KR20140094603A - 칼륨 채널 억제제로서 유용한 싸이에노- 및 퓨로-피리미딘 및 피리딘 - Google Patents
칼륨 채널 억제제로서 유용한 싸이에노- 및 퓨로-피리미딘 및 피리딘 Download PDFInfo
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- KR20140094603A KR20140094603A KR1020147015757A KR20147015757A KR20140094603A KR 20140094603 A KR20140094603 A KR 20140094603A KR 1020147015757 A KR1020147015757 A KR 1020147015757A KR 20147015757 A KR20147015757 A KR 20147015757A KR 20140094603 A KR20140094603 A KR 20140094603A
- Authority
- KR
- South Korea
- Prior art keywords
- optionally substituted
- alkyl
- thieno
- pyrimidin
- phenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
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- 239000003112 inhibitor Substances 0.000 title description 20
- 102000004257 Potassium Channel Human genes 0.000 title description 9
- 108020001213 potassium channel Proteins 0.000 title description 9
- 150000003222 pyridines Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 337
- 238000011282 treatment Methods 0.000 claims abstract description 72
- 239000003814 drug Substances 0.000 claims abstract description 56
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 33
- 201000010099 disease Diseases 0.000 claims abstract description 27
- 230000005764 inhibitory process Effects 0.000 claims abstract description 27
- 230000001404 mediated effect Effects 0.000 claims abstract description 20
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 527
- -1 tetrahydro- Oxazinyl Chemical group 0.000 claims description 422
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 227
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 124
- 238000000034 method Methods 0.000 claims description 123
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 106
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 105
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 95
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 80
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 80
- 229910052757 nitrogen Inorganic materials 0.000 claims description 77
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- 125000001072 heteroaryl group Chemical group 0.000 claims description 66
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 55
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 50
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- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 42
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 37
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 37
- 229910052760 oxygen Inorganic materials 0.000 claims description 35
- 229910052717 sulfur Inorganic materials 0.000 claims description 35
- 125000002757 morpholinyl group Chemical group 0.000 claims description 29
- 125000003118 aryl group Chemical group 0.000 claims description 28
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- 125000003545 alkoxy group Chemical group 0.000 claims description 18
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 18
- 125000005885 heterocycloalkylalkyl group Chemical group 0.000 claims description 17
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- 125000004366 heterocycloalkenyl group Chemical group 0.000 claims description 11
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- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
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- PHKWVGCXERQXLE-UHFFFAOYSA-N 5-phenyl-4-piperidin-1-ylthieno[2,3-d]pyrimidine Chemical compound C1CCCCN1C1=NC=NC2=C1C(C=1C=CC=CC=1)=CS2 PHKWVGCXERQXLE-UHFFFAOYSA-N 0.000 claims description 3
- 125000004847 2-fluorobenzyl group Chemical group [H]C1=C([H])C(F)=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 9
- 210000000133 brain stem Anatomy 0.000 claims 3
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- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims 1
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- 102000003922 Calcium Channels Human genes 0.000 abstract description 2
- 229940125400 channel inhibitor Drugs 0.000 abstract 1
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 164
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 141
- 238000006243 chemical reaction Methods 0.000 description 120
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 90
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 87
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 79
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 78
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 76
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 74
- 239000002904 solvent Substances 0.000 description 62
- 239000000243 solution Substances 0.000 description 54
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 54
- DDWBRNXDKNIQDY-UHFFFAOYSA-N thieno[2,3-d]pyrimidine Chemical class N1=CN=C2SC=CC2=C1 DDWBRNXDKNIQDY-UHFFFAOYSA-N 0.000 description 51
- 125000005843 halogen group Chemical group 0.000 description 44
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 44
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 44
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 43
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 41
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 40
- 102100033063 G protein-activated inward rectifier potassium channel 1 Human genes 0.000 description 40
- 101000944266 Homo sapiens G protein-activated inward rectifier potassium channel 1 Proteins 0.000 description 40
- 238000010992 reflux Methods 0.000 description 38
- 239000007858 starting material Substances 0.000 description 38
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 37
- 239000002585 base Substances 0.000 description 36
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 35
- 230000002829 reductive effect Effects 0.000 description 33
- 101000614712 Homo sapiens G protein-activated inward rectifier potassium channel 4 Proteins 0.000 description 31
- IQHXABCGSFAKPN-UHFFFAOYSA-N pyrrolidine-3-carboxamide Chemical compound NC(=O)C1CCNC1 IQHXABCGSFAKPN-UHFFFAOYSA-N 0.000 description 30
- 239000007787 solid Substances 0.000 description 30
- 102100021237 G protein-activated inward rectifier potassium channel 4 Human genes 0.000 description 28
- 229910052799 carbon Inorganic materials 0.000 description 27
- 235000019439 ethyl acetate Nutrition 0.000 description 27
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 27
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
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- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 19
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- JUADUUBTTVOHHJ-UHFFFAOYSA-N tert-butyl 4-[2-(1-methylpyrrolidin-2-yl)ethoxymethyl]piperidine-1-carboxylate Chemical compound CN1CCCC1CCOCC1CCN(CC1)C(=O)OC(C)(C)C JUADUUBTTVOHHJ-UHFFFAOYSA-N 0.000 description 1
- HDPGSWMTDGGUEB-UHFFFAOYSA-N tert-butyl 5-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate Chemical compound C1C2N(C(=O)OC(C)(C)C)CC1C(O)C2 HDPGSWMTDGGUEB-UHFFFAOYSA-N 0.000 description 1
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- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 1
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- SMZMHUCIDGHERP-UHFFFAOYSA-N thieno[2,3-b]pyridine Chemical compound C1=CN=C2SC=CC2=C1 SMZMHUCIDGHERP-UHFFFAOYSA-N 0.000 description 1
- GKPIFULDHDHNBW-UHFFFAOYSA-N thieno[2,3-d]pyrimidine-6-carboxamide Chemical compound N1=CN=C2SC(C(=O)N)=CC2=C1 GKPIFULDHDHNBW-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
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- 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
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A61P25/08—Antiepileptics; Anticonvulsants
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- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- 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
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Landscapes
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- General Chemical & Material Sciences (AREA)
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- Cardiology (AREA)
- Diabetes (AREA)
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- Endocrinology (AREA)
- Epidemiology (AREA)
- Vascular Medicine (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Emergency Medicine (AREA)
- Psychiatry (AREA)
- Urology & Nephrology (AREA)
- Reproductive Health (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB1119703.5A GB201119703D0 (en) | 2011-11-15 | 2011-11-15 | Compounds |
| GB1119703.5 | 2011-11-15 | ||
| GBGB1214250.1A GB201214250D0 (en) | 2012-08-09 | 2012-08-09 | Compounds |
| GB1214250.1 | 2012-08-09 | ||
| PCT/GB2012/052842 WO2013072694A1 (en) | 2011-11-15 | 2012-11-15 | Thieno- and furo - pyrimidines and pyridines, useful as potassium channel inhibitors |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| KR20140094603A true KR20140094603A (ko) | 2014-07-30 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020147015757A Withdrawn KR20140094603A (ko) | 2011-11-15 | 2012-11-15 | 칼륨 채널 억제제로서 유용한 싸이에노- 및 퓨로-피리미딘 및 피리딘 |
Country Status (15)
| Country | Link |
|---|---|
| US (2) | US9290511B2 (https=) |
| EP (1) | EP2780343A1 (https=) |
| JP (1) | JP2014533259A (https=) |
| KR (1) | KR20140094603A (https=) |
| CN (1) | CN104011054B (https=) |
| AR (1) | AR090037A1 (https=) |
| AU (1) | AU2012338570A1 (https=) |
| BR (1) | BR112014011671A2 (https=) |
| CA (1) | CA2855346A1 (https=) |
| IN (1) | IN2014MN01183A (https=) |
| MX (1) | MX2014005935A (https=) |
| RU (1) | RU2014124101A (https=) |
| TW (1) | TWI498331B (https=) |
| WO (1) | WO2013072694A1 (https=) |
| ZA (1) | ZA201403503B (https=) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20180015261A (ko) * | 2015-06-23 | 2018-02-12 | 르 라보레또레 쎄르비에르 | 신규한 아미노산 유도체, 이의 제조방법, 및 이를 함유한 약제 조성물 |
| KR20180015263A (ko) * | 2015-06-23 | 2018-02-12 | 르 라보레또레 쎄르비에르 | 신규한 하이드록시산 유도체, 이를 제조하는 방법 및 이를 함유하는 약제 조성물 |
Families Citing this family (33)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SG11201509989VA (en) | 2013-06-06 | 2016-01-28 | Astellas Pharma Inc | Benzothiophene compound |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20180015261A (ko) * | 2015-06-23 | 2018-02-12 | 르 라보레또레 쎄르비에르 | 신규한 아미노산 유도체, 이의 제조방법, 및 이를 함유한 약제 조성물 |
| KR20180015263A (ko) * | 2015-06-23 | 2018-02-12 | 르 라보레또레 쎄르비에르 | 신규한 하이드록시산 유도체, 이를 제조하는 방법 및 이를 함유하는 약제 조성물 |
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| US20160152634A1 (en) | 2016-06-02 |
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| EP2780343A1 (en) | 2014-09-24 |
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| MX2014005935A (es) | 2014-09-04 |
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| AR090037A1 (es) | 2014-10-15 |
| JP2014533259A (ja) | 2014-12-11 |
| TWI498331B (zh) | 2015-09-01 |
| ZA201403503B (en) | 2016-09-28 |
| CA2855346A1 (en) | 2013-05-23 |
| US20140371203A1 (en) | 2014-12-18 |
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