IL269599B2 - 11,13-modified saxitoxins for the treatment of pain - Google Patents

Info

Publication number

IL269599B2

IL269599B2 IL269599A IL26959919A IL269599B2 IL 269599 B2 IL269599 B2 IL 269599B2 IL 269599 A IL269599 A IL 269599A IL 26959919 A IL26959919 A IL 26959919A IL 269599 B2 IL269599 B2 IL 269599B2

Authority

IL

Israel

Prior art keywords

compound

halo

6alkyl

formula

pain

Prior art date

2017-03-29

Links

• Espacenet
• Global Dossier
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• 208000002193 Pain Diseases 0.000 title claims description 118
• 238000011282 treatment Methods 0.000 title claims description 44
• 150000001875 compounds Chemical class 0.000 claims description 455
• 239000000203 mixture Substances 0.000 claims description 187
• -1 halo-C1-6alkoxy Chemical group 0.000 claims description 178
• 229910052739 hydrogen Inorganic materials 0.000 claims description 135
• 239000001257 hydrogen Substances 0.000 claims description 135
• 150000003839 salts Chemical class 0.000 claims description 110
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 96
• 238000000034 method Methods 0.000 claims description 79
• 125000003118 aryl group Chemical group 0.000 claims description 60
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 58
• 239000003814 drug Substances 0.000 claims description 54
• 239000008194 pharmaceutical composition Substances 0.000 claims description 52
• 150000002431 hydrogen Chemical class 0.000 claims description 48
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 47
• 125000000623 heterocyclic group Chemical group 0.000 claims description 44
• 102000016913 Voltage-Gated Sodium Channels Human genes 0.000 claims description 43
• 108010053752 Voltage-Gated Sodium Channels Proteins 0.000 claims description 43
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 43
• 239000012453 solvate Substances 0.000 claims description 40
• ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 38
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 33
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 32
• 125000004104 aryloxy group Chemical group 0.000 claims description 24
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 23
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 22
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 21
• 239000004305 biphenyl Substances 0.000 claims description 19
• 235000010290 biphenyl Nutrition 0.000 claims description 19
• 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 18
• 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 18
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 18
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 18
• 241000282414 Homo sapiens Species 0.000 claims description 16
• 229910052760 oxygen Inorganic materials 0.000 claims description 14
• 125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 claims description 13
• 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 13
• 241000124008 Mammalia Species 0.000 claims description 13
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 12
• 239000003085 diluting agent Substances 0.000 claims description 11
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
• 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 claims description 10
• 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 10
• 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 claims description 10
• 125000002047 benzodioxolyl group Chemical group O1OC(C2=C1C=CC=C2)* 0.000 claims description 9
• 238000001356 surgical procedure Methods 0.000 claims description 9
• 230000001154 acute effect Effects 0.000 claims description 8
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 7
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 7
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• 206010015958 Eye pain Diseases 0.000 claims description 6
• 125000001624 naphthyl group Chemical group 0.000 claims description 6
• 208000000094 Chronic Pain Diseases 0.000 claims description 5
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• 208000003251 Pruritus Diseases 0.000 claims description 5
• 208000008765 Sciatica Diseases 0.000 claims description 5
• 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 5
• 208000018737 Parkinson disease Diseases 0.000 claims description 4
• 206010061788 Corneal infection Diseases 0.000 claims description 3
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• 206010036376 Postherpetic Neuralgia Diseases 0.000 claims description 3
• 238000005299 abrasion Methods 0.000 claims description 3
• 208000006561 Cluster Headache Diseases 0.000 claims description 2
• 208000023890 Complex Regional Pain Syndromes Diseases 0.000 claims description 2
• 208000032131 Diabetic Neuropathies Diseases 0.000 claims description 2
• 201000009273 Endometriosis Diseases 0.000 claims description 2
• 208000001640 Fibromyalgia Diseases 0.000 claims description 2
• 208000019695 Migraine disease Diseases 0.000 claims description 2
• 208000005298 acute pain Diseases 0.000 claims description 2
• 230000001684 chronic effect Effects 0.000 claims description 2
• 208000018912 cluster headache syndrome Diseases 0.000 claims description 2
• 201000011384 erythromelalgia Diseases 0.000 claims description 2
• 206010027599 migraine Diseases 0.000 claims description 2
• 201000006417 multiple sclerosis Diseases 0.000 claims description 2
• 201000008482 osteoarthritis Diseases 0.000 claims description 2
• 208000019865 paroxysmal extreme pain disease Diseases 0.000 claims description 2
• 206010044652 trigeminal neuralgia Diseases 0.000 claims description 2
• 125000001475 halogen functional group Chemical group 0.000 claims 9
• 125000004356 hydroxy functional group Chemical group O* 0.000 claims 5
• DFRAKBCRUYUFNT-UHFFFAOYSA-N 3,8-dicyclohexyl-2,4,7,9-tetrahydro-[1,3]oxazino[5,6-h][1,3]benzoxazine Chemical compound C1CCCCC1N1CC(C=CC2=C3OCN(C2)C2CCCCC2)=C3OC1 DFRAKBCRUYUFNT-UHFFFAOYSA-N 0.000 claims 2
• 208000004550 Postoperative Pain Diseases 0.000 claims 2
• YGBMCLDVRUGXOV-UHFFFAOYSA-N n-[6-[6-chloro-5-[(4-fluorophenyl)sulfonylamino]pyridin-3-yl]-1,3-benzothiazol-2-yl]acetamide Chemical compound C1=C2SC(NC(=O)C)=NC2=CC=C1C(C=1)=CN=C(Cl)C=1NS(=O)(=O)C1=CC=C(F)C=C1 YGBMCLDVRUGXOV-UHFFFAOYSA-N 0.000 claims 2
• 206010058019 Cancer Pain Diseases 0.000 claims 1
• 102000051628 Interleukin-1 receptor antagonist Human genes 0.000 claims 1
• 108700021006 Interleukin-1 receptor antagonist Proteins 0.000 claims 1
• 206010003246 arthritis Diseases 0.000 claims 1
• 229940054136 kineret Drugs 0.000 claims 1
• 239000000243 solution Substances 0.000 description 172
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• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 100
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 90
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 87
• 239000000543 intermediate Substances 0.000 description 76
• 239000011541 reaction mixture Substances 0.000 description 71
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• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 66
• 235000019439 ethyl acetate Nutrition 0.000 description 65
• 125000005843 halogen group Chemical group 0.000 description 63
• DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 63
• 239000003795 chemical substances by application Substances 0.000 description 62
• 239000007787 solid Substances 0.000 description 62
• 238000006243 chemical reaction Methods 0.000 description 54
• 239000002552 dosage form Substances 0.000 description 53
• 238000005160 1H NMR spectroscopy Methods 0.000 description 49
• 230000002829 reductive effect Effects 0.000 description 46
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 43
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 43
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 40
• 239000012044 organic layer Substances 0.000 description 38
• 238000002360 preparation method Methods 0.000 description 36
• 239000004480 active ingredient Substances 0.000 description 32
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 31
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 31
• 230000006870 function Effects 0.000 description 31
• 125000002887 hydroxy group Chemical group [H]O* 0.000 description 29
• 229910052799 carbon Inorganic materials 0.000 description 28
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 27
• 208000035475 disorder Diseases 0.000 description 27
• 238000002560 therapeutic procedure Methods 0.000 description 26
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 25
• 238000004587 chromatography analysis Methods 0.000 description 25
• 239000007788 liquid Substances 0.000 description 25
• 230000000069 prophylactic effect Effects 0.000 description 25
• 229910052938 sodium sulfate Inorganic materials 0.000 description 25
• 235000011152 sodium sulphate Nutrition 0.000 description 25
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 24
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 24
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 24
• 239000007832 Na2SO4 Substances 0.000 description 24
• 229940079593 drug Drugs 0.000 description 23
• 239000000047 product Substances 0.000 description 23
• 238000000746 purification Methods 0.000 description 23
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• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 22
• 239000000741 silica gel Substances 0.000 description 22
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• 229940124597 therapeutic agent Drugs 0.000 description 21
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 19
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
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• 230000000155 isotopic effect Effects 0.000 description 18
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• CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 16
• 125000000217 alkyl group Chemical group 0.000 description 16
• 238000010828 elution Methods 0.000 description 16
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• RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 16
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 14
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