CN114920697A - Heterocyclic group substituted indan propionamide compound and application thereof - Google Patents
Heterocyclic group substituted indan propionamide compound and application thereof Download PDFInfo
- Publication number
- CN114920697A CN114920697A CN202210527859.2A CN202210527859A CN114920697A CN 114920697 A CN114920697 A CN 114920697A CN 202210527859 A CN202210527859 A CN 202210527859A CN 114920697 A CN114920697 A CN 114920697A
- Authority
- CN
- China
- Prior art keywords
- compound
- pharmaceutically acceptable
- acceptable salt
- formula
- cough
- 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
- -1 indan propionamide compound Chemical class 0.000 title claims abstract description 39
- 125000000623 heterocyclic group Chemical group 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 121
- 206010011224 Cough Diseases 0.000 claims abstract description 57
- 239000003814 drug Substances 0.000 claims abstract description 12
- 208000006673 asthma Diseases 0.000 claims abstract description 9
- 230000001154 acute effect Effects 0.000 claims abstract description 6
- 150000003839 salts Chemical class 0.000 claims description 38
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 23
- 239000008194 pharmaceutical composition Substances 0.000 claims description 15
- KCDXJAYRVLXPFO-UHFFFAOYSA-N syringaldehyde Chemical compound COC1=CC(C=O)=CC(OC)=C1O KCDXJAYRVLXPFO-UHFFFAOYSA-N 0.000 claims description 14
- COBXDAOIDYGHGK-UHFFFAOYSA-N syringaldehyde Natural products COC1=CC=C(C=O)C(OC)=C1O COBXDAOIDYGHGK-UHFFFAOYSA-N 0.000 claims description 14
- 229910052731 fluorine Inorganic materials 0.000 claims description 12
- 239000011737 fluorine Substances 0.000 claims description 12
- 235000012141 vanillin Nutrition 0.000 claims description 12
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 claims description 12
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 claims description 12
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 11
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 11
- 229910052801 chlorine Inorganic materials 0.000 claims description 11
- 239000000460 chlorine Substances 0.000 claims description 11
- 229940125904 compound 1 Drugs 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical group 0.000 claims description 10
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 8
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical group BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 claims description 8
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical group ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 claims description 8
- 206010006451 bronchitis Diseases 0.000 claims description 7
- NBVXSUQYWXRMNV-UHFFFAOYSA-N monofluoromethane Natural products FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 claims description 6
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 4
- 229940102396 methyl bromide Drugs 0.000 claims description 4
- 206010006458 Bronchitis chronic Diseases 0.000 claims description 3
- 208000007451 chronic bronchitis Diseases 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 229940050176 methyl chloride Drugs 0.000 claims description 3
- 206010020751 Hypersensitivity Diseases 0.000 claims description 2
- 206010035664 Pneumonia Diseases 0.000 claims description 2
- 208000026935 allergic disease Diseases 0.000 claims description 2
- 230000007815 allergy Effects 0.000 claims description 2
- 201000009267 bronchiectasis Diseases 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- NBVXSUQYWXRMNV-OUBTZVSYSA-N fluoromethane Chemical group F[13CH3] NBVXSUQYWXRMNV-OUBTZVSYSA-N 0.000 claims description 2
- 208000009180 laryngeal tuberculosis Diseases 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 201000008827 tuberculosis Diseases 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims 1
- 208000013116 chronic cough Diseases 0.000 abstract description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 6
- 201000010099 disease Diseases 0.000 abstract description 4
- 206010044302 Tracheitis Diseases 0.000 abstract 1
- YKPUWZUDDOIDPM-SOFGYWHQSA-N capsaicin Chemical compound COC1=CC(CNC(=O)CCCC\C=C\C(C)C)=CC=C1O YKPUWZUDDOIDPM-SOFGYWHQSA-N 0.000 description 26
- 230000000694 effects Effects 0.000 description 15
- 108010025083 TRPV1 receptor Proteins 0.000 description 13
- 235000017663 capsaicin Nutrition 0.000 description 13
- 229960002504 capsaicin Drugs 0.000 description 13
- 238000012360 testing method Methods 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 102000003566 TRPV1 Human genes 0.000 description 12
- 108050004388 Transient receptor potential cation channel subfamily V member 1 Proteins 0.000 description 12
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- 235000017166 Bambusa arundinacea Nutrition 0.000 description 9
- 235000017491 Bambusa tulda Nutrition 0.000 description 9
- 235000015334 Phyllostachys viridis Nutrition 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 241001330002 Bambuseae Species 0.000 description 8
- 239000011425 bamboo Substances 0.000 description 8
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 230000005764 inhibitory process Effects 0.000 description 7
- 230000003042 antagnostic effect Effects 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 230000011514 reflex Effects 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 206010062717 Increased upper airway secretion Diseases 0.000 description 5
- 235000019439 ethyl acetate Nutrition 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 208000026435 phlegm Diseases 0.000 description 5
- ITXZGGXWFWJKSF-UHFFFAOYSA-N 2-(2,3-dihydro-1h-inden-5-yl)propanoic acid Chemical compound OC(=O)C(C)C1=CC=C2CCCC2=C1 ITXZGGXWFWJKSF-UHFFFAOYSA-N 0.000 description 4
- PJAAESPGJOSQGZ-DZGBDDFRSA-N Isovelleral Chemical compound O=CC1=C[C@@H]2CC(C)(C)C[C@@H]2[C@@]2(C)C[C@]21C=O PJAAESPGJOSQGZ-DZGBDDFRSA-N 0.000 description 4
- 229940126422 TRPV1 antagonist Drugs 0.000 description 4
- 238000000889 atomisation Methods 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 210000005036 nerve Anatomy 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 230000001953 sensory effect Effects 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- BDFQJOIAYXQHQR-UHFFFAOYSA-N 5-iodo-2,3-dihydro-1h-indene Chemical compound IC1=CC=C2CCCC2=C1 BDFQJOIAYXQHQR-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 102000002322 Egg Proteins Human genes 0.000 description 3
- 108010000912 Egg Proteins Proteins 0.000 description 3
- 239000012981 Hank's balanced salt solution Substances 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 229910001424 calcium ion Inorganic materials 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 229940125898 compound 5 Drugs 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 230000003834 intracellular effect Effects 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- 108010000239 Aequorin Proteins 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 208000004454 Hyperalgesia Diseases 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- YHIPILPTUVMWQT-UHFFFAOYSA-N Oplophorus luciferin Chemical compound C1=CC(O)=CC=C1CC(C(N1C=C(N2)C=3C=CC(O)=CC=3)=O)=NC1=C2CC1=CC=CC=C1 YHIPILPTUVMWQT-UHFFFAOYSA-N 0.000 description 2
- 206010070834 Sensitisation Diseases 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 230000008485 antagonism Effects 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 238000011685 brown norway rat Methods 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 201000004897 cough variant asthma Diseases 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 230000000857 drug effect Effects 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 239000007850 fluorescent dye Substances 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 239000007928 intraperitoneal injection Substances 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 208000023504 respiratory system disease Diseases 0.000 description 2
- 230000008313 sensitization Effects 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- MOXOFSFWYLTCFU-UHFFFAOYSA-N 5,6,7,8-tetrahydronaphthalen-2-amine Chemical compound C1CCCC2=CC(N)=CC=C21 MOXOFSFWYLTCFU-UHFFFAOYSA-N 0.000 description 1
- OAAGDVLVOKMRCQ-UHFFFAOYSA-N 5-piperidin-4-yl-3-pyridin-4-yl-1,2,4-oxadiazole Chemical compound C1CNCCC1C1=NC(C=2C=CN=CC=2)=NO1 OAAGDVLVOKMRCQ-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010061623 Adverse drug reaction Diseases 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 241000209128 Bambusa Species 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 206010008111 Cerebral haemorrhage Diseases 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- 206010008479 Chest Pain Diseases 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 description 1
- 206010014561 Emphysema Diseases 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- 208000035154 Hyperesthesia Diseases 0.000 description 1
- 108010047357 Luminescent Proteins Proteins 0.000 description 1
- 102000006830 Luminescent Proteins Human genes 0.000 description 1
- 208000019693 Lung disease Diseases 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 206010036790 Productive cough Diseases 0.000 description 1
- 108700008625 Reporter Genes Proteins 0.000 description 1
- 208000018569 Respiratory Tract disease Diseases 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 206010046306 Upper respiratory tract infection Diseases 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000036428 airway hyperreactivity Effects 0.000 description 1
- 150000001348 alkyl chlorides Chemical class 0.000 description 1
- 206010053552 allodynia Diseases 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000008365 aqueous carrier Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 210000005056 cell body Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 210000004177 elastic tissue Anatomy 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- 229940079360 enema for constipation Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000005713 exacerbation Effects 0.000 description 1
- 230000003090 exacerbative effect Effects 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- 231100000021 irritant Toxicity 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 208000030500 lower respiratory tract disease Diseases 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229920001992 poloxamer 407 Polymers 0.000 description 1
- 230000003334 potential effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 208000008128 pulmonary tuberculosis Diseases 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 208000020029 respiratory tract infectious disease Diseases 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 206010039083 rhinitis Diseases 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 210000001044 sensory neuron Anatomy 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 208000024794 sputum Diseases 0.000 description 1
- 210000003802 sputum Anatomy 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000001170 unmyelinated nerve fiber Anatomy 0.000 description 1
- 208000011479 upper respiratory tract disease Diseases 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/14—Antitussive agents
Abstract
The invention belongs to the field of medical treatment, and particularly relates to a heterocyclic group substituted indanpropionamide compound and application thereof, wherein the compound has the structure shown in formula I, and the compound can be used for preparing medicaments for treating acute or chronic cough, such as cough caused by asthma, sphagitis, tracheitis and other diseases,
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to synthesis and application of a heterocyclic group-substituted indanpropionamide compound. More specifically, the invention relates to a heterocyclic group substituted indan propionamide compound, a pharmaceutical composition containing the indan propionamide compound, and an application of the indan propionamide compound, the indan propionamide compound and a phenolic acid compound in preparation of a medicine for preventing and/or treating acute or chronic cough diseases.
Technical Field
Coughing (Cough) is the sudden expulsion of air through large breathing passages, which helps to remove liquids, irritants, foreign particles and microorganisms therefrom. Cough is not a disease, but a symptom. Cough, which is a main symptom of respiratory diseases, is no phlegm or little phlegm, and is often seen in the early stages of acute pharyngolaryngitis and bronchitis; acute and sudden cough often occurs in the intrabronchial foreign body; chronic cough is often seen in chronic bronchitis, pulmonary tuberculosis, etc. Cough, while a protective reflex action, may spread the tracheal lesion to the adjacent bronchia, exacerbating the condition. In addition, persistent and severe cough can affect rest, is prone to physical exertion, and can cause destruction of alveolar wall elastic tissue, inducing emphysema.
Chronic cough is a symptomatic manifestation of airway hyperreactivity. Receptors present in airway sensory nerve endings, C fibers, and Ad fiber cell bodies are drug targets for chronic cough. There is increasing evidence that TRPV1 plays an important role in the development of cough. First, there is ample evidence that airway sensory nerves expressing TRPV1 receptors are involved in triggering the cough reflex, and TRPV1 plays a key role in sensory modulation and/or sensitization of the cough reflex in animals. Studies have shown that TRPV1 is upregulated in chronic cough patients and a significant correlation between cough sensitivity to capsaicin inhalation challenge and TRPV1 density of TRPV1 receptor expressing nerves was also observed in chronic cough patients; furthermore, capsaicin induces enhanced cough responses in patients with inflammatory lung diseases such as asthma, bronchitis, chronic obstructive Pulmonary disease, and upper respiratory tract infections, which may be the result of TRPV1 sensitization ([ J ]. Pulmony pharmacological & therapeutic, 2009,22(2): 65-70.).
The fresh bamboo juice is liquid drained from heated bamboos, has the main effects of clearing heat and reducing phlegm, can be clinically used for treating cough with excessive phlegm due to lung heat, asthma and chest distress, abundant sputum and saliva, strong apoplexy and tongue, infantile phlegm-heat convulsion and the like, and also has the effects of improving asthma, sphagitis, cerebral hemorrhage, vomiting and the like. At present, animal experiments show that phenolic acid compounds such as vanillin and syringaldehyde separated from fresh bamboo juice can relieve guinea pig cough caused by citric acid (Yaojinlong, fresh bamboo juice chemical components and cough-relieving activity research [ D ]. Nanchang university, 2019 ].
There are currently a number of TRPV1 antagonists, such as SB-705498, AMG8562, etc., that have good oral bioavailability and efficacy in reducing hyperalgesia and allodynia in animal models, and have been evaluated in clinical trials for the treatment of rhinitis and chronic cough, but all have failed.
Aiming at the current research situation, the invention aims to provide a novel TRPV1 antagonist, which can quickly and effectively relieve cough, has good bioavailability and less adverse reaction, and is combined with the separated active ingredients in the fresh bamboo juice to achieve more prominent effects of relieving cough and relieving asthma.
Disclosure of Invention
The invention aims to provide an indanpropionamide compound with pharmaceutical activity, a pharmaceutical composition containing the compound and a phenolic acid compound separated from fresh bamboo juice, and application of the compound and the phenolic acid compound in the field of medical treatment.
The invention provides a compound shown as a general formula I or a pharmaceutically acceptable salt thereof,
wherein L is- (CH) 2 ) b -b is selected from any integer between 0 and 3; q is any one of O or S; x is halogen; r is selected from halogenated alkanes of C1-C3.
In a particular embodiment of the invention, b is selected from 0, 1, 2,3, preferably 1 or 2, more preferably 1.
In one embodiment of the invention, W is O.
In one embodiment of the invention, the halogen is fluorine, chlorine, bromine or iodine.
In a specific embodiment of the invention, the R is selected from C1-C3 fluorinated alkane, C1-C3 chlorinated alkane or C1-C3 brominated alkane, and is preferably C1-C3 fluorinated alkane or C1-C3 chlorinated alkane.
The present invention provides compounds of formula II or pharmaceutically acceptable salts thereof:
wherein X is halogen; r is selected from C1-C3 fluorinated alkane, C1-C3 chlorinated alkane or C1-C3 brominated alkane, preferably C1-C3 fluorinated alkane or C1-C3 chlorinated alkane.
In one embodiment of the invention, the halogen is fluorine, chlorine, bromine or iodine.
In one embodiment of the invention, the fluoroalkane is CFH 2 、CF 2 H、CF 3 、CH 2 CF 3 The chloroalkane is CClH 2 、CCl 2 H、CCl 3 、CH 2 CCl 3 The brominated alkane is CBrH 2 、CBr 2 H、CBr 3 、CH 2 CBr 3 。
The present invention provides compounds of formula III or pharmaceutically acceptable salts thereof:
wherein X is halogen, and R is fluoromethane, methyl chloride or methyl bromide.
In one embodiment of the invention, the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine, more preferably fluorine.
In one embodiment of the present invention, the fluoromethane is CFH 2 、CF 2 H、CF 3 Preferably CF 3 (ii) a The methyl chloride is CClH 2 、CCl 2 H、CCl 3 Preferably CCl 3 (ii) a The methyl bromide isCBrH 2 、CBr 2 H、CBr 3 Preferably CBr 3 。
In one embodiment of the present invention, the compound represented by the general formula I or a pharmaceutically acceptable salt thereof is selected from any one of the following compounds:
in one embodiment of the present invention, the compound represented by the general formula I or a pharmaceutically acceptable salt thereof is preferably compound 4 or a pharmaceutically acceptable salt thereof:
in one embodiment of the present invention, the compound represented by the general formula I or a pharmaceutically acceptable salt thereof is preferably compound 1 or a pharmaceutically acceptable salt thereof:
in a particular embodiment of the invention, the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, hydrobromide, phosphate, sulfate, acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, benzenesulfonate, benzoate, bisulfate, preferably phosphate, hydrochloride, maleate or hydrobromide, more preferably phosphate.
The invention also provides a pharmaceutical composition containing the compound shown in the general formula I or the pharmaceutically acceptable salt thereof and one or more phenolic acid compounds, wherein the compound shown in the general formula I or the pharmaceutically acceptable salt thereof is shown as follows; x, R, Q are as defined above. The phenolic acid compound is selected from any one of syringaldehyde (a), vanillin (b) or sinapialdehyde (c),
in one embodiment of the invention, the mass ratio (w/w) of the compound represented by the general formula I or the pharmaceutically acceptable salt thereof to the phenolic acid compound is selected from 1: 10-1: 1, preferably 1: 10-1: 2, and more preferably 1: 5-1: 2.
In a specific embodiment of the present invention, the mass ratio (w/w) of the compound represented by the general formula I or the pharmaceutically acceptable salt thereof to the phenolic acid compound is any one selected from 1:10, 1:5, 3:10, 2:5, 6:25, 1:6, 1:4, 1:3, 1:2 and 1:1, preferably any one selected from 1:10, 1:5, 3:10, 2:5 and 6:25, and more preferably any one selected from 1:5, 3:10 and 6: 25.
In one embodiment of the present invention, the phenolic acid compound is preferably syringaldehyde or vanillin.
In one embodiment of the present invention, the compound represented by the general formula I or a pharmaceutically acceptable salt thereof is selected from compound 4 or 1, and more preferably compound 4.
In a specific embodiment of the invention, the mass ratio (w/w) of compound 4 or compound 1, or a pharmaceutically acceptable salt thereof, to vanillin is selected from any one of 1:10, 1:5, 3:10, 2:5, 6:25, 1:6, 1:4, 1:3, 1:2 and 1:1, preferably from any one of 1:10, 1:5, 3:10, 2:5 and 6:25, more preferably from any one of 1:5, 3:10 and 6: 25.
In a specific embodiment of the present invention, the mass ratio (w/w) of the compound 4 or the compound 1, or the pharmaceutically acceptable salt thereof to the syringaldehyde is selected from any one of 1:10, 1:5, 3:10, 2:5, 6:25, 1:6, 1:4, 1:3, 1:2 and 1:1, preferably any one of 1:10, 1:5, 3:10, 2:5 and 6:25, and more preferably any one of 1:5, 3:10 and 6: 25.
In one embodiment of the present invention, the pharmaceutical composition may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. Thus, the active compounds of the present invention may be formulated for oral, buccal, intranasal, parenteral (e.g. intravenous, intramuscular or subcutaneous) or rectal administration or for administration by inhalation or insufflation. The compound of the present invention or a pharmaceutically acceptable salt thereof, or a combination of the compound of the present invention or a pharmaceutically acceptable salt thereof and a phenolic acid compound may also be formulated into sustained-release dosage forms.
In one embodiment of the invention, an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, is administered orally, e.g., with an inert diluent or in a carrier. According to some embodiments of the invention, the compounds, or pharmaceutical compositions, of the invention may be encapsulated in gelatin capsules or compressed into tablets. For the purpose of oral treatment, the compounds of the present invention, or pharmaceutical compositions, may be employed with excipients and in the form of tablets, troches, capsules, suspensions, syrups, and the like. According to an embodiment of the invention, the above-mentioned formulation should contain at least 0.5% (w/w) of the active compound or pharmaceutical composition of the invention, but may vary depending on the particular dosage form, wherein 4% to about 70% by weight of the unit is convenient. The amount of active compound in such pharmaceutical compositions should be such that a suitable dosage is achieved.
In one embodiment of the invention, for oral administration, the active compounds, or pharmaceutical compositions, of the invention, for example, may be formulated by conventional means into tablets or capsules with pharmaceutically acceptable excipients such as binding agents, fillers, lubricants, disintegrants, or wetting agents. Tablets may be coated by methods well known in the art. Liquid preparations for oral administration may, for example, be presented as solutions, syrups or suspensions, or may be evaporated to a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means using pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous carriers and preservatives.
In one embodiment of the invention, when the active compounds, or pharmaceutical compositions, of the invention are intended for parenteral administration, the compounds provided herein may be combined with sterile water or an organic medium to form an injectable solution or suspension.
In one embodiment of the invention, the active compounds, or pharmaceutical compositions, of the invention may be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
The invention also provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for modulating the TRPV1 (transient receptor potential cation channel subfamily V member 1) receptor, wherein the medicament optionally comprises one or more additional agents that modulate cough in a mammal.
The invention also provides application of the compound shown in the general formula I or the medicinal salt thereof and the phenolic acid compound in preparing a medicament for regulating the TRPV1 (transient receptor potential cation channel subfamily V member 1) receptor, wherein the medicament optionally comprises one or more other active agents for regulating the cough disease of the mammal.
In one embodiment of the invention, the modulation includes, but is not limited to, inhibitory activity or antagonistic activity against TRPV1 receptor.
In one embodiment of the invention, the invention also provides application of the compound shown in the general formula I or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof in preparing a medicament for treating cough.
In one embodiment of the invention, the invention also provides application of the compound shown in the general formula I or the pharmaceutically acceptable salt thereof in combination with the phenolic acid compound in preparation of a medicine for treating cough.
In one embodiment of the invention, the invention also provides application of the compound shown as the general formula I or the pharmaceutically acceptable salt thereof in combination with fresh bamboo juice in preparing a medicament for treating cough.
In a particular embodiment of the invention, the cough is selected from acute cough or chronic cough.
In a specific embodiment of the invention, the cough is selected from the group consisting of coughs caused by respiratory tract disorders including, but not limited to, upper or lower respiratory tract disorders.
In a specific embodiment of the present invention, the cough is selected from any one of coughs caused by acute pharyngolaryngitis, acute bronchitis, chronic bronchitis, tuberculosis, pneumonia, asthma, allergy, tuberculosis of larynx, and bronchiectasis.
Detailed Description
The term "comprising" is open-ended, i.e. includes the elements indicated in the present invention, but does not exclude other elements. It should be understood that the term "comprising" may encompass the closed meaning, i.e., "consisting of …".
As described herein, the compounds of the invention may optionally be substituted with one or more substituents, such as those of the general formula above or as specified in the examples, subclasses. It is understood that the term "optionally substituted" may be used interchangeably with the term "substituted or unsubstituted". In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a particular substituent. Unless otherwise indicated, an optionally substituted group may be substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, then the substituents may be substituted at each position, identically or differently.
In addition, unless otherwise explicitly indicated, the description "independently" used in the present invention should be understood in a broad sense, and it may mean that specific items expressed between the same symbols in different groups do not affect each other, or that specific items expressed between the same symbols in the same groups do not affect each other.
Advantageous technical effects of the invention
The compound provided by the invention is a TRPV1 antagonist, and because the involvement of airway sensory nerves expressing a TRPV1 receptor in triggering cough reflex is more and more emphasized, the TRPV1 receptor gradually becomes a target for treating cough related diseases.
In vitro research results show that compared with compound X, the compound provided by the invention has stronger inhibition effect on TRPV1 receptor and is far stronger than compound X, and the compound provided by the invention can be combined with phenolic acid compounds found in fresh bamboo juice, such as vanillin, syringaldehyde and the like, so that the drug effect of inhibiting cough reflex can be remarkably enhanced, and the effect is remarkably better than that of compound X; the compound has better potential effect on treating cough, can be combined with the traditional Chinese medicine extract fresh bamboo juice for application, can improve the life quality of patients with respiratory tract related diseases, and has higher medicinal value.
Examples
The following describes embodiments of the present invention in detail. The following examples are illustrative only and are not to be construed as limiting the invention. Unless otherwise indicated, all ratios, percentages, and the like referred to herein are by weight.
Synthetic examples
Example Synthesis of 12- (2, 3-dihydro-1H-inden-5-yl) -N- ((1- (3-fluoro-5-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) methyl) propanamide (Compound 4)
Step 4-A: synthesis of 5-iodo-2, 3-dihydro-1H-indene (Compound 4-b)
Compound 4-a (0.5g, 0.004mol) was suspended in water (5mL) at 0-5 ℃. Dilute HCl (10%, 30mL, 30mmol) and NaNO were added sequentially 2 (701mg, 10.1mmol) solution, then the solution was stirred for 1h to complete the diazotization. KI (6.37g, 38.4mmol) was then added slowly and the mixture was stirred at room temperature overnight. After the reaction is finished, precipitates are filtered, washed for a plurality of times by water and dried in vacuum to obtain yellow solid, and the yield is as follows: 96 percent.
MS(ESI)m/z 133.09/134.09(M+1) +
Step 4-B: synthesis of ethyl 2- (2, 3-dihydro-1H-inden-5-yl) propionate (Compound 4-c)
Compound 4-b (0.5g, 0.0021mol) was dissolved in anhydrous dimethylformamide (4.2 mL). Simultaneously, compound aa (0.376g,0.0027mol), NiBr2-bipy (0.064g,0.00017mol) and manganese powder (0.23g,0.0042mol) were added. It was degassed and trifluoroacetic acid (4.2 μ L) was added to the solution. It was heated to 60-65 ℃ for 16 hours. After consumption, water (40mL) was added and the mixture was passed through a bed of celite. The filtrate was extracted with ethyl acetate (3X 40 mL). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give crude compound. The crude compound was purified by column chromatography (silica gel: 100-200, eluent: 15% ethyl acetate in hexane) to obtain 0.28g of the pure compound, yield: 51 percent.
MS(ESI)m/z 218.13/219.13(M+1) +
Step 4-C: synthesis of 2- (2, 3-dihydro-1H-inden-5-yl) propionic acid (Compound 4-d)
Compound 4-c (0.240g,0.0012mol) and methanol (1.7mL) were placed in a 30mL two-necked flask, and an aqueous solution of potassium hydroxide (4M,3mL) was slowly added, followed by stirring at 85 ℃ for 3 hours. After completion of the reaction was confirmed by thin layer chromatography, hydrochloric acid (3M, 15mL) was added thereto, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure to give compound 4-d as a white solid 0.214g, yield: 96 percent.
MS(ESI)m/z 190.10/191.10(M+1) +
Step 4-D: synthesis of 2- (2, 3-dihydro-1H-inden-5-yl) -N- ((1- (3-fluorophenyl) -3 (trifluoromethyl) -1H-pyrazol-5-yl) methyl) propanamide (Compound 4-e)
To a solution of compound 4-d (0.5g, 0.003mol) in acetonitrile was added HOBt (0.46g, 0.0034mol), EDC (0.655g, 0.0034mol) and (5- (3-fluorophenyl) -3- (trifluoromethyl) cyclopent-1, 3-dien-1-yl) methylamine (commercially available, 0.659mg, 0.0024 mol). The reaction mixture was stirred at room temperature overnight. Water was added to the mixture and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography to give the pure compound 4-e 0.87g, yield: 85 percent.
MS(ESI)m/z 431.16/432.17(M+1) +
Step 4-E: synthesis of 2- (2, 3-dihydro-1H-inden-5-yl) -N- ((1- (3-fluoro-5-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) methyl) propanamide (Compound 4)
Adding compound 4-e (0.8g, 0.002mol), Pd (OAc) 2 (0.03mmol,10 mol%), ethanol (12mmol), and K 2 S 2 O 8 (0.9mmol) was added to a 15mL pressure tube. The tube was sealed and the resulting mixture was brought to 100 deg.CStirred for 12 hours. After monitoring consumption of compound 4-e by TLC analysis, the mixture was diluted with EtOAc (50mL) and filtered. The combined organic layers were washed with brine (3X 5mL) and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure to give the crude product. Purification by silica gel column chromatography [ EtOAc/PE,1:4]Pure compound 4 was obtained, i.e. 0.40g, yield: 45 percent.
1 H NMR(400MHz,CDCl 3 ):δ1.34(3H,d,J＝7.0Hz),1.99-2.26(2H,2.08(dtt,J＝13.9,8.1,6.6Hz),2.19(dtt,J＝13.9,6.7,1.6Hz)),2.69-2.93(4H,2.77(ddd,J＝8.1,7.4,6.7Hz),2.85(ddd,J＝14.2,8.1,6.7Hz),2.84(ddd,J＝14.2,6.6,1.6Hz),2.83(ddd,J＝7.4,6.6,1.6Hz)),3.80(3H,s),3.94(1H,q,J＝7.0Hz),4.43-4.53(2H,4.48(s),4.48(s)),6.72(1H,t,J＝1.9Hz),6.86-7.26(6H,6.91(s),6.92(t,J＝1.9Hz),7.01(dd,J＝8.4,2.3Hz),7.08(dd,J＝2.3,0.5Hz),7.10(dd,J＝8.4,0.5Hz),7.21(t,J＝1.9Hz)).
MS(ESI)m/z 461.17/462.18(M+1) +
EXAMPLE 2 Synthesis of N- ((1- (3-chloro-5-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) methyl) -2- (5,6,7, 8-tetrahydronaphthalen-2-yl) acetamide (Compound 2)
And replacing the compound 4-a with 5,6,7, 8-tetrahydronaphthalene-2-amine, replacing the compound aa with ethyl 2-chloropropionate, and synthesizing according to the method of the compound 4 to obtain the compound 2.
1 H NMR(400MHz,CDCl 3 ):δ1.62-1.79(4H,1.70(dtdd,J＝13.7,6.9,2.9,1.9Hz),1.71(dtdd,J＝13.8,6.9,2.9,1.9Hz)),2.60-2.77(4H,2.68(ddd,J＝14.2,6.9,2.9Hz),2.69(ddd,J＝13.7,6.9,2.9Hz)),3.67-3.85(5H,3.72(s),3.80(s)),4.48(2H,s),6.72(1H,t,J＝1.9Hz),6.77-6.97(4H,6.83(dd,J＝8.4,0.5Hz),6.86(dd,J＝8.4,2.2Hz),6.91(s),6.92(t,J＝1.9Hz)),7.08-7.26(2H,7.13(dd,J＝2.2,0.5Hz),7.21(t,J＝1.9Hz)).
MS(ESI)m/z 477.14/479.14(M+1) +
EXAMPLE 3 Synthesis of N- ((1- (3-chloro-5-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) methyl) -2- (2, 3-dihydro-1H-inden-5-yl) propanamide (Compound 1)
Compound ab was replaced with (5- (3-chlorophenyl) -3- (trifluoromethyl) cyclopent-1, 3-dien-1-yl) methylamine, synthesized according to the procedure for compound 4, to give compound 1.
1 H NMR(400MHz,CDCl 3 ):δ1.34(3H,d,J＝7.0Hz),1.99-2.26(2H,2.08(dtt,J＝13.9,8.1,6.6Hz),2.19(dtt,J＝13.9,6.7,1.6Hz)),2.69-2.93(4H,2.77(ddd,J＝8.1,7.4,6.7Hz),2.85(ddd,J＝14.2,8.1,6.7Hz),2.84(ddd,J＝14.2,6.6,1.6Hz),2.83(ddd,J＝7.4,6.6,1.6Hz)),3.77(3H,s),3.94(1H,q,J＝7.0Hz),4.46-4.56(2H,4.51(s),4.51(s)),6.77(1H,dd,J＝1.9,1.5Hz),6.86-7.16(5H,6.91(s),6.96(t,J＝1.9Hz),7.01(dd,J＝8.4,2.3Hz),7.08(dd,J＝2.3,0.5Hz),7.10(dd,J＝8.4,0.5Hz)),7.43(1H,dd,J＝1.9,1.5Hz).
MS(ESI)m/z 477.14/479.14(M+1) +
EXAMPLE 4 Synthesis of N- ((1- (3-bromo-5-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) methyl) -2- (2, 3-dihydro-1H-inden-5-yl) propanamide (Compound 5)
Compound ab was replaced with (5- (3-bromophenyl) -3- (trifluoromethyl) cyclopent-1, 3-dien-1-yl) methylamine, synthesized according to the procedure for compound 4, to give compound 5.
1 H NMR(400MHz,CDCl 3 ):δ1.34(3H,d,J＝7.0Hz),1.99-2.26(2H,2.08(dtt,J＝13.9,8.1,6.6Hz),2.19(dtt,J＝13.9,6.7,1.6Hz)),2.69-2.93(4H,2.77(ddd,J＝8.1,7.4,6.7Hz),2.85(ddd,J＝14.2,8.1,6.7Hz),2.84(ddd,J＝14.2,6.6,1.6Hz),2.83(ddd,J＝7.4,6.6,1.6Hz)),3.75(3H,s),3.94(1H,q,J＝7.0Hz),4.47-4.57(2H,4.52(s),4.52(s)),6.75(1H,dd,J＝2.2,1.5Hz),6.81-7.16(5H,6.87(dd,J＝2.2,1.9Hz),6.91(s),7.01(dd,J＝8.4,2.3Hz),7.08(dd,J＝2.3,0.5Hz),7.10(dd,J＝8.4,0.5Hz)),7.38(1H,dd,J＝1.9,1.5Hz).
MS(ESI)m/z 521.09/523.09(M+1) +
Test example
The following compound X of the present invention is prepared by the method described in [ J ]. Bioorganic & Medicinal Chemistry Letters,2020,30(3):126838,
test example 1 antagonistic Activity of the Compound of the present invention against TRPV1 receptor screening
Principle of testing
By adopting an aequorin reporter gene detection technology, the cell strain stably co-expresses aequorin and a TRPV1 receptor. Intracellular Ca when the receptor is excited 2+ Increase in Ca 2+ Coelenterazine reconstitutes the photoprotein, producing a bioluminescent effect at 469 nm. By measuring the rapid chemiluminescent signal produced by the release of stimulated intracellular calcium, test samples can be screened for effects on the TRPV1 receptor.
TRPV1 antagonistic activity screening test method of compound
1. Preparation of test samples: test compounds and capsaicin were brought to an initial concentration of 10mM in DMSO and diluted to a test concentration of 0.1mM in Try's solution, where the capsaicin was diluted to 250 nM.
2. And (3) incubation: the initial concentration of calcium ion fluorescent probe was 5mM and was diluted to a concentration of 0.05mM with HBSS containing 33mg Pluronic F-127 per ml. Approximately 10000 HEK-293-TRPV1 cells per well were incubated at 37 ℃ with 10. mu.l of 0.05mM calcium ion fluorescent probe. After 20 minutes, 30. mu.l of HBSS containing 1% FBS was added and incubation was continued for 40 minutes.
3. And (3) testing: after 40 minutes, the HBSS and other fluids are aspirated from the wells and the wells are washed with Taiwan's solution, followed by 40. mu.L of test compound at a concentration of 0.1mM per well. 3 replicate wells were set for each compound, 3 of which were blanked with only Tschonoki fluid, incubated at 37 ℃ for 30 minutes, and fluorescence intensity was measured at 488nm for excitation and 526nm for emission. Cells were then incubated with 10. mu.l of capsaicin at a concentration of 250nM for 30 minutes at 37 ℃ and fluorescence intensity was measured at an excitation wavelength of 488nM and an emission wavelength of 526 nM.
4. Calculating the antagonism degree: the relative concentration of intracellular calcium ions is characterized by calculating the fluorescence intensity difference between each group before and after capsaicin addition to detect the antagonism degree of the compound to the capsaicin, thereby detectingThe degree of antagonist activity of the compounds against the TRPV1 receptor was determined. Part of the compounds being in 10 -5 Antagonistic activity against TRPV1 receptor at mol dose, results are shown in table 1.
Inhibition rate (blank difference-experimental group difference)/blank difference 100%
Fluorescence intensity after addition of capsaicin to blank group-fluorescence intensity before addition of capsaicin to blank group
Fluorescence intensity after capsaicin addition to the experimental group-fluorescence intensity before capsaicin addition to the experimental group
NE: the blank control group had an inhibition ratio of 0.
Indicates an inhibition of greater than 50%, less than 70%; inhibition greater than 70%, less than 90%; indicates an inhibition of greater than 90%.
Table 1 results of screening for TRPV1 receptor antagonistic activity by each test compound
| Compound (I) | Inhibition ratio (%) |
| Blank control | NE |
| Compound X | * |
| Compound 4 | *** |
| Compound 2 | ** |
| Compound 1 | *** |
| Compound 5 | * |
As a result, the
According to the results in the table 1, in vitro experimental results show that the compounds of the present invention (especially compounds 4 and 1 have stronger antagonistic action on TRPV1, which is far stronger than that of compound X), and suggest that the compounds of the present invention have better potential in relieving cough reflex caused by participation of airway sensory nerves of TRPV1 receptor, alleviating exacerbation of respiratory diseases caused by cough, and improving life quality of patients, and have potential medical application value.
Test example 2 testing in Brown-Norway rat cough variant asthma model
Experimental methods
1. Preparation of model and group administration: rats were randomly divided into three groups (normal control group, model control group, administration group). Day 1 intraperitoneal injection of 2mg egg protein and 100mg Al (OH) 3 3 weeks later, another intraperitoneal injection of 0.01mg egg protein and 100mg Al (OH) 3 The normal control group was injected with an equal amount of physiological saline. After 3 weeks, the model control group and the administration group started to perform the aerosol challenge with 1% egg protein, and the normal control group was administered with physiological saline once every other day for 7 times. Administration was started on the day of atomization, and positive compounds (single administration group and combined administration group) were administered by intragastric administration 30 minutes before atomization, and drinking water of the same amount as that of intragastric administration was administered 1 time per day for 14 times for the model control group and the normal control group.
2. Capsaicin induced cough experiment: after the last administration for 24 hours, each group of rats was placed in an atomization box and inhaled by atomization 10 - 4 The number of coughs in each group of rats was counted for 2 minutes in a 60 second mol/L capsaicin solution, and the results are shown in Table 2.
TABLE 2 number of coughs for each test compound
| Group of | Administration dosage | Number of coughs |
| Normal control group | -- | 4.1±2.5 |
| Model control group | -- | 18.0±6.8 ◎ |
| Compound X | 1.5mpk | 12.6±5.7* |
| Compound 4 | 1.2mpk | 9.3±4.3** |
| Compound 1 | 1.2mpk | 10.2±6.0* |
| Syringaldehyde | 5mpk | 14.4±5.8 |
| Vanillin | 5mpk | 13.9±6.9 |
| High dose of compound X + syringaldehyde | 1.5mpk+5mpk | 11.1±5.7* |
| High dose of compound X + vanillin | 1.5mpk+5mpk | 10.9±6.2* |
| High dose of compound 4+ syringaldehyde | 1.2mpk+5mpk | 4.5±3.2*** |
| Low dose of compound 4+ syringaldehyde | 0.6mpk+3mpk | 7.1±5.4** |
| Compound 4+ vanillin Low dose | 0.6mpk+3mpk | 8.9±6.8** |
| High dose of compound 1+ syringaldehyde | 1.2mpk+5mpk | 7.7±4.9** |
| Compound 1+ syringaldehyde low dose | 0.6mpk+3mpk | 10.4±7.3* |
| Compound 1+ vanillin Low dose | 0.6mpk+3mpk | 11.7±6.5* |
Remarking: ◎ compared with a normal control group, P is less than 0.05; p < 0.05 compared to model control group; p < 0.01 compared to model control group; p < 0.001 compared to model control.
Results
As can be seen from the results in table 2, in the Brown-Norway rat cough variant asthma model, compounds X, 4 and 1 can significantly reduce the number of coughs, and especially, compound 4 of the present invention has a more significant inhibitory effect and a significantly different difference compared to compound X. Compared with the effect of combining a subsequent TRPV1 antagonist and a phenolic acid compound, the effect of inhibiting cough cannot be obviously improved by combining the compound X with syringaldehyde or vanillin compared with the effect of singly administering the compound X. The compound 4 and the compound 1, especially the compound 4, can obviously reduce the cough frequency no matter under high dose or low dose combination compared with single administration, and the TRPV1 antagonist can obviously reduce the administration dose under the condition of maintaining the same relieving effect by combining with the phenolic acid compound, thereby potentially reducing the adverse drug reaction caused by overhigh administration dose and having the synergistic effect of the drug effect.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.
Claims (10)
1. A compound as shown in general formula I or its medicinal salt,
wherein L is- (CH) 2 ) b -, b is selected from any integer of 0 to 3; q is any one of O or S; x is halogen; r is selected from halogenated alkanes of C1-C3.
2. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein b is selected from 0, 1, 2,3, preferably 1 or 2; the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine; the R is selected from C1-C3 fluorinated alkane, C1-C3 chlorinated alkane or C1-C3 brominated alkane, and is preferably C1-C3 fluorinated alkane or C1-C3 chlorinated alkane.
3. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1 or 2, selected from the group consisting of compounds of formula II or pharmaceutically acceptable salts thereof,
wherein, X is fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine; r is selected from C1-C3 fluorinated alkane, C1-C3 chlorinated alkane or C1-C3 brominated alkane, preferably C1-C3 fluorinated alkane or C1-C3 chlorinated alkane.
4. The compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, which is selected from the group consisting of a compound of formula III or a pharmaceutically acceptable salt thereof,
wherein X is halogen, and R is fluoromethane, methyl chloride or methyl bromide.
5. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 4, wherein halogen is fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine, more preferably fluorine or chlorine; the fluoromethane is CFH 2 、CF 2 H、CF 3 Preferably CF 3 (ii) a The chloromethane is CClH 2 、CCl 2 H、CCl 3 Preferably CCl 3 (ii) a The above-mentionedThe methyl bromide is CBrH 2 、CBr 2 H、CBr 3 Preferably CBr 3 。
6. The compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, which is selected from any one of the following compounds or a pharmaceutically acceptable salt thereof:
7. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
8. Use of a compound of formula I or a pharmaceutically acceptable salt thereof in combination with one or more phenolic acid compounds selected from the group consisting of syringaldehyde (a), vanillin (b) and sinapildehyde (c) as defined in any one of claims 1 to 6 for the manufacture of a medicament for the treatment of cough,
9. the use according to claim 8, wherein the mass ratio (w/w) of the compound represented by the general formula I or the pharmaceutically acceptable salt thereof to the phenolic acid compound is any one selected from 1:10, 1:5, 3:10, 2:5, 6:25, 1:6, 1:4, 1:3, 1:2 and 1:1, preferably any one selected from 1:10, 1:5, 3:10, 2:5 and 6:25, more preferably any one selected from 1:5, 3:10 and 6: 25; the phenolic acid compound is preferably syringaldehyde or vanillin, and the compound shown in the general formula I or pharmaceutically acceptable salt thereof is selected from compound 4 or compound 1, preferably compound 4.
10. Use of a compound of general formula I as defined in any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as defined in claim 7 for the manufacture of a medicament for the treatment of cough, wherein the cough is selected from any one of cough caused by acute pharyngolaryngitis, acute bronchitis, chronic bronchitis, tuberculosis, pneumonia, asthma, allergy, tuberculosis of larynx, and bronchiectasis.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210527859.2A CN114920697A (en) | 2022-05-16 | 2022-05-16 | Heterocyclic group substituted indan propionamide compound and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210527859.2A CN114920697A (en) | 2022-05-16 | 2022-05-16 | Heterocyclic group substituted indan propionamide compound and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN114920697A true CN114920697A (en) | 2022-08-19 |
Family
ID=82808373
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210527859.2A Pending CN114920697A (en) | 2022-05-16 | 2022-05-16 | Heterocyclic group substituted indan propionamide compound and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114920697A (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103906736A (en) * | 2011-11-09 | 2014-07-02 | 格吕伦塔尔有限公司 | Substituted pyrazolyl-based carboxamide and urea derivatives bearing a phenyl moiety substituted with an N-containing group as vanilloid receptor ligands |
| CN104066720A (en) * | 2011-11-09 | 2014-09-24 | 格吕伦塔尔有限公司 | Substituted pyrazolyl-based carboxamide and urea derivatives bearing a phenyl moiety substituted with an SO2-containing group as vanilloid receptor ligands |
-
2022
- 2022-05-16 CN CN202210527859.2A patent/CN114920697A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103906736A (en) * | 2011-11-09 | 2014-07-02 | 格吕伦塔尔有限公司 | Substituted pyrazolyl-based carboxamide and urea derivatives bearing a phenyl moiety substituted with an N-containing group as vanilloid receptor ligands |
| CN104066720A (en) * | 2011-11-09 | 2014-09-24 | 格吕伦塔尔有限公司 | Substituted pyrazolyl-based carboxamide and urea derivatives bearing a phenyl moiety substituted with an SO2-containing group as vanilloid receptor ligands |
Non-Patent Citations (3)
| Title |
|---|
| SONGYEON AHN等: "Discovery of indane propanamides as potent and selective TRPV1 antagonists", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 30, pages 1 - 5 * |
| SUPING SHI等: "Palladium-Catalyzed Ortho-Alkoxylation of 2‑ Aryl-1,2,3-triazoles", J. ORG. CHEM., vol. 79, pages 6105 - 6112 * |
| YONGSHENG REN等: "Palladium-catalyzed selective ortho C-H alkoxylation at 4-aryl of 1, 4-disubstituted 1, 2, 3-triazoles", TETRAHEDRON, vol. 76, pages 1 - 5 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US7399754B2 (en) | N2-quinoline or isoquinoline substituted purine derivatives | |
| WO2019042445A1 (en) | Compound having bruton's tyrosine kinase (btk)-inhibition and degradation activity | |
| WO2017114509A1 (en) | Aldehyde and preparation and application thereof | |
| EP2687531B1 (en) | Tetrahydrocarboline derivative | |
| OA12631A (en) | Anthranilic acid amides with a heteroarylsulfonyl side chain, process for their preparation, their use as medicaments or diagnostic agents and pharmaceutical preparations comprising said compounds. | |
| JP4660045B2 (en) | Prophylactic or therapeutic agent for myocarditis, dilated cardiomyopathy and heart failure comprising NF-κB inhibitor as an active ingredient | |
| JP2016520072A (en) | Cycloalkyl acid derivative, process for producing the same, and pharmaceutical application thereof | |
| CN111662294A (en) | Compound with activity of degrading Btk | |
| CN113831338B (en) | Histone deacetylase inhibitor and preparation method and application thereof | |
| US7098364B2 (en) | Phenylethanolamine compounds as β2-receptor agonists, and methods of use and preparation thereof | |
| WO2006007794A1 (en) | Cis-1,2-substituted stilbene derivates and the use thererof for manufacturing medicaments for treating medicaments for treating and/or preventing diabetes | |
| CN104487427B (en) | Terazole derivatives and they as potassium channel modulating agents purposes | |
| JP2022551270A (en) | Quinone, hydroquinone and naphthoquinone analogues for the treatment of mitochondrial diseases | |
| WO2020177657A1 (en) | Chemical compound having btk-degrading activity | |
| WO2004011470A1 (en) | Furoisoquinoline derivative and use thereof | |
| CN114920697A (en) | Heterocyclic group substituted indan propionamide compound and application thereof | |
| SK2722002A3 (en) | Use of bis-sulfonamides for producing medicaments used for preventing or treating hyperlipidaemia | |
| WO2019232662A1 (en) | Indolizine compound having anticancer activity and derivative thereof | |
| JP2023511679A (en) | A disubstituted adamantyl derivative, a pharmaceutically acceptable salt thereof, and a pharmaceutical composition for inhibiting cancer growth containing the same as an active ingredient | |
| AU2021260048B2 (en) | Antiviral 1,3-di-oxo-indene compounds | |
| TWI832045B (en) | Antiviral 1,3-di-oxo-indene compounds | |
| ES2672326T3 (en) | Deuterated thiazolidinone analogues as agonists for the follicle stimulating hormone receptor | |
| CN114671878B (en) | Substituted nitrogen-containing bicyclic compounds and uses thereof | |
| US11731947B2 (en) | Deuterated antimicrobial compounds | |
| CN114685472B (en) | Polysubstituted uracil derivative and use 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 | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20220819 |