ES2246390T3 - Derivados de piperazina como agonistas del receptor de melanocortina. - Google Patents
Derivados de piperazina como agonistas del receptor de melanocortina.Info
- Publication number
- ES2246390T3 ES2246390T3 ES02714719T ES02714719T ES2246390T3 ES 2246390 T3 ES2246390 T3 ES 2246390T3 ES 02714719 T ES02714719 T ES 02714719T ES 02714719 T ES02714719 T ES 02714719T ES 2246390 T3 ES2246390 T3 ES 2246390T3
- Authority
- ES
- Spain
- Prior art keywords
- compound
- baselineskip
- formula
- mmol
- phenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 239000000556 agonist Substances 0.000 title description 20
- 206010057671 Female sexual dysfunction Diseases 0.000 claims abstract description 12
- 208000008589 Obesity Diseases 0.000 claims abstract description 12
- 235000020824 obesity Nutrition 0.000 claims abstract description 12
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 11
- 206010057672 Male sexual dysfunction Diseases 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims description 425
- 238000000034 method Methods 0.000 claims description 112
- 125000000217 alkyl group Chemical group 0.000 claims description 93
- 238000005859 coupling reaction Methods 0.000 claims description 62
- 125000000623 heterocyclic group Chemical group 0.000 claims description 62
- 238000010168 coupling process Methods 0.000 claims description 59
- 230000008878 coupling Effects 0.000 claims description 58
- 229910052739 hydrogen Inorganic materials 0.000 claims description 57
- 239000001257 hydrogen Substances 0.000 claims description 56
- 239000000460 chlorine Substances 0.000 claims description 55
- 150000003839 salts Chemical class 0.000 claims description 46
- 125000003118 aryl group Chemical group 0.000 claims description 44
- 239000002253 acid Substances 0.000 claims description 43
- 125000001072 heteroaryl group Chemical group 0.000 claims description 43
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 40
- 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 claims description 36
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 34
- 150000002431 hydrogen Chemical class 0.000 claims description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- 125000001424 substituent group Chemical group 0.000 claims description 24
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 23
- 229910052757 nitrogen Inorganic materials 0.000 claims description 22
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 21
- 150000001412 amines Chemical class 0.000 claims description 20
- 102000004877 Insulin Human genes 0.000 claims description 18
- 108090001061 Insulin Proteins 0.000 claims description 18
- 125000003545 alkoxy group Chemical group 0.000 claims description 18
- 125000005843 halogen group Chemical group 0.000 claims description 18
- 229940125396 insulin Drugs 0.000 claims description 18
- 239000008194 pharmaceutical composition Substances 0.000 claims description 16
- 125000001188 haloalkyl group Chemical group 0.000 claims description 14
- 238000004519 manufacturing process Methods 0.000 claims description 13
- 241000124008 Mammalia Species 0.000 claims description 12
- 230000004913 activation Effects 0.000 claims description 10
- 239000003112 inhibitor Substances 0.000 claims description 10
- 125000004043 oxo group Chemical group O=* 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 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 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- 238000005984 hydrogenation reaction Methods 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 7
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
- 239000003960 organic solvent Substances 0.000 claims description 7
- 125000001544 thienyl group Chemical group 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 5
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 125000001153 fluoro group Chemical group F* 0.000 claims description 5
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 5
- 125000001624 naphthyl group Chemical group 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- 230000002378 acidificating effect Effects 0.000 claims description 4
- 150000001768 cations Chemical class 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- 239000004615 ingredient Substances 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- 238000006845 Michael addition reaction Methods 0.000 claims description 3
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 3
- 230000007423 decrease Effects 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 150000007529 inorganic bases Chemical class 0.000 claims description 3
- 150000004713 phosphodiesters Chemical class 0.000 claims description 3
- 102000004286 Hydroxymethylglutaryl CoA Reductases Human genes 0.000 claims description 2
- 108090000895 Hydroxymethylglutaryl CoA Reductases Proteins 0.000 claims description 2
- 239000000670 adrenergic alpha-2 receptor antagonist Substances 0.000 claims description 2
- 150000001721 carbon Chemical group 0.000 claims description 2
- 229940125898 compound 5 Drugs 0.000 claims description 2
- 230000001351 cycling effect Effects 0.000 claims description 2
- 230000001856 erectile effect Effects 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 239000002660 neuropeptide Y receptor antagonist Substances 0.000 claims description 2
- 239000003352 sequestering agent Substances 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
- 229940126158 β3 adrenergic receptor agonist Drugs 0.000 claims description 2
- 230000004064 dysfunction Effects 0.000 claims 1
- RISUTSCZAANJJQ-UHFFFAOYSA-N sulfinylurea Chemical compound NC(=O)N=S=O RISUTSCZAANJJQ-UHFFFAOYSA-N 0.000 claims 1
- 239000000336 melanocortin receptor agonist Substances 0.000 abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 409
- 238000002360 preparation method Methods 0.000 description 299
- 239000000243 solution Substances 0.000 description 242
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 228
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 221
- 239000000203 mixture Substances 0.000 description 206
- 235000019439 ethyl acetate Nutrition 0.000 description 169
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 161
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 130
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 104
- 238000006243 chemical reaction Methods 0.000 description 89
- -1 ob / ob Proteins 0.000 description 82
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 80
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 78
- 239000012267 brine Substances 0.000 description 75
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 75
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 69
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 67
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 66
- 229910052938 sodium sulfate Inorganic materials 0.000 description 63
- 235000011152 sodium sulphate Nutrition 0.000 description 63
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 62
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 62
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 62
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 62
- 238000003756 stirring Methods 0.000 description 59
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 57
- 239000007832 Na2SO4 Substances 0.000 description 56
- 239000003921 oil Substances 0.000 description 48
- 235000019198 oils Nutrition 0.000 description 48
- 238000000746 purification Methods 0.000 description 44
- 239000000377 silicon dioxide Substances 0.000 description 43
- 239000007787 solid Substances 0.000 description 43
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 41
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 41
- 229910052681 coesite Inorganic materials 0.000 description 39
- 229910052906 cristobalite Inorganic materials 0.000 description 39
- 235000012239 silicon dioxide Nutrition 0.000 description 39
- 229910052682 stishovite Inorganic materials 0.000 description 39
- 229910052905 tridymite Inorganic materials 0.000 description 39
- 239000000047 product Substances 0.000 description 38
- 238000005481 NMR spectroscopy Methods 0.000 description 34
- ZHGNHOOVYPHPNJ-UHFFFAOYSA-N Amigdalin Chemical compound FC(F)(F)C(=O)OCC1OC(OCC2OC(OC(C#N)C3=CC=CC=C3)C(OC(=O)C(F)(F)F)C(OC(=O)C(F)(F)F)C2OC(=O)C(F)(F)F)C(OC(=O)C(F)(F)F)C(OC(=O)C(F)(F)F)C1OC(=O)C(F)(F)F ZHGNHOOVYPHPNJ-UHFFFAOYSA-N 0.000 description 33
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 33
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 33
- 239000000741 silica gel Substances 0.000 description 33
- 229910002027 silica gel Inorganic materials 0.000 description 33
- 238000003818 flash chromatography Methods 0.000 description 32
- 239000000463 material Substances 0.000 description 32
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 32
- 238000004587 chromatography analysis Methods 0.000 description 31
- 230000002829 reductive effect Effects 0.000 description 31
- 229920006395 saturated elastomer Polymers 0.000 description 29
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 25
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 25
- 235000017557 sodium bicarbonate Nutrition 0.000 description 25
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 25
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 23
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 23
- 238000007792 addition Methods 0.000 description 23
- 210000004027 cell Anatomy 0.000 description 22
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 22
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 21
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 20
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 20
- 239000002904 solvent Substances 0.000 description 20
- 239000008346 aqueous phase Substances 0.000 description 19
- 239000000284 extract Substances 0.000 description 19
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 18
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- 239000012299 nitrogen atmosphere Substances 0.000 description 18
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- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 17
- 108090000950 Melanocortin Receptors Proteins 0.000 description 16
- 102000004378 Melanocortin Receptors Human genes 0.000 description 16
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 16
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 16
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 16
- 235000019341 magnesium sulphate Nutrition 0.000 description 16
- 239000012071 phase Substances 0.000 description 16
- 239000011734 sodium Substances 0.000 description 16
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 15
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 15
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- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 15
- 230000015572 biosynthetic process Effects 0.000 description 15
- LNDQGWAWYKFYAO-UHFFFAOYSA-N tert-butyl 4-(2-aminophenyl)piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C1=CC=CC=C1N LNDQGWAWYKFYAO-UHFFFAOYSA-N 0.000 description 15
- 238000004809 thin layer chromatography Methods 0.000 description 15
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- 239000002585 base Substances 0.000 description 14
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- 229910004298 SiO 2 Inorganic materials 0.000 description 13
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 13
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 13
- 239000003981 vehicle Substances 0.000 description 13
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 description 12
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 11
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- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 10
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 10
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
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- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 9
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
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- 239000007821 HATU Substances 0.000 description 8
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Classifications
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- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
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- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
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- Chemical Kinetics & Catalysis (AREA)
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- Engineering & Computer Science (AREA)
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- Pregnancy & Childbirth (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Indole Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
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| US26347101P | 2001-01-23 | 2001-01-23 | |
| US263471P | 2001-01-23 |
Publications (1)
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| ES2246390T3 true ES2246390T3 (es) | 2006-02-16 |
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| ES02714719T Expired - Lifetime ES2246390T3 (es) | 2001-01-23 | 2002-01-23 | Derivados de piperazina como agonistas del receptor de melanocortina. |
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| ES02701922T Expired - Lifetime ES2247298T3 (es) | 2001-01-23 | 2002-01-23 | Derivados de piperazina y piperidina como agonistas del receptor de melanocortina. |
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| JP (2) | JP2004523529A (enExample) |
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| DE (2) | DE60205727T2 (enExample) |
| ES (2) | ES2247298T3 (enExample) |
| WO (2) | WO2002059117A1 (enExample) |
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| USRE46117E1 (en) | 1999-12-22 | 2016-08-23 | Teva Pharmaceuticals International Gmbh | Modulators of dopamine neurotransmission |
| SE9904723D0 (sv) | 1999-12-22 | 1999-12-22 | Carlsson A Research Ab | New modulators of dopamine neurotransmission II |
| SE9904724D0 (sv) | 1999-12-22 | 1999-12-22 | Carlsson A Research Ab | New modulators of dopamine neurotransmission I |
| CA2433025A1 (en) | 2001-01-23 | 2002-08-01 | Chaoyu Xie | Substituted piperidines/piperazines as melanocortin receptor agonists |
| EP1370558B1 (en) | 2001-01-23 | 2005-08-24 | Eli Lilly And Company | Piperazine- and piperidine-derivatives as melanocortin receptor agonists |
| EP1358163A1 (en) | 2001-01-23 | 2003-11-05 | Eli Lilly And Company | Melanocortin receptor agonists |
| HUP0303484A2 (hu) | 2001-03-02 | 2004-01-28 | Bristol-Myers Squibb Company | Melanokortin receptor modulátoraiként hasznos vegyületek és a vegyületeket tartalmazó gyógyszerkészítmények |
| US6911447B2 (en) | 2001-04-25 | 2005-06-28 | The Procter & Gamble Company | Melanocortin receptor ligands |
| US7115607B2 (en) * | 2001-07-25 | 2006-10-03 | Amgen Inc. | Substituted piperazinyl amides and methods of use |
| US6977264B2 (en) | 2001-07-25 | 2005-12-20 | Amgen Inc. | Substituted piperidines and methods of use |
| US7456184B2 (en) | 2003-05-01 | 2008-11-25 | Palatin Technologies Inc. | Melanocortin receptor-specific compounds |
| US7354923B2 (en) | 2001-08-10 | 2008-04-08 | Palatin Technologies, Inc. | Piperazine melanocortin-specific compounds |
| JP2005504043A (ja) | 2001-08-10 | 2005-02-10 | パラチン テクノロジーズ インク. | 生物学的に活性な金属ペプチド類のペプチド模倣体類 |
| UA81749C2 (uk) * | 2001-10-04 | 2008-02-11 | Х. Луннбек А/С | Фенілпіперазинові похідні як інгібітори зворотного захоплення серотоніну |
| ES2274201T3 (es) | 2002-01-23 | 2007-05-16 | Eli Lilly And Company | Agonistas del receptor de melanocortina. |
| US7026335B2 (en) | 2002-04-30 | 2006-04-11 | The Procter & Gamble Co. | Melanocortin receptor ligands |
| MXPA04011093A (es) * | 2002-05-10 | 2005-02-14 | Neurocrine Biosciences Inc | Piperazina sustituida como ligandos de receptores de melanocortina. |
| US7105526B2 (en) | 2002-06-28 | 2006-09-12 | Banyu Pharmaceuticals Co., Ltd. | Benzimidazole derivatives |
| CA2498272A1 (en) | 2002-09-11 | 2004-03-25 | Merck & Co., Inc. | Piperazine urea derivatives as melanocortin-4 receptor agonists |
| TW200504033A (en) * | 2002-10-23 | 2005-02-01 | Procter & Gamble | Melanocortin receptor ligands |
| WO2004081643A1 (en) * | 2002-12-20 | 2004-09-23 | Kaiser Aerospace & Electronics Corp. | Lenslet array with polarization conversion |
| US7772188B2 (en) | 2003-01-28 | 2010-08-10 | Ironwood Pharmaceuticals, Inc. | Methods and compositions for the treatment of gastrointestinal disorders |
| WO2004078717A1 (en) | 2003-03-03 | 2004-09-16 | Merck & Co., Inc. | Acylated piperazine derivatives as melanocortin-4 receptor agonists |
| US20060178403A1 (en) * | 2003-03-07 | 2006-08-10 | Neurocrine Biosciences, Inc. | Melanin-concentrating hormone receptor antagonists and compositions and methods related thereto |
| EP1608373A4 (en) | 2003-03-19 | 2010-09-29 | Exelixis Inc | TIE-2 MODULATORS AND USE METHOD |
| EP1468999A1 (en) * | 2003-03-20 | 2004-10-20 | MyoContract Ltd. | Substituted piperidine and piperazine derivatives as melanocortin-4 receptor modulators |
| EP1460069A1 (en) * | 2003-03-20 | 2004-09-22 | MyoContract Ltd. | Substituted cyclohexyl and piperidinyl derivatives as melanocortin-4 receptor modulators |
| AU2004226452B2 (en) | 2003-03-26 | 2008-07-24 | Merck Sharp & Dohme Corp. | Bicyclic piperidine derivatives as melanocortin-4 receptor agonists |
| JP2007523861A (ja) * | 2003-06-20 | 2007-08-23 | アリーナ ファーマシューティカルズ, インコーポレイテッド | N−フェニル−ピペラジン誘導体および5ht2cレセプター関連疾患の予防方法または処置方法 |
| CA2551037A1 (en) | 2003-09-22 | 2005-03-31 | Banyu Pharmaceutical Co., Ltd. | Novel piperidine derivative |
| US20050192286A1 (en) * | 2003-10-22 | 2005-09-01 | Neurocrine Biosciences, Inc. | Ligands of melanocortin receptors and compositions and methods related thereto |
| WO2005042516A2 (en) * | 2003-10-22 | 2005-05-12 | Neurocrine Biosciences, Inc. | Ligands of melanocortin receptors and compositions and methods related thereto |
| EP1538159A1 (en) * | 2003-12-05 | 2005-06-08 | Santhera Pharmaceuticals (Schweiz) GmbH | Substituted N-benzyl-lactam derivatives as melanocortin-4 receptor agonists |
| CN100526301C (zh) * | 2003-12-26 | 2009-08-12 | 卫材R&D管理有限公司 | 1,2-二(环式基)取代苯化合物 |
| MY140489A (en) * | 2003-12-26 | 2009-12-31 | Eisai R&D Man Co Ltd | 1,2-di (cyclic) substituted benzene compounds |
| US7410971B2 (en) * | 2003-12-26 | 2008-08-12 | Eisai R&D Management Co., Ltd. | 1,2-di(cyclic)substituted benzene compounds |
| US20060276465A1 (en) * | 2003-12-26 | 2006-12-07 | Eisai R&D Management Co., Ltd. | 1,2-di(cyclic) substituted benzene compounds |
| WO2005097127A2 (en) | 2004-04-02 | 2005-10-20 | Merck & Co., Inc. | Method of treating men with metabolic and anthropometric disorders |
| US7851629B2 (en) | 2004-06-08 | 2010-12-14 | Nsab, Filial Af Neurosearch Sweden Ab, Sverige | Disubstituted phenylpiperidines as modulators of dopamine and serotonin neurotransmission |
| DK1773772T3 (da) * | 2004-06-08 | 2010-09-13 | Nsab Af Neurosearch Sweden Ab | Nye disubstituerede phenylpiperidiner/piperaziner som modulatorer af dopaminneurotransmission |
| KR101245075B1 (ko) | 2004-06-08 | 2013-03-18 | 엔에스아베 필리알 아프 뉴로서치 스웨덴 아베 스베리게 | 도파민 신경전달의 모듈레이터로서 신 2기치환된페닐피페리딘/피페라진 |
| RU2366654C2 (ru) * | 2004-06-08 | 2009-09-10 | ЭнЭсЭйБи, ФИЛИАЛ АФ НЕУРОСЕРЧ СВИДЕН АБ, СВЕРИЙЕ | Новые дизамещенные фенилпиперидины/пиперазины в качестве модуляторов допаминовой нейротрансмиссии |
| SE0401465D0 (sv) | 2004-06-08 | 2004-06-08 | Carlsson A Research Ab | New substituted piperdines as modulators of dopamine neurotransmission |
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2002
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- 2002-01-23 DE DE60205727T patent/DE60205727T2/de not_active Expired - Fee Related
- 2002-01-23 US US10/466,248 patent/US7186715B2/en not_active Expired - Fee Related
- 2002-01-23 DE DE60205465T patent/DE60205465T2/de not_active Expired - Fee Related
- 2002-01-23 ES ES02701922T patent/ES2247298T3/es not_active Expired - Lifetime
- 2002-01-23 JP JP2002559410A patent/JP2004523529A/ja active Pending
- 2002-01-23 EP EP02714719A patent/EP1368340B1/en not_active Expired - Lifetime
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- 2002-01-23 AT AT02701922T patent/ATE302773T1/de not_active IP Right Cessation
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- 2002-01-23 WO PCT/US2002/000517 patent/WO2002059108A1/en not_active Ceased
- 2002-01-23 CA CA002431996A patent/CA2431996A1/en not_active Abandoned
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| ATE302773T1 (de) | 2005-09-15 |
| CA2431996A1 (en) | 2002-08-01 |
| US20040082590A1 (en) | 2004-04-29 |
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| JP2004523529A (ja) | 2004-08-05 |
| EP1368340B1 (en) | 2005-08-10 |
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| WO2002059117A1 (en) | 2002-08-01 |
| ATE301652T1 (de) | 2005-08-15 |
| WO2002059117A8 (en) | 2003-11-06 |
| DE60205727T2 (de) | 2006-06-29 |
| US7291619B2 (en) | 2007-11-06 |
| DE60205465T2 (de) | 2006-04-20 |
| JP2004523530A (ja) | 2004-08-05 |
| WO2002059108A8 (en) | 2003-11-06 |
| EP1370558A1 (en) | 2003-12-17 |
| ES2247298T3 (es) | 2006-03-01 |
| CA2432985A1 (en) | 2002-08-01 |
| EP1368340A1 (en) | 2003-12-10 |
| DE60205465D1 (de) | 2005-09-15 |
| US7186715B2 (en) | 2007-03-06 |
| US20040092507A1 (en) | 2004-05-13 |
| EP1370558B1 (en) | 2005-08-24 |
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