The application is the divisional application of No. 200680055458.0 Chinese invention patent application.The applying date of original application is
On 07 26th, 2006, entitled " the positively charged water-soluble Diflunisal and phase with rapid skin penetration speed
The prodrug of related compounds ".
Summary of the invention
Technical problem
Diflunisal and disalicylic acid have clinically been used more than 20 years, and salicylic acid has been used
More than 100 years.Diflunisal effect in terms of anti-inflammatory and prostaglandin biosynthesis inhibition is better than aspirin.Diflunisal is
One of 200 most common prescription medicines.Diflunisal can treat acute or long-term mild or moderate pain symptom, Bones and joints
Scorching and rheumatoid arthritis.Diflunisal can treat dysmenorrhea and gout either individually or as ancillary drug.
But many side effects, most importantly stomach can be brought by taking Diflunisal, disalicylic acid and salicylic acid
Not just as indigestion, stomach and duodenal hemorrhage, gastric ulcer and gastritis.Their solution and gastric juice not soluble in water.
Solution
The present invention relates to before the novel Diflunisal with positive charge, disalicylic acid, salicylic acid or its analog
Medicine and its application in field of medicaments.There are two functional groups for these compounds, can be modified and be formed with the hydrophilic of positive charge
Branch.As shown in general formula " structural formula 1 " and general formula " structural formula 2 ".
Wherein, R1Represent OH, OCOCH3, OCOC2H5, OCOC3H7, OCOC4H9, OCOC5H11, OCOC6H13, 2- hydroxy benzenes first
Acyloxy (salicyl oxygroup, 2-OCO-C6H4- OH), 2- acetoxyl group benzoyloxy (acetyl salicylic acyloxy, 2-
OCO-C6H4-OCOCH3), 2- propionyloxy benzoyloxy (propionyl salicyl oxygroup, 2-OCO-C6H4-OCOC2H5), or
2- butyryl acyloxy benzoyloxy (butyryl salicyl oxygroup, 2-OCO-C6H4-OCOC3H7);R2Represent H or 2,4- difluorobenzene
Base;R3Represent H, the alkyl of any 1-12 carbon atom, the alkoxy of 1-12 carbon atom, 1-12 carbon atom alkenyl or
The alkynyl or aryl of 1-12 carbon atom;R4Represent H, the alcoxyl of the alkyl of any 1-12 carbon atom, 1-12 carbon atom
The alkynyl or aryl of base, the alkenyl of 1-12 carbon atom or 1-12 carbon atom;R5Represent H, any 1-12 carbon atom
Alkyl, the alkoxy of 1-12 carbon atom, the alkenyl of 1-12 carbon atom or 1-12 carbon atom alkynyl or aryl;
X represents O, S or NH;A-Represent Cl-, Br-, F-, I-, AcO-, citrate or other anions;N=0,1,2,3,4,5,6,7,
8,9,10 ...;All R groups may include C, H, O, S, N atom, can there is singly-bound, double bond and three keys;Any CH2Group
It can be replaced by O, S or NH.
Wherein, X represents O or 2-OCO-C6H4-O);R2Represent H or 2,4- difluorophenyl;R3Represent H, any 1-12 carbon
The alkyl of atom, the alkyl of 1-12 carbon atom, the alkenyl of 1-12 carbon atom or 1-12 carbon atom alkynyl, Huo Zhefang
Base;R4Represent H, the alkyl of any 1-12 carbon atom, the alkoxy of 1-12 carbon atom, 1-12 carbon atom alkenyl or
The alkynyl or aryl of 1-12 carbon atom;R5Represent H, the alkane of the alkyl of any 1-12 carbon atom, 1-12 carbon atom
The alkynyl or aryl of oxygroup, the alkenyl of 1-12 carbon atom or 1-12 carbon atom;R6H is represented, any 1-12 carbon is former
The alkyl of son, the alkoxy of 1-12 carbon atom, the alkenyl of 1-12 carbon atom or 1-12 carbon atom alkynyl, Huo Zhefang
Base;Z represents O or S;A-Represent Cl-, Br-, F-, I-, AcO-, citrate or other anions;N=0,1,2,3,4,5,6,7,
8,9,10 ... all R groups may include C, H, O, S, N atom, can there is singly-bound, double bond and three keys;Any CH2Group can
To be replaced by O, S or NH.
Drug either passes through gastrointestinal tract or other approach absorb, and requires to wear in the form of individual molecule
Cross barrier film.Drug need to dissolve first, and if drug has ideal biopharmaceutical properties, it can be from the region of high concentration
It is diffused into the region of low concentration, enters blood or systemic circulation system across biomembrane.All biomembranes all contain lipid work
It is as the main component.The molecule to play a leading role in biofilm structure all have containing phosphatic highly polar head construction and,
In most cases, the hydrocarbon tails of two very hydrophobics.Biomembrane has double-layer structure, hydrophilic head structure direction two
The aqueous regions of side.Very hydrophilic drug can not be by passing through the very hydrophobic drug of lipid layer of biomembrane because of phase
The reason of patibhaga-nimitta holds stops wherein as a part of biomembrane, so that internal cytoplasm cannot be efficiently entering.
The purpose of the present invention is: by improving the dissolution of Diflunisal, disalicylic acid and salicylic acid in gastric juice
Their skin penetration rates to biomembrane and skin barrier are spent and improved, make it can be by cutaneous penetration (external application), to avoid
Their side effect.There are two identical design features for these novel prodrugs tool: they have a lipophilic part, and (oil is molten
Property part) and level-one, second level or a tertiary amine group (water-soluble portion existing for protonated form under physiological ph conditions
Point).Such molten balance of water-soluble-oil is that drug effectively passes through necessary to barrier film (Susan Milosovich, et
Al., J.Pharm.Sci., 82,227 (1993)).Amino with positive charge considerably increases the solubility of drug.5-(2,
4- difluorophenyl) diethylaminoethyl salicylate acetate, disalicylic acid lignocaine ethyl ester acetate, salicylic acid two
Ethylamino ethyl ester acetate, Diflunisal, the solubility of disalicylic acid and salicylic acid in water are respectively > 400mg, >
350mg, > 400mg, 0.05mg, 0.07 and 0.1mg/ml.In most cases, the dissolution of drug be it is most slow in absorption process and
The step of limiting speed.The solubility of Diflunisal, disalicylic acid and salicylic acid in gastric juice is very low.They are for a long time
Rest on intestines and stomach, it is thus possible to gastric mucosal cell be caused to damage.When these novel prodrugs are with such as tablet, capsule, solution and
The dosage form of suspension can dissolve in gastric juice when oral.Positive charge on these prodrugs amino can be with the phosphorus of biomembrane
Negative electrical charge on acid end group combines.Therefore, local concentration of the drug on the outside of biomembrane is very high logical to facilitate these prodrugs
Excessive concentrations region to the region of low concentration.After these prodrugs enter biomembrane, before hydrophilic parts will push
Medicine enters cytoplasm, a kind of concentrated aqueous solution or suspension of semi liquid state.Since the residence time in the gastrointestinal tract is short, prodrug
Gastric mucosal cell will not be caused to damage.5- (2,4- difluorophenyl) diethylaminoethyl salicylate acetate, salicyloyl bigcatkin willow
Sour lignocaine ethyl ester acetate, diethylaminoethyl salicylate acetate, Diflunisal, disalicylic acid and salicylic acid
Skin penetration rate in human skin passes through the improved pond Franz in vitro and measures, and wherein human skin is isolated from thigh
The human skin tissue (360-400 μm of thickness) of position above or below.Receive the cow's serum ball egg that solution is contained 2% by 10ml
White physiological saline composition is simultaneously stirred with 600 revs/min of speed.5- (2,4- difluorophenyl) diethylaminoethyl salicylate vinegar
Hydrochlorate, disalicylic acid lignocaine ethyl ester acetate, diethylaminoethyl salicylate acetate, Diflunisal, salicyloyl
Salicylic acid and the transdermal accumulation total amount of salicylic acid to the relationship of time are measured with specific high performance liquid chromatography.
With 30%5- (2,4- difluorophenyl) salicylic acid diethylamino containing the phosphate buffered saline solution (0.2M) for being dissolved in 2ml pH 7.4
The solution of base ethyl ester acetate, be dissolved in 2ml pH 7.4 phosphate buffered saline solution (0.2M) 30% disalicylic acid two
The solution of ethylamino ethyl ester acetate or be dissolved in 2ml pH 7.4 phosphate buffered saline solution (0.2M) 30% salicylic acid diethyl
The solution of amino ethyl ester acetate, or it is suspended in 30% Diflunisal of the phosphate buffered saline solution (0.2M) of 2ml pH 7.4
Suspension, be suspended in 2ml pH 7.4 phosphate buffered saline solution (0.2 M) 30% disalicylic acid suspension or
It is suspended in 30% salicylic suspension of the phosphate buffered saline solution (0.2M) of 2ml pH 7.4 as donor solution, as a result
As shown in Figure 1.To 5- (2,4- difluorophenyl) diethylaminoethyl salicylate acetate, disalicylic acid lignocaine second
It is right that its is calculated in ester acetate, diethylaminoethyl salicylate acetate, Diflunisal, disalicylic acid and salicylic acid
The apparent penetrating value of human skin is 100mg, 80mg, 60mg, 0.7mg, 0.8mg and 0.8mg/cm2/h.As a result illustrate, prodrug
Diffusion velocity of 5- (2,4- difluorophenyl) the diethylaminoethyl salicylate acetate in human skin is than Diflunisal itself
Nearly 150 times fast, diffusion velocity of the prodrug disalicylic acid lignocaine ethyl ester acetate in human skin is than salicyloyl water
Poplar acid itself is nearly 100 times fast, and prodrug diethylaminoethyl salicylate acetate is nearly 75 times faster than salicylic acid itself.As a result illustrate
Positive charge on dialkyl amino ethyl passes through biomembrane to drug and skin barrier is extremely important.General formula " structural formula 1 " or
Other prodrug skin penetration rates in " structural formula 2 " are very high, non-with disalicylic acid lignocaine ethyl ester acetate skin penetration rate
Very close to.
Experiment in vivo compares 5- (2,4- difluorophenyl) diethylaminoethyl salicylate acetate, disalicylic acid two
Ethylamino ethyl ester acetate, diethylaminoethyl salicylate acetate, Diflunisal, disalicylic acid and bigcatkin willow acid penetration
The hairless speed without the skin for hurting mouse living.Donor is by being dissolved in 30%5- (2,4- difluorophenyl) bigcatkin willow of 1ml isopropanol
The solution of sour lignocaine ethyl ester acetate, the 30% disalicylic acid lignocaine ethyl ester acetate for being dissolved in 1ml isopropanol
Solution, be dissolved in 1ml isopropanol 30% diethylaminoethyl salicylate acetate solution, be dissolved in the 30% of 1ml isopropanol
The solution of Diflunisal, be dissolved in 1ml isopropanol 30% disalicylic acid solution or be dissolved in 30% water of 1ml isopropanol
The solution composition of poplar acid.It is applied to hairless mouse back 1cm2Position.5- (2,4- difluorophenyl) salicylic acid diethyl in blood plasma
Amino ethyl ester acetate, disalicylic acid lignocaine ethyl ester acetate, diethylaminoethyl salicylate acetate, difluoro
Ni Liu, disalicylic acid and salicylic concentration are measured with specific efficient liquid-phase chromatography method.As a result (Fig. 2, figure
3, Fig. 4) be shown in using donor systems about after forty minutes 5- (2,4- difluorophenyl) diethylaminoethyl salicylate acetate,
The concentration of disalicylic acid lignocaine ethyl ester acetate and diethylaminoethyl salicylate acetate reaches peak value.It is oral
Diflunisal, disalicylic acid and salicylic acid need to can be only achieved within 1-2 hours its respective peak concentration.Diflunisal
Peak value is about 0.02mg/ml, and the peak value of disalicylic acid is about 0.01mg/ml, and salicylic peak value is about 0.01mg/
The peak value of ml, 5- (2,4- difluorophenyl) diethylaminoethyl salicylate acetate is about 5mg/ml, disalicylic acid diethyl
The peak value of amino ethyl ester acetate is about 4mg/ml, the peak value of diethylaminoethyl salicylate acetate be about 4mg/ml (about
200 to 400 times of difference).The Diflunisal of about 5mg/ml is than the Diflunisal blood that can effectively ease pain with effective antiinflammatory in blood plasma
Slurry concentration has been higher by as many as 25 times.This is exciting result.It can be easy to by these prodrugs, it rapidly will be effective
Diflunisal, disalicylic acid and the salicylic acid of plasma concentration are fed in host.Prodrug not only can mouth as the result is shown for these
Clothes, and can be by cutaneous penetration in various treatments.Before other in general formula " structural formula 1 " and general formula " structural formula 2 "
The skin penetration rate of medicine in vivo and 5- (2,4- difluorophenyl) diethylaminoethyl salicylate acetate are close.
In order to check stomach caused by these medicines and duodenal hemorrhage, we give rat daily, and (two groups, every group 10 greatly
Mouse) take orally 100mg/kg 5- (2,4- difluorophenyl) diethylaminoethyl salicylate acetate, disalicylic acid diethylamino
Base ethyl ester acetate, diethylaminoethyl salicylate acetate, Diflunisal, disalicylic acid and salicylic acid, continuous oral
21 days.It was found that averagely having 4mg blood in every gram of mouse excrement in salicylic acid group, put down in every gram of mouse excrement in Diflunisal group
There is 3mg blood, and in 5- (2,4- difluorophenyl) diethylaminoethyl salicylate acetate group, disalicylic acid diethyl
In amino ethyl ester acetate group, diethylaminoethyl salicylate acetate group and disalicylic acid group just without discovery
Blood.
We also study the acute toxicity of prodrug.Oral LD in rat50Are as follows: 5- (2,4- difluorophenyl) water
Poplar acid lignocaine ethyl ester acetate, disalicylic acid lignocaine ethyl ester acetate, diethylaminoethyl salicylate acetic acid
Salt is 1.0 g/kg, 2.0g/kg and 1.6g/kg.As a result illustrate the toxicity of prodrug lower than Diflunisal (LD50=0.5g/kg), water
Salysal (LD50=1.5g/kg) and salicylic acid (LD50=1.3g/kg).
Diflunisal, disalicylic acid and salicylic acid be proved to have it is anti-inflammatory, ease pain, bring down a fever and antirheumatic
Effect.One good prodrug should be able to return to female medicine in blood plasma.5- (2,4- difluorophenyl) diethylaminoethyl salicylate vinegar
The diethylin second of hydrochlorate, disalicylic acid lignocaine ethyl ester acetate and diethylaminoethyl salicylate acetate
Ester group can be sheared rapidly in vitro by the enzyme in human plasma, return to female medicine Diflunisal, salicyloyl more than 90% prodrug
Salicylic acid and salicylic acid.Since the absorptivity of prodrug is higher, the prodrug curative effect of same dose is more preferable than female medicine itself.We
To 5- (2,4- difluorophenyl) diethylaminoethyl salicylate acetate, disalicylic acid lignocaine ethyl ester acetate with
And the analgesia of diethylaminoethyl salicylate acetate, it brings down a fever and is tested with anti-inflammatory effect, and do ratio with Diflunisal
Compared with.Also other compounds in mutual-through type " structural formula 1 " and general formula " structural formula 2 " are tested with identical method, as a result
It is very close with the result of 5- (2,4- difluorophenyl) diethylaminoethyl salicylate acetate.
Analgesic activity: it is surveyed according to the method (J.Pharmacol.Exp.Ther., 72,74 (1941)) of D'Amour-Smith
Determine the extension time of the mouse tail threshold of pain.Mouse oral 200mg/kg Diflunisal, disalicylic acid and salicylic acid, it is transdermal to give
Medicine 200mg/kg 5- (2,4- difluorophenyl) diethylaminoethyl salicylate acetate, disalicylic acid lignocaine ethyl ester
After acetate and diethylaminoethyl salicylate acetate, the tail of mouse is exposed in thermostimulation, the measurement threshold of pain extends
Time.As a result as shown in Fig. 5.Cutaneous penetration 200mg/kg 5- (2,4- difluorophenyl) diethylaminoethyl salicylate acetate
(C), the group ratio of disalicylic acid lignocaine ethyl ester acetate (D) and diethylaminoethyl salicylate acetate (E) is given
The group of medicine 200mg/kg Diflunisal shows stronger analgesic activities.
The writhing number occurred after acetum is administered to mouse peritoneal to count, and writhing is calculated based on control group
Inhibiting rate.54 mouse are divided into 9 groups (every group 6).Diflunisal (50mg/kg and 100mg/ is administered in the mouse of B1 and B2 group
Kg), and C1 and C2 group cutaneous penetration 5- (2,4- difluorophenyl) diethylaminoethyl salicylate acetate (50mg/kg and
100mg/kg).D1 and D2 group cutaneous penetration disalicylic acid lignocaine ethyl ester acetate (50mg/kg and 100mg/kg).
E1 and E2 group cutaneous penetration diethylaminoethyl salicylate acetate (50mg/kg and 100mg/kg).A is control group.It is being administered
Test compound is delivered medicine into mouse before acetum 30 minutes.It the results are shown in Table 1.
The inhibiting rate of 1. Diflunisal of table and its prodrug to mouse writhing
Group |
A |
B1 |
B2 |
C1 |
C2 |
D1 |
D2 |
E1 |
E2 |
Dosage (mg/kg) |
0 |
50 |
100 |
50 |
100 |
50 |
100 |
50 |
100 |
Writhing number |
35.0 |
18.1 |
13.2 |
13.2 |
10.2 |
14.2 |
12.0 |
14.0 |
11.9 |
Percentage (%) |
- |
48 |
62 |
62 |
71 |
59 |
65 |
60 |
66 |
The analgesic effect ratio 5- (2,4- bis- of 5- (2,4- difluorophenyl) diethylaminoethyl salicylate acetate as the result is shown
Fluorophenyl) salicylic acid (Diflunisal) is good.Other compounds in general formula " structural formula 1 " and general formula " structural formula 2 " show phase
As analgesic activities.
Antipyretic effect: rat receives colibacillus deactivating suspension as pyrogen.56 rats are divided into 9 groups.A group is
Control group.After 2 hours, it is administered orally Diflunisal (B1 group is that 100mg/kg and B2 group is 150mg/kg), cutaneous penetration 5-
(2,4- difluorophenyl) diethylaminoethyl salicylate acetate (C1 group is that 100mg/kg and C2 group is 150mg/kg), bigcatkin willow
Acyl diethylaminoethyl salicylate acetate (D1 group is that 100mg/kg and D2 group is 150mg/kg) and salicylic acid lignocaine
Ethyl ester acetate (E1 group is that 100mg/kg and E2 group is 150mg/kg).Compound administration front and back is tested every 90 minutes to big
Mouse surveys body temperature.As a result 2 be see the table below.
The antipyretic effect of 2. Diflunisal of table and its prodrug
5- (2,4- difluorophenyl) diethylaminoethyl salicylate acetate of 100mg/kg dosage is brought down a fever as the result is shown
Activity is better than Diflunisal.Other compounds show similar work of bringing down a fever in general formula " structural formula 1 " and general formula " structural formula 2 "
Property.
Anti-inflammatory effect: to Oral Administration in Rats or cutaneous penetration 50mg/kg 5- (2,4- difluorophenyl) salicylic acid lignocaine second
Ester acetate.50mg/kg Diflunisal is administered orally.After sixty minutes the meat of angle dish sol solution subcutaneous administration to rat claw
Under pad.The volume of the rat hind paw of measurement in every 1 hour, calculates the growth rate of the volume of rear solid end and conduct after administration angle dish glue
Swelling rate (%).Obtained result is as shown in Figure 6.It takes orally and cutaneous penetration 50mg/kg 5- (2,4- difluorobenzenes as the result is shown
Base) diethylaminoethyl salicylate acetate antiphlogistic effects than be administered orally same dose Diflunisal it is good.General formula " knot
Structure formula 1 " is similar with the antiphlogistic effects of other compounds shown in general formula " structural formula 2 ".
It, can be anti-by inhibiting the activities present of Cycloxygenase to go out anti-reactive-when the Diflunisal of high oral dose
The effect of asthma.Since these prodrugs have a higher membrane penetration rate, thus can by way of spraying into mouth or nasal cavity come
Treat asthma.Since with anti-inflammatory effect and higher skin penetration rate, these prodrugs can be used to treat acne.
These prodrugs are water-soluble neutral salt, good to Ocular Tolerability.They can also be used to treat inflammation of eye section, treatment
Ocular pain after operation on cornea treats glaucoma or treatment ear inflammation and/or painful conditions (otitis).
The present invention relates to contain prodrug represented by general formula " structural formula 1 " and " structural formula 2 " and its typical additives, auxiliary material
Pharmaceutical preparation, for example, tablet for oral administration, capsule or solution etc., or the solution for cutaneous penetration, lotion, ointment,
Latex or gel etc..The novel active compound of general formula " structural formula 1 " or " structural formula 2 " can with vitamin such as vitamin A,
B, C, E, beta carotene etc. or other medicines, such as folic acid combine any Diflunisal, water for treating human body or animal
The treatable disease of salysal, salicylic acid.
Skin-penetrating therapeutic application system contains compound or contain at least one that general formula " structural formula 1 " or " structural formula 2 " indicates
Composition of the compound that general formula " structural formula 1 " or " structural formula 2 " indicate as active constituent, can be used for treating human or animal
In any Diflunisal, disalicylic acid, salicylic acid-treatable state.These systems can be bandage or patch,
Hypothallus and an impermeable protective layer containing one comprising active material.Most preferred system is an active substance reservoir, is contained
There is a permeable bottom towards skin.By control rate of release, the system can make Diflunisal, disalicylic acid,
Salicylic acid is stablized in optimal treatment blood concentration to improve curative effect and reduces Diflunisal, disalicylic acid, salicylic
Side effect.These systems can be worn over any position of wrist, ankle-joint, arm, leg or body.
Compound represented by above-mentioned general formula (1) " structural formula 1 " can be by 5- (2,4- difluorophenyl) acetylsalicylic acid, second
Acyl disalicylic acid or acetylsalicylic acid functional derivative, for example, the acid halide of general formula (3) " structural formula 3 " or mixed
It closes acid anhydrides to be reacted with the compound of general formula (4) " structural formula 4 " to prepare, then passes through hydrolysis removal acetyl group.Acetyl group is gone
Except being not required, because it in vitro can be by THE ADIABATIC SHEAR IN in the enzyme of human plasma.
In structural formula 3, R1Represent acetoxyl group (OCOCH3) or 2- acetyl group oxygroup benzoyloxy (salicyl oxygroup,
2-OCO-C6H4-OCOCH3);R2Represent H or 2,4- difluorophenyl;Y represents halogen, alkoxy carbonyl group or substituted aryloxy group carbonyl oxygen
Base.
In structural formula 4, R3H is represented, the alkyl of any 1-12 carbon atom, alkoxy, the 1-12 of 1-12 carbon atom are a
The alkenyl of carbon atom, the alkynyl or aryl of 1-12 carbon atom;R4Represent H, alkyl, the 1-12 of any 1-12 carbon atom
The alkynyl or aryl of the alkoxy of a carbon atom, the alkenyl of 1-12 carbon atom or 1-12 carbon atom;X represents O, S or
NH;N=0,1,2,3,4,5,6,7,8,9,10 ...
Compound represented by above-mentioned general formula " structural formula 1 " can be by 5- (2,4- difluorophenyl) acetylsalicylic acid, second
Acyl disalicylic acid or acetylsalicylic acid, with compound represented by general formula (4) " structural formula 4 " by coupling agent, such as:
N, N '-dicyclohexylcarbodiimide (DCC), N, N '-diisopropylcarbodiimide (DIC), O- (benzotriazole -1- base)-N, N,
N', N'- tetramethylurea tetrafluoro boric acid ester (HBTU), O- (benzotriazole -1- base)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid
(prepared by the coupling reaction of dimethylamino) Phosphonium-hexafluorophosphate etc. for ester (BOP), benzotriazole -1- base-oxygroup-three.
When the X represented by general formula " structural formula 1 " represents O, compound represented by above-mentioned general formula (1) " structural formula 1 " can
By the metal salt or organic base of 5- (2,4- difluorophenyl) acetylsalicylic acid, acetylsalicylsalicylic acid or acetylsalicylic acid
Salt reacts to obtain with compound represented by general formula (5) " structural formula 5 ".
In structural formula 5, R2H is represented, the alkyl of any 1-12 carbon atom, alkoxy, the 1-12 of 1-12 carbon atom are a
The alkynyl or aryl of the alkenyl of carbon atom or 1-12 carbon atom;R3Represent H, alkyl, the 1- of any 1-12 carbon atom
The alkynyl or aryl of the alkoxy of 12 carbon atoms, the alkenyl of 1-12 carbon atom or 1-12 carbon atom;R4H is represented,
The alkyl of any 1-12 carbon atom, the alkoxy of 1-12 carbon atom, 1-12 carbon atom alkenyl or 1-12 carbon atom
Alkynyl or aryl;Z represents halogen or p-toluenesulfonyl;A-Represent Cl-, Br-, F-, I-, AcO-, citrate, or
Other anions;N=0,1,2,3,4,5 ...
When the X represented by general formula (1) " structural formula 1 " represents O, chemical combination represented by above-mentioned general formula (1) " structural formula 1 "
Object can be by 5- (2,4 difluorobenzene base) acetylsalicylic acid, acetylsalicylsalicylic acid represented by general formula (6) " structural formula 6 "
Or the immobilization alkali salt of acetylsalicylic acid reacts to obtain with compound represented by general formula (5) " structural formula 5 ".
In structural formula 6, R represents the resin of interlinkage;R1Represent acetoxyl group (OCOCH3) or 2- acetoxyl group benzoyloxy
(acetyl salicylic acyloxy, 2-OCO-C6H4-OCOCH3), R2Represent H or 2,4 difluorobenzene base;B represents any basic group,
Such as pyridyl group, piperidyl, triethylamine and or other basic groups.
Compound in above-mentioned general formula (2) " structural formula 2 " can be by 5- (the 2,4- difluoro represented by general formula (7) " structural formula 7 "
Phenyl) salicylic acid, disalicylic acid or salicylic acid with the compound in general formula (8) " structural formula 8 " react synthesis.
In structural formula 7, R2Represent H or 2,4 difluorobenzene base;R6Represent H, the alkyl of any 1-12 carbon atom, 1-12
The alkynyl or aryl of the alkoxy of carbon atom, the alkenyl of 1-12 carbon atom or 1-12 carbon atom.
In structural formula 8, R3H is represented, the alkyl of any 1-12 carbon atom, alkoxy, the 1-12 of 1-12 carbon atom are a
The alkynyl or aryl of the alkenyl of carbon atom or 1-12 carbon atom;R4Represent H, alkyl, the 1- of any 1-12 carbon atom
The alkynyl or aryl of the alkoxy of 12 carbon atoms, the alkenyl of 1-12 carbon atom or 1-12 carbon atom;R5H is represented,
The alkyl of any 1-12 carbon atom, the alkoxy of 1-12 carbon atom, 1-12 carbon atom alkenyl or 1-12 carbon atom
Alkynyl or aryl;X represents halogen, alkoxy carbonyl group or the fragrant oxygen carbonyl replaced;A-Represent Cl-, Br-, F-, I-,
AcO-, citrate or other anions;N=0,1,2,3,4,5,6,7,8,9,10 ...
Advantage
These Diflunisals, disalicylic acid, some in salicylic acid prodrug are hydrophobicity, and another part is hydrophilic
Property (with amido existing for protonated form under physiological ph).The positively charged amino of these prodrugs has two big advantages.Firstly, it
Greatly improve the solubility of drug;When these new prodrugs with such as tablet, capsule, solution or suspension by it is oral when,
It can be quickly soluble in gastric juice.Second, the positively charged amino of these prodrugs can negatively charged phosphate head with biomembrane
The bonding of portion's structure.Therefore, the local concentration outside film can be very high, to promote drug from high concentration region through low concentration region.
After these prodrugs enter biomembrane, hydrophilic parts will push drug to enter in cytoplasm, and cytoplasm is concentration
Semi liquid state aqueous solution or suspension.Since residence time is very short in the gastrointestinal tract for these prodrugs, gastric mucosa will not be made
At injury.Experimental result shows that 90% prodrug can become female medicine again.These prodrugs have better absorptivity, so same dose
Under, the curative effect of prodrug is more preferable than Diflunisal, disalicylic acid, salicylic acid.It is demonstrated experimentally that prodrug 5- (2,4- difluorobenzenes
Base) diethylaminoethyl salicylate acetate is fast nearly 150 times through the speed ratio Diflunisal of human skin itself.5- (2,4-
Difluorophenyl) diethylaminoethyl salicylate acetate is very high through the vivo transdermal speed of hairless mouse skin living.Mouthful
Diflunisal blood concentration reaches peak value, but 5- (2,4- difluorophenyl) salicylic acid diethyl after taking diflunisal tablet 1-2 hours
Amino ethyl ester acetate only needs 40 minutes peak plasma concentrations that just can reach Diflunisal.It is the most exciting the result is that preceding
Medicine can not only take orally, and can by way of cutaneous penetration for any drug therapy and can avoid Diflunisal,
Disalicylic acid and salicylic most of side effects, wherein being most importantly avoided that gastrointestinal discomfort such as digestion not
Good, stomach and duodenal hemorrhage, gastric ulcer and gastritis etc..The another of these prodrug cutaneous penetrations is advantageous in that greatly administration more
It is convenient, especially children are administered.
Detailed description of the invention
Fig. 1: by 5- (2,4 difluorobenzene base) salicylic acid diethyl of the human skin tissue separated in the pond Franz (n=5)
Amino ethyl ester acetate (A, 30% solution), disalicylic acid lignocaine ethyl ester acetate (B, 30% solution), salicylic acid
(E, 30% is mixed for lignocaine ethyl ester acetate (C, 30% solution), Diflunisal (D, 30% suspension), disalicylic acid
Suspension) and salicylic acid (F, 30% suspension).Carrier solution under the conditions of various is the phosphate buffer solution of pH 7.4
(0.2M)。
Fig. 2: 30%5- (2,4 difluorobenzene base) water of 1ml isopropanol is dissolved in the back hairless mouse (n=5) local use
Total blood medicine after poplar acid lignocaine ethyl ester Acetate Solution (A) or 5- (2,4- difluorophenyl) salicylic acid (Diflunisal, B)
Concentration.
Fig. 3: 30% disalicylic acid diethylamino of 1ml isopropanol is dissolved in the back hairless mouse (n=5) local use
Total blood concentration after base ethyl ester Acetate Solution (A) or disalicylic acid (B).
Fig. 4: 30% diethylaminoethyl salicylate of 1ml isopropanol is dissolved in the back hairless mouse (n=5) local use
Total blood concentration after Acetate Solution (A) or salicylic acid (B).
Fig. 5: in oral 200mg/kg Diflunisal (B), cutaneous penetration 200mg/kg 5- (2,4- difluorophenyl) salicylic acid
Lignocaine ethyl ester acetate (C), cutaneous penetration disalicylic acid lignocaine ethyl ester acetate (D) and cutaneous penetration
After diethylaminoethyl salicylate acetate (E), the mouse tail threshold of pain extends the time.A is control group.
Fig. 6: the swelling rate (%) after injection angle dish glue.Angle dish glue injects first 1 hour oral 50mg/kg 5- (2,4- difluoros
Phenyl) salicylic acid (Diflunisal, B), take orally (C) and cutaneous penetration (D) 50mg/kg 5- (2,4- difluorophenyl) salicylic acid
Lignocaine ethyl ester acetate.A is control group.
Fig. 7: in structural formula 1, R1Represent OH, OCOCH3, OCOC2H5, OCOC3H7, OCOC4H9, OCOC5H11, OCOC6H13,
2- (2-hydroxybenzoyl) oxygroup (salicyl oxygroup, 2-OCO-C6H4- OH), 2- acetoxyl group benzoyloxy (acetyl salicylic acyl
Base oxygroup, 2-OCO-C6H4-OCOCH3), 2- propionyloxy benzoyloxy (propionyl salicyl oxygroup, 2-OCO-C6H4-
OCOC2H5), 2- butyryl acyloxy benzoyloxy (butyryl salicyl oxygroup, 2-OCO-C6H4-OCOC3H7);R2H or 2 is represented,
4- difluorophenyl;R3Represent H, alkoxy, the 1-12 carbon atom of the alkyl of any 1-12 carbon atom, 1-12 carbon atom
Alkenyl or 1-12 carbon atom alkynyl or aryl;R4H is represented, the alkyl of any 1-12 carbon atom, 1-12 carbon are former
The alkynyl or aryl of the alkoxy of son, the alkenyl of 1-12 carbon atom or 1-12 carbon atom;R5Represent H, any 1-12
The alkyl of a carbon atom, the alkoxy of 1-12 carbon atom, the alkenyl of 1-12 carbon atom or 1-12 carbon atom alkynyl,
Or aryl;X represents O, S or NH;A-Represent Cl-, Br-, F-, I-, AcO-, citrate or other anions;N=0,1,2,
3,4,5,6,7,8,9,10 ... all R groups may include C, H, O, S, N atom, can there is singly-bound, double bond and three keys;Appoint
What CH2Group can be replaced by O, S or NH.
In structural formula 2, X represents O or 2-OCO-C6H4-O);R2Represent H or 2,4- difluorophenyl;R3Represent H, any 1-
The alkyl of 12 carbon atoms, the alkyl of 1-12 carbon atom, the alkenyl of 1-12 carbon atom or 1-12 carbon atom alkynyl,
Or aryl;R4Represent H, the alkyl of any 1-12 carbon atom, the alkoxy of 1-12 carbon atom, 1-12 carbon atom
The alkynyl or aryl of alkenyl or 1-12 carbon atom;R5H is represented, the alkyl of any 1-12 carbon atom, 1-12 carbon are former
The alkynyl or aryl of the alkoxy of son, the alkenyl of 1-12 carbon atom or 1-12 carbon atom;R6Represent H, any 1-12
The alkyl of a carbon atom, the alkoxy of 1-12 carbon atom, the alkenyl of 1-12 carbon atom or 1-12 carbon atom alkynyl,
Or aryl;Z represents O or S;A-Represent Cl-, Br-, F-, I-, AcO-, citrate or other anions;N=0,1,2,3,4,
5,6,7,8,9,10 ... all R groups may include C, H, O, S, N atom, can there is singly-bound, double bond and three keys;Any CH2
Group can be replaced by O, S or NH.
Preferred forms
The synthesis of 5- (2,4 difluorobenzene base) diethylaminoethyl salicylate acetate
11.7g Diethylaminoethanol is dissolved in 10% sodium bicarbonate solution and 100ml acetone of 200ml.By 31.1g
5- (2,4 difluorobenzene base) the acetyl salicylic acyl chlorides of (0.1mol) is added in reaction mixture.Mixture stirs 3 hours at room temperature.
Boil off solvent.Residue is suspended from 500ml ethyl acetate.Into reaction mixture, the sodium bicarbonate of 200ml 5% is added in stirring.
Ethyl acetate layer is collected, is washed with water three times, each 500ml.Ethyl acetate solution is dry with anhydrous sodium sulfate.It is filtered to remove sulphur
Sour sodium.6g acetic acid is added in stirring in reaction mixture.Boil off organic phase.35g target product easy to moisture absorption is obtained after drying, is produced
Rate is 88%.Solubility in water: 400mg/ml;Elemental analysis: C21H25F2NO5;Molecular weight: 409.42.Theoretical value (%): C:
61.60;H:6.15;F:9.28;N:3.42;O:19.54;Measured value (%): C:61.56;H:6.18;F:9.27;N:3.40;
O:19.59.1H-NMR (400MHz, deuterated chloroform solvent): δ: 1.56 (t, 6H), 2.21 (s, 3H), 3.27 (m, 4H), 3.70
(m, 2H), 4.69 (t, 2H), 4.9 (b, 1H), 6.74 (m, 1H), 6.84 (m, 1H), 7.0 (b, H), 7.06 (b, 1H), 7.15
(m, 1H), 7.44 (m, 1H), 7.86 (m, 1H).
Embodiment
1. the synthetic method of disalicylic acid lignocaine ethyl ester acetate
31.8g (0.1mol) acetylsalicylsalicylic acid acyl chlorides is dissolved in 100ml chloroform.Mixture is cooled to 0 DEG C.Instead
It answers and 15ml triethylamine and 8.9g (0.1mol) dimethylaminoethanol is added in mixture.Mixture is stirred at room temperature 3 hours.It boils off
Reaction dissolvent.Residue is dissolved in 300ml methanol, and the sodium bicarbonate aqueous solution of 200ml 5% is added in reaction mixture.Mixing
Object stirs 3 hours.Mixture is evaporated, into residue, 300ml methanol is added in stirring.It is filtered to remove solid, and uses methanol
It washes.It is evaporated solution, 200ml chloroform is added into residue.6g acetic acid is added in stirring in reaction mixture.It is filtered to remove solid.
It is stirred for that 6g acetic acid is added in reaction mixture.Boil off organic phase.32g target product easy to moisture absorption is obtained after drying, is produced
Rate is 82%.Solubility in water: 400mg/ml;Elemental analysis: C20H23NO7;Molecular weight: 389.40.Theoretical value (%) C:
61.69;H:5.95;N:3.60;O:28.76;Measured value (%) C:61.66;H:5.98;N:3.58;O:28.78.1H-NMR
(400MHz, deuterated chloroform solvent): δ: 2.21 (s, 3H), 2.90 (s, 6H), 3.70 (m, 2H), 4.69 (t, 2H), 4.9 (b,
1H), 6.74 (b, 1H), 6.88 (m, 1H), 7.0 (b, H), 7.26 (b, 1H), 7.27 (m, 1H), 7.35 (m, 1H), 7.54 (m,
1H), 7.97 (m, 1H), 8.06 (m, 1H).
2. the synthetic method of salicylic acid dimethylaminoethyl acetate
19.9g (0.1mol) acetyl salicylic acyl chlorides is dissolved in 100ml chloroform.Mixed liquor is cooled to 0 DEG C.Reaction mixing
15ml triethylamine and 8.9g (0.1mol) dimethylaminoethanol are added in object.Mixture is stirred at room temperature 3 hours.Boil off solvent.
Residue is dissolved in 300ml methanol, and the sodium bicarbonate aqueous solution of 200ml 5% is added in reaction mixture.Mixture reflux 2 is small
When.It is evaporated mixture.300ml methanol is added in stirring in residue.It is filtered to remove solid and is washed with methanol.It is evaporated solution and will be residual
Excess is dissolved in 200ml chloroform.6g acetic acid is added in stirring in reaction mixture.It is filtered to remove solid.It is stirred again in reaction mixture
It mixes and 6g acetic acid is added.Boil off organic phase.23g target product easy to moisture absorption, yield 88% are obtained after drying.Solubility in water:
350mg/ml;Elemental analysis: C13H19NO5;Molecular weight: 269.29.Theoretical value (%) C:57.98;H:7.11;N:5.20;O:
29.71;Measured value (%) C:57.96;H:7.13;N:5.17;O:29.74.1H-NMR (400MHz, deuterated chloroform solvent): δ:
2.21 (s, 3H), 2.90 (s, 6H), 3.70 (m, 2H), 4.69 (t, 2H), 4.9 (b, 1H), 6.74 (b, 1H), 6.84 (m, 1H),
6.93 (b, 1H), 6.98 (b, 1H), 7.30 (b, 1H).
The synthesis of 3.S-5- (2,4 difluorobenzene base) salicylic acid dimethylamino second thioesters acetate
31.1g (0.1mol) 5- (2,4 difluorobenzene base) acetyl salicylic acyl chlorides is dissolved in 100ml chloroform.Mix liquid cooling
But to 0 DEG C.15ml triethylamine and 9.3g dimethylamino ethyl mercaptan are added in reaction mixture.Mixture is stirred at room temperature 3 hours.
Boil off solvent.Residue is dissolved in 300ml methanol, and the sodium bicarbonate aqueous solution of 200ml 5% is added in reaction mixture.Mixing
Liquid flows back 2 hours.Mixed liquor is evaporated.300ml methanol is added in stirring in residue.It is filtered to remove solid, and is washed with methanol.It steams
Dry solution, residue are dissolved in 200ml chloroform.6g acetic acid is added in stirring in reaction mixture.It is filtered to remove solid.Reaction is mixed
It closes and is stirred for that 6g acetic acid is added in object.Boil off organic solvent.32g target product easy to moisture absorption is obtained after drying, yield is
80.5%.Solubility in water: 400mg/ml;Elemental analysis: C19H21F2NO4S;Molecular weight: 397.44.Theoretical value (%) C:
57.42;H:5.33;F:9.56;N:3.52;O:16.10, S:8.07;Measured value (%) C:57.40;H:5.35;F:9.53;N:
3.51;O:16.15;S:8.06.1H-NMR (400MHz, deuterated chloroform solvent): δ: 2.20 (s, 3H), 2.90 (s, 6H), 3.31
(t, 2H), 3.91 (t, 2H), 5.0 (b, 1H), 6.7 (b, 1H), 6.74 (m, 1H), 6.84 (m, 1H);7.14 (m, 1H), 7.23
(m, 1H) .7.44 (m, 1H), 7.87 (m, 1H).
The synthetic method of 4.5- (2,4 difluorobenzene base) bigcatkin willow dimethylamino acetamide acetate
31.1g (0.1mol) 5- (2,4 difluorobenzene base) acetyl salicylic acyl chlorides is dissolved in 100ml chloroform.Mixture is cold
But to 0 DEG C.15ml triethylamine and 8.8g (0.1mol) dimethylaminoethylamine are added in reaction mixture.Mixture is stirred at room temperature 3
Hour.Boil off solvent.Residue is dissolved in 300ml methanol, and the sodium bicarbonate aqueous solution of 200ml 5% is added in reaction mixture.
Mixture flows back 2 hours.Mixture is evaporated.300ml methanol is added in stirring in residue.It is filtered to remove solid, and uses methanol
It washes.Solution is evaporated, and residue is dissolved in 200ml chloroform.6g acetic acid is added in stirring in reaction mixture.It is filtered to remove solid.Instead
It answers and is stirred for that 6g acetic acid is added in mixture.Boil off organic solution.33g target product easy to moisture absorption is obtained after drying, yield is
86.8%.Solubility in water: 400mg/ml;Molecular formula: C19H22F2N2O4;Molecular weight: 380.39.Theoretical value (%): C:
59.99;H:5.83;F:9.99;N:7.36;O:16.82;Measured value (%): C:59.97;H:5.85;F:9.98;N:7.35;
O:16.85.1H-NMR (400MHz, deuterated chloroform solvent): δ: 2.20 (s, 3H), 2.90 (s, 6H), 3.54 (t, 2H), 3.64
(t, 2H), 5.0 (b, 1H), 6.7 (b, 1H), 6.73 (m, 1H), 6.80 (m, 1H);7.15 (m, 1H), 7.22 (m, 1H) .7.44
(m, 1H), 7.87 (m, 1H), 8.01 (b, 1H).
The synthetic method of 5.S- salicylic acid lignocaine second thioesters acetate
18g (0.1mol) acetylsalicylic acid is dissolved in 100ml methylene chloride (DCM).Mixture is cooled to 0 DEG C.Instead
Answer addition 20.6g 1,3- dicyclohexylcarbodiimide (DCC) in mixture.Mixture stirs 30 minutes at 0 DEG C.Reaction mixing
13.4g (0.1mol) diethylamino ethanethiol is added in object.Mixture is stirred at room temperature 3 hours.Boil off solvent.Residue is dissolved in
5% sodium bicarbonate aqueous solution of 200ml is added in reaction mixture for 300ml methanol.Mixture is stirred at room temperature 20 hours.It is evaporated
Mixture.300ml methanol is added in stirring in residue.It is evaporated solution, residue is dissolved in 200ml chloroform.It is stirred in reaction mixture
It mixes and 6g acetic acid is added.It is filtered to remove solid.It is stirred for that 6g acetic acid is added in reaction mixture.Boil off organic solution.After drying
The target product easy to moisture absorption to 29g, yield 92.5%.Solubility in water: 400mg/ml;Elemental analysis: C15H23NO4S;Point
Son amount: 313.41.Theoretical value (%): C:57.48;H:7.40;N:4.47;O:20.42, S:10.23;Measured value (%) C:
57.43;H:7.42;N:4.46;O:20.47;S:10.21.1H-NMR (400MHz, deuterated chloroform solvent): δ: 1.56 (t,
6H);2.20 (s, 3H), 3.26 (m, 4H), 3.31 (t, 2H), 3.91 (t, 2H), 5.0 (b, 1H), 6.8 (b, 1H), 6.92 (d,
1H), 7.41 (d, 1H), 7.81 (d, 1H).
The synthetic method of 6.5- (2,4 difluorobenzene base) salicylic acid 3-N, N- lignocaine propyl ester acetate
27.8g (0.1mol) 5- (2,4 difluorobenzene base) salethyl is dissolved in 100ml chloroform.Mixture is cooled to
0℃.21ml triethylamine (0.2mol) and 20.0g (0.1mol) 3-N, N- lignocaine propionyl villaumite is added in reaction mixture
Hydrochlorate.Mixture is stirred at room temperature 3 hours.It is filtered to remove solid.6g acetic acid is added in stirring in reaction mixture.Be added 200ml oneself
Alkane.Solid product is collected by filtration.40g target product easy to moisture absorption, yield 85.9% are obtained after drying.Solubility in water:
400 mg/ml;Elemental analysis: C24H29F2NO6;Molecular weight: 465.49.Theoretical value (%): C:61.93;H:6.28;F:8.16;
N:3.01;O:20.62;Measured value (%): C:61.90;H:6.30;F:8.15;N:3.00;O:20.65.1H-NMR
(400MHz, deuterated chloroform solvent): δ: 1.30 (t, 3H), 1.56 (t, 6H), 2.20 (s, 3H), 2.67 (t, 2H);3.28 (m,
4H), 3.50 (m, 2H), 4.29 (m, 2H), 6.8 (b, 1H), 6.70 (m, 1H), 6.81 (m, 1H), 7.40 (m, 2H), 7.44 (d,
1H), 7.9 (d, 1H).
The synthetic method of 7.5- (2,4 difluorobenzene base) salicylic acid 3-N, N- lignocaine propyl ester acetate
28.6g (0.1mol) disalicylic acid ethyl ester is dissolved in 100ml chloroform.Mixture is cooled to 0 DEG C.Reaction is mixed
It closes and 21ml triethylamine (0.2mol) and 17.2g (0.1mol) 3-N, N- lignocaine propionyl chloride hydrochloride is added in object.Mixture
It stirs 3 hours at room temperature.It is filtered to remove solid.6g acetic acid is added in stirring in reaction mixture.200ml hexane is added.Filtering is received
Collect solid product.42g target product easy to moisture absorption, yield 88.7% are obtained after drying.Solubility in water: 380mg/ml;Member
Element analysis: C25H31NO8;Molecular weight: 473.52.Theoretical value (%) C:63.41;H:6.60;N:2.96;O:27.03;Measured value
(%) C:63.40;H:6.62;N:2.93;O:27.05.1H-NMR (400MHz, deuterated chloroform solvent): δ: 1.30 (t, 3H),
1.57 (t, 6H);2.20 (s, 3H), 2.68 (t, 2H);3.28 (m, 4H), 3.50 (m, 2H), 4.29 (m, 2H), 6.8 (b, 1H),
7.21 (m, 2H), 7.26 (m, 1H), 7.27 (m, 1H), 7.49 (m, 1H), 7.54 (m, 1H);8.05 (m, 1H);8.12 (m,
1H)。
8. the synthetic method of salicylic acid 3-N, N- dimethylamino propyl ester acetate
16.6g (0.1mol) salethyl is dissolved in 100ml chloroform.Mixture is cooled to 0 DEG C.Reaction mixture
21ml triethylamine (0.2mol) and 17.2g (0.1mol) 3-N, N- dimethylaminopropionyl chloride hydrochloride is added in middle stirring.Mixture
It is stirred at room temperature 3 hours.It is filtered to remove solid.6g acetic acid is added in stirring in reaction mixture.200ml hexane is added.It is collected by filtration
Solid product.28g target product easy to moisture absorption, yield 85.9% are obtained after drying.Solubility in water: 400mg/ml;Element
Analysis: C16H23NO6;Molecular weight: 325.36.Theoretical value (%): C:59.06;H:7.13;N:4.31;O:29.50;Measured value
(%): C:59.03;H:7.15;N:4.30;O:29.52.1H-NMR (400MHz, deuterated chloroform solvent): δ: 1.31 (t, 3H),
2.20 (s, 3H), 2.68 (t, 2H);2.92 (m, 4H), 3.50 (m, 2H), 4.30 (m, 2H), 6.8 (b, 1H), 7.18 (m, 2H),
7.44 (m, 1H), 7.92 (m, 1H).
Industrial application
Prodrug shown in general formula (1) " structural formula 1 " and " structural formula 2 " is better than Diflunisal, disalicylic acid and water
Poplar acid.They can be used for treating the shape of any Diflunisal of humans and animals, disalicylic acid and salicylic acid-treatable
State.They can be used for the sign and symptom of rheumatoid arthritis and osteoarthritis, bring down a fever, and treatment dysmenorrhea.They
Bartter syndrome and chronic anterior uveitis and posterior uveitis can be treated individually or as adjuvant.They can also be treated
Intrauterine device uterine hemorrhage prevents and treats patient's caused Nausea and vomiting when pelvic radiation is treated.These prodrugs
It can also be used to treat diabetic neuropathy, acute migraine and hemophilic arthritis.They can treat bone loss, in advance
Anti- or treatment sunburn.They perhaps can be also used for pre- anti-cancer.Due to there is very high membrane penetration rate, these prodrugs are also
Asthma can be treated by way of sucking host.Because these prodrugs have antiinflammation, they also can treat acne.