SG185007A1 - NEW CYCLOHEXYLAMINE DERIVATIVES HAVING ß2 ADRENERGIC AGONIST AND M3 MUSCARINIC ANTAGONIST ACTIVITIES - Google Patents

Info

Publication number

SG185007A1

SG185007A1 SG2012078689A SG2012078689A SG185007A1 SG 185007 A1 SG185007 A1 SG 185007A1 SG 2012078689 A SG2012078689 A SG 2012078689A SG 2012078689 A SG2012078689 A SG 2012078689A SG 185007 A1 SG185007 A1 SG 185007A1

Authority

SG

Singapore

Prior art keywords

hydroxy

methyl

amino

group

trans

Prior art date

2010-05-13

Links

• Espacenet
• Global Dossier
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• 229940121948 Muscarinic receptor antagonist Drugs 0.000 title claims abstract description 16
• 239000003149 muscarinic antagonist Substances 0.000 title claims abstract description 16
• 239000000048 adrenergic agonist Substances 0.000 title claims abstract description 11
• 230000000694 effects Effects 0.000 title claims description 39
• 150000003946 cyclohexylamines Chemical class 0.000 title description 2
• 150000001875 compounds Chemical class 0.000 claims abstract description 209
• 238000000034 method Methods 0.000 claims abstract description 47
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 15
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 230
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 210
• -1 cyclohexyl hydroxy(di-2-thienyl)acetate Chemical compound 0.000 claims description 198
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 43
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 32
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 31
• 239000003814 drug Substances 0.000 claims description 27
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 24
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 24
• 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 23
• 125000001424 substituent group Chemical group 0.000 claims description 23
• QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 22
• 201000010099 disease Diseases 0.000 claims description 22
• 238000011282 treatment Methods 0.000 claims description 19
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 16
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
• 150000003839 salts Chemical class 0.000 claims description 16
• FVEJUHUCFCAYRP-UHFFFAOYSA-N 2-hydroxy-2,2-dithiophen-2-ylacetic acid Chemical compound C=1C=CSC=1C(O)(C(=O)O)C1=CC=CS1 FVEJUHUCFCAYRP-UHFFFAOYSA-N 0.000 claims description 14
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 14
• 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 14
• 125000000217 alkyl group Chemical group 0.000 claims description 13
• 235000019253 formic acid Nutrition 0.000 claims description 13
• 229910052801 chlorine Inorganic materials 0.000 claims description 12
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 12
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 12
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 12
• 125000001544 thienyl group Chemical group 0.000 claims description 12
• OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 11
• 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 11
• 125000004432 carbon atom Chemical group C* 0.000 claims description 11
• 125000002947 alkylene group Chemical group 0.000 claims description 10
• 208000006673 asthma Diseases 0.000 claims description 10
• KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims description 9
• 239000003246 corticosteroid Substances 0.000 claims description 9
• 239000012453 solvate Substances 0.000 claims description 8
• 208000019693 Lung disease Diseases 0.000 claims description 7
• 229940126157 adrenergic receptor agonist Drugs 0.000 claims description 7
• 208000020446 Cardiac disease Diseases 0.000 claims description 6
• 208000010412 Glaucoma Diseases 0.000 claims description 6
• 206010061218 Inflammation Diseases 0.000 claims description 6
• 241001465754 Metazoa Species 0.000 claims description 6
• 208000012902 Nervous system disease Diseases 0.000 claims description 6
• 229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 claims description 6
• 229910052799 carbon Inorganic materials 0.000 claims description 6
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
• 125000005843 halogen group Chemical group 0.000 claims description 6
• 208000019622 heart disease Diseases 0.000 claims description 6
• 230000004054 inflammatory process Effects 0.000 claims description 6
• 230000001575 pathological effect Effects 0.000 claims description 6
• 239000002587 phosphodiesterase IV inhibitor Substances 0.000 claims description 6
• 208000018522 Gastrointestinal disease Diseases 0.000 claims description 5
• 125000003545 alkoxy group Chemical group 0.000 claims description 5
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
• 229910052757 nitrogen Inorganic materials 0.000 claims description 5
• 208000025966 Neurological disease Diseases 0.000 claims description 4
• 229910052731 fluorine Inorganic materials 0.000 claims description 4
• 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 4
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
• WCRHWWWLTNWHQS-ABCZBHHISA-N C12=CC=CC=C2OC2=CC=CC=C2C1(C)C(=O)O[C@H](CC1)CC[C@@H]1N(C)CCCCCCCCCNC[C@H](O)C1=CC=C(O)C2=C1C=CC(=O)N2 Chemical compound C12=CC=CC=C2OC2=CC=CC=C2C1(C)C(=O)O[C@H](CC1)CC[C@@H]1N(C)CCCCCCCCCNC[C@H](O)C1=CC=C(O)C2=C1C=CC(=O)N2 WCRHWWWLTNWHQS-ABCZBHHISA-N 0.000 claims description 3
• AOPUMVRFTQOFIF-ZJTCZQGWSA-N F.O([C@H]1CC[C@@H](CC1)N(CCC(=O)NC=1C(=CC(CNC[C@H](O)C=2C=3C=CC(=O)NC=3C(O)=CC=2)=CC=1)Cl)C)C(C(O)=O)(C=1SC=CC=1)C1=CC=CS1 Chemical compound F.O([C@H]1CC[C@@H](CC1)N(CCC(=O)NC=1C(=CC(CNC[C@H](O)C=2C=3C=CC(=O)NC=3C(O)=CC=2)=CC=1)Cl)C)C(C(O)=O)(C=1SC=CC=1)C1=CC=CS1 AOPUMVRFTQOFIF-ZJTCZQGWSA-N 0.000 claims description 3
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 3
• 238000004519 manufacturing process Methods 0.000 claims description 3
• 238000002560 therapeutic procedure Methods 0.000 claims description 3
• 239000003085 diluting agent Substances 0.000 claims description 2
• 125000001153 fluoro group Chemical group F* 0.000 claims description 2
• AHZPWGGWOSEDTP-WBXFWKJNSA-N COc1cc(NC(=O)CCN(C)[C@H]2CC[C@@H](CC2)OC(=O)C(O)(c2cccs2)c2cccs2)c(Cl)cc1CNC[C@H](O)c1ccc(O)c2[nH]c(=O)ccc12 Chemical compound COc1cc(NC(=O)CCN(C)[C@H]2CC[C@@H](CC2)OC(=O)C(O)(c2cccs2)c2cccs2)c(Cl)cc1CNC[C@H](O)c1ccc(O)c2[nH]c(=O)ccc12 AHZPWGGWOSEDTP-WBXFWKJNSA-N 0.000 claims 1
• XVUHUJZYQSZKPP-UHFFFAOYSA-N F.C=1C=CSC=1C(O)(C(=O)O)C1=CC=CS1 Chemical compound F.C=1C=CSC=1C(O)(C(=O)O)C1=CC=CS1 XVUHUJZYQSZKPP-UHFFFAOYSA-N 0.000 claims 1
• 239000013066 combination product Substances 0.000 claims 1
• 229940127555 combination product Drugs 0.000 claims 1
• 208000037805 labour Diseases 0.000 claims 1
• 238000002360 preparation method Methods 0.000 abstract description 38
• 230000008569 process Effects 0.000 abstract description 11
• 230000009977 dual effect Effects 0.000 abstract description 6
• 238000002644 respiratory therapy Methods 0.000 abstract description 3
• 239000000543 intermediate Substances 0.000 description 506
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 184
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 154
• 239000000243 solution Substances 0.000 description 134
• 239000000203 mixture Substances 0.000 description 130
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 123
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 120
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 118
• 238000002474 experimental method Methods 0.000 description 114
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 109
• 239000007787 solid Substances 0.000 description 106
• 238000000746 purification Methods 0.000 description 90
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 84
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 82
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 71
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 69
• 239000003921 oil Substances 0.000 description 68
• 235000019198 oils Nutrition 0.000 description 67
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 66
• 235000019439 ethyl acetate Nutrition 0.000 description 63
• 238000004440 column chromatography Methods 0.000 description 62
• 239000000741 silica gel Substances 0.000 description 61
• 229910002027 silica gel Inorganic materials 0.000 description 61
• 229940093499 ethyl acetate Drugs 0.000 description 58
• 239000002904 solvent Substances 0.000 description 57
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 55
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 55
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 49
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 49
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 42
• 239000012267 brine Substances 0.000 description 41
• 230000002829 reductive effect Effects 0.000 description 40
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 39
• 238000004007 reversed phase HPLC Methods 0.000 description 37
• 238000005481 NMR spectroscopy Methods 0.000 description 35
• 235000017557 sodium bicarbonate Nutrition 0.000 description 33
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 33
• 239000012044 organic layer Substances 0.000 description 29
• NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 27
• 239000002775 capsule Substances 0.000 description 25
• 229940022663 acetate Drugs 0.000 description 24
• 238000006243 chemical reaction Methods 0.000 description 23
• 238000009472 formulation Methods 0.000 description 23
• IKGLACJFEHSFNN-UHFFFAOYSA-N hydron;triethylazanium;trifluoride Chemical compound F.F.F.CCN(CC)CC IKGLACJFEHSFNN-UHFFFAOYSA-N 0.000 description 23
• 238000012360 testing method Methods 0.000 description 23
• 239000012321 sodium triacetoxyborohydride Substances 0.000 description 22
• 238000003756 stirring Methods 0.000 description 22
• 239000000843 powder Substances 0.000 description 21
• 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 20
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 19
• QRMKTNANRJCRCY-UHFFFAOYSA-N ethylammonium acetate Chemical compound CC[NH3+].CC([O-])=O QRMKTNANRJCRCY-UHFFFAOYSA-N 0.000 description 19
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
• FTBORYLQQPHVQD-JOCQHMNTSA-N C1C[C@@H](NC)CC[C@@H]1OC(=O)C(O)(C=1SC=CC=1)C1=CC=CS1 Chemical compound C1C[C@@H](NC)CC[C@@H]1OC(=O)C(O)(C=1SC=CC=1)C1=CC=CS1 FTBORYLQQPHVQD-JOCQHMNTSA-N 0.000 description 18
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 18
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 18
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• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 12
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 12
• 239000004480 active ingredient Substances 0.000 description 12
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• 238000007792 addition Methods 0.000 description 10
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• 229910000027 potassium carbonate Inorganic materials 0.000 description 9
• 235000011181 potassium carbonates Nutrition 0.000 description 9
• AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 9
• JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 8
• BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 8
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• 239000001828 Gelatine Substances 0.000 description 8
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• OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 8
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• 239000000443 aerosol Substances 0.000 description 8
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• 150000004678 hydrides Chemical class 0.000 description 8
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 8
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• DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 8
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• 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 6
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• 238000001035 drying Methods 0.000 description 6
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