IE58583B1 - 6-aminomethyl-furo-(3,4-c)-pyridine derivatives - Google Patents
6-aminomethyl-furo-(3,4-c)-pyridine derivativesInfo
- Publication number
- IE58583B1 IE58583B1 IE218285A IE218285A IE58583B1 IE 58583 B1 IE58583 B1 IE 58583B1 IE 218285 A IE218285 A IE 218285A IE 218285 A IE218285 A IE 218285A IE 58583 B1 IE58583 B1 IE 58583B1
- Authority
- IE
- Ireland
- Prior art keywords
- dihydro
- pyridine
- furo
- hydroxy
- aminomethyl
- Prior art date
Links
- IWTXSCSLCPQLDM-UHFFFAOYSA-N furo[3,4-c]pyridin-6-ylmethanamine Chemical class C1=NC(CN)=CC2=COC=C21 IWTXSCSLCPQLDM-UHFFFAOYSA-N 0.000 title description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 31
- BFJMHTOBRRZELQ-UHFFFAOYSA-N 3-iodo-2h-pyrazolo[3,4-c]pyridine Chemical compound N1=CC=C2C(I)=NNC2=C1 BFJMHTOBRRZELQ-UHFFFAOYSA-N 0.000 claims description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 150000002923 oximes Chemical class 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- QXMZUYAOYNKDBE-UHFFFAOYSA-N 6-(aminomethyl)-1,3-dihydrofuro[3,4-c]pyridin-7-ol Chemical class NCC1=NC=C2COCC2=C1O QXMZUYAOYNKDBE-UHFFFAOYSA-N 0.000 claims description 2
- KEKQEYBOTHGIGL-UHFFFAOYSA-N 7-hydroxyfuro[3,4-c]pyridine-6-carbaldehyde Chemical class C(=O)C1=C(C=2C(C=N1)=COC2)O KEKQEYBOTHGIGL-UHFFFAOYSA-N 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- VKDVZABUBCNBII-UHFFFAOYSA-N 6-(aminomethyl)-3-(4-methoxyphenyl)-1,3-dihydrofuro[3,4-c]pyridin-7-ol Chemical compound COC1=CC=C(C=C1)C1OCC2=C1C=NC(=C2O)CN VKDVZABUBCNBII-UHFFFAOYSA-N 0.000 claims 1
- XASXDPGYTNGCKV-UHFFFAOYSA-N 6-(aminomethyl)-3-cyclohexyl-1,3-dihydrofuro[3,4-c]pyridin-7-ol Chemical compound C1(CCCCC1)C1OCC2=C1C=NC(=C2O)CN XASXDPGYTNGCKV-UHFFFAOYSA-N 0.000 claims 1
- LYGBFMCXQFCBNU-UHFFFAOYSA-N 6-(aminomethyl)-3-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-ol Chemical compound C1=NC(CN)=C(O)C2=C1C(C)OC2 LYGBFMCXQFCBNU-UHFFFAOYSA-N 0.000 claims 1
- HSJAIAWTKSEMII-UHFFFAOYSA-N 6-(aminomethyl)-3-phenyl-1,3-dihydrofuro[3,4-c]pyridin-7-ol Chemical compound C1(=CC=CC=C1)C1OCC2=C1C=NC(=C2O)CN HSJAIAWTKSEMII-UHFFFAOYSA-N 0.000 claims 1
- GNMILOMZPKZBLH-UHFFFAOYSA-N 6-(aminomethyl)-3-propyl-1,3-dihydrofuro[3,4-c]pyridin-7-ol Chemical compound C(CC)C1OCC2=C1C=NC(=C2O)CN GNMILOMZPKZBLH-UHFFFAOYSA-N 0.000 claims 1
- 108090000623 proteins and genes Proteins 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 20
- 150000003839 salts Chemical class 0.000 abstract description 4
- 229910052801 chlorine Inorganic materials 0.000 abstract description 3
- 230000003266 anti-allergic effect Effects 0.000 abstract description 2
- -1 carbomonocycle Chemical group 0.000 abstract description 2
- 125000000623 heterocyclic group Chemical group 0.000 abstract description 2
- 150000002430 hydrocarbons Chemical class 0.000 abstract description 2
- 125000003884 phenylalkyl group Chemical group 0.000 abstract description 2
- 125000006413 ring segment Chemical group 0.000 abstract description 2
- 239000004215 Carbon black (E152) Substances 0.000 abstract 1
- 229930195733 hydrocarbon Natural products 0.000 abstract 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract 1
- 238000002844 melting Methods 0.000 description 24
- 230000008018 melting Effects 0.000 description 24
- 239000000047 product Substances 0.000 description 24
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 208000024780 Urticaria Diseases 0.000 description 4
- 235000011054 acetic acid Nutrition 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 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
- 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
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 229960003699 evans blue Drugs 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-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
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 230000001387 anti-histamine Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 230000028709 inflammatory response Effects 0.000 description 2
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 2
- 229960003910 promethazine Drugs 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 238000013222 sprague-dawley male rat Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 229960000278 theophylline Drugs 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- QJSDODKCGMHMMX-UHFFFAOYSA-N 3-ethyl-7-hydroxy-3-phenyl-1H-furo[3,4-c]pyridine-6-carbaldehyde Chemical compound C(C)C1(OCC2=C1C=NC(=C2O)C=O)C2=CC=CC=C2 QJSDODKCGMHMMX-UHFFFAOYSA-N 0.000 description 1
- NZOCLVWZHBNOKT-UHFFFAOYSA-N 6-methylfuro[3,4-c]pyridin-7-ol Chemical class OC1=C(C)N=CC2=COC=C21 NZOCLVWZHBNOKT-UHFFFAOYSA-N 0.000 description 1
- IKWMZNFDXDHOOL-UHFFFAOYSA-N 7-hydroxy-3-(4-methoxyphenyl)-1,3-dihydrofuro[3,4-c]pyridine-6-carbaldehyde Chemical compound COC1=CC=C(C=C1)C1OCC2=C1C=NC(=C2O)C=O IKWMZNFDXDHOOL-UHFFFAOYSA-N 0.000 description 1
- NPGWFLVNYKKUMM-UHFFFAOYSA-N 7-hydroxy-3-phenyl-1,3-dihydrofuro[3,4-c]pyridine-6-carbaldehyde Chemical compound C1(=CC=CC=C1)C1OCC2=C1C=NC(=C2O)C=O NPGWFLVNYKKUMM-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 1
- HOKDBMAJZXIPGC-UHFFFAOYSA-N Mequitazine Chemical compound C12=CC=CC=C2SC2=CC=CC=C2N1CC1C(CC2)CCN2C1 HOKDBMAJZXIPGC-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- 125000004984 dialkylaminoalkoxy group Chemical group 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- YVECRCZZSGAGOW-UHFFFAOYSA-N furo[3,4-c]pyridin-1-ol Chemical compound C1=NC=CC2=C(O)OC=C21 YVECRCZZSGAGOW-UHFFFAOYSA-N 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 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
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 239000011572 manganese Substances 0.000 description 1
- 229960005042 mequitazine Drugs 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000003287 optical effect Effects 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
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 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
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Compounds of the general formula (A1,A2 independently = H, C1-C5 hydrocarbon, heterocycle up to 6 ring atoms, carbomonocycle, phenylalkyl, phenylalkenyl; each (except H) unsubstituted or substituted by one or more of F, Cl, CF3, C1-C5alkyl, C1-C5alkoxy, C1-C5alkylthio, di (C1-C5alkyl)amino, di(C1-C5alkyl)amino-(C1-C5alkoxy), alpha - or beta -(C1-C5alkoxy)-N-pyrrolidinyl) and their salts have antiallergic action.
Description
6-Aminomethyl-Furo-(3,4-c HPyridine Derivatives DESCRIPTION: The invention relates to 6-aminomethyl-furo-(3,4-c) pyridine derivatives, to a process for their preparation and to pharmaceutical compositions containing them.
The invention provides the 1,3-dihydro-6-aminomethyl-7hydroxy-furo-(3,4-c) -pyridine derivatives of the general formula I wherein each of A^ and A^ independently represents a hydrogen atom, a straight chain saturated or unsaturated hydrocarbon group having from 1 to 5 carbon atoms, a heterocyclic group having up to 6 ring atoms, a cycloalkyl group, a phenyl group or a phenylalkyl group, each of the groups represented by A^ and A^ being unsubstituted or being substituted by one or more chlorine or fluorine atoms, trifluoromethyl groups, alkyl groups having from 1 to 5 carbon atoms, alkoxy groups having from 1 to 5 carbon atoms, alkylthio groups having from 1 to 5 carbon atoms, dialkylamino groups in which each alkyl group has from 1 to 5 carbon atoms, dialkylaminoalkoxy groups in which each of the two alkyl groups and the alkoxy group has from 1 to 5 carbon atoms oroc-or f}-(μ-pvr ro.i Idinyi )-alkoxy groups in which the alkoxy group has from I to 5 carbon atoms ; and further provides pharmaceutically acceptable salts of such compounds.
The compounds according to the invention are of interest for their therapeutical activity, principally in the field of antiallergic action.
The invention also provides a process for the preparation of the above mentioned compounds, the process comprising reacting the 6-forroy1-7-hydroxy-furo-(3,4-c) pyridine derivatives of the general formula II II HO « OHC wherein A^ and A^ have the < amount of hydroxylamine in water, under basic conditions, and catalytically hydrogenating the resultant oxime. The reaction of the compound H with hydroxylamine is preferably carried out in aqueous sodium hydroxide solution at ambient temperature. The oxime is preferably hydrogenated at room temperature, under normal pressure, in acetic acid, by hydrogen in the presence of a Pc/C catalyst. The process is illustrated by the following reaction scheme: nh2oh h2 * I or M- CHO above meanings with a stoichiometric hi— CHO N — OH Pd/C The 6- formyl -7 -hydroxy- furo- (3,4-c) -pyridine derivatives II may be obtained from corresponding 6-methyl-7hydroxy-furo-(3,4-c)-pyridine derivatives of the general formula III III wherein A^ and A^ have sequence of reactions : the above meanings by the following MnO2 -> The compounds XII are disclosed in our Patent No. 2 092 586 and Patent Application No. 84 07082. (2137618) The preparation of one only of the starting compounds, l,3-dihydro-3-p-chlorophenyl-6-formy 1-7-hydroxy-f uro- (3,4-c) 5 pyridine, is now described in detail, other .starting materials being obtained by the same way. a) Into a one litre reactor fitted with stirring, warming and cooling means, 22.3 g of l,3-dihydro-3-p—chlorophenyl-6-methyl-7-hydroxy-furo-(3,4-c)-pyridine were treated 10 at 0°C, in the presence of 300 ml of methylene dichloride, with 18.2 g of m-peroxybenzoic acid, slowly added. After stirring overnight at room temperature, there were added 150 ml of 10 % sodium sulphate solution. After stirring and decantation, the methylene dichloride phase was washed with the same amount of sodium sulphate solution, twice with 150 ml of sodium bicarbonate solution and three times with 100 ml of water, and then dried over anhydrous sodium sulphate. On evaporation to dryness, there was obtained a beige precipitate which was washed with petroleum ether, filtered and dried.
Yield 22.9 g (96 %) of l,3-dihydro-3-£-chlorophenyl-6-methyl7-hydroxy-furo-(3,4-c)-pyridine-N-oxide. b) In the same reactor as above, the 22.9 g of the compound obtained in the previous step were treated at 0-5°C, in the presence of 175 ml of methylene dichloride, with 4.3 ml of trifluoroacetic anhydride added dropwise under stirring. The mixture was stirred overnight at room temperature, and then cooled and treated dropwise with 95 ml of methanol. After evaporation to dryness, the residue was taken up in 300 ml of chloroform, washed twice with 75 ml of 10 % sodium bicarbonate solution and three times with 100 ml of water and dried on anhydrous sodium sulphate. The chloroform was evaporated off and the residue was washed with diethyl ether and dried under reduced pressure. Yield 21.3 g (93 %) .of l,3-dihydro-3-jochloropheny 1-6-hy dr oxyme thy 1-7-hydroxy-furo- (3,4-c) -pyr idine. c) In a 2 litre reactor, the 21.3 g of the compound obtained in the previous step were treated with 27 g of manganese cioxide in the presence of 0.9 litre of chloroform at 28-30°C, under stirring for 3 hours. After separation, fitration, washing with chloroform and then with ethyl acetate, the solution was evaporated to dryness and the paste treated with isopropyl oxide then with pentane. There was thus obtained 20.1 g (95 %) of 1,3-dihydro-3-jo-chloropheny 1-6f or my 1-7-hydroxy-f uro- (3,4-c) -pyr idine.
The invention further provides a pharmaceutical composition comprising a l,3-dihydro-6-aminomethyl-7-hydroxyfuro-(3,4-c)-pyridine derivative of the general formula I as above defined or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable diluent or carrier .
The invention is illustrated by the following examples; Example 1 1,3-dihydro-3-methyl-6-aminomethyl-7-hydroxy-furo-(3,4-c)pyr idine Into a 2 litre reactor, at room temperature, were poured 71.2 g (0.4 mol) of l,3-dihydro-3-methyl-6-formyl-7hydroxy-furo-(3,4-c)-pyridine, 270 ml of IN sodium hydroxide and then, dropwise under stirring, 27.8 g (0.4 mol) of hydroxyIamine hydrochloride dissolved in 200 ml of water. Stirring was maintained for 10 hours and the reacting mixture was filtered, to give, after washing with water and drying, 74 g (96 %) of the corresponding 6-oxime derivative.
The 74 g of the 6-oxirae derivative were then poured with 0.9 litre of acetic acid into a closed reactor fitted with gaseous circulation means after circulating nitrogen c of Palladium on Carbon catalyst were placed in the reactor and the mixture was stirred at room temperature with a measured hydrogen addition unde.r normal pressure, for 4 hours.
After filtration of the reacting mixture, it was evaporated to dryness. The residue was treated with toluene and then with methanol from which were recrystallized 70 g (76 %) of the acetate of l,3-dihydro-3-methyl-6-aminomethyl-7hydroxy-furo-(3,4—c)-pyridine, a beige product melting at 167°C (Tottoli) , the analysis of which showed a good correspondence with the formula C9H^2N2O2' C2H4°2 * Th^s compound was insoluble in water.
As compounds, following the same route was used for operative details will not examples. The corresponding acetic moiety) and other salts of said usual. all the synthetized be repeated in the bases (without the bases are obtained as Example 2 l,3-dihydro-3-propy1-6-aminomethyl-7-hydroxy-furo-(3,4-c)pyr idine Starting with l,3-dihyaro-3-propyl-6-formyl-7-hydroxyfuro-(3,4-c)-pyridine, there was obtained (yield 77 %) a pale beige product, melting at 187°C (Tottoli), insoluble in water, the analysis of which showed a good correspondence with the formula CllWj. C.,H4O2.
Example 3 l,3-dihydro-3-(31 ,41 ,5' -trimethoxypheny1)-ethyl-6-aminomethyl7-hydroxy-furo-(3,4-c)-pyridine Starting with 1,3-dihydro-3-(3’ ,4’ ,5’-trimethoxyphenyl) -ethyl-6-forrayl-7-hydroxy-furo-(3,4-c)-pyridine, there was obtained (yield 61 %) , a white product, melting at 140-144°C (Tottoli), insoluble in water, the analysis of which showed a good correspondence with the formula C19H24N2°5C2H4°2Example 4 1,3-d ihydro-3-cyclohexy1-6-aminomethy1-7-hydroxy-furo-(3,4-c)pyr idine Starting with l,3-dihydro-3-cyclohexyl-6-formyl-7hydroxy-furo-(3,4-c)-pyridine, there was obtained (yield 67 %) a white product, melting at 173-177°C (Tottoli), insoluble in water, the analysis of which showed a good correspondence with the formula Example 5 1,3-dihvdro-3- a -thienv1-6-aminomethy1-7-hydroxy-furo-(3,4-c)pyr idine Starting with 1,3-dihydro-3- a -thieny1-6-formy1-7hydroxy-furo- (3,4 —c)-pyridine, there was obtained (yield 58 %) a yellowish product, melting at 148°C (Tottoli), insoluble in water, the analysis of which showed a good correspondence with the formula C12H12N2O2S1· C2H4O2.
Example 6 1,3-dihydro-3-phenvl-6-aminomethyl-7-hydroxy-furo-(3,4-c)pyr idine Starting with 1,3-dihydro-3-phenyl-6-formyl-7-hydroxyfuro-(3,4-c)-pyridine, there was obtained (yield 82 %) a pale beige product, melting at 188°C (Tottoli), insoluble in water, the analysis of which showed a good correspondence with the formula C^,^.
Example 7 1.3- dihvdro-3-p-chloroohenvl-6-aminomethvl-7-hydroxv-furo(3,4-c) -pyridine Starting with 1,3-dihydro-3-p-chlorophenyl-6-formy1-7hydroxy-furo- (3 , 4-c) -pyr idine, there was obtained (yield 86 %) a pale beige product, melting at 204-206°C (Tottoli), insoluble in water, the analysis of which showed a good correspondence with the formula C. , H. _,C1N„O„ . C-H.CL·. 13 2 2 2 4 2 Example 8 1.3- dihydro-3-(2* ,3' -dichloropheny1)-6-aminomethyl-7-hydroxyfuro-(3,4-c)-pyr idine Starting with l,3-dihydro-3-(2',3’-aichlorophenyl)-6f ormy 1-7-hydroxy-furo-(3,4-c)-pyridine, there was obtained (yield 72 %) a pale yellow product, melting at -193-196°C (Tottoli), insoluble in water, the analysis of which showed a good correspondence with the formula C, . H, Cl N O C κ n 12 2 2 2 242' Example 9 1,3-dihydro-3-p-f luorophenvl-6-aminomethyl-7-hydroxv-furo(3,4-c)-pvriaine Starting with 1,3-dihydro-3-p-fluorophenyl—6-formy1-75 hydroxy-furo-(3,4-c)-pyridine, there was obtained (yield 69 %) a pale beige product, melting at 183-187°C (Tottoli), insoluble in water, the analysis of which showed a good correspondence with the formula C2H4°2* * Example 10 1,3-dihydro-3-p-tolvl -6-aminomethyl-7-hydroxy-furo-(3,4-c)pyr idine Starting with 1,3-dihydro-3-p-tolyl -6-formy 1-7-hydroxy -furo-(3,4-c)-pyridine, there was obtained (yield 78 %) a pale beige product, melting at 158-160°C (Tottoli), insoluble in water, the analysis of which showed a good correspondence with the formula C.cH,rN_O_. C_H.O_. 16 2 2 242 Example 11 1,3-dihydro-3-p-methoxvphenyl-6-aminomethyl-7-hydroxy-furo(3,4-c)-pyr idine Starting with 1,3-dihydro-3-p-methoxyphenyl-6-formvl7—hydroxy-furo-(3,4-c)-pyridine, there «was obtained (yield * 62 %) a pale beige product, melting at 144-149°C (Tottoli), insoluble in water, the analysis of which showed a good · correspondence with the formula i'2K4°2* Example 12 1,3-dihydro-3-(3' ,4' , 51-trimethoxy)-phenyl-6-aminomethyl-7hydroxy-furo-(3,4-c)-pyridine Starting with 1,3-dihydro-3-(3' ,4' ,5'-trimethoxy)pheny1-6-formy1-7-hydroxy-furo-(3,4-c)-pyr idine , there was obtained (yield 49 %) a whitish product, melting at 137-141°C (Tottoli) , insoluble in water, the analysis of which showed a good correspondence with the formula C17H20N2°5- C2H4°2Example 13 1,3-dihydro-3-m-tr ifluoromethylpheny1-6-aminomethy1-7-hydroxyfuro-(3,4-c)-pyridine Starting with l,3-dihydro-3-m-trifluoromethylphenyl6-formy 1-7-hydroxy-furo-(3,4-c)-pyr idine, there was obtained (yield 84 %) of a white product, melting at 197-203°C (Tottoli), insoluble in water, the analysis of which showed a good correspondence with the formula C15H13F3N2°2· C2H4°2Example 14 1,3-dihydro-3-p-dimethylaminoethoxypheny1-6-aminomethyl-7hvdroxv-furo-(3,4-c)-pyr icine Starting with 1,3-dihydro-3-p-dimethylaminoethoxyphenyl-6-formyl-7-hydroxy-furo-(3,4-c)-pyridine, there was obtained (yield 46 %) a pale yellow product, melting at 160-164°C (Tottoli), insoluble in water, the analysis of which showed good correspondence with the formula C19H23N3°2’ C2H4°2* Example 15 1,3-dihydro-3-methyl-3-a -thienv1-6-aminomethy1-7-hydroxyfuro- (3,4-c)-pyridine Starting with 1,3-dihyaro-3-methy1-3- a -thienyl-625 formy 1-7-hydroxy-furo-(3,4-c)-pyridine, there was obtained (yield 66 %) a white product, melting (Tottoli), poorly soluble in water, showed a good correspondence.
C13H14N2°2S-C2H4°2· at 206-208°C the analysis of which with the formula Example 16 1,3-dihycro-3-e thyl-3-pheny 1-6-aminome thy 1-7-hyaroxy-furo(3,4-c)-pyr idine Starting with 1,3-dihydro-3-ethyl-3-phenyl-6-formyl7-hydroxy-furo-(3,4-c) -pyridine, there was obtained (yield 80 %) a white product, melting at 207°C (Tottoli), insoluble in water, the analysis of which showed a good correspondence with the formula cigH18N2O2· C2H4°2* Example 17 1,3-dihydro-3-phenvl—3-p-trifluoromethylphenyl-6-aminomethyl7-hydroxy-furo-(3 ,4-c) -pyridine Starting with l,3-dihydro-3-phenyl-3-p-trifluoromethylphenyl-6-formyl-7-hydroxy-furo-(3,4-c)-pyridine, there was obtained (yield 65 %) a white product, melting at 221°C (Tottoli) , insoluble in water, the analysis of which showed a good correspondence with the formula ♦ <2H4°2’ Example 18 1,3-di hydro-3-p- (N-pyrrolidinylmethoxy) -phenvl-fi-ami. nomethyl -7-hvdroxy-furo-(3,4-c)-pyridine .
Starting with 1,3-dihydro-3-p-(N-pyrrolidinylmethoxy)phenyl-6-formyl-7-hydroxy-furo-( 3,4-c )-pyridine, there was obtained (yield 41%) a yellowish product, melting at 129132°C (Tottoli), insoluble in water, the analysis of which showed a good correspondence with the formula ^9^23^3^3 C-H.Oz 4 2.
Example 19 1,3-dihydro-3, 3-di-p-fluoropheny1-6-aminomethy1-7-hydroxyfuro-(3 f 4-c)-pyr idine Starting with 1,3-dihydro-3,3-di-p-fluoropheny1-6formy1-7-hydroxy-furo-(3,4-c)-pyridine, there was obtained was (yield 81 %) a pale yellow product, melting at 214°C (Tottoli), insoluble in water, the analysis of which showed a good correspondence with the formula C2OH16F2N2°2· C2H4°2’ Example 20 * 5 1,3-dihydro-3-α -furyl-3-p-thiomethylphenyl-6-aminomethyl-7hydroxy-furo-(3,4-c) -pyridine Starting with 1,3-dihydro-3- α -furyl-3-p-thiomethylphenyl-6-formyl-7-'nydroxy-f uro-(3,4-c)-pyr idine, there was obtained (yield 63 %) a whitish product, melting at 153-157°C (Tottoli) , insoluble in water, the analysis of which showed a good correspondence with the formula CigHlgN2O3S. C2H4O2.
Example 21 1,3-dihydro-3,3-c i-g -furvl-6-aminomethy1-7-hydroxy-furo(3,4-c)-pyr idine Starting with 1,3-dihydro-3,3-di- a-furyl-5-formyl-7hydroxy-furo-(3,4-c)-pyridine, there was obtained (yield 72 %) a white product, melting at 178°C (Tottoli), insoluble in water, the analysis of which showed a good correspondence with the formula C H,.N_O.. C_H.CL·. 14 2 4 242 5 20 Example 22 1,3-dihvdro-3-cyclohexy1-3-(21 ,3' ,-dichloro)-phenv1-6-amino* methyl-7-hvdroxy-furo-(3,4-c)-pyr idine Starting with 1,3-dihydro-3-cyciohexy1-3-(21 ,3’dichlorophenv1)-6- formyl -7-hyaroxy- furo - (3,4-c)-pyridine, there was obtained (yield 59 %) a yellow product, melting at 213°C (Tottoli) , insoluble in water, the analysis of which showed a good correspondence with the formula C20H22C12N2°24 C2H4°2’ Example 23 1,3-d ihydro-3-vinyl-3-p-thiomethylphenyl-6-aminomethyl-7hydroxy-furo-(3,4-c)-pyridine Starting with l,3-dihydro-3-vinyl-3-p-thiomethylphenyl5 6-formy1-7-hydroxy-furo-(3,4-c)-pyridine, there was obtained (yield 66 %) a beige product, melting at 155°C (Tottoli), insoluble in water, the analysis of which showed a good correspondence with the formula Cn_H, ON„CLS. C-H.O-. 18 2 2 2 4 2 Example 24 1,3-dihyaro-3-dimethylaminopropyl-3-p-chlorophenv1-6-aminomethyl-7-hydroxy-furo-(3,4-c)-pyridine Starting with 1,3-dihydro-3-aimethylaminopropyl-3-pchlorophenyl-6-formyl-7-hyaroxy-furo-(3,4-c)-pyr idine, there was obtained (yield 47 %) a white product, melting at 169°C (Tottoli), insoluble in water, the analysis of which showed a good correspondence with the formula cigH24C^ N3°2' C2H4°2' TOXICITY DL^q was determined per os and IP on mice- According to the compounds, it was comprised between 0.7 to over 2.4 g/Kg (per os) and'0.6 to 1.65 g/Kg IP.
PHARMACOLOGY A complete pharmacological experimentation was conducted and the following tests are reported below.
A - Passive cutaneous anaphylaxy This experiment was conducted as described in Ficne Technique n° 48 of J.Pharm. Paris 1979 10 (1) pages 69-72.
Male Sprague-Dawley rats (180-200 g) received two intra-dermal injections of immunserum in the back ; 72 hours later, they received a IV (penis vein) injection of 1 ml of a mixture of ovalbumine (5 mg/ml) and Evans blue (2.5 mg/ml) : this induced the formation of wheals around the places of injection of immunserum. Wheals were taken 30 minutes after this formation, measured then incubated for 24 hours at 65°C in 4 ml of formamide (for extracting the Evans blue). Optical density of the supernatant was determined at 620 nm by a spectrophotometer.
A first batch of 8 rats was used for control ; a second batch (8) was used for treatment by a reference compound (theophylline, 25 mg/Kg) and ten other batches (all of 8 rats) were used for the treatment by 10 of the compounds of the present invention (all at 25 mg/Kg) identified by their example number ; for these eleven batches, the appropriate compound was administered per os, one hour before the injection of ovalbumine/Evans blue mixture. The percentage of wheals reduction, in surface and in colour was determined by comparison with the control. The results are reported on the left part of the following table.
B - Anti-histaminic action This experiment was conducted as described by Doepfner W. and Cerletti A., Int. Arch. Allergy 12 , 89 1958 and J.
Pharmac. and exp. Ther. (1974) 191 (2) pages 300-310.
Male Sprague-Dawley rats (140-160 g) were submitted to hydric fast for 18 hours before receiving 1 ml/Kg of water (for control), 0.2 of an aqueous solution or suspension of experimented compounds. The volume of the left posterior paw was measured by plethysmography, then 0.1 ml of 5 % histamine hydrochloride was injected. The inflammatory response was evaluated by a subsequent volume determination one hour later.
Batches of each 8 animals were used : one for control, ten for tested compounds (the same as in A above) and two for reference compounds mequitazine and promethazine, all at the dose of 25 mg/Kg. The percentage of reduction of inflammatory response was obtained by comparison with control. The results are reported in the right part of the following table.
From these two experiments, it clearly appears that the compounds of the invention present a strong anti-histaminic action.
PRESENTATION - POSOLOGY For human use by oral route, tablets or gelatine capsules containing 0.20 a of a compound according to the invention are preferred. By IV route, phials containing the same amount, to be injected with a perfusion are retained.
Daily coses in human therapy are from 0.20 to 2 g per os and 0.20 to 1 g, IV.
Compounds % of wheals reduction Histamine induced Oedema % of inflammatory reduction Surface Colour Theophylline - 60 - 62 Ex 1 - 77 - 86 - 48 Ex 2 - 58 - 60 - 77 Ex 4 - 61 - 66 - 59 Ex 5 - 49 - 60 Ex 6 - 75 - 84 - 79 Ex 9 - 68 - 72 - 83 Ex 10 - 68 - 72 - 66 Ex 14 - 71 - 81 - 51 Ex 16 - 53 - 59 - 54 Ex 18 - 65 - 69 - 62 Meauitaz ine - 60 Promethaz ine - 41
Claims (1)
1. A 1,3-dihydro-6-aminomethyl-7-hydroxy-furo-(3,4-c)-pyridine derivative having the general formula I as herein defined. 5 2. 1,3-dihydro-3-methyl-6-aminomethyl-7-hydroxy-furo- (3,4-c)-pyridine. 3. 1,3-dihydro-3-propyl-6-aminomethyl-7-hydroxy-furo- (3,4-c)-pyridine. * 4. . 1,3-dihydro-3-(3',4',5’-trimethoxyphenyl )-ethyl-610 -aminomethyl-7-hydroxy-f uro- ( 3,4-c)-pyridine. 5. . 1,3-dihydro-3-cyclohexyl-6-aminomethyl-7-hydroxy-furo-(3,4-c)-pyridine. 6. . 1,3-dihydro-3-rf.-thienyl~6-aminomethyl- 7. -hydroxy-furo-(3,4-c)-pyridine. . 15 7. 1,3-dihydro-3-phenyl-6-aminomethyl-7-hydroxy-furo-(3,4-c)-pyridine. 8. . 1, 3-dihydro-3-p-chlorophenyl-6-aminomethy1-7-hydroxy-furo-(3,4-c)-pyridine. 9. 1,3-dihydro-3-(2',3’-dichlorophenyl )-6-aminomethyl20 -7-hydroxy-f uro- ( 3,4-c ) -pyridine . 10. . 1, 3-dihydro-3-p-fIuorophenyl-6-aminomethyl-7-hydroxy-furo-(3,4-c)-pyridine . 11. 1,3-dihyaro-3-p-to?.yl-6-eminoniethyl- 7-hydroxy-furo-(3,4-c)-pyrid ine. 25 12. 1,3-dihydro-3-p-methoxyphenyl-6-aminomethyl-7-hydroxyfuro-(3,4-c)-pyridine . -1613- 1,3-dihydro-3-(3‘ , 4 ’ , 5 ’-trimethoxy ) -phenyl-6-aminomethy1 -7-hydroxy-f uro- ( 3 , A -c ) -pyridine. 12. 14. 1,3-dihydro-3-m—trif luoromethylphenyl-6-aminomethyl-7-hydroxy-furo-(3,4-c)-pyridine. 5 15. l,3-dihydro-3-p—dimethylaminoethoxyphenyl-6-aniinomethyl-7-hydroxy-furo-(3,4 )-pyridine. « 16. 1,3-dihydro-3-methyl-3-rt-thienyl-6-aminomethyl-7* -hydroxy-furo (3,4-c)-pyridine. 17 . 1,3-dihydro-3-ethyl-3-phenyl-6-aminomethyl-7-hydroxy10 -furo-(3,4-c)-pyridine. 18. 1,3-dihydro-3-phenyl-3-£-trif luoromethylpheny 1-6-aminomethyl-7-hydroxy-furo-(3,4-c)-pyridine. 19 . 1,3-dihydro-3-p- ( M-pyrrolidinylmsthoxy) -phenyl-6-aminomethyl-7-hydroxy-furo-(3,4-c)-pyridine. 13. 15 20. 1,3-dihydro-3,3-di-p-f luorophenyl-6-aminoinethy 1-7-hydroxy-f uro- (3,4-c ) -pyridine. 21. 1,3-dihydro-3-&-f uryl-3-p-thiomethylphenyl -6-aminomethyl-7-hydroxy-furo- ( 3,4-c )-pyridine. » 22. 1,3-dihydro-3,3-di-c(-f uryl-6-aminomethyl-7-hydroxy20 -furo-(3,4-c)-pyridine . * 23 . 1,3-dihydro-3-cyclohexyl-3-(2',3',-dichloro)-phenyl -6-aminomethyl-7-hyaroxy-f uro-(3,4-c)-pyridine. 24 . 1,3-dihydro-3-vinyl-3-p-thiome-thylphenyl-6-aminomethyl -7-hydroxy-furo- ( 3,4 -c ) -pyrit.ine. -1925. 1,3-dihydro-3-dimethylaminopropyl-3-£-chlorophenyl-6-aminomethyl-7-hydroxy-f uro- (3,4-c) -pyridine. 26. Preparation process of the comnounds according to claim I comprising reacting the 6-formyl-7hydroxy-furo-(3,4-C)- pyridine derivatives of the gene of the general formula. wherein Aj. and A^ have the above meanings with a stoichiometric amount of hydroxylamine and of NaOH, in water, at room temperature, then hydrogenating the oxime thus obtained, at room temperature, under normal pressure, in acetic acid, by hydrogen in the presence of Pd/C catalyst. 27. A process for the preparation of a 1,3-dihydro-6-aminomethy 1-7-hydroxy-f uro- ( 3,4-c ) -pyridine derivative having the general formula I as herein defined, the process being substantially as described herein with reference to any of the Examples. 28. a pharmaceutical composition comprising a 1,3-dihvdro-6-aminomethyl-7-hydroxv-f uro- ( 3,4-c ) -pyridine derivative according to any of claims 1 to 25 in admixture with a pharmaceutically acceptable diluent or carrier.
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| 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 |
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| ZA842029B (en) * | 1983-04-05 | 1984-10-31 | Scras | Furo-(3,4-c)-pyridine derivatives preparation thereof and therapeutic compositions containing the same |
| GB8330517D0 (en) * | 1983-11-16 | 1983-12-21 | Scras | 6-vinyl-furo-(3,4-c)pyridine derivatives |
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| Date | Code | Title | Description |
|---|---|---|---|
| MM4A | Patent lapsed |