CN103113202A - (2E, 5E)-2, 5-benzal cyclopentanone analogue and preparation method and application thereof - Google Patents
(2E, 5E)-2, 5-benzal cyclopentanone analogue and preparation method and application thereof Download PDFInfo
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Abstract
The invention provides a (2E, 5E)-2, 5-benzal cyclopentanone analogue which comprises a compound with a structure shown as formula II and pharmaceutically acceptable salt. The analogue has remarkable pharmacological activity. In addition, the invention further provides a preparation method of the compounds and an application thereof as a 11beta-hydroxyoxysterooid dehydrogenase type I, 11b-HSD1 inhibitor for preventing and treating human diabetes.
Description
Technical field
The present invention relates to a kind of new compound, specifically, relate to a kind of (2E, 5E)-2, two benzylidene cyclopentanone analogues of 5-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, and the antagonism insulin response comprises and suppresses the insulin signaling transmission and suppress insulin stimulating glucose uptake (NicholasMichael 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.
(2E, 5E)-2, the two benzylidene cyclopentanone of 5-are that main chain is unsaturated aliphatic and side chain aromatic group.(2E, 5E)-2 that need exploitation to have better inhibition 11b-HSD1 enzymic activity, the two benzylidene cyclopentanone derivatives classes of 5-are 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 (2E, 5E)-2 with the activity that suppresses 1 type 11beta-hydroxysteroid dehydrogenase, the two benzylidene cyclopentanone analogues of 5-.For achieving the above object, the present invention adopts following technical scheme:
A kind of (2E, 5E)-2, the two benzylidene cyclopentanone analogues of 5-comprise compound and pharmacy acceptable salt thereof with structure shown in the general formula I I:
Wherein: R
1And R
2Independently be selected from separately H, Br, CF
3Perhaps F;
Preferably, described R
1And R
2Independently be selected from separately Br, CF
3Or F.
More preferably described R
1Be Br, CF
3Or F, R
2Be CF
3Or F, the concrete structure formula is:
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 above-mentioned (2E, 5E)-2, the preparation method of the two benzylidene cyclopentanone analogues of 5-, for achieving the above object, the present invention adopts following technical scheme:
Above-mentioned (2E, 5E)-2, the preparation method of the two benzylidene cyclopentanone derivative compounds of 5-, be specially: cyclopentanone and halogenated benzaldehyde are in solvent, take potassium hydroxide or sodium methylate as catalyzer, reflux 0.3-3h 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 ℃.
Among the preparation method of the present invention, described halogenated benzaldehyde is 2,6 trifluoromethylated benzaldehydes, 2-bromo-6 fluorobenzaldehydes, 2-fluoro-6 trifluoromethylated benzaldehydes, o-chlorobenzaldehyde, 2,6 dichlorobenzaldehydes or 2-trifluoromethylated benzaldehyde, preferred described halogenated benzaldehyde is 2,6 trifluoromethylated benzaldehydes or 2-bromo-6 fluorobenzaldehydes.
Among the preparation method of the present invention, described solvent is ethanol or methyl alcohol; Preferred 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, 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 cyclopentanone is 3:1-2:1 with the mole dosage ratio of halogenated benzaldehyde, the quality consumption of described catalyzer is the 10%-30% of cyclopentanone and halogenated benzaldehyde total mass, preferred cyclopentanone is 2.2:1 with the mole dosage ratio of halogenated benzaldehyde, and the quality consumption of described catalyzer is 20% of cyclopentanone and halogenated benzaldehyde total mass.
Among the 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, have a large amount of precipitations to produce in the system, it is chilled to room temperature, decompress filter is filtered thing with a small amount of alcohol flushing repeatedly, and drying is carried out separation and purification by silica gel column chromatography, and 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 present invention is claimed above-mentioned (2E, 5E)-2 further, the application of the two benzylidene cyclopentanone analogues of 5-in preparation prevention and treatment human diabetes medicine.
And, claimed above-mentioned (2E, 5E)-2 of containing of the present invention, the pharmaceutical composition of the two benzylidene cyclopentanone analogues of 5-.
Composition of the present invention can contain 0.1%-99% the present invention (2E, 5E)-2, the two benzylidene cyclopentanone analogues of 5-, and all the other be 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: (2E, 5E)-2, the two benzylidene cyclopentanone 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: (2E, 5E)-2, the two benzylidene cyclopentanone 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, has desirable synergy between the auxiliary material, 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 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.
Embodiment 1(2E, 5E)-2, preparation and the evaluation thereof of the two benzylidene cyclopentanone analogues of 5-
Compound:
(2E,5E)-2,5-Bis[2,6-(trifluoromethyl)benzylidene]cyclop?entanone（CYH02）
Structural formula:
The preparation method:
With 0.5g2,6 trifluoromethylated benzaldehydes and cyclopentanone (the mol ratio 2.2:1 of aldehyde and ketone) are dissolved in the 2ml ethanol stirring at normal temperature, syringe drips 2.5ml, 5% potassium hydroxide aqueous solution, 50 ℃ of lower reaction 0.5h to 1h have a large amount of precipitations to produce in the system, be chilled to room temperature, decompress filter is filtered thing with a small amount of alcohol flushing repeatedly, and drying is carried out separation and purification by silica gel column chromatography, products obtained therefrom vacuum-drying obtains target product CYH02.
(2E, 5E)-2,5-Bis[2,6-(trifluoromethyl) benzylidene] cyclopenta none(CYH02): yellow compound, yield are 68.5%, and purity is 99.5%.
1H?NMR(400MHz,CDCl
3)δ7.51(s,2H),7.39–7.29(m,2H),6.95(t,J=8.1Hz,4H),2.79–2.71(m,2H).
13C?NMR(101MHz,CDCl
3)?δ194.41,162.00(d,J=7.3Hz),159.49(d,J=7.4Hz),143.29,130.69(t,J=10.5Hz),120.91,113.34(t,J=18.8Hz),111.65(d,J=6.0Hz),111.45(d,J=6.0Hz),26.36(t,J=5.5Hz).Purity:98.9%by?HPLC.HRMS(ESI):calcd?for(M+Na)+(C19H12F4O)355.0716,found355.0718.
Embodiment 2
Compare with embodiment 1, distinctive points only is: with 0.5g2,6 trifluoromethylated benzaldehydes and cyclopentanone (the mol ratio 2:1 of aldehyde and ketone) are dissolved in the 1.5ml ethanol, stirring at normal temperature, syringe drips the methanol solution sodium methylate 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, be chilled to room temperature, decompress filter is filtered thing with a small amount of alcohol flushing repeatedly, and drying is carried out separation and purification by silica gel column chromatography, products obtained therefrom vacuum-drying obtains target product CYH02.
(2E, 5E)-2,5-Bis[2,6-(trifluoromethyl) benzylidene] cyclopentanone(CYH02): yellow compound, yield are 55.8%, and purity is 97.6%.
1H?NMR(400MHz,CDCl
3)δ7.51(s,2H),7.39–7.29(m,2H),6.95(t,J=8.1Hz,4H),2.79–2.71(m,2H).
13C?NMR(101MHz,CDCl
3)δ194.41,162.00(d,J=7.3Hz),159.49(d,J=7.4Hz),143.29,130.69(t,J=10.5Hz),120.91,113.34(t,J=18.8Hz),111.65(d,J=6.0Hz),111.45(d,J=6.0Hz),26.36(t,J=5.5Hz).Purity:98.9%by?HPLC.HRMS(ESI):calcd?for(M+Na)+(C19H12F4O)355.0716,found355.0718.
Embodiment 3
Compare with embodiment 1, distinctive points only is: with 0.5g2,6 trifluoromethylated benzaldehydes and cyclopentanone (the mol ratio 3:1 of aldehyde and ketone) are dissolved in the 2.5ml ethanol, stirring at normal temperature, syringe drips the methanol solution sodium methylate that contains 0.5% sodium methylate of 3ml, 80 ℃ of lower reaction 1.5h to 2h, there are a large amount of precipitations to produce in the system, be chilled to room temperature, decompress filter is filtered thing with a small amount of alcohol flushing repeatedly, and drying is carried out separation and purification by silica gel column chromatography, products obtained therefrom vacuum-drying obtains target product CYH02.
(2E, 5E)-2,5-Bis[2,6-(trifluoromethyl) benzylidene] cyclopenta none(CYH02): yellow compound, yield are 53.5%, and purity is 95.9%.
1H?NMR(400MHz,CDCl
3)δ7.51(s,2H),7.39–7.29(m,2H),6.95(t,J=8.1Hz,4H),2.79–2.71(m,2H).
13C?NMR(101MHz,CDCl
3)δ194.41,162.00(d,J=7.3Hz),159.49(d,J=7.4Hz),143.29,130.69(t,J=10.5Hz),120.91,113.34(t,J=18.8Hz),111.65(d,J=6.0Hz),111.45(d,J=6.0Hz),26.36(t,J=5.5Hz).Purity:98.9%by?HPLC.HRMS(ESI):calcd?for(M+Na)+(C19H12F4O)355.0716,found355.0718.
Embodiment 4(2E, 5E)-2, preparation and the evaluation thereof of the two benzylidene cyclopentanone analogues of 5-
Compound:
(2E,5E)-2,5-bis(2-bromo-6-fluorobenzylidene)cyclopentan?one（CYH04）
Structural formula:
The preparation method:
0.5g2-bromo-6 fluorobenzaldehydes and cyclopentanone (the mol ratio 2.2:1 of aldehyde and ketone) are dissolved in the 2ml ethanol, stirring at normal temperature, syringe drips 2.5ml, 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, the filter thing 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 CYH04.
(2E, 5E)-2,5-bis (2-bromo-6-fluorobenzylidene) cyclopentan one(CYH04): yellow compound, yield are 64.9%, and purity is 99.7%.
1H?NMR(400?MHz,CDCl
3)δ7.50–7.39(m,4H),7.24–7.18(m,2H),7.09(t,J=8.8Hz,2H),2.76–2.58(m,4H).
13C?NMR(101MHz,CDCl
3)δ194.29,159.87(d,J=253.7Hz),143.11,130.75(d,J=9.4Hz),128.63(d,J=3.3Hz),126.93,125.38(d,J=4.2Hz),124.79(d,J=18.3Hz),115.10(d,J=23.1Hz),25.98(d,J=8.1Hz).Purity:98.8%by?HPLC.HRMS(ESI):calcd?for(M+Na)+(C19H12Br2F2O)474.9115,found474.9089.
Embodiment 5
Compare with embodiment 4, distinctive points only is: 0.5g2-bromo-6 fluorobenzaldehydes and cyclopentanone (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 2.5h to 3h have a large amount of precipitations to produce in the system, be chilled to room temperature, decompress filter is filtered thing with a small amount of alcohol flushing repeatedly, and drying is carried out separation and purification by silica gel column chromatography, products obtained therefrom vacuum-drying obtains target product CYH04.
(2E, 5E)-2,5-bis (2-bromo-6-fluorobenzylidene) cyclopentan one(CYH04): yellow compound, yield are 69.8%, and purity is 99.7%.
1H?NMR(400MHz,CDCl
3)δ7.50–7.39(m,4H),7.24–7.18(m,2H),7.09(t,J=8.8Hz,2H),2.76–2.58(m,4H).
13C?NMR(101MHz,CDCl
3)δ194.29,159.87(d,J=253.7Hz),143.11,130.75(d,J=9.4Hz),128.63(d,J=3.3Hz),126.93,125.38(d,J=4.2Hz),124.79(d,J=18.3Hz),115.10(d,J=23.1Hz),25.98(d,J=8.1Hz).Purity:98.8%by?HPLC.HRMS(ESI):calcd?for(M+Na)+(C19H12Br2F2O)474.9115,found474.9089.
Embodiment 6(2E, 5E)-2, preparation and the evaluation thereof of the two benzylidene cyclopentanone analogues of 5-
Compound:
(2E,5E)-2,5-bis[2-fluoro-6-(trifluoromethyl)benzylidene]cyc?lopentanone（CYH08）
Structural formula:
The preparation method:
0.5g2-fluoro-6 trifluoromethylated benzaldehydes and cyclopentanone (the mol ratio 2.2:1 of aldehyde and ketone) are dissolved in the 2ml ethanol, stirring at normal temperature, syringe drips 2.5ml, 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, the filter thing 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 CYH08.
(2E, 5E)-2,5-bis[2-fluoro-6-(trifluoromethyl) benzylidene] cyclopentanone(CYH08): yellow compound, yield are 66.3%, and purity is 99.1%.1H?NMR(400MHz,CDCl3)δ7.61–7.50(m,1H),7.50–7.42(m,1H),7.33(t,J=8.8Hz,1H),2.66–2.55(m,4H).13CNMR(101MHz,CDCl3)δ193.46,160.92,158.43,144.14,131.06(m,),130.00(d,J=9.1Hz),123.38,122.61(m),122.19(m),119.77(d,J=23.9Hz,),25.51(d,J=7.0Hz).Purity:99.6%by?HPLC.HRMS(ESI):calcd?for(M+Na)+(C22H114F8O)455.0653,found455.0664
Embodiment 7
Compare with embodiment 1, distinctive points only is that present embodiment is with 2,6 trifluoromethylated benzaldehydes in the o-chlorobenzaldehyde alternative embodiment 1, obtain (2E, 5E)-2 of following structure, the two benzylidene cyclopentanone analogues of 5-, wherein, the yield of product is 69.2%, and purity is 98.9%.
Embodiment 8
Compare with embodiment 1, distinctive points only is that present embodiment is with 2 in 2, the 6 dichlorobenzaldehyde alternative embodiments 1,6 trifluoromethylated benzaldehydes obtain respectively (2E, 5E)-2 of following structure, the two benzylidene cyclopentanone analogues of 5-, wherein, the yield of product is 70.0%, and purity is 99.2%.
Embodiment 9
Example hydrochloric acid, sulfuric acid, phosphoric acid etc.; The processing such as organic acid, 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 YH02 that embodiment 1 obtains, be that the ratio of 5:1 adds vehicle and (please replenish the available form of vehicle and concrete kind thereof, consumption according to itself and vehicle weight ratio, such 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 11 pharmaceutical compositions
Get the Compound C YH04 of the method system of embodiment 4, then the injection liquid method for making adds water for injection routinely respectively, smart filter embedding is made injection liquid after sterilizing.Main ingredient concentration is 1%.
Embodiment 12 pharmaceutical compositions
Getting the Compound C YH08 that embodiment 6 obtains, is the ratio adding vehicle of 5:1 according to itself and vehicle weight ratio, main ingredient 83.4%, Microcrystalline Cellulose (weighting agent) 15%, Magnesium Stearate (lubricant) 0.6%, sodium starch glycolate (disintegrating agent) 1%, pelletizing press sheet.
Embodiment 13 pharmaceutical compositions
Compare with embodiment 12, distinctive points only is that the concrete prescription of present embodiment is: the Compound C YH04 of the method system of embodiment 4 is 70g, weighting agent Microcrystalline Cellulose 10g, magnesium stearate lubricant 0.5g, disintegrating agent carboxymethyl base Starch Sodium 0.5g.
Embodiment 14 pharmaceutical compositions
Compare with embodiment 12, distinctive points only is that the concrete prescription of present embodiment is: the Compound C YH02 that embodiment 1 obtains is 85g, weighting agent Microcrystalline Cellulose 10g, magnesium stearate lubricant 0.5g, disintegrating agent carboxymethyl base Starch Sodium 0.5g.
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
(2E, 5E)-2, the two benzylidene cyclopentanone 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, 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., GenesDev, 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(2E, 5E)-2, the two benzylidene cyclopentanone analogues of 5-(are dissolved in the 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 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, (2E, 5E)-2 that the embodiment of the invention is prepared, and the two benzylidene cyclopentanone analogues of 5-have restraining effect to rat testicle microsome 11 β-HSD1 activity, its IC
50Be 673nM-1638nM; Active to people 11 β-HSD1, its IC
50Be 1064nM-152 μ M.More preferably select CYH08.It should be noted that these (2E, 5E)-2, the two benzylidene cyclopentanone analogues of 5-do not have restraining effect (seeing test example 2 for details) substantially to the activity of rat and people 11b-HSD2 enzyme.
Table 1(2E, 5E)-2, the two benzylidene cyclopentanone analogues of 5-are to the restraining effect of rat testicle and people's hepatomicrosome 11b-HSD1 enzymic activity
a%inhibition?at?the100μM?inhibitor.
b(IC50,nΜ).
Test example 2
(2E, 5E)-2, the two benzylidene cyclopentanone 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 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(2E, 5E)-2, the two benzylidene cyclopentanone analogues of 5-(are dissolved in the 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 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, (2E, 5E) of the present invention-2, and the two benzylidene cyclopentanone analogues of 5-are to 11b-HSD2, 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 (10)
1. one kind (2E, 5E)-2, the two benzylidene cyclopentanone analogues of 5-comprise compound and pharmacy acceptable salt thereof with structure shown in the general formula I I:
Wherein: R
1And R
2Independently be selected from separately H, Br, CF
3Perhaps F; Preferred described R
1And R
2Independently be selected from separately Br, CF
3Or F.
2. (2E, 5E) according to claim 1-2, the two benzylidene cyclopentanone analogues of 5-is characterized in that described R
1Be Br, CF
3Or F, R
2Be CF
3Or F; Namely
3. pharmacy acceptable salt according to claim 1 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.
4. each described (2E of claim 1-3,5E)-2, the preparation method of the two benzylidene cyclopentanone analogues of 5-, it is characterized in that, cyclopentanone and halogenated benzaldehyde are in solvent, and take potassium hydroxide or sodium methylate as catalyzer, reflux 0.3-3h reacts, 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, it is characterized in that, described halogenated benzaldehyde is 2,6 trifluoromethylated benzaldehydes, 2-bromo-6 fluorobenzaldehydes, 2-fluoro-6 trifluoromethylated benzaldehydes, o-chlorobenzaldehyde, 2,6 dichlorobenzaldehydes or 2-trifluoromethylated benzaldehyde.
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 cyclopentanone 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 cyclopentanone 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.Described sodium methylate is that mass concentration is 0.5% methanol solution of sodium methylate.
9. each described (2E, 5E)-2 of claim 1-3, the application of the two benzylidene cyclopentanone analogues of 5-in preparation prevention and treatment human diabetes medicine.
10. contain each described (2E, 5E)-2 of claim 1-3, the pharmaceutical composition of the two benzylidene cyclopentanone analogues of 5-.
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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 preparation method and application thereof |
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