JP7322048B2 - エロビキシバットの調製方法 - Google Patents
エロビキシバットの調製方法 Download PDFInfo
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- JP7322048B2 JP7322048B2 JP2020547081A JP2020547081A JP7322048B2 JP 7322048 B2 JP7322048 B2 JP 7322048B2 JP 2020547081 A JP2020547081 A JP 2020547081A JP 2020547081 A JP2020547081 A JP 2020547081A JP 7322048 B2 JP7322048 B2 JP 7322048B2
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- elobixibat
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000009103 reabsorption Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 208000010157 sclerosing cholangitis Diseases 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229910052814 silicon oxide Inorganic materials 0.000 description 1
- 229940083542 sodium Drugs 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 229920001059 synthetic polymer Polymers 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
- ZCERGRXTTGLHFZ-GFCCVEGCSA-N tert-butyl 2-[[(2r)-2-amino-2-phenylacetyl]amino]acetate Chemical compound CC(C)(C)OC(=O)CNC(=O)[C@H](N)C1=CC=CC=C1 ZCERGRXTTGLHFZ-GFCCVEGCSA-N 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- IPILPUZVTYHGIL-UHFFFAOYSA-M tributyl(methyl)azanium;chloride Chemical compound [Cl-].CCCC[N+](C)(CCCC)CCCC IPILPUZVTYHGIL-UHFFFAOYSA-M 0.000 description 1
- 239000001069 triethyl citrate Substances 0.000 description 1
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 1
- 235000013769 triethyl citrate Nutrition 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 201000001862 viral hepatitis Diseases 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D281/02—Seven-membered rings
- C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D281/10—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
-
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- 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
- A61P3/06—Antihyperlipidemics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Genetics & Genomics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Gastroenterology & Hepatology (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Analytical Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Crystallography & Structural Chemistry (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
式(I):
R1及びR2は、それぞれ独立してC1~4アルキルであり、
R3は、C1~4アルキルであり、
R4は、水素、ヒドロキシ、ハロ、ニトロ、シアノ及びC1~4アルキルからなる群から選択され、
R5は、水素、ヒドロキシ、ハロ、ニトロ、シアノ及びC1~4アルキルからなる群から選択される]
の化合物、又はその薬学的に許容される塩の調製方法であって、
式(II):
の化合物と、式(III):
R5は、上に定義された通りであり、
R6は、好適な保護基である]
の化合物とを反応させて、式(IV):
前記式(IV)の化合物を脱保護して、式(I)の化合物を得る工程と
を含む、方法に関する。
式(V):
の化合物と、式(VI):
R7は、好適な保護基であり、
Xは、好適な脱離基である]
の化合物とを反応させて、式(VII):
続いて、エステルR7O-C(O)-の加水分解により、式(II)の化合物を得る工程と
を含む、アルキル化反応により調製される。
(i)粗エロビキシバットを、エタノールと酢酸エチルとの混合物に溶解する工程と、
(ii)工程(i)から得られたエタノールと酢酸エチルとの混合物中の粗エロビキシバットの溶液から、エロビキシバットの結晶性エタノラートを結晶化させる工程と、
(iii)エロビキシバットの結晶性エタノラートを乾燥させて、エロビキシバットの結晶性無水物を得る工程と、
(iv)エロビキシバットの結晶性無水物を水和させて、エロビキシバットの結晶変態IVを得る工程と
を含む、方法に関する。
一般的方法
以下の実施例のための試薬及び出発原料は、市販のもの又は当技術分野で公知の標準的方法により調製されうるもののいずれかである。出発原料3,3-ジブチル-7-(メチルスルファニル)-1,1-ジオキソ-5-フェニル-2,3,4,5-テトラヒドロ-1H-1,5-ベンゾチアゼピン-8-オール及び1,1-ジメチルエチル2-[(2R)-2-ベンジルオキシカルバミド-2-フェニルアセトアミド]アセテートは、WO 02/50051に記載されるように調製されうる(方法26及び85をそれぞれ参照されたい)。
{[3,3-ジブチル-7-(メチルスルファニル)-1,1-ジオキシド-5-フェニル-2,3,4,5-テトラヒドロ-1,5-ベンゾチアゼピン-8-イル]オキシ}酢酸の調製
水酸化ナトリウム溶液(25.04kgの水酸化ナトリウムと225.4kgの水との混合物)を、上記のトルエン層に添加した。この混合物を47℃で3.5時間撹拌した。冷却した後、酢酸エチル(374.74kg)をこの反応溶液に添加し、その後、撹拌しながら、ギ酸をpHが3.6になるまで添加した。水性層を廃棄し、有機層を水(333.84kgで2回)で洗浄した。
有機層を真空下で濃縮し、酢酸エチル(599.24kg)を濃縮残留物に添加した。冷却した後、水酸化ナトリウム溶液(125.19kgの水酸化ナトリウムと709.41kgの水との混合物)を、撹拌しながらゆっくりと添加した。ナトリウム塩の結晶を沈殿させ、その後、遠心分離により単離した。
前記ナトリウム塩、酢酸エチル(599.24kg)及び水(333.8kg)を混合した。ギ酸を、撹拌しながらpHが3.5になるまで添加した。有機層を水(333.8kgで2回)で洗浄し、真空下で濃縮した。n-ヘプタン(228.68kg)を濃縮残留物に添加し、この混合物を撹拌した。沈殿させた結晶を濾過し、真空下で乾燥して、標題化合物の乾燥結晶を灰色がかった白色の固体として得た(65.38kg)。
HRMS(ESI、m/z) C26H34NO5S2[M-H]-に関する計算値:504.1880。実測値:504.1832。
tert-ブチル-N-[(2R)-2-アミノ-2-フェニルアセチル]グリシネートの調製
反応物を濾過し、濾過床を無水エタノール(106.65kg)で洗浄した。濾液を真空下で濃縮し、標題化合物を無色で粘性のある液体として得た(21.70kg)。
HRMS(ESI、m/z)C14H21N2O3[M+H]+に関する計算値:265.1553。実測値:265.1452。
tert-ブチル-N-{(2R)-2-[({[3,3-ジブチル-7-(メチルチオ)-1,1-ジオキシド-5-フェニル-2,3,4,5-テトラヒドロ-1,5-ベンゾチアゼピン-8-イル]オキシ}アセチル)アミノ]-2-フェニルエタノイル}グリシネートの調製
有機層を真空下で濃縮した。アセトニトリル(306.80kg)を添加した後、この混合物を溶解するまで加熱し、次に13℃まで冷却した。結晶を沈殿させ、次にこれを遠心分離にかけ、アセトニトリル(51.35kg)で洗浄した。
アセトニトリル(606.45kg)を、得られた粗結晶の全量に添加した。この混合物を溶解するまで加熱し、次に0℃まで冷却した。結晶を沈殿させ、これを遠心分離にかけ、アセトニトリル(51.35kg)で洗浄した。湿った結晶を真空乾燥し、標題化合物を白色粉末として得た(81.20kg)。
HRMS(ESI、m/z)C40H52N3O7S2[M-H]-に関する計算値:750.3250。実測値:750.3164。
粗エロビキシバットの調製
有機層を濾過した後、濾液を真空下で濃縮した。n-ヘプタン(520.20kg)を濃縮した残留物に添加し、この混合物を撹拌した。沈殿した結晶を遠心分離にかけ、n-ヘプタン(104.04kg)で洗浄した。結晶を真空乾燥し、粗エロビキシバットを灰色がかった白色の固体として得た(64.34kg)。
HRMS(ESI、m/z)C36H44N3O7S2[M-H]-に関する計算値:694.2623。実測値:694.2553。
エロビキシバットの結晶変態IVの調製
濾過した溶液を冷却した後、エロビキシバットの結晶変態IVの種結晶(0.032kg)を25℃で添加し、この混合物を2時間撹拌した。n-ヘプタン(832.00kg)を添加し、この混合物を23℃で撹拌し続けた。結晶を沈殿させ、これを遠心分離にかけ、n-ヘプタン(43.52kg)で洗浄した。湿った結晶を真空下で乾燥して、乾燥結晶を得た。
その後、乾燥結晶を、多湿条件(40±25%RH)に25℃で、2.4%~3.4%の水分含量(カール・フィッシャー滴定により決定)が達成されるまで曝露することにより、水和させた(加湿した)。エロビキシバットの結晶変態IVを、白色粉末として得た(50.64kg)。
Claims (17)
- 式(I):
式(II):
の化合物とを反応させて、式(IV):
前記式(IV)の化合物を脱保護して、式(I)の化合物を得る工程と
を含み、
式(IV)の化合物を、アセトニトリルから再結晶させる、方法。 - R6が、C1~4アルキル及び三置換シリルからなる群から選択される、請求項1に記載の方法。
- R6が、tert-ブチルである、請求項1又は2に記載の方法。
- 式(II)の化合物と式(III)の化合物との間の反応が、2,6-ルチジンの存在下で実施される、請求項1から3のいずれか一項に記載の方法。
- 式(IV)の化合物の加水分解が、トルエン中で実施される、請求項1から4のいずれか一項に記載の方法。
- 式(I)の化合物を、ヘプタンの添加により溶液から沈殿させる、請求項1から5のいずれか一項に記載の方法。
- 式(II)の化合物が、式(V):
R7は、好適な保護基であり、
Xは、好適な脱離基である]
の化合物とを反応させて、式(VII):
続いて、エステルR7O-C(O)-の加水分解により、式(II)の化合物を得る工程と
を含むアルキル化反応により調製される、請求項1から6のいずれか一項に記載の方法。 - R7が、C1~4アルキル及びC1~4ハロアルキルからなる群から選択される、請求項7に記載の方法。
- Xが、ハロ、トリフルオロメタンスルホネート、メタンスルホニル及びp-トルエンスルホニルからなる群から選択される、請求項7又は8に記載の方法。
- 式(II)の化合物を、最初に、対応するナトリウム塩として沈殿させ、その後、プロトン化し結晶化させる、請求項7から9のいずれか一項に記載の方法。
- 式(VII)の中間体化合物の調製が、トルエン中で実施される、請求項7から10のいずれか一項に記載の方法。
- 式(VII)の中間体化合物が、単離されず、次の工程で直ちに使用される、請求項7から11のいずれか一項に記載の方法。
- アルキル化反応及びそれに続く加水分解反応が、同一の溶媒中で実施される、請求項7から12のいずれか一項に記載の方法。
- 式(I)の化合物を、式(I)の安定な結晶性水和物に変換する工程を更に含む、請求項1から13のいずれか一項に記載の方法。
- 式(I)の化合物が、エタノールと酢酸エチルとの混合物に溶解される、請求項14に記載の方法。
- n-ヘプタンが、エタノールと酢酸エチルとの混合物中の式(I)の化合物の溶液に添加される、請求項14又は15に記載の方法。
- 安定な結晶性水和物が、結晶性一水和物である、請求項14から16のいずれか一項に記載の方法。
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US10941127B2 (en) | 2019-02-06 | 2021-03-09 | Albireo Ab | Benzothiadiazepine compounds and their use as bile acid modulators |
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EP4069247A1 (en) | 2019-12-04 | 2022-10-12 | Albireo AB | Benzothiadiazepine compounds and their use as bile acid modulators |
CA3158276A1 (en) * | 2019-12-04 | 2021-06-10 | Per-Goran Gillberg | Benzothia(di)azepine compounds and their use as bile acid modulators |
WO2021110887A1 (en) * | 2019-12-04 | 2021-06-10 | Albireo Ab | Benzothiazepine compounds and their use as bile acid modulators |
EP4069360B1 (en) | 2019-12-04 | 2024-01-03 | Albireo AB | Benzothia(di)azepine compounds and their use as bile acid modulators |
EP4069361B1 (en) | 2019-12-04 | 2024-01-03 | Albireo AB | Benzothia(di)azepine compounds and their use as bile acid modulators |
PT4069360T (pt) * | 2019-12-04 | 2024-03-06 | Albireo Ab | Compostos de benzotia(di)azepina e a sua utilização como moduladores de ácido biliar |
AR120683A1 (es) * | 2019-12-04 | 2022-03-09 | Albireo Ab | Compuestos de benzoti(di)azepina y su uso como ácido biliar |
TW202134220A (zh) * | 2019-12-04 | 2021-09-16 | 瑞典商艾爾比瑞歐公司 | 苯并噻(二)氮呯(benzothia(di)azepine)化合物及其作為膽酸調節劑之用途 |
CN116157389A (zh) | 2020-08-03 | 2023-05-23 | 阿尔比里奥公司 | 苯并硫杂(二)氮杂环庚三烯化合物及其作为胆汁酸调节剂的用途 |
AU2021379076A1 (en) | 2020-11-12 | 2023-06-08 | Albireo Ab | Odevixibat for treating progressive familial intrahepatic cholestasis (pfic) |
CN116583504A (zh) * | 2020-12-04 | 2023-08-11 | 阿尔比里奥公司 | 苯并硫杂(二)氮杂环庚三烯化合物及其作为胆汁酸调节剂的用途 |
CN117980295A (zh) * | 2022-08-02 | 2024-05-03 | 上海皓元医药股份有限公司 | 一种依洛西巴特晶型ii及其制备方法 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2004516285A (ja) | 2000-12-21 | 2004-06-03 | アストラゼネカ アクチボラグ | 1,5ベンゾチアゼピン及び抗高脂質血症剤としてのその使用 |
JP2004521961A (ja) | 2001-09-08 | 2004-07-22 | アストラゼネカ アクチボラグ | 高脂質血症の治療のための回腸胆汁酸運搬(ibat)阻害活性を持つベンゾチアゼピン及びベンゾチアジアゼピン誘導体 |
JP2006506328A (ja) | 2002-06-14 | 2006-02-23 | アストラゼネカ アクチボラグ | 高脂血症状態の治療用のチアゼピン基を含むペプチド誘導体 |
JP2016522181A (ja) | 2013-04-26 | 2016-07-28 | エロビクス・アーベー | エロビキシバットの結晶変態 |
JP2017537061A (ja) | 2014-10-24 | 2017-12-14 | エロビクス・アーベー | エロビキシバットの結晶変態 |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB0307918D0 (en) | 2003-04-05 | 2003-05-14 | Astrazeneca Ab | Therapeutic use |
CN103260625B (zh) | 2010-11-08 | 2016-01-06 | 阿尔比里奥公司 | 用于治疗肝脏疾病的ibat抑制剂 |
KR102560954B1 (ko) | 2014-06-25 | 2023-07-31 | 이에이 파마 가부시키가이샤 | 고형 제제 및 그의 착색 방지 또는 착색 감소 방법 |
WO2015199146A1 (ja) | 2014-06-25 | 2015-12-30 | 味の素株式会社 | 固形製剤及びその安定化方法 |
-
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Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2004516285A (ja) | 2000-12-21 | 2004-06-03 | アストラゼネカ アクチボラグ | 1,5ベンゾチアゼピン及び抗高脂質血症剤としてのその使用 |
JP2004521961A (ja) | 2001-09-08 | 2004-07-22 | アストラゼネカ アクチボラグ | 高脂質血症の治療のための回腸胆汁酸運搬(ibat)阻害活性を持つベンゾチアゼピン及びベンゾチアジアゼピン誘導体 |
JP2006506328A (ja) | 2002-06-14 | 2006-02-23 | アストラゼネカ アクチボラグ | 高脂血症状態の治療用のチアゼピン基を含むペプチド誘導体 |
JP2016522181A (ja) | 2013-04-26 | 2016-07-28 | エロビクス・アーベー | エロビキシバットの結晶変態 |
JP2017537061A (ja) | 2014-10-24 | 2017-12-14 | エロビクス・アーベー | エロビキシバットの結晶変態 |
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CA3091338A1 (en) | 2019-09-12 |
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CN111836804A (zh) | 2020-10-27 |
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AU2019232477A1 (en) | 2020-09-10 |
KR102637395B1 (ko) | 2024-02-15 |
JP2023109894A (ja) | 2023-08-08 |
EP3762370A1 (en) | 2021-01-13 |
BR112020017353A2 (pt) | 2020-12-15 |
MX2020009332A (es) | 2020-10-08 |
WO2019172834A1 (en) | 2019-09-12 |
TW202003480A (zh) | 2020-01-16 |
TWI823573B (zh) | 2023-11-21 |
TW202302546A (zh) | 2023-01-16 |
KR20200130390A (ko) | 2020-11-18 |
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