NO780473L - PROCEDURE FOR THE PREPARATION OF INDOLYLGLYCOCACIC ACID DERIVATIVES - Google Patents
PROCEDURE FOR THE PREPARATION OF INDOLYLGLYCOCACIC ACID DERIVATIVESInfo
- Publication number
- NO780473L NO780473L NO780473A NO780473A NO780473L NO 780473 L NO780473 L NO 780473L NO 780473 A NO780473 A NO 780473A NO 780473 A NO780473 A NO 780473A NO 780473 L NO780473 L NO 780473L
- Authority
- NO
- Norway
- Prior art keywords
- hydroxy
- formula
- acid
- compound
- lower alkyl
- Prior art date
Links
- 238000000034 method Methods 0.000 title description 47
- 239000002253 acid Substances 0.000 title description 37
- 238000002360 preparation method Methods 0.000 title description 10
- 150000001875 compounds Chemical class 0.000 description 96
- 125000000217 alkyl group Chemical group 0.000 description 66
- 150000003839 salts Chemical class 0.000 description 65
- 235000002639 sodium chloride Nutrition 0.000 description 65
- -1 Aethoxy Chemical group 0.000 description 56
- 125000004432 carbon atom Chemical group C* 0.000 description 50
- 239000001257 hydrogen Substances 0.000 description 43
- 229910052739 hydrogen Inorganic materials 0.000 description 43
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 41
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 37
- 239000000243 solution Substances 0.000 description 34
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 31
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 29
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 27
- 238000002844 melting Methods 0.000 description 27
- 230000008018 melting Effects 0.000 description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 26
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 22
- 239000013543 active substance Substances 0.000 description 21
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 20
- 238000011282 treatment Methods 0.000 description 20
- 239000013078 crystal Substances 0.000 description 17
- 125000003545 alkoxy group Chemical group 0.000 description 15
- 238000003756 stirring Methods 0.000 description 15
- 229910052736 halogen Inorganic materials 0.000 description 14
- 150000002367 halogens Chemical class 0.000 description 14
- 239000002585 base Substances 0.000 description 13
- 159000000000 sodium salts Chemical class 0.000 description 13
- 239000007858 starting material Substances 0.000 description 13
- 239000000725 suspension Substances 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 125000002947 alkylene group Chemical group 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- 125000000449 nitro group Chemical class [O-][N+](*)=O 0.000 description 11
- 229910052783 alkali metal Inorganic materials 0.000 description 10
- 150000001340 alkali metals Chemical class 0.000 description 10
- 239000003795 chemical substances by application Substances 0.000 description 10
- 239000000825 pharmaceutical preparation Substances 0.000 description 10
- 235000011121 sodium hydroxide Nutrition 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 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 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000000155 melt Substances 0.000 description 9
- 125000001424 substituent group Chemical group 0.000 description 9
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 8
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 238000006460 hydrolysis reaction Methods 0.000 description 8
- 238000001953 recrystallisation Methods 0.000 description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 7
- 229920002472 Starch Polymers 0.000 description 7
- 239000002775 capsule Substances 0.000 description 7
- 230000007062 hydrolysis Effects 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- 229910052708 sodium Inorganic materials 0.000 description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 7
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 150000007513 acids Chemical group 0.000 description 6
- 150000001450 anions Chemical class 0.000 description 6
- 239000000460 chlorine Substances 0.000 description 6
- 229910052801 chlorine Inorganic materials 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 150000002431 hydrogen Chemical class 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 150000004702 methyl esters Chemical class 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 108010010803 Gelatin Proteins 0.000 description 5
- 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 5
- 229960000583 acetic acid Drugs 0.000 description 5
- 230000002378 acidificating effect Effects 0.000 description 5
- 150000001335 aliphatic alkanes Chemical class 0.000 description 5
- 125000001931 aliphatic group Chemical group 0.000 description 5
- 239000000969 carrier Substances 0.000 description 5
- 125000000753 cycloalkyl group Chemical group 0.000 description 5
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 5
- 235000019439 ethyl acetate Nutrition 0.000 description 5
- 229920000159 gelatin Polymers 0.000 description 5
- 235000019322 gelatine Nutrition 0.000 description 5
- 235000011852 gelatine desserts Nutrition 0.000 description 5
- 239000008101 lactose Substances 0.000 description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 description 5
- 125000004043 oxo group Chemical group O=* 0.000 description 5
- 229920001223 polyethylene glycol Polymers 0.000 description 5
- 239000003381 stabilizer Substances 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- AGULWIQIYWWFBJ-UHFFFAOYSA-N 3,4-dichlorofuran-2,5-dione Chemical compound ClC1=C(Cl)C(=O)OC1=O AGULWIQIYWWFBJ-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 4
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 239000000443 aerosol Substances 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 238000003776 cleavage reaction Methods 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000006196 drop Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000008273 gelatin Substances 0.000 description 4
- 239000012362 glacial acetic acid Substances 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 235000010755 mineral Nutrition 0.000 description 4
- 239000011707 mineral Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 125000003431 oxalo group Chemical group 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 230000007017 scission Effects 0.000 description 4
- 239000007921 spray Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 235000000346 sugar Nutrition 0.000 description 4
- 229940100445 wheat starch Drugs 0.000 description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 3
- 244000215068 Acacia senegal Species 0.000 description 3
- 229920000084 Gum arabic Polymers 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
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 235000010489 acacia gum Nutrition 0.000 description 3
- 239000000205 acacia gum Substances 0.000 description 3
- 125000004423 acyloxy group Chemical group 0.000 description 3
- 150000001350 alkyl halides Chemical class 0.000 description 3
- 150000008051 alkyl sulfates Chemical class 0.000 description 3
- 208000026935 allergic disease Diseases 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 208000006673 asthma Diseases 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 230000032050 esterification Effects 0.000 description 3
- 238000005886 esterification reaction Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 150000002430 hydrocarbons Chemical group 0.000 description 3
- 239000013067 intermediate product Substances 0.000 description 3
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Substances [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 3
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 239000003380 propellant Substances 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- RWSOTUBLDIXVET-UHFFFAOYSA-O sulfonium group Chemical group [SH3+] RWSOTUBLDIXVET-UHFFFAOYSA-O 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 235000012222 talc Nutrition 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- 150000003626 triacylglycerols Chemical class 0.000 description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- 241000416162 Astragalus gummifer Species 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical group O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 229920001615 Tragacanth Polymers 0.000 description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 2
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 239000007859 condensation product Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000010685 fatty oil Substances 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 125000003055 glycidyl group Chemical group C(C1CO1)* 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N methyl acetate Chemical compound COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 239000004033 plastic Substances 0.000 description 2
- 229920003023 plastic Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 210000002345 respiratory system Anatomy 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 2
- 235000012239 silicon dioxide Nutrition 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 235000017550 sodium carbonate Nutrition 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 239000002511 suppository base Substances 0.000 description 2
- 235000010487 tragacanth Nutrition 0.000 description 2
- 239000000196 tragacanth Substances 0.000 description 2
- 229940116362 tragacanth Drugs 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical class [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- NNJPGOLRFBJNIW-HNNXBMFYSA-N (-)-demecolcine Chemical compound C1=C(OC)C(=O)C=C2[C@@H](NC)CCC3=CC(OC)=C(OC)C(OC)=C3C2=C1 NNJPGOLRFBJNIW-HNNXBMFYSA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- RIZUCYSQUWMQLX-UHFFFAOYSA-N 2,3-dimethylbenzoic acid Chemical compound CC1=CC=CC(C(O)=O)=C1C RIZUCYSQUWMQLX-UHFFFAOYSA-N 0.000 description 1
- WNZLDRIGCVYTOQ-UHFFFAOYSA-N 2-(1h-indol-2-yl)-2-oxoacetic acid Chemical class C1=CC=C2NC(C(=O)C(=O)O)=CC2=C1 WNZLDRIGCVYTOQ-UHFFFAOYSA-N 0.000 description 1
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- RDNBEYSGWQHQNB-UHFFFAOYSA-N 3-bromo-4-ethoxy-2,4-dioxobutanoic acid Chemical compound CCOC(=O)C(Br)C(=O)C(O)=O RDNBEYSGWQHQNB-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/36—Oxygen atoms in position 3, e.g. adrenochrome
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/14—Antitussive agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Description
Oppfinnelsen vedrører nye indolylglyoxylsyrederi- The invention relates to new indolylglyoxylic acid derivatives
vater spesielt 3-Hydroxy-indolyl-2-glyoxylsyrederivater med den generelle formel particularly 3-Hydroxy-indolyl-2-glyoxylic acid derivatives of the general formula
hvor Y betyr eventuelt foretret eller acylert hydroxy, R where Y means optionally etherified or acylated hydroxy, R
betyr Hydrogen eventuelt substituert Laverealkyl eller Cycflroalkyl og - OR^ betyr eventuelt foretret Hydroxy hvori means Hydrogen optionally substituted Lower alkyl or Cycflroalkyl and - OR^ means optionally etherified Hydroxy in which
enten R^betyr laverealkyl, Laver éa/lkoxy, Cycloalkyl, Hyd- either R^ means lower alkyl, Lower alkyloxy, Cycloalkyl, Hyd-
roxy, Phenoxy, Halogen eller Nitro, R^betyr Laverealkyl, Laverealcoxy eller Hydroxy R^og R^betyr uavhengig av hver- roxy, Phenoxy, Halogen or Nitro, R^means Lower alkyl, Loweralcoxy or Hydroxy R^and R^means independently of each-
andre Hydrogen eller Laverealkyl i det minst<g>en av restene R^, R^, R^ og R^betyr i 5 - og/eller 6-stilling bundet other Hydrogen or Lower alkyl in at least one of the residues R^, R^, R^ and R^ means in the 5- and/or 6-position bonded
Laverealkyl eller R^og R,, betyr sammen til to naboplasserte Karbonatomer bundet Alkylen med 3 til 5 kjedekarbonatomer Lower alkyl or R^ and R,, together to two adjacent carbon atoms linked Alkylene with 3 to 5 chain carbon atoms
og R^og R^betyr Hydrogen samt deres salter som fremgangs- and R^ and R^ mean Hydrogen and their salts as precursors
måte til deres fremstilling, videre farmasøytiske prepa-- way of their preparation, further pharmaceutical prepa--
rater inneholdene forbindelsene med formelen I eller salter herav, og anvendelsen av de nye forbindelser. rates containing the compounds of the formula I or salts thereof, and the use of the new compounds.
I sammenheng med foreliggende beskrivelse innehol- In the context of the present description, the
der "lavere" betegnede organiske rester og forbindelser spesielt til og med 7»fortrinnsvis til og med h Karbonato- where "lower" designated organic residues and compounds especially up to and including 7»preferably up to and including h Carbonato-
mer • more •
Laverealkyl da for eksempel Meifihyl, Aethyl,n-Pro- Lower alkyl then for example Meifihyl, Aethyl,n-Pro-
pyl, Isopropyl, n-Butyl eller n-Pentyl. pyl, Isopropyl, n-Butyl or n-Pentyl.
Foretret Hydroxy er for eksempel eventuelt substituert Laverealkoxy -OR . Etherated Hydroxy is, for example, optionally substituted Lower Alkoxy -OR.
o o
Substituenter av substituert Laverealkyl Rrresp-ektiv Rq er Hydroxy eller Laverealkoxy idet en eller flere substituenter kan være tilstede. Substituents of substituted Lower alkyl Rrrespectively Rq are Hydroxy or Lower alkyl, one or more substituents may be present.
Laverealkoxy betyr for eksempel Methoxy, Aethoxy, n-Propyloxy', Isopropyloxy, n-Butyloxy, Isobutyloxy, tert. - Butyloxy, n-Pentyloxy eller n-Hexyloxy. Lower alkyl means, for example, Methoxy, Aethoxy, n-Propyloxy', Isopropyloxy, n-Butyloxy, Isobutyloxy, tert. - Butyloxy, n-Pentyloxy or n-Hexyloxy.
Hydroxy- eller Laverealkoxy-laverealkyl er spesielt 2-/eller 3 Hydroxy-laverealkyl for eksempel 2-Hydroxy-athyl, 3-Hydroxyprppyl eller 2,3-Dihydroxy-propyl, eller 2- eller 3 Laverealkoxy-laverealkyl, for eksempel 2-Methoxyathyl, 2-Aéthoxyathyl eller 3-Methoxypropyl. Hydroxy- or Lower-Alkoxy-lower alkyl is especially 2-/or 3-Hydroxy-lower-alkyl, for example 2-Hydroxy-ethyl, 3-Hydroxy-propyl or 2,3-Dihydroxy-propyl, or 2- or 3-Lower-Alkoxy-lower-alkyl, for example 2-Methoxyathyl , 2-Ethoxyethyl or 3-Methoxypropyl.
Cycloalkyl inneholder fortrinnsvis 5 til 8, i første rekke 5-7 ringatomer og er for eksempel Cyclopen-tyl eller Cycloheptyl eller fremfor alt Cyclohexyl. Cycloalkyl preferably contains 5 to 8, primarily 5-7 ring atoms and is, for example, Cyclopentyl or Cycloheptyl or, above all, Cyclohexyl.
I IN
Phenoxy er fortrinnsvis usubstituert Phenoxy, kan imidlertid også være substituert med Laverealkyl<:>som Methyl, Laverealkoxy som Methoxy, Halogen som Klor og/eller Nitro. Phenoxy is preferably unsubstituted Phenoxy, but can also be substituted with Lower alkyl <:> such as Methyl, Lower Alkoxy such as Methoxy, Halogen such as Chlorine and/or Nitro.
Halogen er spesielt Halogen med atomnummer til og med 35, d. v. s. Fluor, Klor eller Brom. Halogen is in particular Halogen with an atomic number up to and including 35, i.e. Fluorine, Chlorine or Bromine.
Acylert Hydroxy er eksempelvis fra en organisk Carboksylsyre avledet Acyloxy. Som karboksyjlsyre kom.r mer det derved fortrinnsvis i betraktning eventuelt substituerte alifatiske eller, aromatiske karboksyisyrer som eventuelt fenylsubstituerte Alkan- eller Alkenkarboksylsy-rer, fortrinnsvis en av de nevnte Laverealkyl - eller der-av avléder Laveralkenylresteholdige Laverealkan - respek-tive Lav eralkenkarboksylsyr er samt aromatiske karboksylsy-rer, for eksempel Benzosyre eller Pyridinkarboksylsyrer. Acylated Hydroxy is, for example, derived from an organic carboxylic acid, Acyloxy. As a carboxylic acid, preferably substituted aliphatic or aromatic carboxylic acids such as optionally phenyl-substituted alkane or alkene carboxylic acids, preferably one of the aforementioned Lower alkyl - or derivatives thereof Lower alkanes containing lower alkenyl residues - respective lower alkene carboxylic acids are as well aromatic carboxylic acids, for example benzoic acid or pyridine carboxylic acids.
I de nevnte syrer kan aromatiske rester eventuelt være substituert med Laverealkyl, Laveralkoxy, Halogen og/eller Nitro. Acylert Hydroxy er således fortrinnsvis rettlinjet eller forgrenet Laverealkanoyloxy, for eksempel Acetoxy, Propionoloxy, i ' Butyryloxy, Isobutyryloxy, Valeroyloxy eller Pivaloyloxy, eller eventuelt som angitt substituert<*>Fenylacetyloxy - alfafenylpropionyloxy-, Benzyoloxy-, Nicotinoyloxy-, Isonicotinoyloxy - eller Picolyloxyrester. In the mentioned acids, aromatic residues can optionally be substituted with Laverealkyl, Laveralkoxy, Halogen and/or Nitro. Acylated Hydroxy is thus preferably straight or branched Laverealkanoyloxy, for example Acetoxy, Propionoloxy, i 'Butyryloxy, Isobutyryloxy, Valeroyloxy or Pivaloyloxy, or optionally as indicated substituted<*>Phenylacetyloxy - alphaphenylpropionyloxy-, Benzyoloxy-, Nicotinoyloxy-, Isonicotinoyloxy - or Picolyloxy ester.
Ved R og R^ sammen dannet Alkylen med 3 til 5 karbonatomer er spesielt rettlinjet Alkylen,som 1,3-Propylen eller 1,4-Butylen eller i annen rekke 1,5-Pentylen. When R and R^ together form Alkylene with 3 to 5 carbon atoms is particularly rectilinear Alkylene, such as 1,3-Propylene or 1,4-Butylene or, in other cases, 1,5-Pentylene.
Salter av forbindelsermSdrtfioimel I er i første rekke farmasøytisk anvendbare salter, idet som salter spesielt kommer på tale syreaddisjonsalter med egnede uorganiske eller organiske syrer for eksempel med fosfor - eller svovelsyre, klor - eller Bromhydrogensyre, eddik-, 'glykol-, malein-fumar -, eple-, vin-, sitron-, benzo-, salicyl-, embon-,ni-kotin-, metansulfonT,22-Hydroxyetansulfon-, 4-Meth^lbenzen-sulfon-, eller 2-Naftalinsulfonsyre, videre også som mellom-produkter anvendbare syreaddisjonsalter, for eksempel med Pikrin-, Pikrolon-, Flavian-, Reinecke- eller Perchlorsyre. Videre kan forbindelser med formel I hvoriRR betyr Hydrogen også danne indre salter eller salter med baser. Salter med baser er for eksempel Alkalimetall - eller Jordalkalimetall-for eksempel Natrium-, Kalium-, Magnesium - eller Kalsium-salter, videre Ammoniumsalter med Ammoniakk eller Aminer som Lavere^^<y->'-eller Hydroxylaverealkylaminer for eksempel Trimethylamin, Triethylamin eller Di (2-hydroxyethyl)-amin. Salts of compounds mSdrtfioimel I are primarily pharmaceutically usable salts, the salts in particular being acid addition salts with suitable inorganic or organic acids, for example with phosphoric - or sulfuric acid, chlorine - or hydrobromic acid, acetic, 'glycol, maleic fumar - , malic, tartaric, citric, benzo, salicylic, embonic, nicotinic, methanesulfonic, 22-Hydroxyethanesulfonic, 4-Meth^lbenzenesulfonic, or 2-Naphthalenesulfonic acid, further also as intermediate products usable acid addition salts, for example with Picric, Picrolonic, Flavian, Reinecke or Perchloric acid. Furthermore, compounds of formula I in which RR stands for Hydrogen can also form internal salts or salts with bases. Salts with bases are, for example, alkali metal - or alkaline earth metal - for example sodium, potassium, magnesium - or calcium salts, further ammonium salts with ammonia or amines such as lower^^<y->'-or hydroxyl lower alkylamines for example trimethylamine, triethylamine or Di(2-hydroxyethyl)amine.
Med forbindelsen med formel I hvor Y betyr Hydroxy, kan også foreligge den ved hjelp av formel With the compound of formula I where Y means Hydroxy, it can also be present by means of formula
omtalte tautomeren (desmotrope) 3-Ketoform. referred to the tautomer (desmotrope) 3-Ketoform.
De nye forbindelser viser verdifulle farmakologi-ske egenskaper. Spesielt har de antiallergiske virkninger som for eksempel kan påvises på rotte i doser fra ca. 0,3 til ca. The new compounds show valuable pharmacological properties. In particular, they have anti-allergic effects which, for example, can be detected in rats in doses from approx. 0.3 to approx.
10 mg. pr. kg. ved intravenøs og iædoser fra ca.il til ca. 100 10 mg. per kg. by intravenous and iædos from approx. il to approx. 100
mg. pr kg. ved oraladminiétrering i passiv kutan Anafylaxdld-prøve (PCA-reaksjon), som gjennomføres analog den av Goose og Blair immunologi bind 16 side 7^9 (1969) omtalte metode idet den passive kutane Anafylaxi frembringes etter den av Ovary progressiv allergi bind 5 side k59 (1958) omtalte fremgangsmåte. Forbindelsen i henhold til oppfinnelsen er derfor anvendbare som hemmere av allergiske reaksjoner for eksempel i behandlingen og Prophylaxe av allergiske sykdommer som mg. per kg. by oral administration in a passive cutaneous Anaphylaxdld test (PCA reaction), which is carried out analogously to the method described by Goose and Blair immunology volume 16 page 7^9 (1969) in that the passive cutaneous Anaphylaxis is produced after that of Ovary progressive allergy volume 5 page k59 (1958) mentioned procedure. The compound according to the invention can therefore be used as inhibitors of allergic reactions, for example in the treatment and prophylaxis of allergic diseases such as
astma såvel extrinsic som også intrinsic astma eller andre asthma both extrinsic and intrinsic asthma or others
allergiske sykdommer som høyfeber, konjunktivitis, urticaria og eksemer. allergic diseases such as hay fever, conjunctivitis, urticaria and eczema.
Oppfinnelsen vedrører i første rekke forbindelse med formel I hvori Y har den angitte, betydning R og Rq betyr uavhengig av hverandre Hydrogen, Laverealkyl med inntil h Karbonatomer Hydroxylaverealkyl med til og med k Karbonatomer, Hydroxylayeralkyl med til og med h Karbonatomer , hvori Hydroxy er bundet i 2dg-/ellér 3-stilling eller Laverealkoxylaverealkyl med til og med 7 Karbonatomer hvori Laver ealkylgruppen er bundet i 2- eller 3- stilling og hvori enten R^betyr Laverealkyl med til og med h Karbonatomer ©^.-G^-Cycloalkyl, Hydroxy, Laver ealkoxy med til og med h Karbonatomer, Halogen med atomnummer til og med 35 eller Nitro og R^, R^og R^uavhengig av hverandre betyr Hydrogen eller Laveralkyl med til og med h Karbonatomer i det minste en av restene Er, R£, R^og R^betyr i 5j_ og/eller 6-stilling bundet Laverealkyl med inntil k Karbonatomer eller R^og R^sammen danner i 5,6 - stilling bundet rettlxnjet Alkylen med 3 til 5 Karbonatomer og R^og R^betyr Hydrogen "§åmt salter av overnevnte forbindelser spesielt tilsvarende far-masøytisk anvendbare salter. The invention primarily relates to a compound of formula I in which Y has the meaning R and Rq independently of each other mean Hydrogen, Lower alkyl with up to h Carbon atoms Hydroxyllower alkyl with up to and including k Carbon atoms, Hydroxylayeralkyl with up to and including h Carbon atoms, in which Hydroxy is bound in the 2dg-/or 3-position or Lower alkyl lower alkyl with up to and including 7 carbon atoms in which the lower alkyl group is bound in the 2- or 3- position and in which either R^means lower alkyl with up to and including h carbon atoms ©^.-G^-Cycloalkyl, Hydroxy, Lower alkyl with up to and including h Carbon atoms, Halogen with atomic number up to and including 35 or Nitro and R^, R^ and R^ independently of each other mean Hydrogen or Lower alkyl with up to and including h Carbon atoms at least one of the residues is, R£, R^ and R^ mean in the 5j_ and/or 6-position bonded lower alkyl with up to k carbon atoms or R^ and R^ together form in the 5,6 - position bonded straight alkylene with 3 to 5 carbon atoms and R^ and R ^means Hydrogen "§amt salts of the above compounds in particular corresponding to pharmaceutically usable salts.
Oppfinnelsen vedrører spesielt forbindelse med The invention relates in particular to connection with
formel formula
hvori Y betyr Hydroxy, C^-C^- Alkoxy som Methoxy eller Eth-oxy eller C^- C^- Alkanoyloxy, som Acetoxy, R^og R^ betyr uavhengig av hverandre Hydrogen eller Laverealkyl med til og med h Karbonatomer for eksempel Mefthyl eller Aethyl, Hydroxylaverealkyl med til og med h Karbonatomer hvori Hydroxy er bundet i 2-/eller 3- stilling for eksempel 2-Hyd-roxyathyl eller 2,3-Di-hydroxy-propyl, eller Laverealkoxy-laverealkyl med til og med 4 Karbonatomer hvori Lavereal/-koxygruppen er bundet til 2- eller 3-stilling for eksempel 2-Methoxyathyl, og hvori enten en av restene Rr. og Rg betyr Laverealkyl med til og med h Karbonatomer for eksempel Methyl, en av de gjenblivene rester Rg, R^, og Rg betyr 7 in which Y means Hydroxy, C^-C^- Alkoxy such as Methoxy or Eth-oxy or C^- C^- Alkanoyloxy, such as Acetoxy, R^ and R^ independently mean Hydrogen or Lower alkyl with even h Carbon atoms for example Methyl or Aethyl, Hydroxyl lower alkyl with up to and including h Carbon atoms in which Hydroxy is bound in the 2-/or 3- position, for example 2-Hydroxyethyl or 2,3-Di-hydroxy-propyl, or Lower alkoxy lower alkyl with up to and including 4 Carbon atoms in which the Lavereal/-oxy group is bound to the 2- or 3-position, for example 2-Methoxyathyl, and in which either one of the residues Rr. and Rg means Lower alkyl with up to and including h Carbon atoms for example Methyl, one of the remaining residues Rg, R^, and Rg means 7
Hydrogen, Laverealkyl med til og med 4 Karbonatomer for eksempel Methyl, Halogen med atomnummer til og med 35 for eksempel Klor, Laverealkoxy med til og med 4 Karbonatomer for eksempel Methoxy, Hydroxy eller Nitro og den tredje av restene Rg, R^ og Rg betyr Hydrogen eller Laverealkyl med inntil 4 Karbonatomer for eksempel Methyl eller Rg betyr Hydrogen og R^ og Rg danner sammen Alkylen med 3 eller 4 kjedekarbonatomer for eksempel 1,3-Propylen samt salter og overnevnte forbindelser spesielt tilsvarende farmasøytisk anvendbare salter. Hydrogen, Lower alkyl with up to and including 4 carbon atoms for example Methyl, Halogen with atomic number up to and including 35 for example Chlorine, Lower alkyl with up to and including 4 carbon atoms for example Methoxy, Hydroxy or Nitro and the third of the residues Rg, R^ and Rg means Hydrogen or Lower alkyl with up to 4 carbon atoms, for example Methyl or Rg means Hydrogen and R^ and Rg together form Alkylene with 3 or 4 chain carbon atoms, for example 1,3-Propylene as well as salts and above-mentioned compounds in particular equivalent to pharmaceutically usable salts.
Oppfinnelsen vedrører i første rekke forbindelse med formel I av hvori Y betyr Hydroxy R^og R,, betyr Hydrogen eller Laverealkyl meddtil og med 4 Karbonatomer for eksempel Merfjhyl eller Aethyl eller i annen rekke Hydroxylave-?e realkyl med til og med 4 Karbonatomer hvori Hydroxy er bundet i 2- og/eller 3-stilling for eksempel 2-Hydroxyethyl eller 2,3- Dihydroxy-propyl, eller Laverealkoxylaverealkyl med til og med 4 Karbona tørrfor hvori den La v er ealkyl gruppen er bundet i 2- eller 3- stilling for eksempel Methoxy-ethyl og hvori Rg, R^, og Rg betyr Hydrogen eller Methyl eller R^ og Rg sammen betyr 1,3—Propylen eller 1,4 Bmtyien^ j idet- minst en av restene R^ og Rg er forskjellig fra Hydrogen spesielt hvori Y betyr Hydroxy Rq betyr Hydrogen eller Laverealkyl med inntill4 Karbonatomer som Methyl eller Aethyl , |rR .betyr Laver ealkyl med inntil 4 Karbonatomer som Methyl eller Aethyl, Rg betyr Hydrogen og minst en av restene R_ og RD betyr Laverealkyl med inntil 4 Karbonatomer som Methyl, og den andre betyr eventuelt Hydrogen eller R,-, og The invention primarily relates to a compound of formula I in which Y means Hydroxy R^ and R,, means Hydrogen or Lower alkyl with up to and including 4 carbon atoms, for example Merphjyl or Aethyl or in another series Hydroxyl-?e realkyl with up to and including 4 carbon atoms in which Hydroxy is bound in the 2- and/or 3-position, for example 2-Hydroxyethyl or 2,3-Dihydroxy-propyl, or Lower alkyl lower alkyl with up to 4 carbons in which the Lower alkyl group is bound in the 2- or 3- position for example Methoxy-ethyl and in which Rg, R^, and Rg mean Hydrogen or Methyl or R^ and Rg together mean 1,3-Propylene or 1,4 Bmtyien^ j in that at least one of the residues R^ and Rg is different from Hydrogen in particular in which Y means Hydroxy Rq means Hydrogen or Lower alkyl with up to 14 Carbon atoms such as Methyl or Aethyl 4 Carbon atoms such as Met howl, and the other possibly means Hydrogen or R,-, and
Rg danner sammen 3- til ^- ledet Laverealkylen som 1,3-propylen som salter av overnevnte forbindelser spesielt tilsvarende farmasøytisk anvendbare salter. Rg together form 3- to 3-linked lower alkylene such as 1,3-propylene as salts of the above-mentioned compounds, particularly corresponding pharmaceutically usable salts.
Forbindelsen med formel I fremstilles i og for seg kjent måte idet en forbindelse med den generelle formel The compound of formula I is prepared in a manner known per se as a compound of the general formula
hvori R, R , R , R„ , R , og R, har den angitte betydning wherein R, R , R , R„ , R , and R, have the indicated meaning
+ 4 pv + 4 pv
betyr en Oniumgruppe og X~betyr anionresten av en syre eller et salt hherav hydrolyseres og hvis ønskelig over-føres en dannet forbindelse med formel I i en annen forbindelse med formel I og/eller hvis ønskeig overføres en dannet fri forbindelse i et salt eller et annet salt i den frie forbindelse eller i et annet salt. means an Onium group and X~means the anionic residue of an acid or a salt from which is hydrolyzed and if desired a formed compound of formula I is transferred into another compound of formula I and/or if desired a free compound formed is transferred into a salt or a other salt in the free compound or in another salt.
I et utgangsmaterigile med formel II som vanligvis dannes in situ forstår man med en oniumgruppe en positivt ladet gruppe hvis frie valens går ut fra det positivt ladede Heteroatom, spesielt Nitrogen videre Svovelatom. In a starting material with formula II, which is usually formed in situ, an onium group is understood as a positively charged group whose free valence starts from the positively charged heteroatom, especially nitrogen and sulfur atom.
Foretrukket som rest X^p er en Ammonium<g>ru<pp>e hvori Nitrogenatomer eventuelt kan være mono - di-eller trisubsti-tuert med mono, eller bivalente substituenter. Slike substituenter er spesielt de/av alifatisk karakter som eventuelt substituerte mono - eller diva-iente alifatiske samt cyclo-aldifatiske, cycloalifatiskalifatisk eller aralifatiske Hydro-karbonrester i første rekke Laverealkyl eller Laverealkylen hvori Karbonatomer kan være erstattet med Heteroatomer som Oksygen -eller eventuelt for eksempel med Laverealkyl, som Methyl substituerte Nitrogenatomer for eksempel Methyl, Aethyl, 3 - Oxa-n-butyl, 1,4-Butylen, 1,5-Pentylen, 3-Oxa-1,5-pentylen eller 3-Methyl-3-aza-1,5-pentylen, videre Cycloalkyl, for eksempel Cyclohexyl, eller Phenyllaverealkyl, Preferred as residue X^p is an Ammonium<g>ru<pp>e in which Nitrogen atoms can optionally be mono - di- or tri-substituted with mono, or bivalent substituents. Such substituents are especially those/of an aliphatic character which optionally substituted mono - or divalent aliphatic as well as cyclo-aldiphatic, cycloaliphatic aliphatic or araliphatic Hydrocarbon residues primarily Lower alkyl or Lower alkylene in which Carbon atoms can be replaced by Heteroatoms such as Oxygen - or optionally for example with Lower alkyl, such as Methyl substituted Nitrogen atoms for example Methyl, Aethyl, 3-Oxa-n-butyl, 1,4-Butylene, 1,5-Pentylene, 3-Oxa-1,5-pentylene or 3-Methyl-3-aza -1,5-pentylene, further Cycloalkyl, for example Cyclohexyl, or Phenyllaverealkyl,
for eksempelBenzyl.Foretrukket Ammoniumgr^uppejii "ff erde'for example Benzyl. Preferred Ammonium group
med formel with formula
hvori Ra og R^betyr Hydrogen eller fortrinnsvis Laverealkyl for eksempel Meithyl eller Aéjfch^l eller sammen danner Laverealkylen hvor et Karbonatom kan være erstattet med et Oksygenatom eller et eventuelt substituert for eksempel La-verealkylert Nitrogenatom for eksempel 1,5-Pentylen, 3-0xa-1,5-pentylen eller 3-Methyl-3-aza-1,5-pentylen. Som ydderligere substituent av Nitrogenatomet i en Ammoniumgruppe kommer det for eksempel på tale en Amidinogruppe i overnevnte delformel Ila kan derfor R& ^ for eksempel "også bety in which Ra and R^ mean Hydrogen or preferably Lower alkyl, for example Methyl or Aljfch^l or together form Lower alkylene where a Carbon atom can be replaced by an Oxygen atom or an optionally substituted, for example Lower alkylated Nitrogen atom, for example 1,5-Pentylene, 3- 0xa-1,5-pentylene or 3-Methyl-3-aza-1,5-pentylene. As an additional substituent of the Nitrogen atom in an Ammonium group, for example, an Amidino group in the above-mentioned partial formula Ila can therefore R& ^ for example "also mean
Amidino og R, Hydrogen. Amidino and R, Hydrogen.
Ydderligere Oniumgrupper er Sulfoniumgrupper, som for eksempel er substituert ved mono- eller divalente substituentral aliphatisk karakter, som de overnevnte spesielt med Laverealkyl eller Laverealkylen hvori Karbonato-mene kan være erstattet med Heteroatomer som Oksygen eller eventuelt'for eksempel med'Laverealkyl som Methyl, substiiu tuerte Nitrogenatomer for eksempel Methyl, Aethyl, 1,4-Butylen eller 1 ,5-Pentylen, /og fortrinnsvis inneholder en 5-0xidogruppe.' Slike grupper ér i første rekke de med for- Further Onium groups are Sulfonium groups, which are, for example, substituted by mono- or divalent substituent central aliphatic character, as those mentioned above especially with Loweralkyl or Loweralkylene in which the Carbon atoms can be replaced with Heteroatoms such as Oxygen or optionally, for example with Loweralkyl such as Methyl, substituted tuated Nitrogen atoms, for example Methyl, Ethyl, 1,4-Butylene or 1,5-Pentylene, /and preferably contains a 5-oxido group.' Such groups are primarily those with
hvori Rcog R^betyr Laverealkyl, for eksempel Methyl, eller sammen danner Laverealkylen for eksempel 1,4 - Butylen eller 1,5-PSntylen og n betyr 0 eUrler fortrinnsvis 1. in which R and R^ mean Lower alkyl, for example Methyl, or together form the Lower alkylene, for example 1,4-Butylene or 1,5-PSntylene and n means 0 or preferably 1.
Anioner X^-* av syrer er i første rekke de av sterke syrer som uorganiske syrer\lfor eksempel en Halogen - som Klor - videre Bromhydrogensyre eller også svovelsyre eller av sterke organiske Carboksyl - eller Sulfonsyrer. Anionet X^1 betyr derfor i første rekke et Halogen spesielt Klorani-onet. Anions X^-* of acids are primarily those of strong acids such as inorganic acids\lfor example a Halogen - such as Chlorine - further Bromic acid or also sulfuric acid or of strong organic Carboxyl - or Sulphonic acids. The anion X^1 therefore primarily means a halogen, especially the chlorine ion.
Hydrolyse foretas fortrinnsvis ,i surt medium spesielt ved behandling med fortynnet syre som mineral - for eksempel Halogenhydrogensyre, som saltsyre elier Bromhydrogensyre videre svovelsyre. Derved kan man arbeide i nærvær av et organisk fortrinnsvist med vann blandbart oppløsning - eller fortynningsmiddel hvis nødvendig under avkjøling eller oppvarming (for eksempel i et temperaturområde fra ca.O°C til ca. 100°C), i et lukket kar og /eller i en inertgassat-mo.sfære. Hydrolysis is preferably carried out in an acidic medium, especially when treated with dilute acid as a mineral - for example hydrohalic acid, such as hydrochloric acid or hydrobromic acid and sulfuric acid. Thereby, one can work in the presence of an organic, preferably water-miscible solution - or diluent if necessary during cooling or heating (for example in a temperature range from approx. 0°C to approx. 100°C), in a closed vessel and/or in an inert gas mo.sphere.
Utgangsmateriale med formel II kan for eksempelvis fåes i det substituert Anilin^itoea formel Starting material with formula II can, for example, be obtained in the substituted Anilin^itoea formula
hvori R'er forskjellig fra Hydrogen og betyr en gruppe R eller Acyl, som Laverealkanoyl eller eventuelt substituert Ben-zyol, for eksempel Formyl, Acetyl eller Benzpyl, eller syre-addisjonssalt herav omsettes med 2,3-Di-X-maleinsyreanhydrid hvori resten X betyr like eller forskjellig reaksjonsdyktig, foresterte Hydroxygrupper for eksempel med 2,3 - Dihalogen-spesielt 2,3-Diklor-maleinsyreanhydride, i nærvær av en Lewis-syre, for eksempel Aluminiumklorid1 og en således dannet forbindelse med formel hvori X haarv overnevnte betydning, og i første rekke betyr Halogen spesielt Klor hvis nødvendig med behandlig med en base som et Alkalimetall-, for eksempel Natriumhydroxid ringsluttes til en forbindelse med formelen in which R' is different from Hydrogen and means a group R or Acyl, such as Laverealkanoyl or optionally substituted Benzyol, for example Formyl, Acetyl or Benzpyl, or acid addition salt thereof is reacted with 2,3-Di-X-maleic anhydride in which the residue X means equally or differently reactive, esterified Hydroxy groups, for example with 2,3 - Dihalogen, especially 2,3-Dichloro-maleic anhydride, in the presence of a Lewis acid, for example Aluminum Chloride1 and a thus formed compound of formula in which X has the above meaning , and in the first place Halogen means especially Chlorine if necessary with treatable with a base such as an Alkali metal-, for example Sodium hydroxide is ring-closed to a compound with the formula
eventuelt under avspaltning av Acyl R.' possibly during cleavage of Acyl R.'
I overnevnte Anilinforbindelse med formel III hår restene R^, R,,, R^, og R^overnevnte betydninger, med det unntak at R^ikke betyr Nitro. En Laverealkoxygruppe R^og/ eller R^kan under reaksjonsbetingelsene få Friedel-Crafts-reaksjon omdannes i Hydroxy, og hvis ønsker,vvéd Alkylering igjen tilbakeføres i en Laverealkoxygruppe. In the above-mentioned Aniline compound of formula III, the residues R^, R^, R^, and R^ have the above-mentioned meanings, with the exception that R^ does not mean Nitro. A Lower Alkoxy group R^ and/or R^ can, under the reaction conditions, undergo a Friedel-Crafts reaction to be converted into Hydroxy, and if desired, vvéd Alkylation again reverts to a Lower Alkoxy group.
I et etter overnevnte fremgangsmåte oppnåelige mellomprodukt/med formel V kan den frie Carboxylgruppe for eksempel ved behandling av syren med formel V forestres med en eventuelt substituert Laverealkanol i nærvær av en syre eller et kondensasjonsmiddel eller for dannelse av en Hydroxylaver ealkylJester, med Epoxylaverealkan, eller ved om-setting av et Alkalimetallsalt av syren med et eventuelt substituert Laverealkylhalogenid eller de laverealkylsulfat eller ved behandling av det tilsvarende syreklorid med en eventuelt substituert Laverealkanol for eksempel i nærvær av et basisk middel. Derved kan i et foresteringsreagens substituentene foreligge i funksjonelt modifisert form og deretter frigjøres i det forestrede mellomprodukt. Således kan man som forestringsreagen for eksempel anvende 2,3-Epoxy-propylklorid og i den dannede ester hydrolysere 2,3-Epoxy-propylgrupperingen efterpå til den ønskede 2,3-Dihyd-r o xy -pr o py 1 gr upp er ing. ■ In an intermediate product/formula V obtainable according to the above-mentioned method, the free carboxyl group can, for example, by treating the acid with formula V be esterified with an optionally substituted Lower alkanol in the presence of an acid or a condensing agent or to form a Hydroxyllower ealkylester, with Epoxylower alkane, or by reacting an alkali metal salt of the acid with an optionally substituted Lower alkyl halide or the lower alkyl sulphate or by treating the corresponding acid chloride with an optionally substituted Lower alkanol, for example in the presence of a basic agent. Thereby, in an esterification reagent, the substituents can be present in a functionally modified form and then released in the esterified intermediate. Thus, for example, 2,3-Epoxy-propyl chloride can be used as the esterification reagent and in the formed ester the 2,3-Epoxy-propyl grouping can then be hydrolysed to the desired 2,3-Dihydro-roxy-propy1 group . ■
Videre kan en Nitrogruppe for eksempel ved behandling med salpetersyre,hvis nødvendig,! nærvær av svovelsyre innføres i den<g>arbocycliskaromatiske del åv Indolringen. Videre kan en Hydroxygruppe , for eksempel med behandling med et Laverealkylsulfat i nærvær av en base for eksempel av Kaliumkarbénat omdannes i en Laverealkoxygruppe. Furthermore, a Nitro group can, for example, by treatment with nitric acid, if necessary,! presence of sulfuric acid is introduced into the<g>arbocyclicaromatic part of the Indole ring. Furthermore, a Hydroxy group can, for example, by treatment with a Lower alkyl sulfate in the presence of a base, for example of Potassium carbonate, be converted into a Lower Alkoxy group.
I et mellomprodukt.med formel V kan gruppen X for In an intermediate product with formula V, the group X can for
i og for seg kjent måte omdannessi oniumgruppen X®, av ut-gangs mat er ial e med formel II idet dannelsen av utgangsmateriale vanligvis foregår in situ. Således kan man behandle en forbindelse med formel V med Ammoniak eller et Amin, for eksempel en forbindelse med formel R a - NH - R, (Vi), og deretter danne den ønskede Ammoniumgruppe hvis nødvendig, Med behandling med en syre eventuelt også i surt medium av Hydrolyseraksjon ifølge oppfinnelsen. Analog kan man behandle et mellomprodukt med formel V et Sulfoxid eller et Sulfid, in a manner known per se, the conversion of the onium group X®, of the starting material is ial e with formula II, since the formation of the starting material usually takes place in situ. Thus, one can treat a compound of formula V with Ammonia or an Amine, for example a compound of formula R a - NH - R, (Vi), and then form the desired Ammonium group if necessary, with treatment with an acid possibly also in acidic medium of the Hydrolysis reaction according to the invention. Analogously, an intermediate with formula V can be treated with a Sulfoxide or a Sulfide,
og således komme til det ønskede utgangsmaterialemed formel II, hvori etyr en Sulfoniumgruppe. and thus arrive at the desired starting material of formula II, in which ether is a sulfonium group.
En forbindelse oppnådd ifølge oppfinnelsen med formel I kan på i for seg kjent måte omdannes i en annen forbindelse med formel I. A compound obtained according to the invention with formula I can be converted in a manner known per se into another compound with formula I.
Forbindelsen med^formel I kan videre fremstilles idet en forbindelse med formel hvori en av restene X og X^betyr en eventuelt funksjonell modifisert karbokygruppe og den annen betyr Hydrogen eller et salt herav, kondenseres intramolekulært og hvis ønsket, en dannet forbindelse med formel I overføres i en annen forbindelse med tf?ormel. I og/eller hvis ønsket et dannet salt overføres i den frie forbindelse eller i et annet salt og/eller en dannet forbindelse med formel I hvori R betyr Hydroxy overføres i et salt. The compound with ^formula I can further be prepared in that a compound with formula in which one of the residues X and X^ means an optionally functional modified carboxy group and the other means Hydrogen or a salt thereof, is condensed intramolecularly and, if desired, a formed compound with formula I is transferred in another connection with t?ormel. I and/or if desired a formed salt is transferred in the free compound or in another salt and/or a formed compound of formula I in which R means Hydroxy is transferred in a salt.
Funksjonelt modifiserte Karboxygrupper er ;eksempelvis Cyano- eller oxogruppeholdig funksjonelt modifiåerte Functionally modified carboxy groups are, for example, functionally modified containing cyano or oxo groups
Carboxygrupper fremfor alt forestrete Karboxygrupper som Laver ealkoxycarbonyl , for eksempel Methoxy- eller Aethoxycarbo-nyl. Salter av forbindelse med formel IX er spesielt Alkalimetall-, som Natrium- eller Kaliumsalter, av forbindelser Formel VI, hvori X2, ,X og/eller -COORQer Carboxy. Carboxy groups above all esterified Carboxy groups such as Lower ealkoxycarbonyl, for example Methoxy- or Aethoxycarbonyl. Salts of compounds of formula IX are especially alkali metal, such as sodium or potassium salts, of compounds of formula VI, in which X 2 , X and/or -COORQ are carboxy.
Den intramolekulare kondensasjon foregår på vanlig måte eksempelvis termisk, for eksempel ved ca. 60 til 300°C, og/eller ved behandling med en base, for eksempel med et Al-kalimetallhydroxyd, -alkoholat, -amid eller -carboxylat som Natrium- eller Kaliumhydroxid, Natrriniunethanplat eller -met-hanolat, Natriumamid eller Lithiumdiisopropylamid eller Natriumacetat, hvis nødvendig i et inert oppløsningsmiddel for eksempel i Benzol, Toluol, en Xylol, Dimethylformamid eller Acetanhydrid. The intramolecular condensation takes place in the usual way, for example thermally, for example at approx. 60 to 300°C, and/or by treatment with a base, for example with an Al-potassium metal hydroxide, -alcoholate, -amide or -carboxylate such as Sodium or Potassium hydroxide, Natriniunethanplat or -methanolate, Sodium amide or Lithium diisopropylamide or Sodium acetate, if necessary in an inert solvent for example in benzene, toluene, a xylene, dimethylformamide or acetic anhydride.
I en foretrukket utførelsesform av fremgangsmåten behandler man eksempelvis en forbindelse med formel VI hvori R betyr Hydrogen, X^forestret Carboxy og X^Hydrogen med et Alkalimetallaverealkanolat fortrinnsvis med Natrium-methanolat eller -ethanolat, i Benzol eller Toluol, i det man fortrinnsvis arbeider ved ca. 60 til 130°C for eksempel ved 80 - 100°C. In a preferred embodiment of the method, for example, a compound of formula VI is treated in which R means Hydrogen, X^esterified Carboxy and X^Hydrogen with an Alkali metal avereal alkanolate, preferably with Sodium methoxide or ethanolate, in Benzol or Toluene, preferably working at about. 60 to 130°C for example at 80 - 100°C.
I en modifikasjon av denne fremgangsmåte kan man også gå ut/\?fra det tilsvarende Nitril, d.v.s. en forbindelse med formel VI hvori1 respektiv X^betyr Cyano. Derved fåes primært den tilsvarende forbindelse med formel som isolerbart mellomprodukt hvis exocycliske NH-gruppe hydroliseres under betingelsene for opparbeidelse til Oxo. In a modification of this method, one can also proceed from the corresponding Nitrile, i.e. a compound of formula VI in which X, respectively, is Cyano. Thereby, the corresponding compound with formula is primarily obtained as an isolable intermediate whose exocyclic NH group is hydrolysed under the conditions for processing to Oxo.
Utgangsstoffene formel VI kan såyidt ikke allerede er kjendt, fremstilles etter i for seg kjendte metoder. The starting materials formula VI can, as far as they are not already known, be prepared according to methods known per se.
Eksempelvis kan forbindelse med formel VI hvori X? betyr Hydrogen og X^betyr eventuelt forestret .Carboxy, fremstilles i det en forbindelse med formel For example, compounds of formula VI in which X? means Hydrogen and X^means possibly esterified .Carboxy, a compound of formula is prepared there
elier et Alkalimetall-, for eksempel Natriumsalt herav, på vanlig måte kondensieres med en Halogenoxaleddiksyreester, for eksempel med Bromoxaleddiksyreethylester, og hvis nød-vendig hydroliseres en forestrert Carboxygruppe X^til Carboxy. Forbindelse med formel VI hvori X^betyr eventuelt funksjonelt modifisert Carboxy. og X^ betyr Hydrogen, kan for eksempel fåes idet en forbindelse med.formel or an Alkali metal, for example Sodium salt thereof, is condensed in the usual way with a Halogenoxaloacetic acid ester, for example with Bromooxaloacetic acid ethyl ester, and if necessary, an esterified Carboxy group X^ is hydrolysed to Carboxy. Compound of formula VI in which X represents optionally functionally modified Carboxy. and X^ means Hydrogen, can for example be obtained as a compound with.formula
eller et Alkalimetall-, for eksempel Natriumsalt herav, omsettes på vanlig måte med en Halogenpyrodruesyreester, for eksempel med'Brompyrodruesyreester. or an Alkali metal, for example sodium salt thereof, is reacted in the usual way with a Halogenpyruvic acid ester, for example with 'Bromopyruvic acid ester.
Forbindelse med formel I kan videre fremstilles i-det i en forbindelse med formel Compound of formula I can further be prepared in-it in a compound of formula
hvori betyr en i gruppen med formel -CO-COOR^overfør- in which means one in the group of formula -CO-COOR^transfer-
bar restoverføres X^i gruppen med formel -CO-COORq og hvis ønsket, overføres en dannet forbindelse med formel I bar residue is transferred X^in the group of formula -CO-COORq and, if desired, a formed compound of formula I is transferred
i en annen forbindelse med formel I og/eller hvis ønsket over-føres et dannet salt i den fri forbindelse eller et annet salt og/eller en dannet forbindelse med formel I hvori X betyr Hydroxy til et salt. in another compound of formula I and/or if desired, a formed salt is transferred in the free compound or another salt and/or a formed compound of formula I in which X stands for Hydroxy to a salt.
Til grupper med formel -CO-COOR^overførbare rester er spesielt hydrolytisk, disse overførbare rester spesielt i Oxalogruppen hydrolyserbare rester for eksempel lav grupper med formel -CO-COORq forskjellig funksjonelt modifiserte Oxalorester. Slike rester er eksempelvis slike med formel - C( =X^) -COORQ-C(=0)-X6og i annen rekke - 6( =X^)- X^, hvori Xg betyr en funksjonelt modifisert Oxogruppe og X^betyr en fra eventuelt forestrete Carboxygruppe -COORq forskjellig funksjonelt modifisert Carboxygruppe. Funksjonelt modifiserte Oxogrupper er spesielt Thioxo- og fortrinnsvis substituerte, Iminogrupper, for eksempel Hydroxy- eller Phenylimino. Funksjonelt modifiserte Caboxygrupper Xg er spesielt Trihalogenmethylgrupper for eksempel Trichlorme-thyl. \ To groups with the formula -CO-COOR^transferable residues are particularly hydrolytic, these transferable residues especially in the Oxalo group hydrolyzable residues for example low groups with the formula -CO-COORq differently functionally modified Oxal residues. Such residues are, for example, those with the formula - C( =X^) -COORQ-C(=0)-X6 and in another row - 6( =X^)- X^, in which Xg means a functionally modified oxo group and X^ means a from optionally esterified Carboxy group -COORq differently functionally modified Carboxy group. Functionally modified Oxo groups are especially Thioxo and preferably substituted Imino groups, for example Hydroxy or Phenylimino. Functionally modified Caboxy groups Xg are especially Trihalogenmethyl groups, for example Trichlormethyl. \
Hydrolyéen av de nevnte grupper i Oxalogrupper foregår eksempelvis i nærvær av sure eller i annen rekke basiske hydrolysemidler hvis nødvendig nærvær av ydderligere hjelpemidler for eksempel utgående fra forbindelser med formel IX, hvori X^betyr en gruppe -C(=X^) -COORQog X^betyr Thixo av Oxydasjonsmidler for eksempel Hypohalogenit-er som Natriumhypochlorid, eller Perforbindelser som Hydro-genperoxid. Sure hydrolysemidler er fortrinnsvis mineral-syrer som saltsyre eller svovelsyre. Basiske hydrolysemidler ervfortrinnsvis Alkalimetallhydroxider, for eksempel Natriumhydroxid, eller Ammoniumbaser, for eksempel Ammoni-umhydroxid. The hydrolysis of the aforementioned groups into Oxalogroups takes place, for example, in the presence of acidic or otherwise basic hydrolysis agents if the necessary presence of additional aids, for example starting from compounds of formula IX, in which X^ means a group -C(=X^) -COORQ and X ^means Thixo of Oxidizing agents, for example Hypohalogenites such as Sodium hypochlorid, or Per compounds such as Hydrogen peroxide. Acid hydrolysis agents are preferably mineral acids such as hydrochloric or sulfuric acid. Basic hydrolysis agents are preferably alkali metal hydroxides, for example sodium hydroxide, or ammonium bases, for example ammonium hydroxide.
I en foretrukket utførelsesform av overnevnte frem-gangsmåter hydrolyser:er man for eksempel en forbindelse med formel IX, hvori X, betyr en gruppe med formel -C(=NOH)-COOH eller -C(=N-Ar)-C00 H3N-Ar' idet Ar betyr en eventuelt med foreeksempel med lavere alkyl, Laverealkoxy, Halogen og/eller Nitro substituert Phenylrest, i nærvær av saltsyre i et vann-holdig oppløsningsmiddel, som vandig eddiksyre. In a preferred embodiment of the above-mentioned methods, one hydrolyzes, for example, a compound of formula IX, in which X means a group of formula -C(=NOH)-COOH or -C(=N-Ar)-C00 H3N- Ar', where Ar means an optionally, for example, lower alkyl, lower alkyl, halogen and/or nitro substituted phenyl radical, in the presence of hydrochloric acid in an aqueous solvent, such as aqueous acetic acid.
Utgangsstoffene med formel IX hvori X^betyr en gruppe med formel -C(=S)-COORq kan eksempelvis fremstilles idet en forbindelse med formel The starting substances of formula IX in which X^means a group of formula -C(=S)-COORq can for example be prepared as a compound of formula
kondenseres på vanlig måte med Rhodanin og kondensasjonspro-duktet hydrolyseres med fortynnede Alkalier, <f>or eksempel med 10$> i natronlut. Av en således dannede forbindelse med formel IX hvori X^betyr -C(=S)-COOH, kan deretter fåes ved vanlig omsetning med Hydroxylamin respektiv en forbindelse med formel H^N-Ar de foretrukkede utgangsstoffer, hvori X betyr en gruppe med formel -C(=NOH)-COOH respektiv -C(=NAr)-C00"H^N+ -Ar. Forbindelsen^ med formel X er på sin side tilgjenge-lig ved omsetning av forbindelser med formlene is condensed in the usual way with Rhodanin and the condensation product is hydrolysed with diluted alkalis, <for example with 10$> in caustic soda. From a thus formed compound of formula IX in which X^means -C(=S)-COOH, the preferred starting substances can then be obtained by ordinary reaction with Hydroxylamine or a compound of formula H^N-Ar, in which X means a group of formula -C(=NOH)-COOH respectively -C(=NAr)-C00"H^N+ -Ar. The compound ^ with formula X is in turn available by reacting compounds with the formulas
Behandling av kondensasjonsproduktri første rekke med Kaliumcyanid og deretter med Ammoniumsulfid og ringslut-ning med svovelsyre. Treatment of condensation products first with potassium cyanide and then with ammonium sulphide and ring closure with sulfuric acid.
Forbindelser oppnåelig ifølge oppfinnelsen kan Compounds obtainable according to the invention can
i in
1 omdannes i hverandre. 1 are converted into each other.
i Således kan man i en forbindelse med formel I hvori ' Y betyr Hydroxy, fore , denne på vanlig måte for eksempel Thus, in a compound of formula I in which 'Y means Hydroxy, this can be done in the usual way, for example
methylere med Dimethylsulfat, eller acylere ved vanlig omsetning med et acylerende middel som et syreanhydrid eller syrehalogenid, for eksempel -chlorid, eller Keten til Acyloxy. Analog kan man omdanne forbindelsene med formel I hvori -OR betyr Hydroxy, for dette i og for seg kjendte foretringsfremgangsmåter i en foretret Hydroxygruppe fortrinnsvis til en eventuelt substituert Laverealkoxygruppe. methylate with Dimethylsulphate, or acylate by ordinary reaction with an acylating agent such as an acid anhydride or acid halide, for example -chloride, or Keten to Acyloxy. Analogously, one can convert the compounds of formula I in which -OR means Hydroxy, for this per se known etherification procedures in an etherified Hydroxy group preferably into an optionally substituted Lower Alkoxy group.
Videre kan man forestre Carboxy for eksempel raed behandling med et Dåazolaverealkan eller en alkohol som en eventuelt substituert laverealkanol i nærvær av en syre som en mineralsyre for eksempel klorhydrogensyre eller svovelsyre eller et egnet kondensasjonsmiddel som et dehydratiser-ende middel, for eksempel Dicyclohexylcarbodimid,eller for dannelsen av et Hydroxylaver ealkyl es t er, med e\ t Epoxylaverealkan, for eksempel Aethylenoxid, i en Carboxygruppe med i orme 1 -C(=0)-ORQ(Ib). Vid ere kan man omsette en forbindelse med formel I hvori en fri Karboxylgruppe med formel Ib foreligger i saltform, for eksempel i Alkalimetall - som Natrium-saltformeiji 1 med en reaksjonsdyktig ester av en alkohol Carboxy can also be esterified, for example, by treatment with a Dazola lower alkane or an alcohol such as an optionally substituted lower alkanol in the presence of an acid such as a mineral acid, for example hydrochloric acid or sulfuric acid, or a suitable condensation agent such as a dehydrating agent, for example Dicyclohexylcarbodiimide, or for the formation of a Hydroxyllower ealkyl es t is, with e\ t Epoxylower alkane, for example Aethylene oxide, in a Carboxy group with i orme 1 -C(=0)-ORQ(Ib). Furthermore, one can react a compound of formula I in which a free carboxyl group of formula Ib is present in salt form, for example in alkali metal - such as sodium salt form 1 with a reactive ester of an alcohol
som eventuelt substituert Laverealkanol, for eksempel med en sterk syre som en tilsvarende Laverealkylhalogenid, for eksempel - chlorid,- bromid eller - jodid, eller ' Dilaverealkylsulfat, eller en forbindelse med formel I hvori en fri Carboxylgruppe av formel Ib foreligger en Anhydridform, fortrinnsvis som Haihogencarbonyl-, for eksempel Chlorcarbonyl-gruppe som man for eksempel kan få ved behandling av en forbindelse med formel I hvori -ORq betyr Hydroxy, med et Halo-generingsmiddel for eksempel Thd/onylklorid, med en evntuelt substituert metallaverealkanolat, som tilsvarende Alkalimetall-, for eksempel Natrium- eller Kaliumalkoholat, eller med en alkohol, som en eventuelt substituert Laverealkanol, hvis nødvendig i nærvær av en base, og således komme til forbindelse med formel I hvori -ORq betyr en som angiitifc foretret Hydroxygruppe. Derved kan et fdrestringsreagen substituenten foreligge i funksjonelt modifisert /form, og deretter frigjøres i en forbindelse med formel I hvori -ORq betyr substituert Laverealkoxy,,hvori substituenten foreligger i funksjonelt modifisert form. Således kan man som forestringsreagen for eksempel anvende 2,3-Epoxy-propylchlorid og i den as optionally substituted Lower alkanol, for example with a strong acid such as a corresponding Lower alkyl halide, for example - chloride, - bromide or - iodide, or ' Dilavere alkyl sulfate, or a compound of formula I in which a free carboxyl group of formula Ib is an anhydride form, preferably as Halogencarbonyl, for example Chlorcarbonyl group which can for example be obtained by treating a compound of formula I in which -ORq means Hydroxy, with a Halo generating agent for example Thd/onyl chloride, with an optionally substituted metal avereal alkanolate, which corresponds to Alkali metal-, for example Sodium or Potassium alcoholate, or with an alcohol, such as an optionally substituted Lower alkanol, if necessary in the presence of a base, and thus arrive at a compound of formula I in which -ORq means an angiitifc ethereal Hydroxy group. Thereby, a hydrogenation reagent can have the substituent present in a functionally modified form, and then be released in a compound of formula I in which -ORq means substituted Lower Alkoxy, in which the substituent is present in a functionally modified form. Thus, as the esterification reagent, for example, 2,3-Epoxy-propyl chloride can be used and in it
dannede ester hydrolysere 2,3- Epoxy-propylgrupperingen ef - terpå til den ønskede 2,3-Dihydroxy-propylgruppering. formed ester subsequently hydrolyze the 2,3-Epoxy-propyl grouping to the desired 2,3-Dihydroxy-propyl grouping.
I en forbindelse med formel I hvori -ORq betyr en foretret Hydroxygruppe, kan denne ved omforestring for eksempel ved behandling med en alkohol som en eventuell substituert Laverealkanol i nærvær av en egnet omforestringskataly-sator, som en eventuelt substituert alkalimetall-, for eksempel Natrium- eller Kalium-laverealkanolatforbindelse, omdannes i en annen foretret Hydroxygruppe. In a compound of formula I in which -ORq denotes an etherified hydroxy group, this can be transesterified, for example by treatment with an alcohol such as a possibly substituted lower alkanol in the presence of a suitable transesterification catalyst, such as an optionally substituted alkali metal, for example sodium or Potassium lavereal akanolate compound, is converted into another etherified Hydroxy group.
I en forbindelse med formel I kan man overføre en forestret Carboxylgruppe med formel -C(=0)-ORq (lb), hvori Rq betyr 'foretret Hydroxygruppe på vanlig måte til en fri Karboxyl,gruppe med formel Ib, hvori RQbetyr Hydrogen, for eksempel ved Hydrolyse vanligvis i alkalisk medium, for eksempel ved behandling med vann i nærvær av et Alkalimetall- eller Jordalkalimetallhydroxid, for eksempel Natriumhydroxdld. Analog kan man også hydrolys/ere Acyloxy Y $il Hydroxy. In a compound of formula I, one can transfer an esterified carboxyl group of formula -C(=0)-ORq (lb), in which Rq means 'esterified hydroxy group in the usual way to a free carboxyl group of formula Ib, in which RQ means hydrogen, for for example by hydrolysis usually in an alkaline medium, for example by treatment with water in the presence of an alkali metal or alkaline earth metal hydroxide, for example sodium hydroxide. Analogously, Acyloxy Y $il Hydroxy can also be hydrolyzed.
Videre kan i en forbindelse med formel I en phen-olisk Hydroxygruppe R^og/eller R^på i og for seg kjendJt i måte overføres i en Laverealkoxygruppe for eksempel ved behandling av Phenol-forbindelsen eller tilsvarende Phenolat som Alkalimetall-, for eksempel Natrium- eller Kaliumpheno-lat, med en reaksjonsdyktig<r>esl; fra en Laverealkanol, som en Laverealkylhalogenid eller Dilaverealkylsulfat, idet man åi anvendelse av den fri Phenolforbindelse arbeider i nærvær av et basisk middel som et Alkalimetall- lor eksempel Natrium- eller Kaliumkarbonat. Furthermore, in a compound of formula I, a phenolic Hydroxy group R^ and/or R^ can be transferred in a manner known per se to a Lower Alkoxy group, for example by treating the Phenol compound or the corresponding Phenolate as an Alkali metal, for example Sodium - or Potassium phenolate, with a reactive<r>esl; from a Lower alkanol, such as a Lower alkyl halide or Dilave alkyl sulfate, when using the free Phenol compound, one works in the presence of a basic agent such as an Alkali metal, for example Sodium or Potassium carbonate.
Dannede fri forbindelser kan på i og.for seg kjent måte overføres i salt, i syreaddisjonssalter bl. a. ved omsetning for eksempel av en oppløsning av den fri forbindelse i et egnet oppløsningsmiddel eller oppløsningsmiddelbland-ing med en syre, som en av de overnevnte syrer eller med en oppløsning herav, eller med en egnet Anioneutveksler, og i salter med baser bl. a. ved behandling med en base eller med et egnet salt.av en Carboxsylsyre vanligvis i nærvær av et opp-løsnings tr ekk eller fortynningsmiddel. Formed free compounds can be transferred in a manner known per se in salt, in acid addition salts, among others. a. by reacting, for example, a solution of the free compound in a suitable solvent or solvent mixture with an acid, such as one of the above-mentioned acids or with a solution thereof, or with a suitable anion exchanger, and in salts with bases i.a. a. by treatment with a base or with a suitable salt of a carboxylic acid usually in the presence of a solvent or diluent.
Dannede salter kan på i og for seg kjent måte omdannes i de fri forbindelser, syreaddisjonssalter for eksempel ved behandling med en base,for eksempel et. Alkalimetallhydroxid, et Metallcarbonat eller - hydrogen-carbonat eller Ammoniak,, samt med en egnet Anioneutveksler, Formed salts can be converted in a manner known per se into the free compounds, acid addition salts, for example by treatment with a base, for example a Alkali metal hydroxide, a metal carbonate or hydrogen carbonate or ammonia, and with a suitable anion exchanger,
og salter med baser for eksempel ved behandling med et surt reagens, som en mineralsyre. and salts with bases, for example by treatment with an acidic reagent, such as a mineral acid.
Dannede salter kan på i og for seg kgent måte over-føres i andre salter, syreaddisjonssålter, for eksempel ved behandling med en Anioneutveksler 'eller ved behandling av et salt av en uorganisk syre med et egnet metallsalt som et Natrium-, Barium- eller sølvsalt av ei syre i et egnet oppløs-ningsmiddel hvori et dannét uorganisk salt er uoppløselig og dermed utskiller seg fra reaksjonsblandingen. Formed salts can in and of themselves be transferred into other salts, acid addition salts, for example by treatment with an anion exchanger or by treatment of a salt of an inorganic acid with a suitable metal salt such as a sodium, barium or silver salt of an acid in a suitable solvent in which a formed inorganic salt is insoluble and thus separates from the reaction mixture.
Forbindelsen innbefattende deres salter,kan også fåes i form av deres hydrater eller inneslutter det til Kri-stallåsasjon anvendt oppløsningsmiddel."' The compound, including its salts, can also be obtained in the form of its hydrates or contains the solvent used for crystallization."'
på grunn av det snevre forhold mellom de nye for- due to the close relationship between the new for-
i in
bindelser i fri form og i form av deres salter er i det fore-gående og følgende med fri forbindelse eller deres salter og-så eventuelt og forstå de tilsvarende salter respektiv fri forbindelser. bonds in free form and in the form of their salts are in the preceding and following with free compounds or their salts and also possibly and understand the corresponding salts respectively free compounds.
Oppfinnelsen vedrører også de utførelsesformer av fremgangsmåten hvor man går ut fra på et eller annet fremgangsmåtetrinn som mellomprodukt dannet forbindelse og gjen-nomføré de manglende fremgangsmåtetrinn, eller i det et ut-gangsstof f dannes under reaksjonsbetingelsene, eller anvendes i form av et derivat,herav eventuelt av et salt. The invention also relates to the embodiments of the method where one starts from one or another process step as an intermediate formed compound and carries out the missing process steps, or in which a starting substance f is formed under the reaction conditions, or is used in the form of a derivative thereof possibly of a salt.
Ved fremgangsmåten ifølge /oppfinnelsen anvendes fortrinnsvis slike utgangsstoffer som fører til i innledningsvis som spesielt verdifulle omtalte forbindelser. In the method according to the invention, such starting materials are preferably used which lead to the initially particularly valuable compounds mentioned.
Oppfinnelsen vedrører likeledes farmasøytiske preparater som inneholder forbindelse med formel I eller farma-søytisk, anvendbare salter herav. Ved de farmasøytiske preparater dreier det seg om slike til enteral, som oral eller rektal,samt parenteral administrering til varmblodsdyr, som inneholder den jBarmakologiske virksomme stoff alene eller sammen med farmasøytisk anvendbart bærematerial. Doseringen av det virksomme stoff avhenger av varmblodstypen, aldri når den individuelle tilstand samt applikasjonsmåten. The invention likewise relates to pharmaceutical preparations containing compounds of formula I or pharmaceutically usable salts thereof. The pharmaceutical preparations are those for enteral, such as oral or rectal, as well as parenteral administration to warm-blooded animals, which contain the pharmacologically active substance alone or together with a pharmaceutically usable carrier material. The dosage of the active substance depends on the type of warm blood, never on the individual condition and the method of application.
De nye farmasøytiske preparater inneholder for eksempel fra ca. 10$ til ca. 95$, fortrinnsvis fra ca. 20 fo The new pharmaceutical preparations contain, for example, from approx. 10$ to approx. 95$, preferably from approx. 20 fo
til ca. 90$ av det virksomme stoff. Farmasøytiske preparat- to approx. 90$ of the active substance. Pharmaceutical preparations-
er er for eksempel slike i for inhalasjon eller insufflasjon egnet for som Aerosol - eller sprayform, eller i dos-is enhetsf ormer som dragéer, tabletter, kapsler, suppositorer, videre ampuller. are, for example, suitable for inhalation or insufflation as aerosol or spray form, or in dosage unit forms such as dragees, tablets, capsules, suppositories, further ampoules.
De farmasøytiske preparater ifølge oppfinnelsen fremstilles på i og for seg kjent måte, for eksempel ved på vanlig blande- granulering- dragering-oppløsning- eller lyo-filiseringfremgangsmåter. Således kan man få farmasøytiske preparater til oral anvendelse idet man kombinerer det virksomme stoff med faste bærestoffer, eventuelt granulerer en dannet blanding, og forarbeider blandingen respektiv granu-latet hvis ønsket eller nødvendig etter tilsetning av egnede hjelpestoffer til tabletter eller dragéfcjerner. The pharmaceutical preparations according to the invention are prepared in a manner known per se, for example by conventional mixing-granulation-coating-dissolution or lyophilization methods. Thus, pharmaceutical preparations for oral use can be obtained by combining the active substance with solid carriers, optionally granulating a formed mixture, and processing the mixture or granulate if desired or necessary after adding suitable excipients for tablets or dragé cores.
Egnede bærestoffer er spesielt fyllstoffer som sukker for eksempel Lactose, Saccharose, Mannit eller Sorbit, Cellulosepreparater og/eller Calciumfosfater, for eksempel Tricalciumfosfat eller Calciumhydrogensulfat, videre bindemidler som stivelsesklister for eksempel mais- hvete- ris-eller potetstivelsesklister, gelatiner, tragakanth, methyli-cellulose og/eller polyvinylpyrrolidon og/eller hvis ønsket," sprengmidler som overnevnte stivelser, videre Carboxymethyl-stivelse, tverrnettdannet Polyvinylpyrrolidon, Agar, Algin-syre eller et salt herav, som Natriumalginat. Hjelpemidler er i første rekke vennings- regulerings- og smøremidler, for eksempel kiselsyre, talkum, stearinsyre eller salter herav, som magnesium- eller calsiumstearat og/eller Polyethylenglykol. Dragékjerner utstyres med egnede eventuelt mavesaftresistente overbrekk idet man blant annet anvender konsen-trerte sukk eropplø sning er som eventuelt inneholder arabisk gummi, talkum, polyvinylporrolidon, polyethylenglykol og/eller Titandioxid,. lakkoppløsningér i egnede organiske oppløsnings» midler eller oppløsningsmiddelblandinger eller for fremstilling av mavesaftresistente overtrekk, oppløsninger av egnede cellulosepreparater som Acetylcellulosephtalat eller Hydroxy-propylmethylc ellulos ephthalat. Til tabletten eller dragéoAter-trekkene kan det settes fargestoffer eller pigmenter, for eksempel til identifisering eller til karakterisering av forskjellig virksomme stoffdoser. Suitable carriers are especially fillers such as sugar, for example Lactose, Sucrose, Mannitol or Sorbitol, Cellulose preparations and/or Calcium phosphates, for example Tricalcium phosphate or Calcium hydrogensulphate, further binders such as starch pastes for example corn, wheat, rice or potato starch pastes, gelatins, tragacanth, methyl- cellulose and/or polyvinylpyrrolidone and/or if desired," blasting agents such as the above-mentioned starches, further Carboxymethyl starch, cross-linked Polyvinylpyrrolidone, Agar, Alginic acid or a salt thereof, such as Sodium Alginate. Aids are primarily weaning, regulating and lubricating agents, for example, silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate and/or polyethylene glycol. Dragon cores are equipped with suitable, possibly stomach-juice-resistant covers, using, among other things, concentrated sugar solutions that may contain gum arabic, talc, polyvinyl porrolidone, polyethylene glycol and/or is Titanium Dioxide,. varnish solutions in suitable organic solvents or solvent mixtures or for the production of gastric juice-resistant coatings, solutions of suitable cellulose preparations such as Acetylcellulose phthalate or Hydroxy-propylmethylcellulose phthalate. Dyes or pigments can be added to the tablet or dragéoAter features, for example for identification or for characterizing different effective drug doses.
Ydderligere oralt anvendbare farmasøytiske preparater er stikkapsler av gelatin, samt myke, lukkede kapsler av gelatin av et mykningsmiddel som glyeerol eller sorbitol. Stikkaplslene kan inneholde det virksomme stoff i form av et Granulat, for eksempel i blanding med fyllstoffer som lakto-se bindemidler som stivelser og/eller glidemidler som talkum eller magnesiumtearat, og eventuelt av stabilisatorer. Further orally usable pharmaceutical preparations are capsules made of gelatin, as well as soft, closed capsules made of gelatin of a plasticizer such as glycerol or sorbitol. The suppositories may contain the active substance in the form of a granulate, for example in a mixture with fillers such as lactose, binders such as starches and/or lubricants such as talc or magnesium tearate, and possibly stabilizers.
I myke kapsler er det virksomme stoff fortrinnsvis oppløst eller substandert i egnede væsker, som fete oljer, para-finolje eller flytende polyethylenglykoler idet eventuelt kan være tilsatt stabilisatorer. In soft capsules, the active substance is preferably dissolved or dissolved in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, where stabilizers may be added.
Som rektalt anvendbare farmasøytiske preparater kommer det for eksempel i betraktning Suppositorier som består av en kombinasjon av det virksomme stoff med en Suppositoriegrunnmasse. Som Suppositoriegrunnmasse egner det seg for eksempel naturlig eller syntetiske Triglycerider, Barafinhydrokarboner, Polyethylenglykoler eller høyere Alk-anoler. Videre kan det, også anvendes gelatin-rektalkapsler som inneholder en kombinasjon av det virksomme stoff med en grunnmasse) som grunnmassestoff kan det for eksempel komme på tale flytende Triglycerider, Polyethylenglykoler eller Parafinhydrokarboner. As rectally applicable pharmaceutical preparations, for example, suppositories which consist of a combination of the active substance with a suppository base material come into consideration. Natural or synthetic Triglycerides, Parafin hydrocarbons, Polyethylene glycols or higher alkanols are suitable as Suppository base material, for example. Furthermore, gelatin rectal capsules can also be used which contain a combination of the active substance with a base material) as a base material, for example, liquid Triglycerides, Polyethylene Glycols or Paraffin Hydrocarbons can be used.
Til parenteral administrering egner det seg i før-ste rekke vannlige oppløsninger et virksomt stoff i vannopp-løselig form, for eksempel et vannoppløselig salt, videre suspensjoner av det virksomme stoff som tilsvarende oljeaktige injeksjonssusp ensjoner idet man anvender egnede lipofil-oppløsningsmidler eller bærere, som fete oljer, for eksempel Sesamolje, eller syntetiske fettsyreester for eksempel Aet-hyloleat eller Triglycerider, eller vannlige injeksjonssus-pensjoner som inneholder viskositetsøkende stoffer, for eksempel Natrium-carboxymethylcellulose, Sorbit og/eller Dextran og eventuelt også stabilisatorer. For parenteral administration, aqueous solutions of an active substance in water-soluble form, for example a water-soluble salt, and suspensions of the active substance, such as corresponding oily injection suspensions, using suitable lipophilic solvents or carriers, are suitable for parenteral administration. fatty oils, for example Sesame oil, or synthetic fatty acid esters, for example Aethyloleate or Triglycerides, or aqueous injection suspensions containing viscosity-increasing substances, for example Sodium carboxymethylcellulose, Sorbit and/or Dextran and optionally also stabilizers.
Inhalasjon- respektiv insufflasjonspreparater for behandling av luftveien ved nasal eller buccal administrering av for eksempel insufflasjonskapsler, som muliggjør å insuf-flere de virksomme stoff i form av et pudder med åndedrettet eller aerosoler eller spray, som kan fordele det farmakolog-iske virksomme stoff i form av et pudder eller i form av i dråper av en oppløsning eller suspensjon. Preparater med pudderfordelene egenskaper inneholder foruten det virksomme stoff, vanligvis hj ejbpemidler, ilnsuf las jonskapsler for eksempel faste bærestoffer som Lactose og Aerosol- respektiv spraytilberedninger, for eksempel en flytende drivgass med et kokepunkt under værelsestemperatur, samt, hvis ønsket ydderligere bærestoffer som flytende eller faste ikke-ioniske eller anioniske overflateaktive midler og/eller faste fortynningsmidler. Preparater hvori det farmakologisk virksomme stoff foreligger i oppløsning, inneholder foruten dette, et egnet drivmiddel, videre, hvis nødvendig et ekstra oppløsningsmiddel og/eller en stabilisator. Foruten driv-gassen kan det også anvendes trykkluft, idet denne kan frembringes ved hjelp av en egnet komprimeringstrekk og avspen-ningsinnretning etter behov. Inhalation or insufflation preparations for treatment of the respiratory tract by nasal or buccal administration of, for example, insufflation capsules, which make it possible to insufflate the active substance in the form of a powder with the breath or aerosols or sprays, which can distribute the pharmacologically active substance in the form of a powder or in the form of in drops of a solution or suspension. Preparations with powder properties contain, in addition to the active substance, usually adjuvants, insufflation capsules, for example solid carriers such as Lactose and Aerosol, respectively spray preparations, for example a liquid propellant with a boiling point below room temperature, as well as, if desired, additional carriers such as liquid or solid non-ionic or anionic surfactants and/or solid diluents. Preparations in which the pharmacologically active substance is present in solution contain, in addition to this, a suitable propellant, further, if necessary, an additional solvent and/or a stabilizer. In addition to the propellant gas, compressed air can also be used, as this can be produced by means of a suitable compression draft and relaxation device as required.
Farmasøytiske preparater for topisk og lokal anvendelse er for eksempel for behandlingen av hud lotioner pg kremer, som inneholder en flytende eller halvfast olje i vann- eller vann i oljeemulsjon, og salver (idet slike fortrinnsvis inneholder et konserveringsmiddel),for behandling av øynene øyendråper, som inneholder den aktive forbindelse Pharmaceutical preparations for topical and local use are, for example, for the treatment of skin lotions and creams, which contain a liquid or semi-solid oil in water or water in oil emulsion, and ointments (as such preferably contain a preservative), for the treatment of the eyes, eye drops, which contains the active compound
i vanndeiigy ol j eoppløsning og øyensalver som< fortrinnsvis fremstilles i steril form, for behandling av nesen pudder, in water deiigy or j esolution and eye ointments which< are preferably produced in sterile form, for treatment of the nose powder,
aerosoler og sprays (tilsvarende de overnevnte for behandling av luftveiene), samt grove pudderep som administreres ved hurtiginhalering gjennom neseborene, og nesedråper som inneholder den aktive forbindelse i stanndelig olj eoppløsning, eller for lokal behandling av munnen sugetabletter som inneholder den aktive forbindelse i en vanligvis av sukker og gummiarabikum eller Tragant dannet masse som kan være tilsatt smaksstoffer, som pastiller som inneholder det aktive stoff i en enert masse, for eksempel av gelatin og glyserol eller sukker og gummiarabicum. aerosols and sprays (similar to those mentioned above for the treatment of the respiratory tract), as well as coarse powders that are administered by rapid inhalation through the nostrils, and nasal drops containing the active compound in a permanent oil solution, or for local treatment of the mouth lozenges containing the active compound in a usually of sugar and gum arabic or tragacanth formed mass which may have added flavourings, such as lozenges containing the active substance in a single mass, for example of gelatin and glycerol or sugar and gum arabic.
Oppfinnelsen vedrører likeledes anvendelsen av de nye forbindelser med formel I og salter herav som farmakologisk aktive forbindelser spesielt som antiallergika, fortrinnsvis i form av farmasøytiske preparater. Den daglige dose, som et varmblodsdyr av ca. 70 kg. administreres ut-gjøres fra ca. 200 mg. til ca. 1200 mg. The invention likewise relates to the use of the new compounds of formula I and salts thereof as pharmacologically active compounds, especially as antiallergic drugs, preferably in the form of pharmaceutical preparations. The daily dose, as a warm-blooded animal of approx. 70 kg. administered from approx. 200 mg. to approx. 1200 mg.
Oppfinnelsen skal forklares nærmere ved hjelp av noen eksempler. The invention will be explained in more detail with the help of some examples.
Eksempel 1 Example 1
a) 10,6 g 2-Carboxychlormethylen-1,5,6-trimethyl-indoxyl oppløses i 150 ml Aethanol. Ved 50°C tildrypper man a) Dissolve 10.6 g of 2-Carboxychloromethylene-1,5,6-trimethyl-indoxyl in 150 ml of ethanol. At 50°C, add in drops
deretter 6,8g Piperidin i 30 ml. Aethanol og hplder oppløs?, ningen en time ved 50<G>C. Man fortynnerisvann til 600 ml. tilsetter 45. ml. konsentrert saltsyre, frafiltrerer råproduktet og renser det på den under punkt c omtalte måte. Etter pm-krystallisering fra methanol smelter • 3-Hydroxy-1,5»6-trimethyl-indolyl-2-gly©:xylsyre ved 195-197°C. then 6.8g piperidine in 30 ml. Ethanol and hplder dissolve?, the ning one hour at 50<G>C. Ice water is diluted to 600 ml. adds 45. ml. concentrated hydrochloric acid, filters off the crude product and cleans it in the manner mentioned under point c. After pm-crystallization from methanol • 3-Hydroxy-1,5»6-trimethyl-indolyl-2-gly©:xylic acid melts at 195-197°C.
Samme produkt lar seg også oppnå ifølge nedenståen-de fremgangsmåtevariant b eller c. b) 7,8 g 2-Carboxychlormethylen-1,5,6-trimethylind-oxyl i 50 ml. is eddik blandes langsomt med 5,4 g Guanidin-carbonat. Man omrører deretter oppløsningen i 24 timer ved 60°C, fortynner med isvann og renser det utskilte råprodukt på den under punkt c omtalte måte. c) En blanding av 5,0 g 2-Carboxychlormethylen 1,5, 6-trimethyl-indoxyl i 26 ml..Dimethylsulf oxid og 4 ml. vann omrøres en time ved 70°C, blandes med 100 ml vann og omrør-es 30 min. ved 65°C. Man avkjøler og frafiltrerer de utskilte krystaller. Man vasker krystallene med 50 ml. koldt vann og oppløser dem i en blanding av 300 ml. vann og 20 ml. 30$ i Natronlut. Oppløsningen filtreres gjennom et schicht "Hyflo". Man gjør filtratet kongosurt med konsentrert saltsyre frafiltrerer de utskilte krystaller vasker det med 100 ml. vann og oppløser dem i 30 ml. 2-n. Natronlut. Den vanlige alkali-ske oppløsning filtereres gjennom et schicht "Hyflo". The same product can also be obtained according to method variant b or c below. b) 7.8 g of 2-Carboxychloromethylene-1,5,6-trimethylindoxyl in 50 ml. glacial acetic acid is mixed slowly with 5.4 g Guanidine carbonate. The solution is then stirred for 24 hours at 60°C, diluted with ice water and the separated crude product is purified in the manner mentioned under point c. c) A mixture of 5.0 g of 2-Carboxychloromethylene 1,5, 6-trimethyl-indoxyl in 26 ml..Dimethylsulf oxide and 4 ml. water is stirred for one hour at 70°C, mixed with 100 ml of water and stirred for 30 min. at 65°C. The separated crystals are cooled and filtered off. The crystals are washed with 50 ml. cold water and dissolve them in a mixture of 300 ml. water and 20 ml. 30$ in soda ash. The solution is filtered through a schicht "Hyflo". The filtrate is made Congolese with concentrated hydrochloric acid, the separated crystals are filtered off and washed with 100 ml. water and dissolve them in 30 ml. 2-n. Baking soda. The usual alkaline solution is filtered through a layer of "Hyflo".
Man gjør filtratet surt med 2-normal saltsyre og frafiltrerer de mørkere krystaller av smeltepunkt 194-196 °C. Etter om-krystalliseringenfra Methanol smelter3-Hydroxy-1,5,6-trimethyl-indolyl-2-glycolsyre ved 195-497°C. The filtrate is acidified with 2-normal hydrochloric acid and the darker crystals of melting point 194-196 °C are filtered off. After the recrystallization from Methanol, 3-Hydroxy-1,5,6-trimethyl-indolyl-2-glycolic acid melts at 195-497°C.
Utgangsmateriale kan fremstilles som følger; Starting material can be prepared as follows;
I en med en HCl-Avledning utstyrt rørkolbe has 60 ml. 1,2-Dichlorethan og 40 g pulverisert vannfri AlCl^(0,3 Mol) og avkjøles med et externt is/Methanol-bad til 0°C. Deretter tildryppes iwed00-3°C i løpet av 20 minutter 13,5 S (0,1 Mol) N-Methyl-3,4-dimethyl-anilin, (nydestill ert) og den dannede suspensjon omrøres ved denne temperatur i 30 min. Nu tilsetter man i småporsjoner 16,7 S (0,1 Mol) Dichlormaleinsyreanhydrid (95$ ig) og omrøre reaksjonsblandingen i 20 timer ved 20-25°C. Deretter heller man den bdanriede mørke-grønne oppløsningenpå ca. 500 g is, omrører i 30 min. og fra-dekanterer den vanlige fase. Til det oljeaktige Residus setter man 10 ml. eddiksyreethylester hvorpå det danner seg viiolette krystaller. Etter f raf il triering og tørkning får man 2«Car.boxychlormethylen-1 , 5 , 6-trimethyl-indoxyl i form av vio-lette krystaller av smeltepunkt over 220°C, som kan videreomsettes uten ydderligere rensning. In a flask equipped with an HCl diverter, have 60 ml. 1,2-Dichloroethane and 40 g of powdered anhydrous AlCl^ (0.3 Mol) and cooled with an external ice/Methanol bath to 0°C. 13.5 S (0.1 Mol) N-Methyl-3,4-dimethyl-aniline (freshly distilled) is then added dropwise at 00-3°C over the course of 20 minutes and the resulting suspension is stirred at this temperature for 30 minutes. Now add in small portions 16.7 S (0.1 Mol) Dichloromaleic anhydride (95 µg) and stir the reaction mixture for 20 hours at 20-25°C. The bdanried dark-green solution is then poured into approx. 500 g ice, stir for 30 min. and decants the common phase. Add 10 ml to the oily residue. acetic acid ethyl ester, on which violet crystals form. After filtration and drying, 2"Carboxychloromethylene-1,5,6-trimethyl-indoxyl is obtained in the form of violet crystals with a melting point above 220°C, which can be converted further without further purification.
Eksempel 2 Example 2
20,0 g 2-Carboxychlormethylen-5,6-dimethyl-indoxyl omsettes i 280 ml Aethanol med 13,6 g Piperidin i løpet, av 3 timer ved 50°C under omrøring og fortynnes deretter med is og vann til 750 ml.Etter tilsetning av 50 ml. konsentrert saltsyre frafUtreres produktet oppløses i 800 ml. vann under tilsetning av 50 ml. 30$ Natronlut og oppløsningen klares ved filtrering. Filtratet gjøres kongosurt med saltsyre, med utskilte 5,6 Dimethyl-3-hydroxyrindolyl-2-glyoxylsyre frafiltreres og vaskes med vann og tørkes. Det viser etter omkrystallisering fra iseddik et smeltepunkt på 238°C under spaltning. 20.0 g of 2-Carboxychloromethylene-5,6-dimethyl-indoxyl is reacted in 280 ml of ethanol with 13.6 g of piperidine during 3 hours at 50°C with stirring and then diluted with ice and water to 750 ml. After addition of 50 ml. concentrated hydrochloric acid is filtered off, the product is dissolved in 800 ml. water while adding 50 ml. 30$ Sodium lye and the solution is clarified by filtration. The filtrate is made Congolese with hydrochloric acid, with secreted 5,6 Dimethyl-3-hydroxyrindolyl-2-glyoxylic acid is filtered off and washed with water and dried. After recrystallization from glacial acetic acid, it shows a melting point of 238°C during cleavage.
Det samme produkt lar seg også fremstille på føl-gende måte: 5,0 g 2-Carboxychlormethylen-5,6-dimethyl-indoxyl i 42 ml. Dimethylsulfoxid og 8 ml. vann holdes under omrøring i 16 timer ved 75°C,blandes deretter med 150 ml. vann og filtreres. Produktet oppløses i 300 ml. vann under tilsetning av 20 ml. 30$ ig natronlut, klares ved filtrering og filtrat gjøres kongosurt ved tilsetning av saltsyre. Det utskilte råprodukt renses som omtalt under punkt a. The same product can also be prepared in the following way: 5.0 g of 2-Carboxychloromethylene-5,6-dimethyl-indoxyl in 42 ml. Dimethyl sulfoxide and 8 ml. water is kept under stirring for 16 hours at 75°C, then mixed with 150 ml. water and filtered. The product is dissolved in 300 ml. water while adding 20 ml. 30% caustic soda, clarified by filtration and the filtrate made congo acid by adding hydrochloric acid. The secreted crude product is purified as described under point a.
Utgangsmateriale kan fremstilles som følger: Starting material can be produced as follows:
I en med en HCl-avledning utstyrt rørkolbe ass. 200 ml. 1,2-Dichlorethan og 350 g pulverisert vannfri AlCl^In a flask equipped with an HCl diverter ass. 200 ml. 1,2-Dichloroethane and 350 g of powdered anhydrous AlCl^
(2,625 Mol) og avkjøles med et yddere isbad til 0°C. Deretter tilsetter man 0-10°C i løpet av ca. 30 min. under omrøring 100 g.(0,6l Mol) 3,4-Dimethylacetanilid i 200 ml. (2.625 Mol) and cooled with a further ice bath to 0°C. Then add 0-10°C over approx. 30 min. while stirring 100 g. (0.6 l Mol) 3,4-Dimethylacetanilide in 200 ml.
Aethylenclalorid og deretter i løpet av 10 min. 102 g (0,61 Mol) fast Dichlormaleinsyreanhydrid (95$)• Etter 30 min. ut-røring ved 20-25°C omrøres reaksjonsblandingen ennu i 22 timer ved 40°C. Reaksjonsblandingen innføres deretter i en blanding av vann og is (Sluttvolum ca. 3-4 liter). Deretter av-dekanderes vannet, og det brungule,seige residus utrøres med 1000 ml. eddiksyreethylester og frasuges. Sugegodset tørkes ved 50 o C i vakuumtørkeskap. Man får 165,5 g av et gult prod<*>ukt. Dette blandes med 600 ml. 10$ig vandig NaOH og avkjøles med is således at reaksjonstemperaturen ikke går over 32°C. Etter 5 1/2 times omrøring ved 20-25°C oppvarmes reaksjonsblandingen i løpet av en time til 40°C. Etter gjentatt avkjøling til 20-25°C frasuges den dannede rød suspensjon. De derved dannede rød|krystaller tørkes etter god vaskning med vann forsiktig ved 40°C i vakuum. Moderluten innstilles med konsentrert HC1 til ph 1, og den dannede rød utfelling frasuges. Etter grundig vasking med vann tørkes sugegodset og forenes med hovedmengden. Man får 2-Carboxychlormethylen-5,6-Dime-thyl-indoxyl, som kan videreomsettes direkte. Ethylene chloride and then within 10 min. 102 g (0.61 Mol) solid Dichloromaleic anhydride ($95)• After 30 min. stirring at 20-25°C, the reaction mixture is stirred for a further 22 hours at 40°C. The reaction mixture is then introduced into a mixture of water and ice (Final volume approx. 3-4 litres). The water is then decanted, and the brown-yellow, tough residue is stirred with 1000 ml. acetic acid ethyl ester and suction. The suction material is dried at 50 o C in a vacuum drying cabinet. You get 165.5 g of a yellow product. This is mixed with 600 ml. 10 µg of aqueous NaOH and cooled with ice so that the reaction temperature does not exceed 32°C. After 5 1/2 hours of stirring at 20-25°C, the reaction mixture is heated to 40°C within one hour. After repeated cooling to 20-25°C, the formed red suspension is suctioned off. The resulting red crystals are dried after careful washing with water at 40°C in a vacuum. The mother liquor is adjusted with concentrated HC1 to pH 1, and the red precipitate formed is suctioned off. After thorough washing with water, the absorbent material is dried and combined with the main quantity. 2-Carboxychlormethylene-5,6-Dime-thyl-indoxyl is obtained, which can be converted directly.
Analog måte vil man når det gåes ut fra N,3-Dimethylacetanilid over 2-Carboxychlormethylen-1,6-dimethyl-indoxyl få 1 , 6-Dimethyl-3-'hydroxy-indolyl-2-glyoxylsyre og smeltepunkt over 150°C. Analogously, when starting from N,3-Dimethylacetanilide over 2-Carboxychloromethylene-1,6-dimethyl-indoxyl, 1,6-Dimethyl-3-'hydroxy-indolyl-2-glyoxylic acid and a melting point above 150°C will be obtained.
Eksempel 3 Example 3
En oppløsning av 7,0 g 5,6-Dimethyl-2-( -methoxycarbonyl- piperidino-methylen)-indoxyl i 80 ml. 10$-ig svovelsyre omrøres 30 minutter ved 60°C og avkjøles. De utskilte krystaller frafUtreres, og vaskes med 20 ml. vann og tørkes under 0,01 torr ved 40° C. Etter omkrystallisering fra Methanol smelte 5»6-Dimethyl-3-hydroxy-indolyl-2-glyox-sylsyremethylesteren, ved 188-192°C. A solution of 7.0 g of 5,6-Dimethyl-2-(-methoxycarbonyl-piperidino-methylene)-indoxyl in 80 ml. 10% sulfuric acid is stirred for 30 minutes at 60°C and cooled. The separated crystals are filtered off and washed with 20 ml. water and dried below 0.01 torr at 40° C. After recrystallization from Methanol, the 5»6-Dimethyl-3-hydroxy-indolyl-2-glyoxyl acid methyl ester melts at 188-192°C.
Utgangsmaterialet kan fremstilles som følger: The starting material can be prepared as follows:
251,5 g (1,0 Mol) 2-Carboxychlormethylen-5,6-dimethylindoxyl suspenderes i 300 ml. vann innstilles med konsentrert Natronlut og Pjj7 . Deretter tilsetter man i løpet av 60timer 378 g (3,0 Mol) Dimethylsulfat ved 20-25°C, idet PH-verdien kontrollert av en P^-stat holdes ved tildrypning 251.5 g (1.0 mol) of 2-Carboxychloromethylene-5,6-dimethylindoxyl are suspended in 300 ml. water is adjusted with concentrated caustic soda and Pjj7. Then, over 60 hours, 378 g (3.0 Mol) of dimethylsulphate are added at 20-25°C, with the PH value controlled by a P^-stat being maintained by dripping
av 10$ sodaoppløsning på 6,8-7,2. Etter 20 timers omrøring of 10$ soda solution of 6.8-7.2. After 20 hours of stirring
ved P„ 6,8-7,2. Etter 20 timers omrøring ved B„ 6,8-7,2 at P„ 6.8-7.2. After 20 hours of stirring at B„ 6.8-7.2
ti titen ten
frafiltreres suspensjonen og vaskes godt med vann og tørkes v ed 60 C/100 t orr. Derved fremkommer 5 > 6-Dimethyl-2,-methoxy-carbonchlormethylen-indoxyl i røde krystaller som smelter ved 208-210°C. Omkrystallisering fra iseddik hever smelte-punktet til 215-218°C. the suspension is filtered off and washed well with water and dried at 60 C/100 t orr. Thereby 5 > 6-Dimethyl-2,-methoxy-carbonchloromethylene-indoxyl appears in red crystals which melt at 208-210°C. Recrystallization from glacial acetic acid raises the melting point to 215-218°C.
Til en suspensjon av 98,0 g 5»6-Dimethyl-2-methoxy-carbonchlormethylen-indoxyl i 1500 ml. Aethanol dryp-pes under omrøring ved værelsestemperatur 79»7ml. Pipi-ridin. Man omrører 30 min. ved værelsestemperatur deretter 18 timer ved 60°C og inndamper til.under nedsatt trykk til tørrhet.'Residuet blander man med 200 ml. vann og 1000 ml. eddiksyreethylester, gjennomryster godt,adskiller den organiske fase og vasker den igjen med 100 ml. vann. Derpå tør-kes og ved Magnesiumsulfat inndampes under nedsatt trykk til tørrhet. Det krystallinske residus chromatograferer man på 2000 g Silicagel. De med hver gang 1000 ml. Eter eluerte fraksjoner 17-23 inneholder det rene 5»6-Dimethyl-2--methoxycarbonyl-cC-piperidino-methylen)-indoxyl. Disse fraksjoner renses og utdrives med 100 ml. eter. Det utkrystallis serte produkt smelter ved<7>0-1 7 3°C • To a suspension of 98.0 g of 5»6-Dimethyl-2-methoxy-carbonchloromethylene-indoxyl in 1500 ml. Ethanol is dripped while stirring at room temperature 79-7ml. Pipi-ridin. One stirs for 30 min. at room temperature, then 18 hours at 60°C and evaporated under reduced pressure to dryness. The residue is mixed with 200 ml. water and 1000 ml. acetic acid ethyl ester, shake well, separate the organic phase and wash it again with 100 ml. water. It is then dried and, with magnesium sulphate, evaporated under reduced pressure to dryness. The crystalline residue is chromatographed on 2000 g of silica gel. Those with each time 1000 ml. Ether eluted fractions 17-23 contain the pure 5'6-Dimethyl-2-methoxycarbonyl-(C-piperidino-methylene)-indoxyl. These fractions are purified and expelled with 100 ml. ether. The crystallized product melts at <7>0-1 7 3°C •
Eksempel h Example h
Analog eksempel 3 kan man når det gåes ut fra 2-Carboxychlormethylen-5,6-trimethylen-indoxyl over 2-Meth-oxycarbonylchlormethylen-5,6-trimethylen-indoxyl av smeltepunkt over 220°C og 2 ( ca—Methoxycarbonyl-cL-piperidino-methylen)-5,6-trimethylen-indoxyl av smeltepunkt l66-l68°Cfå 3-Hydroxy-5,6-trimethylen-indolylr2-glyoxylsyremethyester og smeltepunkt 200-202° C. Analogous to example 3, when starting from 2-Carboxychloromethylene-5,6-trimethylene-indoxyl over 2-Methoxycarbonylchloromethylene-5,6-trimethylene-indoxyl of melting point above 220°C and 2 (ca—Methoxycarbonyl-cL- piperidino-methylene)-5,6-trimethylene-indoxyl of melting point l66-168°C get 3-Hydroxy-5,6-trimethylene-indolylr2-glyoxylic acid methyl ester and melting point 200-202°C.
Eksempel 5 Example 5
En oppløsning av J2 g (0,114 Mol) 2-Methoxycarbo-nylchlormethylen-1,5»6-trimethyl-indoxyl i 100 ml. Aethanol av sin kolbeog i løpet av 30 min. tildryppes en opp-løsning av 19»2 g(o,228 Mol) Piperidin i 50 ml. Aethanol ved 20-25°C. Under mørkerød oppløsning omrøres deretter i h ti-ri mer ved 20-25°C. Deretter tildrypper man under isavkjøling i løpet av 30 min. 200 ml. 10$ -ig vandig svovelsyre og lar det utrøre 1 time ved 20-25°C. Den mørkebrune suspensjon frasuges, vaskes med vann og tørkes ved 60°C og 100 torr. Man får 25,7 g sorteaktige krystaller av 3-Hydroxy-1,5»6-trimethyl-indolyl-2-glyoxylsyremethylester som dessuten inneholder få forurensninger. Omkrystallisering fra eddiksyreethylester med aktivkull tilsetning gir gulgrønne krystaller av smeltepunkt 169-171°C. A solution of 12 g (0.114 Mol) of 2-Methoxycarbonylchloromethylene-1,5»6-trimethyl-indoxyl in 100 ml. Ethanol of its cob and within 30 min. a solution of 19.2 g (0.228 mol) piperidine in 50 ml is added dropwise. Ethanol at 20-25°C. The dark red solution is then stirred for 10-20 minutes at 20-25°C. It is then added drop by drop under ice cooling during 30 min. 200 ml. 10 µg of aqueous sulfuric acid and let it stir for 1 hour at 20-25°C. The dark brown suspension is suctioned off, washed with water and dried at 60°C and 100 torr. 25.7 g of blackish crystals of 3-Hydroxy-1,5»6-trimethyl-indolyl-2-glyoxylic acid methyl ester are obtained, which also contain few impurities. Recrystallization from acetic acid ethyl ester with the addition of activated charcoal gives yellow-green crystals of melting point 169-171°C.
Utgangsmaterialer kan fåes analog eksempel 3 når det gåes ut fra 2-Carboxychlormethylen-1,5»6-trimethyl-indoxyl (ved fremstillingen se eksempel i). Ved smelter omkrystal-lisert fra eddikester ved 134-136°C. Starting materials can be obtained analogously to example 3 when starting from 2-Carboxychlormethylene-1,5»6-trimethyl-indoxyl (for the preparation see example i). It melts recrystallized from ethyl acetate at 134-136°C.
Eksempel 6 Example 6
Analog til eksempel 5 kan man når det gåes ut fra 1- Aethyl-2-carboxychlormethylen-5,6-dimethyl-indoxyl av smeltepunkt 1 30°C under spaltning, som kan få:es analog til den i eksempel 1 og 2 omtalte fremgangsmåte for fremstilling av det der anvendte 2-Carboxychlormethylen-indoxyl over i 1-Aethyl-5,6-dimethyl-2-methoxycarbonylchlormethylen-indoxyl Analogous to example 5, when starting from 1-Aethyl-2-carboxychloromethylene-5,6-dimethyl-indoxyl of melting point 1 30°C during cleavage, which can be obtained analogously to the method mentioned in examples 1 and 2 for the production of the 2-Carboxychloromethylene-indoxyl used there into 1-Aethyl-5,6-dimethyl-2-methoxycarbonylchloromethylene-indoxyl
og smeltepunkt 110-111°C (fra eddikester) få 1-Aethyl-5,6-dimethyl-3-hydroxy-indolyl-2-glyoxylsyremethylester og smeltepunkt 142-143°C (fra Cyclohexan). and melting point 110-111°C (from acetic ester) get 1-Aethyl-5,6-dimethyl-3-hydroxy-indolyl-2-glyoxylic acid methyl ester and melting point 142-143°C (from Cyclohexane).
Eksempel 7 Example 7
Analog til eksempel 5 kan man når det gåes ut fra 2- Carboxycklormethylen-1,5,6-trimethyl-indoxyl-over 2-Aethoxy-carbonylchlormethylen-1,5,6-trimihyl-indoxyl av smeltepunkt 9 3_94°C få 3-Hydroxy-1,5,6-trimethyl-indolyl-2-glyoxylsyre-ethylester av smeltepunkt 126-127°C (fra Cyclohexan). Analogous to example 5, when starting from 2-Carboxychlormethylene-1,5,6-trimethyl-indoxyl-over 2-Aethoxy-carbonylchloromethylene-1,5,6-trimyl-indoxyl of melting point 9 3_94°C you can get 3- Hydroxy-1,5,6-trimethyl-indolyl-2-glyoxylic acid ethyl ester of melting point 126-127°C (from Cyclohexane).
Eksempel 8 Example 8
En oppløsning av 3,0 g 3-Hydroxy-1,5,6-trimethyl-indoxyl-2-glyoxylsyremethylester i 200 ml. Methanol blandes med 2 3 ml. av den ene normalen og den andre i Natriumhydroxyd-oppløsning og omrøres 20 timer ved værelsestemperatur. Deretter inndampes suspensjonen til tørrhet under nedsatt trykk ved kO°C. Residum oppløser man i 300 ml. vann. Den vandige oppløsning surgjøres med 30 ml. 2-normal saltsyre og den utskilte mørkerøde suspensjon ekstraheres med 700 ml. eddiksyreethylester. Deretter ryster man den organiske fase med 100 ml. 0, 5-nortnal Natriumbicarbonatoppløsning idet Natriumsalt av 3-Hydroxy-1,5»6-trimethyl-indolyl-2-glyox-ylsyre utskiller seg som orange krystaller. Produktet frafiltreres og tørkes under 0,01 torr ved 60°C. Det inneholder et Mol krystallvann og smelte ved 235°C under spaltning. Etter omkrystallisering Tra Methanol smelter "det ved Zjk-235°C A solution of 3.0 g of 3-Hydroxy-1,5,6-trimethyl-indoxyl-2-glyoxylic acid methyl ester in 200 ml. Methanol is mixed with 2 3 ml. of one normal and the other in sodium hydroxide solution and stirred for 20 hours at room temperature. The suspension is then evaporated to dryness under reduced pressure at kO°C. The residue is dissolved in 300 ml. water. The aqueous solution is acidified with 30 ml. 2-Normal hydrochloric acid and the secreted dark red suspension are extracted with 700 ml. acetic acid ethyl ester. The organic phase is then shaken with 100 ml. 0, 5-nortnal Sodium bicarbonate solution as Sodium salt of 3-Hydroxy-1,5»6-trimethyl-indolyl-2-glyox-yl acid separates as orange crystals. The product is filtered off and dried below 0.01 torr at 60°C. It contains one mole of crystal water and melts at 235°C during cleavage. After recrystallization Tra Methanol "it melts at Zjk-235°C
Analog kan man når det gåes ut fra 1,5 g 5,6-Dimet-hyl-3-hydroxy-indolyl-2-glyoxylsyremethylester få Natriumsalt av 5»6-Dimethyl-3-hydrOxy-indolyl-2-glyoxylsyre og smeltepunkt 265°C under spaltning samt når det gåes ut fra 1,6-Dimethyl-3-hydroxy-indolyl-2-glyoxylsyre dets Natriumsalt, smeltepunkt over 250°C. Analogously, starting from 1.5 g of 5,6-Dimethyl-3-hydroxy-indolyl-2-glyoxylic acid methyl ester, you can get Sodium salt of 5»6-Dimethyl-3-hydroxy-indolyl-2-glyoxylic acid and melting point 265 °C during decomposition as well as when proceeding from 1,6-Dimethyl-3-hydroxy-indolyl-2-glyoxylic acid its sodium salt, melting point above 250°C.
Eksempel 9 Example 9
Oppløsning av 1,0 g av Natriumsalt av 3-Hydroxy-1,5,6-trimethyl-indolyl-2-glyoxylsyre i 10 ml. absolutt Dimethylformamid blandes under omrøring ved værelsestemperatur med 0,5 g Dimethylsulfat. Oppløsningen omrøres 2 timer ved værelsestemperatur, blandes igjen med 0,5 g Dimethyl-sulf at og omrøres 15 timer ved værelsestemperatur. Deretter fortynner man oppløsningen med 100 ml. vann, frafiltrerer de^utskilte krystaller og oppløser dem i 100 ml. eddiksyreethylester. Oppløsningen ekstraheres med 20 ml. vann, deretter 2 ganger med høer gang 10 ml. Natriumbicarbonatoppløsning og igjen med 20 ml. vann, tørkes over Magnesiumsulfat og inndampes til tørrhet under nedsatt trykk. Reside krys-talliserer man fra eddiksyreethylester. 3-Hydroxy-1,5,6-trimethyl-indolyl-2-glyoxylsyremethylester smelter ved 169-1717<*>0. Solution of 1.0 g of sodium salt of 3-Hydroxy-1,5,6-trimethyl-indolyl-2-glyoxylic acid in 10 ml. absolute Dimethylformamide is mixed with stirring at room temperature with 0.5 g Dimethylsulphate. The solution is stirred for 2 hours at room temperature, mixed again with 0.5 g of dimethylsulphate and stirred for 15 hours at room temperature. The solution is then diluted with 100 ml. of water, filter off the precipitated crystals and dissolve them in 100 ml. acetic acid ethyl ester. The solution is extracted with 20 ml. water, then 2 times with 10 ml each time. Sodium bicarbonate solution and again with 20 ml. water, dried over magnesium sulphate and evaporated to dryness under reduced pressure. Reside is crystallized from acetic acid ethyl ester. 3-Hydroxy-1,5,6-trimethyl-indolyl-2-glyoxylic acid methyl ester melts at 169-1717<*>0.
På analog måte kan man når det gåes ut fra 0,8 g av Natriumsalt av 5»6-Dimethyl-3-hydroxy-indolyl-2glyoxyl-syre få 5»6-Dimethyl-3-hydroxy-indolyl-2-glyoxylsyremethyl ester og smeltepunkt 188-192°C (fra Methanol). In an analogous way, when starting from 0.8 g of sodium salt of 5»6-Dimethyl-3-hydroxy-indolyl-2glyoxylic acid, you can get 5»6-Dimethyl-3-hydroxy-indolyl-2-glyoxylic acid methyl ester and melting point 188-192°C (from Methanol).
Eksempel 10 Example 10
Analog som eksempel 1-9 kan det videre fremstilles: 5-Aethyl-3-hydroxy-1-methyl-indolyl-2-glyoxylsyre og dens Methylest er, Analogously to examples 1-9, the following can also be prepared: 5-Aethyl-3-hydroxy-1-methyl-indolyl-2-glyoxylic acid and its Methylest is,
1.5- Dimethyl-3-hydroxy-indolyl-2-glyoxylsyre og dens Methylester, 1.5- Dimethyl-3-hydroxy-indolyl-2-glyoxylic acid and its Methyl Ester,
6-Aethyl-3-hydroxy-1-methyl-indolyl-2-glyoxylsyre og dens Methylester, 6-Aethyl-3-hydroxy-1-methyl-indolyl-2-glyoxylic acid and its Methyl Ester,
1.6- Dimethyl-3-hydroxy-indolyl-2-glyoxylsyremethyl-ester, 1.6- Dimethyl-3-hydroxy-indolyl-2-glyoxylic acid methyl ester,
1,6-Dimethyl-3-pivaloyloxy-indolyl-2-glyoxylsyre 1,6-Dimethyl-3-pivaloyloxy-indolyl-2-glyoxylic acid
og dens Methylester, and its Methyl Ester,
^-Hydroxy-^-oxo-1,5,6-trimethyl-indolyl-2-glyoxyl-syrebutylester, ^-Hydroxy-^-oxo-1,5,6-trimethyl-indolyl-2-glyoxyl-acid butyl ester,
5,6-Dimethyl-3-hydroxy-indolyl-2-glyoxylsyrebutyl-ester, 5,6-Dimethyl-3-hydroxy-indolyl-2-glyoxylic acid butyl ester,
3-Hydroxy-5,6-trimethylen-indolyl-2-glyoxylsyre, 3-Hydroxy-5,6-trimethylene-indolyl-2-glyoxylic acid,
3-Hydroxy-1-methyl-5,6-trimethylen-indolyl-2-gly-oxylsyremethylester og 3-Hydroxy-1-methyl-5,6-trimethylene-indolyl-2-glyoxylic acid methyl ester and
3-Acetoxy-1,5» 6-trimethyl-indolyl-2-glyoxylsyre. 3-Acetoxy-1,5» 6-trimethyl-indolyl-2-glyoxylic acid.
Eksemepl 11 Example 11
2 g (0,0066 Mol) 3-Hydroxy-1,5,6-trimethyl-indolyl-2-glyoxylsyremethylester omrøres i 35 ml. av Acetanhydrid med 0,2 g vannfri Natriumacetat i en time ved 100 6C. Etter av-kjøling adskilles Natriumacetatet og den brune oppløsning inndampes. Omkrystallisering fra Cyclohexan gir. blågule krystaller av 3- Acetoxy-1,5,6-trimethyl-indolyl-2-glyoxylsyre-methylester av smeltepunkt 153-154°C. 2 g (0.0066 mol) of 3-Hydroxy-1,5,6-trimethyl-indolyl-2-glyoxylic acid methyl ester are stirred in 35 ml. of acetic anhydride with 0.2 g of anhydrous sodium acetate for one hour at 100 6C. After cooling, the sodium acetate is separated and the brown solution is evaporated. Recrystallization from cyclohexane gives blue-yellow crystals of 3-Acetoxy-1,5,6-trimethyl-indolyl-2-glyoxylic acid methyl ester of melting point 153-154°C.
Eksempel 12 Example 12
5 g 3-Hydroxy-1,5,6-trimethyl-indolyl-2-glyoxyl-syremethylester blandes i hO ml. Aethylenglykol under Nitrogen me 2,8 g vannfri Natriumkarbonat og omrøres i 1 time ved 40°C. Reaksjonsblandingen avkgøles til værelsestemperatur og blandes med 100 ml. eddiksyremethylester. Deretter tilsettes 50 ml. 10$-ig svovelsyre, hvorpå 3-Hydroxy-1,5»6-trimethyl-indolyl-2-glyoxylsyre-(2-hydroxyethyl)-esteren faller ut. Denne frafiltreres og omkrystalliseres fra Toluol. Man 5 g of 3-Hydroxy-1,5,6-trimethyl-indolyl-2-glyoxyl acid methyl ester are mixed in 10 ml. Ethylene glycol under nitrogen with 2.8 g of anhydrous sodium carbonate and stirred for 1 hour at 40°C. The reaction mixture is cooled to room temperature and mixed with 100 ml. acetic acid methyl ester. Then add 50 ml. 10% sulfuric acid, whereupon the 3-Hydroxy-1,5»6-trimethyl-indolyl-2-glyoxylic acid (2-hydroxyethyl)-ester precipitates out. This is filtered off and recrystallized from toluene. Mon
får gulorange nåler av smeltepunkt 154-156°C. get yellow-orange needles of melting point 154-156°C.
Idet man erstatter Aethylenglykol i den tilsvarende mengde av den angjeldende alkohol, kan man. By substituting ethylene glycol in the corresponding amount of the alcohol in question, you can.
— i — i
videre fremstille 3-Hydroxy-1,5,6-trimethyl-indolyl-2-gly-oxylsyre-neopentylester, smeltepunkt 115-117°G» 3-Hydroxy-1,5>6-trimethyl-indolyl-2-glyoxylsyre-n-octylester, smeltepunkt 65-67°C og 3-Hydroxy-1,5,6-trimethyl-indolyl-2-glyox-sylsyre-isopropylester, smeltepunkt 154-156°C. further prepare 3-Hydroxy-1,5,6-trimethyl-indolyl-2-glyoxylic acid-neopentyl ester, melting point 115-117°G» 3-Hydroxy-1,5>6-trimethyl-indolyl-2-glyoxylic acid-n -octyl ester, melting point 65-67°C and 3-Hydroxy-1,5,6-trimethyl-indolyl-2-glyox-sylic acid-isopropyl ester, melting point 154-156°C.
Eksempel 13 Example 13
En suspensjon av 15,75 g 3-Hydroxy-1,5»6-trimethyl-indolyl-2-glyoxylsyre i 1500 ml. Aceton blandes under omrør-ing dråpevis med en oppløsning av 9,51 g Triethanolamin i 70 ml. Aceton. Den orange oppløsning inndampes under 11 Torr til et volum på ca. 50 ml. De utskilte krystaller frafiltreres, ettervaskes med litt Aceton og oppløses i 80 ml. varm Aethanol. Ved oppløsningens avkjøling krystalliseres Triet-hanolminsaltet av 3-Hydroxy-1,5»6-trimethyl-indolyl-2-gly-oxylsyre. Krystallene frafiltreres, smeltepunkt 132-134°C. A suspension of 15.75 g of 3-Hydroxy-1,5»6-trimethyl-indolyl-2-glyoxylic acid in 1500 ml. Acetone is mixed dropwise with stirring with a solution of 9.51 g Triethanolamine in 70 ml. Acetone. The orange solution is evaporated below 11 Torr to a volume of approx. 50 ml. The separated crystals are filtered off, washed with a little Acetone and dissolved in 80 ml. hot ethanol. When the solution cools, the triethanolamine salt of 3-Hydroxy-1,5»6-trimethyl-indolyl-2-glyoxylic acid crystallizes. The crystals are filtered off, melting point 132-134°C.
Eksempel l4 Example 14
Analog til eksempel 3 vil man av 1,2 g 2-(<£X-Met-hoxycarbonat- ct-piperidinomethylen)-5,6-trimethylen-indoxyl få 3-Hydroxy-5,6-trimethylen-indolyl-2-glyoxylsyremethyl-ester, av smeltepunkt 198-202°C (fra Aethylacetat). Utgangsmateriale kan fremstilles som følger: Analog ; til eksempel 2 vil man eksempelvis av 10,5 g 6-Acetamido-indan og 10,2 g Dichlormaleinsyreanhydrid få 2-Carbdxychlormethylen-5,6-trimethylen-indoxyl, smeltepunkt 200°C (Spaltning etter omkrystallisering fra iseddik). Analogous to example 3, 1.2 g of 2-(<£X-Methoxycarbonate-ct-piperidinomethylene)-5,6-trimethylene-indoxyl will yield 3-Hydroxy-5,6-trimethylene-indolyl-2-glyoxylic acid methyl -ester, melting point 198-202°C (from ethyl acetate). Output material can be produced as follows: Analog ; for example 2, for example, from 10.5 g of 6-Acetamido-indane and 10.2 g of Dichloromaleic anhydride, 2-Carbdxychlormethylene-5,6-trimethylene-indoxyl, melting point 200°C (Decomposition after recrystallization from glacial acetic acid).
Analog til eksempel 3 vil man av 6,0 g 2-carboxychlormethylen-5,6-trimethylen få 2-Methoxycarbonylchlormet-hylen-5,6-trimethylen-indoxyl, smeltepunkt 183-184°C ( fra Aethylacetat). Analogous to example 3, 6.0 g of 2-carboxychloromethylene-5,6-trimethylene will yield 2-Methoxycarbonylchloromethylene-5,6-trimethylene-indoxyl, melting point 183-184°C (from ethyl acetate).
En suspensjon av 5,5 g 2-Methoxycarbonylchlor-methylen-5,6-trimethylen-indoxyl i 28 ml. Methanol omrøres etter tilsetning av 3,74 g Piperidin under innføring av Nitrogen i løpet av 18 timer ved 60°C. En mørkerød oppløsning blandes deretter med is og vann. Den utskilte olje ekstraheres med 50 ml. Aethylacetat. Man vasker Aethylacetatuttrek-ket med 10 ml. vann, tørker over Magnesiumsulfat og inndamper det under 11 Torr til tørrhet. Residuet, en olje, chromatograf er er man]5å 180 g Silicagel. Fraksjonene 1-3, A suspension of 5.5 g of 2-Methoxycarbonylchloromethylene-5,6-trimethylene-indoxyl in 28 ml. Methanol is stirred after adding 3.74 g of piperidine while introducing nitrogen during 18 hours at 60°C. A dark red solution is then mixed with ice and water. The separated oil is extracted with 50 ml. Ethyl acetate. The ethyl acetate extract is washed with 10 ml. water, drying over magnesium sulfate and evaporating it below 11 Torr to dryness. The residue, an oil, is chromatographed on 180 g of silica gel. Fractions 1-3,
av en med hver 200 ml. Ether, inneholder inneholder utgangsmaterial. Fraksjone 4-7i, eluert med ether, inneholder det rene 2- (cx -Methoxycarbonyl- CC-piperidino-methylen) -5, 6-tri-methylen-indoxyl, smeltepunkt 160-162°C (fra ether). of one with every 200 ml. Ether, contains contains starting material. Fractions 4-7i, eluted with ether, contain the pure 2-(cx-Methoxycarbonyl-CC-piperidino-methylene)-5,6-tri-methylene-indoxyl, melting point 160-162°C (from ether).
Eksempel 15 Example 15
1 g 1,5»6-Trimethyl-3-hydroxy-indolyl-2-glyoxyl-_ syremethylester oppslemmes i 30 ml. 10$-ig Natriumcarbonat-oppløsning og omrøres med k ml. Dimethylsulfat i 2k timer ved værelsestemperatur. Den utfeldte 1,5»6-trimethyl-3-methoxy-indolyl-2-glyoxylsyremethyIester, frafiltreres og om-krystalliserers fra Cyclohexan. Den smelter ved 141-143°C. 1 g of 1,5»6-Trimethyl-3-hydroxy-indolyl-2-glyoxyl-_ acid methyl ester is suspended in 30 ml. 10% sodium carbonate solution and stir with k ml. Dimethylsulfate for 2k hours at room temperature. The precipitated 1,5»6-trimethyl-3-methoxy-indolyl-2-glyoxylic acid methyl ester is filtered off and recrystallized from Cyclohexane. It melts at 141-143°C.
Eksempel 16 Example 16
Tabletter, inneholdene 0,1 g virksomt stoff, for eksempel 3-Hydroxy-1,5» 6-trimethyl-indolyl-2-glyoxylsyremet-hylester, fremstilles som følger: Tablets, containing 0.1 g of active substance, for example 3-Hydroxy-1,5" 6-trimethyl-indolyl-2-glyoxylic acid methyl ester, are prepared as follows:
Det virksomme stoff blandes med en del av hvete-stivelsen med Lactosen og den kolloidale Kiselsyre og blandingen drives1 gjennom en sikt. En ydderligere del av hvete-stivelsen forklistres med fem ganger vannmengden på vannbad og den overnevnte pulverblanding knas med detterklister inntil det,er dannet en svak plastisk masse. Den plastiske masse trykkes gjennom en sikt av ca. 3mm maskevidde, tørker og det tørre granulat drives igjen gjennom en sikt. Derpå til-blandes resterende hvetestivelse, tålkum og magnesiumstearat og den dannede blanding presses til tabletter av 0,25 g. The active substance is mixed with part of the wheat starch with the lactose and the colloidal silicic acid and the mixture is passed through a sieve. A further part of the wheat starch is pasted with five times the amount of water in a water bath and the above-mentioned powder mixture is crushed with this terk paste until a weak plastic mass is formed. The plastic mass is pressed through a sieve of approx. 3mm mesh size, dries and the dry granules are run through a sieve again. The remaining wheat starch, talcum powder and magnesium stearate are then mixed in and the resulting mixture is pressed into tablets of 0.25 g.
Eksempel 17 Example 17
En til innhalasjon egnet, ca 2$-ig vandig oppløsning av etbi fri form av Natriumsalte vannoppløselig virksomt stoff ifølge oppfinnelsen kan for eksempel fremstilles i følgende sammensetning: A suitable for inhalation, approx. 2% aqueous solution of etbi free form of sodium salts water-soluble active substance according to the invention can for example be prepared in the following composition:
Fremstilling: Manufacturing:
Det virksomme stoff oppløses under tilsetning av den aquimolekulare mengde 2normale-Natronlut i nydestillert vann. Deret.ter tilsettes stabilisatoren og konserveringsmid-delet. Etter .fullstendig oppløsning av alle komponenter opp-fylles den ! dandede oppløsning til 100 ml., fylles i flasker og disse lukkes gasstett. The active substance is dissolved while adding the aquimolecular amount of 2 normal sodium hydroxide solution in freshly distilled water. The stabilizer and preservative are then added. After complete dissolution of all components, it is filled up! prepared solution to 100 ml., is filled into bottles and these are closed gas-tight.
Eksempel 18 Example 18
Til insufflasjon egnede ca. 25 mg av et virksomt stoff ifølge oppfinnelsen inneholdende kapsler kan for eksempel fremstilles ifølgende sammensetning: For insufflation suitable approx. 25 mg of an active substance according to the invention containing capsules can, for example, be prepared according to the following composition:
Fremstilling: Manufacturing:
Det virksomme stoff og Lactosen blandes godt. Det dannede pulver blir deretter siktet og fylt i porsjoner på hver gang 50 mg i 1000 gelatinkapsler. The active substance and Lactose mix well. The resulting powder is then sieved and filled in portions of 50 mg each time into 1000 gelatin capsules.
Eksempel 19 Example 19
. Analog måte som i eksemplene 13-15 kan det frem stilles tilsvarende farmasøytiske preparater inneholdene en annen av de i eksemplene 1-12 omtalte forbindelser med den generelle formel il. . Analogous way as in examples 13-15, it can be done corresponding pharmaceutical preparations containing another of the compounds mentioned in examples 1-12 with the general formula il.
Pat entkrav Pat entkrav
Fremgangsmåte til fremstilling av nye 3-Hydroxy-indolyl-2-glyoxylsyrederivate med den generelle formel I Process for the preparation of new 3-Hydroxy-indolyl-2-glyoxylic acid derivatives of the general formula I
hvori Y betyr eventuelt foretret eller acylert Hydroxy, R betyr Hydrogen eventuelt substituert Laverealkyl eller Cycloalkyl og -ORq betyr eventuelt foretret Hydroxy, og hvori enten R^betyr Laverealkyl, Laverealkoxy, Cycloalkyl, Hydroxy, Phenoxy, Halogen eller Nitro, R^ betyr Laverealkyl, Laverealkoxy eller Hydroxy og R^og R^betyr uavhengig av hverandre Hydrogen eller Laverealkyl,idet minst en av restene R.j R^, R^og R^betyr 5- og/eller 6-stilling bundet Laverealkyl, eller R^og R^betyr sammen to naboplasserte Karbonatomer bundet Alkylen, med 3 til 5 kjedekarbonatomer og R^og R^betyr Hydrogen daint deres salter kaa r a k t - erisert ved at en forbindelse med den generelle formel in which Y means optionally etherified or acylated Hydroxy, R means Hydrogen optionally substituted Lower alkyl or Cycloalkyl and -ORq means optionally etherified Hydroxy, and in which either R^ means Lower alkyl, Lower alkyl, Cycloalkyl, Hydroxy, Phenoxy, Halogen or Nitro, R^ means Lower alkyl, Lower alkyl or Hydroxy and R^ and R^ independently mean Hydrogen or Lower alkyl, where at least one of the residues R. j R^, R^ and R^ means 5- and/or 6-position bonded Lower alkyl, or R^ and R^ means together two adjacent carbon atoms bonded Alkylene, with 3 to 5 chain carbon atoms and R^ and R^ means Hydrogen daint their salts are ca r a c t - erized in that a compound with the general formula
hvori R,RQ, R^, R^, R^og R^åv den angitte betydnng, X<*>betyr en Oniumgruppe og X ? betyr Anionresten av en syre, eller et salt herav hydrolyseres, eller in which R,RQ, R^, R^, R^and R^have the indicated meaning, X<*>means an Onium group and X ? means the anion residue of an acid, or a salt thereof is hydrolysed, or
en forbtimdelse med formel a preposition with a formula
hvori en av restene X,-, og X^ betyr en eventuelt funksjonelt modifisert Carboxygruppe og den andre betry Hydrogen eller et salt herav kondenseres intramolekulært eller in which one of the residues X,-, and X^ means an optionally functionally modified Carboxy group and the other means Hydrogen or a salt thereof is condensed intramolecularly or
i en forbindelse med formel in a connection with formula
hvori X^betyr en til Oxalogruppen overførbar rest, overfø-res X^til Oxalogruppen i og hvis ønsker overføres en dannet forbindelse med formel I i en annen forbindelse med formel I og/eller hvis ønsket, overføres en dannet fri forbindelse i et salt eller et dannet salt i den fri forbindelse eller i et annet salt. 2©Fremgangsmåte ifølge kæcav :1.karakterisert vedat den fri valens av Oniumgruppen X<®>i et utgangsmaterial ifølge formel II går ut fra det positivt'ladede Heteroatom. 3. Fremgangsmåte ifølge kiav 1 eller 2karakterisert vedat en Oniumgruppe XV er en Ammoniumgruppe. 4. Fremgangsmåte ifølge krav 1 eller 2karakterisert vedat en Oniumgruppe X<®>er en Sulfo-niumgrupp e. 5. Fremgangsmåte ifølge jet av kravene 1-4karakterisert vedat Hydrolysen gjennomføres i surt medium. ' -' 6. Fremgangsmåte ifølge krav 1karakterisert vedat det gåes ut fra en forbindelse med formel VI,hvori R betyr Hydrogen, X^ betyr forestret Carboxy in which X^ means a residue transferable to the Oxalo group, X^ is transferred to the Oxalo group in and, if desired, a formed compound of formula I is transferred into another compound of formula I and/or if desired, a formed free compound is transferred in a salt or a formed salt in the free compound or in another salt. 2©Procedure according to kæcav: 1. characterized in that the free valence of the Onium group X<®> in a starting material according to formula II proceeds from the positively charged Heteroatom. 3. Method according to claim 1 or 2, characterized in that an Onium group XV is an Ammonium group. 4. Method according to claim 1 or 2 characterized in that an Onium group X<®> is a Sulfonium group e. 5. Method according to claim 1-4 characterized in that the Hydrolysis is carried out in an acidic medium. ' -' 6. Method according to claim 1, characterized in that it starts from a compound of formula VI, in which R means Hydrogen, X^ means esterified Carboxy
og X^betyr Hydrogen. and X^means Hydrogen.
7. Fremgangsmåte ifølge krav 1karakterisert vedat det Hydrolys:er:es en forbindelse med formel IX hvori X^betyr en gruppe med formel -C(=X^)-COORQ, -C(=0)-X6eller -C(=X )-X6' og X^betyr en funksjonelt modifisert Oxogruppe og X^ betyr en fra gruppen -COORQforskjell-lig funksjonelt modifisert Carboxygruppe. 8. Fremgangsmåte ifølge krav 7«karakterisert vedat det gåes ut fra en forbindelse med formel IX, hvori X^betyr en gruppe med formel -C(=S)-COOH eller -C(=NAr)-COO H^N-Ar og Ar betyr en eventuelt substituert Ph:enyl. 9. Fremgangsmåte ifølge krav 7 eller 8karakterisert vedat Hydrolysen gjennomføres i surt medium. 10. Fremgangsmåte ifølge et av kravene 1 - 9karakterisert vedat man går ut fra en på et eller annet fremgangsmåtetrinn som mellomprodukt dannet forbindelse og gjennomfører de manglende fremgangsmåtetrinn. 11. Fremgangsmåte ifølge krav 1-10karakterisert vedat man danner et utgangsstoff under reak-sjonsbetingelsen eller anvender de/i form av et Derivat. 12. Fremgangsmåte ifølge et av kravene 1-11karakterisert vedat det fremstilles forbindelse med den generelle formel I ifølge krav 1, hvori R og R^uavhengig av hverandre betyr Hydrogen, Laverealkyl med inntil k Karbonatomer, Hydroxylaverealkyl med til og med h Karbonatomer, hvori Hydroxy er bundet i 2- og/eller 3-stilling, eller Laverealkoxylaverealkyl med til og med 7 Karbonatomer, hvori Laverealkoxygruppen er bundet til 2- eller 3-stilling, og hvori enten R^betyr Laverelakyl med til og med 4 Karbonatomer, C^-C^-Cycloalkyl, Hydroxy, Laverealkoxy med til og med h Karbonatomer, Halogen og atomnummer til og med 35 eller Nitro, og R2, R^og R^uavhengig av hverandre betyr Hydrogen eller Laverealkyl med til og med h Karbonatomer, idet minst en av restene R^, R^, R^og R^betyr 5- og/eller 6-stilling bundet Laverealkyl med inntil h Karbonatomer eller R^ og R^danner sammen i 5»6-stilling bundet rettlinjet Alkylen med 3 til 5 Karbonatomer, og R^og R^betyr \ 7. Process according to claim 1, characterized in that a compound of formula IX is hydrolyzed, in which X^ means a group of formula -C(=X^)-COORQ, -C(=0)-X6 or -C(=X ) -X6' and X^ mean a functionally modified Oxo group and X^ means a functionally modified Carboxy group from the group -COORQdiffers. 8. Method according to claim 7, characterized in that the starting point is a compound of formula IX, in which X^means a group of formula -C(=S)-COOH or -C(=NAr)-COO H^N-Ar and Ar means an optionally substituted Ph:enyl. 9. Method according to claim 7 or 8, characterized in that the Hydrolysis is carried out in an acidic medium. 10. Method according to one of the claims 1 - 9, characterized in that one starts from one or other method step as an intermediate formed compound and carries out the missing method steps. 11. Method according to claims 1-10 characterized by forming a starting substance under the reaction condition or using it/in the form of a derivative. 12. Method according to one of claims 1-11, characterized in that a compound with the general formula I according to claim 1 is prepared, in which R and R^ independently of each other mean Hydrogen, Lower alkyl with up to k Carbon atoms, Hydroxyllower alkyl with up to and including h Carbon atoms, in which Hydroxy is bonded in the 2- and/or 3-position, or Lower alkyl lower alkyl with up to and including 7 carbon atoms, in which the lower alkyl group is bonded in the 2- or 3-position, and in which either R^means lower alkyl with up to and including 4 carbon atoms, C^- C^-Cycloalkyl, Hydroxy, Lower Alkoxy with up to and including h Carbon atoms, Halogen and atomic number up to and including 35 or Nitro, and R2, R^ and R^ independently of each other mean Hydrogen or Lower Alkyl with up to and including h Carbon atoms, at least one of the residues R^, R^, R^ and R^ means 5- and/or 6-position bonded Lower alkyl with up to h Carbon atoms or R^ and R^ form together in the 5-6-position bonded rectilinear Alkylene with 3 to 5 Carbon atoms , and R^and R^mean \
Hydrogen samt salter av overnevnte forbindelser spesielt tilsvarende farmasøytiskeanvendbare salter. Hydrogen as well as salts of the above-mentioned compounds, particularly equivalent to pharmaceutically usable salts.
13-Fremgangsmåte ifølge et av kravene 1 - 11,karakterisert vedat det fremstilles forbindelse med formel 13-Procedure according to one of claims 1 - 11, characterized in that a compound with formula is prepared
hvori Y betyr Hydroxy eller C^-C^-Alkanoyloxy, R. og R^betyr uavhengig av hverandre Hydrogen eller Laverealkyl med til ogf med h Karbonatomer, for eksempel Methyl eller Aethyl, Hydroxy-laverealkyl med tiib og med h Karbonatomer, hvori Hydroxy er bundet i 2- og/eller 3-stilling,for eksempel 2-Hydroxyethyl in which Y means Hydroxy or C^-C^-Alkanoyloxy, R. and R^ independently mean Hydrogen or Lower alkyl with to and f with h Carbon atoms, for example Methyl or Aethyl, Hydroxy-lower alkyl with tiib and with h Carbon atoms, in which Hydroxy is bound in the 2- and/or 3-position, for example 2-Hydroxyethyl
eller 2,3-Di-hydroxy-propyl, eller Laverealkoxy-laverealkyl med til og med h Karbonatomer, hvori Laverealkoxygruppen er bundet i 2-eller 3-stilling, for eksempel 2-MeMioxyethyl, og hvori enten en av restene R~og RQbetyr Laverealkyl med til or 2,3-Di-hydroxy-propyl, or Lower alkoxy-lower alkyl with up to and including h Carbon atoms, in which the Lower alkoxy group is bound in the 2- or 3-position, for example 2-MeMioxyethyl, and in which either one of the radicals R~ and RQ means Lower alkyl with to
og med h Karbonatomer, for eksempel Methyl, en av de gjenbli-vne rester Rg, R^og Rg betyr Hydrogen Laverealkyl med til og med h Karbonatomer for eksempel Methyl, Halogen med atomnummer til og med 35 for eksempel Chlor, Laverealkoxy med til og med h Karbonatomer, for eksempel Methoxy , Hydroxy eller Nitro, og den tredje av resten Rg, R^, og Rg betyr Hydrogen eller Laverealkyl med til og med k karbonatomer,for eksempel Methyl,eller Rg g betyr Hydrogen og R^og Rg sammen Alky-i:en med 3 eller k k j edekarbonatomer, for eksempel 1 , 3-Propylen, samt salter av overnevnte forbindelse,spesielt tilsvarende farmasøytisk anvendbare salter. and with h Carbon atoms, for example Methyl, one of the remaining residues Rg, R^ and Rg means Hydrogen Lower alkyl with up to and including h Carbon atoms for example Methyl, Halogen with atomic number up to and including 35 for example Chlor, Lower Alkoxy with up to and with h Carbon atoms, for example Methoxy , Hydroxy or Nitro, and the third of the residue Rg, R^, and Rg means Hydrogen or Lower alkyl with even k carbon atoms, for example Methyl, or Rg g means Hydrogen and R^ and Rg together Alky-in with 3 or k chain carbon atoms, for example 1,3-Propylene, as well as salts of the above-mentioned compound, especially corresponding pharmaceutically usable salts.
14. Fremgangsmåte ifølge krav 1-11karakterisert vedat det fremstilles forbindelse med den generelle formel Ia ifølge krav 13»hvori Y betyr Hydroxy, R^14. Method according to claims 1-11, characterized in that a compound of the general formula Ia according to claim 13 is prepared, in which Y means Hydroxy, R
og R^betyr i første rekkerhver Hydrogen eller Laverealkyl med til og med h Karbonatomer, for eksempel Methyl eller , Aethyl, eller i annen rekke"Hydroxylaverealkyl med til og and R^means in the first row each Hydrogen or Lower alkyl with up to and including h Carbon atoms, for example Methyl or , Aethyl, or in the second row"Hydroxylower alkyl with up to and
med. k Karbonatomer hvori Hydroxy er bundet i 2- og/eller 3-stilling, for eksempel 2-Hydroxyethyl eller 2,3-Dihydroxy-propyl, eller Laverealkoxylaverealkyl med tifl> og med k Karbonatomer hvori Laverealkoxygruppen er bundet i 2-eller 3-stilling, for eksempel Methoxy ethyl, og hvori Rg, R,-, og Rg betyr Hydrogen eller Methyl eller R^, og Rg betyr sammen 1,3-Propylen eller 1,4,Butylen, idet minst en av restene R~og Rg er forskjellig fra Hydrogen, samt salter av overnevnte forbindelse spesielt tilsvarende farmasøytisk anvendbare salter. with. k Carbon atoms in which Hydroxy is bound in the 2- and/or 3-position, for example 2-Hydroxyethyl or 2,3-Dihydroxy-propyl, or Lower alkoxy lower alkyl with tifl> and with k Carbon atoms in which the Lower alkoxy group is bound in the 2- or 3-position , for example Methoxy ethyl, and in which Rg, R,-, and Rg mean Hydrogen or Methyl or R^, and Rg together mean 1,3-Propylene or 1,4,Butylene, with at least one of the residues R~ and Rg being different from Hydrogen, as well as salts of the above-mentioned compound, in particular corresponding pharmaceutically usable salts.
15. Fremgangsmåte ifølge et av kravene 1-11karakterisert vedat det fremstilles forbindelse med den generelle formel Ia ifølge krav 13»hvori Y betyr Hydroxy, R^betyr Hydrogen eller Laverealkyl med inntil k Karbonatomer som Methyl eller Aethyl, R betyr Laverealkyl 15. Process according to one of claims 1-11, characterized in that a compound with the general formula Ia according to claim 13 is prepared, in which Y means Hydroxy, R means Hydrogen or Lower alkyl with up to k Carbon atoms such as Methyl or Aethyl, R means Lower alkyl
med inntil k Karbonatomer som Methyl eller Aethyl, Rg betyr Hydrogen og minst en av restene R,,, og Rg betyr Laverealkyl med inntil k Karbonatomer som Methyl, og den andre betyr eventuelt Hydrogen eller R^og Rg betyr sammen 3- til 4-leddet Laverealkylen, som 1,3-Propylen og farmasøytisk anvendbare salter herav. with up to k Carbon atoms such as Methyl or Aethyl, Rg means Hydrogen and at least one of the residues R,,, and Rg means Lower alkyl with up to k Carbon atoms such as Methyl, and the other optionally means Hydrogen or R^ and Rg together means 3- to 4- linked Lower alkylene, such as 1,3-Propylene and pharmaceutically usable salts thereof.
16. Fremgangsmåte ifølge et av kravene 1 - Ilkar-akterisert ved at det fremstilles 3-Hydroxy-1,5» 6-trimethyl-indolyl-2-glyoxylsyremethylester. 17. Fremgangsmåte ifølge et av kravene 1-11karakterisert vedat det fremstilles 1-Aethyl-5,6-dimethyl-3-hydroxy-indolyl-2-glyoxylsyremethylester. 18. Fremgangsmåte ifølge et av kravene 1-11karakterisert vedat det fremstilles 3-Hydroxy-1,5» 6-trimethyl-indolyl-2-glyoxylsyremethylester. 19»Fremgangsmåte ifølge et av kravene 1 -11karakterisert vedat det fremstilles 5»6-Dimethyl-3-hydroxy-indolyl-2-glyoxylsyremethylest er. 20. Fremgangsmåte ifølge et av kravene 1-11karakterisert vedat det fremstilles 3-Hydroxy-5,6-trimethylén-indolyl-2-glyoxylsyremethylester. 21. Fremgangsmåte ifølge et av kravene 1-11karakterisert vedat det fremstilles 3-Hydroxy-1,5»6-trimethyl-indolyl-2-glyoxylsyre eller detsZNatriumsalt. 22. Fremgangsmåte ifølge et av kravene 1 - 11,karakterisert vedat det fremstilles 5»6-Dimethyl-3-hydroxy-indolyl-2-glyoxylsyre eller dets Natriumsalt. 23. Fremgangsmåte ifølge et av kravene 1 - 11,karakterisert vedat det fremstilles 1,6-Dimethyl-3-hydroxy-indolyl-2-glyoxylsyre eller dets Natriumsalt. 2h. Fremgangsmåte ifølge et av kravene 1 - 11,karakterisert vedat det fremstilles 3-Hydroxy-5,6-trimethylen-indolyl-2-glyoxylsyre eller dets Natriumsalt. 25. Fremgangsmåte ifølge et av kravene 1 - 11,karakterisert vedat det fremstilles 3-Hydroxy-1,5»6-trimeth<y>l-indol<y>l-2-<g>l<y>ox<y>ls<y>re/(<2>-h<y>drox<y>aeth<y>l) - est er<.>26. Fremgangsmåte ifølge et av kravene 1 - 11,karakterisert vedat det fremstilles 3-Hydroxy-1,5» 6-trimethyl-indolyl-2-glyoxylsyreneopentylester. 27. Fremgangsmåte ifølge et av kravene 1 - 11,karakterisert vedat det fremstilles 3-Hydroxy-1,5,6-trimethyl-indolyl-2-glyoxylsyre-n-octylester. 28. Fremgangsmåte ifølge et av kravene 1 - 11,karakterisert vedat det fremstilles 3-Hydroxy-1,5» 6-trimethyl-indolyl-2-glyoxylsyre-isopropylester. 16. Process according to one of the claims 1 - Ilkar-acterized in that 3-Hydroxy-1,5" 6-trimethyl-indolyl-2-glyoxylic acid methyl ester is produced. 17. Method according to one of claims 1-11, characterized in that 1-Aethyl-5,6-dimethyl-3-hydroxy-indolyl-2-glyoxylic acid methyl ester is produced. 18. Method according to one of claims 1-11, characterized in that 3-Hydroxy-1,5" 6-trimethyl-indolyl-2-glyoxylic acid methyl ester is produced. 19" Method according to one of the claims 1-11, characterized in that 5" 6-Dimethyl-3-hydroxy-indolyl-2-glyoxylic acid methyl ester is produced. 20. Method according to one of claims 1-11, characterized in that 3-Hydroxy-5,6-trimethylene-indolyl-2-glyoxylic acid methyl ester is produced. 21. Method according to one of claims 1-11, characterized in that 3-Hydroxy-1,5»6-trimethyl-indolyl-2-glyoxylic acid or its sodium salt is produced. 22. Method according to one of claims 1 - 11, characterized in that 5'6-Dimethyl-3-hydroxy-indolyl-2-glyoxylic acid or its sodium salt is produced. 23. Method according to one of claims 1 - 11, characterized in that 1,6-Dimethyl-3-hydroxy-indolyl-2-glyoxylic acid or its sodium salt is produced. 2h. Method according to one of claims 1 - 11, characterized in that 3-Hydroxy-5,6-trimethylene-indolyl-2-glyoxylic acid or its sodium salt is produced. 25. Method according to one of claims 1 - 11, characterized in that 3-Hydroxy-1,5»6-trimeth<y>l-indole<y>l-2-<g>l<y>ox<y> is produced ls<y>re/(<2>-h<y>drox<y>aeth<y>l) - est is<.>26. Method according to one of claims 1 - 11, characterized in that 3-Hydroxy-1,5" 6-trimethyl-indolyl-2-glyoxylic acid neopentyl ester is produced. 27. Method according to one of claims 1 - 11, characterized in that 3-Hydroxy-1,5,6-trimethyl-indolyl-2-glyoxylic acid-n-octyl ester is produced. 28. Method according to one of claims 1 - 11, characterized in that 3-Hydroxy-1,5'' 6-trimethyl-indolyl-2-glyoxylic acid isopropyl ester is produced.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
LU76758A LU76758A1 (en) | 1977-02-11 | 1977-02-11 |
Publications (1)
Publication Number | Publication Date |
---|---|
NO780473L true NO780473L (en) | 1978-08-14 |
Family
ID=19728482
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO780473A NO780473L (en) | 1977-02-11 | 1978-02-10 | PROCEDURE FOR THE PREPARATION OF INDOLYLGLYCOCACIC ACID DERIVATIVES |
Country Status (16)
Country | Link |
---|---|
JP (1) | JPS53101371A (en) |
BE (1) | BE863842A (en) |
DD (1) | DD134765A5 (en) |
DE (1) | DE2804798A1 (en) |
DK (1) | DK62778A (en) |
ES (1) | ES466825A1 (en) |
FI (1) | FI780401A (en) |
FR (1) | FR2380260A1 (en) |
IL (1) | IL54010A0 (en) |
LU (1) | LU76758A1 (en) |
NL (1) | NL7801575A (en) |
NO (1) | NO780473L (en) |
PL (1) | PL204553A1 (en) |
PT (1) | PT67639B (en) |
SE (1) | SE7801581L (en) |
ZA (1) | ZA78819B (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
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KR100451414B1 (en) * | 2001-12-31 | 2004-10-06 | 한국과학기술연구원 | Indol derivatives and a preparation method thereof |
-
1977
- 1977-02-11 LU LU76758A patent/LU76758A1/xx unknown
-
1978
- 1978-02-04 DE DE19782804798 patent/DE2804798A1/en active Pending
- 1978-02-08 FR FR7803563A patent/FR2380260A1/en not_active Withdrawn
- 1978-02-08 FI FI780401A patent/FI780401A/en not_active Application Discontinuation
- 1978-02-09 PT PT67639A patent/PT67639B/en unknown
- 1978-02-09 IL IL54010A patent/IL54010A0/en unknown
- 1978-02-09 ES ES466825A patent/ES466825A1/en not_active Expired
- 1978-02-10 SE SE7801581A patent/SE7801581L/en unknown
- 1978-02-10 NO NO780473A patent/NO780473L/en unknown
- 1978-02-10 PL PL20455378A patent/PL204553A1/en unknown
- 1978-02-10 ZA ZA00780819A patent/ZA78819B/en unknown
- 1978-02-10 DK DK62778A patent/DK62778A/en unknown
- 1978-02-10 BE BE185059A patent/BE863842A/en unknown
- 1978-02-10 JP JP1366578A patent/JPS53101371A/en active Pending
- 1978-02-10 NL NL7801575A patent/NL7801575A/en not_active Application Discontinuation
- 1978-02-10 DD DD78203654A patent/DD134765A5/en unknown
Also Published As
Publication number | Publication date |
---|---|
IL54010A0 (en) | 1978-04-30 |
PT67639A (en) | 1978-03-01 |
JPS53101371A (en) | 1978-09-04 |
DD134765A5 (en) | 1979-03-21 |
FR2380260A1 (en) | 1978-09-08 |
PT67639B (en) | 1979-07-18 |
FI780401A (en) | 1978-08-12 |
SE7801581L (en) | 1978-08-12 |
DE2804798A1 (en) | 1978-08-17 |
BE863842A (en) | 1978-08-10 |
PL204553A1 (en) | 1979-06-04 |
NL7801575A (en) | 1978-08-15 |
LU76758A1 (en) | 1978-10-18 |
ES466825A1 (en) | 1978-10-01 |
ZA78819B (en) | 1979-01-31 |
DK62778A (en) | 1978-08-12 |
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