JP2013521301A5 - - Google Patents

Info

Publication number

JP2013521301A5

JP2013521301A5 JP2012556199A JP2012556199A JP2013521301A5 JP 2013521301 A5 JP2013521301 A5 JP 2013521301A5 JP 2012556199 A JP2012556199 A JP 2012556199A JP 2012556199 A JP2012556199 A JP 2012556199A JP 2013521301 A5 JP2013521301 A5 JP 2013521301A5

Authority

JP

Japan

Prior art keywords

salt

trifluoromethyl

isopropoxy

pyrrolo

dihydro

Prior art date

2011-03-02

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
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• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 72
• 150000003839 salts Chemical class 0.000 claims description 70
• 238000000034 method Methods 0.000 claims description 48
• -1 4-isopropoxy-3- (trifluoromethyl) benzyloxy Chemical group 0.000 claims description 33
• 239000002904 solvent Substances 0.000 claims description 30
• 150000001875 compounds Chemical class 0.000 claims description 24
• 125000000593 indol-1-yl group Chemical group [H]C1=C([H])C([H])=C2N([*])C([H])=C([H])C2=C1[H] 0.000 claims description 18
• 239000000203 mixture Substances 0.000 claims description 17
• 230000007062 hydrolysis Effects 0.000 claims description 15
• 238000006460 hydrolysis reaction Methods 0.000 claims description 15
• 102000011011 Sphingosine 1-phosphate receptors Human genes 0.000 claims description 14
• 108050001083 Sphingosine 1-phosphate receptors Proteins 0.000 claims description 14
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 14
• 208000035475 disorder Diseases 0.000 claims description 14
• 238000013213 extrapolation Methods 0.000 claims description 14
• 238000004519 manufacturing process Methods 0.000 claims description 14
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
• 150000008545 L-lysines Chemical class 0.000 claims description 12
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
• 238000000113 differential scanning calorimetry Methods 0.000 claims description 12
• 238000001757 thermogravimetry curve Methods 0.000 claims description 12
• KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 11
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
• 125000000217 alkyl group Chemical group 0.000 claims description 8
• 239000000843 powder Substances 0.000 claims description 8
• 239000013078 crystal Substances 0.000 claims description 7
• RLGFHVZCVPTTLP-OAHLLOKOSA-N 2-[(3r)-4-chloro-6-[[4-propan-2-yloxy-3-(trifluoromethyl)phenyl]methoxy]-2,3-dihydro-1h-pyrrolo[1,2-a]indol-3-yl]acetic acid Chemical compound C1=C(C(F)(F)F)C(OC(C)C)=CC=C1COC1=CC=C(N2C([C@@H](CC(O)=O)CC2)=C2Cl)C2=C1 RLGFHVZCVPTTLP-OAHLLOKOSA-N 0.000 claims description 6
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
• 238000005660 chlorination reaction Methods 0.000 claims description 6
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
• 230000004580 weight loss Effects 0.000 claims description 6
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 5
• 201000006417 multiple sclerosis Diseases 0.000 claims description 5
• FMRZLMJTOCTKPU-UHFFFAOYSA-N 4-propan-2-yloxy-3-(trifluoromethyl)benzoic acid Chemical compound CC(C)OC1=CC=C(C(O)=O)C=C1C(F)(F)F FMRZLMJTOCTKPU-UHFFFAOYSA-N 0.000 claims description 4
• RNCVVXUSWKAGEL-UHFFFAOYSA-N 4-propan-2-yloxy-3-(trifluoromethyl)benzonitrile Chemical compound CC(C)OC1=CC=C(C#N)C=C1C(F)(F)F RNCVVXUSWKAGEL-UHFFFAOYSA-N 0.000 claims description 4
• 235000019766 L-Lysine Nutrition 0.000 claims description 4
• 239000004472 Lysine Substances 0.000 claims description 4
• 238000002441 X-ray diffraction Methods 0.000 claims description 4
• BOYONATXSZSGEJ-UHFFFAOYSA-N [4-propan-2-yloxy-3-(trifluoromethyl)phenyl]methanol Chemical compound CC(C)OC1=CC=C(CO)C=C1C(F)(F)F BOYONATXSZSGEJ-UHFFFAOYSA-N 0.000 claims description 4
• 239000003795 chemical substances by application Substances 0.000 claims description 4
• 239000003814 drug Substances 0.000 claims description 4
• 239000003937 drug carrier Substances 0.000 claims description 4
• XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 4
• 238000002955 isolation Methods 0.000 claims description 4
• 238000002411 thermogravimetry Methods 0.000 claims description 4
• FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical group ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 4
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
• NGMORLNIWOFWIA-WZNJZOFCSA-N 2-[(3r)-4-chloro-6-[[4-propan-2-yloxy-3-(trifluoromethyl)phenyl]methoxy]-2,3-dihydro-1h-pyrrolo[1,2-a]indol-3-yl]acetic acid;(2s)-2,6-diaminohexanoic acid Chemical compound NCCCC[C@H](N)C(O)=O.C1=C(C(F)(F)F)C(OC(C)C)=CC=C1COC1=CC=C(N2C([C@@H](CC(O)=O)CC2)=C2Cl)C2=C1 NGMORLNIWOFWIA-WZNJZOFCSA-N 0.000 claims description 3
• 208000002874 Acne Vulgaris Diseases 0.000 claims description 3
• 208000008439 Biliary Liver Cirrhosis Diseases 0.000 claims description 3
• 206010004659 Biliary cirrhosis Diseases 0.000 claims description 3
• 206010009900 Colitis ulcerative Diseases 0.000 claims description 3
• 208000011231 Crohn disease Diseases 0.000 claims description 3
• 208000007882 Gastritis Diseases 0.000 claims description 3
• 201000004681 Psoriasis Diseases 0.000 claims description 3
• 206010052779 Transplant rejections Diseases 0.000 claims description 3
• 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 3
• 201000006704 Ulcerative Colitis Diseases 0.000 claims description 3
• 206010047642 Vitiligo Diseases 0.000 claims description 3
• 206010000496 acne Diseases 0.000 claims description 3
• 206010061989 glomerulosclerosis Diseases 0.000 claims description 3
• 208000006454 hepatitis Diseases 0.000 claims description 3
• 231100000283 hepatitis Toxicity 0.000 claims description 3
• 208000031225 myocardial ischemia Diseases 0.000 claims description 3
• 208000005987 polymyositis Diseases 0.000 claims description 3
• 206010039073 rheumatoid arthritis Diseases 0.000 claims description 3
• 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 3
• 206010043778 thyroiditis Diseases 0.000 claims description 3
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
• JTLOHHFDFSRMRS-UHFFFAOYSA-N 1-(chloromethyl)-3-propan-2-yloxy-2-(trifluoromethyl)benzene Chemical compound CC(C)OC1=CC=CC(CCl)=C1C(F)(F)F JTLOHHFDFSRMRS-UHFFFAOYSA-N 0.000 claims description 2
• FMYJSEMKYVIQCF-QCUBGVIVSA-N 2-[(3R)-4-chloro-6-[[4-propan-2-yloxy-3-(trifluoromethyl)phenyl]methoxy]-2,3-dihydro-1H-pyrrolo[1,2-a]indol-3-yl]acetic acid ethane-1,2-diamine hydrate Chemical compound O.NCCN.C1=C(C(F)(F)F)C(OC(C)C)=CC=C1COC1=CC=C(N2C([C@@H](CC(O)=O)CC2)=C2Cl)C2=C1 FMYJSEMKYVIQCF-QCUBGVIVSA-N 0.000 claims description 2
• PNIZRKMCXPNJFR-FRRIPSOJSA-N 2-[(3r)-4-chloro-6-[[4-propan-2-yloxy-3-(trifluoromethyl)phenyl]methoxy]-2,3-dihydro-1h-pyrrolo[1,2-a]indol-3-yl]acetic acid;(2r,3r,4r,5s)-6-(methylamino)hexane-1,2,3,4,5-pentol Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.C1=C(C(F)(F)F)C(OC(C)C)=CC=C1COC1=CC=C(N2C([C@@H](CC(O)=O)CC2)=C2Cl)C2=C1 PNIZRKMCXPNJFR-FRRIPSOJSA-N 0.000 claims description 2
• XLLSQMOGHKEOOC-XFULWGLBSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;2-[(3r)-4-chloro-6-[[4-propan-2-yloxy-3-(trifluoromethyl)phenyl]methoxy]-2,3-dihydro-1h-pyrrolo[1,2-a]indol-3-yl]acetic acid Chemical compound OCC(N)(CO)CO.C1=C(C(F)(F)F)C(OC(C)C)=CC=C1COC1=CC=C(N2C([C@@H](CC(O)=O)CC2)=C2Cl)C2=C1 XLLSQMOGHKEOOC-XFULWGLBSA-N 0.000 claims description 2
• SKOIWBPVBTURJZ-UHFFFAOYSA-N 4-(chloromethyl)-1-propan-2-yloxy-2-(trifluoromethyl)benzene Chemical compound CC(C)OC1=CC=C(CCl)C=C1C(F)(F)F SKOIWBPVBTURJZ-UHFFFAOYSA-N 0.000 claims description 2
• CQZQCORFYSSCFY-UHFFFAOYSA-N 4-fluoro-3-(trifluoromethyl)benzonitrile Chemical compound FC1=CC=C(C#N)C=C1C(F)(F)F CQZQCORFYSSCFY-UHFFFAOYSA-N 0.000 claims description 2
• QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
• GAAPGHJWCBEJEH-HGPPLOODSA-N C(C)(=O)O.ClC1=C2N(C=3C=CC(=CC13)OCC1=CC(=C(C=C1)OC(C)C)C(F)(F)F)CCC2[C@](N)(CCCNC(N)=N)C(=O)O Chemical compound C(C)(=O)O.ClC1=C2N(C=3C=CC(=CC13)OCC1=CC(=C(C=C1)OC(C)C)C(F)(F)F)CCC2[C@](N)(CCCNC(N)=N)C(=O)O GAAPGHJWCBEJEH-HGPPLOODSA-N 0.000 claims description 2
• 206010063837 Reperfusion injury Diseases 0.000 claims description 2
• RRNJROHIFSLGRA-JEDNCBNOSA-N acetic acid;(2s)-2,6-diaminohexanoic acid Chemical compound CC(O)=O.NCCCC[C@H](N)C(O)=O RRNJROHIFSLGRA-JEDNCBNOSA-N 0.000 claims description 2
• 208000033017 acquired idiopathic inflammatory myopathy Diseases 0.000 claims description 2
• VSGNNIFQASZAOI-UHFFFAOYSA-L calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 claims description 2
• 239000001639 calcium acetate Substances 0.000 claims description 2
• 235000011092 calcium acetate Nutrition 0.000 claims description 2
• 229960005147 calcium acetate Drugs 0.000 claims description 2
• 239000003638 chemical reducing agent Substances 0.000 claims description 2
• 239000012320 chlorinating reagent Substances 0.000 claims description 2
• LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
• 238000002560 therapeutic procedure Methods 0.000 claims description 2
• 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 claims 2
• 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims 2
• 206010055171 Hypertensive nephropathy Diseases 0.000 claims 2
• 125000003545 alkoxy group Chemical group 0.000 claims 2
• 229910052736 halogen Inorganic materials 0.000 claims 2
• 150000002367 halogens Chemical class 0.000 claims 2
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 2
• 208000027418 Wounds and injury Diseases 0.000 claims 1
• 230000006378 damage Effects 0.000 claims 1
• 230000001747 exhibiting effect Effects 0.000 claims 1
• 208000014674 injury Diseases 0.000 claims 1
• UEGPKNKPLBYCNK-UHFFFAOYSA-L magnesium acetate Chemical compound [Mg+2].CC([O-])=O.CC([O-])=O UEGPKNKPLBYCNK-UHFFFAOYSA-L 0.000 claims 1
• 239000011654 magnesium acetate Substances 0.000 claims 1
• 229940069446 magnesium acetate Drugs 0.000 claims 1
• 235000011285 magnesium acetate Nutrition 0.000 claims 1
• 230000010412 perfusion Effects 0.000 claims 1
• MJTTXFOUOIHRKO-XFULWGLBSA-M potassium;2-[(3r)-4-chloro-6-[[4-propan-2-yloxy-3-(trifluoromethyl)phenyl]methoxy]-2,3-dihydro-1h-pyrrolo[1,2-a]indol-3-yl]acetate Chemical compound [K+].C1=C(C(F)(F)F)C(OC(C)C)=CC=C1COC1=CC=C(N2C([C@@H](CC([O-])=O)CC2)=C2Cl)C2=C1 MJTTXFOUOIHRKO-XFULWGLBSA-M 0.000 claims 1
• 125000003944 tolyl group Chemical group 0.000 claims 1
• LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical class OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims 1
• 239000008194 pharmaceutical composition Substances 0.000 description 4
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
• 229960003646 lysine Drugs 0.000 description 2
• 206010020772 Hypertension Diseases 0.000 description 1
• 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
• 208000017169 kidney disease Diseases 0.000 description 1
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1