CH514621A - (A) 2,3-Dihydrothieno(3, 2-c) quinolines of general formula (I): (I) R = H or lower alkyl (B) Pharmaceutically acceptable, non-toxic acid addition - Google Patents
(A) 2,3-Dihydrothieno(3, 2-c) quinolines of general formula (I): (I) R = H or lower alkyl (B) Pharmaceutically acceptable, non-toxic acid additionInfo
- Publication number
- CH514621A CH514621A CH117471A CH117471A CH514621A CH 514621 A CH514621 A CH 514621A CH 117471 A CH117471 A CH 117471A CH 117471 A CH117471 A CH 117471A CH 514621 A CH514621 A CH 514621A
- Authority
- CH
- Switzerland
- Prior art keywords
- lower alkyl
- dihydrothieno
- parts
- quinoline
- quinolines
- Prior art date
Links
- 239000002253 acid Substances 0.000 title claims abstract description 8
- 125000000217 alkyl group Chemical group 0.000 title claims abstract description 4
- 231100000252 nontoxic Toxicity 0.000 title abstract description 5
- 230000003000 nontoxic effect Effects 0.000 title abstract description 5
- WUDTTZKUHIULJE-UHFFFAOYSA-N 2,3-dihydrothieno[3,2-c]quinoline Chemical class S1CCC=2C=NC=3C=CC=CC3C21 WUDTTZKUHIULJE-UHFFFAOYSA-N 0.000 title abstract 2
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- KQBIVXHSVQZFHG-UHFFFAOYSA-N 2-methyl-2,3-dihydrothieno[3,2-c]quinoline Chemical compound C1=CC=CC2=C(SC(C)C3)C3=CN=C21 KQBIVXHSVQZFHG-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims description 13
- 150000001875 compounds Chemical class 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 5
- CQMCNAJHSNWQMJ-UHFFFAOYSA-N thieno[3,2-c]quinoline Chemical class C1=CC=CC2=C(SC=C3)C3=CN=C21 CQMCNAJHSNWQMJ-UHFFFAOYSA-N 0.000 claims description 4
- CYQAYERJWZKYML-UHFFFAOYSA-N phosphorus pentasulfide Chemical compound S1P(S2)(=S)SP3(=S)SP1(=S)SP2(=S)S3 CYQAYERJWZKYML-UHFFFAOYSA-N 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 239000012442 inert solvent Substances 0.000 claims description 2
- 206010037660 Pyrexia Diseases 0.000 claims 1
- 239000002552 dosage form Substances 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- 230000001754 anti-pyretic effect Effects 0.000 abstract description 8
- 230000000202 analgesic effect Effects 0.000 abstract description 7
- 239000002221 antipyretic Substances 0.000 abstract description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 5
- 231100000053 low toxicity Toxicity 0.000 abstract description 3
- 238000004821 distillation Methods 0.000 abstract description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 abstract 2
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 abstract 2
- ROYCCMJSURLMLI-UHFFFAOYSA-N 1h-quinoline-4-thione Chemical compound C1=CC=C2C(S)=CC=NC2=C1 ROYCCMJSURLMLI-UHFFFAOYSA-N 0.000 abstract 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 abstract 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 abstract 1
- 239000000706 filtrate Substances 0.000 abstract 1
- 150000007522 mineralic acids Chemical class 0.000 abstract 1
- 239000000203 mixture Substances 0.000 abstract 1
- 150000007524 organic acids Chemical class 0.000 abstract 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- RMMXTBMQSGEXHJ-UHFFFAOYSA-N Aminophenazone Chemical compound O=C1C(N(C)C)=C(C)N(C)N1C1=CC=CC=C1 RMMXTBMQSGEXHJ-UHFFFAOYSA-N 0.000 description 5
- 229960000212 aminophenazone Drugs 0.000 description 5
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 4
- 150000003248 quinolines Chemical class 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- JFPBCBAMFPANBZ-UHFFFAOYSA-N Cl.CC1=NC=2C=CC=CC2C2=C1CCS2 Chemical compound Cl.CC1=NC=2C=CC=CC2C2=C1CCS2 JFPBCBAMFPANBZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229940111121 antirheumatic drug quinolines Drugs 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 2
- YFIMNPZPBHQASL-UHFFFAOYSA-N Cl.CC1CC=2C=NC=3C=CC=CC3C2S1 Chemical compound Cl.CC1CC=2C=NC=3C=CC=CC3C2S1 YFIMNPZPBHQASL-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000000730 antalgic agent Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- NNBZCPXTIHJBJL-UHFFFAOYSA-N decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N thiocyanic acid Chemical compound SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- AXOPWCYFUSVLBN-UHFFFAOYSA-N 2-ethyl-2,3-dihydrothieno[3,2-c]quinoline Chemical compound C(C)C1CC=2C=NC=3C=CC=CC3C2S1 AXOPWCYFUSVLBN-UHFFFAOYSA-N 0.000 description 1
- RLQZIECDMISZHS-UHFFFAOYSA-N 2-phenylcyclohexa-2,5-diene-1,4-dione Chemical compound O=C1C=CC(=O)C(C=2C=CC=CC=2)=C1 RLQZIECDMISZHS-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- WNAYNOQYMHSGBS-UHFFFAOYSA-N 4-methylthieno[3,2-c]quinoline Chemical class CC1=NC2=CC=CC=C2C2=C1C=CS2 WNAYNOQYMHSGBS-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- RWKWSVQXBFLCPF-UHFFFAOYSA-N C(C(C)C)C1CC=2C=NC=3C=CC=CC3C2S1 Chemical compound C(C(C)C)C1CC=2C=NC=3C=CC=CC3C2S1 RWKWSVQXBFLCPF-UHFFFAOYSA-N 0.000 description 1
- HTEICRMETFJQTJ-UHFFFAOYSA-N C(CC)C1CC=2C=NC=3C=CC=CC=3C=2S1 Chemical compound C(CC)C1CC=2C=NC=3C=CC=CC=3C=2S1 HTEICRMETFJQTJ-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000003555 analeptic effect Effects 0.000 description 1
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 description 1
- -1 compound 4-methyl-2,3-dihydrothieno [3.2 -c] quinoline hydrochloride Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- PSXRWZBTVAZNSF-UHFFFAOYSA-N hydron;quinoline;chloride Chemical compound Cl.N1=CC=CC2=CC=CC=C21 PSXRWZBTVAZNSF-UHFFFAOYSA-N 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- PMZDQRJGMBOQBF-UHFFFAOYSA-N quinolin-4-ol Chemical compound C1=CC=C2C(O)=CC=NC2=C1 PMZDQRJGMBOQBF-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- PXXNTAGJWPJAGM-UHFFFAOYSA-N vertaline Natural products C1C2C=3C=C(OC)C(OC)=CC=3OC(C=C3)=CC=C3CCC(=O)OC1CC1N2CCCC1 PXXNTAGJWPJAGM-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/36—Sulfur atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
(A) 2,3-Dihydrothieno(3, 2-c) quinolines of general formula (I): - (I) R = H or lower alkyl - (B) Pharmaceutically acceptable, non-toxic acid addition salts of (I) with organic- and inorganic acids - (I) have antipyretic and analgesic activity with very low toxicity. - To a solution of 3.7 parts 4-mercaptoquinoline in 70 parts ethanol in which 0.76 parts sodium metal is taken up, 4.0 parts allyl bromide are added and the mixture refluxed for 5 hours. After removing the precipitated sodium bromide, the filtrate is concentrated under reduced pressure and the residue extracted with chloroform. The extract is worked up and the oily residue purified by distillation under reduced pressure to give 14 parts 2-methyl-2,3-dihydrothieno (3,2-c) quinoline.
Description
Verfahren zur Herstellung von 2-Niederalkyl-2,3-dihydrothieno[3,2-c]chinolinen Die vorliegende Erfindung bezieht sich auf ein Verfahren zur Herstellung von 2-Niederalkyl-2,3,dihydro thieno[3,2-c]chinolinen der Formel
EMI0001.0002
in der R ein Wasserstoffatom oder eine Niederalkyl gruppe, z. B. Methyl, Äthyl, n-Propyl, Isopropyl oder n-Butyl, ist.
Aus diesen Verbindungen der Formel I lassen sich pharmazeutisch annehmbare Salze herstellen.
H. Andersag und Mitarb. haben schon gewisse 4-Methyl-thieno- [3,2-c]chinolin,-Derivate synthetisch hergestellt und gefunden, dass sie infolge ihrer analgetischen und analeptischen Eigenschaften einen chemotherapeutischen Wert aufweisen (vgl. US Patent Nr. 2 650 226).
Die nach dem erfindungsgemäs- sen Verfahren hergestellten 2-Niederalkyl-2,3-dihydro thieno[3,2-c]chinoline (I) sind jedoch verglichen mit den bereits bekannten Thie- nochinolinderivaten strukturell durch die Abwesenheit von Substituenten am Chinolinkern gekennzeichnet. Es wurde nun gefunden, dass die 2-Niederalkyl-2,3-dihydro thieno [3,2-c] chinoline von Formel I eine unerwartet gute antipyretische und analgetische Wirkung aufweisen, die derjenigen der be- reits bekannten Verbindung von H.
Andersag und Mit- arb. trotz der strukturellen Ähnlichkeit und ebenfalls derjenigen eines im Handel erhältlichen Mittels, Ami- nopyrin, merklich überlegen ist. Es wird ferner darauf aufmerksam gemacht, dass die Toxizität der Verbin dungen von Formel I von sehr geringem Grad sind.
Die nach dem erfindungsgemässen Verfahren er hältlichen neuartigen Thieno[3,2-c]chinolin-Derivate obiger Formel I, weisen bei einer niedrigen Toxizität eine starke antipyretische und analgetische Wirkung auf.
Das erfindungsgemässe Verfahren zur Herstellung der genannten Verbindungen der Formel I ist dadurch gekennzeichnet, dass man eine Verbindung der Formel
EMI0001.0046
mit Phosphorpentasulfid bei einer Temperatur von 50-300 C erhitzt.
Das Patent bezieht sich gleichfalls auf die gemäss obigem Verfahren erzeugten Verbindungen der Formel I.
Beispiele der nach .dem erfindungsgemässen Ver fahren hergestellten Verbindungen der Formel I sind 2-Methyl-2,3-dihydro- thieno[3,2-c]chinolin, 2-Äthyl-2,3-dihydro thieno[3,2-c]chinolin, 2-n-Propyl-2,3-dihydro thieno[3,2-c]chinolin, 2-n-Butyl-2,3-dihydro thieno,[3,2-c]chinolin, 2-Isobutyl-2,3-dihydro- thieno[3,2-c]chinolin und dergleichen.
Die Reaktion wird vorzugsweise in einem geeigne ten inerten Lösungsmittel, wie z. B. Benzol, Toluol, Xylol, Dekalin, Naphthalin, Pyridin, Collidin, Chinolin oder Dioxan, durchgeführt. Die Temperatur der Um setzung liegt im Bereich von 50-300 C; vorzugsweise beträgt sie etwa 100-200 C. Es wird angenommen, dass die Umsetzung über die Verbindung der Formel
EMI0002.0006
vor sich geht, doch kann diese letztere aus den oben erwähnten Gründen gewöhnlich nicht isoliert werden.
Da das auf diese Weise hergestellte 2-Niederalkyl-2,3-dihydro- thieno[3,2-c]chinolin (I) gewöhnlich eine Flüssigkeit ist, kann es z. B. durch Be handlung mit einer Säure, wie z. B. Salzsäure, Brom wasserstoffsäure, Jodwasserstoffsäure, Schwefelsäure, Salpetersäure, Phosphorsäure, Thiocyansäure, Kohlen-
EMI0002.0011
Pharmakologische <SEP> Eigenschaft <SEP> Toxizität <SEP> 1) <SEP> Antipyretische <SEP> z) <SEP> Analgetische <SEP> 3)
<tb> <B>Versuchsverbindung</B> <SEP> (1-D50; <SEP> mg/kg) <SEP> Wirkung <SEP> ( <SEP> C) <SEP> Wirkung
<tb> (ED50;
<SEP> mg/kg)
<tb> 2-Methyl-2,3-dihydrothieno[3,2-c]chinolin-hydxochlorid <SEP> 800-1000 <SEP> -5,22 <SEP> 21
<tb> 4-Methyl-2,3-dihydrothieno[3,2-c]chinolin-hydrochlorid <SEP> 260 <SEP> -1,24 <SEP> 60
<tb> Aminopyrin <SEP> 373 <SEP> -2,99 <SEP> 48
<tb> (100 <SEP> mg/kg) Nota bene: 1) Die Toxizität wird durch subkutane Verabreichung an Mäusen bestimmt.
2) Die antipyretische Wirkung wird durch die Herabsetzung der Körpertemperatur von mit einer Dose von 50 mg/kg Versuchsverbindung behandelten Mäusen veranschaulicht.
3) Die analgetische Wirkung wird durch die Hinderung der durch 2-Phenyl-1,4-benzochinon verursachten Streckung bei Mäusen bestimmt. Aus den Angaben der obigen Tabelle geht hervor, dass die antipyretische und analgetische Wirkung von 2-Methyl-2,3-dihydrothieno [3,2-c] chinolin-hydrochlorid bedeutend stärker als diejenige von 4-Methyl-2,3-dihydrothieno [3,2-c]chinolin-hydrochlorid und Aminopyrin ist. Die Toxizität von 2-Methyl-2,3-dihydrothieno säure, Essigsäure, Propionsäure, Oxalsäure, Zitronen säure, Weinsäure, Bernsteinsäure, Salicylsäure, Ben zoesäure oder Palmitirnsäure, in einem geeigneten Lösungsmittel, wie z. B. Wasser, Methanol, Äthanol, Benzol oder Toluol, in sein Säureadditionssalz umge wandelt werden.
Das Ausgangsmaterial, 3-Allyl- oder 3-(γ,-Niederalkyl- allyl)-4-hydroxy-chinolin (II), kann z. B. aus dem bekannten 4-Hydroxychinolin her- gestellt werden, indem dieses mit einem entsprechen den Alkylhalogenid behandelt und das erzielte 4-Allyl- oder 4-(α-Niederalkyl-allyl)-oxachinolin, unter Erhitzen der sogenannten ortho-Claisen-Umlage- rung unterzogen wird.
Das erfindungsgemäss erzeugte 2-Niederalkyl-2,3-dihydro thieno[3,2-c]chinolin (I) und dessen nichttoxische Salze sind als antipyretische und analgetische Mittel nützlich. Die nachstehende Tabelle zeigt bei Tierversuchen erzielte Ergebnisse, und zwar mit 2-Methyl-2,3-dihydrothieno[3,2-c] chinolin-hydrochlorid, der bereits bekannten verwandten Verbindung 4-Methyl-2,3-dihydrothieno [3,2-c] chinolin-hydrochlorid und einem im Handel erhältlichen und häufig verwen deten Mittel, nämlich Aminopyrin.
[3,2-c]chinolin-hydrochlorid ist übrigens etwa 1/3 bis 1/4 so hoch wie diejenige von 4-Methyl-2,3-dihydrothieno [3,2-c]chinolin-hydrochlorid und etwa 1/2 bis 1/3 so hoch wie diejenige von Ami nopyrin.
Die anderen nach dem erfindungsgemässen Verfah ren hergestellten 2-Niederalkyl-2,3-dihydrothieno[3,2-c]chinoline und deren nichttoxische Säureadditionssalze weisen ebenfalls ähnlich gute pharmakologische Eigenschaften auf.
Infolgedessen sind die Verbindungen der Formel I und deren pharmazeutisch annehmbare nichttoxische Salze .als antipyretische und analgetische Mittel von niedriger Toxizität nützlich, die -dem Menschen insbe- <I>Beispiel</I> Herstellung von 2-Methyl-2,3-dihydrothieno[3,2-c]chinohn aus 3-A1lyl-4-hydroxychinolin
EMI0003.0005
Eine Lösung von 2,0 Gewichtsteilen 3-Allyl-4- hydroxychinolin und 2,2 Gewichtsteilen pulverförmi gem Phosphorpentasulfid in 25 Volumteilen Dioxan wird 12 Stunden bei Rückfluss erhitzt.
Nach der Ab kühlung wird das Reaktionsgemisch mit einer 20%igen Natriumhydlroxydlösung alkalisch gemacht und mit Äther extrahiert. Der Extrakt wird mit Wasser gewa schen, über wasserfreiem Magnesiumsulfat getrocknet und verdampft. Der Rückstand wird auf Aluninium- oxyd chromatographiert und das Produkt mit Benzol eluiert. Es wird durch Destillation unter vermindertem Druck weiter gereinigt, wobei man 0,5 Gewichtsteile 2-Methyl-2,3-dihydro thieno[3,2-c]chinolin, das mit dem authentischen Muster identisch ist, erhält.
Process for the preparation of 2-lower alkyl-2,3-dihydrothieno [3,2-c] quinolines The present invention relates to a process for the preparation of 2-lower alkyl-2,3-dihydrothieno [3,2-c] quinolines the formula
EMI0001.0002
in which R is a hydrogen atom or a lower alkyl group, e.g. B. methyl, ethyl, n-propyl, isopropyl or n-butyl.
Pharmaceutically acceptable salts can be prepared from these compounds of Formula I.
H. Andersag and co-workers. have already produced certain 4-methyl-thieno [3,2-c] quinoline derivatives synthetically and found that they have chemotherapeutic value as a result of their analgesic and analeptic properties (cf. US Pat. No. 2,650,226).
The 2-lower alkyl-2,3-dihydro thieno [3,2-c] quinolines (I) prepared by the process according to the invention are, however, structurally characterized by the absence of substituents on the quinoline nucleus compared with the already known thieveninoline derivatives. It has now been found that the 2-lower alkyl-2,3-dihydro thieno [3,2-c] quinolines of formula I have an unexpectedly good antipyretic and analgesic effect, similar to that of the already known compound by H.
Andersag and co-workers. despite the structural similarity and also that of a commercially available agent, aminopyrine, is markedly superior. Attention is also drawn to the fact that the toxicity of the compounds of formula I are of a very low level.
The novel thieno [3,2-c] quinoline derivatives of the above formula I obtainable by the process according to the invention have a strong antipyretic and analgesic effect with low toxicity.
The process according to the invention for the preparation of the compounds of the formula I mentioned is characterized in that a compound of the formula
EMI0001.0046
heated with phosphorus pentasulfide at a temperature of 50-300 C.
The patent also relates to the compounds of formula I produced according to the above process.
Examples of the compounds of the formula I prepared according to the inventive method are 2-methyl-2,3-dihydro-thieno [3,2-c] quinoline, 2-ethyl-2,3-dihydro thieno [3,2-c ] quinoline, 2-n-propyl-2,3-dihydro thieno [3,2-c] quinoline, 2-n-butyl-2,3-dihydro thieno, [3,2-c] quinoline, 2-isobutyl 2,3-dihydro-thieno [3,2-c] quinoline and the like.
The reaction is preferably carried out in a suitable inert solvent such as. B. benzene, toluene, xylene, decalin, naphthalene, pyridine, collidine, quinoline or dioxane performed. The temperature of the implementation is in the range of 50-300 C; it is preferably about 100-200 C. It is assumed that the reaction occurs via the compound of the formula
EMI0002.0006
is going on, but the latter cannot usually be isolated for the reasons mentioned above.
Since the 2-lower alkyl-2,3-dihydro-thieno [3,2-c] quinoline (I) prepared in this way is usually a liquid, it can e.g. B. by treatment with an acid, such as. B. hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, phosphoric acid, thiocyanic acid, carbon
EMI0002.0011
Pharmacological <SEP> property <SEP> toxicity <SEP> 1) <SEP> antipyretic <SEP> z) <SEP> analgesic <SEP> 3)
<tb> <B> Test compound </B> <SEP> (1-D50; <SEP> mg / kg) <SEP> effect <SEP> (<SEP> C) <SEP> effect
<tb> (ED50;
<SEP> mg / kg)
<tb> 2-methyl-2,3-dihydrothieno [3,2-c] quinoline-hydroxochloride <SEP> 800-1000 <SEP> -5,22 <SEP> 21
<tb> 4-methyl-2,3-dihydrothieno [3,2-c] quinoline hydrochloride <SEP> 260 <SEP> -1,24 <SEP> 60
<tb> aminopyrine <SEP> 373 <SEP> -2.99 <SEP> 48
<tb> (100 <SEP> mg / kg) Nota bene: 1) The toxicity is determined by subcutaneous administration to mice.
2) The antipyretic effect is illustrated by the lowering of the body temperature of mice treated with a dose of 50 mg / kg test compound.
3) The analgesic effect is determined by the inhibition of the stretching caused by 2-phenyl-1,4-benzoquinone in mice. The information in the table above shows that the antipyretic and analgesic effect of 2-methyl-2,3-dihydrothieno [3,2-c] quinoline hydrochloride is significantly stronger than that of 4-methyl-2,3-dihydrothieno [ 3,2-c] quinoline hydrochloride and aminopyrine. The toxicity of 2-methyl-2,3-dihydrothieno acid, acetic acid, propionic acid, oxalic acid, citric acid, tartaric acid, succinic acid, salicylic acid, benzoic acid or palmitic acid in a suitable solvent, such as. B. water, methanol, ethanol, benzene or toluene can be converted into its acid addition salt.
The starting material, 3-allyl- or 3 - (γ, - lower alkyl-allyl) -4-hydroxy-quinoline (II), may e.g. B. from the known 4-hydroxyquinoline by treating it with a corresponding alkyl halide and the 4-allyl- or 4- (α-lower alkyl-allyl) -oxaquinoline, with heating of the so-called ortho-Claisen- Is subject to relocation.
The 2-lower alkyl-2,3-dihydro thieno [3,2-c] quinoline (I) and its non-toxic salts produced by the present invention are useful as antipyretic and analgesic agents. The table below shows results obtained in animal experiments with 2-methyl-2,3-dihydrothieno [3,2-c] quinoline hydrochloride, the already known related compound 4-methyl-2,3-dihydrothieno [3.2 -c] quinoline hydrochloride and a commercially available and frequently used agent, namely aminopyrine.
Incidentally, [3,2-c] quinoline hydrochloride is about 1/3 to 1/4 as high as that of 4-methyl-2,3-dihydrothieno [3,2-c] quinoline hydrochloride and about 1/2 to 1/3 as high as that of Ami nopyrin.
The other 2-lower alkyl-2,3-dihydrothieno [3,2-c] quinolines and their non-toxic acid addition salts produced by the process according to the invention also have similarly good pharmacological properties.
As a result, the compounds of formula I and their pharmaceutically acceptable nontoxic salts are useful as antipyretic and analgesic agents of low toxicity, which -in particular- <I> Example </I> the preparation of 2-methyl-2,3-dihydrothieno [ 3,2-c] quinone from 3-allyl-4-hydroxyquinoline
EMI0003.0005
A solution of 2.0 parts by weight of 3-allyl-4-hydroxyquinoline and 2.2 parts by weight of pulverulent phosphorus pentasulfide in 25 parts by volume of dioxane is refluxed for 12 hours.
After cooling, the reaction mixture is made alkaline with a 20% sodium hydroxide solution and extracted with ether. The extract is washed with water, dried over anhydrous magnesium sulfate and evaporated. The residue is chromatographed on aluminum oxide and the product is eluted with benzene. It is further purified by distillation under reduced pressure to obtain 0.5 part by weight of 2-methyl-2,3-dihydro thieno [3,2-c] quinoline, which is identical to the authentic sample.
Claims (1)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP973166 | 1966-02-17 | ||
| JP972966 | 1966-02-17 | ||
| JP972866 | 1966-02-17 | ||
| JP973066 | 1966-02-17 | ||
| CH225467A CH517774A (en) | 1966-02-17 | 1967-02-16 | (A) 2,3-Dihydrothieno(3, 2-c) quinolines of general formula (I): (I) R = H or lower alkyl (B) Pharmaceutically acceptable, non-toxic acid addition |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH514621A true CH514621A (en) | 1971-10-31 |
Family
ID=27509046
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH117571A CH513917A (en) | 1966-02-17 | 1967-02-16 | Process for the preparation of 2-lower alkyl-2,3-dihydrothieno- (3,2-c) quinolines |
| CH117471A CH514621A (en) | 1966-02-17 | 1967-02-16 | (A) 2,3-Dihydrothieno(3, 2-c) quinolines of general formula (I): (I) R = H or lower alkyl (B) Pharmaceutically acceptable, non-toxic acid addition |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH117571A CH513917A (en) | 1966-02-17 | 1967-02-16 | Process for the preparation of 2-lower alkyl-2,3-dihydrothieno- (3,2-c) quinolines |
Country Status (1)
| Country | Link |
|---|---|
| CH (2) | CH513917A (en) |
-
1967
- 1967-02-16 CH CH117571A patent/CH513917A/en not_active IP Right Cessation
- 1967-02-16 CH CH117471A patent/CH514621A/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| CH513917A (en) | 1971-11-30 |
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