DK172034B1 - 4-OH-quinoline carboxylic acid derivatives, their preparation, intermediates in their preparation, and drugs containing them - Google Patents
4-OH-quinoline carboxylic acid derivatives, their preparation, intermediates in their preparation, and drugs containing them Download PDFInfo
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- 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
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- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
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Abstract
Description
DK 172034 B1DK 172034 B1
BeskrivelseDescription
Opfindelsen angår hidtil ukendte 4-OH-quinolincarboxylsyrederivater, som er substituerede i 2-stillingen, en fremgangsmåde til deres fremstilling, hidtil ukendte mellemprodukter samt et 5 lægemiddel og farmaceutiske præparationer med indhold deraf.This invention relates to novel 4-OH-quinoline carboxylic acid derivatives substituted at the 2-position, to a process for their preparation, to novel intermediates and to a drug and pharmaceutical preparations containing them.
Opfindelsen angår forbindelserne med formlen I samt syre- og baseadditionssaltene derafThe invention relates to the compounds of formula I as well as the acid and base addition salts thereof
OHOH
10 ^0°NH-R1 i ch _r4 or2 or3 15 hvor X i stillingen 5,6, 7 eller 8 betegner et brintatom, et halogenatom, en lineær eller forgrenet alkylgruppe med 1-5 kulstofatomer, en lineær eller forgrenet alkoxygruppe med 1-4 kulstofatomer eller en trifluormethylgruppe, betegner en thiazolylgruppe, en 4,5-dihydrothiazolylgruppe eller en phenylgruppe, R2 og R3, som kan være ens eller forskellige, 20 betegner et brintatom, en alkylgruppe med 1 -4 kulstofatomer eller en gruppe -C-R5, hvor R510 x 0 ° NH-R1 in ch 4 or 2 or 3 where X at the position 5,6, 7 or 8 represents a hydrogen atom, a halogen atom, a linear or branched alkyl group having 1-5 carbon atoms, a linear or branched alkoxy group having 1 4 carbon atoms or a trifluoromethyl group, represents a thiazolyl group, a 4,5-dihydrothiazolyl group or a phenyl group, R 2 and R 3, which may be the same or different, 20 represents a hydrogen atom, an alkyl group having 1 -4 carbon atoms or a group-C-R 5 , where R5
OISLAND
betegner en alkylgruppe med 1-4 kulstofatomer, eller R2 og R3 danner tilsammen en acetonidgruppe, og R4 betegner et brintatom eller en alkylgruppe med 1-4 kulstofatomer.represents an alkyl group of 1-4 carbon atoms, or R 2 and R 3 together form an acetonide group and R 4 represents a hydrogen atom or an alkyl group of 1-4 carbon atoms.
25 Når X betegner et halogenatom, drejer det sig fortrinsvis om et chloratom.When X represents a halogen atom, it is preferably a chlorine atom.
Når X betegner en alkylgruppe, drejer det sig fortrinsvis om methyl, ethyl, n-propyl, n-butyl, n-pentyl, isopropyl eller isobutyl.When X represents an alkyl group, it is preferably methyl, ethyl, n-propyl, n-butyl, n-pentyl, isopropyl or isobutyl.
30 Når X betegner en alkoxygruppe, drejer det sig fortrinsvis om methoxy, ethoxy eller n-propoxy.When X represents an alkoxy group, it is preferably methoxy, ethoxy or n-propoxy.
Når R2 eller R3 eller R4 betegner en alkylgruppe, drejer det sig fortrinsvis om methyl, ethyl, propyl, isopropyl, butyl eller isobutyl.When R 2 or R 3 or R 4 represents an alkyl group, it is preferably methyl, ethyl, propyl, isopropyl, butyl or isobutyl.
35 Når R2 og R3 betegner en gruppe -C-R5 ,When R2 and R3 represent a group -C-R5,
OISLAND
så er R5 fortrinsvis methyl, ethyl, n-propyl eller phenyl.then R 5 is preferably methyl, ethyl, n-propyl or phenyl.
2 DK 172034 B12 DK 172034 B1
Blandt additionssaltene med syrer kan man nævne sådanne, som dannes med uorganiske syrer, såsom saltsyre, hydrogenbromidsyre, svovlsyre eller fosforsyre, eller som dannes med sulfonsyrer såsom alkyl- eller arylsulfonsyrer, f.eks. methansulfonsyre eller p-toluensulfonsyre.Among the addition salts with acids are those formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid, or which are formed with sulfonic acids such as alkyl or arylsulfonic acids, e.g. methanesulfonic acid or p-toluenesulfonic acid.
5 Blandt additionssaltene med baser kan nævnes sådanne, som dannes med alkalimetaller som natrium og kalium samt aminer, f.eks. trimethylamin eller dimethylamin.Among the addition salts with bases are those formed with alkali metals such as sodium and potassium as well as amines, e.g. trimethylamine or dimethylamine.
Opfindelsen angår især de forbindelser, hvor X er i 8-stillingen, samt deres additionssalte med syrer og baser og sådanne, hvor X betegner en trifluormethylgruppe, samt deres additionssalte 10 med syrer og baser.The invention relates in particular to those compounds where X is in the 8-position, as well as their addition salts with acids and bases and those where X represents a trifluoromethyl group, as well as their addition salts 10 with acids and bases.
Opfindelsen angår også de forbindelser, hvor X er i 7-stillingen og betegner et chloratom, samt deres additionssalte med syrer og baser.The invention also relates to the compounds where X is in the 7-position and represents a chlorine atom, as well as their addition salts with acids and bases.
15 Opfindelsen angår især de forbindelser, hvor R-; betegner thiazolyl, samt deres additionssalte med syrer og baser og sådanne, hvor R2 og R3 betegner et brintatom, og R4 betegner et brintatom, en alkylgruppe med 1-4 kulstofatomer samt deres additionssalte med syrer og baser.The invention relates in particular to those compounds wherein R-; represents thiazolyl, as well as their addition salts with acids and bases and those wherein R 2 and R 3 represent a hydrogen atom and R 4 represents a hydrogen atom, an alkyl group of 1-4 carbon atoms, and their addition salts with acids and bases.
Især skal nævnes de forbindelser, som er beskrevet i eksemplerne, specielt: 20 - 2 - (1,2-dihydroxyethyl) - 4 - hydroxy - N - (2-thiazolyl) - 8 - trifluormethyl - 3 - quinolincarboxamid samt dets additionssalte med syrer og baser, 2 - (1,2-dihydroxypropyl) - 4 - hydroxy N - (2-thiazolyl) - 8 - trifluormethyl - 3 -quinolincarboxamid samt dets additionssalte med syrer og baser, 2 - (1,2-bis-(1-oxopropoxy)-ethyl) - 4 - hydroxy - N - (2-thiazolyl) - 8 - trifluormethyl - 3 -25 quinolincarboxamid samt dets additionssalte med syrer og baser.In particular, the compounds described in the Examples should be mentioned in particular: 20 - 2 - (1,2-dihydroxyethyl) - 4 - hydroxy - N - (2-thiazolyl) - 8 - trifluoromethyl - 3 - quinoline carboxamide and its addition salts with acids and bases, 2- (1,2-dihydroxypropyl) -4-hydroxy N - (2-thiazolyl) -8-trifluoromethyl-3-quinoline carboxamide and its addition salts with acids and bases, 2- (1,2-bis- (1) -oxopropoxy-ethyl) -4-hydroxy-N - (2-thiazolyl) -8-trifluoromethyl-3-quinoline carboxamide and its addition salts with acids and bases.
Opfindelsen angår ligeledes fremgangsmåder til fremstilling af forbindelserne med formlen I, entenThe invention also relates to processes for preparing the compounds of formula I, either
a) forbindelsen II(a) compound II
30 a x λ i i j X· r4 35 hvor X og R4 har samme betydning som ovenfor, R'3 betegner en alkylgruppe med 1-4 kulstofatomer og X’ betegner et halogenatom, reagerer med - enten med en forbindelse med formlen lll^ 3 DK 172034 B1Wherein X and R4 have the same meaning as above, R'3 represents an alkyl group having 1-4 carbon atoms and X 'represents a halogen atom, reacting with - or with a compound of formula II B1
CH3-CONH-R-1 lllACH3-CONH-R-11llA
hvor har samme betydning som ovenfor, til opnåelse af en forbindelse med formlen IVwhere has the same meaning as above, to obtain a compound of formula IV
5 . XOCH--CONH-R..5. XOCH - CONH-R ..
fYfY
nh-c-ch-ch-or.4 lv v II I I 3 Λ O X' R4 10 - eller i nærværelse af en base med formlen lllø RO-C-CH--C-NH-R,nh-c-ch-ch-or.4 lv v II I I 3 Λ O X 'R4 10 - or in the presence of a base of formula IIo RO-C-CH - C-NH-R,
,5 II II, 5 II II
o oIsland Island
hvor R-j har samme betydning som ovenfor, og R betegner en alkylgruppe med 1-8 kulstofatomer til opnåelse af en forbindelse med formlen Awherein R 1 is the same meaning as above and R represents an alkyl group of 1-8 carbon atoms to give a compound of formula A
20 ft ?°2R20 ft? ° 2R
^nv/c-ch-co-nh-r1 C ii^ nv / c-ch-co-nh-r1 C ii
X^^^NK-CO-CH-CH-ORj AX ^^^ NK-CO-CH-CH-ORj A
X’ R4 25X 'R4 25
som man decarbalkoxylerer til opnåelse af en forbindelse med formlen IV defineret som ovenfor, hvilken forbindelse med formlen IV man cycliserer i nærværelse af et alkalisk middel til opnåelse af en forbindelse med formlen Vwhich is decarbalkoxylated to give a compound of formula IV defined as above, which compound of formula IV is cyclized in the presence of an alkaline agent to obtain a compound of formula V
30 OH30 OH
.^J^^CONH-R., JL JL v x xh-ch-or! Λ I i 3 35 X' R4 4 DK 172034 B1. ^ J ^^ CONH-R., JL JL v x xh-ch-or! Λ I i 3 35 X 'R4 4 DK 172034 B1
som man omdanner til en forbindelse med formlen VIwhich is converted into a compound of formula VI
9H N-R.9H N-R.
¢1¾ · A CH-ORi¢ 1¾ · A CH-ORi
KK
10 hvilken forbindelse med formlen VI man behandler: - enten med et surt hydrolysemiddel til opnåelse af en forbindelse med formlen I, hvor X, R-j og R4 har samme betydning som ovenfor, R2 betegner et brintatom, og R3 betegner en alkylgruppe med 1-4 kulstofatomer, hvilken forbindelse man om ønsket omdanner til en 15 forbindelse med formlen I, hvor X, R-j, R2 og R4 har samme betydning som ovenfor, og R3 betegner et brintatom, hvorefter man i påkommende tilfælde etherificerer eller esterificerer en eller to hydroxylgrupper til opnåelse af en forbindelse med formlen I, hvor R2 og/eller R3 betegner en alkylgruppe med 1-4 kulstofatomer eller en gruppe -C-R5 o 20 defineret som ovenfor, eller man behandler eventuelt en forbindelse med formlen I, hvor R2 og R3 betegner et brintatom, med acetone i nærværelse af et surt middel til opnåelse af det tilsvarende acetonid, - eller med en syre med formlen R5-COOH, idet R5 har samme betydning som ovenfor, til opnåelse af en forbindelse med formlen I, hvor X, R-j og R4 har samme betydning som 25 ovenfor. Ro betegner en gruppe -C-R5 , «110 which compound of formula VI is treated: - either with an acid hydrolyzing agent to give a compound of formula I wherein X, R 1 and R 4 have the same meaning as above, R 2 represents a hydrogen atom and R 3 represents an alkyl group of 1-4. carbon atoms which, if desired, are converted to a compound of formula I wherein X, R 1, R 2 and R 4 have the same meaning as above and R 3 represents a hydrogen atom, whereupon one or two hydroxyl groups are then etherified or esterified to give of a compound of formula I wherein R 2 and / or R 3 represent an alkyl group having 1-4 carbon atoms or a group -C-R 5 o defined as above, or optionally treating a compound of formula I wherein R 2 and R 3 represent a hydrogen atom, with acetone in the presence of an acidic agent to give the corresponding acetonide, - or with an acid of formula R5-COOH, R5 having the same meaning as above, to give a compound of wherein I, R 1 and R 4 have the same meaning as above. Ro represents a group -C-R5, «1
OISLAND
og R3 betegner en alkylgruppe med 1-4 kulstofatomer, hvorefter man om ønsket omdanner de således opnåede forbindelser med formlen I til salte med indvirkning af en syre eller en base.and R 3 represents an alkyl group of 1-4 carbon atoms and then, if desired, the compounds of formula I thus obtained are converted into salts with the action of an acid or a base.
30 eller b) forbindelsen ll/^ ηΛ 5 DK 172034 B1Or b) the compound II / ηΛ 5 DK 172034 B1
hvor R4 har samme betydning som ovenfor, reagerer med en forbindelse med formlen lllA CHtø-CONH-R-j lllAwherein R4 has the same meaning as above, reacts with a compound of formula IIaA CHtO-CONH-R-11llA
hvor R^ har samme betydning som ovenfor, til opnåelse af en forbindelse med formlen IVAwherein R 1 has the same meaning as above to give a compound of formula IVA
5 OCHj-CONH-R,OCH₂-CONH-R,
som man cycliserer i nærværelse af et alkalisk middel til opnåelse af en forbindelse med 10 formlen VAwhich is cyclized in the presence of an alkaline agent to give a compound of formula VA
OHOH
^\Åj:onh-r1^ \ AAJ: ONH-r1
i TTi TT
15 A H15 A H
som man omdanner til en forbindelse med formlen I, hvor X, R-| og R4 har samme betydning som ovenfor, og R2 og R3 betegner et brintatom, i hvilken forbindelse med formlen I man eventuelt etherificerer eller esterificerer en eller begge hydroxyIgrupper til opnåelse af en 20 forbindelse med formlen I, hvor R2 og/eller R3 betegner en alkylgruppe med 1-4 kulstofatomer eller en gruppe -C-R5 o defineret som ovenfor, eller man behandler eventuelt forbindelsen med formlen I, hvor R2 og R3 betegner et brintatom, med acetone i nærværelse af et surt middel til opnåelse af det 25 tilsvarende acetonid, hvorefter man om ønsket omdanner forbindelserne med formlen I til salte v.hj.a. en syre eller en base.which is converted to a compound of formula I wherein X, R- | and R 4 has the same meaning as above and R 2 and R 3 represent a hydrogen atom in which one or both of the hydroxy groups optionally etherifies or esterifies to give a compound of formula I wherein R 2 and / or R 3 represents an alkyl group with 1-4 carbon atoms or a group -C-R 5 defined as above, or optionally treating the compound of formula I wherein R 2 and R 3 represent a hydrogen atom, with acetone in the presence of an acidic agent to give the corresponding acetone. whereupon, if desired, the compounds of formula I are converted to salts by an acid or a base.
Under foretrukne betingelser ved iværksættelse af fremgangsmåde a) udføres denne på flg. måde: 30 - X’ betegner et chloratom i formel II, - reaktionen mellem forbindelsen med formlen II og forbindelsen med formlen lllA foregår i nærværelse af en lithiumorganoforbindelse eller et lithiumamid, f.eks. i nærværelse af butyllithium eller lithium diisopropylamid. Denne reaktion udføres ved lav temperatur, nemlig af størrelsesordenen -70°C.Under preferred conditions for carrying out process a), it is carried out as follows: - X represents a chlorine atom of formula II, - the reaction between the compound of formula II and the compound of formula IIA takes place in the presence of a lithium organo compound or a lithium amide, f .g. in the presence of butyllithium or lithium diisopropylamide. This reaction is carried out at low temperature, of the order of -70 ° C.
35 Når forbindelsen med formlen II reagerer med forbindelsen med formlen IIIq er den benyttede base f.eks. natriumhydroxid, og reaktionen udføres ved stuetemperatur.When the compound of formula II reacts with the compound of formula IIIq, the base used is e.g. sodium hydroxide and the reaction is carried out at room temperature.
6 DK 172034 B16 DK 172034 B1
Operationsbetingelserne vedr. dette trin af fremgangsmåden samt betingelserne for decarbalkoxyleringen af forbindelsen med formlen A svarer til dem, som er beskrevet i europæisk patentskrift nr. 0141713.The operating conditions regarding this step of the process and the conditions for decarbalkoxylation of the compound of formula A are similar to those described in European Patent Specification No. 0141713.
5 Cycliseringen af forbindelsen med formlen IV udføres i nærværelse af et alkalisk middel såsom et alkalimetalhydrid eller alkaiimetalcarbonat eller en amin, f.eks. i nærværelse af natriumhydrid, natrium- eller kaliumcarbonat, piperidin, 4-aminopyridin, dimethylaminopyridin, triethylamin, 1,5-diazabicyclo[4,3,0]-non-5-en, 1,4-diazabicyclo[2,2,2]-oktan eller 1,5-diazabicyclo[5,4,0]-undec-5-en.The cyclization of the compound of formula IV is carried out in the presence of an alkaline agent such as an alkali metal hydride or alkali metal carbonate or an amine, e.g. in the presence of sodium hydride, sodium or potassium carbonate, piperidine, 4-aminopyridine, dimethylaminopyridine, triethylamine, 1,5-diazabicyclo [4,3,0] non-5-ene, 1,4-diazabicyclo [2,2,2 ] -octane or 1,5-diazabicyclo [5,4,0] -undec-5-ene.
1010
Denne cyclisering udføres i nærværelse af et opløsningsmiddel, som fortrinsvis er tetrahydrofuran, men andre opløsningsmidler såsom dimethylformamid, benzen eller toluen kan også benyttes.This cyclization is carried out in the presence of a solvent which is preferably tetrahydrofuran, but other solvents such as dimethylformamide, benzene or toluene may also be used.
15 Den sure hydrolyse af forbindelsen med formlen VI udføres fortrinsvis v.hj.a. saltsyre,men andre syrer kan også benyttes såsom svovlsyre.The acidic hydrolysis of the compound of formula VI is preferably carried out by hydrochloric acid, but other acids can also be used such as sulfuric acid.
Omdannelsen af en forbindelse med formlen I, hvor R3 betegner en alkylgruppe med 1-4 kulstofatomer, til en forbindelse med formlen I, hvor R3 betegner et hydrogenatom, kan f.eks.The conversion of a compound of formula I wherein R 3 represents an alkyl group of 1-4 carbon atoms to a compound of formula I wherein R 3 represents a hydrogen atom may e.g.
20 udføres i nærværelse af trimethylsilaniodid eller bortribromid.20 is carried out in the presence of trimethylsilaniodide or boron tribromide.
Man kan arbejde i et opløsningsmiddel såsom acetonitril eller methylenchlorid.One can work in a solvent such as acetonitrile or methylene chloride.
Etherificerings- og esterificeringsreaktioneme for forbindelserne med formlen I med en eller to 25 hydroxylgrupper udføres ved gængse metoder.The etherification and esterification reactions of the compounds of formula I with one or two hydroxyl groups are carried out by conventional methods.
Det sure middel, som man omsætter under dannelsen af acetonidet, er f.eks. p-toluensulfonsyre.The acidic agent which is reacted during the formation of the acetonide is e.g. p-toluenesulfonic acid.
30 Ved fremgangsmåde b) udføres omdannelsen af forbindelsen med formlen ll^ til forbindelsen med formlen IV^ efterfulgt af cyclisering af denne til en forbindelse med formlen V^ under de samme foretrukne betingelser som dem, som er beskrevet ovenfor under fremgangsmåde a).In process b), the conversion of the compound of formula II ^ to the compound of formula IV ^ is followed, followed by cyclization thereof to a compound of formula V ^ under the same preferred conditions as those described above in process a).
Omdannelsen af forbindelsen med formlen V^ til dehydroxyleret forbindelse med formlen I 35 udføres fortrinsvis ved indvirkning af kaliumpermanganat i nærværelse af triethylbenzyl-ammoniumchlorid.The conversion of the compound of formula V 1 to dehydroxylated compound of formula I 35 is preferably carried out by the action of potassium permanganate in the presence of triethylbenzyl ammonium chloride.
7 DK 172034 B17 DK 172034 B1
Etherificeringen eller esterificeringen af en eller begge hydroxylgrupper i forbindelse med formlen I udføres efter gængse metoder.The etherification or esterification of one or both hydroxyl groups of formula I is carried out by conventional methods.
Det sure middel, som man lader reagere under dannelsen af acetonidet, er f.eks. som ovenfor 5 p-toluensulfonsyre.The acidic agent which is reacted during the formation of the acetonide is e.g. as above 5 p-toluenesulfonic acid.
Forbindelserne med formlen I er nye i forhold til forbindelserne omtalt i DE 3.320.102 A1.The compounds of formula I are novel compared to the compounds disclosed in DE 3.320.102 A1.
Forbindelserne med formlen I ifølge opfindelsen samt deres additionssalte med syrer og baser 10 har interessante farmakologiske egenskaber. Det er forbindelser med meget virksomme smertestillende og betændelseshæmmende egenskaber i modeller for kronisk betændelse. I forhold til forbindelserne omtalt i DE 3.320.102 A1 er forbindelserne med formlen I ifølge opfindelsen meget mere aktive, hvilket fremgår af afsnittet vedr, farmakologiske undersøgelser, som er placeret sidst i beskrivelsen.The compounds of formula I according to the invention as well as their addition salts with acids and bases 10 have interesting pharmacological properties. These are compounds with very effective painkillers and anti-inflammatory properties in models of chronic inflammation. Compared to the compounds disclosed in DE 3,320,102 A1, the compounds of formula I according to the invention are much more active, as can be seen from the section on pharmacological studies which are located at the end of the description.
1515
Disse egenskaber retfærdiggør deres anvendelse i terapien, idet forbindelserne med formlen I og deres additionssalte med farmaceutisk acceptable syrer og baser kan benyttes som lægemidler.These properties justify their use in the therapy, since the compounds of formula I and their addition salts with pharmaceutically acceptable acids and bases can be used as drugs.
20 Opfindelsen angår specielt flg. lægemidler: - 2 - (1,2-dihydroxyethyl) - 4 - hydroxy - N - (2-thiazolyl) - 8 - trifluormethyl - 3 -quinolincarboxamid samt dets additionssalte med farmaceutisk acceptable syrer og baser og - 2 - (1,2-dihydroxypropyl) - 4 - hydroxy - N - (2-thiazolyl) - 8 - trifluormethyl - 3 -quinolincarboxamid samt dets additionssalte med farmaceutisk acceptable syrer og baser og 25 - 2 - (1,2-bis-(1-oxopropoxy)-ethyl) - 4 - hydroxy - N - (2-thiazolyl) - 8 - trifluormethyl - 3 - quinolincarboxamid samt dets additionssalte med farmaceutisk acceptable syrer og baser.The invention particularly relates to the following drugs: - 2 - (1,2-dihydroxyethyl) - 4 - hydroxy - N - (2-thiazolyl) - 8 - trifluoromethyl - 3-quinoline carboxamide and its addition salts with pharmaceutically acceptable acids and bases and - 2 - (1,2-dihydroxypropyl) - 4 - hydroxy - N - (2-thiazolyl) - 8 - trifluoromethyl - 3 - quinoline carboxamide and its addition salts with pharmaceutically acceptable acids and bases and 25 - 2 - (1,2-bis- 1-oxopropoxy-ethyl) -4-hydroxy-N - (2-thiazolyl) -8-trifluoromethyl-3-quinoline carboxamide and its addition salts with pharmaceutically acceptable acids and bases.
De omhandlede lægemidler kan foreskrives til behandling af degenerative betændelsessygdomme såsom osteoarthrose, forskellige former for collagenose (tendinitis 30 osv.), reumatiske sygdomme (reumatoid polyarthritis, ankylotisk spondylarthritis) samt til behandling af andre sygdomme med autoimmun karakter såsom dissemineret erythematøs lupus, glomerulonephritis og dissemineret sclerose.The drugs in question may be prescribed for the treatment of degenerative inflammatory diseases such as osteoarthrosis, various forms of collagenosis (tendinitis 30, etc.), rheumatic diseases (rheumatoid polyarthritis, ankylosing spondylarthritis) as well as for the treatment of other autoimmune diseases such as disseminated erythematosus, erythematosus, sclerosis.
De omhandlede lægemidler kan ligeledes benyttes til behandling af muskel-, led- og 35 nervesmerter, tandpine, migræne og zoster og ligeledes til komplementær behandling af infektiøse og febrile tilstande.The drugs in question may also be used to treat muscle, joint and nerve pain, toothache, migraine and zoster, and also to complement infectious and febrile conditions.
8 DK 172034 B18 DK 172034 B1
Der kan fremstilles farmaceutiske præparater, der som aktiv bestanddel indeholder de omhandlede lægemidler.Pharmaceutical compositions may be prepared which contain as active ingredient the drugs of the present invention.
Disse farmaceutiske præparater kan indgives ad oral, rektal eller parental vej eller benyttes 5 lokalt på huden og slimhinderne.These pharmaceutical compositions may be administered by oral, rectal or parental route or applied topically to the skin and mucous membranes.
Disse præparater kan være faste eller flydende og kan foreligge i de i den humane medicin gængs benyttede farmaceutiske former såsom f.eks. almindelige eller overtrukne tabletter, gelatinekapsler, granulater, stikpiller, injektionspræparater, salver, cremer, geler og 10 aerosolpræparater. De kan fremstilles på gængs måde. Den aktive bestanddel kan indkorporeres deri sammen med de i disse farmaceutiske præparater normalt benyttede tilsætningsstoffer såsom talkum, arabisk gummi, laktose, stivelse, magnesiumstearat, kakaosmør, vandige eller ikke-vandige bærestoffer, fedtstoffer af animalsk eller vegetabilsk oprindelse, paraffinderivater, glykoler og diverse fugte-, dispergerings eller emulgeringsmidler 15 og konserveringsmidler.These compositions may be solid or liquid and may be present in the pharmaceutical forms commonly used in human medicine such as e.g. ordinary or coated tablets, gelatine capsules, granules, suppositories, injection preparations, ointments, creams, gels and 10 aerosol preparations. They can be manufactured in the usual way. The active ingredient may be incorporated therein together with the additives normally used in these pharmaceutical compositions such as talc, gum, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous carriers, animal or vegetable origin fats, paraffin derivatives, glycols and various moisturizers. -, dispersants or emulsifiers and preservatives.
Den fornødne dosis varierer afhængig af indgiftsmåden, den behandlede lidelse og den pågældende patient.The dose required varies depending on the method of administration, the condition being treated and the patient concerned.
20 Dosen kan f.eks. hos voksne variere mellem 20 mg og 2,0 g aktivt stof pr. dag ad oral vej.The dose may e.g. in adults, vary between 20 mg and 2.0 g of active substance per day. day by mouth.
Forbindelserne med formlen II og ll^ kan fremstilles ved den fremgangsmåde, som er beskrevet i europæisk patentskrift nr. 40573.The compounds of formula II and II may be prepared by the process described in European Patent No. 40573.
25 Forbindelserne med formlen II, ll^, IV, IV^, V, V/^, A og VI er hidtil ukendte kemiske forbindelser.The compounds of formula II, II, IV, IV, V, V, A and VI are novel chemical compounds.
Nedenstående eksempler illustrerer opfindelsen.The following examples illustrate the invention.
30 Eksempel 1:4- hvdroxv - 2 - n-hvdroxv-2-methoxvethvh N - (2-thiazolvP - 8 - trifluormethvl- 3-ouinolincarboxamidExample 1: 4-Hydroxy-2-n-hydroxy-2-methoxyethyl N - (2-thiazolylp-8-trifluoromethyl-3-quinoline carboxamide
Trin A: 2 - ((2-chlor-3-methoxy-1-oxopropyl)-amino) - β - oxo - N - (2-thiazolyl) - 3 -trifluormethylbenzenpropanamid.Step A: 2 - ((2-Chloro-3-methoxy-1-oxopropyl) -amino) - β-oxo - N - (2-thiazolyl) -3-trifluoromethylbenzenepropanamide.
35 Man tilfører ved 0°C 350 ml n-butyllithium opløst i hexan i en suspension af 34 g 2-acetylaminothiazol i 1100 cm^ tetrahydrofuran. Man afkøler til mellem -70 og -75°C og tilsætter DK 172034 B1 g en opløsning af 36,78 g 2 - (1-chlor-2-methoxyethyl) - 8 - trifluormethyl - 4H - 3,1 - benzoxazin - 4 - on (fremstillet i trin A i eksempel 12 i europæisk patentskrift nr. 40573 ud fra 2 - chlor -3 -methoxypropansyre (Chem.Ber 92 1 081-7 (1959)) og 2 - amino - 3 - trifluormethylbenzoesyre i 250 ml tetrahyd rof uran).35 ml of n-butyllithium dissolved in hexane are added at 0 ° C in a suspension of 34 g of 2-acetylaminothiazole in 1100 cm 2 of tetrahydrofuran. Cool to between -70 and -75 ° C and add DK 172034 B1 g to a solution of 36.78 g of 2- (1-chloro-2-methoxyethyl) - 8 - trifluoromethyl - 4H - 3,1 - benzoxazine - 4 - on (prepared in Step A of Example 12 of European Patent No. 40573 based on 2-chloro-3-methoxypropanoic acid (Chem.Ber 92,081-7 (1959)) and 2-amino-3-trifluoromethylbenzoic acid in 250 ml of tetrahydric acid uranium).
5 Man hælder den fremkomne opløsning i en vandig opløsning af saltsyre, ekstraherer med ether, vasker med 1N saltsyre og med vand, tørrer og inddamper under formindsket tryk.The resulting solution is poured into an aqueous solution of hydrochloric acid, extracted with ether, washed with 1N hydrochloric acid and with water, dried and evaporated under reduced pressure.
Man udriver den opnåede rest med ether, frafiltrerer, vasker med ether, tørrer under formindsket tryk og får 33,35 g af den forventede forbindelse med smp. 190°C.The obtained residue is triturated with ether, filtered off, washed with ether, dried under reduced pressure to give 33.35 g of the expected compound, m.p. 190 ° C.
10 Analyse: C-| 7H15N3O4F3SCI: 449,845Analysis: C - 7H15N3O4F3SCI: 449.845
Beregnet: C% 45,39 H% 3,36 N% 9,34 F% 12,67 Cl% 7,88 S%7,13Calculated: C% 45.39 H% 3.36 N% 9.34 F% 12.67 Cl% 7.88 S% 7.13
Fundet: C% 45,6 H% 3.4 N% 9,0 F% 12,4 Cl% 7,8 S% 7,1Found: C% 45.6 H% 3.4 N% 9.0 F% 12.4 Cl% 7.8 S% 7.1
Trin B: 2 - (1-chlor-2-methoxyethyl) - 4 - hydroxy - N - (2-thiazolyl) - 8 - trifluormethyl - 3 -15 quinolincarboxam id.Step B: 2- (1-Chloro-2-methoxyethyl) -4-hydroxy-N - (2-thiazolyl) -8-trifluoromethyl-3-quinoline carboxamide.
Man opvarmer med tilbageløb i 30 min. 33,35 g forbindelse fra trin A og 10 g dimethylaminopyridin i 300 ml tetrahydrofuran.Reflux for 30 min. 33.35 g of compound from step A and 10 g of dimethylaminopyridine in 300 ml of tetrahydrofuran.
Man afkøler til stuetemperatur, hælder i en blanding af vand og 2N saltsyre, ekstraherer med 20 ethylacetat, vasker, tørrer og inddamper under formindsket tryk. Man udriver resten med ether, frafiltrerer, vasker, tørrer under formindsket tryk ved 60°C og får 28,2 g af den forventede forbindelse med smp. 186°CCool to room temperature, pour into a mixture of water and 2N hydrochloric acid, extract with 20 ethyl acetate, wash, dry and evaporate under reduced pressure. The residue is triturated with ether, filtered, washed, dried under reduced pressure at 60 ° C to give 28.2 g of the expected compound, m.p. 186 ° C
Trin C: 1,3 - dihydro - 3 - (methoxymethyl) -1 - ((2-thiazolyl) - imino) - 5 - trifluormethyl - furo -25 (3,4-b) - quinolin - 9 - ol.Step C: 1,3-dihydro-3- (methoxymethyl) -1 - ((2-thiazolyl) imino) -5-trifluoromethyl-furo-25 (3,4-b) -quinolin-9-ol.
Man anbringer med tilbageløb i 30 min. 23,9 g af forbindelsen fra trin B og 7,7 g kalium tert. butylat i 550 ml dioxan. Man eliminerer dioxanet under formindsket tryk, genoptager resten i en blanding af vand og 2N saltsyre, ekstraherer det uopløselige materiale med en blanding af 30 ethylacetet og tetrahydrofuran (80:20) og vasker den organiske fase med vand og forener de vandige faser.Reflux for 30 min. 23.9 g of the compound of step B and 7.7 g of potassium tert. butylate in 550 ml of dioxane. The dioxane is removed under reduced pressure, the residue is taken up again in a mixture of water and 2N hydrochloric acid, the insoluble material is extracted with a mixture of the ethyl acetate and tetrahydrofuran (80:20) and the organic phase is washed with water and the aqueous phases are combined.
Man neutraliserer den vandige fase ved tilsætning af en mættet vandig natriumbicarbonatopløsning, ekstraherer med ethylacetat, vasker med vand, tørrer og inddamper under formindsket tryk. Der fås 22 g af den forventede forbindelse.The aqueous phase is neutralized by the addition of a saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, washed with water, dried and evaporated under reduced pressure. 22 g of the expected compound are obtained.
3535
Trin D: 4 - hydroxy - 2 - (1-hydroxy-2-methoxyethyl) - N - (2-thiazolyl) - 8 - trifluormethyl - 3 -quinoiincarboxamid.Step D: 4 - Hydroxy - 2- (1-hydroxy-2-methoxyethyl) - N - (2-thiazolyl) - 8 - trifluoromethyl - 3 - quinoline carboxamide.
10 DK 172034 B110 DK 172034 B1
Man omrører i 16 timer ved stuetemperatur en opløsning indeholdende 22 g af forbindelsen fra trin C, 70 ml vand og 130 ml koncentreret saltsyre.A solution containing 22 g of the compound of step C, 70 ml of water and 130 ml of concentrated hydrochloric acid is stirred for 16 hours at room temperature.
Man frafiltrerer den dannede udfældning, vasker den med vand, optager den i 200 ml vand, ekstraherer med en blanding af ethylacetat og tetrahyd rof uran (50:50), vasker den organiske 5 fase mad vand, tørrer, inddamper under formindsket tryk og får 15 g forbindelse, som man renser ved kromatografi på silicagel under formindsket tryk (elueringsmiddel: ethylacetat). Der får 12,5 g forbindelse, som man udriver med ether, hvorpå man frafiltrerer, vasker med ether og tørrer under formindsket tryk ved 100°C.The formed precipitate is filtered off, washed with water, taken up in 200 ml of water, extracted with a mixture of ethyl acetate and tetrahydro-uranium (50:50), the organic phase is washed with water, dried, evaporated under reduced pressure and allowed 15 g of compound which is purified by chromatography on silica gel under reduced pressure (eluent: ethyl acetate). There is obtained 12.5 g of compound which is rinsed with ether, which is filtered off, washed with ether and dried under reduced pressure at 100 ° C.
Der får 11,83 g af den forventede forbindelse med smp. 216-218°C.11.83 g of the expected compound are obtained with m.p. 216-218 ° C.
1010
Analyse: C17H14O4N3F3S: 413,384Analysis: C17H14O4N3F3S: 413.384
Beregnet: C% 49,39 H% 3,41 N% 10,16 F% 13,76 S% 7,76%Calculated: C% 49.39 H% 3.41 N% 10.16 F% 13.76 S% 7.76%
Fundet : C% 49,5 H% 3,4 N% 10,2 F% 13,9 S% 7,7 15 Eksempel 2: 2 - (1.2-dihvdoxvethvl) - 4 - hvdroxv - N - (2-thiazolvh - 8 - trifluormethvl - 3 -auinolincarboxamid.Found: C% 49.5 H% 3.4 N% 10.2 F% 13.9 S% 7.7 Example 2: 2- (1,2-Dihydoxethyl) -4-hydroxy-N - (2-thiazolyl) - 8-Trifluoromethyl-3-aolinoline carboxamide.
Man tilfører langsomt under indifferent atmosfære 6,7 ml trimethylsilaniodid i en blanding indeholdende 6,5 g forbindelse fra eksempel 1 og 120 ml acetonitril, omrører 16 timer ved 20 stuetemperatur og hælder over i 400 ml vand tilsat 50 ml natriumbisulfatopløsning.6.7 ml of trimethylsilaniodide are slowly added under an inert atmosphere in a mixture containing 6.5 g of compound of Examples 1 and 120 ml of acetonitrile, stirred for 16 hours at room temperature and poured into 400 ml of water added with 50 ml of sodium bisulfate solution.
Man omrører den fremkomne opløsning 45 min. ved stuetemperatur, tilsætter 100 ml ethylether, omrører 30 min., frafiltrerer, vasker med vand og tørrer under formindsket tryk ved 75°C i 16 timer. Der fås 5,9 g forbindelse, som man opløser i 75 ml dimethylformamid, hvorpå man frafiltrerer, sætter ether til filtratet, isafkøler, hvorefter man frafiltrerer de dannede 25 krystaller, vasker med vand, tørrer under formindsket tryk ved 120°C og får 4,86 g af den forventede forbindelse med smp. 255°C.The resulting solution is stirred for 45 min. at room temperature, add 100 ml of ethyl ether, stir 30 min, filter off, wash with water and dry under reduced pressure at 75 ° C for 16 hours. 5.9 g of compound are obtained which are dissolved in 75 ml of dimethylformamide, which is filtered off, ether is added to the filtrate, ice-cooled, then the 25 crystals formed are filtered, washed with water, dried under reduced pressure at 120 ° C and obtained 4 , 86 g of the expected compound with m.p. 255 ° C.
Analyse: CigH^^C^S: 399,356Analysis: CigHH₂ CC ^S: 399,356
Beregnet: C% 48,12 H% 3,03 N% 10,52 F% 14,27 S% 8,03 30 Fundet: C% 48,00 H% 3,0 N% 10,4 F% 14,1 S% 8,0Calculated: C% 48.12 H% 3.03 N% 10.52 F% 14.27 S% 8.03 Found: C% 48.00 H% 3.0 N% 10.4 F% 14.1 S% 8.0
Eksempel 3: 2 - Π .2-dihvdroxvproovh - 4 - hvdroxv - N - (2-thiazolvh - 8 - trifluormethvl - 3 -auinolincarboxamid.Example 3: 2- [2-Dihydroxypropyl] -4-hydroxy-N - (2-thiazolyl-8-trifluoromethyl-3-aolinoline carboxamide).
35 Trin A: β-οχο - 2 - ((1-oxo-2-butenyl)-amino) - N - (2-thiazolyl) - 3 - trifluormethylbenzen-propanamid.Step A: β-O-2 - ((1-oxo-2-butenyl) amino) - N - (2-thiazolyl) -3-trifluoromethylbenzene-propanamide.
11 DK 172034 B111 DK 172034 B1
Man arbejder som angivet i trin A i eksempel 1 ud fra 19,44 g 2-acetylaminothiazol og 17,3 g af 2 - (1-propenyl) - 8 - trifluormethyl - 4H - 3,1 - benzoxazin - 4 - on. Forbindelsen fremstilles som i trin A i eksempel 12 i europæisk patentskrift nr. 40 573 ud fra 2 - aminotrifluormethylbenzoe-syre og crotonylchlorid.As in Step A of Example 1, one is employed from 19.44 g of 2-acetylaminothiazole and 17.3 g of 2- (1-propenyl) -8-trifluoromethyl-4H-3,1-benzoxazine-4-one. The compound is prepared as in Step A of Example 12 of European Patent No. 40,573 from 2-aminotrifluoromethylbenzoic acid and crotonyl chloride.
5 Der får 19,03 af den forventede forbindelse med smp. 206-208°C5 19.03 of the expected connection with m.p. 206-208 ° C
Trin B: 4 - hydroxy - 2 - (1-propenyl) - N - (2-thiazolyl) - 8 - trifluormethyl - 3 quinolincarboxamid.Step B: 4 - Hydroxy - 2- (1-propenyl) - N - (2-thiazolyl) - 8 - trifluoromethyl - 3 quinoline carboxamide.
10 Man sætter 17,5 g forbindelse fra trin A opløst i 175 ml dimethylacetamid til en blanding indeholdende 2,11 g natriumhydrid i 50% oliedispersion og 100 ml dimethylacetamid.10.5 g of Step A compound dissolved in 175 ml of dimethylacetamide is added to a mixture containing 2.11 g of sodium hydride in 50% oil dispersion and 100 ml of dimethylacetamide.
Man opvarmer til 120°C og holder denne temperatur i 30 min.Heat to 120 ° C and keep this temperature for 30 minutes.
Man afkøler opløsningen og hælder den derpå i en blanding af vand og 2N saltsyre. Man frafiltrerer den fremkomne udfældning, vasker den med vand, tørrer den under formindsket tryk 15 ved 80°C og får 16,7 g af den forventede forbindelse med smp. 265°C.The solution is cooled and then poured into a mixture of water and 2N hydrochloric acid. The resulting precipitate is filtered off, washed with water, dried under reduced pressure 15 at 80 ° C to give 16.7 g of the expected compound, m.p. 265 ° C.
Trin C: 2 - (1,2 dihydroxypropyl) - 4 - hydroxy - N - (2-thiazolyl) - 8 - trifluormethyl - 3 -quinolincarboxamid.Step C: 2- (1,2-dihydroxypropyl) -4-hydroxy-N - (2-thiazolyl) -8-trifluoromethyl-3-quinoline carboxamide.
20 Man omrører 1 time ved 0°C under indifferent atmosfære en blanding indeholdende 12,2 g af forbindelsen fra trin B i 300 ml methylenchlorid, 9,16 g methylbenzylammoniumchlorid og 6,32 g kaliumpermanganat.One is stirred at 0 ° C under inert atmosphere for a mixture containing 12.2 g of the compound of step B in 300 ml of methylene chloride, 9.16 g of methylbenzylammonium chloride and 6.32 g of potassium permanganate.
Derpå tilsætter man 150 ml iskoldt vand og derefter 150 ml natriumbisulfitopløsning, man frafiltrerer det fremkomne uopløselige materiale, vasker det med vand og opløser det delvis i 25 tetrahydrofuran.Then, 150 ml of ice-cold water and then 150 ml of sodium bisulfite solution are filtered off, the resulting insoluble material is filtered off, washed with water and partially dissolved in tetrahydrofuran.
Man tørrer den organiske opløsning, inddamper under formindsket tryk og får 5,8 g råprodukt, som man opløser i lunkent dimethylformamid. Man filtrerer den fremkomne opløsning, inddamper til ca. 40 ml, tilsætter derpå 60 ml ethylether, isafkøler, frafiltrerer krystallerne, vasker dem med ether og tørrer dem under formindsket tryk ved 100°C. Den fremkomne 30 forbindelse opløses i tetrahydrofuran.The organic solution is dried, evaporated under reduced pressure to give 5.8 g of crude product which is dissolved in lukewarm dimethylformamide. The resulting solution is filtered, evaporated to ca. 40 ml, then add 60 ml of ethyl ether, ice-cool, filter the crystals, wash them with ether and dry them under reduced pressure at 100 ° C. The resulting compound is dissolved in tetrahydrofuran.
Man filtrerer, inddamper under formindsket tryk, udriver resten med ethylacetat, frafiltrerer, vasker, tørrer underformindsket tryk ved 100°C og får 3,04 g af den forventede forbindelse med smp. 275°CFilter, evaporate under reduced pressure, elute the residue with ethyl acetate, filter, wash, dry under reduced pressure at 100 ° C to obtain 3.04 g of the expected compound, m.p. 275 ° C
35 Analyse: C17H14N304F3S: 413,384Analysis: C 17 H 14 N 3 O 4 F 3 S: 413.384
Beregnet: C% 49,39 H% 3,41 N% 10,16 F% 13,79 S% 7,76Calculated: C% 49.39 H% 3.41 N% 10.16 F% 13.79 S% 7.76
Fundet: C%49,3 H% 3,3 N% 10,1 F% 14,1 S% 7,8 12 DK 172034 B1Found: C% 49.3 H% 3.3 N% 10.1 F% 14.1 S% 7.8 12 DK 172034 B1
Eksempel 4:2 - (1.2-bis-(1 -oxopropoxvVethvO - 4 - hvdroxv - N - (2-thiazolvfl - 8 - trifluormethvl • 3 - carbexamid.Example 4: 2- (1,2-Bis- (1-oxopropoxyethyletho-4-hydroxy) - N - (2-thiazolyl) -8-trifluoromethyl-3-carbexamide.
Man blander ved 20°C 2,15 g af den i eksempel 2 fremstillede forbindelse, 70 ml 5 methylenchlorid og 0,96 ml propionsyre. Man tilsætter efter 5 minutters forløb 2,9 g dicyclohexylcarbodiimid og derefter 2,4 g dimethylaminopyridin og opretholder omrøring i 1 time og 30 min. Man filtrerer og vasker filtratet med en mættet vandig natriumcarbonatopløsning, med en vandig saltsyreopløsning og derefter med vand. Man tørrer, inddamper til tørhed og omkrystalliserer resten i acetonitril.2.15 g of the compound of Example 2, 70 ml of 5 methylene chloride and 0.96 ml of propionic acid are mixed at 20 ° C. After 5 minutes, 2.9 g of dicyclohexylcarbodiimide and then 2.4 g of dimethylaminopyridine are added and stirring is maintained for 1 hour and 30 minutes. The filtrate is filtered and washed with a saturated aqueous sodium carbonate solution, with an aqueous hydrochloric acid solution and then with water. Dry, evaporate to dryness and recrystallize the residue in acetonitrile.
10 Der fås 1,34 g af den forventede forbindelse med smp. 206°C.1.34 g of the expected compound are obtained with m.p. 206 ° C.
Analyse: C^^H^nF^N^OfiS: 511,479Analysis: C ^^ HH ^ nFFN NO₂S: 511,479
Beregnet: C% 51,66 H% 3,94 N% 8,22 S% 6,27 F% 11,14Calculated: C% 51.66 H% 3.94 N% 8.22 S% 6.27 F% 11.14
Fundet: C%51,7 H% 3,9 N%8,1 S% 6,2 F% 11,1 15Found: C% 51.7 H% 3.9 N% 8.1 S% 6.2 F% 11.1 15
Eksempel 5: 2 - (2-methoxv-1 -(1 -oxopropoxvl-ethvh - 4 - hvdroxv · N - (2-thiazolvh - 8 -trifluormethvl - 3 - auinolincarboxamid.Example 5: 2- (2-Methoxy-1- (1-oxopropoxy-ethyl-4-hydroxy) N - (2-thiazolyl-8-trifluoromethyl-3-auinolinecarboxamide).
Man arbejder i analogi med eksempel 4, idet man som udgangsmateriale benytter 2 g af den i 20 eksempel 1 fremstillede forbindelse, 0,4 ml propionsyre, 1,2 g dicyclohexylcarbodiimid og 0,3 g dimethylaminopyridin. Der fås efter omkrystallisation i ethylacetat 1 g af den forventede forbindelse med smp. 190°C.Analogous to Example 4 is used, starting from 2 g of the compound prepared in Example 1, 0.4 ml of propionic acid, 1.2 g of dicyclohexylcarbodiimide and 0.3 g of dimethylaminopyridine. After recrystallization in ethyl acetate, 1 g of the expected compound is obtained with m.p. 190 ° C.
Analyse: 3F3N3O5S: 469,442 25 Beregnet: C% 51,17 H% 3,87 F% 12,14 N% 8,95 S% 6,83Analysis: 3F3N3O5S: 469.442 Calculated: C% 51.17 H% 3.87 F% 12.14 N% 8.95 S% 6.83
Fundet: C%51,5 H% 4.0 F% 11,9 N% 8,9 S% 6,5Found: C% 51.5 H% 4.0 F% 11.9 N% 8.9 S% 6.5
Eksempel 6: 2 - (1.2-(dibenzovloxv1-ethvh - 4 - hvdroxv - N - (2-thiazolvh - 8 - trifluormethvl - 3 - auinolincarboxamid.Example 6: 2- (1,2- (dibenzovloxy) -ethyl-4-hydroxy-N - (2-thiazolyl-8-trifluoromethyl-3-auinoline carboxamide).
3030
Man arbejder i analogi med eksempel 4, idet man som udgangsmateriale benytter 0,5 g af den i eksempel 2 fremstillede forbindelse, 0,37 g benzoesyre, 0,67 g dicyclohexylcarbodiimid og 0,075 g dimethylaminopyridin. Der fås 0,8 g råprodukt, som man opløser i 15 ml tetrahydrofuran. Man tilsætter 0,3 ml af en 5,7 N opløsning af hydrogenchlorid i ethanol. Man 35 frafiltrerer de dannede krystaller og opløser dem i en blanding af ethylacetat og vand. Man ekstraherer med ethylacetat, tørrer og inddamper til tørhed. Man opløser resten i tetrahydrofuran, tilsætter ethylether, afkøler til 0°C i 2 timer, frafiltrerer krystallerne og tørrer dem. Der fås 0,33 g af den forventede forbindelse med smp. 240°C.An analogy to Example 4 is employed, using as the starting material 0.5 g of the compound prepared in Example 2, 0.37 g of benzoic acid, 0.67 g of dicyclohexylcarbodiimide and 0.075 g of dimethylaminopyridine. 0.8 g of crude product is obtained which is dissolved in 15 ml of tetrahydrofuran. 0.3 ml of a 5.7 N solution of hydrogen chloride in ethanol is added. The crystals formed are filtered off and dissolved in a mixture of ethyl acetate and water. Extract with ethyl acetate, dry and evaporate to dryness. The residue is dissolved in tetrahydrofuran, ethyl ether added, cooled to 0 ° C for 2 hours, the crystals filtered off and dried. 0.33 g of the expected compound are obtained with m.p. 240 ° C.
13 DK 172034 B113 DK 172034 B1
Analyse: C30H20F3N3O6S· 607,568Analysis: C30H20F3N3O6S · 607.568
Beregnet: C% 59,31 H% 3,32 N% 6,91 F% 9,38 S% 5,28Calculated: C% 59.31 H% 3.32 N% 6.91 F% 9.38 S% 5.28
Fundet: C% 59,2 H% 3,2 N% 6,9 F% 9,6 S% 5,4 5 Eksempel 7: 2 · (1.2-(diacetvloxv1-ethvh - 4 - hvdroxv - N - (2-thiazolvO - 8 - trifluormethvl - 3 -auinolincarboxamid.Found: C% 59.2 H% 3.2 N% 6.9 F% 9.6 S% 5.4 5 Example 7: 2 · (1,2- (diacetyloxy) -ethyl-4-hydroxy-N - (2- thiazolvO-8-trifluoromethyl-3-aolinoline carboxamide.
Man arbejder i analogi med eksempel 4, idet man som udgangsmateriale benytter 2 g af den i eksempel 2 fremstillede forbindelse, 0,7 ml eddikesyre, 2,7 g dicyclohexylcarbodiimid Og 0,3 g 10 dimethylaminopyridin. Der fås 0,9 g råprodukt indeholdende lidt dicyclohexylurinstof, som man eliminerer ved vaskning med tetrahydrofuran, ved omkrystallisation i dimethylformamid og derefter ved dannelse af chlorhydratet i tetrahydrofuran, hvortil man sætter ethanolisk opløsning af hydrogenchlorid. Efter omkrystallisation i eddikesyre får man 0,38 g af den forventede forbindelse med smp. 270°C.An analogy to Example 4 is employed, using as the starting material 2 g of the compound prepared in Example 2, 0.7 ml of acetic acid, 2.7 g of dicyclohexylcarbodiimide and 0.3 g of dimethylaminopyridine. 0.9 g of crude product are obtained containing a little dicyclohexylurea which is eliminated by washing with tetrahydrofuran, by recrystallization in dimethylformamide and then by the formation of the chlorohydrate in tetrahydrofuran, to which ethanolic solution of hydrogen chloride is added. After recrystallization in acetic acid, 0.38 g of the expected compound is obtained with m.p. 270 ° C.
1515
Analyse: C20H 16^3^3^6^- 483,432Analysis: C20H163.33.36.6483.432
Beregnet: C% 49,69 H% 3,34 N% 8,69 F% 11,79 S%6,63Calculated: C% 49.69 H% 3.34 N% 8.69 F% 11.79 S% 6.63
Fundet: C% 49,4 H% 3,2 N% 8,4 F%11,9 S% 6,8 20 Eksempel 8: 2 - (2.2-dimethvl-1.3-dioxolan-4-vl1 - 4 - hvdroxv - N - (2-thiazolvl) - 8 trifluormethvl - 3 - auinolincarboxamid.Found: C% 49.4 H% 3.2 N% 8.4 F% 11.9 S% 6.8 Example 8: 2- (2,2-Dimethyl-1,3-dioxolan-4-yl) -4-hydroxy N - (2-thiazolyl) - 8 trifluoromethyl - 3 - auinoline carboxamide.
Man suspenderer 3 g af den i eksempel 2 fremstillede forbindelse i 80 ml acetone. Man fremkalder tilbageløb og tilsætter derpå 0,3 g p-toluensulfonsyre og tilbageløbet holdes i 5 25 timer. Man afkøler til 20°C, frafiltrerer og tørrer krystallerne under formindsket tryk. Man opløser i 100 ml tetrahydrofuran, idet man opvarmer svagt til 40°C, hvorpå man filtrerer, inddamper til halvt rumfang, afkøler til 20°C og tilsætter ethylether. Man frafiltrerer krystallerne, vasker dem med ethylether og tørrer dem. Der fås 1,2 g af den forventede forbindelse med smp. 250°C.3 g of the compound of Example 2 are suspended in 80 ml of acetone. Reflux is induced and then 0.3 g of p-toluenesulfonic acid is added and the reflux is maintained for 25 hours. Cool to 20 ° C, filter and dry the crystals under reduced pressure. Dissolve in 100 ml of tetrahydrofuran, heat slightly to 40 ° C, filter, evaporate to half volume, cool to 20 ° C and add ethyl ether. The crystals are filtered off, washed with ethyl ether and dried. 1.2 g of the expected compound are obtained with m.p. 250 ° C.
3030
Analyse: C-jgh^øFjNgO^S: 439,417Analysis: C -ghH₂ øFjN₂O ^ S: 439.417
Beregnet: C% 51,94 H% 3,67 N%9,56 F% 12,97 S% 7,30Calculated: C% 51.94 H% 3.67 N% 9.56 F% 12.97 S% 7.30
Fundet: C%51,8 H% 3,5 N% 9,4 F% 12,8 S% 7,1 35 Eksempel 9: 4 - hvdroxv - 2 - (1-hvdroxv-2-methoxvethvh - N - (2-thiazolvO - 7 - chlor - 3 -ouinolincarboxamid.Found: C% 51.8 H% 3.5 N% 9.4 F% 12.8 S% 7.1 Example 9: 4 - Hydroxy - 2 - (1-Hydroxy-2-methoxyethyl) - N - (2 -thiazolvO-7-chloro-3-quinoline carboxamide.
14 DK 172034 B114 DK 172034 B1
Trin A: 2 - ((2-chlor-3-methoxy-1-oxopropyl)-amino) · p - oxo - N - (2-thiazolyl) · 4 -chlorbenzenpropanamid.Step A: 2 - ((2-Chloro-3-methoxy-1-oxopropyl) amino) p-oxo-N - (2-thiazolyl) 4-chlorobenzene propanamide.
Man arbejder i analogi med trin A i eksempel 1, idet man som udgangsmateriale benytter 2 -5 (1-chlor-2-methoxyethyl) - 7 - chlor- 4H - 3.1 - benzoxazin - 4 - on (smp. 82°C, fremstillet som beskrevet i trin A i eksempel 12 i europæisk patentskrift nr. 40 573 ud fra 2-chlor-3-methoxypropansyre og 2-amino-4-chlorbenzoesyre). Man får den forventede forbindelse med smp. 180°C i et udbytte på 76%.Analogous to step A of Example 1 is used, using as starting material 2 -5 (1-chloro-2-methoxyethyl) - 7 - chloro - 4H - 3.1 - benzoxazine - 4 - one (mp 82 ° C, prepared as described in Step A of Example 12 of European Patent No. 40,573 (from 2-chloro-3-methoxypropanoic acid and 2-amino-4-chlorobenzoic acid). You get the expected connection with m.p. 180 ° C in a yield of 76%.
10 Trin B: 2 - (1-chlor-2-methoxyethyl) - 4 - hydroxy - N - (2-thiazolyl) - 7 - chlor - 3 -quinolincarboxamid.Step B: 2- (1-Chloro-2-methoxyethyl) -4-hydroxy-N - (2-thiazolyl) -7-chloro-3-quinoline carboxamide.
Man arbejder i analogi med trin B i eksempel 1. Forbindelsen benyttes i det følgende uden isolation.One works in analogy with step B of Example 1. The compound is used in the following without isolation.
1515
Trin C: 1,3 - dihydro - 3 - (methoxymethyl) - 1 - ((2-thiazolyl)-imino) - 6 - chlorfuro - (3,4-b) -quinolin - 9 - ol.Step C: 1,3-dihydro-3- (methoxymethyl) -1 - ((2-thiazolyl) imino) -6-chlorofuro - (3,4-b) -quinolin-9-ol.
Man arbejder i analogi med trin C i eksempel 1 uden mellemliggende isolation af quinolinet fra 20 trin B ovenfor. Man arbejder med tilbageløb af tetrahydrofuran i 24 timer. Man får den forventede forbindelse med et udbytte på 65%. Smp. >270°C.One works in analogy with step C of Example 1 without intermediate isolation of the quinoline from step 20 above. Reflux of tetrahydrofuran is used for 24 hours. The expected compound is obtained with a yield of 65%. Mp. > 270 ° C.
Trin D: 4 - hydroxy - 2 - (1-hydroxy-2-methoxyethyl) - N - (2-thiazolyl) - 7 - chlor - 3 -quinolincarboxid.Step D: 4 - Hydroxy - 2- (1-hydroxy-2-methoxyethyl) - N - (2-thiazolyl) - 7 - chloro - 3 - quinoline carboxide.
2525
Man arbejder i analogi med trin D i eksempel 1, nu under omrøring i 6N saltsyre i 36 timer.Analogously to step D of Example 1, it is now stirred in 6N hydrochloric acid for 36 hours.
Man får den forventede forbindelse med smp. >270°C.You get the expected connection with m.p. > 270 ° C.
Eksempel 10: 2 - (1.2-dihvdroxvethvh - 4 - hvdroxv - N - (2-thiazolyl) - 7 - chlor - 3 -30 quinolincarboxamid.Example 10: 2- (1,2-Dihydroxyethyl) -4-hydroxy-N - (2-thiazolyl) -7-chloro-3-quinoline carboxamide.
Eksempel 11: Eksempel på farmaceutisk præparat.Example 11: Example of pharmaceutical composition.
Man fremstiller tabletter efter recepten: 35 Forbindelse iflg. eksempel 2..................................................................50 mgTablets are prepared according to the recipe: 35 Compound according to. Example 2 ................................................ .................. 50 mg
Tilsætningsstoffer til dannelse af tablet..................................................350 mg (enkeltheder vedr. tilsætningsstof: Laktose, talkum, stivelse, magnesiumstearat) 15 DK 172034 B1Tablet Additives ............................................. ..... 350 mg (details of additive: Lactose, talc, starch, magnesium stearate) 15 DK 172034 B1
Farmakologisk Undersøgelse:Pharmacological Study:
Betændelseshæmmende virkning: Kronisk arthritis frembragt med adjuvant (præventiv behandling).Anti-inflammatory effect: Chronic arthritis produced by adjuvant (preventive treatment).
55
Indsprøjtning af Freund’s adjuvans i en bagpote på en rotte frembringer hurtigt en primær inflammatorisk læsion i denne pote, derpå efter en latenstid på 13-15 dage udløsningen af en sekundær arthritis, som navnlig påvirker den anden bagpote.Testen er praktisk på 42-50 dage gamle hanrotter, som via en intraplantær indsprøjtning får 0,1 ml adjuvant af Freund's type 10 (suspension i vaselineolie af dræbte Mycobacterium butyricum 6 mg/ml).Injecting Freund's adjuvant into a rat's hind paw quickly produces a primary inflammatory lesion in this paw, then after a latency of 13-15 days, the triggering of a secondary arthritis affecting the other hind paw in particular. The test is convenient for 42-50 days. old male rats that receive 0.1 ml of Freund's type 10 adjuvant (suspension in petroleum jelly oil of killed Mycobacterium butyricum 6 mg / ml via intra-implant injection).
Dyrene får den undersøgte forbindelse oralt fra dag 0 (dagen for indsprøjtningen af adjuvant) indtil dagen før aflivning, som udføres på dag 17. Arthritiske kontroldyr og normale kontroldyr får kun vehiklet. Kriterier til vurdering af aktiviteten af de undersøgte stoffer er forøgelsen af 15 rumfanget af de injicerede bagpoter (primær og sekundær inflammation) og af ikke-injicerede bagpoter (sekundær inflammation) i forhold til gennemsnitsrumfanget af de tilsvarende poter hos kontroldyrene.The animals are given the tested compound orally from day 0 (the day of injection of adjuvant) until the day before killing, which is performed on day 17. Arthritic control animals and normal control animals are given vehicle only. Criteria for assessing the activity of the substances studied are the increase in volume of the injected hind paws (primary and secondary inflammation) and of non-injected hind paws (secondary inflammation) relative to the average volume of the corresponding paws in the control animals.
Man bestemmer AD50 , d.v.s. den dosis, som formindsker forøgelsen af rumfanget af 20 bagpoteme med 50% på de behandlede dyr i forhold til de kontroldyrene.AD50 is determined, i.e. the dose which reduces the increase in volume of the 20 hind legs by 50% on the treated animals relative to the control animals.
De fundne værdier for AD50 er ca. 2 mg/kg, 0,7 mg/kg, 3 mg/kg, 1 mg/kg og 5 mg/kg for forbindelserne ifølge henholdsvis eksempel 1,2, 3,4 og 5.The values found for AD50 are approx. 2 mg / kg, 0.7 mg / kg, 3 mg / kg, 1 mg / kg and 5 mg / kg for the compounds of Examples 1.2, 3.4 and 5 respectively.
25 Denne opfindelse omhandler således uventet nye stoffer, som er meget mere aktive end de, der blev nævnt i dokument DE 3 320 102. Stofferne i eksempel 2 og 10 i DE 3 320 102 havde således tilsvarende ADsg-værdier på henholdsvis 15 mg/kg og 12 mg/kg.Thus, this invention unexpectedly relates to novel substances which are much more active than those mentioned in document DE 3 320 102. Thus, the substances in Examples 2 and 10 of DE 3 320 102 had corresponding ADsg values of 15 mg / kg respectively. and 12 mg / kg.
30 3530 35
Claims (12)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8511389A FR2585356B1 (en) | 1985-07-25 | 1985-07-25 | NOVEL DERIVATIVES OF 4-OH QUINOLEINE CARBOXYLIC ACID SUBSTITUTED IN 2 BY TWO POSSIBLE ETHERIFIED OR ESTERIFIED HYDROXYL FUNCTIONS, THEIR PREPARATION PROCESSES, THE NEW INTERMEDIATES OBTAINED, THEIR APPLICATION AS MEDICAMENTS AND THE COMPOSITIONS |
| FR8511389 | 1985-07-25 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK351886D0 DK351886D0 (en) | 1986-07-24 |
| DK351886A DK351886A (en) | 1987-01-26 |
| DK172034B1 true DK172034B1 (en) | 1997-09-22 |
Family
ID=9321642
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK351886A DK172034B1 (en) | 1985-07-25 | 1986-07-24 | 4-OH-quinoline carboxylic acid derivatives, their preparation, intermediates in their preparation, and drugs containing them |
Country Status (16)
| Country | Link |
|---|---|
| EP (1) | EP0214004B1 (en) |
| JP (1) | JPH0710863B2 (en) |
| KR (1) | KR940003759B1 (en) |
| AT (1) | ATE87625T1 (en) |
| AU (1) | AU609377B2 (en) |
| CA (1) | CA1262903A (en) |
| DE (1) | DE3688161T2 (en) |
| DK (1) | DK172034B1 (en) |
| ES (1) | ES2000739A6 (en) |
| FI (1) | FI86426C (en) |
| FR (1) | FR2585356B1 (en) |
| GR (1) | GR861924B (en) |
| HU (1) | HU202526B (en) |
| PT (1) | PT83064B (en) |
| SU (1) | SU1584749A3 (en) |
| ZA (1) | ZA865260B (en) |
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| US4845105A (en) * | 1984-10-30 | 1989-07-04 | Roussel Uclaf | 4-OH-quinoline carboxylic acid amides having analgesic and anti-inflammatory activity |
| US5438344A (en) * | 1990-11-05 | 1995-08-01 | Oliva; Anthony | Portable video book |
| GB9108547D0 (en) * | 1991-04-22 | 1991-06-05 | Fujisawa Pharmaceutical Co | Quinoline derivatives |
| AU3339797A (en) * | 1996-06-20 | 1998-01-07 | Smithkline Beecham Plc | 4h-3,1-benzoxazin-4-one derivatives and analogs as antiviral agents |
| JP3337992B2 (en) * | 1997-11-04 | 2002-10-28 | ファイザー製薬株式会社 | 5-Substituted picolinic acid compound and method for producing the same |
| JP4804590B1 (en) | 2010-04-14 | 2011-11-02 | 帝人テクノプロダクツ株式会社 | Meta-type wholly aromatic polyamide fiber |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JPS593996B2 (en) * | 1975-11-25 | 1984-01-27 | キツセイ薬品工業株式会社 | 2-styryl-3,1-benzoxazin-4-one derivative and method for producing the same |
| JPS593995B2 (en) * | 1975-12-31 | 1984-01-27 | キツセイヤクヒンコウギヨウ カブシキガイシヤ | 2- Styryl -3,1- Benzoxazine -4- |
| FR2509728A1 (en) * | 1981-07-17 | 1983-01-21 | Roussel Uclaf | NOVEL QUINOLINE DERIVATIVES, THEIR SALTS, PREPARATION METHOD, MEDICAMENT APPLICATION AND COMPOSITIONS COMPRISING THE SAME |
| FR2530633A1 (en) * | 1982-06-03 | 1984-01-27 | Roussel Uclaf | NOVEL SUBSTITUTED 2-SUBSTITUTED 4-HYDROXY 3-QUINOLINE CARBOXYLIC ACID DERIVATIVES, THEIR PREPARATION, THEIR USE AS A MEDICINAL PRODUCT, AND THE COMPOSITIONS COMPRISING THE SAME |
| FR2566405B1 (en) * | 1984-06-25 | 1986-09-26 | Roussel Uclaf | NOVEL DERIVATIVES OF 4-HYDROXY 3-QUINOLEINE CARBOXYLIC ACID SUBSTITUTED IN 2 BY AN AMINE FUNCTION, THEIR PREPARATION, THEIR APPLICATION AS MEDICAMENTS, THE COMPOSITIONS CONTAINING THEM AND THE INTERMEDIATES NEW OBTAINED |
| ZA871658B (en) * | 1986-03-27 | 1987-08-28 | Warner-Lambert Company | Chewing gum and confectionery compositions containing a soy flavor enhancer |
-
1985
- 1985-07-25 FR FR8511389A patent/FR2585356B1/en not_active Expired
-
1986
- 1986-07-08 HU HU862842A patent/HU202526B/en not_active IP Right Cessation
- 1986-07-15 ZA ZA865260A patent/ZA865260B/en unknown
- 1986-07-22 JP JP61170961A patent/JPH0710863B2/en not_active Expired - Fee Related
- 1986-07-23 GR GR861924A patent/GR861924B/en unknown
- 1986-07-23 SU SU864027833A patent/SU1584749A3/en active
- 1986-07-24 AU AU60509/86A patent/AU609377B2/en not_active Ceased
- 1986-07-24 ES ES8600554A patent/ES2000739A6/en not_active Expired
- 1986-07-24 CA CA000514629A patent/CA1262903A/en not_active Expired
- 1986-07-24 DE DE86401661T patent/DE3688161T2/en not_active Expired - Fee Related
- 1986-07-24 EP EP86401661A patent/EP0214004B1/en not_active Expired - Lifetime
- 1986-07-24 DK DK351886A patent/DK172034B1/en not_active IP Right Cessation
- 1986-07-24 AT AT86401661T patent/ATE87625T1/en not_active IP Right Cessation
- 1986-07-24 KR KR1019860006045A patent/KR940003759B1/en not_active IP Right Cessation
- 1986-07-24 FI FI863040A patent/FI86426C/en not_active IP Right Cessation
- 1986-07-25 PT PT83064A patent/PT83064B/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| EP0214004A3 (en) | 1989-04-05 |
| PT83064A (en) | 1986-08-01 |
| DK351886A (en) | 1987-01-26 |
| AU6050986A (en) | 1987-01-29 |
| DE3688161D1 (en) | 1993-05-06 |
| FI863040A (en) | 1987-01-26 |
| PT83064B (en) | 1989-02-28 |
| JPH0710863B2 (en) | 1995-02-08 |
| ATE87625T1 (en) | 1993-04-15 |
| HU202526B (en) | 1991-03-28 |
| KR870001206A (en) | 1987-03-12 |
| ES2000739A6 (en) | 1988-03-16 |
| JPS6229585A (en) | 1987-02-07 |
| SU1584749A3 (en) | 1990-08-07 |
| FR2585356B1 (en) | 1987-10-23 |
| FI863040A0 (en) | 1986-07-24 |
| AU609377B2 (en) | 1991-05-02 |
| ZA865260B (en) | 1987-09-30 |
| GR861924B (en) | 1986-11-25 |
| EP0214004B1 (en) | 1993-03-31 |
| KR940003759B1 (en) | 1994-04-30 |
| FI86426C (en) | 1992-08-25 |
| HUT43598A (en) | 1987-11-30 |
| FR2585356A1 (en) | 1987-01-30 |
| CA1262903A (en) | 1989-11-14 |
| DK351886D0 (en) | 1986-07-24 |
| FI86426B (en) | 1992-05-15 |
| DE3688161T2 (en) | 1993-10-14 |
| EP0214004A2 (en) | 1987-03-11 |
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