NO762736L - - Google Patents
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- Publication number
- NO762736L NO762736L NO762736A NO762736A NO762736L NO 762736 L NO762736 L NO 762736L NO 762736 A NO762736 A NO 762736A NO 762736 A NO762736 A NO 762736A NO 762736 L NO762736 L NO 762736L
- Authority
- NO
- Norway
- Prior art keywords
- carbon atoms
- compound
- formula
- alkyl
- hydrogen
- Prior art date
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- 150000001875 compounds Chemical class 0.000 claims description 28
- 125000004432 carbon atom Chemical group C* 0.000 claims description 22
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 5
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 125000000304 alkynyl group Chemical group 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 26
- 229960001340 histamine Drugs 0.000 description 13
- 239000002585 base Substances 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 241000700159 Rattus Species 0.000 description 8
- 239000012981 Hank's balanced salt solution Substances 0.000 description 7
- 150000003839 salts Chemical class 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 4
- 108010058846 Ovalbumin Proteins 0.000 description 4
- 150000008040 ionic compounds Chemical class 0.000 description 4
- 210000002966 serum Anatomy 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 239000001045 blue dye Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 3
- 210000003630 histaminocyte Anatomy 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 3
- 230000002269 spontaneous effect Effects 0.000 description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 206010070834 Sensitisation Diseases 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 2
- 150000008046 alkali metal hydrides Chemical class 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000008313 sensitization Effects 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 1
- BCHZICNRHXRCHY-UHFFFAOYSA-N 2h-oxazine Chemical compound N1OC=CC=C1 BCHZICNRHXRCHY-UHFFFAOYSA-N 0.000 description 1
- QHKFZZRBKMFSAY-UHFFFAOYSA-N 4-hydroxy-1-methyl-3-nitro-1,8-naphthyridin-2-one Chemical compound C1=CC=C2C(O)=C([N+]([O-])=O)C(=O)N(C)C2=N1 QHKFZZRBKMFSAY-UHFFFAOYSA-N 0.000 description 1
- LETPTABXMDGFBW-UHFFFAOYSA-N 4-hydroxy-3-nitro-1h-1,8-naphthyridin-2-one Chemical class C1=CC=C2C(=O)C([N+]([O-])=O)=C(O)NC2=N1 LETPTABXMDGFBW-UHFFFAOYSA-N 0.000 description 1
- 206010027654 Allergic conditions Diseases 0.000 description 1
- 241000588832 Bordetella pertussis Species 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical class [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- 235000001188 Peltandra virginica Nutrition 0.000 description 1
- 244000197580 Poria cocos Species 0.000 description 1
- 235000008599 Poria cocos Nutrition 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000906446 Theraps Species 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 201000009961 allergic asthma Diseases 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229920002055 compound 48/80 Polymers 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- WJJMNDUMQPNECX-UHFFFAOYSA-N dipicolinic acid Chemical compound OC(=O)C1=CC=CC(C(O)=O)=N1 WJJMNDUMQPNECX-UHFFFAOYSA-N 0.000 description 1
- FTKASJMIPSSXBP-UHFFFAOYSA-N ethyl 2-nitroacetate Chemical compound CCOC(=O)C[N+]([O-])=O FTKASJMIPSSXBP-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 229940066827 pertussis vaccine Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
Fremgangsmåte for fremstilling avMethod of manufacture of
organiske forbindelserorganic compounds
Foreliggende oppfinnelse vedrorer en fremgangsmåte for fremstilling åv 3-nitro-4-hydroxy-pyrido (2,3-b)pyridin-2(1H)-on-forbindelser med den generelle formel I: hvori R er hydrogen, alkyl med 1 til 6 karbonatomer, alkenyl med 3 til 6 karbonatomer, alkynyl med 3 til 6 karbonatomer, cycloalkyl med 3 til 6 karbonatomer, cycloalkylalkyl hvori cycloalkyl-gruppen inneholder 3 til 6 karbonatomer og alkyl-delen inneholder 1 til 2 karbonatomer» eller The present invention relates to a process for the preparation of 3-nitro-4-hydroxy-pyrido (2,3-b)pyridin-2(1H)-one compounds of the general formula I: in which R is hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 3 to 6 carbon atoms, alkynyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, cycloalkylalkyl in which the cycloalkyl group contains 3 to 6 carbon atoms and the alkyl portion contains 1 to 2 carbon atoms" or
hvori Y og Y' uavhengig betyr hydrogen, fluor, klor, brom, alkyl med 1 til 3 karbonatomer, alkoxy med 1 til 3 karbonatomer eller trifluorometyl, og wherein Y and Y' independently represent hydrogen, fluorine, chlorine, bromine, alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms or trifluoromethyl, and
n = 0 eller 1,n = 0 or 1,
med den betingelse at umettetheten i en hvilken som helst alkenyl-eller alkynyl-gruppe er ikke på alfa-karbonatomene, og with the proviso that the unsaturation in any alkenyl or alkynyl group is not on the alpha carbon atoms, and
R1og R» er uavhengig av hverandre hydrogen eller alkyl med 1 til 4 R1 and R» are independently hydrogen or alkyl of 1 to 4
1z0 1z0
karbonatomer, med den betingelse at R , og;.^ ikke alle er hydrogen. carbon atoms, with the proviso that R , and;.^ are not all hydrogen.
Det særegne ved fremgangsmåten i henhold til oppfinnelsen for fremstilling av forbindelsene med formel I, er at en forbindelse med formel II: hvori R°, R^ og har den ovennevnte betydning , i et inert organisk losningsmiddel omsettes med produktet fra behandlingen av en forbindelse med formel III The peculiarity of the method according to the invention for the production of the compounds of formula I is that a compound of formula II: in which R°, R^ and have the above meaning, in an inert organic solvent is reacted with the product from the treatment of a compound with formula III
hvori R<1>er alkyl med 1 til 5 karbonatomer, med en sterk base. wherein R<1> is alkyl of 1 to 5 carbon atoms, with a strong base.
Reaksjonen kan gjennomfores ved temperaturer på 20 - 200° C, foretrukket i et aprotisk losningsmiddel, og under i det vesentlige vannfri betingelser. Eksempler på foretrukne 16sningsmiddler omfatter dimethylacetamide, dimethylformamide og tetrahydrofuran, mer foretrukket dimethylacetamide. Foretrukne temperaturer er fra 50 - 150° c og det foretrekkes vanlig og initiere reaksjonen ved en temperatur på fra omtrent 50 - 100° C og deretter å fullfore reaksjonen ved fra 100 - 150° C. Mslforholdet mellom produktet fra behandlingen av forbindelsen III med en sterk base og forbindelsen II er passende i området fra 0,8:1 til 2:1, foretrukket omtrent 1:1. Reaksjonstidene er av størrelsesorden 2 til 30 timer, mer vanlig 5 til 20 timer. The reaction can be carried out at temperatures of 20 - 200° C, preferably in an aprotic solvent, and under essentially anhydrous conditions. Examples of preferred quenching agents include dimethylacetamide, dimethylformamide and tetrahydrofuran, more preferably dimethylacetamide. Preferred temperatures are from 50 - 150° C and it is usually preferred to initiate the reaction at a temperature of from about 50 - 100° C and then to complete the reaction at from 100 - 150° C. The msl ratio of the product from the treatment of compound III with a strong base and compound II is suitably in the range of 0.8:1 to 2:1, preferably about 1:1. The reaction times are of the order of 2 to 30 hours, more commonly 5 to 20 hours.
Passende sterke baser er dem som kan tiltrekke et proton fra forbindelsene méd formel III til å gi den tilsvarende ioniske forbindelse med formel HIA Suitable strong bases are those which can attract a proton from the compounds of formula III to give the corresponding ionic compound of formula HIA
hvori R<1>har den ovennevnte betydning og vr er kationet avledet fra den sterke base. Eksempler på slike baser er alkali metal hydrider, butyl lithium-forbindelser og tertiere aminer, alkali metal hydrider som f.eks. natriumhydrid og kaliumhydrid som spesielt foretrukket. wherein R<1> has the above meaning and vr is the cation derived from the strong base. Examples of such bases are alkali metal hydrides, butyl lithium compounds and tertiary amines, alkali metal hydrides such as sodium hydride and potassium hydride as particularly preferred.
Molforholdet mellom sterk base og forbindelsen med formel IIIThe molar ratio of strong base to the compound of formula III
er passende minst 0,8:1 og foretrukket mellom 0,9:1 og 1,5:1,is suitably at least 0.8:1 and preferably between 0.9:1 and 1.5:1,
mer foretrukket 1:1.more preferably 1:1.
Dannelsen av ioniske forbindelser med formel HIA gjennomfores passende ved en temperatur på fra -100 til +150° C, foretrukket 10 til 50° C, i et organisk losningsmiddel, passende som ovenfor beskrevet for fremstilling av forbindelsen med formel I. The formation of ionic compounds of formula HIA is conveniently carried out at a temperature of from -100 to +150° C, preferably 10 to 50° C, in an organic solvent, suitable as described above for the preparation of the compound of formula I.
Reaksjonen kan gjennomfores ved samtidig å blande forbindelsene IIog ili med den sterke, base i.:det inert organisk losningsmiddel, under temperaturbetingelser slik at den ioniske forbindelse HIA vil reagere direkte med forbindelsen II. Det foretrekkes imidlertid The reaction can be carried out by simultaneously mixing the compounds II and II with the strong base i.: the inert organic solvent, under temperature conditions so that the ionic compound HIA will react directly with the compound II. However, it is preferred
at forbindelsen III hovedsakelig omdannes til den ioniske forbindelse HIA for den underkastes betingelser hvorunder reaksjonen med forbindelsen II foregår. Mest fortrukket omsettes forbindelsen III med sterk base for å fremstille forbindelsen HIA i fravær av forbindelsen II, og forbindelsen HIA omsettes deretter med forbindelsen II.. that the compound III is mainly converted into the ionic compound HIA because it is subjected to conditions under which the reaction with the compound II takes place. Most preferably, compound III is reacted with strong base to produce compound HIA in the absence of compound II, and compound HIA is then reacted with compound II.
Forbindelsen med formeler II og III er kjente eller kan fremstilles på konvensjonell måte fra kjente forbindelser. The compound of formulas II and III are known or can be prepared in a conventional manner from known compounds.
Forbindelsen med formel I kan isoleres fra reaksjonsblandingen på konvensjonell måte, for eksempel omfattende en behandling med en protonkilde som f.eks. en vanlig mineralsyre. The compound of formula I can be isolated from the reaction mixture in a conventional manner, for example comprising a treatment with a proton source such as e.g. a common mineral acid.
Forbindelsen med formel I kan foreligge i den viste form, med en fri sur hydroxylgruppe, eller i form av deres basesalter. Salter og fri syreformer kan omdannes mellom hverandre på konvensjonell måte, og når saltformen er saltet avledet fra den sterke base anvendt ved fremstillingen av forbindelsen med formel I, kan den oppnås fra reaksjonsblandingen uten isolering av den fri syreform. The compound of formula I may exist in the form shown, with a free acidic hydroxyl group, or in the form of their base salts. Salts and free acid forms can be converted between each other in a conventional manner, and when the salt form is the salt derived from the strong base used in the preparation of the compound of formula I, it can be obtained from the reaction mixture without isolation of the free acid form.
Forbindelsen med formel I har farmakologisk virkning. Spesielt har de dinatrium-chromoglykat (DSCG)-liknende virkning, spesielt inhiberende virkning på histamin-frigiving, og de er derfor indikert for anvendelse ved behandling av allergiske tilstander, som f.eks. allergisk astma, som påvist ved passiv kutan amafylakse-test med rotter. Hunrotter (180-200g) sensitiveres ved subkutan tilforsel av 1 mg eggealbumin (merk nr. 967) og 200 mg Al (OH)^ i 1 ml fysiologisk saltlosningcogV 0,5 ml hemofilus-pertussis vaksine (Schweizerisches Serum undImpfinstitut, Bern, Nr. 115 325, 4 x lO<1>^ organism/ml) tilfort intrateritonealt. 14 dogn senere tappes blodet fra dyrene, blodet sentrifugeres, serumet samles og dypfryses. Det således oppnådde serum (antiserum) injiseres The compound of formula I has a pharmacological effect. In particular, they have a disodium-chromoglycate (DSCG)-like effect, especially an inhibitory effect on histamine release, and they are therefore indicated for use in the treatment of allergic conditions, such as e.g. allergic asthma, as demonstrated by the passive cutaneous amaphylaxis test with rats. Female rats (180-200g) are sensitized by subcutaneous administration of 1 mg of egg albumin (mark no. 967) and 200 mg of Al (OH)^ in 1 ml of physiological saline and 0.5 ml of haemophilus-pertussis vaccine (Schweizerisches Serum undImpfinstitut, Bern, No. 115 325, 4 x lO<1>^ organism/ml) added intraperitoneally. 14 days later, the blood is drawn from the animals, the blood is centrifuged, the serum is collected and deep-frozen. The thus obtained serum (antiserum) is injected
. intradermalt (0,1 ml av 1:200 fortynnet serum pr. injeksjonspunkt) på 4 punkter på ryggen av ubehandlede hunrotter. 24 timer senere tilfores hver rotte 5,6 mg/kg i.v. eller 100 mg/kg p.o. av testforbindelsen, og enten umiddelbart eller 5 til 30 minutter etterpå, i tilfellet med intravenos tilforsel, eller 15 eller 60 minutter etterpå i tilfellet med oral tilforsel, eggealbumin (5 mg/ml i.v.) opplost i fysiologisk saltlosning inneholdende 0,25 % Evans Blue-fargestoff (Merk nr. 3169). Eggealbuminet utloser en kutanana-fylaktisk reaksjon med intensitet proporsjonal med den utstrekning hvormed Evans Blue-fargestoffet diffunerer inn i vevet som omgir hver av de fire sensibiliserings-punkter. 30 minutter etter tilforsel av eggealbuminet drepes rottene med eter, undersiden av . intradermally (0.1 ml of 1:200 diluted serum per injection point) at 4 points on the back of untreated female rats. 24 hours later, each rat is administered 5.6 mg/kg i.v. or 100 mg/kg p.o. of the test compound, and either immediately or 5 to 30 minutes afterwards, in the case of intravenous administration, or 15 or 60 minutes afterwards in the case of oral administration, egg albumin (5 mg/ml i.v.) dissolved in physiological saline containing 0.25% Evans Blue -dye (Mark no. 3169). The egg albumin triggers a cutaneous phylactic reaction with intensity proportional to the extent to which the Evans Blue dye diffuses into the tissue surrounding each of the four sensitization points. 30 minutes after administration of the egg albumin, the rats are killed with ether, the underside of
huden på ryggen av hvert dyr avdekkes og diameteren av områdene av blått fargestoff som omgir hver av de fire sensibiliseringspunkter måles» Hver dose testforbindelse undersokes i mellom fire og seks rotter og den midlere diameter sammenliknes med middelverdien the skin on the back of each animal is exposed and the diameter of the areas of blue dye surrounding each of the four sensitization points is measured' Each dose of test compound is examined in between four and six rats and the mean diameter is compared with the mean value
oppnådd ved fire opplosnings-middel-behandlede kontroUrotter. Prosentvis inhibering tas som prosent av den midlere diameter i testdyrene i forhold til den midlere diameter ved kontrolldyrene. obtained in four solvent-treated control rats. Percent inhibition is taken as a percentage of the mean diameter in the test animals in relation to the mean diameter in the control animals.
Den DSCG-liknende aktivitet, spesielt den inhiberende aktivitet for histaminfrigivning, kan bekreftes ved inhiberingeav histamin-frigivning i pertonial mastecelletest i rotter, prinsippielt som beskrevet av Kusner et al.., J. Pharmacol. Exp. Therap. 184, The DSCG-like activity, especially the inhibitory activity for histamine release, can be confirmed by inhibition of histamine release in the pertonial mast cell test in rats, in principle as described by Kusner et al.., J. Pharmacol. Exp. Therap. 184,
41-46 (1973), med den folgende modifisering: Etter sedimentering av mastecellene ved sentrifugering med 350 x g og 4° C opptas sedimentene 1 lijml Hank's balanserte saltlosning (HBSS) (bufferet til pH 6,9) eog] samles. Den resulterende suspensjon sentrifugeres, vaskes på nytt med HBSS og sedmenteres. De således rensede masteceller fremstilles som 2 ml suspensjoner i HBSS. Til disse tilsettes énten 2 ml HBSS for å bestemme den spontane histaminfrigivning, eller 2 ml HBSS og 2,24 yug av forbindelsen 48/80 (N-methylhomoanisylamineformaldehyde condensat, en histamin-liberator fra Burroughs'Wellcome and Co., Inc., Tuckahoe, N.Y., USA) for å bestemme den 48/80 induserte histamin-frigivning, eller 2 ml HBSS med 2,24^ug 48/80 og fra 18 til 180 ^ug/ml av testforbindelsen, for å bestemme den 48/80 induserte histaminfrigivning i nærvær av testforbindelsen. 41-46 (1973), with the following modification: After sedimentation of the mast cells by centrifugation at 350 x g and 4° C, the sediments are taken up in 1 ml of Hank's balanced salt solution (HBSS) (buffered to pH 6.9) and collected. The resulting suspension is centrifuged, washed again with HBSS and sedimented. The thus purified mast cells are prepared as 2 ml suspensions in HBSS. To these are added either 2 ml of HBSS to determine the spontaneous release of histamine, or 2 ml of HBSS and 2.24 ug of compound 48/80 (N-methylhomoanisylamineformaldehyde condensate, a histamine liberator from Burroughs' Wellcome and Co., Inc., Tuckahoe , N.Y., USA) to determine the 48/80 induced histamine release, or 2 ml HBSS with 2.24 µg 48/80 and from 18 to 180 µg/ml of the test compound, to determine the 48/80 induced histamine release in the presence of the test compound.
Den 48/80 induserte histaminfrigivning minus den spontane histamin-frigivning tas som 100 % histaminfrigivning. Den 48/80 induserte histaminfrigivning i nærvær av testforbindelsen minus den spontane histaminfrigivning sammenliknes så med 100 % verdien for å bestemme prosentvis inhibering med testforbindelsen (histaminbestemmelsen gjennomfores på konvensjonell måte, f.eks. som beskrevet i den ovennevnte artikkel av Kusner et al, eller i Kusner and Herzig, Advances in Automated Analyses, 429 1971). Eri indikert passende daglig dose er fra 20 til 200 mg foretrukket tilfort i deldoser på fra 5 til 100 mg 2 til 4 ganger daglig, eller i retard-form. The 48/80 induced histamine release minus the spontaneous histamine release is taken as 100% histamine release. The 48/80 induced histamine release in the presence of the test compound minus the spontaneous histamine release is then compared to the 100% value to determine percent inhibition by the test compound (the histamine determination is carried out in a conventional manner, e.g. as described in the above-mentioned article by Kusner et al, or in Kusner and Herzig, Advances in Automated Analyses, 429 1971). The appropriate daily dose indicated is from 20 to 200 mg, preferably added in partial doses of from 5 to 100 mg 2 to 4 times a day, or in retard form.
Forbindelsene kan anvendes i fri syreform eller i form av deres farmasoytisk tålbare salter, idet saltformene har stort sett den samme aktivitet som de fri syreformer. Egnede salter omfatter natrium-, kalium- og litium-saltene. The compounds can be used in free acid form or in the form of their pharmaceutically acceptable salts, the salt forms having largely the same activity as the free acid forms. Suitable salts include the sodium, potassium and lithium salts.
Forbindelsene med formel I kan blandes med konvensjonelle farma-søytisk tålbare fortynningsmidler eller bærere og eventuelt andre hjelpestoffer og tilfores i form av f.eks. tabletter eller kapsler. The compounds of formula I can be mixed with conventional pharmaceutically acceptable diluents or carriers and optionally other auxiliary substances and supplied in the form of e.g. tablets or capsules.
De foretrukne forbindelser med formel I ers dem hvori R er metyl eller allyl, og dem hvori R1er metyl og R_ ér hydr0ogen eller metyl. Mer foretrukne forbindelser er dem hvori R er metyl eller allyl og samtidig R.^er metyl og R_ er hydrogen eller metyl. Spesielt foretrukket er 1, 7-dimethyl-4-hydroxy-3-nitro-pyrido (2,3-b) pyridin-2 (lH)-onc, og l-allyl-7-metyl-4-hydroxy-3-nitro-pyrido (2,3-b) pyridin-2 (lH)-on. The preferred compounds of formula I are those in which R is methyl or allyl, and those in which R 1 is methyl and R 1 is hydrogen or methyl. More preferred compounds are those in which R is methyl or allyl and at the same time R 1 is methyl and R 1 is hydrogen or methyl. Particularly preferred are 1, 7-dimethyl-4-hydroxy-3-nitro-pyrido (2,3-b) pyridine-2 (1H)-onc, and 1-allyl-7-methyl-4-hydroxy-3-nitro -pyrido (2,3-b)pyridin-2(1H)-one.
De folgende eksempler illustrerer oppfinnelsen:The following examples illustrate the invention:
EKSEMPEL 1; l-metyl-4-hydroxy-3-nitro-pyrido (2,3-b)EXAMPLE 1; l-methyl-4-hydroxy-3-nitro-pyrido (2,3-b)
pyridin-2 (lH)-on.pyridine-2(1H)-one.
Til en losning av 3,75 g etylnitroasetat i 50 ml dimetylasetamid tilsettes porsjonsvis 1,35 g pentan-vasket 50 % natriumhydrid hvorved hydrogengass frigis med noe skumdannelse. Den resulterende opplosning omrores ved romtemperatur i 30 minutter. Temperaturen i den resulterende blanding heves så til 80° C og det tilsettes dråpevis en losning av 5,0 g 4-metyl-3,4-dihydro-l,3-dioxo-lH-pyrido(2,3-b)(1,3)oxazin i 75 ml dimetylasetamid. Den resulterende blanding omrores ved 120° c i 18 timer hvorunder det dannes et bundfall. To a solution of 3.75 g of ethyl nitroacetate in 50 ml of dimethylacetamide, 1.35 g of pentane-washed 50% sodium hydride is added in portions, whereby hydrogen gas is released with some foaming. The resulting solution is stirred at room temperature for 30 minutes. The temperature of the resulting mixture is then raised to 80° C. and a solution of 5.0 g of 4-methyl-3,4-dihydro-1,3-dioxo-1H-pyrido(2,3-b)(1) is added dropwise ,3)oxazine in 75 ml of dimethylacetamide. The resulting mixture is stirred at 120°C for 18 hours during which time a precipitate forms.
Den resulterende blanding inndampes i våkum til det halve volumThe resulting mixture is evaporated in vacuo to half the volume
og bundfallet isoleres ved filtrering og vaskes med etylasetat og eter og gir l-metyl-4-hydroxy-3-nitro-pyrido(2,3-b)pyridin-2 (lH)-on, natriumsalt, smeltepunkt 333 - 336° C. and the precipitate is isolated by filtration and washed with ethyl acetate and ether to give 1-methyl-4-hydroxy-3-nitro-pyrido(2,3-b)pyridin-2 (1H)-one, sodium salt, melting point 333 - 336° C .
Natriumsaltet opploses i vann og losningen syres med 2N saltsyre og ekstraheres med etylasetat. Etylasetat-losningen torkes og inndampes i våkum og gir l-.metyl-4-hydroxy-3-nitro-pyrido (2, 3-b) pyridin-2 (1H)-on, smeltepunkt 156 -' 158° C (spalting). The sodium salt is dissolved in water and the solution is acidified with 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate solution is dried and evaporated in vacuo to give 1-.methyl-4-hydroxy-3-nitro-pyrido (2, 3-b) pyridin-2 (1H)-one, melting point 156 -' 158° C (decomposition) .
a a
EKSEMPLER. 2 - 9:EXAMPLES. 2 - 9:
Ved å folge fremgangsmåten som angitt i eksempel 1, og ved anvendelse av passende utgangsmaterialer i ekvivalente mengder, kan folgende forbindelser med formel I, vist nedenfor i tabellform, oppnå s: By following the procedure as set out in Example 1, and using suitable starting materials in equivalent amounts, the following compounds of formula I, shown below in tabular form, can be obtained s:
Claims (2)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US60515275A | 1975-08-15 | 1975-08-15 |
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| Publication Number | Publication Date |
|---|---|
| NO762736L true NO762736L (en) | 1977-02-16 |
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| Application Number | Title | Priority Date | Filing Date |
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| NO762736A NO762736L (en) | 1975-08-15 | 1976-08-06 |
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| JP (1) | JPS5236694A (en) |
| AU (1) | AU1684576A (en) |
| BE (1) | BE845196A (en) |
| DE (1) | DE2635216A1 (en) |
| DK (1) | DK357676A (en) |
| FI (1) | FI762259A (en) |
| FR (1) | FR2320752A1 (en) |
| IL (1) | IL50262A0 (en) |
| NL (1) | NL7608906A (en) |
| NO (1) | NO762736L (en) |
| NZ (1) | NZ181763A (en) |
| PT (1) | PT65478B (en) |
| SE (1) | SE7608838L (en) |
| ZA (1) | ZA764882B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US4452800A (en) * | 1982-04-26 | 1984-06-05 | Schering Corporation | Salts of 3(n-butyl)-4-hydroxy-1-phenyl-1,8-naphthyridine-2(1H)-one and their use in treating chronic obstructive lung diseases |
| JP2988739B2 (en) * | 1990-04-16 | 1999-12-13 | 協和醗酵工業株式会社 | 1,8-naphthyridin-2-one derivatives |
| FR2913977B1 (en) * | 2007-03-21 | 2015-03-13 | Centre Nat Rech Scient | TRANSANNUAL REARRANGEMENT OF ACTIVE LACTAMS |
-
1976
- 1976-08-05 DE DE19762635216 patent/DE2635216A1/en active Pending
- 1976-08-06 FI FI762259A patent/FI762259A/fi not_active Application Discontinuation
- 1976-08-06 DK DK357676A patent/DK357676A/en unknown
- 1976-08-06 NO NO762736A patent/NO762736L/no unknown
- 1976-08-06 SE SE7608838A patent/SE7608838L/en unknown
- 1976-08-11 NL NL7608906A patent/NL7608906A/en not_active Application Discontinuation
- 1976-08-12 FR FR7624661A patent/FR2320752A1/en active Granted
- 1976-08-13 ZA ZA00764882A patent/ZA764882B/en unknown
- 1976-08-13 BE BE169820A patent/BE845196A/en unknown
- 1976-08-13 IL IL50262A patent/IL50262A0/en unknown
- 1976-08-13 PT PT65478A patent/PT65478B/en unknown
- 1976-08-13 NZ NZ181763A patent/NZ181763A/en unknown
- 1976-08-13 AU AU16845/76A patent/AU1684576A/en not_active Expired
- 1976-08-13 JP JP51096198A patent/JPS5236694A/en active Pending
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| Publication number | Publication date |
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| PT65478B (en) | 1978-05-10 |
| FI762259A (en) | 1977-02-16 |
| BE845196A (en) | 1977-02-14 |
| IL50262A0 (en) | 1976-10-31 |
| AU1684576A (en) | 1978-02-16 |
| PT65478A (en) | 1976-09-01 |
| NL7608906A (en) | 1977-02-17 |
| SE7608838L (en) | 1977-02-16 |
| JPS5236694A (en) | 1977-03-22 |
| DK357676A (en) | 1977-02-16 |
| DE2635216A1 (en) | 1977-03-03 |
| ZA764882B (en) | 1978-03-29 |
| FR2320752B1 (en) | 1978-11-17 |
| NZ181763A (en) | 1978-07-10 |
| FR2320752A1 (en) | 1977-03-11 |
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