DK150508B - Analogifremgangsmaade til fremstilling af benzoxazol- eller benzthiazol-2-carboxylsyreestere eller farmaceutisk acceptable syreadditionssalte eller aminosyre- eller glucuronsyrekonjugatsalte heraf - Google Patents
Analogifremgangsmaade til fremstilling af benzoxazol- eller benzthiazol-2-carboxylsyreestere eller farmaceutisk acceptable syreadditionssalte eller aminosyre- eller glucuronsyrekonjugatsalte heraf Download PDFInfo
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- DK150508B DK150508B DK208981AA DK208981A DK150508B DK 150508 B DK150508 B DK 150508B DK 208981A A DK208981A A DK 208981AA DK 208981 A DK208981 A DK 208981A DK 150508 B DK150508 B DK 150508B
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- DK
- Denmark
- Prior art keywords
- benzoxazole
- salts
- acid
- esters
- pharmaceutically acceptable
- Prior art date
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- 239000002253 acid Substances 0.000 title claims description 12
- 150000003839 salts Chemical class 0.000 title claims description 9
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 title claims description 8
- 238000000034 method Methods 0.000 title claims description 7
- 150000001413 amino acids Chemical class 0.000 title claims description 6
- UUVDQMYRPUHXPB-UHFFFAOYSA-N 1,3-benzothiazole-2-carboxylic acid Chemical class C1=CC=C2SC(C(=O)O)=NC2=C1 UUVDQMYRPUHXPB-UHFFFAOYSA-N 0.000 title claims description 5
- 238000002360 preparation method Methods 0.000 title claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 239000000460 chlorine Substances 0.000 claims description 6
- 229940097043 glucuronic acid Drugs 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- 229910052717 sulfur Inorganic materials 0.000 claims 1
- 150000002148 esters Chemical class 0.000 description 13
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 241000700159 Rattus Species 0.000 description 4
- 235000001014 amino acid Nutrition 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 229960001340 histamine Drugs 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- VKPJOERCBNIOLN-UHFFFAOYSA-N 1,3-benzoxazole-2-carboxylic acid Chemical class C1=CC=C2OC(C(=O)O)=NC2=C1 VKPJOERCBNIOLN-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- AEMOLEFTQBMNLQ-AQKNRBDQSA-N D-glucopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 230000003266 anti-allergic effect Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 210000003630 histaminocyte Anatomy 0.000 description 3
- 206010002198 Anaphylactic reaction Diseases 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 125000005907 alkyl ester group Chemical group 0.000 description 2
- 230000036783 anaphylactic response Effects 0.000 description 2
- 208000003455 anaphylaxis Diseases 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical class C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 2
- -1 benzoxazine ions Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 150000003463 sulfur Chemical class 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 description 1
- UZOFJFWZLUSCKB-UHFFFAOYSA-N 2-ethoxyethyl 1,3-benzothiazole-2-carboxylate Chemical compound C1=CC=C2SC(C(=O)OCCOCC)=NC2=C1 UZOFJFWZLUSCKB-UHFFFAOYSA-N 0.000 description 1
- KKIGWIJVSCPFCN-UHFFFAOYSA-N 2-ethoxyethyl 5,6-dimethoxy-1,3-benzoxazole-2-carboxylate Chemical compound COC1=C(OC)C=C2OC(C(=O)OCCOCC)=NC2=C1 KKIGWIJVSCPFCN-UHFFFAOYSA-N 0.000 description 1
- HNJUBRBHULQQFX-UHFFFAOYSA-N 2-ethoxyethyl 5-chloro-1,3-benzoxazole-2-carboxylate Chemical compound ClC1=CC=C2OC(C(=O)OCCOCC)=NC2=C1 HNJUBRBHULQQFX-UHFFFAOYSA-N 0.000 description 1
- ZCEVLFNMZFGEPU-UHFFFAOYSA-N 2-ethoxyethyl 5-nitro-1,3-benzoxazole-2-carboxylate Chemical compound [O-][N+](=O)C1=CC=C2OC(C(=O)OCCOCC)=NC2=C1 ZCEVLFNMZFGEPU-UHFFFAOYSA-N 0.000 description 1
- CZTWXLWUDOCTAO-UHFFFAOYSA-N 2-ethoxyethyl 6-methyl-1,3-benzoxazole-2-carboxylate Chemical compound C1=C(C)C=C2OC(C(=O)OCCOCC)=NC2=C1 CZTWXLWUDOCTAO-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- USVZHTBPMMSRHY-UHFFFAOYSA-N 8-[(6-bromo-1,3-benzodioxol-5-yl)sulfanyl]-9-[2-(2-chlorophenyl)ethyl]purin-6-amine Chemical compound C=1C=2OCOC=2C=C(Br)C=1SC1=NC=2C(N)=NC=NC=2N1CCC1=CC=CC=C1Cl USVZHTBPMMSRHY-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- LEVWYRKDKASIDU-QWWZWVQMSA-N D-cystine Chemical compound OC(=O)[C@H](N)CSSC[C@@H](N)C(O)=O LEVWYRKDKASIDU-QWWZWVQMSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- RGHNJXZEOKUKBD-QTBDOELSSA-N L-gulonic acid Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O RGHNJXZEOKUKBD-QTBDOELSSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001371 alpha-amino acids Chemical class 0.000 description 1
- 235000008206 alpha-amino acids Nutrition 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000000043 antiallergic agent Substances 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- SXDBWCPKPHAZSM-UHFFFAOYSA-N bromic acid Chemical compound OBr(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 125000000068 chlorophenyl group Chemical group 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 229960003067 cystine Drugs 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229910000043 hydrogen iodide Inorganic materials 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 235000006109 methionine Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000005489 p-toluenesulfonic acid group Chemical class 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
- C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
- C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles 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 in position 2
-
- 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
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
- C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/68—Benzothiazoles 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 in position 2
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pulmonology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Immunology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Description
150503
Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af hidtil ukendte benzoxazol- eller benzthiazol-2-carboxylsyreestere eller farmaceutiskacceptable syreadditions- eller aminosyre- eller glucu-5 ronsyrekonjugatsalte heraf med den i krav l's indledning angivne formel I. Fremgangsmåden er ejendommelig ved det i krav l's kendetegnende del angivne. De omhand-léde forbindelser er lægemidler med kraftig antialler-gisk virkning.
10 Benzoxazol-2-carboxylsyreestere er tidligere blevet be skrevet i litteraturen. F.eks. er estere, hvori den es-terificeren.de: gruppe er alkyl, phenyl, chlorphenyl og allyl, herunder sådanne estere, der er substitueret i benzenoid-ringen med grupper som f.eks. alkoxy, nitro, 15 alkyl, phenyl og chlor, blevet beskrevet i Lieb. Ann.
Chem. 733, 70-87 (1970): ibid 749, 1-11 (1971); Chem.
Soc. Chem. Comm. 2ji, 962-3 (1975). Disse forbindelser udviser antiallergisk virkning.
Det har nu vist sig, at de omhandlede forbindelser har 20 en overraskende kraftigere antiallergisk virkning end de kendte forbindelser.
De ved analogifremgangsmåden fremstillede estere har formlen [0]Γ^οοκ 1 *2 150508 2 hvori X betegner S eller 0; og R£ uafhængigt betegner hydrogen, C^-C^alkyl, hydroxyl, C^-C^alkoxy, halogen, nitro eller trifluormethyl, 5 forudsat at R·^ og R£ ikke begge kan betegne hydrogen i benzoxazolforbindelserne, og R betegner (C. - C,)alkoxy (C2 - Cg)alkyl, eller er farmaceutisk acceptable syreadditions- eller aminosyre- eller glucuronsyrekonjugatsalte heraf.
10 De omhandlede benzoxazol- og benzthiazolcarboxylsyre-estere fremstilles ved at omsætte den tilsvarende 3-halogen-benzoxazin-2-on eller den svovlanaloge deraf med formlen II
"gcC
R2 15 hvori X, R^ og R^ betegner den ovenfor angivne, og Hal betegner halogen fortrinsvis chlor, med en alkohol med formlen ROH, hvori R betegner det tidligere angivne.
Alternativt kan de omhandlede estere fremstilles ud fra den tilsvarende benzoxazol- eller benzthiazol-2-carbo-20 xylsyre eller et acylerende derivat af syren som f.eks. den lavere alkyl (l-5C)-ester, det blandede anhydrid, carbodiimidet eller halogenidet (fortrinsvis chloridet) med en alkohol med formlen ROH.
150508 3
De omhandlede benzthiazolestere er naturligvis de svovlanaloge af benzoxazolestrene.
5 Forbindelserne med formlen II, hvori X er 0, og Hal er chlor, fremstilles ud fra de tilsvarende.benzoxa-zindioner med formlen:
. H
ved omsætning med thionylchlorid til opnåelse af chlor-derivatet R2 10 Benzthiazolestrene fremstilles på analog måde.
De omhandlede estre fremstilles fortrinsvis ved esterombytning under anvendelse af ROH sammen med den tilsvarende lavere alkylester f.eks. methyl- eller ethylesteren.
15 De heterocycliske forbindelser, der anvendes som udgangs materialer i de foranstående præparative fremgangsmåder, 150508 4 er velkendte forbindelser eller kan fremstilles ved velkendte metoder.
Alkoholerne med formlen ROH, der anvendes ved disse fremstillingsmetoder, er de, hvori R betegner det tidligere 5 definerede.
De omhandlede heterocycliske estere er terapeutisk værdifulde som sådan eller de kan anvendes i form af farmaceutisk acceptable salte med en hel række uorganiske og organiske syrer. Saltene med terapeutisk acceptable 10 syrer er naturligvis værdifulde ved anvendelse i præ parater, hvor der ønskes vandopløselighed.
Farmaceutisk acceptable syreadditionssalte omfatter salte af mineralsyrer som f.eks. saltsyre, hydrogeniodidsyre, hydrogenbromidsyre, phosphorsyre, methaphosphorsyre, sal-15 petersyre og svovlsyre såvel som salte af organiske sy rer som f.eks. vinsyre, eddikesyre, citronsyre, æblesyre, benzoesyre, glycolsyre, gluconsyre, gulonsyre, ravsyre, arylsulfonsyré som f.eks. p-toluensulfonsyrer.
De omhandlede forbindelser danner farmaceutisk acceptable 20. konjugater med aminosyrer og glucuronsyrer. F. eks.
kan konjugater dannes med glucuronsyre f. eks. Ø-glucuron-syren såvel som aminosyrer specielt a-aminosyrer som f. eks. glycin, lycin, cystin, methionin, asparaginsyre og alanin.
25 Som terapeutisk virkende midler er de omhandlede hetero cycliske estere særligt værdifulde som antiallergiske midler, idet. de virker via hæmningen af mediatorfrigørelsen. Disse estere er aktive peroralt ved det passivt cu-tane anafylaksiforsøg (PCA); og de hæmmer histaminfrigø-30 reisen fra passivt sensibiliserede rottemastceller.
150508 5 Følgende eksempler illustrerer opfindelsen nærmere.
EKSEMPEL 1 A. 3,6-dichlorbenzoxazin-2-on V(ch2)2-o-ch2ch3
Cl 5 En blanding af 80,5 g 6-chlor-benzoxazin-2,3-dion, 40 ml thionylchlorid, 15 ml dimethylformamid (DMF) og 1,5 liter toluen opvarmedes med tilbagesvaling og under omrøring i 5 timer. Reaktionsblandingen filtreredes varmt, og filtratet koncentreredes til en gummi. Omkrystalli-10 sation med toluen gav forbindelsen med smeltepunkt 136-138 °C.
B. 2-ethoxyethyl-5-chlorbenzoxazol-2-carboxylat V(ch2)2-o-ck2ch3
Cl
En blanding af 36 g af forbindelsen fra afsnit A og 13,7 15 g Na^COj i 250 ml ethoxyethanol opvarmedes i . 14 timer ved 70°.C. Opløsningsmidlet afdampedes, og remanensen ekstraheredes med ethylacetat (200 ml). Opløsningen vaskedes med vand, der torredes og affarvedes med aktivt kul, og herefter inddampedes der til tørhed. Remanensen 20 omkrystalliseredes med ethylacetat-hexan, hvorved der. op- håedes et krystallinsk produkt med smeltepunkt 53 -54° C.
150508 6 EKSEMPEL 2
Under anvendelse af fremgangsmåden fra eksempel 1 og med de passende udgangsmaterialer fremstilledes følgende benzoxazol-2-carboxylater: 5 2-ethoxyethyl-6-methylbenzoxazol-2-carboxylat (snip. 65-67 °C) 2-ethoxyethyl-5-nitrobenzoxazol-2-carboxylat (smp. 90-92 °C) 2-ethoxyethyl-5,6-dimethoxybenzoxazol-2-carboxylat lø (smp. 91-93 °C) 2-ethoxyethylbenzothiazol-2-carboxylat (smp. 55-57 °C).
De omhandlede forbindelser udviser kraftig virkning ved hæmningen af dannelsen af blaser, dersom de undersøges 15 i overensstemmelse med det passivt cutane anafylaksi- forsøg hos rotter (PCA) således som beskrevet af I. Mo-ta, Life Sciences, _7, 465 (1965) og Z. Ovary, et al-,
Proceedings of Society of Experimental Biology and Medicine, 81, 584 (1952).
20 Herudover udviser de omhandlede forbindelser kraftig virkning som hæmmere for histaminfrigørelsen fra passivt sensibiliserede rottemastceller ved det forsøg, der er beskrevet af E. Kusner, et al., Journal of Pharmacology and Experimental Therapeutics, Vol 184, nr. 1, p. 41-46 25 (1973).
Undersøgelsesresultaterne af de omhandlede forbindelser sammenlignedes med de resultater, der opnåedes, dersom flere kendte alkylestere af benzoxazol-2-carboxylsyre afprøvedes på samme måde. Skønt de kendte estere og de 3ø omhandlede estere var næsten lige virkningsfulde til at 150508 7 hæmme blasedannelsen ved PCA-forsøget, viste det sig overraskende, at de omhandlede estere var indtil 200 gange mere effektive end de kendte estere til at hæmme histaminfrigørelsen fra rottemastceller. Resultaterne af denne sam-5 menligning for nogle af de omhandlede estere er opsumme ret i følgende oversigt, hvori resultaterne er angivet som RMC I^g-værdier, dvs. den dosis i yumol, der kræves for at opnå en 50?0's reduktion af histaminfrigørelsen i forhold til kontrollerne.
IC 31 //—coor
10 Forbindelse. RMC
nr. X R 12 (I um) PCA
1 0 kendt CH3 Η H 140 2 0 kendt C^ Η H 100 15 3 0 kendt C η Η H 1000 4 9 4 0 ny (CH2)20Et 6-CH^ H 5 ED5()=25mg/kg (po) 5 0 ny (CH2)20Et 5-N02 H 30 44X 50mg/kg (po) 6 0 ny (CH2)20Et 5-0CH3 6-0CH3 10 59* 50mg/kg (po) 20 7 0 ny (CH2)20Et 5-C1 H 15 ED5(J=13mg/kg (po)
Claims (3)
150503 Pat. entkrav:
1. Analogifremgangsmåde til fremstilling af benzoxazol-eller benzthiazol-2-carboxylsyreestere med den almene formel R1 C0°R R2 ' 5 hvori X betegner S eller 0; og R2 uafhængigt betegner hydrogen, - C^-alkyl, hydroxy, C, - C,-alkoxy, halogen, nitro eller trifluormethyl, for-udsat, at R^ og R2 ikke begge betegner hydrogen i benzoxazol-2o forbindelserne, og R betegner (C^ - C^alkoxytC^ - C6)alkyl, eller farmaceutisk acceptable syreadditions- eller aminosyre-eller glucuronsyrekonjugatsalte heraf, kendetegnet ved, at man a) omsætter den tilsvarende 3-halogenbenz-oxazin-2-on eller -benzthiazin-2-on med den almene formel Wr'
15 A 11 H hvor R^, R2 og X er som ovenfor, og Hal betegner halogent fortrinsvis chlor, med en alkohol med den almene formel ROH, hvori R betegner det ovenfor definerede, eller b) omsætter den tilsvarende benzoxazol- eller benzthiazol-2-
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US14907980 | 1980-05-12 | ||
| US06/149,079 US4298742A (en) | 1980-05-12 | 1980-05-12 | Esters of benzoxa(thia)zole-2-carboxylic acids |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK208981A DK208981A (da) | 1981-11-13 |
| DK150508B true DK150508B (da) | 1987-03-16 |
| DK150508C DK150508C (da) | 1987-12-21 |
Family
ID=22528721
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK208981A DK150508C (da) | 1980-05-12 | 1981-05-12 | Analogifremgangsmaade til fremstilling af benzoxazol- eller benzthiazol-2-carboxylsyreestere eller farmaceutisk acceptable syreadditionssalte eller aminosyre- eller glucuronsyrekonjugatsalte heraf |
Country Status (12)
| Country | Link |
|---|---|
| US (1) | US4298742A (da) |
| EP (1) | EP0039919B1 (da) |
| JP (1) | JPS577474A (da) |
| AU (1) | AU544451B2 (da) |
| CA (1) | CA1182821A (da) |
| DE (1) | DE3161764D1 (da) |
| DK (1) | DK150508C (da) |
| ES (1) | ES8203357A1 (da) |
| FI (1) | FI72514C (da) |
| NO (1) | NO155663C (da) |
| NZ (1) | NZ197073A (da) |
| ZA (1) | ZA813147B (da) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4440935A (en) * | 1981-07-20 | 1984-04-03 | Usv Pharmaceutical Corporation | Bicycloimidazoles |
| US4368201A (en) * | 1981-07-20 | 1983-01-11 | Usv Pharmaceutical Corporation | Tetrahydronaphthoxazoles |
| US4405633A (en) * | 1982-03-01 | 1983-09-20 | Usv Pharmaceutical Corporation | Method of treatment of asthma |
| US4490373A (en) * | 1983-05-20 | 1984-12-25 | Usv Pharmaceutical Corporation | Method of treating asthma |
| US4620010A (en) * | 1984-03-29 | 1986-10-28 | Usv Pharmaceutical Corp. | Process for preparing carboalkoxy substituted benzoxazole compounds |
| RU2290420C1 (ru) * | 2005-04-19 | 2006-12-27 | Институт проблем переработки углеводородов Сибирского отделения Российской Академии Наук (ИППУ СО РАН) | Способ производства технического углерода (сажи) |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE793341A (fr) * | 1971-12-27 | 1973-06-27 | Henkel & Cie Gmbh | Anti-inflamatoires pour compositions cosmetiques |
-
1980
- 1980-05-12 US US06/149,079 patent/US4298742A/en not_active Expired - Lifetime
-
1981
- 1981-05-07 DE DE8181103497T patent/DE3161764D1/de not_active Expired
- 1981-05-07 EP EP81103497A patent/EP0039919B1/en not_active Expired
- 1981-05-08 CA CA000377169A patent/CA1182821A/en not_active Expired
- 1981-05-11 NO NO811600A patent/NO155663C/no unknown
- 1981-05-11 AU AU70452/81A patent/AU544451B2/en not_active Ceased
- 1981-05-12 ES ES502467A patent/ES8203357A1/es not_active Expired
- 1981-05-12 DK DK208981A patent/DK150508C/da not_active IP Right Cessation
- 1981-05-12 FI FI811448A patent/FI72514C/fi not_active IP Right Cessation
- 1981-05-12 NZ NZ197073A patent/NZ197073A/en unknown
- 1981-05-12 ZA ZA00813147A patent/ZA813147B/xx unknown
- 1981-05-12 JP JP7024281A patent/JPS577474A/ja active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| US4298742A (en) | 1981-11-03 |
| FI811448L (fi) | 1981-11-13 |
| DE3161764D1 (en) | 1984-02-02 |
| JPH0124793B2 (da) | 1989-05-15 |
| CA1182821A (en) | 1985-02-19 |
| ES502467A0 (es) | 1982-04-01 |
| NO155663B (no) | 1987-01-26 |
| ES8203357A1 (es) | 1982-04-01 |
| EP0039919B1 (en) | 1983-12-28 |
| NO155663C (no) | 1987-05-06 |
| FI72514C (fi) | 1987-06-08 |
| DK150508C (da) | 1987-12-21 |
| JPS577474A (en) | 1982-01-14 |
| AU7045281A (en) | 1981-11-26 |
| AU544451B2 (en) | 1985-05-30 |
| FI72514B (fi) | 1987-02-27 |
| ZA813147B (en) | 1982-04-28 |
| NO811600L (no) | 1981-11-13 |
| DK208981A (da) | 1981-11-13 |
| NZ197073A (en) | 1984-07-06 |
| EP0039919A1 (en) | 1981-11-18 |
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| Date | Code | Title | Description |
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| PBP | Patent lapsed |