TW200300677A - A pharmaceutical composition - Google Patents

A pharmaceutical composition Download PDF

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Publication number
TW200300677A
TW200300677A TW091135697A TW91135697A TW200300677A TW 200300677 A TW200300677 A TW 200300677A TW 091135697 A TW091135697 A TW 091135697A TW 91135697 A TW91135697 A TW 91135697A TW 200300677 A TW200300677 A TW 200300677A
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Taiwan
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methyl
pharmaceutical composition
compound
composition according
patent application
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TW091135697A
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Chinese (zh)
Inventor
Tomoyuki Shibata
Shinichi Kurakata
Naomi Shimazaki
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Sankyo Co
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Publication of TW200300677A publication Critical patent/TW200300677A/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The present invention relates to a pharmaceutical composition for therapeutic or prophylactic treating a cancer which comprises, as the active component, a cell proliferation inhibitory thiazoridinedione compound of the formula (1) [wherein, Ar: aryl group (substituted with -NR1R2) etc., R1 and R2 independently represent H, C1-6 alkyl group etc. X : 0 or S, Y: =CH- or N] and a RXR activating agent.

Description

200300677 拐『、聲明事項 □本案係符合專利法第二十條第一項口第一款但書或□第二款但書規 定乏期間，其目期爲_ 0本案B向下歹_家（地區)申請專利，申議日期及案號資料如下: 【格式請依：申請國家（地區）；申請日期；申請案號順序註記】 1. 日本 2001.12.11 特願 2001-376954_ 2. _—_ ]]生張專利1法i二十四儀第一項優i權: 【格式_靑依：受理國家（地區）；日期；案號順序註記】 1.日本 2001.12.11 特願 2001-376954_ □主張專利法第二十五條之一第一項價先謹i 【格式請依：申請日；申請案號順序註記】 2. □主張專利法第二十六條微生物： □國內微生物【格式請依：寄存機構；日期；號碼順序註記】 □國外微生物【格式請依：寄存國名；機構；日期；號碼順序註記】 · ΓΊ熟習該項技術者易於獲得，不須寄存。 玫、明說明 (發明說明應I明：發明所屬之技術領域、先前技術、內容、實施方式及圖式簡單說明） (技術領域） 本發明爲有關以1或2種以上噻唑啶二酮化合物或其 藥理容許鹽與1或2種以上RXR (類視網膜X受體）活 性化作用劑或其藥理容許鹽爲有效成分之癌症預防或 200300677 治療用醫藥組成物。 (先前技術） 噻唑啶二酮化合物已知如下式（A)化合物200300677 Abduction ", matters of declaration □ This case is in conformity with the proviso to the first paragraph of the first paragraph of Article 20 of the Patent Law or □ the second paragraph of the proviso has a short period of time. (Region) Patent application, application date and case number information are as follows: [format please follow: application country (region); application date; application case number sequence notes] 1. Japan 2001.12.11 Special wishes 2001-376954_ 2. _—_ ]] The first superior right of the twenty-four instruments of the Zhangzhang patent 1 method: [format_conversion: receiving country (region); date; case number sequence notes] 1. Japan 2001.12.11 Special wishes 2001-376954_ □ I would like to claim the first price of Article 25 of Article 25 of the Patent Law. [Format please follow: application date; note of application number sequence] 2. □ claim 26 of the Patent Law microorganisms: □ domestic microorganisms [format please According to: Depository institution; date; number sequence notes] □ Foreign microorganisms [format please follow: depository country name; institution; date; number sequence notes] · ΓΊ Those who are familiar with this technology are easy to obtain and do not need to deposit. Description of the invention (The description of the invention should be clear: the technical field to which the invention belongs, the prior art, the content, the embodiments, and the drawings are briefly explained) Its pharmacologically acceptable salt and one or two or more RXR (retinal X receptor) activating agents or its pharmacologically acceptable salt are effective pharmaceutical ingredients for cancer prevention or 200300677 treatment. (Prior art) A thiazolidinedione compound is known as a compound of formula (A)

[式中[Where

Ra爲Ra is

{式中{In the

Rd爲苯基{可有胺基（可有選自Cu烷基、Ch。芳基 或<：7.16芳烷基之基取代）等1〜5個取代丨等，Re爲Η等 ^爲C^6烷基等，D爲氧原子等，Ε爲=CH -等}，。爲Η等， R3爲Rd is phenyl {may have an amine group (may be substituted with a group selected from Cu alkyl, Ch. Aryl or < 7.16 aralkyl), etc. 1 to 5 substitutions 丨 etc., Re is Η etc. ^ is C ^ 6 alkyl, etc., D is an oxygen atom, etc., E is = CH-etc.}. Is Η, etc., R3 is

等，Α爲Ch6伸烷基，Β爲氧原子等]，可當作抗癌劑（参 照例如專利文獻1 )。但在此文獻從無記載、暗示此化合 物與RXR活性化作用劑倂用。 已知RXR活性化作用劑當作抗癌劑（参照例如專利 文獻2及3 ,及非專利文獻1 )。但在這些文獻從無記載、 暗示此R X R活性化作用劑與噻唑啶二酮化合物倂用。 200300677 已知由噻唑啶二酮化合物與R X R活性化作用劑而成 之脂肪肉瘤之治療藥（参照例如專利文獻4 )。具體而言， 噻唑啶二酮化合物有5 - [[ 4 - [ 2 -(甲基-2 -耻啶胺基）-乙氧 基]苯基]甲基]-2,4-噻唑啶二酮（羅地克力達宗1或 BRL49653)、5-[[4-[(3,4 -二氫-6-羥基- 2,5,7,8-四甲基 •2H-1-苯并吡喃-2-基）甲氧基]苯基]甲基-2,4-噻唑啶二 酮（托羅克力達宗）及5-[[4-[2-(5-乙基-2-吡啶基）乙氧 基]苯基]甲基-2,4-噻唑啶二酮（匹歐克力達宗），RXR 活性化作用劑有6 - [ 1 - ( 3，5，5，8，8 -五甲基-5,6，7，8 -四氫萘 ® -2-基）環丙基]菸鹼酸（LG100268)及 6·[1-(3,5,5,8,8-五甲 基-5,6,7,8-四氫萘-2_基）乙烯基]菸鹼酸（1^268)、這些化 合物之倂用當作抗癌劑之效果不充分。 [專利文獻1 ] 特開平1 1 - 1 9 3 2 7 6號公報 [專利文獻2 ] 特開平6-107542號公報 [專利文獻3 ] φ 國際公開9 4 / 1 5 9 0 1號手冊 [專利文獻4 ] 國際公開9 8 /2 9 1 2 0號手冊 [非專利文獻1 ] J.Thibonnet et al，Synlett，l，ppl41-143(1999) (發明之揭示） 本發明之課題爲找出具有更優異之對癌細胞之增殖 抑制效果之化合物之組合而提供有用之細胞增殖抑制 200300677 劑或抗癌劑。 [解決課題之手段] 本發明爲以1種或2種以上如下式（I)噻唑啶二酮化 合物或其藥理容許鹽Etc., A is a Ch6 alkylene group, B is an oxygen atom, etc.], and can be used as an anticancer agent (see, for example, Patent Document 1). However, there is no description in this document, suggesting that this compound is used with an RXR activating agent. RXR activation agents are known as anticancer agents (see, for example, Patent Documents 2 and 3, and Non-Patent Document 1). However, there is no description in these documents, suggesting that the R X R activating agent is used in combination with a thiazolidinedione compound. 200300677 A therapeutic agent for liposarcoma made of a thiazolidinedione compound and an R X R activating agent is known (see, for example, Patent Document 4). Specifically, thiazolidinedione compounds have 5-[[4-[2-(methyl-2 -stigmineamino) -ethoxy] phenyl] methyl] -2,4-thiazolidinedione (Rodiclidine 1 or BRL49653), 5-[[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl • 2H-1-benzopyridine Alan-2-yl) methoxy] phenyl] methyl-2,4-thiazolidinediones (Toroclitazon) and 5-[[4- [2- (5-ethyl-2-pyridyl ) Ethoxy] phenyl] methyl-2,4-thiazolidinediones (pioxelidone), RXR activating agents are 6-[1-(3,5,5,8,8 -pentamethyl) -5,6,7,8-Tetrahydronaphthalene®-2-yl) cyclopropyl] nicotinic acid (LG100268) and 6. [1- (3,5,5,8,8-pentamethyl- 5,6,7,8-tetrahydronaphthalene-2_yl) vinyl] nicotinic acid (1 ^ 268), and the effects of these compounds as anticancer agents are insufficient. [Patent Document 1] Japanese Patent Application Laid-Open No. 1 1-1 9 3 2 7 6 [Patent Literature 2] Japanese Patent Application Laid-Open No. 6-107542 [Patent Literature 3] φ International Publication 9 4/1 5 9 0 Manual No. 1 [Patent Document 4] International Publication 9 8/2 9 1 2 0 [Non-Patent Document 1] J. Thibonnet et al, Synlett, 1, ppl 41-143 (1999) (Disclosure of Invention) The object of the present invention is to find The combination of compounds which are more excellent in suppressing the proliferation of cancer cells provides a useful cell proliferation inhibitory 200300677 agent or anticancer agent. [Means for solving the problem] The present invention relates to one or two or more thiazolidinedione compounds of the formula (I) or a pharmacologically acceptable salt thereof.

[式中A r爲芳基（有至少1個- NVR2取代，又可有1〜4 個選自取代基α之基取代）或雜芳基（有至少1個-NVR2 取代，又可有1〜3個選自取代基α之基取代）， R1及R2爲相同或相異之H、Cm烷基、C6_1Q芳基或C7-16 芳烷基， X爲0或S原子，[Where A r is an aryl group (with at least 1 -NVR2 substitution, and may have 1 to 4 substituents selected from substituent α) or a heteroaryl group (with at least 1 -NVR2 substitution, and may have 1 ~ 3 substituents selected from substituent α), R1 and R2 are the same or different H, Cm alkyl, C6_1Q aryl or C7-16 aralkyl, X is 0 or S atom,

Y爲=CH-或NY is = CH- or N

上述取代基^爲由C 1 _ 6院基、C 1 . 6院氧基、鹵素及幾 基而成之取代基群]及1種或2種以上RXR活性化作用 劑或其藥理容許鹽爲有效成分，同時或隔時分別投與之 癌症預防或治療用醫藥組成物。 本發明之噻唑啶二酮化合物記載於特開平1 1 - 1 9 3 2 7 6 號公報。 本發明之式（I )噻唑啶二酮化合物宜如下列化合物： (1) Ar爲苯基（有至少1個- NRiR2取代，又可有1〜 4個選自取代基α之基取代）或吡啶基（有至少1個 -NfR2取代，又可有1〜3個選自取代基α之基取代）者。 200300677 (2) Ar爲苯基（有1個-NfR2取代，又可有1〜4個 CV6烷基取代）或吡啶基（有1個-NW取代，又可有1 〜3個C6烷基取代）者。 (3 ) Ar爲苯基（有至少1個-NRl2取代，又可有1〜 4個選自取代基α之基取代）者。 (4) Ar爲苯基（有1個-NfR2取代，又可有1〜4個 C ! · 6烷基取代）者。 (5) Ar爲苯基（有1個-NRiR2取代）者。 (6) Ar爲苯基（3位或4位有-NWR2取代者。 (7) Ar爲苯基（3位有-NVR2取代者。 (8 ) Ar爲吡啶基（有1個-NW取代，又可有1〜3 個C i · 6烷基取代）者。 (9 ) Αι*爲毗啶基（有1個-NW取代）者。 (10 ) Ar爲2-吡啶基（有1個-NVR2取代）者。 (1 1 ) Ar爲2-毗啶基（5位有-NW取代）者。 (12 ) R1及R2爲相同或相異之Η、Cm烷基或Cno芳 基者。 (13) R1及R2爲相同或相異之Η或Cm烷基者。 (14) …爲Cm烷基，R2爲Η者。 (15) R1爲Cm烷基，R2爲Η者。 (16 ) R1爲異丙基，R2爲Η者。 (17) X爲〇原子者。 (18) Υ 爲=CH-者。 又本發明之式（I )噻唑啶二酮化合物也宜如下如 200300677The above substituent ^ is a substituent group consisting of C 1 -6 alkoxy, C 1.6 alkoxy, halogen, and several groups] and one or two or more RXR activation agents or pharmacologically acceptable salts thereof are The active ingredient is administered to a pharmaceutical composition for cancer prevention or treatment simultaneously or separately. The thiazolidinedione compound of the present invention is described in Japanese Patent Application Laid-Open Nos. 1 1 to 1 9 3 2 7 6. The thiazolidinedione compound of the formula (I) of the present invention is preferably as follows: (1) Ar is phenyl (with at least 1 -NRiR2 substitution, and may have 1 to 4 substituents selected from substituent α) or Pyridyl (having at least one -NfR2 substitution and optionally 1 to 3 substituents selected from the substituent α). 200300677 (2) Ar is phenyl (with 1 -NfR2 substitution, and 1 to 4 CV6 alkyl substitutions) or pyridyl (with 1 -NW substitution, and 1 to 3 C6 alkyl substitutions) )By. (3) Ar is a phenyl group (having at least one -NRl2 substitution and optionally having 1 to 4 substituents selected from the substituent α). (4) Ar is phenyl (1 -NfR2 substituted, and 1 to 4 C! · 6 alkyl substituted). (5) Ar is phenyl (with 1 -NRiR2 substitution). (6) Ar is phenyl (with -NWR2 substituted at the 3- or 4-position. (7) Ar is phenyl (with -NVR2 substituted at the 3-position. (8) Ar is pyridyl (with 1 -NW substitution, And 1 to 3 C i · 6 alkyl substitutions). (9) A * is pyridinyl (with 1 -NW substitution). (10) Ar is 2-pyridyl (with 1- (NVR2 substituted). (1 1) Ar is 2-pyridinyl (with -NW substituted at the 5-position). (12) R1 and R2 are the same or different fluorene, Cm alkyl, or Cno aryl. 13) R1 and R2 are the same or different fluorene or Cm alkyl. (14) ... are Cm alkyl, R2 is 2. (15) R1 is Cm alkyl, and R2 is Η. (16) R1 Is isopropyl, and R2 is 。. (17) X is 0 atom. (18) Υ is = CH-. Also, the thiazolidinedione compound of the formula (I) of the present invention is preferably as follows: 300300677

[式中爲R1’爲分枝C3.6烷基，R2爲11或0.6烷基]。 本發明之噻唑啶二酮化合物更宜如下如下列化合 物： 5-(4-(6-(3-異丙胺基-苯氧基）-1-甲基-1H-苯并咪唑- 2· 基甲氧基）苄基）噻唑啶-2,4 -二酮， ® 5-(4-(6-(3-(異丙基-甲基-胺基）-苯氧基）-1-甲基-1H-苯并咪唑-2-基甲氧基）苄基）噻唑啶-2,4 -二酮， 5-(4-(6-(3-(乙基-異丙基-胺基）-苯氧基）-1-甲基-1H-苯并咪唑-2-基甲氧基）-苄基）噻唑啶-2,4-二酮， ， 5-(4-(6-(3-異丁胺基-苯氧基）-1-甲基-1H-苯并咪唑- 2-基甲氧基）-苄基）噻唑啶-2,4 -二酮， 5-(4-(6-(3-(異丁基-甲基-胺基）-苯氧基）-1-甲基-1H-苯并咪唑-2-基甲氧基）-苄基）噻唑啶-2,4 -二酮， · 5-(4-(6-(3-(乙基-異丁基·胺基）-苯氧基）-1-甲基-1H-苯并咪唑-2-基甲氧基）-苄基）噻唑啶-2,4-二酮， 5-(4-(6-(3-第二丁胺基-苯氧基）-1-甲基-1H-苯并咪唑 -2 -基甲氧基）-苄基）噻唑啶-2,4 -二酮， 5-(4-(6-(3-(第二丁基-甲基-胺基）-苯氧基）-卜甲基 -1H -苯并咪唑-2-基甲氧基）-苄基）噻唑啶-2,4 -二酮， 5-(4-(6-(3-(第二丁基-乙基-胺基）-苯氧基）-1-甲基 -1H -苯并咪唑-2-基甲氧基）-苄基）噻唑啶-2,4 -二酮， -10- 200300677 5-(4-(6-(3-第三丁胺基-苯氧基）-1-甲基-1H-苯并咪唑 -2 -基甲氧基）-苄基）噻唑啶-2,4-二酮， 5-(4-(6-(3 -二異丙胺基-苯氧基）-1-甲基-1H -苯并咪唑 -2 -基甲氧基）-苄基）噻唑啶-2，4 -二酮， 5-(4-(6-(4 -異丙胺基-苯氧基）-1-甲基-1H-苯并咪唑-2 基甲氧基）-苄基）噻唑啶-2,4 -二酮， 5-(4-(6-(4-(異丙基-甲基-胺基）_苯氧基）-1-甲基-1H-苯并咪唑-2-基甲氧基）-苄基）噻唑啶-2,4-二酮， 5-(4-(6-(4-(乙基-異丙胺基）-苯氧基）-1-甲基-1H-苯并 咪唑·2 -基甲氧基）-苄基）-噻唑啶-2,4 -二酮， 5-(4-(6-(4 -異丁胺基-苯氧基）-1-甲基-1H-苯并咪唑-2 基甲氧基）-苄基）噻唑啶-2,4 -二酮， 5-(4-(6-(4-(異丁基-甲基-胺基）·苯氧基）-1-甲基-1H-苯并咪唑-2-基甲氧基）-苄基）噻唑啶-2,4 -二酮， 5-(4-(6-(4-(乙基-異丁基-胺基）-苯氧基）-1-甲基-1H-苯并咪唑-2-基甲氧基）-苄基）噻唑啶-2,4 -二酮， 5-(4-(6-(4-第二丁胺基-苯氧基）-卜甲基-1H_苯并咪唑 -2 -基甲氧基）-苄基）噻唑啶-2,4 -二酮， 5-(4-(6-(4-(第二丁基-甲基-胺基）-苯氧基）-1-甲基 -1H-苯并咪唑-2·基甲氧基）-苄基）噻唑啶-2,4 -二酮， 5-(4-(6-(4-(第二丁基·乙基-胺基）-苯氧基）-1-甲基 -1H-苯并咪唑-2-基甲氧基）-苄基）噻唑啶-2,4 -二酮， 5-(4-(6-(4-第三丁胺基-苯氧基）-1-甲基-1H-苯并咪唑 -2 -基甲氧基）-苄基）-噻唑啶-2,4 -二酮， 5-(4-(6-(4-二異丙胺基-苯氧基）-卜甲基-1H-苯并咪唑 200300677 -2 -基甲氧基）-苄基）噻唑啶-2,4-二酮， 、 5-(4-(6-(2 -異丙胺基-苯氧基）-1-甲基-1H-苯并咪唑- 2-基甲氧基）-苄基）噻唑啶-2,4 -二酮， 5_(4-(6-(2-(異丙基-甲基-胺基）-苯氧基）-1-甲基-1H-苯并咪唑-2-基甲氧基）-苄基）噻唑啶-2,4-二酮， 5-(4-(6-(2-(乙基-異丙基-胺基）-苯氧基）-1-甲基-1H-苯并咪唑-2-基甲氧基）-苄基）噻唑啶-2,4-二酮， 5-(4-(6-(2 -異丁胺基-苯氧基）-1-甲基-1H-苯并咪唑- 2-基甲氧基）-苄基）噻唑啶-2,4 -二酮， ® 5-(4-(6-(2-(異丁基-甲基-胺基）-苯氧基）-1-甲基-1H-苯并咪唑-2-基甲氧基）-苄基）-噻唑啶-2,4 -二酮， 5-(4-(6-(2-(乙基-異丁基-胺基）-苯氧基）-1·甲基-1H· 苯并咪唑-2-基甲氧基）-苄基）噻唑啶-2，4 -二酮， 5-(4-(6-(2-第二丁胺基-苯氧基）-1-甲基-1H-苯并咪唑 -2 -基甲氧基）-苄基）噻唑啶-2，4·二酮， 5-(4-(6-(2-(第二丁基-甲基-胺基）-苯氧基）-卜甲基 -1H-苯并咪唑-2-基甲氧基）-苄基）噻唑啶-2,4 -二酮， Φ 5-(4-(6-(2-(第二丁基·乙基-胺基）-苯氧基）-1-甲基 -1H-苯并咪唑-2-基甲氧基）·苄基）噻唑啶-2,4·二酮， 5-(4-(6-(2 -第三丁胺基-苯氧基）-1-甲基-1H -苯并咪唑 -2 -基甲氧基）-苄基）噻唑啶-2,4 -二酮， 5-(4-(6-(2 -二異丙胺基-苯氧基）-1-甲基-1H-苯并咪唑 -2 -基甲氧基）-苄基）噻唑啶-2,4 -二酮， 5-(4-(6-(4-胺基- 3,5-二甲苯氧基）-卜甲基- -1H-苯并咪 唑-2 -基甲氧基）-苄基）噻唑啶-2,4 -二酮， •12- 200300677 1-胺基-7-[2-[4-(2,4-二氧噻唑啶-5-基甲基）苯氧甲 基]-1-甲基-1H -苯并咪唑-6-基氧基]萘， 1-胺基- 6- [2-[4-(2,4 -二氧噻唑啶-5-基甲基）苯氧甲 基]-1-甲基-1H -苯并咪唑-6-基氧基]萘， 1-胺基- 5-[2-[4-(2,4-二氧噻唑啶-5-基甲基）苯氧甲 基]-1_甲基-111·苯并咪唑-6-基氧基]萘，或 3-[2-[4-(2,4-二氧噻唑啶-5-基甲基）苯氧甲基]-1-甲基 -1H -苯并咪唑-6-基氧基]苯胺。 其中，特宜爲 1-胺基- 7- [2-[4-(2,4-二氧噻唑啶-5-基甲基）苯氧甲 基]-1-甲基-1H-苯并咪唑-6-基氧基]萘， 1-胺基- 6- [2-[4·(2,4-二氧噻唑啶-5-基甲基）苯氧甲 基]-1-甲基-1Η -苯并咪唑-6-基氧基]萘， 1-胺基- 5-[2-[4-(2,4-二氧噻唑啶-5-基甲基）苯氧甲 基]-1-甲基-1Η -苯并咪唑-6-基氧基]萘， 3-[2-[4-(2,4-二氧噻唑啶-5-基甲基）苯氧甲基]-1-甲基 -1Η-苯并咪唑-6-基氧基]苯胺、 5-(4-(6-(3-異丙胺基-本氧基）-1-甲基-1Η·苯并味哇- 2-基甲氧基）-苄基）噻唑啶-2,4 -二酮，或 5-(4-(6-(4 -胺基-3, 5 -二甲苯氧基）-1-甲基-1Η -苯并咪 唑-2-基甲氧基）-苄基）噻唑啶-2,4-二酮。 本發明之有效成分一之RXR活性化作用劑爲藉與 RXR結合而增強具有視黄酸及視黄酸樣生理活性之化 合物（類視黄酸）之作用之化合物。 本發明之RXR活性化作用劑其代表性者可爲如記載 200300677 於 J.Thibonnet et al，Synlett，l，ppl41-143(1999)、特開平 6 - 1 0 7 5 4 2號公報及W〇9 4 / 1 5 9 0 1號之化合物。 本發明之有效成分一之RXR活性化作用劑其代表性 化合物之構造式如下：[Wherein R1 'is a branched C3.6 alkyl group, and R2 is an 11 or 0.6 alkyl group]. The thiazolidinedione compound of the present invention is more preferably as follows: 5- (4- (6- (3-isopropylamino-phenoxy) -1-methyl-1H-benzimidazole-2.methylmethyl (Oxy) benzyl) thiazolidine-2,4-dione, ® 5- (4- (6- (3- (isopropyl-methyl-amino) -phenoxy) -1-methyl- 1H-benzimidazol-2-ylmethoxy) benzyl) thiazolidine-2,4-dione, 5- (4- (6- (3- (ethyl-isopropyl-amino) -benzene) (Oxy) -1-methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) thiazolidine-2,4-dione, 5- (4- (6- (3-isobutyl Amino-phenoxy) -1-methyl-1H-benzimidazole-2-ylmethoxy) -benzyl) thiazolidine-2,4-dione, 5- (4- (6- (3 -(Isobutyl-methyl-amino) -phenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) thiazolidine-2,4-dione, 5- (4- (6- (3- (ethyl-isobutyl · amino) -phenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy) -benzyl ) Thiazolidine-2,4-dione, 5- (4- (6- (3-second butylamino-phenoxy) -1-methyl-1H-benzimidazole-2 -ylmethoxy ) -Benzyl) thiazolidine-2,4-dione, 5- (4- (6- (3- (second butyl-methyl-amino) -phenoxy)- Methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) thiazolidine-2,4-dione, 5- (4- (6- (3- (second butyl-ethyl-amine ) -Phenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) thiazolidine-2,4-dione, -10- 200300677 5- (4- ( 6- (3-Third-butylamino-phenoxy) -1-methyl-1H-benzimidazole-2-ylmethoxy) -benzyl) thiazolidine-2,4-dione, 5- (4- (6- (3-Diisopropylamino-phenoxy) -1-methyl-1H-benzimidazole-2-ylmethoxy) -benzyl) thiazolidine-2,4-dione , 5- (4- (6- (4-isopropylamino-phenoxy) -1-methyl-1H-benzimidazole-2ylmethoxy) -benzyl) thiazolidine-2,4-di Ketone, 5- (4- (6- (4- (isopropyl-methyl-amino) _phenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy) -benzyl ) Thiazolidine-2,4-dione, 5- (4- (6- (4- (ethyl-isopropylamino) -phenoxy) -1-methyl-1H-benzimidazole · 2- Methoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (6- (4-isobutylamino-phenoxy) -1-methyl-1H-benzo Imidazole-2ylmethoxy) -benzyl) thiazolidine-2,4-dione, 5- (4- (6- (4- (isobutyl-methyl-amino)) benzene (Oxy) -1-methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) thiazolidine-2,4-dione, 5- (4- (6- (4- (ethyl) -Isobutyl-amino) -phenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) thiazolidine-2,4-dione, 5- (4 -(6- (4-Second-butylamino-phenoxy) -p-methyl-1H-benzimidazole-2 -ylmethoxy) -benzyl) thiazolidine-2,4-dione, 5- ( 4- (6- (4- (Second-butyl-methyl-amino) -phenoxy) -1-methyl-1H-benzimidazole-2.ylmethoxy) -benzyl) thiazolidine -2,4-dione, 5- (4- (6- (4- (second butyl · ethyl-amino) -phenoxy) -1-methyl-1H-benzimidazole-2- Methoxy) -benzyl) thiazolidine-2,4-dione, 5- (4- (6- (4-third-butylamino-phenoxy) -1-methyl-1H-benzo Imidazole-2 -ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (6- (4-diisopropylamino-phenoxy) -methyl-1H-benzene Benzimidazole 200300677 -2 -methylmethoxy) -benzyl) thiazolidine-2,4-dione, 5- (4- (6- (2-isopropylamino-phenoxy) -1-methyl -1H-benzimidazole-2-ylmethoxy) -benzyl) thiazolidine-2,4-dione, 5- (4- (6- (2- (isopropyl-methyl -Amino) -phenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) thiazolidine-2,4-dione, 5- (4- (6- (2- (ethyl-isopropyl-amino) -phenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) thiazolidine-2,4-di Ketone, 5- (4- (6- (2-isobutylamino-phenoxy) -1-methyl-1H-benzimidazole-2-ylmethoxy) -benzyl) thiazolidine-2, 4-dione, ® 5- (4- (6- (2- (isobutyl-methyl-amino) -phenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy ) -Benzyl) -thiazolidine-2,4-dione, 5- (4- (6- (2- (ethyl-isobutyl-amino) -phenoxy) -1 · methyl- 1H · benzimidazol-2-ylmethoxy) -benzyl) thiazolidine-2,4-dione, 5- (4- (6- (2-second butylamino-phenoxy) -1 -Methyl-1H-benzimidazole-2 -ylmethoxy) -benzyl) thiazolidine-2,4 · diketone, 5- (4- (6- (2- (second butyl-methyl -Amino) -phenoxy) -bumethyl-1H-benzimidazol-2-ylmethoxy) -benzyl) thiazolidine-2,4-dione, Φ 5- (4- (6- (2 -(Second butyl · ethyl-amino) -phenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy) · benzyl) thiazolidine-2,4 · di , 5- (4- (6- (2-Third-butylamino-phenoxy) -1-methyl-1H-benzimidazole-2-ylmethoxy) -benzyl) thiazolidine-2, 4-dione, 5- (4- (6- (2-diisopropylamino-phenoxy) -1-methyl-1H-benzimidazole-2-ylmethoxy) -benzyl) thiazolidine -2,4-dione, 5- (4- (6- (4-amino- 3,5-xyloxy) -p-methyl- -1H-benzimidazole-2 -ylmethoxy) -benzyl ) Thiazolidine-2,4-dione, • 12- 200300677 1-amino-7- [2- [4- (2,4-dioxothiazol-5-ylmethyl) phenoxymethyl] 1-methyl-1H-benzimidazole-6-yloxy] naphthalene, 1-amino-6- [2- [4- (2,4-dioxothiazol-5-ylmethyl) benzene Oxymethyl] -1-methyl-1H-benzimidazole-6-yloxy] naphthalene, 1-amino-5- [2- [4- (2,4-dioxothiazol-5-yl (Methyl) phenoxymethyl] -1-methyl-111 · benzimidazole-6-yloxy] naphthalene, or 3- [2- [4- (2,4-dioxothiazol-5-yl (Methyl) phenoxymethyl] -1-methyl-1H-benzimidazole-6-yloxy] aniline. Among them, particularly preferred is 1-amino-7- [2- [4- (2,4-dioxothiazol-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazole -6-yloxy] naphthalene, 1-amino-6- [2- [4 · (2,4-dioxothiazol-5-ylmethyl) phenoxymethyl] -1-methyl-1 甲基-Benzimidazole-6-yloxy] naphthalene, 1-amino- 5- [2- [4- (2,4-dioxothiazol-5-ylmethyl) phenoxymethyl] -1- Methyl-1Η-benzimidazole-6-yloxy] naphthalene, 3- [2- [4- (2,4-dioxothiazol-5-ylmethyl) phenoxymethyl] -1-methyl -1 fluorene-benzimidazole-6-yloxy] aniline, 5- (4- (6- (3-isopropylamino-benzyloxy) -1-methyl-1fluorene · benzobenzoyl-2- Methoxy) -benzyl) thiazolidine-2,4-dione, or 5- (4- (6- (4-amino-4,3-xylyloxy) -1-methyl-1Η -Benzimidazol-2-ylmethoxy) -benzyl) thiazolidine-2,4-dione. The RXR activating agent of the active ingredient 1 of the present invention is a compound that enhances the action of a compound (retinoic acid) having retinoic acid and retinoic acid-like physiological activity by combining with RXR. Representative examples of the RXR activating agent of the present invention are described in J. Thibonnet et al, Synlett, 1, ppl 41-143 (1999), Japanese Unexamined Patent Publication No. 6-1 0 7 5 4 2 and WO, as described in 200,300,677. 9 4/1 5 9 0 No. 1 compound. The structural formula of the representative compound of the RXR activation agent of active ingredient 1 of the present invention is as follows:

^co2h^ co2h

9 -順-視黄酸9-cis-retinoic acid

co2h LG100268co2h LG100268

co2hco2h

上述化合物中ATRA爲記載於特表平1 0 - 5 1 1 94 8號公 報，其化合物名爲（E，E，E，E) -3,7 -二甲基·9-[2,6,6-三甲 基-1-環己烯-1-基]-2,4,6,8 -壬四烯酸（全反-視黄酸）。 ATRA就此或其一部分轉變成9-順-視黄酸來作用於 RXR。 9-順-視黄酸爲記載於特開平6 - 1 0 7 5 4 2號公報，其化合 物名爲（Ε，Ζ，Ε，Ε) -3,7 -二甲基- 9- [2,6,6 -三甲基-卜環己 烯-1-基]-2,4,6, 8 -壬四烯酸。 LG100268爲記載於W0 94/15901號，其化合物名爲 6-[1-(3,5,5,8,8-五甲基- 5,6,7,8-四氫萘-2-基）環丙基] 菸鹼酸。 達克列丁爲記載於W〇94/ 1 5 9 0 1號，其化合物名爲 6-[1-(3,5,5,8,8-五甲基- 5,6,7,8-四氫萘-2·基）乙烯基]苯 甲酸。 -14- 200300677 本發明之有效成分之噻唑啶二酮化合物與RXR活性化 作用劑依常法作成鹽，這種鹽也包括在本發明，這種鹽可 爲如鈉、鉀、鋰等鹼金屬鹽，鈣、鎂等鹼土類金屬鹽；鋁 、鐵、鋅、銅、鎳、鈷等金屬鹽；銨鹽等無機鹽；第三辛 胺鹽、二苄胺鹽、嗎啉鹽、葡萄糖胺鹽、苯甘胺酸烷酯 鹽、乙二胺鹽、N -甲基葡萄胺鹽、胍鹽、二乙胺鹽、三 乙胺鹽、二環己胺鹽、Ν，Ν’ -二苄基乙二胺鹽 '氯普 羅卡因鹽、普羅卡因鹽、二乙醇胺鹽、Ν-苄基-Ν-苯乙 胺鹽、哌阱鹽、四甲銨鹽、參（羥甲基）胺基甲烷鹽等 有機鹽等胺鹽；氫氟酸鹽、鹽酸鹽、氫溴酸鹽、氫碘酸鹽 等氫鹵酸鹽、硝酸鹽、過氯酸鹽、硫酸鹽、磷酸鹽等無 機酸鹽；甲磺酸鹽、三氟甲磺酸鹽、乙磺酸鹽等低烷磺 酸鹽；苯磺酸鹽、對甲苯磺酸鹽等芳磺酸鹽；麩胺酸鹽 、天冬胺酸鹽等胺基酸鹽；乙酸鹽、蘋果酸鹽、富馬酸鹽 、丁二酸鹽、檸檬酸鹽、抗壞血酸鹽、酒石酸鹽、草酸 鹽、馬來酸鹽等有機酸鹽；及鳥胺酸鹽、麩胺酸鹽、天 冬胺酸鹽、甘胺酸鹽、離胺酸鹽、精胺酸鹽等胺基酸鹽 ，噻唑啶二酮化合物之鹽宜氫鹵酸鹽或有機酸鹽，尤宜 鹽酸鹽。 本發明之有效成分之噻唑啶二酮化合物與RXR活性 化作用劑在大氣中放置或再結晶，則有吸收水分、吸附水 、成水合物之情形，此等水合物也包括在本發明之鹽。 本發明之有效成分之噻唑啶二酮化合物與R X R活性 化作用劑可吸收其他某種溶劑而形成溶劑合物之情形， 其各別或任意比例混合物均包括在本發明。 -15- 200300677 本發明之有效成分之噻唑啶二酮化合物與RXR活性 化作用劑有種種異構物。例如具有前述式（I)構造之噻唑 啶二酮化合物之噻唑啶環含不對稱碳原子而有光學異 構物之情形。各光學異構物及光學異構物之任意比例之 混合物均包括在本發明。 這種異構物可用各異構物之原料化合物來合成本發 明之化合物或將所合成之本發明之化合物應所望而依 通常分割法或分離法分割而得。 本發明中，同時投與」只要爲能大致同時投與之投與 形態，則無特定望，惟宜以單一組成物投與。 又「隔時分別投與」只要爲能不同時間分別投與之投 與形態，則無特定，可例如先投與噻唑啶二酮化合物或其 藥理容許鹽，次在所定時間後，投與RXR活性化作用劑或 其藥理容許鹽之方法。 又投與噻唑啶二酮化合物或其藥理容許鹽之種類，與 RXR活性化作用劑或其藥理容許鹽之種類共3種以上時， 「同時或隔時分別投與」包括將這些全部同時投與之方 法、各隔時分別投與之方法、將2種以上同時投與而隔 時投與其餘之藥劑之方法或將2種以上隔時投與而其餘 之藥劑同時投與之方法等。 本發明中「癌」乃指肉瘤、癌腫、白血病等，包括纖維 瘤、脂肪肉瘤、骨肉瘤、血管肉瘤、肺癌、胃癌、大腸 癌、乳癌、***癌、腎癌、肝癌、胰癌、食道癌、舌 癌、腦腫瘤、咽頭癌、卵巢癌、急性白血病、慢性白血 病、淋巴腫瘤等。 -16 - 200300677 【發明之實施態樣】 本發明之有效成分之一之式（I)噻唑啶二酮化合物 易依記載於特開平1 1 - 1 9 3 2 7 6號公報之方法製造。 本發明之有效成分之式（I )噻唑啶二酮化合物中，如 下如下式（I ’ ）化合物Among the above compounds, ATRA is described in Japanese Patent Publication No. 10-5 1 1 94 8 and its compound name is (E, E, E, E) -3,7 -dimethyl · 9- [2,6, 6-trimethyl-1-cyclohexen-1-yl] -2,4,6,8-nontetraenoic acid (all trans-retinoic acid). At this point, ATRA is converted into 9-cis-retinoic acid to act on RXR. 9-cis-retinoic acid is described in Japanese Unexamined Patent Publication No. 6-1 0 7 5 4 2 and its compound name is (Ε, Z, Ε, Ε) -3,7 -dimethyl-9- [2, 6,6-trimethyl-bucyclohexen-1-yl] -2,4,6,8-nonaerythenoic acid. LG100268 is described in WO 94/15901, and its compound name is 6- [1- (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene-2-yl) Cyclopropyl] Nicotinic acid. Dacletin is described in WO94 / 1599, and its compound name is 6- [1- (3,5,5,8,8-pentamethyl-5,6,7,8- Tetrahydronaphthalene-2.yl) vinyl] benzoic acid. -14- 200300677 The active ingredient of the present invention, the thiazolidinedione compound and the RXR activating agent are formed into a salt according to the usual method. This salt is also included in the present invention. This salt may be an alkali metal such as sodium, potassium, lithium, etc. Salts, alkaline earth metal salts such as calcium and magnesium; metal salts such as aluminum, iron, zinc, copper, nickel, and cobalt; inorganic salts such as ammonium salts; third octylamine, dibenzylamine, morpholine, and glucosamine salts , Phenylglycine alkyl ester salt, ethylenediamine salt, N-methyl glutamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, Ν, Ν'-dibenzylethyl Diamine salt 'chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl-N-phenethylamine salt, pipera salt, tetramethylammonium salt, ginsyl (hydroxymethyl) aminomethane salt Organic salts, such as amine salts; Hydrofluoride, hydrochloride, hydrobromide, and hydroiodate salts, such as hydrohalides, nitrates, perchlorates, sulfates, and phosphates; Low alkane sulfonates such as sulfonate, triflate, and ethane sulfonate; aromatic sulfonates such as benzene sulfonate and p-toluene sulfonate; amines such as glutamate and aspartate Base salt ; Acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleate and other organic acid salts; and ornithine, glutamate Salts, aspartate, glycine, lysine, arginate, and other amino acid salts. Salts of thiazolidinedione compounds are preferably hydrohalide or organic acid salts, especially hydrochloride. . The thiazolidinedione compound and the RXR activating agent, which are the effective ingredients of the present invention, may be placed in the atmosphere or recrystallized, and may absorb water, adsorb water, and hydrates. These hydrates are also included in the salts of the present invention. . In the case where the thiazolidinedione compound and the R X R activating agent, which are the effective ingredients of the present invention, can absorb some other solvent to form a solvate, their respective or any ratio mixtures are included in the present invention. -15- 200300677 There are various isomers of the thiazolidinedione compound and the RXR activating agent, which are the active ingredients of the present invention. For example, the thiazolidine ring of the thiazolidinedione compound having the structure of the aforementioned formula (I) contains an asymmetric carbon atom and has an optical isomer. Each optical isomer and a mixture of the optical isomers in any ratio are included in the present invention. Such isomers can be synthesized by using the raw material compounds of each isomer to synthesize the compound of the present invention or by dividing the synthesized compound of the present invention according to the usual division method or separation method as desired. In the present invention, "simultaneous administration" has no particular expectation as long as it is a form of administration that can be administered at substantially the same time, but it is advisable to use a single composition. In addition, "individual administration at separate intervals" is not specific as long as it is an administration form that can be administered separately at different times. For example, a thiazolidinedione compound or a pharmacologically acceptable salt thereof can be administered first, and RXR can be administered after a predetermined time. Method for activating an agent or a pharmacologically acceptable salt thereof. When three or more kinds of thiazolidinedione compounds or pharmacologically acceptable salts thereof are administered together with RXR activating agents or pharmacologically acceptable salts thereof, "simultaneous or intermittent administration" includes the simultaneous administration of all of them The method of this method, the method of separate administration at intervals, the method of simultaneous administration of 2 or more types and the remaining medicaments, or the method of simultaneous administration of 2 or more types and the remaining medicaments. In the present invention, "cancer" refers to sarcoma, cancer, leukemia, etc., including fibroma, liposarcoma, osteosarcoma, angiosarcoma, lung cancer, gastric cancer, colorectal cancer, breast cancer, prostate cancer, kidney cancer, liver cancer, pancreatic cancer, and esophageal cancer. , Tongue cancer, brain tumor, pharyngeal cancer, ovarian cancer, acute leukemia, chronic leukemia, lymphoma, etc. -16-200300677 [Embodiments of the invention] The thiazolidinedione compound of the formula (I), which is one of the effective ingredients of the present invention, can be easily produced by the method described in Japanese Patent Application Laid-Open No. 1 1-1 9 3 2 7 6. Among the thiazolidinedione compounds of the formula (I) as the active ingredient of the present invention, the compounds of the formula (I ') are as follows

[式中R1’爲分枝C3-6烷基，R「爲11或Cu烷基]也可 依如下方法製造。 以下中，R1’及R2;同前。 A法[Wherein R1 'is a branched C3-6 alkyl group, and R "is 11 or Cu alkyl group" can also be produced by the following method. In the following, R1' and R2; the same as above. Method A

A1工程 -^A1 Project-^

A2工程 -^A2 Engineering-^

A法爲製造R”爲Cm烷基之化合物（la)之方法。 (A 1工程） A1工程爲將胺（1)烷化來製造胺（2)之工程。通常在惰 性溶劑中將胺（1)有還原劑之存在下與醛反應烷化來製 -17- 200300677 造胺（2 )。 所用胺化合物（1)可仿特開平1 1 - 1 9 3 2 7 6號公報實施例 4 6製造。 所用惰性溶劑只要不影響反應則無特定，可用如乙 醚、異丙醚、四氫呋喃、二鸣烷、二甲氧乙烷、二乙二 醇二甲醚等醚；苯、甲苯等芳族烴，尤宜***、四氫呋喃 等醚。 上述反應使用之還原劑可爲如三乙醯氧基硼氫化鈉 或氰基硼氫化鈉，必要時可加乙酸。 鲁 反應溫度隨原料化合物、試劑而異，通常爲0〜 100oC，宜 10 〜30oC。 反應時間隨原料化合物、試劑、反應溫度等而異， 通常爲3 0分〜1週，宜1〜5小時。 反應終了後，目的化合物依常法回收。例如反應終了 後蒸除溶劑，加不與水混合之溶劑（如乙酸乙酯、二氯 甲烷等）來萃取，以水、飽和食鹽水等洗淨，用無水硫酸 鎂乾燥、蒸除溶劑。所得目的物必要時依常法，如再結 φ 晶、再沈澱、層析來分離精製。 (A2工程） A2工程爲從胺（2)製造胺（la)之工程。通常在惰性溶劑 中將胺（2)有還原劑之存在下與醛或酮反應來製造胺 (la)。可仿A1工程施行。 B法 B法爲製造R”爲Η之化合物（lb )之方法。 -18-Method A is a method for producing a compound (la) in which R "is a Cm alkyl group. (A 1 process) A 1 process is a process for alkylating amine (1) to produce amine (2). Usually, the amine ( 1) Alkylation with aldehydes in the presence of a reducing agent to make -17-200300677 Ammonium (2). The amine compound (1) can be modeled as Japanese Patent Application Laid-Open No. 1 1-1 9 3 2 7 6 Example 4 6 The inert solvent used is not specific as long as it does not affect the reaction, and ethers such as diethyl ether, isopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether, and aromatic hydrocarbons such as benzene and toluene can be used. It is particularly suitable for ethers such as diethyl ether, tetrahydrofuran, etc. The reducing agent used in the above reaction may be, for example, sodium triacetoxyborohydride or sodium cyanoborohydride, and acetic acid may be added if necessary. The reaction temperature varies depending on the raw material compounds and reagents. It is usually 0 ~ 100oC, preferably 10 ~ 30oC. The reaction time varies with the raw material compounds, reagents, reaction temperature, etc. It is usually 30 minutes to 1 week, preferably 1 to 5 hours. After the reaction is completed, the target compound is recovered by ordinary methods. For example, after the reaction is completed, the solvent is distilled off, and a solvent not mixed with water (such as Acid ethyl ester, dichloromethane, etc.) for extraction, washed with water, saturated saline, etc., dried over anhydrous magnesium sulfate, and distilled off the solvent. The obtained object is, if necessary, according to the usual method, such as re-crystallizing, reprecipitating, Chromatographic separation and purification. (A2 process) A2 process is a process for producing amine (la) from amine (2). Usually, amine (2) is reacted with aldehyde or ketone in the presence of a reducing agent in an inert solvent to produce amine. (la). It can be carried out in imitation of the A1 project. Method B and method B are methods for producing a compound (lb) in which R "is rhenium. -18-

200300677 B1工程 -^ B2工程 —— (B 1工程） B 1工程爲將胺（1 )烷化來製造胺（I a )之工程。通常在惰 性溶劑中將胺（1)有還原劑之存在下與醛或酮反應烷化 來製造胺（Ia)，可仿A1工程施行。 (B 2工程） B2工程爲將化合物（lb)烷化來製造化合物（la)之工 程。通常在惰性溶劑中將化合物（lb)有還原劑之存在下 與醛反應來製造胺（la)。可仿A1工程施行。 C法 C法爲與上述A法或B法另途製造化合物（Γ )之 方法。200300677 Project B1-^ Project B2 —— (Project B 1) Project B 1 is a process for alkylating amine (1) to produce amine (I a). Usually, the amine (1) is reacted with an aldehyde or ketone in the presence of a reducing agent in an inert solvent to alkylate it to produce the amine (Ia), which can be performed similarly to the A1 project. (B 2 process) B 2 process is a process of alkylating compound (lb) to produce compound (la). The amine (la) is usually produced by reacting the compound (lb) with an aldehyde in an inert solvent in the presence of a reducing agent. It can be implemented like A1 project. Method C Method C is a method for producing a compound (Γ) separately from the method A or B described above.

nh2 j〇C — CI^^^NBoc (3) 6H3nh2 j〇C — CI ^^^ NBoc (3) 6H3

NBoc CH3 -19- 200300677 〇NBoc CH3 -19- 200300677 〇

C4工程 -^C4 Engineering-^

Cl工程爲將氯體（3)醚化來製造苯醚化合物（4)之工 程。通常在惰性溶劑中將氯體（3)有鹼之存在下與在所望 位置被溴取代之酚反應而得化合物（4)之工程。 所用惰性溶劑只要不影響反應則無特定，可用如N，N -二甲基甲醯胺、N，N -二甲基乙醯胺、六甲基磷醯三胺等 醯胺；***、異丙醚、四氫呋喃、二鸣烷、二甲氧乙烷、 二乙二醇二甲醚等醚；苯、甲苯等芳族烴，尤宜N，N -二 甲基甲醯胺、N，N -二甲基乙醯胺等醯胺。 所用鹼只要不影響化合物之其他部分則無特定，可 用如鋰、鉀或鈉等鹼金屬之碳酸鹽類；鋰、鉀或鈉等鹼 金屬之氫化物類。 反應溫度隨原料化合物、試劑而異，通常爲20〜16(TC， 宜 80〜100oC 〇 反應時間隨原料化合物、試劑、反應溫度等而異，通 -20- 200300677 常爲3 0分〜1週，宜1小時〜1日。 反應終了後，目的化合物依常法回收。例如反應終了 後蒸除溶劑，加不與水混合之溶劑（如乙酸乙酯、二氯 甲烷等）來萃取，以水、飽和食鹽水等洗淨，用無水硫酸 鎂乾燥、蒸除溶劑。所得目的物必要時依常法，如再結 晶、再沈澱、層析來、分離精製。 (C 2工程） C2工程爲將溴體化合物（4)胺化來製造胺化合物（5)之 工程。通常在惰性溶劑中將化合物（4)有觸媒、配體、鹼 之存在下與1級或2級胺反應來製造化合物（5)。 所用惰性溶劑只要不影響反應則無特定，可用如苯、 甲苯等芳族烴；***、異丙醚、四氫呋喃、1,4-二鸣烷、 1,2 -二甲氧乙烷、二乙二醇二甲醚等醚；尤宜如苯、甲苯 等芳族烴。 所用觸媒可爲如乙酸鈀（II )或參（二亞苄丙酮）二鈀 肆（0 )等含鈀化合物。 所用配體可爲如2 -(二第三丁膦）聯苯、2 -(二環己膦） 聯苯等磷化合物。 反應溫度隨原料化合物、試劑而異，通常爲2 0〜 160°C，宜 80 〜100°C。 反應時間隨原料化合物、試劑、反應溫度等而異，通 常爲30分〜1週，宜1小時〜1日。 反應終了後，目的化合物依常法回收。例如反應終了 後蒸除溶劑，加不與水混合之溶劑（如乙酸乙酯、二氯 甲烷等）來萃取，以水、飽和食鹽水等洗淨，用無水硫酸 200300677 鎂乾燥、蒸除溶劑。所得目的物必要時依常法，如再結 晶、再沈澱、層析來分離精製。 (C3工程） C3工程爲將硝基體化合物（5)還原來製造胺化合物（6) 之工程。本反應除用觸媒還原反應或一般硝基還原法之 用金屬及酸之方法之外，還原劑用亞二硫磺酸鈉來施行。 觸媒還原反應時所用惰性溶劑只要不影響反應而能 溶解原料及反應劑則無特定，可用如甲醇、乙醇、正丙 醇、異丙醇、正丁醇、異丁醇、第三丁醇、異戊醇等醇 類；***、異丙醚、四氫呋喃、二曙烷、二甲氧乙烷、 二乙二醇二甲醚等醚類；尤宜甲醇、乙醇等醇類。 使用之觸媒可爲如鈀-碳、鈀-氧化鋁、氯化鈀、氧 化鈾等。 反應温度乃依原料化合物、使用之試劑、溶劑等而異， 通常爲0〜80°C，宜10〜30°C。 反應時間乃依原料化合物、使用之試劑、溶劑、反應 温度等而異，通常爲30分〜1週，宜1小時〜1日。 反應終了後，例如濾除觸媒，蒸除溶劑而得。 用金屬及酸時所用惰性溶劑只要不影響反應而能溶 解原料及反應劑則無特定，可用如甲醇、乙醇、正丙醇、 異丙醇、正丁醇、異丁醇、第三丁醇、異戊醇等醇類； 乙酸等有機羧酸類；水或這些之混液。 使用之金屬可爲鋅、鐵、錫等。 所用之酸可爲乙酸等有機羧酸；鹽酸等礦酸之外，氯化 鈉等。 •11- 200300677 反應温度乃依原料化合物、使用之試劑、溶劑等而異， 通常爲0〜100°C，宜10〜80°C 。 反應時間乃依原料化合物、使用之試劑、溶劑、反應 温度等而異，通常爲30分〜1週，宜1小時〜1日。 反應終了後，目的化合物依常法回收。例如反應終了後 蒸除溶劑，加不與水混合之溶劑（如乙酸乙酯、二氯甲 烷等）來萃取，以水、飽和食鹽水等洗淨，用無水硫酸鎂 乾燥、蒸除溶劑。 所得目的物必要時依常法，如再結晶、再沈澱、層析 來分離精製。 (C 4工程） C4工程爲將胺（6)與羧酸（7 )縮合來製造醯胺（8)之工 程，即在惰性溶劑中，將羧酸（7 )在鹼之存在下與混合 酐化劑反應而得混合酐後，與胺（6)反應來製造醯胺（8)。 所用惰性溶劑只要不影響反應而能溶解原料及反應 劑則無特定，可用如己烷、庚烷、石油英、石油醚等脂肪 族烴類；苯、甲苯、二甲苯等芳香族烴類；氯仿、二氯 甲烷、二氯乙烷、四氯化碳等鹵化烴類；***、異丙醚、 四氫呋喃、二鸣烷、二甲氧乙烷、二乙二醇二甲醚等醚 類；丙酮等酮類；甲醯胺、N，N -二甲基甲醯胺、Ν,Ν -二 甲基乙醯胺、六甲基磷醯三胺等醯胺類；二甲亞礪等亞 楓類、環丁砸等，尤宜***、四氫呋喃等醚類。 所用混合酐化劑可爲氯碳酸乙酯、氯碳酸異丁酯等鹵 碳酸低烷酯；特戊醯氯等烷醯鹵；氰基磺酸二乙酯、氰基 磺酸二苯酯等氰基磺酸二酯類。 -23· 200300677 所用鹼只要不影響化合物之其他部分則無特定，可 用如鋰、鉀或鈉等鹼金屬之碳酸鹽類；鋰、鉀或鈉等鹼 金屬之重碳酸鹽類；甲胺、二甲胺、乙胺、三乙胺、三丁 胺、二異丙基乙胺、N-甲基嗎啉、吡啶、4-(Ν,Ν-二甲胺 基）吡啶、Ν，Ν -二甲苯胺、Ν，Ν -二乙苯胺、1，5 -二吖雙環 [4.3.0]壬-5-烯、1，4 -二吖雙環[2.2·2]辛烷（DABCO)或 1,8-二吖雙環[5.4.0]十一碳-7-烯（DBU)等有機胺類。 製造混合酐之反應温度乃依原料化合物、使用之試 劑、溶劑等而異，通常爲0〜100 °C，宜10〜30 °C。 製造混合酐之反應時間乃依原料化合物、使用之試 劑、溶劑、反應温度等而異，通常爲1 5分〜2日，宜3 0 分〜 1 曰。 混合酐與胺（6 )之反應在情性溶劑中有鹼之存在下 施行，所用鹼及惰性溶劑同製造混合酐之反應所用者。 混合酐與胺（6 )之反應温度乃依原料化合物、使用 之試劑、溶劑等而異，通常爲0〜100°C，宜10〜30°C。 混合酐與胺（6 )之反應之反應時間乃依原料化合物、 使用之試劑、溶劑、反應温度等而異，通常爲30分〜1 週，宜1小時〜1日。 若此反應中用氰基磷酸二酯時，也可在惰性溶劑之存 在下胺（6 )與羧酸（7 )直接反應。 反應終了後，目的化合物依常法回收。例如反應終了後 蒸除溶劑，加不與水混合之溶劑（如乙酸乙酯、二氯甲 烷等）來萃取，以水、飽和食鹽水等洗淨，用無水硫酸鎂 乾燥、蒸除溶劑。所得目的物必要時依常法，如再結晶、 -24- 200300677 再沈澱、層析來分離精製。 (C 5工程） C 5工程爲從苯二胺（8)製造本發明之苯并咪唑化合物 (I)之工程。即在有或無惰性溶劑之存在下苯二胺（8 )與 酸反應來製造化合物（Γ )。 所用惰性溶劑只要不影響反應而能溶解原料及反應 劑則無特定，可用如氯仿、二氯甲烷、1，2 -二氯乙烷、四 氯化碳等鹵化烴類；***、異丙醚、四氫呋喃、1,4 -二鸣 烷、二甲氧乙烷、二乙二醇二甲醚等醚類；甲醇、乙醇、 正丙醇、異丙醇、正丁醇、異丁醇、第三丁醇、異戊醇、 二乙二醇等醇類；水或水或上述溶劑之混液；尤宜二氯 甲烷、1，4 -二鸣烷。 使用之酸通常反應當作酸觸媒使用者則無特定，宜如鹽 酸、氫溴酸、過氯酸、硫酸、磷酸等無機酸；或如乙酸、 甲酸、草酸、甲磺酸、對甲苯磺酸、三氟乙酸等有機酸 等布連史脫酸或三氯化硼、三氟化硼、三溴化硼等路易 士酸，或酸性離子交換樹脂等，尤宜鹽酸、乙酸、三氟乙 酸等。 反應温度乃依原料化合物、使用之試劑、溶劑等而異， 通常爲0〜沸點，宜2 0〜7 0 °C。 反應時間乃依原料化合物、使用之試劑、溶劑、反應 温度等而異，通常爲30分〜2日，宜1小時〜1曰。 反應終了後，目的化合物依常法回收。例如反應終了後 蒸除溶劑，加不與水混合之溶劑（如乙酸乙酯、二氯甲 院等）來萃取，以水、飽和食鹽水等洗淨，用無水硫酸鎂 -25- 200300677 乾燥、蒸除溶劑。所得目的物必要時依常法，如再結晶、 再沈澱、層析來分離精製。 D法 D法爲製造C法中之中間體化合物（5 )之另途製法。 R2’爲Cm烷基之化合物（5a )乃經下述D1〜D3工程， 或D1、D4及D5工程；R”爲Η之化合物（5b)乃經下述 D1及D4工程來製造。The Cl project is a process for producing a phenyl ether compound (4) by etherifying the chlorine (3). The process of obtaining the compound (4) by reacting the chlorine (3) in the presence of a base with a phenol substituted with bromine at a desired position, usually in an inert solvent. The inert solvent used is not specific as long as it does not affect the reaction, such as N, N-dimethylformamide, N, N-dimethylacetamide, hexamethylphosphonium triamine, and other amines; ether, isopropyl Ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether and other ethers; aromatic hydrocarbons such as benzene and toluene, especially N, N -dimethylformamide, N, N -di Methylamine, such as methylacetamide. The base used is not specific as long as it does not affect other parts of the compound, and alkali metal carbonates such as lithium, potassium, or sodium; and hydrides of alkali metals such as lithium, potassium, or sodium can be used. The reaction temperature varies depending on the raw material compounds and reagents, and is usually 20 to 16 (TC, preferably 80 to 100oC). The reaction time varies depending on the raw material compounds, reagents, reaction temperature, etc., and -20-200300677 is usually 30 minutes to 1 week. It is preferably 1 hour to 1 day. After the reaction is completed, the target compound is recovered according to the usual method. For example, after the reaction, the solvent is distilled off, and a solvent (such as ethyl acetate, methylene chloride, etc.) that is not mixed with water is used for extraction, and water is used. Wash with saturated brine, dry with anhydrous magnesium sulfate, and evaporate the solvent. If necessary, obtain the desired product according to the usual methods, such as recrystallization, reprecipitation, chromatography, separation and purification. (C 2 project) The C 2 project is to Process for the amination of bromine compound (4) to produce amine compound (5). Generally, compound (4) is reacted with a class 1 or 2 amine in the presence of a catalyst, ligand, or base in an inert solvent to produce a compound (5). The inert solvent used is not specific as long as it does not affect the reaction, and aromatic hydrocarbons such as benzene and toluene can be used; diethyl ether, isopropyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane , Diethylene glycol dimethyl ether, etc .; especially suitable for benzene, toluene, etc. The catalyst used may be a palladium-containing compound such as palladium (II) acetate or di (benzylideneacetone) dipalladium (0). The ligand used may be 2- (di-tertiary butylphosphine) biphenyl , 2-(dicyclohexylphosphine) and other phosphorus compounds such as biphenyl. The reaction temperature varies with the raw material compounds and reagents, usually 20 ~ 160 ° C, preferably 80 ~ 100 ° C. The reaction time varies with the raw material compounds, reagents, and reactions. The temperature varies, usually 30 minutes to 1 week, preferably 1 hour to 1 day. After the reaction is completed, the target compound is recovered according to the usual method. For example, after the reaction, the solvent is distilled off, and a solvent not mixed with water (such as ethyl acetate) is added. Ester, dichloromethane, etc.) for extraction, washed with water, saturated saline, etc., dried over anhydrous sulfuric acid 200300677 magnesium, and evaporated off the solvent. The target object obtained is necessary according to ordinary methods, such as recrystallization, reprecipitation, and chromatography. Isolation and purification. (C3 project) The C3 project is a process for reducing the nitro compound (5) to produce an amine compound (6). In addition to the reaction using a catalyst reduction reaction or a general nitro reduction method using a metal and an acid, In addition, the reducing agent is implemented using sodium disulfite. The inert solvent used in the original reaction is not specific as long as it can dissolve the raw materials and reagents without affecting the reaction. Examples include methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tertiary butanol, and isopentyl. Alcohols such as alcohols; ethers such as diethyl ether, isopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; alcohols such as methanol and ethanol are particularly suitable. The catalyst used may be such as Palladium-carbon, palladium-alumina, palladium chloride, uranium oxide, etc. The reaction temperature varies depending on the raw material compounds, reagents, solvents, etc., which is usually 0 ~ 80 ° C, preferably 10 ~ 30 ° C. The reaction time depends on The raw material compound, the reagents used, the solvent, the reaction temperature, etc. vary, but it is usually 30 minutes to 1 week, preferably 1 hour to 1 day. After the reaction is completed, for example, the catalyst is filtered off, and the solvent is distilled off. The inert solvent used when using metals and acids is not specific as long as it can dissolve the raw materials and reagents without affecting the reaction, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, third butanol, Alcohols such as isoamyl alcohol; organic carboxylic acids such as acetic acid; water or a mixture of these. The metal used may be zinc, iron, tin, or the like. The acid used may be an organic carboxylic acid such as acetic acid; in addition to mineral acids such as hydrochloric acid, sodium chloride and the like. • 11- 200300677 The reaction temperature varies depending on the raw material compounds, reagents used, solvents, etc., usually 0 ~ 100 ° C, preferably 10 ~ 80 ° C. The reaction time varies depending on the raw material compound, the reagents used, the solvent, the reaction temperature, etc. It is usually 30 minutes to 1 week, and preferably 1 hour to 1 day. After the reaction is completed, the target compound is recovered according to a usual method. For example, after the reaction is completed, the solvent is distilled off, and a solvent not mixed with water (such as ethyl acetate, methylene chloride, etc.) is added for extraction, washed with water, saturated saline, etc., dried over anhydrous magnesium sulfate, and the solvent is distilled off. If necessary, the obtained object is separated and purified according to ordinary methods, such as recrystallization, reprecipitation, and chromatography. (C 4 Project) C 4 Project is the process of condensing amine (6) with carboxylic acid (7) to produce amidine (8), that is, in an inert solvent, carboxylic acid (7) and mixed anhydride in the presence of a base After reacting with a chemical agent to obtain a mixed anhydride, it is reacted with an amine (6) to produce amidine (8). The inert solvent used is not specific as long as it can dissolve the raw materials and reagents without affecting the reaction. Aliphatic hydrocarbons such as hexane, heptane, petroleum spirit, and petroleum ether can be used; aromatic hydrocarbons such as benzene, toluene, and xylene; chloroform , Methylene chloride, dichloroethane, carbon tetrachloride and other halogenated hydrocarbons; ether, isopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether and other ethers; acetone, etc. Ketones; methylamine, N, N-dimethylformamide, Ν, Ν-dimethylacetamide, hexamethylphosphonium triamine, and other amines; dimethylamine, etc. Cyclobutadiene and the like, especially ethers such as ether and tetrahydrofuran. The mixed anhydride used may be low alkyl halides such as ethyl chlorocarbonate and isobutyl chlorocarbonate; alkyl halides such as pentamidine chloride; cyanide such as diethyl cyanosulfonate and diphenyl cyanosulfonate Sulfonic acid diesters. -23 · 200300677 The base used is not specific as long as it does not affect other parts of the compound, and alkali carbonates such as lithium, potassium or sodium; bicarbonates of alkali metals such as lithium, potassium or sodium; methylamine, diamine Methylamine, ethylamine, triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethyl Aniline, N, N-diethylaniline, 1,5-diazinebicyclo [4.3.0] non-5-ene, 1,4-diazinebicyclo [2.2 · 2] octane (DABCO) or 1,8- Diazine bicyclic [5.4.0] undecyl-7-ene (DBU) and other organic amines. The reaction temperature for the production of mixed anhydride varies depending on the raw material compound, the reagent used, the solvent, etc., and is usually 0 to 100 ° C, preferably 10 to 30 ° C. The reaction time for preparing mixed anhydride varies depending on the raw material compound, the reagent used, the solvent, and the reaction temperature, etc. It is usually 15 minutes to 2 days, preferably 30 minutes to 1 day. The reaction between the mixed anhydride and the amine (6) is carried out in the presence of a base in an emotional solvent, and the base and the inert solvent used are the same as those used in the reaction for producing the mixed anhydride. The reaction temperature of the mixed anhydride and amine (6) varies depending on the raw material compound, the reagents used, the solvent, etc., and is usually 0 ~ 100 ° C, preferably 10 ~ 30 ° C. The reaction time of the reaction between the mixed anhydride and the amine (6) varies depending on the raw material compound, the reagents used, the solvent, the reaction temperature, etc., and is usually 30 minutes to 1 week, preferably 1 hour to 1 day. When a cyanophosphate diester is used in this reaction, the amine (6) and the carboxylic acid (7) can be reacted directly in the presence of an inert solvent. After the reaction is completed, the target compound is recovered according to a usual method. For example, after the reaction is completed, the solvent is distilled off, and a solvent not mixed with water (such as ethyl acetate, methylene chloride, etc.) is added for extraction, washed with water, saturated saline, etc., dried over anhydrous magnesium sulfate, and the solvent is evaporated. If necessary, the obtained object is isolated and purified according to ordinary methods, such as recrystallization, -24-200300677, and re-precipitation. (C 5 process) The C 5 process is a process for producing the benzimidazole compound (I) of the present invention from phenylenediamine (8). That is, phenylenediamine (8) is reacted with an acid in the presence or absence of an inert solvent to produce a compound (Γ). The inert solvent used is not specific as long as it can dissolve the raw materials and reagents without affecting the reaction. Halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, and carbon tetrachloride can be used; ether, isopropyl ether, Ethers such as tetrahydrofuran, 1,4-dioxane, dimethoxyethane, and diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, and tert-butane Alcohols, alcohols such as isoamyl alcohol, diethylene glycol; water or water or a mixture of the above solvents; especially dichloromethane and 1,4-dioxane. The acid used usually reacts as an acid catalyst, but the user is not specific. It is suitable for inorganic acids such as hydrochloric acid, hydrobromic acid, perchloric acid, sulfuric acid, phosphoric acid; Organic acids such as acids, trifluoroacetic acid, etc. Bronsted acid, or Lewis acids such as boron trichloride, boron trifluoride, boron tribromide, or acidic ion exchange resins, especially hydrochloric acid, acetic acid, and trifluoroacetic acid Wait. The reaction temperature varies depending on the raw material compounds, reagents used, solvents, etc., and is usually 0 ~ boiling point, preferably 20 ~ 70 ° C. The reaction time varies depending on the raw material compound, the reagents used, the solvent, the reaction temperature, etc. It is usually 30 minutes to 2 days, preferably 1 hour to 1 day. After the reaction is completed, the target compound is recovered according to a usual method. For example, after the reaction is completed, the solvent is distilled off, and a solvent that is not mixed with water (such as ethyl acetate, dichloromethane, etc.) is added for extraction, washed with water, saturated saline, etc., dried over anhydrous magnesium sulfate-25- 200300677, The solvent was distilled off. The obtained target substance is separated and purified according to ordinary methods such as recrystallization, reprecipitation and chromatography if necessary. Method D Method D is an alternative method for producing the intermediate compound (5) in Method C. The compound (5a) in which R2 'is a Cm alkyl group is manufactured through the following D1 to D3 processes, or D1, D4, and D5 processes; the compound (5b) in which R "is fluorene is manufactured through the following D1 and D4 processes.

R2，R1，N-r-R2, R1, N-r-

(D 1工程）醚化 D1工程爲從氯體（3)製造苯醚化合物（9)之工程。通常 在惰性溶劑中將氯體（3)有鹼之存在下與所望位置被胺 基取代之酚反應來製造化合物（9)，可仿C1工程施行。 (D2工程） D2工程爲將化合物（9)烷化來製造胺（10)之工程。通常 -26- 200300677 在惰性溶劑中將胺（9 )有還原劑之存在下與所望醛反應 來製造胺（1 0)。可仿A 1工程施行。 (D 3工程） D 3工程爲將胺（1 0)烷化來製造胺（5 a )之工程。通常在 惰性溶劑中將胺（1 0)有還原劑之存在下與醛或酮反應來 製造胺化合物（5a)，可仿A1工程施行。 (D 4工程） D4工程爲將胺（9)烷化來製造胺化合物（5b)之工程。通 常在惰性溶劑中將胺（9)有還原劑之存在下與醛或酮反 應來製造胺（5 b)。可仿A 1工程施行。 (D5工程） D5工程爲將胺化合物（5b)再烷化來製造胺化合物（5a) 之工程。通常在惰性溶劑中將胺化合物（5 a)有還原劑之 存在下與醛反應來製造胺化合物（5 b )，可仿A 1工程施 行。 E法 E法爲與上述C法或D法另途製造C法中之中間體化 合物（5 )之方法。(D 1 process) Etherification The D 1 process is a process for producing a phenyl ether compound (9) from a chlorine body (3). The compound (9) is usually produced by reacting the chlorine (3) in the presence of a base with a phenol substituted with an amine group at a desired position in an inert solvent, which can be performed in the same manner as the C1 process. (D2 process) The D2 process is a process for alkylating compound (9) to produce amine (10). Usually -26- 200300677 makes the amine (10) by reacting the amine (9) with a reducing agent in the presence of a reducing agent in an inert solvent. Can be implemented in imitation of A 1 project. (D 3 process) The D 3 process is a process of alkylating amine (1 0) to produce amine (5 a). Usually, the amine (10) is reacted with an aldehyde or ketone in the presence of a reducing agent in an inert solvent to produce the amine compound (5a), which can be performed similarly to the A1 process. (D 4 process) The D 4 process is a process in which an amine (9) is alkylated to produce an amine compound (5b). The amine (5) is usually produced by reacting the amine (9) with a reducing agent in the presence of a reducing agent in an inert solvent. Can be implemented in imitation of A 1 project. (D5 process) The D5 process is a process for realkylating the amine compound (5b) to produce the amine compound (5a). The amine compound (5a) is usually reacted with an aldehyde in the presence of a reducing agent in an inert solvent to produce the amine compound (5b). Method E The method E is a method for producing the intermediate compound (5) in the method C separately from the method C or the method D described above.

Br-Br-

(11)(11)

E1：E：^ R2，RrN-^ OTBS 、〇TBS E2工程 -►- r2，r1，n|-E1: E: ^ R2, RrN- ^ OTBS, 〇TBS E2 Engineering -►- r2, r1, n |-

(13)(13)

OH (12)OH (12)

(13)(13)

R2R1，N-t- ii + 、〇H ⑶ N〇2 NBoc CH, E3工y r2，ri，n-^R2R1, N-t- ii +, 〇H ⑶ No 〇2 NBoc CH, E3 y r2, ri, n- ^

(5)(5)

0 3 B H NIC (El工程） -27- 2003006770 3 B H NIC (El Project) -27- 200300677

El工程爲將溴體（1 1)胺化來製造胺之化合物（12)之工 程。通常在惰性溶劑中將溴體（η)在觸媒、配體及鹼之 存在下與1級或2級胺反應而得化合物（1 2)之工程，可仿 C 2工程施行。 (Ε 2工程） Ε2工程爲將矽烷基醚化合物（12)脫矽烷基化來製造 酚（1 3 )之工程。通常在惰性溶劑中酚化合物（1 2 )與氟化 物反應而得酚（1 3 )之工程。 所用惰性溶劑只要不影響反應則無特定，可用如氯 仿、二氯甲烷、1，2 -二氯乙烷、四氯化碳等鹵化烴類；乙 醚、異丙醚、四氫呋喃、1，4-二鸣烷、二甲氧乙烷、二 乙二醇二甲醚等醚·類；Ν,Ν-二甲基甲醯胺、Ν，Ν-二甲基 乙醯胺、六甲基磷醯三胺等醯胺；水；尤宜四氫呋喃、1，4-二鸣烷等醚。 所用氟化物可用如氟化鉀、氟化四正丁基銨等。 反應温度乃依原料化合物、使用之試劑、溶劑等而異， 通常爲0〜10(TC，宜10〜30 °C。 反應時間乃依原料化合物、使用之試劑、溶劑、反應 温度等而異，通常爲15分〜2日，宜30分〜1曰。 反應終了後，目的化合物依常法回收。例如反應終了後 蒸除溶劑，加不與水混合之溶劑（如乙酸乙酯、二氯甲 烷等）來萃取，以水、飽和食鹽水等洗淨，用無水硫酸鎂 乾燥、蒸除溶劑。所得目的物必要時依常法，如再結晶、 再沈澱、層析來分離精製。 (E 3工程） 200300677 E3工程爲將酚（13)醚化來製造苯醚化合物（5)之工 程。通常在惰性溶劑中將酚（1 3)在鹼之存在下與氯體（3 ) 反應而得苯醚（5)之工程，可仿C1工程施行。 本發明之有效成分中，RXR活性化作用劑易依例如記 載於；i.Thibonnet et al，Synlett，l，ppl41-143(1999)、特開 平6-107542號公報及W〇94/15901號之方法製造。例 如，ATRA 可依記載於 J.Thibonnet et al，Synlett，l， p p 1 4 1 - 1 4 3 ( 1 9 9 9 )之方法，9 -順-視黄酸可依 Μ . F · B 0 e h m e t al，J.Med.Chem·，37，pp408 -4 1 4( 1 994)之方法，LG 1 0 0 2 6 8 可依W〇94/ 1 5 90 1號之方法，及達克列丁可依記載於WG 9 4 / 1 5 9 0 1號之方法分別製造。 本發明之醫藥組成物之有效成分之噻_ D定二酮化合 物或其藥理容許鹽，及RXR活性化作用劑或其藥理容許 鹽可調製成各單獨分別單位投與形態或混合成物理上 單一投與形態。 將本發明之醫藥組成物當作前述疾病之預防藥或治 療藥時，本發明之醫藥組成物之有效成分之噻唑啶二酮 化合物或其藥理容許鹽，及RXR活性化作用劑或其藥理 容許鹽各別就此，或混合適當藥理容許賦形劑、稀釋劑而 以錠、膠囊、顆粒、散、糖漿等口服或以注射劑、坐劑 等非經口投與。 這些製劑可加混合適當藥理容許之賦形劑、滑劑、結 合劑、崩壞劑、安定劑、矯味劑、稀釋劑等添加劑調製 之製劑投與。 賦形劑如乳糖、白糖、蔔萄糖、甘露糖、山梨糖等 -29- 200300677 糖衍生物；玉米澱粉、馬鈴薯澱粉、澱粉、糊精、羧甲 基澱粉等澱粉衍生物；結晶纖維素、低取代度羥丙基纖 維素、羥丙基甲基纖維素、羧甲基纖維素、羧甲基鈣纖 維素等纖維素衍生物；***膠；聚葡萄糖；聚三葡萄糖 等有機賦形劑；輕質矽酐、合成矽酸鋁、矽酸鈣、偏矽酸 鋁鎂等矽等衍生物；磷酸氫鈣等磷酸鹽；碳酸鈣、硫酸 鈣等無機賦形劑。 滑劑如硬脂酸、硬脂酸鈣、硬脂酸鎂等硬脂酸金屬鹽； 滑石；膠狀矽石；蜂膠、鯨鱲等蠟；硼酸；硬酸鈉等硫 酸鹽；乙二醇；富馬酸；苯甲酸鈉；D L白胺酸；脂肪酸鈉鹽； 十二基硫酸鈉鹽；十二基硫酸鈉、十二基硫酸鎂等十二 基硫酸鹽；矽酐、矽酸水合物等矽酸類；及上述澱粉衍生 物。 結合劑如羥丙基纖維素、羥甲基纖維素、聚乙烯吡咯 啶酮、聚乙二醇及前述賦形劑等。 崩壞劑如低取代羥丙基纖維素、羧甲基纖維素、羧甲 基纖維素鈣、內部架橋羧甲基纖維素鈉等纖維素衍生物； 羧甲基澱粉、羧甲基澱粉鈉、架橋聚乙烯基吡咯啶酮等 化學改質之澱粉纖維素；乳化劑如膨土、矽酸鎂鋁等膠 狀粘土；氫氧化鎂、氫氧化鋁等金屬氫氧化物；十二基 硫酸鈉、硬脂酸鈣等陰離子界面活性劑；苄烷氯化銨等陽 離子界面活性劑；或聚氧乙烯基烷醚、聚氧乙烯基山梨醇 糖脂肪酸酯或蔗糖脂肪酸酯等非離子界面活性劑等。 安定劑如對羥苯甲酸甲酯、對羥苯甲酸丙酯等對羥苯 甲酸酯；如氯丁醇、苄醇、苯乙醇等醇；苄烷氯化銨；如苯 30- 200300677 酚、甲酚等酚；硫柳汞；脫氫乙酸；及山梨酸。 _ 矯味劑如習用之甜味劑、酸味料、香料等稀釋劑。 本發明之醫藥組成物之有效成分之噻唑啶二酮化合 物或其藥理容許鹽，及RXR活性化作用劑或其藥理容許 鹽之投與量及投與比例依症狀、年齡、體重、投與方法 及劑型等而異。 投與量依症狀、年齢等而異，例如口服時每次下限0 . 1， 宜0.5 m g，上限1 0 0 0，宜5 0 0 m g ;非經口投與時每次下限 0.01，宜0.0511^,上限100，宜5〇1112,成人每日作1〜6次 · 依症狀同時或隔時分別投與。 本發明之醫藥組成物之有效成分之噻唑啶二酮化合 物或其藥理容許鹽，及RXR活性化作用劑或其藥理容許 鹽之投與量之比例也可大幅變化，一般依重量比爲1:200 〜2 0 0 : 1 〇 (實施發明之最佳形態） 下面詳細說明製造例、参考例、試驗例及製劑例，但 本發明不限於此。 · (製造例1) 5-(4-(6-(3 -異丙胺基-苯氧基）-1-甲基-1H -苯并咪唑- 2-基甲氧基）-苄基）噻唑啶-2,4 -二酮二鹽酸鹽 混合0.7 4 g參考例2所得之N - ( 2 -胺基-5 - ( 3 -異丙胺基· 苯氧基）-苯基）-N-甲胺甲酸第三丁酯，0.70g4-(2,4-二氧 噻唑啶-5-基甲基）苯氧基乙酸（特開平1 1 - 1 9 3 2 7 6 ),0.4 lg 氰基磺酸二乙酯，0.25g三乙胺及30ml無水四氫呋喃，在 室溫攪拌4.5小時後，將反應混合物濃縮，加水，用乙酸乙 •31- 200300677 酯萃取，以無水硫酸鈉乾燥，蒸除溶劑，所得之殘渣在矽 膠柱層析（乙酸乙酯/正己烷=2/3)精製，得中間體 N-(5-(3-異丙胺基-苯氧基）-2-(4-(2，4-二氧噻唑啶-5·基 甲基）本興乙釀胺基）-苯基）-N-甲胺甲酸第三丁醋。將此 中間體溶在50ml之4N鹽酸/1,4-二噚烷後，在室溫放置 1 6小時，濾取析出之沈澱，用乙酸乙酯洗淨，得標題化合 物（0.76g，產率 64%)。 Ή-NMR (DMS〇-d6) ό : 1.21( 6H，d，J=6.4Hz)，3.11( 1H，dd，J=14 及莎 9.0Hz )，3·34( 1H，dd，J=14 及DU.4Hz )，3·57-3·65( 1H，m )，3·95( 3H，s )， # 4.91( 1H，dd，J=9.0 及 J 4·4Ηζ )，5.63( 2H，s )，6·70·7.20( 3H，m )，7.14 ( 2H，d， J=8.7Hz ), 7.25( 2H, d, J=8.7Hz ), 7.25( 1H, d, J=3.3Hz ), 7.35-7.45( 1H, m ), 7·68( 1H，d, J=1.9Hz ), 7.83( 1H，d, J=8.9Hz )，12.05( 1H, s ;力[]重水而消失）。 (製造例2) 5-(4-(6-(3-(異丁基-甲基-胺基）·苯氧基）-1·甲基-1H-苯 并咪唑-2-基甲氧基）_苄基）噻唑啶-2,4 -二酮二鹽酸鹽 製造例1之Ν - ( 2 ·胺基-5 - ( 3 -異丙胺基-苯氧基）-苯 基）-Ν -甲胺甲酸第三丁酯代之以參考例5所得之Ν — (2 - φ 胺基- 5- (3-(異丁基-甲基-胺基）-苯氧基）-苯基）-Ν-甲胺 甲酸第三丁酯，仿製造例1，得標題化合物。 Ή-NMR ( DMSO-de) δ ： 0.86( 6Η, d, J=6.7Hz ), 1.90-1.99( 1H, m ), 2,91( 3H, s )，3·08-3·14( 3H, m )，3.34( 1H, dd, J=14 及β 4.4Hz )，3.94( 3H，s )，4.91( 1H， dd，J二9.0及β4·4Ηζ)，5.65(2H，s)，6.21( 1H，br)，6.39 ( 1H，br )，6.53( 1H，br ), 7.15-7.27( 6H, m ), 7.62( 1H, d, J=2.lHz ), 7.80( 1H, d, J=8.9Hz ), 12.04( 1H, br;加重水而消失）。 (製造例3) -32- 200300677 5-(4-(6-(4-(異丁基-甲基-胺基）-苯氧基）_卜甲基-11{-苯 并咪唑-2-基甲氧基）-苄基）噻唑啶_2,4 -二酮二鹽酸鹽 製造例1之N-(2 -胺基- 5- (3-異丙胺基-苯氧基）-苯 基）-N -甲胺甲酸第三丁酯代之以參考例8所得之N - ( 2 _ 甲基- 5- (4-(異丁基-甲基-胺基）苯氧基）_苯基）甲胺，仿製 造例1，得標題化合物。 Ή-NMR ( DMSO-de) δ ： 0.90( 6Η, d, J=4.4Hz ), 1.75-2.05( 1H, m ), 1.99( 3H, s ), 2,90·3·10( 2H, m )，3·11( 1H, dd, J=14 及 8.9Hz ), 3.34( 1H, dd, J=14 及a、 4.4Hz )，3.92( 3H, s )，4.91( 1H，dd，J=8.9 及OU.4Hz )，5.62( 2H，s )， 6.65-7.20( 5H, m ), 7.13 ( 2H, d, J=8.7Hz ), 7.25( 2H, d, J=8.7Hz ), 7.45-7.60( 1H, m )，7.78( 1H，d, J=8.9Hz )，12.05( 1H, s ;加重水而消失）。 (製造例4) 5-(4-(6-(3-(乙基-異丙基-胺基）-苯氧基）_卜甲基-1H -苯 并咪唑-2-基甲氧基）-苄基）噻唑啶-2,4 -二酮 混合620mg製造例1所得之5-(4-(6-(3 -異丙胺基-苯氧 基）-1-甲基-1H-苯并咪唑-2-基甲氧基）-苄基）噻唑啶 -2,4-二酮二鹽酸鹽、66111£乙醛，9〇11^乙酸，318111£三乙醯 氧基硼氫化鈉及15ml無水四氫呋喃，在室溫攪拌1小時 後，將反應混合物濃縮，加水，用乙酸乙酯萃取，以無水硫 酸鈉乾燥後，蒸除溶劑，將所得之殘渣在矽膠柱層析（乙 酸乙酯/正己烷=1/1)精製，得標題化合物（2 60mg，產率 4 8%)。 Ή-NMR (DMSO-de) (5 ： 1.06 (3H, t, J=7.0Hz), 1.11 (6H, d, J=6.6Hz), 3.05 (lH, dd, J=14 及 J 9·2Ηζ), 3·18 (2H, q，J=7.0Hz), 3.31 (1H, dd, J=14 及UU.3Hz), 3.79 200300677 (3H，s)，3·94_4·04 (lH, m)，4·87 (1H，dd，J=9.2 及DU.3Hz)，5·63 (2H，S)，6·11 (1Η， dd，J=7.9 及β 2.0Hz )，6.34 (1H，t，J=2.2Hz)，6·46 (1H，dd，J=8.5 及莎 2:3Hz)， 6.92 (1H，dd，J=8.8 及 2·2Ηζ)，7.06-7.11 (3H，m)，7.19 (1H，d，J=8.7Hz)，7.28 (1H, d，J=2.3Hz)，7.63 (1H，d，J=8.7Hz)，12.02 (1H，s ;加重水而消失）。 (製造例5) 5-(4-(6-(4-異丙胺基-苯氧基）-1-甲基-1H-苯并咪唑- 2-基甲氧基）-苄基）噻唑啶-2,4 -二酮 製造例4之5-(4-(6-(3-異丙胺基-苯氧基）-1-甲基-1H-苯并咪唑-2-基甲氧基）-苄基）噻唑啶- 2,4 -二酮二鹽酸鹽 代之以5-(4-(6-(4-胺基-苯氧基）-1-甲基-1H-苯并咪唑- 2-基甲氧基）-苄基）噻唑啶-2,4-二酮二鹽酸鹽（特開平 1 1 - 1 9 3 2 7 6 )，乙醛代之以丙酮，仿實施例4,得標題化合物 Ή-NMR ( DMSOi) (5: 1.13( 6H，d，J=6.3Hz )，3.05( 1H，dd，J=14 及莎 9.1Hz 入 3.31( 1Η，dd，J=14 及莎 4·3Ηζ )，3.45-3.52( 1Η，m )，3.75( 3Η，s )， 4·87( 1H，dd，J=9.1 及I； 4·3Ηζ )，5.24( 1H，br ;加重水而消失）、，5.34( 2H， s )，6.56( 2H，dd，J=12 及 J 3.3Hz )，6.81( 2H，d，J=8.6Hz )，6·83( 1H，dd，J=8.2 及2.3Hz )，7·04·7·07( 3H，m )，7.19( 2H，d，J=8.6Hz )，7·57( 1H, d, J=8.8Hz )， 12.02( 1H，br ;加重水而消失）。 (製造例6) 5-(4-(6·(4·第二丁胺基-苯氧基）-1-甲基-1H-苯并咪唑 -2 -基甲氧基）-苄基）噻唑啶-2,4 -二酮 製造例4之5-(4-(6-(3•異丙胺基-苯氧基）-卜甲基-1H-苯并咪唑-2-基甲氧基）-苄基）噻唑啶·2,4 -二酮二鹽酸鹽 代之以5-(4-(6-(4-胺基-苯氧基）-卜甲基-1Η-苯并咪唑- 2-基甲氧基）-苄基）噻唑啶-2,4 -二酮二鹽酸鹽，乙醛代之以 丁酮，仿製造例4，得標題化合物 -34- 200300677 Ή-NMR ( DMSO-de) δ ： 0.90( 3H, t, J=7.4Hz ), 2.17( 3H, d, J=6.4Hz ), 1.34-1.46( 1H, m ), 1.48-1.59( 1H, m ), 3.06( 1H, dd, J=U RlS 9.2Hz ), 3.24-3.34( 2H, m )，3.75( 3H, s )，4.87( 1H，dd, J=9.2 及UU.3Hz )，5.23( 1H, br ; 加重水而消失） ，5.34( 2H，s )，6.57( 2H，d，J=8.7Hz )，6.81 ( 2H，d， J=8.9Hz )，6.84( 1H，dd，J=8.8 及莎 2.2Hz)，7.01-7.09( 3H，m )，7.19( 2H，d， J=8.7Hz )，7.57( 1H，d，J=8.8Hz )，12.01( 1H，br ;加重水而消失）。 (製造例7) 5-(4-(6-(4-異丁胺基-苯氧基）-1·甲基-1H-苯幷咪唑- 2-基甲氧基）-苄基）噻唑啶-2,4 -二酮 製造例4之5-(4-(6-(3-異丙胺基-苯氧基）-1-甲基-1H-苯并咪唑-2-基甲氧基）-苄基）-噻唑啶-2,4 -二酮二鹽酸鹽 代之以5-(4-(6-(4-胺基-苯氧基）-1-甲基_1H-苯并咪唑- 2-基甲氧基）-苄基）噻唑啶-2,4 -二酮二鹽酸鹽，乙醛代之以 異丁醛，仿製造例4,得標題化合物。 Ή-NMR ( DMSO-de) δ ： 0.94( 6Η, d, J=6.7Hz ), 1.77-1.88( 1H, m ), 2.78-2.81( 2H, m )，3.05( 1H，dd, J=14 及IX 9·3Ηζ )，3.31( 1H, dd，J=14 及IX 4·3Ηζ )，3.74( 3H，s )，4.86( 1H，dd，J=9.3 及β 4.3Hz )，5.34( 2H，s )，5.50( 1H，s ; 加重水而消失） .，6.57( 2H，dd，J=6.8 及I； 2·0Ηζ )，6.81 ( 2H，d，J=8.8Hz )， 6.83( 1H，dd，J=8.6 及β 2.4Hz )，7.04·7·07( 3H，m ), 7.19( 2H, d，J二8.6Hz )， 7.56( 1H，d，J=8.8Hz)，12.01( 1H，s ;加重水而消失）。 (参考例1 ) N - ( 5 - ( 3 -胺苯氧基）· 2 -硝苯基）-N -甲胺甲酸第三丁酯 在含有2.18g氫化鈉（55重量％)之80ml無水N，N - 一甲 基甲醯胺懸浮液中加5.45 g之3-胺酚，在室溫攪拌20 分。次徐徐加14.：3g之N-(5-氯-2-硝苯基）-N-甲胺甲酸第 -35- 200300677 三丁酯（特開平1 1 - 1 9 3 2 7 6)，在1 0 0 °C攪拌6小時。將反應 混合物濃縮，加水，用3 N鹽酸及碳酸氫鈉粉末來中和。濾 取析出之沈澱，水洗後，減壓下乾燥，得標題化合物（1 6 · 6 g， 產率9 2 % )。 Ή-NMR ( DMSO_d6) δ : 1.23 及 1.42(計 9H，各 s )，3.18( 3H，s )，5.38( 2H, s ; 加重水而消失） ，6.25( 1H, dd, J=7.6 及β 2.4Hz )，6.31( 1H, s )，6.46( 1H，dd， J=8.1 及1·0Ηζ )，6·88( 1H，dd，J=9.0 及β 2·ΐΗζ )，7.09( 1H，t，J二8.0Hz )， 7.16( 1H, s ),8.00 ( 1H, d, J=9.0Hz ). (參考例2) N-(2-胺基- 5-(3-異丙胺基-苯氧基）·苯基）-N-甲胺甲酸 第三丁酯 混合14.4g之N-(5-(3-胺苯氧基）-2-硝苯基）-N-甲胺甲 酸第三丁酯，2.90g之丙酮，3.00g之乙酸，l〇.6g之三乙醯 氧基硼氫化鈉及200ml無水四氫呋喃，在室溫攪拌4曰。 將反應混合物濃縮，加水，用乙酸乙酯萃取，以無水硫酸 鈉乾燥後，蒸除溶劑，所得之殘渣在矽膠柱層析（乙酸乙 酯/正己烷=2 / 3 )精製，得中間體N - ( 5 - ( 3 -異丙胺基-苯氧 基2 -硝苯基）-N -甲胺甲酸第三丁酯。將此中間體溶於 200ml之甲醇，加2.02g之10 %鈀-碳，在氫大氣下室溫激 烈攪拌2 · 5小時。反應終了後，濾除觸媒，蒸除溶劑，得標 題化合物（1 2.0 g，產率8 1 % )。 O-NMR ( DMSO-de) δ ： 1.08( 6H, d, J=6.4Hz ), 1.29( 9H, s ), 2.98( 3H, s ), 3.40-3.47( 1H, m )，4.78( 2H, s ;力口重水而消失） ,5.45( 1H, d, J=7.8Hz ； 加重水而消失 ，5.96( 1H，d，J=7.2Hz )，6·07( 1H，t，J=2.2Hz )，6.20 ( 1H，dd， J二8.1 及β 1.9Hz )，6.60( 1H，s )，6.71( 2H，s )，6.93( 1H，t，J=8.lHz ). 200300677 (参考例3 ) N - ( 5 - ( 3 -溴苯氧基）-2 -硝苯基）-N -甲胺甲酸第三丁酯 在含有2.5g氫化鈉（55重量％)50ml之無水N，N-二曱基 甲醯胺懸浮液中加1 〇 · 〇 g之3 -溴酚，冰冷下攪拌1 5分。 次滴加1 6.6 g之N - ( 5 -氯-2 -硝苯基）-N -甲胺甲酸第三丁 酯，70ml溶於無水N，N-二甲基甲醯胺，在100 °C攪拌3小 時。將反應混合物濃縮，加水，用3 N鹽酸來中和，以乙酸 乙酯萃取，用飽和食鹽水洗淨，以無水硫酸鈉乾燥，蒸除 乙酸乙酯，濾取析出不溶性之沈澱用己烷洗淨後，減壓下 乾燥，得標題化合物（2 0.2 g，產率8 3 % )。 O-NMiUCDCldS: 1·24(9Η，s)，3.19(3H, s)，6·97( 1H，dd，J=9.0及β2.4Ηζ)， 7.22( 1H, d, J=7.9Hz ), 7.29 ( 1H, d, J=1.7Hz ), 7.42-7.51( 3H, m ),8.03 ( 1H, d, J=9.0Hz ). (参考例4) N-(5-(3-(異丁基-甲基-胺基）苯氧基）-2-硝苯基）-N-甲胺 甲酸第三丁酯 將7 0 0.0 m g參考例3所得之N ·( 5 - ( 3 -溴苯氧基）-2 -硝苯 基）-N-甲胺甲酸第三丁酯，0.24ml異丁基甲胺，151.Omg参 (二亞苄基丙酮）鈀，115.7mg之2-(二環己膦基）聯苯及 27 7.7 mg之第三丁氧化鉀懸浮於4ml無水甲苯，在lOOt： 攪拌1 · 5小時。在反應混合物加水，用乙酸乙酯萃取，用 飽和食鹽水洗淨，以無水硫酸鈉乾燥後，蒸除溶劑，所得 之殘渣在矽膠柱層析（乙酸乙酯/正己烷=1/7)精製，得標 題化合物（204.2mg，產率29%)。 200300677 Ή-ΝΜΙΙ ( CDCls) δ · 0.80(6Η, d, J=6.6Hz), 1.25( 9Η, s ), 1.88-2.01( 1H, 〜 m ),2.85(3H, s), 2.95(2H, d, J=7.3Hz), 3.14(3H, s), 6.20^6.27( 2H, m ), 6.43( 1H, dd，J=8.8 及β 2.2Hz )，6.72-6.83( 2H, m )，7.11( 1H, t, J=8.lHz )，7.81 ( 1H, d, J 二 9.5Hz)· . (参考例5) N-(2 -胺基- 5- (3-(異丁基-甲基-胺基）苯氧基）_苯基）-N-甲胺甲酸第三丁酯 將204.2mg參考例4所得之N-(5-(3-異丁基-甲基-胺基） 苯氧基）-2-硝苯基）-N-甲胺甲酸第三丁酯溶在乙醇，鲁 加100,0mgl0%Pd-C，在室溫氫氣下激烈攪拌2.5小時。反 應終了後，濾除觸媒，蒸除溶劑，所得之殘瘡在砂膠柱層 析（乙酸乙酯/正己烷=1/4— 1/3)，得標題化合物（I4 5.4mg， 產率7 7 % )。 - Ή-NMR ( CDCls) (5 ： 0.90(6H, d, J=6.6Hz), 1.57( 9H, s ), 1.98-2.09( 1H, m)，2.92(3H, s), 3·〇6(2Η, d，J=7.3Hz), 3.i3(3H, s), 3,64(2H，s;·加重水而消失 ，6.30( 1H，t，J=2.2Hz)，6.35( 1H，dd，J=8· 1 及β 2.2Hz )，6.70-6.88( 3H，m )， 7.08 ( 1H, t, J=8.2Hz ), 7.25-7.3K1H, m). φ (参考例6) (4-(異丁基-甲基-胺基）苯氧基）-第三丁基二甲基砂院 將5ml之（4-溴苯氧基）第三丁基二甲基砂院，2.9ml之 異丁基甲胺，458.0mg乙酸銷，1.2g之2-(—第二丁鱗基） 聯苯及2.9g第三丁氧化鈉懸浮於40ml之無水甲苯，在 1 00 °C攪拌1.5小時後，濾除觸媒後加水，用乙酸乙酯萃取， 用飽和食鹽水洗淨，以無水硫酸鈉乾燥，蒸除溶劑，所得 之殘渣在矽膠柱層析（乙酸乙酯/正己烷=1/40— 1/2 〇)精 -38· 200300677 製，得標題化合物（3 . 8 3 g，產率6 4 % )。 Ή-NMR ( CDCls) (5 ： 0.16(6H, s), 0.9l(6H, d, J=6.6Hz), 0.97(9H, s), 1.94-2.05(1H, m), 2.87(3H, s), 2.98(2H, d, J=7.3Hz), 6.57(2H, d, J=8.8Hz), 6.72(2H, d, J=8.8Hz). (参考例7) N-(5-(4-(異丁基-甲基-胺基）苯氧基）-2-硝苯基）甲胺 將3.83g參考例6所得之（4-(異丁基-甲基-胺基）苯氧 基）_第三丁基二甲基矽烷溶在20ml無水四氫呋喃，加1 20ml之1M四正丁基氟化銨-四氫呋喃溶液，在室溫攪拌 30分後，將反應混合物濃縮，加水，以乙酸乙酯萃取，用飽 和食鹽水洗淨，以無水硫酸鈉乾燥後，蒸除溶劑，所得之 殘渣在矽膠柱層析（乙酸乙酯/正己烷=1/5)精製，所得之 沈澱溶在4 N鹽酸-1，4 -二咢烷，在室溫攪拌3 0分後，將反 應液濃縮，以***洗淨後，得中間體4-異丁基甲胺酚一鹽 酸鹽。將此中間體5 00.0mg及2.6g碳酸鉀懸浮於20ml 無水N，N-二甲基甲醯胺，在室溫攪拌15分後，加6 6 4.7 mg 之N-(5 -氯-2-硝苯基）-N -甲胺甲酸第三丁酯，在150°C攪 拌3小時。將反應混合物濃縮，加水，以乙酸乙酯萃取，用 飽和食鹽水洗淨，以無水硫酸鈉乾燥後，蒸除溶劑，所得 之殘渣在矽膠柱層析（乙酸乙酯/甲苯=1/30)精製，得標題 化合物（2 5 6 · 1 in g，產率3 4 % )。 夢 Ή-NMR ( CDCh) (5 ： 0.96(6H, d, J=6.8Hz), 2.00-2.13(lH, m), 2.92(3H, d, J=5.9Hz), 2.98(3H, s), 3.12(2H, d, J=7.8Hz), 6.19-6.23(2H, m), 6.68(2H, d, J=8.8Hz), 6.96(2H, d, J=8.8Hz), 8.13(lH, d, J=9.8Hz). (参考例8 ) -39- 200300677 N-(2-胺基- 5-(4-(異丁基-甲基-胺基）苯氧基）-苯基）甲 胺 参考例5之N-(5-(3-(異丁基-甲基-胺基）苯氧基）_2-硝 苯基）-N-甲胺甲酸第三丁酯代之以參考例7所得之 N-(5-(4-(異丁基-甲基-胺基）苯氧基）-2-硝苯基）甲胺，仿 参考例5，得標題化合物。 Ή-NMR ( CDCla) <5 ： 0.88(6H, d, J=6.6Hz), 1.94-2.04(lH, m), 2.77(3H, s), 2.87(3H, s)，2.99(2H，d, J=7.3Hz)，3.22(2H, s)，6.16(1H，dd，J=8.1 及5 2.5Hz), 6.33(1H, d, J=2.5Hz), 6.57(lH, d, J=8.1Hz), 6.59(2H, d, J=8.8Hz), 6.87(2H, d, · J=8.'8Hz). (試驗例1)對人急性前骨髓性白血病細胞株HL-60細 胞之抗腫瘤效果之增強。 在每組9隻BALB/c裸鼠（雌，6週齡）之皮下移植人急 性前骨髓性白血病細胞株HL-60細胞之腫瘤片（5mmx 5mm四方）。被檢化合物以含2.5% —甲基乙醯肖女之5% 乳化劑懸浮，在移植次日〜4日，7日-1 1日，1 4日· 1 8曰， 每曰1次，共14次經口投與。 _ 效果之判定以腫瘤增殖抑制效果乃將腫瘤/ ® ® (m m )及長徑（m m )以電子數位尺計測，依下計算式 評價移植後第21曰之腫瘤增殖抑制率（GI%) °The El project is a process for the amination of bromine (1 1) to produce an amine compound (12). The process of obtaining the compound (1 2) by reacting the bromine (η) with a primary or secondary amine in the presence of a catalyst, a ligand, and a base in an inert solvent can generally be performed similarly to the C 2 process. (E 2 process) The E 2 process is a process for desilanizing the silyl ether compound (12) to produce phenol (1 3). The process of obtaining phenol (1 3) by reacting phenol compound (12) with fluoride in an inert solvent. The inert solvent used is not specific as long as it does not affect the reaction, and halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, and carbon tetrachloride can be used; diethyl ether, isopropyl ether, tetrahydrofuran, 1,4-bis Ethers such as naphthene, dimethoxyethane, and diethylene glycol dimethyl ether; N, N-dimethylformamide, N, N-dimethylacetamide, hexamethylphosphonium triamine Isoamidine; water; ethers such as tetrahydrofuran and 1,4-dioxane. The fluoride used may be, for example, potassium fluoride, tetra-n-butylammonium fluoride, or the like. The reaction temperature varies depending on the raw material compound, the reagent used, the solvent, etc., and is usually 0 to 10 (TC, preferably 10 to 30 ° C. The reaction time varies depending on the raw material compound, the reagent, the solvent, the reaction temperature, etc., and is usually 15 minutes to 2 days, preferably 30 minutes to 1 day. After the reaction is completed, the target compound is recovered according to the usual method. For example, after the reaction, the solvent is distilled off, and a solvent (such as ethyl acetate, methylene chloride, etc.) that is not mixed with water is added. It is extracted, washed with water, saturated saline, etc., dried over anhydrous magnesium sulfate, and the solvent is distilled off. The obtained target substance is separated and purified according to ordinary methods such as recrystallization, reprecipitation, and chromatography if necessary. (E 3 Project) 200300677 E3 project is the process of etherifying phenol (13) to produce phenyl ether compound (5). Usually, phenol (1 3) is reacted with chlorine (3) in the presence of a base in an inert solvent to obtain phenyl ether ( 5) The project can be carried out in a manner similar to the C1 project. Among the active ingredients of the present invention, the RXR activating agent is easily described in, for example, i. Thibonnet et al, Synlett, l, ppl 41-143 (1999), JP-A Hei 6- Manufactured by the methods of Publication No. 107542 and WO94 / 15901. Examples ATRA can be according to the method described in J. Thibonnet et al, Synlett, l, pp 1 4 1-1 4 3 (199 9 9), 9-cis-retinoic acid can be determined by M. F · B 0 ehmet al , J. Med. Chem., 37, pp408-4 1 4 (1 994), LG 1 0 0 2 6 8 can be used according to the method of No. 94/1 5 90 1 and daclatinine Manufactured separately according to the method described in WG 9 4/15 9 0 1. The thiazodidinone compound or a pharmacologically acceptable salt thereof, which is an effective ingredient of the pharmaceutical composition of the present invention, and the RXR activation agent or a pharmacologically acceptable method The salt can be adjusted to be administered in the form of separate units or mixed into a single physical administration form. When the pharmaceutical composition of the present invention is used as a preventive or therapeutic agent for the aforementioned diseases, the effective ingredients of the pharmaceutical composition of the present invention A thiazolidinedione compound or a pharmacologically acceptable salt thereof, and an RXR activating agent or a pharmacologically acceptable salt thereof, respectively, or mixed with appropriate pharmacologically acceptable excipients and diluents, and taken orally as tablets, capsules, granules, powder, syrup, etc Or parenteral injections, injections, etc. These preparations can be mixed with appropriate pharmacologically acceptable excipients, Lubricants, binding agents, disintegrating agents, stabilizers, flavoring agents, diluents and other additives are prepared. Excipients such as lactose, white sugar, glucose, mannose, sorbose, etc.-29- 200300677 sugar derivatives Materials; corn starch, potato starch, starch, dextrin, carboxymethyl starch, and other starch derivatives; crystalline cellulose, low-substitution hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, carboxylate Cellulose derivatives such as methyl calcium cellulose; acacia gum; polydextrose; polytriglucose and other organic excipients; light silicic anhydride, synthetic aluminum silicate, calcium silicate, magnesium aluminum metasilicate, and other silicon derivatives ; Phosphates such as calcium hydrogen phosphate; inorganic excipients such as calcium carbonate and calcium sulfate. Lubricants such as stearic acid, calcium stearate, magnesium stearate and other stearic acid metal salts; talc; colloidal silica; propolis and cetacean wax; boric acid; sulfates such as sodium stearate; ethylene glycol; Fumaric acid; sodium benzoate; DL leucine; sodium salt of fatty acids; sodium dodecyl sulfate; dodecyl sulfate such as sodium dodecyl sulfate and dodecyl magnesium sulfate; silicon such as silicic anhydride and silicic acid hydrate Acids; and the above-mentioned starch derivatives. Binding agents such as hydroxypropyl cellulose, hydroxymethyl cellulose, polyvinylpyrrolidone, polyethylene glycol, and the aforementioned excipients. Disintegrating agents such as cellulose derivatives such as low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, and internally bridged carboxymethyl cellulose sodium; carboxymethyl starch, sodium carboxymethyl starch, Crosslinked chemically modified starch cellulose such as polyvinylpyrrolidone; emulsifiers such as bentonite, magnesium aluminum silicate and other colloidal clays; metal hydroxides such as magnesium hydroxide and aluminum hydroxide; sodium dodecyl sulfate, Anionic surfactants such as calcium stearate; cationic surfactants such as benzane ammonium chloride; or nonionic surfactants such as polyoxyvinyl alkyl ether, polyoxyvinyl sorbitol fatty acid ester, or sucrose fatty acid ester Wait. Stabilizers such as parabens such as methyl paraben and propyl paraben; alcohols such as chlorobutanol, benzyl alcohol, and phenethyl alcohol; benzyl ammonium chloride; such as benzene 30- 200300677 phenol, Cresols and other phenols; thimerosal; dehydroacetic acid; and sorbic acid. _ Flavoring agents such as diluents such as conventional sweeteners, sour flavors and spices. The thiazolidinedione compound or a pharmacologically acceptable salt thereof, which is an effective ingredient of the pharmaceutical composition of the present invention, and the administration amount and ratio of the RXR activation agent or a pharmacologically acceptable salt thereof depend on symptoms, age, weight, and method of administration And dosage forms vary. Dosage varies depending on symptoms, age, etc. For example, the lower limit of 0.1 each time when taken orally is 0.5 mg, the upper limit of 100 0, preferably 500 mg; the lower limit of each time is 0.01, preferably 0.0511 ^, The upper limit is 100, preferably 501112, for adults 1 to 6 times a day. The ratio of the dosage of the thiazolidinedione compound or its pharmacologically acceptable salt, and the effective amount of the RXR activation agent or its pharmacologically acceptable salt of the active ingredients of the pharmaceutical composition of the present invention can also be greatly changed, and generally based on the weight ratio of 1: 200 to 2 0 0: 1 0 (the best mode for carrying out the invention) The manufacturing examples, reference examples, test examples, and preparation examples will be described in detail below, but the present invention is not limited thereto. (Production Example 1) 5- (4- (6- (3-isopropylamino-phenoxy) -1-methyl-1H-benzimidazole-2-ylmethoxy) -benzyl) thiazolidine -2,4-dione dihydrochloride mixed with 0.7 4 g of N-(2 -amino-5-(3 -isopropylamino · phenoxy) -phenyl) -N-methylamine obtained in Reference Example 2 Third butyl formate, 0.70 g of 4- (2,4-dioxothiazol-5-ylmethyl) phenoxyacetic acid (Japanese Patent Application Laid-Open No. 1 1-1 9 3 2 7 6), 0.4 lg cyanosulfonic acid di Ethyl acetate, 0.25 g of triethylamine and 30 ml of anhydrous tetrahydrofuran. After stirring at room temperature for 4.5 hours, the reaction mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate 31-200300677, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (ethyl acetate / n-hexane = 2/3) to obtain the intermediate N- (5- (3-isopropylamino-phenoxy) -2- (4- (2,4- Dioxothiazol-5-ylmethyl) Benzo ethyl amine) -phenyl) -N-methylcarbamic acid tert-butyl vinegar. This intermediate was dissolved in 50 ml of 4N hydrochloric acid / 1,4-dioxane, and then left at room temperature for 16 hours. The precipitate was collected by filtration and washed with ethyl acetate to obtain the title compound (0.76 g, yield 64%). Ή-NMR (DMS〇-d6): 1.21 (6H, d, J = 6.4Hz), 3.11 (1H, dd, J = 14 and Sha 9.0Hz), 3.34 (1H, dd, J = 14 and DU.4Hz), 3.57-3.65 (1H, m), 3.95 (3H, s), # 4.91 (1H, dd, J = 9.0 and J4 · 4Ηζ), 5.63 (2H, s) , 6.70 · 7.20 (3H, m), 7.14 (2H, d, J = 8.7Hz), 7.25 (2H, d, J = 8.7Hz), 7.25 (1H, d, J = 3.3Hz), 7.35- 7.45 (1H, m), 7.68 (1H, d, J = 1.9Hz), 7.83 (1H, d, J = 8.9Hz), 12.05 (1H, s; force [] disappeared with heavy water). (Production Example 2) 5- (4- (6- (3- (isobutyl-methyl-amino) · phenoxy) -1 · methyl-1H-benzimidazol-2-ylmethoxy ) _Benzyl) thiazolidine-2,4-dione dihydrochloride Production Example 1 -N-(2 -Amino-5-(3 -isopropylamino-phenoxy) -phenyl) -N- The third butyl methylcarbamate was replaced with N—obtained from Reference Example 5 — (2-φ amino-5-(3- (isobutyl-methyl-amino) -phenoxy) -phenyl)- Tertiary-butyl N-methylcarbamate, following Preparation Example 1, gave the title compound. Ή-NMR (DMSO-de) δ: 0.86 (6Η, d, J = 6.7Hz), 1.90-1.99 (1H, m), 2,91 (3H, s), 3.08-3 · 14 (3H, m), 3.34 (1H, dd, J = 14 and β 4.4 Hz), 3.94 (3H, s), 4.91 (1H, dd, J 9.0 and β4 · 4Ηζ), 5.65 (2H, s), 6.21 (1H , Br), 6.39 (1H, br), 6.53 (1H, br), 7.15-7.27 (6H, m), 7.62 (1H, d, J = 2.lHz), 7.80 (1H, d, J = 8.9Hz ), 12.04 (1H, br; disappears with increasing water). (Production Example 3) -32- 200300677 5- (4- (6- (4- (isobutyl-methyl-amino) -phenoxy) -p-methyl-11 {-benzimidazole-2-ylmethyl (Oxy) -benzyl) thiazolidine_2,4-dione dihydrochloride Production Example 1 N- (2-Amino-5- (3-isopropylamino-phenoxy) -phenyl)- N-methylcarbamic acid tert-butyl ester was replaced with N- (2-Methyl-5- (4- (isobutyl-methyl-amino) phenoxy) _phenyl) methyl obtained in Reference Example 8 Amine, following Preparation Example 1, gave the title compound. Ή-NMR (DMSO-de) δ: 0.90 (6Η, d, J = 4.4Hz), 1.75-2.05 (1H, m), 1.99 (3H, s), 2,90 · 3 · 10 (2H, m) , 3 · 11 (1H, dd, J = 14 and 8.9Hz), 3.34 (1H, dd, J = 14 and a, 4.4Hz), 3.92 (3H, s), 4.91 (1H, dd, J = 8.9 and OU.4Hz), 5.62 (2H, s), 6.65-7.20 (5H, m), 7.13 (2H, d, J = 8.7Hz), 7.25 (2H, d, J = 8.7Hz), 7.45-7.60 (1H , m), 7.78 (1H, d, J = 8.9Hz), 12.05 (1H, s; disappear with increasing water). (Production Example 4) 5- (4- (6- (3- (ethyl-isopropyl-amino) -phenoxy) -p-methyl-1H-benzimidazol-2-ylmethoxy) -benzyl 620 mg of thiazolidine-2,4-dione mixed with 5- (4- (6- (3- (isopropylamino-phenoxy) -1-methyl-1H-benzimidazole-2) obtained in Production Example 1 -Ylmethoxy) -benzyl) thiazolidine-2,4-dione dihydrochloride, 66111 £ acetaldehyde, 9101 ^ acetic acid, 318111 £ sodium triethoxylate borohydride and 15 ml of anhydrous tetrahydrofuran, After stirring at room temperature for 1 hour, the reaction mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the solvent was distilled off, and the resulting residue was subjected to silica gel column chromatography (ethyl acetate / n-hexane = 1). / 1) Purification to obtain the title compound (2 60 mg, yield 48%). Ή-NMR (DMSO-de) (5: 1.06 (3H, t, J = 7.0Hz), 1.11 (6H, d, J = 6.6Hz), 3.05 (lH, dd, J = 14 and J 9 · 2Ηζ) , 3.18 (2H, q, J = 7.0Hz), 3.31 (1H, dd, J = 14 and UU.3Hz), 3.79 200300677 (3H, s), 3.94_4 · 04 (lH, m), 4 · 87 (1H, dd, J = 9.2 and DU.3Hz), 5.63 (2H, S), 6.11 (1Η, dd, J = 7.9 and β 2.0Hz), 6.34 (1H, t, J = 2.2Hz), 6.46 (1H, dd, J = 8.5 and Sha 2: 3Hz), 6.92 (1H, dd, J = 8.8 and 2. · 2Ηζ), 7.06-7.11 (3H, m), 7.19 (1H, d, J = 8.7Hz), 7.28 (1H, d, J = 2.3Hz), 7.63 (1H, d, J = 8.7Hz), 12.02 (1H, s; disappears by adding water) (Production example 5) 5 -(4- (6- (4-isopropylamino-phenoxy) -1-methyl-1H-benzimidazole-2-ylmethoxy) -benzyl) thiazolidine-2,4-dione 5- (4- (6- (3-isopropylamino-phenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) thiazolidine-2 in Production Example 4 , 4-dione dihydrochloride replaced by 5- (4- (6- (4-amino-phenoxy) -1-methyl-1H-benzimidazole- 2-ylmethoxy)- Benzyl) thiazolidine-2,4-dione dihydrochloride (Japanese Unexamined Patent Application No. 1 1-1 9 3 2 7 6), acetaldehyde is replaced by acetone, which is simulated Example 4: The title compound Ή-NMR (DMSOi) (5: 1.13 (6H, d, J = 6.3Hz), 3.05 (1H, dd, J = 14 and Sarah 9.1Hz, 3.31 (1Η, dd, J = 14) And Sha 4 · 3Ηζ), 3.45-3.52 (1Η, m), 3.75 (3Η, s), 4.87 (1H, dd, J = 9.1 and I; 4 · 3Ηζ), 5.24 (1H, br; weighted water And disappeared), 5.34 (2H, s), 6.56 (2H, dd, J = 12 and J 3.3Hz), 6.81 (2H, d, J = 8.6Hz), 6.83 (1H, dd, J = 8.2 And 2.3Hz), 7 · 04 · 7 · 07 (3H, m), 7.19 (2H, d, J = 8.6Hz), 7.57 (1H, d, J = 8.8Hz), 12.02 (1H, br; Aggravates the water and disappears). (Production Example 6) 5- (4- (6 · (4 · Second-butylamino-phenoxy) -1-methyl-1H-benzimidazole-2-ylmethoxy) -benzyl) thiazole 5- (4- (6- (3- (isopropylamino-phenoxy))-methyl-1H-benzimidazol-2-ylmethoxy) -benzyl ) Thiazolidine · 2,4-dione dihydrochloride replaced by 5- (4- (6- (4-amino-phenoxy) -pmethyl-1 甲基 -benzimidazole-2-ylmethoxy ) -Benzyl) thiazolidine-2,4-dione dihydrochloride, replacing acetaldehyde with methyl ethyl ketone, imitating Manufacturing Example 4, to give the title compound -34- 200300677 Ή-NMR (DMSO-de) δ: 0.90 (3H, t, J = 7.4Hz), 2.17 (3H, d, J = 6.4Hz), 1.34-1.46 (1H, m), 1.48-1.59 (1H, m), 3.06 (1H, dd, J = U RlS 9.2Hz), 3.24-3.34 (2H, m), 3.75 (3H, s), 4.87 (1H, dd, J = 9.2 and UU.3Hz), 5.23 (1H, br; disappear with weighted water), 5.34 ( 2H, s), 6.57 (2H, d, J = 8.7Hz), 6.81 (2H, d, J = 8.9Hz), 6.84 (1H, dd, J = 8.8 and Sarah 2.2Hz), 7.01-7.09 (3H, m), 7.19 (2H, d, J = 8.7Hz), 7.57 (1H, d, J = 8.8Hz), 12.01 (1H, br; disappeared by adding water). (Production Example 7) 5- (4- (6- (4-isobutylamino-phenoxy) -1 · methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) thiazolidine 5- (4- (6- (6- (3-isopropylamino-phenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy)- Benzyl) -thiazolidine-2,4-dione dihydrochloride replaced by 5- (4- (6- (4-amino-phenoxy) -1-methyl_1H-benzimidazole- 2-ylmethoxy) -benzyl) thiazolidine-2,4-dione dihydrochloride, and acetaldehyde was replaced by isobutyraldehyde, and the title compound was obtained by imitating Production Example 4. Ή-NMR (DMSO-de) δ: 0.94 (6Η, d, J = 6.7Hz), 1.77-1.88 (1H, m), 2.78-2.81 (2H, m), 3.05 (1H, dd, J = 14 and IX 9 · 3Ηζ), 3.31 (1H, dd, J = 14 and IX 4 · 3Ηζ), 3.74 (3H, s), 4.86 (1H, dd, J = 9.3 and β 4.3Hz), 5.34 (2H, s) , 5.50 (1H, s; disappears with increasing water)., 6.57 (2H, dd, J = 6.8 and I; 2.0 · ΗΗ), 6.81 (2H, d, J = 8.8Hz), 6.83 (1H, dd, J = 8.6 and β 2.4Hz), 7.04 · 07 · 07 (3H, m), 7.19 (2H, d, J = 8.6Hz), 7.56 (1H, d, J = 8.8Hz), 12.01 (1H, s; weighted Water disappears). (Reference Example 1) N-(5-(3-aminophenoxy) · 2-nitrophenyl) -N-methylcarbamic acid third butyl ester in 80 ml of anhydrous N containing 2.18 g of sodium hydride (55% by weight) To the N-methylformamide suspension, 5.45 g of 3-aminophenol was added and stirred at room temperature for 20 minutes. Adding 14 .: 3g of N- (5-chloro-2-nitrophenyl) -N-methanamic acid tri-35- 200300677 tributyl ester (Japanese Patent Application Laid-open No. 1 1-1 9 3 2 7 6) Stir at 100 ° C for 6 hours. The reaction mixture was concentrated, water was added, and neutralized with 3 N hydrochloric acid and sodium bicarbonate powder. The deposited precipitate was collected by filtration, washed with water, and dried under reduced pressure to obtain the title compound (16 · 6 g, yield 9 2%). Ή-NMR (DMSO_d6) δ: 1.23 and 1.42 (count 9H, each s), 3.18 (3H, s), 5.38 (2H, s; disappear with weighted water), 6.25 (1H, dd, J = 7.6 and β 2.4 Hz), 6.31 (1H, s), 6.46 (1H, dd, J = 8.1 and 1.00Ηζ), 6.88 (1H, dd, J = 9.0 and β 2 · ΐΗζ), 7.09 (1H, t, J Two 8.0Hz), 7.16 (1H, s), 8.00 (1H, d, J = 9.0Hz). (Reference Example 2) N- (2-amino- 5- (3-isopropylamino-phenoxy) · Phenyl) -N-methylcarbamic acid tert-butyl ester 14.4 g of N- (5- (3-aminephenoxy) -2-nitrophenyl) -N-methylcarbamic acid tert-butyl ester, 2.90 g of acetone, 3.00 g of acetic acid, 10.6 g of sodium triethoxylate borohydride and 200 ml of anhydrous tetrahydrofuran, and stirred at room temperature for 4 days. The reaction mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (ethyl acetate / n-hexane = 2/3) to obtain intermediate N. -(5-(3 -Isopropylamino-phenoxy 2 -nitrophenyl) -N-methylcarbamic acid third butyl ester. This intermediate was dissolved in 200 ml of methanol, and 2.02 g of 10% palladium-carbon was added. The mixture was stirred vigorously at room temperature under a hydrogen atmosphere for 2.5 hours. After the reaction was completed, the catalyst was filtered off and the solvent was distilled off to obtain the title compound (1 2.0 g, yield 81%). O-NMR (DMSO-de) δ: 1.08 (6H, d, J = 6.4Hz), 1.29 (9H, s), 2.98 (3H, s), 3.40-3.47 (1H, m), 4.78 (2H, s; disappeared with heavy water), 5.45 (1H, d, J = 7.8Hz; disappears with heavy water, 5.96 (1H, d, J = 7.2Hz), 6.07 (1H, t, J = 2.2Hz), 6.20 (1H, dd, J 8.1 and β 1.9 Hz), 6.60 (1H, s), 6.71 (2H, s), 6.93 (1H, t, J = 8.lHz). 200300677 (Reference Example 3) N-(5-(3 -bromobenzene Oxy) -2 -nitrophenyl) -N-methylcarbamate tert-butyl ester in 2.5 ml of sodium hydride (55% by weight) in 50 ml of anhydrous N, N-dimethylformyl Add 1.0 mg of 3-bromophenol to the amine suspension, and stir under ice-cooling for 15 minutes. Add 1 6.6 g of N-(5-chloro-2 -nitrophenyl) -N -methanine Tributyl ester, 70 ml dissolved in anhydrous N, N-dimethylformamide, and stirred at 100 ° C for 3 hours. The reaction mixture was concentrated, water was added, neutralized with 3 N hydrochloric acid, extracted with ethyl acetate, and saturated with The solution was washed with brine, dried over anhydrous sodium sulfate, and ethyl acetate was distilled off. The insoluble precipitate was collected by filtration, washed with hexane, and dried under reduced pressure to obtain the title compound (2 0.2 g, yield 83%). O-NMiUCDCldS: 1.24 (9Η, s), 3.19 (3H, s), 6.97 (1H, dd, J = 9.0 and β2.4Ηζ), 7.22 (1H, d, J = 7.9Hz), 7.29 (1H, d, J = 1.7Hz), 7.42-7.51 (3H, m), 8.03 (1H, d, J = 9.0Hz). (Reference Example 4) N- (5- (3- (isobutyl- Methyl-amino) phenoxy) -2-nitrophenyl) -N-methylaminocarboxylic acid tert-butyl ester 7 0 0.0 mg of N · (5-(3-bromophenoxy) obtained in Reference Example 3 -2-Nitrophenyl) -N-methylcarbamate tert-butyl ester, 0.24 ml isobutyl methylamine, 151.0 mg ginsyl (dibenzylideneacetone) palladium, 115.7 mg 2- (dicyclohexylphosphino) Benzene and 27 7 .7 mg of potassium third butoxide was suspended in 4 ml of anhydrous toluene and stirred at 100 t: 1.5 hours. Water was added to the reaction mixture, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1/7). To give the title compound (204.2 mg, yield 29%). 200300677 Ή-NMILI (CDCls) δ 0.80 (6Η, d, J = 6.6Hz), 1.25 (9Η, s), 1.88-2.01 (1H, ~ m), 2.85 (3H, s), 2.95 (2H, d , J = 7.3Hz), 3.14 (3H, s), 6.20 ^ 6.27 (2H, m), 6.43 (1H, dd, J = 8.8 and β 2.2Hz), 6.72-6.83 (2H, m), 7.11 (1H , t, J = 8.lHz), 7.81 (1H, d, J 9.5Hz) ·. (Reference Example 5) N- (2-amino- 5- (3- (isobutyl-methyl-amine Group) phenoxy) _phenyl) -N-methylcarbamic acid third butyl ester 204.2 mg of N- (5- (3-isobutyl-methyl-amino) phenoxy) obtained in Reference Example 4 -2-Nitrophenyl) -N-methylcarbamic acid third butyl ester was dissolved in ethanol, Lugar 100,0 mg 10% Pd-C, and stirred vigorously under hydrogen at room temperature for 2.5 hours. After the reaction was completed, the catalyst was filtered off, and the solvent was distilled off. The obtained sores were subjected to silica gel column chromatography (ethyl acetate / n-hexane = 1 / 4-1 / 3) to obtain the title compound (I4 5.4mg, yield). 7 7%). -Ή-NMR (CDCls) (5: 0.90 (6H, d, J = 6.6Hz), 1.57 (9H, s), 1.98-2.09 (1H, m), 2.92 (3H, s), 3.0 · 6 ( 2Η, d, J = 7.3Hz), 3.i3 (3H, s), 3,64 (2H, s; · Heavier water disappears, 6.30 (1H, t, J = 2.2Hz), 6.35 (1H, dd , J = 8 · 1 and β 2.2Hz), 6.70-6.88 (3H, m), 7.08 (1H, t, J = 8.2Hz), 7.25-7.3K1H, m). Φ (Reference Example 6) (4- (Isobutyl-methyl-amino) phenoxy) -Third butyl dimethyl sand will be 5ml of (4-bromophenoxy) third butyl dimethyl sand, 2.9ml is different Butyl methylamine, 458.0 mg of acetic acid, 1.2 g of 2-(-second butyl scale) biphenyl and 2.9 g of sodium butyrate were suspended in 40 ml of anhydrous toluene. After stirring at 100 ° C for 1.5 hours, the catalyst was filtered off. Water was added, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography (ethyl acetate / n-hexane = 1 / 40-1 / 2). ) -38 · 200300677 to obtain the title compound (3.83 g, yield 64%). Ή-NMR (CDCls) (5: 0.16 (6H, s), 0.9l (6H, d, J = 6.6Hz), 0.97 (9H, s), 1.94-2.05 (1H, m), 2.87 (3H, s), 2.98 (2H , d, J = 7.3Hz), 6.57 (2H, d, J = 8.8Hz), 6.72 (2H, d, J = 8.8Hz). (Reference Example 7) N- (5- (4- (isobutyl -Methyl-amino) phenoxy) -2-nitrophenyl) methylamine (4- (isobutyl-methyl-amino) phenoxy) obtained from 3.83 g of Reference Example 6 Dimethyl silane was dissolved in 20 ml of anhydrous tetrahydrofuran, and 1 20 ml of a 1 M solution of tetra-n-butylammonium fluoride-tetrahydrofuran was added. After stirring at room temperature for 30 minutes, the reaction mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate. The solution was washed with brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1/5), and the obtained precipitate was dissolved in 4 N hydrochloric acid-1,4. -Dioxane, after stirring at room temperature for 30 minutes, the reaction solution was concentrated and washed with ether to obtain the intermediate 4-isobutylmethylaminophenol monohydrochloride. 500.0 mg of this intermediate and 2.6 g of carbonic acid Potassium was suspended in 20 ml of anhydrous N, N-dimethylformamide, and after stirring at room temperature for 15 minutes, 6 6 4.7 mg of N- (5-chloro-2-nitrophenyl) -N-methylamine formic acid was added. Tributyl ester was stirred at 150 ° C for 3 hours. The reaction mixture was concentrated, water was added, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography (ethyl acetate / toluene = 1/30). Purification gave the title compound (25.6 · 1 in g, yield 34%). Nightmare-NMR (CDCh) (5: 0.96 (6H, d, J = 6.8Hz), 2.00-2.13 (lH, m), 2.92 (3H, d, J = 5.9Hz), 2.98 (3H, s), 3.12 (2H, d, J = 7.8Hz), 6.19-6.23 (2H, m), 6.68 (2H, d, J = 8.8Hz), 6.96 (2H, d, J = 8.8Hz), 8.13 (lH, d , J = 9.8Hz). (Reference Example 8) -39- 200300677 N- (2-amino-5- (4- (isobutyl-methyl-amino) phenoxy) -phenyl) methylamine N- (5- (3- (isobutyl-methyl-amino) phenoxy) _2-nitrophenyl) -N-methylcarbamic acid third butyl ester of Reference Example 5 was obtained in Reference Example 7 N- (5- (4- (isobutyl-methyl-amino) phenoxy) -2-nitrophenyl) methylamine, following Reference Example 5 to obtain the title compound. Ή-NMR (CDCla) < 5: 0.88 (6H, d, J = 6.6Hz), 1.94-2.04 (lH, m), 2.77 (3H, s), 2.87 (3H, s), 2.99 (2H, d, J = 7.3Hz), 3.22 (2H, s), 6.16 (1H, dd, J = 8.1 and 5 2.5Hz), 6.33 (1H, d, J = 2.5Hz), 6.57 (lH, d, J = 8.1Hz), 6.59 (2H, d, J = 8.8Hz), 6.87 (2H, d, · J = 8.'8Hz). (Test Example 1) The antitumor effect on human acute premyeloid leukemia cell line HL-60 cells was enhanced. Group of 9 BALB / c nude mice (female, 6 weeks old) subcutaneously transplanted with human acute premyelocytic leukemia Tumor film of cell line HL-60 cells (5mm x 5mm square). The test compound is suspended with 2.5% -methyl acetazol 5% emulsifier, and the day after transplantation is 4 ~ 7, and 7-11 days. On the 14th and 18th, once a day, a total of 14 administrations were performed orally. _ Judgment of the effect The tumor proliferation inhibition effect is determined by the tumor / ® ® (mm) and the long diameter (mm) with an electronic digital ruler. Measure and evaluate the tumor growth inhibition rate (GI%) at the 21st day after transplantation according to the following formula: °

GI(%)= ( 1-A/B) xlOO A :化合物投與組之第2 1日之平均腫瘤體積（* ) B :無處理對照組之第2 1日之平均腫瘤體積（* ) *:腫瘤體積爲l/2x[腫瘤之長徑]X[腫瘤之短徑]2 (試驗例2)對人胃癌株St-40細胞之抗腫瘤效果之增 -40- 200300677 強。 在每組10隻BALB/c裸鼠（雌，6週齢）之皮下移植人 胃癌株St-40細胞之腫瘤片（5mmx5mm四方）。被檢化 合物以含2.5 %二甲基乙醯胺之5 %乳化劑懸浮，在移植 次日〜4日，7日-11曰，14日-18日，21日-25日，每曰1次， 共1 9次經口投與。 效果之判定以腫瘤增殖抑制效果乃將腫瘤之短徑 (mm )及長徑（mm )以電子數位尺計測，仿試驗例1 評價移植後第28日之腫瘤增殖抑制率（GI%)。 (試驗例3)對人急性前骨髓性白血病細胞株HL-60之 癌細胞增殖抑制活性之增強。 將HL-60細胞在96穴板播種lxlO3細胞/穴，並加溶 在D M S〇之各濃度之藥劑使D M S 0濃度0 . 1 %。藥劑之濃 度乃以噻唑啶二酮化合物爲1 0 // Μ，及R X R活性化作用 劑爲1 μ Μ來檢討。藥劑添加後，細胞培養5日。次添加 Μ T S ( P r 〇 m e g a 公司）試劑各 4 0 // 1 / 穴，在 3 7 °C，5 % 二氧 化碳下培養2小時後，各穴之〇D49。用微板讀機（BIO RAD )測定。細胞增殖抑制活性由各組之平均吸光度依 下式算出。 癌細胞增殖抑制率（％ ) = [ 1 -(平均吸光度（細胞+藥劑） -平均吸光度（培養基））/ (平均吸光度（細胞+ D M S〇） -平均吸光度（培養基））]X 1 0 0 (試驗例4)對人大腸癌細胞COL-2_JCK之倂用效果 就噻唑啶二酮化合物R X R活性化作用劑對癌細胞增 殖抑制活性之倂用效果，用人大腸癌細胞COL-2-JCK來 200300677 檢討。將COL-2-〗CK細胞在96穴板播種4x1 Ο3細胞/穴， 並加溶在DMSO之各濃度之藥劑使DMSO濃度0.1%。藥 劑之濃度乃以噻唑啶二酮化合物爲10 // Μ,及RXR活性 化作用劑爲1 // Μ來檢討（η = 4 )。藥劑添加後，細胞培養 4曰。次添加5 0 %三氯乙酸（和光純藥工業公司）各5 0 // 1/穴，在4°C固定1小時後，以自來水洗淨，加0.4 %磺酸基 玫瑰紅（分子探針公司）-1 %乙酸溶液150 # 1/穴，在室溫 染色30分後，用1%乙酸洗淨。將板風乾後，將10mM Tris 添力卩150 // 1/穴，各穴之OD49〇用微板讀機（BIO RAD )測 定。細胞增殖抑制活性由各組之平均吸光度依下式算 出。 癌細胞增殖抑制率（％ ) = [ 1 -(平均吸光度（細胞+藥劑） -平均吸光度（培養基））/ (平均吸光度（細胞+ DMSO ) -平均吸光度（培養基））]xl〇〇 在本試驗中，噻唑啶二酮化合物用以下化合物。 1-胺基- 7- [2-[4-(2,4-二氧噻唑啶-5 -基甲基）苯氧甲 基]-1-甲基-1H -苯并咪唑-6 -基氧基]萘（以下稱「化合物 A」），GI (%) = (1-A / B) x 100 A: average tumor volume on the 21st day of the compound administration group (*) B: average tumor volume on the 21st day of the untreated control group (*) * : The tumor volume is 1 / 2x [the long diameter of the tumor] X [the short diameter of the tumor] 2 (Experiment Example 2) The antitumor effect of human gastric cancer strain St-40 cells is increased by -40-200300677. Tumor slices (5mm x 5mm square) of human gastric cancer strain St-40 cells were transplanted subcutaneously in 10 BALB / c nude mice (female, 6 weeks old) in each group. The test compound was suspended in a 5% emulsifier containing 2.5% dimethylacetamide, and it was administered once a day from the next day to the 4th, the 7th to the 11th, the 14th to the 18th, and the 21st to the 25th. A total of 19 oral administrations. Judgment of the effect The tumor proliferation inhibitory effect was measured by measuring the short diameter (mm) and long diameter (mm) of the tumor with an electronic digital ruler, and the tumor growth inhibition rate (GI%) on the 28th day after transplantation was evaluated following the test example 1. (Experimental example 3) The cancer cell proliferation inhibitory activity of human acute premyeloid leukemia cell line HL-60 was enhanced. HL-60 cells were seeded on a 96-well plate with 1 × 10 3 cells / well, and medicaments dissolved in each concentration of D M S0 were added so that the D M S 0 concentration was 0.1%. The concentration of the medicament was reviewed with a thiazolidinedione compound of 10 / M and an R X R activating agent of 1 μM. After the agent was added, the cells were cultured for 5 days. Add M T S (Pr om ge a) reagent 40 × 1/1 / well each time, and incubate for 2 hours at 37 ° C, 5% carbon dioxide, OD49 in each well. Measured with a microplate reader (BIO RAD). The cell proliferation inhibitory activity was calculated from the average absorbance of each group according to the following formula. Cancer cell proliferation inhibition rate (%) = [1-(average absorbance (cell + agent)-average absorbance (medium)) / (average absorbance (cell + DMS〇)-average absorbance (medium))] X 1 0 0 ( Test Example 4) Effect on human colorectal cancer cell COL-2_JCK For the effect of thiazidinedione compound RXR activator on cancer cell proliferation inhibitory activity, use human colorectal cancer cell COL-2-JCK to 200300677 to review . COL-2-〗 CK cells were seeded in a 96-well plate with 4 × 10 cells / well, and the medicaments dissolved in each concentration of DMSO were added to the DMSO concentration of 0.1%. The concentration of the drug was reviewed with a thiazolidinedione compound of 10 // M and an RXR activating agent of 1 // M (η = 4). After the agent was added, the cells were cultured for 4 days. Add 50% trichloroacetic acid (Wako Pure Chemical Industries, Ltd.) 50/1/1 / times. After fixing at 4 ° C for 1 hour, wash with tap water and add 0.4% sulfo rose red (molecular probe). Company) -1% acetic acid solution 150 # 1 / hole, after 30 minutes of dyeing at room temperature, wash with 1% acetic acid. After the plate was air-dried, 10 mM Tris was added at 150 // 1 / hole, and the OD49 of each hole was measured with a microplate reader (BIO RAD). The cell proliferation inhibitory activity was calculated from the average absorbance of each group according to the following formula. Cancer cell proliferation inhibition rate (%) = [1-(average absorbance (cell + drug)-average absorbance (medium)) / (average absorbance (cell + DMSO)-average absorbance (medium))] x 100 in this test In the thiazolidinedione compound, the following compounds are used. 1-amino-7- [2- [4- (2,4-dioxothiazol-5-yl) phenoxymethyl] -1-methyl-1H-benzimidazole-6-yloxy []] Naphthalene (hereinafter referred to as "compound A"),

1-胺基- 6- [2-[4-(2,4 -二氧噻唑啶-5-基甲基）苯氧甲 基]-1-甲基-1H -苯并咪唑-6 -基氧基]萘（以下稱「化合物 B」）， -42- 2003006771-amino-6- [2- [4- (2,4-dioxothiazol-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazole-6-yloxy Yl] naphthalene (hereinafter referred to as "compound B"), -42- 200300677

1-胺基- 5- [2-[4-(2,4-二氧噻唑啶-5-基甲基）苯氧甲 基]-1-甲基-1H -苯并咪唑-6-基氧基]萘（以下稱「化合物 C」），1-amino- 5- [2- [4- (2,4-dioxothiazol-5-ylmethyl) phenoxymethyl] -1-methyl-1H -benzimidazole-6-yloxy []] Naphthalene (hereinafter referred to as "compound C"),

3-[2-[4-(2,4-二氧噻唑啶-5-基甲基）苯氧甲基]-1-甲基 -1H-苯并咪唑-6-基氧基]苯胺（以下稱「化合物D」），3- [2- [4- (2,4-dioxothiazol-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazole-6-yloxy] aniline (hereinafter Called "Compound D"),

製造例1之化合物Compound of Production Example 1

(以下稱「化合物E」）。 及5-(4-(6-(4 -胺基-3, 5 -二甲苯氧基）-1-甲基-1H -苯 并咪唑-2 -基甲氧基）-苄基）噻唑啶-2，4 -二酮二鹽酸鹽（以 -43- 200300677 下稱「化合物F」），(Hereinafter referred to as "compound E"). And 5- (4- (6- (4-amino-4,5-xylyloxy) -1-methyl-1H-benzimidazole-2-ylmethoxy) -benzyl) thiazolidine- 2,4-dione dihydrochloride (hereinafter referred to as "compound F" as -43- 200300677),

CHUCHU

至於R X R活性化作用劑，用前述L G 1 0 0 2 6 8及達克列 丁。 結果如表1。 [表1】 · 被檢化合物 増殖抑制率（％) 化合物A 1 4 % LG100268 6 % 化合物A + L G 100268 4 8 %As the R X R activating agent, the aforementioned L G 1 0 2 68 and daclidene were used. The results are shown in Table 1. [Table 1] · Test compound Spore inhibition rate (%) Compound A 1 4% LG100268 6% Compound A + L G 100268 4 8%

化合物C 2 2% 達克列丁 1 0 % LG100268 3 % 化合物C+達克列丁 4 2 % 化合物C + L G 1 0 0 2 6 8 3 7 % 化合物D 2 7 % 達克列丁 1 0 % L G 1 0 0 2 6 8 3 % 化合物D+達克列丁 4 0 % 化合物D + LG 1 0 0 2 6 8 3 9 % -44- 200300677 化合物B 2 1 % L G 1 0 0 2 6 8 1 % 化合物B + LG 1 0 0 2 6 8 3 9 % 化合物E 2 6 % LG100268 1 % 化合物E + L G 1 0 0 2 6 8 3 7 % 化合物F 2 8 % 達克列丁 1 1 % 化合物F+達克列丁 4 2 % 由表1得知，將屬於噻唑啶二酮化合物之化合物A、 B、C、D、E或F，及屬於RXR活性化作用劑之LG100268或 達克列丁組合使用，則比各單獨使用更顯著增強增殖抑 制效果。 (製劑例） 錠劑 製造例1之化合物4.0mg、達克列丁 l〇〇.〇mg、乳糖 244.0mg、玉米澱粉50.0g及硬脂酸鎂2.0mg混合而打錠 成每錠400mg之錠劑。 [產業上利用可能性] 本發明之噻唑啶二酮化合物或其藥理容許鹽，及 R X R活性化作用劑或其藥理容許鹽組合使用，則比各單 獨使用更顯著增強增殖抑制效果。 本發明之噻唑啶二酮化合物或其藥理容許鹽，及RXR 活性化作用劑或其藥理容許鹽同時或隔時分別投與之 醫藥組成物具有優異之細胞增殖抑制作用，故可當作癌 (尤其肺癌、胃癌或大腸癌）之治療劑或預防劑（尤其 治療劑）。 -45-Compound C 2 2% Dacletin 10% LG 100268 3% Compound C + Dacletin 4 2% Compound C + LG 1 0 0 2 6 8 3 7% Compound D 2 7% Dacletin 10% LG 1 0 0 2 6 8 3% Compound D + Dacletin 40% Compound D + LG 1 0 0 2 6 8 3 9% -44- 200300677 Compound B 2 1% LG 1 0 0 2 6 8 1% Compound B + LG 1 0 0 2 6 8 3 9% Compound E 2 6% LG100268 1% Compound E + LG 1 0 0 2 6 8 3 7% Compound F 2 8% Daclidine 1 1% Compound F + Daclidine 4 2% It is known from Table 1 that the compound A, B, C, D, E or F belonging to the thiazolidinedione compound and the LG100268 or daclitin which is an RXR activating agent are used in combination. When used alone, the proliferation inhibitory effect is more significantly enhanced. (Formulation example) 4.0 mg of compound, daltelide 10 mg, 244.0 mg of lactose, 50.0 g of corn starch, and 2.0 mg of magnesium stearate were mixed in a tablet manufacturing example 1 to form a tablet of 400 mg per tablet Agent. [Industrial Applicability] The combined use of the thiazolidinedione compound or its pharmacologically acceptable salt and the R X R activating agent or its pharmacologically acceptable salt of the present invention can significantly enhance the effect of inhibiting proliferation than when used alone. The thiazolidinedione compound or a pharmacologically acceptable salt thereof and the pharmaceutical composition of the RXR activation agent or a pharmacologically acceptable salt thereof administered at the same time or at separate intervals have excellent cell proliferation inhibitory effects, so they can be regarded as cancer ( Especially for lung cancer, stomach cancer or colorectal cancer). -45-

Claims (1)

200300677 拾、申請專利範圍 1 . 一種癌症預防或治療用醫藥組成物，內含有效成分 1種或2種以上如下式（I)噻唑啶二酮化合物或其藥 理容許鹽200300677 Patent application scope 1. A pharmaceutical composition for cancer prevention or treatment, containing one or more active ingredients of one or more of the following formula (I) thiazolidinedione compounds or pharmacologically acceptable salts thereof [式中Ar爲芳基（有至少1個-NVR2取代，又可有1 〜4個選自取代基α之基取代）或雜芳基（有至少1 個- NWR2取代，又可有1〜3個選自取代基α之基取 代）， R1及R2爲相同或相異之Η、Cm烷基、Cu。芳基或 C 7 - 1 6芳院基， X爲0或S原子， Y爲=CH-或N 上述取代基α爲由Cl-6院基、Cl_6院氧基、鹵素及經 基而成之取代基群]及1種或2種以上RXR活性化作 用劑或其藥理容許鹽同時或隔時分別投與。 2 .如申請專利範圍第1項之醫藥組成物，其中Ar爲苯基 (有至少1個-NfR2取代，又可有1〜4個選自取代基 α之基取代）或吡啶基（有至少1個-NWR2取代，又可 有1〜3個選自取代基α之基取代）者。 3 .如申請專利範圍第1項之醫藥組成物，其中Ar爲苯基 (有1個-NRiR2取代，又可有1〜4個Ci-6烷基取代）或 -46 - 200300677 吡啶基（有1個-N R 1 R 2取代，又可有1〜3個C !. 6烷基取 ， 代）者。 4 .如申請專利範圍第1項之醫藥組成物，其中Ar爲苯基 (有至少1個- NVR2取代，又可有1〜4個選自取代基α 之基取代）者。 5 .如申請專利範圍第1項之醫藥組成物，其中Ar爲苯基 (有1個-N R 1 R 2取代，又可有1〜4個C !· 6烷基取代）者。 6.如申請專利範圍第1項之醫藥組成物，其中Αι*爲苯基 (有1個-N R | R 2取代）者。 β 7 .如申請專利範圍第1〜6項中任一項之醫藥組成物，其 中R1及R2爲相同或相異之H、Cm烷基或Cm芳基者。 8 .如申請專利範圍第1〜6項中任一項之醫藥組成物，其 中R1及R2爲相同或相異之Η或Cm烷基者。 9.如申請專利範圍第1〜6項中任一項之醫藥組成物，其 中R1爲Cm烷基，R2爲Η者。 1 〇.如申請專利範圍第1〜9項中任一項之醫藥組成物，其 中X爲〇原子者。 鲁 1 1.如申請專利範圍第1〜1 〇項中任一項之醫藥組成物，其 中Υ爲=CH-者。 1 2.如申請專利範圍第1項之醫藥組成物，其中噻唑啶二酮 化合物爲： 1 -胺基-7 - [ 2 - [ 4 - ( 2,4 -二氧噻唑啶-5 -基甲基）苯氧甲 基]_丨-甲基-苯并咪唑-6-基氧基]萘， 1-胺基-6-[2-[4-(2,4-二氧噻唑啶-5-基甲基）苯氧甲 基]甲基-苯并咪唑-6-基氧基]萘， -47- 200300677 1-胺基-5 - [ 2 - [ 4 - ( 2,4 -二氧噻唑啶-5 -基甲基）苯氧甲 / 基卜1-甲基-1H -苯并咪唑-6-基氧基]萘， 3-[2-[4-(2,4 -二氧噻唑啶-5-基甲基）苯氧甲基]-1-甲基 ’ -1H -苯并咪唑-6-基氧基]苯胺、 5-(4-(6-(3-異丙胺基-苯氧基）-1-甲基-1H-苯并咪唑- 2-基甲氧基）-苄基）噻唑啶-2,4 -二酮，或 5-(4-(6-(4 -胺基-3, 5 -二甲苯氧基）-1-甲基-1H -苯并咪 唑-2 -基甲氧基）-苄基）噻唑啶-2,4 -二酮 或這些之藥理容許鹽。 φ 1 3 .如申請專利範圍第1〜1 2項中任一項之醫藥組成物，其 中RXR活性化作用劑爲ATRA、9-順-視黄酸、LG 1 0026 8 或達克列丁。 1 4.如申請專利範圍第1〜1 3項中任一項之醫藥組成物，用 以預防或治療肺癌、胃癌或大腸癌。[Wherein Ar is an aryl group (with at least one -NVR2 substitution, and may have 1 to 4 substituents selected from the substituent α) or a heteroaryl group (with at least one -NWR2 substitution, and may also have 1 to 3 substituents selected from the substituent α), R1 and R2 are the same or different fluorene, Cm alkyl, Cu. Aryl or C 7-1 6 aromatic radical, X is 0 or S atom, Y is = CH- or N The above-mentioned substituent α is formed by Cl-6 radical, Cl_6 radical oxygen, halogen and the radical Substituent group] and one or two or more RXR activating agents or pharmacologically acceptable salts thereof are administered at the same time or separately. 2. The pharmaceutical composition according to item 1 of the scope of patent application, wherein Ar is phenyl (with at least 1 -NfR2 substitution, and may have 1 to 4 substituents selected from substituent α) or pyridyl (with at least 1 1 -NWR2 substitution, and 1 ~ 3 substituents selected from substituent α). 3. The pharmaceutical composition according to item 1 of the scope of patent application, wherein Ar is phenyl (with 1 -NRiR2 substitution, and may have 1 to 4 Ci-6 alkyl substitutions) or -46-200300677 pyridyl (with 1 -NR 1 R 2 substitution, and 1 ~ 3 C !. 6 alkyl groups can be substituted. 4. The pharmaceutical composition according to item 1 of the scope of patent application, wherein Ar is phenyl (having at least one -NVR2 substitution, and optionally having 1 to 4 substituents selected from substituent α). 5. The pharmaceutical composition according to item 1 of the patent application range, in which Ar is phenyl (1 -N R 1 R 2 substituted, and 1 to 4 C! · 6 alkyl substituted). 6. The pharmaceutical composition according to item 1 of the patent application scope, wherein A * is a phenyl group (with 1 -N R | R 2 substituted). β 7. The pharmaceutical composition according to any one of claims 1 to 6 in the scope of patent application, wherein R1 and R2 are the same or different H, Cm alkyl or Cm aryl. 8. The pharmaceutical composition according to any one of the claims 1 to 6, wherein R1 and R2 are the same or different fluorene or Cm alkyl groups. 9. The pharmaceutical composition according to any one of claims 1 to 6, in which R1 is a Cm alkyl group, and R2 is an amalgam. 10. The pharmaceutical composition according to any one of claims 1 to 9 in the scope of patent application, wherein X is 0 atom. Lu 1 1. The pharmaceutical composition according to any one of claims 1 to 10 in the scope of patent application, wherein Υ = CH-. 1 2. The pharmaceutical composition according to item 1 of the scope of patent application, wherein the thiazolidinedione compound is: 1-amino-7-[2-[4-(2,4-dioxothiazol-5 -ylmethyl) ) Phenoxymethyl] _ 丨 -methyl-benzimidazole-6-yloxy] naphthalene, 1-amino-6- [2- [4- (2,4-dioxothiazol-5- Methyl) phenoxymethyl] methyl-benzimidazole-6-yloxy] naphthalene, -47- 200300677 1-amino-5-[2-[4-(2,4 -dioxothiazole -5 -Methyl) phenoxymethyl / 1-methyl-1H-benzimidazole-6-yloxy] naphthalene, 3- [2- [4- (2,4 -dioxothiazole- 5-ylmethyl) phenoxymethyl] -1-methyl '-1H-benzimidazole-6-yloxy] aniline, 5- (4- (6- (3-isopropylamino-phenoxy) ) -1-methyl-1H-benzimidazole-2-ylmethoxy) -benzyl) thiazolidine-2,4-dione, or 5- (4- (6- (4-aminoamino-3) , 5-xylyloxy) -1-methyl-1H-benzimidazole-2-ylmethoxy) -benzyl) thiazolidine-2,4-dione or a pharmacologically acceptable salt of these. φ 1 3. The pharmaceutical composition according to any one of claims 1 to 12 in the scope of patent application, wherein the RXR activating agent is ATRA, 9-cis-retinoic acid, LG 1 0026 8 or daclidene. 1 4. The pharmaceutical composition according to any one of claims 1 to 13 of the scope of patent application, which is used to prevent or treat lung cancer, gastric cancer or colorectal cancer. -48- 200300677 陸、（一）、本案指定代表圖爲·弟—匱 (二）、本代表圖之元件代表符號簡單說明： 渠、卒案若有化學式時，請揭7^最能顯75發明ί寸徵的体學 -4^ · --48- 200300677 Lu, (1), the designated representative of this case is · Brother-Kui (II), the component representative symbols of this representative map are simply explained: If there is a chemical formula in the case of a canal or a death, please disclose 7 ^ The most significant 75 Invented the physical science of 寸 inch sign-4 ^ ·-
TW091135697A 2001-12-11 2002-12-10 A pharmaceutical composition TW200300677A (en)

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