TWI585089B - Novel condensed pyrimidine compounds or salts thereof - Google Patents

Info

Publication number

TWI585089B

TWI585089B TW103127536A TW103127536A TWI585089B TW I585089 B TWI585089 B TW I585089B TW 103127536 A TW103127536 A TW 103127536A TW 103127536 A TW103127536 A TW 103127536A TW I585089 B TWI585089 B TW I585089B

Authority

TW

Taiwan

Prior art keywords

group

amino

pyrimidine

pyrazolo

zin

Prior art date

2013-08-12

Links

• Espacenet
• Global Dossier
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• 150000003839 salts Chemical class 0.000 title claims description 76
• 150000003230 pyrimidines Chemical class 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims description 399
• -1 C1 -C6 alkyl Chemical group 0.000 claims description 214
• 125000001424 substituent group Chemical group 0.000 claims description 96
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 70
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 65
• 125000005605 benzo group Chemical group 0.000 claims description 50
• 229910052757 nitrogen Inorganic materials 0.000 claims description 45
• 125000003277 amino group Chemical group 0.000 claims description 43
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 43
• 125000005843 halogen group Chemical group 0.000 claims description 38
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 34
• 125000000623 heterocyclic group Chemical group 0.000 claims description 32
• UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 31
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 29
• 150000001412 amines Chemical class 0.000 claims description 29
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 22
• 229910052717 sulfur Inorganic materials 0.000 claims description 22
• 125000004434 sulfur atom Chemical group 0.000 claims description 22
• 125000002950 monocyclic group Chemical group 0.000 claims description 21
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 19
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 18
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 18
• 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 claims description 18
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 16
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 15
• 238000004519 manufacturing process Methods 0.000 claims description 15
• 125000005842 heteroatom Chemical group 0.000 claims description 14
• QDXGKRWDQCEABB-UHFFFAOYSA-N pyrimidine-5-carboxamide Chemical compound NC(=O)C1=CN=CN=C1 QDXGKRWDQCEABB-UHFFFAOYSA-N 0.000 claims description 14
• 125000002029 aromatic hydrocarbon group Chemical group 0.000 claims description 13
• 125000005647 linker group Chemical group 0.000 claims description 13
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 13
• 125000000217 alkyl group Chemical group 0.000 claims description 12
• 239000000523 sample Substances 0.000 claims description 12
• 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 11
• 125000003367 polycyclic group Chemical group 0.000 claims description 11
• LPCQBTAOTIZGAE-UHFFFAOYSA-N 2h-pyrimidine-1-carboxamide Chemical compound NC(=O)N1CN=CC=C1 LPCQBTAOTIZGAE-UHFFFAOYSA-N 0.000 claims description 10
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 10
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 10
• 229910052721 tungsten Inorganic materials 0.000 claims description 10
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
• 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 8
• 229940124291 BTK inhibitor Drugs 0.000 claims description 8
• 125000004429 atom Chemical group 0.000 claims description 8
• 125000006264 diethylaminomethyl group Chemical group [H]C([H])([H])C([H])([H])N(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 claims description 8
• 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 claims description 8
• 125000003386 piperidinyl group Chemical group 0.000 claims description 7
• 125000002393 azetidinyl group Chemical group 0.000 claims description 6
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 6
• 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 6
• 239000002246 antineoplastic agent Substances 0.000 claims description 5
• ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 5
• 239000004480 active ingredient Substances 0.000 claims description 4
• 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 4
• 239000008194 pharmaceutical composition Substances 0.000 claims description 4
• IHWDSEPNZDYMNF-UHFFFAOYSA-N 1H-indol-2-amine Chemical compound C1=CC=C2NC(N)=CC2=C1 IHWDSEPNZDYMNF-UHFFFAOYSA-N 0.000 claims description 3
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
• 239000001257 hydrogen Substances 0.000 claims description 2
• 229910052739 hydrogen Inorganic materials 0.000 claims description 2
• 239000011593 sulfur Substances 0.000 claims description 2
• VVJKKWFAADXIJK-UHFFFAOYSA-N allylamine Natural products NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 claims 1
• 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims 1
• 239000003550 marker Substances 0.000 claims 1
• QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 claims 1
• USRYWZFLGFQQEB-UHFFFAOYSA-N pyrimidin-5-ylmethanamine Chemical compound NCC1=CN=CN=C1 USRYWZFLGFQQEB-UHFFFAOYSA-N 0.000 claims 1
• 238000003786 synthesis reaction Methods 0.000 description 208
• 230000015572 biosynthetic process Effects 0.000 description 206
• 239000007787 solid Substances 0.000 description 144
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 93
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 86
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 80
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 76
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 72
• 238000006243 chemical reaction Methods 0.000 description 71
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 70
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 69
• 239000002904 solvent Substances 0.000 description 68
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 67
• 235000002639 sodium chloride Nutrition 0.000 description 67
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 63
• 108010029445 Agammaglobulinaemia Tyrosine Kinase Proteins 0.000 description 56
• 102000001714 Agammaglobulinaemia Tyrosine Kinase Human genes 0.000 description 56
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 51
• 239000000243 solution Substances 0.000 description 51
• 238000003756 stirring Methods 0.000 description 46
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 45
• 238000000034 method Methods 0.000 description 39
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 36
• 239000002585 base Substances 0.000 description 35
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 34
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 32
• 235000019439 ethyl acetate Nutrition 0.000 description 32
• 239000000203 mixture Substances 0.000 description 32
• 206010028980 Neoplasm Diseases 0.000 description 29
• 238000001816 cooling Methods 0.000 description 29
• 230000002401 inhibitory effect Effects 0.000 description 29
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 28
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
• 210000004027 cell Anatomy 0.000 description 27
• 230000000704 physical effect Effects 0.000 description 27
• 238000000746 purification Methods 0.000 description 27
• 229940125904 compound 1 Drugs 0.000 description 26
• 150000001335 aliphatic alkanes Chemical class 0.000 description 25
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 24
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 24
• 239000012044 organic layer Substances 0.000 description 23
• SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 22
• 238000000926 separation method Methods 0.000 description 21
• UUHNQHFOIVLAQX-BJILWQEISA-N (e)-4-(dimethylamino)but-2-enoic acid;hydrochloride Chemical compound Cl.CN(C)C\C=C\C(O)=O UUHNQHFOIVLAQX-BJILWQEISA-N 0.000 description 20
• 125000004287 oxazol-2-yl group Chemical group [H]C1=C([H])N=C(*)O1 0.000 description 20
• 238000012360 testing method Methods 0.000 description 20
• ACTKAGSPIFDCMF-UHFFFAOYSA-N 1,3-oxazol-2-amine Chemical compound NC1=NC=CO1 ACTKAGSPIFDCMF-UHFFFAOYSA-N 0.000 description 19
• 102000001301 EGF receptor Human genes 0.000 description 19
• 108060006698 EGF receptor Proteins 0.000 description 19
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 19
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 19
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 18
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 17
• 230000000052 comparative effect Effects 0.000 description 17
• 230000000694 effects Effects 0.000 description 17
• 238000004128 high performance liquid chromatography Methods 0.000 description 17
• 230000005764 inhibitory process Effects 0.000 description 17
• 230000002829 reductive effect Effects 0.000 description 17
• 230000002441 reversible effect Effects 0.000 description 17
• HGINCPLSRVDWNT-UHFFFAOYSA-N Acrolein Chemical compound C=CC=O HGINCPLSRVDWNT-UHFFFAOYSA-N 0.000 description 16
• QSAMQSXFHVHODR-UHFFFAOYSA-N Cl.C=CC#N Chemical compound Cl.C=CC#N QSAMQSXFHVHODR-UHFFFAOYSA-N 0.000 description 16
• 239000002253 acid Substances 0.000 description 16
• LPQZERIRKRYGGM-UHFFFAOYSA-N tert-butyl pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC1 LPQZERIRKRYGGM-UHFFFAOYSA-N 0.000 description 16
• 208000031648 Body Weight Changes Diseases 0.000 description 15
• FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 15
• 230000004579 body weight change Effects 0.000 description 15
• DNUTZBZXLPWRJG-UHFFFAOYSA-N 1-Piperidine carboxylic acid Chemical compound OC(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-N 0.000 description 14
• QDKSGHXRHXVMPF-UHFFFAOYSA-N 2,2-dimethylundecane Chemical compound CCCCCCCCCC(C)(C)C QDKSGHXRHXVMPF-UHFFFAOYSA-N 0.000 description 14
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 14
• 235000017557 sodium bicarbonate Nutrition 0.000 description 14
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 14
• 229910052938 sodium sulfate Inorganic materials 0.000 description 14
• 235000011152 sodium sulphate Nutrition 0.000 description 14
• CSOYDALHEQEMAK-UHFFFAOYSA-N 2h-pyrimidine-1-carboxylic acid Chemical compound OC(=O)N1CN=CC=C1 CSOYDALHEQEMAK-UHFFFAOYSA-N 0.000 description 13
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 13
• ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 13
• 150000001732 carboxylic acid derivatives Chemical class 0.000 description 13
• 239000003153 chemical reaction reagent Substances 0.000 description 13
• 238000002425 crystallisation Methods 0.000 description 13
• 239000011591 potassium Substances 0.000 description 13
• 229910052700 potassium Inorganic materials 0.000 description 13
• 125000006239 protecting group Chemical group 0.000 description 13
• 230000006824 pyrimidine synthesis Effects 0.000 description 13
• OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 12
• HQAIUXZORKJOJY-UHFFFAOYSA-N 3-iodo-2h-pyrazolo[3,4-d]pyrimidin-4-amine Chemical compound NC1=NC=NC2=NNC(I)=C12 HQAIUXZORKJOJY-UHFFFAOYSA-N 0.000 description 12
• OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 12
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
• WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 12
• HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 12
• 201000011510 cancer Diseases 0.000 description 12
• PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 12
• 230000008025 crystallization Effects 0.000 description 12
• 235000019253 formic acid Nutrition 0.000 description 12
• 229910000027 potassium carbonate Inorganic materials 0.000 description 12
• 229920006395 saturated elastomer Polymers 0.000 description 12
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• UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 11
• 229910002091 carbon monoxide Inorganic materials 0.000 description 11
• 238000004587 chromatography analysis Methods 0.000 description 11
• 238000001914 filtration Methods 0.000 description 11
• 238000000638 solvent extraction Methods 0.000 description 11
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 11
• 239000007821 HATU Substances 0.000 description 10
• MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 10
• 238000000338 in vitro Methods 0.000 description 10
• 230000035484 reaction time Effects 0.000 description 10
• 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 10
• DIIIISSCIXVANO-UHFFFAOYSA-N 1,2-Dimethylhydrazine Chemical compound CNNC DIIIISSCIXVANO-UHFFFAOYSA-N 0.000 description 9
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 9
• DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 9
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• 125000003545 alkoxy group Chemical group 0.000 description 9
• 239000003054 catalyst Substances 0.000 description 9
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 9
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• 239000011734 sodium Substances 0.000 description 9
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• ITGIYLMMAABTHC-ONEGZZNKSA-N (e)-4-(dimethylazaniumyl)but-2-enoate Chemical class CN(C)C\C=C\C(O)=O ITGIYLMMAABTHC-ONEGZZNKSA-N 0.000 description 8
• SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 8
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• 125000003710 aryl alkyl group Chemical group 0.000 description 8
• FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 8
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• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 8
• 230000004663 cell proliferation Effects 0.000 description 8
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• 125000001309 chloro group Chemical group Cl* 0.000 description 7
• 150000002430 hydrocarbons Chemical group 0.000 description 7
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• 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 7
• 238000005191 phase separation Methods 0.000 description 7
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• WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 6
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• XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 6
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 6
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
• 241000700159 Rattus Species 0.000 description 6
• 230000037396 body weight Effects 0.000 description 6
• 229910052801 chlorine Inorganic materials 0.000 description 6
• HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 6
• 201000010099 disease Diseases 0.000 description 6
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
• RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical group C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 description 6
• 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 6
• 125000000524 functional group Chemical group 0.000 description 6
• 229910052744 lithium Inorganic materials 0.000 description 6
• 239000011159 matrix material Substances 0.000 description 6
• 150000007530 organic bases Chemical class 0.000 description 6
• 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 6
• 230000035755 proliferation Effects 0.000 description 6
• AMLFJZRZIOZGPW-UHFFFAOYSA-N prop-1-en-1-amine Chemical compound CC=CN AMLFJZRZIOZGPW-UHFFFAOYSA-N 0.000 description 6
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
• QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 6
• 239000000126 substance Substances 0.000 description 6
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