SI9600102A - Quinazoline derivatives - Google Patents
Quinazoline derivatives Download PDFInfo
- Publication number
- SI9600102A SI9600102A SI9600102A SI9600102A SI9600102A SI 9600102 A SI9600102 A SI 9600102A SI 9600102 A SI9600102 A SI 9600102A SI 9600102 A SI9600102 A SI 9600102A SI 9600102 A SI9600102 A SI 9600102A
- Authority
- SI
- Slovenia
- Prior art keywords
- amine
- quinazolin
- phenyl
- ethynyl
- alkyl
- Prior art date
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- 125000002294 quinazolinyl group Chemical class N1=C(N=CC2=CC=CC=C12)* 0.000 title 1
- -1 4-(substitutedphenylamino)quinazoline Chemical class 0.000 claims abstract description 215
- 150000001875 compounds Chemical class 0.000 claims abstract description 111
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 12
- 201000010099 disease Diseases 0.000 claims abstract description 9
- 230000003463 hyperproliferative effect Effects 0.000 claims abstract description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 53
- 125000000217 alkyl group Chemical group 0.000 claims description 39
- 238000000034 method Methods 0.000 claims description 37
- 229910052739 hydrogen Inorganic materials 0.000 claims description 34
- 239000001257 hydrogen Substances 0.000 claims description 34
- 229910052757 nitrogen Inorganic materials 0.000 claims description 31
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 30
- 150000001412 amines Chemical class 0.000 claims description 28
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 25
- 150000002431 hydrogen Chemical class 0.000 claims description 22
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 21
- 229910052760 oxygen Inorganic materials 0.000 claims description 18
- 229910052717 sulfur Inorganic materials 0.000 claims description 18
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 15
- 238000002360 preparation method Methods 0.000 claims description 15
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 15
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 14
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 14
- 125000003282 alkyl amino group Chemical group 0.000 claims description 14
- 239000001301 oxygen Substances 0.000 claims description 14
- 239000011593 sulfur Substances 0.000 claims description 14
- 125000005842 heteroatom Chemical group 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- 125000004432 carbon atom Chemical group C* 0.000 claims description 12
- 125000004122 cyclic group Chemical group 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 9
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 8
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 125000004546 quinazolin-4-yl group Chemical group N1=CN=C(C2=CC=CC=C12)* 0.000 claims description 8
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 claims description 7
- 229920000642 polymer Polymers 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 7
- 241000124008 Mammalia Species 0.000 claims description 6
- 125000004423 acyloxy group Chemical group 0.000 claims description 6
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- XSMVZQAPXNUGBP-UHFFFAOYSA-N 2-[4-(3-ethynylanilino)-7-(2-methoxyethoxy)quinazolin-6-yl]oxyethyl acetate Chemical compound C=12C=C(OCCOC(C)=O)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 XSMVZQAPXNUGBP-UHFFFAOYSA-N 0.000 claims description 5
- 150000001721 carbon Chemical group 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 5
- MYRTYDVEIRVNKP-UHFFFAOYSA-N 1,2-Divinylbenzene Chemical group C=CC1=CC=CC=C1C=C MYRTYDVEIRVNKP-UHFFFAOYSA-N 0.000 claims description 4
- MTLKTHNRZJKPRP-UHFFFAOYSA-N 2-[4-(3-ethynylanilino)-6-(2-methoxyethoxy)quinazolin-7-yl]oxyethanol Chemical compound N1=CN=C2C=C(OCCO)C(OCCOC)=CC2=C1NC1=CC=CC(C#C)=C1 MTLKTHNRZJKPRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- TZHTWWZUWBDHPB-UHFFFAOYSA-N 2-[4-(3-ethynylanilino)-6-(2-methoxyethoxy)quinazolin-7-yl]oxyethyl acetate Chemical compound N1=CN=C2C=C(OCCOC(C)=O)C(OCCOC)=CC2=C1NC1=CC=CC(C#C)=C1 TZHTWWZUWBDHPB-UHFFFAOYSA-N 0.000 claims description 3
- YWSAEKIQJPQSDJ-UHFFFAOYSA-N 2-[4-(3-ethynylanilino)-7-(2-hydroxyethoxy)quinazolin-6-yl]oxyethanol Chemical compound C=12C=C(OCCO)C(OCCO)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 YWSAEKIQJPQSDJ-UHFFFAOYSA-N 0.000 claims description 3
- 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- NRKMCAKKJSZIRN-UHFFFAOYSA-N 4-n-(3-ethynylphenyl)quinazoline-4,6-diamine Chemical compound C12=CC(N)=CC=C2N=CN=C1NC1=CC=CC(C#C)=C1 NRKMCAKKJSZIRN-UHFFFAOYSA-N 0.000 claims description 3
- MLFVZJQGCZIVJI-UHFFFAOYSA-N 4-n-(3-ethynylphenyl)quinazoline-4,7-diamine Chemical compound N=1C=NC2=CC(N)=CC=C2C=1NC1=CC=CC(C#C)=C1 MLFVZJQGCZIVJI-UHFFFAOYSA-N 0.000 claims description 3
- AZMJCKIZWVLDEH-UHFFFAOYSA-N 6,7-diethoxy-n-(3-ethynylphenyl)-2h-quinazolin-1-amine Chemical compound C1=2C=C(OCC)C(OCC)=CC=2C=NCN1NC1=CC=CC(C#C)=C1 AZMJCKIZWVLDEH-UHFFFAOYSA-N 0.000 claims description 3
- 125000004399 C1-C4 alkenyl group Chemical group 0.000 claims description 3
- XOTGKYTUNDYTBS-UHFFFAOYSA-N N-(3-ethynylphenyl)-6,7-dimethoxy-4-quinazolinamine Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 XOTGKYTUNDYTBS-UHFFFAOYSA-N 0.000 claims description 3
- 150000001345 alkine derivatives Chemical class 0.000 claims description 3
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims description 3
- OVBFNQKSLJYVCB-UHFFFAOYSA-N n-(4-ethynylphenyl)-6,7-dimethoxyquinazolin-4-amine Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1NC1=CC=C(C#C)C=C1 OVBFNQKSLJYVCB-UHFFFAOYSA-N 0.000 claims description 3
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 3
- 125000005544 phthalimido group Chemical group 0.000 claims description 3
- 229910052727 yttrium Inorganic materials 0.000 claims description 3
- 125000004760 (C1-C4) alkylsulfonylamino group Chemical group 0.000 claims description 2
- KOQIAZNBAWFSQM-UHFFFAOYSA-N 2-[4-(3-ethynylanilino)-7-(2-methoxyethoxy)quinazolin-6-yl]oxyethanol Chemical compound C=12C=C(OCCO)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 KOQIAZNBAWFSQM-UHFFFAOYSA-N 0.000 claims description 2
- RPBDPTCBOMUIEM-UHFFFAOYSA-N 2-[4-(3-ethynylanilino)quinazolin-6-yl]guanidine Chemical compound C12=CC(NC(=N)N)=CC=C2N=CN=C1NC1=CC=CC(C#C)=C1 RPBDPTCBOMUIEM-UHFFFAOYSA-N 0.000 claims description 2
- OPZQXOBOVGSGMM-UHFFFAOYSA-N 6,7-bis(2-chloroethoxy)-n-(3-ethynylphenyl)quinazolin-4-amine Chemical compound C=12C=C(OCCCl)C(OCCCl)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 OPZQXOBOVGSGMM-UHFFFAOYSA-N 0.000 claims description 2
- KNIMCHSAQRHRKH-UHFFFAOYSA-N 6,7-dibutoxy-n-(3-ethynylphenyl)-2h-quinazolin-1-amine Chemical compound C1=2C=C(OCCCC)C(OCCCC)=CC=2C=NCN1NC1=CC=CC(C#C)=C1 KNIMCHSAQRHRKH-UHFFFAOYSA-N 0.000 claims description 2
- DBLVDARHJKFUSK-UHFFFAOYSA-N 6-(2-chloroethoxy)-n-(3-ethynylphenyl)-7-(2-methoxyethoxy)quinazolin-4-amine Chemical compound C=12C=C(OCCCl)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 DBLVDARHJKFUSK-UHFFFAOYSA-N 0.000 claims description 2
- BIHHIONDWPZXJC-UHFFFAOYSA-N 7-(2-chloroethoxy)-n-(3-ethynylphenyl)-6-(2-methoxyethoxy)quinazolin-4-amine Chemical compound N1=CN=C2C=C(OCCCl)C(OCCOC)=CC2=C1NC1=CC=CC(C#C)=C1 BIHHIONDWPZXJC-UHFFFAOYSA-N 0.000 claims description 2
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- 229910021386 carbon form Inorganic materials 0.000 claims description 2
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 claims description 2
- MJGHBVDYEIMCDA-UHFFFAOYSA-N methyl 4-(3-ethynylanilino)quinazoline-6-carboxylate Chemical compound C12=CC(C(=O)OC)=CC=C2N=CN=C1NC1=CC=CC(C#C)=C1 MJGHBVDYEIMCDA-UHFFFAOYSA-N 0.000 claims description 2
- YVEQUSIQTPNUHB-UHFFFAOYSA-N n-(3-ethynyl-2-methylphenyl)-6,7-bis(2-methoxyethoxy)-2h-quinazolin-1-amine Chemical compound C1=2C=C(OCCOC)C(OCCOC)=CC=2C=NCN1NC1=CC=CC(C#C)=C1C YVEQUSIQTPNUHB-UHFFFAOYSA-N 0.000 claims description 2
- FFNSJZNWHNDAKT-UHFFFAOYSA-N n-(3-ethynyl-4-fluorophenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=C(F)C(C#C)=C1 FFNSJZNWHNDAKT-UHFFFAOYSA-N 0.000 claims description 2
- UEKLAZGZLXRYAO-UHFFFAOYSA-N n-(3-ethynyl-4-fluorophenyl)-6,7-dimethoxyquinazolin-4-amine Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(C#C)=C1 UEKLAZGZLXRYAO-UHFFFAOYSA-N 0.000 claims description 2
- FKTOOVAYMNBBOM-UHFFFAOYSA-N n-(3-ethynylphenyl)-6,7-di(propan-2-yloxy)-2h-quinazolin-1-amine Chemical compound C1=2C=C(OC(C)C)C(OC(C)C)=CC=2C=NCN1NC1=CC=CC(C#C)=C1 FKTOOVAYMNBBOM-UHFFFAOYSA-N 0.000 claims description 2
- XNMSCKOLUZHGET-UHFFFAOYSA-N n-(3-ethynylphenyl)-6-methylsulfonylquinazolin-4-amine Chemical compound C12=CC(S(=O)(=O)C)=CC=C2N=CN=C1NC1=CC=CC(C#C)=C1 XNMSCKOLUZHGET-UHFFFAOYSA-N 0.000 claims description 2
- AWQMPORAKHHXOC-UHFFFAOYSA-N n-(3-ethynylphenyl)-7-methoxyquinazolin-4-amine Chemical compound N=1C=NC2=CC(OC)=CC=C2C=1NC1=CC=CC(C#C)=C1 AWQMPORAKHHXOC-UHFFFAOYSA-N 0.000 claims description 2
- PXVOMAUMUFQFKF-UHFFFAOYSA-N n-(3-ethynylphenyl)-7-nitroquinazolin-4-amine Chemical compound N=1C=NC2=CC([N+](=O)[O-])=CC=C2C=1NC1=CC=CC(C#C)=C1 PXVOMAUMUFQFKF-UHFFFAOYSA-N 0.000 claims description 2
- LBAXXGJEHLZEQP-UHFFFAOYSA-N n-(3-ethynylphenyl)-[1,3]dioxolo[4,5-g]quinazolin-8-amine Chemical compound C#CC1=CC=CC(NC=2C3=CC=4OCOC=4C=C3N=CN=2)=C1 LBAXXGJEHLZEQP-UHFFFAOYSA-N 0.000 claims description 2
- MZSAGCRPYHVVDD-UHFFFAOYSA-N n-(5-ethynyl-2-methylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC(C#C)=CC=C1C MZSAGCRPYHVVDD-UHFFFAOYSA-N 0.000 claims description 2
- 239000002243 precursor Substances 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 26
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 7
- DUGLQQONGNNEMW-UHFFFAOYSA-N 2-[4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl]acetamide Chemical compound C=12C=C(CC(N)=O)C(OC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 DUGLQQONGNNEMW-UHFFFAOYSA-N 0.000 claims 2
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 claims 2
- 125000003118 aryl group Chemical group 0.000 claims 2
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims 1
- COYVNRXIBHVWOA-UHFFFAOYSA-N 2-[4-(3-ethynylanilino)-7-propan-2-yloxyquinazolin-6-yl]acetamide Chemical compound C=12C=C(CC(N)=O)C(OC(C)C)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 COYVNRXIBHVWOA-UHFFFAOYSA-N 0.000 claims 1
- TYRDQXAAPHCGHJ-UHFFFAOYSA-N 2-[4-(3-ethynylanilino)-7-propoxyquinazolin-6-yl]acetamide Chemical compound C=12C=C(CC(N)=O)C(OCCC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 TYRDQXAAPHCGHJ-UHFFFAOYSA-N 0.000 claims 1
- OLQYOMSHERWQMA-UHFFFAOYSA-N 2-[7-ethoxy-4-(3-ethynylanilino)quinazolin-6-yl]acetamide Chemical compound C=12C=C(CC(N)=O)C(OCC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 OLQYOMSHERWQMA-UHFFFAOYSA-N 0.000 claims 1
- NWUMMKLVEFBCRV-UHFFFAOYSA-N 2-[[1-(3-ethynyl-2-methylanilino)-7-(2-hydroxyethoxy)-2h-quinazolin-6-yl]oxy]ethanol Chemical compound C1=CC=C(C#C)C(C)=C1NN1C2=CC(OCCO)=C(OCCO)C=C2C=NC1 NWUMMKLVEFBCRV-UHFFFAOYSA-N 0.000 claims 1
- BLEIGNISAJGLGG-UHFFFAOYSA-N 2-[[1-(3-ethynylanilino)-7-(2-hydroxyethoxy)-2h-quinazolin-6-yl]oxy]ethanol Chemical compound C1=2C=C(OCCO)C(OCCO)=CC=2C=NCN1NC1=CC=CC(C#C)=C1 BLEIGNISAJGLGG-UHFFFAOYSA-N 0.000 claims 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims 1
- XCMVOGXJGDEPQM-UHFFFAOYSA-N 3-[4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl]propanamide Chemical compound C=12C=C(CCC(N)=O)C(OC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 XCMVOGXJGDEPQM-UHFFFAOYSA-N 0.000 claims 1
- HZDFRVLTROVMEI-UHFFFAOYSA-N 3-[4-(3-ethynylanilino)-7-propan-2-yloxyquinazolin-6-yl]propanamide Chemical compound C=12C=C(CCC(N)=O)C(OC(C)C)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 HZDFRVLTROVMEI-UHFFFAOYSA-N 0.000 claims 1
- OIESHIYYNQZRCL-UHFFFAOYSA-N 3-[4-(3-ethynylanilino)-7-propoxyquinazolin-6-yl]propanamide Chemical compound C=12C=C(CCC(N)=O)C(OCCC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 OIESHIYYNQZRCL-UHFFFAOYSA-N 0.000 claims 1
- JIKUZGKMYUACPU-UHFFFAOYSA-N 3-[7-ethoxy-4-(3-ethynylanilino)quinazolin-6-yl]propanamide Chemical compound C=12C=C(CCC(N)=O)C(OCC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 JIKUZGKMYUACPU-UHFFFAOYSA-N 0.000 claims 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims 1
- SRGSZEVWWPMFLC-UHFFFAOYSA-N methyl 4-(3-ethynylanilino)quinazoline-7-carboxylate Chemical compound N=1C=NC2=CC(C(=O)OC)=CC=C2C=1NC1=CC=CC(C#C)=C1 SRGSZEVWWPMFLC-UHFFFAOYSA-N 0.000 claims 1
- RMTOBWAVMBQAOO-UHFFFAOYSA-N n-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-2h-quinazolin-1-amine Chemical compound C1=2C=C(OCCOC)C(OCCOC)=CC=2C=NCN1NC1=CC=CC(C#C)=C1 RMTOBWAVMBQAOO-UHFFFAOYSA-N 0.000 claims 1
- YHGQPRLZLURJKG-UHFFFAOYSA-N n-(3-ethynylphenyl)-6,7-dimethoxy-2h-quinazolin-1-amine Chemical compound C1=2C=C(OC)C(OC)=CC=2C=NCN1NC1=CC=CC(C#C)=C1 YHGQPRLZLURJKG-UHFFFAOYSA-N 0.000 claims 1
- 238000011282 treatment Methods 0.000 abstract description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 138
- 239000000047 product Substances 0.000 description 129
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 100
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 73
- 239000007787 solid Substances 0.000 description 64
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 54
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 48
- 239000000203 mixture Substances 0.000 description 46
- 239000011541 reaction mixture Substances 0.000 description 42
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 34
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 32
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 31
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 30
- 238000004128 high performance liquid chromatography Methods 0.000 description 30
- 239000000243 solution Substances 0.000 description 30
- 239000002904 solvent Substances 0.000 description 30
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 29
- 206010028980 Neoplasm Diseases 0.000 description 27
- 239000012267 brine Substances 0.000 description 26
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 26
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 25
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
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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 24
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 24
- 239000011734 sodium Substances 0.000 description 22
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 22
- 238000006243 chemical reaction Methods 0.000 description 21
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 20
- 239000002585 base Substances 0.000 description 20
- 125000005843 halogen group Chemical group 0.000 description 20
- 239000000741 silica gel Substances 0.000 description 19
- 229910002027 silica gel Inorganic materials 0.000 description 19
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 18
- NNKQLUVBPJEUOR-UHFFFAOYSA-N 3-ethynylaniline Chemical compound NC1=CC=CC(C#C)=C1 NNKQLUVBPJEUOR-UHFFFAOYSA-N 0.000 description 17
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- FXNPOBUEIRDARI-UHFFFAOYSA-N n-(3-ethynylphenyl)-7-(2-imidazol-1-ylethoxy)-6-(2-methoxyethoxy)quinazolin-4-amine;dihydrochloride Chemical compound Cl.Cl.N1=CN=C2C=C(OCCN3C=NC=C3)C(OCCOC)=CC2=C1NC1=CC=CC(C#C)=C1 FXNPOBUEIRDARI-UHFFFAOYSA-N 0.000 description 1
- VITDPUGQQDQGEF-UHFFFAOYSA-N n-(3-ethynylphenyl)-7-methoxyquinazolin-4-amine;hydrochloride Chemical compound Cl.N=1C=NC2=CC(OC)=CC=C2C=1NC1=CC=CC(C#C)=C1 VITDPUGQQDQGEF-UHFFFAOYSA-N 0.000 description 1
- QNXPBWBRUTVOIE-UHFFFAOYSA-N n-(3-ethynylphenyl)-7-nitroquinazolin-4-amine;hydrochloride Chemical compound Cl.N=1C=NC2=CC([N+](=O)[O-])=CC=C2C=1NC1=CC=CC(C#C)=C1 QNXPBWBRUTVOIE-UHFFFAOYSA-N 0.000 description 1
- MANKXCCTWMBZAA-UHFFFAOYSA-N n-(3-ethynylphenyl)-7-propylsulfanylquinazolin-4-amine;hydrochloride Chemical compound Cl.N=1C=NC2=CC(SCCC)=CC=C2C=1NC1=CC=CC(C#C)=C1 MANKXCCTWMBZAA-UHFFFAOYSA-N 0.000 description 1
- WMJUQSKPKWEBOC-UHFFFAOYSA-N n-(3-ethynylphenyl)-[1,3]dioxolo[4,5-g]quinazolin-8-amine;hydrochloride Chemical compound Cl.C#CC1=CC=CC(NC=2C3=CC=4OCOC=4C=C3N=CN=2)=C1 WMJUQSKPKWEBOC-UHFFFAOYSA-N 0.000 description 1
- RSGPYKWXSSTIGC-UHFFFAOYSA-N n-(4-azidophenyl)-6,7-dimethoxyquinazolin-4-amine;hydrochloride Chemical compound Cl.C=12C=C(OC)C(OC)=CC2=NC=NC=1NC1=CC=C(N=[N+]=[N-])C=C1 RSGPYKWXSSTIGC-UHFFFAOYSA-N 0.000 description 1
- VIKZXHATNZVSPZ-UHFFFAOYSA-N n-(5-ethynyl-2-methylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine;hydrochloride Chemical compound Cl.C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC(C#C)=CC=C1C VIKZXHATNZVSPZ-UHFFFAOYSA-N 0.000 description 1
- NPWROGXMBGWEJT-UHFFFAOYSA-N n-[4-(3-ethynylanilino)quinazolin-6-yl]methanesulfonamide Chemical compound C12=CC(NS(=O)(=O)C)=CC=C2N=CN=C1NC1=CC=CC(C#C)=C1 NPWROGXMBGWEJT-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000027405 negative regulation of phosphorylation Effects 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 231100000590 oncogenic Toxicity 0.000 description 1
- 230000002246 oncogenic effect Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 239000006201 parenteral dosage form Substances 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- DGTNSSLYPYDJGL-UHFFFAOYSA-N phenyl isocyanate Chemical compound O=C=NC1=CC=CC=C1 DGTNSSLYPYDJGL-UHFFFAOYSA-N 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- FJVZDOGVDJCCCR-UHFFFAOYSA-M potassium periodate Chemical compound [K+].[O-]I(=O)(=O)=O FJVZDOGVDJCCCR-UHFFFAOYSA-M 0.000 description 1
- OKBMCNHOEMXPTM-UHFFFAOYSA-M potassium peroxymonosulfate Chemical compound [K+].OOS([O-])(=O)=O OKBMCNHOEMXPTM-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- XAIQADWTFHMCOS-UHFFFAOYSA-N quinazoline-6-carbonitrile Chemical compound N1=CN=CC2=CC(C#N)=CC=C21 XAIQADWTFHMCOS-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 230000001850 reproductive effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000000565 sealant Substances 0.000 description 1
- 150000003335 secondary amines Chemical group 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 125000004469 siloxy group Chemical group [SiH3]O* 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- ZVCDLGYNFYZZOK-UHFFFAOYSA-M sodium cyanate Chemical compound [Na]OC#N ZVCDLGYNFYZZOK-UHFFFAOYSA-M 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- KIMPPGSMONZDMN-UHFFFAOYSA-N sodium;dihydrogen phosphite Chemical compound [Na+].OP(O)[O-] KIMPPGSMONZDMN-UHFFFAOYSA-N 0.000 description 1
- QJDUDPQVDAASMV-UHFFFAOYSA-M sodium;ethanethiolate Chemical compound [Na+].CC[S-] QJDUDPQVDAASMV-UHFFFAOYSA-M 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 210000004272 stretch cell Anatomy 0.000 description 1
- 150000003440 styrenes Chemical class 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 150000003461 sulfonyl halides Chemical class 0.000 description 1
- 150000003463 sulfur Chemical class 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 208000013076 thyroid tumor Diseases 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- WFVAXJGPWUHVSD-UHFFFAOYSA-N trimethyl-[2-(4-methyl-3-nitrophenyl)ethynyl]silane Chemical compound CC1=CC=C(C#C[Si](C)(C)C)C=C1[N+]([O-])=O WFVAXJGPWUHVSD-UHFFFAOYSA-N 0.000 description 1
- IHIXIJGXTJIKRB-UHFFFAOYSA-N trisodium vanadate Chemical compound [Na+].[Na+].[Na+].[O-][V]([O-])([O-])=O IHIXIJGXTJIKRB-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- LSGOVYNHVSXFFJ-UHFFFAOYSA-N vanadate(3-) Chemical compound [O-][V]([O-])([O-])=O LSGOVYNHVSXFFJ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Dermatology (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
DERIVATI KINAZOLINA Ozadje izuma
Ta izum se nanaša na 4-(substituiranefenilamino) derivate kinazolina, ki se uporabljajo za zdravljenje hiperproliferativnih bolezni, kot je na primer rak, pri sesalcih.
Večina sodobnih oblik zdravljenja raka uporablja spojine, ki zavirajo sintezo DNA. Take spojine so toksične za vse celice, vendar je koristno njihovo delovanje na tumorne celice, ki se hitro razmnožujejo. Raziskani so bili alternativni dostopi do spojin, ki delujejo na rakave celice še na drugačne načine, kot z zaviranjem sinteze DNA, s ciljem, da bi povečali selektivnost pri delovanju na rakave celice.
Znano je, da lahko celica postane rakava z učinkovanjem transformacije dela njene DNA na onkogen (gen, ki vodi do tvorbe malignih tumornih celic). Veliko onkogenov kodira proteine, ki odstopajo od tirozin kinaz sposobnih povzročiti transformacijo celice. Alternativno lahko prevelike količine normalne proto-onkogenetske tirozin kinaze prav tako povzroče motnje pri delitvi, ki se včasih pokažejo kot maligni fenotipi.
Receptor tirozin kinaze so veliki encimi,ki raztezajo celične membrane in vsebuje ekstracelularna področja vezave za rastni faktor, kot je epidermalni rastni faktor, transmembransko področje in intracelularni del, ki deluje kot kinaza, da fosforilizira specifične ostanke tirozina v proteinih in zato vpliva na množenje celic. Znano je, da se takšne kinaze pogosto izražajo pri pogostih oblikah raka, kot je rak na prsih, rak na gastrointestinalnem sistemu, kot je rak debelega črevesja, danke ali želodca, levkemija in rak jajčnikov, bronhijev ali trebušne slinavke. Prav tako je bila dokazana prisotnost povečanih količin receptorjev epidermalnega rastnega faktorja (EGFR), ki vsebujejo tirozin kinazo, s spremenjeno aktivnostjo pri veliko oblikah raka kot so rak na možganih, pljučih, epidermalnih celicah, na mehurju, želodcu, prsih, na glavi in vratu, požiralniku ter ginekološki in ščitnični tumorji.
Prav tako so inhibitorji receptorjev tirozin kinaz uporabni kot selektivni inhibitorji rasti rakavih celic pri sesalcih. Na primer erbstatin, inhibitor tirozin kinaze, selektivno zmanjšuje rast človeških rakavih celic transplantiranih na poskusne gole miši, ki izraža receptorje epidermalnega rastnega faktorja tirozin kinaze (EGFR), vendar je brez učinka na rast drugih vrst raka, ki nima EGF receptorja.
Lastnosti inhibitorjev tirozin kinaz kaže tudi veliko drugih spojin, kot so na primer derivati stirena. Najnovejših pet evropskih patentnih objav s številkami EP 0 566 226 Al, EP 0 602 851 Al, EP 0 635 507 Al, EP 0 635 498 Al in EP 0 520 722 Al, odkriva, da določeni kinazolonski derivati delujejo citostatično, kot inhibitorji tirozin kinaz. Prav tako so v PCT objavi št. W0 92/20642 objavili odkritje delovanja bis-mono in bicikličnih arilnih in heteroarilnih spojin kot inhibitorjev tirozin kinaz.
Zgoraj opisane protirakave spojine dajejo pomemben prispevek k nadaljnim raziskavam na tem področju in k boljšim ter zanesljivejšim zdravilom.
Povzetek izuma
Ta izum se nanaša na 4-(substituiranefenilamino)-derivate kinazolina s formulo I
in farmacevtsko sprejemljive soli ter njihove predhodnice zdravil, značilne po tem, da je m 1, 2 ali 3;
je vsak R1 samostojno izbran med hidrogen, halo, hidroksi, amino, hidroksiamino, karboksi, (Ci-Cu) alkoksikarbonll, nitro, gvanidino, ureido, karbamoil, ciano, trifluorometil, (R6) 2N~karbonil in fenil-W-alkil, značilen po tem, da je W izbran med enojno vezjo, 0, S in NH;
ali, da je vsak R1 samostojno izbran med ciano- (Ci~C4) alkil in R9, kjer je R9 izbran iz skupin, ki jih sestavljajo R5, R50, (R6)2N, R7C(=0), R50NH, A in R5Y; R5 je (Ci-C4) alkil;
R6 je vodik ali R5, kjer so vsi R5 enaki ali pa različni; R7 je R5, R50 ali (R6)2N; A izberemo med piperidino-, morfolino, pirolidino in 4-R6 piperazin-l-il, imidazol-l-il, 4-piridon1-il, karboksi-(C1-C4)-alkil, fenoksi, fenil, fenilsulfanil, (C2-C4) -alkenil, (R6) 2-N-karbonil- (C1-C4)-alkil; in Y izberemo med S, SO, S02; alkilni deleži v (Re)2N so lahko substituirni s halo ali R9, pri čemer je R5 definiran zgoraj in alkilni deleža R5 in R50 sta lahko substitu j. rana s halo, R60 ali R9' kjer sta R6 in R9 definirana kot zgoraj in se dobljene skupine lahko substituirajo s halo ali R9 pod pogojem, da se dušik, kisik, žveplo ali kateri drug heteroatom ne morejo vezati na isti ogljikov atom ter, da lahko R1 vsebuje največ tri R9 enote;
ali vsak R1 je neodvisno izbran med R5-sulfonamino, ftalimido-(C1-C4)-alkilsulfonamino, benzamido, benzensulfonamino, 3-fenilureido, 2-oksopirolidin-l-il,
2,5-dioksopirolidin-l-il in R10-(C2-C4)-alkilamino, kjer je R10 izbran med halo, R60, (C2-C4)-alkanoiloksi, R7C(=O) in (R6)2N; in kjer lahko benzamido, benzensulfonamino, fenil, fenoksi, anilino ali fenilsulfanil substituent v R1 nosi še enega ali dva halogena, (C1-C4)alkil, ciano, metansulfonil ali (Ci~C4)-alkoksi substituente;
ali da katerakoli dva R1 vzeta skupaj, z ogljikovimi atomi, na katere sta vezana vsebujeta 5-8 členi obroč z vsaj enim ali dvema heteroatomoma, ki so lahko kisik, žveplo ali dušik; kjer so alkilne skupine ali alkilni del v alkoksi ali alkilamino skupini v ravni verigi ali, če vsebujejo vsaj tri ogljikove atome, v razvejani ali ciklični obliki;
R2 je vodik ali neobvezno substituiran (Ci-C6) -alkil; n je 1 ali 2 in vsak R3 je neodvisno vodik, neobvezno substituiran (Ci-C6)-alkil, neobvezno substituiran amino, halo, hidroksi, neobvezno substituiran hidroksi;
R4 je azido ali R11-etinil, kjer je R11 hidrogen, neobvezno substituiran (C!-C6)alkil, kjer so substituenti izbrani iz skupine, ki obsega hidrogen, amino, hidroksi, R50, R^H in (R5)2N.
Natančneje se izum nanaša na spojine s formulo I, kjer so m, n, R1 in R3 definirani kot zgoraj. R2 je hidrogen, R4 je Rn-etinil, kjer je R11 hidrogen, neobvezno substituiran (Ci-C6)-alkil, pri čemer so substituenti izbrani izmed hidrogen, amino, hidroksi, R50, R5NH in (R5)2N ali R4 je azido.
Izum se nanaša tudi na spojine s formulo I, pri čemer je m med 1 in 2, n je definiran zgoraj, R1 pa je neodvisno izbran med hidrogen, hidroksi, amino, hidroksiamino, karboksi, nitro, karbamoil, ureido;
R5 lahko substituiramo s halo, R60, HOC(=O), (R6)2NC(=O), A in (R6)2N;
R120, za kjer je R12 = HK, K pa je (C2-C4) alkil, lahko substituiran s halo, R60, (C2-C4)- alkanoiloksi, HOC(=O), A in (R6)2N, R6OKO, R6OKNH, CN in fenil; R5NH je lahko substituiran halo, (C2-C4)-alkanoiloksi, R60, R7C(=O), (R6)2N,
A, R6OKO, R6OKNH, C6H5Y, CN;
(R6)2N(C=O), R5ONH, R5S, (Ci-C4) -alkilsulfonilamino, ftalimido-(Cx-C4)-alkilsulfonilamino, 3-fenilureido, 2oksopirolidin-I-il, 2, 5-dioksopirolidin-l-il, halo-(C2-C4)alkanoilamino, hidroksi-(C2-C4)-alkanoilamino, (C2-C4)alkanoiloksi- (C2-C4) -alkanoilamino, (Ci-C4) -alkoksi- (C2_C4) alkanoilamino, karboksi- (C2-C4) -alkanoilamino, (Ci-C4)alkoksikarbonil- (C2-C4) -alkanoilamino, karbamoil- (C2-C4) alkanoilamino, N- (Ci~C4) -alkilkarbamoil- (C2-C4) alkanoilamino, N, N-di- [ (Ci~C4) -alkil] karbamoil- (C2.C4) alkanoilamino, amino-(C2-C4)-alkanoilamino, (Ci~C4) -alkilamino- (C2-C4) -alkanoilamino, di- (Ci~C4) -alkil-amino- (C2-C4) alkanoilamino, kjer imajo fenil, fenoksi ali anilino substituenti v R1 lahko enega ali dva halogena, (Ci~C4)-alkil ali (Ci~C4)-alkoksi substituente. Katerakoli dva R1 povezana preko ogljika tvorita 5-8 členi obroč, z vsaj enim ali dvema heteroatomoma kisika, žvepla ali dušika; značilne po tem, da so alkilne skupine ali alkilni del alkoksi ali alkilamino skupine v obliki ravne verige ali če vsebuje vsaj tri ogljikove atome v ciklični obliki ali razvejana;
vsak R3 je neodvisno hidrogen, metil, etil, amino, halo in hidroksi;
R4 je R11-etinil, pri čemer je R11 hidrogen.
Zlasti pa se izum nanaša na spojine v formuli I, pri čemer so m, n, R1, R2 in R3 definirani zgoraj in vsak R1 je neodvisno izbran med hidrogen, hidroksi, amino, hidroksiamino, nitro, karbamoil, ureido, R5 lahko substituiran s halo, R60, HOC(=O), H2NC(=O);
R50 je lahko substituiran s halo, R60, (C2-C4)alkanoiloksi, HOC(=O), (R6)2N, A, fenil;
R5NH, (R5)2N, R5NH2, (R5)2NH, R5NHC(=O), (R5)2NC(=O), r5s, fenil-(C2-C4)-alkoksi, kjer je lahko fenil v R1 nosi enega ali dva substituenta halo, R5 ali R50 in kjer katerakoli dva R1 vzeta skupaj z ogljikoma na katera sta vezana, obsegata 5-8 členi obroč, z vsaj enim ali dvema heteroatomoma kisika, žvepla ali dušika; značilne po tem, da so alkilne skupine ali alkilni del alkoksi ali alkilamino skupine v obliki ravne verige ali če vsebuje vsaj tri ogljikove atome v ciklični obliki ali razvejana.
Izum se največkrat nanaša na spojine s formulo I, izbranih iz skupin, ki jih sestavljajo (6,7-dimetoksikinazolin-4-il)-(3-etinilfenil)-amin);
(6,7-dimetoksikinazolin-4-il)-[3-(3'-hidroksipropin-1il)fenil)-amin;
(6,7-dimetoksikinazolin-4-il)-[(3-(2'-(aminometil)etinil)fenil)-amin;
[ (3-etinilfenil)-(6-nitrokinazolin-4-il)-amin;
(6,7-dimetoksikinazolin-4-il)-(4-etinilfenil)-amin;
(6,7-dimetoksikinazolin-4-il)-(3-etinil-2-metilfenil)amin;
(6-aminokinazolin-4-il)-(3-etinilfenil)-amin;
(3-etinilfenil)-(6-metansulfonilaminokinazolin-4-il)amin;
(3-etinilfenil)-(6,7-metilendioksikinazolin-4-il)-amin;
(6,7-dimetoksikinazolin-4-il)-(3-etinil-6-metilfenil)amin;
(3-etinilfenil) -(7-nitrokinazolin-4-il)-amin; (3-etinilfenil) -[6- (4' -toluensulfonilami.no) -kinazolin-4il]-amin;
(3-etinilfenil)-{6-[2'-ftalimido-etan-1'-ilsulfonilamino]kinazolin-4-il}-amin;
(3-etinilfenil)-(6-gvanidinokinazolin-4-il)-amin; (7-aminokinazolin-4-il)-(3-etinilfenil)-amin; (3-etinilfenil)-(7-metoksikinazolin-4-il)-amin; (6-karbometoksikinazolin-4-il)-(3-etinilfenil)-amin; (7-karbornetoksikinazolin-4-il) - (3-etinilfenil) -amin; [6,7-bis(2-metoksi-etoksi)kinazolin-4-il]-(3-etinilfenil) amin;
(3-azidofenil)-(6,7-dimetoksikinazolin-4-il)amin; (4-azidofenil)-(6,7-dimetoksikinazolin-4-il)amin; (3-azido-5-klorofenil)- (6,7-dimetoksikinazolin-4il)amin;
(3-etinilfenil)-(6-metansulfonil-kinazolin-4-il)-amin; (6-etansulfanil-kinazolin-4-il)-(3-etinilfenil)-amin;
(6,7-dimetoksi-kinazolin-4-il)-(3-etinil-4-fluoro-fenil) amin;
(6,7-dimetoksi-kinazolin-4-il)-[3-propin-l-il-fenil]amin;
[6,7-bis(2-metoksi-etoksi)-kinazolin-4-il]-(5-etinil-2metil-fenil)-amin;
[6, 7-bis(2-metoksi-etoksi)-kinazolin-4-il]-(3-etinil-4fluoro-fenil)-amin;
[6,7-bis(2-kloro-etoksi)-kinazolin-4-il]-(3-etinilfenil) -amin;
[6,7-bis-(2-acetoksi-etoksi)kinazolin-4-il]-(3-etinilfenil)amin;
[6-(2-kloro-etoksi)-7-(2-metoksi-etoksi)-kinazolin-4-il] (3-etinil-fenil)-amin;
2-(4-(3-etinil-fenilamino)-7-(2-hidroksi-etoksi)kinazolin-6-iloksi]-etanol;
[6-(2-acetoksi-etoksi)-7-(2-metoksi-etoksi)-kinazolin-4 il]-(3-etinil-fenil)-amin;
[7-(2-kloro-etoksi)-6-(2-metoksi-etoksi)kinazolin-4-il] (3-etinil-fenil)-amin;
[7-(2-acetoksi-etoksi)-6-(2-metoksi-etoksi)kinazolin-4il]-(3-etinil-fenil)-amin;
2-[4-(3-etinil-fenilamino)-6-(2-hidroksi-etoksi)kinazolin-7-iloksi]-etanol;
2-[4-(3-et inil-fenilamino)-7-(2-metoksi-etoksi)kinazolin-6-iloksi]-etanol;
2-[4-(3-etinil-fenilamino)-6-(2-metoksi-etoksi)kinazolin-7-iloksi]-etanol;
[6-(2-acetoksi-etoksi)-7-(2-metoksi-etoksi)-kinazolin-4 il]-(3-etinil-fenil)-amin;
(3-etinil-fenil)-{6-(2-metoksi-etoksi)-7-[2-(4-metilpiperazin-l-il)-etoksij-kinazolin-4-il}-amin;
(3-etinil-fenil)-[7-(2-metoksi-etoksi)-6-(2-morfolin-4il)-etoksi)-kinazolin-4-il]-amin;
(6,7-dietoksikinazolin-l-il)-(3-etinilfenil)-amin;
(6,7-dibutoksikinazolin-l-il)-(3-etinilfenil)-amin;
(6,7-diisopropoksikinazolin-l-il)-(3-etinilfenil)-amin;
(6,7-dietoksikinazolin-l-il)-(3-etinil-2-metil-fenil)amin;
[6,7-bis(2-metoksi-etoksi)-kinazolin-l-il]-(3-etini1-2metil-fenil)-amin;
(3-etinil-fenil)-[6-(2-hidroksi-etoksi)-7-[2-metoksietoksi) kinazolin-l-il]-amin;
[6,7-bis(2-hidroksi-etoksi)-kinazolin-l-il]-(3-etini1-2 metil-fenil) -arnin; in
2-[4-(3-etinil-fenilamino)-6-(2-metoksi-etoksi)kinazolin-7-iloksi]-etanol.
Drug cilj tega izuma je zagotoviti proces za pripravo spojine po formuli I
za katero je značilno, da m je 1, 2 ali 3;
je vsak R1 samostojno izbran med hidrogen, halo, hidroksi, amino, hidroksiamino, karboksi, (C^-CJ alkoksikarbonil, nitro, gvanidino, ureido, karbamoil, ciano, trifluorometil, (R6) 2N-karbonil in fenil-W-alkil, značilen po tem, da je W izbran med enojno vezjo, 0, S in NH;
ali, da je vsak R1 samostojno izbran med ciano-(0χ-04) alkil in R9, kjer je R9 izbran iz skupin, ki jih sestavljajo R5, R50, (R6)2N, R7C(=O), R50NH, A in R5Y; R5je (Ci~C4) alkil;
R6 je hidrogen ali R5, kjer so vsi R5 enaki ali pa različni; R7 je R5, R50 ali (R6)2N; A izberemo med piperidino-, morfolino, pirolidino in 4-R6piperazin-l-il, imidazol-l-il, 4-piridon-l-il, karboksi-(Cx—C4)-alkil, fenoksi, fenil, fenilsulfanil, (C2-C4)-alkenil, (R6) 2-N-karbonil-(Ci~C4)alkil; in Y izberemo med S, SO, S02; alkilni deleži v (RS)2N je lahko tudi substituiran s halo ali R9, pri čemer je R9 definiran zgoraj in alkilni deleži v R5 in R50 so lahko substituiraj ni s halo, R60 ali R9 in se dobljene skupine lahko substituirajo s halo ali R9 pod pogojem, da se dušik, kisik, žveplo ali kateri drug heteroatom ne morejo vezati na isti ogljikov atom ter, da lahko R1 vsebuje največ tri R9 enote;
vsak R1 je neodvisno izbran med R5-sulfonamino, ftalimido(C1-C4)-alkilsulfonamino, benzamido, benzensulfonamino, 3fenilureido, 2-oksopirolidin-l-il, 2,5-dioksopirolidin-l-il in R10-(C2-C4)-alkilamino, kjer je R10 izbran med halo,
R60, (C2-C4)-alkanoiloksi, R7C(=O) in (R6)2N; in kjer lahko benzamido, benzensulfonamino, fenil, fenoksi, anilino ali fenilsulfanil substituent v R1 nosi še enega ali dva halogena, (C1-C4) alkil, ciano, metansulfonil ali (C1-C4)alkoksi substituente;
ali katerakoli dva R1 vzeta skupaj z ogljikoma na katera sta vezana vsebujeta 5-8 členi obroč z vsaj enim ali dvema heteroatomoma, ki so lahko kisik, žveplo ali dušik; značilne po tem, da se alkilne skupine ali alkilni del v alkoksi ali alkilamino skupini v ravni verigi ali, če vsebujejo vsaj tri ogljikove atome, razvejane ali v ciklični obliki;
R2 je hidrogen ali neobvezno substituiran (Ci~C6) -alkil; n je 1 ali 2 in vsak R3 je neodvisno hidrogen, neobvezno substituiran(Ci-Ce)-alkil, neobvezno substituiran amino, halo, hidroksi, neobvezno substituiran hidroksi;
R4 je azido ali R11-etinil, značilen po tem, da je R11 hidrogen, lahko alkil substituiran, amino, hidroksi,
R5O, R^H in (R5)2N.
Le-ta vsebuje
a) obdelavo spojine s formulo
kjer sta R1 in m definirana zgoraj, s CC14 in neobvezno substituiranim triarilfosfinom, lahko nanesenim na inertni nosilec, s formulo Ar3P, za katerega je značilno, da je Ar lahko substituiran s (C6-Ci0) arilno skupino in vsak od substituentov je neodvisno izbran med (Ci-Ce) alkil in
b) obdelava produkta iz koraka a), s spojino s formulo
pri čemer so R2, R3 in n definirani zgoraj in J je Y ali R4, kjer je R4 definiran zgoraj, pod pogojem, da kadar je J enak Y, mora biti produkt koraka b) nadalje obdelan še z alkinom.
Del tega izuma je usmerjen na metode zdravljenja hiperproliferativnih bolezni pri sesalcih z določenimi količinami spojin s formulo I.
Ta izum se prav tako nanaša na farmacevtsko zmes spojine s formulo I in farmacevtsko sprejemljivih nosilcev, za zdravljenje hiperproliferativnih bolezni pri sesalcih.
Kot halo je mišljen kloro, bromo, jodo ali fluoro.
Kot alkil je mišljen cikličen, razvejan ali v obliki ravne verige, nasičen ali nenasičen hidrokarbilni delež, pod pogojem, da alkil vsebuje tri ali več ogljikovih atomov, če je cikličen ali razvejan.
Izraz reakcijsko inertno topilo se nanaša na topilo, ki ne reagira z izhodnimi spojinami, reagenti, vmesnimi spojinami ali produkti na način, ki bi kakorkoli vplival na nastanek željenega produkta.
Ostale značilnosti in prednosti bodo očitne iz podrobnih opisov in zahtevkov, ki opisujejo ta izum.
ζι /¼
SHEMA
Podrobnejši opis izuma
Spojine s formulo I, njihove farmacevtsko sprejemljive soli in aktivne komponente v zdravilih lahko pripravimo po kateremkoli postopku, ki je uporabljan za pripravo kemijsko sorodnih spojin.
Na splošno aktivne substance pripravimo iz primerno substituiranega kinazolina in primerno substituiranega amina.
Kot je prikazano na shemi primeren 4-substituiran kinazolin (2), kjer je X primerna zamenljiva izstopajoča skupina kot so halo, ariloksi, alkilsulfinil, alkilsulfonil, kot so trifluorometansuifoniloksi, arilsulfinil, arilsulfonil, siloksi, ciano, pirazolo, triazolo ali tetrazolo, najbolje 4-klorokinazolin, reagiramo z primernim aminom ali aminhidrokloridom (4) ali (5), pri čemer je R4opisan zgoraj in Y ja Br, I ali trifluorometan-sulfoniloksi v topilu kot je (Ci-C6)alkohol, dimetilformamid (DMF), N-metilpirolidin-2-on, kloroform, acetonitril, terahidrofuran (THF), 1,4-dioksan, piridin ali drugo aprotično topilo. Reakcija lahko poteka v prisotnosti baze, najbolje na alkalijski ali zemljoalkalijski kovinski karbonatni, hidroksidni ali terciarni aminski bazi, kot je piridin, 2,6-lutinid, kolidin, N-metil-morfolin, trietilamin, 4-dimetilamino-piridin ali N,N-dimetilanilin. Te baze so v sledečem besedilu navedene kot primerne baze. Reakcijsko zmes zadržujemo pri sobni temperaturi do temperature refluksa topila, najbolje med 35°C do temperature refluksa, doker ni več prisotnega 4halokinazolina, ponavadi je to od 2 do 24 ur. Najbolje je, če reakcijo izvajamo v inertni atmosferi, kot je npr. dušikova atmosfera.
Reaktanti so na splošno v stehiometričnem razmerju. Ko uporabljamo arninske baze za tiste spojine, kjer uporabljamo sol (ponavadi s HC1) amina (4) ali (5), je priporočljiv presežek aminske baze, ponavadi dodaten ekvivalent aminske baze.(Če ne uporabljamo aminske baze dodamo presežek amina (4) ali (5) .)
Pri spojinah, kjer uporabljamo sterično oviran amin (4) (kot je 2-alkil-3-etinilanilin) ali zelo reaktiven 4halokinazolin je priporočljiva uporaba t-butil alkohola ali polarnega aprotičnega topila, kot je npr. DMF ali Nmetilpirolidin-2-ona.
Alternativno lahko 4-substituiran kinazolin (2), kjer je X hidroksil ali okso (in 2-nitrogen je hidrogeniran), reagiramo z ogljikovim tetrakloridom in opcionalno substituiranim triarilfosfinom, lahko nanesenim na inerten nosilec (npr. trifenilfosfin, nanesen na polimer, Aldrich Cat. No. 36, 645-5, ki je 2% divinilbenzen povezan z polistirenom, ki vsebuje 3 mmole fosforja na gram smole) v topilu, kot je ogljikov tetraklorid, kloroform, dikloroetan, tetrahidrofuran, acetonitril ali drugo aprotično topilo ali njihove zmesi. Reakcijsko zmes zadržujemo pri sobni temperaturi pa do refluksa, najbolje od 35° do refluksa, 2 do 24 ur. To zmes reagiramo direktno ali po odstranitvi topila (npr. z vakumsko evaporacijo) s primernim aminom ali amin hidrokloridom (4) ali (5) ob dodatku primernega topila, kot je (Ci-C6) alkohol, DMF, Nmetilpirolidin-2-on, piridin ali 1-4 dioksan. Reakcijsko zmes zadržujemo pri sobni temperaturi pa do refluksa, najbolje od 35° do refluksa, dokler ni dosežena popolna tvorba produkta, najbolje od 2 do 24 ur.
Reakcija je najbolje izvedena v inertni atmosferi suhega dušika.
Ko spojino (4), kjer je Y Br, I ali trifluorometansulfoniloksi, uporabimo kot izhodno spojino pri reakciji z kinazolinom (2) se tvori spojina s formulo (3), R1, R2, R3 in Y pa so opisani zgoraj. Spojino (3) konvertiramo v spojine s formulo (I), kjer je R4 in R11 etinil, in R11 je definiran zgoraj, z reakcijo primernega paladijevega reagenta, kot je tetrakis(trifenilfosfin)paladijev diklorid v prisotnosti primerne Lewisove kisline, kot je bakrov klorid in primeren alkin npr. trimetilsililacetilen, propargil alkohol ali 3(N,N-dimetilamino)-propin v topilu kot je dietilamin ali trietilamin. Spojina (3), kjer je Y NH2, lahko pretvorimo v spojino (1), kjer je R4 azid, z diazotiranjem spojine (3) s kislino in nitritom (npr.ocetna kislina in NaNO2) ter nato še obdelava z azidom (NaN3) .
Za produkcijo spojine s formulo I, kjer je R1 amino ali hidroksilamino skupina, je potrebna redukcija ustrezne spojine, kjer je R1 skupina nitro.
Redukcijo lahko izvedemo z mnogo postopki, npr. z hidrogenacijo nitro skupine v reakcijsko inertnem topilu v prisotnosti primernega kovinskega katalizatorja, kot je paladij, platina ali nikelj. Primeren reducent je tudi aktivirana kovina, kot je npr. aktivirano železo (železo v prahu spiramo z razredčeno raztopino HC1). Prav tako redukcija poteče, če segrevamo zmes nitro spojine in aktiviranega žvepla z koncentrirano HC1 v topilu, kot je npr. zmes vode in metanola ali etanola, do temperature 50150°C , najbolje okrog 70°C. Drug primeren razred reducentov so alkalijski kovinski ditioni, kot je natrijev ditionit, ki se lahko uporablja pri (Cj-CJalkanojskih kislinah, (Ci~C6) alkanolih, vodi in njihovih zmeseh.
Za pripravo spojine s formulo I, kjer R1 ali RJ vključuje primarni ali sekundarni aminski del (drug, kot aminska skupina, ki namerava reagirati s kinazolinom), je najbolje, da zaščitimo prosto aminsko skupino, kot je opisano zgoraj nato pa zgoraj opisani reakciji z 4(substituiranim)kinazolinom (2) sledi deprotekcija te skupine.
Uporabimo lahko kar nekaj dobro znanih skupin za zaščito dušika. Takšne skupine vključujejo (Ci-C6) alkoksikarbonil, opcionalno substituiran benziloksikarbonil, ariloksikarbonil, tritil, viniloksikarbonil, onitrofenilsulfonil, difenilfosfinil, p-toluensulfonil in benzil. Adicijo skupine za zaščito dušika lahko izvedemo v kloriranem hidrokarbonatnem topilu, kot je metilen klorid ali 1,2-dikloroetan ali v eternih topilih, kot so glim, diglim ali THF, v prisotnosti ali odsotnosti terciarne aminske baze kot je trietilamin, diisopropiletilamin ali piridin, najboljši je trietilamin, pri temperaturi med 0°C in 50°C, najbolje pri sobni temperaturi. Zaščitne skupine se prav tako lepo vežejo ob Schotten-Baumannovih pogojih.
Zgoraj opisani reakciji spajanja spojin (2) in (5), sledi odstranitev zaščitne skupine z reakcijo deprotekcije, ki je znana kot obdelava t-butoksikarbonil zaščitenih produktov z trifluorocetno kislino v metilen kloridu.
Za opis zaščitnih skupin in njihovo uporabo glej T.W. Greene in P.G.M. Wuts, Protective Groups in Organic Synthesis Second Ed., John Wiley&Sons, New York, 1991.
Za pripravo spojine s formulo I, za katero je značilno, da je R1 ali R2 hidroksi je najboljše cepljenje spojine s formulo I, kjer je R1 ali R2 (Cj-CJ alkoksi.
Reakcija cepljenja lahko poteče po mnogih znanih postopkih. Obdelava zaščitenega derivata s formulo I s staljenim piridin hidrokloridom (20-30 ekv.) pri 150-175°C je O-dekalinacija. Alternativno lahko reakcija cepljenja poteče npr. z obdelavo zaščitenega derivata kinazolina z alkalijsko kovino (Ci-CJ alkilsulfidom, kot je natrijev etanetiolat ali z obdelavo z alkalijsko kovino diarilfosfidom, kot je litijev difenilfosfid. Reakcija cepljenja lahko prav tako primerno poteče, če zaščiten derivat kinazolina obdelujemo z borovim ali aluminijevim trihalidom, kot je npr. borov tribromid. Te reakcije najbolje potečejo v prisotnosti reakcijsko inertnega topila in pri primerni temperaturi.
Spojine s formulo I, za katere je značilno, da je R1 ali R2 (Ci-C4) alkilsulfinil ali (C1-C4) alkilsulfonilna skupina, ki so pripravljene z oksidacijo spojine s formulo I, kjer je R1 ali R2 (Ci~C4)alkilsulfanilna skupina. Primerni oksidanti pri oksidaciji sulfanilne skupine do sulfinilne in/ali sulfonilne so npr. vodikov peroksid, peroksi kisline (kot je npr. 3-kloroperoksibenzojska ali peroksiocetna kislina), alkalijsko kovinski peroksisulfati (kot je kalijev peroksimonosulfat), kromov trioksid ali plinast kisik v prisotnosti platine. Oksidacija ponavadi poteka pod milimi pogoji, če je le možno s stehiometričnimi količinami oksidanta, zato da bi zmanjšali možnost prevelike oksidacije in škode na drugih funkcionalnih skupinah. Na splošno reakcija poteka v primernih topilih, kot je metilen klorid, kloroform, aceton, tetrahidrofuran ali t-butil metil eter in pri temperaturi med -25 in 50°C, najbolje pri ali blizu sobni temperaturi, to je v obsegu od 15 do 35°C.
Če skupina nosi sulfinilno skupino so zaželjeni milejši oksidanti, kot so npr. natrijev ali kalijev metaperjodat, v polarnem topilu npr. ocetni kislini ali etanolu. Spojine s formulo I, ki vsebujejo (Ci~C4)alkilsulfonilno skupino lahko dobimo pri oksidaciji tako ustrezne (C1-C4) alkilsulf inilne skupine, kot tudi pri oksidaciji ustrezne (C1-C4) alkilsulfanilne skupine.
Spojine s formulo I, za katere je značilno, da je R1 lahko substituiran (C2-C4)alkanoilamino, ureido, 3-fenilureido, benzamido ali sulfonamido, lahko pripravimo z aciliranjem ali sulfoniliranjem ustrezne spojine, pri kateri je R1 amino. Primerne spojine za aciliranje so vse spojine znane pri aciliranju amino skupine v acilamino, to so acil halidi, npr.(C2-C4)alkanoil kloridi ali bromidi ali benzil kloridi ali bromidi, alkan kislinski anhidridi ali mešani anhidridi (npr. ocetni anhidrid ali mešani anhidrid, ki nastane pri reakciji med alkanojsko kislino in (C1-C4) alkoksikarbonil halidom, npr. (C1-C4)alkoksikarbonil klorid v prisotnosti primerne baze). Za pripravo spojine s formulo I, kjer je R1 ureido ali 3-fenilureido, je primerna spojina za aciliranje cianat, npr. alkalijsko kovinski cianat, kot je natrijev cianat ali isocianat, kot je fenil izocianat. N-sulfonilacijo lahko izvedemo z primernimi sulfonil halidi ali sulfonil anhidridi v prisotnosti terciarne aminske baze. Na splošno potekata aciliranje in sulfoniliranje v reakcijsko inertnem topilu in pri temperaturi v območju med -30 in 120°C, najbolje blizu sobne temperature.
Spojine s formulo I, kjer je R1 (C1-C4) alkoksi ali substituiran (C1-C4) alkoksi ali pa je R1 (C1-C4) alkilamino ali substituirana mono-N- ali di-N,N-(C1-C4)alkilamino, pripravimo z alkiliranjem, najbolje v prisotnosti primerne baze odgovarjajoče substance, kjer je R1 hidroksi ali amino. Primerne spojine za alkiliranje vsebujejo alkil ali substituirane alkil halide, npr. opcionalno substituiran (Ci-C4)alkil klorid, bromid ali jodid v prisotnosti primerne baze pri temperaturi med 10 in 140°C, najbolje blizu sobne temperature.
Za pripravo spojine s formulo I, kjer je R1 amino-, oksiali ciano substituiran (C1-C4)alkil substituent, ki vsebuje še skupino zamenljivo z amino-, oksi- ali ciano skupino, reagiramo s primernim aminom, alkoholom ali cianidom v prisotnosti baze. Reakcija najbolje poteče v reakcijsko inertnem topilu, pri temperaturi med 10 in 100°C, najbolje pri ali blizu sobne temperature.
Spojine s formulo I, za katero je značilno, da je R1 karboksi substituent ali substituent, ki vključuje karboksi skupino. Te pripravimo s hidrolizo ustrezne spojine, kjer je R1 (C1-C4)alkoksikarbonil substituent ali substituent, ki vključuje (C1-C4)alkoksikarbonil skupino. Hidrolizo lahko izvedemo pod bazičnimi pogoji npr. v prisotnosti alkalijskih kovinskih hidroksidov, kot je prikazano v spremljajočih primerih.
Spojine s formulo I, kjer je R1 amino, (Ci~C4) alkilamino, di-[(C1-C4)alkil]amino, pirolidin-l-il, piperidino, morfolino, piperazin-l-il, 4-(C1-C4) alkilpiperazin-l-il ali (C1-C4)alkilsulfanil, lahko pripravimo z reakcijo odgovarjajoče spojine, ki ima amin ali tiol zamenljivo skupino, v prisotnosti primerne baze, s primernim amniom ali tiolom. Reakcija najlepše poteče v reakcijsko inertnem topilu, v temperaturnem razmaku med 10 in 180°C, najbolje med 100 in 150°C.
Spojine s formulo I, kjer je R1 2-oksopirolidin-l-il ali 2-oksopiperidin-l-il, pripravimo s ciklizacijo v prisotnosti primerne baze in ustrezne substance, kjer je R1 halo-(C2-C4)alkilamino skupina. Reakcija najlepše poteče v reakcijsko inertnem topilu, v temperaturnem razmaku med 10 in 100°C, najbolje blizu ali pri sobni temperaturi.
Za pripravo spojine s formulo I, kjer je R1 karbamoil, substituiran karbamoil, alkanoiloksi ali substituiran alkanoiloksi, je primerno karbamoiliranje in aciliranje ustrezne spojine, pri kateri je R1 hidroksi.
Primerne spojine za aciliranje hidroksiarilnih delov do alkanoiloksiarilnih skupin vključujejo npr. (C2-C4) alkanoil halidi, (C2-C4) alkanoil anhidridi, in mešani anhidridi, kot so opisani zgoraj ter njihovi primerno substituirani derivati, seveda v prisotnosti primernih baz.
(C2-C4)alkanojske kisline ali njihovi primerno substituirani derivati lahko reagirajo s spojinami s formulo I, kjer je R1 hidroksi, ob dodatku kondenzatorja, kot je karbodiimid. Za pripravo spojin s formulo I, kjer je R1 karbamoil ali substituiran karbamoil, so primerni reagenti za karbamoiliranje npr. cianati, alkil ali aril izocianati, v prisotnosti primerne baze. Pripravimo lahko tudi ustrezne intermediate (vmesne spojine; Op.prev.),kot je kloroformiat ali karbonilimidazolil derivate spojine s formulo I, kjer je R1 hidroksi, z obdelavo s fosgenom (ali njegovim ekvivalentom) ali karbonildiimidazolom. Te intermediate lahko nato reagiramo s primernim aminom ali substituiranim aminom in tako dobimo željene derivate karbamoila.
Spojine s formulo I, kjer je R1 aminokarbonil ali substituiran aminokarbonil, lahko pripravimo z aminolizo primernega intermediata, kjer je R1 karboksi.
Aktivacijo in spajanje spojine s formulo I, značilne po tem, da je R1 karboksi, lahko izvedemo z mnogo različnimi metodami. Primerne metode vključujejo aktivacijo karboksila kot kislinskega halida, azida, simetričnega ali mešanega anhidrida ali aktivnega estra primerne reaktivnostiza spajanje z željenim aminom. Primere takšnih tipov intermediatov, njihovih produktov in njihove uporabe pri spajanju z amini lahko najdemo v velikem obsegu v literaturi; npr. M. Bodanski in A. Bodanski, The Practice of Peptide Synthesis, Springer, Verlag, New York, 1984. Končne spojine s formulo I izoliramo in prečistimo s standardnimi metodami, kot so odstranjevanje topila in rekristalizacija ali kromatografija.
Izhodne spojine za zgoraj opisano reakcijsko shemo (npr. amini, kinazolini in amino zaščitne skupine) so lahko dostopne in se lahko sintetizirajo z uporabo običajnih metod organske sinteze. Na primer, priprava 2,3-dihidro1,4-benzoksazinskih derivatov je opisana v R.C.
Elderfield, W.H. Todd, S. Gerber, Ch.12 v Heterocyclic Compounds,Vol.6, R.C. Elderfield ed.,John Wiley and Sons, Inc., Ν.Υ., 1957. Substituirani 2,3-dihidro-benzotiazinili so opisani v R.C.Elderfield in E.E.Harris v poglavju 13, volumen 6 v Elderfieldovi knjigi Heterocyclic Compounds.
Določeni kinazolini s formulo I lahko obstajajo tako v raztopljeni, kot v neraztopljeni in hidratirani obliki.
Izum zajema tako raztopljene kot neraztopljene oblike spojine, ki delujejo proti hiperproliferativnim boleznim.
Primerne farmacevtsko sprejemljive spojine s formulo I so npr. z dodatkom kisline nastale soli ustreznih spojine, ki so prvotno bazične, kisline pa so lahko organske ali anorganske, kot je klorovodikova, bromovodikova, žveplena, fosforjeva, metansulfonska, benzensulfonska, trifluorocetna, citronska, mlečna ali maleinska kislina. Primerne farmacevtsko sprejemljive soli nastale z dodatkom baze spojinam s formulo I, ki so kisle, so soli alkalijskih kovin, npr. litijeva, natrijeva ali kalijeva sol; soli zemljoalkalijskih kovin, npr. kalcijeva ali magnezijeva sol; amonijeva sol; ali sol z organsko bazo, ki ima fiziološko sprejemljiv kation, npr. sol z metilaminom, dimetilaminom, trimetilaminom, piperidinom, morfolinom ali tris-(2-hidroksietil)aminom. Te soli so za ta izum zelo pomembne, pripravimo pa jih lahko s povsem običajnimi metodami. Pripravimo jih lahko na primer preprosto s kontaktom kislih in bazičnih delov, ponavadi v stehiometričnem razmerju, v vodnem, nevodnem ali le delno vodnem mediju. Soli dobimo s filtracijo, precipitacijo s topilom v katerem se ne topi, najbolje v eternem ali hidrokarbonatnem topilu, kateremu sledi filtracija in evaporacija topila ali liofilizacija, če je raztopina vodna.
Nekatere spojine s formulo I imajo asimetričen ogljikov atom. Takšne diastereoizomerne zmesi se lahko ločijo na individualne diastereoizomere na osnovi fizikalno kemijskih razlik z znanimi metodami, npr. z frakcionalno kristalizacijo ali/in kromatografijo. Enantiomere lahko ločimo s spremembo enantiomerne zmesi v diastereoizomerno zmes z reakcijo s primerno optično aktivno spojino (npr. alkohol), diastereoizomere ločimo in individualne diastereoizomere spremenimo (npr. s hidrolizo) v ustrezne čiste enantiomere. Vsi taki izomeri, vključujoč zmesi diastereoizomer in čiste enantiomere, so del tega izuma.
Aktivne spojine pri tem izumu so učinkoviti inhibitorji erbB družine onkogenskih in protoonkogenskih protein tirozin kinaz, kot so receptorji epidermalnega rastnega faktorja (EGFR), erbB2, HER3 ali HER4 in tako so vsi prilagojeni na terapevtsko uporabo, kot proliferativno delujoče spojine (npr. protirakavo) pri sesalcih, posebej še pri človeku. Substance dobljene pri tem izumu so profilaktiki ali terapevtiki za zdravljenje mnogih različnih človeških tumorjev (jetrni, ledvični,na mehurju, na prsih, želodčni,na jajčnikih, prostati, zadnjični, pljučni, na trebušni slinavki, ščitnici, ženskem vnanjem splovilu, sarkomi, glioblastomati ter različni tumorji na vratu in glavi) in drugih hiperplastičnih stanj, ki se prično kot hiperplazija kože (npr. psoriaza) ali prostate (npr. BPH). Poleg tega pa kinazolini tega izuma pa delujejo na različne oblike levkemij in limfoidnih malignih tvorb.
Pričakujemo lahko, da bodo aktivne substance učinkovite tudi pri zdravljenju motenj ob abnormalnih interakcijah med ligandom in receptorjem, ki jih aktivirajo ali signalizirajo različni proteini tirozin kinaz, katerih aktivnost zavirajo spojine s formulo I.
Takšne motnje lahko vključujejo živčne, glialne, hipotalamične in druge glandularne, makrofagalne, epitelijske, stromalne in blastokoelične narave, pri katerih se pojavijo odstopanja v funkciji, izražanju, aktivaciji in signaliziranju, verjetno zaradi erbB tirozin kinaz. Spojine s formulo I imajo terapevtske učinke na inflamatorne, angiogenske in imunološke motnje, vključujoč oboje, tako identificirane kot še nedoločene tirozin kinaze.
In vitro delovanje aktivnih spojin na zaviranje receptorjev tirozin kinaz (in posrednim delovanjem na rakava obolenja) lahko določimo po spodaj opisanem postopku.
Delovanje aktivnih spojin in vitro lahko določimo s količino inhibicije fosforilacije eksogenskega substrata (npr. Lys3-Gastrin ali poliGluTyr (4:1) kopolimer (I. Posner et.al., J.Biol.Chem. 267(29), 20638-47 (1992))) na tirozin z EGFR kinazo z testno spojino. Soroden, prečiščen, topen človeški EGFR (96 ng) dobimo po postopku opisanem v G.N. Gill, W.Weber, Methods in Enzymology 146, 82-88 (1987) iz A4 31 celic (American Type Culture Collection, Rockville,
MD) in preinkubiran v mikrofugirani tubi z EGF (2pg/ml) v fosfatnem pufru in vanadatu (PBV: 50 mM HEPES, pH 7.4; 125 mM NaCl; 24 mM MgCl2; 100 μΜ natrijevega ortovanadata), s skupnim volumnom 10 pl, 20-30 min pri sobni temperaturi. Testno spojino, raztopljeno v dimetilsulfoksidu (DMSO), diluiramo v PVB in 10 pl zmešamo z EGFR ter inkubiramo 1030 min pri 30°C. Reakcija fosforilacije steče po dodatku 20 pl 33P-ATP/substratna zmes (120 pM Lys3-Gastrin (zaporedje enočrkovnih kod za amino kisline, KKKGPWLEEEEEAYGWLDF), 50 mM Hepes pH 7.4, 40 pM ATP, 2 pCi y-[33P]-ATP) k EGFr/EGF zmesi, nato inkubiramo 20 minut pri sobni temperaturi. Reakcijo ustavimo z dodatkom 10 pl zmesi raztopine 0.5 M EDTA, pH 8 in 2 mM ATP ter 6 pl 2N HC1. Epruveto centrifugiramo pri 14,000 obratih na minuto (RPM), 4°C, 10 minut. 35 pl spojine iz vsake epruvete odpipetiramo na 2.5 cm krožni Whatmanov P81 papir, količinsko spiramo štirikrat v 5% ocetni kislini, 1 1 na spiranje in nato posušimo na zraku. To rezultira vezavo substrata na papir z izgubo prostega ATP-ja pri spiranju. Vgrajen [33P] merimo s štetjem scintilacije raztopine. Vgrajevanje, ko ni substrata (lys3gastrin), odštejemo od vseh vrednosti kot ozadje in procent inhibicije izračunamo relativno, brez prisotnosti testne spojine.
Takšne analize, izvedene z vrsto različnih količin testne spojine, dovoljujejo določitev približne IC50 vrednosti za in vitro inhibicijo aktivnosti EGFR kinaze. Čeprav inhibitorske lastnosti spojine s formulo I pričakovano variirajo s spremembami strukture, je aktivnost teh spojin, določena po zgoraj opisani metodi v mejah IC50=0.0001-30 μΜ.
Delovanje aktivnih spojin in vivo pa lahko določimo relativno z inhibicijo testne spojine na rast tumorja. Učinek inhibicije različnih spojin na rast tumorja merimo po metodah opisanih v delu Corbett T.H., et al.Tumor Induction Relationships in Development of Transplatable Cancers of the Colon in Mice for Chemotherapy Assays, with a Note on Carcinogen Structure”, Cancer Res., 35,2434-2439 (1975) in Corbett, T.H., et al., A Mouse Colon-tumor Model for Eksperimental Therapy”, Cancer Chemother. Rep. (Part 2), 5, 169-186 (1975), z nekaj spremembami. Tumor uvedemo v levi bok s subkutano injekcijo 1 χ 106 log faze kultiviranih celic tumorja (človeške MDA-MB-468 celice raka prsi ali človeške HN5 celice raka na vratu in glavi), suspendirane v 0.10 ml RPMI 1640. Po določenem času, ko postanejo tumorji otipljivi (23 mrn v premeru), testne živali (miši) zdravijo z aktivno spojino (dobljeno z raztapljanjem v DMSO, običajno v koncentraciji 50 do 100 mg/ml, katermu sledi 1:9 razredčevanje v soline ali 1:9 razredčevanje v 0.1%
Pluronic P105 v 0.9% solini) in sicer intraperitonealno (ip) ali oralno (po) po napotkih dvakrat dnevno (to je vsakih 12 h), 5 zaporednih dni. Da bi določili protitumorno delovanje, tumor merimo v milimetrih z Vernierjevim kaliperjem šez dva premera in velikost tumorja (mg) izračunamo po formuli: teža tumorja= (dolžina x [širina]2)/!, glede na metodo Geran, R.I., et.al.Protocols for Screening Chemical Agents and Natural Products Against Anirnal Tumors and Other Biological Systems, Third Edition,
Cancer Chemother. Rep., 3, 1-104 (1972). Rezultate izrazimo v odstotkih inhibicije, izračunane po formuli: inhibicija (%) = (TuWkontrolna-TuWtestna)/TuWkor,troina x 100%. Lega tumornega implatanta zagotavlja reproduktivne količine/odgovore učinka različnih kemoterapevtskih spojin, način merjenja (premer tumorja) pa je zanesljiva metoda za ocenjevanje razmerja rasti tumorjev. Porazdelitev aktivnih spojin lahko onemogočijo ali spremenijo metode, ki onemogočijo dostop spojine do mesta delovanja (do rakavih celic). Te metode vključujejo oralne, intraduodenalne poti, parenteralna injiciranja (vključujoč intravenozna, subkutana, intramuskularna, intravaskularna injiciranja ali infuzije)in druge.
Količina porazdeljene aktivne substance bo seveda odvisna od vsake zdravljene osebe posebej, glede na resnost obolenja in glede na presojo osebnega zdravnika. Kakorkoli, učinkovita količina zdravila je v obsegu med 0.001 do 100 mg/kg, najbolje med 1 in 35 mg/kg v enkratni ali razdeljeni količini. Za povprečnega 70 kg človeka to pomeni 0.05 do 7 g na dan, najbolje 0.2 do 2.5 g na dan.
Zmes je v obliki primerni za oralno aplikacijo kot tablete, kapsule, pilule, prašek, suspenzije, emulzije ali v počasi se sproščujoči obliki, za parenteralne injekcije kot sterilne raztopine, suspenzije ali emulzije, za zunanjo aplikacijo kot mazila ali kreme ali za rektalno aplikacijo kot svečke. Farmacevtske zmesi so lahko v obliki enkratne doze za enkratno aplikacijo natančnih količin. Farmacevtske zmesi vključujejo farmacevtsko primeren nosilec ali ekscipient in glede na izum tudi spojino kot aktivno učinkovino. Vključuje lahko tudi druge farmacevtske učinkovine, nosilce, dodatke in drugo.
Glede na ta izum, lahko farmacevtske zmesi vsebujejo od 0.1% do 95% učinkovine, najbolje med 1 in 70%. Aplicirana zmes bo vsebovala aktivno spojino v odmerku, ki bo vplival na razvoj ali zaviranje znakov prek celega poteka zdravljenja, pri osebi zdravljeni zaradi hiperproliferativne bolezni.
Primer parenteralne oblike aplikacije zdravilne učinkovine so raztopine ali suspenzije učinkovine v sterilni vodni raztopini, na primer vodni propilen glikol ali raztopina dekstroze. Takšne raztopine so lahko po želji tudi pufrne.
Farmacevtsko primerni nosilci so inertna redčila ali mašila, voda in različna organska topila. Farmacevtske zmesi lahko po želji vsebujejo dodatne primesi, kot so arome, vezalci, ekscipienti in drugo. Za oralno aplikacijo tablete vsebujejo različne ekscipiense, kot je citronska kislina in lahko se vgradijo z različnimi dezintegranti, kot je škrob, alginska kislina in določeni kompleksni silikati, z vezalci, kot je sukroza, želatina in akacija. Poleg tega za tablete velikokrat uporabljajo lubrikatorje, kot so magnezijev stearat, natrijev lauril sulfat in smukec. Podobne trdne zmesi lahko prav tako polnimo v mehke in trdno polnjene želatinaste kapsule. Priporočljive spojine za to so laktoza ali mlečni sladkor in polietilenglikoli z visoko molekulsko maso. Ko vodne suspenzije ali eliksirje apliciramo oralno, so lahko aktivne spojine kombinirane z aromatičnimi spojinami, sladkorji, barvili in emulgatorji in suspendiranje, skupaj z diluenti oz. razredčili, kot so voda, etanol, propilenglikol, glicerin in njihove kombinacije.
Znane so metode za pripravo različnih farmacevtskih zmesi s točno določeno količino aktivne spojine. Opisane so npr. v Remington's Pharmaceutical Sciences., Mačk Publishing Company, Easter, Pa., 15th Edition (1975).
Zdravljenje hiperproliferativnih bolezni z aktivnimi spojinami opisano zgoraj lahko poteka samostojno ali v kombinaciji z eno ali več drugimi antitumornimi spojinami.
Takšno zdravljenje lahko dosežemo z različnimi načini simultanega, zaporednega, cikličnega ali ločenega doziranja individualnih komponent.
Visokotlačna tekočinska kromatografija (HPLC) uporabljana v sledečih primerih in pripravah poteka po naslednji metodi razen, če je spremenjena pri posameznih primerih. PerkinElmer Pecosphere 3X3C kolona (3mm X 3cm, C18; proizvajalec Perkin Elmer Corp., Norwalk, CT 06859) z Brownlee™ RP-8 Newguard kolono (7 mikronov, 3.2mm x 15 mm, proizvajalec Applied Biosystems Inc. San Jose, CA 95134), ki je bil prej uravnotežen na pH 4.50, 200 mM amonij acetatnega pufra. Vzorce eluiramo z metodo linearnega gradienta z 0-100% acetonitrilom/pH 4.50, 200 mM amonijevega acetata, 10 minut, s pretokom 3.0 mL/min. Kromatograme razvijemo v območju 200-400 nm z uporabo diodnega detektorja.
Potrebno je poudariti, da izum ni omejen le na določene spojine in uporabnost prikazano in opisano tu, možne so številne spremembe in modifikacije, ne da bi pri tem odstopali od smisla in cilja izuma, kot je opisano v zahtevkih.
PRIMER 1 (4-azidofenil)-(6,7-dimetoksikinazolin4-il)amin hidroklorid
4-kloro-6,7-dimetoksikinazolin (250 mg, 1.12 mmol) in 4azidoanilin hidroklorid (200 mg, 1.11 mmol) refluktiramo v 10 mL izopropilnega alkohola, 0.5 ure. To ohladimo in filtriramo, da dobimo trden glavni produkt, ki ga spiramo z 10 mL izopropilnega alkohola in posušimo pri 70°C, 392 g (98%); temperatura tališča 200-205°C.
PRIMER 2 (6,7-dimetoksikinazolin-4-il)-(3-etinilfenil)amin hidroklorid
4-kloro-6,7-dimetoksikinazolin (250 mg, 1.12 mmol) in 3etinil-anilin (137 mg, 1.17 mmol) refluktiramo v 10 mL izopropilnega alkohola 0.5 ure, ohladimo in filtriramo, da dobimo trden glavni produkt, ki ga spiramo z 10 mL izopropilnega alkohola in sušimo pri 70°C, 338 mg (99%); Ttal=269-270°C.
PRIMER 3 (6,7-dimetoksikinazolin-4-il)-[3-(3' hidroksi propin-l-il)fenil]-amin
Zmes (3'-bromofenil)-(6,7-dimetoksikinazolin-4-il)-amin hidroklorida (250 mg, 0.591 mmol), tetrakis(trifenilfosfin)paladija (100 mg), propargil alkohola (600 pL), 7 mL s suhim dušikom očiščenega dietilamina in bakrov jodid (10 mg) refluktiramo 5 ur, ohladimo in filtriramo. Trden glavni produkt speremo dvakrat z 2 mL 50% dietilamina: metanol; 136 mg. Trdnega prekristaliziramo iz metanola in čist glavni produkt sušimo pri 70°C,dobimo ga 73 mg (37%); Ttal= 267-268°C.
PRIMER 4 [ (3- (2'-aminometil-etinil)fenil]-(6, 7dimetoksikinazolin-4-il)amin hidroklorid
Naslovni produkt Primera 3 (50 mg, 0.149 mmol), trifenilfosfin (60 mg, 0.225 mmol), ftalimid (165 mg, 1.12 mmol) in dietil azodikarboksilat (36 pL, 0.228 mmol) mešamo pri sobni temperaturi, v 3 mL suhega tetrahidrofurana, 16 ur. Reakcijsko zmes koncentriramo do trdnega, kromatografiramo na silikagelu in eluiramo z 15% acetonom: metilen klorid, da dobimo [3-(2'-{ftaloimidometil}etinil)fenil]-(6,7-dimetoksikinazolin-4-il)amin, ki ga pretvorimo v hidrokloridno sol z dodatkom 1 mL brezvodnega IM HCl v metanolu, kateremu sledi dodatek 3 mL izopropilnega alkohola. Sol zberemo s filtracijo ter takoj osušimo, dobimo 15 mg produkta. Teh 15 mg, 0.0323 mmol obdelujemo z 0.5 ml hidrazin hidrata in 1 mL metanola 0.5 ure. Reakcijsko zmes evaporiramo, produkt izoliramo s kolonsko hitro kromatografijo ter eluiramo z 10% alkoholom v metilen kloridu.Čist glavni produkt izoliramo po pretvorbi v hidrokloridno sol z 1 mL IM HC1 v metanolu, obarjanju z izopropilnim alkoholom in dietiletrom in sušenju. Dobimo 5.6 mg (47%) produkta, Ttal= 275°C.
PRIMER 5 (3-etinilfenil)-(6-nitrokinazolin-4-il)amin hidroklorid
4-kloro-6-nitrokinazolin (1.06 g, 5.00 mmol) in 3etinilanilin (1.00 g, 5.30 mmol)refluktiramo v 10 mL izopropil alkohola 3 ure, ohladimo in po 16 urah pri sobni temperaturi filtriramo. Trden glavni produkt speremo z 10 mL izopropilnega alkohola in osušimo pri 70°C, 1.27 g (78%); Ttal= 255-256°C.
PRIMER 6 (6,7-dimetoksi kinazolin-4-il)(4-etinilfenil)-amin
Glavni produkt pripravimo v naslednjih treh stopnjah, brez čiščenja intermediatov. 4-kloro-6,7-dimetoksikinazolin (250 mg, 1.113 mmol) in 4-jodoanilin(268 mg, 1.224 mmol) refluktiramo v 10 mL izopropilnega alkohola 3 ure, ohladimo na sobno temperaturo in filtriramo, da dobimo trdni (4jodofenil)-(6,7-dimetoksikinazolin-4-il)amin hidroklorid, ki ga speremo z 10 mL izopropilnega alkohola in sušimo pri 70°C. Dobimo 396 mg (76%) produkta. Zmes (4-jodofenil)(6,7-dimetoksikinazolin-4-il)amin hidroklorida (250 mg, 0.564 mmol), tetrakis(trifenilfosfin)paladij (50 mg), trimetilsililacetilen (160 pL, 1.13 mmol), 4 mL s suhim dušikom očiščenega dietilamina in bakrovega jodida (10 mg) refluktiramo 2 uri, ohladimo ter koncentriramo in dobimo ostanek, ki je razdeljen med kloroform in IN HC1. Trden [4(2'-{trimetilsilil}-etinil)fenil]-(6,7-dimetoksikinazolin4-il)amin nastane med obema tekočima fazama, po filtriranju ga posušimo in dobimo 170 mg (80%) produkta.
[4-(2'-{trimetilsilil}-etinil)fenil]-(6,7— dimetoksikinazolin-4-il)amin (100 mg, 0.265 mmol) in brezvoden kalijev karbonat (125 mg, 0.906 mmol) mešamo v 3 mL metanola in 1 mL vode, pri sobni temperaturi, 2.5 uri. Reakcijsko zmes koncentriramo ter porazdelimo med 20 mL kloroforma in 20 mL IN HC1. Organsko plast sušimo z magnezijevim sulfatom, filtriramo in vakumsko evaporiramo. Tako dobimo glavni produkt, ki ga sušimo pri 70°C, 81 mg (90%); Ttal= 239°C.
PRIMER 7 (6,7-dimetoksikinazolin-4-il)-(3-etinil2-metilfenil)-amin
Glavni produkt pripravimo v sledečih treh stopnjah, brez vmesnega čiščenja intermediatov. Zmes, ki jo sestavljajo 3bromo-2-metilanilin (1.00 g, 5.37 mmol), tetrakis(trifenilfosfin)paladij (200 mg), trimetilsililacetilen (1.053 g, 10.75 mmol), 10 mL s suhim dušikom očiščenega dietilamina in bakrovega jodida (910 mg) refluktiramo 16 ur, ohladimo ter koncentriramo in dobimo ostanek, ki je razdeljen med kloroform in IN Hcl. Organski ostanek speremo s slano vodo, sušimo z magnezijevim sulfatom , vakumsko evaporiramo do ostanka in dobimo 3-[2'(trimetilsilil)etinil]-2-metilanilin, ki ga očistimo s kolonsko hitro kromatografijo na silikagelu, eluiranim z 1:1 heksan:metilenklorid; 200 mg (18%).
4-kloro-6,7-dimetoksikinazolin (104 mg, 0.466 mmol) in 3[2'-(trimetilsilil)etinil]-2-metilanilin (100 mg, 0.491 mmol) refluktiramo v 3 mL izopropanola 16 ur, ohladimo na sobno temperaturo in filtriramo, da dobimo trden {3—[2'— (trimetilsilil)etinil]-2'-metilfenil]}-(6,7dimetoksikinazolin-4-il)amin hidroklorid. Tega speremo z 10 mL izopropilnega alkohola in trituriramo 16 ur z dietiletrom. Tankoplastna kromatografija na silikagelu, eluirano z 9:1 kloroform:metanol kaže, da je dobljen produkt nečist, zato ga očistimo s tenkoplastno kromatografijo na silikagelu z 9:1 metilen klorid: metanol. Po kromatografiji koncentriramo in osušimo ter tako dobimo 64 mg (33%) čistega produkta. Produkt raztopimo v 3 mL metanola in obdelujemo z 64 mg brezvodnega kalijevega karbonata, pri sobni temperaturi, 3 ure. Reakcijsko zmes koncentriramo in porazdelimo med IN HC1 in kloroform. Trden glavni produkt se formira ned obema tekočima fazama, nato ga odfiltriramo in osušimo ter tako dobimo 40 mg (84%) spojine z Ttal= 225°C.
PRIMER 8 (6-amino-kinazolin-4-il)-(3-etinilfenil)-amin (3-etinil-fenil)-(6-nitro-kinazolin-4-il)-amin hidroklorid (500 mg, 1.50 mmol) raztopimo v 10 mL mravljične kisline in obdelamo po delih z natrijevim ditionitom (1.10 g, 6.28 mmol) pri sobni temperaturi. Po dveh urah mešanja zmesi dodamo 120 mL vode in filtriramo. Filtrat evaporiramo do trdnega ostanka, ki ga nato raztopimo v 100 mL 1:1 metanol:kloroform, filtriramo in evaporiramo do drugega ostanka. To trituriramo z 200 mL 5% natrijevega bikarbonata 30 minut, filtriramo, speremo z vodo in sušimo 16 ur. Tenkoplastna kromatografija na silikagelu z etil acetatom da 140 mg (34%) čistega (6-amino-kinazolin-4-il)-(3-etinilfenil)-amina s Ttal= 165°C.
PRIMER 9 (3-etinilfenil)-(6-metansulfonilaminokinazolin-4-il)-amin
Glavni produkt primera 8 (100 mg, 0.384 mmol), piridin (140pL, 1.68 mmol) in metansulfonil klorid (99pL, 1.26 mmol) refluktiramo 7 ur v 10 mL 1,2-dikloroetana.
Reakcijsko zmes ohladimo in evaporiramo do trdnega ostanka, ki ga trituriramo v 10 mL IN HC1, filtriramo in osušimo. Tako dobimo 102 mg (78%) (3-etinilfenil)-(6-metansulfonilamino-kinazolin-4-il)-amina, s Ttal= 248°C.
PRIMER 10 (3-etinilfenil)-(6,7-metilendioksikinazolin4-il)-amin hidroklorid
4-kloro-6,7-metilendioksikinazolin (200 mg, 1.04 mmol) in
3-etinilanilin (127 mg, 1.09 mmol) refluktiramo v 5 mL izopropil alkohola, ohladimo, filtriramo, speremo z 10 mL izopropanola, osušimo pri 70°C ter tako dobimo 266 mg (79%) produkta, s Ttal= >350°C.
PRIMER 11 ( (6,7-dimetoksikinazolin-4-il)-3-etinil6-metilfenil)-amin hidroklorid
Glavni produkt pripravimo v naslednjih treh stopnjah brez čiščenja intermediatov. Zmes 4-bromo-2-nitrotoluena (1.50 g, 6.94 mmol), tetrakis(trifenilfosfin)paladij (750 mg), trimetilsililacetilen (3.00 mL, 21.21 mmol), 20 mL s suhim dušikom očiščenega dietilamina in bakrovega jodida (20 mg) refluktiramo 2 uri, ohladimo ter koncentriramo in dobimo ostanek, ki je razdeljen med 100 mL etilacetata in 100 mL IN HC1. Organski ostanek speremo dvakrat s 50 mL IN Hcl, nato še s solno raztopino, osušimo z magnezijevim sulfatom in vakumsko evaporiramo do ostanka. Ostanek raztopimo v 10 mL etilacetata in razredčimo z 200 mL petroletra. Trdne spojine odfiltriramo, olje, dobljeno po vakumski evaporaciji filtrata, pa da 4-[2'-(trimetilsilil) etinil]2-nitrotoluen. Le tega reduciramo v amino produkt z železom v prahu (1.76 g, 98.5 mmol) v 30 mL metanola in 5 mL koncentrirane HC1 pri 80°C 2 uri. Ohlajeno reakcijsko zmes filtriramo skozi Celite in filtrat evaporiramo v vakuumu. Ostanek porazdelimo med etil acetat in 5% vodno raztopino natrijevega bikarbonata. Organski ostanek speremo s solno raztopino, osušimo z magnezijevim sulfatom, filtriramo, vakumsko evaporiramo do oljnatega ostanka, ki je 5-[2'(trimetilsilil)etinil]-2-metilanilin, ki ga je v trdni obliki 1.37 g.
Zgornji produkt (185 mg, 0.909 mmol) in 4-kloro-6,7dimetoksi-kinazolin (200 mg, 0.890 mmol) refluktiramo v tbutil alkoholu 16 ur. Ko reakcijsko zmes ohladimo, jo filtriramo in dobimo čist [2-metil-5-(2'-{trimetilsilil}etinil)-fenil]-(6,7-dimetoksikinazolin-4-il)amin hidroklorid, po spiranju z etrom in sušenju v vakuumu, količinsko ga je 326 nig (85%) . Trimetilsililno skupino odstranimo z raztapljanjem zgornjega produkta v 5 mL metanola in 1 mL vode in obdelamo z 320 mg kalijevega karbonata. Po enournem mešanju filtriramo in koncentriramo. Ostanek se porazdeli med 100 mL metilen klorida in 100 mL IN HC1. Vodni del ekstrahiramo z dodatkom 100 mL metilen klorida. Združen organski del sušimo z magnezijevim sulfatom, filtriramo in vakumsko evaporiramo do ostanka, ki ga raztopimo v brezvodni IN HC1 in metanolu, koncetriran in oborjen z etrom. Trden glavni produkt filtriramo, speremo v dietiletru, sušimo pri 70°C in dobimo 236 mg (88%), s Ttal= 266-267°C.
PRIMER 12 (3-etinilfenil)-(7-nitrokinazolin-4-il) amin hidroklorid
4-kloro-7-nitrokinazolin (7.97 g, 38.0 mmol) in (3etinilanilin (4.54 g, 38.8 mmol) refluktiramo v 125 mL tbutil alkohola 3 ure, ohladimo na sobno temperaturo, filtriramo, trden produkt spiramo z 10 mL izopropil alkohola in sušimo pri 70°C ter tako dobimo 9.95 g (80%) produkta s Ttal= 209-210°C.
PRIMER 13 (3-etinilfenil)-[6-(4'-toluensulfonilamino) -kinazolin-4-il]-amin hidroklorid
Glavni produkt primera 8 (0.201 mg, 0.774 mmol) in 4toluensulfonil klorid (0.441 mg, 2.31 mmol) refluktiramo v 3 mL 1,2-dikloroetan in 0.5 mL piridina 5 minut. Reakcijsko zmes ohladimo do sobne temperature, razredčimo s 75 mL etilacetata in speremo dvakrat s 75 mL vode, enkrat s 75 mL 3% natrijevega karbonata in enkrat s 75 mL solne raztopine. Organski del sušimo z magnezijevim sulfatom, filtriramo in vakumsko vaporiramo do ostanka, ki ga očistimo s kromatografijo. Pri kromatografiji uporabljamo Cromatotron™ in eluiramo z etilacetatom. Dobimo 86.7 mg (27%) produkta s Ttal= 220-222°C.
PRIMER 14 (3-etinilfenil)-{6-[2'-ftalimido-etan1'-ilsulfonilamino]kinazolin-4-il}-amin hidroklorid
Glavni produkt primera 8 (0.20 mg, 0.768 mmol) in 2ftalimido-l-etansulfonil klorid (0.615 mg, 2.25 mmol) refluktiramo 16 ur v 2 mL 1,2-dikloroetana in 0,5 mL piridina, ohladimo na sobno temperaturo, diluiramo s 100 mL kloroforma in spiramo z 50 mL 3% natrijevega bikarbonata ter 50 mL solne raztopine. Organski del sušimo z magnezijevim sulfatom, filtriramo iin vakumsko evaporiramo do trdnega ostanka, ki ga raztopimo v minimalni količini metilen klorida in oborimo s 188 mg petroletra. Očistimo ga s kromatografijo z uporabo Chromatotrona@, eluiramo z etil acetatom in dobimo 53.4 mg (14%) produkta s Ttal= 197200°C.
PRIMER 15 (3-etinilfenil)-(6-gvanidinokinazolin4-il)-amin hidroklorid
Glavni produkt primera 8 (0.302 mg, 1.16 mmol) in 3,5dimetilpirazol-l-karboksamidin (0.328 mg, 2.36 mmol)refluktiramo v 10 mL 1,2-dikloroetana in 0.97 mL ocetne kisline 24 ur, ohladimo na sobno temperaturo in filtriramo, da ločimo surov acetat od glavnega produkta. Produkt raztopimo v 35 mL metanola in obdelamo z 75 mL dietiletra. Trden glavni produkt filtriramo, osušimo pri 70°C in dobimo 91.2 mg (23%), Ttal= >400°C.
PRIMER 16 (7-aminokinazolin-4-il)-(3-etinilfenil )-amin
Glavni produkt primera 12 (1.039 g, 3.18 mmol) raztopimo v 50 mL THF, 10 mL metanola in 5 mL kloroforma pri 50°C. Dodamo natrijev dihidrogen fosfit (NaH2PO2, 3.822 g, 36 mmol) in 10% paladij na ogljiku (0.19 g) z dodajanjem 10 mL vode po kapljicah. Ko zmesi dodamo 3 mL vode, le-ta postane znatno homogenejša. Po 1 uri zmes prefiltriramo skozi Celite. Dobro speremo z metanolom in kloroformom. Kombinirano organsko raztopino vakumsko odparimo do trdnega ostanka, ki ga trituriramo z vodo, 3% vodnim natrijevim bikarbonatom in filtriramo. Trden produkt speremo z vodo, dietiletrom, osušimo in dobimo 1.054 mg (127%, mokrega).Del zgornjega produkta rekristaliziramo iz minimalne količine vročega etanola in vode, da dobimo, po odstranitvi prvih, majhnih delov nečistoč, čist glavni produkt (43%), Ttal= 180°C.
PRIMER 17 (3-etinilfenil)-(7-metoksikinazolin-4-il) amin hidroklorid
4-kloro-7-metoksikinazolin (274 mg, 3.72 mmol) in 3etinilanilin (436 mg, 3.72 mmol) refluktiramo v 15 mL tbutil alkohola 3 ure, da dobimo trden glavni produkt, ki ga spiramo z 10 mL izopropil alkohola in osušimo pri 70°C. Dobimo 977 mg (84%) produkta s Ttal= 229-231°C.
PRIMER 18 (6-karbometoksikinazolin-4-il)-(3-etinilfenil) -amin hidroklorid
4-kloro-6-karbometoksikinazolin (100 mg, 0.450 mmol) in
3-etinilanilin hidroklorid (53.4 mg, 0.456 mmol) refluktiramo v 2 mL t-butil alkohola 2 uri, ohladimo, redčimo z 2 mL izopropil alkohola in filtriramo. Trden glavni produkt spiramo z 10 mL dietiletra, sušimo pri 70°C in dobimo 122 mg (80%) produkta s Ttal= 232-233°C.
PRIMER 19 (7-karbometoksikinazolin-4-il)-(3-etinilfenil) -amin hidroklorid
4-kloro-7-karbometoksikinazolin (202 mg, 0.907 mmol) in 3-etinilanilin (110 mg, 0.939 mmol) refluktiramo 2 uri v 4 mL t-butil alkohola, filtriramo in glavni produkt spiramo z 10 mL dietiletra in sušimo pri 70°C. Dobimo 248 mg (80%) s Ttal= 219.5-221°C.
PRIMER 20 [6,7-bis-(metoksietoksi)-kinazolin-4-il]37 (3-etinilfenil)amin hidroklorid 3-etinilanilin (37 mg, 0.32 mmol) in 4-kloro-6,7-bis-(2metoksi-etoksi)-kinazolin (90 mg, 0.29 mmol) dodamo izopropanolu (1.5 mL), ki vsebuje piridin (25 pL, 0.32 mmol) in zmes refluktiramo 4 ure v dušikovi atmosferi. Topilo odstranimo in ostanek porazdelimo med 10% metanol v CHC13 in nasičeni vodni raztopini NaHCO3. Organsko fazo osušimo v Na2SO4, filtriramo in koncentriramo. Ostanek kromatografiramo s tenkoplastno kromatografijo na silikagelu z uporabo 30% acetona v heksanu in tako dobimo 81 mg glavnega produkta v obliki trdne, bledo rumene proste baze. To raztopimo v minimalni količini CHC13, razredčimo z etrom, titriramo z IM HC1 v etru in glavni produkt oborimo kot hidrokloridno sol. Dobimo jo 90 mg (71%) s Ttal= 228230°C.
PRIMER 21 (3-azidofenil)-(6, 7-dimetoksikinazolin4-il) amin
4-kloro-6,7-dimetoksikinazolin (5.01 g, 22.3 mmol) dodamo v delih v roku 1.5 ure k m-fenilendiaminu (2.66 g, 24.6 mmol) in refluktiramo v izopropanolu (100 mL) v dušikovi atmosferi. Ko je dodajanje končano, segrevamo pod refluksom 4 ure. Zmes ohladimo na 20°C, oborino filtriramo, speremo z ohlajenim izopropanolom in osušimo. Tako dobimo 6.97 g (93%) (3-aminofenil)-(6,7-dimetoksikinazolin-4-il amin hidroklorida (LC-MS: 2 97 (MH+) . Raztopini zgornjega produkta (50 mg, 0.169 mmol) v 80% ocetni kislini/H2O (2 mL) pri 0°C, dodamo raztopino NaNO2 (18.4 mg, 0.186 mmol) v vodi (100 pL). Po 10 minutnem mešanju pri 0’C dodamo raztopino NaN3 (12 mg, 0.185 mmol) v vodi (100 pL). Raztopino segrejemo na 20°C in mešamo 1.5 ure. Reakcijsko zmes liofiliziramo in ostanek porazdelimo med etil acetat in nasičeno raztopino NaHCO3. Organsko fazo še nadalje spiramo s solno raztopino, osušimo z Na2SO4, filtriramo in koncetriramo. Z rekristalizacijo iz CHCl3/heksan dobimo 36 mg belega trdnega produkta s Ttal= 110-113°C.
PRIMER 22 (3-azido-5-klorofenil)-(6,7-dimetoksikinazolin-4-il) amin
4-kloro-6,7-dimetoksikinazolin (200 mg, 0.89 mmol) in 5amino-3-kloroanilin (253 mg, 1.78 mmol) kombiniramo z izopropanolom (3 mL) in segrevamo na refluksu v dušikovi atmosferi 16 ur. Po ohladitvi na 20°C zmes razredčimo v metanolu (5 mL) in dobljeno oborino filtriramo in osušimo in tako dobimo 252 mg (77%) (3-azido-5-klorofenil)-(6,7dimetoks kinazolin-4-il)-amin hidroklorida (Ttal= 298301°C, LC-MS:331 (MH+)). Del tega produkta (175 mg, 0.476 mmol) raztopimo v 80% ocetni kislini/H2O (12 mL) , ohladimo na 0°C in dodamo raztopino NaN02 (36 mg, 0.516 mmol) v vodi (300 pL). Raztopino mešamo 10 minut pri 0°C, nato dodamo NaN3 (33 mg, 0.50 mmol) v 300 pL vode.Reakcijsko zmes segrejemo do 20°C in mešamo 16 ur. Oborino filtriramo in raztopimo v 10% metanolu v CHC13 in raztopino spiramo z nasičeno vodno raztopino NaHCO3 in solno raztopino, sušimo nad Na2SO4, filtriramo in koncentriramo. Tako dobimo 59 mg (35%) rumenega, trdnega glavnega produkta s Ttal= 205206°C.
PRIMER 23 (3-etinilfenil)-(6-metansulfonilkinazolin-4-il)-amin hidroklorid
6-metansulfonil-kinazolin-4-on (200 mg, 0.89 mmol), trifenilfosfin (566 mg, 2.15 mmol) in ogljikov tetraklorid (815 pL, 8.92 mmol) refluktiramo v 3 mL kloroforma 3.5 ure Topilo vakurnsko odparimo in ostanek raztopimo v 5 mL izopropanola in 3-etinilanilinu (156 mg, 1.33 mmol) in segrevamo na refluksu 16 ur. Ohlajeno reakcijsko zmes filtriramo, speremo z minimalno količino izopropanola in sušimo pri 70°C 16 ur. Dobimo 63 mg (20%) čistega trdnega produkta sTtal= 281-282°C.
PRIMER 24 (6-etansulfanil-kinazolin-4-il)-(3etinilfenil)-amin hidroklorid
6-etansulfanil-kinazolin-4-on (100 mg, 0.48 mmol), trifenilfosfin (305 mg, 1.16 mmol) in 3 mL ogljikovega tetraklorida refluktiramo 16 ur. Topilo vakumsko odparimo in ostanek raztopimo v 5 mL izopropanola in 3-etinilanilinu (68 mg, 0.58 mmol) in segrevamo na refluksu 1 uro. Ohlajeno reakcijsko zmes filtriramo, speremo z minimalno količino izopropanola in sušimo pri 70°C 16 ur. Dobimo 70 mg (42%) čistega trdnega produkta sTtal= 293-240°C.
PRIMER 25 (6,7-dimetoksi-kinazoiin-4-il)-(3-etinil 4-fluoro-fenil)-amin hidroklorid 4-kloro-6,7-dimetoksikinazolin (500 mg, 2.23mmol) in 3(2'-trimetilsilil-etinil)-4-fluoroanilin (507 mg, 2.44 mmol) refluktiramo v 5 mL t-butil alkohola 16 ur, ohladimo in filtriramo ter tako dobimo trden (6,7-dimetoksikinazolin-4-il)-(3'-etinil-fenil)-amin hidroklorid, ki ga spiramo z 10 mL izopropil alkohola in sušimo pri 70°C. Tako dobimo 832 mg produkta (83%). To damo v 10 mL metanola in kapljico vode z 250 mg kalijevega karbonata ter pustimo 3 ure. Zmes filtriramo in filtrat vakumsko evaporiramo. Ostanek trituriramo 1 uro z IN HC1, filtriramo in speremo z minimalno količino metanola ter sušimo. Dobimo 506 mg (63%) produkta s Ttal= 229°C.
3-(2'-trimetilsilil-etinil)-4-fluoroanilin, uporabljan zgoraj, pripravimo iz 3-bromo-4-fluoroanilina (7.0 mg, 36.8 mmol), tetrakis (trifenilfosfin) paladij (1.4 mg), trimetilsilil-acetilena (7.2 mg, 74mmol) in ogljikov tetraklorid (40 mg) refluktiramo v 140 mL z dušikom očiščenega suhega dietilamina 16 ur. Ohlajeno reakcijsko zmes filtriramo skozi Celite, ki ga nato spiramo z etrom. Filtrate vakumsko odparimo do ostanka, ki ga očistimo z tenkoplastno kromatografijo na silikagelu, eluirano z 35% heksanom v metilen kloridu. Frakcije, ki vsebujejo čist 3(2'-trimetilsilil-etinil)-4-fluoroanilin vakumsko odparimo do ostanka in uporabimo brez nadaljnega čiščenja.
PRIMER 26 (6,7-dimetoksi-kinazolin-4-il)-(3-propin1-il)fenil)-amin hidroklorid
4-kloro-6,7-dimetoksikinazolin (585 mg, 2.60 mmol) in 3(propin-l-il)anilin (361 mg, 2.74 mmol) refluktiramo v 5 mL t-butil alkohola 16 ur, ohladimo in filtriramo, da dobimo trden (6,7-dimetoksi-kinazolin-4-il)-[3-(propin-lil) fenil) ] amin hidroklorid, ki ga spiramo s 5 mL izopropanola in 25 mL etra ter nato sušimo pri 70°C. Dobimo 869 mg (94%) produkta s Ttal= 260-261°C.
3-(propin-l-il)anilin, uporabljan zgoraj, pripravimo iz 3-bromo-nitrobenzena v štirih korakih. 3-bromo-nitrobenzen (5.0 mg, 24.7 mmol), tetrakis(trifenilfosfin)paladij (1.0), trimetilsililacetilen (3.6 mg, 37 mmol), 20 mL s suhim dušikom očiščenega dietilamina in bakrovega jodida (20 mg) refluktiramo 16 ur. Ohlajeno reakcijsko zmes vakumsko evaporiramo ter spiramo s 50 mL metilen klorida in 50 mL IN HCl ter filtriramo. Organski ostanek osušimo z magnezijevim sulfatom, filtriramo in vakumsko evaporiramo do ostanka. 3trimetilsililetinilnitrobenzen očistimo s tenkoplastno kromatografijo na silikagelu, elurarno z heksan:metilen klorid 2:1. Frakcije, ki vsebujejo čisto spojino vakumsko odparimo in dobimo čist 3-trimetilsilil-etinil nitrobenzen (4.6 mg). 4.0 mg ga raztopimo v 30 mL metanola in kapljici vode z 1.16 mg kalijevega karbonata. Po eni uri zmes vakumsko evaporiramo in speremo s 100 mL metilen klorida. Organski ostanek speremo s 100 mL IN HC1, osušimo z magnezijevim sulfatom, filtriramo in vakumsko evaporiramo do ostanka (2.96 gm). 790 mg tega raztopimo v 10 mL benzena in obdelamo z uprašenim 87% kalijevim hidroksidom (377 mg, 5.91 mmol), metil jodidom (2 mL) in 10 mg 18-Crown-6 (Aldrich) in refluktiramo 16 ur. Po dodatku 0.5 mL metil jodida refluktiramo še 2 uri. Ohlajeno reakcijsko zmes vakumsko evaporiramo do ostanka, ki ga razredčimo s 100 mL metilen klorida, speremo s 100 mL IN HCl, osušimo z magnezijevim sulfatom, filtriramo in vakumsko evaporiramo do olja. Tega očistimo s tenkoplastno hitro kromatografijo na silikagelu in spiramo z heksan:metilen klorid 1:1. Frakcije, ki vsebujejo čist 3-(propin-l-il)-nitrobenzen, vakumsko evaporiramo do olja, ki ga uporabimo brez nadaljnega čiščenja. Dobimo 530 mg (61%) produkta. 3(propin-l-il)-nitrobenzen (530 mg, 3.3 mmol), železo v prahu (400 mg, 7.27 mmol), 3 mL koncentrirane HCl in 10 mL metanola refluktiramo 1 uro. Reakcijsko zmes filtriramo in vakumsko evaporiramo do trdnega ostanka, ki ga porazdelimo med 100 mL metilen klorida in 100 mL IN natrijevega hidroksida. Obe fazi filtriramo, nato odločimo organsko fazo, jo osušimo z magnezijevim sulfatom, filtriramo in vakumsko evaporiramo do olja, ki ga uporabimo brez predhodnega čiščenja za pripravo glavnega produkta. Tega dobimo 321 mg, kar je 78%.
PRIMER 27 [6,7-bis-(2-metoksi-etoksi)-kinazolin-4-il](3-etinil-4-fluoro-fenil)-amin hidroklorid
4-kloro-6,7-bis-(2-metoksi-etoksi)-kinazolin (140 mg, 0.446 mmol) in 3-etinil-4-fluoroanilin (66 mg, 0.452 mmol) reagiramo pod refluksom v dušikovi atmosferi s 5 mL izopropanola 16 ur. Topilo odstranimo vakuumsko in ostanek porazdelimo med CHC13 in nasičeno vodno raztopino NaHCO3. Organske ekstrakte speremo s solno raztopino, osušimo nad Na2SO4, filtriramo in koncentriramo v vakuumu. Surov produkt kromatografiramo na silikagelu z 40% acetonom/CH2Cl2, da dobimo 116 mg čistega glavnega produkta v obliki proste baze. To olje raztopimo v minimalni količini CHC13, nekajkrat speremo z etrom in titriramo s IM Hcl v etru, da glavni produkt oborimo v obliki bele oborine (99 mg, 50%; ttal 170-190°C; LC-MS:412 (MH+) ; anal.RP18-HPLC RT: 4.33 min.).
PRIMER 28 [6,7-bis-(2-metoksi-etoksi)-kinazolin-4-il](5-etinil-2-metil-fenil)-amin hidroklorid
4-kloro-6,7-bis-(2-metoksi-etoksi)-kinazolin (153 mg,
0.49 mmol), piridin(40 pL) in 3-etinil-6-metilanilin (71 mg, 0.54 mmol) reagiramo pri 110°C v dušikovi atmosferi v 3 mL DMF 36 ur. Topilo odstranimo vakuumsko in ostanek porazdelimo med CHC13 in nasičeno vodno raztopino NaHC03. Organske ekstrakte speremo s solno raztopino, osušimo nad Na2SO4, filtriramo in koncentriramo v vakuumu. Surov produkt kromatografiramo na silikagelu z 40% acetonom/CH2Cl2, da dobimo 40 mg (19%) čistega glavnega produkta v obliki proste baze. To olje raztopimo v minimalni količini CHC13, nekajkrat speremo z etrom in titriramo s IM HC1 v etru, da glavni produkt oborimo v obliki bele oborine (ttal 170-185°C; LC-MS:408 (MH+) ; anal.RP18-HPLC RT: 3.93 min.).
PRIMER 29 [6,7-bis-(2-kloro-etoksi)-kinazolin-4-il](3-etinil-fenil)-amin hidroklorid
4-kloro-6, 7-bis-(2-kloro-etoksi)-kinazolin (600 mg, 1.87 mmol) in 3-etinil-anilin (219 mg, 1.87 mmol) reagiramo pod refluksom v dušikovi atmosferi s 15 mL izopropanola 2.5 ure. Zmes ohladimo na 20°C, filtriramo, speremo z izopropanolom in etrom in sušimo v vakuumu. (707 mg, 86%; TTAL 230-240°C; LC-MS:402 (MH+) ; anal.RP18-HPLC RT: 5.35 min.).
PRIMER 30 [6-(2-kloro-etoksi)-7-(2-metoksi-etoksi)kinazolin-4-il]-(3-etinil-fenil)-amin hidroklorid Glavni produkt pripravimo iz 4-kloro-6-(2-kloro-etoksi)7-(2-metoksi-etoksi)-kinazolina (399 mg, 1.26 mmol) in 3etinil-anilin (147 mg, 1.26 mmol) kot je opisano pod primerom 29.(515 mg, 94%; ttAL 215-225°C; LC-MS:398 (MH+) ; anal.RP18-HPLC RT: 4.85 min.).
PRIMER 31 [6,7-bis-(2-acetoksi-etoksi)-4-(3-etinilfenilamino)-kinazolin
Glavni produkt primera 29 (200 mg, 0.456 mmol) obdelujemo s cezijevim acetatom (1.75 g, 9.12 mmol) v DMF (3 mL) pri 120°C v dušikovi atmosferi 16 ur. Reakcijsko zmes porazdelimo med CHC13 in solno raztopino NaHCO3. Organski ekstrakt speremo s solno raztopino, osušimo nad Na2SO4, filtriramo in koncentriramo v vakuumu, da dobimo olje (277 mg), ki ga rekristaliziramo iz CH2Cl2/heksan. (184 mg, 90%; ttal 137-138°C; LC-MS.-450 (MH+) ; anal. RP18-HPLC RT: 4.64 min.).
PRIMER 32
2-[4-(3-etinil-fenilamino)-7-(2-hidroksietoksi-kinazolin-6-iloksi)-etanol hidroklorid
6,7-bis-(2-acetoksi-etoksi)-4-(3-etinil-fenilamino)kinazolin (199 mg, 0.443 mmol) v 3 mL metanola obdelamo s
7Μ vodno raztopino KOH (0.25 ml). Pred vakumsko odstranitvijo topila zmes mešamo 2 uri pri 20°C. Trden ostanek speremo z vodo, da odstranimo soli in azetropsko osušimo z dvakratnim raztapljanjem v acetonitrilu in po vakumski koncentraciji dobimo 116 mg glavnega produkta v obliki proste baze. Po metodi uporabljani v primeru 28, to spojino pretvorimo v klorid (115 mg, 65%; TTal 215-218°C; LCMS:366 (MH+); anal.RP18-HPLC RT: 3.08 min.).
PRIMER 33
6-(2-acetoksi-etoksi)-4- (3-etinilfenilamino)-7-(2-metoksi-etoksi)-kinazolin
Glavni produkt primera 30 (160 mg, 0.368 mmol) obdelamo s cezijevim acetatom (707 mg, 3.68 mmol) v DMF (3 ml) pri 120°C v dušikovi atmosferi 16 ur. Reakcijsko zmes porazdelimo med solno raztopino in CHC13, organski ekstrakt speremo s solno raztopino, osušimo nad Na2SO4, filtriramo in koncentriramo v vakuumu. Tako dobimo trden ostanek (285 mg), ki ga rekristaliziramo iz zmesi etilacetat/heksan.
(134 mg; TTAL 84-87°C; LC-MS:422 (MH+) ; anal.RP18-HPLC RT: 4.38 min.).
PRIMER 34 [7-(2-kloro-etoksi) -6-(2-metoksi-etoksi)kinazolin-4-il]-(3-etinil-fenil)-amin hidroklorid
Ta produkt pripravimo iz 4-kloro-7-(2-kloro-et.oksi)-6-(2metoksi-etoksi)-kinazolin (600 mg, 1.89 mmol) in 3-etinil anilina (147 mg, 1.26 mmol), kot je opisano v primeru 29.
(7 37 mg, 90%; TTAL 225-235°C; LC-MS:398 (MH+) ; anal. RP18-HPLC RT: 4.89 min.).
PRIMER 35
7-(2-acetoksi-etoksi)-4- (3-etinilfenilamino)-6-(2-metoksi-etoksi)-kinazolin
Glavni produkt primera 34 (160 mg, 0.368 mmol) obdelamo s cezijevim acetatom (707 mg, 3.68 mmol) v DMF (3 ml) pri 120°C v dušikovi atmosferi 16 ur. Reakcijsko zmes porazdelimo med solno raztopino in CHC13, organski ekstrakt speremo s solno raztopino, osušimo nad Na2SO4, filtriramo in koncentriramo v vakuumu. Tako dobimo trden ostanek (288 mg), ki ga rekristaliziramo iz zmesi etilacetat/heksan.
(134 mg; TTAL134-135°C; LC-MS:422 (MH+) ; anal.RP18-HPLC RT: 4.43 min.).
PRIMER 36
2-[4- (3-etinil-fenilamino)-6-(2-metoksietoksi) -kinazolin-7-il-oksi]-etanol hidroklorid
Glavni produkt primera 35 (149 mg, 0.354 mmol) v metanolu (3 mL) obdelamo z 5M vodno raztopino KOH (0.25 mL). Zmes mešamo pri 20°C 30 min, nato vakuumsko odstranimo topilo. Trden ostanek speremo z vodo, da odstranimo soli in azeotropsko osušimo z dvakratnim raztapljanjem v acetonitrilu in vakuumski koncentraciji. Tako dobimo 100 mg glavnega produkta v obliki proste baze. Pretvorimo ga v klorid, po metodi uporabljeni v primeru 28. (87 mg; TTAL230235°C; LC-MS:380 (MH+) ; anal.RP18-HPLC RT: 3.42 min.).
PRIMER 37 (3-etinil-fenil)- j 6-(2-metoksi-etoksi)7-[2-(4-metil-piperazin-l-il)-etoksi]
-kinazolin-4-il}-amin hidroklorid
Glavni produkt primera 34 (110 mg, 0.253 mmol) v 2 mL DMF obdelujemo z N-metil-piperazinom (281 pL, 2.53 mmol) pri 110°C 16 ur.Reakcijsko zmes porazdelimo med CHC13 in nasičeno vodno raztopino NaHCO3. Organske ekstrakte speremo s solno raztopino, osušimo nad Na2SO4, filtriramo in koncentriramo v vakuumu. Surov produkt kromatografiramo na silikagelu z 15% metanol/CH2Cl2, da dobimo 56 mg čistega produkta v obliki proste baze. Belo trdno snov raztopimo v minimalnem volumnu CHC13, titriramo z 2 ekvivalentoma IM HC1 v etru, da oborimo bel, trden glavni produkt. (65 mg, 48%; „AL130-142°C; LC-MS:462 (MH+) ; anal.RP18-HPLC RT: 3.69 min.).
PRIMER 38 (3-etinil-fenil)-[7-(2-imidazol-l-il -etoksi]-6-(2-metoksi-etoksi)-kinazolin-4-il]-amin dihidroklorid Glavni produkt primera 34 (110 mg, 0.253 mmol) v 2 mL DMF obdelujemo z imidazolom (172 mg, 2.53 mmol) pri 110°C 48 ur.Reakcijsko zmes porazdelimo med CHC13 in nasičeno vodno raztopino NaHC03. Organske ekstrakte speremo s solno raztopino, osušimo nad Na2SO4, filtriramo in koncentriramo v vakuumu. Surov produkt (119 mg) kromatografiramo na silikagelu z 10% metanol/CH2Cl2, da dobimo 85 mg čistega produkta v obliki proste baze. Belo trdno snov raztopimo v minimalnem volumnu CHC13, titriramo z 2 ekvivalentoma IM HC1 v etru, da oborimo bel, trden glavni produkt. (95 mg, 75%; ttAIi220-227 °C; LC-MS:43O (MH+) ; anal.RP18-HPLC RT: 3.75 min.).
PRIMER 39 (3-etinil-fenil)-[6-(2-imidazol-l-il -etoksi]-7-(2-metoksi-etoksi)-kinazolin-4-il]-amin dihidroklorid Glavni produkt primera 30 (110 mg, 0.253 mmol) v 2 mL DMF obdelujemo z imidazolom (172 mg, 2.53 mmol) pri 110°C 48 ur.Reakcijsko zmes porazdelimo med CHC13 in nasičeno vodno raztopino NaHCO3. Organske ekstrakte speremo s solno raztopino, osušimo nad Na2SO4, filtriramo in koncentriramo v vakuumu. Surov produkt (125 mg) kromatografiramo na silikagelu z 10% metanol/CH2Cl2, da dobimo 86 mg čistega produkta v obliki proste baze. Belo trdno snov raztopimo v minimalnem volumnu CHC13, titriramo z 2 ekvivalentoma IM HCl v etru, da oborimo bel, trden glavni produkt. (95 mg, 78%; ttal85-100°C; LC-MS:430 (MH+) ; anal.RP18-HPLC RT: 4.13 min.).
PRIMER 40 (3-etinil-fenil)-[7-(2-metoksi-etoksi)
-6-(2-morfolin-4-il-etoksi)
-kinazolin-4-il]-amin dihidroklorid Glavni produkt primera 30 (107 mg, 0.245 mmol) v 2 mL DMF obdelujemo z morfolinom (214 pL, 2.45 mmol) pri 80°C 24 ur.Reakcijsko zmes porazdelimo med CHC13 in nasičeno vodno raztopino NaHCO3. Organske ekstrakte speremo s solno raztopino, osušimo nad Na2SO4, filtriramo in koncentriramo v vakuumu. Surov produkt (168 mg) kromatografiramo na silikagelu z 7.5% metanol/CH2Cl2, da dobimo 65 mg čistega produkta v obliki proste baze. Belo trdno snov raztopimo v minimalnem volumnu CHC13, titriramo z 2 ekvivalentoma IM HCl v etru, da oborimo bel, trden glavni produkt. (88 mg, 59%; ttal115-130°C; LC-MS:449 (MH+) ; anal. RP18-HPLC RT: 4.00 min.).
PRIMER 41
2-[4-(3-etinil-fenilamino)-7-(2-metoksietoksi) -kinazolin-6-iloksi]-etanol hidroklorid
Glavni produkt primera 33 (149 mg, 0.354 mmol) v metanolu (3 mL) obdelamo z 5M vodno raztopino KOH (0.25 mL). Zmes mešamo pri 20°C 30 min, nato vakuumsko odstranimo topilo. Trden ostanek speremo z vodo, da odstranimo soli in azeotropsko osušimo z dvakratnim raztapljanjem v acetonitrilu in vakuumski koncentraciji. Tako dobimo 95 mg glavnega produkta v obliki proste baze. Pretvorimo ga v klorid, po metodi uporabljeni v primeru 28.(89 mg, 61%;
ttal190-215°C; LC-MS:380 (MH+) ; anal.RP18-HPLC RT: 3.66 min.).
PRIMER 42 (6,7-dietoksi-kinazolin-4-il)-(3etinilfenil)-amin hidroklorid
6,7-dietoksikinazolin-4-on (120 mg, 0.512 mmol), trifenilfosfin (295 mg, 1.126 mmol) in 3 mL ogljikovega tetraklorida refluktiramo 16 ur. Topilo vakumsko odparimo in ostanek raztopimo v 3 mL izopropanola in 3-etinilanilinu (66 mg, 0.563 mmol) in segrevamo na refluksu 3 ure.
Ohlajeno reakcijsko zmes filtriramo, speremo z 10 mL izopropanola in sušimo pri 70°C . Dobimo 140 mg (75%) čistega trdnega produkta s Ttal= 269-270°C.
PRIMER 43 (6,7-dietoksi-kinazolin-4-il) -(3etinil-2-metil-fenil)-amin hidroklorid
4-kloro-6,7-dietoksikinazolin (200 mg, 0.792 mmol) in 3(2'-trimetilsililetinil-2-metil-anilin (168 mg, 0.871 mmol) refluktiramo 16 ur v 4 mL t-butil alkohola. Ohlajeno reakcijsko zmes razredčimo s 5 mL etil etra in filtriramo, da dobimo trdno snov (6,7-dietoksi-kinazolin-4-il)-(3-(2'trimetilsilil-etinil)-2-metil-fenil)-amin hidroklorid, ki ga speremo z 10 mL etil etra in osušimo pri 70°C. To reagiramo z 2 mL metanola, ki vsebuje kapljico vode in 100 mg kalijevega karbonata 0.5 ure. Heterogeno reakcijsko zmes filtriramo skozi Celite in vakumsko uparimo do ostanka, ki ga raztopimo v prebitku IN HC1 v metanolu, oborimo z etil etrom, filtriramo in osušimo pri 70°C. Dobimo 160 mg (75%) produkta s Ttal= 258-259.5°C.
PRIMER 44 (3-etinil-fenil)-(6-metil-kinazolin-4-il) amin hidroklorid
6-metil-kinazolin-4-on (350 mg, 2.18 mmol) dodamo suspenziji polimerno nanesenega trifenilfosfina (Fluka,
3.63 g 3 mmol P/g smole; 10.9 mmol) v zmesi Ccl4 (3.35 g, 21.80 mmol) in 1,2 dikloroetan (10 mL). Zmes segrevamo pri 60°C 2 uri, polimer odstranimo s filtracijo in speremo z dikloroetanom. Filtrate zberemo v epruveti z 3-etinilanilinom (0.644 g, 2.18 mmol) in koncentriramo do 5 mL z evaporacijo. Po 4 urah refluktiranja v dušikovi atmosferi, ki mu sledi ohlajanje na 20°C, glavni produkt zberemo s filtracijo (551 mg, 86%; Ttal256-257 °C; LC-MS:260 (MH+) ; anal.RP18-HPLC RT: 4.41 min.).
PRIMER 45
2-{2-[4-(3-etinil-fenilamino)-6-(2-metoksietoksi)kinazolin-7-iloksi]-etilsulfanil}propionske kisline amonijeva sol
Glavni produkt primera 34(150 mg, 0.34 mmol)dodamo raztopini tiomlečne kisline (100 pL, 1.14 mmol) in KOH (150 mg, 2.7 mmol) v razplinjeni DMF (5 mL)/H20 (0.5 mL) . Reakcijsko zmes mešamo pri 50°C v dušikovi atmosferi 72 ur in ohladimo na sobno temperaturo. Z ocetno kislino prilagodimo pH raztopine na približno 4.0 in nato porazdelimo med CHC13 in nasičeno vodno raztopino NaHCO3. Organske ekstrakte speremo s solno raztopino, osušimo nad Na2SO4, filtriramo in koncentriramo v vakuumu. Surov produkt očistimo s preparativno RP18 HPLC z gradient.no elucijo od 15 do 100% CH3CN/pH 4.5, 50 mM amonijevega acetata, ki mu sledi liofilizacija primerne čiste frakcije, da dobimo glavni produkt. (28 mg, 18%; TTAL95-103oC; LC-MS:468 (MH+) ; anal.RP18-HPLC RT: 3.57 min.).
PRIMER 46 {2-[4-(3-etinil-fenilamino)-6-(2-metoksietoksi)-kinazolin-7-iloksi]-etilsulfanil }ocetne kisline amonijeva sol
Glavni produkt pripravimo iz glavnega produkta primera 34 in merkaptoocetne kisline po metodi opisani v primeru 45.(3%; LC-MS:454 (MH+) ; anal.RP18-HPLC RT: 3.37 min.).
PRIMER 47
4-(3-etinil-fenilamino)-6-(2-metoksietoksi)-kinazolin-7-ol
Ta produkt izoliramo kot bolj lipofilni produkt (z preparativno RP18 HPLC) pri reakciji, ki jo uporabljamo za pridobitev glavnega produkta primera 46 (5%; LC-MS:336 (MH+); anal.RP18-HPLC RT: 3.60 min.).
PRIMER 48 (3-etinil-fenil)-[7-(2-metoksi-etoksi) -6-viniloksi-kinazolin-4-il] in [6-(2-etoksi-etoksi)-7-(2-metoksi-etoksi) kinazolin-4-il]-(3-etinil-fenil)-amin hidroklorid
Glavni produkt primera 30 (107 mg, 0.254 mmol) reagiramo z natrijevim etoksidom (0.582 mmol) v etanolu (3 mL) pod refluksom 24 ur. Topilo vakuumsko odstranimo in produkt izoliramo s tenkoplastno hitro kromatografijo na silikagelu z 10% acetonom/CH2Cl2, da dobimo 30 mg 6-viniloksi produkta (33%; TTAL113-114 °C; LC-MS:362 (MH+) ; anal. RP18-HPLC RT: 4.35 min.). 6-(2-etoksi-etoksi) derivat eluiramo kot bolj polarni produkt (45 mg) in ga pretvorimo v klorid po postopku opisanem v primeru 28 (43%; TTAL220-225°C; LC-MS:408 (MH+); anal.RP18-HPLC RT: 4.35 min.).
PRIMER 49
4-(3-etinil-fenilamino)-7-(2-metoksietoksi) -kinazolin-6-ol hidroklorid (3-etinil-fenil)-[7-(2-metoksi-etoksi)-6-viniloksikinazolin-4-il]-amin (20 mg; iz primera 48) hidroliziramo z 6M Hcl/metanolu (30:70; 3 mL) pri 50°C 5 dni. Raztopino koncentriramo v vakuumu in ostanek porazdelimo med CHC13 in nasičeno vodno raztopino NaHC03 pri pH približno 7. Organske ekstrakte speremo s solno raztopino, osušimo nad Na2SO4, filtriramo in koncentriramo v vakuumu ter tako dobimo glavni produkt v obliki proste baze (15 mg). Pretvorimo jo v kloridno sol po postopku opisanem v primeru 28 (ttal135150°C; LC-MS:336 (MH+) ; anal.RP18-HPLC RT: 3.77 min.).
PRIMER 50
1-{2- [4-(3-etinil-fenilamino)-6-(2-metoksietoksi) -kinazolin-7-iloksi]-etil}lH-piridin-4-on hidroklorid
NaH (30 mg 60% mineralnega olja, 0.77 mmol) dodamo brezvodnemu DMF (2.0 mL) in pirid-4-οη (97 mg, 0.83 mmol). Zmes mešamo 40 minut pri 22°C, dokler se ne raztopijo vse trdne spojine in preneha izhajati H2.Glavni produkt primera 34 (120 mg, 0.28 mmol) in t-butilamonijev jodid (15 mg) dodamo reakcijski zmesi in mešamo 7 dni pri 22°C v dušikovi atmosferi.Dodatni pirid-4-οη (79 mg) in NaH (30 mg 60%) raztopimo v DMF (2mL) in to raztopino dodamo reakcijski zmesi. Po nadaljnih 4 dnevih mešanja zmes porazdelimo med CHC13 in solno raztopino. Organske ekstrakte osušimo nad Na2SO4, filtriramo in koncentriramo v vakuumu. Tako dobimo glavni produkt, ki ga očistimo z tenkoplastno kromatografijo na silikagelu z 10% metanolom/CH2Cl2, da dobimo 65 mg proste baze, ki jo po postopku opisanem v primeru 28 pretvorimo v mono-hidrokloridno sol (66 mg, ttal240-248°C; LC-MS:457 (MH+) ; anal.RP18-HPLC RT: 3.23 min.).
PRIMER 51
1-{2-[4-(3-etinil-fenilamino)-7-(2-metoksietoksi) -kinazolin-6-iloksi]-etil}lH-piridin-4-on hidroklorid
Produkt v obliki proste baze pripravimo iz glavnega produkta primera 30 kot natrijevo sol piridin-4-ona, kot je opisano v primeru 50. Prosto bazo izoliramo z tenkoplastno kromatografijo z 15% metanolom/CHCl3 in jo pretvorimo v naslovni produkt po postopku opisanem v primeru 28 (32%,tol155-168°C; LC-MS:457 (MH+) ; anal.RP18-HPLC RT: 3.45 min.).
PRIMER 52 (3-etinil-fenil)-(6-metoksi-kinazolin4-il)-amin hidroklorid mM raztopina 6-metoksi-3H-kinazolin-4-ona in 1,2dikloroetan dodamo polimerno nanesenemu trifenilfosfinu (Fluka, okrog 3 mmol P/g smole; 2.5 mmol ekv.) in Ccl4 ( 100 rnol ekv.). Zmes segrevamo s stresanjem pri 60°C 21 ur, ohladimo na 22°C in dodamo 30 mM raztopine 3-etinilanilina (1.5 mla ekv.) v t-butanolu. Dobljeno zmes segrevamo med stresanjem pri 60°C 18 ur in nato ohladimo na 22°C. Polimer odfiltriramo in dvakrat speremo z metanolom. Ta metanol dodamo filtratom in raztopino koncentriramo v vakuumu ter tako dobimo glavni produkt (73%; LC-MS:276 (MH+) ; anal.RP18HPLC RT: 5,82 min.). Za te primere je analitični RP18-HPLC sistem sestavljen iz Waters 717™ autosampler, Waters 996 Photodiode Array Detector™, Waters 600™ sistem za dotok štirih topil, nadzira pa ga Millennium™ programska oprema. Alikvote vzorcev kromatografiramo z uporabo linearnega gradienta od 0 do 100% acetonitrila v 0.2 M acetatnem pufru (ρΗ 4.5) v 10 minutah, s pretokom 3 mL/min z uporabo Perkin-Elmer Pecosphere™ (3 mm X 3 cm) C18 kolono.
Spojine primerov 53-94 in njihove hidrokloride pripravimo po podobnem postopku kot tega v primeru 52, iz primernega 3H-kinazolin-4-on derivata in 3-et.inil-anilina:
PRIMER | PRODUKT | % DONOSA | LC-MS (MH+) | HPLC RT (mins |
53 | (6-kloro-kinazolin-4- il)-(3-etinil-fenil)- amin | 60 | 280,282 | 6.44 |
54 | [7-kloro-6-(2,5-dikloro- fenilsulfanil)- kinazolin-4-il]-(3- etinil-fenil)-amin | 51 | 456, 458 | 8.74 |
55 | 7-kloro-4-(3-etinil- fenil-amino)kinazolin-6- karbonitril | 12 | 305,307 | 6.51 |
56 | (6-bromo-7-(4-kloro- fenoksi)-kinazolin-4- i1]- (3-etinil-fenil)- amin | 28 | 450,452 | 8.05 |
57 | [6-(4-bromo- benzilsultanil)- kinazolin-4-il]-{3- etinil-fenil)-amin | 50 | 446, 448 | 7.99 |
58 | (7-bromo-6- metilsulfanil-kinazolin- 4-il)-(3-etinil-fenil)- amin | 46 | 370,372 | 6.99 |
59 | {7-kloro-6-[4-(4-kloro- | 82 | 514,516 | 9.4 5 |
fenilsulfanil)-fenoksi]kinazolin-4-il}—(3— etinil-fenil)-amin (3-etinil-fenil)-(7fenil-sulfanilkinazolin-4-il)-amin (3-etinil-fenil)-(6jodo-kinazolin-4-il)amin (3-etinil-fenil)-(6trifluorometilkinazolin-4-il)-amin [7-kloro-6-(4-klorofenoksi)-kinazolin-4il]- (3-etinil-fenil)amin [7-kloro-6-(4-klorofenilsulfanil)kinazolin-4-il]-(3etinil-fenil)-amin [7-kloro-6-(4-metoksifenoksi)-kinazolin-4il]-(3-etinil-fenil)amin [7-kloro-6-(4-fluorofenoksi)-kinazolin-4il]-(3-et.inil-fenil)~ amin [ 6-(4-kloro-fenoksi)kinazolin-4-il]-(3etinil-fenil)-amin 7-bromo-4-fluoro-(3etinil-fenilamino)kinazolin-6-sulfonska kislina (6-bromo-7-kloro88 354
372
314
406,408
422,424
402,404
390
372,374
431,433
358,360
7.40
6.81
6.73
8.06
8.45
7.55
7.61
6.44 kinazolin-4-il)-(3etinil-fenil)-amin 4- (3-etinil-fenilamino)kinazolin-6-karbonitril [6-(4-bromofenilsulfanil)-7-klorokinazolin-4-il)- (3etinil-fenil)-amin {6-[2-(4-bromo-fenoksi)etilsulfanil]-kinazolin4-il}-(3-etinil-fenil)amin
4- [7-kloro-4-(3-etinilfenilamino)-kinazolin-6ilsulfanil-metil)benzonitril [7-kloro-6-(3-klorofenoksi)-kinazolin-4-il(3-etinil-fenil)-amin [ 6-(3-bromo-fenoksi)-7kloro-kinazolin-4-il](3-etinii-fenil)-amin (7-kloro-6-fenoksikinazolin-i-ilJ-iSetinil-fenil)-amin (7-kloro-6-(4metilsulfanil-fenoksi)kinazolin-4-il]-(3etinil-fenil)-amin [7-kloro-6-(4metansulfonil-fenoksi)kinazolin-4-il]-(3etinil-fenil)-amin (7-kloro-6-p-toliloksikinazolin-4-il)-(3etinil-fenil)-amin
271
466, 468
476,478
427,429
406,408
450,452
372,374
418,420
450,452
386,388
5.84
8.56
8.11
7.56
8,10
8.22
7.59
8.02
6.73
7.95 (3-etinil-fenil) -[6-(4fenoksi-fenoksi)kinazolin-4-ϋ]-amin (7-kloro-6fenilsulfanil-kinazolin4-il) -(3-etinil-fenil)amin [6-(3-kloro-fenoksi)kinazolin-4-ilj-(3etinil-fenil)-amin [6-(3,5-diklorofenoksi)-kinazolin-4il]-(3-etinil-fenil)amin [6-(2-kloro-fenoksi)kinazolin-4-il]-(3etinil-fenil)-amin (7-kloro-6metansulfonil-kinazolin4-il)-(3-etinil-fenil)amin [ 6-(3,4-diklorofenoksi)-kinazolin-4i1]-(3-etinil-fenil)amin [6-(4-bromo-fenoksi)kinazolin-4-il]-(3etinil-fenil)-amin [6-(4-kloro-2-metilfenoksi)-kinazolin-4il]-(3-etinil-fenil)arnin [7-kloro-4-(3-etinilfenilamino)-kinazolin-6ilsulfanil]-acetonitril
430
388,390
372,374
406,408
372,374
358,360
406,408
416,418
386,388
351
8.29
7.96
7.71
8.30
7.38
5.74
8.14
7.81
8.02
6.44 [6-alilsulfanilkinazolin-4-il]-(3etini 1-fenil)-amin (7-kloro-6propilsulfanilkinazolin-4-il)-(3etinil-fenil)-amin (7-kloro-6metilsulfanil-kinazolin4-il]-(3-etinil-fenil)amin [7-kloro-6-(2-metilsulfanil-etilsulfanil)kinazolin-4-il]-(3etinil-fenil)-amin (6-kloro-7-metoksikinazolin-4-il)- (3etinil-fenil)-amin
318 6.93
354,356 7.79
326,328 6.94
386,388 7.56
310,312 6.65 ** [7-kloro-4-(3-etinil-fenilamino)-kinazolin-6ilsulfanil]-acetonitril dobimo iz 2-(7-kloro-4-okso-3,4dihidro-kinazolin-6-ilsulfanil)-acetamid pod temi pogoji.
PRIMER 95 (6,7-dibutoksi-kinazolin-4-il)-(3-etinil -fenil)-amin hidroklorid
6,7-dibutoksikinazolin-4-on (105 mg, 0.362 mmol), trifenilfosfin (208 mg, 0.796 mmol) in 5 mL ogljikovega tetraklorida refluktiramo 16 ur. Topilo vakurnsko odparimo in ostanek raztopimo v 3 mL izopropanola in 3-etinilanilinu (47 mg, 0.398 mmol) in segrevamo na refluksu 3 ure.
Ohlajeno reakcijsko zmes filtriramo, da dobimo glavni produkt, ki ga speremo z 10 mL izopropanola in sušimo pri 70°C. Dobimo 92 mg (60%) čistega trdnega produkta s Ttal= 247-248°C.
PRIMER 96 (6,7-diisopropoksi-kinazolin-4-il)- (3-etinil -fenil)-amin hidroklorid
6,7-diizopropoksikinazolin-4-on (55 mg, 0.210 mmol), trifenilfosfin (121 mg, 0.462 mmol) in 3 mL ogljikovega tetraklorida refluktiramo 16 ur. Topilo vakumsko odparimo in ostanek raztopimo v 3 mL izopropanola in 3-etinilanilinu (30 mg, 0.257 mmol) in segrevamo na refluksu 3 ure.
Ohlajeno reakcijsko zmes vakumsko evaporiramo, da dobimo glavni produkt, ki ga kolonsko kromatografijo na silikagelu spirano z 5% acetonom v metilen kloridu, ki vsebuje 0.25% trietilamina. Frakcije, ki vsebujejo čisti produkt koncentriramo v vakuumu do trdnega in nato raztopimo v 2 mL IN HC1 v metanolu, oborimo z etiletrom, filtriramo in osušimo v vakuumu pri 70°C. Dobimo 140 mg (75%) čistega trdnega produkta s Ttal= 241-242°C.
PRIMER 97 (6-kloro-7-(2-metoksietilsulfanil)-kinazolin -4-il) - (3-etinil-fenil) -arnin hidroklorid
6-kloro-7-(2-metoksietilsulfanil)-kinazolin-4-on (200 mg, 0.739 mmol), trifenilfosfin (427 mg, 1.63 mmol) in 0.7 mL ogljikovega tetraklorida refluktiramo 4 ure v 4 mL 1,2dikloroetana. Topilo vakumsko odparimo in ostanek raztopimo v 4 mL izopropanola in 3-etinilanilinu (129 mg, 1.104 mmol) in segrevamo na refluksu 16 ur. Vročo reakcijsko zmes filtriramo, da izoliramo glavni produkt, ki ga kolonsko kromatografiramo na silikagelu, spiramo z 5% metanolom v kloroformu. Produkt koncentriramo v vakuumu do trdnega. Dobimo 23 mg (8.4%) čistega trdnega produkta s Ttal= 230232°C.
PRIMER 98 (6,7-bis-[2-metoksietoksi]-kinazolin4-il)-(3-etinil-2-metil-fenil)-amin
6,7-bis-[2-metoksietoksi]-4-kloro-kinazolin (90 mg, 0.288 mmol) in 3-(2'-trimetilsililetinil-2-metil-anilin (62 mg, 0.317 mmol) refluktiramo 16 ur v 4 mL t-butil alkohola. Ohlajeno reakcijsko zmes razredčimo z 1 mL izopropanola in filtriramo, da dobimo trden (6,7-bis-(metoksietoksi)kinazolin-4-il)-(3-(2'-trimetilsilil-etin-l-il)-2-metilfenil)-amin hidroklorid, ki ga speremo z 10 mL etra in osušimo pri 70 °C dobimo 70 mg produkta.
mg tega produkta reagiramo z 3 mL metanola, ki vsebuje kapljico vode in 50 mg kalijevega karbonata 0.5 ure. Heterogeno reakcijsko zmes filtriramo skozi Celite in vakumsko uparimo do ostanka, ki ga osušimo pri 70°C. Dobimo 38 mg (75%) produkta s Ttal= 232°C.
PRIMER 99 (6,7-bis-[2-metoksietoksi]-kinazolin4-il)-(3-etinil-5'-fluoro-fenil)-amin hidroklorid
6,7-bis-[2-metoksietoksi]-4-kloro-kinazolin (90 mg, 0.288 mmol) in 3-(2'-trimetilsililetinil-5-fluoro-anilin (69 mg, 0.317 mmol) refluktiramo 5 ur v 3 mL t-butil alkohola. Ohlajeno reakcijsko zmes razredčimo z 2 mL izopropanola in filtriramo, da dobimo trden (6,7-bis-(metoksietoksi)kinazolin-4-il)-(3-(2'-trimetilsilil-etin-l-il)-2-metilfenil)-amin hidroklorid, ki ga speremo z 10 mL etra in osušimo pri 70 °C dobimo 131 mg produkta.
Produkt reagiramo z 3 mL metanola, ki vsebuje kapljico vode in 35 mg kalijevega karbonata 0.5 ure pri sobni temperaturi. Reakcijski zmesi pred filtriranjem prilagodimo pH na 2.5 z IN HCl in osušimo pri 70°C. Dobimo 92 mg (78%) produkta s Ttal= 249-250°C.
PRIMER 100 (7-propilsulfanil-kinazolin-4-il)(3-etinil-fenil)-amin hidroklorid
7-propilsulfanil-kinazolin-4-on (300 mg, 1.36 mmol), trifenilfosfin (785 mg, 2.99 mmol), 5 mL kloroforma in 1.31 mL ogljikovega tetraklorida refluktiramo 16 ur. Topilo vakumsko odparimo in ostanek raztopimo v 5 mL izopropanola in 3-etinilanilinu (175 mg, 1.49 mmol) in segrevamo na refluksu 3 ure. Ohlajeno reakcijsko zmes vakumsko evaporiramo, da dobimo glavni produkt, ki ga očistimo s kolonsko kromatografijo na silikagelu spirano z 10% metanolom v kloroformu. Frakcije, ki vsebujejo čisti produkt, kot prosti amin, koncentriramo v vakuumu do trdnega in nato raztopimo v 3 mL IN HCl v metanolu. Raztopino evaporiramo do ostanka, ki ga trituriramo z 4 mL vročega izopropanola, ohladimo in filtriramo ter osušimo v vakuumu pri 70°C. Dobimo 293 mg (55%) čistega trdnega produkta s Ttal= 229-230°C.
PRIMER 101 [7-(2-metoksietilsulfanil-kinazolin-4-il)(3-etinil-fenil)-amin hidroklorid
Enako kot v primeru 42 pripravimo glavni produkt iz [7(2-metoksietoksisulfanil-kinazolin-4-on (200 mg, 2.03 mmol), trifenilfosfin (533 mg, 2.03 mmol) in 3 mL ogljikovega tetraklorida. Dobimo 233 mg (74%) produkta s Ttal= 208-2 09 °C.
PRIMER 102 (7-kloro-6-nitro-kinazolin-4-il)(3-etinil-fenil)-amin hidroklorid
7-kloro-6-nitro-kinazolin-4-on (1.002 g, 4.44 mmol), fosforjev oksiklorid (11.5 g, 7.51 mmol) in fosforjev pentaklorid (1.62 g, 7.74 mmol) refluktiramo 2 uri in reakcijsko zmes koncentriramo do ostanka, ki ga trituriramo s toluenom in nato še s kloroformom. Po sušenju dobimo surov 4,7-dikloro-6-nitro-kinazolin, ki ga raztopimo v 35 mL izopropanola in 3-etinilanilina (639 mg, 5.45 mmol) in refluktiramo 3 ure. Ohlajeno reakcijsko zmes filtriramo, da dobimo trden glavni produkt, ki ga speremo z 10 mL izopropanola in osušimo pri 70°C. Produkta je 1.055 g (66%) s Ttai= 230.8-232.6°C.
PRIMER 103 (6-amino-7-kloro-kinazolin-4-il)(3-etinil-fenil)-amin hidroklorid (7-kloro-6-nitro-kinazolin-4-il)-(3-etinil-fenil)-amin hidroklorid (166 mg, 0.295 mmol) in natrijev ditionit (207 mg, 1.19 mmol) mešamo z 1.5 mL mravljične kisline 4 ure pri sobni temperaturi. Reakcijski zmesi dodamo 45 mL metanola in pustimo stati 16 ur pri sobni temperaturi. Nastalo oborino prefiltriramo in trituriramo z 3% natrijevim bikarbonatom 0.5 ure in refiltriramo. Oborino raztopimo v 20 mL IN HC1 v metanolu in oborimo z 200 mL etiletra. To filtriramo, osušimo in dobimo 72 mg (83%) produkta s Ttai= 260-265°C.
PRIMER 104 (3-etinil-fenil) - (7-metoksi-6-nit.rokinazolin-4-il)-amin (7-kloro-6-nitro-kinazolin-4-il)-(3-etinil-fenil)-amin hidroklorid (100 mg, 0.306 mmol) in suh natrijev metoksid (120 mg, 2.22 mmol) mešamo v 2 mL suhega 2-metilpirolidin1-ona 8 ur pri 30°C. Ohlajeni reakcijski zmesi dodamo 0.93 mL 3N in 1 mL vode. zmes razredčimo z 60 mL vode in dvakrat ekstrahiramo z 60 mL etil acetata. Združene organske dele speremo trikrat s 50 mL vode in 50 mL solne raztopine, osušimo z magnezijevim sulfatom, filtriramo in vakuumsko evaporiramo do ostanka. Dobimo 80 mg (82%) produkta s Ttai= 213-218°C.
PRIMER 105 {2—[4—(3-etinil-fenilamino)-7-(2-metoksietoksi) -kinazolin-6-iloksi]-etilsulfanil}ocetne kisline amonijeva sol
Glavni produkt pripravimo iz glavnega produkta primera 30 in merkaptoocetne kisline pri 22°C v 10 dneh, po metodi opisani v primeru 45.(16%; Ttai= 98-113°C; LC-MS:454 (MH+) ; anal.RP18-HPLC RT: 3.24 min).
PRIPRAVA 1
6,7-bis(2-metoksi-etoksi)-kinazolon
Zmesi etil 3,4-dihidroksibenzoata (36.4 g, 0.200 mol), K2CO3 (60.8 g, 0.44 mol) in t-butilamonijevega jodida (750 mg) v razplinjenem acetonu (400 mL) dodamo 2-bromoetil metil eter (69.5 g, 47 mL). Zmes mešamo v dušikovi atmosferi pod refluksom 64 ur. Zmesi dodamo po 0.5 ure 600 mL etra pri 20°C in nastalo oborino odstranimo s filtracijo. Filtrate koncentriramo v vakuumu da trdnega ostanka, ki ga trituriramo 30 min z heksanom (500 mL). Belo oborino etil 3,4-bis(2-metoksi-etoksi)benzoata pa filtriramo in sušimo ter tako dobimo 55.5 g (93%) produkta s Ttai= 50-51°C. Del tega produkta (45.7 g, 0.158 mol) v ocetni kislini (150 mL) reagiramo z dodajanjem po kapljicah 40 mL cone. HNO3 pri 5°C in raztopino mešamo 24 ur ter jo nato zlijemo v 1.6 L mrzle H20. Zmes ekstrahiramo z etil acetatom (1.1 L) in organsko fazo speremo trikrat z 200 mL vode in solne raztopine, osušimo nad Na2SO4, filtriramo in koncentriramo v vakuumu, da dobimo etil 4,5-bis-(2-metoksi63 etoksi)-2-nitro-benzoat (54.3 g) v obliki rjavega olja. Ta nitro produkt (52.0 g. 0.15 mol) raztopimo v etanolu (1000 mL), ki vsebuje 1 ekvivalent HC1 (naredimo v etanolu ob predhodnem dodatku 11 mL acetil klorida), dodamo še PtO2*H2O (1.0 g) in zmes hidrogeniramo pod 310.5 kPa 6 ur. Katalizator odstranimo s filtracijo skozi Celite in filtrat koncentriramo v vakumu do trdnega ostanka, ki ga raztopimo v 400 mL etra. Trdno, belo hidrokloridno sol etil-2-amino4,5-bis-(2-rnetoksi-etoksi) benzoata filtriramo in sušimo v vakuumu ter dobimo 44.7 g (88%) produkta. Del (42 g, 0.12 mola) in amonijev formiat (7.6g, 0.12 mol) raztopimo v formamidu (63 mL) in raztopino med mešanjem segrevamo pri 160-165°C v dušikovi atmosferi 3 ure. Dodamo 200 mL vode in po ohladitvi s filtracijo odstranimo surov produkt, ga speremo z vodo in vakumsko osušimo. Filtrat ekstrahiramo petkrat z CHC13 in združene organske ekstrakte speremo s solno raztopino, osušimo nad Na2SO4 in vakuumsko koncentriramo. Ostanek zmešamo s surovim kinazolonom, trituriramo v vročem acetonitrilu (250 mL) 30 minut, ohladimo na 20°C in obdelamo z etrom (250 mL). Po ohladitvi na 4°C belo trdno snov odfiltriramo in vakumsko osušimo. Dobimo 30.4 g (86%) produkta (GC-MS m/z 294(M+)).
PRIPRAVA 2
4-kloro-6,7-bis-(2-metoksi-etoksi)-kinazolin
6,7-bis(2-metoksi-etoksi)-kinazolonu (priprava 1, 500 mg,
1.7 mmol) v CHC13 (10 mL) , ki vsebuje kapljico DMF dodamo oksalilklorid (490 pL, 5.6 mmol) v nekaj delih v petminutnem intervalu. Ko se pojavi penjenje raztopino refluktiramo 1.5 ure. Topilo vakumsko odstranimo in ostanek raztopimo v 1,2-dikloroetanu (20 rnL) in dvakrat speremo z 80 mL nasičene vodne raztopine Na2CO3. Organske faze osušimo nad Na2SO4, vakumsko koncentriramo, da dobimo trden glavni produkt (520 mg, 92%; Ttai^ 108-109°C.
PRIPRAVA 3
4-kloro-6,7-bis-(2-kloro-etoksi)-kinazolin, 4kloro-6-(2-kloro-etoksi)-7-(2-metoksi-etoksi)-kinazolin, 4kloro-6,7-bis-(2-metoksi-etoksi)-kinazolin in 4-kloro-7-(2kloro-etoksi)-6-(2-metoksi-etoksi)-kinazolin
6,7-bis-(2-metoksi-etoksi)-kinazolon (5.4 g, 18.3 mmol, priprava 1) in piridin (3.0 mL, 37 mmol)segrevame pod refluksom v 22 mL POC13 v dušikovi atmosferi 2.5 ure. Sledi vakumska koncentracija zmesi pri 60 °C do ostanka, ki ga raztopimo v CHC13 (150 mL) in raztopino previdno, med mešanjem dodamo k mrzli nasičeni raztopini NaHCO3 (100 mL) . Ko dodamo vse mešamo še 10 minut, nato ločimo organsko fazo, speremo z solno raztopino, osušimo nad Na2SO4 in vakumsko koncentriramo. Ostanek tenkoplastno kromatografiramo na silikagelu z gradientno elucijo od 20 do 60% etil acetat/heksan, da dobimo 3.41 g 4-kloro-6,7bis-(2-metoksi-etoksi)-kinazolin, 234 mg 4-kloro-6-(2kloro-etoksi)-7-(2-metoksi-etoksi)-kinazolin, 330 mg 4kloro-6,7-bis-(2-metoksi-etoksi)-kinazolin in 532 mg 4kloro-7-(2-kloro-etoksi)-6-(2-metoksi-etoksi)-kinazolina.
Claims (19)
- PATENTNI ZAHTEVKI1. Spojina s formulo in njene farmacevtsko sprejemljive soli ter predhodnice zdravil, značilna po tem, da je m je 1, 2 ali 3 vsak R1 je neodvisni hidrogen, halo, hidroksi, amino, hidroksiamino, karboksi, (C1-C4) alkoksikarbonil, nitro, gvanidino, ureido, karbamoil, ciano, trifluorometil, (R6)2Nkarbonil in fenil-W-alkil, kjer je W enojna vez, 0, S ali NH;ali, da je vsak R1 samostojno izbran med ciano- (C1-C4) alkil in R9, kjer je R9 izbran iz skupin, ki jih sestavljajo R5, R50, (R6)2N, R7C(=0), R5ONH, A in R5Y; R5 je (C1-C4) alkil; R6 je hidrogen ali R5, kjer so vsi R5 enaki ali pa različni; R7 je R5, R50 ali (R6)2N; A izberemo med piperidino-, morfolino, pirolidino in 4-R6 piperazin-l-il, imidazol-l-il, 4-piridon-l-il, karboksi-(C1-C4)-alkil, fenoksi, fenil, fenilsulfanil, (C2-C4)-alkenil, (R6) 2-N-karbonil-(C1-C4)alkil; in Y izberemo med S, SO, S02; alkilni deleži v (R°)2N so lanko subsrituirni s halo ali R9, pri čemer je R9 definiran zgoraj in alkilna deleža R5 in R50 sta lahko substituirana s halo, R60 ali R9' kjer sta R6 in R9 definirana kot zgoraj, in kjer so dobljene skupine lahko substituirane s halo ali R9 pod pogojem, da se dušikov, kisikov, žveplov ali kateri drug heteroatom ne morejo vezati na isti ogljikov atom ter, da lahko R1 vsebuje največ tri R9 enote;ali, da je vsak R1 je neodvisno izbran med R5-sulfonamino, ftalimido-(Ci~C4)-alkilsulfonamino, benzamido, benzensulfonamino, 3-fenilureido, 2-oksopirolidin-l-il,
- 2, 5-dioksopirolidin-l-il in R10- (C2-C4) -alkilamino, kjer je R10 izbran med halo, R60, (C2-C4)-alkanoiloksi, R7C(=O) in (R6)2N; in kjer lahko benzamido, benzensulfonamino, fenil, fenoksi, anilino ali fenilsulfanil substituent v R1 nosi še enega ali dva halogena, (C1-C4)alkil, ciano, metansulfonil ali (Ci-C4)-alkoksi substituente;ali da katerakoli dva R1 vzeta skupaj z ogljikoma, na katera sta vezana, vsebujeta 5-8 členi obroč z vsaj enim ali dvema heteroatomoma, ki so lahko kisik, žveplo ali dušik, kjer so alkilne skupine ali alkilni del v alkoksi ali alkilamino skupini ravne verige ali, če vsebujejo vsaj tri ogljikove atome, razvejane ali ciklične;R2 je izbran izmed H in neobvezno substituiranim(Ci-C6) alkilom;n je 1 ali 2 in vsak R3 je neodvisno izbran izmed H, neobvezno substituiranim (Ci~C6)-alkilom, neobvezno substituiranim amino, halo, hidroksi, neobvezno substituirani hidroksi;R4 je azido ali Ru-etinil, kjer je R11 hidrogen, neobvezno substituiran (Ci-Ce)alkil, kjer so substituenti izbrani iz skupine, ki obsega hidrogen, amino, hidroksi, Rs0, R^H in (R5)2N.2. Spojina po zahtevku 1, značilna po tem, da je R2 vodik in R4 je Ru-etinil, kjer je R11 izbran med hidrogen, neobvezno substituiranim (Ci-C4)alkilom in so substituenti izbrani med vodikom, amino, hidroksi, R50, R5NH in (R5)2N.
- 3. Spojina po zahtevku 2, značilna po tem, da je m 1 ali 2, R1 pa je neodvisno izbran med hidrogen, hidroksi, amino, hidroksiamino, karboksi, nitro, karbamoil, ureido,R5 pa lahko substituiramo z halo, R60, HOC(=O), (R6)2NC(=O), A in (R6)2N;R50 je lahko substituiran z halo, R60, (C2-C4)alkanoiloksi, HOC(=O), (R6) 2N, A, fenil;R*NH, (R5)2N, R5NH2, (R5)2NH, R^HCt-O), (R5)2NC(=O), R5S, fenil-(C2-C4)-alkoksi, R120, kjer je R12 HK, K pa je (C2-C4) alkil, lahko substituiran z halo, R60, (C2-C4)- alkanoiloksi, HOC(=O), A in (R6)2N, R6OKO, R6OKNH, CN in fenil; R5NH je lahko substituiran halo, (C2-C4) -alkanoiloksi, R60, R7C(=O), (R6)2N, A, R6OKO, R6OKNH, C6H5Y, CN;(R6)2N(C=O), R5ONH, R5S, (Ci-C4) -alkilsulfonilamino, ftalimido-(Ci~C4)-alkilsulfonilamino, 3-fenilureido, 2oksopirolidin-l-il, 2,5-dioksopirolidin-l-il, halo-(C2-C4)alkanoilamino, hidroksi-(C2-C4)-alkanoilamino, (C2-C4)alkanoiloksi- (C2-C4) -alkanoilamino, (Ci-C4) -alkoksi- (C2_C4) alkanoilamino, karboksi-(C2-C4)-alkanoilamino, (Ci-C4)alkoksikarbonil- (C2-C4) -alkanoilamino, karbamoil- (C2-C4) alkanoilamino, N- (Ci~C4) -alkilkarbamoil- (C2-C4) alkanoilamino, N,N-di-[ (Ci~C4) -alkil] karbamoil- (C2_C4) alkanoilamino, amino-(C2-C4)-alkanoilamino, (Ci~C4)-alkilamino- (C2-C4) -alkanoilamino, di- (Ci~C4) -alkil-amino- (C2-C4) alkanoilamino, kjer imajo fenilni, fenoksi ali anilino substituenti v R1 lahko enega ali dva halogena, (Ci-C4)-alkil ali (Ci~C4)-alkoksi substituente, katerakoli dva R1 povezana preko ogljika tvorita 5-8 členi obroč, z vsaj enim ali dvema heteroatomoma kisika, žvepla ali dušika in kjer so alkilne skupine ali alkilni del alkoksi ali alkilamino skupine v obliki ravne verige ali, če vsebuje vsaj tri ogljikove atome ciklične ali razvejane;vsak R3 je neodvisno izbran med hidrogen, metil, etil, amino, halo in hidroksi;R4 je Ru-etinil, pri čemer je R11 vodik.
- 4. Spojina po zahtevku 3, značilna po tem, da je R1 neodvisno izbran med hidrogen, hidroksi, amino, hidroksiamino, nitro, karbamoil, ureido; R5 je lahko substituiran s halo, R60,HOC(=O), H2NC (=0) ;R50 je lahko substituiran s halo, R60, (C2-C4) -alkanoiloksi, HOC(=0), (R6)2N, A, fenil;R5NH, (R5)2N, RsNH2, (R5)2NH, R5NHC(=O), (R5)2NC(=O), R5S, fenil(C2-C4)-alkoksi in kjer lahko omenjeni fenilni substituent v R1 nosi enega ali dva halogena, R5 ali R50 substituenta; ali katerakoli dva R1 vzeta skupaj z ogljiki na katere sta vezana obsegata 5-8 členi obroč, z vsaj enim ali dvema heteroatomoma kisika, žvepla ali dušika; in kjer so lahko alkilne skupine in alkilni del alkoksi ali alkilamino skupin, v obliki ravne verige ali pa so lahko, če vsebujejo vsaj tri ogljikove atome ciklične ali razvejane.
- 5. Spojina po zahtevku 1, značilna po tem, da je R2 vodik in da je R4 azido.
- 6. Spojina po zahtevku 5, značilna po tem, da je m 1 ali 2, R1 pa je neodvisno izbran med H, hidroksi, amino, hidroksiamino karboksi, nitro, karbamoil, ureido, R5 lahko substituiran s halo, R60, HOC(=O), (R6)2NC(=O), A in (R6)2N;R120, kjer je R12 HK, K pa je (C2-C4) alkil, lahko substituiran s halo, R60, (C2-C4)-alkanoiloksi, HOC(=O), A in (R6)2N, R6OKO,R6OKNH, CN in fenil; R5NH je lahko substituiran halo, (C2—C4)— alkanoiloksi, R60, R7C(=O), (R6)2N, A, R6OKO, R6OKNH, C6H5Y, CN;(R6)2NC=O), R5ONH, RsS, (C1-C4)-alkilsulfonilamino, ftalimido(C1-C4)-alkilsulfonilamino, 3-fenilureido, 2-oksopirolidin-l-il, 2,5-dioksopirolidin-l-il, halo-(C2-C4)-alkanoilamino, hidroksi(C2-C4) -alkanoilamino, (C2-C4) -alkanoiloksi- (C2-C4) -alkanoilamino (C1-C4) -alkoksi- (C2_C4) -alkanoilamino, karboksi- (C2-C4) alkanoilamino, (C1-C4) -alkoksikarbonil- (C2-C4) -alkanoilamino, karbamoil- (C2-C4) -alkanoilamino, N- (C1-C4) -alkilkarbamoil- (C2-C4) alkanoilamino, N, N-di- [ (C1-C4) -alkil] karbamoil- (C2-C4) alkanoilamino, amino-(C2-C4)-alkanoilamino, (C1-C4)-alkilamino- (C2-C4) -alkanoilamino, di- (C1-C4) -alkil-amino- (C2-C4) alkanoilamino, ki imajo fenil, fenoksi ali anilino substituenti v R1 lahko enega ali dva halogena, (C4-C4) -alkil ali (Ci-C4)-alkoksi substituente, katerakoli dva R1 vzeta skupaj z ogljikoma na katera sta vezana obsegata 5-8 členi obroč, z vsaj enim ali dvema heteroatomoma kisika, žvepla ali dušika; kjer so alkilne skupine ali alkilni del alkoksi ali alkilamino skupine v obliki ravne verige ali če vsebuje vsaj tri ogljikove atome v ciklični obliki ali razvejana;vsak R3 je neodvisno izbran med H, metil, etil, amino, halo in hidroksi.
- 7. Spojina po zahtevku 6, značilna po tem, da je vsak R1 neodvisno izbran med H, hidroksi, amino, hidroksiamino, nitro, karbamoil, ureido, R5 lahko substituirane s halo,R60, HOC(=O), H2NC(=O);R50 je lahko substituiran z halo, R60, (C2-C4)alkanoiloksi, HOC(=0), (R6)2N, A, fenil;R®NH, (R5)2N, R^Hz, (R5)2NH, R^HCf^O), (R5)2NC(=O), R5S, fenil-(C2-C4)-alkoksi in kjer lahko omenjeni fenilni substituent v R1 nosi enega ali dva halo, R5 ali R50 ali katerakoli dva R1 vzeta skupaj z ogljikovima atomoma na katera sta vezana obsegata 5-8 členi obroč, z vsaj enim ali dvema heteroatomoma kisika, žvepla ali dušika, alkilne skupine ali alkilni del pa je alkoksi ali alkilamino skupina v obliki ravne verige ali če vsebuje vsaj tri ogljikove atome ciklična ali razvejana.
- 8. Spojina po zahtevku 7 značilna po tem, da je R3halo in R1 hidrogen ali R50.
- 9. Spojina po zahtevku 8 značilna po tem, da je R5 metil.
- 10. Spojina po zahtevku 1, značilna po tem, da je izbrana iz skupine, ki obsega:(6,7-dimetoksikinazolin-4-il)-(3-etinilfenil)-amin);(6,7-dimetoksikinazolin-4-il)-[3-(3'-hidroksipropin-1il)fenil]-amin;(6,7-dimetoksikinazolin-4-il)-[(3-(2'-(aminometil)etinil)fenil]-amin;[(3-etinilfenil)-(6-nitrokinazolin-4-il)-amin;(6,7-dimetoksikinazolin-4-il)-(4-etinilfenil)-amin;(6,7-dimetoksikinazolin-4-il)-(3-etinil-2-metilfenil)amin;(6-aminokinazolin-4-il)-(3-etinilfenil)-amin; (3-etinilfenil)-(6-metansulfonilaminokinazolin-4-il)amin;(3-etinilfenil)-(6,7-metilendioksikinazolin-4-il)-amin; (6,7-dimetoksikinazolin-4-il)-(3-etinil-6-metilfenil)amin;(3-etinilfenil)-(7-nitrokinazolin-4-il)-amin; (3-etinilfenil)-[6-(4'-toluensulfonilamino)-kinazolin-4il]-amin;(3-etinilfenil)-{6-[2'-ftalimido-etan-1'-ilsulfonilamino]kinazolin-4-il}-amin;(3-etinilfenil)-(6-gvanidinokinazolin-4-il)-amin; (7-aminokinazolin-4-il)-(3-etinilfenil)-amin; (3-etinilfenil)-(7-metoksikinazolin-4-il)-amin;(6-karbometoksikinazolin-4-il)-(3-etinilfenil)-amin; (7-karbometoksikinazolin-4-il)-(3-etinilfenil)-amin;[ 6,7-bis(2-metoksi-etoksi)kinazolin-4-il]-(3-etinilfenil )amin;(3-azidofenil)-(6,7-dimetoksikinazolin-4-il)amin; (4-azidofenil)-(6,7-dimetoksikinazolin-4-il)amin; (3-azido-5-klorofenil)- (6,7-dimetoksikinazolin-4il)amin;(3-etinilfenil)-(6-metansulfonil-kinazolin-4-il)-amin;(6-etansulfanil-kinazolin-4-il)-(3-etinilfenil)-amin;(6,7-dimetoksi-kinazolin-4-il)-(3-etinil-4-fluoro-fenil) amin;(6,7-dimetoksi-kinazolin-4-il)-[3-propin-l-il-fenil]amin;[6,7-bis(2-metoksi-etoksi)-kinazolin-4-il]-(5-etinil-2metil-fenil)-amin;[6,7-bis(2-metoksi-etoksi)-kinazolin-4-il]-(3-etinil-4fluoro-fenil)-amin;[6,7-bis(2-kloro-etoksi)-kinazolin-4-il]-(3-etinilfenil) -amin;[6,7-bis-(2-acetoksi-etoksi)kinazolin-4-il]-(3-etinilfenil )amin;[6-(2-kloro-etoksi)-7-(2-metoksi-etoksi)-kinazolin-4-il] (3-etinil-fenil)-amin;2-[4-(3-etinil-fenilamino)-7-(2-hidroksi-etoksi)kinazolin-6-iloksi]-etanol;[6-(2-acetoksi-etoksi)-7-(2-metoksi-etoksi)-kinazolin-4il]- (3-etinil-fenil)-amin;[7-(2-kloro-etoksi)-6-(2-metoksi-etoksi)kinazolin-4-il](3-etinil-fenil)-amin;[7- (2-acetoksi-etoksi)-6-(2-metoksi-etoksi)kinazolin-4il]- (3-etinil-fenil)-amin;2-[4-(3-etinil-fenilamino)-6-(2-hidroksi-etoksi)kinazolin-7-iloksi]-etanol;2-[4-(3-etinil-fenilamino)-7-(2-metoksi-etoksi)kinazolin-6-iloksi]-etanol ;2-[4-(3-etinil-fenilamino)-6-(2-metoksi-etoksi)kinazolin-7-iloksi]-etanol;[6-(2-acetoksi-etoksi)-7-(2-metoksi-etoksi)-kinazolin-4il]- (3-etinil-fenil)-amin;(3-etinil-fenil)-{6-(2-metoksi-etoksi)-7-(2-(4-metilpiperazin-l-il)-etoksi]-kinazolin-4-il}-amin;(3-etinil-fenil)-[7-(2-metoksi-etoksi)-6-(2-morfolin-4il) -etoksi) -kinazolin-4-il] -arnin;(6,7-dietoksikinazolin-l-il)-(3-etinilfenil)-amin;(6,7-dibutoksikinazolin-l-il)- (3-etinilfenil)-amin;(6, 7-diisopropoksikinazolin-l-il)-(3-etinilfenil)-amin;(6,7-dietoksikinazolin-l-il)-(3-etinil-2-metil-fenil)amin;[6, 7-bis (2-metoksi-etoksi) -kinazolin-1-ϋ] - (3-etinil-2metil-fenil)-amin;(3-etinil-fenil)-[6-(2-hidroksi-etoksi)-7-[2-metoksietoksi) kinazolin-l-il]-amin;[6, 7-bis(2-hidroksi-etoksi)-kinazolin-l-il]- (3-etini1-2metil-fenil)-amin; in2-[4-(3-etinil-fenilamino)-6-(2-metoksi-etoksi)kinazolin-7-iloksi]-etanol.
- 11. Spojina po zahtevku 1, značilna po tem, da je izbrana iz skupine, ki obsega (6,7-(dipropoksi-kinazolin-4-il)-(3-etinil-fenil)-amin; (6,7-(dietoksi-kinazolin-4-il)-(3-etinil-5-fluoro-fenil) amin;(6,7-(dietoksi-kinazolin-4-il)-(3-etinil-4-fluoro-fenil) amin;(6,7-(dietoksi-kinazolin-4-il)-(5-etinil-2-metil-fenil)amin;(6,7-(dietoksi-kinazolin-4-il)-(3-etinil-4-metil-fenil)amin;(6-aminometil-7-metoksi-kinazolin-4-il)-(3-etinil-fenil)amin;(6-aminometil-7-metoksi-kinazolin-4-il)-(3-etinilfenil)amin;(6-aminokarbonilmetil-7-metoksi-kinazolin-4-il)- (3etinilfenil)-amin;(6-aminokarboniletil-7-metoksi-kinazolin-4-il)-(3etinilfenil)-amin;(6-aminokarbonilmetil-7-etoksi-kinazolin-4-il)-(3etinilfenil)-amin;(6-aminokarboniletil-7-etoksi-kinazolin-4-il)-(3etinilfenil)-amin;(6-aminokarbonilmetil-7-izopropoksi-kinazolin-4-il)-(3etinilfenil)-amin;(6-aminokarbonilmetil-7-propoksi-kinazolin-4-il)-(3etinilfenil)-amin;(6-aminokarbonilmetil-7-metoksi-kinazolin-4-il)-(3etinilfenil)-amin;(6-aminokarboniletil-7-izopropoksi-kinazolin-4-il)-(3etinilfenil)-amin; in (6-aminokarboniletil-7-propoksi-kinazolin-4-il)-(3etinilfenil)-amin;
- 12. Spojina po zahtevku 1, značilna po tem, da je izbrana iz skupine, ki obsega:(6,7-dietoksikinazolin-l-il)-(3-etinilfenil)-amin;(3-etinilfenil)-[6-[2-hidroksi-etoksi)-7-(2-metoksietoksi )-kinazolin-l-il]-amin;[6,7-bis-(2-hidroksi-etoksi)-kinazolin-l-il]-(3etinilfenil)-amin;[6,7-bis-(2-metoksi-etoksi)-kinazolin-l-il]-(3etinilfenil)-amin;(6,7-dimetoksikinazolin-l-il)-(3-etinilfenil)-amin; (3-etinilfenil)-(β-metansulfonamino-kinazolin-l-il)-amin;
- 13. Postopek priprave spojine s formulo II kjer je: m 1, 2 ali 3;vsak R1 je neodvisno hidrogen, halo, hidroksi, amino, hidroksiamino, karboksi, (C1-C4) alkoksikarbonil, nitro, gvanidino, ureido, karbamoil, ciano, trifluorometil, (R6)2Nkarbonil in fenil-W-alkil, kjer je W izbran med enojno vezjo, 0, S in NH ali, pa je vsak R1 neodvisno ciano-(C1-C4) alkil in R9, kjer je R9 enak R5, R50, (R6)2N, R7C(=O), R50NH,A in R^; R5 je (C1-C4) alkil; R6 je hidrogen ali R5, kjer so vsi R5 enaki ali pa različni; R7 je R5, R50 ali (R6)2N; A izberemo med piperidino-, morfolino, pirolidino in 4-R6 piperazin-l-il, imidazol-l-il, 4-piridon-l-il, karboksi-(CiC4)-alkil, fenoksi, fenil, fenilsulfanil, (C2-C4)-alkenil, (R6) 2-N-karbonil-(C1-C4)-alkil; in Y izberemo med S, SO, S02; alkilni deleži v (R6)2N je lahko tudi substituiran s halo ali R9, pri čemer je R9 definiran zgoraj in alkilni deleži v R5 in R50 so lahko substituirajni s halo, R60 ali R9, pod pogojem, da se dušik, kisik, žveplo ali kateri drug heteroatom ne morejo vezati na isti ogljikov atom ter, da lahko R2 vsebuje največ tri R9 enote;vsak R1 je neodvisno izbran med R5-sulfonamino, ftalimido(C1-C4)-alkilsulfonamino, benzamido, benzensulfonamino, 3fenilureido, 2-oksopirolidin-l-il, 2,5-dioksopirolidin-l-il in R10- (C2--C4) -alkilamino, kjer je R10 izbran med halo,R60, (C2-C4)-alkanoiloksi, R7C(=O) in (R6)2N; in kjer lahko benzamido, benzensulfonamino, fenil, fenoksi, anilino ali fenilsulfanil substituent v R1 nosi še enega ali dva halogena, (Ci-C4) alkil, ciano, metansulfonil ali (C1-C4)alkoksi substituente;katerakoli dva R1 vzeta skupaj z ogljikoma na katera sta vezana obsegata 5-8 členi obroč z vsaj enim ali dvema heteroatomoma, ki so lahko kisik, žveplo ali dušik; in kjer so alkilne skupine ali alkilni del v alkoksi ali alkilamino skupini v ravni verigi ali, če vsebujejo vsaj 3 ogljikove atome, razvejane ali v ciklični obliki;R2 je hidrogen ali neobvezno substituiran (Ci~C6) alkil; n je 1 ali 2 in vsak R3 je neodvisno izbran med H, neobvezno substituiranim (Ci-C6) alkilom, neobvezno substituiranim amino, halo, hidroksi neobvezno substituiran hidroksi;R4 je azido ali Ru-etinil, kjer je R11 izbran med H, neobvezno substituiranim (Ci~C6)alkilom in so substituenti izbrani med H, amino, hidroksi, R50, R5NH in (R5)2N, značilen po tem, da obsega:a) obdelavo spojine s formulo kjer sta R1 in m definirana kot zgoraj, s CC14 in neobvezno substituiranim triarilfosfinom, lahko nanesenim na inertni polimer, s formulo Ar3P, kjer je vsak Ar lahko substituiran z (C6~Cio) arilno skupino in vsak izmed substituentov pa je neodvisno (Ci-C6) alkil inb) obdelavo produkta, iz koraka a) s spojino s formulo kjer so Rz, R3 in n definirani kot zgoraj in J je Y ali R4, kjer je R4 definiran zgoraj, pod pogojem, da moramo produkt b), kadar je J = Y še nadalje obdelati z alkini.
- 14. Postopek po zahtevku 13, značilen po tem, da je vsaka arilna skupina izbrana med fenil, naft-l-il in naft-2-il.
- 15. Postopek po zahtevku 14, značilen po tem, da je vsaka arilna skupina neodvisno substituirana z od 0 do maksimalnega števila (Ci-C6) alkilnih skupin.
- 16. Postopek po zahtevku 14, značilen po tem, da je vsak Ar fenil.
- 17. Postopek po zahtevku 13, značilen po tem, da je triarilfosfin nanesen na inerten polimer.
- 18. Postopek po zahtevku 17, značilen po tem, da je omenjeni polimer divinilbenzen križno povezan polimer stirena.
- 19. Farmacevtski sestavek za zdravljenje hiperproliferativnih bolezni pri sesalcih, značilen po tem, da vsebuje terapevtsko učinkovito količino spojine po zahtevku I in farmacevtsko sprejemljiv nosilec.
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