CA2735048A1 - 6-substituted 2-(benzimidazolyl)purine and purinone derivatives and 6-substituted 2-(imidazolo[4,5- c]pyridinyl)purine and purinone derivatives for immunosuppression - Google Patents

Info

Publication number

CA2735048A1

CA2735048A1 CA2735048A CA2735048A CA2735048A1 CA 2735048 A1 CA2735048 A1 CA 2735048A1 CA 2735048 A CA2735048 A CA 2735048A CA 2735048 A CA2735048 A CA 2735048A CA 2735048 A1 CA2735048 A1 CA 2735048A1

Authority

CA

Canada

Prior art keywords

substituted

alkyl

mmol

chosen

aryl

Prior art date

2008-08-22

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

Links

• Espacenet
• Global Dossier
• CIPO
• Discuss

• -1 6-substituted 2-(benzimidazolyl)purine Chemical class 0.000 title claims description 81
• UFZNZKGKBWOSJG-UHFFFAOYSA-N purin-2-one Chemical class O=C1N=CC2=NC=NC2=N1 UFZNZKGKBWOSJG-UHFFFAOYSA-N 0.000 title abstract description 15
• 206010062016 Immunosuppression Diseases 0.000 title description 4
• 230000001506 immunosuppresive effect Effects 0.000 title description 4
• 150000001875 compounds Chemical class 0.000 claims abstract description 97
• 125000000623 heterocyclic group Chemical group 0.000 claims description 47
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 46
• 229910052739 hydrogen Inorganic materials 0.000 claims description 41
• 239000001257 hydrogen Substances 0.000 claims description 38
• 125000003118 aryl group Chemical group 0.000 claims description 33
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 30
• 125000000217 alkyl group Chemical group 0.000 claims description 30
• 229910052736 halogen Inorganic materials 0.000 claims description 29
• 150000002367 halogens Chemical group 0.000 claims description 29
• 229910052757 nitrogen Inorganic materials 0.000 claims description 28
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 20
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 19
• 125000003107 substituted aryl group Chemical group 0.000 claims description 16
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 15
• 125000003545 alkoxy group Chemical group 0.000 claims description 14
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 13
• 229910052731 fluorine Chemical group 0.000 claims description 13
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 12
• 125000001072 heteroaryl group Chemical group 0.000 claims description 11
• 125000000547 substituted alkyl group Chemical group 0.000 claims description 10
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 9
• 125000006528 (C2-C6) alkyl group Chemical group 0.000 claims description 8
• 239000001301 oxygen Substances 0.000 claims description 8
• 229910052760 oxygen Inorganic materials 0.000 claims description 8
• 239000008194 pharmaceutical composition Substances 0.000 claims description 8
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
• 229910052799 carbon Inorganic materials 0.000 claims description 7
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 7
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 6
• 125000003725 azepanyl group Chemical group 0.000 claims description 6
• 125000002393 azetidinyl group Chemical group 0.000 claims description 6
• QYJXLKYOBNZROU-UHFFFAOYSA-N carboxysulfonylformic acid Chemical group OC(=O)S(=O)(=O)C(O)=O QYJXLKYOBNZROU-UHFFFAOYSA-N 0.000 claims description 6
• 125000005959 diazepanyl group Chemical group 0.000 claims description 6
• 239000011737 fluorine Chemical group 0.000 claims description 6
• 125000002757 morpholinyl group Chemical group 0.000 claims description 6
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
• 125000003386 piperidinyl group Chemical group 0.000 claims description 6
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 6
• 125000004076 pyridyl group Chemical group 0.000 claims description 6
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 6
• 125000002252 acyl group Chemical group 0.000 claims description 5
• 239000000039 congener Substances 0.000 claims description 4
• 239000003937 drug carrier Substances 0.000 claims description 4
• 125000006575 electron-withdrawing group Chemical group 0.000 claims description 4
• 125000005415 substituted alkoxy group Chemical group 0.000 claims description 4
• 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
• JAAJQSRLGAYGKZ-UHFFFAOYSA-N 1,2,3,4-tetrahydronaphthalen-1-ol Chemical compound C1=CC=C2C(O)CCCC2=C1 JAAJQSRLGAYGKZ-UHFFFAOYSA-N 0.000 claims description 3
• 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 3
• 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 3
• 125000000676 alkoxyimino group Chemical group 0.000 claims description 3
• 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 3
• 125000004619 benzopyranyl group Chemical group O1C(C=CC2=C1C=CC=C2)* 0.000 claims description 3
• 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims description 3
• HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 claims description 3
• 125000004438 haloalkoxy group Chemical group 0.000 claims description 3
• 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 3
• KYNSBQPICQTCGU-UHFFFAOYSA-N Benzopyrane Chemical compound C1=CC=C2C=CCOC2=C1 KYNSBQPICQTCGU-UHFFFAOYSA-N 0.000 claims description 2
• 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 2
• UHHKSVZZTYJVEG-UHFFFAOYSA-N oxepane Chemical compound C1CCCOCC1 UHHKSVZZTYJVEG-UHFFFAOYSA-N 0.000 claims description 2
• 125000003551 oxepanyl group Chemical group 0.000 claims description 2
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
• 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 claims description 2
• 150000002431 hydrogen Chemical group 0.000 claims 7
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 4
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 3
• 208000023275 Autoimmune disease Diseases 0.000 abstract description 9
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 9
• 210000003630 histaminocyte Anatomy 0.000 abstract description 9
• 208000027866 inflammatory disease Diseases 0.000 abstract description 6
• 230000001404 mediated effect Effects 0.000 abstract description 6
• 201000010099 disease Diseases 0.000 abstract description 5
• 150000003212 purines Chemical class 0.000 abstract description 5
• 206010052779 Transplant rejections Diseases 0.000 abstract description 2
• 230000002265 prevention Effects 0.000 abstract 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 164
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 159
• YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 123
• 239000007787 solid Substances 0.000 description 122
• OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 112
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 92
• 239000011541 reaction mixture Substances 0.000 description 88
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 75
• 238000005481 NMR spectroscopy Methods 0.000 description 71
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• 239000000047 product Substances 0.000 description 68
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• 239000002904 solvent Substances 0.000 description 62
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• 229910001868 water Inorganic materials 0.000 description 54
• 101150041968 CDC13 gene Proteins 0.000 description 53
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 53
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 52
• 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 42
• 238000000746 purification Methods 0.000 description 37
• 238000004128 high performance liquid chromatography Methods 0.000 description 34
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 33
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 32
• 239000000460 chlorine Substances 0.000 description 32
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 31
• FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 31
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 30
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 29
• 101150069380 JAK3 gene Proteins 0.000 description 29
• PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 28
• 238000003756 stirring Methods 0.000 description 27
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 26
• 239000000741 silica gel Substances 0.000 description 26
• 229910002027 silica gel Inorganic materials 0.000 description 26
• 238000001035 drying Methods 0.000 description 25
• 238000012544 monitoring process Methods 0.000 description 24
• LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 23
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• 238000010828 elution Methods 0.000 description 22
• JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 21
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• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 21
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 18
• XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 18
• 239000012044 organic layer Substances 0.000 description 18
• 238000004440 column chromatography Methods 0.000 description 17
• 238000002953 preparative HPLC Methods 0.000 description 17
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 16
• 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 16
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• 235000017557 sodium bicarbonate Nutrition 0.000 description 15
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 15
• 150000003839 salts Chemical class 0.000 description 14
• YLKYOEVXPMJDQM-UHFFFAOYSA-N 6-chloropurin-2-one Chemical class ClC1=NC(=O)N=C2N=CN=C12 YLKYOEVXPMJDQM-UHFFFAOYSA-N 0.000 description 13
• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 13
• 239000007832 Na2SO4 Substances 0.000 description 13
• 239000004677 Nylon Substances 0.000 description 13
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 13
• 239000007864 aqueous solution Substances 0.000 description 13
• 229920001778 nylon Polymers 0.000 description 13
• 210000000056 organ Anatomy 0.000 description 13
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• 235000011152 sodium sulphate Nutrition 0.000 description 13
• 238000005160 1H NMR spectroscopy Methods 0.000 description 12
• 239000012267 brine Substances 0.000 description 12
• 210000004027 cell Anatomy 0.000 description 12
• YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 12
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