KR20170035993A - 가용성 구아닐레이트 사이클라제의 활성제로서의 헤테로사이클릭 카복실산 - Google Patents
가용성 구아닐레이트 사이클라제의 활성제로서의 헤테로사이클릭 카복실산 Download PDFInfo
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- KR20170035993A KR20170035993A KR1020177004761A KR20177004761A KR20170035993A KR 20170035993 A KR20170035993 A KR 20170035993A KR 1020177004761 A KR1020177004761 A KR 1020177004761A KR 20177004761 A KR20177004761 A KR 20177004761A KR 20170035993 A KR20170035993 A KR 20170035993A
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- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 230000010118 platelet activation Effects 0.000 description 1
- 231100000683 possible toxicity Toxicity 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
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- 230000000750 progressive effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- TVDSBUOJIPERQY-UHFFFAOYSA-N prop-2-yn-1-ol Chemical compound OCC#C TVDSBUOJIPERQY-UHFFFAOYSA-N 0.000 description 1
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- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
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- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
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- HDACQVRGBOVJII-JBDAPHQKSA-N ramipril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](C[C@@H]2CCC[C@@H]21)C(O)=O)CC1=CC=CC=C1 HDACQVRGBOVJII-JBDAPHQKSA-N 0.000 description 1
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- WXXSNCNJFUAIDG-UHFFFAOYSA-N riociguat Chemical compound N1=C(N)C(N(C)C(=O)OC)=C(N)N=C1C(C1=CC=CN=C11)=NN1CC1=CC=CC=C1F WXXSNCNJFUAIDG-UHFFFAOYSA-N 0.000 description 1
- 229960000529 riociguat Drugs 0.000 description 1
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
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- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
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- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000008279 sol Substances 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000007480 spreading Effects 0.000 description 1
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- 239000007858 starting material Substances 0.000 description 1
- 239000000021 stimulant Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000007920 subcutaneous administration 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
- NVBFHJWHLNUMCV-UHFFFAOYSA-N sulfamide Chemical compound NS(N)(=O)=O NVBFHJWHLNUMCV-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
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- 230000004083 survival effect Effects 0.000 description 1
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- 238000001308 synthesis method Methods 0.000 description 1
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- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- ROUYFJUVMYHXFJ-UHFFFAOYSA-N tert-butyl 4-oxopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(=O)CC1 ROUYFJUVMYHXFJ-UHFFFAOYSA-N 0.000 description 1
- TZRQZPMQUXEZMC-UHFFFAOYSA-N tert-butyl n-(2-bromoethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCBr TZRQZPMQUXEZMC-UHFFFAOYSA-N 0.000 description 1
- DSPYCWLYGXGJNJ-UHFFFAOYSA-N tert-butyl n-prop-2-ynylcarbamate Chemical compound CC(C)(C)OC(=O)NCC#C DSPYCWLYGXGJNJ-UHFFFAOYSA-N 0.000 description 1
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 1
- YMYHIIMNMWCDJZ-UHFFFAOYSA-N tert-butyl-ethyl-dimethylsilane Chemical compound CC[Si](C)(C)C(C)(C)C YMYHIIMNMWCDJZ-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
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- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 1
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- HFRXJVQOXRXOPP-UHFFFAOYSA-N thionyl bromide Chemical compound BrS(Br)=O HFRXJVQOXRXOPP-UHFFFAOYSA-N 0.000 description 1
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 1
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- 125000004306 triazinyl group Chemical group 0.000 description 1
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- RMZAYIKUYWXQPB-UHFFFAOYSA-N trioctylphosphane Chemical compound CCCCCCCCP(CCCCCCCC)CCCCCCCC RMZAYIKUYWXQPB-UHFFFAOYSA-N 0.000 description 1
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- UTODFRQBVUVYOB-UHFFFAOYSA-P wilkinson's catalyst Chemical compound [Cl-].C1=CC=CC=C1P(C=1C=CC=CC=1)(C=1C=CC=CC=1)[Rh+](P(C=1C=CC=CC=1)(C=1C=CC=CC=1)C=1C=CC=CC=1)P(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 UTODFRQBVUVYOB-UHFFFAOYSA-P 0.000 description 1
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Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- 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
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- Y10S514/866—
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- Y10S514/913—
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
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- Public Health (AREA)
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- Neurology (AREA)
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- Urology & Nephrology (AREA)
- Endocrinology (AREA)
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- Reproductive Health (AREA)
- Pain & Pain Management (AREA)
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Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201462027376P | 2014-07-22 | 2014-07-22 | |
| US62/027,376 | 2014-07-22 | ||
| PCT/US2015/041245 WO2016014463A1 (en) | 2014-07-22 | 2015-07-21 | Heterocyclic carboxylic acids as activators of soluble guanylate cyclase |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| KR20170035993A true KR20170035993A (ko) | 2017-03-31 |
Family
ID=53783363
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020177004761A Withdrawn KR20170035993A (ko) | 2014-07-22 | 2015-07-21 | 가용성 구아닐레이트 사이클라제의 활성제로서의 헤테로사이클릭 카복실산 |
Country Status (26)
| Country | Link |
|---|---|
| US (1) | US9353090B2 (enExample) |
| EP (1) | EP3172202B1 (enExample) |
| JP (1) | JP6602840B2 (enExample) |
| KR (1) | KR20170035993A (enExample) |
| CN (1) | CN106459017B (enExample) |
| AP (1) | AP2016009615A0 (enExample) |
| AR (1) | AR101265A1 (enExample) |
| AU (1) | AU2015292833B2 (enExample) |
| BR (1) | BR112017000943A2 (enExample) |
| CA (1) | CA2955937A1 (enExample) |
| CL (1) | CL2017000071A1 (enExample) |
| CO (1) | CO2017000438A2 (enExample) |
| DK (1) | DK3172202T3 (enExample) |
| EA (1) | EA032972B1 (enExample) |
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Families Citing this family (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11357777B2 (en) | 2016-02-01 | 2022-06-14 | Cyclerion Therapeutics, Inc. | Use of sGC stimulators for the treatment of nonalcoholic steatohepatitis (NASH) |
| US10570074B2 (en) | 2016-09-14 | 2020-02-25 | Genomatica, Inc. | 1,3-fatty diol compounds and derivatives thereof |
| CN109890379A (zh) | 2016-10-11 | 2019-06-14 | 拜耳制药股份公司 | 包含sGC活化剂和盐皮质激素受体拮抗剂的组合产品 |
| CN106495999B (zh) * | 2016-10-18 | 2019-08-16 | 亳州学院 | 一种芳香醛及其合成方法 |
| WO2019012093A1 (en) | 2017-07-14 | 2019-01-17 | Glaxosmithkline Intellectual Property Development Limited | INHIBITORS OF REACTION KINASE 2 RICH IN LEUCINE |
| WO2019036000A1 (en) * | 2017-08-17 | 2019-02-21 | Acuitas Therapeutics, Inc. | LIPIDS FOR USE IN LIPID NANOPARTICLE FORMULATIONS |
| WO2019081456A1 (en) | 2017-10-24 | 2019-05-02 | Bayer Aktiengesellschaft | USE OF SGC ACTIVATORS AND STIMULATORS COMPRISING A BETA2 SUBUNIT |
| EP3498298A1 (en) | 2017-12-15 | 2019-06-19 | Bayer AG | The use of sgc stimulators and sgc activators alone or in combination with pde5 inhibitors for the treatment of bone disorders including osteogenesis imperfecta (oi) |
| EP3784238A4 (en) * | 2018-04-27 | 2021-12-29 | Hetero Labs Ltd. | Process for preparation of ((3r,11br)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy-d)-3-(2-methylpropyl)-2h-benzo[a]quinolizin-2-one |
| CN112055584A (zh) | 2018-04-30 | 2020-12-08 | 拜耳公司 | sGC活化剂和sGC刺激剂用于治疗认知障碍的用途 |
| CN112384213A (zh) | 2018-05-15 | 2021-02-19 | 拜耳公司 | 用于治疗与神经纤维敏化有关的疾病的1,3-噻唑-2-基取代的苯甲酰胺 |
| US11508483B2 (en) | 2018-05-30 | 2022-11-22 | Adverio Pharma Gmbh | Method of identifying a subgroup of patients suffering from dcSSc which benefits from a treatment with sGC stimulators and sGC activators in a higher degree than a control group |
| US12234217B2 (en) | 2018-12-03 | 2025-02-25 | Fmc Corporation | Method for preparing N-phenylpyrazole-1-carboxamides |
| US20220128561A1 (en) | 2019-01-17 | 2022-04-28 | Bayer Aktiengesellschaft | Methods to determine whether a subject is suitable of being treated with an agonist of soluble gyanylyl cyclase (sgc) |
| WO2021028645A1 (en) | 2019-08-09 | 2021-02-18 | Kalvista Pharmaceuticals Limited | Plasma kallikrein inhibitors |
| CN116096702A (zh) | 2020-07-16 | 2023-05-09 | 爱康泰生治疗公司 | 用于脂质纳米颗粒的阳离子脂质 |
| CN114957087A (zh) * | 2022-04-13 | 2022-08-30 | 湖南复瑞生物医药技术有限责任公司 | 一种帕罗韦德中间体制备方法 |
| TW202412753A (zh) | 2022-06-09 | 2024-04-01 | 德商拜耳廠股份有限公司 | 用於治療女性心臟衰竭合併保留射出分率的可溶性鳥苷酸環化酶活化劑 |
Family Cites Families (24)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040067938A1 (en) | 2000-09-29 | 2004-04-08 | Penglie Zhang | Quaternary amines and related inhibitors of factor xa |
| KR20080030669A (ko) | 2005-07-18 | 2008-04-04 | 바이엘 헬스케어 아게 | 신장병의 예방 또는 치료를 위한 가용성 구아닐레이트시클라제 활성화제 및 자극제의 신규 용도 |
| US20080045560A1 (en) | 2006-08-15 | 2008-02-21 | Wyeth | Pyrrolidine and related derivatives useful as PR modulators |
| CA2686906A1 (en) | 2007-05-12 | 2008-11-20 | Bayer Schering Pharma Aktiengesellschaft | Sgc stimulators, sgc activators and combinations for the treatment of urological disorders |
| AU2008296974B2 (en) | 2007-09-06 | 2013-10-10 | Merck Sharp & Dohme Corp. | Soluble guanylate cyclase activators |
| CA2706241C (en) | 2007-10-05 | 2015-12-22 | Sanofi-Aventis Deutschland Gmbh | Use of sulfonyl-substituted 2-sulfonylaminobenzoic acid n-phenylamides in the treatment of pain |
| WO2009068652A1 (en) | 2007-11-30 | 2009-06-04 | Smithkline Beecham Corporation | 2, 6-disubstituted pyridines and 2, 4-disubstituted pyrimidines as soluble guanylate cyclase activators |
| WO2009071504A1 (en) | 2007-12-03 | 2009-06-11 | Smithkline Beecham Corporation | 2,6-disubstituted pyridines as soluble guanylate cyclase activators |
| CN102056907B (zh) | 2008-04-04 | 2014-12-31 | 武田药品工业株式会社 | 杂环衍生物及其用途 |
| WO2010015653A1 (en) | 2008-08-07 | 2010-02-11 | Smithkline Beecham Corporation | Pyrimidine derivatives as activators of soluble guanylate cyclase |
| WO2010015652A2 (en) | 2008-08-07 | 2010-02-11 | Smithkline Beecham Corporation | Thiazole compounds as activators of soluble guanylate cyclase |
| WO2010065275A1 (en) | 2008-11-25 | 2010-06-10 | Merck Sharp & Dohme Corp. | Soluble guanylate cyclase activators |
| JP5780430B2 (ja) | 2009-01-17 | 2015-09-16 | アドヴェリオ・ファーマ・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング | 勃起不全の処置用のＰＤＥ５阻害剤と組み合わせたｓＧＣ刺激剤またはｓＧＣ活性化剤 |
| WO2010099054A2 (en) | 2009-02-26 | 2010-09-02 | Merck Sharp & Dohme Corp. | Soluble guanylate cyclase activators |
| SG182819A1 (en) | 2010-02-05 | 2012-09-27 | Bayer Ip Gmbh | sGC STIMULATORS OR sGC ACTIVATORS ALONE AND IN COMBINATION WITH PDE5 INHBITORS FOR THE TREATMENT OF CYSTIC FIBROSIS |
| WO2011095553A1 (en) | 2010-02-05 | 2011-08-11 | Bayer Schering Pharma Aktiengesellschaft | Sgc stimulators or sgc activators in combination with pde5 inhbitors for the treatment of erectile dysfunction |
| MY170094A (en) | 2010-05-26 | 2019-07-05 | Adverio Pharma Gmbh | The use of sgc stimulators, sgc activators, alone and combinations with pde5 inhibitors for the treatment of systemic sclerosis (ssc). |
| CA2803688A1 (en) | 2010-06-25 | 2011-12-29 | Bayer Intellectual Property Gmbh | Use of stimulators and activators of soluble guanylate cyclase for treating sickle-cell anemia and conserving blood substitutes |
| WO2012058132A1 (en) | 2010-10-28 | 2012-05-03 | Merck Sharp & Dohme Corp. | Soluble guanylate cyclase activators |
| WO2012122340A1 (en) * | 2011-03-10 | 2012-09-13 | Boehringer Ingelheim International Gmbh | Soluble guanylate cyclase activators |
| US8815857B2 (en) | 2011-08-12 | 2014-08-26 | Boehringer Ingelheim International Gmbh | Soluble guanylate cyclase activators |
| EP2594270A3 (en) | 2011-11-18 | 2013-07-31 | BIP Patents | The use of sGC stimulators, sGC activators, alone and combinations with PDE5 inhibitors for the treatment of systemic sclerosis (SSc) |
| WO2014039434A1 (en) | 2012-09-07 | 2014-03-13 | Boehringer Ingelheim International Gmbh | Alkoxy pyrazoles as soluble guanylate cyclase activators |
| WO2015095515A1 (en) | 2013-12-20 | 2015-06-25 | Novartis Ag | Sgc activators for the treatment of glaucoma |
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