TW200932755A - Benzylphenyl cyclohexane derivatives and methods of use - Google Patents
Benzylphenyl cyclohexane derivatives and methods of use Download PDFInfo
- Publication number
- TW200932755A TW200932755A TW097148259A TW97148259A TW200932755A TW 200932755 A TW200932755 A TW 200932755A TW 097148259 A TW097148259 A TW 097148259A TW 97148259 A TW97148259 A TW 97148259A TW 200932755 A TW200932755 A TW 200932755A
- Authority
- TW
- Taiwan
- Prior art keywords
- group
- alkyl
- cycloalkyl
- alkyloxy
- compound
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 54
- MPFUMJUOVJWWAI-UHFFFAOYSA-N (1-benzylcyclohexyl)benzene Chemical class C1CCCCC1(C=1C=CC=CC=1)CC1=CC=CC=C1 MPFUMJUOVJWWAI-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 152
- 239000003814 drug Substances 0.000 claims abstract description 42
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 28
- 201000010099 disease Diseases 0.000 claims abstract description 23
- 102000000070 Sodium-Glucose Transport Proteins Human genes 0.000 claims abstract description 16
- 108010080361 Sodium-Glucose Transport Proteins Proteins 0.000 claims abstract description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 16
- 229940124597 therapeutic agent Drugs 0.000 claims abstract description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 121
- -1 chloro, hydroxy Chemical group 0.000 claims description 113
- 125000003545 alkoxy group Chemical group 0.000 claims description 96
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 82
- 229910052739 hydrogen Inorganic materials 0.000 claims description 51
- 239000001257 hydrogen Substances 0.000 claims description 50
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 42
- 125000001424 substituent group Chemical group 0.000 claims description 40
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 35
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 33
- 125000000304 alkynyl group Chemical group 0.000 claims description 32
- 150000002431 hydrogen Chemical class 0.000 claims description 30
- 239000007789 gas Substances 0.000 claims description 29
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 28
- 229940079593 drug Drugs 0.000 claims description 27
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 26
- 150000003839 salts Chemical class 0.000 claims description 26
- 125000003342 alkenyl group Chemical group 0.000 claims description 25
- 239000000651 prodrug Substances 0.000 claims description 24
- 229940002612 prodrug Drugs 0.000 claims description 24
- 125000005133 alkynyloxy group Chemical group 0.000 claims description 23
- 125000003118 aryl group Chemical group 0.000 claims description 22
- 239000003795 chemical substances by application Substances 0.000 claims description 22
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 21
- 125000005843 halogen group Chemical group 0.000 claims description 19
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 19
- 239000001301 oxygen Substances 0.000 claims description 19
- 229910052760 oxygen Inorganic materials 0.000 claims description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 18
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 18
- 125000003396 thiol group Chemical class [H]S* 0.000 claims description 18
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 16
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 15
- 125000001072 heteroaryl group Chemical group 0.000 claims description 15
- 229910052717 sulfur Inorganic materials 0.000 claims description 15
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 14
- 206010012601 diabetes mellitus Diseases 0.000 claims description 14
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims description 13
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 12
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 12
- 239000000460 chlorine Substances 0.000 claims description 12
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 12
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 10
- 150000001412 amines Chemical class 0.000 claims description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 9
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 8
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 8
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 claims description 8
- 125000004104 aryloxy group Chemical group 0.000 claims description 8
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 8
- 125000000524 functional group Chemical group 0.000 claims description 8
- 201000001320 Atherosclerosis Diseases 0.000 claims description 7
- 125000004465 cycloalkenyloxy group Chemical group 0.000 claims description 7
- 238000006467 substitution reaction Methods 0.000 claims description 7
- 125000000081 (C5-C8) cycloalkenyl group Chemical group 0.000 claims description 6
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 6
- 206010007558 Cardiac failure chronic Diseases 0.000 claims description 6
- 208000002249 Diabetes Complications Diseases 0.000 claims description 6
- 206010012655 Diabetic complications Diseases 0.000 claims description 6
- 125000003282 alkyl amino group Chemical group 0.000 claims description 6
- 239000003472 antidiabetic agent Substances 0.000 claims description 6
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 6
- 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 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 6
- 201000001431 Hyperuricemia Diseases 0.000 claims description 5
- 239000002220 antihypertensive agent Substances 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- ORTFAQDWJHRMNX-UHFFFAOYSA-N hydroxidooxidocarbon(.) Chemical group O[C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-N 0.000 claims description 5
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 claims description 5
- ZUTUOVOVWRMPGU-UHFFFAOYSA-N 1-(hydroxymethyl)cyclohexane-1,2,3,5-tetrol Chemical compound OCC1(O)CC(O)CC(O)C1O ZUTUOVOVWRMPGU-UHFFFAOYSA-N 0.000 claims description 4
- KAKZBPTYRLMSJV-UHFFFAOYSA-N Butadiene Chemical compound C=CC=C KAKZBPTYRLMSJV-UHFFFAOYSA-N 0.000 claims description 4
- 206010036790 Productive cough Diseases 0.000 claims description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
- 125000002947 alkylene group Chemical group 0.000 claims description 4
- 229940125708 antidiabetic agent Drugs 0.000 claims description 4
- 239000003524 antilipemic agent Substances 0.000 claims description 4
- 125000005708 carbonyloxy group Chemical group [*:2]OC([*:1])=O 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 125000003003 spiro group Chemical group 0.000 claims description 4
- 210000003802 sputum Anatomy 0.000 claims description 4
- 208000024794 sputum Diseases 0.000 claims description 4
- 239000011593 sulfur Substances 0.000 claims description 4
- 239000000052 vinegar Substances 0.000 claims description 4
- 235000021419 vinegar Nutrition 0.000 claims description 4
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 3
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 3
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 3
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 3
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 claims description 2
- 229910002651 NO3 Inorganic materials 0.000 claims description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 2
- 239000003741 agents affecting lipid metabolism Substances 0.000 claims description 2
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 2
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims description 2
- 125000005097 aminocarbonylalkyl group Chemical group 0.000 claims description 2
- 229940127088 antihypertensive drug Drugs 0.000 claims description 2
- 125000004658 aryl carbonyl amino group Chemical group 0.000 claims description 2
- 125000004657 aryl sulfonyl amino group Chemical group 0.000 claims description 2
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 2
- 125000005110 aryl thio group Chemical group 0.000 claims description 2
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 2
- 125000005149 cycloalkylsulfinyl group Chemical group 0.000 claims description 2
- 125000005366 cycloalkylthio group Chemical group 0.000 claims description 2
- RMBPEFMHABBEKP-UHFFFAOYSA-N fluorene Chemical compound C1=CC=C2C3=C[CH]C=CC3=CC2=C1 RMBPEFMHABBEKP-UHFFFAOYSA-N 0.000 claims description 2
- 125000005223 heteroarylcarbonyl group Chemical group 0.000 claims description 2
- 125000005224 heteroarylcarbonylamino group Chemical group 0.000 claims description 2
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 claims description 2
- 229910052753 mercury Inorganic materials 0.000 claims description 2
- NIHNNTQXNPWCJQ-UHFFFAOYSA-N o-biphenylenemethane Natural products C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 claims description 2
- 150000002923 oximes Chemical class 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000005567 fluorenylene group Chemical group 0.000 claims 3
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims 1
- 125000006528 (C2-C6) alkyl group Chemical group 0.000 claims 1
- XATKTZSGLJUBMR-UHFFFAOYSA-N [N]OCc1ccccc1 Chemical compound [N]OCc1ccccc1 XATKTZSGLJUBMR-UHFFFAOYSA-N 0.000 claims 1
- XOCUXOWLYLLJLV-UHFFFAOYSA-N [O].[S] Chemical compound [O].[S] XOCUXOWLYLLJLV-UHFFFAOYSA-N 0.000 claims 1
- 239000003242 anti bacterial agent Substances 0.000 claims 1
- 125000005135 aryl sulfinyl group Chemical group 0.000 claims 1
- 230000003115 biocidal effect Effects 0.000 claims 1
- VRVSHOSUSHYQIQ-UHFFFAOYSA-N hex-4-ene-1,2,3-triol Chemical compound CC=CC(O)C(O)CO VRVSHOSUSHYQIQ-UHFFFAOYSA-N 0.000 claims 1
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 claims 1
- 230000001404 mediated effect Effects 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 15
- 230000005764 inhibitory process Effects 0.000 abstract description 9
- 230000002401 inhibitory effect Effects 0.000 abstract description 5
- 102100037202 Sodium/myo-inositol cotransporter 2 Human genes 0.000 abstract 1
- 101710090560 Sodium/myo-inositol cotransporter 2 Proteins 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 132
- 239000000203 mixture Substances 0.000 description 110
- 235000019439 ethyl acetate Nutrition 0.000 description 58
- 238000002360 preparation method Methods 0.000 description 57
- 239000000243 solution Substances 0.000 description 48
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 42
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 38
- 238000009472 formulation Methods 0.000 description 31
- 238000006243 chemical reaction Methods 0.000 description 28
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- 238000005481 NMR spectroscopy Methods 0.000 description 23
- 239000002253 acid Substances 0.000 description 23
- 239000002585 base Substances 0.000 description 21
- 239000003112 inhibitor Substances 0.000 description 21
- 239000011734 sodium Substances 0.000 description 21
- 229910001868 water Inorganic materials 0.000 description 21
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- 238000007792 addition Methods 0.000 description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 13
- 210000004027 cell Anatomy 0.000 description 13
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 13
- 239000011541 reaction mixture Substances 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 239000007864 aqueous solution Substances 0.000 description 12
- 229910052786 argon Inorganic materials 0.000 description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 12
- 239000012044 organic layer Substances 0.000 description 12
- 101150041968 CDC13 gene Proteins 0.000 description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 11
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 11
- 230000009102 absorption Effects 0.000 description 11
- 238000010521 absorption reaction Methods 0.000 description 11
- 239000003921 oil Substances 0.000 description 11
- 235000019198 oils Nutrition 0.000 description 11
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 10
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 10
- 239000012267 brine Substances 0.000 description 10
- 239000011777 magnesium Substances 0.000 description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 10
- 229920006395 saturated elastomer Polymers 0.000 description 10
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 239000008103 glucose Substances 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 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 description 8
- 108091006269 SLC5A2 Proteins 0.000 description 8
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 8
- 125000003277 amino group Chemical group 0.000 description 8
- 238000002347 injection Methods 0.000 description 8
- 239000007924 injection Substances 0.000 description 8
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- 238000002953 preparative HPLC Methods 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- 229910052708 sodium Inorganic materials 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- 238000013268 sustained release Methods 0.000 description 8
- 239000012730 sustained-release form Substances 0.000 description 8
- 241000208340 Araliaceae Species 0.000 description 7
- 235000005035 Panax pseudoginseng ssp. pseudoginseng Nutrition 0.000 description 7
- 235000003140 Panax quinquefolius Nutrition 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 102000058081 Sodium-Glucose Transporter 2 Human genes 0.000 description 7
- 239000000872 buffer Substances 0.000 description 7
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 7
- 235000008434 ginseng Nutrition 0.000 description 7
- 229940125396 insulin Drugs 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- 230000001225 therapeutic effect Effects 0.000 description 7
- 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 description 6
- BDDLHHRCDSJVKV-UHFFFAOYSA-N 7028-40-2 Chemical compound CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O BDDLHHRCDSJVKV-UHFFFAOYSA-N 0.000 description 6
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical class NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 6
- 102000004877 Insulin Human genes 0.000 description 6
- 108090001061 Insulin Proteins 0.000 description 6
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 238000003556 assay Methods 0.000 description 6
- 239000012298 atmosphere Substances 0.000 description 6
- 229910052796 boron Inorganic materials 0.000 description 6
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000013265 extended release Methods 0.000 description 6
- 239000000284 extract Substances 0.000 description 6
- 239000000499 gel Substances 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 6
- 239000000546 pharmaceutical excipient Substances 0.000 description 6
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 6
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 6
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 6
- RXWNCPJZOCPEPQ-NVWDDTSBSA-N puromycin Chemical compound C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO RXWNCPJZOCPEPQ-NVWDDTSBSA-N 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 5
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- 206010022489 Insulin Resistance Diseases 0.000 description 5
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 5
- 108091006277 SLC5A1 Proteins 0.000 description 5
- 102000058090 Sodium-Glucose Transporter 1 Human genes 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- 239000000556 agonist Substances 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 229910052801 chlorine Inorganic materials 0.000 description 5
- 238000013270 controlled release Methods 0.000 description 5
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 5
- 239000008298 dragée Substances 0.000 description 5
- 239000012091 fetal bovine serum Substances 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 238000007429 general method Methods 0.000 description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 5
- 201000001421 hyperglycemia Diseases 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- 239000003381 stabilizer Substances 0.000 description 5
- 235000000346 sugar Nutrition 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 4
- 101000716682 Homo sapiens Sodium/glucose cotransporter 2 Proteins 0.000 description 4
- 239000002841 Lewis acid Substances 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- 206010030113 Oedema Diseases 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 239000007983 Tris buffer Substances 0.000 description 4
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 4
- 235000009754 Vitis X bourquina Nutrition 0.000 description 4
- 235000012333 Vitis X labruscana Nutrition 0.000 description 4
- 240000006365 Vitis vinifera Species 0.000 description 4
- 235000014787 Vitis vinifera Nutrition 0.000 description 4
- 125000001931 aliphatic group Chemical group 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 229940125898 compound 5 Drugs 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 4
- MWKFXSUHUHTGQN-UHFFFAOYSA-N decan-1-ol Chemical compound CCCCCCCCCCO MWKFXSUHUHTGQN-UHFFFAOYSA-N 0.000 description 4
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 230000001419 dependent effect Effects 0.000 description 4
- NZZFYRREKKOMAT-UHFFFAOYSA-N diiodomethane Chemical compound ICI NZZFYRREKKOMAT-UHFFFAOYSA-N 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 238000010828 elution Methods 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 4
- 102000052543 human SLC5A2 Human genes 0.000 description 4
- 150000002430 hydrocarbons Chemical group 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 150000002500 ions Chemical class 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- 208000017169 kidney disease Diseases 0.000 description 4
- 150000007517 lewis acids Chemical class 0.000 description 4
- 150000002632 lipids Chemical class 0.000 description 4
- 238000001972 liquid chromatography-electrospray ionisation mass spectrometry Methods 0.000 description 4
- 229910052749 magnesium Inorganic materials 0.000 description 4
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- DHHVAGZRUROJKS-UHFFFAOYSA-N phentermine Chemical compound CC(C)(N)CC1=CC=CC=C1 DHHVAGZRUROJKS-UHFFFAOYSA-N 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 description 4
- 230000002265 prevention Effects 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 229940044601 receptor agonist Drugs 0.000 description 4
- 239000000018 receptor agonist Substances 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 208000011580 syndromic disease Diseases 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 229930192474 thiophene Natural products 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- PHIQHXFUZVPYII-ZCFIWIBFSA-N (R)-carnitine Chemical class C[N+](C)(C)C[C@H](O)CC([O-])=O PHIQHXFUZVPYII-ZCFIWIBFSA-N 0.000 description 3
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 3
- 108010005094 Advanced Glycation End Products Proteins 0.000 description 3
- 229940123208 Biguanide Drugs 0.000 description 3
- XNCOSPRUTUOJCJ-UHFFFAOYSA-N Biguanide Chemical compound NC(N)=NC(N)=N XNCOSPRUTUOJCJ-UHFFFAOYSA-N 0.000 description 3
- 239000004135 Bone phosphate Substances 0.000 description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 3
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 3
- 108020004414 DNA Proteins 0.000 description 3
- 208000008960 Diabetic foot Diseases 0.000 description 3
- 208000032928 Dyslipidaemia Diseases 0.000 description 3
- 241000237858 Gastropoda Species 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- 239000007818 Grignard reagent Substances 0.000 description 3
- 101000716688 Homo sapiens Sodium/glucose cotransporter 1 Proteins 0.000 description 3
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 3
- 206010020772 Hypertension Diseases 0.000 description 3
- 208000017170 Lipid metabolism disease Diseases 0.000 description 3
- 208000001145 Metabolic Syndrome Diseases 0.000 description 3
- OHRGSJZEJVGUTJ-UHFFFAOYSA-N O1CCOCC1.C=C Chemical compound O1CCOCC1.C=C OHRGSJZEJVGUTJ-UHFFFAOYSA-N 0.000 description 3
- 208000008589 Obesity Diseases 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- 102100038831 Peroxisome proliferator-activated receptor alpha Human genes 0.000 description 3
- 239000004698 Polyethylene Substances 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- 208000017442 Retinal disease Diseases 0.000 description 3
- 206010038923 Retinopathy Diseases 0.000 description 3
- 229940100389 Sulfonylurea Drugs 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 208000025865 Ulcer Diseases 0.000 description 3
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 229940030600 antihypertensive agent Drugs 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- 229960002781 bisoprolol Drugs 0.000 description 3
- VHYCDWMUTMEGQY-UHFFFAOYSA-N bisoprolol Chemical compound CC(C)NCC(O)COC1=CC=C(COCCOC(C)C)C=C1 VHYCDWMUTMEGQY-UHFFFAOYSA-N 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 3
- 239000003638 chemical reducing agent Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 239000002299 complementary DNA Substances 0.000 description 3
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 3
- HSUGRBWQSSZJOP-RTWAWAEBSA-N diltiazem Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 HSUGRBWQSSZJOP-RTWAWAEBSA-N 0.000 description 3
- 229960004166 diltiazem Drugs 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 238000000105 evaporative light scattering detection Methods 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 230000002641 glycemic effect Effects 0.000 description 3
- 229930182470 glycoside Natural products 0.000 description 3
- 150000002338 glycosides Chemical class 0.000 description 3
- 150000004795 grignard reagents Chemical class 0.000 description 3
- 230000002440 hepatic effect Effects 0.000 description 3
- 102000052194 human SLC5A1 Human genes 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 210000003734 kidney Anatomy 0.000 description 3
- 239000007937 lozenge Substances 0.000 description 3
- 229910001629 magnesium chloride Inorganic materials 0.000 description 3
- 238000004949 mass spectrometry Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 201000001119 neuropathy Diseases 0.000 description 3
- 230000007823 neuropathy Effects 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 235000020824 obesity Nutrition 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- 208000033808 peripheral neuropathy Diseases 0.000 description 3
- 108091008725 peroxisome proliferator-activated receptors alpha Proteins 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 3
- 239000006187 pill Substances 0.000 description 3
- 229960002797 pitavastatin Drugs 0.000 description 3
- 210000002706 plastid Anatomy 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 238000012746 preparative thin layer chromatography Methods 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 229950010131 puromycin Drugs 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 229960002920 sorbitol Drugs 0.000 description 3
- 239000007921 spray Substances 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 3
- 230000037317 transdermal delivery Effects 0.000 description 3
- 231100000397 ulcer Toxicity 0.000 description 3
- 239000003039 volatile agent Substances 0.000 description 3
- HMJIYCCIJYRONP-UHFFFAOYSA-N (+-)-Isradipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1C1=CC=CC2=NON=C12 HMJIYCCIJYRONP-UHFFFAOYSA-N 0.000 description 2
- ZGGHKIMDNBDHJB-NRFPMOEYSA-M (3R,5S)-fluvastatin sodium Chemical compound [Na+].C12=CC=CC=C2N(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)=C1C1=CC=C(F)C=C1 ZGGHKIMDNBDHJB-NRFPMOEYSA-M 0.000 description 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 2
- METKIMKYRPQLGS-GFCCVEGCSA-N (R)-atenolol Chemical compound CC(C)NC[C@@H](O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-GFCCVEGCSA-N 0.000 description 2
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 description 2
- ZEUITGRIYCTCEM-KRWDZBQOSA-N (S)-duloxetine Chemical compound C1([C@@H](OC=2C3=CC=CC=C3C=CC=2)CCNC)=CC=CS1 ZEUITGRIYCTCEM-KRWDZBQOSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 2
- KVGOXGQSTGQXDD-UHFFFAOYSA-N 1-decane-sulfonic-acid Chemical compound CCCCCCCCCCS(O)(=O)=O KVGOXGQSTGQXDD-UHFFFAOYSA-N 0.000 description 2
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- KUZXQXCWRNFIHK-UHFFFAOYSA-N 3,3-diethyldodecane Chemical compound CCCCCCCCCC(CC)(CC)CC KUZXQXCWRNFIHK-UHFFFAOYSA-N 0.000 description 2
- SWLAMJPTOQZTAE-UHFFFAOYSA-N 4-[2-[(5-chloro-2-methoxybenzoyl)amino]ethyl]benzoic acid Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(C(O)=O)C=C1 SWLAMJPTOQZTAE-UHFFFAOYSA-N 0.000 description 2
- QBQLYIISSRXYKL-UHFFFAOYSA-N 4-[[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]methyl]-1,2-oxazolidine-3,5-dione Chemical compound CC=1OC(C=2C=CC=CC=2)=NC=1CCOC(C=C1)=CC=C1CC1C(=O)NOC1=O QBQLYIISSRXYKL-UHFFFAOYSA-N 0.000 description 2
- RZTAMFZIAATZDJ-HNNXBMFYSA-N 5-o-ethyl 3-o-methyl (4s)-4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC(Cl)=C1Cl RZTAMFZIAATZDJ-HNNXBMFYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 2
- 229910015845 BBr3 Inorganic materials 0.000 description 2
- 229910015900 BF3 Inorganic materials 0.000 description 2
- FMMWHPNWAFZXNH-UHFFFAOYSA-N Benz[a]pyrene Chemical compound C1=C2C3=CC=CC=C3C=C(C=C3)C2=C2C3=CC=CC2=C1 FMMWHPNWAFZXNH-UHFFFAOYSA-N 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- 102100034159 Beta-3 adrenergic receptor Human genes 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 229920001268 Cholestyramine Polymers 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- 102000018711 Facilitative Glucose Transport Proteins Human genes 0.000 description 2
- 208000011514 Familial renal glucosuria Diseases 0.000 description 2
- 108091052347 Glucose transporter family Proteins 0.000 description 2
- RPTUSVTUFVMDQK-UHFFFAOYSA-N Hidralazin Chemical compound C1=CC=C2C(NN)=NN=CC2=C1 RPTUSVTUFVMDQK-UHFFFAOYSA-N 0.000 description 2
- OMCPLEZZPVJJIS-UHFFFAOYSA-N Hypadil (TN) Chemical compound C1C(O[N+]([O-])=O)COC2=C1C=CC=C2OCC(O)CNC(C)C OMCPLEZZPVJJIS-UHFFFAOYSA-N 0.000 description 2
- 206010060378 Hyperinsulinaemia Diseases 0.000 description 2
- 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 2
- WTOVRSWDBLIFHU-UHFFFAOYSA-N Lemildipine Chemical compound COC(=O)C1=C(C)NC(COC(N)=O)=C(C(=O)OC(C)C)C1C1=CC=CC(Cl)=C1Cl WTOVRSWDBLIFHU-UHFFFAOYSA-N 0.000 description 2
- 239000012097 Lipofectamine 2000 Substances 0.000 description 2
- 206010054805 Macroangiopathy Diseases 0.000 description 2
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 description 2
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- 108010025020 Nerve Growth Factor Proteins 0.000 description 2
- 108010016731 PPAR gamma Proteins 0.000 description 2
- 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 description 2
- 108090000029 Peroxisome Proliferator-Activated Receptors Proteins 0.000 description 2
- 102100038825 Peroxisome proliferator-activated receptor gamma Human genes 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 description 2
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- 102000003673 Symporters Human genes 0.000 description 2
- 108090000088 Symporters Proteins 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- NGBFQHCMQULJNZ-UHFFFAOYSA-N Torsemide Chemical compound CC(C)NC(=O)NS(=O)(=O)C1=CN=CC=C1NC1=CC=CC(C)=C1 NGBFQHCMQULJNZ-UHFFFAOYSA-N 0.000 description 2
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 2
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 2
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 description 2
- 229960001138 acetylsalicylic acid Drugs 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000012190 activator Substances 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 239000000048 adrenergic agonist Substances 0.000 description 2
- 229940126157 adrenergic receptor agonist Drugs 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- 235000010419 agar Nutrition 0.000 description 2
- MKOMESMZHZNBIZ-UHFFFAOYSA-M alagebrium Chemical compound [Cl-].CC1=C(C)SC=[N+]1CC(=O)C1=CC=CC=C1 MKOMESMZHZNBIZ-UHFFFAOYSA-M 0.000 description 2
- 125000005194 alkoxycarbonyloxy group Chemical group 0.000 description 2
- WQZGKKKJIJFFOK-DVKNGEFBSA-N alpha-D-glucose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-DVKNGEFBSA-N 0.000 description 2
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 2
- PQLAYKMGZDUDLQ-UHFFFAOYSA-K aluminium bromide Chemical compound Br[Al](Br)Br PQLAYKMGZDUDLQ-UHFFFAOYSA-K 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 229940127218 antiplatelet drug Drugs 0.000 description 2
- 229960002274 atenolol Drugs 0.000 description 2
- 230000004888 barrier function Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- 229960003665 bepridil Drugs 0.000 description 2
- UIEATEWHFDRYRU-UHFFFAOYSA-N bepridil Chemical compound C1CCCN1C(COCC(C)C)CN(C=1C=CC=CC=1)CC1=CC=CC=C1 UIEATEWHFDRYRU-UHFFFAOYSA-N 0.000 description 2
- 108010014502 beta-3 Adrenergic Receptors Proteins 0.000 description 2
- 239000003613 bile acid Substances 0.000 description 2
- 229910052797 bismuth Inorganic materials 0.000 description 2
- JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 description 2
- GJPICJJJRGTNOD-UHFFFAOYSA-N bosentan Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2N=CC=CN=2)OCCO)=C1NS(=O)(=O)C1=CC=C(C(C)(C)C)C=C1 GJPICJJJRGTNOD-UHFFFAOYSA-N 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- OZVBMTJYIDMWIL-AYFBDAFISA-N bromocriptine Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@]2(C(=O)N3[C@H](C(N4CCC[C@H]4[C@]3(O)O2)=O)CC(C)C)C(C)C)C2)=C3C2=C(Br)NC3=C1 OZVBMTJYIDMWIL-AYFBDAFISA-N 0.000 description 2
- 229960002802 bromocriptine Drugs 0.000 description 2
- 239000001110 calcium chloride Substances 0.000 description 2
- 235000011148 calcium chloride Nutrition 0.000 description 2
- 229910001628 calcium chloride Inorganic materials 0.000 description 2
- 125000002837 carbocyclic group Chemical group 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- NPAKNKYSJIDKMW-UHFFFAOYSA-N carvedilol Chemical compound COC1=CC=CC=C1OCCNCC(O)COC1=CC=CC2=NC3=CC=C[CH]C3=C12 NPAKNKYSJIDKMW-UHFFFAOYSA-N 0.000 description 2
- 229960004195 carvedilol Drugs 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- PQANGXXSEABURG-UHFFFAOYSA-N cyclohex-2-en-1-ol Chemical compound OC1CCCC=C1 PQANGXXSEABURG-UHFFFAOYSA-N 0.000 description 2
- FWFSEYBSWVRWGL-UHFFFAOYSA-N cyclohex-2-enone Chemical compound O=C1CCCC=C1 FWFSEYBSWVRWGL-UHFFFAOYSA-N 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- DOBMPNYZJYQDGZ-UHFFFAOYSA-N dicoumarol Chemical compound C1=CC=CC2=C1OC(=O)C(CC=1C(OC3=CC=CC=C3C=1O)=O)=C2O DOBMPNYZJYQDGZ-UHFFFAOYSA-N 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 description 2
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 2
- 150000002013 dioxins Chemical class 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 150000004141 diterpene derivatives Chemical class 0.000 description 2
- 229960002866 duloxetine Drugs 0.000 description 2
- 238000000132 electrospray ionisation Methods 0.000 description 2
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 2
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 239000013604 expression vector Substances 0.000 description 2
- 239000010685 fatty oil Substances 0.000 description 2
- 229960003580 felodipine Drugs 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 229960003765 fluvastatin Drugs 0.000 description 2
- ASUTZQLVASHGKV-JDFRZJQESA-N galanthamine Chemical compound O1C(=C23)C(OC)=CC=C2CN(C)CC[C@]23[C@@H]1C[C@@H](O)C=C2 ASUTZQLVASHGKV-JDFRZJQESA-N 0.000 description 2
- 238000002309 gasification Methods 0.000 description 2
- 229960004580 glibenclamide Drugs 0.000 description 2
- 230000006377 glucose transport Effects 0.000 description 2
- ZNNLBTZKUZBEKO-UHFFFAOYSA-N glyburide Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZNNLBTZKUZBEKO-UHFFFAOYSA-N 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 229960005150 glycerol Drugs 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 230000003451 hyperinsulinaemic effect Effects 0.000 description 2
- 201000008980 hyperinsulinism Diseases 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 238000002513 implantation Methods 0.000 description 2
- NDDAHWYSQHTHNT-UHFFFAOYSA-N indapamide Chemical compound CC1CC2=CC=CC=C2N1NC(=O)C1=CC=C(Cl)C(S(N)(=O)=O)=C1 NDDAHWYSQHTHNT-UHFFFAOYSA-N 0.000 description 2
- 229960004569 indapamide Drugs 0.000 description 2
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 229960004427 isradipine Drugs 0.000 description 2
- 125000000468 ketone group Chemical group 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 229950001530 lemildipine Drugs 0.000 description 2
- NRYBAZVQPHGZNS-ZSOCWYAHSA-N leptin Chemical compound O=C([C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CC(C)C)CCSC)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CS)C(O)=O NRYBAZVQPHGZNS-ZSOCWYAHSA-N 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 2
- 229960004844 lovastatin Drugs 0.000 description 2
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 2
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 229950004994 meglitinide Drugs 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 229960002237 metoprolol Drugs 0.000 description 2
- IUBSYMUCCVWXPE-UHFFFAOYSA-N metoprolol Chemical compound COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 IUBSYMUCCVWXPE-UHFFFAOYSA-N 0.000 description 2
- 206010062198 microangiopathy Diseases 0.000 description 2
- 229960001785 mirtazapine Drugs 0.000 description 2
- RONZAEMNMFQXRA-UHFFFAOYSA-N mirtazapine Chemical compound C1C2=CC=CN=C2N2CCN(C)CC2C2=CC=CC=C21 RONZAEMNMFQXRA-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 229950000754 nipradilol Drugs 0.000 description 2
- 239000003791 organic solvent mixture Substances 0.000 description 2
- 210000000496 pancreas Anatomy 0.000 description 2
- 230000000149 penetrating effect Effects 0.000 description 2
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
- 125000005981 pentynyl group Chemical group 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 2
- 229960003562 phentermine Drugs 0.000 description 2
- 229960005095 pioglitazone Drugs 0.000 description 2
- VGYFMXBACGZSIL-MCBHFWOFSA-N pitavastatin Chemical compound OC(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1 VGYFMXBACGZSIL-MCBHFWOFSA-N 0.000 description 2
- 230000036470 plasma concentration Effects 0.000 description 2
- 239000000106 platelet aggregation inhibitor Substances 0.000 description 2
- 229920001296 polysiloxane Polymers 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- KMUONIBRACKNSN-UHFFFAOYSA-N potassium dichromate Chemical compound [K+].[K+].[O-][Cr](=O)(=O)O[Cr]([O-])(=O)=O KMUONIBRACKNSN-UHFFFAOYSA-N 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 2
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 2
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 125000002098 pyridazinyl group Chemical group 0.000 description 2
- NHZMQXZHNVQTQA-UHFFFAOYSA-N pyridoxamine Chemical compound CC1=NC=C(CO)C(CN)=C1O NHZMQXZHNVQTQA-UHFFFAOYSA-N 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 239000002464 receptor antagonist Substances 0.000 description 2
- 229940044551 receptor antagonist Drugs 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 229960002073 sertraline Drugs 0.000 description 2
- VGKDLMBJGBXTGI-SJCJKPOMSA-N sertraline Chemical compound C1([C@@H]2CC[C@@H](C3=CC=CC=C32)NC)=CC=C(Cl)C(Cl)=C1 VGKDLMBJGBXTGI-SJCJKPOMSA-N 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- LLDXOPKUNJTIRF-QFIPXVFZSA-N solabegron Chemical compound C([C@H](O)C=1C=C(Cl)C=CC=1)NCCNC(C=1)=CC=CC=1C1=CC=CC(C(O)=O)=C1 LLDXOPKUNJTIRF-QFIPXVFZSA-N 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- RMMXLENWKUUMAY-UHFFFAOYSA-N telmisartan Chemical compound CCCC1=NC2=C(C)C=C(C=3N(C4=CC=CC=C4N=3)C)C=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C(O)=O RMMXLENWKUUMAY-UHFFFAOYSA-N 0.000 description 2
- CXGTZJYQWSUFET-IBGZPJMESA-N tesaglitazar Chemical compound C1=CC(C[C@H](OCC)C(O)=O)=CC=C1OCCC1=CC=C(OS(C)(=O)=O)C=C1 CXGTZJYQWSUFET-IBGZPJMESA-N 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 229960005461 torasemide Drugs 0.000 description 2
- CMSGWTNRGKRWGS-NQIIRXRSSA-N torcetrapib Chemical compound COC(=O)N([C@H]1C[C@@H](CC)N(C2=CC=C(C=C21)C(F)(F)F)C(=O)OCC)CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 CMSGWTNRGKRWGS-NQIIRXRSSA-N 0.000 description 2
- 239000012096 transfection reagent Substances 0.000 description 2
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 2
- 125000004306 triazinyl group Chemical group 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 229940116269 uric acid Drugs 0.000 description 2
- 230000002485 urinary effect Effects 0.000 description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 229960001722 verapamil Drugs 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- AHOUBRCZNHFOSL-YOEHRIQHSA-N (+)-Casbol Chemical compound C1=CC(F)=CC=C1[C@H]1[C@H](COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-YOEHRIQHSA-N 0.000 description 1
- DBGIVFWFUFKIQN-VIFPVBQESA-N (+)-Fenfluramine Chemical compound CCN[C@@H](C)CC1=CC=CC(C(F)(F)F)=C1 DBGIVFWFUFKIQN-VIFPVBQESA-N 0.000 description 1
- GJJFMKBJSRMPLA-HIFRSBDPSA-N (1R,2S)-2-(aminomethyl)-N,N-diethyl-1-phenyl-1-cyclopropanecarboxamide Chemical compound C=1C=CC=CC=1[C@@]1(C(=O)N(CC)CC)C[C@@H]1CN GJJFMKBJSRMPLA-HIFRSBDPSA-N 0.000 description 1
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 1
- KIOUIMVIZXYLFV-BRFIBAHXSA-N (1r,7s,9ar,11ar)-3a-(1-hydroxyprop-2-enyl)-6,6,9a,11a-tetramethyl-1-(6-methylheptan-2-yl)-1,2,4,5,5a,7,8,9,10,11-decahydronaphtho[1,2-g][1]benzofuran-7-ol Chemical compound C([C@]12C)C[C@H](O)C(C)(C)C1CCC1=C2CC[C@]2(C)[C@@H](C(C)CCCC(C)C)COC21C(O)C=C KIOUIMVIZXYLFV-BRFIBAHXSA-N 0.000 description 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- DZLOHEOHWICNIL-QGZVFWFLSA-N (2R)-2-[6-(4-chlorophenoxy)hexyl]-2-oxiranecarboxylic acid ethyl ester Chemical compound C=1C=C(Cl)C=CC=1OCCCCCC[C@]1(C(=O)OCC)CO1 DZLOHEOHWICNIL-QGZVFWFLSA-N 0.000 description 1
- XUFXOAAUWZOOIT-SXARVLRPSA-N (2R,3R,4R,5S,6R)-5-[[(2R,3R,4R,5S,6R)-5-[[(2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl-5-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-1-cyclohex-2-enyl]amino]-2-oxanyl]oxy]-3,4-dihydroxy-6-(hydroxymethyl)-2-oxanyl]oxy]-6-(hydroxymethyl)oxane-2,3,4-triol Chemical compound O([C@H]1O[C@H](CO)[C@H]([C@@H]([C@H]1O)O)O[C@H]1O[C@@H]([C@H]([C@H](O)[C@H]1O)N[C@@H]1[C@@H]([C@@H](O)[C@H](O)C(CO)=C1)O)C)[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O XUFXOAAUWZOOIT-SXARVLRPSA-N 0.000 description 1
- BOOOLEGQBVUTKC-NVQSDHBMSA-N (2e,4e)-3-methyl-5-[(1s,2s)-2-methyl-2-(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)cyclopropyl]penta-2,4-dienoic acid Chemical compound OC(=O)\C=C(/C)\C=C\[C@@H]1C[C@]1(C)C1=CC=C2C(C)(C)CCC(C)(C)C2=C1 BOOOLEGQBVUTKC-NVQSDHBMSA-N 0.000 description 1
- HNODNXQAYXJFMQ-LQUSFLDPSA-N (2e,4e,6z)-3-methyl-7-(5,5,8,8-tetramethyl-3-propoxy-6,7-dihydronaphthalen-2-yl)octa-2,4,6-trienoic acid Chemical compound CC1(C)CCC(C)(C)C2=C1C=C(\C(C)=C/C=C/C(/C)=C/C(O)=O)C(OCCC)=C2 HNODNXQAYXJFMQ-LQUSFLDPSA-N 0.000 description 1
- VLPIATFUUWWMKC-SNVBAGLBSA-N (2r)-1-(2,6-dimethylphenoxy)propan-2-amine Chemical compound C[C@@H](N)COC1=C(C)C=CC=C1C VLPIATFUUWWMKC-SNVBAGLBSA-N 0.000 description 1
- FONCZICQWCUXEB-RUZDIDTESA-N (2r)-2-[4-(9-bromo-2,3-dimethylbenzo[f][1]benzothiol-4-yl)-2,6-dimethylphenoxy]-3-phenylpropanoic acid Chemical compound C([C@@H](OC1=C(C)C=C(C=C1C)C=1C2=CC=CC=C2C(Br)=C2SC(=C(C2=1)C)C)C(O)=O)C1=CC=CC=C1 FONCZICQWCUXEB-RUZDIDTESA-N 0.000 description 1
- GRYSXUXXBDSYRT-WOUKDFQISA-N (2r,3r,4r,5r)-2-(hydroxymethyl)-4-methoxy-5-[6-(methylamino)purin-9-yl]oxolan-3-ol Chemical compound C1=NC=2C(NC)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1OC GRYSXUXXBDSYRT-WOUKDFQISA-N 0.000 description 1
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- SEAQTHCVAGBRFY-INWYIAFRSA-N (2r,4s)-6-fluoro-2-methylspiro[2,3-dihydrochromene-4,5'-imidazolidine]-2',4'-dione Chemical compound C([C@H](OC1=CC=C(F)C=C11)C)[C@@]21NC(=O)NC2=O SEAQTHCVAGBRFY-INWYIAFRSA-N 0.000 description 1
- IGAAICGMRRWZJW-QMMMGPOBSA-N (2s)-1-(5-fluoro-6-methylsulfanyl-2,3-dihydroindol-1-yl)propan-2-amine Chemical compound C1=C(F)C(SC)=CC2=C1CCN2C[C@H](C)N IGAAICGMRRWZJW-QMMMGPOBSA-N 0.000 description 1
- QGRQJMXAQYGAKK-QMMMGPOBSA-N (2s)-1-(6-bromo-2,3-dihydroindol-1-yl)propan-2-amine Chemical compound C1=C(Br)C=C2N(C[C@@H](N)C)CCC2=C1 QGRQJMXAQYGAKK-QMMMGPOBSA-N 0.000 description 1
- KEGOAFNIGUBYHZ-SANMLTNESA-N (2s)-2-(2-methoxycarbonylanilino)-3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]propanoic acid Chemical compound COC(=O)C1=CC=CC=C1N[C@H](C(O)=O)CC(C=C1)=CC=C1OCCC1=C(C)OC(C=2C=CC=CC=2)=N1 KEGOAFNIGUBYHZ-SANMLTNESA-N 0.000 description 1
- GKYIONYOYVKKQI-MPGHIAIKSA-N (2s)-2-[[(2s,3r)-2-(benzoylsulfanylmethyl)-3-phenylbutanoyl]amino]propanoic acid Chemical compound C([C@H](C(=O)N[C@@H](C)C(O)=O)[C@@H](C)C=1C=CC=CC=1)SC(=O)C1=CC=CC=C1 GKYIONYOYVKKQI-MPGHIAIKSA-N 0.000 description 1
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 1
- LPUDGHQMOAHMMF-JBACZVJFSA-N (2s)-2-[[[(2s)-6-amino-2-(methanesulfonamido)hexanoyl]amino]methyl]-3-[1-[[(1s)-1-carboxy-2-(4-hydroxyphenyl)ethyl]carbamoyl]cyclopentyl]propanoic acid Chemical compound N([C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C(=O)C1(C[C@@H](CNC(=O)[C@H](CCCCN)NS(=O)(=O)C)C(O)=O)CCCC1 LPUDGHQMOAHMMF-JBACZVJFSA-N 0.000 description 1
- YKFCISHFRZHKHY-NGQGLHOPSA-N (2s)-2-amino-3-(3,4-dihydroxyphenyl)-2-methylpropanoic acid;trihydrate Chemical compound O.O.O.OC(=O)[C@](N)(C)CC1=CC=C(O)C(O)=C1.OC(=O)[C@](N)(C)CC1=CC=C(O)C(O)=C1 YKFCISHFRZHKHY-NGQGLHOPSA-N 0.000 description 1
- ZXEIEKDGPVTZLD-NDEPHWFRSA-N (2s)-2-dodecylsulfanyl-n-(4-hydroxy-2,3,5-trimethylphenyl)-2-phenylacetamide Chemical compound O=C([C@@H](SCCCCCCCCCCCC)C=1C=CC=CC=1)NC1=CC(C)=C(O)C(C)=C1C ZXEIEKDGPVTZLD-NDEPHWFRSA-N 0.000 description 1
- QNDFBOXBUCDYNZ-NRFANRHFSA-N (2s)-2-ethoxy-3-[4-[2-[4-[(2-methylpropan-2-yl)oxycarbonylamino]phenyl]ethoxy]phenyl]propanoic acid Chemical compound C1=CC(C[C@H](OCC)C(O)=O)=CC=C1OCCC1=CC=C(NC(=O)OC(C)(C)C)C=C1 QNDFBOXBUCDYNZ-NRFANRHFSA-N 0.000 description 1
- KWSPYUOBNIMILB-SANMLTNESA-N (2s)-2-methyl-3-[4-[2-(5-methyl-2-thiophen-2-yl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-phenoxypropanoic acid Chemical compound O([C@@](C)(CC1=CC=C(C=C1)OCCC=1N=C(OC=1C)C=1SC=CC=1)C(O)=O)C1=CC=CC=C1 KWSPYUOBNIMILB-SANMLTNESA-N 0.000 description 1
- RDGUFKZGMLPVHL-QFIPXVFZSA-N (2s)-3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-(propylamino)propanoic acid Chemical compound C1=CC(C[C@H](NCCC)C(O)=O)=CC=C1OCCC1=C(C)OC(C=2C=CC=CC=2)=N1 RDGUFKZGMLPVHL-QFIPXVFZSA-N 0.000 description 1
- CRUVAUSVWLATAE-ZDUSSCGKSA-N (2s)-3-dibenzofuran-3-yl-2-(phosphonomethylamino)propanoic acid Chemical compound C1=CC=C2C3=CC=C(C[C@@H](C(=O)O)NCP(O)(O)=O)C=C3OC2=C1 CRUVAUSVWLATAE-ZDUSSCGKSA-N 0.000 description 1
- ZWVMLYRJXORSEP-LURJTMIESA-N (2s)-hexane-1,2,6-triol Chemical compound OCCCC[C@H](O)CO ZWVMLYRJXORSEP-LURJTMIESA-N 0.000 description 1
- OAEWNSKRLBVVBV-QSEAXJEQSA-N (2s,3r,4s)-1-[2-(dibutylamino)-2-oxoethyl]-2-(2,2-dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylic acid Chemical compound OC(=O)[C@H]1[C@H](CC(C)(C)CCC)N(CC(=O)N(CCCC)CCCC)C[C@@H]1C(C=C1OC)=CC2=C1OCO2 OAEWNSKRLBVVBV-QSEAXJEQSA-N 0.000 description 1
- OOBHFESNSZDWIU-GXSJLCMTSA-N (2s,3s)-3-methyl-2-phenylmorpholine Chemical compound C[C@@H]1NCCO[C@H]1C1=CC=CC=C1 OOBHFESNSZDWIU-GXSJLCMTSA-N 0.000 description 1
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 description 1
- BIDNLKIUORFRQP-XYGFDPSESA-N (2s,4s)-4-cyclohexyl-1-[2-[[(1s)-2-methyl-1-propanoyloxypropoxy]-(4-phenylbutyl)phosphoryl]acetyl]pyrrolidine-2-carboxylic acid Chemical compound C([P@@](=O)(O[C@H](OC(=O)CC)C(C)C)CC(=O)N1[C@@H](C[C@H](C1)C1CCCCC1)C(O)=O)CCCC1=CC=CC=C1 BIDNLKIUORFRQP-XYGFDPSESA-N 0.000 description 1
- JSYGLDMGERSRPC-FQUUOJAGSA-N (2s,4s)-4-fluoro-1-[2-[[(1r,3s)-3-(1,2,4-triazol-1-ylmethyl)cyclopentyl]amino]acetyl]pyrrolidine-2-carbonitrile Chemical compound C1[C@@H](F)C[C@@H](C#N)N1C(=O)CN[C@H]1C[C@@H](CN2N=CN=C2)CC1 JSYGLDMGERSRPC-FQUUOJAGSA-N 0.000 description 1
- FEOHYDSNGHIXOM-WLDMJGECSA-N (3R,4R,5S,6R)-3-amino-6-(hydroxymethyl)-2-methyloxane-2,4,5-triol Chemical compound CC1(O)[C@H](N)[C@@H](O)[C@H](O)[C@H](O1)CO FEOHYDSNGHIXOM-WLDMJGECSA-N 0.000 description 1
- BDURKQYFVDQCFR-GASJEMHNSA-N (3R,4R,5S,6R)-3-amino-6-(hydroxymethyl)-2-sulfanyloxane-2,4,5-triol Chemical compound SC1(O)[C@H](N)[C@@H](O)[C@H](O)[C@H](O1)CO BDURKQYFVDQCFR-GASJEMHNSA-N 0.000 description 1
- DNXIKVLOVZVMQF-UHFFFAOYSA-N (3beta,16beta,17alpha,18beta,20alpha)-17-hydroxy-11-methoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]-yohimban-16-carboxylic acid, methyl ester Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(C(=O)OC)C(O)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 DNXIKVLOVZVMQF-UHFFFAOYSA-N 0.000 description 1
- LPYQDDHAJRABQA-DYESRHJHSA-N (3r)-3-[(13r)-13-hydroxy-10-oxotetradecyl]-5,7-dimethoxy-3h-2-benzofuran-1-one Chemical compound COC1=CC(OC)=CC2=C1C(=O)O[C@@H]2CCCCCCCCCC(=O)CC[C@@H](C)O LPYQDDHAJRABQA-DYESRHJHSA-N 0.000 description 1
- HLCHESOMJVGDSJ-LOYHVIPDSA-N (3r)-n-[(2r)-3-(4-chlorophenyl)-1-[4-cyclohexyl-4-(1,2,4-triazol-1-ylmethyl)piperidin-1-yl]-1-oxopropan-2-yl]-1,2,3,4-tetrahydroisoquinoline-3-carboxamide Chemical compound C1=CC(Cl)=CC=C1C[C@H](C(=O)N1CCC(CN2N=CN=C2)(CC1)C1CCCCC1)NC(=O)[C@@H]1NCC2=CC=CC=C2C1 HLCHESOMJVGDSJ-LOYHVIPDSA-N 0.000 description 1
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 description 1
- JVLBPIPGETUEET-WIXLDOGYSA-O (3r,4r,4as,7ar,12bs)-3-(cyclopropylmethyl)-4a,9-dihydroxy-3-methyl-2,4,5,6,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-3-ium-7-one Chemical compound C([N@+]1(C)[C@@H]2CC=3C4=C(C(=CC=3)O)O[C@@H]3[C@]4([C@@]2(O)CCC3=O)CC1)C1CC1 JVLBPIPGETUEET-WIXLDOGYSA-O 0.000 description 1
- CKFWDLFFXXVSBJ-DHIUTWEWSA-N (3r,5r)-3-butyl-3-ethyl-7,8-dimethoxy-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepine 1,1-dioxide Chemical compound C1([C@@H]2C3=CC(OC)=C(OC)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 CKFWDLFFXXVSBJ-DHIUTWEWSA-N 0.000 description 1
- HPFIYXJJZZWEPC-MMKWGKFASA-N (3r,5s,6e)-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(1-methyltetrazol-5-yl)nona-6,8-dienoic acid Chemical compound CN1N=NN=C1C(\C=C\[C@@H](O)C[C@@H](O)CC(O)=O)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 HPFIYXJJZZWEPC-MMKWGKFASA-N 0.000 description 1
- RICKQPKTSOSCOF-HKUYNNGSSA-N (3s)-2-[(2s)-2-amino-3-(1h-indol-3-yl)propanoyl]-3,4-dihydro-1h-isoquinoline-3-carboxylic acid Chemical compound C1C2=CC=CC=C2C[C@@H](C(O)=O)N1C(=O)[C@@H](N)CC1=CNC2=CC=CC=C12 RICKQPKTSOSCOF-HKUYNNGSSA-N 0.000 description 1
- KJEAKWPQCIAVGR-MERQFXBCSA-N (3s)-3-[(5-methoxy-2,3-dihydro-1h-inden-4-yl)oxy]pyrrolidine;hydrochloride Chemical compound Cl.COC1=CC=C2CCCC2=C1O[C@H]1CCNC1 KJEAKWPQCIAVGR-MERQFXBCSA-N 0.000 description 1
- DLOJBPLQFCFYKX-QQYYTUMTSA-N (3s)-4-[[(2r)-1-[2-[[(2s)-2-[[1h-indol-3-ylmethyl-[2-[[(2s)-2-[3-(4-sulfooxyphenyl)propanoylamino]hexanoyl]amino]acetyl]carbamoyl]amino]hexanoyl]carbamoyl]phenyl]propan-2-yl]amino]-3-(methylamino)-4-oxobutanoic acid Chemical compound N([C@@H](CCCC)C(=O)NCC(=O)N(CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCC)C(=O)NC(=O)C=1C(=CC=CC=1)C[C@@H](C)NC(=O)[C@H](CC(O)=O)NC)C(=O)CCC1=CC=C(OS(O)(=O)=O)C=C1 DLOJBPLQFCFYKX-QQYYTUMTSA-N 0.000 description 1
- VMDKRSNUUUUARH-MQDBWYGVSA-N (3s)-4-[[(2s)-1-[[(2s)-2-[[(2s)-3-(1h-indol-3-yl)-2-[[2-[[(2s)-2-[[2-(4-sulfooxyphenyl)acetyl]amino]hexanoyl]amino]acetyl]amino]propanoyl]amino]hexanoyl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(methylamino)-4-oxobutanoic acid Chemical compound N([C@@H](CCCC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCC)C(=O)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CC(O)=O)NC)C(=O)CC1=CC=C(OS(O)(=O)=O)C=C1 VMDKRSNUUUUARH-MQDBWYGVSA-N 0.000 description 1
- KNHCBYMGWWTGSO-ZYADHFCISA-N (3s)-4-[[(2s)-1-amino-1-oxo-3-phenylpropan-2-yl]-methylamino]-3-[[(2s)-2-[[(2s)-3-(1h-indol-3-yl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoyl]amino]-6-[(2-methylphenyl)carbamoylamino]hexanoyl]amino]-4-oxobutanoic acid Chemical compound C([C@H](N(C)C(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCCCNC(=O)NC=1C(=CC=CC=1)C)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)OC(C)(C)C)C(N)=O)C1=CC=CC=C1 KNHCBYMGWWTGSO-ZYADHFCISA-N 0.000 description 1
- NMOVJBAGBXIKCG-VKAVYKQESA-N (3z)-n-(2-hydroxy-3-piperidin-1-ylpropoxy)pyridine-3-carboximidoyl chloride Chemical compound C1CCCCN1CC(O)CO\N=C(/Cl)C1=CC=CN=C1 NMOVJBAGBXIKCG-VKAVYKQESA-N 0.000 description 1
- 108010040581 (4-hydroxy-3-(2-(2-propenyl)-4-quinoline)benzoyl)-(3-chloro-4-hydroxyarginyl)-(3-hydroxy-3-methylprolyl)-dehydrovaline Proteins 0.000 description 1
- BMHZAHGTGIZZCT-LJQANCHMSA-N (4r)-2-[(4-bromo-2-fluorophenyl)methyl]-6-fluorospiro[isoquinoline-4,3'-pyrrolidine]-1,2',3,5'-tetrone Chemical compound C1([C@]2(C(NC(=O)C2)=O)C2=O)=CC(F)=CC=C1C(=O)N2CC1=CC=C(Br)C=C1F BMHZAHGTGIZZCT-LJQANCHMSA-N 0.000 description 1
- VDSBXXDKCUBMQC-HNGSOEQISA-N (4r,6s)-6-[(e)-2-[2-(4-fluoro-3-methylphenyl)-4,4,6,6-tetramethylcyclohexen-1-yl]ethenyl]-4-hydroxyoxan-2-one Chemical compound C1=C(F)C(C)=CC(C=2CC(C)(C)CC(C)(C)C=2\C=C\[C@H]2OC(=O)C[C@H](O)C2)=C1 VDSBXXDKCUBMQC-HNGSOEQISA-N 0.000 description 1
- AIEZUMPHACQOGT-BJESRGMDSA-N (4s,7s,12br)-7-[[(2s)-2-acetylsulfanyl-3-phenylpropanoyl]amino]-6-oxo-2,3,4,7,8,12b-hexahydro-1h-pyrido[2,1-a][2]benzazepine-4-carboxylic acid Chemical compound C([C@H](SC(=O)C)C(=O)N[C@@H]1C(N2[C@@H](CCC[C@@H]2C2=CC=CC=C2C1)C(O)=O)=O)C1=CC=CC=C1 AIEZUMPHACQOGT-BJESRGMDSA-N 0.000 description 1
- IUHMIOAKWHUFKU-YINIXLNUSA-N (5s,6r,7r)-5-(1,3-benzodioxol-5-yl)-2-butyl-7-[2-[(2s)-2-carboxypropyl]-4-methoxyphenyl]-6,7-dihydro-5h-cyclopenta[b]pyridine-6-carboxylic acid Chemical compound C1([C@H]2[C@@H]([C@H](C3=CC=C(N=C32)CCCC)C=2C=C3OCOC3=CC=2)C(O)=O)=CC=C(OC)C=C1C[C@H](C)C(O)=O IUHMIOAKWHUFKU-YINIXLNUSA-N 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 description 1
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 description 1
- 125000006766 (C2-C6) alkynyloxy group Chemical group 0.000 description 1
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 1
- WSEQXVZVJXJVFP-HXUWFJFHSA-N (R)-citalopram Chemical compound C1([C@@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 WSEQXVZVJXJVFP-HXUWFJFHSA-N 0.000 description 1
- RTHCYVBBDHJXIQ-MRXNPFEDSA-N (R)-fluoxetine Chemical compound O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-MRXNPFEDSA-N 0.000 description 1
- PVHUJELLJLJGLN-INIZCTEOSA-N (S)-nitrendipine Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC([N+]([O-])=O)=C1 PVHUJELLJLJGLN-INIZCTEOSA-N 0.000 description 1
- TWBNMYSKRDRHAT-RCWTXCDDSA-N (S)-timolol hemihydrate Chemical compound O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 TWBNMYSKRDRHAT-RCWTXCDDSA-N 0.000 description 1
- KOHIRBRYDXPAMZ-YHBROIRLSA-N (S,R,R,R)-nebivolol Chemical compound C1CC2=CC(F)=CC=C2O[C@H]1[C@H](O)CNC[C@@H](O)[C@H]1OC2=CC=C(F)C=C2CC1 KOHIRBRYDXPAMZ-YHBROIRLSA-N 0.000 description 1
- LONWRQOYFPYMQD-DTQAZKPQSA-N (e)-n-[6-methoxy-5-(2-methoxyphenoxy)-2-pyrimidin-2-ylpyrimidin-4-yl]-2-phenylethenesulfonamide Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2N=CC=CN=2)OC)=C1NS(=O)(=O)\C=C\C1=CC=CC=C1 LONWRQOYFPYMQD-DTQAZKPQSA-N 0.000 description 1
- UPFPBOLHKZHRQR-DUTNZQCHSA-N (nz)-n-[(8r,9s,13s,14s)-3-methoxy-13-methyl-7,8,9,11,12,14,15,16-octahydro-6h-cyclopenta[a]phenanthren-17-ylidene]hydroxylamine Chemical compound C1C[C@]2(C)C(=N\O)/CC[C@H]2[C@@H]2CCC3=CC(OC)=CC=C3[C@H]21 UPFPBOLHKZHRQR-DUTNZQCHSA-N 0.000 description 1
- APQIUTYORBAGEZ-UHFFFAOYSA-N 1,1-dibromoethane Chemical compound CC(Br)Br APQIUTYORBAGEZ-UHFFFAOYSA-N 0.000 description 1
- AKHXXQAIVSMYIS-UHFFFAOYSA-N 1,1-dioxo-3-pentyl-6-(trifluoromethyl)-3,4-dihydro-2h-1$l^{6},2,4-benzothiadiazine-7-sulfonamide Chemical compound FC(F)(F)C1=C(S(N)(=O)=O)C=C2S(=O)(=O)NC(CCCCC)NC2=C1 AKHXXQAIVSMYIS-UHFFFAOYSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- VZXTWGWHSMCWGA-UHFFFAOYSA-N 1,3,5-triazine-2,4-diamine Chemical compound NC1=NC=NC(N)=N1 VZXTWGWHSMCWGA-UHFFFAOYSA-N 0.000 description 1
- ZOBPZXTWZATXDG-UHFFFAOYSA-N 1,3-thiazolidine-2,4-dione Chemical compound O=C1CSC(=O)N1 ZOBPZXTWZATXDG-UHFFFAOYSA-N 0.000 description 1
- KVGZZAHHUNAVKZ-UHFFFAOYSA-N 1,4-Dioxin Chemical compound O1C=COC=C1 KVGZZAHHUNAVKZ-UHFFFAOYSA-N 0.000 description 1
- VHFVKMTVMIZMIK-UHFFFAOYSA-N 1-(3-chlorophenyl)piperazine Chemical compound ClC1=CC=CC(N2CCNCC2)=C1 VHFVKMTVMIZMIK-UHFFFAOYSA-N 0.000 description 1
- UUOJIACWOAYWEZ-UHFFFAOYSA-N 1-(tert-butylamino)-3-[(2-methyl-1H-indol-4-yl)oxy]propan-2-yl benzoate Chemical compound C1=CC=C2NC(C)=CC2=C1OCC(CNC(C)(C)C)OC(=O)C1=CC=CC=C1 UUOJIACWOAYWEZ-UHFFFAOYSA-N 0.000 description 1
- 102000016752 1-Alkyl-2-acetylglycerophosphocholine Esterase Human genes 0.000 description 1
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 1
- GEVQMCFWDDZLMU-UHFFFAOYSA-N 1-[1-(3-ethoxyphenyl)propyl]-7-(pyrimidin-5-ylmethoxy)-4,5-dihydrobenzo[g]indazole-3-carboxylic acid Chemical compound CCOC1=CC=CC(C(CC)N2C=3C4=CC=C(OCC=5C=NC=NC=5)C=C4CCC=3C(C(O)=O)=N2)=C1 GEVQMCFWDDZLMU-UHFFFAOYSA-N 0.000 description 1
- POQMHHDKXWTFHB-HKBQPEDESA-N 1-[5-[(s)-(4,5-diphenyl-1h-imidazol-2-yl)sulfinyl]pentyl]-3,5-dimethylpyrazole Chemical compound N1=C(C)C=C(C)N1CCCCC[S@](=O)C1=NC(C=2C=CC=CC=2)=C(C=2C=CC=CC=2)N1 POQMHHDKXWTFHB-HKBQPEDESA-N 0.000 description 1
- AKJWTZIUYIFCCS-UHFFFAOYSA-N 1-cycloheptyl-1-[[3-[[cycloheptyl-[[4-(dimethylamino)phenyl]carbamoyl]amino]methyl]phenyl]methyl]-3-[4-(dimethylamino)phenyl]urea;dihydrochloride Chemical compound Cl.Cl.C1=CC(N(C)C)=CC=C1NC(=O)N(C1CCCCCC1)CC1=CC=CC(CN(C2CCCCCC2)C(=O)NC=2C=CC(=CC=2)N(C)C)=C1 AKJWTZIUYIFCCS-UHFFFAOYSA-N 0.000 description 1
- SIHFCVXQGXGQQO-UHFFFAOYSA-N 1-cyclohexyl-1-[[4-[[cyclohexyl-[[4-(dimethylamino)phenyl]carbamoyl]amino]methyl]cyclohexyl]methyl]-3-[4-(dimethylamino)phenyl]urea Chemical compound C1=CC(N(C)C)=CC=C1NC(=O)N(C1CCCCC1)CC1CCC(CN(C2CCCCC2)C(=O)NC=2C=CC(=CC=2)N(C)C)CC1 SIHFCVXQGXGQQO-UHFFFAOYSA-N 0.000 description 1
- LLJFMFZYVVLQKT-UHFFFAOYSA-N 1-cyclohexyl-3-[4-[2-(7-methoxy-4,4-dimethyl-1,3-dioxo-2-isoquinolinyl)ethyl]phenyl]sulfonylurea Chemical compound C=1C(OC)=CC=C(C(C2=O)(C)C)C=1C(=O)N2CCC(C=C1)=CC=C1S(=O)(=O)NC(=O)NC1CCCCC1 LLJFMFZYVVLQKT-UHFFFAOYSA-N 0.000 description 1
- LBGWMVXVPMPEID-UHFFFAOYSA-N 1-hydroxyhexane-3,4-dione Chemical compound CCC(=O)C(=O)CCO LBGWMVXVPMPEID-UHFFFAOYSA-N 0.000 description 1
- VSWPGAIWKHPTKX-UHFFFAOYSA-N 1-methyl-10-[2-(4-methyl-1-piperazinyl)-1-oxoethyl]-5H-thieno[3,4-b][1,5]benzodiazepin-4-one Chemical compound C1CN(C)CCN1CC(=O)N1C2=CC=CC=C2NC(=O)C2=CSC(C)=C21 VSWPGAIWKHPTKX-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- 101710175516 14 kDa zinc-binding protein Proteins 0.000 description 1
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 description 1
- NVYSVDRYESXWBD-UHFFFAOYSA-N 2-(1h-benzimidazol-2-ylsulfanyl)-1-(3,4-dihydroxyphenyl)ethanone Chemical compound C1=C(O)C(O)=CC=C1C(=O)CSC1=NC2=CC=CC=C2N1 NVYSVDRYESXWBD-UHFFFAOYSA-N 0.000 description 1
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 description 1
- DEMLYXMVPJAVFU-UHFFFAOYSA-N 2-(chloromethyl)oxirane;2-methyl-1h-imidazole Chemical compound ClCC1CO1.CC1=NC=CN1 DEMLYXMVPJAVFU-UHFFFAOYSA-N 0.000 description 1
- VTAKZNRDSPNOAU-UHFFFAOYSA-M 2-(chloromethyl)oxirane;hydron;prop-2-en-1-amine;n-prop-2-enyldecan-1-amine;trimethyl-[6-(prop-2-enylamino)hexyl]azanium;dichloride Chemical compound Cl.[Cl-].NCC=C.ClCC1CO1.CCCCCCCCCCNCC=C.C[N+](C)(C)CCCCCCNCC=C VTAKZNRDSPNOAU-UHFFFAOYSA-M 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- XMQODGUTLZXUGZ-RPBOFIJWSA-N 2-[(3s)-3-[[1-[(2r)-2-ethoxycarbonyl-4-phenylbutyl]cyclopentanecarbonyl]amino]-2-oxo-4,5-dihydro-3h-1-benzazepin-1-yl]acetic acid Chemical compound C([C@@H](C(=O)OCC)CC1(CCCC1)C(=O)N[C@@H]1C(N(CC(O)=O)C2=CC=CC=C2CC1)=O)CC1=CC=CC=C1 XMQODGUTLZXUGZ-RPBOFIJWSA-N 0.000 description 1
- CUADMYMMZWFUCY-FQEVSTJZSA-N 2-[(4-methoxyphenoxy)carbonyl-[(1s)-1-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]ethyl]amino]acetic acid Chemical compound C1=CC(OC)=CC=C1OC(=O)N(CC(O)=O)[C@@H](C)C(C=C1)=CC=C1OCCC1=C(C)OC(C=2C=CC=CC=2)=N1 CUADMYMMZWFUCY-FQEVSTJZSA-N 0.000 description 1
- IRGLQUMAHASUTG-IUCAKERBSA-N 2-[(6s,9s)-3-ethoxycarbonyl-6-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-9-yl]acetic acid Chemical compound OC(=O)C[C@@H]1CC[C@H](C)N2C(=O)C(C(=O)OCC)=CN=C21 IRGLQUMAHASUTG-IUCAKERBSA-N 0.000 description 1
- NNBGCSGCRSCFEA-UHFFFAOYSA-N 2-[2-[(2,3-difluorophenyl)methylsulfanyl]-4-oxoquinolin-1-yl]-n-[1-(2-methoxyethyl)piperidin-4-yl]-n-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]acetamide Chemical compound C1CN(CCOC)CCC1N(C(=O)CN1C2=CC=CC=C2C(=O)C=C1SCC=1C(=C(F)C=CC=1)F)CC1=CC=C(C=2C=CC(=CC=2)C(F)(F)F)C=C1 NNBGCSGCRSCFEA-UHFFFAOYSA-N 0.000 description 1
- HTFNVAVTYILUCF-UHFFFAOYSA-N 2-[2-ethoxy-4-[4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl]anilino]-5-methyl-11-methylsulfonylpyrimido[4,5-b][1,4]benzodiazepin-6-one Chemical compound CCOc1cc(ccc1Nc1ncc2N(C)C(=O)c3ccccc3N(c2n1)S(C)(=O)=O)C(=O)N1CCC(CC1)N1CCN(C)CC1 HTFNVAVTYILUCF-UHFFFAOYSA-N 0.000 description 1
- DLZGQGBHYCAKQA-UHFFFAOYSA-N 2-[3-[(4,5,7-trifluoro-1,3-benzothiazol-2-yl)methyl]indol-1-yl]acetic acid;hydrate Chemical compound O.C12=CC=CC=C2N(CC(=O)O)C=C1CC1=NC2=C(F)C(F)=CC(F)=C2S1 DLZGQGBHYCAKQA-UHFFFAOYSA-N 0.000 description 1
- LKBFFDOJUKLQNY-UHFFFAOYSA-N 2-[3-[(4-bromo-2-fluorophenyl)methyl]-4-oxo-1-phthalazinyl]acetic acid Chemical compound O=C1C2=CC=CC=C2C(CC(=O)O)=NN1CC1=CC=C(Br)C=C1F LKBFFDOJUKLQNY-UHFFFAOYSA-N 0.000 description 1
- XNGGRURGYIXOBY-UHFFFAOYSA-N 2-[3-[1-(4-fluorobenzoyl)piperidin-4-yl]phenoxy]-2-methylpropanoic acid Chemical compound OC(=O)C(C)(C)OC1=CC=CC(C2CCN(CC2)C(=O)C=2C=CC(F)=CC=2)=C1 XNGGRURGYIXOBY-UHFFFAOYSA-N 0.000 description 1
- ZGGNJJJYUVRADP-ACJLOTCBSA-N 2-[4-[(2R)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]phenoxy]acetic acid Chemical compound C([C@@H](C)NC[C@H](O)C=1C=C(Cl)C=CC=1)C1=CC=C(OCC(O)=O)C=C1 ZGGNJJJYUVRADP-ACJLOTCBSA-N 0.000 description 1
- RVMBDLSFFNKKLG-SFHVURJKSA-N 2-[4-[2-[[(2s)-2-hydroxy-3-phenoxypropyl]amino]ethoxy]phenoxy]-n-(2-methoxyethyl)acetamide Chemical compound C1=CC(OCC(=O)NCCOC)=CC=C1OCCNC[C@H](O)COC1=CC=CC=C1 RVMBDLSFFNKKLG-SFHVURJKSA-N 0.000 description 1
- MUGOTNWCTZMBLV-UHFFFAOYSA-N 2-[4-oxo-2-(2-propan-2-ylidenehydrazinyl)-1,3-thiazol-5-yl]-n-phenylacetamide Chemical compound S1C(NN=C(C)C)=NC(=O)C1CC(=O)NC1=CC=CC=C1 MUGOTNWCTZMBLV-UHFFFAOYSA-N 0.000 description 1
- MCHCGWZNXSZKJY-OEAKJJBVSA-N 2-[[2-[2-butyl-4-[(e)-2-carboxy-3-(6-methoxy-1,3-benzodioxol-5-yl)prop-1-enyl]pyrazol-3-yl]-5-methoxyphenoxy]methyl]benzoic acid Chemical compound CCCCN1N=CC(\C=C(/CC=2C(=CC=3OCOC=3C=2)OC)C(O)=O)=C1C1=CC=C(OC)C=C1OCC1=CC=CC=C1C(O)=O MCHCGWZNXSZKJY-OEAKJJBVSA-N 0.000 description 1
- FHEYFIGWYQJVDR-ACJLOTCBSA-N 2-[[3-[(2r)-2-[[(2r)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1h-indol-7-yl]oxy]acetic acid Chemical compound C1([C@@H](O)CN[C@@H](CC=2C3=CC=CC(OCC(O)=O)=C3NC=2)C)=CC=CC(Cl)=C1 FHEYFIGWYQJVDR-ACJLOTCBSA-N 0.000 description 1
- SVAHMQCUSNJPRX-UHFFFAOYSA-N 2-[[hydroxy-[(2,3,4,5,6-pentafluorophenyl)methyl]phosphoryl]methyl]pentanedioic acid Chemical compound OC(=O)CCC(C(O)=O)CP(O)(=O)CC1=C(F)C(F)=C(F)C(F)=C1F SVAHMQCUSNJPRX-UHFFFAOYSA-N 0.000 description 1
- BJBCSGQLZQGGIQ-QGZVFWFLSA-N 2-acetamidoethyl (2r)-2-(4-chlorophenyl)-2-[3-(trifluoromethyl)phenoxy]acetate Chemical compound O([C@@H](C(=O)OCCNC(=O)C)C=1C=CC(Cl)=CC=1)C1=CC=CC(C(F)(F)F)=C1 BJBCSGQLZQGGIQ-QGZVFWFLSA-N 0.000 description 1
- CCTREOMTIFSZAU-OGFXRTJISA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;5-[(3r)-dithiolan-3-yl]pentanoic acid Chemical compound OCC(N)(CO)CO.OC(=O)CCCC[C@@H]1CCSS1 CCTREOMTIFSZAU-OGFXRTJISA-N 0.000 description 1
- MVNILNMAOCFOOH-UHFFFAOYSA-N 2-aminoundecan-1-ol Chemical compound CCCCCCCCCC(N)CO MVNILNMAOCFOOH-UHFFFAOYSA-N 0.000 description 1
- JIVPVXMEBJLZRO-CQSZACIVSA-N 2-chloro-5-[(1r)-1-hydroxy-3-oxo-2h-isoindol-1-yl]benzenesulfonamide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC([C@@]2(O)C3=CC=CC=C3C(=O)N2)=C1 JIVPVXMEBJLZRO-CQSZACIVSA-N 0.000 description 1
- NTWBHJYRDKBGBR-UHFFFAOYSA-N 2-ethylbenzaldehyde Chemical compound CCC1=CC=CC=C1C=O NTWBHJYRDKBGBR-UHFFFAOYSA-N 0.000 description 1
- SGUAFYQXFOLMHL-UHFFFAOYSA-N 2-hydroxy-5-{1-hydroxy-2-[(4-phenylbutan-2-yl)amino]ethyl}benzamide Chemical compound C=1C=C(O)C(C(N)=O)=CC=1C(O)CNC(C)CCC1=CC=CC=C1 SGUAFYQXFOLMHL-UHFFFAOYSA-N 0.000 description 1
- HZLCGUXUOFWCCN-UHFFFAOYSA-N 2-hydroxynonadecane-1,2,3-tricarboxylic acid Chemical compound CCCCCCCCCCCCCCCCC(C(O)=O)C(O)(C(O)=O)CC(O)=O HZLCGUXUOFWCCN-UHFFFAOYSA-N 0.000 description 1
- YZQLWPMZQVHJED-UHFFFAOYSA-N 2-methylpropanethioic acid S-[2-[[[1-(2-ethylbutyl)cyclohexyl]-oxomethyl]amino]phenyl] ester Chemical compound C=1C=CC=C(SC(=O)C(C)C)C=1NC(=O)C1(CC(CC)CC)CCCCC1 YZQLWPMZQVHJED-UHFFFAOYSA-N 0.000 description 1
- 125000006024 2-pentenyl group Chemical group 0.000 description 1
- WFCSWCVEJLETKA-UHFFFAOYSA-N 2-piperazin-1-ylethanol Chemical compound OCCN1CCNCC1 WFCSWCVEJLETKA-UHFFFAOYSA-N 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- BCSVCWVQNOXFGL-UHFFFAOYSA-N 3,4-dihydro-4-oxo-3-((5-trifluoromethyl-2-benzothiazolyl)methyl)-1-phthalazine acetic acid Chemical compound O=C1C2=CC=CC=C2C(CC(=O)O)=NN1CC1=NC2=CC(C(F)(F)F)=CC=C2S1 BCSVCWVQNOXFGL-UHFFFAOYSA-N 0.000 description 1
- HPOIPOPJGBKXIR-UHFFFAOYSA-N 3,6-dimethoxy-10-methyl-galantham-1-ene Natural products O1C(C(=CC=2)OC)=C3C=2CN(C)CCC23C1CC(OC)C=C2 HPOIPOPJGBKXIR-UHFFFAOYSA-N 0.000 description 1
- TVXOXGBTADZYCZ-UHFFFAOYSA-N 3-(2,4-difluorophenyl)-1-[5-[(4,5-diphenyl-1h-imidazol-2-yl)sulfanyl]pentyl]-1-heptylurea Chemical compound C=1C=C(F)C=C(F)C=1NC(=O)N(CCCCCCC)CCCCCSC(N1)=NC(C=2C=CC=CC=2)=C1C1=CC=CC=C1 TVXOXGBTADZYCZ-UHFFFAOYSA-N 0.000 description 1
- VMJQLPNCUPGMNQ-HNNXBMFYSA-N 3-[(2s)-6-hydroxy-2,7,8-trimethyl-3,4-dihydrochromen-2-yl]propanoic acid Chemical compound C1C[C@@](C)(CCC(O)=O)OC2=C(C)C(C)=C(O)C=C21 VMJQLPNCUPGMNQ-HNNXBMFYSA-N 0.000 description 1
- CABBMMXFOOZVMS-PMERELPUSA-N 3-[[(3s)-2,4-dioxo-1-[2-oxo-2-(n-propan-2-ylanilino)ethyl]-5-phenyl-1,5-benzodiazepin-3-yl]carbamoylamino]benzoic acid Chemical compound C=1C=CC=CC=1N(C(C)C)C(=O)CN(C([C@H](NC(=O)NC=1C=C(C=CC=1)C(O)=O)C1=O)=O)C2=CC=CC=C2N1C1=CC=CC=C1 CABBMMXFOOZVMS-PMERELPUSA-N 0.000 description 1
- 125000004080 3-carboxypropanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C(O[H])=O 0.000 description 1
- UIAGMCDKSXEBJQ-IBGZPJMESA-N 3-o-(2-methoxyethyl) 5-o-propan-2-yl (4s)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)[C@H]1C1=CC=CC([N+]([O-])=O)=C1 UIAGMCDKSXEBJQ-IBGZPJMESA-N 0.000 description 1
- ZGRIPYHIFXGCHR-UHFFFAOYSA-N 3-o-[2-[(4-fluorophenyl)methyl-methylamino]ethyl] 5-o-propan-2-yl 4-(1,3-benzodioxol-4-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound C=1C=CC=2OCOC=2C=1C1C(C(=O)OC(C)C)=C(C)NC(C)=C1C(=O)OCCN(C)CC1=CC=C(F)C=C1 ZGRIPYHIFXGCHR-UHFFFAOYSA-N 0.000 description 1
- LINVVMHRTUSXHL-GGVPDPBRSA-N 3beta-hydroxy-5alpha-cholest-8(14)-en-15-one Chemical compound C([C@@H]1CC2)[C@@H](O)CC[C@]1(C)[C@@H]1C2=C2C(=O)C[C@H]([C@H](C)CCCC(C)C)[C@@]2(C)CC1 LINVVMHRTUSXHL-GGVPDPBRSA-N 0.000 description 1
- LUPJXXHWXBKHOO-DYVFJYSZSA-N 4-[(2r)-2-[[(2r)-2-hydroxy-2-phenylethyl]amino]propyl]benzoic acid Chemical compound C([C@@H](C)NC[C@H](O)C=1C=CC=CC=1)C1=CC=C(C(O)=O)C=C1 LUPJXXHWXBKHOO-DYVFJYSZSA-N 0.000 description 1
- LGSOKZOQANLOEU-UHFFFAOYSA-N 4-[2-(2,4-dioxo-1,3-thiazolidin-5-yl)ethoxy]benzonitrile Chemical compound S1C(=O)NC(=O)C1CCOC1=CC=C(C#N)C=C1 LGSOKZOQANLOEU-UHFFFAOYSA-N 0.000 description 1
- FXIPXWLVYIHFEP-OAQYLSRUSA-N 4-[4-[3-[(3r)-3-(dimethylamino)pyrrolidin-1-yl]propoxy]phenyl]benzonitrile Chemical compound C1[C@H](N(C)C)CCN1CCCOC1=CC=C(C=2C=CC(=CC=2)C#N)C=C1 FXIPXWLVYIHFEP-OAQYLSRUSA-N 0.000 description 1
- 125000004860 4-ethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])C([H])([H])[H] 0.000 description 1
- MJRGSRRZKSJHOE-UHFFFAOYSA-N 5-(dimethylamino)-N-(3,4-dimethyl-5-isoxazolyl)-1-naphthalenesulfonamide Chemical compound C1=CC=C2C(N(C)C)=CC=CC2=C1S(=O)(=O)NC=1ON=C(C)C=1C MJRGSRRZKSJHOE-UHFFFAOYSA-N 0.000 description 1
- 102000006902 5-HT2C Serotonin Receptor Human genes 0.000 description 1
- 108010072553 5-HT2C Serotonin Receptor Proteins 0.000 description 1
- JEDJMKTVUPSHFW-ABAIWWIYSA-L 5-[(2r)-2-[[(2r)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1,3-benzodioxole-2,2-dicarboxylate Chemical compound C1([C@@H](O)CN[C@@H](CC=2C=C3OC(OC3=CC=2)(C([O-])=O)C([O-])=O)C)=CC=CC(Cl)=C1 JEDJMKTVUPSHFW-ABAIWWIYSA-L 0.000 description 1
- HGLFNRGXRCKGSW-UHFFFAOYSA-N 5-[(3,5-ditert-butyl-4-hydroxyanilino)-[[4-(2,2-dimethylpropyl)phenyl]methyl-hexylamino]methylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione Chemical compound C=1C(C(C)(C)C)=C(O)C(C(C)(C)C)=CC=1NC(=C1C(OC(C)(C)OC1=O)=O)N(CCCCCC)CC1=CC=C(CC(C)(C)C)C=C1 HGLFNRGXRCKGSW-UHFFFAOYSA-N 0.000 description 1
- YROKAAIPBSCMJN-UHFFFAOYSA-N 5-hydroxy-2,4-dimethyl-8-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]pyrido[2,3-d]pyrimidin-7-one Chemical compound C12=NC(C)=NC(C)=C2C(O)=CC(=O)N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=NN1 YROKAAIPBSCMJN-UHFFFAOYSA-N 0.000 description 1
- OTTHUQAYARCXLP-UHFFFAOYSA-N 5-o-[2-[4-(4-benzhydrylpiperazin-1-yl)phenyl]ethyl] 3-o-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCCC=2C=CC(=CC=2)N2CCN(CC2)C(C=2C=CC=CC=2)C=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 OTTHUQAYARCXLP-UHFFFAOYSA-N 0.000 description 1
- VFFZWMWTUSXDCB-ZDUSSCGKSA-N 6-[2-[[2-[(2s)-2-cyanopyrrolidin-1-yl]-2-oxoethyl]amino]ethylamino]pyridine-3-carbonitrile Chemical compound N1([C@@H](CCC1)C#N)C(=O)CNCCNC1=CC=C(C#N)C=N1 VFFZWMWTUSXDCB-ZDUSSCGKSA-N 0.000 description 1
- RBSGUQYXRDKPAE-QFIPXVFZSA-N 6-[4-[2-[[(2s)-3-(9h-carbazol-4-yloxy)-2-hydroxypropyl]amino]-2-methylpropyl]phenoxy]pyridine-3-carboxamide Chemical compound C([C@H](O)COC=1C=2C3=CC=CC=C3NC=2C=CC=1)NC(C)(C)CC(C=C1)=CC=C1OC1=CC=C(C(N)=O)C=N1 RBSGUQYXRDKPAE-QFIPXVFZSA-N 0.000 description 1
- BKYKPTRYDKTTJY-UHFFFAOYSA-N 6-chloro-3-(cyclopentylmethyl)-1,1-dioxo-3,4-dihydro-2H-1$l^{6},2,4-benzothiadiazine-7-sulfonamide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(S(N2)(=O)=O)=C1NC2CC1CCCC1 BKYKPTRYDKTTJY-UHFFFAOYSA-N 0.000 description 1
- 108010023016 A 71378 Proteins 0.000 description 1
- DTDZLJHKVNTQGZ-GOSISDBHSA-N AZD7545 Chemical compound C1=CC(C(=O)N(C)C)=CC=C1S(=O)(=O)C1=CC=C(NC(=O)[C@@](C)(O)C(F)(F)F)C(Cl)=C1 DTDZLJHKVNTQGZ-GOSISDBHSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 229940100578 Acetylcholinesterase inhibitor Drugs 0.000 description 1
- 108010013043 Acetylesterase Proteins 0.000 description 1
- DJQOOSBJCLSSEY-UHFFFAOYSA-N Acipimox Chemical compound CC1=CN=C(C(O)=O)C=[N+]1[O-] DJQOOSBJCLSSEY-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical group OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 229930024421 Adenine Natural products 0.000 description 1
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 101100047644 Arabidopsis thaliana ATHX gene Proteins 0.000 description 1
- 108010024976 Asparaginase Proteins 0.000 description 1
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 description 1
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 description 1
- PTQXTEKSNBVPQJ-UHFFFAOYSA-N Avasimibe Chemical compound CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1CC(=O)NS(=O)(=O)OC1=C(C(C)C)C=CC=C1C(C)C PTQXTEKSNBVPQJ-UHFFFAOYSA-N 0.000 description 1
- ZKFQEACEUNWPMT-UHFFFAOYSA-N Azelnidipine Chemical compound CC(C)OC(=O)C1=C(C)NC(N)=C(C(=O)OC2CN(C2)C(C=2C=CC=CC=2)C=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 ZKFQEACEUNWPMT-UHFFFAOYSA-N 0.000 description 1
- 239000005552 B01AC04 - Clopidogrel Substances 0.000 description 1
- 239000005528 B01AC05 - Ticlopidine Substances 0.000 description 1
- FBMCYYWIBYEOST-GJFSDDNBSA-N BIBO-3304 Chemical compound OC(=O)C(F)(F)F.N([C@H](CCCNC(=N)N)C(=O)NCC=1C=CC(CNC(N)=O)=CC=1)C(=O)C(C=1C=CC=CC=1)C1=CC=CC=C1 FBMCYYWIBYEOST-GJFSDDNBSA-N 0.000 description 1
- 102100023995 Beta-nerve growth factor Human genes 0.000 description 1
- QVZCXCJXTMIDME-UHFFFAOYSA-N Biopropazepan Trimethoxybenzoate Chemical compound COC1=C(OC)C(OC)=CC(C(=O)OCCCN2CCN(CCCOC(=O)C=3C=C(OC)C(OC)=C(OC)C=3)CCC2)=C1 QVZCXCJXTMIDME-UHFFFAOYSA-N 0.000 description 1
- 201000004569 Blindness Diseases 0.000 description 1
- RHLJLALHBZGAFM-UHFFFAOYSA-N Bunazosinum Chemical compound C1CN(C(=O)CCC)CCCN1C1=NC(N)=C(C=C(OC)C(OC)=C2)C2=N1 RHLJLALHBZGAFM-UHFFFAOYSA-N 0.000 description 1
- ISMDILRWKSYCOD-GNKBHMEESA-N C(C1=CC=CC=C1)[C@@H]1NC(OCCCCCCCCCCCNC([C@@H](NC(C[C@@H]1O)=O)C(C)C)=O)=O Chemical compound C(C1=CC=CC=C1)[C@@H]1NC(OCCCCCCCCCCCNC([C@@H](NC(C[C@@H]1O)=O)C(C)C)=O)=O ISMDILRWKSYCOD-GNKBHMEESA-N 0.000 description 1
- 229930182476 C-glycoside Natural products 0.000 description 1
- 150000000700 C-glycosides Chemical class 0.000 description 1
- 239000002083 C09CA01 - Losartan Substances 0.000 description 1
- 239000002080 C09CA02 - Eprosartan Substances 0.000 description 1
- 239000004072 C09CA03 - Valsartan Substances 0.000 description 1
- 239000002947 C09CA04 - Irbesartan Substances 0.000 description 1
- 239000002081 C09CA05 - Tasosartan Substances 0.000 description 1
- 239000005537 C09CA07 - Telmisartan Substances 0.000 description 1
- 239000002051 C09CA08 - Olmesartan medoxomil Substances 0.000 description 1
- AQGKERWMIBDHLF-UHFFFAOYSA-N CCON(C#N)OC Chemical compound CCON(C#N)OC AQGKERWMIBDHLF-UHFFFAOYSA-N 0.000 description 1
- UMQUQWCJKFOUGV-UHFFFAOYSA-N CGP 12177 Chemical compound CC(C)(C)NCC(O)COC1=CC=CC2=C1NC(=O)N2 UMQUQWCJKFOUGV-UHFFFAOYSA-N 0.000 description 1
- 108010055448 CJC 1131 Proteins 0.000 description 1
- QLTVVOATEHFXLT-UHFFFAOYSA-N Cadralazine Chemical compound CCOC(=O)NNC1=CC=C(N(CC)CC(C)O)N=N1 QLTVVOATEHFXLT-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- GHOSNRCGJFBJIB-UHFFFAOYSA-N Candesartan cilexetil Chemical compound C=12N(CC=3C=CC(=CC=3)C=3C(=CC=CC=3)C3=NNN=N3)C(OCC)=NC2=CC=CC=1C(=O)OC(C)OC(=O)OC1CCCCC1 GHOSNRCGJFBJIB-UHFFFAOYSA-N 0.000 description 1
- 229940123158 Cannabinoid CB1 receptor antagonist Drugs 0.000 description 1
- 244000025254 Cannabis sativa Species 0.000 description 1
- 235000012766 Cannabis sativa ssp. sativa var. sativa Nutrition 0.000 description 1
- 235000012765 Cannabis sativa ssp. sativa var. spontanea Nutrition 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- JOATXPAWOHTVSZ-UHFFFAOYSA-N Celiprolol Chemical compound CCN(CC)C(=O)NC1=CC=C(OCC(O)CNC(C)(C)C)C(C(C)=O)=C1 JOATXPAWOHTVSZ-UHFFFAOYSA-N 0.000 description 1
- LPCKPBWOSNVCEL-UHFFFAOYSA-N Chlidanthine Natural products O1C(C(=CC=2)O)=C3C=2CN(C)CCC23C1CC(OC)C=C2 LPCKPBWOSNVCEL-UHFFFAOYSA-N 0.000 description 1
- RKWGIWYCVPQPMF-UHFFFAOYSA-N Chloropropamide Chemical compound CCCNC(=O)NS(=O)(=O)C1=CC=C(Cl)C=C1 RKWGIWYCVPQPMF-UHFFFAOYSA-N 0.000 description 1
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 description 1
- 229940122502 Cholesterol absorption inhibitor Drugs 0.000 description 1
- CVKNDPRBJVBDSS-UHFFFAOYSA-N Cicletanine Chemical compound O1CC2=C(O)C(C)=NC=C2C1C1=CC=C(Cl)C=C1 CVKNDPRBJVBDSS-UHFFFAOYSA-N 0.000 description 1
- KJEBULYHNRNJTE-DHZHZOJOSA-N Cinalong Chemical compound COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC\C=C\C=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 KJEBULYHNRNJTE-DHZHZOJOSA-N 0.000 description 1
- 235000005979 Citrus limon Nutrition 0.000 description 1
- 244000131522 Citrus pyriformis Species 0.000 description 1
- BMOVQUBVGICXQN-UHFFFAOYSA-N Clinofibrate Chemical compound C1=CC(OC(C)(CC)C(O)=O)=CC=C1C1(C=2C=CC(OC(C)(CC)C(O)=O)=CC=2)CCCCC1 BMOVQUBVGICXQN-UHFFFAOYSA-N 0.000 description 1
- 229920002905 Colesevelam Polymers 0.000 description 1
- 229920000230 Colestilan Polymers 0.000 description 1
- 229920002911 Colestipol Polymers 0.000 description 1
- 229940126639 Compound 33 Drugs 0.000 description 1
- OCUCCJIRFHNWBP-IYEMJOQQSA-L Copper gluconate Chemical class [Cu+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O OCUCCJIRFHNWBP-IYEMJOQQSA-L 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical group N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 1
- 229930105110 Cyclosporin A Natural products 0.000 description 1
- 108010036949 Cyclosporine Proteins 0.000 description 1
- 101710088194 Dehydrogenase Proteins 0.000 description 1
- 108010016626 Dipeptides Proteins 0.000 description 1
- 229940124213 Dipeptidyl peptidase 4 (DPP IV) inhibitor Drugs 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 108010061435 Enalapril Proteins 0.000 description 1
- 229940118365 Endothelin receptor antagonist Drugs 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102400001368 Epidermal growth factor Human genes 0.000 description 1
- 101800003838 Epidermal growth factor Proteins 0.000 description 1
- 241000588722 Escherichia Species 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- HTQBXNHDCUEHJF-XWLPCZSASA-N Exenatide Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)NCC(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 HTQBXNHDCUEHJF-XWLPCZSASA-N 0.000 description 1
- 108010011459 Exenatide Proteins 0.000 description 1
- 206010073689 Familial renal glycosuria Diseases 0.000 description 1
- 102000030914 Fatty Acid-Binding Human genes 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- 102000027487 Fructose-Bisphosphatase Human genes 0.000 description 1
- 108010017464 Fructose-Bisphosphatase Proteins 0.000 description 1
- GGUVRMBIEPYOKL-WMVCGJOFSA-N GW 409544 Chemical compound C([C@H](NC(/C)=C\C(=O)C=1C=CC=CC=1)C(O)=O)C(C=C1)=CC=C1OCCC(=C(O1)C)N=C1C1=CC=CC=C1 GGUVRMBIEPYOKL-WMVCGJOFSA-N 0.000 description 1
- YDBLKRPLXZNVNB-UHFFFAOYSA-N GW 501516 Chemical compound CC=1N=C(C=2C=CC(=CC=2)C(F)(F)F)SC=1CSC1=CC=C(OCC(O)=O)C(C)=C1 YDBLKRPLXZNVNB-UHFFFAOYSA-N 0.000 description 1
- XQLWNAFCTODIRK-UHFFFAOYSA-N Gallopamil Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC(OC)=C(OC)C(OC)=C1 XQLWNAFCTODIRK-UHFFFAOYSA-N 0.000 description 1
- HEMJJKBWTPKOJG-UHFFFAOYSA-N Gemfibrozil Chemical compound CC1=CC=C(C)C(OCCCC(C)(C)C(O)=O)=C1 HEMJJKBWTPKOJG-UHFFFAOYSA-N 0.000 description 1
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical class C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 1
- 229940089838 Glucagon-like peptide 1 receptor agonist Drugs 0.000 description 1
- FAEKWTJYAYMJKF-QHCPKHFHSA-N GlucoNorm Chemical compound C1=C(C(O)=O)C(OCC)=CC(CC(=O)N[C@@H](CC(C)C)C=2C(=CC=CC=2)N2CCCCC2)=C1 FAEKWTJYAYMJKF-QHCPKHFHSA-N 0.000 description 1
- 102000003638 Glucose-6-Phosphatase Human genes 0.000 description 1
- 108010086800 Glucose-6-Phosphatase Proteins 0.000 description 1
- 102000017278 Glutaredoxin Human genes 0.000 description 1
- 108050005205 Glutaredoxin Proteins 0.000 description 1
- NMWQEPCLNXHPDX-UHFFFAOYSA-N Glybuzole Chemical compound S1C(C(C)(C)C)=NN=C1NS(=O)(=O)C1=CC=CC=C1 NMWQEPCLNXHPDX-UHFFFAOYSA-N 0.000 description 1
- HNSCCNJWTJUGNQ-UHFFFAOYSA-N Glyclopyramide Chemical compound C1=CC(Cl)=CC=C1S(=O)(=O)NC(=O)NN1CCCC1 HNSCCNJWTJUGNQ-UHFFFAOYSA-N 0.000 description 1
- 102000001895 Gonadotropin Receptors Human genes 0.000 description 1
- 108010040490 Gonadotropin Receptors Proteins 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- WDZVGELJXXEGPV-YIXHJXPBSA-N Guanabenz Chemical compound NC(N)=N\N=C\C1=C(Cl)C=CC=C1Cl WDZVGELJXXEGPV-YIXHJXPBSA-N 0.000 description 1
- INJOMKTZOLKMBF-UHFFFAOYSA-N Guanfacine Chemical compound NC(=N)NC(=O)CC1=C(Cl)C=CC=C1Cl INJOMKTZOLKMBF-UHFFFAOYSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- 102000003746 Insulin Receptor Human genes 0.000 description 1
- 108010001127 Insulin Receptor Proteins 0.000 description 1
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 1
- 102100037852 Insulin-like growth factor I Human genes 0.000 description 1
- 108010041872 Islet Amyloid Polypeptide Proteins 0.000 description 1
- 102000036770 Islet Amyloid Polypeptide Human genes 0.000 description 1
- KLDXJTOLSGUMSJ-JGWLITMVSA-N Isosorbide Chemical compound O[C@@H]1CO[C@@H]2[C@@H](O)CO[C@@H]21 KLDXJTOLSGUMSJ-JGWLITMVSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-M L-tartrate(1-) Chemical compound OC(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-M 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 description 1
- XUIIKFGFIJCVMT-LBPRGKRZSA-N L-thyroxine Chemical compound IC1=CC(C[C@H]([NH3+])C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-LBPRGKRZSA-N 0.000 description 1
- 102000000853 LDL receptors Human genes 0.000 description 1
- 108010001831 LDL receptors Proteins 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 102000016267 Leptin Human genes 0.000 description 1
- 108010092277 Leptin Proteins 0.000 description 1
- 229940127470 Lipase Inhibitors Drugs 0.000 description 1
- 239000000867 Lipoxygenase Inhibitor Substances 0.000 description 1
- YSDQQAXHVYUZIW-QCIJIYAXSA-N Liraglutide Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)CC[C@H](NC(=O)CCCCCCCCCCCCCCC)C(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=C(O)C=C1 YSDQQAXHVYUZIW-QCIJIYAXSA-N 0.000 description 1
- 108010019598 Liraglutide Proteins 0.000 description 1
- 108010007859 Lisinopril Proteins 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- ZPXSCAKFGYXMGA-UHFFFAOYSA-N Mazindol Chemical compound N12CCN=C2C2=CC=CC=C2C1(O)C1=CC=C(Cl)C=C1 ZPXSCAKFGYXMGA-UHFFFAOYSA-N 0.000 description 1
- SMNOERSLNYGGOU-UHFFFAOYSA-N Mefruside Chemical compound C=1C=C(Cl)C(S(N)(=O)=O)=CC=1S(=O)(=O)N(C)CC1(C)CCCO1 SMNOERSLNYGGOU-UHFFFAOYSA-N 0.000 description 1
- 102000001796 Melanocortin 4 receptors Human genes 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- CESYKOGBSMNBPD-UHFFFAOYSA-N Methyclothiazide Chemical compound ClC1=C(S(N)(=O)=O)C=C2S(=O)(=O)N(C)C(CCl)NC2=C1 CESYKOGBSMNBPD-UHFFFAOYSA-N 0.000 description 1
- FNQQBFNIYODEMB-UHFFFAOYSA-N Meticrane Chemical compound C1CCS(=O)(=O)C2=C1C=C(C)C(S(N)(=O)=O)=C2 FNQQBFNIYODEMB-UHFFFAOYSA-N 0.000 description 1
- 229940127308 Microsomal Triglyceride Transfer Protein Inhibitors Drugs 0.000 description 1
- IBAQFPQHRJAVAV-ULAWRXDQSA-N Miglitol Chemical compound OCCN1C[C@H](O)[C@@H](O)[C@H](O)[C@H]1CO IBAQFPQHRJAVAV-ULAWRXDQSA-N 0.000 description 1
- WPNJAUFVNXKLIM-UHFFFAOYSA-N Moxonidine Chemical compound COC1=NC(C)=NC(Cl)=C1NC1=NCCN1 WPNJAUFVNXKLIM-UHFFFAOYSA-N 0.000 description 1
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 description 1
- WGZDBVOTUVNQFP-UHFFFAOYSA-N N-(1-phthalazinylamino)carbamic acid ethyl ester Chemical compound C1=CC=C2C(NNC(=O)OCC)=NN=CC2=C1 WGZDBVOTUVNQFP-UHFFFAOYSA-N 0.000 description 1
- QKDDJDBFONZGBW-UHFFFAOYSA-N N-Cyclohexy-4-(imidazol-4-yl)-1-piperidinecarbothioamide Chemical compound C1CC(C=2NC=NC=2)CCN1C(=S)NC1CCCCC1 QKDDJDBFONZGBW-UHFFFAOYSA-N 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- RJMJKGLPUURIPR-UHFFFAOYSA-N NC(C)(C)C1C(=CC2=CC=CC=C12)O Chemical compound NC(C)(C)C1C(=CC2=CC=CC=C12)O RJMJKGLPUURIPR-UHFFFAOYSA-N 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- WJBLNOPPDWQMCH-MBPVOVBZSA-N Nalmefene Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=C)O)CC1)O)CC1CC1 WJBLNOPPDWQMCH-MBPVOVBZSA-N 0.000 description 1
- UIQMVEYFGZJHCZ-SSTWWWIQSA-N Nalorphine Chemical compound C([C@@H](N(CC1)CC=C)[C@@H]2C=C[C@@H]3O)C4=CC=C(O)C5=C4[C@@]21[C@H]3O5 UIQMVEYFGZJHCZ-SSTWWWIQSA-N 0.000 description 1
- OKJHGOPITGTTIM-DEOSSOPVSA-N Naveglitazar Chemical compound C1=CC(C[C@H](OC)C(O)=O)=CC=C1OCCCOC(C=C1)=CC=C1OC1=CC=CC=C1 OKJHGOPITGTTIM-DEOSSOPVSA-N 0.000 description 1
- 102000007072 Nerve Growth Factors Human genes 0.000 description 1
- 101100258328 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) crc-2 gene Proteins 0.000 description 1
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical class OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- ZBBHBTPTTSWHBA-UHFFFAOYSA-N Nicardipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN(C)CC=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 ZBBHBTPTTSWHBA-UHFFFAOYSA-N 0.000 description 1
- KUEUWHJGRZKESU-UHFFFAOYSA-N Niceritrol Chemical compound C=1C=CN=CC=1C(=O)OCC(COC(=O)C=1C=NC=CC=1)(COC(=O)C=1C=NC=CC=1)COC(=O)C1=CC=CN=C1 KUEUWHJGRZKESU-UHFFFAOYSA-N 0.000 description 1
- VRAHPESAMYMDQI-UHFFFAOYSA-N Nicomol Chemical compound C1CCC(COC(=O)C=2C=NC=CC=2)(COC(=O)C=2C=NC=CC=2)C(O)C1(COC(=O)C=1C=NC=CC=1)COC(=O)C1=CC=CN=C1 VRAHPESAMYMDQI-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- APSUXPSYBJVPPS-YAUKWVCOSA-N Norbinaltorphimine Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CC=2C=3C[C@]4(O)[C@]67CCN(CC8CC8)[C@@H]4CC=4C7=C(C(=CC=4)O)O[C@H]6C=3NC=25)O)CC1)O)CC1CC1 APSUXPSYBJVPPS-YAUKWVCOSA-N 0.000 description 1
- KYYIDSXMWOZKMP-UHFFFAOYSA-N O-desmethylvenlafaxine Chemical compound C1CCCCC1(O)C(CN(C)C)C1=CC=C(O)C=C1 KYYIDSXMWOZKMP-UHFFFAOYSA-N 0.000 description 1
- CUDJOCJWYVMHIV-UHFFFAOYSA-N OC(CCCCCCCCCNC)(O)O Chemical compound OC(CCCCCCCCCNC)(O)O CUDJOCJWYVMHIV-UHFFFAOYSA-N 0.000 description 1
- 108010038807 Oligopeptides Proteins 0.000 description 1
- 102000015636 Oligopeptides Human genes 0.000 description 1
- 239000005480 Olmesartan Substances 0.000 description 1
- UQGKUQLKSCSZGY-UHFFFAOYSA-N Olmesartan medoxomil Chemical compound C=1C=C(C=2C(=CC=CC=2)C2=NNN=N2)C=CC=1CN1C(CCC)=NC(C(C)(C)O)=C1C(=O)OCC=1OC(=O)OC=1C UQGKUQLKSCSZGY-UHFFFAOYSA-N 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 102000004316 Oxidoreductases Human genes 0.000 description 1
- 108090000854 Oxidoreductases Proteins 0.000 description 1
- 229910019213 POCl3 Inorganic materials 0.000 description 1
- AHOUBRCZNHFOSL-UHFFFAOYSA-N Paroxetine hydrochloride Natural products C1=CC(F)=CC=C1C1C(COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-UHFFFAOYSA-N 0.000 description 1
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 1
- 102000003992 Peroxidases Human genes 0.000 description 1
- 229940122054 Peroxisome proliferator-activated receptor delta agonist Drugs 0.000 description 1
- MFOCDFTXLCYLKU-CMPLNLGQSA-N Phendimetrazine Chemical compound O1CCN(C)[C@@H](C)[C@@H]1C1=CC=CC=C1 MFOCDFTXLCYLKU-CMPLNLGQSA-N 0.000 description 1
- 229940123898 Phospholipase A2 inhibitor Drugs 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- TUZYXOIXSAXUGO-UHFFFAOYSA-N Pravastatin Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(O)C=C21 TUZYXOIXSAXUGO-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical class CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 1
- 229940123924 Protein kinase C inhibitor Drugs 0.000 description 1
- LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 description 1
- QEVHRUUCFGRFIF-SFWBKIHZSA-N Reserpine Natural products O=C(OC)[C@@H]1[C@H](OC)[C@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)C[C@H]2[C@@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cc(OC)cc3 QEVHRUUCFGRFIF-SFWBKIHZSA-N 0.000 description 1
- 229940121908 Retinoid X receptor agonist Drugs 0.000 description 1
- NCDNCNXCDXHOMX-UHFFFAOYSA-N Ritonavir Natural products C=1C=CC=CC=1CC(NC(=O)OCC=1SC=NC=1)C(O)CC(CC=1C=CC=CC=1)NC(=O)C(C(C)C)NC(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-UHFFFAOYSA-N 0.000 description 1
- XSVMFMHYUFZWBK-NSHDSACASA-N Rivastigmine Chemical compound CCN(C)C(=O)OC1=CC=CC([C@H](C)N(C)C)=C1 XSVMFMHYUFZWBK-NSHDSACASA-N 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 description 1
- AJLFOPYRIVGYMJ-UHFFFAOYSA-N SJ000287055 Natural products C12C(OC(=O)C(C)CC)CCC=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 AJLFOPYRIVGYMJ-UHFFFAOYSA-N 0.000 description 1
- 229910006124 SOCl2 Inorganic materials 0.000 description 1
- 241000239226 Scorpiones Species 0.000 description 1
- 206010070834 Sensitisation Diseases 0.000 description 1
- 229940121991 Serotonin and norepinephrine reuptake inhibitor Drugs 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- PJANXHGTPQOBST-VAWYXSNFSA-N Stilbene Natural products C=1C=CC=CC=1/C=C/C1=CC=CC=C1 PJANXHGTPQOBST-VAWYXSNFSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229920000439 Sulodexide Polymers 0.000 description 1
- NAVMQTYZDKMPEU-UHFFFAOYSA-N Targretin Chemical compound CC1=CC(C(CCC2(C)C)(C)C)=C2C=C1C(=C)C1=CC=C(C(O)=O)C=C1 NAVMQTYZDKMPEU-UHFFFAOYSA-N 0.000 description 1
- HTWFXPCUFWKXOP-UHFFFAOYSA-N Tertatalol Chemical compound C1CCSC2=C1C=CC=C2OCC(O)CNC(C)(C)C HTWFXPCUFWKXOP-UHFFFAOYSA-N 0.000 description 1
- 229940123464 Thiazolidinedione Drugs 0.000 description 1
- 108010036928 Thiorphan Proteins 0.000 description 1
- 229940123876 Thyroid hormone receptor beta agonist Drugs 0.000 description 1
- AUYYCJSJGJYCDS-LBPRGKRZSA-N Thyrolar Chemical compound IC1=CC(C[C@H](N)C(O)=O)=CC(I)=C1OC1=CC=C(O)C(I)=C1 AUYYCJSJGJYCDS-LBPRGKRZSA-N 0.000 description 1
- 229910003074 TiCl4 Inorganic materials 0.000 description 1
- JLRGJRBPOGGCBT-UHFFFAOYSA-N Tolbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(C)C=C1 JLRGJRBPOGGCBT-UHFFFAOYSA-N 0.000 description 1
- KJADKKWYZYXHBB-XBWDGYHZSA-N Topiramic acid Chemical compound C1O[C@@]2(COS(N)(=O)=O)OC(C)(C)O[C@H]2[C@@H]2OC(C)(C)O[C@@H]21 KJADKKWYZYXHBB-XBWDGYHZSA-N 0.000 description 1
- 229940123468 Transferase inhibitor Drugs 0.000 description 1
- GSNOZLZNQMLSKJ-UHFFFAOYSA-N Trapidil Chemical compound CCN(CC)C1=CC(C)=NC2=NC=NN12 GSNOZLZNQMLSKJ-UHFFFAOYSA-N 0.000 description 1
- FNYLWPVRPXGIIP-UHFFFAOYSA-N Triamterene Chemical compound NC1=NC2=NC(N)=NC(N)=C2N=C1C1=CC=CC=C1 FNYLWPVRPXGIIP-UHFFFAOYSA-N 0.000 description 1
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical compound ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 102100040411 Tripeptidyl-peptidase 2 Human genes 0.000 description 1
- 108010021436 Type 4 Melanocortin Receptor Proteins 0.000 description 1
- ICMGLRUYEQNHPF-UHFFFAOYSA-N Uraprene Chemical compound COC1=CC=CC=C1N1CCN(CCCNC=2N(C(=O)N(C)C(=O)C=2)C)CC1 ICMGLRUYEQNHPF-UHFFFAOYSA-N 0.000 description 1
- 206010047141 Vasodilatation Diseases 0.000 description 1
- 206010047571 Visual impairment Diseases 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- JVVXZOOGOGPDRZ-SLFFLAALSA-N [(1R,4aS,10aR)-1,4a-dimethyl-7-propan-2-yl-2,3,4,9,10,10a-hexahydrophenanthren-1-yl]methanamine Chemical compound NC[C@]1(C)CCC[C@]2(C)C3=CC=C(C(C)C)C=C3CC[C@H]21 JVVXZOOGOGPDRZ-SLFFLAALSA-N 0.000 description 1
- NWLFOBZKYXKBOF-NSVAZKTRSA-N [(1s,2s)-2-[[2,2-dimethylpropyl(nonyl)carbamoyl]amino]cyclohexyl] 3-[[(4r)-2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl]amino]propanoate Chemical compound CCCCCCCCCN(CC(C)(C)C)C(=O)N[C@H]1CCCC[C@@H]1OC(=O)CCNC(=O)[C@H]1C(C)(C)COC(C)(C)O1 NWLFOBZKYXKBOF-NSVAZKTRSA-N 0.000 description 1
- FLRQOWAOMJMSTP-JJTRIOAGSA-N [(2s)-2-[(2r)-3,4-dihydroxy-5-oxo-2h-furan-2-yl]-2-hydroxyethyl] (6z,9z,12z)-octadeca-6,9,12-trienoate Chemical compound CCCCC\C=C/C\C=C/C\C=C/CCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O FLRQOWAOMJMSTP-JJTRIOAGSA-N 0.000 description 1
- GYKFWCDBQAFCLJ-RTWAWAEBSA-N [(2s,3s)-8-chloro-5-[2-(dimethylamino)ethyl]-2-(4-methoxyphenyl)-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl] acetate Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=C(Cl)C=C2S1 GYKFWCDBQAFCLJ-RTWAWAEBSA-N 0.000 description 1
- JNLNXPCQHIQTRM-ACJLOTCBSA-N [4-[(2r)-2-[[(2r)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]phenoxy]methanesulfonic acid Chemical compound C([C@@H](C)NC[C@H](O)C=1C=C(Cl)C=CC=1)C1=CC=C(OCS(O)(=O)=O)C=C1 JNLNXPCQHIQTRM-ACJLOTCBSA-N 0.000 description 1
- WUEHURHTEPWPPO-QZTJIDSGSA-N [4-[(4r,5r)-2-[[[2,6-di(propan-2-yl)phenyl]carbamoylamino]methyl]-4,5-dimethyl-1,3-dioxolan-2-yl]phenyl] dihydrogen phosphate Chemical compound CC(C)C1=CC=CC(C(C)C)=C1NC(=O)NCC1(C=2C=CC(OP(O)(O)=O)=CC=2)O[C@H](C)[C@@H](C)O1 WUEHURHTEPWPPO-QZTJIDSGSA-N 0.000 description 1
- UUMKQZVEZSXWBY-HNNXBMFYSA-N [[(1s)-2-(4-phenylphenyl)-1-(2h-tetrazol-5-yl)ethyl]amino]methylphosphonic acid Chemical compound C([C@H](NCP(O)(=O)O)C1=NNN=N1)C(C=C1)=CC=C1C1=CC=CC=C1 UUMKQZVEZSXWBY-HNNXBMFYSA-N 0.000 description 1
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 1
- WREOTYWODABZMH-DTZQCDIJSA-N [[(2r,3s,4r,5r)-3,4-dihydroxy-5-[2-oxo-4-(2-phenylethoxyamino)pyrimidin-1-yl]oxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O[C@H]1N(C=C\1)C(=O)NC/1=N\OCCC1=CC=CC=C1 WREOTYWODABZMH-DTZQCDIJSA-N 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 229960002632 acarbose Drugs 0.000 description 1
- XUFXOAAUWZOOIT-UHFFFAOYSA-N acarviostatin I01 Natural products OC1C(O)C(NC2C(C(O)C(O)C(CO)=C2)O)C(C)OC1OC(C(C1O)O)C(CO)OC1OC1C(CO)OC(O)C(O)C1O XUFXOAAUWZOOIT-UHFFFAOYSA-N 0.000 description 1
- 229960002122 acebutolol Drugs 0.000 description 1
- GOEMGAFJFRBGGG-UHFFFAOYSA-N acebutolol Chemical compound CCCC(=O)NC1=CC=C(OCC(O)CNC(C)C)C(C(C)=O)=C1 GOEMGAFJFRBGGG-UHFFFAOYSA-N 0.000 description 1
- 229960002054 acenocoumarol Drugs 0.000 description 1
- VABCILAOYCMVPS-UHFFFAOYSA-N acenocoumarol Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=C([N+]([O-])=O)C=C1 VABCILAOYCMVPS-UHFFFAOYSA-N 0.000 description 1
- 229960000571 acetazolamide Drugs 0.000 description 1
- BZKPWHYZMXOIDC-UHFFFAOYSA-N acetazolamide Chemical compound CC(=O)NC1=NN=C(S(N)(=O)=O)S1 BZKPWHYZMXOIDC-UHFFFAOYSA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 229960001466 acetohexamide Drugs 0.000 description 1
- VGZSUPCWNCWDAN-UHFFFAOYSA-N acetohexamide Chemical compound C1=CC(C(=O)C)=CC=C1S(=O)(=O)NC(=O)NC1CCCCC1 VGZSUPCWNCWDAN-UHFFFAOYSA-N 0.000 description 1
- WEVYAHXRMPXWCK-FIBGUPNXSA-N acetonitrile-d3 Chemical compound [2H]C([2H])([2H])C#N WEVYAHXRMPXWCK-FIBGUPNXSA-N 0.000 description 1
- 229960003526 acipimox Drugs 0.000 description 1
- 229950010285 acitemate Drugs 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- WSLOHMLGIVSUPR-UHFFFAOYSA-N adn-138 Chemical compound C1COC2=CC(Cl)=CC3=C2N1C(=O)C31CC(=O)NC1=O WSLOHMLGIVSUPR-UHFFFAOYSA-N 0.000 description 1
- 229940040563 agaric acid Drugs 0.000 description 1
- 238000000246 agarose gel electrophoresis Methods 0.000 description 1
- 239000003288 aldose reductase inhibitor Substances 0.000 description 1
- 229940090865 aldose reductase inhibitors used in diabetes Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001336 alkenes Chemical group 0.000 description 1
- 125000004849 alkoxymethyl group Chemical group 0.000 description 1
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 description 1
- 125000005233 alkylalcohol group Chemical group 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 125000005225 alkynyloxycarbonyl group Chemical group 0.000 description 1
- OFCNXPDARWKPPY-UHFFFAOYSA-N allopurinol Chemical compound OC1=NC=NC2=C1C=NN2 OFCNXPDARWKPPY-UHFFFAOYSA-N 0.000 description 1
- 229960003459 allopurinol Drugs 0.000 description 1
- 229960002414 ambrisentan Drugs 0.000 description 1
- OUJTZYPIHDYQMC-LJQANCHMSA-N ambrisentan Chemical compound O([C@@H](C(OC)(C=1C=CC=CC=1)C=1C=CC=CC=1)C(O)=O)C1=NC(C)=CC(C)=N1 OUJTZYPIHDYQMC-LJQANCHMSA-N 0.000 description 1
- 229960000959 amineptine Drugs 0.000 description 1
- VDPUXONTAVMIKZ-UHFFFAOYSA-N amineptine hydrochloride Chemical compound [Cl-].C1CC2=CC=CC=C2C([NH2+]CCCCCCC(=O)O)C2=CC=CC=C21 VDPUXONTAVMIKZ-UHFFFAOYSA-N 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- HAMNKKUPIHEESI-UHFFFAOYSA-N aminoguanidine Chemical compound NNC(N)=N HAMNKKUPIHEESI-UHFFFAOYSA-N 0.000 description 1
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 1
- PECIYKGSSMCNHN-UHFFFAOYSA-N aminophylline Chemical compound NCCN.O=C1N(C)C(=O)N(C)C2=NC=N[C]21.O=C1N(C)C(=O)N(C)C2=NC=N[C]21 PECIYKGSSMCNHN-UHFFFAOYSA-N 0.000 description 1
- 229960003556 aminophylline Drugs 0.000 description 1
- HTIQEAQVCYTUBX-UHFFFAOYSA-N amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-UHFFFAOYSA-N 0.000 description 1
- 229960000528 amlodipine Drugs 0.000 description 1
- LVEXHFZHOIWIIP-UHFFFAOYSA-N amosulalol Chemical compound COC1=CC=CC=C1OCCNCC(O)C1=CC=C(C)C(S(N)(=O)=O)=C1 LVEXHFZHOIWIIP-UHFFFAOYSA-N 0.000 description 1
- 229950010351 amosulalol Drugs 0.000 description 1
- 229940025084 amphetamine Drugs 0.000 description 1
- APKFDSVGJQXUKY-INPOYWNPSA-N amphotericin B Chemical class O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-INPOYWNPSA-N 0.000 description 1
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 1
- 229960000723 ampicillin Drugs 0.000 description 1
- 239000002269 analeptic agent Substances 0.000 description 1
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 229960002138 anisindione Drugs 0.000 description 1
- XRCFXMGQEVUZFC-UHFFFAOYSA-N anisindione Chemical compound C1=CC(OC)=CC=C1C1C(=O)C2=CC=CC=C2C1=O XRCFXMGQEVUZFC-UHFFFAOYSA-N 0.000 description 1
- 230000001539 anorectic effect Effects 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 229940127003 anti-diabetic drug Drugs 0.000 description 1
- 230000003178 anti-diabetic effect Effects 0.000 description 1
- 239000000883 anti-obesity agent Substances 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 230000009118 appropriate response Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 239000008135 aqueous vehicle Substances 0.000 description 1
- 125000001204 arachidyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000002102 aryl alkyloxo group Chemical group 0.000 description 1
- 125000005199 aryl carbonyloxy group Chemical group 0.000 description 1
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 1
- 125000005279 aryl sulfonyloxy group Chemical group 0.000 description 1
- 229950005963 ascorbyl gamolenate Drugs 0.000 description 1
- 229960002430 atomoxetine Drugs 0.000 description 1
- VHGCDTVCOLNTBX-QGZVFWFLSA-N atomoxetine Chemical compound O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=CC=C1C VHGCDTVCOLNTBX-QGZVFWFLSA-N 0.000 description 1
- 229960005370 atorvastatin Drugs 0.000 description 1
- 229950010046 avasimibe Drugs 0.000 description 1
- 108010014210 axokine Proteins 0.000 description 1
- 229950004646 azelnidipine Drugs 0.000 description 1
- 229960004988 azosemide Drugs 0.000 description 1
- IIOPLILENRZKRV-UHFFFAOYSA-N azosemide Chemical compound C=1C=CSC=1CNC=1C=C(Cl)C(S(=O)(=O)N)=CC=1C1=NN=N[N]1 IIOPLILENRZKRV-UHFFFAOYSA-N 0.000 description 1
- 229960002992 barnidipine Drugs 0.000 description 1
- VXMOONUMYLCFJD-DHLKQENFSA-N barnidipine Chemical compound C1([C@@H]2C(=C(C)NC(C)=C2C(=O)OC)C(=O)O[C@@H]2CN(CC=3C=CC=CC=3)CC2)=CC=CC([N+]([O-])=O)=C1 VXMOONUMYLCFJD-DHLKQENFSA-N 0.000 description 1
- YWQGBCXVCXMSLJ-UHFFFAOYSA-N beclobrate Chemical compound C1=CC(OC(C)(CC)C(=O)OCC)=CC=C1CC1=CC=C(Cl)C=C1 YWQGBCXVCXMSLJ-UHFFFAOYSA-N 0.000 description 1
- 229950009252 beclobrate Drugs 0.000 description 1
- 229960003515 bendroflumethiazide Drugs 0.000 description 1
- HDWIHXWEUNVBIY-UHFFFAOYSA-N bendroflumethiazidum Chemical compound C1=C(C(F)(F)F)C(S(=O)(=O)N)=CC(S(N2)(=O)=O)=C1NC2CC1=CC=CC=C1 HDWIHXWEUNVBIY-UHFFFAOYSA-N 0.000 description 1
- 229960004916 benidipine Drugs 0.000 description 1
- QZVNQOLPLYWLHQ-ZEQKJWHPSA-N benidipine Chemical compound C1([C@H]2C(=C(C)NC(C)=C2C(=O)OC)C(=O)O[C@H]2CN(CC=3C=CC=CC=3)CCC2)=CC=CC([N+]([O-])=O)=C1 QZVNQOLPLYWLHQ-ZEQKJWHPSA-N 0.000 description 1
- 229960002529 benzbromarone Drugs 0.000 description 1
- WHQCHUCQKNIQEC-UHFFFAOYSA-N benzbromarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC(Br)=C(O)C(Br)=C1 WHQCHUCQKNIQEC-UHFFFAOYSA-N 0.000 description 1
- 229940076134 benzene Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- BMWITAUNXBHIPO-OZZZDHQUSA-N benzenesulfonic acid;(2s,4s)-4-fluoro-1-[2-[(1-hydroxy-2-methylpropan-2-yl)amino]acetyl]pyrrolidine-2-carbonitrile Chemical compound OS(=O)(=O)C1=CC=CC=C1.OCC(C)(C)NCC(=O)N1C[C@@H](F)C[C@H]1C#N BMWITAUNXBHIPO-OZZZDHQUSA-N 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 125000004619 benzopyranyl group Chemical group O1C(C=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- YXKTVDFXDRQTKV-HNNXBMFYSA-N benzphetamine Chemical compound C([C@H](C)N(C)CC=1C=CC=CC=1)C1=CC=CC=C1 YXKTVDFXDRQTKV-HNNXBMFYSA-N 0.000 description 1
- 229960002837 benzphetamine Drugs 0.000 description 1
- KKBIUAUSZKGNOA-HNAYVOBHSA-N benzyl (2s)-2-[[(2s)-2-(acetylsulfanylmethyl)-3-(1,3-benzodioxol-5-yl)propanoyl]amino]propanoate Chemical compound O=C([C@@H](NC(=O)[C@@H](CSC(C)=O)CC=1C=C2OCOC2=CC=1)C)OCC1=CC=CC=C1 KKBIUAUSZKGNOA-HNAYVOBHSA-N 0.000 description 1
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 229950005357 bervastatin Drugs 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 1
- 108010051210 beta-Fructofuranosidase Proteins 0.000 description 1
- DRTQHJPVMGBUCF-PSQAKQOGSA-N beta-L-uridine Natural products O[C@H]1[C@@H](O)[C@H](CO)O[C@@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-PSQAKQOGSA-N 0.000 description 1
- 229960004324 betaxolol Drugs 0.000 description 1
- CHDPSNLJFOQTRK-UHFFFAOYSA-N betaxolol hydrochloride Chemical compound [Cl-].C1=CC(OCC(O)C[NH2+]C(C)C)=CC=C1CCOCC1CC1 CHDPSNLJFOQTRK-UHFFFAOYSA-N 0.000 description 1
- 229960003588 bevantolol Drugs 0.000 description 1
- HXLAFSUPPDYFEO-UHFFFAOYSA-N bevantolol Chemical compound C1=C(OC)C(OC)=CC=C1CCNCC(O)COC1=CC=CC(C)=C1 HXLAFSUPPDYFEO-UHFFFAOYSA-N 0.000 description 1
- 229960002938 bexarotene Drugs 0.000 description 1
- KUWBXRGRMQZCSS-HSZRJFAPSA-N bibp-3226 Chemical compound N([C@H](CCCN=C(N)N)C(=O)NCC=1C=CC(O)=CC=1)C(=O)C(C=1C=CC=CC=1)C1=CC=CC=C1 KUWBXRGRMQZCSS-HSZRJFAPSA-N 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 150000004283 biguanides Chemical class 0.000 description 1
- 229950002409 bimoclomol Drugs 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 239000004621 biodegradable polymer Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229960001035 bopindolol Drugs 0.000 description 1
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 1
- 229960003065 bosentan Drugs 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 229950001730 budralazine Drugs 0.000 description 1
- DQGFCLJXYFXXIJ-LFIBNONCSA-N budralazine Chemical compound C1=CC=C2C(N/N=C(C)/C=C(C)C)=NN=CC2=C1 DQGFCLJXYFXXIJ-LFIBNONCSA-N 0.000 description 1
- 229960004111 buformin Drugs 0.000 description 1
- XSEUMFJMFFMCIU-UHFFFAOYSA-N buformin Chemical compound CCCC\N=C(/N)N=C(N)N XSEUMFJMFFMCIU-UHFFFAOYSA-N 0.000 description 1
- MAEIEVLCKWDQJH-UHFFFAOYSA-N bumetanide Chemical compound CCCCNC1=CC(C(O)=O)=CC(S(N)(=O)=O)=C1OC1=CC=CC=C1 MAEIEVLCKWDQJH-UHFFFAOYSA-N 0.000 description 1
- 229960004064 bumetanide Drugs 0.000 description 1
- 229960002467 bunazosin Drugs 0.000 description 1
- 229960001058 bupropion Drugs 0.000 description 1
- SNPPWIUOZRMYNY-UHFFFAOYSA-N bupropion Chemical compound CC(C)(C)NC(C)C(=O)C1=CC=CC(Cl)=C1 SNPPWIUOZRMYNY-UHFFFAOYSA-N 0.000 description 1
- VIHAEDVKXSOUAT-UHFFFAOYSA-N but-2-en-4-olide Chemical compound O=C1OCC=C1 VIHAEDVKXSOUAT-UHFFFAOYSA-N 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 229960005211 cadralazine Drugs 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 229960004349 candesartan cilexetil Drugs 0.000 description 1
- 239000003555 cannabinoid 1 receptor antagonist Substances 0.000 description 1
- FAKRSMQSSFJEIM-RQJHMYQMSA-N captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 description 1
- 229960000830 captopril Drugs 0.000 description 1
- 235000013877 carbamide Nutrition 0.000 description 1
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 229940096529 carboxypolymethylene Drugs 0.000 description 1
- 229960004203 carnitine Drugs 0.000 description 1
- 229960001222 carteolol Drugs 0.000 description 1
- LWAFSWPYPHEXKX-UHFFFAOYSA-N carteolol Chemical compound N1C(=O)CCC2=C1C=CC=C2OCC(O)CNC(C)(C)C LWAFSWPYPHEXKX-UHFFFAOYSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 229960002320 celiprolol Drugs 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 229940083181 centrally acting adntiadrenergic agent methyldopa Drugs 0.000 description 1
- 229960005110 cerivastatin Drugs 0.000 description 1
- SEERZIQQUAZTOL-ANMDKAQQSA-N cerivastatin Chemical compound COCC1=C(C(C)C)N=C(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC(O)=O)=C1C1=CC=C(F)C=C1 SEERZIQQUAZTOL-ANMDKAQQSA-N 0.000 description 1
- MVCQKIKWYUURMU-UHFFFAOYSA-N cetilistat Chemical compound C1=C(C)C=C2C(=O)OC(OCCCCCCCCCCCCCCCC)=NC2=C1 MVCQKIKWYUURMU-UHFFFAOYSA-N 0.000 description 1
- 229950002397 cetilistat Drugs 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- ZWGWSFHAZWNQQE-VPLSKCCHSA-N chembl1836102 Chemical compound Cl.C1=CC=C2C(N)=NC(NC[C@@H]3CC[C@@H](CNS(=O)(=O)C=4C=C5C=CC=CC5=CC=4)CC3)=NC2=C1 ZWGWSFHAZWNQQE-VPLSKCCHSA-N 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 229960001761 chlorpropamide Drugs 0.000 description 1
- 229960001523 chlortalidone Drugs 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 239000003354 cholesterol ester transfer protein inhibitor Substances 0.000 description 1
- 239000000544 cholinesterase inhibitor Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229960001932 cicletanine Drugs 0.000 description 1
- 229960001265 ciclosporin Drugs 0.000 description 1
- 230000001886 ciliary effect Effects 0.000 description 1
- 229960003020 cilnidipine Drugs 0.000 description 1
- 229960004588 cilostazol Drugs 0.000 description 1
- RRGUKTPIGVIEKM-UHFFFAOYSA-N cilostazol Chemical compound C=1C=C2NC(=O)CCC2=CC=1OCCCCC1=NN=NN1C1CCCCC1 RRGUKTPIGVIEKM-UHFFFAOYSA-N 0.000 description 1
- 229960001653 citalopram Drugs 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 229950000308 clentiazem Drugs 0.000 description 1
- 229950003072 clinofibrate Drugs 0.000 description 1
- UCAIEVHKDLMIFL-UHFFFAOYSA-N clobenpropit Chemical compound C1=CC(Cl)=CC=C1CNC(=N)SCCCC1=CNC=N1 UCAIEVHKDLMIFL-UHFFFAOYSA-N 0.000 description 1
- 229960001214 clofibrate Drugs 0.000 description 1
- KNHUKKLJHYUCFP-UHFFFAOYSA-N clofibrate Chemical compound CCOC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 KNHUKKLJHYUCFP-UHFFFAOYSA-N 0.000 description 1
- GKTWGGQPFAXNFI-HNNXBMFYSA-N clopidogrel Chemical compound C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl GKTWGGQPFAXNFI-HNNXBMFYSA-N 0.000 description 1
- 229960003009 clopidogrel Drugs 0.000 description 1
- 229960001152 colesevelam Drugs 0.000 description 1
- 229960004095 colestilan Drugs 0.000 description 1
- GMRWGQCZJGVHKL-UHFFFAOYSA-N colestipol Chemical compound ClCC1CO1.NCCNCCNCCNCCN GMRWGQCZJGVHKL-UHFFFAOYSA-N 0.000 description 1
- 229960002604 colestipol Drugs 0.000 description 1
- 229950010523 colestolone Drugs 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940125877 compound 31 Drugs 0.000 description 1
- JGBBVDFNZSRLIF-UHFFFAOYSA-N conivaptan Chemical compound C12=CC=CC=C2C=2[N]C(C)=NC=2CCN1C(=O)C(C=C1)=CC=C1NC(=O)C1=CC=CC=C1C1=CC=CC=C1 JGBBVDFNZSRLIF-UHFFFAOYSA-N 0.000 description 1
- 229960000562 conivaptan Drugs 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 239000010779 crude oil Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 150000001924 cycloalkanes Chemical class 0.000 description 1
- 125000004981 cycloalkylmethyl group Chemical group 0.000 description 1
- 125000005144 cycloalkylsulfonyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- SZIUXKBNJBUQDA-UHFFFAOYSA-N cyclohex-4-ene-1,2,3-triol Chemical compound OC1CC=CC(O)C1O SZIUXKBNJBUQDA-UHFFFAOYSA-N 0.000 description 1
- 150000001934 cyclohexanes Chemical class 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- DZFSTAUMUPHORN-NRFANRHFSA-N cyclohexyl-[[4-[2-[[(2s)-2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino]ethyl]phenoxy]methyl]phosphinic acid Chemical compound C([C@H](O)COC=1C=CC(O)=CC=1)NCCC(C=C1)=CC=C1OCP(O)(=O)C1CCCCC1 DZFSTAUMUPHORN-NRFANRHFSA-N 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 229960003206 cyclopenthiazide Drugs 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- ACQBHJXEAYTHCY-UHFFFAOYSA-N cyclopropyl-[4-[3-(1H-imidazol-5-yl)propoxy]phenyl]methanone Chemical compound C=1C=C(OCCCC=2NC=NC=2)C=CC=1C(=O)C1CC1 ACQBHJXEAYTHCY-UHFFFAOYSA-N 0.000 description 1
- 229930182912 cyclosporin Natural products 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 229950003040 dalvastatin Drugs 0.000 description 1
- 229950004456 darapladib Drugs 0.000 description 1
- FEJVSJIALLTFRP-LJQANCHMSA-N darusentan Chemical compound COC1=CC(OC)=NC(O[C@H](C(O)=O)C(OC)(C=2C=CC=CC=2)C=2C=CC=CC=2)=N1 FEJVSJIALLTFRP-LJQANCHMSA-N 0.000 description 1
- 229950008833 darusentan Drugs 0.000 description 1
- DIOQZVSQGTUSAI-NJFSPNSNSA-N decane Chemical compound CCCCCCCCC[14CH3] DIOQZVSQGTUSAI-NJFSPNSNSA-N 0.000 description 1
- 206010061428 decreased appetite Diseases 0.000 description 1
- 125000006612 decyloxy group Chemical group 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 229940124447 delivery agent Drugs 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 229960001623 desvenlafaxine Drugs 0.000 description 1
- 239000011903 deuterated solvents Substances 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 229960000632 dexamfetamine Drugs 0.000 description 1
- 229960004597 dexfenfluramine Drugs 0.000 description 1
- 239000012954 diazonium Substances 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-O diazynium Chemical compound [NH+]#N IJGRMHOSHXDMSA-UHFFFAOYSA-O 0.000 description 1
- YMWUJEATGCHHMB-DICFDUPASA-N dichloromethane-d2 Chemical compound [2H]C([2H])(Cl)Cl YMWUJEATGCHHMB-DICFDUPASA-N 0.000 description 1
- 229960001912 dicoumarol Drugs 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- XXEPPPIWZFICOJ-UHFFFAOYSA-N diethylpropion Chemical compound CCN(CC)C(C)C(=O)C1=CC=CC=C1 XXEPPPIWZFICOJ-UHFFFAOYSA-N 0.000 description 1
- 229960004890 diethylpropion Drugs 0.000 description 1
- 125000005594 diketone group Chemical group 0.000 description 1
- 229960001079 dilazep Drugs 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- DXVWRJRZCMCNEU-UHFFFAOYSA-N dimercaptoamine Chemical compound SNS DXVWRJRZCMCNEU-UHFFFAOYSA-N 0.000 description 1
- AXAZMDOAUQTMOW-UHFFFAOYSA-N dimethylzinc Chemical compound C[Zn]C AXAZMDOAUQTMOW-UHFFFAOYSA-N 0.000 description 1
- 239000003603 dipeptidyl peptidase IV inhibitor Substances 0.000 description 1
- 229960002768 dipyridamole Drugs 0.000 description 1
- IZEKFCXSFNUWAM-UHFFFAOYSA-N dipyridamole Chemical compound C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 IZEKFCXSFNUWAM-UHFFFAOYSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- VDQVEACBQKUUSU-UHFFFAOYSA-M disodium;sulfanide Chemical compound [Na+].[Na+].[SH-] VDQVEACBQKUUSU-UHFFFAOYSA-M 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229930004069 diterpene Natural products 0.000 description 1
- 125000000567 diterpene group Chemical group 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- DLNKOYKMWOXYQA-UHFFFAOYSA-N dl-pseudophenylpropanolamine Natural products CC(N)C(O)C1=CC=CC=C1 DLNKOYKMWOXYQA-UHFFFAOYSA-N 0.000 description 1
- 229940052760 dopamine agonists Drugs 0.000 description 1
- 239000003136 dopamine receptor stimulating agent Substances 0.000 description 1
- 239000000221 dopamine uptake inhibitor Substances 0.000 description 1
- RUZYUOTYCVRMRZ-UHFFFAOYSA-N doxazosin Chemical compound C1OC2=CC=CC=C2OC1C(=O)N(CC1)CCN1C1=NC(N)=C(C=C(C(OC)=C2)OC)C2=N1 RUZYUOTYCVRMRZ-UHFFFAOYSA-N 0.000 description 1
- 229960001389 doxazosin Drugs 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 229940125542 dual agonist Drugs 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- ODUOJXZPIYUATO-LJQANCHMSA-N ecadotril Chemical compound C([C@H](CSC(=O)C)C(=O)NCC(=O)OCC=1C=CC=CC=1)C1=CC=CC=C1 ODUOJXZPIYUATO-LJQANCHMSA-N 0.000 description 1
- 229950001184 ecadotril Drugs 0.000 description 1
- 229950005925 eflucimibe Drugs 0.000 description 1
- 229950007075 eldacimibe Drugs 0.000 description 1
- 229950010020 elgodipine Drugs 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- GBXSMTUPTTWBMN-XIRDDKMYSA-N enalapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)CC1=CC=CC=C1 GBXSMTUPTTWBMN-XIRDDKMYSA-N 0.000 description 1
- 229960000873 enalapril Drugs 0.000 description 1
- 239000002857 endothelin converting enzyme inhibitor Substances 0.000 description 1
- 239000002308 endothelin receptor antagonist Substances 0.000 description 1
- 239000002792 enkephalinase inhibitor Substances 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- CHNUOJQWGUIOLD-NFZZJPOKSA-N epalrestat Chemical compound C=1C=CC=CC=1\C=C(/C)\C=C1/SC(=S)N(CC(O)=O)C1=O CHNUOJQWGUIOLD-NFZZJPOKSA-N 0.000 description 1
- 229950010170 epalrestat Drugs 0.000 description 1
- CHNUOJQWGUIOLD-UHFFFAOYSA-N epalrestate Natural products C=1C=CC=CC=1C=C(C)C=C1SC(=S)N(CC(O)=O)C1=O CHNUOJQWGUIOLD-UHFFFAOYSA-N 0.000 description 1
- 229940116977 epidermal growth factor Drugs 0.000 description 1
- 230000001037 epileptic effect Effects 0.000 description 1
- 229960004563 eprosartan Drugs 0.000 description 1
- OROAFUQRIXKEMV-LDADJPATSA-N eprosartan Chemical compound C=1C=C(C(O)=O)C=CC=1CN1C(CCCC)=NC=C1\C=C(C(O)=O)/CC1=CC=CS1 OROAFUQRIXKEMV-LDADJPATSA-N 0.000 description 1
- 229960004341 escitalopram Drugs 0.000 description 1
- WSEQXVZVJXJVFP-FQEVSTJZSA-N escitalopram Chemical compound C1([C@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 WSEQXVZVJXJVFP-FQEVSTJZSA-N 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 229960003199 etacrynic acid Drugs 0.000 description 1
- AVOLMBLBETYQHX-UHFFFAOYSA-N etacrynic acid Chemical compound CCC(=C)C(=O)C1=CC=C(OCC(O)=O)C(Cl)=C1Cl AVOLMBLBETYQHX-UHFFFAOYSA-N 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical class CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- SSQPWTVBQMWLSZ-AAQCHOMXSA-N ethyl (5Z,8Z,11Z,14Z,17Z)-icosapentaenoate Chemical compound CCOC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CC SSQPWTVBQMWLSZ-AAQCHOMXSA-N 0.000 description 1
- ZADJRRFMOOACHL-WQICJITCSA-N ethyl (e,3s,5r)-7-[4-(4-fluorophenyl)spiro[chromene-2,1'-cyclopentane]-3-yl]-3,5-dihydroxyhept-6-enoate Chemical compound C12=CC=CC=C2OC2(CCCC2)C(/C=C/[C@H](O)C[C@H](O)CC(=O)OCC)=C1C1=CC=C(F)C=C1 ZADJRRFMOOACHL-WQICJITCSA-N 0.000 description 1
- NQIZCDQCNYCVAS-RQBPZYBGSA-N ethyl 2-[[(7s)-7-[[(2r)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-5,6,7,8-tetrahydronaphthalen-2-yl]oxy]acetate;hydron;chloride Chemical compound Cl.C1([C@@H](O)CN[C@H]2CCC3=CC=C(C=C3C2)OCC(=O)OCC)=CC=CC(Cl)=C1 NQIZCDQCNYCVAS-RQBPZYBGSA-N 0.000 description 1
- PWRYMMTWSPKRJD-NSLUPJTDSA-N ethyl 3-[(7r)-7-[[(2r)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-5,6,7,8-tetrahydronaphthalen-2-yl]propanoate;hydrochloride Chemical compound Cl.C1([C@@H](O)CN[C@@H]2CCC3=CC=C(C=C3C2)CCC(=O)OCC)=CC=CC(Cl)=C1 PWRYMMTWSPKRJD-NSLUPJTDSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 229960003501 etofibrate Drugs 0.000 description 1
- XXRVYAFBUDSLJX-UHFFFAOYSA-N etofibrate Chemical compound C=1C=CN=CC=1C(=O)OCCOC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 XXRVYAFBUDSLJX-UHFFFAOYSA-N 0.000 description 1
- KYAKGJDISSNVPZ-UHFFFAOYSA-N etofylline clofibrate Chemical compound C1=2C(=O)N(C)C(=O)N(C)C=2N=CN1CCOC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 KYAKGJDISSNVPZ-UHFFFAOYSA-N 0.000 description 1
- 229950009036 etofylline clofibrate Drugs 0.000 description 1
- 229950006213 etomoxir Drugs 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 229960001519 exenatide Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- OLNTVTPDXPETLC-XPWALMASSA-N ezetimibe Chemical compound N1([C@@H]([C@H](C1=O)CC[C@H](O)C=1C=CC(F)=CC=1)C=1C=CC(O)=CC=1)C1=CC=C(F)C=C1 OLNTVTPDXPETLC-XPWALMASSA-N 0.000 description 1
- 229960000815 ezetimibe Drugs 0.000 description 1
- ZZCHHVUQYRMYLW-HKBQPEDESA-N farglitazar Chemical compound N([C@@H](CC1=CC=C(C=C1)OCCC=1N=C(OC=1C)C=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1C(=O)C1=CC=CC=C1 ZZCHHVUQYRMYLW-HKBQPEDESA-N 0.000 description 1
- 229950003707 farglitazar Drugs 0.000 description 1
- 229950005203 fasidotril Drugs 0.000 description 1
- NGOGFTYYXHNFQH-UHFFFAOYSA-N fasudil Chemical compound C=1C=CC2=CN=CC=C2C=1S(=O)(=O)N1CCCNCC1 NGOGFTYYXHNFQH-UHFFFAOYSA-N 0.000 description 1
- 229960002435 fasudil Drugs 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 108091022862 fatty acid binding Proteins 0.000 description 1
- 229960002297 fenofibrate Drugs 0.000 description 1
- YMTINGFKWWXKFG-UHFFFAOYSA-N fenofibrate Chemical compound C1=CC(OC(C)(C)C(=O)OC(C)C)=CC=C1C(=O)C1=CC=C(Cl)C=C1 YMTINGFKWWXKFG-UHFFFAOYSA-N 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- WAAPEIZFCHNLKK-PELKAZGASA-N fidarestat Chemical compound C([C@@H](OC1=CC=C(F)C=C11)C(=O)N)[C@@]21NC(=O)NC2=O WAAPEIZFCHNLKK-PELKAZGASA-N 0.000 description 1
- 229950007256 fidarestat Drugs 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- YLQWCDOCJODRMT-UHFFFAOYSA-N fluoren-9-one Chemical compound C1=CC=C2C(=O)C3=CC=CC=C3C2=C1 YLQWCDOCJODRMT-UHFFFAOYSA-N 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 229960002464 fluoxetine Drugs 0.000 description 1
- 229960004038 fluvoxamine Drugs 0.000 description 1
- CJOFXWAVKWHTFT-XSFVSMFZSA-N fluvoxamine Chemical compound COCCCC\C(=N/OCCN)C1=CC=C(C(F)(F)F)C=C1 CJOFXWAVKWHTFT-XSFVSMFZSA-N 0.000 description 1
- 229960002490 fosinopril Drugs 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 229960002737 fructose Drugs 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 229960003883 furosemide Drugs 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- AIWAEWBZDJARBJ-PXUUZXDZSA-N fz7co35x2s Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCCNC(=O)COCCOCCNC(=O)CCN1C(C=CC1=O)=O)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 AIWAEWBZDJARBJ-PXUUZXDZSA-N 0.000 description 1
- 229960003980 galantamine Drugs 0.000 description 1
- BGLNUNCBNALFOZ-WMLDXEAASA-N galanthamine Natural products COc1ccc2CCCC[C@@]34C=CCC[C@@H]3Oc1c24 BGLNUNCBNALFOZ-WMLDXEAASA-N 0.000 description 1
- ASUTZQLVASHGKV-UHFFFAOYSA-N galanthamine hydrochloride Natural products O1C(=C23)C(OC)=CC=C2CN(C)CCC23C1CC(O)C=C2 ASUTZQLVASHGKV-UHFFFAOYSA-N 0.000 description 1
- 229960000457 gallopamil Drugs 0.000 description 1
- 229960003627 gemfibrozil Drugs 0.000 description 1
- 229940029988 ginseng preparation Drugs 0.000 description 1
- 229960001764 glibornuride Drugs 0.000 description 1
- RMTYNAPTNBJHQI-LLDVTBCESA-N glibornuride Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)N[C@H]1[C@H](C2(C)C)CC[C@@]2(C)[C@H]1O RMTYNAPTNBJHQI-LLDVTBCESA-N 0.000 description 1
- WIGIZIANZCJQQY-RUCARUNLSA-N glimepiride Chemical compound O=C1C(CC)=C(C)CN1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)N[C@@H]2CC[C@@H](C)CC2)C=C1 WIGIZIANZCJQQY-RUCARUNLSA-N 0.000 description 1
- 229960004346 glimepiride Drugs 0.000 description 1
- 229960001381 glipizide Drugs 0.000 description 1
- ZJJXGWJIGJFDTL-UHFFFAOYSA-N glipizide Chemical compound C1=NC(C)=CN=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZJJXGWJIGJFDTL-UHFFFAOYSA-N 0.000 description 1
- 229960003468 gliquidone Drugs 0.000 description 1
- 229960003236 glisoxepide Drugs 0.000 description 1
- ZKUDBRCEOBOWLF-UHFFFAOYSA-N glisoxepide Chemical compound O1C(C)=CC(C(=O)NCCC=2C=CC(=CC=2)S(=O)(=O)NC(=O)NN2CCCCCC2)=N1 ZKUDBRCEOBOWLF-UHFFFAOYSA-N 0.000 description 1
- 239000003877 glucagon like peptide 1 receptor agonist Substances 0.000 description 1
- 229960002442 glucosamine Drugs 0.000 description 1
- 230000009229 glucose formation Effects 0.000 description 1
- 125000004383 glucosinolate group Chemical group 0.000 description 1
- 229950005232 glybuzole Drugs 0.000 description 1
- 239000001087 glyceryl triacetate Substances 0.000 description 1
- 235000013773 glyceryl triacetate Nutrition 0.000 description 1
- 229950002888 glyclopyramide Drugs 0.000 description 1
- 229950005514 glycyclamide Drugs 0.000 description 1
- RIGBPMDIGYBTBJ-UHFFFAOYSA-N glycyclamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NC1CCCCC1 RIGBPMDIGYBTBJ-UHFFFAOYSA-N 0.000 description 1
- AIHKAQUFJMNPAR-UHFFFAOYSA-N glyphoside Chemical compound O1C(CO)C(O)C(O)C(OC(=O)C)C1OC1=C(C=2C=C(O)C(O)=CC=2)OC2=CC(O)=CC(O)=C2C1=O AIHKAQUFJMNPAR-UHFFFAOYSA-N 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 229960003050 guanabenz acetate Drugs 0.000 description 1
- 229960002048 guanfacine Drugs 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 150000002402 hexoses Chemical class 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 229960002474 hydralazine Drugs 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 150000002429 hydrazines Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 229960002003 hydrochlorothiazide Drugs 0.000 description 1
- 239000000416 hydrocolloid Substances 0.000 description 1
- DMDGGSIALPNSEE-UHFFFAOYSA-N hydroflumethiazide Chemical compound C1=C(C(F)(F)F)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O DMDGGSIALPNSEE-UHFFFAOYSA-N 0.000 description 1
- 229960003313 hydroflumethiazide Drugs 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- TWTMQRXNAZGSCE-UHFFFAOYSA-N hydron;[6-(methylamino)-1-(2-methylpropanoyloxy)-5,6,7,8-tetrahydronaphthalen-2-yl] 2-methylpropanoate;chloride Chemical compound Cl.C1=CC(OC(=O)C(C)C)=C(OC(=O)C(C)C)C2=C1CC(NC)CC2 TWTMQRXNAZGSCE-UHFFFAOYSA-N 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 229920001600 hydrophobic polymer Polymers 0.000 description 1
- 125000004464 hydroxyphenyl group Chemical group 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 229960002600 icosapent ethyl Drugs 0.000 description 1
- 150000002462 imidazolines Chemical class 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- MZCJWLAXZRFUPI-UHFFFAOYSA-N impentamine Chemical compound NCCCCCC1=CN=CN1 MZCJWLAXZRFUPI-UHFFFAOYSA-N 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- MGXWVYUBJRZYPE-YUGYIWNOSA-N incretin Chemical class C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)[C@@H](C)O)[C@@H](C)CC)C1=CC=C(O)C=C1 MGXWVYUBJRZYPE-YUGYIWNOSA-N 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 239000001573 invertase Substances 0.000 description 1
- 235000011073 invertase Nutrition 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 238000000534 ion trap mass spectrometry Methods 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 229960002198 irbesartan Drugs 0.000 description 1
- YCPOHTHPUREGFM-UHFFFAOYSA-N irbesartan Chemical compound O=C1N(CC=2C=CC(=CC=2)C=2C(=CC=CC=2)C=2[N]N=NN=2)C(CCCC)=NC21CCCC2 YCPOHTHPUREGFM-UHFFFAOYSA-N 0.000 description 1
- 125000001977 isobenzofuranyl group Chemical group C=1(OC=C2C=CC=CC12)* 0.000 description 1
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 229960002479 isosorbide Drugs 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 229960001632 labetalol Drugs 0.000 description 1
- 229960004340 lacidipine Drugs 0.000 description 1
- GKQPCPXONLDCMU-CCEZHUSRSA-N lacidipine Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1C1=CC=CC=C1\C=C\C(=O)OC(C)(C)C GKQPCPXONLDCMU-CCEZHUSRSA-N 0.000 description 1
- 229950005959 lecimibide Drugs 0.000 description 1
- 229940039781 leptin Drugs 0.000 description 1
- 102000005861 leptin receptors Human genes 0.000 description 1
- 108010019813 leptin receptors Proteins 0.000 description 1
- 229960004294 lercanidipine Drugs 0.000 description 1
- ZDXUKAKRHYTAKV-UHFFFAOYSA-N lercanidipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)(C)CN(C)CCC(C=2C=CC=CC=2)C=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 ZDXUKAKRHYTAKV-UHFFFAOYSA-N 0.000 description 1
- 229960001518 levocarnitine Drugs 0.000 description 1
- 229950008325 levothyroxine Drugs 0.000 description 1
- 239000008206 lipophilic material Substances 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 229960002701 liraglutide Drugs 0.000 description 1
- 229960002394 lisinopril Drugs 0.000 description 1
- CZRQXSDBMCMPNJ-ZUIPZQNBSA-N lisinopril dihydrate Chemical compound O.O.C([C@H](N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(O)=O)C(O)=O)CC1=CC=CC=C1 CZRQXSDBMCMPNJ-ZUIPZQNBSA-N 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- CCZVEWRRAVASGL-UHFFFAOYSA-N lithium;2-methanidylpropane Chemical compound [Li+].CC(C)[CH2-] CCZVEWRRAVASGL-UHFFFAOYSA-N 0.000 description 1
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- PPHTXRNHTVLQED-UHFFFAOYSA-N lixivaptan Chemical compound CC1=CC=C(F)C=C1C(=O)NC(C=C1Cl)=CC=C1C(=O)N1C2=CC=CC=C2CN2C=CC=C2C1 PPHTXRNHTVLQED-UHFFFAOYSA-N 0.000 description 1
- 229950011475 lixivaptan Drugs 0.000 description 1
- KSMAGQUYOIHWFS-UHFFFAOYSA-N lofexidine Chemical compound N=1CCNC=1C(C)OC1=C(Cl)C=CC=C1Cl KSMAGQUYOIHWFS-UHFFFAOYSA-N 0.000 description 1
- 229960005209 lofexidine Drugs 0.000 description 1
- MBBCVAKAJPKAKM-UHFFFAOYSA-N lomitapide Chemical compound C12=CC=CC=C2C2=CC=CC=C2C1(C(=O)NCC(F)(F)F)CCCCN(CC1)CCC1NC(=O)C1=CC=CC=C1C1=CC=C(C(F)(F)F)C=C1 MBBCVAKAJPKAKM-UHFFFAOYSA-N 0.000 description 1
- 229960003566 lomitapide Drugs 0.000 description 1
- 229960005060 lorcaserin Drugs 0.000 description 1
- XTTZERNUQAFMOF-QMMMGPOBSA-N lorcaserin Chemical compound C[C@H]1CNCCC2=CC=C(Cl)C=C12 XTTZERNUQAFMOF-QMMMGPOBSA-N 0.000 description 1
- 229960004773 losartan Drugs 0.000 description 1
- KJJZZJSZUJXYEA-UHFFFAOYSA-N losartan Chemical compound CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C=2[N]N=NN=2)C=C1 KJJZZJSZUJXYEA-UHFFFAOYSA-N 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- IYVSXSLYJLAZAT-NOLJZWGESA-N lycoramine Natural products CN1CC[C@@]23CC[C@H](O)C[C@@H]2Oc4cccc(C1)c34 IYVSXSLYJLAZAT-NOLJZWGESA-N 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 description 1
- 229910001623 magnesium bromide Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 229960003963 manidipine Drugs 0.000 description 1
- ANEBWFXPVPTEET-UHFFFAOYSA-N manidipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2CCN(CC2)C(C=2C=CC=CC=2)C=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 ANEBWFXPVPTEET-UHFFFAOYSA-N 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 229960000299 mazindol Drugs 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- 229960004678 mefruside Drugs 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 1
- 229960003105 metformin Drugs 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- 229960001252 methamphetamine Drugs 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- CKJNUZNMWOVDFN-UHFFFAOYSA-N methanone Chemical compound O=[CH-] CKJNUZNMWOVDFN-UHFFFAOYSA-N 0.000 description 1
- FLOSMHQXBMRNHR-DAXSKMNVSA-N methazolamide Chemical compound CC(=O)\N=C1/SC(S(N)(=O)=O)=NN1C FLOSMHQXBMRNHR-DAXSKMNVSA-N 0.000 description 1
- 229960004083 methazolamide Drugs 0.000 description 1
- 229960003739 methyclothiazide Drugs 0.000 description 1
- NSZBOSJMBQKKKB-ZCBOBATRSA-N methyl (3r,5s,6e)-3,5-dihydroxy-9,9-diphenylnona-6,8-dienoate Chemical compound C=1C=CC=CC=1C(=C/C=C/[C@@H](O)C[C@@H](O)CC(=O)OC)C1=CC=CC=C1 NSZBOSJMBQKKKB-ZCBOBATRSA-N 0.000 description 1
- FWMHZWMPUWAUPL-NDEPHWFRSA-N methyl (4s)-3-[3-[4-(3-acetamidophenyl)piperidin-1-yl]propylcarbamoyl]-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,4-dihydropyrimidine-5-carboxylate Chemical compound N1([C@H](C(=C(NC1=O)COC)C(=O)OC)C=1C=C(F)C(F)=CC=1)C(=O)NCCCN(CC1)CCC1C1=CC=CC(NC(C)=O)=C1 FWMHZWMPUWAUPL-NDEPHWFRSA-N 0.000 description 1
- IVAQJHSXBVHUQT-ZVHZXABRSA-N methyl (e)-3-(3,5-dimethoxyphenyl)-2-[4-[4-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]phenoxy]phenyl]prop-2-enoate Chemical compound C=1C=C(OC=2C=CC(CC3C(NC(=O)S3)=O)=CC=2)C=CC=1/C(C(=O)OC)=C\C1=CC(OC)=CC(OC)=C1 IVAQJHSXBVHUQT-ZVHZXABRSA-N 0.000 description 1
- ZFLBZHXQAMUEFS-KUHUBIRLSA-N methyl 2-[4-[(2r)-2-[[(2r)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]phenoxy]acetate Chemical compound C1=CC(OCC(=O)OC)=CC=C1C[C@@H](C)NC[C@H](O)C1=CC=CC(Cl)=C1 ZFLBZHXQAMUEFS-KUHUBIRLSA-N 0.000 description 1
- MVQOMOXWRUVMOG-UHFFFAOYSA-N methyl 2-[4-[2-[(2-hydroxy-3-phenoxypropyl)amino]ethoxy]phenoxy]acetate;hydrochloride Chemical compound Cl.C1=CC(OCC(=O)OC)=CC=C1OCCNCC(O)COC1=CC=CC=C1 MVQOMOXWRUVMOG-UHFFFAOYSA-N 0.000 description 1
- VKQFCGNPDRICFG-UHFFFAOYSA-N methyl 2-methylpropyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCC(C)C)C1C1=CC=CC=C1[N+]([O-])=O VKQFCGNPDRICFG-UHFFFAOYSA-N 0.000 description 1
- OIZISCUUSLPUEN-LMORPYAASA-N methyl 4-[(2s)-2-[[(2s)-2-hydroxy-2-phenylethyl]amino]propyl]benzoate;(e)-4-oxopent-2-enoic acid Chemical compound CC(=O)\C=C\C(O)=O.C1=CC(C(=O)OC)=CC=C1C[C@H](C)NC[C@@H](O)C1=CC=CC=C1 OIZISCUUSLPUEN-LMORPYAASA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 229960002921 methylnaltrexone Drugs 0.000 description 1
- 229960003738 meticrane Drugs 0.000 description 1
- AQCHWTWZEMGIFD-UHFFFAOYSA-N metolazone Chemical compound CC1NC2=CC(Cl)=C(S(N)(=O)=O)C=C2C(=O)N1C1=CC=CC=C1C AQCHWTWZEMGIFD-UHFFFAOYSA-N 0.000 description 1
- 229960002817 metolazone Drugs 0.000 description 1
- 229950009116 mevastatin Drugs 0.000 description 1
- AJLFOPYRIVGYMJ-INTXDZFKSA-N mevastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=CCC[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 AJLFOPYRIVGYMJ-INTXDZFKSA-N 0.000 description 1
- BOZILQFLQYBIIY-UHFFFAOYSA-N mevastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CCC=C21 BOZILQFLQYBIIY-UHFFFAOYSA-N 0.000 description 1
- 229960003404 mexiletine Drugs 0.000 description 1
- 210000000110 microvilli Anatomy 0.000 description 1
- BMGQWWVMWDBQGC-IIFHNQTCSA-N midostaurin Chemical compound CN([C@H]1[C@H]([C@]2(C)O[C@@H](N3C4=CC=CC=C4C4=C5C(=O)NCC5=C5C6=CC=CC=C6N2C5=C43)C1)OC)C(=O)C1=CC=CC=C1 BMGQWWVMWDBQGC-IIFHNQTCSA-N 0.000 description 1
- 229950010895 midostaurin Drugs 0.000 description 1
- 229960001110 miglitol Drugs 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 229960000600 milnacipran Drugs 0.000 description 1
- 229950002259 minalrestat Drugs 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 229960003365 mitiglinide Drugs 0.000 description 1
- WPGGHFDDFPHPOB-BBWFWOEESA-N mitiglinide Chemical compound C([C@@H](CC(=O)N1C[C@@H]2CCCC[C@@H]2C1)C(=O)O)C1=CC=CC=C1 WPGGHFDDFPHPOB-BBWFWOEESA-N 0.000 description 1
- VYQNWZOUAUKGHI-UHFFFAOYSA-N monobenzone Chemical compound C1=CC(O)=CC=C1OCC1=CC=CC=C1 VYQNWZOUAUKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 229960003938 moxonidine Drugs 0.000 description 1
- 229950000546 mozavaptan Drugs 0.000 description 1
- WRNXUQJJCIZICJ-UHFFFAOYSA-N mozavaptan Chemical compound C12=CC=CC=C2C(N(C)C)CCCN1C(=O)C(C=C1)=CC=C1NC(=O)C1=CC=CC=C1C WRNXUQJJCIZICJ-UHFFFAOYSA-N 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- DGHUWPWPAXVRQG-UHFFFAOYSA-N n,n-didecylpyridin-4-amine Chemical compound CCCCCCCCCCN(CCCCCCCCCC)C1=CC=NC=C1 DGHUWPWPAXVRQG-UHFFFAOYSA-N 0.000 description 1
- IAYNHDZSSDUYHY-UHFFFAOYSA-N n-(2-acetyl-4,6-dimethylphenyl)-3-[(3,4-dimethyl-1,2-oxazol-5-yl)sulfamoyl]thiophene-2-carboxamide Chemical compound CC(=O)C1=CC(C)=CC(C)=C1NC(=O)C1=C(S(=O)(=O)NC2=C(C(C)=NO2)C)C=CS1 IAYNHDZSSDUYHY-UHFFFAOYSA-N 0.000 description 1
- YFJUSGDKCDQMNE-UHFFFAOYSA-N n-(2-acetyl-4,6-dimethylphenyl)-3-[(4-chloro-3-methyl-1,2-oxazol-5-yl)sulfamoyl]thiophene-2-carboxamide Chemical compound CC(=O)C1=CC(C)=CC(C)=C1NC(=O)C1=C(S(=O)(=O)NC2=C(C(C)=NO2)Cl)C=CS1 YFJUSGDKCDQMNE-UHFFFAOYSA-N 0.000 description 1
- LJGUZUROJOJEMI-UHFFFAOYSA-N n-(3,4-dimethyl-1,2-oxazol-5-yl)-2-[4-(1,3-oxazol-2-yl)phenyl]benzenesulfonamide Chemical compound CC1=NOC(NS(=O)(=O)C=2C(=CC=CC=2)C=2C=CC(=CC=2)C=2OC=CN=2)=C1C LJGUZUROJOJEMI-UHFFFAOYSA-N 0.000 description 1
- WDPFJWLDPVQCAJ-UHFFFAOYSA-N n-[2-(diethylamino)ethyl]-2-[2-[(4-fluorophenyl)methylsulfanyl]-4-oxo-6,7-dihydro-5h-cyclopenta[d]pyrimidin-1-yl]-n-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]acetamide Chemical compound C1=2CCCC=2C(=O)N=C(SCC=2C=CC(F)=CC=2)N1CC(=O)N(CCN(CC)CC)CC(C=C1)=CC=C1C1=CC=C(C(F)(F)F)C=C1 WDPFJWLDPVQCAJ-UHFFFAOYSA-N 0.000 description 1
- CMCWIHQJEQYHPX-UHFFFAOYSA-N n-[2-[(2-aminohydrazinyl)methylideneamino]ethyl]acetamide;hydrochloride Chemical compound Cl.CC(=O)NCCN=CNNN CMCWIHQJEQYHPX-UHFFFAOYSA-N 0.000 description 1
- DSEGFUSAJVUFLK-OFNKIYASSA-N n-[5-[(1r)-2-[[(1r)-2-(3-chlorophenyl)-1-[4-(difluoromethoxy)phenyl]ethyl]amino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide Chemical compound C1=C(O)C(NS(=O)(=O)C)=CC([C@@H](O)CN[C@H](CC=2C=C(Cl)C=CC=2)C=2C=CC(OC(F)F)=CC=2)=C1 DSEGFUSAJVUFLK-OFNKIYASSA-N 0.000 description 1
- FUKHGCVTMAEHRG-NRFANRHFSA-N n-[5-[(1r)-2-[bis[4-(difluoromethoxy)phenyl]methylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide Chemical compound C1=C(O)C(NS(=O)(=O)C)=CC([C@@H](O)CNC(C=2C=CC(OC(F)F)=CC=2)C=2C=CC(OC(F)F)=CC=2)=C1 FUKHGCVTMAEHRG-NRFANRHFSA-N 0.000 description 1
- LFWCJABOXHSRGC-UHFFFAOYSA-N n-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-[2-(2h-tetrazol-5-yl)pyridin-4-yl]pyrimidin-4-yl]-5-methylpyridine-2-sulfonamide Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(N=CC=2)C2=NNN=N2)OCCO)=C1NS(=O)(=O)C1=CC=C(C)C=N1 LFWCJABOXHSRGC-UHFFFAOYSA-N 0.000 description 1
- TUYWTLTWNJOZNY-UHFFFAOYSA-N n-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-[2-(2h-tetrazol-5-yl)pyridin-4-yl]pyrimidin-4-yl]-5-propan-2-ylpyridine-2-sulfonamide Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(N=CC=2)C2=NNN=N2)OCCO)=C1NS(=O)(=O)C1=CC=C(C(C)C)C=N1 TUYWTLTWNJOZNY-UHFFFAOYSA-N 0.000 description 1
- ORJRYNKVKJAJPY-UHFFFAOYSA-N n-[[2-[2-[(4,5-dimethyl-1,2-oxazol-3-yl)sulfamoyl]phenyl]-5-(1,3-oxazol-2-yl)phenyl]methyl]-n,3,3-trimethylbutanamide Chemical compound CC(C)(C)CC(=O)N(C)CC1=CC(C=2OC=CN=2)=CC=C1C1=CC=CC=C1S(=O)(=O)NC1=NOC(C)=C1C ORJRYNKVKJAJPY-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- DIOQZVSQGTUSAI-UHFFFAOYSA-N n-butylhexane Natural products CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229960004255 nadolol Drugs 0.000 description 1
- VWPOSFSPZNDTMJ-UCWKZMIHSA-N nadolol Chemical compound C1[C@@H](O)[C@@H](O)CC2=C1C=CC=C2OCC(O)CNC(C)(C)C VWPOSFSPZNDTMJ-UCWKZMIHSA-N 0.000 description 1
- 229960005297 nalmefene Drugs 0.000 description 1
- 229960000938 nalorphine Drugs 0.000 description 1
- UZHSEJADLWPNLE-GRGSLBFTSA-N naloxone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4CC=C UZHSEJADLWPNLE-GRGSLBFTSA-N 0.000 description 1
- 229960004127 naloxone Drugs 0.000 description 1
- DQCKKXVULJGBQN-XFWGSAIBSA-N naltrexone Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=O)O)CC1)O)CC1CC1 DQCKKXVULJGBQN-XFWGSAIBSA-N 0.000 description 1
- 229960003086 naltrexone Drugs 0.000 description 1
- 239000002090 nanochannel Substances 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- OELFLUMRDSZNSF-BRWVUGGUSA-N nateglinide Chemical compound C1C[C@@H](C(C)C)CC[C@@H]1C(=O)N[C@@H](C(O)=O)CC1=CC=CC=C1 OELFLUMRDSZNSF-BRWVUGGUSA-N 0.000 description 1
- 229960000698 nateglinide Drugs 0.000 description 1
- 229950003494 naveglitazar Drugs 0.000 description 1
- 229960000619 nebivolol Drugs 0.000 description 1
- 229940053128 nerve growth factor Drugs 0.000 description 1
- PKWDZWYVIHVNKS-UHFFFAOYSA-N netoglitazone Chemical compound FC1=CC=CC=C1COC1=CC=C(C=C(CC2C(NC(=O)S2)=O)C=C2)C2=C1 PKWDZWYVIHVNKS-UHFFFAOYSA-N 0.000 description 1
- 229950001628 netoglitazone Drugs 0.000 description 1
- BPGXUIVWLQTVLZ-OFGSCBOVSA-N neuropeptide y(npy) Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=C(O)C=C1 BPGXUIVWLQTVLZ-OFGSCBOVSA-N 0.000 description 1
- 239000003900 neurotrophic factor Substances 0.000 description 1
- 229960001783 nicardipine Drugs 0.000 description 1
- 229960000827 niceritrol Drugs 0.000 description 1
- 229950005171 nicofibrate Drugs 0.000 description 1
- RARQHAFNGNPQCZ-UHFFFAOYSA-N nicofibrate Chemical compound C=1C=CN=CC=1COC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 RARQHAFNGNPQCZ-UHFFFAOYSA-N 0.000 description 1
- 229950001071 nicomol Drugs 0.000 description 1
- 229960002497 nicorandil Drugs 0.000 description 1
- LBHIOVVIQHSOQN-UHFFFAOYSA-N nicorandil Chemical compound [O-][N+](=O)OCCNC(=O)C1=CC=CN=C1 LBHIOVVIQHSOQN-UHFFFAOYSA-N 0.000 description 1
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 1
- 229960001597 nifedipine Drugs 0.000 description 1
- 229960005366 nilvadipine Drugs 0.000 description 1
- KJWGEXJCWCYEMI-UHFFFAOYSA-N nilvadipine Chemical compound COC(=O)C1=C(C#N)N=C(C)C(C(=O)OC(C)C)C1C1=CC=CC(N(=O)=O)=C1 KJWGEXJCWCYEMI-UHFFFAOYSA-N 0.000 description 1
- 229960000715 nimodipine Drugs 0.000 description 1
- 229960000227 nisoldipine Drugs 0.000 description 1
- 229960005425 nitrendipine Drugs 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- ZNPKAOCQMDJBIK-UHFFFAOYSA-N nitrocyanamide Chemical compound [O-][N+](=O)NC#N ZNPKAOCQMDJBIK-UHFFFAOYSA-N 0.000 description 1
- 239000002767 noradrenalin uptake inhibitor Substances 0.000 description 1
- CCTHTLJWXPUNGT-UHFFFAOYSA-L nysted reagent Chemical compound C1CCOC1.Br[Zn]C[Zn]C[Zn]Br CCTHTLJWXPUNGT-UHFFFAOYSA-L 0.000 description 1
- IOQPZZOEVPZRBK-UHFFFAOYSA-N octan-1-amine Chemical compound CCCCCCCCN IOQPZZOEVPZRBK-UHFFFAOYSA-N 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- VTRAEEWXHOVJFV-UHFFFAOYSA-N olmesartan Chemical compound CCCC1=NC(C(C)(C)O)=C(C(O)=O)N1CC1=CC=C(C=2C(=CC=CC=2)C=2NN=NN=2)C=C1 VTRAEEWXHOVJFV-UHFFFAOYSA-N 0.000 description 1
- 229960005117 olmesartan Drugs 0.000 description 1
- 229960001199 olmesartan medoxomil Drugs 0.000 description 1
- LVRLSYPNFFBYCZ-VGWMRTNUSA-N omapatrilat Chemical compound C([C@H](S)C(=O)N[C@H]1CCS[C@H]2CCC[C@H](N2C1=O)C(=O)O)C1=CC=CC=C1 LVRLSYPNFFBYCZ-VGWMRTNUSA-N 0.000 description 1
- 229950000973 omapatrilat Drugs 0.000 description 1
- 238000000238 one-dimensional nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- QZYYPQAYSFBKPW-UHFFFAOYSA-N org 12962 Chemical compound N1=C(Cl)C(C(F)(F)F)=CC=C1N1CCNCC1 QZYYPQAYSFBKPW-UHFFFAOYSA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- AHLBNYSZXLDEJQ-FWEHEUNISA-N orlistat Chemical compound CCCCCCCCCCC[C@H](OC(=O)[C@H](CC(C)C)NC=O)C[C@@H]1OC(=O)[C@H]1CCCCCC AHLBNYSZXLDEJQ-FWEHEUNISA-N 0.000 description 1
- 229960001243 orlistat Drugs 0.000 description 1
- YDCVQGAUCOROHB-UHFFFAOYSA-N oxadiazolidine-4,5-dione Chemical class O=C1NNOC1=O YDCVQGAUCOROHB-UHFFFAOYSA-N 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 150000003901 oxalic acid esters Chemical class 0.000 description 1
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- CTRLABGOLIVAIY-UHFFFAOYSA-N oxcarbazepine Chemical compound C1C(=O)C2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 CTRLABGOLIVAIY-UHFFFAOYSA-N 0.000 description 1
- 229960001816 oxcarbazepine Drugs 0.000 description 1
- 125000005429 oxyalkyl group Chemical group 0.000 description 1
- HXNFUBHNUDHIGC-UHFFFAOYSA-N oxypurinol Chemical compound O=C1NC(=O)N=C2NNC=C21 HXNFUBHNUDHIGC-UHFFFAOYSA-N 0.000 description 1
- 239000003973 paint Substances 0.000 description 1
- 229960002296 paroxetine Drugs 0.000 description 1
- 229950000811 peliglitazar Drugs 0.000 description 1
- 229960002035 penbutolol Drugs 0.000 description 1
- KQXKVJAGOJTNJS-HNNXBMFYSA-N penbutolol Chemical compound CC(C)(C)NC[C@H](O)COC1=CC=CC=C1C1CCCC1 KQXKVJAGOJTNJS-HNNXBMFYSA-N 0.000 description 1
- 229950001707 penflutizide Drugs 0.000 description 1
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 229960002582 perindopril Drugs 0.000 description 1
- IPVQLZZIHOAWMC-QXKUPLGCSA-N perindopril Chemical compound C1CCC[C@H]2C[C@@H](C(O)=O)N(C(=O)[C@H](C)N[C@@H](CCC)C(=O)OCC)[C@H]21 IPVQLZZIHOAWMC-QXKUPLGCSA-N 0.000 description 1
- 229940083254 peripheral vasodilators imidazoline derivative Drugs 0.000 description 1
- 108040007629 peroxidase activity proteins Proteins 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 229960000436 phendimetrazine Drugs 0.000 description 1
- ICFJFFQQTFMIBG-UHFFFAOYSA-N phenformin Chemical compound NC(=N)NC(=N)NCCC1=CC=CC=C1 ICFJFFQQTFMIBG-UHFFFAOYSA-N 0.000 description 1
- 229960003243 phenformin Drugs 0.000 description 1
- 229960000280 phenindione Drugs 0.000 description 1
- NFBAXHOPROOJAW-UHFFFAOYSA-N phenindione Chemical compound O=C1C2=CC=CC=C2C(=O)C1C1=CC=CC=C1 NFBAXHOPROOJAW-UHFFFAOYSA-N 0.000 description 1
- 229960003209 phenmetrazine Drugs 0.000 description 1
- 229960004923 phenprocoumon Drugs 0.000 description 1
- DQDAYGNAKTZFIW-UHFFFAOYSA-N phenprocoumon Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC)C1=CC=CC=C1 DQDAYGNAKTZFIW-UHFFFAOYSA-N 0.000 description 1
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 description 1
- 229940067157 phenylhydrazine Drugs 0.000 description 1
- 150000004031 phenylhydrazines Chemical class 0.000 description 1
- DLNKOYKMWOXYQA-APPZFPTMSA-N phenylpropanolamine Chemical compound C[C@@H](N)[C@H](O)C1=CC=CC=C1 DLNKOYKMWOXYQA-APPZFPTMSA-N 0.000 description 1
- 229960000395 phenylpropanolamine Drugs 0.000 description 1
- 108010031256 phosducin Proteins 0.000 description 1
- 239000003358 phospholipase A2 inhibitor Substances 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 229960003890 pimagedine Drugs 0.000 description 1
- 229960002508 pindolol Drugs 0.000 description 1
- PHUTUTUABXHXLW-UHFFFAOYSA-N pindolol Chemical compound CC(C)NCC(O)COC1=CC=CC2=NC=C[C]12 PHUTUTUABXHXLW-UHFFFAOYSA-N 0.000 description 1
- RMHMFHUVIITRHF-UHFFFAOYSA-N pirenzepine Chemical compound C1CN(C)CCN1CC(=O)N1C2=NC=CC=C2NC(=O)C2=CC=CC=C21 RMHMFHUVIITRHF-UHFFFAOYSA-N 0.000 description 1
- 229960004633 pirenzepine Drugs 0.000 description 1
- 229950000957 pirifibrate Drugs 0.000 description 1
- YJBIJSVYPHRVCI-UHFFFAOYSA-N pirifibrate Chemical compound C=1C=CC(CO)=NC=1COC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 YJBIJSVYPHRVCI-UHFFFAOYSA-N 0.000 description 1
- RHGYHLPFVJEAOC-FFNUKLMVSA-L pitavastatin calcium Chemical compound [Ca+2].[O-]C(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1.[O-]C(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1 RHGYHLPFVJEAOC-FFNUKLMVSA-L 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229950010884 ponalrestat Drugs 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- RKCAIXNGYQCCAL-UHFFFAOYSA-N porphin Chemical compound N1C(C=C2N=C(C=C3NC(=C4)C=C3)C=C2)=CC=C1C=C1C=CC4=N1 RKCAIXNGYQCCAL-UHFFFAOYSA-N 0.000 description 1
- 150000004032 porphyrins Chemical class 0.000 description 1
- 229960000206 potassium canrenoate Drugs 0.000 description 1
- JTZQCHFUGHIPDF-RYVBEKKQSA-M potassium canrenoate Chemical compound [K+].O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@](CC4)(O)CCC([O-])=O)[C@@H]4[C@@H]3C=CC2=C1 JTZQCHFUGHIPDF-RYVBEKKQSA-M 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- MZWCHWWQSPPZRH-UHFFFAOYSA-M potassium;4-(7-ethyl-1,3-benzodioxol-5-yl)-1,1-dioxo-2-[2-(trifluoromethyl)phenyl]-1$l^{6},2-benzothiazine-3-carboxylate Chemical compound [K+].C=1C=2OCOC=2C(CC)=CC=1C(C1=CC=CC=C1S1(=O)=O)=C(C([O-])=O)N1C1=CC=CC=C1C(F)(F)F MZWCHWWQSPPZRH-UHFFFAOYSA-M 0.000 description 1
- 229960003611 pramlintide Drugs 0.000 description 1
- 108010029667 pramlintide Proteins 0.000 description 1
- NRKVKVQDUCJPIZ-MKAGXXMWSA-N pramlintide acetate Chemical compound C([C@@H](C(=O)NCC(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CS)NC(=O)[C@@H](N)CCCCN)[C@@H](C)O)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 NRKVKVQDUCJPIZ-MKAGXXMWSA-N 0.000 description 1
- 229960002965 pravastatin Drugs 0.000 description 1
- TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 description 1
- IENZQIKPVFGBNW-UHFFFAOYSA-N prazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1=CC=CO1 IENZQIKPVFGBNW-UHFFFAOYSA-N 0.000 description 1
- 229960001289 prazosin Drugs 0.000 description 1
- GCYXWQUSHADNBF-AAEALURTSA-N preproglucagon 78-108 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 GCYXWQUSHADNBF-AAEALURTSA-N 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- DBABZHXKTCFAPX-UHFFFAOYSA-N probenecid Chemical compound CCCN(CCC)S(=O)(=O)C1=CC=C(C(O)=O)C=C1 DBABZHXKTCFAPX-UHFFFAOYSA-N 0.000 description 1
- 229960003081 probenecid Drugs 0.000 description 1
- FYPMFJGVHOHGLL-UHFFFAOYSA-N probucol Chemical compound C=1C(C(C)(C)C)=C(O)C(C(C)(C)C)=CC=1SC(C)(C)SC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 FYPMFJGVHOHGLL-UHFFFAOYSA-N 0.000 description 1
- 229960003912 probucol Drugs 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 229960003712 propranolol Drugs 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 239000003881 protein kinase C inhibitor Substances 0.000 description 1
- 239000003801 protein tyrosine phosphatase 1B inhibitor Substances 0.000 description 1
- 210000000512 proximal kidney tubule Anatomy 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 235000008151 pyridoxamine Nutrition 0.000 description 1
- 239000011699 pyridoxamine Substances 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 239000001397 quillaja saponaria molina bark Substances 0.000 description 1
- JSDRRTOADPPCHY-HSQYWUDLSA-N quinapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CC2=CC=CC=C2C1)C(O)=O)CC1=CC=CC=C1 JSDRRTOADPPCHY-HSQYWUDLSA-N 0.000 description 1
- 229960001455 quinapril Drugs 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 108700040249 racecadotril Proteins 0.000 description 1
- 229950010561 radafaxine Drugs 0.000 description 1
- RCOBKSKAZMVBHT-TVQRCGJNSA-N radafaxine Chemical compound C[C@@H]1NC(C)(C)CO[C@@]1(O)C1=CC=CC(Cl)=C1 RCOBKSKAZMVBHT-TVQRCGJNSA-N 0.000 description 1
- HDACQVRGBOVJII-JBDAPHQKSA-N ramipril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](C[C@@H]2CCC[C@@H]21)C(O)=O)CC1=CC=CC=C1 HDACQVRGBOVJII-JBDAPHQKSA-N 0.000 description 1
- 229960003401 ramipril Drugs 0.000 description 1
- 238000009790 rate-determining step (RDS) Methods 0.000 description 1
- 229960003770 reboxetine Drugs 0.000 description 1
- CBQGYUDMJHNJBX-RTBURBONSA-N reboxetine Chemical compound CCOC1=CC=CC=C1O[C@H](C=1C=CC=CC=1)[C@@H]1OCCNC1 CBQGYUDMJHNJBX-RTBURBONSA-N 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000008085 renal dysfunction Effects 0.000 description 1
- 230000030558 renal glucose absorption Effects 0.000 description 1
- 229960002354 repaglinide Drugs 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- QEVHRUUCFGRFIF-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C(C5=CC=C(OC)C=C5N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 QEVHRUUCFGRFIF-MDEJGZGSSA-N 0.000 description 1
- 229960003147 reserpine Drugs 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 229940100486 rice starch Drugs 0.000 description 1
- 229950004360 rilapladib Drugs 0.000 description 1
- JZCPYUJPEARBJL-UHFFFAOYSA-N rimonabant Chemical compound CC=1C(C(=O)NN2CCCCC2)=NN(C=2C(=CC(Cl)=CC=2)Cl)C=1C1=CC=C(Cl)C=C1 JZCPYUJPEARBJL-UHFFFAOYSA-N 0.000 description 1
- 229960003015 rimonabant Drugs 0.000 description 1
- CRPGRUONUFDYBG-UHFFFAOYSA-N risarestat Chemical compound C1=C(OCC)C(OCCCCC)=CC=C1C1C(=O)NC(=O)S1 CRPGRUONUFDYBG-UHFFFAOYSA-N 0.000 description 1
- 229950006433 risarestat Drugs 0.000 description 1
- NCDNCNXCDXHOMX-XGKFQTDJSA-N ritonavir Chemical compound N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-XGKFQTDJSA-N 0.000 description 1
- 229960000311 ritonavir Drugs 0.000 description 1
- 229960004136 rivastigmine Drugs 0.000 description 1
- XMSXOLDPMGMWTH-UHFFFAOYSA-N rivoglitazone Chemical compound CN1C2=CC(OC)=CC=C2N=C1COC(C=C1)=CC=C1CC1SC(=O)NC1=O XMSXOLDPMGMWTH-UHFFFAOYSA-N 0.000 description 1
- 229950010764 rivoglitazone Drugs 0.000 description 1
- HJORMJIFDVBMOB-UHFFFAOYSA-N rolipram Chemical compound COC1=CC=C(C2CC(=O)NC2)C=C1OC1CCCC1 HJORMJIFDVBMOB-UHFFFAOYSA-N 0.000 description 1
- 229950005741 rolipram Drugs 0.000 description 1
- MDMGHDFNKNZPAU-UHFFFAOYSA-N roserpine Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(OC(C)=O)C(OC)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 MDMGHDFNKNZPAU-UHFFFAOYSA-N 0.000 description 1
- 229960004586 rosiglitazone Drugs 0.000 description 1
- 229960000672 rosuvastatin Drugs 0.000 description 1
- BPRHUIZQVSMCRT-VEUZHWNKSA-N rosuvastatin Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC(O)=O BPRHUIZQVSMCRT-VEUZHWNKSA-N 0.000 description 1
- ZCBUQCWBWNUWSU-SFHVURJKSA-N ruboxistaurin Chemical compound O=C1NC(=O)C2=C1C(C1=CC=CC=C11)=CN1CCO[C@H](CN(C)C)CCN1C3=CC=CC=C3C2=C1 ZCBUQCWBWNUWSU-SFHVURJKSA-N 0.000 description 1
- 229950000261 ruboxistaurin Drugs 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 229950001780 sampatrilat Drugs 0.000 description 1
- 229930182490 saponin Natural products 0.000 description 1
- 150000007949 saponins Chemical class 0.000 description 1
- QWAXKHKRTORLEM-UGJKXSETSA-N saquinavir Chemical compound C([C@@H]([C@H](O)CN1C[C@H]2CCCC[C@H]2C[C@H]1C(=O)NC(C)(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)C=1N=C2C=CC=CC2=CC=1)C1=CC=CC=C1 QWAXKHKRTORLEM-UGJKXSETSA-N 0.000 description 1
- 229960001852 saquinavir Drugs 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 108010033693 saxagliptin Proteins 0.000 description 1
- 229960004937 saxagliptin Drugs 0.000 description 1
- QGJUIPDUBHWZPV-SGTAVMJGSA-N saxagliptin Chemical compound C1C(C2)CC(C3)CC2(O)CC13[C@H](N)C(=O)N1[C@H](C#N)C[C@@H]2C[C@@H]21 QGJUIPDUBHWZPV-SGTAVMJGSA-N 0.000 description 1
- IMNTVVOUWFPRSB-JWQCQUIFSA-N sch-48461 Chemical compound C1=CC(OC)=CC=C1[C@H]1N(C=2C=CC(OC)=CC=2)C(=O)[C@@H]1CCCC1=CC=CC=C1 IMNTVVOUWFPRSB-JWQCQUIFSA-N 0.000 description 1
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 239000003775 serotonin noradrenalin reuptake inhibitor Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 229960004425 sibutramine Drugs 0.000 description 1
- UNAANXDKBXWMLN-UHFFFAOYSA-N sibutramine Chemical compound C=1C=C(Cl)C=CC=1C1(C(N(C)C)CC(C)C)CCC1 UNAANXDKBXWMLN-UHFFFAOYSA-N 0.000 description 1
- 229960002855 simvastatin Drugs 0.000 description 1
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 description 1
- 229960004034 sitagliptin Drugs 0.000 description 1
- MFFMDFFZMYYVKS-SECBINFHSA-N sitagliptin Chemical compound C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F MFFMDFFZMYYVKS-SECBINFHSA-N 0.000 description 1
- PHWXUGHIIBDVKD-UHFFFAOYSA-N sitaxentan Chemical compound CC1=NOC(NS(=O)(=O)C2=C(SC=C2)C(=O)CC=2C(=CC=3OCOC=3C=2)C)=C1Cl PHWXUGHIIBDVKD-UHFFFAOYSA-N 0.000 description 1
- 229960002578 sitaxentan Drugs 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910052979 sodium sulfide Inorganic materials 0.000 description 1
- NTDIRNUKAZNMSW-IYVGUKHKSA-M sodium;(3s,5r,6e)-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(1-methyltetrazol-5-yl)nona-6,8-dienoate Chemical compound [Na+].CN1N=NN=C1C(\C=C\[C@H](O)C[C@H](O)CC([O-])=O)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 NTDIRNUKAZNMSW-IYVGUKHKSA-M 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 229950009659 solabegron Drugs 0.000 description 1
- 239000012439 solid excipient Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- LXANPKRCLVQAOG-NSHDSACASA-N sorbinil Chemical compound C12=CC(F)=CC=C2OCC[C@@]21NC(=O)NC2=O LXANPKRCLVQAOG-NSHDSACASA-N 0.000 description 1
- 229950004311 sorbinil Drugs 0.000 description 1
- FOEYMRPOKBCNCR-UHFFFAOYSA-N spiro[2.5]octane Chemical compound C1CC11CCCCC1 FOEYMRPOKBCNCR-UHFFFAOYSA-N 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- PJANXHGTPQOBST-UHFFFAOYSA-N stilbene Chemical compound C=1C=CC=CC=1C=CC1=CC=CC=C1 PJANXHGTPQOBST-UHFFFAOYSA-N 0.000 description 1
- 235000021286 stilbenes Nutrition 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- MBGGBVCUIVRRBF-UHFFFAOYSA-N sulfinpyrazone Chemical compound O=C1N(C=2C=CC=CC=2)N(C=2C=CC=CC=2)C(=O)C1CCS(=O)C1=CC=CC=C1 MBGGBVCUIVRRBF-UHFFFAOYSA-N 0.000 description 1
- 229960003329 sulfinpyrazone Drugs 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical compound OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 1
- 229960003491 sulodexide Drugs 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000002889 sympathetic effect Effects 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229960000651 tasosartan Drugs 0.000 description 1
- ADXGNEYLLLSOAR-UHFFFAOYSA-N tasosartan Chemical compound C12=NC(C)=NC(C)=C2CCC(=O)N1CC(C=C1)=CC=C1C1=CC=CC=C1C=1N=NNN=1 ADXGNEYLLLSOAR-UHFFFAOYSA-N 0.000 description 1
- 229950004351 telenzepine Drugs 0.000 description 1
- 229960005187 telmisartan Drugs 0.000 description 1
- VCKUSRYTPJJLNI-UHFFFAOYSA-N terazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1CCCO1 VCKUSRYTPJJLNI-UHFFFAOYSA-N 0.000 description 1
- 229960001693 terazosin Drugs 0.000 description 1
- ZGPUJIKBVXJDGJ-UHFFFAOYSA-N tert-butyl 2-[4-[[1-(1h-indol-3-yl)-3,4-dioxonaphthalen-2-yl]methyl]phenoxy]acetate Chemical compound C1=CC(OCC(=O)OC(C)(C)C)=CC=C1CC(C(C(=O)C1=CC=CC=C11)=O)=C1C1=CNC2=CC=CC=C12 ZGPUJIKBVXJDGJ-UHFFFAOYSA-N 0.000 description 1
- PUGUQINMNYINPK-UHFFFAOYSA-N tert-butyl 4-(2-chloroacetyl)piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCN(C(=O)CCl)CC1 PUGUQINMNYINPK-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- 229960003352 tertatolol Drugs 0.000 description 1
- 229950004704 tesaglitazar Drugs 0.000 description 1
- VCVWXKKWDOJNIT-ZOMKSWQUSA-N tesofensine Chemical compound C1([C@H]2C[C@@H]3CC[C@@H](N3C)[C@@H]2COCC)=CC=C(Cl)C(Cl)=C1 VCVWXKKWDOJNIT-ZOMKSWQUSA-N 0.000 description 1
- 229950009970 tesofensine Drugs 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229950000584 tezosentan Drugs 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- LJJKNPQAGWVLDQ-SNVBAGLBSA-N thiorphan Chemical compound OC(=O)CNC(=O)[C@@H](CS)CC1=CC=CC=C1 LJJKNPQAGWVLDQ-SNVBAGLBSA-N 0.000 description 1
- XUIIKFGFIJCVMT-UHFFFAOYSA-N thyroxine-binding globulin Natural products IC1=CC(CC([NH3+])C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-UHFFFAOYSA-N 0.000 description 1
- PHWBOXQYWZNQIN-UHFFFAOYSA-N ticlopidine Chemical compound ClC1=CC=CC=C1CN1CC(C=CS2)=C2CC1 PHWBOXQYWZNQIN-UHFFFAOYSA-N 0.000 description 1
- 229960005001 ticlopidine Drugs 0.000 description 1
- TWVUMMQUXMYOOH-UHFFFAOYSA-N tilisolol Chemical compound C1=CC=C2C(=O)N(C)C=C(OCC(O)CNC(C)(C)C)C2=C1 TWVUMMQUXMYOOH-UHFFFAOYSA-N 0.000 description 1
- 229950008411 tilisolol Drugs 0.000 description 1
- 229960004605 timolol Drugs 0.000 description 1
- RBKASMJPSJDQKY-RBFSKHHSSA-N tirilazad Chemical compound O=C([C@@H]1[C@@]2(C)CC=C3[C@@]4(C)C=CC(=O)C=C4CC[C@H]3[C@@H]2C[C@H]1C)CN(CC1)CCN1C(N=1)=CC(N2CCCC2)=NC=1N1CCCC1 RBKASMJPSJDQKY-RBFSKHHSSA-N 0.000 description 1
- 229960005155 tirilazad Drugs 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 229950001089 todralazine Drugs 0.000 description 1
- 229960002277 tolazamide Drugs 0.000 description 1
- OUDSBRTVNLOZBN-UHFFFAOYSA-N tolazamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1CCCCCC1 OUDSBRTVNLOZBN-UHFFFAOYSA-N 0.000 description 1
- 229960005371 tolbutamide Drugs 0.000 description 1
- 229960003069 tolrestat Drugs 0.000 description 1
- LUBHDINQXIHVLS-UHFFFAOYSA-N tolrestat Chemical compound OC(=O)CN(C)C(=S)C1=CC=CC2=C(C(F)(F)F)C(OC)=CC=C21 LUBHDINQXIHVLS-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000003325 tomography Methods 0.000 description 1
- 229960004394 topiramate Drugs 0.000 description 1
- 229950004514 torcetrapib Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 229940118436 tracleer Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 239000003558 transferase inhibitor Substances 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 229960000363 trapidil Drugs 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- 229960001288 triamterene Drugs 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 229960004813 trichlormethiazide Drugs 0.000 description 1
- LMJSLTNSBFUCMU-UHFFFAOYSA-N trichlormethiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NC(C(Cl)Cl)NS2(=O)=O LMJSLTNSBFUCMU-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 229940035722 triiodothyronine Drugs 0.000 description 1
- UHLOVGKIEARANS-QZHINBJYSA-N tripamide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(=O)NN2C[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3C2)=C1 UHLOVGKIEARANS-QZHINBJYSA-N 0.000 description 1
- 229950004678 tripamide Drugs 0.000 description 1
- 108010039189 tripeptidyl-peptidase 2 Proteins 0.000 description 1
- 239000003174 triple reuptake inhibitor Substances 0.000 description 1
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 description 1
- 229960001130 urapidil Drugs 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 229940045145 uridine Drugs 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
- NPTIPEQJIDTVKR-STQMWFEESA-N vabicaserin Chemical compound C1CNCC2=CC=CC3=C2N1C[C@@H]1CCC[C@@H]13 NPTIPEQJIDTVKR-STQMWFEESA-N 0.000 description 1
- 229950009968 vabicaserin Drugs 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 229960004699 valsartan Drugs 0.000 description 1
- ACWBQPMHZXGDFX-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=NN1 ACWBQPMHZXGDFX-QFIPXVFZSA-N 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 229950005709 vatanidipine Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 229960004688 venlafaxine Drugs 0.000 description 1
- PNVNVHUZROJLTJ-UHFFFAOYSA-N venlafaxine Chemical compound C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 PNVNVHUZROJLTJ-UHFFFAOYSA-N 0.000 description 1
- 229960001254 vildagliptin Drugs 0.000 description 1
- SYOKIDBDQMKNDQ-XWTIBIIYSA-N vildagliptin Chemical compound C1C(O)(C2)CC(C3)CC1CC32NCC(=O)N1CCC[C@H]1C#N SYOKIDBDQMKNDQ-XWTIBIIYSA-N 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 208000029257 vision disease Diseases 0.000 description 1
- 230000004393 visual impairment Effects 0.000 description 1
- 229960005080 warfarin Drugs 0.000 description 1
- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 1
- 239000011534 wash buffer Substances 0.000 description 1
- XOSKJKGKWRIMGV-DGCLKSJQSA-N way-163909 Chemical compound C1NCCN2[C@@H]3CCC[C@@H]3C3=CC=CC1=C32 XOSKJKGKWRIMGV-DGCLKSJQSA-N 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- 229940100445 wheat starch Drugs 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
- ZXIBCJHYVWYIKI-PZJWPPBQSA-N ximelagatran Chemical compound C1([C@@H](NCC(=O)OCC)C(=O)N2[C@@H](CC2)C(=O)NCC=2C=CC(=CC=2)C(\N)=N\O)CCCCC1 ZXIBCJHYVWYIKI-PZJWPPBQSA-N 0.000 description 1
- 229960001522 ximelagatran Drugs 0.000 description 1
- SXONDGSPUVNZLO-UHFFFAOYSA-N zenarestat Chemical compound O=C1N(CC(=O)O)C2=CC(Cl)=CC=C2C(=O)N1CC1=CC=C(Br)C=C1F SXONDGSPUVNZLO-UHFFFAOYSA-N 0.000 description 1
- 229950006343 zenarestat Drugs 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229960002911 zonisamide Drugs 0.000 description 1
- UBQNRHZMVUUOMG-UHFFFAOYSA-N zonisamide Chemical compound C1=CC=C2C(CS(=O)(=O)N)=NOC2=C1 UBQNRHZMVUUOMG-UHFFFAOYSA-N 0.000 description 1
- 229950005346 zopolrestat Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H7/00—Compounds containing non-saccharide radicals linked to saccharide radicals by a carbon-to-carbon bond
- C07H7/04—Carbocyclic radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Diabetes (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Biotechnology (AREA)
- Obesity (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Hematology (AREA)
- Hospice & Palliative Care (AREA)
- Child & Adolescent Psychology (AREA)
- Endocrinology (AREA)
- Vascular Medicine (AREA)
- Emergency Medicine (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pyrane Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
200932755 九、發明說明: 本申請案主張2007年12月13日申請之美國臨時申請案第 61/〇13,517號之權益,該案之揭示内容係以弓丨用的方式併 入本文中。 [關於在聯邦資助之研究及開發下所進行之發明之權利 的聲明] 不適用 【先前技術】 β 根據世界衛生組織(World Health 〇rganizati〇n)報導全 世界有約1.5億人患有糖尿病(diabetes mellitus) 〇糖尿病之 兩種主要形式為1型糖尿病(其中胰腺不能產生胰島素)及2 型糖尿病(其中身體不能對所產生之胰島素適當地反應(抗 胰島素症))。2型糖尿病目前最為常見,其占所有糖尿病病 例之約90〇/〇。在兩種類型之糖尿病中,胰島素作用或對胰 島素之適當反應之缺乏導致血糖含量增加(高血糖症與 • 糖尿病相關之嚴重併發症包括視網膜病(導致視覺受損或 失明)、心血管疾病、腎病、神經病、潰瘍及糖尿病足 病。 患有1型糖尿病之個體目前需要胰島素療法。雖然在許 多情況下,2型糖尿病可利用膳食及運動控制,但通常亦 需要藥物干預。除約三分之一患有2型糖尿病之患者需要 之肤島素之外’目前之抗糖尿病療法包括雙胍類 (biguanide)(其減少肝臟中之葡萄糖產生且提高對胰島素之 敏感性)、磺醯基脲類及美袼列奈類(megHtinide)(其刺激胰 136781.doc 200932755 島素產生)、α•葡糖普酶抑制劑(其減緩殿粉吸收 產生)及㈣咬二嗣類(其提高姨島素敏感性)。該,糖 常組合使用,且即使如此亦無法提供充分血糖控制或3 產生不當副作用。該等副作用包括乳酸性❹毒 類)、低血糖«酿基脲類)以及水腫及體重增加(嗔 • _)。因此’非常需要提供改良之血糖控制且無:; • 作用之新穎抗糖尿病藥。 針對糖尿病及相_症之治療性干預之-種有前景的標 把為腎臟之葡萄糖轉運系統。細胞葡萄糖轉運係藉由易化 (”被動")葡萄糖轉運體(GLUT)或納依賴性("主動")葡萄糖 共轉運體(SGLT)進行^ SGLT1主要見於腸刷狀緣,而 SGLT2位於腎近端小管中,且據報導其負責大多數由腎臟 達成之葡萄糖再吸收。新近研究表明抑制腎SGLT可為藉 由提高尿中所排泄之葡萄糖之量治療高血糖症的有用方法 (Arakawa K等人,Br J Pharmacol 132:578-86,2001 ; 〇ku 參 A等人,Diabetes 48:1794-1800, 1999) »以下新近發現進一 步支持該治療方法之可能性:在家族性腎性糖尿之情況下 存在SGLT2基因之突變,該家族性腎性糖尿為一種表面上 良性症候群,其由在存在正常血清葡萄糖含量的情況下尿 .葡萄糖排泄及不存在常見腎功能障礙或其他疾病表徵 (Santer R等人 ’ j Am Soc Nephrol 14:2873-82,2003)。因 此’抑制SGLT、尤其SGLT2之化合物為適用作抗糖尿病 藥之有前景之候選者。前述適用於抑制SGLT之化合物包 括環已烷衍生物(諸如W02006011469中所述之彼等環己烷 13678l.doc 200932755 衍生物)、C-醣苷衍生物(諸如US6414126 、 US20040138439 、 US20050209166 、 US20050233988 、 W02005085237 ' US7094763 ' US20060009400 ' US20060019948 、 US20060035841 、 US20060122126 及 W02006108842中所述之彼等C-醣苷衍生物)、Ο-醣苷衍生 物(諸如 US6683056、US20050187168、US20060166899、 US20060234954、US20060247179 及 US20070185197 中所述 之彼等Ο-醣苷衍生物)、螺縮酮-醣苷衍生物(描述於 W02006080421中)及硫代葡萄哌喃糖苷衍生物(諸如 US20050209309及W02006073197中所述之彼等硫代葡萄 哌喃糖苷衍生物)。 【發明内容】 本發明提供對鈉依賴性葡萄糖共轉運體SGLT具有抑制 作用之化合物。本發明亦提供醫藥組合物;製備該等化合 物、合成中間物之方法,及使用獨立地或與其他治療劑組 合之該等化合物治療受SGLT抑制影響之疾病及病狀的方 法。 【實施方式】 定義 如本文中所使用之術語”齒基”意謂選自氟基、氣基、溴 基及蛾基之單價ii素基團或原子。較佳齒基為氟基、氣基 及溴基。 如本文中所使用之術語"合適取代基"意謂化學及醫藥學 上可接受之基團’亦即不顯著干擾本發明之化合物之製備 136781.doc 200932755 或不會使本發明之化合物之功效無效的部分。該等合適取 代基可由熟習此項技術者常規地選擇。合適取代基可選自 由以下基團組成之群:函基、C]_C6烷基、c2_C6烯基、C丨 函烧基、CVQ貌氧基、Cl_C6_院氧基、C2_Q块基、
環稀基、環院基)Cl-c6炫基、(C3_C8環烧基)C2_cj 基、(c3-c8環烷基)Cl_c6烷氧基、C3_C7雜環烷基、(C3_C7 雜環烷基)CVC6烷基、(CVC7雜環烷基)^^^烯基、(q-q 雜環燒基)CVC6烧氧基、經基、缓基、側氧基、硫基、 燒基硫基、芳基、雜芳基、芳基氧基、雜芳基氧基、^炫6 基、雜芳絲、芳絲基、㈣絲基、硝基 '氰基、= 基、C】-C6^基胺基、二·((ν(:6烧基)胺基、胺甲酿基、 (CVC,烧基)幾基、((VC6院氧基浪基、(c^烧基飧基羰 基、二-(q-c:6烷基)胺基羰基、芳基羰基、芳基氧基羰 基、(c,-c:6烷基)磺醯基及芳基磺醯基。以上所列之作為合 適取代基之基團如下文所定義,其巾例外為合適取代基4 能視情況不經進一步取代。 除非另有所m彳如本文中所使用之單獨或組合形式 ,:語"烧基”係指具有指定數目之碳原子的單價飽和脂族 烴基。該基團可為直鏈或支鏈,且若指定,則視情㈣一 =二個如上所定義之合適取代基取代。燒基之說明性 =旦不限於)甲基、乙基、正丙基、正丁基、正戊基、 基、異丁基、異戊基、戊基、第二丁基、第 基、第三戊基、正庚基、正辛基、正壬基、正癸基、 正十一絲、正十四烧基、正十六貌基、正十人貌基、正 136781,doe 200932755 二十烷基及其類似基團。較佳烷基包括甲基、乙基、正丙 基及異丙基。較佳視情況選用之合適取代基包括函基、甲 氧基、乙氧基、氰基、硝基及胺基。 除非另有所述,否則如本文中所使用之單獨或組合形式 之術π烯基"係指具有指定數目之碳原子及至少一個碳·碳 雙鍵的單價月日族烴基。該基團可為£型或ζ型直鏈或支鍵, . 且右私疋,則視情況經一至三個如上所定義之合適取代基 參取代。烯基之說明性實例包括(但不限於)乙婦基、卜丙烯 基2丙稀基、異丙稀基、j•丁烯基、2_丁稀基、異丁稀 基、2-甲基·ι_丙稀基、卜戊缔基、2-戊稀基、心甲基-2-戊 烯基、1,3_戊二烯基、2,4.戊二烯基、υ•丁二烯基及其類 似基團。較佳烯基包括乙稀基、^丙婦基及2丙稀基。較 佳視情況選用之合適取代基包括鹵基、甲氧基、乙氧基、 氰基、硝基及胺基。 除非另有所述’否則如本文中所使用之單獨或組合形式 Φ 之術語"炔基"係指具有指定數目之碳原子及至少一個碳-碳 參鍵的單價脂族烴基。該基團可為直鏈或支鏈,且若指 定,則視情況經一至三個如上所定義之合適取代基取代。 炔基之說明性實例包括(但不限於)乙炔基、1·丙炔基、2-丙炔基1-丁炔基、2· 丁炔基、戊炔基、2•戊炔基、% 甲基_1_戊炔基、3_戊炔基、1-己炔基、2-己炔基、3·己炔 基及其類似基團。較佳炔基包括乙炔基、卜丙炔基及2_丙 炔基。較佳視情況選用之合適取代基包括自基、曱氧基、 乙氧基、氰基、硝基及胺基。 136781.doc 200932755 除非另有所述,否則如本文中所使用之單獨或組合形式 環烷基”係指具有三個或三個以上形成碳環之碳且 若指定則視情況經一至三個如上所定義之合適取代基取代 的單價料飽和烴基。環烧基之說明性實例包括(但不限 於)環丙基、環丁基、環戊基、環己基、環庚基、環辛 基、環壬基及其類似基團。較佳視情況選用之合適取代基 包括齒基、曱基、乙基、甲氧基、乙氧基、氰 胺基。
除非另有所4,否則如本文中所使用之單獨或組合形式 之術語”環烯基”係指具有三個或三個以上形成碳環之碳及 ,少一個碳-碳雙鍵且若指定則視情況經一至三個如上所 定義之合適取代基取代的單錢環烴基。環縣之說明性 實例包括(但不限於)環戊烯基、環己烯基及其類似基圈。 較佳視情況選用之合適取代基包括齒基、尹基、乙基、甲 氧基、乙氧基、氰基、硝基及胺基。 除非另有所述,否則如本文中所使用之術語"伸烷基"、 ”伸婦基"、,,伸環職"及”伸環稀基,,分別指藉由自烧基、 ,基、環炫基或環烯基(該等術語如上文所^義)移除一個 氫原子形成之二價烴基。 如本文中所使用之術語"(C3_c]〇伸環炫基)(Ci C6 > J υ *Τ衣机悉八伸炫 基)"係指藉由將C3.ClD伸環貌基與Ci_c6伸縣(該等術語如 上文所定義)鍵結所形成之二價烴基。 _另有㈣如本以所使用之單獨或組合形式 之街語”芳基”係指具有六至十個形成碳環之碳原子且若指 l367Sl.doc 200932755 定則視情況經-至三個如上所定義之 價芳族烴基。若甚k取代基取代的單 … 說明性實例包括(但不限於)苯基、苯 基、四虱萘基、二氫昂基及兑類 ’、 況經選自以下基團之相佳芳基為視情 取代的苯Α及蓉其Η或不同之合適取代基單取代或二 :代的本基及萘基4基、氰基、c 基、二敦甲基、三氣f基、Ci_ A環坑 三說甲氧基。 &说氧基、二鼠T氧基及 :非另有所述,否則如本文中所使用之單獨 之術語"雜環烷基丨,係指環中之一 士夕加* ❿式 之雜盾;^ 之-或多個碳經選自N、8及〇 例勺、、的如上所定義之我基。雜環院基之說明性 實例包括(但不限於叫基、四氯㈣"底嗪基、四 風0底喃基及其類似基團。 ❹ 除非另有所述’否則如本文令所使用之單獨或組合形式 之術語"雜芳基"係指具有形成五至十員單環或稠合雙環之 二至九個碳及一至四個選自N、S及〇之雜原子且若指定則 視情況經-至三個如上所定義之合適取代基取代的單價芳 矣雜衣基#芳基之說明性實例包括(但不限於)吡啶基、 噠嗪基、吡嗪基、嘧啶基、三嗪基、喹啉基、異喹啉基、 嗜°若琳基、料琳基、苯并三唤基、笨并味唾基、笨并呢 絲、笨并三絲、苯并異㈣基、異苯并Μ基、異% °木基"引嗓基、嗟吩并吼咬基、嘆吩并喷d定基"比唾并嘧 咬基、味唾并対、苯并嗟峻基、苯并吱喃基、苯并嗔吩 基"引絲、異喧唾基"比唾基"引唾基"米唾基、三唾 基四坐基、嗯《坐基、異嗯唾基、。惡二唾基"塞二唾基、 136781.doc -13- 200932755 吼哈基、售唾基、呋喃基、噻吩基及其類似基團。五或六 員單環雜务基環包括:吼咬基、達嗪基、n比唤基、鳴咬 基、三嗪基、異噻唑基、吡唑基、咪唑基、三唑基、四唑 基、噁唑基、異噁唑基、噁二唑基、噻二唑基、吡咯基、 嗟。坐基、吱喃基、售吩基及其類似基團。具有一至四個雜 原子之八至十員雙環雜芳基環包括:啥琳基、異喧琳基、 • 喹喏啉基、喹唑啉基、苯并三嗪基、苯并咪唑基、苯并吼 ©°坐基、苯并三嗤基、苯并異噁唑基、異苯并呋喃基、異吲 Ρ朵基、吲嗪基、嗟吩并D比咬基、嗟吩并嘴咬基、η比峻并〇密 。定基、咪唾并η比啶基、苯并噻唑基、苯并呋喃基、苯并噻 吩基、。引β朵基、吲峻基及其類似基團。較佳視情況選用之 合適取代包括一或兩個選自以下基團之相同或不同取代 基:豳基、氰基、(VC3烷基、C3-C6環烷基、二氟曱基、 二氟甲基、Ci-C3烷氧基、二氟甲氧基及三氟甲氧基。 除非另有所述’否則如本文中所使用之單獨或組合形式 φ 之術語"烷氧基"及"烷基氧基"係指形式烷基-〇-之脂族基, 其中烧基係如上所定義。烷氧基之說明性實例包括(但不 p艮於)曱氧基、乙氧基、丙氡基、#丙氧基、丁氧基、異 丁氧基、第三丁氧基、戊氧基、異戊氧基、新戊氧基、第 一戊氧基、己氧基、異己氧基、庚氧基、辛氧基及其類似 基團。較佳院氧基包括曱氧基及乙氧基。 除非另有所述,否則如本文中所使用之術語"自烷基"係 才曰經或多個齒素取代之上述烷基。_烷基之說明性實例 包括(但不限於)氯甲基、二氣甲基、氟甲基、二氟甲基、 1367Bl.doc •14- 200932755 三氟甲基、2,2,2-三氯乙基及其類似基團。 除非另有所述,否則如本文中所使用之術語"纽氧基" 係指經-或多個自素取代之上㈣氧f纽氧基之說明 性實例包括(但不限於)三氟f氧基、二氟甲氧基及其類似 基團。 除非另有所述’㈣如本文中所❹之術語"芳烧基"係 指經上述芳基取代之上述具有—至六個碳之烧基。 ❹
除非另有所述,否則如本文中所使用之術語"雜芳烧基" 係指經上述雜芳基取代之上述具有—至六個碳之统基。 除非另有所述,否則如本文中所使用之術語"芳烷氧基" 係指經上述芳基取代之上述具有一至六個碳之烷氧基。 除非另有所述,否則如本文中所使用之術語"雜芳烷氧 基係扣經上述雜芳基取代之上述具有一至六個碳之烷氧 基。 除非另有所述,否則如本文中所使用之術語"胺甲醯基" 係指形式-C(〇)NH(R)之單價基團,其中R為氫、[^匕烷 基、C^C:6烯基、CrC6環烷基或芳基(該等術語如上文所定 義)0 除非另有所述,否則如本文中所使用之單獨或組合形式 之術語"二-(CVC^基)胺基"及,,二_(Ci_c6烧基)胺基"分別 指經兩個獨立地選自Cl-C3烷基或Cl_C6烷基之基團取代之 胺基。 如本文中所使用之術語"治療"係指延緩該術語所適用之 疾病或病狀或者該疾病或病狀之—或多種症狀之發作、延 136781.doc 15 200932755 遲或逆轉該術語所適用之疾病或病狀或者該疾病或病狀之 一或多種症狀之進展’或減輕或預防該術語所適用之疾病 或病狀或者該疾病或病狀之一或多種症狀。 如本文中所使用之術語”投藥”意謂對個體經口投藥、以 权劑形式杈藥、局部接觸、經靜脈内、腹膜内、肌肉内、 病灶内、鼻内或皮下投藥,或植入緩釋裝置,例如微量滲 . 透泵。投藥係藉由包括非經腸及經黏膜之任何途徑(例如 經口、經鼻、經陰道、經直腸或經皮)達成。非經腸投藥 包括(例如)經靜脈内、肌肉内、小動脈内、皮内、皮下、 腹膜内〜至内及顧内投藥。其他傳遞方式包括(但不限 於)使用脂質調配物、靜脈内輸注、經皮貼片及其類似方 式。 如本文中所使用之術語"前藥"係指投藥之後在活體内經 由 a化予或生理過程釋放生物活性化合物之前軀體化合 物(例如,前藥在達到生理學pH值之後或經由酶作用轉化 φ 為生物活性化合物)。前藥本身可缺乏或具有所需生物活 性。 如本文中所使用之術語"化合物”係指藉由任何方法產生 之分子,該等方法包括(但不限於)活體外合成或者 : 活體内產生。 〆 術語"控制釋放”、"持續釋放”、"延長釋放"及”定時釋放" 預期可互換地指任何含藥物調配物,其中藥物之釋放並非 快速的,亦即,對於"控制釋放”調配物而言,經口投藥並 不使藥物快速釋放至吸收池(abs〇rpti〇n ρ〇〇ι)中。令等货任 136781.doc -16 - 200932755 可與如 Remington:The Science and Practice of Pharmacy , 第 21 版,Gennaro 編,Lippencott Williams & Wilkins (2003)中所定義之"非快速釋放(no nimmedi ate release)"互 換使用。如該文獻中所討論,快速及非快速釋放可參考以 下方程式以動力學方式定義: 劑型-►吸收池 藥物釋放 (Ce -►標乾區 -> 吸收 消除 φ "吸收池"表示投與特定吸收位點之藥物之溶液,且、 ka及ke分別為(1)自調配物釋放藥物、(2)吸收及(3)消除之 一級速率常數。對於快速釋放劑型而言,藥物釋放之速率 常數kr大大超過吸收速率常數!^。對於控制釋放調配物而 吕’實際情況相反’亦即kr<<ka ’以致劑型中藥物之釋放 速率為將藥物傳遞至標乾區之限速步驟。 術語”持續釋放"及"延長釋放"係以其習知意義使用以指 使藥物經延長之時段(例如丨2小時或丨2小時以上)逐漸釋放 ❹ 且杈佳(但非必需)在延長之時段内產生大體上恆定之藥物 血液含量的藥物調配物。 如本文中所使用之術語"延緩釋放"係指完整地通過胃且 溶解於小腸中之醫藥製劑。 總則 本發明提供對鈉依賴性葡萄糖共轉運體SGLT、較佳 具有抑制作用之化合物。本發明之一些化合物亦對 納依賴性葡萄糖共轉運體SGLT1具有抑制作用。由於本發 136781.doc 200932755 明之化合物具有抑制SGLT之能力,故其適於治療及/或預 防受抑制SGLT活性、尤其SGLT2活性影響之任何及所有 病狀及疾病。因此,本發明之化合物適於預防及治療疾病 及病狀,尤其代謝障礙,包括(但不限於型及2型糖尿 病、高血糖症、糖尿病併發症(諸如視網膜病、腎病[例如 進仃性腎病]、神經病、潰瘍、微血管病變及大血管病變 . 以及糖尿病足病)、抗胰島素症、代謝症候群(X症候群)、 ❹ 间胰島素血症、高血壓、高尿酸血症、肥胖症、水腫、血 脂異常、慢性心臟衰竭、動脈粥樣硬化及相關疾病。 本發明亦提供本發明之化合物的醫藥學上可接受之鹽 前藥。 ι 本發明另外提供醫藥組合物,其包含醫藥學上可接受之 載劑中的有效量之本發明之化合物或本發明之化合物之混 合物’或其醫藥學上可接受之鹽或前藥。 本發明另外提供合成中間減用於製備纟發明之化 _ 的方法。 本發明亦提供使用獨立地或與其他治療劑組合之本發明 之化合物治療可受SGLT抑制影響之疾病及病狀的方法。 本發明亦S供使用本發明之化合物製備供治療可典 SGLT抑制影響之疾病及病狀之藥劑的方法。 ^ 詳細實施例 化合物及製備方法 在一態樣中’本發明提供式I化合物: 136781.doc 200932755
其中 A表示氧;NH ;亞甲基;或一單鍵; Q係選自下式Q1至Q4中之一者;
其中波形線表示與分子剩餘部分之連接點; Z表示氧;硫;SO ; S〇2 ; 1,1·伸環丙基;羰基;或亞甲 基,其視情況經一至兩個獨立地選自以下基團之取代基取 代:齒基、經基、CrC6院基、CVC6烧氧基、C3_C6環烷基 及c3-c6環烷基氧基; R、R2及R3各自獨立地表示氫、鹵基、經基、C丨烧 基、C2-C6烯基、C2-C6炔基、c3-C1()環烧基、C5_Ciq環缔 基、q-C6烷基氧基、C3-ClQ環烷基氧基、氰基、胺基或硝 基,其中烷基、烯基、炔基、環烷基及環烯基基團或部分 可視情況經部分或完全氟化且可經選自以下基團之相同或 136781.doc •19- 200932755 不同取代基單取代或二取代:氣、羥基、氧基及 G-C3烷基’且在環烷基及環烯基基團或部分中,一或兩 個亞甲基視情況彼此獨立地經以下基團置換:NRa、〇、 s、CO、SO或S〇2,且一或兩個次甲基可視情況經N置 換,或
在R1及R2結合至笨環之兩個鄰近C原子的情況下,尺〖與 R2可接合在一起以致Ri與R2—起形成可經部分或完全氟化 且可經選自以下基團之相同或不同取代基單取代或二取代 之CrC5伸烧基、CrC5伸烯基或伸丁二烯基橋:氣、羥 基、C^-C3烧氧基及〇〗-(:3烧基,且其中一或兩個亞甲基視 情況彼此獨立地經以下基團置換:0、S、CO、so、so2 或NR ’且其_ 一或兩個次甲基可視情況經N置換; R獨立地表示氫、齒基、氰基、硝基、胺基、羥基、 cvc6燒基、c2-c6稀基、C2_C6炔基、C3_Ci〇環烧基、C5-Ci〇 環烯基、c,-C6烷基氧基、C3_ClG環烷基氧基、(Ci_C6烷基 氧基)c^-c:6烷基氧基、Cs_C7環烯基氧基、芳基、雜芳基、 芳基氧基、雜芳基氧基、(C2_C4烯基)Ci_c3烷基氧基、(C2_C4 炔基)CVW基氧基、(芳基)(^3烧基氧基、(雜芳基)Ci_c3 烷基氧基、(CVC1G環貌基)Ci_C3貌基、(CVCiQ環炫基)C|_C3 烷基氧基、(C5_C1G環稀基)Ci_C3烧基、(c5_CiG環稀基)Ci_c3 烷基氧基、(CA烷基氧基)Ci_C3烷基、(C3_C7環烷基氧 基)c,-C3烧基、(C3_C7環烧基氧基)婦基、(C3_C7環烷 基氧基)c2-c4炔基、(CVC7環烧基氧基)Ci_c3燒基氧基、 (CVC:4烧基胺基)Cl_C3燒基、二_(Ci_C3^基胺基)CiC^ 136781.doc -20- 200932755 基、三-(Ci-C4烷基)矽烷基-Ci-C6烷基、三-(cvc^烷基)矽 烷基-c2-c6烯基、三-(q-CU烷基)矽烷基-c2-c6炔基、三-(CVC4烷基)矽烷基-CVC6烷基氧基、(c3-c7環烷基)c2-c5烯 基、(C3-C7環烷基)C3-C5稀基氧基、(C3-C7環烷基)(:3-<:5炔 基氧基、(c5-c8環烯基)c3_c5烯基氧基、(c5-c8環烯基)c3-c5 炔基氧基、C3-C6#環烷基甲基、(CrC^烷基)羰基、芳基 羰基、雜芳基羰基、胺基羰基、(Ci-C^烷基)胺基羰基、 二-(Crq烷基)胺基羰基、羥基羰基、烷基氧基)羰 基、CVC4烷基胺基、二-((VC3烷基)胺基、(CVC4烷基)羰 基胺基、芳基羰基胺基、雜芳基羰基胺基、Ci-CU烷基磺 醯基胺基、芳基磺醯基胺基、CrC4烷基硫基、烷基 亞磺醯基、Crq烷基磺醯基、C3-C1()環烷基硫基、c3-c10 環烧基亞磺醯基、c3-c1G環烷基磺醯基、C5-C1G環烯基硫 基、C5-C】G環烯基亞磺醯基、c5-C1G環烯基磺醯基、芳基 硫基、务基亞續酼基或芳基績醢基,其中烧基、稀基、炔 基、環烧基及環烯基基團或部分可視情況經部分或完全氟 化且可經選自以下基團之相同或不同取代基單取代或二取 代:氯、羥基、CrCs烷氧基及(^-(:3烷基,且在環烷基及 環稀基基團或部分中一或兩個亞甲基視情況彼此獨立地經 以下基團置換:NRa、0、s、CO、SO或S02,且一或兩個 次曱基可視情況經N置換; 及R各自獨立地表不風、自基、氣基、确基、經基、 Cl-C6烧基、C2-C6烯基、c2-c6炔基、C3-C1()環烷基、Cl_c3 炫基氧基或C3-C1Q環烷基氧基,其中烷基、烯基、炔基、 136781.doc •21 · 200932755 環烧基及環烯基基團或部分可視情況經部分或完全氟化且 可經選自以下基團之相同或不同取代基單取代或二取代: 氣、經基、CrC3烷氧基及匸广^烷基,且在環烷基及環烯 基基團或部分中’一或兩個亞甲基視情況彼此獨立地經以 • 下基團置換:NRa、〇、S、C〇、8〇或s〇2,且一或兩個次 •. 曱基可視情況經N置換,或 • 若R5及R6結合至苯環之兩個鄰近C原子,則R5與R6可視 ® 情況接合在一起以致R5與R6 一起形成可經部分或完全氟化 且可經選自以下基團之相同或不同取代基單取代或二取代 之Cs-C5伸烷基、Cj-C:5伸烯基或伸丁二烯基橋:氯、羥 基、C丨-C3燒氧基及c丨-C3烷基,且其中一或兩個亞甲基視 情況彼此獨立地經以下基團置換:〇、S、CO、so、so2 或NRa ’且其中一或兩個次甲基可視情況經N置換; R、R8、R9及r1g各自獨立地表示羥基、(Ci_Ci8烷基)羰 基氧基、(C^-Cu烷基)氧基羰基氧基、芳基羰基氧基、芳 φ 基-(C:1-C3烷基)羰基氧基、(c3-c1()環烷基)羰基氧基、氫、 鹵基、c〗-c6烧基、C2-C6}lf基、c2-c6快基、(C3-C10環烷 基)CVC3烧基、(c5-c7環稀基A-Cs烧基、(芳基)烷 基、(雜芳基)C丨-C3烷基、q-C6烷基氧基、c2_c6烯基氧 基、Cz-C6炔基氧基、C3_C?環烷基氧基、c5_c7環烯基氧 基、芳基氧基、雜芳基氧基、(C3_C7環烷基)Ci_c3烷基氧 基、(Cs-C7環烯基)C「C3烷基氧基、(芳基)C〗_C3烷基氧 基、(雜芳基)Ci-C3烷基氧基、胺基羰基、羥基羰基、(Ci_C4 烷基)胺基羰基、二-(Cl_C3烷基)胺基羰基、(Ci_c4烷基氧 I3678I.doc -22- 200932755 基)羰基、(胺基羰基烧基、(CVC4烧基)胺基羰基-(CVC3)烷基、二-(CVC3烷基)胺基羰基-(CVC3)烷基、(羥 基羰基)CVC3烷基、(CVC4烷基氧基)羰基-(CVC3)烷基、 (C3-C7環烧基乳基)C1-C3烧基、(C5-C7環稀基氧基)(^-Cs院 基、(芳基氧基KVC3烷基、(雜芳基氧基)(VC3烷基、CVC4 . 烷基磺醯基氧基、芳基磺醯基氧基、(芳基)烷基磺醯 ' 基氧基、三甲基矽烷基氧基、第三丁基二曱基矽烷基氧基 ©或氰基;其中烷基、烯基、炔基、環烷基及環烯基基團或 部分可視情況經部分或完全I化且可經選自以下基團之相 同或不同取代基單取代或二取代:氯、羥基、C1_C3烷氧 基及CrC3烷基,且在環烷基及環烯基基團或部分中,一 或兩個亞甲基視情況彼此獨立地經以下基團置換:NRa、 0、S、CO、so或 so2 ; 且視情況,R1G及R11可與其各自所連接之碳原子組合以 形成視情況經部分或完全氟化且可經選自以下基團之相同 〇 或不同取代基單取代或二取代之五至七員稠合環烷烴或環 、C〗-C3烷氧基及C丨-C3烷基,且其中在
完全氣化,或 烯烴環:氣、羥基、Cy 環烷基環及環烯基環中, 地經以下基團置換:NRa I3678l.doc •23· 200932755 R與R可視情況接合在一起以致R11及Rl2與其所連接 之碳原子一起形成可視情況經部分或完全氟化且可經選自 二下基團之相同或不同取代基單取代或二取代之螺 衣烧故% .氯、經基、Ci_C3烷氧基及Ci_c3烷基; 其中當Q為Q1且R1丨與Ru均為氫時,則R10或R14中之至少 r …者為鹵基’或尺13不為氫’或R、c2-C6炔基、c3-c丨❶環 烷基氧基、C5-C7環烯基氧基、(C3_Ci()環烷基)Ci_C3烷基氧 % 基、(C3-C7環烷基)c3-c5烯基氧基、(c3-c7環烷基)C3-C5炔 基氧基、(C5_C1()環烯基)Ci_c3烷基氧基、(C5_C8環烯基)C3_C5 烯基氧基或(C5_C8環烯基)c3-c5炔基氧基,或 田Q為Q且Rl1為氫時,則至少R10為鹵基,或R4為C2-C6 炔基、C3_C1Q環烷基氧基、Cs_C7環烯基氧基、(C3_CiQ環烷 基)Cl_C3烷基氧基、(C3_C7環烷基)c3-c5烯基氧基、(c3-c7 裱烷基)(VCs炔基氧基、(C5_Ciq環烯基)Ci_c3烷基氧基、 (C5_C8環烯基)CVC5烯基氧基或(C5-C8環烯基)c3-c5炔基氧 ❹ 基,或 田Q為Q且Ru為氫時,則至少Rl0為鹵基,或R〗3不為 虱,或R4為CVC6炔基、C3_CiQ環烷基氧基、C5_C7環烯基 ; 氧基、(CrC1G環烷基)Ci_C3烷基氧基、(C3_C7環烷基)C3_C5 烯基氧基、(CVC7環烷基)CVC5炔基氧基、(CVCiQ環烯 基)Cl-C3烷基氧基、(Cs-Cs環烯基)c3-c5烯基氧基或(c5_c8 環烯基)C3_C5炔基氧基; R及R各自獨立地表示氫、羥基、鹵基、C]_C6烷基、 c2 C6稀基、c2_c6炔基、環烷基、烧基氧基、 136781.doc -24· 200932755 C2-C6稀基氧基、C2_C6炔基氧基或C3_C6環烷基氧基,其中 烧基、稀基、炔基及環烷基基團或部分可視情況經部分或 完全氟^化; R15獨立地表示氧或CRbRc ; R獨立地表示氫、c丨-C:4烷基或(C「C4烷基)羰基,其中 烷基基團或部分可視情況經部分或完全氟化;且
R及Rc各自獨立地表示氫、鹵基或Ci_C4烷基,其中烷 基可視情況經部分或完全氟化。 除非另有說明,否則上文及下文所用之型式(其中展示 苯基上取代基之鍵在苯環中心附近封端)表示該取代基可 與攜帶氫原子之苯基之任何空位結合。 本發明包括混合物或者純或大體上純形式之式〗化合物 之所有互變異構物&立體異構物。纟發明之化合物可在碳 原子處具有不對稱中心’且因此該等式“匕合物可以非對 映異構或對映異構形式或其混合物形式存在。所有構形異 構物(例如順式及反式異構物)及所#光學異構物(例如對映 異構物及非對映異構物)、該等異構物之外消旋物、非對 映異構物及其他混合物’以及溶劑合物、水合物、同曰型 物、多晶型物及互變異構物均在本發明之㈣内。可: 非對映異構物、對映異構物或外消旋混合㈣以料_ 本發明之化合物。此外’可藉由層析法、分步結晶法或熟 習=術者已知之其他方法分離非對映異構產物及對映 本發明之化合物之前 本發明亦提供式I化合物之前藥 136781.doc -25· 200932755 、碳酸酯、半酯、磷酸酯、硝酸
酯、乙 藥包括(但不限於)羧酸酯 醋、硫酸酯、亞碾、醯胺 酸甲知、苯甲酸甲|旨、特戊酸甲醋及其類似物來形成前藥 酯及碳酸酯。本發明化合物之前藥酯之說明性實例包括 (仁不限於)具有羧基部分之式J化合物,其中游離氫經以下 基團置換.烷基、Ci-C·?烷醯基氧基甲基、l-GCVCs) 烷酿基氧基)乙基、丨_甲基烷醯基氧基卜乙基、 Ci-Cs烷氧基羰基氧基曱基、^((CrC5)烷氧基羰基氧基)乙 基、曱基-1-((CVC5)烷氧基羰基氧基)乙基、n_((Ci_c5) 烷氧基羰基)胺基甲基、l^N-iXCi-C5)烷氧基羰基)胺基)乙 基、3-酞基、4-巴豆酸内酯基、γ-丁内酯-4_基、二-N,N_ (CrC2)烷基胺基(CyC:3)烷基(例如β_二甲基胺基乙基)、胺 φ 甲醯基-(C1-C2)烷基、Ν,Ν-二(Ci-C2)烷基胺曱醯基_(c]_c2) 烧基及N-略咬基-、N-D比哈咬基-或N-嗎琳基(C2-C3)燒基。 寡肽修飾及可生物降解聚合物衍生物(如(例如)Int Pharm. 115,61-67,1995中所述)係在本發明之範疇内。選 擇及製備合適前藥之方法例如提供於以下文獻中:τ.
Higuchi 及 V. Stella, "Prodrugs as Novel Delivery
Systems",第 14 卷,ACS Symposium Series,1975 ; H.
Bundgaard, "Design of Prodrugs," Elsevier, 1985 ;及 "Bioreversible Carriers in Drug Design," Edward Roche 136781.doc -26- 200932755 編 ’ American Pharmaceutical Association and Pergam〇n Press,1987。 本發明亦提供式I化合物之醫藥學上可接受之鹽及其前 樂可用作製備本發明之驗性化合物之醫藥學上可接受的 - 酸加成鹽之試劑的酸為彼等形成無毒酸加成鹽之酸,亦 , 即’该等無毒酸加成鹽為含有藥理學上可接受之陰離子的 • 鹽(諸如鹽酸鹽、氫溴酸鹽、氫碘酸鹽、硝酸鹽、硫酸 φ 鹽、硫酸氫鹽、磷酸鹽、酸式磷酸鹽、乙酸鹽、乳酸鹽、 檸檬酸鹽、酸式檸檬酸鹽、酒石酸鹽、酒石酸氫鹽、琥珀 酸鹽、順丁烯二酸鹽、反丁烯二酸酯、葡糖酸鹽、已醣二 酸鹽、苯甲酸鹽、甲烷磺酸鹽、乙烷磺酸鹽、苯磺酸鹽、 對甲苯磺酸鹽及雙羥萘酸鹽(1,1·-亞甲基-雙-2-羥基-3-萘曱 酸鹽))。可用作製備本發明之酸性化合物之醫藥學上可接 又的鹼式鹽之試劑的驗為彼等與該等化合物形成無毒鹼式 鹽之鹼,該等無毒鹼式鹽包括(但不限於)彼等衍生自藥理 © 學上可接受之陽離子(諸如鹼金屬陽離子(例如鉀、鋰及鈉) 2驗土金屬陽離子(例如鈣及鎂))之鹽、銨或水溶性胺加成 (諸如N甲基葡糖胺(葡甲胺(megiumine)))以及低碳烷醇 及醫藥學上可接受之有機胺(例如甲基胺、乙基胺、丙 &胺、一甲基胺、三乙醇胺、二乙基胺、第三丁基胺、第 。辛基胺、二曱基胺、三乙基胺、乙二胺、羥基乙基胺、 馬琳、派°秦、脫氫松香胺、離胺酸及胍)的其他驗式鹽。 本發明亦包括同位素標記之式I化合物,其中一或多個 原子經—或多個具有特定原子質量或質量數之原子置換。 136781.doc -27- 200932755 可併入本發明之化合舲 於 ^ 中之同位素的實例包括(但不限於) 氫石反氮氧、氧、硫及氣之同位素<諸&2^ 13C、,4c、”N、18〇、17〇 b S及Cl)。同位素標記 之式I化合物及其前藥以及同位素標記之幻化合物之醫藥 • ^上可接受之鹽及其前藥均在本發明之範嘴内。同位素標 e之本發明之化合物適用於該等化合物以及其前藥及代: • 3 物之^織分布之檢定中;用於該等檢定之較佳同位素包括 Φ 『及14c。此外,在某些情況下,以較重同位素(諸如氘 (2H))取代可提供增加之代謝穩定性,此提供治療優勢,諸 如延長活體内+衰期或降低劑量需求。同位素標記之本發 明之化合物及其前藥通常可根據本文所述之方法藉由以同 位素標記之試劑取代未經同位素標記之試劑來製備。 在較佳實施例中,A表示氧或一單鍵。在尤佳實施例 中,A表示一單鍵。 在較佳實施例中,Z表示氧、硫,或視情況經一至兩個 φ 獨立地選自以下基團之取代基取代之亞甲基:函基、經 基、Ci-C6烧基、CVC6烷氧基、(:3-(:6環烧基及c3-C6環烷 基氧基。在尤佳實施例中,z表示亞甲基。 • 在較佳實施例中,R1、R2及R3各自獨立地表示氫、齒 基起·基、C!-C6烧基、C2-C6稀基、C2-C6快基、C3-Ci〇環 烧基、(:广匕烷基氧基或氰基。在尤佳實施例中,Rl、R2 及汉3各自獨立地表示氫、鹵基或Ci-C6烷基。在更尤佳實 施例中,R1表示氫、鹵基或(^-(:6烷基,且R2及R3均表示 氯0 136781.doc -28- 200932755 在較佳實施例中,R4表示Ci_C6烷基、C2-C6烯基、C2-C6 炔基、C3_c1G環烷基、Cl-C6烷基氧基、C3_ClG環烷基氡 基、(C3-c10環烷基)Ci_C3烧基氧基、⑷3々環垸基心义缔 基氧基或(Cs-C7環烷基)C3-C5炔基氧基。 . 在較佳實施例中,R5及R6各自獨立地表示氫、鹵基、羥 • 基、Cl_C6燒基、C2-C6烯基、C2-C6块基、c3-CIG環烷基、
Cl-<:6燒基氧基或氰基。在尤佳實施例中,R5及R6各自獨 也表示虱、鹵基或C〗-C6烧基。在更尤佳實施例中,汉5 及R6均表示氫β 在較佳實施例中’ R7、R8、R9及R10各自獨立地表示羥 基、鹵基、(VC6烷基、CVC6烷基氧基、(c3-c7)環烷基氧 基、芳基氧基或(CrC7)環烷基-(CrCs)烷基氧基,其中烷 基及環垸基基團或部分可經部分或完全氟化。在尤佳實施 例中’ R7、R8、r^rh)各自表示羥基。 在較佳實施例中’ R11表示氫或羥基。 φ 在較佳實施例中,R12、R!3及R!4表示氫。 在較佳實施例中’ R15表示氧或CRbRc,其中!^及1^各自 獨立地表示氫或_基。 如上所述’式IA表示其他較佳實施例··
〇xm:A 其中R1表示氫、鹵基或^ — ^烷基;R4表示Cl_c6烷基、 c2-c6稀基、c2-c6炔基、c3_Cig環烧基、Ci_C6烧基氧基、 136781.doc -29· 200932755 C3'Cl0環烧基氧基、(C3-Ci〇環烧基)c,-c3烧基氧基、(c3_c7 環烷基)C3-C5烯基氧基或(C3_C7環烷基)C3_C5炔基氧基;且 Q係選自下式(51/1至()4八:
其中R11表示氫或羥基,且R〖5表示氧或CRbRc,其中Rb 及Rc各自獨立地表示氫或鹵基;其中當Rii為氣時,則r4 為C2-C6炔基、C3-C]Q環烧基氧基、(C3-C〗。環烷基)Crq烷 基氧基、(CVC7環烧基)C3_CS烯基氧基或(C3_C7環烷基)c3_ c5炔基氧基。 在尤佳實施例中’本發明之化合物係選自:
(/足2足足5尺650-4-(4-氯-3-(4-乙基苄基)苯基)_6_(羥基 曱基)環己烷-1,2,3,5-四醇
(π,Μ,3Κ足5凡65>4-(4-氣-3-(4-乙氧基苄基)苯基)_6-(羥 基甲基)環己烷_1,2,3,5_四醇 136781.doc -30- 200932755
足5足π)-4-(4-氣-3-(4-環丙基苄基)苯基)-6-(羥 基甲基)環己烷-1,2,3,5·四醇
(7足2足35W足5足^S>4-(4-氯-3-(4-丙基苄基)苯基)-6-(羥基 曱基)環己烷-1,2,3,5-四醇
(/足2足3*S,^?,5i?,^S)-4-(4-氯-3-(4-環己基苄基)苯基)-6-(羥 基甲基)環己烷-1,2,3,5-四醇
(7足2兄3U/〇-4-(4-氯-3-(4-(3-環丙基丙-2-炔基氧基)苄基) 苯基)-6-(羥基曱基)環己-4-烯-1,2,3-三醇 136781.doc -31 - 200932755
Cl
乙酸((18,2尺,311,48,511,611)-3-(4-氯-3-(4-乙基苄基)笨 基)-2,4,5,6-四羥基環己基)曱酯
(lR,2S,3R,4R,5S,6R>4-(2-(4-己基苄基)苯氧基)-6-(羥基曱 基)環己烷-1,2,3,5-四醇 Φ
(/足况3KS,M)-4-(4-氣-3-(4-乙基节基)苯基)-6-(羥基 曱基)-5-亞甲基環己烷_丨,2,3-三醇
(48,58’6尺,711,811)-4-(4-氣_3-(4-乙基苄基)苯基)_8_(羥基甲 基)螺[2.5]辛烷-5,6,7-三醇 136781.doc -32- 200932755
1-(4-(2 -氣- 5-((lR,2S,3R,4R,5S,6R)-2,3,4,6-四經基- 5-(經 基曱基)環己基)苄基)苯基)乙酮 及
(7足 2/?, 35*,¥ 及,5^,65)-4-(4-氯-3-(4-(1-經基乙基)节基)苯 基)-6-(羥基甲基)環己烷-1,2,3,5-四醇。 在另一態樣中,本發明包括式I化合物及其醫藥學上可 接受之鹽、前藥及/或同位素標記之化合物,其中炫基、 烯基、炔基、環烷基、環烯基、芳基及雜芳基基團或部分 ® 視情況經一至三個如上所定義之合適取代基取代。 在其他態樣中,本發明提供中間物及適用於製備以下中 帛物以及式I化合物及其醫藥學上可接受之鹽及前藥的方 法。 該等方法概述於以下圓i及圖2之流程中所述之通用製備 方法中,且更詳述之特定實例呈現於下文描述操作實例之 實驗4 77中(®3·8)。按照下文所論述之通用製備方法或使 或替代方法,可易於藉由❹熟習此項技術者已知 予反應及程序來製備本發明之化合物。除非另外規 136781.doc •33· 200932755 定,否則在下述通用方法中表示基團之變數(例如R基團) 具有上文所定義之含義。 熟習此項技術者應認知,通常使用下文所列通用方法之 略微變化可製備具有所述各官能基之本發明化合物。在各 ' #法之範嗓内,使用適於反應條件之官能基。若需要,可 . 能干擾特定反應之官能基以經保護形式存在,且在適當階 . 段藉由熟習此項技術者所熟知之方法完成該等保護基之移 除。 φ 在某些情況下,可自本發明之其他化合物藉由存在之官 能基之加工、轉化、交換等製備本發明之化合物。該加工 包括(但不限於)水解、還原、氧化、烷基化、醯化、酯 化、酿胺化及脫水。在-些情況下,該等轉化可能需要使 用保護基藉由 T. W. Greene 及 p.G.M. Wuts,Pr〇tective Groups in 0rganic Synthesis,第 4版;y〇rk, (2007)^P.J. Kocienski, Protecting Groups ; Georg ❹ Thieme Verlag:Stuttgart,(2005)(兩者均以引用的方式併入 本文中)中所揭示之方法。該等方法可在合成所需化合物 之後或在合成途徑中之另一處起始’輕易為熟習此項技術 者顯而易見。 在另一態樣中,本發明提供適用於根據下文所論述之通 用製備方法及熟習此項技術者已知之其他方法製備式I化 合物及其醫藥學上可接受之鹽及前藥的合成中間物。 乙酸; 當使用以下縮寫及簡稱於本揭示中時,其具有以下含 義:Ac2〇 :乙酸酐;Ac〇Et •乙酸乙酯;Ac〇h 136781.doc -34- 200932755
AlBr3 :溴化鋁;A1C13 :氯化鋁;BBr3 :三溴化硼; BF3-Et20 :醚合三氟化硼;n-BuLi :正丁基鋰;s-BuLi : 第二丁基鋰;t-BuLi :第三丁基鋰;t-BuOK :第三丁氧化 鉀;CaCl2 :氣化鈣;calc :計算;CD3OD :甲醇; CDC13 :氣仿; CF3S03H :三氟甲烷磺酸;CH2C12 :二 氯甲烷;CH2I2 :二碘甲烷;CH3CN :乙腈;(COCl)2 :乙 二醯氯;DAST :三氟化(二乙基胺基)硫;DCM :二氣甲 烷;DIAD :偶氮二曱酸二異丙酯;DMAP : 4-二甲基胺基 吡啶;DMEM :杜爾貝科氏改良之伊格爾培養基 (Dulbecco's Modified Eagle Medium) ; DMF : N,N-二曱基 甲酿胺;DMP : 戴斯-馬丁高块炫(Dess-Martin periodinane) ; DMSO :二曱亞颯;EA :乙酸乙 S旨;eq :當 量;ESI :電喷霧電離;Et :乙基;Et3SiH :三乙基矽烷; EtOAc :乙酸乙酯;EtOH :乙醇;FBS :胎牛血清;h :小 時;H2 :氫氣;H2SO4 ’·硫酸;Hepes : 4-(2-經基乙基)-1-哌嗪乙烷磺酸;1H NMR :質子核磁共振;HPLC :高效液 相層析法;K2C03 :碳酸鉀;K2Cr07 :重鉻酸鉀;ΚΟΗ : 氫氧化鉀;LC-ESI-MS :液相層析電噴霧電離質譜;LC-MS :液相層析-質譜;Me :曱基;MeOH :曱醇; MeS03H :曱烷磺酸;Mg :鎂;MgCl2 :氯化鎂;min :分 鐘;MS :質譜;MsOH :曱烷磺酸;NaH :氫化鈉; NaHC03 :碳酸氫鈉;NaOAc :乙酸鈉;NaOH :氫氧化 鈉;Na2S04 :硫酸鈉;NH4C1 :氯化銨;Pd/C :碳載鈀; PE :石油醚;Ph :苯基;POCl3 :氧氯化磷;PPh3 :三苯 136781.doc -35· 200932755 基膦;Rf :滯留因子;rt :室溫;S0C12 :亞硫醯氣; TBAI :四丁基碘化銨;TFA :三氟乙酸;THF :四氫呋 喃;TLC :薄層層析法;TMS :三甲基矽烷基;Tris :三 羥基曱基胺基甲烷(或2-胺基-2-(羥基曱基)丙烷4,3—二 醇)。 流程I之通用合成方法 本發明之式I化合物可便利地根據如流程1(圓1)所示之反 應順序製備。 如流程I所示,藉由酿化劑(諸如乙二醯氯、SOC12或 POCI3等)將市售或根據標準文獻方法製備之酸A1轉化為酸 氯化物A2。使酸氣化物A2與經取代之苯A3在路易斯酸 (Lewis acid)(諸如AlCh或ΑΙΒη)存在下反應以提供酮A4。 在路易斯酸(諸如BFrEhO或TFA)存在下,利用還原劑(諸 如EhSiH)將中間物A4之酮基選擇性還原為亞甲基。在適 當溫度下’於諸如THF之溶劑中利用活化劑(諸如„_BuLi、 s-BuLi或i-BuLi,或Mg)處理A5,繼而與中間物A6加成提 供中間物A7。藉由在路易斯酸(諸如BF3.Et20或TFA)存在 下利用諸如EtsSiH之還原劑處理A7獲得中間物A8。隨後使 A8氧化以形成中間物A9,將A9去保護以提供本發明之化 合物A10。另外,亦可藉由氧化中間物A9來製備A11。 流程II之通用合成方法 本發明之式I化合物亦可便利地根據如流程π(圖2)所示 之反應順序製備。 如流程11所示’藉由醯化劑(諸如乙二醯氣、SOCl2或 136781.doc -36· 200932755 P0C13等)將市售或根據標準文獻方法製備之酸A12轉化為 酸氯化物A13。使酸氣化物A13與經取代之苯A3在路易斯 酸(諸如A1C13或AlBr3)存在下反應以提供酮A14。在路易斯 酸(諸如BF3’Et20或TFA)存在下,利用諸如Et3SiH之還原劑 將中間物A14之酮基選擇性還原為亞甲基,且隨後去保護 產生中間物A15。使A15與A16偶合提供中間物A17。氧化 A17產生中間物A18,隨後將A18去保護以提供本發明之化 合物A19。 醫藥組合物及使用方法 本發明另外提供一種醫藥組合物,其包含醫藥學上可接 受之載劑中的有效量之式I化合物或式I化合物之混合物, 或其醫藥學上可接受之鹽或前藥。 本發明之化合物可併入多種調配物中以供治療性投藥。 更具體言之,本發明之化合物可藉由與適當之醫藥學上可 接受之載劑或稀釋劑一起或單獨地調配而調配成醫藥組合 物,且可調配成固體、半固體、液體或氣體形式之製劑, 諸如鍵劑、膠囊、丸劑、散劑、顆粒劑、糖衣藥丸、凝膠 劑、聚液、軟膏劑、溶液、栓劑、注射劑、吸入劑及喷霧 劑。因此,投與本發明之化合物可以多種方式達成,包括 經口、頻内(buccal)、非經腸、靜脈内、皮内(例如皮下、 肌肉内)、經皮投與等。此外,化合物可以局部而非全身 方式例如以儲槽式或持續釋放調配物投與。 用於本發明之適當調配物可見於The and Practice of Pharmacy ,第 21 版,Gennaro 編, 136781.doc -37- 200932755
LlPPenC〇tt WilHams & Wilkins (2003),該文獻係以引用的 方式併入本文中。本文所述之醫藥組合物可以熟習此項技 術者已知之方式,亦即藉助於習知混合、溶解、造粒、糖 衣藥丸製備、粉碎、乳化、封入膠囊、覆埋或凍乾製程來 製造°以下方法及賦形劑僅為例示性的且並非限制。 在一較佳實施例中,將本發明之化合物製備為於例如含 有治療劑之固體疏水性聚合物之半透性基質中之持續釋 放、控制釋放、延長釋放、定時釋放或延緩釋放調配物形 式以供傳遞。已確定各種類型之持續釋放材料且其為熟習 此項技術者熟知。當前延長釋放調配物包括薄膜塗佈錠 劑、多粒子或顆粒系統、使用親水性或親脂性材料之基質 技術及具有成孔賦形劑之基於蠟之錠劑(參見(例如)Huang 等人 ’ Drwg £)ev. 29:79 (2003) ; Pearnchob等 人 ’ Z)ev. /«c/· 29:925 (2003) ; Maggi等人, 五wr. 乂 ΡΛαπ 55:99 (2003) ; Khanvilkar等人,
DrMg Dev. /«c/. P/mrw. 228:601 (2002);及 Schmidt等人, /wi. ·/·户/zar/w. 216:9 (2001)) 〇持續釋放傳遞系統可視其設 計而經數小時或數曰(例如經4、6、8、10、12、16、2 0、 24小時或24小時以上)之時間釋放化合物。一般而言,可 使用天然存在或合成之聚合物製備持續釋放調配物,該等 聚合物例如聚合乙烯基吡咯啶酮,諸如聚乙烯基吡咯啶酮 (PVP);缓基乙烯基親水性聚合物;疏水性及/或親水性水 膠體,諸如曱基纖維素、乙基纖維素、羥基丙基纖維素及 羥基丙基甲基纖維素;及羧基聚亞甲基。 136781.doc •38· 200932755 持續或延長釋放調配物亦可使用天然成份(諸如礦物 質,包括二氧化欽、二氧化碎、氧化辞及黏土)來製備(參 見美國專利6,638,521,該案係以引用的方式併入本文 中)。可用於傳遞本發明之化合物的例示性延長釋放調配 • 物包括美國專利第6,635,680號;第6,624,200號;第 _ 6,613,361 號;第 6,613,358 號;第 6,596,308 號;第 6,589,563 號;第 6,562,375 號;第 6,548,084 號;第 6,541,020 號;第 6,537,579 號;第 6,528,080 號及第 ® 6,524,621號中所述之彼等調配物,該等專利中之每一者均 係以引用的方式併入本文中》備受關注之控制釋放調配物 包括彼等美國專利第6,607,751號;第6,599,529號;第 6,569,463 號 ’第 6,565,883 號 第 6,482,440 號 第 6,403,597 號 •,第 6,319,919 號 第 6,150,354 號 第 6,080,736 號 ;第 5,672,356 號 第 5,472,704 號 第 5,445,829號; 第5,312,817號及第5,296,483號中所述之調 配物,該等專利中之每一者均係以引用的方式併入本文 中。熟習此項技術者應易於瞭解其他適用之持續釋放調配 物0 對於經口投藥而言,本發明之化合物可易於藉由與此項 技術中所熟知之醫藥學上可接受之載劑組合來調配。該等 載劑使得能將化合物調配為錠劑、丸劑、糖衣藥丸、膠 囊、乳液、親脂性及親水性料液、液體、凝膠劑、糖 漿、漿液、懸浮液及其類似物以供待治療患者經口攝取。 可藉由將化口物與固體賦形劑混合,視情況研磨所得混合 136781.doc -39- 200932755 物且(若需要)在添加合適助劑之後加工顆粒之混合物以 獲传旋劑或糖衣藥丸核心來獲得經口使用之醫藥製劑。特 定言之’合適賦形劑為填充劑,諸如糖,包括乳糖、蔗 糖甘露糖醇或山梨糖酵;纖維素製劑,諸如玉米殿粉、 小麥澱粉、米澱粉、馬鈐薯澱粉、明膠、黃蓍膠' 甲基纖 維素、羥基丙基甲基纖維素、羧甲基纖維素鈉及/或聚乙 烯基吡咯啶酮(PVP)。若需要’可添加崩解劑,諸如交聯
聚乙烯基吡咯啶酮、瓊脂或者海藻酸或其鹽(諸如海藻酸 納)〇 了; 口使用之醫藥製劑包括由明膠製成之推入配合膠囊 (push-fit capsule),以及由明膠及諸如甘油或山梨糖醇之 增塑劑製成之軟密封膠囊。推入配合膠囊可含有活性成份 與填充劑(諸如乳糖)、黏合劑(諸如澱粉)及/或潤滑劑(諸如 滑石粉或硬脂酸鎂)及視情況之穩定劑之混合物。在軟膠 囊中,活性化合物可溶解或懸浮於合適之液體(諸如脂肪 油、液體石蠛或液體聚乙二醇)中。此外,可添加穩定 劑。所有經口投與之調配物應為適於該投藥之劑量。 糖衣藥丸核心具有合適包衣。出於該目的,可使用濃糖 液,其可視情況含有阿拉伯膠、滑石粉、聚乙烯基吡咯啶 酮、卡波姆凝膠(carbopol gel)、聚乙二醇及/或二氧化欽、 漆液及適當有機溶劑或溶劑混合物。可將染料或顏料添加 至錢劑或糖衣藥丸包衣上以便鐘別或表徵活性化合物劑量 之不同組合。 化合物可經調配以藉由注射(例如藉由推注或連續輸注) 136781.doc •40· 200932755 非經腸投藥。對於注射而言,可藉由將化合物(若需要)與 習知添加劑(諸如增溶劑、等張劑、懸浮劑、乳化劑、穩 定劑及Βίτ腐劑)在水性或非水性溶劑(諸如植物油或其他類 似油、合成脂族酸甘油酯、高級脂族酸或丙二醇之酯)中 ' 賴、懸浮或乳化來將該等化合物調配成製劑。較佳地可 : ☆水溶液中、較佳於生理學相容之緩衝液(諸如亨克氏溶 • 液(HankS,S S〇luti〇n)、林葛爾氏溶液(Ringer's solution)或 纟理鹽水緩衝液)中調配本發明之化合物。用於注射之調 配物可以單位劑型提供於(例如)添加有防腐劑之安瓿或多 劑量令器中。組合物可採用諸如油性或水性媒劑中之懸浮 液’合液或乳液的形式且可含有調配劑,諸如懸浮劑、穩 定劑及/或分散劑。 用於非經腸投與之醫藥調配物包括呈 活性化合物之水溶液。另外,該等活性化合物之== 製備為適备油性注射懸浮液。合適之親脂性溶劑或媒劑包 ❿ 曰肪油諸如芝麻油,或合成脂肪酸酯,諸如油酸乙酯 或甘油三醋;或脂質體。水性注射懸浮液可含有增加懸浮 :¾黏度之物質’諸如叛基甲基纖維素納、山梨糖醇或葡聚 -冑?見It;兄’該懸浮液亦可含有合適穩㈣或增加該等化 合物之溶解性以使得可製備高濃度溶液之試劑。或者,活 性成份可為粉末形式以在使狀前與合適媒劑(例如無菌 無熱原質水)組合。 亦可藉由經黏膜或經皮方式來全身投藥。對於經黏臈或 經皮投藥而言,在調配物中使用適於滲透障壁的浸透劑。 13678I.doc • 41 · 200932755 對於局部投藥而言,將藥劑調配成軟膏劑、乳膏劑、油 膏、散劑及凝膠劑。在一實施例中,經皮傳遞劑可為 DMSO。經皮傳遞系統可包括(例如)貼片*對於經黏膜投 藥而言’在調配物中使用適於滲透障壁的浸透劑。該等浸 透劑通常為此項技術中已知。可用於本發明中之例示性經 皮傳遞調配物包括美國專利第6,589,549號;第6,544,548 號;第 6,517,864號;第 6,512,01〇號;第 6,465,〇〇6號;第 6,379,696號;第6,312,717號及第6,31〇,177號中所述之彼 等調配物,該等專利中之每一者均係以引用的方式併入本 文中。 對於頰内投藥而言,組合物可採用以習知方式調配之錠 劑或口含劑之形式。 除前述之調配物外,本發明之化合物亦可調配為儲槽式 製劑。該等長效調配物可藉由植入(例如經皮下或㈣⑴ 或藉由肌肉内注射投與。因此,舉例來說,該等化合物可 鲁 利用合適聚合或疏水性材料(例如調配為可接受之油 乳液)或離子交換樹脂調 微溶性鹽)。 戈調配為微溶性衍生物(例如 醫藥組合物亦可包含合適固體或 該等載劑或賦形劑之㈣U賦形劑。 約、各種糖 (不限於)碳酸舞、碟酸 、澱粉、纖維素衍生物、 聚乙二醇)。 初S膠及聚合物(諸如 適用於本發明中之醫藥組合物包括含有治 陡成伤的μ合物^本發m ’、 之’舌 窗樂組合物,其包含式工 136781.doc • 42· 200932755 化口物與有效量之作為組合搭配物之其他治療劑、尤其彼 等用於/U療可受SGLT抑制影響之疾病及病狀之治療劑的 奶合物,該等治療劑諸如抗糖尿病藥、降脂劑/脂質調節 劑、治療糖尿病併發症之藥劑、減肥藥、抗高血壓藥、抗 - 间尿酸血症藥及治療慢性心臟衰竭、動脈粥樣硬化或相關 • 病症之藥劑。當然,化合物及/或組合搭配物之有效量應 、視所治療之個體、病痛之嚴重程度及投藥方式而定。有效 ©量之確定完全在熟習此項技術者能力範疇内,尤其根據本 文所提供之詳細揭示内容而定。一般而言,化合物之有效 量係藉由以下方法確定:首先投與低劑量或較少量,且隨 後遞增地增加所投與之劑量直至在所治療個體中觀察到所 需治療作用而具有最小或無毒副作用。確定本發明投藥之 適_劑量及給樂方案之可用方法(例如)描述於Goodman及
Gilvc^n之 The Pharmacological Basis of Therapeutics',第 \ \ 版,Brunton,Lazo 及 Parker 編,McGraw-Hill (2006)及 • Remington:The Science and Practice of Pharmacy,% 7Λ 版 ’ Gennaro編,Lippencott Williams及 Wilkins (2003)中’ 兩者均以引用的方式併入本文中。 本發明另外提供使用式I化合物預防及治療疾病之方 法。在一實施例中,本發明提供治療1型糖尿病及2型糖尿 病、高血糖症、糖尿病併發症(諸如視網膜病、腎病、神 經病、潰瘍、微血管病變及大血管病變、痛風及糖尿病足 病)、抗胰島素症、代謝症候群(X症候群)、高胰島素血 症、高血壓、高尿酸血症、肥胖症、水腫、血脂異常、慢 136781.doc •43- 200932755 性心職衰蝎、動脈粥樣硬化及相關疾病之方法,其包含向 有需要之個體投與有效量之式I化合物或式I化合物之混合 物’或其醫藥學上可接受之鹽或前藥。在另一實施例中, 本發明提供使用式I化合物或式I化合物之混合物或其醫藥 ' 學上可接受之鹽或前藥製備用於治療1型及2型糖尿病、高 • 血糖症、糖尿病併發症、抗胰島素症、代謝症候群、高胰 島素血症、高血壓、高尿酸血症、肥胖症、水腫、血脂異 常、慢性心臟衰竭、動脈粥樣硬化及相關疾病之藥劑的方 ® 法。 本發明亦涵蓋式〗化合物或其醫藥學上可接受之鹽或前 藥與其他治療劑、尤其彼等用於治療上述疾病及病狀之治 療劑(諸如抗糖尿病藥、降脂劑/脂質調節劑、治療糖尿病 併發症之藥劑、減肥藥、抗高血壓藥、抗高尿酸血症藥及 治療慢性心臟衰竭、動脈粥樣硬化或相關病症之藥劑)組 合之使用。熟習此項技術者應理解下文所論述之其他治療 馨劑可具有多種治療用途,且一個特定類別中藥劑之列表不 應視為以任何方式限制其在與本發明之化合物的組合療法 中之有效性。 - 適於與本發明之化合物組合使用之抗糖尿病藥的實例包 括騰島素及擬胰島素;磺醯基脲類(諸如乙醯苯續酿環己 腺(acetohexamide)、胺續丁腺(earbutamide)、氣續丙脈 (chlorpropamide)、格列本脲(glibencUmide)、格列波脲 (glibornuride)、格列齊特(gliciazide)、格列美脲 (glimepiride) > 格列吡嗪(glipizide)、格列啥網 136781.doc -44· 200932755 (gliquidone)、格列帕特(glisoxepide)、格列本腺 (glyburide)、格列 °比腺(glyclopyramide)、妥拉橫腺 (tolazamide)、甲續環已腺(tolcyclamide)、甲苯罐丁腺 (tolbutamide)及其類似物);胰島素分泌增強劑(諸如JTT-. 608、格列丁峻(glybuzole)及其類似物);雙胍(諸如二曱雙 •胍、丁福明(buformin)、苯乙雙胍及其類似物);磺醯基脲/ .雙胍組合(諸如格列本脲/二曱雙胍及其類似物);美格列奈 類(meglitinide)(諸如瑞格列奈(repaglinide)、那格列奈 ® (nateglinide)、米格列奈(mitiglinide)及其類似物);嗔嗤咬 二酮類(諸如羅格列酮(rosiglitazone)、β比格列酮 (pioglitazone)、伊格列酮(isaglitazone)、萘格列洞 (netoglitazone)、利格列酮(rivoglitazone)、巴格列明 (balaglitazone)、達格列酮(darglitazone)、CLX-0921 及其 類似物);噻唑啶二酮/雙胍組合(諸如吡格列酮/二甲雙胍 及其類似物);噁二唑啶二酮類(諸如YM440及其類似物); 過氧化體增殖物活化受體(peroxisome proliferator-activated receptor,PPAR)-y促效劑(諸如法格列酮 (farglitazar)、美格列森(metaglidasen)、MBX-2044、GI : 262570、GW1929、GW7845 及其類似物);PPAR-α/γ雙重 促效劑(諸如莫格列紮(muraglitazar)、那格列紮 (naveglitazar)、替格列紫(tesaglitazar)、佩格列紮 (peliglitazar)、JTT-501、GW-409544、GW-501516及其類 似物);PPAR-α/γ/δ全促效劑(諸如PLX204 、 GlaxoSmithKline 625019、GlaxoSmithKline 677954及其類 136781.doc • 45- 200932755 似物);類視色素X受體促效劑(諸如八1^丁-268、八0冰 4204、MX-6054、AGN-194204、LG-100754、貝瑟羅汀 (bexarotene)及其類似物);α-葡糖發酶抑制劑(諸如阿卡波 糖(acarbose)、米格列醇(miglitol)及其類似物);胰島素受 . 體酪胺酸激酶刺激劑(諸如TER-17411、L-783281、KRX- - 613及其類似物);三肽基肽酶II抑制劑(諸如UCL-1397及其 . 類似物);二肽基肽酶IV抑制劑(諸如西他列汀 (sitagliptin)、維格列汀(vildagliptin)、德格列汀 ❹ (denagliptin)、薩格列丁(saxagliptin)、NVP-DPP728、 P93/01 、P32/98、FE 99901 、TS-021 、TSL-225、 GRC8200,美國專利第 6,869,947號、第 6,727,261 號、第 6,710,040 號、第 6,432,969 號、第 6,172,081 號、第 6,011,155號中所述之化合物,及其類似物);蛋白質酪胺 酸磷酸酶-1B抑制劑(諸如KR61639、IDD-3、PTP-3848、 PTP-112、OC-86839、PNU-177496,Vats,R.K.等人, Current Science,第 88 卷,第 2期,2005年 1 月 25 日,第 241-249頁中所述之化合物,及其類似物);肝糖磷酸化酶 抑制劑(諸如NN-4201、CP-368296及其類似物);葡萄糖-6--磷酸酶抑制劑;果糖1,6-二磷酸酶抑制劑(諸如CS-917、 MB05032及其類似物);丙酮酸脫氫酶抑制劑(諸如AZD-7545及其類似物);咪唑啉衍生物(諸如BL1 1282及其類似 物);肝臟葡糖新生抑制劑(諸如FR-225659及其類似物); D-對掌性肌醇(D-chiroinositol);肝糖合成酶激酶-3抑制劑 (諸如 Vats,R.K.等人,Current Science,第 88卷,第 2期, 136781.doc -46- 200932755 2005年1月25日,第241-249頁中所述之化合物及其類似 物);腸促胰液素模擬劑(諸如艾塞那肽(exenatide)及其類 似物);升糖素受體拮抗劑(諸如BAY-27-9955、NN-2501、 NNC-92-1687及其類似物);類升糖素肽-l(GLP-l)、GLP-1 類似物(諸如利戈魯泰(liraglutide)、CJC-1131、AVE-0100 • 及其類似物);GLP-1受體促效劑(諸如八乙]^-134、1^- . 315902、GlaxoSmithKline 716155 及其類似物);胰澱素 (amylin)、胰殿素類似物及促效劑(諸如普蘭林肽 ® (pramlintide)及其類似物);脂肪酸結合蛋白(aP2)抑制劑 (諸如美國專利第6,984,645號;第6,919,323號;第 6,670,380號;第6,649,622號;第6,548,529號中所述之化 合物及其類似物);β-3腎上腺素受體促效劑(諸如索拉格隆 (solabegron)、CL-316243、L-771047、FR-149175及其類 似物);及其他胰島素敏感性增強劑(諸如瑞格列烷 (reglixane)、ONO-5816、MBX_102、CRE-1625、FK-614、CLX-0901、CRE-1633、NN-2344、BM-13125、BM- ❹ 501050、HQL-975、CLX-0900、MBX-668、MBX-675、S-15261、GW-544、AZ-242、LY-510929、AR-H049020、 GW-501516及其類似物)。 適合於與本發明之化合物組合使用的治療糖尿病併發症 之藥劑之實例包括醛糖還原酶抑制劑(諸如依帕司他 (epalrestat)、w米瑞司他(imirestat)、托瑞司他(tolrestat)、 米那司他(minalrestat)、泊那司他(ponalrestat)、唾泊司他 (zopolrestat)、非達司他(fidarestat)、加莫利酸抗壞血基醋 136781.doc -47- 200932755 (ascorbyl gamolenate)、ADN-138、BAL-ARI8、ZD-5522、 ADN-311、GP-1447、IDD-598、瑞薩司他(risarestat)、折 那司他(zenarestat)、曱索比尼爾(methosorbinil)、AL-1567、M-16209、TAT、AD-5467、AS-3201、NZ-314、 SG-210、JTT-811、林多司他(lindolrestat)、索比尼爾 • (sorbinil)及其類似物);晚期糖基化終末產物(AGE)形成抑 • 制劑(諸如 °比吟胺(pyridoxamine)、OPB-9195、ALT-946、 ALT-711、匹馬吉定(pimagedine)及其類似物);AGE裂解 ® 劑(諸如ALT-711及其類似物);舒洛地特(sulodexide) ; 5- 羥基-1-甲基乙内醯;類胰島素生長因子-I ;血小板源性生 長因子;血小板源性生長因子類似物;表皮生長因子;神 經生長因子;尿苷;蛋白激酶C抑制劑(諸如魯伯斯塔 (ruboxistaurin)、米 朵妥林(midostaurin)及其類似物);納 通道拮抗劑(諸如美西律(mexiletine)、奥卡西平 (oxcarbazepine)及其類似物);核因子kB(NF-kB)抑制劑(諸 如德力波坦(dexlipotam)及其類似物);脂質過氧化酶抑制 劑(諸如甲續酸替拉紮特(tirilazad mesylate)及其類似物); N-乙醯化-α-鍵聯酸性二肽酶抑制劑(諸如GPI-5232、GPI-5 693及其類似物)及肉驗(carnitine)衍生物(諸如肉驗、左卡 胺(levacecamine)、左卡尼汀(levocarnitine)、ST-261 及其 類似物)。 適合於與本發明之化合物組合使用的抗高尿酸血症藥之 實例包括尿酸合成抑制劑(諸如別嘌呤醇(allopurinol)、奥 昔嗓醇(oxypurinol)及其類似物);排尿酸藥(諸如丙績舒 136781.doc -48- 200932755 (probenecid)、績 °比明(sulfinpyrazone)、苯漠馬隆 (benzbromarone)及其類似物)及尿驗化劑(urinary alkalinizer)(諸如碳酸氫鈉、檸檬酸鉀、檸檬酸鈉及其類似 物)。 . 適合於與本發明之化合物組合使用之降脂劑/脂質調節 劑的實例包括羥基甲基戊二醯基輔酶A還原酶抑制劑(諸如 . 阿昔替S旨(acitemate)、阿托伐他、;丁(atorvastatin)、柏伐他 丁(bervastatin)卡伐他汀(carvastatin)、西立伐他汀 ® (cerivastatin)、考來網(colestolone)、克伐他汀 (crilvastatin)、達伐他.汀(dalvastatin)、氟伐他·;丁 (fluvastatin)、格命伐地汀(glenvastatin)、洛伐他 ίΤ (lovastatin)、美伐他丁(mevastatin)、尼伐他 ί丁 (nisvastatin)、匹伐他汀(pitavastatin)、普伐他 (pravastatin)、利托那韋(ritonavir)、羅素伐他汀 (rosuvastatin)、沙奎那韋(saquinavir)、辛伐他 ίτ (simvastatin)、維薩他汀(visastatin)、SC-45355、SQ_ 33600、CP-83101、BB-476、L-669262、S-2468、DMP-565、U-20685、BMS-180431、BMY-21950,美國專利第 5,753,675 號;第 5,691,322 號;第 5,506,219 號;第 • 4,686,237 號;第 4,647,576 號;第 4,613,610 號;第 4,499,289號中所述之化合物,及其類似物);纖維酸衍生 物(諸如吉非羅齊(gemfibrozil)、非諾貝特(fenofibrate)、 苯紮貝特(bezaHbrate)、苄氣貝特(beclobrate)、比尼貝特 (biniflbrate)、環丙貝特(ciproHbrate)、克利貝特 136781.doc -49- 200932755 (clinofibrate)、氣貝特(clofibrate)、依託貝特(etofibrate)、 尼可貝特(nicofibrate)、0比貝特(pirifibrate)、氯煙貝特 (roniHbrate)、雙貝特(simHbrate)、羥乙茶驗安妥明 (theofibrate)、AHL-157及其類似物);PPAR-α促效劑(諸如 GlaxoSmithKline 590735及其類似物);PPAR-δ促效劑(諸 如GlaxoSmithKline 501516及其類似物);醯基輔酶A :膽 固醇醯基轉移酶抑制劑(諸如阿伐麥布(avasimibe)、依魯麥 布(eflucimibe)、依達麥布(eldacimibe)、來西貝特 (lecimibide)、NTE-122、MCC-147、PD-132301-2、C1-1011 、 DUP-129 、 U-73482 、 U-76807 、 TS-962 、RP- 70676、P-06139、CP-113818、RP-73163、FR-129169、 FY-038、EAB-309、KY-455、LS-3115、FR-145237、T-2591、J-104127、R-755、FCE-27677、FCE-28654、YIC- C8-434 ' CI-976 > RP-64477 ' F-1394 ' CS-505 ' CL-283546、YM-17E、447C88、YM-750、E-5324、KW-3033、HL-004及其類似物);普羅布可(probucol);曱狀腺 激素受體促效劑(諸如蛾塞羅寧(liothyronine)、左曱狀腺素 (levothyroxine)、KB-2611、GC-1 及其類似物);膽固醇吸 收抑制劑(諸如依澤替米貝(ezetimibe)、SCH48461及其類 似物);脂蛋白相關磷脂酶A2抑制劑(諸如瑞拉帕地 (rilapladib)、達拉帕地(darapladib)及其類似物);微粒體 甘油三酯轉移蛋白抑制劑(諸如CP-346086、BMS-201038,美國專利第5,595,872號;第5,739,135號;第 5,712,279 號;第 5,760,246 號;第 5,827,875 號;第 136781.doc -50- 200932755 5,885,983 號;第 5,962,440 號;第 6,197,798 號;第 6,617,325號;第6,821,967號;第6,878,707號中所述之化 合物,及其類似物);低密度脂蛋白受體活化劑(諸如 LY295427、MD-700及其類似物);脂肪加氧酶抑制劑(諸 如 WO 97/12615、WO 97/12613、WO 96/38144 中所述之化 •合物及其類似物);肉鹼軟脂醯基轉移酶抑制劑(諸如乙莫 .克舍(etomoxir)及其類似物);裳稀合成酶抑制劑(諸如YM-53601、TAK-475、SDZ-268-198、BMS-188494、A-© 87049、RPR-101821、ZD-9720、RPR-107393、ER- 27856,美國專利第5,712,396號;第4,924,024號;第 4,871,721號中所述之化合物,及其類似物);菸鹼酸衍生 物(諸如阿昔莫司(acipimox)、於驗酸、於驗醯胺、尼可莫 耳(nicomol)、戊四煙酯(niceritrol)、尼可地爾(nicorandil) 及其類似物);膽汁酸錯隔劑(諸如考來替潑(colestipol)、 消膽胺(cholestyramine)、考來替蘭(colestilan)、考來維余 (colesevelam)、GT-102-279及其類似物);鈉/膽汁酸共轉 運體抑制劑(諸如264W94、S-8921、SD-5613及其類似 物);及膽固醇酯轉移蛋白抑制劑(諸如托徹普 (torcetrapib)、JTT-705、PNU-107368E、SC-795、CP-529414及其類似物)。 適合於與本發明之化合物組合使用之減肥藥的實例包括 血清素-正腎上腺素再吸收抑制劑(諸如西布曲明 (sibutramine)、米那普侖(milnacipran)、米氮平 (mirtazapine)、文拉法辛(venlafaxine)、度洛西汀 136781.doc •51 200932755 (duloxetine)、去甲文拉法辛(desvenlafaxine)及其類似 物);正腎上腺素-多巴胺再吸收抑制劑(諸如瑞達法辛 (radafaxine)、布普品(bupropion)、安啼奈丁(amineptine) 及其類似物);血清素-正腎上腺素-多巴胺再吸收抑制劑 • (諸如泰索紛辛(tesofensine)及其類似物);選擇性血清素再 • 吸收抑制劑(諸如西醜普蘭(citalopram)、依地普蘭 . (escitalopram)、氟西汀(fluoxetine)、氟伏沙明 (fluvoxamine)、帕羅西汀(paroxetine)、舍曲林(sertraline) ® 及其類似物);選擇性正腎上腺素再吸收抑制劑(諸如瑞波 西汀(reboxetine)、托莫西汀(atomoxetine)及其類似物); 正腎上腺素釋放刺激劑(諸如咯利普蘭(rolipram)、YM-992 及其類似物);減食慾藥(諸如安非他命(amphetamine)、甲 基安非他命(methamphetamine)、右旋安非他命 (dextroamphetamine)、芬特明(phentermine)、苄非他明 (benzphetamine)、苯甲曲秦(phendimetrazine)、芬美曲秦 (phenmetrazine)、安非拉酮(diethylpropion)、馬 0弓丨 0朵 參 (mazindol)、芬敗拉明(fenHuramine)、右芬氟拉明 (dexfenfluramine)、苯基丙醇胺及其類似物);多巴胺促效 劑(諸如ER-230、多普瑞辛(doprexin)、曱項酸溴隱亭 (bromocriptine mesylate)及其類似物);H3-組織胺括抗劑 (諸如咪戊胺(impentamine)、硫丙味胺(thioperamide)、西 若昔凡(ciproxifan)、環苯普匹(clobenpropit)、GT-233 1、 GT-2394、A-331440及其類似物);5-HT2c受體促效劑(諸 如1 -(間氣苯基)旅唤(m-CPP)、米氮平(mirtazapine)、APD- 136781.doc -52- 200932755 356(羅卡色林(lorcaserin)) 、SCA-136(戊卡色林 (vabicaserin))、ORG-12962、ORG-37684、ORG-36262、 ORG-8484、Ro-60-175、Ro-60-0332、VER-3323、VER-5593、VER-5384 ' VER-8775 ' LY-448100 ' WAY- 161503 > WAY-470 > WAY-163909 ' MK-212 ' BVT.933 ' YM-348、IL-639、IK-264、ATH-88651、ATHX-105 及其 . 類似物(參見(例如)Nilsson BM,J. Med. Chem. 2006, 49:4023-4034)) ; β-3腎上腺素受體促效劑(諸如L-796568、 ® CGP 12177 ' BRL-28410 ' SR-58611A ' ICI-198157 ' ZD- 2079 ' BMS-194449 ' BRL-37344 ' CP-331679 ' CP-331648 ' CP-1 14271 ' L-750355 ' BMS-187413 ' SR-59062A、BMS-210285、LY-377604、SWR-0342SA、AZ-40140、SB-226552、D-7114、BRL-35135、FR-149175、 BRL-26830A、CL-316243、AJ-9677、GW-427353、N-5984、GW-2696及其類似物);縮膽激肽促效劑(諸如呂尺-146131、SSR-125180、BP-3.200、A-71623、A-71378、 FPL-15849、GI-248573、GW-7178、GI-181771、GW-7854、GW-5 823及其類似物);抗抑鬱劑/乙醯膽鹼酯酶抑 制劑組合(諸如文拉法辛/雷斯替明(rivastigmine)、舍曲林/ 加蘭他敏(galanthamine)及其類似物);脂肪酶抑制劑(諸如 奥利司他(orlistat)、ATL-962及其類似物);抗癲癇藥(諸如 托0比S旨(topiramate)、嗤尼沙胺(zonisamide)及其類似物); 痩素(leptin)、瘦素類似物及瘦素受體促效劑(諸如LY-3 55 101及其類似物);神經肽Y(NPY)受體拮抗劑及調節劑 136781.doc -53- 200932755 (諸如 SR-120819-A、PD-160170 ' NGD-95-1 > BIBP-3226 > 1229-U-91 ' CGP-71683 ' BIBO-3304 > CP-671906-01、J-ll58 14及其類似物);睫狀神經營養因子(諸如阿索 開(Axokine)及其類似物)、甲狀腺激素受體-β促效劑(諸如 ΚΒ-141、GC-1、GC-24、GB98/284425及其類似物);大麻 驗CB1受體拮抗劑(諸如利莫納班(rimonabant)、 .811147778、81^319及其類似物(參見(例如)八1^611等人, /. Mei C/zew. 2006,49:4008-4016));黑色素濃集激素受 © 體拮抗劑(諸如 GlaxoSmithKline 803430X 、
GlaxoSmithKline 856464、SNAP-7941、T-226296及其類似 物(參見(例如)Handlon AL及 Zhou H,·/_ Met/· C/iew. 2006, 49:4017-4022));黑素皮質素-4受體促效劑(包括PT-15、 Ro27-3225、THIQ ' ΝΒΙ 55886 ' ΝΒΙ 56297、ΝΒΙ 56453、 NBI 58702、NBI 58704、MB243 及其類似物(參見(例 如)Nargund RP 等人,*/. Med. Chem. 2006, 49:4035-4043));選擇性蕈毒鹼受體拮抗劑(諸如替侖西平 (telenzepine)、略命西平(pirenzepine)及其類似物);類捣 片受體括抗劑(諸如納曲酮(naltrexone)、曱基納曲酮 (methylnaltrexone)、納美芬(nalmefene)、納洛酮 (naloxone)、 愛維莫潘(alvimopan) ' 諾賓妥芬 (norbinaltorphimine)、稀丙嗎啡(nalorphine)及其類似物); 及其組合。 適合於與本發明之化合物組合使用之抗高血壓藥及治療 慢性心臟衰竭、動脈粥樣硬化或相關疾病之藥劑的實例包 136781.doc 54· 200932755 括氣°比派醇(bimoclomol);企管緊縮素轉化酶抑制劑(諸如 卡托普利(captopril)、依那普利(enalapril)、福辛普利 (fosinopril)、賴諾普利(lisinopril)、培 B朵普利 (perindopril)、喧那普利(quinapril)、雷米普利(ramipril)及 其類似物);中性内肽酶抑制劑(諸如塞奥芬(thiorphan)、 •奥帕曲拉(omapatrilat)、MDL-100240 、法西多曲 • (fasidotril)、山帕曲拉(sampatrilat)、GW-66051 1、密仙皮 瑞(mixanpril)、SA-7060、E-4030、SLV-306、依卡多曲 ® (ecadotril)及其類似物);血管收縮素II受體拮抗劑(諸如坎 地沙坦醋(candesartan cilexetil)、 依普羅沙坦 (eprosartan)、伊貝沙坦(irbesartan)、洛沙坦(losartan)、奥 美沙坦醋 (olmesartan medoxomil)、 替米沙坦 (telmisartan)、绳沙坦(valsartan)、他索沙坦(tasosartan)、 伊諸沙坦(enoltasosartan)及其類似物);内皮素轉化酶抑制 劑(諸如 CGS 35066、CGS 26303、CGS-3 1447、SM-19712 及其類似物);内皮素受體拮抗劑(諸如全可利(tracleer)、 ❹ 塞塔生坦(sitaxsentan)、安貝生坦(ambrisentan)、L-749805、TBC-3214、BMS-182874、BQ-610、TA-0201、 SB-215355、PD-180988、BMS-193884、達盧生坦 (darusentan)、TBC-3711、波生坦(bosentan)、替0坐生坦 (tezosentan)、J-104132、YM-598、S-0139、SB-234551、 RPR-1 18031A、ATZ-1993、RO-61-1790、ABT-546、恩拉 生坦(enlasentan)、BMS-207940及其類似物);利尿劑(諸如 氫氣嘆嗪(hydrochlorothiazide)、节 H 喧 °秦 136781.doc -55- 200932755 (bendroflumethiazide)、三氯甲嘆嗓(trichlormethiazide)、
❹ 0引達帕胺(indapamide)、美托拉宗(metolazone)、0夫塞米 (furosemide)、布美他尼(bumetanide)、托西邁 (torsemide)、氯嚷 _ (chlorthalidone)、美托拉宗 (metolazone)、環戊喧嗓(cyclopenthiazide)、氫氣嗔唤 (hydroflumethiazide)、曲帕胺(tripamide)、美夫西特 (mefruside)、苄基氫氯嗟嗓、戊氟0塞唤(penflutizide)、甲 氣嗟嗪(methyclothiazide)、阿佐塞米(azosemide)、依他尼 酸(etacrynic acid)、托拉塞米(torasemide)、吼哈他尼 (piretanide)、美替克命(meticrane)、坎利酸 _ (potassium canrenoate)、螺内S旨、胺苯嗓咬(triamterene)、胺茶驗 (aminophylline) ' 西氣他寧(cicletanine)、LLU-α、 80873A、異山梨醇(isosorbide)、D-甘露糖醇、D-山梨糖 醇、果糖、丙三醇、乙酿吐胺(acetazolamide)、醋甲唾胺 (methazolamide)、FR-179544、OPC-31260、利昔瓦坦 (lixivaptan)、克尼瓦坦(conivaptan)及其類似物);_通道 括抗劑(諸如胺氣地平(amlodipine)、苄普地爾(bepridil)、 地爾硫卓(diltiazem)、非洛地平(felodipine)、伊拉地平 (isradipine)、尼卡地平(nicardipen)、尼莫地平 (nimodipine)、維拉帕米(verapamil)、S-維拉帕米、阿雷地 平(aranidipine)、依福地平(efonidipine)、巴尼地平 (barnidipine)、貝尼地平(benidipine)、馬尼地平 (manidipine)、西尼地平(cilnidipine)、尼索地平 (nisoldipine)、尼群地平(nitrendipine)、确’苯地平 136781.doc -56- 200932755 (nifedipine) 尼伐地平(nilvadipine)、非洛地平 (felodipine) 普拉地平(pranidipine)、樂卡地平 (lercanidipine)、伊拉地平(isradipine)、依高地平 (elgodipine)、阿折地平(azelnidipine)、拉西地平 (lacidipine)、伐尼地平(vatanidipine)、來米地平 (lemildipine)、地爾硫卓(diltiazem)、克侖硫卓 (clentiazem)、法舒地爾(fasudil)、苄普地爾(bepridil)、戈 洛帕米(gallopamil)及其類似物);血管舒張抗高血壓藥(諸 如0引達帕胺(indapamide)、托屈嗓(todralazine)、肼屈嗪 (hydralazine)、卡屈嗪(cadralazine)、布屈嗪(budralazine) 及其類似物);β阻斷劑(諸如醋丁洛爾(acebutolol)、比索 洛爾(bisoprolol)、艾司洛爾(esin〇l〇l)、普萘洛爾 (propanolol)、阿替洛爾(atenolol)、拉貝洛爾(labetalol)、 卡維地洛(carvedilol)、美托洛爾(metoprolol)及其類似 物)’·交感神經阻斷劑(諸如胺績洛爾(amosulalol)、特拉η坐 口秦(terazosin)、布那 α坐♦ (bunazosin)、e底嗤噪(prazosin)、 多沙唑嗪(doxazosin)、普萘洛爾(propranolol)、阿替洛爾 (atenolol)、 美托洛爾(metoprolol)、 卡維地洛 (carvedilol)、尼普地洛(nipradilol)、塞利洛爾 (celiprolol)、奈必洛爾(nebivolol)、倍他洛爾(betaxolol)、 品多洛爾(pindolol)、特他洛爾(tertatolol)、貝凡洛爾 (bevantolol)、噻嗎洛爾(tim〇l〇l)、卡替洛爾(carteolol)、 比索洛爾(bisoprolol)、波〇引洛爾(bopindolol)、尼普地洛 (nipradilol)、喷布洛爾(penbutolol)、醋 丁洛爾 -57- 136781.doc 200932755 (acebutolol)、替利洛爾(tilisolol)、納多洛爾(nadolol)、烏 拉地爾(urapidil) ' η引〇朵略胺(indoramin)及其類似物);α-2-腎上腺素受體促效劑(諸如可樂定(clonidine)、曱基多巴 (methyldopa)、CHF-1035、乙酸胍那苄(guanabenz acetate)、胍法辛(guanfacine)、莫索尼定(moxonidine)、洛 非西定(lofexidine)、他利克索(talipexole)及其類似物);十 樞作用抗高金壓藥(諸如利血平(reserpine)及其類似物); 血小板凝集抑制劑(諸如華法林(warfarin)、雙香豆素 (dicumarol)、苯丙香豆素(phenprocoumon)、醋硝香豆素 (acenocoumarol)、茴節二酮(anisindione)、苯茚二酮 (phenindione)、希美加群(ximelagatran)及其類似物);及 抗血小板劑(諸如阿司匹林(aSpirin)、克羅匹多 (clopidogrel)、噻氣匹定(ticlopidine)、雙嘧達莫 (dipyridamole)、西洛他唆(cilostazol)、廿六烧五稀酸乙醋 (ethyl icosapentate)、沙格雷酯(sarp0greiate)、地拉齊普 (dilazep)、曲匹地爾(trapidil)、貝前列素(berapr〇st)及其類 似物)。 此外’在另一態樣中’本發明提供一種醫藥組合物,其 包含醫藥學上可接受之載劑中的有效量之化合物或式工 化合物之混合物或其醫藥學上可接受之鹽或前藥,及至少 種選自上文所列之作為組合搭配物之治療劑之群的成 員。 本發明之治療可預防性投與以預防或延緩疾病或病狀 (諸如咼血糖症)之發作或進展,或治療性投與以達成所需 136781.doc -58· 200932755 作用(諸如所需之血糖含量)歷時持續之時段。 本發明之化合物可以其醫藥學上可接受之鹽或前藥之形 式或以醫藥組合物(其中化合物及/或組合搭配物與合適載 劑或賦形劑以治療有效量混合)之形式獨立地或與組合搭 配物一起向個體(例如人類患者、諸如貓或犬之家畜)投 與。因此,式I化合物或式I化合物之混合物或其醫藥學 上可接受之鹽或前藥,及欲與其組合之另一活性劑可以單
-調配物形式(例如膠囊或錠劑)或以兩個單獨調配物形式 (其可相同或不同,例如以包含所選各藥劑劑量數量之套 組之形式)存在。 化合物之適當劑量將根據所選投藥途徑及組合物之配方 以及其他因素(諸如患者反應)而變化。劑量可視個別患者 之需要隨時間增加或減少。最初可給予患者低劑量,隨後 將該劑量增加至患者可耐受之有效劑量。—般而t,成人 之有效劑量當藉由經口途徑投與時可為丨至如⑼mg,較佳 為1至200 mg,且當藉由靜脈内途徑投與時可為❹丨至丨⑽ mg ’較佳為1至30 mg ’在各種情況下均每日投與1至4次。 田將本發明之化合物與另一治療劑組合投與肖,組合搭配 物之有用劑量可為通常推薦劑量之2〇%至丨〇〇%。 可個別地調節劑量量及時間間隔以提供足以維持治療作 用之活性化合物之血漿含量。較佳地,治療有效血清含量 可藉由投與單次日劑量達成,但有效多次日劑量方案亦包 括在本發明中。在局部投藥或選擇吸收之情況下,藥物之 有效局部濃度可能與血漿濃度無關。熟習此項技術者應能 136781.doc -59- 200932755 夠不經過度實驗而優化治療有效之局部劑量。 本說明書中所引用之所有公開案及專财請案均係以引 用的方式併入本文中,如同特定且個別地表示各個別公開 案或專利申請案係以引用的方式併入。本文中所引用之任 - 冑參考文獻與本說明書中之教^間的任何矛盾將以支持 • &者的方式解決。類似地,詞語或短語之技㈣可之定義 • 肖本說明書中所提供之詞語或短語之定義之間的任何矛盾 冑以支持後者的方式解決。儘管為清晰理解,已經由說明 及實例略為詳細地描述前述發明,但一般熟習此項技術者 易於根據本發明之教示顯而易見,在不背離隨附申請專利 範圍之精神或範嘴之情況下可進行某些變化及修改。本發 明將經由特定實例更為詳細地進行描述。 實例 以下㈣係出於說明之目的提供,且並不意欲以任何方 式限制本發明。熟習此項技術者將易於識別各種可經改變 ❿ 或修改以產生基本上相同之結果之非關鍵性參數。 乂下實例中所不之化合物之名稱係來源於使用 cambridgeSoft Struct==N_算法以―謂⑴的 1〇 〇版
- 執4丁所展不之結構。降兆女、_L 降非另有所述,否則使用以下程序確 疋以下實例中所合成化合物之結構: ⑴利用配備有具有Hp_5 Ms管柱(〇25叫塗層;3〇 m 0.25 mm)之 Agilent 689〇 氣相層析儀的 Agiient 5973Ν 質 -曰儀獲知氣相層析-電噴霧電離質譜(ms Es”。將離子源 保持在230 C下’且以每次掃描3 〇9似自255〇〇謹掃描 136781.doc -60· 200932755 光譜。 (2) 使用配備有四元泵、設定為254 nm之可變波長偵測 器、XB-C18 管柱(4.6x50 mm,5 μιη)的 Finnigan Surveyor HPLC及利用電噴霧電離之Finnigan LCQ離子阱質譜儀獲 . 得高壓液相層析質譜(LC-MS)。根據離子源之離子數使用 可變離子時間自80-2000 amu掃描光譜。溶離劑為B :乙腈 .及D :水。使用在1.0 mL/min之流速下達8 min之10%至 90% B之梯度溶離,其中最終在90% B下保持7 min。總運 ® 行時間為15 min。
(3) 在 400 MHz 或 300 MHz Varian Mercury-Plus 光譜儀上 執行常規一維NMR光譜。將樣品溶解於由Qingdao Tenglong Weibo Technology Co.,Ltd.獲得之氘化溶劑中, 且將其轉移至5 mm ID NMR管中。在293 K下獲取光譜。 化學位移係以ppm標度記錄,且參考適當溶劑信號,諸如 對於1H光譜而言,對於DMSO-d6為2.49ppm,對於CD3CN 為 1.93 ppm,對於 CD3OD 為 3.30 ppm,對於 CD2C12 為 5.32 9 ppm且對於 CDC13為 7.26 ppm。 實例1 -本實例說明根據圖3中所提供之方法製備化合物 _ 5(R=Et)。化合物編號對應於圖中所提供之彼等編號。該 通用方法適用於本發明之其他化合物。 (lR,2R,3S,4R,5R,6S)-4-(4-氣-3·(4-乙基苄基)苯基)-6- (羥基甲基)環己烷-1,2,3,5-四酵之製備 -61 - 136781.doc 200932755
5 (R = Et) {\、格林納試劑(Grignard reagent)之製備 在氬氣下,將Mg 粉(0.216 g ’ 8.98 mmol,1.2 eq)裝入= 頸燒瓶中,繼而添加一部分4-溴-1-氯-2-(4-乙基苄基)笨 8(0.769 g,2.49 mmol)於無水 THF(6 mL)及 1,2-二漠乙乾 ❿ (1〇莫耳%)中之溶液。將混合物加熱至回流。起始反應(玫 熱且消耗Mg)之後,逐滴添加剩餘2-(4-乙基苄基)-4-漠 氣苯8(1.539 8,4.99 111111〇1)於無水11^(14 1111〇中之溶液。 隨後使混合物在溫和回流下再反應一小時直至大部分Mg 已消耗。 之製備
2(R = Et) 在鼠氣下’在室溫(約25°C )下將上述格林納試劑逐滴添 加至(4R,5S,6R)-4,5,6-參(苄基氧基)-3-(苄基氧基曱基)環 己-2-烯酮 1(2 g,3.74 mmo卜 1 eq)於無水THF(20 mL)中之 溶液中,隨後使其反應超過3小時。將NH4C1(飽和水溶液) 添加至混合物中以使反應中止。將混合物以乙酸乙酯(2〇 mLx3)萃取,將有機層以鹽水洗滌,用Na2S〇4乾燥,過 136781.doc • 62 · 200932755 濾,將濾液蒸發至乾。將殘餘物以矽膠層析法(溶離劑: 石油醚:乙酸乙酯=20:1)純化以產生呈黃色油狀物之目標化 合物 2(2.428 g,3.17 mmol,84.8%之產率)。h-NMR (400
MHz, CDC13):5 7.42 (1H, s), 7.28-7.41 (17H, m), 7.04-7.254 (8H, m), 5.83 (1H, s), 4.74 (1H, d, 7=11.2 Hz), 4.39-4.64 (7H, m), 4.33 (1H, d, J=12.4 Hz), 4.23 (1H, s), 4.08 (2H, s), 4.03 (1H, d, /=12.8 Hz), 3.70-3.73 (2H, m), 2.93 (1H, s), 2.58 (2H, q, J=7.6 Hz), 1.19 (3H, t, 7=7.6 Hz) ; MS (ESI+):765 [M+H] +,782 [M+H2〇]+,787 [M+ Na]+。 (3)3(R=Et)之製備
3(R = Et) 在氮氣下’在- 2〇C下將二乙基梦烧(1 rnL,7.44 mmol, φ 3 eq)及醚合三氟化硼(0.44 mL,4.96 mmol,2 eq)以該次 序添加至2(1.9 g ’ 2.48 mmol,1 eq)於CH2C12中之溶液 中,隨後在維持-20°C之溫度的情況下,使其反應超過4小 • 時。添加NaCl(飽和水溶液)以中止反應。將混合物以 - CH2C12(20 mLx3)萃取’且將有機層以鹽水洗滌,用
NajO4乾燥’過濾,將濾液蒸發至乾。將殘餘物以石夕膠層 析法(溶離劑:石油醚:乙酸乙酯=20:1)純化以產生呈黃色 油狀物之目標化合物(1.67 g,2.23 mmol,89.9%)。 136781.doc -63- 200932755 NMR (400 MHz,CDC13):S 7.26-7.40 (16H,m),7.15-7.25 (7H, m), 7.04-7.06 (4H, m), 6.85-6.87 (2H, m), 5.89 (1H, s), 4.85-4.98 (3H, m), 4.75-4.77 (1H, m), 4.45-4.56 (4H, m), 4.32 (1H, d, 7=10.8 Hz), 3.97-4.09 (4H, m), 3.74 (1H, t, J=10A Hz), 3.62-3.65(lH, m), 3.54-3.57 (1H, m), 2.63-2.71 (1H, m), 2.59 (2H, q, J=7.6 Hz), 1.21 (3H, t, 7=7.6 Hz); MS (ESI+) 749 [M+H] + , 766 [M+H20]+。 (4)4(R=Et)之製備
4 (R = Et)
在氬氣下,在0°C下將硼院-二曱基硫錯合物(2 m於THF 中)(1.678 mL ’ 3.34 mmo卜 10 eq)添加至 3(250 mg,0.334 mmol,1 eq)於無水TUFGO mL·)中之溶液中,隨後加溫至 ❹ 回流歷時1 h。在(TC下將混合物以NaOH(3 Μ於H20中,1 mL,3,34 mmol,1〇 eq)處理,隨後在室溫(3()°c以上)下以 3 0/〇 Η2〇2(0.11 mL,3.3 4 mmol,10 eq)處理,且使其在室 ' 溫(約25°C)下反應隔夜。將NH4C1(飽和水溶液)添加至混合 物中以使反應中止。將混合物以乙酸乙酯(1〇 mLx3)萃 取,將有機層以鹽水洗滌,用NajO4乾燥,過濾,且將濾 液蒸發至乾。將殘餘物藉由製備型TLc純化以產生白色固 體狀之目標化合物4(1〇8.811^,0.142111111〇1,42.5%)。1玨- NMR (400 MHz,CDC13) δ 7.29-7.40 (15H,m),7.12-7.24 136781.doc • 64 · 200932755 (7H, m), 7.03-7.07 (4H, m), 6.74 (2H, d, 7=6.8 Hz), 4.94 (1H, d, y=10.8 Hz), 4.91 (2H, s), 4.46-4.58 (4H, m), 4.01-4.13 (2H, m), 3.83-3.93 (3H, m), 3.68-3.73 (2H, m), 3.52-3.62 (2H, m), 2.74 (1H, t, 7=10.8 Hz), 2.59 (2H, q, J=7.6
Hz),1.89-1.96 (1H,m),1.19 (3H,t, «7=7.6 Hz) ; MS (ESI+) 767 [M+H] +,784 [M+H2〇] +,789 [M+Na]+。 (5)5(R=Et)之製備
5 (R = Et) 將 4(12 mg ’ 1.57xl〇-2 mm〇h i eq)於THF:CH3OH=2:l(9 mL)中之溶液以1,2·二氣苯(1莫耳%^Pd/c(含1〇0/〇質量, 12 mg,100%質量比率)處理,且在&氣氛下在室溫(超過 30C)下授拌2 h。藉由LC-MS監測反應以確定反應完成。 將混合物過濾,且將濾液蒸發至乾。將殘餘物藉由製備型 HPLC純化以產生白色固體狀之目標化合物5(2 82 mg, 0.69><1〇2]111]1〇1,43.9%之產率)。111^]\111(400 河1^, CD3〇D) δ 7.33 (1Η, d, /=8.0 Hz), 7.07-7.17 (6H, m), 4.05 (2H, s), 3.91 (2H, d, J=3.2 Hz), 3.65 (1H, t, /=10.4 Hz), 3.39-3.49 (2H, m), 3.31 (1H, t, J=8.8 Hz), 2.51-2.62 (3H, m), 2.53 (1H, m), 1.19 (3H, t, /=8.0 Hz) ; MS (ESI+):407 [M+H] + , 424 [M+NH4]+, 448 [M+H+CH3CN] + , 813 [2M+H]+, (ESI’): 405 [M-H]% 451 [M+HCOO]· 〇 136781.doc -65- 200932755 以下製程係自US 2〇06/〇〇63722 A1中所揭示之程序修改 付到。 澳-2-氣笨基)(4_乙基笨基)γ鲷7之製備
0 7 (R = Et)
Br
向含有市售5-溴-2-氣苯甲酸(410 g’ 1.74 mol)於700 mL 〇 CHei2中之電磁搜拌懸浮液的2 l圓底燒瓶中添加乙二醯 氣(235 g ’ 1.85 mol) ’繼而添加1.5 mL DMF。為收集所得 HC1 ’將燒瓶裝備導管以使氣體在經攪拌KOH水溶液表面 上排出。當兩小時之後氣體劇烈釋放停止時,將均相反應 物授拌隔夜,隨後使用旋轉蒸發器在真空下移除揮發物。 使所得油狀物在隨後之抽空期間凝固。在將粗5_溴_2_氣节 酿基氣溶解於530 mL乙基苯中之後,將黃色溶液冷卻至 -3°C,隨後經 60 min 以約 30 g 逐份添加 A1C13(257 g,1.93 ❹ m〇l)以確保溫度不超過1(TC。藉由使在添加60% A1C13之後 開始排放之大量HC1氣體通過經攪拌之濃NaOH溶液來收集 ,該氣體。若反應液較濃,則電磁攪拌在完成A1C13添加後 無法保持攪拌。攪拌1 h之後,當浴槽加溫至約15°C時,將 • 該浴槽移除。在2(TC下4 h之後,將濃糖漿傾於冰(1.5 kg) 上。隨後,在攪拌懸浮液冷卻之後添加H20(1 L),之後以 IN HC1萃取四次,以1 Μ KOH萃取三次,且以鹽水萃取兩 次,隨後用Na2S04乾燥。首先使用旋轉蒸發器且隨後藉由 136781.doc -66- 200932755 在1托下於60°C下加熱來移除揮發物。所得深色油狀物之 H-NMR分析揭示該殘餘物為丨:14之鄰位/對位異構物之混 合物。將其溶解於己烷中且繼而經由矽膠墊過濾移除大部 分有色物質。濃縮溶離劑產生56〇 g(99% 14:1之(5-溴-2-氣 苯基)(4-乙基苯基)曱嗣/(5_溴·2_氣苯基)(2_乙基苯基)甲酮) 之混合物)。 溴-1-氯乙基苄基)苯8之製備
8 (R = Et) 在30°C下’向Et3SiH(400 g,3.45 mol)及含有約7%異構 _之(5-溴-2-氣苯基)(4-乙基苯基)甲酮(534 g,1.65 mol)於 300 mL TFA中之攪拌溶液中添加cf3S03H(1.5 g,0.01 mol) »使溫度在數分鐘内增加以使溶液劇烈回流。注意: 該適度放熱需要用外部冰浴冷卻。1 hr之後,HPLC揭示反 φ 應完成90%。再添加Et3SiH(20 g)且在70°C下加熱隔夜之 後’藉由HPLC分析發現反應完成>95%。冷卻之後,在減 壓下藉由減壓蒸餾裝置(bulb to bulb distillation)移除揮發 物。將所得約1 L之淺灰色油狀物傾入1 L H20中。將混合 . 物以己烷萃取三次’將經組合之有機層以H20洗滌三次, 以NazCOs水溶液洗滌兩次,且以鹽水洗滌兩次,隨後用 NazSO4乾燥。使用旋轉蒸發器濃縮之後,剩餘約1 l澄清 淺破拍色油狀物。將該物質進一步濃縮,藉由蒸餾移除 (Et3Si)2〇(450 mL)直至蒸餾頭溫度達至75°C為止,且將殘 136781.doc -67- 200932755 餘物冷卻。殘餘物之iHNMR分析揭示其含有約8:1之二芳 基甲烷與(EtJiho之混合物。藉由將產物傾入用力攪拌之 85。/。EtQH:H2〇之冷(1〇。〇混合物〇 2 L)中來達成該混合物 之、纟〇明。攪拌數小時之後,將晶體藉由過濾收集,以冷 1:1 EtOH/H2〇洗滌且在真空下乾燥。獲得含有約1% (EhSihO之呈低熔點固體之4_溴_丨_氣_2_(4_乙基苄基)苯 (500 g) ’且其不經進一步純化即加以使用。 實例2 本實例說明(lR,2R,3S,4R,5R,6S)-4_(4_ 氯 _3_(4·乙氧基苄 基)苯基)-6-(羥基曱基)環己烷_1,2,3,5-四醇(9)之製備。
藉由與實例1中所述類似之方法製備化合物9: iH_NMr φ (400 MHz, CD3OD):5 7.32 (1H, d, /=8.0), 7.11-7.16 (4H, m), 6.79 (2H, d, J=6.8 Hz), 3.96-4.02 (4H, m), 3.91 (1H, d, J=3.2 Hz), 3.63 (1H, t, 7=10.4 Hz), 3.39-3.47 (2H, m), 3.32 (1H, t, J=8.8 Hz), 2.54 (1H, t, /=10.4 Hz), 1.53 (1H, tt, /=3.2, 10.4 Hz), 1.36 (3H, t, J=\2 Hz) ; MS (ESI+): 423 [M+H] + , 440 [M+NH4] + , 845 [2M+H]+, 862 [2M+NH4] + , (ESI ): 467 [M+HCOO]·。 實例3 本實例說明(lR,2R,3S,4R,5R,6S)-4-(4-氯-3-(4-環丙基节 136781.doc -68- 200932755 基)苯基)-6-(羥基甲基)環己烷-1,2,3,5-四醇(10)之製備β
藉由與實例1中所述類似之方法製備化合物10 :NMr
(400 MHz, CDC13):3 7.33 (1H,d,*7=8.0 Hz),7.16-7,12 (2H φ m),7.09 (2H,d,·7=8.0 Hz),6.96 (2H,d,J=8.〇 HZ),4 〇4 (2H, s), 3.91 (2H, d, 7=3.2 Hz), 3.65 (1H, t, J=i〇>6 Hz)
3·48 (1H,t, /=10.0 Hz), 3.42 (1H,t,《7=10.0 Hz),3,32 (1H t, J=9.0 Hz), 2.54 (1H, t, 7=10.8 Hz), 1.87-1.82 (in m) 1.57-1.51 (1H, m), 0.94-0.89 (2H, m), 0.64-0.60 (2H m) · MS (ESI+): 419 [M+H] + , 436 [M+NH4]+。 實例4 本實例說明(111,2尺,38,411,511,68)-4-(4-氣-3-(4>_丙基节基) © 苯基)-6-(羥基曱基)環己烷-1,2,3,5·四醇(11)之製備。
11 藉由與實例1中所述類似之方法製備化合物u : nmr (400 MHz,CDC13):S 7.35 (1H,d, /=8.4 Hz), 7.20 (1H d J=1.6 Hz), 7.16-7.13 (3H, m), 7.08 (2H, d5 7-8.〇 Hz)} 4 〇7 136781.doc -69- 200932755 (2H, s), 3.93 (2H, d, 7=3.2 Hz), 3.67 (1H, t, J=l〇.4 Hz) 3.49 (1H, t, 7=10.4 Hz), 3.43 (1H, t, /=10.4 Hz), 3.33 (iH t, 7=9.0 Hz), 2.58-2.53 (3H, m), 1.67-1.58 (2H, m), i 58 1·52 (1H,m),〇·94 (3H, t,J=7.2 Hz) ; MS (ESI+): 438 [M+NH4]+ 〇 實例5 本實例說明(111,211,38,411,511,68)-4-(4-氣-3-(4-環己基节 基)苯基)-6-(羥基甲基)環己烷-1,2,3,5-四醇(12)之製備。
藉由與實例1中所述類似之方法製備化合物1H NMR (400 MHz, CDC13):S 7.34 (1H, d, 7=8.0 Hz), 7.19 (1H, d, /=2.0 Hz), 7.15-7.12 (3H, m), 7.09 (2H, d, J=8.4 Hz), 4.05 (2H, s), 3.92 (2H, d, 7=3.2 Hz), 3.66 (1H, t, J=10.6 Hz), 3.48 (1H, t, 7=10.0 Hz), 3.43 (1H, t, 7=10.2 Hz), 3.32 (1H, ^=9 〇 Hz), 2.55 (1H, t, J=10.6 Hz), 2.48-2.42 (1H, m), 1.84-1.81 (4H, m), 1.76-1.73 (1H, m), 1.57-1.50 (1H, m), 1.47-1.36 (4H, m), 1.34-1.22 (1H, m) ; MS (ESI+): 478 [M+NH4]+。 實例6 本實例說明(1R,2S,3S,6 R)-4-(4 -氣-3-(4-(3-環丙基丙-2- 136781.doc -70- 200932755 炔基氧基)苄基)苯基)-6-(羥基甲基)環己_4-烯-1,2,3·三醇 (13)之製備。
!H-NMR (400 MHz, CD3OD):8 7.27-7.31 (2H, m), 7.20-7.23 (1H,m),7.09 (2H,d,7=8.8 Hz),6.82-6.84 (2H,m), 5.83-5.84 (1H, m), 4.02 (2H, dd, /=14.8 Hz), 3.83-3.86 (1H, m), 3.48-3.65 (3H, m), 2.36 (1H, b), 0.72-0.77 (2H, m), 0.57-0.60 (2H, m) ; MS (ESI+):472 [M+NH4]+,479 [M+Na] +,(ESI·): 499 [M+HCOO]·。 實例7 φ 本實例說明使用圖4中所概述之合成方法製備 (2S,3S,4R,5R,6R)-2-(4-氣- 3-(4-乙基苄基)苯基)-3,4,5-三經 基- 6- (經基曱基)環己網(15)。
在〇°C下,將戴斯-馬丁試劑(MW 424.5,白色粉末, 136781.doc • 71 · 200932755 eq)添加至(111,28,311,411,58,611)-3,4,5-參(苄基氧基)-2-(苄 基氧基曱基)-6-(4-氣-3-(4-乙基苄基)苯基)環己醇(4, R=Et)(1.0 g,1·3 mmol)於無水 CH2C12(20 mL)中之溶液 中,隨後將混合物在室溫下攪拌隔夜。將反應混合物以IN NaOH中止反應,分離’且將水層以CH2C12萃取。將有機 層組合,用NazSCU乾燥’且過濾。將濾液蒸發至乾,且將 殘餘物藉由製備型TLC純化以產生化合物14(0.92 g,白色 固體,純度為 95%,產率為 92.3%)。W-NMR (400 MHz, CDC13):5 7.29-7.37 (14H, m), 7.13-7.23 (5H, m), 7.03-7.08 (4H, dd, 7=8.4 Hz), 6.97-6.99 (2H, m), 6.76 (2H, d, /=7.6 Hz), 4.91-4.95 (3H, m), 4.64 (1H, d, J=10.8 Hz), 4.50-4.57 (3H, m), 3.91-4.14 (6H, m), 3.74-3.76 (3H, m), 2.80 (1H, d, */=8.4 Hz), 2.58 (2H, dd, 7=7.6 Hz), 1.20 (3H, t, /=7.6); MS (ESI+):765 [M+H] +,782 [M+H20]+,787 [M+Na]+。 將 14(0.92 g,純度為 95%,1.20 mmol,1 eq)於 THF:CH3OH(2:l)(12 mL)中之溶液以 l,2-二氣苯(0.354 g, 0.3 mL,2·41 mmol ’ 2 eq)及 Pd/C(10%,74 mg,8 重量 0/〇) 處理,且在室溫(約25°C)下在H2氣氛下攪拌4 h。藉由LC-MS監測反應直至反應完成》將混合物過濾,且將濾液蒸 發至乾。將殘餘物(黃色油狀物)藉由製備型HPLC純化以獲 得化合物15(450 mg,白色固體,純度為98%,產率為 92.6%)。i-NMR (400 HMz,CD3OD):3 7.34 (1H,d,*7=8.0 Hz), 6.99-7.12 (6H, m), 4.05 (2H, s), 3.98 (lH,dd, J=2.8, 10.8 Hz), 3.88 (1H, dd, /=5.6, 11 Hz), 3.77-3.81 (2H, m), 136781.doc -72- 200932755 3.57-3.67 (2H, m), 2.65-2.79 (1H, m), 2.59 (2H, d, 7=7.6, 15.2 Hz), 1.20 (3H, t, 7=7.6 Hz) ; MS (ESI+): 405 [M+H] + , 422 [M+NH4] + , (ESI-): 403 [Μ-ΗΓ,449 [M+HCOO]·。 實例8 (111,211,38,48,511,61〇-4-(4-氣-3-(4-乙基苄基)苯基)-6-(羥 基甲基)-5-甲氧基環己烷-1,2,3-三醇(16)之製備
(1)4-((111,28,3尺,411,58,611)-2,3,4-參(苄基氧基)-5-(苄基 乳基甲基)-6-曱氧基環己基)-2-(4-乙基节基)-1-氣苯之製 備: 在〇°C下,將NaH(157 g ’ 1.5 eq,含於油中之60%)添加 至(111,28,3尺,411,58,6尺)-3,4,5-參(节基氧基)-2-(苄基氧基甲 基)-6-(4-氣-3-(4-乙基苄基)苯基)環己醇(4,R=Et,2 g, 2.61 mmol)於無水THF( 10 mL)中之溶液中。在相同溫度下 攪拌 1 h 之後’將 TBAI(0.1 eq)及 CH3I(760 mg,2 eq)添加 至反應混合物中,且將反應混合物在室溫下撲拌隔夜。添 加飽和NH4C1水溶液以中止反應且將所得混合物以Et〇Ac 萃取。將經組合之有機層用Na2S〇4乾燥,過濾,且將據液 蒸發至乾。將殘餘物(黃色油狀物,2.05 g)溶解於 THF:CH3OH=2:l 中,以 1,2-二氣苯(1〇/〇莫耳比率)及 pd/c (10%,1/1重量比率)處理,且在室溫下在氣氛下挽掉2 13678I.doc -73- 200932755 h。藉由LC-MS監測反應直至反應完成。將混合物過濾, 且將濾液蒸發至乾且藉由製備型HPLC純化以產生目標化 合物16(987 mg,白色固體,產率為90.0%)。W-NMR (400 MHz, CD3COCD3):8 7.32-7.34 (2H, m), 7.22 (1H, dd, /=2.4, 8.0 Hz), 7.12 (4H, dd, J=8.4 Hz), 4.15 (2H, s), 3.93-3.98 (1H, m), 3.70-3.75 (1H, m), 3.65-3.67 (1H, m), 3.54-3.60 (2H, m), 3.37 (1H, t, /=10.4 Hz), 3.30 (1H, t, J=8.8 Hz), 2.84 (3H, s), 2.52-2.65 (3H, m), 1.51-1.58 (1H, m), 1.17 (3H, t, J=7.2 Hz) ; MS (ESI+): 421 [M+H]+, 438 fM+NH4]+, 841 [2M+H] +,858 [2M+NH4]+, (ESI ): 465 [M+HCOO].。 實例9 乙酸((lS,2R,3R,4S,5R,6R)-3-(4-氣-3-(4-乙基苄基)苯 基)-2,4,5,6-四羥基環己基)甲基酯(1*7)之製備
17 在0°C下,將Ac20(377 mg,1.5 eq)逐滴添加至 (111,211,38,411,5尺,63)-4-(4-氣-3-(4-乙基苄基)苯基)_6_(羥基 曱基)環己烧·1,2,3,5 -四醇(5,R=Et ’ 1 g,2.46 mmol)及 DMAP(催化劑)於CHbCbUO mL)中之溶液中,繼而添加吡 咬(292 mg,1.5 eq),且將混合物在室溫下擾拌隔夜。將 反應混合物以3N HC1洗滌’且將有機層組合,用Na2S〇4乾 I36781.doc • 74- 200932755 燥,過濾,且將濾液蒸發至乾。將殘餘物藉由製備型 HPLC純化以產生目標化合物(566 mg,白色固體,產率為 50.4%)。h-NMR (400 MHz,CD3OD):S 7·32 (1H,d,《/=8.4 Hz),7.06-7.14 (6H,m),4.37 (2H,ddd,《7=2.0,1〇·8,16.8
Hz), 4.04 (2H, s), 3.57 (1H, t, J=10.8 Hz), 3.40-3.47 (1H, m), 2.49-2.60 (3H, m), 2.04 (3H, s), 1.60-1.66 (1H, m), 1.18 (3H, t, 7=8.0 Hz) ; MS (ESI+): 449 [M+H]+, 466 [M+NH4]+,897 [2M+H]+, (ESI_): 492 [M+HCOO]·,941 ❹[2M+HCOO]·。 實例10 (4aR,5R,6R,7S,8S,8aR)-8-(4-氣-3-(4-乙基节基)苯基)_ 2,2-二曱基六氫-4H-苯并[d][l,3]二氧雜環己烯_5,6,7_三醇 (18)之製備。
18 將 IN HC1(5 mL)逐滴添加至(ir,2R,3S,4R,5R,6S)-4-(4-氯-3-(4-乙基苄基)苯基)-6-(羥基甲基)環己烷qjj,5-四醇 (5, R=Et,1 g,2.46 mmol)於 MeOH(80 mL)及丙酮(20 mL) 中之溶液中,且攪拌隔夜,隨後將該混合物蒸發至乾。將 殘餘物藉由製備型HPLC純化以產生目標化合物(864 mg,白 色固體’產率為 75.3%) 。 W-NMR (400 MHz, I367SI.doc •75. 200932755 CD3COCD3):5 7.26-7.29 (2H, m), 7.10-7.16 (5H, m), 3.74-4.21 (6H, m), 3.46-3.51 (1H, m), 3.35-3.37 (1H, m), 2.56-2.66 (3H, m), 1.72-1.75 (1H, m), 1.28 (3H, s), 1.18 (3H, t, •7=7.6 Hz), 1·13 (3H,s) ; MS (ESI+): 447 [M+H] +,488 [M+H+CH3CN] + , 910 [2M+NH4] + , 491 [M+HCOO]', 937 [2M+HCOO]-。 實例11 四乙酸(lS,2R,3R,4S,5R,6R)4-(乙醯氧基曱基)_6-(4-氣-3-(4-乙基苄基)苯基)環己烷-l,2,3,5-四酯(19)之製備。
如實例20中所述自化合物5(R=Et)製備化合物:^。1!!-NMR (400 MHz, CDC13):6 7.29 (1H, d, J=8.4 Hz), 7.30-7.12 (6H, m),5.27-5.38 (3H, m),5.20 (1H,t,/=9.6 Hz), 4.03-4.06 (3H, m), 3.93-3.96 (1H, m), 2.98 (1H, t, J=11.6), 2.61 (2H, q, J=7.6 Hz), 2.14-2.20 (1H, m), 2.08 (3H, s), 2.06 (3H, s),2.00 (3H,s),i.66 (6H,s),l21 (3H,t, J=7.6 Hz) ; MS (ESI+): 617 (M+H)+,934 [M-NH4] +,(ESI-): 661 [M+HCOO]-。 136781.doc -76- 200932755 實例12 本實例提供使用圖5中所概述之合成方法製備 (111’211,311,48,58)-1-(4-氣-3-(4-乙基节基)苯基)_5-(經基甲 基)環己烷-1,2,3,4,5-五醇(22, R=Et)。
22 (R = Et) 藉由與實例1中所述類似之方法製備化合物22。W-NMR (400 MHz, CD3OD):5 7.45 (1H, s), 7.32-7.33 (2H, m), 7.05-7.10 (4H, m), 4.05 (2H, s), 3.86 (1H, t, 7=9.6 Hz), 3.67 (1H, d, /=9.2 Hz), 3.54-3.57 (2H, m), 3.31-3.35 (2H, m), 2.57 (2H, q, /=8.0 Hz), 2.00 (1H, d, */=15.2 Hz), 1.81 (1H, d,《7=15.2 Hz),1.18 (3H,t,《/=8.0 Hz)。 實例13 (111,211,311,48,53)-1-(3-(4-乙基苄基)苯基)-5-(羥基曱基) 環己烷-1,2,3,4,5-五醇(23)之製備。
23 藉由與實例12中所述類似之方法製備化合物】]。1!!-NMR (400 MHz, CD3OD):5 7.39 (1H, s), 7.29-7.31 (1H, m), 136781.doc -77- 200932755 7.21-7.25 (1H, m), 7.03-7.11 (5H, m), 3.92 (2H, s), 3.83 (1H, t, J=9.2 Hz), 3.72 (1H, d, 7=9.6 Hz), 3.56 (1H, d> J=\0.4 Hz), 3.32-3.35 (1H, m), 2.58 (2H, q, 7=7.6 Hz), 2.〇2 (1H, d, 7=15.2 Hz), 1.82 (lH,d, 7=15.2 Hz), 1.18 (3H t „ *7=7.6 Hz)。 實例14 本實例說明如圖6中所概述製備(ir,2S,3R,4R,5S,6R^4_ (4-氣-2-(4-乙基苄基)苯氧基)-6-(羥基甲基)環己烷-1,2,3,5_ β 四醇(29)。
Cl
(5-氣-2·羥基苯基)(4·乙基苯基)甲酮
CI
24 在室溫下,在氬氣下攪拌2_曱氧基_5_氣苯甲酸(2〇 10.5 mmol)於無水CH2Cl2(10 mL)中之溶液。將乙二醯氣 (2.0 g,15.8 mmol)逐滴添加至反應混合物中,繼而添加 DMF(0.〇4mL)。搜拌隔夜之|,使用旋轉蒸發器將揮發^ 136781.doc •78- 200932755 蒸發’且在室溫下’在氬氣下將殘餘物溶解於無水 CH2C12(10 mL) _。冷卻至-5°C之後,添加乙基苯(2.57 mL,21 mmol),繼而逐份添加 A1C13(2.80 g,21 mmol), 同時將反應溫度維持在-5°C與0°C之間。在室溫下將反應混 合物攪拌4 h,且隨後傾入冰水中且以CH2C12(50 mLx2)萃 :取。隨後將有機層以 IN HC1(50 mL)、IN NaOH(50 mL)、 水(50 mL)及鹽水(50 mL)洗滌,且用無水Na2S〇4乾燥。將 濾液濃縮且將粗產物藉由管柱層析法(PE:EA==1 〇: 1)純化以 ® 產生目標化合物(1.944 g)。 4·氣- 2-(4·乙基节基)苯盼
以使溫度保持在約0°c之速度向Et3SiH(2.26 ml , 14.2 ❹ mm〇l)及(5-氣-2-羥基苯基)(4·乙基苯基)曱酮(1 944 g, 7.08 mmol)於10 mL TFA中之經攪拌溶液中添加 CF3S〇3H(30 μΙ〇。完成添加之後,將混合物加溫至室溫且 在室溫下攪拌隔夜。在減壓下蒸發揮發物之後,使殘餘物 在乙酸乙酯及水中分溶。將有機層分離且以水、Na2C〇3水 溶液、鹽水洗滌,隨後用NkSCU乾燥且濃縮。將粗產物藉 由管柱層析法(ΡΕ:ΕΑ=1〇:1)純化以產生目標化合物(1 659 g)。 13678l.doc -79- 200932755 ((lS’2S,3R,6R)-4-(节基氧基甲基)_6 (4氣_2_(4乙基节 基)苯氧基)環己·4养li2,3.三基)參(氧基)參(亞?基)三苯 (27) ~
CI
在室溫下’在氬氣流中將(18,411,58,68)-4,5,6-參(节基氧 基)-3-(苄基氧基甲基)環己·2_烯醇(0 5 g,〇 933 mm〇1)及 三苯基膦(367 mg,1.400 mmol)添加至4-氣-2-(4-乙基节 基)笨酚(345 mg’ 1.400 mmol)之THF(6 mL)溶液中。在相 同溫度下向其中添加DIAD(0.276 mL,1.400 mmol)。將反 應混合物攪拌48 h。將反應混合物在減壓下濃縮,且將所 ❹ 得殘餘物藉由製備型LC-MS純化以獲得157 mg((lS,2S,3R,6R)-4-(苄基氧基曱基)-6-(4-氯-2-(4-乙基苄 基)苯氧基)環己-4-烯-1,2,3-三基)參(氧基)參(亞甲基)三苯 (27) 〇 •(18,28,3尺,48,511,611)-3,4,5-參(苄基氧基)-2-(苄基氧基甲 基)-6-(4-氣-2-(4-乙基苄基)苯氧基)環己醇(28) 136781.doc -80- 200932755
Cl
28 向((18,28,311,611)-4-(苄基氧基甲基)-6-(4-氣-2-(4-乙基 苄基)苯氧基)環己-4-烯-1,2,3-三基)參(氧基)參(亞甲基)三 苯(27,150 mg,0.196 mmol)之0°C攪拌THF溶液中逐滴添 加 BH3OEt2(2 Μ,0.98 mL,1.962 mmol)。在(TC 下授拌2 h 之後,將混合物加溫至25。(:且攪拌隔夜。在〇°C下向反應 混合物中添加H2O2(3 0%,4.2 mL),繼而添加NaOH水溶液 (1 Μ ’ 3.93 mL ’ 3.93 mmol)。完成添加之後,將反應混合 物加溫至25°C且攪拌3 h。藉由添加稀HC1(1N,10 mL)中 止反應且以乙酸乙酯(3x30 mL)萃取。將有機層以水及鹽 水洗滌’隨後用無水Na2S04乾燥》將殘餘物藉由製備型 TLC(EA:PE=1:8 v/v)純化以獲得 59 mg (1S,2S,3R,4S, 5R,6R)-3,4,5-參(苄基氧基)_2-(苄基氧基甲基)_6_(4_氯_2· (4-乙基苄基)苯氧基)環己醇(28)。 (lR,2S,3R,4R,5S,6R)-4-(4-氣-2-(4-乙基苄基)苯氧基)-6- (羥基曱基)環己烷-1,2,3,5-四醇(29) 136781.doc -81 - 200932755
Cl
29 將14 mL THF及甲醇(1:1)添加至含有(1S2S3R4s, 5R,6R)-3,4,5_參(苄基氧基)-2-(苄基氧基甲基)_6_(4·氣_2_ (4-乙基 > 基)本氧基)環己醇(28,55 mg,0.070 mmol)之燒 瓶中。將55 mg Pd/C(10o/〇)—次性添加至反應混合物中。 將混合物以Η:脫氣五次’且在環境溫度下,在出氣氛下將 所得懸浮液攪拌3 h。將反應混合物過濾且濃縮,且將殘 餘物藉由製備型LC-MS純化以獲得25 mg (1尺,23,311,411,58,6尺)-4-(4-氣-2-(4-乙基苄基)苯氧基)-6-(羥 基甲基)環己烷-1,2,3,5- 7.2 (1H, d, J=9.2 Hz), 7.17-7.11 (4H, q), 7.08-7.06 (1H, dd), 6.92-6.91 (1H, d, J=3.2 Hz), 4.11-4.08 (1H, t J=9.2 Hz), 4.01 (2H, s), 3.92-3.91 (2H, m), 3.69-3.665 (1H, dd, /=10.8, 8.8 Hz), 3.46-3.39 (2H, m), 3.35-3.30 (1H, m), 2.66-2.58 (2H,q),1.52-1.46 (1H,tt), 1.24-1.19 (3H, t)。 實例15 (lR,2S,3R,4R,5S,6R)-4-(2-(4-乙基苄基)苯氧基)-6-(羥基 甲基)環己烷-1,2,3,5-四醇(30)之製備 136781.doc • 82 - 200932755
藉由與實例14中所述類似之方法製備化合物,!)。1^ NMR (ϋ20):δ 7.24-7.22 (1H,d,《/=8 Hz),7.17-7.08 (5H, m),7.02-6.99 (1H,d,J=7.2 Hz), 6.83-6.79 (1H,t,*7=7.2
Hz),4.14-4.09 (1H,t,*/=9.2 Hz),4.03 (2H,s),3.94·3.87 (2H, m), 3.68-3.63 (lH, dd, 7=10.8, 9.2 Hz), 3.46-3.38 (2H, m), 3.34-3.30 (1H, m), 2.62-2.56 (2H, q), 1.53-1.46 (1H, tt),1.22-1.18 (3H,t)。 實例16 (1尺,28,311,411,611)-4-(3-(4-乙基苄基)苯基)_4_氟_6_(羥基 甲基)環己烷-1,2,3-三醇(31)之製備
在-78°C下,在氬氣氣氛下將DAST(7 μι)添加至2(30 mg) 於CH2C12(1 mL)中之溶液中。2 h之後,將MeOH(0.5 mL) 添加至混合物中’隨後將其加溫至室溫。將飽和NaCl水溶 液(5 mL)添加至殘餘物中,且將混合物以乙酸乙酯(3xl〇 mL)萃取。蒸發經組合之有機萃取物,且將殘餘物溶解於
Me〇H/THF(l:l ’ 5 mL)中,隨後在h2氣氛下以Pd/C 136781.doc •83- 200932755 10%(10 mg)處理。4 h之後,將化合物31(1.4 mg)藉由製備 型 HPLC分離。h-NMR (300 ΜΗζ):δ 7.18-7.01 (8H,m), 3.90-3-86 (3H,m),3.77-3.72 (1H,m),3.61-3.31(3H,m), 2.62-2.54 (2H, q, 7=7.5 Hz), 2.45-2.60 (2HS m), 1.53 (1H, m), 1.20-1.17 (3H, t, J=7.6 Hz) ; MS (ESI+): 375 [M+H] + , 392 [M+H20] +,416 [M+CH3CN+H]+。 實例17 (lR,2S,3S,6S)-4-(4 -氯-3-(4-乙基节基)苯基)-6-(氟甲基) 環己_4·烯-1,2,3-三醇(33)之製備
Φ 在-78°C下,在氬氣下,將BBr3(0.33 mL)逐滴添加至 3(R=Et)(122 mg)於CH2C12(5 mL)中之溶液中。攪拌2 h之 後’將飽和NaHC03水溶液(1 mL)添加至混合物中,隨後 將其加溫至室溫且以乙酸乙酿(3 X 1 〇 mL)萃取。將經組合 •之有機萃取物用Na2S04乾燥,濃縮且藉由製備型HPLC純 化以提供 18 mg化合物 32。h-NMR (400 ΜΗζ):δ 7.33-7.30 (2Η, m), 7.25-7.23 (1H, m), 7.10 (4H, s), 5.85 (1H, d), 4.58 (2H, s), 4.51-4.49 (1H, m), 4.12-4.01 (2H, q, J=15.2 Hz), 136781.doc 84 - 200932755 3.89-3.85 (1H, dd, J=4, 10.4 Hz), 3.68-3.53 (3H, m), 2.63-2.57 (2H, q, J=7.6 Hz), 1.23-1.19 (3H, t, J=7.6 Hz) ; MS (ESI+): 406 [M+H2〇]+ 〇 在-78°C下,在氬氣下將32(11 mg)於CH2C12(2 mL)中之 溶液以 DAST(3 eq ’ 0.02 mL)處理。2 h之後,將 MeOH(0.5 mL)添加至混合物中’隨後將其加溫至室溫。將飽和NaC1 溶液(5 mL)添加至殘餘物中,且將水性部分以乙酸乙酯 (3 X 10 mL)萃取《蒸發經組合之有機萃取物且將殘餘物藉 由製備型HPLC純化以提供1.8 mg化合物33。b-NMR (400 MHz) δ 7.30-7.08(7H, m), 5.85 (1Η, m), 4.59-4.57 (1H, m), 4.54 (2H, s), 4.13-4.03 (2H, q, /=15.2 Hz), 3.90-3.86 (1H, dd, J=4, 10.4 Hz), 3.70-3.58 (3H, m), 2.60-2.55 (2H, q, J=1.6 Hz), 1.22-1.18 (3H, t, 7=7.6 Hz); MS (ESI+): 391 [M+H] + ; 408[M+H2O]+。 實例18 本實例說明如圓7所概述製備(lR,2R,3S,4S,6R)-4-(4-氣-3-(4-乙基苄基)苯基)-6-(羥基甲基)_5_亞曱基環己烷-l,2,3-三醇(35)。 在實例18及19中,使用以下程序確定所合成之化合物之 結構:在Varian Mercury 300光譜儀上在300 MHz下獲取 NMR資料,其中化學位移參考内部TMS。在由Shimadzu LC-10AD vp系列HPLC泵及雙波長UV偵測器、Gilson 215 自動進樣器、Sedex 75c蒸發光散射(ELS)偵測器及 PE/Sciex API 150EX質譜儀組成之儀器上執行液相層析電 136781.doc • 85 - 200932755 喷霧電離質譜(lc-esi-ms)分析。將ELS偵測器設定為溫 度為40 c,增益設定值為7,且N2壓力為3.3 atm。在API 150上採用Turbo IonSpray源,其中離子喷霧電壓為5 kv, 溫度為300°C,且孔口及環電壓分別為5 乂及175 v。在Q1 中自160至650 m/z掃描正離子。在Phen〇menex Gemini 5 μηι C18管柱上執行各樣品之5·0 kL注射。移動相係由使用 以下梯度及2 mL/min流速的於HPLC級水(Α)及HPLC級乙 腈(B)中之 0.05% 曱酸組成:〇.〇〇 min,95% A,5。/。B ; 4.00 min,0〇/〇 A,100% B ; 5.80 min,〇% A,100% B ; 6.00 min,95% A,5% B ; 7.00 min,95% A,5% B。 (2R,3R,4R,5S,6S)-3,4,5-參(苄基氧基)_2_(苄基氧基甲 基)-6-(4-氣-3-(4-乙基苄基)苯基)環己酮(14)之製備: 向第三丁醇(28.2 pL ’ 296 μΜ〇1)於二氯曱烷(4 mL)中之 溶液中添加戴斯馬丁高碘烷[1,1,1-參(乙醯基氧基卜匕卜二 H-l,2-苯并蛾氧雜環戊-3-(1Η)-酮](116 mg,274 μΜοΙ), 且將所得混合物在室溫下在氬氣下攪拌1〇分鐘。將醇 4(R=Et ’異構物之混合物)於二氯曱烷(2 mL)中之溶液添加 至混合物中且在室溫下攪拌3小時。將混合物以4 mL乙酸 乙酯稀釋且與1.5:1:1之飽和亞硫酸鈉:飽和碳酸氫鈉:鹽水 水溶液(3.5 mL)—起用力攪拌1小時。將各相分離且將水相 以乙酸乙酯(3 mL)再萃取。將經組合之有機相以鹽水(2 mL)洗膝’乾燥(無水NajO4),過渡且蒸發。使用二氣甲 烧作為展開溶劑之製備型TLC提供91 mg(52%)白色固體狀 之化合物 14。NMR (300 MHz, CDC13) δ 7.35-6.90 (m, 136781.doc -86 200932755 25H), 6.80 (m, 2H), 4.96 (m, 3H), 4.55 (m, 4H), 4.11 (m, 3H), 3.94 (m, 2H), 3.79 (m, 3H), 3.47 (s, 1H), 2.83 (m, 1H), 2.62 (q, J 7.8 Hz, 2H), M6 (t, 7=7.5 Hz, 3H) 〇 LC-ESI- MS m/z 766 (M+H),788 (M+Na)。 ((18,211,把风68)-4-(节基氧基甲基)-6-(4-氣-3-(4_乙基 节基)苯基)-5-亞甲基環已烷-υ,%三基)參(氧基)參(亞甲 基)三苯(34): 在氮氣層下向小瓶中之〇.5 ml無水THF中添加環二漠二_ μ-亞曱基[μ·(四氫呋喃)]三鋅[尼斯特德試劑(Nysted reagent)](179 mg ’ 151 ,78 μπιοί,20重量 %於丁财中之 懸浮液)’且將所得混合物冷卻至_78eC。向該混合物中以 逐滴方式添加於0.5 mL無水THF中之(2R,3R,4R,5S,6S)-3,4,5-參(苄基氧基)-2-(苄基氧基曱基)-6-(4-氣-3-(4-乙基苄 基)苯基)環己酮(14,40 mg,52 μηαοί),繼而添加TiCl4(78 μΐ^,78 μιηοΐ,1 Μ於DCM中)。將混合物在-78。。下攪拌20 分鐘,且隨後移除冷卻浴且將混合物在室溫下攪拌3 h。 添加飽和碳酸氫鈉水溶液(2 mL)且將所得混合物攪拌30 min。將混合物萃取至乙酸乙酯(2x4 mL)中,且將有機層 以鹽水(2 mL)洗滌,用Na2S04乾燥,過濾且蒸發。製備型 TLC(8:1 H/EtOAc)提供 25 mg(63°/〇)化合物 34。4 NMR (300 MHz, CDCI3) δ 7.34-6.99 (m, 25H), 6.63 (m, 2H), 5.14 (s, 1H), 4.90 (m, 1H), 4.53 (m, 5H), 4.2(m, 3H), 3.78 (m, 3H), 3.60 (m, 2H), 3.47 (s, 1H), 3.35 (m, 1H), 2.56 (q, J=7.8 Hz, 2H), 2.42 (m, 1H), 1.16 (t, «7=7.5 Hz,3H)。LC- 136781.doc -87- 200932755 ESI-MS m/z 764 (M+H),786 (M+Na)。 (111,2尺,38’48,611)-4-(4-氣-3_(4_乙基苄基)苯基)_6_(羥基 甲基)-5-亞甲基i哀己貌三醇(μ): 在-78 C下’在氮氣層下經15分鐘向小瓶中之 ((lS,2R,3R,4R,6S)-4-(苄基氧基甲基)_6_(4·氣 _3_(4 乙基苄 基)苯基)-5·亞甲基環己烷_123_三基)參(氧基)參(亞曱基) 三苯(34 ’ 24 mg,31.4 mmol)於無水Dcm(0.8 mL)中之溶 液中逐滴添加BC13(1 Μ於DCM中,0.25 mL)。將所得混合 物在-78 C下攪拌30分鐘且逐漸加溫至_2〇〇c。將所得混合 物在-20°C下再攪拌30分鐘。此時,]明反應完成。 將溶液冷卻至-78°C且緩慢添加甲醇mL) ^將所得溶液加 溫至室溫且在減壓下濃縮。將殘餘物溶解於〇.5 mL之1:1 DCM:MeOH中且將其裝載於製備型tcl板上,將其在 15:l(DCM:MeOH)中展開以獲得9 mg(71%)白色固體狀之化 合物 35。4 NMR (300 MHz,CDC13) δ 7.29-6.89 (m,7H), 4.80 (s, 1H), 4.28 (s, 1H), 3.95 (m, 4H), 3.64 (m, 2H), 3.51(m, 3H), 3.22 (m, 1H), 2.58 (q, /=7.2 Hz, 2H), 2.25 (m, 1H),1·18 (t,《7=7.5 Hz,3H)。LC-ESI-MS m/z 425 (M+Na)。 實例19 本實例說明如® 8所概述製備(4S,5S,6R,7R,8R)-4-(4-氣- 3-(4-乙基苄基)苯基)_8_(羥基甲基)螺[2 5]辛烷_5 6 7_三醇 (37)。 (4R,5R,6R,7S,8S)-5,6,7-參(苄基氧基)-4-(苄基氧基曱 136781.doc -88 · 200932755 基)-8-(4-氣-3-(4-乙基苄基)苯基)螺[2·5]辛烷(36): 在氮氣下,在-l〇°C下向((18,211,311,411,68)-4-(苄基氧基 甲基)-6-(4-氯-3-(4-乙基苄基)苯基)-5-亞甲基環己烷-1,2,3-三基)參(氧基)參(亞甲基)-三苯(34, 25 mg,32.7 μιηοΐ)於無 水曱苯(2 mL)中之用力攪拌之溶液中逐滴添加2 Μ二曱基 鋅(146 pL,291 μιηοΐ)之溶液且攪拌15分鐘。逐滴添加二 - 碘甲烷(47 μΐ^,583 μηιοί),且將所得混合物攪拌隔夜。觀 察到40%產物形成。再添加二甲基鋅(再分兩批經48小時添 W 加18當量)及二碘甲烷(分兩批經48小時添加35當量),且該 反應在反應96小時之後完成80%。添加NH4C1(1 mL)之飽 和溶液且將該混合物攪拌30分鐘。將混合物以水(1 mL)稀 釋且將其萃取至乙酸乙S旨(3x1 mL)中。將經組合之有機萃 取物以10%硫酸(1.5 mL)、飽和NaHC03(1.5 mL)及鹽水(1.5 mL)洗滌,乾燥(Na2S04),過濾且蒸發。製備型TLC(9:1之 己烷:乙酸乙酯)提供85%化合物36,將其直接用於下一反 ▲ 應中。 (48,58,611,711,811)-4-(4-氣-3-(4-乙基节基)苯基)_8_(經基 甲基)螺[2.5]辛烷-5,6,7-三醇(37) 向(411,511,611,78,88)-5,6,7-參(苄基氧基)-4-(苄基氧基甲 .基)-8·(4_氣-3-(4-乙基苄基)苯基)螺[2.5]辛烷(36,20 mg, 25.7 μηιοί)於THF(0.2 mL)與甲醇(0.8 mL)之混合物中之溶 液中添加1,2-二氣苯(5 8μΙ^,515 μιηοΐ),繼而添加14 mg炭 載把(10%)。將混合物在1個大氣壓之氫氣下攪拌4〇分鐘。 將混合物經由6 mL注射器中之小矽藻土墊過濾且將石夕藻土 136781.doc •89- 200932755 墊以曱醇(1 mL)洗滌。將溶劑在減壓下蒸發且將殘餘物在 製備型TCL板(8:1之DCM:EtOH)上純化以獲得4 mg(37%)白 色固體狀之化合物37。111~]^尺(3 00 \1112,€〇(:13)3 7.27· 6.85 (m, 7H), 4.01 (s, 2H), 3.80 (m, 2H), 3.63 (m, Η), 3.35 (d, J=5.1 Hz, 2H), 3.02 (d, /=11.1 Hz, 1H), 2.62 (q, J=7.5 Hz, 2H), 2.06 (m, 1H), 1.21 (t, J=7.5 Hz, 3H), 0.40 (m, 1H),0.29 (m,1H), 0.076 (m,1H), -0.326 (m,1H)。LC_ ESI-MS m/z 418 (M+H),440 (M+Na) 〇
實例20 本實例說明化合物5(R=Et)之大規模製備。 (lR,2R,3S,4R,5R,6S)-4-(4·氟-3-(4-乙基苄基)苯基)-6-(羥基曱基)環己烷-I,2,3,5-四醇之製備
❿ 5 (R = Et) (1)(411,58,611)-4,5,6-參(苄基氧基)-3-(苄基氧基甲基)環 己·2_稀酮之製備
7ΟΒη OBn 在室溫下,在氬氣下向(33,48,58,211)-5-羥基-5-[(苯基甲 氧基)曱基]-2,3,4-參(苯基甲氧基;)環己-1_酮(;580.0 §, 136781.doc -90- 200932755 1.051 mol)於無水二氣甲烧(3.6 L)中之溶液中添加三氟乙 酸野(3 31.1 g,222 mL ’ 1.577 mol),繼而添加 n 比咬(149.7 g ’ 153 mL ’ 1.892 mol)。將混合物在室溫下攪拌24 h且藉 由添加冰水(1.0 L)中止反應。將有機層分離且將水層以二 氣甲烷(3x2 L)萃取。將經組合之有機層以碳酸氫鈉(飽和 水溶液’ 3x〇.5 L)、鹽水(飽和水溶液,3x1.0 L)洗條,用 硫酸鈉乾燥,過濾且濃縮以產生黃色油狀物(476.7 g,純 度為 90%,產率為 85%)。NMR (CDC13,400 ΜΗζ):δ 7.26-7.48 (m, 20H), 6.26 (s, 1H), 5.15 (d, 7=11.2 Hz, 1H), 5.05 (d, 7=10.8 Hz, 1H), 4.95 (d, 7=10.8 Hz, 1H), 4.77-4.81 (m, 2H), 4.72 (d, 7=11.2 Hz), 4.55 (S, 2H), 4.40-4.42 (m, 1H),4.31 (d,J=16 Hz, 1H), 4.03-4.13 (m,3H)。 (2)(4-氣-3-(4-乙基苄基)苯基)溴化鎂之製備
BrMg ® 在氬氣下將鎂粉(34.7 g ’ 1.446 mol)裝入三頸燒瓶中, 繼而添加一部分2-(4·乙基苄基)-4-溴-1-氣苯(丨22.5 g, 0.3 98 mol)於無水四氫呋喃(〇 4 L)中之溶液及12二溴乙烷 (2·89 g,1·34 mL·,0.015 mol)。將混合物加熱至回流且在 反應起始(放熱且消耗鎂)之後,逐滴添加剩餘2 (4_乙基苄 基)-4-/臭-1-氣苯(245.0 g,0.796 mol)於無水四氫呋喃(0.81 L)中之溶液。隨後使混合物在溫和回流下再反應1 h直至 大部分鎂已消耗。 136781.doc •91· 200932755 (3)(111,411,58,611)-4,5,6-參(节基氧基)_3_(节基氧基曱基)-1-(4-氣- 3-(4-乙基节基)苯基)環己-2-締醇之製備
在室溫(約25 °C)下,在氬氣下將前一步驟之格林納試劑 逐滴添加至(4尺,58,611)-4,5,6-參(苄基氧基)_3_(苄基氧基曱 〇 基)環己-2-烯酮(476.7 g ’ 90%純度,0.893 mol)於無水四 氫呋喃(1.0 L)中之溶液中’且將混合物攪拌3 h。添加氣化 銨(飽和水溶液’ 100 mL)且將混合物以乙酸乙酯(3 X1 L)萃 取。將有機層以鹽水(3χ〇.5 L)洗滌,用硫酸鈉乾燥,過渡 且濃縮以產生黃色油狀物(614 g,產率為9〇%p將 (111,411,58,6尺)-4,5,6-參(苄基氧基)-3-(苄基氧基曱基)小(4_ 氣-3-(4-乙基苄基)苯基)環己-2-稀醇粗品直接用於下一步 驟中。MS (ESI+) (m/z):782 (M+18)+,787 (M+23).。 ® (4)((111,28,38,61〇-6-苄基氧基甲基)_4_(4_氣_3_(4_己基:^ 基)苯基)環己-4-烯-1,2,3-三基)參(氧基)參(亞曱基)三笨之 製備
在-20°C下,在氬氣下將三乙基矽烷(167.9 g,229 7 136781.doc -92· 200932755 mL,1.446 mol,2 eq)及醚合三氟化硼(205.2 g,204.1 mL,1.446 mol,2 eq)依次添加至(lR,4R,5S,6R)-4,5,6-# (苄基氧基)-3-(苄基氧基甲基)-1-(4_氣_3_(4_乙基苄基)苯 基)環己-2-烯醇(614.0 g,粗品,約0.723 mol,1 eq)於二 氯曱烷(2.6 L)中之溶液中’且在_2〇。〇下攪拌混合物達j h。添加氣化敍(飽和水溶液,1 〇〇 mL)且將混合物以二氣 甲烧(3x1 L)萃取,將有機層以鹽水(3x〇.5 L)洗滌,用硫酸 納乾燥’過遽且濃縮。將殘餘物藉由於回流無水乙醇/異 丙醚中再結晶純化以產生白色固體(513 g,純度為95〇/〇, 產率為95%)。 (5)(lR,2S,3R,4R,5S,6R)-3,4,5-參(苄基氧基)·2·(苄基氧 基曱基)-6-(4-氯-3-(4-乙基苄基)苯基)環己醇之製備
在〇°C下’在氬氣下將硼烷-四氫呋喃錯合物(丨μ於四氫 咬喃中)(1.31 L ’ 1.302 mol,2 eq·)添加至高壓反應不鏽鋼 容器中之((111,28,38,6尺)-6-苄基氧基甲基)_4_(4-氣_3-(4_乙 基苄基)苯基)環己-4-烯-1,2,3-三基)參(氧基)參(亞曱基)三 笨(513 g ’純度為95% ’ 0.651 mol,1 eq)及蝴氫化經(7.1 g,2 Μ於四氫呋喃中,〇·326 m〇1,〇 5 eq)於無水四氫呋喃 (5 L)中之溶液中’且將混合物加熱至約7〇_8〇〇c,隨後反 應器中之壓力達至約2-2.5 atm。將混合物在該溫度下攪拌 136781.doc •93· 200932755 40 min。將反應容器冷卻至室溫且將内容物轉移至三頸燒 瓶中且冷卻至-20°C。添加氫氧化鈉(78.1 g,3 Μ於水中, 1.953 mo卜3 eq)之冷(〇。〇溶液,繼而添加30%過氧化氫 (442.8 g,43 8.4 mL,1.953 mol ’ 20 eq),且將混合物加溫 至室溫隔.仪。將反應混合物以1 N鹽酸酸化至pH 6且將溶 :劑在減壓下移除。將水(5 L)添加至殘餘物中且以乙酸乙酯 . (3x2 L)萃取。將有機層以鹽水(3x1 L)洗滌,用硫酸鈉乾 燥,過濾且濃縮。將殘餘物藉由於乙醚/正已烷 β (ν/ν=1:10 ’ 10 mL/g(粗產物))中再結晶純化以產生白色固 體(3 14.7 g,純度為95%,產率為60%)。 (6)(111,211,38,411,511,68)-4-(4-氣-3-(4-乙基苄基)苯基)-6- (羥基曱基)環己烷-1,2,3,5-四醇粗品之製備
向(1尺,28,311,411,58,61〇-3,4,5-參(苄基氧基)-2-(苄基氧基 甲基)-6-(4-氣-3-(4-乙基苄基)苯基)環己醇(60 g,純度為 98%,0.077 mol,1 .eq)於四氫咬喊:甲醇(v/v=2:1)(600 mL) 中之溶液中添加 1,2-二氣苯(21.5 g,16.54 mL,0.82 mol, 2 eq)、碳載鈀(10%,4.8 g),且在室溫(約25°C)下,在大 氣壓力之氫氣下將其攪拌4 h。將混合物過濾且將濾液蒸 發至乾以產生黃色油狀物(80°/。純)。 (7)四乙酸(lS,2R,3R,4S,5R,6R)-4-(乙醯氧基曱基)-6-(4- 136781.doc -94- 200932755 氣-3-(4-乙基苄基)苯基)環己烷-1,2,3,5-四酯(19)之製備
.在 0°C下將乙酸酐(78.8 g,72.9 mL,0.77 mol,10 eq)、 N,N-二異丙基乙基胺(99·5 g,134.1 mL,0.77 mol,10 ec}) 及4-二曱基胺基吡啶(DMAP,0.47 g,3,85 mmol,〇.〇5 O eq)緩慢添加至上述粗油狀物(lR,2R,3S,4R,5R,6S)-4-(3-(4_ 乙基苄基)-4-氣苯基)-6-(羥基甲基)環己烷4,2,3,5-四醇 (0.077 mol,純度為80%)於二氣曱烷(300 mL)中之溶液 中’且將混合物在室溫下攪拌隔夜。將混合物以1N鹽酸酸 化至pH 6且將有機層以1 N鹽酸(3x200 mL)洗滌,用硫酸 鈉乾燥,過濾且濃縮。將殘餘物於沸騰乙醇/乙酸乙酯 (v/v=3:l,15 mL/g(粗產物))中再結晶。在約58t下出現第 _©體,且將混合物在耽下授拌2 h。將、混合物經2 _ W至至溫以產生白色固體(42.2 g,純度為99.4%,兩個步 驟之產率為88.7%)。 (8)(1R,2R,3S,4R,5R,6S)-4-(4-^-3-(4-6 ^ ^ (經基甲基)環己烧·1,2,3,5·四醇之製備
I36781.doc -95- 200932755 向四乙酸(lS,2R,3R,4S,5R,6R)-4-(乙醯氧基曱基)_6·(4_ 氣-3-(4-乙基苄基)苯基)環己烷-1,2,3,5-四酯(98 g, >99°/。,0.158 mol ’ 1 eq)於甲醇(1 L)中之攪拌溶液中添加 氫氧化鈉(粉末,12.6 g,0.315 mol,2 eq)且使混合物回流 隔夜。將反應混合物以1 N鹽酸酸化至pH 6且將揮發物在 減壓下移除。將殘餘物溶解於乙酸乙酯(3 L)中,以水(1 L) 隨後以鹽水(1 L)洗滌,用硫酸鈉乾燥,過濾且濃縮以產生 白色泡沫狀物。將該泡洙狀物於回流乙醇/水(v/v=l :3,2() ® mL/g(粗產物))中再結晶兩次以產生白色固體(58 g,純度 為99.3%,產率為90%)。 實例21 本實例說明 1-(4-(2-氣-5-((lR,2S,3R,4R,5S,6R)-2,3,4,6- 四羥基-5-(羥基甲基)環己基)苄基)苯基)乙酮(39)之製備。 四乙酸(18,211,311,48,511,61〇-4-(乙醢氧基甲基)-6-(3-(4-乙酿基苄基)_4·氣苯基)環己烷-1,2,3,5-四酯(38)之製備
向四乙酸(lS,2R,3R,4S,5R,6R)-4-(乙醯氧基曱基)-6-(4· 氣-3-(4-乙基苄基)苯基)環己烷-l,2,3,5-四酯(19)(300 mg, 48.7 μηιοί)於乙酸(5mL)中之用力攪拌之溶液中添加 K2Cr2〇7(172 mg,0.58 mmol)且在 125°C 下將混合物攪拌 22 小時。將混合物冷卻至室溫,以水(20 mL)稀釋且以乙酸 136781.doc -96· 200932755 乙酯(3x20 mL)萃取。將經組合之有機萃取物以飽和 NaHC03(3xlO mL)洗滌且隨後以鹽水(20 mL)洗滌,乾燥 (Na2S04),過濾且濃縮。製備型TLC(2:1之己烧:乙酸乙酯) 提供 100 mg所需化合物。MS (ESI+): 631 [M+H] +,648 [m+h2o]+。 1-(4-(2-氣-5-((111,28,311,4只,58,61〇,2,3,4,6-四羥基-5-(羥 基甲基)環己基)苄基)苯基)乙酮(39)之製備
向四乙酸(lS,2R,3R,4S,5R,6R)-4-(乙醯氧基甲基)-6-(3-(4-乙醯基苄基)-4-氣苯基)環己烷-1,2,3,5-四酯(38)(300 mg,47.6 μπιοί)於MeOH(5 mL)中之溶液中添加氫氧化納 (29 mg ’ 72 μιηοΐ)且在回流下攪拌丨.5 h。將混合物以1 N鹽 酸酸化至pH 6且將溶劑在減壓下移除。將該殘餘物藉由製 備型HPLC純化以提供3〇 mg所需化合物。h-NMR (400 MHz, CD3OD):5 7.90 (2h, d, 7=8.4 Hz), 7.35 (3H, m), 7.22 (H, d, *7=1.6 Hz), 7.18 (1H, d, J=S.4, 1.6 Hz), 4.17 (2H, s), 3.91 (2H, d, 7=3.2 Hz), 3.66 (1H, t, /=10.4 Hz), 3.49-3.40 (2H, m), 3.30 (1H, m)} 2.57-2.52 (4H, m), 1.55-1.50 (1H, m) ; MS (ESI+):42i [M+H]+, 443 [M+Na] + , (ESI'):465 [M+HCOO]_。 136781.doc -97- 200932755 實例22 (1只,2心38,411,511,68)-4-(4-氣-3-(4-(1-羥基乙基)苄基)苯 基)-6-(羥基甲基)環己烷-1,2,3,S-四醇(40)之製備
藉由以過量氫硼化鈉還原四乙酸(13,211,311,48,511,611)-4-(乙醯氧基甲基)-6-(3-(4-乙醯基苄基)-4-氣苯基)環己烷-1,2,3,5-四酯(38)且藉由製備型HPLC純化以產生0.6 mg透 明薄膜來製備化合物 40。MS (ESI+): 445 [M+Na]+,(ESI·): 467 [M+HCOO]-。 實例23 藉由以下程序展示本發明之化合物的SGLT抑制作用。 人類SGLT2表現載體之製備 將表現人類SGLT2之全長cDNA純系(GenScript Corporation)次選殖至pEAK15表現載體之///及 / 位點中。藉由限制性分析鑑別具有cDNA插入物之純系。 穩定表現人類SGLT2之細胞株的製備 將含有人類SGLT2之質體以iVh人線性化且藉由瓊脂糖凝 膠電泳純化。使用Lipofectamine 2000轉染劑(Invitrogen Corporation),將DNA轉染至HEK293.ETN細胞中,且在 37°C下在5% C02下於含有10%胎牛血清(FBS)之杜爾貝科 氏經改良伊格爾培養基(DMEM)中培養24 h。在補充有嘌 136781.doc -98· 200932755 吟徽素(Invitrogen Corporation)之相同生長培養基中歷時 兩週選擇轉染株。將嘌呤黴素抗性細胞回收且接種於新鮮 96孔板(每孔單個細胞)上,且在嘌呤黴素存在下進行培養 直至細胞長滿。在下述曱基4C]葡萄派喃糖皆吸 收檢定中評估嘌呤黴素抗性純系之SGLT2活性。將展現最 高信號與背景比率之純系用於甲基-tx_D-[U-14C]葡萄哌喃 . 糖苷吸收檢定。 表現人類SGLT1之細胞之製備 © 自GenScript Corporation獲得pDream2.1表現載醴上之全 長人類SGLT1 cDNA,且使用含有安比西林(ampicillin)之 魯利亞-貝爾塔尼(Luria-Bertani,LB)培養基使其在大腸桿 菌(Escherichia co/i)菌株 DH5a 中增殖。使用 QIAGEN Plasmid Midi套組(QIAGEN Inc.)分離質體DNA。根據製造 商建議之方案,使用Lipofectamine 2000轉染劑將人類 SGLT1表現質體DNA轉染至COS-7細胞(American Type Culture Collection)中。在-80°C下將經轉染細胞儲存於含 參 有10%二甲亞砜(DMSO)之DMEM中。 甲基-a-D-【U-14C】葡萄旅喃糖苷吸收檢定 將表現SGLT1或SGLT2之細胞接種於96孔ScintiPlate閃 爍板(PerkinElmer, Inc_)上含有 10% FBS 之 DMEM 中(每孔 100 μΐ培養基中lxlO5個細胞),在檢定之前在37°C下於5% C02下培育48 h。將細胞以150 μΐ鈉緩衝液(137 mM NaCl, 5.4 mM KC卜 2.8 mM CaCl2,1.2 mM MgCl2,10 mM參(羥 基甲基)胺基曱烷/N-2-羥基乙基哌嗪-Ν’-乙烷磺酸 136781.doc -99· 200932755
[丁148/七?63],?117.2)或無鈉緩衝液(137 111:^>1-曱基-葡糖 胺、5.4 mM KCn、2_8 mM CaCl2、1.2 mM MgCl2、10 mM Tris/Hepes,pH7.2)洗蘇兩次。將50μl含有40μCi/ml甲 基-a-D-[U-14C]葡萄旅 0南糖苦(Amersham Biosciences/ GE Healthcare)及25°/。人類血清之鈉或無鈉緩衝液中之每一者 中的測試化合物添加至96孔板之每一孔中,且在37°C下, 在震盪下培育2 h(SGLTl檢定)或1.5 h(SGLT2檢定)。將細 胞以150 μΐ洗滌緩衝液(137 mM N-曱基葡糖胺,10 mM 丁1^爪6卩63,卩117.2)洗蘇兩次,且使用丁0卩(1;011111;閃爍計數 器(PerkinElmer,Inc.)測定曱基-a-D-[U-14C]葡萄哌喃糖苷 吸收的量。藉由自使用鈉緩衝液獲得之值中減去由無鈉緩 衝液獲得之值來量測鈉依賴性葡萄哌喃糖苷吸收(三次測 定值之平均值)。 表1 ICso* 化合物 SGLT2 SGLT1 5 (R=Et) + + 9 + ++ 10 + + 11 + ++ 12 + 13 + •f++ 17 + -H- 30 + +++ 35 + ++ 37 + ++ 39 + -H- 40 + ++ *圖例: + <1 μΜ ++ 1 μΜ 至 10 μΜ +++ >10 μΜ 136781.doc •100· 200932755 【圖式簡單說明】 圖1-2提供本發明之化合物的通用合成流程。 圖3-8提供下文實例中之化合物的更具體之合成流程。
136781.doc 101 ·
Claims (1)
- 200932755 十、申請專利範圍· 1. 一種式I化合物:其中 A係選自由以下組成之群:氧;NH ;亞甲基;及一單 鍵, ❹ q係選自由式Q1至Q4組成之群:R13R;1.R12Q3Q4 z係選自由以下組成之群·氧;硫;s〇; s〇2; ^•伸環 c 丙基,叛基,及亞甲基,視情況經一至兩個獨立地選 下之取代基取代:鹵基羥基、烷基 C6;^氡基、C”C6環燒基及環烧基氧基; R 1、R2及卩3夂A 谷自獨立地選自由以下組成之群:氣、 基經基、CVC6燒基、C2_C6稀基、CVC6&基南 ClO衰燒基、C5_Ci〇環稀基炫基氧基 3 3~C10 環 136781.doc 200932755 烷基氧基、氰基、胺基及硝基,其中烷基、烯基、炔 基、環烷基及環烯基等基團或部分視情況經部分或完 全氟化,及視情況經相同或不同之選自由以下組成之 群之取代基單取代或二取代:氯、羥基、烷氧基 及(^-〇:3烷基,在環烷基及環烯基基團或部分中,一或 兩個亞曱基視情況彼此獨立地經以下置換:NRa、〇、 S、CO、SO或S〇2,一或兩個次甲基視情況經N置換, 或在R1及R2結合至苯環之兩個相鄰C原子的情況下, R1與R2視情況接合在一起形成CrC5伸烷基、(:3-<:5伸 烯基或伸丁二烯基橋,其視情況經部分或完全氟化, 及視情況經相同或不同之選自以下之取代基單取代或 二取代:氣、羥基、C^-C3烷氧基及(:!-(:3烷基,其中 一或兩個亞曱基視情況彼此獨立地經以下置換:0、 S、CO、SO、S〇2或NRa,其中一或兩個次甲基可視情 況經N置換; R為選自由以下組成之群之成員:氫、鹵基、氰基、確 基、胺基、羥基、CVC6烷基、C2-C6烯基、c2-c6炔 基、C3-C1G環烷基、C5-C1G環烯基、CVC6烷基氧基、 C3_C丨〇環烷基氧基、(C丨-C6烷基氧基)Cl-C6烷基氧基、 C5_C?環稀基氧基、芳基、雜芳基、芳基氧基、雜芳基 氧基、(C2-C4稀基)CVC3烧基氧基、(C2-C4缺基)CVC3 烧基氧基、(芳基)C^C:3烷基氧基、(雜芳基)烷基 氧基、(C3-C1Q環烷基烷基、(C3-C1G環烷基)cv c3烧基氧基、(C5-C1G環烯基烷基、(c5-C1Q環稀 136781.doc -2 - 200932755 基)CVC3烷基氧基、(Cl_c4烷基氧基)G^-Cs烷基、(C3-C7環烷基氧基)CVC3烷基、(c3-c7環烷基氧基)c2-c4烯 基、(Cs-C:7環烷基氧基)c2_c4炔基、(c3-c7環烷基氧 基)CVC3烷基氧基、(CVC4烷基胺基)CVC3烷基、二-(C丨-C3烷基胺基)CrCs烷基、三-(CVC4烷基)矽烷基-(VC:6烷基、三-(C丨-c4烷基)矽烷基-c2-c6烯基、三-(CrC:4烷基)矽烷基-C2-C6炔基、三-(Ci-CU烷基)矽烷 基- Ci-C6烧基氧基、(C3-C7環烧基)C2-C5稀基、(C3-C7 環烷基)c3-c5烯基氧基、(c3-c7環烷基)c3-c5炔基氧 基、(c5-c8環烯基)c3-c5烯基氧基、(c5-c8環烯基)c3-C5炔基氧基、C3_C6亞環烷基甲基、烷基)羰 基、芳基羰基、雜芳基羰基、胺基羰基、(C^-Q烷基) 胺基羰基、二-(CrQ烷基)胺基羰基、羥基羰基、(C,-C4烷基氧基)羰基、CrC*烷基胺基、二-(CrC^烷基)胺 基、烷基)羰基胺基、芳基羰基胺基、雜芳基羰 基胺基、CrC*烷基磺醯基胺基、芳基磺醯基胺基、 c^-cu烷基硫基、c「c4烷基亞磺醯基、0:,-(:4烷基磺醯 基、c3-c1()環烷基硫基、c3-c1()環烷基亞磺醯基、c3-C10環烷基磺醯基、C5-C1Q環烯基硫基、c5_ClG環烯基 亞磺醯基、c5-c1G環烯基磺醯基、芳基硫基、芳基亞 磺醯基及芳基磺醯基’其中烷基、烯基、炔基、環烷 基及環烯基基團或部分視情況經部分或完全氟化,及 視情況經相同或不同之選自以下之取代基單取代或二 取代:氣、羥基、Ci-C3烷氧基及(:1-(:3烷基,在環烷 136781.doc 200932755 基及環稀基基團或部分中,一或兩個亞甲基視情況彼 此獨立地經以下置換:NRa、〇、s、CO、SO或S02, 一或兩個次甲基視情況經N置換; R及R6各自獨立地選自由以下組成之群:氫、鹵基、氰 基、硝基、羥基、CpC6烷基、C2-C6烯基、C2-C6炔 基、CVCw環烷基、c^C:3烷基氧基及c3-C1G環烷基氧 基’其中烷基、烯基、炔基、環烷基及環烯基基團或 部分視情況經部分或完全氟化,及視情況經相同或不 ® 同之選自以下之取代基單取代或二取代:氣、經基、 C1-C3烷氧基及(^-(:3烷基,在環烷基及環烯基基團或 部分中,一或兩個亞曱基視情況彼此獨立地經以下置 換:NRa、0、S、CO、SO或S02,一或兩個次甲基視 情況經N置換,或 若R5及R6結合至該苯環之兩個相鄰C原子,則R5與尺6視 情況接合在一起形成Ca-Cs伸烷基、C3-C5伸烯基或伸 ^ 丁一稀基橋,視情況經部分或完全氟*化,及經相同或 不同之選自以下之取代基單取代或二取代:氣、經 基、CVC3烧氧基及c〗-C3烧基,其中一或兩個亞甲基 視情況彼此獨立地經以下置換:0、S、CO、so、S〇2 或NRa,其中一或兩個次曱基視情況經N置換; R7、R8、R9及R10各自獨立地選自由以下組成之群:經 基、(G-Cu烷基)羰基氧基、(C^Cu烷基)氧基幾基氧 基、芳基幾·基氧基、芳基-(C1-C3烧基)幾基氧基、(c3_ C10環娱》基)幾基氧基、氮、齒基、Ci_C6^基、C2-C6婦 136781.doc -4- 200932755 基、C2-C6炔基、(C3-C1G環烷基Wi-Cs烷基、(c5-c7環 稀基)G-C3烷基、(芳基)CVC3烷基、(雜芳基)(VC3烷 基、CVC6烷基氧基、c2-c6烯基氧基、c2-c6炔基氧 基、CrC7環烷基氧基、c5-c7環烯基氧基、芳基氧 基、雜芳基氧基、(C3-C7環烷基)(ν<:3烷基氧基、(c5-環烯基β,-Ο:3烷基氧基、(芳基)烷基氧基、(雜 芳基)Crq烷基氧基、胺基羰基、羥基羰基、(Cl_c4 烧基)胺基羰基、二-(CrCs烷基)胺基羰基、(CrQ烷 基氧基)羰基、(胺基羰基烷基、(CrC^烷基)胺 基幾基-(CVC3)烷基、二-(CrCs烷基)胺基羰基-(C^CJ 烧基、(羥基羰基)〇ν(:3烷基、(CVC4烷基氧基)羰基· (Ci-C3)烷基、(c3-c7環院基氧基)烷基、((:5-〇7環 烯基氧基)C^-C:3烷基、(芳基氧基)(^_(:3烷基、(雜芳基 乳基)C^-C3烧基、Ci-C4烧基續醯基氧基、芳基續酿基 氧基、(芳基)C1-C3烧基績酿基氧基、三曱基矽烧基氧 基、第三丁基二甲基矽烷基氧基及氰基;其中烷基、 烯基、炔基、環烷基及環烯基基團或部分視情況經部 分或完全氟化’及視情況經相同或不同之選自以下之 取代基單取代或二取代:氣、羥基、烧氧基及 Cj-C3烷基,在環烷基及環烯基基團或部分中,一或兩 個亞曱基視情況彼此獨立地經以下置換:NRa、0、 S、CO、so或 so2 ; 及視情況’ R1Q及Rn可與各自所連接之碳原子組合形成 五至七員稠合環烧烴或環烯烴環,其視情況經部分或 136781.doc 200932755 完全氟1化’及可經相同或不同之選自以下之取代基單 取代或二取代:氣、羥基、Cl-C3烷氧基及 基’其中在該環烷基環及該環烯基環中,一或兩個亞 甲基視情況彼此獨立地經以下置換:NRa、〇、s、 CO、so或 so2; R及R各自獨立地選自由以下組成之群:氫、經基、 齒基、烧基、c2-c6稀基、c2-c6炔基、C3_Cl〇環 烧基、Ci-C6烧基氧基、CrC6稀基氧基、c2_c6炔基氧 基或C3-C6環烷基氧基,其中烷基、烯基、炔基及環烷 基基團或部分視情況經部分或完全氟化,或 Rn及R12視情況與其所連接之碳原子接合在一起形成 C7螺環烷烴環,其視情況經部分或完全氟化及視情 況經相同或不同之選自以下之取代基單取代或二取 代:氣、羥基、CVC3烷氧基及Ci_c3烷基; 其中 ⑴當Q為Q〗且R11與R12均為氫時,則尺⑺或尺“中之至少 -者為i基’或Rh為氫,或w2_c6炔基^ c10環烧基氧基' C5_C7環稀基氧基、(C3_Ci。環院 基)Cl_C3烧基氧基、(C3_C7環烷基)C3_C5稀基氧基、 (C3_C7環烧基)C3_C5块基氧基、⑹心。環稀基)Ci· C3烧基氧基、(C5-C8環稀基)(:3{5縣氧基或(C”C8 環烯基)c3-c5炔基氧基; …)當Q為Q2且R"為氫時,則至少尺〗。為齒基或 CVC6炔基、C3-Cl。環燒基4 1〇艰沉基氧基、cvq環烯基氧 136781.doc 200932755 其 土、(c3-c丨〇環烷基)Cl_c3烷基氧基、(C3_C7環烷基) C3-C5歸基氧基、(C3_C7環烷基)c3-c5炔基氧基、 (C5-c1Q環烯基)Cl_c3烷基氧基、(C5_C8環烯基)(:3% 婦基氧基或(CVCs環烯基)c3-C5炔基氧基; (lU)當Q為Q4且RH為氫時,則至少R10為齒基,或Rl3 不為氫,或R4為CVC6炔基、C3_C1(>環烷基氧基、 Q-C7環烯基氧基、(C3_Ci〇環烷基)Ci_C3烷基氧基、 (c3-c7環烷基)c3_C5烯基氧基、(C3_C7環烷基)c3_q 炔基氧基、(c5-c1Q環烯基)Cl_c3烷基氧基、(C^C8 環烯基)C3-C5稀基氧基或(C5_C8環烯基)C;3_C5炔基氧基 R1及R14各自獨立地選自由以下組成之群:氫、羥基、 鹵基、CVC6貌基、c2-c6稀基、C2_c6块基、c3 Ci環 烧基、CVC6炫基氧基、c2_C6稀基氧基、C2_C6块基0氧 基及C3_C6環烧基氧基’其中烷基、烯基、炔基及環院 基基團或部分視情況經部分或完全氣化. R15係選自由氧及CRbRc組成之群; 各Ra獨立地選自由以下組成之群:氫、㈣烷基及(C C 烷基德基’其中烷基基團或部分視情況經部分或丄全4 氣化;及 自獨立地選自由以下組成之群:氫、南基及Cl·。 烧基’其中烧基視情況經部分或完全襄化. 4 及其醫藥學上可接受之鹽。 2.如請求項1之化合物,其中A為氧或一單鍵。 136781.doc 200932755 3. 如明求化合物,其中a為一單鍵。 4. ^求項1之化合物,其中2係選自由氧硫及視情況 ^至兩個獨立地選自以下之取代基取代之亞甲基組成 之群·自基、經基、c〗-c6院基、CVC6统氧基、c c環 烷基及C3-C6環烷基氧基。 5. 如明求項4之化合物,其十z為亞曱基。 6. 如凊求項!之化合物,其中Rl、尺2及尺3各自獨立地選自 由以下組成之群:氫、鹵基、羥基、Ci_c6烷基、c2 C6 烯基' cvc6炔基、C3_Cig環烷基、Ci_Q烷基氧基及 基。 7. 8. 9. ❹ 如請求項6之化合物,其中Ri、R2及R3各自獨立地選自 由以下組成之群:氫、鹵基及匚丨—匕烷基。 如叫求項6之化合物,其中R!係選自由以下組成之群: 氫、鹵基及(^-(:6烷基,R2及R3各自為氫。 如請求項1之化合物,其中R4係選自由以下組成之群: Ci-C6燒基、c2-c6烯基、C2_C6炔基、C3_Ci〇環烷基、Ci_C6 烷基氧基、C3-C1G環烷基氧基、(C3-CiG環烷基…^。烷 基氧基、(CVC7環烷基)(:3-(:5烯基氧基及(C3_C7環烷 基)C3-C5炔基氧基。 1〇.如請求項1之化合物,其中R5及R6各自獨立地選自由以 下組成之群:氫、鹵基、羥基、Cl_c6烷基' c2-c6烯 基、CyC6炔基、C3-C10環烷基、cvc6烷基氧基及氰基。 在更尤佳之實施例中’ R5及R6均表示氫。 U.如請求項10之化合物,其中R5及R6各自獨立地選自由以 136781.doc 200932755 下組成之群:氫、鹵基及(^_〇:6烷基。 12. 如請求項〇之化合物,其中“及尺6各自為氫。 13. 如請求们之化合物,其中r7、r8、r、r,〇各自獨立地 選自由以下組成之群:羥基、函基、C〗_C6烷基、 烷基氧基、(q-c:7)環烷基氧基、芳基氧基及(C3_C7)環烷 基-(CrC3)烷基氧基,其中烷基及環烷基基團或部分視 情況經部分或完全氟化。 e 14. 如請求項13之化合物,其中R7、R8、R9及R10各自為羥 基。 15. 如明求項j之化合物,其中Ri丨係選自由以下組成之群: 氫及羥基。 16. 如請求項1之化合物,其具有式IA : QIA 其中 Rl為選自由以下組成之群之成員:氫、鹵基及C丨-C6燒 基; & R4為選自由以下組成之群之成員:Ci-C6烷基、C2-C6^ 基、c2-c6炔基、c3_ClG環烷基、Cl-C6烷基氧基、 3 ^1〇 環垸基氧基、(C3-C丨〇環烷基)c丨-c3烷基氧基、 環燒基)C3_CS烯基氧基及(CrC7環烷基)C3-C5炔基氧 基;及 Q為選自式(^丨八至以々之成員: 136781.doc 200932755 811 f , I15 , Γ j HO、 rr1 h〇^cV H0 八 HO、、, ^OH ηο'Ύ'οη HO° V0H ho'' OH OH OH OH 其中 q1A Q2A q3A Q4A R11為選自由以下組成之群之成員:氫及羥基;及 R15為選自由以下組成之群之成員:氧及CRbRc,其中Rb 及Re各自獨立地為選自由以下組成之群之成員:氫及 鹵基; 其中當Rn為氫時,則R4為CVC6炔基、c3_c10環烷基氧 基、(c3-c1Q環烷基)Cl_C3烷基氧基、(C3_c7環烷基) CVCs烯基氧基或(C3_C7環烷基)c3_C5炔基氧基。 17.如請求項1之化合物,其選自由以下組成之群: (lR,2R’3S,4R,5R,6S)-4-(4-氣-3-(4-乙基苄基)苯基)_6_ (羥基甲基)環己烷-1,2,3,5-四醇; (1R,2R,3 S,4R,5R,6S)-4-(4 -氣- 3-(4-乙氡基苄基)苯基)_ 6-(羥基甲基)環己烷-1,2,3,5-四醇; (111,211,3 8,4尺,5尺,68)-4-(4-氯-3-(4-環丙基苄基)苯基)_ 6-(羥基甲基)環己烷-1,2,3,5-四醇; (lR,2R,3S,4R,5R,6S)-4-(4-氣-3-(4·丙基苄基)苯基)-6_ (羥基曱基)環己烷-1,2,3,5-四醇; (lR,2R,3S,4R,5R,6S)-4-(4-氣-3-(4-環己基节基)苯基)_ 6-(羥基曱基)環己烷·1,2,3,5-四醇; (111,28,3 8,611)-4-(4-氣-3-(4-(3-環丙基丙_2_快基氧基) 苄基)苯基)-6-(羥基曱基)環己-4-烯-1,2,3_三醇; 136781.doc -10- 200932755 乙酸((1 S,2R,3R,4S,5R,6R)-3-(4-氯-3-(4-乙基苄基)笨 基)-2,4,5,6-四羥基環己基)曱酯; (111,28,311,411,58,611)-4-(2-(4-乙基节基)苯氧基)_6_(羥 基甲基)環己烷-1,2,3,5-四醇; . (111,211,38,48,611)-4-(4-氣-3-(4-乙基苄基)苯基)_6-(羥 基甲基)-5-亞曱基環己烷-1,2,3-三醇; (4S,5S,6R,7R,8R)-4_(4-氣 _3_(4_ 乙基节基)苯基)_8 (經 基甲基)螺[2.5]辛烷-5,6,7-三醇; © 氯巧-((111,28,311,411,58,611)-2,3,4,6-四羥基-5- (羥基甲基)環己基)苄基)苯基)乙酮;及 (111,211,3 8,411,511,68)-4-(4-氣-3-(4-(1-羥基乙基)苄基) 苯基)-6-(經基甲基)環己院_1,2,3,5-四醇。 1 8.如請求項1之化合物,其經同位素標記。 19. 一種如請求項1之化合物的前藥醋。 20. —種醫藥組合物,其包含醫藥學上可接受之載劑及如請 求項1之化合物。 21 _ —種治療SGLT所介導之疾病或病狀之方法,該方法包含 向需要之個體投與治療有效量之如請求項j之化合物。 22. -種治療糖尿病之方法,該方法包含向需要之個體投與 治療有效量之如請求項1之化合物。 23. 如請求項22之方法,其中該糖尿病為丨型糖尿病。 24. 如請求項22之方法,其中該糖尿病為2型糖尿病。 25. 如請求項22之方法,其中該化合物係與第二治療劑組合 投與。 136781.doc 200932755 26.如請求項25之方法,其中該第二治療劑係選自抗糖尿病 藥、降脂劑/脂質調節劑、治療糖尿病併發症之藥劑、減 肥藥、抗高血壓藥、抗高尿酸血症藥,及治療慢性心臟 衰竭、動脈粥樣硬化或相關病症之藥劑。136781.doc •12-
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US1351707P | 2007-12-13 | 2007-12-13 |
Publications (2)
Publication Number | Publication Date |
---|---|
TW200932755A true TW200932755A (en) | 2009-08-01 |
TWI426081B TWI426081B (zh) | 2014-02-11 |
Family
ID=40754059
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW097148259A TWI426081B (zh) | 2007-12-13 | 2008-12-11 | 苄基苯基環己烷衍生物及使用方法 |
Country Status (16)
Country | Link |
---|---|
US (1) | US8129434B2 (zh) |
EP (1) | EP2230907B1 (zh) |
JP (1) | JP5507464B2 (zh) |
KR (1) | KR101567969B1 (zh) |
CN (1) | CN101938902B (zh) |
AR (2) | AR071268A1 (zh) |
AU (1) | AU2008335080B2 (zh) |
BR (1) | BRPI0819930A2 (zh) |
CA (1) | CA2707909C (zh) |
IL (1) | IL206234A0 (zh) |
NZ (1) | NZ586639A (zh) |
RU (1) | RU2505521C2 (zh) |
TW (1) | TWI426081B (zh) |
UA (1) | UA101004C2 (zh) |
WO (1) | WO2009076550A1 (zh) |
ZA (1) | ZA201004400B (zh) |
Families Citing this family (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2312944B1 (en) * | 2008-07-15 | 2018-09-05 | Theracos, Inc. | Deuterated benzylbenzene derivatives and methods of use |
WO2011107494A1 (de) | 2010-03-03 | 2011-09-09 | Sanofi | Neue aromatische glykosidderivate, diese verbindungen enthaltende arzneimittel und deren verwendung |
US8530413B2 (en) | 2010-06-21 | 2013-09-10 | Sanofi | Heterocyclically substituted methoxyphenyl derivatives with an oxo group, processes for preparation thereof and use thereof as medicaments |
TW201221505A (en) | 2010-07-05 | 2012-06-01 | Sanofi Sa | Aryloxyalkylene-substituted hydroxyphenylhexynoic acids, process for preparation thereof and use thereof as a medicament |
TW201215388A (en) | 2010-07-05 | 2012-04-16 | Sanofi Sa | (2-aryloxyacetylamino)phenylpropionic acid derivatives, processes for preparation thereof and use thereof as medicaments |
TW201215387A (en) | 2010-07-05 | 2012-04-16 | Sanofi Aventis | Spirocyclically substituted 1,3-propane dioxide derivatives, processes for preparation thereof and use thereof as a medicament |
JP5844888B2 (ja) * | 2011-05-26 | 2016-01-20 | テーエフシム | アリール、ヘテロアリール、o−アリール及びo−ヘテロアリールカルバ糖ファミリー |
WO2013037390A1 (en) | 2011-09-12 | 2013-03-21 | Sanofi | 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
WO2013045413A1 (en) | 2011-09-27 | 2013-04-04 | Sanofi | 6-(4-hydroxy-phenyl)-3-alkyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
CN103570671B (zh) * | 2012-09-26 | 2016-03-30 | 上海天慈生物谷生物工程有限公司 | 一种降糖化合物及其制法和应用 |
CN105611920B (zh) | 2013-10-12 | 2021-07-16 | 泰拉科斯萨普有限责任公司 | 羟基-二苯甲烷衍生物的制备 |
US10759729B2 (en) * | 2016-11-07 | 2020-09-01 | The Chinese University Of Hong Kong | Compounds for treating diabetes |
CN116785268A (zh) * | 2022-03-14 | 2023-09-22 | 江苏万邦生化医药集团有限责任公司 | 一种sglt-2抑制剂的药物组合物 |
Family Cites Families (62)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PT68543A (en) * | 1977-09-13 | 1978-10-01 | Pfizer | Process for the preparation of 3-2-hydroxi-4-substituted -phenyl cycloalkanone and cycloalkanol analgesic agents andintermediates therefor |
CN1020944C (zh) | 1990-01-30 | 1993-05-26 | 阿图尔-费希尔股份公司费希尔厂 | 紧固件 |
EP0671953A4 (en) | 1992-11-13 | 1996-01-10 | Univ Ohio State Res Found | ANALOGS OF N- (4-HYDROXYPHENYL) RETINAMIDE-O-GLUCURONIDE ARYLAMIDE. |
WO1998031697A1 (en) | 1997-01-15 | 1998-07-23 | Sankyo Company, Limited | Aryl c-glycoside compounds and sulfated esters thereof |
US6069238A (en) | 1998-09-30 | 2000-05-30 | Eli Lilly And Company | Spirocyclic C-glycosides |
US7407978B2 (en) | 1999-04-06 | 2008-08-05 | Theracos, Inc. | Heterocyclic analogs of diphenylethylene compounds |
US6515117B2 (en) | 1999-10-12 | 2003-02-04 | Bristol-Myers Squibb Company | C-aryl glucoside SGLT2 inhibitors and method |
PH12000002657B1 (en) | 1999-10-12 | 2006-02-21 | Bristol Myers Squibb Co | C-aryl glucoside SGLT2 inhibitors |
US6555519B2 (en) | 2000-03-30 | 2003-04-29 | Bristol-Myers Squibb Company | O-glucosylated benzamide SGLT2 inhibitors and method |
US6683056B2 (en) | 2000-03-30 | 2004-01-27 | Bristol-Myers Squibb Company | O-aryl glucoside SGLT2 inhibitors and method |
CA2429426A1 (en) | 2000-11-17 | 2002-05-23 | Takeda Chemical Industries, Ltd. | Isoxazole derivatives |
TWI255817B (en) | 2001-02-14 | 2006-06-01 | Kissei Pharmaceutical | Glucopyranosyloxybenzylbenzene derivatives and medicinal use thereof |
US6936590B2 (en) | 2001-03-13 | 2005-08-30 | Bristol Myers Squibb Company | C-aryl glucoside SGLT2 inhibitors and method |
DK1385856T3 (da) | 2001-04-11 | 2006-05-15 | Bristol Myers Squibb Co | Aminosyrekomplekser af C-aryl-glucosider til behandling af diabetes og fremgangsmåder |
EP1432720A1 (en) | 2001-09-05 | 2004-06-30 | Bristol-Myers Squibb Company | O-pyrazole glucoside sglt2 inhibitors and method of use |
ATE469161T1 (de) | 2002-08-08 | 2010-06-15 | Kissei Pharmaceutical | Pyrazolderivat, dieses enthaltende medizinische zusammensetzung, medizinische verwendung davon, und zwischenprodukt für dessen herstellung |
NZ535229A (en) | 2002-08-09 | 2006-05-26 | Taisho Pharmaceutical Co Ltd | Aryl 5-thio-beta-D-glucopyranoside derivatives and therapeutic agents for diabetes containing the same |
DE10258008B4 (de) | 2002-12-12 | 2006-02-02 | Sanofi-Aventis Deutschland Gmbh | Heterocyclische Fluorglycosidderivate, diese Verbindungen enthaltende Arzneimittel und Verfahren zur Herstellung dieser Arzneimittel |
DE10258007B4 (de) | 2002-12-12 | 2006-02-09 | Sanofi-Aventis Deutschland Gmbh | Aromatische Fluorglycosidderivate, diese Verbindungen enthaltende Arzneimittel und Verfahren zur Herstellung dieser Arzneimittel |
BR0317929A (pt) | 2003-01-03 | 2006-04-11 | Bristol Myers Squibb Co | métodos de produzir inibidores de sglt2 de glicosìdeo de c-arila |
KR101001848B1 (ko) | 2003-03-14 | 2010-12-17 | 고토부키 세이야쿠 가부시키가이샤 | C-글리코시드 유도체 또는 이의 염, 및 이를 포함하는 의약 조성물 |
JP2004300102A (ja) | 2003-03-31 | 2004-10-28 | Kissei Pharmaceut Co Ltd | 縮合複素環誘導体、それを含有する医薬組成物およびその医薬用途 |
CA2549015A1 (en) | 2003-08-01 | 2005-02-10 | Janssen Pharmaceutica N.V. | Substituted fused heterocyclic c-glycosides |
ME00411B (me) | 2003-08-01 | 2011-10-10 | Tanabe Seiyaku Co | Nova jedinjenja koja imaju inhibitorno dejstvo na transporter glukoze zavistan od natrijuma |
TW200524951A (en) | 2003-08-01 | 2005-08-01 | Janssen Pharmaceutica Nv | Substituted benzimidazole-, benztriazole-, and benzimidazolone-O-glucosides |
DE502004008951D1 (de) | 2003-08-26 | 2009-03-19 | Boehringer Ingelheim Pharma | Glucopyranosyloxy-pyrazole, diese verbindungen enthaltende arzneimittel, deren verwendung und verfahren zu ihrer herstellung |
US7375090B2 (en) | 2003-08-26 | 2008-05-20 | Boehringer Ingelheim International Gmbh | Glucopyranosyloxy-pyrazoles, pharmaceutical compositions containing these compounds, the use thereof and processed for the preparation thereof |
US7371732B2 (en) | 2003-12-22 | 2008-05-13 | Boehringer Ingelheim International Gmbh | Glucopyranosyloxy-substituted aromatic compounds, medicaments containing such compounds, their use and process for their manufacture |
DE10361133A1 (de) | 2003-12-22 | 2005-07-21 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Glucopyranosyloxy-substituierte Aromaten, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
EP1721904A4 (en) | 2004-03-04 | 2010-07-14 | Kissei Pharmaceutical | HETEROCYCLIC DERIVED FADE; MEDICAL COMPOSITION CONTAINING THE DERIVATIVE AND MEDICAL USE |
KR20120007088A (ko) | 2004-03-16 | 2012-01-19 | 베링거 인겔하임 인터내셔날 게엠베하 | 글루코피라노실-치환된 벤졸 유도체, 당해 화합물을 함유하는 약제, 이의 용도 및 이의 제조 방법 |
CA2560005A1 (en) | 2004-03-31 | 2005-10-13 | Kissei Pharmaceutical Co., Ltd. | Phenol derivative, medicinal composition containing the same, and medicinal use thereof |
US7393836B2 (en) | 2004-07-06 | 2008-07-01 | Boehringer Ingelheim International Gmbh | D-xylopyranosyl-substituted phenyl derivatives, medicaments containing such compounds, their use and process for their manufacture |
DE102004034690A1 (de) | 2004-07-17 | 2006-02-02 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Methyliden-D-xylopyranosyl-und Oxo-D-xylopyranosyl-substituierte Phenyle, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
CN101010276B (zh) * | 2004-07-26 | 2011-01-12 | 中外制药株式会社 | 环己烷衍生物、其前体药物及其盐、以及含有它的糖尿病治疗药 |
TW200606129A (en) | 2004-07-26 | 2006-02-16 | Chugai Pharmaceutical Co Ltd | Novel cyclohexane derivative, its prodrug, its salt and diabetic therapeutic agent containing the same |
JP2008508213A (ja) | 2004-07-27 | 2008-03-21 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | D−グルコピラノシル−フェニル置換環状体、そのような化合物を含有する医薬品、それらの使用及びその製造方法 |
WO2006018150A1 (de) * | 2004-08-11 | 2006-02-23 | Boehringer Ingelheim International Gmbh | D-xylopyranosyl-phenyl-substituierte cyclen, diese verbindungen enthaltende arzneimittel, deren verwendung und verfahren zu ihrer herstellung |
AR051446A1 (es) | 2004-09-23 | 2007-01-17 | Bristol Myers Squibb Co | Glucosidos de c-arilo como inhibidores selectivos de transportadores de glucosa (sglt2) |
WO2006035796A1 (ja) | 2004-09-29 | 2006-04-06 | Kissei Pharmaceutical Co., Ltd. | 1-(β-D-グリコピラノシル)-3-置換含窒素ヘテロ環化合物、それを含有する医薬組成物及びその医薬用途 |
DE102004048388A1 (de) | 2004-10-01 | 2006-04-06 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | D-Pyranosyl-substituierte Phenyle, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
ATE407938T1 (de) | 2004-12-16 | 2008-09-15 | Boehringer Ingelheim Int | Glucopyranosyl-substituierte benzen-derivate, medikamente mit solchen verbindungen, ihre verwendung und herstellungsverfahren dafür |
TW200637839A (en) | 2005-01-07 | 2006-11-01 | Taisho Pharmaceutical Co Ltd | 1-thio-d-glucitol derivatives |
TW200637869A (en) | 2005-01-28 | 2006-11-01 | Chugai Pharmaceutical Co Ltd | The spiroketal derivatives and the use as therapeutical agent for diabetes of the same |
CA2595257A1 (en) | 2005-02-23 | 2006-08-31 | Boehringer Ingelheim International Gmbh | Glucopyranosyl-substituted ((hetero)arylethynyl-benzyl)-benzene derivatives and use thereof as sodium-dependent glucose cotransporter 2 (sglt2) inhibitors |
AR053710A1 (es) | 2005-04-11 | 2007-05-16 | Xenon Pharmaceuticals Inc | Compuestos espiroheterociclicos y sus usos como agentes terapeuticos |
ATE453656T1 (de) | 2005-04-15 | 2010-01-15 | Boehringer Ingelheim Int | Glucopyranosyl-substituierte (heteroaryloxy- benzyl)-benzen-derivate als sglt-inhibitoren |
UA91546C2 (uk) | 2005-05-03 | 2010-08-10 | Бьорінгер Інгельхайм Інтернаціональ Гмбх | КРИСТАЛІЧНА ФОРМА 1-ХЛОР-4-(β-D-ГЛЮКОПІРАНОЗ-1-ИЛ)-2-[4-((S)-ТЕТРАГІДРОФУРАН-3-ІЛОКСИ)-БЕНЗИЛ]-БЕНЗОЛУ, СПОСІБ ЇЇ ОДЕРЖАННЯ ТА ЇЇ ЗАСТОСУВАННЯ ПРИ ПРИГОТУВАННІ ЛІКАРСЬКИХ ЗАСОБІВ |
US7723309B2 (en) | 2005-05-03 | 2010-05-25 | Boehringer Ingelheim International Gmbh | Crystalline forms of 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((R)-tetrahydrofuran-3-yloxy)-benzyl]-benzene, a method for its preparation and the use thereof for preparing medicaments |
US7772191B2 (en) | 2005-05-10 | 2010-08-10 | Boehringer Ingelheim International Gmbh | Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives and intermediates therein |
WO2007000445A1 (en) | 2005-06-29 | 2007-01-04 | Boehringer Ingelheim International Gmbh | Glucopyranosyl-substituted benzyl-benzene derivatives, medicaments containing such compounds, their use and process for their manufacture |
DE602006014411D1 (de) | 2005-07-27 | 2010-07-01 | Boehringer Ingelheim Pharma | Glucopyranosyl-substituierte ((hetero)cycloalyklethynyl-benzyl)-benzenderivative und deren verwendung als inhibitoren des natriumabhängigen glucose-cotransporters (sglt) |
GB0516156D0 (en) | 2005-08-05 | 2005-09-14 | Eisai London Res Lab Ltd | JNK inhibitors |
CA2620566A1 (en) | 2005-08-30 | 2007-03-08 | Boehringer Ingelheim International Gmbh | Glucopyranosyl-substituted benzyl-benzene derivatives, medicaments containing such compounds, their use and process for their manufacture |
AU2006289093A1 (en) | 2005-09-08 | 2007-03-15 | Boehringer Ingelheim International Gmbh | Crystalline forms of 1-chloro-4-(beta-D-glucopyranos-1-yl)-2-(4-ethynyl-benzyl)-benzene, methods for its preparation and the use thereof for preparing medicaments |
TWI370818B (en) | 2006-04-05 | 2012-08-21 | Astellas Pharma Inc | Cocrystal of c-glycoside derivative and l-proline |
JP5067644B2 (ja) | 2006-05-19 | 2012-11-07 | 大正製薬株式会社 | C−フェニルグリシト−ル化合物 |
EP2019679B1 (en) * | 2006-05-23 | 2018-06-20 | Theracos, Inc. | Glucose transport inhibitors and methods of use |
US7919598B2 (en) | 2006-06-28 | 2011-04-05 | Bristol-Myers Squibb Company | Crystal structures of SGLT2 inhibitors and processes for preparing same |
US20080027014A1 (en) | 2006-07-28 | 2008-01-31 | Tanabe Seiyaku Co., Ltd. | Novel SGLT inhibitors |
JP5583003B2 (ja) * | 2007-04-02 | 2014-09-03 | セラコス・インコーポレイテッド | ベンジルグルコシド誘導体およびその用途 |
CA2697349C (en) | 2007-08-23 | 2012-04-24 | Theracos, Inc. | Benzylbenzene derivatives and methods of use |
-
2008
- 2008-11-12 UA UAA201008620A patent/UA101004C2/uk unknown
- 2008-12-11 JP JP2010538165A patent/JP5507464B2/ja not_active Expired - Fee Related
- 2008-12-11 TW TW097148259A patent/TWI426081B/zh not_active IP Right Cessation
- 2008-12-11 BR BRPI0819930A patent/BRPI0819930A2/pt not_active IP Right Cessation
- 2008-12-11 AU AU2008335080A patent/AU2008335080B2/en not_active Ceased
- 2008-12-11 CA CA2707909A patent/CA2707909C/en not_active Expired - Fee Related
- 2008-12-11 RU RU2010128940/04A patent/RU2505521C2/ru not_active IP Right Cessation
- 2008-12-11 WO PCT/US2008/086472 patent/WO2009076550A1/en active Application Filing
- 2008-12-11 NZ NZ586639A patent/NZ586639A/en not_active IP Right Cessation
- 2008-12-11 US US12/333,190 patent/US8129434B2/en not_active Expired - Fee Related
- 2008-12-11 KR KR1020107015420A patent/KR101567969B1/ko not_active IP Right Cessation
- 2008-12-11 EP EP08859426.2A patent/EP2230907B1/en active Active
- 2008-12-11 CN CN200880126441.9A patent/CN101938902B/zh not_active Expired - Fee Related
- 2008-12-12 AR ARP080105417A patent/AR071268A1/es not_active Application Discontinuation
-
2010
- 2010-06-07 IL IL206234A patent/IL206234A0/en unknown
- 2010-06-22 ZA ZA2010/04400A patent/ZA201004400B/en unknown
-
2018
- 2018-02-21 AR ARP180100403A patent/AR113211A2/es unknown
Also Published As
Publication number | Publication date |
---|---|
IL206234A0 (en) | 2010-12-30 |
CA2707909A1 (en) | 2009-06-18 |
UA101004C2 (en) | 2013-02-25 |
EP2230907A4 (en) | 2015-04-08 |
EP2230907B1 (en) | 2018-05-09 |
AU2008335080A1 (en) | 2009-06-18 |
AU2008335080B2 (en) | 2014-06-05 |
JP2011506469A (ja) | 2011-03-03 |
CA2707909C (en) | 2016-10-18 |
ZA201004400B (en) | 2014-10-29 |
KR20100098690A (ko) | 2010-09-08 |
AR113211A2 (es) | 2020-02-19 |
RU2505521C2 (ru) | 2014-01-27 |
US20090156516A1 (en) | 2009-06-18 |
CN101938902B (zh) | 2014-07-02 |
BRPI0819930A2 (pt) | 2016-05-17 |
RU2010128940A (ru) | 2012-01-20 |
TWI426081B (zh) | 2014-02-11 |
AR071268A1 (es) | 2010-06-09 |
CN101938902A (zh) | 2011-01-05 |
JP5507464B2 (ja) | 2014-05-28 |
EP2230907A1 (en) | 2010-09-29 |
WO2009076550A1 (en) | 2009-06-18 |
NZ586639A (en) | 2011-06-30 |
US8129434B2 (en) | 2012-03-06 |
KR101567969B1 (ko) | 2015-11-10 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
RU2641905C2 (ru) | Кристаллические формы комплексов, полезные в качестве ингибиторов sglt2, и способы их получения | |
TWI405575B (zh) | 苄基醣苷衍生物及其使用方法 | |
JP5230613B2 (ja) | グルコース輸送体阻害剤およびその使用方法 | |
TWI523652B (zh) | 氘化苄基苯衍生物及使用方法 | |
TWI434691B (zh) | 苄基苯衍生物及使用方法 | |
TWI589295B (zh) | 苄基苯sglt2抑制劑之結晶型 | |
CA2707909C (en) | Benzylphenyl cyclohexane derivatives and methods of use | |
JP2009538339A5 (zh) |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
MM4A | Annulment or lapse of patent due to non-payment of fees |