公开(公告)号：US08063046B2

公开(公告)日：2011-11-22

申请号：US12730093

申请日：2010-03-23

Applicant: Hiroshi Koyano ,  Atsushi Suda ,  Kousuke Aso ,  Kihito Hada ,  Miyuki Asai ,  Masami Hasegawa ,  Yasuko Sato

Inventor： Hiroshi Koyano ,  Atsushi Suda ,  Kousuke Aso ,  Kihito Hada ,  Miyuki Asai ,  Masami Hasegawa ,  Yasuko Sato

IPC: A61K31/435 ,  A61K31/415 ,  A61K31/40 ,  A61K31/34 ,  A61K31/17 ,  C07D213/00 ,  C07D233/00 ,  C07D209/00 ,  C07D307/00 ,  C07C239/00

CPC classification number: C07C323/62 ,  C07C233/66 ,  C07C235/46 ,  C07C235/48 ,  C07C235/54 ,  C07C235/64 ,  C07C237/22 ,  C07C237/40 ,  C07C243/38 ,  C07C255/29 ,  C07C255/57 ,  C07C259/10 ,  C07C309/65 ,  C07C323/42 ,  C07C2601/02 ,  C07C2601/08 ,  C07C2601/14 ,  C07C2602/08 ,  C07C2602/10 ,  C07D209/08 ,  C07D213/40 ,  C07D213/56 ,  C07D213/75 ,  C07D215/38 ,  C07D233/64 ,  C07D249/08 ,  C07D277/82 ,  C07D295/155 ,  C07D295/32 ,  C07D307/14 ,  C07D307/52 ,  C07D319/08 ,  C07D333/36

Abstract: Compounds having high angiogenesis inhibiting activity useful as agents for effective treatment and prevention of diseases involving pathologic angiogenesis, e.g. cancer and cancer metastasis, are of formula (II), where A1 is C—X1 or N; Q1 is -A2=A3-, or a heteroatom selected from —O—, —S—, and —N(R10)—; Q2 is -A4=A5-, or a heteroatom selected from —O—, —S—, and —N(R10)—; provided that Q1 and Q2 are not heteroatoms at the same time; A2 is C—X2 or N, A3 is C—X3 or N, A4 is C—X4 or N, and A5 is C—X5 or N; Y is C1-6alkyl, C3-9cycloalkyl, C2-7alkenyl, C2-7alkynyl, C1-6alkoxy, C2-7alkenyloxy, C2-7alkynyloxy, or C1-6alkylthio; Z is a hydrogen atom, hydroxy, C1-6alkyl, C3-9 cycloalkyl, or —NR1R2; and L is selected from the formula:

Abstract translation: 具有高血管生成抑制活性的化合物可用作有效治疗和预防涉及病理性血管发生的疾病的药剂，例如， 癌症和癌症转移，具有式（II），其中A1是C-X1或N; Q1是-A2 = A3-或选自-O - ， - S - 和-N（R10） - 的杂原子。 Q2是-A4 = A5-或选自-O - ， - S - 和-N（R10） - 的杂原子。 条件是Q1和Q2不是同时的杂原子; A2是C-X2或N，A3是C-X3或N，A4是C-X4或N，A5是C-X5或N; Y是C 1-6烷基，C 3-9环烷基，C 2-7烯基，C 2-7炔基，C 1-6烷氧基，C 2-7烯醇基氧基，C 2-7炔基氧基或C 1-6烷硫基; Z是氢原子，羟基，C 1-6烷基，C 3-9环烷基或-NR 1 R 2; L选自下式：

公开(公告)号：US20100179326A1

公开(公告)日：2010-07-15

申请号：US12730093

申请日：2010-03-23

Applicant: Hiroshi KOYANO ,  Atsushi Suda ,  Kousuke Aso ,  Kihito Hada ,  Miyuki Asai ,  Masami Hasegawa ,  Yasuko Sato

Inventor： Hiroshi KOYANO ,  Atsushi Suda ,  Kousuke Aso ,  Kihito Hada ,  Miyuki Asai ,  Masami Hasegawa ,  Yasuko Sato

IPC: C07C233/66 ,  C07D215/38 ,  C07D233/64 ,  C07D209/08 ,  C07D307/16 ,  C07C235/64

CPC classification number: C07C323/62 ,  C07C233/66 ,  C07C235/46 ,  C07C235/48 ,  C07C235/54 ,  C07C235/64 ,  C07C237/22 ,  C07C237/40 ,  C07C243/38 ,  C07C255/29 ,  C07C255/57 ,  C07C259/10 ,  C07C309/65 ,  C07C323/42 ,  C07C2601/02 ,  C07C2601/08 ,  C07C2601/14 ,  C07C2602/08 ,  C07C2602/10 ,  C07D209/08 ,  C07D213/40 ,  C07D213/56 ,  C07D213/75 ,  C07D215/38 ,  C07D233/64 ,  C07D249/08 ,  C07D277/82 ,  C07D295/155 ,  C07D295/32 ,  C07D307/14 ,  C07D307/52 ,  C07D319/08 ,  C07D333/36

Abstract: Compounds having high angiogenesis inhibiting activity useful as agents for effective treatment and prevention of diseases involving pathologic angiogenesis, e.g. cancer and cancer metastasis, are of formula (II), where A1 is C—X1 or N; Q1 is -A2=A3-, or a heteroatom selected from —O—, —S—, and —N(R10)—; Q2 is -A4=A5-, or a heteroatom selected from —O—, —S—, and —N(R10)—; provided that Q1 and Q2 are not heteroatoms at the same time; A2 is C—X2 or N, A3 is C—X3 or N, A4 is C—X4 or N, and A5 is C—X5 or N; Y is C2-6alkyl, C3-9cycloalkyl, C2-7alkenyl, C2-7alkynyl, C2-6alkoxy, C2-7alkenyloxy, C2-7alkynyloxy, or C1-6alkylthio; Z is a hydrogen atom, hydroxy, C1-6alkyl, C3-9cycloalkyl, or —NR1R2; and L is selected from the formula:

Abstract translation: 具有高血管生成抑制活性的化合物可用作有效治疗和预防涉及病理性血管发生的疾病的药剂，例如， 癌症和癌症转移，具有式（II），其中A1是C-X1或N; Q1是-A2 = A3-或选自-O - ， - S - 和-N（R10） - 的杂原子。 Q2是-A4 = A5-或选自-O - ， - S - 和-N（R10） - 的杂原子。 条件是Q1和Q2不是同时的杂原子; A2是C-X2或N，A3是C-X3或N，A4是C-X4或N，A5是C-X5或N; Y是C 2-6烷基，C 3-9环烷基，C 2-7烯基，C 2-7炔基，C 2-6烷氧基，C 2-7烯基氧基，C 2-7炔基氧基或C 1-6烷硫基; Z是氢原子，羟基，C 1-6烷基，C 3-9环烷基或-NR 1 R 2; L选自下式：

公开(公告)号：US07705053B2

公开(公告)日：2010-04-27

申请号：US10584233

申请日：2004-12-27

Applicant: Hiroshi Koyano ,  Atsushi Suda ,  Kousuke Aso ,  Kihito Hada ,  Miyuki Asai ,  Masami Hasegawa ,  Yasuko Sato

Inventor： Hiroshi Koyano ,  Atsushi Suda ,  Kousuke Aso ,  Kihito Hada ,  Miyuki Asai ,  Masami Hasegawa ,  Yasuko Sato

IPC: A61K31/166 ,  C07C233/12

CPC classification number: C07C323/62 ,  C07C233/66 ,  C07C235/46 ,  C07C235/48 ,  C07C235/54 ,  C07C235/64 ,  C07C237/22 ,  C07C237/40 ,  C07C243/38 ,  C07C255/29 ,  C07C255/57 ,  C07C259/10 ,  C07C309/65 ,  C07C323/42 ,  C07C2601/02 ,  C07C2601/08 ,  C07C2601/14 ,  C07C2602/08 ,  C07C2602/10 ,  C07D209/08 ,  C07D213/40 ,  C07D213/56 ,  C07D213/75 ,  C07D215/38 ,  C07D233/64 ,  C07D249/08 ,  C07D277/82 ,  C07D295/155 ,  C07D295/32 ,  C07D307/14 ,  C07D307/52 ,  C07D319/08 ,  C07D333/36

Abstract: To provide compounds which have high angiogenesis inhibiting activity, and are useful as agents for effective treatment and prevention of diseases involving pathologic angiogenesis, for example, cancer and cancer metastasis, methods for producing the compounds, intermediate compounds useful for their production, and pharmaceutical compositions containing these compounds.The present invention provides compounds of formula (II), or prodrugs thereof, or pharmaceutically acceptable salts of the compounds or the prodrugs, and pharmaceuticals, and pharmaceutical compositions containing these compounds: where A1 is C—X1 or N; Q1 is —A2═A3—, or a heteroatom selected from —O—, —S—, and —N(R10)—; Q2 is —A4═A5—, or a heteroatom selected from —O—, —S—, and —N(R10)—; provided that Q1 and Q2 are not heteroatoms at the same time; A2 is C—X2 or N, A3 is C—X3 or N, A4 is C—X4 or N, and A5 is C—X5 or N; Y is C1-6alkyl, C3-9cycloalkyl, C2-7alkenyl, C2-7alkynyl, C1-6alkoxy, C2-7alkenyloxy, C2-7alkynyloxy, or C1-6alkylthio; Z is a hydrogen atom, hydroxy, C1-6alkyl, C3-9cycloalkyl, or —NR1R2; and L is selected from the formula:

Abstract translation: 提供具有高血管生成抑制活性的化合物，并且可用作有效治疗和预防涉及病理血管发生的疾病，例如癌症和癌症转移的药物，用于制备化合物的方法，可用于其制备的中间体化合物和药物组合物 含有这些化合物。 本发明提供式（II）化合物或其前药或化合物或前药的药学上可接受的盐，和药物，以及含有这些化合物的药物组合物：其中A1为C-X1或N; Q1是-A2 = 3A-或选自-O - ， - S - 和-N（R10） - 的杂原子。 Q2是-A4 = A5-或选自-O - ， - S - 和-N（R10） - 的杂原子。 条件是Q1和Q2不是同时的杂原子; A2是C-X2或N，A3是C-X3或N，A4是C-X4或N，A5是C-X5或N; Y是C 1-6烷基，C 3-9环烷基，C 2-7烯基，C 2-7炔基，C 1-6烷氧基，C 2-7烯醇基氧基，C 2-7炔基氧基或C 1-6烷硫基; Z是氢原子，羟基，C 1-6烷基，C 3-9环烷基或-NR 1 R 2; L选自下式：

公开(公告)号：US20070123493A1

公开(公告)日：2007-05-31

申请号：US10584233

申请日：2004-12-27

Applicant: Hiroshi Koyano ,  Atsushi Suda ,  Kousuke Aso ,  Kihito Hada ,  Miyuki Asai ,  Masami Hasegawa ,  Yasuko Sato

Inventor： Hiroshi Koyano ,  Atsushi Suda ,  Kousuke Aso ,  Kihito Hada ,  Miyuki Asai ,  Masami Hasegawa ,  Yasuko Sato

IPC: A61K31/675 ,  A61K31/44 ,  A61K31/277 ,  A61K31/165 ,  C07F9/58

CPC classification number: C07C323/62 ,  C07C233/66 ,  C07C235/46 ,  C07C235/48 ,  C07C235/54 ,  C07C235/64 ,  C07C237/22 ,  C07C237/40 ,  C07C243/38 ,  C07C255/29 ,  C07C255/57 ,  C07C259/10 ,  C07C309/65 ,  C07C323/42 ,  C07C2601/02 ,  C07C2601/08 ,  C07C2601/14 ,  C07C2602/08 ,  C07C2602/10 ,  C07D209/08 ,  C07D213/40 ,  C07D213/56 ,  C07D213/75 ,  C07D215/38 ,  C07D233/64 ,  C07D249/08 ,  C07D277/82 ,  C07D295/155 ,  C07D295/32 ,  C07D307/14 ,  C07D307/52 ,  C07D319/08 ,  C07D333/36

Abstract: To provide compounds which have high angiogenesis inhibiting activity, and are useful as agents for effective treatment and prevention of diseases involving pathologic angiogenesis, for example, cancer and cancer metastasis, methods for producing the compounds, intermediate compounds useful for their production, and pharmaceutical compositions containing these compounds. The present invention provides compounds of formula (II), or prodrugs thereof, or pharmaceutically acceptable salts of the compounds or the prodrugs, and pharmaceuticals, and pharmaceutical compositions containing these compounds: where A1 is C—X1 or N; Q1 is —A2═A3—, or a heteroatom selected from —O—, —S—, and —N(R10)—; Q2 is —A4═A5—, or a heteroatom selected from —O—, —S—, and —N(R10)—; provided that Q1 and Q2 are not heteroatoms at the same time; A2 is C—X2 or N, A3 is C—X3 or N, A4 is C—X4 or N, and A5 is C—X5 or N; Y is C1-6alkyl, C3-9cycloalkyl, C2-7alkenyl, C2-7alkynyl, C1-6alkoxy, C2-7alkenyloxy, C2-7alkynyloxy, or C1-6alkylthio; Z is a hydrogen atom, hydroxy, C1-6alkyl, C3-9cycloalkyl, or —NR1R2; and L is selected from the formula:

Abstract translation: 提供具有高血管生成抑制活性的化合物，并且可用作有效治疗和预防涉及病理血管发生的疾病，例如癌症和癌症转移的药物，用于制备化合物的方法，可用于其制备的中间体化合物和药物组合物 含有这些化合物。 本发明提供式（II）化合物或其前药或化合物或前药的药学上可接受的盐，以及药物，以及含有这些化合物的药物组合物：其中A 1是CX _{1 或N; Q 1是-N 2 - ，N 3 - 或选自-O - ， - S - 和-N（R - ; Q 2是 - 或者选自-O - ， - S - 和-N（R（R））的杂原子， - ; 条件是Q 1和Q 2同时不是杂原子; A 2是N 2，或N 3是N 3，或N，A 4， / SUB>是CX 4或N，A 5是CX 5或N; Y是C 1-6烷基，C 3-9环烷基，C 2-7链烯基，C 2-7环烷基， C 1-6烷基，C 2-7链烯氧基，C 2-7炔氧基或C 1〜 6烷硫基; Z是氢原子，羟基，C 1-6烷基，C 3-9环烷基或-NR 1 R 2 L选自下式：}