Claims for Patent: 7,253,286

Summary for Patent: 7,253,286

Title:	Nitrogen-containing aromatic derivatives
Abstract:	Compounds represented by the following general formula: ##STR00001## [wherein A.sup.g is an optionally substituted 5- to 14-membered heterocyclic group, etc.; X.sup.g is --O--, --S--, etc.; Y.sup.g is an optionally substituted C.sub.6-14 aryl group, an optionally substituted 5- to 14-membered heterocyclic group, etc.; and T.sup.g1 is a group represented by the following general formula: ##STR00002## (wherein E.sup.g is a single bond or --N(R.sup.g2)--, R.sup.g1 and R.sup.g2 each independently represent a hydrogen atom, an optionally substituted C.sub.1-6 alkyl group, etc. and Z.sup.g represents a C.sub.1-8 alkyl group, a C.sub.3-8 alicyclic hydrocarbon group, a C.sub.6-14 aryl group, etc.)], salts thereof or hydrates of the foregoing.
Inventor(s):	Funahashi; Yasuhiro (Nagoya, JP), Tsuruoka; Akihiko (Tsukuba, JP), Matsukura; Masayuki (Tsukuba, JP), Haneda; Toru (Ushiku, JP), Fukuda; Yoshio (Tsukuba, JP), Kamata; Junichi (Tsukuba, JP), Takahashi; Keiko (Ushiku, JP), Matsushima; Tomohiro (Ushiku, JP), Miyazaki; Kazuki (Tsukuba, JP), Nomoto; Ken-ichi (Tsukuba, JP), Watanabe; Tatsuo (Inzai, JP), Obaishi; Hiroshi (Tsukuba, JP), Yamaguchi; Atsumi (Tsukuba, JP), Suzuki; Sachi (Tsuchiura, JP), Nakamura; Katsuji (Tsukuba, JP), Mimura; Fusayo (Tsukuba, JP), Yamamoto; Yuji (Tsukuba, JP), Matsui; Junji (Toride, JP), Matsui; Kenji (Tsukuba, JP), Yoshiba; Takako (Tsukuba, JP), Suzuki; Yasuyuki (Kagamigahara, JP), Arimoto; Itaru (Tsukuba, JP)
Assignee:	Eisai Co., Ltd (Bunkyo-ku, Tokyo, JP)
Application Number:	10/420,466
Patent Claims:	1. A compound represented by the following general formula: ##STR01204## wherein: R.sup.1 and R.sup.2 are each independently a hydrogen atom, an optionally substituted C.sub.1-6 alkyl group, an optionally substituted C.sub.2-6 alkenyl group, an optionally substituted C.sub.2-6 alkynyl group, an optionally substituted C.sub.3-8 alicyclic hydrocarbon group, an optionally substituted C.sub.2-7 acyl group or an optionally substituted C.sub.2-7 alkoxycarbonyl group; Z.sup.12 is a hydrogen atom, an optionally substituted C.sub.1-6 alkyl group, an optionally substituted C.sub.2-6 alkenyl group, an optionally substituted C.sub.2-6 alkynyl group, an optionally substituted C.sub.3-8 alicyclic hydrocarbon group, an optionally substituted C.sub.6-14 aryl group, an optionally substituted 5- to 14-membered heterocyclic group, an optionally substituted 5- to 14-membered aromatic heterocyclic group or a group represented by the formula: ##STR01205## wherein Z.sup.31, Z.sup.33 and Z.sup.34 are each independently a methylene group, --CO--, --NH-- or --O--, and Z.sup.32 is a single bond, a methylene group, --CO--, --NH-- or --O--; and wherein Z.sup.12 is not pyrazolyl; Y.sup.a1 is a group represented by the formula: ##STR01206## wherein W.sup.31 and W.sup.32 are each independently an optionally substituted carbon atom or a nitrogen atom; R.sup.300 and R.sup.301 are each independently a hydrogen atom, a halogen atom, a cyano group, a nitro group, an amino group, an optionally substituted C.sub.1-6 alkyl group, an optionally substituted C.sub.3-8 alicyclic hydrocarbon group, an optionally substituted C.sub.1-6 alkoxy group, an optionally substituted C.sub.2-7 alkoxycarbonyl group, a formyl group, a group represented by the formula ##STR01207## wherein V.sup.300 and V.sup.301 are each independently a hydrogen atom or an optionally substituted C.sub.1-6 alkyl group, or an optionally substituted C.sub.2-7 acyl group; R.sup.a11 is a group represented by the formula --V.sup.a21--V.sup.a22--V.sup.a23, wherein: V.sup.a21 is an optionally substituted C.sub.1-6 alkylene group, a single bond or a group represented by the formula: ##STR01208## V.sup.a22 is a single bond, an oxygen atom, a sulfur atom, --CO--, --SO--, --SO.sub.2--, --CONR.sup.a14--, --SO.sub.2NR.sup.a14--, --NR.sup.a14SO.sub.2--, --NR.sup.a14CO-- or --NR.sup.a14--; wherein R.sup.a14 is a hydrogen atom, an optionally substituted C.sub.1-6 alkyl group or an optionally substituted C.sub.3-8 alicyclic hydrocarbon group; and V.sup.a23 is a hydrogen atom, an optionally substituted C.sub.1-6 alkyl group, an optionally substituted C.sub.2-6 alkenyl group, an optionally substituted C.sub.2-6 alkynyl group, an optionally substituted C.sub.3-8 alicyclic hydrocarbon group, an optionally substituted C.sub.6-14 aryl group, an optionally substituted 5- to 14-membered heterocyclic group or an optionally substituted 5- to 14-membered aromatic heterocyclic group; and R.sup.a12 is a cyano group or a group represented by the formula: ##STR01209## wherein: V.sup.a11 is --CO-- or --SO.sub.2--; and V.sup.a12, V.sup.a13 and V.sup.a14 are each independently a hydrogen atom, an optionally substituted C.sub.1-6 alkyl group, an optionally substituted C.sub.2-6 alkenyl group, an optionally substituted C.sub.2-6 alkynyl group, an optionally substituted C.sub.3-8 alicyclic hydrocarbon group, an optionally substituted C.sub.6-14 aryl group, an optionally substituted 5- to 14-membered heterocyclic group or an optionally substituted 5- to 14-membered aromatic heterocyclic group; with the exception of the following compounds (1) and (2): (1) a compound wherein R.sup.a12 is a group represented by the formula: ##STR01210## wherein: V.sup.a12 and V.sup.a13 are each independently a hydrogen atom, an optionally substituted C.sub.1-6 alkyl group, an optionally substituted C.sub.2-6 alkenyl group, an optionally substituted C.sub.2-6 alkynyl group, an optionally substituted C.sub.3-8 alicyclic hydrocarbon group, an optionally substituted C.sub.6-14 aryl group, an optionally substituted 5- to 14-membered heterocyclic group or an optionally substituted 5- to 14-membered aromatic heterocyclic group; R.sup.1 and R.sup.2 are hydrogen atoms; and Z.sup.12 is a C.sub.6-14 aryl group, a 6- to 14-membered heterocyclic group or a 6- to 14-membered aromatic heterocyclic group; (2) a compound wherein R.sup.a12 is a group selected from the group consisting of the formulae: ##STR01211## wherein: V.sup.a11 is --CO-- or --SO.sub.2--; V.sup.a12, V.sup.a13 and V.sup.a14 are each independently a hydrogen atom, an optionally substituted C.sub.1-6 alkyl group, an optionally substituted C.sub.2-6 alkenyl group, an optionally substituted C.sub.2-6 alkynyl group, an optionally substituted C.sub.3-8 alicyclic hydrocarbon group, an optionally substituted C.sub.6-14 aryl group, an optionally substituted 5- to 14-membered heterocyclic group or an optionally substituted 5- to 14-membered aromatic heterocyclic group; R.sup.2 is a hydrogen atom; and Z.sup.12 is (a) a C.sub.6-14 aryl group, (b) a 5- to 14-membered heterocyclic group, (c) a 5- to 14-membered aromatic heterocyclic group, (d) a C.sub.1.6 alkyl group substituted with a 5- to 10-membered heterocyclic group or a C.sub.5-10 alicyclic hydrocarbon group, (e) a C.sub.2-6 alkenyl group substituted with a 5- to 10-membered heterocyclic group or a C.sub.5-10 alicyclic hydrocarbon group, (f) a C.sub.2-6 alkynyl group substituted with a 5- to 10-membered heterocyclic group or a C.sub.5-10 alicyclic hydrocarbon group, or (g) a C.sub.3-8 alicyclic hydrocarbon group substituted with a 5- to 10-membered heterocyclic group or a C.sub.5-10 alicyclic hydrocarbon group, or a pharmacologically acceptable salt or hydrate thereof. 2. The compound according to claim 1, a pharmacologically acceptable salt or hydrate thereof, wherein R.sup.a11 is a methyl group, a 2-methoxyethyl group or a group represented by the formula: ##STR01212## wherein: R.sup.a53 is a methyl group, a cyclopropylmethyl group or a cyanomethyl group; R.sup.a51 is a hydrogen atom, a fluorine atom or a hydroxyl group; and R.sup.a52 is a 1-pyrrolidinyl group, a 1-piperidinyl group, a 4-morpholinyl group, a dimethylamino group or a diethylamino group. 3. The compound according to either of claims 1 or 2, a pharmacologically acceptable salt or hydrate thereof, wherein Z.sup.12 is a methyl group, an ethyl group, a cyclopropyl group, a 2-thiazolyl group or a 4-fluorophenyl group. 4. The compound according to any one of claims 1 to 3, a pharmacologically acceptable salt or hydrate thereof, wherein Y.sup.a1 is a group represented by the formula: ##STR01213## wherein R.sup.a61 is a hydrogen atom, a methyl group, a trifluoromethyl group, a chlorine atom or a fluorine atom. 5. The compound according to any one of claims 1 to 4, a salt or hydrate thereof, wherein R.sup.a12 is a cyano group or a group represented by the formula --CONHR.sup.a62, wherein R.sup.a62 is a hydrogen atom, an optionally substituted C.sub.1-6 alkyl group, an optionally substituted C.sub.3-8 is alicyclic hydrocarbon group, an optionally substituted C.sub.1-6 alkoxy group or an optionally substituted C.sub.3-8 cycloalkoxy group. 6. The compound according to claim 1, a pharmacologically acceptable salt or hydrate thereof, wherein said compound is a compound selected from: N-(4-(6-cyano-7-(3-(4-pyridyl)propoxy)-4-quinolyl)oxyphenyl)-N'-(4-methox- yphenyl)urea, N-(4-(6-cyano-7-(2-(1,2,3-triazol-2-yl)ethoxy)-4-quinolyl)oxyphenyl)-N'-(- 4-fluorophenyl)urea, N-(4-(6-cyano-7-(2-(1,2,3-triazol-1-yl)ethoxy)-4-quinolyl)oxyphenyl)-N'-(- 4-fluorophenyl)urea, N-(4-(6-cyano-7-(2-(1,2,3-triazol-2-yl)ethoxy)-4-quinolyl)oxyphenyl)-N'-(- 2,4-difluorophenyl)urea, N-(4-(6-cyano-7-(2-(1,2,3-triazol-1-yl)ethoxy)-4-quinolyl)oxyphenyl)-N'-(- 2,4-difluorophenyl)urea, N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N'-(4-fluoropheny- l)urea, N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N'-(1,3-th- iazol-2-yl)urea, N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N'-(3-cyanophenyl- )urea, N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N'-(3-(meth- ylsulfonyl)phenyl)urea, N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N'-cyclopropylure- a, N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)-N'-(1,- 3-thiazol-2-yl)urea, N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)-N'-cyclo- propylurea, N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N'-cyclopropylmet- hylurea, N-(4-(6-cyano-7-(3-(morpholin-4-yl)propoxy)quinolin-4-yloxy)-2-fl- uorophenyl)-N'-(2,4-difluorophenyl)urea, N-(4-(6-cyano-7-(3-(diethylamino)propoxy)-4-quinolyloxy)phenyl)-N'-(4-flu- orophenyl)urea, N-(4-(6-cyano-7-(3-(4-morpholino)propoxy)-4-quinolyl)oxyphenyl)-N'-(4-flu- orophenyl)urea, N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)-N'-(3-(m- ethylsulfonyl)phenyl)urea, N-(4-(6-cyano-7-(3-(diethylamino)propoxy)-4-quinolyl)oxy-2-fluorophenyl)-- N'-(2,4-difluorophenyl)urea, N-(4-(6-cyano-7-(3-(1-(4-ethylpiperazino))propoxy)-4-quinolyl)oxyphenyl)-- N'-(4-methoxyphenyl)urea, N-(4-(6-cyano-7-(3-cyanopropoxy)-4-quinolyl)oxy-2-fluorophenyl)-N'-(2,4-d- ifluorophenyl)urea, N-(4-(6-cyano-7-(2-(methylsulfonyl)ethoxy)-4-quinolyl)oxy-2-fluorophenyl)- -N'-(2,4-difluorophenyl)urea, N-(4-(6-cyano-7-(2-(methylsulfonyl)ethoxy)-4-quinolyl)oxyphenyl)-N'-(4-fl- uorophenyl)urea, N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N'-phenylurea, N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)-N'-(2,4-- difluorophenyl)urea, N-(4-(6-cyano-7-(3-methoxycarbonylpropoxy)-4-quinolyl)oxyphenyl)-N'-(4-me- thoxyphenyl)urea, N-(4-(6-cyano-7-(3-carboxypropoxy)-4-quinolyl)oxyphenyl)-N'-(4-methoxyphe- nyl)urea, N-(4-(6-cyano-7-(2-(2-hydroxyethoxy)ethoxy)-4-quinolyl)oxyphenyl- )-N'-(4-methoxyphenyl)urea, N-(4-(6-cyano-7-(3-(diethylamino)propoxy)-4-quinolyloxy)phenyl)-N'-(3-(me- thylsulfonyl)phenyl)urea, N-(4-(6-cyano-7-(3-(4-morpholino)propoxy)-4-quinolyl)oxyphenyl)-N'-(3-(me- thylsulfonyl)phenyl)urea, N-(4-(6-cyano-7-(3-(diethylamino)propoxy)-4-quinolyloxy)phenyl)-N'-phenyl- urea, N-(4-(6-cyano-7-(3-(4-morpholino)propoxy)-4-quinolyl)oxyphenyl)-N'-p- henylurea, N-(4-(6-cyano-7-(3-(4-morpholino)propoxy)-4-quinolyl)oxyphenyl)- -N'-(2-oxo -1,2,3,4-tetrahydro-6-quinolyl)urea, N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N'-(3-acetamidoph- enyl)urea, N-(4-(6-cyano-7-benzyloxy-4-quinolyl)oxy-2-fluorophenyl)-N'-(2,- 4-difluorophenyl)urea, N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)-N'-(4-fl- uorophenyl)urea, N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)-N'-pheny- lurea, 4-(4-((4-fluoroanilino)carbonyl)aminophenoxy)-7-(2-methoxyethoxy)-6- -quinolinecarboxamide, 7-(2-methoxyethoxy)-4-(4-((1,3-thiazol-2-ylamino)carbonyl)aminophenoxy)-6- -quinolinecarboxamide, 4-(4-((anilinocarbonyl)amino)-3-fluorophenoxy)-7-(2-methoxyethoxy)-6-quin- olinecarboxamide, 4-(4-((4-fluoroanilino)carbonyl)aminophenoxy)-7-methoxy-6-quinolinecarbox- amide, 4-(4-((cyclopropylamino)carbonyl)aminophenoxy)-7-(2-methoxyethoxy)-- 6-quinolinecarboxamide, 7-methoxy-4-(4-((1,3-thiazol-2-ylamino)carbonyl)aminophenoxy)-6-quinoline- carboxamide, 4-(4-((2,4-difluoroanilino)carbonyl)amino-3-fluorophenoxy)-7-methoxy-6-qu- inolinecarboxamide, 4-(4-((cyclopropylamino)carbonyl)aminophenoxy)-7-methoxy-6-quinolinecarbo- xamide, 4-(5-((anilinocarbonyl)amino)-2-pyridyloxy)-7-methoxy-6-quinolinec- arboxamide, 4-(4-(anilinocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, 4-(4-(anilinocarbonyl)aminophenoxy)-7-(2-methoxyethoxy)-6-quinolinecarbox- amide, 4-(4-((2,4-difluoroanilino)carbonyl)amino-3-fluorophenoxy)-7-(2-met- hoxyethoxy)-6-quinolinecarboxamide, 4-(4-((4-fluoroanilino)carbonyl)amino-3-fluorophenoxy)-7-(2-methoxyethoxy- )-6-quinolinecarboxamide, 7-(2-methoxyethoxy)-4-(4-((1,3-thiazol-2-ylamino)carbonyl)amino-3-fluorop- henoxy)-6-quinolinecarboxamide; and 4-(4-((4-fluoroanilino)carbonyl)amino-3-fluorophenoxy)-7-methoxy-6-quinol- inecarboxamide. 7. The compound according to claim 1, a pharmacologically acceptable salt or hydrate thereof, wherein said compound is a compound selected from N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)-N'-(4-fl- uorophenyl)urea, N-(2-chloro-4-((6-cyano-7-((1-methyl-4-piperidyl)methoxy)-4-quinolyl)oxy)- phenyl)-N'-cyclopropylurea, N-(4-((6-cyano-7-(((2R)-3-(diethylamino)-2-hydroxypropyl)oxy)-4-quinolyl)- oxy)phenyl)-N'-(4-fluorophenyl)urea, N-(4-((6-cyano-7-(((2R)-2-hydroxy-3-(1-pyrrolidino)propyl)oxy)-4-quinolyl- )oxy)phenyl)-N'-(4-fluorophenyl)urea, N-{4-[6-cyano-7-(2-hydroxy-3-pyrrolidin-1-yl-propoxy)-quinolin-4-yloxy]-2- -methylphenyl}-N'-cyclopropyl-urea, 4-(4-(4-fluoroanilino)carbonyl)-4-methylaminophenoxy)-7-methoxy-6-quinoli- necarboxamide, 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinoli- necarboxamide, 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-(2methoxy-6-quino- linecarboxamide, N6-cyclopropyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino) phenoxy)-7-methoxy-6-quinolinecarboxamide, N6-(2-methoxyethyl)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phen- oxy)-7-methoxy -6-quinolinecarboxamide, N6-(2-pyridyl)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-- 7-methoxy-6-quinolinecarboxamide, N6-(2-fluoroethyl)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)pheno- xy)-7-methoxy-6-quinolinecarboxamide, N6-methoxy-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-me- thoxy-6-quinolinecarboxamide, N6-methyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-met- hoxy-6-quinolinecarboxamide, and N6-ethyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-meth- oxy-6-quinolinecarboxamide. 8. The compound according to claim 1, a pharmacologically acceptable salt or hydrate thereof, wherein said compound is a compound selected from 4-(3-chloro-4-(cyclopropylaminocarbonyl) aminophenoxy)-7-methoxy-6-quinolinecarboxamide, 4-(3-chloro-4-(ethylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarb- oxamide, N6-methoxy-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)pheno- xy)-7-methoxy-6-quinolinecarboxamide, 4-(3-chloro-4-(methylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecar- boxamide, and N6-methoxy-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-mcthoxy-- 6-quinolinecarboxamide. 9. A pharmaceutical composition comprising a compound according to claim 1, and a pharmaceutically acceptable carrier. 10. A pharmaceutical composition comprising a compound according to claim 1 in an amount effective to inhibit angiogenesis. 11. A compound having the formula 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinoli- necarboxamide, or a pharmacologically acceptable salt or hydrate thereof. 12. A compound having the formula 4-(3-chloro-4-(ethylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarb- oxamide, or a pharmacologically acceptable salt or hydrate thereof. 13. A compound having the formula N6-methoxy-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-me- thoxy-6-quinolinecarboxamide, or a pharmacologically acceptable salt or hydrate thereof. 14. A compound having the formula 4-(3-chloro-4-(methylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecar- boxamide, or a pharmacologically acceptable salt or hydrate thereof. 15. A compound having the formula N6-methoxy-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-methoxy-- 6-quinolinecarboxamide, or a pharmacologically acceptable salt or hydrate thereof.