DK158266B - METHOD OF ANALOGY FOR PREPARATION OF PYRANOQUINOLINON DERIVATIVES - Google Patents
METHOD OF ANALOGY FOR PREPARATION OF PYRANOQUINOLINON DERIVATIVES Download PDFInfo
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- C—CHEMISTRY; METALLURGY
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- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/24—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 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 in position 2
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Description
Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af hidtil ukendte pyranoquinolinon-derivater med den almene formel I 0The present invention relates to an analogous process for the preparation of novel pyranoquinolinone derivatives of the general formula
.. DK 158266B.. DK 158266B
, -L· Jl Jl—i COOH, -L · Jl Jl — in COOH
βύϊ; c. n c o hvor R° og R danner en kæde -COCH=C(COOH)-0-, og R og R f der kan være ens eller forskellige, hver er hydrogen eller alkyl, og Rg er hydrogen eller alkyl, eller farmaceutisk acceptable salte, alkylestre eller mono- eller di-alkylamider deraf, hvilken fremgangsmåde er ejendommelig ved det i krav 1's kendetegnende del anførte.βύϊ; c. nco where R ° and R form a chain -COCH = C (COOH) -O-, and R and R f which may be the same or different, each being hydrogen or alkyl, and Rg being hydrogen or alkyl, or pharmaceutically acceptable salts, alkyl esters or mono- or di-alkylamides thereof, the process of which is characterized by the characterizing part of claim 1.
De omhandlede forbindelser er anvendelige på grund af deres farmakologiske aktivitet.The compounds of the invention are useful because of their pharmacological activity.
Fra US patentskrift nr. 3.959.289 kendes antiallergisk aktive 4,6-dioxopyrido[3,2-g]quinoliner. Disse kendte forbindelser har imidlertid den ulempe, at der kræves store doser deraf til opnåelse af den ønskede aktivitet. Ifølge den foreliggende opfindelse er der tilvejebragt en gruppe hidtil ukendte pyranoquino-linoær, der har fordelagtige egenskaber sammenlignet med nævnte kendte forbindelser, navnlig en stærkere aktivitet, som nedenfor dokumenteret.U.S. Patent No. 3,959,289 discloses antiallergically active 4,6-dioxopyrido [3.2-g] quinolines. However, these known compounds have the disadvantage that large doses thereof are required to achieve the desired activity. According to the present invention, there is provided a group of novel pyranoquino-linear having advantageous properties compared to said known compounds, in particular a stronger activity, as documented below.
De omhandlede forbindelser fremstilles ved, at (a) en forbindelse med formlen IIThe compounds of this invention are prepared by (a) a compound of formula II
R5a n R7aJ^s, \-d R83 · hvor Rg er som ovenfor defineret, R^a og R8a har saitme betydninger som R^ og R8 ovenfor, og R8a og 7a 1 R repræsenterer en kæde med formlen -C0CH=C(D )-0- og . 1 den ene af eller bade D og D' repræsenterer en gruppe, der kan hydrolyseres eller oxideres til en gruppe -COOH, og den anden kan repræsentere en gruppe -COOH, underkastes selektiv hydrolyse eller oxidation,R5a n R7aJ ^ s, \ -d R83 · where Rg is as defined above, R ^ a and R8a have the same meanings as R ^ and R8 above, and R8a and 7a 1 R represent a chain of the formula -COCH = C (D ) -0- and. In one or both of D and D 'represents a group which can be hydrolyzed or oxidized to a group -COOH, and the other may represent a group -COOH, subjected to selective hydrolysis or oxidation,
DK 158266 BDK 158266 B
22
(b) en forbindelse med formlen III eller IV(b) a compound of formula III or IV
R5b ?5b r6^J\hooc. /coohR5b? 5b r6 ^ J \ hooc. / COOH
R7b4sA JLcOOH R7bJ^AN^C00HR7b4sA JLcOOH R7bJ ^ AN ^ C00H
^8b Rg jjeb Rg^ 8b Rg jjeb Rg
III IVIII IV
eller en ester af hver af disse, hvor Rg er som ovenfor defineret, og 5 b 8b 5 8 R3 og R° har samme betydninger som R og R ovenfor, og R^'° og R^k repræsenterer gruppeparret -H og -0-C(COOH)=CH-COOH, underkastes ringslutning,or an ester of each of these, wherein R 9 is as defined above and 5 b 8b 5 8 R 3 and R ° have the same meanings as R and R above, and R 1 and R 2 represent the group pair -H and -O -C (COOH) = CH-COOH, is cyclized,
(c) en forbindelse med formlen V(c) a compound of formula V
R5C 0R5C 0
R7cAyJLNJ—COOHR7cAyJLNJ-COOH
r8c Rgr8c Rg
eller en ester deraf, Vor an ester thereof, V
hvor Rg er som ovenfor defineret, 5C 8c 5 8 R og R har samme betydninger som R og R ovenfor, og R8c og R^c repræsenterer gruppeparrene: (i) -COCH2COCOR" eller -COCHCiCOOHj-NL1!.2, eller et egnet salt-, ester-eller amid-derivat deraf, og -OM eller et halogenatom, eller (ii) -H og -0-C(COR")-CH-COR", idet R" er -OM eller en ester eller et amid deraf, 1 2 L og L , der kan være ens eller forskellige, hver er hydrogen, aryl eller alkyl, eller de danner tilsammen en mættet eller umættet alkylenkæde, og M er hydrogen eller et alkalimetal, underkastes ringslutning og, om nødvendigt eller om ønsket, hydrolyse af gruppen -COR" til en gruppe -COOM, hvor M er som ovenfor defineret,where Rg is as defined above, 5C 8c 5 8 R and R have the same meanings as R and R above, and R8c and R4c represent the group pairs: (i) -COCH2COCOR "or -COCHCiCOOHj-NL1.2 or a suitable salt, ester or amide derivative thereof, and -OM or a halogen atom, or (ii) -H and -O-C (COR ") - CH-COR", where R "is -OM or an ester or an amide thereof, 1 2 L and L, which may be the same or different, each being hydrogen, aryl or alkyl, or together forming a saturated or unsaturated alkylene chain, and M being hydrogen or an alkali metal, are cyclized and, if necessary or if desired hydrolysis of the group -COR "to a group -COOM where M is as defined above,
DK 158266 BDK 158266 B
33
(d) en forbindelse med formlen VI(d) a compound of formula VI
R5a 9 „10 »6d Ax rwii R I8a ågR5a 9 „10» 6d Ax rwii R I8a yoke
eller en ester deraf VIor an ester thereof VI
hvor Rg er som ovenfor defineret, 5d sd 5 8 R3 og R har samme betydninger som R og R ovenfor, og R^ og R^ repræsenterer kæden -C(R9R^)CH=C(C00H)-0-, og mindst ét af gruppeparrene R9 og R10 tilsammen danner =S eller tilsammen danner en kæde -S(CH„) S-, hvor n er 2 eller 9 10 2 n 3, og det andet par R , R kan repræsentere =0, omdannes til en tilsvarende forbindelse med formlen I ved hydrolyse eller oxidativ hydrolyse, (e) grupperne A og B fjernes selektivt ved dehydratation, hydrogenolyse eller dehydrohalogenering fra en forbindelse med formlen VII 5e 'ΑΛΑ/*wherein Rg is as defined above, 5d sd 5 8 R3 and R have the same meanings as R and R above and R4 and R4 represent the chain -C (R9R4) CH = C (C00H) -O-, and at least one of the group pairs R9 and R10 together form = S or together form a chain -S (CH 2) S-, where n is 2 or 9 10 2 n 3, and the second pair R, R can represent = 0, is converted into a corresponding (e) groups A and B are selectively removed by dehydration, hydrogenolysis or dehydrohalogenation from a compound of formula VII 5e 'ΑΛΑ / *
^X-COOH^ X-COOH
Γδβ ? \ bΓδβ? \ b
K Rg VIIK Rg VII
eller en ester deraf, hvor Rg er som ovenfor defineret, R^e og R^e har samme betydninger som R^ og R^ ovenfor, og R^e og R^e repræsenterer en kæde -C0CHA-CB(C00H)-0-, og i mindst ét af gruppeparrene A og B både A og B er hydrogen, eller den ene af A og B er hydrogen, og den anden er halogen eller hydroxy, og det andet par A, B tilsammen kan danne en dobbeltbinding, elleror an ester thereof, wherein R 9 is as defined above, R 1 e and R 2 e have the same meanings as R 2 and R 2 above, and R 2 e and R 2 e represent a chain -COCHA-CB (C00H) -0 -, and in at least one of the group pairs A and B, both A and B are hydrogen, or one of A and B is hydrogen and the other is halogen or hydroxy, and the other pair A, B together can form a double bond, or
DK 158266BDK 158266B
44
(f) en forbindelse med formlen VIII(f) a compound of formula VIII
R5f OR5f O
VyVVYV
. i Jl--COOH. in Jl - COOH
1st I1st I
K Rg VIIIK Rg VIII
eller en ester deraf, hvor Rg er som ovenfor defineret, og 5 f 8 f 5 8 R og R° har samme betydninger som R og R ovenfor, og R^f og R7f repræsenterer gruppeparret -COCH(SOR^)-CH(OH)-COOR" og -OM, idet R" og M er som ovenfor defineret, og 1 1 R er en alkylgruppe med 1-10 C-atomer underkastes ringslutning, og at, om nødvendigt eller om ønsket, en opnået ester af en forbindelse med formlen I hydrolyseres gg/eller en opnået forbindelse med formlen I omdannes til et farmaceutisk acceptabelt salt-, alkylester- eller mono- eller di-alkylamid-derivat deraf, og/eller et sådant derivat omdannes til et andet farmaceutisk acceptabelt salt-, alkylester- eller mono- eller di-alkylamid-derivat.or an ester thereof, wherein R 9 is as defined above and 5 f 8 f 5 8 R and R ° have the same meanings as R and R above, and R 2 f and R 7f represent the group pair -COCH (SOR 2) - CH (OH) ) -COOR "and -OM, where R" and M are as defined above, and 1 1 R is an alkyl group having 1-10 C atoms is cyclized and, if necessary or desired, an ester obtained from a compound of formula I, gg / or a compound of formula I obtained is hydrolyzed to a pharmaceutically acceptable salt, alkyl ester or mono or di-alkylamide derivative thereof and / or such derivative is converted to another pharmaceutically acceptable salt, alkyl ester - or mono- or di-alkylamide derivatives.
Ved fremgangsmåden (a) kan gruppen D for eksempel være en ester-, syrehalogenid-, amid- eller nitril-gruppe, der kan hydrolyseres til en gruppe -COOH. Hydrolysen kan gennemføres under anvendelse af sædvanlig teknik, for eksempel under mildt basiske betingelser, f.eks. under anvendelse af natriumcarbonat, natriumhydroxid eller natriumbicarbonat, eller under sure betingelser, f.eks. en blanding af vandig dioxan og saltsyre, eller hydrogenbromid i eddikesyre. Hydrolysen kan gennemføres ved en temperatur på fra 25°C til 120°C alt efter de anvendte forbindelser. Alternativt kan gruppen D være en alkylgruppe, f.eks. en lavere alkylgruppe, såsom methyl, en hydroxymethyl-, en aralkenyl-, f.eks. styryl-, en acyl-, f.eks. lavere alkanoyl-, såsom acetyl-, eller en formyl-gruppe. Oxidationen kan gennemføres under anvendelse af sædvanlig teknik, der ikke på anden måde modificerer molekylet i en sådan grad, at udbyttet af det ønskede produkt er uøkonomisk. For eksempel kan en alkyl- eller en hydroxymethyl-gruppe oxideres under anvendelse af selendioxid, f.eks.In process (a), for example, group D may be an ester, acid halide, amide or nitrile group which can be hydrolyzed to a group -COOH. The hydrolysis can be carried out using conventional techniques, for example under mildly basic conditions, e.g. using sodium carbonate, sodium hydroxide or sodium bicarbonate, or under acidic conditions, e.g. a mixture of aqueous dioxane and hydrochloric acid, or hydrogen bromide in acetic acid. The hydrolysis can be carried out at a temperature of from 25 ° C to 120 ° C depending on the compounds used. Alternatively, the group D may be an alkyl group, e.g. a lower alkyl group such as methyl, a hydroxymethyl, an aralkenyl, e.g. styryl, an acyl, e.g. lower alkanoyl, such as acetyl, or a formyl group. The oxidation can be carried out using conventional techniques that do not otherwise modify the molecule to such an extent that the yield of the desired product is uneconomical. For example, an alkyl or a hydroxymethyl group can be oxidized using selenium dioxide, e.g.
DK 158266 BDK 158266 B
5 under tilbagesvaling i vandig dioxan, eller af chromsyre, f.eks. under tilbagesvaling i vandig eddikesyre. Aralkenylgrupper kan oxideres ved anvendelse af for eksempel neutralt eller alkalisk kalium-permanganat i vandig ethanol, og acylgrupper kan oxideres under anvendelse af for eksempel chromsyre eller et vandigt hypochlorit, f.eks. natriumhypochlorit. Formylgruppen kan oxideres under anvendelse af for eksempel chromsyre eller sølvoxid.5 under reflux in aqueous dioxane, or of chromic acid, e.g. under reflux in aqueous acetic acid. Aralkenyl groups can be oxidized using, for example, neutral or alkaline potassium permanganate in aqueous ethanol, and acyl groups can be oxidized using, for example, chromic acid or an aqueous hypochlorite, e.g. sodium hypochlorite. The formyl group can be oxidized using, for example, chromic acid or silver oxide.
Ved fremgangsmåden (b) kan ringslutningen gennemføres ved at behandle forbindelsen med formlen III eller IV med et ringslutningsmiddel, f.eks. et dehydrationsmiddel, såsom chlorsulfonsyre svovlsyre eller polyphosphorsyre. Reaktionen gennemføres fortrinsvis under vandfri betingelser og kan gennemføres ved en temperatur på fra 25°C til 150°C og fortrinsvis fra 75°C til 150°C. Det har vist sig, at isomerisation af maleinsyrederivatet med formlen IV til det tilsvarende fumarsyrederivat med formlen III finder sted, når polyphosphorsyre anvendes til at ringslutte disse forbindelser til en forbindelse med formlen I, hvorved det bliver muligt at vinde et tilfredsstillende udbytte af forbindelsen med formlen I ud fra en ved en umiddelbar betragtning utilfredsstillende blanding af forbindelser med formlerne III og IV. Forbindelser med formlen III kan også ringsluttes ved at udsætte forbindelsen for en forhøjet temperatur, f.eks. på fra 200° til 250°C, eventuelt i nærværelse af et højtkogende opløsningsmiddel, der er indifferent under reaktionsbetingelserne, f.eks. diphenylether.In process (b), the cyclization can be carried out by treating the compound of formula III or IV with a cyclizing agent, e.g. a dehydrating agent such as chlorosulfonic acid sulfuric acid or polyphosphoric acid. The reaction is preferably carried out under anhydrous conditions and can be carried out at a temperature of from 25 ° C to 150 ° C and preferably from 75 ° C to 150 ° C. It has been found that isomerization of the maleic acid derivative of formula IV to the corresponding fumaric acid derivative of formula III takes place when polyphosphoric acid is used to cyclize these compounds to a compound of formula I, thereby obtaining a satisfactory yield of the compound of formula In view of an unsatisfactory mixture of compounds of formulas III and IV. Compounds of formula III can also be cyclized by subjecting the compound to an elevated temperature, e.g. of from 200 ° to 250 ° C, optionally in the presence of a high boiling solvent which is inert under the reaction conditions, e.g. diphenyl ether.
Når én af grupperne er -OM, kan ringslutningsprocessen (c)(i) gennemføres ved opvarmning, eller under basiske eller neutrale betingelser. Det foretrækkes imidlertid at gennemføre ringslutningen i nærværelse af en syre, f.eks. saltsyre, og i et opløsningsmiddel, der er indifferent under reaktionsbetingelserne, f.eks. ethanol. Reaktionen kan gennemføres ved fra 20° til 150°C. Gruppen -COR" er fortrinsvis en estergruppe, idet R" f.eks. kan være en lavere al- koxygruppe. Når én af grupperne er -C0CH=C(COOH)-NL L , kan deriva- 12 12 tet af gruppen -COOH være en gruppe -CONL L , hvor L og L er som 1 2 ovenfor defineret. Det foretrækkes, at L og L er hydrogen, phenyl, alkyl med 1-6 C-atomer eller tilsammen danner en 4- eller 5-leddet alkylenkæde, f.eks. sammen med nitrogenatomet danner en piperidin-ring. Når én af grupperne er halogen, kan ringslutningen gennemføres i et opløsningsmiddel, der er indifferent under reaktionsbetingelserne, fortrinsvis et højtkogende polært opløsningsmiddel, f.eks. pyri-din, dimethylformamid eller hexamethylphosphoramid. Reaktionen genWhen one of the groups is -OM, the cyclization process (c) (i) can be carried out by heating, or under basic or neutral conditions. However, it is preferred to carry out the cyclization in the presence of an acid, e.g. hydrochloric acid, and in a solvent which is inert under the reaction conditions, e.g. ethanol. The reaction can be carried out at from 20 ° to 150 ° C. The group -COR "is preferably an ester group, with R" e.g. may be a lower alkoxy group. When one of the groups is -COCH = C (COOH) -NL L, the derivative of the group -COOH can be a group -CONL L, where L and L are as defined above. It is preferred that L and L are hydrogen, phenyl, alkyl of 1-6 C atoms or together form a 4- or 5-membered alkylene chain, e.g. together with the nitrogen atom forms a piperidine ring. When one of the groups is halogen, the cyclization can be carried out in a solvent which is inert under the reaction conditions, preferably a high boiling polar solvent, e.g. pyridine, dimethylformamide or hexamethylphosphoramide. The reaction gene
DK 158266 BDK 158266 B
6 nemføres fortrinsvis ved hjælp af en stærk base, f.eks. et alkali-metalhydrid, såsom natriumhydrid. Reaktionen gennemføres fortrinsvis ved en temperatur på fra 80° til 200°C i fravær af frit oxygen, f.eks. under en indifferent atmosfære, såsom nitrogen.6 is preferably carried out by means of a strong base, e.g. an alkali metal hydride such as sodium hydride. The reaction is preferably carried out at a temperature of from 80 ° to 200 ° C in the absence of free oxygen, e.g. under an inert atmosphere such as nitrogen.
Ringslutningsprocessen (c)(ii) kan gennemføres ved at behandle forbindelsen med formlen V med et ringslutningsmiddel, f.eks. et dehydratationsmiddel, såsom chlorsulfonsyre, polyphosphorsyre eller svovlsyre. Reaktionen gennemføres fortrinsvis under vandfri betingelser og kan gennemføres ved en temperatur på fra 0° til 100°C. Alternativt kan ringslutningen opnås ved at omdanne de frie carboxygrup-per fra forbindelsen med formlen V til acylhalogenidgrupper og underkaste det resulterende acylhalogenid for en intramolekylær Friedel-Crafts-reaktion.The cyclization process (c) (ii) can be carried out by treating the compound of formula V with a cyclizing agent, e.g. a dehydrating agent such as chlorosulfonic acid, polyphosphoric acid or sulfuric acid. The reaction is preferably carried out under anhydrous conditions and can be carried out at a temperature of from 0 ° to 100 ° C. Alternatively, the cyclization can be achieved by converting the free carboxy groups of the compound of formula V into acyl halide groups and subjecting the resulting acyl halide to an Friedam-Crafts intramolecular reaction.
9 109 10
Ved fremgangsmåderne (d) kan, når R og R tilsammen danner en kæde -S- (C^) -S-, omdannelsen omfatte oxidativ hydrolyse og kan gennemføres i et vandigt polært organisk opløsningsmiddel, f.eks. vandig ethanol, acetone eller tetrahydrofuran. Den oxidative hydrolyse kan gennemføres i nærværelse af et oxiderende middel, for eksempel mercurichlorid, et N-halogensuccinimid, såsom N-brom- eller N-chlor-succlnimid , en per-syre, såsom periodsyre, eller p-toluen-sulfonchloramid eller et salt deraf. Når der anvendes mercurichlorid, kan reaktionen gennemføres i nærværelse af en base, f.eks. mer-curioxid, cadmiumcarbonat eller calciumcarbonat. N-Halogensuccin-imider kan anvendes alene eller i nærværelse af et sølvsalt, f.eks. sølvperchlorat eller sølvnitrat. Reaktionen kan hensigtsmæssigt gennemføres ved en temperatur på fra - 15° til 100°C.In processes (d), when R and R together form a chain -S- (C C) -S-, the conversion may comprise oxidative hydrolysis and may be carried out in an aqueous polar organic solvent, e.g. aqueous ethanol, acetone or tetrahydrofuran. The oxidative hydrolysis may be carried out in the presence of an oxidizing agent, for example mercuric chloride, an N-halo succinimide such as N-bromo or N-chloro succinimide, a peracid such as periodic acid, or p-toluene sulfone chloramide or a salt. thereof. When mercuric chloride is used, the reaction can be carried out in the presence of a base, e.g. mercuric oxide, cadmium carbonate or calcium carbonate. N-Halogen succinimides can be used alone or in the presence of a silver salt, e.g. silver perchlorate or silver nitrate. The reaction may conveniently be carried out at a temperature of from -15 ° to 100 ° C.
9 10 Når R og R tilsammen danner en gruppe =S, kan omdannelsen omfatte (oxidativ) hydrolyse og kan gennemføres i nærværelse af en tungmetalforbindelse, f.eks. en forbindelse fra gruppe Ib, Ilb eller Hib i det periodiske system ifølge Mendeleef, som katalysator. Egnede forbindelser omfatter kviksølv-, thallium- og sølvforbindelser, f.eks. kviksølv(II)acetat eller -chlorid, thallium(III)trifluoracetat eller sølvoxid. Reaktionen kan gennemføres i nærværelse af vand og et organisk opløsningsmiddelsystem, såsom acetone-eddikesyre, al-kanoler, tetrahydrofuran/methanol eller tetrahydrofuran. Alternativt kan reaktionen gennemføres ved alkylering efterfulgt af hydrolyse.When R and R together form a group = S, the conversion may comprise (oxidative) hydrolysis and may be carried out in the presence of a heavy metal compound, e.g. a compound of group Ib, Ilb or Hib in the periodic system of Mendeleef as catalyst. Suitable compounds include mercury, thallium and silver compounds, e.g. mercury (II) acetate or chloride, thallium (III) trifluoroacetate or silver oxide. The reaction can be carried out in the presence of water and an organic solvent system such as acetone-acetic acid, alpha-channels, tetrahydrofuran / methanol or tetrahydrofuran. Alternatively, the reaction may be carried out by alkylation followed by hydrolysis.
I sådanne tilfælde kan reaktionen gennemføres med (i) et alkylhalo-genid eller -sulfonat (f.eks. methyliodid) i et fugtigt opløsningsmiddel, f.eks. acetone, (ii) et alkylfluorsulf onat og vand i svovldioxid, eller (iii) et trialkyloxoniumfluorborat efterfulgt af van-In such cases, the reaction may be carried out with (i) an alkyl halide or sulfonate (e.g., methyl iodide) in a moist solvent, e.g. acetone, (ii) an alkyl fluorosulfonate and water in sulfur dioxide, or (iii) a trialkyloxonium fluoroborate followed by water.
DK 158266 BDK 158266 B
7 dig natriumhydroxid.7 deg sodium hydroxide.
Når både A og B er hydrogen, er fremgangsmåde (e) en dehydro-genering og kan gennemføres ved oxidation under anvendelse af et mildt oxiderende middel, f. eks. selendioxid, palladiumsort, chlor-anil, blytetraacetat eller triphenylmethylperchlorat. Alternativt kan dehydrogeneringen af en forbindelse med formlen VII, hvori både A og B er hydrogen, gennemføres indirekte ved halogenering efterfulgt af dehydrohalogenering, f.eks. ved behandling med N-broitisuccinimid eller pyridiniumbromidperbromid til dannelse af en forbindelse med formlen VII, hvor A er halogen, og B er hydrogen, der derefter de-hydrobromeres. Når den ene af A og B er hydroxy, kan dehydratationen katalyseres med en syre, f.eks. svovlsyre eller oxalsyre, en base, f.eks. kaliumhydroxid, eller et salt, f.eks. kaliumbisulfat, eller N-bromsuccinimid. Reaktionen kan gennemføres i et opløsningsmiddel, der er indifferent under reaktionsbetingelserne, f.eks. et halogeneret carbonhydrid, xylen eller iseddike. Reaktionen kan gennemføres ved forhøjet temperatur, f.eks. fra 20. til 150°C.When both A and B are hydrogen, process (s) is a dehydrogenation and can be carried out by oxidation using a mild oxidizing agent, e.g., selenium dioxide, palladium black, chloranil, lead tetraacetate or triphenylmethyl perchlorate. Alternatively, the dehydrogenation of a compound of formula VII wherein both A and B are hydrogen can be indirectly carried out by halogenation followed by dehydrohalogenation, e.g. by treatment with N-broitisuccinimide or pyridinium bromide perbromide to form a compound of formula VII wherein A is halogen and B is hydrogen which is then dehydrobrominated. When one of A and B is hydroxy, the dehydration can be catalyzed with an acid, e.g. sulfuric or oxalic acid, a base, e.g. potassium hydroxide, or a salt, e.g. potassium bisulfate, or N-bromosuccinimide. The reaction may be carried out in a solvent which is inert under the reaction conditions, e.g. a halogenated hydrocarbon, xylene or glacial acetic acid. The reaction can be carried out at elevated temperature, e.g. from 20 to 150 ° C.
Ringslutningsprocessen (f) kan gennemføres i et opløsningsmiddel, der er indifferent under reaktionsbetingelserne, f.eks. diethyl-ether eller benzen. Reaktionen kan også, om Ønsket, gennemføres i nærværelse af en Lewis syre, f.eks. bortrifluorid. Reaktionen gennemføres fortrinsvis ved en temperatur på fra 10 til 120°C i nærværelse af en organisk base, f.eks. piperidin.The cyclization process (f) can be carried out in a solvent which is inert under the reaction conditions, e.g. diethyl ether or benzene. The reaction may also, if desired, be carried out in the presence of a Lewis acid, e.g. boron trifluoride. The reaction is preferably carried out at a temperature of from 10 to 120 ° C in the presence of an organic base, e.g. piperidine.
Udgangsmaterialerne til fremgangsmåde (b) kan fremstilles ved at omsætte en forbindelse med formlen IX jj5b % ix R7b/ss>^N^ NHRg j8b hvor Rg, R^*5, r^*3, ^7b R8b er som ovenfor defineret, med en forbindelse med formlen X:The starting materials of process (b) can be prepared by reacting a compound of formula IXj5b% ix R7b / ss> NN NHRg j8b wherein Rg, R ^ * 5, r ^ * 3, ^ 7b R8b are as defined above, with a compound of formula X:
Da-C=C-Da XDa-C = C-Da X
hvor Da er en estergruppe, til dannelse af en blanding af forbindelser med formlerne XI og XIIwherein Da is an ester group to form a mixture of compounds of formulas XI and XII
88
DK 1 58266 BDK 1 58266 B
R5b R5b VS c Vin •’viV V?V“R5b R5b VS c Vin • 'viV V? V'
XI XIIXI XII
hvor Rg, Da, R^b, R^b, R^b og R^b er som ovenfor defineret.wherein Rg, Da, R ^ b, R ^ b, R ^ b and R ^ b are as defined above.
Forbindelserne med formlen XI og XII kan hydrolyseres til dannelse af forbindelser med formlerne IV og III. Alternativt kan grupperne Da i forbindelserne med formlen XI og XII omdannes, under anvendelse af i og for sig kendt teknik, til andre grupper D, og de resulterende forbindelser kan ringsluttes, under anvendelse af de samme betingelser som ved fremgangsmåde (b) ovenfor, til dannelse af en forbindelse med formlen II. Som et yderligere og foretrukket alternativ kan forbindelserne med formlen XI og XII ringsluttes, under anvendelse af de samme betingelser som ved fremgangsmåde (b) ovenfor, til dannelse af en forbindelse med formlen II, hvor D er en estergruppe, og den resulterende forbindelse med formlen II anvendes selv til fremgangsmåde (a), eller D-gruppen omdannes til en anden gruppe D, f.eks. en syrehalogenid-, amid- eller nitril-gruppe, under anvendelse af i og for sig kendt teknik.The compounds of formula XI and XII can be hydrolyzed to form compounds of formulas IV and III. Alternatively, the groups Da of the compounds of formula XI and XII can be converted, using prior art, into other groups D, and the resulting compounds may be cyclized, using the same conditions as in process (b) above, to forming a compound of formula II. As a further and preferred alternative, the compounds of formula XI and XII can be cyclized, using the same conditions as in process (b) above, to form a compound of formula II wherein D is an ester group and the resulting compound of formula II is itself used for process (a), or the D group is converted to another group D, e.g. an acid halide, amide or nitrile group, using techniques known in the art.
Den fumarat-isomere med formlen XII (eller den tilsvarende forbindelse, hvor Da er blevet omdannet til D) er den eneste isomere, der kan ringslutte under dannelse af de ønskede forbindelser med formlen II. Mængderne af de to isomere kan let bestemmes ved NMR-spektroskopi, og det har vist sig, at det ønskede fumarsyre-derivat i almindelighed kun udgør en mindre del af den ved reaktionen vundne blanding af isomere.The fumarate isomer of formula XII (or the corresponding compound where Da has been converted to D) is the only isomer capable of cyclization to form the desired compounds of formula II. The amounts of the two isomers can be readily determined by NMR spectroscopy, and it has been found that the desired fumaric acid derivative generally constitutes only a minor part of the mixture of isomers obtained in the reaction.
De forbindelser med formlen V, hvor R6c og 7c R repræsenterer grupperne -COCH2COCOR" og -OM eller haloThe compounds of formula V wherein R6c and 7c R represent the groups -COCH2COCOR "and -OM or halo
gen, kan fremstilles ved at omsætte en forbindelse med formlen XIIIgene, can be prepared by reacting a compound of formula XIII
R59 0R59 0
'VVS'plumbing
-7 J-C00H-7 J-C00H
Η79γ\Ν/~Η79γ \ Ν / ~
^8g Rg XIII^ 8g Rg XIII
eller en ester deraf, hvoror an ester thereof, wherein
DK 158266 BDK 158266 B
99
Rg er som ovenfor defineret, og R^, R^, R^ og R®^ har samme betydninger som R'*, R^, R^ og R® ovenfor, bortset fra at R6g og R7g,i stedet for at danne en kæde -COCH=CH(COOH)-0-, repræsenterer grupperne -COCH^ og -OM eller halogen, hvor M er som ovenfor defineret, med en forbindelse med formlen XIV:R 9 is as defined above and R 2, R 2, R 2 and R 2 have the same meanings as R 1, R 2, R 2 and R 2 above, except that R 6 and R 7, instead of forming a chain -COCH = CH (COOH) -O-, the groups represent -COCH 2 and -OM or halogen, where M is as defined above, with a compound of formula XIV:
R'CZ-CZR" XXVR'CZ-CZR "XXV
hvor R" er som ovenfor defineret, R1 er en passende, bortgående gruppe, f.eks. en alkoxy-, halogen- ·, amino-, alkylamino-, substitueret amino- (f.eks. en aryl-sulfonylamino-gruppe) eller substitueret alkylamino-gruppe, der kan reagere med carbanionen af gruppen -COCH^ fra forbindelsen med formlen XIII, og hvert Z er et carbonyl-oxygenatom, eller det ene Z kan repræsentere to halogenatomer, og det andet et carbonyl-oxygenatom, og om nødvendigt hydrolysere den resulterende forbindelse til en forbindelse med formlen V. De foretrukne forbindelser med fomlen XIV er dialkyloxalater, f.eks. diethyloxalat.wherein R "is as defined above, R 1 is a suitable leaving group, for example, an alkoxy, halogeno, amino, alkylamino, substituted amino (e.g., an aryl sulfonylamino group) or substituted alkylamino group which can react with the carbanion of the group -COCH 2 from the compound of formula XIII and each Z is a carbonyl oxygen atom or one Z may represent two halogen atoms and the other a carbonyl oxygen atom and if necessary hydrolyzing the resulting compound to a compound of formula V. The preferred compounds of formula XIV are dialkyloxalates, for example diethyl oxalate.
Forbindelser med formlen V, der bærer en gruppe 1 2 -C0CH=C(COOH)-NL L , eller et derivat deraf, kan fremstilles ud fra kendte forbindelser i ét eller flere trin under anvendelse af i og for sig kendte fremgangsmåder.Compounds of formula V bearing a group 1 2 -COCH = C (COOH) -NL L, or a derivative thereof, can be prepared from known compounds in one or more steps using methods known per se.
Forbindelserne med formlen II kan fremstilles som beskrevet ovenfor eller ved en fremgangsmåde analog med fremgangsmåde (c) (i).The compounds of formula II may be prepared as described above or by a method analogous to process (c) (i).
Alternativt kan forbindelserne med fomlen II, for eksempel i tilfælde af syrehalogenidet, amidet og nitrilen, fremstilles ud fra forbindelser med fomlen I under anvendelse af sædvanlig teknik, f.eks. omsætning af en ester af forbindelsen med fomlen I med ammoniak til dannelse af amidet efterfulgt af dehydratation af amidet til dannelse af nitrilen.Alternatively, the compounds of the formula II, for example in the case of the acid halide, amide and nitrile, can be prepared from compounds of the formula I using conventional techniques, e.g. reacting an ester of the compound of the formula I with ammonia to form the amide followed by dehydration of the amide to form the nitrile.
De forbindelser med fomlen V, der bærer substituenter -H og -0-C(COR")=CH-C0R", kan fremstilles ved at omsætte en forbindelse med formlen XV 5h λ R irThe compounds of formula V bearing substituents -H and -O-C (COR ") = CH-COR" can be prepared by reacting a compound of formula XV 5h λ R ir
r7AJ^^-C00Hr7AJ ^^ - C00H
j^h Rg XVj ^ h Rg XV
.. DK 158266B.. DK 158266B
10 eller en ester deraf, hvor R~^f R^h Qg R8h ^ar gamme betyd ninger som , R^, R^ og R^ ovenfor, bortset fra at R^^1 og R^*1, i stedet for at danne en kæde -C0CH=C(C00H)-0-, repræsenterer grupperne -H og -OH, med et dialkylacetylendicarboxylat på sædvanlig måde efterfulgt, om nødvendigt, af hydrolyse af reaktionsproduktet.Or an ester thereof, wherein R ~ f f R ^ h Qg R8h ^ are gamma meanings such as, R ^, R ^ and R ^ above, except that R ^^ 1 and R ^ * 1, instead of forming a chain -COCH = C (C00H) -O-, the groups -H and -OH, with a dialkylacetylene dicarboxylate, are represented in the usual manner followed, if necessary, by hydrolysis of the reaction product.
Forbindelserne med formlen VIII kan fremstilles ved at omsætte en forbindelse med formlen XVIThe compounds of formula VIII can be prepared by reacting a compound of formula XVI
R5i OR5i O
ΟΛ .nAjJU»»ΟΛ .nAjJU »»
I 8i II 8i I
R Rg eller en ester deraf, hvorR Rg or an ester thereof, where
Rg er som ovenfor defineret, R'**, R^, R^ og R^ har samme betydninger som R^, R^, R^ og R ovenfor, bortset fra at Rbl og R71, i stedet for at danne en kæde -COCH=C(COOH)-O-, repræsenterer gruppeparret -OH og -COO-Alkyl, med en methylalkylsulfoxidanion, f.eks. anionen af dimethylsulfoxid, og omsætte den resulterende o-hydroxy-2-alkylsulfinyl-forbindelse med glyoxalsyre eller en ester deraf.Rg is as defined above, R '**, R ^, R ^ and R ^ have the same meanings as R ^, R ^, R ^ and R above, except that Rbl and R71, instead of forming a chain - COCH = C (COOH) -O-, represents the group-paired -OH and -COO-Alkyl, with a methyl alkyl sulfoxide anion, e.g. the anion of dimethyl sulfoxide, and reacting the resulting o-hydroxy-2-alkylsulfinyl compound with glyoxalic acid or an ester thereof.
Forbindelser med formlerne VI, VII, IX, XIII, XIV, XV og XVI er enten kendte, eller de kan fremstilles ud fra kendte forbindelser under anvendelse af i og for sig kendt teknik.Compounds of formulas VI, VII, IX, XIII, XIV, XV and XVI are either known or can be prepared from known compounds using techniques known per se.
Forbindelserne med formlen I og mellemprodukterne for disse kan isoleres fra deres reaktionsblandinger under anvendelse af sædvanlig teknik.The compounds of formula I and their intermediates can be isolated from their reaction mixtures using conventional techniques.
Egnede farmaceutisk acceptable salte af forbindelserne med formlen I omfatter ammonium-, alkalimetal- (f.eks. natrium-, kalium-og lithium-) og jordalkalimetal- (f.eks. calcium eller magnesium-)-salte og salte med egnede organiske baser, f.eks. salte med hydroxylamin, lavere alkylaminer, såsom methylamin eller ethyl-amin, med substituerede lavere alkylaminer, f.eks. hydroxysubsti-tuerede alkylaminer, såsom tris(hydroxymethyl)methylamin, eller med simple monocycliske nitrogen-heterocycliske forbindelser, f.eks. piperidin eller morpholin.Suitable pharmaceutically acceptable salts of the compounds of formula I include ammonium, alkali metal (e.g. sodium, potassium and lithium) and alkaline earth metal (e.g. calcium or magnesium) salts and salts with suitable organic bases , eg. salts with hydroxylamine, lower alkylamines such as methylamine or ethylamine, with substituted lower alkylamines, e.g. hydroxy-substituted alkylamines, such as tris (hydroxymethyl) methylamine, or with simple monocyclic nitrogen-heterocyclic compounds, e.g. piperidine or morpholine.
. DK 158266B. DK 158266B
11 I almindelighed foretrækkes det, at danne det farmaceutisk acceptable salt ved at behandle den fri syre med formlen I med en passende base, f.eks. med et jordalkalimetal- eller alkali-metal-hydroxid, -carbonat eller -bicarbonat i vandig opløsning eller ved en metatetisk proces med et passende salt. Når der anvendes en stærkt basisk forbindelse, må der, f.eks. ved at holde temperaturen tilstrækkeligt lav, drages omsorg for at sikre, at forbindelsen med formlen I ikke hydrolyseres eller på anden måde nedbrydes. Det farmaceutisk acceptable salt kan udvindes fra reaktionsblandingen ved for eksempel udfældning med opløsningsmiddel og/eller fjernelse af opløsningsmidlet ved fordampning, f.eks. ved frysetørring.In general, it is preferred to form the pharmaceutically acceptable salt by treating the free acid of formula I with a suitable base, e.g. with an alkaline earth metal or alkali metal hydroxide, carbonate or bicarbonate in aqueous solution or by a metathetic process with an appropriate salt. When a strongly basic compound is used, e.g. by keeping the temperature sufficiently low, care is taken to ensure that the compound of formula I is not hydrolyzed or otherwise degraded. The pharmaceutically acceptable salt can be recovered from the reaction mixture by, for example, precipitation with solvent and / or removal of the solvent by evaporation, e.g. by freeze drying.
Egnede farmaceutisk acceptable estre omfatter simple lavere alkylestre, f.eks. ethylesteren. Estrene kan fremstilles ved sædvanlig teknik, f.eks. esterificering eller transesterificering. Egnede farmaceutisk acceptable mono- eller di-alkylamider kan være sådanne, hvor alkyl har 1-6 C-atomer, og kan fremstilles ved sædvanlig teknik, f.eks. ved omsætning af en ester af den tilsvarende syre med en passende amin.Suitable pharmaceutically acceptable esters include simple lower alkyl esters, e.g. ethyl ester. The esters can be prepared by conventional techniques, e.g. esterification or transesterification. Suitable pharmaceutically acceptable mono- or di-alkylamides may be those wherein alkyl has 1-6 C atoms and can be prepared by conventional techniques, e.g. by reacting an ester of the corresponding acid with an appropriate amine.
Forbindelserne med formlen I og farmaceutisk acceptable salt-, alkylester-og mono- eller di-alkylamid-derivater deraf er som nævnt anvendelige på grund af deres farmakologiske virkning på dyr. De er navnlig anvendelige, fordi de hæmmer frigøringen og/eller virkningen af farmakologiske mediatorer, der stammer fra in vivo-kombinationen af visse typer antistof og specifikt antigen, f.eks. kombinationen af reaginisk antistof med specifikt antigen (se eksempel 27 i britisk patentskrift nr. 1.292.601).The compounds of formula I and pharmaceutically acceptable salt, alkyl ester and mono- or di-alkylamide derivatives thereof are useful as mentioned, because of their pharmacological effect on animals. They are particularly useful because they inhibit the release and / or action of pharmacological mediators derived from the in vivo combination of certain types of antibody and specific antigen, e.g. the combination of reagent antibody with specific antigen (see Example 27 of British Patent No. 1,292,601).
Til dokumentation af denne aktivitet hos de omhandlede forbindelser blev der gennemført følgende sammenligningsforsøg.To document this activity of the compounds of the present invention, the following comparative experiments were performed.
Charles River France/Fisons-opdrættede rotter (han eller hun-) med en legemsvægt på fra 100 til 150 g blev inficeret subcutant med ugentlige intervaller med N.brasiliensis-larver i doser stigende fra ca. 2000 larver pr. dyr til 12.000 larver pr. dyr for at etablere infektionen. Efter 8 uger blev rotterne blodtappet ved hjertepunktur, og 15-20 ml blod blev opsamlet fra hvert dyr. Blodprøverne blev derefter centrifugeret ved 3500 rpm i 30 minutter for at fjerne blodcellerne fra blodplasmaet. Serum'et blev indsamlet og anvendt til at tilvejebringe et serum indeholdendeCharles River France / Fisons-reared rats (male or female) weighing from 100 to 150 g were subcutaneously infected at weekly intervals with N. brasiliensis larvae at doses increasing from ca. 2000 larvae per animals to 12,000 larvae per animals to establish the infection. After 8 weeks, the rats were blood drawn at cardiac puncture and 15-20 ml of blood were collected from each animal. The blood samples were then centrifuged at 3500 rpm for 30 minutes to remove the blood cells from the blood plasma. The serum was collected and used to provide a serum containing
DK 158266 BDK 158266 B
12 N.brasiliensis-antistof. En forsøgs-sensibilitetstest gennemførtes for at bestemme den mindste mængde serum, der kræves for ved den nedenfor beskrevne test at tilvejebringe en skindstrime på 2 cm i diameter hos kontroldyr. Det fandtes, at optimal sensibilitet hos rotter i legemsvægtområdet 100-130 g opnås ved anvendelse af et serum fortyndet med otte dele fysiologisk saltopløsning. Denne fortyndede opløsning er betegnet antistofserum A.12 N. brasiliensis antibody. An experimental sensitivity test was performed to determine the minimum amount of serum required to provide a skin strip of 2 cm in diameter in control animals by the test described below. It was found that optimum sensitivity in rats in the body weight range of 100-130 g is obtained using a serum diluted with eight parts of physiological saline solution. This diluted solution is termed antibody serum A.
Det antigen, der skulle reagere med antistoffet i serum A, blev fremstillet ved at fjerne N. brasiliensis-orme fra tarmen hos inficerede rotter, centrifugere homogenatet og indsamle super-natantvæsken. Denne væske blev fortyndet med saltopløsning til opnåelse af et proteinindhold på 1 mg/ml og er kendt som opløsning B.The antigen to react with the antibody in serum A was prepared by removing N. brasiliensis worms from the intestine of infected rats, centrifuging the homogenate and collecting the supernatant fluid. This liquid was diluted with saline to give a protein content of 1 mg / ml and is known as solution B.
Charles River France/Fisons-opdrættede rotter med legemsvægtområdet 100 til 130 g blev sensibiliseret ved intradermal injektion af 0,1 ml serum A i den højre flanke. Sensibilitet fik lov at udvikles i 24 timer, og rotterne fik derefter intravenøs injektion med 1 ml/100 g legemsvægt af en blanding'af opløsning B (0,25 ml), Evans Blue-farvestofopløsning (0,25 ml) og opløsningen af testforbindelsen (0,5 ml med varierende procentindhold af aktivt materialer). For hvert procentniveau af aktivt materiale i testopløsningen blev der foretaget injektion på fem rotter. Fem rotter anvendtes som kontrol ved hver test. Doseringen af testforbindelsen valgtes således, at der blev opnået et område af inhibitionsværdier .Charles River France / Fisons-reared rats with body weight range 100 to 130 g were sensitized by intradermal injection of 0.1 ml of serum A in the right flank. Sensitivity was allowed to develop for 24 hours and the rats were then given intravenous injection with 1 ml / 100 g body weight of a mixture of solution B (0.25 ml), Evans Blue dye solution (0.25 ml) and the solution of the test compound. (0.5 ml with varying percentages of active materials). For each percent level of active material in the test solution, five rats were injected. Five rats were used as controls in each test. The dosage of the test compound was chosen such that a range of inhibition values were obtained.
Tredive minutter efter injektion af opløsning B blev rotterne dræbt, og skindet blev fjernet og krænget. Intensiteten af den anafylaktiske reaktion blev vurderet ved at sammenligne størrelsen af den karakteristiske blå strime, frembragt ved spredning af Evans Blue-farvestoffet fra sensibiliseringsstedet, med størrelsen af strimen hos kontroldyrene. Størrelsen af strimen blev givet en værdi fra 0 (ingen påvist strime, dvs. 100% inhibition) til 4 (ingen forskel i strimestørrelse, dvs. ingen inhibition), og den procentuelle inhibition for hvert dosisniveau blev beregnet som: (Kontrolgruppetal - Behandlingsgruppetal) x 100 % inhibition = -Thirty minutes after injection of Solution B, the rats were killed and the skin removed and incised. The intensity of the anaphylactic reaction was assessed by comparing the size of the characteristic blue streak produced by dispersing the Evans Blue dye from the site of sensitization to the size of the streak of the control animals. The size of the strip was given a value from 0 (no detected strip, ie 100% inhibition) to 4 (no difference in strip size, ie no inhibition), and the percent inhibition for each dose level was calculated as: (Control group number - Treatment group number) x 100% inhibition = -
KontrolgruppetalKontrolgruppetal
DK 158266 BDK 158266 B
1313
De procentuelle inhibitioner for de forskellige dosisniveauer blev optegnet grafisk for hver forbindelse. Ud fra disse diagrammer bestemtes den dosis, der kræves for at opnå en 50% inhibition af den anafylaktiske reaktion (ID^q)- Resultaterne er vist i nedenstående tabel.The percent inhibitions for the different dose levels were plotted graphically for each compound. From these charts, the dose required to achieve a 50% inhibition of the anaphylactic reaction (ID ^ q) was determined. The results are shown in the table below.
TabelTable
Forbindelse , IDq mg/kgCompound, IDq mg / kg
Forbindelse fra Eksempel 2 Dinatrium-4,6-dioxo-9-ethyl-10-propyl-4H,6H-pyrano[3,2-g]quinolin-2,8-dicar-boxylat 0,02Compound of Example 2 Disodium 4,6-dioxo-9-ethyl-10-propyl-4H, 6H-pyrano [3,2-g] quinoline-2,8-dicarboxylate 0.02
Forbindelse fra US nr. 3.959.289 (Eks.3)Compound of US No. 3,959,289 (Ex.3)
Dinatrium-1,4,6,9-tetrahydro-10-methyl- 4,6-dioxypyrido[3,2-g]quinolin-2,8-dicarboxylat 0,056Disodium 1,4,6,9-tetrahydro-10-methyl-4,6-dioxypyrido [3,2-g] quinoline-2,8-dicarboxylate 0.056
Disse forsøgsresultater viser klart de omhandlede forbindelsers overlegne evne til at inhibere anafylaktisk reaktion hos rotter sammenlignet med de fra det ovenfor omtalte patentskrift nr. 3.959.289 kendte forbindelser.These test results clearly demonstrate the superior ability of the compounds of this invention to inhibit anaphylactic reaction in rats compared to the compounds known from the above-mentioned patent specification No. 3,959,289.
De hidtil ukendte forbindelser har også vist sig at interferere med refleks-banerne hos forsøgsdyr og mennesker og navnlig de reflekser, der er forbundet med lungefunktion. Hos mennesker bliver både subjektive og objektive ændringer, der skyldes sensibiliserede personers inhalering af specifikt antigen, hæmmet ved forudgående indgift af de hidtil ukendte forbindelser. De hidtil ukendte forbindelser anvises derfor til anvendelse af behandlingen af reversabel, luftvejs-obstruktion og/eller til at hindre overdreven slim-sekretion. De hidtil ukendte forbindelser anvises såltil behandling af allergisk astma, såkaldt "indre" astma (hvor der ikke kan påvises nogen følsomhed over for ydre antigen) , bronchitis, hoste og nasale og bronchiale obstruktioner forbundet med almindelige forkølelser. De hidtil ukendte forbindelser kan også være af værdi ved behandlingen af andre tilstande, hvor antigen-antistof-reaktioner eller overdreven slim-sekretion er ansvarlig for eller er en biomstændighed ved sygdom, f.eks. høfeber, visse øjen-tilstande, f.eks. trachoma, ernærings-allergi, f.eks. urticaria og atopisk eksem, og tilstande i mave-tarm-kanalen, f.eks. gastrointestinal allergi, navnlig hos børn, f.eks. mælkeallergi, eller ulcera-tiv colitis.The novel compounds have also been shown to interfere with the reflex pathways of laboratory animals and humans, and in particular the reflexes associated with lung function. In humans, both subjective and objective changes resulting from the inhalation of specific antigen by sensitized individuals are inhibited by prior administration of the novel compounds. Therefore, the novel compounds are disclosed for use in the treatment of reversible, airway obstruction and / or to prevent excessive mucus secretion. The novel compounds are allotted for the treatment of allergic asthma, so-called "internal" asthma (where no sensitivity to external antigen can be detected), bronchitis, cough and nasal and bronchial obstructions associated with common colds. The novel compounds may also be of value in the treatment of other conditions in which antigen-antibody responses or excessive mucus secretion are responsible for or are a bioavailability of disease, e.g. hay fever, certain eye conditions, e.g. trachoma, nutritional allergy, e.g. urticaria and atopic eczema, and conditions of the gastrointestinal tract, e.g. gastrointestinal allergies, especially in children, e.g. milk allergy, or ulcerative colitis.
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Til ovennævnte anvendelser vil den anvendte dosis naturligvis variere med den anvendte forbindelse, anvendelsesmåden og den ønskede behandling. I almindelighed opnås imidlertid tilfredsstillende resultater, når forbindelserne anvendes i en dosis på fra 0,001 til 50 mg pr. kg dyre-legemsvægt ved det forsøg, der er beskrevet i eksempel 27 i britisk patentskrift nr. 1.292.601. Por mennesker ligger den foreskrevne totale daglige dosis inden for området fra 0,01 mg til 1.000 mg, fortrinsvis fra 0,01 mg til 200 mg og navnlig fra 1 mg til 60 mg, der kan indgives i opdelte doser fra 1 til 6 gange daglig eller i en form med forhalet frigivelse. Enhedsdosisformer, der er egnede for anvendelser (ved inhalering eller gennem spiserøret) omfatter således fra 0,01 mg til 50 mg, fortrinsvis 0,01 til 20 mg og navnlig fra 0,01 mg til 19 mg af forbindelsen, fortrinsvis i blanding med et fast eller flydende farmaceutisk acceptabelt fortyndingsmiddel, bærestof eller hjælpemiddel.Of course, for the above applications, the dose used will vary with the compound used, the mode of application and the treatment desired. Generally, however, satisfactory results are obtained when the compounds are used at a dose of from 0.001 to 50 mg per day. in the test described in Example 27 of British Patent Specification No. 1,292,601. For humans, the prescribed total daily dose is within the range of 0.01 mg to 1,000 mg, preferably from 0.01 mg to 200 mg, and in particular from 1 mg to 60 mg, which may be administered in divided doses from 1 to 6 times daily. or in a delayed release form. Thus, unit dosage forms suitable for applications (by inhalation or through the esophagus) comprise from 0.01 mg to 50 mg, preferably 0.01 to 20 mg, and especially from 0.01 mg to 19 mg of the compound, preferably in admixture with solid or liquid pharmaceutically acceptable diluent, carrier or adjuvant.
Forbindelserne med formlen I, og farmaceutisk acceptable salt-, alkylester- og mono- eller di-alkylamid-derivater deraf, har den fordel, at de er mere effektive ved visse farmakologiske modeller, eller er længere virkende end forbindelser af tilsvarende struktur som forbindelserne med formlen I. Endvidere er forbindelserne med formlen I, og nævnte farmakologisk acceptable derivater deraf, fordelagtige ved, at de er mere effektive til at interferere med refleks-baner og til at hæmme slim-sekretion, end tilfældet er med forbindelser af tilsvarende struktur som forbindelserne med formlen I.The compounds of formula I, and pharmaceutically acceptable salt, alkyl ester and mono- or di-alkylamide derivatives thereof, have the advantage that they are more effective in certain pharmacological models, or are longer effective than compounds of similar structure to the compounds of In addition, the compounds of formula I and said pharmacologically acceptable derivatives thereof are advantageous in that they are more effective in interfering with reflex pathways and in inhibiting mucus secretion than in compounds of similar structure to the compounds. of formula I.
5 85 8
Det foretrækkes, at hver af R og R , når de er alkyl, indeholder op til 8 C-atomer og fortrinsvis op til 4 C-atomer. Den 6 7 af R og R dannede kæde -C0CH=C(C00H)-0- er fortrinsvis bundet til benzenringen på en sådan måde, at delen -0- af kædet er i stilling R7.It is preferred that each of R and R, when alkyl, contains up to 8 C atoms and preferably up to 4 C atoms. Preferably, the 6 7 of R and R formed -COCH = C (C00H) -O- is bonded to the benzene ring in such a way that the part -0- of the chain is in position R7.
Farmaceutiske kompositioner indeholder (fortrinsvis i en mængde på mindre end 80 vægtprocent og-navnlig mindre end 50 vægtprocent) en forbindelse med formlen I, eller et farmaceutisk acceptabelt salt-, alkylester- eller mono- eller di-alkylamid-derivat deraf, i kombination med et farmaceutisk acceptabelt hjælpestof, fortyndingsmiddel eller bærestof. Eksempler på egnde hjælpemidler, fortyndingsmidler eller bærestoffer er til tabletter, kapsler og dragéer: mikro-krystallinsk cellulose, calciumphosphat, diatoméjord, et sukker, såsom lactose, dextrose eller mannitol, talkum, stearinsyre,Pharmaceutical compositions contain (preferably in an amount of less than 80% by weight and especially less than 50% by weight) a compound of formula I, or a pharmaceutically acceptable salt, alkyl ester or mono or di-alkylamide derivative thereof, in combination with a pharmaceutically acceptable excipient, diluent or carrier. Examples of suitable aids, diluents or carriers are for tablets, capsules and dragees: microcrystalline cellulose, calcium phosphate, diatomaceous earth, a sugar such as lactose, dextrose or mannitol, talc, stearic acid,
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15 stivelse, natriumbicarbonat og/eller gelatine, til suppositorier: naturlige eller hærdede olier eller voksarter, og til inhalationskompositioner: grov lactose. Forbindelsen med formlen I, eller nævnte farmaceutisk acceptable salt-, ester- eller amid-derivat deraf, foreligger fortrinsvis i en form med en gennemsnitlig partikeldiameter på fra 0,01 til 10 mikron. Kompositionerne kan også indeholde egnede præserverings-, stabiliserings- og béfugtnings-midler, opløseliggørende midler, sødestoffer, farvningsmidler og duft/smags-stoffer. Kompositionerne kan, om ønsket, oparbejdes i en form med forhalet frigivelse. Der foretrækkes kompositioner, der er bestemt til indtagelse gennem spiserøret og. til at frigive deres indhold i mave-tarm-kanalen.15 starch, sodium bicarbonate and / or gelatin, for suppositories: natural or hardened oils or waxes, and for inhalation compositions: coarse lactose. The compound of formula I, or said pharmaceutically acceptable salt, ester or amide derivative thereof, is preferably in a form having an average particle diameter of from 0.01 to 10 microns. The compositions may also contain suitable preservative, stabilizing and wetting agents, solubilizers, sweeteners, coloring agents and fragrances / flavors. The compositions may, if desired, be worked up in a delayed release form. Preferred compositions intended for ingestion through the esophagus and. to release their contents into the gastrointestinal tract.
Fremgangsmåden ifølge opfindelsen beskrives nærmere gennem følgende eksempler.The process according to the invention is further described by the following examples.
Eksempel 1 4,6-Dioxo-10-propyl~4H,6H-pyrano[3,2-g]quinolin-2,8-dicarboxylsyre.Example 1 4,6-Dioxo-10-propyl ~ 4H, 6H-pyrano [3,2-g] quinoline-2,8-dicarboxylic acid.
(a) 4-Acetamido-2-allyloxyacetophenon.(a) 4-Acetamido-2-allyloxyacetophenone.
4-Acetamido-2-hydroxyacetophenon (19,3 g), allylbromid (12,1 ml) og vandfrit kaliumcarbonat (21,5 g) blev omrørt i tørt di-methylformamid (250 ml) ved stuetemperatur i 24 timer. Reaktionsblandingen blev hældt i vand, og produktet blev ekstraheret med ethyl-acetat. Den organiske opløsning blev derefter vasket godt med vand, tørret over magnesiumsulfat og inddampet til tørhed. Undertitel-produktet vandtes som brungult fast stof (20,5 g). Strukturen af produktet blev bekræftet ved NMR- og masse-spektroskopi.4-Acetamido-2-hydroxyacetophenone (19.3 g), allyl bromide (12.1 ml) and anhydrous potassium carbonate (21.5 g) were stirred in dry dimethylformamide (250 ml) at room temperature for 24 hours. The reaction mixture was poured into water and the product was extracted with ethyl acetate. The organic solution was then washed well with water, dried over magnesium sulfate and evaporated to dryness. The subtitle product was obtained as a brown-yellow solid (20.5 g). The structure of the product was confirmed by NMR and mass spectroscopy.
(b) '4-Acetamido-3-allyl-2-hydroxyacetophenon.(b) 4-Acetamido-3-allyl-2-hydroxyacetophenone.
Den ovennævnte allylether (18,4 g) blev opvarmet ved 200-210°C i 4 timer. Der vandtes 17,1 g af det termisk omlejrede undertitel-produkt som et brunt fast stof. Strukturen blev atter bekræftet ved NMR- og masse-spektroskopi.The above allyl ether (18.4 g) was heated at 200-210 ° C for 4 hours. 17.1 g of the thermally rearranged subtitle product was obtained as a brown solid. The structure was again confirmed by NMR and mass spectroscopy.
(c) 4-Acetamido-2-hydroxy-3-propyl-acetophenon.(c) 4-Acetamido-2-hydroxy-3-propyl-acetophenone.
Produktet fra trin (b) (17 g) blev opløst i iseddike og hydrogeneret i nærværelse af Adams-katalysator, indtil hydrogenoptagningen ophørte. Katalysatoren blev frafiltreret gennem et kiselgur-filter, og filtratet blev inddampet, hvorved der som inddampningsrest vandtes 13,0 g af næsten farveløst fast stof. Masse- og NMR-spektre-ne bekræftede strukturen af produktet.The product of step (b) (17 g) was dissolved in glacial acetic acid and hydrogenated in the presence of Adams catalyst until hydrogen uptake ceased. The catalyst was filtered off through a diatomaceous earth filter and the filtrate was evaporated to give 13.0 g of almost colorless solid as the evaporation residue. The mass and NMR spectra confirmed the structure of the product.
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16 (d) Ethyl-7-acetamido-4-oxo-8-propyl-4H-l-benzopyran-2-carboxylat.(D) Ethyl 7-acetamido-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylate.
En blanding af diethyloxalat (19,3 g, 17,9 ml) og det ovennævnte produkt fra trin (c) (12,4 g) i tør ethanol (100 ml) blev sat til en omrørt opløsning af natriumethoxid i ethanol (fremstillet ved at opløse natrium (6,1 g) i tør ethanol (200 ml)) . Reaktionsblandingen blev tilbagesvalet i 3 timer og derefter hældt i fortyndet saltsyre og chloroform. Chloroformlaget blev fraskilt, vasket med vand og tørret. Opløsningsmidlet blev afdampet, hvorved vandtes et brunt fast stof, der blev opløst i ethanol (300 ml) indeholdende koncentreret saltsyre (3 ml), og det hele blev tilbagesvalet i 1 time. Reaktionsblandingen blev hældt i vand, og produktet blev ekstraheret over i ethylacetat, der blev vasket med vand og tørret. Opløsningsmidlet blev afdampet, hvorved vandtes 10 g af et klæbrigt fast stof, der havde masse- og NMR-spektre overensstemmende med det forventede produkt.A mixture of diethyl oxalate (19.3 g, 17.9 ml) and the above product from step (c) (12.4 g) in dry ethanol (100 ml) was added to a stirred solution of sodium ethoxide in ethanol (prepared by dissolving sodium (6.1 g) in dry ethanol (200 ml). The reaction mixture was refluxed for 3 hours and then poured into dilute hydrochloric acid and chloroform. The chloroform layer was separated, washed with water and dried. The solvent was evaporated to give a brown solid which was dissolved in ethanol (300 ml) containing concentrated hydrochloric acid (3 ml) and the whole was refluxed for 1 hour. The reaction mixture was poured into water and the product was extracted into ethyl acetate which was washed with water and dried. The solvent was evaporated to give 10 g of a sticky solid having mass and NMR spectra consistent with the expected product.
(e) Ethyl-7-amino-4-oxo-8-propyl-4H-l-benzopyran-2-carboxylat.(e) Ethyl 7-amino-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylate.
En opløsning af amidet fra trin (d) (10 g) i ethanol (300 ml) indeholdende koncentreret saltsyre (5 ml) blev tilbagesvalet i 8 timer. Reaktionsblandingen blev fortyndet med vand og ekstraheret med ethylacetat. Ekstrakten blev vasket med vand og tørret, og opløsningsmidlet blev afdampet, hvorved vandtes et mørkebrunt halvfast stof. Dette blev chromatograferet på en silicagelsøjle, under anvendelse af ether som eluent, hvorved vandtes 4,8 g af det ønskede produkt, hvis struktur blev bekræftet ved masse- og NMR-spektre, smp. 84-87°C.A solution of the amide from step (d) (10 g) in ethanol (300 ml) containing concentrated hydrochloric acid (5 ml) was refluxed for 8 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water and dried and the solvent was evaporated to give a dark brown semi-solid. This was chromatographed on a silica gel column, using ether as eluent to give 4.8 g of the desired product, the structure of which was confirmed by mass and NMR spectra, m.p. 84-87 ° C.
(f) 8-Ethoxycarbonyl-2-methoxycarbonyl-4,6-dioxo-10-propyl-4H,6H-pyrano[3,2-g]quinolin.(f) 8-Ethoxycarbonyl-2-methoxycarbonyl-4,6-dioxo-10-propyl-4H, 6H-pyrano [3,2-g] quinoline.
Aminobenzopyranen fra trin (e) (2,0 g) og dimethylacetylen-dicarboxylat (1,24 g, 1,01 ml) blev tilbagesvalet i ethanol (30 ml) i 26 timer. Reaktionsblandingen blev afkølet til 0°C, og det uopløselige gulbrune faste stof blev opsamlet ved filtrering og vasket med en lille smule ethanol og tørret, hvorved vandtes 2,0 g af et produkt, der var en blanding af maleinsyre- og fumarsyre-estre vundet ved Michael-addition af aminen til acetylenet.The aminobenzopyran from step (e) (2.0 g) and dimethylacetylene dicarboxylate (1.24 g, 1.01 ml) was refluxed in ethanol (30 ml) for 26 hours. The reaction mixture was cooled to 0 ° C and the insoluble yellow-brown solid was collected by filtration and washed with a small amount of ethanol and dried to give 2.0 g of a product which was a mixture of maleic and fumaric acid esters obtained by Michael addition of the amine to the acetylene.
Denne blanding af estre (2,0 g) blev behandlet med polyphos-phorsyre (30 ml) og opvarmet på dampbad under omrøring i 20 minutter. Reaktionsblandingen blev derefter hældt på is og omrørt med ethylacetat. Det organiske lag blev fraskilt, vasket med vand og tørret.This mixture of esters (2.0 g) was treated with polyphosphoric acid (30 ml) and heated on a steam bath with stirring for 20 minutes. The reaction mixture was then poured onto ice and stirred with ethyl acetate. The organic layer was separated, washed with water and dried.
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Opløsningsmidlet blev afdampet, hvorved vandtes 1,6 g af et gulorange fast stof. Omkrystallisation af dette faste stof af ethyl-acetat gav det ønskede produkt som fnugagtige orangefarvede nåle, smp. 187-188°C.The solvent was evaporated to give 1.6 g of a yellow-orange solid. Recrystallization of this ethyl acetate solid gave the desired product as fluffy orange needles, m.p. 187-188 ° C.
Analyse:Analysis:
Fundet: C: 62,0%, H: 5,1%, H: 3,7%Found: C: 62.0%, H: 5.1%, H: 3.7%
Beregnet for C2oH19N07: C: 62,3%, H: 4,9%, N: 3,6% (g) 4,6-Dioxo-10-propyl-4H,6H-pyrano[3,2-g]quinolin-2,8-dicarboxyl-syre.Calculated for C 20 H 19 NO 7: C: 62.3%, H: 4.9%, N: 3.6% (g) 4,6-Dioxo-10-propyl-4H, 6H-pyrano [3,2-g] quinoline -2,8-dicarboxylic acid.
Den ovennævnte bis-ester (2,5 g) blev tilbagesvalet med nat-riumbicarbonat (1,64 g) i ethanol (100 ml) og vand (50 ml) i 1½ time. Det hele blev hældt i vand og syrnet for at udfælde et gelati-nøst fast stof. Dette blev opsamlet ved filtrering og tilbagesvalet med ethanol, og produktet blev fraskilt ved centrifugering (1,4 g), smp, 303-304°C (dek.). Strukturen af produktet blev bekræftet ved masse- og NMR-spektre.The above bis ester (2.5 g) was refluxed with sodium bicarbonate (1.64 g) in ethanol (100 ml) and water (50 ml) for 1½ hours. The whole was poured into water and acidified to precipitate a gelatinous solid. This was collected by filtration and refluxed with ethanol and the product was separated by centrifugation (1.4 g), mp, 303-304 ° C (dec). The structure of the product was confirmed by mass and NMR spectra.
(h) Dinatrium-4,6-dioxo-10-propyl-4H,6H-pyrano[3,2-g]quinolin-2,8- dicarboxylat.(h) Disodium 4,6-dioxo-10-propyl-4H, 6H-pyrano [3,2-g] quinoline-2,8-dicarboxylate.
Bis-syren fra trin (g) (1,35 g) og natriumbicarbonat (0,661 g) i vand (150 ml) blev opvarmet og omrørt, indtil der forelå en klar opløsning. Denne opløsning blev filtreret, og filtratet blev frysetørret, hvorved vandtes 1,43 g af det ønskede dinatriumsalt.The bis acid from step (g) (1.35 g) and sodium bicarbonate (0.661 g) in water (150 ml) was heated and stirred until a clear solution was available. This solution was filtered and the filtrate was lyophilized to give 1.43 g of the desired disodium salt.
Analyse:Analysis:
Fundet: C: 46,1%, H: 4,0%, N: 2,9%Found: C: 46.1%, H: 4.0%, N: 2.9%
Beregnet for C17HllN07Na2'12'5% H20: C: 46'1%' H: 3'8%' N: 3,15%Calculated for C17H11NO7Na2'12'5% H2O: C: 46'1% 'H: 3'8%' N: 3.15%
Eksempel 2 4,6-Dioxo-9-ethyl~10-propyl-4H,6H-pyrano[3,2-g]quinolin-2,8-di-carboxylsyre.Example 2 4,6-Dioxo-9-ethyl ~ 10-propyl-4H, 6H-pyrano [3,2-g] quinoline-2,8-dicarboxylic acid.
(a) 4-(N-Acetyl-N-ethyl)amino-2-allyloxyacetophenon.(a) 4- (N-Acetyl-N-ethyl) amino-2-allyloxyacetophenone.
4-(N-Acetyl-N-ethyl)amino-2-hydroxyacetophenon (92,6 g), ally lbromid (51 ml) og vandfrit kaliumcarbonat (90,4 g) blev omrørt i tørt dimethylformamid (500 ml) i 17 timer. Reaktionsblandingen blev hældt i vand, og produktet blev ekstraheret med ether. Den organiske opløsning blev derefter vasket godt med vand, tørret over magnesiumsulfat og inddampet til tørhed. Produktet vandtes som en olie (102,5 g). Strukturen af produktet blev bekræftet ved NMR- og masse-4- (N-Acetyl-N-ethyl) amino-2-hydroxyacetophenone (92.6 g), allyl bromide (51 ml) and anhydrous potassium carbonate (90.4 g) were stirred in dry dimethylformamide (500 ml) for 17 hours. . The reaction mixture was poured into water and the product extracted with ether. The organic solution was then washed well with water, dried over magnesium sulfate and evaporated to dryness. The product was obtained as an oil (102.5 g). The structure of the product was confirmed by NMR and mass.
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18 spektroskop!.18 spectroscope !.
(b) 4-(N-Acetyl-N-ethyl)amino-3-propyl-2-hydroxyacetophenon.(b) 4- (N-Acetyl-N-ethyl) amino-3-propyl-2-hydroxyacetophenone.
Allylether-produktet fra trin (a) (100,5 g) blev tilbagesva-let i diethylanilin (300 ml) i 3 timer. Reaktionsblandingen blev afkølet og hældt i fortyndet saltsyre og ekstraheret over i ether, der blev vasket med fortyndet saltsyre og derefter med vand. Den organiske opløsning blev ekstraheret med 10% natriumhydroxidopløsning, der derefter blev syrnet. Det udfældede produkt blev ekstraheret med ether, der blev tørret over magnesiumsulfat. Den resulterende ether-opløsning blev inddampet til tørhed, hvorved vandtes en gulbrun olie (78,7 g). Denne olie var en blanding af 4-(N-acetyl-N-ethyl)amino- 3-allyl-2-hydroxyacetophenon og 6-(N-acetyl-N-ethyl)amino-3-allyl-2-hydroxyacetophenon.The allyl ether product of step (a) (100.5 g) was refluxed in diethylaniline (300 ml) for 3 hours. The reaction mixture was cooled and poured into dilute hydrochloric acid and extracted into ether which was washed with dilute hydrochloric acid and then with water. The organic solution was extracted with 10% sodium hydroxide solution which was then acidified. The precipitated product was extracted with ether which was dried over magnesium sulfate. The resulting ether solution was evaporated to dryness to give a tan oil (78.7 g). This oil was a mixture of 4- (N-acetyl-N-ethyl) amino-3-allyl-2-hydroxyacetophenone and 6- (N-acetyl-N-ethyl) amino-3-allyl-2-hydroxyacetophenone.
Denne blanding blev opløst i ethanol (500 ml) og iseddike (20 ml) og hydrogeneret i nærværelse af Adams-katalysator, indtil hydrogenoptagningen var ophørt. Katalysatoren blev frafiltreret gennem kiselgur, og filtratet blev inddampet, hvorved vandtes 79,9 g brun olie. Denne brune olie var en blanding og blev opdelt ved høj-tryks-væskechromatografi under anvendelse af ether/petroleumsether (1:1) som opløsningsmiddel, hvorved vandtes 44,2 g af undertitelproduktet og 23,8 g 6-(N-acetyl-N-ethyl)amino-3-propyl-2-hydroxyacetophenon.This mixture was dissolved in ethanol (500 ml) and glacial acetic acid (20 ml) and hydrogenated in the presence of Adams catalyst until hydrogen uptake was stopped. The catalyst was filtered through diatomaceous earth and the filtrate was evaporated to give 79.9 g of brown oil. This brown oil was a mixture and was partitioned by high pressure liquid chromatography using ether / petroleum ether (1: 1) as the solvent to give 44.2 g of the subtitle product and 23.8 g of 6- (N-acetyl-N -ethyl) amino-3-propyl-2-hydroxyacetophenone.
(c) 4-N-Ethylamino-3-propyl-2-hydroxyacetophenon.(c) 4-N-Ethylamino-3-propyl-2-hydroxyacetophenone.
4-(N-Acetyl-N-ethyl)amino-3-propyl-2-hydroxyacetophenon (44 g) blev tilbagesvalet i 48% hydrogenbromid i iseddike- (100 ml), iseddike (500 ml) og vand (20 ml) i 6 timer. Reaktionsblandingen blev hældt på is-vand og ekstraheret med ethylacetat, der blev vasket med vand, natriumbicarbonatopløsning, derefter igen med vand og tørret over magnesiumsulfat. Det organiske opløsningsmiddel blev af-dampet indtil tørhed, hvorved vandtes undertitel-forbindelsen som en rød olie (34 g). Strukturen blev bekræftet ved NMR- og masse-spektroskopi.4- (N-Acetyl-N-ethyl) amino-3-propyl-2-hydroxyacetophenone (44 g) was refluxed in 48% hydrogen bromide in glacial acetic acid (100 ml), glacial acetic acid (500 ml) and water (20 ml) in 6 hours. The reaction mixture was poured onto ice-water and extracted with ethyl acetate, washed with water, sodium bicarbonate solution, then again with water and dried over magnesium sulfate. The organic solvent was evaporated to dryness to give the subtitle compound as a red oil (34 g). The structure was confirmed by NMR and mass spectroscopy.
(d) Methyl-6-acetyl-l-ethyl-7-hydroxy-4-oxo-8-propyl-4H-quinolin-2-carboxylat.(d) Methyl 6-acetyl-1-ethyl-7-hydroxy-4-oxo-8-propyl-4H-quinoline-2-carboxylate.
Aminproduktet fra trin (c) (17 g) og dimethacetylendicarboxy-lat (11,3 ml) blev tilbagesvalet i ethanol (300 ml) i 17 timer. Reaktionsblandingen blev afkølet og inddampet til tørhed, hvorved vandtes en dybrød olie. Denne olie blev chromatograferet på en sili-The amine product of step (c) (17 g) and dimethacetylene dicarboxylate (11.3 ml) was refluxed in ethanol (300 ml) for 17 hours. The reaction mixture was cooled and evaporated to dryness to give a deep red oil. This oil was chromatographed on a silica gel.
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19 cagelsøjle under anvendelse af ether/petroleumsether (1:1) som eluent, hvorved vandtes 19,1 g dimethyl-l-(4-acetyl-3-hydroxy-2-propyl-phenyl)-N-ethylamino-maleat, smp. 83-87°C.19 column column using ether / petroleum ether (1: 1) as eluent to give 19.1 g of dimethyl-1- (4-acetyl-3-hydroxy-2-propyl-phenyl) -N-ethylamino maleate, m.p. 83-87 ° C.
Maleinsyreesteren (5 g) blev opvarmet og omrørt i polyphos-phorsyre (100 ml) på dampbad i 10 minutter. Reaktionsblandingen blev afkølet og hældt på en blanding af is-vand og ethylacetat. Den organiske opløsning blev fraskilt, vasket med vand og tørret over magnesiumsulfat. Opløsningsmidlet blev afdampet indtil tørhed, hvorved vandtes et bleggult fast stof. Dette produkt blev renset ved høj-tryks-væskechromatografi, hvorved vandtes 2,6 g af undertitel-forbindelsen, smp. 121-123°C.The maleic ester (5 g) was heated and stirred in polyphosphoric acid (100 ml) on a steam bath for 10 minutes. The reaction mixture was cooled and poured onto a mixture of ice-water and ethyl acetate. The organic solution was separated, washed with water and dried over magnesium sulfate. The solvent was evaporated to dryness to give a pale yellow solid. This product was purified by high-pressure liquid chromatography to give 2.6 g of the subtitle compound, m.p. 121-123 ° C.
Analyse:Analysis:
Fundet: C: 65,5%, H: 6,6%, N: 4,2%Found: C: 65.5%, H: 6.6%, N: 4.2%
Beregnet for ci8H21N05: C: 65,3%, H: 6,34%, N: 4,23%.Calcd for c18 H21 NO5: C: 65.3%, H: 6.34%, N: 4.23%.
Methyl-6-acetyl-l-ethyl-5-hydroxy-4-oxo-4H-quinolin-2-carbo-xylat vandtes fra rensningen som et bleggult fast stof (100 mg).Methyl 6-acetyl-1-ethyl-5-hydroxy-4-oxo-4H-quinoline-2-carboxylate was recovered from the purification as a pale yellow solid (100 mg).
(e) Diethyl-4,6-dioxo-9.-ethyl-10-propyl-4H,6H-pyrano[3,2-g]guinolin- 2,8-dicarboxylat.(e) Diethyl 4,6-dioxo-9-ethyl-10-propyl-4H, 6H-pyrano [3,2-g] guinoline-2,8-dicarboxylate.
Hydroxyketonproduktet fra trin (d) (1,0 g) og diethyloxalat (3,3 ml) i tørt dimethylformamid (25 ml) blev sat til ethervasket 50% natriumhydrid (0,581 g) i tørt dimethylformamid (20 ml), og reaktionsblandingen blev omrørt i 4 timer. Reaktionsblandingen blev derefter hældt i vand, syrnet og ekstraheret med ethylacetat, der derefter blev vasket med vand og tørret over magnesiumsulfat. Opløsningsmidlet blev afdampet indtil tørhed, hvorved vandtes en olie, der blev opløst i ethanol (100 ml), og koncentreret saltsyre (nogle få dråber) blev tilsat. Opløsningen blev tilbagesvalet i ½ time, afkølet, hældt i vand og ekstraheret med ethylacetat, der blev vasket med vand og tørret over magnesiumsulfat. Opløsningsmidlet blev afdampet indtil tørhed, hvorved vandtes en olie, der størknede ved rivning med 40-60° petroleumsether (1,2 g). Strukturen af forbindelsen blev bekræftet ved NMR.The hydroxyketone product of step (d) (1.0 g) and diethyl oxalate (3.3 ml) in dry dimethylformamide (25 ml) was added to ether washed 50% sodium hydride (0.581 g) in dry dimethylformamide (20 ml) and the reaction mixture was stirred. for 4 hours. The reaction mixture was then poured into water, acidified and extracted with ethyl acetate, then washed with water and dried over magnesium sulfate. The solvent was evaporated to dryness to give an oil which was dissolved in ethanol (100 ml) and concentrated hydrochloric acid (a few drops) added. The solution was refluxed for ½ hour, cooled, poured into water and extracted with ethyl acetate, washed with water and dried over magnesium sulfate. The solvent was evaporated to dryness to give an oil which solidified by grating with 40-60 ° petroleum ether (1.2 g). The structure of the compound was confirmed by NMR.
(f) 4,6-Dioxo-9.-ethyl-10-propyl-4H,6H-pyranO[3,2-g]quinolin-2,8-di-carboxylsyre.(f) 4,6-Dioxo-9-ethyl-10-propyl-4H, 6H-pyrano [3,2-g] quinoline-2,8-dicarboxylic acid.
Den ovennævnte bis-ester (1,0 g) og natriumbicarbonat (0,787 g) i ethanol (85 ml) og vand (32 ml) blev tilbagesvalet i 4 timer. Reaktionsblandingen blev hældt i vand og syrnet, og bundfaldet blev opsamlet ved filtrering og tørret. Produktet blev rensetThe above bis ester (1.0 g) and sodium bicarbonate (0.787 g) in ethanol (85 ml) and water (32 ml) were refluxed for 4 hours. The reaction mixture was poured into water and acidified, and the precipitate was collected by filtration and dried. The product was purified
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20 ved rivning med kogende ethanol, derefter to gange med kogende acetone. Efter hver rivning blev blandingen centrifugeret, og den overliggende væske blev fjernet ved dekantering. Det resterende faste stof blev tørret, hvorved vandtes 0,547 g af den ønskede disyre som et gult pulver, smp. 298-300°C (dek.).20 by grating with boiling ethanol, then twice with boiling acetone. After each grating, the mixture was centrifuged and the supernatant removed by decantation. The residual solid was dried to give 0.547 g of the desired diacid as a yellow powder, m.p. 298-300 ° C (dec.).
Analyse:Analysis:
Fundet: C: 61,3%, H: 5,0%, N: 3,6%Found: C: 61.3%, H: 5.0%, N: 3.6%
Beregnet for C^gH^NO^: C: 61,5%, H: 4,6%, N: 3,79%.Calculated for C C ^HHNO ^: C: 61.5%, H: 4.6%, N: 3.79%.
(g) Dinatrium-4,6-dioxo-9.-ethyl-10-propyl-4H,6H-pyrano [3,2-g] quino-lin-2,8-dicarboxylat.(g) Disodium 4,6-dioxo-9-ethyl-10-propyl-4H, 6H-pyrano [3,2-g] quinoline-2,8-dicarboxylate.
Den ovennævnte disyre (4,098 g) blev suspenderet i vand (100 ml) og behandlet med natriumbicarbonat (1,82 g). Den resulterende opløsning blev filtreret, og filtratet blev behandlet med acetone, indtil fuldstændig udfældning af produktet havde fundet sted.The above diacid (4.098 g) was suspended in water (100 ml) and treated with sodium bicarbonate (1.82 g). The resulting solution was filtered and the filtrate was treated with acetone until complete precipitation of the product had taken place.
Det ønskede dinatriumsalt blev frafiltreret og tørret, hvorved vandtes 3,39 g af et bleggult pulver.The desired disodium salt was filtered off and dried to yield 3.39 g of a pale yellow powder.
Analyse:Analysis:
Fundet: C: 51,1%, H: 4,3%, N: 3,0%Found: C: 51.1%, H: 4.3%, N: 3.0%
Beregnet for C19H15NNa2°7 (6'9% vand):C: 51,1%, H: 4,1%, N: 3,1%.Calcd for C 19 H 15 NN 2 O 7 (6'9% water): C: 51.1%, H: 4.1%, N: 3.1%.
Eksempel 3Example 3
De følgende forbindelser er også fremstillet ved de ovenfor beskrevne fremgangsmåder: (i) 6,9-Dihydro-4,9-dioxo-4H-pyrano[2,3-qJquinolin-2,7-dicarboxyl-syre NMR: delta (DMS0), 6,6(1H,s), 6,9(1H,s), 7,6(1H,s), 8,6 (1H, s) .The following compounds are also prepared by the procedures described above: (i) 6,9-Dihydro-4,9-dioxo-4H-pyrano [2,3-q] quinoline-2,7-dicarboxylic acid NMR: delta (DMSO) , 6.6 (1H, s), 6.9 (1H, s), 7.6 (1H, s), 8.6 (1H, s).
(ii) 9-(3-Methylbutyl)-4,6-dioxo-4H,6H-pyrano(3,2-g]-quinolin-2,8-dicarboxylsyre, smp. 302-304eC (dek.).(ii) 9- (3-Methylbutyl) -4,6-dioxo-4H, 6H-pyrano (3,2-g] -quinoline-2,8-dicarboxylic acid, mp 302-304 ° C (dec).
( iii) 10-Methyl-4,6-dioxo-4H,6H-pyrano [3,2-g]quåmolin-2,8-dicarboxylsyre, smp. 302°C.(iii) 10-Methyl-4,6-dioxo-4H, 6H-pyrano [3,2-g] quinoline-2,8-dicarboxylic acid, m.p. 302 ° C.
(iv) 4,6-Dioxo-10-propyl-4H,6H-pyrano[3,2-g]quinolin- 2,8-dicarboxylsyre. Diethylester har smp. 211-212eC.(iv) 4,6-Dioxo-10-propyl-4H, 6H-pyrano [3,2-g] quinoline-2,8-dicarboxylic acid. Diethyl ester has m.p. 211-212eC.
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2121
Eksempel 4 9-Ethyl-6,9-dihydro-4,e-dioxo-lQ-propylT^H-pyrano [ 3, 2-g] quinolin-2,8-dicarboxylsyre.Example 4 9-Ethyl-6,9-dihydro-4,4-dioxo-1Q-propylTH-pyrano [3,2-g] quinoline-2,8-dicarboxylic acid.
(a) 6-Acetyl-l-ethyl-l, 4-dihydro—7-hydroxy-4-oxo-9-pro-pylquinolin-2-carboxylsyre.(a) 6-Acetyl-1-ethyl-1,4-dihydro-7-hydroxy-4-oxo-9-propylquinoline-2-carboxylic acid.
Methyl-6-acetyl-l-ethyl-l, 4-dihydro-7-hydroxy-4-oxo-8-propylquinolin-2-carboxylat (20 gi blev opvarmet under tilbagesvaling i iseddike (150 ml) indeholden de 48% vandig HBr (20 ml). Efter 18 timer blev blandingen afkølet og hældt i vand. Ammoniak blev tilsat indtil pH 3. Bundfaldet blev indsamlet og tørret i vakuum og blev identificeret som undertitelforbindelsen (14,3 g) ved NMR og massespektroskopi.Methyl 6-acetyl-1-ethyl-1,4-dihydro-7-hydroxy-4-oxo-8-propylquinoline-2-carboxylate (20 µl was heated under reflux in glacial acetic acid (150 ml) containing the 48% aqueous HBr (20 ml) After 18 hours the mixture was cooled and poured into water, ammonia was added until pH 3. The precipitate was collected and dried in vacuo and identified as the subtitle compound (14.3 g) by NMR and mass spectroscopy.
(b) 2-Ethoxycarbonyl-9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano[3,2-g]quinolin-8-carboxylsyre.(b) 2-Ethoxycarbonyl-9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano [3,2-g] quinoline-8-carboxylic acid.
Produktet fra trin (a) (14,2 g) blev sat til en opløsning af natrium (5,2 g) i ethanol (200 ml), og derefter blev der tilsat diethyloxalat (16 g). Blandingen blev opvarmet under tilbagesvaling i 5 timer og derefter afkølet og hældt i chloroform (1 liter). Blandingen blev rystet med fortyndet saltsyre (150 ml), og derefter blev den organiske fase tørret og inddampet i vakuum. Inddamp-ningsresten blev opløst i ethanol (200 ml) indeholdende koncentreret saltsyre (2 ml) og tilbagesvalet i 18 timer. Opløsningsmidlet blev fordampet, og inddampningsresten blev omkrystalliseret af ethanol, hvorved vandtes undere titelforbindelsen (3,2 g). Strukturen blev bekræftet ved NMR og massespektroskopi.The product of step (a) (14.2 g) was added to a solution of sodium (5.2 g) in ethanol (200 ml) and then diethyl oxalate (16 g) was added. The mixture was heated at reflux for 5 hours and then cooled and poured into chloroform (1 liter). The mixture was shaken with dilute hydrochloric acid (150 ml) and then the organic phase was dried and evaporated in vacuo. The residue was dissolved in ethanol (200 ml) containing concentrated hydrochloric acid (2 ml) and refluxed for 18 hours. The solvent was evaporated and the residue was recrystallized from ethanol to give the title compound (3.2 g). The structure was confirmed by NMR and mass spectroscopy.
(c) 9-Ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano [3,2-g]quinolin-2,8-dicarboxylsyre,(c) 9-Ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano [3,2-g] quinoline-2,8-dicarboxylic acid,
Produktet fra trin (b) blev hydrolyseret ved fremgangsmåden fra trin (a), hvorved vandtes et produkt (1,1 g), der ved sammenligning ved tyndtlagschromatografi viste sig identisk med produktet fra Eksempel 2.The product of step (b) was hydrolyzed by the process of step (a) to give a product (1.1 g) which, by comparison by thin layer chromatography, was identical to the product of Example 2.
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Eksempel 5 9-Ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano [3,2-g] quinolin-2,8-dicarboxylsyre.Example 5 9-Ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano [3,2-g] quinoline-2,8-dicarboxylic acid.
(a) Methyl-9-ethyl-6,9-dihydro-2-methyl-4,6-dioxo-10-propyl-4H-pyrano[3,2-g]quinolin-8-carboxylat.(a) Methyl 9-ethyl-6,9-dihydro-2-methyl-4,6-dioxo-10-propyl-4H-pyrano [3,2-g] quinoline-8-carboxylate.
6-Acetyl-l-ethyl-7-hydroxy-4 (IH) -oxo-8-propylqui-nolin-2-carboxylsyre (3,15 g) blev opløst i tørt dime-thylformamid (50 ml) indeholdende vasket natriumhydrid (1,05 g), og derefter indførtes ethylacetat (4,4 g). Efter omrøring natten over blev luftformigt hydrogenchlorid under isafkøling ledt ind i blandingen indtil mætning. Blandingen blev opvarmet til 75°C i 8 timer, derefter afkølet og hældt i vand, og blandingen blev ekstraheret med ethylacetat. Den organiske fase blev tørret og inddampet, og inddampningsresten blev chromatograferet (SiC^/ethylacetat), hvorved vandtes undertitelforbindelsen (0,8 g). Strukturen blev bekræftet ved NMR og masse-spektroskopi.6-Acetyl-1-ethyl-7-hydroxy-4 (1H) -oxo-8-propylquinoline-2-carboxylic acid (3.15 g) was dissolved in dry dimethylformamide (50 ml) containing washed sodium hydride (1 (05 g) and then ethyl acetate (4.4 g) was introduced. After stirring overnight, gaseous hydrogen chloride, under ice-cooling, was introduced into the mixture until saturation. The mixture was heated to 75 ° C for 8 hours, then cooled and poured into water and extracted with ethyl acetate. The organic phase was dried and evaporated and the residue was chromatographed (SiC 2 / ethyl acetate) to give the subtitle compound (0.8 g). The structure was confirmed by NMR and mass spectroscopy.
(b) 9-Ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano [3,2-g]quinolin-2,8-dicarboxylsyre.(b) 9-Ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano [3,2-g] quinoline-2,8-dicarboxylic acid.
Produktet fra trin (a) (0,75 g) blev opvarmet under tilbagesvaling med selendioxid (1,5 g) i iseddike.The product of step (a) (0.75 g) was heated under reflux with selenium dioxide (1.5 g) in glacial acetic acid.
(50 ml) i 48 timer. Filtrering gennem "Celite" gav et klart filtrat, der blev behandlet med koncentreret saltsyre (25 ml) og opvarmet under tilbagesvaling i 12 timer.(50 ml) for 48 hours. Filtration through "Celite" gave a clear filtrate which was treated with concentrated hydrochloric acid (25 ml) and heated at reflux for 12 hours.
Ved afkøling og udhældning i vand vandtes et bundfald (0,1 g), der ved sammenligning ved tyndtlagschromatografi viste sig identisk med produktet fra Eksempel 2.Upon cooling and pouring into water, a precipitate (0.1 g) was obtained which, when compared by thin layer chromatography, proved identical to the product of Example 2.
Eksempel 6 9-Ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano[3,2-g] quinolin-2,8-dicarboxylsyre.Example 6 9-Ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano [3,2-g] quinoline-2,8-dicarboxylic acid.
(a) N-[3-(1,2-dicarboxyethenyloxy)-2-propylphenyl]-N-ethyl-2-amino-but-2-en-l,4-dionsyre.(a) N- [3- (1,2-dicarboxyethenyloxy) -2-propylphenyl] -N-ethyl-2-amino-but-2-ene-1,4-dione acid.
3-Ethylamino-2-propylphenol (17,9 g), dimethylace-tylendicarboxylat (35 g), kaliumhydroxid (0,56 g), vand (50 ml) og ethanol (100 ml) blev opvarmet under tilbagesvaling i 24 timer. Kaliumhydroxid (1,65 g) blev tilsat, og tilbagesvaling blev fortsat i yderligere 24 timer.3-Ethylamino-2-propylphenol (17.9 g), dimethylacetylenedicarboxylate (35 g), potassium hydroxide (0.56 g), water (50 ml) and ethanol (100 ml) were heated at reflux for 24 hours. Potassium hydroxide (1.65 g) was added and reflux continued for a further 24 hours.
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2323
Koncentreret saltsyre (4 ml) blev tilsat, og opløsningsmidlet blev fordampet. Inddampningsresten blev tørret i vakuum og ekstraheret over i ether. Etheren blev fordampet, hvorved vandtes undertitelforbindelsen (3,6 g).Concentrated hydrochloric acid (4 ml) was added and the solvent was evaporated. The residue was dried in vacuo and extracted into ether. The ether was evaporated to give the subtitle compound (3.6 g).
Strukturen blev bekræftet ved NMR og massespektroskopi.The structure was confirmed by NMR and mass spectroscopy.
(b) 9-Ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano [3,2-g]quinolin-2,8-dicarboxylsyre.(b) 9-Ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano [3,2-g] quinoline-2,8-dicarboxylic acid.
iin
Produktet fra trin (a) (3,55 g) blev i små portioner under omrøring sat til chlorsulfonsyre (100 ml) afkølet til -78eC. Opløsningen fik lov til langsomt at opvarme til stuetemperatur og blev derefter opvarmet til 50eC i 1 time. Reaktionsblandingen blev forsigtigt hældt på is (1 liter) og ekstraheret over i ethylacetat. Efter tørring blev ethylacetatet fordampet, og inddampningsresten blev separeret ved højtryksvæskechromatografi, hvorved vandtes titelforbindelsen (0,2 g), der chromatografisk var identisk med produktet fra Eksempel 2.The product of step (a) (3.55 g) was added in small portions with stirring to chlorosulfonic acid (100 ml) cooled to -78 ° C. The solution was allowed to slowly warm to room temperature and then heated to 50 ° C for 1 hour. The reaction mixture was gently poured onto ice (1 liter) and extracted into ethyl acetate. After drying, the ethyl acetate was evaporated and the residue was separated by high-pressure liquid chromatography to give the title compound (0.2 g), which was chromatographically identical to the product of Example 2.
Eksempel 7 9-Ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano[3,2-g] quinolin-2,8-dicarboxylsyre.Example 7 9-Ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano [3,2-g] quinoline-2,8-dicarboxylic acid.
(a) l-Ethyl-6-(3-carboxy-3-diethylamino-l-oxo-prop-2-enyl)-1,4-dihydro-7-hydroxy-4-oxo-8-propylquinolin- 2-carboxylsyre.(a) 1-Ethyl-6- (3-carboxy-3-diethylamino-1-oxo-prop-2-enyl) -1,4-dihydro-7-hydroxy-4-oxo-8-propylquinoline-2-carboxylic acid .
9-Ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano [3,2-g]quinolin-2,8-dicarboxylsyre (1 g) og diethylamin (5 ml) blev opvarmet sammen i en autoklav i 12 timer ved 100°C, hvorefter de flygtige materialer blev fordampet ved 60°C. Inddampningsresten blev tritureret med ether, hvorved vandtes undertitelforbindelsen (0,78 g). Strukturen blev bekræftet ved NMR og massespektroskopi.9-Ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano [3,2-g] quinoline-2,8-dicarboxylic acid (1 g) and diethylamine (5 ml) were heated together in an autoclave for 12 hours at 100 ° C, after which the volatiles were evaporated at 60 ° C. The residue was triturated with ether to give the subtitle compound (0.78 g). The structure was confirmed by NMR and mass spectroscopy.
(b) 9-Ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano [3,2-g]quinolin-2,8-dicarboxylsyre.(b) 9-Ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano [3,2-g] quinoline-2,8-dicarboxylic acid.
Produktet fra trin (a) (0,77 g) blev suspenderet i ethanolisk hydrogenchlorid (20 ml) og opvarmet under tilbagesvaling i 24 timer. Fordampning af opløsningsmidlet gav en inddampningsrest, der blev separeret ved højtryksvæskechromatografi, hvorved vandtes titelforbindelsenThe product of step (a) (0.77 g) was suspended in ethanolic hydrogen chloride (20 ml) and heated under reflux for 24 hours. Evaporation of the solvent gave an evaporation residue which was separated by high pressure liquid chromatography to give the title compound
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24 (.0,2 g), der chroma tografisk var identisk med produktet fra Eksempel 2.24 (.0.2 g) which was chromatographically identical to the product of Example 2.
Eksempel 8 9-Ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano[3,2-g] guinolin-2,8-dicarboxylsyre.Example 8 9-Ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano [3,2-g] guinoline-2,8-dicarboxylic acid.
(a) Diethyl-9-ethyl-6,9-dihydro-10-propyl-4,6-dithioxo-4H-pyrano[3,2-g]guinolin-2,8-dicarboxylat.(a) Diethyl 9-ethyl-6,9-dihydro-10-propyl-4,6-dithioxo-4H-pyrano [3,2-g] guinoline-2,8-dicarboxylate.
Diethyl-9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano[3,2-g]guinolin-2,8-dicarboxylat (10 g) og pen-taphosphordecasulfid (20 g) blev sammensmeltet ved 160“C i 6 timer og derefter afkølet, og produktblandingen blev ekstraheret over i ethylacetat. Chromatografi (silicagel/ ethylacetat) gav undertitelforbindelsen (5,6 gi. Struktur-ren blev bekræftet ved NMR og massespektroskopi.Diethyl 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano [3,2-g] guinoline-2,8-dicarboxylate (10 g) and pen-taphosphorus decasulfide (20 g ) was fused at 160 ° C for 6 hours and then cooled, and the product mixture was extracted into ethyl acetate. Chromatography (silica gel / ethyl acetate) afforded the subtitle compound (5.6 g. The structure was confirmed by NMR and mass spectroscopy.
(b) 9-Ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano [3,2-g]guinolin-2,8-dicarboxylsyre,(b) 9-Ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano [3,2-g] guinoline-2,8-dicarboxylic acid,
Diesteren fra trin (al blev opvarmet ved 100“C i iseddike (50 ml) indeholdende koncentreret saltsyre (5 ml) i 24 timer. Eddikesyreopløsningsmidlet blev fordampet, og inddampningsresten blev tritureret med ether.The diester from step (al was heated at 100 ° C in glacial acetic acid (50 ml) containing concentrated hydrochloric acid (5 ml) for 24 hours. The acetic acid solvent was evaporated and the residue was triturated with ether.
Den faste rest blev opløst i acetonitril (50 ml) indeholdende vand (1 ml) og blev omrørt kraftigt med mercuri-chlorid (2 g), Efter 48 timer blev opløsningen filtreret, og filtratet blev fortyndet med vand (250 ml) og derefter syrnet. Det udfældede faste stof blev renset ved høj-tryksvæskechromatografi, hvorved vandtes titelforbindelsen (2,1 g), der chromatografisk var identisk med produktet fra Eksempel 2.The solid residue was dissolved in acetonitrile (50 ml) containing water (1 ml) and stirred vigorously with mercuric chloride (2 g). After 48 hours the solution was filtered and the filtrate was diluted with water (250 ml) and then acidified. . The precipitated solid was purified by high-pressure liquid chromatography to give the title compound (2.1 g), which was chromatographically identical to the product of Example 2.
Eksempel 9 9-Ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano[3,2-g] guinolin-2,8-dicarboxylsyre.Example 9 9-Ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano [3,2-g] guinoline-2,8-dicarboxylic acid.
(a) 9-Ethyl-2,3,6,9-tetrahydro-4,6-dioxo-10-propyl-4H-pyrano[3,2-g]guinolin-2,8-dicarboxylsyre.(a) 9-Ethyl-2,3,6,9-tetrahydro-4,6-dioxo-10-propyl-4H-pyrano [3,2-g] guinoline-2,8-dicarboxylic acid.
Diethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano [3,2-g]guinolin-2,8-dicarboxylat (5 g) i iseddike (100 ml) blev hydrogeneret over Adams katalysator (0,5 g) ved 4 atmosfærer, indtil hydrogenoptagningen ophørte. Ka-Diethyl 6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano [3,2-g] guinoline-2,8-dicarboxylate (5 g) in glacial acetic acid (100 ml) was hydrogenated over Adams catalyst (0.5 g) at 4 atmospheres until hydrogen uptake ceased. Ka
DK 158266 BDK 158266 B
25 talysatoren blev fjernet/ og koncentreret saltsyre (5 ml) blev tilsat. Opløsningen blev tilbagesvalet i 24 timer og derefter inddampet. Højtryksvæskechromatografi af inddampningsresten gav undertitelforbindelsen (0,9 g).The talysator was removed / and concentrated hydrochloric acid (5 ml) was added. The solution was refluxed for 24 hours and then evaporated. High pressure liquid chromatography of the evaporation residue gave the subtitle compound (0.9 g).
Strukturen blev bekræftet ved NMR og massespektroskopi.The structure was confirmed by NMR and mass spectroscopy.
(b) 9-Ethyl-6/9-dihydro-4,6-dioxo-10-propyl-4H-pyrano [3/2-g]quinolin-2,8-dicarboxylsyre.(b) 9-Ethyl-6/9-dihydro-4,6-dioxo-10-propyl-4H-pyrano [3/2-g] quinoline-2,8-dicarboxylic acid.
Produktet fra trin (a) (0,85 g) blev suspenderet i cymen (10 ml) og behandlet med 10% Pd/C-katalysator ved tilbagesvaling i 6 timer. Filtrering og inddampning gav en gummi, der blev renset ved højtryksvæskechromatografi, hvorved vandtes titelforbindelsen (0,15 g), der chroma -tografisk var identisk med produktet fra Eksempel 2.The product of step (a) (0.85 g) was suspended in cymene (10 ml) and treated with 10% Pd / C catalyst at reflux for 6 hours. Filtration and evaporation gave a gum which was purified by high pressure liquid chromatography to give the title compound (0.15 g) which was chromatographically identical to the product of Example 2.
Eksempel 10 9-Ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano[3,2-g] quinolin-2,8-dicarboxylsyre.Example 10 9-Ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano [3,2-g] quinoline-2,8-dicarboxylic acid.
(a) l-Ethyl-l,4-dihydro-7-hydroxy-6-methoxycarbonyl-4-oxo-8-propylquinolin-2-carboxylsyre.(a) 1-Ethyl-1,4-dihydro-7-hydroxy-6-methoxycarbonyl-4-oxo-8-propylquinoline-2-carboxylic acid.
Diethyl-9-ethyl-6,8-dihydro-4,6-dioxo-10-propyl-4H-pyranot3,2-g]quinolin-2,8-dicarboxylat (4,27 g) og natriumhydroxid (1,6 g) i vand (10 ml) blev opvarmet til tilbagesvaling i 24 timer, hvorefter vandet blev fordampet, og inddampningsresten blev suspenderet i ethanol (50 ml) mættet med luftformigt hydrogenchlorid og tilbagesvalet i 1 time. Fordampning af opløsningsmidlet gav en rest, der blev chromatograferet (silicagel/ether), hvorved vandtes en diester (1,3 g), der blev kogt med en opløsning af natriumhydroxid (0,139 g) i vand (20 ml). Ved syrning dannedes et bundfald, der ved NMR og massespektroskopi blev påvist at være det ønskede produkt (0,93 g).Diethyl 9-ethyl-6,8-dihydro-4,6-dioxo-10-propyl-4H-pyranot3,2-g] quinoline-2,8-dicarboxylate (4.27 g) and sodium hydroxide (1.6 g ) in water (10 ml) was heated to reflux for 24 hours, then the water was evaporated and the residue was suspended in ethanol (50 ml) saturated with gaseous hydrogen chloride and refluxed for 1 hour. Evaporation of the solvent gave a residue which was chromatographed (silica gel / ether) to give a diester (1.3 g) which was boiled with a solution of sodium hydroxide (0.139 g) in water (20 ml). Upon acidification, a precipitate formed which by NMR and mass spectroscopy was shown to be the desired product (0.93 g).
(b) 9-Ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano [3,2-g.] quinolin-2,8-dicarboxylsyre.(b) 9-Ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano [3,2-g.] quinoline-2,8-dicarboxylic acid.
Produktet fra trin (a) (0,9 g) opløst i tørt dime- thylsulfoxid (10 ml) blev sat til en opløsning af dimsyl-natrium (1 g) i tørt dimethylsulfoxid (50 ml) ved 40“C under N2· Efter 48 timer blev reaktionsblandingen hældt i vand (500 ml) og etherekstraheret. Tørring og inddampningThe product of step (a) (0.9 g) dissolved in dry dimethyl sulfoxide (10 ml) was added to a solution of dimsyl sodium (1 g) in dry dimethyl sulfoxide (50 ml) at 40 ° C under N 2 · After For 48 hours, the reaction mixture was poured into water (500 mL) and extracted. Drying and evaporation
Claims (10)
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GB1859777 | 1977-05-04 | ||
GB1859777 | 1977-05-04 | ||
GB4586577 | 1977-11-04 | ||
GB4586577 | 1977-11-04 |
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DK190178A DK190178A (en) | 1978-11-05 |
DK158266B true DK158266B (en) | 1990-04-23 |
DK158266C DK158266C (en) | 1990-10-08 |
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DK190178A DK158266C (en) | 1977-05-04 | 1978-05-02 | METHOD OF ANALOGY FOR PREPARATION OF PYRANOQUINOLINON DERIVATIVES |
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JP (2) | JPS53137969A (en) |
AU (1) | AU520816B2 (en) |
CA (1) | CA1112644A (en) |
CH (1) | CH634071A5 (en) |
DE (1) | DE2819215A1 (en) |
DK (1) | DK158266C (en) |
ES (1) | ES469391A1 (en) |
FR (1) | FR2389627B1 (en) |
IE (1) | IE47051B1 (en) |
IL (2) | IL54614A (en) |
IT (1) | IT1158699B (en) |
LU (2) | LU79579A1 (en) |
NL (2) | NL184896C (en) |
NO (1) | NO154497C (en) |
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FR2440371A1 (en) * | 1978-10-31 | 1980-05-30 | Fisons Ltd | NOVEL HETEROCYCLIC NITROGEN COMPOUNDS, PHARMACEUTICAL COMPOSITIONS CONTAINING SAME AND METHODS FOR PREPARING THE SAME |
EP0030423B1 (en) * | 1979-12-07 | 1985-02-13 | FISONS plc | A process for the production of 1,4-dihydro-4-oxo-quinoline-2-carboxylic acids, or salts, esters or amides thereof and intermediates therefor |
EP0162556B1 (en) * | 1984-04-13 | 1991-11-06 | FISONS plc | Novels forms and formulations of nedocromil sodium |
ES2058129T3 (en) * | 1986-12-23 | 1994-11-01 | Fisons Plc | PHARMACEUTICAL COMPOSITIONS INCLUDING AN AQUEOUS SOLUTION OF A PYRANOQUINOLINE DERIVATIVE. |
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FR2054503A1 (en) * | 1969-07-18 | 1971-04-23 | Bellon Labor Sa Roger | 1, 4-dihydro-4-oxo quinolyl-3-carboxylic aci |
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1978
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- 1978-05-02 JP JP5240778A patent/JPS53137969A/en active Granted
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- 1978-05-03 NL NLAANVRAGE7804749,A patent/NL184896C/en not_active IP Right Cessation
- 1978-05-03 CH CH482978A patent/CH634071A5/en not_active IP Right Cessation
- 1978-05-03 LU LU79579A patent/LU79579A1/en unknown
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1980
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1986
- 1986-06-02 SE SE8602492A patent/SE463920B/en not_active IP Right Cessation
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1988
- 1988-12-22 JP JP63322239A patent/JPH01199909A/en active Pending
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