NO312365B1 - Substituerte isokinolin-3-karboksylsyreamider, deres fremstilling og deres anvendelse til fremstilling av legemiddel - Google Patents
Substituerte isokinolin-3-karboksylsyreamider, deres fremstilling og deres anvendelse til fremstilling av legemiddel Download PDFInfo
- Publication number
- NO312365B1 NO312365B1 NO19984877A NO984877A NO312365B1 NO 312365 B1 NO312365 B1 NO 312365B1 NO 19984877 A NO19984877 A NO 19984877A NO 984877 A NO984877 A NO 984877A NO 312365 B1 NO312365 B1 NO 312365B1
- Authority
- NO
- Norway
- Prior art keywords
- chlorine
- formula
- hydrogen
- alkoxy
- compounds
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims description 18
- 239000003814 drug Substances 0.000 title claims description 9
- 229940079593 drug Drugs 0.000 title claims description 8
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- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- FMKOJHQHASLBPH-UHFFFAOYSA-N isopropyl iodide Chemical compound CC(C)I FMKOJHQHASLBPH-UHFFFAOYSA-N 0.000 description 1
- 125000004551 isoquinolin-3-yl group Chemical group C1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- XAAKCCMYRKZRAK-UHFFFAOYSA-N isoquinoline-1-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)=NC=CC2=C1 XAAKCCMYRKZRAK-UHFFFAOYSA-N 0.000 description 1
- 210000005228 liver tissue Anatomy 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- NZSBEZMTLFUYJD-UHFFFAOYSA-N methyl 1,6,7-trichloro-4-hydroxyisoquinoline-3-carboxylate Chemical compound C1=C(Cl)C(Cl)=CC2=C(O)C(C(=O)OC)=NC(Cl)=C21 NZSBEZMTLFUYJD-UHFFFAOYSA-N 0.000 description 1
- JCLXQWPJRSUMFT-UHFFFAOYSA-N methyl 1-chloro-4-hydroxyisoquinoline-3-carboxylate Chemical compound C1=CC=CC2=C(O)C(C(=O)OC)=NC(Cl)=C21 JCLXQWPJRSUMFT-UHFFFAOYSA-N 0.000 description 1
- BPSBCFXSFAXTIV-UHFFFAOYSA-N methyl 2-[(1-chloro-4-hydroxyisoquinoline-3-carbonyl)amino]acetate Chemical compound C1=CC=CC2=C(O)C(C(=O)NCC(=O)OC)=NC(Cl)=C21 BPSBCFXSFAXTIV-UHFFFAOYSA-N 0.000 description 1
- SNAIQLNIIAIHIC-UHFFFAOYSA-N methyl 2-[(8-chloro-4-hydroxyisoquinoline-3-carbonyl)amino]acetate Chemical compound ClC1=CC=CC2=C(O)C(C(=O)NCC(=O)OC)=NC=C21 SNAIQLNIIAIHIC-UHFFFAOYSA-N 0.000 description 1
- JOURGLFWVLLAPY-UHFFFAOYSA-N methyl 4-hydroxy-1-oxo-2h-isoquinoline-3-carboxylate Chemical compound C1=CC=C2C(O)=C(C(=O)OC)NC(=O)C2=C1 JOURGLFWVLLAPY-UHFFFAOYSA-N 0.000 description 1
- WMQGVBYZDZCNKC-UHFFFAOYSA-N methyl 6,7-dichloro-4-hydroxy-1-oxo-2h-isoquinoline-3-carboxylate Chemical compound ClC1=C(Cl)C=C2C(O)=C(C(=O)OC)NC(=O)C2=C1 WMQGVBYZDZCNKC-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- VMESOKCXSYNAKD-UHFFFAOYSA-N n,n-dimethylhydroxylamine Chemical compound CN(C)O VMESOKCXSYNAKD-UHFFFAOYSA-N 0.000 description 1
- KWDCBYBOHQWCKS-UHFFFAOYSA-N n-(2-aminoacetyl)-3-hydroxyquinoline-2-carboxamide Chemical class C1=CC=C2C=C(O)C(C(=O)NC(=O)CN)=NC2=C1 KWDCBYBOHQWCKS-UHFFFAOYSA-N 0.000 description 1
- IXAKZRUKCFYOPF-UHFFFAOYSA-N n-(2-hydroxyethyl)isoquinoline-3-carboxamide Chemical class C1=CC=C2C=NC(C(=O)NCCO)=CC2=C1 IXAKZRUKCFYOPF-UHFFFAOYSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 125000001190 organyl group Chemical group 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- NWNGDHADXSESGZ-UHFFFAOYSA-N pentyl 2-[(1-chloro-4-hydroxy-6-methoxyisoquinoline-3-carbonyl)amino]acetate Chemical compound C1=CC(OC)=CC2=C(O)C(C(=O)NCC(=O)OCCCCC)=NC(Cl)=C21 NWNGDHADXSESGZ-UHFFFAOYSA-N 0.000 description 1
- SDEMTXKOSYZTHN-UHFFFAOYSA-N pentyl 2-[(1-chloro-4-hydroxy-7-methoxyisoquinoline-3-carbonyl)amino]acetate Chemical compound C1=C(OC)C=CC2=C(O)C(C(=O)NCC(=O)OCCCCC)=NC(Cl)=C21 SDEMTXKOSYZTHN-UHFFFAOYSA-N 0.000 description 1
- HKTWQRFIHHMWGI-UHFFFAOYSA-N pentyl 2-[(1-chloro-4-hydroxy-7-phenylmethoxyisoquinoline-3-carbonyl)amino]acetate Chemical compound C1=CC2=C(O)C(C(=O)NCC(=O)OCCCCC)=NC(Cl)=C2C=C1OCC1=CC=CC=C1 HKTWQRFIHHMWGI-UHFFFAOYSA-N 0.000 description 1
- OYFQFSFYDOUOGM-UHFFFAOYSA-N pentyl 2-[(1-chloro-4-hydroxy-7-propan-2-yloxyisoquinoline-3-carbonyl)amino]acetate Chemical compound C1=C(OC(C)C)C=CC2=C(O)C(C(=O)NCC(=O)OCCCCC)=NC(Cl)=C21 OYFQFSFYDOUOGM-UHFFFAOYSA-N 0.000 description 1
- 229940111202 pepsin Drugs 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 230000002572 peristaltic effect Effects 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- LGRFSURHDFAFJT-UHFFFAOYSA-N phthalic anhydride Chemical class C1=CC=C2C(=O)OC(=O)C2=C1 LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 description 1
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 210000003240 portal vein Anatomy 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 230000003134 recirculating effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000037390 scarring Effects 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 210000004500 stellate cell Anatomy 0.000 description 1
- 210000000352 storage cell Anatomy 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000011477 surgical intervention Methods 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
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 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
- 229960001722 verapamil Drugs 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- 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
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
-
- 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
-
- 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
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- 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
- A61P39/00—General protective or antinoxious agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
- C07D217/24—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
- C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Dermatology (AREA)
- Urology & Nephrology (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Cardiology (AREA)
- Obesity (AREA)
- Pulmonology (AREA)
- Gastroenterology & Hepatology (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Heart & Thoracic Surgery (AREA)
- Vascular Medicine (AREA)
- Toxicology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19746287A DE19746287A1 (de) | 1997-10-20 | 1997-10-20 | Substituierte Isochinolin-2-Carbonsäureamide, ihre Herstellung und ihre Verwendung als Arzneimittel |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO984877D0 NO984877D0 (no) | 1998-10-19 |
| NO984877L NO984877L (no) | 1999-04-21 |
| NO312365B1 true NO312365B1 (no) | 2002-04-29 |
Family
ID=7846053
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO19984877A NO312365B1 (no) | 1997-10-20 | 1998-10-19 | Substituerte isokinolin-3-karboksylsyreamider, deres fremstilling og deres anvendelse til fremstilling av legemiddel |
Country Status (25)
| Country | Link |
|---|---|
| US (1) | US6093730A (fr) |
| EP (2) | EP1538160B1 (fr) |
| JP (2) | JP3782591B2 (fr) |
| KR (1) | KR100618922B1 (fr) |
| CN (1) | CN1117079C (fr) |
| AR (1) | AR013696A1 (fr) |
| AT (2) | ATE432940T1 (fr) |
| AU (1) | AU755714B2 (fr) |
| BR (1) | BR9804504B1 (fr) |
| CA (2) | CA2250664A1 (fr) |
| CZ (1) | CZ337298A3 (fr) |
| DE (3) | DE19746287A1 (fr) |
| DK (2) | DK1538160T3 (fr) |
| ES (2) | ES2245471T3 (fr) |
| HK (1) | HK1019605A1 (fr) |
| HU (1) | HUP9802422A3 (fr) |
| ID (1) | ID21115A (fr) |
| IL (1) | IL126638A0 (fr) |
| NO (1) | NO312365B1 (fr) |
| NZ (1) | NZ332363A (fr) |
| PL (1) | PL192354B1 (fr) |
| PT (1) | PT911340E (fr) |
| SG (1) | SG87776A1 (fr) |
| TR (1) | TR199802106A3 (fr) |
| ZA (1) | ZA989505B (fr) |
Families Citing this family (57)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001092258A1 (fr) * | 2000-05-30 | 2001-12-06 | Neurogen Corporation | Imidazoloisoquinolines |
| US6762318B2 (en) * | 2001-12-03 | 2004-07-13 | Novo Nordisk A/S | Glucagon antagonists |
| US8318703B2 (en) | 2001-12-06 | 2012-11-27 | Fibrogen, Inc. | Methods for improving kidney function |
| EP2295060B1 (fr) | 2001-12-06 | 2018-10-31 | Fibrogen, Inc. | Traitement de conditions ischémiques ou hypoxiques |
| CA3094774A1 (fr) * | 2001-12-06 | 2003-07-03 | Fibrogen, Inc. | Utilisation d'inhibiteur d'hydroxylase prolyl hif pour le traitement destroubles neurologiques |
| US8124582B2 (en) | 2002-12-06 | 2012-02-28 | Fibrogen, Inc. | Treatment of diabetes |
| US7618940B2 (en) * | 2002-12-06 | 2009-11-17 | Fibrogen, Inc. | Fat regulation |
| WO2005007192A2 (fr) * | 2003-06-06 | 2005-01-27 | Fibrogen, Inc. | Cytoprotection |
| BRPI0411055B1 (pt) * | 2003-06-06 | 2018-08-21 | Fibrogen, Inc | Compostos de heteroarilas contendo nitrogênio. seus usos no aumento da eritropoietina endógena, composição farmacêutica que os compreende e método in vitro de inibição da atividade da enzima hidrolase |
| US8614204B2 (en) * | 2003-06-06 | 2013-12-24 | Fibrogen, Inc. | Enhanced erythropoiesis and iron metabolism |
| US20060276477A1 (en) * | 2005-06-06 | 2006-12-07 | Fibrogen, Inc. | Treatment method for anemia |
| AU2006259352A1 (en) | 2005-06-15 | 2006-12-28 | Fibrogen, Inc. | Use of HIF 1alfa modulators for treatment of cancer |
| EP1960363B1 (fr) * | 2005-12-09 | 2014-01-22 | Amgen, Inc. | Composes a base de quinolone presentant une activite inhibitrice de prolyle hydroxylase, et leurs compositions et utilisations |
| MX2008009581A (es) | 2006-01-27 | 2009-01-07 | Fibrogen Inc | Compuestos de cianoisoquinolina que estabilizan el factor inducible hipoxia (fih). |
| US7745461B1 (en) | 2006-02-27 | 2010-06-29 | Alcon Research, Ltd. | Method of treating dry eye disorders |
| WO2007101204A1 (fr) * | 2006-02-27 | 2007-09-07 | Alcon Research, Ltd. | Méthode de traitement du glaucome |
| EP2005752A4 (fr) * | 2006-03-30 | 2010-06-09 | Lg Electronics Inc | Procede et appareil de decodage/codage d'un signal video |
| JP5111491B2 (ja) | 2006-04-04 | 2013-01-09 | フィブロジェン， インコーポレイテッド | ピロロ−およびピラゾロ−ピリミジン化合物、およびそれらの使用方法 |
| EP2327696A1 (fr) | 2006-06-26 | 2011-06-01 | Warner Chilcott Company, LLC | Inhibiteurs de la prolyl hydroxylase et procédés d'utilisation |
| EP2097416B1 (fr) | 2006-12-18 | 2012-09-12 | Amgen, Inc | Composés d'azaquinolone possédant une activité inhibitrice de prolyl hydroxylase, compositions et utilisations correspondantes |
| CA2672656C (fr) | 2006-12-18 | 2012-03-20 | Amgen Inc. | Composes de naphtalenone presentant une activite inhibititrice de prolyle hydroxylase, compositions et utilisations de ceux-ci |
| US8048894B2 (en) | 2007-04-18 | 2011-11-01 | Amgen Inc. | Quinolones and azaquinolones that inhibit prolyl hydroxylase |
| WO2008130508A1 (fr) | 2007-04-18 | 2008-10-30 | Amgen Inc. | Dérivés d'indanone qui inhibent la prolyle hydroxylase |
| AU2008248234B2 (en) | 2007-05-04 | 2011-02-03 | Amgen Inc. | Thienopyridine and thiazolopyridine derivatives that inhibit prolyl hydroxylase activity |
| AU2008248165B2 (en) | 2007-05-04 | 2011-12-08 | Amgen Inc. | Diazaquinolones that inhibit prolyl hydroxylase activity |
| WO2009002533A1 (fr) * | 2007-06-27 | 2008-12-31 | The Brigham And Women's Hospital, Inc. | Thérapies d'affection abdominale inflammatoire |
| CN101497584B (zh) * | 2008-01-29 | 2010-12-22 | 首都医科大学 | 异喹啉-3-甲酰氨基酸苄酯及其制备和应用 |
| PT2294066E (pt) | 2008-04-28 | 2014-11-21 | Janssen Pharmaceutica Nv | Benzoimidazoles como inibidores da prolil-hidroxilase |
| EP2370422B1 (fr) | 2008-11-14 | 2019-06-05 | Fibrogen, Inc. | Dérivés de thiochromène utiles en tant qu'inhibiteurs de l'hydroxylase hif |
| ME01858B (me) * | 2009-07-17 | 2014-12-20 | Japan Tobacco Inc | Jedinjenje triazolopiridina i njegovo dejstvo kao inhibitora prolil hidroksilaze i induktora proizvodnje eritropoetina |
| NO2686520T3 (fr) | 2011-06-06 | 2018-03-17 | ||
| CA2842730C (fr) * | 2011-07-22 | 2018-08-21 | Beijing Betta Pharmaceuticals Co., Ltd | Formes polymorphes de composes en tant qu'inhibiteur de prolyle hydroxylase et leurs utilisations |
| BR112014009910B1 (pt) | 2011-10-25 | 2020-06-30 | Janssen Pharmaceutica N.V. | sal di-hidrato de meglumina de ácido 1-(5,6-dicloro-1h-benzo[d]imidazol-2-il)-1h-pirazol-4-carboxílico, composição farmacêuticae pomada tópica |
| AU2013229922B2 (en) | 2012-03-09 | 2017-09-28 | Fibrogen, Inc. | 4 -hydroxy- isoquinoline compounds as HIF hydroxylase inhibitors |
| US8883823B2 (en) | 2012-07-16 | 2014-11-11 | Fibrogen, Inc. | Crystalline forms of a prolyl hydroxylase inhibitor |
| RS57795B1 (sr) | 2012-07-16 | 2018-12-31 | Fibrogen Inc | Kristalni oblici inhibitora prolil hidroksilaze |
| HUE034409T2 (en) | 2012-07-16 | 2018-02-28 | Fibrogen Inc | Process for the preparation of isoquinoline compounds |
| WO2014070859A1 (fr) | 2012-10-30 | 2014-05-08 | H. Lee Moffitt Cancer Center And Research Institute, Inc. | Inhibiteurs de dimérisation de stat3 |
| RU2666144C2 (ru) | 2013-01-24 | 2018-09-06 | Фиброген, Инк. | Кристаллические формы { [1-циано-5-(4-хлорофенокси)-4-гидроксиизохинолин-3-карбонил]-амино} -уксусной кислоты |
| CN110448537A (zh) | 2013-06-06 | 2019-11-15 | 菲布罗根有限公司 | Hif羟化酶抑制剂的药物制剂 |
| NZ753905A (en) | 2013-06-13 | 2020-07-31 | Akebia Therapeutics Inc | Compositions and methods for treating anemia |
| TWI788702B (zh) | 2013-11-15 | 2023-01-01 | 美商阿克比治療有限公司 | {[5-(3-氯苯基)-3-羥基吡啶-2-羰基]胺基}乙酸之固體型式，其組合物及用途 |
| WO2015175939A1 (fr) | 2014-05-15 | 2015-11-19 | Insmed Incorporated | Méthodes de traitement d'infections pulmonaires mycobactériennes non-tuberculeuses |
| AU2016209126A1 (en) | 2015-01-23 | 2017-08-10 | Akebia Therapeutics, Inc. | Solid forms of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid, compositions, and uses thereof |
| US11324734B2 (en) | 2015-04-01 | 2022-05-10 | Akebia Therapeutics, Inc. | Compositions and methods for treating anemia |
| KR102473897B1 (ko) * | 2015-05-28 | 2022-12-06 | 니뽄 다바코 산교 가부시키가이샤 | 당뇨병성 신증을 치료 또는 예방하는 방법 |
| US20180200186A1 (en) * | 2015-07-09 | 2018-07-19 | Insmed Incorporated | Compositions and methods for treating lung diseases and lung injury |
| AR108326A1 (es) | 2016-04-27 | 2018-08-08 | Samumed Llc | Isoquinolin-3-il carboxamidas y preparación y uso de las mismas |
| AR108325A1 (es) | 2016-04-27 | 2018-08-08 | Samumed Llc | Isoquinolin-3-il carboxamidas y preparación y uso de las mismas |
| KR20200112872A (ko) * | 2018-01-09 | 2020-10-05 | 코넬 유니버시티 | 장기 섬유증의 예방 및 치료 |
| EP3773505A4 (fr) | 2018-03-30 | 2021-12-22 | Insmed Incorporated | Procédés pour la fabrication continue de produits médicamenteux liposomaux |
| US11713298B2 (en) | 2018-05-09 | 2023-08-01 | Akebia Therapeutics, Inc. | Process for preparing 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]acetic acid |
| EP3829623A4 (fr) * | 2018-08-03 | 2022-10-19 | Cornell University | Procédés de réduction de formation de cicatrice anormale |
| TW202120490A (zh) | 2019-07-30 | 2021-06-01 | 德商拜耳動物保健有限公司 | 新穎異喹啉衍生物 |
| US11524939B2 (en) | 2019-11-13 | 2022-12-13 | Akebia Therapeutics, Inc. | Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino} acetic acid |
| CN112979541B (zh) * | 2019-12-17 | 2022-11-11 | 浙江大学 | 一种基于n-(3-羟基吡啶-2-羰基)甘氨酸的抗肿瘤药物增敏剂及其应用 |
| CN116120340B (zh) * | 2021-11-15 | 2023-10-31 | 艾立康药业股份有限公司 | 一种吡啶并噁嗪类化合物及其制备方法、组合物和用途 |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4015255A1 (de) * | 1990-05-12 | 1991-11-14 | Hoechst Ag | Oxalyl-aminosaeurederivate, verfahren zu ihrer herstellung und ihrer verwendung als arzneimittel zur inhibierung der prolyl-hydroxylase |
| EP0548883A1 (fr) * | 1991-12-24 | 1993-06-30 | Hoechst Aktiengesellschaft | Pyridine-N-oxides substituées, procédé pour leur préparation et leur utilisation comme médicaments |
| TW352384B (en) * | 1992-03-24 | 1999-02-11 | Hoechst Ag | Sulfonamido- or sulfonamidocarbonylpyridine-2-carboxamides, process for their preparation and their use as pharmaceuticals |
| DE4233124A1 (de) * | 1992-10-02 | 1994-04-07 | Hoechst Ag | Acylsulfonamido- und Sulfonamidopyridin-2-carbonsäureester sowie ihre Pyridin-N-oxide, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel |
| DK0650961T3 (da) * | 1993-11-02 | 1997-09-15 | Hoechst Ag | Substituerede heterocykliske carboxylsyreamider, deres fremstilling og deres anvendelse som lægemidler. |
| DE59401923D1 (de) * | 1993-11-02 | 1997-04-10 | Hoechst Ag | Substituierte heterocyclische Carbonsäureamidester, ihre Herstellung und ihre Verwendung als Arzneimittel |
| NZ270267A (en) * | 1993-12-30 | 1997-03-24 | Hoechst Ag | 3-hydroxypyridin-2yl (and -quinolin-2-yl) carboxamide derivatives and pharmaceutical compositions |
| SE9400810D0 (sv) * | 1994-03-10 | 1994-03-10 | Pharmacia Ab | New use of Quinoline-3-carboxamide compounds |
| IL135495A (en) * | 1995-09-28 | 2002-12-01 | Hoechst Ag | Intermediate compounds for the preparation of quinoline-converted amines - 2 - carboxylic acid |
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- 1998-10-16 EP EP05004047A patent/EP1538160B1/fr not_active Expired - Lifetime
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