AP218A - Benzoquinazole derivatives and pharmaceutical compounds thereof. - Google Patents

Info

Publication number

AP218A

AP218A APAP/P/1991/000283A AP9100283A AP218A AP 218 A AP218 A AP 218A AP 9100283 A AP9100283 A AP 9100283A AP 218 A AP218 A AP 218A

Authority

AP

ARIPO

Prior art keywords

group

amino

methyl

compound

hydrogen

Prior art date

1990-06-19

Links

• Espacenet
• Global Dossier
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• 150000001875 compounds Chemical class 0.000 title claims abstract description 166
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 79
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 77
• 239000001257 hydrogen Substances 0.000 claims abstract description 77
• 125000000217 alkyl group Chemical group 0.000 claims abstract description 65
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 48
• 150000003839 salts Chemical class 0.000 claims abstract description 45
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 21
• 150000002431 hydrogen Chemical class 0.000 claims abstract description 16
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 5
• 125000001589 carboacyl group Chemical group 0.000 claims abstract description 5
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 4
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 216
• 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 69
• 239000002253 acid Substances 0.000 claims description 64
• 150000002148 esters Chemical group 0.000 claims description 55
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 55
• 229910052757 nitrogen Inorganic materials 0.000 claims description 50
• 238000006243 chemical reaction Methods 0.000 claims description 48
• 229960002989 glutamic acid Drugs 0.000 claims description 42
• 125000005843 halogen group Chemical group 0.000 claims description 37
• -1 bromo, hydroxy Chemical group 0.000 claims description 34
• 238000000034 method Methods 0.000 claims description 31
• 125000005605 benzo group Chemical group 0.000 claims description 28
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 24
• 125000003118 aryl group Chemical group 0.000 claims description 22
• 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 claims description 22
• 125000001931 aliphatic group Chemical group 0.000 claims description 21
• 125000001424 substituent group Chemical group 0.000 claims description 19
• 125000003545 alkoxy group Chemical group 0.000 claims description 16
• JFCQEDHGNNZCLN-UHFFFAOYSA-N anhydrous glutaric acid Natural products OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 claims description 16
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 16
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 13
• 125000003277 amino group Chemical group 0.000 claims description 12
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 10
• 230000007062 hydrolysis Effects 0.000 claims description 10
• 238000006460 hydrolysis reaction Methods 0.000 claims description 10
• 241001465754 Metazoa Species 0.000 claims description 8
• 239000003814 drug Substances 0.000 claims description 8
• 238000002360 preparation method Methods 0.000 claims description 8
• 125000000539 amino acid group Chemical group 0.000 claims description 7
• 229910052799 carbon Inorganic materials 0.000 claims description 7
• 150000002825 nitriles Chemical class 0.000 claims description 7
• RTBFRGCFXZNCOE-UHFFFAOYSA-N 1-methylsulfonylpiperidin-4-one Chemical compound CS(=O)(=O)N1CCC(=O)CC1 RTBFRGCFXZNCOE-UHFFFAOYSA-N 0.000 claims description 6
• 108010020346 Polyglutamic Acid Proteins 0.000 claims description 6
• 229920002643 polyglutamic acid Polymers 0.000 claims description 6
• 230000009467 reduction Effects 0.000 claims description 5
• 201000011510 cancer Diseases 0.000 claims description 4
• 238000006356 dehydrogenation reaction Methods 0.000 claims description 4
• 125000000623 heterocyclic group Chemical group 0.000 claims description 4
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
• 239000002243 precursor Substances 0.000 claims description 4
• 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 3
• 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 3
• 125000004432 carbon atom Chemical group C* 0.000 claims description 3
• 238000006073 displacement reaction Methods 0.000 claims description 3
• 239000003937 drug carrier Substances 0.000 claims description 3
• 238000003780 insertion Methods 0.000 claims description 3
• 230000037431 insertion Effects 0.000 claims description 3
• 230000008569 process Effects 0.000 claims description 3
• 125000006239 protecting group Chemical group 0.000 claims description 3
• DHMQDGOQFOQNFH-UHFFFAOYSA-M Aminoacetate Chemical compound NCC([O-])=O DHMQDGOQFOQNFH-UHFFFAOYSA-M 0.000 claims description 2
• 125000002947 alkylene group Chemical group 0.000 claims description 2
• 229910002091 carbon monoxide Inorganic materials 0.000 claims description 2
• 230000026030 halogenation Effects 0.000 claims description 2
• 238000005658 halogenation reaction Methods 0.000 claims description 2
• 208000032839 leukemia Diseases 0.000 claims description 2
• 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 claims description 2
• 125000001302 tertiary amino group Chemical group 0.000 claims description 2
• NTNZTEQNFHNYBC-UHFFFAOYSA-N ethyl 2-aminoacetate Chemical group CCOC(=O)CN NTNZTEQNFHNYBC-UHFFFAOYSA-N 0.000 claims 1
• 125000001475 halogen functional group Chemical group 0.000 abstract 3
• 239000000243 solution Substances 0.000 description 225
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 213
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 193
• 238000005481 NMR spectroscopy Methods 0.000 description 179
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 158
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 142
• 239000007787 solid Substances 0.000 description 141
• WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 136
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 135
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 129
• 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 129
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 128
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 127
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 125
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 92
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 87
• WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 81
• 239000000203 mixture Substances 0.000 description 74
• 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 68
• 239000000741 silica gel Substances 0.000 description 66
• 229910002027 silica gel Inorganic materials 0.000 description 66
• 238000010992 reflux Methods 0.000 description 60
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 57
• 239000011541 reaction mixture Substances 0.000 description 56
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 55
• 239000000725 suspension Substances 0.000 description 54
• 238000001819 mass spectrum Methods 0.000 description 50
• 238000004587 chromatography analysis Methods 0.000 description 45
• 229960000583 acetic acid Drugs 0.000 description 44
• XIPFMBOWZXULIA-UHFFFAOYSA-N pivalamide Chemical compound CC(C)(C)C(N)=O XIPFMBOWZXULIA-UHFFFAOYSA-N 0.000 description 44
• 229940093499 ethyl acetate Drugs 0.000 description 42
• 235000019439 ethyl acetate Nutrition 0.000 description 42
• 239000000047 product Substances 0.000 description 42
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 35
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 32
• WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 27
• 239000002244 precipitate Substances 0.000 description 25
• 238000003756 stirring Methods 0.000 description 25
• PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 23
• 239000012299 nitrogen atmosphere Substances 0.000 description 23
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 22
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 22
• 238000001914 filtration Methods 0.000 description 22
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 21
• 238000001816 cooling Methods 0.000 description 20
• 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 20
• 125000001246 bromo group Chemical group Br* 0.000 description 18
• 239000003921 oil Substances 0.000 description 18
• 235000019198 oils Nutrition 0.000 description 17
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 17
• DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 16
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 16
• PGZVFRAEAAXREB-UHFFFAOYSA-N 2,2-dimethylpropanoyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OC(=O)C(C)(C)C PGZVFRAEAAXREB-UHFFFAOYSA-N 0.000 description 15
• 239000000706 filtrate Substances 0.000 description 15
• 238000000746 purification Methods 0.000 description 15
• 229920002554 vinyl polymer Polymers 0.000 description 15
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
• 229940124530 sulfonamide Drugs 0.000 description 14
• 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 14
• QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical class OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 12
• JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 12
• 238000004113 cell culture Methods 0.000 description 12
• 239000012043 crude product Substances 0.000 description 12
• 238000000921 elemental analysis Methods 0.000 description 12
• 239000008194 pharmaceutical composition Substances 0.000 description 12
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 11
• 238000009472 formulation Methods 0.000 description 11
• 239000000543 intermediate Substances 0.000 description 11
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 11
• 239000002904 solvent Substances 0.000 description 11
• 235000011149 sulphuric acid Nutrition 0.000 description 11
• KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 10
• 239000005711 Benzoic acid Substances 0.000 description 10
• WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 10
• 239000002585 base Substances 0.000 description 10
• 235000010233 benzoic acid Nutrition 0.000 description 10
• 231100000135 cytotoxicity Toxicity 0.000 description 10
• 230000003013 cytotoxicity Effects 0.000 description 10
• 239000001117 sulphuric acid Substances 0.000 description 10
• 206010028980 Neoplasm Diseases 0.000 description 9
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
• 238000009835 boiling Methods 0.000 description 9
• 150000005690 diesters Chemical class 0.000 description 9
• SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 9
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• 238000001556 precipitation Methods 0.000 description 9
• 239000011734 sodium Substances 0.000 description 9
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
• 239000002609 medium Substances 0.000 description 8
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
• 229910000027 potassium carbonate Inorganic materials 0.000 description 8
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• 238000005160 1H NMR spectroscopy Methods 0.000 description 7
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• 241000124008 Mammalia Species 0.000 description 7
• 239000004480 active ingredient Substances 0.000 description 7
• 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 7
• 239000003054 catalyst Substances 0.000 description 7
• 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 7
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• 239000003826 tablet Substances 0.000 description 7
• YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 6
• KCKZIWSINLBROE-UHFFFAOYSA-N 3,4-dihydro-1h-naphthalen-2-one Chemical class C1=CC=C2CC(=O)CCC2=C1 KCKZIWSINLBROE-UHFFFAOYSA-N 0.000 description 6
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• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
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• 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 6
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
• SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
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• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 5
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• VGUWZCUCNQXGBU-UHFFFAOYSA-N 3-[(4-methylpiperazin-1-yl)methyl]-5-nitro-1h-indole Chemical compound C1CN(C)CCN1CC1=CNC2=CC=C([N+]([O-])=O)C=C12 VGUWZCUCNQXGBU-UHFFFAOYSA-N 0.000 description 4
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• VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
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• DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
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• CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 4
• UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 4
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• 230000000259 anti-tumor effect Effects 0.000 description 4
• 239000012298 atmosphere Substances 0.000 description 4
• PQIUGRLKNKSKTC-UHFFFAOYSA-N benzo[h]quinazoline Chemical compound N1=CN=C2C3=CC=CC=C3C=CC2=C1 PQIUGRLKNKSKTC-UHFFFAOYSA-N 0.000 description 4
• 210000002798 bone marrow cell Anatomy 0.000 description 4
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• 201000010897 colon adenocarcinoma Diseases 0.000 description 4
• 238000009833 condensation Methods 0.000 description 4
• 230000005494 condensation Effects 0.000 description 4
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