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
Links
- 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
- 150000001875 compounds Chemical class 0.000 claims description 30
- 239000002253 acid Substances 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 13
- ULRPISSMEBPJLN-UHFFFAOYSA-N 2h-tetrazol-5-amine Chemical compound NC1=NN=NN1 ULRPISSMEBPJLN-UHFFFAOYSA-N 0.000 claims description 11
- 239000007822 coupling agent Substances 0.000 claims description 9
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 8
- 238000010168 coupling process Methods 0.000 claims description 8
- 238000005859 coupling reaction Methods 0.000 claims description 8
- 230000008878 coupling Effects 0.000 claims description 7
- 239000000460 chlorine Substances 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 150000001718 carbodiimides Chemical class 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 239000007858 starting material Substances 0.000 claims description 3
- OKRROXQXGNEUSS-UHFFFAOYSA-N 1h-imidazol-1-ium-1-carboxylate Chemical compound OC(=O)N1C=CN=C1 OKRROXQXGNEUSS-UHFFFAOYSA-N 0.000 claims description 2
- OLSFRDLMFAOSIA-UHFFFAOYSA-N 2-chloro-1,3,2-dioxaphospholane Chemical compound ClP1OCCO1 OLSFRDLMFAOSIA-UHFFFAOYSA-N 0.000 claims description 2
- CFMZSMGAMPBRBE-UHFFFAOYSA-N 2-hydroxyisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(O)C(=O)C2=C1 CFMZSMGAMPBRBE-UHFFFAOYSA-N 0.000 claims description 2
- MWOOKDULMBMMPN-UHFFFAOYSA-N 3-(2-ethyl-1,2-oxazol-2-ium-5-yl)benzenesulfonate Chemical compound O1[N+](CC)=CC=C1C1=CC=CC(S([O-])(=O)=O)=C1 MWOOKDULMBMMPN-UHFFFAOYSA-N 0.000 claims description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- ZZTSQZQUWBFTAT-UHFFFAOYSA-N diethylcyanamide Chemical compound CCN(CC)C#N ZZTSQZQUWBFTAT-UHFFFAOYSA-N 0.000 claims description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 2
- WMYNMYVRWWCRPS-UHFFFAOYSA-N ethynoxyethane Chemical group CCOC#C WMYNMYVRWWCRPS-UHFFFAOYSA-N 0.000 claims description 2
- YHHNXMTTWKAUEQ-UHFFFAOYSA-N n-(4-methylphenyl)-2,2-diphenylethenimine Chemical compound C1=CC(C)=CC=C1N=C=C(C=1C=CC=CC=1)C1=CC=CC=C1 YHHNXMTTWKAUEQ-UHFFFAOYSA-N 0.000 claims description 2
- LKPFBGKZCCBZDK-UHFFFAOYSA-N n-hydroxypiperidine Chemical compound ON1CCCCC1 LKPFBGKZCCBZDK-UHFFFAOYSA-N 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- QXKHYNVANLEOEG-UHFFFAOYSA-N Methoxsalen Chemical group C1=CC(=O)OC2=C1C=C1C=COC1=C2OC QXKHYNVANLEOEG-UHFFFAOYSA-N 0.000 claims 2
- AOEOETNVZQDCJK-UHFFFAOYSA-N 1,3,2-dioxaphospholan-2-yl diethyl phosphite Chemical compound CCOP(OCC)OP1OCCO1 AOEOETNVZQDCJK-UHFFFAOYSA-N 0.000 claims 1
- BXGTVNLGPMZLAZ-UHFFFAOYSA-N n'-ethylmethanediimine;hydrochloride Chemical compound Cl.CCN=C=N BXGTVNLGPMZLAZ-UHFFFAOYSA-N 0.000 claims 1
- -1 5-tetrazolyl Chemical group 0.000 abstract description 7
- ZEXKKIXCRDTKBF-UHFFFAOYSA-N quinoline-2-carboxamide Chemical class C1=CC=CC2=NC(C(=O)N)=CC=C21 ZEXKKIXCRDTKBF-UHFFFAOYSA-N 0.000 abstract description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
- 230000000694 effects Effects 0.000 description 19
- 239000000203 mixture Substances 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- 208000003455 anaphylaxis Diseases 0.000 description 13
- 238000012360 testing method Methods 0.000 description 13
- 239000004480 active ingredient Substances 0.000 description 12
- 239000003795 chemical substances by application Substances 0.000 description 12
- 206010002198 Anaphylactic reaction Diseases 0.000 description 11
- 230000036783 anaphylactic response Effects 0.000 description 11
- 241001465754 Metazoa Species 0.000 description 10
- 239000000376 reactant Substances 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 150000007513 acids Chemical class 0.000 description 9
- 206010020751 Hypersensitivity Diseases 0.000 description 8
- 125000003545 alkoxy group Chemical group 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 229940124630 bronchodilator Drugs 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 230000000172 allergic effect Effects 0.000 description 6
- 239000000427 antigen Substances 0.000 description 6
- 102000036639 antigens Human genes 0.000 description 6
- 108091007433 antigens Proteins 0.000 description 6
- 208000006673 asthma Diseases 0.000 description 6
- 208000010668 atopic eczema Diseases 0.000 description 6
- 229940027941 immunoglobulin g Drugs 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 5
- 230000001404 mediated effect Effects 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- GCMNJUJAKQGROZ-UHFFFAOYSA-N 1,2-Dihydroquinolin-2-imine Chemical compound C1=CC=CC2=NC(N)=CC=C21 GCMNJUJAKQGROZ-UHFFFAOYSA-N 0.000 description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
- 206010006482 Bronchospasm Diseases 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 239000000443 aerosol Substances 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 208000026935 allergic disease Diseases 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 230000004856 capillary permeability Effects 0.000 description 4
- 229960000265 cromoglicic acid Drugs 0.000 description 4
- IMZMKUWMOSJXDT-UHFFFAOYSA-N cromoglycic acid Chemical compound O1C(C(O)=O)=CC(=O)C2=C1C=CC=C2OCC(O)COC1=CC=CC2=C1C(=O)C=C(C(O)=O)O2 IMZMKUWMOSJXDT-UHFFFAOYSA-N 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 4
- 230000007306 turnover Effects 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- RZZPDXZPRHQOCG-OJAKKHQRSA-O CDP-choline(1+) Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OCC[N+](C)(C)C)O[C@H]1N1C(=O)N=C(N)C=C1 RZZPDXZPRHQOCG-OJAKKHQRSA-O 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 108060003951 Immunoglobulin Proteins 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 230000007815 allergy Effects 0.000 description 3
- 239000000908 ammonium hydroxide Substances 0.000 description 3
- 230000007885 bronchoconstriction Effects 0.000 description 3
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000000975 dye Substances 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 102000018358 immunoglobulin Human genes 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 2
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 2
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 2
- 229930182837 (R)-adrenaline Natural products 0.000 description 2
- KVNYFPKFSJIPBJ-UHFFFAOYSA-N 1,2-diethylbenzene Chemical compound CCC1=CC=CC=C1CC KVNYFPKFSJIPBJ-UHFFFAOYSA-N 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 241000124008 Mammalia Species 0.000 description 2
- 108010058846 Ovalbumin Proteins 0.000 description 2
- 206010039085 Rhinitis allergic Diseases 0.000 description 2
- 239000000150 Sympathomimetic Substances 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 description 2
- 201000009961 allergic asthma Diseases 0.000 description 2
- 201000010105 allergic rhinitis Diseases 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000004305 biphenyl Substances 0.000 description 2
- 235000010290 biphenyl Nutrition 0.000 description 2
- 125000006267 biphenyl group Chemical group 0.000 description 2
- 239000001045 blue dye Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- 239000000168 bronchodilator agent Substances 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 125000002091 cationic group Chemical group 0.000 description 2
- 230000008602 contraction Effects 0.000 description 2
- NNBZCPXTIHJBJL-UHFFFAOYSA-N decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 229960005139 epinephrine Drugs 0.000 description 2
- 230000000521 hyperimmunizing effect Effects 0.000 description 2
- 230000002163 immunogen Effects 0.000 description 2
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 229940039009 isoproterenol Drugs 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- UDGSVBYJWHOHNN-UHFFFAOYSA-N n',n'-diethylethane-1,2-diamine Chemical compound CCN(CC)CCN UDGSVBYJWHOHNN-UHFFFAOYSA-N 0.000 description 2
- 239000006199 nebulizer Substances 0.000 description 2
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 230000000069 prophylactic effect Effects 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 229960002052 salbutamol Drugs 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 210000002460 smooth muscle Anatomy 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- WZODLFCLKIXWGA-UHFFFAOYSA-N sodium 4-amino-6-[[4-[4-[(8-amino-1-hydroxy-5,7-disulfonaphthalen-2-yl)diazenyl]-3-methylphenyl]-2-methylphenyl]diazenyl]-5-hydroxynaphthalene-1,3-disulfonic acid Chemical compound CC1=C(C=CC(=C1)C2=CC(=C(C=C2)N=NC3=C(C4=C(C=C3)C(=CC(=C4N)S(=O)(=O)O)S(=O)(=O)O)O)C)N=NC5=C(C6=C(C=C5)C(=CC(=C6N)S(=O)(=O)O)S(=O)(=O)O)O.[Na+] WZODLFCLKIXWGA-UHFFFAOYSA-N 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 229960000278 theophylline Drugs 0.000 description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 2
- MNYLXMJEMIDQQV-UHFFFAOYSA-N (4,5-diethyl-1,3,2-dioxaphospholan-2-yl) dihydrogen phosphite Chemical compound CCC1C(OP(O1)OP(O)O)CC MNYLXMJEMIDQQV-UHFFFAOYSA-N 0.000 description 1
- MHCVCKDNQYMGEX-UHFFFAOYSA-N 1,1'-biphenyl;phenoxybenzene Chemical compound C1=CC=CC=C1C1=CC=CC=C1.C=1C=CC=CC=1OC1=CC=CC=C1 MHCVCKDNQYMGEX-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- FRNCMYBGOYDWDC-UHFFFAOYSA-N 1-oxopyrimido[1,2-a]quinoline-2-carbonitrile Chemical compound C1=CC=C2N3C(=O)C(C#N)=CN=C3C=CC2=C1 FRNCMYBGOYDWDC-UHFFFAOYSA-N 0.000 description 1
- APEJRAFJAXCCER-UHFFFAOYSA-N 1h-pyrimido[1,2-a]quinoline Chemical compound C1=CC=C2N3CC=CN=C3C=CC2=C1 APEJRAFJAXCCER-UHFFFAOYSA-N 0.000 description 1
- CYXIKYKBLDZZNW-UHFFFAOYSA-N 2-Chloro-1,1,1-trifluoroethane Chemical compound FC(F)(F)CCl CYXIKYKBLDZZNW-UHFFFAOYSA-N 0.000 description 1
- OFUFXTHGZWIDDB-UHFFFAOYSA-N 2-chloroquinoline Chemical compound C1=CC=CC2=NC(Cl)=CC=C21 OFUFXTHGZWIDDB-UHFFFAOYSA-N 0.000 description 1
- DERAACKMMNJAFU-UHFFFAOYSA-N 2-ethoxy-1,3-dioxane-4,6-dione Chemical compound CCOC1OC(=O)CC(=O)O1 DERAACKMMNJAFU-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 208000035285 Allergic Seasonal Rhinitis Diseases 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 206010002199 Anaphylactic shock Diseases 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 208000009079 Bronchial Spasm Diseases 0.000 description 1
- 208000014181 Bronchial disease Diseases 0.000 description 1
- COXVTLYNGOIATD-HVMBLDELSA-N CC1=C(C=CC(=C1)C1=CC(C)=C(C=C1)\N=N\C1=C(O)C2=C(N)C(=CC(=C2C=C1)S(O)(=O)=O)S(O)(=O)=O)\N=N\C1=CC=C2C(=CC(=C(N)C2=C1O)S(O)(=O)=O)S(O)(=O)=O Chemical compound CC1=C(C=CC(=C1)C1=CC(C)=C(C=C1)\N=N\C1=C(O)C2=C(N)C(=CC(=C2C=C1)S(O)(=O)=O)S(O)(=O)=O)\N=N\C1=CC=C2C(=CC(=C(N)C2=C1O)S(O)(=O)=O)S(O)(=O)=O COXVTLYNGOIATD-HVMBLDELSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- WFZKRNIMSVDNBU-UHFFFAOYSA-N Creatinine sulfate mixture with serotonin Chemical compound [O-]S([O-])(=O)=O.C[NH+]1CC(=O)N=C1N.C1=C(O)C=C2C(CC[NH3+])=CNC2=C1 WFZKRNIMSVDNBU-UHFFFAOYSA-N 0.000 description 1
- 102000006395 Globulins Human genes 0.000 description 1
- 108010044091 Globulins Proteins 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- 206010028735 Nasal congestion Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 208000037656 Respiratory Sounds Diseases 0.000 description 1
- 208000036071 Rhinorrhea Diseases 0.000 description 1
- 206010039101 Rhinorrhoea Diseases 0.000 description 1
- 206010047924 Wheezing Diseases 0.000 description 1
- 238000006959 Williamson synthesis reaction Methods 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 239000013566 allergen Substances 0.000 description 1
- 208000030961 allergic reaction Diseases 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000002052 anaphylactic effect Effects 0.000 description 1
- 230000001088 anti-asthma Effects 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 239000000043 antiallergic agent Substances 0.000 description 1
- 239000000924 antiasthmatic agent Substances 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000000621 bronchi Anatomy 0.000 description 1
- 230000003182 bronchodilatating effect Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 208000027744 congestion Diseases 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- UMNKXPULIDJLSU-UHFFFAOYSA-N dichlorofluoromethane Chemical compound FC(Cl)Cl UMNKXPULIDJLSU-UHFFFAOYSA-N 0.000 description 1
- 229940099364 dichlorofluoromethane Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 229960002179 ephedrine Drugs 0.000 description 1
- SDMSGNXFHZBVSF-UHFFFAOYSA-N ethyl 1-oxopyrimido[1,2-a]quinoline-2-carboxylate Chemical compound C1=CC2=CC=CC=C2N2C1=NC=C(C(=O)OCC)C2=O SDMSGNXFHZBVSF-UHFFFAOYSA-N 0.000 description 1
- IHZBVPOUSIBFHP-UHFFFAOYSA-N ethyl 2-cyano-3-(quinolin-2-ylamino)prop-2-enoate Chemical compound C1=CC=CC2=NC(NC=C(C(=O)OCC)C#N)=CC=C21 IHZBVPOUSIBFHP-UHFFFAOYSA-N 0.000 description 1
- KTMGNAIGXYODKQ-UHFFFAOYSA-N ethyl 2-cyano-3-ethoxyprop-2-enoate Chemical compound CCOC=C(C#N)C(=O)OCC KTMGNAIGXYODKQ-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229960003699 evans blue Drugs 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 208000021760 high fever Diseases 0.000 description 1
- 229960004931 histamine dihydrochloride Drugs 0.000 description 1
- PPZMYIBUHIPZOS-UHFFFAOYSA-N histamine dihydrochloride Chemical compound Cl.Cl.NCCC1=CN=CN1 PPZMYIBUHIPZOS-UHFFFAOYSA-N 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 230000035874 hyperreactivity Effects 0.000 description 1
- 230000009610 hypersensitivity Effects 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 230000000984 immunochemical effect Effects 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910000000 metal hydroxide Inorganic materials 0.000 description 1
- 150000004692 metal hydroxides Chemical class 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 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
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- LOAUVZALPPNFOQ-UHFFFAOYSA-M quinaldate Chemical compound C1=CC=CC2=NC(C(=O)[O-])=CC=C21 LOAUVZALPPNFOQ-UHFFFAOYSA-M 0.000 description 1
- LOAUVZALPPNFOQ-UHFFFAOYSA-N quinaldic acid Chemical compound C1=CC=CC2=NC(C(=O)O)=CC=C21 LOAUVZALPPNFOQ-UHFFFAOYSA-N 0.000 description 1
- 239000012048 reactive intermediate Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 206010041232 sneezing Diseases 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 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
-
- 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
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pulmonology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Immunology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
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.
Claims (3)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US60103975A | 1975-08-01 | 1975-08-01 |
Publications (3)
Publication Number | Publication Date |
---|---|
NO762411L NO762411L (en) | 1977-02-02 |
NO139786B true NO139786B (en) | 1979-01-29 |
NO139786C NO139786C (en) | 1979-05-09 |
Family
ID=24406004
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO762411A NO139786C (en) | 1975-08-01 | 1976-07-09 | ANALOGICAL PROCEDURE FOR PREPARATION OF PHARMACEUTICAL ACTIVE N- (5-TETRAZOLYL) -PYRIMIDO- (1,2-A) QUINOLINE-2-CARBOXAMIDE DERIVATIVES |
Country Status (31)
Country | Link |
---|---|
JP (1) | JPS5231098A (en) |
AR (1) | AR213099A1 (en) |
AT (1) | AT351028B (en) |
AU (1) | AU497412B2 (en) |
BE (1) | BE843952A (en) |
BG (1) | BG31229A3 (en) |
CA (1) | CA1060441A (en) |
CH (1) | CH616679A5 (en) |
CS (1) | CS195731B2 (en) |
DD (1) | DD126735A5 (en) |
DE (1) | DE2630469C2 (en) |
DK (1) | DK311276A (en) |
EG (1) | EG12424A (en) |
ES (1) | ES449777A1 (en) |
FI (1) | FI59409C (en) |
FR (1) | FR2319363A1 (en) |
GB (1) | GB1500666A (en) |
GR (1) | GR60549B (en) |
HU (1) | HU172063B (en) |
IE (1) | IE43028B1 (en) |
IL (1) | IL49924A (en) |
LU (1) | LU75369A1 (en) |
NL (1) | NL163514C (en) |
NO (1) | NO139786C (en) |
NZ (1) | NZ181317A (en) |
PH (1) | PH12132A (en) |
PT (1) | PT65349B (en) |
SE (1) | SE414175B (en) |
SU (1) | SU685156A3 (en) |
YU (1) | YU185076A (en) |
ZA (1) | ZA763876B (en) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2720085A1 (en) | 1977-05-05 | 1978-11-16 | Hoechst Ag | PYRIMIDO (6.1-A) ISOCHINOLIN-2-ON DERIVATIVES |
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 |
-
1976
- 1976-03-12 SU SU762379567A patent/SU685156A3/en active
- 1976-04-06 IE IE714/76A patent/IE43028B1/en unknown
- 1976-06-21 SE SE7607099A patent/SE414175B/en unknown
- 1976-06-28 NZ NZ181317A patent/NZ181317A/en unknown
- 1976-06-28 GR GR51134A patent/GR60549B/en unknown
- 1976-06-28 IL IL49924A patent/IL49924A/en unknown
- 1976-06-29 ZA ZA763876A patent/ZA763876B/en unknown
- 1976-06-29 CA CA255,988A patent/CA1060441A/en not_active Expired
- 1976-07-01 PH PH18640A patent/PH12132A/en unknown
- 1976-07-07 DE DE2630469A patent/DE2630469C2/en not_active Expired
- 1976-07-09 HU HU76PI00000528A patent/HU172063B/en unknown
- 1976-07-09 FI FI762016A patent/FI59409C/en not_active IP Right Cessation
- 1976-07-09 BG BG7633712A patent/BG31229A3/en unknown
- 1976-07-09 NL NL7607618.A patent/NL163514C/en not_active IP Right Cessation
- 1976-07-09 PT PT65349A patent/PT65349B/en unknown
- 1976-07-09 DK DK311276A patent/DK311276A/en not_active Application Discontinuation
- 1976-07-09 BE BE1007495A patent/BE843952A/en not_active IP Right Cessation
- 1976-07-09 AU AU15784/76A patent/AU497412B2/en not_active Expired
- 1976-07-09 NO NO762411A patent/NO139786C/en unknown
- 1976-07-09 FR FR7621101A patent/FR2319363A1/en active Granted
- 1976-07-12 EG EG426/76A patent/EG12424A/en active
- 1976-07-12 DD DD193810A patent/DD126735A5/xx unknown
- 1976-07-12 LU LU75369A patent/LU75369A1/xx unknown
- 1976-07-12 CH CH891276A patent/CH616679A5/en not_active IP Right Cessation
- 1976-07-12 AT AT512676A patent/AT351028B/en not_active IP Right Cessation
- 1976-07-12 JP JP51082862A patent/JPS5231098A/en active Pending
- 1976-07-12 ES ES449777A patent/ES449777A1/en not_active Expired
- 1976-07-12 CS CS764616A patent/CS195731B2/en unknown
- 1976-07-14 GB GB29181/76A patent/GB1500666A/en not_active Expired
- 1976-07-19 AR AR263987A patent/AR213099A1/en active
- 1976-07-27 YU YU01850/76A patent/YU185076A/en unknown
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US4122274A (en) | 3-Tetrazolo-5,6,7,8-substituted-pyrido[1,2-a]pyrimidin-4-ones | |
US4075343A (en) | Anti-allergenic 5-alkoxyimidazo[1,2-A]quinoline-2-carboxylic acids and derivatives thereof | |
NZ227125A (en) | Quinazoline derivatives and pharmaceutical compositions | |
US4041163A (en) | N-(5-Tetrazolyl)-4-oxo-4H-pyrimido(2,1-b)benzothiazole-3-carboxamide antiallergy agents | |
US4017625A (en) | Anti-allergic N-(5-tetrazolyl)-1-oxo-1H-6-alkoxypyrimido-[1,2-a]quinoline-2-carboxamides and intermediates therefor | |
US4128570A (en) | Anti-allergic oxanil compounds | |
NO139786B (en) | ANALOGICAL PROCEDURE FOR PREPARATION OF PHARMACEUTICAL ACTIVE N- (5-TETRAZOLYL) -PYRIMIDO- (1,2-A) QUINOLINE-2-CARBOXAMIDE DERIVATIVES | |
US3852324A (en) | N,n-(cyano-phenylene) dioxamic acids | |
US4066766A (en) | 1-Oxo-6-substituted pyrimido [1,2-a]quinoline-2-carboxylic acids and derivatives thereof and their use as antiallergy agents | |
US4406908A (en) | Tetrazolylcoumarin derivatives and antiallergic compositions containing the same | |
US3962445A (en) | Anti-allergenic carbostyril derivatives | |
US4031093A (en) | 1,6-Dihydro-6-oxo-2-(ortho-substituted phenyl)pyrimidine-5-carboxylic acid derivatives | |
US4112106A (en) | N-(2-thiazolyl)-tetrazole-5-carboxamide derivatives for the prevention of immediate type hypersensitivity reactions | |
US4065457A (en) | 4-Hydroxy-3-nitro-carbostyril compounds | |
NZ203034A (en) | 3-(1h-tetrazol-5-yl)-4(3h)-quinazolinone derivatives | |
US4096153A (en) | Arylene-bis-tetrazole-5-carboxamides | |
US3953598A (en) | Compounds, compositions and methods of use | |
KR790001315B1 (en) | A process for production of n-tetrazolyl-1-oxo-1h-6-(r3-substituted)-pryimido(1,2-a)quinoline-2carboxamides | |
US3838133A (en) | 1,4,5,8,9,12-hexahydro-4,8,12-trioxopyrido(2,3-f) (1,7)phenanthroline-2,6,10-tricarboxylate compounds | |
US3886164A (en) | Quinolyl oxamic acids | |
US4031217A (en) | 1-Oxo-1H-6-substituted-pyrimido(1,2-a)-quinoline-2-carboxylic acids and esters useful as antiulcer agents | |
US4014881A (en) | 1-Oxo-1H-6-piperidinopyrimido[1,2-a]quinoline-2-carboxylic acids and esters | |
FI60864B (en) | FOERFARANDE FOER FRAMSTAELLNING AV NYA FOER BEHANDLING AV ALLERGISJUKDOMAR LAEMPLIGA SUBSTITUERADE 2H-PYRAN-2,6 (3H) -DIONDERIVAT | |
US3959289A (en) | Derivatives of 4,6 dioxopyrido[3,2-g]quinoline 2,8 dicarboxylic acid | |
US4126617A (en) | DI-Tham salt of 10-cl,1,4,6,9 tetrahydro-5-methyl 4,6 dioxopyrido[3,2-g]quinoline-2,8-dicarboxylate |