CN111635433A - Novel enol non-steroid compound and preparation method and application thereof - Google Patents

Novel enol non-steroid compound and preparation method and application thereof Download PDF

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CN111635433A
CN111635433A CN201910157818.7A CN201910157818A CN111635433A CN 111635433 A CN111635433 A CN 111635433A CN 201910157818 A CN201910157818 A CN 201910157818A CN 111635433 A CN111635433 A CN 111635433A
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salt
compound
alkyl
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polymorph
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陆华龙
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Shaanxi Synthetic Pharmaceutical Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
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    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention provides a novel enol non-steroid compound shown in a formula (I) or pharmaceutically acceptable salt, hydrate, solvate, polymorph, enantiomer or racemic mixture thereof,

Description

Novel enol non-steroid compound and preparation method and application thereof
Technical Field
The invention belongs to the field of medicines, and particularly relates to a novel enol non-steroid compound, a preparation method of the compound, a pharmaceutical composition containing the compound, and application of the compound and the pharmaceutical composition in preparation of medicines for treating diseases related to joint inflammation.
Background
Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of acute and chronic pain, inflammation and fever. Some active agents in this category include serpin, ibuprofen, naproxen, diclofenac, indomethacin, celecoxib, and meloxicam. In 2000, meloxicam was first approved for sale in the United states under the trade name Mobic (Boehringer Ingelheim). It is available as oral tablets (7.5 mg and 15 mg) and as oral suspension (7.5 mg/5 ml). Meloxicam is suitable for the treatment of osteoarthritis, rheumatoid arthritis and juvenile rheumatoid arthritis. The recommended initial and maintenance dose is 7.5 mg/day. The maximum recommended daily dose is 15 mg/day. While NSAIDs have significant analgesic, anti-inflammatory and antipyretic activity, they also have serious dose-related side effects such as gastrointestinal perforation and bleeding, cardiovascular events including myocardial infarction, and renal failure. Thus, all FDA approved NSAID products (including meloxicam) marketed in the united states are provided with labeling claims instructing the prescribing physician to use the lowest effective dose for the shortest possible duration. Accordingly, it would be desirable to provide therapeutically effective NSAID products having lower drug doses than those currently available for patients suffering from acute or chronic pain.
Meloxicam is a member of the enolic acid group of NSAIDs and is chemically designated 4-hydroxy-2-methyl-N- (5-methyl-2-thiazolyl) -2H-1, 2-benzothiazine-3-carboxamide-1, 1-dioxide. It is practically insoluble in water. Poor solubility is a significant problem encountered in the development of compositions for the pharmaceutical, cosmetic, agricultural and food industries, particularly those containing biologically active substances that are poorly soluble in water at physiological pH. In many cases, poorly soluble compounds have undesirable pharmacokinetic properties from the gastrointestinal tract to the systemic circulation, such as slow dissolution and slow or incomplete oral absorption. In addition, poorly soluble active agents tend to be disadvantageous or even unsafe for intravenous administration due to the risk of drug particles blocking the blood flow through capillaries.
Therefore, there is still a need in the art to develop novel enol-type nonsteroidal compounds with high oral availability and good solubility, so as to effectively treat related arthritis symptoms.
Disclosure of Invention
The invention aims to provide a novel enol non-steroid compound, so as to develop an anti-inflammatory, analgesic and antipyretic drug with high oral utilization rate and good solubility.
In particular, the invention aims to provide a novel enol non-steroid compound or a pharmaceutically acceptable salt, solvate, polymorph, enantiomer or racemic mixture thereof.
Another object of the present invention is to provide a process for the preparation of the novel enol nonsteroidal compound or a pharmaceutically acceptable salt, solvate, polymorph, enantiomer or racemic mixture thereof.
It is still another object of the present invention to provide a pharmaceutical composition comprising the novel enol nonsteroidal compound or a pharmaceutically acceptable salt, solvate, polymorph, enantiomer or racemic mixture thereof as an active ingredient.
It is a further object of the present invention to provide a use of the novel enol nonsteroidal compound or a pharmaceutically acceptable salt, solvate, polymorph, enantiomer or racemic mixture thereof or a pharmaceutical composition thereof for the manufacture of a medicament.
It is still another object of the present invention to provide a method for treating related diseases using the novel enol nonsteroidal compound or a pharmaceutically acceptable salt, solvate, polymorph, enantiomer or racemic mixture thereof, or using the pharmaceutical composition.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
in one aspect, the invention provides a novel enol nonsteroidal compound shown in formula I or a pharmaceutically acceptable salt, solvate, polymorph, enantiomer or racemic mixture thereof,
Figure 100002_DEST_PATH_DEST_PATH_IMAGE001
wherein m is 0 or 1; n is an integer of 0 to 6; r1, R2 are independently hydrogen or C1-C6 alkyl or optionally substituted C1-C6 alkyl, halogen, amido, sulfonamido, acyloxy or C (o) R ', wherein said R' is hydrogen, C1-C10 alkyl, C1-C10 alkenyl, C1-C10 alkoxy, aryl C1-C10 alkyl, halogen, amido, sulfonamido or acyloxy; r3 or R4 are independently hydrogen or C1-C6 alkyl or optionally substituted C1-C6 alkyl; r5 or R6 are independently hydrogen, sodium salt, potassium salt, magnesium salt, calcium salt, ammonium salt, meglumine salt, choline salt, amino acid salt.
Preferably, the enol non-steroid compound is represented by formula II:
Figure DEST_PATH_IMAGE004
wherein; the groups R1, R2, R3, R4, R5 or R6 and m and n are as defined above.
According to some embodiments of the present invention there is provided an enol nonsteroidal compound or a pharmaceutically acceptable salt, solvate, polymorph, enantiomer or racemic mixture thereof, wherein R1, R2 are both methyl;
preferably, n is 0 or 1;
preferably, R3 or R4 are independently hydrogen.
According to some embodiments of the present invention, there is provided an enol non-steroid compound or a pharmaceutically acceptable salt, solvate, polymorph, enantiomer or racemic mixture thereof, wherein the enol non-steroid compound is as follows:
Figure DEST_PATH_IMAGE006
Figure DEST_PATH_IMAGE008
in another aspect, the present invention also provides the above enol nonsteroidal compound, or a pharmaceutically acceptable salt, solvate, polymorph, enantiomer or racemic mixture thereof, wherein the preparation method comprises the step of reacting the compound represented by the formula III with the compound represented by the formula IV:
Figure DEST_PATH_IMAGE010
wherein R1, R2, R3 and R4 and n are as defined above in the specification; r6 is F, Cl, Br or I; and R7 and R8 are independently protecting groups. Preferably, R6 is Cl.
According to a particular embodiment of the invention, compound 1 of the invention may be prepared by:
Figure DEST_PATH_IMAGE012
compound 2 of the present invention can be prepared by:
Figure DEST_PATH_IMAGE014
in a further aspect, the present invention provides a pharmaceutical composition comprising an enol nonsteroidal compound according to the invention or a pharmaceutically acceptable salt, solvate, polymorph, enantiomer or racemic mixture thereof, and a pharmaceutically acceptable adjuvant.
The pharmaceutically acceptable salt means that the compound of the present invention can form a pharmaceutically acceptable salt with an inorganic base such as sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, calcium hydroxide or an organic base, preferably the inorganic base is sodium hydroxide, ammonia water, sodium carbonate, sodium bicarbonate, potassium hydroxide; such as choline, meglumine, amino acids, preferably choline is choline hydroxide, preferably amino acids arginine, lysine, cysteine.
Such as hydrates, alcoholates and the like.
The selection and preparation of pharmaceutically acceptable salts and solvates, and the like, is well known in the art.
Depending on the particular dosage form and mode of administration, the pharmaceutically acceptable excipients in the pharmaceutical composition may include one or more of the following: diluents, disintegrants, lubricants, binders, fillers, flavoring agents, sweeteners, antioxidants, preservatives, pigments, and the like.
The pharmaceutical composition can be any dosage form for clinical use, such as tablets, suppositories, dispersible tablets, enteric-coated tablets, chewable tablets, orally disintegrating tablets, capsules, sugar-coated agents, granules, dry powders, oral solutions, small injection needles, freeze-dried powder injections or large infusion solutions, and is preferably oral dosage forms or injection dosage forms.
In still another aspect, the present invention provides the use of the above enol non-steroid compound or a pharmaceutically acceptable salt, solvate, polymorph, enantiomer or racemic mixture thereof or the above pharmaceutical composition for the manufacture of a medicament for treating arthritis-related diseases. In particular to a medicine for treating pain and swelling of rheumatoid arthritis, osteoarthritis and the like, soft tissue inflammation, traumatic pain and postoperative pain.
The enol non-steroid compound or the pharmaceutically acceptable salt, solvate, polymorph, enantiomer or racemic mixture thereof or the pharmaceutical composition can be applied together with other therapies or therapeutic agents. The administration may be simultaneous, sequential or at intervals.
The dosage of a compound or pharmaceutical composition required to effect a therapeutic, prophylactic or delay-acting effect, etc., will generally depend on the particular compound being administered, the patient, the particular disease or condition and its severity, route and frequency of administration, etc., and will need to be determined on a case-by-case basis by the attending physician. For example, when the compound or pharmaceutical composition provided by the present invention is administered by oral route, the dose thereof may be 0.1 to 1000 mg/day, preferably 1 to 500 mg/day; the dose may be administered in 1 to 3, preferably 2, divided doses per day.
In conclusion, the invention provides a novel compound with remarkable anti-inflammatory, antipyretic and analgesic effects. Experiments have shown that the oral bioavailability of the novel compounds of the invention is significantly improved compared to meloxicam, thus allowing to solve the problem that poorly soluble compounds have undesired pharmacokinetic properties from the gastrointestinal tract to the systemic circulation, such as slow dissolution and slow or incomplete oral absorption. In addition, poorly soluble active agents tend to be disadvantageous or even unsafe for intravenous administration due to the risk of blocking the blood flow through capillaries by drug particles. Therefore, the composition is more suitable for being prepared into medicines with various dosage forms for treating related diseases.
Detailed Description
The present invention is described in further detail below with reference to specific embodiments, which are given for the purpose of illustration only and are not intended to limit the scope of the invention.
The experimental procedures in the following examples are conventional unless otherwise specified. The raw materials and reagent materials used in the following examples can be purchased from conventional biochemical reagent stores or pharmaceutical operating enterprises unless otherwise specified.
Example 1: preparation of Compound 1
Figure DEST_PATH_IMAGE016
Figure DEST_PATH_IMAGE018
To a stirred solution of 1(10g) in anhydrous DCM (300ml) was added 2(21.4g) dropwise at 0 ℃. The mixture was then stirred at room temperature for 16 hours and the reaction was quenched with water. The organic layer was washed with sodium hydroxide solution and water, dried over anhydrous sodium sulfate, and concentrated to dryness. The residue was passed through an HPLC separation system to give 3 about 7.86g as a white solid.
At room temperature and N2To a solution of 3 (7.5 g) in dry DCM (250ml) was added TMSBr (5.65 g). The mixture was then stirred for 6 hours and the solvent was removed under reduced pressure. The residue was subjected to an HPLC separation system to obtain compound 1(5.45g, 54.5%) as a white solid.
Example 2: preparation of Compound 2
Figure DEST_PATH_IMAGE020
Figure DEST_PATH_IMAGE022
To a stirred solution of 1(10g) in anhydrous DCM (300ml) was added 2(25.8g) dropwise at 0 ℃. The mixture was then stirred at room temperature for 16 hours and the reaction was quenched with water. The organic layer was washed with sodium hydroxide solution and water, dried over anhydrous sodium sulfate, and concentrated to dryness. The residue was passed through an HPLC separation system to give 5.50 g as a white solid.
At room temperature and N2To a solution of 3 (6.0 g) in dry DCM (200ml) was added TFA (20 ml). The mixture was then stirred for 6 hours and the solvent was removed under reduced pressure. The residue was subjected to an HPLC separation system to obtain compound 2(4.57g, 45.7%) as a white solid.
Example 3: preparation of Compound 3
Figure DEST_PATH_IMAGE024
Adding purified water (20 ml) and a compound 1 (1.5 g) into a 100ml reaction bottle, stirring, then slowly dripping a sodium hydroxide solution (5 ml water is dissolved with 0.278g of sodium hydroxide) into the compound 1 solution, adjusting the pH of the solution to 9.0-10.0, filtering, slowly adding a filtrate into stirred isopropanol, stirring until a large amount of solid is separated out, continuing stirring for 1 hour, filtering, and drying a filter cake by blowing at 30-40 ℃ to obtain about 0.85g of a compound 3, wherein the yield is 56.7%.
Example 4: preparation of Compound 5
Figure DEST_PATH_IMAGE026
Prepared as in example 3 except that sodium hydroxide was replaced with lysine.
Example 5: preparation of Compound 6
Figure DEST_PATH_IMAGE028
Methanol (20 ml) and a compound 2 (1.5 g) are taken to be added into a 100ml reaction bottle for stirring, then sodium hydroxide solution (5 ml methanol is dissolved with 0.33g sodium methoxide) is slowly dripped into the compound 1 solution, the pH of the solution is adjusted to be 9.0-10.0, the solution is filtered, and filter cakes are dried by air blowing under the condition of 30-40 ℃ to obtain about 0.82g of the compound 6 with the yield of 54.6%.
Example 6: preparation of Compound 7
Figure DEST_PATH_IMAGE030
Adding purified water (20 ml) and a compound 1 (1.5 g) into a 100ml reaction bottle, stirring, then slowly dripping a sodium hydroxide solution (3 ml water is dissolved with 0.139g of sodium hydroxide) into the compound 1 solution, adjusting the pH of the solution to 8.0-9.0, filtering, slowly adding a filtrate into stirred isopropanol, stirring until a large amount of solid is separated out, continuing stirring for 1 hour, filtering, and drying a filter cake by blowing at 30-40 ℃ to obtain about 0.81g of a compound 7 with the yield of 54.0%.
Example 7: preparation of Compound 8
Figure DEST_PATH_IMAGE032
Adding purified water (20 ml) and a compound 1 (1.5 g) into a 100ml reaction bottle, stirring, then slowly dripping a sodium hydroxide solution (5 ml water is dissolved with 0.278g of sodium hydroxide) into the compound 1 solution, adjusting the pH of the solution to 9.0-10.0, filtering, slowly adding a filtrate into stirred isopropanol, stirring until a large amount of solid is separated out, continuing stirring for 1 hour, filtering, and drying a filter cake by blowing air at 25 ℃ to obtain about 0.82g of a compound 8, wherein the yield is 54.6%.
Example 8 clinical efficacy test of the novel enol-type nonsteroidal Compounds of the present invention
Test animals: 250 clinical patient dogs (patient dogs subjected to a simple tooth extraction operation for various dental diseases) of more than 4 months of age, without limitation to sex and body weight, were divided into seven groups, the first to fourth groups were example groups, the fifth group was a comparative example group, and each group had 50 patient dogs.
The administration method comprises the following steps: the drugs (meloxicam) of examples 3, 4, 5, 7 and comparative example were administered in appropriate amounts for the first time and then in appropriate amounts for 1 time a day for 6 consecutive days, based on the meloxicam active ingredient.
The test method comprises the following steps: the test dog starts to administer the medicament after receiving the tooth extraction operation, and the curative effect judgment is carried out according to the scoring standard in the following table, the curative effect judgment is shown in the table 1, and the test result is shown in the table 2.
TABLE 1 therapeutic effect decision table
Group of Grouping criteria Processing method
Is excellent in All clinical indicators returned to normal Treatment was stopped and recurrence was assessed 2 days later
Good effect At least half of the clinical indicators improved The treatment is continued for 2 days
Go and can Less than half of the improvement in clinical signs The treatment is continued for 2 days
Failure of the product No improvement or deterioration of animal body conditions The physician decides whether to continue treatment or eliminate
TABLE 2 test results
Figure DEST_PATH_IMAGE034
As can be seen from the results of Table four, the drugs described in examples 3, 4, 5, and 7 all had good analgesic effects on dogs after surgery involving soft tissues and alveolar bone tissues, and the analgesic effects of examples 3, 4, 5, and 7 were significantly superior to those of comparative examples, and the treatment period was shortened.
Example 9: in vivo pharmacokinetic testing
The in vivo pharmacokinetics of compound 3, compound 5, compound 6, compound 8 and meloxicam of the present invention were examined. Specifically, compound 3, compound 5, compound 6, compound 8 and meloxicam were orally or intravenously injected into rats, pharmacokinetic characteristics of the compound of the present invention and meloxicam in rats were evaluated, transformation of the compound of the present invention in rats was examined, and bioavailability of the compound of the present invention and meloxicam was compared by measuring blood concentration in rats over time.
The experimental animals are male SD rats aged 6-8 weeks and with a body weight of 190-215 g, purchased from Beijing Weiritong Hua laboratory animals technologies GmbH. The animals were randomly divided into 5 groups of 3 animals each based on the body weight of the SD rats. The formulation of the compound administered, the dose administered, the route of administration, and the time point of the assay for each group of rats are shown in Table 3.
TABLE 3 pharmacokinetic testing conditions
Group of Medicine Preparation Pathway(s) Dosage of drug (mg/kg) Drug concentration (mg/ml)
1 Compound 3 30% PEG400 in saline Through the vein 1 0.2
2 Compound 5 30% PEG400 in saline Is administered orally 1 0.2
3 Compound 6 30% PEG400 in saline Is administered orally 1 0.2
4 Compound 8 30% PEG400 in saline Through the vein 1 0.2
5 Meloxicam 30% PEG400 in saline Through the vein 1 0.2
SD rats were fasted for 16 hours prior to pharmacokinetic testing. Single doses of the compound or blank solution were then administered intravenously or orally as shown in table 1. Blood 200uL was collected periodically after administration by means of jugular venipuncture. Wherein for the group of animals administered intravenously, blood is collected at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours post-administration; for the orally administered animal groups, blood was collected at 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours post-administration. The blood samples were collected in sample tubes with EDTA, immediately centrifuged at 4000rpm for 5 minutes at 4 ℃, and then the plasma was transferred to another sample tube and stored at-20 ℃.
The samples were subjected to pharmacokinetic testing using the following methods and instruments:
column: phenomenex Luna 5um C18 (2.0X 50nm)
Mobile phase: 95% acetonitrile (0.1% formic acid) and 5% acetonitrile (0.1% formic acid)
The quantitative method comprises the following steps: internal standard method
The results are shown in Table 4.
TABLE 4 comparison of pharmacokinetic data
Figure DEST_PATH_IMAGE036
NA: the data is not available.
The data in table 4 show that the bioavailability of the compounds of the invention is significantly higher than that of meloxicam. Therefore, the compound of the invention can obviously reduce the dosage of the medicine and reduce the risk of side effects such as bleeding and the like.

Claims (8)

1. A novel enol non-steroid compound shown in formula I or its pharmaceutically acceptable salt, hydrate, solvate, polymorph, enantiomer or racemic mixture,
Figure DEST_PATH_DEST_PATH_IMAGE001
wherein,
m is 0 or 1; n is an integer of 0 to 6; r1, R2 are independently hydrogen or C1-C6 alkyl or optionally substituted C1-C6 alkyl, halogen, amido, sulfonamido, acyloxy or C (o) R ', wherein said R' is hydrogen, C1-C10 alkyl, C1-C10 alkenyl, C1-C10 alkoxy, aryl C1-C10 alkyl, halogen, amido, sulfonamido or acyloxy; r3 or R4 are independently hydrogen or C1-C6 alkyl or optionally substituted C1-C6 alkyl; r5 or R6 are independently hydrogen, sodium salt, potassium salt, magnesium salt, calcium salt, ammonium salt, meglumine salt, choline salt, amino acid salt.
2. The novel enol non-steroid compound according to claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, enantiomer or racemic mixture thereof, wherein said enol non-steroid compound is represented by formula II:
Figure 74612DEST_PATH_IMAGE002
wherein; the groups R1, R2, R3, R4, R5 or R6 and m and n are as defined above.
3. The novel enol non-steroid compound according to claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, enantiomer or racemic mixture thereof, wherein R1, R2 are both methyl groups.
4. The novel enolic nonsteroidal compound according to any of claims 1 to 3, or pharmaceutically acceptable salt, hydrate, solvate, polymorph, enantiomer, or racemic mixture thereof, characterized in that n is 0 or 1.
5. The novel enolic nonsteroidal compound according to any of claims 1 to 4, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, enantiomer, or racemic mixture thereof, characterized in that it is represented by:
Figure 872672DEST_PATH_IMAGE003
Figure 163977DEST_PATH_IMAGE004
。
6. a process for the preparation of a novel enolic nonsteroidal compound according to any of claims 1 to 5 or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, enantiomer or racemic mixture thereof, comprising the step of reacting a compound of formula III with a compound of formula IV:
Figure 165431DEST_PATH_IMAGE005
wherein R1, R2, R3 and R4 and n are as defined above in the specification; r6 is F, Cl, Br or I; and R7 and R8 are independently protecting groups, preferably, R6 is Cl.
7. A pharmaceutical composition comprising the novel enol nonsteroidal compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, enantiomer, or racemic mixture thereof, and a pharmaceutically acceptable adjuvant.
8. Use of a novel enol non-steroid compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, enantiomer or racemic mixture thereof or a pharmaceutical composition according to claim 7 for the manufacture of a medicament for the treatment of arthritis-related diseases; preferably, the medicament is for the treatment of pain, swelling and soft tissue inflammation, traumatic pain, post-operative pain in rheumatoid arthritis and osteoarthritis and the like.
CN201910157818.7A 2019-03-02 2019-03-02 Novel enol non-steroid compound and preparation method and application thereof Pending CN111635433A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022229576A1 (en) * 2021-04-30 2022-11-03 Atlanthéra Hydroxybisphosphonic derivatives of meloxicam for the treatment of inflammatory joint diseases

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CN103665042A (en) * 2012-09-21 2014-03-26 北京普禄德医药科技有限公司 Optically active 2-hydroxyltetrahydrothienopyridine derivative as well as preparation method and use thereof
CN106554370A (en) * 2015-09-25 2017-04-05 陕西合成药业股份有限公司 Dabigatran derivant containing phosphate ester and its production and use
CN108690078A (en) * 2017-03-29 2018-10-23 江苏恒瑞医药股份有限公司 A kind of benzo plug piperazine phosphate derivative, preparation method and its application in medicine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103665042A (en) * 2012-09-21 2014-03-26 北京普禄德医药科技有限公司 Optically active 2-hydroxyltetrahydrothienopyridine derivative as well as preparation method and use thereof
CN106554370A (en) * 2015-09-25 2017-04-05 陕西合成药业股份有限公司 Dabigatran derivant containing phosphate ester and its production and use
CN108690078A (en) * 2017-03-29 2018-10-23 江苏恒瑞医药股份有限公司 A kind of benzo plug piperazine phosphate derivative, preparation method and its application in medicine

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022229576A1 (en) * 2021-04-30 2022-11-03 Atlanthéra Hydroxybisphosphonic derivatives of meloxicam for the treatment of inflammatory joint diseases
FR3122427A1 (en) * 2021-04-30 2022-11-04 Atlanthéra HYDROXYBISPHOSPHONIC DERIVATIVES OF MELOXICAM FOR THE TREATMENT OF INFLAMMATORY OSTEOARTICULAR DISEASES

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