NO753169L - - Google Patents
Info
- Publication number
- NO753169L NO753169L NO753169A NO753169A NO753169L NO 753169 L NO753169 L NO 753169L NO 753169 A NO753169 A NO 753169A NO 753169 A NO753169 A NO 753169A NO 753169 L NO753169 L NO 753169L
- Authority
- NO
- Norway
- Prior art keywords
- carboxylate
- carboxylic acid
- methyl
- methylsulfinylxanthone
- xanthone
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 claims description 35
- 239000002253 acid Substances 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 23
- 150000002148 esters Chemical class 0.000 claims description 19
- 125000000217 alkyl group Chemical group 0.000 claims description 15
- 125000005907 alkyl ester group Chemical group 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims description 9
- 239000007858 starting material Substances 0.000 claims description 9
- 150000001408 amides Chemical class 0.000 claims description 7
- 150000001350 alkyl halides Chemical class 0.000 claims description 6
- 230000029936 alkylation Effects 0.000 claims description 6
- 238000005804 alkylation reaction Methods 0.000 claims description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 5
- 231100000252 nontoxic Toxicity 0.000 claims description 5
- 230000003000 nontoxic effect Effects 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 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 58
- -1 ester compounds Chemical class 0.000 description 31
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 16
- 239000000243 solution Substances 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-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 11
- 238000006243 chemical reaction Methods 0.000 description 11
- 239000011734 sodium Substances 0.000 description 11
- 229910052708 sodium Inorganic materials 0.000 description 11
- 238000011282 treatment Methods 0.000 description 11
- 230000000694 effects Effects 0.000 description 10
- 239000000047 product Substances 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 150000007513 acids Chemical class 0.000 description 8
- 239000000203 mixture Substances 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
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 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
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 5
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical class CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 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
- 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
- 239000003960 organic solvent Substances 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
- 239000000725 suspension Substances 0.000 description 4
- PNEYBMLMFCGWSK-UHFFFAOYSA-N Alumina Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-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
- 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
- 150000001351 alkyl iodides Chemical class 0.000 description 3
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 3
- 230000000172 allergic effect Effects 0.000 description 3
- 208000030961 allergic reaction Diseases 0.000 description 3
- 229910052782 aluminium Inorganic materials 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
- 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
- 210000004072 lung Anatomy 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
- 239000002244 precipitate Substances 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-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
- 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
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-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
- 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
- 150000001347 alkyl bromides Chemical class 0.000 description 2
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 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
- 229960001948 caffeine Drugs 0.000 description 2
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-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
- 229910052799 carbon Inorganic materials 0.000 description 2
- 150000001733 carboxylic acid esters 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
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- 230000028709 inflammatory response Effects 0.000 description 2
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 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
- 238000004519 manufacturing process Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 230000020477 pH reduction Effects 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000011541 reaction mixture Substances 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
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- VMKOFRJSULQZRM-UHFFFAOYSA-N 1-bromooctane Chemical compound CCCCCCCCBr VMKOFRJSULQZRM-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
- 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
- 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
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-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
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-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
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-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
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-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
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 1
- 206010048232 Yawning Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000001045 blue dye Substances 0.000 description 1
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- 210000000621 bronchi Anatomy 0.000 description 1
- 229940124630 bronchodilator Drugs 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000013068 control sample Substances 0.000 description 1
- 230000002920 convulsive effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000006165 cyclic alkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 125000004985 dialkyl amino alkyl group Chemical group 0.000 description 1
- WLXALCKAKGDNAT-UHFFFAOYSA-N diazoethane Chemical compound CC=[N+]=[N-] WLXALCKAKGDNAT-UHFFFAOYSA-N 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 125000006125 ethylsulfonyl group Chemical group 0.000 description 1
- 229960003699 evans blue Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 235000013312 flour Nutrition 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000002314 glycerols Chemical class 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 150000002337 glycosamines Chemical class 0.000 description 1
- 125000000487 histidyl group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C([H])=N1 0.000 description 1
- 229940125697 hormonal agent Drugs 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000011565 manganese chloride Substances 0.000 description 1
- 235000002867 manganese chloride Nutrition 0.000 description 1
- 229940099607 manganese chloride Drugs 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 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 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229940092253 ovalbumin Drugs 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940117803 phenethylamine Drugs 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000013139 quantization Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 208000013220 shortness of breath Diseases 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- RNVYQYLELCKWAN-UHFFFAOYSA-N solketal Chemical compound CC1(C)OCC(CO)O1 RNVYQYLELCKWAN-UHFFFAOYSA-N 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000003506 spasmogen Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- OBROYCQXICMORW-UHFFFAOYSA-N tripropoxyalumane Chemical compound [Al+3].CCC[O-].CCC[O-].CCC[O-] OBROYCQXICMORW-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Fremgangsmåte for fremstilling av forbindelser med formel: Procedure for the preparation of compounds of formula:
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^-gruppe er alkoksy med 1-12 karbonatomer, og and pharmaceutically acceptable, non-toxic esters, amides, and salts thereof, wherein an R^ group is 1-12 carbon alkoxy, and
den andre R^-gruppe er gruppen the other R^ group is the group
er lavere alkyl.is lower alkyl.
hvor n er 1 eller 2 og R where n is 1 or 2 and R
Fremgangsmåten kjennetegnes ved atThe procedure is characterized by
1) en 5(7)-hydroksy-7(5)-lavere alkyltio-xanton-2-karboksylsyre eller en lavere alkylester derav oksyderes med persyre eller hydrogenperoksyd, eventuelt hydrolyserer et esterprodukt eller eventuelt forestrer et syreprodukt fulgt av alkylering eller eventuelt forestrer et syreprodukt fulgt av alkylering med et alkylhalogenid med 1-12 karbonatomer for oppnåelse av den tilsvarende 5(7)-alkoksy-7(5)-lavere alkylsulfinylxanton-2-karboksylsyre eller en lavere alkylester derav, eller 5(7)-alkoksy-7(5)-lavere alkylsulfonyl-xanton-2-karboksylsyre eller en lavere alkylester derav, respektivt, og 2) eventuelt hydrolyserer et esterprodukt fra trinn 1) til den tilsvarende frie 2-karboksylsyre, og 3) om ønsket omdanner en syre med den ovenstående formel til farmasøytisk akseptable ikke-toksiske estere, amider og salter derav. 1) a 5(7)-hydroxy-7(5)-lower alkylthio-xanthone-2-carboxylic acid or a lower alkyl ester thereof is oxidized with peracid or hydrogen peroxide, optionally hydrolyzes an ester product or optionally esterifies an acid product followed by alkylation or optionally esterifies a acid product followed by alkylation with an alkyl halide of 1-12 carbon atoms to give the corresponding 5(7)-Alkoxy-7(5)-lower alkylsulfinylxanthone-2-carboxylic acid or a lower alkyl ester thereof, or 5(7)-Alkoxy-7 (5)-lower alkylsulfonyl-xanthone-2-carboxylic acid or a lower alkyl ester thereof, respectively, and 2) optionally hydrolyzes an ester product from step 1) to the corresponding free 2-carboxylic acid, and 3) optionally converts an acid with the above formula to 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 antigen-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 gjørdde 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 antigen-antibody (allergic) reactions. When 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 so that they inhibit the release and/or action of toxic products, e.g. histamine, 5-hydroxytryptamine, slow-releasing substance (SRS-A) or other toxic compounds produced as a result of a combination of specific antibody and antigen (allergic reaction). These properties made the prepared compounds 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 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. during treatment
. av lidelser i nyrer eller hjerte.. of 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 med formelen ovenfor. 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 with the formula 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 inhale-ring og enten som fast stoff, væske eller i gassformige doserin-ger, inkludert tabletter, suspensjoner og aerosoler, som også omtalt i det nedenstående. Administrasjonen kan utføres i form av enkle doser under kontinuerlig behandling, eller ved enkelt-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 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 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 dosages, including tablets, suspensions and aerosols, which also mentioned 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 in continuous or
profylaktisk behandling.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 0,00.5 - 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 - 7000 mg pr. dag pr. pasient. Seen against the background 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 0.00.5 - 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 range from approx. 0.5 - 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, pulvere, preparater med forlenget frigjøring av aktive forbindelser, oppløsninger, suspensjoner, eliksirer, aerosoler og lignende. Bærerne kan velges fra forskjellige oljer inkludert petroleum-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, natriumklorid, tørket skummet melk, glycerol, propylenglykol, vann, etanol og lignende. Egnede farmasøytiske bærere og deres preparater er beskrevet i "Remingtons Pharmaceutical Sciences" av E.W. Martin. Slike preparater vil i alle tilfeller 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 petroleum 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 preparations 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 prøver som indikerer slik aktivitet og innebærer passiv kutan anafylakse beskrevet av J. Goose et al, Immunology, 16, 7^9, The new compounds show activity as inhibitors of the effects of allergic reactions as these can be measured by tests that indicate such activity and involve passive cutaneous anaphylaxis described by J. Goose et al, Immunology, 16, 7^9,
(1969)• (1969)•
Fremgangsmåten ifølge nærværende oppfinnelse kan illu-streres ved følgende reaksjonsskjemaer: The method according to the present invention can be illustrated by the following reaction schemes:
Reaksjonsskjerna A'Reaction nucleus 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:
hvor hver av gruppene R<7>, R Q , R<10>og R<11>har den ovenfor angitte where each of the groups R<7>, R Q , R<10>and R<11> 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 + 20a, 21a 20,21 og 17 + 20a, 21a 20,21 ovenfor. 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 + 20a, 21a 20,21 and 17 + 20a, 21a 20,21 above.
Reaksjonsskjema B'-Reaction scheme B'-
7 7' 10 11 13 7 7' 10 11 13
hvor hver av gruppene R<7>, R , R<10>, R<11>og R 1 "5har den ovenfor angitte betydning, .og R<1>^ er en alkylgruppe med 1-12 karbonatomer, og mer spesielt ved trinnene 23 -*■ 24 ->- 26a, 27a -»- 26, 27 og 23. -»■ 26a, 27a 26, 27 ovenfor. ;Under henvisning til de ovenstående reaksjonsskjemaer;A' og B', så blir 5-alkoksy-7_lavere alkyltiosyrene eller estrene (16) og 5-lavere alkyltio-7-metoksysyrene eller estrene (22), fortrinnsvis metoksyforbindelsene, (fremstilt som beskrevet i søknad nr. 744506), 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. eddiksyreanhydrid, eddiksyre eller propionsyre. ;Forbindelsene med formler (17) og (23) blir deretter eventuelt forestret med et alkylhalogenid, 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 esterforbin-delsene med formlene (18) og (24). ;5-hydroksy-7-lavere alkyltioforbindelsene (17) og (18) og 5-lavere alkyltio-7-hydroksyforbindelsene (23) og (24), blir først oksydert til sulfinylforbindelser, formler (20a) og (26a), og sulfonylforbindelser, formler (21a) og (27a), som beskrevet i ovennevnte norske søknader 2495/72 og 744506. Forbindelsene med formler (20a), (26a), (21a) og (27a) blir deretter foretret med et alkylhalogenid, på samme måte som beskrevet i søknad 753167 hvilket gir forbindelsene (20), (26), (21) og (27), respektivt. For mellomproduktene (19), (20a), (21a), (25), (26a) og (27a) ;kan en fri syre forestres og en ester kan hydrolyseres til den frie syre. ;Syreestrene av xanton-2-karboksylsyrene fremstilles;som beskrevet i nevnte norske søknad nr. 2495/72, d.v.s. ved behandling av syren med et eterisk diazoalkan slik som diazo-metan og diazoetan 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 tilbakeløps-koking. Glycerolestrene fremstilles ved behandling av syren med tionylklorid fulgt av behandling med hensiktsmessig beskyttet etylenglykol eller propylenglykol (f.eks. "Solketal") i pyridin, og hydrolysering av den beskyttende gruppe i den således dannede ester med fortynnet syre. ;Amidene av xanton-2-karboksylsyrene fremstilles ved behandling av syrene med tionylklorid fulgt av.behandling med vannfri ammoniakk, alkylamin, dialkylamin, dialkylaminoalkyl-amin, alkoksyalkylamin eller fenetylamin. I lavere alkylsulfi-nylrekken blir karboksylsyreamidene fortrinnsvis fremstilt ved det tilsvarende lavere alkyltio-trinn fulgt av oksydasjon, som beskrevet ovenfor. ;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-, aluminium-, mangani-, trimetylamin-, trietylamin-, tripropylamin-, 6-(di-metylamino)etanol-, trietanolamin-, 3-(dietylamino)etanol-, arginin-, lysin-, histidin-, N-etylpiperidin-, hydrabamin-, ;kolin-, betain-, etylendiamin-, glykosamin-, metylglukamin-, teobromin-, purin-, piperazin-, piperidin-, polyaminharpiks-, kaffein- og prokain-salter. Reaksjonen utføres i vandig oppløs-ning, 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 1/2 molar ekvivalent farmasøytisk aksepta- ;bel base. Når aluminiumsalter av syrene fremstilles, blir om-;kring 1/3 molar ekvivalent av den farmasøytisk akseptable base benyttet. ;I en foretrukken utførelse av oppfinnelsen blir kal-siumsaltene og magnesiumsaltene av syrene fremstilt ved behand- ;ling 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 - 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, xylen, cykloheksan og lignende ved en temperatur fra 20 - 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, t-pentyl, cyklopropyl, cyklobutyl og cyklo- pentyl. Med den benyttede betegnelse "alkyl" menes 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-dod.ekanyl og lignende. Med den benyttede betegnelse "alkoksy" menes gruppen "0-alkyl" hvor "alkyl" har den ovenfor angitte betydning. ;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. ;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. ;Den nomenklatur som er benyttet er i overensstemmelse med Chemical Abstracts, 56, Subject Index (1962, januar-juni). ;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. ;Følgende eksempler illustrerer oppfinnelsen. Når det har vært nødvendig, er eksemplene blitt gjentatt for å få tilveiebragt utgangsmaterialene for de étterfølgende eksempler. ;Eksempel I;Til en suspensjon av 500 mg metyl-5-hydroksy-7-metyltio-xanton-2-karboksylat (fremstilt som i eksempel 5, del B) i 20 ml dimetylformamid, ble det ved romtemperatur dråpevis tilsatt qn oppløsning av 320 mg m-klorperbenzosyre i 3 ml dimetylformamid. Etter omrøring i 15 minutter, ble 50 ml 1% vandig natriumbisulfitt tilsatt, det resulterende bunnfall ble filtrert, vasket med vann, deretter med aceton, og dette ga 480 mg metyl-5-hydroksy-7-metyl-sulfinylxanton-2-karboksylat, smp. 289-291°C (dekomp.). ;Ved å erstatte metyl-5-metyltio-7_hydroksyxanton-2-karboksylat (fremstilt i eksempel1 5,1 del B) med metyl-5~hydroksy- ' 7-metyltioxanton-2-karboksylat får man på samme måte metyl-5-metyl-sulfinyl-7-hydroksyxanton-2-karboksylat, smp. 322-323°C (dekomp.). ;Ved i steden for de ovenfor angitte utgangsmaterialer;å benytte den tilsvarende frie 2-karboksylsyre, eller en annen lavere alkylester derav, kan man på samme måte fremstille f,eks. 5-hydroksy-7-metylsulfinylxanton-2-karboksylsyre, ;etyl-5_hydroksy-7-metylsulfinylxanton-2-karboksylat, pentyl-5-hydroksy-7-metylsulfinylxanton-2-karboksylat, 5-metylsulfinyl-7-hydroksyxanton-2-karboksylsyre, ;etyl-5-metylsulfinyl-7-hydroksyxanton-2-karboksylat og penty1-5-mety1sylfinyl-7-hydroksyxanton-2-karboksylat. ;På lignende måte, ved å bytte ut de ovenfor angitte metyltioutgangsmaterialer, kan.man fremstille tilsvarende etylsulfinyl-, propylsulfinyl-, butylsulfinyl- og pentylsulfinylforbindelsene. ;Eksempel;Ved å utgå fra 5-hydroksy-7_metyltioxanton-2-karboksylsyre, 5_metyltio-7-hydroksyxanton-2-karboksylsyre eller en lavere alkylester derav, og foreta oksydasjonsmetoden som angitt i eksempel 4, kan'man fremstille f.eks. 5-hydroksy-7-metyl-sulfonylxanton-2-karboksylsyre, metyl-5~hydroksy-7~metylsulfonyl-xanton-2-karboksylat,.. pentyl- 5~hydroksy-7-metylsulfonylxanton-2-karboksylat, 5-metylsulfonyl-7-hydroksyxanton-2-karboksylsyre, metyl-5-metylsulfonyl-7_hydroksyxanton-2-karboksylat, og pentyl-5-metylsulfonyl-7-hydroksyxanton-2-karboksylat. ;På samme måte, ved å benytte lavere alkyltioutgangs-materialer i steden for de nevnte metyltioutgangsmaterialene, ;kan man fremstille de tilsvarende etylsulfonyl-, propylsulfonyl-, ;butylsulfonyl- og pentylsulfonylforbindelsene.;Eksempel 3;Ved å starte med de passende 5(7)-hydroksy-7(5)-laverealkylsulfinylforbindelsene^fra eksempel ~i og benytte alkyleringsmetoden i eksempel"5 ,'del C, under anvendelse av det passende alkylhalogenid med 1-12 karbonatomer, og eventuelt hydrolysere en karboksylsyreester ifølge metoden i eksempel5,/del F, kan man f.eks. fremstille: 5-metoksy-7-metylsulfinylxanton-2-karboksylsyre, ;metyl-5-metoksy-7_metylsulfinylxanton-2-karboksylat, pentyl-5-metoksy-7-metylsulfinylxanton-2-karboksylat, 5-etoksy-7-metylsulfinylxanton-2-karboksylsyre, smp. 273-274°C, me*ty 1-5-et oksy-7-metyl sulf inylxant on-2-karboksylat, pentyl-5-etoksy-7-metylsulfinylxanton-2-karboksylat, 5-propoksy-7-metylsulfinylxanton-2-karboksylsyre, smp. 265-267°C,'where each of the groups R<7>, R , R<10>, R<11> and R 1 "5 has the meaning indicated above, and R<1>^ is an alkyl group with 1-12 carbon atoms, and more particularly by steps 23 -*■ 24 ->- 26a, 27a -»- 26, 27 and 23. -»■ 26a, 27a 26, 27 above. ;With reference to the above reaction schemes;A' and B', then 5- the alkoxy-7-lower alkylthio acids or esters (16) and the 5-lower alkylthio-7-methoxy acids or esters (22), preferably the methoxy compounds, (prepared as described in application no. 744506), converted to 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. ;The compounds of formulas (17) and ( 23) is 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-methylpyrrolide on and the like, and lithium carbonate, to obtain the ester compounds with the formulas (18) and (24). The 5-hydroxy-7-lower alkylthio compounds (17) and (18) and the 5-lower alkylthio-7-hydroxy compounds (23) and (24) are first oxidized to sulfinyl compounds, formulas (20a) and (26a), and sulfonyl compounds , formulas (21a) and (27a), as described in the above-mentioned Norwegian applications 2495/72 and 744506. The compounds with formulas (20a), (26a), (21a) and (27a) are then etherified with an alkyl halide, in the same way as described in application 753167 which gives compounds (20), (26), (21) and (27), respectively. For the intermediates (19), (20a), (21a), (25), (26a) and (27a), a free acid can be esterified and an ester can be hydrolyzed to the free acid. The acid esters of the xanthone-2-carboxylic acids are prepared as described in the aforementioned Norwegian application no. 2495/72, i.e. by treating the acid with an ethereal diazoalkane such as diazomethane 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 under reflux. The glycerol esters are prepared by treating the acid with thionyl chloride followed by treatment with suitably protected ethylene glycol or propylene glycol (e.g. "Solketal") in pyridine, and hydrolyzing the protecting group in the thus formed ester with dilute acid. The amides of the xanthone-2-carboxylic acids are prepared by treating the acids with thionyl chloride followed by treatment with anhydrous ammonia, alkylamine, dialkylamine, dialkylaminoalkylamine, 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. 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, aluminum, manganese, trimethylamine, triethylamine -, tripropylamine-, 6-(dimethylamino)ethanol-, triethanolamine-, 3-(diethylamino)ethanol-, arginine-, lysine-, histidine-, N-ethylpiperidine-, hydrabamine-, ;choline-, betaine-, ethylenediamine, glycosamine, 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 production of divalent metal salts, such as calcium salts or magnesium salts of the acids, free acid starting material is treated with about 1/2 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. In a preferred embodiment of the invention, the calcium salts and magnesium salts of the acids are produced 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 - 100°C. In another preferred embodiment of the invention, the aluminum salts of the acids are produced by treating the acids with at least 1/3 molar equivalent of an aluminum alkoxide, such as aluminum trioxide, aluminum tripropoxide and the like, in a hydrocarbon solvent such as benzene, xylene, cyclohexane and the like at a temperature from 20 - 115°C-. With the term "lower alkyl" used is meant 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, t-pentyl, cyclopropyl, cyclobutyl and cyclopentyl. The term "alkyl" used means 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-dod.ecanyl and the like. The term "alkyl" used means the group "O-alkyl" where "alkyl" has the above meaning. 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. ;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. ;The nomenclature used is in accordance with Chemical Abstracts, 56, Subject Index (1962, January-June). ;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. The following examples illustrate the invention. When necessary, the examples have been repeated to obtain the starting materials for the subsequent examples. ;Example I;To a suspension of 500 mg of methyl-5-hydroxy-7-methylthio-xanthone-2-carboxylate (prepared as in example 5, part B) in 20 ml of dimethylformamide, a solution of 320 mg of m-chloroperbenzoic acid in 3 ml of dimethylformamide. After stirring for 15 minutes, 50 ml of 1% aqueous sodium bisulfite was added, the resulting precipitate was filtered, washed with water, then with acetone, and this gave 480 mg of methyl 5-hydroxy-7-methyl-sulfinylxanthone-2-carboxylate, m.p. 289-291°C (decomp.). By replacing methyl-5-methylthio-7-hydroxyxanthone-2-carboxylate (prepared in example 1 5.1 part B) with methyl-5-hydroxy-' 7-methylthioxanthone-2-carboxylate, methyl-5-methyl is obtained in the same way -sulfinyl-7-hydroxyxanthone-2-carboxylate, m.p. 322-323°C (decomp.). By using the corresponding free 2-carboxylic acid, or another lower alkyl ester thereof, instead of the above-mentioned starting materials, one can similarly prepare, e.g. 5-hydroxy-7-methylsulfinylxanthone-2-carboxylic acid, ;ethyl 5_hydroxy-7-methylsulfinylxanthone-2-carboxylate, pentyl 5-hydroxy-7-methylsulfinylxanthone-2-carboxylate, 5-methylsulfinyl-7-hydroxyxanthone-2-carboxylic acid , ;ethyl 5-methylsulfinyl-7-hydroxyxanthone-2-carboxylate and pentyl-5-methylsulfinyl-7-hydroxyxanthone-2-carboxylate. In a similar way, by replacing the above-mentioned methylthio starting materials, the corresponding ethylsulfinyl, propylsulfinyl, butylsulfinyl and pentylsulfinyl compounds can be prepared. ;Example;By starting from 5-hydroxy-7-methylthioxanthone-2-carboxylic acid, 5-methylthio-7-hydroxyxanthone-2-carboxylic acid or a lower alkyl ester thereof, and carrying out the oxidation method as indicated in example 4, one can prepare e.g. 5-Hydroxy-7-methyl-sulfonylxanthone-2-carboxylic acid, methyl 5~hydroxy-7~methylsulfonyl-xanthone-2-carboxylate,.. pentyl- 5~hydroxy-7-methylsulfonylxanthone-2-carboxylate, 5-methylsulfonyl- 7-hydroxyxanthone-2-carboxylic acid, methyl 5-methylsulfonyl-7-hydroxyxanthone-2-carboxylate, and pentyl 5-methylsulfonyl-7-hydroxyxanthone-2-carboxylate. ;Similarly, by using lower alkylthio starting materials in place of the aforementioned methylthio starting materials, ;one can prepare the corresponding ethylsulfonyl, propylsulfonyl, ;butylsulfonyl and pentylsulfonyl compounds.;Example 3;By starting with the appropriate 5(7 )-hydroxy-7(5)-lower alkylsulfinyl compounds^from example ~i and using the alkylation method in example"5,'part C, using the appropriate alkyl halide with 1-12 carbon atoms, and optionally hydrolyzing a carboxylic acid ester according to the method in example 5,/ part F, one can, for example, prepare: 5-methoxy-7-methylsulfinylxanthone-2-carboxylic acid, methyl 5-methoxy-7-methylsulfinylxanthone-2-carboxylate, pentyl 5-methoxy-7-methylsulfinylxanthone-2-carboxylate, 5-ethoxy-7-methylsulfinylxanthone-2-carboxylic acid, m.p. 273-274°C, methyl 1-5-etoxy-7-methyl sulfinylxanthone-2-carboxylate, pentyl-5-ethoxy-7-methylsulfinylxanthone -2-carboxylate, 5-propoxy-7-methylsulfinylxanthone-2-carboxylic acid, mp 265-267°C,'
mety1-5-propoksy-7-metylsulfinylxanton-2-karboksylat, penty1-5-propoksy-7_metylsulfinylxanton-2-karboksylat, methyl1-5-propoxy-7-methylsulfinylxanthone-2-carboxylate, penty1-5-propoxy-7-methylsulfinylxanthone-2-carboxylate,
5-isopropoksy-7-metylsulfinylxanton-2-karboksylsyre, smp. 280-282°C, mety1-5-isopropoksy-7-metylsulfinylxanton-2-karboksylat, pentyl-5-isopropoksy-7-mety1sulfinylxanton-2-karboksylat, 5-butoksy-7-metylsulfinylxanton-2-karboksylsyre, smp. 269-270°C, metyl-5-butoksy-7-metylsulfinylxanton-2-karboksylat, pentyl-5-butoksy-7-metylsulfinylxanton-2-karboksylat, 5-pentoksy-7-metylsulfinylxanton-2-karboksylsyre, smp. 263-265°C , metyl-5-pentoksy-7-metylsulfinylxanton-2-karboksylat, penty1-5-pentoksy-7-metylsulfinylxanton-2-karboksylat, 5-isopentoksy-7-metylsulfinylxanton-2-karboksylsyre, smp. 271-273°C, mety1-5-isopentoksy-7-metylsulfinylxanton-2-karboksylat, pentyl-5-isopentoksy-7-metylsulfinylxanton-2-karboksylat, 5-oktyloksy-7-metylsulfinylxanton-2-karboksylsyre, smp. 258-260°C, mety1-5-oktyloksy-7-metylsulfinylxanton-2-karboksylat, penty1-5-oktyloksy-7-metylsulfinylxanton-2-karboksylat, 5-dodecyloksy-7-metylsulfinylxanton-2-karboksylsyre, smp. 254-255°C, metyl-5-dodecyloksy-7-metylsulfinylxanton-2-karboksylat, pentyl-5-dodecyloksy-7-metylsulfinylxanton-2-karboksylat, 5-isopropoxy-7-methylsulfinylxanthone-2-carboxylic acid, m.p. 280-282°C, methyl 1-5-isopropoxy-7-methylsulfinylxanthone-2-carboxylate, pentyl 5-isopropoxy-7-methylsulfinylxanthone-2-carboxylate, 5-butoxy-7-methylsulfinylxanthone-2-carboxylic acid, m.p. 269-270°C, methyl 5-butoxy-7-methylsulfinylxanthone-2-carboxylate, pentyl 5-butoxy-7-methylsulfinylxanthone-2-carboxylate, 5-pentoxy-7-methylsulfinylxanthone-2-carboxylic acid, m.p. 263-265°C, methyl 5-pentoxy-7-methylsulfinylxanthone-2-carboxylate, penty1-5-pentoxy-7-methylsulfinylxanthone-2-carboxylate, 5-isopentoxy-7-methylsulfinylxanthone-2-carboxylic acid, m.p. 271-273°C, methyl 1-5-isopentoxy-7-methylsulfinylxanthone-2-carboxylate, pentyl-5-isopentoxy-7-methylsulfinylxanthone-2-carboxylate, 5-octyloxy-7-methylsulfinylxanthone-2-carboxylic acid, m.p. 258-260°C, methyl 1-5-octyloxy-7-methylsulfinylxanthone-2-carboxylate, penty1-5-octyloxy-7-methylsulfinylxanthone-2-carboxylate, 5-dodecyloxy-7-methylsulfinylxanthone-2-carboxylic acid, m.p. 254-255°C, methyl 5-dodecyloxy-7-methylsulfinylxanthone-2-carboxylate, pentyl 5-dodecyloxy-7-methylsulfinylxanthone-2-carboxylate,
samt som de tilsvarende 7-etylsulfinyl-, propylsulfinyl-, butylsulfinyl- og pentylsulfinylforbindelsene; og as well as the corresponding 7-ethylsulfinyl, propylsulfinyl, butylsulfinyl and pentylsulfinyl compounds; and
5-metylsulfinyl-7~metoksyxanton-2-karboksylsyre, 5-methylsulfinyl-7~methoxyxanthone-2-carboxylic acid,
metyl-5-metylsulfinyl-7-metoksyxanton-2-karboksylat, pentyl-5_metylsulfinyl-7-metoksyxanton-2-karboksylat, 5-metylsulfinyl-7-etoksyxanton-2-karboksylsyre, methyl 5-methylsulfinyl-7-methoxyxanthone-2-carboxylate, pentyl-5-methylsulfinyl-7-methoxyxanthone-2-carboxylate, 5-methylsulfinyl-7-ethoxyxanthone-2-carboxylic acid,
metyl-5-metylsulfinyl-7-etoksyxanton-2-karboksylat, pentyl-5-metylsulfinyl-7-etoksyxanton-2-karboksylat, 5-metylsulfinyl-7-propoksyxanton-2-karboksylsyre, methyl 5-methylsulfinyl-7-ethoxyxanthone-2-carboxylate, pentyl-5-methylsulfinyl-7-ethoxyxanthone-2-carboxylate, 5-methylsulfinyl-7-propoxyxanthone-2-carboxylic acid,
metyl-5-metylsulfinyl-7_propoksyxanton-2-karboksylat, pentyl-5-metylsulfinyl-7-propoksyxanton-2-karboksylat, 5-metylsulfinyl-7-isopropoksyxanton-2-karboksylsyre, smp. 276-278°C, mety1-5-metylsulfinyl-7-isopropoksyxanton-2-karboksylat, penty1-5-metylsulfinyl-7-isopropoksyxanton-2-karboksylatj5-metylsulfinyl-7-butoksyxanton-2-karboksylsyre, methyl-5-methylsulfinyl-7_propoxyxanthone-2-carboxylate, pentyl-5-methylsulfinyl-7-propoxyxanthone-2-carboxylate, 5-methylsulfinyl-7-isopropoxyxanthone-2-carboxylic acid, m.p. 276-278°C, methyl 1-5-methylsulfinyl-7-isopropoxyxanthone-2-carboxylate, penty1-5-methylsulfinyl-7-isopropoxyxanthone-2-carboxylate, 5-methylsulfinyl-7-butoxyxanthone-2-carboxylic acid,
metyl-5-metylsulfinyl-7-butoksyxanton-2-karboksylat, penty1-5-metylsulfinyl-7-butoksyxanton-2-karboksylat, 5-metylsulfinyl-7-pentoksyxanton-2-karboksylsyre, smp. 242-244°C, metyl-5-metylsulfinyl-7-pentoksyxanton-2-karboksylat, pentyl-5-metylsulfinyl-7_pentoksyxanton-2-karboksylat, 5-metylsulfinyl-7-isopentoksyxanton-2-karboksylsyre, mety1-5-metylsulfinyl-7-isopentoksyxanton-2-karboksylat, penty1-5-metylsulfinyl-7-isopentoksyxanton-2-karboksylat, 5-metylsulfinyl-7-oktyloksyxanton-2-karboksylsyre, smp. 218-219°C, metyl-5-metylsulfinyl-7_oktyloksyxanton-2-karboksylat, pentyl-5-metylsulfinyl-7-oktyloksyxanton-2-karboksylat, 5-metylsulfinyl-7-dodecyloksyxanton-2-karboksylsyre, smp. 196-197°C3mety1-5-mety1sulfinyl-7-dodecyloksyxanton-2-karboksylat, penty1-5-metylsulfinyl-7-dodecyloksyxanton-2-karboksylat, methyl 5-methylsulfinyl-7-butoxyxanthone-2-carboxylate, penty1-5-methylsulfinyl-7-butoxyxanthone-2-carboxylate, 5-methylsulfinyl-7-pentoxyxanthone-2-carboxylic acid, m.p. 242-244°C, methyl 5-methylsulfinyl-7-pentoxyxanthone-2-carboxylate, pentyl-5-methylsulfinyl-7_pentoxyxanthone-2-carboxylate, 5-methylsulfinyl-7-isopentoxyxanthone-2-carboxylic acid, methyl 1-5-methylsulfinyl-7-pentoxyxanthone-2-carboxylate 7-Isopentoxyxanthone-2-carboxylate, Penty1-5-methylsulfinyl-7-isopentoxyxanthone-2-carboxylate, 5-Methylsulfinyl-7-octyloxyxanthone-2-carboxylic acid, m.p. 218-219°C, methyl 5-methylsulfinyl-7-octyloxyxanthone-2-carboxylate, pentyl 5-methylsulfinyl-7-octyloxyxanthone-2-carboxylate, 5-methylsulfinyl-7-dodecyloxyxanthone-2-carboxylic acid, m.p. 196-197°C3methyl1-5-methylsulfinyl-7-dodecyloxyxanthone-2-carboxylate, penty1-5-methylsulfinyl-7-dodecyloxyxanthone-2-carboxylate,
samt som de tilsvarende. 5_etylsulfinyl-, propylsulfinyl-, butylsulfinyl- og pentylsulfinylforbindelser. as well as the corresponding ones. 5_ethylsulfinyl, propylsulfinyl, butylsulfinyl and pentylsulfinyl compounds.
EksempelExample
Ved å starte med de passende 5(7)-hydroksy-7(5)_ laverealkylsulfonylforbindelsene fra eksempel 2, °g følge alkyleringsmetoden i eksempel 5", del C, under anvendelse av det passende alkylhalogenid med 1-12 karbonatomer, og eventuelt hydrolysere en karboksylsyreester ifølge metoden i eksempel ;53del. F, kan man f .eks. fremstille: 5-metoksy-7-metylsulfonylxanton-2-karboksylsyre, metyl-5-metoksy-7-metylsulfonylxanton-2-karboksylat, pentyl-5-metoksy-7-metylsulfonylxanton-2-karboksylat, 5-etoksy-7~metylsulfonylxanton-2-karboksylsyre, metyl- 5-etoksy-7-metylsulfonylxanton-2-karboksylat, penty1-5-etoksy-7-metylsulfonylxanton-2-karboksylat, 5-propoksy-7-metylsulfonylxanton-2-karboksylsyre, mety1-5-propoksy-7-metylsulfonylxanton-2-karboksylat, pentyl-5-propoksy-7-metylsulfonylxanton-2-karboksylat, 5-isopropoksy-7_metylsulfonylxanton-2-karboksylsyre, smp. 3l8°C, mety1-5-isopropoksy-7-metylsulfonylxanton-2-karboksylat, pentyl-5-isopropoksy-7-metylsulfonylxanton-2-karboksylat, 5-butoksy-7-metylsulfonylxanton-2-karboksy1syre, mety1-5-butoksy-7-metylsulfonylxanton-2-karboksylat, pentyl-5-butoksy-7-metylsulfonylxanton-2-karboksylat, 5-pentoksy-7-metylsulfonylxanton-2-karboksylsyre, metyl-5-pentoksy-7-metylsulfonylxanton-2-karboksylat, pentyl-5-pentoksy-7-metylsulfonylxanton-2-karboksylat, 5"isopentoksy-7-metylsulfonylxanton-2-karboksylsyre, metyl-5-isopentoksy-7-metylsulfonylxanton-2-karboksylat, pentyl-5-isopentoksy-7-metylsulfonylxanton-2-karboksylat, 5-oktyloksy-7-metylsulfonylxanton-2-karboksylsyre, metyl-5-oktyloksy-7-metylsulfonylxanton-2-karboksylat, pentyl-5-oktyloksy-7-metylsulfonylxanton-2-karboksylat, 5-dodecyloksy-7-metylsulfonylxanton-2-karboksylsyre, metyl-5-dodecyloksy-7-metylsulfonylxanton-2-karboksylat, penty1-5-dodecyloksy-7-metylsulfonylxanton-2-karboksylat, samt de tilsvarende 7_etylsulfony1-, propylsulfonyl-, butyl-sulf onyl og pentylsulfonylforbindelsene; og 5-metylsulfony1-7-metoksyxanton-2-karboksylsyre, mety1-5-metylsulfonyl-7-metoksyxanton-2-karboksylat, pentyl-5-metylsulfonyl-7-metoksyxanton-2-karboksylat, 5-metylsulfony1-7-etoksyxanton-2-karboksylsyre, metyl-5-metylsulfonyl-7-etoksyxanton-2-karboksylat, pentyl-5-metylsulfonyl-7-etoksyxanton-2-karboksylat, 5-metylsulfony1-7-propoksyxanton-2-karboksy1syre, metyl-5-metylsulfony1-7-propoksyxanton-2-karboksylat, penty1-5-metylsulfony1-7-propoksyxanton-2-karboksylat, 5-metylsulfony1-7-isopropoksyxanton-2-karboksylsyre, smp. 308-309°C, metyl-5-metylsulfonyl-7-isopropoksyxanton-2-karboksylat, penty1-5-metylsulfony1-7-isopropoksyxanton-2-karboksylat, Starting with the appropriate 5(7)-hydroxy-7(5)_ lower alkylsulfonyl compounds from Example 2, °g follow the alkylation method of Example 5", part C, using the appropriate alkyl halide of 1-12 carbon atoms, and optionally hydrolyze a carboxylic acid ester according to the method in example 53 part F, one can, for example, prepare: 5-methoxy-7-methylsulfonylxanthone-2-carboxylic acid, methyl 5-methoxy-7-methylsulfonylxanthone-2-carboxylate, pentyl-5-methoxy -7-methylsulfonylxanthone-2-carboxylate, 5-ethoxy-7~methylsulfonylxanthone-2-carboxylic acid, methyl- 5-ethoxy-7-methylsulfonylxanthone-2-carboxylate, penty1-5-ethoxy-7-methylsulfonylxanthone-2-carboxylate, 5 -propoxy-7-methylsulfonylxanthone-2-carboxylic acid, methyl 1-5-propoxy-7-methylsulfonylxanthone-2-carboxylate, pentyl 5-propoxy-7-methylsulfonylxanthone-2-carboxylate, 5-isopropoxy-7_methylsulfonylxanthone-2-carboxylic acid, m.p. .3l8°C, methyl 1-5-isopropoxy-7-methylsulfonylxanthone-2-carboxylate, pentyl 5-isopropoxy-7-methylsulfonylxanthone-2-carboxylate, 5-butoxy-7-methylsul phenylxanthone-2-carboxylic acid, methyl 1-5-butoxy-7-methylsulfonylxanthone-2-carboxylate, pentyl-5-butoxy-7-methylsulfonylxanthone-2-carboxylate, 5-pentoxy-7-methylsulfonylxanthone-2-carboxylic acid, methyl-5- pentoxy-7-methylsulfonylxanthone-2-carboxylate, pentyl-5-pentoxy-7-methylsulfonylxanthone-2-carboxylate, 5"isopentoxy-7-methylsulfonylxanthone-2-carboxylic acid, methyl 5-isopentoxy-7-methylsulfonylxanthone-2-carboxylate, pentyl-5-isopentoxy-7-methylsulfonylxanthone-2-carboxylate, 5-octyloxy-7-methylsulfonylxanthone-2-carboxylic acid, methyl 5-octyloxy-7-methylsulfonylxanthone-2-carboxylate, pentyl-5-octyloxy-7-methylsulfonylxanthone-2-carboxylate 2-carboxylate, 5-dodecyloxy-7-methylsulfonylxanthone-2-carboxylic acid, methyl 5-dodecyloxy-7-methylsulfonylxanthone-2-carboxylate, penty1-5-dodecyloxy-7-methylsulfonylxanthone-2-carboxylate, as well as the corresponding 7-ethylsulfonylxanthone-2-carboxylate, the propylsulfonyl, butylsulfonyl and pentylsulfonyl compounds; and 5-methylsulfonyl 1-7-methoxyxanthone-2-carboxylic acid, methyl 1-5-methylsulfonyl-7-methoxyxanthone-2-carboxylate, pentyl 5-methylsulfonyl-7-methoxyxanthone-2-carboxylate, 5-methylsulfonyl 1-7-ethoxyxanthone-2-carboxylate -carboxylic acid, methyl-5-methylsulfonyl-7-ethoxyxanthone-2-carboxylate, pentyl-5-methylsulfonyl-7-ethoxyxanthone-2-carboxylate, 5-methylsulfonyl1-7-propoxyxanthone-2-carboxylic acid, methyl-5-methylsulfonyl-7-ethoxyxanthone-2-carboxylate -propoxyxanthone-2-carboxylate, penty1-5-methylsulfonyl1-7-propoxyxanthone-2-carboxylate, 5-methylsulfonyl1-7-isopropoxyxanthone-2-carboxylic acid, m.p. 308-309°C, methyl 5-methylsulfonyl-7-isopropoxyxanthone-2-carboxylate, penty1-5-methylsulfony1-7-isopropoxyxanthone-2-carboxylate,
5-metylsulfonyl-7-butoksyxanton-2-karboksylsyre, 5-methylsulfonyl-7-butoxyxanthone-2-carboxylic acid,
mety1-5-metylsulfony1-7-butoksyxanton-2-karboksylat, methyl 1-5-methylsulfony 1-7-butoxyxanthone-2-carboxylate,
pentyl-5-metylsulfonyl-7-butoksyxanton-2-karboksylat, 5-metylsulfony1-7-pentoksyxanton-2-karboksylsyre, pentyl 5-methylsulfonyl-7-butoxyxanthone-2-carboxylate, 5-methylsulfonyl 1-7-pentoxyxanthone-2-carboxylic acid,
mety1-5-metylsulfony1-7-pentoksyxanton-2-karboksylat, penty1-5-metylsulfonyl-7-pentoksyxanton-2-karboksylat, 5-metylsulfonyl-7-isopentoksyxanton-2-karboksylat, metyl-5-metylsulfonyl-7-isopentoksyxanton-2-karboksylat, pentyl-5-metylsulfony1-7-isopentoksyxanton-2-karboksylat, 5-metylsulfonyl-7-oktyloksyxanton-2-karboksylsyre, metyl-5-metylsulfonyl-7~oktyloksyxanton-2-karboksylat, pentyl-5-metylsulfonyl-7-oktyloksyxanton-2-karboksylat, 5-metylsulfony1-7-dodecyloksyxanton-2-karboksylsyre, metyl-5-metylsulfonyl-7-dodecyloksyxanton-2-karboksylat, pent yl-5-metylsulf ony 1-7- dodecyloksyxant on- 2-karboksy lat', methyl 1-5-methylsulfonyl 1-7-pentoxyxanthone-2-carboxylate, penty 1-5-methylsulfonyl-7-pentoxyxanthone-2-carboxylate, 5-methylsulfonyl-7-isopentoxyxanthone-2-carboxylate, methyl 5-methylsulfonyl-7-isopentoxyxanthone-2-carboxylate 2-carboxylate, pentyl-5-methylsulfonyl1-7-isopentoxyxanthone-2-carboxylate, 5-methylsulfonyl-7-octyloxyxanthone-2-carboxylic acid, methyl-5-methylsulfonyl-7~octyloxyxanthone-2-carboxylate, pentyl-5-methylsulfonyl- 7-octyloxyxanthone-2-carboxylate, 5-methylsulfony1-7-dodecyloxyxanthone-2-carboxylic acid, methyl 5-methylsulfonyl-7-dodecyloxyxanthone-2-carboxylate, pentyl-5-methylsulfony 1-7- dodecyloxyxanthone-2- carboxy lazy',
samt de tilsvarende 5-etylsulfonyl-, propylsulfonyl-, butylsulfonyl- , og pentylsulfonylforbindelsene. as well as the corresponding 5-ethylsulfonyl, propylsulfonyl, butylsulfonyl and pentylsulfonyl compounds.
Eksempel 5Example 5
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' steden 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-karboksylsyre,r og 5-lavere alkyltio-7-hydroksy-xanton-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)-xanton-2-karboksylsyre, 4,5 g tørt litiumkarbonat, 4 ml metyljodid og 70 ml dimetylformamid, omrøres ved romtemperatur i 20 timer. Etter til-setning 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-karbbksylat, smp. 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 metyl-5-metyltio-7-hydroksyxanton-2-karboksylat, smp. 290°C (dekomp.). By using 5-methylthio-7-hydroxyxanthone-2-carboxylic acid in the above method, methyl 5-methylthio-7-hydroxyxanthone-2-carboxylate is also obtained, m.p. 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 penty1-5-metyltio-7-hydroksyxanton-2-karboksylat. C. 1,55 g metyl-5-hydroksy-7-(metyltio)-xanton-2-karboksylat omrøres ved romtemperatur med 2,5 g oktylbromid og 1,0 g kalium-karbonat i 30 ml dimetylformamid i 18 timer. Etter surgjøring 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. The method is repeated using different lower alkyl iodides to thereby prepare lower alkyl acid esters from these, 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 penty1-5-methylthio-7-hydroxyxanthone-2-carboxylate. 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 crude 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-karboksylat, mety1-5-n-heptyloksy-7_(metyltio)-xanton-2-karboksylat, metyl-5-n-dodecyloksy-7-(metyltio)-xanton-2-karboksylat, og mety1-5-metyltio-7-n-heksyloksyxanton-2-karboksylat, metyl-5-metyltio-7-n-heptyloksyxanton-2-karboksylat, og mety1-5-metyltio-7-n-dodecyloksyxanton-2-karboksylat. The above method is repeated using other higher alkyl bromides in order to obtain 5- and 7-higher alkoxy compounds such as e.g. methyl 5-n-hexyloxy-7-(methylthio)-xanthone-2-carboxylate, methyl 1-5-n-heptyloxy-7_(methylthio)-xanthone-2-carboxylate, methyl 5-n-dodecyloxy-7-( methylthio)-xanthone-2-carboxylate, and methyl 1-5-methylthio-7-n-hexyloxyxanthone-2-carboxylate, methyl 5-methylthio-7-n-heptyloxyxanthone-2-carboxylate, and methyl 1-5-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 alkyl-bromid, oppnås f.eks. ety1-5-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, 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 1-5-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-heptyloksy-7-(metyltio)-xanton-2-karboksylat, pentyl 5-n-heptyloxy-7-(methylthio)-xanthone-2-carboxylate,
etyl-5-n-dodecyloksy-7~(metyltio)-xanton-2-karboksylat, etyl-5-metyltio-7-n-oktyloksyxanton-2-karboksylat, penty1-5-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-dodecyloksyxanton-2-karboksylat. 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 mens temperaturen holdes ved ca. 0°C. Etter at tilsetningen.?er ferdig filtreres oppløsningen gjennom aluminiumoksyd (aktivitet III) og inndampes, og dette gir 2,0 g metyl-5_n-oktyloksy-7-metylsulfinyl-xanton-2-karboksylat. ethyl 5-n-dodecyloxy-7~(methylthio)-xanthone-2-carboxylate, ethyl 5-methylthio-7-n-octyloxyxanthone-2-carboxylate, penty1-5-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-dodecyloxyxanthone-2-carboxylate . D. To 2.0 g of methyl-5-n-octyloxy-7-(methylthio)-xanthone-2-carboxylate in 60 ml of chloroform, a solution of 910 mg of m-chloroperoxybenzoic acid in 40 ml of chloroform is slowly added while the temperature is maintained at approx. 0°C. After the addition is complete, the solution is filtered through alumina (activity III) and evaporated, and this gives 2.0 g of methyl-5-n-octyloxy-7-methylsulfinyl-xanthone-2-carboxylate.
Ved i foregående metøde.rår-bényfcte .metyl-5-métyltio-7-n-bktyloksyxåhbon+-2-karboksy lat oppnås på samme måte metyl-5-metyl-sulf inyl-7_n-oktyloksyxanton-2-karboksylat. Methyl-5-methyl-sulfinyl-7-n-octyloxyxanthone-2-carboxylate is obtained in the same way by using in the preceding method.
Ved å benytte de andre forbindelsene fremstilt i del C i dette eksempel i steden for 5_n-oktyloksy-7-(metyltio)-xanton-2-karboksylat, oppnås f.eks.: mety1-5-n-heksyloksy-7-metylsulfinylxanton-2-karboksylat, mety1-5-n-heptyloksy-7-metylsulfinylxanton-2-karboksylat, metyl-5-n-dodecyloksy-7-metylsulfinylxanton-2-karboksylat, etyl-5-n-oktyloksy-7-metylsulfinylxanton-2-karboksylat, penty1-5-n-oktyloksy-7-metylsulfinylxanton-2-karboksylat, etyl-5-n-heksyloksy-7-metylsulfinylxanton-2-karboksylat, pentyl-5-n-heptyloksy-7-metylsulfinylxanton-2-karboksylat, og etyl-5-n-dodecyloksy-7-metylsulfinylxanton-2-karboksylat, og metyl-5-metylsulfinyl-7-n-heksyloksyxanton-2-karboksylat, metyl-5-metylsulfinyl-7-n-heptyloksyxanton-2-karboksylat, metyl-5-metylsulfinyl-7-n-dodecyloksyxanton-2-karboksylat, etyl-5-metylsulfinyl-7-n-okty1oksyxanton-2-karboksylat, penty1-5-metylsulfinyl-7-n-oktyloksyxanton-2-karboksylat, etyl-5-metylsulfinyl-7~n-heksyloksyxanton-2-karboksylat, pentyl-5-metylsulfinyl-7-n-heksyloksyxanton-2-karboksylat, og etyl-5-metylsulfinyl-7_n-dodecyloksyxanton-2-karboksylat. By using the other compounds prepared in part C in this example in place of 5_n-octyloxy-7-(methylthio)-xanthone-2-carboxylate, for example: methyl 1-5-n-hexyloxy-7-methylsulfinylxanthone- 2-carboxylate, methyl 1-5-n-heptyloxy-7-methylsulfinylxanthone-2-carboxylate, methyl 5-n-dodecyloxy-7-methylsulfinylxanthone-2-carboxylate, ethyl 5-n-octyloxy-7-methylsulfinylxanthone-2-carboxylate carboxylate, penty1-5-n-octyloxy-7-methylsulfinylxanthone-2-carboxylate, ethyl 5-n-hexyloxy-7-methylsulfinylxanthone-2-carboxylate, pentyl 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-dodecyloxyxanthone-2-carboxylate, ethyl 5-methylsulfinyl-7-n-octyloxyxanthone-2-carboxylate, penty1-5-methylsulfinyl-7-n-octyloxyxanthone-2-carboxylate, ethyl- 5-methylsulfinyl-7~n-hexyloxyxanthone-2-carboxylate, pentyl-5-methylsulfinyl-7-n-hexylox yxanthone-2-carboxylate, and ethyl 5-methylsulfinyl-7_n-dodecyloxyxanthone-2-carboxylate.
E. Metyl-5-n-oktyloksy-7-(metyltio)-xanton-2-karboksylat (750 mg;);, 2 ml hydrogenperoksyd (30%) og 40 ml eddiksyre oppvarmes på et dampbad (80°C) i 90 minutter. Tynnsjiktskromatografi indikerer fravær av utgangsmateriale. Blandingen fortynnes med 60 ml varmt E. Methyl 5-n-octyloxy-7-(methylthio)-xanthone-2-carboxylate (750 mg);, 2 ml of hydrogen peroxide (30%) and 40 ml of acetic acid are heated on a steam bath (80°C) for 90 minutes. Thin layer chromatography indicates the 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-kårboksylat. 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-(metyltio)-xanton-2-karboksylat, oppnås f.eks.: mety1-5-n-heksyloksy-7-metylsulfonylxanton-2-karboksylat, mety1-5-n-heptyloksy-7-metylsulfonylxanton-2-karboksylat, met y 1-5-n-dod ecy loks y-7-m'e ty lsulf onylxant on-2-karboksy lat, etyl-5-n-oktyloksy-7-metylsulfonylxanton-2-karboksylat, penty1-5-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 mety1-5-metylsulfonyl-7-n-heksyloksyxanton-2-karboksylat, metyl-5-metylsulfonyl-7-n-heptyloksyxanton-2-karboksylat, metyl-5-metylsulfonyl-7-n-dodecyloksyxanton-2-karboksylat, etyl-5-metylsulfony1-7-n-oktyloksyxanton-2-karboksylat, pentyl-5-metylsulfonyl-7~n-oktyloksyxanton-2-karboksylat, etyl-5-metylsulfonyl-7-n-heksyloksyxanton-2-karboksylat, pentyl-5-metylsulfonyl-7-n-heksyloksyxanton-2-karboksylat, og etyl-5-metylsulfonyl-7-n-dodecyloksyxanton-2-karboksylat. Similarly, by 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-methylsulfonylxanthone-2-carboxylate, methyl 1-5-n-heptyloxy-7-methylsulfonylxanthone-2-carboxylate, met y 1-5-n-dod ecy lox y-7-me ty lsulfonylxanthone-2 -carboxylate, ethyl 5-n-octyloxy-7-methylsulfonylxanthone-2-carboxylate, penty1-5-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 1-5-methylsulfonyl-7-n-hexyloxyxanthone-2-carboxylate, methyl 5-methylsulfonyl-7-n-heptyloxyxanthone-2-carboxylate, methyl 5-methylsulfonyl-7-n-dodecyloxyxanthone-2-carboxylate, ethyl 5-methylsulfonyl 1-7-n-octyloxyxanthone-2-carboxylate, pentyl- 5-methylsulfonyl-7~n-octyloxyxanthone-2-carboxylate, ethyl 5-methylsulfonyl-7-n-hexyloxyxanthone-2-carboxylate, pentyl-5-m ethylsulfonyl-7-n-hexyloxyxanthone-2-carboxylate, and ethyl 5-methylsulfonyl-7-n-dodecyloxyxanthone-2-carboxylate.
P. 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/ etanol, hvilket gir 1,8 g 5~n-oktyloksy-7_metylsulfinylxanton-2-karboksylsyre. P. 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/ethanol, which gives 1.8 g of 5~n-octyloxy-7-methylsulfinylxanthone-2-carboxylic acid.
Likeledes, ved som utgangsmateriale å benytte deLikewise, by using them as starting material
andre forbindelsene oppnådd i del D og del E i dette eksempel i steden for metyl-5-n-oktyloksy-7-metylsulfinylxanton-2-karboksylat, oppnås f.eks.: 5-metylsulfinyl-7-n-oktyloksyxanton-2-karboksylsyres5-n-oktyloksy-7-metylsulfonylxanton-2-karboksylsyre, the other compounds obtained in part D and part E in this example instead of methyl 5-n-octyloxy-7-methylsulfinylxanthone-2-carboxylate are obtained, for example: 5-methylsulfinyl-7-n-octyloxyxanthone-2-carboxylic acid5 -n-octyloxy-7-methylsulfonylxanthone-2-carboxylic acid,
5-metylsulfony1-7-n-oktyloksyxanton-2-karboksylsyre, 5-n-heksyloksy-7-metylsulfinylxanton-2-karboksylsyre, 5-methylsulfony1-7-n-octyloxyxanthone-2-carboxylic acid, 5-n-hexyloxy-7-methylsulfinylxanthone-2-carboxylic acid,
5-n-heptyloksy-7-metylsulfinylxanton-2-karboksylsyre, 5-n-dodecyloksy-7-metylsulfinylxanton-2-karboksylsyre, 5-metylsulfinyl-7-n-heksyloksyxanton-2-karboksylsyre, 5-metylsulfinyl-7_n-heptyloksyxanton-2-karboksylsyre, og 5-metylsulfinyl-7-n-dodecyloksyxanton-2-karboksy1syre, 5-n-heksyloksy-7-metylsulfonylxanton-2-karboksylsyre, 5-n-heptyloksy-7-metylsulfonylxanton-2-karboksylsyre, 5-n-dodecyloksy-7-metylsulfonylxanton-2-karboksylsyre, 5-metylsulfonyl-7-n-heksyloksyxanton-2-karboksylsyrej5-metylsulfonyl-7-n-heptyloksyxanton-2-karboksylsyre, og, 5-metylsulfony1-7-n-dodecyloksyxanton-2-karboksylsyre. 5-n-heptyloxy-7-methylsulfinylxanthone-2-carboxylic acid, 5-n-dodecyloxy-7-methylsulfinylxanthone-2-carboxylic acid, 5-methylsulfinyl-7-n-hexyloxyxanthone-2-carboxylic acid, 5-methylsulfinyl-7_n-heptyloxyxanthone-2-carboxylic acid 2-carboxylic acid, and 5-methylsulfinyl-7-n-dodecyloxyxanthone-2-carboxylic acid, 5-n-hexyloxy-7-methylsulfonylxanthone-2-carboxylic acid, 5-n-heptyloxy-7-methylsulfonylxanthone-2-carboxylic acid, 5-n -dodecyloxy-7-methylsulfonylxanthone-2-carboxylic acid, 5-methylsulfonyl-7-n-hexyloxyxanthone-2-carboxylic acidj5-methylsulfonyl-7-n-heptyloxyxanthone-2-carboxylic acid, and, 5-methylsulfonyl-7-n-dodecyloxyxanthone-2-carboxylic acid -carboxylic acid.
Eksempel , 6 ■ Example , 6 ■
En blanding av 4,5 g 5-n-oktyl-7_metylsulfinylxanton-2-karboksylsyre s 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 with 10 g of methyl iodide and 10 g of lithium carbonate in 75 ml of dimethylformamide is 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-okty1-7-metylsulfinylxanton-2-karboksylat, isopropyl-5-n-okty1-7-metylsulfinylxanton-2-karboksylat, n-propyl-5-n-oktyl-7-metylsulfinylxanton-2-karboksylat, isobutyl-5-n-oktyl-7-metylsulfinylxanton-2-karboksylat, sek-butyl-5-n-oktyl-7-metylsulfinylxanton-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-octy1-7-methylsulfinylxanthone-2-carboxylate, isopropyl-5-n-octy1-7-methylsulfinylxanthone-2-carboxylate, n-propyl-5-n-octyl-7-methylsulfinylxanthone-2- carboxylate, isobutyl-5-n-octyl-7-methylsulfinylxanthone-2-carboxylate, sec-butyl-5-n-octyl-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-st Ulingene , 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-oktyl-7_sulfamoylxanton-2-karboksylat, metyl-5_acetyl-7_n-oktylxanton-2-karboksylatj. osv. Likewise, the other xanthone-2-carboxylic acids containing substituents at C-5,7-st Ulingen, prepared as stated 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, methyl 5_acetyl-7_n-octylxanthone-2-carboxylatej. etc.
I sulfoseriene fremstilles estrene ved behandling av syren med den passende lavere alkanol under tilbakeløp og In the sulpho series, the esters are prepared by treating the acid with the appropriate lower alkanol under reflux and
i fravær av syre til f.eks.: mety1-5-n-okty1-7-sulfoxanton-2-karboksylat og in the absence of acid to e.g.: methyl 1-5-n-octyl-7-sulfoxanthone-2-carboxylate and
etyl-5-n-okty1-7-sulfoxanton-2-karboksylat.ethyl 5-n-octyl-7-sulfoxanthone-2-carboxylate.
Eksempel 7 Example 7
Til en oppløsning av 10 g 5_n-oktyl-7-metylsulfinyl-xanton-2-karboksylsyre i 200 ml etanol tilsettes den teoretiske mengde natriumhydroksyd oppløst i.200 ml. 90% etanol. Reaksjons-, blandingen konsentreres deretter i vakuum og dette gir natrium-5-n-oktyl-7-metylsulfonylxanton-2-karboksylat. 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 amount of sodium hydroxide dissolved in 200 ml. 90% ethanol. The reaction mixture is then concentrated in vacuo and this gives 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.: magne sium-5_n-o;ktyl - 7-met yl sulf inylxant on-2-karboksy lat, kalsium-5-n-oktyl-7-metylsulfinylxanton-2-karboksylat, aluminium-5-n-oktyl-7-metylsulfinylxanton-2-karboksylat, ferro-5-n-okty1-7-metylsulfinylxanton-2-karboksylat, sink- 5-n-okt yl-7-mety lsulf inylxanton-2-karboksylat,.. mangan-5-n-oktyl-7-metylsulfinylxanton-2-karboksylat, ferri-5_n-oktyl-7-metyisulfinylxanton-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;ctyl - 7-methyl sulf inylxanthone-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-octyl-7 -methylsulfinylxanthone-2-carboxylate,.. manganese-5-n-octyl-7-methylsulfinylxanthone-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-heksy1-7-metylsulfinylxanton-2-karboksylat, . natrium-5-n-oktyloksy-7-metylsulfinylxanton-2-karboksylat, natrium-5-metylsulfonyl-7-n-oktyloksyxanton-2-karboksylat, natrium-5-metylsulfinyl-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-hexy1-7-methylsulfinylxanthone-2-carboxylate, . sodium 5-n-octyloxy-7-methylsulfinylxanthone-2-carboxylate, sodium 5-methylsulfonyl-7-n-octyloxyxanthone-2-carboxylate, sodium 5-methylsulfinyl-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-methylsulfonylxanthone-2-carboxylate, sodium 5-n-octyloxy-7-methylsulfonylxanthone-2-carboxylate, etc.
Eksempel gExample g
En oppløsning av 10 g 5-n-oktyl-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-octyl-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-metylsulfamoylxanton-2-karboksylsyreamid, N-metyl-5~n-oktyl-7-n-propylsulfinylxanton-2-karboksylsyreamid, N,N-diety1-5-n-okty1-7-etylsulfonylxanton-2-karboksylsyreamid, N-n-propyl-5_n-okty1-7-(propylsulfinylxanton-2-karboksylsyreamid, osv, 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-methyl-5~n-octyl-7-n-propylsulfinylxanthone-2-carboxylic acid amide, N,N-diethy1-5-n -octy1-7-ethylsulfonylxanthone-2-carboxylic acid amide, N-n-propyl-5_n-octy1-7-(propylsulfinylxanthone-2-carboxylic acid amide, etc.,
Eksempel 9,Example 9,
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. "Videre oppnås på lignende måte f.eks. prokain-, lysin-, kaffein- In the same way, lysine-,' is obtained. the caffeine and arginine salts. "Furthermore, 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 10Example 10
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 deretter. 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 11Example 11
Den nedenfor angitte forbindelse ble undersøkt under anvendelse av den rotte-passive kutane anafylakseprøve (.PCA) 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) The compound below was tested using the rat passive cutaneous anaphylaxis test (.PCA) 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 respons som resulterer fra antigen-antistoffreaksjonen fremtrer 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, som uttrykkes som prosent mot kontrollprøve. 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 response resulting from the antigen-antibody reaction appears as a blue-colored skin area that is 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 the inflammatory response, which is expressed as a percentage against control sample.
Eksempel 12<1> Example 12<1>
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 disorientation. 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 human bronchial lung activity, 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 respect to the expiratory function.■ Such measurements include a quantization of the outgoing pulmonary 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 |
|---|---|---|---|
| NO753169A NO753169L (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 | |
| NO753169A NO753169L (en) | 1974-01-08 | 1975-09-17 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO753169L true NO753169L (en) | 1975-07-09 |
Family
ID=27352717
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO753169A NO753169L (en) | 1974-01-08 | 1975-09-17 |
Country Status (1)
| Country | Link |
|---|---|
| NO (1) | NO753169L (en) |
-
1975
- 1975-09-17 NO NO753169A patent/NO753169L/no unknown
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