DK150484B - ANALOGY PROCEDURE FOR PREPARING 4-AMINO-3-THIOPHENCARBOXYLIC ACID DERIVATIVES - Google Patents
ANALOGY PROCEDURE FOR PREPARING 4-AMINO-3-THIOPHENCARBOXYLIC ACID DERIVATIVES Download PDFInfo
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Description
150484150484
Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af hidtil ukendte cycliske forbindelser, nemlig 4-åmino-3-thiophencarboxylsyrederivater med den almene formel IThe present invention relates to an analogous process for the preparation of novel cyclic compounds, namely 4-amino-3-thiophenecarboxylic acid derivatives of the general formula I
00
„>^NH2 - INH2 - I
RR
1 2 hvor R betegner C^_g-alkyl eller phenyl, og R betegner hydroxy eller C^_g-alkoxy, eller syreadditionssalte deraf.Wherein R represents C 1-6 alkyl or phenyl, and R represents hydroxy or C 1-6 alkoxy, or acid addition salts thereof.
2 1504342 150434
Forbindelserne med formlen I og salte deraf er værdifulde til anvendelse som midler mod fedme og til sænkning af blodlipiderne.The compounds of formula I and their salts are valuable for use as obesity agents and for lowering blood lipids.
De skulle også være værdifulde ved behandling af aterosklerose og beslægtede cardiovaskulære sygdomme, der er knyttet til et forhøjet blodlipidspejl.They should also be valuable in treating atherosclerosis and related cardiovascular diseases associated with an elevated blood lipid level.
I nærværende beskrivelse betegner udtrykket "C^_g-alkyl" alene eller i kombination såsom C^_g-alkoxy ligekædede eller forgrenede mættede aliphatiske alkylgrupper med 1-8 carbonatomer, f.eks. methyl, ethyl, propyl og isopropyl.In this specification, the term "C 1-6 alkyl" alone or in combination such as C 1-6 alkoxy means straight or branched saturated aliphatic alkyl groups having 1-8 carbon atoms, e.g. methyl, ethyl, propyl and isopropyl.
Foretrukne forbindelser med formlen I er sådanne, hvor R·^ betegnerPreferred compounds of formula I are those wherein R R represents
OISLAND
C^_g-alkyl, og R betegner C^_g-alkoxy, og salte deraf, især 4-amino--5-ethyl-3-thiophencarboxylsyre-methylester-hydrochlorid og 3-amino--4-methoxycarbonyl-2-n-propylthiophen-hydrochlorid, da der med sådanne forbindelser fås særlig god virkning.C ^g-alkyl, and R bet are C ^ko og alkoxy, and salts thereof, especially 4-amino-5-ethyl-3-thiophenecarboxylic acid methyl ester hydrochloride and 3-amino-4-methoxycarbonyl-2-n propylthiophene hydrochloride, as such compounds have a particularly good effect.
Fremgangsmåden ifølge opfindelsen til fremstilling af forbindelser med formlen X eller salte deraf er ejendommelig ved, at en forbindelse med den almene formel IIThe process of the invention for the preparation of compounds of formula X or salts thereof is characterized in that a compound of general formula II
00
Jl , N-OHJl, N-OH
^ R'^ R '
1 II1 II
2 1 hvor R' betegner C^_g-alkoxy, og R har den ovenfor anførte betydning, behandles med en syre, og i en således vunden forbindelse med den almene formel la 0 ..........,^NH2Wherein R 'is Cner C ^ alkoxy and R has the meaning given above, is treated with an acid, and in a thus obtained compound of the general formula Ia 0 ..........
r'^ FXr '^ FX
3 150484 hvor R'2 og R1 har den ovenfor anførte betydning, C1_g-alkoxycar-bonylgruppen, om ønsket, hydrolyseres til en carboxygruppe, og en forbindelse med formlen I, om -ønsket, omdannes til et syreadditionssalt deraf.Wherein R'2 and R1 are as defined above, the C1-6 alkoxycarbonyl group, if desired, is hydrolyzed to a carboxy group and a compound of formula I, if desired, is converted to an acid addition salt thereof.
Forbindelsen med formlen la kan fremstilles ved behandling af oxi-men med formlen II med en syre, fortrinsvis et hydrogenhalogenid, især hydrogenchlorid, i et inert organisk opløsningsmiddel, f.eks. en ether, især en di(lavere alkyl)ether såsom diethylether, en cyclisk ether såsom tetrahydrofuran eller dioxan, en lavere alkanol eller vand. Temperatur og tryk ved reaktionen er ikke kritisk. Reaktionen kan hensigtsmæssigt udføres ved temperaturer mellem ca. 0 og 70°C, fortrinsvis ved stuetemperatur og ved atmosfæretryk.The compound of formula Ia can be prepared by treating the oxide of formula II with an acid, preferably a hydrogen halide, especially hydrogen chloride, in an inert organic solvent, e.g. an ether, especially a di (lower alkyl) ether such as diethyl ether, a cyclic ether such as tetrahydrofuran or dioxane, a lower alkanol or water. The temperature and pressure of the reaction is not critical. The reaction may conveniently be carried out at temperatures between ca. 0 and 70 ° C, preferably at room temperature and at atmospheric pressure.
Forbindelsen med formlen la kan omdannes til den tilsvarende syre eller til salte deraf ved konventionelle metoder. C^_g-Alkoxy-carbonylgruppen kan ved basehydrolyse i et sædvanligt inert organisk opløsningsmiddel, fortrinsvis en lavere alkanol, især methanol eller ethanol, i en vandig ether, fortrinsvis vandig di(lavere alkyl)ether, især diethylether, eller i en vandig cyclisk ether, fortrinsvis tetrahydrofuran eller dioxan, omdannes til en carboxygruppe. Til de foretrukne baser hører alkalimetal-hydroxider såsom natrium-, kalium- og lithiumhydroxid og jordal-kalimetalhydroxider såsom barium-, calcium- og magnesiumhydroxid, især alkalimetalhydroxiderne. Ved denne hydrolyse er temperatur og tryk ikke kritisk. Reaktionen kan hensigtsmæssigt udføres ved mellem ca. 0 og 100°C, fortrinsvis under reaktionsblandingens tilbagesvalingstemperatur, især ved 70°C og under atmosfæretryk.The compound of formula Ia can be converted to the corresponding acid or to salts thereof by conventional methods. The C 1-6 alkoxy carbonyl group may, by base hydrolysis, in a usually inert organic solvent, preferably a lower alkanol, especially methanol or ethanol, in an aqueous ether, preferably aqueous di (lower alkyl) ether, especially diethyl ether, or in an aqueous cyclic ether. , preferably tetrahydrofuran or dioxane, is converted to a carboxy group. The preferred bases include alkali metal hydroxides such as sodium, potassium and lithium hydroxide and alkaline earth metal hydroxides such as barium, calcium and magnesium hydroxide, especially the alkali metal hydroxides. In this hydrolysis, temperature and pressure are not critical. The reaction may conveniently be carried out at between ca. 0 and 100 ° C, preferably below the reflux temperature of the reaction mixture, especially at 70 ° C and under atmospheric pressure.
Forbindelserne med formlen II kan fremstilles ved omsætning af en forbindelse med den almene formel IIIThe compounds of formula II can be prepared by reacting a compound of general formula III
00
med en forbindelse med den almene formel IVwith a compound of the general formula IV
IIIIII
4 150484 !>γ- ' o4 150484!> Γ- 'o
under dannelse af en forbindelse med den almene formel Vforming a compound of the general formula V
0 1 2 hvor R og R1 har den ovenfor anførte betydning, R betegner la-0 1 2 where R and R1 have the meaning given above, R represents la-
OISLAND
vere alkyl, og R betegner halogen, mesyloxy eller tosyloxy.are alkyl, and R is halogen, mesyloxy or tosyloxy.
Denne reaktion kan udføres i nærværelse af en lavere alkanol og et alkalimetalalkoxid, fortrinsvis methanol og natriummethoxid.This reaction can be carried out in the presence of a lower alkanol and an alkali metal alkoxide, preferably methanol and sodium methoxide.
Selv om temperatur og tryk ikke er kritiske, udføres reaktionen almindeligvis ved atmosfæretryk og ved temperaturer mellem ca. 15 og ca. 60°C, fortrinsvis ved 25°C.Although temperature and pressure are not critical, the reaction is usually carried out at atmospheric pressure and at temperatures between ca. 15 and approx. 60 ° C, preferably at 25 ° C.
Forbindelsen med formlen V behandles derefter med et alkalimetalalkoxid, fortrinsvis natriummethoxid, i nærværelse af et aromatisk carbonhydrid, fortrinsvis benzen, under dannelse af en forbindelse med den almene formel VIThe compound of formula V is then treated with an alkali metal alkoxide, preferably sodium methoxide, in the presence of an aromatic hydrocarbon, preferably benzene, to form a compound of general formula VI
0 ,Λ-γ° 2 hvor R og R' har den ovenfor anførte betydning.0, Λ-γ ° 2 where R and R 'have the meaning given above.
5 1504845 150484
Selv om temperatur og tryk ikke er kritiske, udføres denne reaktion almindeligvis ved atmosfæretryk og ved temperaturer mellem ca. 15 og ca. 60°C, fortrinsvis ved 25°C.Although temperature and pressure are not critical, this reaction is usually carried out at atmospheric pressure and at temperatures between ca. 15 and approx. 60 ° C, preferably at 25 ° C.
Forbindelsen med formlen VI omdannes derefter til en oxim med formlen II efter til omdannelse af ketoner til oximer i og for sig kendte metoder. Fortrinsvis behandles ketonen med formlen VI med et hydroxylamin-hydrohalogenid, fortrinsvis hydroxylamin-hydro-chlorid, i en nitrogenholdig base. Der kan anvendes enhver konventionel nitrogenholdig base, fortrinsvis en amin. Egnede aminer er primære aminer såsom lavere alkylaminer, især methylamin, ethyl-amin eller anilin; sekundære aminer såsom di(lavere alkyl)aminer, især dimethylamin eller diethylamin; eller pyrrol; og tertiære aminer såsom tri(lavere alkyl) aminer, især trimethylamin og tri-ethylamin; eller pyridin eller picolin. Temperatur og tryk er ikke kritisk. Reaktionen udføres hensigtsmæssigt ved temperaturer mellem stuetemperatur og tilbagesvaling, fortrinsvis ved ca. 22°C, og atmosfæretryk i et inert organisk opløsningsmiddel, f.eks. et aliphatisk eller aromatisk carbonhydrid, f.eks. n-hexan eller benzen. Reaktionen udføres fortrinsvis i et overskud af den nitro-genholdige base, der anvendes som opløsningsmiddel.The compound of formula VI is then converted to an oxime of formula II after conversion of ketones to oxymers in methods known per se. Preferably, the ketone of formula VI is treated with a hydroxylamine hydrohalide, preferably hydroxylamine hydrochloride, in a nitrogenous base. Any conventional nitrogen-containing base may be used, preferably an amine. Suitable amines are primary amines such as lower alkyl amines, especially methylamine, ethylamine or aniline; secondary amines such as di (lower alkyl) amines, especially dimethylamine or diethylamine; or pyrrole; and tertiary amines such as tri (lower alkyl) amines, especially trimethylamine and triethylamine; or pyridine or picoline. Temperature and pressure are not critical. The reaction is conveniently carried out at temperatures between room temperature and reflux, preferably at ca. 22 ° C, and atmospheric pressure in an inert organic solvent, e.g. an aliphatic or aromatic hydrocarbon, e.g. n-hexane or benzene. The reaction is preferably carried out in excess of the nitrogen-containing base used as the solvent.
Som ovenfor anført er thiophenderivaterne med den almene formel I og de farmaceutisk tolerable salte deraf hypolipæmisk virksomme midler, dvs. de sænker blodlipidspejlet hos pattedyr. Denne egenskab er demonstreret på normale Charles River-hunrotter med en vægt på 150 - 180 g. Dyrene fodres først nogle dage med en majsolie--glucoseblanding, hvorefter der til dyrene oralt eller parenteralt administreres de forbindelser, der skal afprøves, i dimethylsulf-oxid.As noted above, the thiophene derivatives of the general formula I and the pharmaceutically tolerable salts thereof are hypolipaemically active agents, i.e. they lower blood lipid levels in mammals. This property is demonstrated in normal Charles River female rats weighing 150 - 180 g. The animals are first fed for a few days with a corn oil - glucose mixture, after which the compounds to be tested are administered orally or parenterally in dimethyl sulfoxide. .
Sammenligning af blodspejl-triglycerider, fedtsyre- og cholesterol-spejl hos rotter, der har fået forsøgsforbindelserne, viser en signifikant sænkning i forhold til de tilsvarende værdier hos ubehandlede dyr. Tilsvarende resultater er opnået med rotte-hepatocyter.Comparison of blood triglycerides, fatty acid and cholesterol levels in rats given the test compounds shows a significant decrease in the corresponding values in untreated animals. Similar results have been obtained with rat hepatocytes.
Fedtsyre- og cholesterolsyntesen i isolerede hepatocyter.Fatty acid and cholesterol synthesis in isolated hepatocytes.
Charles River-hunrotter lades faste i 48 timer, hvorefter de i 7-14 dage hver formiddag fra kl. 8 til kl. 11 fodres med en diæt 6 150484 indeholdende 1% majsolie og 70% glucose. De isolerede rottehepa-tocyter fås ved in situ-perfusion af leveren. Hepatocyterne inkuberes i 60 minutter ved 37°C. Hver prøve indeholder et totalvolumen på 2,1 ml, bestående af 1 ml isolerede rottehepatocyter (10 -20 mg tørre celler), 1 ml Krebs-Henseleit hydrogencarbonatpuffer, pH-værdi 7,4, 16,5 millimol glucose, l7umol L-alanin (l,uCi), 3 ' ' 1 mCi H2O og 2 millimol inhibitor i vand eller dimethylsulfoxid ved pH-værdi 7,4. Alle forsøg gentages to gange og udføres hver gang med tre prøver. Det celleholdige medium tilsættes 0,4 ml 62,5%'s citronsyre og inkuberes i 45 minutter. Det udviklede C02 opfanges i 0,3 ml af en blanding af ethanolamin og 2-methoxyethanol i forholdet 1:2. Ved forsøgets afslutning bestemmes i denne opløsning 14 CC>2~indholdet ved hjælp af en scintillationstæller. Cellemediet hydrolyseres, syrnes (kun til bestemmelse af lipogenese-graden) og ekstraheres med hexan. På dette trin enten tælles lipiderne (til bestemmelse af lipogenese-graden) eller udfældes med digi- tonin, vaskes og måles (til bestemmelse af cholesterogenese-graden).Charles River female rats are allowed to fast for 48 hours, then for 7-14 days each morning from 1 p.m. 8 a.m. to 3 p.m. 11 are fed a diet 6 containing 150% corn oil and 70% glucose. The isolated rat hepatocytes are obtained by in situ perfusion of the liver. The hepatocytes are incubated for 60 minutes at 37 ° C. Each sample contains a total volume of 2.1 ml, consisting of 1 ml isolated rat hepatocytes (10-20 mg dry cells), 1 ml Krebs-Henseleit hydrogen carbonate buffer, pH 7.4, 16.5 millimoles glucose, 17umol L-alanine (1, uCi), 3 '1 mCi H 2 O and 2 millimoles inhibitor in water or dimethylsulfoxide at pH 7.4. All experiments are repeated twice and performed each time with three samples. The cell-containing medium is added to 0.4 ml of 62.5% citric acid and incubated for 45 minutes. The developed CO 2 is taken up in 0.3 ml of a mixture of ethanolamine and 2-methoxyethanol in a ratio of 1: 2. At the end of the experiment, in this solution 14 CC> 2 ~ content is determined by means of a scintillation counter. The cell medium is hydrolyzed, acidified (to determine the degree of lipogenesis only) and extracted with hexane. At this stage, the lipids are either counted (to determine the degree of lipogenesis) or precipitated with digitonin, washed and measured (to determine the degree of cholesterogenesis).
3 143 14
Omdannelsen af og [ C]-alanin i fedtsyrer eller steroler bestemmes i en væske-scintillationstæller. Resultaterne er angivet i tabel I som nanomol H20 og alanin, der er omdannet til fedtsyrer eller cholesterol, og nanomol alanin, der er oxideret til CO2» pr· mg tørre celler pr. 60 minutter.The conversion of and [C] alanine into fatty acids or sterols is determined in a liquid scintillation counter. The results are given in Table I as nanomol H2 O and alanine converted to fatty acids or cholesterol, and nanomol alanine oxidized to CO2 »per mg dry cells per ml. 60 minutes.
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Tabel ITable I
Virkning af 3-amino-4-methoxycarbonyl-2-n-propylthiophen-hydro-chlorid på lipidsyntesen og CC^-produktionen i isolerede rotte--hepatocyter.Effect of 3-amino-4-methoxycarbonyl-2-n-propylthiophene hydrochloride on lipid synthesis and CC1 production in isolated rat hepatocytes.
Mængde Fedtsyresyntese Cholesterolsyntese CO^-produktion nanoM omdannet omdannet omdannet H2O Alanin H2O Alanin AlaninAmount of fatty acid synthesis Cholesterol synthesis CO 2 production nanoM converted converted converted converted H2O Alanine H2O Alanine Alanine
Procent af kontrolværdierPercentage of control values
Kontrolværdi (DMSO) — 100 100 100 100 100Control Value (DMSO) - 100 100 100 100 100
Forsøgsforbindelse 0,05 17 9 28 19 49 0,25 21 10 29 21 50 0,10 18 10 35 23 53 0,05 18 11 33 26 54 0,01 30 19 49 31 73Test compound 0.05 17 9 28 19 49 0.25 21 10 29 21 50 0.10 18 10 35 23 53 0.05 18 11 33 26 54 0.01 30 19 49 31 73
Fedtsyre- og cholesterolsyntese in vivo«Fatty acid and cholesterol synthesis in vivo «
Rotter lades faste i 48 timer og fodres derefter i 5 - 15 dage med en diæt indeholdende 1% majsolie og 70% glucose. På forsøgsdagen administreres forsøgsforbindelsen 30 - 60 minutter før den 3 timer lange fodringsperiode ved oral intubation eller 60 minutter efter den 3 timer lange fodringsperiode ved intraperitoneal injektion.Rats are fixed for 48 hours and then fed for 5 - 15 days with a diet containing 1% corn oil and 70% glucose. On the test day, the test compound is administered 30 - 60 minutes before the 3 hour feeding period by oral intubation or 60 minutes after the 3 hour feeding period by intraperitoneal injection.
3 30 minutter senere gives der til dyrene en injektion af 1 mCi I^O, 12,3 mg alanin (5/uCi) og 30,6 mg α-keto-glutarsyre i 0,25 ml kogsaltopløsning i halevenen. Yderligere 30 minutter senere dekapiteres dyrene, leverne skæres hurtigt ud, hydrolyseres og syrnes (kun til bestemmelse af lipogenese-graden) og ekstraheres med hexan. Lipiderne bliver enten målt (til bestemmelse af 8 150484 lipogenesegraden) eller udfældet med digitonin, vasket og talt (til bestemmelse af cholesterogenesen). Omdannelsen af I^O og alanin til fedtsyrer eller steroler bestemmes i en væske-scintilla-tionstæller. Resultaterne er angivet nedenfor i tabel II - VI.30 minutes later, the animals are given an injection of 1 mCi I 2 O, 12.3 mg alanine (5 µCi) and 30.6 mg of α-keto-glutaric acid in 0.25 ml of saline solution in the tail vein. A further 30 minutes later, the animals are decapitated, the livers are rapidly excised, hydrolyzed and acidified (only to determine the degree of lipogenesis) and extracted with hexane. The lipids are either measured (to determine the degree of lipogenesis) or precipitated with digitonin, washed and counted (to determine cholesterogenesis). The conversion of IO and alanine to fatty acids or sterols is determined in a liquid scintillation counter. The results are given below in Tables II - VI.
Tabel IITable II
Virkning af intraperitoneal administration af 3-amino-4-methoxy-carbonyl-2-n-propylthiophen-hydrochlorid på lipogenesen og cholesterogenesen in vivo.Effect of intraperitoneal administration of 3-amino-4-methoxy-carbonyl-2-n-propylthiophene hydrochloride on lipogenesis and cholesterogenesis in vivo.
a & Mængde Fedtsyresyntese Cholesterolsyntese millimol/kg yumol Alanin yumol HjO ^umol Alanina & Amount of fatty acid synthesis Cholesterol synthesis millimol / kg yumol Alanine yumol HjO ^ umol Alanine
Kontrolværdi --- 614 - 66 1,36 - 0,07 35,7 - 3,2Control value --- 614 - 66 1.36 - 0.07 35.7 - 3.2
Testforbindelse 0,1 251 - 36 0,85 - 0,06 17,6 - 1,9 a Angivelserne er beregnet på de i løbet af 30 minutter til fedt syrer eller cholesterol omdannede mængder alanin eller HjO pr. g lever.Test compound 0.1 251 - 36 0.85 - 0.06 17.6 - 1.9 a The data is calculated on the amounts of alanine or H 2 O per minute converted into fatty acids or cholesterol per 30 minutes. g liver.
Tabel IIITable III
Virkning af 3-amino-4-methoxycarbonyl-2-n-propylthiophen-hydro-chlorid på serumlipider.Effect of 3-amino-4-methoxycarbonyl-2-n-propylthiophene hydrochloride on serum lipids.
Dosis Triglycerider Cholesterol millimol/kg mg-% mg-% i.p.Dose of Triglycerides Cholesterol millimol / kg mg-% mg-% i.p.
Kontrolværdi — 67-4 116-7Control Value - 67-4 116-7
Testforbindelse 0,1 51-3 105 - 11 9 150484Test compound 0.1 51-3 105 - 11 9 150484
Tabel IVTable IV
Virkning af oral administration af 3-amino-4-methoxycarbonyl--2-n-propylthiophen-hydrochlorid på fedtsyresyntesen in vivo.Effect of oral administration of 3-amino-4-methoxycarbonyl-2-n-propylthiophene hydrochloride on fatty acid synthesis in vivo.
Dosis Fedtsyresyntese a millimol/ /Uino]_ η„0 % af kon- ,umol % af kon-Dose of fatty acid synthesis a millimole // Uino] η
Kg φ.ο.; / z troiværdi /aianin trolværdiKg φ.ο .; / z troy value / aianin troll value
Kontrolværdi --- 19,6 - 2,4 100 473 - 76 100Control value --- 19.6 - 2.4 100 473 - 76 100
Testforbindelse 1,2 7,1 - 1,7 . 36 162 - 60 34 a Angivelserne er beregnet på de i løbet af 30 minutter til fedtsyrer omdannede mængder H20 og aianin pr. g lever.Test compound 1.2 7.1 - 1.7. 36 162 - 60 34 a The information is calculated on the amounts of H 2 O and alianine converted to fatty acids in 30 minutes. g liver.
Tabel VTable V
Virkning af oral administration af 3-amino-4-methoxycarbonyl-2-n--propylthiophen-hydrochlorid på cholesterogenesen.Effect of oral administration of 3-amino-4-methoxycarbonyl-2-n-propylthiophene hydrochloride on cholesterogenesis.
Dosis ,umol H20a % af kon- nano- Alanina % af kon-' tro1vær- mol trolvær- S/kg dien dienDose, umol H20a% of canonanalanina% of control 1 mole of trolley S / kg of diene
Kontrolværdi --- 1,35 - 0,04 100 33,0 - 3,1 100Control value --- 1.35 - 0.04 100 33.0 - 3.1 100
Testforbindelse 1,2 0,88 - 0,16 65 15,2 - 3,2 46 0,4 0,96 ± 0,05 71 17,4 ± 0,9 53 a Angivelserne er beregnet på de i løbet af 30 minutter til cholesterol omdannede mængder H20 og aianin.Test compound 1.2 0.88 - 0.16 65 15.2 - 3.2 46 0.4 0.96 ± 0.05 71 17.4 ± 0.9 53 a The data is calculated on those within 30 minutes to cholesterol converted amounts of H2 O and alianine.
ίο 150484ίο 150484
Tabel VITable VI
Sammenligning af virkningen af forskellige forbindelser med formlen I. .Comparison of the effect of various compounds of formula I.
Forbindelse med formlen I Hæmning af fedtsyresyntesen _ (i % af forbindelse 1) R1 R2 -CH2CH2CH3 och3 100 (forbindelse 1) -ch3 och3 . 100 -ch2ch3 och3 100 -CH(CH3)2 och3 ioo -CH3 oh ioo -CH2CH3 oh ioo -CH(CH3)2 OH 100 -CH2CH2CH3 OH 100 —CcHc OH 19 -(CH2)3CH3 OCH3 11 -C6H5 OCB3 16Compound of Formula I Inhibition of fatty acid synthesis (% of Compound 1) R1 R2 -CH2CH2CH3 och3 100 (Compound 1) -ch3 och3. 100 -CH2CH3 and3 100 -CH (CH3) 2 and 3ioo -CH3 oh ioo -CH2CH3 ohioo -CH (CH3) 2 OH 100 -CH2CH2CH3 OH 100 -CcHc OH 19 - (CH2) 3CH3 OCH3 11 -C6H5 OCB3 16
Forbindelserne med fonalen I og de farmaceutisk tolerable salte kan administreres parenteralt og oralt. Til parenteral administration kan anvendes opløsninger og suspensioner af forbindelserne i dimethylsulfoxid, vand eller gummi arabicum. Sterile vandige opløsninger af de tilsvarende vandopløselige salte er særlig velegnede .The compounds with the phonal I and the pharmaceutically tolerable salts can be administered parenterally and orally. For parenteral administration, solutions and suspensions of the compounds in dimethyl sulfoxide, water or gum arabic may be used. Sterile aqueous solutions of the corresponding water-soluble salts are particularly suitable.
De til sænkning af blodlipidspejlet nødvendige doseringer afhænger af symptomernes art og udstrækning. Ved oral administration er det nødvendigt med større mængder af det aktive stof end ved parenteral administration. Almindeligvis anvendes doseringer på ca. 0,1 - 1,2 mg aktivstof/kg legemsvægt for at opnå en signifikant sænkning af blodlipidspejlet.The dosages needed to lower blood lipid levels depend on the nature and extent of the symptoms. Oral administration requires greater amounts of the active substance than parenteral administration. Generally, dosages of approx. 0.1 - 1.2 mg of active substance / kg body weight to achieve a significant decrease in blood lipid levels.
Fremgangsmåden ifølge opfindelsen belyses nærmere ved nedenstående eksempler: n 150484The process of the invention is illustrated in more detail by the following examples: n 150484
Eksempel 1.Example 1.
Ind i en opløsning af 100 g 4-methoxycarbonyl-3-keto-2-propyl-tetra-hydrothiophen-oxim i 1 liter vandfrit ether ledes ved 0°C i 1 time gasformigt hydrogenchlorid. Reaktionsbeholderen lukkes med et tørrerør og omrøres natten over ved stuetemperatur. Opløsningsmidlet afdampes, indtil produktet krystalliserer. Det hvide faste stof frafiltreres og vaskes med ether. Der fås 60 g 3-amino-4-methoxy-carbonyl-2-n-propylthiophen-hydrochlorid med smeltepunkt 178 -180°C. Ved omkrystallisation af methanol/ether fås et produkt med smeltepunkt 180 - 181°C.Into a solution of 100 g of 4-methoxycarbonyl-3-keto-2-propyl-tetrahydrothiophene oxime in 1 liter of anhydrous ether is passed at 0 ° C for 1 hour gaseous hydrogen chloride. The reaction vessel is closed with a drying tube and stirred overnight at room temperature. The solvent is evaporated until the product crystallizes. The white solid is filtered off and washed with ether. 60 g of 3-amino-4-methoxy-carbonyl-2-n-propylthiophene hydrochloride are obtained, mp 178-180 ° C. Recrystallization from methanol / ether gives a product of m.p. 180 - 181 ° C.
Udgangsmaterialet kan fremstilles på følgende mådes a) Til en opløsning af 116,55 g 3-mercaptopropionsyre-methylester i 220 ml tørt methanol sættes ved -20°C 52,46 g natriummethoxid.The starting material can be prepared as follows: a) To a solution of 116.55 g of 3-mercaptopropionic acid methyl ester in 220 ml of dry methanol is added at -20 ° C 52.46 g of sodium methoxide.
Efter 20 minutters forløb tilsættes dråbevis en opløsning af 203 g 2-bromvalerianesyre-ethylester i 150 g tørt methanol. Reaktionsblandingen lades opvarme til stuetemperatur under omrøring natten over. Methanolet afdampes, og remanensen fordeles mellem ether og vand. Den organiske fase vaskes med 10%'s hydrogencarbonatopløsning og vand, tørres over magnesiumsulfat og inddampes. Der fås 130 g 4-thia-5-methoxycarbonyloctansyremethylester i form af en farveløs olie.After 20 minutes, a solution of 203 g of 2-bromovaleric acid ethyl ester in 150 g of dry methanol is added dropwise. The reaction mixture is allowed to warm to room temperature with stirring overnight. The methanol is evaporated and the residue partitioned between ether and water. The organic phase is washed with 10% hydrogen carbonate solution and water, dried over magnesium sulfate and evaporated. 130 g of 4-thia-5-methoxycarbonyloctanoic acid methyl ester are obtained in the form of a colorless oil.
b) Til en suspension af 54,0 g natriummethoxid i 500 ml vandfrit benzen dryppes ved 25°C 130 g 4-thia-5-methoxycarbonyloctansyre-methylester. Blandingen omrøres natten over og hældes ud i isvand.b) To a suspension of 54.0 g of sodium methoxide in 500 ml of anhydrous benzene, drop 130 g of 4-thia-5-methoxycarbonyloctanoic acid methyl ester at 25 ° C. The mixture is stirred overnight and poured into ice water.
Den vandige fase ekstraheres med benzen/ether i forholdet 1:1 og syrnes derefter til pH-værdi 1 ved tilsætning af 6N HCl. Produktet, der delvis udskilles af den vandige opløsning, optages i methylen-chlorid. Den vandige fase efterekstraheres med methylenchlorid.The aqueous phase is extracted with benzene / ether in a ratio of 1: 1 and then acidified to pH 1 by the addition of 6N HCl. The product, which is partially separated by the aqueous solution, is taken up in methylene chloride. The aqueous phase is post-extracted with methylene chloride.
De samlede organiske faser tørres og inddampes, og der fås 94 g rent 4-methoxycarbonyl-3-keto-2-propyl-tetrahydrothiophen i form af en farveløs olie.The combined organic phases are dried and evaporated to give 94 g of pure 4-methoxycarbonyl-3-keto-2-propyl-tetrahydrothiophene as a colorless oil.
c) Til en opløsning af 94,0 g 4-methoxycarbonyl-3-keto-2-propyl--tetrahydrothiophen i 250 ml tørt pyridin sættes ved 25°C 40,0 g hydroxylamin-hydrochlorid. Reaktionsblandingen omrøres natten over 12 150484 ved stuetemperatur, opløsningsmidlet afdampes, og remanensen fordeles mellem IN saltsyre og methylenchlorid. Den organiske fase tørres over natriumsulfat og inddampes, og der fås 100 g rent 4-methoxycarbonyl-3-keto-2-propyl-tetrahydrothiophen-oxim i form af en farveløs olie.c) To a solution of 94.0 g of 4-methoxycarbonyl-3-keto-2-propyl-tetrahydrothiophene in 250 ml of dry pyridine is added at 25 ° C 40.0 g of hydroxylamine hydrochloride. The reaction mixture is stirred overnight at room temperature, the solvent is evaporated and the residue partitioned between 1N hydrochloric acid and methylene chloride. The organic phase is dried over sodium sulfate and evaporated to give 100 g of pure 4-methoxycarbonyl-3-keto-2-propyl-tetrahydrothiophene oxime as a colorless oil.
Eksempel 2.Example 2.
En opløsning af 41,1 g 4-methoxycarbonyl-3-keto-2-methyl-tetra-hydrothiophen-oxim i 600 ml vandfrit ether mættes ved 0°C med hy-drogenchlorid og omrøres derefter natten over ved 25°C. Det udskilte faste stof isoleres, vaskes med ether og tørres. Efter omkrystallisation og oparbejdning af moderluden fås i alt 37,4 g 3-amino--4-raethoxycarbonyl-2-methylthiophen-hydrochlorid med smeltepunkt 191 - 192°C.A solution of 41.1 g of 4-methoxycarbonyl-3-keto-2-methyl-tetrahydrothiophene oxime in 600 ml of anhydrous ether is saturated at 0 ° C with hydrogen chloride and then stirred overnight at 25 ° C. The separated solid is isolated, washed with ether and dried. After recrystallization and reprocessing of the mother liquor, a total of 37.4 g of 3-amino-4-methoxycarbonyl-2-methylthiophene hydrochloride is obtained, m.p. 191 - 192 ° C.
På lignende måde omdannes 49,12 g 4-methoxycarbonyl-2-isopropyl--3-keto-tetrahydrothiophen-oxim til 18,49 g 3-amino-4-methoxycar-bonyl-2-isopropylthiophen-hydrochlorid med smeltepunkt 185°C (sønderdeling).Similarly, 49.12 g of 4-methoxycarbonyl-2-isopropyl-3-keto-tetrahydrothiophene oxime are converted to 18.49 g of 3-amino-4-methoxycarbonyl-2-isopropylthiophene hydrochloride, m.p. 185 ° C ( dec).
Udgangsmaterialet kan fremstilles på følgende måde: a) Til en opløsning af 66,29 g 3-mercaptopropionsyre-methylester i 50 ml vandfrit methanol sættes ved 0°C 120 ml 25%'s natriummethoxid-opløsning i methanol. Til opløsningen sættes dråbevis en opløsning af 100 g 2-brompropionsyre-ethylester i 100 ml vandfrit methanol. Reaktionsblandingen lades opvarme natten over til 25°C. Opløsningsmidlet afdampes, og remanensen fordeles mellem ether og 10%'s natri-umhydrogencarbonatopløsning. Den vandige fase efterekstraheres med ether. De samlede organiske ekstrakter tørres over magnesiumsulfat og inddampes, og der fås 121,40 g 2-methyl-3-thia-adipinsyre-l--ethyl-6-methylester i form af en lysegul olie.The starting material can be prepared as follows: a) To a solution of 66.29 g of 3-mercaptopropionic acid methyl ester in 50 ml of anhydrous methanol is added at 0 ° C 120 ml of 25% sodium methoxide solution in methanol. To the solution is added dropwise a solution of 100 g of 2-bromopropionic acid ethyl ester in 100 ml of anhydrous methanol. The reaction mixture is allowed to warm to 25 ° C overnight. The solvent is evaporated and the residue partitioned between ether and 10% sodium hydrogen carbonate solution. The aqueous phase is post-extracted with ether. The combined organic extracts are dried over magnesium sulfate and evaporated to give 121.40 g of 2-methyl-3-thia-adipic acid 1- ethyl-6-methyl ester as a pale yellow oil.
På lignende, måde omsættes 61,4 g 3-mercaptopropionsyre-methylester med 106,8 g 2-bromisovalerianesyre-ethylester til dannelse af 120,91 g 2-isopropyl-3-thia-adipinsyre-l-ethyl-6-methylester.Similarly, 61.4 g of 3-mercaptopropionic acid methyl ester is reacted with 106.8 g of 2-bromoisovalerianic acid ethyl ester to give 120.91 g of 2-isopropyl-3-thia-adipic acid-1-ethyl-6-methyl ester.
13 150484 b) En opløsning af 121,4 g 2-methyl-3-thia-adipinsyre-l-ethyl-6--methylester i 90 ml tørt benzen sættes dråbevis til en suspension af 30 g vandfrit natriummethoxid i 200 ml tørt benzen. Reaktionsblandingen lades opvarme natten over til stuetemperatur, hvorefter den fordeles mellem vand og ether. Den vandige fase efterekstraheres med benzen. Den vandige fase syrnes til pH-værdi 1 ved tilsætning af 6N HC1 og ekstraheres tre gange med methylenchlorid. Methylen-chloridekstrakterne tørres over natriumsulfat og inddampes, og der fås 79,17 g rent 4-methoxycarbonyl-3-keto-2-methyltetrahydrothiophen i form af en farveløs olie.B) A solution of 121.4 g of 2-methyl-3-thia-adipic acid-1-ethyl-6-methyl ester in 90 ml of dry benzene is added dropwise to a suspension of 30 g of anhydrous sodium methoxide in 200 ml of dry benzene. The reaction mixture is allowed to warm overnight to room temperature and then partitioned between water and ether. The aqueous phase is post-extracted with benzene. The aqueous phase is acidified to pH 1 by the addition of 6N HCl and extracted three times with methylene chloride. The methylene chloride extracts are dried over sodium sulfate and evaporated to give 79.17 g of pure 4-methoxycarbonyl-3-keto-2-methyltetrahydrothiophene as a colorless oil.
På lignende måde omdannes 120,91 g 2-isopropyl-3-thia-adipinsyre--l-ethyl-6-methylester til 91 g 4-methoxycarbonyl-2-isopropyl-3--keto-tetrahydrothiophen.Similarly, 120.91 g of 2-isopropyl-3-thia-adipic acid-1-ethyl-6-methyl ester is converted to 91 g of 4-methoxycarbonyl-2-isopropyl-3-keto-tetrahydrothiophene.
c) Til en opløsning af 37,26 g 4-methoxycarbonyl-3-keto-2-methyl--tetrahydrothiophen i 100 ml vandfrit pyridin sættes 18,0 g hydro-xylamin-hydrochlorid. Blandingen omrøres i 24 timer ved 25°C, hvorefter den inddampes og fordeles mellem IN saltsyreopløsning og methylenchlorid. Den vandige fase ekstraheres to gange med methylenchlorid, de samlede organiske ekstrakter tørres og inddampes, og der fås 40,1 g rent 4-methoxycarbonyl-3-keto-2-methyltetrahydro-thiophen-oxim i form af en farveløs olie.c) To a solution of 37.26 g of 4-methoxycarbonyl-3-keto-2-methyl-tetrahydrothiophene in 100 ml of anhydrous pyridine is added 18.0 g of hydroxylamine hydrochloride. The mixture is stirred for 24 hours at 25 ° C, then evaporated and partitioned between 1N hydrochloric acid solution and methylene chloride. The aqueous phase is extracted twice with methylene chloride, the combined organic extracts are dried and evaporated and 40.1 g of pure 4-methoxycarbonyl-3-keto-2-methyltetrahydrothiophene oxime are obtained as a colorless oil.
På lignende måde omdannes 52,8 g 4-methoxycarbonyl-2-isopropyl-3--keto-tetrahydrothiophen til 49,0 g 4-methoxycarbonyl-2-isopropyl--3-keto-tetrahydrothiophen-oxim.Similarly, 52.8 g of 4-methoxycarbonyl-2-isopropyl-3-keto-tetrahydrothiophene are converted to 49.0 g of 4-methoxycarbonyl-2-isopropyl-3-keto-tetrahydrothiophene oxime.
Eksempel 3.Example 3
En opløsning af 2,07 g 3-amino-4-methoxycarbonyl-2-methylthiophen--hydrochlorid i 35 ml methanol behandles med 23 ml IN natriumhydroxidopløsning. Blandingen koges i 1/2 time under tilbagesvaling, afkøles og hældes ud i kogsaltopløsning. pH-Værdien i opløsningen indstilles på 5, og opløsningen ekstraheres 7 gange med methylen/ methanol i forholdet 4:1. De organiske ekstrakter tørres og inddampes, og der fås 1,23 g rent 3-amino-4-carboxy-2-methylthiophen med smeltepunkt 162 - 164°C. Et analysepræparat omkrystalliseres af ethylacetat/pentan, smeltepunkt 163 - 164°C.A solution of 2.07 g of 3-amino-4-methoxycarbonyl-2-methylthiophene hydrochloride in 35 ml of methanol is treated with 23 ml of 1 N sodium hydroxide solution. The mixture is refluxed for 1/2 hour, cooled and poured into brine. The pH of the solution is adjusted to 5 and the solution is extracted 7 times with 4: 1 methylene / methanol. The organic extracts are dried and evaporated to give 1.23 g of pure 3-amino-4-carboxy-2-methylthiophene, mp 162 - 164 ° C. An assay preparation is recrystallized from ethyl acetate / pentane, mp 163 - 164 ° C.
,. 150434 På lignende måde omdannes 5 g 3-amino-4-methoxycarbonyl-2-isopro-pylthiophen-hydrochlorid til 3,3 g 3-amino-4-carboxy-2-isopropyl-thiophen med smeltepunkt 117 - 118°C og 1,41 g 3-amino-4-methoxy-carbonyl-2-propylthiophen-hydrochlorid til 0,625 g 3-amino-4-car-boxy-2-propylthiophen med smeltepunkt 144 - 145°C.,. Similarly, 5 g of 3-amino-4-methoxycarbonyl-2-isopropylthiophene hydrochloride is converted to 3.3 g of 3-amino-4-carboxy-2-isopropylthiophene, mp 117-118 ° C and 1, 41 g of 3-amino-4-methoxy-carbonyl-2-propylthiophene hydrochloride to 0.625 g of 3-amino-4-carboxy-2-propylthiophene, m.p. 144-145 ° C.
Eksempel 4.Example 4
Ind i en opløsning af 80,0 g 4-methoxycarbonyl-3-keto-2-phenyl--tetrahydrothiophen-oxim i 600 ml vandfri ether ledes gasformigt hydrogenchlorid ved 0°C i 1 time. Til suspensionen sættes 300 ml methanol, og der omrøres natten over ved 25°C. Reaktionsproduktet frafiltreres og vaskes med ether. Der fås 70,0 g 4-amino-5-phenyl-thiophen-3-carboxylsyre-methylester-hydrochlorid i form af et lysegult fast stof med smeltepunkt 181 - 182°C. Denne forbindelse kan omkrystalliseres af methanol.Into a solution of 80.0 g of 4-methoxycarbonyl-3-keto-2-phenyl-tetrahydrothiophene oxime in 600 ml of anhydrous ether is passed gaseous hydrogen chloride at 0 ° C for 1 hour. To the suspension is added 300 ml of methanol and stirred overnight at 25 ° C. The reaction product is filtered off and washed with ether. 70.0 g of 4-amino-5-phenyl-thiophene-3-carboxylic acid methyl ester hydrochloride is obtained in the form of a pale yellow solid, mp 181 - 182 ° C. This compound can be recrystallized from methanol.
Udgangsmaterialet kan fremstilles på følgende måde: a) Til en opløsning af 104,95 g 3-mercaptopropionsyre-methylester i 200 ml methanol sættes ved 0°C 207,5 g 25%'s natriummethoxidopløs-ning i methanol. Til den vundne homogene opløsning sættes dråbevis under argonatmosfære en opløsning af 200 g a-brom-phenyleddikesyre--methylester i 200 ml methanol. Reaktionsblandingen omrøres natten over ved 25°C, opløsningsmidlet afdampes, og remanensen fordeles mellem vand og methylenchlorid. Der fås 234 g 2-phenyl-3-thia-adi-pinsyre-dimethylester i form af en farveløs olie.The starting material can be prepared as follows: a) To a solution of 104.95 g of 3-mercaptopropionic acid methyl ester in 200 ml of methanol is added at 0 ° C 207.5 g of 25% sodium methoxide solution in methanol. To the homogeneous solution obtained, a solution of 200 g of a-bromo-phenylacetic acid-methyl ester in 200 ml of methanol is added dropwise under an argon atmosphere. The reaction mixture is stirred overnight at 25 ° C, the solvent is evaporated and the residue partitioned between water and methylene chloride. 234 g of 2-phenyl-3-thia-adi-pinic acid dimethyl ester are obtained in the form of a colorless oil.
b) En opløsning af 234 g 2-phenyl-3-thia-adipinsyre-dimethylester i 300 ml tørt benzen sættes ved 25°C dråbevis til 54,05 g natriumme-thoxid. Reaktionsblandingen omrøres natten over og hældes ud i vand. Det faste stof frafiltreres, og filtratet ekstraheres-to gange med 15 • 150434 diethylether. Det faste stof sættes til den vandige fase, som ved tilsætning af 6N HC1 er indstillet på pH-værdi 1. Blandingen ek-straheres tre gange med methylenchlorid, og de organiske ekstrakter tørres over natriumsulfat og inddampes, hvorved der fås 145,24 g 4-methoxycarbonyl-3-keto-2-phenyl-tetrahydrothiophen i form af en gul olie.b) A solution of 234 g of 2-phenyl-3-thia-adipic acid dimethyl ester in 300 ml of dry benzene is added dropwise at 25 ° C to 54.05 g of sodium methoxide. The reaction mixture is stirred overnight and poured into water. The solid is filtered off and the filtrate is extracted twice with diethyl ether. The solid is added to the aqueous phase which is adjusted to pH 1. With the addition of 6N HCl, the mixture is extracted three times with methylene chloride and the organic extracts are dried over sodium sulfate and evaporated to give 145.24 g of 4 -methoxycarbonyl-3-keto-2-phenyl-tetrahydrothiophene in the form of a yellow oil.
c) Til en opløsning af 82,24 g 4-methoxycarbonyl-3-keto-2-phenyl--tetrahydrothiophen i 120 ml vandfrit pyridin sættes 28,85 g hydroxylamin-hydrochlorid. Opløsningen omrøres i 2 dage ved 25°C, opløsningsmidlet afdampes under reduceret tryk, og remanensen fordeles mellem IN saltsyre og methylenchlorid. Den vandige fase ef-terekstraheres med methylenchlorid. De organiske ekstrakter tørres over natriumsulfat og inddampes, og der fås 90,0 g 4-methoxycarbonyl--3-keto-2-phenyltetrahydrothiophen-oxim i form af en farveløs olie.c) To a solution of 82.24 g of 4-methoxycarbonyl-3-keto-2-phenyl-tetrahydrothiophene in 120 ml of anhydrous pyridine is added 28.85 g of hydroxylamine hydrochloride. The solution is stirred for 2 days at 25 ° C, the solvent is evaporated under reduced pressure and the residue partitioned between 1N hydrochloric acid and methylene chloride. The aqueous phase is extracted with methylene chloride. The organic extracts are dried over sodium sulfate and evaporated to give 90.0 g of 4-methoxycarbonyl-3-keto-2-phenyltetrahydrothiophene oxime as a colorless oil.
Eksempel 5 .Example 5
Til en opløsning af 10,0 g 4-amino-5-phenylthiophen-3-carboxylsyre--methylester-hydrochlorid i 80 ml methanol sættes 82 ml IN natriumhydroxidopløsning. Blandingen opvarmes i 30 minutter under tilbagesvaling, afkøles til stuetemperatur og indstilles på pH-værdi 5.To a solution of 10.0 g of 4-amino-5-phenylthiophene-3-carboxylic acid methyl ester hydrochloride in 80 ml of methanol is added 82 ml of 1 N sodium hydroxide solution. The mixture is heated at reflux for 30 minutes, cooled to room temperature and adjusted to pH 5.
Det udskilte produkt frafiltreres og tørres, og der fås 8,2 g ren 4-amino-5-phenylthiophen-3-carboxylsyre, smeltepunkt 201 -202°C (ethylacetat/pentan).The separated product is filtered off and dried, yielding 8.2 g of pure 4-amino-5-phenylthiophene-3-carboxylic acid, mp 201 -202 ° C (ethyl acetate / pentane).
Eksempel 6.Example 6
Fremstilling af 4-amino-5-ethyl-3-thiophencarboxylsyre-methylester--hydrochlorid.Preparation of 4-amino-5-ethyl-3-thiophenecarboxylic acid methyl ester hydrochloride.
Til en opløsning af 125 g methyl-3-mercapto-propionat i 75 ml tørt methanol sættes dråbevis ved 0°C 249 ml methanol indeholdende 25% natriummethoxid. Til blandingen sættes dråbevis ved 0°C 200 gTo a solution of 125 g of methyl 3-mercaptopropionate in 75 ml of dry methanol is added dropwise at 0 ° C 249 ml of methanol containing 25% sodium methoxide. To the mixture is added dropwise at 0 ° C 200 g
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| US71685476A | 1976-08-23 | 1976-08-23 | |
| US71685376A | 1976-08-23 | 1976-08-23 | |
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| US82052177 | 1977-08-01 |
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| DK372177A DK372177A (en) | 1978-02-24 |
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| JP (1) | JPS5340755A (en) |
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| US5811447A (en) | 1993-01-28 | 1998-09-22 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
| US6251920B1 (en) | 1993-05-13 | 2001-06-26 | Neorx Corporation | Prevention and treatment of cardiovascular pathologies |
| US6491938B2 (en) | 1993-05-13 | 2002-12-10 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
| ATE406909T1 (en) | 1993-05-13 | 2008-09-15 | Poniard Pharmaceuticals Inc | PREVENTION AND TREATMENT OF PATHOLOGIES ASSOCIATED WITH ABNORMAL PROLIFERATION OF SMOOTH MUSCLE CELLS |
| WO1998046588A2 (en) * | 1997-04-11 | 1998-10-22 | Neorx Corporation | Compounds and therapies for the prevention of vascular and non-vascular pathologies |
| DE102004063191A1 (en) | 2004-12-29 | 2006-07-13 | Bayer Cropscience Ag | Process for the preparation of substituted 2-alkoxycarbonyl-3-aminothiophenes |
| EP2246343B1 (en) | 2008-02-29 | 2016-05-18 | Nissan Chemical Industries, Ltd. | Process for production of thiophene compound and intermediate thereof |
| WO2024079734A1 (en) | 2022-10-14 | 2024-04-18 | Adama Agan Ltd. | Process for the preparation of substituted aminothiophene |
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| US2502424A (en) * | 1944-12-23 | 1950-04-04 | Parke Davis & Co | 3-acylamino-4-carboalkoxy-2-omega-ralkylthiophenes |
| US2443598A (en) * | 1944-12-23 | 1948-06-22 | Parke Davis & Co | 3-amino-4-carbethoxy-2-alkyl derivatives of thiophene |
| US2502423A (en) * | 1944-12-23 | 1950-04-04 | Parke Davis & Co | 4-carbalkoxy-3-keto-2-substituted tetrahydrothiophene oximes |
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- 1977-08-22 AR AR268888A patent/AR222453A1/en active
- 1977-08-22 GB GB35098/77A patent/GB1587084A/en not_active Expired
- 1977-08-22 DE DE19772737738 patent/DE2737738A1/en active Granted
- 1977-08-22 HU HU77HO2009A patent/HU179484B/en not_active IP Right Cessation
- 1977-08-22 DK DK372177A patent/DK150484C/en active
- 1977-08-22 NO NO772917A patent/NO148673C/en unknown
- 1977-08-22 NZ NZ184981A patent/NZ184981A/en unknown
- 1977-08-22 NL NL7709246A patent/NL7709246A/en not_active Application Discontinuation
- 1977-08-22 ES ES461796A patent/ES461796A1/en not_active Expired
- 1977-08-22 BE BE180354A patent/BE858012A/en not_active IP Right Cessation
- 1977-08-22 MC MC771256A patent/MC1156A1/en unknown
- 1977-08-22 AT AT607477A patent/AT359486B/en not_active IP Right Cessation
- 1977-08-22 AU AU28092/77A patent/AU509956B2/en not_active Expired
- 1977-08-22 JP JP9963877A patent/JPS5340755A/en active Granted
- 1977-08-22 FI FI772494A patent/FI66859C/en not_active IP Right Cessation
- 1977-08-22 IE IE1751/77A patent/IE45470B1/en unknown
- 1977-08-22 IL IL52792A patent/IL52792A/en unknown
- 1977-08-22 LU LU78003A patent/LU78003A1/xx unknown
- 1977-08-22 IT IT26845/77A patent/IT1143757B/en active
Also Published As
| Publication number | Publication date |
|---|---|
| ATA607477A (en) | 1980-04-15 |
| DK150484C (en) | 1987-10-05 |
| BE858012A (en) | 1978-02-22 |
| NO772917L (en) | 1978-02-24 |
| FR2365566B1 (en) | 1980-12-26 |
| LU78003A1 (en) | 1978-09-14 |
| IL52792A (en) | 1981-06-29 |
| MC1156A1 (en) | 1978-04-17 |
| ES461796A1 (en) | 1978-12-16 |
| NL7709246A (en) | 1978-02-27 |
| JPS6121235B2 (en) | 1986-05-26 |
| HU179484B (en) | 1982-10-28 |
| DE2737738A1 (en) | 1978-03-09 |
| AU509956B2 (en) | 1980-06-05 |
| IT1143757B (en) | 1986-10-22 |
| FI66859B (en) | 1984-08-31 |
| IE45470L (en) | 1978-02-23 |
| AT359486B (en) | 1980-11-10 |
| JPS5340755A (en) | 1978-04-13 |
| DE2737738C2 (en) | 1987-01-29 |
| DK372177A (en) | 1978-02-24 |
| AR222453A1 (en) | 1981-05-29 |
| FR2365566A1 (en) | 1978-04-21 |
| IL52792A0 (en) | 1977-10-31 |
| AU2809277A (en) | 1979-03-01 |
| IE45470B1 (en) | 1982-09-08 |
| NO148673B (en) | 1983-08-15 |
| FI772494A (en) | 1978-02-24 |
| NO148673C (en) | 1983-11-23 |
| NZ184981A (en) | 1980-08-26 |
| GB1587084A (en) | 1981-03-25 |
| FI66859C (en) | 1984-12-10 |
| CH628628A5 (en) | 1982-03-15 |
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