DK159318B - 1,3-DIHYDRO-6-AMINOMETHYL-7-HYDROXY-FURO- (3,4-C) -PYRIDINE DERIVATIVES AND MEDICINALS CONTAINING SUCH COMPOUNDS - Google Patents
1,3-DIHYDRO-6-AMINOMETHYL-7-HYDROXY-FURO- (3,4-C) -PYRIDINE DERIVATIVES AND MEDICINALS CONTAINING SUCH COMPOUNDS Download PDFInfo
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- 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
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Description
DK 159318 8 iDK 159318 8 i
Den foreliggende opfindelse angår 1,3-dihydro-6-amino-methyl-7-hydroxy-furo-(3,4-c)-pyridin-derivater og lægemidler indeholdende sådanne forbindelser.The present invention relates to 1,3-dihydro-6-amino-methyl-7-hydroxy-furo- (3,4-c) -pyridine derivatives and drugs containing such compounds.
5 1,3-dihydro-6-amino-methyl-7-hydroxy-furo-(3,4-c)- pyridin-derivaterne ifølge opfindelsen er ejendommelig ved det i krav l’s kendetegnende del anførte.The 1,3-dihydro-6-amino-methyl-7-hydroxy-furo (3,4-c) pyridine derivatives of the invention are characterized by the characterizing part of claim 1.
Lægemidlet ifølge opfindelsen er ejendommeligt ved det i 10 krav 2's kendetegnende del anførte.The medicament according to the invention is characterized by the characterizing part of claim 10.
Forbindelserne ifølge opfindelsen er af interesse på grund af deres terapeutiske aktivitet, især deres anti-allergiske virkning.The compounds of the invention are of interest because of their therapeutic activity, especially their anti-allergic effect.
1515
Forbindelserne ifølge opfindelsen fremstilles ved, at man i vand og ved stuetemperatur omsætter 6-formyl-7-hydroxy-furo-(3,4-c)-pyridin-derivater med den almene formel: 20 MIMMM 0 1 >Ai (ii) ΛΓ2The compounds of the invention are prepared by reacting in water and at room temperature 6-formyl-7-hydroxy-furo (3,4-c) pyridine derivatives of the general formula: 20 MIMMM 0 1> Ai (ii) ΛΓ2
25 0HC N eller forkortet M-CHO25 OH HC N or abbreviated M-CHO
hvori A^ og har den ovenfor anførte betydning, med en støkiometrisk mængde hydroxylamin og NaOH og ved, at man 30 derpå hydrogenerer den således opnåede oxim ved stuetemperatur under normaltryk i eddikesyre med hydrogen i nærvær af en Pd/C-katalysator i overensstemmelse med følgende reaktionsskema: 35 2wherein A 2 and have the meaning given above, with a stoichiometric amount of hydroxylamine and NaOH, and then hydrogenating the oxime thus obtained at room temperature under normal pressure in acetic acid with hydrogen in the presence of a Pd / C catalyst according to the following reaction scheme: 2
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nh2°h ^ h2 M—CHO ---> M-CH = N-OH -> (i)nh2 ° h ^ h2 M-CHO ---> M-CH = N-OH -> (i)
Pd/CPd / C
5 og derpå eventuelt omdanner den således opnåede aminomethyl-forbindelse til et farmaceutisk acceptabelt salt deraf.5 and then optionally converting the thus obtained aminomethyl compound to a pharmaceutically acceptable salt thereof.
6-formyl-7-hydroxy-furo-(3Λ-c)-pyridin-der ivaterne med form-len (II).· kan opnås iud fra de tilsvarende 6-methyl-7-hydroxy-furo-(3,4-c)-pyridin-derivater med den almene formel:6-Formyl-7-hydroxy-furo- (3Λ-c) -pyridine ivates of formula (II) can be obtained from the corresponding 6-methyl-7-hydroxy-furo- c) -pyridine derivatives of the general formula:
_O_ISLAND
La H0 —& it* (111) 15 L l| a2 H3c n hvori A1 og A2 har den tidligere anførte betydning, idet man 2o anvender følgende rækkefølge af reaktioner:La H0 - & it * (111) 15 L l | a2 H3c n wherein A1 and A2 have the previously stated meaning, using 2o the following sequence of reactions:
_O_ISLAND
L,A1L, A1
25 HO25 HO
IJ 2 m-chlorperoxybenzoesyr^ r Nm/ r h3cIJ 2 m-chloroperoxybenzoic acid Nm / r h3c
30 _O30 _O
' HO—(CF3C0)20 IJ A2 -*HO (CF3CO) 20 IJ A2 - *
35 H„C N35 H ° C N
iin
OISLAND
33
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__O__ISLAND
y>kly> at
HO -MnC>2 HO-— CH^ NHO -MnC> 2 HO-— CH ^ N
__O__ISLAND
10 OHC N 1510 OHC N 15
Pyridinforbindelserne med formlen (III) er omtalt i fransk patentansøgning nr. 82 543 og i dansk patentansøgning nr. 1780/84.The pyridine compounds of formula (III) are disclosed in French Patent Application No. 82 543 and in Danish Patent Application No. 1780/84.
20 I det følgende er fremstillingen af én af udgangsforbindelserne, 1,3-dihydro-3-p-chlorphenyl-6-formyl-7-hydroxy-furo-(3,4-c)-pyridin beskrevet detaljeret, idet man kan opnå andre udgangsmaterialer på tilsvarende måde.In the following, the preparation of one of the starting compounds, 1,3-dihydro-3-p-chlorophenyl-6-formyl-7-hydroxy-furo- (3,4-c) -pyridine, is described in detail, obtaining other starting materials in a similar manner.
25 a) Man behandlede i en reaktor på 1 liter, som var udstyret med midler til omrøring, til opvarmning og til afkøling, 22,3 g 1,3-dihydro-3-p-chlorphenyl-6-formyl-7-hydroxy-furo-(3,4-c)-pyridin ved 0°C og i nærvær af 300 ml méthylendichlo-30 rid med 18,2 g m-peroxybenzoesyre, der langsomt blev tilsat. Efter omrøring natten over ved stuetemperatur tilsatte man 150 ml 10% natriumsulfatopløsning. Efter omrøring og dekantering ble.v methylendichloridfasen vasket med den samme mængde natriumsulfatopløsning, to gange med 150 ml natriumhydrogen-35 carbonatopløsning og tre gange med 100jml vand, hvorpå den blev tørret over vandfrit natriumsulfat. Man opnåede ved ind-dampning til tørhed et beigefarvet bundfald, som blev vasketA) In a 1 liter reactor equipped with stirring, heating and cooling agents, 22.3 g of 1,3-dihydro-3-p-chlorophenyl-6-formyl-7-hydroxy hydrochloride were treated. furo- (3,4-c) -pyridine at 0 ° C and in the presence of 300 ml of methylene dichloride with 18.2 g of m-peroxybenzoic acid which was slowly added. After stirring overnight at room temperature, 150 ml of 10% sodium sulfate solution was added. After stirring and decanting, the methylene dichloride phase was washed with the same amount of sodium sulfate solution, twice with 150 ml of sodium hydrogencarbonate solution and three times with 100 µl of water, and then dried over anhydrous sodium sulfate. Evaporation to dryness gave a beige precipitate which was washed
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4 ! i med petroleumsether, filtreret og tørret. Udbytte 22,9 g ! (96%) l,3-dihydro-3-p-chlorphenyl-6-methyl-7-hydroxy-furo-(3,4-c)-pyridin-N-oxid.4! in with petroleum ether, filtered and dried. Yield 22.9 g! (96%) 1,3-dihydro-3-p-chlorophenyl-6-methyl-7-hydroxy-furo- (3,4-c) -pyridine N-oxide.
i 5 b) Man behandlede i den samme reaktor som ovenfor anvendt 22,9 g af den i det forudgående syntesetrin opnåede forbindelse ved 0-5°C i nærvær af 175 ml methylendichlorid med 4,5 ml trifluoreddikesyrearihydrid, som blev tilsat dråbe for dråbe under omrøring. Blandingen blev omrørt natten over ved 10 I stuetemperatur og derpå afkølet og behandlet ved dråbevis til-1 sætning af ialt 75 ml methanol. Efter inddampning til tørhed ! blev inddampningsresten opløst i 500 ml chloroform, vasket i : to gange med 75 ml 10% natriumhydrogencarbonatopløsning og I tre gange med 100 ml vand og tørret over vandfrit natriumsul-15 fat. Chloroformen blev afdampet, og inddampningsresten blev vasket med diethylether og tørret under reduceret tryk. Udbytte 21,5 g (95%) l,5-dihydro-5-p-chlorphenyl-6-hydroxy-methyl-7-hydroxy-furo-(5,4-c)-pyridin.in 5 b) 22.9 g of the compound obtained in the previous synthesis step were treated at 0-5 ° C in the presence of 175 ml of methylene dichloride with 4.5 ml of trifluoroacetic anhydride, which was added drop by drop under stirring. The mixture was stirred overnight at 10 L at room temperature and then cooled and treated by dropwise addition of 1 ml of a total of 75 ml of methanol. After evaporation to dryness! the residue was dissolved in 500 ml of chloroform, washed in: twice with 75 ml of 10% sodium bicarbonate solution and three times with 100 ml of water and dried over anhydrous sodium sulfate. The chloroform was evaporated and the residue was washed with diethyl ether and dried under reduced pressure. Yield 21.5 g (95%) of 1,5-dihydro-5-p-chlorophenyl-6-hydroxy-methyl-7-hydroxy-furo- (5,4-c) -pyridine.
20 c) Man behandlede i en reaktor på 2 liter 21,5 g af den i det forudgående syntesetrin opnåede forbindelse med 27 g : mangandioxid i nærvær af 0,9 liter chloroform ved 28-50°C j og under omrøring i 5 timer. Efter separering, filtrering, I vask med chloroform og derpå med ethylacetat blev opløsnin- 25 ί gen inddampet til tørhed, og den opnåede pasta blev behandlet med isopropyloxid og derpå med pentan. På denne måde opnåede man 20,1 g (95%) l,5-dihydro-5-p-chlorphenyl-6-formyl-7-! hydroxy-furo-(5»4-c)-pyridin.C) 21.5 g of the compound obtained in the preceding synthesis step were treated with 27 g of: manganese dioxide in the presence of 0.9 liters of chloroform at 28-50 ° C and with stirring for 5 hours. After separation, filtration, washing with chloroform and then with ethyl acetate, the solution was evaporated to dryness and the obtained paste was treated with isopropyloxide and then with pentane. In this way, 20.1 g (95%) of 1,5-dihydro-5-p-chlorophenyl-6-formyl-7- yl were obtained. hydroxy-furo- (5 '4-c) -pyridine.
[ 30 j Opfindelsen angår ligeledes et lægemiddel indeholdende et 1,5-dihydro-6-aminomethyl-7-hydroxy-furo-(5»4-c)-pyridin-de-rivat med den almene formel (i) som ovenfor defineret eller 1 et farmaceutisk acceptabelt salt deraf i kombination med et farmaceutisk acceptabelt excipiens eller bærestof. De efter-35 følgende eksempler belyser opfindelsen nærmere.The invention also relates to a medicament containing a 1,5-dihydro-6-aminomethyl-7-hydroxy-furo (5,4-c) pyridine derivative of the general formula (i) as defined above or 1 is a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable excipient or carrier. The following examples further illustrate the invention.
i i 5i i 5
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EKSEMPEL 1 1,3-dihydro-3-methyl-6-aminomethyl-7-hydroxy-furo-(3,4-c)-pyridin_ 5Example 1 1,3-dihydro-3-methyl-6-aminomethyl-7-hydroxy-furo- (3,4-c) -pyridine
Man anbragte ved stuetemperatur i en reaktor på 2 liter 71,2 g (0,4 mol) l,3-dihydro-3-methyl-6-formyl-7-hydroxy-furo-(3,4-c)-pyridin, 270 ml 1 N natriumhydroxid og derpå dråbevis og under omrøring 27,8 g (0,4 mol) hydroxylaminhydrochlorid opløst i 200 ml vand. Omrøringen blev opretholdt i 10 timer, 10 hvorpå reaktionsblandingen blev filtreret til dannelse af, efter vask med vand og tørring, 74 g (96%) af det tilsvarende 6-oxim-derivat.71.2 g (0.4 mole) of 1,3-dihydro-3-methyl-6-formyl-7-hydroxy-furo- (3,4-c) -pyridine were reacted at room temperature in a 2 liter reactor. 270 ml of 1 N sodium hydroxide and then dropwise and with stirring, 27.8 g (0.4 mole) of hydroxylamine hydrochloride dissolved in 200 ml of water. Stirring was maintained for 10 hours, then the reaction mixture was filtered to give, after washing with water and drying, 74 g (96%) of the corresponding 6-oxime derivative.
Dette 6-oxim-derivat (74 g) blev derpå hældt sammen med 0,9 li-15 ter eddikesyre i en lukket reaktor, som var udstyret med midler til cirkulation af en gasart. Efter cirkulation af nitrogen anbragte man 15 g palladium-på-carbon-katalysator i reaktoren, og blandingen blev omrørt ved stuetemperatur i 4 timer 20 under normaltryk, idet man tilledte en afmålt mængde hydrogen.This 6-oxime derivative (74 g) was then poured with 0.9 liters of acetic acid into a closed reactor equipped with gaseous circulation means. After circulating nitrogen, 15 g of palladium-on-carbon catalyst was placed in the reactor and the mixture was stirred at room temperature for 4 hours under normal pressure, allowing a metered amount of hydrogen.
Reaktionsblandingen blev efter filtrering inddampet til tørhed. Inddampningsresten blev behandlet med toluen og derpå 25 med methanol, hvorfra man omkrystalliserede 70 g (76%) af acetatet af l,3-dihydro-3-methyl-6-aminomethyl-7-hydroxy-furo-(3,4-c)-pyridin, et beigefarvet produkt, som smeltede ved 167°C (Tottoli), og hvis analyse viste en god overensstemmelse med formlen C9%2N2^2’ Denne forbindelse var uop løselig i vand.After filtration, the reaction mixture was evaporated to dryness. The residue was treated with toluene and then with methanol to give 70 g (76%) of the acetate of 1,3-dihydro-3-methyl-6-aminomethyl-7-hydroxy-furo- (3,4-c) -pyridine, a beige colored product which melted at 167 ° C (Tottoli) and whose analysis showed a good conformity to the formula C9% 2N2 ^ 2 'This compound was insoluble in water.
OUOU
35 635 6
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Eftersom den samme syntesevej blev anvendt for alle de syntetiserede forbindelser, vil man ikke i de efterfølgende eksempler gentage detaljer vedrørende behandlingen. De tilsvarende baser (uden syredelen) og andre salte af disse baser opnås på sædvanlig måde.Since the same synthetic route was used for all the synthesized compounds, details of the treatment will not be repeated in the following examples. The corresponding bases (without the acid moiety) and other salts of these bases are obtained in the usual manner.
5 EKSEMPEL 2 1.3- dihydro-3-propyl-6-aminomethyl-7-hydroxy-furo-(3,4-c)-pyridin 10EXAMPLE 2 1,3-dihydro-3-propyl-6-aminomethyl-7-hydroxy-furo- (3,4-c) -pyridine 10
Idet man gik ud fra 1,3-dihydro-3-propyl-6-formyl-7-hydroxy-furo-(3,4-c)-pyridin, opnåede man (udbytte 77%) et lyst bei-gefarvet reaktionsprodukt, som smeltede ved 187°C (Tottoli), som var uopløseligt i vand, og hvis elementæranalyse viste 15 god overensstemmelse med formlen C2H^02· EKSEMPEL 3 1.3- dihydro-3-(3',4',51-trimethoxyphenyl)-ethyl-6-aminomethyl- 20 7-hvdroxy-furo-(3.4-c)-pyridin_Starting from 1,3-dihydro-3-propyl-6-formyl-7-hydroxy-furo- (3,4-c) -pyridine, there was obtained (yield 77%) a bright bi-colored reaction product which melted at 187 ° C (Tottoli), which was insoluble in water and whose elemental analysis showed good agreement with the formula C2H2O2 · EXAMPLE 3 1,3-dihydro-3- (3 ', 4', 51-trimethoxyphenyl) ethyl 6-Aminomethyl-7-hydroxy-furo- (3.4-c) -pyridine
Idet man gik ud fra l,3-dihydro-3-(3,,4,,5f-trimethoxyphenyl)-ethyl-6-formyl-7-hydroxy-furo-(3,4-c)-pyridin, opnåede man (61%) af et hvidt reaktionsprodukt, der smeltede ved 140-25 144°C (Tottoli), som var uopløseligt i vand, og hvis elemen tæranalyse viste god overensstemmelse med formlen C-^H2^N20^, c2h4o2.Starting from 1,3-dihydro-3- (3,4,4,5-trimethoxyphenyl) -ethyl-6-formyl-7-hydroxy-furo- (3,4-c) -pyridine, 61%) of a white reaction product, melting at 140-25 144 ° C (Tottoli), which was insoluble in water and whose elemental analysis showed good agreement with the formula C-H2 H2 N2 O2, c2h4o2.
30 35 EKSEMPEL 4 7EXAMPLE 4 7
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1.3- dihydro-3-cyclohexyl-6-aminomethyl-7-hydroxy-furo-(3,4-c)- pyridin_ 51,3-dihydro-3-cyclohexyl-6-aminomethyl-7-hydroxy-furo- (3,4-c) pyridine
Idet man gik ud fra l,3-dihydro-3-cyclohexyl-6~formyl-7-hy-droxy-furo-(3»4-c)-pyridin, opnåede man (udbytte 67%) et hvidt reaktionsprodukt, som smeltede ved 173-177°C (Tottoli), som var uopløseligt i vand, og hvis elementæranalyse viste en 10 god overensstemmelse med formlen CgH^C^· EKSEMPEL 3 1.3- dihydro-3-a-thienyl-6-aminomethyl-7-hydroxy-furo-(3,4-c)- 15 pyridin_Starting from 1,3-dihydro-3-cyclohexyl-6-formyl-7-hydroxy-furo (3,4-c) pyridine, a white reaction product was obtained (yield 67%) which melted at 173-177 ° C (Tottoli), which was insoluble in water and whose elemental analysis showed a good conformity to the formula CgH2C3. EXAMPLE 3 1,3-dihydro-3-a-thienyl-6-aminomethyl-7-hydroxy -furo- (3,4-c) pyridine
Idet man gik ud fra l,3-dihydro-3-a-thienyl-6-formyl-7-hy-droxy-furo-(3,4-c)-pyridin, opnåede man (udbytte 58%) et gul-ligtfarvet reaktionsprodukt, som smeltede ved 148°C (Totto-20 li), som var uopløseligt i vand, og hvis elementæranalyse viste en god overensstemmelse med formlen ¢^2^12^2^2¾, c2h4o2.Starting from 1,3-dihydro-3-a-thienyl-6-formyl-7-hydroxy-furo- (3,4-c) -pyridine, a yellowish-colored yield (yield 58%) was obtained. reaction product, melting at 148 ° C (Totto-20 µl), which was insoluble in water and whose elemental analysis showed good agreement with the formula ¢ ^ 2 ^ 12 ^ 2 ^ 2¾, c2h4o2.
EKSEMPEL 6 25 1,3“dihydro-3-phenyl-6-aminomethyl-7-hydroxy-furo-(3,4-c) -pyridin__EXAMPLE 6 1,3 'dihydro-3-phenyl-6-aminomethyl-7-hydroxy-furo- (3,4-c) -pyridine
Idet man gik ud fra 1,3-dihydro-3-phenyl-6-formyl-7-hydroxy-30 furo-(3j4-c)-pyridin, opnåede man (udbytte 82%) et lyst beige-farvet reaktionsprodukt, som smeltede ved 188°C (Tottoli), som var uopløseligt i vand, og hvis elementæranalyse viste god overensstemmelse med formlen 35 EKSEMPEL 7 8Starting from 1,3-dihydro-3-phenyl-6-formyl-7-hydroxy-furo- (3,4-c) -pyridine, there was obtained (yield 82%) a light beige colored reaction product which melted at 188 ° C (Tottoli), which was insoluble in water and whose elemental analysis showed good conformity to formula 35 EXAMPLE 7 8
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1.3- dihy dr o - 3-p- chlorpheny 1-6 - aminomethyl- 7-hydro xy- fur o -(5.4-c)-pyridin1,3-dihydro-3-p-chlorophenyl 1-6-aminomethyl-7-hydroxyfur o - (5.4-c) -pyridine
Idet man gik ud fra l,3-dihydro-3-p-chlorphenyl-6-formyl-5 7-hydroxy-furo-(3,4-c)-pyridin, opnåede man (udbytte 86%) et lyst beigefarvet reaktionsprodukt, som smeltede ved 204-206°C (Tottoli), som var uopløseligt i vand, og hvis elementæranalyse viste god overensstemmelse med formlen 0-^4^^01^025 * 10 EKSEMPEL 8 1.3- dihydro-3-(2',3'-dichlorphenyl)-6-aminomethyl-7-hydroxy- .Starting from 1,3-dihydro-3-p-chlorophenyl-6-formyl-5,7-hydroxy-furo- (3,4-c) -pyridine, a pale beige reaction product was obtained (yield 86%). which melted at 204-206 ° C (Tottoli) which was insoluble in water and whose elemental analysis showed good conformity to the formula 0- ^ 4 ^^ 01 ^ 025 * 10 EXAMPLE 8 1.3-dihydro-3- (2 ', 3 (-dichlorophenyl) -6-aminomethyl-7-hydroxy-.
furo- (3 Λ-c) -pyridin__furo- (3Λ-c) -pyridine
Idet man gik ud fra l,3-dihydro-3-(2,,3,-dichlorphenyl)-6-fomyl-7-hydroxy-furo-(3,4-c)-pyridin, opnåede man (udbytte 15 72%) et lysegult reaktionsprodukt, som smeltede ved 193-196°CStarting from 1,3-dihydro-3- (2,3,3-dichlorophenyl) -6-phenyl-7-hydroxy-furo- (3,4-c) -pyridine, yield (72% yield) ) a pale yellow reaction product which melted at 193-196 ° C
(Tottoli), aqm var uopløseligt i vand, og hvis elementser analyse viste god overensstemmelse med formlen C14H12C12N2°2> C2H4°2· EKSEMPEL 9 20 l,3-dihydro-3-p-fluorphenyl-6-aminomethyl-7-hydroxy-furo- (3,4-c)-pyridin_(Tottoli), aqm was insoluble in water and whose elements analysis showed good agreement with the formula C14H12C12N2 ° 2> C2H4 ° 2 · EXAMPLE 9 1,3-dihydro-3-p-fluorophenyl-6-aminomethyl-7-hydroxy furo (3,4-c) pyridine
Idet man gik ud fra l,3-dihydro-3-p-fluorphenyl-6-formyl-7-hydroxy-furo-(3,4-c)-pyridin, opnåede man (udbytte 69%) et svagt beigefarvet reaktionsprodukt, som smeltede ved 183-187°C 25 (Tottoli), som var uopløseligt i vand, og hvis elementæranalyse viste god overensstemmelse med formlen C14H13FN2°2’ c2h4q2.Starting from 1,3-dihydro-3-p-fluorophenyl-6-formyl-7-hydroxy-furo- (3,4-c) -pyridine, there was obtained (yield 69%) a pale beige reaction product which melted at 183-187 ° C (Tottoli), which was insoluble in water and whose elemental analysis showed good agreement with the formula C14H13FN2 ° 2 'c2h4q2.
99
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EKSEMPEL 10 1.3- dihydro-3-p-toluyl-6-aminomethyl-7“· hydroxy-furo-(3,4-c)-•pyridinEXAMPLE 10 1,3-dihydro-3-p-toluyl-6-aminomethyl-7β-hydroxy-furo (3,4-c) pyridine
Idet man gik ud fra l,3-dihydro-3-p-toluyl-6-£ormyl-7-hydroxy-5 furo-(3,4-c)-pyridin, opnåede man (udbytte 78%) et lyst beige-farvet reaktionsprodukt, som smeltede ved 158-160°C (Tottoli), som var uopløseligt i vand, og hvis elementæranalyse viste god overensstemmelse med formlen 2°2* C2H402* EKSEMPEL 11 10 1,3-dihydro-3-p-methoxyphenyl-6-aminomethyl-7-hydroxy-furo- (3,4-c)-pyridin_Starting from 1,3-dihydro-3-p-toluyl-6-formyl-7-hydroxy-5-puro- (3,4-c) -pyridine, a pale beige (yield 78%) was obtained. colored reaction product, melting at 158-160 ° C (Tottoli), which was insoluble in water and whose elemental analysis showed good conformity to the formula 2 ° 2 * C 2 H 40 2 * EXAMPLE 11 1,3-dihydro-3-p-methoxyphenyl 6-Aminomethyl-7-hydroxy-furo- (3,4-c) -pyridine
Idet man gik ud fra 1,3-dihydro-3-p-methoxyphenyl-6-formyl- 7-hydroxy-furo-(3>4-c)-pyridin, opnåede man (udbytte 62%) et lyst beigefarvet reaktionsprodukt, som smeltede ved 144-15 149°C (Tottoli), som var uopløseligt i vand, og hvis elemen tæranalyse viste god overensstemmelse med formlen C15H16N2°3> C2H4°2· EKSEMPEL 12 1.3- dihydro-3-(31, 4', 5' -trimethoxy)-phenyl-6-aminomethyl-7- 20 hydroxy-furo-(3,4-c)-pyridin_Starting from 1,3-dihydro-3-p-methoxyphenyl-6-formyl-7-hydroxy-furo- (3> 4-c) -pyridine, there was obtained (yield 62%) a light beige colored reaction product which melted at 144-15 149 ° C (Tottoli), which was insoluble in water and whose elemental analysis showed good conformity with the formula C15H16N2 ° 3> C2H4 ° 2 · EXAMPLE 12 1.3-dihydro-3- (31, 4 ', 5 (-trimethoxy) -phenyl-6-aminomethyl-7- hydroxy-furo- (3,4-c) -pyridine
Idet man. gik ud fra 1,3-dihydro-3-(3’ ,4·' >5'-trimethoxy)-phenyl- 6-formyl-7-hydroxy-furo-(3,4-c)-pyridin, opnåede man (udbytte 49%) et hvidligt reaktionsprodukt, som smeltede ved 137-141°C (Tottoli), som var uopløseligt i vand, og hvis elementærana-25 lyse viste god overensstemmelse med formlen C17H20N2°5’ C2H4O2· 10The man. starting from 1,3-dihydro-3- (3 ', 4''5'-trimethoxy) -phenyl-6-formyl-7-hydroxy-furo- (3,4-c) -pyridine, obtained ( yield 49%) a whitish reaction product which melted at 137-141 ° C (Tottoli), which was insoluble in water and whose elemental analysis showed good conformity with the formula C17H20N2 ° 5 'C2H4O2 · 10
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EKSEMPEL 13 1.3- dihydro-3-m-trifluormethylphenyl-6-aminomethyl-7-hydroxy- furo- (3,4-c) -pyridin_EXAMPLE 13 1,3-dihydro-3-m-trifluoromethylphenyl-6-aminomethyl-7-hydroxy-furo- (3,4-c) -pyridine
Idet man gik ud fra 1,3-dihydro-3-m-trifluormethylphenyl-5 6-formyl-7-hydroxy-furo-(3,4-c)-pyridin, opnåede man (udbytte 84%) et hvidt reaktionsprodukt, som smeltede ved 197-203°C (Tottoli), som var uopløseligt i vand, og hvis elementæranalyse viste en god overensstemmelse med formlen C15H13F3N2°2> ^2¾^ 2 * 10 EKSEMPEL 14 1.3- dihydro-3-p-dimethylaminoethoxyphenyl-6-aminomethyl-7- hydroxy-furo-(3,4-c)-pyridin_Starting from 1,3-dihydro-3-m-trifluoromethylphenyl-5,6-formyl-7-hydroxy-furo- (3,4-c) -pyridine, a white reaction product was obtained (yield 84%). melted at 197-203 ° C (Tottoli), which was insoluble in water and whose elemental analysis showed a good conformity to the formula C15H13F3N2 ° 2> ^ 2¾ ^ 2 * 10 EXAMPLE 14 1,3-dihydro-3-p-dimethylaminoethoxyphenyl-6- aminomethyl-7-hydroxy-furo- (3,4-c) -pyridine
Idet man gik ud fra l,3-dihydro-3-p-dimethylaminoethoxyphenyl-Starting from 1,3-dihydro-3-p-dimethylaminoethoxyphenyl
6- formyl-7-hydroxy-furo-(3,4-c)-pyridin, opnåede man (udbyt-15 te 46%) et svagt gult produkt, som smeltede ved 160-l64°C6- Formyl-7-hydroxy-furo (3,4-c) pyridine gave (yield 46%) a pale yellow product melting at 160-164 ° C
(Tottoli), som var uopløseligt i vand, og hvis elementæranalyse viste en god overensstemmelse med formlen c19h23N3°2, C2H4°2 * EKSEMPEL 15 20 1,3-dihydro-3-niethyl-3-a-thi enyl-6-aminomethyl-7-hydroxy-furo- (3,4-c)-pyridin_(Tottoli), which was insoluble in water and whose elemental analysis showed good agreement with the formula c19h23N3 ° 2, C2H4 ° 2 * EXAMPLE 15 1,3-dihydro-3-methyl-3-a-thi-enyl-6-aminomethyl -7-hydroxy-furo- (3,4-c) -pyridine
Idet man gik ud fra 1,3-dihydro-3-methyl-3-a-thienyl-6-formyl- 7- hydroxy-furo-(3,4-c)-pyridin, opnåede man (udbytte 66%) et hvidt reaktionsprodukt, som smeltede vad 206-208°C (Totto-25 li), som var ganske lidt opløseligt i vand, og hvis elementæranalyse viste en god overensstemmelse med formlen C13H14N2°2S’ <W>2· EKSEMPEL 16 11Starting from 1,3-dihydro-3-methyl-3-a-thienyl-6-formyl-7-hydroxy-furo (3,4-c) -pyridine, a white (yield 66%) was obtained. reaction product, melting at 206-208 ° C (Totto-25 µl), which was rather slightly soluble in water and whose elemental analysis showed good conformity with the formula C13H14N2 ° 2S <Example 2 11
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1,3-dihydro-3-ethyl-3-phenyl-6-aminomethyl-7-bydroxy-furo-(3,4-c)-pyridin_______1,3-dihydro-3-ethyl-3-phenyl-6-aminomethyl-7-Hydroxy-furo- (3,4-c) -pyridine _______
Idet man gik ud fra 1,3-dihydro-3-ethyl-3-phenyl-6-formyl-7-5 hydroxy-furo-(3,4-c)-pyridin, opnåede man (udbytte 80%) et hvidt reaktionsprodukt, som smeltede ved 207°C (Tottoli), som var uopløseligt i vand, og hvis elementæranalyse viste god overensstemmelse med formlen ^16^18^2^2* C2H4°2* EKSEMPEL 17 10 1,3-dihydro-3-phenyl-3-p-trifluormethylphenyl-6-aminomethyl- 7-hydroxv^furo-(3.4-c)-pyridin_Starting from 1,3-dihydro-3-ethyl-3-phenyl-6-formyl-7-5 hydroxy-furo- (3,4-c) -pyridine, a white reaction product was obtained (yield 80%). which melted at 207 ° C (Tottoli), which was insoluble in water and whose elemental analysis showed good conformity with the formula ^ 16 ^ 18 ^ 2 ^ 2 * C2H4 ° 2 * EXAMPLE 17 10 1,3-dihydro-3-phenyl -3-p-trifluoromethylphenyl-6-aminomethyl-7-hydroxyphuro- (3,4-c) pyridine
Idet man gik ud fra 1,3-dihydro-3-phenyl-3-p-trifluormethyl-phenyl-6-formyl-7-hydroxy-furo-(3,4-c)-pyridin, opnåede man (udbytte 65%) et hvidt reaktionsproåukt, som smeltede ved 15 221*0 (Tottoli), som var uopløseligt i vand, og hvis elemen tæranalyse viste god overensstemmelse med formlen C2H4°2* 20 25 12Starting from 1,3-dihydro-3-phenyl-3-p-trifluoromethyl-phenyl-6-formyl-7-hydroxy-furo (3,4-c) -pyridine (yield 65%) a white reaction sample melting at 15 221 * 0 (Tottoli) which was insoluble in water and whose elemental analysis showed good conformity with the formula C2H4 ° 2 * 20 25 12
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EKSEMPEL 18 1.3- dihydro-3,3-di-p-fluorphenyl-6-aminomethyl-7-hydroxy- furo-(3,4-c)-pyridin_EXAMPLE 18 1,3-dihydro-3,3-di-p-fluorophenyl-6-aminomethyl-7-hydroxy-furo- (3,4-c) -pyridine
Idet man gik ud fra 1,3-dihydro-3,3-di-p-fluorphenyl-6-formyl-5 7-hydroxy-furo-(3,4-c)-pyridin, opnåede man (udbytte 81%) et svagt gult reaktionsprodukt, som smeltede ved 214°C (Totto-li), som var uopløseligt i vand, og hvis elementæranalyse viste en god overensstemmelse med formlen C20¾6F2N2^2, ^2^4^2* 10 EKSEMPEL 19 1.3- dihydro-3-a-furyl-3-p-thiomethylphenyl-6-aminomethyl-7- hvdroxy-furo-(3,4-c)-pyridin_Starting from 1,3-dihydro-3,3-di-p-fluorophenyl-6-formyl-7-hydroxy-furo- (3,4-c) -pyridine, there was obtained (yield 81%) a pale yellow reaction product, melting at 214 ° C (Totto-li), which was insoluble in water and whose elemental analysis showed good conformity to the formula C20¾6F2N2 ^ 2, ^ 2 ^ 4 ^ 2 * 10 EXAMPLE 19 1.3-dihydro-3 -α-furyl-3-p-thiomethylphenyl-6-aminomethyl-7-hydroxy-furo- (3,4-c) -pyridine
Idet man gik ud fra 1,3-dihydro-3~a-furyl-3--p-thiomethylphe-nyl-6—formyl—7-hydroxy-furo-(3,4-c)-pyridin, opnåede man 15 (udbytte 63%) et hvidligt reaktionsprodukt, som smeltede ved 153-157°C (Tottoli), som var uopløseligt i vand, og hvis elementær analyse viste god overensstemmelse med formlen C19^18^2^3^’ ^2H4^2* EKSEMPEL 20 20 1,3-dihydro-3,3-di-a-furyl-6-aminomethyl-7-hydroxy-furo- (3,4-c)-pyridinStarting from 1,3-dihydro-3-a-furyl-3-p-thiomethylphenyl-6-formyl-7-hydroxy-furo (3,4-c) pyridine, 15 ( yield 63%) a whitish reaction product which melted at 153-157 ° C (Tottoli), which was insoluble in water and whose elemental analysis showed good agreement with the formula C19 ^ 18 ^ 2 ^ 3 ^ '^ 2H4 ^ 2 * EXAMPLE 20 1,3-dihydro-3,3-di-α-furyl-6-aminomethyl-7-hydroxy-furo- (3,4-c) -pyridine
Idet man gik ud fra l,3-dihydro-3>3-di-o:-furyl-6-formyl-7-hydroxy-furo-(3,4-c)-pyridin, opnåede man (udbytte 72%) et hvidt reaktionsprodukt, der smeltede ved 178°C (Tottoli), som 25 var uopløseligt i vand, og hvis elementæranalyse viste en god overensstemmelse med formlen C16H14N2°4> C2H4°2· EKSEMPEL 21 13Starting from 1,3-dihydro-3> 3-di-o: -furyl-6-formyl-7-hydroxy-furo- (3,4-c) -pyridine, there was obtained (yield 72%) a white reaction product, melting at 178 ° C (Tottoli), which was insoluble in water and whose elemental analysis showed good conformity to the formula C16H14N2 ° 4> C2H4 ° 2 · EXAMPLE 21 13
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1.3- dihydro-3-cyclohexyl-3-(2T,3’-dichlorphenyl)-6-amino- methyl-7-hydroxy-furo-(5,4-c) -pyridin_1,3-dihydro-3-cyclohexyl-3- (2T, 3'-dichlorophenyl) -6-amino-methyl-7-hydroxy-furo- (5,4-c) -pyridine
Idet man gik ud fra 1,3-dihydro-3-cyclohexyl-3-(2’,3'-d.ichlor-5 phenyl)-6-formyl-7-hydroxy-furo-(3,4-c)-pyridin, opnåede man (udbytte 59%) et gult reaktionsprodukt, der smeltede ved 213°C (Tottoli), som var uopløseligt i vand, og hvis elementæranalyse viste god overensstemmelse med formlen ^20^22^^2^2^2’ ^2^4^2* 10 EKSEMPEL 22 1.3- dihydro-3-vinyl-3-p-thiomethylphenyl-6-aminomethyl-7- hvdroxy-furo-(3,4-c)-pyridin_Starting from 1,3-dihydro-3-cyclohexyl-3- (2 ', 3'-dichloro-5-phenyl) -6-formyl-7-hydroxy-furo- (3,4-c) - pyridine, there was obtained (yield 59%) a yellow reaction product, melting at 213 ° C (Tottoli), which was insoluble in water and whose elemental analysis showed good agreement with the formula ^ 20 ^ 22 ^^ 2 ^ 2 ^ 2 '^ EXAMPLE 22 1,3-Dihydro-3-vinyl-3-p-thiomethylphenyl-6-aminomethyl-7-hydroxy-furo (3,4-c) pyridine
Idet man gik ud fra l,3-dihydro-.3-vinyl-3-p-thiomethylphenyl- 6-formyl-7-hydroxy-furo-(3>4-c)-pyridin, opnåede man (udbyt-15 te 66%) et beigefarvet reaktionsprodukt, som smeltede ved 155°C (Tottoli), som var uopløseligt i vand, og hvis elementæranalyse viste en god overensstemmelse med formlen ^17^18^2^2^’ C2H4°2* EKSEMPEL 23 20 1,3-dihydro-3-dimethylaminopropyl-3-p-chlorphenyl-6-amino- methyl-7-hydroxy-furo-(3,4-c)-pyridinStarting from 1,3-dihydro-3-vinyl-3-p-thiomethylphenyl-6-formyl-7-hydroxy-furo (3> 4-c) pyridine, there was obtained (yield 66). %) a beige colored reaction product which melted at 155 ° C (Tottoli) which was insoluble in water and whose elemental analysis showed good conformity with the formula ^ 17 ^ 18 ^ 2 ^ 2 ^ 'C2H4 ° 2 * EXAMPLE 23 20 1, 3-dihydro-3-dimethylaminopropyl-3-p-chlorophenyl-6-amino-methyl-7-hydroxy-furo- (3,4-c) -pyridine
Idet man gik ud fra l,3-dibydro-3-dimethylaminopropyl-3-p-chlorphenyl-6-formyl-7-hydro xy-furo-(3 > 4 “ c)-pyridin, opnå ede man (udbytte 47%) et hvidt reaktionsprodukt, der smeltede 25 ved 169°C (Tottoli), som var uopløseligt i vand, og hvis elementæranalyse viste god overensstemmelse med formlen C19H24CI N^02> .:^2^4^2' 14Starting from 1,3-dibydro-3-dimethylaminopropyl-3-p-chlorophenyl-6-formyl-7-hydroxy-furo (3> 4 ° c) pyridine, one obtained (yield 47%) a white reaction product, melting at 169 ° C (Tottoli), which was insoluble in water and whose elemental analysis showed good agreement with the formula C19H24Cl N2 O2.: ^ 2 ^ 4 ^ 2 '14
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TOKSICITETTOXICITY
Værdien for LD^q blev bestemt pr. os og interperitonealt på mus. Afhængig af de enkelte forbindelser var værdierne mellem 0,7 og mere end 2,4 g/kg (pri os) og mellem 0,6 og 1,65 5 g/kg IP.The value of LD ^ q was determined per. us and interperitoneally on mice. Depending on the individual compounds, the values were between 0.7 and more than 2.4 g / kg (per us) and between 0.6 and 1.65 5 g / kg IP.
FARMAKOLOGIPHARMACOLOGY
Man gennemførte en fuldstændig farmakologisk undersøgelse, og følgende afprøvninger skal her rapporteres: A - Passiv cutan anafylaksi 10 Dette eksperiment blev gennemført som beskrevet i FicheA complete pharmacological study was performed and the following tests should be reported here: A - Passive cutaneous anaphylaxis 10 This experiment was conducted as described in Fiche
Technique nr. 48 i J. Pharm. Paris 1979 10 (1), side 69-72.Technique No. 48 in J. Pharm. Paris 1979 10 (1), pages 69-72.
Han-rotter (180-200 g) af typen Sprague-Dawley modtog to intradermale injektioner af immunserum i ryggen; 72 timer senere modtog de en IV-injektion (penis-venen) på 1 ml af en 15 blanding af ovalbumin (5 mg/ml) og Evans blue (2,5 mg/ml): dette fremkaldte dannelsen af vabler rundt om injektionsstederne for immunserum. Vablerne blev udtaget 30 minutter efter denne dannelse, de blev målt og derpå inkuberet i 24 timer ved 65°C i 4 ml formamid (for at ekstrahere farvestoffet 20 Evans blue). Den optiske densitet af supernatanten blev bestemt ved 620 nm under anvendelse af et spektrofotometer.Male Sprague-Dawley rats (180-200 g) received two intradermal injections of immune serum in the spine; 72 hours later they received an IV injection (penis vein) of 1 ml of a mixture of ovalbumin (5 mg / ml) and Evans blue (2.5 mg / ml): this induced the formation of blisters around the injection sites for immune serum. The blisters were taken 30 minutes after this formation, measured and then incubated for 24 hours at 65 ° C in 4 ml of formamide (to extract the dye 20 Evans blue). The optical density of the supernatant was determined at 620 nm using a spectrophotometer.
Man anvendte et første hold på 8 rotter som kontrol; et andet hold (8) blev anvendt til behandling med en referenceforbindelse (theophyllin, 25 mg/kg), og 17 andre hold (alle 25 bestående af 8 rotter) blev anvendt, .ved behandlingen med 17 af forbindelserne ifølge den foreliggende opfindelse (alle ved 25 mg/kg),som er identificeret ved nummeret på det pågældende eksempel; i disse 18 hold blev den dertil svarende forbindelse indgivet pr. os 1 time før indsprøjtningen af 30 blandingen af ovalbumin og Evans blue. Den procentvise reduktion af vablerne på overfladen og udtrykt ved farven blev 15A first team of 8 rats was used as a control; a second hold (8) was used for treatment with a reference compound (theophylline, 25 mg / kg) and 17 other holdings (all 25 consisting of 8 rats) were used, in the treatment with 17 of the compounds of the present invention (all at 25 mg / kg), identified by the number of the example in question; in these 18 teams, the corresponding compound was administered per. us 1 hour before the injection of the 30 mixture of ovalbumin and Evans blue. The percentage reduction of the blisters on the surface and expressed by the color was 15
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bestemt ved sammenligning med kontrolholdet. De opnåede resultater er vist i venstre del af den senere viste tabel.determined by comparison with the control team. The results obtained are shown in the left part of the table shown later.
B - Antihistamin virkningB - Antihistamine action
Denne undersøgelse blev gennemført, således som det er beskre-5 vet af Doepfner W. og Cerletti A., Int. Arch. Allergy 12, 89 1958 og J. Pharmac. og exp. Ther. (1974) 191 (2), side 300-310.This study was carried out 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.
Han-rotter (140-160 g) af typen Sprague-Dawley blev underkastet en faste med hensyn til vand i 18 timer, før de- modtog 10 1 ml/kg vand (for kontrolgruppen), 0,2 ml af en vandig opløs ning eller suspension af forbindelserne, som skulle undersø ges. Man målte rumfanget af den venstre bagpote under anvendelse af plethysmografi, hvorpå man indsprøjtede 0,1 ml 3% histamin-hydrochlorid. Det inflammatoriske respons blev be-15 dømt ved den påfølgende bestemmelse af rumfanget 1 time senere.Male Sprague-Dawley (140-160 g) rats were subjected to a water fast for 18 hours before receiving 10 1 ml / kg water (for the control group), 0.2 ml of an aqueous solution or suspension of the compounds to be investigated. The volume of the left hind paw was measured using plethysmography, whereupon 0.1 ml of 3% histamine hydrochloride was injected. The inflammatory response was assessed by subsequent determination of the volume 1 hour later.
Man anvendte hold på hver 8 forsøgsdyr: et hold til kontrol og 17 til afprøvning af de relevante forbindelser (de samme som anvendt i ovenstående afsnit A) samt to hold til referen-20 ceforbindelserne mequitazin og promethazin, idet man stedse anvendte en dosis på 25 mg/kg. Den procentvise reduktion af det inflammatoriske respons blev opnået ved sammenligning med kontrolgruppen. De opnåede resultater er vist i den højre del af den efterfølgende tabel.Teams were used on every 8 test animals: one team for control and 17 for testing the relevant compounds (same as used in section A above) and two teams for the reference compounds mequitazine and promethazine, using a dose of 25 mg / kg. The percentage reduction of the inflammatory response was obtained by comparison with the control group. The results obtained are shown in the right part of the following table.
25 Det fremgår klart af disse to undersøgelser, at forbindelserne ifølge opfindelsen udviser en stærk antihistamin virkning.It is clear from these two studies that the compounds of the invention exhibit a strong antihistamine effect.
PRÆPARATFORMER - P0S0L0GIPREPARATION FORMS - P0S0L0GI
Til human anvendelse foretrækker man ved indgift peroralt tabletter eller gelatinekapsler indeholdende 0,20 g af forbindel-30 sen ifølge opfindelsen. Ved intravenøs indgift anvender man 16For human use, oral tablets or gelatin capsules containing 0.20 g of the compound of the invention are preferred upon administration. Intravenous administration 16 is used
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ampuller indeholdende den samme mængde, som skal indsprøjtes i forbindelse med perfusion. De daglige dosis ved human terapi er fra 0,20 til 2 g pr. os og 0,20 til 1 g IV.vials containing the same amount to be injected for perfusion. The daily dose of human therapy is from 0.20 to 2 g per day. us and 0.20 to 1 g IV.
17 DK 159318 B17 DK 159318 B
TABELTABLE
% reduktion af Histamin-fremkaldt ødem vabler________ % inflammatorisk% reduction of Histamine-induced edema blisters________% inflammatory
Forbindelser overflade farve reduktionCompounds surface color reduction
Theophyllin - 60 - 62Theophylline - 60 - 62
Eksempel 1-77 - 86 - 48Examples 1-77 - 86 - 48
Eksempel 2-58 - 60 - 77Examples 2-58 - 60 - 77
Eksempel 4 -61 -66 -59Example 4 -61 -66 -59
Eksempel 5-49 - 60 - 68Examples 5-49 - 60 - 68
Eksempel 6 -75 -84 -79Example 6 -75 -84 -79
Eksempel 9-68 - 72 - 83Examples 9-68 - 72 - 83
Eksempel 10 -68 -72 -66Example 10 -68 -72 -66
Eksempel 11-66 - 70 - 76Example 11-66 - 70 - 76
Eksempel 12 -66 -79 -73Example 12 -66 -79 -73
Eksempel 14-71 - 81 - 51Example 14-71 - 81 - 51
Eksempel 15-70 - 82 - 71Example 15-70 - 82 - 71
Eksempel 16 -53 -59 -54Example 16 -53 -59 -54
Eksempel 19 -59 -67 -70Example 19 -59 -67 -70
Eksempel 20 - 74 - 82 - 85Examples 20 - 74 - 82 - 85
Eksempel 21 -64 -69 -69Example 21 -64 -69 -69
Eksempel 23-60 - 75 - 62Example 23-60 - 75 - 62
Mequitazin ~ 60Mequitazine ~ 60
Promethazin - 41Promethazine - 41
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| ZA786269B (en) * | 1977-11-25 | 1979-10-31 | Scras | New pyridine derivative,its preparation and use |
| IN156817B (en) * | 1981-02-10 | 1985-11-09 | Scras | |
| 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 |
-
1984
- 1984-09-05 GB GB848422379A patent/GB8422379D0/en active Pending
-
1985
- 1985-08-09 GB GB08520007A patent/GB2164037B/en not_active Expired
- 1985-08-12 ZA ZA856089A patent/ZA856089B/en unknown
- 1985-08-22 LU LU86053A patent/LU86053A1/en unknown
- 1985-08-26 BE BE0/215501A patent/BE903121A/en not_active IP Right Cessation
- 1985-08-28 FI FI853288A patent/FI82053C/en not_active IP Right Cessation
- 1985-08-29 CH CH3716/85A patent/CH665642A5/en not_active IP Right Cessation
- 1985-08-30 FR FR8512918A patent/FR2569699A1/en active Pending
- 1985-08-30 FR FR858512919A patent/FR2569562B1/en not_active Expired
- 1985-09-03 CA CA000489880A patent/CA1300150C/en not_active Expired - Fee Related
- 1985-09-03 NL NL8502412A patent/NL8502412A/en active Search and Examination
- 1985-09-04 NO NO853475A patent/NO160143C/en unknown
- 1985-09-04 DK DK402885A patent/DK159318C/en not_active IP Right Cessation
- 1985-09-04 PT PT81087A patent/PT81087B/en not_active IP Right Cessation
- 1985-09-04 ES ES546702A patent/ES8604966A1/en not_active Expired
- 1985-09-04 SE SE8504119A patent/SE461394B/en not_active IP Right Cessation
- 1985-09-04 IE IE218285A patent/IE58583B1/en not_active IP Right Cessation
- 1985-09-05 DE DE19853531747 patent/DE3531747A1/en active Granted
- 1985-09-05 JP JP60195015A patent/JPS6168490A/en active Granted
- 1985-09-05 OA OA58672A patent/OA08157A/en unknown
- 1985-09-05 AT AT0260285A patent/AT394557B/en not_active IP Right Cessation
- 1985-09-05 MA MA20743A patent/MA20517A1/en unknown
- 1985-09-05 IT IT22067/85A patent/IT1188188B/en active
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1988
- 1988-02-16 MY MYPI88000163A patent/MY103211A/en unknown
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1989
- 1989-02-02 HK HK104/89A patent/HK10489A/en not_active IP Right Cessation
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| PBP | Patent lapsed |