CN102659609A - Fenofibric acid salt, and preparation method, application and medicinal composition thereof - Google Patents
Fenofibric acid salt, and preparation method, application and medicinal composition thereof Download PDFInfo
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- CN102659609A CN102659609A CN2012101539532A CN201210153953A CN102659609A CN 102659609 A CN102659609 A CN 102659609A CN 2012101539532 A CN2012101539532 A CN 2012101539532A CN 201210153953 A CN201210153953 A CN 201210153953A CN 102659609 A CN102659609 A CN 102659609A
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- fenofibrate
- hydrochlorate
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- MQOBSOSZFYZQOK-UHFFFAOYSA-N CC(C)(C(O)=O)Oc(cc1)ccc1C(c(cc1)ccc1Cl)=O Chemical compound CC(C)(C(O)=O)Oc(cc1)ccc1C(c(cc1)ccc1Cl)=O MQOBSOSZFYZQOK-UHFFFAOYSA-N 0.000 description 2
- MQOBSOSZFYZQOK-UHFFFAOYSA-M CC(C)(C([O-])=O)Oc(cc1)ccc1C(c(cc1)ccc1Cl)=O Chemical compound CC(C)(C([O-])=O)Oc(cc1)ccc1C(c(cc1)ccc1Cl)=O MQOBSOSZFYZQOK-UHFFFAOYSA-M 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N C1NCCOC1 Chemical compound C1NCCOC1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 1
- NZTPDPGOXTXWSX-UHFFFAOYSA-M CC(C)(C([O-])=O)Oc(cc1)ccc1C(c(cc1)ccc1I)=O Chemical compound CC(C)(C([O-])=O)Oc(cc1)ccc1C(c(cc1)ccc1I)=O NZTPDPGOXTXWSX-UHFFFAOYSA-M 0.000 description 1
- LHIJANUOQQMGNT-UHFFFAOYSA-N NCCNCCO Chemical compound NCCNCCO LHIJANUOQQMGNT-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N OCCN(CCO)CCO Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- XBRDBODLCHKXHI-UHFFFAOYSA-N OCCN1CCCC1 Chemical compound OCCN1CCCC1 XBRDBODLCHKXHI-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention provides a fenofibric acid salt, and a preparation method, application and a medicinal composition thereof. The fenofibric acid salt is prepared by reacting fenofibric acid and amine. The preparation method comprises the following steps: dissolving the fenofibric acid in a solvent, adding the amine into the solution after the fenofibric acid is completely dissolved, and performing reflux reaction; and after the reaction is finished, concentrating, recrystalizing, or free-drying by using a freeze dryer to obtain the fenofibric acid salt. The medicinal composition is prepared from the fenofibric acid salt and an adjuvant. The fenofibric acid salt can be used for preparing medicines for treating hyperlipidemia disease, and has high water solubility, a hypolipidemic medicinal effect and a good application prospect.
Description
Technical field
The present invention relates to medical technical field, more specifically relate to the fenofibrate hydrochlorate, with and pharmaceutical composition.
Background technology
Hyperlipidemia is a kind of systemic disease, is meant that blood cholesterol (TC) and/or triglyceride level (TG) are too high or high density lipoprotein cholesterol (HDL-C) is low excessively.This disease to the infringement of health be concealment, gradually, carrying out property and general.A large amount of research datas show that hyperlipidemia is the Hazard Factor of apoplexy, coronary heart disease, myocardial infarction, sudden death.In addition, hyperlipidemia also is an important risk factor that promotes hypertension, IGT, mellitus.Hyperlipidemia also can cause fatty liver, liver cirrhosis, cholelithiasis, pancreatitis, retinal hemorrhage, blind, peripheral vascular disease, limping, hyperuricemia.So must pay much attention to the harm of hyperlipidemia, prevent energetically and treat.
Fenofibrate has the effect of tangible reduction serum cholesterol, triglyceride level and high density lipoprotein increasing, has obtained widespread use clinically, is one of choice drug of treating at present hyperlipidemia, and annual sales amount is above 1,000,000,000 dollars.
Though the peculiar good curative effect of FENOBRATE, owing in water, do not dissolve, dissulution is not enough, causes oral artifact availability low.At digestive tube, its oral post-absorption only has an appointment 60%.Its bioavailability is incomplete, and varies with each individual, and difference between individuals is bigger.It can be absorbed well when " feed state " descends administration, and relatively poor in " fasting state " next absorption.Require generally speaking to use to improve bioavailability with food.
Fenofibrate acid is fenofibrate meta-bolites in vivo, also is the activity form of medicine, has the effect of tangible reduction serum TC, TG and rising HDL-C level, and good accent fat effect.
In order to solve the low problem of fenofibrate bioavailability; Prior art has been carried out huge effort; As: on December 15th, 2008; Drugs approved by FDA the fenofibrate acid choline salt enteric-soluble controlled-release capsule (Trilipix) of Abbott, be used for reduce fat disease patient's triglyceride level (TG) and low-density lipoprotein (LDL), high density lipoprotein increasing (HDL).Trilipix is first and unique so far special similar drug of shellfish of getting permission to unite with statins use.Trilipix has good absorption at whole gi tract, and absolute bioavailability reaches 81%.Under fasted conditions, single oral dose Trilipix, Plasma Concentration reached the peak in 4 ~ 5 hours.
US 2009/0263477 A1 discloses the physiologically acceptable salt of a series of fenofibrate acid, comprises 1) fenofibrate acid choline salt; 2) fenofibrate acid diethanolamine salt; 3) fenofibrate acid tromethamine salt; 4) fenofibrate acid sodium-salt; 5) fenofibrate acid calcium salt; 6) fenofibrate acid ethanolamine salt; 7) fenofibrate acid Portugal first ammonia salt; 8) fenofibrate acid L-lysine salt; 9) fenofibrate mcpp acid salt.The physiologically acceptable salt of fenofibrate acid becomes the focus of research and development.
CN102304103A discloses the preparation and the application of a series of fenofibrate acid firsts and seconds aminopropanol salt, and has studied the water-soluble of such fenofibrate acid aminopropanol salt emphatically.
In present report; The physiologically acceptable ammonia salt of fenofibrate acid mainly comprises fenofibrate acid one-level amino and the amino ethylate of secondary and propylated and fenofibrate acid level Four ammonium ethylate, and fenofibrate acid tertiary amine base ethylate does not have relevant report as yet.
Summary of the invention
For overcoming the problems referred to above of the prior art, the invention provides the good fenofibrate hydrochlorate of a kind of water capacity property, and its production and application, with and pharmaceutical composition.
The technical scheme that the present invention adopts is: a kind of fenofibrate hydrochlorate, and it is made by fenofibrate acid and amine reaction, and this Fei Beite hydrochlorate has the general structure as shown in the formula (I),
Formula (I)
Wherein, R
1, R
2Be independently selected from methyl, ethyl, hydroxyethyl respectively; Perhaps,
R
1, R
25 ~ 6 yuan of rings for linking to each other and forming can have 1 ~ 2 N or O heteroatoms in these 5 ~ 6 yuan of rings.
Further, above-mentioned fenofibrate hydrochlorate is selected from: fenofibrate acid dimethylaminoethanol salt, fenofibrate acid N-(2-hydroxyethyl) alkylbenzyldimethylasaltsum saltsum, fenofibrate acid N-(2-hydroxyethyl) pyrrolidinium, fenofibrate triethylenetetraminehexaacetic acid alcohol amine salt, fenofibrate acid diethylaminoethanol salt.
The present invention also provides a kind of fenofibrate acid dimethylaminoethanol salt crystal, and it has the chemical structural formula as shown in the formula (II):
Formula (II).
Above-mentioned fenofibrate acid dimethylaminoethanol salt crystalline powder X-ray-diffractogram is as shown in Figure 1.
Further, above-mentioned fenofibrate acid dimethylaminoethanol salt crystal is a single crystal structure, belongs to oblique system, and spacer is P2
1/ c, unit cell parameters:
β=92.094 (2) °, unit cell volume
Molecule number Z=8 in the structure cell, uptake factor μ=0.217mm
-1
The present invention further provides the preparation method of above-mentioned fenofibrate hydrochlorate, and this method may further comprise the steps: fenofibrate acid is dissolved in the solvent, after treating to dissolve fully, in gained solution, adds amine, and carry out back flow reaction; After reaction finishes, concentrate, recrystallization or use the Freeze Drying Equipment freeze-drying, obtain the fenofibrate hydrochlorate.
Further, above-mentioned solvent is selected from one or more in ETHYLE ACETATE, chloroform, methylene dichloride, methyl alcohol, ethanol, acetone, ether and the MTBE.
Preferably, in above-mentioned preparation method, the mol ratio of Procetofenic acid and amine is 1:0.9 ~ 1:1.3, and wherein, the mol ratio of fenofibrate acid and amine is 1:1 ~ 1:1.2 more preferably.
The present invention provides a kind of pharmaceutical composition that comprises above-mentioned fenofibrate hydrochlorate again further, and this pharmaceutical composition is processed by fenofibrate hydrochlorate and auxiliary.
Preferably, above-mentioned auxiliary be selected from starch, amylum pregelatinisatum, dextrin, Icing Sugar, lactose, N.F,USP MANNITOL, calcium sulfate two water things, secondary calcium phosphate, Natural manganese dioxide, lime carbonate, sal epsom, syrup, Microcrystalline Cellulose, Xylo-Mucine, Vltra tears, low-substituted hydroxypropyl cellulose, sodium starch glycolate, magnesium laurylsulfate and the micropowder silica gel any one or multiple.
The present invention also provides a kind of above-mentioned fenofibrate hydrochlorate to be used for treating the application of the medicine of hyperlipidemia disease in preparation more in addition.But metabolism went out the acid of activeconstituents fenofibrate after fenofibrate hydrochlorate of the present invention absorbed in vivo, therefore can be used for preparing the medicine of treatment hyperlipidemia disease.
Compare with fenofibrate acid commonly used at present, the solubleness of fenofibrate hydrochlorate provided by the invention in water significantly improves, and the solubleness in the 1ml pure water reaches as high as more than the 36.0mg all greater than 5mg.
Compared with prior art; The present invention has advantage: the invention provides a series of physiologically acceptable fenofibrate hydrochlorates, it has better water solubility, therefore is absorbed by the body easily; The also corresponding obvious raising of bioavailability has application promise in clinical practice.
Description of drawings
Fig. 1 is for being fenofibrate acid dimethylaminoethanol salt crystalline powder X-ray-diffraction (XRPD) figure in the embodiment of the invention 1;
Fig. 2 is the crystalline structure figure for fenofibrate acid dimethylaminoethanol single-crystal of salt in the embodiment of the invention 1;
Fig. 3 is the structure cell accumulation graph for fenofibrate acid dimethylaminoethanol single-crystal of salt in the embodiment of the invention 1.
Embodiment
Below in conjunction with accompanying drawing and specific embodiment the present invention is done further explain.
Synthesizing of fenofibrate acid dimethylaminoethanol salt
With fenofibrate acid (500mg 1.569mmol) is dissolved in the methyl alcohol (20mL), treat the solid dissolving after, cooling; (140mg 1.569mmol), refluxed 2 hours to add dimethylaminoethanol; Concentrate, get white solid (510mg, 80% yield) with the toluene recrystallization.MP:142-143℃。
1H-NMR(DMSO,400MHZ):1.54(s,6H),2.40(s,6H),2.65(t,2H),3.55(t,2H),6.91(d,2H,J=8.4),7.60(d,2H,J=8.4),7.68(m,4H)。
Fenofibrate acid dimethylaminoethanol salt crystal, this crystalline powder X-ray-diffractogram is as shown in Figure 1, and each peak ownership is as follows:
Fenofibrate acid dimethylaminoethanol single-crystal of salt carries out the test of X-ray single crystal diffraction to this monocrystalline, identifies its structure, confirms that through structure elucidation the structural formula of this monocrystalline is:
Said monocrystalline belongs to oblique system, and spacer is P2
1/ c, unit cell parameters:
β=92.094 (2) °, unit cell volume
Molecule number Z=8 in the structure cell, uptake factor μ=0.217mm
-1The crystalline structure figure of this monocrystalline is as shown in Figure 2, and the structure cell accumulation graph of this monocrystalline is as shown in Figure 3.The actual crystal parameter sees table:
Table 1 crystal data and structural modifications data (Crystal data and structure refinement)
Table 2 atomic coordinate and anisotropic parameters (Atomic coordinates (* 10
4) and equivalent isotropic displacement parameters
U
EqIs defined as one third of the trace of the orthogonalized U
IjTensor.)
| x | y | z | U eq | |
| Cl(1) | 4914(1) | 12725(1) | 1677(1) | 38(1) |
| Cl(2) | -49(1) | 12653(1) | 3422(1) | 38(1) |
| N(1) | 2657(2) | 5815(4) | 6503(4) | 38(1) |
| N(2) | 2272(1) | 4167(3) | 2147(3) | 23(1) |
| O(1) | 6264(1) | 11471(3) | 6075(3) | 28(1) |
| O(2) | 6200(1) | 6275(3) | 6661(2) | 22(1) |
| O(3) | 6436(2) | 4738(3) | 4250(3) | 35(1) |
| O(4) | 6910(1) | 5758(3) | 5332(3) | 39(1) |
| O(5) | 1212(1) | 11422(3) | -896(3) | 29(1) |
| O(6) | 1274(1) | 6250(3) | -1437(2) | 21(1) |
| O(7) | 1467(1) | 4578(3) | 968(2) | 20(1) |
| O(8) | 1942(1) | 5814(3) | 193(3) | 26(1) |
| O(9) | 2342(2) | 7309(4) | 4450(4) | 49(1) |
| O(10) | 2678(2) | 2131(4) | 994(4) | 64(2) |
| C(1) | 5374(2) | 10664(4) | 4033(4) | 19(1) |
| C(2) | 5109(2) | 11130(4) | 3176(4) | 21(1) |
| C(3) | 5233(2) | 12169(4) | 2797(4) | 22(1) |
| C(4) | 5610(2) | 12766(4) | 3257(4) | 22(1) |
| C(5) | 5869(2) | 12300(4) | 4121(4) | 21(1) |
| C(6) | 5761(2) | 11239(3) | 4515(3) | 15(1) |
| C(7) | 6054(2) | 10806(4) | 5465(4) | 18(1) |
| C(8) | 6088(2) | 9590(3) | 5695(3) | 16(1) |
| C(9) | 6053(1) | 8761(4) | 4900(3) | 15(1) |
| C(10) | 6096(2) | 7642(4) | 5177(3) | 15(1) |
| C(11) | 6170(2) | 7335(4) | 6267(3) | 17(1) |
| C(12) | 6220(2) | 8161(4) | 7061(3) | 20(1) |
| C(13) | 6180(2) | 9273(4) | 6779(4) | 20(1) |
| C(14) | 6132(2) | 5312(4) | 5957(3) | 17(1) |
| C(15) | 6517(2) | 5290(4) | 5084(4) | 22(1) |
| C(16) | 6241(2) | 4344(4) | 6732(4) | 19(1) |
| C(17) | 5620(2) | 5239(4) | 5513(4) | 28(1) |
| C(18) | 369(2) | 10607(4) | 1090(3) | 17(1) |
| C(19) | 119(2) | 11067(4) | 1937(4) | 20(1) |
| C(20) | 254(2) | 12106(4) | 2323(4) | 22(1) |
| C(21) | 627(2) | 12693(4) | 1890(4) | 24(1) |
| C(22) | 871(2) | 12232(4) | 1046(4) | 21(1) |
| C(23) | 748(1) | 11182(3) | 640(3) | 15(1) |
| C(24) | 1017(2) | 10751(4) | -310(3) | 19(1) |
| C(25) | 1049(1) | 9539(4) | -540(4) | 17(1) |
| C(26) | 1139(2) | 9224(4) | -1609(4) | 19(1) |
| C(27) | 1205(2) | 8118(4) | -1883(3) | 18(1) |
| C(28) | 1189(1) | 7294(3) | -1074(3) | 14(1) |
| C(29) | 1097(2) | 7600(4) | -12(3) | 17(1) |
| C(30) | 1030(1) | 8710(4) | 247(3) | 16(1) |
| C(31) | 1204(2) | 5271(4) | -764(3) | 19(1) |
| C(32) | 1566(2) | 5247(3) | 221(3) | 16(1) |
| C(33) | 682(2) | 5156(4) | -461(4) | 24(1) |
| C(34) | 1352(2) | 4309(4) | -1504(4) | 24(1) |
| C(35) | 2752(2) | 7349(5) | 5117(5) | 44(2) |
| C(36) | 2703(2) | 7013(5) | 6350(5) | 47(2) |
| C(37) | 2690(2) | 5474(7) | 7648(5) | 58(2) |
| C(38) | 2186(2) | 5366(6) | 6030(5) | 47(2) |
| C(39) | 2623(2) | 3210(5) | 539(5) | 35(1) |
| C(40) | 2689(2) | 4079(4) | 1416(4) | 27(1) |
| C(41) | 2325(2) | 5167(5) | 2854(4) | 34(1) |
| C(42) | 2206(2) | 3154(5) | 2812(4) | 34(1) |
Table 3 bond distance and bond angle (Bond lengths
and angles [deg])
| Cl(1)-C(3) | 1.745(5) | C(8)-C(9) | 1.396(6) | C(27)-H(27) | 0.9500 |
| Cl(2)-C(20) | 1.748(5) | C(8)-C(13) | 1.401(6) | C(28)-C(29) | 1.389(6) |
| N(1)-C(36) | 1.457(8) | C(9)-C(10) | 1.390(6) | C(29)-C(30) | 1.384(6) |
| N(1)-C(37) | 1.466(8) | C(9)-H(9) | 0.9500 | C(29)-H(29) | 0.9500 |
| N(1)-C(38) | 1.517(8) | C(10)-C(11) | 1.398(6) | C(30)-H(30) | 0.9500 |
| N(1)-H(1A) | 0.9300 | C(10)-H(10) | 0.9500 | C(31)-C(33) | 1.523(6) |
| N(2)-C(42) | 1.482(6) | C(11)-C(12) | 1.395(6) | C(31)-C(34) | 1.535(6) |
| N(2)-C(41) | 1.487(6) | C(12)-C(13) | 1.383(6) | C(31)-C(32) | 1.550(6) |
| N(2)-C(40) | 1.499(6) | C(12)-H(12) | 0.9500 | C(33)-H(33A) | 0.9800 |
| N(2)-H(2A) | 0.9300 | C(13)-H(13) | 0.9500 | C(33)-H(33B) | 0.9800 |
| O(1)-C(7) | 1.230(5) | C(14)-C(17) | 1.516(6) | C(33)-H(33C) | 0.9800 |
| O(2)-C(11) | 1.364(5) | C(14)-C(16) | 1.527(6) | C(34)-H(34A) | 0.9800 |
| O(2)-C(14) | 1.452(5) | C(14)-C(15) | 1.546(6) | C(34)-H(34B) | 0.9800 |
| O(3)-C(15) | 1.235(6) | C(16)-H(16A) | 0.9800 | C(34)-H(34C) | 0.9800 |
| O(4)-C(15) | 1.260(6) | C(16)-H(16B) | 0.9800 | C(35)-C(36) | 1.580(9) |
| O(5)-C(24) | 1.222(5) | C(16)-H(16C) | 0.9800 | C(35)-H(35A) | 0.9900 |
| O(6)-C(28) | 1.354(5) | C(17)-H(17A) | 0.9800 | C(35)-H(35B) | 0.9900 |
| O(6)-C(31) | 1.454(5) | C(17)-H(17B) | 0.9800 | C(36)-H(36A) | 0.9900 |
| O(7)-C(32) | 1.260(5) | C(17)-H(17C) | 0.9800 | C(36)-H(36B) | 0.9900 |
| O(8)-C(32) | 1.250(5) | C(18)-C(19) | 1.389(6) | C(37)-H(37A) | 0.9800 |
| O(9)-C(35) | 1.386(8) | C(18)-C(23) | 1.398(6) | C(37)-H(37B) | 0.9800 |
| O(9)-H(9A) | 0.8400 | C(18)-H(18) | 0.9500 | C(37)-H(37C) | 0.9800 |
| O(10)-C(39) | 1.417(7) | C(19)-C(20) | 1.381(7) | C(38)-H(38A) | 0.9800 |
| O(10)-H(10A) | 0.8400 | C(19)-H(19) | 0.9500 | C(38)-H(38B) | 0.9800 |
| C(1)-C(2) | 1.382(6) | C(20)-C(21) | 1.382(7) | C(38)-H(38C) | 0.9800 |
| C(1)-C(6) | 1.398(6) | C(21)-C(22) | 1.378(7) | C(39)-C(40) | 1.507(7) |
| C(1)-H(1) | 0.9500 | C(21)-H(21) | 0.9500 | C(39)-H(39A) | 0.9900 |
| C(2)-C(3) | 1.380(7) | C(22)-C(23) | 1.393(6) | C(39)-H(39B) | 0.9900 |
| C(2)-H(2) | 0.9500 | C(22)-H(22) | 0.9500 | C(40)-H(40A) | 0.9900 |
| C(3)-C(4) | 1.377(7) | C(23)-C(24) | 1.503(6) | C(40)-H(40B) | 0.9900 |
| C(4)-C(5) | 1.382(6) | C(24)-C(25) | 1.486(6) | C(41)-H(41A) | 0.9800 |
| C(4)-H(4) | 0.9500 | C(25)-C(30) | 1.391(6) | C(41)-H(41B) | 0.9800 |
| C(5)-C(6) | 1.400(6) | C(25)-C(26) | 1.399(6) | C(41)-H(41C) | 0.9800 |
| C(5)-H(5) | 0.9500 | C(26)-C(27) | 1.384(6) | C(42)-H(42A) | 0.9800 |
| C(6)-C(7) | 1.494(6) | C(26)-H(26) | 0.9500 | C(42)-H(42B) | 0.9800 |
| C(7)-C(8) | 1.489(6) | C(27)-C(28) | 1.404(6) | C(42)-H(42C) | 0.9800 |
| C(36)-N(1)-C(37) | 113.4(5) | O(3)-C(15)-C(14) | 118.4(4) | O(7)-C(32)-C(31) | 115.3(4) |
| C(36)-N(1)-C(38) | 112.4(5) | O(4)-C(15)-C(14) | 116.4(4) | C(31)-C(33)-H(33A) | 109.5 |
| C(37)-N(1)-C(38) | 107.0(5) | C(14)-C(16)-H(16A) | 109.5 | C(31)-C(33)-H(33B) | 109.5 |
| C(36)-N(1)-H(1A) | 108.0 | C(14)-C(16)-H(16B) | 109.5 | H(33A)-C(33)-H(33B) | 109.5 |
| C(37)-N(1)-H(1A) | 108.0 | H(16A)-C(16)-H(16B) | 109.5 | C(31)-C(33)-H(33C) | 109.5 |
| C(38)-N(1)-H(1A) | 108.0 | C(14)-C(16)-H(16C) | 109.5 | H(33A)-C(33)-H(33C) | 109.5 |
| C(42)-N(2)-C(41) | 110.6(4) | H(16A)-C(16)-H(16C) | 109.5 | H(33B)-C(33)-H(33C) | 109.5 |
| C(42)-N(2)-C(40) | 112.9(4) | H(16B)-C(16)-H(16C) | 109.5 | C(31)-C(34)-H(34A) | 109.5 |
| C(41)-N(2)-C(40) | 110.2(4) | C(14)-C(17)-H(17A) | 109.5 | C(31)-C(34)-H(34B) | 109.5 |
| C(42)-N(2)-H(2A) | 107.7 | C(14)-C(17)-H(17B) | 109.5 | H(34A)-C(34)-H(34B) | 109.5 |
| C(41)-N(2)-H(2A) | 107.7 | H(17A)-C(17)-H(17B) | 109.5 | C(31)-C(34)-H(34C) | 109.5 |
| C(40)-N(2)-H(2A) | 107.7 | C(14)-C(17)-H(17C) | 109.5 | H(34A)-C(34)-H(34C) | 109.5 |
| C(11)-O(2)-C(14) | 121.6(3) | H(17A)-C(17)-H(17C) | 109.5 | H(34B)-C(34)-H(34C) | 109.5 |
| C(28)-O(6)-C(31) | 122.1(3) | H(17B)-C(17)-H(17C) | 109.5 | O(9)-C(35)-C(36) | 117.5(5) |
| C(35)-O(9)-H(9A) | 109.5 | C(19)-C(18)-C(23) | 120.6(4) | O(9)-C(35)-H(35A) | 107.9 |
| C(39)-O(10)-H(10A) | 109.5 | C(19)-C(18)-H(18) | 119.7 | C(36)-C(35)-H(35A) | 107.9 |
| C(2)-C(1)-C(6) | 120.5(4) | C(23)-C(18)-H(18) | 119.7 | O(9)-C(35)-H(35B) | 107.9 |
| C(2)-C(1)-H(1) | 119.8 | C(20)-C(19)-C(18) | 118.6(4) | C(36)-C(35)-H(35B) | 107.9 |
| C(6)-C(1)-H(1) | 119.8 | C(20)-C(19)-H(19) | 120.7 | H(35A)-C(35)-H(35B) | 107.2 |
| C(3)-C(2)-C(1) | 119.3(4) | C(18)-C(19)-H(19) | 120.7 | N(1)-C(36)-C(35) | 112.7(5) |
| C(3)-C(2)-H(2) | 120.3 | C(19)-C(20)-C(21) | 121.9(4) | N(1)-C(36)-H(36A) | 109.0 |
| C(1)-C(2)-H(2) | 120.3 | C(19)-C(20)-Cl(2) | 118.1(4) | C(35)-C(36)-H(36A) | 109.0 |
| C(4)-C(3)-C(2) | 121.9(4) | C(21)-C(20)-Cl(2) | 119.9(4) | N(1)-C(36)-H(36B) | 109.0 |
| C(4)-C(3)-Cl(1) | 119.1(4) | C(22)-C(21)-C(20) | 119.1(4) | C(35)-C(36)-H(36B) | 109.0 |
| C(2)-C(3)-Cl(1) | 119.0(4) | C(22)-C(21)-H(21) | 120.5 | H(36A)-C(36)-H(36B) | 107.8 |
| C(3)-C(4)-C(5) | 118.5(4) | C(20)-C(21)-H(21) | 120.5 | N(1)-C(37)-H(37A) | 109.5 |
| C(3)-C(4)-H(4) | 120.8 | C(21)-C(22)-C(23) | 120.8(4) | N(1)-C(37)-H(37B) | 109.5 |
| C(5)-C(4)-H(4) | 120.8 | C(21)-C(22)-H(22) | 119.6 | H(37A)-C(37)-H(37B) | 109.5 |
| C(4)-C(5)-C(6) | 121.4(4) | C(23)-C(22)-H(22) | 119.6 | N(1)-C(37)-H(37C) | 109.5 |
| C(4)-C(5)-H(5) | 119.3 | C(22)-C(23)-C(18) | 119.0(4) | H(37A)-C(37)-H(37C) | 109.5 |
| C(6)-C(5)-H(5) | 119.3 | C(22)-C(23)-C(24) | 117.8(4) | H(37B)-C(37)-H(37C) | 109.5 |
| C(1)-C(6)-C(5) | 118.4(4) | C(18)-C(23)-C(24) | 123.1(4) | N(1)-C(38)-H(38A) | 109.5 |
| C(1)-C(6)-C(7) | 123.5(4) | O(5)-C(24)-C(25) | 120.1(4) | N(1)-C(38)-H(38B) | 109.5 |
| C(5)-C(6)-C(7) | 118.0(4) | O(5)-C(24)-C(23) | 118.5(4) | H(38A)-C(38)-H(38B) | 109.5 |
| O(1)-C(7)-C(8) | 119.6(4) | C(25)-C(24)-C(23) | 121.3(4) | N(1)-C(38)-H(38C) | 109.5 |
| O(1)-C(7)-C(6) | 119.1(4) | C(30)-C(25)-C(26) | 118.3(4) | H(38A)-C(38)-H(38C) | 109.5 |
| C(8)-C(7)-C(6) | 121.3(4) | C(30)-C(25)-C(24) | 124.3(4) | H(38B)-C(38)-H(38C) | 109.5 |
| C(9)-C(8)-C(13) | 118.6(4) | C(26)-C(25)-C(24) | 117.2(4) | O(10)-C(39)-C(40) | 110.0(5) |
| C(9)-C(8)-C(7) | 124.2(4) | C(27)-C(26)-C(25) | 121.2(4) | O(10)-C(39)-H(39A) | 109.7 |
| C(13)-C(8)-C(7) | 117.1(4) | C(27)-C(26)-H(26) | 119.4 | C(40)-C(39)-H(39A) | 109.7 |
| C(10)-C(9)-C(8) | 120.9(4) | C(25)-C(26)-H(26) | 119.4 | O(10)-C(39)-H(39B) | 109.7 |
| C(10)-C(9)-H(9) | 119.6 | C(26)-C(27)-C(28) | 119.7(4) | C(40)-C(39)-H(39B) | 109.7 |
| C(8)-C(9)-H(9) | 119.6 | C(26)-C(27)-H(27) | 120.2 | H(39A)-C(39)-H(39B) | 108.2 |
| C(9)-C(10)-C(11) | 119.9(4) | C(28)-C(27)-H(27) | 120.2 | N(2)-C(40)-C(39) | 113.7(4) |
| C(9)-C(10)-H(10) | 120.1 | O(6)-C(28)-C(29) | 126.5(4) | N(2)-C(40)-H(40A) | 108.8 |
| C(11)-C(10)-H(10) | 120.1 | O(6)-C(28)-C(27) | 114.0(4) | C(39)-C(40)-H(40A) | 108.8 |
| O(2)-C(11)-C(12) | 114.2(4) | C(29)-C(28)-C(27) | 119.4(4) | N(2)-C(40)-H(40B) | 108.8 |
| O(2)-C(11)-C(10) | 126.3(4) | C(30)-C(29)-C(28) | 120.2(4) | C(39)-C(40)-H(40B) | 108.8 |
| C(12)-C(11)-C(10) | 119.5(4) | C(30)-C(29)-H(29) | 119.9 | H(40A)-C(40)-H(40B) | 107.7 |
| C(13)-C(12)-C(11) | 120.3(4) | C(28)-C(29)-H(29) | 119.9 | N(2)-C(41)-H(41A) | 109.5 |
| C(13)-C(12)-H(12) | 119.8 | C(29)-C(30)-C(25) | 121.3(4) | N(2)-C(41)-H(41B) | 109.5 |
| C(11)-C(12)-H(12) | 119.8 | C(29)-C(30)-H(30) | 119.4 | H(41A)-C(41)-H(41B) | 109.5 |
| C(12)-C(13)-C(8) | 120.8(4) | C(25)-C(30)-H(30) | 119.4 | N(2)-C(41)-H(41C) | 109.5 |
| C(12)-C(13)-H(13) | 119.6 | O(6)-C(31)-C(33) | 111.1(4) | H(41A)-C(41)-H(41C) | 109.5 |
| C(8)-C(13)-H(13) | 119.6 | O(6)-C(31)-C(34) | 103.1(3) | H(41B)-C(41)-H(41C) | 109.5 |
| O(2)-C(14)-C(17) | 111.2(4) | C(33)-C(31)-C(34) | 110.9(4) | N(2)-C(42)-H(42A) | 109.5 |
| O(2)-C(14)-C(16) | 102.4(3) | O(6)-C(31)-C(32) | 111.3(3) | N(2)-C(42)-H(42B) | 109.5 |
| C(17)-C(14)-C(16) | 110.1(4) | C(33)-C(31)-C(32) | 114.2(4) | H(42A)-C(42)-H(42B) | 109.5 |
| O(2)-C(14)-C(15) | 110.5(3) | C(34)-C(31)-C(32) | 105.5(4) | N(2)-C(42)-H(42C) | 109.5 |
| C(17)-C(14)-C(15) | 114.8(4) | O(8)-C(32)-O(7) | 125.1(4) | H(42A)-C(42)-H(42C) | 109.5 |
| C(16)-C(14)-C(15) | 107.1(3) | O(8)-C(32)-C(31) | 119.5(4) | H(42B)-C(42)-H(42C) | 109.5 |
| O(3)-C(15)-O(4) | 124.9(5) |
Table 4 Wasserstoffatoms coordinate and anisotropic parameters (Hydrogen coordinates (* 10
4) and isotropic displacement parameters
| x | y | z | U eq | |
| H(1A) | 2904 | 5469 | 6145 | 45 |
| H(2A) | 1997 | 4261 | 1708 | 28 |
| H(9A) | 2181 | 7892 | 4534 | 74 |
| H(10A) | 2810 | 1711 | 547 | 95 |
| H(1) | 5291 | 9947 | 4295 | 23 |
| H(2) | 4845 | 10739 | 2852 | 25 |
| H(4) | 5689 | 13482 | 2988 | 26 |
| H(5) | 6127 | 12709 | 4454 | 25 |
| H(9) | 6000 | 8965 | 4159 | 18 |
| H(10) | 6074 | 7086 | 4627 | 18 |
| H(12) | 6282 | 7958 | 7799 | 24 |
| H(13) | 6214 | 9828 | 7326 | 24 |
| H(16A) | 6572 | 4403 | 7020 | 29 |
| H(16B) | 6199 | 3638 | 6339 | 29 |
| H(16C) | 6020 | 4368 | 7334 | 29 |
| H(17A) | 5400 | 5374 | 6101 | 42 |
| H(17B) | 5561 | 4495 | 5208 | 42 |
| H(17C) | 5567 | 5800 | 4942 | 42 |
| H(18) | 280 | 9893 | 815 | 21 |
| H(19) | -139 | 10676 | 2245 | 24 |
| H(21) | 715 | 13405 | 2170 | 29 |
| H(22) | 1126 | 12634 | 738 | 25 |
| H(26) | 1156 | 9780 | -2156 | 22 |
| H(27) | 1261 | 7916 | -2614 | 22 |
| H(29) | 1081 | 7046 | 537 | 20 |
| H(30) | 971 | 8909 | 977 | 19 |
| H(33A) | 599 | 5768 | 25 | 35 |
| H(33B) | 637 | 4443 | -91 | 35 |
| H(33C) | 476 | 5185 | -1121 | 35 |
| H(34A) | 1149 | 4315 | -2172 | 36 |
| H(34B) | 1311 | 3599 | -1124 | 36 |
| H(34C) | 1688 | 4399 | -1687 | 36 |
| H(35A) | 2880 | 8117 | 5095 | 53 |
| H(35B) | 2994 | 6853 | 4801 | 53 |
| H(36A) | 2989 | 7281 | 6774 | 56 |
| H(36B) | 2419 | 7388 | 6638 | 56 |
| H(37A) | 2992 | 5746 | 7982 | 87 |
| H(37B) | 2680 | 4659 | 7694 | 87 |
| H(37C) | 2420 | 5789 | 8032 | 87 |
| H(38A) | 1920 | 5665 | 6441 | 71 |
| H(38B) | 2186 | 4551 | 6077 | 71 |
| H(38C) | 2147 | 5593 | 5266 | 71 |
| H(39A) | 2300 | 3283 | 188 | 42 |
| H(39B) | 2863 | 3325 | -23 | 42 |
| H(40A) | 2981 | 3899 | 1864 | 33 |
| H(40B) | 2740 | 4812 | 1070 | 33 |
| H(41A) | 2055 | 5205 | 3340 | 51 |
| H(41B) | 2328 | 5839 | 2400 | 51 |
| H(41C) | 2626 | 5118 | 3287 | 51 |
| H(42A) | 2506 | 2981 | 3217 | 51 |
| H(42B) | 2118 | 2527 | 2336 | 51 |
| H(42C) | 1951 | 3283 | 3324 | 51 |
Embodiment 2
Fenofibrate acid N-(2-hydroxyethyl) alkylbenzyldimethylasaltsum saltsum
Fenofibrate acid (500mg 1.569mmol) is dissolved in the methyl alcohol (20mL), treat the solid dissolving after; Cooling, and adding N-(2-hydroxyethyl) morpholine (205.7mg, 1.569mmol); Refluxed 2 hours, and concentrated, use toluene: the solvent of sherwood oil=2:1 carries out recrystallization; Get white solid (540mg, 76% yield).MP：93-96℃。
1H-NMR(DMSO,400MHZ):1.589(s,6H),2.43(m,6H),3.53(m,2H),3.57(m,4H),6.93(d,2H,J=8.4),7.61(d,2H,J=8.4),7.70(m,4H)。
Embodiment 3
Fenofibrate acid N-(2-hydroxyethyl) pyrrolidinium
Fenofibrate acid (500mg 1.569mmol) is dissolved in the methyl alcohol (20mL), treat the solid dissolving after; Cooling, and adding N-(2-hydroxyethyl) tetramethyleneimine (180.6mg, 1.569mmol); Refluxed 2 hours, and concentrated the solvent recrystallization of toluene: sherwood oil=6:1; Get white solid (520mg, 76% yield).MP：101-102℃。
1H-NMR(DMSO,400MHZ):1.529(s,6H),1.758(m,4H),2.86(m,6H),3.58(t,2H),6.91(d,2H,J=8.4),7.60(d,2H,J=8.4),7.68(m,4H)。
Embodiment 4
Fenofibrate triethylenetetraminehexaacetic acid alcohol amine salt
Fenofibrate acid (500mg 1.569mmol) is dissolved in the methyl alcohol (20mL), treat the solid dissolving after, cooling; (275mg 1.569mmol), refluxed 2 hours, concentrated to add trolamine; The solvent recrystallization of methyl alcohol: t-butyl methyl ether=1:20 gets white solid (500mg, 68% yield).MP：92-93℃。
1H-NMR(DMSO,400MHZ):1.564(s,6H),2.70(t,6H),3.47(t,6H),6.92(d,2H,J=8.4),7.59(d,2H,J=8.4),7.69(m,4H)。
Embodiment 5
Fenofibrate acid diethylaminoethanol salt
Fenofibrate acid (500mg 1.569mmol) is dissolved in the methyl alcohol (20mL), treat the solid dissolving after, cooling, (184mg 1.569mmol), refluxed 2 hours, concentrated, and freeze-drying on the Freeze Drying Equipment gets colorless solid (500mg, 73% yield) to add diethylaminoethanol.MP：56-57℃。
1H-NMR(DMSO,400MHZ):1.06(t,6H),1.54(s,6H),2.83(m,6H),3.59(t,2H),6.91(d,2H,J=8.4),7.60(d,2H,J=8.4),7.69(m,4H)。
Compound disclosed by the invention is novel reducing blood-fat candidate compound; The method of evaluating drug effect of its reducing blood-fat is according to the technical requirements of new drug pharmacodynamic study, adopts the reducing blood lipid of male C57 mouse (Yangzhou University comparative medicine center) through continuous several times administration experimental observation The compounds of this invention.Concrete grammar is following:
1, the C57 mouse is raised in SPF level Animal House, and temperature is controlled at 20～25 ℃, and relative humidity (55 ± 15) % per hour ventilates 10 times, the MC illumination, and day alternates with night in 12 hours.With the mouse random packet, normal diet after 1 week that conformed, is given the normal diet except the normal control group according to body weight, and other are respectively organized mouse and all give high lipid food.
2, raise with high lipid food after 26 days mouse irritate stomach respectively and give the acid of 100mg/kg fenofibrate, 100mg/kg fenofibrate, 100mg/kg fenofibrate hydrochlorate and test-compound.The dosage of test-compound is respectively 10,30,100mg/kg.The volume of administration is 0.1ml/10g, and n=8 gave 4 days continuously.
3, after the last administration 5 ~ 6 hours, get blood, be statically placed in blood is fully solidified after; Centrifugal 5 minutes of 10000rpm; Shift supernatant, serum sample is positioned over 4 ℃ of preservations, is used to measure serum triglyceride, total cholesterol, RHDL, low-density lipoprotein white level.
4, statistical study: mice serum triglyceride level, total cholesterol, RHDL, low-density lipoprotein white level are represented with means standard deviation; At first carry out statistical study between each group, check the difference between each group with Student ' s t-test again with single factor variance.
Embodiment of the invention compound is estimated through above-mentioned animal pharmacodynamics, result such as following table:
Table 5 medicine is to the influence of C57 mice serum lipid level
More than specific embodiment of the present invention is illustrated; But protection content of the present invention is not only limited to above embodiment; In the technical field, the common knowledge of a GPRS just can be carried out diversified change in its technological main idea scope under of the present invention.
Claims (10)
1. fenofibrate hydrochlorate is characterized in that: said fenofibrate hydrochlorate is made by fenofibrate acid and amine reaction, and said Fei Beite hydrochlorate has the general structure as shown in the formula (I),
Formula (I)
Wherein, R
1, R
2Be independently selected from methyl, ethyl, hydroxyethyl respectively; Perhaps,
R
1, R
2Be 5 ~ 6 yuan of rings that link to each other and form.
2. fenofibrate hydrochlorate according to claim 1 is characterized in that: have 1 ~ 2 N or O heteroatoms in said 5 ~ 6 yuan of rings.
3. fenofibrate hydrochlorate according to claim 1 is characterized in that: said fenofibrate hydrochlorate is selected from: fenofibrate acid dimethylaminoethanol salt, fenofibrate acid N-(2-hydroxyethyl) alkylbenzyldimethylasaltsum saltsum, fenofibrate acid N-(2-hydroxyethyl) pyrrolidinium, fenofibrate triethylenetetraminehexaacetic acid alcohol amine salt, fenofibrate acid diethylaminoethanol salt.
4. fenofibrate acid dimethylaminoethanol salt crystal is characterized in that: have the chemical structural formula as shown in the formula (II):
Formula
（II）。
5. fenofibrate acid dimethylaminoethanol salt crystal according to claim 4, it is characterized in that: said crystal is a single crystal structure, belongs to oblique system, spacer is P2
1/ c, unit cell parameters:
β=92.094 (2) °, unit cell volume
Molecule number Z=8 in the structure cell, uptake factor μ=0.217mm
-1
6. the preparation method of the described fenofibrate hydrochlorate of one of claim 1-3 is characterized in that may further comprise the steps: fenofibrate acid is dissolved in the solvent, after treating to dissolve fully, in gained solution, adds amine, and carry out back flow reaction; After reaction finishes, concentrate, recrystallization or use the Freeze Drying Equipment freeze-drying, obtain the fenofibrate hydrochlorate.
7. the preparation method of fenofibrate hydrochlorate according to claim 6 is characterized in that: said solvent is selected from one or more in ETHYLE ACETATE, chloroform, methylene dichloride, methyl alcohol, ethanol, acetone, ether and the MTBE.
8. the preparation method of fenofibrate hydrochlorate according to claim 6 is characterized in that: the mol ratio of said Procetofenic acid and amine is 1:0.9 ~ 1:1.3.
9. pharmaceutical composition that comprises the described fenofibrate hydrochlorate of claim 1; It is characterized in that: process by fenofibrate hydrochlorate and auxiliary, said auxiliary be selected from starch, amylum pregelatinisatum, dextrin, Icing Sugar, lactose, N.F,USP MANNITOL, calcium sulfate two water things, secondary calcium phosphate, Natural manganese dioxide, lime carbonate, sal epsom, syrup, Microcrystalline Cellulose, Xylo-Mucine, Vltra tears, low-substituted hydroxypropyl cellulose, sodium starch glycolate, magnesium laurylsulfate and the micropowder silica gel any one or multiple.
10. the described fenofibrate hydrochlorate of one of claim 1-3 is used for treating the application of the medicine of hyperlipidemia disease in preparation.
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| CN104803842A (en) * | 2015-03-02 | 2015-07-29 | 郑州泰基鸿诺药物科技有限公司 | Fenofibric acid glycine ethyl ester crystal form and preparation method thereof |
| CN108558655A (en) * | 2014-10-31 | 2018-09-21 | 扬子江药业集团有限公司 | 2- [4- (4- chlorobenzene formacyls) phenoxy group] -2 Methylpropionic acid polymorph and preparation method thereof and pharmaceutical composition |
| US10577379B1 (en) | 2018-12-05 | 2020-03-03 | Jiangxi Fushine Pharmaceutical Co., Ltd. | Fenofibric acid salt with berberine or its analogues, crystalline forms, methods of preparation, and applications thereof |
| JP2021529206A (en) * | 2018-07-06 | 2021-10-28 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングＭｅｒｃｋ Ｐａｔｅｎｔ Ｇｅｓｅｌｌｓｃｈａｆｔ ｍｉｔ ｂｅｓｃｈｒａｅｎｋｔｅｒ Ｈａｆｔｕｎｇ | Crystalline salt containing 5-methyl (6S) -tetrahydrofolic acid and 4- (2-hydroxyethyl) -morpholine |
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| CN104803842A (en) * | 2015-03-02 | 2015-07-29 | 郑州泰基鸿诺药物科技有限公司 | Fenofibric acid glycine ethyl ester crystal form and preparation method thereof |
| JP2021529206A (en) * | 2018-07-06 | 2021-10-28 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングＭｅｒｃｋ Ｐａｔｅｎｔ Ｇｅｓｅｌｌｓｃｈａｆｔ ｍｉｔ ｂｅｓｃｈｒａｅｎｋｔｅｒ Ｈａｆｔｕｎｇ | Crystalline salt containing 5-methyl (6S) -tetrahydrofolic acid and 4- (2-hydroxyethyl) -morpholine |
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Application publication date: 20120912 |