CA2464068C - .alpha.-form or .beta.-form crystal of (r)-2-(2-aminothiazol-4yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl)acetanilide - Google Patents
.alpha.-form or .beta.-form crystal of (r)-2-(2-aminothiazol-4yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl)acetanilide Download PDFInfo
- Publication number
- CA2464068C CA2464068C CA002464068A CA2464068A CA2464068C CA 2464068 C CA2464068 C CA 2464068C CA 002464068 A CA002464068 A CA 002464068A CA 2464068 A CA2464068 A CA 2464068A CA 2464068 C CA2464068 C CA 2464068C
- Authority
- CA
- Canada
- Prior art keywords
- form crystal
- ethyl
- amino
- crystal
- acetanilide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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- 239000013078 crystal Substances 0.000 title claims abstract description 147
- PBAPPPCECJKMCM-IBGZPJMESA-N mirabegron Chemical compound S1C(N)=NC(CC(=O)NC=2C=CC(CCNC[C@H](O)C=3C=CC=CC=3)=CC=2)=C1 PBAPPPCECJKMCM-IBGZPJMESA-N 0.000 title claims abstract description 28
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 8
- FZERHIULMFGESH-UHFFFAOYSA-N N-phenylacetamide Chemical compound CC(=O)NC1=CC=CC=C1 FZERHIULMFGESH-UHFFFAOYSA-N 0.000 claims description 22
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 16
- 229960001413 acetanilide Drugs 0.000 claims description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
- 238000010521 absorption reaction Methods 0.000 claims description 10
- 238000000113 differential scanning calorimetry Methods 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims 4
- 239000008194 pharmaceutical composition Substances 0.000 claims 2
- OJYGBLRPYBAHRT-UHFFFAOYSA-N alphachloralose Chemical compound O1C(C(Cl)(Cl)Cl)OC2C(O)C(C(O)CO)OC21 OJYGBLRPYBAHRT-UHFFFAOYSA-N 0.000 abstract description 35
- 239000003814 drug Substances 0.000 abstract description 17
- 238000004519 manufacturing process Methods 0.000 abstract description 17
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 239000004615 ingredient Substances 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 238000010586 diagram Methods 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- 229940079593 drug Drugs 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 238000010438 heat treatment Methods 0.000 description 9
- 239000007864 aqueous solution Substances 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 238000001953 recrystallisation Methods 0.000 description 8
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- QILVTBCJVNFIDP-NTISSMGPSA-N (1r)-2-[2-(4-aminophenyl)ethylamino]-1-phenylethanol;hydrochloride Chemical compound Cl.C1=CC(N)=CC=C1CCNC[C@H](O)C1=CC=CC=C1 QILVTBCJVNFIDP-NTISSMGPSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 239000008103 glucose Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- 239000011259 mixed solution Substances 0.000 description 5
- 238000010899 nucleation Methods 0.000 description 5
- -1 2-HYDROXY-2-PHENYLETHYL Chemical class 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 238000002076 thermal analysis method Methods 0.000 description 4
- LUAUJCGKCGBAKA-NTISSMGPSA-N (1r)-2-[2-(4-nitrophenyl)ethylamino]-1-phenylethanol;hydrochloride Chemical compound Cl.C([C@H](O)C=1C=CC=CC=1)NCCC1=CC=C([N+]([O-])=O)C=C1 LUAUJCGKCGBAKA-NTISSMGPSA-N 0.000 description 3
- YWGDTDSOHPHFAQ-OAHLLOKOSA-N (2r)-2-hydroxy-n-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide Chemical compound O=C([C@H](O)C=1C=CC=CC=1)NCCC1=CC=C([N+]([O-])=O)C=C1 YWGDTDSOHPHFAQ-OAHLLOKOSA-N 0.000 description 3
- DYCLHZPOADTVKK-UHFFFAOYSA-N 2-(2-azaniumyl-1,3-thiazol-4-yl)acetate Chemical compound NC1=NC(CC(O)=O)=CS1 DYCLHZPOADTVKK-UHFFFAOYSA-N 0.000 description 3
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 3
- 206010022489 Insulin Resistance Diseases 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- IWYDHOAUDWTVEP-SSDOTTSWSA-N (R)-mandelic acid Chemical compound OC(=O)[C@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-SSDOTTSWSA-N 0.000 description 2
- IOXOZOPLBFXYLM-UHFFFAOYSA-N 2-(4-nitrophenyl)ethanamine Chemical compound NCCC1=CC=C([N+]([O-])=O)C=C1 IOXOZOPLBFXYLM-UHFFFAOYSA-N 0.000 description 2
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000003579 anti-obesity Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000003795 desorption Methods 0.000 description 2
- QUPDWYMUPZLYJZ-UHFFFAOYSA-N ethyl Chemical class C[CH2] QUPDWYMUPZLYJZ-UHFFFAOYSA-N 0.000 description 2
- 201000005577 familial hyperlipidemia Diseases 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 230000002218 hypoglycaemic effect Effects 0.000 description 2
- 230000003914 insulin secretion Effects 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 239000008247 solid mixture Substances 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000009736 wetting Methods 0.000 description 2
- CYSGHNMQYZDMIA-UHFFFAOYSA-N 1,3-Dimethyl-2-imidazolidinon Chemical compound CN1CCN(C)C1=O CYSGHNMQYZDMIA-UHFFFAOYSA-N 0.000 description 1
- WSYDYHKUJOXZMK-TXEPZDRESA-N 2-(2-amino-1,3-thiazol-4-yl)-n-[4-[2-[[(2r)-2-hydroxy-2-phenylethyl]amino]ethyl]phenyl]acetamide;dihydrochloride Chemical compound Cl.Cl.S1C(N)=NC(CC(=O)NC=2C=CC(CCNC[C@H](O)C=3C=CC=CC=3)=CC=2)=C1 WSYDYHKUJOXZMK-TXEPZDRESA-N 0.000 description 1
- JVMHULJEYUQYSH-UHFFFAOYSA-N 2-(4-nitrophenyl)ethylazanium;chloride Chemical compound Cl.NCCC1=CC=C([N+]([O-])=O)C=C1 JVMHULJEYUQYSH-UHFFFAOYSA-N 0.000 description 1
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- PTHCMJGKKRQCBF-UHFFFAOYSA-N Cellulose, microcrystalline Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC)C(CO)O1 PTHCMJGKKRQCBF-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 239000004366 Glucose oxidase Substances 0.000 description 1
- 108010015776 Glucose oxidase Proteins 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 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
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000000654 additive Substances 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
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 229940116332 glucose oxidase Drugs 0.000 description 1
- 235000019420 glucose oxidase Nutrition 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hcl hcl Chemical compound Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000000314 lubricant Substances 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
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 238000010183 spectrum analysis Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/40—Unsubstituted amino or imino radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Diabetes (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Steroid Compounds (AREA)
Abstract
To provide novel crystals useful as an ingredient for the production of a diabetes remedy. The invention is concerned with a-form crystal and .beta.-form crystal of (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenyleth-yl)amino]ethyl]acetanilide. The .alpha.-form crystal does not exhibit hygroscopicity and has stability such that it can be used as a medicine, and is useful for mass synthesis in the industrial production. The .beta.-form crystal does not relatively exhibit hygroscopicity and is also useful as a production intermediate of the .alpha.-form crystal.
Description
Description a-FORM OR (3-FORM CRYSTAL OF (R)-2-(2-AMINOTHIAZOL-4-YL)-4'-[2-[(2-HYDROXY-2-PHENYLETHYL)AMINO] ETHYL)AMINO] ETHYL]
ACETANILIDE
TECHNICAL FIELD
The present invention relates to an a-form crystal or D-form crystal of (R)-2-(2-aminothia-zol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide which is useful as a diabetes remedy and to a drug containing the same, especially a diabetes remedy.
BACKGROUND ART
The present inventors have reported that (R)-2-(2-aminothia-zo1-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide dihydrochloride represented by the following chemical structural formula has both an insulin secretion promoting action and an insulin sensitivity.potentiating action, further has anti-obesity and anti-hyperlipemia actions due to a selective stimulating action to 03-receoptors and is a useful compound for remedy of diabetes (WO 99/20607, Example. 41) .
OH
H
N
~ \ ~ \ I --NH
ACETANILIDE
TECHNICAL FIELD
The present invention relates to an a-form crystal or D-form crystal of (R)-2-(2-aminothia-zol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide which is useful as a diabetes remedy and to a drug containing the same, especially a diabetes remedy.
BACKGROUND ART
The present inventors have reported that (R)-2-(2-aminothia-zo1-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide dihydrochloride represented by the following chemical structural formula has both an insulin secretion promoting action and an insulin sensitivity.potentiating action, further has anti-obesity and anti-hyperlipemia actions due to a selective stimulating action to 03-receoptors and is a useful compound for remedy of diabetes (WO 99/20607, Example. 41) .
OH
H
N
~ \ ~ \ I --NH
2HCi H
However, since this dihydrochloride has strong hygroscopicity and is unstable, its use as a medicine was still problematic.
Medicines are required to be stable against humidity, temperature, light, and the like over a long period of time and also to have stability in the formulation step. If medicines have strong hygroscopicity, they physically and chemically change or cause such an inconvenience that the water content is different depending upon lots. Accordingly, it is necessary to always store them in a drying chamber or to provide a drying step, which is not preferable from the standpoint of industrial use.
DISCLOSURE OF THE INVENTION
Under such technical circumstances, the present inventors have made extensive and intensive investigations about the foregoing compound described in Example 41 of WO
99/20607 and found novel a-form crystal (hereinafter simply referred to as "a-form crystal") and 0-form crystal (hereinafter simply referred to as "(3-form crystal") of (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenyleth-yl)amino]ethyl]acetanilide. Both of these two novel crystals are of a free base and are distinguished from each other by powder X-ray diffraction spectrum and DSC analysis. The previously obtained dihydrochloride crystal was a strongly hygroscopic and unstable crystal such that it exhibits a rapid increase in hygroscopicity from a relative humidity of 80 %
and holds moisture of about 14 % at a relative humidity of 90 %.
In contrast, the "a-form crystal" of the invention has a moisture-holding amount of not more than 0.2 % over the entire range of relative humidity from 5 % to 95 %, is a stable crystal not exhibiting hygroscopicity, and is suitable for use as a medicine. Further, in the "P-form crystal", an increase in the weight is observed from a relative humidity of about 20 %, and it holds moisture of about 3 % and has weak hygroscopicity. However, this crystal is a metastable-form crystal and can be used as a medicine. Also, the "(3-form crystal" is useful as a production intermediate of the "a-form crystal".
Each of the a-form crystal and the (3-form crystal is characterized by the following crystal lattice spacings [20( )] of powder X-ray diffraction spectrum and heat absorption peak of DSC analysis. Incidentally, with respect to the powder X-ray diffraction, in determining the identity of crystal, crystal lattice spacings and an overall pattern are important in the nature of data. On the other hand, since a relative intensity can vary a little depending upon the direction of crystal growth, particle size and measurement condition, it should not be strictly interpreted.
However, since this dihydrochloride has strong hygroscopicity and is unstable, its use as a medicine was still problematic.
Medicines are required to be stable against humidity, temperature, light, and the like over a long period of time and also to have stability in the formulation step. If medicines have strong hygroscopicity, they physically and chemically change or cause such an inconvenience that the water content is different depending upon lots. Accordingly, it is necessary to always store them in a drying chamber or to provide a drying step, which is not preferable from the standpoint of industrial use.
DISCLOSURE OF THE INVENTION
Under such technical circumstances, the present inventors have made extensive and intensive investigations about the foregoing compound described in Example 41 of WO
99/20607 and found novel a-form crystal (hereinafter simply referred to as "a-form crystal") and 0-form crystal (hereinafter simply referred to as "(3-form crystal") of (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenyleth-yl)amino]ethyl]acetanilide. Both of these two novel crystals are of a free base and are distinguished from each other by powder X-ray diffraction spectrum and DSC analysis. The previously obtained dihydrochloride crystal was a strongly hygroscopic and unstable crystal such that it exhibits a rapid increase in hygroscopicity from a relative humidity of 80 %
and holds moisture of about 14 % at a relative humidity of 90 %.
In contrast, the "a-form crystal" of the invention has a moisture-holding amount of not more than 0.2 % over the entire range of relative humidity from 5 % to 95 %, is a stable crystal not exhibiting hygroscopicity, and is suitable for use as a medicine. Further, in the "P-form crystal", an increase in the weight is observed from a relative humidity of about 20 %, and it holds moisture of about 3 % and has weak hygroscopicity. However, this crystal is a metastable-form crystal and can be used as a medicine. Also, the "(3-form crystal" is useful as a production intermediate of the "a-form crystal".
Each of the a-form crystal and the (3-form crystal is characterized by the following crystal lattice spacings [20( )] of powder X-ray diffraction spectrum and heat absorption peak of DSC analysis. Incidentally, with respect to the powder X-ray diffraction, in determining the identity of crystal, crystal lattice spacings and an overall pattern are important in the nature of data. On the other hand, since a relative intensity can vary a little depending upon the direction of crystal growth, particle size and measurement condition, it should not be strictly interpreted.
Table 1 (a-Form Crystal) Crystal lattice spacing Relative intensity C stal lattice s acin Relative intensity 5.32 Strong 19.04 Slightly strong 8.08 Strong 20.20 Sli htl strong 15.28 Sli htl strong 23.16 ~ Slightly strong 17.88 Slightly strong 24.34 Sli htl strong Table 2 (P-Form Crystal) Crystal lattice spacing Relative intensity Crystal lattice s acin Relative intensity 9.68 Medium 22.10 Medium 19.76 Sli htl strong 23.52 Medium 20.72 Medium Also, in the DSC analysis, the a-form crystal had a heat absorption peak at 142 to 146 C, and the 0-form crystal had heat absorption peaks at 90 to 110 C and at 142 to 146 C, respectively.
The measurement of the powder X-ray diffraction was carried out using MAC Science MXP18TAHF22 under the following conditions. Tube: Cu, tube current: 40 mA, tube voltage: 40 kV, sampling width: 0.020 , scanning rate: 3 /min, wavelength:
1.54056 angstrom, measurement diffraction angle range (20):
to 40 .
Thermal analyses (DSC and TGA) were respectively carried out under the following conditions.
DSC: Perkin-Elmer Pyris 1, from 25 C to 250 C (10 C/min) , N2 (20 mL/min), aluminum-made sample pan. TGA: Perkin-Elmer *-trademark 4 TGA 7, from 25 C to 250 C (10 C/min) , N2 (20 mL/min), platinum-made sample pan.
Nuclear magnetic resonance (NMR) spectra were measured using JEOL JNM-LA400 and JEOL JNM-A500, and tetramethylsilane (TMS) was used as an internal standard.
Mass analysis spectra were measured using JEOL DX-300 and JEOL LX-2000.
Further, the invention relates to a drug containing the a-form crystal or (3-form crystal of (R)-2-(2-aminothia-zol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide, especially a diabetes remedy having both an anti-obesity action and an anti-hyperlipemia action.
Administration of a drug containing the crystal of the invention as a starting material for the production of medicines may be either oral administration by, for example, tablet, pill, capsule, granule, or powder, or parenteral administration by, for example, inhaling agent. Examples of the solid composition for oral administration include tables, powders, and granules. In such a solid composition, one or more active substances are mixed with at least one inert excipient such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, and magnesium metasilicate aluminate.
The composition may also contain inert additives such as lubricants such as magnesium stearate; disintegrants such as carboxylmethyl starch sodium; and auxiliary solubilizers according to customary manners. If desired, tablets or pills may be coated with sugar coat or with gastric or enteric coating agents. The dose may be appropriately decided depending upon each particular case while taking into consideration of symptom, age, sex, etc. of the subject to be administered but is usually from about 0.01 mg/kg to 100 mg/kg per day for an adult in the case of oral administration, and that is administered at a time or by dividing into 2 to 4 times.
(Production method) The a-form crystal can be obtained by adding a recrystallization solvent (37 % to 50 % ethanol aqueous solution) to the (3-form crystal of (R)-2-(2-aminothia-zol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide, dissolving the P-form crystal by heating at about 70 to 80 C, and then gradually cooling the solution at a rate of about 10 C per hour. Though the a-form crystal is likely crystallized in the large-scale production in the industrial production, it can be preferentially crystallized upon seeding with the a-form crystal.
The (3-form crystal can be obtained by adding 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide monohydrochloride to a mixed solution of (R)-2-[[2-(4-aminophenyl)ethyl]amino]-1-phenylethanol monohydrochloride, 2-aminothiazol-4-yl-acetic acid, concentrated hydrochloric acid and water at room temperature and neutralizing the resulting acidic solution to form a wet cake of the 0-form crystal. (The wet cake as referred to herein means the state where the crystal is wetted by the solvent.) Also, the (3-form crystal can be obtained by adding a recrystallization solvent (37 % to 50 % ethanol aqueous solution) to the present P-form crystal, dissolving the 0-form crystal by heating at about 70 to 80 C, and after setting up an external temperature at 20 C, rapidly cooling the solution.
Also, the (3-form crystal can be preferentially crystallized upon seeding with the (3-form crystal.
As described previously, since the isolated 0-form crystal can be again converted into the a-form after dissolution by heating, the (3-form crystal is useful as a production intermediate of the a-form crystal.
BEST MODE FOR CARRYING OUT THE INVENTION
The invention will be specifically described below with reference to Examples 1 to 4, but it should not be construed that the scope of the invention is limited thereto. Since the starting compound was produced by a different method from that described in WO 99/20607, it will be described as Referential Examples 1 to 3. The synthesis routes of Referential Examples 1 to 3 and Examples 1 to 4 are illustrated below. Further, the production method of a crystal of (R) -2- (2-aminothia-zol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide dihydrochloride will be described as Comparative Referential Example.
Synthesis Route OH
0-11"YO OH + H2N Referential Example 1 pH H
NO2 -~ i i 0 NOZ
N
Hydrochloride or 1/2-sulfate Referential Example 2 OH H Referential Example 3 OH H
NO I~ N I~ NH
z z Hydrochloride Hydrochloride ~ ~NH Example 1 Drying A"- ~NHz N
H
(3 -Form crystal Example 2 Example 2 at the time of recrystalli.zation and quenching .............................
~ ~NH OH H /
2 HO N c'-'ou:'>-NH2 H
...............................................................................
................................................ :
Example 3 at the time of Wet cake of a-f;rm crystal recrystallization and seeding Example 4 at the time of recrystallization and seeding OH H
N
~ S N
H
cr-Form crystal Referential Example 1:
To a mixture of 5.90 kg of 4-nitrophenylethylamine monohydrochloride, 4.43 kg of (R)-mandelic acid, 2.94 kg of triethylamine and 22 L of N,N-dimethylformamide, 3.93 kg of hydroxybenztriazole and 5.58 kg of 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide monohydrochloride (EDC) were added, and the mixture was stirred at around room temperature for 2 hours. 0. 28 kg of EDC was further added, and the mixture was stirred at around room temperature overnight. The reaction solution was diluted with 110 L of water and extracted with ethyl acetate (60 L and 30 L). The organic layer was washed successively with 60 L of a 1M hydrochloric acid aqueous solution, 60 L of a 20 % potassium carbonate aqueous solution and water (60 L and 60 L), and then concentrated in vacuo at to 19 C. The residue was dissolved in 35 L of toluene by heating (at 87 C) , cooled, and then stirred at 20 C overnight.
A formed crystal was collected by filtration and washed with 10 L of toluene, followed by drying in vacuo. There was thus obtained 7.66 kg of (R)-2-hydroxy-N-[2-(4-nitro-phenyl)ethyl)-2-phenylacetamide as a pale yellow crystal.
1H-NMR (DMSO-d6, 400 MHz) 8(ppm) = 2.87 (2H, t, J= 7.2 Hz) , 3. 30 to 3. 46 (2H, m) , 4. 85 (1H, d, J= 4. 8 Hz) , 6.12 (1H, d, J= 4. 8 Hz) , 7.20 to 7. 33 (5H, m) , 7. 40 (2H, d, J= 8.0 Hz) , 8.04 to 8.12 (3H, m). FAB-MS m/z: 301 (M+H)+.
(Another method) Production method using 4-nitrophenyl-ethylamine 1/2 sulfate:
To a mixture of 9.77 g of 4-nitrophenylethylamine 1/2 sulfate, 6.00 g of (R)-mandelic acid, 4.70 g of potassium carbonate and 60 mL of N,N-dimethylformamide, 6.14 g of hydroxybenztriazole and 8.70 g of 1-(3-dimethylamino-propyl)-3-ethylcarbodii.mide monohydrochloride (EDC) were added, and the mixture was stirred at around room temperature for 2 hours. 0. 87 g of EDC was further added, and the mixture was stirred at around room temperature overnight. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with 1M hydrochloric acid aqueous solution, 20 % potassium carbonate aqueous solution and water, and then concentrated in vacuo. The residue was recrystallized from toluene to obtain 10.4 g of (R)-2-hydroxy-N-[2-(4-nitro-phenyl)ethyl]-2-phenylacetamide as a pale yellow crystal.
Referential Example 2:
A mixture of 7.51 kg of (R)-2-hydroxy-N-[2-(4-nitro-phenyl)ethyl]-2-phenylacetamide, 23 L of 1,3-dimeth-yl-2-imidazolidinone and 23 L of tetrahydrofuran was cooled to -18 C, to which was then dropped 49.4 kg of 1M
borane-tetrahydrofuran solution at not higher than -7 C.
Thereafter, the temperature was increased to 70 C, and the mixture was stirred for 5 hours. The reaction mixture was cooled to -12 C, to which were then added 2.9 kg of methanol and 5. 9 kg of concentrated hydrochloric acid at not higher than C. The mixture was stirred at 68 C for one hour and concentrated in vacuo such that the inner volume became 50 L.
60 kg of 30 % K2C03 aqueous solution and 6 L of water were added, and the mixture was extracted with 75 L of ethyl acetate. The organic layer was washed with 75 L and concentrated in vacuo.
The residue was added with and dissolved in 75 L of isopropanol at 40 C, and the solution was crystallized from 2.46 kg of concentrated hydrochloric acid, followed by stirring at 23 C
overnight. A crystal was collected by filtration and washed with 38 L of isopropanol, followed by drying in vacuo. There was thus obtained 7.29 kg of (R)-2-[[2-(4-nitrophenyl)-ethyl]amino]-1-phenylethanol monohydrochloride.
1H-NMR (DMSO-d6, 400 MHz) 8(ppm) = 3.00 to 3.08 (1H, m) , 3.15 to 3.30 (5H, m), 5.00 to 5.05 (1H, m), 6.23 (1H, d, J
The measurement of the powder X-ray diffraction was carried out using MAC Science MXP18TAHF22 under the following conditions. Tube: Cu, tube current: 40 mA, tube voltage: 40 kV, sampling width: 0.020 , scanning rate: 3 /min, wavelength:
1.54056 angstrom, measurement diffraction angle range (20):
to 40 .
Thermal analyses (DSC and TGA) were respectively carried out under the following conditions.
DSC: Perkin-Elmer Pyris 1, from 25 C to 250 C (10 C/min) , N2 (20 mL/min), aluminum-made sample pan. TGA: Perkin-Elmer *-trademark 4 TGA 7, from 25 C to 250 C (10 C/min) , N2 (20 mL/min), platinum-made sample pan.
Nuclear magnetic resonance (NMR) spectra were measured using JEOL JNM-LA400 and JEOL JNM-A500, and tetramethylsilane (TMS) was used as an internal standard.
Mass analysis spectra were measured using JEOL DX-300 and JEOL LX-2000.
Further, the invention relates to a drug containing the a-form crystal or (3-form crystal of (R)-2-(2-aminothia-zol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide, especially a diabetes remedy having both an anti-obesity action and an anti-hyperlipemia action.
Administration of a drug containing the crystal of the invention as a starting material for the production of medicines may be either oral administration by, for example, tablet, pill, capsule, granule, or powder, or parenteral administration by, for example, inhaling agent. Examples of the solid composition for oral administration include tables, powders, and granules. In such a solid composition, one or more active substances are mixed with at least one inert excipient such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, and magnesium metasilicate aluminate.
The composition may also contain inert additives such as lubricants such as magnesium stearate; disintegrants such as carboxylmethyl starch sodium; and auxiliary solubilizers according to customary manners. If desired, tablets or pills may be coated with sugar coat or with gastric or enteric coating agents. The dose may be appropriately decided depending upon each particular case while taking into consideration of symptom, age, sex, etc. of the subject to be administered but is usually from about 0.01 mg/kg to 100 mg/kg per day for an adult in the case of oral administration, and that is administered at a time or by dividing into 2 to 4 times.
(Production method) The a-form crystal can be obtained by adding a recrystallization solvent (37 % to 50 % ethanol aqueous solution) to the (3-form crystal of (R)-2-(2-aminothia-zol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide, dissolving the P-form crystal by heating at about 70 to 80 C, and then gradually cooling the solution at a rate of about 10 C per hour. Though the a-form crystal is likely crystallized in the large-scale production in the industrial production, it can be preferentially crystallized upon seeding with the a-form crystal.
The (3-form crystal can be obtained by adding 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide monohydrochloride to a mixed solution of (R)-2-[[2-(4-aminophenyl)ethyl]amino]-1-phenylethanol monohydrochloride, 2-aminothiazol-4-yl-acetic acid, concentrated hydrochloric acid and water at room temperature and neutralizing the resulting acidic solution to form a wet cake of the 0-form crystal. (The wet cake as referred to herein means the state where the crystal is wetted by the solvent.) Also, the (3-form crystal can be obtained by adding a recrystallization solvent (37 % to 50 % ethanol aqueous solution) to the present P-form crystal, dissolving the 0-form crystal by heating at about 70 to 80 C, and after setting up an external temperature at 20 C, rapidly cooling the solution.
Also, the (3-form crystal can be preferentially crystallized upon seeding with the (3-form crystal.
As described previously, since the isolated 0-form crystal can be again converted into the a-form after dissolution by heating, the (3-form crystal is useful as a production intermediate of the a-form crystal.
BEST MODE FOR CARRYING OUT THE INVENTION
The invention will be specifically described below with reference to Examples 1 to 4, but it should not be construed that the scope of the invention is limited thereto. Since the starting compound was produced by a different method from that described in WO 99/20607, it will be described as Referential Examples 1 to 3. The synthesis routes of Referential Examples 1 to 3 and Examples 1 to 4 are illustrated below. Further, the production method of a crystal of (R) -2- (2-aminothia-zol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide dihydrochloride will be described as Comparative Referential Example.
Synthesis Route OH
0-11"YO OH + H2N Referential Example 1 pH H
NO2 -~ i i 0 NOZ
N
Hydrochloride or 1/2-sulfate Referential Example 2 OH H Referential Example 3 OH H
NO I~ N I~ NH
z z Hydrochloride Hydrochloride ~ ~NH Example 1 Drying A"- ~NHz N
H
(3 -Form crystal Example 2 Example 2 at the time of recrystalli.zation and quenching .............................
~ ~NH OH H /
2 HO N c'-'ou:'>-NH2 H
...............................................................................
................................................ :
Example 3 at the time of Wet cake of a-f;rm crystal recrystallization and seeding Example 4 at the time of recrystallization and seeding OH H
N
~ S N
H
cr-Form crystal Referential Example 1:
To a mixture of 5.90 kg of 4-nitrophenylethylamine monohydrochloride, 4.43 kg of (R)-mandelic acid, 2.94 kg of triethylamine and 22 L of N,N-dimethylformamide, 3.93 kg of hydroxybenztriazole and 5.58 kg of 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide monohydrochloride (EDC) were added, and the mixture was stirred at around room temperature for 2 hours. 0. 28 kg of EDC was further added, and the mixture was stirred at around room temperature overnight. The reaction solution was diluted with 110 L of water and extracted with ethyl acetate (60 L and 30 L). The organic layer was washed successively with 60 L of a 1M hydrochloric acid aqueous solution, 60 L of a 20 % potassium carbonate aqueous solution and water (60 L and 60 L), and then concentrated in vacuo at to 19 C. The residue was dissolved in 35 L of toluene by heating (at 87 C) , cooled, and then stirred at 20 C overnight.
A formed crystal was collected by filtration and washed with 10 L of toluene, followed by drying in vacuo. There was thus obtained 7.66 kg of (R)-2-hydroxy-N-[2-(4-nitro-phenyl)ethyl)-2-phenylacetamide as a pale yellow crystal.
1H-NMR (DMSO-d6, 400 MHz) 8(ppm) = 2.87 (2H, t, J= 7.2 Hz) , 3. 30 to 3. 46 (2H, m) , 4. 85 (1H, d, J= 4. 8 Hz) , 6.12 (1H, d, J= 4. 8 Hz) , 7.20 to 7. 33 (5H, m) , 7. 40 (2H, d, J= 8.0 Hz) , 8.04 to 8.12 (3H, m). FAB-MS m/z: 301 (M+H)+.
(Another method) Production method using 4-nitrophenyl-ethylamine 1/2 sulfate:
To a mixture of 9.77 g of 4-nitrophenylethylamine 1/2 sulfate, 6.00 g of (R)-mandelic acid, 4.70 g of potassium carbonate and 60 mL of N,N-dimethylformamide, 6.14 g of hydroxybenztriazole and 8.70 g of 1-(3-dimethylamino-propyl)-3-ethylcarbodii.mide monohydrochloride (EDC) were added, and the mixture was stirred at around room temperature for 2 hours. 0. 87 g of EDC was further added, and the mixture was stirred at around room temperature overnight. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with 1M hydrochloric acid aqueous solution, 20 % potassium carbonate aqueous solution and water, and then concentrated in vacuo. The residue was recrystallized from toluene to obtain 10.4 g of (R)-2-hydroxy-N-[2-(4-nitro-phenyl)ethyl]-2-phenylacetamide as a pale yellow crystal.
Referential Example 2:
A mixture of 7.51 kg of (R)-2-hydroxy-N-[2-(4-nitro-phenyl)ethyl]-2-phenylacetamide, 23 L of 1,3-dimeth-yl-2-imidazolidinone and 23 L of tetrahydrofuran was cooled to -18 C, to which was then dropped 49.4 kg of 1M
borane-tetrahydrofuran solution at not higher than -7 C.
Thereafter, the temperature was increased to 70 C, and the mixture was stirred for 5 hours. The reaction mixture was cooled to -12 C, to which were then added 2.9 kg of methanol and 5. 9 kg of concentrated hydrochloric acid at not higher than C. The mixture was stirred at 68 C for one hour and concentrated in vacuo such that the inner volume became 50 L.
60 kg of 30 % K2C03 aqueous solution and 6 L of water were added, and the mixture was extracted with 75 L of ethyl acetate. The organic layer was washed with 75 L and concentrated in vacuo.
The residue was added with and dissolved in 75 L of isopropanol at 40 C, and the solution was crystallized from 2.46 kg of concentrated hydrochloric acid, followed by stirring at 23 C
overnight. A crystal was collected by filtration and washed with 38 L of isopropanol, followed by drying in vacuo. There was thus obtained 7.29 kg of (R)-2-[[2-(4-nitrophenyl)-ethyl]amino]-1-phenylethanol monohydrochloride.
1H-NMR (DMSO-d6, 400 MHz) 8(ppm) = 3.00 to 3.08 (1H, m) , 3.15 to 3.30 (5H, m), 5.00 to 5.05 (1H, m), 6.23 (1H, d, J
4. 0 Hz) , 7.29 to 7.35 (1H, m) , 7. 36 to 7.43 (4H, m) , 7. 57 (2H, d, J= 8.4 Hz), 8.21 (2H, d, J= 8.4 Hz), 9.12 (2H, br) . FAB-MS
m/z: 287 (M+H) +.
Referential Example 3:
A mixture of 11.0 kg of (R)-2-[[2-(4-nitrophenyl)-ethyl]amino]-1-phenylethanol monohydrochloride, 110 L of methanol and 1.20 kg of wet 10 % palladium-carbon (wetting rate: 54.2 %) was stirred under a hydrogen atmosphere until absorption of hydrogen stopped. The reaction solution was filtered, and the filtrate was concentrated in vacuo. The residue was added with and dissolved in 40 L of methanol at 40 C, and the solution was crystallized from 220 L of diisopropyl ether, followed by stirring at 20 C overnight. A
crystal was collected by filtration and washed with 30 L of diisopropyl ether, followed by drying in vacuo. There was thus obtained 9.43 kg of (R)-2-[[2-(4-aminophenyl)ethyl]-amino]-1-phenylethanol monohydrochloride.
(Another method) Method of using ethyl acetate as crystallization solvent:
A mixture of 15.0 g of (R)-2-[[2-(4-nitrophenyl)-ethyl]amino]-1-phenylethanol monohydrochloride, 90 mL of methanol and 655 mg of wet 10 % palladium-carbon (wetting rate:
54.2 %) was stirred under a hydrogen atmosphere until absorption of hydrogen stopped. The reaction solution was filtered. The filtrate was heated, to which was then intezmittently added ethyl acetate while concentrating the methanol solution by heating, to form a slurry. A generated crystal was collected by filtration and washed with ethyl acetate, followed by drying in vacuo. There was thus obtained 12.9 g of (R)-2-[[2-(4-aminophenyl)ethyl]-amino]-1-phenylethanol monohydrochloride.
1H-NMR (DMSO-d6, 400 MHz) 8(ppm) = 2. 76 to 2. 90 (2H, m) , 2.95 to 3.16 (4H, m), 4.95 to 5.11 (3H, m), 6.20 (1H, d, J=
4.0 Hz), 6.53 (2H, d, J = 8.4 Hz), 6.89 (2H, d, J = 8.4 Hz), 7.28 to 7.43 (5H, m), 8.97 (1H, br), 9.29 (1H, br). FAB-MS
m/z: 257 (M+H)+.
Example 1 (Production of the (3-form crystal):
To a mixed solution of 8.00 g of (R)-2-[[2-(4-amino-phenyl)ethyl]amino]-1-phenylethanol monohydrochloride, 4.32 g of 2-aminothiazol-4-yl-acetic acid, 2.64 g of concentrated hydrochloric acid and 120 mL of water, S. 76 g of 1- (3-dimethyl-aminopropyl)-3-ethylcarbodiimide monohydrochloride (EDC) was added at room temperature, and the mixture was stirred for one hour. A mixed solution of 2.40 g of sodium hydroxide and 40 mL of water was dropped in the reaction solution, thereby undergoing crystallization. A generated crystal was collected by filtration and washed with water, followed by drying in vacuo. There was thus obtained 9.93 g of the (3-form crystal of (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hy-droxy-2-phenylethyl)amino]ethyl]acetanilide.
Example 2 (Production of the (3-form crystal through wet cake of the J3-form crystal ) :
To a mixed solution of 13. 50 kg of (R) -2- [[2- (4-amino-phenyl)ethyl]amino]-1-phenylethanol monohydrochloride, 7.29 kg of 2-aminothiazol-4-yl-acetic acid, 4.46 kg of concentrated hydrochloric acid and 270 L of water, 9.73 kg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide monohydrochloride (EDC) was added at 15 C, and the mixture was stirred for one hour. A mixed solution of 4.10 kg of sodium hydroxide and 110 L of water was dropped in the reaction solution, thereby undergoing crystallization. A generated crystal was collected by filtration and washed with water to obtain 26.2 kg of a wet cake of the (3-form crystal of (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenyleth-yl)amino]ethyl]acetanilide. This crystal was used for recrystallization as it was in the wet state.
26.2 kg of the wet cake of the P-form crystal was added with and dissolved in 180 L of water and 140 L of ethanol by heating at about 80 C, and an external temperature was set up at 20 C, thereby rapidly cooling the solution. A generated crystal was filtered and dried to obtain 15.40 kg of the (3-form crystal of (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hy-droxy-2-phenylethyl)amino]ethyl]acetanilide.
Powder X-ray diffraction diagram and thermal analysis diagram of the (3-form crystal are shown in Fig. 1 and Fig. 2, respectively.
(Another method) (Recrystallization upon seeding with the (3-form crystal ) :
A mixture of 7.54 g of the (3-form crystal, 60 mL of ethanol and 90 mL of water was dissolved by heating and cooled, to which was then added 380 mg of the P-form crystal at 45 C.
Thereafter, the mixture was stirred under ice cooling for 15 minutes. A crystal was filtered and dried to obtain 6.93 g of the (3-form crystal.
Example 3 (Production of the a-form crystal from the 0-form crystal):
A mixture of 15.30 kg of the P-form crystal of (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenyleth-yl) amino] ethyl] acetanilide, 180 L of water and 120 L of ethanol was dissolved by heating at about 80 C and cooled, to which was then added 15.0 g of the a-form crystal at 50 C.
Thereafter, the mixture was cooled to 20 C. A crystal was filtered and dried to obtain 14.24 kg of the a-form crystal of (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenyl-ethyl)amino]ethyl]acetanilide.
A powder X-ray diffraction diagram of the a-form crystal is shown in Fig. 3.
Example 4 (Production of the a-form crystal from wet cake of the (3-form crystal) :
The same procedures as in Example 2 were followed to obtain 23.42 kg of a wet cake of the (3-form crystal of (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenyleth-yl)amino]ethyl]acetanilide from 6.66 kg of (R)-2-[[2-(4-aminophenyl)ethyl]amino]-1-phenylethanol monohydrochloride. This cake was added with and dissolved in 92 L of water and 76 L of ethanol by heating at about 80 C, and the solution was cooled at a rate of about 10 C per hour, to which was then added 8.4 g of the a-form crystal at 55 C.
Thereafter, the mixture was cooled to 20 C. A crystal was filtered and dried to obtain 6.56 kg of the a-form crystal of (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenyleth-yl)amino]ethyl]acetanilide.
Powder X-ray diffraction diagram and thermal analysis diagram of the a-form crystal are shown in Fig. 4 and Fig. 5, respectively.
1H-NMR (DMSO-d6r 500 MHz) 6 (ppm) = 1.60 (1H, s), 2.59 to 2. 66 (4H, m) , 2. 68 to 2. 80 (2H, m) , 3. 45 (2H, s) , 4. 59 (1H, br), 5.21 (1H, br), 6.30 (1H, s), 6.89 (2H, s), 7.11 (2H, d, J= 8.5 Hz), 7.19 to 7.23 (1H, m), 7.27 to 7.33 (4H, m), 7.49 (2H, d, J= 8.5 Hz), 9.99 (1H,s). FAB-MS m/z: 397 (M+H)+.
Comparative Referential Example (Production of dihydro-chloride):
20.0 g of (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hy-droxy-2-phenylethyl)amino]ethyl]acetanilide was dissolved in l, 4-dioxane, to which was then added 8. 41 mL of concentrated hydrochloric acid. A generated crystal was collected by filtration to obtain 25.0 g of (R)-2-(2-aminothia-zol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide dihydrochloride.
A powder X-ray diffraction diagram of the dihydro-chloride crystal is shown in Fig. 6.
1H-NMR (DMSO-d6r 400 MHz) 8(ppm) = 2. 90 to 3. 08 (3H, m) , 3.10 to 3.21 (3H, m) , 3.75 (2H, s) , 4. 99 to 5.03 (1H, m) , 6.69 (1H, s), 7.20 (2H, d, J= 8.8 Hz), 7.28 to 7.43 (5H, m), 7.59 (2H, d, J= 8.8 Hz), 8.94 (1H, brs), 9.17 (2H, br), 9.40 (1H, brs). FAB-MS m/z: 397 (M+H)+.
INDUSTRIAL APPLICABILITY
The a-form crystal of the invention does not exhibit hygroscopicity and is stable, and therefore, can be used as a medicine and is useful as a medicine. Though the (3-form crystal of the invention exhibits weak hygroscopicity, it is stable and useful as a production intermediate of the a-form crystal. Also, these crystals have both an insulin secretion promoting action and an insulin sensitivity potentiating action and are useful for remedy of diabetes. The usefulness of these crystals as medicines has been ascertained by the following hygroscopicity test and hypoglycemic test.
1. Hygroscopicity test:
The hygroscopicity was measured using VTI SGA-100 under the following conditions. Temperature: 25 C, measurement range: from 5 to 95 % of relative humidity, measurement interval: 5 % of relative humidity.
As a result, the crystal of (R)-2-(2-aminothia-zol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide dihydrochloride exhibited a rapid increase in the weight from a relative humidity of about 80 %, held moisture of about 14 % at a relative humidity of 90 %, and exhibited strong hygroscopicity (see Fig. 7). On the other hand, the a-form crystal of the invention had a moisture-holding amount of not more than 0.2 % over the entire range of relative humidity from 5 % to 95 % and did not exhibit hygroscopicity (see Fig. 9) . Also, in the P-form crystal, an increase in the weight was observed from a relative humidity of about 20 %, and it held moisture of about 3 % and exhibited weak hygroscopicity (see Fig. 8).
The foregoing crystal of (R)-2-(2-aminothia-zol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide dihydrochloride exhibits strong hygroscopicity, and the physical and chemical nature and physical properties of the crystal vary and are unstable. On the other hand, the a-form crystal of the invention does not exhibit hygroscopicity and is excellent in stability, and therefore, is suitable as a starting material for the production of medicines. Though the "(3-form crystal" has weak hygroscopicity, it is a metastable-form crystal and can be used as a medicine.
2. Hypoglycemic test in kk mice (insulin resistance model:
obesity and hyperglycemia) Male kk mice (blood glucose level: 200 mg/dL or more) were measured for blood glucose level under feeding and then randomly classified into groups. The drug to be tested was compulsorily orally administered once daily for 7 days, and the blood glucose level after 15 to 18 hours from the final administration was compared with that before the administration (n = 6). The blood was collected from a tail vein of the mouse using a glass capillary (previously treated with heparin) , a protein was removed therefrom, and the amount of glucose in the supernatant (mg/dL) was measured by colorimetric determination by means of the glucose oxidase method. Further, a dose by which the blood glucose level was reduced by 30 % as compared with that before the administration of the drug to be tested was expressed as an ED30 value.
As a result, the a-form crystal exhibited a strong activity such that the ED30 value in the oral administration was not more than 3.5 mg/kg/day.
3. Usefulness of the P-form crystal as a production inter-mediate:
The (3-form crystal is also useful as a production intermediate of the a-form crystal. The (3-form crystal can be surely and simply obtained by quenching in the industrial production. Since the (i-form crystal has high solubility in a recrystallization solvent (37 % to 50 % ethanol aqueous solution) as compared with the a-form crystal, the a-form crystal can be easily obtained by recrystallization of the 0-form crystal.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 is a powder X-ray diffraction diagram of the (3-form crystal of (R)-2-(2-aminothia-zol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide (crystal of the invention).
Fig. 2 is a thermal analysis diagram of the (3-form crystal of (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hy-droxy-2-phenylethyl)amino]ethyl]acetanilide (crystal of the invention).
Fig. 3 is a powder X-ray diffraction diagram of the a-form crystal of (R)-2-(2-aminothia-zol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide (crystal of the invention).
Fig. 4 is a powder X-ray diffraction diagram of the a-form crystal of (R)-2-(2-aminothia-zol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide (crystal of the invention).
Fig. 5 is a thermal analysis diagram of the a-form crystal of (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hy-droxy-2-phenylethyl)amino]ethyl]acetanilide (crystal of the invention).
Fig. 6 is a powder X-ray diffraction diagram of the crystal of (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hy-droxy-2-phenylethyl)amino]ethyl]acetanilide dihydro-chloride.
Fig. 7 is a hygroscopicity curve diagram of the crystal of (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenyl-ethyl)amino]ethyl]acetanilide dihydrochloride.
Fig. 8 is a hygroscopicity curve diagram of the (3-form crystal of (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hy-droxy-2-phenylethyl)amino]ethyl]acetanilide (crystal of the invention).
Fig. 9 is a hygroscopicity curve diagram of the a-form crystal of (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hy-droxy-2-phenylethyl)amino]ethyl]acetanilide (crystal of the invention).
In the drawings, "Intensity" stands for the intensity;
"Temperature" stands for the temperature; "Heat Flow Endo Up"
stands for the heat absorption; "Weight" stands for the weight; "Adsorption" stands for the adsorption; "Desorption"
stands for the desorption; "Isotherm" stands for the curve;
and "RH" stands for the relative humidity, respectively.
m/z: 287 (M+H) +.
Referential Example 3:
A mixture of 11.0 kg of (R)-2-[[2-(4-nitrophenyl)-ethyl]amino]-1-phenylethanol monohydrochloride, 110 L of methanol and 1.20 kg of wet 10 % palladium-carbon (wetting rate: 54.2 %) was stirred under a hydrogen atmosphere until absorption of hydrogen stopped. The reaction solution was filtered, and the filtrate was concentrated in vacuo. The residue was added with and dissolved in 40 L of methanol at 40 C, and the solution was crystallized from 220 L of diisopropyl ether, followed by stirring at 20 C overnight. A
crystal was collected by filtration and washed with 30 L of diisopropyl ether, followed by drying in vacuo. There was thus obtained 9.43 kg of (R)-2-[[2-(4-aminophenyl)ethyl]-amino]-1-phenylethanol monohydrochloride.
(Another method) Method of using ethyl acetate as crystallization solvent:
A mixture of 15.0 g of (R)-2-[[2-(4-nitrophenyl)-ethyl]amino]-1-phenylethanol monohydrochloride, 90 mL of methanol and 655 mg of wet 10 % palladium-carbon (wetting rate:
54.2 %) was stirred under a hydrogen atmosphere until absorption of hydrogen stopped. The reaction solution was filtered. The filtrate was heated, to which was then intezmittently added ethyl acetate while concentrating the methanol solution by heating, to form a slurry. A generated crystal was collected by filtration and washed with ethyl acetate, followed by drying in vacuo. There was thus obtained 12.9 g of (R)-2-[[2-(4-aminophenyl)ethyl]-amino]-1-phenylethanol monohydrochloride.
1H-NMR (DMSO-d6, 400 MHz) 8(ppm) = 2. 76 to 2. 90 (2H, m) , 2.95 to 3.16 (4H, m), 4.95 to 5.11 (3H, m), 6.20 (1H, d, J=
4.0 Hz), 6.53 (2H, d, J = 8.4 Hz), 6.89 (2H, d, J = 8.4 Hz), 7.28 to 7.43 (5H, m), 8.97 (1H, br), 9.29 (1H, br). FAB-MS
m/z: 257 (M+H)+.
Example 1 (Production of the (3-form crystal):
To a mixed solution of 8.00 g of (R)-2-[[2-(4-amino-phenyl)ethyl]amino]-1-phenylethanol monohydrochloride, 4.32 g of 2-aminothiazol-4-yl-acetic acid, 2.64 g of concentrated hydrochloric acid and 120 mL of water, S. 76 g of 1- (3-dimethyl-aminopropyl)-3-ethylcarbodiimide monohydrochloride (EDC) was added at room temperature, and the mixture was stirred for one hour. A mixed solution of 2.40 g of sodium hydroxide and 40 mL of water was dropped in the reaction solution, thereby undergoing crystallization. A generated crystal was collected by filtration and washed with water, followed by drying in vacuo. There was thus obtained 9.93 g of the (3-form crystal of (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hy-droxy-2-phenylethyl)amino]ethyl]acetanilide.
Example 2 (Production of the (3-form crystal through wet cake of the J3-form crystal ) :
To a mixed solution of 13. 50 kg of (R) -2- [[2- (4-amino-phenyl)ethyl]amino]-1-phenylethanol monohydrochloride, 7.29 kg of 2-aminothiazol-4-yl-acetic acid, 4.46 kg of concentrated hydrochloric acid and 270 L of water, 9.73 kg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide monohydrochloride (EDC) was added at 15 C, and the mixture was stirred for one hour. A mixed solution of 4.10 kg of sodium hydroxide and 110 L of water was dropped in the reaction solution, thereby undergoing crystallization. A generated crystal was collected by filtration and washed with water to obtain 26.2 kg of a wet cake of the (3-form crystal of (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenyleth-yl)amino]ethyl]acetanilide. This crystal was used for recrystallization as it was in the wet state.
26.2 kg of the wet cake of the P-form crystal was added with and dissolved in 180 L of water and 140 L of ethanol by heating at about 80 C, and an external temperature was set up at 20 C, thereby rapidly cooling the solution. A generated crystal was filtered and dried to obtain 15.40 kg of the (3-form crystal of (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hy-droxy-2-phenylethyl)amino]ethyl]acetanilide.
Powder X-ray diffraction diagram and thermal analysis diagram of the (3-form crystal are shown in Fig. 1 and Fig. 2, respectively.
(Another method) (Recrystallization upon seeding with the (3-form crystal ) :
A mixture of 7.54 g of the (3-form crystal, 60 mL of ethanol and 90 mL of water was dissolved by heating and cooled, to which was then added 380 mg of the P-form crystal at 45 C.
Thereafter, the mixture was stirred under ice cooling for 15 minutes. A crystal was filtered and dried to obtain 6.93 g of the (3-form crystal.
Example 3 (Production of the a-form crystal from the 0-form crystal):
A mixture of 15.30 kg of the P-form crystal of (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenyleth-yl) amino] ethyl] acetanilide, 180 L of water and 120 L of ethanol was dissolved by heating at about 80 C and cooled, to which was then added 15.0 g of the a-form crystal at 50 C.
Thereafter, the mixture was cooled to 20 C. A crystal was filtered and dried to obtain 14.24 kg of the a-form crystal of (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenyl-ethyl)amino]ethyl]acetanilide.
A powder X-ray diffraction diagram of the a-form crystal is shown in Fig. 3.
Example 4 (Production of the a-form crystal from wet cake of the (3-form crystal) :
The same procedures as in Example 2 were followed to obtain 23.42 kg of a wet cake of the (3-form crystal of (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenyleth-yl)amino]ethyl]acetanilide from 6.66 kg of (R)-2-[[2-(4-aminophenyl)ethyl]amino]-1-phenylethanol monohydrochloride. This cake was added with and dissolved in 92 L of water and 76 L of ethanol by heating at about 80 C, and the solution was cooled at a rate of about 10 C per hour, to which was then added 8.4 g of the a-form crystal at 55 C.
Thereafter, the mixture was cooled to 20 C. A crystal was filtered and dried to obtain 6.56 kg of the a-form crystal of (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenyleth-yl)amino]ethyl]acetanilide.
Powder X-ray diffraction diagram and thermal analysis diagram of the a-form crystal are shown in Fig. 4 and Fig. 5, respectively.
1H-NMR (DMSO-d6r 500 MHz) 6 (ppm) = 1.60 (1H, s), 2.59 to 2. 66 (4H, m) , 2. 68 to 2. 80 (2H, m) , 3. 45 (2H, s) , 4. 59 (1H, br), 5.21 (1H, br), 6.30 (1H, s), 6.89 (2H, s), 7.11 (2H, d, J= 8.5 Hz), 7.19 to 7.23 (1H, m), 7.27 to 7.33 (4H, m), 7.49 (2H, d, J= 8.5 Hz), 9.99 (1H,s). FAB-MS m/z: 397 (M+H)+.
Comparative Referential Example (Production of dihydro-chloride):
20.0 g of (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hy-droxy-2-phenylethyl)amino]ethyl]acetanilide was dissolved in l, 4-dioxane, to which was then added 8. 41 mL of concentrated hydrochloric acid. A generated crystal was collected by filtration to obtain 25.0 g of (R)-2-(2-aminothia-zol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide dihydrochloride.
A powder X-ray diffraction diagram of the dihydro-chloride crystal is shown in Fig. 6.
1H-NMR (DMSO-d6r 400 MHz) 8(ppm) = 2. 90 to 3. 08 (3H, m) , 3.10 to 3.21 (3H, m) , 3.75 (2H, s) , 4. 99 to 5.03 (1H, m) , 6.69 (1H, s), 7.20 (2H, d, J= 8.8 Hz), 7.28 to 7.43 (5H, m), 7.59 (2H, d, J= 8.8 Hz), 8.94 (1H, brs), 9.17 (2H, br), 9.40 (1H, brs). FAB-MS m/z: 397 (M+H)+.
INDUSTRIAL APPLICABILITY
The a-form crystal of the invention does not exhibit hygroscopicity and is stable, and therefore, can be used as a medicine and is useful as a medicine. Though the (3-form crystal of the invention exhibits weak hygroscopicity, it is stable and useful as a production intermediate of the a-form crystal. Also, these crystals have both an insulin secretion promoting action and an insulin sensitivity potentiating action and are useful for remedy of diabetes. The usefulness of these crystals as medicines has been ascertained by the following hygroscopicity test and hypoglycemic test.
1. Hygroscopicity test:
The hygroscopicity was measured using VTI SGA-100 under the following conditions. Temperature: 25 C, measurement range: from 5 to 95 % of relative humidity, measurement interval: 5 % of relative humidity.
As a result, the crystal of (R)-2-(2-aminothia-zol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide dihydrochloride exhibited a rapid increase in the weight from a relative humidity of about 80 %, held moisture of about 14 % at a relative humidity of 90 %, and exhibited strong hygroscopicity (see Fig. 7). On the other hand, the a-form crystal of the invention had a moisture-holding amount of not more than 0.2 % over the entire range of relative humidity from 5 % to 95 % and did not exhibit hygroscopicity (see Fig. 9) . Also, in the P-form crystal, an increase in the weight was observed from a relative humidity of about 20 %, and it held moisture of about 3 % and exhibited weak hygroscopicity (see Fig. 8).
The foregoing crystal of (R)-2-(2-aminothia-zol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide dihydrochloride exhibits strong hygroscopicity, and the physical and chemical nature and physical properties of the crystal vary and are unstable. On the other hand, the a-form crystal of the invention does not exhibit hygroscopicity and is excellent in stability, and therefore, is suitable as a starting material for the production of medicines. Though the "(3-form crystal" has weak hygroscopicity, it is a metastable-form crystal and can be used as a medicine.
2. Hypoglycemic test in kk mice (insulin resistance model:
obesity and hyperglycemia) Male kk mice (blood glucose level: 200 mg/dL or more) were measured for blood glucose level under feeding and then randomly classified into groups. The drug to be tested was compulsorily orally administered once daily for 7 days, and the blood glucose level after 15 to 18 hours from the final administration was compared with that before the administration (n = 6). The blood was collected from a tail vein of the mouse using a glass capillary (previously treated with heparin) , a protein was removed therefrom, and the amount of glucose in the supernatant (mg/dL) was measured by colorimetric determination by means of the glucose oxidase method. Further, a dose by which the blood glucose level was reduced by 30 % as compared with that before the administration of the drug to be tested was expressed as an ED30 value.
As a result, the a-form crystal exhibited a strong activity such that the ED30 value in the oral administration was not more than 3.5 mg/kg/day.
3. Usefulness of the P-form crystal as a production inter-mediate:
The (3-form crystal is also useful as a production intermediate of the a-form crystal. The (3-form crystal can be surely and simply obtained by quenching in the industrial production. Since the (i-form crystal has high solubility in a recrystallization solvent (37 % to 50 % ethanol aqueous solution) as compared with the a-form crystal, the a-form crystal can be easily obtained by recrystallization of the 0-form crystal.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 is a powder X-ray diffraction diagram of the (3-form crystal of (R)-2-(2-aminothia-zol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide (crystal of the invention).
Fig. 2 is a thermal analysis diagram of the (3-form crystal of (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hy-droxy-2-phenylethyl)amino]ethyl]acetanilide (crystal of the invention).
Fig. 3 is a powder X-ray diffraction diagram of the a-form crystal of (R)-2-(2-aminothia-zol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide (crystal of the invention).
Fig. 4 is a powder X-ray diffraction diagram of the a-form crystal of (R)-2-(2-aminothia-zol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide (crystal of the invention).
Fig. 5 is a thermal analysis diagram of the a-form crystal of (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hy-droxy-2-phenylethyl)amino]ethyl]acetanilide (crystal of the invention).
Fig. 6 is a powder X-ray diffraction diagram of the crystal of (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hy-droxy-2-phenylethyl)amino]ethyl]acetanilide dihydro-chloride.
Fig. 7 is a hygroscopicity curve diagram of the crystal of (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenyl-ethyl)amino]ethyl]acetanilide dihydrochloride.
Fig. 8 is a hygroscopicity curve diagram of the (3-form crystal of (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hy-droxy-2-phenylethyl)amino]ethyl]acetanilide (crystal of the invention).
Fig. 9 is a hygroscopicity curve diagram of the a-form crystal of (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hy-droxy-2-phenylethyl)amino]ethyl]acetanilide (crystal of the invention).
In the drawings, "Intensity" stands for the intensity;
"Temperature" stands for the temperature; "Heat Flow Endo Up"
stands for the heat absorption; "Weight" stands for the weight; "Adsorption" stands for the adsorption; "Desorption"
stands for the desorption; "Isotherm" stands for the curve;
and "RH" stands for the relative humidity, respectively.
Claims (12)
1. An .alpha.-form crystal of (R)-2-(2-aminothia-zol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide.
2. An .alpha.-form crystal of (R)-2-(2-aminothia-zol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide having a heat absorption peak at 142 to 146°C in the DSC analysis.
3. An .alpha.-form crystal of (R)-2-(2-aminothia-zol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide having main peaks at around 5.32, 8.08, 15.28, 17.88, 19.04, 20.20, 23.16 and 24.34 in the terms of 2.theta. (°) in the powder X-ray diffraction.
4. An .alpha.-form crystal of (R)-2-(2-aminothia-zol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide having a heat absorption peak at 142 to 146°C in the DSC analysis and having main peaks at around 5.32, 8.08, 15.28, 17.88, 19.04, 20.20, 23.16 and 24.34 in the terms of 2.theta.(°) in the powder X-ray diffraction.
5. A pharmaceutical composition comprising the .alpha.-form crystal of (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hy-droxy-2-phenylethyl)amino]ethyl]acetanilide according to claim 1 and a pharmaceutically acceptable carrier.
6. A diabetes remedy comprising the .alpha.-form crystal of (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenyleth-yl)amino]ethyl]acetanilide according to claim 1 and a pharmaceutically acceptable carrier.
7. A .beta.-form crystal of (R)-2-(2-aminothia-zol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide.
8. A .beta.-form crystal of (R)-2-(2-aminothia-zol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide having heat absorption peaks at 90 to 110°C and at 142 to 146°C in the DSC analysis.
9. A .beta.-form crystal of (R)-2-(2-aminothia-zol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide having main peaks at around 9.68, 19.76, 20.72, 22.10 and 23.52 in the terms of 2.theta.(°) in the powder X-ray diffraction.
10. A .beta.-form crystal of (R)-2-(2-aminothia-zol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide having heat absorption peaks at 90 to 110°C and at 142 to 146°C in the DSC analysis and having main peaks at around 9.68, 19.76, 20.72, 22.10 and 23.52 in the terms of 2.theta. (°) in the powder X-ray diffraction.
11. A pharmaceutical composition comprising the .beta.-form crystal of (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hy-droxy-2-phenylethyl)amino]ethyl]acetanilide according to claim 7 and a pharmaceutically acceptable carrier.
12. A diabetes remedy comprising the .beta.-form crystal of (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenyleth-yl)amino]ethyl]acetanilide according to claim 7 and a pharmaceutically acceptable carrier.
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---|---|---|---|---|
US7342117B2 (en) * | 2001-10-30 | 2008-03-11 | Astellas Pharma Inc. | α-form or β-form crystal of acetanilide derivative |
ZA200503510B (en) | 2002-11-07 | 2006-12-27 | Yamanouchi Pharma Co Ltd | Remedy for overactive bladder comprising acetic acid anilide derivative as the active ingredient |
US7772188B2 (en) | 2003-01-28 | 2010-08-10 | Ironwood Pharmaceuticals, Inc. | Methods and compositions for the treatment of gastrointestinal disorders |
WO2005097127A2 (en) | 2004-04-02 | 2005-10-20 | Merck & Co., Inc. | Method of treating men with metabolic and anthropometric disorders |
EA020466B1 (en) | 2007-06-04 | 2014-11-28 | Синерджи Фармасьютикалз Инк. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
US8969514B2 (en) | 2007-06-04 | 2015-03-03 | Synergy Pharmaceuticals, Inc. | Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases |
US20100240697A1 (en) | 2007-11-02 | 2010-09-23 | Astellas Pharma Inc. | Pharmaceutical composition for treating overactive bladder |
EP2810951B1 (en) | 2008-06-04 | 2017-03-15 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
ES2624828T3 (en) | 2008-07-16 | 2017-07-17 | Synergy Pharmaceuticals Inc. | Guanylate cyclase agonists useful for the treatment of gastrointestinal disorders, inflammation, cancer and others |
TWI478712B (en) * | 2008-09-30 | 2015-04-01 | Astellas Pharma Inc | Pharmaceutical composition for modified release |
WO2010047982A1 (en) | 2008-10-22 | 2010-04-29 | Merck Sharp & Dohme Corp. | Novel cyclic benzimidazole derivatives useful anti-diabetic agents |
CA2741672A1 (en) | 2008-10-31 | 2010-05-06 | Merck Sharp & Dohme Corp. | Novel cyclic benzimidazole derivatives useful anti-diabetic agents |
US8586760B2 (en) | 2009-06-15 | 2013-11-19 | Auspex Pharmaceuticals, Inc. | Aminothiazole modulators of beta-3-adrenoreceptor |
AU2011218830B2 (en) | 2010-02-25 | 2014-07-24 | Merck Sharp & Dohme Corp. | Novel cyclic benzimidazole derivatives useful anti-diabetic agents |
WO2011122524A1 (en) | 2010-03-29 | 2011-10-06 | アステラス製薬株式会社 | Controlled release pharmaceutical composition |
TWI511967B (en) * | 2010-06-16 | 2015-12-11 | Takeda Pharmaceutical | Crystal of amide compound |
US9616097B2 (en) | 2010-09-15 | 2017-04-11 | Synergy Pharmaceuticals, Inc. | Formulations of guanylate cyclase C agonists and methods of use |
EP3243385B1 (en) | 2011-02-25 | 2021-01-13 | Merck Sharp & Dohme Corp. | Novel cyclic azabenzimidazole derivatives useful as anti-diabetic agents |
US9655885B2 (en) | 2011-05-18 | 2017-05-23 | Dr. Reddy's Laboratories Ltd. | Amorphous mirabegron and processes for crystal forms of mirabegron |
US9283210B2 (en) * | 2011-05-18 | 2016-03-15 | Dr. Reddy's Laboratories Ltd. | Amorphous mirabegron and processes for crystal forms of mirabegron |
JPWO2013147134A1 (en) | 2012-03-30 | 2015-12-14 | アステラス製薬株式会社 | Mirabegron-containing pharmaceutical composition |
CN103387500A (en) * | 2012-05-11 | 2013-11-13 | 上海医药工业研究院 | Preparation methods for mirabegron and intermediate thereof |
JP2015525782A (en) | 2012-08-02 | 2015-09-07 | メルク・シャープ・アンド・ドーム・コーポレーションMerck Sharp & Dohme Corp. | Antidiabetic tricyclic compounds |
EA201590449A1 (en) | 2012-08-31 | 2015-06-30 | Астеллас Фарма Инк. | ORAL PREPARED MEDICINE COMPOSITION |
CN104994848A (en) | 2013-02-22 | 2015-10-21 | 默沙东公司 | Antidiabetic bicyclic compounds |
WO2014132270A2 (en) * | 2013-02-27 | 2014-09-04 | Msn Laboratories Limited | Process for the preparation of 2-(2-aminothiazol-4-yl)-n-[4-(2-{[(2r)-2-hydroxy-2-phenyl ethyl]amino}ethyl)phenyl]acetamide monohydrochloride, its intermediates and polymorph thereof |
WO2014139388A1 (en) | 2013-03-14 | 2014-09-18 | Merck Sharp & Dohme Corp. | Novel indole derivatives useful as anti-diabetic agents |
CA2905438A1 (en) | 2013-03-15 | 2014-09-25 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase and their uses |
CA2905435A1 (en) | 2013-03-15 | 2014-09-25 | Synergy Pharmaceuticals Inc. | Compositions useful for the treatment of gastrointestinal disorders |
CN103193730A (en) * | 2013-04-17 | 2013-07-10 | 苏州永健生物医药有限公司 | Synthesis method of mirabegron |
CN103232368B (en) * | 2013-04-18 | 2015-08-12 | 苏州永健生物医药有限公司 | A kind of synthetic method of (R)-4-nitrophenethyl-(2-hydroxyl-2-styroyl)-t-butyl carbamate |
CN103232352B (en) * | 2013-05-11 | 2015-12-23 | 苏州永健生物医药有限公司 | (R)-4-(2-(2-hydroxyl-2-phenylethylamine base) ethyl) anilino carboxylate |
PT3004138T (en) | 2013-06-05 | 2024-06-18 | Bausch Health Ireland Ltd | Ultra-pure agonists of guanylate cyclase c, method of making and using same |
WO2015040573A1 (en) | 2013-09-23 | 2015-03-26 | Ranbaxy Laboratories Limited | Mirabegron dimethyl sulphoxide solvate and its use for the treatment of overactive bladder |
WO2015040605A1 (en) | 2013-09-23 | 2015-03-26 | Ranbaxy Laboratories Limited | Crystalline form of mirabegron |
WO2015044965A1 (en) | 2013-09-30 | 2015-04-02 | Megafine Pharma (P) Ltd. | A process for preparation of mirabegron and alpha crystalline form thereof |
ITMI20131653A1 (en) | 2013-10-07 | 2015-04-08 | Dipharma Francis Srl | CRYSTALLINE FORMS OF AN ADRENERGIC AGONIST |
WO2015051496A1 (en) | 2013-10-08 | 2015-04-16 | Merck Sharp & Dohme Corp. | Antidiabetic tricyclic compounds |
CN103641792B (en) * | 2013-12-27 | 2015-07-22 | 国药集团国瑞药业有限公司 | Mirabegron related substance or salt thereof, and preparation method and use thereof |
CN104876889B (en) * | 2014-02-27 | 2017-02-22 | 人福医药集团股份公司 | A synthesis method of a compound |
WO2015155664A1 (en) * | 2014-04-08 | 2015-10-15 | Suven Life Sciences Limited | An improved process for the preparation of 2-(2-aminothiazol-4-yl)-n-[4-(2-[[(2r)-2-hydroxy-2- phenylethyl]amino]-ethyl)phenyl]acetamide |
CN103896872A (en) * | 2014-04-29 | 2014-07-02 | 黑龙江大学 | Method for synthesizing mirabegron |
CN104016943A (en) * | 2014-05-23 | 2014-09-03 | 苏州凯瑞医药科技有限公司 | Synthetic method of mirabegron |
CN104016877B (en) * | 2014-06-13 | 2017-02-15 | 南京海融制药有限公司 | Acetylaniline compounds and application thereof in preparation of mirabegron |
ES2676586T3 (en) | 2014-08-06 | 2018-07-23 | Interquim, S.A. | Procedure for the synthesis of mirabegron and its derivatives |
WO2016024284A2 (en) | 2014-08-07 | 2016-02-18 | Wanbury Ltd. | A process for the preparation of mirabegron and its intermediates |
CN105481705A (en) * | 2014-08-23 | 2016-04-13 | 南京海纳医药科技有限公司 | Preparation and application of (R)-2-[[2-(4-aminophenyl)ethyl]amino]-1-phenylethyl alcohol |
CN104230840A (en) * | 2014-09-05 | 2014-12-24 | 安徽联创药物化学有限公司 | Synthesis method of mirabegron |
EP3197449B1 (en) | 2014-09-26 | 2018-11-21 | Universita' Degli Studi di Bari | Selective agonists of beta-adrenergic type 3 receptors (bar3) for the treatment of nephrogenic diabetes insipidus |
EP3253741A1 (en) | 2015-02-02 | 2017-12-13 | Lupin Limited | Process for preparation of polymorphic form of mirabegron |
JP2018090490A (en) | 2015-03-31 | 2018-06-14 | アステラス製薬株式会社 | Mirabegron-containing pharmaceutical composition |
FR3043555B1 (en) * | 2015-11-17 | 2019-10-25 | Centre National De La Recherche Scientifique (Cnrs) | MIRABEGRON FOR THE TREATMENT OF RETINAL DISEASES |
EP3184516A1 (en) | 2015-12-23 | 2017-06-28 | Enantia, S.L. | Crystalline inclusion complexes of mirabegron with beta-cyclodextrin |
CN105801438A (en) * | 2016-04-12 | 2016-07-27 | 济南大学 | Synthetic method of mirabegron intermediate |
CN107963976A (en) * | 2016-10-20 | 2018-04-27 | 中国动物疫病预防控制中心 | A kind of preparation method of phenyl ethyl amine compounds intermediate |
US11072602B2 (en) | 2016-12-06 | 2021-07-27 | Merck Sharp & Dohme Corp. | Antidiabetic heterocyclic compounds |
US10968232B2 (en) | 2016-12-20 | 2021-04-06 | Merck Sharp & Dohme Corp. | Antidiabetic spirochroman compounds |
EP3360866B1 (en) | 2017-02-14 | 2019-01-02 | Alfred E. Tiefenbacher (GmbH & Co. KG) | Mirabegron prodrugs |
KR101868438B1 (en) | 2017-04-13 | 2018-06-20 | (주) 성운파마코피아 | Method for preparing amide derivatives |
KR102398639B1 (en) | 2017-06-20 | 2022-05-17 | (주) 성운파마코피아 | Salts of amide derivatives and method for preparing the same |
CN108658797A (en) * | 2018-06-19 | 2018-10-16 | 安徽德信佳生物医药有限公司 | A kind of synthesis of Mirabegron intermediate (R) -2- (4- nitrophenethyls amino) -1- phenylethanol hydrochlorides |
CN108947853A (en) * | 2018-06-29 | 2018-12-07 | 黑龙江鑫创生物科技开发有限公司 | A kind of method of micro passage reaction synthesis Mirabegron intermediate |
KR101928987B1 (en) * | 2018-08-28 | 2018-12-13 | (주) 성운파마코피아 | A New and Highly Pure Crystalline monohydrate of mirabegron, Method for Preparing or Use Thereof |
KR20200117091A (en) | 2019-04-02 | 2020-10-14 | 제이투에이치바이오텍 (주) | Prodrug compound of mirabegron and its medical use for treating or alleviating overactive bladder diseases |
CN110590699B (en) * | 2019-09-29 | 2022-11-15 | 广东先强药业有限公司 | Refining method of mirabegron |
EP3722285B1 (en) | 2020-04-08 | 2022-03-30 | Alfred E. Tiefenbacher (GmbH & Co. KG) | Process for preparing mirabegron enacarbil |
CN113816864B (en) * | 2020-06-18 | 2024-03-29 | 南京正大天晴制药有限公司 | Preparation method of (R) -2-hydroxy-N- [2- (4-aminophenyl) ethyl ] -2-phenethylamine |
CN114539182B (en) * | 2020-11-24 | 2024-08-09 | 威智医药股份有限公司 | Crystal-transition solvent and application thereof, and preparation method of mirabegron alpha crystal form |
CN114539084B (en) * | 2020-11-24 | 2024-04-02 | 威智医药股份有限公司 | Preparation method of mirabegron and intermediate thereof |
KR20220081033A (en) | 2020-12-08 | 2022-06-15 | 주식회사 한서켐 | Manufacturing method of α-type crystalline Mirabegron |
CN112574137A (en) * | 2021-01-19 | 2021-03-30 | 南京美瑞制药有限公司 | Preparation method of alpha crystal form mirabegron |
KR20240116208A (en) | 2023-01-20 | 2024-07-29 | 이니스트에스티 주식회사 | New crystalline salts of mirabegron, preparation method thereof and pharmaceutical composition comprising the same |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE1921577B2 (en) * | 1969-04-28 | 1972-04-06 | Nixdorf Computer Ag, 4790 Paderborn | DRUM-LIKE DEVICE ZN BOOKING AND WRITING MACHINES WITH GRIPPING DEVICE FOR CAPTURING AND REMOVING ACCOUNT CARDS O THE LIKE |
JPH02279685A (en) | 1989-04-18 | 1990-11-15 | Yoshitomi Pharmaceut Ind Ltd | Thiadiazine having novel crystal structure and its compound production |
US6346532B1 (en) * | 1997-10-17 | 2002-02-12 | Yamanouchi Pharmaceutical Co., Ltd. | Amide derivatives or salts thereof |
JP3901832B2 (en) | 1998-03-13 | 2007-04-04 | 大日本インキ化学工業株式会社 | Quinolinone derivative preparation and production method thereof |
JP2000212168A (en) | 1999-01-22 | 2000-08-02 | Yamanouchi Pharmaceut Co Ltd | New crystal of hexahydro-1,4-diazepine derivative salt hydrate |
EP1129712A4 (en) * | 1999-09-10 | 2002-11-05 | Dainippon Ink & Chemicals | Quinolinone derivative preparations and process for producing the same |
US6706733B2 (en) * | 2001-05-08 | 2004-03-16 | Dainippon Ink And Chemicals, Inc. | Quinolinone derivative formulation and its production method |
US7342117B2 (en) * | 2001-10-30 | 2008-03-11 | Astellas Pharma Inc. | α-form or β-form crystal of acetanilide derivative |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2016049749A1 (en) * | 2014-10-01 | 2016-04-07 | Apotex Inc. | Solid forms of mirabegron |
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