ZA200510178B - Alkaline salts of proton pump inhibitors - Google Patents
Alkaline salts of proton pump inhibitors Download PDFInfo
- Publication number
- ZA200510178B ZA200510178B ZA200510178A ZA200510178A ZA200510178B ZA 200510178 B ZA200510178 B ZA 200510178B ZA 200510178 A ZA200510178 A ZA 200510178A ZA 200510178 A ZA200510178 A ZA 200510178A ZA 200510178 B ZA200510178 B ZA 200510178B
- Authority
- ZA
- South Africa
- Prior art keywords
- pantoprazole
- hydrates
- compatible metal
- magnesium
- positive
- Prior art date
Links
- 229940126409 proton pump inhibitor Drugs 0.000 title claims description 20
- 239000000612 proton pump inhibitor Substances 0.000 title description 4
- 159000000011 group IA salts Chemical class 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 71
- 229960005019 pantoprazole Drugs 0.000 claims description 43
- IQPSEEYGBUAQFF-UHFFFAOYSA-N Pantoprazole Chemical compound COC1=CC=NC(CS(=O)C=2NC3=CC=C(OC(F)F)C=C3N=2)=C1OC IQPSEEYGBUAQFF-UHFFFAOYSA-N 0.000 claims description 27
- 150000004677 hydrates Chemical class 0.000 claims description 27
- 239000011777 magnesium Substances 0.000 claims description 26
- 239000003814 drug Substances 0.000 claims description 25
- 150000003839 salts Chemical class 0.000 claims description 22
- 229910052749 magnesium Inorganic materials 0.000 claims description 16
- 208000018522 Gastrointestinal disease Diseases 0.000 claims description 14
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 13
- IQPSEEYGBUAQFF-AREMUKBSSA-N 6-(difluoromethoxy)-2-[(r)-(3,4-dimethoxypyridin-2-yl)methylsulfinyl]-1h-benzimidazole Chemical compound COC1=CC=NC(C[S@@](=O)C=2NC3=CC=C(OC(F)F)C=C3N=2)=C1OC IQPSEEYGBUAQFF-AREMUKBSSA-N 0.000 claims description 11
- 229910052751 metal Inorganic materials 0.000 claims description 11
- 239000002184 metal Substances 0.000 claims description 11
- 229960000381 omeprazole Drugs 0.000 claims description 10
- 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 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 8
- 229960003174 lansoprazole Drugs 0.000 claims description 7
- MJIHNNLFOKEZEW-UHFFFAOYSA-N lansoprazole Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1CS(=O)C1=NC2=CC=CC=C2N1 MJIHNNLFOKEZEW-UHFFFAOYSA-N 0.000 claims description 7
- 229960004157 rabeprazole Drugs 0.000 claims description 7
- YREYEVIYCVEVJK-UHFFFAOYSA-N rabeprazole Chemical compound COCCCOC1=CC=NC(CS(=O)C=2NC3=CC=CC=C3N=2)=C1C YREYEVIYCVEVJK-UHFFFAOYSA-N 0.000 claims description 7
- ZBFDAUIVDSSISP-UHFFFAOYSA-N 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulfinyl]-1H-imidazo[4,5-b]pyridine Chemical compound N=1C2=NC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C ZBFDAUIVDSSISP-UHFFFAOYSA-N 0.000 claims description 6
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 6
- 229910021645 metal ion Inorganic materials 0.000 claims description 6
- 229950008375 tenatoprazole Drugs 0.000 claims description 6
- 239000011575 calcium Substances 0.000 claims description 4
- 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 description 4
- 229960004770 esomeprazole Drugs 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 3
- 229910052791 calcium Inorganic materials 0.000 claims description 3
- ZBFDAUIVDSSISP-DEOSSOPVSA-N 5-methoxy-2-[(s)-(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]-1h-imidazo[4,5-b]pyridine Chemical compound C([S@](=O)C=1NC2=CC=C(N=C2N=1)OC)C1=NC=C(C)C(OC)=C1C ZBFDAUIVDSSISP-DEOSSOPVSA-N 0.000 claims description 2
- YREYEVIYCVEVJK-VWLOTQADSA-N 2-[(s)-[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl]-1h-benzimidazole Chemical compound COCCCOC1=CC=NC(C[S@](=O)C=2NC3=CC=CC=C3N=2)=C1C YREYEVIYCVEVJK-VWLOTQADSA-N 0.000 claims 1
- ZBFDAUIVDSSISP-XMMPIXPASA-N 5-methoxy-2-[(r)-(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]-1h-imidazo[4,5-b]pyridine Chemical compound C([S@@](=O)C=1NC2=CC=C(N=C2N=1)OC)C1=NC=C(C)C(OC)=C1C ZBFDAUIVDSSISP-XMMPIXPASA-N 0.000 claims 1
- SGPGESCZOCHFCL-UHFFFAOYSA-N Tilisolol hydrochloride Chemical compound [Cl-].C1=CC=C2C(=O)N(C)C=C(OCC(O)C[NH2+]C(C)(C)C)C2=C1 SGPGESCZOCHFCL-UHFFFAOYSA-N 0.000 claims 1
- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 44
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 36
- 239000000243 solution Substances 0.000 description 30
- 238000003756 stirring Methods 0.000 description 21
- 229960004048 pantoprazole sodium Drugs 0.000 description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 239000002244 precipitate Substances 0.000 description 15
- 238000000354 decomposition reaction Methods 0.000 description 14
- IQPSEEYGBUAQFF-SANMLTNESA-N 6-(difluoromethoxy)-2-[(s)-(3,4-dimethoxypyridin-2-yl)methylsulfinyl]-1h-benzimidazole Chemical compound COC1=CC=NC(C[S@](=O)C=2NC3=CC=C(OC(F)F)C=C3N=2)=C1OC IQPSEEYGBUAQFF-SANMLTNESA-N 0.000 description 13
- 229940091250 magnesium supplement Drugs 0.000 description 13
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 12
- 239000000725 suspension Substances 0.000 description 12
- 238000004458 analytical method Methods 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- 238000011282 treatment Methods 0.000 description 8
- 159000000003 magnesium salts Chemical class 0.000 description 7
- 239000006186 oral dosage form Substances 0.000 description 7
- 238000003860 storage Methods 0.000 description 7
- -1 sulphinyl Chemical class 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 229960002337 magnesium chloride Drugs 0.000 description 6
- 229910001629 magnesium chloride Inorganic materials 0.000 description 6
- 229940050906 magnesium chloride hexahydrate Drugs 0.000 description 6
- DHRRIBDTHFBPNG-UHFFFAOYSA-L magnesium dichloride hexahydrate Chemical compound O.O.O.O.O.O.[Mg+2].[Cl-].[Cl-] DHRRIBDTHFBPNG-UHFFFAOYSA-L 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 239000012266 salt solution Substances 0.000 description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 230000009471 action Effects 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 239000011701 zinc Substances 0.000 description 5
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 4
- 241000282414 Homo sapiens Species 0.000 description 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 210000004211 gastric acid Anatomy 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- YNWDKZIIWCEDEE-UHFFFAOYSA-N pantoprazole sodium Chemical compound [Na+].COC1=CC=NC(CS(=O)C=2[N-]C3=CC=C(OC(F)F)C=C3N=2)=C1OC YNWDKZIIWCEDEE-UHFFFAOYSA-N 0.000 description 4
- 238000011321 prophylaxis Methods 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 229910052725 zinc Inorganic materials 0.000 description 4
- 206010013710 Drug interaction Diseases 0.000 description 3
- 238000003109 Karl Fischer titration Methods 0.000 description 3
- 230000009858 acid secretion Effects 0.000 description 3
- KLTWGRFNJPLFDA-UHFFFAOYSA-N benzimidazolide Chemical compound C1=CC=C2[N-]C=NC2=C1 KLTWGRFNJPLFDA-UHFFFAOYSA-N 0.000 description 3
- 230000002496 gastric effect Effects 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- RDRUTBCDIVCMMX-UHFFFAOYSA-N magnesium;5-(difluoromethoxy)-2-[(3,4-dimethoxypyridin-2-yl)methylsulfinyl]benzimidazol-1-ide Chemical compound [Mg+2].COC1=CC=NC(CS(=O)C=2[N-]C3=CC=C(OC(F)F)C=C3N=2)=C1OC.COC1=CC=NC(CS(=O)C=2[N-]C3=CC=C(OC(F)F)C=C3N=2)=C1OC RDRUTBCDIVCMMX-UHFFFAOYSA-N 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 230000028327 secretion Effects 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- 239000011592 zinc chloride Substances 0.000 description 3
- 235000005074 zinc chloride Nutrition 0.000 description 3
- MHCVCKDNQYMGEX-UHFFFAOYSA-N 1,1'-biphenyl;phenoxybenzene Chemical group C1=CC=CC=C1C1=CC=CC=C1.C=1C=CC=CC=1OC1=CC=CC=C1 MHCVCKDNQYMGEX-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 2
- 208000012895 Gastric disease Diseases 0.000 description 2
- 241000590002 Helicobacter pylori Species 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 229960003022 amoxicillin Drugs 0.000 description 2
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
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- 239000001110 calcium chloride Substances 0.000 description 2
- 229910001628 calcium chloride Inorganic materials 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 2
- 229960002626 clarithromycin Drugs 0.000 description 2
- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@](C)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AGOYDEPGAOXOCK-KCBOHYOISA-N 0.000 description 2
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- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 208000002551 irritable bowel syndrome Diseases 0.000 description 2
- 229960000282 metronidazole Drugs 0.000 description 2
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 2
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 2
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- 230000003287 optical effect Effects 0.000 description 2
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 description 2
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- 239000011734 sodium Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000004448 titration Methods 0.000 description 2
- SUBDBMMJDZJVOS-XMMPIXPASA-N (R)-omeprazole Chemical compound C([S@@](=O)C=1NC2=CC=C(C=C2N=1)OC)C1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-XMMPIXPASA-N 0.000 description 1
- MJIHNNLFOKEZEW-VWLOTQADSA-N 2-[(s)-[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methylsulfinyl]-1h-benzimidazole Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1C[S@](=O)C1=NC2=CC=CC=C2N1 MJIHNNLFOKEZEW-VWLOTQADSA-N 0.000 description 1
- RYOOHIUJEJZCFT-UHFFFAOYSA-N 2-[2-(diethylamino)ethylamino]-2-phenylacetic acid 3-methylbutyl ester Chemical compound CCN(CC)CCNC(C(=O)OCCC(C)C)C1=CC=CC=C1 RYOOHIUJEJZCFT-UHFFFAOYSA-N 0.000 description 1
- XILVEPYQJIOVNB-UHFFFAOYSA-N 2-[3-(trifluoromethyl)anilino]benzoic acid 2-(2-hydroxyethoxy)ethyl ester Chemical compound OCCOCCOC(=O)C1=CC=CC=C1NC1=CC=CC(C(F)(F)F)=C1 XILVEPYQJIOVNB-UHFFFAOYSA-N 0.000 description 1
- 231100000699 Bacterial toxin Toxicity 0.000 description 1
- GNWUOVJNSFPWDD-XMZRARIVSA-M Cefoxitin sodium Chemical compound [Na+].N([C@]1(OC)C(N2C(=C(COC(N)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)CC1=CC=CS1 GNWUOVJNSFPWDD-XMZRARIVSA-M 0.000 description 1
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
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- XIURVHNZVLADCM-IUODEOHRSA-N cefalotin Chemical compound N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC(=O)C)C(O)=O)C(=O)CC1=CC=CS1 XIURVHNZVLADCM-IUODEOHRSA-N 0.000 description 1
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Description
© WO 2005/011692 PCT/EP2004/051578
ALKALINE SALTS OF PROTON PUMP INHIBITORS
Sublect-matter of the invention
The present invention relates to alkaline salts of proton pump inhibitors. The novel salts can be used in the pharmaceutical industry for preparing medicaments.
Technical back
Owing to their HK -ATPase-inhibitory action, pyridin-2-ylmethylsulphinyi-1H-benzimidazoles. such as those known, for example, from EP-A-0005129, EP-A-0166287, EP-A-0174726 and EP-A-0268958, are of considerable importance in the therapy of disorders associated with an increased secretion of gastric acid.
Examples of active compounds from this group which are commercially available or in clinical develop- ment are 5 methoxy-2.[(4-methory-3,5-dimethyl-2-pyridinymethyisuiphinyl1 H-benzimidazole (INN: omeprazole), (Sy 6 methory-2-(4-methory-35-dmethyt-2-pyrdinymetnyisuptiny H-benzimidazole (INN: esomeprazole), "ih oromethoxy-2-[(3.4-dmethoxy-2-pyrdinymelhylsuiphinyl- tH benzimice zole (INN: pantoprazole), 2 3 methyt-4-(2.2.2 fuoroethony) 2 pyrdinynetnyisuphinyl tr benz dazole (INN: lansoprazole), 2-4-3 methoxypropoxy)-3-methyipyridin-2-yjmethylsuiphiny-1 H-benz- imidazole (INN: rabeprazole) and & methaxy-2-((4-methoxy-3,5-dimethy-2-pyridyimettiysuiphiny)-F- imidazol4,5-blpyridine (INN: tenatoprazole).
The abovementioned sulphinyl derivatives are, owing to their mechanism of action, also referred to as proton pump inhibitors or, abbreviated, as PPL.
Prior art
For the first ime, the European Patent Application 80602 describes the specific preparation of a sodium and of a calcium salt of a certain pyridin-2-yimethyisulphinyi-1 H-benzimidazole compound.
Later on, the European Patent Application 124405 (US 4738974) describes and claims novel salts of omeprazole with cations, such as the LI*, Na*, K*, Mg", Ca”" or Ti** cation.
A common property of all of the abovementioned PPI is their sensitivity to acids (ultimately essential for effectiveness) which becomes apparent in their strong tendency to decompose in a neutral and in par- ticular an acidic environment, giving rise fo intensely coloured decomposition products. In the past, there has been no lack of considerable efforts, in spite of the sensitivity of the PPI to acids, to obtain stable and storable oral dosage forms comprising these PPI. A very common procedure to obtain stable oral PPI dosage forms, such as tablets, is the addition of an alkaline reacting compound, such as sodium carbonate, to the oral dosage form in order to render the micro-environment of the acid-
1212WOORDO01 2004-07 02 lablle PPI a pH of 7-12 (cf. European Patent 244380). Accordingly, stable and storable oral dosage forms (for example tablets or capsules) are now obtainable. However, the preparation of these oral dosage forms is relatively complicated, and with respect to the packaging too, certain complicated precautions have to be taken so that the dosage forms are sufficiently stable on storage even under extreme storage conditions (for example in tropical regions at high temperatures and high atmospheric humidity). Furthermore, in the past, there has been no lack of efforts to tailor the release of the PPI in the human body in the best possible manner to the respective requirements.
The international patent application W092/08716 describes a chemical process, which allows pyridin- 2-yimethylsulphinyi-1 H-bsnzimidazoles to be separated into their optical antipodes. The compounds mentioned as being prepared in an exemplary manner include, inter alia, the compounds (+) and (-)-5- difluoromethoxy-2-[(3.4-dimethoxy-2-pyridinylmethylsulphinyf}-1 H-benzimidazole [= (+)- and (-}- pantoprazole]. The international patent application WO092/08716 mentions that the optical antipodes of the pyridin-2-yimethylsulphinyl-1H-benzimidazoles, i.e. the (+)- and (-)}-enantiomers or the (R)- and (S)- enantiomers, are useful as active compounds in medicaments for the treatment of gastrointestinal disorders. For the mode of application and the dosage of the active compounds, reference is made, inter alia, to the European patent 166 287.
During a symposium held in Montreal in September 1993, a poster of Kohl et al. was presented which showed synthesis and biological activity of enantiomers of pantoprazole.
The intemational patent applications WO094/24867 and W(094/25028 claim the use of the compounds (-y- and (+)-pantoprazole for treating gastric disorders in humans. Each sterecisomer is sald to have medical advantages compared to the respective other stereoisomers. The descriptions also mention a number of different possible salts of the stereoisomers, and particular preference is given to the sodium salt in intemational patent application WO94/27988 (US 5693818), certain salts of (+) and (-)-omeprazole and methods for their preparation are disclosed.
The intemational patent application WO97/411 14 describes a certain process for preparing magnesium salts of pyridin-2-yimethyisulphinyl-1 H-benzimidazoles. What Is described in an exemplary manner is, inter alia, the preparation of the magnesium salt of pantoprazole. According to the given analytical data, the salt that is prepared is pantoprazole magnesium in anhydrous form.
The intemational patent application WO00/ 10995 (US 6410569) describes the dihydrate of the magnesium salt of racemic pantoprazole.
1212WOORD01 2004-07 02
U. S. Patent 6369085 relates to a novel form of the magnesium salt of the S-enantiomer of omeprazole trihydrate and to processes for preparing such a form of the magnesium salt of S-omeprazole and phamaceutical compositions containing it
The intemational patent application W002/045693 (DE 10061137) describes a novel preparation, which Is suitable for producing pharmaceutical dosage forms. In the new preparation the active ingredient, which is for example a PP! or a salt thereof, is present essentially uniformly dispersed in an excipient matrix composed of one or more excipients selected from the group of fatty alcohol, triglyceride, partial glyceride and fatty acid ester.
U. S. Patent 5997903 relates to oral presentation forms for pantoprazole, which consist of a core, an intermediate layer and an outer layer which is resistant to gastric juice.
The intemational patent application WO004/013126 describes (S)pantoprazole magnesium and hydrates thereof.
Description of the invention it has now been found that alkaline reacting salts of PPI can be produced, which on account of thelr properties and high stability are outstandingly suited for the further processing in oral dosage forms, even without addition of another alkaline reacting compound.
Accordingly, the invention provides in a general aspect alkaline reacting salts of pyridin-2-ylmethyt- sulphinyl-1H-benzimidazoles with H*/Kt-ATPase-inhibitory activity.
According to the invention, "alkaline reacting salts" is understood to include phamacologically compatible metal salts of pyridin-2-yimethylsulphinyl-1 H-benzimidazoles with H*/K*-ATPase-inhibitory activity, in which at least one positive charge equivalent of the metal ion is counterbalanced by a hydroxyl ion.
According to the invention, “pyridin-2-yimethylsulphinyl-1 H-benzimidazoles with H*/K*-ATPase- inhibitory activity” is understood to include pantoprazole, omeprazole, lansoprazole, rabeprazole and tenatoprazole in racemic form, as well as the enantiomers of these compounds, such as (R)- and (S)- pantoprazole, (R) and (S)-omeprazole, (R)- and (S)-lansoprazole, (R)- and (S)-rebeprazole and (R)- and (S)-tenatoprazole in pure form, mixtures thereof in any desired ratio, including in particular an enantiomer being substantially free of the respective other enantiomer.
1212WOORD01 2004-07 02
In particular, the alkaline reacting salts of pyridin-2-yimethylsulphinyi-1H-benzimidazoles with HK
ATPase-inhibitory activity according to the invention can be characterized by the general formula 1 [MelPPIMOH] (1) in which
Me is a pharmacologically acceptable two-valued metal ion,
PP! is a compound selected from pantoprazole, omeprazole, lansoprazole, rabeprazole and tenatoprazole and their enantiomers,
OH is a hydroxyl lon,
X is a positive, whole number from 1to3,
Y is a positive, whole number from 1 to 5 and
Z is a positive, whole number from 1 to 5, whereby the equation (Y + Z) = 2X applies.
More particularly, the invention provides compounds of the formula 1, in which
Me is a pharmacologically acceptable two-valued metal ion selected from magnesium, calcium and zinc,
PP! is a compound selected from pantoprazole, omeprazole, lansoprazole and rabeprazole and their enantiomers,
OH is a hydroxyl lon,
X is the number 1 of 2,
Y is a positive, whole number from 1 to 3 and
Z is a positive, whole number from 1t03, whereby the equation (Y + Z) = 2X applies.
A preferred subject of the invention are compounds of the formula 1, in which
Me is magnesium,
PPI is a compound selected from pantoprazole, (R)-pantoprazole and (S)-pantoprazole,
OH is a hydroxyl ion,
X is the number 1 or 2,
Y is the number 1 or 3 and
Z is the number 1 or 3, whereby the equation (Y + Z) = 2X applies.
A particular preferred subject of the invention are compounds of the formula 1, in which
Me Is magnesium,
1212WOORD01 2004-07 02
PP is (S)-pantoprazole, substantially free of (R)-pantoprazole,
OH is a hydroxyl ion,
X is the number 1 of 2,
Y is the number 1 or 3 and
Z is the number 1 or 3, whereby the equation (Y + Z) = 2X applies. it has now been found that the sodium salt of (-)- or (S)-pantoprazole, which is particularly preferred in the international patent application WO 04/24867, does not form a stable storage form. During attempts to obtain a stable oral dosage form for (-)-pantoprazaie, it has now been found that alkaline reacting magnesium salts of (S)-pantoprazole, in particular in hydrate form, have highly surprising stability properties, making them particularly suitable candidates for use in solid or oral dosage forms.
Compared to the sodium salt of (-)-pantoprazole, they has considerably improved stability properties.
Thus, for example, the compound of formula 1, in which Me is magnesium, PPlis (S)-pantoprazole, X is1,YistandZis 1 in its hydrate form is, at 70°C, completely stable for one week and shows virtually no discolouration or decomposition, whereas over the same period of ime and under identical conditions, the colour of the hydrate of (-}pantoprazole sodium changes to brown, with formation of considerable amounts of decomposition products. in addition, the compound of formula 1, in which Me is magnesium, PPL is (S)-pantoprazole, Xis1,Yis1andZis1in its hydrate form shows a surprising and unexpected faster dissolution than the racemic pantoprazole magnesium dihydrate.
The compounds according {o the invention and their hydrates can be used for the treatment and prevention of all disorders, which can be treated or prevented by using PPL. In particular, the compounds according to the invention and thek hydrates can be used for treating gastric disorders. In this context, particular mention should be made of the relatively high stability of compounds according to the invention and their hydrates. For example, on storage under atmospheric conditions, the sum of by-products in [MgJi(S)-pantoprazole][OH}xH.0 remains virtually constant, whereas in the case of (-}- pantoprazole sodium, under identical conditions (storage at 60-70°C) the purity (according to HPLC) decreases from 99.5 to 96-97 %. This relatively high storage stability makes the compounds according to the invention and their hydrates particularly suitable for use In medicaments.
The compounds according to the invention and their hydrates are preparedin a specific manner by reacting the PPI with a Me-salt in the presence of an alkali-hydroxide, or from a readily soluble PP! salt (for example (-)-pantoprazole sodium), using for example a magnesium salt, such as magnesium chloride, an sodium hydroxide solution, in water or in mixtures of water with polar organic solvents (for example alcohols, preferably methanol, ethanol or isopropanol, or ketones, preferably acetone).
Me-salts suitable for use in the process are, for example, Me-chloride, Me-bromide, Me-fluoride, Me- iodide, Me-formate, Me-acetate, Me-propionate, Me-gluconate or Me-carbonate. it is also possible to react Me-alkoxides (for example Me-methoxide, Me-ethoxide, Me-(iso)propoxide, Me-butoxide, Me-
1212WOORD01 2004-07 02 hexoxide or Me-phenoxide) in alkoholate medium with a reackly soluble PPI salt in the presence of an alkali-hydroxide solution and to crystallise the alkaline PP! sait in its hydrate form by addition of water.
Furthermore it is possible to recrystallise the compounds according to the invention and their hydrates from e.g. methanol/water mixtures.
The examples below illustrate the invention in more detail, without limiting it. m. p. denotes melting point, min. denotes minute(s), h denotes hour(s).
1212WOORD01 2004-07 02
Examples 1. nesium {[5-{d! methoxy}]- -dimethoxy-2 dl thylsulphiny(}-1H- benzimidazolide} hydroxy monohydrate
Formula [Pantoprazole’ OH’ Mg?" H,0]: C1sHizF2NsOsSMg 10.7 g of pantoprazole sodium sesquihydrate are dissolved in 110 mi of water. 2.48 g of NaOH 40 % are added at 25 °C and the solution is stirred for 1 h. 5.01 g of magnesium chloride hexahydrate are dissolved in 20 mi of water, the solution is added drop wise under stirring at 25 °C to the pantoprazole sodium salt solution. Stirring is continued for 1 h. The resulting suspension is filtered with suction, the pracipitate washed with 50 ml of water. The precipitate is re-suspended in 100 mi of water and again filtered and dried in a vacuum dryer (< 50 mbar) at 40 — 45 °C to give 10.76 g (94.6 %) of the title compound of m. p. 184-187 °C (decomposition) as off-white solid.
Analysis: expected found
Cc 43,51 43,87
H 3,88 4,10
N 9,51 9,68
Mg 550 52 2. Magnesium (3-{[5-{ifluoromethoxy)}-2-I(3 A-dimethoxy-2-pyridinylmethylsulphinyli-tH: benzimidazolide} hydroxy monohydrate
Formula [(S)-Pantoprazole’ OH Mg?" H.0]): C1eHi7F2Ns0:SMg 10.9 g of (-)-pantoprazole sodium salt are dissolved in 110 mi of water. 2.48 g of NaOH 40 % are added at 50 °C and the solution Is stirred for 1 hour. The solution is cooled to room temperature. 5.01 g of magnesium chioride hexahydrate are dissolved in 20 mi of water. The magnesium chloride solution is added drop wise under stirring at 25 °C to the (-}-pantoprazole sodium salt solution. Stirring is continued for 18 h. The resulting suspension is filtered with suction, the precipitate washed with 50 ml of water. The precipitate is re-suspended in 100 ml of water and again filtered and dried in a vacuum dryer (< 50 mbar) at 40 — 45 °C to give 10.01 g (88.0 %) of the title compound of m. p. 164-167 °C (decomposition) as off-white solid
Specific rotation: ap?” = -123 (c= 0.5, methanol)
Analysis: axpected found
Cc 43.51 43.66
H 3.88 4.16
N 9.51 9.63
Mg 5.50 5.6
1212WOORDO01 2004-07 02 3. Magnesium (+){f5-{cfiuoromethoxy}}-2-{(3.4-dimethoxy-2-pyridinyl)methylsulphinyll- 1H: benzimidazolide} hydroxy sesquihydrate
Formula [2 (R)-Pantoprazole 20H 2Mg™" 3H,0]): CaoHxaFNgO1: SMa: 5.0 g of (+)-pantoprazole sodium salt are dissolved in 50 mi of water. 1.23 g of NaOH 40 % are added at 35 °C and the solution is stirred for 1 h. The solution is cooled to room temperature. 2.50 g of magnesium chloride hexahydrate are dissolved in 15 mi of water. The magnesium chloride solution is added drop wise under stirring at 25 °C to the (+)-pantoprazole sodium salt solution. Stiring is continued for 18 h. The resulting suspension is filtered with suction, the precipitate washed in 3 portions with 50 ml of water and dried in an vacuum dryer (< 50 mbar) at 50 — 55 °Ctogive 4.339 (74.6 %) of the title compound of m. p. 161-165 °C (decomposition) as off-white solid
Specific rotation: ap?” = +112 (c= 0.5, methanol)
Analysis: expected found
Cc 42.64 42.44
H 4.03 4.02
N 9.32 9.31 4. Di-Magnesium tris -{T5-(difluoromethoxy}l-2-(3.4-dimethoxy-2-pyridinyi)methylsulphinyfl-4H- benzimidazolide} hydroxy tetrahydrate
Formula [3 Pantoprazole’ OH 2Mg®* 4H,0): CssHs1FsNsO1rS:Mg2 25.0 g of pantoprazole sodium sesquihydrate are dissolved in 250 mi of water. 1.33 ml of NaOH 40 % are added at 25 °C and the solution is stirred for 15 min. 3.92 g of magnesium chloride hexahydrate are dissolved in 31 mi of water. The magnesium chloride solution is added drop wise under stirring at °C to the pantoprazole sodium salt solution. Stirring is continued for 2.5 h. The resulting suspension is filtered with suction, the precipitate washed In 3 portions with 150 ml of water. The precipitate is dried in a vacuum dryer (< 50 mbar) at 40 —45 °C to give 12.47 g (52.7 %) of the tite compound of m. p. 182-185 °C (decomposition) as off-white solid.
Analysis: ___ expected” found
Cc 44,87 45,50
H 4,00 4,03
N 9,81 10,01
Mg 3,78 3,9 *as tetrahydrate
1212WOORD01 2004-07 02 5. Di-Magnesium (-)-tris{I5 difluoromethoxy)]-2-{(3.4-dimethox 2 dinyl}methylisulphinyl}- 1H-benzimidazolide} hydroxy pentahydrate
Formula [3 (S)-Pantoprazole’ OH 2Mg** 54,0]: C «sHasFeNgO1sS3Mg2 6.0 g of (-)-pantoprazole sodium are dissolved in 60 mi of water. 0.49 g of NaOH 40 % are added at 30 - 35 °C and stirred for 15 min. 1.02 g of magnesium chloride hexahydrate are dissolved in 8 mt of water. The magnesium chloride solution is added drop wise under stirring at 25 °Cto the (-)- pantoprazole sodium salt solution. Stirring is continued for 18 h. The resulting suspension is filtered with suction, the precipitate washed in 2 portions with 50 ml of water. The precipitate is dried Ina vacuum dryer (< 50 mbar) at 80 °C to give 2.41 g (48.3 %) of the tite compound of m. p. 162-166°C (decomposition) as off-white solid.
Specific rotation: ox” = -125 (c= 0,5 in Methanol)
Analysis: expected” found
Cc 44,25 44.34
H 410 4,29
N 9,68 9,80 *as pentahydrate 6. Di-Magnesium (#)-tris-{15-{dfluoromathoxyl]-2-[(3.&-dimethoxy-2-pyridinvi)methyisulphinyll {H-benzimldazolide} hydroxy pentahydrate
Formula [3 (R)-Pantoprazole’ OH 2Mg”* 5H.0}): CHssFeNs016S:Mg2 5.0 g of (+)-pantoprazole sodium are dissolved in 50 mi of water. 0.27 mi of NaOH 40 % are added at - 35 °C and the solution is stirred for 15 min. 0.78 g of magnesium chloride hexahydrate are dissolved in 6 ml of water. The magnesium chloride solution is added drop wise under stirring at 25 °C to the (+)-pantoprazole sodium salt solution. Stirring is continued for 2 days. The resulting suspension is filtered with suction, the precipitate washed in 3 portions with 25 ml of water. The precipitate Is dried in a vacuum dryer (< 50 mbar) at 40 °C to give 2.10 g (40.1 %) of the title compound of m. p. 161- 166°C (decomposition)as off-white solid.
Specific rotation: ap? = +114,5 (c= 0.5 in Methanol)
Analysis: expected” found [o] 44,25 44.81
H 4,10 4,05
N 9,68 9,79
M 3,73 42 *as pentahydrate
1212WOO0RD01 2004-07 02 7. Calclum diftuoromethoxy)]-2-(3.4-dimetho: -2 dinyl)methylsuiphinyl]-1H-
Idazolide roxy monoh
Formula [Pantoprazole” OH Ca” H,0]: C1gHirF2N0SC3 21.6 g of pantoprazole sodium sesquihydrate are dissolved in 250 mi of water. 2.00 g of NaOH are added at 25 °C and the solution is stirred for 1 hour. 5.55g of calcium chloride (dry) are dissolved in 50 mi of water. The calcium chloride solution is added drop by drop under stirring at 25 °C to the pantoprazole sodium solution. Stirring is continued for 20 hours. The resulting suspension is filtered with suction, the precipitate is washed with 200 mi of water and dried in a vacuum dryer (< 50 mbar) at 40 — 45 °C to afford 21.86 g (91.8 %) of the title compound as off-white solid.
Water (Karl-Fischer titration): 7.6%
Melting point: 157-160 °C (decomposition)
Analysis: expected found [o] 42.01 42,63
H 3.75 3.95
N_ 910 913 8. Calcium ()-{I5-{difiuoromethoxy)]-2-i(3 4-dimethoxy-2-pyridinylimethyisulphiny[-1H: benzimidazollde} hydroxy monohydrate
Formula [Pantoprazole’ OH Ca” H;0]: C1sH1F2N30SCa 22.7 g of (-)-pantoprazole sodium (wet, 0.05 mol) are dissolved in 250 ml of water. 2.00 g of NaOH are added at 25 °C and the solution is stirred for 1 hour at 40 °C. 5.559 of calcium chloride (dry) are dissolved in 50 mi of water. The calcium chloride solution is added drop by drop under stirring at 25 °C to the pantoprazole sodium solution. Stirring is continued for 20 hours. The resulting suspension is filtered with suction, the precipitate is washed with 200 ml of water and dried in a vacuum dryer (< 50 mbar) at 40 — 45 °C to afford 21.44 g (89.9 %) of the title compound as off-white solid.
Water (Kari-Fischer titration): 7.8%
Melting point 137-147 °C (decomposition)
Analysis: I — expected found
Cc 42.01 41.74
H 3.75 3.81
N 9.19 8.99
1212WOO0RD01 2004-07 02 9. Zinc {I5-(difluoromethoxy)}-2-{(3.4-dIimetho -2-pyridinyl)methylsulphinyi]-1H- ml lide} h nohyd
Formula [Pantoprazole’ OH Zn** H,0]: C1eHuF2NsOeSZN 21.6 g of pantoprazole sodium sesquihydrate are dissolved in 250 mi of water. 2.00 g of NaOH are added at 25 °C and the solution is stirred for 1 hour. 6.80 g of zinc chloride (dry) are dissolved in 50 mi of water. The zinc chioride solution is added drop by drop under stirring at 25 °C to the pantoprazole sodium solution. Stirring is continued for 20 hours. The resulting suspension is filtered with suction, the precipitate is washed with 200 mi of water and dried in a vacuum dryer (< 50 mbar) at 40 -45°Cto afford 23.08 g (94.2 %) of the title compound as off-white solid.
Water (Karl-Fischer titration): 5.1 %
Melting point 167-179 °C (decomposition)
Analysis: expected _ found o] 39.81 40.55
H 3.65 3.25
N 8.70 8.74 10. Zinc (A-{I5-(difluoromethoxy)]-2-{(34-dimethoxy-2-pyridiny()methylsulphiny(}-1 H- benzimidazolide} hydroxy monohydrate
Formula [(S)-Pantopr azole OH’ mn HO}: CHy7F2N:052Zn 22.7 g of (-)-pantoprazole sodium (wet, 0.05 mol) are dissolved in 250 ml of water. 2.00 g of NaOH are added at 25 °C and the solution is stirred for 1 hour. 6.80 g of zinc chloride (dry) are dissolved in 50 ml of water. The zinc chloride solution is added drop by drop under stirring at 25 °C to the pantoprazole sodium solution. Stirring is continued for 20 hours. The resulting suspension is filtered with suction, the precipitate is washed with 200 mi of water and dried in a vacuum dryer (< 50 mbar) at 40-45 °C to afford 22.87 g (94.2 %) of the title compound as off-white solid.
Water (Karl-Fischer titration): 4.3 %
Melting point: 169-173 °C (decomposition)
Analysis: et ——————————— expected found
Cc 39.81 40.81
H 3.55 3.24
N 8.70 8.80
1212WOORD01 2004-07 02 : 11. Magnesium ()-{[5-dlfiuoromethoxy]l:2-{(34-dimethoxy-2-pyridinylimethyisulphinyl}-1H: benzimidazolide} hydroxy monohydrate
Formula [(S)-Pantoprazole’ OH’ Mg?" H,0]: CyeHirFaN:;0:SMg 6.20 kg of (-)-pantoprazole sodium (wet, 14.06 mol) are dissolved in 64 | of water. 0.56 kg of NaOH are added at room temperature and the solution is stirred for 1 hour at 40 °G. The solution is cooled to room temperature. 2.86 kg of magnesium chloride hexahydrate are dissolved in 11.41 of water. The magnesium chioride solution is added under stirring at 25 °C to the (-}pantoprazole sodium solution.
Stirring is continued for 18 hours. The resulting suspension is centrifuged, the precipitate is washed with 41 1 of water and dried in a vacuum dryer (< 50 mbar) at 40 -45°C to afford 3.97 kg (58.84 % of the title compound as off-white solid).
Purity (HPLC): 99.4 % ee: >89 %
Water (Kar-Fischer titration): 7.7 %
Analysis: expected found
Cc 43.51 43.05
H 3.88 397
N 9.51 9.35
Ss 126 724
1212WOORD01 2004-07 02
Commercial utllity
The compounds according to the invention and their hydrates have useful pharmacological properties, rendering them commercially utilizable. In particular, they have a pronounced inhibitory offoct on the secretion of gastric acid and excellent gastrointestinal protective action in warm-blooded animals, in particular man. Due to their unique stability characteristics, the compounds according to the invention and their hydrates are particularly suited for the production of stable oral PPI dosage forms. By the presence of the hydroxyl jon in the compounds according to the invention, the PP, which are acid- labile and susceptible to traces of acid, have a self-protection against undesired decomposition on storage.
In context of the invention, “gastrointestinal protection” is to be understood as the prevention and treatment of gastrointestinal disorders, in particular gastrointestinal inflammatory disorders and lesions (such as, for example, Ulcus ventriculi, Ulcus duodeni, gastiitis, irritable bowel owing to an increased production of acid or as a result of medicaments, GERD, Crohn's disease, IBD) which may be caused, for example, by microorganisms (for example Helicobacter pylori), bacterial toxins, medicaments (for example certain antiphlogistics and antirheumatic drugs), chemicals (for example ethanol), gastric acid or stress.
With their excellent properties, selected compounds according to the invention and their hydrates are, in various models for the determination of antiulcerogenic and antisecretory properties, surprisingly clearly superior to the prior-art compounds, in particular with respect to their stability and their phamacological properties. Owing to these properties, the compounds Mgll(S) pantoprazole][OH]xH-0 and [Mg]:[(S)-pantoprazole]{OH]xH0 for example are highly suitable for use in human and veterinary medicine, where they are used, in particular, for the treatment and/or prophylaxis of gastrointestinal disorders.
Accordingly, the invention furthermore provides compounds according to the invention and their hydrates for use in the treatment and/or prophylaxis of the abovementioned diseases.
The invention also embraces the use of compounds according to the invention and their hydrates for preparing medicaments used for the treatment and/or prophylaxis of the abovementioned diseases.
Furthermore, the invention embraces the use of compounds according to the invention and their hydrates for the treatment and/or prophylaxis of the abovementioned diseases.
The invention also provides medicaments comprising compounds according to the invention and their hydrates.
1212WOORDO1 2004-07 02
The medicaments are prepared by processes known per se which are familiar to the person skilled in the art. As medicaments, the compounds according to the invention and thelr hydrates are employed either as such or, preferably, in combination with suitable pharmaceutical auxiliaries or carriers in the form of tablets, coated tablets, capsules, suppositories, plasters (for example as TTS), emulsions, suspensions or solutions, where the content of active compound is advantageously from 0.1 to 95% and where it is possible to produce pharmaceutical dosage forms (for example flow-release forms or enteric forms) which, by the appropriate choice of auxiiiaries and carriers, are tailored for the active compound and/or the desired onset of action and/or the duration of action.
The auxiliaries or carriers suitable for the desired pharmaceutical formulations are known to the person skilled in the art owing to his expert knowledge. in addition to sotvents, gel formers, suppository bases, tabletting auxiliaries and other carriers for active compounds, it is possible to use, for example, anti- oxidants, dispersants, emulsifiers, antifoams, flavour-masking agents, preservatives, solubilizers, colo~ rants or, in particular, permeation promoters and complex formers (for example cyclodextrins).
The compounds according to the invention and their hydrates can be administered orally, parenterally or percutaneously. in human medicine, it has generally been found to be advantageous to administer the compounds according to the invention and their hydrates, when given orally, in a daily dose of from about 0.1 to 2, preferably 0.2 to 1.5 and in particular 0.3 to 1.1, mg/kg of body weight [based on the PPI), if appropriate in the form of a plurality of, preferably 1 to 4, individual doses, to obtain the desired result. For parenteral treatment, it is possible to use similar or (in particular when the active compounds are administered intravenously) generally lower dosages. The optimum dosage and the type of administration of the active compounds required in each case can easily be determined by the person skilled in the art, owing to his expert knowledge.
A further aspect of the invention is thus a medicament, comprising a compound according to the invention or its hydrate together with customary auxiliaries, where the single dose comprises from 10to 100 mg of PPL.
A further aspect of the Invention Is a medicament, comprising a compound according to the invention or its hydrate together with customary auxiliaries, where the single dose comprises from 20 to 80 mg of (-)y-pantoprazole.
A further aspect of the invention is the use of a compound according to the invention or its hydrate for treating gastrointestinal disorders.
A further aspect of the invention is the use of a compound according to the invention or its hydrate for treating gastrointestinal disorders in patients who are slow metabolizers.
1212WOORD01 2004-07 02
A further aspect of the invention Is the use of a compound according to the invention or its hydrate for treating gastrointestinal disorders in patients who have a risk for drug interactions.
A further aspect of the invention is the use of a compound according to the invention or its hydrate for treating gastrointestinal disorders in patients who need an inhibition of acid secretion for a longer period of time.
A further aspect of the Invention is a medicament for treating gastrointestinal disorders for use in patients who are slow metabolizers, comprising a compound according to the invention or its hydrate together with customary auxiliaries, where the single dose comprises from 10 to 100 mg of the PPL.
A further aspect of the invention is a medicament for treating gastrointestinal disorders for use in patients who are slow metabolizers, comprising a compound according to the invention or its hydrate together with customary auxiliaries, where the single dose comprises from 20 to 80 mg of the PPI.
A further aspect of the invention is a medicament for treating gastrointestinal disorders for use in patients who have a risk for drug interactions, comprising a compound according to the invention or its hydrate together with customary auxiliaries, where the single dose comprises from 10 to 100 mg of the
PPL.
A further aspect of the invention is a medicament for treating gastrointestinal disorders for use in patients who have a risk for drug interactions, comprising a compound according to the invention or its hydrate together with customary auxiliaries, whare the single dose comprises from 20 to 80 mg of the
PPL.
A further aspect of the invention is a medicament for treating gastrointestinal disorders for use in patients who need an inhibition of acid secretion for a longer period of time, comprising a compound according to the invention or its hydrate together with customary auxiliaries, where the single dose comprises from 10 to 100 mg of the PPI.
A further aspect of the invention is a medicament for treating gastrointestinal disorders for use in patients who need an inhibition of acid secretion for a longer period of ime, comprising a compound according to the invention or its hydrate together with customary auxiliaries, where the single dose comprises from 20 fo 80 mg of the PPI.
If a compound according to the invention or its hydrate is to be used for treating the abovementioned diseases, the pharmaceutical preparations may also comprise one or more phammacologically active ingredients from other groups of medicaments. Examples which may be mentioned are: tranquilizers (for example from the group of the benzodiazepines, e. g. diazepam), spasmolytic drugs (e. g. bletami-
1212WOORD01 2004-07 02 verine or camylofine), anticholinergic drugs (e. g- oxyphencyclimine or phencarbamide), local anesthe- tics (e. g. tetracaine or procaine), optionally also enzymes, vitamins or amino acids. in this context, particular emphasis Is given to the combination of the compounds according to the invention with other pharmaceuticals which buffer or neutralize gastric acid or which inhibit the secre- tion of acid, such as, for example, antacids (such as, for example, magaldrate) of H, blockers (e. @. cimetidine, ranitidine), and with gastrin antagonists with the aim to enhance the main action in an additive or superadditive sense and/or to eliminate or reduce side-effects or to obtain a more rapid onset of action.
Mention may also be made of the fixed or free combination with NSAIDs (such as, for example, etofenamate, diclofenac, indometacin, ibuprofen or piroxicam) for preventing the gastrointe- stinal damage caused by the NSAIDs, or with antibacterial substances (such as, for example, cepha- fosporins, tetracyclins, penicillins, macrolides, nitroimidazoles or else bismuth salt) for controlling Heli- cobacter pylori.
Antibacterial combination partners which may be mentioned are, for example, mezlo- ciftin, ampicillin, amoxicillin, cefalothin, cefoxitin, cefotaxim, imipenem, gentamycin, amicacin, erythro- mycin, ciprofloxacin, metronidazole, clarithromycin, azithromycin and combinations thereof (e.g. da- rithromycin + metronidazole or amoxicillin + clarithromycin).
Claims (1)
1212WOORD01 2004-07 02 Claims
1. Pharmacologically compatible metal salts of pyridin-2-yimethytsulphinyl-1H-benzimidazoles with HHKF-ATPase-inhibitory activity, in which at least one positive charge equivalent of the metal ion is counterbalanced by a hydroxyl ion, and hydrates thereof.
2. Pharmacologically compatible metal salts according to claim 1, in which the pyridin-2-yimethyl- sulphinyl-1H-benzimidazoles with HH/K*-ATPase-inhibitory activity is selected from the group of pantoprazole, omeprazole, lansoprazole, rabeprazole and tenatoprazole, (R)- and (S)-pantoprazole, (R)- and (S)-omeprazole, (R)- and (S)4ansoprazole, (R)- and (S)-rabeprazole and (R)- and (S)- tenatoprazole, and hydrates thereof.
3. Pharmacologically compatible metal salts according to claim 1, characterized by the general formula 1 (Mel{PPIMOH]z (1) in which Me is a pharmacologically acceptable two-valued metal ion, PPI is a compound selected from pantoprazole, omeprazole, lansoprazole, rabeprazole and tenatoprazole and their enantiomers, OH is a hydroxyl ion, X is a positive, whole number from 1 to 3, Y is a positive, whole number from 1 to 5 and Z is a positive, whole number from 1 10 5, whereby the equation (Y + Z) = 2X applies, and hydrates thereof.
4. Phamacologically compatible metal salts according to claim 1, characterized by the general formula 1 of claim 3, in which Me is a pharmacologically acceptable two-valued metal ion selected from magnesium, calcium and zing, PP! is a compound selected from pantoprazole, omeprazole, lansoprazole, rabeprazole and tenatoprazole and their enantiomers, OH is a hydroxyl ion, X is the number 1 or 2, Y is a positive, whole number from 1 to 3 and Z is a positive, whole number from 1 to 3, whereby the equation (Y + Z) = 2X applies, and hydrates thereof.
1212WQORD01 2004-07 02
5. Pharmacologically compatible metal salts according to claim 1, characlerized by the general formula 1 of claim 3, in which Me Is magnesium, PP1 is a compound selected from pantoprazole, (R)-pantoprazole and (S)-pantoprazale, OH is a hydroxyl ion, Xs the number 1 or 2, Y ig the number t or 3 and Zs the number 1 or 3, whereby the equation (Y + Z) = 2X applies, and hydrates thereof.
8. Pharmacalogically compatible metal salts according to daim 1, characterized by the general formula 1 of claim 3, in which Me Is magnesium, PPtis (S)-pantoprazole, OH is a hydroxy ion, X is the number 1 or 2, Y is the number 1 or 3 and Z is the number 1 or 3, whereby the equation (Y + 2) = 2X applies, and hydrates thereof.
7. Pharmacolegically compatible metal sait according to claim 1, which is Mg[Pantoprazole]OH, and hydrates thereof.
8. Phamacologically compatible metal salt according to claim 1, which is Mgf(S)-Pantoprazole]OH, and hydrates thereof.
9. Pharmacologically compatible metal salt according to claim 1, which Is Mg,[Pantoprazole];OH, and hydrates thereof.
10. Phamacclogically compatible metal salt according to claim 1, which is Mg.[(S)-Pantoprazole];CH, and hydrates thereof.
11. Medicament, comprising a compound according to any of claims 1 to 10 tcgather with customary auxiliaries.
12. Use of a compound according to any of claims | to 10 in the manufacture of a medicament for treatin gastrointestinal disorders. & AMENDED SHEET
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EP03016759 | 2003-07-23 |
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ZA200510178A ZA200510178B (en) | 2003-07-23 | 2005-12-14 | Alkaline salts of proton pump inhibitors |
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SE8301182D0 (en) * | 1983-03-04 | 1983-03-04 | Haessle Ab | NOVEL COMPOUNDS |
JPH08509738A (en) * | 1993-04-27 | 1996-10-15 | セプラコー,インコーポレイテッド | Methods and compositions for the treatment of gastric disorders using optically pure (+) pantoprazole |
SE9301830D0 (en) * | 1993-05-28 | 1993-05-28 | Ab Astra | NEW COMPOUNDS |
SE510650C2 (en) * | 1997-05-30 | 1999-06-14 | Astra Ab | New association |
DE19843413C1 (en) * | 1998-08-18 | 2000-03-30 | Byk Gulden Lomberg Chem Fab | New salt form of pantoprazole |
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