JP2010511636A - イミダゾール−5−カルボン酸誘導体の塩、製造方法及びその医薬組成物 - Google Patents
イミダゾール−5−カルボン酸誘導体の塩、製造方法及びその医薬組成物 Download PDFInfo
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- JP2010511636A JP2010511636A JP2009539584A JP2009539584A JP2010511636A JP 2010511636 A JP2010511636 A JP 2010511636A JP 2009539584 A JP2009539584 A JP 2009539584A JP 2009539584 A JP2009539584 A JP 2009539584A JP 2010511636 A JP2010511636 A JP 2010511636A
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- Prior art keywords
- salt
- imidazole
- carboxylic acid
- methyl
- group
- Prior art date
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- FMRLDPWIRHBCCC-UHFFFAOYSA-L Zinc carbonate Chemical compound [Zn+2].[O-]C([O-])=O FMRLDPWIRHBCCC-UHFFFAOYSA-L 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 150000008063 acylals Chemical group 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 229910001413 alkali metal ion Inorganic materials 0.000 description 1
- 229910001420 alkaline earth metal ion Inorganic materials 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 229940058303 antinematodal benzimidazole derivative Drugs 0.000 description 1
- 239000008365 aqueous carrier Substances 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 150000001556 benzimidazoles Chemical class 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 235000011148 calcium chloride Nutrition 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- SGZAIDDFHDDFJU-UHFFFAOYSA-N candesartan Chemical compound CCOC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SGZAIDDFHDDFJU-UHFFFAOYSA-N 0.000 description 1
- 229960000932 candesartan Drugs 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- JHYNXXBAHWPABC-UHFFFAOYSA-N chloromethyl propan-2-yl carbonate Chemical compound CC(C)OC(=O)OCCl JHYNXXBAHWPABC-UHFFFAOYSA-N 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 230000000916 dilatatory effect Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- GWTCIAGIKURVBJ-UHFFFAOYSA-L dipotassium;dodecyl phosphate Chemical compound [K+].[K+].CCCCCCCCCCCCOP([O-])([O-])=O GWTCIAGIKURVBJ-UHFFFAOYSA-L 0.000 description 1
- CNXJITYCNQNTBD-UHFFFAOYSA-L dipotassium;hexadecyl phosphate Chemical compound [K+].[K+].CCCCCCCCCCCCCCCCOP([O-])([O-])=O CNXJITYCNQNTBD-UHFFFAOYSA-L 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- YVIGPQSYEAOLAD-UHFFFAOYSA-L disodium;dodecyl phosphate Chemical compound [Na+].[Na+].CCCCCCCCCCCCOP([O-])([O-])=O YVIGPQSYEAOLAD-UHFFFAOYSA-L 0.000 description 1
- LEHZBQJZYMFYMK-UHFFFAOYSA-L disodium;hexadecyl phosphate Chemical compound [Na+].[Na+].CCCCCCCCCCCCCCCCOP([O-])([O-])=O LEHZBQJZYMFYMK-UHFFFAOYSA-L 0.000 description 1
- TVACALAUIQMRDF-UHFFFAOYSA-N dodecyl dihydrogen phosphate Chemical compound CCCCCCCCCCCCOP(O)(O)=O TVACALAUIQMRDF-UHFFFAOYSA-N 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 229940014259 gelatin Drugs 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- ZUVCYFMOHFTGDM-UHFFFAOYSA-N hexadecyl dihydrogen phosphate Chemical compound CCCCCCCCCCCCCCCCOP(O)(O)=O ZUVCYFMOHFTGDM-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 229940079865 intestinal antiinfectives imidazole derivative Drugs 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 229910052808 lithium carbonate Inorganic materials 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- HQRPHMAXFVUBJX-UHFFFAOYSA-M lithium;hydrogen carbonate Chemical compound [Li+].OC([O-])=O HQRPHMAXFVUBJX-UHFFFAOYSA-M 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- QWDJLDTYWNBUKE-UHFFFAOYSA-L magnesium bicarbonate Chemical compound [Mg+2].OC([O-])=O.OC([O-])=O QWDJLDTYWNBUKE-UHFFFAOYSA-L 0.000 description 1
- 239000002370 magnesium bicarbonate Substances 0.000 description 1
- 235000014824 magnesium bicarbonate Nutrition 0.000 description 1
- 229910000022 magnesium bicarbonate Inorganic materials 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000014380 magnesium carbonate Nutrition 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 235000011147 magnesium chloride Nutrition 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- 210000002464 muscle smooth vascular Anatomy 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- VTRAEEWXHOVJFV-UHFFFAOYSA-N olmesartan Chemical compound CCCC1=NC(C(C)(C)O)=C(C(O)=O)N1CC1=CC=C(C=2C(=CC=CC=2)C=2NN=NN=2)C=C1 VTRAEEWXHOVJFV-UHFFFAOYSA-N 0.000 description 1
- 229960005117 olmesartan Drugs 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000007310 pathophysiology Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
- BEBPTRYPELOERP-UHFFFAOYSA-M potassium;methanethiolate Chemical compound [K+].[S-]C BEBPTRYPELOERP-UHFFFAOYSA-M 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- AAZYNPCMLRQUHI-UHFFFAOYSA-N propan-2-one;2-propan-2-yloxypropane Chemical compound CC(C)=O.CC(C)OC(C)C AAZYNPCMLRQUHI-UHFFFAOYSA-N 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- RMBAVIFYHOYIFM-UHFFFAOYSA-M sodium methanethiolate Chemical compound [Na+].[S-]C RMBAVIFYHOYIFM-UHFFFAOYSA-M 0.000 description 1
- VYPDUQYOLCLEGS-UHFFFAOYSA-M sodium;2-ethylhexanoate Chemical compound [Na+].CCCCC(CC)C([O-])=O VYPDUQYOLCLEGS-UHFFFAOYSA-M 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- LYBFGZZXTTYWGW-UHFFFAOYSA-N sodium;dihydroxy-methyl-oxidosilane Chemical compound [Na+].C[Si](O)(O)[O-] LYBFGZZXTTYWGW-UHFFFAOYSA-N 0.000 description 1
- 239000007962 solid dispersion Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- UAEJRRZPRZCUBE-UHFFFAOYSA-N trimethoxyalumane Chemical compound [Al+3].[O-]C.[O-]C.[O-]C UAEJRRZPRZCUBE-UHFFFAOYSA-N 0.000 description 1
- AAPLIUHOKVUFCC-UHFFFAOYSA-N trimethylsilanol Chemical class C[Si](C)(C)O AAPLIUHOKVUFCC-UHFFFAOYSA-N 0.000 description 1
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 1
- 230000003639 vasoconstrictive effect Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- 239000011667 zinc carbonate Substances 0.000 description 1
- 229910000010 zinc carbonate Inorganic materials 0.000 description 1
- 235000004416 zinc carbonate Nutrition 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- PCHQDTOLHOFHHK-UHFFFAOYSA-L zinc;hydrogen carbonate Chemical compound [Zn+2].OC([O-])=O.OC([O-])=O PCHQDTOLHOFHHK-UHFFFAOYSA-L 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
-
- 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
- C07D403/10—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 linked by a carbon chain containing aromatic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
-
- 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
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Epidemiology (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
【選択図】なし
Description
本発明の目的は、溶解性が改善されたイミダゾール−5−カルボン酸系誘導体の塩ならびにその製造方法および使用を提供することにある。
Rは、水素、C1−C4の直鎖状もしくは分岐状のアルキル基またはC3−C7のシクロアルキル基から選択され;
ここにおいて、前記アルキル基またはシクロアルキル基は、非置換のものであり、または、F、Cl、BrおよびOHから選択される1〜3の置換基で置換されたものであり;
Mは金属イオン又はアンモニウムイオンである。
(a)不活性有機溶媒中にて、式(II)の化合物を、金属イオン又はアンモニウムイオンを提供可能な試薬と反応させることにより、式(I)で表される塩を形成する工程;
Rは、水素、C1−C4の直鎖状もしくは分岐状のアルキル基またはC3−C7のシクロアルキル基から選択され、
ここにおいて、前記アルキル基またはシクロアルキル基は、非置換のものであり、または、F、Cl、BrおよびOHから選択される1〜3の置換基で置換されたものであり、
Mは金属イオンまたはアンモニウムイオンである。
本発明者らは幅広く深く検討した結果、イミダゾール−5−カルボン酸系誘導体の特定の塩類(特に、アルカリ金属塩及びアルカリ土類金属塩)の溶解性は非常に良いことを見出し、これに基づいて本発明を完成させた。
本文に用いられる「本発明の化合物」または「本発明の塩」は交換的に使用でき、いずれも式(II)の化合物から形成する式(I)で表される薬学的に許容される塩、特にアルカリ金属塩又はアルカリ土類金属塩を示す。具体的には、本発明の化合物は一般式(I)で表されるイミダゾール−5−カルボン酸系誘導体の薬学的に許容される塩である。
Mは金属イオン又はアンモニウムイオンである。
さらに、本発明は、一般式(1)で表されるイミダゾール−5−カルボン酸系誘導体を原料としてこれらの薬学的に許容される塩(特にアルカリ金属塩又はアルカリ土類金属塩)を製造する方法であって、(a)不活性有機溶媒にて、式(I)の化合物を、金属イオンを提供可能な試薬と反応させることにより、式(I)で表される塩(例えば、アンモニウム塩、アルカリ金属塩又はアルカリ土類金属塩)を形成する工程を含む方法を提供する。
(i)有機溶媒にて、2−ブチル−4−クロロ−1−[2’−(1H−テトラゾール−5−イル)1,1’−ビフェニル−メチル]イミダゾール−5−カルボン酸,1−[(イソプロポキシ)カルボニルオキシ]メチルエステルを、金属イオンを提供可能な試薬と反応させること、
(ii)反応液から直接的に固形産物を得ること、または、反応液を減圧濃縮して固形産物の粗製品を得ること、
(iii)有機溶媒で再結晶し、目的産物を得ること。
本発明の化合物はヒトへの投与に適しており、経口、直腸内、非胃腸(静脈内、筋肉内又は皮下)、局所の投与ができる。前記化合物は単独で投与されてもよく、または他の薬学的に許容される化合物と併用されてもよい。なお、本発明の化合物は混合して投与されても良い。
(a)本発明の塩は、水、メタノールなどの通常の溶媒への溶解性が良好で、通常の製剤に適している;
(b)本発明の塩は、動物生体内で良好な生物学的利用能を持つことが判明している。
2−ブチル−4−クロロ−1−[2’−(1H−テトラゾール−5−イル)1,1’−ビフェニル−メチル]イミダゾール−5−カルボン酸,1−[(イソプロポキシ)カルボニルオキシ]メチルエステル(化合物1)
2−ブチル−4−クロロ−1−[2’−(1H−テトラゾール−5−イル)1,1’−ビフェニル−メチル]イミダゾール−5−カルボン酸(US5138069に記載の方法で製造された)をトリフェニルクロロメタンと反応させ、2−ブチル−4−クロロ−1−[2’−(1−トリフェニルメチル−テトラゾール−5−イル)1,1’−ビフェニル−メチル]イミダゾール−5−カルボン酸を得た。100mlの一つ口フラスコに2−ブチル−4−クロロ−1−[2’−(1−トリフェニルメチル−テトラゾール−5−イル)1,1’−ビフェニル−メチル]イミダゾール−5−カルボン酸を0.523g、K2CO3を0.124g、N,N−ジメチルアセトアミドを5ml、順次添加し、室温で20分攪拌し、室温でイソプロポキシカルボン酸クロロメチル0.562gを添加し、45−50℃で16時間反応させた。反応終了後、ろ過し、ろ液に水30mlを加え、酢酸エチル30mlで2回抽出し、有機層を乾燥させ、濃縮後、油状物が1.724g得られた。精製せずに、そのまま以下の反応に用いた。
δH(ppm): 0.89(t, 3H, J=14.6), 1.24(d, 6H, J=6.3), 1.37(m, 2H, J=22.1), 1,69(m, 2H, J=30.5), 2.64(t, 2H, J=15.5), 4.81(m, 1H, J=12.4), 5.54(s, 2H), 5.86(s, 2H), 6.95-7.64(8H), 8.08(d, 1H, J=7.42)
ESI(+)m/z: 552.7
Mp: 134.5-136℃。
2−ブチル−4−クロロ−1−[2’−(1H−テトラゾール−5−イル)1,1’−ビフェニル−メチル]イミダゾール−5−カルボン酸,1−[(イソプロポキシ)カルボニルオキシ]メチルエステル,カリウム塩(化合物2)
2−ブチル−4−クロロ−1−[2’−(1H−テトラゾール−5−イル)1,1’−ビフェニル−メチル]イミダゾール−5−カルボン酸,1−[(イソプロポキシ)カルボニルオキシ]メチルエステル,カリウム塩(化合物2)
2−ブチル−4−クロロ−1−[2’−(1H−テトラゾール−5−イル)1,1’−ビフェニル−メチル]イミダゾール−5−カルボン酸,1−[(イソプロポキシ)カルボニルオキシ]メチルエステル,カリウム塩(化合物2)
2−ブチル−4−クロロ−1−[2’−(1H−テトラゾール−5−イル)1,1’−ビフェニル−メチル]イミダゾール−5−カルボン酸,1−[(イソプロポキシ)カルボニルオキシ]メチルエステル,ナトリウム塩(化合物3)
2−ブチル−4−クロロ−1−[2’−(1H−テトラゾール−5−イル)1,1’−ビフェニル−メチル]イミダゾール−5−カルボン酸,1−[(イソプロポキシ)カルボニルオキシ]メチルエステル,ナトリウム塩(化合物3)
2−ブチル−4−クロロ−1−[2’−(1H−テトラゾール−5−イル)1,1’−ビフェニル−メチル]イミダゾール−5−カルボン酸,1−[(イソプロポキシ)カルボニルオキシ]メチルエステル,カルシウム塩(化合物4)
2−ブチル−4−クロロ−1−[2’−(1H−テトラゾール−5−イル)1,1’−ビフェニル−メチル]イミダゾール−5−カルボン酸,1−[(イソプロポキシ)カルボニルオキシ]メチルエステル,カルシウム塩(化合物4)
2−ブチル−4−クロロ−1−[2’−(1H−テトラゾール−5−イル)1,1’−ビフェニル−メチル]イミダゾール−5−カルボン酸,1−[(イソプロポキシ)カルボニルオキシ]メチルエステル,カルシウム塩(化合物4)
上記の通り製造した各化合物を秤量し、所定の容量の溶媒に入れ、5分間ごとに30秒間激しく振盪し、30分間内の溶解状況を観察した。溶解性は以下の通り記述される:
易溶: 化合物1gは1ml〜10mlの溶媒に溶解できる、
溶解: 化合物1gは10ml〜30mlの溶媒に溶解できる、
少量溶解: 化合物1gは30ml〜100mlの溶媒に溶解できる、
微量溶解: 化合物1gは100ml〜1000mlの溶媒に溶解できる。
各化合物を20mg/kgの投与量で経口で胃に灌入することで、SDラットに投与した。投与後、異なる時点で眼窩採血し、前処理した後、HPLC法で血漿における親化合物の量を分析した。その結果、血液においては親化合物を検出できなかったが、2−ブチル−4−クロロ−1−[2’−(1H−テトラゾール−5−イル)1,1’−ビフェニル−メチル]イミダゾール−5−カルボン酸(EXP3174と略称する)の薬物血中濃度が次第に増大した。構造の特徴から、各化合物は生体内で迅速にEXP3174に変換することが推定された。したがって、EXP3174を化合物の生体内における吸収の指標とする。
ラットの静脈内投与:健康なSDラットに、EXP3174を7.9mg/kgの投与量でラットの尾静脈より注射投与し(投与容積は10ml/kg)、投与前と投与後の異なる時点で眼窩静脈叢から採血し、単離して血漿とした。液体クロマトグラフィー−タンデム質量分析法を用いて血漿におけるEXP3174の濃度を測定し、薬物濃度−時間曲線からEXP3174の薬物動態パラメータを算出した。
化合物2 23g
澱粉 140g
微晶質セルロース 67g
上記の物質を通常の方法で均一に混合後、通常のゼラチンカプセルに充填し、1000個のカプセルを得た。
Claims (10)
- Rが、C1−C4の直鎖状もしくは分岐状のアルキル基から選択されることを特徴とする請求項1に記載の塩。
- Rが、エチル基、イソプロピル基およびt−ブチル基からなる群から選択されることを特徴とする請求項1に記載の塩。
- Rが、イソプロピル基であることを特徴とする請求項1に記載の塩。
- 前記塩が、アルカリ金属塩またはアルカリ土類金属塩であることを特徴とする請求項4に記載の塩。
- 前記塩が、カリウム塩、ナトリウム塩またはカルシウム塩であることを特徴とする請求項5に記載の塩。
- (b)反応混合物から式(I)で表される塩を分離する工程を含むことを特徴とする請求項7に記載の方法。
- 薬学的に許容される担体と請求項1に記載の塩とを含む医薬組成物。
- 抗高血圧薬物の製造のための請求項1に記載の塩の使用。
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WO2012039447A1 (ja) * | 2010-09-24 | 2012-03-29 | 第一三共株式会社 | 置換シクロアルケン誘導体の結晶 |
JP2017518351A (ja) * | 2014-06-20 | 2017-07-06 | シェンヅェン サルブリス ファーマシューティカルズ カンパニー リミテッドShenzhen Salubris Pharmaceuticals Co., Ltd | アリサルタン・イソプロキシル結晶、その製造方法及び該結晶を含む医薬組成物 |
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CN101024643A (zh) | 2006-02-20 | 2007-08-29 | 上海艾力斯医药科技有限公司 | 咪唑-5-羧酸类衍生物、制备方法及其应用 |
CN101214242A (zh) * | 2007-01-05 | 2008-07-09 | 上海艾力斯医药科技有限公司 | 新的药用组合物 |
CN101317842A (zh) * | 2007-06-07 | 2008-12-10 | 上海艾力斯医药科技有限公司 | 一种咪唑-5-羧酸衍生物的治疗用途 |
CN101407511B (zh) * | 2007-10-11 | 2013-01-09 | 上海艾力斯生物医药有限公司 | 一种结晶型的咪唑-5-羧酸衍生物 |
CN101596189A (zh) * | 2008-06-05 | 2009-12-09 | 上海艾力斯生物医药有限公司 | 含有咪唑-5-羧酸类衍生物的药用组合物 |
CA2778807A1 (en) * | 2009-10-26 | 2011-05-05 | Lexicon Pharmaceuticals, Inc. | Methods of preparing 1-(4-((1r,2s,3r)-1,2,3,4-tetrahydroxybutyl)-1h-imidazol-2-yl)ethanone |
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JP2017518351A (ja) * | 2014-06-20 | 2017-07-06 | シェンヅェン サルブリス ファーマシューティカルズ カンパニー リミテッドShenzhen Salubris Pharmaceuticals Co., Ltd | アリサルタン・イソプロキシル結晶、その製造方法及び該結晶を含む医薬組成物 |
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