CN103044322B - (3E, 5E)-3,5-bipiperidyl-4-ketone analogue and preparation method and application thereof - Google Patents
(3E, 5E)-3,5-bipiperidyl-4-ketone analogue and preparation method and application thereof Download PDFInfo
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Abstract
The invention provides a (3E, 5E)-3,5-bipiperidyl-4-ketone analogue and a preparation method and application thereof. The (3E, 5E)-3,5-bipiperidyl-4-ketone analogue comprises a compound with a structure shown by a general formula IV and a pharmaceutically acceptable salt thereof, wherein the compound has obvious pharmacological activity. The invention further provides a preparation method of the compound and application thereof in preventing and treating human diabetes as an 11beta-hydroxysteroid dehydrogenase type I (11b-HSD1) inhibitor.
Description
Technical field
The present invention relates to a kind of new compound, specifically, relate to a kind of (3E, 5E)-3, two piperidin-4-one-analogues of 5-and preparation method thereof and application.
Background technology
Diabetes (Diabetes mellitus, DM) are a kind of worldwide diseases, and according to WHO report, add up in December, 2012, and the whole world has 3.46 hundred million people to suffer from diabetes at present.If expect the year two thousand thirty and will double without any intervening these data, wherein 80% occur in low Countries with moderate incomes.DM has become the large disease in third place in the world, and its sickness rate and the danger to human health, be only second to cancer and cardiovascular and cerebrovascular disease.In China, nearly 4,000 ten thousand diabetic subjects, occupy the whole world the second at present, and wherein 2 type DM (T2DM) patients account for 90%～95% of whole DM.At present, the direction of type 1 diabetes treatment research is insulin preparation and the Regular Insulin surrogate of exploitation convenient drug administration; And diabetes B can impel the more Regular Insulin of β emiocytosis with chemicals, or improve target tissue the susceptibility of Regular Insulin is treated, the antidiabetic medicine of the high-efficiency low-toxicity of research and development novel mechanism or new texture type has become the focus of new drug development in the world.
Glucocorticosteroid is the antagonist of insulin action, and it weakens glucose uptake and the increase lipolysis that relies on Regular Insulin, improves liver glyconeogenesis and increases matrix (Andrew McMaster etc. by proteolyzing, Nature Reviews Endocrinology, 2008,4,91), and directly suppress beta Cell of islet excreting insulin (Posp í silov á Y etc., Vnitr Lek, 2007,53,1,18).Regular Insulin suppresses glycogen heteroplasia, and glucocorticosteroid increases glyconeogenesis, directly or indirectly activate oligogene or the hormone that participates in this process, as: the genetic expression (PEPCK) of phosphoric acid enol acetone carboxylase in hyperglycemic-glycogenolytic factor, liver, PEPCK is the rate-limiting enzyme of glyconeogenesis, it is regulated and controled by glucocorticoid responsive element, it also can be to cAMP r controlling element binding albumen (CREB) effect (Gavin P., Molecular and Cellular Endocrinology, 2009,300,2).Glucocorticosteroid and CREB synergy induction peroxisome increment activated receptor-gamma coactivator 1 (PGC-1), it is the main activator of glycogen heteroplasia (Yoon JC etc., Nature, 2001,413,131).In addition, glucocorticosteroid is by suppressing the translation of translocator 4, antagonism insulin response comprises and suppresses insulin signaling transmission and suppress insulin stimulating glucose uptake (Nicholas Michael Morton, Molecular and cellular endocrinology, 2010,316,154).So the height of glucocorticoid levels directly affects the effect of Regular Insulin.
Glucocorticosteroid is under hypothalamic-pituitary-adrenal-axis (HPA) is controlled, by acth secretion in blood.Yet when HPA determines blood glucocorticoid levels, outstanding research recently shows 11beta hydroxysteroid dehydrogenase 11b-HSDs in cell) adjusting glucocorticoid levels.Although therefore there is normal glucocorticoid levels in some cells, but make sometimes it in inactive state, sometimes by the inactive active condition that is converted into, these are all to carry out catalysis by 11b-HSD, 11b-HSD has two kinds of isomer, the precursor (prednisone or 11-dehydrocorticosterone) that 11b-HSD1 can activate inertia becomes the glucocorticosteroid (hydrocortisone or Kendall compound) of activation, it mainly has reductibility (T.M.Stulnig1 in liver, fatty tissue, brain, skeletal muscle, smooth muscle cell, Diabetologia, 2004,47,1).
In daily change procedure, the active concentration of cortisol of blood plasma changes (1 – 100nmol/L) greatly.In contrast, nonactive cortisone does not have large daily variation, in 50-100nmol/L fluctuation, relatively has higher plasma concentration freely (Stewart PM etc., Vitam Horm, 1999,57,249) with hydrocortisone.Therefore, blood plasma cortisone can constantly provide 11b-HSD1 reductibility to maintain Topically active glucocorticosteroid concentration as the storage pool that is inactive glucocorticosteroid, glucocorticosteroid and insulin function antagonism in the active tissue of metabolism.
Foreign scholar show that with transgenic mice research in data presentation 11b-HSD1-/-mouse cell, glucocorticosteroid is damaged, it no longer with insulin resistant (Erika Harno etc., Trends in Endocrinology & Metabolism, 2010,21,619)
Therefore the research of 11b-HSD1 inhibitor enjoys the attention of Chinese scholars, and 11b-HSD1 restraining effect has positive impact to glycosuria patient's insulin sensitivity.Because most of diabetes B patients are obese persons, its interior fat hypertrophy and 11b-HSD1 high expression level, inhibitor or 11b-HSD1 can improve glycemia.With nonspecific inhibitor 11 β-HSD contrast, kidney 11b-HSD2 inhibitor can cause hypertension and hypokalemia, muroid selective depressant 11b-HSD1 (BVT.2733) is presented in spontaneous ground hyperglycemia KKAy mouse can reduce liver phosphoric acid ketenes formula pyruvic acid carboxylic kinases PEPCK and G-6-Pase mrna expression, reduce blood sugar and serum insulin concentration (Malgorzata Wamil etc. simultaneously, Drug Discovery Today, 2007,12,504).11b-HSD1 people's selective depressant is synthetic (Barf T etc., J Med Chem, 2002,45,3813), and 11b-HSD1 selective depressant can be helpful to insulin resistant or diabetes B obese patient.Because at these imbalance states, 11b-HSD1 expresses with the unusual regulation and control of tissue specificity mode, at fatty tissue high expression level, but in liver low activity, the clinical effect of 11b-HSD1 selective depressant can change and change along with they partial concns in fatty tissue and liver organization.Except having impact at the active tissue of metabolism, we expect that in HPA axis, 11b-HSD1 induction changes, because the restraining effect of central nervous system 11b-HSD1 is destroyed the reverse feedback of hypothalamus hypophysis suprarenal gland.11b-HSD1 is very important for glucocorticoid activity in brain, and regulation and control hpa axis.Therefore the inhibitor of hypothalamus 11 β-HSD1 can be benumbed reverse feedback regulation by reducing local concentration of cortisol, and causes acth secretion glucocorticosteroid to increase.For fear of 11b-HSD1 specific inhibitor, to hypothalamic intervention, these medicines can not pass hemato encephalic barrier.On the other hand; the restraining effect of 11b-HSD1 in central nervous system can protect brain to avoid receiving negative impact (the Adam J.Rose etc. of glucocorticosteroid when aging; The Journal of Steroid Biochemistry and Molecular Biology; 2010; 122,10).Therefore 11b-HSD1 inhibitor, will be expected to become interesting novel medicine in future, is not even only confined to treat obesity and diabetes B.
(3E, 5E)-3, the two piperidin-4-one-analogues of 5-are that main chain is unsaturated aliphatic and side chain aromatic group.Need exploitation to have (3E, 5E)-3 of better inhibition 11b-HSD1 enzymic activity, the two piperidin-4-one-analogue classes of 5-, are drug provision experiment and the Clinical Basis of exploitation prevention in the future and treatment knot diabetes.
Summary of the invention
The object of this invention is to provide a kind of active (3E, 5E)-3 that suppress 1 type 11beta-hydroxysteroid dehydrogenase that have, the two piperidin-4-one-analogues of 5-.For achieving the above object, the present invention adopts following technical scheme:
A kind of (3E, 5E)-3, the two piperidin-4-one-analogues of 5-, comprise compound and the pharmacy acceptable salt thereof with structure shown in general formula I V:
Wherein: R
1and R
2independently be selected from separately H, Br or F.
R preferably
1and R
2independently be selected from separately Br or F.
More preferably the R described in
1for Br, R
2for F, that is:
Pharmacy acceptable salt of the present invention comprises the salt that forms with mineral acid, the salt forming with organic acid and the salt being formed by element negatively charged ion or positively charged ion; Preferably described mineral acid is hydrochloric acid, sulfuric acid or phosphoric acid; Described organic acid is acetic acid, tartrate, citric acid, xitix or oxalic acid; Described element negatively charged ion is chlorine, bromine or iodine; Described element positively charged ion comprises potassium, sodium, calcium or magnesium.
Another object of the present invention is to provide above-mentioned (3E, 5E)-3, the preparation method of the two piperidin-4-one-analogues of 5-, for achieving the above object, the present invention adopts following technical scheme:
Above-mentioned (3E, 5E)-3, the preparation method of the two piperidin-4-one-analogues of 5-, be specially: piperidone and halogenated benzaldehyde are in solvent, take potassium hydroxide or sodium methylate as catalyzer, reflux 0.3-2h reacts, and temperature of reaction is 20 ℃-80 ℃, and separation and purified product obtain target compound; The preferred reaction time is 1h-1.5h, and temperature of reaction is 45 ℃-55 ℃, and more preferably the reaction times is 1h, and temperature of reaction is 50 ℃.
In preparation method of the present invention, described halogenated benzaldehyde is bromo-6 fluorobenzaldehydes of 2-, 2,6 dichlorobenzaldehydes, 2,6 difluorobenzaldehydes, 2,6 dibromo benzaldehydes or fluoro-6 bromobenzaldehydes of 2-, and described piperidone is piperidine hydrochloride ketone; Preferably described halogenated benzaldehyde is bromo-6 fluorobenzaldehydes of 2-.
In preparation method of the present invention, described solvent is ethanol or methyl alcohol; Preferably described solvent is ethanol.The volumetric usage of described solvent is 3-5 times of reactant total mass, and wherein volume unit is ml, and mass unit is g, and if the total mass of ketone and aldehyde is 0.5g, the consumption of solvent should be 1.5-2.5ml.
In preparation method of the present invention, described piperidone is 3:1-2:1 with the mole dosage ratio of halogenated benzaldehyde, the quality consumption of described catalyzer is the 10%-30% of piperidone and halogenated benzaldehyde total mass, preferred described piperidone is with the mole dosage of halogenated benzaldehyde than being 2.2:1, and the quality consumption of described catalyzer is 20% of piperidone and halogenated benzaldehyde total mass.
In preparation method of the present invention, described potassium hydroxide is that mass concentration is 5% potassium hydroxide aqueous solution, and described sodium methylate is that mass concentration is 0.5% methanol solution of sodium methylate.
After above-mentioned reaction finishes, in system, there are a large amount of precipitations to produce, are chilled to room temperature, decompress filter, screening with a small amount of alcohol flushing repeatedly, is dried and carries out separation and purification by silica gel column chromatography, and products obtained therefrom vacuum-drying, obtains target product.Separation and purifying that the present invention finishes after product to reaction are not done specific restriction, and the disclosed multiple Isolation and purification method of prior art may be used to realize the present invention, and those skilled in the art can select this rationally.
In addition, the present invention is claimed above-mentioned (3E, 5E)-3 further, the application of the two piperidin-4-one-analogues of 5-in preparation prevention and treatment human diabetes medicine.
And, claimed above-mentioned (3E, 5E)-3 of containing of the present invention, the pharmaceutical composition of the two piperidin-4-one-analogues of 5-.Composition of the present invention can contain 0.1%-99% the compounds of this invention, and all the other are acceptable on pharmacology, pharmaceutically acceptable carrier or the vehicle of and inertia nontoxic to humans and animals.Pharmaceutically acceptable carrier or vehicle are one or more solids, semisolid, liquid diluent, filler and pharmaceutical preparation.Concrete pharmaceutical carrier or the selection of vehicle and the those skilled in the art that are prepared as of preparation grasp, and the present invention is not particularly limited this.Described pharmaceutical composition of the present invention is used with the form of per weight volume of services, can be through various ways, and for example oral, rectum hypogloeeis, vein or transdermal administration, but preferred oral administration.
Pharmaceutical composition of the present invention, is preferably tablet, and in described tablet, the mass ratio of main ingredient and auxiliary material is 4:1-6:5, preferably 5:1.Concrete prescription can be: (3E, 5E)-3, the two piperidin-4-one-analogue 70-85 parts of 5-, weighting agent 10-18 part, lubricant 0.5-1 part, disintegrating agent 0.5-2 part.
As the preferred forms of tablet of the present invention, concrete prescription adopts: (3E, 5E)-3, the two piperidin-4-one-analogues 83.4% of 5-, Microcrystalline Cellulose (weighting agent) 15%, Magnesium Stearate (lubricant) 0.6%, sodium starch glycolate (disintegrating agent) 1%.Concrete preparation method can be referring to prior art.Because this prescription is scientific and reasonable, between auxiliary material, there is desirable synergy, the stability of gained tablet is high, and drug effect is particularly remarkable.
Adopt technique scheme, the present invention has following beneficial effect:
Clinical easy to use, be easy to accept, not only drug dose is accurate, has increased the stability of medicine simultaneously, also can reduce toxic side effect, be also convenient to medicine storage, transport and carry.
Embodiment
Following examples are used for illustrating the present invention, but are not used for limiting the scope of the invention.If do not specialize, the conventional means that in embodiment, technique means used is well known to those skilled in the art, the raw materials used commercial goods that is.
Embodiment 1(3E, 5E)-3, preparation and the evaluation thereof of the two piperidin-4-one-analogues of 5-
Compound:
(3E,5E)-3,5-bis(2-bromo-6-fluorobenzylidene)piperidin-4-one（CYH07）
Structural formula:
Preparation method:
Bromo-6 fluorobenzaldehydes of 0.5g2-and piperidine hydrochloride ketone (the mol ratio 2.2:1 of aldehyde and ketone) are dissolved in 2ml ethanol, stirring at normal temperature, syringe drips 2ml, 5% potassium hydroxide aqueous solution, at 50 ℃, react 0.5h to 1h, in system, there are a large amount of precipitations to produce, are chilled to room temperature, decompress filter, screening with a small amount of alcohol flushing repeatedly, be dried and carry out separation and purification by silica gel column chromatography, products obtained therefrom vacuum-drying, obtains target product CYH07.
(3E, 5E)-3,5-bis (2-bromo-6-fluorobenzylidene) piperidin-4-one(CYH07): yellow compound, yield is 64.8%, purity is 98.8%.1H?NMR(400MHz,CDCl3)δ7.57(s,2H),7.46(d,J=8.0Hz,2H),7.26–7.21(m,2H),7.11(t,J=8.8Hz,2H),3.78–3.73(m,2H).13C?NMR(101MHz,CDCl3)δ186.38,159.59(d,J=252.2Hz),138.40,130.92(d,J=9.3Hz),128.81,128.63(d,J=3.4Hz),125.10(d,J=3.8Hz),124.23(d,J=18.5Hz),114.95(d,J=23.2Hz),48.03(d,J=8.4Hz).Purity:99.2%by?HPLC.HRMS(ESI):calcd?for(M+Na)+(C19H13NBr2F2O)467.9405,found467.9406.
Embodiment 2
Compare with embodiment 1, distinctive points is only:
Bromo-6 fluorobenzaldehydes of 0.5g2-and piperidine hydrochloride ketone (the mol ratio 2:1 of aldehyde and ketone) are dissolved in 1.5ml methyl alcohol, stirring at normal temperature, syringe drips 2ml, 5% potassium hydroxide aqueous solution, at 80 ℃, react 0.3h to 0.5h, in system, there are a large amount of precipitations to produce, are chilled to room temperature, decompress filter, screening with a small amount of alcohol flushing repeatedly, be dried and carry out separation and purification by silica gel column chromatography, products obtained therefrom vacuum-drying, obtains target product CYH07.
(3E, 5E)-3,5-bis (2-bromo-6-fluorobenzylidene) piperidin-4-one(CYH07): yellow compound, yield is 50.7%, purity is 96.5%.1H?NMR(400MHz,CDCl3)δ7.57(s,2H),7.46(d,J=8.0Hz,2H),7.26–7.21(m,2H),7.11(t,J=8.8Hz,2H),3.78–3.73(m,2H).13C?NMR(101MHz,CDCl3)δ186.38,159.59(d,J=252.2Hz),138.40,130.92(d,J=9.3Hz),128.81,128.63(d,J=3.4Hz),125.10(d,J=3.8Hz),124.23(d,J=18.5Hz),114.95(d,J=23.2Hz),48.03(d,J=8.4Hz).Purity:99.2%by?HPLC.HRMS(ESI):calcd?for(M+Na)+(C19H13NBr2F2O)467.9405,found467.9406.
Embodiment 3
Compare with embodiment 1, distinctive points is only:
Bromo-6 fluorobenzaldehydes of 0.5g2-and piperidine hydrochloride ketone (the mol ratio 3:1 of aldehyde and ketone) are dissolved in 2.5ml methyl alcohol, stirring at normal temperature, syringe drips 2ml, 5% potassium hydroxide aqueous solution, at 20 ℃, react 1.5h to 2h, in system, there are a large amount of precipitations to produce, are chilled to room temperature, decompress filter, screening with a small amount of alcohol flushing repeatedly, be dried and carry out separation and purification by silica gel column chromatography, products obtained therefrom vacuum-drying, obtains target product CYH07.
(3E, 5E)-3,5-bis (2-bromo-6-fluorobenzylidene) piperidin-4-one(CYH07): yellow compound, yield is 53.8%, purity is 96.1%.1H?NMR(400MHz,CDCl3)δ7.57(s,2H),7.46(d,J=8.0Hz,2H),7.26–7.21(m,2H),7.11(t,J=8.8Hz,2H),3.78–3.73(m,2H).13C?NMR(101MHz,CDCl3)δ186.38,159.59(d,J=252.2Hz),138.40,130.92(d,J=9.3Hz),128.81,128.63(d,J=3.4Hz),125.10(d,J=3.8Hz),124.23(d,J=18.5Hz),114.95(d,J=23.2Hz),48.03(d,J=8.4Hz).Purity:99.2%by?HPLC.HRMS(ESI):calcd?for(M+Na)+(C19H13NBr2F2O)467.9405,found467.9406.
Embodiment 4
Compare with embodiment 1, distinctive points is only, the present embodiment is with bromo-6 fluorobenzaldehydes of the 2-in 2,6 difluorobenzaldehyde alternative embodiments 1, obtain (3E, 5E)-3 of following structure, the two piperidin-4-one-analogues of 5-, wherein, the yield of product is 69.2%, and purity is 99.0%.
Embodiment 5
Compare with embodiment 1, distinctive points is only, the present embodiment is with bromo-6 fluorobenzaldehydes of the 2-in 2,6 dichlorobenzaldehyde alternative embodiments 1, obtain (3E, 5E)-3 of following structure, the two piperidin-4-one-analogues of 5-, wherein, the yield of product is 69.8%, and purity is 99.5%.
Embodiment 6
Compare with embodiment 1, distinctive points is only, the present embodiment is with bromo-6 fluorobenzaldehydes of the 2-in 2,6 dibromo benzaldehyde alternative embodiments 1, obtain (3E, 5E)-3 of following structure, the two piperidin-4-one-analogues of 5-, wherein, the yield of product is 71.2%, and purity is 99.7%.
Embodiment 7
By embodiment 1 gained compound respectively through mineral acid example hydrochloric acid, sulfuric acid, phosphoric acid etc.; Organic acid is as processing such as acetic acid, tartrate, citric acid, xitix, oxalic acid, and the salt being formed by element negatively charged ion, as chlorine, bromine, iodine.The positively charged ion that forms salt comprises potassium, sodium, calcium, magnesium etc.Concrete preparation treatment process is understood by those skilled in the art and is grasped, and the present invention is not particularly limited this.
Embodiment 8 pharmaceutical compositions
Get the Compound C YH07 that embodiment 1 obtains, the ratio that is 5:1 according to itself and vehicle weight ratio adds vehicle (please supplement the available form of vehicle and concrete kind thereof, consumption, as lubricant, weighting agent etc.), main ingredient 83.4%, Microcrystalline Cellulose (weighting agent) 15%, Magnesium Stearate (lubricant) 0.6%, sodium starch glycolate (disintegrating agent) 1%, pelletizing press sheet.
Embodiment 9 pharmaceutical compositions
Compare with embodiment 8, distinctive points is only that the concrete prescription of the present embodiment is: the Compound C YH07 that embodiment 1 obtains is 70g, weighting agent Microcrystalline Cellulose 10g, magnesium stearate lubricant 0.5g, disintegrating agent carboxymethyl base Starch Sodium 0.5g.
Embodiment 10 pharmaceutical compositions
Compare with embodiment 8, distinctive points is only that the concrete prescription of the present embodiment is: the Compound C YH07 that embodiment 1 obtains is 85g, weighting agent Microcrystalline Cellulose 10g, magnesium stearate lubricant 0.5g, disintegrating agent carboxymethyl base Starch Sodium 0.5g.
Embodiment 11 pharmaceutical compositions
Get the Compound C YH07 of the method system of embodiment 1, then injection liquid method for making is made injection liquid after adding water for injection, essence filter embedding sterilizing routinely respectively.The concentration of main ingredient is 1.5%.
For the further performance of checking compound of the present invention, the compound that contriver further prepares with above-described embodiment has launched a large amount of special items tests, and length is limit, and only exemplifies the part of tool cogency herein.
Test example 1
(3E, 5E)-3, the two piperidin-4-one-analogues of 5-suppress the detection of rat testicle and people's hepatomicrosome 1 type 11b-hydroxy steroid dehydrogenase type activity
1 type 11b-hydroxysteroid dehydrogenase (11 β-hydroxysteroid dehydrogenase type I, be 11b-HSD1) a kind of enzyme that Reduced nicotinamide-adenine dinucleotide is coenzyme of take, mainly in the microsome of the tissues such as liver, fat, brain and testis, express.Containing 11b-HSD1 microsome can method routinely prepare (Brennan, J. etc., Genes Dev, 2003.17,800), also can buy from reagent company.According to existing research method, carry out the detection (Haider, S.G.I t.Rev.Cytol., 2004,233,181) of 11b-HSD1 enzymic activity.In brief, labeled reactant pipe first, every pipe adds 40 μ g rat testicles and people's hepatomicrosome albumen and 10nM-0.1mM(3E, 5E)-3, the two piperidin-4-one-analogues of 5-(are dissolved in dimethyl benzene sulfone, DMSO), then add PBS to 100 μ l.Then prepare steroid and detect mixture: 2 μ l[1,2-3H] cortisone (40,000cpm), the unlabelled cortisone 25 μ mol/L of 2 μ l), 1 μ lNADPH(50mmol/L) and 45 μ l PBS, vibration mixes.Get 50 μ l steroid detection mixtures and join in reaction tubes, cultivate 45min for 34 ℃.With after the pre-cold diethyl ether termination reaction of 1ml, vortex vibration 1min.Then supernatant is transferred in 5ml Glass tubing, nitrogen drying is also separated out solid.Add the heavy molten solid of 70 μ l ether, after vibration 1min, point sample in thin layer chromatography board, and thin layer chromatography board is put into and contained chloroform: methyl alcohol (volume ratio 90:10) chromatography cylinder 20min.Finally, thin layer chromatography board is placed on to scanning radiometer and detects on (System AR2000, Bioscan Inc., Washington, DC, USA) and read radiation peak value, and the transformation efficiency of compute classes sterol, thereby obtain the activity of conversion of 11b-HSD1 enzyme.This experiment with DMSO in contrast.
Experimental result shows, the embodiment of the present invention prepared (3E, 5E)-3, and the two piperidin-4-one-analogues of 5-have restraining effect, its IC to rat testicle microsome 11 β-HSD1 activity
50for 3443nM; More obvious to people's hepatomicrosome 11 β-HSD1 activity inhibition, its IC
50for 1100nM.This (3E, 5E)-3 ironically, the two piperidin-4-one-analogues of 5-do not have restraining effect (referring to test example 2) substantially to the activity of rat and people 11b-HSD2 enzyme.
Table 1(3E, 5E)-3, the restraining effect of the two piperidin-4-one-analogues of 5-to rat testicle and people's hepatomicrosome 11b-HSD1 enzymic activity
b(IC50,nΜ).
Test example 2
(3E, 5E)-3, the two piperidin-4-one-analogues of 5-suppress the detection of rat and people's microsome II type 11b-hydroxy steroid dehydrogenase type activity
II type 11b-hydroxysteroid dehydrogenase (11 β-hydroxysteroid dehydrogenase type II, 11b-HSD2) is a kind of enzyme that nicotinamide-adenine Nucleotide is coenzyme of take, and mainly in the microsome of the tissues such as kidney, placenta, expresses.Containing 11b-HSD2 microsome can method routinely prepare (Brennan, J. etc., Genes Dev, 2003.17,800), also can buy from reagent company.According to existing research method, carry out the detection (Haider, S.G.Int.Rev.Cytol., 2004,233,181) of 11b-HSD2 enzymic activity.In brief, labeled reactant pipe first, every pipe adds 40 μ g rats and people's microsomal protein and 10nM-0.1mM(3E, 5E)-3, the two piperidin-4-one-analogues of 5-(are dissolved in dimethyl benzene sulfone, DMSO), then add PBS to 100 μ l.Then prepare steroid and detect mixture: 2 μ l[1,2-
3h] hydrocortisone (40,000cpm), the unlabelled hydrocortisone of 2 μ l (25 μ mol/L), 1 μ lNAD+(50mmol/L) and 45 μ lPBS, vibration mixes.Get 50 μ l steroid detection mixtures and join in reaction tubes, 37C cultivates 45min.With after the pre-cold diethyl ether termination reaction of 1ml, vortex vibration 1min.Then supernatant is transferred in 5ml Glass tubing, nitrogen drying is also separated out solid.Add the heavy molten solid of 70 μ l ether, after vibration 1min, point sample in thin layer chromatography board, and thin layer chromatography board is put into and contained chloroform: methyl alcohol (volume ratio 90:10) chromatography cylinder 20min.Finally, thin layer chromatography board is placed on to scanning radiometer and detects on (System AR2000, Bioscan Inc., Washington, DC, USA) and read radiation peak value, and the transformation efficiency of compute classes sterol, thereby obtain the activity of conversion of 11b-HSD2 enzyme.This experiment with DMSO in contrast.
Experimental result shows, the embodiment of the present invention 1 gained (3E, 5E)-3, and the two piperidin-4-one-analogues of 5-are to 11b-HSD2, and its IC50 is >100 μ M.
Although above the present invention is described in detail with a general description of the specific embodiments, on basis of the present invention, can make some modifications or improvements it, this will be apparent to those skilled in the art.Therefore, these modifications or improvements, all belong to the scope of protection of present invention without departing from theon the basis of the spirit of the present invention.
Claims (4)
1. one kind (3E, 5E)-3, the two piperidin-4-one-compounds of 5-, structural formula is as follows:
。
2. (3E described in claim 1,5E)-3, the preparation method of the two piperidin-4-one-compounds of 5-, it is characterized in that, bromo-6 fluorobenzaldehydes of 0.5g 2-and piperidine hydrochloride ketone are dissolved in 2ml ethanol to the mol ratio 2.2:1 of aldehyde and ketone wherein, stirring at normal temperature, syringe drips 2 ml, 5% potassium hydroxide aqueous solution, reacts 0.5h to 1h at 50 ℃, has a large amount of precipitations to produce in system, be chilled to room temperature, decompress filter, screening with a small amount of alcohol flushing repeatedly, is dried and carries out separation and purification by silica gel column chromatography, products obtained therefrom vacuum-drying, obtains target product.
3. (3E, 5E)-3 described in claim 1, the application of the two piperidin-4-one-compounds of 5-in preparation prevention and treatment human diabetes medicine.
4. contain (3E, 5E)-3 described in claim 1, the pharmaceutical composition of the two piperidin-4-one-compounds of 5-.
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| CN103626692B (en) * | 2013-11-12 | 2015-10-28 | 中国人民解放军第二军医大学 | The two aryl methene phenylpiperidines ketone derivatives of 3,5-and preparing the application in hypoglycemic medicine |
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| US3931169A (en) * | 1975-01-29 | 1976-01-06 | E. R. Squibb & Sons, Inc. | 5-Substituted-pyrazolo(4,3-c)pyridines |
| CN102477013A (en) * | 2011-07-28 | 2012-05-30 | 暨南大学 | Preparation and application of curcumin compound capable of inhibiting activity of human type 1 11beta-hydroxysteroid dehydrogenase |
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| US3931169A (en) * | 1975-01-29 | 1976-01-06 | E. R. Squibb & Sons, Inc. | 5-Substituted-pyrazolo(4,3-c)pyridines |
| CN102477013A (en) * | 2011-07-28 | 2012-05-30 | 暨南大学 | Preparation and application of curcumin compound capable of inhibiting activity of human type 1 11beta-hydroxysteroid dehydrogenase |
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