JP2023505587A - 化合物及びα1-アンチトリプシン欠損症の治療のためのそれらの使用 - Google Patents
化合物及びα1-アンチトリプシン欠損症の治療のためのそれらの使用 Download PDFInfo
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- VWLWTJHKQHRTNC-UHFFFAOYSA-L dipotassium;8-anilino-5-(4-anilino-5-sulfonatonaphthalen-1-yl)naphthalene-1-sulfonate Chemical compound [K+].[K+].C=12C(S(=O)(=O)[O-])=CC=CC2=C(C=2C3=CC=CC(=C3C(NC=3C=CC=CC=3)=CC=2)S([O-])(=O)=O)C=CC=1NC1=CC=CC=C1 VWLWTJHKQHRTNC-UHFFFAOYSA-L 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000007938 effervescent tablet Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 238000013265 extended release Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 208000016361 genetic disease Diseases 0.000 description 1
- 229940035482 glassia Drugs 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 229940097042 glucuronate Drugs 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 229940121372 histone deacetylase inhibitor Drugs 0.000 description 1
- 239000003276 histone deacetylase inhibitor Substances 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 150000004694 iodide salts Chemical class 0.000 description 1
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical class OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 210000003292 kidney cell Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- RIWRFSMVIUAEBX-UHFFFAOYSA-N n-methyl-1-phenylmethanamine Chemical compound CNCC1=CC=CC=C1 RIWRFSMVIUAEBX-UHFFFAOYSA-N 0.000 description 1
- NCCHARWOCKOHIH-UHFFFAOYSA-N n-methylbenzamide Chemical compound CNC(=O)C1=CC=CC=C1 NCCHARWOCKOHIH-UHFFFAOYSA-N 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 229940014662 pantothenate Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 229950009215 phenylbutanoic acid Drugs 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 229940099982 prolastin Drugs 0.000 description 1
- 235000019833 protease Nutrition 0.000 description 1
- 239000002510 pyrogen Substances 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 150000003873 salicylate salts Chemical class 0.000 description 1
- 239000003001 serine protease inhibitor Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 239000012089 stop solution Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003826 tablet Substances 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
- 229940095064 tartrate Drugs 0.000 description 1
- GSIBTIUXYYFCPU-UHFFFAOYSA-N tert-butyl 4-(bromomethyl)benzoate Chemical compound CC(C)(C)OC(=O)C1=CC=C(CBr)C=C1 GSIBTIUXYYFCPU-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- UYPYRKYUKCHHIB-UHFFFAOYSA-N trimethylamine N-oxide Chemical compound C[N+](C)(C)[O-] UYPYRKYUKCHHIB-UHFFFAOYSA-N 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000011534 wash buffer Substances 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 229940032528 zemaira Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pulmonology (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
Description
・R1及びR2は、独立して、水素又は置換されていてもよいC1~C6アルキル基である、かつ
・R1及びR2は、縮合して複素環を形成していてもよい、
かつ式(1)の化合物が、
・4-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メチル)-N,N-ジメチルベンズアミド又は
・4-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メチル)-N-メチルベンズアミド又は
・4-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メチル)-N-イソプロピルベンズアミド又は
・4-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メチル)-N-(4-フルオロベンジル)ベンズアミド又は
・4-((2,6-ジオキソ-3,6-ジヒドロピリミジン-1(2H)-イル)メチル)-N,N-ジメチルベンズアミド又は
・4-((2,6-ジオキソ-3,6-ジヒドロピリミジン-1(2H)-イル)メチル)-N-エチル-N-メチルベンズアミド又は
・4-((2,6-ジオキソ-3,6-ジヒドロピリミジン-1(2H)-イル)メチル)-N-イソプロピル-N-メチルベンズアミド又は
・N-ベンジル-4-((2,6-ジオキソ-3,6-ジヒドロピリミジン-1(2H)-イル)メチル)-N-メチルベンズアミド又は
・4-((2,6-ジオキソ-3,6-ジヒドロピリミジン-1(2H)-イル)メチル)-N-メチル-N-(2,2,2-トリフルオロエチル)ベンズアミド
である、化合物が提供される。
以下の逐次的な合成手順を使用して4-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メチル)-N,N-ジメチルベンズアミドを調製した。
ウラシル(5g)及び炭酸セシウム(50.85g)をジメチルホルムアミド(50ml)中、室温で10分間撹拌した。tert-ブチル 4-(ブロモメチル)ベンゾエート(14.11g)を加え、反応液を3時間撹拌した。反応液を水で希釈し、得られた黄色沈殿物を濾過により収集した。粗生成物を酢酸エチル/ヘキサン(30%から50%)で溶出させるシリカ上のカラムクロマトグラフィーにより精製してtert-ブチル 4-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メチル)ベンゾエート(3.5g、最も極性の生成物)及びtert-ブチル 4-((2,6-ジオキソ-3,6-ジヒドロピリミジン-1(2H)-イル)メチル)ベンゾエート(420mg、最小の極性の生成物)を得た。
tert-ブチル 4-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メチル)ベンゾエート(3g)をジクロロメタン(20ml)中に溶解させ、トリフルオロ酢酸(30ml)を緩徐に加えた。反応液を室温で3時間撹拌した。反応液を減圧下で濃縮し、得られた油をジエチルエーテル(100ml)と共に室温で20分間撹拌した。得られた固体を濾過により収集し、ジエチルエーテル(2×30ml)で洗浄し、真空中で乾燥させて4-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メチル)安息香酸を得た。
4-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メチル)安息香酸(64mg、0.27mmol)及びN-(3-ジメチルアミノプロピル)-N’-エチルカルボジイミドヒドロクロリド(86mg、0.54mmol)をテトラヒドロフラン(1ml)中、窒素下0℃で10分間撹拌した。反応液を次に室温に温めた。トリエチルアミン(0.11ml、81mmol)及びジメチルアミン(テトラヒドロフラン中の2M溶液、69mmol)を加え、反応液を2時間撹拌した。反応液を減圧下で濃縮し、残留物を、ジクロロメタン中の4%のメタノールで溶出させるシリカのカラムに流した。生成物含有画分を濃縮して4-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メチル)-N,N-ジメチルベンズアミドを得た。
1H NMR(400MHz,d6 DMSO) δ 11.35、(1H,s)、7.78(1H,d)、7.38(2H,d)、7.32(2H,d)、5.60(1H,d)、4.90(2H,s)、2.96-2.86(6H,br)。
1H NMR(400MHz,d6 DMSO) δ 11.34(1H,s)、8.44-8.39(1H,m)、7.84-7.74(3H,m)、7.39-7.32(2H,m)、5.61(1H,dd)、4.91(2H,s)、2.77(3H,d)。
1H NMR(400MHz,d6 DMSO) δ 11.34(1H,s)、8.18(1H,d)、7.84-7.79(2H,m)、7.77(1H,d)、7.39-7.30(2H,m)、5.61(1H,dd)、4.91(2H,s)、4.08(1H,sept.)、1.15(6H,d)。
1H NMR(400MHz,d6 DMSO) δ 11.27(1H,s)、9.04(1H,t)、7.91-7.82(2H,m)、7.77(1H,d)、7.42-7.30(4H,m)、7.18-7.10(2H,m)、5.61(1H,s)、4.92(2H,s)、4.45(2H,d)。
以下の逐次的な合成手順を使用して4-((2,6-ジオキソ-3,6-ジヒドロピリミジン-1(2H)-イル)メチル)-N,N-ジメチルベンズアミドを調製した。
tert-ブチル 4-((2,6-ジオキソ-3,6-ジヒドロピリミジン-1(2H)-イル)メチル)ベンゾエート(2g)をジクロロメタン(10ml)中に溶解させ、トリフルオロ酢酸(15ml)を緩徐に加えた。反応液を室温で3時間撹拌した。反応液を減圧下で濃縮し、得られた油をジエチルエーテル(50ml)と共に室温で20分間撹拌した。得られた固体を濾過により収集し、ジエチルエーテル(2×15ml)で洗浄し、真空中で乾燥させて4-((2,6-ジオキソ-3,6-ジヒドロピリミジン-1(2H)-イル)メチル)安息香酸を得た。
4-((2,6-ジオキソ-3,6-ジヒドロピリミジン-1(2H)-イル)メチル)安息香酸(32mg)及びN-(3-ジメチルアミノプロピル)-N’-エチルカルボジイミドヒドロクロリド(43mg)をテトラヒドロフラン(1ml)中、窒素下0℃で10分間撹拌した。反応液を次に室温に温めた。トリエチルアミン(0.06ml)及びジメチルアミン(テトラヒドロフラン中の2M溶液)を加え、反応液を2時間撹拌した。反応液を減圧下で濃縮し、残留物を、ジクロロメタン中の4%のメタノールで溶出させるシリカのカラムに流した。生成物含有画分を濃縮して4-((2,6-ジオキソ-3,6-ジヒドロピリミジン-1(2H)-イル)メチル)-N,N-ジメチルベンズアミドを得た。
1H NMR(400MHz,d6 DMSO) δ 7.48(1H,d)、7.32(2H,d)、7.27(2H,d)、5.61(1H,d)、4.95(2H,s)、2.95-2.85(6H,br)。
1H NMR(400MHz,d6 DMSO) δ 7.49(1H,d)、7.28(4H,br s)、5.64(1H,d)、4.95(2H,d)、3.4-3.2(2H,m)、2.95-2.85(3H,br)、1.1-1.0(3H,br)。
1H NMR(400MHz,d6 DMSO) δ 11.20(1H,s)、7.49(1H,d)、7.28(4H,br s)、5.65(1H,d)、4.95(2H,d)、3.78(2H,br m)、2.78-2.60(3H,br)、1.2-1.0(6H,br)。
1H NMR(400MHz,d6 DMSO) δ 11.20(1H,s)、7.48(1H,d)、7.35-7.29(8H,br m)、7.15(1H,br m)、5.62(1H,br)、4.95(2H,br)、4.64及び4.44(2H,br)、2.84-2.79(3H,br)。
1H NMR(400MHz,d6 DMSO) δ 11.25(1H,s)、7.49(1H,d)、7.36-7.31(4H,br m)、5.65(1H,br)、4.96(2H,s)、4.34及び4.11(2H,br)、3.00(3H,br)。
方法
ヒトZ A1AT遺伝子を安定的にトランスフェクトされたヒト胚性腎臓細胞株HEK-Z細胞を、5%のCO2を含有する加湿雰囲気中37℃で終夜、96ウェルプレート中にプレーティングした(3.0×105細胞/ml、200μlの培地/ウェル)。インキュベーション後に細胞を200μlの無血清培地で3回洗浄し、37℃のインキュベーター中で48h、200μlの最終体積においてビヒクル、10μMのスベラニロヒドロキサム酸(SAHA)又は本発明の化合物(10、33、100及び333nMの濃度)のいずれかを含有する無血清培地を使用して4連の処理で培地を置き換えた。インキュベーション工程の終わりに上清をウェルから除去し、1000×gにおいて4℃で10分間遠心分離し、製造者の使用説明書の通りにELISA(Human Serpin A1/α1-antitrypsin duo set ELISA、R& D Systems、DY1268)によりヒトA1ATレベルについてアッセイした。
実施例1~9の化合物は300nMにおいてHEK-Z細胞からのZ A1ATの分泌を増加させることを表1のデータは示す。
Claims (11)
- 式(1)
・Y又はZのうちの1つはHであり、かつY又はZのうちの他のものは
・R1及びR2は、独立して、水素又は置換されていてもよいC1~C6アルキル基である、かつ
・R1及びR2は、縮合して複素環を形成していてもよい、
かつ式(1)の前記化合物が、
・4-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メチル)-N,N-ジメチルベンズアミド又は
・4-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メチル)-N-メチルベンズアミド又は
・4-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メチル)-N-イソプロピルベンズアミド又は
・4-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メチル)-N-(4-フルオロベンジル)ベンズアミド又は
・4-((2,6-ジオキソ-3,6-ジヒドロピリミジン-1(2H)-イル)メチル)-N,N-ジメチルベンズアミド又は
・4-((2,6-ジオキソ-3,6-ジヒドロピリミジン-1(2H)-イル)メチル)-N-エチル-N-メチルベンズアミド又は
・4-((2,6-ジオキソ-3,6-ジヒドロピリミジン-1(2H)-イル)メチル)-N-イソプロピル-N-メチルベンズアミド又は
・N-ベンジル-4-((2,6-ジオキソ-3,6-ジヒドロピリミジン-1(2H)-イル)メチル)-N-メチルベンズアミド又は
・4-((2,6-ジオキソ-3,6-ジヒドロピリミジン-1(2H)-イル)メチル)-N-メチル-N-(2,2,2-トリフルオロエチル)ベンズアミド
である、化合物。 - 医薬的に許容可能な塩形態又は結晶形態の請求項1に記載の化合物。
- 請求項1又は2に記載の化合物及び医薬的に又は治療的に許容可能な賦形剤又は担体を含む、医薬組成物。
- 疾患又は障害の治療用の医薬の製造における請求項1又は2に記載の化合物の使用。
- 疾患又は障害の治療における使用のための請求項1又は2に記載の化合物。
- Z A1AT分泌の誘導剤としての使用のための請求項1又は2に記載の化合物。
- 請求項1若しくは2に記載の化合物、又は請求項3に記載の医薬組成物をそれを必要とする患者に投与するステップを含む、疾患又は障害を治療する方法。
- 疾患又は障害の治療における請求項1又は2に記載の化合物の使用。
- Z A1AT分泌の誘導剤としての治療における請求項8に記載の使用。
- インビトロで行われる、請求項8又は9に記載の使用。
- 前記疾患又は障害がAATDである、請求項4に記載の使用、請求項5に記載の使用のための化合物、請求項7に記載の治療方法、又は請求項8~10のいずれか一項に記載の使用。
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GBGB1918414.2A GB201918414D0 (en) | 2019-12-13 | 2019-12-13 | Compounds and their use for the treatment of Alpha1-Antitrypsin deficiency |
PCT/GB2020/053194 WO2021116709A1 (en) | 2019-12-13 | 2020-12-11 | COMPOUNDS AND THEIR USE FOR THE TREATMENT OF α1-ANTITRYPSIN DEFICIENCY |
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CA (1) | CA3164303A1 (ja) |
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BR112020026314A2 (pt) | 2018-06-22 | 2021-03-30 | Ucl Business Ltd | Novos compostos |
BR112021006392A2 (pt) | 2018-10-05 | 2021-07-06 | Vertex Pharma | moduladores da alfa-1 antitripsina |
US11884672B2 (en) | 2019-05-14 | 2024-01-30 | Vertex Pharmaceuticals Incorporated | Modulators of alpha-1 antitrypsin |
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BR112022011566A2 (pt) | 2022-08-30 |
WO2021116709A1 (en) | 2021-06-17 |
MX2022007219A (es) | 2022-09-07 |
US20230096524A1 (en) | 2023-03-30 |
CN115003381B (zh) | 2024-07-26 |
AU2020401779A1 (en) | 2022-07-21 |
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