CA1222257A - Derivatives having expectorant activity, the procedure for their preparation and the pharmaceutical compositions which contain them - Google Patents
Derivatives having expectorant activity, the procedure for their preparation and the pharmaceutical compositions which contain themInfo
- Publication number
- CA1222257A CA1222257A CA000438475A CA438475A CA1222257A CA 1222257 A CA1222257 A CA 1222257A CA 000438475 A CA000438475 A CA 000438475A CA 438475 A CA438475 A CA 438475A CA 1222257 A CA1222257 A CA 1222257A
- Authority
- CA
- Canada
- Prior art keywords
- amino
- trans
- process according
- dibromobenzyl
- acid
- 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.)
- Expired
Links
- 238000000034 method Methods 0.000 title claims description 47
- 238000002360 preparation method Methods 0.000 title claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 title abstract description 7
- 239000003172 expectorant agent Substances 0.000 title abstract description 5
- 230000003419 expectorant effect Effects 0.000 title abstract description 5
- 230000000694 effects Effects 0.000 title abstract description 3
- IMLXLGZJLAOKJN-UHFFFAOYSA-N 4-aminocyclohexan-1-ol Chemical compound NC1CCC(O)CC1 IMLXLGZJLAOKJN-UHFFFAOYSA-N 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 37
- 230000008569 process Effects 0.000 claims description 37
- 235000013350 formula milk Nutrition 0.000 claims description 34
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 33
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 27
- -1 guaiacolglycolyl Chemical group 0.000 claims description 20
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 19
- 239000002253 acid Substances 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 13
- PETRWTHZSKVLRE-UHFFFAOYSA-N 2-Methoxy-4-methylphenol Chemical compound COC1=CC(C)=CC=C1O PETRWTHZSKVLRE-UHFFFAOYSA-N 0.000 claims description 10
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 10
- OANCNUIHUFDJQT-DCODBCQHSA-N Cl.NC1=C(Br)C=C(Br)C=C1CN[C@@H]1CC[C@@H](Br)CC1 Chemical compound Cl.NC1=C(Br)C=C(Br)C=C1CN[C@@H]1CC[C@@H](Br)CC1 OANCNUIHUFDJQT-DCODBCQHSA-N 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 8
- SYMPFBURZFGXAS-UHFFFAOYSA-N 2-hydroxy-2-(2-hydroxy-3-methoxyphenyl)acetic acid Chemical compound COC1=CC=CC(C(O)C(O)=O)=C1O SYMPFBURZFGXAS-UHFFFAOYSA-N 0.000 claims description 6
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Inorganic materials [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 6
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 5
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 5
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 4
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 claims description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 4
- JJSYJYVKPGBOAK-IZLXSQMJSA-N N[C@H]1CC[C@H](Br)CC1 Chemical compound N[C@H]1CC[C@H](Br)CC1 JJSYJYVKPGBOAK-IZLXSQMJSA-N 0.000 claims description 4
- 125000000350 glycoloyl group Chemical group O=C([*])C([H])([H])O[H] 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- RCPAZWISSAVDEA-UHFFFAOYSA-N 2-amino-3,5-dibromobenzaldehyde Chemical compound NC1=C(Br)C=C(Br)C=C1C=O RCPAZWISSAVDEA-UHFFFAOYSA-N 0.000 claims description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Natural products OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 claims description 3
- LGRFSURHDFAFJT-UHFFFAOYSA-N Phthalic anhydride Natural products C1=CC=C2C(=O)OC(=O)C2=C1 LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 claims description 3
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric Acid Chemical compound [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 3
- JHIWVOJDXOSYLW-UHFFFAOYSA-N butyl 2,2-difluorocyclopropane-1-carboxylate Chemical compound CCCCOC(=O)C1CC1(F)F JHIWVOJDXOSYLW-UHFFFAOYSA-N 0.000 claims description 3
- 235000009518 sodium iodide Nutrition 0.000 claims description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 3
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 2
- XMDBHYXOIVMFPR-UHFFFAOYSA-N 2-hydroxy-2-(2-hydroxy-5-methylphenyl)acetic acid Chemical compound CC1=CC=C(O)C(C(O)C(O)=O)=C1 XMDBHYXOIVMFPR-UHFFFAOYSA-N 0.000 claims description 2
- BGQVKBRKUUVHEP-UHFFFAOYSA-N 2-hydroxy-2-(2-hydroxy-6-methylphenyl)acetic acid Chemical compound CC1=CC=CC(O)=C1C(O)C(O)=O BGQVKBRKUUVHEP-UHFFFAOYSA-N 0.000 claims description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 claims description 2
- 239000007868 Raney catalyst Substances 0.000 claims description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 2
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- 239000011668 ascorbic acid Substances 0.000 claims description 2
- 229960005070 ascorbic acid Drugs 0.000 claims description 2
- 235000010323 ascorbic acid Nutrition 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 239000001630 malic acid Substances 0.000 claims description 2
- 235000011090 malic acid Nutrition 0.000 claims description 2
- 229940099690 malic acid Drugs 0.000 claims description 2
- 229960002510 mandelic acid Drugs 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 10
- 229960004839 potassium iodide Drugs 0.000 claims 9
- 235000007715 potassium iodide Nutrition 0.000 claims 9
- 239000011780 sodium chloride Substances 0.000 claims 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims 2
- HFVMEOPYDLEHBR-UHFFFAOYSA-N (2-fluorophenyl)-phenylmethanol Chemical compound C=1C=CC=C(F)C=1C(O)C1=CC=CC=C1 HFVMEOPYDLEHBR-UHFFFAOYSA-N 0.000 claims 1
- QJVXBRUGKLCUMY-UHFFFAOYSA-N 2-(2-methylphenoxy)acetic acid Chemical compound CC1=CC=CC=C1OCC(O)=O QJVXBRUGKLCUMY-UHFFFAOYSA-N 0.000 claims 1
- QISOBCMNUJQOJU-UHFFFAOYSA-N 4-bromo-1h-pyrazole-5-carboxylic acid Chemical compound OC(=O)C=1NN=CC=1Br QISOBCMNUJQOJU-UHFFFAOYSA-N 0.000 claims 1
- PXRKCOCTEMYUEG-UHFFFAOYSA-N 5-aminoisoindole-1,3-dione Chemical compound NC1=CC=C2C(=O)NC(=O)C2=C1 PXRKCOCTEMYUEG-UHFFFAOYSA-N 0.000 claims 1
- VQOGSLNFYSGENA-XIDRFSJUSA-N CC1=C(O)C=CC=C1C(O)C(=O)[C@@H]1CC[C@@H](NCC=2C(=C(Br)C=C(Br)C=2)N)CC1 Chemical compound CC1=C(O)C=CC=C1C(O)C(=O)[C@@H]1CC[C@@H](NCC=2C(=C(Br)C=C(Br)C=2)N)CC1 VQOGSLNFYSGENA-XIDRFSJUSA-N 0.000 claims 1
- YLHDZFXGOPIAMW-XIDRFSJUSA-N CC1=CC=C(O)C(C(O)C(=O)[C@@H]2CC[C@H](CC2)NCC=2C(=C(Br)C=C(Br)C=2)N)=C1 Chemical compound CC1=CC=C(O)C(C(O)C(=O)[C@@H]2CC[C@H](CC2)NCC=2C(=C(Br)C=C(Br)C=2)N)=C1 YLHDZFXGOPIAMW-XIDRFSJUSA-N 0.000 claims 1
- HKNXRFQNWXGAKD-XIDRFSJUSA-N CC1=CC=CC(O)=C1C(O)C(=O)[C@@H]1CC[C@@H](NCC=2C(=C(Br)C=C(Br)C=2)N)CC1 Chemical compound CC1=CC=CC(O)=C1C(O)C(=O)[C@@H]1CC[C@@H](NCC=2C(=C(Br)C=C(Br)C=2)N)CC1 HKNXRFQNWXGAKD-XIDRFSJUSA-N 0.000 claims 1
- OQBHVOBHNRRDDD-BKPXRJTESA-N NC1=C(CN[C@@H]2CC[C@H](CC2)C(C(O)C=2C(=C(C=CC2)OC)O)=O)C=C(C=C1Br)Br Chemical compound NC1=C(CN[C@@H]2CC[C@H](CC2)C(C(O)C=2C(=C(C=CC2)OC)O)=O)C=C(C=C1Br)Br OQBHVOBHNRRDDD-BKPXRJTESA-N 0.000 claims 1
- UVENERLTVKTZHR-ONQDNWTHSA-N NC1=C(CN[C@@H]2CC[C@H](CC2)C(C(O)C=2C(=C(C=CC2C)OC)O)=O)C=C(C=C1Br)Br Chemical compound NC1=C(CN[C@@H]2CC[C@H](CC2)C(C(O)C=2C(=C(C=CC2C)OC)O)=O)C=C(C=C1Br)Br UVENERLTVKTZHR-ONQDNWTHSA-N 0.000 claims 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims 1
- WXBLLCUINBKULX-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1 WXBLLCUINBKULX-UHFFFAOYSA-N 0.000 claims 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Natural products OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims 1
- WZHCOOQXZCIUNC-UHFFFAOYSA-N cyclandelate Chemical compound C1C(C)(C)CC(C)CC1OC(=O)C(O)C1=CC=CC=C1 WZHCOOQXZCIUNC-UHFFFAOYSA-N 0.000 claims 1
- 239000012458 free base Substances 0.000 claims 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims 1
- 230000007059 acute toxicity Effects 0.000 abstract description 5
- 231100000403 acute toxicity Toxicity 0.000 abstract description 5
- 238000002347 injection Methods 0.000 abstract description 4
- 239000007924 injection Substances 0.000 abstract description 4
- 150000002148 esters Chemical class 0.000 abstract 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 abstract 1
- 230000000699 topical effect Effects 0.000 abstract 1
- 239000000047 product Substances 0.000 description 12
- 239000000243 solution Substances 0.000 description 10
- 241000700199 Cavia porcellus Species 0.000 description 8
- 150000004705 aldimines Chemical class 0.000 description 7
- JBDGDEWWOUBZPM-XYPYZODXSA-N ambroxol Chemical class NC1=C(Br)C=C(Br)C=C1CN[C@@H]1CC[C@@H](O)CC1 JBDGDEWWOUBZPM-XYPYZODXSA-N 0.000 description 7
- 238000010183 spectrum analysis Methods 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 229960005174 ambroxol Drugs 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- IPNPIHIZVLFAFP-UHFFFAOYSA-N phosphorus tribromide Chemical compound BrP(Br)Br IPNPIHIZVLFAFP-UHFFFAOYSA-N 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- BTKSHGDKGFWRCX-HOMQSWHASA-N NC1=C(Br)C=C(Br)C=C1CN[C@@H]1CC[C@@H](Br)CC1 Chemical compound NC1=C(Br)C=C(Br)C=C1CN[C@@H]1CC[C@@H](Br)CC1 BTKSHGDKGFWRCX-HOMQSWHASA-N 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- LHGVFZTZFXWLCP-UHFFFAOYSA-N guaiacol Chemical compound COC1=CC=CC=C1O LHGVFZTZFXWLCP-UHFFFAOYSA-N 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- QNVKOSLOVOTXKF-UHFFFAOYSA-N 4-[(2-amino-3,5-dibromophenyl)methylamino]cyclohexan-1-ol;hydron;chloride Chemical compound Cl.NC1=C(Br)C=C(Br)C=C1CNC1CCC(O)CC1 QNVKOSLOVOTXKF-UHFFFAOYSA-N 0.000 description 1
- PECMAHZPJIYUNR-UHFFFAOYSA-N 4-bromocyclohexan-1-amine;hydrochloride Chemical compound Cl.NC1CCC(Br)CC1 PECMAHZPJIYUNR-UHFFFAOYSA-N 0.000 description 1
- PVFOHMXILQEIHX-UHFFFAOYSA-N 8-[(6-bromo-1,3-benzodioxol-5-yl)sulfanyl]-9-[2-(2-bromophenyl)ethyl]purin-6-amine Chemical compound C=1C=2OCOC=2C=C(Br)C=1SC1=NC=2C(N)=NC=NC=2N1CCC1=CC=CC=C1Br PVFOHMXILQEIHX-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 241000282472 Canis lupus familiaris Species 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
- 229910020667 PBr3 Inorganic materials 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- 241000906446 Theraps Species 0.000 description 1
- 229960000985 ambroxol hydrochloride Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 229960002598 fumaric acid Drugs 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229960001867 guaiacol Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- ASTNLROMDNGJLS-UHFFFAOYSA-N hot-7 Chemical compound CCCSC1=CC(OC)=C(CCNO)C=C1OC ASTNLROMDNGJLS-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000008279 sol Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
- C07D209/49—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide and having in the molecule an acyl radical containing a saturated three-membered ring, e.g. chrysanthemumic acid esters
-
- 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
- A61P11/10—Expectorants
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pulmonology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP83109579A EP0147475B1 (en) | 1983-09-26 | 1983-09-26 | Aminocyclohexanol derivatives having an expectorant activity, process for their preparation and pharmaceutical compositions containing them |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1222257A true CA1222257A (en) | 1987-05-26 |
Family
ID=8190703
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000438475A Expired CA1222257A (en) | 1983-09-26 | 1983-10-06 | Derivatives having expectorant activity, the procedure for their preparation and the pharmaceutical compositions which contain them |
Country Status (7)
| Country | Link |
|---|---|
| US (1) | US4528393A (en, 2012) |
| EP (1) | EP0147475B1 (en, 2012) |
| JP (1) | JPS6081156A (en, 2012) |
| AT (1) | ATE25966T1 (en, 2012) |
| AU (1) | AU563831B2 (en, 2012) |
| CA (1) | CA1222257A (en, 2012) |
| DE (1) | DE3370320D1 (en, 2012) |
Families Citing this family (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU574360B2 (en) * | 1983-05-13 | 1988-07-07 | Reichert, D. | Antisnoring agent |
| JP2003034681A (ja) * | 2001-07-18 | 2003-02-07 | Tosoh Corp | Ｎ−（ω−ブロモアルキル）フタルイミド類の製造方法 |
| US20030166732A1 (en) * | 2002-02-27 | 2003-09-04 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Ambroxol for the treatment of painful conditions in the mouth and pharyngeal cavity |
| JP2004359673A (ja) * | 2003-05-12 | 2004-12-24 | Nippon Nohyaku Co Ltd | 置換アミノキナゾリノン誘導体の製造方法 |
| DE602004030443D1 (de) * | 2003-05-12 | 2011-01-20 | Nihon Nohyaku Co Ltd | Verfahren zur herstellung eines substituierten aminochinazolinonderivats, als ein schädlingsbekämpfungsmittel |
| EP2386555A1 (en) | 2010-05-13 | 2011-11-16 | Almirall, S.A. | New cyclohexylamine derivatives having beta2 adrenergic agonist and m3 muscarinic antagonist activities |
| CN102351720B (zh) * | 2011-10-21 | 2013-11-06 | 南京理工大学 | 一种简易高效的氨溴素合成方法 |
| EP2592078A1 (en) | 2011-11-11 | 2013-05-15 | Almirall, S.A. | New cyclohexylamine derivatives having beta2 adrenergic agonist and M3 muscarinic antagonist activities |
| CN102964257B (zh) * | 2012-11-24 | 2014-08-06 | 沈阳新马药业有限公司 | 一种盐酸氨溴索化合物及其药物组合物 |
| CA2892931A1 (en) | 2012-12-18 | 2014-06-26 | Almirall, S.A. | Cyclohexyl and quinuclidinyl carbamate derivatives having ss2 adrenergic agonist and m3 muscarinic antagonist activities |
| TWI643853B (zh) | 2013-02-27 | 2018-12-11 | 阿爾米雷爾有限公司 | 同時具有β2腎上腺素受體促效劑和M3毒蕈鹼受體拮抗劑活性之2-氨基-1-羥乙基-8-羥基喹啉-2(1H)-酮衍生物之鹽類 |
| TW201517906A (zh) | 2013-07-25 | 2015-05-16 | Almirall Sa | 含有ｍａｂａ化合物和皮質類固醇之組合 |
| TWI641373B (zh) | 2013-07-25 | 2018-11-21 | 阿爾米雷爾有限公司 | 具有蕈毒鹼受體拮抗劑和β２腎上腺素受體促效劑二者之活性的２－胺基－１－羥乙基－８－羥基喹啉－２（１Ｈ）－酮衍生物之鹽 |
| CN103739502B (zh) * | 2014-01-17 | 2016-06-08 | 浙江浙邦制药有限公司 | 一种氨溴索碱的分离精制工艺 |
| TW201617343A (zh) | 2014-09-26 | 2016-05-16 | 阿爾米雷爾有限公司 | 具有β２腎上腺素促效劑及Ｍ３蕈毒拮抗劑活性之新穎雙環衍生物 |
| CN115108939A (zh) * | 2021-03-17 | 2022-09-27 | 成都施贝康生物医药科技有限公司 | 反式-4-[(2-氨基-3,5-二溴苄基)氨基]-金刚烷-1-醇的中间体及制法 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1593579B1 (de) * | 1966-05-10 | 1972-02-03 | Thomae Gmbh Dr K | Hydroxy-cyclohexylamine,deren physiologisch vertraeglichen Saeureadditionssalze und Verfahren zu ihrer Herstellung |
-
1983
- 1983-09-26 DE DE8383109579T patent/DE3370320D1/de not_active Expired
- 1983-09-26 EP EP83109579A patent/EP0147475B1/en not_active Expired
- 1983-09-26 AT AT83109579T patent/ATE25966T1/de not_active IP Right Cessation
- 1983-09-28 US US06/536,737 patent/US4528393A/en not_active Expired - Fee Related
- 1983-09-29 AU AU19761/83A patent/AU563831B2/en not_active Ceased
- 1983-10-03 JP JP58183244A patent/JPS6081156A/ja active Granted
- 1983-10-06 CA CA000438475A patent/CA1222257A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| ATE25966T1 (de) | 1987-04-15 |
| DE3370320D1 (en) | 1987-04-23 |
| US4528393A (en) | 1985-07-09 |
| AU563831B2 (en) | 1987-07-23 |
| JPH0251540B2 (en, 2012) | 1990-11-07 |
| EP0147475A1 (en) | 1985-07-10 |
| JPS6081156A (ja) | 1985-05-09 |
| EP0147475B1 (en) | 1987-03-18 |
| AU1976183A (en) | 1985-04-04 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |