OA12760A - Metabolites of (3-ÄÄ4-tert-butyl-benzyl)-(pyridine-3-sulfonyl)-aminoÜ-methylÜ-phenoxy)-acetic acid. - Google Patents

Info

Publication number

OA12760A

OA12760A OA1200400198A OA1200400198A OA12760A OA 12760 A OA12760 A OA 12760A OA 1200400198 A OA1200400198 A OA 1200400198A OA 1200400198 A OA1200400198 A OA 1200400198A OA 12760 A OA12760 A OA 12760A

Authority

OA

OAPI

Prior art keywords

methyl

pyridine

sulfonyl

benzyl

amino

Prior art date

2002-01-31

Links

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• QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 title claims abstract description 130
• 239000002207 metabolite Substances 0.000 title abstract description 8
• 150000001875 compounds Chemical class 0.000 claims description 170
• -1 hydroxy-phenoxy Chemical group 0.000 claims description 36
• QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 32
• 238000000034 method Methods 0.000 claims description 21
• 210000000941 bile Anatomy 0.000 claims description 19
• 210000002700 urine Anatomy 0.000 claims description 18
• 208000001132 Osteoporosis Diseases 0.000 claims description 16
• 239000002253 acid Substances 0.000 claims description 13
• 229930182480 glucuronide Natural products 0.000 claims description 11
• 230000035876 healing Effects 0.000 claims description 11
• XKQNMAZMTKTTIA-UHFFFAOYSA-N 2-[3-[[[4-(1-hydroxy-2-methylpropan-2-yl)phenyl]methyl-pyridin-3-ylsulfonylamino]methyl]phenoxy]acetic acid Chemical compound C1=CC(C(C)(CO)C)=CC=C1CN(S(=O)(=O)C=1C=NC=CC=1)CC1=CC=CC(OCC(O)=O)=C1 XKQNMAZMTKTTIA-UHFFFAOYSA-N 0.000 claims description 8
• 230000002550 fecal effect Effects 0.000 claims description 8
• HJFXNHIJZXNYSB-UHFFFAOYSA-N n-[[4-(1-hydroxy-2-methylpropan-2-yl)phenyl]methyl]pyridine-3-sulfonamide Chemical compound C1=CC(C(C)(CO)C)=CC=C1CNS(=O)(=O)C1=CC=CN=C1 HJFXNHIJZXNYSB-UHFFFAOYSA-N 0.000 claims description 8
• RHSCSNLXWMXZJZ-UHFFFAOYSA-N 2-[4-(aminomethyl)phenyl]-2-methylpropan-1-ol Chemical compound CC(C)(CO)C1=CC=C(CN)C=C1 RHSCSNLXWMXZJZ-UHFFFAOYSA-N 0.000 claims description 7
• 208000010392 Bone Fractures Diseases 0.000 claims description 7
• XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 7
• 239000008194 pharmaceutical composition Substances 0.000 claims description 7
• PAQVSTUVBKFCSE-UHFFFAOYSA-N 2-[3-[[(4-prop-1-en-2-ylphenyl)methyl-pyridin-3-ylsulfonylamino]methyl]phenoxy]acetic acid Chemical compound C1=CC(C(=C)C)=CC=C1CN(S(=O)(=O)C=1C=NC=CC=1)CC1=CC=CC(OCC(O)=O)=C1 PAQVSTUVBKFCSE-UHFFFAOYSA-N 0.000 claims description 6
• 210000002381 plasma Anatomy 0.000 claims description 6
• 229940095574 propionic acid Drugs 0.000 claims description 6
• PUZBOEISUBJHKQ-UHFFFAOYSA-N 2-[3-[[[4-(1,2-dihydroxypropan-2-yl)phenyl]methyl-pyridin-3-ylsulfonylamino]methyl]phenoxy]acetic acid Chemical compound C1=CC(C(O)(CO)C)=CC=C1CN(S(=O)(=O)C=1C=NC=CC=1)CC1=CC=CC(OCC(O)=O)=C1 PUZBOEISUBJHKQ-UHFFFAOYSA-N 0.000 claims description 5
• JOJLHDZTZBZWSZ-UHFFFAOYSA-N 2-[4-[[[3-(carboxymethoxy)phenyl]methyl-pyridin-3-ylsulfonylamino]methyl]phenyl]-2-methylpropanoic acid Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1CN(S(=O)(=O)C=1C=NC=CC=1)CC1=CC=CC(OCC(O)=O)=C1 JOJLHDZTZBZWSZ-UHFFFAOYSA-N 0.000 claims description 5
• PNCHTNBMWFKGKF-UHFFFAOYSA-N 2-[5-[[(4-tert-butylphenyl)methyl-pyridin-3-ylsulfonylamino]methyl]-2-hydroxyphenoxy]acetic acid Chemical compound C1=CC(C(C)(C)C)=CC=C1CN(S(=O)(=O)C=1C=NC=CC=1)CC1=CC=C(O)C(OCC(O)=O)=C1 PNCHTNBMWFKGKF-UHFFFAOYSA-N 0.000 claims description 5
• SKMRHCOWINZBQG-UHFFFAOYSA-N 2-methyl-2-[4-[(pyridin-3-ylsulfonylamino)methyl]phenyl]propanoic acid Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1CNS(=O)(=O)C1=CC=CN=C1 SKMRHCOWINZBQG-UHFFFAOYSA-N 0.000 claims description 4
• 238000004519 manufacturing process Methods 0.000 claims description 4
• QCKBNFRFJGPPNF-UHFFFAOYSA-N 2-[3-[[[4-(2-hydroxypropan-2-yl)phenyl]methyl-pyridin-3-ylsulfonylamino]methyl]phenoxy]acetic acid Chemical compound C1=CC(C(C)(O)C)=CC=C1CN(S(=O)(=O)C=1C=NC=CC=1)CC1=CC=CC(OCC(O)=O)=C1 QCKBNFRFJGPPNF-UHFFFAOYSA-N 0.000 claims description 3
• JEUHKODDXNRYIK-UHFFFAOYSA-N 2-[3-[[[4-(2-methyl-1-oxopropan-2-yl)phenyl]methyl-pyridin-3-ylsulfonylamino]methyl]phenoxy]acetic acid Chemical compound C1=CC(C(C)(C=O)C)=CC=C1CN(S(=O)(=O)C=1C=NC=CC=1)CC1=CC=CC(OCC(O)=O)=C1 JEUHKODDXNRYIK-UHFFFAOYSA-N 0.000 claims description 3
• 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 3
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 3
• 125000003352 4-tert-butyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])*)C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
• 125000006296 sulfonyl amino group Chemical group [H]N(*)S(*)(=O)=O 0.000 claims 1
• 150000002500 ions Chemical class 0.000 description 146
• 229960000583 acetic acid Drugs 0.000 description 103
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 50
• 238000001360 collision-induced dissociation Methods 0.000 description 45
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 44
• 239000000047 product Substances 0.000 description 43
• 238000001228 spectrum Methods 0.000 description 40
• 238000004128 high performance liquid chromatography Methods 0.000 description 39
• 239000000243 solution Substances 0.000 description 36
• 150000001793 charged compounds Chemical class 0.000 description 34
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 33
• 125000000217 alkyl group Chemical group 0.000 description 33
• 241000700159 Rattus Species 0.000 description 28
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 23
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• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
• 239000000556 agonist Substances 0.000 description 22
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• 239000000203 mixture Substances 0.000 description 20
• 229940011871 estrogen Drugs 0.000 description 19
• 239000000262 estrogen Substances 0.000 description 19
• 239000000651 prodrug Substances 0.000 description 19
• 229940002612 prodrug Drugs 0.000 description 19
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
• 239000005557 antagonist Substances 0.000 description 18
• 125000002887 hydroxy group Chemical group [H]O* 0.000 description 18
• 238000006243 chemical reaction Methods 0.000 description 17
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 16
• 239000002775 capsule Substances 0.000 description 16
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 16
• PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical compound [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 description 16
• 239000002904 solvent Substances 0.000 description 16
• SXERGJJQSKIUIC-UHFFFAOYSA-N 2-Phenoxypropionic acid Chemical group OC(=O)C(C)OC1=CC=CC=C1 SXERGJJQSKIUIC-UHFFFAOYSA-N 0.000 description 15
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 15
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• 210000001853 liver microsome Anatomy 0.000 description 14
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 14
• 238000004587 chromatography analysis Methods 0.000 description 13
• 230000000694 effects Effects 0.000 description 13
• 238000011534 incubation Methods 0.000 description 13
• 238000005160 1H NMR spectroscopy Methods 0.000 description 12
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
• QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 12
• 150000003839 salts Chemical class 0.000 description 12
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 12
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
• 239000007864 aqueous solution Substances 0.000 description 11
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
• 150000001732 carboxylic acid derivatives Chemical group 0.000 description 10
• 238000013467 fragmentation Methods 0.000 description 10
• 238000006062 fragmentation reaction Methods 0.000 description 10
• 125000004435 hydrogen atom Chemical class [H]* 0.000 description 10
• 239000012528 membrane Substances 0.000 description 10
• 230000011164 ossification Effects 0.000 description 10
• 238000007254 oxidation reaction Methods 0.000 description 10
• 125000006488 t-butyl benzyl group Chemical group 0.000 description 10
• 238000004458 analytical method Methods 0.000 description 9
• 239000003085 diluting agent Substances 0.000 description 9
• 210000003608 fece Anatomy 0.000 description 9
• 230000003647 oxidation Effects 0.000 description 9
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 9
• 102000005962 receptors Human genes 0.000 description 9
• 108020003175 receptors Proteins 0.000 description 9
• 239000000126 substance Substances 0.000 description 9
• OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 8
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 8
• 125000004432 carbon atom Chemical group C* 0.000 description 8
• 235000019253 formic acid Nutrition 0.000 description 8
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• 229910052943 magnesium sulfate Inorganic materials 0.000 description 8
• 235000019341 magnesium sulphate Nutrition 0.000 description 8
• 235000012054 meals Nutrition 0.000 description 8
• 239000003921 oil Substances 0.000 description 8
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• 239000001301 oxygen Substances 0.000 description 8
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• 239000000523 sample Substances 0.000 description 8
• 239000011775 sodium fluoride Substances 0.000 description 8
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• 241001465754 Metazoa Species 0.000 description 7
• 150000001204 N-oxides Chemical class 0.000 description 7
• 125000004423 acyloxy group Chemical group 0.000 description 7
• 125000004429 atom Chemical group 0.000 description 7
• 125000004093 cyano group Chemical class *C#N 0.000 description 7
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• LCPDWSOZIOUXRV-UHFFFAOYSA-N phenoxyacetic acid Chemical group OC(=O)COC1=CC=CC=C1 LCPDWSOZIOUXRV-UHFFFAOYSA-N 0.000 description 7
• 238000000746 purification Methods 0.000 description 7
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• 125000001424 substituent group Chemical group 0.000 description 7
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