CN1800195A - Chemical compound synthesized by carboxylic acid analog non-steroid anti-inflammatory agent and aminoglucose or its salt, and its synthesis method and uses - Google Patents
Chemical compound synthesized by carboxylic acid analog non-steroid anti-inflammatory agent and aminoglucose or its salt, and its synthesis method and uses Download PDFInfo
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Abstract
The invention discloses a compound which is synthesized by alcoholic acid type non-steroidal anti-inflammatory agent and amide dextrose and its salt and the synthesizing method and it's applied. The compound has general formula (I) and general formula (II).
Description
Technical field
The invention belongs to pharmacy field, relate to and a kind ofly possess good physiologically active and, the invention still further relates to the synthetic method and the application of this compound than carboxylic-acid NSAID (non-steroidal anti-inflammatory drug) and glucosamine or its salt synthetic compound of low irritant.
Background technology
NSAID (non-steroidal anti-inflammatory drug) (NSAIDs) is the treatment rheumatic arthritis (RA) widely used clinically and the active drug of osteoarthritis (OA), also is usually used in heating, myalgia, pain in the back, acute gout and TREATMENT OF DYSMENORRHOEA.See that but the untoward reaction of NSAIDs is more modal untoward reaction is digestive tube damage, show as mainly that stomach, duodenum fester, ulcer and life-threatening gastric-intestinal perforation and hemorrhage.Its reason mainly be NSAIDs in the inflammation-inhibiting position prostaglandin(PG) (PGs), also suppressed PGs synthetic that gi tract have the mucous membrane protection effect.In addition, though anti-inflammatory and analgesic are the medicines of normal use of treatment osteoarthritis, yet their main effect is the pain that palliates a disease, and can not slow down and stops advancing of disease.Show that on evidence oral Whitfield's ointment preparation can make osteoarthritis patient's joint cartilage protein-polysaccharide and hyaluronic synthetic minimizing, surface fiberization easily takes place in joint cartilage, and the pathology damage of osteoarthritis is increased the weight of.
Glucosamine (glucosamine) be chitin through the white crystal that hydrolysis obtains, be a kind of amino monose.It also is present in human body particularly in the joint cartilage, is the base substance of synthesizing amino glycan, also is the moiety of protein-polysaccharide in the joint cartilage, can promote the growth of articular chondrocytes and the formation of articular cartilage tissue, thus the generation of prevention osteoarthritis.It can not only stimulate cartilaginous tissue synthetic proteins polysaccharide and collagen protein, suppresses the activity of collagenase and protein-polysaccharide degrading enzyme, can also reduce the morphologic change of joint cartilage.Studies show that; glucosamine can effectively be treated joint and connective tissue disease as the joint cartilage protective material; comprise osteoarthritis, rheumatoid arthritis and cartilage degradation; and can suppress the destruction of free radical; repair reticular tissue; make impaired joint cartilage recover normal, the protection joint cartilage exempts from the destruction of enzyme.
Reducing gastrointestinal side effect is the basic point of departure of Recent study and development of new NSAIDs, once adopts several different methods to reduce the toxic side effect of NSAID (non-steroidal anti-inflammatory drug) in recent years, improves bioavailability.The carbohydrate derivative of synthetic NSAID (non-steroidal anti-inflammatory drug) is one of them.The 2-bromo acetyl glucose derivative that has synthesized the NSAID (non-steroidal anti-inflammatory drug) that comprises indomethacin, acetylsalicylic acid, diclofenac as Borowiecka of Poland etc.; and compare with bulk drug by the 2-bromo acetyl glucose derivative of pharmacological evaluation proof diclofenac; pungency reduces, and multiple dosing is not seen gastrointestinal reaction.But reaction must be reacted 12-16h in ebullient phenol, and need add silver carbonate and molecular sieve in addition, is unfavorable for the enforcement (Il Farmaco 56 (2001) 257-262) of industrialized production.
The Rainer K.Uhrig of Germany etc. has synthesized henzylate Trichloroacetonitrile-O-acyl group-glucosyl group-Ibuprofen BP/EP, but reaction needs to adopt hydrogen, palladium carbon catalysis, condition harshness; And product stability is poor, even slow decomposition (Carbohydrate Research 325 (2000) 72-80) also can take place under-20 ℃ low temperature.
Chinese patent CN1660870A has synthesized ramification of diclofenac of glucosamine, is glucosamine hydrochloride and phenyl aldehyde are condensed into schiff base compound, sloughs phenyl aldehyde and hydrochloric acid after the acetylize, obtains the target derivative.Exist complex steps equally, problem such as the organic solvent toxicity of employing is big.The pharmacological properties of this new compound is also needed confirmation badly.Chinese patent CN1616474A has synthesized the acetylglucosamine derivative of indomethacin, but reactions steps is many, needs to adopt organic solvents such as methylene dichloride, chloroform, tetrahydrofuran (THF), and toxicity is big.2 pairs of mice ear inhibiting rates of acetylglucosamine derivative compound 1 and compound of pharmacological evaluation proof indomethacin are compared than indomethacin, there is no significance and improve.
Summary of the invention
The purpose of this invention is to provide a kind of by carboxylic-acid NSAID (non-steroidal anti-inflammatory drug) and glucosamine or its salt synthetic compound.
Another object of the present invention provides the synthetic method of above-claimed cpd.
A further object of the invention provides the application of above-claimed cpd in preparation anti-inflammatory, analgesic.
The objective of the invention is to realize by following measures:
A kind of carboxylic-acid NSAID (non-steroidal anti-inflammatory drug) and glucosamine or its salt synthetic compound, this compound are general formula (I) or the described compound of general formula (II):
Described carboxylic-acid NSAID (non-steroidal anti-inflammatory drug) and glucosamine or its salt synthetic compound, wherein the carboxylic-acid NSAID (non-steroidal anti-inflammatory drug) is selected from formic acid non-steroid antiphlogistic, acetate non-steroid antiphlogistic or propionic non-steroid antiphlogistic.
Described carboxylic-acid NSAID (non-steroidal anti-inflammatory drug) and glucosamine or its salt synthetic compound, wherein the formic acid non-steroid antiphlogistic is selected from acetylsalicylic acid, diflunisal, or their derivative; Preferred acetylsalicylic acid.
Described carboxylic-acid NSAID (non-steroidal anti-inflammatory drug) and glucosamine or its salt synthetic compound, acetate non-steroid antiphlogistic wherein, be selected from indomethacin, R-ETODOLAC, sulindac, diclofenac, fenbufen, Tolmetin, acemetacin, or their derivative; Preferred diclofenac or its salt.
Described carboxylic-acid NSAID (non-steroidal anti-inflammatory drug) and glucosamine or its salt synthetic compound, wherein propionic non-steroid antiphlogistic is selected from Ibuprofen BP/EP, Flurbiprofen, fenoprofen, tiaprofenic acid, Naproxen Base, Evil promazine, ketorolac, or their derivative; Preferred Naproxen Base or its salt.
The synthetic method of described carboxylic-acid NSAID (non-steroidal anti-inflammatory drug) and glucosamine or its salt synthetic compound comprises the following steps:
Moles such as carboxylic-acid NSAID (non-steroidal anti-inflammatory drug) and glucosamine are mixed, in water or alcohol or pure water medium, react completely, remove down by freeze-drying and/or decompression and/or high temperature and desolvate, obtain the described compound of general formula (I); Perhaps
The carboxylic-acid NSAID (non-steroidal anti-inflammatory drug) is mixed with moles such as glucosamine salt, in water or alcohol or acetonitrile or their mixed solvent with dewatering agent in the presence of, the linked reaction of dewatering, underpressure distillation is except that desolvating, with ethanol-water recrystallization, obtain the described compound of general formula (II).
Described synthetic method, wherein glucosamine salt is selected from glucosamine hydrochloride, vitriol or its mixture; Preferred glucosamine hydrochloride.
Described synthetic method, wherein dewatering agent is dicyclohexylcarbodiimide, N-ethyl-N '-(3-dimethylamino-propyl) carbodiimide hydrochloride.
The application in preparation anti-inflammatory, analgesic of described carboxylic-acid NSAID (non-steroidal anti-inflammatory drug) and glucosamine or its salt synthetic compound.
The chemical name of glucosamine is 2-amino-D-glucosamine, and molecular formula is C
6H
11O
4N is a kind of water-soluble glucosamine.
Beneficial effect of the present invention:
1, the present invention is with the chemical intermediate of free glucosamine as pharmacy, with a kind of simple economy and the easy method of suitability for industrialized production that realizes free glucosamine and carboxylic-acid NSAID (non-steroidal anti-inflammatory drug) are reacted, the glucosamine salt that has prepared a series of carboxylic-acid NSAID (non-steroidal anti-inflammatory drug), mild condition, reactions steps are few, the productive rate height;
2, the present invention adds the dewatering agent reaction with glucosamine salt and carboxylic-acid NSAID (non-steroidal anti-inflammatory drug) in appropriate medium, has prepared the glucosamine acid amides of a series of carboxylic-acid NSAID (non-steroidal anti-inflammatory drug), and mild condition, reactions steps are few, the productive rate height;
3, majority is reflected under normal temperature or a little higher than normal temperature and carries out among the present invention, save energy, and can in water, alcohol or pure water medium, carry out, toxicity is little, pollutes few;
4, the present invention utilizes NSAIDs and glucosamine or its salt addition complementary characteristic aspect therapeutics, they are synthesized the glucosamine of a series of carboxylic-acid NSAID (non-steroidal anti-inflammatory drug) or the compound of its salt, strengthen the antiphlogistic effects of NSAID (non-steroidal anti-inflammatory drug), the corresponding NSAID (non-steroidal anti-inflammatory drug) of the curative effect of compound provided by the invention has been compared significance and has been improved, using dosage significantly reduces than the former medicine of NSAID (non-steroidal anti-inflammatory drug), pungency decreases, and improved the effect target, reduce toxic side effect, improve drug safety, application prospect is extensive.
Description of drawings
Fig. 1. the The compounds of this invention on Carrageenan causes the influence of the swelling degree of the right sole of the foot swelling of rat.
Fig. 2. the The compounds of this invention on Carrageenan causes the influence of the edema inhibiting rate of the right sole of the foot swelling of rat.
Fig. 3. The compounds of this invention is to the influence of rat body weight.
Embodiment
Below by embodiment the present invention is described, these embodiment also do not mean that limitation of the present invention.
The glucosamine that the embodiment of the invention adopts can prepare by the method for CN99116649.3 patent disclosure, also can buy by market to obtain.
The preparation of embodiment 1 diclofenac
The 20g diclofenac sodium adds in the 400ml water, be heated to 70 ℃ all the dissolving back slowly drip 3mol/L HCl until regeneration precipitation not.Room temperature is put cold filtration, and throw out washes with water, the diclofenac crude product, the dehydrated alcohol recrystallization promptly gets the diclofenac highly finished product, mp=158～159 ℃.
The preparation of embodiment 2 diclofenacs-glucosamine salt---method one
Glucosamine is water-soluble, add equimolar diclofenac, stirring at room 5h, vacuum-drying is removed moisture and is promptly got diclofenac-glucosamine salt.Through nucleus magnetic resonance
1HNMR and mass spectrum MS measure and confirm its structure.
Preparation---the method two of embodiment 3 diclofenacs-glucosamine salt
Diclofenac is dissolved in the ethanol, adds equimolar glucosamine, stirring at room 5h, and organic solvent is removed in decompression, and the gained solid is diclofenac-glucosamine salt.Through nucleus magnetic resonance
1HNMR and mass spectrum MS measure and confirm its structure.
The preparation of embodiment 4 diclofenacs-glucosamine acid amides
The glucosamine hydrochloride of 12mmol is added in the acetonitrile solution of 60ml 50%, add and the equimolar triethylamine of glucosamine hydrochloride again, stirring at room, treat to add and the equimolar diclofenac of glucosamine hydrochloride after vial becomes transparent liquid, in the presence of the dewatering agent dicyclohexylcarbodiimide, stirred five hours.Underpressure distillation removes and desolvates, and with ethanol-water recrystallization, obtains a kind of white, needle-shaped crystals of the present invention.M.p.=173～175 ℃ are through nucleus magnetic resonance
1HNMR and mass spectrum MS measure, and confirm its structure.
The preparation of embodiment 5 Naproxen Bases-glucosamine salt
Operation is with embodiment 2,3.
The preparation of embodiment 6 Naproxen Bases-glucosamine acid amides
Operation is with embodiment 4.
The preparation of embodiment 7 acetylsalicylic acid-glucosamine salt
Operation is with embodiment 2,3.
The preparation of embodiment 8 acetylsalicylic acid-glucosamine acid amides
Operation is with embodiment 4.
Embodiment 9: general formula I, II compound are used to prepare anti-inflammatory, anodyne.
With the diclofenac is example, and the pharmacological evaluation of diclofenac-glucosamine salt, diclofenac-glucosamine acid amides is as follows.
1 anti-inflammatory activity
1.1 mice caused by dimethylbenzene xylene ear swelling experiment
Diclofenac sodium, diclofenac-glucosamine salt, diclofenac-glucosamine acid amides are made into 1.57 * 10 with 0.5% Xylo-Mucine (CMCNa)
-3The suspension of mol/L, abundant mixing, the dosage of diclofenac sodium is set at 20mg/kg, is converted by human dosage.Diclofenac-glucosamine salt, diclofenac-glucosamine acid amides wait the mole administration with it.
Every group of 15 mouse, with mouse fasting 12 hours (but can't help water), to the mouse stomach administration, the administration volume is 0.4ml/10g before the experiment, and administration evenly is coated with dimethylbenzene 20 μ l with the wide both sides of mouse right ear with microsyringe after 1 hour and causes inflammation, and left auricle compares.After causing scorching 30 minutes mouse is taken off cervical vertebra and put to death, take off two ears, respectively get an auricle in same position with punch tool (diameter is 8mm) and weigh along the auricle baseline.Causing the inflammation sheet weight of picking up the ears deducts control sides auricle weight and is the swelling degree.Each group data is carried out the t check, and the significance of comparative group differences the results are shown in Table 1.
Table 1 compound p-Xylol causes influence (n=10, the X ± S) of mice ear
| Compound | Swelling degree (mg) |
| CMCNa diclofenac sodium diclofenac-glucosamine salt diclofenac-glucosamine acid amides | 11.26±2.51 7.75±3.89 ** 4.98±1.22 **# 5.95±1.93 **# |
Compare with CMCNa
*P＜0.01,
*P＜0.05; Compare ##P＜0.01 with diclofenac sodium, #P＜0.05.
The t check shows: diclofenac sodium, diclofenac-glucosamine salt, diclofenac-glucosamine acid amides all have remarkable anti-inflammatory action (P＜0.01).Diclofenac-glucosamine salt, diclofenac-glucosamine acid amides anti-inflammatory activity be significantly increased (P＜0.05) of comparing with diclofenac sodium.
1.2 carrageenin causes the right sole of the foot swelling experiment of rat
The dosage of diclofenac sodium is set at 10mg/kg (3.14 * 10
-2Mmol/kg), convert by human dosage.Diclofenac-glucosamine salt is made into suspension with 0.5% CMCNa, fully mixing.The dosage of diclofenac-glucosamine salt is made as 1/5th of diclofenac sodium dosage according to the preliminary experiment result, and promptly 0.63 * 10
-2Mmol/kg.
Every group of 10 rats, fasting is 18～22 hours before the experiment, but can't help water.To the rat oral gavage administration, the administration volume is 1ml/100g.After the administration 30 minutes, to following injection 1% carrageenin (sterile saline preparation) 0.1ml of the right back aponeurosis (aponeuroses) of rat, measure cause scorching before and cause scorching after 0.5,1.5,2.5, the right sole of the foot thickness of 3.5,4.5 hours rats, and cause scorching before and cause scorching back 1,2,3,4,5 hours right sole of the foot volumes of rat.
By formula (1) and (2) calculates rat paw edema degree and compound to the edema inhibiting rate:
Formula (1): swelling degree=administration metapedes sole of the foot volume-administration front foot sole of the foot volume (ml)
Formula (2):
Experimental result is seen Fig. 1 and 2, and with the significance of difference between variance analysis check administration group and the control group swelling degree of the paw.
The t check shows: the diclofenac of diclofenac sodium, 1/5th dosage-glucosamine salt all has significant anti-inflammatory action, and the two has significant difference (P＜0.01).The result shows that diclofenac-glucosamine salt is compared with diclofenac sodium, and anti-inflammatory action improves more than five times.
The influence of 2 pairs of rat gastrointestinal tracts
As being tried thing, dosage and medicine preparation are with 1.2 with diclofenac sodium, diclofenac-glucosamine salt.Diclofenac sodium dosage is 3.14 * 10
-2Mmol/kg, diclofenac-glucosamine salt dosage be its 1/5th, be 0.63 * 10
-2Mmol/kg.Every group of 10 rats, gastric infusion is 7 days continuously, measures before the administration and the variation of administration body weight in latter stage, observes the influence of comparative drug to rat gastrointestinal tract after the last administration, rat is put to death to dissect take out gi tract, vertically cuts open and carries out visual inspection.
2.1 influence to rat body weight
The results are shown in Figure 3, rat is through continuous 7 days diclofenac sodium gastric infusions, weight loss; And diclofenac-glucosamine salt administration group and blank group be through 7 days successive administrations, and body weight has the increase of similarity degree.
The result shows that the stimulation of diclofenac-glucosamine salt pair rat gastrointestinal tract improves significantly than diclofenac sodium.
2.2 the Anatomical Observation of rat gastrointestinal tract
Table 2. compound is to the influence of rat gastrointestinal tract
| Compound | Animal dead rate during the administration | Surviving animals gi tract opinion rating |
| CMCNa diclofenac sodium diclofenac- | 0/10 8/10 0/10 | 0 3 0 |
Annotate: 0 grade: no ulcer
1 grade: mucous membrane shows erosion
2 grades: deep ulcer or chamber face diffuse necrosis
3 grades: perforated ulcer
By table 2 as seen, diclofenac sodium has two death after administration in the 5th day, and six death were arranged at the 6th day, other group there is no death, by the gi tract score value as can be known, diclofenac-glucosamine salt and CMCNa control group almost do not have gastrointestinal side effect, have high security.
3 muscle irritations
Get body weight 10 of healthy rabbit more than 2 kilograms, male femalely disregards, be divided into two groups at random, 5 every group.In the right leg quadriceps muscle of thigh of one group of rabbit, inject the normal saline solution 1ml (8.33 * 10 of diclofenac sodium with aseptic method
-3Mol/l is according to the commercial preparation concentration conversion), another group rabbit is then injected the normal saline solution (1.66 * 10 of diclofenac-glucosamine salt
-3Mol/1, for diclofenac sodium dosage 1/5), every group of rabbit all self left leg quadriceps muscle of thigh injecting normal saline solution 1ml as negative control.Inject and put to death animal in back 48 hours, dissect and take out quadriceps muscle of thigh, vertically cut, observe injection site irritant reaction (should do pathologic finding in case of necessity) and the according to the form below corresponding reaction order that converts.
| Reaction | Irritant reaction | |
| 0 1 2 3 4 5 | No considerable change mild hyperaemia, its scope is at mild hyperaemia below 0.5 * 1.0 centimetre, its scope is in severe hyperemia more than 0.5 * 1.0 centimetre, necrosis occurs with myodegeneration, have the brown sex change popularity necrosis to occur |
The reaction order of diclofenac sodium is judged as 3 grades, and the reaction order of diclofenac-glucosamine salt is judged as 1 grade.Diclofenac-glucosamine salt is compared with diclofenac sodium, and muscular irritation obviously reduces.
3 hemolytic experiments
Get and remove defibrinated rabbit blood 5ml, move in the graduated centrifuge tube, add physiological saline 5～10ml, behind the mixing centrifugal 5 minutes (2000～2500r/min), remove supernatant liquor, it is centrifugal to add the physiological saline mixing again, wash repeatedly 3～4 times, be water white transparency to supernatant and can be used for test.The gained red corpuscle is pressed its volume, be diluted to 2% suspension (red corpuscle 2mL adds physiological saline to 100mL) with physiological saline.In each test tube, add 1.66 * 10 by table 3
-3The normal saline solution of the diclofenac of mol/l-glucosamine salt shakes up rearmounted 37 ℃ of water bath heat preservations gently.No. 6 pipes and No. 7 pipes are respectively 0% haemolysis and 100% haemolysis.37 ℃ hatch 3h after, the centrifugal 10min of 3000rpm gets supernatant liquor, measures its absorption value in the 416nm ultraviolet spectrophotometer, is contrast with the blank sample.By formula (3) calculate haemolysis percentage ratio.
Formula (3):
The design of table 3. hemolytic experiment
| The | 1 | 2 | 3 | 4 | 5 | 6 | 7 |
| Trial-product (mL) | 0.7 | 1.4 | 2.1 | 2.8 | 3.5 | - | - |
| Physiological saline (mL) | 3.05 | 2.35 | 1.65 | 0.95 | 0.25 | 3.75 | 3.75(H 2O) |
| Red blood cell suspension (mL) | 1.25 | 1.25 | 1.25 | 1.25 | 1.25 | 1.25 | 1.25 |
Annotate: trial-product is: 1. diclofenac sodium normal saline solution, concentration is 8.33 * 10
-3Mmol/ml.
2. diclofenac-glucosamine salt normal saline solution, concentration is 1.66 * 10
-3Mmol/ml,
Be 1/5th of diclofenac sodium dosage.
Experimental result sees Table 4.
Each compound of table 4 is hatched haemolysis percentage ratio behind the 3h
| Numbering |
| 1 | 2 | 3 | 4 | 5 | |
| Diclofenac sodium (%) diclofenac-glucosamine salt (%) | -0.15 -0.66 | -0.15 -0.62 | 0.09 -0.65 | 17.8 -0.43 | 79.8 -0.22 |
Diclofenac-glucosamine salt and diclofenac sodium are carried out control experiment, and experimental result finds that the hemolytic action of diclofenac sodium is strong, and the 4th pipe laky blood 17.8%, the five pipe is up to 79.8%, and pungency is bigger, unsuitable intravenous injection.No any hemolytic action in diclofenac-glucosamine salt 3h, nonirritant is expected to injection for intravenous.
Claims (9)
1, a kind of carboxylic-acid NSAID (non-steroidal anti-inflammatory drug) and glucosamine or its salt synthetic compound is characterized in that this compound is general formula (I) or the described compound of general formula (II):
2, according to the carboxylic-acid NSAID (non-steroidal anti-inflammatory drug) described in the claim 1 and glucosamine or its salt synthetic compound, it is characterized in that the carboxylic-acid NSAID (non-steroidal anti-inflammatory drug), be selected from formic acid non-steroid antiphlogistic, acetate non-steroid antiphlogistic or propionic non-steroid antiphlogistic.
3, carboxylic-acid NSAID (non-steroidal anti-inflammatory drug) according to claim 2 and glucosamine or its salt synthetic compound is characterized in that the formic acid non-steroid antiphlogistic, are selected from acetylsalicylic acid, diflunisal, or their derivative; Preferred acetylsalicylic acid.
4, carboxylic-acid NSAID (non-steroidal anti-inflammatory drug) according to claim 2 and glucosamine or its salt synthetic compound, it is characterized in that the acetate non-steroid antiphlogistic, be selected from indomethacin, R-ETODOLAC, sulindac, diclofenac, fenbufen, Tolmetin, acemetacin, or their derivative; Preferred diclofenac or its salt.
5, carboxylic-acid NSAID (non-steroidal anti-inflammatory drug) according to claim 2 and glucosamine or its salt synthetic compound, it is characterized in that propionic non-steroid antiphlogistic, be selected from Ibuprofen BP/EP, Flurbiprofen, fenoprofen, tiaprofenic acid, Naproxen Base, Evil promazine, ketorolac, or their derivative; Preferred Naproxen Base or its salt.
6, the synthetic method of described carboxylic-acid NSAID (non-steroidal anti-inflammatory drug) of claim 1 and glucosamine or its salt synthetic compound is characterized in that comprising the following steps:
Moles such as carboxylic-acid NSAID (non-steroidal anti-inflammatory drug) and glucosamine are mixed, in water or alcohol or pure water medium, react completely, remove down by freeze-drying and/or decompression and/or high temperature and desolvate, obtain the described compound of general formula (I); Perhaps the carboxylic-acid NSAID (non-steroidal anti-inflammatory drug) is mixed with moles such as glucosamine salt, in water or alcohol or acetonitrile or their mixed solvent with dewatering agent in the presence of, the linked reaction of dewatering, underpressure distillation is except that desolvating, with ethanol-water recrystallization, obtain the described compound of general formula (II).
7, synthetic method according to claim 6 is characterized in that glucosamine salt is selected from glucosamine hydrochloride, vitriol or its mixture; Preferred glucosamine hydrochloride.
8, synthetic method according to claim 6 is characterized in that dewatering agent is dicyclohexylcarbodiimide, N-ethyl-N '-(3-dimethylamino-propyl) carbodiimide hydrochloride.
9, described carboxylic-acid NSAID (non-steroidal anti-inflammatory drug) of claim 1 and glucosamine or its salt synthetic compound application in preparation anti-inflammatory, analgesic.
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| IT1298214B1 (en) * | 1998-01-28 | 1999-12-20 | Dompe Spa | SALTS OF (R) 2- (3-BENZOYLFENYL) PROPIONIC ACID AND THEIR PHARMACEUTICAL COMPOSITIONS. |
| WO1999052528A1 (en) * | 1998-04-11 | 1999-10-21 | Errekappa Euroterapici S.P.A. | Pharmaceutical preparations containing hydrosoluble ketoprofen salts and their application |
| CN1256342C (en) * | 2004-09-02 | 2006-05-17 | 中国海洋大学 | Acetamido glucose devicative of indomethacin and its synthetic method and use |
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| CN1271079C (en) * | 2004-12-08 | 2006-08-23 | 梅县梅雁螺旋藻养殖有限公司 | Method for synthesizing ramification of diclofenac of glucosamine |
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| CN102391323A (en) * | 2011-10-18 | 2012-03-28 | 首都医科大学 | Tetrahydro-beta-carboline derivative, preparation method thereof and use thereof |
| CN102391323B (en) * | 2011-10-18 | 2013-09-25 | 首都医科大学 | Tetrahydro-beta-carboline derivative, preparation method thereof and use thereof |
| CN107459538A (en) * | 2016-06-03 | 2017-12-12 | 首都医科大学 | The acetyl lysylamino glucose of two indoles, 2 propane, 2 indoles 3, it is synthesized, activity and application |
| CN107459538B (en) * | 2016-06-03 | 2020-10-16 | 首都医科大学 | Diindole-2-propane-2-indole-3-acetyl lysyl glucosamine, synthesis, activity and application thereof |
| CN107137387A (en) * | 2017-07-07 | 2017-09-08 | 中国科学技术大学 | A kind of synthetic method of aryl propionic non-steroid antiphlogistic |
| CN107137387B (en) * | 2017-07-07 | 2020-05-12 | 中国科学技术大学 | Synthetic method of aryl propionic acid non-steroidal anti-inflammatory drug |
| CN112154158A (en) * | 2018-03-22 | 2020-12-29 | 持田制药株式会社 | Alginic acid derivatives with non-steroidal anti-inflammatory compounds attached |
| CN109847067A (en) * | 2018-12-20 | 2019-06-07 | 药大制药有限公司 | A kind of Diclofenac-glycine-resveratrol conjugate, preparation method and application |
| CN109847067B (en) * | 2018-12-20 | 2022-06-07 | 药大制药有限公司 | Diclofenac-glycine-resveratrol conjugate, preparation method and application |
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