DK157932B - 1,3-dihydro-6-methyl-furo-(3,4-c)-pyridin-derivater og farmaceutiske acceptable salte deraf samt farmaceutisk praeparat indeholdende disse - Google Patents
1,3-dihydro-6-methyl-furo-(3,4-c)-pyridin-derivater og farmaceutiske acceptable salte deraf samt farmaceutisk praeparat indeholdende disse Download PDFInfo
- Publication number
- DK157932B DK157932B DK545684A DK545684A DK157932B DK 157932 B DK157932 B DK 157932B DK 545684 A DK545684 A DK 545684A DK 545684 A DK545684 A DK 545684A DK 157932 B DK157932 B DK 157932B
- Authority
- DK
- Denmark
- Prior art keywords
- furo
- dihydro
- methyl
- pyridine
- formula
- Prior art date
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- IHWMIFMVQLOHLG-UHFFFAOYSA-N 6-methyl-1,3-dihydrofuro[3,4-c]pyridine Chemical class C1=NC(C)=CC2=C1COC2 IHWMIFMVQLOHLG-UHFFFAOYSA-N 0.000 title description 4
- 150000003839 salts Chemical class 0.000 title description 4
- 239000000825 pharmaceutical preparation Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 33
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 239000013543 active substance Substances 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000000047 product Substances 0.000 description 19
- 238000000921 elemental analysis Methods 0.000 description 17
- 238000000034 method Methods 0.000 description 17
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- -1 ethoxy-N-pyrrolidinyl Chemical group 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 241000700159 Rattus Species 0.000 description 5
- 230000001387 anti-histamine Effects 0.000 description 4
- 239000000739 antihistaminic agent Substances 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- COXVTLYNGOIATD-HVMBLDELSA-N CC1=C(C=CC(=C1)C1=CC(C)=C(C=C1)\N=N\C1=C(O)C2=C(N)C(=CC(=C2C=C1)S(O)(=O)=O)S(O)(=O)=O)\N=N\C1=CC=C2C(=CC(=C(N)C2=C1O)S(O)(=O)=O)S(O)(=O)=O Chemical compound CC1=C(C=CC(=C1)C1=CC(C)=C(C=C1)\N=N\C1=C(O)C2=C(N)C(=CC(=C2C=C1)S(O)(=O)=O)S(O)(=O)=O)\N=N\C1=CC=C2C(=CC(=C(N)C2=C1O)S(O)(=O)=O)S(O)(=O)=O COXVTLYNGOIATD-HVMBLDELSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000002934 diuretic Substances 0.000 description 3
- 230000001882 diuretic effect Effects 0.000 description 3
- 229960003699 evans blue Drugs 0.000 description 3
- BFJMHTOBRRZELQ-UHFFFAOYSA-N 3-iodo-2h-pyrazolo[3,4-c]pyridine Chemical class N1=CC=C2C(I)=NNC2=C1 BFJMHTOBRRZELQ-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- PWWVAXIEGOYWEE-UHFFFAOYSA-N Isophenergan Chemical compound C1=CC=C2N(CC(C)N(C)C)C3=CC=CC=C3SC2=C1 PWWVAXIEGOYWEE-UHFFFAOYSA-N 0.000 description 2
- HOKDBMAJZXIPGC-UHFFFAOYSA-N Mequitazine Chemical compound C12=CC=CC=C2SC2=CC=CC=C2N1CC1C(CC2)CCN2C1 HOKDBMAJZXIPGC-UHFFFAOYSA-N 0.000 description 2
- 108010058846 Ovalbumin Proteins 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 229960005042 mequitazine Drugs 0.000 description 2
- 229940092253 ovalbumin Drugs 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 229960003910 promethazine Drugs 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 229960000278 theophylline Drugs 0.000 description 2
- GHTWTWDSJLSJPA-UHFFFAOYSA-N 2-[(3,6-dimethyl-3-pentyl-1h-furo[3,4-c]pyridin-7-yl)oxy]acetic acid Chemical compound C1=NC(C)=C(OCC(O)=O)C2=C1C(CCCCC)(C)OC2 GHTWTWDSJLSJPA-UHFFFAOYSA-N 0.000 description 1
- MYLUTUZSWPOIMC-UHFFFAOYSA-N 2-[(3-butyl-3-ethyl-6-methyl-1h-furo[3,4-c]pyridin-7-yl)oxy]acetic acid Chemical compound C1=NC(C)=C(OCC(O)=O)C2=C1C(CCCC)(CC)OC2 MYLUTUZSWPOIMC-UHFFFAOYSA-N 0.000 description 1
- CQCPTPPPRPYILP-UHFFFAOYSA-N 2-[(3-butyl-4-chloro-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl)oxy]acetic acid Chemical compound C(CCC)C1OCC2=C1C(=NC(=C2OCC(=O)O)C)Cl CQCPTPPPRPYILP-UHFFFAOYSA-N 0.000 description 1
- HETVMPXLRIBHPB-UHFFFAOYSA-N 2-[(3-ethyl-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl)oxy]acetic acid Chemical compound C1=NC(C)=C(OCC(O)=O)C2=C1C(CC)OC2 HETVMPXLRIBHPB-UHFFFAOYSA-N 0.000 description 1
- BSCJLMOJVKMPLM-UHFFFAOYSA-N 2-[(4-chloro-3,3,6-trimethyl-1h-furo[3,4-c]pyridin-7-yl)oxy]acetic acid Chemical compound CC1=NC(Cl)=C2C(C)(C)OCC2=C1OCC(O)=O BSCJLMOJVKMPLM-UHFFFAOYSA-N 0.000 description 1
- HTVZABPSDHVMDS-UHFFFAOYSA-N 2-[(4-chloro-3,6-dimethyl-3-phenyl-1h-furo[3,4-c]pyridin-7-yl)oxy]acetic acid Chemical compound OC(=O)COC=1C(C)=NC(Cl)=C2C=1COC2(C)C1=CC=CC=C1 HTVZABPSDHVMDS-UHFFFAOYSA-N 0.000 description 1
- LRDLAQUPXWBSJX-UHFFFAOYSA-N 2-[(6-methyl-3-phenyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl)oxy]acetic acid Chemical compound O1CC2=C(OCC(O)=O)C(C)=NC=C2C1C1=CC=CC=C1 LRDLAQUPXWBSJX-UHFFFAOYSA-N 0.000 description 1
- NROQVFMIKHXZEE-UHFFFAOYSA-N 2-[[3-(3-chlorophenyl)-3,6-dimethyl-1H-furo[3,4-c]pyridin-7-yl]oxy]acetic acid Chemical compound ClC=1C=C(C=CC1)C1(OCC2=C1C=NC(=C2OCC(=O)O)C)C NROQVFMIKHXZEE-UHFFFAOYSA-N 0.000 description 1
- PGHRBYISODHGNF-UHFFFAOYSA-N 2-[[3-(4-chlorophenyl)-3,6-dimethyl-1h-furo[3,4-c]pyridin-7-yl]oxy]acetic acid Chemical compound OC(=O)COC=1C(C)=NC=C2C=1COC2(C)C1=CC=C(Cl)C=C1 PGHRBYISODHGNF-UHFFFAOYSA-N 0.000 description 1
- RHMKBLSGUNJRJY-UHFFFAOYSA-N 2-[[3-(4-fluorophenyl)-3,6-dimethyl-1h-furo[3,4-c]pyridin-7-yl]oxy]acetic acid Chemical compound OC(=O)COC=1C(C)=NC=C2C=1COC2(C)C1=CC=C(F)C=C1 RHMKBLSGUNJRJY-UHFFFAOYSA-N 0.000 description 1
- CLQNYNHDJQJWNT-UHFFFAOYSA-N 2-[[3-(4-fluorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl]oxy]acetic acid Chemical compound O1CC2=C(OCC(O)=O)C(C)=NC=C2C1C1=CC=C(F)C=C1 CLQNYNHDJQJWNT-UHFFFAOYSA-N 0.000 description 1
- SFRMZEBQCDKAKE-UHFFFAOYSA-N 2-[[4-bromo-3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl]oxy]acetic acid Chemical compound O1CC2=C(OCC(O)=O)C(C)=NC(Br)=C2C1C1=CC=C(Cl)C=C1 SFRMZEBQCDKAKE-UHFFFAOYSA-N 0.000 description 1
- ICMVCSDQLPEXIZ-UHFFFAOYSA-N 2-[[4-bromo-3-(4-chlorophenyl)-6-methyl-3-propyl-1h-furo[3,4-c]pyridin-7-yl]oxy]acetic acid Chemical compound O1CC(C(=C(C)N=C2Br)OCC(O)=O)=C2C1(CCC)C1=CC=C(Cl)C=C1 ICMVCSDQLPEXIZ-UHFFFAOYSA-N 0.000 description 1
- LAXBXEFVMKXAKS-UHFFFAOYSA-N 2-[[4-chloro-3-(4-methoxyphenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl]oxy]acetic acid Chemical compound C1=CC(OC)=CC=C1C1C(C(Cl)=NC(C)=C2OCC(O)=O)=C2CO1 LAXBXEFVMKXAKS-UHFFFAOYSA-N 0.000 description 1
- IQHSSYROJYPFDV-UHFFFAOYSA-N 2-bromo-1,3-dichloro-5-(trifluoromethyl)benzene Chemical group FC(F)(F)C1=CC(Cl)=C(Br)C(Cl)=C1 IQHSSYROJYPFDV-UHFFFAOYSA-N 0.000 description 1
- LOPQXLOIRYZLMN-UHFFFAOYSA-N 3,6-dimethylfuro[3,4-c]pyridin-7-ol Chemical compound CC=1OC=C2C=1C=NC(=C2O)C LOPQXLOIRYZLMN-UHFFFAOYSA-N 0.000 description 1
- HKUOMRSPQVGCHJ-UHFFFAOYSA-N 3-(3-chlorophenyl)-3,6-dimethyl-1h-furo[3,4-c]pyridin-7-ol Chemical compound OC=1C(C)=NC=C2C=1COC2(C)C1=CC=CC(Cl)=C1 HKUOMRSPQVGCHJ-UHFFFAOYSA-N 0.000 description 1
- GONPALGLQOQSAR-UHFFFAOYSA-N 3-(4-chlorophenoxy)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-ol Chemical compound O1CC2=C(O)C(C)=NC=C2C1OC1=CC=C(Cl)C=C1 GONPALGLQOQSAR-UHFFFAOYSA-N 0.000 description 1
- LQEMUWNIWKVWOP-UHFFFAOYSA-N 3-(4-chlorophenyl)-3,6-dimethyl-1h-furo[3,4-c]pyridin-7-ol Chemical compound OC=1C(C)=NC=C2C=1COC2(C)C1=CC=C(Cl)C=C1 LQEMUWNIWKVWOP-UHFFFAOYSA-N 0.000 description 1
- JWXDAFDYHBKRJI-UHFFFAOYSA-N 3-(4-fluorophenyl)-3,6-dimethyl-1h-furo[3,4-c]pyridin-7-ol Chemical compound OC=1C(C)=NC=C2C=1COC2(C)C1=CC=C(F)C=C1 JWXDAFDYHBKRJI-UHFFFAOYSA-N 0.000 description 1
- ANEYGXYUZGDDGH-UHFFFAOYSA-N 3-(4-fluorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-ol Chemical compound O1CC2=C(O)C(C)=NC=C2C1C1=CC=C(F)C=C1 ANEYGXYUZGDDGH-UHFFFAOYSA-N 0.000 description 1
- XIUDHWARDNZSSX-UHFFFAOYSA-N 3-butyl-3-ethyl-6-methyl-1h-furo[3,4-c]pyridin-7-ol Chemical compound C1=NC(C)=C(O)C2=C1C(CCCC)(CC)OC2 XIUDHWARDNZSSX-UHFFFAOYSA-N 0.000 description 1
- PZMWHUMWOMSCRX-UHFFFAOYSA-N 3-butyl-4-chloro-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-ol Chemical compound ClC1=NC(C)=C(O)C2=C1C(CCCC)OC2 PZMWHUMWOMSCRX-UHFFFAOYSA-N 0.000 description 1
- MEVOEUZLYUNXHS-UHFFFAOYSA-N 3-ethyl-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-ol Chemical compound C1=NC(C)=C(O)C2=C1C(CC)OC2 MEVOEUZLYUNXHS-UHFFFAOYSA-N 0.000 description 1
- GBXNEXHTLHJCCQ-UHFFFAOYSA-N 4-bromo-3-(4-chlorophenyl)-3,6-dimethyl-1h-furo[3,4-c]pyridin-7-ol Chemical compound OC=1C(C)=NC(Br)=C2C=1COC2(C)C1=CC=C(Cl)C=C1 GBXNEXHTLHJCCQ-UHFFFAOYSA-N 0.000 description 1
- OBNHXVFMYJQKCY-UHFFFAOYSA-N 4-bromo-3-(4-chlorophenyl)-3-ethyl-6-methyl-1h-furo[3,4-c]pyridin-7-ol Chemical compound O1CC(C(=C(C)N=C2Br)O)=C2C1(CC)C1=CC=C(Cl)C=C1 OBNHXVFMYJQKCY-UHFFFAOYSA-N 0.000 description 1
- DBOIDOGSKUFJCP-UHFFFAOYSA-N 4-bromo-3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-ol Chemical compound O1CC2=C(O)C(C)=NC(Br)=C2C1C1=CC=C(Cl)C=C1 DBOIDOGSKUFJCP-UHFFFAOYSA-N 0.000 description 1
- GFSWLZBRAKTADY-UHFFFAOYSA-N 4-bromo-3-(4-chlorophenyl)-6-methyl-3-propyl-1h-furo[3,4-c]pyridin-7-ol Chemical compound O1CC(C(=C(C)N=C2Br)O)=C2C1(CCC)C1=CC=C(Cl)C=C1 GFSWLZBRAKTADY-UHFFFAOYSA-N 0.000 description 1
- WYAPBLOJYSXOBY-UHFFFAOYSA-N 4-bromo-3-(4-methoxyphenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-ol Chemical compound C1=CC(OC)=CC=C1C1C(C(Br)=NC(C)=C2O)=C2CO1 WYAPBLOJYSXOBY-UHFFFAOYSA-N 0.000 description 1
- FXNRMPYJNRGEAG-UHFFFAOYSA-N 4-chloro-3,3,6-trimethyl-1h-furo[3,4-c]pyridin-7-ol Chemical compound CC1=NC(Cl)=C2C(C)(C)OCC2=C1O FXNRMPYJNRGEAG-UHFFFAOYSA-N 0.000 description 1
- JNXCOPPTXGMZCF-UHFFFAOYSA-N 4-chloro-3,3-bis(4-chlorophenyl)-6-methyl-1h-furo[3,4-c]pyridin-7-ol Chemical compound OC=1C(C)=NC(Cl)=C2C=1COC2(C=1C=CC(Cl)=CC=1)C1=CC=C(Cl)C=C1 JNXCOPPTXGMZCF-UHFFFAOYSA-N 0.000 description 1
- MZLLECZYEGRZSK-UHFFFAOYSA-N 4-chloro-3,6-dimethyl-3-phenyl-1h-furo[3,4-c]pyridin-7-ol Chemical compound OC=1C(C)=NC(Cl)=C2C=1COC2(C)C1=CC=CC=C1 MZLLECZYEGRZSK-UHFFFAOYSA-N 0.000 description 1
- VBLXCSRFMPHRMN-UHFFFAOYSA-N 4-chloro-3-ethyl-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-ol Chemical compound ClC1=NC(C)=C(O)C2=C1C(CC)OC2 VBLXCSRFMPHRMN-UHFFFAOYSA-N 0.000 description 1
- MIZMBPVMDKMQQN-UHFFFAOYSA-N 6-methyl-3-(4-methylphenyl)-3-phenyl-1h-furo[3,4-c]pyridin-7-ol Chemical compound C1=CC(C)=CC=C1C1(C=2C=CC=CC=2)C(C=NC(C)=C2O)=C2CO1 MIZMBPVMDKMQQN-UHFFFAOYSA-N 0.000 description 1
- AWSNANLRLHTJCZ-UHFFFAOYSA-N 6-methyl-3-phenyl-1,3-dihydrofuro[3,4-c]pyridin-7-ol Chemical compound O1CC2=C(O)C(C)=NC=C2C1C1=CC=CC=C1 AWSNANLRLHTJCZ-UHFFFAOYSA-N 0.000 description 1
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 208000004880 Polyuria Diseases 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 101100054666 Streptomyces halstedii sch3 gene Chemical group 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 230000004531 blood pressure lowering effect Effects 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 230000035619 diuresis Effects 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 210000000548 hind-foot Anatomy 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- PPZMYIBUHIPZOS-UHFFFAOYSA-N histamine dihydrochloride Chemical compound Cl.Cl.NCCC1=CN=CN1 PPZMYIBUHIPZOS-UHFFFAOYSA-N 0.000 description 1
- 229960000645 histamine hydrochloride Drugs 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 210000005164 penile vein Anatomy 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D497/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms
- C07D497/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D497/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/10—Antioedematous agents; Diuretics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
DK 157932 B
Den foreliggende opfindelse angår hidtil ukendte 1,3-di-hydro-6-methyl-furo-(3/4-c)-pyridin-derivater, farmaceutisk acceptable salte af disse samt farmaceutiske præparater indeholdende disse.
5
Den foreliggende opfindelse angår hidtil ukendte 1,3-di-hydro-6-methyl-furo-(3,4-c)-pyridin-derivater samt farmaceutiske acceptable salte af disse, som er ejendommelige ved, at pyridinderivaterne har den almene formel 10 ru hooc-cii2-o—Y jj 1 1 15 I il 2 20 i hvilken og A2 uafhængigt af hinanden betyder et hydrogenatom, en ligekædet, mættet carbonhydridgruppe med 1-5 carbonatomer, en vinylgruppe, en thienyl-, furyl-eller phenylgruppe, eller en phenylgruppe, der er substitueret med halogen, CF3, CH3, OCH3, SCH3, ethoxy-N-25 pyrrolidinyl og diethylaminoethoxy, og R betyder et hydrogen- eller halogenatom.
Forbindelserne ifølge opfindelsen er interessante på grund af deres terapeutiske virkning, især i forbindelse 30 med diurese, blodtrykssænkning og nyrebeskyttelse, samt som anti-histaminer.
35
2 DK 157932 B
1,3-dihydro-6-methyl-furo-(3,4-c)-pyridin-derivaterne i-følge opfindelsen fremstilles ved, at man i nærværelse af dimethylformamid omsætter en forbindelse med den almene formel 5 _O . ' HO 1 11 JL I! *2
10 H3 n/"\ R
i hvilken A^, og R har den ovenfor angivne betydning, 15 med ethylbromacetat ved 10-70 °C og hydrolyserer den dannede ester med natriumhydroxid.
Udgangsforbindelserne med formel (II) kan fremstilles som beskrevet i dansk patentansøgning nr. 543/82.
20
Opfindelsen angår endvidere farmaceutiske præparater, som er ejendommelige ved, at de som aktivt middel indeholder en effektiv mængde af en forbindelse med den almene formel (I) eller et farmaceutisk salt af en sådan for-25 bindelse i blanding med et farmaceutisk acceptabelt fortyndingsmiddel eller bærestof.
Fra GB-A-2 008 582 og GB-A-2 092 586 kendes andre 1,3-di-hydro-6-methyl-furo-(3,4-c)-pyridin-derivater med hen-30 holdsvis diuretisk og diuretisk samt blodtrykssænkende virkning. I modsætning til de her omhandlede forbindelser, udviser nævnte kendte forbindelser ingen antihistamin-virkning . 1 I det følgende illustreres opfindelsen ved en række eksempler .
3
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EKSEMPEL 1 1,3-Dihydro-3-ethyl-6-methyl-7-carboxymethoxy-furo-(3,4-c)-pyridin«_ I en 2 liters reaktor forsynet med organer til opvarmning, 5 afkøling og omrøring anbragtes 300 ml tør dimethylformamid, 4,8 g natriumhydrid samt langsomt og under omrøring 38,1 g (0,1 mol) 1,3-dihydro-3-ethyl-6-methyl-7-hydroxy-furo-(3,4-c)-pyridin. Temperaturen blev hævet til 40 °C, og blandingen henstod i 1 time ved denne temperatur un-10 der omrøring. Derpå blev der langsomt tilsat 11,4 ml (0,11 mol) ethylbromacetat ved 20 °C. Reaktionsblandingen blev omrørt i 6 timer, hvorefter der inddampedes til tørhed. Remanensen blev taget op i dichlormethan, vasket med vand, genudfældet, frafiltreret, tørret og 15 omkrystalliseret af petroleumsether. Udbytte: 21 g (79 %) af et hvidt krystallinsk produkt. Elementæranalysen af dette produkt udviste god overensstemmelse med formlen C-^H^NO^ (dvs. ethylesteren af den i overskriften angivne forbindelse). 1 2 3 4 5 6 7 8 9 10 11 I samme reaktor blev 20 g (0,74 mol) af den således 2 fremstillede ester behandlet med 100 ml ethanol, 11 g 3 (0,275 mol) sodatabletter og 200 ml vand under tilbage 4 svaling i 2 timer. Efter afkøling tilsattes 200 ml 10 %1 s 5 eddikesyre og 100 ml vand dråbevis under omrøring, medens 6 temperaturen blev holdt under 20 °C. Herved fremkom et 7 udfældet materiale, som blev fraskilt, vasket med vand 8 to gange, tørret og omkrystalliseret fra en varm opløs 9 ning i en blanding af acetonitril og methanol (50/50).
10
Herved fremkom 10 g (udbytte 80 %) af et hvidt krystal- 11 linsk produkt, hvis elementæranalyse udviste god overensstemmelse med formlen ci2^15^4' Smeltepunkt 212 °C (Tottoli).
4
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EKSEMPEL 2 l,3-Dihydro-3-vinyl-3-p-thiomethylphenyl-6-methyl-7-carboxymethoxy-furo-(3,4-c)-pyridin ._
Denne forbindelse bliver fremstillet ved den i eksempel 5 1 beskrevne fremgangsmåde ud fra l,3-dihydro-3-vinyl-3- p-thiomethylphenyl-6-methyl-7-hydroxy-furo-(3,4-c)-pyri-din. Udbytte 42 ft af et hvidt krystallinsk produkt. Elementæranalysen af dette viser god overensstemmelse med formlen C^gH^^NO^S. Smp. 191-194 °C.
10 EKSEMPEL 3 ~1,3-Dihydro-3-phenyl-6-methyl-7-carboxymethoxy-furo-(3,4-c)-pyridin.__
Denne forbindelse bliver fremstillet ved den i eksempel 1 beskrevne fremgangsmåde ud fra 1,3-dihydro-3-phenyl-6-15 methyl-7-hydroxy-furo-(3,4-c)-pyridin. Udbytte 67 % af et hvidt krystallinsk produkt. Elementæranalysen af dette viser god overensstemmelse med formlen C^gH^NO^. Smp.
220 °C.
EKSEMPEL 4 20 1,3-Dihydro-3-chlorphenyl-6-methyl-7-carboxymethoxy- furo-(3,4-c)-pyridin._
Denne forbindelse bliver fremstillet ved den i eksempel 1 beskrevne fremgangsmåde ud fra 1,3-dihydro-3-p-chlor-phenoxy-6-methyl-7-hydroxy-furo-(3,4-c)-pyridin. Udbyt-25 te 63 % af et hvidt krystallinsk produkt. Elementærana lysen af dette viser god overensstemmelse med formlen C16H14N04C1' Smp* 226-230 °C* 5 EKSEMPEL 5
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1.3- Dihydro-3-p-fluorphenyl-6-methyl-7-carboxymethoxy- furo-(3,4-c)-pyridin._
Denne forbindelser bliver fremstillet ved den i eksempel 5 1 beskrevne fremgangsmåde ud fra l,3-dihydro-3-p-fluor- phenyl-6-methyl-7-hydroxy-furo-(3,4-c)-pyridin. Udbytte 47 % af et hvidt krystallinsk produkt. Elementær-analysen af dette viser god overensstemmelse med formlen C16H14FN04* Smp* 214 °C‘ 10 EKSEMPEL 6 1.3- Dihydro-3-p-trifluormethyl-phenyl-6-methyl-7-carboxy- methoxy-furo-(3,4-c)-pyridin._
Denne forbindelser bliver fremstillet ved den i eksempel 1 beskrevne fremgangsmåde ud fra 1,3-dihydro-3-p-tri -< 15 fluormethyl-phenyl-6-methyl-7-hydroxy-furo-(3,4-c)-pyri-din. Udbytte 58 % af et hvidt krystallinsk produkt. Elementæranalysen af dette viser god overensstemmelse med formlen ^yH-^F^NO^. Smp. 200 °C.
EKSEMPEL 7 20 l,3-Dihydro-3-p-(ethoxy-N-pyrrolidinyl) phenyl-6-methyl-7-carboxymethoxy-furo-(3,4-c)-pyridin._
Denne forbindelser bliver fremstillet ved den i eksempel 1 beskrevne fremgangsmåde ud fra 1,3-dihydro-3-p-(ethoxy-N-pyrrolidinyl)phenyl-6-methyl-7-hydroxy-furo-(3,4-c)-25 pyridin. Udbytte 71 % af et hvidt krystallinsk produkt.
Elementæranalysen af dette viser god overensstemmelse med formlen C22^26^2^5‘ DC.
6
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EKSEMPEL 8 1.3- Dihydro-3-a-thienyl-6-methyl-7-carboxymethoxy-furo- (3,4-c)-pyridin._
Denne forbindelse bliver fremstillet ved den i eksempel 5 1 beskrevne fremgangsmåde ud fra l,3-dihydro-3-a-thie- nyl-6-methyl-7-hydroxy-furo-(3,4-c)-pyridin, Udbytte 73 ίο af et svagt beigefarvet krystallinsk produkt. Elementæranalysen af dette viser god overensstemmelse med formlen C24H13N^4^‘ ^mP* 172-174 °C.
10 EKSEMPEL 9 1.3- Dihydro-3-n-pentyl-3,6-dimethyl-7-carboxymethoxy- furo-(3,4-c)-pyridin._
Denne forbindelse bliver fremstillet ved den i eksempel 1 beskrevne fremgangsmåde ud fra 1,3-dihydro-3-n-pentyl-13 3,6-dimethyl-7-hydroxy-furo-(3,4-c)-pyridin. Udbytte 76 .
% af et hvidt krystallinsk produkt. Elementæranalysen af dette viser god overensstemmelse med formlen C16H23N04* Smp* 211 °C* EKSEMPEL 10 20 1,3-Dihydro-3-p-chlorphenyl-3,6-dimethyl-7-carboxymethoxy- furo-(3,4-c)-pyridin._
Denne forbindelse bliver fremstillet ved den i eksempel 1 beskrevne fremgangsmåde ud fra 1,3-dihydro-3-p-chlor-phenyl-3,6-dimethyl-7-hydroxy-furo-(3,4-c)-pyridin.
25 Udbytte 61 % af et krystallinsk produkt. Elementæranalysen af dette viser acceptabel overensstemmelse med formlen C^H-^CINO^. Smp. 184 °C.
EKSEMPEL 11 7
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V 1,3- dihydrc 3,6-dimethyl-3-m-chlorphenyl-7-carboxymethoxy- furo-(3,4-c)-pyridin._
Denne forbindelse bliver fremstillet ved den i eksempel 5 1 beskrevne fremgangsmåde ud fra 1,3-dihydro-3,6-dimethyl- 3-m-chlorphenyl-7-hydroxy-furo-(3,4-c)-pyridin. Udbytte 43 % af et hvidt krystallinsk produkt. Elementæranalysen af dette viser god overensstemmelse med formlen C17H16C1N04' Smp* 201-206 °c* 10 EKSEMPEL 12 l,3-Dihydro-3-p-fluorphenyl-3,6-dimethyl-7-carboxymethoxy-furo (3,4-c)-pyridin♦_
Denne forbindelse bliver fremstillet ved den i eksempel 1 beskrevne fremgangsmåde ud fra 1,3-dihydro-3-p-fluor-15 phenyl-3,6-dimethyl-7-hydroxy-furo-(3,4-c)-pyridin. Ud bytte 68 % af et krystallinsk produkt. Elementæranalysen af dette viser god overensstemmelse med formlen C^yH^FNO^. Smp. 184-186 °C.
EKSEMPEL 13 20 1,3-Dihydro-3-ethyl-3-n-butyl-6-methyl-7-carboxymethoxy- furo-(3,4-c)-pyridin._
Denne forbindelse bliver fremstillet ved den i eksempel 1 beskrevne fremgangsmåde ud fra 1,3-dihydro-3-ethyl-3-n-butyl-6-methyl-7-hydroxy-furo-(3,4-c)-pyridin. Ud-25 bytte 78 % af et hvidt krystallinsk produkt. Elementær- analysen af dette viser god overensstemmelse med formlen C16H23N04‘ Smp' 193 °C' 8
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EKSEMPEL 14 1.3- Dihydro-3-ethyl-3-ot-f uryl-6-methyl-7-carboxymethoxy- furo-(3,4-c)-pyridin«_
Denne forbindelse bliver fremstillet ved den i eksempel 5 1 beskrevne fremgangsmåde ud fra l,3-diihydro-3-ethyl-a-furyl- 6-methyl-7-hydroxy-furo-(3,4-c)-pyridin. Udbytte 71 % af et krystallinsk produkt. Elementæranalysen af dette viser god overensstemmelse med formlen C, ,Η.-.NO,-. Smp.
16 1/ J
169 °C.
10 EKSEMPEL 15 1.3- dihydro-3-vinyl-3-p-methylthiophenyl-6-methy1-7- carboxymethoxy-furo-(3,4-c)-pyridin._
Denne forbindelse bliver fremstillet ved den i eksempel 1 beskrevne fremgangsmåde ud fra 1,3-dihydro-3-vinyl-15 3-p-methylthiophenyl-6-methyl-7-hydroxy-furo-(3,4-c)- pyridin. Udbytte 81 % krystallinsk produkt. Elementær-analysen af dette viser god overensstemmelse med formlen C19H19N04S* Smp’ 191-194 °c-EKSEMPEL 16 20 l,3-Dihydro-3-phenyl-3-p-toluyl-6-methyl-7-carboxy- methoxy-furo-(3,4-c)-pyridin ·_
Denne forbindelse bliver fremstillet ved den i eksempel 1 beskrevne fremgangsmåde ud fra 1,3-dihydro-3-phenyl-3-p-toluyl-6-methyl-7-hydroxy-furo-(3,4-c)-pyridin.
25 Udbytte 57 % af et hvidt krystallinsk produkt. Elementæranalysen af dette viser god overensstemmelse med formlen ^23^21^4- Smp. 223 DC.
9
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EKSEMPEL 17 1.3- Dihydro-3-a-furyl-3-p-methylthiophenyl-6-methyl-7- carboxymethoxy-furo-(3,4-c)-pyridin·_
Denne forbindelse bliver fremstillet ved den i eksempel 5 1 beskrevne fremgangsmåde ud fra 1,3-dihydro-3-a-furyl- 3- p-methylthiophenyl-6-methyl-7-hydroxy-furo-(3,4-c)-pyridin. Udbytte 43 % af et krystallinsk produkt. Elementæranalysen af dette viser god overensstemmelse med formlen ^^^pNO^S. Smp. 139 °C.
10 På tilsvarende måde fremstilledes følgende 4-brom- eller 4- chlor-7-carboxymethoxy-derivater: EKSEMPEL 18 1.3- dihydrG-3-ethyl-4-chlor-6-methyl-7-carboxymetlnoxy- furo-(3,4-c)-pyridin·_ 15 Ud fra 1,3-dihydro-3-ethyl-4-chlor-6-methy1-7-hydroxy-furo-(3,4-c)-pyridin. Udbytte 55 %. Formel ^^I^^CINO^.
Smp. 181 °C.
EKSEMPEL 19 1.3- Dihydro-3-n-butyl-4-chlor-6-methyl-7-carboxymethoxy- 20 furo-(3,4-c)-pyridin ._
Ud fra 1,3-dihydro-3-n-butyl-4-chlor-6-methy1-7-hydroxy-furo-(3,4-c)-pyridin. Udbytte 58 %. Formel C23H2QC1N0^.
Smp. 170 °C.
EKSEMPEL 20 25 1,3-dihydro-3-p-chlorphenyl-4-brom-6-methyl-7-carboxy- methoxy-f uro-(3,4-c )-pyridin .__ 10
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Ud fra 1,3-dihydro-3-p-chlorphenyl-4-brom-6-methyl-7-hydroxy-furo-(3,4-c)-pyridin. Udbytte 53 %. Formel C16H13BrC1N°4* Smp* 194-196 °C.
EKSEMPEL 21 5 1,3-Dihydro-3-m~trifluormethylphenyl-4-brom-6-methyl-7- carboxymethoxy-furo-(3,4-c)-pyridin._
Ud fra l,3-dihydro-3-m-trifluormethylphenyl-4-brom-6-methyl-7-hydroxy-furo-(3,4-c)-pyridin. Udbytte 43 %.
Formel c17H13BrF3NtV Smp. 207-209 °C.
10 EKSEMPEL 22 1.3- Dihydro-3-p-methoxyphenyl-4-chlor-6-methyl-7-carboxy- methoxy-furo-(3,4-c)-pyridin._
Ud fra 1,3-dihydro-3-p-methoxyphenyl-4-brom-6-methyl-7-hydroxy-furo-(3,4-c)-pyridln. Udbytte 48 %. Formel 15 C17H16C1N05* Smp· 178 °C· EKSEMPEL 23 1.3- Dihydro-3-p-methylthiophenyl-4-brom-6-methyl-7- carboxymethoxy-furo-(3,4-c)-pyridin._
Ud fra 1,3-dihydro-3-p-methylthiophenyl-4-brom-6-methyl-20 7-hydroxy-furo-(3,4-c)-pyridin. Udbytte 38 Formel C17H16BrN04S· Smp‘ 157-159 °C* EKSEMPEL 24 1.3- Dihydro-3-a-thienyl-4-chlor-6-methyl-7-carboxymethoxy- furo-(3,4-c)-pyridin._ 11
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Ud fra 1,3-dihydro-3-a-thienyl-4-chlor-6-methyl-7-hydroxy-furo-(3,4-c)-pyridin. Udbytte 35 %. Formel Cj^H^ClNO^S.
Smp. 149-151 °C.
EKSEMPEL 25 5 l,3-Dihydro-3,3,6-trimethyl-4-chlor~7-carboxymethoxy- furo-(3,4-c)-pyridin._
Ud fra 1,3-dihydro-3,3,6-trimethyl-4-chlor-7-hydroxy-furo-(3,4-c )-pyridin. Udbytte 51 %. Formel °;[201401^04‘
Smp. 192 °C.
10 EKSEMPEL 26 1.3- Dihydro-3-phenyl-3,6-dimethyl-4-chlor-7-carboxy- methoxy-furo-(3,4-c)-pyridin._
Ud fra l,3-dihydro-3-phenyl-3,6-dimethyl-4-chlor-7-hydroxy-furo-(3,4-c)-pyridin. Udbytte 47 %. Formel 15 C17H16C1N04· Smp· 181-183 °C- EKSEMPEL 27 1.3- Dihydro-3-p-cHlorphenyl-3,6-dimethyl-4-brom-7-car- boxymethoxy-furo-(3,4-c)-pyridin._
Ud fra 1,3-dihydro-3-p-chlorphenyl-3,6-dimethyl-4-brom-20 7-hydroxy-furo-(3,4-c)-pyridin. Udbytte 46 ?□. Formel C17H15BrC1N04* Smp· 180-182 °C-EKSEMPEL 28 1.3- Dihydro-3-a-thienyl-3,6-dimethyl-4-brom-7-carboxy- methoxy-furo-(3,4-c)-pyridin._ 1
Ud fra 1,3-dihydro-3-a-thienyl-3,6-dimethyl-4-brom-7- hydroxy-furo-(3,4-c)-pyridin. Udbytte 36 %. Formel 12
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C15H14BrN04S* Smp* 163-165 °C· EKSEMPEL 29 1.3- Dihydro-3-ethyl-3-p-chlorphenyl-4-brom-6-methyl-7- carboxymethoxy-furo-(3,4-c)-pyridin._ 5 Ud fra l,3-dihydro-3-ethyl-3-p-chlorphenyl-4-brom-6-methyl- 7-hydroxy-furo-(3,4-c)-pyridin. Udbytte 38 %. Formel C18H17BrC1N04* Smp* 135-138 °C* EKSEMPEL 30 1.3- Dihydro-3-propyl-3-p-chlorphenyl-4-brom-6-methyl-7- 10 carboxymethoxy-furo-(3,4-c)-pyridin._
Ud fra 1,3- dihydro-3-propyl-3-p-chlorphenyl-4-brom-6-methyl-7-hydroxy“furo-(3,4-c)-pyridin. Udbytte 41 %.
Formel C^gH^^BrClNO^. Smp. 130 °C.
EKSEMPEL 31 15 1,3-Dihydro-3-p-diethylaminoethoxyphenyl-3-phenyl-4- chlor-6-methyl-7-carboxymethoxy-furo-(3,4-c)-pyridin.
Ud fra l,3-dihydro-3-p-diethylaminoethoxyphenyl-3-phenyl-4-chlor-6-methyl-7-hydroxy-furo-(3,4-c)-pyridin. Udbytte 33 %. Formel C27H29C1N205. Smp. 143-146 °C.
20 EKSEMPEL 32 1.3- Dihydro-3,3-di(p-chlorphenyl)-4-chlor-6-methyl-Ί- carboxymethoxy-furo-(3,4-c)-pyridin._
Ud fra l,3-dihydro-3,3-di(p-chlorphenyl)-4-chlor-6-methyl-7-hydroxy-furo-(3,4-c)-pyridin. Udbytte 44 %. Formel
DK 157932B
13 C22H16C13N04‘ Smp* 126-128 °C-Toxicitet LD^g blev bestemt per os og IP på mus. Afhængigt af forbindelserne udgjorde de fra 0,8 til over 2 g/kg (per os) 5 og 0,45-1,35 g/kg IP.
Farmakologisk virkning
Der blev gennemført en komplet farmakologisk undersøgelse hvorfra følgende prøver beskrives i det følgende.
A - Passiv cutan anaphylaxi 10 Dette forsøg blev gennemført som beskrevet i Fiche
Technique nr. 48 J. Pharm. Paris 1979, ljO, (1), side 69-72.
Sprague-Dou/ley hanrotter (180-200 g) fik to intraéermale injektioner af immunserum i ryggen. 72 timer senere fik 15 de en IV injektion (penisvene) med 1 ml af en blanding af ovalbumin (5 mg/ml) og Evans-blåt (2,5 mg/ml). Dette inducerede dannelsen af vabler omkring stederne f-οτ injektion af immunserum. Vablerne blev taget 30 minutter efter dannelsen, målt og derpå inkuberet i 24 timer 20 ved 65 °C i 4 ml formamid (til ekstraktion af Evans-blåt). Den optiske tæthed af den ovenstående væske blev bestemt spektrofotometrisk ved 620 nm.
En første gruppe på 8 rotter blev anvendt til kontrolforsøg, en anden gruppe (også på 8 rotter) blev anvendt 25 til behandling med en referenceforbindelse (theophyllin, 25 mg/kg) og ti andre grupper (alle på 8 rotter) blev anvendt til behandling med ti af forbindelserne ifølge den foreliggende opfindelse (alle doseringer: 25 mg/kg), som identificeres ved deres eksempelnummer. For alle elleve
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14 gruppers vedkommende blev forbindelserne indgivet per os 1 time før injektionen af blandingen af ovalbumin og Evans-blåt. Den procentvise reduktion af vablerne i henseende til overflade og til farve bestemtes i for-5 hold til kontrolgruppen. Resultaterne fremgår af venstre side af nedenstående tabel.
B Antihistaminvirkning
Dette eksperiment b:lfevi gennemført som beskrevet af W. Doepfner og A. Cerletti i Int. Arch. Allergy, 12, 10 89, (1958) og J. Pharmac. and exp. Ther. (1974) 191 (2) side 300-310.
Srague-Dowley hanrotter (140-160 g) blev holdt vandfastende i 18 timer før de modtog 1 ml/kg vand (til kontrol), 0,2 af en vandig opløsning af suspension af 15 de afprøvede forbindelser. Volumenet af den venstre bagpote blev målt plethysmografisk, og derpå injiceredes 0,1 ml 5 %1 s histaminhydrochlorid. Den inflammatoriske virkning blev bestemt ved en påfølgende volumenbestemmelse 1 time senere.
20 Der blev brugt en række grupper på hver 8 dyr: En til kontrol, ti til afprøvede forbindelser (de samme som i det foregående eksempel A) samt to til referenceforbindelserne mequitazin og promethazin alle doseret i en mængde på 25 mg/kg. Den procentvise reduktion af den 25 inflammatoriske virkning blev bestemt ved sammenligning med kontrolgruppen. Resultaterne fremgår af højre del af nedenstående tabel.
Det fremgår klart af disse to eksperimenter, at forbindelserne ifølge opfindelsen udviser en stærk anti-30 histaminvirkning.
15
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Præparatformer
Foretrukne orale former til human indgift omfatter tabletter eller gelatinekapsler indeholdende 0,25 g af en forbindelse ifølge opfindelsen. Til IV indgift anvendes ampuller indeholdende samme mængde til indgift med en perfusion. Daglige doser i humanterapien er fra 0,25 til 2 g per os og 0,25 til 1 g, IV.
Forbin- Reduktion af vabler Histamininduceret delse i % ødem-Reduktionaf inflammation i %
Eks. nr. Overflade farve
Theophyllin__-63__-61_ 1__^49__-56__=_80_ 3 __^61__^62__-58_ 4 __-53__-64__-54_ 5 __^56__=_81__:-48_ 8__249__2^0__zél_ 11 __2M__zAJ.__221_ 12 __2^0__2^6__2^4_ 15__zl6__2^5__2^1_ 20__z59__2^3__221_ 27_ -48__-56 2^6_
Mequitazin -—_-61_
Promethazin ____-39__
Claims (1)
- 2. Farmaceutisk præparat, kendetegnet ved, at det som aktivt middel indeholder en effektiv mængde af en forbindelse ifølge krav 1 i blanding med et farmaceutisk acceptabelt fortyndingsmiddel eller bærestof. 1 35
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8330658 | 1983-11-17 | ||
| GB838330658A GB8330658D0 (en) | 1983-11-17 | 1983-11-17 | 7-carboxymethoxy-furo-(3,4-c)-pyridine derivatives |
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| DK545684D0 DK545684D0 (da) | 1984-11-16 |
| DK545684A DK545684A (da) | 1985-05-18 |
| DK157932B true DK157932B (da) | 1990-03-05 |
| DK157932C DK157932C (da) | 1990-08-06 |
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| DK545684A DK157932C (da) | 1983-11-17 | 1984-11-16 | 1,3-dihydro-6-methyl-furo-(3,4-c)-pyridin-derivater og farmaceutiske acceptable salte deraf samt farmaceutisk praeparat indeholdende disse |
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| Country | Link |
|---|---|
| US (1) | US4569938A (da) |
| JP (1) | JPS60116685A (da) |
| AT (1) | AT391868B (da) |
| BE (1) | BE900941A (da) |
| CA (1) | CA1257272A (da) |
| CH (1) | CH660737A5 (da) |
| DE (1) | DE3441975A1 (da) |
| DK (1) | DK157932C (da) |
| DZ (1) | DZ702A1 (da) |
| ES (1) | ES537666A0 (da) |
| FI (1) | FI80701C (da) |
| FR (2) | FR2555181B1 (da) |
| GB (2) | GB8330658D0 (da) |
| HK (1) | HK77987A (da) |
| IE (1) | IE58097B1 (da) |
| IT (1) | IT1177185B (da) |
| LU (1) | LU85634A1 (da) |
| MA (1) | MA20263A1 (da) |
| MY (1) | MY100665A (da) |
| NL (1) | NL8403318A (da) |
| OA (1) | OA07865A (da) |
| SE (1) | SE458277B (da) |
| SG (1) | SG52687G (da) |
| ZA (1) | ZA848128B (da) |
Families Citing this family (22)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8402740D0 (en) * | 1984-02-02 | 1984-03-07 | Scras | Furo-(3 4-c)-pyridine derivatives |
| GB8808001D0 (en) * | 1988-04-06 | 1988-05-05 | Scras | Stereospecific preparative process for furol(3,4-c)pyridine derivatives |
| GB8907480D0 (en) * | 1989-04-03 | 1989-05-17 | Scaras Societe De Conseils De | Separation of insomers of furo(3,4-c)pyridine derivatives |
| US5130252A (en) * | 1990-05-14 | 1992-07-14 | Synthetech, Inc. | Resolution of furopyridine enantiomers and synthetic precursors thereof |
| ES2250112T3 (es) | 1999-03-08 | 2006-04-16 | Medicure Inc. | Analogos de piridoxal para el tratamiento de trastornos causados por carencia de vitamina b6. |
| US6489345B1 (en) | 1999-07-13 | 2002-12-03 | Medicure, Inc. | Treatment of diabetes and related pathologies |
| WO2001013900A2 (en) * | 1999-08-24 | 2001-03-01 | Medicure International Inc. | Compositions for the treatment of cardiovascular diseases containing pyridoxal compounds and cardiovascular compounds |
| US7442689B2 (en) * | 2000-02-29 | 2008-10-28 | Medicure International Inc. | Cardioprotective phosphonates and malonates |
| AU2001237185B2 (en) | 2000-02-29 | 2006-02-02 | Medicure International Inc. | Cardioprotective phosphonates and malonates |
| WO2001072309A2 (en) | 2000-03-28 | 2001-10-04 | Medicure International Inc. | Treatment of cerebrovascular disease |
| US6897228B2 (en) | 2000-07-07 | 2005-05-24 | Medicure International Inc. | Pyridoxine and pyridoxal analogues: new uses |
| WO2002004421A2 (en) | 2000-07-07 | 2002-01-17 | Medicure International Inc. | Pyridoxine and pyridoxal analogues: cardiovascular therapeutics |
| US6548519B1 (en) | 2001-07-06 | 2003-04-15 | Medicure International Inc. | Pyridoxine and pyridoxal analogues: novel uses |
| US20040121988A1 (en) * | 2001-03-28 | 2004-06-24 | Medicure International Inc. | Treatment of cerebrovascular disease |
| US20040186077A1 (en) * | 2003-03-17 | 2004-09-23 | Medicure International Inc. | Novel heteroaryl phosphonates as cardioprotective agents |
| US20060019929A1 (en) * | 2004-07-07 | 2006-01-26 | Albert Friesen | Combination therapies employing platelet aggregation drugs |
| US20070060549A1 (en) * | 2004-08-10 | 2007-03-15 | Friesen Albert D | Combination therapies employing ace inhibitors and uses thereof for the treatment of diabetic disorders |
| CA2585165A1 (en) * | 2004-10-28 | 2006-05-18 | Medicure International Inc. | Dual antiplatelet/anticoagulant pyridoxine analogs |
| US20060094749A1 (en) * | 2004-10-28 | 2006-05-04 | Medicure International Inc. | Substituted pyridoxines as anti-platelet agents |
| US7459468B2 (en) * | 2004-10-28 | 2008-12-02 | Medicure International, Inc. | Aryl sulfonic pyridoxines as antiplatelet agents |
| US20070105817A1 (en) * | 2005-11-09 | 2007-05-10 | Jim Page | Use of cicletanine and other furopyridines for treatment of systolic-predominant hypertension, isolated systolic hypertension, elevated pulse pressure, and general hypertension |
| JP2009517411A (ja) * | 2005-11-28 | 2009-04-30 | メディキュア インターナショナル インコーポレーテッド | 心血管及び関連病状の処置のための調剤 |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AT297442B (de) * | 1970-04-01 | 1972-03-27 | Unilever Nv | Verfahren zum Reinigen, Entfetten, Entzundern und Beizen von Metallen |
| ZA786269B (en) * | 1977-11-25 | 1979-10-31 | Scras | New pyridine derivative,its preparation and use |
| GB2008582B (en) * | 1977-11-25 | 1982-04-28 | Scras | Pyridine derivative |
| IN156817B (da) * | 1981-02-10 | 1985-11-09 | Scras |
-
1983
- 1983-11-17 GB GB838330658A patent/GB8330658D0/en active Pending
-
1984
- 1984-10-17 ZA ZA848128A patent/ZA848128B/xx unknown
- 1984-10-19 GB GB08426489A patent/GB2149781B/en not_active Expired
- 1984-10-26 CH CH5127/84A patent/CH660737A5/fr not_active IP Right Cessation
- 1984-10-30 BE BE0/213925A patent/BE900941A/fr not_active IP Right Cessation
- 1984-11-01 NL NL8403318A patent/NL8403318A/nl not_active Application Discontinuation
- 1984-11-05 US US06/668,394 patent/US4569938A/en not_active Expired - Lifetime
- 1984-11-07 LU LU85634A patent/LU85634A1/fr unknown
- 1984-11-08 FI FI844383A patent/FI80701C/fi not_active IP Right Cessation
- 1984-11-08 MA MA20487A patent/MA20263A1/fr unknown
- 1984-11-14 IT IT23564/84A patent/IT1177185B/it active
- 1984-11-14 DZ DZ847329A patent/DZ702A1/fr active
- 1984-11-14 CA CA000467829A patent/CA1257272A/en not_active Expired
- 1984-11-15 ES ES537666A patent/ES537666A0/es active Granted
- 1984-11-16 IE IE294784A patent/IE58097B1/en not_active IP Right Cessation
- 1984-11-16 DE DE19843441975 patent/DE3441975A1/de active Granted
- 1984-11-16 DK DK545684A patent/DK157932C/da not_active IP Right Cessation
- 1984-11-16 FR FR8417478A patent/FR2555181B1/fr not_active Expired
- 1984-11-16 FR FR8417479A patent/FR2555049B1/fr not_active Expired
- 1984-11-16 SE SE8405754A patent/SE458277B/sv not_active IP Right Cessation
- 1984-11-16 OA OA58442A patent/OA07865A/xx unknown
- 1984-11-16 JP JP59240900A patent/JPS60116685A/ja active Granted
- 1984-11-19 AT AT0365584A patent/AT391868B/de not_active IP Right Cessation
-
1987
- 1987-06-17 SG SG52687A patent/SG52687G/en unknown
- 1987-07-01 MY MYPI87000926A patent/MY100665A/en unknown
- 1987-10-22 HK HK779/87A patent/HK77987A/xx not_active IP Right Cessation
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PBP | Patent lapsed |