EA014495B1 - Соединения пиримидина в качестве модуляторов серотониновых рецепторов - Google Patents

Info

Publication number

EA014495B1

EA014495B1 EA200800525A EA200800525A EA014495B1 EA 014495 B1 EA014495 B1 EA 014495B1 EA 200800525 A EA200800525 A EA 200800525A EA 200800525 A EA200800525 A EA 200800525A EA 014495 B1 EA014495 B1 EA 014495B1

Authority

EA

Eurasian Patent Office

Prior art keywords

alkyl

tetrahydropyrido

pyrimidine

group

fluorophenyl

Prior art date

2005-08-04

Links

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• Global Dossier
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• 102000040125 5-hydroxytryptamine receptor family Human genes 0.000 title abstract description 16
• 108091032151 5-hydroxytryptamine receptor family Proteins 0.000 title abstract description 16
• 150000003230 pyrimidines Chemical class 0.000 title description 16
• 229940075993 receptor modulator Drugs 0.000 title 1
• CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims abstract description 305
• 150000001875 compounds Chemical class 0.000 claims abstract description 203
• QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 claims abstract description 72
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 49
• 201000010099 disease Diseases 0.000 claims abstract description 15
• 230000001404 mediated effect Effects 0.000 claims abstract description 14
• 229940076279 serotonin Drugs 0.000 claims abstract description 7
• -1 phenoxy, pyridyl Chemical group 0.000 claims description 349
• 125000000217 alkyl group Chemical group 0.000 claims description 310
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 220
• 229910052799 carbon Inorganic materials 0.000 claims description 92
• 238000000034 method Methods 0.000 claims description 74
• 150000001721 carbon Chemical group 0.000 claims description 70
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 68
• IDXKTTNFXPPXJY-UHFFFAOYSA-N pyrimidin-1-ium;chloride Chemical compound Cl.C1=CN=CN=C1 IDXKTTNFXPPXJY-UHFFFAOYSA-N 0.000 claims description 57
• JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 54
• 125000001424 substituent group Chemical group 0.000 claims description 49
• 229910052736 halogen Inorganic materials 0.000 claims description 48
• 150000002367 halogens Chemical class 0.000 claims description 48
• 125000004432 carbon atom Chemical group C* 0.000 claims description 44
• XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 claims description 43
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 43
• 229910052700 potassium Inorganic materials 0.000 claims description 39
• 125000003386 piperidinyl group Chemical group 0.000 claims description 38
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 36
• 208000035475 disorder Diseases 0.000 claims description 34
• 125000004429 atom Chemical group 0.000 claims description 33
• 229910052757 nitrogen Inorganic materials 0.000 claims description 33
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 33
• 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 32
• 125000002029 aromatic hydrocarbon group Chemical group 0.000 claims description 32
• 125000002950 monocyclic group Chemical group 0.000 claims description 32
• 125000002757 morpholinyl group Chemical group 0.000 claims description 32
• 125000004193 piperazinyl group Chemical group 0.000 claims description 32
• 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 32
• 125000003342 alkenyl group Chemical group 0.000 claims description 31
• 150000003839 salts Chemical class 0.000 claims description 29
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 27
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 26
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 26
• 229910052739 hydrogen Inorganic materials 0.000 claims description 26
• 125000000304 alkynyl group Chemical group 0.000 claims description 23
• 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 claims description 22
• 150000002148 esters Chemical class 0.000 claims description 21
• 150000001408 amides Chemical class 0.000 claims description 20
• 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 18
• 125000004076 pyridyl group Chemical group 0.000 claims description 18
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 17
• 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 17
• 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 16
• 125000002947 alkylene group Chemical group 0.000 claims description 16
• 125000003368 amide group Chemical group 0.000 claims description 16
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 14
• 125000001931 aliphatic group Chemical group 0.000 claims description 14
• 239000001257 hydrogen Substances 0.000 claims description 14
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
• 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 14
• 125000003118 aryl group Chemical group 0.000 claims description 13
• 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 13
• 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 13
• 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 claims description 12
• 125000002971 oxazolyl group Chemical group 0.000 claims description 12
• 125000001544 thienyl group Chemical group 0.000 claims description 12
• 241000124008 Mammalia Species 0.000 claims description 11
• 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 10
• 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 10
• 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 10
• 125000004122 cyclic group Chemical group 0.000 claims description 10
• 150000002431 hydrogen Chemical class 0.000 claims description 10
• AJUMGSLQADLWKL-UHFFFAOYSA-N 1h-azepine;hydrochloride Chemical compound Cl.N1C=CC=CC=C1 AJUMGSLQADLWKL-UHFFFAOYSA-N 0.000 claims description 9
• 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 9
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 9
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
• 125000005842 heteroatom Chemical group 0.000 claims description 9
• 229910052760 oxygen Inorganic materials 0.000 claims description 9
• 239000012453 solvate Substances 0.000 claims description 9
• 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 8
• 208000019901 Anxiety disease Diseases 0.000 claims description 8
• 208000019695 Migraine disease Diseases 0.000 claims description 8
• 125000004450 alkenylene group Chemical group 0.000 claims description 8
• 125000004419 alkynylene group Chemical group 0.000 claims description 8
• 230000036506 anxiety Effects 0.000 claims description 8
• 125000001072 heteroaryl group Chemical group 0.000 claims description 8
• 150000004677 hydrates Chemical class 0.000 claims description 8
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 8
• 125000003831 tetrazolyl group Chemical group 0.000 claims description 8
• 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 claims description 7
• 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 7
• 125000004863 4-trifluoromethoxyphenyl group Chemical group [H]C1=C([H])C(OC(F)(F)F)=C([H])C([H])=C1* 0.000 claims description 7
• 239000008194 pharmaceutical composition Substances 0.000 claims description 7
• 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 7
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 6
• 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims description 6
• XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 6
• 208000002551 irritable bowel syndrome Diseases 0.000 claims description 6
• 201000000980 schizophrenia Diseases 0.000 claims description 6
• JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 6
• ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 5
• 208000021384 Obsessive-Compulsive disease Diseases 0.000 claims description 5
• 206010027599 migraine Diseases 0.000 claims description 5
• 125000004504 1,2,4-oxadiazolyl group Chemical group 0.000 claims description 4
• 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 claims description 4
• 125000004506 1,2,5-oxadiazolyl group Chemical group 0.000 claims description 4
• 125000001781 1,3,4-oxadiazolyl group Chemical group 0.000 claims description 4
• 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 claims description 4
• 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 claims description 4
• 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 4
• 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 4
• 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 claims description 4
• 125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 claims description 4
• 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 4
• UDDNBGLDSGXOCT-UHFFFAOYSA-N 4-(4-fluorophenyl)-2-propan-2-yl-7-pyrrolidin-1-yl-5,6,7,8-tetrahydroquinazoline Chemical compound N=1C(C(C)C)=NC=2CC(N3CCCC3)CCC=2C=1C1=CC=C(F)C=C1 UDDNBGLDSGXOCT-UHFFFAOYSA-N 0.000 claims description 4
• 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 4
• 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 4
• 125000004860 4-ethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])C([H])([H])[H] 0.000 claims description 4
• 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
• 208000020925 Bipolar disease Diseases 0.000 claims description 4
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• 208000011688 Generalised anxiety disease Diseases 0.000 claims description 4
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
• VQTUBCCKSQIDNK-UHFFFAOYSA-N Isobutene Chemical group CC(C)=C VQTUBCCKSQIDNK-UHFFFAOYSA-N 0.000 claims description 4
• 208000019022 Mood disease Diseases 0.000 claims description 4
• GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 4
• 208000028017 Psychotic disease Diseases 0.000 claims description 4
• 201000001880 Sexual dysfunction Diseases 0.000 claims description 4
• 206010046543 Urinary incontinence Diseases 0.000 claims description 4
• 125000005605 benzo group Chemical group 0.000 claims description 4
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
• 125000005724 cycloalkenylene group Chemical group 0.000 claims description 4
• 125000002993 cycloalkylene group Chemical group 0.000 claims description 4
• 125000004976 cyclobutylene group Chemical group 0.000 claims description 4
• 125000004979 cyclopentylene group Chemical group 0.000 claims description 4
• 125000004980 cyclopropylene group Chemical group 0.000 claims description 4
• 238000001514 detection method Methods 0.000 claims description 4
• ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 4
• 235000014632 disordered eating Nutrition 0.000 claims description 4
• 239000003937 drug carrier Substances 0.000 claims description 4
• 125000002541 furyl group Chemical group 0.000 claims description 4
• 208000029364 generalized anxiety disease Diseases 0.000 claims description 4
• 125000002883 imidazolyl group Chemical group 0.000 claims description 4
• 125000001786 isothiazolyl group Chemical group 0.000 claims description 4
• 125000000842 isoxazolyl group Chemical group 0.000 claims description 4
• 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims description 4
• 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 4
• 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 4
• 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 4
• 238000002600 positron emission tomography Methods 0.000 claims description 4
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
• MWWATHDPGQKSAR-UHFFFAOYSA-N propyne Chemical group CC#C MWWATHDPGQKSAR-UHFFFAOYSA-N 0.000 claims description 4
• 125000003373 pyrazinyl group Chemical group 0.000 claims description 4
• 125000002098 pyridazinyl group Chemical group 0.000 claims description 4
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• 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 4
• 125000000335 thiazolyl group Chemical group 0.000 claims description 4
• 125000004502 1,2,3-oxadiazolyl group Chemical group 0.000 claims description 3
• YBTQDQATZUHXFT-UHFFFAOYSA-N 1-[2-benzyl-6-(4-methylphenyl)pyrimidin-4-yl]-n,n-dimethylmethanamine Chemical compound N=1C(CN(C)C)=CC(C=2C=CC(C)=CC=2)=NC=1CC1=CC=CC=C1 YBTQDQATZUHXFT-UHFFFAOYSA-N 0.000 claims description 3
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• 125000004484 1-methylpiperidin-4-yl group Chemical group CN1CCC(CC1)* 0.000 claims description 3
• BOJLLFFKHKHUGQ-UHFFFAOYSA-N 2-[2-benzyl-6-(4-methylphenyl)pyrimidin-4-yl]ethanamine Chemical compound C1=CC(C)=CC=C1C1=CC(CCN)=NC(CC=2C=CC=CC=2)=N1 BOJLLFFKHKHUGQ-UHFFFAOYSA-N 0.000 claims description 3
• KYSIDQYDCRTDJH-UHFFFAOYSA-N 2-benzyl-4-(4-methylphenyl)-6-[(4-methylpiperazin-1-yl)methyl]pyrimidine Chemical compound C1CN(C)CCN1CC1=CC(C=2C=CC(C)=CC=2)=NC(CC=2C=CC=CC=2)=N1 KYSIDQYDCRTDJH-UHFFFAOYSA-N 0.000 claims description 3
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• CZFYSRJTOJIVPQ-UHFFFAOYSA-N 4-(4-fluorophenyl)-2-propan-2-yl-5,6,7,8-tetrahydroquinazoline Chemical compound N=1C(C(C)C)=NC=2CCCCC=2C=1C1=CC=C(F)C=C1 CZFYSRJTOJIVPQ-UHFFFAOYSA-N 0.000 claims description 3
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