DE60022042T2 - Thieno- und furopyrimidin derivate als a2a-rezeptor antagonisten - Google Patents

Info

Publication number

DE60022042T2

DE60022042T2 DE60022042T DE60022042T DE60022042T2 DE 60022042 T2 DE60022042 T2 DE 60022042T2 DE 60022042 T DE60022042 T DE 60022042T DE 60022042 T DE60022042 T DE 60022042T DE 60022042 T2 DE60022042 T2 DE 60022042T2

Authority

DE

Germany

Prior art keywords

pyrimidin

thieno

alkyl

compound according

group

Prior art date

1999-07-01

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 - Lifetime

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• Global Dossier
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• JUQAECQBUNODQP-UHFFFAOYSA-N furo[3,2-d]pyrimidine Chemical class C1=NC=C2OC=CC2=N1 JUQAECQBUNODQP-UHFFFAOYSA-N 0.000 title description 3
• 229940044551 receptor antagonist Drugs 0.000 title description 2
• 239000002464 receptor antagonist Substances 0.000 title description 2
• 150000001875 compounds Chemical class 0.000 claims abstract description 164
• 102000000033 Purinergic Receptors Human genes 0.000 claims abstract description 9
• 108010080192 Purinergic Receptors Proteins 0.000 claims abstract description 9
• 230000000903 blocking effect Effects 0.000 claims abstract description 7
• 125000000217 alkyl group Chemical group 0.000 claims description 93
• 125000003118 aryl group Chemical group 0.000 claims description 57
• 239000001257 hydrogen Substances 0.000 claims description 49
• 229910052739 hydrogen Inorganic materials 0.000 claims description 49
• 238000000034 method Methods 0.000 claims description 49
• -1 aryloxycarbonylalkyl Chemical group 0.000 claims description 47
• 238000011282 treatment Methods 0.000 claims description 34
• 208000018737 Parkinson disease Diseases 0.000 claims description 33
• 125000003545 alkoxy group Chemical group 0.000 claims description 33
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 31
• 125000000623 heterocyclic group Chemical group 0.000 claims description 25
• 125000003277 amino group Chemical group 0.000 claims description 24
• 239000003814 drug Substances 0.000 claims description 24
• 102000005962 receptors Human genes 0.000 claims description 24
• 108020003175 receptors Proteins 0.000 claims description 24
• 125000001424 substituent group Chemical group 0.000 claims description 24
• 229910052736 halogen Inorganic materials 0.000 claims description 23
• 208000016285 Movement disease Diseases 0.000 claims description 22
• 150000002367 halogens Chemical class 0.000 claims description 22
• 239000000203 mixture Substances 0.000 claims description 22
• 125000004104 aryloxy group Chemical group 0.000 claims description 20
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 20
• 150000002431 hydrogen Chemical class 0.000 claims description 18
• 229940079593 drug Drugs 0.000 claims description 17
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 16
• 208000035475 disorder Diseases 0.000 claims description 15
• 229920006395 saturated elastomer Polymers 0.000 claims description 15
• 125000004122 cyclic group Chemical group 0.000 claims description 14
• 150000003839 salts Chemical class 0.000 claims description 14
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 13
• 125000002541 furyl group Chemical group 0.000 claims description 13
• 102000009346 Adenosine receptors Human genes 0.000 claims description 12
• 108050000203 Adenosine receptors Proteins 0.000 claims description 12
• 125000001544 thienyl group Chemical group 0.000 claims description 12
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 10
• 238000002360 preparation method Methods 0.000 claims description 10
• 125000004076 pyridyl group Chemical group 0.000 claims description 10
• 208000002193 Pain Diseases 0.000 claims description 9
• 125000004663 dialkyl amino group Chemical group 0.000 claims description 9
• 229910052760 oxygen Inorganic materials 0.000 claims description 9
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 9
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 8
• 125000005842 heteroatom Chemical group 0.000 claims description 8
• 125000005597 hydrazone group Chemical group 0.000 claims description 8
• 125000002757 morpholinyl group Chemical group 0.000 claims description 8
• 125000003544 oxime group Chemical group 0.000 claims description 8
• 125000004193 piperazinyl group Chemical group 0.000 claims description 8
• 125000004414 alkyl thio group Chemical group 0.000 claims description 7
• 125000000879 imine group Chemical group 0.000 claims description 7
• 208000015122 neurodegenerative disease Diseases 0.000 claims description 7
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
• 230000000750 progressive effect Effects 0.000 claims description 7
• 125000000168 pyrrolyl group Chemical group 0.000 claims description 7
• 125000000335 thiazolyl group Chemical group 0.000 claims description 7
• HUVSXFBXVUJVPQ-UHFFFAOYSA-N (2-aminothieno[3,2-d]pyrimidin-4-yl)-thiophen-2-ylmethanone Chemical compound C=12SC=CC2=NC(N)=NC=1C(=O)C1=CC=CS1 HUVSXFBXVUJVPQ-UHFFFAOYSA-N 0.000 claims description 6
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 6
• 230000004112 neuroprotection Effects 0.000 claims description 6
• 239000001301 oxygen Substances 0.000 claims description 6
• 229910052717 sulfur Inorganic materials 0.000 claims description 6
• 238000002560 therapeutic procedure Methods 0.000 claims description 6
• 208000024827 Alzheimer disease Diseases 0.000 claims description 5
• 208000012661 Dyskinesia Diseases 0.000 claims description 5
• 125000004103 aminoalkyl group Chemical group 0.000 claims description 5
• 125000005110 aryl thio group Chemical group 0.000 claims description 5
• 210000004227 basal ganglia Anatomy 0.000 claims description 5
• 201000010099 disease Diseases 0.000 claims description 5
• 125000002883 imidazolyl group Chemical group 0.000 claims description 5
• 150000002825 nitriles Chemical class 0.000 claims description 5
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 5
• 125000002971 oxazolyl group Chemical group 0.000 claims description 5
• 125000003386 piperidinyl group Chemical group 0.000 claims description 5
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 5
• 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 5
• BCNVTWOLTPPWTA-UHFFFAOYSA-N 1-prop-2-enyl-3-[2-[[4-(thiophene-2-carbonyl)thieno[3,2-d]pyrimidin-2-yl]amino]ethyl]urea Chemical compound C=12SC=CC2=NC(NCCNC(=O)NCC=C)=NC=1C(=O)C1=CC=CS1 BCNVTWOLTPPWTA-UHFFFAOYSA-N 0.000 claims description 4
• 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
• AXCXYXQXMXRXFK-UHFFFAOYSA-N 3-methyl-n-[2-[[4-(thiophene-2-carbonyl)thieno[3,2-d]pyrimidin-2-yl]amino]ethyl]butanamide Chemical compound C=12SC=CC2=NC(NCCNC(=O)CC(C)C)=NC=1C(=O)C1=CC=CS1 AXCXYXQXMXRXFK-UHFFFAOYSA-N 0.000 claims description 4
• 206010003694 Atrophy Diseases 0.000 claims description 4
• 208000002972 Hepatolenticular Degeneration Diseases 0.000 claims description 4
• WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 claims description 4
• WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 claims description 4
• 208000001089 Multiple system atrophy Diseases 0.000 claims description 4
• 208000008238 Muscle Spasticity Diseases 0.000 claims description 4
• 208000018839 Wilson disease Diseases 0.000 claims description 4
• 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 4
• 230000037444 atrophy Effects 0.000 claims description 4
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
• 208000010877 cognitive disease Diseases 0.000 claims description 4
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
• 238000009472 formulation Methods 0.000 claims description 4
• 125000001188 haloalkyl group Chemical group 0.000 claims description 4
• 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 4
• 125000001715 oxadiazolyl group Chemical group 0.000 claims description 4
• 230000002265 prevention Effects 0.000 claims description 4
• 125000003373 pyrazinyl group Chemical group 0.000 claims description 4
• 125000002098 pyridazinyl group Chemical group 0.000 claims description 4
• 208000018198 spasticity Diseases 0.000 claims description 4
• 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 4
• 125000001113 thiadiazolyl group Chemical group 0.000 claims description 4
• MBVFRSJFKMJRHA-UHFFFAOYSA-N 4-fluoro-1-benzofuran-7-carbaldehyde Chemical compound FC1=CC=C(C=O)C2=C1C=CO2 MBVFRSJFKMJRHA-UHFFFAOYSA-N 0.000 claims description 3
• 125000001960 7 membered carbocyclic group Chemical group 0.000 claims description 3
• 208000011990 Corticobasal Degeneration Diseases 0.000 claims description 3
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 3
• 125000002015 acyclic group Chemical group 0.000 claims description 3
• 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 3
• 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 claims description 3
• 125000005093 alkyl carbonyl alkyl group Chemical group 0.000 claims description 3
• 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 3
• 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 3
• 125000005197 alkyl carbonyloxy alkyl group Chemical group 0.000 claims description 3
• 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 3
• 125000004687 alkyl sulfinyl alkyl group Chemical group 0.000 claims description 3
• 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 3
• 125000004688 alkyl sulfonyl alkyl group Chemical group 0.000 claims description 3
• 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 3
• 125000006350 alkyl thio alkyl group Chemical group 0.000 claims description 3
• 125000005097 aminocarbonylalkyl group Chemical group 0.000 claims description 3
• 125000005099 aryl alkyl carbonyl group Chemical group 0.000 claims description 3
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 3
• 125000005100 aryl amino carbonyl group Chemical group 0.000 claims description 3
• 125000004658 aryl carbonyl amino group Chemical group 0.000 claims description 3
• 125000005129 aryl carbonyl group Chemical group 0.000 claims description 3
• 125000005135 aryl sulfinyl group Chemical group 0.000 claims description 3
• 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 3
• 125000005164 aryl thioalkyl group Chemical group 0.000 claims description 3
• 125000005325 aryloxy aryl group Chemical group 0.000 claims description 3
• 150000001540 azides Chemical class 0.000 claims description 3
• 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 3
• 125000004619 benzopyranyl group Chemical group O1C(C=CC2=C1C=CC=C2)* 0.000 claims description 3
• 125000004622 benzoxazinyl group Chemical group O1NC(=CC2=C1C=CC=C2)* 0.000 claims description 3
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 3
• 125000004623 carbolinyl group Chemical group 0.000 claims description 3
• 125000004181 carboxyalkyl group Chemical group 0.000 claims description 3
• 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 claims description 3
• 125000004230 chromenyl group Chemical group O1C(C=CC2=CC=CC=C12)* 0.000 claims description 3
• 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 claims description 3
• 125000000332 coumarinyl group Chemical group O1C(=O)C(=CC2=CC=CC=C12)* 0.000 claims description 3
• 125000004985 dialkyl amino alkyl group Chemical group 0.000 claims description 3
• 125000002632 imidazolidinyl group Chemical group 0.000 claims description 3
• 125000002636 imidazolinyl group Chemical group 0.000 claims description 3
• 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 3
• 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 claims description 3
• 125000001041 indolyl group Chemical group 0.000 claims description 3
• 125000001977 isobenzofuranyl group Chemical group C=1(OC=C2C=CC=CC12)* 0.000 claims description 3
• 125000003384 isochromanyl group Chemical group C1(OCCC2=CC=CC=C12)* 0.000 claims description 3
• 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 claims description 3
• 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 3
• 125000001786 isothiazolyl group Chemical group 0.000 claims description 3
• 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 claims description 3
• 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 claims description 3
• 125000005936 piperidyl group Chemical group 0.000 claims description 3
• 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 claims description 3
• 125000003072 pyrazolidinyl group Chemical group 0.000 claims description 3
• 125000004590 pyridopyridyl group Chemical group N1=C(C=CC2=C1C=CC=N2)* 0.000 claims description 3
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 3
• 125000001422 pyrrolinyl group Chemical group 0.000 claims description 3
• 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 3
• 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 3
• 239000011593 sulfur Substances 0.000 claims description 3
• 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims description 2
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
• 208000000094 Chronic Pain Diseases 0.000 claims description 2
• 208000002603 Dopa-responsive dystonia Diseases 0.000 claims description 2
• YHZVBPJLMKPEHB-UHFFFAOYSA-N [2-(1-hydroxypropan-2-ylamino)thieno[3,2-d]pyrimidin-4-yl]-thiophen-2-ylmethanone Chemical compound C=12SC=CC2=NC(NC(CO)C)=NC=1C(=O)C1=CC=CS1 YHZVBPJLMKPEHB-UHFFFAOYSA-N 0.000 claims description 2
• RDDZRWPAJRJYIB-UHFFFAOYSA-N [2-(2,3-dihydroxypropylamino)thieno[3,2-d]pyrimidin-4-yl]-thiophen-2-ylmethanone Chemical compound C=12SC=CC2=NC(NCC(O)CO)=NC=1C(=O)C1=CC=CS1 RDDZRWPAJRJYIB-UHFFFAOYSA-N 0.000 claims description 2
• FQFCKXXHGAHJRN-UHFFFAOYSA-N [2-(2-hydroxyethylamino)thieno[3,2-d]pyrimidin-4-yl]-(3-methylthiophen-2-yl)methanone Chemical compound C1=CSC(C(=O)C=2C=3SC=CC=3N=C(NCCO)N=2)=C1C FQFCKXXHGAHJRN-UHFFFAOYSA-N 0.000 claims description 2
• PGCHQXADUKRVDJ-UHFFFAOYSA-N [2-(2-hydroxyethylamino)thieno[3,2-d]pyrimidin-4-yl]-thiophen-2-ylmethanone Chemical compound C=12SC=CC2=NC(NCCO)=NC=1C(=O)C1=CC=CS1 PGCHQXADUKRVDJ-UHFFFAOYSA-N 0.000 claims description 2
• BEHFCCCUBYKLIL-UHFFFAOYSA-N [2-(3-hydroxypropylamino)thieno[3,2-d]pyrimidin-4-yl]-thiophen-2-ylmethanone Chemical compound C=12SC=CC2=NC(NCCCO)=NC=1C(=O)C1=CC=CS1 BEHFCCCUBYKLIL-UHFFFAOYSA-N 0.000 claims description 2
• AWFDTAUYZWDHCT-UHFFFAOYSA-N [2-(3-imidazol-1-ylpropylamino)thieno[3,2-d]pyrimidin-4-yl]-(3-methylthiophen-2-yl)methanone Chemical compound C1=CSC(C(=O)C=2C=3SC=CC=3N=C(NCCCN3C=NC=C3)N=2)=C1C AWFDTAUYZWDHCT-UHFFFAOYSA-N 0.000 claims description 2
• UNEXEZQHKDRHHO-UHFFFAOYSA-N [2-(3-imidazol-1-ylpropylamino)thieno[3,2-d]pyrimidin-4-yl]-thiophen-2-ylmethanone Chemical compound N=1C(NCCCN2C=NC=C2)=NC=2C=CSC=2C=1C(=O)C1=CC=CS1 UNEXEZQHKDRHHO-UHFFFAOYSA-N 0.000 claims description 2
• SLRLHYPXCOIOJR-UHFFFAOYSA-N [2-(oxolan-2-ylmethylamino)thieno[3,2-d]pyrimidin-4-yl]-thiophen-2-ylmethanone Chemical compound N=1C(NCC2OCCC2)=NC=2C=CSC=2C=1C(=O)C1=CC=CS1 SLRLHYPXCOIOJR-UHFFFAOYSA-N 0.000 claims description 2
• IVQBRHHYYXDKNW-UHFFFAOYSA-N [2-(pyridin-2-ylmethylamino)thieno[3,2-d]pyrimidin-4-yl]-thiophen-2-ylmethanone Chemical compound N=1C(NCC=2N=CC=CC=2)=NC=2C=CSC=2C=1C(=O)C1=CC=CS1 IVQBRHHYYXDKNW-UHFFFAOYSA-N 0.000 claims description 2
• FAFSUKUFAUCLQF-UHFFFAOYSA-N [2-[2-(1h-imidazol-5-yl)ethylamino]thieno[3,2-d]pyrimidin-4-yl]-thiophen-2-ylmethanone Chemical compound N=1C(NCCC=2N=CNC=2)=NC=2C=CSC=2C=1C(=O)C1=CC=CS1 FAFSUKUFAUCLQF-UHFFFAOYSA-N 0.000 claims description 2
• YHZVBPJLMKPEHB-MRVPVSSYSA-N [2-[[(2r)-1-hydroxypropan-2-yl]amino]thieno[3,2-d]pyrimidin-4-yl]-thiophen-2-ylmethanone Chemical compound C=12SC=CC2=NC(N[C@@H](CO)C)=NC=1C(=O)C1=CC=CS1 YHZVBPJLMKPEHB-MRVPVSSYSA-N 0.000 claims description 2
• XWXRYDGWIIFROW-MRVPVSSYSA-N [2-[[(2r)-2-hydroxypropyl]amino]thieno[3,2-d]pyrimidin-4-yl]-thiophen-2-ylmethanone Chemical compound C=12SC=CC2=NC(NC[C@H](O)C)=NC=1C(=O)C1=CC=CS1 XWXRYDGWIIFROW-MRVPVSSYSA-N 0.000 claims description 2
• YHZVBPJLMKPEHB-QMMMGPOBSA-N [2-[[(2s)-1-hydroxypropan-2-yl]amino]thieno[3,2-d]pyrimidin-4-yl]-thiophen-2-ylmethanone Chemical compound C=12SC=CC2=NC(N[C@H](CO)C)=NC=1C(=O)C1=CC=CS1 YHZVBPJLMKPEHB-QMMMGPOBSA-N 0.000 claims description 2
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• 125000004171 alkoxy aryl group Chemical group 0.000 claims description 2
• 125000006550 alkoxycarbonyl aryl group Chemical group 0.000 claims description 2
• 125000005125 aryl alkyl amino carbonyl group Chemical group 0.000 claims description 2
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• PNZXMIKHJXIPEK-UHFFFAOYSA-N cyclohexanecarboxamide Chemical compound NC(=O)C1CCCCC1 PNZXMIKHJXIPEK-UHFFFAOYSA-N 0.000 claims 1
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• 239000007787 solid Substances 0.000 description 41
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• 238000012360 testing method Methods 0.000 description 10
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• 239000003921 oil Substances 0.000 description 9
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• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
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