DK169870B1 - Azulenderivater, fremgangsmåde til deres syntese og anti-ulcerative og anti-inflammatoriske midler omfattende disse derivater - Google Patents
Azulenderivater, fremgangsmåde til deres syntese og anti-ulcerative og anti-inflammatoriske midler omfattende disse derivater Download PDFInfo
- Publication number
- DK169870B1 DK169870B1 DK377984A DK377984A DK169870B1 DK 169870 B1 DK169870 B1 DK 169870B1 DK 377984 A DK377984 A DK 377984A DK 377984 A DK377984 A DK 377984A DK 169870 B1 DK169870 B1 DK 169870B1
- Authority
- DK
- Denmark
- Prior art keywords
- sodium
- compound
- azulene
- isopropyl
- lower alkyl
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 12
- 150000001545 azulenes Chemical class 0.000 title description 4
- 230000000767 anti-ulcer Effects 0.000 title description 3
- 229940121363 anti-inflammatory agent Drugs 0.000 title description 2
- 239000002260 anti-inflammatory agent Substances 0.000 title description 2
- 230000015572 biosynthetic process Effects 0.000 title 1
- 238000003786 synthesis reaction Methods 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 61
- 239000011734 sodium Substances 0.000 claims description 32
- 229910052708 sodium Inorganic materials 0.000 claims description 29
- 125000000217 alkyl group Chemical group 0.000 claims description 22
- 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 15
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 claims description 12
- 239000004480 active ingredient Substances 0.000 claims description 9
- KXGWXVVNYQOMQZ-UHFFFAOYSA-M egualen sodium Chemical group [Na+].C1=C(C(C)C)C=CC=C2C(CC)=CC(S([O-])(=O)=O)=C21 KXGWXVVNYQOMQZ-UHFFFAOYSA-M 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid group Chemical group S(O)(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 229940124597 therapeutic agent Drugs 0.000 claims description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 229910052782 aluminium Inorganic materials 0.000 claims description 3
- 206010061218 Inflammation Diseases 0.000 claims description 2
- 208000008469 Peptic Ulcer Diseases 0.000 claims description 2
- 125000003828 azulenyl group Chemical group 0.000 claims description 2
- NARQSHREEUXZBT-UHFFFAOYSA-N egualen Chemical group C1=C(C(C)C)C=CC=C2C(CC)=CC(S(O)(=O)=O)=C21 NARQSHREEUXZBT-UHFFFAOYSA-N 0.000 claims description 2
- 230000004054 inflammatory process Effects 0.000 claims description 2
- 208000011906 peptic ulcer disease Diseases 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- AKEJUJNQAAGONA-UHFFFAOYSA-N sulfur trioxide Inorganic materials O=S(=O)=O AKEJUJNQAAGONA-UHFFFAOYSA-N 0.000 claims description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims 1
- HPJYKMSFRBJOSW-JHSUYXJUSA-N Damsin Chemical compound C[C@H]1CC[C@H]2C(=C)C(=O)O[C@H]2[C@]2(C)C(=O)CC[C@@H]12 HPJYKMSFRBJOSW-JHSUYXJUSA-N 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 238000002844 melting Methods 0.000 description 39
- 230000008018 melting Effects 0.000 description 39
- 229950002760 sodium gualenate Drugs 0.000 description 31
- 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
- 239000004615 ingredient Substances 0.000 description 10
- 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 10
- 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 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 235000013339 cereals Nutrition 0.000 description 9
- 239000008101 lactose Substances 0.000 description 9
- 229920000609 methyl cellulose Polymers 0.000 description 9
- 239000001923 methylcellulose Substances 0.000 description 9
- 235000010981 methylcellulose Nutrition 0.000 description 9
- 238000000354 decomposition reaction Methods 0.000 description 8
- -1 -isopropyl azulene sulfonate Chemical compound 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 229940126214 compound 3 Drugs 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 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
- 238000002360 preparation method Methods 0.000 description 4
- 238000006277 sulfonation reaction Methods 0.000 description 4
- LIKMAJRDDDTEIG-UHFFFAOYSA-N 1-hexene Chemical compound CCCCC=C LIKMAJRDDDTEIG-UHFFFAOYSA-N 0.000 description 3
- IMWBJQYMBZPPPN-UHFFFAOYSA-N C(C)C=1C=CC2=CC(=CC=CC12)C(C)C.[Na] Chemical compound C(C)C=1C=CC2=CC(=CC=CC12)C(C)C.[Na] IMWBJQYMBZPPPN-UHFFFAOYSA-N 0.000 description 3
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 3
- 229930182816 L-glutamine Natural products 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 208000025865 Ulcer Diseases 0.000 description 3
- 150000001299 aldehydes Chemical class 0.000 description 3
- 230000002467 anti-pepsin effect Effects 0.000 description 3
- NEHNMFOYXAPHSD-UHFFFAOYSA-N citronellal Chemical compound O=CCC(C)CCC=C(C)C NEHNMFOYXAPHSD-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- GDVKFRBCXAPAQJ-UHFFFAOYSA-A dialuminum;hexamagnesium;carbonate;hexadecahydroxide Chemical compound [OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Al+3].[Al+3].[O-]C([O-])=O GDVKFRBCXAPAQJ-UHFFFAOYSA-A 0.000 description 3
- 229960001545 hydrotalcite Drugs 0.000 description 3
- 229910001701 hydrotalcite Inorganic materials 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 2
- WSQIUQGZWDQMEL-UHFFFAOYSA-N 1-methylazulene Chemical compound C1=CC=CC=C2C(C)=CC=C21 WSQIUQGZWDQMEL-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 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 2
- 241001465754 Metazoa Species 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 150000002081 enamines Chemical class 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000008177 pharmaceutical agent Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 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 2
- 239000007787 solid Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 230000001225 therapeutic effect Effects 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
- 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
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- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
- QIVUCLWGARAQIO-OLIXTKCUSA-N (3s)-n-[(3s,5s,6r)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl]-2-oxospiro[1h-pyrrolo[2,3-b]pyridine-3,6'-5,7-dihydrocyclopenta[b]pyridine]-3'-carboxamide Chemical compound C1([C@H]2[C@H](N(C(=O)[C@@H](NC(=O)C=3C=C4C[C@]5(CC4=NC=3)C3=CC=CN=C3NC5=O)C2)CC(F)(F)F)C)=C(F)C=CC(F)=C1F QIVUCLWGARAQIO-OLIXTKCUSA-N 0.000 description 1
- ZYZCALPXKGUGJI-DDVDASKDSA-M (e,3r,5s)-7-[3-(4-fluorophenyl)-2-phenyl-5-propan-2-ylimidazol-4-yl]-3,5-dihydroxyhept-6-enoate Chemical compound C=1C=C(F)C=CC=1N1C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)=C(C(C)C)N=C1C1=CC=CC=C1 ZYZCALPXKGUGJI-DDVDASKDSA-M 0.000 description 1
- 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
- CBRJPFGIXUFMTM-WDEREUQCSA-N 1-[(2S,5R)-2-methyl-5-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl]prop-2-en-1-one Chemical compound N1=CN=C(C2=C1NC=C2)N[C@@H]2CC[C@@H](N(C2)C(C=C)=O)C CBRJPFGIXUFMTM-WDEREUQCSA-N 0.000 description 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- 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
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- NOJXKOFSGZLELR-UHFFFAOYSA-N 1-methoxybutan-2-yl azulene-1-sulfonate;sodium Chemical compound [Na].C1=CC=CC=C2C(S(=O)(=O)OC(COC)CC)=CC=C21 NOJXKOFSGZLELR-UHFFFAOYSA-N 0.000 description 1
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- 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
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- 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 1
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- 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
- 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 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
- 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 1
- 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 1
- 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 1
- 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 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
- 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 1
- 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 1
- 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 1
- 230000000707 stereoselective effect Effects 0.000 description 1
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- 125000001424 substituent group Chemical group 0.000 description 1
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- 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
- KMIOJWCYOHBUJS-HAKPAVFJSA-N vorolanib Chemical compound C1N(C(=O)N(C)C)CC[C@@H]1NC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C KMIOJWCYOHBUJS-HAKPAVFJSA-N 0.000 description 1
Classifications
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- 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)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
DK 169870 B1
Den foreliggende opfindelse angår hidtil ukendte azulenderivater, en fremgangsmåde til at syntetisere dem samt terapeutiske midler omfattende disse.
5 Azulenderivater har været velkendt som havende en virkning mod mavesår, en antigastrisk virkning og en anti-inflammationsvirkning. På grund af deres manglende stabilitet over for lys og varme har man dog længe ønsket et forbedret stabilt og kraftigt deri vat.
10
Hovedformålet med den foreliggende opfindelse er at angive hidtil ukendte forbindelser, der har fordelagtige farmaceutiske egenskaber.
15 Formålet med den foreliggende opfindelse er også at tilvejebringe et farmaceutisk middel, der er nyttigt som antipeptisk, ulcerativt middel.
Formålet med opfindelsen er desuden tilvejebringelse af et 20 farmaceutisk middel, der er nyttigt som anti-inflammatorisk middel.
Formålet med opfindelsen er yderligere at anvise en fremgangsmåde til fremstilling af de hidtil ukendte azulenderivater.
25
Disse og andre formål med opfindelsen vil fremgå af følgende beskrivelse.
Forbindelserne ifølge opfindelsen er ejendommelige ved, at de 30 har den almene formel I
35 R4 R1 H R6 2 DK 169870 B1 hvor R1 er H, lavere alkyl, -1-(CH2)n-CH=C. eller benzyl, * R5 R7 5 hvor R5, R6 og R7 hver er H eller lavere alkyl, R2 og R3 er H eller lavere alkyl, R* er H eller en alkyloxygruppe, og X er Na eller Al(0H)2·
Visse af forbindelserne med den almene formel I har en kraftig 10 antigastrisk ulcerativ og ant i - i nf 1 animator i sk virkning, hvorfor de betragtes som værende terapeutisk nyttige. Til disse formål har man hidtil anvendt natrium-guaiazu1en-3-su1fonat. Forbindelserne ifølge opfindelsen er kemisk mere stabile end førnævnte forbindelse, 15 1 2 3 4 5
Den lavere alkylgruppe, der er vist som R , R , R , R , R , 6 7 R og R i den almene formel I, betyder en ligekædet alkylgruppe eller en forgrenet alkylgruppe, der har 1-6 carbon- atomer. Disse forbindelser er ønskelige, når stillingen af 20 3 4 substituenterne R og R er i 4-, 6- eller 7-stillingen på den 7-leddede ring med den almene formel I.
De følgende forbindelser har særlig interesse: 25 1) Natrium-3-methyl-azulensulfonat.
2) Natrium-3-ethyl-azulensulfonat.
3) Natrium-3-ethyl-7-isopropyl-azulensulfonat.
4) Natrium-3-ethyl-6-isopropyl-azulensulfonat.
5) Natrium-3-(1'-R,S-1',5'-dimethyl-4'-hexen)azulensulfonat.
30 6) Natrium-3-n-butyl-azulensulfonat.
7) Natrium-3-methyl-2-ethyl-azulensulfonat.
8) Natrium-3-(l'-S-l',5'-dimethyl-4'-hexen)azulensulfonat.
9) Natrium-3-(1'-R-l',5'-dimethyl-41-hexen)azulensulfonat.
10) Natrium-3-(l'-S-l',5'-dimethyl-4'-hexen)-7-isopropyl-3 5 azulensulfonat.
11) Natrium-3-(1'-R-l1,5'-dimethyl-4'-hexen)-7-isopropyl-azulensulfonat.
3 DK 169870 B1 12) Natrium-3-propyl-azulensulfonat.
13) Natrium-3-methyl-7-isopropyl-azulensulfonat.
14) Natrium-3-n-butyl-azulensulfonat.
15) Natrium-3-n-pentyl-azulensulfonat.
5 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-11,5'-dimethyl-4'-hexen)- 10 azulensulfonat.
21) Natrium-7-isopropyl-3-(1'-R-l',5'-dimethyl-4'-hexen)-azulensulfonat.
22) Natrium-7-isopropyl-3-(1'-S-l',5'-dimethyl-4'-hexen)- azulensulfonat.
15 23) Natrium-7-isopropyl-3-benzyl-azulensulfonat.
24) Natrium-4-methoxy-3-methyl-azulensulfonat.
25) Natrium-4-methoxy-3-ethyl-azulensulfonat.
26) Natrium-4-methoxy-3-propyl-azulensulfonat.
27) Natrium-4-methoxy-3-butyl-azulensulfonat.
20 28) Natrium-4-methoxy-3-pentyl-azulensulfonat.
29) Natrium-4-methoxy-3-hexyl-azulensulfonat.
30) Natrium-7-isopropy1-4-methoxy-3-methyl-azulensulfonat.
31) Natrium-7-isopropyl-4-methoxy-3-ethyl-azulensulfonat.
32) Natrium-7-isopropyl-4-methoxy-3-propyl-azulensulfonat.
25 33) Natrium~7-isopropyl-4-methoxy-3-butyl-azulensulfonat.
34) Natrium-7-isopropyl-4-methoxy-3-pentyl-azulensulfonat.
35) 3-methyl-azulensulfonsyre, aluminiumsalt.
36) 3-ethyl-azulensulfonsyre, aluminiumsalt.
37) 7-isopropyl-3-methyl-azulensulfonsyre, aluminiumsalt.
50 38) 7-isopropyl-3-ethyl-azulensulfonsyre, aluminiumsalt.
De ovennævnte forbindelser, der er nummereret fra 1 til 38, vil i det følgende blive omtalt ved deres numre.
35 Fremgangsmåden ifølge opfindelsen til fremstilling af de hid til ukendte azu1 ender i vater med den almene formel I er ejendommelig ved det i den kendetegnende del af krav 11 anførte.
4 DK 169870 B1
De præ-sulfonerede forbindelser vist med formlen II fremstilles på flere måder som vist nedenfor.
13 i) Forbindelserne, hvori R og R er H eller lavere alkyl, 2 5 og R er H, fås på den måde, der er beskrevet af L.T.Scott (J.Am.Chem.Soc. 102, 6311 p.,1980) eller af M.Yasunami (Chemistry Letters, 579 p., 1980), som er en af opfinderne af den foreliggende opfindelse.
z*6 10 ii) Hvis R^ er -CH-(CH„) -CH=C eller benzyl, fås den på- • 5 Δ n \ 7 R R7 gældende forbindelse ved reaktion af 2H-cyklohepta(b)furan- 2-on med en enamin, der er fremkommet af de tilsvarende aldehyder,med formlen R^-CH^HO ifølge M.Yasunami (Chem.
15 Lett., 579 p., 1980) .
1 2 iii) For at få forbindelser, hvori både R og R er lavere alkyler, anvendes samme fremgangsmåde som i (ii) ved at 1 2 anvende en enamin,fremkommet af en keton (R -CH0-C-R ),
* II
20 O
i stedet for et aldehyd (R^-Oi^CHO) i reaktion (ii) .
Selv om udgangsaldehydet indeholder en stereospecifik isomer, f.eks. hvis R^ er d- eller 1-citronellal og d-eller 1-limonen, viser det fremkomne produkt sig at holde 25 sin stereospecificitet.
iv) De andre forbindelser fremstilles også ifølge M.Yasunami (Chem.Lett., 579 p, 1980), 30 Forbindelserne, der er fremstillet som ovenfor, renses ved destillation under reduceret tryk eller søjlekromatografi og underkastes så sulfonering. Sulfonering udføres i almindelighed i eddikesyreanhydrid ved at tilsætte svovlsyre under afkøling, og i andre tilfælde kan også komplekset af svovlsyre-35 anhydrid ogpyridin anvendes. Den fremkomne sulfonerede forbindelse omdannes til sit natriumsalt med en natriumhydroxid-opløsning eller natriumethylat og omkrystalliseres så af alkoholer .
5 DK 169870 B1
For at få aluminiumsalte omdannes natriumsulfonater med en aluminiumsaltopløsning, f.eks. en vandig opløsning af Al(OH)^, AlCl^ eller aluminiumpropoxid.
De således fremstillede forbindelser ifølge opfindelsen har 5 forbedret stabilitet over for lys og varme, og nogle af disse forbindelser har udmærket anti-peptisk og anti-gastrisk ulcer-virkning og er lovende til terapeutisk anvendelse. De følgende eksempler viser biologisk virkning sammenlignet med natrium-guaiazulen-3-sulfonat (GAS) som standardlægemiddel, fremstillo ling af typiske midler ifølge opfindelsen samt fremgangsmåder til at syntetisere dem.
Opfindelsen angår desuden et terapeutisk middel omfattende en farmaceutisk anvendelig bærer og som aktiv bestanddel en forbindelse ifølge krav 1, hvori R1 er H; lavere alkyl, som re-15 præsenterer C-pC^ lavere alkyl i det tilfælde, hvor R3 er en 7-alkylgruppe; H R6 I / -C-(CH2) -ch=c 20 I \ R5 R7 (hvor R5, R6, R7 hver repræsenterer H eller lavere alkyl, og n er 1 eller 2), som ikke omfatter en S-konfigurationsgruppe til azulenring i det tilfælde, hvor R3 er en 7-alkylgruppe; eller 2 5 benzyl; R2 og R3 hver repræsenterer H eller lavere alkyl; R4 er H eller en alkoxygruppe; og X er Na eller AMOH^; i en mængde, der er effektiv til at behandle peptisk ulcer.
30 Opfindelsen angår endvidere et terapeutisk middel omfattende · en farmaceutisk anvendelig bærer og som aktiv bestanddel en forbindelse ifølge krav 1 i en mængde, der er effektiv til at behandle inflammation.
e
Farmakologiske data - 1.
DK 169870 B1
Anti-peptisk virkning af forbindelserne afprøves in vitro iføl- * ge V.K.Thiemer (Arznei-Forsch 22 (6), side 1086, 1972) under anvendelse af okseserumalbumin som substrat og industrielt tilgængeligt pepsin.
5
Aktiviteten udtrykkes som % hæmning i forhold til kontrolværdien (ingen inhibitor tilsat) som vist i tabel 1. ID5q (50% hæmmende dosis) fås grafisk.
TABEL 1.
10 ________ % hæmning
Prøve Forbindelse Forbindelse Forbindelse
345 GAS
15 Koncentration (mg/ml) 0,125 17,304 17,305 0,260 14,578 0,250 47,596 28,864 3,570 50,357 0,500 63,570 65,747 24,480 58,604 20 1,000 97,142 55,844 50,356 75,130 ID50(mg/ml) 0,297 0,510 1,207 0,358 ID5Q: 50% hæmningsdosis.
25
Farmakologiske data - 2.
For at bestemme den anti-ulcerative virkning in vitro benyttes Shay's rotte (Gastro Enterology 26, side 906). Rotter fastes 3Q i 48 timer, og underbinding af pylorus udføres under svag anæstesi. Lægemiddel gives oralt. 16 timer efter underbindingen dræbes dyrene, og maven udtages. Den inducerede erosion måles i areal og bedømmes som ulcer-indeks (U.I.). Dataene udtrykkes som % hæmning i forhold til kontrolværdien ud fra ne- * denstående ligning: kontrolværdi - prøveværdi % hæmning ---x 100.
kontrolværdi 7 DK 169870 B1
Prøveforbindelse Dosis nr. (mg/kg) % hæmning 1 500 52,4 2 500 100 3 500 100 4 500 100 5 500 95,5 8 500 69,9 12 100 78,5 13 100 69,7 14 100 32,7 15 100 64,3 16 100 62,0 17 100 31,2 18 100 17,2 19 100 -56,3 20 100 43,8 21 100 14,5 22 100 -19,5 23 100 9,8 24 100 63,4 25 100 75,6 26 100 75,6 27 100 66,3 28 100 42,0 29 100 38,0 30 100 58,7 31 100 67,6 32 100 44,1 33 100 64,8 34 100 -14,6 35 100 16,5 36 100 28,6 37 100 58,4 38 100 40,3 8 DK 169870 B1
Toksicitet.
Den akutte toksicitet af forbindelse 3 bestemmes ved Litchfield & Wilcoxon's metode under anvendelse af SD-rotter.
5 LDsQ-vasrdierne af forbindelsen er vist nedenfor.
LD^q-værdi (mg/kg).
10 Administrations- vej ί ? P.o. 1000(833,3-1200) 1200(983,6-146,4) I.P. 165(136,4-199,8) 180(153,8-210,6) 15 I.V. 130 153(111,7-209,6) 95% konfidensgrænse.
Det skal understreges, at stabiliteten af forbindelse 3 er 2Q meget forbedret sammenlignet med stabiliteten af natriumguaia- zulensulfonat, der har været anvendt klinisk tidligere.
Fordi den manglende stabilitet af natriumguaiazulensulfonat har begrænset dets farmaceutiske anvendelighed, er den forbed-25 rede stabilitet af forbindelserne ifølge den foreliggende op findelse en anden fordel ved disse.
Følgende data viser stabiliteten af denne forbindelse. Dataene er udtrykt i % rest af de oprindelige forbindelser efter 30 lagring under hver betingelse.
35 * 9 DK 169870 B1 40°C, 60°C, 70°C, 80°C,
Lagring 96 timer 192 timer 240 timer 288 timer 5 --------------------------------------------------------------
Natriumguaiazulen- sulfonat 100% 51,3% 9,3% 1/5%
Forbindelse 3 100% 100% 100% 100% 1°
Ved et forsøg blev stabiliteten udtrykt i %rest af de oprindelige forbindelser bestemt for forbindelserne nr. 1 til 38 og til sammenligning hermed for natriumguaiazulen-3-sulfonat (GAS). Forbinde!serne blev anbragt i brune flasker, som var 15 tæt tillukket, i en termostat ved 60°C. Der blev udtaget prøver med intervaller, som blev analyseret ved hjælp af tyndt-lagskromatografi under anvendelse af CHCH3=3:1-opløsning som opløsningsmiddel.
20 Efter 6 timer begyndte GAS at blive opløst, mens forbindelserne 1-38 ifølge den foreliggende opfindelse på dette tidspunkt overhovedet ikke var begyndt at blive opløst, idet procentresterne for disse forbindelser var 100%. GAS opløstes gradvis i løbet af de næste 6 timer, hvorimod forbindelserne 25 nr. 1-38 slet ikke var begyndt at blive opløst efter 12 timer.
Til terapeutiske formål administreres forbindelserne ifølge opfindelsen til dyr og mennesker peroralt, parenteralt eller rek- talt som aktiv bestanddel i sædvanlige enhedsdosispræparater, 3 0 * d.v.s. præparater i enhedsdosisform bestående i det væsentlige af en indifferent farmaceutisk bærer og en effektiv enhedsdosis af den aktive bestanddel, såsom tabletter, korn, kapsler, suspensioner og lignende. En effektiv enhedsdosis af forbindelserne ifølge opfindelsen er fra 2 mg til 60 mg 3 gange om dagen 35 til en voksen.
10 DK 169870 B1 ?
De følgende eksempler illustrerer typiske farmaceutiske enheds-dosismidler omfattende en forbindelse ifølge opfindelsen som * aktiv bestanddel og repræsenterer måder, hvorpå opfindelsen kan δ anvendes i praksis.
Farmaceutisk eksempel - 1.
Korn med følgende bestanddele: 10
Natrium-3-ethyl-7-isopropyl-azulensulfonat 3 mg Laktose 433 " L-glutamin 60 "
Methylcellulose 4 w 15 total 500 mg
Fremstilling.
20
Bestanddelene blandes grundigt med hinanden, og blandingen granuleres på sædvanlig måde.
Farmaceutisk eksempel - 2.
25
Korn med følgende bestanddele:
Natrium-3-ethyl-7-isopropyl-azulensulfonat 6 mg Laktose 430 " 30 L-glutamin 60 "
Methylcellulose 4 w total 500 mg Λ 35 *
Farmaceutisk eksempel - 3.
11 DK 169870 B1
Korn med følgende bestanddele: 5
Natrium-3-ethyl-7-isopropyl-azulensulfonat 9 mg
Laktose 427 " L-glutamin 60 "
Methylcellulose 4 " total 500 mg
Farmaceutisk eksempel - 4.
15 Korn med følgende bestanddele:
Natrium-3-ethyl-7-isopropyl-azulensulfonat 3 mg
Laktose 393 "
Syntetisk hydrotalcit 100 " 20 Methylcellulose 4 11 total 500 mg
Farmaceutisk eksempel - 5.
25
Korn med følgende bestanddele:
Natrium-3-ethyl-7-isopropyl-azulensulfonat 6 mg
Laktose 390 " 30 Syntetisk hydrotalcit 100 "
Methylcellulose 4 " total 500 mg 35
Farmaceutisk eksempel - 6.
12 DK 169870 B1
Korn med følgende bestanddele: 5
Natrium-3-ethyl-7-isopropyl-azulensulfonat 9 mg Laktose 387 "
Syntetisk hydrotalcit 100 "
Methylcellulose 4 " total 500 mg 10 ______
Farmaceutisk eksempel - 7.
Korn med følgende bestanddele: 15
Natrium-3-ethyl-7-isopropyl-azulensulfonat 3 mg Laktose 150 "
Stivelse 343 "
Methylcellulose 4 " 2° total 500 mg
Farmaceutisk eksempel - 8.
25
Korn med følgende bestanddele:
Natrium-3-ethyl-7-isopropyl-azulensulfonat 6 mg
Laktose 150 "
Stivelse 340 " 30
Methylcellulose 4 " total 500 mg 'i * 35
Farmaceutisk eksempel - 9.
13 DK 169870 B1
Korn med følgende bestanddele: 5
Natrium-3-ethyl-7-isopropyl-azulensulfonat 9 mg
Laktose 150 "
Stivelse 337 " i
Methylcellulose 4 " 10 - total 500 mg
Enhver af de andre forbindelser, der er omfattet af formlen I# kan anvendes i stedet for den særlige aktive bestanddel i oven-15 stående farmaceutiske eksempler 1-9. Ligeledes kan mængden af aktiv bestanddel i disse illustrerende farmaceutiske eksempler varieres for at opnå det tidligere anførte enhedsdosisinterval, og mængderne og karakteren af de indifferente farmaceutiske bærere kan varieres for at tilfredsstille særlige 20 behov.
EKSEMPEL 1 - natrium-1-methyl-azulen-3-sulfonat.
25
Udgangsforbindelsen, 1-methyl-azulen, kan fremstilles som vist nedenfor ifølge Yasunami m.fl. (Chemistry Letters, side 579-582, 1980).
30 cooch3 cooch3
/—CH-CEUCHO / pOS 100% H_P0„ / K'X
VA0>° 3 2 Wy—W-f CH3 CH3 35 (A) (B) (C) 14 DK 169870 B1
Trin 1 - l-methyl-3-carboxymethyl-azulen (B).
En opløsning af oxazulen (A), 6 g, propionaldehyd, 5,22 g, ? og morpholin, 7,84 g, i 120 mg EtOH opvarmes under tilbage-5 svaling i 4 timer. Blandingen afkøles, og det organiske opløsningsmiddel fjernes under reduceret tryk. Remanensen eks-traheres med benzen, og det organiske lag vaskes med vand og tørres.
10 Efter fjernelse af benzen føres remanensen på en kromatografi søjle med silicagel under anvendelse af benzen som eluent og giver 5,9 g produkt som fast stof efter fjernelse af opløsningsmiddel .
Udbytte 5,9 g (98,5%).
Smeltepunkt 69 - 71°C.
IR: 2950, 1690, 1450, 1440, 1421, 1202, 1027, 774, 746 (cm"1).
1H-NMR (CDCI3) : 2,58 (3H,S,Me) , 3,92 (3H,S,OMe) , 7,28(lH,dd,J=9,6,9,6,H-5), 20 7,37(lH,dd,J=9,6,9,6,H-7), 7,67(lH,dd,J=9,6,9,6,H-6), 8,14(1H,S,H-2), 8,24(IH,dd,J=9,6,1,4,H-4), 9,49 (lH,dd,J=9',6,1,4,H-8) .
25
Trin 2 - 1-methyl-azulen (C).
5,91 g af forbindelse B opløses i 60 ml phosphorsyre, og blandingen opvarmes (90°C) i vandbad i 15 minutter. Efter afkøling hældes blandingen på 300 ml isvand og ekstraheres med n-hexan.
Det organiske lag fraskilles, vaskes med vand, tørres over vandfri natriumsulfat og fraktioneres ved søjlekromatografi på silicagel under anvendelse af benzen som eluent til dannelse af 3,72 g (90,1%) af forbindelsen.
» 35 15 DK 169870 B1 IR: 3012, 2930, 1577, 1510, 1455, 1396, 947, 880 (cm"1).
1H-NMR (CDC13): 2,58(3H,S,Me), 3,92(3H,S,OMe), 7,28(lH,dd,J=9,6,9,6,H-5), 5 7,37 (lH,dd,J=9,6,9,6,H-7), 7,67(lH,dd,J=9,6,9,6,H-6), 8,14(1h,S,H-2), 8,24(lH,dd,I=9,6,l,4,H-4), 9,49(lH,dd,J=9,6,1,4,H-8).
10
Trin 3 - natrium-3-methyl-azulensulfonat(forbindelse 1) .
10 ml eddikesyreanhydrid sættes til 1,0 g 1-methyl-azulen, og under afkøling med isvand tilsættes dråbevis 3,4 g svovlsyre, 16 o og reaktionsblandingen omrøres i 4 timer ved 0 C. Derefter gøres reaktionsblandingen alkalisk til pH 8-9 ved tilsætning aj 40% natriumhydroxidopløsning, og det udviklede faste stof opsamles og tøfres. Produktet omkrystalliseres af 95% ethanol til dannelse af 1,1 g af forbindelsen.
20 Smeltepunkt 35 - 38°C.
IR: 1630, 1420, 1220, 750 (cm-1).
Forbindelserne 2-34 fås ved samme sulfoneringsmetode som 25 ovenfor ud fra de tilsvarende udgangsmaterialer, der er kendt fra litteraturen (M.Yasunami, Chem.Lett., side 579, 1980).
EKSEMPEL 2 - natrium-3-ethyl-azulensulfonat (forbindelse 2).
30
Forbindelse 2 fås ved at anvende n-butylaldehyd i stedet for propionaldehyd som i trin 1 i eksempel 1.
Smeltepunkt 28 - 30°C.
IR: 1630, 1425, 1400, 1220, 850 (cm-1).
35 16 DK 169870 B1 EKSEMPEL 3 - natrium-3-ethyl-7-isopropyl-azulensulfonat (forbindelse 3).
5 -------------------------------------------------------
Forbindelse 3 fremstilles ved at følge fremgangsmåden fra eksempel 1 under anvendelse af et 5-isopropyl-substitueret derivat af oxazulen som udgangsmateriale i stedet for oxazulen (A), 10 og n-butyraldehyd i stedet for propionaldehyd. Sulfoneringen udføres efter fremgangsmåderne i trin 3 i eksempel 1.
Smeltepunkt 85 - 88°C.
IR: 1650, 1640, 1565, 1418, 1180, 1050 (cm-1).
1H-NMR (DMSO): 1,30(3H,t,J=7,4,CH3), I5 l,33(6H,d,J=6,6, (CH3)2-) , 3,00 (2H,q,J=7,4 (CH2) , 3,50(lH,sept,J=6,6,-CH-(CH3)2), 4,10(lH,bs,H20), 7,20(lH,d,J=10,H-7), 20 7,90 (IH,s,H-2) , 8,23(1H,J=10,H-4), 9,17(lH,s,H-8).
25 30 35
M
17 DK 169870 B1 EKSEMPEL 4 - natrium-3-ethyl-6-isopropyl-azulensulfonat (forbindelse 4).
5 Smeltepunkt 55 - 58°C.
IR: 1640, 1580, 1410, 1190, 1060 (cm"1).
1H-NMR (DMSO): 1,27(3H, t,J=7,4,CH3), l,30(6H,d,J=6,6, (CH3)2-) , 2,96(IH,sept,J=6,6,isopropyl), 10 3,02(2H,q,J=7,4,CH2), 7,17(2H,d,J=10,H-5,7) , 7,70(IH,s,H-2), 8,20(lH,d,J=10,H-8), 8,90(lH,d,J=10,H-4).
15 EKSEMPEL 5 - natrium-3-(l’-R,S-lf-5'-diiTethyl-4-hexen)azulensulfon (forbindelse 5) .
9 Ω
Forbindelse 5 fremstilles ifølge eksempel 1 under anvendelse d,l-citronellal i stedet for propionaldehyd som i eksempel 1. Smeltepunkt 78 - 81°C.
IR: 1630, 1560, 1420, 1400, 1190, 1120, 1050, 750 (cm-1).
25 EKSEMPEL 6 - natrium-3-n-butyl-azulensulfonat (forbindelse 6)
Smeltepunkt 83 - 85°C.
IR: 1630, 1420, 1400, 1220, 750 (cm-1).
30 EKSEMPEL 7 - natrium--3-methyl-2-ethyl-azulensulfonat (forbindelse 7).
O C
Forbindelse 7 fremstilles ifølge eksempel 1 under anvendelse 18 DK 169870 B1 3-(1-pyrrolidinyl)-2-penten i stedet for propionaldehyd og morpholin som i trin 1 i eksempel 1.
Smeltepunkt 280 - 283°C.
IR: 1640, 1560, 1420, 1190, 1040, 740 (cm-1).
5 EKSEMPEL 8 - natrium-3-(11-S-l1,5'-dimethyl-4'-hexen)azulen-sulfonat (forbindelse 8).
10 Forbindelse 8 fremstilles ifølge eksempel 1 under anvendelse af d-citronellal i stedet for propionaldehyd som i trin 1 i eksempel 1.
Smeltepunkt 78 - 81°C.
IR: 1630, 1560, 1420, 1400, 1190, 1120, 1050, 750 (cm"1).
15 EKSEMPEL 9 - natrium-3-(1'-R-l1,5'-dimethyl-4'-hexen)azulen-sulfonat (forbindelse 9).
20 Forbindelse 9 fremstilles ifølge eksempel 1 under anvendelse af 1-citronellal i stedet for propionaldehyd som i trin 1 i eksempel 1.
Smeltepunkt 78 - 81°C.
IR: 1630, 1560, 1420, 1400, 1190, 1120, 1050, 750 (cm"1).
25 EKSEMPEL 10 - natrium-3-(11-S-l.',5 '-dimethyl-4 1-hexen)-7-isopropyl-azulensulfonat (forbindelse 10).
30 Smeltepunkt 108 - 110°C.
IR: 1630, 1560, 1420, 1220, 1050 (cm-1).
ή * 35 19 DK 169870 B1 EKSEMPEL 11 - natrium-3-(1 '-R-l' ,5 '-dimethyl-4 '-hexen) -7-isopropyl-azulensulfonat (forbindelse 11).
5 Smeltepunkt 108 - 110°C.
IR: 1630, 1560, 1420, 1220, 1050 (cm”1).
EKSEMPEL 12 - natrium-3-propyl-azulensulfonat (forbindelse i: 10
Smeltepunkt 210 - 215°C (under dekomponering).
IR: 3400, 2940, 2850, 1580, 1420, 1400, 1200, 1090, 1020, 960, 880, 750, 740, 670 (cm”1).
15 EKSEMPEL 13 - natrium-3-methyl-7-isopropyl-azulensulfonat (forbindelse 13) .
Smeltepunkt 91 - 93°C.
20 IR: 3450, 2950, 1640, 1250, 1070, 1010, 790 (cm”1).
EKSEMPEL 14 - natrium-3-n-butyl-azulensulfonat (forbindelse ; 25 Smeltepunkt 215 - 220°C (under dekomponering).
IR: 3450, 2900, 1570, 1390, 1190 (cm”1).
EKSEMPEL 15 - natrium-3-n-pentyl-azulensulfonat (forbindelse 30 o
Smeltepunkt 217 - 220 C (under dekomponering).
* IR: 3450, 2900, 1570, 1390, 1190 (cm"1).
EKSEMPEL 16 - natrium-5-isopropyl-azulensulfonat (forbindelse 16).
20 DK 169870 B1 5 Smeltepunkt 241 - 248°C.
IR: 3450, 2950, 1640, 1200, 1050 (cm-1).
EKSEMPEL 17 - natrium-7-isopropyl-3-n-propyl-aziilensulfonat (forbindelse 17).
10 -----------------------------------------------------------
Smeltepunkt 138 - 143°C.
IR: 3450, 2950, 1630, 1575, 1470, 1415, 1390, 1220, 1050, 930 (cm"1).
15 EKSEMPEL 18 - natrium-7-isopropyl-3-n-butyl-azulensulfonat (forbindelse 18).
20 Smeltepunkt 150 - 152°C.
IR: 3450, 2950, 1640, 1575, 1465 (cm-1).
EKSEMPEL 19 - natrium-7-isopropyl-3-n·-penty1-azulensulfonat (forbindelse 19).
25 -----------------------------------------------------------
Smeltepunkt 168 - 170°C.
IR: 3400, 2950, 2930, 2860, 1620, 1580, 1470, 1440, 1390, 1190, 1060 (cm-1).
30 EKSEMPEL 20 - natrium-7-isopropyl-3-(1'-R,S-1',5'-dimethyl-4'- 4 hexen)azulensulfonat (forbindelse 20).
Smeltepunkt 113 - 116°C.
IR: 3450, 2950, 1640, 1380, 1240, 1180 (cm-1).
EKSEMPEL 21 - natrium-7-isopropyl-3-(1'-R-l',5'-dimethyl-4'- hexen)azulensulfonat (forbindelse 21).
21 DK 169870 B1 5 Smeltepunkt 114 - 117°C.
IR: 3450, 2950, 1640, 1380, 1240, 1180 (cm"1).
EKSEMPEL 22 - natrium-7-isopropyl-3-(1'-S-1',5'-dimethyl-4'-hexen)azulensulfonat (forbindelse 22).
10 ------------------------------------------------------------
Smeltepunkt 115 - 118°C.
IR: 3450, 2950, 1640, 1380, 1240, 1180 (cm"1).
2 5 EKSEMPEL 23 - natrium-7-isopropyl-3-benzyl-azulensulfonat (forbindelse 23).
Smeltepunkt 250° C (under dekomponering) .
20 IR: 3450, 2950, 1640, 1560, 1530, 1460, 1420 (cm"1).
EKSEMPEL 24 - natrium-4-methoxy-3-methyl-azulensulfonat (forbindelse 24).
25
Smeltepunkt 186 - 188°C (under dekomponering).
IR: 3400, 1600, 1570, 1540, 1460, 1370, 1270 (cm-1).
EKSEMPEL 25 - natrium-4-methoxy-3-ethyl-azulensulfonat 30 (forbindelse 25).
Smeltepunkt 60°C.
IR: 3400, 2950, 1600, 1570, 1540, 1450, 1370, 1270 (cm"1).
EKSEMPEL 26 - natrium-4-methoxy--3-propyl-azulensulfonat (forbindelse 26).
22 DK 169870 B1 5 Smeltepunkt 108 - 110°C.
IR: 3450, 2910, 2850, 1600, 1570, 1530 (cm"1).
EKSEMPEL 27 - natrium-4-methoxy-3-butyl-azulensulfonat (forbindelse 27).
10 ------------------------------------------------------
Smeltepunkt 188 - 190°C (under dekomponering).
IR: 3450, 2950, 1600, 1570, 1530, 1460 (cm-1).
15 EKSEMPEL 28 - natrium-4-methoxy-3-penty1-azulensulfonat (forbindelse 28).
Smeltepunkt 189 - 192°C (under dekomponering).
20 IR: 3450, 2950, 1600, 1560, 1530, 1450 (cm"1).
EKSEMPEL 29 - natrium-4-methoxy-3-hexyl-azulensulfonat (forbindelse 29).
25
Smeltepunkt 225 - 228°C (under dekomponering).
IR: 3450, 2900, 1650, 1560, 1520, 1460 (cm"1).
EKSEMPEL 30 - natrium-7-isopropyl-4-methoxy-3-methyl-azulen-30 sulfonat (forbindelse 30).
Smeltepunkt 95 - 97°C.
IR: 3450, 2950, 1650, 1540, 1280, 1180 (cm"1).
35 EKSEMPEL 31 - natrium-7-isopropyl-4-methoxy-3-ethyl-azulen· sulfonat (forbindelse 31).
23 DK 169870 B1 5 Smeltepunkt 108 - 110°C.
IR: 3450, 2950, 1650, 1540, 1260, 1180 (cm-1).
EKSEMPEL 32 - natrium~7-isopropyl-4--methoxy-3-propyl-azulen· sulfonat (forbindelse 32) .
10 ------------------------------------------------------------
Smeltepunkt 188 - 190°C.
IR: 3450, 2950, 1640, 1560, 1530 (cm"1).
15 EKSEMPEL 33 - natrium-7-isopropyl-4-methoxy-3-butyl-azulen- sulfonat (forbindelse 33).
Smeltepunkt 166 - 168°C.
20 IR: 3450, 2950, 1640, 1560, 1530, 1470 (cm"1).
EKSEMPEL 34 - natrium-7-isopropyl-4-methoxy-3-pentyl-azulen sulfonat (forbindelse 34).
25
Smeltepunkt 123 - 125°C.
IR: 3450, 2950, 1650, 1520, 1260, 1010 (cm”1).
EKSEMPEL 35 - 3-methyl-azulensulfonsyre, aluminiumsalt 30 (forbindelse 35). 1 g natrium-3-methyl-azulensulfonat opløses i vand. Til de: ne opløsning sættes 2,73 g AlCl^ i 40 ml vand efter filtrer. 35 af resten, og der omrøres i 30 minutter ved stuetemperatur.
24 DK 169870 B1
Reaktionsblandingen indstilles til pH 4 - 4f5 ved tilsætning af 10% NaOH. Det dannede bundfald opsamles ved filtrering og vaskes med vand og tørres.
Smeltepunkt over 250°C.
5 IR: 3400, 1630, 1580, 1395, 1140, 1040, 740 (cm"1).
Al-indhold: 13,96%.
Følgende forbindelser (forbindelse 36 - 38) fremstilles på samme måde som i eksempel 35 ud fra de tilsvarende natriumsulfonat-10 derivater.
EKSEMPEL 36 - 3-ethyl-azulensulfonsyre, aluminiumsalt (forbindelse 36) .
15
Smeltepunkt over 250°C.
IR: 3400, 2950, 1580, 1400, 1150, 1050, 750 (cm-1).
Al-indhold: 13,00%.
20 EKSEMPEL 37 - 7-isopropyl-3-methyl-azulensulfonsyre, aluminiumsalt (forbindelse 37).
Smeltepunkt over 250°C.
25 IR: 3400, 2950, 1420, 1150, 1040 (cm"1).
Al-indhold: 9,46%.
EKSEMPEL 38 - 7-isopropyl-3-ethyl-azulensulfonsyre, aluminiumsalt (forbindelse 38).
30 ---------------------------------------------------
Smeltepunkt over 250°C.
IR: 3400, 2950, 1580, 1420, 1390, 1150 (cm"1).
Al-indhold: 10,58%.
35
Claims (14)
- 25 DK 169870 B1 Patentkrav.
- 1. Azulenderivat med formlen I 5 so3x 10 R H R6 . I y hvor R1 er H, lavere alkyl, -C-(CH2)n-CH=CT eller benzyl,
- 15 R5 R1 hvor R5, R® og R1 hver repræsenterer H eller lavere alkyl, n er et tal på 1 eller 2, R2 og R3 hver repræsenterer H eller lavere alkyl, R4 er H eller en alkoxygruppe, og X er Na eller Al (OH)2 - 20
- 2. Forbindelse ifølge krav 1, kendetegnet ved, at Ri er en lavere alkylgruppe.
- 3. Forbindelse ifølge krav 1, kendetegnet ved, at R1 er -CH-(CH2)n_CHi=0—R6, hvor R5, R6, R1 og n har de ovenfor 25 t \ R® R1 anførte betydninger.
- 4. Forbindelse ifølge krav 1, kendetegnet ved, at R4 er en alkoxygruppe. 30
- 5. Forbindelse ifølge krav 1, kendetegnet ved, at X er Na.
- 6. Forbindelse ifølge krav 1, kendetegnet ved, at X 33 er A1(0H)2. Forbindelse ifølge krav 1, kendetegnet ved, at den er natrium-3-ethyl-7-isopropyl-azulensulfonat. DK 169870 B1 26
- 8. Forbindelse ifølge krav 1, kendetegnet ved, at den er 3-ethyl-7-isopropyl-azulensulfonsyre, aluminiumsalt.
- 9. Terapeutisk middel omfattende en farmaceutisk anvendelig bærer og som aktiv bestanddel en forbindelse ifølge krav 1, hvori r! er H; lavere alkyl, som repræsenterer C1-C4 lavere alkyl i det tilfælde, hvor R3 er en 7-alkylgruppe; 10 Ϊ -C-(CH2)n-CH=C I \ R5 R7 (hvor R5, R3, R? hver repræsenterer H eller lavere alkyl, og n 15 er 1 eller 2), som ikke omfatter en S-konfigurationsgruppe til azulenring i det tilfælde, hvor R3 er en 7-alkylgruppe; eller benzyl ; R2 og R3 hver repræsenterer H eller lavere alkyl; R4 er H eller en alkoxygruppe; og 20. er Na eller A1(0H)2j i en mængde, der er effektiv til at behandle peptisk ulcer.
- 10. Terapeutisk middel omfattende en farmaceutisk anvendelig bærer og som aktiv bestanddel en forbindelse ifølge krav 1 i 25 en mængde, der er effektiv til at behandle inflammation.
- 11. Fremgangsmåde til fremstilling af azulender ivater med formlen 30 s°3x :©t' - .
- 35 R·*· * 27 DK 169870 B1 β·6 hvor R1 er H, lavere alkyl, -CH-(CH2)n-CH=C eller benzyl, I \ R5 r7 hvor R5, R6 og R7 hver repræsenterer H eller lavere alkyl, og 5 n er 1 eller 2, og hvor R2 og R3 hver repræsenterer H eller lavere alkyl, R4 er en alkoxygruppe eller H, og X er Na eller Al(OH)2, kendetegnet ved, at man omsætter en forbindelse med formlen 10 ::ες>- * R1 15 hvor Ri, R2, R3 og R4 er som defineret ovenfor, med et sul foner ingsmiddel og omdanner den fremkomne sulfonsyre til dens natrium- eller aluminiumsalt.
- 12. Fremgangsmåde ifølge krav 11, kendetegnet ved, at sulfoneringsmidlet er svovlsyre eller et kompleks af svovl-syreanhydrid og pyridin. 25 30 35
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP15318783 | 1983-08-24 | ||
| 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 |
| JP1402884 | 1984-01-28 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK377984D0 DK377984D0 (da) | 1984-08-03 |
| DK377984A DK377984A (da) | 1985-02-25 |
| DK169870B1 true DK169870B1 (da) | 1995-03-20 |
Family
ID=26349908
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK377984A DK169870B1 (da) | 1983-08-24 | 1984-08-03 | Azulenderivater, fremgangsmåde til deres syntese og anti-ulcerative og anti-inflammatoriske midler omfattende disse derivater |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US4595694A (da) |
| EP (1) | EP0147915B1 (da) |
| KR (1) | KR920000956B1 (da) |
| AR (1) | AR240554A1 (da) |
| AU (1) | AU571554B2 (da) |
| CA (1) | CA1228862A (da) |
| DE (1) | DE3463502D1 (da) |
| DK (1) | DK169870B1 (da) |
| ES (1) | ES535381A0 (da) |
| HU (1) | HU195478B (da) |
| NO (1) | NO158673C (da) |
| PT (1) | PT79119B (da) |
| SU (1) | SU1311618A3 (da) |
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 | Boehringer Mannheim Gmbh | Verwendung von Azulenderivaten als Metalloproteaseinhibitoren |
| US6420435B1 (en) | 1999-11-01 | 2002-07-16 | Joe S. Wilkins, Jr. | Method for treating gastrointestinal disorders |
| JP4202250B2 (ja) | 2001-07-25 | 2008-12-24 | バイオマリン ファーマシューティカル インコーポレイテッド | 血液脳関門輸送を調節するための組成物および方法 |
| US7041706B2 (en) * | 2002-04-19 | 2006-05-09 | Wilkins Jr Joe S | Method for treating crohn's disease |
| EP2671507A3 (en) | 2005-04-28 | 2014-02-19 | Proteus Digital Health, Inc. | Pharma-informatics system |
| MX2009002893A (es) | 2006-09-18 | 2009-07-10 | Raptor Pharmaceutical Inc | Tratamiento de trastornos hepaticos mediante la administracion de conjugados de la proteina asociada al receptor (rap). |
| CA2752373C (en) | 2009-02-20 | 2017-10-10 | To-Bbb Holding B.V. | Glutathione-based drug delivery system |
| IL255113B (en) | 2009-05-06 | 2022-09-01 | Laboratory Skin Care Inc | Dermal delivery compositions comprising active agent-calcium phosphate particle complexes and methods of using the same |
| 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 |
| US4283347A (en) * | 1979-04-13 | 1981-08-11 | Scm Corporation | Para-menth-1-ene-7-sulfonic acid and salts thereof |
| US4224240A (en) * | 1979-04-13 | 1980-09-23 | Scm Corporation | Preparation of para-menth-1-ene-7-sulfonate salts and corresponding acids |
-
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 ES ES535381A patent/ES535381A0/es active Granted
- 1984-08-23 SU SU3785251A patent/SU1311618A3/ru active
- 1984-08-23 KR KR1019840005107A patent/KR920000956B1/ko not_active Expired
- 1984-08-23 NO NO843377A patent/NO158673C/no unknown
- 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 EP EP84305775A patent/EP0147915B1/en not_active Expired
- 1984-08-23 AR AR29767884A patent/AR240554A1/es active
- 1984-08-23 DE DE8484305775T patent/DE3463502D1/de not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| PT79119B (en) | 1986-07-17 |
| US4595694A (en) | 1986-06-17 |
| NO843377L (no) | 1985-02-25 |
| HUT37393A (en) | 1985-12-28 |
| DE3463502D1 (en) | 1987-06-11 |
| CA1228862A (en) | 1987-11-03 |
| EP0147915A1 (en) | 1985-07-10 |
| NO158673B (no) | 1988-07-11 |
| SU1311618A3 (ru) | 1987-05-15 |
| PT79119A (en) | 1984-09-01 |
| KR920000956B1 (ko) | 1992-01-31 |
| DK377984D0 (da) | 1984-08-03 |
| ES8506607A1 (es) | 1985-07-16 |
| KR850001731A (ko) | 1985-04-01 |
| DK377984A (da) | 1985-02-25 |
| EP0147915B1 (en) | 1987-05-06 |
| ES535381A0 (es) | 1985-07-16 |
| HU195478B (en) | 1988-05-30 |
| AU3139684A (en) | 1985-02-28 |
| AU571554B2 (en) | 1988-04-21 |
| NO158673C (no) | 1988-10-19 |
| AR240554A1 (es) | 1990-05-31 |
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