CA2670788A1

CA2670788A1 - A2a adenosine receptor antagonists

A2a adenosine receptor antagonists Download PDF

Info

Publication number: CA2670788A1
Authority: CA; Canada
Prior art keywords: methyl; dione; pyrimidine; dihydrothiopheno; ethyl
Prior art date: 2006-12-01
Legal status : Abandoned

Application number

CA002670788A

Other languages

English (en)

French (fr)

Inventor

Tetsuya Kobayashi

Rao Kalla

Elfatih Elzein

Jeff Zablocki

Brent Blackburn

Current Assignee

Gilead Palo Alto Inc

Original Assignee

Individual

Priority date

2006-12-01

Filing date

2007-11-29

Publication date

2008-06-12

2007-11-29 Application filed by Individual filed Critical Individual

2008-06-12 Publication of CA2670788A1 publication Critical patent/CA2670788A1/en

Status Abandoned legal-status Critical Current

Links

101150051188 Adora2a gene Proteins 0.000 title claims abstract description 18
239000000296 purinergic P1 receptor antagonist Substances 0.000 title claims abstract description 8
229940121359 adenosine receptor antagonist Drugs 0.000 title claims abstract description 7
150000001875 compounds Chemical class 0.000 claims abstract description 230
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 69
238000000034 method Methods 0.000 claims abstract description 50
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 22
201000010099 disease Diseases 0.000 claims abstract description 17
208000009132 Catalepsy Diseases 0.000 claims abstract description 11
206010047853 Waxy flexibility Diseases 0.000 claims abstract description 11
241000124008 Mammalia Species 0.000 claims abstract description 10
208000018737 Parkinson disease Diseases 0.000 claims abstract description 10
ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 claims abstract description 10
206010013663 drug dependence Diseases 0.000 claims abstract description 8
230000003492 excitotoxic effect Effects 0.000 claims abstract description 8
231100000063 excitotoxicity Toxicity 0.000 claims abstract description 8
239000008194 pharmaceutical composition Substances 0.000 claims abstract description 8
208000011117 substance-related disease Diseases 0.000 claims abstract description 8
208000023105 Huntington disease Diseases 0.000 claims abstract description 6
206010008118 cerebral infarction Diseases 0.000 claims abstract description 6
201000006474 Brain Ischemia Diseases 0.000 claims abstract description 5
206010008120 Cerebral ischaemia Diseases 0.000 claims abstract description 5
208000015114 central nervous system disease Diseases 0.000 claims abstract description 5
229960003920 cocaine Drugs 0.000 claims abstract description 5
230000001149 cognitive effect Effects 0.000 claims abstract description 5
208000035475 disorder Diseases 0.000 claims abstract description 5
230000028993 immune response Effects 0.000 claims abstract description 5
229940005483 opioid analgesics Drugs 0.000 claims abstract description 5
SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 claims abstract description 4
208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 claims abstract description 4
208000036864 Attention deficit/hyperactivity disease Diseases 0.000 claims abstract description 4
208000016285 Movement disease Diseases 0.000 claims abstract description 4
229930003827 cannabinoid Natural products 0.000 claims abstract description 4
239000003557 cannabinoid Substances 0.000 claims abstract description 4
229940065144 cannabinoids Drugs 0.000 claims abstract description 4
229960002715 nicotine Drugs 0.000 claims abstract description 4
SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 claims abstract description 4
KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 claims abstract description 3
206010016654 Fibrosis Diseases 0.000 claims abstract description 3
206010019668 Hepatic fibrosis Diseases 0.000 claims abstract description 3
229940025084 amphetamine Drugs 0.000 claims abstract description 3
230000007882 cirrhosis Effects 0.000 claims abstract description 3
208000019425 cirrhosis of liver Diseases 0.000 claims abstract description 3
210000004185 liver Anatomy 0.000 claims abstract description 3
125000001072 heteroaryl group Chemical group 0.000 claims description 49
229910052739 hydrogen Inorganic materials 0.000 claims description 49
239000001257 hydrogen Substances 0.000 claims description 45
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 28
150000002431 hydrogen Chemical group 0.000 claims description 27
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 23
125000000623 heterocyclic group Chemical group 0.000 claims description 22
125000002947 alkylene group Chemical group 0.000 claims description 15
150000003839 salts Chemical class 0.000 claims description 15
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 12
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 11
229910052757 nitrogen Chemical group 0.000 claims description 11
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 10
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
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239000001301 oxygen Substances 0.000 claims description 7
229910052760 oxygen Inorganic materials 0.000 claims description 7
125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 7
229910052717 sulfur Inorganic materials 0.000 claims description 7
239000011593 sulfur Chemical group 0.000 claims description 7
125000005842 heteroatom Chemical group 0.000 claims description 6
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125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 4
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JPDDMSDKBBPCEK-CSKARUKUSA-N 6-[(e)-2-(3,4-dimethoxyphenyl)ethenyl]-3-ethyl-1,5-dimethylthieno[2,3-d]pyrimidine-2,4-dione Chemical compound CC=1C=2C(=O)N(CC)C(=O)N(C)C=2SC=1\C=C\C1=CC=C(OC)C(OC)=C1 JPDDMSDKBBPCEK-CSKARUKUSA-N 0.000 claims description 3
125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 3
VVTDOAWVBUHYMP-MDZDMXLPSA-N 3-ethyl-1-(2-hydroxyethyl)-5-methyl-6-[(e)-2-phenylethenyl]thieno[2,3-d]pyrimidine-2,4-dione Chemical compound CC=1C=2C(=O)N(CC)C(=O)N(CCO)C=2SC=1\C=C\C1=CC=CC=C1 VVTDOAWVBUHYMP-MDZDMXLPSA-N 0.000 claims description 2
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235000020824 obesity Nutrition 0.000 claims description 2
VWRJRTRNYFJZAS-VAWYXSNFSA-N 1,3-diethyl-5-methyl-6-[(e)-2-phenylethenyl]thieno[2,3-d]pyrimidine-2,4-dione Chemical compound CC=1C=2C(=O)N(CC)C(=O)N(CC)C=2SC=1\C=C\C1=CC=CC=C1 VWRJRTRNYFJZAS-VAWYXSNFSA-N 0.000 claims 1
WFAMKSGWIMBDLH-ZHACJKMWSA-N 1,5-dimethyl-6-[(e)-2-phenylethenyl]-3-prop-2-ynylthieno[2,3-d]pyrimidine-2,4-dione Chemical compound S1C=2N(C)C(=O)N(CC#C)C(=O)C=2C(C)=C1\C=C\C1=CC=CC=C1 WFAMKSGWIMBDLH-ZHACJKMWSA-N 0.000 claims 1
ZWQZMOOECQNJRH-ZHACJKMWSA-N 3-ethyl-1,5-dimethyl-6-[(e)-2-phenylethenyl]thieno[2,3-d]pyrimidine-2,4-dione Chemical compound CC=1C=2C(=O)N(CC)C(=O)N(C)C=2SC=1\C=C\C1=CC=CC=C1 ZWQZMOOECQNJRH-ZHACJKMWSA-N 0.000 claims 1
VVTDOAWVBUHYMP-KTKRTIGZSA-N 3-ethyl-1-(2-hydroxyethyl)-5-methyl-6-[(z)-2-phenylethenyl]thieno[2,3-d]pyrimidine-2,4-dione Chemical compound CC=1C=2C(=O)N(CC)C(=O)N(CCO)C=2SC=1\C=C/C1=CC=CC=C1 VVTDOAWVBUHYMP-KTKRTIGZSA-N 0.000 claims 1
PGKMFTICSBOZHW-ZHACJKMWSA-N 3-ethyl-1-(3-hydroxypropyl)-5-methyl-6-[(e)-2-phenylethenyl]thieno[2,3-d]pyrimidine-2,4-dione Chemical compound CC=1C=2C(=O)N(CC)C(=O)N(CCCO)C=2SC=1\C=C\C1=CC=CC=C1 PGKMFTICSBOZHW-ZHACJKMWSA-N 0.000 claims 1
JRJYNEYIILYZEI-MDZDMXLPSA-N 3-ethyl-5-methyl-6-[(e)-2-(4-methylphenyl)ethenyl]-1h-thieno[2,3-d]pyrimidine-2,4-dione Chemical compound CC=1C=2C(=O)N(CC)C(=O)NC=2SC=1\C=C\C1=CC=C(C)C=C1 JRJYNEYIILYZEI-MDZDMXLPSA-N 0.000 claims 1
QGLVDTJLFFMKDQ-SDNWHVSQSA-N 3-ethyl-5-methyl-6-[(e)-2-(4-phenylphenyl)ethenyl]-1h-thieno[2,3-d]pyrimidine-2,4-dione Chemical compound CC=1C=2C(=O)N(CC)C(=O)NC=2SC=1\C=C\C(C=C1)=CC=C1C1=CC=CC=C1 QGLVDTJLFFMKDQ-SDNWHVSQSA-N 0.000 claims 1
VPTDBYKUWMMYES-RMKNXTFCSA-N 3-ethyl-5-methyl-6-[(e)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1h-thieno[2,3-d]pyrimidine-2,4-dione Chemical compound CC=1C=2C(=O)N(CC)C(=O)NC=2SC=1\C=C\C1=CC=C(C(F)(F)F)C=C1 VPTDBYKUWMMYES-RMKNXTFCSA-N 0.000 claims 1
LHSOGOXUANFNEJ-VOTSOKGWSA-N 3-ethyl-5-methyl-6-[(e)-2-pyridin-3-ylethenyl]-1h-thieno[2,3-d]pyrimidine-2,4-dione Chemical compound CC=1C=2C(=O)N(CC)C(=O)NC=2SC=1\C=C\C1=CC=CN=C1 LHSOGOXUANFNEJ-VOTSOKGWSA-N 0.000 claims 1
BLSAUMXBWNUVHN-CMDGGOBGSA-N 3-ethyl-6-[(e)-2-(2-fluorophenyl)ethenyl]-5-methyl-1h-thieno[2,3-d]pyrimidine-2,4-dione Chemical compound CC=1C=2C(=O)N(CC)C(=O)NC=2SC=1\C=C\C1=CC=CC=C1F BLSAUMXBWNUVHN-CMDGGOBGSA-N 0.000 claims 1
UIOYXSFRGJIAAB-MDZDMXLPSA-N 3-ethyl-6-[(e)-2-(2-methoxyphenyl)ethenyl]-5-methyl-1h-thieno[2,3-d]pyrimidine-2,4-dione Chemical compound CC=1C=2C(=O)N(CC)C(=O)NC=2SC=1\C=C\C1=CC=CC=C1OC UIOYXSFRGJIAAB-MDZDMXLPSA-N 0.000 claims 1
DNAWLGURDUWARK-BQYQJAHWSA-N 3-ethyl-6-[(e)-2-(3-fluorophenyl)ethenyl]-5-methyl-1h-thieno[2,3-d]pyrimidine-2,4-dione Chemical compound CC=1C=2C(=O)N(CC)C(=O)NC=2SC=1\C=C\C1=CC=CC(F)=C1 DNAWLGURDUWARK-BQYQJAHWSA-N 0.000 claims 1
XDAYENCKGPZWCY-CMDGGOBGSA-N 3-ethyl-6-[(e)-2-(3-methoxyphenyl)ethenyl]-5-methyl-1h-thieno[2,3-d]pyrimidine-2,4-dione Chemical compound CC=1C=2C(=O)N(CC)C(=O)NC=2SC=1\C=C\C1=CC=CC(OC)=C1 XDAYENCKGPZWCY-CMDGGOBGSA-N 0.000 claims 1
BMLNLXDZFDTYAY-RMKNXTFCSA-N 3-ethyl-6-[(e)-2-(4-fluorophenyl)ethenyl]-5-methyl-1h-thieno[2,3-d]pyrimidine-2,4-dione Chemical compound CC=1C=2C(=O)N(CC)C(=O)NC=2SC=1\C=C\C1=CC=C(F)C=C1 BMLNLXDZFDTYAY-RMKNXTFCSA-N 0.000 claims 1
ZRJQUNQLJKVWET-JXMROGBWSA-N 3-ethyl-6-[(e)-2-(4-methoxyphenyl)ethenyl]-5-methyl-1h-thieno[2,3-d]pyrimidine-2,4-dione Chemical compound CC=1C=2C(=O)N(CC)C(=O)NC=2SC=1\C=C\C1=CC=C(OC)C=C1 ZRJQUNQLJKVWET-JXMROGBWSA-N 0.000 claims 1
GZVSGFUGESSPEP-MDZDMXLPSA-N 5-methyl-3-(2-methylpropyl)-6-[(e)-2-phenylethenyl]-1h-thieno[2,3-d]pyrimidine-2,4-dione Chemical compound CC=1C=2C(=O)N(CC(C)C)C(=O)NC=2SC=1\C=C\C1=CC=CC=C1 GZVSGFUGESSPEP-MDZDMXLPSA-N 0.000 claims 1
ZYRNLFPSWWUWDQ-WYMLVPIESA-N 6-[(e)-2-(3,4-dimethoxyphenyl)ethenyl]-3-ethyl-5-methyl-1-(phenylmethoxymethyl)thieno[2,3-d]pyrimidine-2,4-dione Chemical compound C1=2SC(\C=C\C=3C=C(OC)C(OC)=CC=3)=C(C)C=2C(=O)N(CC)C(=O)N1COCC1=CC=CC=C1 ZYRNLFPSWWUWDQ-WYMLVPIESA-N 0.000 claims 1
OFJVDOIYGSHIBE-VQHVLOKHSA-N 6-[(e)-2-(3,4-dimethoxyphenyl)ethenyl]-3-ethyl-5-methyl-1h-thieno[2,3-d]pyrimidine-2,4-dione Chemical compound CC=1C=2C(=O)N(CC)C(=O)NC=2SC=1\C=C\C1=CC=C(OC)C(OC)=C1 OFJVDOIYGSHIBE-VQHVLOKHSA-N 0.000 claims 1
DPDSWYCAAFJAOY-VQHVLOKHSA-N 6-[(e)-2-(3,4-dimethoxyphenyl)ethenyl]-5-methyl-3-(2-methylpropyl)-1h-thieno[2,3-d]pyrimidine-2,4-dione Chemical compound C1=C(OC)C(OC)=CC=C1\C=C\C1=C(C)C(C(=O)N(CC(C)C)C(=O)N2)=C2S1 DPDSWYCAAFJAOY-VQHVLOKHSA-N 0.000 claims 1
IYNDDQQFQKDYFH-VOTSOKGWSA-N 6-[(e)-2-(3,5-dimethoxyphenyl)ethenyl]-3-ethyl-5-methyl-1h-thieno[2,3-d]pyrimidine-2,4-dione Chemical compound CC=1C=2C(=O)N(CC)C(=O)NC=2SC=1\C=C\C1=CC(OC)=CC(OC)=C1 IYNDDQQFQKDYFH-VOTSOKGWSA-N 0.000 claims 1
BDWPDJBPUQVUCM-RMKNXTFCSA-N 6-[(e)-2-(4-chlorophenyl)ethenyl]-3-ethyl-5-methyl-1h-thieno[2,3-d]pyrimidine-2,4-dione Chemical compound CC=1C=2C(=O)N(CC)C(=O)NC=2SC=1\C=C\C1=CC=C(Cl)C=C1 BDWPDJBPUQVUCM-RMKNXTFCSA-N 0.000 claims 1
238000002360 preparation method Methods 0.000 abstract description 73
ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 89
239000000203 mixture Substances 0.000 description 77
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 72
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VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 42
238000006243 chemical reaction Methods 0.000 description 39
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235000019441 ethanol Nutrition 0.000 description 27
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 27
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150000002367 halogens Chemical class 0.000 description 23
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 22
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125000004093 cyano group Chemical group *C#N 0.000 description 22
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235000019439 ethyl acetate Nutrition 0.000 description 21
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LNEPOXFFQSENCJ-UHFFFAOYSA-N haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 0.000 description 14
HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 14
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XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 8
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