NO139786B - ANALOGICAL PROCEDURE FOR PREPARATION OF PHARMACEUTICAL ACTIVE N- (5-TETRAZOLYL) -PYRIMIDO- (1,2-A) QUINOLINE-2-CARBOXAMIDE DERIVATIVES - Google Patents
ANALOGICAL PROCEDURE FOR PREPARATION OF PHARMACEUTICAL ACTIVE N- (5-TETRAZOLYL) -PYRIMIDO- (1,2-A) QUINOLINE-2-CARBOXAMIDE DERIVATIVES Download PDFInfo
- Publication number
- NO139786B NO139786B NO762411A NO762411A NO139786B NO 139786 B NO139786 B NO 139786B NO 762411 A NO762411 A NO 762411A NO 762411 A NO762411 A NO 762411A NO 139786 B NO139786 B NO 139786B
- Authority
- NO
- Norway
- Prior art keywords
- quinoline
- pyrimido
- tetrazolyl
- methoxy
- approx
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 13
- 238000002360 preparation method Methods 0.000 title claims abstract description 5
- IIVOKVCOQAGREM-UHFFFAOYSA-N n-(2h-tetrazol-5-yl)-1h-pyrimido[1,2-a]quinoline-2-carboxamide Chemical class C=1N=C2C=CC3=CC=CC=C3N2CC=1C(=O)NC=1N=NNN=1 IIVOKVCOQAGREM-UHFFFAOYSA-N 0.000 title description 2
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- ACTNHJDHMQSOGL-UHFFFAOYSA-N n',n'-dibenzylethane-1,2-diamine Chemical class C=1C=CC=CC=1CN(CCN)CC1=CC=CC=C1 ACTNHJDHMQSOGL-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
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- LOAUVZALPPNFOQ-UHFFFAOYSA-M quinaldate Chemical compound C1=CC=CC2=NC(C(=O)[O-])=CC=C21 LOAUVZALPPNFOQ-UHFFFAOYSA-M 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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- Pharmacology & Pharmacy (AREA)
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- Pulmonology (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract
Analogifremgangsmåte for fremstilling av farmasøytisk aktive N-(5-tetrazolyl)-pyrimido-i_l, 2-a] kinolin-2-karboksamid-derivater.Analogous process for the preparation of pharmaceutically active N- (5-tetrazolyl) -pyrimido-1,2-a] quinoline-2-carboxamide derivatives.
Description
Denne oppfinnelse vedrører fremstilling av N-(5-tetra-zolyl) -pyrimido[1,2-a]kinolin-2-karboksamider og derivater derav. This invention relates to the preparation of N-(5-tetrazolyl)-pyrimido[1,2-a]quinoline-2-carboxamides and derivatives thereof.
Mer spesielt vedrører den fremstilling More particularly, it relates to manufacturing
av N-tetrazolyl-l-okso-lH-6-(R^-substituert)pyrimido[1,2-a] - kinolin-2-karboksamider hvor 6-substituenten er klor, brom eller lavere alkoksy; farmasøytisk akseptable kationiske salter derav; og derivater av slike forbindelser hvor benzenringen bærer en eller flere substituenter, hvilke er nyttige som midler for behandling av allergiske reaksjoner, og spesielt allergisk bronkial astma. of N-tetrazolyl-1-oxo-1H-6-(R^-substituted)pyrimido[1,2-a]-quinoline-2-carboxamides where the 6-substituent is chlorine, bromine or lower alkoxy; pharmaceutically acceptable cationic salts thereof; and derivatives of such compounds in which the benzene ring bears one or more substituents, which are useful as agents for the treatment of allergic reactions, and especially allergic bronchial asthma.
Allergiske reaksjoner, de symptomer som kommer av en gjensidig innvirkning mellom antigen og antilegeme, utfolder seg på en rekke måter og i forskjellige organer og vev. Vanlige allergiske forstyrrelser er for eksempel allergisk rhinitis som er en tilstand som er kjennetegnet ved nysing, enten visse tider av året eller hele året, rennende nese, nasal kongestion, med kløe og kongestion i øynene; høy-feber, en type av allergiske rhinitiser som stammer fra hypersensitivitet overfor blomster- Allergic reactions, the symptoms resulting from a mutual impact between antigen and antibody, unfold in a number of ways and in different organs and tissues. Common allergic disorders are, for example, allergic rhinitis which is a condition characterized by sneezing, either certain times of the year or all year round, runny nose, nasal congestion, with itching and congestion in the eyes; hay fever, a type of allergic rhinitis originating from hypersensitivity to floral
støv fra gressbevokst mark; og bronkial astma, en av de mest svekkende og avkreftende av allergiske reaksjoner, en sykdom som er kjennetegnet ved hyper-reaktivitet for bronkiene ved ut-settelse for forskjellige immunogene eller ikke-immunogene stimuli, hvilket resulterer i bronkospasme med kvesende, kort- dust from grassy ground; and bronchial asthma, one of the most debilitating and debilitating of allergic reactions, a disease characterized by hyper-reactivity of the bronchi upon exposure to various immunogenic or non-immunogenic stimuli, resulting in bronchospasm with wheezing, short-
varige paroksysmer og omfattende sammentrekning av luftveis- lasting paroxysms and extensive contraction of the respiratory
gangene. Den mekaniske hindring av luftstrømmen i luftveiene blir vanligvis reversert ved anvendelse av bronkodilatorer, the times. The mechanical obstruction of airflow in the airways is usually reversed by the use of bronchodilators,
hvilke tilveiebringer symptomatisk lindring. I motsetning til dette hindrer antiallergene midler frigjørelse av anafylaksi-formidlere fra vev-forråd, og virker derved på en profylaktisk måte til å utelukke frembringelse av bronkiesammentrekning med formidlerne. which provides symptomatic relief. In contrast, antiallergic agents prevent the release of anaphylaxis mediators from tissue stores, thereby acting in a prophylactic manner to preclude the production of bronchoconstriction by the mediators.
Det har i utstrakt grad vært gjort forsøk på å oppdage medisinske midler for å lindre symptomene på den unormale fysiologiske tilstand. Så tidlig som i 1910 omtalte Matthews, Extensive attempts have been made to discover medicinal agents to alleviate the symptoms of the abnormal physiological condition. As early as 1910, Matthews mentioned,
Brit. Med. J., _1, 441 (1910), bronkodilatorisk effekt av Brit. With. J., _1, 441 (1910), bronchodilatory effect of
epinefrin. Siden da har Chen og Schmidt, J. Pharmacol. Exper. Therap. , 24, 339 (1924) , omtalt anvendelse av et alkaloid epinephrine. Since then, Chen and Schmidt, J. Pharmacol. Exper. Therapy. , 24, 339 (1924) , discussed the use of an alkaloid
efedrin som oralt effektiv bronkodilator med det samme, aktivitets-spektrum som epinefrin. I 1940 gav Konzett, Arch. Exp. Path. Pharmak., 197, 27 (1940), en oversikt over virkningene av den kraftige aerosol-bronkodilatoren isoproterenol. Cullum et al., ephedrine as an orally effective bronchodilator with the same spectrum of activity as epinephrine. In 1940 Konzett, Arch. Exp. Path. Pharmak., 197, 27 (1940), a review of the effects of the potent aerosol bronchodilator isoproterenol. Cullum et al.,
Brit. J. Pharmacol. Exp., 35_, 141 (1969), omtalte farmakologien Brit. J. Pharmacol. Exp., 35_, 141 (1969), discussed the pharmacology
til salbutamol, som er en kraftig bronkodilator med forlenget varighet som er aktiv både via oral og aerosol administrasjon. to salbutamol, which is a powerful bronchodilator with extended duration that is active both via oral and aerosol administration.
Mange bronkodilator-preparater inneholder teofyllin. Disse er vanligvis ikke så kraftige som de sympatomimetiske aminer, så Many bronchodilator preparations contain theophylline. These are usually not as potent as the sympathomimetic amines, so
som isoproterenol og salbutamol, og de er ineffektive ved aerosol administrasjon. such as isoproterenol and salbutamol, and they are ineffective in aerosol administration.
Nylig har Cox og medarbeidere, Adv. i Drug Res., _5, Recently, Cox et al., Adv. in Drug Res., _5,
115 (1970), beskrevet farmakologien til ett slikt middel, dinatrium-cromoglykat [1,3-bis(2-karboksy-cromon-5-yloksy)-2-hydroksypropan, Intall. Dette er ikke en bronkodilator, men dens terapeutiske effekt formidles ved en enestående virknings-mekanisme som omfatter inhibering av frigivelse av anafylaksi-formidlere, og forbindelsen administreres profylaktisk. Den lider av mangel på oral effektivitet og for å oppnå optimale resultater administreres den ved inhalering som et fast inhalerings-middel. Dessuten, selv om den er effektiv mot anafylaksi som skyldes immunoglobulin E (IgE), så er den effektiv mot anafyl- 115 (1970), described the pharmacology of one such agent, disodium cromoglycate [1,3-bis(2-carboxy-cromon-5-yloxy)-2-hydroxypropane, Intall. This is not a bronchodilator, but its therapeutic effect is mediated by a unique mechanism of action involving inhibition of the release of anaphylaxis mediators, and the compound is administered prophylactically. It suffers from a lack of oral efficacy and to achieve optimal results it is administered by inhalation as a solid inhalant. Moreover, although it is effective against anaphylaxis due to immunoglobulin E (IgE), it is effective against anaphylaxis
aksi som skyldes immunoglobulin G (IgG) bare ved høye dosiser (60-70 % beskyttelse ved 100 og 300 mg/kg). action due to immunoglobulin G (IgG) only at high doses (60-70% protection at 100 and 300 mg/kg).
Selv om de forannevnte midler betyr fremragende bidrag Although the aforementioned funds mean outstanding contributions
til behandling av astma, så utøver mange av dem uønskede bi-virkninger på hjertestimuleringen. for the treatment of asthma, many of them exert unwanted side effects on the cardiac stimulation.
Syntesen av lH-pyrimido[1,2-a]kinolin synes først å ha blitt omtalt av Antaki et al., J. Chem. Soc., sidene 551-555 (1951), som kondenserte 2-klorkinolin med etyl-/3-amino-krotonat i nærvær av vannfritt kaliumkarbonat og spor av kobber-bronse for å danne l-okso-lH-3-metylpyrimido[l,2-a]kinolin. Det ble ikke angitt noen utnyttelse av forbindelsen. The synthesis of 1H-pyrimido[1,2-a]quinoline appears to have been first reported by Antaki et al., J. Chem. Soc., pp. 551-555 (1951), who condensed 2-chloroquinoline with ethyl .beta.-3-amino-crotonate in the presence of anhydrous potassium carbonate and traces of copper-bronze to form 1-oxo-1H-3-methylpyrimido[l ,2-a]quinoline. No utilization of the compound was indicated.
Antaki, J. Am. Chem. Soc, 80, 3066-9 (1958), omtaler kondensasjon av 2-aminokinolin og etyl-etoksymetylencyanoacetat for å danne etyl-2-kinolylaminometylencyanoacetat som, når det ble destillert under redusert trykk, gav 1-okso-lH-pyrimido[1,2-a]kinolin-2-karbonitril. Forbindelsen fremviste antischistoso-mal virkning. Antaki, J. Am. Chem. Soc, 80, 3066-9 (1958), reports the condensation of 2-aminoquinoline and ethyl ethoxymethylene cyanoacetate to form ethyl 2-quinolylaminomethylene cyanoacetate which, when distilled under reduced pressure, gave 1-oxo-1H-pyrimido[1, 2-a]quinoline-2-carbonitrile. The compound exhibited antischistosoma activity.
Richardson et al., J. Med. Chem., _15, 1203-6 (1972), be-skriver etyl-l-okso-lH-pyrimido[1,2-a]kinolin-2-karboksylat og angir at det er inaktivt som antimikrobielt middel. Når det ble testet med hensyn til antiallergen aktivitet ved PCA-testen, ble det funnet at det fremviste 100 % inhibering ved 3 mg/kg ved intravenøs (I.V.) administrasjon men var uten aktivitet ved 1 mg/kg I.V. Tilnærmet 90 % inhibering ble vist ved 30 mg/kg ved oral administrasjon, men oral aktivitet var ikke til stede ved en dosis på 10 mg/kg ved oral administrasjon. Richardson et al., J. Med. Chem., 15, 1203-6 (1972), describes ethyl 1-oxo-1H-pyrimido[1,2-a]quinoline-2-carboxylate and states that it is inactive as an antimicrobial agent. When tested for antiallergenic activity by the PCA test, it was found to exhibit 100% inhibition at 3 mg/kg by intravenous (I.V.) administration but was without activity at 1 mg/kg I.V. Approximately 90% inhibition was shown at 30 mg/kg by oral administration, but oral activity was not present at a dose of 10 mg/kg by oral administration.
Det har nå blitt funnet at forbindelser med formelen It has now been found that compounds with the formula
er verdifulle antiallergene midler, det vil si midler som inhi- are valuable antiallergenic agents, i.e. agents that inhibit
berer frigivelse av anafylaksi-formidlere i pattedyr, innbefattet mennesker, og utelukker på denne måte frembringelse av bronkiesammentrekning ved formidlerne. De er ikke bronkodilatorer. De er, i motsetning til dinatrium-cromoglykat, av praktisk betydning mot anafylaksi formidlet av både IgG og IgE ved oral, intranasal og intraperitoneal administrasjon, og ved inhalering. I denne formel er hver av R^ og R2 valgt fra gruppen bestående av hydrogen, lavere alkyl, lavere alkoksy, fluor og klor; R^ og R£induces the release of anaphylaxis mediators in mammals, including humans, and thus excludes the production of bronchoconstriction by the mediators. They are not bronchodilators. They are, in contrast to disodium cromoglycate, of practical importance against anaphylaxis mediated by both IgG and IgE by oral, intranasal and intraperitoneal administration, and by inhalation. In this formula, each of R 1 and R 2 is selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, fluorine and chlorine; R^ and R£
er, når de tas sammen, metylendioksy eller etylendioksy; og R^ er valgt fra gruppen bestående av klor, brom og lavere alkoksy; are, taken together, methylenedioxy or ethylenedioxy; and R 1 is selected from the group consisting of chlorine, bromine and lower alkoxy;
og de farmasøytisk akseptable salter derav. and the pharmaceutically acceptable salts thereof.
Når uttrykkene "lavere alkyl" og "lavere alkoksy" an- When the terms "lower alkyl" and "lower alkoxy" an-
1 1
vendes her, er det meningen at de skal referere til alkyl- og alkoksygrupper som har fra ett til fem karbonatomer, siden de reaktanter som er nødvendige for å fremstille slike forbindelser er lettere tilgjengelige enn slike som har større alkyl-eller alkoksy-grupper. referred to herein, they are intended to refer to alkyl and alkoxy groups having from one to five carbon atoms, since the reactants necessary to prepare such compounds are more readily available than those having larger alkyl or alkoxy groups.
Ved uttrykket "farmasøytisk akseptable By the expression “pharmaceutically acceptable
salter" er det ment slike salter som alkalimetallsalter, for eksempel natrium- og kaliumsalter; jordalkalimetallsalter, så som kalsium- og magnesium-salter; aluminiumsalter; ammonium-salter; og salter med organiske baser, for eksempel med aminer så som trietylamin, tri-n-butylamin, piperidin, trietanolamin, dietylaminoetylamin, N,N'-dibenzyletylendiamin og pyrrolidin. "salts" means such salts as alkali metal salts, for example sodium and potassium salts; alkaline earth metal salts, such as calcium and magnesium salts; aluminum salts; ammonium salts; and salts with organic bases, for example with amines such as triethylamine, tri- n-butylamine, piperidine, triethanolamine, diethylaminoethylamine, N,N'-dibenzylethylenediamine and pyrrolidine.
De 5-substituerte tetrazoler, som er kjent, kan forekomme i to isomere former, nemlig: The 5-substituted tetrazoles, which are known, can occur in two isomeric forms, namely:
som eksisterer sammen i en dynamisk, tautomer likevekts- which coexist in a dynamic, tautomeric equilibrium
blanding. Begge former av tetrazolylamidene er innbefattet i omfanget av denne oppfinnelse. mixture. Both forms of the tetrazolylamides are included within the scope of this invention.
Den antiallergene aktivitet til de tilsvarende syrer, The antiallergenic activity of the corresponding acids,
nemlig l-okso-lH-6-alkoksypyrimido[1,2-a]kinolin-2-karboksyl- namely 1-oxo-1H-6-alkoxypyrimido[1,2-a]quinoline-2-carboxyl-
syrer og estere derav, er beskrevet i acids and esters thereof, are described in
US-patent 4.066.766. De her be- US Patent 4,066,766. They here be-
skrevne forbindelser fremviser et betydelig bredere spektrum med antiallergen aktivitet enn de tilsvarende syrer og estere gjør. Deres antiallergene aktivitet er virkelig overraskende siden de tilsvarende enkle amider [for eksempel -C0NH2, -C0N(C2- written compounds exhibit a significantly wider spectrum of antiallergenic activity than the corresponding acids and esters do. Their antiallergenic activity is really surprising since the corresponding simple amides [for example -C0NH2, -C0N(C2-
Hc)0] er inaktive som antiallergene midler når de blir testet Hc)0] are inactive as antiallergenic agents when tested
ved metodene beskrevet nedenfor. by the methods described below.
Forbindelser av spesiell interesse for denne opp- Compounds of special interest for this up-
finnelse, er slike hvor R., er metoksy eller etoksy og de benzenoid-variable (R^, R2) er hydrogen, og slike hvor R3 er metoksy og minst en av benzenoid-substituentene er lavere alkoksy eller fluor og den gjenværende benzenoid-substituent er hydrogen. invention, are those where R 1 is methoxy or ethoxy and the benzenoid variables (R 1 , R 2 ) are hydrogen, and those where R 3 is methoxy and at least one of the benzenoid substituents is lower alkoxy or fluorine and the remaining benzenoid substituent is hydrogen.
De antiallergene egenskaper til forbindelsene i henhold The antiallergenic properties of the compounds according to
til denne oppfinnelse blir vurdert ved den passive kutane anafylaksi (PCA) test (Ovary, J. Immun., 81., 355, 1958). Ved PCA-testen blir normale dyr injisert intradermalt (i.d.) med antilegemer som inneholdes i serum erholdt fra aktivt sensiti- to this invention is assessed by the passive cutaneous anaphylaxis (PCA) test (Ovary, J. Immun., 81., 355, 1958). In the PCA test, normal animals are injected intradermally (i.d.) with antibodies contained in serum obtained from active sensi-
serte dyr. Dyrene blir så provosert intravenøst med antigen blandet med et fargestoff så som Evans' blått. Den økede kapillare permeabilitet forårsaket av antigen-antilegeme-reaksjonen, fører til at fargestoffet lekker bort fra injiseringsstedet for anti-legemet. Test-dyrene blir så asfyksiert og intensiteten ved reaksjonen bestemmes ved å måle diameteren og intensiteten av blåfargingen på den indre overflate av dyrenes hud. cute animals. The animals are then challenged intravenously with antigen mixed with a dye such as Evans' blue. The increased capillary permeability caused by the antigen-antibody reaction causes the dye to leak away from the injection site of the antibody. The test animals are then asphyxiated and the intensity of the reaction is determined by measuring the diameter and intensity of the blue staining on the inner surface of the animals' skin.
Forbindelsene med formel I fremstilles ifølge foreliggende oppfinnelse ved dehydratiserende kobling av en tilsvarende 1-okso-1H-6-(R^-substituert)pyrimido[1,2-a]kinolin-2-karboksylsyre (formel II i krav 1) med 5-aminotetrazol. Den dehydratiserende kobling blir utført ved hjelp av et koblingsmiddel som vanligvis blir anvendt ved peptid-synteser. Representative midler inn- The compounds of formula I are prepared according to the present invention by dehydrating coupling of a corresponding 1-oxo-1H-6-(R^-substituted)pyrimido[1,2-a]quinoline-2-carboxylic acid (formula II in claim 1) with 5 -aminotetrazole. The dehydrating coupling is carried out using a coupling agent which is usually used in peptide syntheses. Representative funds in-
befatter N,N '-karbonyldiimidazol, N ,N '-karbonyl-di-s-triazin, etoksyacetylen, 1,1-diklordietyleter, difenyl-keten p-tolylimin, N-hydroksyftalimid, N-hydroksysuccinimid, N-hydroksypiperidin, etylen-klorfosfitt, dietyletylen-pyrofosfitt, N-etyl-5-feny1-isoksazolium-3'-sulfonat, fenylfosforodi(1-imidazolat) og karbodiimider så som dicykloheksylkarbodiimid, l-cykloheksyl-3-(2-morfolino-metyl)karbodiimid, N-(3-dimetylaminopropy1)-N '-etyl-karbodiimid-hydroklorid, l-etyl-3-(3'-dimetylaminopropyl)karbo-diimidhydroklorid og dietyl-cyanamid. comprises N,N '-carbonyldiimidazole, N,N'-carbonyl-di-s-triazine, ethoxyacetylene, 1,1-dichlorodiethyl ether, diphenyl-ketene p-tolylimine, N-hydroxyphthalimide, N-hydroxysuccinimide, N-hydroxypiperidine, ethylene- chlorophosphite, diethylethylene pyrophosphite, N-ethyl-5-phenyl-isoxazolium-3'-sulfonate, phenylphosphorodi(1-imidazolate) and carbodiimides such as dicyclohexylcarbodiimide, l-cyclohexyl-3-(2-morpholino-methyl)carbodiimide, N- (3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride and diethylcyanamide.
De ovenfor beskrevne koblingsmidler omsettes vanligvis The coupling agents described above are usually traded
først med syrereaktanten og det resulterende produkt omsettes så first with the acid reactant and the resulting product is then reacted
uten isolering med 5-aminotetrazol for å oppnå de ønskede N-(5-tetrazolyl)-l-okso-lH-6-(R3~substituert)pyrimido[1,2-a]-kinolin-2-karboksamider. Omsetningen blir utført i et reaksjons- without isolation with 5-aminotetrazole to obtain the desired N-(5-tetrazolyl)-1-oxo-1H-6-(R3-substituted)pyrimido[1,2-a]-quinoline-2-carboxamides. The turnover is carried out in a reaction
inert oppløsningsmiddel-1 system hvori syre-reaktanten ikke behøver inert solvent-1 system in which the acid reactant does not need
å være oppløselig. Det eneste krav til oppløsningsmiddel- to be soluble. The only requirement for solvent-
systemet er at det ikke inngår i noen merkbar omsetning med reaktantene eller produktene. Den mangfoldighet med koblings- system is that it does not enter into any appreciable exchange with the reactants or products. The diversity of coupling
midler som kan anvendes for å foreta den dehydratiserende kobling, gir anledning til et bredt valg av oppløsningsmidler. Representative oppløsningsmidler er N,N-dimetylformamid, tetra-hydrofuran, dioksan, metylenklorid, nitrometan og acetonitril. means that can be used to carry out the dehydrating coupling, give rise to a wide choice of solvents. Representative solvents are N,N-dimethylformamide, tetrahydrofuran, dioxane, methylene chloride, nitromethane and acetonitrile.
Omsetningen av syre-reaktanten med koblingsmidlet blir The reaction of the acid reactant with the coupling agent becomes
utført ved en temperatur på fra ca. 20 til ca. 110°C. Det reaktive mellomprodukt blir så omsatt med 5-aminotetrazol ved fra ca. 20 til 110°C. Hvert av disse trinn blir fordelaktig utført ved fra ca. 50 til ca. 100°C siden dette gir forbedret hastighet og utbytte ved omsetningen. carried out at a temperature of from approx. 20 to approx. 110°C. The reactive intermediate is then reacted with 5-aminotetrazole at from approx. 20 to 110°C. Each of these steps is advantageously carried out by from approx. 50 to approx. 100°C since this gives improved speed and yield at turnover.
Mol-forholdet syre:koblingsmidde1:5-aminotetrazol er The molar ratio of acid:coupling agent is 1:5-aminotetrazole
vanligvis fra ca. 1:1:1 til ca. 1:1,1:1,1. Det kan anvendes høyere forhold mellom koblingsmiddel og 5-aminotetrazol, men dette gir ingen fordeler. Overskudd på 10 mol% er tilfreds- usually from approx. 1:1:1 to approx. 1:1,1:1,1. A higher ratio between coupling agent and 5-aminotetrazole can be used, but this offers no advantages. An excess of 10 mol% is satis-
stillende . silent.
Som fagfolk i industrien vil være oppmerksom på, kan As industry professionals will note, can
alle reaktanter tilsettes straks i stedet for ved den trinnvise måten som er beskrevet ovenfor. Imidlertid gir forhåndsdannelse av av det reaktive (syre-koblingsmiddel-produkt)-mellomprodukt vanligvis bedre utbytte av de ønskede N-(5-tetrazolyl)amider. all reactants are added at once rather than in the stepwise manner described above. However, preformation of the reactive (acid-coupling agent-product) intermediate usually gives better yields of the desired N-(5-tetrazolyl)amides.
Et foretrukket koblingsmiddel er N,N'-karbonyldiimidazol„ siden dette gir en glatt omsetning og rimelig utbytte av det ønskede produkt uten å optimalisere reaksjonsforholdene. Når man anvender dette koblingsmiddel, er N,N-dimetylformamid og en temperatur på fra 85 til 100°C foretrukne forhold, av årsaker som er nevnt ovenfor. A preferred coupling agent is N,N'-carbonyldiimidazole, since this gives a smooth conversion and reasonable yield of the desired product without optimizing the reaction conditions. When using this coupling agent, N,N-dimethylformamide and a temperature of from 85 to 100°C are preferred conditions, for reasons mentioned above.
De forbindelser hvor er alkoksy blir også bekvemt The compounds where is alkoxy also become convenient
fremstilt ved Williamson-reaksjonen mellom et passende N-(5-tetrazolyl)-l-okso-lH-6-klor(eller brom)pyrimido[1,2-a]kinolin-2-karboksamid og et passende alkanol som eksemplifisert her. prepared by the Williamson reaction between an appropriate N-(5-tetrazolyl)-1-oxo-1H-6-chloro(or bromo)pyrimido[1,2-a]quinoline-2-carboxamide and an appropriate alkanol as exemplified herein.
De nødvendige l-okso-lH-6-(R^-substituert)pyrimido[1,2-a]-kinolin-2-karboksylsyrer blir fremstilt ved kondensasjon av et passende 2-amino-4-(R^-substituertJkinolin med et passende dialkyl-etoksymetylenmalonat for å danne det tilsvarende dialkyl-4-(R^-substituert)-2-kinolyl-aminometylenmalonat-mellomprodukt som så The required 1-oxo-1H-6-(R^-substituted)pyrimido[1,2-a]-quinoline-2-carboxylic acids are prepared by condensation of an appropriate 2-amino-4-(R^-substituted)quinoline with a appropriate dialkyl-ethoxymethylenemalonate to form the corresponding dialkyl-4-(R^-substituted)-2-quinolyl-aminomethylenemalonate intermediate which then
blir ringsluttet til det ønskede alkyl-l-okso-lH-6-(R^-substituert)-pyrimido[1,2-a]kinolin-2-karboksylat. is ring-closed to the desired alkyl-1-oxo-1H-6-(R 1 -substituted)-pyrimido[1,2-a]quinoline-2-carboxylate.
Kondensasjonen blir utført ved å oppvarme en støkio-metrisk blanding av 2-aminokinolin-reaktanten og dialkyl-etoksymetylenmalonatet ved en temperatur på fra ca. 80 til ca. 125°C. Det er ikke ønskelig med lavere temperaturer på grunn av at omsetningen da går for sakte. Det kan anvendes høyere temperaturer, men dette gir ikke noen fordeler. Omsetningen blir således bekvemt utført i smelte. Den kan selvsagt utføres i et oppløsningsmiddel eller en blanding av oppløsningsmidler, for eksempel etanol, N,N-dimetylformamid, acetonitril. Men fra et praktisk synspunkt synes det unødvendig med oppløsningsmiddel. The condensation is carried out by heating a stoichiometric mixture of the 2-aminoquinoline reactant and the dialkyl ethoxymethylene malonate at a temperature of from approx. 80 to approx. 125°C. It is not desirable to have lower temperatures because the turnover is then too slow. Higher temperatures can be used, but this does not offer any advantages. The turnover is thus conveniently carried out in melt. It can of course be carried out in a solvent or a mixture of solvents, for example ethanol, N,N-dimethylformamide, acetonitrile. But from a practical point of view, solvent seems unnecessary.
Det således fremstilte dialkyl-4-(R^-substituert)-2-kinolylaminometylenmalonat-mellomprodukt blir så ringsluttet, fortrinnsvis termisk, ved oppvarming til en temperatur på fra ca. 175 til ca. 250°C i et egnet reaksjons-inert fortynningsmiddel, det vil si en forbindelse som gir anledning til at man kan regulere reaksjonstemperaturen, som er stabil ved de relativt høye temperaturer som anvendes og som ikke omsettes med utgangsmaterialene eller produktene av ringslutningen. Eksempler på slike fortynningsmidler er høyt-kokende hydro-karboner så som perhydronaftalen, mineralolje, dietylbenzen, eddiksyreanhydrid inneholdende svovelsyre, difenyleter og difenyl, spesielt de som inneholder 26,5 % difenyl og 73,5 % difenyleter og selges under varemerket "Dowtherm A". The thus prepared dialkyl-4-(R^-substituted)-2-quinolylaminomethylenemalonate intermediate is then ring-closed, preferably thermally, by heating to a temperature of from approx. 175 to approx. 250°C in a suitable reaction-inert diluent, i.e. a compound which allows the reaction temperature to be regulated, which is stable at the relatively high temperatures used and which does not react with the starting materials or the products of the ring closure. Examples of such diluents are high-boiling hydrocarbons such as perhydronaphthalene, mineral oil, diethylbenzene, acetic anhydride containing sulfuric acid, diphenyl ether and diphenyl, especially those containing 26.5% diphenyl and 73.5% diphenyl ether and sold under the trademark "Dowtherm A" .
Alkyl-l-okso-lH-6-(R^-substituert)pyrimido[1,2-a] - kinolin-2-karboksylåtene blir omdannet til de tilsvarende syrer ved hydrolyse, fortrinnsvis syrehydrolyse. De vanlige forhold omfatter oppvarming av en vandig blanding av en passende ester og en mineralsyre, så som saltsyre, svovelsyre, fosforsyre eller salpetersyre, fra ca. 50 til ca. 100°C i perioder på opp til 4 timer eller inntil hydrolysen i alt vesentlig er fullført. The alkyl-1-oxo-1H-6-(R^-substituted)pyrimido[1,2-a]-quinoline-2-carboxylates are converted to the corresponding acids by hydrolysis, preferably acid hydrolysis. The usual conditions include heating an aqueous mixture of a suitable ester and a mineral acid, such as hydrochloric, sulfuric, phosphoric or nitric acid, from about 50 to approx. 100°C for periods of up to 4 hours or until the hydrolysis is substantially complete.
Den foretrukne mineralsyre er saltsyre i en konsentrasjon på The preferred mineral acid is hydrochloric acid at a concentration of
fra 3n til 12n. Desto mindre oppløselig ester-reaktanten er i vann, desto mer konsentrert er syren som anvendes ved hydrolysen. De fri syrer krystalliserer vanligvis fra hydrolysereaksjons-blandingen etter avkjøling, og utvinnes ved filtrering. Når det ikke foregår krystallisering, utvinnes syrene ved inndamping av reaksjonsblandingen. Syrene blir renset ved omkrystallisering fra egnede oppløsningsmidler, så som N,N-dimetylformamid. from 3n to 12n. The less soluble the ester reactant is in water, the more concentrated the acid used in the hydrolysis. The free acids usually crystallize from the hydrolysis reaction mixture after cooling, and are recovered by filtration. When no crystallization takes place, the acids are recovered by evaporation of the reaction mixture. The acids are purified by recrystallization from suitable solvents, such as N,N-dimethylformamide.
Salt-dannelsen blir utført ved å omsette en passende syre med et passende metallsalt, så som et karbonat, bikarbonat, The salt formation is carried out by reacting a suitable acid with a suitable metal salt, such as a carbonate, bicarbonate,
acetat, heksanoat, hydroksyd, i et egnet medium, så som vann, acetate, hexanoate, hydroxide, in a suitable medium, such as water,
metanol eller etanol, i henhold til velkjente fremgangsmåter. methanol or ethanol, according to well-known methods.
Saltene blir utvunnet ved standard-metoder, så som ved fil- The salts are extracted by standard methods, such as by
trering dersom de er uoppløselige i mediet, ved inndamping av oppløsningsmidlet dersom de er løselige i mediet eller ved utfelning ved tilsetning av et ikke-oppløsningsmiddel for saltet. triring if they are insoluble in the medium, by evaporation of the solvent if they are soluble in the medium or by precipitation by adding a non-solvent for the salt.
Som angitt ovenfor, fremviser N-(5-tetrazolyl)amidene fremstilt ifølge oppfinnelsen et tydelig bredere spektrum av antiallergen aktivitet enn forløper-syrene. Disse syrer er effektive til å inhibere bare anafylaktiske fenomener formidlet av immunoglobin E (IgE). I motsetning til dette er N-(5-tetrazolyl)amidene ikke bare effektive mot reaginisk indusert anafylaksi (IgE, immunoglobin E), men også mot anafylaksi indusert av immunoglobin G (IgG). Denne oppførsel står også As stated above, the N-(5-tetrazolyl)amides prepared according to the invention exhibit a clearly wider spectrum of antiallergenic activity than the precursor acids. These acids are effective in inhibiting only anaphylactic phenomena mediated by immunoglobin E (IgE). In contrast, the N-(5-tetrazolyl)amides are effective not only against reaginin-induced anaphylaxis (IgE, immunoglobin E), but also against anaphylaxis induced by immunoglobin G (IgG). This behavior also stands
i kontrast til virkningen av dinatrium-cromoglykat som ikke inhiberer reaksjoner formidlet av IgG unntatt ved høye dosiser. in contrast to the action of disodium cromoglycate which does not inhibit reactions mediated by IgG except at high doses.
Produktene fremstilt ifølge oppfinnelsen og de The products manufactured according to the invention and those
farmasøytisk akseptable kationiske salter derav er nyttige som profylaktiske midler til å inhibere eller hindre frigjøring av anafylaksi-formidlere (allergi, umiddelbare hypertensive reak- pharmaceutically acceptable cationic salts thereof are useful as prophylactic agents to inhibit or prevent the release of anaphylaxis mediators (allergy, immediate hypertensive reactions
sjoner) og forekomsten av allergiske symptomer hos pattedyr, og de kan for slike anvendelser administreres enkeltvis eller som blandinger med andre midler, for eksempel med teofyllin eller sympatomimetiske aminer. De kan administreres alene, men vanligvis administreres de sammen med en farmasøytisk bærer som velges på basis av den valgte administrasjonsmåte og vanlig farmasøytisk praksis. De kan for eksempel kombineres med forskjellige farmasøytisk akseptable inerte bærere i form av tions) and the occurrence of allergic symptoms in mammals, and for such applications they can be administered singly or as mixtures with other agents, for example with theophylline or sympathomimetic amines. They can be administered alone, but usually they are administered together with a pharmaceutical carrier which is selected on the basis of the chosen route of administration and common pharmaceutical practice. They can, for example, be combined with various pharmaceutically acceptable inert carriers in the form of
tabletter, kapsler, terninger, trochéer, hårdt sukkertøy, tablets, capsules, cubes, troches, hard candy,
pulvere, aerosol-spray, vandige suspensjoner eller oppløsninger, injiserbare oppløsninger, eliksirer, siruper og lignende. Slike bærere innbefatter faste fortynningsmidler eller fyllstoffer, powders, aerosol sprays, aqueous suspensions or solutions, injectable solutions, elixirs, syrups and the like. Such carriers include solid diluents or fillers,
sterile vandige medier og forskjellige ikke-toksiske organiske oppløsningsmidler. Dessuten kan de orale farmasøytiske bland- sterile aqueous media and various non-toxic organic solvents. Moreover, the oral pharmaceutical mix-
inger i henhold til denne oppfinnelse på passende måte gjøres søte og aromatiserte ved hjelp av forskjellige midler av den type som vanligvis anvendes for dette formål. ings according to this invention are suitably sweetened and flavored by means of various agents of the type commonly used for this purpose.
Forbindelsene kan administreres til astmatiske personer The compounds can be administered to asthmatic subjects
som lider av bronkiesammentrekning ved hjelp av inhalasjons- who suffer from bronchoconstriction by means of inhalation
apparater eller andre midler som tillater at de aktive for- devices or other means that allow the active
bindelser kommer i direkte kontakt med de sammentrukne steder på vevet til personen. Når blandingene administreres ved inhalering, kan de omfatte (1) en oppløsning eller suspensjon av den aktive ingrediens i et flytende medium av den type som er nevnt ovenfor for administrasjon via en tåkedanner, (2) en suspensjon eller oppløsning av den aktive ingrediens i et flytende drivmiddel, så som dikloridfluormetan eller klortri-fluoretan, for administrasjon fra en beholder under trykk, bonds come into direct contact with the contracted places on the tissue of the person. When the compositions are administered by inhalation, they may comprise (1) a solution or suspension of the active ingredient in a liquid medium of the type mentioned above for administration via a nebulizer, (2) a suspension or solution of the active ingredient in a liquid propellant, such as dichlorofluoromethane or chlorotrifluoroethane, for administration from a pressurized container,
eller (3) en blanding av den aktive ingrediens og et fast fortynningsmiddel (for eksempel laktose) for administrasjon fra en pulver-inhaleringsanordning. Blandinger som er egnet for inhalering ved hjelp av en konvensjonell tåkedanner, vil omfatte fra ca. 0,1 til ca. 1 % med aktiv bestanddel, og blandinger for anvendelse i beholdere under trykk vil omfatte fra ca. 0,5 til ca. 2 % med aktiv ingrediens. Blandinger for anvendelse som pulverinhaleringsmidler kan omfatte forhold mellom aktiv ingrediens og fortynningsmiddel på fra ca. 1:0,5 or (3) a mixture of the active ingredient and a solid diluent (eg lactose) for administration from a powder inhalation device. Mixtures suitable for inhalation using a conventional nebulizer will include from approx. 0.1 to approx. 1% with active ingredient, and mixtures for use in pressurized containers will include from approx. 0.5 to approx. 2% with active ingredient. Mixtures for use as powder inhalants may comprise ratios between active ingredient and diluent of from approx. 1:0.5
til ca. 1:1,5. to approx. 1:1.5.
Det er nødvendig at den aktive ingrediens utgjør en slik andel av blandingen at det erholdes en egnet dosisform. Det er åpenbart at det kan administreres flere dosis-enhetsformer om- It is necessary that the active ingredient constitutes such a proportion of the mixture that a suitable dosage form is obtained. It is obvious that several dosage unit forms can be administered if
trent samtidig. Selv om det kan anvendes blandinger med mindre enn 0,005 vekt% med aktiv ingrediens i visse tilfeller, så er det foretrukket å anvende blandinger som ikke inneholder mindre enn 0,005 % med aktiv ingrediens, for ellers vil mengden med bærer bli overdrevent stor. Aktiviteten øker med konsentra- trained at the same time. Although mixtures with less than 0.005% by weight of active ingredient can be used in certain cases, it is preferred to use mixtures that do not contain less than 0.005% of active ingredient, because otherwise the amount of carrier will be excessively large. The activity increases with concentra-
sjonen av den aktive ingrediens. Blandingen kan inneholde 10, tion of the active ingredient. The mixture may contain 10,
50, 75, 95 eller endog høyere vektprosenter med aktiv ingre- 50, 75, 95 or even higher weight percentages with active ingredients
diens . service
Med hensyn til dosis-kuren med forbindelsene fremstilt With respect to the dosage regimen with the compounds prepared
ifølge oppfinnelsen, så vil legene til sist bestemme den dosis som vil være mest egnet for en spesiell person, og den vil variere med alder, vekt og mottagelignet hos den spesielle pasient, og også med naturen og graden av symptomene, de farmakodynamiske egenskaper til det spesielle middel som skal administreres og den valgte administrasjonsmåte. Det vil vanlig- according to the invention, the doctors will ultimately determine the dose that will be most suitable for a particular person, and it will vary with the age, weight and susceptibility of the particular patient, and also with the nature and degree of the symptoms, the pharmacodynamic properties of the particular agent to be administered and the chosen method of administration. It will usually-
vis bli administrert små dosiser til å begynne med, og med gradvis økning av dosisen inntil en optimal mengde er bestemt. small doses should be administered to begin with, and gradually increasing the dose until an optimal amount is determined.
Man vil ofte finne at når blandingen administreres oralt, vil It will often be found that when the mixture is administered orally,
det være nødvendig med større mengder av aktiv ingrediens for å larger amounts of active ingredient may be required to
oppnå samme virkning som erholdes med en mindre mengde admini- achieve the same effect as is obtained with a smaller amount of administration
strert parenteralt. stred parenterally.
Under fullstendig hensynstagen til de foregående In full consideration of the foregoing
faktorer, mener man at en effektiv daglig oral eller intraperi- factors, it is believed that an effective daily oral or intraperi-
toneal dosis av forbindelsene fremstilt ifølge foreliggende oppfinnelse til mennesker på fra ca. 10 til ca. 1500 mg pr. dag, toneal dose of the compounds produced according to the present invention to humans of from approx. 10 to approx. 1500 mg per day,
med et foretrukket område på fra ca. 10 til ca. 600 mg pr. with a preferred range of from approx. 10 to approx. 600 mg per
dag, i en enkelt eller i oppdelte dosiser, eller på ca. 0,2 day, in a single or divided doses, or in approx. 0.2
til ca. 12 mg/kg kroppsvekt, effektivt vil lindre bronkiesammentrekning hos mennesker. Disse verdier er illustrerende, to approx. 12 mg/kg body weight, will effectively relieve bronchial constriction in humans. These values are illustrative,
og det kan selvsagt være enkelte tilfeller hvor det er fordel- and there may of course be certain cases where it is advantageous
aktig med høyere eller lavere dosis-områder. similar to higher or lower dose ranges.
Ved intravenøs administrasjon eller inhalering, er By intravenous administration or inhalation, is
den effektive dosis på fra ca. 0,05 til ca. 400 mg pr. dag, og fortrinnsvis fra ca. 0,25 til 200 mg pr. dag, eller fra ca. the effective dose of from approx. 0.05 to approx. 400 mg per day, and preferably from approx. 0.25 to 200 mg per day, or from approx.
0,005 til 4 mg/kg kroppsvekt, i enkeltvise eller oppdelte dosiser. 0.005 to 4 mg/kg body weight, in single or divided doses.
De samme to basis-forandringer er til stede når det The same two base changes are present when
dreier seg om anafylaktisk sjokk: (1) en økning i kaplllar-permeabiliteten og (2) sammentrekning av glatte muskler. Den økede kapillar-permeabilitet er et resultat av gjensidig på- involves anaphylactic shock: (1) an increase in capillary permeability and (2) contraction of smooth muscles. The increased capillary permeability is a result of mutual
virkning mellom antigen og antilegeme. Den, og sammentrek- interaction between antigen and antibody. The, and contraction-
ningen av glatte muskler, kan iakttas og lett måles. Denne økning i kapillar-permeabilitet danner basis for PCA-testen. the development of smooth muscles can be observed and easily measured. This increase in capillary permeability forms the basis for the PCA test.
PCA-testen er et mål på den anti-allergene (spesielt anti-astmatiske) aktivitet til en forbindelse. Forbindelser som inhiberer en positiv PCA-test som er forårsaket av den rotte-immunokjemiske motpart til menneskelig immunoglobulin E The PCA test is a measure of the anti-allergenic (especially anti-asthmatic) activity of a compound. Compounds that inhibit a positive PCA test caused by the rat immunochemical counterpart of human immunoglobulin E
(IgE), eller reagin, anses for å ha antiallergen aktivitet (C. Mota, Ann. N.Y. Acad. Sei., 103, 264, 1963). (Reagin er (IgE), or reagin, is considered to have antiallergenic activity (C. Mota, Ann. N.Y. Acad. Sei., 103, 264, 1963). (Reagin is
primært immunoglobulin E[IgE] og er det prinsipale immuno- primarily immunoglobulin E[IgE] and is the principal immuno-
globulin som er ansvarlig for allergisk astma, anafylaksi, globulin responsible for allergic asthma, anaphylaxis,
høy-feber, næringsmiddel-sensitiviteter og visse utslag av medikament-sensitiviteter). Når slike forbindelser administreres til et sensitisert forsøksobjekt, menneske eller dyr, high fever, food sensitivities and certain effects of drug sensitivities). When such compounds are administered to a sensitized test subject, human or animal,
før den tiden da forsøksobjektet kommer i kontakt med antigener eller substanser som det er allergisk overfor, vil de hindre den allergiske reaksjon som ellers vil forekomme. De tilveiebringer derfor en metode for profylaktisk behandling av allergi eller anafylaktiske reaksjoner av en reagin-formidlet natur. before the time when the test subject comes into contact with antigens or substances to which he is allergic, they will prevent the allergic reaction that would otherwise occur. They therefore provide a method for the prophylactic treatment of allergy or anaphylactic reactions of a reagin-mediated nature.
Sagt på en annen måte, så blokkerer slike forbindelser frigjøringen av formidlere som stammer fra antigen-antilegeme-reaksjonen (allergisk), så som illustrert ved PCA-testen ved anvendelse av rotte-homocytotropisk antilegeme - et kjent korre-lat på menneskelig reaginisk antilegeme. Inhibering av reaginiske antigen-antilegeme-reaksjoner i rotter, som er test-dyret ved PCA-testen, blir betraktet som representativt for inhibering In other words, such compounds block the release of mediators derived from the antigen-antibody (allergic) reaction, as illustrated by the PCA test using rat homocytotropic antibody - a known correlate of human reaginic antibody. Inhibition of reaginic antigen-antibody reactions in rats, which is the test animal of the PCA test, is considered representative of inhibition
av menneskelige reaginiske antigen-antilegeme-reaksjoner som forekommer under allergiske episoder. of human reaginic antigen-antibody reactions occurring during allergic episodes.
PCA-reaksjonstest-fremgangsmåten som blir anvendt The PCA reaction test method used
for å vurdere forbindelsene i henhold til foreliggende oppfinnelse, fremviser en utmerket korrelasjon mellom aktiviteten til forbindelsene ved denne test og deres anvendbarhet ved behandling av allergisk astma. Evnen for midlene til å inn-virke på PCA-reaksjoner blir målt på Charles River Wistar hann-rotter på 170-210 g. Reaginisk antiserum som er rikt på IgE antilegemer, blir fremstilt i henhold til Petillo et al., Int. Arch. Allergy, 44, 309 (1973). Hyperimmunt antiserum som er to evaluate the compounds of the present invention, shows an excellent correlation between the activity of the compounds in this test and their utility in the treatment of allergic asthma. The ability of the agents to affect PCA reactions is measured on 170-210 g male Charles River Wistar rats. Reaginic antiserum rich in IgE antibodies is prepared according to Petillo et al., Int. Arch. Allergy, 44, 309 (1973). Hyperimmune antiserum that is
rikt på IgG antilegemer til hønse-egg-albumin, blir fremstilt i henhold til Orange et al., J. Exptl. Med., 127, 767 (1968). rich in IgG antibodies to hen-egg albumin is prepared according to Orange et al., J. Exptl. Med., 127, 767 (1968).
48 timer før antigen-provoseringen blir det reaginiske antiserum injisert intradermalt (i.d.) i den barberte hud på en normal rotte-rygg, og 5 timer før provoseringen blir de hyperimmune antisera injisert på samme måte. På et tredje sted blir 60 meg histamin-dihydroklorid og .0,5 meg serotonin-kreatinin-sulfat injisert i.d. like før antigen-provoseringen som en kontroll av antihistaminisk, antiserotoninisk og uspesi-fiserte typer av blokkering, og forbindelsene i henhold til foreliggende oppfinnelse eller saltoppløsninger blir så administrert i.v. og dette blir øyeblikkelig fulgt av provosering av 5 mg egg-albumin og 2,5 mg Evans' blått fargestoff i saltopp-løsning. Når det dreier seg om oral administrasjon blir Evans' blått fargestoff og egg-albumin gitt 5 minutter etter admini-streringen av medikamentet. 30 minutter senere blir dyrene asfyksiert ved anvendelse av kloroform og huden på ryggen blir fjernet og snudd om for iakttagelse. Det blir tildelt poeng for hvert injiseringssted som. er lik produktet av diameteren til stedet i mm og en gradering på 0,1, 0,5, 1, 2, 3 og 4 som er proporsjonal med intensiteten av fargingen med fargestoffet. Poengene for et gitt injeksjonssted blir summert for hver gruppe på 5 dyr og blir sammenlignet med sammenligningsdyrene som er behandlet med saltoppløsning. Differansen blir uttrykt som % blokkering som skyldes den anvendte forbindelse. 48 hours before the antigen challenge, the reaginic antiserum is injected intradermally (i.d.) into the shaved skin of a normal rat back, and 5 hours before the challenge, the hyperimmune antisera are injected in the same way. At a third site, 60 meg histamine dihydrochloride and .0.5 meg serotonin-creatinine sulfate are injected i.d. just before the antigen challenge as a control of antihistaminic, antiserotoninic and unspecified types of blockade, and the compounds according to the present invention or saline solutions are then administered i.v. and this is immediately followed by challenge with 5 mg of egg albumin and 2.5 mg of Evans blue dye in saline. In the case of oral administration, Evans' blue dye and egg albumin are given 5 minutes after the administration of the drug. 30 minutes later the animals are asphyxiated using chloroform and the skin on the back is removed and turned over for observation. Points are awarded for each injection site which. is equal to the product of the diameter of the spot in mm and a gradation of 0.1, 0.5, 1, 2, 3 and 4 which is proportional to the intensity of staining with the dye. The scores for a given injection site are summed for each group of 5 animals and compared to the saline-treated control animals. The difference is expressed as % blocking due to the compound used.
Forbindelser som er representative for forbindelsene fremstilt ifølge oppfinnelsen, blir testet med hensyn til antiallergen aktivitet ved den ovenfor beskrevne fremgangsmåte, og de resulterende aktiviteter blir angitt som beskyttelsesgrad (%). Inital, dinatrium-cromoglykat, et kommersielt anti-allergent middel, tas med for sammenligning. Compounds which are representative of the compounds prepared according to the invention are tested with respect to antiallergenic activity by the method described above, and the resulting activities are indicated as degree of protection (%). Inital, disodium cromoglycate, a commercial anti-allergen agent, is included for comparison.
De testede forbindelser har formelen The tested compounds have the formula
Eksempel I Example I
N-(5-tetrazolyl)-l-okso-lH-6-metoksypyrimido[1,2-a]-kinolin- 2- karboksamid N-(5-tetrazolyl)-1-oxo-1H-6-methoxypyrimido[1,2-a]-quinoline-2-carboxamide
En blanding av l-okso-lH-6-metoksypyrimido[l,2-a]-kinolin-2-karboksylsyre (540 mg, 2,0 mmol) og N,N'-karbonyldiimidazol (357 mg, 2,2 mmol) i N,N-dimetylformamid (15 ml) A mixture of 1-oxo-1H-6-methoxypyrimido[1,2-a]-quinoline-2-carboxylic acid (540 mg, 2.0 mmol) and N,N'-carbonyldiimidazole (357 mg, 2.2 mmol) in N,N-dimethylformamide (15 mL)
blir rørt og oppvarmet på et dampbad i 15 minutter. Etter tilnærmet 5 minutters oppvarming dannes det en klar oppløsning, fulgt av dannelse av en utfelning. Reaksjonsblandingen blir rørt i ytterligere 45 minutter ved omgivelsenes temperatur og blir så behandlet med 5-aminotetrazol (187 mg, 2,2 mmol). Blandingen blir oppvarmet på et dampbad i 40 minutter og blir is stirred and heated on a steam bath for 15 minutes. After approximately 5 minutes of heating, a clear solution is formed, followed by the formation of a precipitate. The reaction mixture is stirred for an additional 45 minutes at ambient temperature and is then treated with 5-aminotetrazole (187 mg, 2.2 mmol). The mixture is heated on a steam bath for 40 minutes and remains
så avkjølt og filtrert for å utvinne produktet (540 mg med gult fast stoff) , sm.p. 220°C (spalting). then cooled and filtered to recover the product (540 mg of yellow solid), m.p. 220°C (decomposition).
Det blir renset ved oppløsning i varmt N,N-dimetyl-formamid med et forhold på 200 mg urenset produkt pr. 20 ml oppløsningsmidde1, og så filtreres den varme oppløsning og filtratet bråkjøles. De gule krystaller filtreres og tørkes, sm.p. 255°C (spalting). It is purified by dissolving in hot N,N-dimethylformamide at a ratio of 200 mg of impure product per 20 ml of solution mite1, and then the hot solution is filtered and the filtrate is quenched. The yellow crystals are filtered and dried, m.p. 255°C (decomposition).
Analyse: Beregnet for ci5Hn°3<N>7<:><c>» <5>3,41, H, 3,29, N, 29,07 % Analysis: Calculated for ci5Hn°3<N>7<:><c>» <5>3.41, H, 3.29, N, 29.07%
Funnet: C, 53,12, H, 3,67, N, 28,75 % De følgende forbindelser blir fremstilt på lignende Found: C, 53.12, H, 3.67, N, 28.75% The following compounds are prepared similarly
måte fra passende reaktanter: way from suitable reactants:
Produktet fra eksempel VIII blir renset ved oppløsning i ammoniumhydroksyd (6n) hvorfra produktet utfelles ved hen-stand. Det faste stoff blir filtrert, oppløst i vann og utfelt fra oppløsningen ved surgjøring med 3n saltsyre. Det blir filtrert, tørket og omkrystallisert fra N,N-dimetylformamid. The product from example VIII is purified by dissolving in ammonium hydroxide (6n) from which the product precipitates on standing. The solid is filtered, dissolved in water and precipitated from the solution by acidification with 3N hydrochloric acid. It is filtered, dried and recrystallized from N,N-dimethylformamide.
Produktet fra eksempel IX blir renset ved omkrystallisering fra N,N-dimetylformamid, fulgt av samme rensemetode som for produktet i eksempel VIII. The product from example IX is purified by recrystallization from N,N-dimethylformamide, followed by the same purification method as for the product in example VIII.
Eksempel X Example X
De forbindelser som er angitt i tabellen, blir fremstilt fra passende reaktanter ved fremgangsmåten angitt i eksempel I. The compounds indicated in the table are prepared from suitable reactants by the method indicated in Example I.
Eksempel XI Example XI
N- (5-tetrazolyl)-l-okso-lH-6-etoksypyrimido[1,2-a]-kinolin- 2- karboksamid N-(5-tetrazolyl)-1-oxo-1H-6-ethoxypyrimido[1,2-a]-quinoline-2-carboxamide
En blanding av p-toluensulfonsyre-monohydrat (20 ml) og N- (5-tetrazolyl)-l-okso-lH-6-klorpyrimido[1,2-a]kinolin-2-karboksamid (1,79 g) i etanol (75 ml) blir oppvarmet med til-bakeløpskjøling i 24 timer. Oppløsningsmidlet blir fjernet under redusert trykk og residuet blir fordelt mellom 3n saltsyre (25 ml) og etylacetat (100 ml). Fasene blir separert og etylacetat-fasen blir ekstrahert med 3n saltsyre (2 x 20 ml). Syre-ekstraktene blir forenet, gjort nøytrale (pH 7-8) med 20 % ammoniumhydroksyd og den resulterende utfelning blir utvunnet ved filtrering (235 mg). A mixture of p-toluenesulfonic acid monohydrate (20 mL) and N-(5-tetrazolyl)-1-oxo-1H-6-chloropyrimido[1,2-a]quinoline-2-carboxamide (1.79 g) in ethanol (75 mL) is heated under reflux for 24 h. The solvent is removed under reduced pressure and the residue is partitioned between 3N hydrochloric acid (25 mL) and ethyl acetate (100 mL). The phases are separated and the ethyl acetate phase is extracted with 3N hydrochloric acid (2 x 20 ml). The acid extracts are combined, neutralized (pH 7-8) with 20% ammonium hydroxide and the resulting precipitate is recovered by filtration (235 mg).
Fremgangsmåten ovenfor blir gjentatt, men ved anvendelse av /3-klor (eller brom) produktene fra eksempel X og passende alkanol, for å gi forbindelsene i tabellen nedenfor: The above procedure is repeated, but using the /3-chloro (or bromo) products of Example X and the appropriate alkanol, to give the compounds in the table below:
Eksempel XII Example XII
Salt- dannelse Salt formation
Produktene fra eksemplene I-XI blir omdannet til natrium-, kalium-, ammonium-, kalsium-, magnesium-, aluminium-, trietylamin-, tri-n-butylamin-, piperidin-, trietanolamin-, dietylaminoetylamin-, pyrrolidin- og N,N-dibenzyletylendiamin-salter ved omsetning med en ekvivalent av et passende metall-hydroksyd, ammoniumhydroksyd eller amin i vann eller etanol, fulgt av filtrering av saltet dersom det er uoppløselig eller ved inndamping av oppløsningsmidlet dersom saltet er opp-løselig i dette. The products of Examples I-XI are converted into sodium, potassium, ammonium, calcium, magnesium, aluminum, triethylamine, tri-n-butylamine, piperidine, triethanolamine, diethylaminoethylamine, pyrrolidine, and N ,N-dibenzylethylenediamine salts by reaction with one equivalent of a suitable metal hydroxide, ammonium hydroxide or amine in water or ethanol, followed by filtration of the salt if it is insoluble or by evaporation of the solvent if the salt is soluble therein.
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US4127720A (en) * | 1977-09-21 | 1978-11-28 | Bristol-Myers Company | Pyrimido[2,1-a]isoquinoline derivatives having antiallergy activity |
US4192944A (en) * | 1978-04-03 | 1980-03-11 | Bristol-Myers Company | Optionally substituted 4-oxo-4H-pyrido[1,2-a]pyrimidine-3-N-(1H-tetrazol-4-yl)carboxamides and their use as antiallergy agents |
JPS55138593U (en) * | 1979-03-27 | 1980-10-02 | ||
WO1997037999A1 (en) * | 1996-04-04 | 1997-10-16 | University Of Nebraska Board Of Regents | Synthetic triple helix-forming compounds |
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