RU2333210C2 - Соединения пиперидинила, селективно связывающие интегрины - Google Patents

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Publication number

RU2333210C2

RU2333210C2 RU2005104115/04A RU2005104115A RU2333210C2 RU 2333210 C2 RU2333210 C2 RU 2333210C2 RU 2005104115/04 A RU2005104115/04 A RU 2005104115/04A RU 2005104115 A RU2005104115 A RU 2005104115A RU 2333210 C2 RU2333210 C2 RU 2333210C2

Authority

RU

Russia

Prior art keywords

tetrahydro

naphthyridin

formula

compounds

alkyl

Prior art date

2002-08-16

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• 125000003386 piperidinyl group Chemical group 0.000 title abstract description 6
• 239000003814 drug Substances 0.000 claims abstract description 44
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
• 230000003042 antagnostic effect Effects 0.000 claims abstract 4
• 150000001875 compounds Chemical class 0.000 claims description 662
• 125000000217 alkyl group Chemical group 0.000 claims description 299
• -1 hydroxy halogen Chemical class 0.000 claims description 273
• 108010044426 integrins Proteins 0.000 claims description 93
• 102000006495 integrins Human genes 0.000 claims description 93
• 229910052739 hydrogen Inorganic materials 0.000 claims description 86
• 239000001257 hydrogen Substances 0.000 claims description 83
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 67
• 125000001424 substituent group Chemical group 0.000 claims description 49
• 229960005222 phenazone Drugs 0.000 claims description 46
• 125000003545 alkoxy group Chemical group 0.000 claims description 41
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 37
• 229920006395 saturated elastomer Polymers 0.000 claims description 36
• 125000003118 aryl group Chemical group 0.000 claims description 34
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 31
• VEQOALNAAJBPNY-UHFFFAOYSA-N antipyrine Chemical compound CN1C(C)=CC(=O)N1C1=CC=CC=C1 VEQOALNAAJBPNY-UHFFFAOYSA-N 0.000 claims description 27
• 229910052799 carbon Inorganic materials 0.000 claims description 26
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 25
• 150000003839 salts Chemical class 0.000 claims description 25
• 125000004432 carbon atom Chemical group C* 0.000 claims description 21
• 229910052736 halogen Inorganic materials 0.000 claims description 21
• 150000002367 halogens Chemical class 0.000 claims description 20
• 125000001072 heteroaryl group Chemical group 0.000 claims description 19
• 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 claims description 18
• 125000000623 heterocyclic group Chemical group 0.000 claims description 17
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 17
• 229910052757 nitrogen Inorganic materials 0.000 claims description 17
• 229910052760 oxygen Inorganic materials 0.000 claims description 17
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 16
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
• 125000004076 pyridyl group Chemical group 0.000 claims description 15
• 239000003937 drug carrier Substances 0.000 claims description 13
• 238000002360 preparation method Methods 0.000 claims description 12
• 102000005962 receptors Human genes 0.000 claims description 12
• 108020003175 receptors Proteins 0.000 claims description 12
• 125000004548 quinolin-3-yl group Chemical group N1=CC(=CC2=CC=CC=C12)* 0.000 claims description 11
• 125000004434 sulfur atom Chemical group 0.000 claims description 10
• 125000005037 alkyl phenyl group Chemical group 0.000 claims description 9
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
• 125000005842 heteroatom Chemical group 0.000 claims description 8
• 150000002431 hydrogen Chemical class 0.000 claims description 7
• 125000001624 naphthyl group Chemical group 0.000 claims description 6
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 6
• 229910052717 sulfur Inorganic materials 0.000 claims description 6
• 125000002877 alkyl aryl group Chemical group 0.000 claims description 5
• 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 4
• 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
• 229910052731 fluorine Inorganic materials 0.000 claims description 2
• 239000011737 fluorine Substances 0.000 claims description 2
• 125000004552 isoquinolin-4-yl group Chemical group C1=NC=C(C2=CC=CC=C12)* 0.000 claims description 2
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
• 125000002619 bicyclic group Chemical group 0.000 claims 3
• 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
• 239000000203 mixture Substances 0.000 abstract description 221
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• 230000000694 effects Effects 0.000 abstract description 6
• 238000000034 method Methods 0.000 description 164
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• IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 99
• 238000006243 chemical reaction Methods 0.000 description 97
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• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 87
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 84
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• 239000011734 sodium Substances 0.000 description 42
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 41
• YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 40
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 39
• 201000010099 disease Diseases 0.000 description 39
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 36
• 235000019439 ethyl acetate Nutrition 0.000 description 32
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• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 25
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• 238000003818 flash chromatography Methods 0.000 description 25
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 24
• 238000004007 reversed phase HPLC Methods 0.000 description 24
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 23
• 235000002639 sodium chloride Nutrition 0.000 description 23
• HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 23
• WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 23
• 239000002246 antineoplastic agent Substances 0.000 description 22
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• 230000002829 reductive effect Effects 0.000 description 22
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• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 19
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• 229940127089 cytotoxic agent Drugs 0.000 description 19
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• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 19
• 239000002904 solvent Substances 0.000 description 19
• NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 18
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• 210000004027 cell Anatomy 0.000 description 16
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• HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 15
• 150000002148 esters Chemical class 0.000 description 15
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• 239000007858 starting material Substances 0.000 description 15
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 14
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• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 12
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