CN103044224A - Penta-1,4-diene-3-ketone analogue and preparation method and application thereof - Google Patents
Penta-1,4-diene-3-ketone analogue and preparation method and application thereof Download PDFInfo
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- CN103044224A CN103044224A CN2013100326285A CN201310032628A CN103044224A CN 103044224 A CN103044224 A CN 103044224A CN 2013100326285 A CN2013100326285 A CN 2013100326285A CN 201310032628 A CN201310032628 A CN 201310032628A CN 103044224 A CN103044224 A CN 103044224A
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- penta
- diene
- preparation
- isosorbide
- acid
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Abstract
本发明提供了一种具有通式I所示结构的化合物及其药学上可接受的盐，该类化合物具有显著的药理活性。此外，本发明进一步提供了该类化合物的制备方法及作为1型11beta-羟基类固醇脱氢酶（11beta-hydroxysteroid dehydrogenase type I，11b-HSD1）抑制剂在预防和治疗人类糖尿病中的应用。 The present invention provides a compound with a structure represented by general formula I and a pharmaceutically acceptable salt thereof, and this type of compound has significant pharmacological activity. In addition, the present invention further provides a preparation method of the compound and its application as a type 1 11beta-hydroxysteroid dehydrogenase (11beta-hydroxysteroid dehydrogenase type I, 11b-HSD1) inhibitor in the prevention and treatment of human diabetes.
Description
Technical field
The present invention relates to a kind of new compound, specifically, relate to a kind of penta-Isosorbide-5-Nitrae-diene-3-keto analog and preparation method thereof and application.
Background technology
Diabetes (Diabetes mellitus, DM) are a kind of worldwide diseases, and according to the 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 to the danger of human health is 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 in the world focus of new drug development.
Glucocorticosteroid is the antagonist of insulin action, and it weakens the glucose uptake that relies on Regular Insulin and increases lipolysis, improves the 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 the glycogen heteroplasia, and glucocorticosteroid increases glyconeogenesis, directly or indirectly activate oligogene or the hormone of this process of participation, as: the genetic expression (PEPCK) of phosphoric acid enol acetone carboxylase in hyperglycemic-glycogenolytic factor, the liver, PEPCK is the rate-limiting enzyme of glyconeogenesis, it is regulated and control 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 are induced peroxisome increment activated receptor-gamma coactivator 1 (PGC-1), and 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, the antagonism insulin response comprises and suppresses the 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) control, by acth secretion in blood.Yet when HPA determines the blood glucocorticoid levels, outstandingly recently studies show that 11beta hydroxysteroid dehydrogenase 11b-HSDs in the cell) regulate glucocorticoid levels.Although therefore normal glucocorticoid levels is arranged in some cells, but make sometimes it be in inactive state, sometimes by the inactive active condition that is converted into, these all are to come 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).
The active concentration of cortisol of blood plasma changes greatly (1 – 100nmol/L) in daily change procedure.In contrast, nonactive cortisone does not have large daily variation, in the 50-100nmol/L fluctuation, with hydrocortisone higher freely plasma concentration (Stewart PM etc., Vitam Horm, 1999,57,249) is arranged relatively.Therefore, the blood plasma cortisone can constantly provide the 11b-HSD1 reductibility to keep Topically active glucocorticosteroid concentration, glucocorticosteroid and insulin function antagonism in the active tissue of metabolism as the storage pool that is inactive glucocorticosteroid.
The foreign scholar with transgenic mice research draw data presentation 11b-HSD1-/-mouse cell in glucocorticosteroid be damaged, it no longer with insulin resistant (Erika Harno etc., Trends in Endocrinology ﹠amp; Metabolism, 2010,21,619)
Therefore the research of 11b-HSD1 inhibitor enjoys the attention of Chinese scholars, and the 11b-HSD1 restraining effect has positive influence to glycosuria patient's insulin sensitivity.Because most of diabetes B patients are the 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 the spontaneous ground hyperglycemia KKAy mouse can reduce liver phosphoric acid ketenes formula pyruvic acid carboxylic kinases PEPCK and G-6-Pase mrna expression, while lowering blood glucose and serum insulin concentration (Malgorzata Wamil etc., Drug Discovery Today, 2007,12,504).11b-HSD1 people's selective depressant is synthetic (Barf T etc., J Med Chem, 2002,45,3813), and the 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 the 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 metabolism active organize influentially, we expect that 11b-HSD1 induces change among the HPA axis, 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 the brain, and the 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 the acth secretion glucocorticosteroid to increase.To hypothalamic intervention, these medicines can not pass hemato encephalic barrier for fear of the 11b-HSD1 specific inhibitor.On the other hand; the restraining effect of 11b-HSD1 in the central nervous system can protect brain to avoid receiving negative impact (the Adam J.Rose etc. of glucocorticosteroid when wearing out; The Journal of Steroid Biochemistry and Molecular Biology; 2010; 122,10).Therefore the 11b-HSD1 inhibitor will be expected to become interesting novel medicine in future, not even only is not confined to treat obesity and diabetes B.
Penta-Isosorbide-5-Nitrae-diene-3-keto analog is that main chain is unsaturated aliphatic and side chain aromatic group.Needing exploitation to have penta-Isosorbide-5-Nitrae of better inhibition 11b-HSD1 enzymic activity-diene-3-ketone derivatives class, is drug provision experiment and the Clinical Basis of in the future exploitation prevention and treatment knot diabetes.
Summary of the invention
The purpose of this invention is to provide a kind of penta-Isosorbide-5-Nitrae with the activity that suppresses 1 type 11beta-hydroxysteroid dehydrogenase-diene-3-ketone derivative compound.For achieving the above object, the present invention adopts following technical scheme:
A kind of penta-Isosorbide-5-Nitrae-diene-3-keto analog comprises compound and pharmacy acceptable salt thereof with structure shown in the general formula I:
Wherein: R
1And R
2Independently be selected from separately H, Cl, Br, CF
3Or F.
Wherein, preferred described R
1And R
2Independently be selected from separately Br, H or F.
Wherein, more preferably described R
1Be Br, R
2Be H or F, the concrete structure formula is as follows:
Pharmacy acceptable salt of the present invention comprises the salt that forms with mineral acid, the salt that forms with organic acid and the salt that is formed by element negatively charged ion or positively charged ion; Preferred 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 the preparation method of above-mentioned penta-Isosorbide-5-Nitrae-diene-3-keto analog, for achieving the above object, the present invention adopts following technical scheme:
The preparation method of above-mentioned penta-Isosorbide-5-Nitrae-diene-3-keto analog is specially: acetone and halogenated benzaldehyde are in solvent, take potassium hydroxide or sodium methylate as catalyzer, temperature of reaction is 20 ℃-80 ℃, and reflux 0.3-2h reacts, and separation and purified product obtain target compound; The preferred reaction time is 1h-1.5h, and temperature of reaction is 45 ℃-55 ℃.
Among the preparation method of the present invention, described halogenated benzaldehyde is o-bromobenzaldehye, 2-bromo-6 fluorobenzaldehydes, o-chlorobenzaldehyde, 2,6 dichlorobenzaldehydes, 2-(Trifluoromethyl) benzaldehyde or 2-fluoro-6 bromobenzaldehydes; Preferred described halogenated benzaldehyde is o-bromobenzaldehye, 2-bromo-6 fluorobenzaldehydes.
Among the preparation method of the present invention, described solvent is ethanol or methyl alcohol; Preferred described solvent is ethanol, and 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, is 0.5g such as the total mass when acetone and halogenated benzaldehyde, and the consumption of solvent should be 1.5-2.5ml.
Among the preparation method of the present invention, described acetone is 3:1-2:1 with the mole dosage ratio of halogenated benzaldehyde, and the quality consumption of described catalyzer is the 10%-30% of acetone and halogenated benzaldehyde total mass.Preferred described acetone is 2.2:1 with the mole dosage ratio of halogenated benzaldehyde, and the quality consumption of catalyzer is 20% of acetone and halogenated benzaldehyde total mass.
In the catalyzer of the present invention, described potassium hydroxide is that mass concentration is 5% potassium hydroxide aqueous solution.Described sodium methylate is that mass concentration is 0.5% methanol solution of sodium methylate.
After above-mentioned reaction finishes, have a large amount of precipitations to produce in the system, it be chilled to room temperature, decompress filter, screening with a small amount of alcohol flushing repeatedly, drying is carried out separation and purification by silica gel column chromatography, products obtained therefrom vacuum-drying obtains target product.The present invention does not do specific restriction to separation and purifying that reaction finishes after product, 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 further application of claimed above-mentioned penta-Isosorbide-5-Nitrae-diene-3-keto analog in preparation prevention and treatment human diabetes medicine of the present invention.
And, the claimed pharmaceutical composition that contains above-mentioned penta-Isosorbide-5-Nitrae-diene-3-keto analog of the present invention.Composition of the present invention can contain 0.1%-99% the present invention penta-Isosorbide-5-Nitrae-diene-3-keto analog, and all the other are acceptable on the 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 uses 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 the described tablet, the mass ratio of main ingredient and auxiliary material is 4:1-6:5, preferred 5:1.Concrete prescription can be: penta-Isosorbide-5-Nitrae-diene-3-keto analog 70-85 part, 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: penta-Isosorbide-5-Nitrae-diene-3-keto analog 83.4%, 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, have desirable synergy between the auxiliary material, gained tablet stable high, 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 simultaneously the stability of medicine, also can reduce toxic side effect, also be convenient to medicine storage, transport and carry.
Embodiment
Following examples are used for explanation the present invention, but are not used for limiting the scope of the invention.If do not specialize, the conventional means that used technique means is well known to those skilled in the art among the embodiment, the raw materials used commercial goods that is.
Preparation and the evaluation thereof of embodiment 1 penta-Isosorbide-5-Nitrae-diene-3-keto analog
Compound:
(1E,4E)-1,5-bis(2-bromophenyl)penta-1,4-dien-3-one（CYH01）
Structural formula:
The preparation method:
0.5g o-bromobenzaldehye and acetone (the mol ratio 2.2:1 of aldehyde and ketone) are dissolved in the 2ml ethanol, stirring at normal temperature, syringe drips 2ml, 5% potassium hydroxide aqueous solution, 50 ℃ of lower reaction 0.5h to 1h, there are a large amount of precipitations to produce in the system, are chilled to room temperature, decompress filter, screening with a small amount of alcohol flushing repeatedly, drying is carried out separation and purification by silica gel column chromatography, and products obtained therefrom vacuum-drying obtains target product CYH01.
(1E, 4E)-1,5-bis (2-bromophenyl) penta-1,4-dien-3-one(CYH01): yellow compound, yield are 70.2%, and purity is 99.7%.
1H?NMR(500MHz,DMSO)δ:10.23(s,2H),7.86(s,2H),7.61(dd,J=8.7,5.5Hz,4H),7.41-7.30(m,4H),4.45(d,J=1.4Hz,4H).
13C?NMR(75MHz,DMSO)δ:182.1,164.2,160.9,137.8,133.0,132.8,130.2,127.6,116.0,115.8,43.7.EIMS?m/z:311(M-HCl).HREIMS?Calcd.for?C
19H
15O
1N
1F
2:311.1116,Found:311.1116.
Embodiment 2
Compare with embodiment 1, distinctive points only is: the total mass of o-bromobenzaldehye and acetone is 0.5g in the present embodiment, the mol ratio of the two is 3:1, be dissolved in the 1.5ml ethanol, stirring at normal temperature, syringe drips the methanol solution that contains 0.5% sodium methylate of 3ml, 40 ℃ of lower reaction 0.3h to 0.5h, there are a large amount of precipitations to produce in the system, are chilled to room temperature, decompress filter, screening with a small amount of alcohol flushing repeatedly, drying is carried out separation and purification by silica gel column chromatography, and products obtained therefrom vacuum-drying obtains target product CYH01.
(1E, 4E)-1,5-bis (2-bromophenyl) penta-1,4-dien-3-one(CYH01): yellow compound, yield are 56.1%, and purity is 98.5%.
1H?NMR(500MHz,DMSO)δ:10.23(s,2H),7.86(s,2H),7.61(dd,J=8.7,5.5Hz,4H),?7.41-7.30(m,4H),4.45(d,J=1.4Hz,4H).
13C?NMR(75MHz,DMSO)δ:182.1,164.2,160.9,137.8,133.0,132.8,130.2,127.6,116.0,115.8,43.7.EIMS?m/z:311(M-HCl).HREIMS?Calcd.for?C
19H
15O
1N
1F
2:311.1116,Found:311.1116.
Embodiment 3
Compare with embodiment 1, distinctive points only is: the total mass of o-bromobenzaldehye and acetone is 0.5g in the present embodiment, the mol ratio of the two is 2:1, be dissolved in the 2.5ml ethanol, stirring at normal temperature, the mass concentration of syringe dropping 2ml is 5% potassium hydroxide aqueous solution, 80 ℃ of lower reaction 1h to 1.5h, there are a large amount of precipitations to produce in the system, are chilled to room temperature, decompress filter, screening with a small amount of alcohol flushing repeatedly, drying is carried out separation and purification by silica gel column chromatography, and products obtained therefrom vacuum-drying obtains target product CYH01.
(1E, 4E)-1,5-bis (2-bromophenyl) penta-1,4-dien-3-one(CYH01): yellow compound, yield are 62.5%, and purity is 98.5%.
1H?NMR(500MHz,DMSO)δ:10.23(s,2H),7.86(s,2H),7.61(dd,J=8.7,5.5Hz,4H),7.41-7.30(m,4H),4.45(d,J=1.4Hz,4H).
13C?NMR(75MHz,DMSO)δ:182.1,164.2,160.9,137.8,133.0,132.8,130.2,127.6,116.0,115.8,43.7.EIMS?m/z:311(M-HCl).HREIMS?Calcd.for?C
19H
15O
1N
1F
2:311.1116,Found:311.1116.
Preparation and the evaluation thereof of embodiment 4 penta-Isosorbide-5-Nitraes-diene-3-keto analog
Compound:
(1E,4E)-1,5-bis(2-bromo-6-fluorophenyl)penta-1,4-dien-3-one（CYH05）
Structural formula:
The preparation method:
0.5g2-bromo-6 fluorobenzaldehydes and acetone (the mol ratio 2.2:1 of aldehyde and ketone) are dissolved in the 2ml ethanol, stirring at normal temperature, syringe drips 1ml, 5% potassium hydroxide aqueous solution, 50 ℃ of lower reaction 0.5h to 1h, there are a large amount of precipitations to produce in the system, are chilled to room temperature, decompress filter, screening with a small amount of alcohol flushing repeatedly, drying is carried out separation and purification by silica gel column chromatography, and products obtained therefrom vacuum-drying obtains target product CYH05.
(1E, 4E)-1,5-bis (2-bromo-6-fluorophenyl) penta-1,4-dien-3-one(CYH05): yellow compound, yield are 71.1%, and purity is 99.2%.
1H NMR (400MHz, CDCl
3) δ 7.89 (d, J=16.2Hz, 2H), 7.47 (d, J=7.9Hz, 2H), 7.24 – 7.16 (m, 2H), 7.15 – 7.08 (m, 2H).
13C NMR (101MHz, CDCl
3) δ 189.26,161.81 (d, J=257.6Hz), (136.44 d, J=2.6Hz), 131.88 (d, J=13.8Hz), 131.23 (d, J=10.1Hz), (129.39 d, J=3.4Hz), 126.70 (d, J=4.0Hz), 123.64 (d, J=13.4Hz), (115.62 d, J=23.5Hz) .Purity:98.9%by HPLC.HRMS (ESI): calcd for (M+Na)
+(C
17H
10Br
2F
2O) 448.8959, found448.8963. embodiment 5
Compare with embodiment 4, distinctive points only is: 0.5g2-bromo-6 fluorobenzaldehydes and acetone (the mol ratio 2.5:1 of aldehyde and ketone) are dissolved in the 2ml methyl alcohol stirring at normal temperature, syringe drips 2ml, 5% potassium hydroxide aqueous solution, 55 ℃ of lower reaction 1.5h to 2h have a large amount of precipitations to produce in the system, be chilled to room temperature, decompress filter, screening with a small amount of alcohol flushing repeatedly dry carry out separation and purification by silica gel column chromatography, products obtained therefrom vacuum-drying obtains target product CYH05.
(1E, 4E)-1,5-bis (2-bromo-6-fluorophenyl) penta-1,4-dien-3-one(CYH05): yellow compound, yield are 69.5%, and purity is 99.1%.
1H?NMR(400MHz,CDCl
3)δ7.89(d,J=16.2Hz,2H),7.47(d,J=7.9Hz,2H),7.24–7.16(m,2H),7.15–7.08(m,2H).
13C?NMR(101?MHz,CDCl
3)δ189.26,161.81(d,J=257.6Hz),136.44(d,J=2.6Hz),131.88(d,J=13.8Hz),131.23(d,J=10.1Hz),129.39(d,J=3.4Hz),126.70(d,J=4.0Hz),123.64(d,J=13.4Hz),115.62(d,J=23.5Hz).Purity:98.9%by?HPLC.HRMS(ESI):calcd?for(M+Na)
+(C
17H
10Br
2F
2O)448.8959,found448.8963.
Embodiment 6
Compare with embodiment 1, distinctive points only is, the present embodiment is with the o-bromobenzaldehye in the o-chlorobenzaldehyde alternative embodiment 1, obtains respectively penta-Isosorbide-5-Nitrae of following structure-diene-3-keto analog CYH10, and the yield of this product is 70.8%, and purity is 99.0%.
Embodiment 7
Compare with embodiment 1, distinctive points only is, the present embodiment is with the o-bromobenzaldehye in 2, the 6 dichlorobenzaldehyde alternative embodiments 1, obtains respectively penta-Isosorbide-5-Nitrae of following structure-diene-3-keto analog CYH11, and the yield of this product is 72.2%, and purity is 99.4%.
Embodiment 8
Compare with embodiment 4, distinctive points only is, the present embodiment is with 2-bromo-6 fluorobenzaldehydes in the 2-(Trifluoromethyl) benzaldehyde alternative embodiment 4, obtain penta-1 of following structure, 4-diene-3-keto analog CYH12, this product is 69.8% with respect to the yield of acetone, purity is 99.3%.
Embodiment 9
With embodiment 1 gained compound respectively through mineral acid example hydrochloric acid, sulfuric acid, phosphoric acid etc.; The processing such as organic acid such as acetic acid, tartrate, citric acid, xitix, oxalic acid, and the salt that is formed by the element negatively charged ion are such 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 10 pharmaceutical compositions
Get the Compound C YH01 that embodiment 1 obtains, be that the ratio of 5:1 adds vehicle according to itself and vehicle weight ratio. wherein main ingredient 83.4%, Microcrystalline Cellulose (weighting agent) 15%, Magnesium Stearate (lubricant) 0.6%, sodium starch glycolate (disintegrating agent) 1%, pelletizing press sheet.
Embodiment 11 pharmaceutical compositions
Compare with embodiment 10, distinctive points only is that the concrete prescription of the present embodiment is: the Compound C YH01 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 12 pharmaceutical compositions
Compare with embodiment 10, distinctive points only is that the concrete prescription of the present embodiment is: the Compound C YH01 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 13 pharmaceutical compositions
Get the Compound C YH05 of the method system of embodiment 4, then the injection liquid method for making adds water for injection routinely respectively, essence filter embedding is made injection liquid after sterilizing.Wherein, the concentration of main ingredient is 1%.
For the further performance of checking compound of the present invention, the contriver has further launched a large amount of special items tests with the compound of above-described embodiment preparation, and length is limit, and only exemplifies the part of tool cogency herein.
Test example 1
Penta-Isosorbide-5-Nitrae-diene-3-keto analog suppresses 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, 11b-HSD1) be a kind of enzyme take Reduced nicotinamide-adenine dinucleotide as coenzyme, mainly in the microsome of the tissues such as liver, fat, brain and testis, express.Contain the 11b-HSD1 microsome and can method routinely prepare (Brennan, J. etc., Genes Dev, 2003.17,800), also can buy from reagent company.Carry out the detection (Haider, S.G.Int.ReV.Cytol., 2004,233,181) of 11b-HSD1 enzymic activity according to existing research method.In brief, labeled reactant pipe at first, every pipe adds 40 μ g rat testicles and people's hepatomicrosome albumen and 10nM-0.1mM penta-Isosorbide-5-Nitrae-diene-3-keto analog and (is dissolved in the dimethyl benzene sulfone, DMSO), then adds 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 mixture and join in the reaction tubes, cultivate 45min for 34 ℃.After the pre-cold diethyl ether termination reaction of 1ml, vortex vibration 1min.Then supernatant is transferred in the 5ml Glass tubing, nitrogen drying is also separated out solid.Add the heavy molten solid of 70 μ l ether, behind the vibration 1min, point sample on thin layer chromatography board, and thin layer chromatography board put into contain chloroform: methyl alcohol (volume ratio 90:10) chromatography cylinder 20min.At last, thin layer chromatography board is placed on scanning radiometer detects on (System AR2000, Bioscan Inc., Washington, DC, USA) and read the 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, penta-Isosorbide-5-Nitrae of the present invention-diene-3-keto analog has restraining effect to rat testicle microsome 11 β-HSD1 activity, and wherein, the IC50 of embodiment 1 and embodiment 4 is respectively 422nM and 407nM; Active to people 11 β-HSD1, embodiment 1IC50 is 1400nM, and embodiment 4IC50 is 111 μ M, if its inhibiting rate is 45% when using 100 μ M.More preferably select CYH01.It should be noted that these penta-Isosorbide-5-Nitraes-diene-3-keto analog does not have restraining effect (seeing test example 2) substantially to the activity of rat and people 11b-HSD2 enzyme.Make identical test with other embodiments of the invention, obtain same test-results.
Table 1 penta-Isosorbide-5-Nitrae-diene-3-keto analog is to the restraining effect of rat testicle and people's hepatomicrosome 11b-HSD1 enzymic activity
a%inhibition?at?the?100μM?inhibitor.
b(IC50,nΜ).
Test example 2
Penta-Isosorbide-5-Nitrae-diene-3-keto analog suppresses 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 take nicotinamide-adenine Nucleotide as coenzyme, mainly expresses in the microsome of the tissues such as kidney, placenta.Contain the 11b-HSD2 microsome and can method routinely prepare (Brennan, J. etc., Genes Dev, 2003.17,800), also can buy from reagent company.Carry out the detection (Haider, S.G.Int.Rev.Cytol., 2004,233,181) of 11b-HSD2 enzymic activity according to existing research method.In brief, labeled reactant pipe at first, every pipe adds 40 μ g rats and people's microsomal protein and 10nM-0.1mM penta-Isosorbide-5-Nitrae-diene-3-keto analog and (is dissolved in the dimethyl benzene sulfone, DMSO), then adds 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 l NAD+(50mmol/L) and 45 μ l PBS, vibration mixes.Get 50 μ l steroid detection mixture and join in the reaction tubes, 37C cultivates 45min.After the pre-cold diethyl ether termination reaction of 1ml, vortex vibration 1min.Then supernatant is transferred in the 5ml Glass tubing, nitrogen drying is also separated out solid.Add the heavy molten solid of 70 μ l ether, behind the vibration 1min, point sample on thin layer chromatography board, and thin layer chromatography board put into contain chloroform: methyl alcohol (volume ratio 90:10) chromatography cylinder 20min.At last, thin layer chromatography board is placed on scanning radiometer detects on (System AR2000, Bioscan Inc., Washington, DC, USA) and read the 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, to 11b-HSD2, its IC50 is equal for penta-Isosorbide-5-Nitrae of the present invention-diene-3-keto analog (embodiment 1 and embodiment 4)〉100 μ M.
Make identical test with other embodiments of the invention, obtain same test-results.
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 (10)
1. penta-Isosorbide-5-Nitrae-diene-3-keto analog comprises compound and pharmacy acceptable salt thereof with structure shown in the general formula I:
Wherein: R
1And R
2Independently be selected from separately H, Cl, CF
3, Br or F; Preferred described R
1And R
2Independently be selected from separately Br, H or F.
2. penta-Isosorbide-5-Nitrae according to claim 1-diene-3-keto analog is characterized in that, described R
1Be Br, R
2Be H or F, namely described compound is:
3. penta-Isosorbide-5-Nitrae according to claim 1-diene-3-keto analog is characterized in that, described pharmacy acceptable salt comprises the salt that forms with mineral acid, the salt that forms with organic acid and the salt that is formed by element negatively charged ion or positively charged ion;
Preferred 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.
Claim 1-3 each described penta-1, the preparation method of 4-diene-3-keto analog, it is characterized in that, acetone 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 ℃.
5. preparation method according to claim 4 is characterized in that, described halogenated benzaldehyde is o-bromobenzaldehye, o-chlorobenzaldehyde, 2,6 two pairs of chlorobenzaldehydes, 2-(Trifluoromethyl) benzaldehyde, 2-bromo-6 fluorobenzaldehydes or 2-fluoro-6 bromobenzaldehydes.
6. preparation method according to claim 4 is characterized in that, described solvent is ethanol or methyl alcohol, and the volumetric usage of described solvent is 3-5 times of reactant total mass.
7. preparation method according to claim 4 is characterized in that, described acetone is 3:1-2:1 with the mole dosage ratio of halogenated benzaldehyde, and the quality consumption of described catalyzer is the 10%-30% of acetone and halogenated benzaldehyde total mass.
8. preparation method according to claim 4 is characterized in that, 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.
9. the application of each described penta-Isosorbide-5-Nitrae of claim 1-3-diene-3-keto analog in preparation prevention and treatment human diabetes medicine.
10. the pharmaceutical composition that contains each described penta-Isosorbide-5-Nitrae of claim 1-3-diene-3-keto analog.
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| CN112062665A (en) * | 2020-09-24 | 2020-12-11 | 温州医科大学附属第二医院、温州医科大学附属育英儿童医院 | 2,5-bis(2,6-difluorobenzylidene)-cyclopentanone and its preparation method and application |
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| WO2001040188A1 (en) * | 1999-12-03 | 2001-06-07 | Emory University | Curcumin analogues for treating cancer |
| WO2001046110A2 (en) * | 1999-12-23 | 2001-06-28 | The University Of Georgia Research Foundation, Inc. | Chalcone and its analogs as agents for the inhibition of angiogenesis and related disease states |
| WO2011029359A1 (en) * | 2009-09-12 | 2011-03-17 | 温州医学院 | MEDICAMENTS CONTAINING 11β HYDROXYSTEROID DEHYDROGENASE 1 DOUBLE REGULATORS AND USES THEREOF |
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| WO2001040188A1 (en) * | 1999-12-03 | 2001-06-07 | Emory University | Curcumin analogues for treating cancer |
| WO2001046110A2 (en) * | 1999-12-23 | 2001-06-28 | The University Of Georgia Research Foundation, Inc. | Chalcone and its analogs as agents for the inhibition of angiogenesis and related disease states |
| WO2011029359A1 (en) * | 2009-09-12 | 2011-03-17 | 温州医学院 | MEDICAMENTS CONTAINING 11β HYDROXYSTEROID DEHYDROGENASE 1 DOUBLE REGULATORS AND USES THEREOF |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112062665A (en) * | 2020-09-24 | 2020-12-11 | 温州医科大学附属第二医院、温州医科大学附属育英儿童医院 | 2,5-bis(2,6-difluorobenzylidene)-cyclopentanone and its preparation method and application |
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