LV11688B - Prodrugs of morpholine tachykinin receptor antagonists - Google Patents

Info

Publication number

LV11688B

LV11688B LVP-96-355A LV960355A LV11688B LV 11688 B LV11688 B LV 11688B LV 960355 A LV960355 A LV 960355A LV 11688 B LV11688 B LV 11688B

Authority

LV

Latvia

Prior art keywords

phenyl

already mentioned

methyl

morpholine

trifluoromethyl

Prior art date

1994-03-04

Links

• Espacenet
• Global Dossier
• Discuss

• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 title claims description 103
• 239000002462 tachykinin receptor antagonist Substances 0.000 title abstract description 14
• 229940002612 prodrug Drugs 0.000 title description 23
• 239000000651 prodrug Substances 0.000 title description 23
• 238000011282 treatment Methods 0.000 claims abstract description 53
• 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 25
• 208000019695 Migraine disease Diseases 0.000 claims abstract description 17
• 206010027599 migraine Diseases 0.000 claims abstract description 17
• 230000036407 pain Effects 0.000 claims abstract description 17
• 206010047700 Vomiting Diseases 0.000 claims abstract description 15
• 208000006673 asthma Diseases 0.000 claims abstract description 15
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 307
• 150000001875 compounds Chemical class 0.000 claims description 241
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 223
• -1 2-pyridinyl Chemical group 0.000 claims description 91
• 125000000217 alkyl group Chemical group 0.000 claims description 74
• 238000000034 method Methods 0.000 claims description 67
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 67
• 239000001257 hydrogen Substances 0.000 claims description 66
• 229910052739 hydrogen Inorganic materials 0.000 claims description 66
• 125000003545 alkoxy group Chemical group 0.000 claims description 64
• 125000001424 substituent group Chemical group 0.000 claims description 62
• 150000003839 salts Chemical class 0.000 claims description 53
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 52
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 52
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 47
• 125000005843 halogen group Chemical group 0.000 claims description 39
• 102100024304 Protachykinin-1 Human genes 0.000 claims description 33
• 150000002367 halogens Chemical class 0.000 claims description 31
• 229910052736 halogen Inorganic materials 0.000 claims description 30
• 239000003814 drug Substances 0.000 claims description 28
• QDZOEBFLNHCSSF-PFFBOGFISA-N (2S)-2-[[(2R)-2-[[(2S)-1-[(2S)-6-amino-2-[[(2S)-1-[(2R)-2-amino-5-carbamimidamidopentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-N-[(2R)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]pentanediamide Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](N)CCCNC(N)=N)C1=CC=CC=C1 QDZOEBFLNHCSSF-PFFBOGFISA-N 0.000 claims description 23
• 101800003906 Substance P Proteins 0.000 claims description 22
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 16
• 125000001153 fluoro group Chemical group F* 0.000 claims description 15
• 238000004519 manufacturing process Methods 0.000 claims description 15
• 208000033808 peripheral neuropathy Diseases 0.000 claims description 15
• 208000002193 Pain Diseases 0.000 claims description 14
• 125000003342 alkenyl group Chemical group 0.000 claims description 14
• 150000001768 cations Chemical class 0.000 claims description 14
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 13
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 12
• 230000002265 prevention Effects 0.000 claims description 12
• 239000003937 drug carrier Substances 0.000 claims description 11
• 230000000694 effects Effects 0.000 claims description 11
• 102000005962 receptors Human genes 0.000 claims description 11
• 125000001246 bromo group Chemical group Br* 0.000 claims description 10
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• 230000007823 neuropathy Effects 0.000 claims description 10
• 239000008194 pharmaceutical composition Substances 0.000 claims description 10
• 108020003175 receptors Proteins 0.000 claims description 10
• 241000124008 Mammalia Species 0.000 claims description 9
• 108010040718 Neurokinin-1 Receptors Proteins 0.000 claims description 9
• 125000002837 carbocyclic group Chemical group 0.000 claims description 9
• 102000002002 Neurokinin-1 Receptors Human genes 0.000 claims description 8
• 238000002512 chemotherapy Methods 0.000 claims description 8
• 125000002346 iodo group Chemical group I* 0.000 claims description 8
• 150000002431 hydrogen Chemical class 0.000 claims description 7
• 206010003246 arthritis Diseases 0.000 claims description 6
• 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 6
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
• 208000032131 Diabetic Neuropathies Diseases 0.000 claims description 5
• 125000002541 furyl group Chemical group 0.000 claims description 5
• 125000002883 imidazolyl group Chemical group 0.000 claims description 5
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
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• 125000003386 piperidinyl group Chemical group 0.000 claims description 5
• 125000004076 pyridyl group Chemical group 0.000 claims description 5
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 5
• 125000000168 pyrrolyl group Chemical group 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
• 230000003042 antagnostic effect Effects 0.000 claims description 4
• 239000000460 chlorine Substances 0.000 claims description 4
• 125000000464 thioxo group Chemical group S=* 0.000 claims description 4
• 208000030507 AIDS Diseases 0.000 claims description 3
• 229910052794 bromium Inorganic materials 0.000 claims description 3
• 230000008569 process Effects 0.000 claims description 3
• 238000011321 prophylaxis Methods 0.000 claims description 3
• 230000001629 suppression Effects 0.000 claims description 3
• 229910052727 yttrium Inorganic materials 0.000 claims description 3
• QQHOFZNACVKNHK-UHFFFAOYSA-N 3-amino-4-[[1-[[1-[[1-[[1-[[1-[(1,6-diamino-1-oxohexan-2-yl)amino]-3-(1h-indol-3-yl)-1-oxopropan-2-yl]amino]-3-(1h-indol-3-yl)-1-oxopropan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-3-(1h-indol-3-yl)-1-oxopropan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropa Chemical compound C=1NC2=CC=CC=C2C=1CC(C(=O)NC(CC=1C2=CC=CC=C2NC=1)C(=O)NC(CCCCN)C(N)=O)NC(=O)C(C(C)C)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(NC(=O)C(N)CC(O)=O)CC1=CC=C(O)C=C1 QQHOFZNACVKNHK-UHFFFAOYSA-N 0.000 claims description 2
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
• 229940088368 Neurokinin 2 receptor antagonist Drugs 0.000 claims description 2
• 230000000903 blocking effect Effects 0.000 claims description 2
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
• 239000003795 chemical substances by application Substances 0.000 claims description 2
• 229910052801 chlorine Inorganic materials 0.000 claims description 2
• 239000002746 neurokinin 2 receptor antagonist Substances 0.000 claims description 2
• 229910052760 oxygen Inorganic materials 0.000 claims description 2
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 27
• 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims 8
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 8
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims 7
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 4
• LDDMACCNBZAMSG-BDVNFPICSA-N (2r,3r,4s,5r)-3,4,5,6-tetrahydroxy-2-(methylamino)hexanal Chemical compound CN[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO LDDMACCNBZAMSG-BDVNFPICSA-N 0.000 claims 2
• KPCZJLGGXRGYIE-UHFFFAOYSA-N [C]1=CC=CN=C1 Chemical group [C]1=CC=CN=C1 KPCZJLGGXRGYIE-UHFFFAOYSA-N 0.000 claims 2
• PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims 2
• OBSLWIKITOYASJ-YDEIVXIUSA-N (3r,4r,5s,6r)-6-(hydroxymethyl)-3-(methylamino)oxane-2,4,5-triol Chemical class CN[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O OBSLWIKITOYASJ-YDEIVXIUSA-N 0.000 claims 1
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 1
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 1
• 229940082496 Adrenoreceptor antagonist Drugs 0.000 claims 1
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 1
• 229910052731 fluorine Inorganic materials 0.000 claims 1
• 239000011737 fluorine Substances 0.000 claims 1
• 239000002504 physiological saline solution Substances 0.000 claims 1
• 230000008673 vomiting Effects 0.000 claims 1
• 208000027866 inflammatory disease Diseases 0.000 abstract description 6
• 230000008693 nausea Effects 0.000 abstract description 5
• 206010065390 Inflammatory pain Diseases 0.000 abstract description 4
• 206010028813 Nausea Diseases 0.000 abstract description 4
• SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 469
• 229940113083 morpholine Drugs 0.000 description 372
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 204
• 239000000243 solution Substances 0.000 description 201
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 198
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 148
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 142
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 134
• 239000000203 mixture Substances 0.000 description 115
• FHQRDEDZJIFJAL-UHFFFAOYSA-N 4-phenylmorpholine Chemical compound C1COCCN1C1=CC=CC=C1 FHQRDEDZJIFJAL-UHFFFAOYSA-N 0.000 description 101
• 238000005481 NMR spectroscopy Methods 0.000 description 97
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 74
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• 235000019439 ethyl acetate Nutrition 0.000 description 73
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 72
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 68
• 235000002639 sodium chloride Nutrition 0.000 description 62
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