CA2432985A1 - Piperazine- and piperidine-derivatives as melanocortin receptor agonists - Google Patents
Piperazine- and piperidine-derivatives as melanocortin receptor agonists Download PDFInfo
- Publication number
- CA2432985A1 CA2432985A1 CA002432985A CA2432985A CA2432985A1 CA 2432985 A1 CA2432985 A1 CA 2432985A1 CA 002432985 A CA002432985 A CA 002432985A CA 2432985 A CA2432985 A CA 2432985A CA 2432985 A1 CA2432985 A1 CA 2432985A1
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- CA
- Canada
- Prior art keywords
- compound
- alkyl
- formula
- phenyl
- aryl
- 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.)
- Abandoned
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- 239000000336 melanocortin receptor agonist Substances 0.000 title abstract description 10
- 208000008589 Obesity Diseases 0.000 claims abstract description 11
- 235000020824 obesity Nutrition 0.000 claims abstract description 11
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims description 434
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 191
- 238000000034 method Methods 0.000 claims description 148
- 125000000217 alkyl group Chemical group 0.000 claims description 119
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 102
- 238000005859 coupling reaction Methods 0.000 claims description 102
- 230000008878 coupling Effects 0.000 claims description 98
- 238000010168 coupling process Methods 0.000 claims description 98
- 229910052739 hydrogen Inorganic materials 0.000 claims description 97
- 239000001257 hydrogen Substances 0.000 claims description 96
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 91
- -1 chloro, bromo, iodo, benzyloxy, methoxy Chemical group 0.000 claims description 80
- 125000003118 aryl group Chemical group 0.000 claims description 78
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 70
- 229910052757 nitrogen Inorganic materials 0.000 claims description 62
- 150000002431 hydrogen Chemical class 0.000 claims description 58
- 150000003839 salts Chemical class 0.000 claims description 50
- 125000000623 heterocyclic group Chemical group 0.000 claims description 49
- 125000001424 substituent group Chemical group 0.000 claims description 40
- 229910052760 oxygen Inorganic materials 0.000 claims description 36
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 36
- 239000001301 oxygen Substances 0.000 claims description 33
- 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 32
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 31
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 31
- 229910052799 carbon Inorganic materials 0.000 claims description 31
- 125000001624 naphthyl group Chemical group 0.000 claims description 31
- 125000005843 halogen group Chemical group 0.000 claims description 30
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 28
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 claims description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 25
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 24
- 230000008569 process Effects 0.000 claims description 22
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 20
- 239000008194 pharmaceutical composition Substances 0.000 claims description 19
- 125000001544 thienyl group Chemical group 0.000 claims description 19
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 18
- 125000005842 heteroatom Chemical group 0.000 claims description 18
- 102000004877 Insulin Human genes 0.000 claims description 16
- 108090001061 Insulin Proteins 0.000 claims description 16
- 229940125396 insulin Drugs 0.000 claims description 16
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 15
- 125000003545 alkoxy group Chemical group 0.000 claims description 15
- 150000001412 amines Chemical class 0.000 claims description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
- 239000003054 catalyst Substances 0.000 claims description 14
- 206010057671 Female sexual dysfunction Diseases 0.000 claims description 13
- 241000124008 Mammalia Species 0.000 claims description 12
- 238000004519 manufacturing process Methods 0.000 claims description 12
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 11
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 claims description 10
- 150000002466 imines Chemical class 0.000 claims description 10
- 206010057672 Male sexual dysfunction Diseases 0.000 claims description 9
- 238000006845 Michael addition reaction Methods 0.000 claims description 9
- 239000004480 active ingredient Substances 0.000 claims description 9
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 9
- 239000003937 drug carrier Substances 0.000 claims description 9
- 201000001881 impotence Diseases 0.000 claims description 9
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 9
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 9
- 208000010228 Erectile Dysfunction Diseases 0.000 claims description 8
- 230000002378 acidificating effect Effects 0.000 claims description 8
- 238000005984 hydrogenation reaction Methods 0.000 claims description 8
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 8
- 125000006239 protecting group Chemical group 0.000 claims description 8
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 7
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical group C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 claims description 7
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 6
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 6
- RQEUFEKYXDPUSK-UHFFFAOYSA-N 1-phenylethylamine Chemical compound CC(N)C1=CC=CC=C1 RQEUFEKYXDPUSK-UHFFFAOYSA-N 0.000 claims description 6
- 230000003213 activating effect Effects 0.000 claims description 6
- 239000003638 chemical reducing agent Substances 0.000 claims description 6
- 239000003112 inhibitor Substances 0.000 claims description 6
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 238000010626 work up procedure Methods 0.000 claims description 6
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 5
- 125000001153 fluoro group Chemical group F* 0.000 claims description 5
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 claims description 4
- 150000001768 cations Chemical class 0.000 claims description 4
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 claims description 4
- 239000012279 sodium borohydride Substances 0.000 claims description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 4
- 229940122355 Insulin sensitizer Drugs 0.000 claims description 3
- 229940100389 Sulfonylurea Drugs 0.000 claims description 3
- 239000003529 anticholesteremic agent Substances 0.000 claims description 3
- 229940127226 anticholesterol agent Drugs 0.000 claims description 3
- 229940125898 compound 5 Drugs 0.000 claims description 3
- 150000007529 inorganic bases Chemical class 0.000 claims description 3
- 150000004713 phosphodiesters Chemical class 0.000 claims description 3
- 239000003352 sequestering agent Substances 0.000 claims description 3
- 229940077274 Alpha glucosidase inhibitor Drugs 0.000 claims description 2
- 239000000670 adrenergic alpha-2 receptor antagonist Substances 0.000 claims description 2
- 239000003888 alpha glucosidase inhibitor Substances 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 150000001721 carbon Chemical group 0.000 claims description 2
- 230000003635 deoxygenating effect Effects 0.000 claims description 2
- 239000002660 neuropeptide Y receptor antagonist Substances 0.000 claims description 2
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 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
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims 65
- 101100533877 Hypocrea jecorina (strain QM6a) sor8 gene Proteins 0.000 claims 4
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 claims 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims 1
- 201000001880 Sexual dysfunction Diseases 0.000 abstract description 3
- 231100000872 sexual dysfunction Toxicity 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 399
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 256
- 239000000203 mixture Substances 0.000 description 238
- 238000002360 preparation method Methods 0.000 description 193
- 239000000243 solution Substances 0.000 description 172
- 235000019439 ethyl acetate Nutrition 0.000 description 160
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 128
- 229910001868 water Inorganic materials 0.000 description 93
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 92
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 88
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 85
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 78
- 229940093499 ethyl acetate Drugs 0.000 description 77
- 239000003921 oil Substances 0.000 description 77
- 235000019198 oils Nutrition 0.000 description 77
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 69
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 68
- 239000000047 product Substances 0.000 description 68
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 60
- 239000012267 brine Substances 0.000 description 57
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 57
- 238000006243 chemical reaction Methods 0.000 description 55
- 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 54
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 53
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 50
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 49
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 46
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 41
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 40
- 239000007787 solid Substances 0.000 description 39
- 239000000463 material Substances 0.000 description 38
- 239000002904 solvent Substances 0.000 description 36
- 230000002829 reductive effect Effects 0.000 description 35
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 34
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 34
- 238000005160 1H NMR spectroscopy Methods 0.000 description 32
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 32
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 32
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 31
- 239000000741 silica gel Substances 0.000 description 31
- 229910002027 silica gel Inorganic materials 0.000 description 31
- 239000010410 layer Substances 0.000 description 28
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 26
- 229920006395 saturated elastomer Polymers 0.000 description 26
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 25
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 25
- 238000003818 flash chromatography Methods 0.000 description 25
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 25
- 238000000746 purification Methods 0.000 description 25
- 239000002253 acid Substances 0.000 description 24
- 210000004027 cell Anatomy 0.000 description 24
- 238000007792 addition Methods 0.000 description 23
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 23
- 229940086542 triethylamine Drugs 0.000 description 23
- 230000015572 biosynthetic process Effects 0.000 description 22
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 22
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 22
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 21
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 21
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 21
- 238000010898 silica gel chromatography Methods 0.000 description 21
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 20
- 229910052681 coesite Inorganic materials 0.000 description 20
- 229910052906 cristobalite Inorganic materials 0.000 description 20
- 125000001188 haloalkyl group Chemical group 0.000 description 20
- 239000012044 organic layer Substances 0.000 description 20
- 229910052682 stishovite Inorganic materials 0.000 description 20
- 229910052905 tridymite Inorganic materials 0.000 description 20
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 19
- 239000011541 reaction mixture Substances 0.000 description 19
- 238000003756 stirring Methods 0.000 description 19
- 241001465754 Metazoa Species 0.000 description 17
- 238000012799 strong cation exchange Methods 0.000 description 17
- 235000017557 sodium bicarbonate Nutrition 0.000 description 16
- 101150041968 CDC13 gene Proteins 0.000 description 15
- 238000003786 synthesis reaction Methods 0.000 description 15
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
- 239000000556 agonist Substances 0.000 description 14
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 14
- 238000004587 chromatography analysis Methods 0.000 description 14
- 238000010511 deprotection reaction Methods 0.000 description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- 238000004809 thin layer chromatography Methods 0.000 description 14
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 13
- GWVMLCQWXVFZCN-UHFFFAOYSA-N isoindoline Chemical compound C1=CC=C2CNCC2=C1 GWVMLCQWXVFZCN-UHFFFAOYSA-N 0.000 description 13
- 235000019341 magnesium sulphate Nutrition 0.000 description 13
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- 238000003556 assay Methods 0.000 description 12
- 150000002148 esters Chemical class 0.000 description 12
- 239000007858 starting material Substances 0.000 description 12
- VADKRMSMGWJZCF-UHFFFAOYSA-N 2-bromophenol Chemical compound OC1=CC=CC=C1Br VADKRMSMGWJZCF-UHFFFAOYSA-N 0.000 description 11
- 108090000950 Melanocortin Receptors Proteins 0.000 description 11
- 102000004378 Melanocortin Receptors Human genes 0.000 description 11
- 239000006260 foam Substances 0.000 description 11
- 230000037406 food intake Effects 0.000 description 11
- 235000012631 food intake Nutrition 0.000 description 11
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 11
- 238000006268 reductive amination reaction Methods 0.000 description 11
- 238000010992 reflux Methods 0.000 description 11
- 229910052938 sodium sulfate Inorganic materials 0.000 description 11
- 235000011152 sodium sulphate Nutrition 0.000 description 11
- 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 11
- NAVNZNNUGSIEPA-UHFFFAOYSA-N 4-(2-hydroxyphenyl)piperazine-1-carboxylic acid Chemical compound C1CN(C(=O)O)CCN1C1=CC=CC=C1O NAVNZNNUGSIEPA-UHFFFAOYSA-N 0.000 description 10
- 239000007821 HATU Substances 0.000 description 10
- 238000005481 NMR spectroscopy Methods 0.000 description 10
- 241000700159 Rattus Species 0.000 description 10
- 239000012230 colorless oil Substances 0.000 description 10
- 229960004132 diethyl ether Drugs 0.000 description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 10
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- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
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- 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
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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
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- 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
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- 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
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- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
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- Life Sciences & Earth Sciences (AREA)
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- Chemical Kinetics & Catalysis (AREA)
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- 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 (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US26347101P | 2001-01-23 | 2001-01-23 | |
| US60/263,471 | 2001-01-23 | ||
| PCT/US2002/000515 WO2002059117A1 (en) | 2001-01-23 | 2002-01-23 | Piperazine- and piperidine-derivatives as melanocortin receptor agonists |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2432985A1 true CA2432985A1 (en) | 2002-08-01 |
Family
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Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002432985A Abandoned CA2432985A1 (en) | 2001-01-23 | 2002-01-23 | Piperazine- and piperidine-derivatives as melanocortin receptor agonists |
| CA002431996A Abandoned CA2431996A1 (en) | 2001-01-23 | 2002-01-23 | Melanocortin receptor agonists |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002431996A Abandoned CA2431996A1 (en) | 2001-01-23 | 2002-01-23 | Melanocortin receptor agonists |
Country Status (8)
| Country | Link |
|---|---|
| US (2) | US7186715B2 (enExample) |
| EP (2) | EP1370558B1 (enExample) |
| JP (2) | JP2004523529A (enExample) |
| AT (2) | ATE301652T1 (enExample) |
| CA (2) | CA2432985A1 (enExample) |
| 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 |
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2002
- 2002-01-23 EP EP02701922A patent/EP1370558B1/en not_active Expired - Lifetime
- 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
- 2002-01-23 AT AT02714719T patent/ATE301652T1/de not_active IP Right Cessation
- 2002-01-23 WO PCT/US2002/000515 patent/WO2002059117A1/en not_active Ceased
- 2002-01-23 AT AT02701922T patent/ATE302773T1/de not_active IP Right Cessation
- 2002-01-23 JP JP2002559419A patent/JP2004523530A/ja active Pending
- 2002-01-23 CA CA002432985A patent/CA2432985A1/en not_active Abandoned
- 2002-01-23 US US10/466,121 patent/US7291619B2/en not_active Expired - Fee Related
- 2002-01-23 ES ES02714719T patent/ES2246390T3/es not_active Expired - Lifetime
- 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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| DE60205727D1 (de) | 2005-09-29 |
| JP2004523529A (ja) | 2004-08-05 |
| EP1368340B1 (en) | 2005-08-10 |
| WO2002059108A1 (en) | 2002-08-01 |
| 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 |
| 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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