UA80437C2 - Diaryl ethers as opioid receptor antagonist - Google Patents
Diaryl ethers as opioid receptor antagonist Download PDFInfo
- Publication number
- UA80437C2 UA80437C2 UAA200502384A UA2005002384A UA80437C2 UA 80437 C2 UA80437 C2 UA 80437C2 UA A200502384 A UAA200502384 A UA A200502384A UA 2005002384 A UA2005002384 A UA 2005002384A UA 80437 C2 UA80437 C2 UA 80437C2
- Authority
- UA
- Ukraine
- Prior art keywords
- phenoxy
- nicotinamide
- methyl
- ethyl
- phenyl
- Prior art date
Links
- 229940123257 Opioid receptor antagonist Drugs 0.000 title description 4
- 239000003401 opiate antagonist Substances 0.000 title description 2
- 150000001987 diarylethers Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 421
- 208000008589 Obesity Diseases 0.000 claims abstract description 40
- 235000020824 obesity Nutrition 0.000 claims abstract description 40
- 150000003839 salts Chemical class 0.000 claims abstract description 30
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 28
- 201000010099 disease Diseases 0.000 claims abstract description 23
- 239000012453 solvate Substances 0.000 claims abstract description 17
- 230000002265 prevention Effects 0.000 claims abstract description 12
- 239000011570 nicotinamide Substances 0.000 claims description 391
- 229960003966 nicotinamide Drugs 0.000 claims description 391
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 51
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 43
- 230000037396 body weight Effects 0.000 claims description 9
- 150000001408 amides Chemical class 0.000 claims description 8
- 206010012601 diabetes mellitus Diseases 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 239000003085 diluting agent Substances 0.000 claims description 7
- 125000004897 3-methylbutylamino group Chemical group CC(CCN*)C 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 6
- 229910052748 manganese Inorganic materials 0.000 claims description 6
- 208000024891 symptom Diseases 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 5
- 125000004911 3,3-dimethylbutylamino group Chemical group CC(CCN*)(C)C 0.000 claims description 4
- NYFIRDWZRSBSFQ-UHFFFAOYSA-N 5-[2-fluoro-4-[(pentylamino)methyl]phenoxy]pyrazine-2-carboxamide Chemical compound FC1=CC(CNCCCCC)=CC=C1OC1=CN=C(C(N)=O)C=N1 NYFIRDWZRSBSFQ-UHFFFAOYSA-N 0.000 claims description 4
- 208000031226 Hyperlipidaemia Diseases 0.000 claims description 4
- 229940079593 drug Drugs 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 229940126601 medicinal product Drugs 0.000 claims description 4
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 4
- KXIFIKGCMNZIRR-UHFFFAOYSA-N 5-[2-methoxy-4-[(pentylamino)methyl]phenoxy]pyrazine-2-carboxamide Chemical compound COC1=CC(CNCCCCC)=CC=C1OC1=CN=C(C(N)=O)C=N1 KXIFIKGCMNZIRR-UHFFFAOYSA-N 0.000 claims description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 3
- 239000000945 filler Substances 0.000 claims description 3
- COOCONHDRCJRDK-UHFFFAOYSA-N 6-[2,3-difluoro-4-[(pentylamino)methyl]phenoxy]pyridine-3-carboxamide Chemical compound FC1=C(F)C(CNCCCCC)=CC=C1OC1=CC=C(C(N)=O)C=N1 COOCONHDRCJRDK-UHFFFAOYSA-N 0.000 claims description 2
- 201000001320 Atherosclerosis Diseases 0.000 claims description 2
- 206010012689 Diabetic retinopathy Diseases 0.000 claims description 2
- 201000001421 hyperglycemia Diseases 0.000 claims description 2
- 208000020346 hyperlipoproteinemia Diseases 0.000 claims description 2
- 208000006575 hypertriglyceridemia Diseases 0.000 claims description 2
- 229940095064 tartrate Drugs 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- SAJFMMKQYCEDNF-UHFFFAOYSA-N COC1=C(OC=2N=CC(=NC=2)C(=O)O)C=CC(=C1)CNCCCCC Chemical compound COC1=C(OC=2N=CC(=NC=2)C(=O)O)C=CC(=C1)CNCCCCC SAJFMMKQYCEDNF-UHFFFAOYSA-N 0.000 claims 1
- 241000511343 Chondrostoma nasus Species 0.000 claims 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims 1
- 238000012876 topography Methods 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 146
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 310
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 221
- 238000005481 NMR spectroscopy Methods 0.000 description 190
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- 238000000034 method Methods 0.000 description 181
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- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 142
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 123
- 238000001819 mass spectrum Methods 0.000 description 114
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 105
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- 239000011541 reaction mixture Substances 0.000 description 87
- 239000000741 silica gel Substances 0.000 description 85
- 229910002027 silica gel Inorganic materials 0.000 description 85
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 84
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 75
- 238000000132 electrospray ionisation Methods 0.000 description 71
- 235000019439 ethyl acetate Nutrition 0.000 description 71
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 68
- 239000000243 solution Substances 0.000 description 67
- DFPAKSUCGFBDDF-ZQBYOMGUSA-N [14c]-nicotinamide Chemical compound N[14C](=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-ZQBYOMGUSA-N 0.000 description 66
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- 239000007787 solid Substances 0.000 description 59
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 54
- 239000012299 nitrogen atmosphere Substances 0.000 description 52
- 239000012043 crude product Substances 0.000 description 51
- 239000001257 hydrogen Substances 0.000 description 48
- 229910052739 hydrogen Inorganic materials 0.000 description 48
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- 238000007787 electrohydrodynamic spraying Methods 0.000 description 44
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- 125000001424 substituent group Chemical group 0.000 description 40
- 238000004587 chromatography analysis Methods 0.000 description 39
- 239000000047 product Substances 0.000 description 39
- 125000003118 aryl group Chemical group 0.000 description 38
- 238000003818 flash chromatography Methods 0.000 description 38
- 150000002431 hydrogen Chemical class 0.000 description 36
- WMRYYTSBKKACAN-UHFFFAOYSA-N 6-(4-formylphenoxy)pyridine-3-carboxamide Chemical compound N1=CC(C(=O)N)=CC=C1OC1=CC=C(C=O)C=C1 WMRYYTSBKKACAN-UHFFFAOYSA-N 0.000 description 35
- 238000004544 sputter deposition Methods 0.000 description 35
- 239000002904 solvent Substances 0.000 description 34
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 33
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 32
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 32
- 229960000583 acetic acid Drugs 0.000 description 31
- 229910052736 halogen Inorganic materials 0.000 description 31
- 150000002367 halogens Chemical class 0.000 description 31
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- 238000006268 reductive amination reaction Methods 0.000 description 29
- 238000012360 testing method Methods 0.000 description 28
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- 239000011572 manganese Substances 0.000 description 27
- 229910052757 nitrogen Inorganic materials 0.000 description 27
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- 125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 26
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 21
- 239000007858 starting material Substances 0.000 description 21
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Classifications
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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 ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
- C07D213/643—2-Phenoxypyridines; Derivatives thereof
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- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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- C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/46—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
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US7381719B2 (en) * | 2002-09-19 | 2008-06-03 | Eli Lilly And Company | Diaryl ethers as opioid receptor antagonist |
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MXPA05006567A (es) | 2002-12-20 | 2005-08-16 | Glaxo Group Ltd | Derivados de benzazepina para el tratamiento de trastornos neurologicos. |
US7399774B2 (en) | 2003-03-07 | 2008-07-15 | Eli Lilly And Company | 6-substituted nicotinamide derivatives as opioid receptor antagonists |
CN1874991A (zh) | 2003-08-29 | 2006-12-06 | 小野药品工业株式会社 | 能够结合s1p受体的化合物及其药物用途 |
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JP2007516256A (ja) * | 2003-12-12 | 2007-06-21 | イーライ リリー アンド カンパニー | オピオイド受容体拮抗物質 |
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US8207147B2 (en) | 2003-12-24 | 2012-06-26 | Prosidion Limited | Heterocyclic derivatives as GPCR receptor agonists |
US7288543B2 (en) | 2004-03-12 | 2007-10-30 | Eli Lilly And Company | Opioid receptor antagonists |
ATE475640T1 (de) | 2004-03-12 | 2010-08-15 | Lilly Co Eli | Antagonisten des opioidrezeptors |
JP2007529523A (ja) | 2004-03-15 | 2007-10-25 | イーライ リリー アンド カンパニー | 肥満症を治療するためのオピオイド受容体拮抗物質としての4−(5−アミノメチル)−インドール−1−イルメチル)−ベンズアミド誘導体および関連化合物 |
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US7786141B2 (en) * | 2004-08-19 | 2010-08-31 | Vertex Pharmaceuticals Incorporated | Dihydrospiroindene modulators of muscarinic receptors |
AU2005309365B2 (en) * | 2004-11-29 | 2011-10-06 | Vertex Pharmaceuticals Incorporated | Modulators of muscarinic receptors |
JP4318087B2 (ja) * | 2004-12-13 | 2009-08-19 | 小野薬品工業株式会社 | アミノカルボン酸誘導体およびその医薬用途 |
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