JPH0335320B2 - - Google Patents
Info
- Publication number
- JPH0335320B2 JPH0335320B2 JP16661985A JP16661985A JPH0335320B2 JP H0335320 B2 JPH0335320 B2 JP H0335320B2 JP 16661985 A JP16661985 A JP 16661985A JP 16661985 A JP16661985 A JP 16661985A JP H0335320 B2 JPH0335320 B2 JP H0335320B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- formula
- dimethylxanthine
- methyl
- mono
- 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
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 173
- -1 1,3-dimethylxanthine-7 -yl Chemical group 0.000 claims description 93
- 150000001875 compounds Chemical class 0.000 claims description 79
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 claims description 68
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 57
- 125000004432 carbon atom Chemical group C* 0.000 claims description 43
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 31
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 24
- 210000003097 mucus Anatomy 0.000 claims description 24
- 125000000217 alkyl group Chemical group 0.000 claims description 23
- 230000000954 anitussive effect Effects 0.000 claims description 11
- 239000002585 base Substances 0.000 claims description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 10
- 125000005843 halogen group Chemical group 0.000 claims description 10
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 10
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 8
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 6
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 5
- 230000000694 effects Effects 0.000 claims description 5
- 125000001033 ether group Chemical group 0.000 claims description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 5
- 125000000101 thioether group Chemical group 0.000 claims description 5
- 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 4
- 229940124630 bronchodilator Drugs 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 150000001350 alkyl halides Chemical class 0.000 claims description 3
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 3
- 229910021529 ammonia Inorganic materials 0.000 claims description 3
- 150000008064 anhydrides Chemical class 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 230000001105 regulatory effect Effects 0.000 claims description 3
- 229940014800 succinic anhydride Drugs 0.000 claims description 3
- 150000003573 thiols Chemical class 0.000 claims description 3
- 125000005208 trialkylammonium group Chemical group 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 125000005012 alkyl thioether group Chemical group 0.000 claims description 2
- 150000001540 azides Chemical class 0.000 claims description 2
- VANNPISTIUFMLH-UHFFFAOYSA-N glutaric anhydride Chemical compound O=C1CCCC(=O)O1 VANNPISTIUFMLH-UHFFFAOYSA-N 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims 9
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 5
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 3
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims 3
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims 3
- 229910052731 fluorine Inorganic materials 0.000 claims 3
- 125000001153 fluoro group Chemical group F* 0.000 claims 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims 2
- 238000006957 Michael reaction Methods 0.000 claims 1
- 150000001342 alkaline earth metals Chemical class 0.000 claims 1
- 230000000269 nucleophilic effect Effects 0.000 claims 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 59
- 238000002844 melting Methods 0.000 description 46
- 230000008018 melting Effects 0.000 description 46
- 239000000243 solution Substances 0.000 description 42
- 206010011224 Cough Diseases 0.000 description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 31
- 239000000203 mixture Substances 0.000 description 29
- 239000002904 solvent Substances 0.000 description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- 239000012074 organic phase Substances 0.000 description 14
- 238000003756 stirring Methods 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 229910052938 sodium sulfate Inorganic materials 0.000 description 9
- 235000011152 sodium sulphate Nutrition 0.000 description 9
- 238000011282 treatment Methods 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 241000282472 Canis lupus familiaris Species 0.000 description 7
- 206010036790 Productive cough Diseases 0.000 description 7
- 229940124584 antitussives Drugs 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 7
- 206010006451 bronchitis Diseases 0.000 description 7
- 208000024794 sputum Diseases 0.000 description 7
- 210000003802 sputum Anatomy 0.000 description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 230000009471 action Effects 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 6
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 6
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 5
- GBFLZEXEOZUWRN-VKHMYHEASA-N S-carboxymethyl-L-cysteine Chemical compound OC(=O)[C@@H](N)CSCC(O)=O GBFLZEXEOZUWRN-VKHMYHEASA-N 0.000 description 5
- 238000005917 acylation reaction Methods 0.000 description 5
- 239000000443 aerosol Substances 0.000 description 5
- 150000001298 alcohols Chemical class 0.000 description 5
- 239000012298 atmosphere Substances 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 239000012442 inert solvent Substances 0.000 description 5
- 239000011591 potassium Substances 0.000 description 5
- 229910052700 potassium Inorganic materials 0.000 description 5
- 235000007686 potassium Nutrition 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 230000004044 response Effects 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 230000000638 stimulation Effects 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- DZLNHFMRPBPULJ-UHFFFAOYSA-N thioproline Chemical compound OC(=O)C1CSCN1 DZLNHFMRPBPULJ-UHFFFAOYSA-N 0.000 description 5
- DKSZLDSPXIWGFO-BLOJGBSASA-N (4r,4ar,7s,7ar,12bs)-9-methoxy-3-methyl-2,4,4a,7,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-ol;phosphoric acid;hydrate Chemical compound O.OP(O)(O)=O.OP(O)(O)=O.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC DKSZLDSPXIWGFO-BLOJGBSASA-N 0.000 description 4
- YNCPXBIZAPNQIJ-UHFFFAOYSA-N 1h-imidazole;sodium Chemical compound [Na].C1=CNC=N1 YNCPXBIZAPNQIJ-UHFFFAOYSA-N 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 4
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 4
- 241000700199 Cavia porcellus Species 0.000 description 4
- SHZGCJCMOBCMKK-UHFFFAOYSA-N D-mannomethylose Natural products CC1OC(O)C(O)C(O)C1O SHZGCJCMOBCMKK-UHFFFAOYSA-N 0.000 description 4
- PNNNRSAQSRJVSB-SLPGGIOYSA-N Fucose Natural products C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C=O PNNNRSAQSRJVSB-SLPGGIOYSA-N 0.000 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 description 4
- SHZGCJCMOBCMKK-DHVFOXMCSA-N L-fucopyranose Chemical compound C[C@@H]1OC(O)[C@@H](O)[C@H](O)[C@@H]1O SHZGCJCMOBCMKK-DHVFOXMCSA-N 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- SQVRNKJHWKZAKO-UHFFFAOYSA-N beta-N-Acetyl-D-neuraminic acid Natural products CC(=O)NC1C(O)CC(O)(C(O)=O)OC1C(O)C(O)CO SQVRNKJHWKZAKO-UHFFFAOYSA-N 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 229960004415 codeine phosphate Drugs 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000011261 inert gas Substances 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 238000007912 intraperitoneal administration Methods 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 230000007935 neutral effect Effects 0.000 description 4
- 230000001575 pathological effect Effects 0.000 description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 4
- SQVRNKJHWKZAKO-OQPLDHBCSA-N sialic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@](O)(C(O)=O)OC1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-OQPLDHBCSA-N 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 235000015424 sodium Nutrition 0.000 description 4
- 238000010626 work up procedure Methods 0.000 description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- 241000700198 Cavia Species 0.000 description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 235000011054 acetic acid Nutrition 0.000 description 3
- 150000001299 aldehydes Chemical class 0.000 description 3
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- 229960004126 codeine Drugs 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 150000002170 ethers Chemical class 0.000 description 3
- 229930182830 galactose Natural products 0.000 description 3
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 230000007794 irritation Effects 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- 150000003904 phospholipids Chemical class 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 235000018102 proteins Nutrition 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 241000894007 species Species 0.000 description 3
- 150000003548 thiazolidines Chemical class 0.000 description 3
- 125000003396 thiol group Chemical group [H]S* 0.000 description 3
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 2
- QIJRTFXNRTXDIP-UHFFFAOYSA-N (1-carboxy-2-sulfanylethyl)azanium;chloride;hydrate Chemical compound O.Cl.SCC(N)C(O)=O QIJRTFXNRTXDIP-UHFFFAOYSA-N 0.000 description 2
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 2
- MPGQQQKGAXDBDN-UHFFFAOYSA-N 1,3-thiazolidin-3-ium;chloride Chemical compound Cl.C1CSCN1 MPGQQQKGAXDBDN-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- JYWKEVKEKOTYEX-UHFFFAOYSA-N 2,6-dibromo-4-chloroiminocyclohexa-2,5-dien-1-one Chemical compound ClN=C1C=C(Br)C(=O)C(Br)=C1 JYWKEVKEKOTYEX-UHFFFAOYSA-N 0.000 description 2
- LXIWYKGAOIXZFO-UHFFFAOYSA-N 2-(1,3-dimethyl-2,6-dioxopurin-7-yl)acetaldehyde Chemical compound O=C1N(C)C(=O)N(C)C2=C1N(CC=O)C=N2 LXIWYKGAOIXZFO-UHFFFAOYSA-N 0.000 description 2
- NULDEVQACXJZLL-UHFFFAOYSA-N 2-(2-aminoethyldisulfanyl)ethylazanium;chloride Chemical compound Cl.NCCSSCCN NULDEVQACXJZLL-UHFFFAOYSA-N 0.000 description 2
- GLVYLTSKTCWWJR-UHFFFAOYSA-N 2-carbonoperoxoylbenzoic acid Chemical compound OOC(=O)C1=CC=CC=C1C(O)=O GLVYLTSKTCWWJR-UHFFFAOYSA-N 0.000 description 2
- SJSOFNCYXJUNBT-UHFFFAOYSA-N 3,4,5-trimethoxybenzoic acid Chemical compound COC1=CC(C(O)=O)=CC(OC)=C1OC SJSOFNCYXJUNBT-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
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- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
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[Industrial Field of Application] The present invention relates to a pharmaceutical composition containing xanthinelmethylthiazolidine, which has antitussive properties that regulate mucus, regulates mucus, and dilates the bronchial tubes, and a method for producing the same. [Means for solving the problem] The present invention is based on the formula (): (In the formula, R is 1,3-dimethylxanthine-7
-yl or 3,7-dimethylxanthine-1-
R 2 is an oxygen atom or a free or esterified carboxyl group; R 3 and R 4 are a hydrogen atom or a methyl group; P is 0 or 1; R 1 is a hydrogen atom, alkylsulfonyl having 1 to 2 carbon atoms; group, unsubstituted or mono- or polysubstituted phenylsulfonyl group, formula
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[Formula] (In the formula, R 5 is a hydrogen atom, (-CH 2 )- o Q or
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Typical examples of saturated or unsaturated heterocycles containing one or more heteroatoms such as O, S, N are morpholin-1-yl, pyrrolido-1
-yl, piperidin-1-yl, 4-methylpiperazin-1-yl, thiomorpholin-1-yl,
4-ethylpiperazin-1-yl, 4-(2'-hydroxyethyl)piperazin-1-yl, 4-
(4'-fluorophenyl)piperazin-1-ylimidazol-1-yl, 3-pyridyl and 4
- It is pyridyl. Typical examples of pharmacologically acceptable non-toxic bases are methylamine, dimethylamine, trimethylamine, ethylamine, diisopropylamine,
N-Methyl-N-hexylamine, thromethamine, cyclohexylamine, N
-Methyl-N-cyclohexylamine, α-phenylethylamine, β-phenylethylamine,
Organic base materials such as N,N-dimethylethanolamine, N-N-diethylethanolamine, ethylenediamine, piperazine, morpholine, piperazine, galactamine, N-methylglucamine, ephedrine, lysine, arginine, and alkaline and alkaline earths. Inorganic bases such as metal hydroxides. Typical examples of pharmacologically acceptable non-toxic acids are acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, malic acid, malonic acid, benzoic acid, salicylic acid, 3,4,5-trimethoxybenzoic acid. organic acids such as methanesulfonic acid, benzenesulfonic acid, camphosulfonic acid, lactic acid, aspartic acid, glutamic acid, L- and D-2-thiazolidine-5-carboxylic acid, cystine and cysteine, and nitric acid, phosphoric acid, Inorganic acids such as sulfuric acid, hydrochloric acid, and hydrobromic acid. Preferred salts for use in the present invention are compounds of formula () in which R 2 is a carboxyl group salted with one of the bases listed above. More preferred are salts of piperazine and imidazole derivatives. In the formulas herein, the wavy bond () is
Substituents do not have defined stereochemical identity.
In other words, a substituent can have either the (R) or (S) configuration, and a broken line (â) indicates a substituent with absolute stereochemistry (S), and a thick wedge line () indicates that the substituent has the absolute stereochemistry (S). represents a substituent of absolute structure (R). The compound of the present invention in which R 2 , R 3 and R 4 are hydrogen atoms and R 1 is an acyl group is particularly preferred as a mucus regulator. In formula (), R 2 , R 3 and R 4 are hydrogen atoms, and R 1 is a substituted or unsubstituted cinnamoyl group, which is particularly preferred as a bronchodilator. Specific examples of preferred compounds of the invention are as follows. 2-[(1â²,3â²-dimethylxanthine-7â²-yl)
2-[(3â²,7â²-dimethylxanthine-1â²-yl)
2-[(3â²,7â²-dimethylxanthine-1â²-yl)
methyl]-3-[(imidazol-1'-yl)acetyl]thiazolidine;2-[(1',3'-dimethylxanthine-7'-yl)
methyl]-3-[(3â²,4â²-hydroxy)cinnamoyl]thiazolidine; 2-[(3â²,7â²-dimethylxanthine-1â²-yl)
methyl]-3-[(3â²,4â²-dihydroxy)cinnamoyl]thiazolidine; 2-[(1â²,3â²-dimethylxanthine-7â²-yl)
methyl]-3-[3'-methoxy-4'-hydroxy)
cinnamoyl]thiazolidine; 2-[(3',7'-dimethylxanthine-1'-yl)
methyl]-3-(3'methoxy-4'-hydroxy)cinnamoyl-thiazolidine;2-[(3',7'-dimethylxanthine-1'-yl)
methyl]-3-(3'-methoxy-4'-hydroxy)
Cinnamoyl-thiazolidine;2-[(3',7'-dimethylxanthine-1'-yl)
methyl]-3-[3â²-(4â³-hydroxyethylpiperdin-1â³-yl)propionyl]thiazolidine; 2-[(1â²,3â²-dimethylxanthine-7â²-yl)
methyl]-3-(3'-morpholinomethyl-4'-hydroxy-3'-methoxy-cinnamoyl)thiazolidine;2-[(1',3'-dimethylxanthine-7'-yl)
2-[(3â²,7â²-dimethylxanthine-1â²-yl)
methyl]-3-(3'-pyrrolidinylmethyl-4'-hydroxy-3'-methoxy-cinnamoyl)thiazolidine;2-[(1',3'-dimethylxanthine-7'-yl)
methyl]-3-[3'-thia-5'-carboxyl-
5â²-acetylamino-pentanoyl]thiazolidine; 2-[(1â²,3â²-dimethylxanthine-7â²-yl)
methyl]-3-[4'-thia-6'-carboxy-6'-
acetyl-amino-hexanoyl]thiazolidine; 2-[(1',3'-dimethylxanthine-7'-yl)
methyl]-3-[3â²-(2â³-ethoxyethyloxy)
acetyl]thiazolidine; 2-[(1',3'-dimethylxanthine-7'-yl)
methyl]-3-[3'-(imidazol-1'-yl)
2-[(1â²,3â²-dimethylxanthine-7â²-yl)
methyl]-3-glycinyl-thiazolidine; 2-[(3',7'-dimethylxanthine-1'-yl)
methyl]-3-glycinyl-thiazolidine; 2-[(1',3'-dimethylxanthine-7'-yl)
methyl]-3-(N-acetyl)glycinyl-thiazolidine; 2-[(1',3'-dimethylxanthine-7'-yl)
methyl]-3-[3â²-(2â³-hydroxyethylamino)ethylaminopropynyl]thiazolidine; 2-[(3â²,7â²-dimethylxanthine-1â²-yl)
methyl]-3-[3â²-(2â³-hydroxyethylamino)ethylamino-propionyl]thiazolidine; 2-[(1â²,3â²-dimethylxanthine-7â²-yl)
methyl]-3-[3â²-(4â³-hydroxyethylpiperazin-1â³-yl)propionyl]thiazolidine. The compound of the present invention has the formula (): (wherein R is the group defined above, Y and
Yâ² is an alkoxy group having 1 to 2 carbon atoms, or together represents a carbonyl group), and the compound is represented by the formula (): (In the formula, R 2 , R 3 and R 4 are the same as above) by reacting with an amine alkane alkanethiol represented by the formula (a): (wherein R, R 2 , R 3 and R 4 represent the groups defined above). Compounds of formula () in which R 2 is a hydrogen atom may optionally be subjected to optical resolution. If R 2 is a free or esterified carboxyl group, one diastereoisomer and/or a racemic mixture of diastereoisomers can optionally be obtained. Thiazolidines of formula (a) and enantiomers or diastereoisomers thereof are cyclic anhydrides such as succinic anhydride, glutaric anhydride, etc.; activated species of carboxylic acids of formulas (a) and (b); and the expression (
Sulfonyl halide of c): Q( -CH2 ) -o COZ...(a) P 5 âSO 2 âHal ... (c) (In each formula, Q, P 1 , P 2 and n are defined above, and P 5 is an alkyl group having 1 to 2 carbon atoms, or a substituted unsubstituted or mono- or polysubstituted phenyl ring, Hal is chlorine, bromine and iodine, Z is chlorine, bromine, azide, formula: -O-CO-D (wherein D is the number of carbon atoms 1 to 5 lower alkoxy groups or benzyloxy groups, lower alkyl groups having 1 to 5 carbon atoms (mixed anhydrides and anhydrides), and activated esters). The resulting acylated thiazolidine has the formula (
b): (wherein R, R 3 , R 4 and R 2 have the above meanings, Râ² 1 is the formula SO 2 âP 5 or the formula COâR 5 (wherein,
P 5 and R 5 are as defined above). When a carbodiide is used as the active molecular species of the carboxyl group in the acylation reaction, the acylation reaction converts the thiazolidine of the formula () to the formula (
This can optionally be done by reacting with acids a) and (b). A compound of formula (b) is optionally oxidized by a suitable reagent to give a compound of formula (c): A compound represented by the formula (wherein R, R 1 , R 2 , R 3 and R 4 represent the groups defined above) is obtained. General formula (d): (In the formula, R, R 2 , R 3 , R 4 , and P are as defined above, and at least one of P 1 and P 2 is a hydrogen atom, and the other is a hydrogen atom, a methyl group, or a phenyl group. group, Q' is a halogen atom and n is preferably 0) has the formula: P 3 (-CH 2 ) -o CO-S Base (wherein P 3 is a group as defined above; Base is
A group selected from the group consisting of sodium, potassium, magnesium, calcium, lower trialkylammonium, and phenyl dialkylammonium) may be optionally reacted with a thiocarboxylic acid salt of a group consisting of sodium, potassium, magnesium, calcium, lower trialkylammonium, and phenyl dialkylammonium. 3 (âCH 2 )â n COS
(where P 3 and n are the same as above) is the formula (
Compound d) is obtained. These latter compounds optionally react with ammonia to form compounds of formula (d) in which Q' is a free thiol group.
by optionally reacting it with an alkyl halide in the presence of a base.
Formula (d) where Q' is an alkylthioether group
Compounds are obtained. Finally, compounds in which n is O, P 1 and P 2 are hydrogen atoms, and Q' is chlorine, bromine, or iodine in formula (d) can be prepared using inert solvents such as benzene, acetonitrile, and tetrahydrofuran (THF). The corresponding phosphonium salt of formula (d) in which Q' is P (C 6 H 5 ) 3 Formula (d)
The compound has formula (e): (wherein R, R 3 , R 4 , R 2 and P represent the groups defined above). The compound of formula (e) is
Next, after optionally reacting with an aldehyde of the formula (): T-CHO...() (in the formula, T represents the group defined above) and removing the protecting group, the formula (f): 3-thiazolidine acrylamide (wherein R, R 2 , R 3 , R 4 , T and P are the same as above) is
When T is a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms, or a phenyl group, an amine, that is,
H2N ( -CH2 ) -nT1 (wherein m and T1 are the same as above), mono- or di - substituted amines or thiols (i.e. HS( -CH2 ) -nT1 ( In the formula, m
and T 1 as above), unsubstituted or mono- or polysubstituted thiophenol)
Optionally reacts with a nucleophile such as formula (g): (In the formula, R, R 2 , R 3 , R 4 , T and P are the groups defined above, and Q' is HN(-CH 2 ) -n T 1 (In the formula, m and T 1 are the same as above. ), mono- and di - substituted amino groups, S( -CH2 ) -oT1 (where m, n and
T 1 is the same as defined above), indicating an unsubstituted or polysubstituted phenylthio group)
obtain adduct). Cyclization of a compound of formula () with an aminoalkanethiol of formula () to give a 2-substituted thiazolidine ring can be carried out in an aqueous solvent with a stoichiometric amount or small excess of the aminoalkanethiol;
in the presence of a catalytic amount of its ammonium salt, such as acetate, formate, camphosulfonate, hydrochloride;
Alternatively, the reaction may be carried out in the absence of the compound. Suitable solvents are, for example, water, methanol, ethanol, acetic acid and mixtures thereof. The reaction is preferably carried out at about -20°C to the reflux temperature of the solvent, more preferably at room temperature. Reaction times range from a minute or two to several days, but usually reaction times do not exceed two hours, and often a few minutes are sufficient to drive the reaction to completion. The optical resolution of the compound of formula (a) is, for example, d
- and l-camphosulfonic acid, d- and l-
lactic acid, d- and l-mandelic acid, d- and l
-6-exochloro-7-syncarboxy-bicyclo[2,2,1]heptan-3-one-3,
Optionally, by forming a salt with an optically active acid such as 3-ethylenedioxy, followed by crystallization until a certain degree of light extinction is obtained, and recovering the optically active 2-substituted-thiazolidine. It may be done. Suitable solvents are, for example, alcohols such as methanol, ethanol, 1-propanol, 2-propanol, ethers such as ethyl ether, isopropyl ether, dioxane, tetrahydrofuran, esters such as ethyl formate, ethyl acetate, benzene. , hydrocarbons such as toluene, cyclohexane, hexane and mixtures thereof. Optical resolution is preferably carried out at room temperature, with 1,2
Multiple crystallizations are generally required to obtain a certain degree of light absorption. Acylation of a compound of formula (a) with an acylating agent of formula () is carried out in the presence of a stoichiometric amount or a small excess of a base in an insoluble solvent. This is done by reacting with an agent. Suitable solvents include, for example, CH 2 Cl 2 , CHCl 3 ,
Halogenated hydrocarbons such as ClCH 2 CH 2 Cl, ketones such as acetone and butane-2one, hydrocarbons such as hexane, cyclohexane, benzene, toluene, pyridine and mixtures thereof. Near stoichiometric amounts of base are useful for any species of acylating agent. Such bases include, for example, CaO, CaCO 3 , K 2 CO 3 ,
Inorganic bases such as alkali or alkaline earth metal oxide carbonates or bicarbonates such as Na 2 CO 3 , NaHCO 3 etc.; e.g. trimethylamine,
Organic bases such as tertiary amines such as tributylamine; or aromatic bases such as pyridine, alkyl-substituted pyridine, N,N-dialkylaniline; or anionic ion exchange resins. The acylation reaction is preferably carried out at a temperature ranging from about -40°C to about the reflux temperature of the solvent. More preferably the reaction is carried out at room temperature. When carboxylic acids of formula (a) and formula (b) (wherein Z represents an OH group) are used in the acylation reaction, the reaction is carried out in an inert solvent at room temperature, optionally as a catalyst. of 4-dimethylaminopyridine in the presence of an excess of a condensing agent such as a carbodiimide, preferably dicyclohexylcarbodiimide. The reaction of oxidizing the compound of formula (b) to obtain the thiazolidine sulfoxide of formula (c) involves monoperphthalic acid, m-chloroperbenzoic acid, peracetic acid,
It is obtained by reacting a stoichiometric amount or a small excess of an organic peroxide such as performic acid or perbenzoic acid in an inert solvent in the presence or absence of a base. The preferred oxidizing agent is a stoichiometric amount of monoperphthalic acid, the preferred solvent is ethyl acetate, and the reaction is preferably carried out in the presence of excess NaHCO 3 . Preferably, the oxidation reaction is carried out at a temperature ranging from about -25°C to room temperature. More preferably the reaction is carried out at 0°C. The thiolation of compounds in which Q' is a halogen atom in formula (d) is carried out in situ with an organic base such as sodium, potassium and/or trimethylamine, triethylamine, tributylamine in an inert solvent. This is accomplished by treatment with a stoichiometric or excess amount of a thiocarboxylic acid salt, such as a thiocarboxylate salt. Preferred solvents are, for example, halogenated hydrocarbons,
Ketones, esters, ethers, alcohols and mixtures thereof. The reaction preferably takes place at room temperature, and the reaction time ranges from 1-2 minutes to several hours, but usually does not exceed 2 hours at room temperature. Free thiol groups are obtained by reacting the thioacyl compound with an excess of aqueous ammonia in an inert gas atmosphere. The reaction is carried out at room temperature, and suitable solvents are alcohols such as metal, ethanol, glycols; ethers miscible with aqueous ammonia such as dimethoxyethane, dioxane, tetrahydrofuran, and mixtures thereof. Acrylation of free thiols may be accomplished as described above. Alkylation of free thiol groups may be carried out by treating potassium and/or sodium salts of thiol compounds with alkyl halides. The reaction of the stabilized ylide of formula (e) and the aldehyde of formula () is the well-known Witzig reaction, but this experimental procedure is also well known to those in the art.
Generally the reaction is carried out in an inert solvent such as halogenated solvents, ethereal solvents (THF, dimethoxyethane), acetonitrile, cyclohexane, benzene, toluene, hexane, dimethyl sulfoxide or mixtures thereof, preferably at room temperature. This is done by mixing the reagents in equimolar ratios. The Michael addition of the above-defined nucleophile of formula (f) to acrylamide is also a well-known reaction. The preferred solvent is an alcohol and the reaction is carried out by mixing the solvents and heating at reflux temperature. The compound of formula () is a known compound and can be prepared by a known method (De Martiis et al., "Il Farmaco", Ed.Sc., 9 ).
526 (1956)). In particular, compounds of formula () in which Y and Y' are methoxy or ethoxy groups can be prepared by dissolving a suitable α-halogenated acetaldehyde-acetal in a suitable solvent such as dimethylformamide, dimethylsulfoxide or water, and mixtures thereof. Among them, it is produced by reacting 1,3-dimethylxanthine or 3,7-dimethylxanthine with an alkali salt such as lithium, sodium or potassium. The compounds according to the invention are therapeutically active substances and have no acute, subacute or chronic toxic effects;
Suitable for use as an antitussive, mucus regulator or bronchodilator. In fact, for example, the compounds according to the invention do not exhibit acute toxic effects in mice and rats. After oral and intraperitoneal administration of the compounds according to the invention, LD 50 values of more than 1 g/Kg are determined with systemic administration. The compound according to the invention, 2-[(1',3'-dimethylxanthine-7'-yl)methyl]thiazolidine, contains 0.6 g/Kg (oral) and 0.48 g/Kg
It differs from other compounds of the invention because it exhibits LD 50 (intraperitoneal) values in mice. Charlie et al.
Pharmacodynamie), vol. 134, p. 306, 1961.
(References) and Stefko et al. (J.Pharm.Exp.
108, p. 217, 1953) can be used, with few modifications, to investigate the antitussive action of the compounds according to the invention. Codeine phosphate is used as a positive reference compound. According to Chillier's method, guinea pigs are exposed to an aerosol of citric acid (7.5%), treated with an antitussive intraperitoneally, and their coughs are recorded for 60 minutes. Male animals weighing 300-400 g are used in all experiments. Morimotsu is a transparent box (20 x 30 x 30 cm) connected to an aerosol spray device.
60 minutes after intraperitoneal administration of the compound according to the invention (0.1 M and 0.3 M solutions, 1 ml/Kg).
Animals are subjected to a citric acid saturated atmosphere. The total number of cough episodes and first cough delay time are recorded during the first 5 minutes. Five guinea pigs are used for each dose level and the results are compared to the control (vehicle treatment) and 0.07M solution of codeine phosphate (standard treatment). The ED 50 and the corresponding first cough attack delay time are calculated. Data obtained with intraperitoneal administration are confirmed with oral administration. In Stefko's method, unanesthetized Mongrel dogs (15±3 kg) are used. Compounds according to the invention are tested for their ability to inhibit cough induced by electrical stimulation. Under general anesthesia, two insulated nichrome wires (0.4 mm in diameter) are surgically implanted into the submucosa of the trachea. After about 2 days, the dog was suspended in a sling and the exposed electrodes were placed in a glass.
Connect to an electrical stimulation device such as the S48 Mod. Delay time 0.01ms, duration 1ms and frequency
Stimulation parameters such as 30Hz are used. To determine the minimum voltage required to elicit a reproducible cough response, 10 1 second electrical stimulations are applied at 5 second intervals. Next, the cough response to electrical stimulation was determined at 15 minutes, 30 minutes, 60 minutes, and 90 minutes after oral administration of the compound according to the present invention.
recorded after minutes, 120 minutes, 150 minutes, 180 minutes, 240 minutes, 300 minutes and 360 minutes. The cough response is scored as follows: 1: No response 2: Sigh or loud exhalation 3: Prominent cough 4: 1 pronounced cough and 1 loud exhalation 5: 2 pronounced coughs Six dogs were used for each determination; Calculate the average activity. Compare percent inhibition of cough response and duration of action with codeine. In the guinea pig cough test, codeine phosphate has an ED 50 value of 23 mg/Kg and a delay of 170%. In the dog cough test, codeine phosphate was found to be 52% more likely to cause cough irritation when tested at 8mg/Kg.
% inhibition for a long time (approximately 2-4 hours). The mucus-modulating properties of the compounds according to the invention are investigated "in vivo" by experiments carried out on male New Zealand white rabbits. The animals were subjected to inhalation of 5% H 2 SO 3 aqueous solution by aerosol (3 hours a day, every other day for 3 days) to induce chronic bronchitis, which caused pathological lesions in the bronchi. Sputum is produced. The purpose of the experiment was to determine the dry weight, viscosity, and content of proteins, phospholipids, galactose, sialic acid, and fucose of the sputum caused by pharmacological treatment of the compounds of the invention in this pathological sputum. evaluation of changes in selected parameters. For this purpose, one of the compounds of the invention
Twice daily (9:00 a.m. and 4:00 p.m.) before and after oral treatment, intrabronchial injection is performed using a âTâ-shaped glass cannula inserted into the trachea. Collect the sputum produced daily. The schedule of the processing procedure is shown in the following figure. In the figure, 0 represents the day the tracheal cannula was implanted, and -7, -5 and -3
Represents the day (H) of H 2 SO 3 treatment, 1, 2, 3
and 4 represent the day (T) of oral administration of the compound of the present invention and the time (M) of mucus collection. Mucus collected in the morning of day 1 is considered a blank, and 7 indicates the day the animal is sacrificed after mucus collection. Sputum samples were kept in the freezer (â20
â). Samples were measured using a Burckfield viscometer (model LT) equipped with a 1565° coneplate.
Relative viscosity was measured at 37 °C using VD) and then divided and subjected to biological analysis of protein, phospholipid, galactose, sialic acid and fucose contents, respectively. The dry weight of mucus is also determined. For each parameter, cumulative data are from the first 7 days of treatment and are removed using the AUC (area under the curve) method calculated by the trapezoidal rule. Finally, the data is
Data are compared to control (vehicle treated), non-bronchitis rabbits (vehicle treated) and positive control bronchitis rabbits treated with 0.153M S-carboxymethylcysteine. Table 1 shows the AUC values determined for various parameters after treatment of bronchitis rabbits with S-carboxymethylcysteine in % compared to bronchitis controls.
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ãšããŠæ¯èŒããAUCå€ã§ç¬¬ïŒè¡šã«ç€ºãã[Table] As is clear from Table 1, all parameters varied with the treatment with S-carboxymethylcysteine. The ideal mucus modifier should reduce the viscosity and protein content of mucus. In pathological conditions, the protein content of mucus increases, which may be associated with abnormal production of mucus large molecules and an abnormally enhanced passive transport of serum proteins from capillaries. At the same time, the mucoprotein content should decrease with a decrease in the content of galactose and sialic acid in the sputum, indicating a decrease in the production of mucins that contribute to mucus viscosity. Fucose content is involved in the production of neutral mucin. The increase in mucus volume is involved in local repair processes that cause mucus dissolution and liquefaction. This process is particularly desirable when the patient's mucus is sticky and highly viscous, such as in certain pathological conditions, resulting in respiratory tract obstruction. The results obtained by oral administration of equimolar doses of the two compounds of the invention compared to standard S-carboxymethylcysteine are useful for the control of bronchitis.
Table 2 shows the AUC values compared as 100%.
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ãã[Table] 2-[(1,3-dimethylxanthine-7'-yl)methyl]thiazolidine-4-carboxylic acid is a typical compound of the present invention, and has good antitussive and mucus regulating effects. In fact, in a guinea pig cough test, this compound showed a
It shows an ED 50 value (213% delay) and a better duration of action compared to codeine. At a dose of 20 mg/Kg, this compound shows a 32% inhibition of cough irritation in dogs and compares favorably with codeine in its duration of action. 4-Carboxyxanthinyl-methylthiazolidine with a free or esterified carboxyl group is also effective as an antitussive, showing ED 50 values of 50-65 mg/Kg in the guinea pig cough test and causing cough irritation in dogs. Tests can induce 38% to 50% inhibition. This action as an antitussive is also combined with mucus-regulating action, which is at least as potent as S-carboxymethylcysteine. The guinea pig cough test and the dog cough test are valid and reliable methods for screening substances useful in treating coughs of different origins and in alleviating the pain caused by cough attacks. The compounds of the invention may therefore be useful in treating patients to prevent or reduce cough attacks. Therefore, the compounds of the invention are also useful for inhibiting cough attacks that can lead to syncope. Prevention and control of severe coughing is also very helpful, since coughing may cause emphysematous bleb rupture and rib fractures. Although cough-induced rib fractures may occur in otherwise normal patients, their occurrence is similar to pathological fractures seen in multiple myeloma, osteoporosis, and osteolytic metastases. That would at least increase the chances. Particularly preferred compounds according to the invention as antitussive agents are: 2-[(1â²,3â²-dimethylxanthine-7â²-yl)
methyl]thiazolidine-4-carboxylic acid, and
Its esters with C1 - C5 alcohols, 2-[(3',7'-dimethylxanthine-1'-yl)
methyl]thiazolidine-4-carboxylic acid, and
C1 - C5 alcohols and their esters, 2-[(1',3'-dimethylxanthine-7'-yl)
methyl]-3-[3â²-(2â³-hydroxyethyl-aminoethylamino)propionyl]thiazolidine, 2-[(1â²,3â²-dimethylxanthine-7â²-yl)
methyl]-3-[3â²-(4â³-hydroxyethyl-piperazin-1â³-yl)propionyl]thiazolidine. In certain pathological conditions, such as chronic bronchitis, suppressing a cough that produces large amounts of sputum is not necessarily desirable, and a moderate antitussive action with very strong mucus-regulating action is highly desirable. . In some cases, suppressing a cough too early can cause mucus to build up in the bronchi, blocking alveolar ventilation and inhibiting the lungs' ability to fight infections. As a result, the changes caused to mucus by treating selective mucus regulators reduce the number of cough attacks. Particularly useful and preferred compounds exhibiting reduced antitussive action and high mucus regulating action for this purpose are as follows. 2-[(1â²,3â²-dimethylxanthine-7â²-yl)
methyl]thiazolidine, 2-[(3â²,7â²-dimethylxanthine-7â²-yl)
methyl]thiazolidine and its 3-acetylthioacetyl derivative, 2-[(1',3'-dimethylxanthine-7'-yl)
methyl]-3-[3'-thia-5'-carboxy-acetylamino-hexanoyl]thiazolidine, 2-[(1',3'-dimethylxanthine-7'-yl)
methyl]-3-[3â²-(imidazol-1â³-yl)
propionyl]thiazolidine. Particularly preferred mucus regulators are 2-[(1',3'-dimethylxanthine-7'-yl)methyl]-thiazolidine and imidazol-1'-yl-alkanoic, caffeic acid. acids, such as ferulic acid, (3-phorforinylmethyl-4-hydroxy-3-methoxy)cinnamic acid and (3-pyrrolidinylmethyl-4-hydroxy-3-methoxy)cinnamic acid. It is an amide. The above compounds change the numerically expressed rheological parameters (proteins, phospholipids, fucose, sialic acid and viscosity) similar to those obtained with the starting thiazolidines, but at lower dosages. In particular, these latter compounds according to the invention are also characterized by a pronounced effect on causing relaxation of tracheal and bronchial smooth muscles. For example, the compound 2-[(1',3'-dimethylxanthine-7'-yl)
[Methyl]-3-[3'-morpholinylmethyl-4'-hydroxy-5'-methoxycinnamoyl]thiazolidine was used to induce 1.9Ã
It can be relaxed with an ED 50 value of 10 â4 M. The antispasmodic action of this new substance compares favorably with that of dihydroxypropyltheophylline (ED 50 value 0.76Ã10 â4 M). After intrajugular administration, the compound was found to be more effective than aminophylline in the resolution of bronchospasm induced by intravenous administration of histamine in minced guinea pigs (Konzett-Ressler test). is also at least 4
It appears to have twice the activity. Therefore, the compound represented by the general formula () is effective as an antitussive, a bronchodilator, and a mucus regulator. These compounds can be used orally, sublingually,
It may be administered intravenously, subcutaneously, intramuscularly, rectally, or by the inhalation route. The inhalation route is particularly preferred when a mucus-regulating effect is required. The preferred dosage of the compounds of the present invention is 0.05% depending on the condition, weight and age of the patient, and the route of administration.
It fluctuates between about 5mg/Kg/day. The preferred dose for the inhalation route is 0.05 to 1 mg/
Kg/day. As mentioned above, the compounds of the present invention can be administered to both humans and animals in various dosage forms: orally as a tablet, capsule or solution; rectally as a lozenge; parenterally as subcutaneously. , or intramuscularly; in emergency cases, intravenous administration is preferable;
By inhalation in the form of an aerosol or in the form of a solution for a nebulizer; for long-term action it may be administered in sterile implant form. Pharmaceutical compositions containing compounds of the invention may be manufactured by conventional methods and may contain conventional carriers and/or diluents. For example, for intravenous administration or infusion, sterile isotonic aqueous solutions are preferred. For subcutaneous or intramuscular injection, sterile solutions or suspensions in aqueous or non-aqueous media may be used, and for tissue implantation, sterile tablets or silicone containing or impregnated with the compound. Rubber capsules are used. Common carriers or diluents include, for example, water, gelatin, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, talc, stearic acid, calcium or magnesium stearate, glycols, starch, gum arabic, gum tragacanth, alginic acid or These include alginates, lecithin, polysorbates and vegetable oils. For administration by nebulizer, suspensions or solutions of the compounds of the invention, preferably in salt form, such as the sodium salt (and/or nitrate) in water may be used. Alternatively, the formulation may be in the form of a solution or suspension of the compound of the invention in one of the common liquefied propellants, such as dichlorodifluoromethane or dichlorotetrafluoroethane, and may be placed in an aerosol bomb. may be administered from a pressurized container such as If the compound is not soluble in the propellant, it may be necessary to add a co-solvent such as ethanol, dipropylene glycol and/or a surfactant to the formulation. The present invention will be described below with reference to Examples, but the present invention is not limited to the Examples. Example 1 Cystamine hydrochloride 1.65g and potassium acetate 1.47g
Add 10 ml of a 70% acid aqueous solution containing 2.4 g of theophylline acetaldehyde dimethyl acetal,
The mixture was heated at reflux temperature for 3 hours. The resulting suspension was diluted with water and the precipitate was filtered and washed with water to yield 2.4 g of 2-[(1',3'-dimethylxanthine-7'-yl)methyl]thiazolidine. Melting point 141
~143°C, (crystallized from ethanol) Example 2 70 ml of an ethanol solution containing 2.4 g of theobromine acetaldehyde was added to 10 ml of an aqueous solution containing 2.12 g of cysteine hydrochloride and 1.4 g of potassium acetate.
The suspension was stirred at room temperature overnight, diluted with water and filtered. Crystallized from ethanol, melting point 157-160
2-[(3â²,7â²)-dimethylxanthine-1â²- at °C
yl)methyl]thiazolidine-4-carboxylic acid was obtained. Example 3 Cysteine ethyl ester hydrochloride, cysteine hydrochloride,
D- and l-penicillamine were reacted with theophylline acetaldehyde, theobromine acetaldehyde and the corresponding dialkyl acetals to produce the compounds listed below. 2-[(3â²,7â²)-dimethylxanthine-1â²-yl)methyl]thiazolidine; Melting point: 166-167°C 2-[(1â²,3â²-dimethylxanthine-7â²-yl)
methyl]thiazolidine-4-carboxylic acid; melting point:
147-150â 2-[(1â²,3â²-dimethylxanthine-7â²-yl)
methyl]-4-carboethoxythiazolidine; melting point: 111-113°C 2-[(3',7'-dimethylxanthine-1'-yl)
methyl]-4-carboethoxythiazolidine; melting point: 129-130°C 2-[(3',7'-dimethylxanthine-1'-yl)
methyl]-5,5-dimethylthiazolidine-4-
Carboxylic acid; melting point: 132-135â 2-[(1',3'-dimethylxanthine-7'-yl)
methyl]-5,5-dimethylthiazolidine-4-
Carboxylic acid; melting point: 125-130°C Example 4 Stirring 0.15 ml of methanesulfonyl chloride 2
The mixture was added dropwise to 3.5 ml of pyridine containing 0.25 g of -[(1',3'-dimethylxanthine-7'-yl)methyl]thiazoline and cooled at 0°C. After 30 minutes the mixture was heated to room temperature and after 1 hour diluted with aqueous sulfuric acid and extracted with chloroform. After the usual work-up, the residue was crystallized from ethanol to give 0.24 g of 2-[(1',3'-dimethylxanthine-7'-yl)methyl]-3-methanesulfonyl-thiazolidine, melting point 206°C. Example 5 The following compound was obtained in the same manner as in Example 4 using methanesulfonyl chloride, benzenesulfonyl chloride, and p-toluenesulfonyl chloride. 2-[(1â²,3â²-dimethylxanthine-7â²-yl)
methyl]-3-ethanesulfonylthiazolidine;
Melting point: 208â 2-[(1â²,3â²-dimethylxanthine-7â²-yl)
methyl]-3-phenylsulfonylthiazolidine; melting point: 215-220°C 2-[(1',3'-dimethylxanthine-7'-yl)
methyl]-3-p-toluenesulfonylthiazolidine; melting point: 215-218°C 2-[(3',7'-dimethylxanthine-1'-yl)
methyl]-3-methanesulfonylthiazolidine;
Melting point: 210-213â 2-[(3',7'-dimethylxanthine-1'-yl)
methyl]-3-ethanesulfonylthiazolidine;
Melting point: 210-215â 2-[(3',7'-dimethylxanthine-1'-yl)
methyl]-3-methanesulfonylthiazolidine;
Melting point: 220-222â 2-[(3',7'-dimethylxanthine-1'-yl)
methyl]-3-p-toluenesulfonylthiazolidine; melting point: 220-222°C Example 6 α-chloroacetyl chloride cooled to 0°C
A solution of 2 ml of dichloroethane containing 0.31 ml of 2-[(1',3'-dimethylxanthine-7'-
yl) methyl]thiazolidine and 0.54 ml of triethylamine in 10 ml of dichloroethane. After 30 minutes at 0°C and 2 hours at room temperature, the mixture was partitioned between 50 ml of water and 50 ml of dichloroethane, the organic phase was washed with 5% aqueous sodium bicarbonate and water, dried over sodium sulfate, and the solvent was evaporated under vacuum. The residue was crystallized from ethanol to give 1 g of 2-[(1',3'-dimethylxanthine-7'-yl)methyl]-3-chloroacetylthiazolidine with a melting point of 205-207°C. Example 7 In the same manner as in Example 6, 2-[(3â²,7â²-dimethylxanthine-1â²-yl)methyl]thiazolidine, 2-[(1â²,3â²-dimethylxanthine-7â²-yl) The following compounds were obtained using methyl]thiazolidine, α-chloroacetyl chloride, α-bromopropionyl chloride, cyclopropylcarbonyl chloride, cyclohexylpropionyl chloride, cyclopentylpropionyl chloride, and ethyloxalyl chloride. 2-[(3â²,7â²-dimethylxanthine-1â²-yl)
methyl]-3-chloroacetylthiazolidine; melting point: 208-210â 2-[(3',7'-dimethylxanthine-1'-yl)
methyl]-3-cyclopropylcarbonyl-thiazolidine; melting point: 210-212°C 2-[(3',7'-dimethylxanthine-1'-yl)
methyl]-3-(2'-bromo)-propionyl-thiazolidine; melting point: 215-218°C 2-[(3',7'-dimethylxanthine-1'-yl)
methyl]-3-(3'-cyclohexyl)propionyl-thiazolidine; melting point: 170-172â 2-[(3',7'-dimethylxanthine-1'-yl)
methyl]-3-(3'-cyclopentyl)propionyl-thiazolidine; melting point: 175-177°C 2-[(3',7')-dimethylxanthine-1'-yl)methyl]-3-ethyloxalylthiazolidine; Melting point: 142-144â 2-[(1',3'-dimethylxanthine-7'-yl)
methyl]-3-cyclopropylcarbonyl-thiazolidine; melting point: 210-212â 2-[(1',3'-dimethylxanthine-7'-yl)
methyl]-3-(2'-bromo)propionyl-thiazolidine; melting point: 220-222°C 2-[(1',3'-dimethylxanthine-7'-yl)
methyl]-3-(3'-cyclohexyl)propionyl-thiazolidine; melting point: 165-166°C 2-[(1',3'-dimethylxanthine-7'-yl)
methyl]-3-(3'-cyclopentyl)propionyl-thiazolidine; melting point: 168-170â 2-[(1',3'-dimethylxanthine-7'-yl)
methyl]-3-ethyloxalyl-thiazolidine; melting point: 150-152°C Example 8 Under a nitrogen atmosphere, a solution of 5 ml of anhydrous sym-dichloroethane containing 1.14 ml of ethyl chlorocarbonate was
Stirring acetylthioacetic acid cooled to -20°C
Anhydrous containing 1.6g and 1.7ml of triethylamine.
It was added dropwise to a solution of sym-dichloroethane. After 1 hour, the mixture was diluted with 2-[(1',3'-dimethylxanthine-7'-yl)methyl]thiazolidine.
It was treated with a solution of 2.8 g in 10 ml of anhydrous sym-dichloroethane and heated to room temperature. After 3 hours, water and ice were added. The organic phase was washed with 5% sodium bicarbonate and water until neutral, dried over sodium sulphate and evaporated under vacuum. 2- with a melting point of 202-204°C by crystallization from ethanol.
[(1',3'-dimethylxanthine-7'-yl)methyl]-3-acetylthioacetyl-thiazolidine was obtained. Example 9 2- Stirring 2.4 g of potassium thioacetate
A suspension of 3.5 g of [(3',7'-dimethylxanthine-1'-yl)methyl]-3-chloroacetyl-thiazolidine in 100 ml of anhydrous acetone was added.
After 3 hours, the solvent was evaporated and the residue was partitioned between 100 ml of water and 150 ml of chloroform. 5 organic phase
% aqueous sodium bicarbonate solution and water until neutral, and evaporated to dryness. The residue was crystallized from ethanol to give 3.2 g of 2-[(3',7'-dimethylxanthine-1'-yl)methyl]-3-acetylthioacetyl-thiazolidine with a melting point of 116-120°C. Example 10 Dichloroethane containing 0.9 g of 2-[(2',4'-dimethylxanthine-7'-yl)methyl]-3-α-chloroacetylthiazolidine under a nitrogen atmosphere
50 ml of the solution was treated with 0.55 g of thiobenzoic acid and 0.15 g of tetrabutylammonium bromide and with 25 ml of an aqueous solution containing 0.53 g of potassium carbonate. The mixture was stirred overnight. Pour the organic phase into 25 ml of water.
Washed twice with
0.85 g of [(1',3'-dimethylxanthine-7'-yl)methyl]-3-benzoylthioacetyl-thiazolidine was obtained (precipitation solvent: ethanol). Example 11 In the same manner as in Example 10, benzoyl ester, cyclohexylpropionyl ester, cyclopentylpropionyl ester and 3,4-diacetoxy-cinnamoyl ester of α-mercaptoacetic acid were converted to 2-[(1â²,3â²-dimethylxanthine). â
7â²-yl)methyl]thiazolidine and 2-
Reaction with [(3',7'-dimethylxanthine-1'-yl]methyl]thiazolidine gave the following compound: 2-[(3',7'-dimethylxanthine-1'-yl]
methyl]-3-benzoyl-thioacetyl-thiazolidine; melting point: 220-223°C 2-[(3',7'-dimethylxanthine-1'-yl]
methyl]-3-(3'-cyclopentylpropionyl-thio)acetyl-thiazolidine; melting point: 210~
213â 2-[(3â²,7â²-dimethylxanthine-1â²-yl)
methyl]-3-(3'-cyclopentylpropionyl-thio)acetyl-thiazolidine; melting point: 215~
217â 2-[(1â²,3â²-dimethylxanthine-7â²-yl)
methyl]-3-(3'-cyclohexylpropionyl-thio)acetyl-thiazolidine; melting point: 200~
203â 2-[(1â²,3â²-dimethylxanthine-7â²-yl)
methyl]-3-(3,4-diacetoxy-cinnamoyl-thio)acetyl-thiazolidine; Melting point:
200-205â Example 12 2-[(1',3'-dimethylxanthine-7'-yl)
methyl]-3-α-chloroacetylthiazolidine
A suspension of 50 ml of methyl ethyl ketone containing 3.5 g of sodium iodide and 2.1 g of sodium iodide was refluxed for 12 hours with stirring. After removing the solvent, the residue was partitioned between chloroform and water. The organic phase was washed with aqueous sodium bicarbonate and sodium thiosulfate and once again with water. After evaporation of the solvent, the resulting residue was crystallized from ethanol and the melting point
3.4 g of 2-[(1',3'-dimethylxanthine-7'-yl)methyl]-3-α-iodoacetyl-thiazolidine was obtained at 210-212°C. Example 13 2-[(1â²,3â²-dimethylxanthine-7â²-yl)methyl]-3-acetylthioacetyl-thiazolidine is stirred in 1.5 ml of 30% ammonium hydroxide aqueous solution under an inert gas atmosphere. Added to a solution of cymethoxyethane containing 0.5 g. After 2 hours, the mixture was diluted with water, excess ammonia was removed under vacuum, and the resulting solid was filtered. After washing with ethanol, 2-[(1',3'-dimethylxanthine-7'-yl)methyl]-3-α- with a melting point of 276-278°C
0.25 g of mercapto-acetyl-thiazolicine was obtained. Similarly, 2-[(3',7'-
dimethylxanthine-1'-yl)methyl]-3-
α-Mercaptoacetyl-thiazolisine was produced. Example 14 A solution of 6 ml of methylene chloride containing 1.44 ml of isobutyl chlorocarbonate was cooled to -20°C. A solution of 50 methylene chloride containing 1.73 g of (4-methyl-piperazin-1-yl)acetic acid and 1.52 ml of triethylamine was cooled to -20°C.
ml of solution dropwise. The mixture was kept at â20° C. for 45 minutes, after which a solution of methylene chloride containing 4.6 g of 2-[(1â²,3â²-dimethylxanthine-7â²-yl)methyl]-3-mercaptoacetyl-thiazolidine was added. . The mixture was kept at -20°C for 45 minutes and it was heated to room temperature. After conventional treatment, 2-[(1',3'-dimethylxanthine-7'-yl)methyl]-3-(4'-methylpiperazin-1'-yl)acetyl- Thioacetyl-thiazolidine was obtained. Similarly, 2-[(3',7'-dimethylxanthine-7'-yl)methyl]-3-(4'-
Methylpiperazin-1'-yl)acetyl-thioacetyl-thiazolidine was obtained. Example 15 2-[(1',3'-dimethylxanthine-7'-yl)
methyl]-3-chloroacetyl-thiazolidine 1
A solution of 10 ml of DMSO containing 0.5 g of sodium imidazole was treated with 0.5 g of sodium imidazole. After stirring overnight at room temperature, the mixture was diluted with water and extracted with chloroform. 2-[(1',3'-dimethylxanthine-7'-yl)methyl]-3-(imidazol-1-yl), having a melting point of 235-238°C, is crystallized from ethyl ether after the usual work-up. ) Acetyl-thiazolidine
I gained 0.6g. In a similar manner, 2-[(3',
7â²-dimethylxanthine-1â²-yl)methyl]-
3-(imidazol-1-yl)acetyl-thiazolidine was produced. Example 16 0.48 g of succinic anhydride was added to 2-[(3â²,7â²-dimethylxanthine-7â²-yl)methyl]-thiazolicine.
to an anhydrous pyridine solution containing 1.9 g and 63 mg of dimethylaminopyridine. After leaving it overnight. The solution was diluted with water and acidified with 2N sulfuric acid. The aqueous phase was extracted with chloroform and the collected organic phases were washed with water. After evaporation of the solvent, the residue was crystallized from methanol/ethyl ether to give 2-[(3',7'-dimethylxanthine-1'-yl) with a melting point of 200-202 °C.
0.4 g of methyl]-3-(3'-carboxypropionyl)thiazolidine was obtained. Similarly, 2-[(1',3'-dimethylxanthine-7'-yl)methyl]-3-(3'-
(carboxypropionyl) thiazolidine was obtained. Example 17 In a similar manner to Example 15, using potassium thioacetate instead of sodium imidazole, 2-[(3',7'-dimethylxanthine-1'-yl)methyl with a melting point of 116-120°C was prepared. ]-3-acetylthioacetyl-thiazolidine was obtained. Example 18 In the same manner as in Example 15, using potassium thiobenzoate in place of sodium imidazole,
2-[(1',3'-dimethylxanthine-7'-yl)methyl]-3-benzoylthioacetyl-thiazolidine having a melting point of 210-213°C was obtained. Example 19 1.38 g of potassium carbonate and 1.275 ml of N-methylpiperazine containing 3.57 g of 2-[(1',3'-dimethylxanthine-7'-yl)methyl]-3-α-chloroacetyl-thiazolidine Added to a solution of 50 ml of anhydrous acetonitrile. The suspension was refluxed for 1 hour while stirring. After removing the solvent, the residue was partitioned between water and chloroform, the organic phase was washed with water, dried over sodium sulfate and concentrated under vacuum. The residue was crystallized from ethyl ether, melting point 222~
2-[(1â²,3â²-dimethylxanthine-7â²-
yl)methyl]-3-(4'-methylpiperazine-
2.85 g of 1'-yl)acetyl-thiazolidine was obtained. Example 20 Using 2-[(3â²,7â²-dimethylxanthine-1â²-yl)methyl]-3-α-chloroacetyl-thiazolidine as a raw material, the melting point was 175 to 180 in the same manner as in Example 19. 2-[(3',7'-dimethylxanthine-1'-yl)methyl]-3-α-(4'-methylpiperazin-1'-yl)acetyl-thiazolidine was produced. Example 21 1.23 g of triphenylphosphine was dissolved in 2-[(1â²,
3'-dimethylxanthine-7'-yl)methyl]-
A solution containing 1.3 g of 3-α-chloroacetyl-thiazolidine in 15 ml of anhydrous acetonitrile was added.
The mixture was heated under reflux for 4 hours, cooled and diluted with 15 ml of ethyl ether. The crystalline precipitate was filtered, washed with ethyl ether, and 2-
2 g of [(1',3'-dimethylxanthine-7'-yl)methyl]-3-α-triphenylphosphonium-acetyl-thiazoline chloride was obtained. 30 ml of methylene chloride and a few drops of phenolphthalein alcohol solution were added to 30 ml of aqueous solution containing this product. Then add 0.1N aqueous sodium hydroxide solution until the pink color persists.
The organic phase was separated, washed with water, evaporated to dryness, and the mp
1.6 g of 2-[(1',3'-dimethylxanthine-7'-yl)methyl]-3-triphenylphosphylidenemethylcarbonyl-thiazolidine at 122-126°C
I got it. A solution of 0.9 g of this compound in 6 ml of dimethyl sulfoxide was treated with 0.3 g of 4-acetoxy-3-methoxybenzaldehyde. 2 at room temperature
After holding for an hour, the solution was diluted with 100 ml of water and extracted with methylene chloride. After removing the solvent, the residue was crystallized from ethyl acetate, melting point 208
2-[(1â²,3â²-dimethylxanthine-
7â²-yl)methyl]-3-(4â²-acetoxy-3â²-
0.7 g of cinnamoyl-thiazolidine (methoxy) was obtained. Example 22 0.44 ml of ethyl chlorocarbonate under inert gas atmosphere
was added to a solution of 15 ml of methylene chloride containing 1 g of 3,4-diacetoxycinnamic acid and 0.55 ml of triethylamine under stirring. The mixture was stirred at -20°C for 1 hour. 2-
A solution of 1.02 g of [(1',3'-dimethylxanthine-7'-yl)methyl]thiazolidine in 10 ml of methylene chloride was added dropwise and the resulting mixture was stirred overnight at room temperature. After the usual work-up, the residue was crystallized from ethyl ether, melting point 190-195°C.
2-[(1â²,3â²-dimethylxanthine-7â²-yl)
0.9 g of methyl]-3-(3',4'-diacetoxy)cinnamoyl-thiazolidine was obtained. Example 23 0.32 g of finely powdered potassium carbonate was added to 2-[(1',
3'-dimethylxanthine-7'-yl)methyl]-
A solution of 0.5 g of 3-(3',4'-diacetoxy)cinnamoyl-thiazolidine in 5 ml of ethanol was added and the suspension was stirred for 2 hours. The solvent was evaporated under vacuum and the residue was partitioned between aqueous sodium hydrogen phosphate and chloroform. Wash with water until neutral, dry the organic phase over sodium sulfate,
Evaporated to dryness under vacuum. The resulting residue was crystallized from ethyl ether to give 2-[(1',
3'-dimethylxanthine-7'-yl)methyl]-
0.2 g of 3-(3',4'-dihydroxy)cinnamoyl-thiazolidine was obtained. Example 24 2-[(3',7'-dimethylxanthine-1'-yl)
2-[(3â²,7â²-dimethylxanthine-1â²-yl)methyl]-3-(3â²,
4'-dihydroxy)cinnamoyl-thiazolidine was obtained. Example 25 Contains 2.26 g of dicyclohexylcarboimide
A solution of 10 ml of DMF was added to 2.81 g of 2-[(1â²,3â²-dimethylxanthine-7â²-yl)methyl]thiazolidine,
A suspension of 1.28 g of N-acetylcysteine and 4-dimethylamino-pyridine in 25 ml of DMF was added with stirring and cooling at 0°C. 12 hours later,
After the usual work-up, in which the dicyclohexyl urea was filtered off and the solvent was concentrated in vacuo, the residue was crystallized from isopropanol to give 2-
3.5 g of [(1',3'-dimethylxanthine-7'-yl)methyl]-3-(N-acetylglycinyl)thiazolidine was obtained. In a similar manner, using 2-[(3â²,7â²-dimethylxanthine-1â²-yl)methyl]thiazolidine, 2-[(3â²,7â²-dimethylxanthine-1â²-yl)methyl] -3-(N-acetylglycinyl)thiazolidine was obtained. Example 26 In a similar manner to Example 25, 25 g of N-formylglycine was reacted with the appropriate thiazolidine to give the following product. 2-[(1â²,3â²-dimethylxanthine-7â²-yl)
methyl]-3-(N-formylglycinyl)thiazolidine 2-[(3',7'-dimethylxanthine-1'-yl)
Methyl]-3-(N-formylglycinyl)thiazolidine A solution of the last N-formylglycinyl derivative in methanol is mixed with a solution of 8N hydrochloric acid in methanol and a solution of 8N hydrochloric acid in isopropanol at room temperature. Process for 8 hours and reduce to 1/3 of the original volume.
The mixture was concentrated to give 2-[(1',3'-dimethylxanthine-7'-yl)methyl]-3-(glycinyl)thiazolidine hydrochloride. Example 27 3,5-dibromo-salicylaldehyde 2.79
g, 2-[(1â²,3â²-dimethylxanthine-7â²-yl)methyl]-3-(glycinyl)thiazolicine
A solution of 3.6 g and 1.38 ml of triethylamine in 250 ml of methanol was heated with stirring at reflux temperature for 3 hours and then cooled to room temperature. 2-
To precipitate [(1â²,3â²-dimethylxanthine-7â²-yl)methyl]-3-[2â²-(3â³,5â³-dibromo-2â³-hydroxy-benzylidene-amino)acetyl-thiazolidine , stirring was continued for 8 hours.
10% sodium borohydride supported on 8 g of alumina in dichloroethane containing 5.3 g of this compound
Added to 250ml of solution with stirring. 6 hours later,
The organic phase was filtered, washed with water and dried over sodium sulfate. Next, it was treated with 4.8 ml of isopropanol containing 8N-hydrochloric acid, and 2-[(1',3'-dimethylxanthine-7'-yl)methyl]-3-[(3',
4.7 g of 5'-dibromo-6'-hydroxyphenyl)methyl-aminoacetyl]-thiazolidine were obtained. Example 28 0.88 ml of acryloyl chloride was cooled to 0°C, 2.8 g of 2-[(1',3'-dimethylxanthine-7'-yl)methyl]thiazolisine, 1.52 ml of triethylamine and 50 ml of anhydrous methylene chloride.
was added dropwise to the mixture under stirring. The mixture was warmed to room temperature and heated to reflux for 1 hour. The organic phase was washed sequentially with water, 5% sodium hydroxide, and then water. After drying over sodium sulfate, the solvent was evaporated to dryness under vacuum and the crude product was crystallized from isopropyl alcohol to give 2-
2.7 g of [(1',3'-dimethylxanthine-7'-yl)methyl]-3-(propenoyl)thiazolidine was obtained. Example 29 2-(2-aminoethylamino)ethanol
0.21ml of 2-[(1',3'-dimethylxanthine-
7'-yl)methyl]-3-(propenoyl)thiazolidine in 10 ml of ethanol and the solution was refluxed for 2 hours. The solvent was evaporated to dryness under vacuum and the crude product was dissolved in methylene chloride 20
The resulting solution was washed twice with 10 ml of water, dried over sodium sulfate and the solvent was evaporated to dryness under vacuum. The crude product solid was crystallized from ethanol,
2-[(1â²,3â²-dimethylxanthine-7â²-yl)methyl]-3-[3â²-(2â³-hydroxyethyl-aminoethyl-amine)propionyl]thiazolidine with a melting point of 140-142°C was obtained. In the same manner as this, 2-[(1',3'-dimethylxanthine-7'-yl) was prepared using N-(2'-hydroxyethyl)piperazine and imidazole.
methyl]-3-[3â²-[2â³-hydroxyethylpiperazin-1â³-yl)propionyl]thiazolidine and 2-[(1â²,3â²-dimethylxanthine-7â²-yl)
methyl]-3-[3â²-(imidazol-1â³-yl)
propionyl]thiazolidine, respectively. Example 30 N,N'-dicyclohexylcarbodiimide 2.26
2-[(3â²,7â²-dimethylxanthine-1â²-yl)methyl]thiazolidine 2.81 g cooled to 0°C
g, 3-(2'-morpholinoethyl)thioacetic acid 2.19
g and 0.12 g of 4-dimethylaminopyridine in 30 ml of DMF. After 12 hours, the dicyclohexylurea was removed by filtration, the organic phase was concentrated in vacuo and the residue dissolved in 150 ml of chloroform was washed with a 5% aqueous sodium bicarbonate solution and then with water and dried over sodium sulfate. The solvent was removed under vacuum and the oily residue was crystallized from ethanol to give 2-[(1â²,3â²-dimethylxanthine-7â²-yl)methyl]-3-[3â²-(2â³-morpholin). 3.5 g of 2-[(1â²,3â²-dimethylxanthine-7â²-yl)methyl]-3-[2â²-(4â³-methyl-piperazinoethyl) ) thioacetyl]thiazolidine was produced. Example 31 2-[(1',3'-dimethylxanthine-7'-yl)
Methyl]-3-(triphenylphosphylidene)-
A solution of 0.9 g of methyl-carbonyl)thiarizone in 6 ml of anhydrous DMSO was treated with 0.38 g of 3-morphorinylmethyl-4-hydroxy-5-methoxy-benzaldehyde at room temperature under stirring. After 24 hours, the mixture was diluted with 50 ml of chloroform and washed with water. The organic phase was dried over sodium sulfate and concentrated under vacuum. Crystallization several times from ethyl acetate and then from ethanol gives pure 2-[(1â²,3â²-dimethylxanthine-7â²-
0.7 g of cinnamoyl]thiazolidine was obtained. The following compounds were produced in a similar manner. 2-[(1â²,3â²-dimethylxanthine-7â²-yl)
methyl]-3-[(3'-pyrrolidinylmethyl-4'-
hydroxy-5â²-methoxy)cinnamoyl]thiazolidine 2-[(1â²,3â²-dimethylxanthine-7â²-yl)
methyl]-3-[(3'-dimethylamino-methyl-
4â²-hydroxy-5â²-methoxy)cinnamoyl]
Thiazolidine Example 32 In the same manner as in Example 31, 2 as aldehyde
The following compound was obtained using -(4'-methylpiperazin-1'-yl)ethanal, 2-(morpholin-1'-yl)ethanal and p-fluorobenzaldehyde. 2-[(1â²,3â²-dimethylxanthine-7â²-yl)
methyl]-3-(5-morphorinyl)-2-butenoyl-thiazolidine 2-[(1',3'-dimethylxanthine-7'-yl)
methyl]-3-[(4'-methylpiperazin-1'-yl)-2-butenoyl]thiazolidine 2-[(1',3'-dimethylxanthine-7'-yl)
methyl]-3-(4â²-fluoro)cinnamoyl-thiazolidine Example 33 Phenoxyacetic acid, (2â²-ethoxy-ethyloxy)acetic acid, and (2â²-diethylamino-ethyloxy) were prepared as acids in a similar manner to Examples 25 and 26. ) The following compounds were produced using acetic acid. 2-[(1â²,3â²-dimethylxanthine-7â²-yl)
methyl]-3-phenoxyacetyl-thiazolidine 2-[(1',3'-dimethylxanthine-7'-yl)
methyl]-3-[(2'-ethoxy)-ethyloxyacetyl]thiazolidine 2-[(1',3'-dimethylxanthine-7'-yl)
methyl]-3-[(2-diethylamino)ethyloxy-acetyl]thiazolidine Example 34 Cystamine hydrochloride 1.13 g under inert gas atmosphere
2-[(1â²,3â²-dimethylxanthine-7â²-yl)
2.6 g of methyl]-3-propenoyl-thiazolidine
The mixture was treated with 100 ml of methanol containing 100 ml of alcohol at reflux temperature for 8 hours. The reaction mixture was cooled and after 2 days the crystalline precipitate was filtered and 2-[(1',3'-dimethylxanthine-7'-
yl)methyl]-3-[3â²-(2â³-ethyl-amino-thio)propionyl]thiazolidine hydrochloride 3.5
I got g. In a similar manner, 2-[(1â²,3â²-dimethylxanthine-7â²-yl)methyl]- 3-[(4â²-thia-5â²-
carboxy-5-acetylamino)hexanoyl]
I received thiazolidine. Example 35 2.5 g of N-acetylcysteine disodium salt
A solution in 20 ml of methanol containing 2-[(1',3'-dimethylxanthine-7'-yl)methyl]-3-chloroacetyl-thiazolidine containing 3 g
Treated with a solution of 10 ml of DMSO. After being kept at room temperature for 3 hours, the mixture was evaporated and the residue was partitioned between chloroform and 20% aqueous sodium hydrogen phosphate. 2-[(1',3'-dimethylxanthine-7'-yl) was extracted from the organic phase after conventional treatment.
methyl]-3-(3'thia-5'-carboxy-5'-acetylamino-pentanoyl)thiazolidine was obtained.
Claims (1)
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å»è¬çµæç©ã[Claims] 1 Formula (): (In the formula, R is 1,3-dimethylxanthine-7
-yl or 3,7-dimethylxanthine-1-
R 2 is an oxygen atom or a free or esterified carboxyl group; R 3 and R 4 are a hydrogen atom or a methyl group; P is 0 or 1; R 1 is a hydrogen atom, alkylsulfonyl having 1 to 2 carbon atoms; group, unsubstituted or mono- or polysubstituted phenylsulfonyl group, formula [formula] (wherein R 5 is a hydrogen atom, (-CH 2 ) -o Q or [formula] (wherein n is 0 or an integer of 1 to 7; P 1 and P 2 are both hydrogen atoms or one of them is a hydrogen atom and the other is a lower alkyl group having 1 to 4 carbon atoms or a phenyl group; Q is a hydrogen atom;
Alkyl group having ~4 branched chains; cycloalkyl group having 3 to 7 carbon atoms; free or esterified carboxyl group; halogen atom; SH; NH2 ;
A mono- or di-substituted amino group, a t-butoxycarbonylamino group, or an acrylamino group having 1 to 2 carbon atoms; an ether group represented by an O-T chain, a thioether group represented by an S-T chain (where T is an unsubstituted or mono- or polysubstituted phenyl ring or a formula ( CH2 ) -nT1 (wherein T1 is H, OH, OCH3 ,
OC2H5 , HOCH2 - CH2- , free or esterified carboxyl group, NH2 , carbon number 1-2
(acrylamino group or mono- or di-substituted amino group) and the formula [formula] (wherein Re represents a hydrogen atom, a methyl group, or an ethyl group), m is an integer of 1 to 3 phenyl, phenoxy or phenylthio ring, unsubstituted or mono- or polysubstituted in meta, ortho and para positions;
) -n SCO( -CH2 ) -o P3 (wherein, m and n are the same as above, P3 is a linear or branched alkyl chain having 1 to 7 carbon atoms, 3 to 6 carbon atoms a cycloalkyl group, a substituted amino group, a phenyl group or a phenoxy ring optionally mono- or polysubstituted at the ortho, meta and para positions; and a compound represented by the formula: (wherein T may be a hydrogen atom in addition to the above definition); a mono-substituted amino group has 1 to 6 carbon atoms; an alkyl group having a straight or branched chain or -CH2 - CH2- O- CH2 - CH3 , -CH2 - CH2- O- CH2 - CH2 -OH, -CH2 - CH2 âNHâCH 2 âCH 3 , âCH 2 âCH 2 âNHâCH 2 âCH 2 âOH or represents an amino group substituted with a group represented by morphonyl-1
-yl, pyrrolidin-1-yl, piperazine-1
-yl, 4-methyl-piperazin-1-yl, thiomorpholin-1-yl, 4-ethyl-piperazin-1-yl, 4-(2'-fluorophenyl)piperazin-1-yl, imidazol-1-yl Ile, 3
- represents an unsaturated or saturated nitrogen ring such as pyridyl or 4-pyridyl;
A mono- or polysubstituted phenyl group is a phenyl group substituted in the para position by a fluorine atom, in the meta and/or para position by a chlorine atom, or in the meta position by CF3 , or : (In the formula, Z 1 is H or COCH 3 , Z 2 is H, CH 3
or COCH 3 and P 4 are hydrogen atoms, aminomethyl groups, and P 4 has 1 carbon number as defined above.
- 2 acylaminomethyl groups or a group selected from the group consisting of mono- or di-substituted aminomethyl groups; 2 Claims in which R 2 , R 3 and R 4 are hydrogen atoms, and R 1 is an acyl group represented by the formula R 5 CO (wherein R 5 is as defined above) Xanthinenylmethylthiazolidine according to item 1. 3. The xanthinenylmethylthiazolidine according to claim 1, wherein in formula (), R 2 , R 3 and R 4 are hydrogen atoms, and R 1 is a substituted or unsubstituted cinnamoyl group. 4 The compound of formula () is 2-[(1',3'-dimethylxanthine-7'-yl)
2-[(3â²,7â²-dimethylxanthine-1â²-yl)
2-[(1â²,3â²-dimethylxanthine-7â²-yl)
methyl]thiazolidine; 2-[(3â²,7â²-dimethylxanthine-1â²-yl)
methyl]thiazolidine; 2-[(1â²,3â²-dimethylxanthine-7â²-yl)
methyl]-3-(imidazol-1'-yl)acetyl]thiazolidine;2-[(3',7'-dimethylxanthine-1'-yl)
methyl]-3-(imidazol-1'-yl)acetyl]thiazolidine;2-[(1',3'-dimethylxanthine-7'-yl)
methyl]-3-[(3â²,4â²-hydroxy)cinnamoyl]thiazolidine; 2-[(3â²,7â²-dimethylxanthine-1â²-yl)
methyl]-3[(3â²,4â²-dihydroxy)cinnamoyl]thiazolidine; 2-[(1â²,3â²-dimethylxanthine-7â²-yl)
methyl]-3-(3'-methoxy-4'-hydroxy)
Cinnamoyl-thiazolidine; 2-[(3',7'-dimethylxanthine-1'-yl)
methyl]-3-(3'-methoxy-4'-hydroxy)
Cinnamoyl-thiazolidine; 2-[(3',7'-dimethylxanthine-1'-yl)
methyl]-3-[3â²-(4â³-hydroxyethylpiperazin-1â³-yl)propynyl]thiazolidine; 2-[1â²,3â²-dimethylxanthine-7â²-yl)
methyl]-3-(3'-morpholinomethyl-4'-hydroxy-3'-methoxy-cinnamoyl)thiazolidine;2-[(1',3'-dimethylxanthine-7'-yl)
2-[(3â²,7â²-dimethylxanthine-1â²-yl)
methyl]-3-[3'-pyrrolidinylmethyl-4'-hydroxy-3'-methoxy-cinnamoyl)thiazolidine;2-[(1',3'-dimethylxanthine-7'-yl)
methyl]-3-[3'-thia-5'-carboxy-5'-
acetylamino-pentanoyl]thiazolidine;2-[(1',3'-dimethylxanthine-7'-yl)
methyl]-3-[4'-thia-6'-carboxy-6'-
acetyl-amino-hexanoyl]thiazolidine;2-[(1',3'-dimethylxanthine-7'-yl)
methyl]-3-[3â²-(2â³-ethoxyethyloxy)
acetyl]thiazolidine; 2-[(1',3'-dimethylxanthine-7'-yl)
methyl]-3-[3'-(imidazol-1'-yl)
2-[(1â²,3â²-dimethylxanthine-7â²-yl)
methyl]-3-glycinyl-thiazolidine; 2-[(3',7'-dimethylxanthine-1'-yl)
methyl]-3-glycinyl-thiazolidine; 2-[(1',3'-dimethylxanthine-7'-yl)
methyl]-3-(N-acetyl)glycinyl-thiazolidine; 2-[(1',3'-dimethylxanthine-7'-yl)
methyl]-3-[3â²-(2â³-hydroxyethylamino)ethylamino-propionyl]thiazolidine; 2-[(3â²,7â²-dimethylxanthine-1â²-yl)
methyl]-3-[3â²-(2â³-hydroxyethylamino)ethylamino-propionyl]thiazolidine; and 2-[(1â²,3â²-dimethylxanthine-7â²-yl)
The xanthinelmethylthiazolidine according to claim 1, which is a compound selected from the group consisting of methyl]-3-[3'-(4''-hydroxyethylpiperazin-1''-yl)propionyl]thiazolidine. 5 Formula (): (In the formula, R is 1,3-dimethylxanthine-7
-yl or 3,7-dimethylxanthine-1-
yl, Y and Y' each represent an alkoxy group having 1 to 2 carbon atoms, or together represent a carboxyl group) with the formula (): (wherein, R 2 is an oxygen atom or a free or esterified carboxyl group; R 3 and R 4 are a hydrogen atom or a methyl group), and the resulting formula (a) : (wherein R, R 2 , R 3 , R 4 represent the groups defined above), then optionally succinic anhydride, glutaric anhydride or formulas (a), (b), (c ) Q(-CH 2 )- o COZ (a) P 5 -SO 2 -Hal (c) (wherein, n is 0 or an integer of 1 to 7; P 1 and P 2 are both hydrogen atoms, or one of them is a hydrogen atom, and the other has 1 to 4 carbon atoms. lower alkyl group or phenyl group, Q is hydrogen atom; carbon number 3
Alkyl group having ~4 branched chains; cycloalkyl group having 3 to 7 carbon atoms; free or esterified carboxyl group; halogen atom; SH; NH2 ;
Mono- or di-substituted amino group; t-butoxycarbonylamino group or acrylamino group having 1 to 2 carbon atoms; ether group represented by an O-T chain, thioether group represented by an S-T chain (where T is an unsubstituted or mono- or polysubstituted phenyl ring or a compound of the formula (CH 2 ) ân T 1 , in which
T 1 is H, OH, OCH 3 , OC 2 H 5 , HOCH 2 âCH 2
-, free or esterified carboxyl group, NH 2 , acrylamino group having 1 to 2 carbon atoms or mono- or di-substituted amino group) and formula [formula] (where Re is a hydrogen atom, a methyl group or an ethyl phenyl, phenoxy or phenylthio rings, unsubstituted or mono- or polysubstituted in the meta, ortho and para positions; Formula ( -CH2 ) -n SCO( -CH2 ) -o
P 3 (where m and n are the same as above, P 3 is a linear or branched alkyl chain having 1 to 7 carbon atoms,
A compound represented by a cycloalkyl group having 3 to 6 carbon atoms, a substituted amino group, a phenyl group or a phenoxy ring optionally mono- or polysubstituted at the ortho, meta and para positions; and the formula: (wherein T may be a hydrogen atom in addition to the above definition), P 5 is an alkyl group having 1 to 2 carbon atoms or a substituted a mono- or polysubstituted phenyl ring, Hal is a halogen atom, Z is a halogen atom, an azide, an activated ester or an anhydride); (In the formula, R is 1,3-dimethylxanthine-7
-yl or 3,7-dimethylxanthine-1-
R 2 is an oxygen atom or a free or esterified carboxyl group; R 3 and R 4 are a hydrogen atom or a methyl group; P is 0 or 1; R 1 is a hydrogen atom, alkylsulfonyl having 1 to 2 carbon atoms; group, unsubstituted or mono- or polysubstituted phenylsulfonyl group, formula [formula] (wherein R 5 is a hydrogen atom, (-CH 2 ) -o Q or [formula] (wherein n is 0 or an integer of 1 to 7; P 1 and P 2 are both hydrogen atoms or one of them is a hydrogen atom and the other is a lower alkyl group having 1 to 4 carbon atoms or a phenyl group; Q is a hydrogen atom; Alkyl group having ~4 branches; cycloalkyl group having 3 to 7 carbon atoms; free or esterified carboxyl group; halogen atom; SH; NH2 ; mono- or di-substituted amino group, t-butoxy Carbonylamino group or acrylamino group having 1 to 2 carbon atoms; ether group represented by an O-T chain, S-T
a thioether group represented by a chain, where T is an unsubstituted or mono- or polysubstituted phenyl ring or a group of the formula ( CH2 ) -nT1 , where T1 is H ,
OH, OCH3 , OC2H5 , HOCH2 - CH2- , free or esterified carboxyl group, NH2 ,
(acrylamino group or mono- or di-substituted amino group having 1 to 2 carbon atoms) and the formula [formula] (wherein Re represents a hydrogen atom, a methyl group, or an ethyl group), m is 1-3
phenyl, phenoxy or phenylthio ring, unsubstituted or mono- or polysubstituted in the meta, ortho and para positions; formula ( -CH2 ) -n SCO( -CH2 ) -o P3 (In the formula, m and n are the same as above, P 3 is a linear or branched alkyl chain having 1 to 7 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a substituted amino group, ortho, (representing a phenyl group or phenoxy ring optionally mono- or polysubstituted at the meta- and para-positions); and a compound represented by the formula: (wherein T may be a hydrogen atom in addition to the above definition); a mono-substituted amino group has 1 to 6 carbon atoms; an alkyl group having a straight or branched chain or -CH2 - CH2- O- CH2 - CH3 , -CH2 - CH2- O- CH2 - CH2 -OH, -CH2 - CH2 âNHâCH 2 âCH 3 , âCH 2 âCH 2 âNHâCH 2 âCH 2 âOH or Represents an amino group substituted with a group represented by morphonyl-1
-yl, pyrrolidin-1-yl, piperazine-1
-yl, 4-methyl-piperazin-1-yl, thiomorpholin-1-yl, 4-ethyl-piperazin-1-yl, 4-(2'-fluorophenyl)piperazin-1-yl, imidazol-1-yl Ile, 3
- represents an unsaturated or saturated nitrogen ring such as pyridyl or 4-pyridyl;
A mono- or polysubstituted phenyl group is a phenyl group substituted in the para position by a fluorine atom, in the meta and/or para position by a chlorine atom, or in the meta position by CF3 , or : (In the formula, Z 1 is H or COCH 3 , Z 2 is H, CH 3
or COCH 3 and P 4 are hydrogen atoms, aminomethyl groups, and P 4 has 1 carbon number as defined above.
-2 acylaminomethyl groups or a group selected from the group consisting of mono- or di-substituted aminomethyl groups). 6 Formula (e): (In the formula, R is 1,3-dimethylxanthine-7
-yl or 3,7-dimethylxanthine-1-
R2 is an oxygen atom or a free or esterified carboxyl group; R3 and R4 are a hydrogen atom or a methyl group; P represents 0 or 1)
A compound represented by the formula (): T-CHO ... () (wherein T is an unsubstituted mono- or polysubstituted phenyl ring or a formula (CH 2 ) -n T 1 (wherein, T 1 are H, OH, OCH 3 , OC 2 H 5 , HOCH 2 â
CH 2 -, free or esterified carboxyl group, NH 2 , acrylamino group having 1 to 2 carbon atoms or mono- or di-substituted amino group) and formula [formula] (where Re is a hydrogen atom, a methyl group or (indicating a group selected from the group consisting of (indicating an ethyl group)), and the resulting compound has the formula ; ,
T 1 is H, OH, OCH 3 , OC 2 H 5 , HOCH 2 âCH 2
-, free or esterified carboxyl group, NH 2 , acrylamino group having 1 to 2 carbon atoms or mono- or di-substituted amino group) and formula [formula] (where Re is a hydrogen atom, a methyl group or an ethyl group) HS(-CH 2 ) -o T 1 (in which n
is 0 or an integer of 1 to 7, T 1 is the same as above) thiol, optionally subjected to a Michael reaction with a nucleophilic compound selected from the group consisting of mono- or di-substituted thiophenol. The expression (): (In the formula, R 1 is -CH=CH-T; R 2 , R 3 , R 4 ,
R and P are the same as above). 7 Formula (d) (In the formula, R is 1,3-dimethylxanthine-7
-yl or 3,7-dimethylxanthine-1-
R 2 is an oxygen atom or a free or esterified carboxyl group; R 3 and R 4 are a hydrogen atom or a methyl group; P is 0 or 1; at least one of P 1 and P 2 is a hydrogen atom, the other is a hydrogen atom, methyl group or phenyl group, Q ' is a halogen atom, n preferably represents 0 ) ; as defined above,
Base represents an alkali or alkaline earth metal, lower trialkylammonium or phenyl dialkylammonium), and the resulting compound is reacted with ammonia to form the formula: Q=SH (wherein, Q is the same as above), which can be optionally alkylated with an alkyl halide in the presence of a base; (In the formula, R, R 2 , R 3 , R 4 and S are the same as above;
R 1 is a formula: [Formula] (where n is 0 or an integer from 1 to 7, P 1 and P 2 are both hydrogen atoms, or one of them is a hydrogen atom and the other is a hydrogen atom with a carbon number of 1 to 4. Lower alkyl group or phenyl group; Q' is SH, alkylthioether group or formula: P 3 (-CH 2 )- o COS (in the formula,
P3 is a linear or branched alkyl chain having 1 to 7 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms,
substituted amino group, phenyl group or phenoxy ring optionally mono- or polysubstituted at the ortho, meta and para positions, n and S are the same as above)
). 8 Formula for therapeutically effective amount (): (In the formula, R is 1,3-dimethylxanthine-7
-yl or 3,7-dimethylxanthine-1-
R2 is an oxygen atom or a free or esterified carboxyl group; R3 and R4 are a hydrogen atom or a methyl group; P is 0 or 1; R1 is a hydrogen atom, alkylsulfonyl having 1 to 2 carbon atoms; group, unsubstituted or mono- or polysubstituted phenylsulfonyl group, formula [formula] (wherein R 5 is a hydrogen atom, (-CH 2 ) -o Q or [formula] (wherein n is 0 or an integer from 1 to 7; P 1 and P 2 are both hydrogen atoms, or one of them is a hydrogen atom and the other has 1 carbon number
~4 lower alkyl group or phenyl group, Q is a hydrogen atom; a branched alkyl group having 3 to 4 carbon atoms; a cycloalkyl group having 3 to 7 carbon atoms; a free or esterified carboxyl group; a halogen atom ; SH; NH 2 ; Mono- or di-substituted amino group, t-butoxycarbonylamino group or acrylamino group having 1 to 2 carbon atoms; ether group represented by an OT chain, represented by an S-T chain a thioether group (where T is an unsubstituted or mono- or polysubstituted phenyl ring or a formula ( CH2 ) -nT1 , where T1 is H, OH, OCH3 ,
OC2H5 , HOCH2 - CH2- , free or esterified carboxyl group, NH2 , carbon number 1-2
(acrylamino group or mono- or di-substituted amino group) and a group selected from the group consisting of the formula âCH | NH 2 âCO 2 Re (wherein Re represents a hydrogen atom, a methyl group or an ethyl group), m is 1~
(representing an integer of 3); unsubstituted or mono- or polysubstituted phenyl, phenoxy or phenylthio ring in the meta, ortho and para positions; formula ( CH2 ) -n SCO( -CH2 ) -o P3 (In the formula, m and n are the same as above, P 3 is a linear or branched alkyl chain having 1 to 7 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a substituted amino group, ortho, (representing a phenyl group or phenoxy ring optionally mono- or polysubstituted at the meta- and para-positions); and a compound represented by the formula: (wherein T may be a hydrogen atom in addition to the above definition); a mono-substituted amino group has 1 to 6 carbon atoms; an alkyl group having a straight or branched chain or -CH2 - CH2- O- CH2 - CH3 , -CH2 - CH2- O- CH2 - CH2 -OH, -CH2 - CH2 âNHâCH 2 âCH 3 , âCH 2 âCH 2 âNHâCH 2 âCH 2 âOH or represents an amino group substituted with a group represented by morphonyl-1
-yl, pyrrolidin-1-yl, piperazine-1
-yl, 4-methyl-piperazin-1-yl, thiomorpholin-1-yl, 4-ethyl-piperazin-1-yl, 4-(2'-fluorophenyl)piperazin-1-yl, imidazol-1-yl Ile, 3
- represents an unsaturated or saturated nitrogen ring such as pyridyl or 4-pyridyl;
A mono- or polysubstituted phenyl group is a phenyl group substituted in the para position by a fluorine atom, in the meta and/or para position by a chlorine atom, or in the meta position by CF3 , or : (In the formula, Z 1 is H or COCH 3 , Z 2 is H, CH 3
or COCH 3 and P 4 are hydrogen atoms, aminomethyl groups, and P 4 has 1 carbon number as defined above.
-2 acylaminomethyl groups or a group selected from the group consisting of mono- or di-substituted aminomethyl groups). A pharmaceutical composition having a mucus regulating effect, a bronchodilator effect and/or an antitussive effect.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT22088A/84 | 1984-07-27 | ||
IT8422088A IT1213197B (en) | 1984-07-27 | 1984-07-27 | XANTYLMETHYL-THIAZOLIDINE AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
IT21323A/85 | 1985-06-27 |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS6169777A JPS6169777A (en) | 1986-04-10 |
JPH0335320B2 true JPH0335320B2 (en) | 1991-05-27 |
Family
ID=11191324
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP16661985A Granted JPS6169777A (en) | 1984-07-27 | 1985-07-26 | Xanthinylmethylthiazolidine, manufacture and medicinal composition |
Country Status (2)
Country | Link |
---|---|
JP (1) | JPS6169777A (en) |
IT (1) | IT1213197B (en) |
-
1984
- 1984-07-27 IT IT8422088A patent/IT1213197B/en active
-
1985
- 1985-07-26 JP JP16661985A patent/JPS6169777A/en active Granted
Also Published As
Publication number | Publication date |
---|---|
IT8422088A0 (en) | 1984-07-27 |
JPS6169777A (en) | 1986-04-10 |
IT1213197B (en) | 1989-12-14 |
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