CN101851238B - 取代的8-杂芳基黄嘌呤 - Google Patents

Info

Publication number

CN101851238B

CN101851238B CN2010101556967A CN201010155696A CN101851238B CN 101851238 B CN101851238 B CN 101851238B CN 2010101556967 A CN2010101556967 A CN 2010101556967A CN 201010155696 A CN201010155696 A CN 201010155696A CN 101851238 B CN101851238 B CN 101851238B

Authority

CN

China

Prior art keywords

alkyl

compound

pyridyl

xanthine

methyl

Prior art date

2003-08-25

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.)

Expired - Fee Related

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• 229940065721 systemic for obstructive airway disease xanthines Drugs 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 190
• 239000003814 drug Substances 0.000 claims abstract description 14
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 9
• -1 heterocyclic radical Chemical class 0.000 claims description 135
• 239000001257 hydrogen Substances 0.000 claims description 72
• 229910052739 hydrogen Inorganic materials 0.000 claims description 72
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 50
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 47
• 229910052736 halogen Inorganic materials 0.000 claims description 35
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 34
• 150000002367 halogens Chemical class 0.000 claims description 34
• 150000002431 hydrogen Chemical class 0.000 claims description 33
• 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 32
• 125000005843 halogen group Chemical group 0.000 claims description 32
• 125000001072 heteroaryl group Chemical group 0.000 claims description 31
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 29
• 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 26
• 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 24
• 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims description 21
• 125000000217 alkyl group Chemical group 0.000 claims description 21
• 125000000304 alkynyl group Chemical group 0.000 claims description 20
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 20
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 19
• OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 claims description 18
• 125000003118 aryl group Chemical group 0.000 claims description 18
• 150000003839 salts Chemical class 0.000 claims description 17
• 238000011282 treatment Methods 0.000 claims description 16
• 230000000694 effects Effects 0.000 claims description 14
• 241000124008 Mammalia Species 0.000 claims description 13
• 238000006243 chemical reaction Methods 0.000 claims description 12
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 10
• 239000002126 C01EB10 - Adenosine Substances 0.000 claims description 9
• 229960005305 adenosine Drugs 0.000 claims description 9
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
• 125000004076 pyridyl group Chemical group 0.000 claims description 9
• 208000006673 asthma Diseases 0.000 claims description 8
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 8
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 8
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
• 229910052740 iodine Inorganic materials 0.000 claims description 8
• 125000002757 morpholinyl group Chemical group 0.000 claims description 8
• 229910052757 nitrogen Inorganic materials 0.000 claims description 8
• 229910052760 oxygen Inorganic materials 0.000 claims description 8
• 125000004429 atom Chemical group 0.000 claims description 7
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 7
• 229910052794 bromium Inorganic materials 0.000 claims description 7
• 229910052801 chlorine Inorganic materials 0.000 claims description 7
• 229910052731 fluorine Inorganic materials 0.000 claims description 7
• 239000001301 oxygen Substances 0.000 claims description 7
• 125000004193 piperazinyl group Chemical group 0.000 claims description 7
• GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims description 6
• 206010022489 Insulin Resistance Diseases 0.000 claims description 6
• 206010028980 Neoplasm Diseases 0.000 claims description 6
• 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 6
• 229920006395 saturated elastomer Polymers 0.000 claims description 6
• 208000024891 symptom Diseases 0.000 claims description 6
• 125000001544 thienyl group Chemical group 0.000 claims description 6
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 5
• 206010012689 Diabetic retinopathy Diseases 0.000 claims description 5
• 206010012735 Diarrhoea Diseases 0.000 claims description 5
• 208000017442 Retinal disease Diseases 0.000 claims description 5
• 206010038923 Retinopathy Diseases 0.000 claims description 5
• 230000001575 pathological effect Effects 0.000 claims description 5
• 230000002265 prevention Effects 0.000 claims description 5
• 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 5
• 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 4
• 206010063837 Reperfusion injury Diseases 0.000 claims description 4
• 208000026935 allergic disease Diseases 0.000 claims description 4
• 208000023275 Autoimmune disease Diseases 0.000 claims description 3
• XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 claims description 2
• 201000011510 cancer Diseases 0.000 claims description 2
• 125000001207 fluorophenyl group Chemical group 0.000 claims description 2
• 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
• 150000003254 radicals Chemical class 0.000 claims 3
• 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims 1
• 206010003497 Asphyxia Diseases 0.000 claims 1
• 230000003042 antagnostic effect Effects 0.000 claims 1
• UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims 1
• RDOXTESZEPMUJZ-UHFFFAOYSA-N methyl phenyl ether Natural products COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims 1
• 150000002978 peroxides Chemical class 0.000 claims 1
• 125000005936 piperidyl group Chemical group 0.000 claims 1
• 125000002769 thiazolinyl group Chemical group 0.000 claims 1
• 230000009466 transformation Effects 0.000 claims 1
• 102000009346 Adenosine receptors Human genes 0.000 abstract description 24
• 108050000203 Adenosine receptors Proteins 0.000 abstract description 24
• 239000000203 mixture Substances 0.000 abstract description 24
• 229940079593 drug Drugs 0.000 abstract description 8
• 239000005557 antagonist Substances 0.000 abstract description 7
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 183
• 125000004209 (C1-C8) alkyl group Chemical group 0.000 description 129
• 125000000041 C6-C10 aryl group Chemical group 0.000 description 85
• 238000005481 NMR spectroscopy Methods 0.000 description 58
• LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical compound O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 46
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 35
• 239000002585 base Substances 0.000 description 33
• 125000001424 substituent group Chemical group 0.000 description 33
• 229940075420 xanthine Drugs 0.000 description 31
• 125000004093 cyano group Chemical group *C#N 0.000 description 26
• 125000000623 heterocyclic group Chemical group 0.000 description 26
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 25
• 210000004027 cell Anatomy 0.000 description 24
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 21
• 125000003342 alkenyl group Chemical group 0.000 description 19
• 238000000034 method Methods 0.000 description 19
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 18
• 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 description 17
• 102000005962 receptors Human genes 0.000 description 17
• 108020003175 receptors Proteins 0.000 description 17
• 0 C1CC*CC1 Chemical compound C1CC*CC1 0.000 description 16
• 239000000243 solution Substances 0.000 description 13
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 12
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
• 239000007788 liquid Substances 0.000 description 12
• 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 12
• 238000002360 preparation method Methods 0.000 description 12
• 125000006413 ring segment Chemical group 0.000 description 12
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 11
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 10
• 239000002904 solvent Substances 0.000 description 10
• 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 10
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
• 125000003710 aryl alkyl group Chemical group 0.000 description 9
• 239000000872 buffer Substances 0.000 description 9
• 239000007787 solid Substances 0.000 description 9
• ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 9
• 125000006714 (C3-C10) heterocyclyl group Chemical group 0.000 description 8
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
• 230000027455 binding Effects 0.000 description 8
• 239000000460 chlorine Substances 0.000 description 8
• 125000005842 heteroatom Chemical group 0.000 description 8
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 8
• DFKVQPMXXSMIRH-UHFFFAOYSA-N 1,3-diethyl-8-(6-hydrazinylpyridin-3-yl)-7h-purine-2,6-dione Chemical compound N1C=2C(=O)N(CC)C(=O)N(CC)C=2N=C1C1=CC=C(NN)N=C1 DFKVQPMXXSMIRH-UHFFFAOYSA-N 0.000 description 7
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
• KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 7
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 7
• 125000003545 alkoxy group Chemical group 0.000 description 7
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 7
• 201000010099 disease Diseases 0.000 description 7
• 239000002552 dosage form Substances 0.000 description 7
• 210000004379 membrane Anatomy 0.000 description 7
• 239000012528 membrane Substances 0.000 description 7
• 125000003386 piperidinyl group Chemical group 0.000 description 7
• 125000000719 pyrrolidinyl group Chemical group 0.000 description 7
• 150000003573 thiols Chemical class 0.000 description 7
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
• JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 6
• 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 6
• LFXCYVITBNVTHL-UHFFFAOYSA-N 8-(6-chloropyridin-3-yl)-1,3-dipropyl-7h-purine-2,6-dione Chemical compound N1C=2C(=O)N(CCC)C(=O)N(CCC)C=2N=C1C1=CC=C(Cl)N=C1 LFXCYVITBNVTHL-UHFFFAOYSA-N 0.000 description 6
• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
• 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 6
• 239000007995 HEPES buffer Substances 0.000 description 6
• MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical group OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 6
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
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• 239000004480 active ingredient Substances 0.000 description 6
• 150000001412 amines Chemical class 0.000 description 6
• 125000000477 aza group Chemical group 0.000 description 6
• 125000002619 bicyclic group Chemical group 0.000 description 6
• 230000015572 biosynthetic process Effects 0.000 description 6
• 238000011534 incubation Methods 0.000 description 6
• 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 6
• 238000003786 synthesis reaction Methods 0.000 description 6
• FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
• LRANPJDWHYRCER-UHFFFAOYSA-N 1,2-diazepine Chemical compound N1C=CC=CC=N1 LRANPJDWHYRCER-UHFFFAOYSA-N 0.000 description 5
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• 238000001816 cooling Methods 0.000 description 5
• 238000007429 general method Methods 0.000 description 5
• 125000002883 imidazolyl group Chemical group 0.000 description 5
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• 239000000296 purinergic P1 receptor antagonist Substances 0.000 description 5
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• 125000004568 thiomorpholinyl group Chemical group 0.000 description 5
• POXWDTQUDZUOGP-UHFFFAOYSA-N 1h-1,4-diazepine Chemical compound N1C=CC=NC=C1 POXWDTQUDZUOGP-UHFFFAOYSA-N 0.000 description 4
• 101710169336 5'-deoxyadenosine deaminase Proteins 0.000 description 4
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• BRZYSWJRSDMWLG-CAXSIQPQSA-N geneticin Natural products O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](C(C)O)O2)N)[C@@H](N)C[C@H]1N BRZYSWJRSDMWLG-CAXSIQPQSA-N 0.000 description 4
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• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
• 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 4
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• 125000003373 pyrazinyl group Chemical group 0.000 description 4
• 125000000714 pyrimidinyl group Chemical group 0.000 description 4
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• 238000012360 testing method Methods 0.000 description 4
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• 238000004809 thin layer chromatography Methods 0.000 description 4
• 125000004306 triazinyl group Chemical group 0.000 description 4
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• FMEBIWNKYZUWFV-UHFFFAOYSA-N 6-chloropyridine-3-carbonyl chloride Chemical compound ClC(=O)C1=CC=C(Cl)N=C1 FMEBIWNKYZUWFV-UHFFFAOYSA-N 0.000 description 3
• BLHCMGRVFXRYRN-UHFFFAOYSA-N 6-hydroxynicotinic acid Chemical compound OC(=O)C1=CC=C(O)N=C1 BLHCMGRVFXRYRN-UHFFFAOYSA-N 0.000 description 3
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
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• 125000004649 C2-C8 alkynyl group Chemical group 0.000 description 3
• FFBDFADSZUINTG-UHFFFAOYSA-N DPCPX Chemical compound N1C=2C(=O)N(CCC)C(=O)N(CCC)C=2N=C1C1CCCC1 FFBDFADSZUINTG-UHFFFAOYSA-N 0.000 description 3
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• LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 3
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• 102000004169 proteins and genes Human genes 0.000 description 3
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• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
• 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 3
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• 125000001113 thiadiazolyl group Chemical group 0.000 description 3
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• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 2
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