WO2010053233A1 - The new telmisartan zinc salt and the preparation thereof - Google Patents
The new telmisartan zinc salt and the preparation thereof Download PDFInfo
- Publication number
- WO2010053233A1 WO2010053233A1 PCT/KR2009/001139 KR2009001139W WO2010053233A1 WO 2010053233 A1 WO2010053233 A1 WO 2010053233A1 KR 2009001139 W KR2009001139 W KR 2009001139W WO 2010053233 A1 WO2010053233 A1 WO 2010053233A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- telmisartan
- zinc
- zinc salt
- salt
- diseases
- Prior art date
Links
- RMMXLENWKUUMAY-UHFFFAOYSA-N Telmisartan Natural products CCCC1=NC2=C(C)C=C(C=3N(C4=CC=CC=C4N=3)C)C=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C(O)=O RMMXLENWKUUMAY-UHFFFAOYSA-N 0.000 title claims abstract description 192
- 239000005537 C09CA07 - Telmisartan Substances 0.000 title claims abstract description 116
- 229960005187 telmisartan Drugs 0.000 title claims abstract description 114
- -1 telmisartan zinc salt Chemical class 0.000 title claims abstract description 43
- 238000002360 preparation method Methods 0.000 title claims description 13
- 238000000034 method Methods 0.000 claims abstract description 11
- 150000003751 zinc Chemical class 0.000 claims abstract description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 206010020772 Hypertension Diseases 0.000 claims description 16
- 239000011701 zinc Substances 0.000 claims description 16
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 15
- 229910052725 zinc Inorganic materials 0.000 claims description 15
- 239000008194 pharmaceutical composition Substances 0.000 claims description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- 230000002265 prevention Effects 0.000 claims description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 239000011592 zinc chloride Substances 0.000 claims description 6
- 235000005074 zinc chloride Nutrition 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical class CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 4
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 claims description 4
- UAYWVJHJZHQCIE-UHFFFAOYSA-L zinc iodide Chemical compound I[Zn]I UAYWVJHJZHQCIE-UHFFFAOYSA-L 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 3
- 229940011051 isopropyl acetate Drugs 0.000 claims description 3
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- 241000124008 Mammalia Species 0.000 claims description 2
- ZOIORXHNWRGPMV-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O.CC(O)=O ZOIORXHNWRGPMV-UHFFFAOYSA-N 0.000 claims description 2
- 150000001298 alcohols Chemical class 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- 229960004132 diethyl ether Drugs 0.000 claims description 2
- 150000002170 ethers Chemical class 0.000 claims description 2
- 229940052303 ethers for general anesthesia Drugs 0.000 claims description 2
- 150000008282 halocarbons Chemical class 0.000 claims description 2
- 229930195733 hydrocarbon Natural products 0.000 claims description 2
- 150000002430 hydrocarbons Chemical class 0.000 claims description 2
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims description 2
- 239000004246 zinc acetate Substances 0.000 claims description 2
- 229960000314 zinc acetate Drugs 0.000 claims description 2
- 229940102001 zinc bromide Drugs 0.000 claims description 2
- 229960001939 zinc chloride Drugs 0.000 claims description 2
- UGZADUVQMDAIAO-UHFFFAOYSA-L zinc hydroxide Chemical group [OH-].[OH-].[Zn+2] UGZADUVQMDAIAO-UHFFFAOYSA-L 0.000 claims description 2
- 229940007718 zinc hydroxide Drugs 0.000 claims description 2
- 229910021511 zinc hydroxide Inorganic materials 0.000 claims description 2
- 239000012458 free base Substances 0.000 claims 1
- 150000002576 ketones Chemical class 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 13
- 150000003839 salts Chemical class 0.000 abstract description 7
- 102000005862 Angiotensin II Human genes 0.000 abstract 1
- 101800000733 Angiotensin-2 Proteins 0.000 abstract 1
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 abstract 1
- 229950006323 angiotensin ii Drugs 0.000 abstract 1
- 230000003042 antagnostic effect Effects 0.000 abstract 1
- 239000002253 acid Substances 0.000 description 24
- 239000007787 solid Substances 0.000 description 17
- 230000000052 comparative effect Effects 0.000 description 16
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 14
- 239000000203 mixture Substances 0.000 description 13
- 238000003756 stirring Methods 0.000 description 13
- 229940079593 drug Drugs 0.000 description 11
- 239000003814 drug Substances 0.000 description 11
- 238000004128 high performance liquid chromatography Methods 0.000 description 11
- 239000011541 reaction mixture Substances 0.000 description 9
- 150000004100 telmisartan derivatives Chemical class 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 239000000843 powder Substances 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 150000003752 zinc compounds Chemical class 0.000 description 6
- 229940088679 drug related substance Drugs 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 230000006872 improvement Effects 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 235000021023 sodium intake Nutrition 0.000 description 4
- 229940123413 Angiotensin II antagonist Drugs 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 239000002220 antihypertensive agent Substances 0.000 description 3
- 229940127088 antihypertensive drug Drugs 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 235000005911 diet Nutrition 0.000 description 3
- 230000000378 dietary effect Effects 0.000 description 3
- 230000005611 electricity Effects 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- RSGAIWOEJXRYRV-UHFFFAOYSA-M sodium;2-[4-[[4-methyl-6-(1-methylbenzimidazol-2-yl)-2-propylbenzimidazol-1-yl]methyl]phenyl]benzoate Chemical compound [Na+].CCCC1=NC2=C(C)C=C(C=3N(C4=CC=CC=C4N=3)C)C=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C([O-])=O RSGAIWOEJXRYRV-UHFFFAOYSA-M 0.000 description 3
- 230000003068 static effect Effects 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 230000002792 vascular Effects 0.000 description 3
- 206010019280 Heart failures Diseases 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 206010048259 Zinc deficiency Diseases 0.000 description 2
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- 159000000007 calcium salts Chemical class 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 230000008021 deposition Effects 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 230000001631 hypertensive effect Effects 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 229940101564 micardis Drugs 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 229940127557 pharmaceutical product Drugs 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000010079 rubber tapping Methods 0.000 description 2
- 102000008873 Angiotensin II receptor Human genes 0.000 description 1
- 108050000824 Angiotensin II receptor Proteins 0.000 description 1
- 229940123073 Angiotensin antagonist Drugs 0.000 description 1
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 description 1
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 1
- 206010012667 Diabetic glaucoma Diseases 0.000 description 1
- 206010013883 Dwarfism Diseases 0.000 description 1
- 238000001159 Fisher's combined probability test Methods 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 206010058359 Hypogonadism Diseases 0.000 description 1
- 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
- 241001465754 Metazoa Species 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- 108091005461 Nucleic proteins Proteins 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 description 1
- WHMDKBIGKVEYHS-IYEMJOQQSA-L Zinc gluconate Chemical compound [Zn+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O WHMDKBIGKVEYHS-IYEMJOQQSA-L 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- PBAYDYUZOSNJGU-UHFFFAOYSA-N chelidonic acid Natural products OC(=O)C1=CC(=O)C=C(C(O)=O)O1 PBAYDYUZOSNJGU-UHFFFAOYSA-N 0.000 description 1
- 229910052729 chemical element Inorganic materials 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 238000000748 compression moulding Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000013583 drug formulation Substances 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 230000005686 electrostatic field Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000013020 final formulation Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000013373 food additive Nutrition 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 229960002003 hydrochlorothiazide Drugs 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- CRGZYKWWYNQGEC-UHFFFAOYSA-N magnesium;methanolate Chemical compound [Mg+2].[O-]C.[O-]C CRGZYKWWYNQGEC-UHFFFAOYSA-N 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000003087 receptor blocking agent Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000000518 rheometry Methods 0.000 description 1
- 230000009645 skeletal growth Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 235000019871 vegetable fat Nutrition 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000011670 zinc gluconate Substances 0.000 description 1
- 229960000306 zinc gluconate Drugs 0.000 description 1
- 235000011478 zinc gluconate Nutrition 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 description 1
- 229960001763 zinc sulfate Drugs 0.000 description 1
- 229910000368 zinc sulfate Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic System
- C07F3/06—Zinc compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/20—Two benzimidazolyl-2 radicals linked together directly or via a hydrocarbon or substituted hydrocarbon radical
Definitions
- the present invention relates to a telmisartan zinc salt with improved physicochemical properties of the free acid of telmisartan which is an angiotensin II antagonist that is useful for the treatment of hypertensive diseases, and a method for preparing the same.
- telmisartan The compound 2-[4-[[4-methyl-6-(1-methylbenzoimidazol-2-yl)-2-propylbenzoimidazol-1-yl]methyl]phenyl]benzoic acid (hereinafter, referred to as "telmisartan”) is known from European Patent EP 502 314 B1 and has the following chemical structure:
- Telmisartan is known to be an angiotensin antagonist, particularly an angiotensin II antagonist which, by virtue of its pharmacological properties, may be used, for example, to treat hypertension and cardiac insufficiency, to treat ischemic peripheral circulatory disorders and myocardial ischaemia, to prevent the progression of cardiac insufficiency after myocardial infarction, and to treat diabetic neuropathy, glaucoma, and the like.
- Telmisartan was discovered and developed by Boehringer Ingelheim. Under the trademarks MICARDIS R and MICARDISPLUS R (combination with hydrochlorothiazide) the company markets telmisartan in 84 countries around the world, including the USA, Japan and European countries. Telmisartan is a member of the angiotensin II receptor blocker (ARB) class and is being investigated in the most ambitious and far-reaching research programme conducted with an ARB. In the clinical trial programmes ONTARGET, PROTECTION and PROFESS, over 58,000 patients have been enrolled to investigate the cardiovascular protective effects of MICARDIS R .
- ARB angiotensin II receptor blocker
- telmisartan The free acid of telmisartan has a very limited solubility. For this reason, in the industrial production of telmisartan, commercially available free acid formulations of telmisartan are prepared by direct contact of telmisartan with a strong alkalizer such as sodium hydroxide. Such a production process is potentially dangerous to human health. In addition, quality reproducibility of the final formulation may vary depending on a period of reaction time. Physicochemical properties of telmisartan in the solid free acid form may also pose difficulties of direct application thereof to the human body, so many researches have been actively conducted to overcome the limited applicability of telmisartan.
- telmisartan In order to overcome these disadvantages of telmisartan, for example, International Publication Nos. WO 2003/037876 and WO 2006/044754 disclose acid or base addition salts of telmisartan, and telmisartan preparations containing alkali metal excipients.
- European Patent EP 1 144 386 B1 disclose sodium salts of telmisartan which are intended to overcome the disadvantages of the free acid of telmisartan.
- telmisartan sodium salt of telmisartan may be an approximate solution to the problems associated with poor physicochemical properties of the free acid of telmisartan such as limited solubility and the like.
- telmisartan sodium salt as an antihypertensive drug inevitably involves problems in terms of safety.
- telmisartan magnesium and calcium salts suffer from disadvantages associated with poor properties of pharmaceutically important factors, e.g. high hygroscopicity and low thermal stability, as compared to the free acid form of telmisartan.
- telmisartan which is of high purity and high quality thus making it suitable for application to a pharmaceutical composition, in conjunction with improvements of formulation-related factors of tablet preparations such as solubility, solid rheology and electrostaticity, including high hygroscopicity and low stability which are disadvantages of telmisartan in the free acid form.
- Zinc is a metallic chemical element with the symbol Zn, atomic number 30 and atomic weight 65.39. Zinc was recognized as useful mineral since the 1950's. With the revelation that "dwarfism” and “hypogonadism” are due to zinc deficiency, a great deal of interest has been focused on the importance of zinc in human health. In the United States, the recommended intake for zinc was established in the 1970's. In Korea, the recommended dietary allowance (RDA) for zinc was first presented in 1995. Zinc is the ubiquitous mineral which is found in all animal tissues and is involved in epithelial healing or prostate function. In addition, it is known that zinc is essential for dermal or skeletal growth and maintenance and for the synthesis of nucleic acids and proteins.
- zinc sulfate preparations As examples of pharmaceutical products utilizing these pharmacological actions of zinc, commercially available zinc sulfate preparations may be mentioned.
- KDRIs Dietary Reference Intakes for Koreans (KDRIs) published by The Korean Nutrition Society in 2005
- the recommended daily intake of zinc is in the range of 8 to 10 mg for adult males, 7 to 8 mg for adult females, 10 to 11 mg for pregnant women, and 13 mg for lactating women, respectively.
- the tolerable upper intake level of zinc is 35 mg for both adult males and females. Due to the above-mentioned validated safety of zinc, zinc gluconate, zinc oxide, and the like are used as food additives, whereas zinc stearate and the like are used as pharmaceutical excipients.
- telmisartan As a result of a variety of extensive and intensive studies and experiments to solve the problems suffered by conventional free acids of telmisartan as discussed before, the inventors of the present invention have developed zinc salts of telmisartan which are pharmaceutically very excellent and are also superior in terms ofsafety.
- the present invention has been made in view of the above problems, and it is an object of the present invention to provide a novel zinc salt of telmisartan which exhibits excellent pharmaceutical properties and high safety, by improving disadvantages of the free acid of telmisartan that is an angiotensin II antagonist.
- telmisartan 2-[4-[[4-methyl-6-(1-methylbenzoimidazol-2-yl)-2-propylbenzoimidazol-1-yl]methyl]phenyl]benzoic acid (telmisartan), which is pharmaceutically acceptable and is very useful as a pharmaceutical composition for the prevention or treatment of hypertensive diseases and/or cardiovascular diseases due to improved physicochemical properties of a drug compound and which is represented by Formula 1 below:
- the telmisartan zinc salt of the present invention is provided in the form of an ionically-bonded salt produced by the combination of two telmisartan molecules into a divalent zinc ion.
- the telmisartan zinc salt in accordance with the present invention may be prepared directly from telmisartan of Formula 1 per se , or otherwise may be obtained from the conversion of the ready-made telmisartan salt into a desired form.
- a method for preparing a zinc salt of telmisartan including reacting telmisartan with a zinc compound in the presence of an organic solvent.
- the preparation of the telmisartan zinc salt includes a) dissolving or suspending the free acid of telmisartan in an organic solvent at a given temperature higher than room temperature; b) dissolving the zinc compound in the organic solvent or adding the zinc compound in the solid form to the solution or suspension of Step a) to obtain a reaction mixture; and c) solidifying the mixture of Step b) under various temperature and solvent conditions, followed by filtration, washing and drying of the resulting solid to prepare a desired zinc salt of telmisartan.
- Preferred examples of the zinc compound that can be used in the preparation method of the present invention may include zinc hydroxide, zinc acetate, zinc chloride, zinc bromide, zinc iodide, and the like. Although various equivalents of the zinc compound may be used relative to one mole of the telmisartan free acid, an amount of the zinc compound is preferably 0.5 mol or higher.
- the reaction temperature is in the range of 25°C to 100°C.
- the salt deposition temperature is preferably in the range of -10°C to 100°C.
- Preferred examples of the organic solvent that can be used in the preparation method of the present invention may include lower alcohols such as methanol, ethanol, isopropanol and butanol; ethers such as 1,4-dioxane, tetrahydrofuran, diethylether and isopropylether; amides such as dimethylformamide and diethylacetamide ketones such as acetone and methylethylketone; esters such as isopropylacetate; halogenated hydrocarbons such as chloroform and dichloromethane; lower hydrocarbons such as hexane, heptane and octane; dimethylsulfoxide and water. These solvent compounds may be used alone or in any combination thereof.
- the telmisartan zinc salt of the present invention exhibits significantly improved physicochemical properties of specific volume and electrostaticity of solids in conjunction with high solubility, good stability and non-hygroscopicity, as compared to known telmisartan. Therefore, pharmaceutical compositions containing the telmisartan zinc salt of the present invention can be effectively used for the treatment and prevention ofhypertension-related diseases.
- telmisartan zinc salt of the present invention even if the patient of interest takes the telmisartan zinc salt of the present invention at a maximum daily dose (80 mg in terms of telmisartan), an amount of the zinc salt to be absorbed into the body is only 5 mg which is below the recommended daily intake of zinc. Further, upon considering the recent report demonstrating that hypertension may be caused due to zinc deficiency (Pediatr. Res. 58(4), 672, 2005), it can be said that the telmisartan zinc salt is therapeutically or prophylactically beneficial for hypertension.
- the present invention provides a pharmaceutical composition for treatment or prevention of hypertensive diseases and/or cardiovascular diseases, containing a telmisartan zinc salt as an active ingredient and one or more pharmaceutically acceptable carriers.
- a dose of the telmisartan zinc salt in the composition of the present invention is very variable.
- an effective daily dose of the telmisartan zinc salt is in the range of about 10 to 100 mg, preferably 20 to 90 mg.
- the dosage and number of dosages can be easily determined by the attending physician, depending on characteristics of formulations, weight and condition of the subject, administration routes, etc.
- the term "pharmaceutically acceptable carrier” encompasses any of the standard pharmaceutically accepted carriers which are used in known pharmaceutical formulations such as sterile solutions, tablets, coated tablets and capsules. Typically such carriers contain excipients such as starch, milk, sugar, certain types of clay, gelatin, stearic acid, talc, vegetable fats or oils, gums, glycols, or other known excipients. Such carriers may also include flavor and color additives or other ingredients. Compositions containing such carriers may be formulated by well known conventional methods.
- Administration of the pharmaceutical composition in accordance with the present invention is by any route including oral, rectal, injection. Most preferred are oral compositions such as tablets, capsules, granules, etc.
- telmisartan zinc salt for the preparation of a pharmaceutical composition for the treatment or prevention of hypertensive diseases and/or cardiovascular diseases.
- a method for preventing or treating of hypertensive diseases and/or cardiovascular diseases in comprising administering a therapeutically effective amount of a telmisartan zinc salt to mammal including a human in need of treatment or prevention of hypertensive diseases and/or cardiovascular diseases.
- the present invention enables high-purity production of a telmisartan zinc salt with no introduction of an additional purification process.
- the thus-produced telmisartan zinc salt exhibits excellent pharmaceutical properties associated with the solubility, stability and non-hygroscopicity, as well as improvements in physicochemical properties such as specific volume and electrostaticity of solids, which are required for practical commercializationof drug compounds. Therefore, the telmisartan zinc salt of the present invention in combination with a pharmaceutically acceptable carrier can be usefully employed as an active ingredient of antihypertensive drugs or cardio and vascular protective-pharmaceutical compositions.
- 1 H NMR data given in the following Examples are the values measured using a Bruker UltraShield TM 400 (400 MHz) spectrometer. Unless otherwise specified, all reagents and solvents were purchased from Aldrich and Acros.
- HPLC conditions used for the measurement of the purity and content of telmisartan zinc saltsin the present invention were the same as those of the telmisartan analysis in the European Pharmacopoeia 6.2.
- telmisartan and 600 mL of acetone were refluxed at 53°C to prepare a suspension to which 4.4 g of zinc chloride was then added, followed by stirring at that temperature for 2 hours.
- the reaction mixture was concentrated to 300 mL at 40°C and 50 mbar under reduced pressure, followed by stirring at room temperature for 2 hours to precipitate a white solid.
- the resulting solid was washed with cold acetone, filtered, and dried under vacuum to obtain a telmisartan zinc salt.
- telmisartan zinc salt 150 mL of dimethylsulfoxide was added to 30 g of telmisartan, and the mixture was heated with stirring to 50°C until a clear solution was obtained. To the resulting solution was added 4.4 g of zinc chloride, followed by stirring at that temperature for about one hour. The reaction mixture was cooled to room temperature and 600 mL of acetone was added thereto, followed by stirring to precipitate a white solid. The resultingsolid was washed with cold acetone, filtered and dried under vacuum to obtain a telmisartan zinc salt.
- telmisartan and 600 mL of tetrahydrofuran were refluxed at 65°C to prepare a suspension to which 4.4 g of zinc chloride was then added, followed by stirring at that temperature for 2 hours.
- the reaction mixture was concentrated to 300 mL at 40°C and 50 mbar under reduced pressure, followed by stirring at room temperature for 2 hours to precipitate a white solid.
- the resulting solid was washed with cold tetrahydrofuran, filtered, and dried under vacuum to obtain a telmisartan zinc salt.
- telmisartan and mL of dimethylsulfoxide were mixed and heated with stirring to 50°C until a clear solution was obtained.
- 4.4 g of zinc chloride was added to the resulting solution, followed by stirring at that temperature for about one hour.
- the reaction mixture was cooled to room temperature and 300 mL of tetrahydrofuran was added thereto, followed by stirring at 5°C for 2 hours to precipitate a white solid.
- the resultingsolid was washed with cold tetrahydrofuran, filtered and dried under vacuum to obtain a telmisartan zinc salt.
- telmisartan sodium salt 30 g was dissolved in 600 mL of ethanol and 2.4 g of sodium hydroxide was added thereto, followed by stirring at room temperature for about 1 hour. Ethanol which was used as a solvent of the reaction mixture was removed by distillationunder reduced pressure. 100 mL of ethanol was added to the resulting solid and the mixture was dissolved under reflux. 500 mL of methyl t-butyl ether was added to the reaction mixture over one hour, and the mixture was cooled to room temperature to precipitate a white solid. The resulting solid was filtered and dried under vacuum to obtain a telmisartan sodium salt.
- telmisartan magnesium salt 30 g was suspended with stirring in 1500 mL of methanol. 2.4 g of magnesium methoxide was added to the resulting suspension which was then refluxed at a temperature of 60 to 65°C for about 12 hours. The reaction mixture was filtered and methanol was removed by distillation under reduced pressure. The residue was dried under vacuum to obtain a telmisartan magnesium salt.
- telmisartan calcium salt 30 g was suspended with stirring in 1500 mL of methanol. To the resulting suspension was added 2.4 g of calcium hydroxide, followed by reflux at 60 to 65°C for about 12 hours. The reaction mixture was filtered and methanol was removed by distillationunder reduced pressure. The residue was dried under vacuum to obtain a telmisartan calcium salt.
- test samples were prepared according to the procedure described in Examples 1 to 4 and Comparative Examples 1 to 3. Purity of the samples was measured by HPLC. The results obtained are given in Table 1 below.
- the commercially available telmisartan free acid was almost precipitated leaving only about 5% of the original mass, whereas Examples 1 and 3 exhibited significantly improved properties in precipitability, as compared to the free acid form of telmisartan. Therefore, the telmisartan zinc salts of the present invention have superior solubility in aqueous solutions, and very low probability of deposition and consequent precipitation (low precipitability) in an aqueous solution state, which are advantageous for the absorption of drugs.
- hygroscopicity is a very important factor for practical processing and storage of pharmaceutical products, among various properties required for drug compounds to be used as pharmaceutical raw materials.
- a telmisartan free acid and individual samples of Examples 1 and 2, and Comparative Examples 1 to 3 were dried under vacuum (P 2 O 5 , for one day or more), and initial water contents of the samples were measured using a Karl Fisher method. Thereafter, amounts of sorbed water were automatically measured at 25°C and relative humidity (RH) of 15, 35, 55, 75 and 95%, respectively, using a hygroscopicity measurement apparatus (Model No. Hydrosorb 1000, manufactured by Quantachrome Instruments). The results obtained are given in Table 3 below.
- the initial water content was defined as a water content of the test sample which will exhibit no further decrease in weight, after the drying wascontinuously and thoroughly conducted.
- telmisartan should be managed to have a water content of less than 1% according to the national standards for drug substances published by the Food and Drug Administration (FDA) and telmisartan having the above-specified water content of more than 1% should not be used for pharmaceutical applications
- the samples of Comparative Examples 1 to 3 were found to have excessively high hygroscopicity which is not acceptable for drug formulations.
- the telmisartan zinc salts of the present invention have excellent non-hygroscopic properties thus making it not absorb moisture, even when they were exposed to ambient humidity conditions.
- the samples of Examples 1 and 3 exhibited decreased static electricity (low electrostaticity), as compared to the telmisartan free acid and the samples of Comparative Examples 1 to 3, thus confirming that the compounds of the present invention have excellent processability taking into consideration instrument rubbing that may take place during the preparation of pharmaceutical formulations.
- telmisartan salts of the present invention have a low specific volume
- the telmisartan free acid and the samples of Examples 1 and 3, and Comparative Examples 1 to 3 were placed in graduated cylinders. From a vertical height of 10 cm, free fall of the cylinders was repeated 20 times or more such that tapping of the samples was carried out to achieve sufficient compacting of the contents.
- the specific volume values of test samples were measured before and after tapping. The results obtained are given in Table 6 below.
- the samples of Examples 1 and 3 When compared with the telmisartan free acid and the samples of Comparative Examples 1 to 3, the samples of Examples 1 and 3 exhibited a noticeable reduction of the specific volume. Powdered drug substances usually have high specific volumes and are therefore designed into suitable dosage forms (tablets or capsules) always after compression molding thereof. Therefore, when the specific volume is large, the pharmaceutical processability of the drug substance becomes very poor.
- the telmisartan zinc salts of the present invention have excellent physicochemical properties in terms of pharmaceutical processability.
- the present invention enables high-purity production of a telmisartan zinc salt with no introduction of an additional purification process.
- the thus-produced telmisartan zinc salt exhibits excellent pharmaceutical properties associated with the solubility, stability and non-hygroscopicity, as well as improvements in physicochemical properties such as specific volume and electrostaticity of solids,which are required for practical commercialization of drug compounds. Therefore, the telmisartan zinc salt of the present invention in combination with a pharmaceutically acceptable carrier can be usefully employed as an active ingredient of antihypertensive drugs or cardio and vascular protective-pharmaceutical compositions.
Abstract
The present invention provides a novel zinc salt of 2-[4-[[4-methyl-6-(1-methylbenzoimidazol-2-yl)-2-propylbenzoimidazol-1-yl]methyl]phenyl]benzoic acid (telmisartan) and a method for preparing the same. The telmisartan zinc salt of the present invention exhibits excellent physicochemical properties as compared to conventional telmisartan and addition salts thereof, as well as sufficient safety as a novel salt compound. Therefore, the telmisartan zinc salt of the present invention is useful as a compound having angiotensin II antagonistic activity.
Description
The present invention relates to a telmisartan zinc salt with improved physicochemical properties of the free acid of telmisartan which is an angiotensin II antagonist that is useful for the treatment of hypertensive diseases, and a method for preparing the same.
The compound 2-[4-[[4-methyl-6-(1-methylbenzoimidazol-2-yl)-2-propylbenzoimidazol-1-yl]methyl]phenyl]benzoic acid (hereinafter, referred to as "telmisartan") is known from European Patent EP 502 314 B1 and has the following chemical structure:
Telmisartan is known to be an angiotensin antagonist, particularly an angiotensin II antagonist which, by virtue of its pharmacological properties, may be used, for example, to treat hypertension and cardiac insufficiency, to treat ischemic peripheral circulatory disorders and myocardial ischaemia, to prevent the progression of cardiac insufficiency after myocardial infarction, and to treat diabetic neuropathy, glaucoma, and the like.
Telmisartan was discovered and developed by Boehringer Ingelheim. Under the trademarks MICARDISR and MICARDISPLUSR (combination with hydrochlorothiazide) the company markets telmisartan in 84 countries around the world, including the USA, Japan and European countries. Telmisartan is a member of the angiotensin II receptor blocker (ARB) class and is being investigated in the most ambitious and far-reaching research programme conducted with an ARB. In the clinical trial programmes ONTARGET, PROTECTION and PROFESS, over 58,000 patients have been enrolled to investigate the cardiovascular protective effects of MICARDISR.
The free acid of telmisartan has a very limited solubility. For this reason, in the industrial production of telmisartan, commercially available free acid formulations of telmisartan are prepared by direct contact of telmisartan with a strong alkalizer such as sodium hydroxide. Such a production process is potentially dangerous to human health. In addition, quality reproducibility of the final formulation may vary depending on a period of reaction time. Physicochemical properties of telmisartan in the solid free acid form may also pose difficulties of direct application thereof to the human body, so many researches have been actively conducted to overcome the limited applicability of telmisartan.
In order to overcome these disadvantages of telmisartan, for example, International Publication Nos. WO 2003/037876 and WO 2006/044754 disclose acid or base addition salts of telmisartan, and telmisartan preparations containing alkali metal excipients.
Further, European Patent EP 1 144 386 B1, and International Publication Nos. WO 2003/037876 and WO 2006/050509 disclose sodium salts of telmisartan which are intended to overcome the disadvantages of the free acid of telmisartan.
However, considering the ongoing discussion of the possibility that the blood pressure of hypertensive patients may be susceptible to changes in dietary sodium intake, sodium salts of telmisartan may cause additional problems in antihypertensive treatment (Hypertension 27, 481-490, 1996). Generally, additional intake of sodium over the normal level results in the presence of more fluids in blood vessels, which makes the heart to supply more blood to the body. Further, vascular constriction influenced by sodium intake inhibits the amount and flow of blood entering the heart, so the heart must pump more blood into a closed circulatory system of the human body. As a consequence, high sodium intake increases blood pressure.
Taking into consideration only the easy manufacturability of a telmisartan formulation, a sodium salt of telmisartan may be an approximate solution to the problems associated with poor physicochemical properties of the free acid of telmisartan such as limited solubility and the like. However, giving consideration to the above-mentioned adverse effects of sodium intake on hypertensive patients, it can be seen that application of the telmisartan sodium salt as an antihypertensive drug inevitably involves problems in terms of safety.
Further, WO 2006/050921 and EP 1 719 766 B1 disclose magnesium and calcium salts of telmisartan. However, the telmisartan magnesium and calcium salts suffer from disadvantages associated with poor properties of pharmaceutically important factors, e.g. high hygroscopicity and low thermal stability, as compared to the free acid form of telmisartan.
To this end, there is a need for an addition salt of telmisartan which is of high purity and high quality thus making it suitable for application to a pharmaceutical composition, in conjunction with improvements of formulation-related factors of tablet preparations such as solubility, solid rheology and electrostaticity, including high hygroscopicity and low stability which are disadvantages of telmisartan in the free acid form.
Zinc is a metallic chemical element with the symbol Zn, atomic number 30 and atomic weight 65.39. Zinc was recognized as useful mineral since the 1950's. With the revelation that "dwarfism" and "hypogonadism" are due to zinc deficiency, a great deal of interest has been focused on the importance of zinc in human health. In the United States, the recommended intake for zinc was established in the 1970's. In Korea, the recommended dietary allowance (RDA) for zinc was first presented in 1995. Zinc is the ubiquitous mineral which is found in all animal tissues and is involved in epithelial healing or prostate function. In addition, it is known that zinc is essential for dermal or skeletal growth and maintenance and for the synthesis of nucleic acids and proteins. As examples of pharmaceutical products utilizing these pharmacological actions of zinc, commercially available zinc sulfate preparations may be mentioned. According to the Dietary Reference Intakes for Koreans (KDRIs) published by The Korean Nutrition Society in 2005, the recommended daily intake of zinc is in the range of 8 to 10 mg for adult males, 7 to 8 mg for adult females, 10 to 11 mg for pregnant women, and 13 mg for lactating women, respectively. The tolerable upper intake level of zinc is 35 mg for both adult males and females. Due to the above-mentioned validated safety of zinc, zinc gluconate, zinc oxide, and the like are used as food additives, whereas zinc stearate and the like are used as pharmaceutical excipients.
As a result of a variety of extensive and intensive studies and experiments to solve the problems suffered by conventional free acids of telmisartan as discussed before, the inventors of the present invention have developed zinc salts of telmisartan which are pharmaceutically very excellent and are also superior in terms ofsafety.
Therefore, the present invention has been made in view of the above problems, and it is an object of the present invention to provide a novel zinc salt of telmisartan which exhibits excellent pharmaceutical properties and high safety, by improving disadvantages of the free acid of telmisartan that is an angiotensin II antagonist.
It is another object of the present invention to provide a method for preparing a novel zinc salt of telmisartan.
In accordance with an aspect of the present invention, the above and other objects can be accomplished by the provision of a high-purity zinc salt of 2-[4-[[4-methyl-6-(1-methylbenzoimidazol-2-yl)-2-propylbenzoimidazol-1-yl]methyl]phenyl]benzoic acid (telmisartan), which is pharmaceutically acceptable and is very useful as a pharmaceutical composition for the prevention or treatment of hypertensive diseases and/or cardiovascular diseases due to improved physicochemical properties of a drug compound and which is represented by Formula 1 below:
The telmisartan zinc salt of the present invention is provided in the form of an ionically-bonded salt produced by the combination of two telmisartan molecules into a divalent zinc ion. The telmisartan zinc salt in accordance with the present invention may be prepared directly from telmisartan of Formula 1 per se, or otherwise may be obtained from the conversion of the ready-made telmisartan salt into a desired form.
In accordance with another aspect of the present invention, there is provided a method for preparing a zinc salt of telmisartan including reacting telmisartan with a zinc compound in the presence of an organic solvent.
For example, the preparation of the telmisartan zinc salt includes a) dissolving or suspending the free acid of telmisartan in an organic solvent at a given temperature higher than room temperature; b) dissolving the zinc compound in the organic solvent or adding the zinc compound in the solid form to the solution or suspension of Step a) to obtain a reaction mixture; and c) solidifying the mixture of Step b) under various temperature and solvent conditions, followed by filtration, washing and drying of the resulting solid to prepare a desired zinc salt of telmisartan.
Preferred examples of the zinc compound that can be used in the preparation method of the present invention may include zinc hydroxide, zinc acetate, zinc chloride, zinc bromide, zinc iodide, and the like. Although various equivalents of the zinc compound may be used relative to one mole of the telmisartan free acid, an amount of the zinc compound is preferably 0.5 mol or higher. The reaction temperature is in the range of 25℃ to 100℃. The salt deposition temperature is preferably in the range of -10℃ to 100℃.
Preferred examples of the organic solvent that can be used in the preparation method of the present invention may include lower alcohols such as methanol, ethanol, isopropanol and butanol; ethers such as 1,4-dioxane, tetrahydrofuran, diethylether and isopropylether; amides such as dimethylformamide and diethylacetamide ketones such as acetone and methylethylketone; esters such as isopropylacetate; halogenated hydrocarbons such as chloroform and dichloromethane; lower hydrocarbons such as hexane, heptane and octane; dimethylsulfoxide and water. These solvent compounds may be used alone or in any combination thereof.
The telmisartan zinc salt of the present invention exhibits significantly improved physicochemical properties of specific volume and electrostaticity of solids in conjunction with high solubility, good stability and non-hygroscopicity, as compared to known telmisartan. Therefore, pharmaceutical compositions containing the telmisartan zinc salt of the present invention can be effectively used for the treatment and prevention ofhypertension-related diseases.
Further, even if the patient of interest takes the telmisartan zinc salt of the present invention at a maximum daily dose (80 mg in terms of telmisartan), an amount of the zinc salt to be absorbed into the body is only 5 mg which is below the recommended daily intake of zinc. Further, upon considering the recent report demonstrating that hypertension may be caused due to zinc deficiency (Pediatr. Res. 58(4), 672, 2005), it can be said that the telmisartan zinc salt is therapeutically or prophylactically beneficial for hypertension.
Accordingly, the present invention provides a pharmaceutical composition for treatment or prevention of hypertensive diseases and/or cardiovascular diseases, containing a telmisartan zinc salt as an active ingredient and one or more pharmaceutically acceptable carriers.
A dose of the telmisartan zinc salt in the composition of the present invention is very variable. As to the usual adult dose, an effective daily dose of the telmisartan zinc salt is in the range of about 10 to 100 mg, preferably 20 to 90 mg. The dosage and number of dosages can be easily determined by the attending physician, depending on characteristics of formulations, weight and condition of the subject, administration routes, etc.
As used herein, the term "pharmaceutically acceptable carrier" encompasses any of the standard pharmaceutically accepted carriers which are used in known pharmaceutical formulations such as sterile solutions, tablets, coated tablets and capsules. Typically such carriers contain excipients such as starch, milk, sugar, certain types of clay, gelatin, stearic acid, talc, vegetable fats or oils, gums, glycols, or other known excipients. Such carriers may also include flavor and color additives or other ingredients. Compositions containing such carriers may be formulated by well known conventional methods.
Administration of the pharmaceutical composition in accordance with the present inventionis by any route including oral, rectal, injection. Most preferred are oral compositions such as tablets, capsules, granules, etc.
In accordance with a further aspect of the present invention, there is provided a use of a telmisartan zinc salt for the preparation of a pharmaceutical composition for the treatment or prevention of hypertensive diseases and/or cardiovascular diseases.
In accordance with another aspect of the present invention, there is provided a method for preventing or treating of hypertensive diseases and/or cardiovascular diseases, in comprising administering a therapeutically effective amount of a telmisartan zinc salt to mammal including a human in need of treatment or prevention of hypertensive diseases and/or cardiovascular diseases.
As will be specifically demonstrated hereinafter, the present invention enables high-purity production of a telmisartan zinc salt with no introduction of an additional purification process. The thus-produced telmisartan zinc salt exhibits excellent pharmaceutical properties associated with the solubility, stability and non-hygroscopicity, as well as improvements in physicochemical properties such as specific volume and electrostaticity of solids, which are required for practical commercializationof drug compounds. Therefore, the telmisartan zinc salt of the present invention in combination with a pharmaceutically acceptable carrier can be usefully employed as an active ingredient of antihypertensive drugs or cardio and vascular protective-pharmaceutical compositions.
Now, the present invention will be described in more detail with reference to the following Examples. These examples are provided only for illustrating the present invention and should not be construed as limiting the scope and spirit of the present invention.
Hereinafter, 1H NMR data given in the following Examples are the values measured using a Bruker UltraShieldTM 400 (400 ㎒) spectrometer. Unless otherwise specified, all reagents and solvents were purchased from Aldrich and Acros.
HPLC conditions used for the measurement of the purity and content of telmisartan zinc saltsin the present invention were the same as those of the telmisartan analysis in the European Pharmacopoeia 6.2.
Example 1: Synthesis of telmisartan zinc salt
30 g of telmisartan and 600 mL of acetone were refluxed at 53℃ to prepare a suspension to which 4.4 g of zinc chloride was then added, followed by stirring at that temperature for 2 hours. The reaction mixture was concentrated to 300 mL at 40℃ and 50 mbar under reduced pressure, followed by stirring at room temperature for 2 hours to precipitate a white solid. The resulting solid was washed with cold acetone, filtered, and dried under vacuum to obtain a telmisartan zinc salt.
Yield: 30 g (93%), white powder
Purity (HPLC): 99.81%
1H NMR (400MHz, DMSO-d6)δ(ppm): 7.73-7.60 (4H, m), 7.49-7.40 (3H, m), 7.31-7.22 (5H, m), 7.17-7.16 (2H, m), 5.59 (3H, s), 3.79 (3H, s), 2.95-2.91 (2H, t), 2.61 (3H, s), 1.86-1.77 (2H, m), 1.01-0.97 (3H, t)
Example 2: Synthesis of telmisartan zinc salt
150 mL of dimethylsulfoxide was added to 30 g of telmisartan, and the mixture was heated with stirring to 50℃ until a clear solution was obtained. To the resulting solution was added 4.4 g of zinc chloride, followed by stirring at that temperature for about one hour. The reaction mixture was cooled to room temperature and 600 mL of acetone was added thereto, followed by stirring to precipitate a white solid. The resultingsolid was washed with cold acetone, filtered and dried under vacuum to obtain a telmisartan zinc salt.
Yield: 27 g (85%), white powder
Purity (HPLC): 99.91%
1H NMR (400MHz, DMSO-d6)δ(ppm): 7.73-7.60 (4H, m), 7.49-7.40 (3H, m), 7.31-7.22 (5H, m), 7.17-7.16 (2H, m), 5.59 (3H, s), 3.79 (3H, s), 2.95-2.91 (2H, t), 2.61 (3H, s), 1.86-1.77 (2H, m), 1.01-0.97 (3H, t)
Example 3: Synthesis of telmisartan zinc salt
30 g of telmisartan and 600 mL of tetrahydrofuran were refluxed at 65℃ to prepare a suspension to which 4.4 g of zinc chloride was then added, followed by stirring at that temperature for 2 hours. The reaction mixture was concentrated to 300 mL at 40℃ and 50 mbar under reduced pressure, followed by stirring at room temperature for 2 hours to precipitate a white solid. The resulting solid was washed with cold tetrahydrofuran, filtered, and dried under vacuum to obtain a telmisartan zinc salt.
Yield: 29 g (90%), white powder
Purity (HPLC): 99.79%
1H NMR (400MHz, DMSO-d6)δ(ppm): 7.73-7.60 (4H, m), 7.49-7.40 (3H, m), 7.31-7.22 (5H, m), 7.17-7.16 (2H, m), 5.59 (3H, s), 3.79 (3H, s), 2.95-2.91 (2H, t), 2.61 (3H, s), 1.86-1.77 (2H, m), 1.01-0.97 (3H, t)
Example 4: Synthesis of telmisartan zinc salt
30 g of telmisartan and 100 mL of dimethylsulfoxide were mixed and heated with stirring to 50℃ until a clear solution was obtained. To the resulting solution was added 4.4 g of zinc chloride, followed by stirring at that temperature for about one hour. The reaction mixture was cooled to room temperature and 300 mL of tetrahydrofuran was added thereto, followed by stirring at 5℃ for 2 hours to precipitate a white solid. The resultingsolid was washed with cold tetrahydrofuran, filtered and dried under vacuum to obtain a telmisartan zinc salt.
Yield: 27.8 g (87%), white powder
Purity (HPLC): 99.93%
1H NMR (400MHz, DMSO-d6)δ(ppm) : 7.73-7.60 (4H, m), 7.49-7.40 (3H, m), 7.31-7.22 (5H, m), 7.17-7.16 (2H, m), 5.59 (3H, s), 3.79 (3H, s), 2.95-2.91 (2H, t), 2.61 (3H, s), 1.86-1.77 (2H, m), 1.01-0.97 (3H, t)
Comparative Example 1: Synthesis of telmisartan sodium salt
30 g of telmisartan was dissolved in 600 mL of ethanol and 2.4 g of sodium hydroxide was added thereto, followed by stirring at room temperature for about 1 hour. Ethanol which was used as a solvent of the reaction mixture was removed by distillationunder reduced pressure. 100 mL of ethanol was added to the resulting solid and the mixture was dissolved under reflux. 500 mL of methyl t-butyl ether was added to the reaction mixture over one hour, and the mixture was cooled to room temperature to precipitate a white solid. The resulting solid was filtered and dried under vacuum to obtain a telmisartan sodium salt.
Yield: 35.3 g (81%), white powder
Purity (HPLC): 99.14%
1H NMR (400MHz, DMSO-d6)δ(ppm): 7.73-7.60 (4H, m), 7.49-7.40 (3H, m), 7.31-7.22 (5H, m), 7.17-7.16 (2H, m), 5.59 (3H, s), 3.79 (3H, s), 2.95-2.91 (2H, t), 2.61 (3H, s), 1.86-1.77 (2H, m), 1.01-0.97 (3H, t)
Comparative Example 2: Synthesis of telmisartan magnesium salt
30 g of telmisartan was suspended with stirring in 1500 mL of methanol. 2.4 g of magnesium methoxide was added to the resulting suspension which was then refluxed at a temperature of 60 to 65℃ for about 12 hours. The reaction mixture was filtered and methanol was removed by distillation under reduced pressure. The residue was dried under vacuum to obtain a telmisartan magnesium salt.
Yield: 28.9 g (83%), pale yellow powder
Purity (HPLC): 99.21%
1H NMR (400MHz, DMSO-d6)δ(ppm): 7.73-7.60 (4H, m), 7.49-7.40 (3H, m), 7.31-7.22 (5H, m), 7.17-7.16 (2H, m), 5.59 (3H, s), 3.79 (3H, s), 2.95-2.91 (2H, t), 2.61 (3H, s), 1.86-1.77 (2H, m), 1.01-0.97 (3H, t)
Comparative Example 3: Synthesis of telmisartan calcium salt
30 g of telmisartan was suspended with stirring in 1500 mL of methanol. To the resulting suspension was added 2.4 g of calcium hydroxide, followed by reflux at 60 to 65℃ for about 12 hours. The reaction mixture was filtered and methanol was removed by distillationunder reduced pressure. The residue was dried under vacuum to obtain a telmisartan calcium salt.
Yield: 29.7 g (87%), light white powder
Purity (HPLC): 99.24%
1H NMR (400MHz, DMSO-d6)δ(ppm): 7.73-7.60 (4H, m), 7.49-7.40 (3H, m), 7.31-7.22 (5H, m), 7.17-7.16 (2H, m), 5.59 (3H, s), 3.79 (3H, s), 2.95-2.91 (2H, t), 2.61 (3H, s), 1.86-1.77 (2H, m), 1.01-0.97 (3H, t)
Experimental Example 1: Purity of telmisartan salts prepared in Examples 1 to 4 and Comparative Examples 1 to 3
Using telmisartan free salts with purity of 99.2% and 98.5%, test samples were prepared according to the procedure described in Examples 1 to 4 and Comparative Examples 1 to 3. Purity of the samples was measured by HPLC. The results obtained are given in Table 1 below.
[Table 1]
As can be seen from the results of Table 1, the samples of Comparative Examples 1 to 3 exhibited no improvement in purity upon the preparation of telmisartan salts, whereas the samples of Examples 1 to 4 exhibited a significant increase in purity, thus confirming excellent purifying effects. With simple preparation of telmisartan addition salts (as illustrated in Examples 1 to 4) from poorly-soluble free acid forms of telmisartan which suffers from difficulties in the introduction of an additional purification process due to low solubility, it was found possible to achieve high purity of telmisartan which is pharmaceutically very suitable.
Experimental Example 2: Precipitability of telmisartan salts
Generally, a poorly-soluble drug, even if it is dissolved in a medium, is deposited and precipitated again when solubility of the drug is poor. This poor solubility may be a factor that decreases oral absorption of the drug, so the evaluation of the precipitability of the drug becomes an evaluation item for the stability of an oral drug. Taking into account 900 mL of purified water as a medium typically used in a dissolution test and the maximum daily dose, purified water was added to the free acid of telmisartan and the samples of Examples 1 and 3, Comparative Examples 1 to 3, which were each dissolved in 1 mg/mL of methanol, thereby preparing aqueous solutions containing 0.1 mg telmisartan/mL. Thereafter, these aqueous solutions were allowed to stand at room temperature under shading, and telmisartan contents of the samples were measured by HPLC, at zero time and after 24 hours of placement of the samples in containers. The results obtained are given in Table 2 below.
[Table 2]
As can be seen from the results of Table 2, the commercially available telmisartan free acid was almost precipitated leaving only about 5% of the original mass, whereas Examples 1 and 3 exhibited significantly improved properties in precipitability, as compared to the free acid form of telmisartan. Therefore, the telmisartan zinc salts of the present invention have superior solubility in aqueous solutions, and very low probability of deposition and consequent precipitation (low precipitability) in an aqueous solution state, which are advantageous for the absorption of drugs.
Experimental Example 3: Hygroscopicity of telmisartan salts
Low hygroscopicity is a very important factor for practical processing and storage of pharmaceutical products, among various properties required for drug compounds to be used as pharmaceutical raw materials. For the measurement of hygroscopicity, a telmisartan free acid and individual samples of Examples 1 and 2, and Comparative Examples 1 to 3 were dried under vacuum (P2O5, for one day or more), and initial water contents of the samples were measured using a Karl Fisher method. Thereafter, amounts of sorbed water were automatically measured at 25℃ and relative humidity (RH) of 15, 35, 55, 75 and 95%, respectively, using a hygroscopicity measurement apparatus (Model No. Hydrosorb 1000, manufactured by Quantachrome Instruments). The results obtained are given in Table 3 below. In this connection, it should be noted that the initial water content was defined as a water content of the test sample which will exhibit no further decrease in weight, after the drying wascontinuously and thoroughly conducted.
[Table 3]
As can be seen from the results of Table 3, the telmisartan free acid and the samples of Examples 1 and 2 exhibited very low hygroscopicity of about 0.5% over the entire range of relative humidity where the experiments were carried out, thus representing that a pharmaceutical raw material can be stably stored even when it is exposed to moisture in the air. On the other hand, each sample of Comparative Examples 1 to 3 had very poor properties as a pharmaceutical raw material, since they exhibit geometrically increased absorption of atmospheric moisture as the relative humidity increases. Giving particular consideration to the regulations that telmisartan should be managed to have a water content of less than 1% according to the national standards for drug substances published by the Food and Drug Administration (FDA) and telmisartan having the above-specified water content of more than 1% should not be used for pharmaceutical applications, the samples of Comparative Examples 1 to 3 were found to have excessively high hygroscopicity which is not acceptable for drug formulations. On the other hand, it was confirmed that the telmisartan zinc salts of the present invention have excellent non-hygroscopic properties thus making it not absorb moisture, even when they were exposed to ambient humidity conditions.
Experimental Example 4: Stability of telmisartan salts
Excellent solid-state stability of drug substances is very important for the formulation of tablets and capsules. In order to evaluate the stability of the drug compound of interest, the samples of Examples 1 and 2,and Comparative Examples 1 to 3 were stored under severe conditions of 100℃ (airtight state) for one week, and the relative thermal stability of the samples was measured by HPLC. The results obtained are given in Table 4 below.
[Table 4]
As a result, it was demonstrated that the telmisartan free acid and the samples of Examples 1 and 2 exhibited excellent thermal stability, whereas the samples of Comparative Examples 1 to 3 exhibited relatively poor thermal stability.
Experimental Example 5: Electrostaticity of telmisartan salts
Generally, compounds with a large build up of static electricity may cause problems associated with sticking of the compounds to the equipment and apparatus during the quantitative analysis and manufacture of pharmaceutical formulations. Therefore, in order to confirm the low electrostaticity of the compounds of the present invention, electrostatic properties of the telmisartan free acid and the samples of Examples 1 and 3, and Comparative Examples 1 to 3 were tested using a Faraday Cage apparatus (Model No. 325 Faraday Cage with SmartStirTM, manufactured by AMETEK PAR) that is designed to measure static electricity of a subject material under the shielding of an external electrostatic field.The results obtained are given in Table 5 below.
[Table 5]
As a result, the samples of Examples 1 and 3, exhibited decreased static electricity (low electrostaticity), as compared to the telmisartan free acid and the samples of Comparative Examples 1 to 3, thus confirming that the compounds of the present invention have excellent processability taking into consideration instrument rubbing that may take place during the preparation of pharmaceutical formulations.
Experimental Example 6: Specific volume (volume per unit weight) of telmisartan salts
Generally when a certain compound as a drug substance is formulated into a tablet, the specific volume of solid (volume per same unit weight) may affect the process convenience and formulation size. When the specific volume is large, this may result in very poor processability. Therefore, in order to confirm that telmisartan salts of the present invention have a low specific volume, the telmisartan free acid and the samples of Examples 1 and 3, and Comparative Examples 1 to 3 were placed in graduated cylinders. From a vertical height of 10 cm, free fall of the cylinders was repeated 20 times or more such that tapping of the samples was carried out to achieve sufficient compacting of the contents. The specific volume values of test samples were measured before and after tapping. The results obtained are given in Table 6 below.
[Table 6]
When compared with the telmisartan free acid and the samples of Comparative Examples 1 to 3, the samples of Examples 1 and 3 exhibited a noticeable reduction of the specific volume. Powdered drug substances usually have high specific volumes and are therefore designed into suitable dosage forms (tablets or capsules) always after compression molding thereof. Therefore, when the specific volume is large, the pharmaceutical processability of the drug substance becomes very poor. The telmisartan zinc salts of the present invention have excellent physicochemical properties in terms of pharmaceutical processability.
As apparent from the above description, the present invention enables high-purity production of a telmisartan zinc salt with no introduction of an additional purification process. The thus-produced telmisartan zinc salt exhibits excellent pharmaceutical properties associated with the solubility, stability and non-hygroscopicity, as well as improvements in physicochemical properties such as specific volume and electrostaticity of solids,which are required for practical commercialization of drug compounds. Therefore, the telmisartan zinc salt of the present invention in combination with a pharmaceutically acceptable carrier can be usefully employed as an active ingredient of antihypertensive drugs or cardio and vascular protective-pharmaceutical compositions.
Claims (7)
- A method for preparing a zinc salt of telmisartan, comprising reacting telmisartan free base with a zinc reagent in the presence of an organic solvent.
- The method according to claim 2, wherein the zinc reagent is zinc hydroxide, zinc acetate, zinc chloride, zinc bromide or zinc iodide.
- The method according to claim 2, wherein theorganic solvent is selected from the group consisting of lower alcohols such as methanol, ethanol, isopropanol and butanol; ethers such as 1,4-dioxane, tetrahydrofuran, diethylether and isopropylether; amides such as dimethylformamide and diethyacetamide; ketones such as acetone and methylethylketone esters such as isopropylacetate; halogenated hydrocarbons such as chloroform and dichloromethane; lower hydrocarbons such as hexane, heptane and octane; dimethylsulfoxide, isopropylacetate, water, and any combination thereof.
- A pharmaceutical composition for the treatment or prevention of hypertensive diseases and/or cardiovascular diseases, comprising a telmisartan zinc salt as an active ingredient and one or more pharmaceutically acceptable carriers.
- A use of a telmisartan zinc salt for the preparation of a pharmaceutical composition for the treatment or prevention of hypertensive diseases and cardiovascular diseases.
- A method for preventing or treating of hypertensive diseases and cardiovascular diseases, in comprising administering a therapeutically effective amount of a telmisartan zinc salt to mammal including a human in need of treatment or prevention of hypertensive diseases and/or cardiovascular diseases.
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR10-2008-0110743 | 2008-11-10 | ||
KR20080110743 | 2008-11-10 | ||
KR1020080135292A KR100893652B1 (en) | 2008-11-10 | 2008-12-29 | The new telmisartan zinc salt and the preparation thereof |
KR10-2008-0135292 | 2008-12-29 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2010053233A1 true WO2010053233A1 (en) | 2010-05-14 |
Family
ID=40757843
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/KR2009/001139 WO2010053233A1 (en) | 2008-11-10 | 2009-03-06 | The new telmisartan zinc salt and the preparation thereof |
Country Status (2)
Country | Link |
---|---|
KR (1) | KR100893652B1 (en) |
WO (1) | WO2010053233A1 (en) |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050004107A1 (en) * | 2003-04-30 | 2005-01-06 | Boehringer Ingelheim International Gmbh | Telmisartan sodium salt pharmaceutical formulation |
WO2005108375A1 (en) * | 2004-05-11 | 2005-11-17 | Cipla Limited | Process for the preparation of telmisartan |
KR20050120714A (en) * | 2003-04-15 | 2005-12-22 | 상꾜 가부시키가이샤 | Drug for preventing or treating angiogenic eye diseases |
WO2006050921A2 (en) * | 2004-11-11 | 2006-05-18 | Lek Pharmaceuticals D.D. | Preparation of telmisartan salts with improved solubility |
WO2007001066A1 (en) * | 2005-06-27 | 2007-01-04 | Daiichi Sankyo Company, Limited | Pharmaceutical preparation containing an angiotensin ii receptor antagonist and a calcium channel blocker |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6737432B2 (en) | 2001-10-31 | 2004-05-18 | Boehringer Ingelheim Pharma Kg | Crystalline form of telmisartan sodium |
DE10301371A1 (en) | 2003-01-16 | 2004-08-05 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Treatment or prophylaxis of cardiovascular, cardiopulmonary or renal diseases, e.g. hypertension combined with hyperlipidemia or atherosclerosis, using combination of telmisartan and atorvastatin |
-
2008
- 2008-12-29 KR KR1020080135292A patent/KR100893652B1/en not_active IP Right Cessation
-
2009
- 2009-03-06 WO PCT/KR2009/001139 patent/WO2010053233A1/en active Application Filing
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20050120714A (en) * | 2003-04-15 | 2005-12-22 | 상꾜 가부시키가이샤 | Drug for preventing or treating angiogenic eye diseases |
US20050004107A1 (en) * | 2003-04-30 | 2005-01-06 | Boehringer Ingelheim International Gmbh | Telmisartan sodium salt pharmaceutical formulation |
WO2005108375A1 (en) * | 2004-05-11 | 2005-11-17 | Cipla Limited | Process for the preparation of telmisartan |
WO2006050921A2 (en) * | 2004-11-11 | 2006-05-18 | Lek Pharmaceuticals D.D. | Preparation of telmisartan salts with improved solubility |
WO2007001066A1 (en) * | 2005-06-27 | 2007-01-04 | Daiichi Sankyo Company, Limited | Pharmaceutical preparation containing an angiotensin ii receptor antagonist and a calcium channel blocker |
Also Published As
Publication number | Publication date |
---|---|
KR100893652B1 (en) | 2009-04-17 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
KR101221864B1 (en) | Hydrates and polymorphs of 4-[[(7R)-8-cyclopentyl-7-ethyl-5,6,7,8-tetrahydro-5-methyl-6-oxo-2-pteridinyl]amino]-3-methoxy-N-(1-methyl-4-piperidinyl)benzamide, methods for the production thereof, and use thereof as medicaments | |
US8362253B2 (en) | Solid forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide | |
EP2855478A1 (en) | Solid forms of an antiviral compound | |
CZ299554B6 (en) | Compound with quinolone structure, pharmaceutical composition containing thereof and use of such compound | |
SA98190410B1 (en) | omeprazole sodium salt | |
EP1838716B1 (en) | Olanzapine pamoate dihydrate | |
JPH02184674A (en) | Novel compound,preparation thereof and drug composition containing same | |
JPS6229566A (en) | Novel guanidinomthylbenzoic acid derivative | |
HU186473B (en) | Process for preparing 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazinyl-1,8-naphthyridine-3-carboxylic acid-sesquihydrate | |
WO2017047970A1 (en) | Linagliptin crystal form, and preparation method therefor | |
WO2010151008A2 (en) | Piperazine dithioctate and pharmaceutical composition comprising the same | |
CN112759545B (en) | 3- (dimethylamino methyl) piperidine-4-alcohol derivative and preparation method and pharmaceutical application thereof | |
JPH0526782B2 (en) | ||
WO2017179914A1 (en) | Composition for preventing or treating gout, containing biotin-tagged caffeic acid compound as active ingredient | |
CN112759587A (en) | 3- (dimethylamino methyl) piperidine-4-alcohol derivative and preparation method and pharmaceutical application thereof | |
WO2010053233A1 (en) | The new telmisartan zinc salt and the preparation thereof | |
WO2011152657A2 (en) | Acetyl-l-carnitine malate, process for preparing the same, and pharmaceutical composition comprising the same | |
JPH02191257A (en) | Benzo-heterocyclic compound | |
WO2010062147A2 (en) | Crystal form of adefovir dipivoxil, preparation method thereof, and pharmaceutical composition containing the same | |
JP2008531544A (en) | Ocaperidone salts and pharmaceutical compositions containing them | |
US7521472B2 (en) | Crystal of two-ring heterocyclic sulfonamide compound | |
US20040019214A1 (en) | Novel ester or amide derivatives | |
WO2022220601A1 (en) | Pharmaceutically acceptable salt of sphingosine-1-phosphate receptor agonist, and crystalline form thereof | |
WO2019107986A1 (en) | Pharmaceutical composition comprising fimasartan | |
WO2011013992A2 (en) | R-7-(3-aminomethyl-4-methoxyimino-3-methyl-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid and l-aspartic acid salt, process for the preparation thereof and pharmaceutical composition comprising the same for antimicrobial |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 09824916 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 09824916 Country of ref document: EP Kind code of ref document: A1 |