DK170245B1 - Pyridine-2,4- and -2,5-dicarboxylic acid derivatives for use as drugs - Google Patents
Pyridine-2,4- and -2,5-dicarboxylic acid derivatives for use as drugs Download PDFInfo
- Publication number
- DK170245B1 DK170245B1 DK090992A DK90992A DK170245B1 DK 170245 B1 DK170245 B1 DK 170245B1 DK 090992 A DK090992 A DK 090992A DK 90992 A DK90992 A DK 90992A DK 170245 B1 DK170245 B1 DK 170245B1
- Authority
- DK
- Denmark
- Prior art keywords
- pyridine
- dicarboxylic acid
- ester
- methyl
- methylene chloride
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- 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
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
Description
i DK 170245 B1in DK 170245 B1
Opfindelsen angår pyridin-2,4- og -2,5-dicarboxylsyre-derivater med den i det følgende angivne almene formel (I) og deres fysiologisk acceptable salte til anvendelse som lægemidler.This invention relates to pyridine-2,4- and -2,5-dicarboxylic acid derivatives of the general formula (I) hereinafter and their physiologically acceptable salts for use as drugs.
5 Forbindelser# som inhiberer prolin- og lysin- hydroxylasen# bevirker en særdeles selektiv hæmning af collagenbiosyntesen ved påvirkning af de collagenspeci-fikke hydroxyleringsreaktioner. Under forløbet af disse hydroxyleres protein-bunden prolin eller lysin ved ind-10 virkning af enzymerne prolin- eller lysinhydroxylase.Compounds # which inhibit the proline and lysine hydroxylase # cause a highly selective inhibition of collagen biosynthesis by affecting the collagen-specific hydroxylation reactions. In the course of these, protein-bound proline or lysine is hydroxylated by the action of the enzymes proline or lysine hydroxylase.
Såfremt denne reaktion hindres ved inhibitorer# fremkommer der et ikke funktionsdygtigt# underhydroxyleret collagenmolekyle# som fra cellen kun kan afgives til det ekstracellulære rum i ringe mængde. Det underhydroxy-15 lerede collagen kan desuden ikke indbygges i collagen-matriksen og nedbrydes -proteolytisk særdeles let. Som følge af disse virkninger forringes den totale mængde af det ekstracellulært udfældede collagen.If this reaction is inhibited by inhibitors #, a non-functioning # subhydroxylated collagen molecule # which can be delivered from the cell to the extracellular compartment only in small amount appears. Furthermore, the underhydroxylated collagen cannot be incorporated into the collagen matrix and degrades proteolytically very easily. As a result of these effects, the total amount of the extracellularly precipitated collagen is degraded.
Det er kendt# at inhiberingen af prolinhydroxy-20 lasen med kendte inhibitorer såsom α,α'-dipyridyl fører til en hæmning af Clg-biosyntesen af makrofager (jf. W.It is known # that the inhibition of the proline hydroxylase by known inhibitors such as α, α'-dipyridyl leads to an inhibition of the Clg biosynthesis of macrophages (cf.
Muller et al.# FEBS Lett. 90/ 218 (1978); Immunbiology 155, 47 (1978)). Herved bortfalder den klassiske vej til komplementaktivering. Inhibitorer af prolinhydroxylase virker 25 derfor også som immunsuppresive stoffer, f.eks. ved immunkom-plekssygdomme.Muller et al # FEBS Easy. 90/218 (1978); Immunobiology 155, 47 (1978)). This eliminates the classic path to complement activation. Therefore, inhibitors of proline hydroxylase also act as immunosuppressants, e.g. in immune complex diseases.
Det er kendt, at prolinhydroxylase hæmmes effektivt ved hjælp af pyridin-2,4- og -2,5-dicarboxylsyre (jf. K.It is known that proline hydroxylase is effectively inhibited by pyridine-2,4- and -2,5-dicarboxylic acid (cf. K.
Mayama et al., Eur. J. Biochem. 138. 239-245 (1984). Disse 30 forbindelser er i cellekulturen ganske vist kun virksomme som hæmmende stoffer i meget høje koncentrationer (jf. V. Gunsler et al., Collagen and Rel. Research 3, 71 (1983)).Mayama et al., Eur. J. Biochem. 138. 239-245 (1984). Admittedly, in these cell cultures these 30 compounds act only as inhibitors of very high concentrations (cf. V. Gunsler et al., Collagen and Rel. Research 3, 71 (1983)).
I DE-A 3.432.094, jf. også EP-A-176.741, beskrives pyridin-2,4- og -2,5-dicarboxylsyrediestere med 1-6 C-atomer 35 i esteralkyldelen som lægemidler til inhibering af prolin-og lysinhydroxylasen.In DE-A 3,432,094, cf. also EP-A-176,741, pyridine-2,4- and -2,5-dicarboxylic acid diesters having 1-6 C atoms 35 in the ester alkyl portion are described as drugs for inhibiting the proline and lysine hydroxylase. .
DK 170245 B1 2DK 170245 B1 2
Disse lav-alkylerede diestere har imidlertid den ulempe, at de spaltes for hurtigt i organismen til syrerne og ikke når frem til deres virkningssted i cellen i tilstrækkelig høj koncentration og således er mindre egnede til en 5 eventuel indgivelse som lægemidler.However, these low-alkylated diesters have the disadvantage that they are cleaved too quickly in the organism to the acids and do not reach their site of action in the cell at a sufficiently high concentration and thus are less suitable for possible administration as drugs.
På overraskende måde har det vist sig, at bestemte estere af pyridin-2,4- og -2,5-dicarboxylsyre og ligeledes visse substituerede dialkylestere deraf er udmærkede hæmningsstoffer for collagenbiosyntesen ved dyremodelforsøg, 10 og det fremgår af de følgende resultater af sammenligningsforsøg, at forbindelserne ifølge opfindelsen har uventet bedre virkninger end forbindelser, der er nært beslægtede hermed og kendt fra EP-A-176.741.Surprisingly, it has been found that certain esters of pyridine-2,4- and -2,5-dicarboxylic acid and also certain substituted dialkyl esters thereof are excellent inhibitors of collagen biosynthesis in animal model experiments, 10 and the following results of comparison experiments show, that the compounds of the invention unexpectedly have better effects than compounds closely related thereto and known from EP-A-176,741.
Ved sammenligningsforsøg med pyridin-2,4-dicarboxyl-15 syre-dimethylester (forbindelse 2, jf. EP-A-176.741) og pyridin-2,4-dicarboxylsyre-di-(1-ethoxycarbonyl-l-ethoxyme-thyl)-ester (forbindelse 1 ifølge opfindelsen) har man bestemt stabiliteten i serum (hundeplasma) ved hjælp af T ^ for forbindelserne samt polariteten ved hjælp af log P-vær-20 dier ifølge Eur. J. Med. Chem. 14» 479 (1979) med følgende resultater:In comparison experiments with pyridine-2,4-dicarboxylic acid dimethyl ester (compound 2, cf. EP-A-176,741) and pyridine-2,4-dicarboxylic acid di- (1-ethoxycarbonyl-1-ethoxymethyl) - ester (compound 1 of the invention) has been determined the stability of serum (dog plasma) by T ^ for the compounds as well as the polarity by log P values according to Eur. J. Med. Chem. 14 »479 (1979) with the following results:
T ½ log PT ½ log P
Forbindelse 1 100 min. -0,99Connection 1 100 min. -0.99
Forbindelse 2 <60 min. 1,48.Compound 2 <60 min. 1.48.
2525
Det egentlige virksomme stof, pyridin-2,4- eller -2,5-dicarboxylsyre, fremkommer først ved hydrolyse af esterne i cellen. Esterne kan på grund af deres højere lipofili og den kendsgerning, at de under transporten på overraskende 30 måde kun meget langsomt hydrolyseres, transporteres ind i cellerne. Først her frigøres det egentlige virksomme stof, ‘ pyridin-2,4- eller -2,5-dicarboxylsyre.The actual active substance, pyridine-2,4- or -2,5-dicarboxylic acid, first appears by hydrolysis of the esters in the cell. The esters, due to their higher lipophilia and the fact that during transport, surprisingly only hydrolyze very slowly during transport, are transported into the cells. It is only here that the actual active substance, 'pyridine-2,4- or -2,5-dicarboxylic acid is released.
Den foreliggende opfindelse angår således pyridin--2,4- og -2,5-dicarboxylsyre-derivater med den almene formel 35 DK 170245 B1 3 0 2 * n-o-c-s- Τχ 5 N"\ C-O-R1 (I) μ 0 i hvilken 10 R1 betyder CS^.^-alkyl, som er substitueret én gang eller i tilfælde af C2-12-a-'-kyler °9S^ flere gange med halogen, hydroxy, cyano, carboxyl, ^.4-alkoxy, C^-alkoxycarbonyl, C^^-alkylcarbonyloxy eller phenyl, der på sin side eventuelt er substitueret 15 med halogen, nitro, C1_4-alkyl eller C1_4-alkoxy, eller R1 betyder mættet C5_7-cycloalkyl, som er benzoannel-leret, eller R1 betyder phenyl eller naphthyl, der eventuelt er sub-20 stitueret med halogen, nitro, C1_4-alkyl eller 0^,4- alkoxy, eller R1 betyder 2-oxo-l,3-dioxolylmethyl, der eventuelt er methylsubstitueret, og R2 uafhasngigt af R1 betyder hydrogen eller R1, 25 og deres fysiologisk acceptable salte til anvendelse som lægemidler, dog med undtagelse af sådanne forbindelser, hvori R1 og/eller R2 betyder halogenethyl, hydroxyethyl, cyanoethyl eller carboxyethyl.Thus, the present invention relates to pyridine-2,4- and -2,5-dicarboxylic acid derivatives of the general formula 35 N 170-45 N * \ CO-R1 (I) µ 0 in which R 1 represents C 1-4 alkyl which is substituted once or in the case of C 2-12 -a-'-cyls ° 9S ^ several times with halogen, hydroxy, cyano, carboxyl, 1-4 alkoxy, C -alkoxycarbonyl, C 1-4 -alkylcarbonyloxy or phenyl, which in turn is optionally substituted with halogen, nitro, C 1-4 -alkyl or C 1-4 -alkoxy, or R 1 is saturated C 5 -7 cycloalkyl, which is a benzo-alloy or R 1 is phenyl or naphthyl optionally substituted with halogen, nitro, C1-4 alkyl or O4-4 alkoxy, or R1 means 2-oxo-1,3-dioxolylmethyl optionally methyl substituted and R2 independently of R1 hydrogen or R 1, 25 and their physiologically acceptable salts for use as drugs, with the exception of such compounds wherein R 1 and / or R 2 are haloethyl, hydroxyethyl, cyanoet or carboxyethyl.
Opfindelsen angår i særdeleshed pyridin-2,4- og -2,5-30 -dicarboxylsyre-derivater som ovenfor defineret, i hvilke R·*- betyder 01-4-alkyl, der er substitueret én gang eller i tilfælde af C3- og C4-alkyler også flere gange med C]__3-alkoxy og/eller C1_3-alkoxycarbonyl, og/eller phenyl, eller 35 R1 betyder C5- eller Cg-cycloalkyl, der er benzoannel-leret, eller DK 170245 B1 4 R1 betyder phenyl, der eventuelt er nitrosubstitueret, eller R1 betyder naphthyl, eller R1 betyder 5-methyl-2-oxo-l,3-dioxol-4-yl-methyl, og 5 R2 uafhængigt af R·^ betyder hydrogen eller R-^-, samt deres fysiologisk acceptable salte til anvendelse som lægemidler.In particular, the invention relates to pyridine-2,4- and -2,5-30 -dicarboxylic acid derivatives as defined above, in which R · - means O-4-4-alkyl substituted once or in the case of C C 4 -alkyls also several times with C 1-6 alkoxy and / or C 1-3 alkoxycarbonyl, and / or phenyl, or R 1 represents C 5 or C 8 cycloalkyl which is benzo-labeled, or DK 170245 B 4 optionally nitrosubstituted or R 1 is naphthyl or R 1 is 5-methyl-2-oxo-1,3-dioxol-4-yl-methyl and R 2 is independently R 2 their physiologically acceptable salts for use as drugs.
Disse forbindelser har bl.a. en særlig virkning ved den orale anvendelse, ligesom også de ganske særligt fore-10 trukne pyridin-2,4- og 2,5-dicarboxylsyre-derivater med formlen I, hvori R1 og R2 er 1-isopropoxycarbonylethyl-grup-per, (f.eks. pyridin-2,5-dicarboxylsyre-bis-(l-isopropoxycar-bonylethyl)ester (eks. 3) eller pyridin-2,4-dicarboxylsyre-bis-(1-isopropoxycarbonylethyl)-ester (eks. 15)), og deres 15 fysiologisk acceptable salte.These compounds include: a particular effect in the oral use, as well as the particularly preferred pyridine-2,4- and 2,5-dicarboxylic acid derivatives of formula I wherein R 1 and R 2 are 1-isopropoxycarbonylethyl groups, (f e.g., pyridine-2,5-dicarboxylic acid bis (1-isopropoxycarbonylethyl) ester (Example 3) or pyridine-2,4-dicarboxylic acid bis (1-isopropoxycarbonylethyl) ester (Example 15) , and their 15 physiologically acceptable salts.
Ved halogen skal der forstås fluor, chlor, brom og iod.By halogen is meant fluorine, chlorine, bromine and iodine.
"Flere gange substitueret" betyder i det ovenstående og nedenfor, at mindst 2 og højst alle i alkylgrupperne 20 tilstedeværende hydrogenatomer er erstattet af de nævnte substituenter. Fortrinsvis er der tale om én substituent pr. methyl- eller methylengruppe."Several times substituted" means above and below that at least 2 and at most all hydrogen atoms present in the alkyl groups 20 are replaced by said substituents. Preferably, there is one substituent per methyl or methylene group.
Ved multisubstitutioner kan substituenterne også uafhængigt af hinanden være forskellige.In the case of multisubstitutions, the substituents may also differ independently.
25 Forbindelserne med formlen I kan fremstilles ved, at a) en forbindelse med formlen 0 2 “ R -0-C— 30 Π *·Η*\ (II) c-y li o omsættes med en forbindelse med formlen 35 HO -R1 (III) DK 170245 B1 5 hvori R1 og R2 har de i formel I angivne betydninger, og Y betyder halogen eller hydroxy, eller at b) en forbindelse med formlen 0 5 * Z-C— tx , c-0 -R1The compounds of formula I can be prepared by reacting a) a compound of formula 0 2 “R-O-C-30 Π * · Η * \ (II) cy li o with a compound of formula 35 HO-R1 (III DK 170245 B1 wherein R 1 and R 2 have the meanings given in formula I and Y is halogen or hydroxy or b) a compound of formula 0 5 * ZC - tx, c-O-R
IIII
0 10 omsættes med en forbindelse med formlen HO-R2 (V) hvori R1 og R2 har de i formel I angivne betydninger, og Z 15 betyder halogen, eller at c) en forbindelse med formlen 00 10 is reacted with a compound of formula HO-R2 (V) wherein R 1 and R 2 have the meanings given in formula I and Z 15 is halogen or c) a compound of formula 0
IIII
Z-C—~ 20 , .Z-C— ~ 20 ,.
cx c-zcx c-z
IIII
o 25 2 omsættes med en alkohol HO-R eller en alkohol med formlen HO-R1 (VII) 30 12 hvori R og R har de i formel I angivne betydninger, og Z betyder halogen, eller at d) et alkalimetalsalt af pyridin-2,4- eller -2,5-dicarboxylsyren omsættes med et halogenid med formlen 35 DK 170245 B1 6 0 ! R -Z (VIII)o is reacted with an alcohol HO-R or an alcohol of formula HO-R1 (VII) wherein R and R have the meanings given in formula I and Z is halogen or d) an alkali metal salt of pyridine-2 The 4-, or -2,5-dicarboxylic acid is reacted with a halide of the formula. R -Z (VIII)
hvori R1 har de i formel I angivne betydninger, og Zwherein R1 has the meanings given in formula I, and Z
& betyder halogen, 5 og at reaktionsprodukterne eventuelt omdannes til deres fysiologisk acceptable salte.and means halogen, and optionally the reaction products are converted to their physiologically acceptable salts.
Fremstillingen af forbindelser med formlen I og fremstillingen af de dertil nødvendige udgangsforbindel- i ser - såfremt de ikke kan fås i handelen - beskrives nær-jo mere nedenfor.The preparation of compounds of formula I and the preparation of the necessary starting compounds - if they are not commercially available - are described in more detail below.
Fremstillingen af forbindelserne ifølge opfindelsen lykkes på den simpleste måde ved, at de to komponenter, pyridin-derivatet med formlen (II), (IV) eller (VI), og alkoholen med formlen (III) , (V) eller (VII) 15 blandes i ækvimolære mængder eller indtil ca. et 5-dobbelt overskud af III, V eller VII og omsættes ved temperaturer mellem -30 og 150°C, fortrinsvis ved 20-100°C, indtil reaktionen ophører. Reaktionens afslutning bestemmes ved hjælp af tyndtlagschromatografi (TC-kontrol).The preparation of the compounds of the invention succeeds in the simplest way in that the two components, the pyridine derivative of formula (II), (IV) or (VI), and the alcohol of formula (III), (V) or (VII) 15 mix in equimolar amounts or until approx. a 5-fold excess of III, V or VII and reacted at temperatures between -30 and 150 ° C, preferably at 20-100 ° C, until the reaction ceases. The completion of the reaction is determined by thin layer chromatography (TC control).
20 En variant af denne fremgangsmåde består i, at der arbejdes i et egnet opløsningsmiddel, f.eks. diethylether eller dimethoxyethan eller tetrahydrofuran, chlorerede carbonhydrider, f.eks. methylenchlorid, chloroform, tri- eller tetrachlorethylen, benzen, toluen eller polære 25 opløsningsmidler, f.eks. dimethylformamid eller acetone eller dimethylsulfoxid. Også i denne forbindelse kan der anvendes et overskud af alkohol med formlen (III), (V) eller (VII) , der kan andrage indtil ca. den 5-dobbelte mængde. Reaktionstemperaturerne ligger herved 30 mellem stuetemperatur og opløsningsmidlets kogepunkt, idet særligt foretrukne temperature^ ligger i området * fra stuetemperatur til 130°C.A variant of this process consists in working in a suitable solvent, e.g. diethyl ether or dimethoxyethane or tetrahydrofuran, chlorinated hydrocarbons, e.g. methylene chloride, chloroform, tri- or tetrachlorethylene, benzene, toluene or polar solvents, e.g. dimethylformamide or acetone or dimethyl sulfoxide. Also in this connection, an excess of alcohol of formula (III), (V) or (VII) may be used which may be up to approx. the 5-fold quantity. The reaction temperatures are hereby between room temperature and the boiling point of the solvent, particularly preferred temperatures being in the range * from room temperature to 130 ° C.
Eventuelt kan omsætningen også ske i nærværelse „ af baser. Som yderligere baser kommer uorganiske syre-35 bindende midler såsom carbonater eller hydrogencarbonater i betragtning, f.eks. natrium- eller kaliumcarbonat DK 170245 Bl 0 7 eller natrium- eller kaliumhydrogencarbonat, eller organiske syrebindende midler såsom tertiære aminer/ f.eks. triethy1amin, tributylamin, ethyldiisopropylamin eller heterocycliske aminer, f.eks. N-alkylmorpholin, pyridin, guinolin eller dialkylaniliner.Optionally, the turnover may also be in the presence 'of bases. As additional bases, inorganic acid-binding agents such as carbonates or hydrogen carbonates are considered, e.g. sodium or potassium carbonate or sodium or potassium hydrogen carbonate, or organic acid binding agents such as tertiary amines / e.g. triethylamine, tributylamine, ethyl diisopropylamine or heterocyclic amines, e.g. N-alkylmorpholine, pyridine, guinoline or dialkylanilines.
Fortrinsvis sker omsætningen af forbindelserne med formlen (II) med alkoholer med formlen (III) under tilsætning af et vandfraspaltende middel, f.eks. et dialkylcarbodiimid, idet alkylgrupperne har 10 1-8 C-atomer, der i tilfælde af C^g-forbindelserne også kan være forgrenede eller cycliske; der anvendes fortrinsvis dicyclohexylcarbodiimid. En tilsvarende metode er beskrevet i Houben-Weyl, bd. XV/2, side 103-111,Preferably, the compounds of formula (II) are reacted with alcohols of formula (III) with the addition of a water-scavenging agent, e.g. a dialkylcarbodiimide, the alkyl groups having 10 to 8 C atoms which in the case of the C C g compounds can also be branched or cyclic; preferably dicyclohexylcarbodiimide is used. A similar method is described in Houben-Weyl, vol. XV / 2, pages 103-111,
Methoden der Organischen Chemie, 4. opl., Georg Thieme 15 Verlag, Stuttgart, 1974.Methods of Organic Chemistry, 4th ed., Georg Thieme 15 Verlag, Stuttgart, 1974.
Eventuelt kan oparbejdningen af produkterne eksempelvis ske ved ekstraktion eller ved chromatografi, f.eks. over kiselgel. Det isolerede produkt kan omkrystalliseres og eventuelt omsættes med en egnet syre til 20 et fysiologisk acceptabelt salt. Som egnede syrer kommer f.eks. følgende i betragtning: mineralsyrer, f.eks. hydro- •genchlorid- og hydrogenbromidsyre samt svovl-, phosphor-, salpeter- eller perchlorsyre, eller organiske syrer, f.eks. myre- eddike-, propion-, rav-, glycol-, mælke-, 25 æble-, vin-, citron-, malein-, fumar-, phenyleddike-, benzoe-, methansulfon-, toluensulfon-, oxal-, 4-amino-benzoe-, naphthalen-1,5-disulfon- eller ascorbinsyre.Optionally, the products may be reprocessed by extraction or by chromatography, e.g. over silica gel. The isolated product can be recrystallized and optionally reacted with a suitable acid to a physiologically acceptable salt. As suitable acids, e.g. the following considerations: mineral acids, e.g. hydrogen chloride and hydrogen bromic acid as well as sulfuric, phosphorus, nitric or perchloric acid, or organic acids, e.g. formic vinegar, propionic, amber, glycol, milk, apple, wine, lemon, maleic, fumaric, phenylacetic, benzoic, methanesulfone, toluenesulfone, oxalic, 4- amino-benzoic, naphthalene-1,5-disulfonic or ascorbic acid.
Udgangsforbindelserne med formlen (III), (V) og (VII) kan, såfremt de ikke kan fås i handelen, synte-30 tiseres på simpel måde (jfr. Organikum, Organisch Chemi-sches Grundpraktikum, 15. opl., VEB Deutscher Verlag der Wissenschaften, 1976; en oversigt over de forskellige muligheder findes i metoderegisteret: alkoholer: s.821.The starting compounds of formulas (III), (V) and (VII) can, if they are not commercially available, be synthesized in a simple manner (cf. Organikum, Organisch Chemisches Grundpraktikum, 15th ed., VEB Deutscher Verlag der Wissenschaften, 1976; An overview of the various options is found in the method register: alcohols: p.821.
35 DK 170245 B1 835 DK 170245 B1 8
Udgangsforbindelserne med formlen (II) opnås f.eks. ved omsætning af pyridin-2,4- eller -2,5-dicarb- oxylsyre til det tilsvarende pyridin-2,4- eller -2,5-di-5 carboxylsyrehalogenid (VI), fortrinsvis -chlorid (ifølge s i litteraturen kendte metoder, f.eks. Organikum, Orga- nisch Chemisches Grundpraktikuml 15. opl., VEB DeutscherThe starting compounds of formula (II) are obtained e.g. by reacting pyridine-2,4- or -2,5-dicarboxylic acid to the corresponding pyridine-2,4- or -2,5-dicarboxylic acid halide (VI), preferably chloride (methods known in the literature) , eg Organic, Organic Chemisches Grundpraktikuml 15th ed., VEB Deutscher
Verlag der Wissenschaften, 1976, s. 595 ff), som derefter • 2 omsættes med en alkohol med formlen R -OH (V) til den 10 tilsvarende 2,4- eller 2,5-diester. Ved selektiv forsæbning af esteren i pyridin-derivatets 2-stilling (f.eks. via et kobberkompleks, jf . Pharm. Acta Helv. 44, 1969, s. 637) eller partiel alkalisk forsæbning (jf. J. Org. Chem. 39 (8), 1974, s. 1158) opnås pyri-15 din-4- eller -5-carboxylsyreester-2-carboxylsyren, der enten anvendes direkte (II, Y=0H) eller kan omdannes til syrehalogenidet (II, Y=Cl,Br, J), fortrinsvis syrechlo-ridet.Verlag der Wissenschaften, 1976, p. 595 ff), which is then reacted with an alcohol of the formula R -OH (V) to the corresponding 2,4- or 2,5-diester. By selective saponification of the ester in the 2-position of the pyridine derivative (e.g. via a copper complex, cf. Pharm. Acta Helv. 44, 1969, p. 637) or partial alkaline saponification (cf. J. Org. Chem. 39 (8), 1974, p. 1158), the pyridine-4- or -5-carboxylic acid ester-2-carboxylic acid is obtained, which is either used directly (II, Y = OH) or can be converted to the acid halide (II, Y = Cl , Br, J), preferably acid chloride.
20 Udgangsforbindelserne med formlen (IV) kan eksempelvis syntetiseres på følgende måde:For example, the starting compounds of formula (IV) can be synthesized as follows:
Omsætning af pyridin-2,4- eller -2,5-dicarboxyl-syrehalogenidet, fortrinsvis -chloridet, med benzylalko— hol til pyridin-2,4- eller -2,5-dicarboxylsyrebenzyleste-25 ren; derefter selektiv forsæbning af esteren i 2-stilling (f.eks. i nærværelse af en kobberkatalysator, loc.cit.Reaction of the pyridine-2,4- or -2,5-dicarboxylic acid halide, preferably the chloride, with benzyl alcohol to the pyridine-2,4- or -2,5-dicarboxylic acid benzyl ester; then selectively saponifying the ester in the 2-position (e.g., in the presence of a copper catalyst, loc.cit.
Pharm.Acta Helv.), omdannelse af den frie syre i 2-stilling til syrehalogenidet, omsætning med en forbindelse med formlen HO -R·*- (III) til pyridin-4- eller -5-carboxyl-3 0 syrebenzylester-2-carboxylsyre- (R1) -esteren, hydrogenolytisk fraspaltning af den tilbageblivende benzylbeskyttelsesgruppe *· (f.eks. med H2/Pt, jfr. Houben-Weyl, bd. IV/lc (1980), s.Pharm.Acta Helv.), Converting the free acid in 2-position to the acid halide, reacting with a compound of the formula HO -R · * - (III) to pyridine-4 or -5-carboxylic acid benzyl ester-2 -carboxylic acid (R 1) ester, hydrogenolytic cleavage of the residual benzyl protecting group * (e.g. with H2 / Pt, cf. Houben-Weyl, vol. IV / lc (1980), p.
381-82) og påfølgende omdannelse af den frie syre i pyridin- T, ringens 4- eller 5-stilling til syrehalogenidet (IV).381-82) and subsequent conversion of the free acid into pyridine T, the 4- or 5-position of the ring to the acid halide (IV).
35 DK 170245 B1 9 o35 DK 170245 B1 9 o
Pyridin-2,4- eller -2,5-dicarboxylsyrehalogenidet ifølge formel VI kan opnås ifølge kendte metoder, f.eks.The pyridine-2,4- or -2,5-dicarboxylic acid halide of formula VI can be obtained by known methods, e.g.
ved omsætning af pyridin-2,4- eller -2,5-dicarboxylsyre med phosphortrihalogenid (jfr. f.eks- Organikum, Organischby reacting pyridine-2,4- or -2,5-dicarboxylic acid with phosphorus trihalide (cf. eg Organicum, Organic
Chemisches Grundpraktikum, 15. opl-, VEB Deutscher Verlag 5 der Wissenschaften, 1976, s. 527 og 595 ff).Chemisches Grundpraktikum, 15. opl-, VEB Deutscher Verlag 5 der Wissenschaften, 1976, pp. 527 and 595 et seq.
Omsætningen af alkalimetalsalte af pyridin-2,4-eller -2,5-dicarboxylsyren med et halogenid med form- . len VIII sker ifølge fra litteraturen kendte metoder (jfr. f.eks. Organikum, Organisch Chemisches Grundpraktikum, 15. opl-, VEB Deutscher Verlag der Wissenschaften, 1976, s. 255 ff).The reaction of the alkali metal salts of the pyridine-2,4- or -2,5-dicarboxylic acid with a halide of form. Lien VIII follows methods known in the literature (cf., for example, Organikum, Organisch Chemisches Grundpraktikum, 15th ed., VEB Deutscher Verlag der Wissenschaften, 1976, p. 255 et seq.).
De her omhandlede forbindelser med formlen I har som nævnt værdifulde farmakologiske egenskaber og er især virksomme som hæmmende midler af prolin- og 15 lysinhydroxylase, som fibrosuppresive og immunsuppre-sive midler.The compounds of formula I, as mentioned, have valuable pharmacological properties and are particularly effective as inhibitors of proline and lysine hydroxylase, as fibrosuppressive and immunosuppressive agents.
Aktiviteten af fibrogenasen kan bestemmes i serumet ved radioimmunologisk bestemmelse af det N-termi-2Q nåle propeptid af collagenet type.III eller af det N- eller C-terminale tværbindingsdomæne af collagenet type IV (7s-collagen eller type-IV-collagen-NC^).The activity of the fibrogenase can be determined in the serum by radioimmunologically determining the N-termi-2Q needle propeptide of the collagen type IIII or of the N or C-terminal cross-linking domain of the collagen type IV (7s collagen or type IV collagen NC) ^).
Til dette formål er hydroxyprolin-, procollagen- III-peptid-, 7s-collagen- og type-IV-collagen-NC^-kon-25 centrationer blevet målt i leveren hos a) ubehandlede rotter (kontrol) b) rotter, som har fået indgivet carbontetrachlorid (CC1 ^**kontr o 1) c) rotter, som først har fået indgivet CCl^ og derefter 30 en forbindelse ifølge opfindelsen (denne forsøgsmetode beskrives af Rouiller, C., Experimental toxic injury of the liver; i The Liver, c. Rouiller, Vol. 2, s. 335-476, New York, Academic Press, 1964) .For this purpose, hydroxyproline, procollagen III peptide, 7β collagen and type IV collagen NC ^ concentrations have been measured in the liver of a) untreated rats (control) b) rats that have (c) rats which have first been administered CC1 and then a compound of the invention (this experimental method is described by Rouiller, C., Experimental toxic injury of the liver; in The Liver , c. Rouiller, Vol. 2, pp. 335-476, New York, Academic Press, 1964).
35 DK 170245 B1 10 0 Den farmakologiske virkning af de her omhand lede forbindelser undersøges i en række forsøg (jfr. tabel I) . Herved viser der sig en tydelig hæmning af prolin- og lysinhydroxylasen. * 5 Tabel I sThe pharmacological effect of the compounds in question is investigated in a number of experiments (cf. Table I). This shows a clear inhibition of the proline and lysine hydroxylase. * 5 Table I p
Forb. fra Dosering Hydroxy- Procolla- 7s-Colla- Type-IV- eks. prolin gen-III- gen colla- pg/frg lever peptid gen NC^ 10 ng/ml ng/fel ng/nl 4 2 x 25 mg 0/482 37,2 121,4 100,8 OCl.-kon- 4 trol 0,773 73,9 308,7 168,4 16 Kontrol 0,289 11,1 22,8 23,5Conn. from Dosage Hydroxy-Procolla- 7s-Colla- Type-IV ex proline gene-III gene collapg / frg liver peptide gene NC ^ 10 ng / ml ng / fel ng / nl 4 2 x 25 mg 0/482 37.2 121.4 100.8 OCl.control 0.773 73.9 308.7 168.4 16 Control 0.289 11.1 22.8 23.5
Forbindelserne med formlen I kan anvendes som medikamenter i form af farmaceutiske præparater, som indeholder disse eventuelt sammen med acceptable 20 farmaceutiske bærere. De nævnte forbindelser kan anvendes som lægemidler, f.eks. i form af farmaceutiske præparater, som indeholder disse forbindelser i blanding med en til enteral, perkutan eller parenteral anvendelse egnet farmaceutisk, organisk eller uorganisk bærer, f.eks.The compounds of formula I may be used as medicaments in the form of pharmaceutical compositions which optionally contain them together with acceptable pharmaceutical carriers. Said compounds may be used as drugs, e.g. in the form of pharmaceutical compositions containing these compounds in admixture with a pharmaceutical, organic or inorganic carrier suitable for enteral, percutaneous or parenteral use, e.g.
25 vand, gummi arabicum, gelatine, mælkesukker, stivelse, magnesiumstearat, talk, vegetabilske olier, polyalkylen- glycoler eller vaseline.25 water, gum arabic, gelatin, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols or vaseline.
De farmaceutiske præparater kan foreligge i fast form, f.eks. som tabletter, dragées, suppositorier eller 30 kapsler, i halvfast form, f.eks. som salver, eller i fly- ** * dende form, f.eks- som opløsninger, suspensioner eller emulsioner. De nævnte præparater er eventuelt sterilise-rede og/eller indeholder hjælpestoffer, f.eks. konserverings-, stabiliserings-, fugte- eller emulgeringsmidler, salte til ændring af det osmotiske tryk eller pufferstoffer. Præparaterne kan også indeholde andre terapeutisk virksomme stoffer.The pharmaceutical compositions may be in solid form, e.g. as tablets, dragees, suppositories or capsules, in semi-solid form, e.g. as ointments, or in liquid form, for example, as solutions, suspensions or emulsions. Said compositions are optionally sterilized and / or contain adjuvants, e.g. preservatives, stabilizers, wetting or emulsifying agents, salts for changing the osmotic pressure or buffering agents. The compositions may also contain other therapeutically active substances.
35 DK 170245 B1 11 0 Opfindelsen forklares nærmere ved hjælp af føl gende eksempler:The invention is explained in more detail by means of the following examples:
Eksempel 1 s Pyridin-2,5-dicarboxylsyre-bis (1-methoxycarbonylethyl) -esterExample 1 s Pyridine-2,5-dicarboxylic acid bis (1-methoxycarbonylethyl) ester
Der sættes 10-g pyridin-2,5-dicarboxylsyre til 60 ml tørt methylenchlorid, og hertil sættes der 80 ml 10 frisk destilleret thionylchlorid og 2 ml tørt dimethyl-formamid. Blandingen koges i tre timer under tilbagesvaling, det overskydende thionylchlorid og methylenchlori-det afdestilleres derefter, og remanensen afdampes én gang med tør toluen. Til reaktionsblandingen sættes der 15 ved fra -30 til -20°C dråbevis en opløsning af 12,5 g mælkesyremethylester, opløst i methylenchlorid. Blandingen får lov til at opvarme langsomt til stuetemperatur, der omrøres natten over ved stuetemperatur, og opløsningen vaskes med natriumbicarbonat-opløsning. Den 20 organiske fase befries for opløsningsmidlet efter tørring og chromatograferes over kiselgel med eddikéester som løbemiddel. Produktet omkrystalliseres fra isopropanol. Smeltepunkt 78°C. Udbytte 7,2 g.10 g of pyridine-2,5-dicarboxylic acid are added to 60 ml of dry methylene chloride, to which are added 80 ml of 10 fresh distilled thionyl chloride and 2 ml of dry dimethylformamide. The mixture is refluxed for three hours, the excess thionyl chloride and methylene chloride are then distilled off and the residue is evaporated once with dry toluene. To the reaction mixture is added dropwise a solution of 12.5 g of lactic acid methyl ester dissolved in methylene chloride at -30 to -20 ° C. The mixture is allowed to warm slowly to room temperature, stirred overnight at room temperature, and the solution is washed with sodium bicarbonate solution. The organic phase is freed from the solvent after drying and chromatographed over silica gel with vinegar ester as the solvent. The product is recrystallized from isopropanol. Melting point 78 ° C. Yield 7.2 g.
25 , _25, _
Eksempel 2Example 2
Pyridin-2,5-dicarboxylsyre-bis(1-ethoxycarbonylethyl)-ester 30Pyridine-2,5-dicarboxylic acid bis (1-ethoxycarbonylethyl) ester 30
Der sættes 10 g pyridin-2,5-dicarboxylsyre til 60 ml tørt methylenchlorid, og hertil sættes der 80 ml frisk destilleret thionylchlorid og 2 ml tørt dimethyl-formamid. Blandingen koges i tre timer under tilbagesvaling, det overskydende thionylchlorid og methylenchlo-35 ridet afdestilleres derefter, og remanensen afdampes DK 170245 B1 12 0 én gang med tør toluen. Til reaktionsblandingen sættes der ved fra -30 til -20°C dråbevis en opløsning af 14,1 g mælkesyreethylester, opløst i 1 liter methylen-chlorid. Blandingen får lov til at opvarme langsomt til * stuetemperatur, der omrøres natten over ved stuetempera-5 tur, og opløsningen vaskes med natriumbicarbonat-opløs- s ning. Den organiske fase befries for opløsningsmidlet efter tørring og chromatograferes over kiselgel med eddikeester som løbemiddel. Produktet fremkommer som en olie.10 g of pyridine-2,5-dicarboxylic acid are added to 60 ml of dry methylene chloride and 80 ml of freshly distilled thionyl chloride and 2 ml of dry dimethylformamide are added. The mixture is refluxed for three hours, the excess thionyl chloride and methylene chloride are then distilled off and the residue is evaporated once with dry toluene. To the reaction mixture is added dropwise at -30 to -20 ° C a solution of 14.1 g of lactic acid ethyl ester, dissolved in 1 liter of methylene chloride. The mixture is allowed to warm slowly to room temperature, which is stirred overnight at room temperature and the solution is washed with sodium bicarbonate solution. The organic phase is freed of the solvent after drying and chromatographed over silica gel with vinegar ester as the solvent. The product appears as an oil.
10 Udbytte 16,6 g.Yield 16.6 g.
Eksempel 3Example 3
Pyridin-2,5-dicarboxylsyre-bis(1-isopropoxycarbonylethyl)-15 esterPyridine-2,5-dicarboxylic acid bis (1-isopropoxycarbonylethyl) ester
Der sættes 10 g pyridin-2,5-dicarboxylsyre til 60 ml tørt methylenchlorid, og hertil sættes der 80 ml frisk destilleret thionylchlorid og 2 ml tørt dimethyl-20 formamid. Blandingen koges i tre timer under tilbagesvaling, det overskydende thionylchlorid og methylenchlori-det afdestilleres derefter, og remanensen afdampes én gang med tør toluen. Til reaktionsblandingen sættes der ved fra -30 til -20°C dråbevis en opløsning af 15,8 g 25 mælkesyreisopropylester, opløst i 100 ml methylenchlorid. Blandingen får lov til at opvarme langsomt til stuetemperatur, der omrøres natten over ved stuetemperatur, og opløsningen vaskes med natriumbicarbonat-opløsning. Den organiske fase befries for opløsningsmidlet efter tør-30 ring og røres sammen med diisopropylether. Der fraskil- *ft les fra monoesteren, og moder luden chroma tograf er es over kiselgel med en blanding af fire dele toluen og én del eddikeester som løbemiddel. Det olieagtige produkt gennem-krystalliserer langsomt.10 g of pyridine-2,5-dicarboxylic acid are added to 60 ml of dry methylene chloride and 80 ml of freshly distilled thionyl chloride and 2 ml of dry dimethylformamide are added. The mixture is refluxed for three hours, the excess thionyl chloride and methylene chloride are then distilled off and the residue is evaporated once with dry toluene. To the reaction mixture is added dropwise from -30 to -20 ° C a solution of 15.8 g of lactic acid propyl ester dissolved in 100 ml of methylene chloride. The mixture is allowed to warm slowly to room temperature, stirred overnight at room temperature, and the solution is washed with sodium bicarbonate solution. The organic phase is freed from the solvent after drying and stirred with diisopropyl ether. The mono ester is separated and the mother liquor chroma tograf is ace over silica gel with a mixture of four parts of toluene and one part of vinegar ester as a solvent. The oily product slowly crystallizes.
35 Smeltepunkt 52-53°C. Udbytte 13,5 g.Melting point 52-53 ° C. Yield 13.5 g.
DK 170245 B1 13 0 Eksempel 4Example 170
Pyridin-2,5-dicarboxylsyre-bis (2-methoxycarbonyl-2,2-dimethylethyl)ester 5 Der sættes 10 g pyridin-2/5-dicarboxylsyre til 60 ml tørt methylenchlorid, og hertil sættes der 80 ml frisk destilleret thionylchlorid og 2 ml tørt dimethyl-formaraid- Blandingen koges i tre timer under tilbagesvaling , det overskydende thionylchlorid og methylenchloridet 10 afdestilleres derefter, og remanensen afdampes én gang med tør toluen- Til reaktionsblandingen sættes der ved fra -30 til -20°C en opløsning af 15,8 g 2,2-dimethyl-3-hydroxypropionsyremethylester, opløst i 100 ml methylenchlorid. Blandingen får lov til at opvarme langsomt til 15 stuetemperatur, der omrøres natten over ved stuetemperatur, og opløsningen vaskes med natriumbicarbonat-opløs-ning. Den organiske fase befries for opløsningsmidlet efter tørring, og produktet omkrystalliseres fra isopro-panol.Pyridine-2,5-dicarboxylic acid bis (2-methoxycarbonyl-2,2-dimethylethyl) ester 5 Add 10 g of pyridine-2/5-dicarboxylic acid to 60 ml of dry methylene chloride, to which 80 ml of freshly distilled thionyl chloride is added and 2 The mixture is boiled for three hours under reflux, the excess thionyl chloride and methylene chloride 10 are then distilled off and the residue is evaporated once with dry toluene. To the reaction mixture is added a solution of 15 at -30 to -20 ° C. 8 g of 2,2-dimethyl-3-hydroxypropionic acid methyl ester, dissolved in 100 ml of methylene chloride. The mixture is allowed to warm slowly to room temperature, stirred overnight at room temperature, and the solution is washed with sodium bicarbonate solution. The organic phase is freed from the solvent after drying and the product is recrystallized from isopropanol.
20 Smeltepunkt 114-115°C. Udbytte 18,6 g.Mp 114-115 ° C. Yield 18.6 g.
Eksempel 5Example 5
Pyridin-2,4-dicarboxylsyre-bis (2-methoxycar bony 1-2,2-25 dimethylethyl)esterPyridine-2,4-dicarboxylic acid bis (2-methoxycarboxy 1-2,2-25 dimethylethyl) ester
Der sættes 7,5 g pyridin-2,4-dicarboxylsyre til 45 ml tørt methylenchlorid, og hertil sættes der 60 ml frisk destilleret thionylchlorid og 2 ml tørt 30 dimethylformamid. Blandingen koges i tre timer under tilbagesvaling, det overskydende thionylchlorid og methylenchloridet afdestilleres, og remanensen afdampes én gang med tør toluen. Til reaktionsblandingen sættes der ved fra -30 til -20°C en opløsning af 35 11,9 g 2,2-dimethyl-3-hydroxypropionsyremethylester, opløst i 100 ml methylenchlorid. Blandingen får lov til at opvarme langsomt til stuetemperatur, der omrøres DK 170245 B1 14 0 natten over ved stuetemperatur, og opløsningen vaskes med natriumbicarbonat-opløsning. Den organiske fase befries for opløsningsmidlet efter tørring og chromatograf eres over kiselgel med eddikeester som løbemiddel.7.5 g of pyridine-2,4-dicarboxylic acid are added to 45 ml of dry methylene chloride and 60 ml of freshly distilled thionyl chloride and 2 ml of dry dimethylformamide are added thereto. The mixture is refluxed for three hours, the excess thionyl chloride and methylene chloride are distilled off and the residue is evaporated once with dry toluene. To the reaction mixture is added at -30 to -20 ° C a solution of 11.9 g of 2,2-dimethyl-3-hydroxypropionic acid methyl ester dissolved in 100 ml of methylene chloride. The mixture is allowed to warm slowly to room temperature, stirring at room temperature overnight, and the solution is washed with sodium bicarbonate solution. The organic phase is freed of the solvent after drying and chromatographed over silica gel with vinegar ester as the solvent.
Produktet fremkommer som en olie. s 5 Udbytte 6,7 g.The product appears as an oil. s 5 Yield 6.7 g.
m.m.
Eksempel 6Example 6
Pyridin-2,4-dicarboxylsyre-bis(1-ethoxycarbonylethyl)-10 esterPyridine-2,4-dicarboxylic acid bis (1-ethoxycarbonylethyl) ester
Der sættes 7,5 g pyridin-2,4-dicarboxylsyre til 45 ml tørt methylenchlorid, og hertil sættes der 60 ml frisk destilleret thionylchlorid og 2 ml tørt dimethyl-15 formamid. Blandingen koges i tre timer, det overskydende thionylchlorid og methylenchloridet afdestilleres derefter, og remanensen afdampes én gang med tør toluen.7.5 g of pyridine-2,4-dicarboxylic acid are added to 45 ml of dry methylene chloride and 60 ml of freshly distilled thionyl chloride and 2 ml of dry dimethylformamide are added. The mixture is boiled for three hours, the excess thionyl chloride and methylene chloride are then distilled off and the residue is evaporated once with dry toluene.
Til reaktionsblandingen sættes der ved fra -30 til -20°C dråbevis en opløsning af 10,6 g mælkesyreethylester i 20 100 ml methylenchlorid. Blandingen får lov til at opvarme langsomt til stuetemperatur, der omrøres natten over ved stuetemperatur, og opløsningen vaskes med natriumbicarbonat-opløsning. Den organiske fase befries for opløsningsmidlet efter tørring og chromatograferes over kiselgel 25 med eddikeester som løbemiddel. Produktet fremkommer som en olie, der langsomt gennemkrystalliserer.To the reaction mixture is added dropwise at -30 to -20 ° C a solution of 10.6 g of lactic acid ethyl ester in 100 ml of methylene chloride. The mixture is allowed to warm slowly to room temperature, stirred overnight at room temperature, and the solution is washed with sodium bicarbonate solution. The organic phase is freed of the solvent after drying and chromatographed over silica gel 25 with vinegar ester as the solvent. The product appears as an oil which slowly crystallizes.
Smeltepunkt 59-60°C. Udbytte 3,7 g.Melting point 59-60 ° C. Yield 3.7 g.
Eksempel 7 30Example 7 30
Pyridin-2,4-dicarboxylsyre-bis (5-methyl-2-oxo-l, 3-dioxol- 4-ylmethyl)ester 6,3 9 pyridin-2,4-dicarboxylsyre-natriumsalt 1 koges sammen med 14,3 g 5-methyl-2-oxo-l,3-dioxol-4-yl-35 methylbromid og 4,5 g kaliumcarbonat i 125 ml tør acetone i 40 timer under tilbagesvaling. Opløsningen DK 170245 B1 15 0 skilles fra carbonatet ved filtrering og chromatografe-res over kiselgel med en blanding af toluen og eddikeester i forholdet 4:1.Pyridine-2,4-dicarboxylic acid bis (5-methyl-2-oxo-1,3-dioxol-4-ylmethyl) ester 6.3 9 Pyridine-2,4-dicarboxylic acid sodium salt 1 is boiled with 14.3 g 5-methyl-2-oxo-1,3-dioxol-4-yl-methyl bromide and 4.5 g of potassium carbonate in 125 ml of dry acetone for 40 hours at reflux. The solution DK 170245 B1 15 0 is separated from the carbonate by filtration and chromatographed over silica gel with a mixture of toluene and vinegar ester in the ratio 4: 1.
Smeltepunkt 113°C. Udbytte 2,6 g.Melting point 113 ° C. Yield 2.6 g.
5 Eksempel 8Example 8
Pyridin-2,5-di(4-nitro-phenyl)carboxylsyreesterPyridine-2,5-di (4-nitro-phenyl) carboxylic acid ester
Der sættes 16,7 g pyridin-2,5-dicarboxylsyre til 10 100 ml tørt methylenchlorid, og hertil sættes der 135 ml frisk destilleret thionylchlorid og 3 ml tørt dimethyl-formamid. Blandingen koges i tre timer under tilbagesvaling, det overskydende thionylchlorid og methylenchlori-det afdestilleres derefter, og remanensen afdampes én 15 gang med tør toluen. Til reaktionsblandingen sættes der ved fra -30 til -20°C dråbevis en opløsning af 27,8 g 4-nitrophenol i 50 ml pyridin. Blandingen får lov til at opvarme langsomt til stuetemperatur, der omrøres natten over ved stuetemperatur, og opløsningen vaskes med natri-20 umbicarbonat-opløsning. Den organiske fase befries for opløsningsmidlet efter tørring og chromatograferes over kiselgel med eddikeester som løbemiddel.16.7 g of pyridine-2,5-dicarboxylic acid are added to 100 ml of dry methylene chloride, to which are added 135 ml of freshly distilled thionyl chloride and 3 ml of dry dimethylformamide. The mixture is refluxed for three hours, the excess thionyl chloride and methylene chloride are then distilled off and the residue is evaporated once with dry toluene. To the reaction mixture is added dropwise at -30 to -20 ° C a solution of 27.8 g of 4-nitrophenol in 50 ml of pyridine. The mixture is allowed to warm slowly to room temperature, stirred overnight at room temperature, and the solution is washed with sodium bicarbonate solution. The organic phase is freed of the solvent after drying and chromatographed over silica gel with vinegar ester as the solvent.
Smeltepunkt 190°C. Udbytte 12,5 g.Melting point 190 ° C. Yield 12.5 g.
25 Eksempel 9Example 9
Pyridin-2,5-dicarboxylsyre-bis(5-methyl-2-oxo-l,3-dioxol-4-yl-methyl)ester 30 6,3 g pyridin-2,5-dicarboxylsyre-natriumsalt omsættes analogt med eksempel 7 med 14,3 g 5-methyl-2-oxo-l,3-dioxol-4-yl-methylbromid og koges i acetone i 2,5 timer under tilbagesvaling. Efter chromatografering over kiselgel med eddikeester som løbemiddel omkrystalli-35 seres produktet fra eddikeester i varm tilstand.Pyridine-2,5-dicarboxylic acid bis (5-methyl-2-oxo-1,3-dioxol-4-yl-methyl) ester 6.3 g of pyridine-2,5-dicarboxylic acid sodium salt is reacted analogously to Example 7 with 14.3 g of 5-methyl-2-oxo-1,3-dioxol-4-yl-methyl bromide and boiled in acetone for 2.5 hours at reflux. After chromatography over silica gel with vinegar ester as the solvent, the product of vinegar ester is recrystallized in hot state.
Smeltepunkt 118°C. Udbytte 0,23 g.Melting point 118 ° C. Yield 0.23 g.
0 DK 170245 B1 160 DK 170245 B1 16
Eksempel loExample laughed
Pyridin-2,5-dicarboxylsyredibenzylester 20 g pyridin-2,5-dicarboxylsyre omdannes analogt med eksempel 1 til syrechloridet med 160 ml thionylchlorid * og omsættes med 25,9 g benzylalkohol. Produktet omkrystal— liseres fra eddikeester under tilsætning af aktivt kul.Pyridine-2,5-dicarboxylic acid dibenzyl ester 20 g of pyridine-2,5-dicarboxylic acid is converted analogously to Example 1 to the acid chloride with 160 ml of thionyl chloride * and reacted with 25.9 g of benzyl alcohol. The product is recrystallized from vinegar ester with the addition of activated carbon.
Smeltepunkt 110°C. Udbytte: 20/4 g.Melting point 110 ° C. Yield: 20/4 g.
10 Eksempel 11Example 11
Pyridin-2,5-di (5-methyl-2-nitro-benzyl) carboxylsyreester 5 g pyridin-2,5-dicarboxylsyre omdannes analogt 15 med eksempel 1 til syrechloridet med 40 ml thionylchlorid i 30 ml methylenchlorid og omsættes med 10 g 5-methyl-2-nitro-benzylalkohol i 50 ml methylenchlorid. Reaktionsblandingen omrøres natten over ved stuetemperatur/ der tilsættes derefter natriumbicarbonatopløsning, der ekstra-20 heres med methylenchlorid/ og den organiske fase tørres.Pyridine-2,5-di (5-methyl-2-nitro-benzyl) carboxylic acid ester 5 g of pyridine-2,5-dicarboxylic acid is converted analogously to Example 1 into the acid chloride with 40 ml of thionyl chloride in 30 ml of methylene chloride and reacted with 10 g of 5 -methyl-2-nitro-benzyl alcohol in 50 ml of methylene chloride. The reaction mixture is stirred overnight at room temperature / then sodium bicarbonate solution is added, which is extracted with methylene chloride / and the organic phase is dried.
Efter afdestillation af opløsningsmidlet røres remanensen sammen med eddikeester, og der fraskilles ved sugning og omkrystalliseres to gange med methylenchlorid.After distilling off the solvent, the residue is stirred with vinegar ester and separated by suction and recrystallized twice with methylene chloride.
Smeltepunkt 182°C. Udbytte 2,9 g.Melting point 182 ° C. Yield 2.9 g.
2525
Eksempel 12Example 12
Pyridin-2,5-dicarboxylsyre-bis (2-ethoxy-ethyl) ester 30 10 g pyridin-2,5-dicarboxylsyre omdannes analogt med eksempel 1 til syrechloridet med 80 ml thionylchlorid i 60 ml methylenchlorid og omsættes med 10,78 g ethylen-glycolmonomethylether i 100 ml methylenchlorid. Oparbejdningen sker ved tilsætning af natriumbicarbonatopløs -Pyridine-2,5-dicarboxylic acid bis (2-ethoxyethyl) ester 30 g of pyridine-2,5-dicarboxylic acid are converted, analogously to Example 1, to the acid chloride with 80 ml of thionyl chloride in 60 ml of methylene chloride and reacted with 10.78 g of ethylene. -glycol monomethyl ether in 100 ml of methylene chloride. The work-up is done by adding sodium bicarbonate solution -
QCQC
ning, fraskillelse af den organiske fase og afdestilla- DK 170245 B1 17 0 tion af opløsningsmidlet. Produktet chromatograferes to gange over kiselgel roed eddikeester, opløses i varm eddikeester, klares med aktivt kul og befries for opløsningsmidlet. Produktet fremkommer som en olie.separation, separation of the organic phase and distillation of the solvent. The product is chromatographed twice over silica gel red vinegar ester, dissolved in hot vinegar ester, clarified with activated charcoal and freed from the solvent. The product appears as an oil.
Udbytte 7,2 g.Yield 7.2 g.
55
Eksempel 13Example 13
Pyridin-2,5-dicarboxylsyre-bis(2-methoxy-ethyl)ester 10 10 g pyridin-2,5-dicarboxylsyre omdannes analogt med eksempel 12 til syrechloridet og omsættes med 9,1 g •ethylenglycolmonomethylether. Oparbejdningen sker ifølge eksempel 26. Produktet fremkommer som en olie.Pyridine-2,5-dicarboxylic acid bis (2-methoxyethyl) ester 10 g of pyridine-2,5-dicarboxylic acid is converted analogously to Example 12 into the acid chloride and reacted with 9.1 g of ethylene glycol monomethyl ether. The work-up is done according to Example 26. The product appears as an oil.
15 Udbytte: 6,5 g.Yield: 6.5 g.
Eksempel 14Example 14
Pyridin-2,4-dicarboxylsyre-bis(2-ethoxy-ethyl)ester 20 10 g pyridin-2,4-dicarboxylsyre omsættes som beskrevet i eksempel 12 med ethylenglycolmonoethylester via syrechloridet. Reaktionsblandingen oparbejdes analogt med eksempel 26. Produktet fremkommer som en olie.Pyridine-2,4-dicarboxylic acid bis (2-ethoxyethyl) ester 20 g of pyridine-2,4-dicarboxylic acid is reacted as described in Example 12 with ethylene glycol monoethyl ester via the acid chloride. The reaction mixture is worked up analogously to Example 26. The product appears as an oil.
25 Udbytte: 7,2 g.Yield: 7.2 g.
Eksempel 15Example 15
Pyridin-2,4-dicarboxylsyre-bis(1-isopropoxycarbonylethyl)-30 esterPyridine-2,4-dicarboxylic acid bis (1-isopropoxycarbonylethyl) ester
Der sættes 10 g pyridin-2,4-dicarboxylsyre til 60 ml tørt methylenchlorid, og hertil sættes der 80 ml frisk destilleret thionylchlorid og 2 ml tørt dimethyl-35 formamid. Blandingen koges i tre timer under tilbagesvaling, hvorefter det overskydende thionylchlorid og methy- DK 170245 B1 18 lenchloridet afdestilleres/ og remanensen afdampes én gang med tør toluen. Til reaktionsblandingen sættes der ved fra -30 til -20°C dråbevis en opløsning af 15,8 g mælkesyreisopropylester, opløst i 100 ml methylenchlorid.10 g of pyridine-2,4-dicarboxylic acid are added to 60 ml of dry methylene chloride, to which 80 ml of freshly distilled thionyl chloride and 2 ml of dry dimethylformamide are added. The mixture is refluxed for three hours, after which the excess thionyl chloride and methylene chloride are distilled off and the residue is evaporated once with dry toluene. To the reaction mixture is added dropwise from -30 to -20 ° C a solution of 15.8 g of lactic acid propyl ester dissolved in 100 ml of methylene chloride.
5 Blandingen får lov til at opvarme langsomt til stuetem- -ς peratur, der omrøres natten over ved stuetemperatur, og opløsningen vaskes med natriumbicarbonat-opløsning. Den organiske fase befries for opløsningsmidlet efter tørring og røres sammen med diisopropylether. Der fraskilles fra -1-0 monoesteren, og moderluden chromatograferes over kiselgel med en blanding af fire dele toluen og én del eddikeester som løbemiddel. Produktet fremkommer som en olie.The mixture is allowed to warm slowly to room temperature, stirred overnight at room temperature, and the solution is washed with sodium bicarbonate solution. The organic phase is freed from the solvent after drying and stirred with diisopropyl ether. It is separated from the -1-0 monoester, and the mother liquor is chromatographed over silica gel with a mixture of four parts of toluene and one part of vinegar ester as a solvent. The product appears as an oil.
Udbytte: 11,2 g.Yield: 11.2 g.
1515
Eksempel 16Example 16
Di-(2-methoxyethyl)-pyridin-2,4-dicarboxylat 20 Denne forbindelse fremstilles under anvendelse af ethylenglycolmonomethylether.Di- (2-methoxyethyl) -pyridine-2,4-dicarboxylate This compound is prepared using ethylene glycol monomethyl ether.
Smp.: olie NMR (CDC13): S = 3,47 (6H, s)? 3,67-3,90 (4H, 25 m): 4,47-4,73 (4H, m): 8,00- 8,17 (IH, m); 8,67-8,73 (IH, m)? 8,90-9,03 (IH, m)Mp: oil NMR (CDCl3): δ = 3.47 (6H, s)? 3.67-3.90 (4H, 25 m): 4.47-4.73 (4H, m): 8.00- 8.17 (1H, m); 8.67-8.73 (1H, m)? 8.90-9.03 (1H, m)
Eksempel 17 30Example 17
Di-(2-methoxycarbonylethyl)-pyridin-2,4-dicarboxylatDi- (2-methoxycarbonylethyl) -pyridine-2,4-dicarboxylate
Denne forbindelse fremstilles under anvendelse af *' 2-acetoxyethanol.This compound is prepared using * 2-acetoxyethanol.
35 Smp.: olie DK 170245 B1 19 NMR (CDC13): δ 2,13 (6H, s)? 4,17-4,83 (8H, m) ? 8,00-8,16 (IH, m) ; 8,67- , 8,73 (IH, m); 8,91-9,04 (IH, m) 5 Eksempel 18Mp: oil DK 170245 B1 19 NMR (CDCl3): δ 2.13 (6H, s)? 4.17-4.83 (8H, m)? 8.00-8.16 (1H, m); 8.67-, 8.73 (1H, m); 8.91-9.04 (1H, m) Example 18
Di-(1-tert.-butylcarbonyloxyethyl)-pyridin-2,4-dicarboxylatDi- (1-tert-butylcarbonyloxyethyl) -pyridine-2,4-dicarboxylate
Denne forbindelse fremstilles under anvendelse af Ι-ΙΟ tert.-butylcarbonyloxyethyl-iodid.This compound is prepared using Ι-ΙΟ tert.-butylcarbonyloxyethyl iodide.
Smp.: olie NMR (CDCI3): δ = 1,20 (18H, s); 1,57-1,77 (6H, 15 m) ; 7,00-7,27 (2H, m); 7,99- 8,14 (IH, m); 8,67-8,73 (IH, m); 8,89-9,05 (IH, m)Mp: oil NMR (CDCl 3): δ = 1.20 (18H, s); 1.57-1.77 (6H, 15 m); 7.00-7.27 (2H, m); 7.99- 8.14 (1H, m); 8.67-8.73 (1H, m); 8.89-9.05 (1H, m)
De følgende forbindelser fremstilles på samme måde: 20The following compounds are prepared in the same way: 20
Eksempel 19Example 19
Pyridin-di-(2-acetoxyethyl)-2,4-dicarboxylat 25 MS = 340 (M+H) MG = C15H17N08 (341)Pyridine di- (2-acetoxyethyl) -2,4-dicarboxylate MS = 340 (M + H) MG = C15H17N08 (341)
Eksempel 20 30 Pyridin-di-(4-chlorbutyl)-2,4-dicarboxylat MS = 349 (M+H) MG = C15H19C12N04 (348) 35 20 DK 170245 B1Example 20 Pyridine di- (4-chlorobutyl) -2,4-dicarboxylate MS = 349 (M + H) MG = C 15 H 19 Cl 2 NO 4 (348) DK 170245 B1
Eksempel 21Example 21
Pyridin-di-(3-chlorphenyl)-2,4-dicarboxylat 5 5 Smp.: 103-105°C.Pyridine di- (3-chlorophenyl) -2,4-dicarboxylate mp: 103-105 ° C.
Eksempel 22Example 22
Pyridin-di-(methoxycarbonylmethyl)-2,4-dicarboxylat 10Pyridine di- (methoxycarbonylmethyl) -2,4-dicarboxylate 10
Smp.: 63-65’C.Mp: 63-65 ° C.
15 20 2515 20 25
TT
Claims (2)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3703963 | 1987-02-10 | ||
| DE19873703963 DE3703963A1 (en) | 1987-02-10 | 1987-02-10 | PYRIDINE-2,4- AND 2,, 5-DICARBONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, USE THEREOF, AND MEDICINAL PRODUCTS BASED ON THESE COMPOUNDS |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK90992D0 DK90992D0 (en) | 1992-07-10 |
| DK90992A DK90992A (en) | 1992-07-10 |
| DK170245B1 true DK170245B1 (en) | 1995-07-17 |
Family
ID=6320593
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK066088A DK168379B1 (en) | 1987-02-10 | 1988-02-09 | Pyridine-2,4- and -2,5-dicarboxylic acid derivatives and process for their preparation |
| DK090992A DK170245B1 (en) | 1987-02-10 | 1992-07-10 | Pyridine-2,4- and -2,5-dicarboxylic acid derivatives for use as drugs |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK066088A DK168379B1 (en) | 1987-02-10 | 1988-02-09 | Pyridine-2,4- and -2,5-dicarboxylic acid derivatives and process for their preparation |
Country Status (17)
| Country | Link |
|---|---|
| EP (1) | EP0278452B1 (en) |
| JP (1) | JPS63216870A (en) |
| KR (1) | KR960011371B1 (en) |
| AR (1) | AR247816A1 (en) |
| AT (1) | ATE123022T1 (en) |
| AU (1) | AU600084B2 (en) |
| DE (2) | DE3703963A1 (en) |
| DK (2) | DK168379B1 (en) |
| ES (1) | ES2073393T3 (en) |
| FI (1) | FI91524C (en) |
| HU (1) | HU207295B (en) |
| IE (1) | IE67446B1 (en) |
| IL (1) | IL85361A (en) |
| NO (1) | NO173184C (en) |
| NZ (1) | NZ223431A (en) |
| PT (1) | PT86734B (en) |
| ZA (1) | ZA88897B (en) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3707429A1 (en) * | 1987-03-07 | 1988-09-15 | Hoechst Ag | SUBSTITUTED PYRIDINE-2,4-DICARBONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, USE OF THE SAME AND MEDICINAL PRODUCTS BASED ON THESE COMPOUNDS |
| HU202516B (en) * | 1987-10-02 | 1991-03-28 | Egyt Gyogyszervegyeszeti Gyar | Process for producing (2-thenyl)-thiourea derivatives and yield increasing agents comprising such compounds |
| DE3924093A1 (en) | 1989-07-20 | 1991-02-07 | Hoechst Ag | N, N'-BIS (ALKOXY-ALKYL) -PYRIDINE-2,4-DICARBONESAUREDIAMIDES, METHOD FOR THE PRODUCTION AND USE THEREOF |
| DE3938805A1 (en) * | 1989-11-23 | 1991-05-29 | Hoechst Ag | PYRIDINE-2,4- AND 2,5-DICARBONIC ACID DIAMOND, METHOD FOR THE PRODUCTION AND USE THEREOF |
| US5260323A (en) * | 1990-06-28 | 1993-11-09 | Hoechst Aktiengesellschaft | 2,4- and 2,5-substituted pyridine-N-oxides, processes for their preparation and their use |
| DE4020570A1 (en) * | 1990-06-28 | 1992-01-02 | Hoechst Ag | 2,4- AND 2,5-SUBSTITUTED PYRIDINE-N-OXIDES, METHOD FOR THE PRODUCTION AND USE THEREOF |
| DE4030999A1 (en) * | 1990-10-01 | 1992-04-09 | Hoechst Ag | 4- OR 5-SUBSTITUTED PYRIDINE-2-CARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS A MEDICINAL PRODUCT |
| YU9492A (en) * | 1991-02-05 | 1995-03-27 | Hoechst Ag. | 2,4- and 2,5-BIS-TETRAZOLYL pyridines and the process for their preparation |
| CA2085954A1 (en) * | 1991-12-24 | 1993-06-25 | Klaus Weidmann | Substituted pyridine n-oxides, processes for their preparation, and their use |
| DE4233124A1 (en) * | 1992-10-02 | 1994-04-07 | Hoechst Ag | Acylsulfonamido and sulfonamidopyridine-2-carboxylic acid esters and their pyridine N-oxides, processes for their preparation and their use as medicaments |
| EP1027351B1 (en) * | 1997-10-24 | 2003-12-03 | Fibrogen, Inc. | Phenanthroline derivatives |
| KR100579792B1 (en) * | 1998-05-13 | 2006-05-12 | 동화약품공업주식회사 | Novel 2,5-pyridinedicarboxylic acid derivatives |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4093622A (en) * | 1975-05-19 | 1978-06-06 | Zoecon Corporation | Pyridine esters of cyclopropane-carboxylic acid |
| EP0123700A1 (en) * | 1983-04-27 | 1984-11-07 | Byk Gulden Lomberg Chemische Fabrik GmbH | Substituted picolinic acids, processes for their preparation, their use, and pharmaceutical preparations containing them |
| DE3432094A1 (en) * | 1984-08-31 | 1986-03-06 | Hoechst Ag, 6230 Frankfurt | ESTER OF PYRIDINE-2,4- AND -2,5-DICARBONIC ACID AS A MEDICINAL PRODUCT FOR INHIBITING PROLIN AND LYSINE HYDROXYLASE |
| US4757071A (en) * | 1984-12-14 | 1988-07-12 | Nisshin Flour Milling Co., Ltd. | 1,4-dihydropyridine derivatives, and pharmaceutical compositions containing same, useful for treating cardiovascular diseases |
| US4691018A (en) * | 1985-05-23 | 1987-09-01 | Chugai Seiyaku Kabushiki Kaisha | Pyridine derivatives and their use as anti-allergic agents |
| GB8702890D0 (en) * | 1987-02-10 | 1987-03-18 | Zyma Sa | Heterocyclic compounds |
| EP0353668B1 (en) * | 1988-08-04 | 1994-10-19 | Hoechst Aktiengesellschaft | Process for the preparation of N,N-bis(alkoxyalkyl) diamides of pyridine-2,4-dicarboxylic acid |
-
1987
- 1987-02-10 DE DE19873703963 patent/DE3703963A1/en not_active Withdrawn
-
1988
- 1988-02-08 ES ES88101791T patent/ES2073393T3/en not_active Expired - Lifetime
- 1988-02-08 IL IL85361A patent/IL85361A/en not_active IP Right Cessation
- 1988-02-08 DE DE3853839T patent/DE3853839D1/en not_active Expired - Fee Related
- 1988-02-08 FI FI880554A patent/FI91524C/en not_active IP Right Cessation
- 1988-02-08 NZ NZ223431A patent/NZ223431A/en unknown
- 1988-02-08 EP EP88101791A patent/EP0278452B1/en not_active Expired - Lifetime
- 1988-02-08 AT AT88101791T patent/ATE123022T1/en not_active IP Right Cessation
- 1988-02-08 AR AR88310032A patent/AR247816A1/en active
- 1988-02-09 DK DK066088A patent/DK168379B1/en active
- 1988-02-09 ZA ZA880897A patent/ZA88897B/en unknown
- 1988-02-09 KR KR1019880001198A patent/KR960011371B1/en active IP Right Grant
- 1988-02-09 JP JP63026721A patent/JPS63216870A/en active Pending
- 1988-02-09 IE IE35088A patent/IE67446B1/en not_active IP Right Cessation
- 1988-02-09 AU AU11450/88A patent/AU600084B2/en not_active Ceased
- 1988-02-09 PT PT86734A patent/PT86734B/en not_active IP Right Cessation
- 1988-02-09 NO NO880556A patent/NO173184C/en unknown
- 1988-02-10 HU HU88612A patent/HU207295B/en not_active IP Right Cessation
-
1992
- 1992-07-10 DK DK090992A patent/DK170245B1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| JPS63216870A (en) | 1988-09-09 |
| FI880554A0 (en) | 1988-02-08 |
| AU600084B2 (en) | 1990-08-02 |
| IL85361A (en) | 1993-01-31 |
| IE880350L (en) | 1988-08-10 |
| NO880556L (en) | 1988-08-11 |
| KR960011371B1 (en) | 1996-08-22 |
| NZ223431A (en) | 1990-07-26 |
| DE3703963A1 (en) | 1988-08-18 |
| FI91524B (en) | 1994-03-31 |
| IE67446B1 (en) | 1996-04-03 |
| DK66088A (en) | 1988-08-11 |
| AR247816A1 (en) | 1995-04-28 |
| NO173184B (en) | 1993-08-02 |
| FI91524C (en) | 1994-07-11 |
| DK90992D0 (en) | 1992-07-10 |
| ZA88897B (en) | 1988-08-09 |
| ES2073393T3 (en) | 1995-08-16 |
| HUT47249A (en) | 1989-02-28 |
| DK66088D0 (en) | 1988-02-09 |
| PT86734B (en) | 1992-05-29 |
| FI880554A (en) | 1988-08-11 |
| EP0278452A2 (en) | 1988-08-17 |
| DE3853839D1 (en) | 1995-06-29 |
| DK90992A (en) | 1992-07-10 |
| NO880556D0 (en) | 1988-02-09 |
| EP0278452B1 (en) | 1995-05-24 |
| NO173184C (en) | 1993-11-10 |
| KR880009935A (en) | 1988-10-05 |
| EP0278452A3 (en) | 1989-10-18 |
| IL85361A0 (en) | 1988-07-31 |
| HU207295B (en) | 1993-03-29 |
| ATE123022T1 (en) | 1995-06-15 |
| DK168379B1 (en) | 1994-03-21 |
| PT86734A (en) | 1988-03-01 |
| AU1145088A (en) | 1988-08-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| DK167804B1 (en) | PYRIDINE-2,4- AND -2,5-DICARBOXYLIC ACID AMIDES AND THEIR PREPARATION | |
| DK170245B1 (en) | Pyridine-2,4- and -2,5-dicarboxylic acid derivatives for use as drugs | |
| Feely et al. | Cyanation of amine oxide salts. A new synthesis of cyanopyridines | |
| SU446966A1 (en) | Method for producing 1,2,3,6-tetrahydro4-pyridylmethylcarboxylic acid ester derivatives | |
| CS203970B2 (en) | Method of producing novel heterocyclyl-oxy-hydroxy-amino-propanes | |
| EP1723156B1 (en) | Process for the preparation of pyridine derivatives | |
| EP0249950B1 (en) | Aromatic compounds | |
| DK168008B1 (en) | PYRIDINE-2,4- AND -2,5-DICARBOXYL ACID DIAMIDE DERIVATIVES, THEIR PREPARATION AND MEDICINALS CONTAINING THEM | |
| EP0325129A2 (en) | Disubstituted pyridines | |
| EP1455790A1 (en) | Use of pyridine-2,4-dicarboxylic acid diamides and of pyrimidine-4,6-dicarboxylic acid diamides for selective collagenase inhibition | |
| DK167873B1 (en) | SUBSTITUTED PYRIDINE-2,4-DICARBOXYLIC ACID DERIVATIVES, AND MEDICINALS CONTAINING THESE DERIVATIVES | |
| US5364873A (en) | Pyridine-2,4- and dicarboxylic acid derivatives, the use thereof and pharmaceutical composition based on these compounds | |
| US5153208A (en) | Pyridine-2,4- and -2,5-dicarboxylic acid amides and their medicinal compositions and methods of use | |
| US5512586A (en) | Medicaments based on pyridine-2,4- and 2,5-dicarboxylic acid amides | |
| Lin et al. | Versatile approach for the synthesis of novel seven-membered iminocyclitols via ring-closing metathesis dihydroxylation reaction | |
| US5240921A (en) | Cyclic pyridine-2,4- and -2,5-dicarboxylic acid diamides, processes for their preparation and their use | |
| Adamczyk et al. | Transformation of Vitamin B6 to (+)-Deoxypyridinoline, a useful Biochemical Marker for Diagnosis of Bone Diseases | |
| DK152359B (en) | 6-FORMYL-1,4-DIHYDROPYRIDINE DERIVATIVES USED AS INTERMEDIATES IN THE PREPARATION OF PHARMACEUTICAL ACTIVE 6-CYANO-1,4-DIHYDROPYRIDINE DERIVATIVES |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| B1 | Patent granted (law 1993) | ||
| PBP | Patent lapsed |