US20070060556A1 - Barium salt of benzimidazole derivative - Google Patents
Barium salt of benzimidazole derivative Download PDFInfo
- Publication number
- US20070060556A1 US20070060556A1 US10/555,628 US55562804A US2007060556A1 US 20070060556 A1 US20070060556 A1 US 20070060556A1 US 55562804 A US55562804 A US 55562804A US 2007060556 A1 US2007060556 A1 US 2007060556A1
- Authority
- US
- United States
- Prior art keywords
- barium
- omeprazole
- salt
- process according
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 159000000009 barium salts Chemical class 0.000 title claims abstract description 17
- 125000003785 benzimidazolyl group Chemical class N1=C(NC2=C1C=CC=C2)* 0.000 title 1
- SUBDBMMJDZJVOS-DEOSSOPVSA-N esomeprazole Chemical compound C([S@](=O)C1=NC2=CC=C(C=C2N1)OC)C1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-DEOSSOPVSA-N 0.000 claims abstract description 81
- 238000000034 method Methods 0.000 claims abstract description 32
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 8
- 238000011282 treatment Methods 0.000 claims abstract description 6
- 229960004770 esomeprazole Drugs 0.000 claims description 82
- 229910052788 barium Inorganic materials 0.000 claims description 58
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 claims description 57
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- 239000002904 solvent Substances 0.000 claims description 14
- 239000012458 free base Substances 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- -1 alkali metal bicarbonates Chemical class 0.000 claims description 9
- 208000021302 gastroesophageal reflux disease Diseases 0.000 claims description 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 claims description 4
- 229910001863 barium hydroxide Inorganic materials 0.000 claims description 4
- IWOUKMZUPDVPGQ-UHFFFAOYSA-N barium nitrate Chemical compound [Ba+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O IWOUKMZUPDVPGQ-UHFFFAOYSA-N 0.000 claims description 4
- TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Chemical compound [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 claims description 4
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 238000001694 spray drying Methods 0.000 claims description 4
- 208000017189 Gastrointestinal inflammatory disease Diseases 0.000 claims description 3
- 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 3
- 208000025865 Ulcer Diseases 0.000 claims description 3
- 201000010099 disease Diseases 0.000 claims description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 3
- 230000027119 gastric acid secretion Effects 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 2
- 206010057969 Reflux gastritis Diseases 0.000 claims description 2
- 208000007107 Stomach Ulcer Diseases 0.000 claims description 2
- 150000001298 alcohols Chemical class 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 2
- 239000000908 ammonium hydroxide Substances 0.000 claims description 2
- 239000000010 aprotic solvent Substances 0.000 claims description 2
- ITHZDDVSAWDQPZ-UHFFFAOYSA-L barium acetate Chemical compound [Ba+2].CC([O-])=O.CC([O-])=O ITHZDDVSAWDQPZ-UHFFFAOYSA-L 0.000 claims description 2
- WDIHJSXYQDMJHN-UHFFFAOYSA-L barium chloride Chemical compound [Cl-].[Cl-].[Ba+2] WDIHJSXYQDMJHN-UHFFFAOYSA-L 0.000 claims description 2
- 229910001626 barium chloride Inorganic materials 0.000 claims description 2
- 229940006612 barium citrate Drugs 0.000 claims description 2
- GXUARMXARIJAFV-UHFFFAOYSA-L barium oxalate Chemical compound [Ba+2].[O-]C(=O)C([O-])=O GXUARMXARIJAFV-UHFFFAOYSA-L 0.000 claims description 2
- 229940094800 barium oxalate Drugs 0.000 claims description 2
- HQYOWPDUMCBSLQ-UHFFFAOYSA-L barium(2+);2,3-dihydroxybutanedioate Chemical compound [Ba+2].[O-]C(=O)C(O)C(O)C([O-])=O HQYOWPDUMCBSLQ-UHFFFAOYSA-L 0.000 claims description 2
- PAVWOHWZXOQYDB-UHFFFAOYSA-H barium(2+);2-hydroxypropane-1,2,3-tricarboxylate Chemical compound [Ba+2].[Ba+2].[Ba+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O PAVWOHWZXOQYDB-UHFFFAOYSA-H 0.000 claims description 2
- HLKMEIITONDPGG-UHFFFAOYSA-L barium(2+);2-hydroxypropanoate Chemical compound [Ba+2].CC(O)C([O-])=O.CC(O)C([O-])=O HLKMEIITONDPGG-UHFFFAOYSA-L 0.000 claims description 2
- HFAQXXPQBRIXGD-UHFFFAOYSA-L barium(2+);butanedioate Chemical compound [Ba+2].[O-]C(=O)CCC([O-])=O HFAQXXPQBRIXGD-UHFFFAOYSA-L 0.000 claims description 2
- WAKZZMMCDILMEF-UHFFFAOYSA-H barium(2+);diphosphate Chemical compound [Ba+2].[Ba+2].[Ba+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O WAKZZMMCDILMEF-UHFFFAOYSA-H 0.000 claims description 2
- AYJRCSIUFZENHW-DEQYMQKBSA-L barium(2+);oxomethanediolate Chemical compound [Ba+2].[O-][14C]([O-])=O AYJRCSIUFZENHW-DEQYMQKBSA-L 0.000 claims description 2
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 claims description 2
- 150000004292 cyclic ethers Chemical class 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 208000000718 duodenal ulcer Diseases 0.000 claims description 2
- 230000003628 erosive effect Effects 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 210000004211 gastric acid Anatomy 0.000 claims description 2
- 201000005917 gastric ulcer Diseases 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- 208000000689 peptic esophagitis Diseases 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 238000011321 prophylaxis Methods 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims 2
- 230000002401 inhibitory effect Effects 0.000 claims 1
- 150000002825 nitriles Chemical class 0.000 claims 1
- 239000002244 precipitate Substances 0.000 claims 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims 1
- 235000017557 sodium bicarbonate Nutrition 0.000 claims 1
- 229960000381 omeprazole Drugs 0.000 abstract description 7
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 abstract description 5
- 206010061459 Gastrointestinal ulcer Diseases 0.000 abstract description 3
- 230000002265 prevention Effects 0.000 abstract description 2
- 238000002441 X-ray diffraction Methods 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 238000002329 infrared spectrum Methods 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000001556 precipitation Methods 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- 239000011343 solid material Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 239000012296 anti-solvent Substances 0.000 description 2
- 229940118888 barium cation Drugs 0.000 description 2
- XDFCIPNJCBUZJN-UHFFFAOYSA-N barium(2+) Chemical compound [Ba+2] XDFCIPNJCBUZJN-UHFFFAOYSA-N 0.000 description 2
- 238000000113 differential scanning calorimetry Methods 0.000 description 2
- 239000006260 foam Substances 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 159000000003 magnesium salts Chemical class 0.000 description 2
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 206010063655 Erosive oesophagitis Diseases 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- 206010019375 Helicobacter infections Diseases 0.000 description 1
- 241000590002 Helicobacter pylori Species 0.000 description 1
- 208000028861 Helicobacter pylori infectious disease Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 208000008469 Peptic Ulcer Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 102100025490 Slit homolog 1 protein Human genes 0.000 description 1
- 101710123186 Slit homolog 1 protein Proteins 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 206010046274 Upper gastrointestinal haemorrhage Diseases 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001262 anti-secretory effect Effects 0.000 description 1
- 239000003699 antiulcer agent Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- PWHCIQQGOQTFAE-UHFFFAOYSA-L barium chloride dihydrate Chemical compound O.O.[Cl-].[Cl-].[Ba+2] PWHCIQQGOQTFAE-UHFFFAOYSA-L 0.000 description 1
- ZUDYPQRUOYEARG-UHFFFAOYSA-L barium(2+);dihydroxide;octahydrate Chemical compound O.O.O.O.O.O.O.O.[OH-].[OH-].[Ba+2] ZUDYPQRUOYEARG-UHFFFAOYSA-L 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 201000006549 dyspepsia Diseases 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 201000000052 gastrinoma Diseases 0.000 description 1
- 238000012812 general test Methods 0.000 description 1
- 159000000011 group IA salts Chemical class 0.000 description 1
- 208000024798 heartburn Diseases 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229940037467 helicobacter pylori Drugs 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 150000002826 nitrites Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 229940126409 proton pump inhibitor Drugs 0.000 description 1
- 239000000612 proton pump inhibitor Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 150000005621 tetraalkylammonium salts Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000036269 ulceration Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- 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
Definitions
- a barium salt of the S-enantiomer of omeprazole which is (S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole is provided. Further, processes for preparing the barium salt, pharmaceutical compositions comprising the salt and a method of treatment or prevention of gastrointestinal ulcers comprising administration of the salt are provided.
- Omeprazole is a gastric acid secretion inhibitor, useful as an anti-ulcer agent.
- U.S. Pat. No. 5,714,504 describes alkaline salts of (S)-omeprazole, such as sodium, magnesium, lithium, potassium, calcium or tetraalkylammonium salts.
- sodium and magnesium salts of (S)-omeprazole has been exemplified, besides (S)-omeprazole freebase in this patent.
- the potassium salt of (S)-omeprazole has been described as prepared in WO 98/54171 and WO 00/44744.
- the commercially available magnesium salt of (S)-omeprazole is used for treating and preventing peptic ulcers, gastroesophageal reflux disease (GERD or heartburn), erosive esophagitis, other conditions involving excessive stomach acid production, and for treating bacterial infections caused by helicobacter pylori.
- the barium salt of (S)-omeprazole that is, (S)-omeprazole barium.
- Another aspect relates to (S)-omeprazole barium in a crystalline form.
- Yet another aspect relates to (S)-omeprazole barium in an amorphous form.
- a process for preparing (S)-omeprazole barium comprises contacting (S)-omeprazole freebase or its sodium/potassium salt with barium salt of an acid in a suitable solvent to form (S)-omeprazole barium, wherein the process is carried out in the presence of a base whenever (S)-omeprazole freebase is used.
- (S)-omeprazole barium may be prepared by a process which comprises contacting (S)-omeprazole freebase with barium hydroxide in a suitable solvent. Also, processes for preparing (S)-omeprazole barium in amorphous form are provided, which comprise concentrating a solution containing (S)-omeprazole barium to dryness or by spray drying the solution.
- Further aspects include methods for treating or preventing gastrointestinal ulcers which comprise administering (S)-omeprazole barium, or a pharmaceutical composition that comprises (S)-omeprazole barium, along with pharmaceutically acceptable excipients.
- (S)-omeprazole barium as used herein means any salt comprising (S)-omeprazole anions and barium cations. For instance, solid as well as dissolved forms are included, and so are crystalline and amorphous forms.
- (S)-omeprazole barium may exist in an anhydrous and/or solvent-free form or as a hydrate and/or a solvate.
- (S)-omeprazole refers to an omeprazole-containing material which is substantially free of the R-enantiomer of omeprazole, for example, it has an enantiomeric excess of 80%, or for example an enantiomeric excess of 90%. In some particular embodiments, S-omeprazole is in enantiomeric excess of at least about 95%, or at least about 98%, or at least about 99.5%, or at least about 99.8%.
- (S)-omeprazole barium encompasses stoichiometric as well as non-stoichiometric ratios of (S)-omeprazole anion and barium cation.
- the ratio of (S)-omeprazole to barium is not required to be 1:1 in order to be termed (S)-omeprazole barium.
- (S)-omeprazole barium is formed as a salt having a 2:1 molar ratio between (S)-omeprazole anion and barium cation even when an excess of (S)-omeprazole or an excess of barium salt of an acid is used in the salt formation.
- (S)-omeprazole barium obtained in both crystalline and amorphous forms is non-hygroscopic.
- An amorphous form may be advantageous in comparison with the crystalline form as it can be obtained in a finely powdered form with better solubility properties.
- bases which may be used in the process for preparing (S)-omeprazole barium using (S)-omeprazole freebase include alkali metal hydroxides such as sodium hydroxide or potassium hydroxide, alkali metal carbonates such as sodium carbonate or potassium carbonate, alkali metal bicarbonates such as sodium bicarbonate, and ammonium hydroxide.
- the barium salt of an acid to be used in the process can be the salt of any inorganic or organic acid.
- examples of such salts include barium chloride, barium nitrate, barium sulphate, barium phosphate, barium carbonate, barium oxalate, barium acetate, barium lactate, barium succinate, barium citrate, and barium tartrate.
- suitable solvents for carrying out the the salt-forming processes include water, ketones such as acetone and methyl isobutyl ketone, alcohols such as methanol, ethanol and isopropanol, esters such as ethyl acetate and isopropyl acetate, chlorinated hydrocarbons such as methylene chloride and ethylene dichloride, cyclic ethers such as dioxan and tetrahydrofliran, nitrites such as acetonitrile, dipolar aprotic solvents such as dimethylsulfoxide and dimethylformamide, and mixtures thereof.
- ketones such as acetone and methyl isobutyl ketone
- alcohols such as methanol, ethanol and isopropanol
- esters such as ethyl acetate and isopropyl acetate
- chlorinated hydrocarbons such as methylene chloride and ethylene dichloride
- cyclic ethers such as diox
- the precipitation may be facilitated by reducing the volume of the solution and/or by adding an antisolvent, that is, a solvent in which the (S)-omeprazole barium is insoluble or sparingly soluble.
- an antisolvent that is, a solvent in which the (S)-omeprazole barium is insoluble or sparingly soluble.
- the precipitation can also be induced by reducing the temperature of the solvent, especially if the initial temperature at contact is elevated.
- anti solvents that may be added to precipitate out (S)-omeprazole barium include aliphatic hydrocarbons such as hexane, heptane, and octane; aromatic hydrocarbons such as xylene and toluene; lower alkyl ethers such as diethyl ether, and diisopropyl ether; and mixture(s) thereof.
- the (S)-omeprazole freebase or its sodium/potassium salt to be used in the preparation processes can be obtained by methods known in the art including those described in U.S. Pat. Nos. 5,714,504, 5,948,789, and U.S. Pat. No. 6,162,816, and International Patent Applications WO 00/44744, WO 98/54171, and WO92/08716.
- the starting (S)-omeprazole freebase or its sodium/potassium salts may be obtained as a solution directly, from a reaction in which S-omeprazole is formed, and used as such.
- (S)-omeprazole barium may also be obtained in amorphous form by concentrating the solution of (S)-omeprazole barium to dryness or by spray drying the solution. Solutions of (S)-omeprazole barium may be obtained from the salt-forming reaction in a suitable solvent or by dissolving crystalline (S)-omeprazole barium in a suitable solvent.
- (S)-omeprazole barium is a useful proton pump inhibitor and an antibacterial, and thus can be used to treat any condition that would be benefited by administration of a gastric acid secretion inhibitor.
- (S)-omeprazole barium can be used for the treatment or prophylaxis of gastric acid-related diseases and gastrointestinal inflammatory diseases in mammals and man, such as erosive or ulcerative gastroesophageal reflux disease (GERD), gastric ulcer, duodenal ulcer, reflux esophagitis, and gastritis.
- GGID ulcerative gastroesophageal reflux disease
- (S)-omeprazole barium may be useful in the treatment of helicobacter infections and diseases related to these.
- the salt can be administered as a component of a pharmaceutical composition.
- a pharmaceutical composition that comprises (S)-omeprazole barium and pharmaceutically acceptable carriers, diluents or excipients and optionally other therapeutic ingredients.
- the salt may be conveniently formulated into tablets, capsules, suspensions, dispersions, injectables and other pharmaceutical forms. Any suitable route of administration may be employed for example, peroral or parental.
- X-Ray Diffraction (XRD) patterns were taken with a diffractometer manufactured by Rigaku Coorperation, specifically the model RU-H3R.
- the goniometer was a CN2155A3, and the X-Ray tube was equipped with Cu target anode.
- the settings for the divergence slits were 1 0, for the receiving slit 0.15 mm, and for the scatter slit 1 0.
- the operating power was 40 KV, 100 mA, the scanning speed was 2 deg/min step: 0.02 deg, and the wavelength was 1.5406 A.
- Infrarred spectra were take with a Perkin Elmer,16 PC, with scan parameters of 16 scans, 4.0 cm. ⁇ 1 according to the USP 25, general test methods, page 1920. Infrared absorption spectra were obtained by the potassium bromide pellet method.
- Differential Scanning Calorimetry was done by the model DSC821 e, manufactured by Mettler Toledo, with sample weights of 3-5 mg, and the sample temperature range of 25-100° C., heating rate of 1° C./min, nitrogen flow of 80.0 mL/min, with one hole in the crucible.
- (S)-omeprazole free base (5 g,) was added to acetone (60 ml) and stirred at 25-30° C. Barium hydroxide octahydrate (4.6) and water (15 ml) were then added to the above mixture at 25-30° C. The reaction mixture was further stirred for 4 to 5 hours, and then filtered to remove suspended solid material. The solvent was recovered under reduced pressure to obtain the product as a foam. The product was dried at 40 to 45° C. under reduced pressure for 2 to 3 hours to get (S)-omeprazole barium (4.2 g).
Abstract
A barium salt of the S-enantiomer of omeprazole which is (S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole is provided. Further, processes for preparing the barium salt, pharmaceutical compositions comprising the salt and a method of treatment or prevention of gastrointestinal ulcers comprising administration of the salt are provided.
Description
- A barium salt of the S-enantiomer of omeprazole which is (S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole is provided. Further, processes for preparing the barium salt, pharmaceutical compositions comprising the salt and a method of treatment or prevention of gastrointestinal ulcers comprising administration of the salt are provided.
- Omeprazole is a gastric acid secretion inhibitor, useful as an anti-ulcer agent. U.S. Pat. No. 5,714,504 describes alkaline salts of (S)-omeprazole, such as sodium, magnesium, lithium, potassium, calcium or tetraalkylammonium salts. However, only the preparation of sodium and magnesium salts of (S)-omeprazole has been exemplified, besides (S)-omeprazole freebase in this patent. The potassium salt of (S)-omeprazole has been described as prepared in WO 98/54171 and WO 00/44744. The commercially available magnesium salt of (S)-omeprazole is used for treating and preventing peptic ulcers, gastroesophageal reflux disease (GERD or heartburn), erosive esophagitis, other conditions involving excessive stomach acid production, and for treating bacterial infections caused by helicobacter pylori.
- Herein is provided the barium salt of (S)-omeprazole, that is, (S)-omeprazole barium. Another aspect relates to (S)-omeprazole barium in a crystalline form. Yet another aspect relates to (S)-omeprazole barium in an amorphous form.
- In yet another aspect, a process for preparing (S)-omeprazole barium is provided, which comprises contacting (S)-omeprazole freebase or its sodium/potassium salt with barium salt of an acid in a suitable solvent to form (S)-omeprazole barium, wherein the process is carried out in the presence of a base whenever (S)-omeprazole freebase is used.
- Alternatively, (S)-omeprazole barium may be prepared by a process which comprises contacting (S)-omeprazole freebase with barium hydroxide in a suitable solvent. Also, processes for preparing (S)-omeprazole barium in amorphous form are provided, which comprise concentrating a solution containing (S)-omeprazole barium to dryness or by spray drying the solution.
- Further aspects include methods for treating or preventing gastrointestinal ulcers which comprise administering (S)-omeprazole barium, or a pharmaceutical composition that comprises (S)-omeprazole barium, along with pharmaceutically acceptable excipients.
- The term “(S)-omeprazole barium” as used herein means any salt comprising (S)-omeprazole anions and barium cations. For instance, solid as well as dissolved forms are included, and so are crystalline and amorphous forms. (S)-omeprazole barium may exist in an anhydrous and/or solvent-free form or as a hydrate and/or a solvate.
- The expression “(S)-omeprazole,” as used herein, refers to an omeprazole-containing material which is substantially free of the R-enantiomer of omeprazole, for example, it has an enantiomeric excess of 80%, or for example an enantiomeric excess of 90%. In some particular embodiments, S-omeprazole is in enantiomeric excess of at least about 95%, or at least about 98%, or at least about 99.5%, or at least about 99.8%.
- Further, the term “(S)-omeprazole barium,” as used herein, encompasses stoichiometric as well as non-stoichiometric ratios of (S)-omeprazole anion and barium cation. The ratio of (S)-omeprazole to barium is not required to be 1:1 in order to be termed (S)-omeprazole barium. In a particular embodiment, (S)-omeprazole barium is formed as a salt having a 2:1 molar ratio between (S)-omeprazole anion and barium cation even when an excess of (S)-omeprazole or an excess of barium salt of an acid is used in the salt formation.
- (S)-omeprazole barium obtained in both crystalline and amorphous forms is non-hygroscopic. An amorphous form may be advantageous in comparison with the crystalline form as it can be obtained in a finely powdered form with better solubility properties.
- Examples of bases which may be used in the process for preparing (S)-omeprazole barium using (S)-omeprazole freebase include alkali metal hydroxides such as sodium hydroxide or potassium hydroxide, alkali metal carbonates such as sodium carbonate or potassium carbonate, alkali metal bicarbonates such as sodium bicarbonate, and ammonium hydroxide.
- The barium salt of an acid to be used in the process can be the salt of any inorganic or organic acid. Examples of such salts include barium chloride, barium nitrate, barium sulphate, barium phosphate, barium carbonate, barium oxalate, barium acetate, barium lactate, barium succinate, barium citrate, and barium tartrate.
- Examples of suitable solvents for carrying out the the salt-forming processes include water, ketones such as acetone and methyl isobutyl ketone, alcohols such as methanol, ethanol and isopropanol, esters such as ethyl acetate and isopropyl acetate, chlorinated hydrocarbons such as methylene chloride and ethylene dichloride, cyclic ethers such as dioxan and tetrahydrofliran, nitrites such as acetonitrile, dipolar aprotic solvents such as dimethylsulfoxide and dimethylformamide, and mixtures thereof.
- In water and methanol the reactants are more soluble than the (S)-omeprazole barium product. In this way, the salt-forming reaction is accompanied by spontaneous precipitation of the produced barium salt out of the solution. While such a precipitation in methanol gives crystalline (S)-omeprazole barium, in water the amorphous form is obtained.
- Alternatively, the precipitation may be facilitated by reducing the volume of the solution and/or by adding an antisolvent, that is, a solvent in which the (S)-omeprazole barium is insoluble or sparingly soluble. The precipitation can also be induced by reducing the temperature of the solvent, especially if the initial temperature at contact is elevated.
- Examples of anti solvents that may be added to precipitate out (S)-omeprazole barium include aliphatic hydrocarbons such as hexane, heptane, and octane; aromatic hydrocarbons such as xylene and toluene; lower alkyl ethers such as diethyl ether, and diisopropyl ether; and mixture(s) thereof.
- The (S)-omeprazole freebase or its sodium/potassium salt to be used in the preparation processes can be obtained by methods known in the art including those described in U.S. Pat. Nos. 5,714,504, 5,948,789, and U.S. Pat. No. 6,162,816, and International Patent Applications WO 00/44744, WO 98/54171, and WO92/08716. The starting (S)-omeprazole freebase or its sodium/potassium salts may be obtained as a solution directly, from a reaction in which S-omeprazole is formed, and used as such.
- The precipitated barium salt may be isolated in a solid state by conventional methods such as filtration or centrifugation, optionally followed by washing and/or drying.
- (S)-omeprazole barium may also be obtained in amorphous form by concentrating the solution of (S)-omeprazole barium to dryness or by spray drying the solution. Solutions of (S)-omeprazole barium may be obtained from the salt-forming reaction in a suitable solvent or by dissolving crystalline (S)-omeprazole barium in a suitable solvent.
- (S)-omeprazole barium is a useful proton pump inhibitor and an antibacterial, and thus can be used to treat any condition that would be benefited by administration of a gastric acid secretion inhibitor. In particular, (S)-omeprazole barium can be used for the treatment or prophylaxis of gastric acid-related diseases and gastrointestinal inflammatory diseases in mammals and man, such as erosive or ulcerative gastroesophageal reflux disease (GERD), gastric ulcer, duodenal ulcer, reflux esophagitis, and gastritis. Furthermore, it may be used for treatment of other gastrointestinal disorders where a gastric antisecretory effect is desirable, for example in patients on NSAID therapy, in patients with gastrinomas, and in patients with acute upper gastrointestinal bleeding. It may also be used in patients in intensive care situations, and pre- and post-operatively to prevent acid aspiration and stress ulceration. Further, (S)-omeprazole barium may be useful in the treatment of helicobacter infections and diseases related to these.
- The salt can be administered as a component of a pharmaceutical composition. Accordingly, in a further aspect, there is provided a pharmaceutical composition that comprises (S)-omeprazole barium and pharmaceutically acceptable carriers, diluents or excipients and optionally other therapeutic ingredients. The salt may be conveniently formulated into tablets, capsules, suspensions, dispersions, injectables and other pharmaceutical forms. Any suitable route of administration may be employed for example, peroral or parental.
- In the following section preferred embodiments are described by way of examples to illustrate the process of the invention. However, these are not intended in any way to limit the scope of the present invention. Variants of these examples would be evident to persons ordinarily skilled in the art.
- General Experimenal Details—Powder XRD
- X-Ray Diffraction (XRD) patterns were taken with a diffractometer manufactured by Rigaku Coorperation, specifically the model RU-H3R. The goniometer was a CN2155A3, and the X-Ray tube was equipped with Cu target anode. The settings for the divergence slits were 1 0, for the receiving slit 0.15 mm, and for the
scatter slit 1 0. The operating power was 40 KV, 100 mA, the scanning speed was 2 deg/min step: 0.02 deg, and the wavelength was 1.5406 A. - General Experimental Details—FT-Infrared
- Infrarred spectra were take with a Perkin Elmer,16 PC, with scan parameters of 16 scans, 4.0 cm.−1 according to the
USP 25, general test methods, page 1920. Infrared absorption spectra were obtained by the potassium bromide pellet method. - General Experimental Details—Differential Scanning Calorimetry
- Differential Scanning Calorimetry was done by the model DSC821 e, manufactured by Mettler Toledo, with sample weights of 3-5 mg, and the sample temperature range of 25-100° C., heating rate of 1° C./min, nitrogen flow of 80.0 mL/min, with one hole in the crucible.
- (S)-omeprazole free base(5 g,) was added to methanol (25 ml) and stirred at 25-30° C. Barium hydroxide (4.6 g) dissolved in methanol (40 ml) was slowly added to the above solution in 10 minutes at 25-30° C. The reaction mixture was farther stirred for 1 to 2 hours, the obtained solid was filtered and washed with methanol. The product was air dried at 40 to 45° C. for 8 to 10 hours to get (S)-omeprazole barium (5.2 g).
- HPLC Purity=98.56%, Chiral Purity by HPLC=99.89%. MC % w/w by KF=4.12%. XRD, IR spectra are as shown in FIGS. I and II respectively, as shown in the accompanying drawings.
- Potassium salt of (S)-omeprazole (10.0 g) was stirred in water (80 ml) and methylene chloride (80 ml). The suspension was cooled to 10 to 15° C. and dilute hydrochloric acid was added to adjust pH to 7.0 to 8.5. The reaction mixture was stirred for 5 minutes. The organic layer was separated and washed with water. The solvent was recovered under reduced pressure at 30-35° C. to obtain an oily residue. Methanol (40 ml) was added, and the mixture stirred for 10 to 15 minutes. Barium hydroxide (9.0 g) dissolved in methanol (90 ml) was slowly added to the above solution in 10 minutes at 25-30° C. The reaction mixture was further stirred for 1 to 2 hours. The solid obtained was filtered, washed with methanol and air dried at 40 to 45° C. for 8 to 10 hours to get (S)-omeprazole barium (8.1 g).
- HPLC Purity=97.98%, Chiral Purity by HPLC=100%. MC % w/w by KF=7.46%. IR spectrum is as shown in FIG. III, as shown in the accompanying drawings. XRD spectrum is similar to that shown in FIG. II for Example I.
- (S)-omeprazole free base (5 g,) was added to acetone (60 ml) and stirred at 25-30° C. Barium hydroxide octahydrate (4.6) and water (15 ml) were then added to the above mixture at 25-30° C. The reaction mixture was further stirred for 4 to 5 hours, and then filtered to remove suspended solid material. The solvent was recovered under reduced pressure to obtain the product as a foam. The product was dried at 40 to 45° C. under reduced pressure for 2 to 3 hours to get (S)-omeprazole barium (4.2 g).
- HPLC Purity=99.43%, Chiral Purity by HPLC=99.99%, MC % w/w by KF=2.66%. XRD, IR spectra are as shown in FIGS. IV and V respectively, as shown in the accompanying drawings.
- Potassium salt of (S)-omeprazole (5 g,) was dissolved in water (60 ml) at 25-30° C. to get a clear solution. Barium chloride dihydrate (3.2 g) dissolved in water (10 ml) was slowly added to the above solution in 10 minutes at 25-30° C. The reaction mixture was further stirred for 1 to 2 hours, the obtained solid was filtered and washed with water. The product was air dried at 40 to 45° C. for 8 to 10 hours to get (S)-omeprazole barium (3.4 g), MC % w/w by KF=0.10%.
- XRD, IR spectra are as shown in FIGS. VI and VII respectively as shown in the accompanying drawings.
- Crystalline (S)-omeprazole barium (3 g,) was added to acetone (60 ml) and stirred at 25-30° C. The solution was then filtered to remove any suspended solid material. The solvent was recovered under reduced pressure at 40 to 45° C. to obtain the product as a foam. The product was dried at 40 to 45° C. under reduced pressure for 2 to 3 hours to get (S)-omeprazole barium (2.5 g). HPLC Purity=99.27%, MC % w/w by KF=2.10%.
- XRD, IR spectra are similar to those shown in FIGS. IV and V respectively for Example 3.
- Crystalline (S)-omeprazole barium (5.0 g,) was added to acetone (100 ml) and stirred at 25-30° C. The solution was then filtered to remove any suspended solid material and subjected to spray drying under nitrogen atmosphere (
inlet temperature 50 to 60° C. andoutlet temperature 40 to 45° C.). The product so obtained was dried at 40 to 45° C. under reduced pressure for 2 to 3 hours to get (S)-omeprazole barium (3.0 g). MC % w/w by KF=1.2%. - XRD, IR spectra are similar to those shown in FIGS. IV and V respectively for Example 3.
- While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Claims (26)
1. The barium salt of (S)-omeprazole.
2. The salt according to claim 1 in a crystalline form.
3. The salt according to claim 1 in an amorphous form.
4. A process for preparing (S)-omeprazole barium, comprising contacting (S)-omeprazole freebase, or its sodium or potassium salt, with the barium salt of an acid to form (S)-omeprazole barium, wherein the process is carried out in the presence of a base whenever (S)-omeprazole freebase is used.
5. The process according to claim 4 , wherein the barium salt of an inorganic acid is used.
6. The process according to claim 5 , wherein the barium salt is selected from the group consisting of barium chloride, barium nitrate, barium phosphate, barium carbonate, and barium sulphate.
7. The process according to claim 4 , wherein the barium salt of an organic acid is used.
8. The process according to claim 7 , wherein the barium salt is selected from the group consisting of barium oxalate, barium acetate, barium lactate, barium succinate, barium citrate, and barium tartrate.
9. The process according to claim 4 , wherein the base is selected from the group consisting of alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates and ammonium hydroxide.
10. The process according to claim 9 , wherein the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and sodium bicarbonate.
11. A process for preparing (S)-omeprazole barium, which comprises contacting (S)-omeprazole freebase with barium hydroxide in a suitable solvent.
12. The process according to claims 4 or 11, wherein the solvent is selected from the group consisting of water, ketone, alcohols, esters, cyclic ethers, chlorinated hydrocarbons, nitrile, dipolar aprotic solvent, and mixtures thereof.
13. The process according to claim 12 , wherein the solvent is selected from the group consisting of water, acetone, methanol and mixtures thereof.
14. The process according to claim 4 or 11 , wherein (S)-omeprazole barium precipitates spontaneously from the solvent.
15. The process according to claim 4 or 11 , wherein crystalline form of (S)-omeprazole barium is obtained.
16. The process according to claim 4 or 11 , wherein amorphous form of (S)-omeprazole barium is obtained.
17. A process for preparing (S)-omeprazole barium in amorphous form, which comprises concentrating a solution containing (S)-omeprazole barium to dryness, or spray drying the solution.
18. The process according to claim 17 , wherein the solution is obtained by dissolving crystalline (S)-omeprazole barium.
19. A method for treating or preventing gastrointestinal inflammatory diseases, which comprises administering an effective amount of (S)-omeprazole barium.
20. A method of inhibiting gastric acid secretion comprising administering (S)-omeprazole barium.
21. The method according to claim 19 or 20 , wherein (S)-omeprazole barium is used for treatment or prophylaxis of gastric acid-related diseases and gastrointestinal inflammatory diseases selected from the group consisting of erosive or ulcerative gastroesophageal reflux disease (GERD), gastric ulcer, duodenal ulcer, reflux esophagitis, and gastritis.
22. The method according to claim 19 to 21, wherein crystalline form of the (S)-omeprazole barium is used.
23. The method according to claim 19 to 21, wherein amorphous form of the (S)-omeprazole barium is used.
24. A pharmaceutical composition comprising (S)-omeprazole barium and pharmaceutically acceptable carriers, diluents or excipients.
25. The pharmaceutical composition according to claim 24 , wherein a crystalline form of (S)-omeprazole barium is used.
26. The pharmaceutical composition according to claim 24 , wherein an amorphous form of (S)-omeprazole barium is used.
Priority Applications (4)
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US12/467,051 US7872140B2 (en) | 2003-05-05 | 2009-05-15 | Barium salt of benzimidazole derivative |
US12/703,016 US8415478B2 (en) | 2003-05-05 | 2010-02-09 | Barium salt of benzimidazole derivative |
US12/703,004 US8404854B2 (en) | 2003-05-05 | 2010-02-09 | Barium salt of benzimidazole derivative |
US12/973,499 US20110086884A1 (en) | 2003-05-05 | 2010-12-20 | Barium salt of benzimidazole derivative |
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IN665/DEL/2003 | 2003-05-05 | ||
IN665DE2003 | 2003-05-05 | ||
PCT/IB2004/001347 WO2004099181A1 (en) | 2003-05-05 | 2004-05-03 | Barium salt of benzimidazole derivative |
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PCT/IB2004/001347 A-371-Of-International WO2004099181A1 (en) | 2003-05-05 | 2004-05-03 | Barium salt of benzimidazole derivative |
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US12/703,016 Expired - Fee Related US8415478B2 (en) | 2003-05-05 | 2010-02-09 | Barium salt of benzimidazole derivative |
US12/703,004 Expired - Fee Related US8404854B2 (en) | 2003-05-05 | 2010-02-09 | Barium salt of benzimidazole derivative |
US12/973,499 Abandoned US20110086884A1 (en) | 2003-05-05 | 2010-12-20 | Barium salt of benzimidazole derivative |
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US12/703,016 Expired - Fee Related US8415478B2 (en) | 2003-05-05 | 2010-02-09 | Barium salt of benzimidazole derivative |
US12/703,004 Expired - Fee Related US8404854B2 (en) | 2003-05-05 | 2010-02-09 | Barium salt of benzimidazole derivative |
US12/973,499 Abandoned US20110086884A1 (en) | 2003-05-05 | 2010-12-20 | Barium salt of benzimidazole derivative |
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EP (1) | EP1633736A1 (en) |
CN (1) | CN1842525A (en) |
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WO2004099181A1 (en) * | 2003-05-05 | 2004-11-18 | Ranbaxy Laboratories Limited | Barium salt of benzimidazole derivative |
EP1801110A1 (en) | 2005-12-22 | 2007-06-27 | KRKA, tovarna zdravil, d.d., Novo mesto | Esomeprazole arginine salt |
EA200900985A1 (en) | 2007-01-31 | 2009-12-30 | Крка, Товарна Здравил, Д. Д., Ново Место | METHOD OF OBTAINING OPTICAL PURE OMEPRAZOL |
PT2106397E (en) | 2007-09-25 | 2012-01-23 | Hetero Drugs Ltd | A process for preparation of enantiomerically pure esomeprazole |
EP2499125B1 (en) | 2009-11-12 | 2016-01-27 | Hetero Research Foundation | Process for the resolution of omeprazole |
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PT1487818E (en) * | 2002-03-05 | 2007-07-18 | Astrazeneca Ab | Alkylammonium salts of omeprazole and esomeprazole |
AU2003262375A1 (en) * | 2002-04-22 | 2003-11-03 | Sun Pharmaceutical Industries Limited | Optically active substituted pyridinylmethyl-sulphinyl-benzimidazole and salts |
WO2004099181A1 (en) * | 2003-05-05 | 2004-11-18 | Ranbaxy Laboratories Limited | Barium salt of benzimidazole derivative |
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2004
- 2004-05-03 WO PCT/IB2004/001347 patent/WO2004099181A1/en not_active Application Discontinuation
- 2004-05-03 EP EP04730887A patent/EP1633736A1/en not_active Withdrawn
- 2004-05-03 US US10/555,628 patent/US20070060556A1/en not_active Abandoned
- 2004-05-03 CN CNA2004800162570A patent/CN1842525A/en active Pending
-
2009
- 2009-05-15 US US12/467,051 patent/US7872140B2/en not_active Expired - Fee Related
-
2010
- 2010-02-09 US US12/703,016 patent/US8415478B2/en not_active Expired - Fee Related
- 2010-02-09 US US12/703,004 patent/US8404854B2/en not_active Expired - Fee Related
- 2010-12-20 US US12/973,499 patent/US20110086884A1/en not_active Abandoned
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US5399700A (en) * | 1991-12-31 | 1995-03-21 | Sunkyong Industries Co., Ltd. | Method for preparing enteric-coated oral drugs containing acid-unstable compounds |
US5714504A (en) * | 1993-05-28 | 1998-02-03 | Astra Aktiebolag | Compositions |
US5900424A (en) * | 1993-07-09 | 1999-05-04 | Astra Aktiebolag | Omeprazole magnesium salt form |
US5948789A (en) * | 1994-07-15 | 1999-09-07 | Astra Aktiebolag | Process for synthesis of substituted sulphoxides |
US6162816A (en) * | 1996-12-20 | 2000-12-19 | Astrazeneca Ab | Crystalline form of the S-enantiomer of omeprazole |
US6511996B1 (en) * | 1999-01-28 | 2003-01-28 | Astrazeneca Ab | Potassium salt of (s)-omeprazole |
US6262085B1 (en) * | 1999-08-26 | 2001-07-17 | Robert R. Whittle | Alkoxy substituted Benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same |
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Also Published As
Publication number | Publication date |
---|---|
US20100145058A1 (en) | 2010-06-10 |
US20090259047A1 (en) | 2009-10-15 |
US20110086884A1 (en) | 2011-04-14 |
CN1842525A (en) | 2006-10-04 |
US20100137607A1 (en) | 2010-06-03 |
US8415478B2 (en) | 2013-04-09 |
WO2004099181A1 (en) | 2004-11-18 |
US7872140B2 (en) | 2011-01-18 |
US8404854B2 (en) | 2013-03-26 |
EP1633736A1 (en) | 2006-03-15 |
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