CN114805104A - Aminosalicylic acid derivatives and application thereof - Google Patents

Aminosalicylic acid derivatives and application thereof Download PDF

Info

Publication number
CN114805104A
CN114805104A CN202110122640.XA CN202110122640A CN114805104A CN 114805104 A CN114805104 A CN 114805104A CN 202110122640 A CN202110122640 A CN 202110122640A CN 114805104 A CN114805104 A CN 114805104A
Authority
CN
China
Prior art keywords
compound
pharmaceutically acceptable
aminosalicylic acid
brain
acceptable salt
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202110122640.XA
Other languages
Chinese (zh)
Inventor
李福龙
方芳
任健
刁旭
张正平
陈荣
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nanjing Ningdan New Drug Technology Co ltd
Original Assignee
Nanjing Ningdan New Drug Technology Co ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nanjing Ningdan New Drug Technology Co ltd filed Critical Nanjing Ningdan New Drug Technology Co ltd
Priority to CN202110122640.XA priority Critical patent/CN114805104A/en
Publication of CN114805104A publication Critical patent/CN114805104A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C229/64—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring the carbon skeleton being further substituted by singly-bound oxygen atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/38—Separation; Purification; Stabilisation; Use of additives
    • C07C227/40—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C68/00—Preparation of esters of carbonic or haloformic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/36—Systems containing two condensed rings the rings having more than two atoms in common
    • C07C2602/42—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing seven carbon atoms

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Cardiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses an aminosalicylic acid derivative compound, a pharmaceutical composition and application thereof. The aminosalicylic acid derivative can obviously improve the ischemic symptoms of rats with cerebral ischemia reperfusion models, and the compound has wide application prospect in preparing medicaments for preventing and treating cerebral apoplexy.

Description

Aminosalicylic acid derivatives and application thereof
Technical Field
The invention belongs to the field of pharmacy, and provides an aminosalicylic acid compound, a preparation method and a pharmaceutical application thereof.
Background
Acute ischemic stroke is a rapidly developing injury to brain function resulting from an ischemic, obstructed blood supply to the brain. With the rapid aging of population, the incidence of cerebral ischemia is on a continuously increasing trend, and has become the first leading disability and the second leading death of the world, and the burden on society and families is further increased. The pathogenesis of cerebral ischemia is very complex and is a malignant cascade process with multiple factors, multiple mechanisms and multiple links. Over the years, the mechanisms involved in cerebral ischemia and reperfusion injury have been studied including excitotoxicity, ionic imbalance, oxidative stress, cortical diffusional depolarization, inflammatory responses, and the like. The existing clinical commonly used anti-cerebral ischemia drugs mainly comprise platelet aggregation resistant drugs, thrombolytic drugs, neuroprotective agents, free radical scavengers and the like, and although the drugs can play a certain role through different mechanisms, the drugs can not achieve very satisfactory curative effects when used alone. Experts and scholars at home and abroad carry out extensive research on pathogenesis and prevention and treatment of cerebral ischemia and make great progress, but practical and effective clinical prevention and treatment measures are still lacked up to now. Therefore, how to adopt a new strategy to research and develop a novel high-efficiency medicine with multiple functions for preventing and treating cerebral ischemia is an important subject which is generally concerned by medical scientists all over the world currently.
The PSD95-nNOS uncoupler ZL006 can reduce the pathological release of NMDAR-mediated NO on the premise of not influencing the physiological functions of NMDAR and nNOS, has obvious neuroprotective effect on nerve cell injury under the stimulation of glutamic acid, improves animal nerve defect symptoms caused by cerebral middle artery embolism (MCAO) reperfusion, and reduces the infarct volume. ZL006 has avoided directly intervening in side effects such as learning and memory disorder, behavioral abnormality that NMDAR and nNOS may cause, have better security.
Borneol is one of the commonly used Chinese herbs and can be divided into two categories of natural borneol and synthetic borneol. The natural borneol is processed product of borneol aromatic plant borneol aromatic resin. The traditional Chinese medicine believes that the borneol is pungent and bitter in taste and cool in nature, and has the effects of inducing resuscitation, refreshing mind, clearing heat, relieving pain and promoting tissue regeneration, and the borneol enters heart, spleen and lung channels. Borneol has the effects of inducing resuscitation, inducing the flow of the drug upwards, and increasing the therapeutic effect of other drugs. Ben Cao Yan Yi (the Yan Yi of materia Medica) considers that borneol is weak in one way and active in adjuvant therapy. Modern medical research shows that the borneol has the effects of resisting bacteria, inflammation, oxidation, blood coagulation, myocardial ischemia and pain.
The PSD95-nNOS uncoupler target is in the central nervous system, but ZL006 compounds have higher hydrophilicity and are not beneficial to medicine penetration, so that the central nervous system is less distributed. The invention is based on the split principle and the prodrug principle, utilizes substituted carbonic ester to connect ZL006 and borneol, synthesizes and obtains the amino salicylic acid borneol derivative, can obviously improve the concentration of ZL006 in the brain, and has good medicinal prospect.
Disclosure of Invention
The technical problem to be solved is as follows: the invention provides an aminosalicylic acid borneol ester compound which has the obvious characteristic of brain targeting effect, can obviously improve the intracerebral concentration of ZL006, and can be used for preparing medicaments for treating cerebral apoplexy.
The technical scheme is as follows: an aminosalicylic acid compound shown as a formula I or pharmaceutically acceptable salt thereof,
Figure 100002_DEST_PATH_IMAGE001
formula I
Wherein the content of the first and second substances,
r1, R2 is selected from H, C1-C6 alkyl and substituted alkyl;
r3 is selected from H, halogen, C1-C6 alkyl;
the configuration of the chiral center in the molecule is R configuration or S configuration or racemate.
Preferably, R1, R2 are selected from H, C1-C3 alkyl; r3 is selected from H, halogen;
more preferably, R1 is H or methyl; r2 is a H atom; r3 is selected from H, F, Cl, Br;
more preferably, the compound is:
Figure 100002_DEST_PATH_IMAGE002
has the advantages that:
the amino salicylic acid compounds have the characteristics of brain targeting effect, protection effect on cerebral ischemia reperfusion injury, and can be used for preparing medicines for treating cerebral apoplexy.
Detailed Description
The following examples are presented to enable one of ordinary skill in the art to more fully understand the present invention and are not intended to limit the invention in any way.
Example 1: synthesis of Compound S1
The synthetic route is as follows:
Figure DEST_PATH_IMAGE003
the synthesis process comprises the following steps:
intermediate a 1: adding raw materials 2-camphanol (5.0 g, 32.4 mmol) and 50 mL of dimethyl sulfoxide DMSO into a three-neck flask, adding sodium hydride (1.3 g, 32.4 mmol), stirring at room temperature for 2h, adding chloroethyl chloroformate (4.6 g, 32.4 mmol), stirring at 45 ℃ in an oil bath for reaction overnight, monitoring the reaction by TLC until the reaction is complete, cooling to room temperature, pouring into 100mL of ice water, performing suction filtration, washing a filter cake with cold water and cold ethanol in sequence, performing vacuum drying to obtain 6.4 g of white solid with the yield of 76%,
compound S1: ZL006 (1.25 g, 3.83 mmol), sodium bicarbonate (336 mg, 4 mmol) are weighed and placed in a reaction flask, DMSO is added in an amount of 15mL, the mixture is stirred for 1h at room temperature, then intermediate A1 (1.0 g, 3.83 mmol), potassium iodide (16 mg, 0.13 mmol) are sequentially added into the mixture, the mixture is stirred under the condition of oil bath at 45 ℃, TLC is used for monitoring the reaction completion, the mixture is poured into water of 30mL, ethyl acetate is extracted for 3 times, organic phases are combined, saturated sodium chloride is washed, anhydrous sodium sulfate is dried, the mixture is concentrated under reduced pressure, and the crude product is subjected to silica gel column chromatography (petroleum ether/ethyl acetate 4: 1) to obtain 950mg of S1 white solid with the yield of 45%.
ESI- MS: 552.2 [M+H] + ;
1 H NMR (400 MHz, DMSO-d 6 ): δ 10.48 (1H, m), 9.81 (1H, s), 7.46-7.49 (1H, m), 7.40-7.41 (1H, m), 7.29-7.30 (1H, m), 7.10 (1H, m), 6.83-6.84 (1H, m), 6.23-6.25 (1H, m), 5.97 (1H, s), 4.74-4.76 (1H, m), 4.31-4.32 (2H, m), 2.27-2.32 (1H, m), 1.74-1.77 (1H, m), 1.64-1.71 (2H, m), 1.55-1.56 (3H, m), 1.23-1.25 (1H, m), 1.16-1.19 (1H, m), 0.98-1.03 (1H, m), 0.84 (3H, s), 0.82 (3H, s), 0.79 (3H, s).
Example 2: synthesis of Compound S2
Figure DEST_PATH_IMAGE004
The synthesis process comprises the following steps:
intermediate a 2: adding raw materials 2-camphanol (5.0 g, 32.4 mmol) and 50 mL of dimethyl sulfoxide DMSO into a three-neck flask, adding sodium hydride (1.3 g, 32.4 mmol), stirring at room temperature for 2h, adding chloromethyl chloroformate (4.18 g, 32.4 mmol), stirring overnight under 45 ℃ oil bath condition, monitoring by TLC until the reaction is complete, cooling to room temperature, pouring into 100mL of ice water, filtering, washing a filter cake with cold water and cold ethanol in sequence, drying in vacuum to obtain 5.6g of A2 white solid with a yield of 71%,
compound S2: ZL006 (1.25 g, 3.83 mmol), sodium bicarbonate (336 mg, 4 mmol) are weighed and placed in a reaction flask, DMSO is added in an amount of 15mL, the mixture is stirred for 1h at room temperature, then intermediate A2 (0.94 g, 3.83 mmol), potassium iodide (16 mg, 0.13 mmol) are sequentially added into the mixture, the mixture is stirred under the condition of oil bath at 45 ℃, TLC is used for monitoring the reaction to be complete, the mixture is poured into water of 30mL, ethyl acetate is extracted for 3 times, organic phases are combined, the mixture is washed by saturated sodium chloride, dried by anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product is subjected to silica gel column chromatography (petroleum ether/ethyl acetate 4: 1) to obtain 1.05g of S2 white solid with the yield of 51%.
ESI- MS: 538.2 [M+H] + ;
1 H NMR (400 MHz, DMSO-d 6 ): δ 10.47 (1H, s), 9.79 (1H, s), 7.40 (1H, d, J=2), 7.29 (1H, m), 7.10 (1H, d, J=2), 6.83-6.84 (1H, m), 6.61 (2H, s), 6.23 (1H, d, J=7.2), 5.97 (1H, s), 4.74-4.76 (1H, m), 4.32-4.33 (2H, m), 2.27-2.32 (1H, m), 1.74-1.78 (1H, m), 1.65-1.72 (2H, m), 1.23-1.25 (1H, m), 1.17-1.19 (1H, m), 0.99-1.04 (1H, m), 0.85 (3H, s), 0.83 (3H, s), 0.80 (3H, s).
Example 3 measurement of ZL006 concentration in brain tissue
1 preparation of sample solution
30mg of the compound (S1) was weighed into a centrifuge tube, DMA (less than 5% of the total volume) and Tween 80 (less than 5% of the total volume) were added, and dissolved in a 30-degree water bath, and then physiological saline was slowly added thereto to the scale to obtain a 1mg/mL solution.
2 Main instruments and software
LC-MS/MS: comprises an Shimadzu LC-20AD high performance liquid chromatograph, an Shimadzu SIL-20AC automatic sample injector, an Shimadzu CTO-20A column incubator, an Shimadzu CBM-20A controller and an Shimadzu SPD-20A ultraviolet-visible light detector; applied Biosystem API 4000 mass spectrometer.
Table 1 other main instrumentation:
device name Manufacturer(s) Model number
Analytical balance Mettler toledo XA105
Analytical balance Mettler toledo XP205
Electronic scale Double Jie test Instrument factory in ever-maturing market T1000 type
Disposable aseptic syringe Shanghai mishawa Medical Industry Co.,Ltd. 5mL,2mL,1mL
High-speed refrigerated centrifuge DRAGONLAB D3024R
Centrifugal machine SCILOGEX D1008
High-speed refrigerated centrifuge ANHUI USTC ZONKIA SCIENTIFIC INSTRUMENTS Co.,Ltd. KDC-160HR
Multi-tube vortex oscillator TARGIN VX-Ⅱ
TABLE 2 Main software/data System
Software/data system name Version number Use of
Analyst 1.5.2 API4000
3. Test method
9 ICR mice, weighing about 20g, were randomly divided into 3 groups of 3 mice each, and compound S1 was administered by tail vein injection at a dose of 20 mg/kg. Mice were fasted for 12h without water deprivation, and had free access to water during the experiment. Mice were sacrificed at 15min, 30min, 1h after dosing, respectively. Taking brain, carefully peeling off capillary vessels in brain to make brain tissue almost white, sucking surface water with filter paper, and weighing. Adding 3 times of normal saline by weight to prepare homogenate. And (3) after 10min of ultrasonic treatment, removing bubbles, precisely absorbing 100 mu L of brain tissue homogenate in a 1.5mL centrifuge tube, then adding 10 mu L of internal standard solution and 300 mu L of methanol precipitant which are precisely absorbed, uniformly mixing and whirling for 1min, carrying out 12000 r/min in a centrifuge, centrifuging for 10min, precisely absorbing 150 mu L of supernate, adding 50 mu L of ultrapure water, sampling 10 mu L of solution, and detecting by adopting LC-MS/MS. The data system workstation was used to determine the brain tissue internal concentration of ZL 006.
The same method is adopted, the same dose of ZL006 is injected into tail vein, and the intracerebral ZL006 concentration 15min, 30min and 1h after administration is respectively measured. The results of the experimental data are shown in table 3 below.
TABLE 3 comparison of intracerebral ZL006 concentration following intravenous administration of S1 and ZL006
Group of In ZL006 group brain (mu g/g) In-brain (mu g/g) of S1 administration group
15min group 130 205
30min group 95 121
1h group 68 93
Example 4 Effect of S1 on focal cerebral ischemia reperfusion injury
1 materials and methods
1.1 Experimental animals
Sprague-dawley (sd) rat, male, body weight: 250-
1.2 Experimental methods
1.2.1 preparation of focal cerebral ischemia reperfusion model. The method mainly comprises the following steps: 10% chloral hydrate (350 mg/kg) was intraperitoneally injected to anesthetize rats, the right external carotid artery was isolated, ligated and severed, and a nylon plug thread, which was swollen at the tip of the human head, was slowly inserted from the stump of the external carotid artery along the sum of the carotid arteries, approximately 18mm, to block the entrance of the middle cerebral artery, resulting in ischemia. Removing the thrombus line after 2h of ischemia and performing 24h of reperfusion; and the successful preparation of the model is that the Homer and the dyskinesia of the contralateral body appear after the animal revives.
1.2.2 animal groups and administration test animals were randomly divided into 4 groups, i.e., model group, positive control edaravone group (6 mg/kg), S1 (1 mg/kg), S1 (0.1 mg/kg), each group containing 10 to 12 animals. Each group of the test substances and the positive control group were administered 1 time by tail vein injection immediately after reperfusion, and 1 time in total.
Each group was administered at a volume of 0.5mL/100 g.
1.3.3 determination of neurological Defect score and cerebral infarct volume
The symptom of neurological deficit was assessed using a modified Bederson 5-score.
And (4) measuring the volume of the cerebral infarction, and taking the brain of the animal after scoring the last neurological deficit. Removing olfactory brain, lower brainstem and cerebellum, weighing the rest part, cutting the brain into 5 pieces with substantially the same thickness along coronal plane, warm-bathing in 37 deg.C red tetrazolium dye for 30min to obtain deep red brain tissue and pale dead area. Then, the brain slices are fixed in 10% formaldehyde, white tissues are carefully dug down and weighed, and the percentage of the weight of the infarcted tissues to the total weight of the brain is used as an infarct volume judgment index.
2 results
2.1 Effect on post-ischemic reperfusion cerebral infarct volume and neurological deficit score
Compared with the model group, the medicine group can obviously reduce the infarct volume of the cerebral ischemia-reperfusion rat (P is less than 0.05); the influence on the nerve defect symptoms can improve the nerve defect symptoms of rats. The results are shown in Table 4.
TABLE 4 Effect on post-ischemic reperfusion cerebral infarct volume and neurological deficit score: (
Figure DEST_PATH_IMAGE005
±S）
Group of Cerebral infarct volume (%) Neurological deficit scoring (score)
Model set 39.64±2.12 2.57±0.14
Edaravone group (6 mg. kg) -1 ） 25.35±3.86** 1.85±0.25
S1（1 mg·kg -1 ） 28.2±2.76** 2.1±0.29
S1（0.1 mg·kg -1 ） 38.41±4.31 2.2±0.31
P <0.05, P <0.01, compared to model groups.

Claims (5)

1. An aminosalicylic acid compound shown as a formula I or pharmaceutically acceptable salt thereof,
Figure DEST_PATH_IMAGE001
formula I
Wherein the content of the first and second substances,
r1, R2 is selected from H, C1-C6 alkyl and substituted alkyl;
r3 is selected from H, halogen, C1-C6 alkyl;
the configuration of the chiral center in the molecule is R configuration or S configuration or racemate.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein,
r1, R2 is selected from H, C1-C3 alkyl;
r3 is selected from H and halogen.
3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein,
r1 is H or methyl;
r2 is a H atom;
r3 is selected from H, F, Cl, Br.
4. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is:
Figure DEST_PATH_IMAGE002
use of a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of stroke.
5. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
CN202110122640.XA 2021-01-29 2021-01-29 Aminosalicylic acid derivatives and application thereof Pending CN114805104A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202110122640.XA CN114805104A (en) 2021-01-29 2021-01-29 Aminosalicylic acid derivatives and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202110122640.XA CN114805104A (en) 2021-01-29 2021-01-29 Aminosalicylic acid derivatives and application thereof

Publications (1)

Publication Number Publication Date
CN114805104A true CN114805104A (en) 2022-07-29

Family

ID=82526422

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202110122640.XA Pending CN114805104A (en) 2021-01-29 2021-01-29 Aminosalicylic acid derivatives and application thereof

Country Status (1)

Country Link
CN (1) CN114805104A (en)

Similar Documents

Publication Publication Date Title
EP1774968B1 (en) Psycothropic agent and health food containing neferine
US20090131677A1 (en) Substituted beta-phenyl-alpha-hydroxy-propanoic acid, synthesis method and use thereof
EP2829547B1 (en) Sodium hydroxysafflor yellow a and production method and pharmaceutical use thereof
CN101012230A (en) Preparing process of sodium cantharidinate
CN104435034B (en) A kind of arasaponin and preparation method thereof
CN105209439A (en) Process for manufacture of gadofosveset trisodium monohydrate
CN107963987B (en) A stachydrine derivative, its preparation method and application in preparing medicine for treating cardiovascular disease and cerebrovascular disease
JP7050336B2 (en) Deuterated compounds and their pharmaceutical uses
CN114805104A (en) Aminosalicylic acid derivatives and application thereof
CN106928311A (en) Limonin derivative, its preparation method and medical usage
CN104447775B (en) A kind of new alkaloid compound, pharmaceutical composition and its medical usage
CN109912692B (en) YIGSK modified heptacyclic aldehyde, preparation, antithrombotic activity and application thereof
CN103980240B (en) New Hydroxy Carthamus yellow pharmaceutical salts
CN104610153B (en) Ozagrel meglumine salt, as well as composition, preparation method and application thereof
WO2005003146A1 (en) The c-glycosylisoflavones having alkylaminoalkoxyl substituent, the preparation and the use of the same
CN105663102B (en) A kind of application of phenol amides compound in prevention and treatment cerebral injury
CN111995661B (en) Ethyl ARPAK modified bis-carbolino-piperazinediones, preparation, activity and application thereof
CN114957270A (en) S (+) -pranoprofen derivative and preparation method and application thereof
EP2899186B1 (en) New hydroxysafflor yellow pharmaceutical salts
CN109912695B (en) RGDV-modified heptacyclic aldehyde, synthesis, antithrombotic activity and application thereof
CN107056877B (en) A kind of steroid compound and application thereof
CN105732453B (en) A kind of NAD compound
CN101633661B (en) Process for preparing sodium cantharidinate
CN105434335B (en) A kind of liensinine suppository and its preparation method and application
US9624254B2 (en) Hydroxysafflor yellow pharmaceutical salts

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination