Chugai Seiyaku Kabushiki Kaisha

Hiroshi Koyano

Kihito Hada

Atsushi Suda

Masami Hasegawa

Kousuke Aso

Miyuki Asai

Yasuko Sato

Nobuo Shimma

Susumu Komiyama

Kiyoshi Hasegawa

Takuo Tsukuda

Hitoshi Iikura

Tadakatsu Hayase

Yoshiaki Isshiki

Yasunori Kohchi

Masami Kohchi

Ryoichi Saitoh

Toshikazu Yamazaki

Ken-Ichi Kawasaki

Naomi Ono

The present invention provides a novel class of compounds that have the activity of inhibiting HSP90 enzyme and are useful as anti-cancer agents or such, and compounds that are useful as synthetic intermediates thereof. Specifically, the present invention provides compounds represented by the following formula (1), and pharmaceutically acceptable salts thereof: wherein X, R, R, R, R, R, R, R, L, L, and Lare as defined in the specification.

Macrocyclic compound

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 Ais C&#x2014;Xor N; Qis -A=A-, or a heteroatom selected from &#x2014;O&#x2014;, &#x2014;S&#x2014;, and &#x2014;N(R)&#x2014;; Qis -A=A-, or a heteroatom selected from &#x2014;O&#x2014;, &#x2014;S&#x2014;, and &#x2014;N(R)&#x2014;; provided that Qand Qare not heteroatoms at the same time; Ais C&#x2014;Xor N, Ais C&#x2014;Xor N, Ais C&#x2014;Xor N, and Ais C&#x2014;Xor N; Y is Calkyl, Ccycloalkyl, Calkenyl, Calkynyl, Calkoxy, Calkenyloxy, Calkynyloxy, or Calkylthio; Z is a hydrogen atom, hydroxy, Calkyl, Ccycloalkyl, or &#x2014;NRR; and L is selected from the formula: 

Benzamide derivative

The invention provides a process for production of 2,3,4-trifluoro-5-(iodo or bromo)benzoic acid, the process comprising a halogenation step in which direct iodination or bromination of 2,3,4-trifluorobenzoic acid is performed with an iodinating agent or brominating agent in a reaction solvent in the presence of an oxidizing agent. According to the invention, there is provided a process for convenient production of 2,3,4-trifluoro-5-(iodo or bromo)benzoic acid in high yield and high purity in a highly regioselective manner.

Process for production of 2,3,4-trifluoro-5-(iodo or bromo)-benzoic acid

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 Ais C&#x2014;Xor N; Qis &#x2014;A&#x2550;A&#x2014;, or a heteroatom selected from &#x2014;O&#x2014;, &#x2014;S&#x2014;, and &#x2014;N(R)&#x2014;; Qis &#x2014;A&#x2550;A&#x2014;, or a heteroatom selected from &#x2014;O&#x2014;, &#x2014;S&#x2014;, and &#x2014;N(R)&#x2014;; provided that Qand Qare not heteroatoms at the same time; Ais C&#x2014;Xor N, Ais C&#x2014;Xor N, Ais C&#x2014;Xor N, and Ais C&#x2014;Xor N; Y is Calkyl, Ccycloalkyl, Calkenyl, Calkynyl, Calkoxy, Calkenyloxy, Calkynyloxy, or Calkylthio; Z is a hydrogen atom, hydroxy, Calkyl, Ccycloalkyl, or &#x2014;NRR; and L is selected from the formula: 

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Kamakura, Japan

Hiroshi Koyano