TW201000099A - S1P1 receptor agonists and use thereof - Google Patents

Info

Publication number

TW201000099A

TW201000099A TW098119601A TW98119601A TW201000099A TW 201000099 A TW201000099 A TW 201000099A TW 098119601 A TW098119601 A TW 098119601A TW 98119601 A TW98119601 A TW 98119601A TW 201000099 A TW201000099 A TW 201000099A

Authority

TW

Taiwan

Prior art keywords

phenyl

fluoro

phenylcyclopropyl

thiazolo

group

Prior art date

2008-06-20

Links

• Espacenet
• Global Dossier
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• 102000011011 Sphingosine 1-phosphate receptors Human genes 0.000 title claims abstract description 18
• 108050001083 Sphingosine 1-phosphate receptors Proteins 0.000 title claims abstract description 18
• 229940044601 receptor agonist Drugs 0.000 title abstract description 7
• 239000000018 receptor agonist Substances 0.000 title abstract description 7
• 150000001875 compounds Chemical class 0.000 claims abstract description 189
• -1 heterocyclic amine Chemical class 0.000 claims description 445
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 351
• 125000000217 alkyl group Chemical group 0.000 claims description 192
• 201000006417 multiple sclerosis Diseases 0.000 claims description 131
• 239000000203 mixture Substances 0.000 claims description 128
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 123
• OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine group Chemical group NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 120
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 114
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 88
• 125000001188 haloalkyl group Chemical group 0.000 claims description 76
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 69
• 229920006395 saturated elastomer Polymers 0.000 claims description 68
• UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 61
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 60
• 229910052731 fluorine Inorganic materials 0.000 claims description 56
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 55
• 238000000034 method Methods 0.000 claims description 54
• 239000002253 acid Substances 0.000 claims description 51
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 49
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 46
• XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 44
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 40
• 125000003277 amino group Chemical group 0.000 claims description 33
• FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 31
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 29
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 29
• 125000005843 halogen group Chemical group 0.000 claims description 28
• 229910052739 hydrogen Inorganic materials 0.000 claims description 28
• 229910052757 nitrogen Inorganic materials 0.000 claims description 28
• 150000001412 amines Chemical class 0.000 claims description 27
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 27
• 125000004181 carboxyalkyl group Chemical group 0.000 claims description 26
• 239000007789 gas Substances 0.000 claims description 26
• 239000000460 chlorine Substances 0.000 claims description 25
• SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 24
• 229910052799 carbon Inorganic materials 0.000 claims description 24
• 125000001153 fluoro group Chemical group F* 0.000 claims description 24
• 150000003839 salts Chemical class 0.000 claims description 24
• 238000011282 treatment Methods 0.000 claims description 24
• 239000011734 sodium Substances 0.000 claims description 23
• 125000004432 carbon atom Chemical group C* 0.000 claims description 22
• 229910052801 chlorine Inorganic materials 0.000 claims description 22
• 235000019260 propionic acid Nutrition 0.000 claims description 20
• 125000000623 heterocyclic group Chemical group 0.000 claims description 19
• KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical group [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 18
• GFZWHAAOIVMHOI-UHFFFAOYSA-N azetidine-3-carboxylic acid Chemical compound OC(=O)C1CNC1 GFZWHAAOIVMHOI-UHFFFAOYSA-N 0.000 claims description 18
• IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 18
• 229910052707 ruthenium Inorganic materials 0.000 claims description 18
• 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 16
• 229910052708 sodium Inorganic materials 0.000 claims description 16
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 14
• 239000001257 hydrogen Substances 0.000 claims description 14
• 150000002923 oximes Chemical class 0.000 claims description 14
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 14
• 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 claims description 13
• 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims description 13
• FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 12
• WFIHKLWVLPBMIQ-UHFFFAOYSA-N [1,3]thiazolo[5,4-b]pyridine Chemical compound C1=CN=C2SC=NC2=C1 WFIHKLWVLPBMIQ-UHFFFAOYSA-N 0.000 claims description 12
• NIHNNTQXNPWCJQ-UHFFFAOYSA-N fluorene Chemical compound C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 claims description 12
• PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 12
• RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 12
• HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 claims description 11
• 150000001721 carbon Chemical group 0.000 claims description 11
• 125000005842 heteroatom Chemical group 0.000 claims description 10
• BBEAQIROQSPTKN-UHFFFAOYSA-N pyrene Chemical compound C1=CC=C2C=CC3=CC=CC4=CC=C1C2=C43 BBEAQIROQSPTKN-UHFFFAOYSA-N 0.000 claims description 10
• 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 9
• 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 9
• 229910052736 halogen Inorganic materials 0.000 claims description 9
• 150000002367 halogens Chemical class 0.000 claims description 9
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
• TXWOGHSRPAYOML-UHFFFAOYSA-N cyclobutanecarboxylic acid Chemical compound OC(=O)C1CCC1 TXWOGHSRPAYOML-UHFFFAOYSA-N 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 8
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
• 125000005113 hydroxyalkoxy group Chemical group 0.000 claims description 8
• 239000000126 substance Substances 0.000 claims description 8
• 125000004103 aminoalkyl group Chemical group 0.000 claims description 7
• 150000002431 hydrogen Chemical class 0.000 claims description 7
• 125000004011 3 membered carbocyclic group Chemical group 0.000 claims description 6
• 125000001845 4 membered carbocyclic group Chemical group 0.000 claims description 6
• 125000001054 5 membered carbocyclic group Chemical group 0.000 claims description 6
• 125000004008 6 membered carbocyclic group Chemical group 0.000 claims description 6
• 206010036790 Productive cough Diseases 0.000 claims description 6
• 125000005605 benzo group Chemical group 0.000 claims description 6
• 125000001072 heteroaryl group Chemical group 0.000 claims description 6
• 150000002576 ketones Chemical class 0.000 claims description 6
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
• 210000003802 sputum Anatomy 0.000 claims description 6
• 208000024794 sputum Diseases 0.000 claims description 6
• 125000000143 2-carboxyethyl group Chemical group [H]OC(=O)C([H])([H])C([H])([H])* 0.000 claims description 5
• 125000001960 7 membered carbocyclic group Chemical group 0.000 claims description 5
• KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 5
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 5
• GVEPBJHOBDJJJI-UHFFFAOYSA-N fluoranthrene Natural products C1=CC(C2=CC=CC=C22)=C3C2=CC=CC3=C1 GVEPBJHOBDJJJI-UHFFFAOYSA-N 0.000 claims description 5
• 238000004519 manufacturing process Methods 0.000 claims description 5
• IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 claims description 5
• 125000006327 phenyl hydrazinyl group Chemical group [H]N(*)N([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 5
• 150000001335 aliphatic alkanes Chemical class 0.000 claims description 4
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 4
• 229910052802 copper Inorganic materials 0.000 claims description 4
• 125000004663 dialkyl amino group Chemical group 0.000 claims description 4
• WJJMNDUMQPNECX-UHFFFAOYSA-N dipicolinic acid Chemical compound OC(=O)C1=CC=CC(C(O)=O)=N1 WJJMNDUMQPNECX-UHFFFAOYSA-N 0.000 claims description 4
• 210000002216 heart Anatomy 0.000 claims description 4
• 239000001301 oxygen Substances 0.000 claims description 4
• 229910052760 oxygen Inorganic materials 0.000 claims description 4
• BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
• 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 3
• 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims description 3
• YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 3
• 125000002431 aminoalkoxy group Chemical group 0.000 claims description 3
• 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 3
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
• 125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
• 150000007942 carboxylates Chemical class 0.000 claims description 3
• 125000001316 cycloalkyl alkyl group Chemical class 0.000 claims description 3
• 229910052805 deuterium Inorganic materials 0.000 claims description 3
• 239000002689 soil Substances 0.000 claims description 3
• PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical compound [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims description 3
• MWTKSCLVHADHHR-UHFFFAOYSA-N 5-(1-phenylcyclopropyl)-[1,3]thiazolo[5,4-b]pyridine Chemical compound C1CC1(C=1N=C2SC=NC2=CC=1)C1=CC=CC=C1 MWTKSCLVHADHHR-UHFFFAOYSA-N 0.000 claims description 2
• 125000004539 5-benzimidazolyl group Chemical group N1=CNC2=C1C=CC(=C2)* 0.000 claims description 2
• ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical compound N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 claims description 2
• 229930194542 Keto Natural products 0.000 claims description 2
• QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 2
• OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 2
• 125000003545 alkoxy group Chemical group 0.000 claims description 2
• 125000000524 functional group Chemical group 0.000 claims description 2
• 125000000468 ketone group Chemical group 0.000 claims description 2
• 229910052762 osmium Inorganic materials 0.000 claims description 2
• SYQBFIAQOQZEGI-UHFFFAOYSA-N osmium atom Chemical group [Os] SYQBFIAQOQZEGI-UHFFFAOYSA-N 0.000 claims description 2
• HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 claims description 2
• 229940067157 phenylhydrazine Drugs 0.000 claims description 2
• 125000004076 pyridyl group Chemical group 0.000 claims description 2
• QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims 6
• 229960005261 aspartic acid Drugs 0.000 claims 3
• WLAMNBDJUVNPJU-UHFFFAOYSA-N 2-methylbutyric acid Chemical compound CCC(C)C(O)=O WLAMNBDJUVNPJU-UHFFFAOYSA-N 0.000 claims 2
• UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 claims 2
• 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 2
• 125000001769 aryl amino group Chemical group 0.000 claims 2
• 125000004356 hydroxy functional group Chemical group O* 0.000 claims 2
• WYIVDYGTKGEJLC-UHFFFAOYSA-N 2,3-dioxobutanoic acid Chemical compound CC(=O)C(=O)C(O)=O WYIVDYGTKGEJLC-UHFFFAOYSA-N 0.000 claims 1
• YFZGXSSOURPKGL-UHFFFAOYSA-N 3-(azetidin-1-yl)propan-1-amine Chemical compound NCCCN1CCC1 YFZGXSSOURPKGL-UHFFFAOYSA-N 0.000 claims 1
• OSOQQWGQWAAXRR-UHFFFAOYSA-N 3-[[3-fluoro-4-[5-(1-phenylcyclopropyl)-[1,3]thiazolo[5,4-b]pyridin-2-yl]phenyl]methyl]cyclobutane-1,1-dicarboxylic acid Chemical compound C1C(C(=O)O)(C(O)=O)CC1CC(C=C1F)=CC=C1C1=NC2=CC=C(C3(CC3)C=3C=CC=CC=3)N=C2S1 OSOQQWGQWAAXRR-UHFFFAOYSA-N 0.000 claims 1
• ZLHUFFCLRCQOCD-UHFFFAOYSA-N 3-[[3-fluoro-4-[5-(1-phenylcyclopropyl)-[1,3]thiazolo[5,4-b]pyridin-2-yl]phenyl]methylamino]propanoic acid Chemical compound FC1=CC(CNCCC(=O)O)=CC=C1C1=NC2=CC=C(C3(CC3)C=3C=CC=CC=3)N=C2S1 ZLHUFFCLRCQOCD-UHFFFAOYSA-N 0.000 claims 1
• 125000004080 3-carboxypropanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C(O[H])=O 0.000 claims 1
• 125000006284 3-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(F)=C1[H])C([H])([H])* 0.000 claims 1
• GWRSATNRNFYMDI-UHFFFAOYSA-N 4-[(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-8h-pyrimido[4,5-b][1,4]diazepin-2-yl)amino]-2-fluoro-5-methoxy-n-(1-methylpiperidin-4-yl)benzamide Chemical compound FC=1C=C(NC=2N=C3N(C4CCCC4)CC(F)(F)C(=O)N(C)C3=CN=2)C(OC)=CC=1C(=O)NC1CCN(C)CC1 GWRSATNRNFYMDI-UHFFFAOYSA-N 0.000 claims 1
• OBKXEAXTFZPCHS-UHFFFAOYSA-N 4-phenylbutyric acid Chemical compound OC(=O)CCCC1=CC=CC=C1 OBKXEAXTFZPCHS-UHFFFAOYSA-N 0.000 claims 1
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• IRGIFSXKYPXSBD-UHFFFAOYSA-N [3-fluoro-4-[5-(1-phenylcyclopropyl)-[1,3]thiazolo[5,4-b]pyridin-2-yl]phenyl]-morpholin-4-ylmethanone Chemical compound FC1=CC(C(=O)N2CCOCC2)=CC=C1C(SC1=N2)=NC1=CC=C2C1(C=2C=CC=CC=2)CC1 IRGIFSXKYPXSBD-UHFFFAOYSA-N 0.000 claims 1
• 235000004279 alanine Nutrition 0.000 claims 1
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• 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
• 125000004475 heteroaralkyl group Chemical group 0.000 claims 1
• 125000004531 indol-5-yl group Chemical group [H]N1C([H])=C([H])C2=C([H])C(*)=C([H])C([H])=C12 0.000 claims 1
• GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims 1
• 230000001404 mediated effect Effects 0.000 claims 1
• HNQIVZYLYMDVSB-NJFSPNSNSA-N methanesulfonamide Chemical compound [14CH3]S(N)(=O)=O HNQIVZYLYMDVSB-NJFSPNSNSA-N 0.000 claims 1
• 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims 1
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• 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims 1
• 238000009738 saturating Methods 0.000 claims 1
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