KR100644928B1 - 7카르복시메틸옥시3',4',5트리메톡시 플라본·일수화물,이의 제조방법 및 용도 - Google Patents
7카르복시메틸옥시3',4',5트리메톡시 플라본·일수화물,이의 제조방법 및 용도 Download PDFInfo
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- KR100644928B1 KR100644928B1 KR1020057016164A KR20057016164A KR100644928B1 KR 100644928 B1 KR100644928 B1 KR 100644928B1 KR 1020057016164 A KR1020057016164 A KR 1020057016164A KR 20057016164 A KR20057016164 A KR 20057016164A KR 100644928 B1 KR100644928 B1 KR 100644928B1
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- South Korea
- Prior art keywords
- formula
- carboxymethyloxy
- compound
- flavone
- monohydrate
- Prior art date
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- FVVKFCKXYJWGDM-UHFFFAOYSA-N 2-[2-(3,4-dimethoxyphenyl)-5-methoxy-4-oxochromen-7-yl]oxyacetic acid;hydrate Chemical compound O.C1=C(OC)C(OC)=CC=C1C1=CC(=O)C2=C(OC)C=C(OCC(O)=O)C=C2O1 FVVKFCKXYJWGDM-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 80
- 238000000034 method Methods 0.000 claims abstract description 30
- 238000004519 manufacturing process Methods 0.000 claims abstract description 26
- 238000007069 methylation reaction Methods 0.000 claims abstract description 19
- 239000003814 drug Substances 0.000 claims abstract description 15
- 230000002496 gastric effect Effects 0.000 claims abstract description 12
- 210000002429 large intestine Anatomy 0.000 claims abstract description 12
- 229930003944 flavone Natural products 0.000 claims abstract description 11
- 235000011949 flavones Nutrition 0.000 claims abstract description 11
- 230000001681 protective effect Effects 0.000 claims abstract description 10
- GAMYVSCDDLXAQW-AOIWZFSPSA-N Thermopsosid Natural products O(C)c1c(O)ccc(C=2Oc3c(c(O)cc(O[C@H]4[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O4)c3)C(=O)C=2)c1 GAMYVSCDDLXAQW-AOIWZFSPSA-N 0.000 claims abstract description 9
- VHBFFQKBGNRLFZ-UHFFFAOYSA-N vitamin p Natural products O1C2=CC=CC=C2C(=O)C=C1C1=CC=CC=C1 VHBFFQKBGNRLFZ-UHFFFAOYSA-N 0.000 claims abstract description 9
- 150000002212 flavone derivatives Chemical class 0.000 claims abstract description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 57
- QCXAJQVDUHKDEL-UHFFFAOYSA-N 3',4',5'-Trimethoxyflavone Chemical compound COC1=C(OC)C(OC)=CC(C=2OC3=CC=CC=C3C(=O)C=2)=C1 QCXAJQVDUHKDEL-UHFFFAOYSA-N 0.000 claims description 47
- -1 3 ', 4', 5 'trimethoxy flavone monohydrate Chemical compound 0.000 claims description 37
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 29
- 238000006243 chemical reaction Methods 0.000 claims description 28
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 27
- 239000012453 solvate Substances 0.000 claims description 24
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 17
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- 150000004682 monohydrates Chemical class 0.000 claims description 15
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 13
- 239000002585 base Substances 0.000 claims description 12
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 239000003153 chemical reaction reagent Substances 0.000 claims description 9
- 230000011987 methylation Effects 0.000 claims description 9
- 230000008569 process Effects 0.000 claims description 9
- IIOQEHSFZUYICM-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-methoxychromen-4-one Chemical compound C1=C(OC)C(OC)=CC=C1C1=CC(=O)C2=C(OC)C=CC=C2O1 IIOQEHSFZUYICM-UHFFFAOYSA-N 0.000 claims description 8
- 239000004480 active ingredient Substances 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
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- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
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- 239000007810 chemical reaction solvent Substances 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- PKAUVIXBZJUYRV-UHFFFAOYSA-N methane;hydroiodide Chemical group C.I PKAUVIXBZJUYRV-UHFFFAOYSA-N 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
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- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 claims description 3
- FDPIMTJIUBPUKL-UHFFFAOYSA-N dimethylacetone Natural products CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 claims description 3
- 201000005917 gastric ulcer Diseases 0.000 claims description 3
- DNYWOPNUFUAMNA-UHFFFAOYSA-N 2-[2-(3,4-dimethoxyphenyl)-5-methoxy-4-oxochromen-3-yl]oxyacetic acid hydrate Chemical compound O.C(=O)(O)COC1=C(OC2=CC=CC(=C2C1=O)OC)C1=CC(=C(C=C1)OC)OC DNYWOPNUFUAMNA-UHFFFAOYSA-N 0.000 claims description 2
- CSDQQAQKBAQLLE-UHFFFAOYSA-N 4-(4-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical compound C1=CC(Cl)=CC=C1C1C(C=CS2)=C2CCN1 CSDQQAQKBAQLLE-UHFFFAOYSA-N 0.000 claims description 2
- 150000001298 alcohols Chemical class 0.000 claims description 2
- 229910000102 alkali metal hydride Inorganic materials 0.000 claims description 2
- 150000008046 alkali metal hydrides Chemical class 0.000 claims description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 2
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 2
- 230000002554 disease preventive effect Effects 0.000 claims description 2
- 150000004678 hydrides Chemical class 0.000 claims description 2
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- 229910052751 metal Inorganic materials 0.000 claims description 2
- 239000002184 metal Substances 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 229940124597 therapeutic agent Drugs 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims 1
- 239000012312 sodium hydride Substances 0.000 claims 1
- 229910000104 sodium hydride Inorganic materials 0.000 claims 1
- 238000001953 recrystallisation Methods 0.000 abstract description 5
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
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- 238000005481 NMR spectroscopy Methods 0.000 description 12
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
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- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
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- C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
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Abstract
Description
Claims (15)
- 제 2항에 있어서, 상기 용매는 무수 에탄올인 것을 특징으로 하는 7카르복시메틸옥시3',4',5트리메톡시 플라본·용매화물.
- 하기 반응식 3에서 나타나는 바와 같이(1) 화학식 3의 화합물을 염기 존재하에 메틸화 시약과 반응시켜 탄소3'의 히드록시기를 메톡시기로 변형시킨 후, 산 처리하여 화학식 4의 화합물을 제조하는 단계(단계 1);(2) 화학식 4의 화합물을 염기 존재하에 카르복시기가 보호된 알파할로아세테이트와 반응시켜 화학식 5의 화합물을 제조하는 단계(단계 2);(3) 화학식 5의 화합물을 메틸화 시약과 반응시켜 탄소5의 히드록시기를 메톡시기로 변형시켜 화학식 6의 화합물을 제조하는 단계(단계 3); 및(4) 화학식 6의 화합물을 탈보호화 반응시켜 화학식 2의 화합물을 제조하는 단계(단계 4)로 이루어지는 7카르복시메틸옥시3',4',5트리메톡시 플라본의 제조방법.〈반응식 3〉(상기 식에서 R'은 보호기로서 에틸, 메틸, t부틸, 벤질, 트리클로로에틸 또는 실릴기를 나타낸다)
- 제 4항에 있어서, 상기 단계 1에서 사용되는 반응 용매는 디메틸포름아미드, 디메틸술폭사이드 및 아세톤으로 이루어진 군으로부터 선택되고, 염기는 탄산칼륨, 수산화나트륨, 수산화칼륨 및 탄산나트륨으로 이루어진 군으로부터 선택되고, 메틸화 시약은 요오드화 메탄 또는 디메틸황산이고, 산은 염산 또는 황산인 것을 특징으로 하는 제조방법.
- 제 4항에 있어서, 반응 온도는 0∼150℃인 것을 특징으로 하는 제조방법.
- 제 6항에 있어서, 반응 온도는 0∼90℃인 것을 특징으로 하는 제조방법.
- 제 4항에 있어서, 상기 단계 2에서 사용되는 염기가 탄산칼륨, 수산화나트륨, 수산화칼륨 및 탄산나트륨으로 이루어진 군으로부터 선택되는 무기 염기; 소듐 메톡사이드 및 소듐 에톡사이드로 이루어진 군으로부터 선택되는 알콜의 금속염; 수소화 나트륨인 알칼리 금속 수소화물; 또는 수소화 칼슘인 알칼리 토금속의 수소화물인 것을 특징으로 하는 제조방법.
- 제 9항에 있어서, 상기 물을 함유하는 매질이 에탄올 또는 아세톤 수용액인 것을 특징으로 하는 제 1항의 7카르복시메틸옥시3',4',5트리메톡시 플라본·일수화물의 제조방법.
- 제 12항에 있어서, 상기 무수 알콜은 무수 에탄올인 것을 특징으로 하는 제 1항의 7카르복시메틸옥시3',4',5트리메톡시 플라본·일수화물의 제조방법.
- 제 1항의 7카르복시메틸옥시3',4',5트리메톡시 플라본·일수화물을 유효 성분으로 하는 대장을 포함한 위장관 보호제용 및 치료제용 약학적 조성물.
- 제 1항의 7카르복시메틸옥시3',4',5트리메톡시 플라본·일수화물을 유효 성분으로 하는 위염, 위궤양, 궤양성 대장염, 크론병 예방제용 및 보호제용 약학적 조성물.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020030061938 | 2003-09-04 | ||
KR1020030061938A KR20050024121A (ko) | 2003-09-04 | 2003-09-04 | 7-카르복시메틸옥시-3',4',5-트리메톡시 플라본.일수화물, 이의 제조방법 및 용도 |
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Publication Number | Publication Date |
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KR20050108369A KR20050108369A (ko) | 2005-11-16 |
KR100644928B1 true KR100644928B1 (ko) | 2006-11-15 |
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KR1020030061938A KR20050024121A (ko) | 2003-09-04 | 2003-09-04 | 7-카르복시메틸옥시-3',4',5-트리메톡시 플라본.일수화물, 이의 제조방법 및 용도 |
KR1020057016164A KR100644928B1 (ko) | 2003-09-04 | 2004-09-04 | 7카르복시메틸옥시3',4',5트리메톡시 플라본·일수화물,이의 제조방법 및 용도 |
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KR1020030061938A KR20050024121A (ko) | 2003-09-04 | 2003-09-04 | 7-카르복시메틸옥시-3',4',5-트리메톡시 플라본.일수화물, 이의 제조방법 및 용도 |
Country Status (20)
Country | Link |
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US (1) | US7371775B2 (ko) |
EP (2) | EP1660074B1 (ko) |
JP (2) | JP2007504217A (ko) |
KR (2) | KR20050024121A (ko) |
CN (2) | CN100591332C (ko) |
AT (1) | ATE451918T1 (ko) |
AU (1) | AU2004270065B2 (ko) |
BR (1) | BRPI0413163A (ko) |
CA (1) | CA2533301C (ko) |
DE (1) | DE602004024687D1 (ko) |
DK (1) | DK1660074T3 (ko) |
ES (1) | ES2336000T3 (ko) |
HK (1) | HK1089962A1 (ko) |
MX (1) | MXPA06002383A (ko) |
NZ (2) | NZ575796A (ko) |
PT (1) | PT1660074E (ko) |
RU (1) | RU2302416C2 (ko) |
SG (1) | SG136960A1 (ko) |
TR (2) | TR200600987T1 (ko) |
WO (1) | WO2005023244A1 (ko) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8203011B2 (en) | 2007-06-07 | 2012-06-19 | Dong-A Pharm. Co., Ltd. | 3′,4′,5-trimethoxy flavone derivatives as stimulant of mucus secretion, method for the same, and pharmaceutical composition comprising the same |
KR102356603B1 (ko) | 2021-08-05 | 2022-02-08 | 지엘팜텍주식회사 | 안구건조증 치료를 위한 레코플라본 함유 점안 조성물 |
WO2023014117A1 (ko) | 2021-08-05 | 2023-02-09 | 지엘팜텍주식회사 | 안구건조증 치료를 위한 레코플라본 함유 점안 조성물 및 이의 제조방법 |
KR20230021613A (ko) | 2021-08-05 | 2023-02-14 | 지엘팜텍주식회사 | 안구건조증 치료를 위한 레코플라본 함유 점안 조성물 및 이의 제조방법 |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR101381999B1 (ko) * | 2007-07-06 | 2014-04-14 | 동아에스티 주식회사 | 위염 치료제의 효력을 극대화시키기 위한 가용화 위체류시스템 매트릭스 제제 |
ES2575565T3 (es) * | 2008-05-08 | 2016-06-29 | United Therapeutics Corporation | Procedimiento para la preparación de monohidrato de treprostinilo y su utilización para el almacenamiento y el envío |
JP7121986B2 (ja) * | 2018-08-16 | 2022-08-19 | 株式会社常磐植物化学研究所 | アルコキシフラボン誘導体の製造方法 |
Family Cites Families (7)
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FR2623808B1 (fr) * | 1987-12-01 | 1990-03-09 | Adir | Nouveaux derives flavonoides (benzyl-4 piperazinyl-1)-2 oxo-2 ethylene substitues, leurs procedes de preparation et les compositions pharmaceutiques qui les contiennent |
IT1245371B (it) * | 1991-03-28 | 1994-09-20 | Geymonat Spa | Derivati di flavoni, procedimento per la loro preparazione e composizioni farmaceutiche che li contengono |
US5399584A (en) * | 1992-05-05 | 1995-03-21 | The Procter & Gamble Company | Use of flavone derivatives for gastroprotection |
US5525072A (en) | 1995-01-10 | 1996-06-11 | Molex Incorporated | Electrical connector assembly for interconnecting a flat cable to a circuit board |
KR100447918B1 (ko) * | 1996-07-25 | 2005-09-28 | 동아제약주식회사 | 대장을포함한위장관보호작용을갖는플라본및플라바논화합물 |
KR19990041205A (ko) | 1997-11-21 | 1999-06-15 | 이종수 | 전자 브레이크장치 |
KR100327621B1 (ko) * | 1999-09-22 | 2002-03-15 | 유충식 | 7-카르복시메틸옥시-3',4',5-트리메톡시플라본의 제조방법 |
-
2003
- 2003-09-04 KR KR1020030061938A patent/KR20050024121A/ko not_active Application Discontinuation
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2004
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- 2004-09-04 WO PCT/KR2004/002247 patent/WO2005023244A1/en active IP Right Grant
- 2004-09-04 AT AT04774508T patent/ATE451918T1/de active
- 2004-09-04 CN CN200480020608A patent/CN100591332C/zh not_active Expired - Fee Related
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- 2004-09-04 ES ES04774508T patent/ES2336000T3/es not_active Expired - Lifetime
- 2004-09-04 BR BRPI0413163-0A patent/BRPI0413163A/pt not_active IP Right Cessation
- 2004-09-04 TR TR2006/00987T patent/TR200600987T1/xx unknown
- 2004-09-04 DK DK04774508.8T patent/DK1660074T3/da active
- 2004-09-04 SG SG200717035-0A patent/SG136960A1/en unknown
- 2004-09-04 KR KR1020057016164A patent/KR100644928B1/ko active IP Right Grant
- 2004-09-04 NZ NZ544761A patent/NZ544761A/en not_active IP Right Cessation
- 2004-09-04 PT PT04774508T patent/PT1660074E/pt unknown
- 2004-09-04 CA CA2533301A patent/CA2533301C/en not_active Expired - Fee Related
- 2004-09-04 CN CN2009102043829A patent/CN101684113B/zh not_active Expired - Fee Related
- 2004-09-04 TR TR2006/03833T patent/TR200603833T2/xx unknown
- 2004-09-04 JP JP2006525281A patent/JP2007504217A/ja active Pending
- 2004-09-04 AU AU2004270065A patent/AU2004270065B2/en not_active Ceased
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2006
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2010
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Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8203011B2 (en) | 2007-06-07 | 2012-06-19 | Dong-A Pharm. Co., Ltd. | 3′,4′,5-trimethoxy flavone derivatives as stimulant of mucus secretion, method for the same, and pharmaceutical composition comprising the same |
KR102356603B1 (ko) | 2021-08-05 | 2022-02-08 | 지엘팜텍주식회사 | 안구건조증 치료를 위한 레코플라본 함유 점안 조성물 |
WO2023014117A1 (ko) | 2021-08-05 | 2023-02-09 | 지엘팜텍주식회사 | 안구건조증 치료를 위한 레코플라본 함유 점안 조성물 및 이의 제조방법 |
WO2023014113A1 (ko) | 2021-08-05 | 2023-02-09 | 지엘팜텍주식회사 | 안구건조증 치료를 위한 레코플라본 함유 점안 조성물 |
KR20230021613A (ko) | 2021-08-05 | 2023-02-14 | 지엘팜텍주식회사 | 안구건조증 치료를 위한 레코플라본 함유 점안 조성물 및 이의 제조방법 |
KR20230136579A (ko) | 2021-08-05 | 2023-09-26 | 지엘팜텍주식회사 | 안구건조증 치료를 위한 레코플라본 함유 점안 조성물 및 이의 제조방법 |
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