CN117550996A - TRPV1 agonist and preparation method thereof - Google Patents
TRPV1 agonist and preparation method thereof Download PDFInfo
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- CN117550996A CN117550996A CN202311484958.8A CN202311484958A CN117550996A CN 117550996 A CN117550996 A CN 117550996A CN 202311484958 A CN202311484958 A CN 202311484958A CN 117550996 A CN117550996 A CN 117550996A
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- capsaicin
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- trpv1 agonist
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- 102000003566 TRPV1 Human genes 0.000 title claims abstract description 17
- 101150016206 Trpv1 gene Proteins 0.000 title claims abstract description 17
- 239000000556 agonist Substances 0.000 title claims abstract description 15
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- YKPUWZUDDOIDPM-SOFGYWHQSA-N capsaicin Chemical group COC1=CC(CNC(=O)CCCC\C=C\C(C)C)=CC=C1O YKPUWZUDDOIDPM-SOFGYWHQSA-N 0.000 claims abstract description 54
- 150000001875 compounds Chemical class 0.000 claims abstract description 19
- 238000006243 chemical reaction Methods 0.000 claims abstract description 16
- 229960002504 capsaicin Drugs 0.000 claims abstract description 15
- 235000017663 capsaicin Nutrition 0.000 claims abstract description 15
- 239000003960 organic solvent Substances 0.000 claims abstract description 9
- 239000003814 drug Substances 0.000 claims abstract description 7
- 239000007864 aqueous solution Substances 0.000 claims abstract description 5
- 150000001263 acyl chlorides Chemical class 0.000 claims abstract description 3
- 239000007787 solid Substances 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 239000012043 crude product Substances 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical group CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- 239000012074 organic phase Substances 0.000 claims description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical group ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 150000007529 inorganic bases Chemical class 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 239000000047 product Substances 0.000 claims description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- 229910052731 fluorine Chemical group 0.000 claims description 4
- 239000011737 fluorine Chemical group 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 3
- 239000011736 potassium bicarbonate Substances 0.000 claims description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 235000011181 potassium carbonates Nutrition 0.000 claims description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 239000001488 sodium phosphate Substances 0.000 claims description 3
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 3
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 3
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical group COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 238000001704 evaporation Methods 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 235000011008 sodium phosphates Nutrition 0.000 claims description 2
- 238000002844 melting Methods 0.000 abstract description 15
- 230000008018 melting Effects 0.000 abstract description 15
- 239000003513 alkali Substances 0.000 abstract description 6
- 239000000843 powder Substances 0.000 abstract description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 3
- 238000005917 acylation reaction Methods 0.000 abstract description 2
- 125000001424 substituent group Chemical group 0.000 abstract description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 24
- -1 alkaloid compound Chemical class 0.000 description 20
- 238000012360 testing method Methods 0.000 description 14
- 238000003756 stirring Methods 0.000 description 11
- 238000001514 detection method Methods 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 239000011575 calcium Substances 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 6
- 108010025083 TRPV1 receptor Proteins 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000011550 stock solution Substances 0.000 description 5
- 108091006146 Channels Proteins 0.000 description 4
- 229940125904 compound 1 Drugs 0.000 description 4
- 229940125782 compound 2 Drugs 0.000 description 4
- 229940126214 compound 3 Drugs 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 230000001270 agonistic effect Effects 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 239000006285 cell suspension Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000012224 working solution Substances 0.000 description 3
- JDZRIGWDAPNYLT-FNORWQNLSA-N (e)-8-methylnon-6-enoyl chloride Chemical compound CC(C)\C=C\CCCCC(Cl)=O JDZRIGWDAPNYLT-FNORWQNLSA-N 0.000 description 2
- TZZAKSLHHIJRLL-UHFFFAOYSA-N 4-hydroxy-3-methoxybenzamide Chemical compound COC1=CC(C(N)=O)=CC=C1O TZZAKSLHHIJRLL-UHFFFAOYSA-N 0.000 description 2
- UBZNGKUAUXOIKL-UHFFFAOYSA-N 8-methylnonanoyl chloride Chemical compound CC(C)CCCCCCC(Cl)=O UBZNGKUAUXOIKL-UHFFFAOYSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 241000208293 Capsicum Species 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 108091005462 Cation channels Proteins 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 102000003563 TRPV Human genes 0.000 description 2
- 108060008564 TRPV Proteins 0.000 description 2
- 108010062740 TRPV Cation Channels Proteins 0.000 description 2
- 239000004098 Tetracycline Substances 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- NTQYXUJLILNTFH-UHFFFAOYSA-N nonanoyl chloride Chemical compound CCCCCCCCC(Cl)=O NTQYXUJLILNTFH-UHFFFAOYSA-N 0.000 description 2
- 239000013558 reference substance Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 229960002180 tetracycline Drugs 0.000 description 2
- 229930101283 tetracycline Natural products 0.000 description 2
- 235000019364 tetracycline Nutrition 0.000 description 2
- 150000003522 tetracyclines Chemical class 0.000 description 2
- 230000001052 transient effect Effects 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 235000002566 Capsicum Nutrition 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 241000256602 Isoptera Species 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 208000037273 Pathologic Processes Diseases 0.000 description 1
- 108060008646 TRPA Proteins 0.000 description 1
- 102000027549 TRPC Human genes 0.000 description 1
- 108060008648 TRPC Proteins 0.000 description 1
- 102000027545 TRPM Human genes 0.000 description 1
- 108091008847 TRPM Proteins 0.000 description 1
- 108091008846 TRPML Proteins 0.000 description 1
- 102000027544 TRPML Human genes 0.000 description 1
- 108091008849 TRPN Proteins 0.000 description 1
- 108060009332 TRPP Proteins 0.000 description 1
- 102000011040 TRPV Cation Channels Human genes 0.000 description 1
- 102100029613 Transient receptor potential cation channel subfamily V member 1 Human genes 0.000 description 1
- 108010084455 Zeocin Proteins 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 125000003275 alpha amino acid group Chemical group 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000003373 anti-fouling effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 229930189065 blasticidin Natural products 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 230000003185 calcium uptake Effects 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000001390 capsicum minimum Substances 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
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- CWCMIVBLVUHDHK-ZSNHEYEWSA-N phleomycin D1 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC[C@@H](N=1)C=1SC=C(N=1)C(=O)NCCCCNC(N)=N)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C CWCMIVBLVUHDHK-ZSNHEYEWSA-N 0.000 description 1
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- 239000013641 positive control Substances 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 230000002940 repellent Effects 0.000 description 1
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- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
- C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/18—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
- C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/20—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a carbon atom of an acyclic unsaturated carbon skeleton
Abstract
The invention belongs to the field of pharmaceutical chemistry, and particularly discloses a TRPV1 agonist and a preparation method thereof. The structural feature of the TRPV1 agonist is a capsaicin derivative with OH or F substituent introduced at the 3-position of the phenyl ring of capsaicin, the TRPV1 agonist is prepared by reacting 3-position OH or F substituted vanillamine hydrochloride of the phenyl ring with an acyl chloride compound, and the reaction is carried out in a two-phase system consisting of an aqueous solution of inorganic alkali and an organic solvent at room temperature. The melting point of the TRPV1 agonist compound provided by the invention is obviously improved, which has important significance for developing capsaicin micro powder medicaments; according to the preparation method of the capsaicin derivatives, provided by the invention, a two-phase system consisting of the aqueous solution of inorganic alkali and the organic solvent is adopted for reaction, so that the use of the organic alkali is avoided, and the selectivity of the acylation reaction is improved.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and in particular relates to a TRPV1 agonist and a preparation method thereof.
Background
Transient receptor potential (transient receptor potential, TRP) channels are a class of non-selective cation channels of diverse structure and function that regulate intracellular Ca in the transmission of sensory information such as visual, thermal, pain, tactile, auditory and gustatory senses 2+ Plays an important role in balance and the like. To date, 28 members of the TRP channel superfamily have been found in mammals. Amino acid sequences can be divided into 7 subfamilies according to their homology differences: TRPA, TRPC, TRPM, TRPML, TRPN, TRPP and TRPV, wherein TRPV1 is a member of the TRPV subfamily.
TRPV1 was first found to be a receptor capable of being activated by capsaicin and is therefore known as the capsaicin receptor, and is also known earlier as vanilloid derivative receptor 1 (vanilloid receptor, vr1), a non-selective, thermosensitive cation channel. TRPV1 is widely distributed and expressed in a variety of tissues and organs, and it has complex biological functions and is involved in a variety of physiological and pathological processes.
Capsaicin is a vanilloid alkaloid compound in natural plant capsicum, has pungent smell and is poorly soluble in water. Capsaicin is an active ingredient of capsicum, is a representative compound of TRPV1 receptor agonist, has wide application, has pharmacological effects of anti-inflammatory, analgesic, wind-damp expelling, cardiovascular disease preventing and the like in the medical field, and can be used as ship antifouling paint, cable termite and rat preventing repellent, riot controlling agent and the like due to the characteristic of strong irritation.
The melting point of capsaicin compounds is generally lower, wherein the melting point of capsaicin is 62-65 ℃, and the melting point of nonanoylvanillylamine is 57-60 ℃. When capsaicin is used to prepare micropowder as various micropowder medicaments, the lower melting point easily causes melting and caking due to temperature rise in the production, storage and use processes of micropowder, so that the dispersion effect of micropowder is seriously affected. In addition, capsaicin compounds have strong lipophilicity, poor water solubility and difficult absorption after oral administration, thus further limiting the application.
Therefore, the chemical modification and transformation are performed on the basis of the capsaicin structure, so that the melting point of the compound is improved or the water solubility is improved, and the method has important significance for developing the micro powder medicament.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a series of capsaicin derivatives with TRPV1 agonistic activity and a preparation method thereof, wherein the capsaicin derivatives have higher melting points, and no organic alkali is used in the synthesis preparation process.
The technical scheme adopted by the invention is as follows:
in a first aspect, the present invention provides a TRPV1 agonist, capsaicin derivatives having the structures shown in formulas 1, 2 and 3, and pharmaceutically acceptable salts thereof:
wherein R is hydroxyl or fluorine.
Further, the capsaicin derivatives specifically include:
in a second aspect, the present invention provides a preparation method of the capsaicin derivative according to the first aspect, which specifically comprises the following steps:
dissolving a compound shown in a formula 4 in water, adding an inorganic base and an organic solvent, and then reacting with an acyl chloride compound shown in a formula 5, 6 or 7 to generate a compound shown in a formula 1, 2 or 3;
wherein R is hydroxyl or fluorine;
the inorganic base is any one or more than two of sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, sodium phosphate, disodium hydrogen phosphate, potassium phosphate or dipotassium hydrogen phosphate;
the organic solvent is any one of diethyl ether, tertiary methyl ether, toluene, methylene dichloride, chloroform or ethyl acetate.
Preferably, the molar ratio of the compound represented by formula 4, the acid chloride compound represented by formula 5, 6 or 7, and the inorganic base is 1: (1-2.5): (1-1.5).
Preferably, the volume ratio of water to the organic solvent added to dissolve the compound of formula 4 is 1:1 to 1:2.
Preferably, the concentration of the aqueous solution of the compound represented by formula 4 is 0.2 to 0.8mol/L.
Preferably, the reaction conditions are at room temperature.
Preferably, the compound represented by formula 4 is specifically:
preferably, the purification mode of the product after the reaction is as follows: separating out an organic phase after the reaction is stopped, drying, filtering and evaporating to obtain a solid crude product; recrystallizing the crude product by PE/EA to obtain a pure product.
In a third aspect, the present invention provides an application of the capsaicin derivative in the first aspect, for preparing capsaicin micro-powder medicament.
Compared with the prior art, the invention has the advantages that:
according to the capsaicin derivative, OH or F substituent is introduced into the 3-position of the capsaicin benzene ring, so that the melting point of the compound is obviously improved on the basis of keeping a certain TRPV1 agonistic activity, and the capsaicin derivative has important significance in developing capsaicin micro powder medicaments; according to the preparation method of the capsaicin derivatives, provided by the invention, a two-phase system consisting of the aqueous solution of inorganic alkali and the organic solvent is adopted for reaction, so that the use of the organic alkali is avoided, and the selectivity of the acylation reaction is improved.
Detailed Description
The present invention will be further described with reference to examples.
Example 1
Synthesis of N- (3, 4-dihydroxy-5-methoxybenzyl) nonanamide (Compound 1 a):
3, 4-dihydroxy-5-methoxybenzylamine hydrochloride 4a (2.06 g,10 mmol) was dissolved in 20mL of water, sodium carbonate (1.17 g,11 mmol) was added, after stirring well, dichloromethane 20mL was added, then nonanoyl chloride 5 (1.94 g,11 mmol) was added and stirring was performed at room temperature for 2h. The reaction was stopped, the organic phase was separated, dried over anhydrous sodium sulfate, and then filtered and evaporated to dryness to give crude pale yellow solid. The crude product can be recrystallized by PE/EA to obtain pure N- (3, 4-dihydroxyl-5-methoxybenzyl) nonanamide (compound 1 a), 2.7g of white solid is obtained, the crystallization yield is 87%, and the melting point is 96-97 ℃. 1 H NMR(300MHz,CDCl 3 )δ6.50(s,1H),6.39(s,1H),5.79(br,1H),5.57(br,1H),4.30(d,J＝5.6Hz,2H),3.84(s,3H),2.20(t,J＝7.6Hz,2H),1.71-1.54(m,2H),1.37-1.16(m,10H),0.86(t,J＝6.6Hz,3H). 13 C NMR(75MHz,CDCl 3 )δ173.28,147.15,144.15,131.99,129.93,108.27,103.03,56.15,43.68,36.82,31.78,29.28,29.12,25.77,22.61,14.06.
Example 2
Synthesis of N- (3, 4-dihydroxy-5-methoxybenzyl) -8-methylnonanamide (Compound 2 a):
3, 4-dihydroxy-5-methoxybenzylamine hydrochloride 4a (2.06 g,10 mmol) was dissolved in 20mL of water, sodium bicarbonate (1.85 g,22 mmol) was added, after stirring well, 30mL of t-methyl ether was added, then 8-methylnonanoyl chloride 6 (2.1 g,11 mmol) was added and stirring was performed at room temperature for 3h. The reaction was stopped, the organic phase was separated, dried over anhydrous sodium sulfate, and then filtered and evaporated to dryness to give crude pale yellow solid. The crude product can be recrystallized by PE/EA to obtain pure N- (3, 4-dihydroxyl-5-methoxybenzyl) -8-methylnonanamide (compound 2 a), 2.5g of white solid is obtained, the crystallization yield is 77%, and the melting point is 107-109 ℃. 1 H NMR(300MHz,CDCl 3 )δ6.50(s,1H),6.37(s,1H),6.35(br,1H),5.84(br,1H),5.66(br,1H),4.30(d,2H),3.84(s,3H),2.20(t,J＝7.6Hz,2H),1.72-1.57(m,2H),1.50(dt,J＝13.1,6.6Hz,1H),1.38-1.19(m,6H),1.18-1.02(m,2H),0.85(d,J＝6.6Hz,6H). 13 C NMR(75MHz,CDCl 3 )δ173.23,147.13,144.11,131.94,129.96,108.25,103.00,56.14,43.67,38.91,36.84,29.58,29.33,27.91,27.22,25.78,22.60.
Example 3
(E) -synthesis of N- (3, 4-dihydroxy-5-methoxybenzyl) -8-methyl-6-nonenamide (compound 3 a):
3, 4-dihydroxy-5-methoxybenzylamine hydrochloride 4a (2.06 g,10 mmol) was dissolved in 20mL of water, potassium bicarbonate (2.2 g,22 mmol) was added, ethyl acetate 20mL was added after stirring well, then 8-methyl-6-nonenoyl chloride 7 (2.1 g,11 mmol) was added and stirring was performed at room temperature for 3h. The reaction was stopped, the organic phase was separated, dried over anhydrous sodium sulfate, and then filtered and evaporated to dryness to give crude pale yellow solid. The crude product can be recrystallized by PE/EA to obtain pure N- (3, 4-dihydroxy-5-methoxybenzyl) -8-methyl-6-nonenamide (compound 3 a), 2.6g of white solid with crystallization yield of 80 percent and melting point of 104-106 ℃. 1 H NMR(300MHz,CDCl 3 )δ6.50(s,1H),6.39(d,J＝1.2Hz,1H),6.13(br,1H),5.78(br,1H),5.59(br,1H),5.42-5.22(m,2H),4.31(d,J＝5.6Hz,2H),3.84(s,3H),2.31-2.12(m,3H),1.98(dd,J＝13.2,6.9Hz,2H),1.65(dt,J＝15.3,7.5Hz,2H),1.44-1.29(m,2H),0.94(d,J＝6.7Hz,6H). 13 C NMR(75MHz,CDCl 3 )δ173.15,147.15,144.12,138.07,131.96,129.91,126.42,108.26,103.00,56.15,43.68,36.67,32.18,30.94,29.24,25.24,22.61.
Example 4
Synthesis of N- (3-fluoro-4-hydroxy-5-methoxybenzyl) nonanamide (Compound 1 b):
3-fluoro-4-hydroxy-5-methoxybenzylamine hydrochloride 4b (2.08 g,10 mmol) was dissolved in 20mL of water, potassium carbonate (1.52 g,11 mmol) was added, toluene 30mL was added after stirring well, then nonanoyl chloride 5 (1.94 g,11 mmol) was added, and stirring was performed at room temperature for 2h. The reaction was stopped, the organic phase was separated, dried over anhydrous sodium sulfate, and then filtered and evaporated to dryness to give crude pale yellow solid. The crude product can be recrystallized by PE/EA to obtain pure N- (3-fluoro-4-hydroxy-5-methoxybenzyl) nonanamide (compound 1 b), 2.9g of white solid is obtained, the crystallization yield is 90%, and the melting point is 94-95 ℃. 1 H NMR(300MHz,CDCl 3 )δ6.57(d,J＝11.7Hz,1H),6.56(s,1H),6.12(br,1H),6.02(br,1H),4.28(d,J＝5.6Hz,2H),3.82(s,3H),2.19(t,J＝7.5Hz,2H),1.72-1.50(m,2H),1.35-1.15(m,10H),0.91-0.75(m,3H). 13 C NMR(75MHz,CDCl 3 )δ173.35,150.49(d,J＝241.4Hz),148.39(d,J＝6.1Hz),132.91(d,J＝13.9Hz),129.66(d,J＝7.7Hz),108.11(d,J＝19.1Hz),106.15(d,J＝2.4Hz),56.26,43.02,36.64,31.72,29.24,29.08,25.71,22.55,13.99.
Example 5
Synthesis of N- (3-fluoro-4-hydroxy-5-methoxybenzyl) -8-methylnonanamide (Compound 2 b):
3-fluoro-4-hydroxy-5-methoxybenzylamine hydrochloride 4b (2.08 g,10 mmol) was dissolved in 20mL of water, sodium phosphate (2.46 g,15 mmol) was added, and chloroform 20mL was added after stirring wellThen 8-methylnonanoyl chloride 6 (2.1 g,11 mmol) was added and stirred at room temperature for 3h. The reaction was stopped, the organic phase was separated, dried over anhydrous sodium sulfate, and then filtered and evaporated to dryness to give crude pale yellow solid. The crude product can be recrystallized by PE/EA to obtain pure N- (3-fluoro-4-hydroxy-5-methoxybenzyl) -8-methylnonanamide (compound 2 b), 2.7g of white solid, 83% of crystallization yield and 75-77 ℃ of melting point. 1 H NMR(300MHz,CDCl 3 )δ6.58(d,J＝11.5Hz,2H),6.56(s,1H),6.09(br,1H),6.00(br,1H),4.29(d,J＝5.8Hz,2H),3.83(s,3H),2.20(t,J＝7.6Hz,2H),1.70-1.56(m,2H),1.46(td,J＝13.1,6.6Hz,1H),1.37-1.16(m,6H),1.16-1.03(m,2H),0.83(d,J＝6.6Hz,6H). 13 C NMR(75MHz,CDCl 3 )δ173.34,150.47(d,J＝241.5Hz),148.37(d,J＝6.1Hz),132.91(d,J＝13.9Hz),129.64(d,J＝7.7Hz),108.13(d,J＝19.2Hz),106.14(d,J＝2.4Hz),56.27,43.01,38.86,36.66,29.55,29.29,27.85,27.17,25.73,22.54.
Example 6
(E) -synthesis of N- (3-fluoro-4-hydroxy-5-methoxybenzyl) -8-methyl-6-nonenamide (compound 3 b):
3-fluoro-4-hydroxy-5-methoxybenzylamine hydrochloride 4b (2.08 g,10 mmol) was dissolved in 20mL of water, dipotassium hydrogen phosphate (4.4 g,25 mmol) was added, ethyl acetate 20mL was added after stirring well, then 8-methyl-6-nonenoyl chloride 7 (2.1 g,11 mmol) was added and stirring was performed at room temperature for 3h. The reaction was stopped, the organic phase was separated, dried over anhydrous sodium sulfate, and then filtered and evaporated to dryness to give crude pale yellow solid. The crude product can be recrystallized by PE/EA to obtain pure product of N- (3-fluoro-4-hydroxy-5-methoxybenzyl) -8-methyl-6-nonenamide (compound 3 b), 2.5g of white solid with crystallization yield of 77 percent and melting point of 72-75 ℃. 1 H NMR(300MHz,CDCl 3 )δ6.60(d,J＝11.9Hz,2H),6.58(s,1H),5.99(br,1H),5.40-5.22(m,2H),4.30(d,J＝5.8Hz,2H),3.84(s,3H),2.32-2.08(m,3H),1.96(dd,J＝13.2,6.9Hz,2H),1.63(dt,J＝15.3,7.5Hz,2H),1.46-1.26(m,2H),0.93(d,J＝6.7Hz,6H). 13 C NMR(75MHz,CDCl 3 )δ173.23,150.43(d,J＝241.6Hz),148.35(d,J＝6.1Hz),138.05,132.94(d,J＝13.8Hz),129.63(d,J＝7.7Hz),126.36,108.22(d,J＝19.1Hz),106.16(d,J＝2.5Hz),56.32,43.10,36.53,32.15,30.90,29.20,25.20,22.57.
Test effect
Detection of agonistic effects of Compounds on TRPV1 receptor Using FLIPR Caldium 6Assay kit
The calcium flow detection kit is a common method for measuring intracellular calcium change, and is mainly used for drug discovery and basic research, and the detection principle is that lipophilic Acetoxymethyl (AM) carries pair Ca 2+ After the sensitive indicator dye enters the cells, the free Ca is released by cleavage of cytoplasmic enzymes 2+ And the sensitive indicator dye is combined with a large amount of calcium ions after the channel is opened to emit a stronger fluorescent signal, so that the excitation/blocking effect of the reaction medicine on the channel is strong and weak.
1 preparation method of stock solution of administration preparation
Agonists: weigh the appropriate amount of Capsaicin to make up a 100mM stock solution with DMSO. And (5) sub-packaging and storing at-20 ℃.
Test article: weighing a test object with proper mass according to the formula: DMSO volume = actual amount x purity/(molecular weight x theoretical concentration), the volume of DMSO required was calculated, the corresponding volume of DMSO was aspirated, then the weighed test object was dissolved with the aspirated DMSO, the mass of DMSO was weighed, and the actual stock concentration was calculated from the final DMSO usage.
2 preparation method of administration preparation working solution
Prior to TRPV1 receptor testing, agonist and test stock solutions were removed from-20 ℃ and diluted into appropriate buffers as intermediate solutions. The highest detection concentration of the test object is directly diluted by using Buffer.
The stock solution of the test object and the stock solution of the reference substance are stored at-20 ℃, and the working solution of the test object and the working solution of the reference substance are prepared on the same test day and stored at room temperature.
3 concentration selection basis
The agonist Capsaicin was detected at a concentration of 100 μm starting, 5-fold dilution, 10 concentrations, 2 replicates; the test substance was diluted 10. Mu.M, 2-fold or 3-fold, 10 concentrations and 2 replicates.
4 cell culture
hTRPV1 gene information using HEK-293 cell lines stably expressing TRPV1 receptor: TRPV1 NM_080704.
HEK-293 cell line stably expressing TRPV1 receptor was cultured in DMEM medium containing 10% fetal bovine serum, 10. Mu.g/mL Blasticidin, 100. Mu.g/mL Zeocin at 37℃and carbon dioxide concentration of 5%.
Cell passage: the old medium was removed and washed once with PBS, then 0.5mL of 0.25% -Trypsin-EDTA solution was added and incubated at 37℃for about 0.5 min. When the cells were detached from the bottom of the dish, about 3mL of complete medium, pre-warmed at 37℃was added. The cell suspension was gently swirled with a pipette to separate the aggregated cells. The cell suspension was transferred to a sterile centrifuge tube and centrifuged at 1000rpm for 5min to collect the cells. Expanding or maintaining culture, inoculating cells into 6cm cell culture dishes with cell amount of 2.5X10 per cell culture dish 5 cells (final volume: 5 mL).
To maintain the physiological activity of the cells, the experimental cell fusion degree is 80% -90%.
Cells were isolated with 0.25% -Trypsin-EDTA prior to FLIPR assay, the desired cell suspension was calculated at 8000 cells per well, and tetracycline induction (final tetracycline concentration of 2. Mu.g/ml) was plated into 384 well plates and incubated (final volume: 25. Mu.L) in 384 well plates for 12 hours prior to assay.
5FLIPR detection
FLIPR detection method of 5.1TRPV1 target spot
Cells were collected by digestion, counted and seeded and cultured overnight in a black bottom-permeable 384 well plate. 1 Xbuffer is prepared according to the instruction of the kit, and 2 Xdye is prepared for standby by 1 Xbuffer. The medium in 384 well plates was removed by reverse-spin centrifugation and 20. Mu.L of 1 Xbuffer was immediately added. And adding 20 mu L of the prepared dye into a corresponding experimental hole, and placing the experimental hole at 37 ℃ to be incubated for 2 hours in a dark place. 5 Xof agonist and test sample intermediate are formulated and transferred to the corresponding 384source plate. After the cell plate incubation is completed, the instrument is arranged, the 10s substrate value is read, 10 mu L of the test object prepared in the step 5 is taken by the instrument and added into a test hole, and data are collected and recorded for 5min. The excitation light for calcium flux detection is 470-515nm, and the emission light is 515-575nm.
5.2 data analysis
1)Z’factor＝1-3*(SD Max +SD Min )/(AVG Max -AVG Min )；
2)PC(Positive Control)＝Ave(100μM Capsaicin)
3)VC(Vehicle Control)＝Ave(1％DMSO)
4)CV Max ＝(SD Max /AVG Max )*100％；
5)CV Min ＝(SD Min /AVG Min )*100％；
6)S/B＝Singal/Background；
7) Calculation of Compound EC using GraphPad nonlinear fitting equation 50 :
8)Y＝Bottom+(Top-Bottom)/(1+10^((LogEC 50 -X)*HillSlope))
6 TRPV1 agonist activity prepared by the present invention was tested using the assay method described above and the results are shown in table 1.
TABLE 1 in vitro screening results for the Compounds of the invention
| Numbering of compounds | Ca 2+ influx EC 50 (nM) |
| Capsaicin | 7.4 |
| Nonoyl vanillamide | 24.9 |
| 1a | 60.2 |
| 2a | 96.0 |
| 3a | 87.3 |
| 1b | 95.6 |
| 2b | 134.3 |
| 3b | 119.1 |
The above examples of the present invention are merely illustrative of the present invention and are not intended to limit the embodiments of the present invention. Other variations or modifications of the above teachings will be apparent to those of ordinary skill in the art. It is not necessary here nor is it exhaustive of all embodiments. Any modification, equivalent replacement, improvement, etc. which come within the spirit and principles of the invention are desired to be protected by the following claims.
Claims (10)
1. A TRPV1 agonist characterized by capsaicin derivatives having the structures shown in formulas 1, 2 and 3 below and pharmaceutically acceptable salts thereof:
wherein R is hydroxyl or fluorine.
2. The TRPV1 agonist according to claim 1, wherein the capsaicin derivative is specifically:
3. a method for preparing a capsaicin derivative according to claim 1 or 2, comprising the steps of:
dissolving a compound shown in a formula 4 in water, adding an inorganic base and an organic solvent, and then reacting with an acyl chloride compound shown in a formula 5, 6 or 7 to generate a compound shown in a formula 1, 2 or 3;
wherein R is hydroxyl or fluorine;
the inorganic base is any one or more than two of sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, sodium phosphate, disodium hydrogen phosphate, potassium phosphate or dipotassium hydrogen phosphate;
the organic solvent is any one of diethyl ether, tertiary methyl ether, toluene, methylene dichloride, chloroform or ethyl acetate.
4. The method for preparing capsaicin derivatives according to claim 3, wherein the molar ratio of the compound shown in formula 4, the acid chloride compound shown in formula 5, 6 or 7 and the inorganic base is 1: (1-2.5): (1-1.5).
5. The method for producing capsaicin derivatives according to claim 3, wherein the volume ratio of water to the organic solvent is 1:1-1:2.
6. The process for producing capsaicin derivatives according to claim 3, wherein the concentration of the aqueous solution of the compound represented by formula 4 is 0.2-0.8 mol/L.
7. The process for producing capsaicin derivatives according to claim 3, wherein the reaction condition is room temperature.
8. The method for preparing capsaicin derivatives according to claim 3, wherein the compound shown in formula 4 is specifically:
9. the process for the preparation of capsaicin derivatives according to any one of claims 3-9, wherein the purification of the reacted product is as follows: separating out an organic phase after the reaction is stopped, drying, filtering and evaporating to obtain a solid crude product; recrystallizing the crude product by PE/EA to obtain a pure product.
10. Use of a capsaicin derivative according to claim 1 or 2, for the preparation of a capsaicin micropowder medicament.
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