NO753167L - - Google Patents
Info
- Publication number
- NO753167L NO753167L NO753167A NO753167A NO753167L NO 753167 L NO753167 L NO 753167L NO 753167 A NO753167 A NO 753167A NO 753167 A NO753167 A NO 753167A NO 753167 L NO753167 L NO 753167L
- Authority
- NO
- Norway
- Prior art keywords
- carboxylate
- xanthone
- carboxylic acid
- methyl
- acid
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 claims description 33
- 239000002253 acid Substances 0.000 claims description 24
- 150000002148 esters Chemical class 0.000 claims description 23
- 238000000034 method Methods 0.000 claims description 18
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims description 9
- 125000005907 alkyl ester group Chemical group 0.000 claims description 8
- 150000001408 amides Chemical class 0.000 claims description 8
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 231100000252 nontoxic Toxicity 0.000 claims description 5
- 230000003000 nontoxic effect Effects 0.000 claims description 5
- 239000007858 starting material Substances 0.000 claims description 5
- 150000001350 alkyl halides Chemical class 0.000 claims description 4
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 3
- 230000003647 oxidation Effects 0.000 claims description 3
- 238000007254 oxidation reaction Methods 0.000 claims description 3
- 229940071870 hydroiodic acid Drugs 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 150000004965 peroxy acids Chemical class 0.000 claims description 2
- 238000003776 cleavage reaction Methods 0.000 claims 1
- 230000032050 esterification Effects 0.000 claims 1
- 238000005886 esterification reaction Methods 0.000 claims 1
- 230000007017 scission Effects 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 27
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 24
- -1 ester compounds Chemical class 0.000 description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
- 239000000243 solution Substances 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 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 12
- 239000011734 sodium Substances 0.000 description 12
- 229910052708 sodium Inorganic materials 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 230000000694 effects Effects 0.000 description 10
- 238000011282 treatment Methods 0.000 description 10
- 150000007513 acids Chemical class 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 125000004414 alkyl thio group Chemical group 0.000 description 6
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 6
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical class CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- 241000700198 Cavia Species 0.000 description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 206010020751 Hypersensitivity Diseases 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000000443 aerosol Substances 0.000 description 4
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical compound [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 229960001340 histamine Drugs 0.000 description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 4
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 4
- 229910052808 lithium carbonate Inorganic materials 0.000 description 4
- 210000004072 lung Anatomy 0.000 description 4
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 4
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- VMKOFRJSULQZRM-UHFFFAOYSA-N 1-bromooctane Chemical compound CCCCCCCCBr VMKOFRJSULQZRM-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000001347 alkyl bromides Chemical class 0.000 description 3
- 150000001351 alkyl iodides Chemical class 0.000 description 3
- 230000000172 allergic effect Effects 0.000 description 3
- 208000030961 allergic reaction Diseases 0.000 description 3
- 125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 3
- 208000010668 atopic eczema Diseases 0.000 description 3
- 229960001948 caffeine Drugs 0.000 description 3
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- MPPPKRYCTPRNTB-UHFFFAOYSA-N 1-bromobutane Chemical compound CCCCBr MPPPKRYCTPRNTB-UHFFFAOYSA-N 0.000 description 2
- PBLNBZIONSLZBU-UHFFFAOYSA-N 1-bromododecane Chemical compound CCCCCCCCCCCCBr PBLNBZIONSLZBU-UHFFFAOYSA-N 0.000 description 2
- LSXKDWGTSHCFPP-UHFFFAOYSA-N 1-bromoheptane Chemical compound CCCCCCCBr LSXKDWGTSHCFPP-UHFFFAOYSA-N 0.000 description 2
- MNDIARAMWBIKFW-UHFFFAOYSA-N 1-bromohexane Chemical compound CCCCCCBr MNDIARAMWBIKFW-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- NAMYKGVDVNBCFQ-UHFFFAOYSA-N 2-bromopropane Chemical compound CC(C)Br NAMYKGVDVNBCFQ-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- JNPRWSKMJDGYAN-UHFFFAOYSA-N 9-oxoxanthene-2-carboxylic acid Chemical class C1=CC=C2C(=O)C3=CC(C(=O)O)=CC=C3OC2=C1 JNPRWSKMJDGYAN-UHFFFAOYSA-N 0.000 description 2
- PNEYBMLMFCGWSK-UHFFFAOYSA-N Alumina Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 2
- 206010002198 Anaphylactic reaction Diseases 0.000 description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 2
- 206010013975 Dyspnoeas Diseases 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- 230000036783 anaphylactic response Effects 0.000 description 2
- 208000003455 anaphylaxis Diseases 0.000 description 2
- 239000000427 antigen Substances 0.000 description 2
- 102000036639 antigens Human genes 0.000 description 2
- 108091007433 antigens Proteins 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 2
- 239000001110 calcium chloride Substances 0.000 description 2
- 229910001628 calcium chloride Inorganic materials 0.000 description 2
- 159000000007 calcium salts Chemical class 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 125000005265 dialkylamine group Chemical group 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- KWIUHFFTVRNATP-UHFFFAOYSA-N glycine betaine Chemical compound C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 159000000003 magnesium salts Chemical class 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 230000020477 pH reduction Effects 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 229960004919 procaine Drugs 0.000 description 2
- 230000029058 respiratory gaseous exchange Effects 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- YAPQBXQYLJRXSA-UHFFFAOYSA-N theobromine Chemical compound CN1C(=O)NC(=O)C2=C1N=CN2C YAPQBXQYLJRXSA-UHFFFAOYSA-N 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- YXZFFTJAHVMMLF-UHFFFAOYSA-N 1-bromo-3-methylbutane Chemical compound CC(C)CCBr YXZFFTJAHVMMLF-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
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 1
- GIUUCQVKMWBSRT-UHFFFAOYSA-N 2-bromododecane Chemical compound CCCCCCCCCCC(C)Br GIUUCQVKMWBSRT-UHFFFAOYSA-N 0.000 description 1
- HLAUCEOFCOXKNF-UHFFFAOYSA-N 2-bromoheptane Chemical compound CCCCCC(C)Br HLAUCEOFCOXKNF-UHFFFAOYSA-N 0.000 description 1
- 125000003229 2-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- 206010027654 Allergic conditions Diseases 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 240000002470 Amphicarpaea bracteata Species 0.000 description 1
- 206010003591 Ataxia Diseases 0.000 description 1
- 208000009079 Bronchial Spasm Diseases 0.000 description 1
- 208000014181 Bronchial disease Diseases 0.000 description 1
- 206010006482 Bronchospasm Diseases 0.000 description 1
- COXVTLYNGOIATD-HVMBLDELSA-N CC1=C(C=CC(=C1)C1=CC(C)=C(C=C1)\N=N\C1=C(O)C2=C(N)C(=CC(=C2C=C1)S(O)(=O)=O)S(O)(=O)=O)\N=N\C1=CC=C2C(=CC(=C(N)C2=C1O)S(O)(=O)=O)S(O)(=O)=O Chemical compound CC1=C(C=CC(=C1)C1=CC(C)=C(C=C1)\N=N\C1=C(O)C2=C(N)C(=CC(=C2C=C1)S(O)(=O)=O)S(O)(=O)=O)\N=N\C1=CC=C2C(=CC(=C(N)C2=C1O)S(O)(=O)=O)S(O)(=O)=O COXVTLYNGOIATD-HVMBLDELSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 208000000059 Dyspnea Diseases 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 229910021380 Manganese Chloride Inorganic materials 0.000 description 1
- GLFNIEUTAYBVOC-UHFFFAOYSA-L Manganese chloride Chemical compound Cl[Mn]Cl GLFNIEUTAYBVOC-UHFFFAOYSA-L 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- GXCLVBGFBYZDAG-UHFFFAOYSA-N N-[2-(1H-indol-3-yl)ethyl]-N-methylprop-2-en-1-amine Chemical compound CN(CCC1=CNC2=C1C=CC=C2)CC=C GXCLVBGFBYZDAG-UHFFFAOYSA-N 0.000 description 1
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 108010058846 Ovalbumin Proteins 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 241001282135 Poromitra oscitans Species 0.000 description 1
- 206010036790 Productive cough Diseases 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Foreliggende oppfinnelse angår en fremgangsmåte for fremstilling av forbindelser med formelen: The present invention relates to a method for producing compounds with the formula:
og farmasøytisk akseptable, ikke-toksiske estere, amider og salter derav, hvor en R<1->gruppe er alkoksy med 1-12 karbonatomer, and pharmaceutically acceptable, non-toxic esters, amides and salts thereof, where an R<1-> group is alkoxy of 1-12 carbon atoms,
og den andre R^-gruppe er gruppen -S(0)' hvor n er 1 eller 2 ogand the other R^-group is the group -S(0)' where n is 1 or 2 and
, n , n
R er lavere alkyl. RR is lower alkyl. R
Denne fremgangsmåten karakteriseres ved at■ This method is characterized by that■
en 5(7)-hydroksy-7(5)"lavere alkyltio-xanton-2-karboksylsyre eller en lavere alkylester derav alkyleres med et alkylhalogenid med 1-12 karbonatomer,' eventuelt hydrolyserer et esterprodukt eller eventuelt forestrer et syreprodukt, fulgt av oksydasjon med persyre eller hydrogenperoksyd for-oppnåelse av den tilsvarende 5(7)-alkoksy-7(5)-lavere alkylsulfinyl-xanton-2-karboksylsyre eller en lavere alkylester derav, eller 5(7)-alkoksy-7(5)-lavere alkylsulfonyl-xanton-2-karboksylsyre eller lavere alkylester derav, respektivt, a 5(7)-hydroxy-7(5)"lower alkylthio-xanthone-2-carboxylic acid or a lower alkyl ester thereof is alkylated with an alkyl halide of 1-12 carbon atoms,' optionally hydrolyzes an ester product or optionally esterifies an acid product, followed by oxidation with peracid or hydrogen peroxide to obtain the corresponding 5(7)-Alkoxy-7(5)-lower alkylsulfinyl-xanthone-2-carboxylic acid or a lower alkyl ester thereof, or 5(7)-Alkoxy-7(5)-lower alkylsulfonyl-xanthone-2-carboxylic acid or lower alkyl ester thereof, respectively,
2) eventuelt hydrolyserer et esterprodukt fra trinn 1)2) optionally hydrolyzes an ester product from step 1)
til den tilsvarende frie 2-karboksylsyre, ogto the corresponding free 2-carboxylic acid, and
3) om ønsket omdanner en syre med ovenstående formel til 3) if desired, converts an acid with the above formula into
farmasøytisk akseptable, ikke-toksiske estere, amider og salter derav. pharmaceutically acceptable, non-toxic esters, amides and salts thereof.
De nye forbindelser som fremstilles ifølge oppfinnelsen er nyttige for å lette symptomer forbundet med allergiske lidelser av den type som frembringes ved "ahtigen-antistoff (allergiske) reaksjoner. Ved bruk av forbindelsene hemmer man effektene av den allergiske reaksjon når nevnte forbindelser administreres i en effektiv mengde. Uten å være bundet av en spesiell teoretisk virkningsmekanisme antas det at de aktive forbindelser virker slik at de hemmer frigjøringen og/eller virkningen av toksiske produkter, f.eks. histamin, 5-hydroksytriptamin, langsomt fri-gjørende- stoff (SRS-A) eller andre toksiske forbindelser som produseres som et resultat av en kombinasjon av spesifikt antistoff og antigen (allergisk reaksjon). Disse egenskaper gjør de fremstilte forbindelser nyttige ved behandling av forskjellige allergiske tilstander. The new compounds produced according to the invention are useful for alleviating symptoms associated with allergic disorders of the type produced by "ahtigen-antibody (allergic) reactions. By using the compounds, the effects of the allergic reaction are inhibited when said compounds are administered in an effective amount. Without being bound by a particular theoretical mechanism of action, it is assumed that the active compounds act in such a way that they inhibit the release and/or the action of toxic products, e.g. histamine, 5-hydroxytryptamine, slow-release substance (SRS- A) or other toxic compounds produced as a result of a combination of specific antibody and antigen (allergic reaction).These properties make the compounds produced useful in the treatment of various allergic conditions.
De nye forbindelser virker også avslappende på glatte muskler, de virker f.eks. som bronkiedilatorer og kan følgelig brukes ved behandling av tilstander hvor slike midler er ønske-lige, f.eks. ved behandling av bronkiekonstriksjon. Forbindelsene er også ■vasodilatorer og er derfor nyttige ved behandling av tilstander hvor slike midler forordnes, som f.eks. ved behandling av lidelser i nyrer eller hjerte.. The new compounds also have a relaxing effect on smooth muscles, they work e.g. as bronchial dilators and can consequently be used in the treatment of conditions where such agents are desirable, e.g. in the treatment of bronchial constriction. The compounds are also ■vasodilators and are therefore useful in the treatment of conditions where such agents are prescribed, such as e.g. when treating disorders of the kidneys or heart..
Man bruker således de ifølge foreliggende oppfinnelse fremstilte forbindelser til å inhibere effektene ved allergisk reaksjon, ved at man administrerer en effektiv mengde av en forbindelse som ovenfor angitt. The compounds produced according to the present invention are thus used to inhibit the effects of an allergic reaction, by administering an effective amount of a compound as indicated above.
Ved bruk av de ifølge oppfinnelsen fremstilte forbindelser blir en effektiv mengde av en slik forbindelse eller et farmasøytisk preparat derav administrert ved hjelp av vanlige og akseptable metoder, enten alene eller i kombinasjon med en annen forbindelse eller forbindelser fremstilt ifølge oppfinnelsen eller andre farmasøytiske midler, slik som antibiotiske stoffer, hormonelle midler, osv. Disse forbindelser eller preparater kan således administreres oralt, topisk, parenteralt eller ved inha-lering og enten som fast stoff, væske eller i gassformige dose-ringer inkludert tabletter, suspensjoner og aerosoler, som også omtalt i det nedenstående. Administrasjonen kan utføres i form av enkle doser under kontinuerlig behandling, eller ved enke lt-' doseterapi ad libitum. I foretrukne utførelser vil man bruke forbindelsene når det er ønskelig med lettelse av visse symptomer, men forbindelsene kan også brukes ved kontinuerlig eller profylaktisk behandling. When using the compounds produced according to the invention, an effective amount of such a compound or a pharmaceutical preparation thereof is administered by means of common and acceptable methods, either alone or in combination with another compound or compounds produced according to the invention or other pharmaceutical agents, such such as antibiotic substances, hormonal agents, etc. These compounds or preparations can thus be administered orally, topically, parenterally or by inhalation and either as a solid, liquid or in gaseous dosage rings including tablets, suspensions and aerosols, as also discussed in the below. The administration can be carried out in the form of single doses during continuous treatment, or by single dose therapy ad libitum. In preferred embodiments, the compounds will be used when relief of certain symptoms is desired, but the compounds can also be used for continuous or prophylactic treatment.
Sett på bakgrunn av det ovenstående og også.i betrakt-ning av graden av den.tilstand som skal behandles, pasientens alder, osv., og dette er faktorer som lett kan bestemmes ved rutineeksperimenter, vil den effektive dose variere innenfor et vidt område. Vanligvis vil en effektiv mengde variere fra 0,005 - 100 mg/kg legemsvekt pr. dag og fortrinnsvis fra 0,01 - 100 mg/kg legemsvekt pr. dag. Sagt på en annen måte vil en effektiv mengde vanligvis variere fra ca. 0,5 til 7000 mg pr. dag pr. pasient. In view of the above and also in consideration of the degree of the condition to be treated, the patient's age, etc., and these are factors which can be easily determined by routine experiments, the effective dose will vary within a wide range. Generally, an effective amount will vary from 0.005 - 100 mg/kg body weight per day and preferably from 0.01 - 100 mg/kg body weight per day. Put another way, an effective amount will usually vary from approx. 0.5 to 7000 mg per day per patient.
Egnede farmasøytiske bærere for formulering av nevnte preparater kan være faste stoffer, væsker eller gasser. Prepara-tene kan således være i form av tabletter, piller,kapsler, pul-vere, preparater med forlenget frigjøring av aktive forbindelser, oppløsninger, suspensjoner, eliksirer, aerosoler og lignende. Bærerne kan velges fra forskjellige oljer inkludert pétroleum-oljer, animalske, vegetabilske eller syntetiske oljer, f.eks. peanøttolje, soyaolje, mineralolje, sesamolje og lignende. Vann, saltvann, vandig dekstrose og glykoler foretrekkes som flytende bærere, spesielt for injeksjonsoppløsninger. Egnede farmasøy-tiske hjelpemidler er stivelse, cellulose, talk, glukose, laktose, sukrose, gelatin, malt, ris, mel, kritt, silisiumdioksydgel, magnesiumstearat, natriumstearat, glycerylmonostearat, nat.rium-klorid, tørket skummet melk, glycerol, propylenglykol, vann, etanol og lignende. Egnede farmasøytiske bærere og deres prepa-. rater er beskrevet i "Remingtons Pharmaceutical Sciences" av E.W. Martin. Slike preparater vil i alle tilfelle inneholde en effektiv mengde av den aktive forbindelse sammen med en egnet mengde bærer for å danne den riktige doseringsform for korrekt administrasjon til pasienten. Suitable pharmaceutical carriers for formulating said preparations can be solids, liquids or gases. The preparations can thus be in the form of tablets, pills, capsules, powders, preparations with prolonged release of active compounds, solutions, suspensions, elixirs, aerosols and the like. The carriers can be selected from various oils including pétroleum oils, animal, vegetable or synthetic oils, e.g. peanut oil, soya oil, mineral oil, sesame oil and the like. Water, saline, aqueous dextrose and glycols are preferred liquid carriers, especially for injection solutions. Suitable pharmaceutical aids are starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silicon dioxide gel, magnesium stearate, sodium stearate, glyceryl monostearate, sodium chloride, dried skimmed milk, glycerol, propylene glycol, water, ethanol and the like. Suitable pharmaceutical carriers and their preparation. rates are described in "Remington's Pharmaceutical Sciences" by E.W. Martin. Such preparations will in all cases contain an effective amount of the active compound together with a suitable amount of carrier to form the correct dosage form for correct administration to the patient.
De nye forbindelser viser aktivitet som inhibitorer av effektene av allergiske reaksjoner slik disse kan måles ved prø-.ver som indikerer slik aktivitet og innebærer passiv kutan ana-fylakse beskrevet av J. Goose et al.,.Immunology, 16, 7^9 (1969). The new compounds show activity as inhibitors of the effects of allergic reactions as these can be measured by samples that indicate such activity and involve passive cutaneous anaphylaxis described by J. Goose et al., Immunology, 16, 7^9 ( 1969).
Oppfinnelsens fremgangsmåte kan illustreres ved følgende: The method of the invention can be illustrated by the following:
Re. ak. sj onsskj ema A'Re. ouch. sea view A'
Forbindelsene med formel (2') kan alternativt fremstilles i overensstemmelse med følgende reaksjonsskjerna: The compounds of formula (2') can alternatively be prepared in accordance with the following reaction core:
7 q in 11 7 q in 11
hvor hver av gruppene R , R , R og R har den ovenfor angitte where each of the groups R , R , R and R has the above indicated
7 ' 14 7 '14
betydning, R er hydrogen eller lavere alkyl og R er en alkylgruppe med 1-12 .karbonatomer, og mer spesielt ved trinnene 17 + 18<+>19 2 * (20, 21) og 17' 19 2 V (20,21) i skjemaet ovenfor, samt ved meaning, R is hydrogen or lower alkyl and R is an alkyl group of 1-12 carbon atoms, and more particularly at steps 17 + 18<+>19 2 * (20, 21) and 17' 19 2 V (20,21) in the form above, as well as by
Reaksjonsskjema B'Reaction scheme B'
Forbindelsene med formel (4') kan.alternativt fremstilles i overensstemmelse med .følgende reaksjonsskjema: The compounds with formula (4') can alternatively be prepared in accordance with the following reaction scheme:
7 7' 10 11 13 7 7' 10 11 13
hvor hver av gruppene R , R , R , R og R har den ovenfor angitte betydning, og R 15 er en alkylgruppe med 1-12 karbonatomer, og mer spesielt ved trinnene 23"<*>24"<*>25<+>26, 27 og 23 "* 25 26, 27 i skjemaet B' ovenfor. where each of the groups R , R , R , R and R has the above meaning, and R 15 is an alkyl group with 1-12 carbon atoms, and more particularly at steps 23"<*>24"<*>25<+> 26, 27 and 23 "* 25 26, 27 in form B' above.
Under henvisning til de ovenstående reaksjonsskjemaerWith reference to the above reaction forms
A' og B', så blir 5-alkoksy-7-lavere alkyltiosyrene eller estrene (16) og 5,-lavere alkyltio-7-metoksysyrene eller estrene (22), fortrinnsvis metoksyforbindelsene, omdannet til deres tilsvarende 5-hydroksy-7-lavere alkyltiosyrer (17) og 5-lavere alkyltio-7-hydroksysyrer, (23) ved behandling med hydrojod- eller hydrobrom-syre i nærvær av et egnet oppløsningsmiddel, f.eks. eddiksyre anhydrid, eddiksyre eller propionsyre. A' and B', then the 5-hydroxy-7-lower alkylthio acids or esters (16) and the 5,-lower alkylthio-7-methoxy acids or esters (22), preferably the methoxy compounds, are converted into their corresponding 5-hydroxy-7- lower alkylthio acids (17) and 5-lower alkylthio-7-hydroxy acids, (23) by treatment with hydroiodic or hydrobromic acid in the presence of a suitable solvent, e.g. acetic anhydride, acetic acid or propionic acid.
Forbindelsene med formler (17) og (23) blir deretter eventuelt forestret med et alkylhaldgeni'd, f .eks. metyljodid, etylbromid og lignende, i nærvær av et organisk oppløsningsmid-del, f.eks. dimetylformamid, dimetylacetamid, N-metylpyrrolidon og lignende, og litiumkarbonat, for oppnåelse av esterforbindel-sene med formlene (18) og (24). The compounds with formulas (17) and (23) are then optionally esterified with an alkyl halide, e.g. methyl iodide, ethyl bromide and the like, in the presence of an organic solvent, e.g. dimethylformamide, dimethylacetamide, N-methylpyrrolidone and the like, and lithium carbonate, to obtain the ester compounds with the formulas (18) and (24).
5-hydroksy-7_lavere alkyltiosyrene (17) eller estrene (18) og 5-lavere alkyltio-7-hydroksysyrene (23) eller estrene , (24), foretres med et alkylhalogenid, fortrinnsvis alkylbromid, f.eks. etylbromid, 2-brompropan (isopropylbromid), 1-brombutan (n-butylbromid), l-brom-3-metylbutan (isopentylbromid), 1-brom-heksan (heksylbromid), 1-bromheptan (heptylbromid), 2-bromheptan, 1-bromoktan (oktylbromid), 1-bromdodekan (dodecylbromid), 2-bromdodekan, og lignende, i nærvær av et organisk oppløsningsmid-del, f.eks. dimetylformamid, dimetylacetamid, aceton og lignende, og kaliumkarbonat, for oppnåelse av 5_alkoksy-7-lavere alkyltio-forbindelsene (19) og 5-lavere alkyltio-7-alkoksyforbindelsene The 5-hydroxy-7_lower alkylthio acids (17) or esters (18) and the 5-lower alkylthio-7-hydroxy acids (23) or esters, (24), are preferably treated with an alkyl halide, preferably alkyl bromide, e.g. ethyl bromide, 2-bromopropane (isopropyl bromide), 1-bromobutane (n-butyl bromide), l-bromo-3-methylbutane (isopentyl bromide), 1-bromo-hexane (hexyl bromide), 1-bromoheptane (heptyl bromide), 2-bromoheptane, 1 -bromooctane (octyl bromide), 1-bromododecane (dodecyl bromide), 2-bromododecane, and the like, in the presence of an organic solvent, e.g. dimethylformamide, dimethylacetamide, acetone and the like, and potassium carbonate, to obtain the 5-alkoxy-7-lower alkylthio compounds (19) and the 5-lower alkylthio-7-alkoxy compounds
(25) j respektivt.(25) j respectively.
Forbindelsene med formlene. (19) og (25) oksyderes til silfinylforbindelsene med formler (20) og (26) og sulfonylfor-■ bindelsene med formler (21) og (27), som beskrevet i norsk søknad 2495/72. Estrene med formlene (20), (26), (21) og (27) underkastes eventuelt basehydrolysé, ifølge den metode som er beskrevet i nevnte søknad, bg dette gir 5-alkoksy-7-lavere alkyl-sulf onylsyrene ,- 5-lavere alkylsulfinyl-7-alkoksysyrene, 5-alkoksy-7-lavere alkylsulfotrylsyrene og 5-lavere alkylsulfonyl-7-alkoksysyrene. Frie syrer med formler (20), (21), (26) og (27) omdannes eventuelt til deres salter, estere og amider som beskrevet i det nedenstående. The connections with the formulas. (19) and (25) are oxidized to the sulfinyl compounds with formulas (20) and (26) and the sulfonyl compounds with formulas (21) and (27), as described in Norwegian application 2495/72. The esters with the formulas (20), (26), (21) and (27) are optionally subjected to base hydrolysis, according to the method described in the aforementioned application, because this gives the 5-alkoxy-7-lower alkyl-sulfonyl acids,- 5- the lower alkylsulfinyl-7-alkoxy acids, the 5-lower alkylsulfonyl-7-alkoxy acids and the 5-lower alkylsulfonyl-7-alkoxy acids. Free acids with formulas (20), (21), (26) and (27) are optionally converted into their salts, esters and amides as described below.
Syreestrene.av xanton-2-karboksylsyrene fremstilles som beskrevet i nevnte norske søknad 2495/72, dvs. ved behandling av syren med et eterisk diazoalkan slik som diazometah og diazo-etan eller med det ønskede lavere alkyljodid i nærvær av litiumkarbonat ved romtemperatur eller med den ønskede lavere alkanol i nærvær av spor av svovelsyre under tilbakeløpskoking. Glycerol-estrene fremstilles ved behandling av syren med tionylklorid The acid esters of the xanthone-2-carboxylic acids are prepared as described in the aforementioned Norwegian application 2495/72, i.e. by treating the acid with an ethereal diazoalkane such as diazometh and diazoethane or with the desired lower alkyl iodide in the presence of lithium carbonate at room temperature or with the desired lower alkanol in the presence of traces of sulfuric acid during reflux. The glycerol esters are produced by treating the acid with thionyl chloride
fulgt av behandling med hensiktsmessig beskyttet etyienglykolfollowed by treatment with suitably protected ethylene glycol
eller propylenglykol (f.eks. "Solketal") i pyridin, og hydroly-sering av den beskyttende gruppe i den således dannede ester med fortynnet syre. or propylene glycol (e.g. "Solketal") in pyridine, and hydrolyzing the protecting group in the thus formed ester with dilute acid.
Amidene av xanton-2-karboksylsyrene fremstilles ved behandling av syrene med tionylklorid fulgt av-behandling med vannfri ammoniakk, alkylamiri, dialkylamin, dialkylaminoalkyl- The amides of the xanthone-2-carboxylic acids are produced by treating the acids with thionyl chloride followed by treatment with anhydrous ammonia, alkylamiri, dialkylamine, dialkylaminoalkyl-
amin, alkoksyalkylamin eller fenetylamin. I lavere alkylsulfi-nylrekken blir karboksylsyreamidene fortrinnsvis fremstilt ved det tilsvarende lavere alkyltiotrinn fulgt av oksydasjon, som beskrevet ovenfor. amine, alkoxyalkylamine or phenethylamine. In the lower alkylsulfinyl series, the carboxylic acid amides are preferably prepared by the corresponding lower alkylthio step followed by oxidation, as described above.
Saltene av xanton-2-karboksylsyrene fremstilles ved behandling av tilsvarende syrer med farmasøytisk akseptable baser. Representative salter, avledet fra slike farmasøytisk akseptable baser, er natrium-, kalium-, litium-, ammonium-, kalsium-, magnesium-, ferro-, ferri-, sink-, mangano-, The salts of the xanthone-2-carboxylic acids are prepared by treating the corresponding acids with pharmaceutically acceptable bases. Representative salts derived from such pharmaceutically acceptable bases are sodium, potassium, lithium, ammonium, calcium, magnesium, ferrous, ferric, zinc, manganese,
aluminium-, mangani-, trimetylamin-, trietylamin-, tripropyl-amin-, $-(dimetylamino)etanol-, trietanolamin-, B-(dietyl-amino)etanol-, arginin-, lysin-, histidin-, N-etylpiperidin-, aluminium-, manganese-, trimethylamine-, triethylamine-, tripropylamine-, $-(dimethylamino)ethanol-, triethanolamine-, B-(diethylamino)ethanol-, arginine-, lysine-, histidine-, N-ethylpiperidine -,
hydrabamin-, kolin-, betain-, etylendiamin-, glukosamin-, metyl-glukamin-, teobromin-, purin-, piperazin-, piperidin-, polyamin-harpiks-, kaffein- og prokainsalter. Reaksjonen utføres i vandig oppløsning, alene eller i kombinasjon med et inert, vannblandbart organisk oppløsningsmiddel, ved en temperatur på fra ca. 0 til ca.. 100°C, fortrinnsvis ved romtemperatur. Typiske inerte, vannblandbare organiske oppløsningsmidler er metanol, etanol, isopropanol, butanol, aceton, dioksan og tetrahydrofuran. _ Ved fremstilling av toverdige metallsalter, slik som kalsiumsalter eller magnesiumsalter av syrene, blir fri syre-utgangsmateriale behandlet med omkring \ molar ekvivalent farmasøytisk akseptabel base. Når aluminiumsalter av syrene fremstilles, blir omkring 1/3 molar ekvivalent av den farmasøytisk akseptable base benyttet. hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, polyamine resin, caffeine and procaine salts. The reaction is carried out in aqueous solution, alone or in combination with an inert, water-miscible organic solvent, at a temperature of from approx. 0 to approx. 100°C, preferably at room temperature. Typical inert, water-miscible organic solvents are methanol, ethanol, isopropanol, butanol, acetone, dioxane and tetrahydrofuran. In the preparation of divalent metal salts, such as calcium salts or magnesium salts of the acids, free acid starting material is treated with about \molar equivalent of pharmaceutically acceptable base. When aluminum salts of the acids are prepared, about 1/3 molar equivalent of the pharmaceutically acceptable base is used.
I en foretrukken utførelse av oppfinnelsen blir kalsium-saltene og magnesiumsaltene av syrene fremstilt ved behandling av de tilsvarende natrium- eller kaliumsalter av syrene med minst en molar .ekvivalent kalsiumklorid eller magnesiumklorid, respektivt, i en vandig oppløsning, alene eller i kombinasjon med et inert, vannblandbart organisk oppløsningsmiddel ved en temperatur fra 20 til 100°C. In a preferred embodiment of the invention, the calcium salts and magnesium salts of the acids are prepared by treating the corresponding sodium or potassium salts of the acids with at least one molar equivalent of calcium chloride or magnesium chloride, respectively, in an aqueous solution, alone or in combination with an inert , water-miscible organic solvent at a temperature from 20 to 100°C.
I en annen foretrukken utførelse av oppfinnelsen blir aluminiumsaltene av syrene fremstilt ved behandling av syrene med minst 1/3 molar ekvivalent av et aluminiumalkoksyd, slik som aluminiumtrietoksyd, aluminiumtripropoksyd og lignende, i et hydrokarbonoppløsningsmiddel slik som benzen, >fylen, cykloheksan og lignende ved en temperatur fra 20 til 115°C. In another preferred embodiment of the invention, the aluminum salts of the acids are prepared by treating the acids with at least 1/3 molar equivalent of an aluminum alkoxide, such as aluminum trioxide, aluminum triproxide and the like, in a hydrocarbon solvent such as benzene, >phylene, cyclohexane and the like at a temperature from 20 to 115°C.
Med den benyttede betegnelse "lavere alkyl" menes en lavere alkylgruppe inneholdende 1-5 karbonatomer inkludert rette og forgrenede grupper og cykliske alkylgrupper, f.eks. metyl, etyl,, n-propyl, isopropyl, n-butyl, isobutyl, sek-butyl, t-butyl, n-pentyl,. isopentyl, sek-pentyl, tnpentyl, cyklopropyl, cyklobutyl og cyklo-pentyl. Med den benyttede betegnelse "alkyl" mehes rette og forgrenede alkylgrupper med 1-12 karbonatomer inkludert de ovennevnte lavere .alkylgrupper, og f.eks. n-heksyl, isoheksyl, n-heptyl, iso-heptyl, n-oktyl, isooktyl, n-nonanyl, n-dekanyl, n-undekanyl, n-dodekanyl og lignende. Med den benyttede betegnelse "alkoksy" menes gruppen "0-alkyl" hvor "alkyl" har den ovenfor angitte betydning. The term "lower alkyl" used means a lower alkyl group containing 1-5 carbon atoms including straight and branched groups and cyclic alkyl groups, e.g. methyl, ethyl,, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl,. isopentyl, sec-pentyl, tnpentyl, cyclopropyl, cyclobutyl and cyclopentyl. The term "alkyl" refers to straight and branched alkyl groups with 1-12 carbon atoms including the above-mentioned lower alkyl groups, and e.g. n-hexyl, isohexyl, n-heptyl, iso-heptyl, n-octyl, isooctyl, n-nonanyl, n-decanyl, n-undecanyl, n-dodecanyl and the like. The term "alkyl" used means the group "O-alkyl" where "alkyl" has the above meaning.
Med den benyttede betegnelse "farmasøytisk akseptable, ikke-toksiske estere, amider og salter" menes henholdsvis en alkyl-eller glycerolester; et usubstituert monoalkyl, dialkyl, dialkyl-aminoalkyl, alkoksyalkyl eller fenetylsubstituert amid og et salt som definert ovenfor. With the term used "pharmaceutically acceptable, non-toxic esters, amides and salts" is meant respectively an alkyl or glycerol ester; an unsubstituted monoalkyl, dialkyl, dialkylaminoalkyl, alkoxyalkyl or phenethyl substituted amide and a salt as defined above.
I de lavere alkylsulfinylserier har forbindelsene et asymmetrisk karbonatom. Foreliggende fremgangsmåter vil da gi både d- og 1-, samt dl-former hvilke således omfattes av oppfinnelsen. Isomerene kan om ønsket separeres på vanlig måte slik som dannelse av alkaloidsaltene av produktene og anvendelse av fraksjonert krystallisering. In the lower alkylsulfinyl series, the compounds have an asymmetric carbon atom. Present methods will then give both d- and 1-, as well as dl-forms which are thus covered by the invention. If desired, the isomers can be separated in the usual way, such as forming the alkaloid salts of the products and using fractional crystallization.
Den nomenklatur som er benyttet er i overensstemmelse med Chemical Abstracts, 56, Subject Index (1962, januar-juni).' The nomenclature used is in accordance with Chemical Abstracts, 56, Subject Index (1962, January-June).'
Av hensiktsmessige grunner refererer bruken av nomenklaturen 5(7)-substituent A-7(5)-substituent B-xanton til 5-substituent A-7-substituent B-xanton og 5-substituent B-7_substituent A-xanton. For convenience, the use of the nomenclature 5(7)-substituent A-7(5)-substituent B-xanthone refers to 5-substituent A-7-substituent B-xanthone and 5-substituent B-7_substituent A-xanthone.
Følgende eksempler illustrerer oppfinnelsen. Når det har vært nødvendig er eksemplene -blitt.gjentatt for å. få tii-veiebragt utgangsmaterialene for de etterfølgende eksempler. The following examples illustrate the invention. When it has been necessary, the examples have been repeated in order to obtain the starting materials for the subsequent examples.
Eksempel 1Example 1
A. Til en suspensjon av 14,5 g 5-metoksy-7-(metyltio)-xanton-2-karboksylsyre i 350 ml eddiksyreanhydrid, tilsettes •100-ml 47% hydrojodsyre dråpevis under avkjøling med is. Etter tilbakeløpskoking av den resulterende blanding i 20 timer, blir den fortynnet med 750 ml varmt vann og avkjøles,. Det gule produkt frafiltreres, vaskes med vann og tørkes og dette gir 12,8 g 5~hydroksy-7-(metyltioxanton-2-karboksylsyre. A. To a suspension of 14.5 g of 5-methoxy-7-(methylthio)-xanthone-2-carboxylic acid in 350 ml of acetic anhydride, 100 ml of 47% hydroiodic acid is added dropwise while cooling with ice. After refluxing the resulting mixture for 20 hours, it is diluted with 750 ml of hot water and cooled. The yellow product is filtered off, washed with water and dried, and this gives 12.8 g of 5-hydroxy-7-(methylthioxanthone-2-carboxylic acid).
Ved å benytte 5-metyltio-7-metoksyxanton-2-karboksylsyre i stedet for 5-metoksy-7-(metyltio)-xanton-2-karboksylsyre oppnås på samme måte 5_metyltio-7-hydroksyxanton-2-karboksylsyre. By using 5-methylthio-7-methoxyxanthone-2-carboxylic acid instead of 5-methoxy-7-(methylthio)-xanthone-2-carboxylic acid, 5-methylthio-7-hydroxyxanthone-2-carboxylic acid is obtained in the same way.
På lignende måte oppnås andre 5~hydroksy-7-(lavere alkyltio)-xanton-2-karboksylsyrer og 5-lavere alkyltio-7-hydrok-syxanton-2-karboksylsyrer. In a similar manner, other 5-hydroxy-7-(lower alkylthio)-xanthone-2-carboxylic acids and 5-lower alkylthio-7-hydroxy-xanthone-2-carboxylic acids are obtained.
B. En blanding av 6,65 g 5_hydroksy-7-(metyltio)-xantonr 2-karboksylsyre, 4,5 g tørt litiumkarbonat, 4 ml metyljodid og 70 ml dimetylformamid, omrøres ved romtemperatur i 20 timer. Etter tilsetning av et overskudd eddiksyre/vann (1:1) fjernes overskudd metyljodid i en roterende fordamper. Det krystallinske produkt frafiltreres, vaskes og tørkes, og dette gir 6,8 g metyl-5-hydroksy-7-(metyltio)-xanton-2-karboksylat, sm.p. 286°C (dekomp.). B. A mixture of 6.65 g of 5-hydroxy-7-(methylthio)-xanthone 2-carboxylic acid, 4.5 g of dry lithium carbonate, 4 ml of methyl iodide and 70 ml of dimethylformamide is stirred at room temperature for 20 hours. After adding an excess of acetic acid/water (1:1), excess methyl iodide is removed in a rotary evaporator. The crystalline product is filtered off, washed and dried, and this gives 6.8 g of methyl 5-hydroxy-7-(methylthio)-xanthone-2-carboxylate, m.p. 286°C (decomp.).
Ved at man i' ovenstående metode benytter 5-metyltio~7-hydroksyxanton-2-karboksylsyre oppnås likeledes mety1-5-metyltio-7~hydroksyxanton-2-karboksylat, sm.p.'290°C (dekomp.). By using 5-methylthio-7-hydroxyxanthone-2-carboxylic acid in the above method, methyl 1-5-methylthio-7-hydroxyxanthone-2-carboxylate is also obtained, mp 290°C (decomp.).
Metoden gjentas under anvendelse av forskjellige lavere alkyljodider for dermed å fremstille lavere alkylsyreestere herav, f.eks. etyl-5-hydroksy-7-(metyltio)-xanton-2-karboksylat, pentyl-5-hydroksy-7-(metyltio)-xanton-2-karboksylat og etyl-5-metyltio-7-hydroksyxanton-2-karboksylat, og pentyl-5-metylt io--7-hydroksyxanton-2-karboksylat. The method is repeated using different lower alkyl iodides to thereby prepare lower alkyl acid esters thereof, e.g. ethyl 5-hydroxy-7-(methylthio)-xanthone-2-carboxylate, pentyl 5-hydroxy-7-(methylthio)-xanthone-2-carboxylate and ethyl 5-methylthio-7-hydroxyxanthone-2-carboxylate, and pentyl 5-methyl io -7-hydroxyxanthone-2-carboxylate.
C. 1,55 g metyl-5-hydroksy-7-(metyltio)-xanton-2-karbok-sylat omrøres ved romtemperatur med 2,5 g oktylbromid og 1,0 g kaliumkarbonat i 30 ml dimetylformamid i 18 timer. Etter surgjø-ring med fortynnet saltsyre, ekstraheres blandingen med kloroform, ekstraktene vaskes med vann, tørkes over magnesiumsulfat og inndampes. Filtrering av en kloroformoppløsning av det urene . produkt gjennom aluminiumoksyd (.aktivitet II) ga 2,0 g metyl-5-n-oktyloksy-7-(metyltio)-xanton-2-karboksylat. C. 1.55 g of methyl-5-hydroxy-7-(methylthio)-xanthone-2-carboxylate is stirred at room temperature with 2.5 g of octyl bromide and 1.0 g of potassium carbonate in 30 ml of dimethylformamide for 18 hours. After acidification with dilute hydrochloric acid, the mixture is extracted with chloroform, the extracts are washed with water, dried over magnesium sulfate and evaporated. Filtration of a chloroform solution of the impure. product through alumina (activity II) gave 2.0 g of methyl 5-n-octyloxy-7-(methylthio)-xanthone-2-carboxylate.
Ved i foregående metode å benytte metyl-5-metyltio-7-hydroksyxanton-2-karboksylat oppnås på samme måte metyl-5_metyltio-7-n-oktyloksyxanton-2-karboksylat. By using methyl 5-methylthio-7-hydroxyxanthone-2-carboxylate in the preceding method, methyl 5-methylthio-7-n-octyloxyxanthone-2-carboxylate is obtained in the same way.
Ovenstående metode gjentas under anvendelse av andre høyere alkylbromider for dermed å oppnå 5~og 7-høyere. alkoksy-forbindelser som f.eks. metyl-5-n-heksyloksy-7_(metyltio)-xanton-2-kartoksylatjmetyl-5-n-heptyloksy-7_(metyltio)-xanton-2-karboksylat, metyl-5-n-dodecyloksy-7-(metyltio)-xanton-2-karboksylåt, og metyl-5-metyltio-7_n-heksyloksyxanton-2-karboksylat, metyl-5-metyltio-7-n-heptyloksyxanton-2-karboksylat, og metyl-5-metyltio-7-n-dodecyloksyxanton-2-karboksylat. The above method is repeated using other higher alkyl bromides to thereby obtain 5- and 7-higher. Alkoxy compounds such as e.g. methyl 5-n-hexyloxy-7_(methylthio)-xanthone-2-carboxylatejmethyl-5-n-heptyloxy-7_(methylthio)-xanthone-2-carboxylate, methyl 5-n-dodecyloxy-7-(methylthio)- xanthone-2-carboxylate, and methyl 5-methylthio-7_n-hexyloxyxanthone-2-carboxylate, methyl 5-methylthio-7-n-heptyloxyxanthone-2-carboxylate, and methyl 5-methylthio-7-n-dodecyloxyxanthone- 2-carboxylate.
På lignende måter kan andre lavere alkylestere benyttes'i steden for metylesteren og ved bruk av et passende høyere alkylbromid, oppnås f.eks. etyl-5_n-oktyloksy-7_(metyltio)-xanton-2-karboksylat,'pentyl-5-n-oktyloksy-7-(metyltio)-xanton-2-karboksylat, etyl-5-n-heksyloksy-7-(metyltio)-xanton-2-karboksylat, pentyl-5-n-heptyloksy-7_(metyltio)-xanton-2-karboksylat, In similar ways, other lower alkyl esters can be used instead of the methyl ester and by using a suitable higher alkyl bromide, e.g. ethyl 5-n-octyloxy-7-(methylthio)-xanthone-2-carboxylate,'pentyl-5-n-octyloxy-7-(methylthio)-xanthone-2-carboxylate, ethyl 5-n-hexyloxy-7-(methylthio )-xanthone-2-carboxylate, pentyl-5-n-heptyloxy-7-(methylthio)-xanthone-2-carboxylate,
etyl-5-n-dodecyloksy-7~(metyltio)-xanton-2-karboksylat, ety1-5-metyltio-7-n-oktyloksyxanton-2-karboksylat, ethyl 5-n-dodecyloxy-7~(methylthio)-xanthone-2-carboxylate, ethyl 1-5-methylthio-7-n-octyloxyxanthone-2-carboxylate,
pentyl-5-metyltio-7-n-oktyloksyxanton-2-karboksylat, etyl-5-metylt io-7-n-heksyloksyxanton-2-karboksylat, pentyl-5-metyltio-7-n-heksyloksyxanton-2-karboksylat, og etyl-5-metyltio-7-n-dbdecyloksyxanton-2-karboksylat. pentyl 5-methylthio-7-n-octyloxyxanthone-2-carboxylate, ethyl 5-methylthio-7-n-hexyloxyxanthone-2-carboxylate, pentyl 5-methylthio-7-n-hexyloxyxanthone-2-carboxylate, and ethyl 5-methylthio-7-n-dbdecyloxyxanthone-2-carboxylate.
D. Til 2,0 g metyl-5-n-oktyloksy-7-(metyltio)-xanton-2-karboksylat i 60 ml kloroform tilsettes langsomt en oppløsning av. 910 mg m-klorperoksybenzosyre i 40 ml kloroform méns temperaturen holdes ved ca. 0°C. Etter at tilsetningen ;er ferdig filtreres oppløsningen gjennom aluminiumoksyd (aktivitet III) og D. To 2.0 g of methyl-5-n-octyloxy-7-(methylthio)-xanthone-2-carboxylate in 60 ml of chloroform is slowly added a solution of 910 mg of m-chloroperoxybenzoic acid in 40 ml of chloroform while the temperature is kept at approx. 0°C. After the addition is complete, the solution is filtered through aluminum oxide (activity III) and
inndampes, og dette gir 2,0 g metyl-5-n-oktyloksy-7-metylsulfinyl-xanton-2-karboksylat. is evaporated, and this gives 2.0 g of methyl 5-n-octyloxy-7-methylsulfinyl-xanthone-2-carboxylate.
Ved i foregående metode . år-benybte metyl-5-métylt io-7-n-oktyloksyxåhfcon^2-karboksylat.oppnås på samme måte metyl-5-metyl-sulfinyl-7-n-oktyloksyxanton-2-karboksylat. Wood in previous method. year-benybte methyl-5-methyl io-7-n-octyloxyxåhfcon^2-carboxylate. is obtained in the same way methyl 5-methyl-sulfinyl-7-n-octyloxyxanthone-2-carboxylate.
Ved å benytte de andre forbindelsene fremstilt i del Ci dette eksempel i steden for 5-n-oktyloksy-7~(metyltio)-xanton-2-karboksylat, oppnås f.eks.: metyl-5-n-heksyloksy-7-metylsulfinylxanton-2-karboksylat, metyl-5-n-heptyloksy-7-metylsulfinylxanton-2-karboksylat, mety1-5~n-dodecyloksy-7-metylsulfinylxanton-2-karboksylat, By using the other compounds prepared in part Ci of this example in place of 5-n-octyloxy-7~(methylthio)-xanthone-2-carboxylate, for example, methyl 5-n-hexyloxy-7-methylsulfinylxanthone is obtained -2-carboxylate, methyl 5-n-heptyloxy-7-methylsulfinylxanthone-2-carboxylate, methyl 1-5~n-dodecyloxy-7-methylsulfinylxanthone-2-carboxylate,
etyl-5"n-oktyloksy-7-metylsulfinylxanton-2-karboksylatjpentyl-5-n-oktyloksy-7-metylsulfinylxanton-2-karboksylat, ethyl 5"n-octyloxy-7-methylsulfinylxanthone-2-carboxylate pentyl 5-n-octyloxy-7-methylsulfinylxanthone-2-carboxylate,
etyl-5-n-heksyloksy-7_metylsulfinylxanton-2-karboksylat, penty1-5-n-heptyloksy-7-metylsulfinylxanton-2-karboksylat, og etyl-5-n-dodecyloksy-7~metylsulfinylxanton-2-karboksylat,.og metyl-5-metylsulf inyl-7-n-heksyloksyxanton-2-k«arboksylat, metyl-5-metyls'ulf inyl-7-n-heptyloksyxanton-2-karboksylat, metyl-5-metylsulfiny1-7-n-dodeeyloksyxanton-2-karboksylat, etyl-5-metyl'sulf inyl-7-n-oktyloksyxanton-2-karboksylat, pentyl-5-metylsulfiny1-7-n-oktyloksyxanton-2-karboksylat, etyl-5-metylsulfiny1-7-n-heksyloksyxanton-2-karboksylat, pentyl-5-metylsulfiny1-7-n-heksyloksyxanton-2-karboksylat, og etyl-5-metylsulfinyl-7_n-dodecyloksyxanton-2-karboksylat. E. Metyl-5-n-oktyloksy-7-(metyltio)-xanton-2-karboksylat (750 mg;);, 2 ml hydrogenperoksyd ( J>0%) og 40 ml eådiksyre oppvarmes på et dampbad (80°C) i 90 minutter. Tynnsjiktskromatografi. indikerer fravær av utgangsmateriale. Blandingen fortynnes med 60 ml varmt ethyl 5-n-hexyloxy-7-methylsulfinylxanthone-2-carboxylate, penty1-5-n-heptyloxy-7-methylsulfinylxanthone-2-carboxylate, and ethyl 5-n-dodecyloxy-7-methylsulfinylxanthone-2-carboxylate, and methyl -5-methylsulfinyl-7-n-hexyloxyxanthone-2-carboxylate, methyl-5-methylsulfinyl-7-n-heptyloxyxanthone-2-carboxylate, methyl-5-methylsulfinyl-7-n-dodeyloxyxanthone-2 -carboxylate, ethyl 5-methyl'sulfinyl-7-n-octyloxyxanthone-2-carboxylate, pentyl-5-methylsulfiny1-7-n-octyloxyxanthone-2-carboxylate, ethyl 5-methylsulfiny1-7-n-hexyloxyxanthone- 2-carboxylate, pentyl-5-methylsulfinyl-7-n-hexyloxyxanthone-2-carboxylate, and ethyl 5-methylsulfinyl-7_n-dodecyloxyxanthone-2-carboxylate. E. Methyl 5-n-octyloxy-7-(methylthio)-xanthone-2-carboxylate (750 mg);, 2 ml of hydrogen peroxide (J>0%) and 40 ml of acetic acid are heated on a steam bath (80°C) for 90 minutes. Thin layer chromatography. indicates absence of starting material. The mixture is diluted with 60 ml warm
vann og blandingen avkjøles, det faste stoff frafiltreres og tørkes hvilket gir metyl-5-n-oktyloksy-7-metylsulfonylxanton-2-karboksylat som kan omkrystalliseres fra,eddiksyre/vann. water and the mixture is cooled, the solid is filtered off and dried to give methyl 5-n-octyloxy-7-methylsulfonylxanthone-2-carboxylate which can be recrystallized from acetic acid/water.
Likeledes, ved å benytte metyl-5_metyltio-7_n-oktyloksy-2-karboksylat i foregående metode oppnås metyl-5-metylsulfonyl-7~n-oktyloksyxanton-2-karboksylat. Likewise, by using methyl-5-methylthio-7-n-octyloxy-2-carboxylate in the preceding method, methyl-5-methylsulfonyl-7-n-octyloxyxanthone-2-carboxylate is obtained.
På samme måte, ved å benytte de andre forbindelsene fremstilt i del C i dette eksempel i steden for 5-n-oktyloksy-7-(met.yltio )-xanton-2-karboksylat, oppnås f.eks.: mety 1-5-n-heksy loksy-7-me ty lsulf onylxant ort-2-karboksylat, metyl-5-n-heptyloksy-7-metylsulfonylxanton-2-karboksylat,' mety1-5-n-dodecyloksy-7-metylsulfonylxanton-2-karboksylat, .etyl-5-n-oktyloksy-7-metylsulfonylxanton-2-karboksylat, pentyl-5-n-oktyloksy-7-metylsulfonylxanton-2-karboksylat, etyl-5-n-heksyloksy-7-metylsulfonylxanton-2-karboksylat, pentyl-5-n-heptyloksy-7-metylsulfonylxanton-2-karboksylat, og etyl-5-n-dodecyloksy-7-metylsulfonylxanton-2-karboksylat, og metyl-5~metylsulfonyl-7-n-heksyloksyxanton-2-karboksylat, metyl-5-m.etylsulf onyl-7-n-heptyloksyxanton-2-karboksylat, mety1-5-mety1sulfonyl-7-n-dodecyloksyxanton-2-karboksylat, Similarly, using the other compounds prepared in part C of this example in place of 5-n-octyloxy-7-(methylthio)-xanthone-2-carboxylate, for example: methyl 1-5 -n-hexyloxy-7-methylsulfonylxanthate-2-carboxylate, methyl 5-n-heptyloxy-7-methylsulfonylxanthone-2-carboxylate,' methyl 1-5-n-dodecyloxy-7-methylsulfonylxanthone-2-carboxylate, .ethyl 5-n-octyloxy-7-methylsulfonylxanthone-2-carboxylate, pentyl-5-n-octyloxy-7-methylsulfonylxanthone-2-carboxylate, ethyl 5-n-hexyloxy-7-methylsulfonylxanthone-2-carboxylate, pentyl-5-n-heptyloxy-7-methylsulfonylxanthone-2-carboxylate, and ethyl 5-n-dodecyloxy-7-methylsulfonylxanthone-2-carboxylate, and methyl 5-methylsulfonyl-7-n-hexyloxyxanthone-2-carboxylate, methyl 5-m.ethylsulfonyl-7-n-heptyloxyxanthone-2-carboxylate, methyl 1-5-methylsulfonyl-7-n-dodecyloxyxanthone-2-carboxylate ,
etyl-5-metylsulfonyl-7-n-oktyloksyxanton-2-karboksylat, pentyl-5-metylsulfony1-7-n-oktyloksyxanton-2-karboksylat, etyl-5-metylsulfonyl-7-n-heksyloksyxant,on-2-karboksylat, ethyl 5-methylsulfonyl-7-n-octyloxyxanthone-2-carboxylate, pentyl-5-methylsulfonyl 1-7-n-octyloxyxanthone-2-carboxylate, ethyl 5-methylsulfonyl-7-n-hexyloxyxanthone-2-carboxylate,
pentyl-5-metylsulfonyl-7^n-heksyloksyxanton-2-karboksylat, og etyl-5-metylsulfonyl-7-n-dodecyloksyxanton-2-karboksylat. pentyl-5-methylsulfonyl-7-n-hexyloxyxanthone-2-carboxylate, and ethyl 5-methylsulfonyl-7-n-dodecyloxyxanthone-2-carboxylate.
F. 2,0 g metyl-5-n-oktyloksy-7_metylsulfinylxanton-2-karboksylat kokes under tilbakeløp i 30 minutter med 0,5 g kaliumhydroksyd i.80 ml etanol inneholdende 20 ml vann. Etter surgjøring med- fortynnet saltsyre, isoleres bunnfallet ved filtrering med sug og omkrystalliseres fra tetrahydrofuran/ F. 2.0 g of methyl-5-n-octyloxy-7-methylsulfinylxanthone-2-carboxylate is refluxed for 30 minutes with 0.5 g of potassium hydroxide in 80 ml of ethanol containing 20 ml of water. After acidification with dilute hydrochloric acid, the precipitate is isolated by filtration with suction and recrystallized from tetrahydrofuran/
etanol, hvilket gir 1,8 g 5-n-oktyloksy-7-metylsulfinylxanton-2-karboksylsyre, sm.p. 258-260°C. ethanol, giving 1.8 g of 5-n-octyloxy-7-methylsulfinylxanthone-2-carboxylic acid, m.p. 258-260°C.
Likeledes, ved som utgangsmateriale å benytte de andre forbindelsene oppnådd i del D og del E i dette eksempel i steden for metyl-5-n-oktyloksy-7-metylsulfinylxanton-2-karboksylat, Likewise, by using as starting material the other compounds obtained in part D and part E of this example in place of methyl 5-n-octyloxy-7-methylsulfinylxanthone-2-carboxylate,
oppnås f.eks.: 5-metylsulfinyl-7-n-oktyloksyxanton-2-karboksyl-jsyre, sm.p..2l8-219°C. is obtained, for example: 5-methylsulfinyl-7-n-octyloxyxanthone-2-carboxylic acid, m.p..218-219°C.
Eksempel. 2.—.Example. 2.—.
En blanding av 4.,5 g 5-n-oktyl-7-metylsulfinylxanton-. 2-karboksylsyre, 10- g metyljodid og 10 g litiumkarbonat i 75 ml -dimetylformamid omrøres ved romtemperatur i 18 timer. Deretter helles reaksjonsblandingen i fortynnet saltsyre-is og det resulterende bunnfall frafiltreres og vaskes, hvilket gir metyl-5_n-oktyl-7-metylsulfinylxanton-2-karboksylat. A mixture of 4.5 g of 5-n-octyl-7-methylsulfinylxanthone-. 2-carboxylic acid, 10 g of methyl iodide and 10 g of lithium carbonate in 75 ml of -dimethylformamide are stirred at room temperature for 18 hours. The reaction mixture is then poured into dilute hydrochloric acid ice and the resulting precipitate is filtered off and washed, giving methyl 5-n-octyl-7-methylsulfinylxanthone-2-carboxylate.
Ovenstående metode gjentas under anvendelse av forskjellige lavere alkyljodider for dermed å oppnå de tilsvarende lavere alkylsyreestere, f.eks.: etyl-5-n-oktyl-7-metylsulfinylxanton-2-karboksylat, n-propyl-5-n-oktyl-7-metylsulfinylxanton-2-karboksylat, isopropyl-5_n-oktyl-7-metylsulfinylxanton-2-karboksylat, n-propyl-5-n-oktyl-7-metylsulfinylxanton-2-karboksylat, isobutyl-5-n-oktyl-7-metylsulfinylxanton-2-karboksylat, s ek-bu t y 1-5-n-okty 1-7-mety lsulf inylxanton-2-karboksylat ,■ n-pentyl-5-n-oktyl-7-metylsulfinylxanton-2-karboksylat, osv. The above method is repeated using different lower alkyl iodides to thereby obtain the corresponding lower alkyl acid esters, e.g.: ethyl 5-n-octyl-7-methylsulfinylxanthone-2-carboxylate, n-propyl-5-n-octyl-7-methylsulfinylxanthone-2-carboxylate, isopropyl-5_n-octyl-7-methylsulfinylxanthone-2-carboxylate, n-propyl-5-n-octyl-7-methylsulfinylxanthone-2-carboxylate, isobutyl-5-n-octyl-7-methylsulfinylxanthone-2-carboxylate, sec-bu t y 1-5-n-octy 1-7-methylsulfinylxanthone-2-carboxylate ,■ n-pentyl-5-n-octyl -7-methylsulfinylxanthone-2-carboxylate, etc.
Likeledes kan de andre xanton-2-karboksylsyrene inneholdende substituenter ved C-5,7-stillingene, fremstilt som angitt ovenfor, omdannes til de tilsvarende syreestere, f.eks.: metyl-5-n-oktyl-7-metylsulfonylxanton-2-karboksylat, etyl-5-metylsulfonyl-7-n-oktyloksyxanton-2-karboksylat, n-propyl-5-n-okty1-7-sulfamoylxanton-2-karboksylatjmetyl-5-acetyl-7-n-oktylxanton-2-karbokeylat, osv. Likewise, the other xanthone-2-carboxylic acids containing substituents at the C-5,7 positions, prepared as indicated above, can be converted into the corresponding acid esters, e.g.: methyl-5-n-octyl-7-methylsulfonylxanthone-2- carboxylate, ethyl 5-methylsulfonyl-7-n-octyloxyxanthone-2-carboxylate, n-propyl-5-n-octyl-7-sulfamoylxanthone-2-carboxylate jmethyl-5-acetyl-7-n-octylxanthone-2-carboxylate, etc.
I sulfoseriene fremstilles estrene ved behandling av' syren med den passende lavere alkahol under tilbakeløp og In the sulpho series, the esters are prepared by treating the acid with the appropriate lower alcohol under reflux and
i fravær av syre til f.eks.: metyl-5-n-okty1-7-sulfoxanton-2-karboksylat og in the absence of acid to e.g.: methyl 5-n-octyl-7-sulfoxanthone-2-carboxylate and
etyl-5-n-oktyl-7-sulfoxanton-2-karboksylat.ethyl 5-n-octyl-7-sulfoxanthone-2-carboxylate.
Eksempel. 5__._Example. 5__._
Til en oppløsning av 10 g 5-n-oktyl-7-metylsulfinyl-xanton- 2-karboksylsyre i 200 ml etanol tilsettes den teoretiske To a solution of 10 g of 5-n-octyl-7-methylsulfinyl-xanthone-2-carboxylic acid in 200 ml of ethanol is added the theoretical
mengde natriumhydroksyd oppløst i 200 ml 90% etanol. Reaksjons-amount of sodium hydroxide dissolved in 200 ml of 90% ethanol. reaction
. blandingen konsentrere*'deretter i vakuum og dette gir natrium-5-n-oktyl-7-metylsulfonylxanton-2-karboksylat. . the mixture is then concentrated in vacuo to give sodium 5-n-octyl-7-methylsulfonylxanthone-2-carboxylate.
På samme måte fremstilles kalium- og litiumsaltene. The potassium and lithium salts are prepared in the same way.
Likeledes, ved å erstatte natriumsaltet ved hjelp av en passende metallsalt-reagent, f.eks. kalsiumklorid, manganklorid osv., fremstilles de andre xanton-2-karboksylsyresaltene, f.eks.: magnesium-5-n-o;ktyl-7-mety lsulf inylxanton-2-karboksy lat, kalsium-5-n-okty1-7-metylsulfinylxanton-2-karboksylat, aluminium-.5-n-okt yl-7-me ty lsulf inylxanton-2-karboksyl at, ferro-5-n-oktyl-7-metylsulfinylxanton-2-karboksylat, sink- 5-n-okt yl-7-me ty lsulf inylxanton-2-karboksy lat,.. mangan- 5-n-oktyl- 7-metyl sulf inylxanton-2-kar.boksy lat, ferri-5-n-oktyl-7-metylsulfinylxanton-2-karboksylat, osv. Likewise, by replacing the sodium salt with a suitable metal salt reagent, e.g. calcium chloride, manganese chloride, etc., the other xanthone-2-carboxylic acid salts are prepared, e.g.: magnesium 5-n-o;octyl-7-methylsulfinylxanthone-2-carboxylate, calcium 5-n-octyl-7-methylsulfinylxanthone -2-carboxylate, aluminum-.5-n-octyl-7-methylsulfinylxanthone-2-carboxylate, ferro-5-n-octyl-7-methylsulfinylxanthone-2-carboxylate, zinc- 5-n-oct yl-7-methylsulfinylxanthone-2-carboxylate,.. manganese- 5-n-octyl- 7-methyl sulfinylxanthone-2-carboxylate, ferric-5-n-octyl-7-methylsulfinylxanthone-2 -carboxylate, etc.
På lignende måte fremstilles xanton-2-karboksylsyre-saltene av de andre C-5,7-disubstituerte xanton-2-karbokylsyrene, f.eks.: kalium-5-n-oktyl-7-metylsulfonylxanton-2-karboksylat, natrium-5-n-heksyl-7-metylsulfinylxanton-2-karboksylat, natrium-5-n-oktyloksy-7-metylsulfinylxanton-2-karboksylat, natrium-5-metylsulfonyl-7-n-oktyloksyxanton-2-karboksylat, natrium-5-metylsulfiny1-7-n-oktyloksyxanton-2-karboksylat, natrium-5-n-dodecyloksy-7-metylsulfonylxanton-2-karboksylat, natrium-5-n-dodecyloksy-7-metylsulfinylxanton-2-karboksylat, natrium-5-n-heksyloksy-7-metylsulfonylxanton-2-karboksylat, natrium-5-n-heksyloksy-7-metylsulfinylxanton-2-karboksylat, natrium-5-n-oktyloksy-7-metylsulfonylxanton-2-karboksylat, osv. In a similar way, the xanthone-2-carboxylic acid salts are prepared from the other C-5,7-disubstituted xanthone-2-carboxylic acids, e.g.: potassium 5-n-octyl-7-methylsulfonylxanthone-2-carboxylate, sodium 5-n-hexyl-7-methylsulfinylxanthone-2-carboxylate, sodium 5-n-octyloxy-7-methylsulfinylxanthone-2-carboxylate, sodium 5-methylsulfonyl-7-n-octyloxyxanthone-2-carboxylate, sodium 5- methylsulfiny1-7-n-octyloxyxanthone-2-carboxylate, sodium 5-n-dodecyloxy-7-methylsulfonylxanthone-2-carboxylate, sodium 5-n-dodecyloxy-7-methylsulfinylxanthone-2-carboxylate, sodium 5-n- hexyloxy-7-methylsulfonylxanthone-2-carboxylate, sodium 5-n-hexyloxy-7-methylsulfinylxanthone-2-carboxylate, sodium 5-n-octyloxy-7-methylsulfonylxanthone-2-carboxylate, etc.
Eksempel 4.Example 4.
En oppløsning av 10 g 5_n-oT<:tyl-7-metylsulfinylxanton--2-karboksylsyre i 50 ml tionylklorid oppvarmes under tilbakeløp i 1 time. Deretter inndampes oppløsningen til tørrhet til det tilsvarende syreklorid hvortil man tilsetter en konsentrert eterisk ammoniakalsk oppløsning. Den resulterende oppløsning inndampes hvilket gir 5-n-oktyl-7-metylsulfinylxanton-2-karboksylsyre-amid. A solution of 10 g of 5-n-oT<:tyl-7-methylsulfinylxanthone-2-carboxylic acid in 50 ml of thionyl chloride is heated under reflux for 1 hour. The solution is then evaporated to dryness to the corresponding acid chloride, to which a concentrated ethereal ammoniacal solution is added. The resulting solution is evaporated to give 5-n-octyl-7-methylsulfinylxanthone-2-carboxylic acid amide.
På lignende måte kan de lavere alkylamider fremstilles under anvendelse av monoalkylamin eller dialkylamin i steden for ammoniakk i de ovenfor angitte metoder. Således fremstilles f.eks.: 5-n-oktyl-7-mety1sulfamoylxanton-2-karboksylsyreamid, In a similar manner, the lower alkyl amides can be prepared using monoalkylamine or dialkylamine in place of ammonia in the above methods. Thus, for example: 5-n-octyl-7-methylsulfamoylxanthone-2-carboxylic acid amide,
N-metyl-5~n-oktyl- f-n-propylsulfinylxanton-2-karboksylsyreamid, N3N-dietyl-5-n-okty1-7-etylsulfonylxanton-2-karboksylsyreamid, N-n-propyl-5-n-oktyl-7-(propylsulfinylxanton-2-karboksyl syreamid, osv. N-methyl-5~n-octyl-f-n-propylsulfinylxanthone-2-carboxylic acid amide, N3N-diethyl-5-n-octyl-7-ethylsulfonylxanthone-2-carboxylic acid amide, N-n-propyl-5-n-octyl-7-(propylsulfinylxanthone -2-carboxylic acid amide, etc.
Eksempel 5Example 5
Til en blanding av-20 g prokain og 500 ml vandig metanol tilsettes 20 g 5-n-oktyl-7_metylsulfinylxanton-2-karboksylsyre. To a mixture of 20 g of procaine and 500 ml of aqueous methanol, 20 g of 5-n-octyl-7-methylsulfinylxanthone-2-carboxylic acid is added.
Den resulterende blanding omrøres ved romtemperatur i 16 timer.The resulting mixture is stirred at room temperature for 16 hours.
Den inndampes deretter under redusert trykk og dette gir prokainsaltet av 5-n-oktyl-7-metylsulfinylxanton-2-karboksylsyre. It is then evaporated under reduced pressure and this gives the procaine salt of 5-n-octyl-7-methylsulfinylxanthone-2-carboxylic acid.
På samme måte oppnås lysin-, kaffein- og argininsaltene. In the same way, the lysine, caffeine and arginine salts are obtained.
Videre oppnås på lignende måte f.eks. prokain-, lysin-, kaffein-Furthermore, in a similar way, e.g. procaine, lysine, caffeine
og argininsaltene av de andre C-5}7-disubstituerte xanton-2-karboksylsyrene, f.eks.: prokainsaltet av 5-n-oktyl-7-etylsulfonylxanton-2-karboksylsyre, kaffeinsaltet av 5-(propylsulfinyl)~7-n-oktyloksyxanton-2-karboksylsyre, and the arginine salts of the other C-5}7-disubstituted xanthone-2-carboxylic acids, e.g.: the procaine salt of 5-n-octyl-7-ethylsulfonylxanthone-2-carboxylic acid, the caffeic salt of 5-(propylsulfinyl)~7-n -octyloxyxanthone-2-carboxylic acid,
'prokainsaltet av 5-(sek-butylsulfinyl)-7_n-oktyloksyxanton-2-karboksylsyre. the procaine salt of 5-(sec-butylsulfinyl)-7-n-octyloxyxanthone-2-carboxylic acid.
Eksempel 6Example 6
Følgende metode illustrerer den måte hvorved de The following method illustrates the way in which they
farmasøytiske preparater med de nye forbindelser fremstilles. pharmaceutical preparations with the new compounds are produced.
Natriumklorid (0,44 g) oppløses i 80 ml av en (9,47 g/l vann) natriumhydrogenfosfatoppløsning. En natriumdihydrogenfosfat (8,00 g/l vann) oppløsning (20 ml) tilsettes derétter. Den resulterende oppløsning med en pH-verdi på 7,38 steriliseres i en autoklav. Sodium chloride (0.44 g) is dissolved in 80 ml of a (9.47 g/l water) sodium hydrogen phosphate solution. A sodium dihydrogen phosphate (8.00 g/l water) solution (20 ml) is then added. The resulting solution with a pH value of 7.38 is sterilized in an autoclave.
Denne bærer tilsettes deretter-til fast, tørr '5_n-oktyloksy-7-metylsulfinylxanton-2-karboksylsyre og man oppnår dermed et This carrier is then added to solid, dry '5-n-octyloxy-7-methylsulfinylxanthone-2-carboxylic acid and a
preparat egnet for intravenøs injeksjon inneholdende 2,5 mg 5-n-oktyloksy-7-metylsulfinylxanton-2-karboksylsyre pr. ml totalt preparat. preparation suitable for intravenous injection containing 2.5 mg of 5-n-octyloxy-7-methylsulfinylxanthone-2-carboxylic acid per ml total preparation.
Eksempel. 7Example. 7
Den nedenfor angitte forbindelse b»le undersøkt under anvendelse av den rotte-passive kutane anafylakseprøve (PCA) The compound listed below was tested using the rat passive cutaneous anaphylaxis (PCA) test.
med homocytotropisk reaginisk antistoff ifølge I. Mota, Immunology 7, 681 (1964). Denne test måler virkningen av stoffer med hensyn til inhibering av frigjøringen av spasmogener (toksiske produkter) with homocytotropic reaginic antibody according to I. Mota, Immunology 7, 681 (1964). This test measures the effect of substances in inhibiting the release of spasmogens (toxic products)
fra antigen-antistoff (allergisk) reaksjonen.from the antigen-antibody (allergic) reaction.
Normale hunrotter (Spraque-Dawley) med legemsvekt 140-l60 g, ble passivt sensitivert i begge sider ved intradermal injeksjon av rotte anti-eggalbumin reaginisk serum (antistoff). Etter 24 timer ble det i hver rotte injisert 1 ml normal salt-■ vannsoppløsning inneholdende 0, 5% Evans blå fargestyff, 1 mg eggalbumin (antigen) og forsøksforbindelsen. Den inflammatoriske Normal female rats (Spraque-Dawley) with a body weight of 140-160 g were passively sensitized on both sides by intradermal injection of rat anti-ovalbumin reaginic serum (antibody). After 24 hours, 1 ml of normal saline solution containing 0.5% Evans blue dye, 1 mg of egg albumin (antigen) and the test compound was injected into each rat. The inflammatory
.respons som resulterer fra antigen-antistoffreaksjonen fremtrer.response resulting from the antigen-antibody reaction appears
som et blåfarget hudområde som måles 15_25 minutter etter injek-sjonen, idet områdets midlere diameter (mm- S.E.) måles og anvendes for å bestemme inhiberingen av inflammatorisk respons, as a blue-colored skin area measured 15-25 minutes after the injection, the mean diameter (mm- S.E.) of the area being measured and used to determine the inhibition of inflammatory response,
som uttrykkes som prosent mot kontrollprøve.which is expressed as a percentage against the control sample.
Eksempel 8 _ Example 8 _
En dose på 100 mg pr. kg legemsvekt av 5-n-oktyloksy-7-metylsulfinylxanton-2-karboksylsyre ble gitt intraperitonealt til marsvin. Andre marsvin ble holdt som en kontrollgruppe. A dose of 100 mg per kg body weight of 5-n-octyloxy-7-methylsulfinylxanthone-2-carboxylic acid was given intraperitoneally to guinea pigs. Other guinea pigs were kept as a control group.
Etter behandling ble de behandlede marsvin og kontrollgruppen uttatt for en vandig dusj av 0,05% histamindifosfat (beregnet som base), levert ved hjelp av en forstøvningsdyse, inntil dyrene viste tegn til å ha tapt retningsevnen. Under påvirkning av dusjen ble dyrene observert for graden av reaksjon. Denne reaksjonen varierer fra noe dypere pusting.til dyp pusting, videre til krampeaktig gjesping og ataxi og over til kollaps. Marsvinene som mottok 5_n-oktyloksy-7-metylsulfinylxanton-2-karboksylsyre viste en betydelig motstand overfor histaminaerosolen, mens alle kontrollmarsvinene falt sammen under påvirkningen. After treatment, the treated guinea pigs and the control group were subjected to an aqueous shower of 0.05% histamine diphosphate (calculated as base), delivered by means of an atomizing nozzle, until the animals showed signs of loss of directionality. Under the influence of the shower, the animals were observed for the degree of reaction. This reaction varies from somewhat deeper breathing to deep breathing, further to convulsive yawning and ataxia and over to collapse. The guinea pigs receiving 5_n-octyloxy-7-methylsulfinylxanthone-2-carboxylic acid showed a significant resistance to the histamine aerosol, while all the control guinea pigs collapsed under the influence.
En beskyttelse mot histaminaerosolindusert bromko-konstriksjon slik det er beskrevet ovenfor, anses å være .representativ for og kan overføres på bronkie-lungeaktivitet hos mennesker, inkludert bronkodilator aktivitet. Således ble pasienter som led av lidelser i bronkier og lunger studert med hensyn til graden av bronkospasmer og forandringer både observerbare og målbare med hensyn til ekspirasjonsfunksjonen. Slike målinger omfatter en kvantisering av den utgående lunge-luftstrømmen målt med slike instrumenter som en toppstrømnings-måler, og sammenligning av lungevolumene før og etter behandling med de fremstilte forbindelser slik dette kunne måles med spirometriske og/eller plethysmografiske metoder. Subjektive forbedringer med hensyn til symptomene ved administrasjon av forbindelsene kunne påvises ved forbedringer med hensyn til åndenød, gisping, hoste og opphostet spytt. A protection against histamine aerosol-induced bromoconstriction as described above is considered to be representative of and transferable to bronchial lung activity in humans, including bronchodilator activity. Thus, patients suffering from disorders of the bronchi and lungs were studied with regard to the degree of bronchospasm and changes both observable and measurable with regard to the expiratory function. Such measurements include a quantization of the outgoing lung airflow measured with such instruments as a peak flow meter, and comparison of the lung volumes before and after treatment with the manufactured compounds as this could be measured with spirometric and/or plethysmographic methods. Subjective improvements in symptoms upon administration of the compounds could be demonstrated by improvements in shortness of breath, gasping, coughing and expectoration.
Claims (3)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NO753167A NO753167L (en) | 1974-01-08 | 1975-09-17 |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US05431794 US3894049A (en) | 1972-06-05 | 1974-01-08 | Disubstituted xanthone carboxylic acid compounds |
| NO744506A NO744506L (en) | 1974-01-08 | 1974-12-13 | |
| NO753167A NO753167L (en) | 1974-01-08 | 1975-09-17 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO753167L true NO753167L (en) | 1975-07-09 |
Family
ID=27352715
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO753167A NO753167L (en) | 1974-01-08 | 1975-09-17 |
Country Status (1)
| Country | Link |
|---|---|
| NO (1) | NO753167L (en) |
-
1975
- 1975-09-17 NO NO753167A patent/NO753167L/no unknown
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