CN115636799A - Preparation method of double-effect endothelin-angiotensin receptor antagonist - Google Patents
Preparation method of double-effect endothelin-angiotensin receptor antagonist Download PDFInfo
- Publication number
- CN115636799A CN115636799A CN202211373287.3A CN202211373287A CN115636799A CN 115636799 A CN115636799 A CN 115636799A CN 202211373287 A CN202211373287 A CN 202211373287A CN 115636799 A CN115636799 A CN 115636799A
- Authority
- CN
- China
- Prior art keywords
- endothelin
- receptor antagonist
- temperature
- angiotensin receptor
- liquid separation
- 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
Links
Abstract
The invention discloses a preparation method of a double-effect endothelin-angiotensin receptor antagonist, which has the technical key points that: the method comprises the following steps: dissolving the compound A in 3.5L of anhydrous THF, cooling to-75 ℃, slowly dropwise adding 900ml and 2.05eq of DIBAL-H, keeping the temperature below-65 ℃, removing a dry ice acetone bath after dropwise adding is finished, raising the temperature to-25 ℃, keeping the temperature at-25 ℃ for 2 hours, and indicating that the reaction is complete by TLC; pouring the reaction solution into 5L of saturated ammonium chloride solution, controlling the temperature below 15 ℃, separating the solution, extracting the water layer with 2.5L of ethyl acetate for 2 times, combining the ethyl acetate, washing, drying by adopting anhydrous sodium sulfate, filtering, spin-drying the filtrate to obtain 360g of crude product, and performing column chromatography on the crude product to obtain 330g of product. The preparation method of the double-effect endothelin-angiotensin receptor antagonist has the advantages of simple process, high preparation purity and high yield.
Description
Technical Field
The invention relates to the field of antagonist preparation, in particular to a preparation method of a double-effect endothelin-angiotensin receptor antagonist.
Background
Endogenously active vasopeptides are believed to play a role in controlling vascular tone and remodeling of pathological tissues associated with a variety of diseases including diabetic nephropathy, heart failure, and chronic or refractory hypertension. At present, angiotensin receptor blockers blocking the activity of AngII are widely used for the treatment of diabetic nephropathy, heart failure, chronic or refractory hypertension.
Chinese patent publication No. CN102421434A, which discloses a method of treating an endothelin-dependent or angiotensin II-dependent disorder in a human patient in need thereof: comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof in an amount of from about 50 mg/day to about 1000 mg/day. Wherein the endothelin-dependent or angiotensin II-dependent disorder is chronic hypertension, refractory hypertension, or diabetic nephropathy.
The above-mentioned patents, have some drawbacks, such as: the method for preparing the double-effect endothelin-angiotensin receptor antagonist is complex and has low yield.
Disclosure of Invention
In view of the problems mentioned in the background, the present invention aims to provide a method for preparing a dual-effect endothelin-angiotensin receptor antagonist, so as to solve the problems mentioned in the background.
The technical purpose of the invention is realized by the following technical scheme:
a preparation method of a double-effect endothelin-angiotensin receptor antagonist comprises the following steps: dissolving the compound A in 3.5L of anhydrous THF, cooling to-75 ℃, slowly dropwise adding 900ml and 2.05eq of DIBAL-H, keeping the temperature below-65 ℃, removing a dry ice acetone bath after dropwise adding is finished, raising the temperature to-25 ℃, keeping the temperature at-25 ℃ for 2 hours, and indicating that the reaction is complete by TLC; pouring the reaction solution into 5L of saturated ammonium chloride solution, controlling the temperature below 15 ℃, separating the solution, extracting the water layer with 2.5L of ethyl acetate for 2 times, combining the ethyl acetate, washing, drying by adopting anhydrous sodium sulfate, filtering, spin-drying the filtrate to obtain 360g of crude product, and performing column chromatography on the crude product to obtain 330g of product.
Preferably, the synthetic chemical formula of the compound a is formula one, which is:
preferably, after pouring the reaction solution into 5L of saturated ammonium chloride solution, if salt is precipitated, 1N hydrochloric acid is added to adjust pH =6-7 so that no solid is evident.
Preferably, before the liquid separation operation, the liquid separation is kept clear, and a liquid separation port cannot be blocked.
Preferably, the liquid is left for more than one night for further liquid separation if the liquid separation is not kept clear.
Preferably, after the dropwise addition is completed, the dry ice acetone bath is removed, and the temperature is raised to-25 ℃ in a room temperature environment, and then kept in an ice bath at-25 ℃ for 2 hours.
Preferably, the reaction solution is poured into 5L of saturated ammonium chloride solution, the temperature is controlled at 10 ℃, and liquid separation is carried out.
Preferably, the ethyl acetate is combined and washed with saturated brine 1 or more times.
In summary, the invention mainly has the following beneficial effects:
the preparation method of the double-effect endothelin-angiotensin receptor antagonist has the advantages of simple process, high preparation purity and high yield; the compound A is dissolved in anhydrous THF, DIBAL-H is dripped to react, then the reaction solution is poured into an ammonium chloride solution for extraction and liquid separation, and the finished product can be prepared through the steps of washing, drying, filtering, spin-drying the filtrate, column chromatography and the like, and the operation is simple.
Detailed Description
The technical solutions in the embodiments of the present invention are clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be obtained by a person skilled in the art without making any creative effort based on the embodiments in the present invention, belong to the protection scope of the present invention.
Example 1
The present invention provides a method for preparing a dual effect endothelin-angiotensin receptor antagonist, comprising the following steps: dissolving the compound A in 3.5L of anhydrous THF, cooling to-75 ℃, slowly dropwise adding 900ml and 2.05eq of DIBAL-H, keeping the temperature at-72 ℃, removing a dry ice acetone bath after dropwise adding is finished, raising the temperature to-25 ℃, keeping the temperature at-25 ℃ for 2 hours, and indicating that the reaction is complete by TLC; pouring the reaction solution into 5L of saturated ammonium chloride solution, controlling the temperature at 8 ℃, separating liquid, extracting a water layer for 2 times by using 2.5L of ethyl acetate, combining the ethyl acetate, washing, drying by using anhydrous sodium sulfate, filtering, spin-drying the filtrate to obtain 360g of crude product, and performing column chromatography on the crude product to obtain 330g of product.
The synthetic chemical formula of the compound A is shown as the formula I:
the most common form of glomerulonephritis is gA nephropathy (IgAN), the primary IgA nephropathy patients usually have IgA antibody deposition in glomeruli, and many other diseases cause IgA antibody deposition in glomeruli, most commonly Henoch-
Purpura. Henoch-
Purpura often presents with characteristic skin purpura, arthritis, abdominal pain, most common in young people (16-35 years of age). Between 20 and 30% of patients, usually elderly patients, have occult hematuria and proteinuria (less than 2g per day). These patients may be completely asymptomatic and only discovered when a doctor takes a urine test. The Sparsentan has good tolerance and can improve proteinuria of patients.
Some embodiments provide methods of treating an endothelin-dependent or angiotensin II-dependent disorder in a patient in need thereof comprising administering an effective amount of a Sparsentan compound or a pharmaceutically acceptable salt thereof. In some other embodiments, the endothelin-dependent or angiotensin II-dependent disorder is diabetic nephropathy.
In some embodiments, the method comprises administering the product in an amount from about 50 mg/day to about 1000 mg/day. In some embodiments, the amount of Sparsentan compound or a pharmaceutically acceptable salt thereof administered to the human patient is from about 200 mg/day to about 800 mg/day, more preferably about 400 mg/day, and most preferably about 800 mg/day. In some embodiments, the amount of Sparsentan compound or a pharmaceutically acceptable salt thereof administered to the human patient can be about 100 mg/day, about 200 mg/day, about 400 mg/day, or about 800 mg/day.
In some embodiments, the systolic blood pressure of the human patient is reduced to at least 160mmHg or less, at least 140mmHg or less, at least 130mmHg or less, or at least 120mmHg or less. In some embodiments, the diastolic pressure of the human patient is reduced to at least 120mmHg or less, at least 110mmHg or less, at least 100mmHg or less, or at least 90mmHg or less. In some embodiments, the systolic or diastolic blood pressure of the human patient is reduced by at least about 5mmHg, at least about 8mmHg, about 10mmHg, at least about 12mmHg, or about 14mmHg as compared to the systolic or diastolic blood pressure prior to treatment.
In some embodiments, the Sparsentan compound, or a pharmaceutically acceptable salt thereof, is administered at a frequency of no more than four times, two times, or once per day. In some embodiments, the Sparsentan compound, or a pharmaceutically acceptable salt thereof, is administered four times, two times, or once daily.
In some embodiments, a systolic blood pressure of less than 140mmHg or a diastolic blood pressure of less than 90mmHg is achieved within 16 weeks, within 14 weeks, within 12 weeks, within 10 weeks, or within 8 weeks of administration of the Sparsentan compound or a pharmaceutically acceptable salt thereof.
In some embodiments, a systolic blood pressure of less than 140mmHg or a diastolic blood pressure of less than 90mmHg is achieved within 16 weeks, within 14 weeks, within 12 weeks, within 10 weeks, or within 8 weeks of administration of the Sparsentan compound or a pharmaceutically acceptable salt thereof. Some embodiments provide a pharmaceutical composition comprising a Sparsentan compound, or a pharmaceutically acceptable salt thereof, for treating an endothelin-dependent or angiotensin II-dependent disorder in a patient in need thereof. In some embodiments, the amount of the Sparsentan compound, or a pharmaceutically acceptable salt thereof, is from about 50mg to about 1000mg. In some embodiments, the endothelin-dependent or angiotensin II-dependent disorder is chronic hypertension. In some embodiments, the endothelin-dependent or angiotensin II-dependent disorder is refractory hypertension. In some embodiments, the endothelin-dependent or angiotensin II-dependent disorder is diabetic nephropathy. In some embodiments, the endothelin-dependent or angiotensin II-dependent disorder is hypertension. In some embodiments, the amount of Sparsentan compound, or a pharmaceutically acceptable salt thereof, is from about 200mg to about 800mg.
After pouring the reaction solution into 5L of saturated ammonium chloride solution, if salt is precipitated, 1N hydrochloric acid is added to adjust pH =6 so that no solid is evident.
And before the liquid separation operation, the liquid separation is kept clear, and a liquid separation port cannot be blocked.
If the liquid separation is not clear, the mixture is left for more than one night and then liquid separation is carried out.
Wherein, after the dripping is finished, the dry ice acetone bath is removed, the temperature of the bath is raised to-25 ℃ in the room temperature environment, and then the bath is kept in the ice bath at-25 ℃ for 2 hours.
Wherein, after the ethyl acetate is combined, the mixture is washed with saturated saline for 1 time or more.
The preparation method of the double-effect endothelin-angiotensin receptor antagonist has the advantages of simple process, high preparation purity and high yield; the compound A is dissolved in anhydrous THF, DIBAL-H is dripped to react, then the reaction solution is poured into an ammonium chloride solution for extraction and liquid separation, and the finished product can be prepared through the steps of washing, drying, filtering, spin-drying the filtrate, column chromatography and the like, and the operation is simple.
Example 2
The present invention provides a method for preparing a dual effect endothelin-angiotensin receptor antagonist, comprising the following steps: dissolving the compound A in 3.5L of anhydrous THF, cooling to-75 ℃, slowly adding 900ml and 2.05eq of DIBAL-H dropwise, keeping the temperature at-74 ℃, removing a dry ice acetone bath after the dropwise addition is finished, raising the temperature to-25 ℃, keeping the temperature at-25 ℃ for 2 hours, and indicating that the reaction is complete by TLC; pouring the reaction solution into 5L of saturated ammonium chloride solution, controlling the temperature at 9 ℃, separating liquid, extracting a water layer for 2 times by using 2.5L of ethyl acetate, combining ethyl acetate, washing, drying by using anhydrous sodium sulfate, filtering, spin-drying a filtrate to obtain 360g of crude product, and performing column chromatography on the crude product to obtain 330g of product.
The synthetic chemical formula of the compound A is shown as the formula I:
in some examples, the reaction solution is poured into 5L saturated ammonium chloride solution, if salt is precipitated, 1N hydrochloric acid is added to adjust pH =7, and no obvious solid is formed.
In some embodiments, the liquid separation is kept clear without blocking the liquid separation port before the liquid separation operation.
In some embodiments, if the separation cannot be kept clear, the solution is left for more than one night and then separated.
In some embodiments, the dry ice acetone bath was removed after the addition was complete, allowed to rise to-25 ℃ in a room temperature environment, and then held in a-25 ℃ ice bath for 2 hours.
In some examples, when washing is performed after combining the ethyl acetates, washing is performed 1 or more times with saturated brine.
The preparation method of the double-effect endothelin-angiotensin receptor antagonist has the advantages of simple process, high preparation purity and high yield; the compound A is dissolved in anhydrous THF, DIBAL-H is dripped to react, then the reaction solution is poured into ammonium chloride solution for extraction and liquid separation, and the finished product can be prepared through steps of washing, drying, filtering, spin-drying filtrate, column chromatography and the like, and the operation is simple.
Some embodiments provide methods of treating an endothelin-dependent or angiotensin II-dependent disorder in a patient in need thereof comprising administering an effective amount of a Sparsentan compound or a pharmaceutically acceptable salt thereof. In some other embodiments, the endothelin-dependent or angiotensin II-dependent disorder is diabetic nephropathy.
In some embodiments, the method comprises administering the product in an amount from about 60 mg/day to about 800 mg/day. In some embodiments, the amount of Sparsentan compound or a pharmaceutically acceptable salt thereof administered to the human patient is from about 400 mg/day to about 600 mg/day, more preferably about 500 mg/day, and most preferably about 550 mg/day. In some embodiments, the amount of Sparsentan compound or a pharmaceutically acceptable salt thereof administered to the human patient can be about 120 mg/day, about 220 mg/day, about 420 mg/day, or about 620 mg/day.
In some embodiments, the systolic blood pressure of the human subject is reduced to at least 150mmHg or less, at least 130mmHg or less, at least 120mmHg or less, or at least 110mmHg or less. In some embodiments, the diastolic blood pressure of the human patient is reduced to at least 125mmHg or less, at least 115mmHg or less, at least 105mmHg or less, or at least 95mmHg or less. In some embodiments, the systolic or diastolic blood pressure of the human subject is reduced by at least about 8mmHg, at least about 10mmHg, about 12mmHg, at least about 14mmHg, or about 16mmHg as compared to the systolic or diastolic blood pressure prior to treatment.
In some embodiments, the Sparsentan compound, or pharmaceutically acceptable salt thereof, is administered at a frequency of no more than four times, two times, or once per day. In some embodiments, the Sparsentan compound or pharmaceutically acceptable salt thereof is administered four times, two times, or once daily.
In some embodiments, a systolic blood pressure of less than 130mmHg or a diastolic blood pressure of less than 90mmHg is achieved within 15 weeks, within 13 weeks, within 11 weeks, within 9 weeks, or within 8 weeks of administration of the Sparsentan compound or a pharmaceutically acceptable salt thereof.
In some embodiments, a systolic blood pressure of less than 140mmHg or a diastolic blood pressure of less than 90mmHg is achieved within 16 weeks, within 14 weeks, within 12 weeks, within 10 weeks, or within 8 weeks of administration of the Sparsentan compound or a pharmaceutically acceptable salt thereof. Some embodiments provide a pharmaceutical composition comprising a Sparsentan compound, or a pharmaceutically acceptable salt thereof, for treating an endothelin-dependent or angiotensin II-dependent disorder in a patient in need thereof. In some embodiments, the amount of Sparsentan compound, or a pharmaceutically acceptable salt thereof, is from about 50mg to about 1000mg. In some embodiments, the endothelin-dependent or angiotensin II-dependent disorder is chronic hypertension. In some embodiments, the endothelin-dependent or angiotensin II-dependent disorder is refractory hypertension. In some embodiments, the endothelin-dependent or angiotensin II-dependent disorder is diabetic nephropathy. In some embodiments, the endothelin-dependent or angiotensin II-dependent disorder is hypertension. In some embodiments, the amount of the Sparsentan compound, or a pharmaceutically acceptable salt thereof, is from about 200mg to about 800mg.
And (3) yield statistical calculation: the yield of the comparative document was 83%, the yield of example 1 was 94%, and the yield of example 2 was 95%.
Statistics of preparation cost: the cost of the comparison document is 100%, that of example 1 is 80%, and that of example 2 is 75%.
The raw materials and related attributes of the invention are shown in the following table:
| name of raw materials | Dosage of | Molecular weight | Number of moles | Molar ratio of |
| 4 | 360 | 546.63 | 0.659 | 10 |
| DIBAL-H | 900 | 135 | 2.05 | |
| THF | 3.5L |
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (8)
1. A preparation method of a double-effect endothelin-angiotensin receptor antagonist is characterized by comprising the following steps: the method comprises the following steps: dissolving the compound A in 3.5L of anhydrous THF, cooling to-75 ℃, slowly dropwise adding 900ml and 2.05eq of DIBAL-H, keeping the temperature below-65 ℃, removing a dry ice acetone bath after dropwise adding is finished, raising the temperature to-25 ℃, keeping the temperature at-25 ℃ for 2 hours, and indicating that the reaction is complete by TLC; pouring the reaction solution into 5L of saturated ammonium chloride solution, controlling the temperature below 15 ℃, separating the solution, extracting the water layer with 2.5L of ethyl acetate for 2 times, combining the ethyl acetate, washing, drying by adopting anhydrous sodium sulfate, filtering, spin-drying the filtrate to obtain 360g of crude product, and performing column chromatography on the crude product to obtain 330g of product.
2. The method of preparing a dual acting endothelin-angiotensin receptor antagonist of claim 1 wherein: the synthetic chemical formula of the compound A is shown as the formula I:
3. the method of preparing a dual acting endothelin-angiotensin receptor antagonist of claim 1 wherein: after pouring the reaction solution into 5L of saturated ammonium chloride solution, if salt is precipitated, 1N hydrochloric acid is added to adjust pH =6-7 so that no solid is evident.
4. The method of preparing a dual acting endothelin-angiotensin receptor antagonist of claim 1 wherein: before the liquid separation operation, the liquid separation is kept clear, and a liquid separation port cannot be blocked.
5. The method of claim 4, wherein the method comprises the steps of: if the liquid separation can not be kept clear, the mixture is placed for more than one night and then liquid separation is carried out.
6. The method of claim 1, wherein the method comprises the steps of: after the addition was complete, the dry ice acetone bath was removed and the temperature was allowed to rise to-25 ℃ in a room temperature environment, after which it was held in an ice bath at-25 ℃ for 2 hours.
7. The method of claim 1, wherein the method comprises the steps of: and pouring the reaction solution into 5L of saturated ammonium chloride solution, controlling the temperature at 10 ℃, and separating the solution.
8. The method of preparing a dual acting endothelin-angiotensin receptor antagonist of claim 1 wherein: after combining the ethyl acetates, washing was performed by washing with saturated brine 1 time or more.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211373287.3A CN115636799A (en) | 2022-11-04 | 2022-11-04 | Preparation method of double-effect endothelin-angiotensin receptor antagonist |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211373287.3A CN115636799A (en) | 2022-11-04 | 2022-11-04 | Preparation method of double-effect endothelin-angiotensin receptor antagonist |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN115636799A true CN115636799A (en) | 2023-01-24 |
Family
ID=84946123
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211373287.3A Pending CN115636799A (en) | 2022-11-04 | 2022-11-04 | Preparation method of double-effect endothelin-angiotensin receptor antagonist |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115636799A (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001044239A2 (en) * | 1999-12-15 | 2001-06-21 | Bristol-Myers Squibb Co. | Biphenyl sulfonamides as dual angiotensin endothelin receptor antagonists |
| US20020143024A1 (en) * | 1998-07-06 | 2002-10-03 | Natesan Murugesan | Biphenyl sulfonamides as dual angiotensin endothelin receptor antagonists |
| CN102421434A (en) * | 2009-03-31 | 2012-04-18 | 利亘制药公司 | Oral formulations of diphenylsulfonamide endothelin and angiotensin ii receptor agonists to treat elevated blood pressure and diabetic nephropathy |
| CN112876424A (en) * | 2019-11-29 | 2021-06-01 | 上海拓界生物医药科技有限公司 | Dual angiotensin II receptor and endothelin receptor antagonists |
-
2022
- 2022-11-04 CN CN202211373287.3A patent/CN115636799A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020143024A1 (en) * | 1998-07-06 | 2002-10-03 | Natesan Murugesan | Biphenyl sulfonamides as dual angiotensin endothelin receptor antagonists |
| WO2001044239A2 (en) * | 1999-12-15 | 2001-06-21 | Bristol-Myers Squibb Co. | Biphenyl sulfonamides as dual angiotensin endothelin receptor antagonists |
| CN102421434A (en) * | 2009-03-31 | 2012-04-18 | 利亘制药公司 | Oral formulations of diphenylsulfonamide endothelin and angiotensin ii receptor agonists to treat elevated blood pressure and diabetic nephropathy |
| CN112876424A (en) * | 2019-11-29 | 2021-06-01 | 上海拓界生物医药科技有限公司 | Dual angiotensin II receptor and endothelin receptor antagonists |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Green et al. | Bilateral adrenalectomy in malignant hypertension and diabetes | |
| US10314806B2 (en) | Preparation containing chlorogenic acid crystal form and use thereof | |
| WO2008061456A1 (en) | The folacin-metformin compound and its manufacture | |
| CN102140092A (en) | Hydrate of ilaprazole salt, preparation method thereof and application thereof | |
| CN100584835C (en) | Novel medicinal salt for cinepazide and preparation method thereof | |
| CN115636799A (en) | Preparation method of double-effect endothelin-angiotensin receptor antagonist | |
| RU2019136633A (en) | TREATMENT OF GLAUCOMA | |
| JP6511191B2 (en) | Composition for treating or preventing pancreatitis comprising a naphthoquinone type compound | |
| CN109836423B (en) | Novel compound for preventing or treating pulmonary fibrosis diseases, preparation method and application thereof | |
| JP2002514578A (en) | Analogs of 2-phthalimidinoglutaric acid and their use as inhibitors of angiogenesis | |
| CN103193792A (en) | New compound for treating ischemic cardiovascular and cerebrovascular diseases | |
| US7470666B2 (en) | Use of Ulinastatin and its pharmaceutical composition for treating severe acute respiratory syndrome | |
| CN107001262A (en) | The hemifumarate and its crystal formation of the proton pump inhibitor containing pyrrole ring, intermediate and medical usage | |
| TWI599571B (en) | Process for prepararing intermediate compound of ixazomib citrate, and ixazomib citrate made thereby | |
| CN106946866B (en) | A kind of drug and preparation method thereof preventing and treating cerebral apoplexy | |
| US11497722B2 (en) | Use of metformin salt in the treatment of cerebral infarction | |
| CN112028892B (en) | Application of 4-amino-pyrrolotriazine derivative in preparation of anti-pulmonary fibrosis preparation | |
| KR102201940B1 (en) | A pharmaceutical composition for preventing or treating thrombosis related disease and disease related to blood circulation disorder | |
| CN104800200B (en) | The medical usage of Galangin | |
| CN112516121B (en) | Composition containing taurine and allopurinol and medical application thereof | |
| KR102147671B1 (en) | A composition for treating or preventing endothelin mediated disease | |
| CN1413588A (en) | Drug composition containing Fructus Tribuli fruit total saponin and its preparation method | |
| CN103923033B (en) | There is the piperazine derivative of anti-ulcer effect | |
| US20220079920A1 (en) | Pharmaceutical composition containing amlodipine, chlorthalidone, and amiloride and application thereof | |
| CN117551085A (en) | Benzopyran chalcone compound, preparation method and application and pharmaceutical preparation thereof |
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 |