JP2004507533A - 二環式複素環化合物、これらの化合物を含む医薬組成物、それらの使用及びその生成方法 - Google Patents

二環式複素環化合物、これらの化合物を含む医薬組成物、それらの使用及びその生成方法 Download PDF

Info

Publication number: JP2004507533A
Authority: JP; Japan
Prior art keywords: group; alkyl; substituted; oxo; alkylene
Prior art date: 2000-08-26
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Pending

Application number

JP2002523885A

Other languages

English (en)

Japanese (ja)

Inventor

ヒンメルスバッハ　フランク

ラングコツフ　エルケ

ユング　ビルギット

ブレッヒ　シュテファン

ゾルカ　フラフィオ

Original Assignee

ベーリンガー　インゲルハイム　ファルマ　ゲゼルシャフト　ミット　ベシュレンクテル　ハフツング　ウント　コンパニー　コマンディトゲゼルシャフト

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

2000-08-26

Filing date

2001-08-18

Publication date

2004-03-11

2001-08-18 Application filed by ベーリンガー　インゲルハイム　ファルマ　ゲゼルシャフト　ミット　ベシュレンクテル　ハフツング　ウント　コンパニー　コマンディトゲゼルシャフト filed Critical ベーリンガー　インゲルハイム　ファルマ　ゲゼルシャフト　ミット　ベシュレンクテル　ハフツング　ウント　コンパニー　コマンディトゲゼルシャフト

2004-03-11 Publication of JP2004507533A publication Critical patent/JP2004507533A/ja

Status Pending legal-status Critical Current

Links

125000002618 bicyclic heterocycle group Chemical group 0.000 title claims abstract description 6
238000004519 manufacturing process Methods 0.000 title claims abstract description 5
150000001875 compounds Chemical class 0.000 title claims description 61
238000000034 method Methods 0.000 title claims description 9
239000008194 pharmaceutical composition Substances 0.000 title claims 4
150000003839 salts Chemical class 0.000 claims abstract description 22
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 10
201000010099 disease Diseases 0.000 claims abstract description 9
210000004072 lung Anatomy 0.000 claims abstract description 3
150000007522 mineralic acids Chemical class 0.000 claims abstract description 3
150000007524 organic acids Chemical class 0.000 claims abstract description 3
235000005985 organic acids Nutrition 0.000 claims abstract description 3
-1 hydroxy, methoxy, ethoxy, amino, cyano, vinyl Chemical group 0.000 claims description 187
125000000217 alkyl group Chemical group 0.000 claims description 64
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 54
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 32
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 26
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 25
238000006243 chemical reaction Methods 0.000 claims description 20
125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 19
229910052757 nitrogen Inorganic materials 0.000 claims description 16
125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 16
125000002947 alkylene group Chemical group 0.000 claims description 15
125000001841 imino group Chemical group [H]N=* 0.000 claims description 11
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 10
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 8
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 8
125000004433 nitrogen atom Chemical group N* 0.000 claims description 8
229910052760 oxygen Inorganic materials 0.000 claims description 8
239000001301 oxygen Substances 0.000 claims description 8
125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 8
125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 8
229910052717 sulfur Inorganic materials 0.000 claims description 8
125000004434 sulfur atom Chemical group 0.000 claims description 8
KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 7
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
239000000460 chlorine Substances 0.000 claims description 7
229910052801 chlorine Inorganic materials 0.000 claims description 7
125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 7
125000006239 protecting group Chemical group 0.000 claims description 7
125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 6
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
229910052731 fluorine Inorganic materials 0.000 claims description 6
239000011737 fluorine Substances 0.000 claims description 6
125000001153 fluoro group Chemical group F* 0.000 claims description 6
229910052739 hydrogen Inorganic materials 0.000 claims description 6
239000001257 hydrogen Substances 0.000 claims description 6
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
229910052799 carbon Inorganic materials 0.000 claims description 5
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 4
125000003118 aryl group Chemical group 0.000 claims description 4
229910052794 bromium Inorganic materials 0.000 claims description 4
125000005677 ethinylene group Chemical group [*:2]C#C[*:1] 0.000 claims description 4
210000001035 gastrointestinal tract Anatomy 0.000 claims description 4
229910052740 iodine Inorganic materials 0.000 claims description 4
125000003386 piperidinyl group Chemical group 0.000 claims description 4
239000000126 substance Substances 0.000 claims description 4
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 3
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
239000000969 carrier Substances 0.000 claims description 3
239000003085 diluting agent Substances 0.000 claims description 3
125000006518 morpholino carbonyl group Chemical group [H]C1([H])OC([H])([H])C([H])([H])N(C(*)=O)C1([H])[H] 0.000 claims description 3
YOMXVQUOOCYGDN-UHFFFAOYSA-N n-[4-(3-chloro-4-fluoroanilino)-7-[2-[4-(5-oxooxolan-3-yl)piperazin-1-yl]ethoxy]quinazolin-6-yl]prop-2-enamide Chemical compound C1=C(Cl)C(F)=CC=C1NC1=NC=NC2=CC(OCCN3CCN(CC3)C3CC(=O)OC3)=C(NC(=O)C=C)C=C12 YOMXVQUOOCYGDN-UHFFFAOYSA-N 0.000 claims description 3
ZGDLKYKAXFXCAS-PSDZMVHGSA-N n-[7-[2-[4-(5-oxooxolan-3-yl)piperazin-1-yl]ethoxy]-4-[[(1r)-1-phenylethyl]amino]quinazolin-6-yl]prop-2-enamide Chemical compound N([C@H](C)C=1C=CC=CC=1)C(C1=CC=2NC(=O)C=C)=NC=NC1=CC=2OCCN(CC1)CCN1C1COC(=O)C1 ZGDLKYKAXFXCAS-PSDZMVHGSA-N 0.000 claims description 3
125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 3
125000000719 pyrrolidinyl group Chemical group 0.000 claims description 3
125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 2
125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 claims description 2
125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 2
HJAYYFUMHWRGHB-UHFFFAOYSA-N CCOC1=NC=C2C=C(C=CC2=N1)NC(=O)C=C Chemical compound CCOC1=NC=C2C=C(C=CC2=N1)NC(=O)C=C HJAYYFUMHWRGHB-UHFFFAOYSA-N 0.000 claims description 2
125000003277 amino group Chemical group 0.000 claims description 2
125000005002 aryl methyl group Chemical group 0.000 claims description 2
125000004104 aryloxy group Chemical group 0.000 claims description 2
201000011510 cancer Diseases 0.000 claims description 2
125000004093 cyano group Chemical group *C#N 0.000 claims description 2
125000005842 heteroatom Chemical group 0.000 claims description 2
125000002883 imidazolyl group Chemical group 0.000 claims description 2
210000003734 kidney Anatomy 0.000 claims description 2
125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims description 2
125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 claims description 2
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 2
ZMNMJDNOEJXGHL-UHFFFAOYSA-N n-[4-(3-chloro-4-fluoroanilino)-7-[3-[4-(5-oxooxolan-3-yl)piperazin-1-yl]propoxy]quinazolin-6-yl]prop-2-enamide Chemical compound C1=C(Cl)C(F)=CC=C1NC1=NC=NC2=CC(OCCCN3CCN(CC3)C3CC(=O)OC3)=C(NC(=O)C=C)C=C12 ZMNMJDNOEJXGHL-UHFFFAOYSA-N 0.000 claims description 2
125000004430 oxygen atom Chemical group O* 0.000 claims description 2
210000002345 respiratory system Anatomy 0.000 claims description 2
238000006467 substitution reaction Methods 0.000 claims description 2
229920001577 copolymer Chemical group 0.000 claims 6
125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims 3
125000004432 carbon atom Chemical group C* 0.000 claims 2
210000000013 bile duct Anatomy 0.000 claims 1
210000000232 gallbladder Anatomy 0.000 claims 1
150000002391 heterocyclic compounds Chemical class 0.000 claims 1
125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 claims 1
230000002265 prevention Effects 0.000 claims 1
102000004022 Protein-Tyrosine Kinases Human genes 0.000 abstract description 7
108090000412 Protein-Tyrosine Kinases Proteins 0.000 abstract description 7
230000002401 inhibitory effect Effects 0.000 abstract description 4
230000011664 signaling Effects 0.000 abstract description 4
206010028980 Neoplasm Diseases 0.000 abstract description 3
230000000144 pharmacologic effect Effects 0.000 abstract description 2
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 174
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 153
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 48
239000000741 silica gel Substances 0.000 description 45
229910002027 silica gel Inorganic materials 0.000 description 45
238000001819 mass spectrum Methods 0.000 description 42
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
239000013543 active substance Substances 0.000 description 34
VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 31
235000011114 ammonium hydroxide Nutrition 0.000 description 31
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 30
QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 30
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 28
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 28
239000000243 solution Substances 0.000 description 25
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 22
239000000203 mixture Substances 0.000 description 19
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 17
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 16
239000003826 tablet Substances 0.000 description 16
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
210000004027 cell Anatomy 0.000 description 15
238000002360 preparation method Methods 0.000 description 14
235000002639 sodium chloride Nutrition 0.000 description 14
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 14
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 12
239000011541 reaction mixture Substances 0.000 description 12
239000002775 capsule Substances 0.000 description 11
239000002904 solvent Substances 0.000 description 11
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 10
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
229920002261 Corn starch Polymers 0.000 description 8
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
102000001301 EGF receptor Human genes 0.000 description 8
GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 8
239000002253 acid Substances 0.000 description 8
239000008120 corn starch Substances 0.000 description 8
229940099112 cornstarch Drugs 0.000 description 8
GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 8
239000008101 lactose Substances 0.000 description 8
235000019359 magnesium stearate Nutrition 0.000 description 8
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
108060006698 EGF receptor Proteins 0.000 description 7
PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 7
239000001267 polyvinylpyrrolidone Substances 0.000 description 7
229920000036 polyvinylpyrrolidone Polymers 0.000 description 7
235000013855 polyvinylpyrrolidone Nutrition 0.000 description 7
239000002244 precipitate Substances 0.000 description 7
239000000725 suspension Substances 0.000 description 7
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 6
OXVSBNVWOUXHEP-UHFFFAOYSA-N n-[4-(3-chloro-4-fluoroanilino)-7-[3-(4-oxo-3-oxa-9-azaspiro[5.5]undecan-9-yl)propoxy]quinazolin-6-yl]prop-2-enamide Chemical compound C1=C(Cl)C(F)=CC=C1NC1=NC=NC2=CC(OCCCN3CCC4(CC(=O)OCC4)CC3)=C(NC(=O)C=C)C=C12 OXVSBNVWOUXHEP-UHFFFAOYSA-N 0.000 description 6
238000003756 stirring Methods 0.000 description 6
238000010626 work up procedure Methods 0.000 description 6
BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 5
239000005457 ice water Substances 0.000 description 5
229910052943 magnesium sulfate Inorganic materials 0.000 description 5
235000019341 magnesium sulphate Nutrition 0.000 description 5
JCFSPDDSDLVDRE-UHFFFAOYSA-N n-[4-(3-chloro-4-fluoroanilino)-7-[3-[4-[(5-oxooxolan-2-yl)methyl]piperazin-1-yl]propoxy]quinazolin-6-yl]prop-2-enamide Chemical compound C1=C(Cl)C(F)=CC=C1NC1=NC=NC2=CC(OCCCN3CCN(CC4OC(=O)CC4)CC3)=C(NC(=O)C=C)C=C12 JCFSPDDSDLVDRE-UHFFFAOYSA-N 0.000 description 5
239000012074 organic phase Substances 0.000 description 5
239000007787 solid Substances 0.000 description 5
YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 description 4
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
SCQQSJNPIUWOTH-UHFFFAOYSA-N N-(2-propoxyquinazolin-6-yl)prop-2-enamide Chemical compound CCCOC1=NC=C2C=C(C=CC2=N1)NC(=O)C=C SCQQSJNPIUWOTH-UHFFFAOYSA-N 0.000 description 4
208000037062 Polyps Diseases 0.000 description 4
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
229960000583 acetic acid Drugs 0.000 description 4
150000007513 acids Chemical class 0.000 description 4
239000003708 ampul Substances 0.000 description 4
238000004587 chromatography analysis Methods 0.000 description 4
239000012153 distilled water Substances 0.000 description 4
239000002609 medium Substances 0.000 description 4
ILTKAFWPNHYCET-UHFFFAOYSA-N n-[4-(3-bromoanilino)-7-[3-[1-(5-oxooxolan-3-yl)piperidin-4-yl]propoxy]quinazolin-6-yl]prop-2-enamide Chemical compound BrC1=CC=CC(NC=2C3=CC(NC(=O)C=C)=C(OCCCC4CCN(CC4)C4CC(=O)OC4)C=C3N=CN=2)=C1 ILTKAFWPNHYCET-UHFFFAOYSA-N 0.000 description 4
DCJBIZIHJWTCSV-UHFFFAOYSA-N n-[4-(3-chloro-4-fluoroanilino)-7-[3-[1-(5-oxooxolan-3-yl)piperidin-4-yl]propoxy]quinazolin-6-yl]prop-2-enamide Chemical compound C1=C(Cl)C(F)=CC=C1NC1=NC=NC2=CC(OCCCC3CCN(CC3)C3CC(=O)OC3)=C(NC(=O)C=C)C=C12 DCJBIZIHJWTCSV-UHFFFAOYSA-N 0.000 description 4
CEWAGADGGABETR-UHFFFAOYSA-N n-[4-(3-chloro-4-fluoroanilino)-7-[3-[4-[2-(2-oxooxolan-3-yl)sulfanylethyl]piperazin-1-yl]propoxy]quinazolin-6-yl]prop-2-enamide Chemical compound C1=C(Cl)C(F)=CC=C1NC1=NC=NC2=CC(OCCCN3CCN(CCSC4C(OCC4)=O)CC3)=C(NC(=O)C=C)C=C12 CEWAGADGGABETR-UHFFFAOYSA-N 0.000 description 4
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
239000000843 powder Substances 0.000 description 4
239000000829 suppository Substances 0.000 description 4
CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 4
SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 3
NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 3
RPTKRGHYKSBDJL-UHFFFAOYSA-N 6-nitroquinazoline Chemical compound N1=CN=CC2=CC([N+](=O)[O-])=CC=C21 RPTKRGHYKSBDJL-UHFFFAOYSA-N 0.000 description 3
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 3
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 3
FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 3
FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
102000009024 Epidermal Growth Factor Human genes 0.000 description 3
108010002386 Interleukin-3 Proteins 0.000 description 3
102000000646 Interleukin-3 Human genes 0.000 description 3
JTQPMDZFCLVVTG-UHFFFAOYSA-N N-[4-(3-chloro-4-fluoroanilino)-7-[3-(3-oxo-2-oxa-8-azaspiro[4.5]decan-8-yl)propoxy]quinazolin-6-yl]prop-2-enamide Chemical compound C1=C(Cl)C(F)=CC=C1NC1=NC=NC2=CC(OCCCN3CCC4(CC(=O)OC4)CC3)=C(NC(=O)C=C)C=C12 JTQPMDZFCLVVTG-UHFFFAOYSA-N 0.000 description 3
239000002202 Polyethylene glycol Substances 0.000 description 3
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 3
HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 description 3
150000001721 carbon Chemical group 0.000 description 3
235000015165 citric acid Nutrition 0.000 description 3
238000001816 cooling Methods 0.000 description 3
239000012043 crude product Substances 0.000 description 3
125000004122 cyclic group Chemical group 0.000 description 3
239000003814 drug Substances 0.000 description 3
239000003480 eluent Substances 0.000 description 3
239000007902 hard capsule Substances 0.000 description 3
125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 3
239000003112 inhibitor Substances 0.000 description 3
229940076264 interleukin-3 Drugs 0.000 description 3
238000002844 melting Methods 0.000 description 3
230000008018 melting Effects 0.000 description 3
VSLCPCMVFXXGIT-UHFFFAOYSA-N n-[4-(3-chloro-4-fluoroanilino)-7-[3-(1-oxo-3,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl)propoxy]quinazolin-6-yl]prop-2-enamide Chemical compound C1=C(Cl)C(F)=CC=C1NC1=NC=NC2=CC(OCCCN3CC4C(=O)OCCN4CC3)=C(NC(=O)C=C)C=C12 VSLCPCMVFXXGIT-UHFFFAOYSA-N 0.000 description 3
OMCJAJQDRLEXDM-UHFFFAOYSA-N n-[4-(3-chloro-4-fluoroanilino)-7-[3-(2-oxo-1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)propoxy]quinazolin-6-yl]prop-2-enamide Chemical compound C1=C(Cl)C(F)=CC=C1NC1=NC=NC2=CC(OCCCN3CCC4(CC3)OC(=O)COC4)=C(NC(=O)C=C)C=C12 OMCJAJQDRLEXDM-UHFFFAOYSA-N 0.000 description 3
PJVMPTDOYKQVSH-UHFFFAOYSA-N n-[4-(3-chloro-4-fluoroanilino)-7-[3-(3-oxo-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl)propoxy]quinazolin-6-yl]prop-2-enamide Chemical compound C1=C(Cl)C(F)=CC=C1NC1=NC=NC2=CC(OCCCN3CC4COC(=O)CN4CC3)=C(NC(=O)C=C)C=C12 PJVMPTDOYKQVSH-UHFFFAOYSA-N 0.000 description 3
OHJCBOVXWGRXGM-UHFFFAOYSA-N n-[4-(3-methylanilino)-7-[3-[1-(5-oxooxolan-3-yl)piperidin-4-yl]propoxy]quinazolin-6-yl]prop-2-enamide Chemical compound CC1=CC=CC(NC=2C3=CC(NC(=O)C=C)=C(OCCCC4CCN(CC4)C4CC(=O)OC4)C=C3N=CN=2)=C1 OHJCBOVXWGRXGM-UHFFFAOYSA-N 0.000 description 3
150000007530 organic bases Chemical class 0.000 description 3
229920001223 polyethylene glycol Polymers 0.000 description 3
FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
239000000600 sorbitol Substances 0.000 description 3
239000007858 starting material Substances 0.000 description 3
208000011580 syndromic disease Diseases 0.000 description 3
239000011975 tartaric acid Substances 0.000 description 3
235000002906 tartaric acid Nutrition 0.000 description 3
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
NOOLISFMXDJSKH-KXUCPTDWSA-N (-)-Menthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O NOOLISFMXDJSKH-KXUCPTDWSA-N 0.000 description 2
ZENKESXKWBIZCV-UHFFFAOYSA-N 2,2,4,4-tetrafluoro-1,3-benzodioxin-6-amine Chemical group O1C(F)(F)OC(F)(F)C2=CC(N)=CC=C21 ZENKESXKWBIZCV-UHFFFAOYSA-N 0.000 description 2
YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 2
SQUFWROZDHFUNE-UHFFFAOYSA-N 3-[4-(3-chloro-4-fluoroanilino)-6-nitroquinazolin-7-yl]oxypropyl methanesulfonate Chemical compound C=12C=C([N+]([O-])=O)C(OCCCOS(=O)(=O)C)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 SQUFWROZDHFUNE-UHFFFAOYSA-N 0.000 description 2
VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
KNZKBASCFRFMLC-MRXNPFEDSA-N 6-nitro-n-[(1r)-1-phenylethyl]-7-(2-piperazin-1-ylethoxy)quinazolin-4-amine Chemical compound N([C@H](C)C=1C=CC=CC=1)C(C1=CC=2[N+]([O-])=O)=NC=NC1=CC=2OCCN1CCNCC1 KNZKBASCFRFMLC-MRXNPFEDSA-N 0.000 description 2
208000026292 Cystic Kidney disease Diseases 0.000 description 2
NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 2
QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
206010014561 Emphysema Diseases 0.000 description 2
VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
101000851176 Homo sapiens Pro-epidermal growth factor Proteins 0.000 description 2
208000032177 Intestinal Polyps Diseases 0.000 description 2
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
208000019693 Lung disease Diseases 0.000 description 2
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
101001033276 Mus musculus Interleukin-3 Proteins 0.000 description 2
NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
101710098940 Pro-epidermal growth factor Proteins 0.000 description 2
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 2
125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
125000003545 alkoxy group Chemical group 0.000 description 2
150000001408 amides Chemical class 0.000 description 2
RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
239000008346 aqueous phase Substances 0.000 description 2
239000007864 aqueous solution Substances 0.000 description 2
239000002585 base Substances 0.000 description 2
229960000686 benzalkonium chloride Drugs 0.000 description 2
CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 2
125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
230000004071 biological effect Effects 0.000 description 2
206010006451 bronchitis Diseases 0.000 description 2
VIHAEDVKXSOUAT-UHFFFAOYSA-N but-2-en-4-olide Chemical compound O=C1OCC=C1 VIHAEDVKXSOUAT-UHFFFAOYSA-N 0.000 description 2
239000001506 calcium phosphate Substances 0.000 description 2
229910000389 calcium phosphate Inorganic materials 0.000 description 2
235000011010 calcium phosphates Nutrition 0.000 description 2
PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
230000010261 cell growth Effects 0.000 description 2
IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
206010009887 colitis Diseases 0.000 description 2
239000002299 complementary DNA Substances 0.000 description 2
239000013078 crystal Substances 0.000 description 2
239000012024 dehydrating agents‎ Substances 0.000 description 2
DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 2
238000001704 evaporation Methods 0.000 description 2
230000008020 evaporation Effects 0.000 description 2
239000000706 filtrate Substances 0.000 description 2
239000000796 flavoring agent Substances 0.000 description 2
239000012362 glacial acetic acid Substances 0.000 description 2
239000008103 glucose Substances 0.000 description 2
239000008187 granular material Substances 0.000 description 2
FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 2
239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 2
150000007529 inorganic bases Chemical class 0.000 description 2
JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
230000001404 mediated effect Effects 0.000 description 2
QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
239000004292 methyl p-hydroxybenzoate Substances 0.000 description 2
235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 2
XPIRKEABEPJVEB-UHFFFAOYSA-N n-[4-(3-chloro-4-fluoroanilino)-7-[3-(2-oxo-1,9-dioxa-4-azaspiro[5.5]undecan-4-yl)propoxy]quinazolin-6-yl]prop-2-enamide Chemical compound C1=C(Cl)C(F)=CC=C1NC1=NC=NC2=CC(OCCCN3CC4(CCOCC4)OC(=O)C3)=C(NC(=O)C=C)C=C12 XPIRKEABEPJVEB-UHFFFAOYSA-N 0.000 description 2
XVYIRCDVZFNONG-UHFFFAOYSA-N n-[4-(3-chloro-4-fluoroanilino)-7-[3-(4-methyl-2-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)propoxy]quinazolin-6-yl]prop-2-enamide Chemical compound C1N(C)CC(=O)OC11CCN(CCCOC=2C(=CC3=C(NC=4C=C(Cl)C(F)=CC=4)N=CN=C3C=2)NC(=O)C=C)CC1 XVYIRCDVZFNONG-UHFFFAOYSA-N 0.000 description 2
BKNUPYSWMJVRIN-UHFFFAOYSA-N n-[4-(3-chloro-4-fluoroanilino)-7-[3-[2-(2-methoxyethyl)-6-oxomorpholin-4-yl]propoxy]quinazolin-6-yl]prop-2-enamide Chemical compound C1C(=O)OC(CCOC)CN1CCCOC1=CC2=NC=NC(NC=3C=C(Cl)C(F)=CC=3)=C2C=C1NC(=O)C=C BKNUPYSWMJVRIN-UHFFFAOYSA-N 0.000 description 2
JTAUZROSRFDATM-UHFFFAOYSA-N n-[4-(3-chloro-4-fluoroanilino)-7-[3-[2-(methoxymethyl)-6-oxomorpholin-4-yl]propoxy]quinazolin-6-yl]prop-2-enamide Chemical compound C1C(=O)OC(COC)CN1CCCOC1=CC2=NC=NC(NC=3C=C(Cl)C(F)=CC=3)=C2C=C1NC(=O)C=C JTAUZROSRFDATM-UHFFFAOYSA-N 0.000 description 2
ASOMYCWJYXDASW-UHFFFAOYSA-N n-[4-(3-chloro-4-fluoroanilino)-7-[3-[4-(2-methyl-6-oxomorpholin-4-yl)piperidin-1-yl]propoxy]quinazolin-6-yl]prop-2-enamide Chemical compound C1C(=O)OC(C)CN1C1CCN(CCCOC=2C(=CC3=C(NC=4C=C(Cl)C(F)=CC=4)N=CN=C3C=2)NC(=O)C=C)CC1 ASOMYCWJYXDASW-UHFFFAOYSA-N 0.000 description 2
WRWZAEQESXXMRE-UHFFFAOYSA-N n-[4-(3-chloro-4-fluoroanilino)-7-[3-[4-(2-oxomorpholin-4-yl)piperidin-1-yl]propoxy]quinazolin-6-yl]prop-2-enamide Chemical compound C1=C(Cl)C(F)=CC=C1NC1=NC=NC2=CC(OCCCN3CCC(CC3)N3CC(=O)OCC3)=C(NC(=O)C=C)C=C12 WRWZAEQESXXMRE-UHFFFAOYSA-N 0.000 description 2
TYDMVGCCNDWLFI-UHFFFAOYSA-N n-[4-(3-chloro-4-fluoroanilino)-7-[3-[4-(2-oxooxolan-3-yl)sulfanylpiperidin-1-yl]propoxy]quinazolin-6-yl]prop-2-enamide Chemical compound C1=C(Cl)C(F)=CC=C1NC1=NC=NC2=CC(OCCCN3CCC(CC3)SC3C(OCC3)=O)=C(NC(=O)C=C)C=C12 TYDMVGCCNDWLFI-UHFFFAOYSA-N 0.000 description 2
GVUGOAYIVIDWIO-UFWWTJHBSA-N nepidermin Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CS)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CS)NC(=O)[C@H](C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C(C)C)C(C)C)C1=CC=C(O)C=C1 GVUGOAYIVIDWIO-UFWWTJHBSA-N 0.000 description 2
GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 2
230000003287 optical effect Effects 0.000 description 2
239000003208 petroleum Substances 0.000 description 2
229910000027 potassium carbonate Inorganic materials 0.000 description 2
230000035755 proliferation Effects 0.000 description 2
239000004405 propyl p-hydroxybenzoate Substances 0.000 description 2
235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 2
QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
238000000746 purification Methods 0.000 description 2
230000002829 reductive effect Effects 0.000 description 2
230000003248 secreting effect Effects 0.000 description 2
230000028327 secretion Effects 0.000 description 2
239000012312 sodium hydride Substances 0.000 description 2
229910000104 sodium hydride Inorganic materials 0.000 description 2
239000007921 spray Substances 0.000 description 2
230000000638 stimulation Effects 0.000 description 2
VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
125000001412 tetrahydropyranyl group Chemical group 0.000 description 2
DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 2
FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 2
125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
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 2
229940075966 (+)- menthol Drugs 0.000 description 1
NOOLISFMXDJSKH-AEJSXWLSSA-N (+)-menthol Chemical compound CC(C)[C@H]1CC[C@H](C)C[C@@H]1O NOOLISFMXDJSKH-AEJSXWLSSA-N 0.000 description 1
RQEUFEKYXDPUSK-SSDOTTSWSA-N (1R)-1-phenylethanamine Chemical compound C[C@@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-SSDOTTSWSA-N 0.000 description 1
QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
AAWZDTNXLSGCEK-LNVDRNJUSA-N (3r,5r)-1,3,4,5-tetrahydroxycyclohexane-1-carboxylic acid Chemical compound O[C@@H]1CC(O)(C(O)=O)C[C@@H](O)C1O AAWZDTNXLSGCEK-LNVDRNJUSA-N 0.000 description 1
SXXRVFKLFSLMEF-NRFANRHFSA-N (5s)-5-[4-[2-[6-amino-4-(3-chloro-4-fluoroanilino)quinazolin-7-yl]oxyethyl]piperazine-1-carbonyl]oxolan-2-one Chemical compound N1=CN=C2C=C(OCCN3CCN(CC3)C(=O)[C@H]3OC(=O)CC3)C(N)=CC2=C1NC1=CC=C(F)C(Cl)=C1 SXXRVFKLFSLMEF-NRFANRHFSA-N 0.000 description 1
YYVSCEOWTMPFJB-QHCPKHFHSA-N (5s)-5-[4-[4-[6-amino-4-(3-chloro-4-fluoroanilino)quinazolin-7-yl]oxybutyl]piperazine-1-carbonyl]oxolan-2-one Chemical compound N1=CN=C2C=C(OCCCCN3CCN(CC3)C(=O)[C@H]3OC(=O)CC3)C(N)=CC2=C1NC1=CC=C(F)C(Cl)=C1 YYVSCEOWTMPFJB-QHCPKHFHSA-N 0.000 description 1
QVADRSWDTZDDGR-VKHMYHEASA-N (S)-alpha-hydroxyglutaric acid-gamma-lactone Chemical compound OC(=O)[C@@H]1CCC(=O)O1 QVADRSWDTZDDGR-VKHMYHEASA-N 0.000 description 1
MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
LZDKZFUFMNSQCJ-UHFFFAOYSA-N 1,2-diethoxyethane Chemical compound CCOCCOCC LZDKZFUFMNSQCJ-UHFFFAOYSA-N 0.000 description 1
ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
LNSCNEJNLACZPA-UHFFFAOYSA-N 2,3-dihydroxy-2,3-bis(2-methylphenyl)butanedioic acid Chemical compound CC1=CC=CC=C1C(O)(C(O)=O)C(O)(C(O)=O)C1=CC=CC=C1C LNSCNEJNLACZPA-UHFFFAOYSA-N 0.000 description 1
AJWCZOWUVWETBQ-UHFFFAOYSA-N 2-[4-(3-chloro-4-fluoroanilino)-6-nitroquinazolin-7-yl]oxyethanol Chemical compound C=12C=C([N+]([O-])=O)C(OCCO)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 AJWCZOWUVWETBQ-UHFFFAOYSA-N 0.000 description 1
VLJHSUPDIFDNMZ-UHFFFAOYSA-N 2-[4-(3-chloro-4-fluoroanilino)-6-nitroquinazolin-7-yl]oxyethyl methanesulfonate Chemical compound C=12C=C([N+]([O-])=O)C(OCCOS(=O)(=O)C)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 VLJHSUPDIFDNMZ-UHFFFAOYSA-N 0.000 description 1
FVWLTLIRGAPADO-GFCCVEGCSA-N 2-[6-nitro-4-[[(1r)-1-phenylethyl]amino]quinazolin-7-yl]oxyethanol Chemical compound C1([C@H](NC=2C3=CC(=C(OCCO)C=C3N=CN=2)[N+]([O-])=O)C)=CC=CC=C1 FVWLTLIRGAPADO-GFCCVEGCSA-N 0.000 description 1
OFVAYTHZINXMDI-CYBMUJFWSA-N 2-[6-nitro-4-[[(1r)-1-phenylethyl]amino]quinazolin-7-yl]oxyethyl methanesulfonate Chemical compound C1([C@H](NC=2C3=CC(=C(OCCOS(C)(=O)=O)C=C3N=CN=2)[N+]([O-])=O)C)=CC=CC=C1 OFVAYTHZINXMDI-CYBMUJFWSA-N 0.000 description 1
KMGUEILFFWDGFV-UHFFFAOYSA-N 2-benzoyl-2-benzoyloxy-3-hydroxybutanedioic acid Chemical compound C=1C=CC=CC=1C(=O)C(C(C(O)=O)O)(C(O)=O)OC(=O)C1=CC=CC=C1 KMGUEILFFWDGFV-UHFFFAOYSA-N 0.000 description 1
JZQJFSZRLAICJP-UHFFFAOYSA-N 3-(oxan-2-yloxy)propan-1-ol Chemical compound OCCCOC1CCCCO1 JZQJFSZRLAICJP-UHFFFAOYSA-N 0.000 description 1
BPKZYAJPUCWVBL-UHFFFAOYSA-N 3-[4-(3-chloro-4-fluoroanilino)-6-nitroquinazolin-7-yl]oxypropan-1-ol Chemical compound C=12C=C([N+]([O-])=O)C(OCCCO)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 BPKZYAJPUCWVBL-UHFFFAOYSA-N 0.000 description 1
BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
GGSWXJQQJIORJH-UHFFFAOYSA-N 3-piperazin-1-yloxolan-2-one Chemical compound O=C1OCCC1N1CCNCC1 GGSWXJQQJIORJH-UHFFFAOYSA-N 0.000 description 1
ICYUSEGAUSWKAQ-UHFFFAOYSA-N 4-[4-(3-chloro-4-fluoroanilino)-6-nitroquinazolin-7-yl]oxybutan-1-ol Chemical compound C=12C=C([N+]([O-])=O)C(OCCCCO)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 ICYUSEGAUSWKAQ-UHFFFAOYSA-N 0.000 description 1
FIDSRLASFPXJNZ-UHFFFAOYSA-N 4-[4-(3-chloro-4-fluoroanilino)-6-nitroquinazolin-7-yl]oxybutyl methanesulfonate Chemical compound C=12C=C([N+]([O-])=O)C(OCCCCOS(=O)(=O)C)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 FIDSRLASFPXJNZ-UHFFFAOYSA-N 0.000 description 1
XGGLYFLUBJPMSZ-UHFFFAOYSA-N 4-[4-[(2-methylpropan-2-yl)oxy]piperazin-1-yl]oxolan-2-one Chemical compound C1CN(OC(C)(C)C)CCN1C1CC(=O)OC1 XGGLYFLUBJPMSZ-UHFFFAOYSA-N 0.000 description 1
QKHLLPHMCJNDLN-UHFFFAOYSA-N 4-[4-[2-[4-(3-chloro-4-fluoroanilino)-6-nitroquinazolin-7-yl]oxyethyl]piperazin-1-yl]oxolan-2-one Chemical compound N1=CN=C2C=C(OCCN3CCN(CC3)C3CC(=O)OC3)C([N+](=O)[O-])=CC2=C1NC1=CC=C(F)C(Cl)=C1 QKHLLPHMCJNDLN-UHFFFAOYSA-N 0.000 description 1
BMTJUWPOPAOQFJ-UHFFFAOYSA-N 4-[4-[2-[6-amino-4-(3-chloro-4-fluoroanilino)quinazolin-7-yl]oxyethyl]piperazin-1-yl]oxolan-2-one Chemical compound N1=CN=C2C=C(OCCN3CCN(CC3)C3CC(=O)OC3)C(N)=CC2=C1NC1=CC=C(F)C(Cl)=C1 BMTJUWPOPAOQFJ-UHFFFAOYSA-N 0.000 description 1
GUDGMHRDRQTVOW-QSVWIEALSA-N 4-[4-[2-[6-amino-4-[[(1r)-1-phenylethyl]amino]quinazolin-7-yl]oxyethyl]piperazin-1-yl]oxolan-2-one Chemical compound N([C@H](C)C=1C=CC=CC=1)C(C1=CC=2N)=NC=NC1=CC=2OCCN(CC1)CCN1C1COC(=O)C1 GUDGMHRDRQTVOW-QSVWIEALSA-N 0.000 description 1
WOSWWCLIQANYAB-UHFFFAOYSA-N 4-[4-[4-[4-(3-chloro-4-fluoroanilino)-6-nitroquinazolin-7-yl]oxybutyl]piperazin-1-yl]oxolan-2-one Chemical compound N1=CN=C2C=C(OCCCCN3CCN(CC3)C3CC(=O)OC3)C([N+](=O)[O-])=CC2=C1NC1=CC=C(F)C(Cl)=C1 WOSWWCLIQANYAB-UHFFFAOYSA-N 0.000 description 1
QZJDEWZYDMZSJK-UHFFFAOYSA-N 4-[4-[4-[6-amino-4-(3-chloro-4-fluoroanilino)quinazolin-7-yl]oxybutyl]piperazin-1-yl]oxolan-2-one Chemical compound N1=CN=C2C=C(OCCCCN3CCN(CC3)C3CC(=O)OC3)C(N)=CC2=C1NC1=CC=C(F)C(Cl)=C1 QZJDEWZYDMZSJK-UHFFFAOYSA-N 0.000 description 1
UYQMNEZWVKRWMS-UHFFFAOYSA-N 4-chloro-7-fluoro-6-nitroquinazoline Chemical compound N1=CN=C2C=C(F)C([N+](=O)[O-])=CC2=C1Cl UYQMNEZWVKRWMS-UHFFFAOYSA-N 0.000 description 1
MXQIGGGWJTXCTC-UHFFFAOYSA-N 4-piperazin-1-yloxolan-2-one Chemical compound C1OC(=O)CC1N1CCNCC1 MXQIGGGWJTXCTC-UHFFFAOYSA-N 0.000 description 1
FSKXCDLFISAUHD-UHFFFAOYSA-N 6-nitro-2-propoxyquinazoline Chemical compound C(CC)OC1=NC2=CC=C(C=C2C=N1)[N+](=O)[O-] FSKXCDLFISAUHD-UHFFFAOYSA-N 0.000 description 1
PGHNDQKEEVRQBV-XESZBRCGSA-N 6-nitro-7-[2-(oxan-2-yloxy)ethoxy]-n-[(1r)-1-phenylethyl]quinazolin-4-amine Chemical compound N([C@H](C)C=1C=CC=CC=1)C(C1=CC=2[N+]([O-])=O)=NC=NC1=CC=2OCCOC1CCCCO1 PGHNDQKEEVRQBV-XESZBRCGSA-N 0.000 description 1
LPCAMYBCTHSIME-SNVBAGLBSA-N 7-fluoro-6-nitro-n-[(1r)-1-phenylethyl]quinazolin-4-amine Chemical compound C1([C@H](NC=2C3=CC(=C(F)C=C3N=CN=2)[N+]([O-])=O)C)=CC=CC=C1 LPCAMYBCTHSIME-SNVBAGLBSA-N 0.000 description 1
208000003200 Adenoma Diseases 0.000 description 1
208000004804 Adenomatous Polyps Diseases 0.000 description 1
GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
108091003079 Bovine Serum Albumin Proteins 0.000 description 1
206010006458 Bronchitis chronic Diseases 0.000 description 1
238000006418 Brown reaction Methods 0.000 description 1
PDYZGTUKFKFZBY-UHFFFAOYSA-N C(CCC)OC1=NC2=CC=C(C=C2C=N1)NC(=O)C=C Chemical compound C(CCC)OC1=NC2=CC=C(C=C2C=N1)NC(=O)C=C PDYZGTUKFKFZBY-UHFFFAOYSA-N 0.000 description 1
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
206010009900 Colitis ulcerative Diseases 0.000 description 1
208000026372 Congenital cystic kidney disease Diseases 0.000 description 1
AAWZDTNXLSGCEK-UHFFFAOYSA-N Cordycepinsaeure Natural products OC1CC(O)(C(O)=O)CC(O)C1O AAWZDTNXLSGCEK-UHFFFAOYSA-N 0.000 description 1
206010011224 Cough Diseases 0.000 description 1
208000011231 Crohn disease Diseases 0.000 description 1
CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
201000003883 Cystic fibrosis Diseases 0.000 description 1
108090000695 Cytokines Proteins 0.000 description 1
102000004127 Cytokines Human genes 0.000 description 1
208000000321 Gardner Syndrome Diseases 0.000 description 1
206010017807 Gastric mucosal hypertrophy Diseases 0.000 description 1
208000018522 Gastrointestinal disease Diseases 0.000 description 1
206010061459 Gastrointestinal ulcer Diseases 0.000 description 1
WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
241000282412 Homo Species 0.000 description 1
208000000239 Hypertrophic Gastritis Diseases 0.000 description 1
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 1
102000014150 Interferons Human genes 0.000 description 1
108010050904 Interferons Proteins 0.000 description 1
XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
238000006029 Jeger synthesis reaction Methods 0.000 description 1
CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
206010027476 Metastases Diseases 0.000 description 1
229920000168 Microcrystalline cellulose Polymers 0.000 description 1
101000851196 Mus musculus Pro-epidermal growth factor Proteins 0.000 description 1
NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
208000000592 Nasal Polyps Diseases 0.000 description 1
206010029113 Neovascularisation Diseases 0.000 description 1
208000012868 Overgrowth Diseases 0.000 description 1
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
206010056626 Pseudopolyp Diseases 0.000 description 1
201000004681 Psoriasis Diseases 0.000 description 1
AAWZDTNXLSGCEK-ZHQZDSKASA-N Quinic acid Natural products O[C@H]1CC(O)(C(O)=O)C[C@H](O)C1O AAWZDTNXLSGCEK-ZHQZDSKASA-N 0.000 description 1
IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
239000007868 Raney catalyst Substances 0.000 description 1
NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
229910000564 Raney nickel Inorganic materials 0.000 description 1
208000018569 Respiratory Tract disease Diseases 0.000 description 1
206010039085 Rhinitis allergic Diseases 0.000 description 1
239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 1
KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
208000027515 Tracheal disease Diseases 0.000 description 1
102000006747 Transforming Growth Factor alpha Human genes 0.000 description 1
101800004564 Transforming growth factor alpha Proteins 0.000 description 1
208000026911 Tuberous sclerosis complex Diseases 0.000 description 1
201000006704 Ulcerative Colitis Diseases 0.000 description 1
241000251539 Vertebrata <Metazoa> Species 0.000 description 1
JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
230000002159 abnormal effect Effects 0.000 description 1
KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
230000009471 action Effects 0.000 description 1
125000002252 acyl group Chemical group 0.000 description 1
229940009456 adriamycin Drugs 0.000 description 1
239000000443 aerosol Substances 0.000 description 1
150000001298 alcohols Chemical class 0.000 description 1
229910052783 alkali metal Inorganic materials 0.000 description 1
150000001340 alkali metals Chemical class 0.000 description 1
125000005277 alkyl imino group Chemical group 0.000 description 1
230000000172 allergic effect Effects 0.000 description 1
201000010105 allergic rhinitis Diseases 0.000 description 1
208000006682 alpha 1-Antitrypsin Deficiency Diseases 0.000 description 1
BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
230000004075 alteration Effects 0.000 description 1
229910000147 aluminium phosphate Inorganic materials 0.000 description 1
150000003927 aminopyridines Chemical class 0.000 description 1
238000004458 analytical method Methods 0.000 description 1
239000003242 anti bacterial agent Substances 0.000 description 1
239000002260 anti-inflammatory agent Substances 0.000 description 1
230000003110 anti-inflammatory effect Effects 0.000 description 1
230000000259 anti-tumor effect Effects 0.000 description 1
229940088710 antibiotic agent Drugs 0.000 description 1
239000003125 aqueous solvent Substances 0.000 description 1
235000003704 aspartic acid Nutrition 0.000 description 1
208000006673 asthma Diseases 0.000 description 1
235000013871 bee wax Nutrition 0.000 description 1
239000012166 beeswax Substances 0.000 description 1
125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
230000005540 biological transmission Effects 0.000 description 1
230000037396 body weight Effects 0.000 description 1
201000009267 bronchiectasis Diseases 0.000 description 1
229940124630 bronchodilator Drugs 0.000 description 1
230000001813 broncholytic effect Effects 0.000 description 1
KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
235000011089 carbon dioxide Nutrition 0.000 description 1
239000001768 carboxy methyl cellulose Substances 0.000 description 1
235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
239000008112 carboxymethyl-cellulose Substances 0.000 description 1
239000003054 catalyst Substances 0.000 description 1
238000001516 cell proliferation assay Methods 0.000 description 1
201000001352 cholecystitis Diseases 0.000 description 1
208000007451 chronic bronchitis Diseases 0.000 description 1
230000001684 chronic effect Effects 0.000 description 1
208000037976 chronic inflammation Diseases 0.000 description 1
208000037893 chronic inflammatory disorder Diseases 0.000 description 1
DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
229960004316 cisplatin Drugs 0.000 description 1
238000003776 cleavage reaction Methods 0.000 description 1
239000008119 colloidal silica Substances 0.000 description 1
210000001072 colon Anatomy 0.000 description 1
239000012228 culture supernatant Substances 0.000 description 1
229960004397 cyclophosphamide Drugs 0.000 description 1
230000001419 dependent effect Effects 0.000 description 1
238000010790 dilution Methods 0.000 description 1
239000012895 dilution Substances 0.000 description 1
238000006471 dimerization reaction Methods 0.000 description 1
239000003534 dna topoisomerase inhibitor Substances 0.000 description 1
239000012154 double-distilled water Substances 0.000 description 1
229940079593 drug Drugs 0.000 description 1
230000000694 effects Effects 0.000 description 1
150000002148 esters Chemical class 0.000 description 1
125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
229960005420 etoposide Drugs 0.000 description 1
239000003925 fat Substances 0.000 description 1
239000012894 fetal calf serum Substances 0.000 description 1
238000011049 filling Methods 0.000 description 1
239000007941 film coated tablet Substances 0.000 description 1
235000019634 flavors Nutrition 0.000 description 1
235000013355 food flavoring agent Nutrition 0.000 description 1
238000009472 formulation Methods 0.000 description 1
125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
238000001640 fractional crystallisation Methods 0.000 description 1
239000001530 fumaric acid Substances 0.000 description 1
208000020694 gallbladder disease Diseases 0.000 description 1
230000002496 gastric effect Effects 0.000 description 1
229960001031 glucose Drugs 0.000 description 1
235000001727 glucose Nutrition 0.000 description 1
239000004220 glutamic acid Substances 0.000 description 1
235000013922 glutamic acid Nutrition 0.000 description 1
ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
239000003102 growth factor Substances 0.000 description 1
229940093915 gynecological organic acid Drugs 0.000 description 1
125000005843 halogen group Chemical group 0.000 description 1
210000003958 hematopoietic stem cell Anatomy 0.000 description 1
239000003667 hormone antagonist Substances 0.000 description 1
238000005984 hydrogenation reaction Methods 0.000 description 1
230000007062 hydrolysis Effects 0.000 description 1
238000006460 hydrolysis reaction Methods 0.000 description 1
XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
208000013403 hyperactivity Diseases 0.000 description 1
210000000987 immune system Anatomy 0.000 description 1
208000027866 inflammatory disease Diseases 0.000 description 1
230000002757 inflammatory effect Effects 0.000 description 1
230000004054 inflammatory process Effects 0.000 description 1
229940041682 inhalant solution Drugs 0.000 description 1
230000005764 inhibitory process Effects 0.000 description 1
229940079322 interferon Drugs 0.000 description 1
230000000968 intestinal effect Effects 0.000 description 1
238000007918 intramuscular administration Methods 0.000 description 1
238000007912 intraperitoneal administration Methods 0.000 description 1
238000001990 intravenous administration Methods 0.000 description 1
208000017169 kidney disease Diseases 0.000 description 1
239000004310 lactic acid Substances 0.000 description 1
235000014655 lactic acid Nutrition 0.000 description 1
229960001375 lactose Drugs 0.000 description 1
210000002429 large intestine Anatomy 0.000 description 1
239000010410 layer Substances 0.000 description 1
229960004873 levomenthol Drugs 0.000 description 1
239000003446 ligand Substances 0.000 description 1
239000000314 lubricant Substances 0.000 description 1
229940057948 magnesium stearate Drugs 0.000 description 1
VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
239000011976 maleic acid Substances 0.000 description 1
239000001630 malic acid Substances 0.000 description 1
235000011090 malic acid Nutrition 0.000 description 1
229960002510 mandelic acid Drugs 0.000 description 1
239000000155 melt Substances 0.000 description 1
230000004060 metabolic process Effects 0.000 description 1
230000009401 metastasis Effects 0.000 description 1
229940098779 methanesulfonic acid Drugs 0.000 description 1
UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
239000008108 microcrystalline cellulose Substances 0.000 description 1
235000019813 microcrystalline cellulose Nutrition 0.000 description 1
229940016286 microcrystalline cellulose Drugs 0.000 description 1
239000002480 mineral oil Substances 0.000 description 1
235000010446 mineral oil Nutrition 0.000 description 1
230000000394 mitotic effect Effects 0.000 description 1
230000004899 motility Effects 0.000 description 1
210000003097 mucus Anatomy 0.000 description 1
PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
ILBOHJJGUPQMFE-UHFFFAOYSA-N n-(3-chloro-4-fluorophenyl)-6-nitro-7-(3-piperazin-1-ylpropoxy)quinazolin-4-amine Chemical compound N1=CN=C2C=C(OCCCN3CCNCC3)C([N+](=O)[O-])=CC2=C1NC1=CC=C(F)C(Cl)=C1 ILBOHJJGUPQMFE-UHFFFAOYSA-N 0.000 description 1
GLNHUEHTVIRQJW-UHFFFAOYSA-N n-(3-chloro-4-fluorophenyl)-6-nitro-7-(4-piperazin-1-ylbutoxy)quinazolin-4-amine Chemical compound N1=CN=C2C=C(OCCCCN3CCNCC3)C([N+](=O)[O-])=CC2=C1NC1=CC=C(F)C(Cl)=C1 GLNHUEHTVIRQJW-UHFFFAOYSA-N 0.000 description 1
CPSJFPAWIRCWGP-UHFFFAOYSA-N n-(3-chloro-4-fluorophenyl)-6-nitro-7-[2-(oxan-2-yloxy)ethoxy]quinazolin-4-amine Chemical compound N1=CN=C2C=C(OCCOC3OCCCC3)C([N+](=O)[O-])=CC2=C1NC1=CC=C(F)C(Cl)=C1 CPSJFPAWIRCWGP-UHFFFAOYSA-N 0.000 description 1
XJTDXAFVAVOYOG-UHFFFAOYSA-N n-(3-chloro-4-fluorophenyl)-6-nitro-7-[4-(oxan-2-yloxy)butoxy]quinazolin-4-amine Chemical compound N1=CN=C2C=C(OCCCCOC3OCCCC3)C([N+](=O)[O-])=CC2=C1NC1=CC=C(F)C(Cl)=C1 XJTDXAFVAVOYOG-UHFFFAOYSA-N 0.000 description 1
CJOJDNRJDBWZKM-UHFFFAOYSA-N n-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitroquinazolin-4-amine Chemical compound N1=CN=C2C=C(F)C([N+](=O)[O-])=CC2=C1NC1=CC=C(F)C(Cl)=C1 CJOJDNRJDBWZKM-UHFFFAOYSA-N 0.000 description 1
SQXHXDKOLROMEL-UHFFFAOYSA-N n-[4-(3-chloro-4-fluoroanilino)-7-[4-[4-(5-oxooxolan-3-yl)piperazin-1-yl]butoxy]quinazolin-6-yl]prop-2-enamide Chemical compound C1=C(Cl)C(F)=CC=C1NC1=NC=NC2=CC(OCCCCN3CCN(CC3)C3CC(=O)OC3)=C(NC(=O)C=C)C=C12 SQXHXDKOLROMEL-UHFFFAOYSA-N 0.000 description 1
GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
239000006199 nebulizer Substances 0.000 description 1
230000001613 neoplastic effect Effects 0.000 description 1
201000002648 nephronophthisis Diseases 0.000 description 1
125000000449 nitro group Chemical class [O-][N+](*)=O 0.000 description 1
208000037916 non-allergic rhinitis Diseases 0.000 description 1
150000007523 nucleic acids Chemical class 0.000 description 1
102000039446 nucleic acids Human genes 0.000 description 1
108020004707 nucleic acids Proteins 0.000 description 1
239000003921 oil Substances 0.000 description 1
239000012044 organic layer Substances 0.000 description 1
238000004806 packaging method and process Methods 0.000 description 1
230000036961 partial effect Effects 0.000 description 1
239000000546 pharmaceutical excipient Substances 0.000 description 1
239000012071 phase Substances 0.000 description 1
UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
230000000704 physical effect Effects 0.000 description 1
239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 1
208000015768 polyposis Diseases 0.000 description 1
230000008569 process Effects 0.000 description 1
239000000047 product Substances 0.000 description 1
235000018102 proteins Nutrition 0.000 description 1
102000004169 proteins and genes Human genes 0.000 description 1
108090000623 proteins and genes Proteins 0.000 description 1
208000005069 pulmonary fibrosis Diseases 0.000 description 1
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
102000005962 receptors Human genes 0.000 description 1
108020003175 receptors Proteins 0.000 description 1
238000001953 recrystallisation Methods 0.000 description 1
230000009467 reduction Effects 0.000 description 1
208000023504 respiratory system disease Diseases 0.000 description 1
230000001177 retroviral effect Effects 0.000 description 1
230000007017 scission Effects 0.000 description 1
238000000926 separation method Methods 0.000 description 1
239000000377 silicon dioxide Substances 0.000 description 1
238000009097 single-agent therapy Methods 0.000 description 1
201000009890 sinusitis Diseases 0.000 description 1
229910000029 sodium carbonate Inorganic materials 0.000 description 1
235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
235000009518 sodium iodide Nutrition 0.000 description 1
238000007920 subcutaneous administration Methods 0.000 description 1
HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
230000004083 survival effect Effects 0.000 description 1
229960001603 tamoxifen Drugs 0.000 description 1
ZRUQCWFSQDJUJN-UHFFFAOYSA-N tert-butyl 4-[2-[4-(3-chloro-4-fluoroanilino)-6-nitroquinazolin-7-yl]oxyethyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1CCOC1=CC2=NC=NC(NC=3C=C(Cl)C(F)=CC=3)=C2C=C1[N+]([O-])=O ZRUQCWFSQDJUJN-UHFFFAOYSA-N 0.000 description 1
FQGNHHHORPFCLS-LJQANCHMSA-N tert-butyl 4-[2-[6-nitro-4-[[(1r)-1-phenylethyl]amino]quinazolin-7-yl]oxyethyl]piperazine-1-carboxylate Chemical compound N([C@H](C)C=1C=CC=CC=1)C(C1=CC=2[N+]([O-])=O)=NC=NC1=CC=2OCCN1CCN(C(=O)OC(C)(C)C)CC1 FQGNHHHORPFCLS-LJQANCHMSA-N 0.000 description 1
BQLQXCUGZPTCHX-UHFFFAOYSA-N tert-butyl 4-[3-[4-(3-chloro-4-fluoroanilino)-6-nitroquinazolin-7-yl]oxypropyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1CCCOC1=CC2=NC=NC(NC=3C=C(Cl)C(F)=CC=3)=C2C=C1[N+]([O-])=O BQLQXCUGZPTCHX-UHFFFAOYSA-N 0.000 description 1
229940124597 therapeutic agent Drugs 0.000 description 1
229940044693 topoisomerase inhibitor Drugs 0.000 description 1
239000005051 trimethylchlorosilane Substances 0.000 description 1
VLPFTAMPNXLGLX-UHFFFAOYSA-N trioctanoin Chemical compound CCCCCCCC(=O)OCC(OC(=O)CCCCCCC)COC(=O)CCCCCCC VLPFTAMPNXLGLX-UHFFFAOYSA-N 0.000 description 1
125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
208000009999 tuberous sclerosis Diseases 0.000 description 1
210000003556 vascular endothelial cell Anatomy 0.000 description 1
229960003048 vinblastine Drugs 0.000 description 1
JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
208000006542 von Hippel-Lindau disease Diseases 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems

Landscapes

Health & Medical Sciences (AREA)
Organic Chemistry (AREA)
Chemical & Material Sciences (AREA)
General Health & Medical Sciences (AREA)
Veterinary Medicine (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
General Chemical & Material Sciences (AREA)
Pharmacology & Pharmacy (AREA)
Life Sciences & Earth Sciences (AREA)
Animal Behavior & Ethology (AREA)
Chemical Kinetics & Catalysis (AREA)
Public Health (AREA)
Medicinal Chemistry (AREA)
Engineering & Computer Science (AREA)
Bioinformatics & Cheminformatics (AREA)
Gastroenterology & Hepatology (AREA)
Urology & Nephrology (AREA)
Pulmonology (AREA)
Dermatology (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Plural Heterocyclic Compounds (AREA)

JP2002523885A 2000-08-26 2001-08-18 二環式複素環化合物、これらの化合物を含む医薬組成物、それらの使用及びその生成方法 Pending JP2004507533A (ja)

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
DE10042061A DE10042061A1 (de)	2000-08-26	2000-08-26	Bicyclische Heterocyclen,diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
PCT/EP2001/009535 WO2002018370A1 (fr)	2000-08-26	2001-08-18	Heterocycles bicycliques, medicaments contenant lesdits composes, leur utilisation et procedes permettant de les produire

Publications (1)

Publication Number	Publication Date
JP2004507533A true JP2004507533A (ja)	2004-03-11

Family

ID=7653948

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
JP2002523885A Pending JP2004507533A (ja)	2000-08-26	2001-08-18	二環式複素環化合物、これらの化合物を含む医薬組成物、それらの使用及びその生成方法

Country Status (7)

Country	Link
EP (1)	EP1315716A1 (fr)
JP (1)	JP2004507533A (fr)
AU (1)	AU2001289814A1 (fr)
CA (1)	CA2417042A1 (fr)
DE (1)	DE10042061A1 (fr)
MX (1)	MXPA03001510A (fr)
WO (1)	WO2002018370A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
JP2013528189A (ja) *	2010-06-09	2013-07-08	天津和美生物技術有限公司	シアノキノリン誘導体
JP2013536253A (ja) *	2010-08-30	2013-09-19	山東軒竹医薬科技有限公司	アニリンで置換されたキナゾリン誘導体、その調製方法及びその使用

Families Citing this family (22)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
TW200813014A (en)	2002-03-28	2008-03-16	Astrazeneca Ab	Quinazoline derivatives
US6924285B2 (en)	2002-03-30	2005-08-02	Boehringer Ingelheim Pharma Gmbh & Co.	Bicyclic heterocyclic compounds, pharmaceutical compositions containing these compounds, their use and process for preparing them
US20040044014A1 (en)	2002-04-19	2004-03-04	Boehringer Ingelheim Pharma Gmbh & Co. Kg	Bicyclic heterocycles, pharmaceutical compositions containing these compounds, their use and processes for the preparation thereof
DE10217689A1 (de) *	2002-04-19	2003-11-13	Boehringer Ingelheim Pharma	Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, ihre Verwendung und Verfahren zu ihrer Herstellung
US8309562B2 (en)	2003-07-03	2012-11-13	Myrexis, Inc.	Compounds and therapeutical use thereof
AU2004253967B2 (en)	2003-07-03	2010-02-18	Cytovia, Inc.	4-arylamino-quinazolines as activators of caspases and inducers of apoptosis
WO2006074147A2 (fr)	2005-01-03	2006-07-13	Myriad Genetics, Inc.	Composes et utilisation therapeutique associee
GB0317665D0 (en)	2003-07-29	2003-09-03	Astrazeneca Ab	Qinazoline derivatives
PT1667991E (pt)	2003-09-16	2008-07-14	Astrazeneca Ab	Derivados de quinazolina como inibidores da tirosina cinase
UA83252C2 (uk)	2003-09-19	2008-06-25	Астразенека Аб	Похідні хіназоліну, спосіб їх одержання (варіанти), фармацевтична композиція на їх основі, проміжна сполука
US8258145B2 (en)	2005-01-03	2012-09-04	Myrexis, Inc.	Method of treating brain cancer
US8735410B2 (en)	2005-02-26	2014-05-27	Astrazeneca Ab	Quinazoline derivatives as tyrosine kinase inhibitors
EP1921070A1 (fr)	2006-11-10	2008-05-14	Boehringer Ingelheim Pharma GmbH & Co. KG	heterocycles bicycliques, medicaments á base de ces composes, leur usage et procédé pour leur preparation
AU2008212999A1 (en)	2007-02-06	2008-08-14	Boehringer Ingelheim International Gmbh	Bicyclic heterocycles, drugs containing said compounds, use thereof, and method for production thereof
CA2711582A1 (fr)	2008-02-07	2009-08-13	Boehringer Ingelheim International Gmbh	Heterocycles spirocycliques, formules comportant lesdits composes, leur utilisation et procedes de preparation associes
AU2009247782C1 (en)	2008-05-13	2013-09-19	Astrazeneca Ab	Fumarate salt of 4- (3-chloro-2-fluoroanilino) -7-methoxy-6- { [1- (N-methylcarbamoylmethyl) piperidin- 4-yl] oxy } quinazoline
EP2313397B1 (fr)	2008-08-08	2016-04-20	Boehringer Ingelheim International GmbH	Hétérocycles substitués par cyclohexyloxy, médicament contenant ces liaisons, leur utilisation et leur procédé de fabrication
US8507502B2 (en)	2008-11-10	2013-08-13	National Health Research Institutes	Fused bicyclic and tricyclic pyrimidine compounds as tyrosine kinase inhibitors
KR101317809B1 (ko)	2011-06-07	2013-10-16	한미약품 주식회사	암세포의 성장을 억제하는 아마이드 유도체 및 비금속염 활택제를 포함하는 약학 조성물
KR20140096571A (ko)	2013-01-28	2014-08-06	한미약품 주식회사	1-(4-(4-(3,4-디클로로-2-플루오로페닐아미노)-7-메톡시퀴나졸린-6-일옥시)피페리딘-1-일)프로프-2-엔-1-온의 제조방법
MX2021003517A (es)	2018-09-25	2021-08-16	Black Diamond Therapeutics Inc	Composiciones de inhibidor de tirosina quinasa, metodos de fabricacion y metodos de uso.
JP7649289B2 (ja)	2019-08-15	2025-03-19	ブラックダイアモンドセラピューティクス，インコーポレイティド	アルキニルキナゾリン化合物

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
GB9718972D0 (en) *	1996-09-25	1997-11-12	Zeneca Ltd	Chemical compounds

2000
- 2000-08-26 DE DE10042061A patent/DE10042061A1/de not_active Withdrawn
2001
- 2001-08-18 WO PCT/EP2001/009535 patent/WO2002018370A1/fr not_active Application Discontinuation
- 2001-08-18 MX MXPA03001510A patent/MXPA03001510A/es unknown
- 2001-08-18 CA CA002417042A patent/CA2417042A1/fr not_active Abandoned
- 2001-08-18 JP JP2002523885A patent/JP2004507533A/ja active Pending
- 2001-08-18 EP EP01969610A patent/EP1315716A1/fr not_active Withdrawn
- 2001-08-18 AU AU2001289814A patent/AU2001289814A1/en not_active Abandoned

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
JP2013528189A (ja) *	2010-06-09	2013-07-08	天津和美生物技術有限公司	シアノキノリン誘導体
JP2013536253A (ja) *	2010-08-30	2013-09-19	山東軒竹医薬科技有限公司	アニリンで置換されたキナゾリン誘導体、その調製方法及びその使用
US9730934B2 (en)	2010-08-30	2017-08-15	Xuanzhu Pharma Co., Ltd.	Quinazoline derivatives substituted by aniline, preparation method and use thereof
US10507209B2 (en)	2010-08-30	2019-12-17	Xuanzhu Pharma Co, Ltd.	Quinazoline derivatives substituted by aniline, preparation method and use thereof

Also Published As

Publication number	Publication date
EP1315716A1 (fr)	2003-06-04
CA2417042A1 (fr)	2002-03-07
DE10042061A1 (de)	2002-03-07
AU2001289814A1 (en)	2002-03-13
MXPA03001510A (es)	2003-06-09
WO2002018370A1 (fr)	2002-03-07

Publication	Publication Date	Title
JP4901055B2 (ja)	2012-03-21	二環系ヘテロ環、これらの化合物を含有する医薬組成物、それらの使用及びそれらの調製法
JP3754617B2 (ja)	2006-03-15	二環式複素環化合物、その化合物を含む医薬組成物、及び製法
JP2004507533A (ja)	2004-03-11	二環式複素環化合物、これらの化合物を含む医薬組成物、それらの使用及びその生成方法
JP4834282B2 (ja)	2011-12-14	二環式複素環、それを含む医薬組成物、その使用及びその製造方法
US20020082270A1 (en)	2002-06-27	Aminoquinazolines which inhibit signal transduction mediated by tyrosine kinases
JP3686610B2 (ja)	2005-08-24	二環式複素環化合物、その化合物を含む医薬組成物、使用及び調製方法
US6740651B2 (en)	2004-05-25	Aminoquinazolines which inhibit signal transduction mediated by tyrosine kinases
JP4939716B2 (ja)	2012-05-30	二環式複素環化合物、これらの化合物を含む医薬組成物、それらの使用及びそれらの調製方法
US6627634B2 (en)	2003-09-30	Bicyclic heterocycles, pharmaceutical compositions containing them, their use, and processes for preparing them
JP3751201B2 (ja)	2006-03-01	チロシンキナーゼにより媒介されるシグナル伝達に関する抑制効果を有する４−アミノ−キナゾリン誘導体及びキノリン誘導体
US6617329B2 (en)	2003-09-09	Aminoquinazolines and their use as medicaments
JP2004507538A (ja)	2004-03-11	二環式複素環化合物、これらの化合物を含む薬剤、それらの使用、及びその生成方法
JP2004517048A (ja)	2004-06-10	キナゾリン誘導体、これらの化合物を含む医薬組成物、それらの使用及びそれらの調製方法
US20090203683A1 (en)	2009-08-13	Bicyclic heterocycles, pharmaceutical compositions containing them, their use, and processes for preparing them
JP4527406B2 (ja)	2010-08-18	二環式ヘテロ環化合物、これら化合物を含有する医薬組成物、その使用及びその製造方法
JP2006527176A (ja)	2006-11-30	二環式複素環化合物、該化合物を含む医薬品、その使用と製造方法
JP5377332B2 (ja)	2013-12-25	二環式へテロ環、それらの化合物を含む薬剤、その使用及びその製法
JP2002539214A (ja)	2002-11-19	二環式複素環化合物、その化合物を含む医薬組成物、その使用及び調製方法
JP2004507537A (ja)	2004-03-11	キナゾリン化合物、この化合物を含有する医薬組成物、その使用及びその調製方法
TWI230156B (en)	2005-04-01	Quinazoline compounds with inhibitory activity on signal transduction mediated by tyrosine kinases, pharmaceutical compositions containing these compounds and their use
HK1057557B (en)	2008-10-31	Bicyclic heterocycles, medicaments containing these compounds, their use, and methods for the production thereof