HRP20040940A2 - Tropane derivatives as ccr5 modulators - Google Patents

Info

Publication number

HRP20040940A2

HRP20040940A2 HR20040940A HRP20040940A HRP20040940A2 HR P20040940 A2 HRP20040940 A2 HR P20040940A2 HR 20040940 A HR20040940 A HR 20040940A HR P20040940 A HRP20040940 A HR P20040940A HR P20040940 A2 HRP20040940 A2 HR P20040940A2

Authority

HR

Croatia

Prior art keywords

alkyl

compound

formula

image

mmol

Prior art date

2002-04-08

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• 150000003813 tropane derivatives Chemical class 0.000 title description 2
• 150000001875 compounds Chemical class 0.000 claims description 299
• 125000000217 alkyl group Chemical group 0.000 claims description 63
• 238000000034 method Methods 0.000 claims description 57
• 150000003839 salts Chemical class 0.000 claims description 49
• 229920006395 saturated elastomer Polymers 0.000 claims description 45
• 239000012453 solvate Substances 0.000 claims description 37
• 125000001153 fluoro group Chemical group F* 0.000 claims description 28
• 238000011282 treatment Methods 0.000 claims description 24
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 19
• 239000003814 drug Substances 0.000 claims description 17
• 125000000623 heterocyclic group Chemical group 0.000 claims description 16
• 125000004429 atom Chemical group 0.000 claims description 13
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 13
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 12
• 101100134922 Gallus gallus COR5 gene Proteins 0.000 claims description 11
• 229910052736 halogen Inorganic materials 0.000 claims description 11
• 150000002367 halogens Chemical class 0.000 claims description 11
• 208000015181 infectious disease Diseases 0.000 claims description 11
• 208000031886 HIV Infections Diseases 0.000 claims description 10
• 229910052739 hydrogen Inorganic materials 0.000 claims description 10
• 229910052760 oxygen Inorganic materials 0.000 claims description 10
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 9
• 208000027866 inflammatory disease Diseases 0.000 claims description 9
• 125000006239 protecting group Chemical group 0.000 claims description 9
• 229910052717 sulfur Inorganic materials 0.000 claims description 9
• 101100440695 Dictyostelium discoideum corB gene Proteins 0.000 claims description 8
• 208000037357 HIV infectious disease Diseases 0.000 claims description 8
• 229940079593 drug Drugs 0.000 claims description 8
• 229910052731 fluorine Inorganic materials 0.000 claims description 8
• 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 claims description 8
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 7
• 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 7
• 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 7
• 208000030507 AIDS Diseases 0.000 claims description 7
• 102000004274 CCR5 Receptors Human genes 0.000 claims description 7
• 108010017088 CCR5 Receptors Proteins 0.000 claims description 7
• 239000002585 base Substances 0.000 claims description 7
• 208000035475 disorder Diseases 0.000 claims description 7
• 125000005842 heteroatom Chemical group 0.000 claims description 7
• 229940124597 therapeutic agent Drugs 0.000 claims description 7
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 7
• 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 6
• 241001430294 unidentified retrovirus Species 0.000 claims description 6
• 241000124008 Mammalia Species 0.000 claims description 5
• 239000011737 fluorine Substances 0.000 claims description 5
• 229910052799 carbon Inorganic materials 0.000 claims description 4
• 239000003085 diluting agent Substances 0.000 claims description 4
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
• 239000000825 pharmaceutical preparation Substances 0.000 claims description 4
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 3
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 3
• 125000003342 alkenyl group Chemical group 0.000 claims description 3
• 125000000304 alkynyl group Chemical group 0.000 claims description 3
• 125000003118 aryl group Chemical group 0.000 claims description 3
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
• 229910052757 nitrogen Inorganic materials 0.000 claims description 3
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 2
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
• 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 2
• 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 claims description 2
• 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 claims description 2
• 125000003545 alkoxy group Chemical group 0.000 claims description 2
• 125000002947 alkylene group Chemical group 0.000 claims description 2
• 238000004519 manufacturing process Methods 0.000 claims description 2
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 513
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 195
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 140
• 238000002360 preparation method Methods 0.000 description 140
• 239000000243 solution Substances 0.000 description 131
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 121
• 230000002829 reductive effect Effects 0.000 description 113
• 239000002904 solvent Substances 0.000 description 100
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• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 86
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 84
• 239000000203 mixture Substances 0.000 description 79
• 238000005160 1H NMR spectroscopy Methods 0.000 description 74
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• 235000011114 ammonium hydroxide Nutrition 0.000 description 42
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• 239000007787 solid Substances 0.000 description 35
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• 239000007864 aqueous solution Substances 0.000 description 27
• 239000010410 layer Substances 0.000 description 22
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 22
• 238000006243 chemical reaction Methods 0.000 description 21
• DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 21
• 239000002253 acid Substances 0.000 description 19
• 239000012044 organic layer Substances 0.000 description 19
• 230000008569 process Effects 0.000 description 19
• 239000011734 sodium Substances 0.000 description 19
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 18
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 16
• 229960000583 acetic acid Drugs 0.000 description 16
• 239000008346 aqueous phase Substances 0.000 description 16
• 230000008859 change Effects 0.000 description 16
• 239000000284 extract Substances 0.000 description 16
• FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 15
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 15
• 241000725303 Human immunodeficiency virus Species 0.000 description 14
• 150000001412 amines Chemical class 0.000 description 14
• 239000012321 sodium triacetoxyborohydride Substances 0.000 description 13
• 150000001335 aliphatic alkanes Chemical class 0.000 description 12
• VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 12
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• 229910000041 hydrogen chloride Inorganic materials 0.000 description 12
• XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 12
• YNTOKMNHRPSGFU-UHFFFAOYSA-N n-Propyl carbamate Chemical compound CCCOC(N)=O YNTOKMNHRPSGFU-UHFFFAOYSA-N 0.000 description 12
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• 239000000543 intermediate Substances 0.000 description 11
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• 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 9
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