DK147940B - Analogifremgangsmaade til fremstilling af 4-substituerede thiazol-2-oxamsyrederivater eller salte eller estre deraf - Google Patents
Analogifremgangsmaade til fremstilling af 4-substituerede thiazol-2-oxamsyrederivater eller salte eller estre deraf Download PDFInfo
- Publication number
- DK147940B DK147940B DK269879AA DK269879A DK147940B DK 147940 B DK147940 B DK 147940B DK 269879A A DK269879A A DK 269879AA DK 269879 A DK269879 A DK 269879A DK 147940 B DK147940 B DK 147940B
- Authority
- DK
- Denmark
- Prior art keywords
- thiazole
- oxamic acid
- group
- ethanol
- hydrogen
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 5
- 238000002360 preparation method Methods 0.000 title claims description 3
- -1 amine salt Chemical class 0.000 claims description 21
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 125000005518 carboxamido group Chemical group 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims 2
- 125000006526 (C1-C2) alkyl group Chemical group 0.000 claims 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 33
- 150000001875 compounds Chemical class 0.000 description 19
- 235000019441 ethanol Nutrition 0.000 description 15
- 239000002253 acid Substances 0.000 description 13
- 239000000243 solution Substances 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 201000004624 Dermatitis Diseases 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 230000003266 anti-allergic effect Effects 0.000 description 6
- 208000010668 atopic eczema Diseases 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 150000002169 ethanolamines Chemical class 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 230000008020 evaporation Effects 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 108010058846 Ovalbumin Proteins 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 229960001701 chloroform Drugs 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 125000004494 ethyl ester group Chemical group 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 150000002912 oxalic acid derivatives Chemical class 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 125000000335 thiazolyl group Chemical group 0.000 description 2
- 238000010626 work up procedure Methods 0.000 description 2
- RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical compound NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 description 1
- DWPLEOPKBWNPQV-UHFFFAOYSA-N 1-(2-methoxyphenyl)ethanone Chemical compound COC1=CC=CC=C1C(C)=O DWPLEOPKBWNPQV-UHFFFAOYSA-N 0.000 description 1
- UYCUMNRCCJNSBR-UHFFFAOYSA-N 2-ethoxy-2-oxoacetic acid;hydrochloride Chemical compound Cl.CCOC(=O)C(O)=O UYCUMNRCCJNSBR-UHFFFAOYSA-N 0.000 description 1
- GUGQQGROXHPINL-UHFFFAOYSA-N 2-oxobutanoyl chloride Chemical compound CCC(=O)C(Cl)=O GUGQQGROXHPINL-UHFFFAOYSA-N 0.000 description 1
- FXGVKHSZIMCUTR-UHFFFAOYSA-N 4-(2,5-dimethoxyphenyl)-1,3-thiazol-2-amine Chemical compound COC1=CC=C(OC)C(C=2N=C(N)SC=2)=C1 FXGVKHSZIMCUTR-UHFFFAOYSA-N 0.000 description 1
- SFSPDEYUCDQJLH-UHFFFAOYSA-N 4-(2-methoxyphenyl)-1,3-thiazol-2-amine;hydroiodide Chemical compound I.COC1=CC=CC=C1C1=CSC(N)=N1 SFSPDEYUCDQJLH-UHFFFAOYSA-N 0.000 description 1
- NQGPTNZZTJGIDV-UHFFFAOYSA-N 4-(3,4-dimethoxyphenyl)-1,3-thiazole Chemical compound C1=C(OC)C(OC)=CC=C1C1=CSC=N1 NQGPTNZZTJGIDV-UHFFFAOYSA-N 0.000 description 1
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Natural products CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 1
- 208000035285 Allergic Seasonal Rhinitis Diseases 0.000 description 1
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- COXVTLYNGOIATD-HVMBLDELSA-N CC1=C(C=CC(=C1)C1=CC(C)=C(C=C1)\N=N\C1=C(O)C2=C(N)C(=CC(=C2C=C1)S(O)(=O)=O)S(O)(=O)=O)\N=N\C1=CC=C2C(=CC(=C(N)C2=C1O)S(O)(=O)=O)S(O)(=O)=O Chemical compound CC1=C(C=CC(=C1)C1=CC(C)=C(C=C1)\N=N\C1=C(O)C2=C(N)C(=CC(=C2C=C1)S(O)(=O)=O)S(O)(=O)=O)\N=N\C1=CC=C2C(=CC(=C(N)C2=C1O)S(O)(=O)=O)S(O)(=O)=O COXVTLYNGOIATD-HVMBLDELSA-N 0.000 description 1
- 229920001076 Cutan Polymers 0.000 description 1
- 206010012438 Dermatitis atopic Diseases 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 208000024780 Urticaria Diseases 0.000 description 1
- 150000008062 acetophenones Chemical class 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 201000009961 allergic asthma Diseases 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 239000000043 antiallergic agent Substances 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- 238000005422 blasting Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 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
- 239000002775 capsule Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- IMZMKUWMOSJXDT-UHFFFAOYSA-N cromoglycic acid Chemical compound O1C(C(O)=O)=CC(=O)C2=C1C=CC=C2OCC(O)COC1=CC=CC2=C1C(=O)C=C(C(O)=O)O2 IMZMKUWMOSJXDT-UHFFFAOYSA-N 0.000 description 1
- WYACBZDAHNBPPB-UHFFFAOYSA-N diethyl oxalate Chemical compound CCOC(=O)C(=O)OCC WYACBZDAHNBPPB-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 229960003699 evans blue Drugs 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical compound [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 239000008023 pharmaceutical filler Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 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
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 150000003557 thiazoles Chemical class 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/44—Acylated amino or imino radicals
- C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- 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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/40—Unsubstituted amino or imino radicals
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Pulmonology (AREA)
- Immunology (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Description
i 147940
Opfindelsen angår en analogifremgangsmåde til fremstilling af hidtil ukendte 4-substituerede thiazol-2-oxamsyrederivater med den almene formel I: 5 NH - CO - COOR1
io R
hvor: R1 er hydrogen eller en (C-,-C,)alkylgruppe, 2 x « · R er hydrogen, methyl eller -COOH, A er en pyridylgruppe, en benzodioxanylgruppe eller en 15 gruppe:
-X
20 R5 hvor: 3 4 5 R , R og R , der kan være ens eller forskellige, er hydrogen,- hydroxy, (C-p^)alkoxy, (C-^-C2)alkyl, halogen, carboxy(C1~C2)alkyl, di(^-02)alkylamino, car- 25 boxamido, nitro eller cyano, eller én af grupperne 3 4 5 R , R og R er en morpholino-, piperidino-, hydroxy-piperidino- eller phenylgruppe, eller farmaceutisk acceptable salte eller estre deraf.
Disse forbindelser udmærker sig ved deres antial-30 lergiske aktivitet, som nedenfor nærmere omtalt.
Angivelsen "(C^-C^)alkyl" henviser til methyl-, ethyl-, propyl-, isopropyl-, butyl-, sek.butyl- og tert.-butyl-gruppen. Pyridylgruppen kan være forbundet med thiazolringen i 2-, 3- eller 4-stilling i forhold til 35 nitrogenatomet. Betegnelsen "halogen" omfatter halogenatomerne fluor, chlor, brom og iod.
2 147940
Fra US patentskrift 4.054.666 kendes thiazolylderi-vater med formlen:
S
HC C - NHCOCOB
5 II II
hvor B blandt andet kan være OH eller lavere alkoxy, hvilke derivater blandt andet har en antiallergisk aktivitet. Disse kendte thiazolylderivater adskiller sig i-10 midlertid strukturelt fundamentalt fra derivaterne med den ovenfor angivne formel I ved at være usubstituerede i 4-stillingen, hvor de omhandlede forbindelser med formlen I altid har A-substituenten, og endvidere har de kendte derivater en langt ringere antiallergisk aktivitet 15 end de omhandlede forbindelser, således som nedenfor påvist.
Foretrukne forbindelser med den almene formel X er 1 2 sådanne, hvori R er hydrogen eller ethyl, R er hydrogen, A er en pyridylgruppe, en benzodioxanylgruppe eller 20 gruppen: •SØ- 25 R5 3 4 hvor R er hydrogen eller hydroxy, R er hydrogen, methyl 5 eller methoxy, og R er methyl, methoxy eller dimethyl-amino.
30 Inden for denne gruppe er særligt virksomme forbin delser 4-(3',4'-dimethoxyphenyl)-thiazol-2-oxamsyre, 4-(4'-dimethylaminophenyl)-thiazol-2-oxamsyre og 4-benzo-dioxanyl-(6')-thiazol-2-oxamsyre eller farmaceutisk acceptable salte deraf. Blandt andre foretrukne forbindel-35 ser kan nævnes 4-(pyridyl-(2') 1-thiazoloxamsyreethylester, 4-(3',5'-dimethoxyphenyl)-thiazoloxamsyre, 4-(31-hydroxy-phenyl)-thiazoloxamsyre, 4-(41-hydroxyphenyl)-thiazol- 3 147940 oxamsyre, 4—(3 *-methoxyphenyl)-thiazoloxamsyre, 4-(2'-hydroxy-4'-methoxyphenyl)-thiazoloxamsyre-ethylester, 4-(4'-dimethylaminophenyl)-thiazoloxamsyre-ethylester og 4-(21-hydroxy-4',6'-dimethylphenyl)-thiazoloxamsyre-ethyl 5 -ester.
Fremgangsmåden ifølge opfindelsen er ejendommelig ved, at en 2-aminothiazol med den almene formel II: NH_ 10 N / A (II) /—8 R2 15 2 hvor R og A har ovennævnte betydninger, omsættes med et oxalsyreesterhalogenid med formlen Hal-CO-COOR®, hvor R® betyder (C1-C4)alkyl, og Hal er et halogenatom, for trinsvis chlor, eller med en oxalsyredialkylester med 20 formlen R OOC-COOR , hvor R har ovennævnte betydning, og at, eventuelt, den således vundne ester forsæbes, og syren, om ønsket, overføres i et farmaceutisk acceptabelt salt.
Herved bliver udgangsforbindelsen med den almene 25 formel II, der også kan foreligge i form af et egnet syreadditionssalt, opløst eller suspenderet i et indifferent opløsningsmiddel, og oxalsyrederivatet tilsættes dråbevis. Som opløsnings- eller suspensionsmiddel egner sig for eksempel benzen, toluen, xylen, en alkohol eller 30 tetrahydrofuran, der forholder sig indifferent over for reaktionskomponenterne. Fortrinsvis tilsættes yderligere en organisk base, f.eks. pyridin eller triethylamin, til opfangning af den dannede syre. Da reaktionen er stærkt eksoterm, foregår tilsætningen af oxalsyrederivatet kun 35 langsomt, eventuelt under afkøling. I almindelighed er tilsætningen afsluttet i løbet af fra 30 til 180 minutter.
4 147940
Da de fleste thiazolforbindelser er tungtopløseli-gef er det hensigtsmæssigt at lade reaktionsblandingen henstå lamgere tid før oparbejdning, f.eks. natten over, og eventuelt under omrøring.
5 Oparbejdningen foregår på i og for sig kendt måde ved afdampning af opløsningsmidlet, ekstraktion af ind-dampningsresten med et egnet opløsningsmiddel eller en opløsningsmiddelblanding, f.eks. ether, ethylacetat, chloroform eller hexan, rensning af ekstrakten, fordamp-10 ning af opløsningsmidlet og omkrystallisation. I nogle tilfælde har rensning ved søjlechromatografi vist sig egnet.
Hvis der ønskes et slutprodukt med den almene formel I, hvor R1 er hydrogen, bliver estergruppen fraspal-15 tet på sædvanlig måde ved forsæbning. Dette foregår for eksempel ved hydrolyse i nærværelse af en katalysator, for eksempel et basisk eller surt middel, såsom en stærk base, f.eks. natrium- eller kaliumhydroxid, eller en mineralsyre, f.eks. saltsyre, svovlsyre eller phosphorsyre.
20 Sådanne forbindelser med den almene formel I, hvor er hydrogen, kan eventuelt overføres i deres salte.
Hertil opløses eller suspenderes syren i vand, og den ønskede base tilsættes, indtil der er opnået en pH-værdi på 7.
25 Udgangsforbindelserne med den almene formel II er kendte og kan for eksempel vindes ved omsætning af thio-urinstof med en tilsvarende substitueret acetophenon med den almene formel:
Ar - CO - CH3 (III) 30 hvor A har ovennævnte betydning, ifølge Orteleva-King.
Der gås fortrinsvis frem analogt med angivelserne i Che-mische Berichte, bind 92, side 35/36 (1959).
De hidtil ukendte forbindelser har fremragende an-35 tiallergiske egenskaber. De er sammenlignet med kendte antiallergica, såsom 1,3-bis-(2-carboxychromon-5-yloxy)-2-hydroxypropan, navnlig bedre derved, at de også er virksomme ved oral indgift.
5 147940
Endvidere indtræder den hæmmende virkning på allergiske reaktioner allerede ved væsentligt lavere dosering og holder sig længere.
Den antiallergiske virkning blev målt på rotter 5 ved den såkaldte PCA-prøve (passiv cutan anaphylaxis-prøve). Herved bliver rottehuden sensibiliseret ved intradermale injektioner af forskellige fortyndinger (ufor-tyndet og i fortyndingerne 1:3, 1:9, 1:27 osv.) af ægal-bumin-antiserum. Én dag senere får dyrene ægalbumin i 10 Evansblåopløsning i.v. Ved måling af størrelsen af blåfarvningen bestemmes PCA-titeren. Forsøgsforbindelserne indgives i forskellige koncentrationer i.v. eller p.o. sammen med Evansblå-opløsningen. Hver rotte får 5 mg ægalbumin, opløst i 1 ml af en opløsning af 0,25% Evansblå 15 i steril saltopløsning.
Fra 25 til 30 minutter efter indgift af farvestoffet og forsøgsforbindelsen dræbes dyrene, og blåfarvnin-gen på den indvendige overflade af huden måles i mm .
PCA-titeren er den reciprokke værdi af den serum-20 fortynding, ved hvilken en blåfarvning med en diameter på mindst 5 mm netop endnu kan observeres. Reduktionen af PCA-titeren er et mål for hæmningen af allergiske reaktioner, i det foreliggende tilfælde over for ægalbumin.
I følgende tabel er anført den orale og/eller in-25 travenøse virkning af nogle af de hidtil ukendte forbindelser.
6 147940 ED-« ED-q
Forbindelse „ /Λ mg/kg ι.ν. mg/kg p.o.
5 4- (4'-Dimethylaminophenyl)- thiazol-2-oxamsyre 0,02 0,34 4- (Benzodioxanyl- (6T) )-thiazol-2- oxamsyre, ethanolaminsalt 0,02 0,7 4-(Pyridyl-(4'))-thiazol-2- oxamsyre, ethanolaminsalt 0,05 10 4-(31,4'-Dimethoxyphenyl)- thiazol-2-oxamsyre-ethylester 0,12 4-(3',4'-Dimethoxyphenyl)-thiazol-2-oxamsyre 0,13 4-(31-Methoxyphenyl)-thiazol- 2-oxamsyre 0,16 2,0 15 4-(Pyridyl-(31))-thiazol-2- oxamsyre, ethanolaminsalt 0,16 4-Phenyl-5-methyl-thiazol-2- oxamsyre, ethanolaminsalt 0,19 2,04 4-(3'-Dimethylaminophenyl)-thiazol-2-oxamsyre, ethanol- 2q aminsalt 0,34 1,6 4-(21,4'-Dimethoxyphenyl)-thiazol-2-oxamsyre 0,39 4—(21,5'-Dimethoxyphenyl)-thiazol-2-oxamsyre, ethanolaminsalt 0,4 -c 4-(2'-Methoxyphenyl)-thiazol- 2-oxamsyre 1,08 4-(Pyridyl-(4'))-thiazol-2- oxamsyre-ethylester - 1,2 4-(3',4'-Dimethoxyphenyl)- thiazol-2-oxamsyre-methylester - 1,2 , _ 4—(4 *-Ethoxyphenyl)-thiazol-2- oxamsyre-ethylester - 2,07 4—(3'-Methyl-4'-hydroxypheny1)- thiazol-2-oxamsyre-ethylester - 2,1
35 Ved ovennævnte prøve viste den fra ovennævnte US
patentskrift 4.054.666 kendte 2-thiazolyl-oxamsyre-ethyl-ester en ED^q på 98,4 mg/kg p.o.
1479/,0 7
De omhandlede forbindelser skal benyttes ved behandling af allergisk astma, høfeber, nældefeber, eksemer, atopiske dermatitider og andre allergiske sygdomme.
Til anvendelse inden for terapien bliver de omhandl· 5 lede virksomme stoffer blandet med de sædvanlige farmaceutiske fyld- eller bærestoffer, stræk-, spræng-, bindey glide-, fortyknings- eller fortyndingsmidler, opløsningsmidler eller opløsningsformidlere eller midler til opnåelse af depot-virkning, hvilke stoffer og midler passer for enteral el-10 ler parenteral anvendelse. Som farmaceutiske præparatformer kommer for eksempel tabletter, dragée, piller, kapsler, opløsninger, suspensioner, salver, pudderprodukter, tinkturer, injektionsopløsninger eller aerosoler i betragtning, idet der foruden de hidtil ukendte virksomme 15 stoffer også kan tilføjes f.eks. konserverings- eller stabiliseringsmidler, emulgatorer eller pufferstoffer.
De farmaceutiske præparater skal i almindelighed være på 5-50 mg pr.dosis til parenteral anvendelse og til inhalering eller 50-500 mg pr.dosis til oral anvendelse.
20 Fremgangsmåden ifølge opfindelsen beskrives nærme re gennem følgende eksempler.
8 147940
Eksempel 1 4—(2 *-Methoxyphenyl)-thiazol-2-oxamsyre-ethylester.
Til en opslæmning af 6 g 2-amino-4-(2'-methoxyphenyl) -thiazol-hydroiodid i pyridin blev der dråbevis sat 5 2,9 g ethyloxalylchlorid, og blandingen blev omrørt nat ten over ved stuetemperatur. Efter inddampning til tørhed blev inddampningsresten optaget i en natriumbicarbonatop-løsning og ekstraheret flere gange med ethylether. De samlede ekstrakter blev vasket tre gange med vand og én 10 gang med mættet saltopløsning og derefter tørret over MgSO^. Efter inddampning til tørhed og omkrystallisation af ethanol vandtes titelforbindelsen i et udbytte på 4,2 g = 78% af det teoretiske, smp. 118-122°C.
Det som udgangsmateriale anvendte 2-amino-4-(2'-me-15 thoxyphenyl)-thiazol-hydroiodid vandtes på følgende måde: 15 g o-Methoxyacetophenon og 15,2 g thiourinstof blev blandet godt i en formstofkolbe. Til denne blanding blev der i små portioner sat 27,7 g iod. Efter endt tilsætning blev reaktionsblandingen opvarmet natten over på 20 oliebad på 100°C. Efter afkøling blev der tilsat 50 ml methanol, derefter 400-500 ml vand, og den faste masse blev findelt i en morter, opslæmningen blev filtreret, vasket med vand, noget ethanol og ether og derefter tørret.
Der vandtes 27,7 g = 83% af titelforbindelsen, der 25 uden yderligere rensning anvendtes som udgangsmateriale.
Eksempel 2 4—(2',5'-Dimethoxyphenyl)-thiazol-2-oxamsyre-ethylester.
Til en opløsning af 3 g 2-amino-4-(2',5'-dimethoxy-phenyl)-thiazol i tør pyridin blev der dråbevis sat 2 g 30 oxalsyre-ethylesterchlorid i 35 ml tør pyridin. Efter endt tilsætning blev der omrørt 2 1/2 time, og herunder fulgtes reaktionsforløbet ved tyndtlagschromatografi. Efter endt reaktion blev blandingen hældt i isvand, det dannede bundfald blev frafiltreret, vasket med vand og tørret. Efter omkrystallisation af ethanol og n-hexan/-chloroform vandtes 2,9 g af titelforbindelsen med smp.
9 U7940 143-144°C.
Eksempel 3 4-(Pyridyl-(2'))-thiazol-2-oxamsyre-ethylester.
En opløsning af 1 g 2-amino-4-(pyridyl-(2'))-thia-zol i 25 ml diethyloxalat blev opvarmet 20 timer ved 125° C. Blandingen blev afkølet, bundfaldet blev frafiltreret og omkrystalliseret af ethanol og derefter af hexan/chloro form. Udbytte: 0,5 g = 64% af det teoretiske, af titelforbindelsen med smp. 141-144°C.
Eksempel 4 4- (2'-Methoxyphenyl)-thiazol-2-oxamsyre.
En opslæmning af 2 g 4-(2'-methoxyphenyl)-thiazol-2-oxamsyre-ethylester i 30 ml IN natriumhydroxid blev under kraftig omrøring opvarmet, indtil der fremkom en klar opløsning. Ved syrning med 2N saltsyre dannedes et bundfald, der efter afkøling af blandingen og fortynding med vand blev frafiltreret. Filterresten blev opslæmmet to gange i vand (100 ml), frafiltreret og vasket med e-thanol. Syren blev renset ved omkrystallisation af dime-thylformamid/ethanol.
Udbytte: 1 g = 55% af det teoretiske, af titelforbindelsen med smp. 195-197°C.
De følgende forbindelser blev fremstillet på samme måde:
Eksem- _2 _ „ _ „1 cu pel nr. H A R ^P* c s ©- C2H5 209-211 s (oy- c2h5 22e-228 7 °GyN -(O)- C2H5 249-251 (fortsættes) 147940 ίο
Eksem- R2 = η A R1 Snip. °C
pel nr.
8 02N -(Q^- C2H5 227-229 9 CH30 —(Q) C2H5 164-165 10 o —C2H5 207-209 11 (Ο)— C2H5 209-211
' OH
12 <0/~ C2H5 166-169 ch3o—J—' CH3°Vn 13 /Q\— H 221-223 ch3o ^—' 14 CH30 _/q\- C2H5 131-133 ch3o^ 15 133'136 ^^0CH3 16 CH30 -(O)- C2H5 203-207 17 HO -((S)- C2H5 230-233 (fortsættes)
Eksem- = H A Smp. °C
pel nr.
11 1-47940 CH3° 18 CH-O—(O/- H ^200 3 \ / (dek.) CR3°y-\ 19 (O)— H 214"217 0CH3 20 CH30 H 190-193 η°>λ 21 \0/ C2H5 231-235
HO
22 H 211-215 , 1/2 C2H5OH
23 HO H 247-250 OH 3°
24 HO
^2^5 I I
CH-0
OH
25 CH3O —(o)— C2H5 167-170 (fortsættes) 147940 12
Eksem- r2 = H A R1 Smp. °C
pel nr._____
.__OH
26 (O) (O)_ C2H5 189-195 CH3 / \ 27 -(O)- C2H5 210“213 \_/ CH30^—\ 28 CH30 -(O)- C2H5 141-144 CH..0--- — CH: 29 HO C2H5 173-176 30 O^Q)- C2H5 204-207
^-C
CH3 31 \-(OV H >220 CH^ ' ' (άβ1ζ,) ch3°~7—\ 32 CH,0'—(O)— H 158-161 3 / (ethanol· CH3° aminsalt) __CH, Z~ZT\ 195-197 33 HO ——(O /- H (ethanol· \ / aminsalt) CH,0^_ 3 177-180 34 HO -(O)- H (ethanol· \ / aminsalt)
_^OH
35 (Π)-(O)— H >225 I xryxr/ lfortsatte3lI <w U7940
Eksem- R2 = h A R1 smp. °C
pel nr.
13 36 — C2H5 139-140 ^ co2ch3 /r\ 179“181 37 o—( O )— H (ethanol- / \ / aminsalt) '—0 ___OCH, 6 160-162 38 (O H (ethanol- ___ \ / aminsalt) CH^O-1-' 39 CH3CH202C -(5)- C2H5 184-185 40 CH3CH202C CH3 209-211 41 CH3CH202C -(5)- n-butyl 175-177
___.OH
42 CH3-(O)— C2H5 185-187 CH3 ch3° 43 CH30 -/oV CH3 170-174
\-' .---OH
/r\\ 186-190 44 /“ H (ethanol- '-' aminsalt) (CH3)2N^_ 2 2 7pr\ 147-150 45 (O )— H (ethanol- \_/ aminsalt) /T"\__ 230-233 46 02N—(O) H (ethanol- __\ -/ (fortsættes)l_aminsalt)
Eksem- R2 _ H a R1 Smp. °C
pel nr.
147940 14
__^ 0H
47 CH3 -\0/- C2H5 167-170 ch3
CHs'7—V
48 HO—— C2H5 212-215 Λ 215-219 49 \ Q H (ethanol— \ / aminsalt)
___ OH
/-C 207-208 50 CH,-( O )— H (ethanol- J \ / aminsalt) -ch3 CE3*7ZT\ 203-206 51 HO O / H (ethanol- \ / aminsalt) 52 C2H5°-(O)- C2H5 164-167 /-V 167-176 53 N O)— H (ethanol- \ / aminsalt) 54 F C2H5 220-223 /~\ 195-197 55 CoH,-0 —( O /— H (ethanol- ^ b \ / aminsalt) /“T\ 197-199 56 F —( O /“ H (ethanol- \ / aminsalt) (fortsættes)
Claims (4)
- 557. V“ -COOH H (ethanol- \_/ aminsalt) /CT\ 188-190 58 \U/“ -CH3 H (ethanol- \_/ J aminsalt) 10
- 1. Analogifremgangsmåde til fremstilling af 4-sub-stituerede thiazol-2-oxamsyrederivater med den almene formel I:
- 15 NH-CO-COOR1 A-I (I) /-S 20 hvor: R er hydrogen eller en (C,-C.)alkylgruppe, 2 -* q R er hydrogen, methyl eller -COOH, A er en pyridylgruppe, en benzodioxanylgruppe eller en gruppe
- 25 R3 ^é- R5 30 3 4 5 hvor R , R og R , der kan være ens eller forskellige, er hydrogen, hydroxy, (C-^-C^ alkoxy, (C1-C2) alkyl, halogen, carboxy(C^-C2)alkyl, di(C^-C^alkylamino, carboxamido, nitro eller cyano, eller én af grupperne R3, R^ og R5 er en 35 morpholino-, piperidino-, hydroxypiperidino- eller phen-ylgruppe, eller farmaceutisk acceptable salte eller estre deraf,
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19782828091 DE2828091A1 (de) | 1978-06-27 | 1978-06-27 | 4-substituierte thiazoloxamsaeuren sowie ihre salze und ester |
| DE2828091 | 1978-06-27 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK269879A DK269879A (da) | 1979-12-28 |
| DK147940B true DK147940B (da) | 1985-01-14 |
| DK147940C DK147940C (da) | 1985-09-02 |
Family
ID=6042852
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK269879A DK147940C (da) | 1978-06-27 | 1979-06-26 | Analogifremgangsmaade til fremstilling af 4-substituerede thiazol-2-oxamsyrederivater eller salte eller estre deraf |
Country Status (36)
| Country | Link |
|---|---|
| US (1) | US4238496A (da) |
| JP (1) | JPS557290A (da) |
| AT (1) | AT373884B (da) |
| AU (1) | AU525312B2 (da) |
| BE (1) | BE877293A (da) |
| BG (1) | BG30324A3 (da) |
| CA (1) | CA1246071A (da) |
| CH (1) | CH644370A5 (da) |
| CS (1) | CS208114B2 (da) |
| DD (1) | DD144542A5 (da) |
| DE (1) | DE2828091A1 (da) |
| DK (1) | DK147940C (da) |
| ES (1) | ES481917A1 (da) |
| FI (1) | FI69456C (da) |
| FR (1) | FR2429787A1 (da) |
| GB (1) | GB2023580B (da) |
| GR (1) | GR69231B (da) |
| HK (1) | HK66285A (da) |
| HU (1) | HU178996B (da) |
| IE (1) | IE48357B1 (da) |
| IL (1) | IL57659A0 (da) |
| IT (1) | IT1120443B (da) |
| LU (1) | LU81424A1 (da) |
| MY (1) | MY8600653A (da) |
| NL (1) | NL7904957A (da) |
| NO (1) | NO151500C (da) |
| NZ (1) | NZ190842A (da) |
| PH (1) | PH17226A (da) |
| PL (1) | PL117333B1 (da) |
| PT (1) | PT69822A (da) |
| RO (1) | RO77553A (da) |
| SE (1) | SE446182B (da) |
| SG (1) | SG61985G (da) |
| SU (1) | SU791237A3 (da) |
| YU (1) | YU41645B (da) |
| ZA (1) | ZA793176B (da) |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4321372A (en) * | 1980-06-16 | 1982-03-23 | Pfizer Inc. | Antiulcer thiazol-2-ylcarbamoyl-carboxylic acids, esters and amides |
| DE3027527A1 (de) * | 1980-07-19 | 1982-02-18 | Basf Ag, 6700 Ludwigshafen | Neue oxamidsaeure-derivate, verfahren zu ihrer herstellung und diese enthaltende therapeutische mittel |
| DE3027528A1 (de) * | 1980-07-19 | 1982-02-18 | Basf Ag, 6700 Ludwigshafen | Ueberbrueckte thiazolyloxamidsaeure-derivate, verfahren zu ihrer herstellung und diese enthaltende therapeutische mittel |
| FR2494272A1 (fr) * | 1980-11-19 | 1982-05-21 | Fabre Sa Pierre | Derives de l'acide thiazolyl-2 oxamique substitues en position 4 par un radical thienyle ou furyle, leur preparation et leur utilisation comme medicaments |
| DE3135250A1 (de) * | 1981-09-05 | 1983-03-17 | Basf Ag, 6700 Ludwigshafen | Tricyclische thiazolyloxamate, verfahren zu ihrer herstellung und diese enthaltende therapeutische mittel |
| EP0137979B1 (en) * | 1983-09-01 | 1988-10-26 | Boehringer Ingelheim Pharmaceuticals Inc. | Diazine-ethenylphenyl oxamic acids and esters and salts thereof |
| US4681884A (en) * | 1983-09-01 | 1987-07-21 | Boehringer Ingelheim Pharmaceuticals, Inc. | Diazine-ethenylphenyl oxamic acids and esters and salts thereof |
| US4788198A (en) * | 1983-09-01 | 1988-11-29 | Boehringer Ingelheim Pharmaceuticals, Inc. | Diazine-ethyenylphenyl oxamic acids and esters and salts thereof |
| IT1204960B (it) * | 1987-03-25 | 1989-03-10 | Zambon Farmaceutici Spa | Composti dotati di attivita' antiallergica |
| IT1204959B (it) * | 1987-03-25 | 1989-03-10 | Zambon Farmaceutici Spa | Composti dotati di attivita' antiallergica |
| DE3807232A1 (de) * | 1988-03-05 | 1989-09-14 | Bayer Ag | Substituierte acrylsaeureester |
| JPH0667836B2 (ja) * | 1989-03-01 | 1994-08-31 | 東洋紡績株式会社 | アミド系化合物からなる抗アレルギー剤 |
| FR2671552B1 (fr) * | 1991-01-15 | 1993-05-07 | Pf Medicament | Procede de preparation de thiazolyl-2 oxamates d'alkyle. |
| ATE257703T1 (de) * | 1997-10-27 | 2004-01-15 | Takeda Chemical Industries Ltd | 1,3-thiazole als adenosine a3 rezeptor antagonisten zur behandlung von asthma, allergien und diabetes |
| CN116554122B (zh) * | 2023-06-29 | 2023-09-19 | 南京桦冠生物技术有限公司 | α-酮酸酰胺或取代草酸酰胺酯类化合物及其组合物 |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1062245B (de) * | 1957-10-17 | 1959-07-30 | Ciba Geigy | Verfahren zur Herstellung von 2-Amino-4-pyridyl-(2')-thiazol und seinen Salzen |
| FR1526074A (fr) * | 1967-03-22 | 1968-05-24 | Rech S Ind S O R I Soc D | Méthoxy-phényl-amino-2-thiazoles, leurs amides et leurs procédés de préparation |
| BE795907A (fr) * | 1972-02-25 | 1973-06-18 | Luso Farmaco Inst | 2-amino-4-arylthiazoles 5-substitues et leur preparation |
| US4054666A (en) * | 1973-03-23 | 1977-10-18 | American Home Products Corporation | Compositions and methods of treating immediate hypersensitivity reactions with thiazolyl oxamic acid derivatives |
| US3966965A (en) * | 1973-03-23 | 1976-06-29 | American Home Products Corporation | Oxamic acid derivatives for the prevention of immediate type hypersensitivity reactions |
| FR2429210A1 (fr) * | 1978-06-19 | 1980-01-18 | Fabre Sa Pierre | Derives de phenyl-4 thiazolyl-2 oxamates utiles dans le traitement de l'asthme |
-
1978
- 1978-06-27 DE DE19782828091 patent/DE2828091A1/de active Granted
-
1979
- 1979-06-18 US US06/049,173 patent/US4238496A/en not_active Expired - Lifetime
- 1979-06-18 GR GR59370A patent/GR69231B/el unknown
- 1979-06-19 AT AT0431879A patent/AT373884B/de active
- 1979-06-20 SU SU792776204A patent/SU791237A3/ru active
- 1979-06-22 DD DD79213848A patent/DD144542A5/de not_active IP Right Cessation
- 1979-06-22 CH CH588679A patent/CH644370A5/de not_active IP Right Cessation
- 1979-06-25 YU YU1497/79A patent/YU41645B/xx unknown
- 1979-06-25 BG BG044041A patent/BG30324A3/xx unknown
- 1979-06-25 LU LU81424A patent/LU81424A1/de unknown
- 1979-06-25 IT IT49533/79A patent/IT1120443B/it active
- 1979-06-25 FI FI792006A patent/FI69456C/fi not_active IP Right Cessation
- 1979-06-26 NO NO792139A patent/NO151500C/no unknown
- 1979-06-26 IL IL57659A patent/IL57659A0/xx not_active IP Right Cessation
- 1979-06-26 ES ES481917A patent/ES481917A1/es not_active Expired
- 1979-06-26 RO RO7997961A patent/RO77553A/ro unknown
- 1979-06-26 JP JP8062879A patent/JPS557290A/ja active Granted
- 1979-06-26 NZ NZ190842A patent/NZ190842A/xx unknown
- 1979-06-26 BE BE0/195981A patent/BE877293A/xx not_active IP Right Cessation
- 1979-06-26 AU AU48397/79A patent/AU525312B2/en not_active Ceased
- 1979-06-26 CS CS794390A patent/CS208114B2/cs unknown
- 1979-06-26 PL PL1979216608A patent/PL117333B1/pl unknown
- 1979-06-26 HU HU79BO1794A patent/HU178996B/hu not_active IP Right Cessation
- 1979-06-26 CA CA000330575A patent/CA1246071A/en not_active Expired
- 1979-06-26 NL NL7904957A patent/NL7904957A/nl not_active Application Discontinuation
- 1979-06-26 SE SE7905608A patent/SE446182B/sv not_active IP Right Cessation
- 1979-06-26 DK DK269879A patent/DK147940C/da not_active IP Right Cessation
- 1979-06-26 ZA ZA793176A patent/ZA793176B/xx unknown
- 1979-06-26 PH PH22688A patent/PH17226A/en unknown
- 1979-06-26 PT PT69822A patent/PT69822A/pt unknown
- 1979-06-26 GB GB7922155A patent/GB2023580B/en not_active Expired
- 1979-06-27 FR FR7916627A patent/FR2429787A1/fr active Granted
- 1979-08-08 IE IE1200/79A patent/IE48357B1/en not_active IP Right Cessation
-
1985
- 1985-08-23 SG SG619/85A patent/SG61985G/en unknown
- 1985-09-05 HK HK662/85A patent/HK66285A/xx unknown
-
1986
- 1986-12-30 MY MY653/86A patent/MY8600653A/xx unknown
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PBP | Patent lapsed |