KR20100044251A - 특정 화학 물질, 조성물 및 방법 - Google Patents

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Publication number

KR20100044251A

KR20100044251A KR1020107005370A KR20107005370A KR20100044251A KR 20100044251 A KR20100044251 A KR 20100044251A KR 1020107005370 A KR1020107005370 A KR 1020107005370A KR 20107005370 A KR20107005370 A KR 20107005370A KR 20100044251 A KR20100044251 A KR 20100044251A

Authority

KR

South Korea

Prior art keywords

optionally substituted

chemical entity

hydrogen

mmol

alkyl

Prior art date

2007-08-15

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.)

Ceased

Links

• Espacenet
• Global Dossier
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• 238000000034 method Methods 0.000 title claims abstract description 46
• 239000000203 mixture Substances 0.000 title claims description 390
• 150000005829 chemical entities Chemical class 0.000 title claims 59
• 239000000126 substance Substances 0.000 claims abstract description 87
• 102000003505 Myosin Human genes 0.000 claims abstract description 79
• 108060008487 Myosin Proteins 0.000 claims abstract description 78
• 210000002460 smooth muscle Anatomy 0.000 claims abstract description 43
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 42
• 201000010099 disease Diseases 0.000 claims abstract description 37
• 230000003387 muscular Effects 0.000 claims abstract description 22
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 18
• 208000035475 disorder Diseases 0.000 claims abstract description 5
• -1 hydroxy, carboxy, sulfonyl Chemical group 0.000 claims description 399
• 229910052739 hydrogen Inorganic materials 0.000 claims description 119
• 239000001257 hydrogen Substances 0.000 claims description 112
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 105
• 125000000217 alkyl group Chemical group 0.000 claims description 100
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 82
• 125000001072 heteroaryl group Chemical group 0.000 claims description 79
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 56
• 150000001875 compounds Chemical class 0.000 claims description 53
• 125000003107 substituted aryl group Chemical group 0.000 claims description 44
• 125000003118 aryl group Chemical group 0.000 claims description 41
• 125000005843 halogen group Chemical group 0.000 claims description 41
• 125000000547 substituted alkyl group Chemical group 0.000 claims description 39
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 36
• 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 36
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 35
• 125000005017 substituted alkenyl group Chemical group 0.000 claims description 29
• 150000003839 salts Chemical class 0.000 claims description 26
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 24
• 239000000725 suspension Substances 0.000 claims description 24
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 22
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 22
• 125000005415 substituted alkoxy group Chemical group 0.000 claims description 22
• 125000002252 acyl group Chemical group 0.000 claims description 20
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 20
• 229910052799 carbon Inorganic materials 0.000 claims description 20
• 125000004429 atom Chemical group 0.000 claims description 19
• 229910052760 oxygen Inorganic materials 0.000 claims description 18
• 125000004426 substituted alkynyl group Chemical group 0.000 claims description 18
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 17
• 125000003396 thiol group Chemical group [H]S* 0.000 claims description 17
• 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 16
• 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 15
• 241000124008 Mammalia Species 0.000 claims description 14
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 14
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
• 125000004551 isoquinolin-3-yl group Chemical group C1=NC(=CC2=CC=CC=C12)* 0.000 claims description 13
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 11
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 11
• 125000004104 aryloxy group Chemical group 0.000 claims description 11
• 208000024891 symptom Diseases 0.000 claims description 11
• 229910052721 tungsten Inorganic materials 0.000 claims description 11
• 230000036592 analgesia Effects 0.000 claims description 10
• 125000004499 isoxazol-5-yl group Chemical group O1N=CC=C1* 0.000 claims description 10
• 125000005553 heteroaryloxy group Chemical group 0.000 claims description 9
• 125000004284 isoxazol-3-yl group Chemical group [H]C1=C([H])C(*)=NO1 0.000 claims description 9
• 206010020772 Hypertension Diseases 0.000 claims description 8
• 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 8
• 125000004076 pyridyl group Chemical group 0.000 claims description 8
• 125000004521 1,3,4-thiadiazol-2-yl group Chemical group S1C(=NN=C1)* 0.000 claims description 7
• 208000006673 asthma Diseases 0.000 claims description 7
• 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 7
• 208000017667 Chronic Disease Diseases 0.000 claims description 6
• 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 6
• 208000010412 Glaucoma Diseases 0.000 claims description 6
• 208000032843 Hemorrhage Diseases 0.000 claims description 6
• 125000004423 acyloxy group Chemical group 0.000 claims description 6
• 125000005194 alkoxycarbonyloxy group Chemical group 0.000 claims description 6
• 125000001153 fluoro group Chemical group F* 0.000 claims description 6
• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 6
• 239000007788 liquid Substances 0.000 claims description 6
• 239000000843 powder Substances 0.000 claims description 6
• 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 6
• 208000010228 Erectile Dysfunction Diseases 0.000 claims description 5
• 206010021639 Incontinence Diseases 0.000 claims description 5
• 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 5
• 125000005873 benzo[d]thiazolyl group Chemical group 0.000 claims description 5
• 230000008602 contraction Effects 0.000 claims description 5
• 201000001881 impotence Diseases 0.000 claims description 5
• 208000002551 irritable bowel syndrome Diseases 0.000 claims description 5
• 125000004159 quinolin-2-yl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C([H])C(*)=NC2=C1[H] 0.000 claims description 5
• 125000004548 quinolin-3-yl group Chemical group N1=CC(=CC2=CC=CC=C12)* 0.000 claims description 5
• 239000003826 tablet Substances 0.000 claims description 5
• 125000004496 thiazol-5-yl group Chemical group S1C=NC=C1* 0.000 claims description 5
• 125000000335 thiazolyl group Chemical group 0.000 claims description 5
• 125000001544 thienyl group Chemical group 0.000 claims description 5
• 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 4
• 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
• 208000033045 Premenstrual cramps Diseases 0.000 claims description 4
• DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims description 4
• 239000000443 aerosol Substances 0.000 claims description 4
• 210000000576 arachnoid Anatomy 0.000 claims description 4
• 208000029162 bladder disease Diseases 0.000 claims description 4
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
• 238000007634 remodeling Methods 0.000 claims description 4
• 125000004520 1,3,4-thiadiazolyl group Chemical group 0.000 claims description 3
• 230000001154 acute effect Effects 0.000 claims description 3
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
• 239000003937 drug carrier Substances 0.000 claims description 3
• 125000003386 piperidinyl group Chemical group 0.000 claims description 3
• 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 claims description 2
• 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 claims description 2
• 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 2
• 208000006399 Premature Obstetric Labor Diseases 0.000 claims description 2
• 239000002775 capsule Substances 0.000 claims description 2
• 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 2
• 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 2
• 239000000829 suppository Substances 0.000 claims description 2
• 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 2
• 150000002431 hydrogen Chemical class 0.000 claims 9
• 238000003763 carbonization Methods 0.000 claims 2
• 230000004899 motility Effects 0.000 claims 2
• 208000026533 urinary bladder disease Diseases 0.000 claims 2
• 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 364
• 239000000243 solution Substances 0.000 description 329
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 297
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 204
• 235000019439 ethyl acetate Nutrition 0.000 description 177
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 168
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 157
• 239000011734 sodium Substances 0.000 description 125
• 239000011541 reaction mixture Substances 0.000 description 117
• 238000006243 chemical reaction Methods 0.000 description 114
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 105
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 98
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 95
• 239000012267 brine Substances 0.000 description 92
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 92
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 78
• 239000000741 silica gel Substances 0.000 description 75
• 229910002027 silica gel Inorganic materials 0.000 description 75
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 72
• 239000007787 solid Substances 0.000 description 71
• 239000012044 organic layer Substances 0.000 description 70
• 229920006395 saturated elastomer Polymers 0.000 description 64
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 61
• 238000004007 reversed phase HPLC Methods 0.000 description 60
• 239000002904 solvent Substances 0.000 description 56
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 55
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 55
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 55
• 229910000041 hydrogen chloride Inorganic materials 0.000 description 55
• 238000000746 purification Methods 0.000 description 53
• 230000002829 reductive effect Effects 0.000 description 48
• 239000000706 filtrate Substances 0.000 description 40
• 125000001424 substituent group Chemical group 0.000 description 35
• 239000000460 chlorine Substances 0.000 description 33
• 238000003756 stirring Methods 0.000 description 31
• 125000004435 hydrogen atom Chemical class [H]* 0.000 description 30
• 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 description 28
• 125000000753 cycloalkyl group Chemical group 0.000 description 28
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 27
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 26
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 25
• 125000004432 carbon atom Chemical group C* 0.000 description 25
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 23
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
• OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 20
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 20
• DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 20
• 229910019142 PO4 Inorganic materials 0.000 description 19
• ITWNHVUNXRNKFN-UHFFFAOYSA-N isoquinolin-3-ylcarbamic acid Chemical compound C1=CC=C2C=NC(NC(=O)O)=CC2=C1 ITWNHVUNXRNKFN-UHFFFAOYSA-N 0.000 description 19
• 229910052757 nitrogen Inorganic materials 0.000 description 19
• 235000021317 phosphate Nutrition 0.000 description 19
• 229910052708 sodium Inorganic materials 0.000 description 19
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 19
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 18
• 239000010452 phosphate Substances 0.000 description 18
• DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 17
• 239000002244 precipitate Substances 0.000 description 17
• 230000000694 effects Effects 0.000 description 16
• 125000005842 heteroatom Chemical group 0.000 description 16
• 239000010410 layer Substances 0.000 description 16
• RUZLIIJDZBWWSA-INIZCTEOSA-N methyl 2-[[(1s)-1-(7-methyl-2-morpholin-4-yl-4-oxopyrido[1,2-a]pyrimidin-9-yl)ethyl]amino]benzoate Chemical group COC(=O)C1=CC=CC=C1N[C@@H](C)C1=CC(C)=CN2C(=O)C=C(N3CCOCC3)N=C12 RUZLIIJDZBWWSA-INIZCTEOSA-N 0.000 description 15
• 125000004043 oxo group Chemical group O=* 0.000 description 15
• ZKHQWZAMYRWXGA-KQYNXXCUSA-N Adenosine triphosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-N 0.000 description 14
• ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 14
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 14
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
• 239000000872 buffer Substances 0.000 description 14
• 229960000549 4-dimethylaminophenol Drugs 0.000 description 13
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 13
• 229910052717 sulfur Inorganic materials 0.000 description 13
• NXLNNXIXOYSCMB-UHFFFAOYSA-N (4-nitrophenyl) carbonochloridate Chemical compound [O-][N+](=O)C1=CC=C(OC(Cl)=O)C=C1 NXLNNXIXOYSCMB-UHFFFAOYSA-N 0.000 description 12
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
• 239000000543 intermediate Substances 0.000 description 12
• 239000003921 oil Substances 0.000 description 12
• 235000019198 oils Nutrition 0.000 description 12
• KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
• OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 11
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
• SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 11
• 239000002253 acid Substances 0.000 description 11
• 239000012230 colorless oil Substances 0.000 description 11
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 11
• 229910000104 sodium hydride Inorganic materials 0.000 description 11
• CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Substances C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 11
• UGAKDDOYQSBOJJ-UHFFFAOYSA-N 6-fluoroisoquinoline-3-carbonyl azide Chemical compound C1=NC(C(=O)N=[N+]=[N-])=CC2=CC(F)=CC=C21 UGAKDDOYQSBOJJ-UHFFFAOYSA-N 0.000 description 10
• OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 10
• 239000011575 calcium Substances 0.000 description 10
• 229910052791 calcium Inorganic materials 0.000 description 10
• INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 10
• 239000000047 product Substances 0.000 description 10
• FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 10
• 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 9
• 238000002360 preparation method Methods 0.000 description 9
• BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 8
• 208000007101 Muscle Cramp Diseases 0.000 description 8
• 125000003545 alkoxy group Chemical group 0.000 description 8
• 235000019253 formic acid Nutrition 0.000 description 8
• 238000004128 high performance liquid chromatography Methods 0.000 description 8
• 230000007062 hydrolysis Effects 0.000 description 8
• 238000006460 hydrolysis reaction Methods 0.000 description 8
• BKHDVLNPBLSCKA-UHFFFAOYSA-N isoquinoline-3-carbonyl azide Chemical compound C1=CC=C2C=NC(C(=O)N=[N+]=[N-])=CC2=C1 BKHDVLNPBLSCKA-UHFFFAOYSA-N 0.000 description 8
• ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 8
• 239000001301 oxygen Substances 0.000 description 8
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 8
• HNGXTXJLCUFYQL-UHFFFAOYSA-N 1-[(2-chloro-3-fluorophenyl)methyl]-3-methylurea Chemical compound CNC(=O)NCC1=CC=CC(F)=C1Cl HNGXTXJLCUFYQL-UHFFFAOYSA-N 0.000 description 7
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 7
• 208000005392 Spasm Diseases 0.000 description 7
• 125000000304 alkynyl group Chemical group 0.000 description 7
• 125000002837 carbocyclic group Chemical group 0.000 description 7
• 150000003840 hydrochlorides Chemical class 0.000 description 7
• 230000002401 inhibitory effect Effects 0.000 description 7
• 239000003960 organic solvent Substances 0.000 description 7
• 125000006413 ring segment Chemical group 0.000 description 7
• 238000000926 separation method Methods 0.000 description 7
• 239000012312 sodium hydride Substances 0.000 description 7
• JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 7
• DTNYGEBHHWVMBK-UHFFFAOYSA-N (2-chloro-3-fluorophenyl)methanamine Chemical compound NCC1=CC=CC(F)=C1Cl DTNYGEBHHWVMBK-UHFFFAOYSA-N 0.000 description 6
• IONJNTZSNXRLAZ-UHFFFAOYSA-N (2-chloro-3-fluorophenyl)methanamine;hydrochloride Chemical compound Cl.NCC1=CC=CC(F)=C1Cl IONJNTZSNXRLAZ-UHFFFAOYSA-N 0.000 description 6
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
• PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
• DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 6
• 239000013543 active substance Substances 0.000 description 6
• 125000003342 alkenyl group Chemical group 0.000 description 6
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 6
• 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 6
• 238000003818 flash chromatography Methods 0.000 description 6
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• OAIDHDLQRXTTDO-QFIPXVFZSA-N [(2s)-2-[(2-chloro-3-fluorophenyl)methylcarbamoyl-methylamino]-4-oxo-4-(pyrazin-2-ylmethylamino)butyl] n-isoquinolin-3-ylcarbamate Chemical compound C([C@@H](COC(=O)NC=1N=CC2=CC=CC=C2C=1)N(C)C(=O)NCC=1C(=C(F)C=CC=1)Cl)C(=O)NCC1=CN=CC=N1 OAIDHDLQRXTTDO-QFIPXVFZSA-N 0.000 description 1
• ABVBUEHGQRXTRH-IBGZPJMESA-N [(2s)-2-[(2-chloro-3-fluorophenyl)methylcarbamoyl-methylamino]-5-(1,3-dioxoisoindol-2-yl)pentyl] n-(5-chloropyridin-2-yl)carbamate Chemical compound C([C@H](CCCN1C(C2=CC=CC=C2C1=O)=O)N(C)C(=O)NCC=1C(=C(F)C=CC=1)Cl)OC(=O)NC1=CC=C(Cl)C=N1 ABVBUEHGQRXTRH-IBGZPJMESA-N 0.000 description 1
• ARGRUMUFNYJXPM-IBGZPJMESA-N [(2s)-2-[(2-chloro-3-fluorophenyl)methylcarbamoyl-methylamino]-5-(1,3-dioxoisoindol-2-yl)pentyl] n-[5-(trifluoromethyl)pyridin-2-yl]carbamate Chemical compound C([C@H](CCCN1C(C2=CC=CC=C2C1=O)=O)N(C)C(=O)NCC=1C(=C(F)C=CC=1)Cl)OC(=O)NC1=CC=C(C(F)(F)F)C=N1 ARGRUMUFNYJXPM-IBGZPJMESA-N 0.000 description 1
• TYCQFLDGDRUVIS-QHCPKHFHSA-N [(2s)-2-[(2-chloro-3-fluorophenyl)methylcarbamoyl-methylamino]-5-(2-methyl-3,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)-5-oxopentyl] n-isoquinolin-3-ylcarbamate Chemical compound CN([C@@H](CCC(=O)N1CC=2N=C(C)NC=2CC1)COC(=O)NC=1N=CC2=CC=CC=C2C=1)C(=O)NCC1=CC=CC(F)=C1Cl TYCQFLDGDRUVIS-QHCPKHFHSA-N 0.000 description 1
• HNYXHRONVORMHS-QHCPKHFHSA-N [(2s)-2-[(2-chloro-3-fluorophenyl)methylcarbamoyl-methylamino]-5-(6,8-dihydro-5h-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)pentyl] n-isoquinolin-3-ylcarbamate Chemical compound CN([C@@H](CCCN1CC2=NN=CN2CC1)COC(=O)NC=1N=CC2=CC=CC=C2C=1)C(=O)NCC1=CC=CC(F)=C1Cl HNYXHRONVORMHS-QHCPKHFHSA-N 0.000 description 1
• BPFOIAONPUEUDF-QFIPXVFZSA-N [(2s)-2-[(2-chloro-3-fluorophenyl)methylcarbamoyl-methylamino]-5-dimethoxyphosphoryloxy-4,4-dimethylpentyl] n-(6-fluoroisoquinolin-3-yl)carbamate Chemical compound CN([C@H](COC(=O)NC=1N=CC2=CC=C(F)C=C2C=1)CC(C)(C)COP(=O)(OC)OC)C(=O)NCC1=CC=CC(F)=C1Cl BPFOIAONPUEUDF-QFIPXVFZSA-N 0.000 description 1
• QKXVPEHUCUIQOP-BGERDNNASA-N [(2s)-2-[(2-chloro-3-fluorophenyl)methylcarbamoyl-methylamino]-5-dimethoxyphosphoryloxy-4-hydroxypentyl] n-(6-fluoroisoquinolin-3-yl)carbamate Chemical compound CN([C@H](COC(=O)NC=1N=CC2=CC=C(F)C=C2C=1)CC(O)COP(=O)(OC)OC)C(=O)NCC1=CC=CC(F)=C1Cl QKXVPEHUCUIQOP-BGERDNNASA-N 0.000 description 1
• MWSJAWGYORAMDX-FQEVSTJZSA-N [(2s)-2-[(2-chloro-3-fluorophenyl)methylcarbamoyl-methylamino]-5-hydroxy-4,4-dimethylpentyl] n-(6-fluoroisoquinolin-3-yl)carbamate Chemical compound CN([C@H](COC(=O)NC=1N=CC2=CC=C(F)C=C2C=1)CC(C)(C)CO)C(=O)NCC1=CC=CC(F)=C1Cl MWSJAWGYORAMDX-FQEVSTJZSA-N 0.000 description 1
• XODOEZDCMCMFJW-SFHVURJKSA-N [(2s)-2-[(2-chloro-3-fluorophenyl)methylcarbamoyl-methylamino]-5-oxo-5-piperazin-1-ylpentyl] n-(1,3-benzothiazol-2-yl)carbamate Chemical compound C([C@H](N(C)C(=O)NCC=1C(=C(F)C=CC=1)Cl)COC(=O)NC=1SC2=CC=CC=C2N=1)CC(=O)N1CCNCC1 XODOEZDCMCMFJW-SFHVURJKSA-N 0.000 description 1
• PSAOTDWEWWYFDA-QFIPXVFZSA-N [(2s)-2-[(2-chloro-3-fluorophenyl)methylcarbamoyl-methylamino]-5-oxo-5-piperazin-1-ylpentyl] n-(6-fluoroisoquinolin-3-yl)carbamate Chemical compound C([C@H](N(C)C(=O)NCC=1C(=C(F)C=CC=1)Cl)COC(=O)NC=1N=CC2=CC=C(F)C=C2C=1)CC(=O)N1CCNCC1 PSAOTDWEWWYFDA-QFIPXVFZSA-N 0.000 description 1
• VPTALIRDEYAPHX-QFIPXVFZSA-N [(2s)-2-[(2-chloro-3-fluorophenyl)methylcarbamoyl-methylamino]-5-oxo-5-piperazin-1-ylpentyl] n-isoquinolin-3-ylcarbamate Chemical compound C([C@H](N(C)C(=O)NCC=1C(=C(F)C=CC=1)Cl)COC(=O)NC=1N=CC2=CC=CC=C2C=1)CC(=O)N1CCNCC1 VPTALIRDEYAPHX-QFIPXVFZSA-N 0.000 description 1
• ZDXQWEZWCIQXNR-NRFANRHFSA-N [(2s)-2-[(2-chloro-4-fluorophenyl)methylcarbamoyl-methylamino]-6-hydroxyhexyl] n-isoquinolin-3-ylcarbamate Chemical compound CN([C@@H](CCCCO)COC(=O)NC=1N=CC2=CC=CC=C2C=1)C(=O)NCC1=CC=C(F)C=C1Cl ZDXQWEZWCIQXNR-NRFANRHFSA-N 0.000 description 1
• ZQHWADKFWSVESG-NRFANRHFSA-N [(2s)-2-[acetyl-[(2-chloro-3-fluorophenyl)methylamino]amino]-3-(1h-imidazol-5-yl)propyl] n-(6-fluoroisoquinolin-3-yl)carbamate Chemical compound CC(=O)N([C@H](COC(=O)NC=1N=CC2=CC=C(F)C=C2C=1)CC=1NC=NC=1)NCC1=CC=CC(F)=C1Cl ZQHWADKFWSVESG-NRFANRHFSA-N 0.000 description 1
• DLSPEVZOOQLKCA-NRFANRHFSA-N [(2s)-2-[acetyl-[(2-chloro-3-fluorophenyl)methylamino]amino]-4,4-dimethyl-5-phosphonooxypentyl] n-(6-fluoroisoquinolin-3-yl)carbamate Chemical compound CC(=O)N([C@H](COC(=O)NC=1N=CC2=CC=C(F)C=C2C=1)CC(C)(C)COP(O)(O)=O)NCC1=CC=CC(F)=C1Cl DLSPEVZOOQLKCA-NRFANRHFSA-N 0.000 description 1
• VQGVPNKQIIOIOO-XJDOXCRVSA-N [(2s)-2-[acetyl-[(2-chloro-3-fluorophenyl)methylamino]amino]-4-hydroxy-5-phosphonooxypentyl] n-(6-fluoroisoquinolin-3-yl)carbamate Chemical compound CC(=O)N([C@H](COC(=O)NC=1N=CC2=CC=C(F)C=C2C=1)CC(O)COP(O)(O)=O)NCC1=CC=CC(F)=C1Cl VQGVPNKQIIOIOO-XJDOXCRVSA-N 0.000 description 1
• UREUPJWPNLLFKM-KRWDZBQOSA-N [(2s)-3-amino-2-[(2-chloro-3-fluorophenyl)methylcarbamoyl-methylamino]propyl] n-isoquinolin-3-ylcarbamate Chemical compound CN([C@@H](CN)COC(=O)NC=1N=CC2=CC=CC=C2C=1)C(=O)NCC1=CC=CC(F)=C1Cl UREUPJWPNLLFKM-KRWDZBQOSA-N 0.000 description 1
• WYKWOCMQGCPNTH-FQEVSTJZSA-N [(2s)-5-[(2-aminoacetyl)amino]-2-[(2-chloro-3-fluorophenyl)methylcarbamoyl-methylamino]pentyl] n-(6-fluoroisoquinolin-3-yl)carbamate Chemical compound CN([C@@H](CCCNC(=O)CN)COC(=O)NC=1N=CC2=CC=C(F)C=C2C=1)C(=O)NCC1=CC=CC(F)=C1Cl WYKWOCMQGCPNTH-FQEVSTJZSA-N 0.000 description 1
• FGKXUGHKJLGVFL-IBGZPJMESA-N [(2s)-5-[[amino-(carbamoylamino)methylidene]amino]-2-[(2-chloro-3-fluorophenyl)methylcarbamoyl-methylamino]pentyl] n-(6-fluoroisoquinolin-3-yl)carbamate Chemical compound CN([C@@H](CCCN\C(N)=N\C(N)=O)COC(=O)NC=1N=CC2=CC=C(F)C=C2C=1)C(=O)NCC1=CC=CC(F)=C1Cl FGKXUGHKJLGVFL-IBGZPJMESA-N 0.000 description 1
• LNRNJPXEXQOOKV-KRWDZBQOSA-N [(2s)-5-amino-2-[(2-chloro-3-fluorophenyl)methylcarbamoyl-methylamino]-4,4-difluoropentyl] n-[3-(3-fluorophenyl)-1,2-oxazol-5-yl]carbamate Chemical compound C([C@@H](N(C)C(=O)NCC=1C(=C(F)C=CC=1)Cl)CC(F)(F)CN)OC(=O)NC(ON=1)=CC=1C1=CC=CC(F)=C1 LNRNJPXEXQOOKV-KRWDZBQOSA-N 0.000 description 1
• KJSFCNQXSUOQJU-HNNXBMFYSA-N [(2s)-5-amino-2-[(2-chloro-3-fluorophenyl)methylcarbamoyl-methylamino]pentyl] n-(5-chloropyridin-2-yl)carbamate Chemical compound C([C@H](CCCN)N(C)C(=O)NCC=1C(=C(F)C=CC=1)Cl)OC(=O)NC1=CC=C(Cl)C=N1 KJSFCNQXSUOQJU-HNNXBMFYSA-N 0.000 description 1
• MWEJRPDMHABYGY-SFHVURJKSA-N [(2s)-5-azido-2-[(2-chloro-3-fluorophenyl)methylcarbamoyl-methylamino]-4,4-difluoropentyl] n-(6-fluoroisoquinolin-3-yl)carbamate Chemical compound CN([C@H](COC(=O)NC=1N=CC2=CC=C(F)C=C2C=1)CC(F)(F)CN=[N+]=[N-])C(=O)NCC1=CC=CC(F)=C1Cl MWEJRPDMHABYGY-SFHVURJKSA-N 0.000 description 1
• WXWDJYITARJZHP-LEWJYISDSA-N [(2s,4r)-2-[(2,3-difluorophenyl)methylcarbamoyl-methylamino]-5-dimethoxyphosphoryloxy-4-hydroxypentyl] n-isoquinolin-3-ylcarbamate Chemical compound CN([C@H](COC(=O)NC=1N=CC2=CC=CC=C2C=1)C[C@@H](O)COP(=O)(OC)OC)C(=O)NCC1=CC=CC(F)=C1F WXWDJYITARJZHP-LEWJYISDSA-N 0.000 description 1
• DQZHAWOROSIYSB-FCHUYYIVSA-N [(2s,4r)-2-[(2-chloro-3-fluorophenyl)methylcarbamoyl-methylamino]-5-diethoxyphosphoryloxy-4-hydroxypentyl] n-(3-phenyl-1,2-oxazol-5-yl)carbamate Chemical compound C([C@H](C[C@@H](O)COP(=O)(OCC)OCC)N(C)C(=O)NCC=1C(=C(F)C=CC=1)Cl)OC(=O)NC(ON=1)=CC=1C1=CC=CC=C1 DQZHAWOROSIYSB-FCHUYYIVSA-N 0.000 description 1
• HKBDFYAYOOQROT-XZOQPEGZSA-N [(2s,4r)-2-[(2-chloro-3-fluorophenyl)methylcarbamoyl-methylamino]-5-diethoxyphosphoryloxy-4-hydroxypentyl] n-isoquinolin-3-ylcarbamate Chemical compound CN([C@H](COC(=O)NC=1N=CC2=CC=CC=C2C=1)C[C@@H](O)COP(=O)(OCC)OCC)C(=O)NCC1=CC=CC(F)=C1Cl HKBDFYAYOOQROT-XZOQPEGZSA-N 0.000 description 1
• VCVQXLREAWSIIM-LOSJGSFVSA-N [(2s,4r)-5-[bis[(2-methylpropan-2-yl)oxy]phosphoryloxy]-2-[(2,3-difluorophenyl)methylcarbamoyl-methylamino]-4-hydroxypentyl] n-isoquinolin-3-ylcarbamate Chemical compound CN([C@H](COC(=O)NC=1N=CC2=CC=CC=C2C=1)C[C@@H](O)COP(=O)(OC(C)(C)C)OC(C)(C)C)C(=O)NCC1=CC=CC(F)=C1F VCVQXLREAWSIIM-LOSJGSFVSA-N 0.000 description 1
• KJTZIKSUCAAEDR-LOSJGSFVSA-N [(2s,4r)-5-[bis[(2-methylpropan-2-yl)oxy]phosphoryloxy]-2-[(2-chloro-3-fluorophenyl)methylcarbamoyl-methylamino]-4-hydroxypentyl] n-isoquinolin-3-ylcarbamate Chemical compound CN([C@H](COC(=O)NC=1N=CC2=CC=CC=C2C=1)C[C@@H](O)COP(=O)(OC(C)(C)C)OC(C)(C)C)C(=O)NCC1=CC=CC(F)=C1Cl KJTZIKSUCAAEDR-LOSJGSFVSA-N 0.000 description 1
• WXWDJYITARJZHP-SFTDATJTSA-N [(2s,4s)-2-[(2,3-difluorophenyl)methylcarbamoyl-methylamino]-5-dimethoxyphosphoryloxy-4-hydroxypentyl] n-isoquinolin-3-ylcarbamate Chemical compound CN([C@H](COC(=O)NC=1N=CC2=CC=CC=C2C=1)C[C@H](O)COP(=O)(OC)OC)C(=O)NCC1=CC=CC(F)=C1F WXWDJYITARJZHP-SFTDATJTSA-N 0.000 description 1
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