NO147561B - ANALOGUE PROCEDURES FOR THE PREPARATION OF 6,11-DIHYDRO-11-OXODODIBENZ (B, E) OCSEPINALKAN ACIDS, ESTERS AND SALTS THEREOF - Google Patents
ANALOGUE PROCEDURES FOR THE PREPARATION OF 6,11-DIHYDRO-11-OXODODIBENZ (B, E) OCSEPINALKAN ACIDS, ESTERS AND SALTS THEREOF Download PDFInfo
- Publication number
- NO147561B NO147561B NO762647A NO762647A NO147561B NO 147561 B NO147561 B NO 147561B NO 762647 A NO762647 A NO 762647A NO 762647 A NO762647 A NO 762647A NO 147561 B NO147561 B NO 147561B
- Authority
- NO
- Norway
- Prior art keywords
- dihydro
- acid
- oxepin
- oxodibenz
- carbon atoms
- Prior art date
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- 239000002253 acid Substances 0.000 title claims description 16
- 238000000034 method Methods 0.000 title claims description 13
- 150000002148 esters Chemical class 0.000 title description 3
- 150000007513 acids Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 24
- 229910052739 hydrogen Inorganic materials 0.000 claims description 23
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- -1 11-oxodibenz[b,e]oxepin-2-yl Chemical group 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 6
- 125000005907 alkyl ester group Chemical group 0.000 claims description 5
- 238000005727 Friedel-Crafts reaction Methods 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- 239000000243 solution Substances 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 229910052799 carbon Inorganic materials 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- 230000003110 anti-inflammatory effect Effects 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- 150000004820 halides Chemical class 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- VZGUTBFEENNBKX-UHFFFAOYSA-N 4-(11-oxo-6h-benzo[c][1]benzoxepin-2-yl)butanoic acid Chemical compound O1CC2=CC=CC=C2C(=O)C2=CC(CCCC(=O)O)=CC=C21 VZGUTBFEENNBKX-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-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
- 241000700159 Rattus Species 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 3
- 229920000137 polyphosphoric acid Polymers 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 235000009518 sodium iodide Nutrition 0.000 description 3
- 210000002784 stomach Anatomy 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- IYAGXKKFTZCSQY-UHFFFAOYSA-N 2-[[4-(5-carboxypentyl)phenoxy]methyl]benzoic acid Chemical compound C1=CC(CCCCCC(=O)O)=CC=C1OCC1=CC=CC=C1C(O)=O IYAGXKKFTZCSQY-UHFFFAOYSA-N 0.000 description 2
- QCKOKXIFLRLNLH-UHFFFAOYSA-N 2-[[4-(7-carboxyheptyl)phenoxy]methyl]benzoic acid Chemical compound C1=CC(CCCCCCCC(=O)O)=CC=C1OCC1=CC=CC=C1C(O)=O QCKOKXIFLRLNLH-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 150000001242 acetic acid derivatives Chemical class 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 150000005690 diesters Chemical class 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 230000007794 irritation Effects 0.000 description 2
- 125000004323 oxepin-2-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C(*)O1 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 231100001274 therapeutic index Toxicity 0.000 description 2
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 1
- BTEWWBNTAGZPIU-UHFFFAOYSA-N 2-(11-oxo-6h-benzo[c][1]benzoxepin-1-yl)acetic acid Chemical class O1CC2=CC=CC=C2C(=O)C2=C1C=CC=C2CC(=O)O BTEWWBNTAGZPIU-UHFFFAOYSA-N 0.000 description 1
- INRYLPJHQJFFKB-UHFFFAOYSA-N 2-[[4-(3-carboxypropyl)phenoxy]methyl]benzoic acid Chemical compound C1=CC(CCCC(=O)O)=CC=C1OCC1=CC=CC=C1C(O)=O INRYLPJHQJFFKB-UHFFFAOYSA-N 0.000 description 1
- QFLJAOXZEIAJCI-UHFFFAOYSA-N 2-[[4-(5-carboxypentyl)phenoxy]methyl]-4-methoxybenzoic acid Chemical compound C(=O)(O)C1=C(COC2=CC=C(C=C2)CCCCCC(=O)O)C=C(C=C1)OC QFLJAOXZEIAJCI-UHFFFAOYSA-N 0.000 description 1
- ITXHHGARWFFIQS-UHFFFAOYSA-N 2-[[4-(7-carboxyheptyl)phenoxy]methyl]-4-chlorobenzoic acid Chemical compound C(=O)(O)C1=C(COC2=CC=C(C=C2)CCCCCCCC(=O)O)C=C(C=C1)Cl ITXHHGARWFFIQS-UHFFFAOYSA-N 0.000 description 1
- WKGFDLJGSLFCFW-UHFFFAOYSA-N 3-(11-oxo-6h-benzo[c][1]benzoxepin-2-yl)propanoic acid Chemical compound O1CC2=CC=CC=C2C(=O)C2=CC(CCC(=O)O)=CC=C21 WKGFDLJGSLFCFW-UHFFFAOYSA-N 0.000 description 1
- YNXNSTXMKAHDHZ-UHFFFAOYSA-N 4-(10-methyl-11-oxo-6H-benzo[c][1]benzoxepin-2-yl)butanoic acid Chemical compound CC1=CC=CC2=C1C(C1=C(OC2)C=CC(=C1)CCCC(=O)O)=O YNXNSTXMKAHDHZ-UHFFFAOYSA-N 0.000 description 1
- BMWYQRNHZXDPSN-UHFFFAOYSA-N 4-(9-fluoro-11-oxo-6H-benzo[c][1]benzoxepin-2-yl)butanoic acid Chemical compound FC=1C=CC2=C(C(C3=C(OC2)C=CC(=C3)CCCC(=O)O)=O)C1 BMWYQRNHZXDPSN-UHFFFAOYSA-N 0.000 description 1
- DMSJXWKXCAUBHC-UHFFFAOYSA-N 6-(11-oxo-6h-benzo[c][1]benzoxepin-2-yl)hexanoic acid Chemical compound O1CC2=CC=CC=C2C(=O)C2=CC(CCCCCC(=O)O)=CC=C21 DMSJXWKXCAUBHC-UHFFFAOYSA-N 0.000 description 1
- SBUAPJCFLFRBSF-UHFFFAOYSA-N 8-(11-oxo-6h-benzo[c][1]benzoxepin-2-yl)octanoic acid Chemical compound O1CC2=CC=CC=C2C(=O)C2=CC(CCCCCCCC(=O)O)=CC=C21 SBUAPJCFLFRBSF-UHFFFAOYSA-N 0.000 description 1
- SVWCNMUVENBTPF-UHFFFAOYSA-N 8-(8-chloro-11-oxo-6H-benzo[c][1]benzoxepin-2-yl)octanoic acid Chemical compound ClC1=CC2=C(C(C3=C(OC2)C=CC(=C3)CCCCCCCC(=O)O)=O)C=C1 SVWCNMUVENBTPF-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- LTEOHQLUJPPHMP-UHFFFAOYSA-N C(C)O.[P] Chemical compound C(C)O.[P] LTEOHQLUJPPHMP-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- OAWCGHRWFLZBQC-UHFFFAOYSA-N ClC1=CC2=C(C(C3=C(OC2)C=CC(=C3)CCCC(=O)O)=O)C=C1 Chemical compound ClC1=CC2=C(C(C3=C(OC2)C=CC(=C3)CCCC(=O)O)=O)C=C1 OAWCGHRWFLZBQC-UHFFFAOYSA-N 0.000 description 1
- 206010053155 Epigastric discomfort Diseases 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 1
- 238000011887 Necropsy Methods 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000001760 anti-analgesic effect Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 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
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 235000010418 carrageenan Nutrition 0.000 description 1
- 239000000679 carrageenan Substances 0.000 description 1
- 229940113118 carrageenan Drugs 0.000 description 1
- 229920001525 carrageenan Polymers 0.000 description 1
- 229920001429 chelating resin Polymers 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000013256 coordination polymer Substances 0.000 description 1
- 229960002887 deanol Drugs 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 239000012972 dimethylethanolamine Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000003628 erosive effect Effects 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- URBBRTFGJCAELL-UHFFFAOYSA-N ethyl 4-(4-hydroxyphenyl)butanoate Chemical compound CCOC(=O)CCCC1=CC=C(O)C=C1 URBBRTFGJCAELL-UHFFFAOYSA-N 0.000 description 1
- NJAFVYVDZQYPMU-UHFFFAOYSA-N ethyl 6-(4-hydroxyphenyl)hexanoate Chemical compound CCOC(=O)CCCCCC1=CC=C(O)C=C1 NJAFVYVDZQYPMU-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 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
- 239000007903 gelatin capsule Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000001119 stannous chloride Substances 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
- C07D313/02—Seven-membered rings
- C07D313/06—Seven-membered rings condensed with carbocyclic rings or ring systems
- C07D313/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
- C07D313/12—[b,e]-condensed
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pain & Pain Management (AREA)
- Public Health (AREA)
- Rheumatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyrane Compounds (AREA)
Description
Oppfinnelsen vedrører analogifremgangsmåter for fremstilling av w-(6,11-dihydro-ll-oksodibenz[b,e]oksepin-2-yl)alkan-syrer og estere samt farmasøytisk tålbare salter herav med antiinflammatorisk virkning. I tillegg har forbindelsene fremstilt ifølge oppfinnelsen vist analgetisk effekt. The invention relates to analogous methods for the production of w-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)alkane acids and esters as well as pharmaceutically acceptable salts thereof with anti-inflammatory action. In addition, the compounds produced according to the invention have shown an analgesic effect.
Forbindelsene fremstilt ifølge oppfinnelsen er nye. 6,11-dihydro-ll-oksodibenz [b,e]oksepin-eddiksyrer som har antiinflammatorisk aktivitet er omtalt i norsk patent nr. 142.397. Imidlertid 3-(6,11-dihydro-ll-oksodibenz[b,e]oksepin-2-yl) propion-syre, angitt i ovennevnte patent, viste ingen antiinflammatorisk eller analgetisk effekt. Det er derfor uventet at forbindelsene fremstilt ifølge oppfinnelsen, i motsetning til. propionsvreanalogen^ irtø_vex_ al i k ak.tj_vi.te.t-.. The compounds produced according to the invention are new. 6,11-dihydro-11-oxodibenz [b,e]oxepin-acetic acids which have anti-inflammatory activity are discussed in Norwegian patent no. 142,397. However, 3-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)propionic acid, disclosed in the above patent, showed no anti-inflammatory or analgesic effect. It is therefore unexpected that the compounds produced according to the invention, in contrast to propionsvreanalogen^ irtø_vex_ al i k ak.tj_vi.te.t-..
Forbindelsene fremstilt ifølge oppfinnelsen har følgende The compounds produced according to the invention have the following
formel: formula:
hvor R betyr hydrogen eller alkyl med fra 1-4 karbonatomer, R' er hydrogen, halogen, alkoksy med fra 1-4 karbonatomer, alkyl med fra 1-4 karbonatomer eller trifluormetyl og n kan variere fra 1 til 3. Saltene herav fremstilt med fysiologisk tålbare baser er også omfattet. De foretrukkede forbindelser er de hvori R betyr hydrogen, R' er hydrogen og n er 1, 2 eller 3. where R means hydrogen or alkyl with from 1-4 carbon atoms, R' is hydrogen, halogen, alkoxy with from 1-4 carbon atoms, alkyl with from 1-4 carbon atoms or trifluoromethyl and n can vary from 1 to 3. The salts thereof prepared with physiologically tolerable bases are also covered. The preferred compounds are those in which R is hydrogen, R' is hydrogen and n is 1, 2 or 3.
Fremgangsmåten ifølge oppfinnelsen er karakterisert ved at The method according to the invention is characterized in that
a) en forbindelse med formel a) a compound with formula
hvori R<1> og n har ovennevnte betydning, cykliseres i nærvær av et vanntiltrekkende medium eller wherein R<1> and n have the above meaning, is cyclized in the presence of a water-attracting medium or
b) en forbindelse med formel b) a compound of formula
hvori R' og n har ovennevnte betydning og Z betyr halogen, in which R' and n have the above meaning and Z means halogen,
cykliseres under Friedel-Crafts-betingelser, og det dannede oi- (6 ,11-dihydro-ll-oksodibenz [b,e j-oksepin-2-yl) -alkansyre-halogenid hydrolyseres, og is cyclized under Friedel-Crafts conditions, and the formed oi-(6,11-dihydro-11-oxodibenz[b,e j-oxepin-2-yl)-alkanoic acid halide is hydrolyzed, and
eventuelt forestres en. erholdt u>- ( 6_,,_J_^djJiydro_-Ll--ak_3^ possibly one is esterified. obtained u>- ( 6_,,_J_^djJiydro_-Ll--ak_3^
[b,e]-oksepin-2-yl)alkansyre til en alkylester med 1-4 karbonatomer i alkylgruppen eller eventuelt omsettes w-{6,11-dihydro-ll-oksodibenz[b-,e ]oksepin-2-yl) alkansyren med en fysiologisk tålbar base for saltdannelse. [b,e]-oxepin-2-yl)alkanoic acid to an alkyl ester with 1-4 carbon atoms in the alkyl group or optionally react w-{6,11-dihydro-11-oxodibenz[b-,e]oxepin-2-yl) the alkanoic acid with a physiologically tolerable base for salt formation.
En alkylester av hydroksyfenylalkan-syre med formel: An alkyl ester of hydroxyphenylalkanoic acid with the formula:
hvori m er et helt tall fra 1-5, fremstilles i henhold til kjente fremgangsmåter. En foretrukken fremgangsmåte er å omsette w-(hydroksyfenyl)alkan-syre med en alkohol i nærvær av en syre som svovelsyre, saltsyre eller p-toluensulfon-syre ved en temperatur fra 50°C til alkoholens kokepunkt i fra 15 minutter til 20 timer. in which m is an integer from 1-5, is produced according to known methods. A preferred method is to react w-(hydroxyphenyl)alkanoic acid with an alcohol in the presence of an acid such as sulfuric acid, hydrochloric acid or p-toluenesulfonic acid at a temperature from 50°C to the boiling point of the alcohol for from 15 minutes to 20 hours.
En alkylester med formel: An alkyl ester of formula:
hvori Z betyr alkyl med fra 1-4 karbonatomer, omsettes med en alkylester av hydroksyfenylalkan-syre med formel: hvori m er et helt tall fra 1-5, i nærvær av et egnet opp-løsningsmiddel, som aceton, butanon, etanol eller dimetyl-formamid, og en syreopptager, som kaliumkarbonat eller natriumetoksyd, i nærvær eller fravær av en reaksjonsinitiator som natriumiodid, ved en temperatur fra 0 - 120°C i en tid fra 5 minutter til 20 timer for å tilveiebringe en diester av en substituert karboksybenzyloksyfenylalkan-syre med formel: wherein Z means alkyl with from 1-4 carbon atoms, is reacted with an alkyl ester of hydroxyphenylalkanoic acid of formula: in which m is an integer from 1-5, in the presence of a suitable solvent, such as acetone, butanone, ethanol or dimethyl -formamide, and an acid scavenger, such as potassium carbonate or sodium ethoxide, in the presence or absence of a reaction initiator such as sodium iodide, at a temperature from 0 - 120°C for a time from 5 minutes to 20 hours to provide a diester of a substituted carboxybenzyloxyphenylalkane- acid with formula:
Diesteren forsåpes ved å gi en dikarboksyl-syre med formel: The diester is saponified by giving a dicarboxylic acid with the formula:
fortrinnsvis ved anvendelse av en base, som natrium- eller kaliumhydroksyd i et oppløsningsmiddel, som en etanol-vann-blanding, i en tid fra 15 minutter til 2 4 timer ved en temperatur fra værelsetemperatur til 125°C. preferably using a base, such as sodium or potassium hydroxide in a solvent, such as an ethanol-water mixture, for a time from 15 minutes to 24 hours at a temperature from room temperature to 125°C.
Dikarboksylsyren cykliseres ved behandling med et dehydrerende medium, som en polyfosforsyre, etanol-fosforpentoksyd, svovelsyre eller fosforpentaklorid, med eller uten et oppløsnings-middel, som tetrametylensulfon eller eddiksyre, ved en temperatur fra 50 - 125°C og i en tid fra 15 minutter til 12 timer for å danne en forbindelse hvori R betyr hydrogen. The dicarboxylic acid is cyclized by treatment with a dehydrating medium, such as a polyphosphoric acid, ethanol-phosphorus pentoxide, sulfuric acid or phosphorus pentachloride, with or without a solvent, such as tetramethylene sulfone or acetic acid, at a temperature from 50 - 125°C and for a time from 15 minutes to 12 hours to form a compound wherein R is hydrogen.
Eh dikarboksylsyre ifølge fremgangsmåten A, trinn 2 behandles med en tilstrekkelig mengde av et stoff, som tionyi-halogenid eller fosforpentahalogenid, i nærvær eller fravær av et opp-løsningsmiddel, ved en temperatur fra værelsetemperatur til kokepunktet for reaksjonsblandingen i fra 15 minutter til 4 timer for å danne disyrehalogenidet med formel: Eh dicarboxylic acid according to method A, step 2 is treated with a sufficient amount of a substance, such as thionyl halide or phosphorus pentahalide, in the presence or absence of a solvent, at a temperature from room temperature to the boiling point of the reaction mixture for from 15 minutes to 4 hours to form the diacid halide of formula:
hvor Z betyr klor, brom eller fluor. where Z means chlorine, bromine or fluorine.
Disyrehalogenidet cykliseres enten under standard eller modifiserte Friedel-Crafts-betingelser og hydrolyseres deretter for å danne en forbindelse ifølge oppfinnelsen hvor R betyr hydrogen. Modifiserte Friedel-Crafts-betingelser betyr termisk cyklisering som utføres ved oppvarming av et disyre-halogenid fra 10 minutter til 24 timer ved en temperatur fra 80 - 125°C. The diacid halide is cyclized either under standard or modified Friedel-Crafts conditions and then hydrolyzed to form a compound of the invention where R is hydrogen. Modified Friedel-Crafts conditions mean thermal cyclization which is carried out by heating a diacid halide from 10 minutes to 24 hours at a temperature from 80 - 125°C.
En forbindelse hvori R betyr hydrogen, fremstilt ved enten fremgangsmåten A eller B forestres for å danne et tilsvarende ester hvori R betyr alkyl med fra 1-4 karbonatomer. A compound in which R is hydrogen, prepared by either process A or B is esterified to form a corresponding ester in which R is alkyl with from 1-4 carbon atoms.
En foretrukket fremgangsmåte er å omsette en u>-(6,11-dihydro-ll-oksodibenz [b,e]oksepin-2-yl)alkan-syre med en alkohol i nærvær av en syre, som svovelsyre, saltsyre eller p-toluen-sulfonsyre ved en temperatur fra 50°C til alkoholens kokepunkt i fra 15 minutter til 20 timer. A preferred method is to react a u>-(6,11-dihydro-11-oxodibenz [b,e]oxepin-2-yl)alkanoic acid with an alcohol in the presence of an acid, such as sulfuric acid, hydrochloric acid or p- toluene-sulfonic acid at a temperature from 50°C to the boiling point of the alcohol for from 15 minutes to 20 hours.
Som velkjent står reaksjonstiden i forhold hil reaksjons-temperaturene, således at kortere reaksjonstid kreves når det benyttes høyere temperaturer. As is well known, the reaction time is proportional to the reaction temperatures, so that a shorter reaction time is required when higher temperatures are used.
Forbindelsene fremstilt ifølge oppfinnelsen er anvendelige som antiinflammatoriske stoffer på grunn av deres evne til å undertrykke inflammasjon hos pattedyr fra 0,1 til 100 mg/kg legemsvekt. The compounds produced according to the invention are useful as anti-inflammatory substances due to their ability to suppress inflammation in mammals from 0.1 to 100 mg/kg body weight.
Mens forbindelsene fremstilt ifølge oppfinnelsen og de kjente eddiksyrederivater utøver omtrent samme antiinflammatoriske aktivitet, viser forbindelsene fremstilt ifølge oppfinnelsen en lavere virkning med maveirritasjon, en uønsket bivirkning som under tiden er forbundet med antiinflammatorisk aktivitet'. Denne effekt som uttrykkes som en høyere terapeutisk indeks (forholdet mellom den nødvendige dose for å frembringe maveirritasjon og dosen nødvendig for å danne antiinflammatoriske effekter) for forbindelsene i forhold' til eddiksyrederivatene, viser: _ove__leÆ[eriheta__ asr ælka-iisy-r.e-irer-.f reais:L"iTl-tr i±.ø_Lge oppfinn- • eisen i forhold til de kjente forbindelser. While the compounds produced according to the invention and the known acetic acid derivatives exert approximately the same anti-inflammatory activity, the compounds produced according to the invention show a lower effect with stomach irritation, an unwanted side effect which is currently associated with anti-inflammatory activity'. This effect, which is expressed as a higher therapeutic index (the ratio between the dose necessary to produce gastric irritation and the dose necessary to produce anti-inflammatory effects) for the compounds compared to the acetic acid derivatives, shows: _ove__leÆ[eriheta__ asr ælka-iisy-r.e-irer- .f reais:L"iTl-tr i±.ø_Lge invent- • the ice in relation to the known compounds.
Den antiinflammatoriske virkning ble bestemt ved' hjelp av Carrageenan indusert rottepoteødem på rotter, maveirritasjon også på rotter etter oral administrering av forbindelsene og obdusering av dyrene for å undersøke maven for enkle eller multiple lesjoner (erosjon, mavesår eller perforering). The anti-inflammatory effect was determined by means of Carrageenan induced rat paw edema in rats, stomach irritation also in rats after oral administration of the compounds and necropsy of the animals to examine the stomach for single or multiple lesions (erosion, ulcer or perforation).
Resultatene er følgende: The results are the following:
Terapeutisk indeks for første forbindelse (kjent) er således 16,7, for annen forbindelse ifølge oppfinnelsen 21,6. Forbindelsene fremstilt ifølge oppfinnelsen er også anvendelige som analgetika på grunn av deres evne til å lindre smerte hos pattedyr i doser på 0,5 - 5 0 mg/kg legemsvekt. The therapeutic index for the first compound (known) is thus 16.7, for the second compound according to the invention 21.6. The compounds produced according to the invention are also useful as analgesics due to their ability to relieve pain in mammals in doses of 0.5 - 50 mg/kg body weight.
Forbindelsene fremstilt ifølge oppfinnelsen er verdifulle som farmasøytiske produkter og veterinærprodukter og kan admini-streres., til en pasient på en hvilken som helst vanlig måte som oralt, intramuskulært, intravenøst, subkutant eller intra-peritonealt. Den .foretrukne administrasjonsmåte er oral f.eks. med et inert fortynningsmiddel eller med en fordøyelig bærer eller i gelatinkapsler eller tabletter. The compounds of the invention are valuable as pharmaceuticals and veterinary products and can be administered to a patient by any conventional route such as orally, intramuscularly, intravenously, subcutaneously or intraperitoneally. The preferred method of administration is oral, e.g. with an inert diluent or with a digestible carrier or in gelatin capsules or tablets.
Fysiologisk tålbare baser anvendelige til å overføre forbindelsene ifølge oppfinnelsen til salter derav innbefatter uorganiske baser som inneholder kationsnatrium, -kalium eller -kalsium, såvel som forskjellige organiske baser som etanol-amin, die.tanolamin og dimetyletanolamin. Physiologically tolerable bases useful for converting the compounds according to the invention into salts thereof include inorganic bases containing sodium, potassium or calcium cations, as well as various organic bases such as ethanolamine, diethanolamine and dimethylethanolamine.
Oppfinnelsen skal forklares nærmere ved hjelp av noen eks-empler . The invention will be explained in more detail with the help of some examples.
Eksempel IA Example IA
En blanding av 28,8 g etyl 4-(4-hydroksyfenyl)-butyrat, 33,6 g etyl-a-brom-2-toluat, 81,7 g kaliumkarbonat, 580 ml 2-butanon og 1,8 g natriumiodid tilbakeløpt kokes i 17 timer. Reaksjonsblandingen avkjøles, filtreres, vaskes med eter, oppløsnings-middelet fjernes i vakuum og den resulterende gule olje opp-løses i eter. Den eteriske oppløsning vaskes suksessivt med vann, en 5% vandig natriumhydroksydoppløsning og vann, tørkes, filtreres og eteren fjernes i vakuum og etterlater en svak gul olje. Oljen oppløses i en blanding av kaliumhydroksyd, etanol og vann og kokes under tilbakeløp i 17 timer. Oppløsningen avkjøles, oppløsningsmiddelet fjernes i vakuum og det resulterende brune halvfaste stoff oppløses i vann og ekstraheres med eter. Oljen dannes ved å innstille pH av det vandige lag til 2 med konsentrert saltsyre og stivner ved henstand. Det faste stoff samles ved filtrering, vaskes med vann og omkrystalliseres fra acetonitril for å gi et svakt brunaktig stoff, smeltepunkt 149 - 150°C med 4-[4-(2-karboksybenzyloksy)-fenyl]-smørsyre. A mixture of 28.8 g of ethyl 4-(4-hydroxyphenyl)-butyrate, 33.6 g of ethyl α-bromo-2-toluate, 81.7 g of potassium carbonate, 580 ml of 2-butanone and 1.8 g of sodium iodide refluxed boiled for 17 hours. The reaction mixture is cooled, filtered, washed with ether, the solvent is removed in vacuo and the resulting yellow oil is dissolved in ether. The ethereal solution is washed successively with water, a 5% aqueous sodium hydroxide solution and water, dried, filtered and the ether removed in vacuo leaving a pale yellow oil. The oil is dissolved in a mixture of potassium hydroxide, ethanol and water and boiled under reflux for 17 hours. The solution is cooled, the solvent is removed in vacuo and the resulting brown semi-solid is dissolved in water and extracted with ether. The oil is formed by adjusting the pH of the aqueous layer to 2 with concentrated hydrochloric acid and solidifies on standing. The solid is collected by filtration, washed with water and recrystallized from acetonitrile to give a faint brownish substance, mp 149-150°C with 4-[4-(2-carboxybenzyloxy)-phenyl]-butyric acid.
Analyse: Analysis:
Beregnet for C,0H,o0_ : 68,77% C, 5,77% H Calculated for C,0H,o0_ : 68.77% C, 5.77% H
lo io D lol io D
Funnet: 68,52% C, 5,69% H. Found: 68.52% C, 5.69% H.
På tilsvarende måte fremstilles 4-[4-(2-karboksy-4-fluor-benzyloksy)-fenyl]smørsyre og 4-[2-(2-karboksy-3-metylbenzyl-oksy)fenyl]smørsyre. 4-[4-(2-carboxy-4-fluoro-benzyloxy)-phenyl]butyric acid and 4-[2-(2-carboxy-3-methylbenzyloxy)phenyl]butyric acid are prepared in a similar manner.
Eksempel IB Example IB
22,5 g polyfosforsyre settes til en oppløsning av 5.0 g 4- [4- (karhaksybenzyloksyj £e_xyl_Lsm0.r_3.yre.. i_ 1.7 ,5 ml iseddik, 22.5 g of polyphosphoric acid is added to a solution of 5.0 g of 4- [4- (carhexybenzyloxyj £e_xyl_Lsm0.r_3.yre.. in_ 1.7 ,5 ml of glacial acetic acid,
og oppløsningen omrøres ved 95°C i 3 timer. Oppløsningen avkjøles og vann tilsettes for å bevirke utfelling som opp-samles- ved filtrering. Omkrystallisering av benzen gir et hvitt fast stoff, smeltepunkt 116 - 118°C, med 4-(6,11-dihydro-ll-oksodibenz [b,e]oksepin-2-yl)smørsyre. and the solution is stirred at 95°C for 3 hours. The solution is cooled and water is added to cause precipitation which is collected by filtration. Recrystallization from benzene gives a white solid, mp 116 - 118°C, with 4-(6,11-dihydro-11-oxodibenz [b,e]oxepin-2-yl)butyric acid.
Analyse: Analysis:
Beregnet for C18H16°4 : 72,95% C, 5,44% H Calculated for C18H16°4 : 72.95% C, 5.44% H
Funnet: 72,79% C, 5,44% H. Found: 72.79% C, 5.44% H.
På tilsvarende måte fremstilles 4-(6,ll-dihydro-9-fluor-11-oksodibenz[b,e]oksepin-2-yl)smørsyre, 4-(6,ll-dihydro-8-klor-11-oksodibenz[b,e]oksepin-2-yl)smørsyre og 4-(6,11-dihydro-10-metyl-ll-oksodibenz[b,e]oksepin-2-yl)smørsyre. 4-(6,11-dihydro-9-fluoro-11-oxodibenz[b,e]oxepin-2-yl)butyric acid, 4-(6,11-dihydro-8-chloro-11-oxodibenz[ b,e]oxepin-2-yl)butyric acid and 4-(6,11-dihydro-10-methyl-11-oxodibenz[b,e]oxepin-2-yl)butyric acid.
Eksempel 2 Example 2
En blanding av 2,6 g 4-(6,11-dihydro-ll-oksodibenz[b,e]oksepin-2-yl) smørsyre (eksempel 1) og 0,8 g "Amberlite IR-120 H CP" A mixture of 2.6 g of 4-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)butyric acid (Example 1) and 0.8 g of "Amberlite IR-120 H CP"
i 25 ml metanol tilbakeløpt kokes i 16 timer, avkjøles, fortynnes med eter og filtreres. Filtratet vaskes suksessivt med en 5% vandig natriumhydroksydoppløsning og vann, tørkes, filtreres og konsentreres i vakuum og etterlatende et fast stoff som omkrystalliseres fra metanol for å gi hvite krystaller, smeltepunkt 83-85°C, med metyl 4-(6,11-dihydro-ll- in 25 ml of refluxing methanol is boiled for 16 hours, cooled, diluted with ether and filtered. The filtrate is washed successively with a 5% aqueous sodium hydroxide solution and water, dried, filtered and concentrated in vacuo leaving a solid which is recrystallized from methanol to give white crystals, mp 83-85°C, with methyl 4-(6,11- dihydro-II-
oksodibenz[b,e]oksepin-2-yl)butyrat. oxodibenz[b,e]oxepin-2-yl)butyrate.
Analyse: Analysis:
Beregnet for Ci9E18°4 : 73,53% C, 5,85.% H Calculated for Ci9E18°4 : 73.53% C, 5.85.% H
Funnet: 73,61% C, 5,92% H. Found: 73.61% C, 5.92% H.
Eksempel 3A Example 3A
En blanding av 25,0 g etyl 6-(4-hydroksyfenyl)-kaproat, kokepunkt 148 - 150°C (0,15 mm) fremstilt ifølge fremgangsmåte A,' 32,0 g etyl-a-brom-2-toluat, 72,0 g vannfri kaliumkarbonat og A mixture of 25.0 g ethyl 6-(4-hydroxyphenyl)-caproate, boiling point 148 - 150°C (0.15 mm) prepared according to method A,' 32.0 g ethyl-a-bromo-2-toluate, 72.0 g anhydrous potassium carbonate and
■1,0 g natriumiodid i 600 ml 2-butanon tilbakeløpt kokes i 16 timer. Blandingen avkjøles, filtreres, vaskes med eter og filtratet konsentreres i vakuum og etterlater en gul olje. Oljen oppløses i 100 ml 95% etanol og 20 ml vann og 23,5 g ■1.0 g sodium iodide in 600 ml 2-butanone refluxed is boiled for 16 hours. The mixture is cooled, filtered, washed with ether and the filtrate is concentrated in vacuo to leave a yellow oil. The oil is dissolved in 100 ml of 95% ethanol and 20 ml of water and 23.5 g
85% kaliumhydroksyd tilsettes, ag hl a nd i ng-en_.tilbakel.0pt... ko kes 85% potassium hydroxide is added, ag hl a nd i ng-en_.tilbakel.0pt... is boiled
i 14 timer. Oppløsningen konsentreres i vakuum og etterlater et halvfast stoff som oppløses i vann. Den vandige oppløsning vaskes- med" eter og- surgjøres med iskald konsentrert saltsyre for å gi et hvitt fast stoff som samles og omkrystalliseres fra acetonitril for å danne hvite krystaller, smeltepunkt 138 - 140°C, med 6-[4-(2-karboksybenzyloksy)fenyl]kapronsyre. Analyse: for 14 hours. The solution is concentrated in vacuo leaving a semi-solid which dissolves in water. The aqueous solution is washed with ether and acidified with ice-cold concentrated hydrochloric acid to give a white solid which is collected and recrystallized from acetonitrile to form white crystals, mp 138-140°C, with 6-[4-(2- carboxybenzyloxy)phenyl]caproic acid Analysis:
Beregnet for c2oH22°5 : 70'16% c'6'48% H Calculated for c2oH22°5 : 70'16% c'6'48% H
Funnet: 70,22% C, 6,57% H. Found: 70.22% C, 6.57% H.
På tilsvarende måte fremstilles 6-[4-(2-karboksy-4-trifluor-metylbenzyloksy)fenylJkapronsyre og 6-[4-(2-karboksy-5-met-oksybenzyloksy)fenyl]kapronsyre. 6-[4-(2-carboxy-4-trifluoromethylbenzyloxy)phenyl]caproic acid and 6-[4-(2-carboxy-5-methoxybenzyloxy)phenyl]caproic acid are prepared in a similar manner.
Eksempel 3B Example 3B
8,8 g fosforpentaklorid settes til et isbad avkjølt oppløsning av 7,0 g 6-[4-(2-karboksybenzyloksy)fenyl]kapronsyre i 80 ml benzen. Etter at fosforpentaklorid er oppløst, fjernes isbadet og den resulterende gulaktige oppløsning omrøres i 4 timer og benzen fjernes i vakuum ved 80°C og etterlater en gulaktig olje. Oljen oppløses i 80 ml metylenklorid, oppløsningen avkjøles og tilsettes 10,9 g stanniklorid, og det dannes en mørk oppløsning som omrøres i 72 timer ved være Isetemperatur, 8.8 g of phosphorus pentachloride is added to an ice bath cooled solution of 7.0 g of 6-[4-(2-carboxybenzyloxy)phenyl]caproic acid in 80 ml of benzene. After the phosphorus pentachloride has dissolved, the ice bath is removed and the resulting yellowish solution is stirred for 4 hours and the benzene is removed in vacuo at 80°C leaving a yellowish oil. The oil is dissolved in 80 ml of methylene chloride, the solution is cooled and 10.9 g of stannous chloride is added, and a dark solution is formed which is stirred for 72 hours at ice temperature,
hydrolyseres med 80 ml 1-normal saltsyre og omrøres i ytter-ligere 36 timer. Blandingen adskilles og den organiske fase. konsentreres og etterlater et gummiaktig stoff som tritureres med kloroform, tørkes og konsentreres for å gi et fast stoff. Det faste stoff omkrystalliseres fra acetonitril for å gi et hvitt produkt, smeltepunkt 98 - 100°C, med 6-(6,11-dihydro-ll-oksodibenz [b,e]oksepin-2-yl)kapronsyre. hydrolyzed with 80 ml of 1-normal hydrochloric acid and stirred for a further 36 hours. The mixture is separated and the organic phase. is concentrated leaving a gummy substance which is triturated with chloroform, dried and concentrated to give a solid. The solid is recrystallized from acetonitrile to give a white product, mp 98-100°C, with 6-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)caproic acid.
Analyse: Analysis:
Beregnet for C20H20°4 <:><7>4,05% C, 6,22% H Calculated for C20H20°4 <:><7>4.05% C, 6.22% H
Funnet: 73,85% C, 6,29% H. Found: 73.85% C, 6.29% H.
På tilsvarende måte fremstilles 6-(6,ll-dihydro-ll-okso-9-trifluormetyldibenz[b,e]oksepin-2-yl)kapronsyre og 6-(6,ll-ddJiydrjo—a.rfflet^ In a similar manner, 6-(6,11-dihydro-11-oxo-9-trifluoromethyldibenz[b,e]oxepin-2-yl)caproic acid and 6-(6,11-ddJiydrjo—a.rfflet^ are prepared
Eksempel 4A Example 4A
En prøve av etyl 8-(4-hydroksyfenyl)kaprylat, fremstilt ifølge fremgangsmåte A, behandles ifølge behandlingsfremgangsmåten omstalt i eksempel 3A, for å danne farveløse krystaller, smeltepunkt 116 - 118°C, av 8-[4-(2-karboksybenzyloksy)fenyl]-kaprylsyre. A sample of ethyl 8-(4-hydroxyphenyl) caprylate, prepared according to method A, is treated according to the treatment procedure outlined in Example 3A, to form colorless crystals, mp 116 - 118°C, of 8-[4-(2-carboxybenzyloxy) phenyl]-caprylic acid.
Analyse: Analysis:
Beregnet for C22H26°5 <:><7>1'32% c' 7'07% H Calculated for C22H26°5 <:><7>1'32% c' 7'07% H
Funnet: 71,26% C, 7,14% H. Found: 71.26% C, 7.14% H.
På tilsvarende måte fremstilles 8-[4-(2-karboksy-5-klorbenzyl-oksy)fenyl]kaprylsyre. 8-[4-(2-carboxy-5-chlorobenzyloxy)phenyl]caprylic acid is prepared in a similar manner.
Eksempel 4B Example 4B
3,4 g polyfosforsyre settes til en suspensjon under nitrogen med 1,0 g 8-[4-(2-karboksybenzyloksy)fenyl]kaprylsyre i 2,63 ml iseddik. Reaksjonsblandingen omrøres ved 100°C i 4 timer, fortynnes deretter med vann og avkjøles og filtreres. Filter-kaken oppløses i kloroform, filtratet ekstraheres med kloroform og kloroformoppløsningene forenes, vaskes med vann, tørkes og kloroformen fjernes og etterlater et fast stoff som omkrystalliseres fra acetonitril for å gi et fast stoff, smeltepunkt 68 - 70°C, med 8-(6,11-dihydro-ll-oksodibenz[b,e]oksepin-2-yl)-kaprylsyre. 3.4 g of polyphosphoric acid are added to a suspension under nitrogen with 1.0 g of 8-[4-(2-carboxybenzyloxy)phenyl]caprylic acid in 2.63 ml of glacial acetic acid. The reaction mixture is stirred at 100°C for 4 hours, then diluted with water and cooled and filtered. The filter cake is dissolved in chloroform, the filtrate is extracted with chloroform and the chloroform solutions are combined, washed with water, dried and the chloroform removed leaving a solid which is recrystallized from acetonitrile to give a solid, mp 68-70°C, with 8-( 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)-caprylic acid.
Analyse: Analysis:
Beregnet for C22H24°4<:><7>4'97% c' 6,86% H Calculated for C22H24°4<:><7>4'97% c' 6.86% H
Funnet: 74,67% C, 7,03% H. Found: 74.67% C, 7.03% H.
På tilsvarende måte fremstilles 8-( 6,ll-dihydro-8-klor-ll-oksodibenz[b,e]oksepin-2-yl)kaprylsyre. 8-(6,11-dihydro-8-chloro-11-oxodibenz[b,e]oxepin-2-yl)caprylic acid is prepared in a similar manner.
Claims (1)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US60021075A | 1975-07-30 | 1975-07-30 |
Publications (3)
Publication Number | Publication Date |
---|---|
NO762647L NO762647L (en) | 1977-02-01 |
NO147561B true NO147561B (en) | 1983-01-24 |
NO147561C NO147561C (en) | 1983-05-04 |
Family
ID=24402733
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO762647A NO147561C (en) | 1975-07-30 | 1976-07-29 | ANALOGUE PROCEDURES FOR THE PREPARATION OF 6,11-DIHYDRO-11-OXODODIBENZ (B, E) OCSEPINALKAN ACIDS, ESTERS AND SALTS THEREOF |
Country Status (23)
Country | Link |
---|---|
JP (1) | JPS5217487A (en) |
AT (1) | AT359066B (en) |
AU (1) | AU512130B2 (en) |
BE (1) | BE844728A (en) |
CA (1) | CA1088078A (en) |
CH (1) | CH627752A5 (en) |
DE (1) | DE2629569A1 (en) |
DK (1) | DK342476A (en) |
ES (1) | ES450125A1 (en) |
FI (1) | FI63569C (en) |
FR (1) | FR2319339A1 (en) |
GB (1) | GB1560629A (en) |
GR (1) | GR70328B (en) |
HU (1) | HU178243B (en) |
IE (1) | IE43583B1 (en) |
IL (1) | IL50155A (en) |
LU (1) | LU75491A1 (en) |
MX (1) | MX3366E (en) |
NL (1) | NL7608203A (en) |
NO (1) | NO147561C (en) |
PT (1) | PT65421B (en) |
SE (1) | SE426320B (en) |
ZA (1) | ZA764557B (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3573256D1 (en) * | 1984-04-27 | 1989-11-02 | Hoechst Roussel Pharma | (6,11-dihydro-11-oxodibenz(b,e)oxepinyl)pentanoic acids and derivatives, a process and intermediates for their preparation and their use as medicaments |
US5008285A (en) * | 1984-04-27 | 1991-04-16 | Hoechst-Roussel Pharmaceuticals, Inc. | (6,11-dihydro-11-oxodibenz[b,e]oxepin-yl)pentanoic acids and derivatives thereof |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2138257B1 (en) * | 1971-05-21 | 1974-08-23 | Roussel Uclaf | |
YU204274A (en) * | 1973-07-24 | 1982-06-30 | Hoechst Ag | Process for preparing new dibenzoxepin derivatives |
-
1976
- 1976-07-01 DE DE19762629569 patent/DE2629569A1/en not_active Withdrawn
- 1976-07-21 FR FR7622242A patent/FR2319339A1/en active Granted
- 1976-07-23 NL NL7608203A patent/NL7608203A/en not_active Application Discontinuation
- 1976-07-24 ES ES450125A patent/ES450125A1/en not_active Expired
- 1976-07-27 CH CH961676A patent/CH627752A5/en not_active IP Right Cessation
- 1976-07-28 GR GR51369A patent/GR70328B/el unknown
- 1976-07-28 FI FI762154A patent/FI63569C/en not_active IP Right Cessation
- 1976-07-28 HU HU76HO1918A patent/HU178243B/en unknown
- 1976-07-28 GB GB31436/76A patent/GB1560629A/en not_active Expired
- 1976-07-28 IL IL50155A patent/IL50155A/en unknown
- 1976-07-29 LU LU75491A patent/LU75491A1/xx unknown
- 1976-07-29 IE IE1682/76A patent/IE43583B1/en unknown
- 1976-07-29 SE SE7608546A patent/SE426320B/en unknown
- 1976-07-29 MX MX002107U patent/MX3366E/en unknown
- 1976-07-29 CA CA258,122A patent/CA1088078A/en not_active Expired
- 1976-07-29 AU AU16363/76A patent/AU512130B2/en not_active Expired
- 1976-07-29 NO NO762647A patent/NO147561C/en unknown
- 1976-07-29 ZA ZA764557A patent/ZA764557B/en unknown
- 1976-07-29 DK DK342476A patent/DK342476A/en not_active Application Discontinuation
- 1976-07-29 AT AT559976A patent/AT359066B/en not_active IP Right Cessation
- 1976-07-29 PT PT65421A patent/PT65421B/en unknown
- 1976-07-30 BE BE169420A patent/BE844728A/en unknown
- 1976-07-30 JP JP51090428A patent/JPS5217487A/en active Pending
Also Published As
Publication number | Publication date |
---|---|
SE7608546L (en) | 1977-01-31 |
FI762154A (en) | 1977-01-31 |
MX3366E (en) | 1980-10-15 |
AU1636376A (en) | 1978-02-02 |
GB1560629A (en) | 1980-02-06 |
DE2629569A1 (en) | 1977-03-31 |
LU75491A1 (en) | 1977-04-15 |
CA1088078A (en) | 1980-10-21 |
DK342476A (en) | 1977-01-31 |
ZA764557B (en) | 1977-07-27 |
NO147561C (en) | 1983-05-04 |
NO762647L (en) | 1977-02-01 |
CH627752A5 (en) | 1982-01-29 |
AU512130B2 (en) | 1980-09-25 |
JPS5217487A (en) | 1977-02-09 |
FR2319339A1 (en) | 1977-02-25 |
FI63569C (en) | 1983-07-11 |
PT65421B (en) | 1978-04-05 |
ES450125A1 (en) | 1977-09-16 |
SE426320B (en) | 1982-12-27 |
ATA559976A (en) | 1980-03-15 |
IL50155A0 (en) | 1976-09-30 |
PT65421A (en) | 1976-08-01 |
IE43583B1 (en) | 1981-04-08 |
FR2319339B1 (en) | 1978-11-17 |
IE43583L (en) | 1977-01-30 |
BE844728A (en) | 1977-01-31 |
IL50155A (en) | 1979-12-30 |
FI63569B (en) | 1983-03-31 |
GR70328B (en) | 1982-09-15 |
AT359066B (en) | 1980-10-27 |
NL7608203A (en) | 1977-02-01 |
HU178243B (en) | 1982-04-28 |
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