NO781053L - CHINAZOLINE DERIVATIVES. - Google Patents
CHINAZOLINE DERIVATIVES.Info
- Publication number
- NO781053L NO781053L NO781053A NO781053A NO781053L NO 781053 L NO781053 L NO 781053L NO 781053 A NO781053 A NO 781053A NO 781053 A NO781053 A NO 781053A NO 781053 L NO781053 L NO 781053L
- Authority
- NO
- Norway
- Prior art keywords
- formula
- pyrido
- quinazoline
- oxo
- stated
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 claims description 91
- 125000000217 alkyl group Chemical group 0.000 claims description 56
- 238000000034 method Methods 0.000 claims description 50
- 238000002360 preparation method Methods 0.000 claims description 47
- -1 cyano, 5-tetrazolyl Chemical group 0.000 claims description 46
- 239000007787 solid Substances 0.000 claims description 44
- 239000000203 mixture Substances 0.000 claims description 43
- 125000003545 alkoxy group Chemical group 0.000 claims description 38
- 239000001257 hydrogen Substances 0.000 claims description 32
- 229910052739 hydrogen Inorganic materials 0.000 claims description 32
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 22
- 150000003839 salts Chemical class 0.000 claims description 21
- 239000002253 acid Substances 0.000 claims description 20
- 125000004414 alkyl thio group Chemical group 0.000 claims description 18
- 150000002431 hydrogen Chemical class 0.000 claims description 18
- UPGZAERNNNZSPM-UHFFFAOYSA-N quinazoline-8-carboxylic acid Chemical compound N1=CN=C2C(C(=O)O)=CC=CC2=C1 UPGZAERNNNZSPM-UHFFFAOYSA-N 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- PNVRFQIVLRDFMU-UHFFFAOYSA-N 2-methoxy-11-oxopyrido[2,1-b]quinazoline-8-carboxylic acid Chemical compound C1=CC(C(O)=O)=CN2C(=O)C3=CC(OC)=CC=C3N=C21 PNVRFQIVLRDFMU-UHFFFAOYSA-N 0.000 claims description 11
- QBEIZCZOJLXENV-UHFFFAOYSA-N 9h-pyrido[2,1-b]quinazoline Chemical class C1=CC=CC2=CN3CC=CC=C3N=C21 QBEIZCZOJLXENV-UHFFFAOYSA-N 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 8
- 239000002585 base Substances 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 230000003266 anti-allergic effect Effects 0.000 claims description 6
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 6
- 150000005748 halopyridines Chemical class 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- PYBKWRFBLKRVDV-UHFFFAOYSA-N 11-oxo-2-propan-2-yloxypyrido[2,1-b]quinazoline-8-carboxylic acid Chemical compound C1=CC(C(O)=O)=CN2C(=O)C3=CC(OC(C)C)=CC=C3N=C21 PYBKWRFBLKRVDV-UHFFFAOYSA-N 0.000 claims description 4
- WOWXQGVIYOJJJX-UHFFFAOYSA-N 11-oxo-2-propan-2-ylpyrido[2,1-b]quinazoline-8-carboxylic acid Chemical compound C1=CC(C(O)=O)=CN2C(=O)C3=CC(C(C)C)=CC=C3N=C21 WOWXQGVIYOJJJX-UHFFFAOYSA-N 0.000 claims description 4
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 4
- STYICFCLHAZONT-UHFFFAOYSA-N 2-cyclopropyl-11-oxopyrido[2,1-b]quinazoline-8-carboxylic acid Chemical compound C1=C2C(=O)N3C=C(C(=O)O)C=CC3=NC2=CC=C1C1CC1 STYICFCLHAZONT-UHFFFAOYSA-N 0.000 claims description 4
- ULOYTSDTMQNZNZ-UHFFFAOYSA-N 2-methylsulfanyl-11-oxopyrido[2,1-b]quinazoline-8-carboxylic acid Chemical compound C1=CC(C(O)=O)=CN2C(=O)C3=CC(SC)=CC=C3N=C21 ULOYTSDTMQNZNZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 4
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- 150000001350 alkyl halides Chemical class 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 150000007530 organic bases Chemical group 0.000 claims description 4
- LPCONMIBYTZEGU-UHFFFAOYSA-N 2-(2-methoxy-11-oxopyrido[2,1-b]quinazolin-8-yl)acetic acid Chemical compound C1=CC(CC(O)=O)=CN2C(=O)C3=CC(OC)=CC=C3N=C21 LPCONMIBYTZEGU-UHFFFAOYSA-N 0.000 claims description 3
- DJQMJLODWZIUAH-UHFFFAOYSA-N 2-(diethylamino)ethyl 11-oxo-2-propan-2-ylpyrido[2,1-b]quinazoline-8-carboxylate Chemical compound C1=C(C(C)C)C=C2C(=O)N(C=C(C(=O)OCCN(CC)CC)C=C3)C3=NC2=C1 DJQMJLODWZIUAH-UHFFFAOYSA-N 0.000 claims description 3
- 125000004423 acyloxy group Chemical group 0.000 claims description 3
- 125000001246 bromo group Chemical group Br* 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- PELJISAVHGXLAL-UHFFFAOYSA-N iodomethyl 2,2-dimethylpropanoate Chemical group CC(C)(C)C(=O)OCI PELJISAVHGXLAL-UHFFFAOYSA-N 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 238000006136 alcoholysis reaction Methods 0.000 claims description 2
- 238000005915 ammonolysis reaction Methods 0.000 claims description 2
- 230000032050 esterification Effects 0.000 claims description 2
- 238000005886 esterification reaction Methods 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- LYLILIWTSDTYFW-UHFFFAOYSA-N 2-(diethylamino)ethyl 2-cyclopropyl-11-oxo-1H-pyrido[2,1-b]quinazoline-2-carboxylate Chemical compound C1C(C(N2C=CC=CC2=N2)=O)=C2C=CC1(C(=O)OCCN(CC)CC)C1CC1 LYLILIWTSDTYFW-UHFFFAOYSA-N 0.000 claims 2
- OUNMDQGVAGJXJI-UHFFFAOYSA-N 2-(diethylamino)ethyl 2-methoxy-11-oxopyrido[2,1-b]quinazoline-8-carboxylate Chemical compound C1=C(OC)C=C2C(=O)N(C=C(C(=O)OCCN(CC)CC)C=C3)C3=NC2=C1 OUNMDQGVAGJXJI-UHFFFAOYSA-N 0.000 claims 2
- KRFHRAAUBLAPSM-UHFFFAOYSA-N 4-methoxy-11-oxopyrido[2,1-b]quinazoline-8-carboxylic acid Chemical compound N1=C2C=CC(C(O)=O)=CN2C(=O)C2=C1C(OC)=CC=C2 KRFHRAAUBLAPSM-UHFFFAOYSA-N 0.000 claims 2
- PNKHNBKVYZXUMH-UHFFFAOYSA-N 2,4-dimethoxy-11-oxopyrido[2,1-b]quinazoline-8-carboxylic acid Chemical compound C1=CC(C(O)=O)=CN2C(=O)C3=CC(OC)=CC(OC)=C3N=C21 PNKHNBKVYZXUMH-UHFFFAOYSA-N 0.000 claims 1
- 239000000969 carrier Substances 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- 231100000252 nontoxic Toxicity 0.000 claims 1
- 230000003000 nontoxic effect Effects 0.000 claims 1
- 108090000623 proteins and genes Proteins 0.000 claims 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 63
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 60
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 50
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
- 239000000243 solution Substances 0.000 description 45
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 45
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 42
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 40
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 38
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 37
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 34
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 28
- 238000001816 cooling Methods 0.000 description 25
- 229960000583 acetic acid Drugs 0.000 description 23
- 239000011541 reaction mixture Substances 0.000 description 23
- 239000000725 suspension Substances 0.000 description 23
- 238000006243 chemical reaction Methods 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 20
- 238000001953 recrystallisation Methods 0.000 description 20
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 19
- YFNKIDBQEZZDLK-UHFFFAOYSA-N triglyme Chemical compound COCCOCCOCCOC YFNKIDBQEZZDLK-UHFFFAOYSA-N 0.000 description 19
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 18
- 229910052786 argon Inorganic materials 0.000 description 17
- 239000003921 oil Substances 0.000 description 17
- 235000019198 oils Nutrition 0.000 description 17
- 239000000047 product Substances 0.000 description 16
- UAWMVMPAYRWUFX-UHFFFAOYSA-N 6-Chloronicotinic acid Chemical compound OC(=O)C1=CC=C(Cl)N=C1 UAWMVMPAYRWUFX-UHFFFAOYSA-N 0.000 description 13
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical class NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 13
- 239000002904 solvent Substances 0.000 description 13
- 239000012043 crude product Substances 0.000 description 11
- 238000002425 crystallisation Methods 0.000 description 11
- 230000008025 crystallization Effects 0.000 description 11
- 239000000706 filtrate Substances 0.000 description 11
- 238000001914 filtration Methods 0.000 description 10
- 229910000027 potassium carbonate Inorganic materials 0.000 description 10
- 238000010992 reflux Methods 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 239000010410 layer Substances 0.000 description 9
- 239000000463 material Substances 0.000 description 9
- UMKSAURFQFUULT-UHFFFAOYSA-N 2-Amino-5-methoxybenzoic acid Chemical compound COC1=CC=C(N)C(C(O)=O)=C1 UMKSAURFQFUULT-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 238000004821 distillation Methods 0.000 description 8
- 208000009079 Bronchial Spasm Diseases 0.000 description 7
- 208000014181 Bronchial disease Diseases 0.000 description 7
- 206010006482 Bronchospasm Diseases 0.000 description 7
- 239000000538 analytical sample Substances 0.000 description 7
- 239000013078 crystal Substances 0.000 description 7
- PDGKZXSVTBEAFW-UHFFFAOYSA-N (6-chloropyridin-3-yl)methyl benzoate Chemical compound C1=NC(Cl)=CC=C1COC(=O)C1=CC=CC=C1 PDGKZXSVTBEAFW-UHFFFAOYSA-N 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 6
- 238000009835 boiling Methods 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- QWNMKHLBVHTPFW-UHFFFAOYSA-N 2-amino-5-propan-2-ylbenzoic acid Chemical compound CC(C)C1=CC=C(N)C(C(O)=O)=C1 QWNMKHLBVHTPFW-UHFFFAOYSA-N 0.000 description 5
- 150000001204 N-oxides Chemical class 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- 239000000427 antigen Substances 0.000 description 5
- 102000036639 antigens Human genes 0.000 description 5
- 108091007433 antigens Proteins 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000007795 chemical reaction product Substances 0.000 description 5
- 239000012362 glacial acetic acid Substances 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- 239000002002 slurry Substances 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- LKWPCZDBLQUFJQ-UHFFFAOYSA-N 2-amino-5-propan-2-yloxybenzoic acid Chemical compound CC(C)OC1=CC=C(N)C(C(O)=O)=C1 LKWPCZDBLQUFJQ-UHFFFAOYSA-N 0.000 description 4
- RAGSWDIQBBZLLL-UHFFFAOYSA-N 2-chloroethyl(diethyl)azanium;chloride Chemical compound Cl.CCN(CC)CCCl RAGSWDIQBBZLLL-UHFFFAOYSA-N 0.000 description 4
- YCUBIGBFPFQZAU-UHFFFAOYSA-N 6-chloro-n-[2-(diethylamino)ethyl]pyridine-3-carboxamide;hydrochloride Chemical compound Cl.CCN(CC)CCNC(=O)C1=CC=C(Cl)N=C1 YCUBIGBFPFQZAU-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 229920000881 Modified starch Polymers 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 239000012259 ether extract Substances 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000012442 inert solvent Substances 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 238000011282 treatment Methods 0.000 description 4
- UERVAQKRBPRDJP-UHFFFAOYSA-N 2-amino-5-cyclopropylbenzoic acid Chemical compound C1=C(C(O)=O)C(N)=CC=C1C1CC1 UERVAQKRBPRDJP-UHFFFAOYSA-N 0.000 description 3
- BUHKQTKKZAXSMH-UHFFFAOYSA-N 5-hydroxy-2-nitrobenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1[N+]([O-])=O BUHKQTKKZAXSMH-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- XVUDRSZQKGTCPH-UHFFFAOYSA-N acetic acid;n,n-dimethylformamide Chemical compound CC(O)=O.CN(C)C=O XVUDRSZQKGTCPH-UHFFFAOYSA-N 0.000 description 3
- RIEYKVLCMDCSJY-UHFFFAOYSA-N acetic acid;n,n-dimethylformamide;hydrate Chemical compound O.CC(O)=O.CN(C)C=O RIEYKVLCMDCSJY-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 239000008120 corn starch Substances 0.000 description 3
- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 3
- MDKXBBPLEGPIRI-UHFFFAOYSA-N ethoxyethane;methanol Chemical compound OC.CCOCC MDKXBBPLEGPIRI-UHFFFAOYSA-N 0.000 description 3
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- YWDFEVSRIBDNQY-UHFFFAOYSA-N propan-2-yl 2-nitro-5-propan-2-yloxybenzoate Chemical compound CC(C)OC(=O)C1=CC(OC(C)C)=CC=C1[N+]([O-])=O YWDFEVSRIBDNQY-UHFFFAOYSA-N 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- UXSNZYGTQTXRAD-UHFFFAOYSA-N 1-(6-chloropyridin-3-yl)ethanone Chemical compound CC(=O)C1=CC=C(Cl)N=C1 UXSNZYGTQTXRAD-UHFFFAOYSA-N 0.000 description 2
- OIZVMXRXSQFFMQ-UHFFFAOYSA-N 2,2-dimethylpropanoyloxymethyl 2-methoxy-11-oxopyrido[2,1-b]quinazoline-8-carboxylate Chemical compound C1=CC(C(=O)OCOC(=O)C(C)(C)C)=CN2C(=O)C3=CC(OC)=CC=C3N=C21 OIZVMXRXSQFFMQ-UHFFFAOYSA-N 0.000 description 2
- XYHSEANJTLQCQL-UHFFFAOYSA-N 2-methoxy-11-oxopyrido[2,1-b]quinazoline-7-carboxylic acid Chemical compound C1=C(C(O)=O)C=CN2C(=O)C3=CC(OC)=CC=C3N=C21 XYHSEANJTLQCQL-UHFFFAOYSA-N 0.000 description 2
- BZVMHJYYJKXSAS-UHFFFAOYSA-N 2-methoxy-11-oxopyrido[2,1-b]quinazoline-8-carbonitrile Chemical compound C1=CC(C#N)=CN2C(=O)C3=CC(OC)=CC=C3N=C21 BZVMHJYYJKXSAS-UHFFFAOYSA-N 0.000 description 2
- CRXURRMYQKUFNV-UHFFFAOYSA-N 2-methoxy-11-oxopyrido[2,1-b]quinazoline-8-carboxylic acid;hydrochloride Chemical compound Cl.C1=CC(C(O)=O)=CN2C(=O)C3=CC(OC)=CC=C3N=C21 CRXURRMYQKUFNV-UHFFFAOYSA-N 0.000 description 2
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- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- MMOHZZSDBTXXEI-UHFFFAOYSA-M O.[Na+].COC=1C=C2C(N3C(=NC2=CC1)C=CC(=C3)C(=O)[O-])=O Chemical compound O.[Na+].COC=1C=C2C(N3C(=NC2=CC1)C=CC(=C3)C(=O)[O-])=O MMOHZZSDBTXXEI-UHFFFAOYSA-M 0.000 description 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- 108010058846 Ovalbumin Proteins 0.000 description 1
- 206010070834 Sensitisation Diseases 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 240000006394 Sorghum bicolor Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- MZVQCMJNVPIDEA-UHFFFAOYSA-N [CH2]CN(CC)CC Chemical group [CH2]CN(CC)CC MZVQCMJNVPIDEA-UHFFFAOYSA-N 0.000 description 1
- 229960001413 acetanilide Drugs 0.000 description 1
- KDEGRRHCRBMOQN-UHFFFAOYSA-N acetic acid;methanol;hydrochloride Chemical compound Cl.OC.CC(O)=O KDEGRRHCRBMOQN-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 150000001266 acyl halides Chemical class 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000002052 anaphylactic effect Effects 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 230000002804 anti-anaphylactic effect Effects 0.000 description 1
- 239000000043 antiallergic agent Substances 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 125000003435 aroyl group Chemical group 0.000 description 1
- 125000005333 aroyloxy group Chemical group 0.000 description 1
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 1
- 229910001863 barium hydroxide Inorganic materials 0.000 description 1
- RTEXIPZMMDUXMR-UHFFFAOYSA-N benzene;ethyl acetate Chemical compound CCOC(C)=O.C1=CC=CC=C1 RTEXIPZMMDUXMR-UHFFFAOYSA-N 0.000 description 1
- OXUVDEGTBOXDCT-UHFFFAOYSA-N benzoic acid;8-(hydroxymethyl)-2-propan-2-yloxypyrido[2,1-b]quinazolin-11-one Chemical compound OC(=O)C1=CC=CC=C1.C1=CC(CO)=CN2C(=O)C3=CC(OC(C)C)=CC=C3N=C21 OXUVDEGTBOXDCT-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000001231 benzoyloxy group Chemical group C(C1=CC=CC=C1)(=O)O* 0.000 description 1
- 239000001045 blue dye Substances 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 239000000378 calcium silicate Substances 0.000 description 1
- 229910052918 calcium silicate Inorganic materials 0.000 description 1
- 235000012241 calcium silicate Nutrition 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 1
- 229960002327 chloral hydrate Drugs 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000012059 conventional drug carrier Substances 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- SPWVRYZQLGQKGK-UHFFFAOYSA-N dichloromethane;hexane Chemical compound ClCCl.CCCCCC SPWVRYZQLGQKGK-UHFFFAOYSA-N 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 239000012972 dimethylethanolamine Substances 0.000 description 1
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- PSLIMVZEAPALCD-UHFFFAOYSA-N ethanol;ethoxyethane Chemical compound CCO.CCOCC PSLIMVZEAPALCD-UHFFFAOYSA-N 0.000 description 1
- LBAQSKZHMLAFHH-UHFFFAOYSA-N ethoxyethane;hydron;chloride Chemical compound Cl.CCOCC LBAQSKZHMLAFHH-UHFFFAOYSA-N 0.000 description 1
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 1
- OAMZXMDZZWGPMH-UHFFFAOYSA-N ethyl acetate;toluene Chemical compound CCOC(C)=O.CC1=CC=CC=C1 OAMZXMDZZWGPMH-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
- 238000000605 extraction Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 239000011872 intimate mixture Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000014380 magnesium carbonate Nutrition 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- ZVVRNGUAGINQLA-UHFFFAOYSA-N methyl 2-aminobenzoate;hydrochloride Chemical class Cl.COC(=O)C1=CC=CC=C1N ZVVRNGUAGINQLA-UHFFFAOYSA-N 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- UDGSVBYJWHOHNN-UHFFFAOYSA-N n',n'-diethylethane-1,2-diamine Chemical compound CCN(CC)CCN UDGSVBYJWHOHNN-UHFFFAOYSA-N 0.000 description 1
- QOHMWDJIBGVPIF-UHFFFAOYSA-N n',n'-diethylpropane-1,3-diamine Chemical compound CCN(CC)CCCN QOHMWDJIBGVPIF-UHFFFAOYSA-N 0.000 description 1
- RRLNUWRVTRDWIX-UHFFFAOYSA-N n-(4-cyclopropylphenyl)acetamide Chemical compound C1=CC(NC(=O)C)=CC=C1C1CC1 RRLNUWRVTRDWIX-UHFFFAOYSA-N 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- QMYZFEFSEQOZPW-UHFFFAOYSA-N o-methyl 2-amino-5-methylbenzenecarbothioate Chemical compound COC(=S)C1=CC(C)=CC=C1N QMYZFEFSEQOZPW-UHFFFAOYSA-N 0.000 description 1
- HWOLJTHAQMRDQW-UHFFFAOYSA-N o-methyl 2-amino-5-methylbenzenecarbothioate;hydrochloride Chemical compound Cl.COC(=S)C1=CC(C)=CC=C1N HWOLJTHAQMRDQW-UHFFFAOYSA-N 0.000 description 1
- MBJJMQNFXISCGG-UHFFFAOYSA-N o-methyl 5-methyl-2-nitrobenzenecarbothioate Chemical compound COC(=S)C1=CC(C)=CC=C1[N+]([O-])=O MBJJMQNFXISCGG-UHFFFAOYSA-N 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- TZLVRPLSVNESQC-UHFFFAOYSA-N potassium azide Chemical compound [K+].[N-]=[N+]=[N-] TZLVRPLSVNESQC-UHFFFAOYSA-N 0.000 description 1
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- OENLEHTYJXMVBG-UHFFFAOYSA-N pyridine;hydrate Chemical compound [OH-].C1=CC=[NH+]C=C1 OENLEHTYJXMVBG-UHFFFAOYSA-N 0.000 description 1
- UDJFFSGCRRMVFH-UHFFFAOYSA-N pyrido[2,3-d]pyrimidine Chemical compound N1=CN=CC2=CC=CN=C21 UDJFFSGCRRMVFH-UHFFFAOYSA-N 0.000 description 1
- WWABBFPTGJZEDN-UHFFFAOYSA-N quinazoline-6-carboxylic acid Chemical compound N1=CN=CC2=CC(C(=O)O)=CC=C21 WWABBFPTGJZEDN-UHFFFAOYSA-N 0.000 description 1
- GYBHRTQLUQOYID-UHFFFAOYSA-N quinazoline-8-carboxamide Chemical compound N1=CN=C2C(C(=O)N)=CC=CC2=C1 GYBHRTQLUQOYID-UHFFFAOYSA-N 0.000 description 1
- 150000003246 quinazolines Chemical class 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- RSIJVJUOQBWMIM-UHFFFAOYSA-L sodium sulfate decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[O-]S([O-])(=O)=O RSIJVJUOQBWMIM-UHFFFAOYSA-L 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
- C07C205/57—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C205/59—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/61—Halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00Â -Â 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 C07D451/00Â -Â C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Plural Heterocyclic Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Description
Foreliggende oppfinnelse vedrører nye pyrido[2;1-b]kinazolinderivater med den generelle formel The present invention relates to new pyrido[2;1-b]quinazoline derivatives with the general formula
hvor R^, og uavhengig utgjør hydrogen, lavere alkyl, lavere alkoksy, lavere alkyltio, halogen, cyklopropyl, cyklobutyl eller hydroksy, og R^representerer cyano, 5-tetrazolyl, hydroksy-lavere-alky1, acyloksy-lavere-alkyl eller en rest med formelen where R^, and independently represents hydrogen, lower alkyl, lower alkoxy, lower alkylthio, halogen, cyclopropyl, cyclobutyl or hydroxy, and R^ represents cyano, 5-tetrazolyl, hydroxy-lower alkyl, acyloxy-lower alkyl or a residue with the formula
hvor A representerer laverealkyl, hydroksy, where A represents lower alkyl, hydroxy,
laverealkoksy , di-(C-^-C^) alkylamino-(C2-C^) alkoksy , pivaloyloksymetoksy eller en rest med formelen -N^5 ,hvor R,- o-Rg uavhengig representerer hydrogenlaverealkyl eller<6>di-(C-^-C^) alkylamino-(C2_C^) alkyl, Y representerer hydrogen eller metyl og n representerer heltallet 0 lower alkoxy, di-(C-^-C^) alkylamino-(C2-C^) alkoxy, pivaloyloxymethoxy or a residue of the formula -N^5, where R,-o-Rg independently represents hydrogen lower alkyl or<6>di-( C-^-C^) alkylamino-(C2_C^) alkyl, Y represents hydrogen or methyl and n represents the integer 0
eller 1, med det forbehold at minst, én av R-^, R2og R^or 1, with the proviso that at least one of R-^, R 2 and R^
er forskjellig fra hydrogen, is different from hydrogen,
farmasøytisk fordragelige syreaddisjonssalter derav, og når A representere hydroksy, også farmasøytisk fordragelig salt der- pharmaceutically acceptable acid addition salts thereof, and when A represents hydroxy, also a pharmaceutically acceptable salt thereof
av med en base. off with a base.
Slik det her brukes betegner uttrykket "laverealkyl" - alene As used herein, the term "lower alkyl" denotes - alone
eller i kombinasjon - en rett eller forgrenet mettet hydrokarbon-kjede som inneholder 1 til 7 karbonatomer, f.eks. metyl, etyl, or in combination - a straight or branched saturated hydrocarbon chain containing 1 to 7 carbon atoms, e.g. methyl, ethyl,
propyl, isopropyl, butyl, t-butyl, neopentyl, pentyl, heptyl og lignende. Uttrykket "lavere-alkoksy" betegner en alkoksy-gruppe hvor den laverealkyl-gruppen er som ovenfor beskrevet, f.eks. metoksy, etoksy, propdksy, pentoksy og lignende. Uttrykket "halogen" betegner de fire former brom, klor, fluor og jod. Uttrykket "acyl" betegner en "aikanoyl"-gruppe avledet fra en alifatisk karboksylsyre med 1 til 7 karbonatomer, f .eks. formyl, acetyl, propionyl og lignende, og en "aroyl"-gruppe avledet fra en aromatisk karboksylsyre,slik som benzoyl og lignende. Uttrykket "acyloksy" betegner en "alkanoyloksy"-gruppe avledet fra en alifatisk karboksylsyre med 1 til 7 karbonatomer, f.eks. formyl-oksy, acetoksy, propionyloksy og lignende og en "aroyloksy"-gruppe avledet fra en aromatisk karboksylsyre, slik som benzoyloksy og lignende. Eksempler på "di-(C-^-C^) alkylamino-(C2-C^) alkyl-oksy"-grupper er dimetylaminoetoksy, dietylaminoetoksy, di<p>ro-pylaminoetoksy, diisopropylaminoetoksy, dibutylaminoetoksy, dipentylaminoetoksy, og lignende. Eksempler på "di- (C-^-C^) alkylamino-(C2~C^)alkyl"-grupper er dimetylaminoety1, dietylamino-etyl, etylmetylaminoetyl, dipropylaminoetyl og lignende. Eksempler på "acyloksy-lavere alkyl"-grupper er formyloksymetyl, acetyloksymetyl, propionyloksymety1, benzoyloksymetyl og lignende. propyl, isopropyl, butyl, t-butyl, neopentyl, pentyl, heptyl and the like. The term "lower alkoxy" denotes an alkoxy group where the lower alkyl group is as described above, e.g. methoxy, ethoxy, propdoxy, pentoxy and the like. The term "halogen" denotes the four forms bromine, chlorine, fluorine and iodine. The term "acyl" denotes an "alikanoyl" group derived from an aliphatic carboxylic acid of 1 to 7 carbon atoms, e.g. formyl, acetyl, propionyl and the like, and an "aroyl" group derived from an aromatic carboxylic acid, such as benzoyl and the like. The term "acyloxy" denotes an "alkanoyloxy" group derived from an aliphatic carboxylic acid of 1 to 7 carbon atoms, e.g. formyloxy, acetoxy, propionyloxy and the like and an "aroyloxy" group derived from an aromatic carboxylic acid such as benzoyloxy and the like. Examples of "di-(C-^-C^) alkylamino-(C2-C^) alkyloxy" groups are dimethylaminoethoxy, diethylaminoethoxy, dipropylaminoethoxy, diisopropylaminoethoxy, dibutylaminoethoxy, dipentylaminoethoxy, and the like. Examples of "di-(C-C-C-C) alkylamino-(C2-C-C)alkyl" groups are dimethylaminoethyl, diethylaminoethyl, ethylmethylaminoethyl, dipropylaminoethyl and the like. Examples of "acyloxy-lower alkyl" groups are formyloxymethyl, acetyloxymethyl, propionyloxymethyl, benzoyloxymethyl and the like.
Spesielle forbindelser som omfattes av foreliggende' oppfinnelse Special compounds covered by the present invention
er sådanne med den generelle formel are such with the general formula
hvor R-j^' , R?' og R^<1>uavhengig representerer hydrogen, laverealkyl, laverealkoksy, laverealkyltio, halogen eller hydroksy og R^har den ovenfor angitte betydning. Ytterligere spesielle forbindelser er de med formelen .1' ovenfor, hvor minst én av R-^' , R2' og R3<1>representerer lavefe-alkyltio. I et spesielt aspekt omfatter oppfinnelsen også forbindelser med formel I<1,>foran, hvor R^representerer acyloksy-.laverealkyl eller en rest med formelen where R-j^' , R?' and R^<1>independently represents hydrogen, lower alkyl, lower alkoxy, lower alkylthio, halogen or hydroxy and R^ has the meaning indicated above. Further special compounds are those of the formula .1' above, where at least one of R-^' , R 2' and R 3 < 1> represents lower alkylthio. In a particular aspect, the invention also comprises compounds of formula I<1,> in front, where R^ represents acyloxy-lower alkyl or a residue of the formula
hvor Y og A har den foran angitte betydning. Videre er spesielle forbindelser og-så sådanne med formelen I' , hvor R,, répresenterer en rest méd formelen where Y and A have the above meaning. Furthermore, special compounds are also those with the formula I', where R,, represents a residue with the formula
hvor A representerer laverealkyl, di-(C-^-C^) al- where A represents lower alkyl, di-(C-^-C^) al-
kylamino-(C-^-C-y) alkoksy eller pivaloyloksymetoksy . alkylamino-(C-C-C-y) alkoxy or pivaloyloxymethoxy.
En annen gruppe spesielle forbindelser som omfattes av foreliggende oppfinnelse er de med formel I ovenfor, hvor minst én av Rl'R2°9R3representerer cyklopropyl eller cyklobutyl. Another group of special compounds covered by the present invention are those with formula I above, where at least one of R1'R2°9R3 represents cyclopropyl or cyclobutyl.
Foretrukne forbindelser med formel I ovenfor er de, hvor R2og Preferred compounds of formula I above are those wherein R 2 and
Ro representerer hydrogen og R, representerer en rest med forme- Ro represents hydrogen and R, represents a residue with form-
len len
hvor A representerer di-(C-^-C^) alkylamino-(C2~C^) alkok- where A represents di-(C-^-C^)alkylamino-(C2-C^)alco-
sy og R-^har ovenfor angitte betydning. sy and R-^ have the meanings given above.
I et videre foretrukket aspekt omfatter oppfinnelsen forbindelser med formel I, hvor minst én av R-^, R2og R^representerer laverealkyl, laverealkoksy eller laverealkyltio og R^representerer en substituent i 8-stilling. I et ytterligere foretrukket aspekt omfatter oppfinnelsen, forbindelser med formel I, hvor R2 representerer hydrogen, R-^og/eller R^ er forskjellig fra hydrogen og R^representerer en substituent i 8-stilling. Ennå ster-kere foretrukne forbindelser med formel I, hvor R2representerer hydrogen, Rj_ og/eller R^, uavhengig, representerer laverealkyl, laverealkoksy eller laverealkyltio, og R^representerer hydroksy- In a further preferred aspect, the invention comprises compounds of formula I, where at least one of R 1 , R 2 and R 2 represents lower alkyl, lower alkoxy or lower alkylthio and R 2 represents a substituent in the 8-position. In a further preferred aspect, the invention comprises compounds of formula I, where R 2 represents hydrogen, R-^ and/or R^ is different from hydrogen and R^ represents a substituent in the 8-position. Even more strongly preferred compounds of formula I, where R 2 represents hydrogen, R 1 and/or R 2 , independently, represent lower alkyl, lower alkoxy or lower alkylthio, and R 2 represents hydroxy
laverealkyl, 5-tetrazolyl eller lower alkyl, 5-tetrazolyl or
hvor A representerer hydroksy eller di-(C-^-C^) alkylamino-(C2-C7) alkoksy . Mest foretrukket er forbindelser med formel I, hvor én av , R? og R^ representerer laverealkyl, laverealkoksy eller laverealkyltio, og R, representerer where A represents hydroxy or di-(C-3-C4) alkylamino-(C2-C7) alkoxy. Most preferred are compounds of formula I, where one of , R? and R 1 represents lower alkyl, lower alkoxy or lower alkylthio, and R 1 represents
Eksempler på . foretrukne forbindelser med formel I er de føl-gende: 2-metoksy-ll-okso-llH-pyrido[2,1-b]kinazolin-8-karboksylsyre; Examples of . preferred compounds of formula I are the following: 2-methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid;
2-metyltio-ll-okso-llH-pyrido[2,1-b]kinazolin-8-karboksylsyre; 2-methylthio-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid;
2-isopropyl-ll-okso-llH-pyrido[2,1-b]kinazolih-8-karboksylsyre; 2-isopropyl-11-oxo-11H-pyrido[2,1-b]quinazolin-8-carboxylic acid;
2-cyklopropyl-ll-okso-llH-pyrido[2,1-b]kinazolin-8-karboksylsyre, og 2-cyclopropyl-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid, and
2-isopropyl-ll-okso-llH-pyrido[2,1-b]kinazolin-8-karboksylsyre-(2-dietylaminoetyl)ester. 2-Isopropyl-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid (2-diethylaminoethyl) ester.
Eksempler på forbindelsene med formel I er de følgende: 4-isopropyl-ll-okso-llH-pyrido[2,1-b]kinazolin-8-karboksylsyre; Examples of the compounds of formula I are the following: 4-isopropyl-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid;
4-isopropoksy-ll-okso-llH-pyrido t 2,1-b]kinazolin-8-karboksylsyre; 4-mety1-tio-ll-okso-llH-pyrido[2,1-b]kinazolin-8-karboksylsyre; 4-isopropoxy-11-oxo-11H-pyrido t 2,1-b]quinazoline-8-carboxylic acid; 4-methyl-thio-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid;
2,4-diisppropyl-ll-okso-llH-pyrido[2,1-b]kinazolin-8-karboksylsyre; 2,4-diisopropyl-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid;
2,4-diisopropoksy-ll-okso-llH-pyrido[2,1-b]kinazolin-8-karboksylsyre ; 2,4-diisopropoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid;
2,4-dimetyltio-ll-okso-llK-pyrido[2,1-b]kinazolin-8-karboksylsyre; 2,4-dimethylthio-11-oxo-11K-pyrido[2,1-b]quinazoline-8-carboxylic acid;
11-okso-llH-pyrido[2,1-b]kinazolin-8-eddiksyre; 11-oxo-11H-pyrido[2,1-b]quinazoline-8-acetic acid;
2- klor-ll-okso-llH-pyrido[2,1-b]kinazolin-8-eddiksyre; 2-chloro-11-oxo-11H-pyrido[2,1-b]quinazoline-8-acetic acid;
3- metoksy-ll-okso-llH-pyrido[2,1-b]kinazolin-8-eddiksyre; 3-Methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-acetic acid;
3-kloro-ll-okso-llH-pyrido[2,1-b]kinazolin-8-eddiksyre\ 2-metoksy-ll-okso-llH-pyrido[2,1-b]kinazolin-7-eddiksyre; 3-chloro-11-oxo-11H-pyrido[2,1-b]quinazoline-8-acetic acid\ 2-methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-7-acetic acid;
2-kloro-ll-okso-llH-pyrido[2,1-b]kinazolin-7-eddiksyre y 2-metoksy-ll-okso-llH-pyrido t 2,1-b]kinazolin-8-a-metyleddik- 2-chloro-11-oxo-11H-pyrido[2,1-b]quinazoline-7-acetic acid y 2-methoxy-11-oxo-11H-pyrido t 2,1-b]quinazoline-8-a-methylacetic
syre; acid;
2- klor-ll-okso-llH-pyrido 12,1-b]kinazolin-8-a-metyleddiksyre; 2-chloro-11-oxo-11H-pyrido 12,1-b]quinazoline-8-a-methylacetic acid;
3- metoksy-ll-okso-llH-pyrido[2,1-b]kinazolin-8-a-metyleddiksyre; 3-Methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-a-methylacetic acid;
3-kloro-ll-okso-llH-pyrido[2,1-b]kinazolin-8-a-metyleddiksyre; 3-chloro-11-oxo-11H-pyrido[2,1-b]quinazoline-8-a-methylacetic acid;
2-metoksy-ll-okso-llH-pyrido[2,1-b]kinazolin-7-a-metyleddiksyre; 2-kloro-ll-okso-llH-pyrido[2,1-b]kinazolin-7-a-metyleddiksyre; 2-metyltio-ll-okso-llH-pyrido[2,1-b]kinazolin-8-karboksylsyre-(2-dietylaminoetylester; 2-methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-7-a-methylacetic acid; 2-chloro-11-oxo-11H-pyrido[2,1-b]quinazoline-7-a-methylacetic acid; 2-methylthio-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid-(2-diethylaminoethyl ester);
2-isopropyltio-ll-okso-llH-pyrido[2,1-b]kinazolin-8-karboksylsyre-(2-dietylamino-etyl)ester; 2-isopropylthio-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid (2-diethylamino-ethyl) ester;
2-isopropyl-ll-okso-llH-8-(lH-tetrazol-5-yl)pyrido[ 2,1-b]-kino-zolin; 2-isopropyl-11-oxo-11H-8-(1H-tetrazol-5-yl)pyrido[2,1-b]-quinozoline;
2-cyklobutyl-ll-okso-llH-pyrido[ 2,1-b]kinazolin-8-karboksylsyre; 2-cyclobutyl-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid;
4 4
2-metyltio-ll-okso-llH-8-(lH-tetrazol-5-yl)pyrido[2,1-b]kinazolin; 2-methylthio-11-oxo-11H-8-(1H-tetrazol-5-yl)pyrido[2,1-b]quinazoline;
2-isopropyltio-ll-okso-llH-8-(lH-tetrazol-5-yl)pyrido-[2,1-b]kinazolin; 2-isopropylthio-11-oxo-11H-8-(1H-tetrazol-5-yl)pyrido-[2,1-b]quinazoline;
8-hydroksymetyl-2-isopropyl-llH-pyrido[2,1-b]kinazolin-ll-on; 8-hydroksy-metyl-2-isopropoksy-llH-pyrido[2,1-b]kinazolin-ll-on; 8-hydroksymetyl-2-metyltio-llH-pyrido 12,1-b]kinazolin-ll-on; 8-hydroksymetyl-2-isopropyltio-llH-pyrido[2,1-b]kinazolin-ll- 8-hydroxymethyl-2-isopropyl-11H-pyrido[2,1-b]quinazolin-11-one; 8-Hydroxy-methyl-2-isopropoxy-11H-pyrido[2,1-b]quinazolin-11-one; 8-hydroxymethyl-2-methylthio-11H-pyrido 12,1-b]quinazolin-11-one; 8-hydroxymethyl-2-isopropylthio-11H-pyrido[2,1-b]quinazoline-11-
on og lignende, også omfattende forbindelser nevnt nedenfor. on and the like, also including compounds mentioned below.
Ifølge foreliggende oppfinnelse fremstilles forbindelsene med formelen I foran og deres farmasøytisk fordra<g>eli<g>e syreaddisjonssalter, og når A representerer hydroksy,også deres farmasøytisk fordragelige salter med en base, ved at According to the present invention, the compounds with the preceding formula I and their pharmaceutically acceptable acid addition salts are prepared, and when A represents hydroxy, also their pharmaceutically acceptable salts with a base, by
a) forbindelser med formel I ovenfor, hvor R, representerer cyano, acyloksy-laverealkyl eller en rest med formelen a) compounds of formula I above, where R, represents cyano, acyloxy-lower alkyl or a residue of the formula
hvor A representerer laverealkyl, hydroksy, lavere- where A represents lower alkyl, hydroxy, lower-
alkoksy eller en rest med formelen -NR^Rg og , R2, R3, R5/alkoxy or a residue of the formula -NR^Rg and , R2, R3, R5/
Rg, Y og n har ovenfor angitte betydning, franstilles: ved behandling aven forbindelse med den generelle formel Rg, Y and n have the meaning indicated above, except: when treating the compound with the general formula
hvor R representerer hydrogen eller laverealkyl, og R^, R2og R^har ovenfor angitte betydning, med et halogenpyridin-derivat med den generelle formel' hvor -R„ ' representerer cyano, acyloksy-laverealkyl eller en rest med formelen where R represents hydrogen or lower alkyl, and R^, R 2 and R^ have the meanings given above, with a halopyridine derivative of the general formula' where -R„ ' represents cyano, acyloxy-lower alkyl or a residue of the formula
hvor A repre- where A repre-
senterer laverealkyl, hydroksy, laverealkoksy eller en rest med formelen -NR^Rg, Y representerer hydro- centers lower alkyl, hydroxy, lower alkoxy or a residue of the formula -NR^Rg, Y represents hydro-
gen eller metyl og n representerer heltallet 0 eller 1, R^og Rg uavhengig representerer hydrogen, lavere-alkyl' eller di-(C-^-C^) alkylamino (C2-C^) alkyl, og X representerer halogen, gen or methyl and n represents the integer 0 or 1, R^ and Rg independently represent hydrogen, lower-alkyl' or di-(C-^-C^) alkylamino (C2-C^) alkyl, and X represents halogen,
eller or
b) forbindelser med formel I som ovenfor, hvor R^representerer 5-tetrazolyl og R-^, R2og R^har ovenfor angitte betydning, fremstilles ved behandling av en forbindelse med den generelle formel b) compounds of formula I as above, where Râ‚‚ represents 5-tetrazolyl and Râ‚‚, Râ‚‚ and Râ‚‚ have the meanings indicated above, are prepared by treating a compound of the general formula
hvor R-^, R2og R3har ovenfor angitte betydning/ where R-^, R2 and R3 have the meanings given above/
med et alkalimetallazid, eller with an alkali metal azide, or
c) forbindelser med formel I som ovenfor, hvor R^representerer hydroksy-laverealkyl og R-^, R2og R^har ovenfor angitte c) compounds of formula I as above, where Râ‚‚ represents hydroxy-lower alkyl and Râ‚‚, Râ‚‚ and Râ‚‚ have the above indicated
betydning, fremstilles ved hydrolyse av en forbindelse med den generelle formel meaning, is produced by hydrolysis of a compound with the general formula
hvor R7representerer acyloksy-laverealkyl, og R^, R2og R^ har ovenfor angitte betydning, where R 7 represents acyloxy-lower alkyl, and R 1 , R 2 and R 1 have the meanings given above,
eller or
d) forbindelser med formel I som ovenfor, hvor R^represente- , rer en rest med formelen - d) compounds of formula I as above, where R^represent- , solve a remainder with the formula -
hvor A representerer di- where A represents di-
(C1-C7)alkyl amino-(C2_C^) alkoksy og R-^ , R2'R3'^ og^har ovenfor angitte betydning, fremstilles ved behandling av en forbindelse med den generelle formel (C 1 -C 7 )alkyl amino-(C 2 -C 4 ) alkoxy and R 1 , R 2 , R 3 , and ^ have the meanings given above, are prepared by treating a compound with the general formula
hvor R-^, R2;R3, Y og n har ovenfor angitte betydning,. med et di- (C-^-C^) alkylamino- (C2_C7) alkylhalogenid/ eller et syreklorid av en forbindelse med formel Ic ovenfor underkastes alko-holyse med en di-(C-^-C^) alkylamino-(C2-C-,) alkanol, eller e) forbindelser med formel I som ovenfor, hvor R*representerer en rest med formelen hvor A representerer pivaloyloksymetoksy og R-^ , R2;R37Y og n har den ovenfor angitte betydning, fremstilles ved behandling av en forbindelse med formel.Ic som ovenfor med en tertiær organisk base og klor-, brom- eller jodmetylpivalat, eller f) forbindelser med formel I som ovenfor, hvor.R, representerer en rest med formelen hvor A representerer lavere-alkoksy og R-^, R2 1 1 Y og n har ovenfor angitte betydning, fremstilles ved forestring av en forbindelse med. formel Ic som ovenfor, eller g) forbindelser med formel I som ovenfor, hvor R. representerer en rest med formelen hvor A representerer en rest med formelen -NR^R^ og R^, R0, R3, R^, Rg, Y og n har ovenfor angitte betydning, fremstilles ved å underkaste en forbindelse med formel Ic som ovenfor ammonolyse med en aminoforbin-deise med den generelle formel ; 1 hvor R^og Rg har de ovenfor angitte betydninger, ;eller, ;h) forbindelser med formelen Ib som ovenfor, fremstilles ved å behandle en forbindelse med formel II som ovenfor med et halogenpyridin-derivat.med den generelle formel ; hvor R7og X har de ovenfor angitte betydninger, ;og ;i) om ønskes, overføres en erholdt forbindelse i et farma-søytisk fordragelig salt. ;Ifølge fremgangsmåtevariant a) omsettes en antranilsyre eller ;-ester med formel II, en kjent forbindelse, en eller forbindelse som kan fremstilles ifølge kjente metoder, med et halogenpyri- ;din med formel III, som også er en kjent forbindelse eller kan fremstilles ifølge kjente metoder, ved en temperatur innen området fra ca. 100°C til 200°C med eller uten et oppløsningsm.iddel. Reaksjonen utføres i nærvær av en katalytisk mengde av et alkalimetalljodid, som natriumjodid, kaliumjodid, cesiumjodid eller lignende. Løsningsmidler som kan anvendes ved reaksjonen er høyt-kokende løsningsmidler slik som eddiksyre, diglym, triglym eller lignende. Reaksjonen utføres gjerne ved atmosfærisk trykk. Reaksjonsproduktet kan opparbeides ifølge kjente metoder, slik ;som krystallisering eller lignende. ;En forbindelse med formel I, hvor R^er 5-tetrazolyl, kan fremstilles ifølge fremgangsmåtevariant b) fra den tilsvarende forr bindelse med formel Ia. Mere spesifikt behandles den tilsvarende forbindelse med formel Ia méd et alkalimetallazid, slik eom kaliumazid, natriumazid eller lignende i nærvær av ammoniumklorid. Reaksjonen utføres hensiktsmessig i nærvær av- et løs-ningsmiddel, slik som et polart aprotisk løsningsmiddel, f.eks. * dimetylsulfoksyd, dimetylformamid eller lignende. Den ønskete tetrazolylforbindelsen opparbeides deretter ifølge kjente metoder, f.eks. krystallisering eller lignende. where R-^, R2;R3, Y and n have the meaning indicated above. with a di-(C-^-C^) alkylamino-(C2-C7) alkyl halide/ or an acid chloride of a compound of formula Ic above is subjected to alcoholysis with a di-(C-^-C^) alkylamino-(C2- C-,) alkanol, or e) compounds of formula I as above, where R* represents a residue of the formula where A represents pivaloyloxymethoxy and R-^ , R2;R37Y and n have the meaning indicated above, are prepared by treating a compound of formula.Ic as above with a tertiary organic base and chloro, bromo or iodomethylpivalate, or f) compounds of formula I as above, where.R, represents a residue of the formula where A represents lower-alkoxy and R-^, R2 1 1 Y and n have the meanings given above, are produced by esterification of a compound with. formula Ic as above, or g) compounds of formula I as above, where R. represents a residue of the formula where A represents a residue of the formula -NR^R^ and R^, R0, R3, R^, Rg, Y and n has the meaning indicated above, is prepared by subjecting a compound of formula Ic as above to ammonolysis with an amino compound of the general formula; 1 where R^ and Rg have the meanings given above, or, h) compounds of formula Ib as above are prepared by treating a compound of formula II as above with a halopyridine derivative of the general formula; where R 7 and X have the meanings indicated above, ; and ;i) if desired, a compound obtained is transferred in a pharmaceutically acceptable salt. According to method variant a) an anthranilic acid or ;-ester of formula II, a known compound, one or a compound that can be prepared according to known methods, is reacted with a halopyridine of formula III, which is also a known compound or can be prepared according to known methods, at a temperature in the range from approx. 100°C to 200°C with or without a solvent. The reaction is carried out in the presence of a catalytic amount of an alkali metal iodide, such as sodium iodide, potassium iodide, cesium iodide or the like. Solvents that can be used in the reaction are high-boiling solvents such as acetic acid, diglyme, triglyme or the like. The reaction is preferably carried out at atmospheric pressure. The reaction product can be worked up according to known methods, such as crystallization or the like. A compound of formula I, where R 1 is 5-tetrazolyl, can be prepared according to process variant b) from the corresponding precursor compound of formula Ia. More specifically, the corresponding compound of formula Ia is treated with an alkali metal azide, such as potassium azide, sodium azide or the like in the presence of ammonium chloride. The reaction is conveniently carried out in the presence of a solvent, such as a polar aprotic solvent, e.g. * dimethylsulfoxide, dimethylformamide or the like. The desired tetrazolyl compound is then worked up according to known methods, e.g. crystallization or the like.
Ifølge fremgangsmåtevariant c) hydrolyseres forbindelsen med According to method variant c) the compound is hydrolysed with
formel Ib på i og for seg kjent måte, f.eks. ved behandling med én mineralsyre som konsentrert saltsyre, i nærvær av et løs-ningsmiddel, f.eks. en alkanol, slik som etanol, og det ønskete sluttproduktet opparbeides derpå ifølge kjente metoder, f.eks. formula Ib in a manner known per se, e.g. by treatment with one mineral acid such as concentrated hydrochloric acid, in the presence of a solvent, e.g. an alkanol, such as ethanol, and the desired end product is then worked up according to known methods, e.g.
ved rekrystallisering f ra metanolisk hydrogenklorid. by recrystallization from methanolic hydrogen chloride.
Ifølge fremgangsmåtevariant d) kan en forbindelse med formel I, hvor A er di- ( ci~ c- j) alkylamino- { C^- C- j) alkoksy , fremstilles fra den tilsvarende forbindelse med formel Ic ved å behandle denne forbindelse, f.eks. med et di- (C-^-Cy) alkylamino- (C2-Q3) alkylhalogenid under tilbakeløpsbetingelser i et løsningsmiddel, f. According to process variant d), a compound of formula I, where A is di-(ci~c-j)alkylamino-{C^-C-j) alkoxy, can be prepared from the corresponding compound of formula Ic by treating this compound, f .ex. with a di-(C-^-Cy)alkylamino-(C2-Q3)alkyl halide under reflux conditions in a solvent, e.g.
eks. en alkanol slik som isopropanol eller lignende, og opp-arbeide produket ifølge kjente metoder, slik som krystallsering eller lignende, eller behandle denne forbindelsen med tionylklorid, hvorved det tilsvarende syrekloridet oppnåes, og sistnevnte forbindelse omsettes med en di-(C-^-C^)alkylamino-(C2-C^)-alkanol i et inert løsningsmiddel, slik som tetrahydrofuran. e.g. an alkanol such as isopropanol or the like, and work up the product according to known methods, such as crystallization or the like, or treat this compound with thionyl chloride, whereby the corresponding acid chloride is obtained, and the latter compound is reacted with a di-(C-^-C ^)alkylamino-(C 2 -C 4 )-alkanol in an inert solvent, such as tetrahydrofuran.
eller lignende, ved en temperatur i området fra ca. 0°C til 100°C, og deretter opparbeides det ønskete sluttprodukt ved kjente metoder, slik som krystallisering eller lignende. or similar, at a temperature in the range from approx. 0°C to 100°C, and then the desired end product is worked up by known methods, such as crystallization or the like.
Ifølge framgangsmåtevariant e) kan en forbindelse med formel I hvor A er pivaloyloksymetoksy fremstilles fra den tilsvarende forbindelse med formel Ic ved å behandle denne forbindelsen med en tertiær organisk base, slik som et tri-laverealkylamin, og klor-, brom- eller jodmetylpivalat i et inert løsningsmiddel slik som dimetylformamid eller lignende, ved en temperatur innen området romtemperatur til ca. 120°C. Det ønskete sluttproduktet kan opparbeides ifølge kjente metoder, slik som krystallisa- According to process variant e) a compound of formula I where A is pivaloyloxymethoxy can be prepared from the corresponding compound of formula Ic by treating this compound with a tertiary organic base, such as a tri-lower alkylamine, and chloro, bromo or iodomethyl pivalate in a inert solvent such as dimethylformamide or the like, at a temperature within the range of room temperature to approx. 120°C. The desired end product can be prepared according to known methods, such as crystallization
sjon. tion.
Ifølge fremgangsmåtevariant .f) kan en syre med formel Ic over-føres til den tilsvarende ester ifølge kjente metoder. F.eks. According to method variant .f), an acid of formula Ic can be transferred to the corresponding ester according to known methods. E.g.
kan ét alkalimetallsalt av en.syre som ovenfor beskrevet, slik som natriumsaltét, omsettes med et substituert eller usubsti- an alkali metal salt of an acid as described above, such as the sodium salt, can be reacted with a substituted or unsubstituted
tuert alkylhalogenid ved anvendelse av kjente reaksjonsbetingelser, f.eks. i et inert løsningsmiddel som dimetylformamid, eller lignende ved en temperatur i området fra ca. romtempera- tuated alkyl halide using known reaction conditions, e.g. in an inert solvent such as dimethylformamide, or similar at a temperature in the range from approx. room temperature
tur til reaksjonsblandingens tilbakeløpstemperatur. turn to the reflux temperature of the reaction mixture.
Ifølge fremgangsmåtevariant g) kan en syre med formelIc over-føres til det tilsvarende amid ved kjente metoder. F.eks. behandles en syre som ovenfor beskrevet med tionylklorid, hvorved det tilsvarende syreklorid oppnåes. Det sistnevnte behandles med det tilsvarende amin, f.eks. behandles med ammoniakk, dimetylamin, 3-dietylaminopropylamin eller lignende, i nærvær av et løsnings-middel som tetrahydrofuran. Detønskede amid opparbeides derpå ifølge kjente metoder, slik som krystallisasjon. According to process variant g), an acid of formula Ic can be converted to the corresponding amide by known methods. E.g. an acid is treated as described above with thionyl chloride, whereby the corresponding acid chloride is obtained. The latter is treated with the corresponding amine, e.g. is treated with ammonia, dimethylamine, 3-diethylaminopropylamine or the like, in the presence of a solvent such as tetrahydrofuran. The desired amide is then worked up according to known methods, such as crystallization.
Ifølge fremgangsmåtevariant h) kondenseres ethalogenpyridin-derivat med formel V med en antranilsyre eller -ester med for- According to method variant h) the ethhalogenpyridine derivative of formula V is condensed with an anthranilic acid or -ester with for-
mel II, ved en temperatur i området fra ca. 100°C til ca. 200°C med eller uten et løsningsmiddel. Reaksjonen utføres i nærvær av en katalytisk mengde av et alkalimetalljodid, slik som natriumjodid, kaliumjodid, cesiumjodid eller lignende. Løsnings-midler som kan anvendes i reaksjonen er høytkokende løsnings-midler som eddiksyre, diglym, triglym eller lignende. Reaksjonen utføres gjerne ved atmosfæretrykk. Reaksjonsproduktet kan opparbeides ved kjente metoder som krystallisasjon eller lignende. mel II, at a temperature in the range from approx. 100°C to approx. 200°C with or without a solvent. The reaction is carried out in the presence of a catalytic amount of an alkali metal iodide, such as sodium iodide, potassium iodide, cesium iodide or the like. Solvents that can be used in the reaction are high-boiling solvents such as acetic acid, diglyme, triglyme or the like. The reaction is preferably carried out at atmospheric pressure. The reaction product can be worked up by known methods such as crystallization or the like.
Forbindelsene med formel I, hvor A er hydroksy, danner farma-søytisk fordragelige salter med baser. Eksempler på slike baser er alkalimetallhydroksyder, som natriumhydroksyd, kaliumhydroksyd og lignende; jordalkalihydroksyder, slik som kalsiumhy-droksyd, bariumhydroksyd og lignende; natriumalkoksyder som na-triumetanolat, kaliumetanolat og lignende; organiske baser slik som piperidin, dietylamin, N-metylglukamin og lignende. The compounds of formula I, where A is hydroxy, form pharmaceutically acceptable salts with bases. Examples of such bases are alkali metal hydroxides, such as sodium hydroxide, potassium hydroxide and the like; alkaline earth hydroxides, such as calcium hydroxide, barium hydroxide and the like; sodium alkoxides such as sodium ethanolate, potassium ethanolate and the like; organic bases such as piperidine, diethylamine, N-methylglucamine and the like.
Forbindelsene med formel I danner også farmasøytisk fordrageli- The compounds of formula I also form pharmaceutical tolerance
ge salter med syrer. Eksempler på slike syrer er både organiske og uorganiske syrer, slik som metansulfonsyre, p-toluensulfon-syre, saltsyre, bromhydrogensyre, svovelsyre og lignende. give salts with acids. Examples of such acids are both organic and inorganic acids, such as methanesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, sulfuric acid and the like.
Forbindelsene med formel V ovenfor er kjente eller kan fremstilles ved kjente metoder. Således behandles f.eks. et hydroksy-laverealkyl-substituert 2-halogenpyridin med et acylhalogenid som benzoylklorid, ved anvendelse av kjente reaksjonsbetingelser hvilket gir det tilsvarende acyloksy-laverealkyl-substituerte halogenpyridin, som omdannes til det tilsvarende.N-oksyd med formel V med et peroksyderende middel som m-klorperbenzosyre i nærvær av et inert løsningsmiddel, f.eks. et halogenert hydro-karbon som metylenklorid. Den resulterende reaksjonsblanding høytraliserers med et alkalimetallhydroksyd som natriumhydroksyd, og deretter opparbeides det resulterende N-oksydet. The compounds of formula V above are known or can be prepared by known methods. Thus, e.g. a hydroxy-lower alkyl-substituted 2-halopyridine with an acyl halide such as benzoyl chloride, using known reaction conditions which gives the corresponding acyloxy-lower alkyl-substituted halopyridine, which is converted to the corresponding N-oxide of formula V with a peroxidizing agent such as m- chloroperbenzoic acid in the presence of an inert solvent, e.g. a halogenated hydrocarbon such as methylene chloride. The resulting reaction mixture is hypertralized with an alkali metal hydroxide such as sodium hydroxide, and then the resulting N-oxide is worked up.
Forbindelsene med formel I samt deres farmasøytisk fordragelige salter inhiberer kutan anafylokse hos rotter og er derfor anven-delige ved forhindring av allergiske reaksjoner, f.eks. kan de anvendes ved profylaktisk behandling av bronkial-astma. Den an-ti-anafylaktiske aktivitet kan vises ved den passive kutane ana-fylaksiske. prøven(PCA prøve) hos rotter. Denne prøve innbefat- The compounds of formula I as well as their pharmaceutically acceptable salts inhibit cutaneous anaphylaxis in rats and are therefore useful in preventing allergic reactions, e.g. can they be used in the prophylactic treatment of bronchial asthma. The anti-anaphylactic activity can be shown by the passive cutaneous anaphylactic. the test (PCA test) in rats. This sample includes
ter passiv lokal sensibilisering av rotter ved intra-dermal in-jeksjon av anti-sera. Etter en latent periode på 24 timer gis forsøksforbindelsen, i dette tilfelle et pyrido[2,1-b]kinazolin, intraperitonealt fulgt etter 5 minutter av en intravenøs injek-sjon av reagens og Evans blue dye. Resultatene av lokalisert antigen-antistoff-reaksjon fører til dannelsen av hudblærer hvis størrelse måles. Forsøksforbindelsens evne til å nedsette stør-relsen av disse blemmene sammenlignet med kontroller tas som et mål for aktiviteten. ter passive local sensitization of rats by intra-dermal injection of anti-sera. After a latent period of 24 hours, the test compound, in this case a pyrido[2,1-b]quinazoline, is given intraperitoneally followed after 5 minutes by an intravenous injection of reagent and Evans blue dye. The results of localized antigen-antibody reaction lead to the formation of skin blisters whose size is measured. The test compound's ability to reduce the size of these blisters compared to controls is taken as a measure of activity.
Når en forbindelse ifølge oppfinnelsen, slik som 2-metoksy-ll-okso-llH-pyrido[2,1-b]kinazolin-8-karboksylsyre, anvendes som prøveforbindelsen i en dose på 16 mg/kg intraperitonealt, er reduksjonen av blemméstørrelsen 63%. Når natriumsaltet av 2-metoksy-ll-okso-llH-pyrido[2 ,1-b] kina zol in-8-karboksy lsyre anvendes som forsøksforbindelsen i en dose på 16 mg/kg intraperitonealt er reduksjonen av blemméstørrelsen 86%. When a compound according to the invention, such as 2-methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid, is used as the test compound in a dose of 16 mg/kg intraperitoneally, the reduction of blister size is 63 %. When the sodium salt of 2-methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid is used as the test compound in a dose of 16 mg/kg intraperitoneally, the reduction in blister size is 86%.
Den anti-allergiske aktivitet for forbindelsene med formel I The anti-allergic activity of the compounds of formula I
kan også vises hos aktivt sensibilisert marsvin (IgC). I dette forsøk sensibiliseres marsvinet intraperitonealt med heste- can also appear in actively sensitized guinea pigs (IgC). In this experiment, the guinea pig is sensitized intraperitoneally with horse-
serum på dag 1 og deretter gis dyret intravenøst på dagene 11- serum on day 1 and then the animal is given intravenously on days 11-
14 antigen (hesteserum) som øyeblikkelig initierer den øye-blikkelige hypersensitive reaksjon (IHR bronchospasmer).. Når 14 antigen (horse serum) which immediately initiates the immediate hypersensitive reaction (IHR bronchospasm).. When
en anti-allergisk forbindelse gis intravenøst.før antigenet blokkeres IHR og derved forhindres bronchospasmer. an anti-allergic compound is given intravenously.before the antigen, IHR is blocked and thereby bronchospasm is prevented.
NÃ¥r 2-metoksy-ll-okso-llH-pyrido[2,1-b]kinazolin-8-karboksyl- When 2-methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxyl-
syre anvendes i det foregående forsøk med en oral dose på 200 mg pr. kg er prosentinhibering av bronchospasmer 65%. Når den foregående forbindelse gis intravenøst i en dose på 20 mg/kg er prosent inhibering av bronchospasmer 54%. acid is used in the previous experiment with an oral dose of 200 mg per kg is the percentage inhibition of bronchospasm 65%. When the preceding compound is given intravenously at a dose of 20 mg/kg, the percent inhibition of bronchospasm is 54%.
Den anti-allergiske virkning kan også vises i passivt sensibilisert rotte (IgE). Ved dette forsøk får en rotte anti-sera intravenøst 18 timer for den intravenøse antigen-, (egg-albumin) innsprøytning. Antigen-innsprøytningen fremkaller IHR. Når en anti-allergisk forbindelse administreres intravenøst før antigen-innsprøytningen inhiberer den IHR og forhindrer bronchospasmer . The anti-allergic effect can also be shown in passively sensitized rats (IgE). In this experiment, a rat receives anti-sera intravenously 18 hours before the intravenous antigen (egg albumin) injection. The antigen injection induces IHR. When an anti-allergic compound is administered intravenously before the antigen injection, it inhibits IHR and prevents bronchospasm.
Når 2-metoksy-ll-okso-llH-pyrido[2,1-b]kinazolin-8-karboksyl- . syre anvendes i det foregående forsøk ved en oral dosering på 10 mg/kg er prosent inhibering av bronchospasmer 59%. Når den foregående forbindelse gis intravenøst i en dose på 10 mg/kg When 2-methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxyl- . acid is used in the previous experiment at an oral dosage of 10 mg/kg, the percent inhibition of bronchospasm is 59%. When the preceding compound is given intravenously at a dose of 10 mg/kg
er prosent inhibering av bronchospasmer 83%. percent inhibition of bronchospasm is 83%.
Forbindelsene med formel I og deres farmasøytisk fordragelige salter kan gis oralt eller parenteralt som anti-allergiske midler, f.eks. i den profylaktiske behandling av bronchial-atsma, The compounds of formula I and their pharmaceutically acceptable salts can be administered orally or parenterally as anti-allergic agents, e.g. in the prophylactic treatment of bronchial asthma,
med doseringsjusteringer etter individuelle behov. De kan gis terapeutisk, f.eks. oralt eller parenteralt, ved å inkorporere en terapeutisk dose i en konvensjonell doseringsform, som tab-letter, kapsler, eliksirer, suspensjoner, løsninger eller lignende. De kan gis i blanding med konvensjonelle farmasøytiske bærere eller eksipienter, som f.eks. maisstivelse, kalsium-stearat, magnesiumkarbonat, kalciumsilikat, dikalsiumfosfat, talkum, laktose og lignende. Dessuten kan de gis i nærvær av puffere eller midler som brukes for å justere til isotoniske betingelser, og de farmasøytiske doseringsformer kan om ønsket with dosage adjustments according to individual needs. They can be given therapeutically, e.g. orally or parenterally, by incorporating a therapeutic dose in a conventional dosage form, such as tablets, capsules, elixirs, suspensions, solutions or the like. They can be given in admixture with conventional pharmaceutical carriers or excipients, such as e.g. corn starch, calcium stearate, magnesium carbonate, calcium silicate, dicalcium phosphate, talc, lactose and the like. Moreover, they may be administered in the presence of buffers or agents used to adjust to isotonic conditions, and the pharmaceutical dosage forms may, if desired,
underkastes konvensjonelle farmasøytiske behandlinger, som f. are subjected to conventional pharmaceutical treatments, such as
eks. steriliering. Som angitt foran kan doseringen justeres etter individuelle behov. De kan også inneholde andre terapeu- e.g. sterilization. As indicated above, the dosage can be adjusted according to individual needs. They may also contain other therapeutic
tisk verdifulle stoffer. tically valuable substances.
Mengden av aktivt medikament som foreligger i hver av de oven-nevnte doseringsformer er variabel. Det er imidlertid foretrukket å fremstille kapsler eller.tabletter som inneholder fra ca. 10 The amount of active drug present in each of the above-mentioned dosage forms is variable. However, it is preferred to produce capsules or tablets containing from approx. 10
til 20 mg av en base med formel I eller en ekvivalent mengde av et medisinsk foredagelig salt derav. to 20 mg of a base of formula I or an equivalent amount of a medically acceptable salt thereof.
Hyppigheten hvormed en slik doseringsform skal gis til en pa-sient vil variere,, avhengig av mengden av aktivt medikament som foreligger i den og pasientens behov. Under vanlige forhold kan imidlertid opp til ca. 20 mg/kg av forbindelsen gis daglig i flere doseringer. Det må imidlertid være klart at de angitte doserin- The frequency with which such a dosage form is to be given to a patient will vary, depending on the amount of active drug present in it and the patient's needs. Under normal conditions, however, up to approx. 20 mg/kg of the compound is given daily in several doses. However, it must be clear that the indicated dosage
ger bare er eksempler og at de på ingen måte begrenser omfang eller utøvelse av foreliggende oppfinnelse. are only examples and that they in no way limit the scope or practice of the present invention.
De følgende eksempler illustrerer oppfinnelsen. Alle temperatu-rer er gitt i grader Centigrad. The following examples illustrate the invention. All temperatures are given in degrees Centigrade.
EKSEMPEL 1 EXAMPLE 1
Fremstilling av 6- klor- 3-( N- dietylaminoetylkarbamoyl) pyridin-hydroklorid Preparation of 6-chloro-3-(N-diethylaminoethylcarbamoyl)pyridine hydrochloride
En løsning av 5,0 g 6-klornikotinsyre og 8,56 ml difenylfosforyl-azid i 25 ml dimetylformamid ble kjølt i et isbad og 4,27 ml N,N-dietyletylendiamin ble tilsatt dråpevis. Etter at tilsetningen var fullført fikk reaksjonsblandingen stå natten over ved A solution of 5.0 g of 6-chloronicotinic acid and 8.56 ml of diphenylphosphoryl azide in 25 ml of dimethylformamide was cooled in an ice bath and 4.27 ml of N,N-diethylethylenediamine was added dropwise. After the addition was complete, the reaction mixture was allowed to stand overnight
romtemperatur og ble så helt i 500 ml vann. Den vandige løsning ble. ekstrahert med 3 x 500 ml diklormetan og de samlete organiske sjiktene ble vasket med vann, tørket over kaliumkarbonat og inndampet til en olje som ble oppløst i 15 ml etanol og forsiktig surgjort med saltsyre i tetrahydrofuran. Etter kjøling ble 5,62 room temperature and then poured into 500 ml of water. The aqueous solution was extracted with 3 x 500 ml of dichloromethane and the combined organic layers were washed with water, dried over potassium carbonate and evaporated to an oil which was dissolved in 15 ml of ethanol and carefully acidified with hydrochloric acid in tetrahydrofuran. After cooling it was 5.62
g (61%) 6-klor-3-(N-dietylaminoetylkarbamoyl)-pyridin-hydroklorid, smp. 182-184°, erholdt. Filtratet ga ytterligere 1,74 g (19%) 6-klor-3-(N-dietylaminoetylkårbamoyl)pyridinhydroklorid, smp. 171-181°. g (61%) 6-chloro-3-(N-diethylaminoethylcarbamoyl)-pyridine hydrochloride, m.p. 182-184°, obtained. The filtrate gave a further 1.74 g (19%) of 6-chloro-3-(N-diethylaminoethylcarbamoyl)pyridine hydrochloride, m.p. 171-181°.
EKSEMPEL 2 EXAMPLE 2
Fremstilling av N-( 2- dietylaminoetyl)- 2- metoksy- ll- okso- llH-pyrido[ 2, 1- b] kinazolin- 8- karboksamidhydroklorid Preparation of N-(2-diethylaminoethyl)-2-methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxamide hydrochloride
En suspensjon på 4,4 g 6-klor-3-(N-dietylaminoetylkarbamoyl)-pyridinhydroklorid, 3,28 g 5-metoksyantranilsyremetylesterhydro-klorid og 0,2 g kaliumjodid i 4 ml triglym ble oppvarmet til en badtemperatur på 150° under en argonstrøm i 5 timer. Etter kjø-ling ble reaksjonsblandingen revet med eter og filtrert og gir et gult faststoff som ble omkrystallisert fra etanol-eter og gir 3,47 g (57.%) N- (2-dietylaminoetyl)-2-metoksy-ll-okso-llH-pyrido[2,1-b]kinazolin-8-karboksamidhydroklorid, smp. 249-251°. A suspension of 4.4 g of 6-chloro-3-(N-diethylaminoethylcarbamoyl)-pyridine hydrochloride, 3.28 g of 5-methoxyanthranilic acid methyl ester hydrochloride and 0.2 g of potassium iodide in 4 ml of triglyme was heated to a bath temperature of 150° under a argon flow for 5 hours. After cooling, the reaction mixture was triturated with ether and filtered to give a yellow solid which was recrystallized from ethanol-ether to give 3.47 g (57.%) of N-(2-diethylaminoethyl)-2-methoxy-11-oxo- 11H-pyrido[2,1-b]quinazoline-8-carboxamide hydrochloride, m.p. 249-251°.
EKSEMPEL . 3 EXAMPLE . 3
Fremstilling av 2- metoksy- ll- okso- llH- pyrido[ 2, 1- b] kinazolin- 8-karboksamid Preparation of 2-methoxy-ll-oxo-llH-pyrido[2,1-b]quinazoline-8-carboxamide
En suspensjon på 10,24 g 2-klor-5-karbamoylpyridin, 14,26 g A suspension of 10.24 g of 2-chloro-5-carbamoylpyridine, 14.26 g
.5-metoksyantranilsyre og 300 mg kaliumjodid i. 30 ml triglym ble oppvarmet til en badtemperatur på 155° over natten. Etter kjøling ble blandingen fortynnet med 30 ml etanol og fellingen .5-methoxyanthranilic acid and 300 mg of potassium iodide in. 30 ml of triglyme was heated to a bath temperature of 155° overnight. After cooling, the mixture was diluted with 30 ml of ethanol and the precipitate
ble samlet opp og gir 15,21 g (76%) 2-metoksy-ll-okso-llH-pyrido[2,l-b]kinazolin-8-karboksamid, smp. ±310°. Omkrystallisasjon fra dimetylformamid-eddiksyre og fra eddiksyr.e ga den analytiske prøve, smp. 32 6°. was collected to give 15.21 g (76%) of 2-methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxamide, m.p. ±310°. Recrystallization from dimethylformamide-acetic acid and from acetic acid gave the analytical sample, m.p. 32 6°.
EKSEMPEL 4 EXAMPLE 4
Fremstilling av 8- cyano- 2- metoksy- ll- okso- llH- pyrido[ 2, 1- b] kinazolin Preparation of 8-cyano-2-methoxy-ll-oxo-llH-pyrido[2,1-b]quinazoline
En blanding av 8,3 g 2-klor-5-cyanopyridin, 13,04 g 5-metoksyantranilsyre og 0,2 g kaliumjodid i 10 ml triglym ble oppvarmet til en badtemperatur på 170° i 4 timer under en langsom argon-strøm. Etter kjøling ble blandingen revet med metanol og eter A mixture of 8.3 g of 2-chloro-5-cyanopyridine, 13.04 g of 5-methoxyanthranilic acid and 0.2 g of potassium iodide in 10 ml of triglyme was heated to a bath temperature of 170° for 4 hours under a slow stream of argon. After cooling, the mixture was triturated with methanol and ether
og filtrert. Det slik erholdte faste stoff ble omkrystallisert and filtered. The solid thus obtained was recrystallized
fra metanol og gir 6,02 g (40%) 8-cyano-2-metoksy-ll-okso-llH-pyrido[2,1-b]kinazolin, smp. 282-284°. En ytterligere krystallisasjon fra metanol-metylenklorid ga den analytiske prøve, smp. 284-285°. from methanol and gives 6.02 g (40%) of 8-cyano-2-methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline, m.p. 282-284°. A further crystallization from methanol-methylene chloride gave the analytical sample, m.p. 284-285°.
EKSEMPEL 5 EXAMPLE 5
Fremstilling av 2- substituerte pyrido[ 2, 1- b] kinazolin- 8-karboksylsyrer Preparation of 2-substituted pyrido[2,1-b]quinazoline-8-carboxylic acids
Fremgangsmåte A Procedure A
Syntesen for 2-substituerte pyrido[2,1-b]kinazolin-8-karboksyl-syrer via kondensasjon av den egnete antranilsyre med 6-klornikotinsyre vises av syntesen for 2-metyl-ll-okso-llH-pyrido[2,1-b]kinazolin-8-karboksylsyre: En suspensjon av 28,7 g 5-metyl-antranilsyre, 25,0 g 6-klornikotinsyre og 1,32 g kaliumjodid i 50 ml triglym ble oppvarmet til en badtemperatur på 150° over natten under en argonstrøm. Etter kjøling ble blandingen revet med etanol og filtrert og gir 31,8 g av et gult fast stoff, smp. 295-310°. Omkrystallisasjon fra dimetylformamid-eddiksyre ga 15,3 g (38%) 2-metyl-ll-okso-llH-pyrido[2,1-b]kinazolin-8-karboksylsyre, smp. >310°. The synthesis of 2-substituted pyrido[2,1-b]quinazoline-8-carboxylic acids via condensation of the appropriate anthranilic acid with 6-chloronicotinic acid is shown by the synthesis of 2-methyl-11-oxo-11H-pyrido[2,1- b]quinazoline-8-carboxylic acid: A suspension of 28.7 g of 5-methyl-anthranilic acid, 25.0 g of 6-chloronicotinic acid and 1.32 g of potassium iodide in 50 ml of triglyme was heated to a bath temperature of 150° overnight under a argon flow. After cooling, the mixture was triturated with ethanol and filtered to give 31.8 g of a yellow solid, m.p. 295-310°. Recrystallization from dimethylformamide-acetic acid gave 15.3 g (38%) of 2-methyl-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid, m.p. >310°.
Fremgangsmåte B Procedure B
Omsetningen av et antranilsyrehydroklorid med 6-klornikotinsyre illustreres ved fremstillingen av 2-etoksy-ll-okso-llH-pyrido- The reaction of an anthranilic acid hydrochloride with 6-chloronicotinic acid is illustrated by the preparation of 2-ethoxy-11-oxo-11H-pyrido-
[2,1-b]kinazolin-8-karboksylsyre: En suspensjon av 7,5 g 5-etoksy-antranilsyrehydroklorid, 6,3 g 6-klornikotinsyre og 1,2 [2,1-b]quinazoline-8-carboxylic acid: A suspension of 7.5 g of 5-ethoxy-anthranilic acid hydrochloride, 6.3 g of 6-chloronicotinic acid and 1,2
g kaliumjodid i. 12 ml triglym ble oppvarmet til en badtemperatur på 145-150° over natten. Etter kjøling ble blandingen revet med etanol og filtrert og gir 7,7 g, smp. 260-265°. Omkrystallisasjon fra dimetylformamid ga 4,14 g (42%) 2-etoksy-ll-okso-llH-pyrido[2,1-b]kinazolin-8-karboksylsyre, smp. 285-287°. g of potassium iodide in. 12 ml of triglyme was heated to a bath temperature of 145-150° overnight. After cooling, the mixture was triturated with ethanol and filtered to give 7.7 g, m.p. 260-265°. Recrystallization from dimethylformamide gave 4.14 g (42%) of 2-ethoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid, m.p. 285-287°.
Fremgangsmåte C Procedure C
Reaksjonen av substituert metylantranilat-hydroklorider med 6-klornikotinsyre vises ved syntesen av 2-metoksy-ll-okso-llH-pyrido[2,1-b]kinazolin-8-karboksylsyre: En suspensjon på 134 The reaction of substituted methylanthranilate hydrochlorides with 6-chloronicotinic acid is shown in the synthesis of 2-methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid: A suspension of 134
g metyl 5-metoksyantranilathydroklorid,.106,7 g 6-klornikotinsyre og 9,0 g kaliumjodid i 300 ml triglym ble oppvarmet til en badtemperatur på 150° over natten. Den resulterende suspensjon ble fortynnet med 200 ml etanol og ble filtrert og gir 177,9 g, g of methyl 5-methoxyanthranilate hydrochloride, 106.7 g of 6-chloronicotinic acid and 9.0 g of potassium iodide in 300 ml of triglyme were heated to a bath temperature of 150° overnight. The resulting suspension was diluted with 200 ml of ethanol and filtered to give 177.9 g,
smp. 278-290°. Omkrystallisasjon fra 2,5 1 dimetylformamid og 500 ml iseddiksyre ga 93,3 g (56%) 2-metoksy-ll-okso-llH-pyri-dot2,1-b]kinazolin-8-karboksylsyre, smp. 310°. m.p. 278-290°. Recrystallization from 2.5 L of dimethylformamide and 500 ml of glacial acetic acid gave 93.3 g (56%) of 2-methoxy-11-oxo-11H-pyrido-2,1-b]quinazoline-8-carboxylic acid, m.p. 310°.
a) DMF = dimetylformamid; HOAc = eddiksyre; a) DMF = dimethylformamide; HOAc = acetic acid;
Pr = isopropylalkohol, DMEA = N,N-dimetyletanolamin Pr = isopropyl alcohol, DMEA = N,N-dimethylethanolamine
b) Smeltepunkt ble bestemt på et Dupont Instruments Model 900 termisk analyseapparat c) Forbindelser omkrystallisert fra dette løsningsmiddel ble erholdt som de frie syrer ved felling fra vann med b) Melting point was determined on a Dupont Instruments Model 900 thermal analyzer c) Compounds recrystallized from this solvent were obtained as the free acids by precipitation from water with
eddiksyre acetic acid
EKSEMPEL 6 EXAMPLE 6
Fremstilling av 2- metoksy- ll- okso- llH- 8-( lH- tetrazol- 5- yl)-pyrido[ 2, 1- b] kinazolin- hemihydroklorid Preparation of 2-methoxy-11-oxo-11H-8-(1H-tetrazol-5-yl)-pyrido[2,1-b]quinazoline hemihydrochloride
En suspensjon av 7,0 g 8-cyano-2-metoksy-ll-okso-llH-pyrido[2,1-b] kinazolin, 2,24 g natriumazid og 1,89 g ammoniumklorid i 70 ml dimetylformamid ble oppvarmet til en badtemperatur på 100° over natten og ytterligere 2,24 g natriumazid og 1,89 g ammoniumklo- A suspension of 7.0 g of 8-cyano-2-methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline, 2.24 g of sodium azide and 1.89 g of ammonium chloride in 70 ml of dimethylformamide was heated to a bath temperature of 100° overnight and a further 2.24 g of sodium azide and 1.89 g of ammonium chloride
rid ble tilsatt. Etter ytterligere 6 timer fikk reaksjonsblandingen avkjøle seg og ble filtrert. Det oppsamlete gule faste stoff ble omkrystallisert fra vandig metanol som inneholder saltsyre og gir 5,55 g (68%) 2-metoksy-ll-okso-llH-8-(lH-tetrazol-5-yl)pyrido[2,1-b]kinazolin, smp. 286° (spaltning). Filtratet av-leiret et andre utbytte på 2,28 g (29%)., smp. 285° (spaltning). ride was added. After an additional 6 hours, the reaction mixture was allowed to cool and was filtered. The collected yellow solid was recrystallized from aqueous methanol containing hydrochloric acid to give 5.55 g (68%) of 2-methoxy-11-oxo-11H-8-(1H-tetrazol-5-yl)pyrido[2,1- b]quinazoline, m.p. 286° (decomposition). The filtrate gave a second yield of 2.28 g (29%)., m.p. 285° (decomposition).
EKSEMPEL 7 EXAMPLE 7
Fremstilling av metyl 2- metoksy- ll- okso- llH- pyrido[ 2, 1- b] kinazolin- 8- karboksylat- hydroklorid Preparation of methyl 2-methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylate hydrochloride
A. En suspensjon av 6,10 g 2-metoksy-ll-okso-llH-pyrido[2,1-b]-kinazolin-8-karboksylsyre og 2,52 g natriumbikarbonat i 20 ml heksametylfosforamid og 3,0 ml metyljodid ble rørt ved romtemperatur i 72 timer, og ytterligere 2,52 g natriumbikarbonat og A. A suspension of 6.10 g of 2-methoxy-11-oxo-11H-pyrido[2,1-b]-quinazoline-8-carboxylic acid and 2.52 g of sodium bicarbonate in 20 ml of hexamethylphosphoramide and 3.0 ml of methyl iodide was stirred at room temperature for 72 hours, and an additional 2.52 g of sodium bicarbonate and
3,0 ml metyljodid ble tilsatt. Etter ytterligere 48 timer ble 3.0 ml of methyl iodide was added. After a further 48 hours,
.reaksjonsblandingen fortynnet med vann og fellingen ble samlet opp. Rivning av filterkaken med kokende metanol ga 0,69 g (11%) metyl 2-metoksy-ll-okso-llH-pyrido[2,1-b]kinazolin-8-karboksy- .the reaction mixture was diluted with water and the precipitate was collected. Trituration of the filter cake with boiling methanol gave 0.69 g (11%) of methyl 2-methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxy-
lat, smp. 205-208° og et andre utbytte som beløp seg til 0,43 g lazy, smp. 205-208° and a second yield which amounted to 0.43 g
(7%), smp. 195-200°. En del av dette materiale ble krystalli- (7%), m.p. 195-200°. Part of this material was crystallized
sert fra metanol-eter-saltsyre og gir hydrokloridsaltet, smp. 235-238°. separated from methanol-ether-hydrochloric acid and gives the hydrochloride salt, m.p. 235-238°.
B. En suspensjon på 2,40 g 2-metoksy-ll-okso-llH-pyrido[2,1-b]kinazolin-8-karboksylsyre og 2,4 g kaliumkarbonat i 25 ml dimetylformamid og 2,5 ml metyljodid ble rørt ved romtemperatur i 4 8 timer. Den resulterende blanding ble fortynnet med 75 ml vann og den gule felling ble samlet opp, 2,36 g (94%), smp. 188-19 5°. Omkrystallisasjon fra metanol-saltsyre-eddiksyre ga 2,24 B. A suspension of 2.40 g of 2-methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid and 2.4 g of potassium carbonate in 25 ml of dimethylformamide and 2.5 ml of methyl iodide was stirred at room temperature for 4 8 hours. The resulting mixture was diluted with 75 mL of water and the yellow precipitate was collected, 2.36 g (94%), m.p. 188-19 5°. Recrystallization from methanol-hydrochloric acid-acetic acid gave 2.24
g (79%) metyl 2-metoksy-ll-okso-llH-pyrido[2,1-b]kinazolin-8-karboksylathydroklorid, smp. 228^231°. g (79%) methyl 2-methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylate hydrochloride, m.p. 228^231°.
EKSEMPEL 8 EXAMPLE 8
Fremstilling av 2- metoksy- ll- okso- llH- pyrido[ 2, 1- b] kinazolin-8- karboksylsyre-( 2- dietylaminoetyl) esterhydroklorid Preparation of 2-methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid-(2-diethylaminoethyl) ester hydrochloride
En 12,5 g's andel av dietylaminoetylkloridhydroklorid ble delt mellom 50 ml IN natriumhydroksyd og 60 ml eter. De forenete eterlag ble vasket med vann og saltoppløsning, ble tørket over kaliumkarbonat og ble inndampet kaldt. Den resulterende olje ble tilsatt til en mekanisk rørt suspensjon av 5,00 g 2-metoksy-ll-okso-llH-pyrido[2,1-b]kinazolin-8-karboksylsyre i 60 ml tørt isopropanol og blandingen ble oppvarmet til tilbakeløp i 2 ti- A 12.5 g portion of diethylaminoethyl chloride hydrochloride was partitioned between 50 ml of 1N sodium hydroxide and 60 ml of ether. The combined ether layers were washed with water and brine, dried over potassium carbonate and evaporated cold. The resulting oil was added to a mechanically stirred suspension of 5.00 g of 2-methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid in 60 ml of dry isopropanol and the mixture was heated to reflux in 2 ten-
mer. Etter kjøling ble de faste stoffer samlet opp og omkrystallisert fra metanol-eter og gir 5,72 g (76%) 2-metoksy-ll-okso-HH-pyrido [ 2 ,1-b] kina zol in-8-karboksy lsyre- (2-die ty laminoetyl) - esterhydroklorid, smp. 250-253°. En ytterligere krystallisasjon ' fra dimetylformamid-eddiksyre hevet smeltepunkt til 255-258°. more. After cooling, the solids were collected and recrystallized from methanol-ether to give 5.72 g (76%) of 2-methoxy-11-oxo-HH-pyrido[2,1-b]quinazoline-8-carboxylic acid - (2-die ty laminoethyl) - ester hydrochloride, m.p. 250-253°. A further crystallization from dimethylformamide-acetic acid raised the melting point to 255-258°.
EKSEMPEL 9 EXAMPLE 9
Fremstilling av 8-( N, N- dimetylkarbamoyl)- 2- metoksy- ll- okso- llH-pyrido[ 2, 1- b] kinazolin Preparation of 8-(N,N-dimethylcarbamoyl)-2-methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline
En løsning av 6,0 g 2-metoksy-ll-okso-llH-pyridof 2,1-b]kinazolin-8-karboksylsyre i 100 ml tionylklorid ble tilbakeløpsbehand-let i 3 timer. Reaksjonsblandingen ble inndampet til tørrhet og den faste rest ble suspendert i 200 ml tørt tetrahydrofuran. Dimetylamin ble boblet gjennom blandingen inntil farven hadde forandret seg fra gul til grønlig-gul og de faste stoffer ble samlet opp. De faste stoffer ble oppløst i'metanol, løsningen ble filtrert og inndampet til tørrhet. Resten ble omkrystallisert fra 500 ml etylacetat og gir 4,0 g (61%) 0-(N,N-dimetyl-karbamoyl) -2-metoksy-ll-okso-ll'H-pyrido [2 ,1-b] kinazolin, smp. 190-196°. Omkrystallisasjon fra etylacetat-heksan og deretter fra etylacetat hevet smeltepunktet til 19 7-99°. A solution of 6.0 g of 2-methoxy-11-oxo-11H-pyridof 2,1-b]quinazoline-8-carboxylic acid in 100 ml of thionyl chloride was refluxed for 3 hours. The reaction mixture was evaporated to dryness and the solid residue was suspended in 200 ml of dry tetrahydrofuran. Dimethylamine was bubbled through the mixture until the color had changed from yellow to greenish-yellow and the solids were collected. The solids were dissolved in methanol, the solution was filtered and evaporated to dryness. The residue was recrystallized from 500 mL of ethyl acetate to give 4.0 g (61%) of O-(N,N-dimethylcarbamoyl)-2-methoxy-11-oxo-11'H-pyrido[2,1-b]quinazoline , m.p. 190-196°. Recrystallization from ethyl acetate-hexane and then from ethyl acetate raised the melting point to 197-99°.
EKSEMPEL 10 Fremstilling av 6- klor- 3- pyridinmetanolbenzoat EXAMPLE 10 Preparation of 6-chloro-3-pyridine methanol benzoate
Til en isavkjølt løsning av 24,41 g 2-klor-5-hydroksymetyl-pyridin i 250 ml tørt metylenklorid og 27,0 ml tørt trietylamin ble tilsatt 23,0 ml benzoylklorid dråpevis. Den resulterende blanding ble rørt ved 0° i 1 time og ved romtemperatur i 2 timer. Den ble deretterfortynnet med 500 ml metylenklorid og vasket med 100 ml's vannporsjoner, mettet natriumbikarbonat og mettet natriumklorid. Tørking over kaliumkarbonat og.inndampning ga 45,4 g av et gult semi-fast stoff, som b destillert gjennom, kortveis-apparatur og gir 41,51 g (98%) rått 6-klor-3-pyridinmetanolbenzoat, kokepunkt 150-160°/0,1-0,2 mm. To an ice-cooled solution of 24.41 g of 2-chloro-5-hydroxymethyl-pyridine in 250 ml of dry methylene chloride and 27.0 ml of dry triethylamine was added 23.0 ml of benzoyl chloride dropwise. The resulting mixture was stirred at 0° for 1 hour and at room temperature for 2 hours. It was then diluted with 500 ml methylene chloride and washed with 100 ml portions of water, saturated sodium bicarbonate and saturated sodium chloride. Drying over potassium carbonate and evaporation gave 45.4 g of a yellow semi-solid, which was distilled through short-circuit apparatus to give 41.51 g (98%) of crude 6-chloro-3-pyridinemethanolbenzoate, bp 150-160 °/0.1-0.2 mm.
Omkrystallisasjon fra eter-ligroin ga, etter filtrering for å fjerne noe uløselig materiale, 33,42 g (79%), smp. 58-60°. Den analytiske prøve ble erholdt fra eter-heksan og smeltet ved 59-62°. Recrystallization from ether-ligroin gave, after filtration to remove some insoluble material, 33.42 g (79%), m.p. 58-60°. The analytical sample was obtained from ether-hexane and melted at 59-62°.
EKSEMPEL 11 EXAMPLE 11
Fremstilling av 6- klor- 3- pyridinmetanolbenzoat, N- oksyd Preparation of 6-chloro-3-pyridinemethanolbenzoate, N-oxide
En løsning av 33,42 g 6-klor-3-pyridinmetariolbenzoat og 75 g m-klorperbenzosyre i 1800 ml metylenklorid ble.rørt ved romtemperatur i 5 dager og ble vasket med 2 x 500 ml IN natriumhydroksyd, 2 x 500 ml vann og 1 X 500 ml saltløsning og ble tør-ket over kaliumkarbonat. Inndampning ga et gult fast stoff som etter krystallisasjon fra etylacetat-heksan ga 25,87 g (73%) 6-klor-3-pyridinmetanolbenzoat,N-oksyd, smp. 116-121°. Den analytiske prøve ble erholdt fra etylacetat, smp. 120-123°. A solution of 33.42 g of 6-chloro-3-pyridine metriolbenzoate and 75 g of m-chloroperbenzoic acid in 1800 ml of methylene chloride was stirred at room temperature for 5 days and was washed with 2 x 500 ml of 1N sodium hydroxide, 2 x 500 ml of water and 1 X 500 ml salt solution and was dried over potassium carbonate. Evaporation gave a yellow solid which, after crystallization from ethyl acetate-hexane, gave 25.87 g (73%) of 6-chloro-3-pyridinemethanolbenzoate, N-oxide, m.p. 116-121°. The analytical sample was obtained from ethyl acetate, m.p. 120-123°.
EKSEMPEL 12 EXAMPLE 12
Fremstilling av 8- hydroksymetyl- 2- metoksy- llH- pyrido[ 2, 1- b] kinazolin- ll- on- banzoat Preparation of 8-hydroxymethyl-2-methoxy-llH-pyrido[2,1-b]quinazolin-ll-one-benzoate
En suspensjon på 5,00 g 5-metoksyantranilsyre og 3,90 g 6-klor-3-pyridinmetanolbenzoat,N-oksyd i 9 ml triglym ble oppvarmet til en badtemperatur på 120° over natten. Etter kjøling ble reaksjonsblandingen revet med 15 ml etanol og ble filtrert og gir 3,79 g (71%) rått 8-hydroksymetyl-2-metoksy-llH-pyrido[2,1-b]-kinazolin-ll-on-benzoat, smp. 206-219°. Rivning med kokende mé-• tanol ga 1,75 g (33%), smp. 226-229°. To omkrystallisasjoner fra vandig eddiksyre ga en prøve, smp. 228-230°. A suspension of 5.00 g of 5-methoxyanthranilic acid and 3.90 g of 6-chloro-3-pyridinemethanolbenzoate,N-oxide in 9 ml of triglyme was heated to a bath temperature of 120° overnight. After cooling, the reaction mixture was triturated with 15 ml of ethanol and was filtered to give 3.79 g (71%) of crude 8-hydroxymethyl-2-methoxy-11H-pyrido[2,1-b]-quinazolin-11-one benzoate, m.p. 206-219°. Trituration with boiling methanol gave 1.75 g (33%), m.p. 226-229°. Two recrystallizations from aqueous acetic acid gave a sample, m.p. 228-230°.
EKSEMPEL 13 EXAMPLE 13
Fremstilling av 8- hydroksymetyl- 2- metoksy- llH- pyrido[ 2, 1- b]-kinazolin- ll- on- hydroklorid Preparation of 8-hydroxymethyl-2-methoxy-llH-pyrido[2,1-b]-quinazolin-ll-one hydrochloride
En løsning av 1,75 g 8-hydroksymetyl-2-metoksy-llH-pyrido[2,1-b]-kinazolin-ll-on-benzoat i 10 ml konsentrert saltsyre og 7 ml etanol ble tilbakeløpsbehandlet over natten. Etter kjøling ble 0,60 g (42%) 8-hydroksymetyl-2-metoksy-llH-pyrido[2,1-b]kinazolin-ll-on-hydroklroid, smp. 248-251° (spaltning), skilt fra og filtratet ga ytterligere 0,72 g (51%), smp. 244-248°. Den analytiske prøve ble erholdt fra metanolisk saltsyre-eter og. smeltet, 253-255° (spaltet). A solution of 1.75 g of 8-hydroxymethyl-2-methoxy-11H-pyrido[2,1-b]-quinazolin-11-one benzoate in 10 ml of concentrated hydrochloric acid and 7 ml of ethanol was refluxed overnight. After cooling, 0.60 g (42%) of 8-hydroxymethyl-2-methoxy-11H-pyrido[2,1-b]quinazolin-11-one hydrochloride, m.p. 248-251° (dec.), separated and the filtrate yielded an additional 0.72 g (51%), m.p. 244-248°. The analytical sample was obtained from methanolic hydrochloric acid ether and. melted, 253-255° (cleaved).
EKSEMPEL 14 EXAMPLE 14
Fremstilling av 2- nitro- 5- metyltiobenzosyre Preparation of 2-nitro-5-methylthiobenzoic acid
Til en løsning av 50 ml metylmerkaptan i 200 ml dimetylformamid ble tilsatt 48 g natriumhydrid porsjonsvis ved -40°. Etter full-førelse av den følgende, reaksjon ble 100,0 g 5-klor-2-nitrobenzosyre tilsatt. Reaksjonstemperaturen fikk stige til -10°, ble ble igjen senket til -40° og det overskytende reaksjonsmiddel ble bråkjølt med IN saltsyre. Etter 2 timers røring ved romtemperatur ble produktet samlet opp, 102,3 g (97%), smp. 165-169°. Omkrystallisasjon fra metanol-etylacetat ga 52,14 g, smp. 173-174°. Den analytiske prøve ble erholdt fra etylacetat, smp. 174- , 175°. To a solution of 50 ml of methyl mercaptan in 200 ml of dimethylformamide, 48 g of sodium hydride was added in portions at -40°. After completion of the following reaction, 100.0 g of 5-chloro-2-nitrobenzoic acid was added. The reaction temperature was allowed to rise to -10°, was again lowered to -40° and the excess reaction medium was quenched with 1N hydrochloric acid. After 2 hours of stirring at room temperature, the product was collected, 102.3 g (97%), m.p. 165-169°. Recrystallization from methanol-ethyl acetate gave 52.14 g, m.p. 173-174°. The analytical sample was obtained from ethyl acetate, m.p. 174- , 175°.
EKSEMPEL 15 EXAMPLE 15
Fremstilling av metyl 2- amino- 5- metyltiobenzoat Preparation of methyl 2-amino-5-methylthiobenzoate
Til en iskald løsning av 52,1 g 2-nitro-5-metyltiobenzosyré To an ice-cold solution of 52.1 g of 2-nitro-5-methylthiobenzoic acid
i 250 ml metanol ble tilsatt en eterisk løsning av diazometan inntil tynnlagskromatografi viste at reaksjonen var fullført. in 250 ml of methanol was added an ethereal solution of diazomethane until thin layer chromatography showed that the reaction was complete.
Den resulterende løsning ble inndampet til tørrhet og anvendt The resulting solution was evaporated to dryness and used
som sådan. I ett tilfelle ble det rå produkt krystallisert fra metanol og gir gule nåler av metyl-2-nitro-5-metyltiobenzoat, as such. In one case the crude product was crystallized from methanol to give yellow needles of methyl 2-nitro-5-methylthiobenzoate,
smp. 53-54°. m.p. 53-54°.
Det rå produkt fra ovenfor, 55,5 g, ble suspendert sammen med The crude product from above, 55.5 g, was suspended with
55,5 g jernpulver i 280 ml iseddiksyre. Badtemperaturen ble hevet til 125° i løpet av 30 minutter og den resulterende grå suspensjon fikk kjøle seg og ble filtrert gjennom "Celite". Inndampning ga en mørk, oljeaktig rest som ble revet med metanolisk saltsyre og gir et hvitt fast stoff som ble krystallisert.fra metanal-eter og gir 33,32 g (58%) metyl 2-amino-5-metyltiobenzoat-hydroklorid, smp. 193-194°. Et andre utbytte på 7,35 g (13%), smp. 191-192° ble erholdt fra filtratet. Den analytiske prøve ble erholdt fra metanol-eter, smp. 196-197°. 55.5 g iron powder in 280 ml glacial acetic acid. The bath temperature was raised to 125° over 30 minutes and the resulting gray suspension was allowed to cool and filtered through Celite. Evaporation gave a dark oily residue which was triturated with methanolic hydrochloric acid to give a white solid which was crystallized from methanol ether to give 33.32 g (58%) of methyl 2-amino-5-methylthiobenzoate hydrochloride, m.p. 193-194°. A second yield of 7.35 g (13%), m.p. 191-192° was obtained from the filtrate. The analytical sample was obtained from methanol-ether, m.p. 196-197°.
EKSEMPEL 16 EXAMPLE 16
Fremstilling av rått 2- metoksy- ll- okso- llH- pyrido[ 2, 1- b] kinazolin- 8- karboksy 1 sy rehiydroklor id Preparation of crude 2- methoxy- ll- oxo- llH- pyrido[ 2, 1-b] quinazoline- 8- carboxy 1 sy rehydrochlor id
En 1,0 liters tre-halset flaske ble utstyrt med en mekanisk rø-rer, argon-innløp, kortveis-kondensator og mottager, oljebad, varmeplate, termour, temperaturkontrollapparat og badtermometer. Flasken ble spylt med argon og tilført 135 g 5-metoksyantranilsyre, 135 g 6-klornikotinsyre, 2,0 g kaliumjodid og 400 ml tri-etylenglykoldimetyleter (triglym). Denne reaksjonsblanding ble rørt og oppvarmet under en langsom argonstrøm. Når badtemperaturen nådde ca. 140° hadde mesteparten av dét faste stoff opp-løst seg. Etter fortsatt oppvarmning felte produktet langsomt ut som et gult fast stoff. Badtemperaturen ble holdt ved 150° over natten og en langsom argonstrøm ble opprettholdt over den rørte reaksjonsblanding. Den tykke blanding som var resultatet ble kjølt til mindre enn 50° og ble deretter revet med 200 ml etanol. Den resulterende oppslemning ble vakuum-filtert, vasket med 100 ml absolutt etanol, presset tørr og derpå tørket over natten ved 60°C under høyvakuum og gir 326 g rått produkt. Dette materiale er 2-metoksy-ll-okso-llH-pyrido[2,1-b]kinazolin-8-karboksylsyrehydroklorid. A 1.0 liter three-necked bottle was equipped with a mechanical stirrer, argon inlet, short-path condenser and receiver, oil bath, hot plate, thermometer, temperature control device and bath thermometer. The bottle was flushed with argon and 135 g of 5-methoxyanthranilic acid, 135 g of 6-chloronicotinic acid, 2.0 g of potassium iodide and 400 ml of tri-ethylene glycol dimethyl ether (triglyme) were added. This reaction mixture was stirred and heated under a slow flow of argon. When the bath temperature reached approx. At 140°, most of the solid had dissolved. After continued heating, the product slowly precipitated as a yellow solid. The bath temperature was maintained at 150° overnight and a slow flow of argon was maintained over the stirred reaction mixture. The resulting thick mixture was cooled to less than 50° and then triturated with 200 ml of ethanol. The resulting slurry was vacuum filtered, washed with 100 ml of absolute ethanol, pressed dry and then dried overnight at 60°C under high vacuum to give 326 g of crude product. This material is 2-methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid hydrochloride.
EKSEMPEL 17 EXAMPLE 17
Rensning av 2- metoksy- ll- okso- llH- pyrido[ 2, 1- b] kinazolin- 8-karboksylsyrehydroklorid via etylendiaminsaltet Purification of 2-methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid hydrochloride via the ethylenediamine salt
326 g rått hydroklorid i eksempel 16 ble oppløst i 6,2 liter pyridin (25 ml/g forutsatt 100% teoretisk utbytte) og oppvarmet til tilbakeløp i en 12 liters tre-halset flaske. Til den rørte og tilbakeløpsbehandlete løsning ble tilsatt 81,1 ml destillert etylendiamin i løpet av 5 minutter, og den resulterende oppslemning ble tilbakeløpsbehandlet i 10 minutter. Varmémantelen ble derpå fjernet og den rørte reaksjon fikk kjøle seg (ca. 4 timer) til romtemperatur. Krystallene ble samlet opp ved vakuumfiltre-ring, vasket med 3 x 250 ml pyridin, presset tørr og tørket til konstant vekt i vakuum ved 60° over natten og gir 189,8 g av produktets etylendiaminsalt som et gult faststoff. Dette materiale ble omkrystallisert ved å oppløse det i 500 ml varmt vann. Den vandige varme løsning ble innført i en 12 liters tre-halset flaske som inneholder 500 ml tilbakeløpende pyridin og derpå ble 5,2 liter pyridin tilsatt langsomt til den tilbakeløpende løs-ning. Etter fullendelse av tilsetningen ble en atmosfærisk destillasjon av pyridin-vann-azeotropen begynt. Under destilla-sjonen ble ytterligere. 1,0 liter pyridin langsomt tilsatt (i lø-pet av en periode på 1 time), til den rørte blanding og produkt begynte å separere ut. Destillasjon ble fortsatt inntil destilla-sjonstemperaturen hadde nådd 110° og ble deretter stanset (tilnærmet 2,7 liter destillat ble samlet opp), og blandingen fikk av-kjøle seg til under tilbakeløpstemperatur. 27 ml destillert etylendiamin ble deretter tilsatt, og den rørte blanding'fikk avkjøle seg til romtemperatur i 3 timer. De resulterende krystaller ble samlet opp, vasket med en liten mengde pyridin og presset tørre hurtig. Produktet ( ca. 200 g) ble anvendt direkte eller lagret i vakuum. , 326 g of crude hydrochloride in Example 16 was dissolved in 6.2 liters of pyridine (25 ml/g assuming 100% theoretical yield) and heated to reflux in a 12 liter three-necked flask. To the stirred and refluxed solution was added 81.1 ml of distilled ethylenediamine over 5 minutes, and the resulting slurry was refluxed for 10 minutes. The heating mantle was then removed and the stirred reaction was allowed to cool (about 4 hours) to room temperature. The crystals were collected by vacuum filtration, washed with 3 x 250 ml pyridine, pressed dry and dried to constant weight in vacuo at 60° overnight to give 189.8 g of the product ethylenediamine salt as a yellow solid. This material was recrystallized by dissolving it in 500 ml of hot water. The hot aqueous solution was introduced into a 12 liter three-necked bottle containing 500 ml of refluxing pyridine and then 5.2 liters of pyridine was added slowly to the refluxing solution. After completion of the addition, an atmospheric distillation of the pyridine-water azeotrope was begun. During the distillation became further. 1.0 liter of pyridine slowly added (over a period of 1 hour), until the mixture was stirred and product began to separate. Distillation was continued until the distillation temperature had reached 110° and was then stopped (approximately 2.7 liters of distillate was collected) and the mixture was allowed to cool to below reflux temperature. 27 ml of distilled ethylenediamine was then added and the stirred mixture was allowed to cool to room temperature for 3 hours. The resulting crystals were collected, washed with a small amount of pyridine and pressed dry quickly. The product (approx. 200 g) was used directly or stored in a vacuum. ,
EKSEMPEL 18 EXAMPLE 18
Regenerering av renset 2- metoksy- ll- okso- llH- pyrido[ 2, 1- b]-kinazolin- 8- karboksylsyre Regeneration of purified 2-methoxy-11-oxo-11H-pyrido[2,1-b]-quinazoline-8-carboxylic acid
200 g av det totale omkrystalliserte etylendiaminsalt av det ovenfor nevnte kinazolin ble oppløst i 1,0 liter vann og rørt ved romtemperatur mens en løsning av 300 ml iseddiksyre oppløst 1 1,5 liter vann ble tilsatt dråpevis i løpet av 2 timer. Blan-dingens endelige pH var ca. 4 ifølge"Accutint"papir, område.nr. 70. De resulterende krystallene ble samlet opp, vasket med 2 x. 1,0 liter vann og tørket over natten ved 100° i vakuum og gir 95 g gult fast stoff som smelter ved 322°. Dette materiale ble krystallisert ved oppløsning i 1,25 liter tilbakeløpsb.ehandlende pyridin. Den varme løsning ble fort vakuum-filtrert gjennom en Buchner-trakt forsynt med dampkappe. Filteret og flasken ble vasket med 300 ml kokende pyridin. Filtratet ble overført til en 2 liters Erlenmeyer-flaske.med bred åpning og,oppvarmet for å gjenoppløse alle de faste stoffer. Den resulterende løsning fikk avkjøle seg langsomt til romtemperatur og oppslemningen ble derpå omhyggelig kjølt til oo i 2 timer. Krystallene ble filtrert, vasket med 200 ml kold pyridin, presset tørre og tørket i vakuum ved 115° over natten under en langsom nitrogenstrøm og gir 87,6 200 g of the total recrystallized ethylenediamine salt of the above-mentioned quinazoline was dissolved in 1.0 liters of water and stirred at room temperature while a solution of 300 ml of glacial acetic acid dissolved in 1.5 liters of water was added dropwise over the course of 2 hours. The final pH of the mixture was approx. 4 according to "Accutint" paper, area no. 70. The resulting crystals were collected, washed with 2x. 1.0 liters of water and dried overnight at 100° in vacuo to give 95 g of a yellow solid melting at 322°. This material was crystallized by dissolution in 1.25 liters of refluxing pyridine. The hot solution was quickly vacuum-filtered through a Buchner funnel fitted with a steam jacket. The filter and flask were washed with 300 ml of boiling pyridine. The filtrate was transferred to a 2 liter Erlenmeyer flask with a wide mouth and heated to redissolve all the solids. The resulting solution was allowed to cool slowly to room temperature and the slurry was then carefully cooled to 0°C for 2 hours. The crystals were filtered, washed with 200 ml of cold pyridine, pressed dry and dried in vacuo at 115° overnight under a slow stream of nitrogen to give 87.6
g produkt, smp. 32 5°. g product, m.p. 32 5°.
EKSEMPEL 19 EXAMPLE 19
. Fremstilling av 2- metoksy- ll- okso- llH- pyrido[ 2, 1- b] kinazolin- 8-karboksylsyre- natriumsaltmonohydrat . Preparation of 2-methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid sodium salt monohydrate
27,023 g 2-metoksy-ll-okso-llH-pyrido[2,1-b]kinazolin-8-karboksylsyre ble rørt i 50 ml vann ved romtemperatur mens 100 ml 1,0 27.023 g of 2-methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid was stirred in 50 ml of water at room temperature while 100 ml of 1.0
N natriumhydroksydløsning ble tilsatt. Den resulterende Eanding ble rørt i tilnærmet 30 minutter inntil det meste av de faste stoffer hadde oppløst seg. Løsningen ble deretter vakuum-filtrert for å fjerne uoppløselige stoffer, og filtratet ble helt i en 5 liters tre-halset flaske sammen med 1,0 liter pyridin. Den resulterende oppslemning ble oppvarmet til tilbakeløpskjøling, N sodium hydroxide solution was added. The resulting mixture was stirred for approximately 30 minutes until most of the solids had dissolved. The solution was then vacuum-filtered to remove insolubles, and the filtrate was poured into a 5 liter three-necked flask along with 1.0 liter pyridine. The resulting slurry was heated to reflux,
ved hvilken temperatur alle de faste stoffer oppløste seg. Atmosfærisk destillasjon av løsningsmidlet ble begynt mens ytter- at which temperature all the solids dissolved. Atmospheric distillation of the solvent was begun while ex-
ligere 1,0 liter pyridin ble langsomt tilsatt. Kinazolin-produktet begynte å skille seg ut, men destillasjon ble fortsatt inntil en destillasjonstemperatur på 100° var oppnådd (ca. 1 another 1.0 liter of pyridine was slowly added. The quinazoline product began to separate, but distillation was continued until a distillation temperature of 100° was reached (about 1
liter destillat). Oppslemningen ble deretter kjølt til romtemperatur i 3 timer, filtrert, vasket med 2 x 100 ml.pyridin og tør-ket i vakuum ved 9 5° over natten vinder en svak nitrogenstrøm. Dette ga 30,2 g (97,0 %) av det ovenfor nevnte monohydratiserte na-triumsalt som et lysegult fast stoff. liters of distillate). The slurry was then cooled to room temperature for 3 hours, filtered, washed with 2 x 100 ml pyridine and dried in vacuum at 95° overnight under a weak stream of nitrogen. This gave 30.2 g (97.0%) of the above monohydrated sodium salt as a pale yellow solid.
EKSEMPEL 20 Fremstilling av 2- metoksy- ll- okso- llH- pyrido[ 2, 1- b] kinazolin-7- karboksylsyre EXAMPLE 20 Preparation of 2-methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-7-carboxylic acid
Én suspensjon av 2,80 g 5-metoksyantranilsyre, 2,65 g 2-kloriso-nikotinsyre og 0,135 g kaliumjodid i 13 ml triglym ble rørt og oppvarmet ved en badtemperatur på 150° i 21 timer under en ar-gonstrøm. Etter avkjøling ble 40 ml metanol tilsatt, og det gule faste stoff ble fjernet ved filtrering. Det rå produkt ble renset ved omkrystallisasjon av etylendiaminsaltet fra pyridin, omdannelse tilbake til den frie syre ved behandling med eddiksyre og omkrystallisasjon fra eddiksyre og gir 0,42 g (9%) rent 2-metoksy-ll-okso-llH-pyrido[2,1-b]kinazolin-7-karboksylsyre, smp. 32 3-327°. A suspension of 2.80 g of 5-methoxyanthranilic acid, 2.65 g of 2-chloroisonicotinic acid and 0.135 g of potassium iodide in 13 ml of triglyme was stirred and heated at a bath temperature of 150° for 21 hours under an argon stream. After cooling, 40 ml of methanol was added and the yellow solid was removed by filtration. The crude product was purified by recrystallization of the ethylenediamine salt from pyridine, conversion back to the free acid by treatment with acetic acid and recrystallization from acetic acid to give 0.42 g (9%) of pure 2-methoxy-11-oxo-11H-pyrido[2 ,1-b]quinazoline-7-carboxylic acid, m.p. 32 3-327°.
EKSEMPEL 21 EXAMPLE 21
Fremstilling av 2- metoksy- ll- okso- llH- pyrido[ 2, 1- b] kinazolin- 6-karboksylsyre Preparation of 2-methoxy-ll-oxo-llH-pyrido[2,1-b]quinazoline-6-carboxylic acid
En suspensjon av 1,05 g 5-metoksyantranilsyre, 0,99 g 2-klornikotinsyre og 0,050 g kaliumjodid i 5 ml triglym ble rørt og oppvarmet ved en badtemperatur på 150° i 17 timer under en strøm av argon. Etter kjøling ble 15 ml metanol tilsatt og det gule faste stoff ble fjernet ved filtrering. Det rå materiale ble renset ved omkrystallisasjon fra N,N-dimetylformamid/eddiksyre. A suspension of 1.05 g of 5-methoxyanthranilic acid, 0.99 g of 2-chloronicotinic acid and 0.050 g of potassium iodide in 5 ml of triglyme was stirred and heated at a bath temperature of 150° for 17 hours under a stream of argon. After cooling, 15 ml of methanol was added and the yellow solid was removed by filtration. The crude material was purified by recrystallization from N,N-dimethylformamide/acetic acid.
og gir 0,67 g (40%) rent 2-metoksy-ll-okso-llH-pyrido[2,1-b]-kinazolin-6-karboksylsyre, smp. 272-273,5°. and gives 0.67 g (40%) of pure 2-methoxy-11-oxo-11H-pyrido[2,1-b]-quinazoline-6-carboxylic acid, m.p. 272-273.5°.
EKSEMPEL 2 2 EXAMPLE 2 2
Fremstilling av pivaloyloksymetyl- 2- metoksy- ll- okso- llH-pyrido[ 2, 1- b] kinazolin- 8- karboksylat Preparation of pivaloyloxymethyl-2-methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylate
Til 0,40 g 2-metoksy-ll-okso-llH-pyri.do [2 ,1-b] kinazolin-8-karboksylsyre suspendert i 30 ml dimetylformamid ble tilsatt 0,4 ml trietylamin. Til den klare løsning ble tilsatt 0,4 ml klormetyl-pivalat og blandingen ble rørt og oppvarmet ved en badtemperatur-på 100° i 19 timer. Ytterligere 0,3 ml klormetylpivalåt ble tilsatt og oppvarmning ble fortsatt ved 100° i 4 1/2 time. Løsnings-midlet ble fjernet ved hjelp av oljepumpen, vann ble tilsatt, og det rå produkt ble fjernet ved filtrering.Rensning ble utført ved kromatografi på 15 g silikagel og eluering med 60%<1>s etylacetat-benzen. Omkrystallisasjon fra metanol-vann ga 0,37 g (65 %) rent pivaloyloksymetyl-2-metoksy-ll-okso-llH-pyrido[2,1-b]kinazolin-8-karboksylat,, smp. 129-131°. To 0.40 g of 2-methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid suspended in 30 ml of dimethylformamide was added 0.4 ml of triethylamine. To the clear solution was added 0.4 ml of chloromethyl pivalate and the mixture was stirred and heated at a bath temperature of 100° for 19 hours. An additional 0.3 mL of chloromethylpivalate was added and heating was continued at 100° for 4 1/2 hours. The solvent was removed by means of the oil pump, water was added, and the crude product was removed by filtration. Purification was carried out by chromatography on 15 g of silica gel and elution with 60%<1>s ethyl acetate-benzene. Recrystallization from methanol-water gave 0.37 g (65%) of pure pivaloyloxymethyl-2-methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylate, m.p. 129-131°.
EKSEMPEL 2 3 EXAMPLE 2 3
Fremstilling av 2- metoksy- 8- acetyl- ll- okso- llH- pyrido[ 2, 1- b]-kinazolin Preparation of 2-methoxy-8-acetyl-ll-oxo-llH-pyrido[2,1-b]-quinazoline
En suspensjon av 0,526 g 5-metoksyantranilsyre, 0,490 g 2-klor-5-acetylpyridin og 0,030 g kaliumjodid i 2,5 ml triglym ble rørt og oppvarmet ved en badtemperatur på 150° i 21 timer under en argonstrøm. Etter kjøling ble 8 ml metanol tilsatt og det brune faste stoff ble fjernet ved filtrering. Rensning ble utført ved kromatografi på silikagel og eluering med 40%'s etyl-acetat-benzen. De forenete rene fraksjoner ble omkrystallisert fra metylenklorid-eter og gir 0,13 g (14%) rent 2-metoksy-8-acetyl-11-okso-llH-pyrido[2,1-b]kinazolin, smp. 194^196°. A suspension of 0.526 g of 5-methoxyanthranilic acid, 0.490 g of 2-chloro-5-acetylpyridine and 0.030 g of potassium iodide in 2.5 ml of triglyme was stirred and heated at a bath temperature of 150° for 21 hours under an argon stream. After cooling, 8 ml of methanol was added and the brown solid was removed by filtration. Purification was carried out by chromatography on silica gel and elution with 40% ethyl acetate-benzene. The combined pure fractions were recrystallized from methylene chloride-ether to give 0.13 g (14%) of pure 2-methoxy-8-acetyl-11-oxo-11H-pyrido[2,1-b]quinazoline, m.p. 194^196°.
EKSEMPEL 24 EXAMPLE 24
Fremstilling av 2- metoksy- ll- okso- llH- pyrido[ 2, 1- b] kinazolin- 8-eddiksyre Preparation of 2-methoxy-ll-oxo-llH-pyrido[2,1-b]quinazoline-8-acetic acid
En blanding av 0,836 g 5-metoksyantranilsyre, 0,858 g 2-klor-pyridin-5-eddiksyre og 15 mg kaliumjodid ble rørt og oppvarmet ved en badtemperatur på 150° under argon i 1 1/4 time. Etter kjøling ble den faste masse revet med isopropylalkohol, og det gule faste stoff ble filtrert. Det rå produkt ble renset ved omkrystallisas jon av etylendiaminsaltet fra pyridin og omdannelse tilbake til den frie syre ved behandling med eddiksyre og ga 0,054 g (3,8 %) rent 2-metoksy-ll-okso-llH-pyrido[2,1-b]kinazolin-8-eddiksyre, smp. 281-282°. A mixture of 0.836 g of 5-methoxyanthranilic acid, 0.858 g of 2-chloro-pyridine-5-acetic acid and 15 mg of potassium iodide was stirred and heated at a bath temperature of 150° under argon for 1 1/4 hours. After cooling, the solid was triturated with isopropyl alcohol and the yellow solid was filtered. The crude product was purified by recrystallization of the ethylenediamine salt from pyridine and conversion back to the free acid by treatment with acetic acid to give 0.054 g (3.8%) of pure 2-methoxy-11-oxo-11H-pyrido[2,1- b]quinazoline-8-acetic acid, m.p. 281-282°.
EKSEMPEL 25 EXAMPLE 25
Fremstilling av 2- n- butyl- ll- okso- llH- pyrido[ 2, 1- b] kinazolin-8~ karboksylsyre Preparation of 2-n-butyl-ll-oxo-llH-pyrido[2,1-b]quinazoline-8~ carboxylic acid
En suspensjon av 11,6 g 5-n-butylantranilsyre, 9,4 g 6-klornikotinsyre og 0,1 g kaliumjodid i 20 ml triglym ble oppvarmet til en badtemperatur på 150° over natten under en argonstrøm. Etter kjøling ble blandingen revet.med etanol og vann og filtrert og ga 7,6 g av et mørkegult fast stoff, smp. 265-292°. Dannelse av etylendiaminsaltet i varmt pyridin gir et salt oppløselig i rent vann. Dette salt oppløses i vann og den rene syre bunn-felles med fortynnet eddiksyre og omkrystallisasjon fra dimetyl-formamid—eddiksyre-vann og gir 1,8 g (10,1%) rent 2-n-butyl-ll-okso-llH-pyrido[2,1-b]kinazolin-8-karboksylsyre, smp. 250-25 3°. A suspension of 11.6 g of 5-n-butylanthranilic acid, 9.4 g of 6-chloronicotinic acid and 0.1 g of potassium iodide in 20 ml of triglyme was heated to a bath temperature of 150° overnight under an argon stream. After cooling, the mixture was triturated with ethanol and water and filtered to give 7.6 g of a dark yellow solid, m.p. 265-292°. Formation of the ethylenediamine salt in hot pyridine gives a salt soluble in pure water. This salt is dissolved in water and the pure acid bottom is combined with dilute acetic acid and recrystallized from dimethylformamide-acetic acid-water to give 1.8 g (10.1%) of pure 2-n-butyl-11-oxo-11H- pyrido[2,1-b]quinazoline-8-carboxylic acid, m.p. 250-25 3°.
EKSEMPEL 2 6 EXAMPLE 2 6
Fremstilling av 2- etyl- ll- okso- llH- pyrido[ 2, 1- b] kinazolin- 8-karboksylsyre Denne forbindelse ble syntetisert ifølge fremgangsmpten beskrevet i eksempel 25, utbytte 26,4 %, smp. 313-315°. Preparation of 2-ethyl-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid This compound was synthesized according to the procedure described in example 25, yield 26.4%, m.p. 313-315°.
EKSEMPEL 2 7 EXAMPLE 2 7
Fremstilling av 2- isopropoksy- ll- okso- llH- pyrido[ 2, 1- b] kinazolin- 8- karboksylsyre-( 2- dietylaminoetyl) ester- hydroklQrid Preparation of 2-isopropoxy-ll-oxo-llH-pyrido[2,1-b]quinazoline-8-carboxylic acid-(2-diethylaminoethyl) ester hydrochloride
En 9,2 g's porsjon dietylaminoetylklorid-hydroklorid ble opp- A 9.2 g portion of diethylaminoethyl chloride hydrochloride was prepared
delt mellom 50 ml 4N natriumhydroksyd og 100 ml eter. De forenete etersjikt ble vasket med vann og mettet saltoppløsning, partitioned between 50 ml of 4N sodium hydroxide and 100 ml of ether. The combined ether layers were washed with water and brine,
ble tørket over kaliumkarbonat og ble inndampet til en svakt farvet olje. Til denne olje ble tilsatt 100 ml tørt isopropanol og 4,0 g rent 2-isopropoksy-ll-okso-llH-pyrido[ 2,1-b]kinazolin-8-karboksylsyre. Blandingen ble oppvarmet til tilbakeløp was dried over potassium carbonate and was evaporated to a faintly colored oil. To this oil were added 100 ml of dry isopropanol and 4.0 g of pure 2-isopropoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid. The mixture was heated to reflux
i 3 timer og avkjølt. De faste stoffer ble samlét opp og omkrystallisert fra metanol og gir 3,22 g (57,5%) 2-isopropoksy-ll-okso-llH-pyrido[2,1-b]kinazolin-8-karboksylsyre-(2-dietylamino-etyl) esterhydroklorid, smp. 208-209°. for 3 hours and cooled. The solids were collected and recrystallized from methanol to give 3.22 g (57.5%) of 2-isopropoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid-(2-diethylamino -ethyl) ester hydrochloride, m.p. 208-209°.
EKSEMPEL 28 EXAMPLE 28
Fremstilling a? 8- cyano- 2- isopropoksy- ll- okso- llH- pyrido[ 2, 1- b]-kinazolin Manufacturing a? 8- cyano- 2- isopropoxy- ll- oxo- llH- pyrido[ 2, 1-b]-quinazoline
En blanding av 16,7 g. 5-isopropoksyantranilsyre, 10,0 g 2-klor-5-cyanopyridin og 0,01 g kaliumjodid.i 30 ml triglym ble oppvarmet til en badtemperatur på 150° over natten udner en argonstrøm. Etter kjøling ble blandingen revet med etanol og vann. Et gummi-aktig faststoff ble samlet opp, oppløst i varmt etylacetat, filtrert og filtratet ble inndampet og ga 8,4 g rått produkt (38% utbytte). To omkrystallisasjoner av dette faste stoff fra dime-tylf ormamid-eddiksyre-vann gir rent 8-cyano-2-isopropoksy-ll-okso-llH-pyridot2,1-b]kinazolin, smp. 234-236°. A mixture of 16.7 g of 5-isopropoxyanthranilic acid, 10.0 g of 2-chloro-5-cyanopyridine and 0.01 g of potassium iodide in 30 ml of triglyme was heated to a bath temperature of 150° overnight under an argon stream. After cooling, the mixture was triturated with ethanol and water. A gummy solid was collected, dissolved in hot ethyl acetate, filtered and the filtrate was evaporated to give 8.4 g of crude product (38% yield). Two recrystallizations of this solid from dimethylformamide-acetic acid-water give pure 8-cyano-2-isopropoxy-11-oxo-11H-pyridot2,1-b]quinazoline, m.p. 234-236°.
EKSEMPEL 29 EXAMPLE 29
Fremstilling av 8- hydroksymetyl- 2- isopropoksy- llH- pyrido[ 2, 1- b]-kinazolin- ll- on- benzoat Preparation of 8-hydroxymethyl-2-isopropoxy-llH-pyrido[2,1-b]-quinazolin-ll-one-benzoate
En suspensjon av 1,0 g 5-isopropoksyantranilsyre, 1,1 g 6-klor-3-pyridinmetanolbenzoat og 0,01 g kaliumjodid i 10 ml triglym. ble oppvarmet til 150° over natten under en argonstrøm. Etter kjø-ling ble reaksjonsblandingen oppløst i varm metanol, filtrert og inndampet til en oransjefarget olje. Kromatografisk separa-sjon og omkrystallisasjon fra heksan-diklormetan ga 8-hydroksymetyl-2-isopropoksy-llH-pyrido[2,1-b]kinazolin-ll-on-benzoat, A suspension of 1.0 g of 5-isopropoxyanthranilic acid, 1.1 g of 6-chloro-3-pyridine methanol benzoate and 0.01 g of potassium iodide in 10 ml of triglyme. was heated to 150° overnight under an argon stream. After cooling, the reaction mixture was dissolved in hot methanol, filtered and evaporated to an orange colored oil. Chromatographic separation and recrystallization from hexane-dichloromethane gave 8-hydroxymethyl-2-isopropoxy-11H-pyrido[2,1-b]quinazolin-11-one benzoate,
smp. 123-126°. m.p. 123-126°.
EKSEMPEL 30 EXAMPLE 30
Fremstilling av 2- brom- 4- isopropyl- acetanilid Preparation of 2-bromo-4-isopropyl-acetanilide
En oppløsning av 50 g 4-isopropylanilin i 160 ml iseddiksyre A solution of 50 g of 4-isopropylaniline in 160 ml of glacial acetic acid
blé rørt og tilbakeløpsbehandlet i 2 timer. Løsningen ble derpå kjølt til 45° og dråpevis tilsetning av 60' g brom ble begynt. Tilsetningen ble fortsatt i en slik mengde at temperaturen for was stirred and refluxed for 2 hours. The solution was then cooled to 45° and the dropwise addition of 60 g of bromine was begun. The addition was continued in such an amount that the temperature for
reaksjonsløsningen ble holdt under 55°. Etter fullførelse av tilsetningen fikk reaksjonen bli omrørt i 1 time. Den mørke væske ble deretter helt på 2 liter knust is under røring. Den resulterende suspensjon fikk bli rørt i 10 minutter mens 5,0 g natriumbisulfitt ble tilsatt. Denne suspensjon ble rørt inntil brom-fargen var fjernet. Det faste stoff ble deretter filtrert, vasket med vann og luft-tørket over natten. the reaction solution was kept below 55°. After completion of the addition, the reaction was allowed to stir for 1 hour. The dark liquid was then poured onto 2 liters of crushed ice with stirring. The resulting suspension was allowed to stir for 10 minutes while 5.0 g of sodium bisulfite was added. This suspension was stirred until the bromine color was removed. The solid was then filtered, washed with water and air-dried overnight.
Det fuktige faste stoff (115 g) ble omkrystallisert fra 1,0 liter 50% 's vandig etanol og ga 64,4 g (68,2%) 4-isopropyl-2-b-rom-acetanilid, smp. 12 2-126°. The moist solid (115 g) was recrystallized from 1.0 L of 50% aqueous ethanol to give 64.4 g (68.2%) of 4-isopropyl-2-b-rom-acetanilide, m.p. 12 2-126°.
EKSEMPEL 31 EXAMPLE 31
Fremstilling av 2- cyano- 4- isopropylacetanilid Preparation of 2-cyano-4-isopropylacetanilide
En løsning av 1,0075 g 2-brom-4-isopropylacetanilid og 0,7308 A solution of 1.0075 g of 2-bromo-4-isopropylacetanilide and 0.7308
g kuprocyanid i 10 ml N-metylpyrrolidinon ble oppvarmet og rørt ved 180° i 7 timer. Reaksjonsblandingen ble helt i 1 ml etylendiamin i 50 ml vann og rørt kraftig i 5 minutter. Etter eks-traksjon med kloroform ble ekstraktet vasket med 10%<1>s natrium-cyanidoppløsning, vasket med vann, tørket over magnesiumsulfat og konsentrert i vakuum til en olje. Gjenværende N-metylpyrrolidinon ble fjernet ved destillasjon (kp. 33-37°/0,l mm) og den viskøse rest krystalliserte ved kjøling. Omkrystallisasjon fra eter-heksan ga 2-cyano-4-isopropylacetanilid (0,5920 g, smp. 98--100°). g cuprocyanide in 10 ml N-methylpyrrolidinone was heated and stirred at 180° for 7 hours. The reaction mixture was poured into 1 ml of ethylenediamine in 50 ml of water and stirred vigorously for 5 minutes. After extraction with chloroform, the extract was washed with 10% sodium cyanide solution, washed with water, dried over magnesium sulfate and concentrated in vacuo to an oil. Remaining N-methylpyrrolidinone was removed by distillation (b.p. 33-37°/0.1 mm) and the viscous residue crystallized on cooling. Recrystallization from ether-hexane gave 2-cyano-4-isopropylacetanilide (0.5920 g, mp 98--100°).
EKSEMPEL 32 EXAMPLE 32
Fremstilling av 5- isopropylantranilsyre Preparation of 5-isopropylanthranilic acid
En løsning av 0,4870 g 2-cyano-4-isopropylacetanilid i 5 ml eddiksyre og 10 ml 50%'s svovelsyre ble tilbakeløpsbehandlet i 2 1/2 time. Løsningen ble konsentrert ved hjelp av oljepum- A solution of 0.4870 g of 2-cyano-4-isopropylacetanilide in 5 ml of acetic acid and 10 ml of 50% sulfuric acid was refluxed for 2 1/2 hours. The solution was concentrated using an oil pump
pen til et lite volum. Vann (5 ml) ble tilsatt, og pH ble justert til 4 ved tilsetning av 6N natriumhydroksyd. Etter kjø- pretty for a small volume. Water (5 mL) was added and the pH was adjusted to 4 by addition of 6N sodium hydroxide. After queuing
ling ble bunnfallet filtrert og tørket og ga 0,3426 g materiale. Omkrystallisasjon fra ligroin ga 5-isopropylantranilsyre ling, the precipitate was filtered and dried to give 0.3426 g of material. Recrystallization from ligroin gave 5-isopropylanthranilic acid
(0,3010 g, smp. 75-80°. (0.3010 g, m.p. 75-80°.
I IN
r r
EKSEMPEL 33 EXAMPLE 33
Fremstilling av 2- brom- 4- cyklopropylacetanilid Preparation of 2-bromo-4-cyclopropylacetanilide
Til 15,20 g 4-cyklopropylacetanilid (R.C.Hahn et al., J, Amer. Chem.Soc, 9Q, 3404 (1968) og 10,45 g acetamid oppløst i 1 li- To 15.20 g of 4-cyclopropylacetanilide (R.C.Hahn et al., J, Amer. Chem.Soc, 9Q, 3404 (1968) and 10.45 g of acetamide dissolved in 1 li-
ter kloroform og kjølt ved -25° ble tilsatt en løsning av 13,8 ter chloroform and cooled at -25° was added a solution of 13.8
g brom i 300 ml kloroform dråpevis under røring i løpet av 2 timer. Reaksjonsblandingen ble rørt ved -25° i 70 timer og fikk deretter bli oppvarmet til 5°. Etter filtrering for å fjerne fellingen ble filtratet konsentrert i vakuum. Det rå produkt ble oppløst i etylacetat, tørket over vannfritt natriumsulfat og konsentrert i vakuum til et oransjefarget fast stoff. Dette ble kromatografert på 1,2 kg silikagel og eluert med 40%<1>s etylacetat-toluen. De forenete rene fraksjoner ble konsentrert i vakuum og ga 11,22 g, smp. 108,5-110°, rent 2-brom-4-cyklopropyl-acetanilid. g of bromine in 300 ml of chloroform dropwise with stirring over the course of 2 hours. The reaction mixture was stirred at -25° for 70 hours and then allowed to warm to 5°. After filtration to remove the precipitate, the filtrate was concentrated in vacuo. The crude product was dissolved in ethyl acetate, dried over anhydrous sodium sulfate and concentrated in vacuo to an orange solid. This was chromatographed on 1.2 kg of silica gel and eluted with 40% ethyl acetate-toluene. The combined pure fractions were concentrated in vacuo to give 11.22 g, m.p. 108.5-110°, pure 2-bromo-4-cyclopropyl-acetanilide.
EKSEMPEL 34 EXAMPLE 34
Fremstilling av 2- cyano- 4- cyklopropylacetanilid Preparation of 2-cyano-4-cyclopropylacetanilide
En løsning av 11,22 g 2-brom-4-cyklopropylacetanilid i 500 ml vannfritt dimetylformamid og 3,9 6 g kuprocyanid ble rørt og til-bakeløpsbehandlet i 3 timer. Etter kjøling til 25° ble dimetyl-formamidet fjernet i vakuum,Resten ble rørt med 15 ml etylendiamin i 500 ml vann i 30 minutter og deretter ekstrahert med etylacetat.. Ekstraktet ble tørket over natriumsulf at og konsentrert i vakuum til et fast stoff. Krystallisasjon fra etylacetat-heksan ga 6,45 g, smp. 140-141°, rent 2-cyano-4-cyklopropylacetanilid. A solution of 11.22 g of 2-bromo-4-cyclopropylacetanilide in 500 ml of anhydrous dimethylformamide and 3.96 g of cuprocyanide was stirred and refluxed for 3 hours. After cooling to 25°, the dimethylformamide was removed in vacuo. The residue was stirred with 15 ml of ethylenediamine in 500 ml of water for 30 minutes and then extracted with ethyl acetate. The extract was dried over sodium sulfate and concentrated in vacuo to a solid. Crystallization from ethyl acetate-hexane gave 6.45 g, m.p. 140-141°, pure 2-cyano-4-cyclopropylacetanilide.
EKSEMPEL 35 EXAMPLE 35
Fremstilling av 5- cyklopropylantranilsyre Preparation of 5-cyclopropylanthranilic acid
Til en løsning av 6,30 g 2-cyano-4-cyklopropylacetanilid i en blanding av 60 ml etylenglykol og 60 ml vann ble tilsatt 8,86 g kaliumhydroksyd. Reaksjonsblandingen ble rørt og tilbakeløps-behandlet i 19 timer. Etter kjøling ble 1 liter vann tilsatt. Det faste stoff som bunnfelte ble fjernet ved filtrering, og filtratet ble ekstrahert flere ganger med etylacetat. Det ba-siske vandige lag ble surgjort til pH 3 med eddiksyre og eks- To a solution of 6.30 g of 2-cyano-4-cyclopropylacetanilide in a mixture of 60 ml of ethylene glycol and 60 ml of water was added 8.86 g of potassium hydroxide. The reaction mixture was stirred and refluxed for 19 hours. After cooling, 1 liter of water was added. The solid which settled was removed by filtration, and the filtrate was extracted several times with ethyl acetate. The basic aqueous layer was acidified to pH 3 with acetic acid and ex-
trahert med etylacetat. Det tørkede (over natriumsulfat) eks- extracted with ethyl acetate. The dried (over sodium sulfate) ex-
trakt ble konsentrert i vakuum til et fast stoff. Krystallisa- funnel was concentrated in vacuo to a solid. Krystallisa-
sjon fra eter-heksan ga 2,31 g, smp. 157,5-158,5°, rent 5-cyklopropylantranilsyre. tion from ether-hexane gave 2.31 g, m.p. 157.5-158.5°, pure 5-cyclopropylanthranilic acid.
EKSEMPEL 36 EXAMPLE 36
Fremstilling av 2- isopropyl- ll- okso- llH- pyrido[ 2, 1- b] kinazolin-8- karboksylsyre Preparation of 2-isopropyl-ll-oxo-llH-pyrido[2,1-b]quinazoline-8-carboxylic acid
En suspensjon på 6,0 g 5-isopropylantranilsyre, 5,4 g 6-klornikotinsyre og 0,05 g kaliumjodid i 10 ml triglym ble oppvarmet over natten (badtemperatur 150°) under en argonstrøm. Etter kjø-ling ble blandingen revet med etanol og vann og filtrert og ga 5,89 g rått produkt, smp. 280-287°. Dette materiale ble oppløst i varmt pyridin og behandlet med etyléndiamin og ga det tilsvarende salt som ble samlet opp ved filtrering. Dette salt ble oppløst i vann og den rene syre ble bunnfelt med fortynnet eddiksyre. Omkrystallisas jon fra dimetylformamid-eddiksyre-.vann ga 2,5 g (26,6%)' 2-isopropyl-ll-okso-llH-pyrido[2,1-b]kinazolin-8-karboksylsyre, smp. 314-316°. A suspension of 6.0 g of 5-isopropylanthranilic acid, 5.4 g of 6-chloronicotinic acid and 0.05 g of potassium iodide in 10 ml of triglyme was heated overnight (bath temperature 150°) under an argon stream. After cooling, the mixture was triturated with ethanol and water and filtered to give 5.89 g of crude product, m.p. 280-287°. This material was dissolved in hot pyridine and treated with ethylenediamine to give the corresponding salt which was collected by filtration. This salt was dissolved in water and the pure acid was precipitated with dilute acetic acid. Recrystallization from dimethylformamide-acetic acid-water gave 2.5 g (26.6%) of 2-isopropyl-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid, m.p. 314-316°.
EKSEMPEL 3 7 EXAMPLE 3 7
Fremstilling av 2- isopropyl- ll- okso- llH- pyrido[ 2, 1- b] kinazolin-8- karboksylsyre-( 2- dietylaminoetyl) esterhydroklorid Preparation of 2-isopropyl-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid-(2-diethylaminoethyl) ester hydrochloride
5,8 g dietylaminoetylkloridhydroklorid ble delt mellom 100 ml 2N natriumhydroksyd og 100 ml eter. Det eteriske lag ble skilt fra, vasket med vann og mettet saltoppløsning, tørket over kaliumkarbonat og inndampet til en svakt farget olje. Til denne olje ble tilsatt 200 ml isopropanol og 2,4 g ren 2-isopropyl-11-okso-llH-pyrido[2,1-b]kinazolin-8-karboksylsyre. Blandingen ble tilbakeløpsbehandlet i 3 timer og kjølt- De faste stoffer ble samlet opp og omkrystallisert fra metanol og ga 1,87 g 5.8 g of diethylaminoethyl chloride hydrochloride was partitioned between 100 ml of 2N sodium hydroxide and 100 ml of ether. The ethereal layer was separated, washed with water and saturated brine, dried over potassium carbonate and evaporated to a faintly colored oil. To this oil were added 200 ml of isopropanol and 2.4 g of pure 2-isopropyl-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid. The mixture was refluxed for 3 hours and cooled. The solids were collected and recrystallized from methanol to give 1.87 g
(53,4%) 2-isopropyl-ll-okso-llH-pyrido[2,1-b]kinazolin-S-karboksylsyre- ( 2-dietylaminoetyl) esterhydroklorid, smp. 220-222°. (53.4%) 2-isopropyl-11-oxo-11H-pyrido[2,1-b]quinazoline-S-carboxylic acid-(2-diethylaminoethyl) ester hydrochloride, m.p. 220-222°.
EKSEMPEL 38 EXAMPLE 38
Fremstilling av 5- hydroksy- 2- nitrobenzosyre Preparation of 5-hydroxy-2-nitrobenzoic acid
En blanding av 5,0 liter vann, 800 g natriumhydroksyd og 504 g 5-klor-2-nitrobenzosyre ble tilbakeløpsbehandlet i 24 timer. Oppløsningen ble kjølt og surgjort med 1,75 liter konsentrert saltsyre. Den sure vandige blanding ble ekstrahert tre ganger A mixture of 5.0 liters of water, 800 g of sodium hydroxide and 504 g of 5-chloro-2-nitrobenzoic acid was refluxed for 24 hours. The solution was cooled and acidified with 1.75 liters of concentrated hydrochloric acid. The acidic aqueous mixture was extracted three times
med 1,5 liter eter. De forenete eterekstrakter ble tørket over vannfritt magnesiumsulfat, filtrert gjennom'Celite^og inndampet with 1.5 liters of ether. The combined ether extracts were dried over anhydrous magnesium sulfate, filtered through Celite, and evaporated
til et svakt gult fast stoff (473 g). Dette materiale ble omkrystallisert fra eter-petroleter og ga 298 g 5-hydroksy-2-nitrobenzosyre, smp. 167-169° (65,2%). to a pale yellow solid (473 g). This material was recrystallized from ether-petroleum ether to give 298 g of 5-hydroxy-2-nitrobenzoic acid, m.p. 167-169° (65.2%).
EKSEMPEL 39 EXAMPLE 39
Fremstilling av 5- isopropoksy- 2- nitrobenzosyre- isopropylester Preparation of 5-isopropoxy-2-nitrobenzoic acid isopropyl ester
En blanding av 55,3 g 5-hydroksy-2-nitrobenzosyre, 450 ml di-metylf ormamid og 93,9 g vannfritt kaliumkarbonat ble rørt ved romtemperatur i 10 minutter. 100 ml isopropylbromid ble derpå tilsatt og blandingen ble rørt og oppvarmet til 100° i fem timer. Reaksjonsblandingen ble derpå kjølt og fortynnet med is-vann. pH for blandingen ble justert til -~8 med 4N natriumhy-droksydoppløsning. Blandingen ble deretter ekstrahert tre gan- A mixture of 55.3 g of 5-hydroxy-2-nitrobenzoic acid, 450 ml of dimethylformamide and 93.9 g of anhydrous potassium carbonate was stirred at room temperature for 10 minutes. 100 ml of isopropyl bromide was then added and the mixture was stirred and heated to 100° for five hours. The reaction mixture was then cooled and diluted with ice water. The pH of the mixture was adjusted to -~8 with 4N sodium hydroxide solution. The mixture was then extracted three times
ger med 500 ml eter. De forenete eterekstrakter ble vasket med 500 ml mettet saltoppløsning, tørket over vannfritt kaliumkarbonat, filtrert gjennom "Celite"og inndampet til en gul olje som krystalliserte etter kjøling og ga 74,0 g 5-isopropoksy-2-nitrobenzosyre-isopropylester, smp. 45-50° (91,7%). Dette materiale kan destilleres under høyvakuum og ga rent produkt, smp. 51-52°. ger with 500 ml of ether. The combined ether extracts were washed with 500 ml of saturated brine, dried over anhydrous potassium carbonate, filtered through "Celite" and evaporated to a yellow oil which crystallized on cooling to give 74.0 g of 5-isopropoxy-2-nitrobenzoic acid isopropyl ester, m.p. 45-50° (91.7%). This material can be distilled under high vacuum and gave pure product, m.p. 51-52°.
EKSEMPEL 40 EXAMPLE 40
Fremstilling av 5- isopropoksy- antranilsyre Production of 5-isopropoxy-anthranilic acid
74,0 g 5-isopropoksy-2-nitrobenzosyre-isopropylester ble oppløst i 650 ml etanol og 145 ml 4N natriumhydroksydoppløsning. Denne løsning ble rørt ved romtemperatur i 16 timer. Reaksjonsblandingen ble fortynnet med 2,0 liter vann og vasket tre ganger med , 1 liter diklormetan. Det vandige lag ble deretter surgjort til 74.0 g of 5-isopropoxy-2-nitrobenzoic acid isopropyl ester was dissolved in 650 ml of ethanol and 145 ml of 4N sodium hydroxide solution. This solution was stirred at room temperature for 16 hours. The reaction mixture was diluted with 2.0 liters of water and washed three times with 1.1 liters of dichloromethane. The aqueous layer was then acidified
pH <. 2 med konsentrert saltsyre og ekstrahert tre ganger med 1,0 liter eter. De forenete eterekstrakter ble vasket med 1,0 liter mettet saltoppløsning, tørket over vannfritt natriumsulfat, filtrert gjennom"celite og inndampet til en oransjefarget olje (65,9 g) som størknet etter kjøling, smp. 129-131°. Det pH <. 2 with concentrated hydrochloric acid and extracted three times with 1.0 liters of ether. The combined ether extracts were washed with 1.0 L of saturated brine, dried over anhydrous sodium sulfate, filtered through celite and evaporated to an orange oil (65.9 g) which solidified on cooling, mp 129-131°.
■ovenfor nevnte faste stoff ble oppløst i 1,0 liter etylacetat og hydrogenert under anvendelse av 3,1 g 10%'s palladium på karbon som katalysator. Når hydrogenopptaket hadde opphørt ble katalysatoren fjernet ved filtrering; og filtratet ble inndampet til et gult fast stoff, 49,5 g (smp. 120-122°). The above-mentioned solid was dissolved in 1.0 liters of ethyl acetate and hydrogenated using 3.1 g of 10% palladium on carbon as a catalyst. When the hydrogen uptake had ceased, the catalyst was removed by filtration; and the filtrate was evaporated to a yellow solid, 49.5 g (m.p. 120-122°).
EKSEMPEL 41 Fremstilling av 2- isopropoksy- ll- okso- llH- pyrido[ 2, 1- b] kinazolin- 8- karboksylsyre EXAMPLE 41 Preparation of 2-isopropoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid
En blanding av 23,2 g 5-isopropoksyantranilsyre, 15,7 g 6-klornikotinsyre, 0,1 g kaliumjodid og 50 ml triglym ble oppvarmet til 150° under en konstant strøm av argon i 16 timer. Reaksjonsblandingen ble kjølt, fortynnet med ca. 50 ml etanol og filtrert og ga 18,9 g rått produkt, smp. 256-267°. Dette materiale ble oppløst i ca. 50 ml varm pyridin. Til den kokende løsning ble tilsatt 4,8 ml etylendiamin. Denne blanding fikk avkjøle seg, og krystallene som hadde felt ut, ble filtrert, vasket med pyridin, presset tørre og oppløst i 50 ml vann. Denne vandige opp-løsning ble rørt og omhyggelig surgjort med fortynnet eddiksyre. Krystallene som felt ut ble samlet opp, vasket med vann, etanol og eter og tørket og ga 9,8 g 2-isopropoksy-ll-okso-llH-pyrido-[2,1-b]kinazolin-8-karboksylsyre, smp. 278-280°. A mixture of 23.2 g of 5-isopropoxyanthranilic acid, 15.7 g of 6-chloronicotinic acid, 0.1 g of potassium iodide and 50 ml of triglyme was heated to 150° under a constant flow of argon for 16 hours. The reaction mixture was cooled, diluted with approx. 50 ml of ethanol and filtered to give 18.9 g of crude product, m.p. 256-267°. This material was dissolved in approx. 50 ml of hot pyridine. To the boiling solution was added 4.8 ml of ethylenediamine. This mixture was allowed to cool, and the crystals that had precipitated were filtered, washed with pyridine, pressed dry and dissolved in 50 ml of water. This aqueous solution was stirred and carefully acidified with dilute acetic acid. The crystals that precipitated were collected, washed with water, ethanol and ether and dried to give 9.8 g of 2-isopropoxy-11-oxo-11H-pyrido-[2,1-b]quinazoline-8-carboxylic acid, m.p. 278-280°.
EKSEMPEL 4 2 EXAMPLE 4 2
Fremstilling av 2- metyltio- ll- okso- llH- pyrido[ 2, 1- b] kinazolin-8- karboksylsyre Preparation of 2-methylthio-ll-oxo-llH-pyrido[2,1-b]quinazoline-8-carboxylic acid
En rørt intim blanding av 50 g metyl-5-mety1-merkapto-antranilat-hydroklorid, 34,7 g 6-klornikotinsyre og 0,1 g kaliumjodid ble neddykket i et oljebad forvarmet til 150°. 40 ml triglym ble omhyggelig tilsatt til blandingen. Reaksjonsblandingen ble oppvarmet til 175° i 16 timer under en langsom argonstrøm. Reaksjonen ble kjølt og den faste rest ble oppløst i varmt dimetylformamid og iseddiksyre, filtrert og kjølt. Det utfelte produkt ble samlet opp, vasket med etanol og tørket og ga 31,3 g (51%) 2-metyltio-ll-okso-llH-pyrido[2,1-b]kinazolin-8-karboksylsyre, smp. 303-320°.. A stirred intimate mixture of 50 g of methyl 5-methyl-mercapto-anthranilate hydrochloride, 34.7 g of 6-chloronicotinic acid and 0.1 g of potassium iodide was immersed in an oil bath preheated to 150°. 40 ml of triglyme was carefully added to the mixture. The reaction mixture was heated to 175° for 16 hours under a slow stream of argon. The reaction was cooled and the solid residue was dissolved in hot dimethylformamide and glacial acetic acid, filtered and cooled. The precipitated product was collected, washed with ethanol and dried to give 31.3 g (51%) of 2-methylthio-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid, m.p. 303-320°..
Det rå materiale (10 g) ble oppløst i 150 ml varmt pyridin. Til denne varme løsning ble tilsatt ca. 1,25 ml etylendiamin. Den resulterende blanding ble rørt under avkjøling. De resulterende krystaller ble samlet opp, presset tørre og oppløst i vann. Denne løsning ble omhyggelig surgjort med fortynnet eddiksyre og det utfelte produkt ble filtrert og tørket og ga 1,7 g renset produkt, smp. 337°. The crude material (10 g) was dissolved in 150 ml of hot pyridine. To this warm solution was added approx. 1.25 ml of ethylenediamine. The resulting mixture was stirred while cooling. The resulting crystals were collected, pressed dry and dissolved in water. This solution was carefully acidified with dilute acetic acid and the precipitated product was filtered and dried to give 1.7 g of purified product, m.p. 337°.
EKSEMPEL 4 3 Fremstilling av 2- metyltio- ll- okso- llH- pyrido[ 2, 1- b] kinazolin- 8-karboksylsyre-( 2- dietylaminoetyl) esterhydroklorid EXAMPLE 4 3 Preparation of 2-methylthio-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid-(2-diethylaminoethyl) ester hydrochloride
2,5 g N,N-dietylaminoetylkloridhydroklorid ble delt mellom 50 ml' eter og 50 ml 2N natriumhydroksydløsning. Det vandige lag ble ekstrahert to ganger med 50 ml eter og de forenete eterlag ble vasket med 50 ml vann og 50 ml mettet saltoppløsning. Den orga— niske fase ble derpå tørket over vannfritt kaliumkarbonat, filtrert gjennom Celite og inndampet til en svakt farget olje (1,61 g). Denne olje ble oppløst i 35 ml isopropanol og til denne rørte løsning ble tilsatt 1,15 g renset 2-metyltio-ll-okso-ll.H-pyrido-[2,1-b]kinazolin-8-karboksylsyre. Den resulterende reaksjonsblanding ble tilbakeløpsbehandlet i 4 timer og kjølt. Det krystallin-ske produkt ble samlet opp ved filtrering og omkrystallisert fra metanol og ga 1,16 g (92%) av det ønskede 2-metyltio-ll-okso-llH-pyrido[2,1-b]kinazolin-8-karboksylsyre-(2-dietylaminoetyl)ester som dets hydrokloridsalt, smp. 236-238°.. 2.5 g of N,N-diethylaminoethyl chloride hydrochloride was partitioned between 50 ml of ether and 50 ml of 2N sodium hydroxide solution. The aqueous layer was extracted twice with 50 ml of ether and the combined ether layers were washed with 50 ml of water and 50 ml of saturated saline. The organic phase was then dried over anhydrous potassium carbonate, filtered through Celite and evaporated to a slightly colored oil (1.61 g). This oil was dissolved in 35 ml of isopropanol and to this stirred solution was added 1.15 g of purified 2-methylthio-11-oxo-11.H-pyrido-[2,1-b]quinazoline-8-carboxylic acid. The resulting reaction mixture was refluxed for 4 hours and cooled. The crystalline product was collected by filtration and recrystallized from methanol to give 1.16 g (92%) of the desired 2-methylthio-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid -(2-Diethylaminoethyl)ester as its hydrochloride salt, m.p. 236-238°..
EKSEMPEL 4 4 EXAMPLE 4 4
Fremstilling av 2- cyklopropyl- ll- okso- llH- pyrido[ 2, 1- b] kinazolin- 8- karboksylsyre Preparation of 2-cyclopropyl-ll-oxo-llH-pyrido[2,1-b]quinazoline-8-carboxylic acid
En løsning av 2,12 g 5-cyklopropylantranilsyre og 1,89 g 6-klornikotinsyre i 20 ml toluen ble kokt for å fjerne toluenet. Den resulterende faste blanding ble oppvarmet ved 150 i 25 minut- A solution of 2.12 g of 5-cyclopropylanthranilic acid and 1.89 g of 6-chloronicotinic acid in 20 ml of toluene was boiled to remove the toluene. The resulting solid mixture was heated at 150 for 25 min-
ter. Etter kjøling ble den faste rest revet ned eter og fil- ter. After cooling, the solid residue was triturated with ether and
trert. Det resulterende faste stoff ble krystallisert fra eddiksyre og deretter fra etanol og ga 0,275 g,smp. 316-313°, rent 2-cyklopropyl-ll-okso-llH-pyrido[2,1-b]kinazolin-8-karboksylsyre. tired. The resulting solid was crystallized from acetic acid and then from ethanol to give 0.275 g, m.p. 316-313°, pure 2-cyclopropyl-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid.
Syren omsettes med 2-dietylaminoetylklorid i isopropanol, slik The acid is reacted with 2-diethylaminoethyl chloride in isopropanol, as follows
som beskrevet i eksempel 37, og ga 2-cyklopropyl-ll-okso-llH-pyrido[2,1-b]kinazolin-8-karboksylsyre-(2-dietylaminoetyl)-esterhydroklorid. as described in Example 37, giving 2-cyclopropyl-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid-(2-diethylaminoethyl)-ester hydrochloride.
EKSEMPEL 4 5 EXAMPLE 4 5
Fremstilling av 8- acetyl- 2- brom- ll- okso- llH- pyrido[ 2, 1- b]-kinazolin Preparation of 8-acetyl-2-bromo-ll-oxo-llH-pyrido[2,1-b]-quinazoline
En suspensjon av 15,50 g 5-bromantranilsyre, 11,9 g 2-klor-5-acetylpyridin og 0,50 g kaliumjodid i 20 ml triglym ble oppvarmet ved en badtemperatur på 150° under en argonatmosfære i 7.timer . 40 ml metanol ble tilsatt, og blandingen ble rørt i et isbad i 30 minutter og filtrert.. Produktet ble suspendert i 500 ml mettet natriumbikarbonatoppløsning og ekstrahert med kloroform. Ekstraktet ble konsentrert til et gult fast stoff (9,70 g) som A suspension of 15.50 g of 5-bromoanthranilic acid, 11.9 g of 2-chloro-5-acetylpyridine and 0.50 g of potassium iodide in 20 ml of triglyme was heated at a bath temperature of 150° under an argon atmosphere for 7 hours. 40 ml of methanol was added and the mixture was stirred in an ice bath for 30 minutes and filtered. The product was suspended in 500 ml of saturated sodium bicarbonate solution and extracted with chloroform. The extract was concentrated to a yellow solid (9.70 g) which
ble krystallisert og omkrystallisert fra metylenklorid-eter og ga 5,10 g (smp. 221-224°) rent 8-acetyl-2-brom-ll-okso-llH-pyrido[2,1-b]kinazolin. was crystallized and recrystallized from methylene chloride-ether to give 5.10 g (m.p. 221-224°) of pure 8-acetyl-2-bromo-11-oxo-11H-pyrido[2,1-b]quinazoline.
EKSEMPEL 4 6 EXAMPLE 4 6
Fremstilling av 4- isopropyl- isonitrosoacetanilid Preparation of 4- isopropyl isonitrosoacetanilide
Til en rørt løsning av 1480 g natriumsulfatdekahydrat oppløst To a stirred solution of 1480 g sodium sulfate decahydrate dissolved
i 1,8 liter vann ble tilsatt de følgende løsninger: 100 g p-isopropylanilin oppløst i 440 ml vann og 66 ml konsentrert saltsyre, 244 g kloralhydrat oppløst i 2,6 liter 90%'s vandig eta- in 1.8 liters of water the following solutions were added: 100 g of p-isopropylaniline dissolved in 440 ml of water and 66 ml of concentrated hydrochloric acid, 244 g of chloral hydrate dissolved in 2.6 liters of 90% aqueous ether
nol og 162 g hydroksylaminhydroklorid oppløst i 700 ml vann. nol and 162 g of hydroxylamine hydrochloride dissolved in 700 ml of water.
Denne reaksjonsblanding ble tilbakeløpsbehandlet i 12 timer, This reaction mixture was refluxed for 12 hours,
kjølt til romtemperatur og ekstrahert med 1,8 liter diklormetan. Det organiske lag ble skilt ut og inndampet til en mørk olje. Denne olje ble delt mellom 1,0 liter 10%'s natriumhydroksyd-oppløsning og 500 ml eter. Det vandige lag ble separert og vasket med 2 500 ml's porsjoner eter. Det vandige lag ble derpå surgjort cooled to room temperature and extracted with 1.8 liters of dichloromethane. The organic layer was separated and evaporated to a dark oil. This oil was partitioned between 1.0 liters of 10% sodium hydroxide solution and 500 ml of ether. The aqueous layer was separated and washed with 2500 mL portions of ether. The aqueous layer was then acidified
med konsentrert saltsyre og ekstrahert med tre 500-ml's porsjo- - ner eter. De forenete eterekstrakter ble tørket over vannfritt natriumsulfat, filtrert gjennom "Celite"og inndampet til tørrhet og ga 160 g 4-isopropyl-isonitrosoacetanilid. Dette rå produkt ble omkrystallisert fra 250 ml benzen og ga 46,6 g produkt, with concentrated hydrochloric acid and extracted with three 500-ml portions of ether. The combined ether extracts were dried over anhydrous sodium sulfate, filtered through "Celite" and evaporated to dryness to give 160 g of 4-isopropyl-isonitrosoacetanilide. This crude product was recrystallized from 250 ml of benzene to give 46.6 g of product,
smp. 126-130°. m.p. 126-130°.
EKSEMPEL 4 7 EXAMPLE 4 7
Fremstilling av 5- isopropylantranilsyre Preparation of 5-isopropylanthranilic acid
460 ml konsentrert svovelsyre ble rørt og oppvarmet til 70°. 460 ml of concentrated sulfuric acid was stirred and heated to 70°.
46,6 g 4-isopropylisonitrosoacetanilid ble deretter tilsatt i en slik mengde at temperaturen for reaksjonsblandingen ble holdt ved mellom 70-80°. Vannavkjøling ble utført om nødvendig. Etter fullendelse av tilsetningen ble temperaturen for blandingen holdt ved 80° i 30 minutter. Reaksjonsblandingen ble kjølt til romtemperatur og helt på 4 liter knust is. Den resulterende suspensjon ble rørt i 15 minutter og det utfelte 5-isopropylisatin ble filtrert. Det faste stoff ble vasket med vann, samlet opp og oppløst i 460 ml IN natriumhydroksydoppløsning. Denne blanding ble filtrert for å fjerne uoppløselige stoffer, og filtratet ble behandlet med 30%<1>s peroksyd inntil en positiv prøve med stivelsesjo-did ble erholdt. 46.6 g of 4-isopropylisonitrosoacetanilide was then added in such an amount that the temperature of the reaction mixture was maintained at between 70-80°. Water cooling was carried out if necessary. After completion of the addition, the temperature of the mixture was maintained at 80° for 30 minutes. The reaction mixture was cooled to room temperature and poured onto 4 liters of crushed ice. The resulting suspension was stirred for 15 minutes and the precipitated 5-isopropylisatin was filtered. The solid was washed with water, collected and dissolved in 460 mL of 1N sodium hydroxide solution. This mixture was filtered to remove insolubles, and the filtrate was treated with 30% peroxide until a positive starch iodide sample was obtained.
Den ovenfor nevnte reaksjonsblanding ble kjølt i et isbad og surgjort med 6N saltsyreoppløsning inntil en pH på tilnærmet 4 The above-mentioned reaction mixture was cooled in an ice bath and acidified with 6N hydrochloric acid solution until a pH of approximately 4
ble erholdt. Det utfelte produkt ble samlet opp og tørket og ga 28,0 g 5-isopropylantranilsyre, smp. 90-9 6°. Dette produkt var was obtained. The precipitated product was collected and dried to give 28.0 g of 5-isopropylanthranilic acid, m.p. 90-96°. This product was
av tilstrekkelig renhet for ytterligere anvendelse. of sufficient purity for further application.
EKSEMPEL 4 8 EXAMPLE 4 8
Fremgangsmåte: Approach:
Bland den aktive bestanddel med formel I,, laktose og maisstivelse i en egnet blandeanordning. Mal gjennom egnet mølle. Bland med magnésiumstearat og talkum og fyll på kapselmaskin. Mix the active ingredient with formula I, lactose and corn starch in a suitable mixing device. Grind through a suitable mill. Mix with magnesium stearate and talc and fill in capsule machine.
EKSEMPEL 49 EXAMPLE 49
Fremgangsmåte: Approach:
Bland den aktive bestanddel med formel I, laktose, mikrokry-stallinsk cellulose, modifisert stivelse og maisstivelse i en egnet blandeanordning i 1 til 15 minutter. Tilsett deretter magnésiumstearat og bland i 5 minutter. Komprimer på en egnet pressemaskin. Mix the active ingredient with formula I, lactose, microcrystalline cellulose, modified starch and corn starch in a suitable mixing device for 1 to 15 minutes. Then add magnesium stearate and mix for 5 minutes. Compress on a suitable press machine.
EKSEMPEL 50 EXAMPLE 50
Fremgangsmåte: Approach:
Bland den aktive bestanddel med formel I, laktose og pregelati-nisert stivelse i en egnet blandeanordning. Mal gjennom egnet mølle. Bland med modifisert stivelse og magnésiumstearat og fyll på kapselmaskin. Mix the active ingredient with formula I, lactose and pregelatinized starch in a suitable mixing device. Grind through a suitable mill. Mix with modified starch and magnesium stearate and fill in capsule machine.
Claims (8)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US78093977A | 1977-03-24 | 1977-03-24 | |
US87156478A | 1978-01-23 | 1978-01-23 |
Publications (1)
Publication Number | Publication Date |
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NO781053L true NO781053L (en) | 1978-09-26 |
Family
ID=27119777
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
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NO781053A NO781053L (en) | 1977-03-24 | 1978-03-22 | CHINAZOLINE DERIVATIVES. |
NO781051A NO781051L (en) | 1977-03-24 | 1978-03-22 | CHINAZOLINE DERIVATIVES. |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
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NO781051A NO781051L (en) | 1977-03-24 | 1978-03-22 | CHINAZOLINE DERIVATIVES. |
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JP (2) | JPS53119897A (en) |
AR (3) | AR218480A1 (en) |
AT (2) | AT367050B (en) |
AU (2) | AU521352B2 (en) |
DE (2) | DE2812585A1 (en) |
DK (2) | DK128878A (en) |
ES (13) | ES468127A1 (en) |
FI (2) | FI780918A (en) |
FR (2) | FR2384770A1 (en) |
GB (2) | GB1601991A (en) |
GR (2) | GR73170B (en) |
HU (1) | HU180782B (en) |
IE (1) | IE46505B1 (en) |
IL (2) | IL54328A (en) |
IT (2) | IT1093710B (en) |
LU (2) | LU79290A1 (en) |
MC (2) | MC1185A1 (en) |
NL (2) | NL7803112A (en) |
NO (2) | NO781053L (en) |
NZ (2) | NZ186760A (en) |
PH (2) | PH13915A (en) |
PT (2) | PT67820A (en) |
SE (2) | SE7803419L (en) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
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DE2557425C2 (en) * | 1975-12-19 | 1987-03-19 | C.H. Boehringer Sohn, 6507 Ingelheim | 11-Oxo-11-H-pyrido[2,1-b]-quinazoline-2-carboxylic acid and its salts, processes for their preparation and medicaments |
DE2845766A1 (en) * | 1978-10-18 | 1980-04-30 | Schering Ag | PYRIDO ANGLE CLAMP ON 2,1-B ANGLE CLAMP ON -CHINAZOLINONE DERIVATIVES, THEIR PRODUCTION AND USE |
US4395549A (en) | 1981-10-02 | 1983-07-26 | Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara Rt. | 6-Hydrazono-pyrido[2,1-b] quinazoline-11 ones |
ES8306729A1 (en) * | 1982-04-30 | 1983-06-01 | Lafarquim | Novel 2-isopropyl-pyrido[2,1-b]quinazolines and their non-toxic salts, process for their preparation and pharmaceutical compositions containing these compounds |
US4551460A (en) * | 1982-05-10 | 1985-11-05 | Hoffmann-La Roche Inc. | Pyrido[2,1-b]quinazoline derivatives useful as agents for treatment of allergic conditions and vascular disorders involving thrombosis |
DE3300477A1 (en) * | 1983-01-08 | 1984-07-12 | Boehringer Ingelheim KG, 6507 Ingelheim | NEW HETEROCYCLIC COMPOUNDS, THEIR PRODUCTION AND USE |
JPS62238264A (en) * | 1986-04-04 | 1987-10-19 | Nippon Tokushu Noyaku Seizo Kk | 2-halo-5-acetylpyridine |
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US4012387A (en) * | 1975-09-18 | 1977-03-15 | Warner-Lambert Company | Benzo-[g]pyrido[2,1-b]quinazolinones |
US4033961A (en) * | 1975-10-07 | 1977-07-05 | Warner-Lambert Company | Pyrido[2-1-b]quinazolin-ones and their methods of preparation |
-
1978
- 1978-03-22 FR FR7808316A patent/FR2384770A1/en active Granted
- 1978-03-22 NO NO781053A patent/NO781053L/en unknown
- 1978-03-22 DE DE19782812585 patent/DE2812585A1/en not_active Withdrawn
- 1978-03-22 DE DE19782812586 patent/DE2812586A1/en not_active Withdrawn
- 1978-03-22 LU LU79290A patent/LU79290A1/en unknown
- 1978-03-22 IL IL54328A patent/IL54328A/en unknown
- 1978-03-22 DK DK128878A patent/DK128878A/en not_active Application Discontinuation
- 1978-03-22 HU HU78HO2058A patent/HU180782B/en unknown
- 1978-03-22 ES ES468127A patent/ES468127A1/en not_active Expired
- 1978-03-22 DK DK132778A patent/DK132778A/en not_active IP Right Cessation
- 1978-03-22 NL NL7803112A patent/NL7803112A/en not_active Application Discontinuation
- 1978-03-22 NL NL7803122A patent/NL7803122A/en not_active Application Discontinuation
- 1978-03-22 PH PH20917A patent/PH13915A/en unknown
- 1978-03-22 IL IL54326A patent/IL54326A/en unknown
- 1978-03-22 NZ NZ186760A patent/NZ186760A/en unknown
- 1978-03-22 MC MC781291A patent/MC1185A1/en unknown
- 1978-03-22 MC MC781292A patent/MC1186A1/en unknown
- 1978-03-22 FR FR7808317A patent/FR2384771A1/en active Granted
- 1978-03-22 PH PH20918A patent/PH14130A/en unknown
- 1978-03-22 NZ NZ186759A patent/NZ186759A/en unknown
- 1978-03-22 LU LU79293A patent/LU79293A1/en unknown
- 1978-03-22 ES ES468126A patent/ES468126A1/en not_active Expired
- 1978-03-22 NO NO781051A patent/NO781051L/en unknown
- 1978-03-23 PT PT67820A patent/PT67820A/en unknown
- 1978-03-23 GR GR55782A patent/GR73170B/el unknown
- 1978-03-23 AU AU34474/78A patent/AU521352B2/en not_active Expired
- 1978-03-23 SE SE7803419A patent/SE7803419L/en unknown
- 1978-03-23 AU AU34475/78A patent/AU521096B2/en not_active Expired
- 1978-03-23 SE SE7803418A patent/SE7803418L/en unknown
- 1978-03-23 FI FI780918A patent/FI780918A/en not_active Application Discontinuation
- 1978-03-23 FI FI780917A patent/FI780917A/en not_active Application Discontinuation
- 1978-03-23 IT IT7821578A patent/IT1093710B/en active
- 1978-03-23 GB GB11705/78A patent/GB1601991A/en not_active Expired
- 1978-03-23 GR GR55781A patent/GR72948B/el unknown
- 1978-03-23 AT AT0210278A patent/AT367050B/en not_active IP Right Cessation
- 1978-03-23 GB GB11704/78A patent/GB1601371A/en not_active Expired
- 1978-03-23 IE IE582/78A patent/IE46505B1/en unknown
- 1978-03-23 AT AT0210478A patent/AT367051B/en not_active IP Right Cessation
- 1978-03-23 PT PT67821A patent/PT67821B/en unknown
- 1978-03-24 JP JP3400278A patent/JPS53119897A/en active Pending
- 1978-03-24 JP JP3320578A patent/JPS53119896A/en active Pending
- 1978-03-24 IT IT21655/78A patent/IT1095493B/en active
- 1978-03-27 AR AR271537A patent/AR218480A1/en active
- 1978-03-27 AR AR271538A patent/AR218060A1/en active
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1979
- 1979-02-16 ES ES478333A patent/ES478333A1/en not_active Expired
- 1979-02-16 ES ES478328A patent/ES478328A1/en not_active Expired
- 1979-02-16 ES ES478331A patent/ES478331A1/en not_active Expired
- 1979-02-16 ES ES478326A patent/ES478326A1/en not_active Expired
- 1979-02-16 ES ES478332A patent/ES478332A1/en not_active Expired
- 1979-02-16 ES ES478329A patent/ES478329A1/en not_active Expired
- 1979-02-16 ES ES478325A patent/ES478325A1/en not_active Expired
- 1979-02-16 ES ES478327A patent/ES478327A1/en not_active Expired
- 1979-02-16 ES ES478324A patent/ES478324A1/en not_active Expired
- 1979-02-16 ES ES478323A patent/ES478323A1/en not_active Expired
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