CN1684971A - Novel structures and compositions comprising sterols and/or stanols and specific classes of anti-inflammatory agents and use thereof in treating or preventing cardiovascular disease, its underlying co - Google Patents

Novel structures and compositions comprising sterols and/or stanols and specific classes of anti-inflammatory agents and use thereof in treating or preventing cardiovascular disease, its underlying co Download PDF

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CN1684971A
CN1684971A CNA038230283A CN03823028A CN1684971A CN 1684971 A CN1684971 A CN 1684971A CN A038230283 A CNA038230283 A CN A038230283A CN 03823028 A CN03823028 A CN 03823028A CN 1684971 A CN1684971 A CN 1684971A
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stanols
acid
sterol
inflammation
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詹姆斯·P·库特奈伊
P·海登·普里查德
丁阳兵
基肖尔·M·瓦桑
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Forbes Medi-Tech Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • A—HUMAN NECESSITIES
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    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane

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Abstract

The present invention provides, in one aspect, novel derivatives comprising sterols and/or stanols and an NSAID selected from salicylic acids and arylalkanoic acids, including salts of these derivatives, and having one or more of the following formulae: a) R2-(CH2)n-CO-OR b) R2-R c) R2-CO-CO-OR d) formula (I), wherein R is a sterol or stanol moiety, R2 is derived from a salicylic acid or an arylalkanoic acid and n=1-5. Also provided are pharmaceutical compositions comprising one or more of these novel derivatives and methods of treating or preventing cardiovascular disease and its underlying conditions including, without limitation, atherosclerosis, hypercholesterolemia, hyperlipidemia, hypertension, thrombosis, coronary artery disease, and for treating and reducing inflammation including coronary plaque inflammation, bacterial-induced inflammation, viral induced inflammation and inflammation associated with acute pain and surgical procedures which comprises administering to an animal, particularly a human, a non-toxic and therapeutically effective amount of one or more of these compounds or a biologically acceptable salt thereof.

Description

The new texture and the composition that comprise sterol and/or stanols, and the antiphlogiston of special category and its treatment or prevent cardiovascular diseases and the purposes of the situation of hiding comprise that treatment hyperlipidaemia and other are the illness of the part cause of disease or symptom with the inflammation
Technical field
The field that the present invention relates to is sterol and stanols and novel derivative and their purposes in treatment and prevention cardiovascular diseases and other illness.
Background technology
Although recent progress of science and technology helps people to improve life quality, prolonged the life-span, also successfully do not find the method for prevention of arterial atherosis (situation of hiding of cardiovascular diseases (" CVD ")).Atherosclerosis is a kind of degeneration process that is influenced each other and caused by heredity (gene) factor and environmental factors (as diet and mode of life).Studies show that up to now cholesterol may play an important role in atherosclerosis, it forms atherosclerosis plaque in blood vessel, the final blood supply of cutting off to cardiac muscle, or selectively cut off the blood supply (depending on the position of spot) of brain or four limbs in rete arteriosum (1,2).Overview is that the onset risk of every minimizing 1% coronary artery disease of human serum cholesterol level just reduces 2% (3).Statistic data shows that the average serum cholesterol reduces by 10% (for example, reducing to 5.3mmol/L from 6.0mmol/L) can prevent 100,000 examples dead (4) every year in the U.S..
Sterol is naturally occurring compound, is used to finish many very important cell functions.Ergosterol in campesterol in plant sterol such as the plant, Stigmasterol and β-Gu Zaichun, the fungi and the cholesterol in the animal are its cell in cell type and the main ingredient in the ubcellular film separately.The diet source form plant of human body implants sterol, i.e. vegetables and vegetables oil.According to estimates, plant sterol content is about 60-80mg every day in the conventional Western-style diet, and the diet of opposite vegetarian every day can provide about 500mg plant sterol.
Plant sterol has caused very big concern, because it is being fed to behind the Mammals (comprising the people) of many species, they can reduce serum cholesterol level.Although the definite mechanism of action does not know that still the relation between cholesterol and the plant sterol is obviously in part because there is similarity (difference is arranged on the molecular side chain) between both chemical structures.Estimate that thereby plant sterol has replaced the cholesterol of micellar phase to reduce absorption, or may in the cholesterol absorption process, compete acceptor and/or carrier location.
According to reporting (5) first, before 40 years, Eli Lilly company sells the sterol formulations from Yatall MA, sells the Cytellin that is called from soya-bean oil afterwards TMPreparation, find that these preparations can make serum cholesterol reduce about 9%.Various research subsequently the influence (6) of Cytellin for blood plasma lipide and lipoprotein concentration, and from the influence (7) of the Sitosterol of soybean and Yatall MA and campesterol to serum cholesterol.The phytosterol compositions that discovery can reduce serum cholesterol highly effectively is disclosed in people's such as Kutney United States Patent (USP) 5,770, in 749, said composition comprises β-Gu Zaichun, at least 10% (weight) campesterol and the stigmastanol (β-sitostanol) that is no more than 70% (weight).Notice the synergy that some form is arranged between the plant sterol component in this patent, provide than the better result of reducing cholesterol in the past.
Recently, the effect of inflammation in cardiovascular diseases becomes more obvious.Ridker etc. (8) have described the effect that inflammation may play in CVD.J.Boyle (9) has described the contact between breaking of spot and the atherosclerosis inflammation.
Prostaglandin(PG) plays an important role in inflammatory process, prostaglandin inhibitor product, especially product P GG2, and PGH2 and PGE2 have become the target spot commonly used in the anti-inflammatory drug exploitation.Yet the activity of conventional NSAID (non-steroidal anti-inflammatory drug) (NSAID ' s) is to reduce pain due to the prostaglandin(PG) and the swelling due to the inflammation, and can influence other prostaglandin(PG) and participate in the process of regulating.Thereby the prevailing NSAID of heavy dose of use also can produce severe side effect, comprises life-threatening ulcer, so limited its potentiality in treatment.Be reflunomide with respect to another selectable purposes of NSAID ' s but also return the generation severe side effect, when especially needing to carry out long-term treatment.
Have been found that NSAIDs is by suppressing the generation that enzyme in human body arachidonic acid/prostaglandin(PG) approach stops prostaglandin(PG), comprising cyclo-oxygenase (C0X). (10).Be well known that now COX has two kinds of isomer, cyclo-oxygenase-1 (COX-1) cyclooxygenase-2 (COX-2) or " prostaglandin G/H sythase II t.COX-1 is the composing type isomer, be present in blood vessel, stomach and the kidney, and COX-2 induces under cytokine and inflammatory mediator environment when inflammation takes place.The different fate of PGG2/PHG2 cyclo-oxygenase products between tissue depends on the activity performance of concrete PGG2/PHG2 metabolic enzyme.Arachidonic acid also can be converted to 12-HPETE and 12-HETE through the 12-lipoxygenase, or is converted to various leukotrienes through the 5-lipoxygenase pathway.Acetylsalicylic acid and other NSAID (non-steroidal anti-inflammatory drug) suppress the generation of cyclo-oxygenase enzyme and prostaglandin(PG); They are the lipoxygenase inhibitor approach not, therefore, can not suppress the generation of leukotriene.
The objective of the invention is to relax the compound of the known CVD of being used for the treatment of of prior art and the illness of hiding thereof, comprise with the inflammation being the illness or the situation of the part cause of disease or illness.
Summary of the invention
One aspect of the present invention provides a kind of new derivative, comprises sterol and/or stanols and the NSAID (NSAID (non-steroidal anti-inflammatory drug)) that is selected from Whitfield's ointment and aryl-alkanoic, and comprising the salt of these derivatives, they have one or more following molecular formula:
a)R 2-(CH2) n-CO-OR
b)R 2-R
c)R 2-CO-CO-OR
d)
Wherein R is sterol or stanols part, R 2Derived from Whitfield's ointment aryl-alkanoic and n=1-5.
The present invention also provides a kind of composition on the other hand, comprising at least a sterol and/or stanols and at least a NSAID that is selected from Whitfield's ointment and aryl-alkanoic.
The present invention also comprises the method for producing the novel derivative with above-mentioned molecular formula.
The present invention also comprises a kind of pharmaceutical composition, be used for the treatment of or prevent CVD and the situation of hiding, it is too high to include, without being limited to the atherosclerosis blood cholesterol, hyperlipidaemia, hypertension, thrombosis, coronary artery disease, comprise the coronary pluques inflammation, bacterial inflammation, viral inflammation and the inflammation that accompanies with severe pain (acute pain) and surgical operation are comprising one or more sterols and/or stanols and the derivative that is selected from the NASID of Whitfield's ointment and aryl-alkanoic, they have one or more above-mentioned molecular formula, and pharmaceutically acceptable carrier.
The present invention also comprises a kind of pharmaceutical composition, be used for the treatment of or prevent CVD and the situation of hiding, it is too high to include, without being limited to the atherosclerosis blood cholesterol, hyperlipidaemia, hypertension, thrombosis, coronary artery disease, be used for the treatment of and minimizing comprises coronary pluques inflammation (coronaryplaque inflammation), bacterial inflammation, viral inflammation and the inflammation that accompanies with severe pain (acute pain) and surgical operation are comprising one or more sterols and/or stanols and the derivative that is selected from the NASID of Whitfield's ointment and aryl-alkanoic, they have one or more above-mentioned molecular formula, and pharmaceutically acceptable carrier.
The present invention also comprises the derivative that contains sterol and/or stanols and be selected from the NASID of Whitfield's ointment and aryl-alkanoic, or it has food, beverage and the nutritious supplementary of the composition of one or more above-mentioned molecular formula.
The present invention also comprises food, beverage and the nutritious supplementary that contains a kind of composition, comprises one or more sterols and/or stanols and the NASID that is selected from Whitfield's ointment and aryl-alkanoic in the said composition.
The present invention also provides a kind of and treats or prevent CVD and the method for the situation of hiding, include, without being limited to atherosclerosis, blood cholesterol is too high, hyperlipidaemia, hypertension, thrombosis, coronary artery disease, be used for the treatment of and minimizing comprises the coronary pluques inflammation, bacterial inflammation, viral inflammation and the inflammation that accompanies with severe pain and surgical operation, comprising giving animal nontoxic and treatment one or more sterols of significant quantity and/or stanols and be selected from the derivative of the NASID of Whitfield's ointment and aryl-alkanoic, they have one or more above-mentioned molecular formula.
The present invention also provides a kind of and treats or prevent CVD and the method for the situation of hiding, include, without being limited to atherosclerosis, blood cholesterol is too high, hyperlipidaemia, hypertension, thrombosis, coronary artery disease, comprise the coronary pluques inflammation, bacterial inflammation, viral inflammation and the inflammation that accompanies with severe pain and surgical operation are comprising giving comprising one or more sterols and/or stanols and being selected from the composition of derivative of the NASID of Whitfield's ointment and aryl-alkanoic of the nontoxic and treatment significant quantity of animal.
Have been found that derivative of the present invention and composition treatment or prevent CVD and the situation of hiding in all show good activity, particularly hyperlipidaemia and treatment is the situation of the part cause of disease or illness with the inflammation.Aspect two, all may there be curative effect adduction or collaborative.It is also important that, it is believed that when Whitfield's ointment and/or aryl-alkanoic, no matter be use as described here sterol composition derivatize or only with sterol with the composition forms co-administered, just can obtain expected effect by selected NSAIDs than low dosage.This point is extremely important, takes the side effect that the back produces for a long time because bibliographical information is crossed many antiphlogistons, for example comprises that from Whitfield's ointment and aryl-alkanoic be the NSAIDs (NSAID (non-steroidal anti-inflammatory drug)) of part moiety.These curative effects and other significant advantage will will be more obvious in following content.
Description of drawings
The present invention is illustrated by following non-limiting type accompanying drawing, wherein:
The formation of graphical presentation a kind of derivative of the present invention of Fig. 1, plant gonane base-acetylsalicylate is by the hydroxyl reaction of hydrochloric acid and phytostanols composition;
The formation of the graphical presentation another kind of derivative of the present invention of Fig. 2, acetoxyl group plant gonane base salicylate is by the carboxyl reaction of active plant gonane base muriate and Whitfield's ointment composition;
The column diagram of Fig. 3 is represented the inhibition that a kind of derivative of the present invention absorbs cholesterol;
The bar chart of Fig. 4 is shown in the inhibition percentage of COX-1 under the situation that the present invention " FDC-2-4 " exists.SC-560 is a kind of COX-1 inhibitor, IC 50Be 10nM.FDC-2-4 is expressed as (PL+) and is expressed as (PL-) when handling without PL/C when handling with PL/C." PLonly " group is only used PL/C (non-medicine) individual curing.Data represent with respect to activity ± standard error of 100% that with the percentage that average absorption suppresses n=3, * represent p＜0.05vs.0.45mM ASA;
The bar chart of Fig. 5 is shown in the inhibition percentage of COX-2 under the situation that the present invention " FDC-2-4 " exists.DuP-697 is a cox 2 inhibitor, IC 50Be 50nM.FDC-2-4 is expressed as (PL+) and is expressed as (PL-) when handling without PL/C when handling with PL/C." PLonly " group is only used PL/C (non-medicine) individual curing, and data represent with respect to activity ± standard error of 100% that with the percentage that average absorption suppresses n=3, * represent p＜0.05vs.0.45mM ASA;
Fig. 6 is the digital image of the 1ml aqueous solution under black background that contains 4mg a kind of compound F 17-hydroxy-corticosterone DC-24 of the present invention and 120mg tween 80.
Fig. 7 is the transmission type microscope image that contains the aqueous solution of FDC-24 (4mg/ml) and tween 80 (120mg/ml), may be micellelike;
The figure of Fig. 8 represents the size distribution of the tween 80 aqueous solution of 4mg/ml FDC-24 120mg/ml;
The figure of Fig. 9 represents the size distribution of 120mg/ml tween 80 solution (control group); With
Figure 10 shows the structure of a kind of preferred compound of the present invention " FDC-2-4 ".
Preferred implementation of the present invention
Following detailed description is used to help those of ordinary skills to implement the present invention.Yet detailed explanation should not be construed as the excessive qualification to the scope of the invention.Those of ordinary skills can make amendment and change embodiment discussed here, but all can not break away from flesh and blood of the present invention or scope of the present invention.
According to an aspect of the present invention, sterol and/or stanols and the new derivative that is selected from the NASID of Whitfield's ointment and aryl-alkanoic are provided, itself have been applicable to treatment or prevention CVD and potential situation thereof, included, without being limited to atherosclerosis, blood cholesterol is too high, hyperlipidaemia, hypertension, thrombosis, coronary artery disease, comprise the coronary pluques inflammation, bacterial inflammation, viral inflammation and the inflammation that accompanies with severe pain and surgical operation.
Derivative of the present invention is represented with one or more following molecular formula:
a)R2-(CH2)n-CO-OR
b)R2-R
c)R2-CO-CO-OR
d)
Wherein R is sterol or stanols part, R 2Derived from the NSAID that is selected from Whitfield's ointment or aryl-alkanoic and n=1-5.
Should be noted in the discussion above that in disclosure term " derivative ", " structure " and " analogue " and " compound " can be exchanged use, are used to describe the new single group of compound.
According to another aspect of the present invention, provide new composition, comprising sterol and/or stanols and the NSAID that is selected from Whitfield's ointment and aryl-alkanoic, itself be applicable to treatment or prevention CVD and potential situation thereof, include, without being limited to atherosclerosis, blood cholesterol is too high, hyperlipidaemia, hypertension, thrombosis, coronary artery disease comprises the coronary pluques inflammation, bacterial inflammation, viral inflammation and the inflammation that accompanies with severe pain and surgical operation.
Sterol
Terminology used here " sterol " comprises all sterols, such as but not limited to, Sitosterol, campesterol, Stigmasterol, brassicasterol (brassicasterol) (comprising Neospongosterol,dihydro-), desmosterol, spongosterol (chalinosterol), poriferasterol, clionasterol, ergosterol, stercorin (coprosterol), codisterol, isofucosterol, fucosterol, Clerosterol, neural sterol, 7-alkene cholesterol (lathosterol), stellasterol (stellasterol), spinasterol (spinasterol), spinasterol (chondrillasterol), peposterol, avenasterol, different avenasterol, stercorin (fecosterol), pollen sterol and cholesterol and all natural or synthetic form or derivative, comprise isomer.Term " stanols " refers to saturated or the hydrogenation sterol, comprising its all natural or synthesized form and derivatives, and isomer.The sterol and the stanols that are to be understood that modification comprise that promptly side chain also falls within the scope of the invention.For example, scope of the present invention comprises 24 β-ethyl Dihydrocholesterol obviously, 24-α-ethyl-22-dihydro Dihydrocholesterol.It is apparent that equally, exist at specification sheets under the situation of doubt that except as otherwise noted, term " sterol " comprises sterol and stanols.
Sterol and stanols that the present invention forms derivative can obtain from multiple natural origin.For example, from the vegetables oil production of (comprising waterplant), obtain for example Semen Maydis oil and other vegetable oil, Wheat germ oils, soybean extraction, big rice extracts, rice bran, rapeseed oil, sunflower oil, sesame oil and fish oil (and other marine products).They can originate from fungi, ergosterol for example, or originate from animal, as cholesterol.
Correspondingly, the invention is not restricted to the sterol in any one source.United States Patent (USP) 4,420, how 427 instructions use solvent such as methyl alcohol to produce sterol from vegetable oil sludge thing.Selectable, plant sterol and phytostanols can obtain from Yatall MA resin (pitch) or soap, from United States Patent (USP) 5,770, obtain in the by product of 749 described productions of forestry, are incorporated herein this specification sheets.
Of the present invention one preferred embodiment in, derivative of the present invention forms and derives or synthetic β-Gu Zaichun, campestanol, sitostanol, cholesterol or campesterol from natural, and formed derivative each can mix in the composition and send with different ratios.Another preferred embodiment in, derivative of the present invention forms and derives or synthetic sitostanol or natural deriving or synthetic campestanol or its mixture from natural.The most preferred form of derivative of the present invention comprises sitostane base ester and rape oil steroid alkyl ester or cholestane base ester, also has further in the literary composition and describes.
Whitfield's ointment/aryl-alkanoic
Be suitable for use as the following concrete NSAIDs of being selected from of anti-inflammatory agent in the scope of the present invention, promptly animal, particularly show on the person anti-inflammatory activity medicine, but do not have steroidal spline structure element.More specifically, " aryl-alkanoic " here tends to comprise:
Arylacetic acids compound such as acemetacin, Fenazox, Bendazac, indomethacin glucosamide, oxametacin;
Arylpropionic acid compound such as alminoprofen, Ibuprofen BP/EP, Ketoprofen, flurbiprofen, fenoprofen, the Ao Shapu piperazine,
Aryl butyric acid compound such as bumadizone, Butibufen (butibufen), fenbufen, and xenbucin (xenbucin); Comprise the salt that they are all with aryl valeric acid (arylvaleric) compound.
Here employed term " Whitfield's ointment " tends to comprise:
Salicylic acid compound such as acetylsalicylic acid (ASA), ASA aluminium, ASA sodium, the ASA oxyacetate, Whitfield's ointment, Whitfield's ointment oxyacetate, saligenin, salicortin (salicortin), Tremulacine (tremulacin), salophen, Balsalazide, Benorilate, gentisinic acid, imidazoles Whitfield's ointment, lysine acetylsalicylate, 5-aminosalicylic acid, morpholine Whitfield's ointment, naphthyl Whitfield's ointment, olsalazine, parsalimide, salol, salicylyl sulfuric acid, choline magnesium trisalicylate, and other salt, diflunisal, etherylate, Fosfosal, salol, salsalate, salacetamide, Sasapyrin, sulfasalazine, olsalazone comprises synthetic and all these compounds of natural deutero-;
And all salt.
For example can be according to technology well known in the art from Salix alba, S.prupurea L extracts in the bark of S.fragilis L (being also referred to as willow, a kind of machaka) and obtains natural deutero-salicylate or salt.
In the most of preferred form of the present invention, NSAID is a salicyclic acid derivatives, more preferably a kind of in ASA and its derivative.
In an embodiment of the invention, derivative forms between salicylic acid compound and sterol part, has a kind of in the following structure:
i)
Wherein R is selected from H and CH 3, and R 1, R 2, R 3, R 4, R 5Be selected from OH independently of one another, ethanoyl, halogen (Cl, Br, I or F) and have the moieties of 1-5 carbon atom;
ii)
Wherein R is selected from H and CH 3, and R 1, R 2, R 3, R 4, R 5Be selected from OH independently of one another, ethanoyl, halogen (Cl, Br, I or F) and have the moieties of 1-5 carbon atom;
iii)
Figure A0382302800231
R wherein 1, R 2, R 3, R 4, R 5Be selected from OH independently of one another, ethanoyl, halogen (Cl, Br, I or F) and have the moieties of 1-5 carbon atom; With
iv)
R wherein 1, R 2, R 3, R 4, R 5Be selected from OH independently of one another, ethanoyl, halogen (Cl, Br, I or F) and have the moieties of 1-5 carbon atom.
In the preferred form of major part, derivative of the present invention is selected from plant gonane base acetylsalicylate, plant gonane base salicylate, acetoxyl group plant gonane base acetylsalicylate, acetoxyl group plant gonane base Whitfield's ointment, acetoxyl group plant gonane yl acetate, cholestane base salicylate, acetoxyl group cholestane salicylate and acetoxyl group plant gonane base aminosallcylic acid ester, represent with following molecular formula:
Plant gonane base acetylsalicylate (wherein R=H or CH 3)
Plant gonane base salicylate (wherein R=H or CH 3)
Figure A0382302800242
Acetoxyl group plant gonane base acetylsalicylate (wherein R=H or CH 3)
Acetoxyl group plant gonane base salicylate (wherein R=H or CH 3)
Figure A0382302800244
Acetoxyl group plant gonane yl acetate (wherein R=H or CH 3)
Cholestane base salicylate
Figure A0382302800252
Acetoxyl group cholestane salicylate
Acetoxyl group plant gonane base aminosallcylic acid ester (wherein R=H or CH 3)
The forming process of deriving
A) formation of ester
Formation comprises that the method for sterol and/or the stanols and the new texture of the antiphlogiston of selecting has many.In a method, with selected sterol or stanols (or halophosphates; Halocarbon hydrochlorate or its halogenation oxalate derivative) and antiphlogiston under reaction conditions, mix, make " acid " part and " alcohol " (plant sterol) part that condensation take place.Reaction conditions is identical with used condition in other general ester condensation reaction, and wherein acyl chlorides forms by acid moieties that pure composition can directly react or reacts under the condition that suitably acid catalyst exists, as mineral acid, sulfuric acid, phosphoric acid, tosic acid.General used organic solvent is ester such as diethyl ester, tetrahydrofuran (THF) or benzene, toluene or similar aromatic solvent in this class ester condensation reaction, and temperature variation from room temperature to high temperature, this depends on the reactive behavior that reactant reacts.
One preferred embodiment in, the method that forms ester derivative comprises " protection " antiphlogiston or derivatives thereof oh group, make it to be ester (as acetic ester) or ether (as methyl ether), under appropriate reaction conditions, the sterol of shielded antiphlogiston and reaction is carried out condensation reaction (or halophosphates then; Halocarbon hydrochlorate or its halogenation oxalate derivative).In general, this class condensation reaction is carried out in organic solvent, as diethyl ether, and tetrahydrofuran (THF) or benzene, toluene or similar aromatic solvent.Rely on the reactive behavior of self property or reactant, temperature of reaction can change between the high temperature at low temperature (15 ℃).
By embodiment, shielded antiphlogiston of the graphical presentation of Fig. 1 (acetylsalicylic acid chlorine) and phytostanols generate a kind of novel derivative of the present invention in condensation reaction.
Selectively, shown in the chart among Fig. 2, on the whole, be the ester that obtains generating, in sterol or gonane composition, generate reactive chlorine, its subsequently with or the carboxylic acid carboxyl unit process of antiphlogiston.In this way, between antiphlogiston and sterol, set up carboxyl " link ".Link preferably includes 1-5 carbon atom.Monochloro acetate and stanols mixture reaction generate gonane monochloro acetic ester in following embodiment 2.Similarly, monochloro propionic acid, monochloro butyric acid and monochloro valeric acid, or similarly acid can be used for increasing as required carbochain.Although reaction mechanism is not clear, find that in fact these derivatives that contain the carboxyl carbochain are very effectively (reduction cholesterol) in lipid is regulated, also be like this reducing aspect the deleterious inflammation influence.
As for the formation of these derivatives, clearly, when selected synthetic method is designed, can be by disclosed with the claimed different derivatives of many other method preparations.In the scope known to this chemical field those of ordinary skill,, just can use the conventional otherwise effective technique in this area to synthesize in case selected a concrete derivative.Because this reason is described the synthetic of all derivatives of asking for protection no longer one by one.
When possible, (promptly when parent contain the free hydroxyl group group), the present invention has been contained disclosed derivative at biologically acceptable metal, alkaline-earth metal, or an alkali metal salt.Than corresponding parent compound, these salt are easier to be water-soluble, and therefore, usefulness and evaluation all are improved in their the external and body.
Derivative of the present invention can be easy to salify, by handling the parent compound that contains phenolic hydroxyl group arbitrarily with a series of alkali (as sodium methylate or other metal alkoxide), makes corresponding alkali metal salt.The metal-salt of other calcium, magnesium, manganese, copper, zinc and analogue also can obtain by parent and proper metal alcohol reactant salt.
Terminology used here " FDC2-4 " structure as shown in figure 10, it is steroid alkanol derivative (mixture that sitostanol and campestanol link to each other with ASA).According to the present invention, it is a kind of preferred compound.
Using method
The invention provides a kind of method: 1) treatment or prevention CVD and its situation of hiding, comprising and be not limited to atherosclerosis, blood cholesterol is too high, hyperlipidaemia, hypertension, thrombosis, coronary artery disease and coronary pluques inflammation; 2) treat and improve general inflammation, comprising bacterial inflammation, viral inflammation and the inflammation that accompanies with severe pain and surgical operation, comprise and give animal one or more compositions nontoxic and the treatment significant quantity, comprise one or more sterols or stanols and at least a derivative that is selected from NSAID or one or more sterols and/or the stanols of Whitfield's ointment and aryl-alkanoic and is selected from the NSAID of Whitfield's ointment and aryl-alkanoic, have one or more following structures:
a)R 2-(CH2) n-CO-OR
b)R 2-R
c)R 2-CO-CO-OR
d)
Wherein R is sterol or stanols part, R 2Derived from Whitfield's ointment or aryl-alkanoic and n=1-5.
The present invention comprises that also any disclosed compound is used for the treatment of the purposes of these indications.
Term " treatment is effectively " is that the consumption of wanting to guarantee institute's administered compound or composition is enough to obtain one or more following targets:
A) the general situation that links to each other with CVD of treatment;
B) treatment atherosclerosis;
C) the treatment blood cholesterol is too high;
D) the high fat illness of treatment;
E) treatment hypertension;
F) treatment thrombosis;
G) treatment coronary artery disease;
H) treatment coronary pluques inflammation;
I) treat inflammation arbitrarily, comprising bacterial inflammation, viral inflammation and the inflammation that accompanies with severe pain and surgical operation; And/or
J) suppress COX-1 and/or COX-2 activity,
Especially found that compound of the present invention is very effective when tackling at least two kinds of factors that obviously cause the multifactor presentation of cardiovascular diseases: the cholesterol level and the inflammation of rising.Existing bibliographical information endothelium inflammatory reaction, (11) with the blood plasma ornitrol level, play an important role in atherosclerosis.Correspondingly, give a kind of compound, it reduces the cholesterol absorption simultaneously, thereby reduces serum ornitrol, and reduces inflammation association and that be considered to a progression of disease part simultaneously, and this is very favourable.There is not other compound exhibits to go out to have useful double effects.
Intended effect described herein can obtain in several ways.Compound of the present invention and composition can carry out administration by any conventional mode, are suitable for uniting use with medicine, nutrition agent, food, beverage and analogue.
The used in amounts of compound or composition will obtain expected effect, thereby depends on various factors such as selected particular compound or composition, mode of administration and patient's situation.
Compound of the present invention and composition can be only with self administrations or with the pharmaceutical composition administration, wherein they and appropriate carriers and mixed with excipients in pharmaceutical composition.
Implementing when of the present invention, using pharmaceutically acceptable carrier to prepare compound disclosed herein and composition and reach the medicament that is suitable for being administered systemically and fall within the scope of the present invention.Select suitably and manufacturing practice when suitable at carrier, compound of the present invention and composition, particularly those wiring solution-formings can parenterai administration, as intravenous injection.Compound and composition are easy to use pharmaceutically acceptable carrier well known in the art, are mixed with the dosage that is suitable for oral administration.This class carrier can make compound of the present invention and composition make tablet, pill, capsule, liquid, gel, syrup, slurry, suspension and analogue, and patient is by oral absorption.
Pharmaceutical composition comprises one or more compounds of the present invention, comprise composition comprising effective amount of actives to reach therapeutic purpose.The mensuration of significant quantity is that those of ordinary skills are known, especially under the disclosed in the text situation of detailed content.
Outside activeconstituents, these pharmaceutical compositions also can contain suitable pharmaceutically acceptable carrier, comprise vehicle and auxiliary material, and it helps activeconstituents is processed into pharmaceutically available preparation.Made oral preparations can be tablet, drageeing, capsule or solution.
Pharmaceutical composition of the present invention can be prepared by known method, for example by conventional mixing, dissolving, granulation, system drageeing, levigate, emulsification, encapsulation, entrapping or freeze drying process.
The medicament that is used for parenterai administration comprises the aqueous solution of active compound water-soluble form.In addition, the suspension of active compound also can be made into the oleo-injection suspension.
Suitable fat phase solvent or carrier comprise fatty oil such as sesame oil, or the synthetic fat oleic acid ester, as ethyl oleic acid ester or triglyceride level, or liposome.Water-soluble injection suspension can contain the material that improves suspension viscosity, as Xylo-Mucine, sorbyl alcohol or dextran.At random, suspension also can contain suitable stablizer or promote the medicament of compound dissolution degree, is used for obtaining highly spissated pharmaceutical solutions.
Medicament for oral use can obtain in solid excipient by the coupling active compound, at random grinds the gained mixture, and is processed into particle after adding suitable auxiliary material, is processed into tablet or drageeing kernel as needs.Appropriate excipients comprises lactose, sucrose, N.F,USP MANNITOL, sorbyl alcohol, W-Gum, barley starch, Starch rice, potato starch, gelatin, tragacanth, methylcellulose gum, hydroxypropyl methyl-Mierocrystalline cellulose, Xylo-Mucine, and Polyvinylpyrolidone (PVP) (PVP).If necessary, can add disintegrating agent, as cross-linking polyethylene pyrrolidone, agar, or alginic acid or its salt such as sodiun alginate.
The drageeing kernel is surrounded by suitable dressing.Dressing can use spissated sugar soln, wherein can contain gum arabic, talcum, Polyvinylpyrolidone (PVP) arbitrarily, carbomer glue, polyoxyethylene glycol, and/or titanium dioxide, lacquer solution and suitable organic solvent or solvent mixture.Tablet or drageeing dressing can add dyestuff or pigment, in order to differentiate or to characterize the various combination of active compound doses.
The pharmaceutical preparation that can orally use comprises the suitable capsule that pushes away that gelatin makes, and the sealing soft capsule made of gelatin and softening agent, softening agent such as glycerine and sorbyl alcohol.Push away suitable capsule and can contain and filler blended and filler such as lactose, binding agent such as starch, and/or lubricant such as talcum or Magnesium Stearate and the stablizer of choosing wantonly blended activeconstituents mutually.In soft capsule, active compound solubilized or be suspended in the suitable liquid, for example lipid acid, whiteruss, or liquid macrogol.In addition, also can add stablizer.
Oral liquid can emulsion, syrup, or elixir, or form that can the dry labor thing occurs, and can add water or other suitable carrier reduction before use.This class I liquid I preparation can contain conventional additive such as suspensoid, as sorbyl alcohol, syrup, methylcellulose gum, gelatin, Natvosol, carboxymethyl cellulose, stearic acid aluminium glue, hydrogenation edible fat; Emulsifying agent such as LECITHIN, dehydrated sorbitol mono-fatty acid ester, or gum arabic; Non-hydrophilic carrier (comprising deuterium oil), Prunus amygdalus oil for example, the Oleum Cocois of fraction, grease such as glyceryl ester, propylene glycol ester, or ethanol ester; Sanitas such as right-methyl hydroxybenzoate or propyl ester or Sorbic Acid; Also can add conventional seasonings and pigment if desired.
Because sterol portion water dissolubility is very poor, compound of the present invention can be prepared to make and almost completely be dissolved in the carrier, and it is higher water-soluble or fat-soluble that compound is had.
Preferably, add selected solubilizing agent in the compound of the present invention, mix with nonpoisonous organic solvent, through a step or multistep heat suddenly, ultrasonic and evaporation is with dissolved compound and except that desolvating.
Expect wherein compound of the present invention (mainly being lipophilic) is dissolved in the aqueous solution that the hydrophilic coefficient (" HLB ") that preferably selected solubilizing agent has is 12 or higher.Expect wherein with compound dissolution of the present invention that in lipid such as fat or oils medium the HLB of preferred selected solubilizing agent is 8 or lower.The HLB numerical range shows its lipophilic tendency, i.e. polar group and non-polar group ratio in molecular formula with respect to dissolving power of a molecule.
The preferred solubilizing agent that increases water and fat phased soln ability includes but not limited to tensio-active agent such as tween-80 and Tween-60, and (commercially available trade mark is respectively Tween-80 TMAnd Tween-60 TM), poly-(vinyl oxide compound)-poly-(propenyl oxide compound) three-block copolymer surfactant (Pluron:C TMAs Pluronic P-85, PluronicF-127, and PluronicF-108, poly-(vinyl oxide compound) (PEO)-contain nonionic surface active agent) and macrogolycerol (C 8-C 18Glycerides; Fatty Acid C8-C18Ethoxylated) general name such as Gelcire TMRefer to that for Gelucire 44/14,44 fusing point is 44 ℃ as Gelcire 44/14. with concrete, and 14 finger HLB values 14.
Organic solvent is selected from any nontoxic solvent commonly used, includes but not limited to all halogenation aliphatic hydrocarbons and all straight chains and side chain C 3-C 5Fatty Alcohol(C12-C14 and C12-C18).More preferably, organic solvent is selected from propyl alcohol, Virahol, butanols, isopropylcarbinol, amylalcohol, primary isoamyl alcohol, chloroform, methylene dichloride (methylene chloride) and methyl-sulphoxide (" DMSO ").
Depend on concrete solubilizing agent and selected organic solvent, may require heated solvent to dissolve compound of the present invention.Under these circumstances, solution can be heated to from about 25-75 ℃, more preferably from about 50-70 ℃, most preferably to about 65 ℃.Jia Re mode as an alternative need not be exposed to compound the deleterious temperature that has raise, and can use ultrasonicly to make compound dissolution of the present invention in selected organic solvent.
Remove organic solvent and can include but not limited to vaporized nitrogen and rotation or rotor evaporation (roto-evaporation) by any suitable evaporation type.
In operation, preferably The compounds of this invention dissolved pattern in water or Lipid carriers there are two kinds, as described below:
Preference pattern A:
1) one or more compounds of the present invention mix with selected solubilizing agent, preferred tween-80;
2) approximately adding a kind of organic solvent under the room temperature condition, preferred Virahol;
3) by heating (preferably being heated to about 65 ℃), ultrasonic or other dissolving method compound and solubilizing agent are dissolved in the solvent,
4) evaporation organic solvent; With
6) adding entry stirs the solution eddy current or thoroughly mixing by any proper method.
Preference pattern B:
1) one or more compounds of the present invention mix with selected solubilizing agent, preferred tween-80;
2) approximately adding a kind of organic solvent under the room temperature condition, preferred chloroform, and mix;
3) the evaporation organic solvent preferably passes through rotary evaporation; With
6) adding entry stirs the solution eddy current or thoroughly mixing by any proper method.
Another kind of form of the present invention, compound and composition can be taken by the form of food, beverage and nutrition agent, include, without being limited to following:
1) milk-product-as cheese, butter, milk and other newborn class beverage, spread and newborn class mixture, ice cream and yogourt;
2) oleomargarine, spread, coating, shortening, boiling and the fried oil of lipid product-for example, and seasonings;
3) no matter they are boilings, cure or other technology is made cereal product-comprise grain (for example bread and batter);
4) candy-as chocolate, preserved fruit, chewing gum, dessert, non-newborn toppings (for example Cool Whip), with frozen water, ice and other filler of fruit juice;
5) no matter beverage-alcohol or do not have alcohol, comprising can happy other soft drink, nectar, dietary supplement, meal replacement beverage is as with trade name Boost TMAnd Ensure TMThe commodity of selling; With
6) various products-comprise egg and egg product, processed food be as soup, prefabricated batter sauce, pre-ripe meals and analogue.
Compound of the present invention and composition can be by various technology such as mixing, immersion, injection, fusion, dispersion, emulsification, dipping, spraying and kneadings, in not modified direct adding food, nutrition agent (nutraceutical) or the beverage.Selectively, compound and composition are taken in after can being directly used in food and drink by the human consumer.These all are the delivery modality of simple economy.
Embodiment-the present invention is described by the embodiment of following indefiniteness.
Synthesizing of embodiment 1-plant gonane base acetylsalicylate
R＝Me，H
Synthesizing of i acetylsalicylic acid chlorine
Acetylsalicylic acid (1g) is suspended in the oxalyl chloride (5ml) and with mixed-liquor return 1 hour.Remaining oxalyl chloride distillation reclaims, and residue adds yellow wax (1.1g) one night again in vacuum-drying.
Synthesizing of ii plant gonane base acetylsalicylate
Add stanols mixture (2g, campestanol: 36.4%w/w in the muriate of above-mentioned preparation; Sitostanol: 62.3%w/w) and pyridine (10ml), mixture at room temperature stirs a night then.Pour red solution in the water (100ml), filter, collect solid (2.1g).Silicagel column on the crude product (100ml), with oil (30-50 ℃): ethyl acetate (100: 3) thus wash-out obtains white powder (1.5g, productive rate 55%).
Synthesizing of embodiment 2-acetoxyl group plant gonane base acetylsalicylate
Figure A0382302800332
R＝Me，H
(i) plant gonane base chloroacetate salt is synthetic.
With the stanols mixture in the monochloroacetic acid (10ml) (4g, campestanol: 36.4%w/w; Sitostanol: 62.3%w/w) stir 120 ℃ of heating 3 hours.Under the cool to room temperature, in post reaction mixture, add entry (50ml), collecting precipitation thing and washing (10ml * 2), vacuum-drying obtains the plant gonane base chloroacetate salt (4.5g, productive rate 95%) of white solid sample.
1H?NMR(CDCl 3)：4.75(1H，m)，4.00(2H，s).
MS (E1): 492 (M + Sitostanol ester), 478 (M + The campestanol ester).
(ii) acetoxyl group phytostanols acetylsalicylate is synthetic
Add O-Sodium o-acetyloxybenzoate (0.5g) and exsiccant DMF (10ml) in the plant gonane base chloroacetate salt (1.5g) of above-mentioned preparation, mixture was in 140 ℃ of stirring heating 1 hour.Cool to room temperature is poured mixture in the water (100ml), collects linen solid, drying weigh (1.8g, productive rate 93.4%).Crude product utilizes silica gel chromatography to carry out purifying, and elutriant is an ethyl acetate isohexane=100: 5, thereby obtains white powder (1.2g).
1H?NMR(CDCl 3)：8.12(1H，d)，7.55(1H，t)，7.30(1H，t)，7.10(1H，d)，4.80(1H，m)，4.75(2H，s).
13C?NMR(CDCl 3)：169.58，167.02，163.71，150.85，134.19，131.96，126.02，123.83，122.56，75.29，61.39.
MS (E1): 636 (M + Sitostanol ester), 622 (M +Dish The oil stanol ester), 594 (M + s-15), 580 (M + c-15).
IR(cm -1)：2934.5(C-H)，1764.03(C＝O)，1731.08(C＝O).
Synthesizing of embodiment 3-acetoxyl group Dihydrocholesterol salicylate
Figure A0382302800351
(iii) the Dihydrocholesterol chloroacetate salt is synthetic
120 ℃ of stirring heating of Dihydrocholesterol (4g) in the chloroacetate salt (10ml) 3 hours.Cool to room temperature adds entry (50ml) in post reaction mixture, the collecting precipitation thing, and washing (10ml * 2), vacuum-drying obtains the Dihydrocholesterol chloroacetate salt (4.5g, productive rate 96%) of white solid sample.
1H?NMR(CDCl 3)：4.75(1H，m)，4.00(2H，s).
(iv) acetoxyl group Dihydrocholesterol acetylsalicylate is synthetic
Add O-Sodium o-acetyloxybenzoate (0.5g) and exsiccant DMF (10ml) in the Dihydrocholesterol chloroacetate salt (1.5g) of above-mentioned preparation, mixture was in 140 ℃ of stirring heating 1 hour.Cool to room temperature is poured mixture in the water (100ml), extracts with hexane (150ml), goes up drying at sodium sulfate (20g), concentrates to reclaim solvent, and collects wax sample solid.After the drying, crude product (2.8g) is in ethyl acetate: recrystallization in the methanol solution obtains white powder (2.2g).
1H?NMR(CDCl 3)：10.4(1H，s)，7.90(1H，d)，7.50(1H，t)，7.00(1H，d)，6.90(1H，t)，4.80(1H，m)，4.80(2H，s).
13C?NMR(CDCl 3)：169.3，166.8，161.71，136.1，130.2，119.3，126.02，117.6，111.8，75.5，61.4.
MS (E1): 566 (M +) .IR (cm -1): 2930.5 (C-H), 1759 (C=O), 1687.4 (C=O). synthesizing of embodiment 4-acetoxyl group plant gonane base salicylate
Figure A0382302800361
R＝H，Me
(v) acetoxyl group plant gonane base salicylate is synthetic
Add the sodium salicylate (0.5g) among the exsiccant DMF (10ml) in the phytostanols chloroacetate salt (1.5g) of above-mentioned preparation, mixture was in 140 ℃ of stirring heating 1 hour.Cool to room temperature is poured mixture in the water (100ml), collects pale solid, drying weigh (1.8g, productive rate 93.4%).In methyl alcohol, after the recrystallization, obtain a kind of white powder (1.5g).
1H?NMR(CDCl 3)：10.4(1H，s)，7.90(1H，d)，7.46(1H，t)，7.00(1H，d)，6.90(1H，t)，4.80(1H，m)，4.80(2H，s).
13C?NMR(CDCl 3)：169.3，166.8，161.7，136.1，130.3，131.96，119.3，117.6，111.7，75.5，61.4.
MS (E1): 594 (M + Sitostanol ester), 580 (M + The campestanol ester).
IR(cm -1)：2934.0(C-H)，1755.9(C＝O)，1680.6(C＝O).
Synthesizing of embodiment 5-acetoxyl group plant gonane yl acetate
Figure A0382302800371
R＝Me，H
Except that having substituted the sodium salicylate with sodium-acetate, identical shown in other preparation method and the embodiment 4.
1H?NMR(CDCl 3)：4.90(1H，m)，4.52(2H，s)，2.15(3H，s).
13C?NMR(CDCl 3)：170.3，167.3，75.1，60.9，56.4，56.1，54.1.
MS (E1): 516 (M + Sitostanol ester), 502 (M + The campestanol ester).
IR(cm -1)：2933.0(C-H)，1765.9(C＝O)，1741.8(C＝O).
Synthesizing of embodiment 6-acetoxyl group plant gonane base aminosallcylic acid ester
Figure A0382302800372
R＝H，Me
Except that having substituted the sodium salicylate with the 4-sodium aminosalicylate, identical shown in other preparation method and the embodiment 4.
1H?NMR(CDCl 3)：10.6(1H，s)，7.68(1H，d)，6.30(2H，s)，4.78(1H，m)，4.72(2H，s)，4.10(2H，br).
13C?NMR(CDCl 3)：169.0，167.3，163.7，153.4，132.0，107.2，102.4，100.9，75.3，60.9，56.4，56.1，54.1.
MS (E1): 609 (M + Sitostanol ester), 595 (M + The campestanol ester).
IR(cm -1)：3377.2(N-H)，2933.1(C-H)，1742(C＝O)，1660(C＝O).
The cholesterol of embodiment 7-rat reduces to be measured
(350g) circulation is in 12 hours illumination (0700-1900)/dark surrounds male adult Sprague Dawley rat, and standard diet and quantity-unlimiting water when testing before beginning to test.
Subsequently the fasting rat at one night (12-16 hour) is divided into two groups: control group (n=3) and new compound (being appointed as the acetoxyl group plant gonane base salicylate of " FDC-2-4 ") group (n=3).At 0700 time, two groups are all adopted the single dose feeding,mouth.Mouth was collected blood sample in 10 hours by cardiac puncture after raising.After the tube feed, animal is by fasting.In whole experiment, can feed water arbitrarily.The blood that obtains by cardiac puncture is collected in the EDTA bag by also centrifugal in the test tube.Utilize [3H] cholesterol in the radioactive method analysed for plasma sample.
Give the oral preparations of male adult Sprague Dawley rat a kind of derivative of the present invention, comprise: 20mg/kg sterol analogue, the unlabelled cholesterol of 1mg, 25 μ Ci[3H in the emulsion that contains Intralipid 10%] cholesterol 10 hours after mouth is raised 12-16 hour before finishing and finished are to the animal fasting.After mouth is raised, collected blood sample in 10 hours by cardiac puncture.[3H] cholesterol of the plasma sample of analysis centrifugal gained, the result demonstrates the systemic inhibiting rate of cholesterol intestines.
Phytostanols [3H] cholesterol mouth is raised the development of preparation.
[25 μ Ci (approximately 227ng) use a kind of emulsion (Kabi Pharmacia) that contains 10% Intralipid in order to dissolve the radiolabeled cholesterol of external source.
Intralipid is a kind of lipomul of apyrogenetity of sterilization, as the thermal source and the indispensable fatty acid of administration.It is by 10% Soybean Oil (purified contains the natural product of neutral glycerine three esters and unsaturated fatty acids), 1.2% egg phospholipids, 2.25% G ﹠ W.In addition, add sodium hydroxide and transfer pH value, the pH value that makes finished product is 8.0; The pH value scope is at 6.0-8.9.Main component lipid acid is linolic acid (50%), oleic acid (26%), palmitinic acid (10%), linolenic acid (9%) and stearic acid (3.5%).Give the vehicle of the rat same dose of control group.
Cardiac puncture
Mouth is raised the back by cardiac puncture collection blood sample 10 hours and in 40C and 4, centrifugal 15 minutes preparation blood plasma under the condition of 000rpm.By [3H] cholesterol in the radioactive method analysed for plasma sample, and the cholesterol absorption inhibiting rate of comparing new sterol compound with control group.
Fig. 3 has shown the comparative result of FDC-2-4 and control group, as with other the effective inhibitors of cholesterol absorption that is called VP4 relatively.The result shows that clearly FDC-2-4 obviously is better than control group and VP4.The degree that FDC-2-4 reduces the cholesterol absorption is surprising and unexpected.
Embodiment 8-FDC-2-4 is to the restraining effect of cyclo-oxygenase
The purpose of this research is to determine whether steapsase/colipase activatory acetoxyl group plant of the present invention gonane base salicylic acid ester derivative (being appointed as " FDC-2-4 ") can suppress the activity of cyclo-oxygenase (COX).
In a word, FDC-2-4 is by 1: 1 porcine pancreatic lipase and colipase (PL/C) activation.Utilize the screening of cyclooxygenase inhibitors (sheep) colorimetric to measure the restraining effect of determining cyclo-oxygenase.Arachidonic acid monitors by colorimetric reaction to the conversion of PGH2.In the damping fluid of the 1M Tris-HCl of 1 μ M hemochrome pH8.0, PL/C activatory FDC-2-4 concentration is 0,0.45,4.5-μ M.After adding 100-μ M arachidonic acid and 100-μ M tetramethyl--p-phenylenediamine (TMPD-colorimetric matrix), reaction begins to start.The optical density(OD) of dyeing product is measured at the 620nm place.Acetylsalicylic acid all is used as positive reference substance in all experiments.
Steapsase/colipase activation: enzyme reaction is mensuration damping fluid (30mM Tris-HCI, pH8.0, the 1.0mMCaCl of 50mL at final volume 2, the 4mM taurodeoxycholate), among the 0.312mM friolein, under the situation that has or do not exist FDC-2-4 of the present invention, carry out.Before adding 2.5mg porcine pancreatic lipase and 2.5mg pig colipase, the solution vortex was stirred 2 minutes, and ultrasonic 5 minutes.Reaction at room temperature insulation was carried out 2 hours.
The restraining effect of cyclo-oxygenase: utilize the screening of (sheep) cyclooxygenase inhibitors colorimetric to measure (Cayman Chemicals) and determine restraining effect.Arachidonic acid monitors by colorimetric reaction to the conversion of PGH2.Cyclo-oxygenase is exposed in the inhibitor 5 minutes.After adding 100-μ M arachidonic acid and 100-μ M tetramethyl--p-phenylenediamine (TMPD-colorimetric matrix), reaction begins to start.After reaction starts 5 minutes, measure the optical density(OD) of dyeing product at the 620nm place.In the damping fluid of 1 μ M hemochrome/1M Tris-HCl of pH8.0, PL/C activatory FDC-2-4 concentration is 0,0.45,4.5-μ M.Relatively PL/C activatory FDC-2-4, do not use the cyclooxygenase restraining effect of PL/C activatory FDC-2-4 and reference substance (for adding FDC-2-4).Acetylsalicylic acid in all experiments (ASA) all is used as positive reference substance.Utilize ANOVA and Tukey Posthoc test that all treatment group are carried out statistical study.
Relatively PL/C activatory FDC-2-4, do not use the cyclooxygenase restraining effect of PL/C activatory FDC-2-4 and reference substance (for adding FDC-2-4).With do not use PL/C activatory FDC-2-4 (20%) and reference substance (5%), n=3 compares, 0.45uM PL/C activatory FDC-2-4 is 69% to the inhibition activity of COX-1.4.5 μ M PL/C activatory FDC-2-4 is 88% to the inhibition activity of COX-2.
Figure 4 and 5 show that FDC-2-4 can effectively suppress two hypotypes (COX-1 and COX-2) of cyclo-oxygenase.PL/C activatory FDC-2-4 is than not demonstrating stronger restraining effect with PL/C activatory FDC-2-4.These discoveries have hinted that FDC-2-4 is a kind of effectively by steapsase/colipase activatory anti-inflammatory agent.
Although not further processing, to such an extent as to foregoingly so fully be enough to illustrate the present invention other people can carry out identical modification under the described herein or desired various conditions by using knowledge existing or future.
Embodiment 9--utilizes solubilizing agent that water-insoluble FDC-2-4 (the plant gonane base analogue with plant gonane base-O-acetylsalicylic acid fluoroacetate chemical name, and molecular weight is 631.66g/mol) is mixed with 4mg/ml to the 8mg/ml aqueous solution.
General method: the FDC-2-4 and the solubilizing agent dissolving that utilize appropriate organic solvent to test; Can heat if desired.Evaporate by nitrogen and to reclaim organic solvent and in test tube, to add water.The opacity or the granularity of range estimation mixture.The preparation of gained utilizes the optical microphotograph inspection, and granulometry, zeta potential energy are measured and the transmission type microscope inspection comes qualitative.
Special methods:
The solubility test of FDC2-4 in various organic solvents:
1. open the nitrogen vaporizer and with temperature regulation to 65 ℃ (not having the nitrogen vaporizer of nitrogen to use as hot water bath at first)
2. 4mg FDC2-4 is packed in the test tube of 16 * 100mm, add the 120mg tween 80 with glass pipette.
3. preparation reference substance is not with 120mg tween 80 pack into (having FDC2-4) in the test tube of 16 * 100mm in reference substance
4. utilize the transfer pipet of 5ml in each test tube, to add the 7mL Virahol.Test tube is covering with Parafilm and thoroughly vortex stirring.
5. sample places the nitrogen vaporizer, and close cap-nitrogen vaporizer is at first as 65 ℃ of hot water baths.
6. approximately after 45-60 minute, although FDC2-4 is dissolved in the Virahol-asynchronism(-nization) (the framework inside vortex stirs test tube 1 or 2 times to accelerate the dissolving process at this moment).
7. in a single day determine that by estimating FDC2-4 dissolves, just the Parafilm on the test tube removed that the temperature of nitrogen vaporizer is reduced to 60 ℃, and opens nitrogen.Nitrogen gas pressure is approximately 7psi at first, guarantees to splash out without any solution in lasting about 30 minutes.After 30 minutes, psi drops to 15-20.Sample was placed about altogether 2.5 hours at the nitrogen vaporizer.
8.2.5 after hour, close the nitrogen valve, but the nitrogen vaporizer still remains on 60 ℃.Sample is placed in the nitrogen vaporizer.Take out a duplicate samples and add 1mL water rapidly.Sample quilt vortex immediately stirs up to dissolving.
The opacity that detects by an unaided eye and granularity
Carry out the optical microphotograph inspection, granularity and zeta potential energy are measured and the transmission type microscope inspection.
The solubleness overview of table 1:FDC2-4 in different solvents
Solvent Quantity of solvent The amount of FDC2-4 Temperature Dissolving?
Propyl carbinol ??5ml ??4mg ??65℃ Be
Chloroform ??- ??- Room temperature Be
??DMSO ??1ml ??2mg ??70℃ Be
??DMSO ??2ml ??4mg ??80℃ Be
Virahol ??5ml ??4mg ??65℃ Be
Table 2: be used for the solubleness overview of FDC2-4 solubilising to the different solubilizing agent of aqueous formulation.
Excipient The solubleness of FDC2-4 Propose
??PluronicP-85 It is (ratio of FDC2-4:Pluronic, 1: 25-1: 35) Organic solvent: chloroform and Virahol
??Gelucire44/14 It is (ratio of FDC2-4:Gelucire, 1: 20-1: 75) Organic solvent: chloroform
Pluronic P85 and Pluronic F127 Be Organic solvent: chloroform
Tween
80 Be Organic solvent: Virahol
Result: tested after many tensio-active agents and the organic solvent, used tween 80 can obtain more successful preparation.Preparation contains the solution of 4mg and 8mg FDC-2-4 respectively, and wherein tween 80 is 120mg and 240mg (every ml of formulation).
Strength of solution: the 1mL preparation contains 4mg FDC2-4 and 120mg tween 80 or 8mgFDC2-4 and 240mg tween 80.Therefore, the mass ratio of FDC2-4 and tween 80 is 1: 30 in the preparation.
Naked-eye observation: the solution clarification is slightly yellow.Throw out or particle do not appear.Reference substance looks identical with FDC2-4.
Shown in Figure 6 is the 1mL aqueous solution digital picture that contains 4mg FDC2-4 and 120mg tween 80, is shown as settled solution under black background.
The light microscopy of resolving power 40x and 100x: the microscopy that enlarges multiple and be 40x and 100x shows selected FDC-2-4 preparation and reference substance indifference on the quantity of particulate matter or type.
Granulometry: the preparation granularity is measured in Zetasizer 3000HS.The mean value of analyzing resulting peak height by the amount in the 4mg/mL preparation (particle size average) is 4.3nm.This can demonstrate compound of the present invention and selected solubilizing agent, and tween 80 forms micella, as shown in Figure 7.The mean particle size of 120mg/ml Polysorbate 80 reference substance is 5.7nm.Fig. 8 and Fig. 9 have shown the similarity of FDC-2-4 preparation and reference substance size-grade distribution.
Conclusion: in the compound of the present invention solution more soluble in water.
Cholesterol absorption experiment in the qualitative and rat body of embodiment 10-embodiment 9 preparations
Thereby the cholesterol that gives under the rat preparation measurement of the present invention FDC-2-4 existence absorbs.
The method general introduction of rat fasting trace model:
1. prepare three parts and contain 4mg FDC2-4, the preparation of 120mg Polysorbate 80 and 1mL water
2. prepare and only contained 120mg Polysorbate 80 (tween in three minutes TM80) and the reference substance of 1mL water
3. add radiolabeled and unlabelled cholesterol in the sample, the rat to the male fasting of Sprague-Dawley is raised in the parallel port
4.10 after hour, utilize cardiac puncture that their blood is put to death and collected to rat
5. measure [ 3H] cholesterol (radiolabeled cholesterol) plasma concentration.
Conclusion:
Table 3: the single mouth raise [ 3H] after the cholesterol 10 hours [ 3H] cholesterol blood plasma concentration, unlabelled cholesterol, and FDC 2-4 merging tween 80 gives Sprague-Dawley male fasting rat.
Compound Dosage (mg/kg) Time after the administration (hour) [ 3H] cholesterol blood plasma concentration (pg/ml) Percentage with respect to contrast changes
Tween
80 contrast (n=5) ????- 10 hours 4980+/-968 ?-----
FDC2-4/ tween 80 (n=6) ????10 10 hours 2708+/-1379** -45.6％
*P＜0.05vs. tween 80 contrast (tween reference substance be 120 and the mixture of 240mg).The weight of rat is between 360-400g.
Compare with control group, the preparation that gives rat 4mg/ml can produce 45.6% cholesterol absorption inhibiting rate.
The concentration value of selecting 4mg/mL-8mg/mL is because a kind of similar water-soluble plant stanols (" FM-VP4 ") known for inventor shows that the best inhibiting dosage of cholesterol is 10mg/kg-20mg/kg.The weight of used rat is 400g, and this is owing to the dosage of 4mg-8mg.In rat fasting trace model, give rat 1mL medicine; The water soluble preparation that for this reason, prepare 4mg/mL-8mg/mL FDC 2-4.
Reference:
1．Law?M.R.，Wald?N.J.，Wu.，Hacksaw?ZA.，Bailey?A.；Systemic?underestimation?of?association?between?serumcholesterol?concentration?and?ischemic?heart?disease?inObservational?studies：Data?from?BUPA?Study：Br.Med.J.1994：308：363-366
2．Law?M.R.，Wald?N.J.，Thompson?S.G.；By?how?muchand?how?quickly?does?reduction?in?serum?cholesterolconcentration?lower?risk?of?ischemic?heart?disease??Br.Med.J.1994；308：367-373
3.La?Rosa?J.C.，Hunninghake?D..Bush?D.et?al.；Thecholesterol?facts：A?summary?of?the?evidence?relating?todietary?fats，serum?cholesterol?and?coronary?heart?disease：A?joint?statement?by?the?American?Heart?Association?and?theNational?Heart，Lung?and?Blood?Institute.Circulation?1990；81：1721-1733
4.Havel?R.J.，Rapaport?E..Drug?Therapy：Managementof?Primary?Hyperlipidemia.NewEngland?Journal?of?Medicine，1995；332：1491-1498
5.Kuccodkar?et?al.；Effects?of?plant?sterols?oncholesterol?metabolism.Atherosclerosis，1976；23：239-248
6.Lees?R.S.，Lees?A.M.Effects?of?sitosteroltherapy?on?plasma?lipid?and?lipoprotein?concentrations.In：Greten?H(Ed)Lipoprotein?Metabolism.Springer-Verlag，Berlin，Heidelberg，New?York，1976：119-124
7.Lees?A.M.，Mok?H.Y.I.，Lees?R.S.，McCluskey?M.A.，Grundy?S.M.Plant?sterols?as?cholesterol-loweringagents：clinical?trials?in?patients?withhypercholesterolemia?and?studies?of?sterol?balance.Atherosclerosis?1977；28：325-3388.New?Eng.J.Med.，336，973-9(1999)
9.J.Path.181，93-9(1997)
10.Goodman?&?Gilman′s?The?Pharmaceutical?Basis?ofTherapeutics，Ninth?Edition(1996)，McGraw-Hill，page?620.
11.Taubes，G.2002.Cardiovascular?disease：Doesinflammation?cut?to?the?heart?of?the?matter？Science.296(5566)：242-245

Claims (60)

1. the compound that comprises sterol or stanols, comprising its biologically acceptable salt, this compound has one or more following molecular formula:
a)R 2-(CH2) n-CO-OR
b)R 2-R
c)R 2-CO-CO-OR
d)
Wherein R is sterol or stanols part, R 2Aryl-alkanoic derived from Whitfield's ointment or n=1-5.
2. the compound of claim 1, wherein sterol is selected from Sitosterol, campesterol, Stigmasterol, brassicasterol (comprising Neospongosterol,dihydro-), desmosterol, spongosterol, poriferasterol, clionasterol, ergosterol, stercorin, codisterol, isofucosterol, fucosterol, Clerosterol, neural sterol, 7-alkene cholesterol, stellasterol, spinasterol, spinasterol, peposterol, avenasterol, different avenasterol, stercorin, pollen sterol, and cholesterol.
3. the compound of claim 1, wherein stanols is selected from sitostanol, campestanol, stigmastanol, vegetable seeds stanols (comprising dihydro vegetable seeds stanols), chain stanols, the sponge stanols, the porous stanols is worn shellfish sponge stanols, ergostanol, coprostanol, codistanol, different rock algae stanols, rock algae stanols, red paulownia stanols, neural stanols, lathosterol, star fish stanols, the spinach stanols, spinach stanols (chondrillastanol), pepostanol, oat stanols, different oat stanols, coprostanol, pollen stanols, and Dihydrocholesterol.
4. the compound of claim 1, wherein sterol and stanols are natural or synthetic.
5. the compound of claim 1, wherein sterol and stanols are their any one isomer.
6. the compound of claim 1, wherein aryl-alkanoic is selected from aromatic acid, fragrant acetate, fragrant propionic acid, fragrant butyric acid and fragrant valeric acid.
7. the compound of claim 1, wherein aryl-alkanoic is selected from acemetacin, Fenazox, Bendazac, indomethacin glucosamide, oxametacin, alminoprofen, Ibuprofen BP/EP, Ketoprofen, flurbiprofen, fenoprofen, the Ao Shapu piperazine, bumadizone, Butibufen, fenbufen, and xenbucin.
8. the compound of claim 1, wherein Whitfield's ointment is selected from acetylsalicylic acid (ASA), ASA aluminium, ASA sodium, the ASA oxyacetate, Whitfield's ointment, Whitfield's ointment oxyacetate, saligenin, salicortin, Tremulacine, choline magnesium trisalicylate, diflunisal, etherylate, Fosfosal, salol, salsalate, salacetamide, the acid of salicyl salicylyl, sulfasalazine, and olsalazine (olsalazone).
9. the compound of claim 1 has following structural formula:
Figure A038230280003C1
Wherein R is selected from H and CH 3, R 1, R 2, R 3, R 4, R 5Be selected from OH independently of one another, ethanoyl, halogen (Cl, Br, I or F) and have the moieties of 1-5 carbon atom.
10. the compound of claim 1 has following structural formula:
Wherein R is selected from H and CH 3, R 1, R 2, R 3, R 4, R 5Be selected from OH independently of one another, ethanoyl, halogen (Cl, Br, I or F) and have the moieties of 1-5 carbon atom.
11. the compound of claim 1 has following structural formula:
R wherein 1, R 2, R 3, R 4, R 5Be selected from OH independently of one another, ethanoyl, halogen (Cl, Br, I or F) and have the moieties of 1-5 carbon atom.
12. the compound of claim 1 has following structural formula:
R wherein 1, R 2, R 3, R 4, R 5Be selected from OH independently of one another, ethanoyl, halogen (Cl, Br, I or F) and have the moieties of 1-5 carbon atom.
13. the compound of claim 1, be selected from plant gonane base acetylsalicylate, plant gonane base salicylate, acetoxyl group plant gonane base acetylsalicylate, acetoxyl group plant gonane base salicylate, acetoxyl group plant gonane yl acetate, cholestane base salicylate, acetoxyl group cholestane base salicylate and acetoxyl group plant gonane base aminosallcylic acid ester.
14. the compound of claim 1 has structural formula:
Wherein R is selected from H and CH 3
15. the compound of claim 1 has structural formula:
Figure A038230280005C1
Wherein R is selected from H and CH 3
16. the compound of claim 1 has structural formula:
Figure A038230280005C2
Wherein R is selected from H and CH 3
17. the compound of claim 1 has structural formula:
Figure A038230280005C3
Wherein R is selected from H and CH 3
18. the compound of claim 1 has structural formula:
Wherein R is selected from H and CH 3
19. the compound of claim 1 has structural formula:
20. the compound of claim 1 has structural formula:
21. the compound of claim 1 has structural formula:
Figure A038230280006C3
22. a pharmaceutical composition is used for the treatment of or prevents cardiovascular diseases and the method for the situation of hiding, and includes, without being limited to atherosclerosis, blood cholesterol is too high, hyperlipidaemia, hypertension, thrombosis, coronary artery disease is used for the treatment of and reduces inflammation, comprises the coronary pluques inflammation, bacterial inflammation, viral inflammation and the inflammation that accompanies with severe pain and surgical operation, described composition comprises at least a compound, this compound has one or more following molecular formula:
a)R 2-(CH2) n-CO-OR
b)R 2-R
c)R 2-CO-CO-OR
d)
Figure A038230280007C1
Wherein R is sterol or stanols part, R 2Derived from Whitfield's ointment or aryl-alkanoic and n=1-5, comprise its all biologically acceptable salt and pharmaceutically acceptable carriers.
23. the composition of claim 22, wherein aryl-alkanoic is selected from aromatic acid, fragrant acetate, fragrant propionic acid, fragrant butyric acid and fragrant valeric acid.
24. the composition of claim 22, wherein aryl-alkanoic is selected from acemetacin, Fenazox, Bendazac, indomethacin glucosamide, oxametacin, alminoprofen, Ibuprofen BP/EP, Ketoprofen, flurbiprofen, fenoprofen, the Ao Shapu piperazine, bumadizone, Butibufen, fenbufen, and xenbucin.
25. the composition of claim 22, wherein Whitfield's ointment is selected from acetylsalicylic acid (ASA), ASA aluminium, ASA sodium, the ASA oxyacetate, Whitfield's ointment, Whitfield's ointment oxyacetate, saligenin, salicortin, Tremulacine, choline magnesium trisalicylate, diflunisal, etherylate, Fosfosal, salol, salsalate, salacetamide, the acid of salicyl salicylyl, sulfasalazine, and olsalazine (olsalazone).
26. the compound of claim 22, wherein compound has following molecular formula:
Wherein R is selected from H and CH 3, R 1, R 2, R 3, R 4, R 5Be selected from OH independently of one another, ethanoyl, halogen (Cl, Br, I or F) and have the moieties of 1-5 carbon atom.
27. the compound of claim 22, wherein compound has following molecular formula:
Figure A038230280008C1
Wherein R is selected from H and CH 3, R 1, R 2, R 3, R 4, R 5Be selected from OH independently of one another, ethanoyl, halogen (Cl, Br, I or F) and have the moieties of 1-5 carbon atom.
28. the composition of claim 22, wherein compound has following molecular formula:
Figure A038230280008C2
R wherein 1, R 2, R 3, R 4, R 5Be selected from OH independently of one another, ethanoyl, halogen (Cl, Br, I or F) and have the moieties of 1-5 carbon atom.
29. the composition of claim 22, compound wherein has following molecular formula:
R wherein 1, R 2, R 3, R 4, R 5Be selected from OH independently of one another, ethanoyl, halogen (Cl, Br, I or F) and have the moieties of 1-5 carbon atom.
30. the composition of claim 22, wherein compound is selected from plant gonane base acetylsalicylate, plant gonane base salicylate, acetoxyl group plant gonane base acetylsalicylate, acetoxyl group plant gonane base salicylate, acetoxyl group plant gonane yl acetate, cholestane base salicylate, acetoxyl group cholestane base salicylate and acetoxyl group plant gonane base aminosallcylic acid ester.
31. a method for the treatment of or preventing the cardiovascular diseases and the situation of hiding thereof includes, without being limited to atherosclerosis, blood cholesterol is too high, hyperlipidaemia, hypertension, thrombosis, coronary artery disease, be used for the treatment of and reduce inflammation, comprise the coronary pluques inflammation, bacterial inflammation, viral inflammation and the inflammation that accompanies with severe pain and surgical operation, comprising giving animal one or more compounds nontoxic and the treatment significant quantity, it is as follows to have molecular formula:
a)R 2-(CH2) n-CO-OR
b)R 2-R
c)R 2-CO-CO-OR
d)
Figure A038230280009C1
Wherein R is sterol or stanols part, R 2Derived from Whitfield's ointment or aryl-alkanoic and n=1-5, or its any biologically acceptable salt.
32. the method for claim 31, wherein aryl-alkanoic is selected from aromatic acid, fragrant acetate, fragrant propionic acid, fragrant butyric acid and fragrant valeric acid.
33. the method for claim 31, wherein aryl-alkanoic is selected from acemetacin, Fenazox, Bendazac, indomethacin glucosamide, oxametacin, alminoprofen, Ibuprofen BP/EP, Ketoprofen, flurbiprofen, fenoprofen, the Ao Shapu piperazine, bumadizone, Butibufen, fenbufen, and xenbucin.
34. the method for claim 31, wherein Whitfield's ointment is selected from acetylsalicylic acid (ASA), ASA aluminium, ASA sodium, the ASA oxyacetate, Whitfield's ointment, Whitfield's ointment oxyacetate, saligenin, salicortin, Tremulacine, choline magnesium trisalicylate, diflunisal, etherylate, Fosfosal, salol, salsalate, salacetamide, the acid of salicyl salicylyl, sulfasalazine, and olsalazine (olsalazone).
35. the method for claim 31, wherein compound has molecular formula:
Wherein R is selected from HCH 3, R 1, R 2, R 3, R 4, R 5Be selected from OH independently of one another, ethanoyl, halogen (Cl, Br, I or F) and have the moieties of 1-5 carbon atom.
36. the method for claim 31, wherein compound has molecular formula:
Figure A038230280010C2
Wherein R is selected from H and CH 3, R 1, R 2, R 3, R 4, R 5Be selected from OH independently of one another, ethanoyl, halogen (Cl, Br, I or F) and have the moieties of 1-5 carbon atom.
37. the method for claim 31, wherein compound has molecular formula:
R wherein 1, R 2, R 3, R 4, R 5Be selected from OH independently of one another, ethanoyl, halogen (Cl, Br, I or F) and have the moieties of 1-5 carbon atom.
38. the method for claim 31, wherein compound has molecular formula:
R wherein 1, R 2, R 3, R 4, R 5Be selected from OH independently of one another, ethanoyl, halogen (Cl, Br, I or F) and have the moieties of 1-5 carbon atom.
39. compound comprises sterol or stanols, and biologically acceptable salt, has one or more following molecular formula:
a)R 2-(CH2) n-CO-OR
b)R 2-R
c)R 2-CO-CO-OR
d)
Figure A038230280011C2
Wherein R is sterol or stanols part, R 2Derived from the aryl-alkanoic of Whitfield's ointment or n=1-5, almost completely be dissolved in fat and be dissolved in the aqueous phase solution mutually or by following manner,
I) compound and selected solubilizing agent are mixed;
Ii) add at least a organic solvent;
Iii) compound and solubilizing agent are dissolved in organic solvent; With
Iv) therefrom evaporate organic solvent.
40. the compound of claim 39, wherein to be selected from those hydrophilic coefficients (" HLB ") be 12 or greater than 12 compound to solubilizing agent.
41. the compound of claim 39, wherein to be selected from those hydrophilic coefficients (" HLB ") be 8 or less than 8 compound to solubilizing agent.
42. the compound of claim 39, wherein solubilizing agent is selected from tensio-active agent such as tween 80 and polysorbate60, poly-(ethylene oxide)-poly-(propylene oxide) three-block copolymer surfactant such as PluronicP-85, PluronicF-127, and PluronicF-108, and macrogolycerol (C 8-C 18Glyerides; Fatty Acids C8-C18Ethoxylated) as Gelcire TM
43. the compound of claim 39, wherein organic solvent is selected from halogenation aliphatic hydrocarbon and all side chain and straight chain C 3-C 5Fatty Alcohol(C12-C14 and C12-C18).
44. the compound of claim 39, organic solvent wherein are selected from propyl alcohol, Virahol, butanols, isopropylcarbinol, amylalcohol, primary isoamyl alcohol, chloroform, methylene dichloride (carrene) and methyl-sulphoxide (" DMSO ").
45. the compound of claim 39, step I ii) in compound use heating or ultrasonic method to be dissolved in the solvent.
46. the compound of claim 39, wherein step I v) in the evaporation organic solvent use vaporized nitrogen or rotary evaporation.
47. dissolve the method for one or more following compounds in the fat base or the aqueous solution, compound comprises sterol or stanols, and biologically acceptable salt, has one or more following molecular formula:
a)R 2-(CH2) n-CO-OR
b)R 2-R
c)R 2-CO-CO-OR
d)
Figure A038230280012C1
Wherein R is sterol or stanols part, R 2Derived from the aryl-alkanoic of Whitfield's ointment or n=1-5, comprising:
I) compound and selected solubilizing agent are mixed;
Ii) add at least a organic solvent in addition;
Iii) compound and solubilizing agent are dissolved in organic solvent; With
Iv) therefrom evaporate organic solvent.
48. the method for claim 47, wherein to be selected from those hydrophilic coefficients (" HLB ") be 12 or greater than 12 compound to solubilizing agent.
49. the method for claim 47, wherein to be selected from those hydrophilic coefficients (" HLB ") be 8 or less than 8 compound to solubilizing agent.
50. the method for claim 47, wherein solubilizing agent is selected from tensio-active agent such as tween 80 and polysorbate60, poly-(ethylene oxide)-poly-(propylene oxide) three-block copolymer surfactant such as PluronicP-85, PluronicF-127 and PluronicF-108, and macrogolycerol (C 8-C 18Glycerides; Fatty Acid C8-C18Ethoxylated) as Gelcire TM
51. the method for claim 47, wherein organic solvent is selected from halogenation aliphatic hydrocarbon and all side chain and straight chain C 3-C 5Fatty Alcohol(C12-C14 and C12-C18).
52. the method for claim 47, wherein organic solvent is selected from propyl alcohol, Virahol, butanols, isopropylcarbinol, amylalcohol, primary isoamyl alcohol, chloroform, methylene dichloride (carrene) and methyl-sulphoxide.
53. the method for claim 47, wherein step I ii) in compound use heating or ultrasonic method to be dissolved in the solvent.
54. the method for claim 47, wherein the v) middle evaporation organic solvent of step I uses vaporized nitrogen or rotary evaporation.
55. the method for claim 47, wherein solubilizing agent is tween 80, and organic solvent is a Virahol.
56. the method for claim 55, wherein step I ii) in, compound is in the high dissolving during to 65 ℃ of heating.
57. the method for claim 55 is wherein used vaporized nitrogen in step I in v).
58. the method for claim 47, wherein solubilizing agent is tween 80, and organic solvent is a chloroform.
59. the method for claim 58, wherein step I ii) in, compound is at room temperature or approximately room temperature condition dissolving down.
60. the method for claim 58 is wherein used rotary evaporation in step I in v).
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Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080182801A1 (en) 2003-12-22 2008-07-31 Btg International Limited Core 2 glcnac-t inhibitors
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DE102004008035A1 (en) * 2004-02-19 2005-09-08 Symrise Gmbh & Co. Kg Use of (2-hydroxyphenyl) alcohols and cosmetic or therapeutic formulations containing these compounds
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Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19518221A1 (en) * 1995-05-10 1996-11-14 Schering Ag Use of non-steroidal anti-inflammatories to improve the physiological tolerance of particulate pharmaceutical preparations
AU4891699A (en) * 1998-07-20 2000-02-14 Forbes Medi-Tech Inc. Compositions comprising phytosterol, phytostanol or mixtures of both and omega-3fatty acids or derivatives thereof and use of the composition in treating or preventing cardiovascular disease and other disorders
DE60017128T2 (en) * 1999-06-21 2006-01-26 Forbes Medi-Tech Inc., Vancouver Aromatic and heterocyclic derivatives of phytosterols and / or phytostanols for the treatment of vascular diseases
WO2001000653A1 (en) * 1999-06-23 2001-01-04 Forbes Medi-Tech Inc. Conjugates of phytosterol or phytostanol with ascorbic acid and use thereof in treating or preventing cardiovascular disease
AU2001242130A1 (en) * 2000-03-07 2001-09-17 Forbes Medi-Tech Inc. Novel derivatives comprising phytosterols and/or phytostanols and alpha-lipoic and use thereof in treating or preventing cardiovascular disease, its underlying conditions and other disorders
DK1333838T3 (en) * 2000-10-25 2007-04-10 Forbes Medi Tech Inc Compounds comprising a phytosterol and / or phytostanol moiety and ascorbic acid, and use thereof as weight regulators
MXPA04007128A (en) * 2002-01-30 2005-03-31 Pharmacia Corp Aldosterone antagonist and non-steroidal anti-inflammatory agent combination therapy to prevent or treat cardiovascular disorders.

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104434927A (en) * 2014-12-16 2015-03-25 吉林农业大学 Application of bicyclopentanoperhydrophenanthrene malonate B in preparing hypotensive drugs
CN104530167A (en) * 2014-12-16 2015-04-22 吉林农业大学 Salicylic acid cyclopentanoperhydrophenanthrene ester A, extraction method and pharmaceutical application thereof
CN104530167B (en) * 2014-12-16 2016-02-24 吉林农业大学 The luxuriant and rich with fragrance ester A of Whitfield's ointment pentamethylene many hydrogen and extracting method thereof and pharmaceutical use
CN111053741A (en) * 2019-12-31 2020-04-24 江苏省中医院 Oral multi-sensitive micelle prodrug based on β -sitosterol and 5-ASA for treating inflammatory bowel disease
CN111053741B (en) * 2019-12-31 2021-09-28 江苏省中医院 Oral multi-sensitive micelle prodrug based on beta-sitosterol and 5-ASA for treating inflammatory bowel disease
CN114014905A (en) * 2021-12-03 2022-02-08 浙江科技学院 PPAR gamma targeted glycyrrhetinic acid derivative and preparation method and application thereof

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