EP0901484A1 - Substituierte 1, 3-benzodioxole - Google Patents
Substituierte 1, 3-benzodioxoleInfo
- Publication number
- EP0901484A1 EP0901484A1 EP97924720A EP97924720A EP0901484A1 EP 0901484 A1 EP0901484 A1 EP 0901484A1 EP 97924720 A EP97924720 A EP 97924720A EP 97924720 A EP97924720 A EP 97924720A EP 0901484 A1 EP0901484 A1 EP 0901484A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- propyl
- phenyl
- chloro
- dioxole
- hydroxy
- 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.)
- Withdrawn
Links
- 150000005529 1,3-benzodioxoles Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 285
- 150000003839 salts Chemical class 0.000 claims abstract description 129
- 238000000034 method Methods 0.000 claims abstract description 96
- -1 arylakyl Chemical group 0.000 claims abstract description 81
- 239000001257 hydrogen Substances 0.000 claims abstract description 81
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 81
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 39
- 239000000203 mixture Substances 0.000 claims abstract description 35
- 125000003118 aryl group Chemical group 0.000 claims abstract description 32
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 24
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 24
- 125000006539 C12 alkyl 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])C([H])([H])C([H])([H])* 0.000 claims abstract description 21
- 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 abstract description 19
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 18
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 11
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 11
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims abstract description 10
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 10
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 9
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 9
- 150000002367 halogens Chemical class 0.000 claims abstract description 9
- 125000004665 trialkylsilyl group Chemical group 0.000 claims abstract description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 8
- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 claims abstract description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
- 150000002148 esters Chemical class 0.000 claims description 181
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 107
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 53
- 239000002253 acid Substances 0.000 claims description 29
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 26
- 241000124008 Mammalia Species 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 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 8
- 201000001421 hyperglycemia Diseases 0.000 claims description 7
- 206010012601 diabetes mellitus Diseases 0.000 claims description 6
- 208000008589 Obesity Diseases 0.000 claims description 5
- 235000020824 obesity Nutrition 0.000 claims description 5
- 150000001408 amides Chemical class 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 230000003301 hydrolyzing effect Effects 0.000 claims description 4
- LGTHRBXRBOVOKE-UHFFFAOYSA-N 1-(furan-2-yl)-n-(furan-2-ylmethyl)methanamine Chemical compound C=1C=COC=1CNCC1=CC=CO1 LGTHRBXRBOVOKE-UHFFFAOYSA-N 0.000 claims description 3
- BWLUMTFWVZZZND-UHFFFAOYSA-N Dibenzylamine Chemical compound C=1C=CC=CC=1CNCC1=CC=CC=C1 BWLUMTFWVZZZND-UHFFFAOYSA-N 0.000 claims description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 3
- BBYGZUBFEWQBBH-UHFFFAOYSA-N [4-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-2-[(3-chlorophenyl)methoxycarbonyloxy]phenyl] (3-chlorophenyl)methyl carbonate Chemical compound C=1C=CC(Cl)=CC=1C(O)CNC(C)CC(C=C1OC(=O)OCC=2C=C(Cl)C=CC=2)=CC=C1OC(=O)OCC1=CC=CC(Cl)=C1 BBYGZUBFEWQBBH-UHFFFAOYSA-N 0.000 claims description 3
- JQVDAXLFBXTEQA-UHFFFAOYSA-N dibutylamine Chemical compound CCCCNCCCC JQVDAXLFBXTEQA-UHFFFAOYSA-N 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- FTQWRYSLUYAIRQ-UHFFFAOYSA-N n-[(octadecanoylamino)methyl]octadecanamide Chemical compound CCCCCCCCCCCCCCCCCC(=O)NCNC(=O)CCCCCCCCCCCCCCCCC FTQWRYSLUYAIRQ-UHFFFAOYSA-N 0.000 claims description 3
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- AMOYMEBHYUTMKJ-UHFFFAOYSA-N 2-(2-phenylethoxy)ethylbenzene Chemical compound C=1C=CC=CC=1CCOCCC1=CC=CC=C1 AMOYMEBHYUTMKJ-UHFFFAOYSA-N 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 1
- 125000003562 2,2-dimethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])* 0.000 claims 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 claims 1
- VMWDZLGFBFBQST-UHFFFAOYSA-N bis(3,3-dimethylbutanoyloxymethyl) 1,3-dioxole-2,2-dicarboxylate Chemical compound CC(C)(C)CC(=O)OCOC(=O)C1(C(=O)OCOC(=O)CC(C)(C)C)OC=CO1 VMWDZLGFBFBQST-UHFFFAOYSA-N 0.000 claims 1
- BFUSPRCMZMZPNZ-UHFFFAOYSA-N bis(cyclopropylmethyl) 5-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1,3-benzodioxole-2,2-dicarboxylate Chemical compound C=1C=CC(Cl)=CC=1C(O)CNC(C)CC(C=C1O2)=CC=C1OC2(C(=O)OCC1CC1)C(=O)OCC1CC1 BFUSPRCMZMZPNZ-UHFFFAOYSA-N 0.000 claims 1
- 150000004702 methyl esters Chemical class 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 18
- 230000003579 anti-obesity Effects 0.000 abstract description 9
- 230000008569 process Effects 0.000 abstract description 5
- 230000003178 anti-diabetic effect Effects 0.000 abstract description 4
- 239000003472 antidiabetic agent Substances 0.000 abstract description 3
- 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 abstract description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 147
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 118
- 239000007787 solid Substances 0.000 description 96
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 87
- 238000005481 NMR spectroscopy Methods 0.000 description 76
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 60
- 239000011541 reaction mixture Substances 0.000 description 51
- 239000000243 solution Substances 0.000 description 50
- 235000019439 ethyl acetate Nutrition 0.000 description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 38
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 33
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 30
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 30
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 26
- 235000019341 magnesium sulphate Nutrition 0.000 description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 23
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 23
- 239000000725 suspension Substances 0.000 description 23
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 21
- 239000000741 silica gel Substances 0.000 description 20
- 229910002027 silica gel Inorganic materials 0.000 description 20
- 238000005160 1H NMR spectroscopy Methods 0.000 description 19
- 239000012153 distilled water Substances 0.000 description 19
- 239000012230 colorless oil Substances 0.000 description 18
- 239000010410 layer Substances 0.000 description 18
- 241001465754 Metazoa Species 0.000 description 16
- 238000004458 analytical method Methods 0.000 description 14
- 239000003921 oil Substances 0.000 description 14
- 235000019198 oils Nutrition 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
- 239000012267 brine Substances 0.000 description 13
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 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 9
- 241000699670 Mus sp. Species 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 9
- 239000003814 drug Substances 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 238000003818 flash chromatography Methods 0.000 description 9
- 235000021588 free fatty acids Nutrition 0.000 description 9
- 239000008103 glucose Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 239000006260 foam Substances 0.000 description 8
- 235000020997 lean meat Nutrition 0.000 description 8
- 102000005962 receptors Human genes 0.000 description 8
- 108020003175 receptors Proteins 0.000 description 8
- 241000400611 Eucalyptus deanei Species 0.000 description 7
- 239000004480 active ingredient Substances 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 7
- 108060003345 Adrenergic Receptor Proteins 0.000 description 6
- 102000017910 Adrenergic receptor Human genes 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 230000002058 anti-hyperglycaemic effect Effects 0.000 description 6
- 230000037396 body weight Effects 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 230000004044 response Effects 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 244000144977 poultry Species 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 239000007832 Na2SO4 Substances 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 241000282898 Sus scrofa Species 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 4
- 230000008021 deposition Effects 0.000 description 4
- 235000012054 meals Nutrition 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 230000000638 stimulation Effects 0.000 description 4
- 239000003981 vehicle Substances 0.000 description 4
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 3
- KVJUIGSWTPMWJL-UHFFFAOYSA-N 1,3-dioxole-2,2-dicarboxylic acid Chemical compound OC(=O)C1(C(O)=O)OC=CO1 KVJUIGSWTPMWJL-UHFFFAOYSA-N 0.000 description 3
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 description 3
- 229940093475 2-ethoxyethanol Drugs 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 239000000556 agonist Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 3
- GUDMZGLFZNLYEY-UHFFFAOYSA-N cyclopropylmethanol Chemical compound OCC1CC1 GUDMZGLFZNLYEY-UHFFFAOYSA-N 0.000 description 3
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 3
- 239000008188 pellet Substances 0.000 description 3
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- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 3
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- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 3
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- 241000282412 Homo Species 0.000 description 2
- 101001033280 Homo sapiens Cytokine receptor common subunit beta Proteins 0.000 description 2
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 2
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- 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 2
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- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- HFEHLDPGIKPNKL-UHFFFAOYSA-N allyl iodide Chemical compound ICC=C HFEHLDPGIKPNKL-UHFFFAOYSA-N 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 102000012740 beta Adrenergic Receptors Human genes 0.000 description 2
- 108010079452 beta Adrenergic Receptors Proteins 0.000 description 2
- 102000016959 beta-3 Adrenergic Receptors Human genes 0.000 description 2
- 108010014502 beta-3 Adrenergic Receptors Proteins 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- WPOPOPFNZYPKAV-UHFFFAOYSA-N cyclobutylmethanol Chemical compound OCC1CCC1 WPOPOPFNZYPKAV-UHFFFAOYSA-N 0.000 description 2
- MWKFXSUHUHTGQN-UHFFFAOYSA-N decan-1-ol Chemical compound CCCCCCCCCCO MWKFXSUHUHTGQN-UHFFFAOYSA-N 0.000 description 2
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- 229910000366 copper(II) sulfate Inorganic materials 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 1
- WRBLBPRJIBIRBP-UHFFFAOYSA-N cyclohexyl 1-iodoethyl carbonate Chemical compound CC(I)OC(=O)OC1CCCCC1 WRBLBPRJIBIRBP-UHFFFAOYSA-N 0.000 description 1
- VSSAZBXXNIABDN-UHFFFAOYSA-N cyclohexylmethanol Chemical compound OCC1CCCCC1 VSSAZBXXNIABDN-UHFFFAOYSA-N 0.000 description 1
- FHADSMKORVFYOS-UHFFFAOYSA-N cyclooctanol Chemical compound OC1CCCCCCC1 FHADSMKORVFYOS-UHFFFAOYSA-N 0.000 description 1
- XCIXKGXIYUWCLL-UHFFFAOYSA-N cyclopentanol Chemical compound OC1CCCC1 XCIXKGXIYUWCLL-UHFFFAOYSA-N 0.000 description 1
- 150000001470 diamides Chemical class 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- ARFLASKVLJTEJD-UHFFFAOYSA-N ethyl 2-bromopropanoate Chemical compound CCOC(=O)C(C)Br ARFLASKVLJTEJD-UHFFFAOYSA-N 0.000 description 1
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 1
- IIEWJVIFRVWJOD-UHFFFAOYSA-N ethyl cyclohexane Natural products CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000010685 fatty oil Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- DDRPCXLAQZKBJP-UHFFFAOYSA-N furfurylamine Chemical compound NCC1=CC=CO1 DDRPCXLAQZKBJP-UHFFFAOYSA-N 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 230000008570 general process Effects 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 230000003345 hyperglycaemic effect Effects 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- NZDJTVSTIFYISQ-UHFFFAOYSA-N iodomethyl acetate Chemical compound CC(=O)OCI NZDJTVSTIFYISQ-UHFFFAOYSA-N 0.000 description 1
- GLQOBGUEBABWDN-UHFFFAOYSA-N iodomethyl propanoate Chemical compound CCC(=O)OCI GLQOBGUEBABWDN-UHFFFAOYSA-N 0.000 description 1
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 description 1
- 239000000944 linseed oil Substances 0.000 description 1
- 235000021388 linseed oil Nutrition 0.000 description 1
- 230000004130 lipolysis Effects 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- YDCHPLOFQATIDS-UHFFFAOYSA-N methyl 2-bromoacetate Chemical compound COC(=O)CBr YDCHPLOFQATIDS-UHFFFAOYSA-N 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 235000013379 molasses Nutrition 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- KPSSIOMAKSHJJG-UHFFFAOYSA-N neopentyl alcohol Chemical compound CC(C)(C)CO KPSSIOMAKSHJJG-UHFFFAOYSA-N 0.000 description 1
- SLCVBVWXLSEKPL-UHFFFAOYSA-N neopentyl glycol Chemical compound OCC(C)(C)CO SLCVBVWXLSEKPL-UHFFFAOYSA-N 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 239000007968 orange flavor Substances 0.000 description 1
- ROTONRWJLXYJBD-UHFFFAOYSA-N oxan-2-ylmethanol Chemical compound OCC1CCCCO1 ROTONRWJLXYJBD-UHFFFAOYSA-N 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- PCPUMGYALMOCHF-UHFFFAOYSA-N oxolan-3-ylmethanol Chemical compound OCC1CCOC1 PCPUMGYALMOCHF-UHFFFAOYSA-N 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229960005323 phenoxyethanol Drugs 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- JCWLEWKPXYZHGQ-UHFFFAOYSA-N propan-2-yl 2-bromoacetate Chemical compound CC(C)OC(=O)CBr JCWLEWKPXYZHGQ-UHFFFAOYSA-N 0.000 description 1
- ISYUCUGTDNJIHV-UHFFFAOYSA-N propyl 2-bromoacetate Chemical compound CCCOC(=O)CBr ISYUCUGTDNJIHV-UHFFFAOYSA-N 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 238000002821 scintillation proximity assay Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000004455 soybean meal Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- BSYVTEYKTMYBMK-UHFFFAOYSA-N tetrahydrofurfuryl alcohol Chemical compound OCC1CCCO1 BSYVTEYKTMYBMK-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004001 thioalkyl group Chemical group 0.000 description 1
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 238000009827 uniform distribution Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 210000000636 white adipocyte Anatomy 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
-
- 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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
-
- 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
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1896—Compounds having one or more Si-O-acyl linkages
Definitions
- This invention relates to novel substituted 1,3-benzodioxole compounds which have antidiabetic, antihyperglycemic, and antiobesity properties.
- the present invention also relates to pharmaceutical compositions containing these compounds, methods for the preparation of these compounds, and methods for the use of these compounds in treating diabetes and/or hyperglycemia and/or obesity in mammals.
- Ri and R4 may be one or more groups which may be the same or different and are selected from the group consisting of hydrogen, Cl to C4 alkyl, Ci to C4 alkoxy, hydroxy, halogen, trifluoromethyl, carboxy, hydroxyalkyl, alkoxycarbonyl, Ci to C4 thioalkyl, sulfonyl and sulfinyl;
- X is a divalent radical consisting of
- R' is selected from the group consisting of hydrogen, Cl to C4 alkyl and Ci to C4 acyl and Y is selected from the group consisting of carbonyl and thiocarbonyl;
- R2 and R3 may be the same or different and are selected from the group consisting of hydrogen and Cl to C4 alkyl;
- R5 and R6 are selected from the group consisting of hydrogen, carboxy, alkoxycarbonyl, hydroxymethyl, -CH2OCH2COOR7 and - CH2OCH2CH2OR7, where R7 is hydrogen or Cl to C4 alkyl; with the provision that R5 and R6 may not both be hydrogen; which have antihyperglycemic and antiobesity activity.
- the compounds of the present invention possess greatly increased potency at human ⁇ 3 receptors in comparison to the compounds in Bloom, et al., U.S. Patent 5,061 ,727. They retain high selectivity for the ⁇ 3 receptor and show much higher antiobesity and antihyperglycemic activity in animal models than the compounds of the prior art.
- the compounds have intrinsic activity at human ⁇ 3 receptors and can directly bring about antihyperglycemic and antiobesity effects, but may also be hydrolyzed in vivo to deliver a compound of the type disclosed in Bloom, et al., U.S. Patent 5,061,727 where R5 and R6 are carboxy. Thus the compounds may act as prodrugs. Therefore, the compounds of this invention are useful in treating diabetes, hyperglycemia, and obesity, exhibiting minimal side effects such as heart rate increase and muscle tremor in humans and animals, when formulated into pharmaceutical compositions.
- the compounds of the present invention achieve their antidiabetic, antihyperglycemic, and antiobesity effects by acting as selective agonists at ⁇ adrenergic receptors.
- the stimulation of these receptors on white and brown adipocytes promotes both lipolysis (breakdown of fat) and energy expenditure.
- Selective stimulation of ⁇ 3 adrenergic receptors is important for chronic treatment. Stimulation of other ⁇ -receptors could cause side effects such as increased heart rate ( ⁇ l effect) and muscle tremor ( ⁇ 2 effect).
- the compounds of the present invention show high selectivity for ⁇ 3 adrenergic receptors.
- Rl and R6 are independently hydrogen, Ci to C6 alkyl, trifluoromethyl, cyano, Cl to C6 alkoxy, or halogen;
- R2 is hydrogen or Cl to C6 trialkylsilyl
- R3 is hydrogen or Cl to C6 alkoxycarbonyl
- R2 and R3 are joined to form a ring:
- R' is hydrogen, Ci to C6 alkyl, or aryl
- R4 and R5 are independently hydrogen or Ci to C ⁇ alkyl
- R7 and Rs are independently OR9 or NRioRl i;
- Ro is hydrogen, Ci to C12 alkyl, Ci to C12 cycloalkyl, Ci to C12 silylalkyl, aryl, arylalkyl, alkoxyalkyl, heteroaryl, -CHR12COOR13, -CHRi2C(O)Ri3, - CHR12CONR10RH, -CHR12OCOOR13, or -CHRi2OC(O)Ri3, with the provision that R9 is not hydrogen in both R7 and Rs;
- RlO and Rn are independently hydrogen, Q to C12 alkyl, arylalkyl, aryl, furanylalkyl, or alkoxycarbonylalkyl;
- Rl2 and R13 are independently hydrogen, Ci to C12 alkyl, aryl, or aralkyl; and the pharmaceutically acceptable salts thereof, the enantiomers thereof, the racemic mixtures thereof, and the diastereomeric mixtures thereof.
- aryl may be phenyl or napthyl; arylalkyl may be phenyl Cl to Co alkyl or naphthyl Ci to C ⁇ alkyl; alkoxy alkyl may be Ci to C(, alkoxy Ci to C6 alkyl; and heteroaryl may be pyridyl, thiophenyl, furanyl, imidazolyl, oxazolyl, or thiazolyl.
- aryl, arylalkyl and heteroaryl groups referred to above may be optionally substituted with one or more moieties selected from halogens, C,-C 6 alkyl, C j -C 6 alkoxy, -CF 3 , -CN, or -OH groups.
- the phenyl Cl to Co alkyl group may be optionally substituted by one or more substituents selected from F, Cl, Br, CH3 or CF3.
- This invention also provides processes for preparing the compounds of the invention which comprise one of the following:
- R2 - R ⁇ are as defined above and Rs' is OAg or Rs as defined above excepting OH with a compound of formula:
- R12 and R13 are as defined above to give a compound of formula II wherein R9 is -CHRi2OC(O)Ri3 or b) reacting a compound of formula:
- Ri, R.1 , Rs , R ⁇ , R7 and Rs are as defined above and R2 is trialkylsilyl and R3 is (Ci-C ⁇ alkoxy)carbonyl to give a corresponding compound of formula 1 wherein R2 and R3 are both hydrogen,
- R' is as defined above to give a corresponding compound of formula I wherein R 2 and R3 are joined to form a ring:
- Ri, R2, R3 ' R4, R5 and R6 are as defined in Claim 1
- Rs is OR9' or NRloRl l an( * ⁇ 9' * s ⁇ 12 a ⁇ yl.
- Rl-R6 and R8 are as defined above and R9' is as defined above, with a compound of formula:
- R ⁇ -R6 R ⁇ > Rll and R12 are as defined above.
- 2,2-dicarboxylic acid bis-(2-ethoxy-ethyl) ester 5- ⁇ 2-f 2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl ⁇ -benzof 1 ,3 Jdioxole- 2,2-dicarboxylic acid bis-(2-tert-butoxy-ethyl) ester;
- a method of treating diabetes and/or hyperglycemia and/or obesity in humans or other mammals which comprises administering to a human or other mammal an antiobesity effective amount or an antihyperglycemia effective amount of a compound of the present invention.
- the effective dosage of the active compounds of this invention may vary depending upon the particular compound utilized, the mode of administration, the condition, and severity thereof, of the condition being treated, as well as the various physical factors related to the individual being treated.
- a daily dosage of from about 0.1 mg to about 1 mg per kilogram of body weight, preferably administered in divided doses two to six times per day, or in a sustained release form.
- the total daily dosage is from about 3.5 mg to about 140 mg. This regimen may be adjusted to provide the optimal therapeutic response.
- the compounds of this invention are administered at a daily dosage of from about 0.1 mg to about 1 mg per kg of body weight, preferably given in divided doses two to six times per day or in a sustained release form.
- the total daily dosage is from about 3.5 to about 140 mg, preferably from about 3.5 to about 5 mg.
- the total daily dose will generally be from about 7 mg to about 70 mg and may be adjusted to provide the optimal therapeutic result.
- the tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin.
- a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
- Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both.
- a syrup or elexir may contain, in addition to the active ingredients, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
- active compounds may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, there preparations contain a preservative to prevent the growth of micoorganisms.
- the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
- the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
- the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
- the compounds of the present invention also possess utility for increasing lean meat deposition and/or improving lean meat to fat ratio in edible animals, i.e. ungulate animals and poultry.
- Animal feed compositions effective for increasing lean meat deposition and for improving lean meat to fat ratio in poultry, swine, sheep, goats, domestic pets and cattle are generally prepared by mixing the compounds of the present invention with a sufficient amount of animal feed to provide from about 1 to 1000 ppm of the compound in the feed.
- Animal feed supplements can be prepared by admixing about 75% to 95% by weight of a compound of the present invention with about 5% to about 25% by weight of a suitable carrier or diluent.
- Carriers suitable for use to make up the feed supplement compositions include the following: alfalfa meal, soybean meal, cottonseed oil meal, linseed oil meal, sodium chloride, cornmeal, cane molasses, urea, bone meal, corncob meal and the like.
- the carrier promotes a uniform distribution of the active ingredients in the finished feed into which the supplement is blended. It thus performs an important function by ensuring proper distribution of the active ingredient throughout the feed.
- the supplement is used as a top dressing for the feed, it likewise helps to ensure uniformity of distribution of the active material across the top of the dressed feed.
- the preferred medicated swine, cattle, sheep and goat feed generally contain from 0.01 to 400 grams of active ingredient per ton of feed, the optimum amount for these animals usually being about 50 to 300 grams per ton of feed.
- the preferred poultry and domestic pet feed usually contain about 0.01 to 400 grams and preferably
- the compounds of the present invention may be prepared in the form of a paste or a pellet and administered as an implant, usually under the skin of the head or ear of the animal in which increase in lean meat deposition and improvement in lean mean to fat ratio is sought.
- parenteral administration involves injection of a sufficient amount of the compounds of the present invention to provide the animal with 0.001 to 100 mg/kg/day of body weight of the active ingredient.
- the preferred dosage for swine, cattle, sheep and goats is in the range of from 0.001 to 50 mg/kg/day of body weight of active ingredient; whereas, the preferred dose level for poultry and domestic pets is usually in the range of from 0.001 to 35 mg/kg/day of body weight.
- Paste formulations can be prepared by dispersing the active compounds in a pharmaceutically acceptable oil such as peanut oil, sesame oil, corn oil or the like.
- Pellets containing an effective amount of the compounds of the present invention can be prepared by admixing the compounds of the present invention with a diluent such as carbowax, carnuba wax, and the like, and a lubricant, such as magnesium or calcium stearate, can be added to improve the pelleting process. It is, of course, recognized that more than one pellet may be administered to an animal to achieve the desired dose level which will provide the increase in lean meat deposition and improvement in lean meat to fat ratio desired.
- implants may also be made periodically during the animal treatment period in order to maintain the proper drug level in the animal's body.
- the method of the present invention has several advantages; for the pet owner or veterinarian who wishes to increase leanness and trim unwanted fat from pet animals, the present invention provides the means by which this can be accomplished. For the poultry and swine raisers, using the method of the present invention yields leaner animals which command higher prices from the meat industry.
- compositions of matter comprising an effective amount of the compounds of the present invention in combination with a pharmaceutically acceptable carrier; as well as a method for increasing the content of lean meat in edible animals, which comprises administering to edible mammals an effective amount of the compound.
- the compounds of the present invention may be prepared according to one of the general processes outlined below. As outlined in Scheme I, a disodium carboxylate 1 is converted to a disilver carboxylate and treated with an iodo derivative 2 to yield the diester compounds 3 wherein Ri, R4, R5, R6, Rl2, and R13 are as defined above.
- a dicarboxylic acid 4 (Scheme II) is treated with an alcohol R9OH and an acid catalyst to yield the diester compounds 5 wherein R ⁇ , R4, R5, R6, and R9 are as defined above.
- the diester compounds 5 can also be produced by protecting the hydroxy and amino groups of compound 6 with R2 and R3 groups, respectively, basic hydrolysis of the ethyl esters, alkylation of the carboxyl groups of compound 7 with an alkylating agent Z-R9, and removing the protecting groups R2 and R3, wherein Ri , R2, R3, R4. R5» &6. and R9 are as defined above and Z is Cl, Br, I, methanesulfonate, trifluoromethanesulfonate, or para-toluenesulfonate.
- the diester compounds 5 can be hydrolyzed under basic conditions to a monoester 9a and/or 9b, wherein Ri, R4, R5, R6, and R9 are as defined above.
- One or both of the diastereomers 9a and 9 b may be produced in the hydrolysis reaction.
- the compounds of this invention were tested for antihyperglycemic and antiobesity activity according to the following procedures.
- test compounds on human ⁇ -adrenergic receptors were determined with Chinese hamster ovary (CHO) cells transfected with human ⁇ 2, or ⁇ l adrenergic receptors. Agonist activity is indicated by increased cAMP levels in the CHO cells. Selectivity of the test compounds for the ⁇ 3 receptor was assessed by comparison with results in ⁇ 2 and ⁇ l adrenergic receptor transfected cells.
- Activities for the test compounds are expressed as a percentage of the isoproterenol response.
- Rats respond to a single oral dose of ⁇ 3 agonists by increasing plasma free fatty acids (FFA) in response to ⁇ 3 receptor stimulation on the plasma membrane of the fat cell.
- FFA plasma free fatty acids
- 5- ⁇ 2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl ⁇ -benzof 1 ,3]dioxole- 2,2-dicarboxylic acid diisopropyl ester (Standard 2) was used as a standard compound. All test compounds were dosed at 0.1 mg/kg and compared to the response by Standard 2.
- Methyl cellulose:tween-80 drug suspension was given via gavage (1 mL/200g body weight; or 0.1 mg/kg) to rats and blood was collected 50 min later. 4). Plasma was analyzed for free fatty acids using a kit supplied by Biochemical Diagnostics Inc. (Brentwood, N.Y.). 5). Drug response was calculated from the formula below.
- mice Male, db/db (C57BL/KsJ), Jackson Laboratories, 2 to 7 months of age and 35 to 60 g
- a baseline blood sample was collected from the tail-tip of each mouse without anesthesia, placed directly into a fluoride-containing tube, mixed, and maintained on ice. Food was then returned to the mice.
- the plasma was seperated and the levels of glucose in the plasma were dertermined by an Abbot VP Analyzer.
- mice having the most extreme (i.e., highest or lowest) plasma glucose levels were excluded and the remaining 30 mice were randomly assigned into 7 groups of equivalent mean plasma glucose level (vehicle control, ciglitazone (Standard 3), and 5 test compound groups).
- vehicle 0.2 mL of 2% Tween 80/saline w/v
- test compounds were administered (p.o.) to the ad libitum fed mice.
- the food was removed from the cages for 3 h, a blood sample was collected, and the mice were then given the fourth administration of test compound or vehicle.
- Plasma glucose levels were determined. To assess test compound activity, the percent change of an animal's plasma glucose level on Day 4 (mean of 2 and 4 h values) from its level before test compound administration (Day 1 baseline sample) was determined as follows:
- EXAMPLE 6 and EXAMPLE 7 5- ⁇ 2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl ⁇ - benzo[l,3]dioxole-2,2-dicarboxylic acid bis-(2-tert-butoxy-ethyl) ester and
- Step 1 5-(2- ⁇ tert-ButoxycarbonyI- [2- (3-chloro- phenyl )-2-hydroxy-ethyl]- amino ⁇ -propyl)-benzo[l,3]dioxole-2,2-dicarboxylic acid bis-ethyl ester
- Step 4 5- ⁇ 2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl ⁇ -benzo[l,3]- dioxole-2,2-dicarboxylic acid bis-methoxycarbonylmethyl ester
- Step 2 5- ⁇ 2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl ⁇ - benzofl ,3]dioxole-2,2-dicarboxylic acid bis-(l-methoxycarbonyl- ethyl)ester
- Step 1 5-(2- ⁇ tert-Butoxycarbonyl-[2-(3-chloro-phenyl)-2-hydroxy-ethyl]- amino ⁇ -propyl)-benzofl,3]dioxole-2,2-dicarboxylic acid bis- isopropoxycarbonyl-methyl ester
- the title compound was prepared from 5-(2- ⁇ tert-buto ⁇ ycarbonyl-[2-(3-chloro- phenyl)-2-hydroxy-ethyl]-amino)-propyl)-benzofl,3]dioxole-2,2-dicarboxylic acid and isopropyl 2-bromoacetate according to the procedure of Example 24, step 3 as a colorless oil: J H NMR (300 MHz, CDCI3): ⁇ 1.15-1.30 (m, 15H), 1.40 (s, 9H), 2.45- 2.70 (m, 2H), 3.06-3.15 (m, IH), 3.45-3.60 (m, IH), 4.
- Step 2 5- ⁇ 2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl ⁇ -benzo [l,3]dioxole-2,2-dicarboxylic acid bis-isopropoxycarbonylmethyl ester
- Step 1 5-(2- ⁇ tert-Butoxycarbonyl-[2-(3-chloro-phenyl)-2-hydroxy-ethyl]- amino ⁇ -propyl)-benzof l,3]dioxole-2,2-dicarboxylic acid bis-(l- ethoxycarbonyl-ethyl) ester
- Acetyl chloride (0.59 g, 7.5 mmol) was added to trimethylsilylmethanol (4.03 g, 37.5 mmol) with stirring at room temperature. After 0.5 h, 5- ⁇ 2-[2-(3-chloro- phenyl)-2-hydroxy-ethylamino] -propyl) -benzof 1 ,3]dioxole-2,2-dicarboxylic acid
- esters were prepared by reacting the appropriate acid chlorides with formaldehyde or acetaldehyde in the presence of a catalytic amount of anhyrous ZnCl2 according to Ulich, L. H. and Adams, R. J. Amer. Chem. Soc. 1921 , 43 , 660- 666.
- the resultant acyloxyalkyl chlorides were converted in to the corresponding acyloxyalkyl iodide derivatives by reacting them with Nal in boiling benzene according to Fujimoto, K., Ishihara, S., Yanagisawa, H., Ide, J., Nakayama, E., Nakao, H. , Sugawara, S., Iwata, M. J. Antibiotics 1987, 19, 370.
- reaction mixture was quenched with 10 mL sat. aq. NaHCO 3 , and extracted with 3 x 100 mL Et 2 O. The combined organics were washed with 1 x 100 IN HCI, 1 x 100 mL brine, dried over MgSO 4 , filtered and evaporated to a yellow oil.
- Step 5 5- ⁇ (2R)-2-[[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethyl]-(2,2,2- trichloro-ethoxycarbonyl)-amino]-propyl ⁇ -benzofl,3]dioxole-2,2- dicarboxylic acid diallyl ester
- Step 2 5- ⁇ (2R)-2-[[(2R)2-(3-Chloro-phenyl)-2-hydroxy-ethyl]-(2,2,2- trichloro-ethoxycarbonyl)-amino]-propyl ⁇ -benzo[l,3]dioxole-2,2- dicarboxylic acid bis-(3-phenyl-allyl) ester
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Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US64597096A | 1996-05-14 | 1996-05-14 | |
US645970 | 1996-05-14 | ||
PCT/US1997/008148 WO1997043273A1 (en) | 1996-05-14 | 1997-05-09 | Substituted 1, 3-benzodioxoles |
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Publication Number | Publication Date |
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EP0901484A1 true EP0901484A1 (de) | 1999-03-17 |
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Application Number | Title | Priority Date | Filing Date |
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EP97924720A Withdrawn EP0901484A1 (de) | 1996-05-14 | 1997-05-05 | Substituierte 1, 3-benzodioxole |
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EP (1) | EP0901484A1 (de) |
JP (1) | JP2000510150A (de) |
KR (1) | KR20000011001A (de) |
AU (1) | AU730659B2 (de) |
BR (1) | BR9708948A (de) |
CA (1) | CA2254120A1 (de) |
HU (1) | HUP9902088A2 (de) |
IL (1) | IL126780A0 (de) |
NZ (1) | NZ332713A (de) |
WO (1) | WO1997043273A1 (de) |
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CA3100977A1 (en) | 2018-05-21 | 2019-11-28 | Constellation Pharmaceuticals, Inc. | Modulators of methyl modifying enzymes, compositions and uses thereof |
AU2020316072A1 (en) * | 2019-07-24 | 2022-02-24 | Constellation Pharmaceuticals, Inc. | EZH2 inhibition in combination therapies for the treatment of cancers |
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US5061727A (en) * | 1990-05-04 | 1991-10-29 | American Cyanamid Company | Substituted 5-(2-((2-aryl-2-hydroxyethyl)amino)propyl)-1,3-benzodioxoles |
US5482971A (en) * | 1993-10-01 | 1996-01-09 | American Cyanamid Company | Beta3 -adrenergic agents and their use in pharmaceutical compositions |
-
1997
- 1997-05-05 EP EP97924720A patent/EP0901484A1/de not_active Withdrawn
- 1997-05-05 HU HU9902088A patent/HUP9902088A2/hu unknown
- 1997-05-09 BR BR9708948A patent/BR9708948A/pt unknown
- 1997-05-09 WO PCT/US1997/008148 patent/WO1997043273A1/en not_active Application Discontinuation
- 1997-05-09 JP JP09541097A patent/JP2000510150A/ja active Pending
- 1997-05-09 CA CA002254120A patent/CA2254120A1/en not_active Abandoned
- 1997-05-09 KR KR1019980709151A patent/KR20000011001A/ko not_active Application Discontinuation
- 1997-05-09 NZ NZ332713A patent/NZ332713A/xx unknown
- 1997-05-09 IL IL12678097A patent/IL126780A0/xx unknown
- 1997-05-09 AU AU30067/97A patent/AU730659B2/en not_active Ceased
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See references of WO9743273A1 * |
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Publication number | Publication date |
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HUP9902088A2 (hu) | 2001-04-28 |
KR20000011001A (ko) | 2000-02-25 |
CA2254120A1 (en) | 1997-11-20 |
JP2000510150A (ja) | 2000-08-08 |
AU730659B2 (en) | 2001-03-08 |
BR9708948A (pt) | 1999-08-03 |
NZ332713A (en) | 2000-07-28 |
IL126780A0 (en) | 1999-08-17 |
WO1997043273A1 (en) | 1997-11-20 |
AU3006797A (en) | 1997-12-05 |
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