AU2007292347A1 - Heteroaromatic compounds having sphingosine-1-phosphate (S1P) receptor agonist and/or antagonist biological activity - Google Patents

Info

Publication number

AU2007292347A1

AU2007292347A1 AU2007292347A AU2007292347A AU2007292347A1 AU 2007292347 A1 AU2007292347 A1 AU 2007292347A1 AU 2007292347 A AU2007292347 A AU 2007292347A AU 2007292347 A AU2007292347 A AU 2007292347A AU 2007292347 A1 AU2007292347 A1 AU 2007292347A1

Authority

AU

Australia

Prior art keywords

compound

mmol

group

phenyl

ethyl

Prior art date

2006-09-07

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.)

Abandoned

Links

• Espacenet
• Global Dossier
• Discuss

• DUYSYHSSBDVJSM-KRWOKUGFSA-N sphingosine 1-phosphate Chemical compound CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H](N)COP(O)(O)=O DUYSYHSSBDVJSM-KRWOKUGFSA-N 0.000 title description 20
• 230000004071 biological effect Effects 0.000 title description 5
• 229940044601 receptor agonist Drugs 0.000 title description 3
• 239000000018 receptor agonist Substances 0.000 title description 3
• 150000002390 heteroarenes Chemical class 0.000 title description 2
• 239000002464 receptor antagonist Substances 0.000 title description 2
• 229940044551 receptor antagonist Drugs 0.000 title description 2
• 150000001875 compounds Chemical class 0.000 claims description 164
• 125000000217 alkyl group Chemical group 0.000 claims description 34
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 29
• 229910052739 hydrogen Inorganic materials 0.000 claims description 29
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 27
• 125000003118 aryl group Chemical group 0.000 claims description 25
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 13
• 125000004432 carbon atom Chemical group C* 0.000 claims description 11
• 125000005843 halogen group Chemical group 0.000 claims description 11
• 125000004076 pyridyl group Chemical group 0.000 claims description 11
• 230000000694 effects Effects 0.000 claims description 9
• 125000001072 heteroaryl group Chemical group 0.000 claims description 9
• 229910052757 nitrogen Inorganic materials 0.000 claims description 9
• ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 claims description 8
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 8
• 125000002541 furyl group Chemical group 0.000 claims description 7
• 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 claims description 7
• 125000001544 thienyl group Chemical group 0.000 claims description 7
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
• 125000005907 alkyl ester group Chemical group 0.000 claims description 6
• 229910052799 carbon Inorganic materials 0.000 claims description 6
• 125000006413 ring segment Chemical group 0.000 claims description 6
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
• 125000005157 alkyl carboxy group Chemical group 0.000 claims description 4
• 150000005215 alkyl ethers Chemical class 0.000 claims description 4
• 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 4
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
• 102000005962 receptors Human genes 0.000 claims description 4
• 108020003175 receptors Proteins 0.000 claims description 4
• 239000005557 antagonist Substances 0.000 claims description 3
• 150000005840 aryl radicals Chemical class 0.000 claims description 3
• 150000003839 salts Chemical class 0.000 claims description 3
• 125000004414 alkyl thio group Chemical group 0.000 claims 3
• 108091008585 IP3 receptors Proteins 0.000 claims 1
• 102000007640 Inositol 1,4,5-Trisphosphate Receptors Human genes 0.000 claims 1
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 159
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 112
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 93
• 238000000034 method Methods 0.000 description 72
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 52
• 238000005481 NMR spectroscopy Methods 0.000 description 46
• 239000007787 solid Substances 0.000 description 46
• 239000000243 solution Substances 0.000 description 43
• 235000019439 ethyl acetate Nutrition 0.000 description 38
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 36
• 239000000203 mixture Substances 0.000 description 28
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 22
• 239000003921 oil Substances 0.000 description 22
• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 20
• 238000006243 chemical reaction Methods 0.000 description 19
• 239000000741 silica gel Substances 0.000 description 19
• 229910002027 silica gel Inorganic materials 0.000 description 19
• 238000004440 column chromatography Methods 0.000 description 18
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 17
• 210000004027 cell Anatomy 0.000 description 17
• -1 hydrocarbyl radical Chemical class 0.000 description 17
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
• 239000011734 sodium Substances 0.000 description 14
• 239000002904 solvent Substances 0.000 description 13
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
• 238000003820 Medium-pressure liquid chromatography Methods 0.000 description 11
• 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 11
• 239000012267 brine Substances 0.000 description 11
• 229940079593 drug Drugs 0.000 description 11
• 239000003814 drug Substances 0.000 description 11
• 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 11
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 11
• RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 11
• 229910052786 argon Inorganic materials 0.000 description 10
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
• 239000000047 product Substances 0.000 description 10
• UDJZTGMLYITLIQ-UHFFFAOYSA-N 1-ethenylpyrrolidine Chemical compound C=CN1CCCC1 UDJZTGMLYITLIQ-UHFFFAOYSA-N 0.000 description 9
• 208000004454 Hyperalgesia Diseases 0.000 description 9
• 241000700159 Rattus Species 0.000 description 9
• 229940127573 compound 38 Drugs 0.000 description 9
• PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 9
• 239000012044 organic layer Substances 0.000 description 9
• 150000003408 sphingolipids Chemical class 0.000 description 9
• 125000001424 substituent group Chemical group 0.000 description 9
• GSZQTIFGANBTNF-UHFFFAOYSA-N (3-aminopropyl)phosphonic acid Chemical compound NCCCP(O)(O)=O GSZQTIFGANBTNF-UHFFFAOYSA-N 0.000 description 8
• 238000005160 1H NMR spectroscopy Methods 0.000 description 8
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
• 229910052717 sulfur Inorganic materials 0.000 description 8
• IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 7
• XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 7
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
• 125000003545 alkoxy group Chemical group 0.000 description 7
• 210000004369 blood Anatomy 0.000 description 7
• 239000008280 blood Substances 0.000 description 7
• 229940125807 compound 37 Drugs 0.000 description 7
• 125000004093 cyano group Chemical group *C#N 0.000 description 7
• 125000002887 hydroxy group Chemical group [H]O* 0.000 description 7
• WWUZIQQURGPMPG-UHFFFAOYSA-N (-)-D-erythro-Sphingosine Natural products CCCCCCCCCCCCCC=CC(O)C(N)CO WWUZIQQURGPMPG-UHFFFAOYSA-N 0.000 description 6
• HEJNSWMMYRXBQA-UHFFFAOYSA-N 5-(4-ethylphenyl)-6-phenylpyridine-2-carbaldehyde Chemical compound C1=CC(CC)=CC=C1C1=CC=C(C=O)N=C1C1=CC=CC=C1 HEJNSWMMYRXBQA-UHFFFAOYSA-N 0.000 description 6
• 208000002193 Pain Diseases 0.000 description 6
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
• 125000003342 alkenyl group Chemical group 0.000 description 6
• 125000000304 alkynyl group Chemical group 0.000 description 6
• 125000001309 chloro group Chemical group Cl* 0.000 description 6
• 229940125773 compound 10 Drugs 0.000 description 6
• 229910052736 halogen Inorganic materials 0.000 description 6
• 150000002367 halogens Chemical class 0.000 description 6
• JYJVVHFRSFVEJM-UHFFFAOYSA-N iodosobenzene Chemical compound O=IC1=CC=CC=C1 JYJVVHFRSFVEJM-UHFFFAOYSA-N 0.000 description 6
• ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 6
• 230000004044 response Effects 0.000 description 6
• WWUZIQQURGPMPG-KRWOKUGFSA-N sphingosine Chemical compound CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H](N)CO WWUZIQQURGPMPG-KRWOKUGFSA-N 0.000 description 6
• UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 5
• JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 5
• XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 5
• 239000012981 Hank's balanced salt solution Substances 0.000 description 5
• 241001465754 Metazoa Species 0.000 description 5
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 5
• 125000002877 alkyl aryl group Chemical group 0.000 description 5
• 206010053552 allodynia Diseases 0.000 description 5
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• 239000000706 filtrate Substances 0.000 description 5
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• 239000001257 hydrogen Substances 0.000 description 5
• 125000004435 hydrogen atom Chemical group [H]* 0.000 description 5
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 5
• 229910000041 hydrogen chloride Inorganic materials 0.000 description 5
• 238000007912 intraperitoneal administration Methods 0.000 description 5
• 239000002207 metabolite Substances 0.000 description 5
• 229910052760 oxygen Inorganic materials 0.000 description 5
• 239000001301 oxygen Chemical group 0.000 description 5
• KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 5
• 150000003410 sphingosines Chemical class 0.000 description 5
• 239000000126 substance Substances 0.000 description 5
• 239000011593 sulfur Substances 0.000 description 5
• 238000001356 surgical procedure Methods 0.000 description 5
• 239000000725 suspension Substances 0.000 description 5
• 238000012360 testing method Methods 0.000 description 5
• CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Substances C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 5
• 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 5
• AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 4
• GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 4
• GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 4
• GCTFTMWXZFLTRR-GFCCVEGCSA-N (2r)-2-amino-n-[3-(difluoromethoxy)-4-(1,3-oxazol-5-yl)phenyl]-4-methylpentanamide Chemical compound FC(F)OC1=CC(NC(=O)[C@H](N)CC(C)C)=CC=C1C1=CN=CO1 GCTFTMWXZFLTRR-GFCCVEGCSA-N 0.000 description 4
• IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 4
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