JP2010519299A - ムスカリン受容体アンタゴニストとして有用な第四級アンモニウムジフェニルメチル化合物 - Google Patents
ムスカリン受容体アンタゴニストとして有用な第四級アンモニウムジフェニルメチル化合物 Download PDFInfo
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- JP2010519299A JP2010519299A JP2009550918A JP2009550918A JP2010519299A JP 2010519299 A JP2010519299 A JP 2010519299A JP 2009550918 A JP2009550918 A JP 2009550918A JP 2009550918 A JP2009550918 A JP 2009550918A JP 2010519299 A JP2010519299 A JP 2010519299A
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- Prior art keywords
- alkyl
- compound
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- alkylene
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- Prior art date
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- 229940121948 Muscarinic receptor antagonist Drugs 0.000 title abstract description 29
- 150000001875 compounds Chemical class 0.000 claims abstract description 383
- 238000000034 method Methods 0.000 claims abstract description 81
- 150000003839 salts Chemical group 0.000 claims abstract description 32
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 31
- 230000008569 process Effects 0.000 claims abstract description 30
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims abstract description 19
- 208000019693 Lung disease Diseases 0.000 claims abstract description 15
- 208000006673 asthma Diseases 0.000 claims abstract description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 197
- 239000000203 mixture Substances 0.000 claims description 132
- -1 —C 3-6 cycloalkyl Chemical group 0.000 claims description 81
- 239000003814 drug Substances 0.000 claims description 50
- 125000002947 alkylene group Chemical group 0.000 claims description 48
- 229910052739 hydrogen Inorganic materials 0.000 claims description 44
- 239000001257 hydrogen Substances 0.000 claims description 41
- 102000014415 Muscarinic acetylcholine receptor Human genes 0.000 claims description 39
- 108050003473 Muscarinic acetylcholine receptor Proteins 0.000 claims description 39
- 125000000304 alkynyl group Chemical group 0.000 claims description 39
- 125000003342 alkenyl group Chemical group 0.000 claims description 37
- 125000001153 fluoro group Chemical group F* 0.000 claims description 34
- 229940079593 drug Drugs 0.000 claims description 33
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 31
- 239000002253 acid Substances 0.000 claims description 26
- 125000005843 halogen group Chemical group 0.000 claims description 25
- 125000000623 heterocyclic group Chemical group 0.000 claims description 25
- 238000011282 treatment Methods 0.000 claims description 24
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 23
- 125000001424 substituent group Chemical group 0.000 claims description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 20
- 125000003118 aryl group Chemical group 0.000 claims description 20
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 19
- 229910052757 nitrogen Inorganic materials 0.000 claims description 19
- 239000000048 adrenergic agonist Substances 0.000 claims description 14
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 14
- 239000003937 drug carrier Substances 0.000 claims description 14
- 125000001072 heteroaryl group Chemical group 0.000 claims description 14
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- 229940124597 therapeutic agent Drugs 0.000 claims description 13
- 229940126157 adrenergic receptor agonist Drugs 0.000 claims description 11
- 125000005842 heteroatom Chemical group 0.000 claims description 11
- 229940124599 anti-inflammatory drug Drugs 0.000 claims description 10
- 150000001450 anions Chemical group 0.000 claims description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 claims description 9
- 238000011160 research Methods 0.000 claims description 9
- 230000003637 steroidlike Effects 0.000 claims description 9
- 230000003042 antagnostic effect Effects 0.000 claims description 8
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical group OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 8
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical group I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 8
- 239000000758 substrate Substances 0.000 claims description 8
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical group [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 7
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical group CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 6
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical group OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical group CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 239000001301 oxygen Substances 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- 239000011593 sulfur Substances 0.000 claims description 6
- SJJCQDRGABAVBB-UHFFFAOYSA-N 1-hydroxy-2-naphthoic acid Chemical group C1=CC=CC2=C(O)C(C(=O)O)=CC=C21 SJJCQDRGABAVBB-UHFFFAOYSA-N 0.000 claims description 5
- 210000000621 bronchi Anatomy 0.000 claims description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical group [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 4
- 230000000916 dilatatory effect Effects 0.000 claims description 4
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical group OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Chemical group OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical group CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical group [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical group [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 3
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical group CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 claims description 3
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 3
- 150000002431 hydrogen Chemical group 0.000 claims description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical group OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 3
- PYHXGXCGESYPCW-UHFFFAOYSA-M 2,2-diphenylacetate Chemical group C=1C=CC=CC=1C(C(=O)[O-])C1=CC=CC=C1 PYHXGXCGESYPCW-UHFFFAOYSA-M 0.000 claims description 2
- ALKYHXVLJMQRLQ-UHFFFAOYSA-M 3-carboxynaphthalen-2-olate Chemical group C1=CC=C2C=C(C([O-])=O)C(O)=CC2=C1 ALKYHXVLJMQRLQ-UHFFFAOYSA-M 0.000 claims description 2
- XRHGYUZYPHTUJZ-UHFFFAOYSA-M 4-chlorobenzoate Chemical group [O-]C(=O)C1=CC=C(Cl)C=C1 XRHGYUZYPHTUJZ-UHFFFAOYSA-M 0.000 claims description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-M 4-hydroxybenzoate Chemical group OC1=CC=C(C([O-])=O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-M 0.000 claims description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical group CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 claims description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical group [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 claims description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical group [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 claims description 2
- 229910002651 NO3 Inorganic materials 0.000 claims description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical group [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical group CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical group [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- 229940077388 benzenesulfonate Drugs 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical group [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 claims description 2
- 229940049920 malate Drugs 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical group [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000010452 phosphate Chemical group 0.000 claims description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical group OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical group [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 2
- 229940095064 tartrate Drugs 0.000 claims description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 claims 1
- 150000001649 bromium compounds Chemical group 0.000 claims 1
- 238000003556 assay Methods 0.000 description 74
- 238000012360 testing method Methods 0.000 description 45
- 230000000694 effects Effects 0.000 description 36
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- 238000006243 chemical reaction Methods 0.000 description 33
- 239000003795 chemical substances by application Substances 0.000 description 32
- 239000002904 solvent Substances 0.000 description 31
- 102000005962 receptors Human genes 0.000 description 30
- 108020003175 receptors Proteins 0.000 description 30
- 239000000243 solution Substances 0.000 description 29
- 239000013543 active substance Substances 0.000 description 28
- 210000004027 cell Anatomy 0.000 description 25
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 23
- RSDOPYMFZBJHRL-UHFFFAOYSA-N Oxotremorine Chemical compound O=C1CCCN1CC#CCN1CCCC1 RSDOPYMFZBJHRL-UHFFFAOYSA-N 0.000 description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- 238000002360 preparation method Methods 0.000 description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
- 239000007858 starting material Substances 0.000 description 20
- 230000027455 binding Effects 0.000 description 19
- 239000003153 chemical reaction reagent Substances 0.000 description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- 239000000556 agonist Substances 0.000 description 18
- 238000009739 binding Methods 0.000 description 18
- 201000010099 disease Diseases 0.000 description 17
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- 239000002245 particle Substances 0.000 description 17
- 239000000725 suspension Substances 0.000 description 17
- 229910052799 carbon Inorganic materials 0.000 description 16
- 239000003149 muscarinic antagonist Substances 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 241000700159 Rattus Species 0.000 description 15
- 238000009472 formulation Methods 0.000 description 15
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 14
- 239000012528 membrane Substances 0.000 description 14
- 125000006239 protecting group Chemical group 0.000 description 14
- 230000002829 reductive effect Effects 0.000 description 14
- 239000007787 solid Substances 0.000 description 14
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 13
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 13
- 239000008101 lactose Substances 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 241001465754 Metazoa Species 0.000 description 12
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 150000001721 carbon Chemical group 0.000 description 12
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 12
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- 235000011152 sodium sulphate Nutrition 0.000 description 12
- 241000124008 Mammalia Species 0.000 description 11
- 230000000178 bronchoprotective effect Effects 0.000 description 11
- 239000011575 calcium Substances 0.000 description 11
- 229940112141 dry powder inhaler Drugs 0.000 description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 11
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- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 11
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 10
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 10
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 10
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
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- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropyl acetate Chemical compound CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 9
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- OHCQJHSOBUTRHG-KGGHGJDLSA-N FORSKOLIN Chemical compound O=C([C@@]12O)C[C@](C)(C=C)O[C@]1(C)[C@@H](OC(=O)C)[C@@H](O)[C@@H]1[C@]2(C)[C@@H](O)CCC1(C)C OHCQJHSOBUTRHG-KGGHGJDLSA-N 0.000 description 8
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 8
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- 125000001309 chloro group Chemical group Cl* 0.000 description 8
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- XOFLBQFBSOEHOG-UUOKFMHZSA-N γS-GTP Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=S)[C@@H](O)[C@H]1O XOFLBQFBSOEHOG-UUOKFMHZSA-N 0.000 description 8
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- LERNTVKEWCAPOY-DZZGSBJMSA-N tiotropium Chemical compound O([C@H]1C[C@@H]2[N+]([C@H](C1)[C@@H]1[C@H]2O1)(C)C)C(=O)C(O)(C=1SC=CC=1)C1=CC=CS1 LERNTVKEWCAPOY-DZZGSBJMSA-N 0.000 description 7
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- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 5
- OGCSWAYKOXSEDZ-XMMPIXPASA-N 2-[(3s)-1-benzylpyrrolidin-3-yl]-2,2-diphenylacetonitrile Chemical compound C([C@H](C1)C(C#N)(C=2C=CC=CC=2)C=2C=CC=CC=2)CN1CC1=CC=CC=C1 OGCSWAYKOXSEDZ-XMMPIXPASA-N 0.000 description 5
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 5
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- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
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- QCHFTSOMWOSFHM-UHFFFAOYSA-N SJ000285536 Natural products C1OC(=O)C(CC)C1CC1=CN=CN1C QCHFTSOMWOSFHM-UHFFFAOYSA-N 0.000 description 5
- DFFINYKUAYHRBO-KRWDZBQOSA-N [(3s)-1-benzylpyrrolidin-3-yl] 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)O[C@@H]1CN(CC=2C=CC=CC=2)CC1 DFFINYKUAYHRBO-KRWDZBQOSA-N 0.000 description 5
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- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
- C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
-
- A—HUMAN NECESSITIES
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Abstract
Description
aおよびbは独立に0または1〜5の整数であり;
R1およびR2は各々独立に、−C1〜4アルキル、−C2〜4アルケニル、−C2〜4アルキニル、−C3〜6シクロアルキル、シアノ、ハロ、−ORa、−CH2OH、−COOH、−C(O)O−C1〜4アルキル、−C(O)NRbRc、−SRa、−S(O)Ra、−S(O)2Raおよび−NRbRcから選択され;Raは各々独立に、水素、−C1〜4アルキル、−C2〜4アルケニル、−C2〜4アルキニルおよび−C3〜6シクロアルキルから選択され;RbおよびRcは各々独立に、水素、−C1〜4アルキル、−C2〜4アルケニル、−C2〜4アルキニルまたは−C3〜6シクロアルキルから選択され;またはRbおよびRcは、それらが結合している窒素原子と一緒になってC3〜6複素環を形成し;または隣接する2つのR1基または隣接する2つのR2基は、一緒になって−C3〜6アルキレン、−C2〜4アルキレン−O−または−O−C1〜4アルキレン−O−を形成し;
R3は、−C(O)NR3aR3b、−C(O)O−C1〜4アルキル、−CN、−OH、−CH2OHおよび−CH2NH2から選択され;
R3aおよびR3bは独立に、水素、−C1〜6アルキル、−C2〜6アルケニル、−C2〜6アルキニル、−C3〜6シクロアルキル、−C6〜10アリール、−C2〜9ヘテロアリール、−C3〜6複素環および−(CH2)1〜2−R3cから選択され、R3cは、−OH、−O−C1〜6アルキル、−C3〜6シクロアルキル、−C6〜10アリール、−C2〜9ヘテロアリールおよび−C3〜6複素環から選択され;またはR3aおよびR3bは、それらが結合している窒素原子と一緒になって、窒素、酸素または硫黄から選択されるさらに1個のヘテロ原子を任意に含むC3〜6複素環を形成し;
cは0または1〜3の整数であり;
R4は各々独立に、フルオロまたは−C1〜4アルキルであり;
dは1または2であり、
R5は、−C1〜6アルキル、−CH2−C2〜6アルケニル、−CH2−C2〜6アルキニルおよび−CH2COR5aから選択され;R5aは、−OH、−O−C1〜6アルキルおよび−NR5bR5cから選択され;R5bおよびR5cは独立に、Hおよび−C1〜6アルキルから選択され;
Qは、−C0〜5アルキレン−Q’−C0〜1アルキレン−であり、Q’は、−CH2−、−CH=CH−、−C≡C−、−O−、−S−、−S(O)−、−SO2−、−SO2−NRQ1−、−NRQ1−SO2−、−C(O)−、−OC(O)−、−C(O)O−、−NRQ1C(O)−、−C(O)NRQ1−、−NRQ2−C(O)−NRQ3−、−NRQ2−C(S)−NRQ3−、−C=N−O−、−S−S−および−C(=N−O−RQ4)−から選択され、RQ1は、水素または−C1〜4アルキルであり、RQ2およびRQ3は独立に、水素、−C1〜4アルキルおよび−C3〜6シクロアルキルから選択されるか、またはRQ2およびRQ3は一緒になって−C2〜4アルキレンまたは−C2〜3アルケニレンを形成し、RQ4は−C1〜4アルキルまたはベンジルであり;
eは0または1〜5の整数であり;
R6は各々独立に、ハロ、−C1〜4アルキル、−C0〜4アルキレン−OH、シアノ、−C0〜2アルキレン−COOH、−C(O)O−C1〜4アルキル、−O−C1〜4アルキル、−S−C1〜4アルキル、−NH−C(O)−C1〜4アルキル、−N(C1〜4アルキル)2および−N+(O)Oから選択され;
R1〜3、R3a〜3c、R4〜6およびRa〜Rcにおけるアルキル基、アルケニル基、アルキレン基、アルキニル基およびシクロアルキル基はそれぞれ任意に、1〜5個のフルオロ原子で置換されており;R5におけるアルキル基、アルケニル基およびアルキニル基はそれぞれ任意に、−O−C1〜6アルキル、−OHおよびフェニルから独立に選択される1〜2個の置換基で置換されており;R1〜2、R3a〜3cおよびRa〜cにおけるシクロアルキル基、アリール基、ヘテロアリール基および複素環基はそれぞれ任意に、−C1〜4アルキル、−C2〜4アルケニル、−C2〜4アルキニル、シアノ、ハロ、−O−C1〜4アルキル、−S−C1〜4アルキル、−S(O)(C1〜4アルキル)、−S(O)2(C1〜4アルキル)、−NH2、−NH(C1〜4アルキル)および−N(C1〜4アルキル)2から独立に選択される1〜3個の置換基で置換されており、アルキル基、アルケニル基およびアルキニル基はそれぞれ任意に、1〜5個のフルオロ置換基で置換されており;Qにおける−CH2−基はそれぞれ任意に、−C1〜2アルキル、−OHおよびフルオロから独立に選択される1個または2個の置換基で置換されている、化合物
またはその薬学的に許容される塩に関する。
以下の置換基および値は、本発明の種々の態様および実施形態の代表的な例を提供することを意図している。こうした代表的な値は、そうした態様および実施形態をさらに規定および説明することを意図するものであるが、他の実施形態を除外したり、本発明の範囲を限定したりすることを意図するものではない。この点で、特に記載がない限り、特定の値または置換基を好ましいと表現しても、他の値または置換基を本発明から除外することを決して意図するものではない。
本発明の化合物、組成物、方法およびプロセスについて記載する際、以下の用語は、他に記載がない限り、以下の意味を持つ。さらに、本明細書で使用する場合、単数形「a」、「an」および「the」は、文脈上明らかに他の意味に解すべき場合を除き、対応する複数形を含む。「含む(comprising)」、「含む(including)」および「持つ(having)」という語は、排他的でないことを意図しており、記載された要素以外に他の要素が存在する場合があることを意味する。
本発明の化合物については、以下の一般的な方法、実施例に記載の手順を用いて、容易に入手できる出発材料から調製してもよいし、当業者に知られている他の方法、試薬および出発材料を用いて調製してもよい。以下の手順は、本発明の特定の実施形態を説明し得るものであるが、同一または類似の方法を用いて、または当業者に知られている他の方法、試薬および出発材料を用いることで、本発明の他の実施形態も同様に調製することができる理解されよう。さらに、典型的または好ましいプロセス条件(すなわち、反応温度、時間、反応物のモル比、溶媒、圧力など)を示す場合、他に記載がない限り、他のプロセス条件を用いてもよいことも理解されよう。最適な反応条件は一般に、使用する個々の反応物、溶媒および量など様々な反応パラメータによって異なるものであるが、当業者であれば、通常の最適化手順により好適な反応条件を容易に判定できる。
(a)式II:
式IIと式IIIの化合物間の反応であるプロセス(a)では、L1で表す脱離基は、たとえば、クロロ、ブロモまたはヨードなどのハロでも、メシラートまたはトシラートなどのスルホン酸エステル基でもよい。一実施形態では、L1はブロモである。この反応は、たとえば、ジイソプロピルエチルアミンのような第三級アミンなど、塩基の存在下で行うと都合がよい。簡便な溶媒として、アセトニトリル、ジメチルホルムアミド(DMF:dimethylformamide)およびジメチルアセトアミド(DMA:dimethylacetamide)などのニトリルがある。この反応は、0℃〜100℃の範囲の温度で実施すると都合がよい。その後、反応生成物を、抽出、再結晶、クロマトグラフィーおよび同種のものなど通常の手順を用いて単離する。
プロセス(b)では、式Vの化合物および式IIIの化合物間の反応を、ピロリジンをハロゲン化化合物と反応させる既知の手順を用いて行ってもよい。この反応は、約20〜120℃の範囲、より一般的には約20〜80℃の範囲の温度で有機溶媒中において行うのが一般的である。好適な有機溶媒として、アセトニトリル、ジメチルスルホキシド、ジメチルアセトアミド、エーテルおよびアセトンが挙げられる。式Vの化合物については、式IIの化合物を、プロセス(a)に記載されているようなR5基を含む有機基質と反応させることで調製してもよい。
プロセス(c)では、式V、式VIおよび式VIIIの化合物間の反応条件は、それぞれA基およびB基によって異なる。L3で表す脱離基は、たとえば、ハロ、一般にはブロモであってもよい。式VIおよび式VIIIの化合物は、一般に知られており、あるいは、よく知られている合成方法を用いて、容易に入手できる出発材料から調製することができる。
本発明の化合物は一般に、医薬組成物または製剤の形で患者に投与する。そうした医薬組成物については、以下に限定されるものではないが、経口的、経鼻的、局所的(経皮など)および非経口的投与モードなど、許容可能な任意の投与経路により、患者に投与することができる。さらに、本発明の化合物を、たとえば1日複数回、1日1回または週1回で経口投与してもよい。個々の投与モードに好適であれば、本発明の化合物のどのような形態(すなわち、遊離塩基、薬学的に許容される塩、溶媒和物など)も、本明細書で考察した医薬組成物中に用いることができることが理解されよう。
経口投与に好適な液体剤形として、たとえば、薬学的に許容されるエマルジョン、マイクロエマルジョン、溶液、懸濁液、シロップおよびエリキシル剤が挙げられる。液体剤形は一般に、作用薬と、たとえば、水または他の溶媒、溶解補助剤および乳化剤(エチルアルコール、イソプロピルアルコール、エチルカルボナート、酢酸エチル、ベンジルアルコール、ベンジルベンゾアート、プロピレングリコール、1,3−ブチレングリコール、油(たとえば、綿実油、ラッカセイ油、トウモロコシ油、胚芽油、オリーブ油、ヒマシ油およびゴマ油)、グリセロール、テトラヒドロフリルアルコール、ポリエチレングリコールおよびソルビタンの脂肪酸エステルならびにこれらの混合物など)のような不活性希釈液とを含む。懸濁液は、たとえば、エトキシル化イソステアリルアルコール、ポリオキシエチレンソルビトールエステル、ソルビタンエステル、微結晶性セルロース、アルミニウムメタヒドロキシド、ベントナイト、寒天(agar−agar)およびトラガントならびにこれらの混合物などの懸濁化剤を含んでもよい。
本発明の化合物(0.2mg)を微粉化してから、ラクトース(25mg)とブレンドする。次いで、このブレンドした混合物をゼラチン吸入カートリッジに充填する。DPIなどを用いて、カートリッジの内容物を投与する。
本発明の微粉化した化合物(10g)を、レシチン(0.2g)を脱イオン水(200mL)に溶解して調製した溶液に分散させる。得られた懸濁液を噴霧乾燥させてから、微粉化し、平均径が約1.5μm未満の粒子を含む微粉化組成物を形成する。その後、MDIで投与する際は、1用量当たり約10μg〜約500μgの本発明の化合物を与えるのに十分な量で、微粉化組成物を、加圧した1,1,1,2−テトラフルオロエタンを含むMDIカートリッジに充填する。
本発明の化合物(25mg)をクエン酸塩緩衝(pH5)等張食塩水(125mL)に溶解する。この混合物を撹拌し、化合物が溶解するまで超音波で分解する。溶液のpHを点検し、必要に応じて、1Nの水性水酸化ナトリウムをゆっくりと加えてpH5に調整する。この溶液を、1用量当たり約10μg〜約500μgの本発明の化合物を与えるネブライザー装置を用いて投与する。
本発明の化合物(50g)、噴霧乾燥したラクトース(440g)およびステアリン酸マグネシウム(10g)を十分にブレンドする。次いで、得られた組成物を硬ゼラチンカプセルに充填する(1カプセル当たり組成物500mg)。
以下の成分を混合し、懸濁液10mL当たり100mgの化合物を含む懸濁液を形成する:
本発明の化合物(0.2g)を0.4Mの酢酸ナトリウム緩衝液溶液(2.0mL)とブレンドする。必要に応じて、0.5Nの水性塩酸または0.5Nの水性水酸化ナトリウムを用いて、得られた溶液のpHをpH4に調整し、次いで、十分な注射用蒸留水を加えて総容量を20mLにする。その後、この混合物を無菌フィルター(0.22ミクロン)で濾過し、注射による投与に好適な無菌溶液を得る。
本発明の化合物は、ムスカリン受容体アンタゴニスト活性を持ち、一実施形態では、ナノモル濃度で作用する。一実施形態では、本発明の化合物は、M2ムスカリン受容体サブタイプの活性よりもM3ムスカリン受容体サブタイプの活性の阻害に対して選択的である。別の実施形態では、本発明の化合物は、M1、M4およびM5ムスカリン受容体サブタイプの活性よりもM3およびM2ムスカリン受容体サブタイプの活性の阻害に対して選択的である。さらに、本発明の化合物は、望ましい作用持続時間を持つと期待されている。このため、別の特定の実施形態では、本発明は、約24時間を超える作用持続時間を持つ化合物を対象とする。さらに、本発明の化合物は、吸入で投与した場合、吸入で投与する他の既知のムスカリン受容体アンタゴニスト(チオトロピウムなど)に比べて、有効な用量での口内乾燥などの副作用が少ないと期待されている。
AC アデニリルシクラーゼ
ACN アセトニトリル
BSA ウシ血清アルブミン
cAMP 3’−5’サイクリックアデノシン一リン酸
CHO チャイニーズハムスターの卵巣
cM5 クローン化チンパンジーM5受容体
DCM ジクロロメタン(すなわち、塩化メチレン)
DIPEA N,N−ジイソプロピルエチルアミン
dPBS ダルベッコのリン酸塩緩衝生理食塩水
DMA N,N−ジメチルアセトアミド
EDTA エチレンジアミン四酢酸
EtOAc 酢酸エチル
EtOH エタノール
FBS ウシ胎仔血清
FLIPR 蛍光イメージングプレートリーダー
HBSS ハンクス緩衝塩溶液
HEPES 4−(2−ヒドロキシエチル)−1−ピペラジンエタンスルホン酸
hM1 クローン化ヒトM1受容体
hM2 クローン化ヒトM2受容体
hM3 クローン化ヒトM3受容体
hM4 クローン化ヒトM4受容体
hM5 クローン化ヒトM5受容体
IPAc 酢酸イソプロピル
MCh メチルコリン
MeOH メタノール
MTBE メチルt−ブチルエーテル
TFA トリフルオロ酢酸
TFA塩 トリフルオロアセタート塩
THF テトラヒドロフラン。
2,2−ジフェニル−2−(S)−ピロリジン−3−イルアセトアミド
2−[(S)−1−(3−フェノキシプロピル)ピロリジン−3−イル]−2,2−ジフェニルアセトアミド
(実施例1)
(S)−3−(カルバモイルジフェニルメチル)−1−メチル−1−(3−フェノキシプロピル)ピロリジニウム
2−((S)−1−メチルピロリジン−3−イル)−2,2−ジフェニルアセトアミド
(実施例2)
(S)−3−(カルバモイルジフェニルメチル)−1−メチル−1−(3−フェニルスルファニルプロピル)ピロリジニウム
(S)−1−(3−ブロモプロピル)−3−(カルバモイルジフェニルメチル)−1−メチルピロリジニウムブロミド
(実施例3)
(S)−3−(カルバモイルジフェニルメチル)−1−[3−(3,5−ジフルオロフェノキシ)プロピル]−1−メチル−ピロリジニウム
1−(3−ブロモプロピルスルファニル)−3,5−ジフルオロベンゼン
(実施例4)
(1R,3S)−3−(カルバモイルジフェニルメチル)−1−[3−(3,5−ジフルオロフェニルスルファニル)プロピル]−1−メチルピロリジニウム
(実施例5)
前の実施例に記載した手順に従い、適切な出発材料および試薬を代用し、以下の式を持つ化合物5−1〜5−23をTFA塩としてさらに調製した:
(5−2) 3−(カルバモイルジフェニルメチル)−1−メチル−1−(3−フェニルプロピル)ピロリジニウム。MS m/z:[M+]C28H33N2Oの計算値413.26;実測値413.0。
(5−3) 3−(カルバモイルジフェニルメチル)−1−メチル−1−(6−フェニルヘキシル)ピロリジニウム。MS m/z:[M+]C31H39N2Oの計算値455.31;実測値455.4。
(5−4) 3−[(S)−3−(カルバモイルジフェニルメチル)−1−メチルピロリジン−1−イル]−プロピオン酸フェニルエステル。MS m/z:[M+]C28H31N2O3の計算値443.23;実測値443.2。
(5−5) 2−[(S)−1−(2−ベンジルオキシエチル)−1−メチルピロリジン−3−イル]−2,2−ジフェニルアセトアミド。MS m/z:[M+]C28H33N2O2の計算値429.25;実測値429.2。
(5−6) N−{2−[(S)−3−(カルバモイルジフェニルメチル)−1−メチルピロリジン−1−イル]エチル}ベンズアミド。MS m/z:[M+]C28H32N3O2の計算値442.25;実測値442.2。
(5−7) 2−[(S)−1−メチル−1−(4−フェニルブチル)ピロリジン−3−イル]−2,2−ジフェニルアセトアミド。MS m/z:[M+]C29H35N2Oの計算値427.28;実測値427.2。
(5−8) 安息香酸2−[(S)−3−(カルバモイルジフェニルメチル)−1−メチルピロリジン−1−イル]エチルエステル。MS m/z:[M+]C28H31N2O3の計算値443.23;実測値443.2。
(5−9) (R)−3−(カルバモイルジフェニルメチル)−1−メチル−1−(4−フェニルブチル)ピロリジニウム。MS m/z:[M+]C29H35N2Oの計算値427.28;実測値427.2。
(5−10) (R)−3−(カルバモイルジフェニルメチル)−1−メチル−1−(3−フェノキシプロピル)ピロリジニウム。MS m/z:[M+]C28H33N2O2の計算値429.25;実測値429.2。
(5−11) (R)−3−(カルバモイルジフェニルメチル)−1−メチル−1−(3−フェニルスルファニルプロピル)ピロリジニウム。MS m/z:[M+]C28H33N2OSの計算値445.23;実測値445.2。
(5−12) (R)−1−(2−ベンゾイルオキシエチル)−3−(カルバモイルジフェニルメチル)−1−メチルピロリジニウム。MS m/z:[M+]C28H31N2O3の計算値443.23;実測値443.2。
(5−13) (S)−3−(カルバモイルジフェニルメチル)−1−メチル−1−(4−オキソ−4−フェニルブチル)ピロリジニウム。MS m/z:[M+]C29H33N2O2の計算値441.25;実測値441.2。
(5−14) (S)−3−(カルバモイルジフェニルメチル)−1−メチル−1−(5−フェニルペンチル)ピロリジニウム。MS m/z:[M+]C30H37N2Oの計算値441.29;実測値441.2。
(5−15) (S)−3−(カルバモイルジフェニルメチル)−1−メチル−1−[2−(3−フェニルウレイド)エチル]ピロリジニウム。MS m/z:[M+]C28H33N4O2の計算値457.26;実測値457.2。
(5−16) (S)−1−(ベンジルカルバモイルメチル)−3−(カルバモイルジフェニルメチル)−1−メチルピロリジニウム。MS m/z:[M+]C28H32N3O2の計算値442.25;実測値442.2。
(5−17) (S)−1−ベンジルオキシカルボニルメチル−3−(カルバモイルジフェニルメチル)−1−メチルピロリジニウム。MS m/z:[M+]C28H31N2O3の計算値443.23;実測値443.2。
(5−18) 2−((S)−1−{4−[(E)−メトキシイミノ]−4−フェニルブチル}−1−メチルピロリジン−3−イル)−2,2−ジフェニルアセトアミド。MS m/z:[M+]C30H36N3O2の計算値470.28;実測値470.2。
(5−19) 2−((S)−1−{4−[(E)−ベンジルオキシイミノ]−4−フェニルブチル}−1−メチルピロリジン−3−イル)−2,2−ジフェニルアセトアミド。MS m/z:[M+]C36H40N3O2の計算値546.31;実測値546.4。
(5−20) 2−[(1S,3S)−1−メチル−1−(3−フェニルスルファニルプロピル)−ピロリジン−3−イル]−2,2−ジフェニルアセトアミド。MS m/z:[M+]C28H33N2OSの計算値445.23;実測値445.2。
(5−21) 2−[(1R,3S)−1−メチル−1−(3−フェニルスルファニルプロピル)−ピロリジン−3−イル]−2,2−ジフェニルアセトアミド。MS m/z:[M+]C28H33N2OSの計算値445.23;実測値445.2。
(5−22) (S)−3−(カルバモイルジフェニルメチル)−1−メチル−1−(4−フェニル−ブト−3−イニル)ピロリジニウム。MS m/z:[M+]C29H31N2Oの計算値423.24;実測値423.2。
(5−23) (S)−3−(カルバモイルジフェニルメチル)−1−メチル−1−((E)−4−フェニル−ブト−3−エニル)ピロリジニウム。MS m/z:[M+]C29H33N2Oの計算値425.26;実測値425.2。
(5−24) (S)−3−(カルバモイルジフェニルメチル)−1−メチル−1−(2−フェノキシイミノエチル)ピロリジニウム。MS m/z:[M+]C27H30N3O2の計算値429.23;実測値428.2。
(5−25) (S)−3−(カルバモイルジフェニルメチル)−1−メチル−1−(3−フェニルジスルファニルプロピル)ピロリジニウム MS m/z:[M+]C28H33N2OS2の計算値478.20;実測値477.2。
(実施例6)
前の実施例に記載した手順に従い、適切な出発材料および試薬を代用し、以下の式を持つ化合物6−1〜6−30をTFA塩としてさらに調製した:
(6−2) 3−(カルバモイルジフェニルメチル)−1−[3−(4−フルオロフェノキシ)プロピル]−1−メチルピロリジニウム。MS m/z:[M+]C28H32FN2O2の計算値447.24;実測値447.0。1H NMR(CDCl3,300 MHz)δ(ppm):2.20(3H,m),2.73(4H,d),2.90(1H,m),3.35(5H,s),3.53(1H,t),3.68(2H,t)4.29(1H,t), 4.31(1H,t),5.74(1H,s),6.15(1H,d),6.77(2H,m)6.79(2H,m)7.26(11H,m)。
(6−3) 3−(カルバモイルジフェニルメチル)−1−[2−(4−ヒドロキシフェニル)エチル]−1−メチルピロリジニウム。MS m/z:[M+]C27H31N2O2の計算値415.24;実測値415.0。
(6−4) 4−トリフルオロメトキシ安息香酸2−[(S)−3−(カルバモイルジフェニルメチル)−1−メチルピロリジン−1−イル]エチルエステル。MS m/z:[M+]C29H30F3N2O4の計算値527.22;実測値527.2。
(6−5) N−{2−[(S)−3−(カルバモイルジフェニルメチル)−1−メチルピロリジン−1−イル]エチル}−4−メトキシベンズアミド。MS m/z:[M+]C29H34N3O3の計算値472.26;実測値472.2。
(6−6) 4−ジメチルアミノ安息香酸2−[(S)−3−(カルバモイルジフェニルメチル)−1−メチルピロリジン−1−イル]エチルエステル。MS m/z:[M+]C30H36N3O3の計算値486.28;実測値486.2。
(6−7) 4−メトキシ安息香酸2−[(S)−3−(カルバモイルジフェニルメチル)−1−メチルピロリジン−1−イル]エチルエステル。MS m/z:[M+]C29H33N2O4の計算値473.24;実測値473.2。
(6−8) 2−{(S)−1−[4−(4−メトキシフェニル)ブチル]−1−メチルピロリジン−3−イル}−2,2−ジフェニルアセトアミド。MS m/z:[M+]C3OH37N2O2の計算値457.29;実測値457.4。
(6−9) 2−[(S)−1−メチル−1−(3−p−トリルオキシプロピル)ピロリジン−3−イル]−2,2−ジフェニルアセトアミド。MS m/z:[M+]C29H35N2O2の計算値443.27;実測値443.2。
(6−10) 4−{3−[(S)−3−(カルバモイルジフェニルメチル)−1−メチルピロリジン−1−イル]プロポキシ}安息香酸メチルエステル。MS m/z:[M+]C30H35N2O4の計算値487.26;実測値487.2。
(6−11) 2−{(S)−1−[(S)−3−(4−フルオロフェノキシ)−2−ヒドロキシプロピル]−1−メチルピロリジン−3−イル}−2,2−ジフェニルアセトアミド。MS m/z:[M+]C28H32FN2O3の計算値463.24;実測値463.2。
(6−12) 2−{(S)−1−[3−(4−ヒドロキシフェノキシ)プロピル]−1−メチルピロリジン−3−イル}−2,2−ジフェニルアセトアミド。MS m/z:[M+]C28H33N2O3の計算値445.25;実測値445.2。
(6−13) 2−{(S)−1−[3−(4−クロロフェノキシ)プロピル]−1−メチルピロリジン−3−イル}−2,2−ジフェニルアセトアミド。MS m/z:[M+]C28H32ClN2O2の計算値463.22;実測値463.2。
(6−14) 2−{(S)−1−[3−(4−ブロモフェニルスルファニル)プロピル]−1−メチルピロリジン−3−イル}−2,2−ジフェニルアセトアミド。MS m/z:[M+]C28H32BrN2OSの計算値523.14;実測値523.2。
(6−15) 2−{(S)−1−[3−(4−クロロフェニルスルファニル)プロピル]−1−メチルピロリジン−3−イル}−2,2−ジフェニルアセトアミド。MS m/z:[M+]C28H32ClN2OSの計算値479.19;実測値479.2。
(6−16) 2−{(S)−1−[3−(4−メトキシフェニルスルファニル)プロピル]−1−メチルピロリジン−3−イル}−2,2−ジフェニルアセトアミド。MS m/z:[M+]C29H35N2O2Sの計算値475.24;実測値475.2。
(6−17) 2−{1−[4−(4−ブロモフェニル)−4−オキソ−ブチル]−1−メチルピロリジン−3−イル}−2,2−ジフェニルアセトアミド。MS m/z:[M+]C29H32BrN2O2の計算値519.16;実測値519.2。
(6−18) 2−{1−メチル−1−[3−(4−ニトロフェノキシ)プロピル]ピロリジン−3−イル}−2,2−ジフェニルアセトアミド。MS m/z:[M+]C28H32N3O4の計算値474.24;実測値474.2。
(6−19) 2−{1−[3−(4−メトキシフェノキシ)プロピル]−1−メチルピロリジン−3−イル}−2,2−ジフェニルアセトアミド。MS m/z:[M+]C29H35N2O3の計算値459.26;実測値459.2。
(6−20) (S)−3−(カルバモイルジフェニルメチル)−1−[4−(4−フルオロフェニル)−4−オキソブチル]−1−メチルピロリジニウム。MS m/z:[M+]C29H32FN2O2の計算値459.24;実測値459.2。
(6−21) (S)−3−(カルバモイルジフェニルメチル)−1−[4−(4−ヒドロキシフェニル)−4−オキソブチル]−1−メチルピロリジニウム。MS m/z:[M+]C29H33N2O3の計算値457.25;実測値457.2。
(6−22) (S)−3−(カルバモイルジフェニルメチル)−1−[4−(4−メトキシフェニル)−4−オキソブチル]−1−メチルピロリジニウム。MS m/z:[M+]C30H35N2O3の計算値471.26;実測値471.2。
(6−23) (S)−3−(カルバモイルジフェニルメチル)−1−メチル−1−(4−オキソ−4−p−トリルブチル)ピロリジニウム。MS m/z:[M+]C30H35N2O2の計算値455.27;実測値455.2。
(6−24) (S)−1−[3−(4−アセチルアミノフェニルスルファニル)プロピル]−3−(カルバモイルジフェニルメチル)−1−メチルピロリジニウム。MS m/z:[M+]C30H36N3O2Sの計算値502.25;実測値502.2。
(6−25) (S)−3−(カルバモイルジフェニルメチル)−1−メチル−1−[3−(4−メチルスルファニルフェニルスルファニル)プロピル]ピロリジニウム。MS m/z:[M+]C29H35N2OS2の計算値491.22;実測値491.2。
(6−26) (S)−3−(カルバモイルジフェニルメチル)−1−[3−(4−フルオロフェニルスルファニル)プロピル]−1−メチルピロリジニウム。MS m/z:[M+]C28H32FN2OSの計算値463.22;実測値463.6。
(6−27) (S)−3−(カルバモイルジフェニルメチル)−1−メチル−1−(3−p−トリルスルファニルプロピル)ピロリジニウム。MS m/z:[M+]C29H35N2OSの計算値459.25;実測値459.2。
(6−28) (S)−3−(カルバモイルジフェニルメチル)−1−メチル−1−[3−(4−メチルスルファニルフェノキシ)プロピル]ピロリジニウム。MS m/z:[M+]C29H35N2O2Sの計算値475.24;実測値475.2。
(6−29) (S)−3−(カルバモイルジフェニルメチル)−1−[4−(4−クロロフェニル)−4−オキソブチル]−1−メチルピロリジニウム。MS m/z:[M+]C29H32ClN2O2の計算値475.22;実測値475.2。
(6−30) (S)−3−(カルバモイルジフェニルメチル)−1−[3−(4−ヒドロキシフェニルスルファニル)プロピル]−1−メチルピロリジニウム。MS m/z:[M+]C28H33N2O2Sの計算値461.23;実測値461.2。
(実施例7)
前の実施例に記載した手順に従い、適切な出発材料および試薬を代用し、以下の式を持つ化合物7−1〜7−8をTFA塩としてさらに調製した:
(7−2) 2−{(S)−1−[3−(2−ブロモフェノキシ)プロピル]−1−メチルピロリジン−3−イル}−2,2−ジフェニルアセトアミド。MS m/z:[M+]C28H32BrN2O2の計算値507.16;実測値507.2。
(7−3) 2−{(S)−1−[3−(2−フルオロフェノキシ)プロピル]−1−メチルピロリジン−3−イル}−2,2−ジフェニルアセトアミド。MS m/z:[M+]C28H32FN2O2の計算値447.24;実測値447.2。
(7−4) (S)−3−(カルバモイルジフェニルメチル)−1−[3−(2−フルオロフェニルスルファニル)プロピル]−1−メチルピロリジニウム。MS m/z:[M+]C28H32FN2OSの計算値463.22;実測値463.2。
(7−5) (S)−3−(カルバモイルジフェニルメチル)−1−[3−(2−クロロフェニルスルファニル)プロピル]−1−メチルピロリジニウム。MS m/z:[M+]C28H32ClN2OSの計算値479.19;実測値479.2。
(7−6) (S)−3−(カルバモイルジフェニルメチル)−1−[4−(2−クロロフェニル)−4−オキソブチル]−1−メチルピロリジニウム。MS m/z:[M+]C29H32ClN2O2の計算値475.22;実測値475.2。
(7−7) (S)−3−(カルバモイルジフェニルメチル)−1−[3−(2−ヒドロキシフェノキシ)プロピル]−1−メチルピロリジニウム。MS m/z:[M+]C28H33N2O3の計算値445.25;実測値445.2。
(7−8) (S)−3−(カルバモイルジフェニルメチル)−1−[3−(2−ヒドロキシフェニルスルファニル)プロピル]−1−メチルピロリジニウム。MS m/z:[M+]C28H33N2O2Sの計算値461.23;実測値461.2。
(実施例8)
前の実施例に記載した手順に従い、適切な出発材料および試薬を代用し、以下の式を持つ化合物8−1〜8−17をTFA塩としてさらに調製した:
(8−2) 2−{(S)−1−[3−(3−クロロフェノキシ)プロピル]−1−メチルピロリジン−3−イル}−2,2−ジフェニルアセトアミド。MS m/z:[M+]C28H32ClN2O2の計算値463.22;実測値463.2。
(8−3) 2−{(S)−1−[3−(3−シアノフェノキシ)プロピル]−1−メチルピロリジン−3−イル}−2,2−ジフェニルアセトアミド。MS m/z:[M+]C29H32N3O2の計算値454.25;実測値454.2。
(8−4) 2−{(S)−1−[3−(3−クロロフェニルスルファニル)プロピル]−1−メチルピロリジン−3−イル}−2,2−ジフェニルアセトアミド。MS m/z:[M+]C28H32ClN2OSの計算値479.19;実測値479.2。
(8−5) (S)−3−(カルバモイルジフェニルメチル)−1−[3−(3−フルオロ−フェニルスルファニル)プロピル]−1−メチルピロリジニウム。MS m/z:[M+]C28H32FN2OSの計算値463.22;実測値463.2。1H NMR(CDCl3,300 MHz)δ(ppm):1.90(2H,m),2.05(1H,m),2.14(2H,br m),2.62(3H,s),2.86(2H,t),3.02(2H,m),3.22(1H,s),3.33(1H,s),3.45(1H,t),3.59(1H,d),3.70(1H,t),3.87(2H,m),4.18(1H,m),5.87(1H,d),6.35(1H,s),7.0(4H,m),7.3(10H,m)。
(8−6) (S)−3−(カルバモイルジフェニルメチル)−1−メチル−1−[3−(3−トリフルオロメチルフェニルスルファニル)プロピル]ピロリジニウム。MS m/z:[M+]C29H32F3N2OSの計算値513.22;実測値513.2。
(8−7) (S)−3−(カルバモイルジフェニルメチル)−1−メチル−1−[3−(3−トリフルオロメトキシフェニルスルファニル)プロピル]ピロリジニウム。MS m/z:[M+]C29H32F3N2O2Sの計算値529.21;実測値529.2。
(8−8) (S)−3−(カルバモイルジフェニルメチル)−1−[(3−フルオロベンジルカルバモイル)メチル]−1−メチルピロリジニウム。MS m/z:[M+]C28H31FN3O2の計算値460.24;実測値460.2。
(8−9) (S)−3−(カルバモイルジフェニルメチル)−1−[3−(3−メトキシフェノキシ)プロピル]−1−メチルピロリジニウム。MS m/z:[M+]C29H35N2O3の計算値459.26;実測値459.2。
(8−10) (S)−3−(カルバモイルジフェニルメチル)−1−[3−(3−フルオロフェノキシ)プロピル]−1−メチルピロリジニウム。MS m/z:[M+]C28H32FN2O2の計算値447.24;実測値447.2。1H NMR(CDCl3,300 MHz)δ(ppm):2.06(1H,s),2.18(2H,s),2.67(2H,s),2.79(1H,s),3.26(3H,s),3.38(1H,s),3.53(1H,t),3.68(1H,s),3.88(2H,t),4.03(2H,t),4.16(1H,m),5.82(1H,d),6.6(3H,m),6.51(1H,s),7.18(1H,m),7.3(10H,m)。
(8−11) (S)−3−(カルバモイルジフェニルメチル)−1−メチル−1−(3−m−トリルスルファニルプロピル)ピロリジニウム。MS m/z:[M+]C29H35N2OSの計算値459.25;実測値459.2。
(8−12) (S)−3−(カルバモイルジフェニルメチル)−1−[4−(3−メトキシフェニル)−4−オキソブチル]−1−メチルピロリジニウム。MS m/z:[M+]C30H35N2O3の計算値471.26;実測値471.2。
(8−13) (S)−3−(カルバモイルジフェニルメチル)−1−[3−(3−ヒドロキシフェノキシ)プロピル]−1−メチルピロリジニウム。MS m/z:[M+]C28H33N2O3の計算値445.25;実測値445.2。
(8−14) (S)−3−(カルバモイルジフェニルメチル)−1−[2−(3−フルオロベンゾイルオキシ)エチル]−1−メチルピロリジニウム。MS m/z:[M+]C28H30FN2O3の計算値461.22;実測値461.2。
(8−15) (S)−3−(カルバモイルジフェニルメチル)−1−[3−(3−ヒドロキシフェニルスルファニル)プロピル]−1−メチルピロリジニウム。MS m/z:[M+]C28H33N2O2Sの計算値461.23;実測値461.2。
(8−16) (R)−3−(カルバモイルジフェニルメチル)−1−[3−(3−フルオロフェノキシ)プロピル]−1−メチルピロリジニウム。MS m/z:[M+]C28H32FN2O2の計算値448.24;実測値447.2。
(8−17) (S)−3−(カルバモイルジフェニルメチル)−1−[4−(3−フルオロフェニル)ブト−3−イニル]−1−メチルピロリジニウム。MS m/z:[M+]C29H30FN2Oの計算値442.23;実測値441.2。
(実施例9)
前の実施例に記載した手順に従い、適切な出発材料および試薬を代用し、以下の式を持つ化合物9−1〜9−10をTFA塩としてさらに調製した:
(9−2) (S)−3−(カルバモイルジフェニルメチル)−1−{2−[3−(3,5−ジフルオロフェニル)ウレイド]エチル}−1−メチルピロリジニウム。MS m/z:[M+]C28H31F2N4O2の計算値493.24;実測値493.2。
(9−3) (S)−3−(カルバモイルジフェニルメチル)−1−(3,5−ジフルオロベンジルオキシカルボニルメチル)−1−メチルピロリジニウム。MS m/z:[M+]C28H29F2N2O3の計算値479.21;実測値479.2。
(9−4) (S)−3−(カルバモイルジフェニルメチル)−1−[3−(3,5−ジフルオロベンジルオキシ)プロピル]−1−メチルピロリジニウム。MS m/z:[M+]C29H33F2N2O2の計算値479.25;実測値479.2。
(9−5) (S)−3−(カルバモイルジフェニルメチル)−1−[3−(3,5−ジフルオロベンゼンスルフィニル)プロピル]−1−メチルピロリジニウム。MS m/z:[M+]C28H31F2N2O2Sの計算値497.21;実測値497.2。
(9−6) (S)−3−(カルバモイルジフェニルメチル)−1−[3−(3,5−ジフルオロベンゼンスルホニル)プロピル]−1−メチル−ピロリジニウム。MS m/z:[M+]C28H31F2N2O3Sの計算値513.20;実測値513.2。
(9−7) (1S,3S)−3−(カルバモイルジフェニルメチル)−1−[3−(3,5−ジフルオロフェニルスルファニル)プロピル]−1−メチルピロリジニウム。MS m/z:[M+]C28H31F2N2OSの計算値482.21;実測値482.2。
(9−8) (1S,3S)−3−(カルバモイルジフェニルメチル)−1−[3−(3,5−ジフルオロフェノキシ)プロピル]−1−メチルピロリジニウム。MS m/z:[M+]C28H31F2N2O2の計算値466.24;実測値465.2。
(9−9) (S)−3−(カルバモイルジフェニルメチル)−1−[4−(3,5−ジフルオロフェニル)ブト−3−イニル]−1−メチルピロリジニウム。MS m/z:[M+]C29H29F2N2Oの計算値460.22;実測値459.2。
(9−10) (R)−3−(カルバモイルジフェニルメチル)−1−[3−(3,5−ジフルオロフェノキシ)プロピル]−1−メチルピロリジニウム。MS m/z:[M+]C28H31F2N2O2の計算値466.24;実測値465.2。
(3−メトキシフェニル)フェニルアセトニトリル
((S)−1−ベンジルピロリジン−3−イル)(3−メトキシフェニル)フェニルアセトニトリル
2−(3−ヒドロキシフェニル)−2−フェニル−2−(S)−ピロリジン−3−イル−アセトアミド
(実施例10)
前の実施例に記載した手順に従い、適切な出発材料および試薬を代用し、以下の式を持つ化合物10−1〜10−3をTFA塩としてさらに調製した:
(10−2) (S)3−[(S)−カルバモイル−(4−ヒドロキシフェニル)フェニルメチル]−1−[3−(3,5−ジフルオロフェニルスルファニル)プロピル]−1−メチルピロリジニウム。MS m/z:[M+]C28H31F2N2O2Sの計算値498.21;実測値497.2。
(10−3) (S)3−[カルバモイル−(3−ヒドロキシフェニル)フェニルメチル]−1−[3−(3,5−ジフルオロフェニルスルファニル)プロピル]−1−メチルピロリジニウム。MS m/z:[M+]C28H31F2N2O2Sの計算値498.21;実測値497.2。
(実施例11)
前の実施例に記載した手順に従い、適切な出発材料および試薬を代用し、以下の式を持つ化合物11−1〜11−3をTFA塩としてさらに調製した:
(11−2) (S)−3−(カルバモイルジフェニルメチル)−1−[3−(3,4−ジフルオロフェノキシ)プロピル]−1−メチルピロリジニウム。MS m/z:[M+]C28H31F2N2O2の計算値465.24;実測値465.2。
(11−3) (S)−3−(カルバモイルジフェニルメチル)−1−[3−(3,4−ジフルオロフェニルスルファニル)プロピル]−1−メチルピロリジニウム。MS m/z:[M+]C28H31F2N2OSの計算値481.21;実測値481.2。
(実施例12)
前の実施例に記載した手順に従い、適切な出発材料および試薬を代用し、以下の式を持つ化合物12−1〜12−2をTFA塩としてさらに調製した:
(12−2)(S)−3−(カルバモイルジフェニルメチル)−1−[2−(2,3−ジフルオロベンゾイルオキシ)エチル]−1−メチルピロリジニウム。MS m/z:[M+]C28H29F2N2O3の計算値479.21;実測値479.2。
(実施例13)
前の実施例に記載した手順に従い、適切な出発材料および試薬を代用し、以下の式を持つ化合物13−1〜13−2をTFA塩としてさらに調製した:
(13−2) (S)−3−(カルバモイルジフェニルメチル)−1−[3−(2,4−ジフルオロフェニルスルファニル)プロピル]−1−メチルピロリジニウム。MS m/z:[M+]C28H31F2N2OSの計算値481.21;実測値481.2。
(実施例14)
前の実施例に記載した手順に従い、適切な出発材料および試薬を代用し、以下の式を持つ化合物14をTFA塩としてさらに調製した:
(実施例15)
前の実施例に記載した手順に従い、適切な出発材料および試薬を代用し、以下の式を持つ化合物15をTFA塩としてさらに調製した:
(実施例16)
前の実施例に記載した手順に従い、適切な出発材料および試薬を代用し、以下の式を持つ化合物16−1〜16−3をTFA塩としてさらに調製した:
(16−2) (S)−3−(カルバモイルフェニル−p−トリルメチル)−1−メチル−1−(4−フェニルブチル)ピロリジニウム(R1=4−メチル)。MS m/z:[M+]C30H37N2Oの計算値441.29;実測値441.2。
(16−3) (S)−3−[カルバモイル(4−ヒドロキシフェニル)フェニルメチル]−1−メチル−1−(4−フェニルブチル)ピロリジニウム(R1=4−ヒドロキシ)。MS m/z:[M+]C29H35N2O2の計算値443.27;実測値443.2。
放射性リガンド結合アッセイ
hM1、hM2、hM3およびhM4ムスカリン受容体サブタイプを発現している細胞から調製した膜
クローン化ヒトhM1、hM2、hM3およびhM4ムスカリン受容体サブタイプを安定発現しているCHO細胞株をそれぞれ、10%FBSおよび250μg/mLのGeneticinを補充したHAM’s F−12からなる培地で、コンフルエントに近い状態まで増殖させた。この細胞を、37℃、5%CO2インキュベーターで増殖させ、dPBSに溶かした2mMのEDTAで剥離した。650×gで5分遠心分離して細胞を集めて、細胞ペレットを−80℃で凍結保存するか、あるいは、すぐに膜を調製した。膜の調製では、細胞ペレットを溶解緩衝液に再懸濁し、Polytron PT−2100組織破砕機(Kinematica AG;20秒×2バースト)でホモジナイズした。粗膜を、40,000×g、4℃で15分間遠心した。次いで、この膜ペレットを再懸濁緩衝液で再懸濁し、Polytron組織破砕機で再びホモジナイズした。この膜懸濁液のタンパク質濃度を、Lowry,O.et al.,Journal of Biochemistry 193:265(1951)に記載の方法で判定した。膜をすべてアリコートとして−80℃で凍結保存するか、すぐに使用した。調製済みhM5受容体膜のアリコートをPerkin Elmerから直接購入し、使用時まで−80℃で保存した。
総アッセイ容積1000μLの96ウェルマイクロタイタープレートで、放射性リガンド結合アッセイを行った。hM1、hM2、hM3、hM4またはhM5ムスカリンサブタイプのいずれかを安定発現しているCHO細胞膜をアッセイ緩衝液で希釈し、以下の指定の標的タンパク質濃度(μg/ウェル)とした:hM1の場合10μg、hM2の場合10〜15μg、hM3の場合10〜20μg、hM4の場合10〜20μgおよびhM5の場合10〜12μg。膜を、アッセイプレートへの添加前にPolytron組織破砕機(disruptor)を用いて短時間(10秒)ホモジナイズした。放射性リガンドのKD値を判定する飽和結合研究を、0.001nM〜20nMの範囲の濃度でL−[N−メチル−3H]スコポラミンメチルクロリド([3H]−NMS)(TRK666,84.0 Ci/mmol,Amersham Pharmacia Biotech,Buckinghamshire,England)を用いて行った。被検化合物のKi値を判定するための置換アッセイを、1nMおよび11種の被検化合物濃度で[3H]−NMSを用いて行った。最初に、被検化合物を希釈緩衝液で40μMの濃度に溶解し、次いで、希釈緩衝液で400fM〜4μMの範囲の最終濃度に5倍段階希釈した。アッセイプレートへの添加順序および添加量は、以下のとおりであった:0.1%BSAを含む825μLのアッセイ緩衝液、25μLの放射性リガンド、100μLの希釈被検化合物および50μLの膜。アッセイプレートを6時間37℃でインキュベートした。結合反応を、0.3%ポリエチレンイミン(PEI:polyethyleneimine)で前処理したGF/Bガラス繊維フィルタープレート(Perkin Elmer Inc.,Wellesley,MA)での急速濾過により停止させた。フィルタープレートを洗浄用緩衝液(10mM HEPES)で3回リンスして、非結合放射能を除去した。次いで、プレートを風乾し、50μLのMicroscint−20液体シンチレーション流体(PerkinElmer Inc.,Wellesley,MA)を各ウェルに加えた。次いで、このプレートを、PerkinElmer Topcount液体シンチレーションカウンター(PerkinElmer Inc.,Wellesley,MA)でカウントした。結合データについては、1部位競合モデルを用いてGraphPad Prism Softwareパッケージ(GraphPad Software,Inc.,San Diego,CA)で非線形回帰分析により解析した。Cheng−Prusoff式(Cheng Y;Prusoff W.H.Biochemical Pharmacology 22(23):3099−108(1973))を用いて、観察されたIC50値および放射性リガンドのKD値から被検化合物のKi値を算出した。Ki値をpKi値に変換して、幾何平均および95%信頼区間を決定した。次いで、データ報告のため、これらの要約統計量をKi値に逆変換した。
ムスカリン受容体機能効力アッセイ
cAMP蓄積のアゴニストによる阻害を阻止
このアッセイでは、hM2受容体を発現しているCHO−K1細胞を用いて、フォルスコリンが関与するcAMP蓄積へのオキソトレモリンの阻害作用を阻止する被検化合物の能力を測定することで、被検化合物の機能効力を判定する。
第2の機能アッセイでは、hM2受容体を発現しているCHO−K1細胞を用いて、オキソトレモリン刺激による[35S]GTPγS結合を遮断する被検化合物の能力を測定することで、化合物の機能効力を判定できる。
Gqタンパク質に結合するムスカリン受容体サブタイプ(M1、M3およびM5受容体)は、アゴニストがこの受容体に結合すると、ホスホリパーゼC(PLC:phospholipase C)回路を活性化する。その結果、活性化されたPLCは、ホスファチルイノシトールジホスファート(PIP2)をジアシルグリセロール(DAG:diacylglycerol)およびホスファチジル−1,4,5−トリホスファート(IP3)に加水分解し、次いで、細胞内貯蔵から、すなわち、小胞体および筋小胞体からカルシウム放出が起こる。FLIPR(Molecular Devices,Sunnyvale,CA)アッセイは、遊離カルシウムの結合時に蛍光を発するカルシウム感受性色素(Fluo−4AM,Molecular Probes,Eugene,OR)を用いて、こうした細胞内カルシウムの増加を利用するものである。FLIPRによりこの蛍光現象をリアルタイムで測定する。FLIPRは、ヒトM1およびM3受容体ならびにチンパンジーM5受容体を含むクローン化細胞の単層から、蛍光の変化を検出する。アンタゴニスト効力については、アゴニストが関与する細胞内カルシウムの増加を阻害するアンタゴニストの能力により判定することができる。
ラットEinthovenアッセイ
このインビボアッセイを用いて、ムスカリン受容体アンタゴニスト活性を示す被検化合物の気管支保護作用を評価する。
ラットEinthovenアッセイにおいて、投薬1.5時間後の標準的なムスカリンアンタゴニストを評価した。検査対象の5種類の標準物質の効力(ID50)の順序を、イプラトロピウム(4.4μg/ml)>チオトロピウム(6μg/ml)>デス−メチル−チオトロピウム(12μg/ml)>グリコピロラート(15μg/ml)>LAS−34237(24μg/ml)と判定した。同様に、投薬1.5時間後の被検化合物の効力を判定する。
さらに、標準物質チオトロピウムおよびイプラトロピウムについては、ラットEinthovenアッセイで投薬24時間後および/または6時間後も評価した。イプラトロピウム(10および30μg/ml)は、投薬6時間後の効力が1.5時間の効力に比べて約3倍低かった。この時点(6時間)で観察された活性の低下は、臨床現場でその作用持続時間が比較的短いことと整合している。チオトロピウムは、作用の発現が遅く、気管支保護作用がピークに達したのは投薬6時間後であった。チオトロピウムの6時間と24時間の効力値には有意差が認められず、その効力値は、1.5時間の効力と比べて約2倍であった。同様に、被検化合物の作用の発現ならびに6時間および24時間の効力値を判定する。
ラット唾液分泌抑制剤アッセイ
アッセイ3に記載したとおり、ラット(Sprague−Dawley、雄性、250−350g)に投薬、麻酔およびカニューレ処置を行う。手術後の所定時点に、動物を、背側を上に頭が傾斜(20°の傾斜)の下方になるように置く。あらかじめ秤量しておいたガーゼパッドを動物の口に挿入し、ムスカリンアゴニストピロカルピン(PILO:pilocarpine)(3mg/kg、静脈内)を投与する。PILOの前後のガーゼパッドの重量を判定することにより、PILO投薬後10分間に産生される唾液を重量測定法で測定する。唾液分泌抑制剤の作用は、対照動物と比較した唾液分泌の阻害率で表す。
全身曝露の評価および被検化合物の肺選択性インデックス(LSI:lung selectivity index)の算出を行うため、ラット唾液分泌抑制剤アッセイを開発した。標準物質のチオトロピウムを、投薬1時間後、6時間後および24時間後にこのモデルで評価した。ピロカルピン誘導唾液分泌反応のチオトロピウムによる阻害は、投薬6時間後に最も強力であることが明らかになった。この知見は、Einthovenアッセイで観察されたピーク作用と整合している。
Claims (50)
- 塩形態または双性イオン形態の式I:
aおよびbは独立に0または1〜5の整数であり;
R1およびR2は各々独立に、−C1〜4アルキル、−C2〜4アルケニル、−C2〜4アルキニル、−C3〜6シクロアルキル、シアノ、ハロ、−ORa、−CH2OH、−COOH、−C(O)−O−C1〜4アルキル、−C(O)NRbRc、−SRa、−S(O)Ra、−S(O)2Raおよび−NRbRcから選択され;Raは各々独立に、水素、−C1〜4アルキル、−C2〜4アルケニル、−C2〜4アルキニルおよび−C3〜6シクロアルキルから選択され;RbおよびRcは各々独立に、水素、−C1〜4アルキル、−C2〜4アルケニル、−C2〜4アルキニルまたは−C3〜6シクロアルキルから選択され;またはRbおよびRcは、それらが結合している窒素原子と一緒になってC3〜6複素環を形成し;または隣接する2つのR1基または隣接する2つのR2基は、一緒になって−C3〜6アルキレン、−C2〜4アルキレン−O−または−O−C1〜4アルキレン−O−を形成し;
R3は、−C(O)NR3aR3b、−C(O)O−C1〜4アルキル、−CN、−OH、−CH2OHおよび−CH2NH2から選択され;R3aおよびR3bは独立に、水素、−C1〜6アルキル、−C2〜6アルケニル、−C2〜6アルキニル、−C3〜6シクロアルキル、−C6〜10アリール、−C2〜9ヘテロアリール、−C3〜6複素環および−(CH2)1〜2−R3cから選択され、R3cは、−OH、−O−C1〜6アルキル、−C3〜6シクロアルキル、−C6〜10アリール、−C2〜9ヘテロアリールおよび−C3〜6複素環から選択され;またはR3aおよびR3bは、それらが結合している窒素原子と一緒になって、窒素、酸素または硫黄から選択されるさらに1個のヘテロ原子を任意に含むC3〜6複素環を形成し;
cは0または1〜3の整数であり;
R4は各々独立に、フルオロまたは−C1〜4アルキルであり;
dは1または2であり、
R5は、−C1〜6アルキル、−CH2−C2〜6アルケニル、−CH2−C2〜6アルキニルおよび−CH2COR5aから選択され;R5aは、−OH、−O−C1〜6アルキルおよび−NR5bR5cから選択され;R5bおよびR5cは独立に、Hおよび−C1〜6アルキルから選択され;
Qは、−C0〜5アルキレン−Q’−C0〜1アルキレン−であり、Q’は、−CH2−、−CH=CH−、−C≡C−、−O−、−S−、−S(O)−、−SO2−、−SO2−NRQ1−、−NRQ1−SO2−、−C(O)−、−OC(O)−、−C(O)O−、−NRQ1C(O)−、−C(O)NRQ1−、NRQ2−C(O)−NRQ3−、−NRQ2−C(S)−NRQ3−、−C=N−O−、−S−S−および−C(=N−O−RQ4)−から選択され、RQ1は、水素または−C1〜4アルキルであり、RQ2およびRQ3は独立に、水素、−C1〜4アルキルおよび−C3〜6シクロアルキルから選択され、またはRQ2およびRQ3は一緒になって−C2〜4アルキレンまたは−C2〜3アルケニレンを形成し、RQ4は、−C1〜4アルキルまたはベンジルであり;
eは0または1〜5の整数であり;
R6は各々独立に、ハロ、−C1〜4アルキル、−C0〜4アルキレン−OH、シアノ、−C0〜2アルキレン−COOH、−C(O)O−C1〜4アルキル、−O−C1〜4アルキル、−S−C1〜4アルキル、−NH−C(O)−C1〜4アルキル、−N(C1〜4アルキル)2および−N+(O)Oから選択され;
R1〜3、R3a〜3c、R4〜6およびRa〜Rcにおけるアルキル基、アルケニル基、アルキレン基、アルキニル基およびシクロアルキル基はそれぞれ任意に、1〜5個のフルオロ原子で置換されており;R5におけるアルキル基、アルケニル基およびアルキニル基はそれぞれ任意に、−O−C1〜6アルキル、−OHおよびフェニルから独立に選択される1〜2個の置換基で置換されており;R1〜2、R3a〜3cおよびRa〜cにおけるシクロアルキル基、アリール基、ヘテロアリール基および複素環基はそれぞれ任意に、−C1〜4アルキル、−C2〜4アルケニル、−C2〜4アルキニル、シアノ、ハロ、−O−C1〜4アルキル、−S−C1〜4アルキル、−S(O)(C1〜4アルキル)、−S(O)2(C1〜4アルキル)、−NH2、−NH(C1〜4アルキル)および−N(C1〜4アルキル)2から独立に選択される1〜3個の置換基で置換されており、アルキル基、アルケニル基およびアルキニル基はそれぞれ任意に、1〜5個のフルオロ置換基で置換されており;Qにおける−CH2−基はそれぞれ任意に、−C1〜2アルキル、−OHおよびフルオロから独立に選択される1個または2個の置換基で置換されている、化合物
またはその薬学的に許容される塩。 - aは0または1である、請求項1に記載の化合物。
- bは0である、請求項1に記載の化合物。
- R3は−C(O)NR3aR3bである、請求項1に記載の化合物。
- R3aおよびR3bは独立に、水素および−C1〜4アルキルから選択される、請求項4に記載の化合物。
- R3aおよびR3bは水素である、請求項5に記載の化合物。
- cは0である、請求項1に記載の化合物。
- aおよびbは0である、請求項7に記載の化合物。
- aは1であり、bは0である、請求項7に記載の化合物。
- dは1であり、前記二重結合が存在しない、請求項1に記載の化合物。
- dは2であり、前記二重結合が存在する、請求項1に記載の化合物。
- R5は−C1〜6アルキルである、請求項1に記載の化合物。
- R5は−CH3である、請求項12に記載の化合物。
- −C0〜5アルキレン−Q’−C0〜1アルキレン−は、−C1〜3アルキレン−Q’−C0〜1アルキレン−である、請求項1に記載の化合物。
- −C0〜5アルキレン−Q’−C0〜1アルキレン−は、−C3アルキレン−Q’−C0〜1アルキレン−である、請求項14に記載の化合物。
- Q’は、−CH2−、−O−、−S−、−S(O)−、−C(O)−、−OC(O)−、−C(O)O−、−NRQ1C(O)−、−NRQ2−C(O)−NRQ3−、−NRQ2−C(S)−NRQ3−および−C(=N−O−RQ4)−から選択される、請求項1に記載の化合物。
- Q’は−NRQ1C(O)−であり、RQ1は水素である、請求項16に記載の化合物。
- Q’は−NRQ2−C(O)−NRQ3−および−NRQ2−C(S)−NRQ3−から選択され、RQ2およびRQ3は水素である、請求項16に記載の化合物。
- Q’は−C(=N−O−RQ4)−であり、RQ4は−CH3またはベンジルである、請求項16に記載の化合物。
- Q’は、−O−、−S−、−C(O)−および−OC(O)−から選択される、請求項16に記載の化合物。
- −C0〜5アルキレン−Q’−C0〜1アルキレン−は、−(CH2)、−、−(CH2)3−、−(CH2)4−、−(CH2)5−、−(CH2)6−、−(CH2)2−CH=CH−、−(CH2)2−C≡C−、−(CH2)2−O−CH2−、−(CH2)3−O−、−CH2−CH(OH)−CH2−O−、−(CH2)3−O−CH2−、−(CH2)3−S−、−(CH2)3−S(O)−、−(CH2)3−SO2−、−(CH2)3−C(O)−、−(CH2)2−OC(O)−、−(CH2)2−C(O)O−、−CH2−C(O)O−CH2−、−(CH2)2−NRQ1C(O)−、−CH2−C(O)NRQ1−CH2、−(CH2)2−NRQ2−C(O)−NRQ3−、−CH2−C=N−O−、−(CH2)2−S−S−および−(CH2)3−C(=N−O−RQ4)−から選択され、式中、RQ1、RQ2およびRQ3は水素であり、RQ4は−C1〜4アルキルまたはベンジルである、請求項1に記載の化合物。
- −C0〜5アルキレン−Q’−C0〜1アルキレン−は、−C0〜5アルキレン−Q’−である、請求項1に記載の化合物。
- eは0である、請求項1に記載の化合物。
- eは1である、請求項1に記載の化合物。
- R6は、ハロ、−C1〜4アルキル、−OH、シアノ、−C(O)O−C1〜4アルキル、−O−C1〜4アルキル、−S−C1〜4アルキル、−NH−C(O)−C1〜4アルキル、−N(C1〜4アルキル)2および−N+(O)Oから選択される、請求項24に記載の化合物。
- eは2であり、R6の1個はハロであり、第二のR6はハロおよび−O−C1〜4アルキルから選択される、請求項1に記載の化合物。
- Xは、アセタート、ベンゼンスルホナート、ベンゾアート、ブロミド、ブチラート、クロリド、p−クロロベンゾアート、シトラート、ジフェニルアセタート、ホルマート、フッ化物、o−ヒドロキシベンゾアート、p−ヒドロキシベンゾアート、1−ヒドロキシナフタレン−2−カルボキシラート、3−ヒドロキシナフタレン−2−カルボキシラート、ヨウ化物、ラクタート、マラート、マレアート、メタンスルホナート、ニトラート、ホスファート、プロピオナート、スクシナート、スルファート、タルトラート、トリフルオロアセタートおよびトリフェニルアセタートから選択される、請求項27に記載の化合物。
- Xは、ブロミド、ヨウ化物およびトリフルオロアセタートから選択される、請求項28に記載の化合物。
- 式I’d:
Qは、−(CH2)2−、−(CH2)3−、−(CH2)4−、−(CH2)5−、−(CH2)6−、−(CH2)2−CH=CH−、−(CH2)2−C≡C−、−(CH2)2−O−CH2−、−(CH2)3−O−、−CH2−CH(OH)−CH2−O−、−(CH2)3−O−CH2−、−(CH2)3−S−、−(CH2)3−S(O)−、−(CH2)3−SO2−、−(CH2)3−C(O)−、−(CH2)2OC(O)−、−(CH2)2−C(O)O−、−CH2−C(O)O−CH2−、−(CH2)2−NRQ1C(O)−、−CH2−C(O)NRQ1−CH2、−(CH2)2−NRQ2−C(O)−NRQ3−、−CH2−C=N−O−、−(CH2)2−S−S−および−(CH2)3−C(=N−O−RQ4)−から選択され、RQ1、RQ2およびRQ3は水素であり、RQ4は−C1〜4アルキルまたはベンジルであり;eは0、1または2であり;R6は各々独立に、ハロ、−C1〜4アルキル、−C0〜4アルキレン−OH、シアノ、−C(O)O−C1〜4アルキル、−O−C1〜4アルキル、−S−C1〜4アルキル、−NH−C(O)−C1〜4アルキル、−N(C1〜4アルキル)2および−N+(O)Oから選択される、請求項31に記載の化合物。 - R6における前記アルキルは任意に3個のフルオロ原子で置換されており;Qにおける−CH2−基の1個は任意に−OHで置換されている、請求項32に記載の化合物。
- 任意に置換されていない、請求項34に記載の化合物。
- 請求項1に記載の化合物および薬学的に許容されるキャリアを含む、医薬組成物。
- 前記化合物は微粉化された形態である、請求項38に記載の組成物。
- 第二の治療薬をさらに含む、請求項38に記載の組成物。
- 前記第二の治療薬は、β2アドレナリン受容体アゴニスト、ステロイド系抗炎症薬、ホスホジエステラーゼ−4阻害剤およびこれらの組み合わせから選択される、請求項40に記載の組成物。
- β2アドレナリン受容体アゴニストおよびステロイド系抗炎症薬をさらに含む、請求項38に記載の組成物。
- 請求項43に記載のプロセスにより調製される、化合物。
- 薬物の製造のための請求項1に記載の化合物の使用。
- 前記薬物は肺障害の処置に有用である、請求項45に記載の使用。
- 前記肺障害は慢性閉塞性肺疾患または喘息である、請求項46に記載の使用。
- 前記薬物は気管支を拡張させるのに有用である、請求項45に記載の使用。
- 前記薬物は哺乳動物のムスカリン受容体に拮抗するのに有用である、請求項45に記載の使用。
- 請求項1に記載の化合物のリサーチツールとしての使用。
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AU2008218962A1 (en) | 2008-08-28 |
IL199922A0 (en) | 2010-04-15 |
IL199922A (en) | 2014-08-31 |
US20080207736A1 (en) | 2008-08-28 |
KR20090117948A (ko) | 2009-11-16 |
US20110020231A1 (en) | 2011-01-27 |
AU2008218962B2 (en) | 2013-03-14 |
KR101495708B1 (ko) | 2015-02-25 |
US8802856B2 (en) | 2014-08-12 |
BRPI0807615A8 (pt) | 2017-12-05 |
JP5528817B2 (ja) | 2014-06-25 |
BRPI0807615A2 (pt) | 2017-10-31 |
CN101616893B (zh) | 2014-01-29 |
JP2014098031A (ja) | 2014-05-29 |
EP2121594B1 (en) | 2015-10-21 |
EP2121594A1 (en) | 2009-11-25 |
US7834185B2 (en) | 2010-11-16 |
WO2008103426A1 (en) | 2008-08-28 |
CA2675942A1 (en) | 2008-02-28 |
US20110021787A1 (en) | 2011-01-27 |
US8592453B2 (en) | 2013-11-26 |
CN101616893A (zh) | 2009-12-30 |
RU2452728C2 (ru) | 2012-06-10 |
RU2009135389A (ru) | 2011-03-27 |
MX2009008527A (es) | 2009-08-27 |
US20140051864A1 (en) | 2014-02-20 |
ES2554646T3 (es) | 2015-12-22 |
US8378121B2 (en) | 2013-02-19 |
CA2675942C (en) | 2016-04-12 |
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