CN110845475A - Preparation method of loratadine impurity - Google Patents
Preparation method of loratadine impurity Download PDFInfo
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- CN110845475A CN110845475A CN201911358515.8A CN201911358515A CN110845475A CN 110845475 A CN110845475 A CN 110845475A CN 201911358515 A CN201911358515 A CN 201911358515A CN 110845475 A CN110845475 A CN 110845475A
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- 229960003088 loratadine Drugs 0.000 title claims abstract description 59
- JCCNYMKQOSZNPW-UHFFFAOYSA-N loratadine Chemical compound C1CN(C(=O)OCC)CCC1=C1C2=NC=CC=C2CCC2=CC(Cl)=CC=C21 JCCNYMKQOSZNPW-UHFFFAOYSA-N 0.000 title claims abstract description 45
- 239000012535 impurity Substances 0.000 title claims abstract description 40
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- -1 methyl loratadine Chemical compound 0.000 claims abstract description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 12
- 239000001257 hydrogen Substances 0.000 claims abstract description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000002253 acid Substances 0.000 claims abstract description 8
- 239000003054 catalyst Substances 0.000 claims abstract description 8
- 238000001914 filtration Methods 0.000 claims abstract description 8
- 239000002904 solvent Substances 0.000 claims abstract description 8
- 238000001816 cooling Methods 0.000 claims abstract description 7
- 238000010438 heat treatment Methods 0.000 claims abstract description 7
- 238000000034 method Methods 0.000 claims description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 239000000126 substance Substances 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 5
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 3
- 235000019253 formic acid Nutrition 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 229940079593 drug Drugs 0.000 description 4
- 150000002431 hydrogen Chemical class 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000010998 test method Methods 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- ZGEGCLOFRBLKSE-UHFFFAOYSA-N 1-Heptene Chemical group CCCCCC=C ZGEGCLOFRBLKSE-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- 208000024780 Urticaria Diseases 0.000 description 1
- 206010052568 Urticaria chronic Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 208000024376 chronic urticaria Diseases 0.000 description 1
- 238000006298 dechlorination reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- SDLAKRCBYGZJRW-UHFFFAOYSA-N n-tert-butylformamide Chemical compound CC(C)(C)NC=O SDLAKRCBYGZJRW-UHFFFAOYSA-N 0.000 description 1
- 238000005935 nucleophilic addition reaction Methods 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000003087 receptor blocking agent Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The invention provides a preparation method of loratadine impurities, which comprises the following steps: dissolving methyl loratadine in a solvent, adding acid and a catalyst, heating to react in a hydrogen atmosphere, cooling, filtering, concentrating and purifying to obtain the loratadine impurity shown in the formula II. The technical scheme of the invention makes up the blank that the preparation method is not available in China, can also reduce the cost of developing the medicine by pharmaceutical enterprises, and has very good industrial application prospect.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemical synthesis, and particularly relates to a preparation method of loratadine impurities.
Background
The chemical name of Loratadine (Loratadine, formula I) is 4- (8-chloro-5, 6-dihydro-11H-benzo [5,6]]-cyclohepta [1,2-b ]]Pyridin-11-enyl) -1-piperidinecarboxylic acid ethyl ester, developed by Schering-Plough, USA, was first marketed in Belgium in 1988 under the trade name Clarityne (Keristan), and used for the treatment of allergic rhinitis, acute or chronic urticaria and other allergies, 2 nd generation H1The receptor blocker has the characteristics of long acting, no central inhibition or choline resistance.
The adverse reaction of the medicine in the clinical use process is related to the pharmacological activity of the raw material medicine and the impurities in the medicine. The loratadine impurity (formula II) is one of the process impurities possibly generated in the loratadine generation process, and the chemical name of the loratadine impurity is 6, 11-dihydro-11- (1-methyl-4-piperidylidene) -5H-benzo [5,6] heptylene [1,2-b ] pyridine.
The literature (J.Med.chem.1991,34, 457-:
the synthesis of the compound of formula II is completed by using 3-methyl-2-pyridine formyl tert-butylamine as a raw material and performing five steps of nucleophilic substitution, dehydration, nucleophilic addition, hydrolysis and final dehydration. The method adopts a highly toxic compound phosphorus oxychloride as a synthetic reagent, and anhydrous reaction is required in the first step and the third step, so that the method has the defects of complicated steps, harsh conditions, low yield and the like, and is not suitable for industrial production.
The research on impurities in medicines is an important content of the research on the quality of medicines, and the research and control on impurities are one of key factors for ensuring the quality of medicines and ensuring the safety of medicines. The loratadine impurity (formula II) is one of the important impurities of loratadine, the deep research on the loratadine impurity has great significance for developing the loratadine product, the synthetic research on the loratadine impurity (formula II) can make up the blank that no preparation method is available in China, and convenience is provided for pharmaceutical enterprises to develop the loratadine product.
Disclosure of Invention
Aiming at the technical problems, the invention discloses a preparation method of loratadine impurities, which adopts a one-step reduction method to realize dechlorination of methyl loratadine to obtain the loratadine impurities, and has the advantages of cheap and easily-obtained raw materials, simple operation and post-treatment, mild reaction conditions, stable process, high yield and good reproducibility.
In contrast, the technical scheme adopted by the invention is as follows:
a method of preparing loratadine impurities comprising:
dissolving methyl loratadine in a solvent, adding acid and a catalyst, heating to react in a hydrogen atmosphere, and then cooling, filtering, concentrating and purifying to obtain loratadine impurities shown in a formula II.
As a further improvement of the invention, the ratio of the amount of the substance added by the acid to the amount of the methyl loratadine substance is 1-3: 1.
As a further improvement of the present invention, the acid includes any one of formic acid, acetic acid, succinic acid, hydrobromic acid, and hydrochloric acid.
As a further improvement of the invention, the ratio of the amount of the added substance of the catalyst to the amount of the methyl loratadine substance is 0.05-0.20: 1.
As a further improvement of the present invention, the catalyst comprises any one of palladium on carbon and palladium on carbon hydroxide.
As a further improvement of the present invention, the ratio of the added volume of the solvent to the mass of the methyl loratadine is V: and M is 5-20: 1.
As a further improvement of the invention, the solvent is any one of methanol, ethanol, isopropanol, n-butanol, tetrahydrofuran, ethyl acetate and acetone.
As a further improvement of the method, the reaction temperature is 40-70 ℃.
As a further improvement of the invention, the reaction time is 5-24 h.
Compared with the prior art, the invention has the beneficial effects that:
according to the technical scheme, methyl loratadine is dissolved in a solvent, acid and a catalyst are added, the temperature is raised in a hydrogen atmosphere for reaction for a certain time, then the temperature is lowered, the filtration, the concentration and the purification are carried out, and the loratadine impurity (shown in a formula II) is obtained. The technical scheme of the invention makes up the blank that the preparation method is not available in China, can also reduce the cost of developing the medicine by pharmaceutical enterprises, and has very good industrial application prospect.
Drawings
FIG. 1 is a MS spectrum of loratadine impurity (formula II) of example 1 of the present invention.
FIG. 2 shows the loratadine impurity (formula II) of example 1 of the present invention1HNMR spectrogram.
FIG. 3 is an HPLC chromatogram of loratadine impurity (formula II) of example 1 of the present invention.
Detailed Description
Preferred embodiments of the present invention are described in further detail below.
Example 1
The loratadine impurity (formula II) is prepared by the following steps:
to a 100mL three-necked flask was added methyl loratadine (3.25g, 10mmol, 1.0eq) and ethanol (25mL), followed by acetic acid (1.2g, 20mmol, 2.0eq) and 10% palladium on carbon (1.60g, 1.5mmol, 0.15 eq). Then vacuumizing, replacing 3 times with hydrogen, finally heating to 60 ℃ in a hydrogen balloon atmosphere, stirring for reacting for 20 hours, cooling to room temperature, filtering to remove palladium carbon, concentrating, and purifying the residue by silica gel column chromatography to obtain 2.54g of loratadine impurity, wherein the yield is 87.5%, and the HPLC purity is 99.57%.
MS(m/z)：291.2(M+H)+；
1H NMR(400MHz,CDCl3)：δ8.38(dd,J＝4Hz，4Hz，1H),7.40(d,J＝12Hz,1H),7.20-7、22(m,1H),7.11-7.19(m,3H),7.03-7.06(m,1H),3.33-3.48(m,2H),2.78-2.87(m,2H),2.67-2.73(m,2H),2.53-2.57(m,1H),2.33-2.49(m,3H),2.27(s,3H),2.08-2.13(m,2H)。
MS spectrogram and of loratadine impurity (formula II)1HNMR spectra are shown in FIGS. 1 and 1, respectivelyAs shown in fig. 2.
The loratadine impurity (formula II) prepared above is subjected to HPLC detection, an HPLC spectrogram is shown in figure 3, and the detection conditions are as follows:
a chromatographic column: h & E C18A31 SPS 100-104.6X 250mm, 10 μm
Mobile phase:
a: methanol; b: 0.1% phosphoric acid aqueous solution
Mobile phase ratio: a, B and 60:40
Column temperature: 35 deg.C
Detection wavelength: 215nm
Flow rate: 0.7mL/min
Time: 15.00 min.
Example 2
The preparation method and the test method of loratadine in the embodiment are mainly the same as those in embodiment 1, except that the method specifically comprises the following steps:
to a 100mL three-necked flask were added methyl loratadine (3.25g, 10mmol, 1.0eq) and methanol (16mL), followed by acetic acid (0.60g, 10mmol, 1.0eq) and 10% palladium on carbon (0.53g, 0.5mmol, 0.05 eq). Then vacuumizing, replacing 3 times with hydrogen, finally heating to 40 ℃ in a hydrogen balloon atmosphere, stirring for reacting for 5 hours, cooling to room temperature, filtering to remove palladium carbon, concentrating, and purifying the residue by silica gel column chromatography to obtain 2.18g of loratadine impurity, wherein the yield is 75.1%, and the HPLC purity is 97.32%.
Example 3
The preparation method and the test method of loratadine in the embodiment are mainly the same as those in embodiment 1, except that the method specifically comprises the following steps:
to a 100mL three-necked flask was added methyl loratadine (3.25g, 10mmol, 1.0eq) and isopropanol (65mL), followed by formic acid (1.38g, 30mmol, 3.0eq) and 10% palladium on carbon (2.13g, 2.0mmol, 0.20 eq). Then vacuumizing, replacing 3 times with hydrogen, finally heating to 70 ℃ in a hydrogen balloon atmosphere, stirring for reacting for 24 hours, cooling to room temperature, filtering to remove palladium carbon, concentrating, and purifying the residue by silica gel column chromatography to obtain 2.48g of loratadine impurity, wherein the yield is 85.4%, and the HPLC purity is 98.92%.
Example 4
The preparation method and the test method of loratadine in the embodiment are mainly the same as those in embodiment 1, except that the method specifically comprises the following steps:
to a 100mL three-necked flask were added methyl loratadine (3.25g, 10mmol, 1.0eq) and tetrahydrofuran (25mL), followed by acetic acid (1.2g, 20mmol, 2.0eq) and palladium on carbon hydroxide (2.11g, 1.5mmol, 0.15 eq). Then vacuumizing, replacing 3 times with hydrogen, finally heating to 60 ℃ in a hydrogen balloon atmosphere, stirring for reacting for 20 hours, cooling to room temperature, filtering to remove palladium carbon hydroxide, concentrating, and purifying the residue by silica gel column chromatography to obtain 2.48g of loratadine impurity, wherein the yield is 85.32%, and the HPLC purity is 98.44%.
The foregoing is a more detailed description of the invention in connection with specific preferred embodiments and it is not intended that the invention be limited to these specific details. For those skilled in the art to which the invention pertains, several simple deductions or substitutions can be made without departing from the spirit of the invention, and all shall be considered as belonging to the protection scope of the invention.
Claims (9)
1. A preparation method of loratadine impurities is characterized by comprising the following steps:
dissolving methyl loratadine in a solvent, adding acid and a catalyst, heating to react in a hydrogen atmosphere, then cooling, filtering, concentrating and purifying to obtain loratadine impurities shown in the following formula,
2. the method for preparing loratadine impurity according to claim 1, characterized by: the ratio of the amount of the substance added to the acid to the amount of the substance of methyl loratadine is 1-3: 1.
3. The method for preparing loratadine impurity according to claim 2, characterized in that: the acid includes any one of formic acid, acetic acid, succinic acid, hydrobromic acid and hydrochloric acid.
4. The method for preparing loratadine impurity according to claim 1, characterized by: the ratio of the amount of the substance added to the catalyst to the amount of the methyl loratadine substance is 0.05-0.20: 1.
5. The method for preparing loratadine impurity according to claim 4, characterized in that: the catalyst comprises any one of palladium carbon and palladium hydroxide carbon.
6. The method for preparing loratadine impurity according to claim 1, characterized by: the ratio of the added volume of the solvent to the mass of the methyl loratadine is V: and M is 5-20: 1.
7. The method for preparing loratadine impurity according to claim 6, characterized in that: the solvent is any one of methanol, ethanol, isopropanol, n-butanol, tetrahydrofuran, ethyl acetate and acetone.
8. The method for preparing loratadine impurity according to any of claims 1-7, characterized by: the reaction temperature is 40-70 ℃.
9. The method for preparing loratadine impurity according to claim 8, characterized by: the reaction time is 5-24 h.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3717647A (en) * | 1971-04-09 | 1973-02-20 | Schering Corp | Alpha-nicotinoyl phenylacetonitriles |
| CN105777638A (en) * | 2016-01-06 | 2016-07-20 | 北京修正创新药物研究院有限公司 | Method for preparing lorcaserin impurity |
| CN107176906A (en) * | 2016-03-09 | 2017-09-19 | 湖南华腾制药有限公司 | A kind of synthetic method of substitution indone |
| CN109265399A (en) * | 2018-08-09 | 2019-01-25 | 石家庄诚志永华显示材料有限公司 | Compound and organic electroluminescent device |
-
2019
- 2019-12-25 CN CN201911358515.8A patent/CN110845475A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3717647A (en) * | 1971-04-09 | 1973-02-20 | Schering Corp | Alpha-nicotinoyl phenylacetonitriles |
| CN105777638A (en) * | 2016-01-06 | 2016-07-20 | 北京修正创新药物研究院有限公司 | Method for preparing lorcaserin impurity |
| CN107176906A (en) * | 2016-03-09 | 2017-09-19 | 湖南华腾制药有限公司 | A kind of synthetic method of substitution indone |
| CN109265399A (en) * | 2018-08-09 | 2019-01-25 | 石家庄诚志永华显示材料有限公司 | Compound and organic electroluminescent device |
Non-Patent Citations (2)
| Title |
|---|
| JAMES J. SAHN ET AL.: "Sigma 2 Receptor/Tmem97 Agonists Produce Long Lasting Antineuropathic Pain Effects in Mice", 《ACS CHEMICAL NEUROSCIENCE》 * |
| PIWINSKI, JOHN J. ET AL.: "Dual Antagonists of Platelet Activating Factor and Histamine. Identification of Structural Requirements for Dual Activity of N-Acyl-4-(5,6-dihydro-llif-benzo[5,6]cyclohepta-[1,2-]pyridin-11--ylidene) piperidines", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
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Application publication date: 20200228 |