |
| US20110039853A1 (en) * | 2007-02-23 | 2011-02-17 | High Point Pharmaceuticals, Llc | N-adamantyl benzamides as inhibitors of 11-beta-hydroxysteroid dehydrogenase |
| CN102933558A (en) * | 2010-01-22 | 2013-02-13 | 埃斯泰隆制药公司 | Reverse amide compounds as protein deacetylase inhibitor and methods of use thereof |
| CN102947295A (en) * | 2010-04-29 | 2013-02-27 | 爱丁堡大学 | 3,3-disubstituted-(8-aza-bicyclo [3.2.1]oct-8-y)-[5-(1 -pyrazol-4-yl)-thiophe-3-yl] methanones as inhibitors of 11[beta]-HSD1 |
| CN103025721A (en) * | 2010-05-07 | 2013-04-03 | Sk化学公司 | Picolinamide and pyrimidine-4-carboxamide compounds, process for preparing and pharmaceutical composition comprising the same |
Non-Patent Citations (1)
| Title |
|---|
| 万小莉,等: "11β-羟基类固醇脱氢酶1与2型糖尿病", 《重庆医学》 * |
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Application publication date: 20151014 |