NO125971B - - Google Patents
Download PDFInfo
- Publication number
- NO125971B NO125971B NO210969A NO210969A NO125971B NO 125971 B NO125971 B NO 125971B NO 210969 A NO210969 A NO 210969A NO 210969 A NO210969 A NO 210969A NO 125971 B NO125971 B NO 125971B
- Authority
- NO
- Norway
- Prior art keywords
- naphthyl
- methoxy
- methyl
- compounds
- acid
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 claims description 39
- 238000000034 method Methods 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 230000003287 optical effect Effects 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 2
- 239000003638 chemical reducing agent Substances 0.000 claims 1
- 239000000203 mixture Substances 0.000 description 28
- -1 methoxy, methyl Chemical group 0.000 description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 238000002844 melting Methods 0.000 description 12
- 230000008018 melting Effects 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 230000001754 anti-pyretic effect Effects 0.000 description 10
- 239000007858 starting material Substances 0.000 description 8
- 206010061218 Inflammation Diseases 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 230000003110 anti-inflammatory effect Effects 0.000 description 7
- 230000004054 inflammatory process Effects 0.000 description 7
- 229910052938 sodium sulfate Inorganic materials 0.000 description 7
- 235000011152 sodium sulphate Nutrition 0.000 description 7
- CMWTZPSULFXXJA-UHFFFAOYSA-N 2-(6-methoxy-2-naphthalenyl)propanoic acid Chemical compound C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 241000700159 Rattus Species 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 239000000284 extract Substances 0.000 description 6
- DZFJDDMBLJXLJL-UHFFFAOYSA-N 2-(6-methylsulfanylnaphthalen-2-yl)propanoic acid Chemical compound C1=C(C(C)C(O)=O)C=CC2=CC(SC)=CC=C21 DZFJDDMBLJXLJL-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 230000000202 analgesic effect Effects 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000012280 lithium aluminium hydride Substances 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- 150000008046 alkali metal hydrides Chemical class 0.000 description 4
- 230000001139 anti-pruritic effect Effects 0.000 description 4
- 239000002221 antipyretic Substances 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 208000002193 Pain Diseases 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- 208000003251 Pruritus Diseases 0.000 description 3
- 206010037660 Pyrexia Diseases 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 3
- 230000036760 body temperature Effects 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- LJRVHSWMFDDXLN-UHFFFAOYSA-N 2-(6-methylnaphthalen-2-yl)propanoic acid Chemical compound C1=C(C)C=CC2=CC(C(C(O)=O)C)=CC=C21 LJRVHSWMFDDXLN-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 208000034656 Contusions Diseases 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- 201000005569 Gout Diseases 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229960001138 acetylsalicylic acid Drugs 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000008135 aqueous vehicle Substances 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 2
- 235000010418 carrageenan Nutrition 0.000 description 2
- 229920001525 carrageenan Polymers 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 230000009519 contusion Effects 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000027950 fever generation Effects 0.000 description 2
- 208000021760 high fever Diseases 0.000 description 2
- 210000000548 hind-foot Anatomy 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- NWIMPGMAVYLECN-UHFFFAOYSA-N methyl 2-(6-methoxynaphthalen-2-yl)acetate Chemical compound C1=C(OC)C=CC2=CC(CC(=O)OC)=CC=C21 NWIMPGMAVYLECN-UHFFFAOYSA-N 0.000 description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 229960002895 phenylbutazone Drugs 0.000 description 2
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 201000003068 rheumatic fever Diseases 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- ZNDAYUSMXBELKE-UHFFFAOYSA-N 2-(1-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)acetic acid Chemical compound C1=CC=C2C(O)C(CC(O)=O)CCC2=C1 ZNDAYUSMXBELKE-UHFFFAOYSA-N 0.000 description 1
- LYIIAXBYAXXHTG-UHFFFAOYSA-N 2-(1-hydroxy-6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)acetic acid Chemical compound OC1C(CC(O)=O)CCC2=CC(OC)=CC=C21 LYIIAXBYAXXHTG-UHFFFAOYSA-N 0.000 description 1
- DRYXTNBSASTONM-UHFFFAOYSA-N 2-(1-oxo-3,4-dihydro-2h-naphthalen-2-yl)acetic acid Chemical compound C1=CC=C2C(=O)C(CC(=O)O)CCC2=C1 DRYXTNBSASTONM-UHFFFAOYSA-N 0.000 description 1
- HFCQYKCGYMWUAH-UHFFFAOYSA-N 2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)acetic acid Chemical compound C1C(CC(O)=O)CCC2=CC(OC)=CC=C21 HFCQYKCGYMWUAH-UHFFFAOYSA-N 0.000 description 1
- SMXYHTZAHLNPIV-UHFFFAOYSA-N 2-(6-methoxy-1-oxo-3,4-dihydro-2h-naphthalen-2-yl)acetic acid Chemical compound O=C1C(CC(O)=O)CCC2=CC(OC)=CC=C21 SMXYHTZAHLNPIV-UHFFFAOYSA-N 0.000 description 1
- LOWWSYWGAKCKLG-UHFFFAOYSA-N 2-(6-methoxynaphthalen-1-yl)acetic acid Chemical compound OC(=O)CC1=CC=CC2=CC(OC)=CC=C21 LOWWSYWGAKCKLG-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- DKVIPUUJSKIQFZ-UHFFFAOYSA-N 2-naphthalen-2-ylpropanoic acid Chemical compound C1=CC=CC2=CC(C(C(O)=O)C)=CC=C21 DKVIPUUJSKIQFZ-UHFFFAOYSA-N 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- MNALUTYMBUBKNX-UHFFFAOYSA-N 6-methoxy-3,4-dihydro-2h-naphthalen-1-one Chemical compound O=C1CCCC2=CC(OC)=CC=C21 MNALUTYMBUBKNX-UHFFFAOYSA-N 0.000 description 1
- XZGVYHGIPAJECB-UHFFFAOYSA-N 6-methyl-3,4-dihydro-2h-naphthalene-1-thione Chemical compound S=C1CCCC2=CC(C)=CC=C21 XZGVYHGIPAJECB-UHFFFAOYSA-N 0.000 description 1
- 206010027654 Allergic conditions Diseases 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 206010012442 Dermatitis contact Diseases 0.000 description 1
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 1
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 208000005171 Dysmenorrhea Diseases 0.000 description 1
- 206010013935 Dysmenorrhoea Diseases 0.000 description 1
- 206010017076 Fracture Diseases 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical class CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 206010029240 Neuritis Diseases 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 208000037386 Typhoid Diseases 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 125000005910 alkyl carbonate group Chemical group 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- KMPWYEUPVWOPIM-KODHJQJWSA-N cinchonidine Chemical compound C1=CC=C2C([C@H]([C@H]3[N@]4CC[C@H]([C@H](C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-KODHJQJWSA-N 0.000 description 1
- KMPWYEUPVWOPIM-UHFFFAOYSA-N cinchonidine Natural products C1=CC=C2C(C(C3N4CCC(C(C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-UHFFFAOYSA-N 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 208000010247 contact dermatitis Diseases 0.000 description 1
- 239000013068 control sample Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- POLCUAVZOMRGSN-UHFFFAOYSA-N dipropyl ether Chemical compound CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- GSAATXFTFSUBJM-UHFFFAOYSA-N ethyl 2-(2-ethoxy-2-oxoethyl)-6-methoxy-1-oxo-3,4-dihydronaphthalene-2-carboxylate Chemical compound COC1=CC=C2C(=O)C(CC(=O)OCC)(C(=O)OCC)CCC2=C1 GSAATXFTFSUBJM-UHFFFAOYSA-N 0.000 description 1
- URNAYRDBUUZOIU-UHFFFAOYSA-N ethyl 2-(6-methoxynaphthalen-2-yl)propanoate Chemical compound C1=C(OC)C=CC2=CC(C(C)C(=O)OCC)=CC=C21 URNAYRDBUUZOIU-UHFFFAOYSA-N 0.000 description 1
- UKGQINOQDPAYBX-UHFFFAOYSA-N ethyl 6-methoxy-1-oxo-3,4-dihydro-2h-naphthalene-2-carboxylate Chemical compound COC1=CC=C2C(=O)C(C(=O)OCC)CCC2=C1 UKGQINOQDPAYBX-UHFFFAOYSA-N 0.000 description 1
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 210000002683 foot Anatomy 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 210000001503 joint Anatomy 0.000 description 1
- ZFYFBPCRUQZGJE-UHFFFAOYSA-N methyl 2-(6-methoxynaphthalen-2-yl)propanoate Chemical compound C1=C(OC)C=CC2=CC(C(C)C(=O)OC)=CC=C21 ZFYFBPCRUQZGJE-UHFFFAOYSA-N 0.000 description 1
- TUHSYVVRJZWTKY-UHFFFAOYSA-N methyl 2-(6-methylnaphthalen-2-yl)propanoate Chemical compound C1=C(C)C=CC2=CC(C(C)C(=O)OC)=CC=C21 TUHSYVVRJZWTKY-UHFFFAOYSA-N 0.000 description 1
- IMXPVBWBIFOAPB-UHFFFAOYSA-N methyl 2-(6-methylsulfanylnaphthalen-2-yl)propanoate Chemical compound C1=C(SC)C=CC2=CC(C(C)C(=O)OC)=CC=C21 IMXPVBWBIFOAPB-UHFFFAOYSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 210000002346 musculoskeletal system Anatomy 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000000711 polarimetry Methods 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 201000000306 sarcoidosis Diseases 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 201000008297 typhoid fever Diseases 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Analogifremgangsmåte til fremstilling av Analogy method for the production of
nye terapeutisk virksomme naftylalkanoler. new therapeutically active naphthylalkanols.
Foreliggende oppfinnelse vedrører en analogifremgangsmåte til fremstilling av nye naftylalkanoler, og mer spesielt 3-(2-naftyl) a-metyletanoler og derivater derav, som har anti-inflammatorisk, analgetisk, anti-pyretisk og anti-pruritisk aktivitet, og som har den generelle formel: The present invention relates to an analogous process for the production of new naphthyl alkanols, and more particularly 3-(2-naphthyl) α-methylethanols and derivatives thereof, which have anti-inflammatory, analgesic, anti-pyretic and anti-pruritic activity, and which have the general formula:
hvor R1 er hydroksy eller acetoksy og R^ er metoksy, metyl eller metyl-tio. where R 1 is hydroxy or acetoxy and R 1 is methoxy, methyl or methyl-thio.
Forbindelsene med formel I kan foreligge som enantiomorfe par. Hver av de optiske isomerene av de fremstilte naftylalkanoler omfattes av foreliggende oppfinnelse. I noen tilfeller utviser en enantiomorf forbindelse større anti-inflammatorisk, analgetisk, anti-pyretisk og/eller anti-pruritisk- aktivitet enn den andre enantiomorfe forbindelse. Den venstredreiende form, 1 eller (-)-formen, av 0-(6-metoksy-2-naftyl)-3-metyletanol, utviser f.eks. større anti-inflammatorisk aktivitet enn den tilsvarende høyredreiende form. The compounds of formula I can exist as enantiomorphic pairs. Each of the optical isomers of the produced naphthyl alkanols is covered by the present invention. In some cases, one enantiomorphic compound exhibits greater anti-inflammatory, analgesic, anti-pyretic and/or anti-pruritic activity than the other enantiomorphic compound. The levorotatory form, 1 or (-)-form, of 0-(6-methoxy-2-naphthyl)-3-methylethanol exhibits e.g. greater anti-inflammatory activity than the corresponding dextrorotatory form.
De ifølge oppfinnelsen fremstilte naftylalkanoler som foreligger som enantiomorfe forbindelser kan administreres som blandinger av enantiomorfe forbindelser eller som rene, adskilte enantiomorfer. The naphthyl alkanols produced according to the invention which are present as enantiomorphic compounds can be administered as mixtures of enantiomorphic compounds or as pure, separated enantiomorphs.
De adskilte eller optisk aktive forbindelser med formel I kan fremstilles fra de tilsvarende optisk aktive utgangsforbindelser som benyttes for fremstilling av forbindelsene med formel I. De adskilte eller optisk aktive forbindelser med formel I og deres respek-tive optisk aktive utgangsforbindelser behøver nødvendigvis ikke å ha den. samme optiske rotasjon selv om de har den samme absolutte konfigurasjon. 1-3-(6-metoksy-2-naftyl)-3-metyletanol fremstilles f.eks. fra d-6-metoksy-2-naftyl-a-metyledddiksyre. The separated or optically active compounds of formula I can be prepared from the corresponding optically active starting compounds used for the preparation of the compounds of formula I. The separated or optically active compounds of formula I and their respective optically active starting compounds do not necessarily have to have the . same optical rotation even though they have the same absolute configuration. 1-3-(6-methoxy-2-naphthyl)-3-methylethanol is prepared, e.g. from d-6-methoxy-2-naphthyl-α-methylacetic acid.
Forbindelsene med formel I utviser anti-inflammatorisk, analgetisk, anti-pyretisk og anti-pruritisk aktivitet hos pattedyr. The compounds of formula I exhibit anti-inflammatory, analgesic, anti-pyretic and anti-pruritic activity in mammals.
Disse forbindelser er nyttige ved behandling av betennelser i huden, åndedrettsystemet, muskel-skjelettsystemet, ledd, indre or-ganer og i vev. Forbindelsene er følgelig nyttige ved behandling av tilstander som er kjennetegnet ved inflammasjon, slik som kontakt der-matitis, allergiske tilstander, brannsår, reumatisme, kontusjon, ar-tritis, brudd, post-traumatiske tilstander og podagra. I de tilfeller hvor de ovennevnte tilstander omfatter smerte, pyrexia og pruritus sammen med inflammasjon, er de fremstilte forbindelser nyttige for helbredning av disse tilstander og inflammasjon. De fremstilte forbindelser er videre egnet for behandling av smerte i forbindelse med post-operative tilstander, post-traumatiske tilstander, post-partum tilstander, dysmenorrhea, brannsår, podagra, kontusjoner, neuralgia, neuritis, hodepine og reumatisk feber. Forbindelsene utviser som tidligere nevnt også anti-pyretisk aktivitet og de er derfor nyttige ved behandling av pyrexia hvor det antydes en opphevelse av feberen, f. eks. tilfeller hvor høy feber er forbundet med sykdommer slik som reu-matisk feber, bronkitt, pneumonia, tyfoidfeber og lymfogranulomatosis. These compounds are useful in the treatment of inflammation in the skin, respiratory system, musculoskeletal system, joints, internal organs and tissues. The compounds are consequently useful in the treatment of conditions characterized by inflammation, such as contact dermatitis, allergic conditions, burns, rheumatism, contusion, arthritis, fractures, post-traumatic conditions and gout. In those cases where the above conditions include pain, pyrexia and pruritus together with inflammation, the prepared compounds are useful for healing these conditions and inflammation. The prepared compounds are further suitable for the treatment of pain in connection with post-operative conditions, post-traumatic conditions, post-partum conditions, dysmenorrhea, burns, gout, contusions, neuralgia, neuritis, headaches and rheumatic fever. As previously mentioned, the compounds also exhibit anti-pyretic activity and are therefore useful in the treatment of pyrexia where a cessation of the fever is suggested, e.g. cases where high fever is associated with diseases such as rheumatic fever, bronchitis, pneumonia, typhoid fever and lymphogranulomatosis.
De fremstilte forbindelser er .også nyttige ved behandling av pruritus hvor denne tilstand forekommer sammen med inflammasjon, smerte og/eller høy feber. Forbindelsene er dessuten egnet for behandling av pruritus per se. The prepared compounds are also useful in the treatment of pruritus where this condition occurs together with inflammation, pain and/or high fever. The compounds are also suitable for the treatment of pruritus per se.
De ifølge oppfinnelsen fremstilte forbindelser utviser i alminnelighet større anti-inflammatorisk, analgetisk, anti-pyretisk og anti-pruritisk aktivitet enn de tidligere kjente konvensjonelle forbindelser med samme virkning. Bedømmelse av f.eks. den anti-inf lammatoriske aktivitet ifølge det carrageenin-induserte ødem for-søk (Winter et al., Proceedings of the Society for Experimental Biology and Fedicin 111, 5^4 (1962)) viser at 1 3-(6-metoksy-2-naftyl)-6-metyletanol har en aktivitet som er syv ganger større enn aktiviteten for fenylbutazon. Lignende standardprøver for måling av analgetiske og anti-pyretiske aktiviteter viser at g-(6-metoksy-2-naftyl)-g-metyletanol har en aktivitet som er tre og åtte ganger større enn aktivi-tetene for aspirin i de to nevnte kategorier, respektivt. The compounds produced according to the invention generally exhibit greater anti-inflammatory, analgesic, anti-pyretic and anti-pruritic activity than the previously known conventional compounds with the same effect. Assessment of e.g. the anti-inflammatory activity in the carrageenin-induced edema study (Winter et al., Proceedings of the Society for Experimental Biology and Dieticin 111, 5^4 (1962)) shows that 1 3-(6-methoxy-2 -naphthyl)-6-methylethanol has an activity that is seven times greater than the activity of phenylbutazone. Similar standard tests for measuring analgesic and anti-pyretic activities show that g-(6-methoxy-2-naphthyl)-g-methylethanol has an activity that is three and eight times greater than the activities of aspirin in the two categories mentioned, respectively.
Forbindelsene med formel I fremstilles ifølge oppfinnelsen fra de tilsvarende 2-naftyl a-metyleddiksyrer eller estere derav via en fremgangsmåte som kan illustreres som følger: The compounds of formula I are prepared according to the invention from the corresponding 2-naphthyl α-methylacetic acids or esters thereof via a method which can be illustrated as follows:
5 11 5 11
hvori R har den ovenfor angitte betydning og R er hydrogen eller lavere alkyl. wherein R has the meaning given above and R is hydrogen or lower alkyl.
Den ovenfor illustrerte fremgangsmåte foretas ved behandling av forbindelsene med formel VI med litiumaluminiumhydrid. Dersom den frie karboksylsyreformen av forbindelsen med formel VI (hvor R^1 er hydrogen) anvendes som utgangsmateriale, benyttes minst 0.75 molarekvivalenter litiumaluminiumhydrid og fortrinnsvis ca. 1.0 - 2.5 molarekvivalenter. Dersom esterformen av forbindelsen med formel VI (hvor R<11> er alkyl) benyttes som utgangsmateriale, anvendes 0.5 molarekvivalenter og fortrinnsvis ca. 0,6 - 2.0 molarekvivalenter litiumaluminiumhydrid. Fremgangsmåten utføres i en inert organisk ester, slik Bom dietyleter, dipropyleter, diisopropyleter, dibutyleter. og tetrahydrofuran. Reaksjonen utføres ved en temperatur mellom 0°C og kokepunktet for det benyttede oppløsningsmiddel, fortrinnsvis mellom 15° og 35°C. The process illustrated above is carried out by treating the compounds of formula VI with lithium aluminum hydride. If the free carboxylic acid form of the compound with formula VI (where R^1 is hydrogen) is used as starting material, at least 0.75 molar equivalents of lithium aluminum hydride and preferably approx. 1.0 - 2.5 molar equivalents. If the ester form of the compound with formula VI (where R<11> is alkyl) is used as starting material, 0.5 molar equivalents are used and preferably approx. 0.6 - 2.0 molar equivalents of lithium aluminum hydride. The process is carried out in an inert organic ester, such as Bom diethyl ether, dipropyl ether, diisopropyl ether, dibutyl ether. and tetrahydrofuran. The reaction is carried out at a temperature between 0°C and the boiling point of the solvent used, preferably between 15° and 35°C.
Forbindelsene med formel VII isoleres ved ødeleggelse av eventuelt tilstedeværende overskudd litiumaluminiumhydrid, f.eks. ved tilsetning av et overskudd etylacetat eller vandige oppløsninger av natriumhydroksyd eller ammoniumklorid. Blandingen fortynnes deretter med vann, filtreres og ekstraheres med et inert organisk oppløsnings-middel som ikke er blandbart med vann. Forbindelsene med formel VII kan ytterligere renses ved hjelp av standard teknikker slik som krystallisering og kromatografi.'The compounds of formula VII are isolated by destroying any excess lithium aluminum hydride, e.g. by adding an excess of ethyl acetate or aqueous solutions of sodium hydroxide or ammonium chloride. The mixture is then diluted with water, filtered and extracted with an inert organic solvent which is not miscible with water. The compounds of formula VII can be further purified using standard techniques such as crystallization and chromatography.
Forbindelsene med formel VI kan alternativt reduseres ved behandling med diboran i tetrahydrofuran ved en temperatur på mellom 0° og ca. 65°C. The compounds of formula VI can alternatively be reduced by treatment with diborane in tetrahydrofuran at a temperature of between 0° and approx. 65°C.
Forbindelsene med formel VII kan forestres ved hjelp av vanlige metoder. Forbindelsene kan f.eks. forestres ved behandling med et syreanhydrid slik som eddiksyreanhydrid i pyridin, eller ved behandling med et syreklorid slik som acetylklorid The compounds of formula VII can be esterified by conventional methods. The connections can e.g. esterified by treatment with an acid anhydride such as acetic anhydride in pyridine, or by treatment with an acid chloride such as acetyl chloride
i pyridin, eller ved behandling med en karboksylsyre i nærvær av en syrekatalysator slik som p-toluensulfonsyre. in pyridine, or by treatment with a carboxylic acid in the presence of an acid catalyst such as p-toluenesulfonic acid.
Når en optisk aktiv enantiomorf forbindelse med formel VI anvendes som utgangsmateriale i den ovenfor beskrevne fremgangsmåte, oppnåes den tilsvarende optisk aktive enantiomorfe forbindelse med formel VII. Selv om den absolutte konfigurasjon av 2-naftyl-a-metyl-eddiksyre-utgangsforbindelsen og det tilsvarende 3-(2-naftyl)-a-metyl-etanolprodukt som nevnt ovenfor vil være identisk, er den optiske rotasjon av utgangsforbindelsen og produktet motsatt. When an optically active enantiomorphic compound of formula VI is used as starting material in the method described above, the corresponding optically active enantiomorphic compound of formula VII is obtained. Although the absolute configuration of the 2-naphthyl-α-methyl-acetic acid starting compound and the corresponding 3-(2-naphthyl)-α-methyl-ethanol product as mentioned above will be identical, the optical rotation of the starting compound and the product is opposite.
Forbindelsene med formel VI kan fremstilles som følger. En metode er å behandle en tetralonforbindelse substituert i C-6-stilling med en metoksy- eller metyltiogruppe, fortløpende med (1) et alkyl-karbonat og et alkalimetallhydrid, (2) et alkalimetallhydrid og en a-halogeneddiksyre og (3) vandig mineralsyre for oppnåelse av tilsvarende 2-(karboksymetyl)-l-tetralon. Denne sistnevnte forbindelse reduseres med natriumborhydrid for dannelse av den tilsvarende 1,2,3,4-tetrahydro-l-hydroksy-2-naftyleddiksyre, og dette produkt hydrogenolyseres med hydrogen i nærvær av en hydrogeneringskatalysator, det resulterende produkt forestres og blir deretter dehydrogenert med palladium-trekull-katalysator ved ca. 180°C for å oppnå det tilsvarende 2-naftyleddiksyreesterderivat. The compounds of formula VI can be prepared as follows. One method is to treat a tetralone compound substituted at the C-6 position with a methoxy or methylthio group, successively with (1) an alkyl carbonate and an alkali metal hydride, (2) an alkali metal hydride and an α-haloacetic acid, and (3) aqueous mineral acid to obtain the corresponding 2-(carboxymethyl)-1-tetralone. This latter compound is reduced with sodium borohydride to form the corresponding 1,2,3,4-tetrahydro-1-hydroxy-2-naphthylacetic acid, and this product is hydrogenolyzed with hydrogen in the presence of a hydrogenation catalyst, the resulting product is esterified and then dehydrogenated with palladium-charcoal catalyst at approx. 180°C to obtain the corresponding 2-naphthylacetic acid ester derivative.
a-metylsubstituentene adderes til de a-usubstituerte forbindelser (dvs. 6-metoksy-2-naftyleddiksyre) ved forestring av sistnevnte forbindelser og behandling av disse med en molarekvivalent av et alkalimetallhydrid slik som natriumhydrid og deretter med et molart overskudd av et metylhalogenid slik som metyljodid. The α-methyl substituents are added to the α-unsubstituted compounds (ie 6-methoxy-2-naphthylacetic acid) by esterifying the latter compounds and treating these with a molar equivalent of an alkali metal hydride such as sodium hydride and then with a molar excess of a methyl halide such as methyl iodide.
Forbindelsene med formel VI kan adskilles ved fremstilling av deres alkaloidbase-salter, resolvering av de resulterende diastereo-isomersalter ved fraksjonert krystallisering og spalting av de resol-verte salter. Den optiske rotasjon av en spesiell enantiomorf forbindelse bestemmes ved hjelp av polarimetri. The compounds of formula VI can be separated by preparation of their alkaloid base salts, resolution of the resulting diastereoisomeric salts by fractional crystallization and cleavage of the resolved salts. The optical rotation of a particular enantiomorphic compound is determined by polarimetry.
Fremstilling av utgangsmaterialer: Preparation of starting materials:
Fremstilling 1 Production 1
En blanding av 3.6 g 6-metoksy-l-tetralon, 12 g dietylkarbo-nat, 0.5 g natriumhydrid og 40 ml toluen, oppvarmes til 60°C i 5 timer. Blandingen avkjøles, surgjøres ved tilsetning av 40 ml 1 N saltsyre A mixture of 3.6 g of 6-methoxy-1-tetralone, 12 g of diethyl carbonate, 0.5 g of sodium hydride and 40 ml of toluene is heated to 60° C. for 5 hours. The mixture is cooled, acidified by adding 40 ml of 1 N hydrochloric acid
og ekstraheres deretter med tre 75 ml porsjoner benzen. Ekstraktene kombineres, vaskes med vann til nøytralitet og tørkes over natriumsulfat. and then extracted with three 75 ml portions of benzene. The extracts are combined, washed with water to neutrality and dried over sodium sulfate.
Blandingen som inneholder 6-metoksy-2-etoksykarbonyl-l-tetralon, behandles med 0.5 g natriumhydrid ved romtemperatur under omrøring. Deretter tilsettes 20 g etyl-a-bromacetat og blandingen hensettes ved romtemperatur i 12 timer. Blandingen tilsettes til 500 ml vann og ekstraheres med metylenklorid. Ekstraktene kombineres, vaskes med vann til nøytralitet, tørkes over natriumsulfat og inndampes. Resten, inneholdende 6-metoksy-2-etoksykarbonyl-2-(etoksykar-bonylmetyl)-l-tetralon, kokes under tilbakeløp i 40 ml 6 N saltsyre i 24 timer hvoretter blandingen inndampes. The mixture containing 6-methoxy-2-ethoxycarbonyl-1-tetralone is treated with 0.5 g of sodium hydride at room temperature with stirring. 20 g of ethyl-α-bromoacetate are then added and the mixture is allowed to stand at room temperature for 12 hours. The mixture is added to 500 ml of water and extracted with methylene chloride. The extracts are combined, washed with water until neutral, dried over sodium sulfate and evaporated. The residue, containing 6-methoxy-2-ethoxycarbonyl-2-(ethoxycarbonylmethyl)-1-tetralone, is refluxed in 40 ml of 6 N hydrochloric acid for 24 hours, after which the mixture is evaporated.
Resten, som inneholder 6-metoksy-2-(karboksymetyl)-l-tetralon, reduseres ved behandling med 40 ml etanol inneholdende 1.6 g natriumborhydrid. Etter 1 time surgjøres blandingen ved tilsetning av 20 ml 3 N saltsyre og den resulterende blanding ekstraheres med flere porsjoner metylenklorid. Ekstraktene kombineres, vaskes med vann til nøytralitet, tørkes over natriumsulfat og inndampes. The residue, which contains 6-methoxy-2-(carboxymethyl)-1-tetralone, is reduced by treatment with 40 ml of ethanol containing 1.6 g of sodium borohydride. After 1 hour, the mixture is acidified by adding 20 ml of 3 N hydrochloric acid and the resulting mixture is extracted with several portions of methylene chloride. The extracts are combined, washed with water until neutral, dried over sodium sulfate and evaporated.
Resten, som inneholder 6-metoksy-l-hydroksy-l,2,3,4-tetra-hydro-2-naftyleddiksyre, hydrogenolyseres ved hydrogenering med en ekvivalent hydrogen i eddiksyre inneholdende 60 mg 5 % palladium-på-bariumsulfat. Hydrogeneringsblandingen filtreres og inndampes. Resten, som inneholder 6-metoksy-l,2,3,4-tetrahydro-2-naftyleddiksyre, oppløses i 40 ml dietyleter og blandingen tilsettes deretter til en 20 ml's oppløsning av dietyleter inneholdende 1.3 g diazometan. Blandingen inndampes deretter til tørrhet. Den forestrede rest dehydro-generes ved å tilsette den til 1 g 10 % palladium-på-trekull og opp-varmning av den resulterende blanding i 6 timer ved 200°C. Den av-kjølte blanding fortynnes med 4.0 ml kloroform, filtreres og inndampes hvilket gir metyl-6-metoksy-2-naftylacetat. The residue, containing 6-methoxy-1-hydroxy-1,2,3,4-tetrahydro-2-naphthylacetic acid, is hydrogenolyzed by hydrogenation with one equivalent of hydrogen in acetic acid containing 60 mg of 5% palladium-on-barium sulfate. The hydrogenation mixture is filtered and evaporated. The residue, which contains 6-methoxy-1,2,3,4-tetrahydro-2-naphthylacetic acid, is dissolved in 40 ml of diethyl ether and the mixture is then added to a 20 ml solution of diethyl ether containing 1.3 g of diazomethane. The mixture is then evaporated to dryness. The esterified residue is dehydrogenated by adding it to 1 g of 10% palladium-on-charcoal and heating the resulting mixture for 6 hours at 200°C. The cooled mixture is diluted with 4.0 ml of chloroform, filtered and evaporated to give methyl 6-methoxy-2-naphthyl acetate.
Til en blanding av 22 g metyl-6-metoksy-2-naftylacetat, 0.25 g natriumhydrid og 15 ml 1,2-rdimetoksyetan, tilsettes 25 g metyljodid. Reaksjonsblandingen settes til side i flere timer, hvoretter den fortynnes med etanol og deretter vann og ekstraheres med metylenklorid. Ekstraktene kombineres, vaskes med vann til nøytralitet, tørkes over natriumsulfat, filtreres og inndampes og dette gir metyl-6-metoksy-2-naftyl-a-metylacetat. To a mixture of 22 g of methyl-6-methoxy-2-naphthyl acetate, 0.25 g of sodium hydride and 15 ml of 1,2-dimethoxyethane, 25 g of methyl iodide is added. The reaction mixture is set aside for several hours, after which it is diluted with ethanol and then water and extracted with methylene chloride. The extracts are combined, washed with water to neutrality, dried over sodium sulfate, filtered and evaporated and this gives methyl-6-methoxy-2-naphthyl-α-methylacetate.
Metyl-6-metoksy-2-naftyl- ot-metylacetatet, 1.5 g natrium-karbonat, 200 ml metanol og 25 ml vann settes til side i 24 timer. Reaksjonsblandingen surgjøres deretter med 200 ml 2 N saltsyre og ekstraheres med metylenklorid. Ekstraktene kombineres, vaskes med vann, tørkes over natriumsulfat og inndampes og dette gir 6-metoksy-2-naftyl-a-metyleddiksyre, smeltepunkt 151°C. The methyl-6-methoxy-2-naphthyl-o-methylacetate, 1.5 g of sodium carbonate, 200 ml of methanol and 25 ml of water are set aside for 24 hours. The reaction mixture is then acidified with 200 ml of 2 N hydrochloric acid and extracted with methylene chloride. The extracts are combined, washed with water, dried over sodium sulfate and evaporated and this gives 6-methoxy-2-naphthyl-α-methylacetic acid, melting point 151°C.
Ved å gjenta den ovenfor beskrevne fremgangsmåte med 6-metyl-tio-l-tetralon oppnåes 6-metyltio-2-naftyl-a-metyleddiksyre, smeltepunkt 140°C By repeating the procedure described above with 6-methyl-thio-1-tetralone, 6-methylthio-2-naphthyl-α-methylacetic acid is obtained, melting point 140°C
Fremstilling 2 Manufacturing 2
En blanding av 1 g dl 6-metoksy-2-naftyl-a-metyleddiksyre, 1.26 g cinchonidin og 22 ml metanol omrøres i 2 timer hvoretter blandingen hensettes inntil krystalliseringen er fullstendig. Krystallene frafiltreres og vaskes med metanol. Deretter omkrystalliseres krystallene fra metanol, filtreres, vaskes og tørkes. De rene krystaller tilsettes til 60 ml 0.2 N saltsyre. Den resulterende blanding omrøres i 2 timer og ekstraheres deretter med dietyleter. Ekstraktene kombineres, vaskes med vann til nøytralitet, tørkes over natriumsulfat og inndampes og dette gir d 6-metoksy-2-naftyl-a-metyleddiksyre, smeltepunkt 153°C. A mixture of 1 g dl of 6-methoxy-2-naphthyl-α-methylacetic acid, 1.26 g of cinchonidine and 22 ml of methanol is stirred for 2 hours, after which the mixture is allowed to stand until crystallization is complete. The crystals are filtered off and washed with methanol. The crystals are then recrystallized from methanol, filtered, washed and dried. The pure crystals are added to 60 ml of 0.2 N hydrochloric acid. The resulting mixture is stirred for 2 hours and then extracted with diethyl ether. The extracts are combined, washed with water to neutrality, dried over sodium sulfate and evaporated and this gives d 6-methoxy-2-naphthyl-α-methylacetic acid, melting point 153°C.
Ved å gjenta denne fremgangsmåte ved gjentatt omkrystallisering med dl 6-metyl-2-naftyl-a-metyleddiksyre og dl 6-metyltio-2-naftyl-a-metyleddiksyre oppnås henholdsvis d 6-.metyl-2-nafty 1-a-metyl-eddiksyre, smeltepunkt 149°C, og d 6-metyltio-2-naftyl-a-metyleddik-syre, smeltepunkt 188° - 191°C. By repeating this procedure by repeated recrystallization with dl 6-methyl-2-naphthyl-a-methylacetic acid and dl 6-methylthio-2-naphthyl-a-methylacetic acid, d 6-.methyl-2-naphthy 1-a-methyl is obtained respectively -acetic acid, melting point 149°C, and d 6-methylthio-2-naphthyl-α-methylacetic acid, melting point 188° - 191°C.
■ Følgende eksempler illustrerer oppfinnelsen. ■ The following examples illustrate the invention.
Eksempel 1 Example 1
Til en blanding av 0.4 g litiumaluminiumhydrid og 100 ml etyleter, tilsettes en blanding av 2.3 g av en d 6-metoksy-2-naftyl-a-metyleddiksyre og 100 ml etyleter. Blandingen omrøres ved 0°C i 30 minutter hvoretter 10 ml etylacetat tilsettes, og 1 time senere tilsettes 4 ml vann. Den resulterende blanding filtreres og inndampes under redusert trykk og dette gir 1 3-(6-metoksy-2-naftyl)-3-metyletanol, smeltepunkt 88° - 89°C. To a mixture of 0.4 g of lithium aluminum hydride and 100 ml of ethyl ether, a mixture of 2.3 g of a d 6-methoxy-2-naphthyl-α-methylacetic acid and 100 ml of ethyl ether is added. The mixture is stirred at 0°C for 30 minutes, after which 10 ml of ethyl acetate is added, and 1 hour later, 4 ml of water is added. The resulting mixture is filtered and evaporated under reduced pressure to give 1 3-(6-methoxy-2-naphthyl)-3-methylethanol, melting point 88°-89°C.
Ved å gjenta den ovenfor angitte metode med dl 6-metoksy-2-naftyl-a-metyleddiksyre, dl 6-metyltio-2-naftyl-a-metyleddiksyre, d 6-metyltio-2-naftyl-a-metyleddiksyre, dl 6-metyl-2-naftyl-a-metyleddik-syre og d 6-metyl-2-naftyl-a-metyleddiksyre oppnås dl 3-(6-metoksy-2-naftyl)-3-metyletanol, smeltepunkt 88.6°C og dl 3-(6-metyltio-2-naftyl)-3-metyletanol, smeltepunkt 82° - 83°C, 1 3-(6-metyltio-2-naftyl)-3-metyletanol, smeltepunkt 102° - 103°C, dl 3-(6-metyl-2-naftyl)-3-metyletanol, smeltepunkt 99° - 100°C, og 1 3-(6-metyl-2-naftyl)-3-metyletanol, smeltepunkt 93° - 94°C. o By repeating the above method with dl 6-methoxy-2-naphthyl-α-methylacetic acid, dl 6-methylthio-2-naphthyl-α-methylacetic acid, d 6-methylthio-2-naphthyl-α-methylacetic acid, dl 6- methyl-2-naphthyl-α-methylacetic acid and d 6-methyl-2-naphthyl-α-methylacetic acid are obtained dl 3-(6-methoxy-2-naphthyl)-3-methylethanol, melting point 88.6°C and dl 3- (6-methylthio-2-naphthyl)-3-methylethanol, melting point 82° - 83°C, 1 3-(6-methylthio-2-naphthyl)-3-methylethanol, melting point 102° - 103°C, dl 3- (6-methyl-2-naphthyl)-3-methylethanol, melting point 99° - 100°C, and 1 3-(6-methyl-2-naphthyl)-3-methylethanol, melting point 93° - 94°C. o
Ved å gjenta den ovenfor angitte metode, men ved å erstatte karboksylsyrene med de tilsvarende laverealky1-estrene oppnåes, i hvert tilfelle, den tilsvarende propanol, f.eks.: By repeating the method stated above, but by replacing the carboxylic acids with the corresponding lower alkyl esters, the corresponding propanol is obtained, in each case, e.g.:
metyl 2-.(6-metoksy-2-naft<y>l)-a-metylacetat, methyl 2-(6-methoxy-2-naphth<y>1)-α-methylacetate,
etyl 2-(6-metoksy-2-naftyl)-a-metylacetat, ethyl 2-(6-methoxy-2-naphthyl)-α-methylacetate,
isobutyl 2-(6-metoksy-2-naftyl)-a-metylacetat, isobutyl 2-(6-methoxy-2-naphthyl)-α-methylacetate,
n-pentyl 2- (6-metoksy-.2-naf tyl )-a-metylacetat, n-pentyl 2-(6-methoxy-.2-naphthyl)-α-methylacetate,
isopentyl 2-(6-metoksy-2-naftyl)-a-metylacetat, isopentyl 2-(6-methoxy-2-naphthyl)-α-methylacetate,
gir i hvert tilfelle, 2-(6-metoksy-2-naftyl)-3-metyletanol; gives in each case, 2-(6-methoxy-2-naphthyl)-3-methylethanol;
metyl 2-(6-metyltio-2-naftyl)-a-metylacetat, methyl 2-(6-methylthio-2-naphthyl)-α-methylacetate,
etyl 2-(6-metyltio-2-naftyl)-a-metylacetat, isobutyl 2-(6-metyltio-2-naftyl)-a-metylacetat, n-pentyl 2-(6-metyltio-2-naftyl)-a-metylacetat, ethyl 2-(6-methylthio-2-naphthyl)-α-methylacetate, isobutyl 2-(6-methylthio-2-naphthyl)-α-methylacetate, n-pentyl 2-(6-methylthio-2-naphthyl)-α -methyl acetate,
isopentyl 2-(6-metyltio-2-naftyl)-a-metylacetat, isopentyl 2-(6-methylthio-2-naphthyl)-α-methylacetate,
gir i hvert tilfelle 2- (6-metyltio-2-naftyl)-3-metyletanol, og gives in each case 2-(6-methylthio-2-naphthyl)-3-methylethanol, and
metyl 2-(6-metyl-2-naftyl)-a-metylacetat, methyl 2-(6-methyl-2-naphthyl)-α-methylacetate,
etyl 2-(6-metyl-2-naftyl)-a-metylacetat, ethyl 2-(6-methyl-2-naphthyl)-α-methylacetate,
isobutyl 2- (6-metyl-2-naftyl)-a-metylacetat, isobutyl 2-(6-methyl-2-naphthyl)-α-methylacetate,
n-pentyl 2-(6-metyl-2-naftyl)-a-metylacetat, n-pentyl 2-(6-methyl-2-naphthyl)-α-methylacetate,
isopentyl 2-(6-metyl-2-naftyl)-a-metylacetat, isopentyl 2-(6-methyl-2-naphthyl)-α-methylacetate,
gir i hvert tilfelle 2-(6-metyl-2-naftyl)-3-metyletanol. gives in each case 2-(6-methyl-2-naphthyl)-3-methylethanol.
Eksempel 2 Example 2
En blanding av 46 g 6-metoksy-2-naftyl-a-metyleddiksyre, A mixture of 46 g of 6-methoxy-2-naphthyl-α-methylacetic acid,
6 g diboran og 220 ml tetrahydrofuran omrøres i" 8 timer ved romtemperatur (ca. 23°C). Blandingen settes til side i 1 time etter å ha blitt fortynnet med 50 ml vandig aceton, hvoretter 300 ml dietyleter tilsettes. Den resulterende blanding vaskes med vann, tørkes over natriumsulfat og inndampes hvilket gir 3-(6-metoksy-2-naftyl)-3-metyletanol. 6 g of diborane and 220 ml of tetrahydrofuran are stirred for 8 hours at room temperature (about 23°C). The mixture is set aside for 1 hour after being diluted with 50 ml of aqueous acetone, after which 300 ml of diethyl ether is added. The resulting mixture is washed with water, dried over sodium sulfate and evaporated to give 3-(6-methoxy-2-naphthyl)-3-methylethanol.
Ved å gjenta den ovenfor beskrevne metode med 6-metyltio-2-naftyl-a-metyleddiksyre oppnåes 3-(6-metyltio-2-naftyl)-3-metyletanol. By repeating the method described above with 6-methylthio-2-naphthyl-α-methylacetic acid, 3-(6-methylthio-2-naphthyl)-3-methylethanol is obtained.
Eksempel 3 Example 3
En blanding av 1 g 3-(6-metyltio-2-naftyl)-3-metyletanol, A mixture of 1 g of 3-(6-methylthio-2-naphthyl)-3-methylethanol,
4 ml pyridin og 2 ml' eddiksyreanhydrid hensettes ved romtemperatur i 15 timer. Blandingen helles deretter i isvann og det dannede faste stoff oppsamles ved filtrering, vaskes med vann og tørkes til acetat-esteren av 3-(6-metoksy~2-naftyl)-3-metyletanol som kan renses ytterligere ved omkrystallisering fra aceton:heksan, smeltepunkt 49°-50°C. 4 ml of pyridine and 2 ml of acetic anhydride are allowed to stand at room temperature for 15 hours. The mixture is then poured into ice water and the solid formed is collected by filtration, washed with water and dried to the acetate ester of 3-(6-methoxy~2-naphthyl)-3-methylethanol which can be further purified by recrystallization from acetone:hexane, melting point 49°-50°C.
Eksempel 4 Example 4
Den anti-inflammatoriske aktivitet av -3-(6-metoksy-2-naftyl)~ 3-metyletanol ble sammenlignet med den til fenylbutazon ved hjelp av The anti-inflammatory activity of -3-(6-methoxy-2-naphthyl)~ 3-methylethanol was compared with that of phenylbutazone using
0 0
et forsøk med carrageenin-indusert betennelse i en rottepote som be-skrevet av CA. Winter et al., Proceedings in Experimental Biology & M-dicine 111, 544-547 (1962). an experiment with carrageenin-induced inflammation in a rat paw as described by CA. Winter et al., Proceedings in Experimental Biology & Medicine 111, 544-547 (1962).
Forsøket ble modifisert idet det ble benyttet hunrotter med en vekt på 80 - 90 g og betennelsesgraden ble målt i enheter av vekten av bakre pote snarere enn i enheter av volumet av bakre pote. Resultatene er vist i den nedenstående tabell. The experiment was modified in that female rats with a weight of 80 - 90 g were used and the degree of inflammation was measured in units of the weight of the hind paw rather than in units of the volume of the hind paw. The results are shown in the table below.
Eksempel 5 Example 5
Den anti-pyretiske aktivitet for 3-(6-metoksy-2-naftyl)-3-metyletanol ble sammenlignet med den anti-pyretiske aktivitet for aspirin. The anti-pyretic activity of 3-(6-methoxy-2-naphthyl)-3-methylethanol was compared with the anti-pyretic activity of aspirin.
Anti- pyretisk aktivitet - Det ble benyttet hunrotter med en vekt på 90 - 100 g. Den "normale" rektale temperatur hos rottene ble målt ved tid 0, fulgt av subkutan injeksjon (1 ml dorsalt, 1 ml ven-tralt) av 2 ml av en gjærsuspensjon (gjærsuspensjonen fremstilles ved suspendering av en kake av Fleischman's gjær i 22 ml 0.9 % NaCl). In-jeksjonsstedene masseres for å fordele suspensjonen under huden. Gjær-injeksjonen forårsaker forhøyet legemstemperatur. Ved tid 17 ble rottene igjen massert for å stimulere' en ytterligere økning i legemstemperatur. (Det ble funnet at behandling av rottene på det tidspunkt den andre temperaturen ble notert, resulterte i en stigning i legemstemperatur). Ved tid 18 ble den andre rektale temperatur notert hvoretter forsøksforbindelsen ble administrert oralt ved gavage i 1 ml vandig bærer. (Den vandige bæreren besto av 0.9 % NaCl, 0.4 % "poly-sorbat 80", 0.5 % karboksymetylcellulose, 0.9 % benzylalkohol og vann). Den tredje rektale temperatur ble notert 2 timer etter administrering av forsøksforbindelsen. Antipyretic activity - Female rats weighing 90 - 100 g were used. The "normal" rectal temperature of the rats was measured at time 0, followed by subcutaneous injection (1 ml dorsal, 1 ml ventral) of 2 ml of a yeast suspension (the yeast suspension is prepared by suspending a cake of Fleischman's yeast in 22 ml of 0.9% NaCl). The injection sites are massaged to distribute the suspension under the skin. The yeast injection causes an elevated body temperature. At time 17, the rats were again massaged to stimulate a further increase in body temperature. (It was found that treating the rats at the time the second temperature was noted resulted in a rise in body temperature). At time 18, the second rectal temperature was noted after which the test compound was administered orally by gavage in 1 ml aqueous vehicle. (The aqueous vehicle consisted of 0.9% NaCl, 0.4% "poly-sorbate 80", 0.5% carboxymethylcellulose, 0.9% benzyl alcohol and water). The third rectal temperature was noted 2 hours after administration of the test compound.
Graden av anti-pyretisk aktivitet ble målt som en senkning The degree of anti-pyretic activity was measured as a lowering
i temperatur (°F) fra den andre til den tredje temperaturavlesning (temperatur ved tid 18 - temperatur ved tid 20) i forhold til en kon-trollprøve. Resultatene er vist i nedenstående tabell. in temperature (°F) from the second to the third temperature reading (temperature at time 18 - temperature at time 20) relative to a control sample. The results are shown in the table below.
Claims (2)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NO210969A NO125971B (en) | 1969-05-22 | 1969-05-22 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NO210969A NO125971B (en) | 1969-05-22 | 1969-05-22 |
Publications (1)
Publication Number | Publication Date |
---|---|
NO125971B true NO125971B (en) | 1972-12-04 |
Family
ID=19878649
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO210969A NO125971B (en) | 1969-05-22 | 1969-05-22 |
Country Status (1)
Country | Link |
---|---|
NO (1) | NO125971B (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DK156642B (en) * | 1973-09-11 | 1989-09-18 | Beecham Group Ltd | ANALOGY PROCEDURE FOR THE PREPARATION OF NAPTHALEND DERIVATIVES |
-
1969
- 1969-05-22 NO NO210969A patent/NO125971B/no unknown
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DK156642B (en) * | 1973-09-11 | 1989-09-18 | Beecham Group Ltd | ANALOGY PROCEDURE FOR THE PREPARATION OF NAPTHALEND DERIVATIVES |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
NO142441B (en) | ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY EFFECTIVE CARBOXYLIC ACID DERIVATIVES | |
US2489236A (en) | Synthesis of biotin and related compounds | |
SU1053743A3 (en) | Process for preparing phenylacetic acid derivatives or their salts | |
US3468939A (en) | 4- and 5-aryl-1-naphthaleneacetic acid compounds | |
US4057641A (en) | Method of treating inflammation with 2-(2,3-dihydro-2-isopropyl-4-oxo-4H-1-benzopyran-6-yl)propionic acid | |
NO138061B (en) | ANALOGICAL PROCEDURE FOR THE PREPARATION OF NEW THERAPEUTICALLY ACTIVE SUBSTITUTED DIFENYLPROPIONIC ACID DERIVATIVES | |
US3385887A (en) | 4-isobutylphenylacetic acid | |
IL32161A (en) | Beta-(2-naphyhyl)beta-methyl methanol derivatives and their preparation | |
NO125971B (en) | ||
US4337353A (en) | Novel carboxylic acids, benzoyl phenyl alkanoic acids and use thereof | |
NO131930B (en) | ||
US4473583A (en) | Compositions containing certain derivatives of 4-phenyl-4-oxobuten-2-oic acid and methods of treatment using them | |
US4116972A (en) | Anti-inflammatory 1-oxo-isoindoline derivatives and processes for their preparation | |
US4008269A (en) | Phenylacetic acids | |
US3906038A (en) | 2-(6-Sulfo-2-naphthyl)propionic acid | |
US3792167A (en) | Naphthyl alkanols and derivatives thereof,methods of use thereof,and processes for the preparation thereof | |
NO143402B (en) | ANALOGY PROCEDURE FOR THE PREPARATION OF A THERAPEUTICALLY EFFECTIVE PHENYLEDIC ACETIC ACID DERIVATIVE | |
NO131507B (en) | ||
CS199550B2 (en) | Process for preparing derivatives of thianthrene,thioxanthene and phenoxathiine | |
NO792589L (en) | PROCEDURE FOR THE PREPARATION OF A HYDROXYDE DIETIC ACID DERIVATIVE | |
NO150878B (en) | ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 1-Naphthyl Acetic Acid Derivatives | |
NO783933L (en) | PROCEDURE FOR THE PREPARATION OF NAFTALENDER DERIVATIVES | |
NO144852B (en) | PROCEDURE FOR THE PREPARATION OF POLYMER DISPERSIONS AS A BASIS FOR LATEX PAINTING WITH HIGH WATER FABILITY, AND LATE PAINTING CONTAINING SUCH A DISPERSION | |
US4181736A (en) | Phenylacetic acid derivatives and therapeutic composition containing same | |
US3352903A (en) | Phenylalkanoic acids |