CN109912681A - Derivative containing pentamethylene and more hydrogen phenanthrene class skeletons and its application in the drug that preparation prevents and treats infarct disease - Google Patents
Derivative containing pentamethylene and more hydrogen phenanthrene class skeletons and its application in the drug that preparation prevents and treats infarct disease Download PDFInfo
- Publication number
- CN109912681A CN109912681A CN201910254042.0A CN201910254042A CN109912681A CN 109912681 A CN109912681 A CN 109912681A CN 201910254042 A CN201910254042 A CN 201910254042A CN 109912681 A CN109912681 A CN 109912681A
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- Prior art keywords
- acid
- compound
- solution
- derivative
- hydrogen phenanthrene
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- 239000001257 hydrogen Substances 0.000 title claims abstract description 65
- 229910052739 hydrogen Inorganic materials 0.000 title claims abstract description 65
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 title claims abstract description 51
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 title claims abstract description 49
- 239000003814 drug Substances 0.000 title claims abstract description 30
- 229940079593 drug Drugs 0.000 title claims abstract description 28
- 206010061216 Infarction Diseases 0.000 title claims abstract description 20
- 230000007574 infarction Effects 0.000 title claims abstract description 20
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims abstract description 12
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 claims abstract description 29
- 229960001138 acetylsalicylic acid Drugs 0.000 claims abstract description 28
- 150000001875 compounds Chemical class 0.000 claims description 60
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 31
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- -1 acetoxyl group Chemical group 0.000 claims description 18
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 12
- 230000002785 anti-thrombosis Effects 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 9
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
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- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 claims description 7
- 239000008280 blood Substances 0.000 claims description 7
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 claims description 7
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 6
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 claims description 6
- YNPNZTXNASCQKK-UHFFFAOYSA-N phenanthrene Chemical compound C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 claims description 6
- 230000002265 prevention Effects 0.000 claims description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 3
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- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 3
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 3
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 3
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- 239000011975 tartaric acid Substances 0.000 claims description 3
- 235000002906 tartaric acid Nutrition 0.000 claims description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 3
- KSEBMYQBYZTDHS-HWKANZROSA-M (E)-Ferulic acid Natural products COC1=CC(\C=C\C([O-])=O)=CC=C1O KSEBMYQBYZTDHS-HWKANZROSA-M 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 2
- 235000015165 citric acid Nutrition 0.000 claims description 2
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- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 claims description 2
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- 235000001785 ferulic acid Nutrition 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 239000011976 maleic acid Substances 0.000 claims description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 2
- QURCVMIEKCOAJU-UHFFFAOYSA-N trans-isoferulic acid Natural products COC1=CC=C(C=CC(O)=O)C=C1O QURCVMIEKCOAJU-UHFFFAOYSA-N 0.000 claims description 2
- QSLPNSWXUQHVLP-UHFFFAOYSA-N $l^{1}-sulfanylmethane Chemical compound [S]C QSLPNSWXUQHVLP-UHFFFAOYSA-N 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 claims 1
- WQLVFSAGQJTQCK-UHFFFAOYSA-N diosgenin Natural products CC1C(C2(CCC3C4(C)CCC(O)CC4=CCC3C2C2)C)C2OC11CCC(C)CO1 WQLVFSAGQJTQCK-UHFFFAOYSA-N 0.000 abstract description 24
- DWCSNWXARWMZTG-UHFFFAOYSA-N Trigonegenin A Natural products CC1C(C2(CCC3C4(C)CCC(O)C=C4CCC3C2C2)C)C2OC11CCC(C)CO1 DWCSNWXARWMZTG-UHFFFAOYSA-N 0.000 abstract description 22
- WQLVFSAGQJTQCK-VKROHFNGSA-N diosgenin Chemical compound O([C@@H]1[C@@H]([C@]2(CC[C@@H]3[C@@]4(C)CC[C@H](O)CC4=CC[C@H]3[C@@H]2C1)C)[C@@H]1C)[C@]11CC[C@@H](C)CO1 WQLVFSAGQJTQCK-VKROHFNGSA-N 0.000 abstract description 22
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 82
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- 241000699666 Mus <mouse, genus> Species 0.000 description 31
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Abstract
The present invention provides the derivatives containing pentamethylene and more hydrogen phenanthrene class skeletons, and should application of the derivative containing pentamethylene and more hydrogen phenanthrene class skeletons in the drug that preparation prevents and treats infarct disease.The present invention is experiments prove that the derivative containing pentamethylene and more hydrogen phenanthrene class skeletons has antiplatelet effects, the formation of pulmonary embolism, arterial thrombus and phlebothrombosis is all significantly inhibited, and it can effectively reduce brain infarction area and infarct size, it improves significantly to cerebral infarction and myocardial infarction tool, and positive effect is better than positive control drug aspirin and parent nucleus diosgenin.
Description
Technical field
The invention belongs to drug field, it is related to derivative and the derivative containing pentamethylene and more hydrogen phenanthrene class skeletons
Application in the drug that preparation prevents and treats infarct disease.
Background technique
Pentamethylene and more hydrogen phenanthrene class compounds are prevalent in animal and plant body, and during animals and plants vital movement from
Important function.Diosgenin is mainly derived from the dioscoreas such as dioscorea zingiberensis wright, dioscorea nipponica, Dioscorea Panthcica, Rhizoma Curcumae Longae.
Pharmacological evaluation shows that diosgenin can inhibit platelet aggregation and arteriovenous thrombosis, while can extend the APTT time.
The diosgenin for including belongs to the natural steroid saponin(e Chinese patent drug of effective component group, clinically for treat cerebral arteriovenous malformation,
The diseases such as sequelae caused by myocardial ischemia, coronary heart disease and cerebral thrombosis, and obtain the specific curative effect of comparison.Because of such compound
So far still to social important role and huge Social benefit and economic benefit is brought.In order to enrich compound library, and it is
The screening of reactive compound provides new skeleton, lead compound of looking for novelty, it is necessary to carry out structural modification to diosgenin and change
It makes, to improve its pharmacological activity, develops new and effective less toxic antithrombotic reagent.
Summary of the invention
In view of the above-mentioned deficiencies in the prior art, it is an object of the present invention to which an object of the present invention is to provide containing pentamethylene simultaneously
The derivative of more hydrogen phenanthrene class skeletons, it is living by the antithrombotic for improving the existing antithrombotic reagent developed based on diosgenin
Property, the second object of the present invention is to provide application of the derivative in the drug that preparation prevents and treats infarct disease.
Derivative provided by the invention containing pentamethylene and more hydrogen phenanthrene class skeletons is with diosgenin for guide's chemical combination
Object is obtained by carrying out to it structural modification and optimization.It is provided by the invention containing pentamethylene and more hydrogen phenanthrene class skeletons spread out
Shown in the structural formula such as formula (I) of biology or derivative is formula (I) compound represented pharmaceutically acceptable salt,
In formula (I), R1For or R1From non-steroidal anti-inflammatory drugs, R2For hydroxyl or R2From non-steroidal anti-inflammatory drugs.
Preferably, in the technical solution of the above-mentioned derivative containing pentamethylene and more hydrogen phenanthrene class skeletons, the non-steroidal is anti-
Scorching medicine includes aspirin, brufen, Indomethacin, naproxen and Diclofenac.
It is further preferred that in the technical solution of the above-mentioned derivative containing pentamethylene and more hydrogen phenanthrene class skeletons, formula (I)
In, R1For acetoxyl group,
R2For hydroxyl,
Still further preferably, described in the technical solution of the above-mentioned derivative containing pentamethylene and more hydrogen phenanthrene class skeletons
Pentamethylene and more hydrogen phenanthrene framework compounds are any one in following compounds 4~12,17~20, or are following compounds
Any one pharmaceutically acceptable salt in 4~12,17~20:
In the technical solution of the above-mentioned derivative containing pentamethylene and more hydrogen phenanthrene class skeletons, formula (I) compound represented exists
Pharmaceutically acceptable salt is any one in formula (I) compound represented and hydrochloric acid, hydrobromic acid, sulfuric acid, carbonic acid, lemon
Acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid or Ah
The addition salts that Wei's acid is formed.Pharmaceutically acceptable salt is in compound 4~12,17~20 to compound 4~12,17~20
Any one and hydrochloric acid, hydrobromic acid, sulfuric acid, carbonic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, horse
Carry out the addition salts that sour, methanesulfonic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid or ferulic acid are formed.
Derivative provided by the invention containing pentamethylene and more hydrogen phenanthrene class skeletons can mutually be tied with the carrier pharmaceutically received
It amounts to the activity for playing the infarct disease of prevention and treatment.Derivative provided by the invention containing pentamethylene and more hydrogen phenanthrene class skeletons can
The preparations such as oral, injection are prepared into using drug conventional method.
The synthetic route of the above-mentioned derivative containing pentamethylene and more hydrogen phenanthrene class skeletons is as follows:
Wherein: R be acetoxyl group, hydroxyl or derive from non-steroidal anti-inflammatory drugs.
The preparation method of the above-mentioned derivative containing pentamethylene and more hydrogen phenanthrene class skeletons mainly comprises the steps that
A. diosgenin C-3 hydroxyls and acetic anhydride act on, and obtain the change of the pentamethylene of acetylation and more hydrogen phenanthrene skeletons
Close object；
B. the compound of pentamethylene and more hydrogen phenanthrene skeletons and catalyst in acid condition, open oxygen-containing six rings reaction,
Obtain the compound that C-26 are hydroxyl；
C. the compound and non-steroidal anti-inflammatory drugs of pentamethylene and more hydrogen phenanthrene skeletons occur under catalyst and condensing agent effect
Esterification obtains the compound of esters pentamethylene and more hydrogen phenanthrene skeletons.
By taking compound 4 as an example, synthetic method is as follows:
Acetic anhydride and anhydrous sodium acetate, high temperature of 120 DEG C reaction is added using anhydrous methylene chloride as solvent in the step a；
The step b is using anhydrous methylene chloride and glacial acetic acid as mixed solvent, volume ratio 2:1, adds in batches at room temperature
Enter sodium cyanoborohydride, ring-opening reaction occurs；
The step c is using anhydrous methylene chloride as solvent, with 1- (3- dimethylamino-propyl) -3- ethyl carbodiimide
EDC is condensing agent, carries out esterification by promotor of 4-dimethylaminopyridine DMAP.
The present invention has carried out relevant pharmacological evaluation, provided by the invention in the experiment for inhibiting platelet aggregation in vivo
Derivative Dioscin derivative containing pentamethylene and more hydrogen phenanthrene class skeletons can inhibit platelet aggregation in ADP inducing mouse body
Collection, effect is better than parent nucleus diosgenin and positive drug aspirin, and compound provided by the invention 17~20 is with excellent
The different activity for inhibiting platelet aggregation in ADP inducing mouse body.
It is provided by the invention containing pentamethylene and more hydrogen phenanthrene classes in the experiment of collagen and adrenalin inducing mouse pulmonary embolism
The derivative Dioscin derivative of skeleton can protect collagen and adrenalin inducing mouse pulmonary embolism, and effect is better than parent nucleus Chinese yam
Sapogenin and positive drug aspirin, and compound provided by the invention 17~20 protects collagen and adrenalin inducing mouse
The activity of pulmonary embolism is very excellent.
It is provided by the invention containing pentamethylene and more hydrogen phenanthrene class skeletons in arterial thrombus model and venous thrombosis models
Derivative Dioscin derivative can inhibit the weight and length of arterial thrombus and venous thronbosis, and effect is better than Dioscin
Member and positive drug aspirin, wherein effect is the most it is evident that compound provided by the invention 18 is able to suppress FeCl3It lures
The SD rat carotid artery thrombosis led, can also inhibit venous thronbosis caused by Ligation of inferior vena cava, have significant anti-
Thrombus effect.
It is provided by the invention containing pentamethylene and more hydrogen phenanthrene class skeletons in the experiment for improving rat cerebral infarction and mouse heart infarction
Derivative Dioscin derivative can reduce rat cerebral infarction area and mouse heart infarct size, effect is better than positive drug
Aspirin, wherein more preferable with the improvement result that 17,18,20 pairs of rat cerebral infarctions of compound and mouse heart obstruct.
Based on the above experimental result, the present invention also provides the above-mentioned derivatives containing pentamethylene and more hydrogen phenanthrene class skeletons to exist
Preparation prevents and treats the application in the drug of infarct disease.Further, the drug of the infarct disease of prevention and treatment includes anti-
Antiplatelet drug and antithrombotic reagent.
Compared with prior art, technical solution of the present invention has technical effect beneficial below:
The present invention is experiments prove that the derivative provided by the invention containing pentamethylene and more hydrogen phenanthrene class skeletons has
Antiplatelet effects all significantly inhibit the formation of pulmonary embolism, arterial thrombus and phlebothrombosis, and can be effective
Brain infarction area and infarct size are reduced, is improved significantly to cerebral infarction and myocardial infarction tool, and positive effect is excellent
In positive control drug aspirin and parent nucleus diosgenin.In addition, provided by the invention containing pentamethylene and more hydrogen phenanthrene class bones
The derivant structure and synthesis technology of frame are simple, are adapted to industrialized production, can reduce production cost, economical high excellent
Gesture.
Detailed description of the invention
Fig. 1 is that the derivative containing pentamethylene and more hydrogen phenanthrene class skeletons in embodiment 7 and 8 forms artery and vein thrombus
Influence result.
Specific embodiment
It to the derivative provided by the invention containing pentamethylene and more hydrogen phenanthrene class skeletons and its is making by the following examples
Application in the standby drug for preventing and treating infarct disease is described further.It is necessary to note that following embodiment is served only for this hair
It is bright to be described further, it should not be understood as limiting the scope of the invention, one of ordinary skill in the art are according to foregoing invention
Content is made some nonessential modifications and adaptations to the present invention and is embodied, and the range of invention protection is still fallen within.
In Examples 1 to 4 below, the synthetic method of compound 4~20 is provided, the synthetic route of compound 4~20 is such as
Under:
R be acetoxyl group, hydroxyl,
Raw material compound 3, compound 8 involved in Examples 1 to 3 are by compound 1 (diosgenin) through conventional anti-
It should obtain, according to above-mentioned reaction route, those skilled in the art can voluntarily synthesize compound 3 and compound 8.
Embodiment 1
In the present embodiment, 3- acetyl group furostan ester type compound is synthesized, specifically includes synthesis compound 4~7.
1. synthesizing compound 4:3- acetyl-aspirin furostan ester
By compound 3 (459mg, 1mmol), aspirin (216mg, 1.2mmol) and 4-dimethylaminopyridine (DMAP,
24mg, 0.2mmol) it is dissolved in anhydrous methylene chloride (30mL) and stirs 10min formation solution A, by 1- ethyl-(3- dimethyl
Aminopropyl) phosphinylidyne diimmonium salt hydrochlorate (EDC.HCl, 383mg, 2mmol) is dissolved in 8mL anhydrous methylene chloride and forms solution B,
Solution B is slowly added dropwise into solution A at room temperature, is gradually heated to 35~40 DEG C of reaction 8h or so, TCL detection reaction
Process, reaction is substantially completely.Gained reaction solution is successively used into 5% sodium chloride solution, saturated sodium bicarbonate solution and 5% sodium chloride
Solution washing, separation organic phase is simultaneously dry with anhydrous sodium sulfate, then uses petroleum ether: ethyl acetate=10:1 (v/v) is as washing
Silicagel column is crossed in de- agent, and isolated white powder product is compound 4, yield 72%.
1H NMR (400MHz, CDCL3) δ 12.12 (s, 1H), 7.40 (dd, J=17.5,8.0Hz, 2H), 6.97 (t, J=
8.3Hz, 2H), 6.85 (t, J=7.5Hz, 1H), 5.39 (s, 1H), 4.79-4.60 (m, 2H), 4.40 (dd, J=14.7,
7.4Hz, 1H), 3.47 (d, J=8.6Hz, 1H), 3.41-3.32 (m, 1H), 2.43-2.26 (m, 2H), 2.08-1.82 (m,
5H), 1.04 (s, 3H), 0.96 (d, J=6.8Hz, 3H), 0.78 (s, 6H).(M+H+)=621.3791.
2. synthesizing compound 5:3- acetyl-brufen furostan ester
Compound 3 (459mg, 1mmol), brufen (247mg, 1.2mmol) and DMAP (24mg, 0.2mmol) are dissolved in
In anhydrous methylene chloride (30mL) and 10min formation solution A is stirred, EDC.HCl (383mg, 2mmol) is dissolved in 8mL anhydrous two
Solution B is formed in chloromethanes, solution B is slowly added dropwise into solution A at room temperature, is gradually heated to 35~40 DEG C of reactions
8h or so, TCL detect reaction process, and reaction is substantially completely.Gained reaction solution is successively used into 5% sodium chloride solution, unsaturated carbonate
Hydrogen sodium solution and the washing of 5% sodium chloride solution, separation organic phase is dry with simultaneously anhydrous sodium sulfate, then uses petroleum ether: acetic acid second
Ester=10:1 (v/v) crosses silicagel column as eluant, eluent, and isolated white powder product is compound 5, and yield is
83%.
1H NMR (400MHz, Chloroform-d) δ 7.19 (t, J=8.0Hz, 2H), 7.07 (dd, J=8.2,6.6Hz,
2H), 5.35 (dd, J=4.3,2.7Hz, 1H), 4.59 (tdd, J=10.6,6.5,4.1Hz, 1H), 3.89 (dddd, J=
38.0,13.7,10.7,6.2Hz, 2H), 3.68 (qd, J=7.2,2.5Hz, 1H), 3.57-3.37 (m, 1H), 3.24 (tdd, J
=8.0,6.5,4.2Hz, 1H), 2.42 (dd, J=7.2,1.5Hz, 2H), 1.90-1.77 (m, 3H), 1.44-1.37 (m, 1H),
1.37-1.20 (m, 4H), 1.18-1.04 (m, 3H), 1.02 (s, 2H), 0.98-0.93 (m, 3H), 0.87 (dd, J=6.6,
2.1Hz, 6H), 0.81 (dd, J=6.7,4.3Hz, 3H), 0.78 (s, 2H).(M+H+)=647.4675.
3. synthesizing compound 6:3- acetyl-Indomethacin furostan ester
Compound 3 (459mg, 1mmol), Indomethacin (429mg, 1.2mmol) and DMAP (24mg, 0.2mmol) is molten
In anhydrous methylene chloride (30mL) and 10min formation solution A is stirred, it is anhydrous that EDC.HCl (383mg, 2mmol) is dissolved in 8mL
Solution B is formed in methylene chloride, solution B is slowly added dropwise into solution A at room temperature, is gradually heated to 35~40 DEG C instead
8h or so, TCL is answered to detect reaction process, reaction is substantially completely.Gained reaction solution is successively used into 5% sodium chloride solution, saturated carbon
Sour hydrogen sodium solution and the washing of 5% sodium chloride solution, separation organic phase is simultaneously dry with anhydrous sodium sulfate, then uses petroleum ether: acetic acid
Ethyl ester=10:1 (v/v) crosses silicagel column as eluant, eluent, and isolated product as yellow powder is compound 6, and yield is
85%.
1H NMR (400MHz, Chloroform-d) δ 7.63 (ddd, J=8.6,4.0,1.9Hz, 2H), 7.44 (ddd, J
=8.6,4.0,1.9Hz, 2H), 6.94 (dd, J=4.1,2.4Hz, 1H), 6.85 (dd, J=9.0,3.9Hz, 1H), 6.69-
6.59 (m, 1H), 4.31-4.18 (m, 1H), 3.98 (dt, J=10.1,4.5Hz, 1H), 3.88 (ddd, J=10.8,6.8,
4.0Hz, 1H), 3.19 (dt, J=8.2,4.2Hz, 1H), 2.36 (d, J=3.7Hz, 3H), 2.29 (q, J=4.0Hz, 2H),
2.01 (d, J=3.8Hz, 3H), 1.79-1.38 (m, 11H), 1.38-1.19 (m, 4H), 0.87 (dd, J=6.9,3.7Hz,
3H), 0.75 (d, J=3.6Hz, 3H).(M+H+)=798.4137.
4. synthesizing compound 7:3- acetyl-naproxen furostan ester
Compound 3 (459mg, 1mmol), naproxen (276mg, 1.2mmol) and DMAP (24mg, 0.2mmol) are dissolved in
In anhydrous methylene chloride (30mL) and 10min formation solution A is stirred, EDC.HCl (383mg, 2mmol) is dissolved in 8mL anhydrous two
Solution B is formed in chloromethanes, solution B is slowly added dropwise into solution A at room temperature, is gradually heated to 35~40 DEG C of reactions
8h or so, TCL detect reaction process, and reaction is substantially completely.Gained reaction solution is successively used into 5% sodium chloride solution, unsaturated carbonate
Hydrogen sodium solution and the washing of 5% sodium chloride solution, separation organic phase is simultaneously dry with anhydrous sodium sulfate, then uses petroleum ether: acetic acid second
Ester=10:1 (v/v) crosses silicagel column as eluant, eluent, and isolated white powder product is compound 7, and yield is
82%.
1H NMR (400MHz, Chloroform-d) δ 7.71-7.62 (m, 3H), 7.39 (dd, J=8.5,1.9Hz, 1H),
4.58 (tdd, J=10.6,6.6,4.2Hz, 1H), 4.23 (td, J=7.7,5.1Hz, 1H), 3.96 (dd, J=10.7,
5.7Hz,1H),2.35–2.26(m,2H),2.01(s,3H),1.99–1.92(m,2H),1.89–1.80(m,2H),1.53–
1.38 (m, 5H), 1.32-1.21 (m, 4H), 1.15-1.03 (m, 3H), 0.89 (d, J=6.7Hz, 3H), 0.82 (d, J=
6.7Hz,3H),0.74(s,3H)。(M+H+)=671.4312.
Embodiment 2
In the present embodiment, furostan di esters compound is synthesized, compound 9~12 is specifically included.
1. synthesizing compound 9: aspirin furostan dibasic acid esters
Compound 8 (416mg, 1mmol), aspirin (432mg, 2.4mmol) and DMAP (48mg, 0.4mmol) is molten
In anhydrous methylene chloride (30mL) and 10min formation solution A is stirred, it is anhydrous that EDC.HCl (766mg, 4mmol) is dissolved in 8mL
Methylene chloride forms solution B, and solution A is slowly added dropwise into solution B at room temperature, is gradually heated to 35~40 DEG C of reactions
8h or so, TCL detect reaction process, and reaction is substantially completely.Gained reaction solution is successively used into 5% sodium chloride solution, unsaturated carbonate
Hydrogen sodium solution and the washing of 5% sodium chloride solution, separation organic phase is simultaneously dry with anhydrous sodium sulfate, then uses petroleum ether: acetic acid second
Ester=10:1 (v/v) crosses silicagel column as eluant, eluent, and isolated white powder product is compound 9, yield 72%.
1H NMR(400MHz,Chloroform-d)δ8.13–7.90(m,2H),7.58–7.37(m,2H),7.35–7.16
(m, 2H), 4.78 (tdd, J=19.7,10.8,5.2Hz, 1H), 4.63-4.52 (m, 1H), 4.31-4.25 (m, 1H), 4.18-
4.00 (m, 2H), 1.71 (ddq, J=15.6,6.6,4.1,3.4Hz, 5H), 1.65-1.34 (m, 12H), 1.12 (dd, J=
12.8,4.3Hz,2H),1.05–0.93(m,9H)。(M+H+)=741.4003.
2. synthesizing compound 10: brufen furostan dibasic acid esters
Compound 8 (416mg, 1mmol), brufen (494mg, 2.4mmol) and DMAP (48mg, 0.4mmol) are dissolved in
In anhydrous methylene chloride (30mL) and 10min formation solution A is stirred, EDC.HCl (766mg, 4mmol) is dissolved in 8mL anhydrous two
Chloromethanes forms solution B, and solution B is slowly added dropwise into solution A at room temperature, is gradually heated to 35~40 DEG C of reaction 8h
Left and right, TCL detect reaction process, and reaction is substantially completely.Gained reaction solution is successively used into 5% sodium chloride solution, unsaturated carbonate hydrogen
Sodium solution and the washing of 5% sodium chloride solution, separation organic phase is simultaneously dry with anhydrous sodium sulfate, then uses petroleum ether: ethyl acetate
=10:1 (v/v) crosses silicagel column as eluant, eluent, and isolated white powder product is compound 10, and yield is
80%.
1H NMR (400MHz, Chloroform-d) δ 7.20 (s, 2H), 7.18 (s, 2H), 7.08 (d, J=2.1Hz,
2H), 4.28 (tdd, J=7.5,5.1,1.9Hz, 2H), 3.24 (qd, J=7.5,4.3Hz, 2H), 2.44 (d, J=2.3Hz,
2H), 1.74-1.67 (m, 4H), 1.47 (dd, J=8.2,7.2Hz, 12H), 1.31 (ddd, J=16.7,11.8,9.2Hz,
4H), 1.10 (qd, J=11.7,11.3,6.0Hz, 4H), 0.89 (d, J=2.3Hz, 6H), 0.88 (d, J=2.3Hz, 6H),
0.82 (dd, J=6.7,4.5Hz, 3H), 0.78 (s, 3H).(M+H+)=793.5771.
3. synthesizing compound 11: Indomethacin furostan dibasic acid esters
Compound 8 (416mg, 1mmol), Indomethacin (858mg, 2.4mmol) and DMAP (48mg, 0.4mmol) is molten
In anhydrous methylene chloride (30mL) and 10min formation solution A is stirred, it is anhydrous that EDC.HCl (766mg, 4mmol) is dissolved in 8mL
Methylene chloride forms solution B, and solution B is slowly added dropwise into solution A at room temperature, is gradually heated to 35~40 DEG C of reactions
8h or so, TCL detect reaction process, and reaction is substantially completely.Gained reaction solution is successively used into 5% sodium chloride solution, unsaturated carbonate
Hydrogen sodium solution and the washing of 5% sodium chloride solution, separation organic phase is simultaneously dry with anhydrous sodium sulfate, then uses petroleum ether: acetic acid second
Ester=10:1 (v/v) crosses silicagel column as eluant, eluent, and isolated product as yellow powder is compound 11, and yield is
85%.
1H NMR (400MHz, Chloroform-d) δ 7.63 (dd, J=8.6,2.6Hz, 4H), 7.44 (d, J=8.4Hz,
4H), 5.33 (d, J=5.0Hz, 1H), 4.00-3.85 (m, 3H), 3.81 (d, J=3.1Hz, 6H), 3.62 (d, J=11.7Hz,
4H), 3.19 (td, J=8.1,4.0Hz, 2H), 1.83 (dt, J=13.4,3.4Hz, 2H), 1.71-1.64 (m, 2H), 1.62-
1.46 (m, 8H), 1.36-1.20 (m, 5H), 0.93 (d, J=6.7Hz, 3H), 0.87 (d, J=6.7Hz, 3H), 0.75 (s,
3H)。(M+H+)=1095.4693.
4. synthesizing compound 12: naproxen furostan dibasic acid esters
Compound 8 (416mg, 1mmol), naproxen (552mg, 2.4mmol) and DMAP (48mg, 0.4mmol) are dissolved in
In anhydrous methylene chloride (30mL) and 10min formation solution A is stirred, EDC.HCl (766mg, 4mmol) is dissolved in 8mL anhydrous two
Chloromethanes forms solution B, and solution A is slowly added dropwise into solution B at room temperature, is gradually heated to 35~40 DEG C of reaction 8h
Left and right, TCL detect reaction process, and reaction is substantially completely.Gained reaction solution is successively used into 5% sodium chloride solution, unsaturated carbonate hydrogen
Sodium solution and the washing of 5% sodium chloride solution, separation organic phase is dry with anhydrous sodium sulfate, then with petroleum ether: ethyl acetate=
10:1 (v/v) crosses silicagel column as eluant, eluent, and isolated white powder product is compound 12, yield 81%.
1H NMR (400MHz, Chloroform-d) δ 7.73-7.62 (m, 6H), 7.40 (dt, J=8.5,1.2Hz, 2H),
7.17-7.05 (m, 4H), 3.96 (dd, J=10.8,5.7Hz, 1H), 3.89 (d, J=3.0Hz, 6H), 3.88-3.75 (m,
3H), 3.16 (td, J=8.1,4.0Hz, 1H), 1.66-1.59 (m, 2H), 1.56 (t, J=7.4Hz, 6H), 1.53-1.37 (m,
6H), 1.34-1.19 (m, 5H), 1.16-1.01 (m, 3H), 0.97 (s, 3H), 0.89 (d, J=6.7Hz, 3H), 0.82 (d, J=
6.7Hz,3H),0.73(s,3H)。(M+H+)=841.5043.
Embodiment 3
In the present embodiment, spirostan ester type compound is synthesized, compound 13~16 is specifically included.
1. synthesizing compound 13: aspirin spirostan ester
Compound 1 (414mg, 1mmol), aspirin (216mg, 1.2mmol) and DMAP (24mg, 0.2mmol) is molten
In anhydrous methylene chloride (30mL) and 10min formation solution A is stirred, it is anhydrous that EDC.HCl (383mg, 2mmol) is dissolved in 5mL
Methylene chloride forms solution B, and solution B is slowly added dropwise into solution A at room temperature, is gradually heated to 35~40 DEG C of reactions
8h or so, TCL detect reaction process, and reaction is substantially completely.Gained reaction solution is successively used into 5% sodium chloride solution, unsaturated carbonate
Hydrogen sodium solution, the washing of 5% sodium chloride solution, separation organic phase is simultaneously dry with anhydrous sodium sulfate, then uses petroleum ether: ethyl acetate
=10:1 (v/v) crosses silicagel column as eluant, eluent, and the isolated white powder product that obtains is compound 13, and yield is
70%.
1H NMR (400MHz, CDCl3) δ 8.02 (d, J=7.7Hz, 1H), 7.55 (t, J=7.7Hz, 1H), 7.31 (t, J
=7.6Hz, 1H), 7.10 (d, J=8.0Hz, 1H), 5.42 (d, J=4.1Hz, 1H), 4.83 (tt, J=10.4,5.1Hz,
1H), 4.42 (dd, J=14.9,7.4Hz, 1H), 3.52-3.44 (m, 1H), 3.39 (t, J=10.9Hz, 1H), 2.51-2.40
(m, 2H), 2.36 (s, 3H), 2.00 (dd, J=14.8,9.9Hz, 3H), 1.94-1.84 (m, 2H), 1.07 (s, 3H), 0.98
(d, J=6.8Hz, 3H), 0.80 (d, J=5.2Hz, 6H).(M+Na+)=599.3349.
2. synthesize compound 14: brufen spirostan ester by compound 1 (414mg, 1mmol), brufen (247mg,
1.2mmol) it is dissolved in anhydrous methylene chloride (30mL) with DMAP (24mg, 0.2mmol) and stirs 10min and form solution A, it will
EDC.HCl (383mg, 2mmol) is dissolved in 5mL anhydrous methylene chloride and forms solution B, and solution B is slowly added dropwise at room temperature
Into solution A, 35~40 DEG C of reaction 8h or so are gradually heated to, TCL detects reaction process, and reaction is substantially completely.Gained is anti-
It answers liquid successively to be washed with 5% sodium chloride solution, saturated sodium bicarbonate solution, 5% sodium chloride solution, separates organic phase and with anhydrous
Sodium sulphate is dry, and then use petroleum ether: ethyl acetate=10:1 (v/v) crosses silicagel column, isolated white as eluant, eluent
Powdery product is compound 14, yield 93%.
1H-NMR (400MHz, CDCl3) δ: 7.20 (d, J=7.8Hz, 2H), 7.08 (d, J=7.7Hz, 2H), 5.34
(dd, J=15.8,4.2Hz, 1H), 4.63-4.55 (m, 1H), 4.40 (dd, J=14.8,7.4Hz, 1H), 3.67-3.62 (q, J
=7.0Hz, 1H), 3.48-3.45 (m, 1H), 3.37 (t, J=10.9Hz, 1H), 2.44 (d, J=7.1Hz, 2H).(M+Na+)
=625.4233.
3. synthesizing compound 15: Indomethacin spirostan ester
Compound 1 (414mg, 1mmol), Indomethacin (429mg, 1.2mmol) and DMAP (24mg, 0.2mmol) is molten
In anhydrous methylene chloride (30mL) and 10min formation solution A is stirred, it is anhydrous that EDC.HCl (383mg, 2mmol) is dissolved in 5mL
Methylene chloride forms solution B, and solution B is slowly added dropwise into solution A at room temperature, is gradually heated to 35~40 DEG C of reactions
8h or so, TCL detect reaction process, and reaction is substantially completely.Gained reaction solution is successively used into 5% sodium chloride solution, unsaturated carbonate
Hydrogen sodium solution, the washing of 5% sodium chloride solution, separation organic phase is simultaneously dry with anhydrous sodium sulfate, then uses petroleum ether: ethyl acetate
=10:1 (v/v) crosses silicagel column as eluant, eluent, and isolated product as yellow powder is compound 15, and yield is
82%.
1H NMR (400MHz, Chloroform-d) δ 7.64 (d, J=8.5Hz, 2H), 7.45 (d, J=8.5Hz, 2H),
6.96 (d, J=2.5Hz, 1H), 6.87 (d, J=9.0Hz, 1H), 6.65 (dd, J=9.0,2.5Hz, 1H), 5.34 (d, J=
5.0Hz, 1H), 4.60 (tdd, J=10.6,6.5,4.2Hz, 1H), 4.39 (td, J=7.7,6.4Hz, 1H), 3.45 (ddd, J
=10.8,4.5,1.9Hz, 1H), 1.96 (ddt, J=12.0,7.7,3.8Hz, 2H), 1.90-1.79 (m, 3H), 1.79-1.69
(m, 2H), 1.31-1.22 (m, 2H), 1.17-1.05 (m, 3H), 1.01 (s, 3H), 0.95 (d, J=7.0Hz, 3H), 0.77 (t,
J=3.2Hz, 6H).(M+H+)=754.3874.
4. synthesizing compound 16: naproxen spirostan ester
Compound 1 (414mg, 1mmol), naproxen (276mg, 1.2mmol) and DMAP (24mg, 0.2mmol) are dissolved in
In anhydrous methylene chloride (30mL) and 10min formation solution A is stirred, EDC.HCl (383mg, 2mmol) is dissolved in 5mL anhydrous two
Chloromethanes forms solution B, and solution B is slowly added dropwise into solution A at room temperature, is gradually heated to 35~40 DEG C of reaction 8h
Left and right, TCL detect reaction process, and reaction is substantially completely.Gained reaction solution is successively used into 5% sodium chloride solution, unsaturated carbonate hydrogen
Sodium solution and the washing of 5% sodium chloride solution, separation organic phase is dry with anhydrous sodium sulfate, then with petroleum ether: ethyl acetate=
10:1 (v/v) crosses silicagel column as eluant, eluent, and isolated white powder product is compound 16, yield 80%.
1H NMR (400MHz, Chloroform-d) δ 7.72-7.62 (m, 3H), 7.39 (dd, J=8.5,1.8Hz, 1H),
7.16-7.07 (m, 2H), 5.33-5.26 (m, 1H), 4.60 (tt, J=10.6,5.2Hz, 1H), 4.44-4.33 (m, 1H),
3.89 (s, 3H), 3.80 (q, J=7.1Hz, 1H), 3.51-3.42 (m, 1H), 3.36 (t, J=10.9Hz, 1H), 2.17 (dd, J
=12.3,3.8Hz, 2H), 1.95 (ddd, J=12.2,7.4,5.1Hz, 2H), 1.89-1.57 (m, 10H), 1.54 (d, J=
7.0Hz,3H),1.51–1.37(m,4H),1.33–1.19(m,3H),1.17–1.04(m,3H),0.99–0.92(m,6H),
0.82–0.70(m,6H)。(M+H+)=627.4049.
Embodiment 4
In the present embodiment, 26- hydroxyl furostan ester type compound is synthesized, compound 17~20 is specifically included.
1. synthesizing compound 17:26- hydroxyl-aspirin furostan ester
Compound 13 (577mg, 1mmol) is dissolved in anhydrous methylene chloride solution (50mL), it is completely molten wait be stirred at room temperature
Glacial acetic acid solution (30mL) is added after solution, is gradually heated to 35~40 DEG C and continues to stir 30min, cyano boron hydrogen is then added portionwise
Change sodium (NaBH3CN, 94mg, 1.5mmol), TLC detects reaction process.It reacts substantially completely, adds into gained reaction solution afterwards for 24 hours
Enter 30mL pure water to terminate reaction and stir 15min, then (each 20mL) three times is extracted with dichloromethane, collects and merge organic phase.
Gained organic phase is successively washed with 5% sodium chloride solution, saturated sodium bicarbonate solution and 5% sodium chloride solution, is collected organic
Xiang Bingyong anhydrous sodium sulfate is dry, and then use petroleum ether: ethyl acetate=4:1 (v/v) crosses silicagel column as eluant, eluent, separates
To white powder product be compound 17, yield 75%.
1H NMR (400MHz, Chloroform-d) δ 7.96 (ddd, J=15.6,7.8,1.7Hz, 1H), 7.83 (ddd, J
=12.5,8.0,1.8Hz, 1H), 7.59-7.46 (m, 1H), 7.45-7.36 (m, 1H), 5.34-5.28 (m, 1H), 3.33
(ddd, J=8.7,6.4,3.3Hz, 2H), 2.31-2.23 (m, 2H), 1.81 (d, J=3.8Hz, 3H), 1.63-1.41 (m,
10H), 1.22 (s, 3H), 1.01-0.94 (m, 6H), 0.94-0.81 (m, 6H), 0.76 (d, J=8.0Hz, 3H).(M+H+)=
579.3686。
2. synthesizing compound 18:26- hydroxyl-brufen furostan ester
Compound 14 (603mg, 1mmol) is dissolved in anhydrous methylene chloride solution (50mL), it is completely molten wait be stirred at room temperature
Glacial acetic acid solution (30mL) is added after solution, is gradually heated to 35~40 DEG C and continues to stir 30min, cyano boron hydrogen is then added portionwise
Change sodium (NaBH3CN, 94mg, 1.5mmol), TLC detects reaction process.It reacts substantially completely, adds into gained reaction solution afterwards for 24 hours
Enter 30mL pure water to terminate reaction and stir 15min, then (each 20mL) three times is extracted with dichloromethane, collects and merge organic phase.
Gained organic phase is successively washed with 5% sodium chloride solution, saturated sodium bicarbonate solution and 5% sodium chloride solution, is collected organic
Mutually dry with anhydrous sodium sulfate, then use petroleum ether: ethyl acetate=4:1 (v/v) crosses silicagel column as eluant, eluent, isolated
White powder product be compound 18, yield 82%.
1H NMR (400MHz, Chloroform-d) δ 7.17 (d, J=8.1Hz, 2H), 7.08-7.03 (m, 2H), 5.36-
5.26 (m, 1H), 4.57 (tdd, J=10.9,6.7,4.4Hz, 1H), 3.51-3.36 (m, 2H), 3.31 (td, J=8.1,
4.0Hz, 1H), 2.42 (d, J=7.2Hz, 2H), 2.33-2.25 (m, 1H), 2.19 (d, J=6.6Hz, 1H), 2.05-1.90
(m, 4H), 1.88-1.78 (m, 2H), 1.78-1.66 (m, 3H), 0.88 (t, J=6.8Hz, 9H), 0.78 (s, 3H).(M+H+)
=605.4570.
3. synthesizing the pungent furostan ester of compound 19:26- hydroxy-indole U.S.
Compound 15 (754mg, 1mmol) is dissolved in anhydrous methylene chloride solution (50mL), it is completely molten wait be stirred at room temperature
Glacial acetic acid solution (30mL) is added after solution, is gradually heated to 35~40 DEG C and continues to stir 30min, cyano boron hydrogen is then added portionwise
Change sodium (NaBH3CN, 94mg, 1.5mmol), TLC detects reaction process.It reacts substantially completely, adds into gained reaction solution afterwards for 24 hours
Enter 30mL pure water to terminate reaction and stir 15min, then (each 20mL) three times is extracted with dichloromethane, collects and merge organic phase.
Gained organic phase is successively washed with 5% sodium chloride solution, saturated sodium bicarbonate solution and 5% sodium chloride solution, is collected organic
Mutually dry with anhydrous sodium sulfate, then use petroleum ether: ethyl acetate=4:1 (v/v) crosses silicagel column as eluant, eluent, isolated
Product as yellow powder be compound 19, yield 88%.
1H NMR (400MHz, Chloroform-d) δ 7.64 (d, J=8.5Hz, 2H), 7.44 (d, J=8.5Hz, 2H),
6.95 (d, J=2.5Hz, 1H), 4.60 (ddt, J=15.9,7.1,4.1Hz, 1H), 4.28 (td, J=7.7,5.2Hz, 1H),
3.82 (s, 3H), 3.61 (s, 2H), 3.51-3.38 (m, 2H), 3.31 (td, J=8.1,4.0Hz, 1H), 2.35 (s, 3H),
1.15-1.05 (m, 3H), 1.01 (s, 3H), 0.97 (d, J=6.7Hz, 3H), 0.89 (d, J=6.8Hz, 3H), 0.78 (s,
3H)。(M+H+)=756.4031.
4. synthesizing compound 20:26- hydroxyl-naproxen furostan ester
Compound 16 (627mg, 1mmol) is dissolved in anhydrous methylene chloride solution (50mL), it is completely molten wait be stirred at room temperature
Glacial acetic acid solution (30mL) is added after solution, is gradually heated to 35~40 DEG C and continues to stir 30min, cyano boron hydrogen is then added portionwise
Change sodium (NaBH3CN, 94mg, 1.5mmol), TLC detects reaction process.It reacts substantially completely, adds into gained reaction solution afterwards for 24 hours
Enter 30mL pure water to terminate reaction and stir 15min, then (each 20mL) three times is extracted with dichloromethane, collects and merge organic phase.
Gained organic phase is successively washed with 5% sodium chloride solution, saturated sodium bicarbonate solution and 5% sodium chloride solution, is collected organic
Mutually dry with anhydrous sodium sulfate, then use petroleum ether: ethyl acetate=4:1 (v/v) crosses silicagel column as eluant, eluent, isolated
Product as yellow powder be compound 20, yield 82%.
1H NMR (400MHz, Chloroform-d) δ 7.71-7.62 (m, 3H), 7.39 (dd, J=8.5,1.9Hz, 1H),
7.16-7.05 (m, 2H), 5.28 (d, J=5.0Hz, 1H), 43.89 (s, 3H), 3.79 (q, J=7.1Hz, 1H), 3.48 (d, J
=23.5Hz, 2H), 3.31 (td, J=8.0,3.8Hz, 1H), 2.23-2.12 (m, 2H), 2.06-1.89 (m, 3H), 1.88-
1.77 (m, 3H), 1.76-1.62 (m, 4H), 1.37-1.21 (m, 3H), 1.14-1.02 (m, 3H), 0.89 (d, J=6.5Hz,
3H),0.77(s,3H)。(M+H+)=629.4206.
Embodiment 5
In the present embodiment, tests the derivative provided by the invention containing pentamethylene and more hydrogen phenanthrene class skeletons and ADP is induced
Internal platelet aggregation influence.
Male Balb/c mouse is taken, it is random to be grouped, every group 10.Before detecting platelet aggregation, each group mouse difference
Gastric infusion is intervened 7 days in advance.The dosage of 1~compound of compound 20 is 100mg/kg/d, is administered twice a day；A Si
The dosage of woods is 30mg/kg/d, is administered twice a day；Also phase is given in stomach-filling simultaneously for blank control group and model control group
The solvent PBS of same volume.Experiment evening before that day is deprived of food but not water experiment mice.Amobarbital is injected intraperitoneally in experimental day
Sodium solution (40mg/kg) is by Balb/c mouse anesthesia, heart puncturing extracting blood, and with the ratio of volume ratio 9:1 immediately with 3.8% Chinese holly
Rafter acid sodium anti-coagulants mixes.Mixed plasma sample is taken into supernatant with 100g centrifugation 10min, obtains platelet rich plasma (PRP),
Remaining blood sample takes supernatant again with 1000g centrifugation 5min, obtains platelet poor plasma (PPP), and finally diluting adjustment PRP with PPP makes blood
Platelet number is 2 × l06Blood platelet/μ L.Platelet aggregation is measured using LBY-NJ4 platelet aggregation instrument, uses micro syringe
Final concentration of 20 μM of the ADP of 20 μ L is added, observes and records curve of platelet aggregation figure and maximum concentration class in 5min.
Embodiment 6
In the present embodiment, the derivative provided by the invention containing pentamethylene and more hydrogen phenanthrene class skeletons is tested to collagen-kidney
The influence of the mouse pulmonary embolism of upper parathyrine induction.
Male Balb/c mouse, it is random to be grouped, every group 10.Before constructing pulmonary embolism model, each group mouse shifts to an earlier date respectively
Gastric infusion is intervened 7 days.The dosage of 1~compound of compound 20 is 100mg/kg/d, is administered twice a day；Aspirin
Dosage be 30mg/kg/d, be administered twice a day；Also same volume is given in stomach-filling simultaneously for blank control group and model control group
Long-pending solvent PBS.Experiment evening before that day is deprived of food but not water experiment mice.Experimental day is logical with the speed of about 20 μ L/s
Balb/c mouse tail vein injection embolism inducer (0.45mg/kg adrenaline and 3mg/kg collagen) is crossed to induce lung bolt
Plug, then observes and records the quantity of dead mouse or paralysis, finally calculates pulmonary embolism protective rate.
In embodiment 5 and 6,1~compound of compound 20 and aspirin are to the ADP platelet aggregation induced and glue
The influence of original-adrenaline induction pulmonary embolism is as shown in table 1, and the numerical value in table 1 is indicated with testing mean+/-standard error
(n=10).
As shown in Table 1, the derivative Dioscin derivative provided by the invention containing pentamethylene and more hydrogen phenanthrene class skeletons
It can inhibit platelet aggregation in ADP inducing mouse body, can also protect collagen and adrenalin inducing mouse pulmonary embolism, and of the same race
Compound is strong to internal Platelet aggregation inhibitor effect, also strong to mouse pulmonary embolism protective effect.Relative to aspirin and potato
For Chinese yam sapogenin (compound 1), compound 4~12,17~20 provided by the invention inhibits blood platelet in ADP inducing mouse body
The effect of aggregation and the effect of protection collagen and adrenalin inducing mouse pulmonary embolism are obviously more preferable, disclose compared with the prior art
The compound 13 with antithrombotic acitivity for, compound 17~20 provided by the invention inhibits blood in ADP inducing mouse body
The activity of platelet aggregation and the activity of protection collagen and adrenalin inducing mouse pulmonary embolism, which have, to be significantly improved.
Derivative of the table 1 containing pentamethylene and more hydrogen phenanthrene class skeletons is to the ADP platelet aggregation induced and collagen-adrenal gland
The influence of the pulmonary embolism of element induction
Embodiment 7
In the present embodiment, influence of the compound 18 provided by the invention to rat carotid artery thrombus model is tested.
Male SD rat, experiment is at least raised 7 days before starting in feeding standard environment, if adaptation process is not observed not
Good reaction is then randomly divided into 4 groups, is model group, diosgenin (compound 1) group, 18 groups of compound and positive drug respectively
Aspirin group, every group 10.It is dry that the SD rat of administration group gives diosgenin, compound 18 and aspirin in advance respectively
Pre- 7 days.Diosgenin dosage is 100mg/kg/d, twice daily；18 dosage of compound is 100mg/kg/d, often
Day is twice；Aspirin dosage is 30mg/kg/d, twice daily.Model group gives the drug dissolving medium of same volume
Pure water, twice daily.After last dose 2h, intraperitoneal injection Nembutal sodium solution (40mg/kg) is by rat anesthesia, completely to it
After anesthesia, line position is hit exactly along SD rat neck, its outer skin is cut with surgical scissors, is then gone out with tweezers blunt separation
Rats with left arteria carotis communis, length of vessel about expose 1.3cm, the envelope of 1.1cm × 1.1cm size are then put into strata submucosum
Membrana oralis, then with 10 μ L20%FeCl3Solution will be infiltrated having a size of the filter paper item of 0.8cm × 1.0cm, and filter paper ring is wrapped up in exposure
Arteria carotis communis out, finally uses ParafilmTM.Filter paper item is removed after crossing 30min, the appropriate physiological saline of supplement in rat body,
90min is waited to allow thrombosis.Filter paper both ends blood vessel is ligatured with suture, prolongs the blood vessel that filter paper item package is accurately cut at edge
Section is placed on dried and clean filter paper and blots intravascular remaining blood, after carefully removing connective tissue of blood vessels, with slide calliper rule precise measurement thrombus
Length and the thrombus weight that weighs with scale.
Embodiment 8
In the present embodiment, influence of the compound 18 provided by the invention to rat inferior vena cava thrombosis model is tested.
Male SD rat, experiment is at least raised 7 days before starting in feeding standard environment, if adaptation process is not observed not
Good reaction is then randomly divided into 4 groups, is model group, diosgenin (compound 1) group, 18 groups of compound and positive drug respectively
Aspirin group, every group 10.It is dry that the SD rat of administration group gives diosgenin, compound 18 and aspirin in advance respectively
Pre- 7 days.Diosgenin dosage is 100mg/kg/d, twice daily；18 dosage of compound is 100mg/kg/d, often
Day is twice；Aspirin dosage is 30mg/kg/d, twice daily.Model group gives the drug dissolving medium of same volume
Pure water, twice daily.After last dose 2h, intraperitoneal injection Nembutal sodium solution (40mg/kg) is by rat anesthesia, completely to it
After anesthesia, allows SD rat on operation towel in appearance of lying on the back, and sterilize, preserved skin, cut length using scalpel in lower abdomen center position
The stringer notch of 3cm-4cm, appears abdominal cavity, moves to outside abdominal cavity part small intestine with cotton swab, and cover sterile gauze, uses physiology salt
Water-soaked then uses tweezers blunt separation Rat renal lower section inferior caval vein to prevent small intestine dehydration.After the separation of left kidney inferior caval vein,
It is ligatured, is knotted after completing ligation twice below inferior caval vein with operation suture thread, whether there is or not bleedings for observation rat abdominal cavity.It builds
Mould for 24 hours after, carry out out abdomen to it, separation inferior caval vein simultaneously cuts the thrombosed vessel segment below ligature, is placed in drying
On clean filter paper, after carefully removing connective tissue of blood vessels, with slide calliper rule precise measurement thrombus length and the thrombus weight that weighs with scale.
The result of embodiment 7 and 8 is as shown in Figure 1, in embodiment 7, model control group, Dioscin tuple, compound 18
Group, positive drug aspirin group be formed by arterial thrombus weight and length (weight, length) be respectively (11.0 ± 0.4mg,
13.5 ± 0.4mm), (9.4 ± 0.5mg, 11.7 ± 0.6mm), (5.6 ± 0.3mg, 6.6 ± 0.4mm) and (7.6 ± 0.5mg,
9.6 ± 0.8mm), A figure and B figure in Fig. 1 are the weight of the arterial thrombus of each group rat and length testing result in embodiment 7.
In embodiment 8, model control group, Dioscin tuple, 18 groups of derivative, positive drug aspirin group are formed by venous blood
Bolt weight and length (weight, length) be respectively (16.9 ± 1.0mg, 13.5 ± 0.6mm), (12.5 ± 0.8mg, 10.2 ±
0.5mm), (7.9 ± 0.6mg, 6.4 ± 0.3mm) and (10.2 ± 0.7mg, 8.7 ± 0.5mm), C figure and D figure in Fig. 1 are reality
Apply the weight and length of the phlebothrombosis of each group rat in example 8.Numerical value is indicated in figure with mean value ± SED, n=8-10, * P <
0.05vs Model,#P<0.05vs Diosgenin and Aspirin。
As shown in Figure 1, compound 18 provided by the invention is able to suppress FeCl3The SD rat carotid artery thrombus shape of induction
At with obvious antithrombotic effect, and the activity of the anti-Arterial thrombosis of compound 18 is compared with parent nucleus diosgenin and the positive
Drug aspirin is compared and is significantly improved.Meanwhile compound 18 is able to suppress phlebothrombosis shape caused by Ligation of inferior vena cava
At with obvious antithrombotic effect, and the activity of the anti-Arterial thrombosis of compound 18 is compared with parent nucleus diosgenin and the positive
Drug aspirin is compared and is significantly improved.
Embodiment 9
In the present embodiment, investigates the derivative provided by the invention containing pentamethylene and more hydrogen phenanthrene class skeletons and cerebral infarction is changed
Kind effect.
Adult healthy male SD rat only, at least raise in feeding standard environment before starting by 300~350g of weight, experiment
It is 7 days, random to be grouped if adaptation process does not observe adverse reaction, every group 10.Carrying out modeling operation consent, each group mouse point
Indescribably preceding gastric infusion is intervened 7 days.The dosage of 1~compound of compound 20 is 100mg/kg/d, is administered twice a day；Ah
The dosage for taking charge of a woods is 30mg/kg/d, is administered twice a day；Model group is given once daily isometric molten in the same way
Medium pure water.7th day evening carried out fasting (can't help water) to experiment SD rat.8th day, after last dose 1h, abdominal cavity note
Penetrate 10% chloraldurate 1.0-1.5mL (dosage 0.3mL/kg) anesthetized rat.Using improvement Zea-Longa line brush production
Middle cerebral artery occlusion (middle cerebralartery occlusion, MCAO) model on the right side of rat.Model is included in standard
Survival 6h or more after SD rat modeling, postoperative 12h sampling do TCC dyeing, detect infarction of brain area.
The knot of derivative rat cerebral infarction area reduced rate provided by the invention containing pentamethylene and more hydrogen phenanthrene class skeletons
Fruit is as shown in table 2, and the numerical value in table 2 indicates (n=10) to test mean+/-standard error.
As shown in Table 2, the derivative Dioscin derivative provided by the invention containing pentamethylene and more hydrogen phenanthrene class skeletons
Rat cerebral infarction area can be reduced.For aspirin and diosgenin (compound 1), chemical combination provided by the invention
Object 4~12,17~20 can effectively reduce rat cerebral infarction area, compared with the prior art the disclosed chemical combination with antithrombotic acitivity
For object 13, the improvement result of 10,17,18,20 pairs of rat cerebral infarctions of compound provided by the invention is more preferable.
Influence of derivative of the table 2 containing pentamethylene and more hydrogen phenanthrene class skeletons to rat cerebral infarction model
Embodiment 10
In the present embodiment, investigates the derivative provided by the invention containing pentamethylene and more hydrogen phenanthrene class skeletons and heart infarction is changed
Kind effect.
SPF grades of male C57BL/6 mouse, experiment is at least raised 7 days before starting in feeding standard environment, if adaptation process
Adverse reaction is not observed, it is random to be grouped, every group 10.Modeling operation consent is being carried out, each group mouse shifts to an earlier date gastric infusion respectively
Intervene 7 days.The dosage of 1~compound of compound 20 is 100mg/kg/d, is administered twice a day；Aspirin gives medicament
Amount is 30mg/kg/d, is administered twice a day；Isometric solvent medium pure water is given once daily in model group in the same way.
7th day evening carried out fasting (can't help water) to experiment SD rat.
8th day, after last dose 1h, C57BL/6 mouse took dorsal position after 3.0% isoflurane inhalation anesthesia, head and
Four limbs are fixed on operating table, and four limbs coat conducting resinl and are fixed on electrode, real using MPA biological signal collecting analysis system
When monitor mouse physiological indexes.Enter carry out trachea cannula from oral cavity using No. 20 canula puncture needle stylophores, is intubated successfully
Afterwards, connection anesthetic gas machine maintains anesthesia.After being intubated and anaesthetize successfully, left chest depilation, along left chest the 2nd, 3 intercostal incision skins
Skin, intercostal muscle open thoracic cavity, cut off pericardium and sufficiently expose heart.It is to indicate with left auricle of heart lower edge, under left auricle of heart root
2~3mm noninvasive suture of 6-0 passes through coronary artery left anterior descending branch, and depth of needle 0.8mm ligatures coronary artery slowly with the anti-tear heart
Flesh.Observe local myocardial variation (the left outdoor film of 1min or so is in pale) after ligation and ST sections of dynamic ecg monitoring raise or
It forces down, it was initially believed that modeling successfully.Then, conventional to close thoracic cavity and squeeze mouse thoracic cavity in last close, avoid the formation of gas
Chest pulls out trachea cannula after heartbeating recovery is normal.The heat preservation of mouse Postoperative and prevention infection.Sham-operated control group opens chest
Afterwards, the noninvasive suture of 6-0 passes through coronary artery left anterior descending branch, but does not ligature, and other operations are consistent with heart infarction operation.
The knot of derivative mouse brain infarction area reduced rate provided by the invention containing pentamethylene and more hydrogen phenanthrene class skeletons
Fruit is as shown in table 3, and the numerical value in table 3 indicates (n=10) to test mean+/-standard error.
As shown in Table 3, the derivative Dioscin derivative provided by the invention containing pentamethylene and more hydrogen phenanthrene class skeletons
Mouse heart infarct size can be reduced.For aspirin and diosgenin (compound 1), provided by the inventionization
Mouse heart infarct size can be reduced by closing object 4~12,17~20, compared with the prior art the disclosed chemical combination with antithrombotic acitivity
For object 13, the improvement result of 17,18,20 pairs of mouse hearts of compound stalk provided by the invention is more preferable.
Influence of derivative of the table 3 containing pentamethylene and more hydrogen phenanthrene class skeletons to rat cerebral infarction model
Claims (7)
1. the derivative containing pentamethylene and more hydrogen phenanthrene class skeletons, which is characterized in that the structural formula of the derivative such as formula (I) institute
Show or derivative be formula (I) compound represented pharmaceutically acceptable salt,
In formula (I), R1For or R1From non-steroidal anti-inflammatory drugs, R2For hydroxyl or R2From non-steroidal anti-inflammatory drugs.
2. the derivative containing pentamethylene and more hydrogen phenanthrene class skeletons according to claim 1, which is characterized in that the non-steroidal
Anti-inflammatory agent includes aspirin, brufen, Indomethacin, naproxen and Diclofenac.
3. the derivative containing pentamethylene and more hydrogen phenanthrene class skeletons according to claim 2, which is characterized in that in formula (I), R1
For acetoxyl group,OrR2For
Hydroxyl,Or
4. the derivative containing pentamethylene and more hydrogen phenanthrene class skeletons according to claim 3, which is characterized in that the pentamethylene is simultaneously
More hydrogen phenanthrene framework compounds are any one in following compounds 4~12,17~20, or are following compounds 4~12,17
Any one pharmaceutically acceptable salt in~20:
5. special according to claim 1 to the derivative described in any claim in 3 containing pentamethylene and more hydrogen phenanthrene class skeletons
Sign is, formula (I) compound represented pharmaceutically acceptable salt, be in formula (I) compound represented any one with
Hydrochloric acid, hydrobromic acid, sulfuric acid, carbonic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methylsulphur
The addition salts that acid, benzene sulfonic acid, p-methyl benzenesulfonic acid or ferulic acid are formed.
6. the derivative in claim 1 to 5 containing pentamethylene and more hydrogen phenanthrene class skeletons described in any claim is anti-in preparation
Control the application in the drug of infarct disease.
7. application according to claim 6, which is characterized in that the drug of the infarct disease of prevention and treatment includes that anti-blood is small
Plate drug and antithrombotic reagent.
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