CN102702303A - Tanshinone derivative, medicinal composition thereof and application of tanshinone derivative to pharmacy - Google Patents
Tanshinone derivative, medicinal composition thereof and application of tanshinone derivative to pharmacy Download PDFInfo
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Abstract
The present invention provides tanshinone derivative shown in general formula I, using it as the pharmaceutical composition of active constituent, and its application in preparation 1 type 11- beta-hydroxysteroid dehydrogenase (11 β-HSD1) inhibitor, while application of the logical formula (I) compound in the drug of preparation treatment diabetes, obesity, senile dementia and high blood pressure disease being provided.
Description
Technical field:
The invention belongs to technical field of pharmaceuticals; Specifically; Relating to one type has selectivity and suppresses 1 type 11-beta-hydroxysteroid dehydrogenase (the active tanshinone derivative of 11 β-HSD1); Its application in treatment mellitus, obesity, senile dementia and hypertension agents, and above-claimed cpd is as the pharmaceutical composition of activeconstituents.
Background technology:
(diabetes mellitus DM) is the chronic metabolic trouble that is caused by the Regular Insulin disappearance to mellitus.According to World Health Organization's statistics, the whole world had diabetic subject 1.71 hundred million approximately in 2000, predicted this numeral in 2025 and will reach 2.99 hundred million.At present China has ten thousand people surplus the diabetic subject 5000 approximately, occupies the second place of the world.Whole nation diabetic subject's annual growth is more than 10%, net increase every year on average 1500000 (Mo Wen, Reading is always profitable, seeks medical advice and medicine 2009,1,8).Mellitus have become the third-largest NCD after cardiovascular and cerebrovascular diseases and tumour, are one of principal diseases of present serious harm human health.Mellitus mainly are divided into two types, type 1 diabetes and diabetes B.Wherein, diabetes B accounts for more than 95% of the overall crowd of mellitus.Diabetes B is the complicated metabolism disorder that one group of pathogenesis is only partly known.Its clinical insulin resistance that is characterized by, excessive glycogen generates, and the Regular Insulin of glucose induction is secreted decay in the β cell.The oral pharmaceutical that are used to treat diabetes B at present all have spinoff separately to exist with limitation, and treatment mellitus that all can't be permanently effective (Nathan, D. M. N., Engl J Med. 2002; 347,1342.) (Ross, S. A., Gulve; E. A., Wang, M. H., Chem. Rev.; 2004,104,1255).Therefore, press for and seek new, highly effective and safe, through the medicine of multiple path treatment patient of diabetes.
(11 β-HSD) are a kind of microsomal enzymes to 11 beta-hydroxysteroid dehydrogenases; Mutual conversion between the glucocorticosteroid of catalysis biologically active (HYDROCORTISONE INJECTIONS) and its non-active ingredient (KE); Regulate the activity of local glucocorticosteroid, participate in the pathophysiological process of insulin resistant, obesity, mellitus, senile dementia and hypertension etc.(Schwenger, P., Bellosta, P., Vietor; I., Basilico, C., Skolnik, E. Y.; Proc. Natl. Acad. Sci. U.S.A. 1997,94,2869) 11 β-HSD exists two kinds of isozyme, 11 β-HSD1 and 11 β-HSD2.Research shows, suppresses 11 β-HSD2 and can cause sodium to keep, and hypertension is disturbed the metabolism of steroid hormone (Kershaw, E. E., Morton, N. M.; Dhillon, H., Ramage, L., Seckl, J. R.; Flier, J. S., Diabetes, 2005,54,1023).It is active to suppress 11 β-HSD1, can reduce the concentration of hydrocortisone in liver or the fat, increases the susceptibility of Regular Insulin, reduces glycogen heteroplasia and potential lipophilia, thereby suppresses generation and development (Kannisto, K., Pietilainen, the K. H. of mellitus and metabolic syndrome; Ehrenborg, E., Rissanen, A., Kaprio, J., Hamsten, A.; Yki-Jarvinen, H., J. Clin. Endocrinol. Metab., 2004,89,4414) (Masuzaki, H., Paterson; J., Shinyama, H., Morton, N. M., Mullins, J. J., Seckl; J. R., Flier, J. S., Science 2001,294, and 2166) (Mullins, J. J., Seckl; J. R., J. Biol. Chem., 2001,276,41293) (Schuster, D., Maurer, E. M.; Laggner, C., Nashev, L. G., Wilckens, T., Langer; T., Odermatt, A., J. Med. Chem., 2006,49,3454).Therefore, develop the selective depressant of 11 β-HSD1, receive extensive concern with treatment diabetes B and relative metabolic syndrome (obesity, hypertension etc.).
The red sage root is the dry root and rhizome of the Labiatae salvia red sage root (Salvia miltiorrhiza Bge.), and the beginning is stated from Shennong Bencaojing, and later successive dynasties book on Chinese herbal medicine is all included.Its bitter, cold nature, the thoughts of returning home, liver two warps.As traditional Chinese medicine, the red sage root is widely used, and promoting blood circulation to restore menstrual flow is arranged, the relieving restlessness that clears away heart-fire, the effect of apocenosis pain relieving.The fat-soluble component of the red sage root is abietane type diterpene a kind of jade compounds, mainly comprises tanshinone I, Tanshinone II A, Tanshinone II B and VSZ3505.This compounds pharmacological action is extensive, is used to treat cardiovascular disorder (Xue Ming, Shi Yanbin, Cui Ying, Zhang Bin such as coronary heart disease, atherosclerosis, myocardial infarction clinically; Luo Yongjiang, Zhou Zongtian, Xia Wenjiang, Zhao Rongcai, natural drug research and development; 2000,12,27-32) (application of Tanshinone II A in pharmacy, Qin Yinlin, Yan Peiling; He Longqi, publication number CN 1631364 A) (Tanshinone I verivate and the application in pharmacy thereof, Qin Yinlin, publication number CN 1837200 A) (tanshinone derivative and the application in the preparation aldose reduction enzyme inhibitor pharmaceutical, Du Zhiyun; open Kun, Fang Yanxiong, ancient power, Huang Baohua of practicing; Zhao Suqing, Zhou Lihua, Zheng Jie, publication number CN 101012270 A) (Tanshinone II A is used for the preparation prevention and treats atherosclerotic medicine; Ancient power, Liu Peiqing, Li Guihua, publication number CN 1426782 A of practicing).But tanshinone derivative does not also appear in the newspapers as 1 type 11-beta-hydroxysteroid dehydrogenase suppressor factor and the application on treatment mellitus, obesity, hypertension and related complication thereof thereof.
Summary of the invention:
Above-mentioned deficiency to the prior art existence; The object of the present invention is to provide one type to have selectivity and suppress the active tanshinone derivative of 11 β-HSD1, and this compounds is through suppressing the application of 11 β-HSD1 in treatment mellitus, obesity, hypertension and senile dementia.
In order to realize above-mentioned purpose of the present invention, the invention provides following technical scheme:
But have tanshinone derivative or its pharmacy acceptable salt that general structure is formula I,
Wherein, R
1, R
2, R
3, R
4Be hydrogen or hydroxyl or carbonyl or sulfonic group or carboxyl, or benzene sulfonamido or tetrahydroglyoxaline and verivate, imidazoles and verivate thereof, piperazine and verivate thereof, piperidines and verivate thereof, morpholine and verivate thereof, or C
1-C
10Alkyl, naphthenic base, aromatic nucleus, fragrant heterocycle or C
1-C
10Oxygen ether or C
2-C
10Acyl-oxygen group, or C
1-C
10Carboxyl;
Or, work as R
1, with R
2, between when being two key, R
1, R
2Be hydrogen or hydroxyl or sulfonic group or benzene sulfonamido or tetrahydroglyoxaline and verivate, imidazoles and verivate thereof, piperazine and verivate thereof, piperidines and verivate thereof, morpholine and verivate thereof, or C
1-C
10Alkyl, naphthenic base, aromatic nucleus, fragrant heterocycle or C
1-C
10Oxygen ether or C
2-C
10Acyl-oxygen group, or C
2-C
10Carboxyl;
Or, work as R
3With R
4Between when being two key, R
3, R
4Be hydrogen or hydroxyl or sulfonic group or benzene sulfonamido or tetrahydroglyoxaline and verivate, imidazoles and verivate thereof, piperazine and verivate thereof, piperidines and verivate thereof, morpholine and verivate thereof, or C
1-C
10Alkyl, naphthenic base, aromatic nucleus, fragrant heterocycle or C
1-C
10Oxygen ether or C
2-C
10Acyl-oxygen group, or C
2-C
10Carboxyl;
R
5, R
6Be hydrogen or hydroxyl or carbonyl or sulfonic group or carboxyl, or benzene sulfonamido or tetrahydroglyoxaline and verivate, imidazoles and verivate thereof, piperazine and verivate thereof, piperidines and verivate thereof, morpholine and verivate thereof, or C
1-C
10Alkyl, naphthenic base, aromatic nucleus, fragrant heterocycle or C
1-C
10Oxygen ether or C
2-C
10Acyl-oxygen group, or C
2-C
10Carboxyl;
Or work as R
5With R
6Between when two key is arranged, R
2,R
3Be hydrogen or sulfonic group or carboxyl, or benzene sulfonamido or tetrahydroglyoxaline and verivate, imidazoles and verivate thereof, piperazine and verivate thereof, piperidines and verivate thereof, morpholine and verivate thereof, or C
1-C
10Alkyl, naphthenic base, aromatic nucleus, fragrant heterocycle or C
1-C
10Oxygen ether or C
2-C
10Acyl-oxygen group, or C
2-C
10Carboxy derivatives.Or, work as R
4With R
5Between when two key is arranged, R
4,R
5Be hydrogen or sulfonic group or carboxyl, or benzene sulfonamido or tetrahydroglyoxaline and verivate, imidazoles and verivate thereof, piperazine and verivate thereof, piperidines and verivate thereof, morpholine and verivate thereof, or C
1-C
10Alkyl, naphthenic base, aromatic nucleus, fragrant heterocycle or C
1-C
10Oxygen ether or C
2-C
10Acyl-oxygen group, or C
2-C
10Carboxyl;
X is oxygen or sulphur;
Y is a carbon, oxygen, sulphur, nitrogen-atoms.
According to the tanshinone derivative of general formula (I), described compound is selected from
The salt of allowing on its pharmacology of tanshinone derivative of the present invention for example can be enumerated and mineral acids such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, Hydrogen bromide, perhaps toxilic acid, fumaric acid, tartrate, lactic acid, Hydrocerol A, acetate, methylsulfonic acid, tosic acid; Hexanodioic acid, palmitinic acid, organic acids such as Weibull; Lithium; Basic metal such as sodium, potassium, earth alkali metal such as calcium, magnesium, the salt that basic aminoacidss such as Methionin become.
The present invention also provides pharmaceutical composition, wherein contains each compound or its pharmacy acceptable salt and at least a pharmaceutically acceptable carrier and/or thinner in the above-mentioned general formula (I) of treating significant quantity.
Described pharmaceutical composition is as the dosage form of suitable for oral administration or drug administration by injection.
The present invention also provides the salt or the application of described compound 1-9 in preparation 1 type 11-beta-hydroxysteroid dehydrogenase 11 beta-HSD 1 inhibitors of allowing on described formula (I) compound or its pharmacology in addition.
The salt or the application of described compound 1-9 in the medicine of preparation treatment obesity of allowing on described formula (I) compound or its pharmacology also are provided.
The salt or the application of described compound 1-9 in the medicine of preparation treatment senile dementia of allowing on described formula (I) compound or its pharmacology also are provided.
The salt or the application of described compound 1-9 in the hypertensive medicine of preparation treatment of allowing on described formula (I) compound or its pharmacology also are provided.
When tanshinone derivative according to the invention is used as medicine as 11 beta-HSD 1 inhibitors, can directly use, perhaps use with the form of pharmaceutical composition.This pharmaceutical composition contains 0.1%-99%, is preferably the compound of the present invention of 0.5-95%, and all the other are pharmaceutically acceptable, nontoxic and inert pharmaceutically acceptable carrier to humans and animals.
Pharmaceutically acceptable carrier recited above is meant the pharmaceutical carrier that pharmaceutical field is conventional, for example: thinner, vehicle such as water etc., weighting agent such as starch, sucrose etc.; Tamanori such as derivatived cellulose, alginate, gelatin and Vinylpyrrolidone polymer; Wetting agent such as glycerine; Disintegrating agent such as agar, lime carbonate and sodium hydrogencarbonate; Absorption enhancer such as quaternary ammonium compound; Tensio-active agent such as cetyl alcohol; Absorption carrier such as kaolin and soap clay; Lubricant such as talcum powder, calcium stearate and Magnesium Stearate and polyoxyethylene glycol etc.Can also in compsn, add other assistant agent such as sweeting agent, flavouring agent etc. in addition.
The compounds of this invention can be gone into form administered through oral, the snuffing of compsn, the mode of rectum or administered parenterally is applied to the patient who needs this treatment.Be used for when oral, can be made into conventional solid preparation such as tablet, pulvis, granula, capsule etc., process liquid preparation such as extreme misery oil-suspending agent or other liquid preparation such as syrup etc.; When being used for administered parenterally, can be made into the solution of injection, water or oiliness suspension agent etc.The various formulations of pharmaceutical composition of the present invention can be according to the conventional working method preparation of pharmaceutical field.Activeconstituents is mixed with one or more carriers, be made into the formulation that needs then.
The amount of application of The compounds of this invention can be according to variations such as the type of route of administration, patient's age, body weight, the disease of being treated and severity, and its per daily dose can be a 0.01-10 mg/kg body weight, preferred 0.1-5 mg/kg body weight.Can use by one or many.
Tanshinone derivative of the present invention can be obtained by extraction separation in the red sage root and other salvias through existing method, also can pass through the Tanshinone I high to content in the plant, Tanshinone II A, and compound structures such as VSZ3505 are modified and are obtained.
Description of drawings:
Fig. 1. Tanshinone II A and VSZ3505 are active to the inhibition of 11 β-HSD1 in the 3T3-L1 adipocyte
Fig. 2. after Tanshinone II A and the administration of VSZ3505 single oral to the restraining effect of C57 mouse liver 11 β-HSD1
Fig. 3. after Tanshinone II A and the administration of VSZ3505 single oral to the restraining effect of C57 mouse interior fat 11 β-HSD1
Embodiment:
Essence for a better understanding of the present invention below in conjunction with accompanying drawing, further specifies essentiality content of the present invention with embodiments of the invention, but does not limit the present invention with this.Essence according to the present invention all belongs to scope of the present invention to the improvement that the present invention carries out.
Embodiment 1:
The separation and Extraction of tanshinone derivative (1-9):
Tanshinone derivative can be obtained by extraction separation in the red sage root and other salvias through existing method, also can pass through the Tanshinone I high to content in the plant, Tanshinone II A, and compound structures such as VSZ3505 are modified and are obtained.Tanshinone derivative 1 – 9 (seeing table 1) that relates among the application obtains by separating early from three leaf mouse tails: get dry threeleaf sage root (herb) sample 19.5 kg; Pulverize the back with 100% acetone (each 50 liters) cold soaking three times at room temperature; Each 3 days; Extracting solution concentrates the back with ethyl acetate extraction three times (each 5 liters), gets ETHYLE ACETATE part 785 g.ETHYLE ACETATE part is with acetone solution, and silicagel column on the 900 g 100-200 order silica gel mixed samples (the 100-200 order, 2000g); With Petroleum ether-Acetone is the eluent gradient wash-out; Detect with TLC, merge identical fraction, decolour with the MCI post respectively then; Methanol-water wash-out with 90% obtains five parts.Second section is placed and is separated out a large amount of red powder (compound 1 is a Tanshinone II A, 10.0 g), and its mother liquor is with Petroleum ether-EtOAc or Petroleum ether-CHCl
3-EtOAc is that moving phase goes up behind the silicagel column again through Sephadex LH-20 (CHCl repeatedly
3: purifying MeOH 1:1) obtains compound 9 (30 mg), 5 (35 mg), 3 (5 mg), 4 (30 mg) and 6 (5 mg).The long-term placement of third part separated out a large amount of scarlet powder, and obtaining compound 2 through repetitive scrubbing again is VSZ3505 (8.0 g), and its mother liquor is through Rp-18 reversed phase column chromatography (MeOH:H
2O, 5:5,6:4 10:0) is divided into three components, component 1 with Petroleum ether-EtOAc (95:5,9:1,85:15,8:2) be on the moving phase behind the silicagel column again through Sephadex LH-20 (CHCl
3: MeOH 1:1), obtain compound 7 (320 mg), 8 (18 mg).
The structure of tanshinone derivative 1-9 is following:
The structure appraising datum of tanshinone derivative 1-9 is following:
Tanshinone derivative 1: red powder; Molecular weight: C
19H
18O
3;
1H NMR (400 MHz, CDCl
3): δ
H1.82 (2H, m, H-1), 1.68 (2H, m, H-2), 3.21 (2H; M, H-3), 7.66 (1H, d, J=6.4 Hz, H-6), 7.56 (1H; D, J=6.4 Hz, H-7), 7.29 (1H, s, H-16); 2.24 (3H, s, Me-17), 1.29 (6H, s, Me-18 and Me-19);
13C NMR (100 MHz, CDCl
3): δ
C29.9 (t, C-1), 19.4 (t, C-2), 37.7 (t, C-3), 34.9 (s, C-4), 150.4 (s; C-5), 133.6 (d, C-6), 120.5 (d, C-7), 127.7 (s, C-8), 126.7 (s, C-9); 144.7 (s, C-10), 183.3 (s, C-11), 175.9 (s, C-12), 121.4 (s, C-13), 161.9 (s; C-14), 120.5 (s, C-15), 141.5 (d, C-16), 9.0 (q, C-17), 32.1 (q, C-18 and C-19); EI-MS:m/z 294 ([M]
+, 100), 279 (59), 261 (78), 251 (75), 178 (30), 165 (43).
Tanshinone derivative 2: red oily; Molecular weight: C
19H
20O
3;
1H NMR (400 MHz, CDCl
3): δ
H3.18 (2H, m, H-1), 1.76 (2H, m, H-2), 1.62 (2H, m, H-3), 7.60 (1H; D, J=8.0 Hz, H-6), 7.45 (1H, d, J=8.0 Hz, H-7), 3.55 (1H, m, H-15); 4.86 (1H, t, J=9.2 Hz, H-16a), 4.32 (1H, dd, J=6.0,9.2 Hz, H-16b); 1.18 (3H, s, Me-17), 1.33 (3H, s, Me-18), 1.31 (3H, s, Me-19);
13C NMR (100 MHz, CDCl
3): δ
C29.6 (t, C-1), 19.0 (t, C-2), 37.7 (t, C-3), 34.8 (s, C-4); 152.3 (s, C-5), 132.6 (d, C-6), 122.5 (d, C-7), 128.3 (s, C-8); 126.8 (s, C-9), 143.7 (s, C-10), 184.2 (s, C-11), 175.6 (s, C-12); 118.4 (s, C-13), 170.8 (s, C-14), 34.5 (d, C-15), 81.4 (t; C-16), 18.8 (q, C-17), 31.9 (q, C-18), 31.8 (q, C-19); EI-MS:m/z 296 ([M]
+, 100), 281 (10), 268 (72), 253 (80), 235 (12), 171 (16).
Tanshinone derivative 3: red powder; Molecular weight: C
18H
12O
3;
1H NMR (400 MHz, CDCl
3): δ
H9.25 (1H, d, J=8.8, H-1), 7.55 (1H, dd, J=8.8, H-2); 7.35 (1H, d, J=8.8, H-3), 8.30 (1H, d, J=8.8; H-6), 7.82 (1H, d, J=8.8, H-7), 7.30 (1H, s; H-16), 2.29 (3H, s, Me-17), 2.69 (3H, s, Me-18);
13C NMR (100 MHz, CDCl
3): δ
C124.6 (d, C-1), 130.7 (d, C-2), 128.4 (d, C-3), 135.2 (s, C-4), 133.7 (s; C-5), 132.9 (d, C-6), 118.8 (d, C-7), 129.7 (s, C-8), 123.3 (s, C-9); 132.8 (s, C-10), 183.6 (s, C-11), 175.7 (s, C-12), 121.8 (s, C-13), 161.2 (s; C-14), 120.5 (s, C-15), 142.1 (d, C-16), 8.8 (q, C-17), 19.8 (q, C-18); EI-MS:m/z 276 ([M]
+, 30), 248 (100), 191 (32), 189 (29).
Tanshinone derivative 4: red powder; Molecular weight: C
18H
14O
3;
1H NMR (400 MHz, CDCl
3): δ
H9.28 (1H, d, J=8.8 Hz, H-1), 7.57 (1H, t, J=8.8 Hz, H-2); 7.38 (1H, d, J=8.8 Hz, H-3), 8.29 (1H, d, J=8.8 Hz, H-6); 7.74 (1H, d, J=8.8 Hz, H-7), 3.63 (1H, m, H-15), 4.95 (1H; T, J=9.6 Hz, H-16a), 4.42 (1H, dd, J=6.4,9.6 Hz, H-16b); 1.39 (3H, d, J=7.0 Hz, Me-17), 2.69 (3H, s, Me-18);
13C NMR (100 MHz, CDCl
3): δ
C125.1 (d, C-1), 130.4 (d, C-2), 128.9 (d, C-3), 135.0 (s, C-4), 134.8 (s; C-5), 131.9 (d, C-6), 120.3 (d, C-7), 128.3 (s, C-8), 126.2 (s, C-9); 132.2 (s, C-10), 184.4 (s, C-11), 175.8 (s, C-12), 118.4 (s, C-13), 170.5 (s; C-14), 34.8 (d, C-15), 81.6 (t, C-16), 18.8 (q, C-17), 19.8 (q, C-18).
Tanshinone derivative 5: yellow oil; Molecular weight: C
21H
20O
4;
1H NMR (400 MHz, CDCl
3): δ
H1.37 (3H, d, J=6.8 Hz, Me-17), 1.97 (3H, s, Me-23), 2.71 (3H, s; Me-18), 3.05 (1H, d, J=13.2 Hz, H-21a), 3.28 (1H, d, J=13.2 Hz, H-21b); 3.61 (1H, m, H-15), 4.41 (1H, dd, J=9.3,4.4 Hz, H-16a), 4.92 (1H; Dd, J=9.3,4.4 Hz, H-16b), 7.42 (1H, d, J=7.4 Hz, H-3), 7.50 (1H; Dd, J=8.8,7.4 Hz, H-2), 7.77 (1H, d, J=8.8 Hz, H-7); 8.08 (1H, d, J=8.8 Hz, H-8), 9.00 (1H, d, J=8.8 Hz, H-1);
13C NMR (100 MHz, CDCl
3): δ
C125.7 (d, C-1), 126.7 (d, C-2), 128.5 (d, C-3), 135.2 (s, C-4), 134.8 (s; C-5), 125.5 (d, C-6), 120.0 (d, C-7), 120.4 (s, C-8), 141.3 (s, C-9); 131.1 (s, C-10), 79.4 (s, C-11), 196.1 (s, C-12), 113.3 (s, C-13); 171.5 (s, C-14), 34.8 (d, C-15), 81.6 (t, C-16), 19.4 (q, C-17); 20.1 (q, C-18), 57.2 (t, C-21), 205.1 (s, C-22), 31.9 (q, C-23).
Tanshinone derivative 6: scarlet oily
; Molecular weight: C
18H
16O
4;
13C NMR (125 MHz, C
5D
5N): δ
C29.5 (t, C-1), 20.5 (t, C-2), 38.8 (t, C-3), 69.8 (s, C-4); 149.3 (s, C-5), 133.9 (d, C-6), 120.6 (d, C-7), 128.6 (s; C-8), 126.9 (s, C-9), 143.2 (s, C-10), 183.6 (s, C-11); 176.1 (s, C-12), 121.1 (s, C-13), 161.4 (s, C-14), 120.6 (s; C-15), 142.2 (d, C-16), 8.8 (q, C-17), 31.9 (q, C-18). EI-MS:m/z 296 ([M]
+, 13), 278 (100), 263 (30).
Tanshinone derivative 7: red crystallization
; Molecular weight: C
19H
18O
4;
13C NMR (100 MHz, C
5D
5N): δ
C30.3 (t, C-1), 19.2 (t, C-2), 32.5 (t, C-3), 40.4 (s, C-4); 147.4 (s, C-5), 134.2 (d, C-6), 120.4 (d, C-7), 127.7 (s, C-8); 127.4 (s, C-9), 145.2 (s, C-10), 183.7 (s, C-11), 176.2 (s, C-12); 121.0 (s, C-13), 161.4 (s, C-14), 120.2 (s, C-15), 142.1 (d; C-16), 8.9 (q, C-17), 27.0 (q, C-18), 70.8 (t, C-19).
Tanshinone derivative 8: yellow oily; Molecular weight: C
18H
16O
4;
1H NMR (500 MHz, CDCl
3-CD
3OD, 1:1): δ
H1.32 (3H, d, J=7.0 Hz, Me-17), 2.73 (3H, s, Me-18), 3.51 (1H, m; H-15), 3.92 (1H, dq, J=10.6,7.3 and, 6.2 Hz, H-16a), 3.96 (1H, dq; J=10.6,7.3 and, 6.2 Hz, H-16b), 7.45 (1H, d, J=6.6 Hz, H-3), 7.58 (1H; T, J=8.4,6.6 Hz, H-2), 8.21 (1H, d, J=8.7 Hz, H-7); 8.40 (1H, d, J=8.7 Hz, H-6), 9.40 (1H, d, J=8.4 Hz, H-1);
13C NMR (125 MHz, CDCl
3-CD
3OD, 1:1): δ
C126.1 (d, C-1), 130.5 (d, C-2), 129.5 (d, C-3), 135.7 (s, C-4), 133.8 (s; C-5), 132.3 (d, C-6), 122.7 (d, C-7), 130.9 (s, C-8), 125.7 (s, C-9); 135.7 (s, C-10), 184.3 (s, C-11), 156.1 (s, C-12), 122.4 (s, C-13), 186.4 (s; C-14), 33.4 (d, C-15), 65.6 (t, C-16), 15.0 (q, C-17), 19.9 (q, C-18); EI-MS:m/z 296 ([M]
+, 40), 278 (55), 266 (100), 235 (45), 178 (45), 169 (80).
Tanshinone derivative 9: faint yellow crystallization; Molecular weight: C
18H
14O
4;
13C NMR (100 MHz, CDCl
3): δ
C119.8 (d, C-1), 127.3 (d, C-2), 122.6 (d, C-3), 144.4 (s, C-4); 124.1 (s, C-5), 131.0 (d, C-6), 121.1 (d, C-7), 134.9 (s; C-8), 119.9 (s, C-9), 135.4 (s, C-10), 158.8 (s, C-11); 153.9 (s, C-12), 131.3 (s, C-13), 176.2 (s, C-14), 73.2 (t; C-15), 26.4 (d, C-16), 16.6 (q, C-17), 19.6 (q, C-18). EI-MS:m/z 294 ([M]
+, 35), 249 (100).
Embodiment 2:
Tanshinone derivative (compound 1-9) the vitro inhibition mouse that is obtained by embodiment 1 and people 11 β-HSD1 and 11 β-HSD2 active function is estimated.
1. TP: adopt molecular biology method; To be cloned into the PcDNA3-VSVtag carrier for expression of eukaryon available from the mouse of NIH Mammalian Gene Collection (NIH MGC) or people's 11 β-HSD1 or 2 gene orders; Transfection obtains the cell mixing clone of stable transfection in the HEK293 cell after G418 (0.75 g/L) screening after restriction enzyme digestion and dna sequencing checking.The trysinization cell mixing is cloned and with unicellular inoculation 96 well culture plates, is given conditionality cell culture fluid (HEK293 cell culture supernatant) simultaneously, after 14-20 days, obtains unicellular propagation clone.Amplification back trysinization collecting cell, centrifugal after the ultrasonication (4 ℃, 1500 rpm, 10 min), supernatant once more ultracentrifugation (4 ℃, 100000 g, 1h), phosphate buffered saline buffer (40 mM Na
2HPO
4, 1 mM EDTA, 5% glycerol) and the mouse that obtains of resuspended post precipitation or people's 11 β HSD1 or 2 purifying enzyme ,-80 ℃ are frozen subsequent use.Glycyrrhetinic acid (GA) is as positive control.
Adopting SPA (Scintillation proximity assay) is that liquid dodges near determination techniques, measures compound to mouse or people's 11 β HSD1 or restraining effect (Yang, the H. Y. of 11 β HSD2; Dou, W.; Lou, J.; Leng, Y.; Shen. J. H. Bioorg. Med. Chem. Lett. 2008,1340 – 1345; Yang, H. Y.; Shen, Y.; Chen, J. H.; Jiang, Q. F.; Leng, Y.; Shen, J. H. Eur. J. Med. Chem. 2009,44,1167 – 1171), calculate IC
50Value.
2. experimental result: test result shows that tanshinone derivative has the effect of remarkable inhibition mouse or people 11 β-HSD1, IC
50The value scope is between 13.29 nM –, 5.98 uM.Concrete data are seen table 1.Wherein, Tanshinone II A (compound 1) and VSZ3505 (compound 2) show remarkable restraining effect, IC to 11 β-HSD1 of mouse and people
50Value is respectively: 13.29 nM, 17.78 nM (people 11 β-HSD1), 43.89 nM, (mouse 11 β-HSD1), GA is suitable with positive control for 58.59 nM.
Tanshinone II A (1) and VSZ3505 (2) are launched further activity rating; The result shows, Tanshinone II A (1) and VSZ3505 (2) are to the people, and mouse 11 β-HSD1 shows the remarkable restraining effect while; 11 β-HSD2 is shown extremely excellent selectivity, IC
50Ratio between 207 to 75273 (table 2).
Table 1 tanshinone derivative (1-9) is to the restraining effect of people and mouse 11 β-HSD1
Table 2 Tanshinone II A (compound 1), VSZ3505 (compound 2)
Restraining effect and selectivity to people and mouse 11 β-HSD1
Embodiment 3:
Tanshinone II A and VSZ3505 are to the active evaluation of the inhibition of 11 β-HSD1 in the 3T3-L1 adipocyte:
Further estimate the restraining effect of TANSHINONES and VSZ3505 11 β-HSD1 on molecular level.Shown in accompanying drawing 1, positive control compound MK544 has significant inhibitory effect to 11 β in the 3T3-L1 adipocyte-HSD1, its IC
50Be 0.269 μ M, Tanshinone II A and VSZ3505 also all have comparatively obvious suppression effect, its IC to 11 β in the 3T3-L1 adipocyte-HSD1
50Be respectively 1.438 and 2.134 μ M.
Embodiment 4:
After Tanshinone II A and the administration of VSZ3505 single oral to the restraining effect of C57 mouse liver and fatty 11 β-HSD1:
1. experimental technique: male C57 mouse single oral is given and 300mg/kg Fst2 or Fst6, respectively at 2h, 4h, 8h and 16h after the administration.Put to death animal, separate liver and interior fat (mesentery fat is adopted in this experiment), adopt the SPA method to measure its 11 β-HSD1.
2. experimental result: the result shows (Fig. 2); Male C57 mouse single oral give with 300mg/kg Tanshinone II A or VSZ3505 2h after can significantly reduce by the activity of 11 β in the mouse liver-HSD1; And this restraining effect can be maintained to 16h after the administration; Wherein, VSZ3505 slightly is better than Tanshinone II A to the restraining effect of mouse liver 11 β-HSD1.After Tanshinone II A and the administration of VSZ3505 single oral to the restraining effect of mouse fat obviously than a little less than the liver; And onset is late; The obvious suppression effect only appears during 8h after administration; And after administration 2, the 4h effect is all not obvious, VSZ3505 also slightly is better than Tanshinone II A to the restraining effect of fatty 11 β-HSD1.
To sum up; The present invention has carried out suppressing on vitro human, the mouse model 11 β-HSD1 activity rating to a series of tanshinone derivatives; The result shows this compounds to the people, and mouse 11 β-HSD1 shows remarkable restraining effect (the IC50 value reaches the nM rank), simultaneously; 11 β-HSD2 is shown extremely excellent selectivity, IC
50Ratio between 207 to 75273.Further the cell levels test shows that Tanshinone II A and VSZ3505 show comparatively obvious suppression effect to 11 β-HSD1 in the 3T3-L1 adipocyte, its IC
50Be respectively 1.438 and 2.134 μ M.
The mouse in vivo tests shows, male C57 mouse single oral give with 300mg/kg Tanshinone II A and VSZ3505 2h after can significantly reduce by the activity of 11 β in the mouse liver-HSD1, and this restraining effect can be maintained to 16h after the administration.
It is active that the 11 β-HSD1 of the inside and outside of the excellence that shows based on tanshinone derivative suppresses, and this compounds can be used for preparing 11 beta-HSD 1 inhibitors, and preparation is through suppressing 11 β-HSD1 treatment mellitus, obesity, senile dementia and hypertension drug.
Characteristics of the present invention and superiority be, reported first one type of novel tanshinone derivative 11 beta-HSD 1 inhibitors, such suppressor factor, novel structure, significantly active, in the multiple disease that is closely related with 11 β-HSD1 of treatment, good application prospects is arranged all.Superiority of the present invention is that also tanshinone derivative exists in a large number, and is easy to obtain through semi-synthetic, synthesis mode in salvia, the present invention has enlarged the range of application of tanshinone derivative.
Embodiment 5:
Method by embodiment 1 makes tanshinone derivative (compound 1-9) earlier, adds the injection water by routine, smart filter, and injection liquid is processed in the embedding sterilization.
Embodiment 6:
Method by embodiment 1 makes tanshinone derivative (compound 1-9) earlier, and it is dissolved in the sterile water for injection, and stirring makes molten, filters with aseptic suction funnel, and aseptic more smart filter is sub-packed in 2 ampoules, and aseptic sealing by fusing gets powder injection behind the frozen drying.
Embodiment 7:
With embodiment 1 resulting tanshinone derivative (compound 1-9) and vehicle weight ratio is the ratio adding vehicle of 9:1, processes pulvis.
Embodiment 8:
Method by embodiment 1 makes tanshinone derivative (compound 1-9) earlier, is the ratio adding vehicle of 1:5-1:10 in itself and vehicle weight ratio, pelletizing press sheet.
Embodiment 9:
Method by embodiment 1 makes tanshinone derivative (compound 1-9) earlier, processes oral liquid by conventional oral liquid method for making.
Embodiment 10:
Method by embodiment 1 makes tanshinone derivative (compound 1-9) earlier, is the ratio adding vehicle of 5:1 in itself and vehicle weight ratio, processes capsule or granule or electuary.
Embodiment 11:
Method by embodiment 1 makes tanshinone derivative (compound 1-9) earlier, is the ratio adding vehicle of 3:1 in itself and vehicle weight ratio, processes capsule or granule or electuary.
Claims (9)
1. but one kind has tanshinone derivative or its pharmacy acceptable salt that general structure is formula I,
Wherein, R
1, R
2, R
3, R
4Be hydrogen or hydroxyl or carbonyl or sulfonic group or carboxyl, or benzene sulfonamido or tetrahydroglyoxaline and verivate, imidazoles and verivate thereof, piperazine and verivate thereof, piperidines and verivate thereof, morpholine and verivate thereof, or C
1-C
10Alkyl, naphthenic base, aromatic nucleus, fragrant heterocycle or C
1-C
10Oxygen ether or C
2-C
10Acyl-oxygen group, or C
1-C
10Carboxyl;
Or, work as R
1, with R
2, between when being two key, R
1, R
2Be hydrogen or hydroxyl or sulfonic group or benzene sulfonamido or tetrahydroglyoxaline and verivate, imidazoles and verivate thereof, piperazine and verivate thereof, piperidines and verivate thereof, morpholine and verivate thereof, or C
1-C
10Alkyl, naphthenic base, aromatic nucleus, fragrant heterocycle or C
1-C
10Oxygen ether or C
2-C
10Acyl-oxygen group, or C
2-C
10Carboxyl;
Or, work as R
3With R
4Between when being two key, R
3, R
4Be hydrogen or hydroxyl or sulfonic group or benzene sulfonamido or tetrahydroglyoxaline and verivate, imidazoles and verivate thereof, piperazine and verivate thereof, piperidines and verivate thereof, morpholine and verivate thereof, or C
1-C
10Alkyl, naphthenic base, aromatic nucleus, fragrant heterocycle or C
1-C
10Oxygen ether or C
2-C
10Acyl-oxygen group, or C
2-C
10Carboxyl;
R
5, R
6Be hydrogen or hydroxyl or carbonyl or sulfonic group or carboxyl, or benzene sulfonamido or tetrahydroglyoxaline and verivate, imidazoles and verivate thereof, piperazine and verivate thereof, piperidines and verivate thereof, morpholine and verivate thereof, or C
1-C
10Alkyl, naphthenic base, aromatic nucleus, fragrant heterocycle or C
1-C
10Oxygen ether or C
2-C
10Acyl-oxygen group, or C
2-C
10Carboxyl;
Or work as R
5With R
6Between when two key is arranged, R
2,R
3Be hydrogen or sulfonic group or carboxyl, or benzene sulfonamido or tetrahydroglyoxaline and verivate, imidazoles and verivate thereof, piperazine and verivate thereof, piperidines and verivate thereof, morpholine and verivate thereof, or C
1-C
10Alkyl, naphthenic base, aromatic nucleus, fragrant heterocycle or C
1-C
10Oxygen ether or C
2-C
10Acyl-oxygen group, or C
2-C
10Carboxy derivatives.Or, work as R
4With R
5Between when two key is arranged, R
4,R
5Be hydrogen or sulfonic group or carboxyl, or benzene sulfonamido or tetrahydroglyoxaline and verivate, imidazoles and verivate thereof, piperazine and verivate thereof, piperidines and verivate thereof, morpholine and verivate thereof, or C
1-C
10Alkyl, naphthenic base, aromatic nucleus, fragrant heterocycle or C
1-C
10Oxygen ether or C
2-C
10Acyl-oxygen group, or C
2-C
10Carboxyl;
X is oxygen or sulphur;
Y is a carbon, oxygen, sulphur, nitrogen-atoms.
2. according to the tanshinone derivative of claim 1, described formula (I) compound is selected from
3. pharmacy acceptable salt as claimed in claim 1 includes but not limited to mineral acid example hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, Hydrogen bromide, perhaps organic acid such as toxilic acid, fumaric acid, tartrate, lactic acid, Hydrocerol A, acetate, methylsulfonic acid, tosic acid; Hexanodioic acid, palmitinic acid, Weibull; Basic aminoacids such as lithium; Sodium, potash metal, alkaline earth metals calcium, magnesium, the salt that Methionin becomes.
4. pharmaceutical composition, wherein contain the treatment significant quantity according to each described compound of claim 1-2 or its pharmacy acceptable salt and at least a pharmaceutically acceptable carrier and/or thinner.
5. pharmaceutical composition according to claim 4 is characterized in that the dosage form as suitable for oral administration or drug administration by injection.
6. the application in preparation 1 type 11-beta-hydroxysteroid dehydrogenase 11 beta-HSD 1 inhibitors of salt of allowing on the described formula of claim 1 (I) compound or its pharmacology or the described compound of claim 2.
7. the application in the medicine of preparation treatment obesity of salt of allowing on described (I) compound of claim 1 or its pharmacology or the described compound of claim 2.
8. the application in the medicine of preparation treatment senile dementia of salt of allowing on described (I) compound of claim 1 or its pharmacology or the described compound of claim 2.
9. the application in the medicine of preparation treatment essential hypertension of salt of allowing on described (I) compound of claim 1 or its pharmacology or the described compound of claim 2.
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| CN102603861A (en) * | 2012-02-25 | 2012-07-25 | 中国科学院昆明植物研究所 | Tanshinone derivatives, medicine compositions thereof, and purposes thereof in medicine |
| CN107698652A (en) * | 2017-09-28 | 2018-02-16 | 中山大学 | A kind of indoleamine 2 containing tanshinone compound, 3 dioxygenase inhibitors |
| CN110330545B (en) * | 2019-04-30 | 2020-11-06 | 中山大学 | Tanshinone IIA derivative TAN20, and preparation method and application thereof |
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