NO158673B - Analogifremgangsm te ved fremstilling av terapeutisk aktive azurenderivater. - Google Patents
Analogifremgangsm te ved fremstilling av terapeutisk aktive azurenderivater. Download PDFInfo
- Publication number
- NO158673B NO158673B NO843377A NO843377A NO158673B NO 158673 B NO158673 B NO 158673B NO 843377 A NO843377 A NO 843377A NO 843377 A NO843377 A NO 843377A NO 158673 B NO158673 B NO 158673B
- Authority
- NO
- Norway
- Prior art keywords
- sodium
- compound
- azulenesulfonate
- isopropyl
- compounds
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 9
- 238000002360 preparation method Methods 0.000 title claims description 5
- 230000001225 therapeutic effect Effects 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 44
- 239000011734 sodium Substances 0.000 claims description 28
- 229910052708 sodium Inorganic materials 0.000 claims description 26
- 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 claims description 23
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims 1
- 229950002760 sodium gualenate Drugs 0.000 description 24
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 description 14
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N butyric aldehyde Natural products CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000000354 decomposition reaction Methods 0.000 description 8
- GEYJUFBPCGDENK-UHFFFAOYSA-M sodium;3,8-dimethyl-5-propan-2-ylazulene-1-sulfonate Chemical compound [Na+].CC(C)C1=CC=C(C)C2=C(S([O-])(=O)=O)C=C(C)C2=C1 GEYJUFBPCGDENK-UHFFFAOYSA-M 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- -1 Sodium 7-isopropyl-3 -benzyl azulene Chemical compound 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- BRRRJLZILWOZEO-UHFFFAOYSA-M sodium;2-ethyl-3-methylazulene-1-sulfonate Chemical compound [Na+].C1=CC=CC2=C(S([O-])(=O)=O)C(CC)=C(C)C2=C1 BRRRJLZILWOZEO-UHFFFAOYSA-M 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 229940126214 compound 3 Drugs 0.000 description 4
- IMSYLDRQZHJGJB-UHFFFAOYSA-M sodium;3-methylazulene-1-sulfonate Chemical compound [Na+].C1=CC=CC=C2C(C)=CC(S([O-])(=O)=O)=C21 IMSYLDRQZHJGJB-UHFFFAOYSA-M 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000006277 sulfonation reaction Methods 0.000 description 4
- WSQIUQGZWDQMEL-UHFFFAOYSA-N 1-methylazulene Chemical compound C1=CC=CC=C2C(C)=CC=C21 WSQIUQGZWDQMEL-UHFFFAOYSA-N 0.000 description 3
- BOKBNQLZXUNCOG-UHFFFAOYSA-N C1(=CC=C2C=CC=CC=C12)S(=O)(=O)OC(CC)C.[Na] Chemical compound C1(=CC=C2C=CC=CC=C12)S(=O)(=O)OC(CC)C.[Na] BOKBNQLZXUNCOG-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 150000001299 aldehydes Chemical class 0.000 description 3
- 150000001545 azulenes Chemical class 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 230000003389 potentiating effect Effects 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- ATURQTBVCVCOJX-UHFFFAOYSA-M sodium;3-butylazulene-1-sulfonate Chemical compound [Na+].C1=CC=CC=C2C(CCCC)=CC(S([O-])(=O)=O)=C21 ATURQTBVCVCOJX-UHFFFAOYSA-M 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 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
- 208000007107 Stomach Ulcer Diseases 0.000 description 2
- 208000025865 Ulcer Diseases 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- ZLOFCFJGSMWUPY-UHFFFAOYSA-K bis[(3-ethyl-7-propan-2-ylazulen-1-yl)sulfonyloxy]alumanyl 3-ethyl-7-propan-2-ylazulene-1-sulfonate Chemical compound [Al+3].C(C)C=1C=C(C2=CC(=CC=CC12)C(C)C)S(=O)(=O)[O-].C(C)C=1C=C(C2=CC(=CC=CC12)C(C)C)S(=O)(=O)[O-].C(C)C=1C=C(C2=CC(=CC=CC12)C(C)C)S(=O)(=O)[O-] ZLOFCFJGSMWUPY-UHFFFAOYSA-K 0.000 description 2
- ZMZXPKGZMZWIAR-UHFFFAOYSA-K bis[(3-ethylazulen-1-yl)sulfonyloxy]alumanyl 3-ethylazulene-1-sulfonate Chemical compound CCC1=CC(=C2C1=CC=CC=C2)S(=O)(=O)O[Al](OS(=O)(=O)C3=C4C=CC=CC=C4C(=C3)CC)OS(=O)(=O)C5=C6C=CC=CC=C6C(=C5)CC ZMZXPKGZMZWIAR-UHFFFAOYSA-K 0.000 description 2
- YMIVNRFSTOXDNZ-UHFFFAOYSA-K bis[(3-methyl-7-propan-2-ylazulen-1-yl)sulfonyloxy]alumanyl 3-methyl-7-propan-2-ylazulene-1-sulfonate Chemical compound CC1=CC(=C2C1=CC=CC(=C2)C(C)C)S(=O)(=O)O[Al](OS(=O)(=O)C3=C4C=C(C=CC=C4C(=C3)C)C(C)C)OS(=O)(=O)C5=C6C=C(C=CC=C6C(=C5)C)C(C)C YMIVNRFSTOXDNZ-UHFFFAOYSA-K 0.000 description 2
- RUMIGLAYHHUAOA-UHFFFAOYSA-K bis[(3-methylazulen-1-yl)sulfonyloxy]alumanyl 3-methylazulene-1-sulfonate Chemical compound CC1=CC(=C2C1=CC=CC=C2)S(=O)(=O)O[Al](OS(=O)(=O)C3=C4C=CC=CC=C4C(=C3)C)OS(=O)(=O)C5=C6C=CC=CC=C6C(=C5)C RUMIGLAYHHUAOA-UHFFFAOYSA-K 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 229940127573 compound 38 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- KXGWXVVNYQOMQZ-UHFFFAOYSA-M egualen sodium Chemical compound [Na+].C1=C(C(C)C)C=CC=C2C(CC)=CC(S([O-])(=O)=O)=C21 KXGWXVVNYQOMQZ-UHFFFAOYSA-M 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 150000002081 enamines Chemical class 0.000 description 2
- 201000005917 gastric ulcer Diseases 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- JSPKXBKHTQVZPM-UHFFFAOYSA-M sodium;3-butyl-4-methoxy-7-propan-2-ylazulene-1-sulfonate Chemical compound [Na+].C1=C(C(C)C)C=CC(OC)=C2C(CCCC)=CC(S([O-])(=O)=O)=C21 JSPKXBKHTQVZPM-UHFFFAOYSA-M 0.000 description 2
- NGJHRFVEMDXRGU-UHFFFAOYSA-M sodium;3-butyl-4-methoxyazulene-1-sulfonate Chemical compound [Na+].C1=CC=CC(OC)=C2C(CCCC)=CC(S([O-])(=O)=O)=C21 NGJHRFVEMDXRGU-UHFFFAOYSA-M 0.000 description 2
- FJYPWCUPSBKWIR-UHFFFAOYSA-M sodium;3-butyl-7-propan-2-ylazulene-1-sulfonate Chemical compound [Na+].C1=C(C(C)C)C=CC=C2C(CCCC)=CC(S([O-])(=O)=O)=C21 FJYPWCUPSBKWIR-UHFFFAOYSA-M 0.000 description 2
- MBXVGAMPJWASRZ-UHFFFAOYSA-M sodium;3-hexyl-4-methoxyazulene-1-sulfonate Chemical compound [Na+].C1=CC=CC(OC)=C2C(CCCCCC)=CC(S([O-])(=O)=O)=C21 MBXVGAMPJWASRZ-UHFFFAOYSA-M 0.000 description 2
- VVUPWRGDMBEIIO-UHFFFAOYSA-M sodium;3-methyl-7-propan-2-ylazulene-1-sulfonate Chemical compound [Na+].CC(C)C1=CC=CC2=C(C)C=C(S([O-])(=O)=O)C2=C1 VVUPWRGDMBEIIO-UHFFFAOYSA-M 0.000 description 2
- JQOXTPXDSZSKMD-UHFFFAOYSA-M sodium;3-pentyl-7-propan-2-ylazulene-1-sulfonate Chemical compound [Na+].C1=C(C(C)C)C=CC=C2C(CCCCC)=CC(S([O-])(=O)=O)=C21 JQOXTPXDSZSKMD-UHFFFAOYSA-M 0.000 description 2
- VJAFGTALRVDWND-UHFFFAOYSA-M sodium;3-pentylazulene-1-sulfonate Chemical compound [Na+].C1=CC=CC=C2C(CCCCC)=CC(S([O-])(=O)=O)=C21 VJAFGTALRVDWND-UHFFFAOYSA-M 0.000 description 2
- YRCMLISKTWBKQS-UHFFFAOYSA-M sodium;4-methoxy-3-methyl-7-propan-2-ylazulene-1-sulfonate Chemical compound [Na+].COC1=CC=C(C(C)C)C=C2C(S([O-])(=O)=O)=CC(C)=C12 YRCMLISKTWBKQS-UHFFFAOYSA-M 0.000 description 2
- JJPJHCJTZBHPHR-UHFFFAOYSA-M sodium;4-methoxy-3-pentyl-7-propan-2-ylazulene-1-sulfonate Chemical compound [Na+].C1=C(C(C)C)C=CC(OC)=C2C(CCCCC)=CC(S([O-])(=O)=O)=C21 JJPJHCJTZBHPHR-UHFFFAOYSA-M 0.000 description 2
- YBIFRVAWKGBZKW-UHFFFAOYSA-M sodium;4-methoxy-3-pentylazulene-1-sulfonate Chemical compound [Na+].C1=CC=CC(OC)=C2C(CCCCC)=CC(S([O-])(=O)=O)=C21 YBIFRVAWKGBZKW-UHFFFAOYSA-M 0.000 description 2
- HJBFSEBRGPIEBT-UHFFFAOYSA-M sodium;4-methoxy-7-propan-2-yl-3-propylazulene-1-sulfonate Chemical compound [Na+].C1=C(C(C)C)C=CC(OC)=C2C(CCC)=CC(S([O-])(=O)=O)=C21 HJBFSEBRGPIEBT-UHFFFAOYSA-M 0.000 description 2
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 1
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 1
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 1
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
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- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 1
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- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- LIKMAJRDDDTEIG-UHFFFAOYSA-N 1-hexene Chemical compound CCCCC=C LIKMAJRDDDTEIG-UHFFFAOYSA-N 0.000 description 1
- LSQXOLFOAOCMSS-UHFFFAOYSA-N 1-pent-2-en-3-ylpyrrolidine Chemical compound CCC(=CC)N1CCCC1 LSQXOLFOAOCMSS-UHFFFAOYSA-N 0.000 description 1
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 1
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 1
- NPRYCHLHHVWLQZ-TURQNECASA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynylpurin-8-one Chemical compound NC1=NC=C2N(C(N(C2=N1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C NPRYCHLHHVWLQZ-TURQNECASA-N 0.000 description 1
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 1
- PDDCVQJUFDCEJZ-UHFFFAOYSA-N 5-propan-2-ylazulene-1-sulfonic acid Chemical compound CC(C)C1=CC=CC2=C(S(O)(=O)=O)C=CC2=C1 PDDCVQJUFDCEJZ-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- VFPYVKUIOPAYSH-UHFFFAOYSA-N COC=1C2=C(C=CC2=CC=CC1)CCC.[Na] Chemical compound COC=1C2=C(C=CC2=CC=CC1)CCC.[Na] VFPYVKUIOPAYSH-UHFFFAOYSA-N 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- 229940126639 Compound 33 Drugs 0.000 description 1
- 208000007882 Gastritis Diseases 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 1
- 102000057297 Pepsin A Human genes 0.000 description 1
- 108090000284 Pepsin A Proteins 0.000 description 1
- PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 241000251778 Squalus acanthias Species 0.000 description 1
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000001949 anaesthesia Methods 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000002467 anti-pepsin effect Effects 0.000 description 1
- 230000002788 anti-peptide Effects 0.000 description 1
- 230000000767 anti-ulcer Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 1
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 1
- NEHNMFOYXAPHSD-UHFFFAOYSA-N beta-citronellal Natural products O=CCC(C)CCC=C(C)C NEHNMFOYXAPHSD-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- RHDGNLCLDBVESU-UHFFFAOYSA-N but-3-en-4-olide Chemical compound O=C1CC=CO1 RHDGNLCLDBVESU-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940126086 compound 21 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940125833 compound 23 Drugs 0.000 description 1
- 229940125961 compound 24 Drugs 0.000 description 1
- 229940125846 compound 25 Drugs 0.000 description 1
- 229940125851 compound 27 Drugs 0.000 description 1
- 229940127204 compound 29 Drugs 0.000 description 1
- 229940125877 compound 31 Drugs 0.000 description 1
- 229940125878 compound 36 Drugs 0.000 description 1
- 229940125807 compound 37 Drugs 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000003628 erosive effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 229940087305 limonene Drugs 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229940111202 pepsin Drugs 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- OTGHQNAZTCHCPQ-UHFFFAOYSA-M sodium;3-benzyl-7-propan-2-ylazulene-1-sulfonate Chemical compound [Na+].C1=C(S([O-])(=O)=O)C2=CC(C(C)C)=CC=CC2=C1CC1=CC=CC=C1 OTGHQNAZTCHCPQ-UHFFFAOYSA-M 0.000 description 1
- CBGSKWCCLULJPS-UHFFFAOYSA-M sodium;3-ethyl-4-methoxy-7-propan-2-ylazulene-1-sulfonate Chemical compound [Na+].C1=C(C(C)C)C=CC(OC)=C2C(CC)=CC(S([O-])(=O)=O)=C21 CBGSKWCCLULJPS-UHFFFAOYSA-M 0.000 description 1
- CFVIIDQFTKFLBO-UHFFFAOYSA-M sodium;3-ethyl-4-methoxyazulene-1-sulfonate Chemical compound [Na+].C1=CC=CC(OC)=C2C(CC)=CC(S([O-])(=O)=O)=C21 CFVIIDQFTKFLBO-UHFFFAOYSA-M 0.000 description 1
- WNITZVDODVXYEM-UHFFFAOYSA-M sodium;3-ethyl-6-propan-2-ylazulene-1-sulfonate Chemical compound [Na+].C1=CC(C(C)C)=CC=C2C(CC)=CC(S([O-])(=O)=O)=C21 WNITZVDODVXYEM-UHFFFAOYSA-M 0.000 description 1
- IFNWBZPEJSGLNB-UHFFFAOYSA-M sodium;3-ethylazulene-1-sulfonate Chemical compound [Na+].C1=CC=CC=C2C(CC)=CC(S([O-])(=O)=O)=C21 IFNWBZPEJSGLNB-UHFFFAOYSA-M 0.000 description 1
- NTZQXFPWRIYGBS-UHFFFAOYSA-M sodium;3-propylazulene-1-sulfonate Chemical compound [Na+].C1=CC=CC=C2C(CCC)=CC(S([O-])(=O)=O)=C21 NTZQXFPWRIYGBS-UHFFFAOYSA-M 0.000 description 1
- RJLOZMFQQISKDR-UHFFFAOYSA-M sodium;4-methoxy-3-methylazulene-1-sulfonate Chemical compound [Na+].COC1=CC=CC=C2C(S([O-])(=O)=O)=CC(C)=C12 RJLOZMFQQISKDR-UHFFFAOYSA-M 0.000 description 1
- AHMFECHECPAAGK-UHFFFAOYSA-M sodium;4-methoxy-3-propylazulene-1-sulfonate Chemical compound [Na+].C1=CC=CC(OC)=C2C(CCC)=CC(S([O-])(=O)=O)=C21 AHMFECHECPAAGK-UHFFFAOYSA-M 0.000 description 1
- UBFASBLGCIMJLB-UHFFFAOYSA-M sodium;5-propan-2-ylazulene-1-sulfonate Chemical compound [Na+].CC(C)C1=CC=CC2=C(S([O-])(=O)=O)C=CC2=C1 UBFASBLGCIMJLB-UHFFFAOYSA-M 0.000 description 1
- UXCZTNOEKMDZBD-UHFFFAOYSA-M sodium;7-propan-2-yl-3-propylazulene-1-sulfonate Chemical compound [Na+].C1=C(C(C)C)C=CC=C2C(CCC)=CC(S([O-])(=O)=O)=C21 UXCZTNOEKMDZBD-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- OBROYCQXICMORW-UHFFFAOYSA-N tripropoxyalumane Chemical compound [Al+3].CCC[O-].CCC[O-].CCC[O-] OBROYCQXICMORW-UHFFFAOYSA-N 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/45—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton
- C07C309/47—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton having at least one of the sulfo groups bound to a carbon atom of a six-membered aromatic ring being part of a condensed ring system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/255—Esters, e.g. nitroglycerine, selenocyanates of sulfoxy acids or sulfur analogues thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Emergency Medicine (AREA)
- Epidemiology (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Foreliggende oppfinnelse vedrører fremstilling av nye kjemi-ske forbindelser med verdifulle terapeutiske egenskaper.
Azulenderivater har vært kjent i lang tid og utviser anti-gastrikk ulcer, anti-gastritis og anti-inflammatorisk aktivitet. Imidlertid, på grunn av deres manglende stabilitet mot lys og varme har det lenge vært et ønske om et forbedret sta-bilt og potent derivat derav.
En hovedhensikt med foreliggende oppfinnelse er å tilveiebrin-ge nye forbindelser med fordelaktige farmasøytiske egenskaper.
En ytterligere hensikt med f oieliggende oppfinnelse er tilveie-bringelse av natriumsulfonater av nye azulenderivater og en fremgangsmåte for fremstilling derav.
Disse og andre hensikter vil fremgå av den etterfølgende be-skrivelse .
Forbindelsene i henhold til oppfinnelsen er representert ved den generelle formel I
(hvori R- er h", lavere a lky 1,
eller benzyl,
(R , R , R hver betyr hydrogen eller en lavere alkylgruppe),
2 3 4
R og R er hydrogen eller en lavere alkylgruppe. R er hydrogen eller en alkyloksygruppe, og X er Na eller A1(0H)2-)
Forbindelsene representert ved den generelle formel I utvi^ ser en potent anti-gastrisk ulcerativ og anti-inflammatorisk aktivitet, og er derfor ansett som terapeutisk anvendelige. For disse formål har tidligere natrium-guaiazulen-3-sulfo-nat vært anvendt. Forbindelsene fremstilt i henhold til oppfinnelsen er mere potente og kjemisk mere stabile enn den ovenfor nevnte forbindelse.
De lavere alkylgrupper representert av R^", R^, R^, R<4>, R^, R*> og R^ i den generelle formel I er ment å omfatte forgrenete eller uforgrenete alkylgrupper med 1-6 karbonatomer. Slike 3 4 forbindelser er ønskelige fordi substituentene R og R er i 4-, 6- eller 7-stillingen i en 7-leddet ring med den generelle formel I. ;De følgende forbindelser ifølge oppfinnelsen er av spesiell interesse. ;1) Natrium 3-metyl-azulensulfonat ;2) Natrium 3-etyl-azulensulfonat ;3) Natrium 3-etyl-7-isopropyl-azulensulfonat ;4) Natrium 3-etyl-6-isopropyl-azulensulfonat ;5) Natrium 3-(l'-R, S-l<1>, 5<1->dimetyl-4'-heksen)azulensulfonat ;6) Natrium 3-n-butyl-azulensulfonat ;7) Natrium 3-metyl-2-etyl-azulensulfonat ;8) Natrium 3-(l'-S-l', 5<1->dimetyl-4'-heksen)-azulensulfonat 9) Natrium S-d^R-l1, 5 1-dimetyl-4 '-heksen)-azulensulf onat. 10) Natrium 3-(l<1->S-l', 5<1->dimetyl-4'-heksen)-7-isopropyl-azulensulfonat 11) Natrium 3-(l'-R-l', 5<1->dimetyl-4'-heksen)-7-isopropyl-azulensulfonat ;12) Natrium 3-propylazulensulfonat ;13) Natrium 3-metyl-7-isopropyl-azulensulfonat ;14) Natrium 3-n-butyl-azulensulf onat ;15) Natrium 3-n-pentyl-azulensulfonat ;16) Natrium 5-isopropyl-azulensulfonat ;17) Natrium 7-isopropyl-3-n-propyl-azulensulfonat ;18) Natrium 7-isopropyl-3-n-butyl-azulensulfonat ;19) Natrium 7-isopropyl-3-n-pentyl-azulensulfonat ;20) Natrium 7-isopropyl-3-(1'-R, ~S-1' , 5'-dimetyl-4'-heksen)-azulensulfonat 21) Natrium 7-isopropyl-3-(1<1->R-l', 5<1->dimetyl-4'-heksen)-azulensulfonat 22) Natrium 7-isopropyl-3-(1'-S-l', 5<1->dimetyl-4'-heksen)-azulensulfonat ;23) Natrium 7-isopropyl-3-benzyl-azulensulfonat ;24) Natrium 4-metoksy-3-metyl-azulensulfonat ;25) Natrium 4-metoksy-3-etyl-azulensulfonat ;26) Natrium 4-metoksy-3-propyl-azulensulfonat ;27) Natrium 4-metoksy-3-butyl-azulensulfonat ;28) Natrium 4-metoksy-3-pentyl-azulensulfonat ;29) Natrium 4-metoksy-3-heksyl-azulensulfonat ;30) Natrium 7-isopropyl-4-metoksy-3-metyl-azulensulfonat ;31) Natrium 7-isopropyl-4-metoksy-3-etyl-azulensulfonat ;32) Natrium 7-isopropyl-4-metoksy-3-propyl-azulensulfonat ;33) Natrium 7-isopropyl-4-metoksy-3-butyl-azulensulfonat ;34) Natrium 7-isopropyl-4-metoksy-3-pentyl-azulensulfonat ;35) 3-metyl-azulensulfonsyrealuminiumsalt ;36) 3-etyl-azulensulfonsyrealuminiumsalt. ;37) 7-isopropyl-3-metyl-azulensulfonsyrealuminiumsalt ;38) 7-isopropyl-3-etyl-azulensulfonsyrealuminiumsalt ;De ovenfor nevnte forbindelser nummerert fra 1 til 38 vil i det etterfølgende bli betegnet som henholdsvis forbindelse 1, forbindelse 2, .... forbindelse 38. ;De nye azulenderivater med den generelle formel (I) erholdes ved sulfonering av en forbindelse med den generelle formel (II) for omdannelse til et natrium eller aluminiumsalt ;;12 3 4 ;(hvori RT>.,R ,R og R har de ovenfor angitte betydninger) . ;Forbindelsene representert med formelen (II) kan fremstilles på flere forskjellige måter, slik som angitt i det et-terfølgende. ;i) Forbindelsene, hvori R 1 og R 3 er hydrogen eller en lavere alkylgruppe og R 2 er hydrogen, erholdes ved fremgangsmåten i henhold til L. T. Scott (J. Am. Chem. Soc. 102 6311p 1980) eller M. Yasunami (Chemistry Letters 579p 1980), ;ii) I det tilfelle hvor R<1> er ;;eller ;benzyl, kan forbindelsen erholdes ved å omsette 2H-cyklohep-ta(b)furan-2-on med et enamin erholdt fra tilsvarende aldehy-der med formelen : R -CH2CH0, i henhold til M. Yasunami (Chem. Lett. 579p 1980). ;iii) For å erholde forbindelser, hvori både R 1 og R 2 er lavere alkyl, kan anvendes den samme fremgangsmåte som i henhold til (ii) under anvendelse av et enamin erholdt fra en ke-tonforbindelse (R^-CH2-C-R2) i stedet for aldehydet R^-CI^CHO) som ble anvendt i omsetning (ii), selv om utgangs-aldehydet inneholder en stereospesifikk isomer, eksempelvis hvis R"<*>" er d- eller 1-citronellal og d- eller 1-limonen, så er det funnet at det erholdte produkt erholder dets stereo-spesif isitet .
iv) De andre forbindelser kan også fremstilles i henhold til M. Yasunami (Chem. Lett. 579p 1980).
Forbindelsene erholdt som angitt ovenfor renses ved destilla-sjon under nedsatte trykk eller ved kolonnekromatografi og blir deretter underkastet sulfonering. Sulfonering utføres generelt i eddiksyreanhydrid ved tilsetning av svovelsyre under avkjølte betingelser, i visse tilfeller kan også svovel-syreanhydridpyridinkompleks anvendes. Den resulterende sulfo-nerte forbindelse omdannes til det tilsvarende natriumsalt ved hjelp av en natriumhydroksydoppløsning eller natrium-etylat og omkrystalliseres deretter fra alkoholer.
For å fremstille aluminiumsaltene kan natriumsulfonatene omdannes ved hjelp av en aluminiumsaltoppløsning, eksempelvis en vandig oppløsning av A1(0H)3, A1C13 eller aluminium-propoksyd.
De fremstilte forbindelser utviser forbedret lysstabilitet og varmestabilitet og noen
av disse forbindelser har utmerket anti-peptid- og anti-gastrisk ulcer aktivitet og er lovende for terapeutisk anvendelse. De følgende eksempler viser biologisk aktivitet sammenlignet med natrium-guaiazulen-3-sulfonat (GAS) som standard middel, preparater av typiske blandinger ifølge oppfinnelsen, samt deres fremstilling.
( Farmakologiske data 1)
Anti-peptisk aktivitet av forbindelsene ble undersøkt in vitro i henhold til V. K. Thiemer (Arznei-Forsch 22^ (6) , PP. 1086, 19 72) under anvendelse av storkvegserumalbumin som et substrat og kommersielt tilgjengelig pepsin.
Aktiviteten er uttrykt som % inhibering i forhold til kontrollverdien (ingen inhibitor tilsatt) slik som vist i tabell 1. Også den 50%'ige inhiberende dose 1D5Q ble erholdt grar fisk.
( Farmakologiske data 2)
For å vise den anti-ulcerative aktivitet in vitro ble Shay's rotte (Gastro enterology 2_6, P906) valgt. Rottene fikk faste i 48 timer og pylorus ligation ble utført under lett be-døvelse. Midlet ble gitt peroralt. 16 timer etter ligation ble dyrene avlivet og maven fjernet. Indusert erosion ble målt i områder vurdert som ulcer indeks (U.I.). Dataene er uttrykt som % inhibering i forhold til kontrollverdien i henhold til den etterfølgende ligning
(Toksisitet)
Den akutte toksisitet for forbindelse 3 ble bestemt i henhold til Litchfield & Wilcoxon metode under anvendelse av SD rotter.
LD^q verdier for forbindelsen er vist nedenfor
LD50 VERDI (mg/kg)
Det bør understrekes at stabiliteten for forbindelsen 3 er vesentlig forbedret sammenlignet med den for natriumguaiazulen-sulfonat som nå anvendes klinisk.
Som følge av den manglende stabilitet har natriumguaiazulen-sulfonat begrenset farmasøytisk anvendelse, og den forbedrete stabilitet for forbindelsene i henhold til oppfinnelsen vil derfor være en ytterligere fordel ved denne forbindelse.
De følgende data viser stabiliteten for den nevnte forbindelse. De viste data er uttrykt som % gjenværende del av de opprinnelige forbindelser etter lagring i hver av de gitte betingelser.
For farmasøytiske formål kan forbindelsene i henhold til foreliggende oppfinnelse administreres til dyr eller mennesker peroralt, parenteralt eller rektalt som aktive bestanddeler i vanlige doseenhétsblandinger, dvs. blandinger i doseenhets-former bestående hovedsakelig av en inert farmasøytisk bærer og en effektiv doseenhet av den aktive bestanddel, i form av tabletter, granuler, kapsler, suspensjoner og lignende. En effektiv doseenhet av forbindelsene i henhold til foreliggende oppfinnelse er fira 2 mg til 60 mg, 3 ganger døgnet for en voksen person.
De følgende eksempler viser fremstilling av de nye forbindelser.
EKSEMPEL 1
Natrium l-metyl-azulen-3-sulfonat
Utgangsforbindelsen, 1-metyl azulen, kan fremstilles som vist nedenfor i henhold til Yasunami et al (Chemistry Letters, s. 579-582, 1980).
Trinn 1 l-metyl^-3-karboksymetylazulen (B)
En oppløsning av oksazulen (A) 6 g, propionaldehyd 5,22 g
og morfolin 7,84 g i 120 mg EtOH ble kokt under tilbakeløp i 4 timer. Blandingen ble avkjølt og det organiske oppløs-ningsmiddel fjernet under redusert trykk. Resten ble ekstrahert med benzen og det organiske sjikt vasket med vann og tørket.
Etter fjerning av benzen ble resten underkastet silikagelkolonnekromatografi under anvendelse av benzen som elueringsr middel til å gi 5,9 g av det faste produkt etter fjerning av oppløsningsmidlet. Utbytte: 5,9 g (98,5 %) Smp. 69-71°C. ir: 2950, 1690, 1450, 1440, 1421, 1202, 1027, 774, 746 (cm"<1>)
■'"H-NMR: (CDC13) 2,58 (3H, S, Me), 3,92 (3H, S, OMe ) ,
7,28 (1H, dd, J=9,6, 9,6, H-5) ,
7,37 (1H, dd, J=9,6, 9,6, H-7i,
7,67 (1H, dd, J=9,6, 9,6, H-6)
8,14 (1H, H-2),
8,24 (1H, dd, J=9,6, 1,4, H-4) ,
<<>3,49 (1H, dd, J=9,6, 1,4, H-8)
Trinn 2 1-metylazulen (C)
5,91 g av forbindelse B oppløses i 60 ml fosforsyre og blandingen oppvarmes (90-90°C) på et vannbad i 15 min.. Etter avkjøling ble blandingen helt i 300 ml isvann og ekstrahert med n-heksan. Det organiske lag ble separert, vasket med vann, tørket over vannfritt natriumsulfat og fraksjonert under anvendelse av silikagelkolonnekromatografi under anven-
deise av benzen som elueringsmiddel til å gi 3,72 g (90,1%) av den ønskede forbindelse.
ir: 3012, 2930, 1577, 1510, 1455, 1396, 947, 880 (cm"<1>)
■"-H-NMR: (CDC13) 2,58 (3H, S, Me)y 3,92 (3H, S, OMe),
7,28 (1H, dd, J=9,6, 9,6, H-5),
7,37 (1H, dd, J=9,6, 9,6, H-7),
7,67 (1H, dd, J=9,6, 9,6, H-6.) ,
8,14 (1H, S, H-2),
8,24 (1H, dd, 1=9,6, 1,4, H-4),
9,49 (1H, dd, J=9,6, 1,4, H-8).
Trinn 3 Natrium-3-metyl-azulensulfonat (forbindelse 1)
10 ml eddiksyreanhydrid ble tilsatt til 1,0 g 1-metyl-azulen under avkjøling i isvann, hvoretter 3,4 g svovelsyre
ble tilsatt dråpevis og reaksjonsblandingen ble omrørt i 4 timer ved 0°C. Deretter ble reaksjonsblandingen gjort alka-lisk til pH 8 - 9 ved tilsetning av 40%'ig natriumhydrok-sydoppløsning og det dannete faststoff ble oppsamlet og tørket. Produktet ble omkrystallisert fra 95%'ig etanol til å gi 1,1 g av den ønskete forbindelse. Smp. 35-38°C
ir: 1630, 1420, 1220, 750 (cm"<1>)
Forbindelsene 2-34 ble erholdt ved den samme sulfonerings-fremgangsmåte angitt i trinn 3 fra tilsvarende utsgangsma-terialer som er kjent fra litteraturen (M. Yasunami, Chem, lett, P, 579, 1980) .
EKSEMPEL 2
Natrium 3-etyl-azulensulfonat (forbindelse 2) Forbindelæ2 ble erholdt ved å anvende n-butylaldehyd i ste---det for propionaldehyd i trinn 1 i eksempel 1.
Smp. 28-30°
ir: 1630, 1425, 1400, 1220, 850 (cm"<1>)
EKSEMPEL 3
Natrium 3-etyl-7-isopropyl-azulensulfonat (forbindelse 3) Forbindelse 3 ble fremstilt ved å følge fremgangsmåten ifølge eksempel 1 ved.å anvende et 5-isopropyl-substituert derivat av oksazulen som utgangsmateriale i stedet for oksazulen (A) og n-butyraldehyd i stedet for propionaldehyd. Sulfo-neringen utføres ifølge fremgangsmåten i trinn 3 i eksempel 1. Smp. 85-88°C.
ir: 1650, 1640, 1565. 1418, 1180, 1050 (cm"<1>) 1H-NMR (DMS0) : 1,30 (3H, t, J=7,4, CHj ,
1,33 (6H, d, J=6,6, (CH3)2~),
3,00 (2H, q, J=7,4, CH2),
3,50 (1H, sept, J=6,6, -CH-(CH3)2), 4,10 (1H, bs, H20)
7,20 (1H, d, J=10, H-7),
7,90 (1H, s, H-2),
8,23 (1H, d, J=10, H-4),
9,17 (1H, s, H-8)
EKSEMPEL 4
Natrium 3-etyl-6-iso<p>rooyl-azulensulfonat (forbindelse 4) Smp: 55-58°C
ir: 1640, 1580, 1410, 1190, 1060 (cm<-1>)
<1>H-NMR (DMSO): 1,27 (3H, t, J=7,4, CH3),
1,30 (6H, d, J=6,6, (CH3)2~),
2,96 (1H, sept, J=6,6, isopropyl),
3,02 (2H, q, J=7,4, CH2),
7,17 (2H, d, J=10, H-5,7),
7,70 (1H, s. H-2)
8,20 (1H, d. J=10, H-8),
8,90 (1H, d, J=10, H-4)
EKSEMPEL 5
Natrium 3-(l'-R, S-l1-5 1-dimetyl-4-heksen)-azulensulfonat
(forbindelse 5)
Forbindelse 5 fremstilles ifølge eksempel 1 under anvendelse av d,1-citronellali stedet for propionaldehyd i henhold til eksempel 1. Smp. 78-81°C.
ir: 1630, 1560, 1420, 1400, 1190, 1120, 1050, 750 (cm"<1>)
EKSEMPEL 6
Natrium 3-n-butyl-azulensulfonat (forbindelse 6)
Smp. 83-85°C
ir: 1630, 1420, 1400, 1220, 750 (cm"<1>)
EKSEMPEL 7
Natrium 3-metyl-2-etyl-azulensulfonat (forbindelse 7) Forbindelse 7 fremstilles i henhold til eksempel 1, under anvendelse av 3- (1-pirrolidinyl)-2-penten i stedet for propionaldehyd og morfolin i trinn 1 i eksempel 1.
Smp. 280-2 83°C
ir: 1640, 1560, 1420, 1190, 1040, 740 (cm<-1>)
EKSEMPEL 8
Natrium 3-(1<1->S-l',5'-dimetyl-4'-heksen)-azulensulfonat
(forbindelse 8)
Forbindelse 8 fremstilles i henhold til eksempel
1 under anvendelse av d-citronellal i stedet for propionaldehyd i trinn 1 i eksempel 1. Smp. 78 - 81°C
ir: 1630, 1560, 1420, 1400, 1190, 1120, 1050, 750 (cm"<1>)
EKSEMPEL ; 9
Natrium 3-(1'-R-l',5'-dimetyl-4'-heksen)azulensulfonat
(forbindelse 9)
Forbindelse 9 fremstilles i henhold til eksempel 1 under anvendelse av 1-citronellal i stedet for propionaldehyd i trinn 1 i eksempel 1. Smp. 78-81°C.
ir: 1630, 1560, 1420, 1400, 1190, 1120, 1050, 750 (cm<-1>)
EKSEMPEL 10
Natrium 3- (1'-S-l',5'-dimetyl-4'-heksen)-7-isopropyl-azulensulfonat (forbindelse 10). Smp. 108-110°C
ir: 1630, 1560, 1420, 1220, 1050 (cm"<1>)
EKSEMPEL 11
Natrium 3-(1'-R-l',5'-dimetyl-4'-heksen)-7-isopropyl-azulensulfonat (forbindelse 11) Smp. 108-110°C
ir: 1630, 1560, 1420, 1220, 1050 (cm"<1>)
EKSEMPEL 12
Natrium 3-propylazulensulfonat (forbindelse 12)
Smp. 210-215°C (spaltning)
("Spaltning" står for spaltningspunkt i det følgende)
ir: 3400, 2940, 2850, 1580, 1420, 1400, 1200, 1090, 1020, 960, 880, 750, 740, 670 (cm"<1>).
EKSEMPEL 13
Natrium 3-metyl-7-isopropylazulensulfonat (forbindelse 13) Smp. 91-9 3°C
ir: 3450, 2950, 1640, 1250, 1070, 1010, 790 (cm"<1>)
EKSEMPEL 14
Natrium 3-n-butylazulensulfonat (forbindelse 14)
Smp.: 215-220°C (spaltningspunkt)
ir: 3450, 2900, 1570, 1390, 1190 (cm<-1>)
EKSEMPEL 15
Natrium 3-n-pentylazulensulfonat (forbindelse 15)
Smp.: 217-220°C (spaltning)
ir: 3450, 2900, 1570, 1390, 1190 (cm"<1>)
EKSEMPEL 16
Natrium, 5-isopropylazulensulfonat (forbindelse 16)
Smp.: 241-248°C
ir: 3450, 2950, 1640, 1200, 1050 (cm<-1>)
EKSEMPEL 17
Natrium 7-isopropyl-3-n-propylaz ulensulfonat (forbindelse 17) Smp.: 138-143°C
ir: 3450, 2950, 1630, 1575, 1470, 1415, 1390, 1220, 1050, 9 30 (cm<-1>)
EKSEMPEL 18
Natrium 7-isopropyl-3-n-butyl-azulensulfonat (forbindelse 18) SnP.: 150-152°C
ir: 3450, 2950, 1640, 1575, 1465 (cm"<1>)
eksempel; 19
Natrium 7-isopropyl-3-n-pentylazulensulfonat (forbindelse 1 ) Smp.: 16 8-170°C.
ir: 3400, 2950, 2930, 2860, 1620, 1580, 1470, 1440, 1390,
1190, 1060 (cm"<1>)
EKSEMPEL 20
Natrium 7-isopropyl-3-(1'-R.S-1<1>,5'-dimetyl-4<1->heksen)-azulensulfonat (forbindelse 20)
Smp.: 113-116°C
ir: 3450, 2950, 1640, 1380, 1240, 1180 (cm<-1>)
EKSEMPEL 21
Natrium 7-isopropyl-3-(1'-R-l1, 5 '-dimetyl-4'-heksen) azulensulfonat (forbindelse 21) Smp.: 114 - 117°C
ir: 3450, 2950, 1640, 1380, 1240, 1180 (cm<-1>)
EKSEMPEL' 22
Natrium 7-isopropyl-3-(1'-S-l',5'-dimetyl-4'-heksen)azulensulfonat (forbindelse 22); Smp. 115-118°C
ir: 3450, 2950, 1640, 1380, 1240, 1180 (cm"<1>)
EKSEMPEL 2 3
Natrium 7-isopropyl-3-benzylazulensulfonat (forbindelse 23) Smp.: 250°C (spaltning)
ir: 3450, 2950, 1640, 1560, 1530, 1460, 1420 (cm"<1>)
EKSEMPEL ' 24
Natrium 4-metoksy-3-metyl-azulensulfonat (forbindelse 24) Smp.: 186-188°C (spaltning)
ir: 340,, 1600, 1570, 1540, 1460, 1370, 1270 (cm"<1>)
EKSEMPEL ' 25
Natrium 4-metoksy-3-etylazulensulfonat (forbindelse 25)
Smp. 60°C
ir: 3400, 2950, 1600, 1570, 1540, 1450, 1370, 1270 (cm"<1>)
EKSEMPEL 26
Natrium 4-metoksy-3-propylazulensulfonat (forbindelse 26)
Smp.: 108-110°C
ir: 3450, 2910, 2850, 1600, 1570, 1530 (cm"<1>)
EKSEMPEL 27
Natrium 4-metoksy-3-butylazulensulfonat (forbindelse 27) Smp.: 188-190°C (spaltning)
ir: 3450, 2950, 1600, 1570, 1530, 1460 (cm"<1>)
EKSEMPEL 28
Natrium 4-metoksy-3-pentylazulensulfonat (forbindelse 28) Smp.: 189-192°C (spaltning)
ir: 3450, 2950, 1600, 1560, 1530, 1450 (cm"<1>)
EKSEMPEL 29
Natrium 4-metoksy-3-heksylazulensulfonat (forbindelse 29) Smp.: 225-228°C (spaltning)
ir: 3450, 2900, 1650, 1560, 1520, 1460 (cm"<1>)
EKSEMPEL 30
Natrium 7-isopropyl-4-metoksy-3-metylazulensulfonat (forbindelse 30); smp. 95-97°C
ir: 3450, 2950, 1650, 1540, 1280, 1180 (cm"<1>)
EKSEMPEL 31
Natrium 7-isopropyl-4-metoksy-3-etylazulensulfonat (forbindelse 31); smp. 108-110°C
ir: 3450, 2950, 1650, 1540, 1260, 1180 (cm"<1>)
EKSEMPEL 32
Natrium 7-isopropyl-4-metoksy-3-propylazulensulfonat (forbindelse 32); smp. 188-190°C
ir: 3450, 2950, 1640, 1560, 1530 (cm"<1>)
EKSEMPEL 33
Natrium 7-isopropyl-4-metoksy-3-butylazulensulfonat (forbindelse 33); smp. 166-168°C
ir: 3450, 2950, 1640, 1560, 1530, 1470 (cm<-1>)
EKSEMPEL 34
Natrium 7-isopropyl-4-metoksy-3-pentylazulensulfonat (forbindelse 34); smp. 123-125°C
ir: 3450, 2950, 1650, 1520, 1260, 1010 (cm"<1>).
EKSEMPEL 35
3-metylazulensulfonsyrealuminiumsalt (forbindelse 35)
5 g natrium 3-metylazulensulfonat oppløses i vann, og til denne oppløsning ble tilsatt 2,73 g AlCl-, i 40 ml vann etter filtrering av resten og ble omrørt i 30 minutter ved rom temperatur . Reaksjonsblandingen justeres til pH 4 - 4,5 ved å tilsette 10%<1>ig NaOH. De dannete presipitater ble oppsamlet og filtrert og vasket med vann og tørket. Smp.: over 250°C.
ir: 3400, 1630, 1580, 1395, 1140, 1040, 740 (cm"<1>)
Al innhold: 13.9 6 %
De følgende forbindelser (forbindelse 36-38) fremstilles på samme måte som i eksempel 35, fra de tilsvarende natriumsul-fonatderivater.
EKSEMPEL 36
3-etylazulensulfonsyrealuminiumsalt (forbindelse 36) Smp.: over 250°C
ir: 3400, 2950, 1580, 1400, 1150, 1050, 750 (cm<-1>) Al-innhold: 13,00 %.
EKSEMPEL 37
7-isopropyl-3-metylazulensulfonsyrealuminiumsalt (forbindelse 37). Smp.: over 250°C
ir: 3400, 2950, 1420, 1150, 1040 (cm"<1>)
Al-innhold: 9,46 %
EKSEMPEL 38
7-isopropyl-3-etylazulensulfonsyrealuminiumsalt (forbindelse 38). Smp.: over 250°C
ir: 3400, 2950, 1580, 1420, 1390, 1150 (cm<-1>)
Al-innhold: 10,58 %.
Claims (1)
1. Analogifremgangsmåte ved fremstilling av en terapeutisk aktiv forbindelse med formel
hvori R<1> er H, lavere alkyl,
eller benzyl (R<5>, R<b>, R' hver betyr H eller lavere alkyl, og n er 1 eller 2), R<2> og R<3> hver betyr H eller lavere alkyl, R<4> er en alkoksygruppe eller H og X er Na eller A1(0H)2,
karakterisert ved å omsette forbindelsene med formelen:
hvori R<1>, R<2>, R<3> og R<4> har den tidligere angitte betydning, med et sulfoneringsmiddel og omdanne den resulterende sulfonsyre til det tilsvarende natrium- eller aluminiumsalt.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP15318783A JPS6048960A (ja) | 1983-08-24 | 1983-08-24 | アズレン誘導体及びその製法並びにこの化合物を有効成分とする抗潰瘍剤 |
| JP1402884A JPS60158160A (ja) | 1984-01-28 | 1984-01-28 | アズレン誘導体スルホン酸塩、抗潰瘍、抗炎症剤及びその製法 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO843377L NO843377L (no) | 1985-02-25 |
| NO158673B true NO158673B (no) | 1988-07-11 |
| NO158673C NO158673C (no) | 1988-10-19 |
Family
ID=26349908
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO843377A NO158673C (no) | 1983-08-24 | 1984-08-23 | Analogifremgangsmaate ved fremstilling av terapeutisk aktive azurenderivater. |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US4595694A (no) |
| EP (1) | EP0147915B1 (no) |
| KR (1) | KR920000956B1 (no) |
| AR (1) | AR240554A1 (no) |
| AU (1) | AU571554B2 (no) |
| CA (1) | CA1228862A (no) |
| DE (1) | DE3463502D1 (no) |
| DK (1) | DK169870B1 (no) |
| ES (1) | ES535381A0 (no) |
| HU (1) | HU195478B (no) |
| NO (1) | NO158673C (no) |
| PT (1) | PT79119B (no) |
| SU (1) | SU1311618A3 (no) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5081152A (en) * | 1989-07-05 | 1992-01-14 | Kotobuki Seiyaku Co., Ltd. | Azulene derivatives as thromboxane a2 and prostaglandin endoperoxide receptor antagonist |
| EP0887077A1 (de) * | 1997-06-27 | 1998-12-30 | Roche Diagnostics GmbH | Verwendung von Azulenderivaten als Metalloproteaseinhibitoren |
| US6420435B1 (en) | 1999-11-01 | 2002-07-16 | Joe S. Wilkins, Jr. | Method for treating gastrointestinal disorders |
| ATE445838T1 (de) | 2001-07-25 | 2009-10-15 | Raptor Pharmaceutical Inc | Zusammensetzungen und verfahren zur modulation des transports durch die blut-hirn-schranke |
| US7041706B2 (en) * | 2002-04-19 | 2006-05-09 | Wilkins Jr Joe S | Method for treating crohn's disease |
| EP2671508B1 (en) | 2005-04-28 | 2020-09-16 | Proteus Digital Health, Inc. | Pharma-informatics system |
| CA2663377A1 (en) | 2006-09-18 | 2008-03-27 | Raptor Pharmaceutical Inc. | Treatment of liver disorders by administration of receptor-associated protein (rap)-conjugates |
| HUE059078T2 (hu) | 2009-02-20 | 2022-10-28 | Enhanx Biopharm Inc | Glutation-alapú hatóanyagszállító rendszer |
| JP2012526144A (ja) | 2009-05-06 | 2012-10-25 | ラボラトリー スキン ケア インコーポレイテッド | 活性物質−リン酸カルシウム粒子複合体を含む経皮送達組成物およびその使用方法 |
| US20120077778A1 (en) | 2010-09-29 | 2012-03-29 | Andrea Bourdelais | Ladder-Frame Polyether Conjugates |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1227896B (de) * | 1965-12-02 | 1966-11-03 | Degussa | Verfahren zur Herstellung wasserloeslicher stabiler Salze von Azulensulfonsaeureamiden |
| US3816612A (en) * | 1967-03-23 | 1974-06-11 | Degussa | Process for the production of basically reacting pharmaceuticals |
| US3974299A (en) * | 1974-07-08 | 1976-08-10 | Dynapol | Ionic sweetener |
| US4224240A (en) * | 1979-04-13 | 1980-09-23 | Scm Corporation | Preparation of para-menth-1-ene-7-sulfonate salts and corresponding acids |
| US4283347A (en) * | 1979-04-13 | 1981-08-11 | Scm Corporation | Para-menth-1-ene-7-sulfonic acid and salts thereof |
-
1984
- 1984-08-01 AU AU31396/84A patent/AU571554B2/en not_active Expired
- 1984-08-03 DK DK377984A patent/DK169870B1/da not_active IP Right Cessation
- 1984-08-15 CA CA000461108A patent/CA1228862A/en not_active Expired
- 1984-08-17 US US06/642,043 patent/US4595694A/en not_active Expired - Lifetime
- 1984-08-23 KR KR1019840005107A patent/KR920000956B1/ko not_active IP Right Cessation
- 1984-08-23 PT PT79119A patent/PT79119B/pt unknown
- 1984-08-23 HU HU843172A patent/HU195478B/hu not_active IP Right Cessation
- 1984-08-23 NO NO843377A patent/NO158673C/no unknown
- 1984-08-23 ES ES535381A patent/ES535381A0/es active Granted
- 1984-08-23 EP EP84305775A patent/EP0147915B1/en not_active Expired
- 1984-08-23 AR AR29767884A patent/AR240554A1/es active
- 1984-08-23 SU SU3785251A patent/SU1311618A3/ru active
- 1984-08-23 DE DE8484305775T patent/DE3463502D1/de not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| AR240554A1 (es) | 1990-05-31 |
| DK169870B1 (da) | 1995-03-20 |
| EP0147915A1 (en) | 1985-07-10 |
| KR920000956B1 (ko) | 1992-01-31 |
| ES8506607A1 (es) | 1985-07-16 |
| DK377984A (da) | 1985-02-25 |
| EP0147915B1 (en) | 1987-05-06 |
| AU3139684A (en) | 1985-02-28 |
| DK377984D0 (da) | 1984-08-03 |
| CA1228862A (en) | 1987-11-03 |
| NO158673C (no) | 1988-10-19 |
| KR850001731A (ko) | 1985-04-01 |
| NO843377L (no) | 1985-02-25 |
| HUT37393A (en) | 1985-12-28 |
| DE3463502D1 (en) | 1987-06-11 |
| PT79119A (en) | 1984-09-01 |
| ES535381A0 (es) | 1985-07-16 |
| AU571554B2 (en) | 1988-04-21 |
| PT79119B (en) | 1986-07-17 |
| HU195478B (en) | 1988-05-30 |
| SU1311618A3 (ru) | 1987-05-15 |
| US4595694A (en) | 1986-06-17 |
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