NO323191B1 - Amid-derivater og anvendelse derav, samt fremgangsmate for fremstilling derav og farmasoytisk preparat - Google Patents

Info

Publication number

NO323191B1

NO323191B1 NO20014492A NO20014492A NO323191B1 NO 323191 B1 NO323191 B1 NO 323191B1 NO 20014492 A NO20014492 A NO 20014492A NO 20014492 A NO20014492 A NO 20014492A NO 323191 B1 NO323191 B1 NO 323191B1

Authority

NO

Norway

Prior art keywords

alkyl

methyl

dihydroquinazolin

formula

phenyl

Prior art date

1999-03-17

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• 238000000034 method Methods 0.000 title claims description 53
• 150000001408 amides Chemical class 0.000 title claims description 46
• 238000002360 preparation method Methods 0.000 title claims description 31
• 230000008569 process Effects 0.000 title claims description 4
• 239000000825 pharmaceutical preparation Substances 0.000 title description 3
• -1 homopiperazinyl Chemical group 0.000 claims description 477
• 125000000217 alkyl group Chemical group 0.000 claims description 146
• 150000001875 compounds Chemical class 0.000 claims description 95
• 125000001424 substituent group Chemical group 0.000 claims description 79
• 125000003282 alkyl amino group Chemical group 0.000 claims description 73
• 125000003545 alkoxy group Chemical group 0.000 claims description 50
• 125000000623 heterocyclic group Chemical group 0.000 claims description 50
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 43
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 37
• 150000003839 salts Chemical class 0.000 claims description 36
• 125000003118 aryl group Chemical group 0.000 claims description 32
• 125000005236 alkanoylamino group Chemical group 0.000 claims description 31
• 238000006243 chemical reaction Methods 0.000 claims description 31
• 229910052739 hydrogen Inorganic materials 0.000 claims description 30
• 239000001257 hydrogen Substances 0.000 claims description 29
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 29
• 125000001072 heteroaryl group Chemical group 0.000 claims description 28
• 102000004127 Cytokines Human genes 0.000 claims description 22
• 108090000695 Cytokines Proteins 0.000 claims description 22
• 239000002253 acid Substances 0.000 claims description 21
• 150000002148 esters Chemical class 0.000 claims description 21
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 19
• 125000006239 protecting group Chemical group 0.000 claims description 19
• PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 18
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 18
• 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 16
• 125000002541 furyl group Chemical group 0.000 claims description 16
• 238000004519 manufacturing process Methods 0.000 claims description 16
• 201000010099 disease Diseases 0.000 claims description 15
• 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 14
• 229910052736 halogen Inorganic materials 0.000 claims description 14
• 150000002367 halogens Chemical class 0.000 claims description 14
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 13
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
• 125000002757 morpholinyl group Chemical group 0.000 claims description 12
• 125000004193 piperazinyl group Chemical group 0.000 claims description 12
• 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 11
• 230000015572 biosynthetic process Effects 0.000 claims description 11
• 125000003386 piperidinyl group Chemical group 0.000 claims description 11
• 238000011282 treatment Methods 0.000 claims description 11
• BGASEZKJFFGWSB-UHFFFAOYSA-N 4-methoxy-n-[4-methyl-3-(2-methyl-4-oxoquinazolin-3-yl)phenyl]benzamide Chemical compound C1=CC(OC)=CC=C1C(=O)NC1=CC=C(C)C(N2C(C3=CC=CC=C3N=C2C)=O)=C1 BGASEZKJFFGWSB-UHFFFAOYSA-N 0.000 claims description 10
• 125000000524 functional group Chemical group 0.000 claims description 10
• 238000001727 in vivo Methods 0.000 claims description 10
• 125000004076 pyridyl group Chemical group 0.000 claims description 10
• 125000001544 thienyl group Chemical group 0.000 claims description 10
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 9
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 9
• 150000001412 amines Chemical class 0.000 claims description 9
• 239000000460 chlorine Substances 0.000 claims description 9
• 229910052801 chlorine Inorganic materials 0.000 claims description 9
• 229910052731 fluorine Inorganic materials 0.000 claims description 9
• 239000011737 fluorine Substances 0.000 claims description 9
• 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 9
• SSSDCHOJYWJLKM-UHFFFAOYSA-N 4-methyl-n-[4-methyl-3-(2-methyl-4-oxoquinazolin-3-yl)phenyl]benzamide Chemical compound C1=CC(C)=CC=C1C(=O)NC1=CC=C(C)C(N2C(C3=CC=CC=C3N=C2C)=O)=C1 SSSDCHOJYWJLKM-UHFFFAOYSA-N 0.000 claims description 8
• 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 8
• 125000004432 carbon atom Chemical group C* 0.000 claims description 8
• 125000005844 heterocyclyloxy group Chemical group 0.000 claims description 8
• 125000001786 isothiazolyl group Chemical group 0.000 claims description 8
• 125000000842 isoxazolyl group Chemical group 0.000 claims description 8
• 206010039073 rheumatoid arthritis Diseases 0.000 claims description 8
• 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 8
• 125000000335 thiazolyl group Chemical group 0.000 claims description 8
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
• 125000002393 azetidinyl group Chemical group 0.000 claims description 7
• 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 7
• 239000003814 drug Substances 0.000 claims description 7
• HRGRYWJTIGGDTB-UHFFFAOYSA-N n-[4-methyl-3-(2-methyl-4-oxoquinazolin-3-yl)phenyl]benzamide Chemical compound C1=C(N2C(C3=CC=CC=C3N=C2C)=O)C(C)=CC=C1NC(=O)C1=CC=CC=C1 HRGRYWJTIGGDTB-UHFFFAOYSA-N 0.000 claims description 7
• 206010040070 Septic Shock Diseases 0.000 claims description 6
• 230000029936 alkylation Effects 0.000 claims description 6
• 238000005804 alkylation reaction Methods 0.000 claims description 6
• 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 6
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 6
• 125000005493 quinolyl group Chemical group 0.000 claims description 6
• FDPVTENMNDHFNK-UHFFFAOYSA-N 2-amino-n-phenylbenzamide Chemical compound NC1=CC=CC=C1C(=O)NC1=CC=CC=C1 FDPVTENMNDHFNK-UHFFFAOYSA-N 0.000 claims description 5
• 208000030507 AIDS Diseases 0.000 claims description 5
• 125000005530 alkylenedioxy group Chemical group 0.000 claims description 5
• 208000006673 asthma Diseases 0.000 claims description 5
• 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 5
• 125000001422 pyrrolinyl group Chemical group 0.000 claims description 5
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
• 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 4
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
• 201000004681 Psoriasis Diseases 0.000 claims description 4
• 230000010933 acylation Effects 0.000 claims description 4
• 238000005917 acylation reaction Methods 0.000 claims description 4
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
• 229910052794 bromium Inorganic materials 0.000 claims description 4
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
• 125000001207 fluorophenyl group Chemical group 0.000 claims description 4
• 150000002431 hydrogen Chemical class 0.000 claims description 4
• 125000004628 isothiazolidinyl group Chemical group S1N(CCC1)* 0.000 claims description 4
• 201000006417 multiple sclerosis Diseases 0.000 claims description 4
• 230000036303 septic shock Effects 0.000 claims description 4
• 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 claims description 3
• 239000003085 diluting agent Substances 0.000 claims description 3
• 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
• 125000006534 ethyl amino methyl group Chemical group [H]N(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 claims description 3
• 208000002551 irritable bowel syndrome Diseases 0.000 claims description 3
• 230000001404 mediated effect Effects 0.000 claims description 3
• 208000031225 myocardial ischemia Diseases 0.000 claims description 3
• CQPGVFNVBPKXTQ-UHFFFAOYSA-N n-[4-methyl-3-[6-(4-methylpiperazin-1-yl)-4-oxoquinazolin-3-yl]phenyl]-2-pyrrolidin-1-ylpyridine-4-carboxamide Chemical compound C1CN(C)CCN1C1=CC=C(N=CN(C=2C(=CC=C(NC(=O)C=3C=C(N=CC=3)N3CCCC3)C=2)C)C2=O)C2=C1 CQPGVFNVBPKXTQ-UHFFFAOYSA-N 0.000 claims description 3
• 125000000586 2-(4-morpholinyl)ethoxy group Chemical group [H]C([H])(O*)C([H])([H])N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 claims description 2
• 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 2
• 125000004364 3-pyrrolinyl group Chemical group [H]C1=C([H])C([H])([H])N(*)C1([H])[H] 0.000 claims description 2
• 238000010976 amide bond formation reaction Methods 0.000 claims description 2
• 125000000723 dihydrobenzofuranyl group Chemical group O1C(CC2=C1C=CC=C2)* 0.000 claims description 2
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
• YIADZIODFRUGHP-UHFFFAOYSA-N n-[3-[6-[3-(dimethylamino)propyl-methylamino]-4-oxoquinazolin-3-yl]phenyl]-2-morpholin-4-ylpyridine-4-carboxamide Chemical compound O=C1C2=CC(N(C)CCCN(C)C)=CC=C2N=CN1C(C=1)=CC=CC=1NC(=O)C(C=1)=CC=NC=1N1CCOCC1 YIADZIODFRUGHP-UHFFFAOYSA-N 0.000 claims description 2
• BLSPWFIREKMTOA-UHFFFAOYSA-N n-[4-methyl-3-[6-(4-methylpiperazin-1-yl)-4-oxoquinazolin-3-yl]phenyl]-2-morpholin-4-ylpyridine-4-carboxamide Chemical compound C1CN(C)CCN1C1=CC=C(N=CN(C=2C(=CC=C(NC(=O)C=3C=C(N=CC=3)N3CCOCC3)C=2)C)C2=O)C2=C1 BLSPWFIREKMTOA-UHFFFAOYSA-N 0.000 claims description 2
• WQDXNLSFVMCBEV-UHFFFAOYSA-N n-[4-methyl-3-[6-(4-methylpiperazin-1-yl)-4-oxoquinazolin-3-yl]phenyl]-2-piperidin-1-ylpyridine-4-carboxamide Chemical compound C1CN(C)CCN1C1=CC=C(N=CN(C=2C(=CC=C(NC(=O)C=3C=C(N=CC=3)N3CCCCC3)C=2)C)C2=O)C2=C1 WQDXNLSFVMCBEV-UHFFFAOYSA-N 0.000 claims description 2
• UICJDYQTBCEDQP-UHFFFAOYSA-N n-[4-methyl-3-[6-(4-methylpiperazin-1-yl)-4-oxoquinazolin-3-yl]phenyl]dibenzofuran-4-carboxamide Chemical compound C1CN(C)CCN1C1=CC=C(N=CN(C=2C(=CC=C(NC(=O)C=3C=4OC5=CC=CC=C5C=4C=CC=3)C=2)C)C2=O)C2=C1 UICJDYQTBCEDQP-UHFFFAOYSA-N 0.000 claims description 2
• 239000008194 pharmaceutical composition Substances 0.000 claims description 2
• 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims 1
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 213
• 239000000203 mixture Substances 0.000 description 206
• 238000001819 mass spectrum Methods 0.000 description 163
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 156
• 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 156
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 116
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 81
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 79
• 239000000047 product Substances 0.000 description 79
• 239000007858 starting material Substances 0.000 description 67
• 239000000243 solution Substances 0.000 description 61
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 60
• 239000000463 material Substances 0.000 description 53
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 45
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 40
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 39
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 39
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• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 38
• 239000007787 solid Substances 0.000 description 37
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 36
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• 239000012258 stirred mixture Substances 0.000 description 33
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• 239000011541 reaction mixture Substances 0.000 description 31
• 239000000706 filtrate Substances 0.000 description 28
• 229920006395 saturated elastomer Polymers 0.000 description 27
• CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 26
• 239000002244 precipitate Substances 0.000 description 24
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• 239000003054 catalyst Substances 0.000 description 23
• 238000004440 column chromatography Methods 0.000 description 23
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• 241000282414 Homo sapiens Species 0.000 description 19
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 19
• 235000017557 sodium bicarbonate Nutrition 0.000 description 19
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• 229960000583 acetic acid Drugs 0.000 description 13
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• 238000012360 testing method Methods 0.000 description 12
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• 239000002158 endotoxin Substances 0.000 description 9
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• 241000700159 Rattus Species 0.000 description 8
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• 102100040247 Tumor necrosis factor Human genes 0.000 description 8
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• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 6
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