TW200404540A - Drug delivery system of substituted hydropyridine compound, and conjugate of substituted hydroxypyridine compound - Google Patents
Drug delivery system of substituted hydropyridine compound, and conjugate of substituted hydroxypyridine compound Download PDFInfo
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Abstract
Description
200404540 玖、發明說明： 【發明所屬之技術領域】 本發明係關於輕基具取代基之此淀化合物的藥物傳送 系統，詳言之，係關於具有第iv型磷酸二酯酶 (phosphodiesterase)(簡稱 PDE IV)之阻遏（inhibition) 作用，可抑制氣喘、慢性閉塞性呼吸器疾病、呼吸道炎症 性疾病等之治療劑之副作用，而為促進送達標的組織用之 藥物傳送系統。本發明並係關於利用該藥物傳送系統之新 穎的幾基具取代基之毗嗓化合物的共輛物。 【先前技術】 第IV型磷酸二酯酶廣泛分布於以支氣管平滑肌、嗜 酸性球為首之炎症性細胞，其係以環腺苷酸（以下簡稱 c AMP )之分解為觸酶之酵素。阻遏第IV型磷酸二酿酶者 係被廣泛認定與抑制支氣管平滑肌之收縮，並與抑制炎症 性細胞之活性化相關[現代醫樂化學；2卷，561-572頁（1995 年）]。 具有第IV型磷酸二g旨酶阻遏作用之化合物中，環戊 苯吡酮（Rolipram)等多個化合物廣為所知（US41 93926 號、WO90/1 2961 號、W093/19749 號）。在 w〇〇〇/2〇391 號中則揭示有下述式（A )所示2，3 —二取代毗啶衍生物 具有第IV型磷酸二酯酶阻遏作用者。 3 r r- 200404540200404540 (1) Description of the invention: [Technical field to which the invention belongs] The present invention relates to a drug delivery system for a lightly substituted compound, and in particular, it relates to a type iv phosphodiesterase (referred to as The inhibitory effect of PDE IV) can suppress the side effects of therapeutic agents such as asthma, chronic obstructive respiratory disease, and respiratory inflammatory diseases, and is a drug delivery system for promoting the delivery of targeted tissues. The present invention also relates to a total of several novel substituent-adjacent compounds using the drug delivery system. [Prior technology] Type IV phosphodiesterase is widely distributed in inflammatory cells led by bronchial smooth muscle and eosinophils. It is an enzyme that breaks down cyclic adenylate (hereinafter referred to as c AMP) into a catalase. Blockers of type IV phosphodiesterase are widely recognized as related to inhibiting the contraction of bronchial smooth muscle and related to inhibiting the activation of inflammatory cells [Modern Medical Music Chemistry; Vol. 2, pp. 561-572 (1995)]. Among the compounds having a type IV phosphoric acid diglyceride repressive effect, many compounds such as cyclopentazone (Rolipram) are widely known (US41 93926, WO90 / 1 2961, W093 / 19749). No. WO / 2〇391 discloses that the 2,3-disubstituted pyrimidine derivative represented by the following formula (A) has a type IV phosphodiesterase repressor. 3 r r- 200404540
(A) 式中，Α為乳原子’硫原子，chrI或NR2 ; R1石 氯原子或低碳數燒基；X1及χ2為相同或相異之氫 _原子，硝基，氰基，羥基，低碳數烷基，羥基3 數烷基等；Υ1為氫原子或低碳數烷基；ζ1及Ζ2為 相異之氫原子，齒原子，氰基，#i基，低碳數烷』 取代低碳數燒基等；η為2〜4之整數 然而該等具有第IV型磷納 a㉟^:二酯酶阻遏作用之 合物，係以刺激嘔吐中樞，袢山 k成嘔吐等之副作用| 知。因此遂需開發一種不且5丨丨仏 ， 〃 Μ作用或副作用較小二 目前非常盛行之研究為抑 — Ρ制樂物之副作用並^ 效率之藥效，物送達目的地之組織或臟器，』 部集中送達之所！胃藥物傳送“。此藥物傳送系^ 係謀求使藥物送達標的處所之靶標（targeUng)， 外，並可在活體中改善藥物吸收或控制活體内藥； 方式進行。 R2為 承子， 代低碳 :目同或 ，羥基 &數化 廣為所 藥物。 揮更有 者對局 之研究 除此以 释出等 4 200404540 【發明内容】 本發明人等為發現具第iv型磷酸二酯酶阻遏作用化 合物，JL盡可能抑制該等化合物副作用，以充分發揮所要 效果之藥物傳送系統，乃進行一連串有關第IV型磷酸二 酯酶陬遏化合物中經口投藥之藥物動態的調查，在種種重 覆之探讨中’終於發現某種羥基具取代基之毗啶化合物在 經口投藥後’會在活體内吸收過程中變化成某種共軛物， 其藥效玎集中送達於所要之標的組織，並可大幅發揮其藥 理活性。 /般經口投藥之藥物被消化遒所吸收，主要由肝臟以 藥物代謝酵素進行共輛等化學變化，該共輛物並無賦予藥 效，而被認為係由尿中及膽汁中***[參照Mulder，G.J. (1 99〇年）：在藥物代謝過程中之共軛反應，英國倫敦： 泰勒及法蘭西氏]。 依本發明人等之研究發現，特定羥基具取代基之吡啶 化合物之共輛物其本身具有藥理活性，同時可集中送達至 所要之臟器「肺」，而可發揮其藥理活性，進而在該臟器 内徐徐地變換成原來之羥基毗啶化合物，進而可發揮藥理 作用，故可持續的得到所要之效果，因而完成本發明。 因此本發明係提供一種羥基具取代基之吡啶化八物之 藥物傳送系統，其包含·· 口 I )經口投藥給予該羥基具取代基之毗啶化合物， II )在活體内之吸收過程使該羥基具取代基之吡啶 化合物變換成共軛物， 5 200404540 iii ) 將該共輛物送達於標的組織。 本發明之藥物傳送系統中，進一步送達標的組織之共 軛物不僅可達到藥效，同時可徐徐地變換成原來的具羥基 取代基之毗啶化合物，進而可發揮第IV型磷酸二酯酶之 阻遏活性，使藥理效果更長期之持續。 本發明之藥物傳送系統中之羥基具取代基之也啶化合 物係為下式（I )所示之化合物及其生理上可容許之鹽：(A) In the formula, A is a milk atom, a sulfur atom, chrI or NR2; R1 is a chlorine atom or a low carbon number alkyl group; X1 and χ2 are the same or different hydrogen atom, nitro group, cyano group, hydroxyl group, Low carbon number alkyl, hydroxy 3 number alkyl, etc .; Υ1 is a hydrogen atom or a low carbon number alkyl; ζ1 and Zn2 are different hydrogen atoms, tooth atoms, cyano, #i group, low carbon number Low carbon number, etc .; η is an integer of 2 ~ 4. However, these compounds have type IV phosphona a㉟ ^: diesterase inhibitory effects, which are used to stimulate the center of vomiting and side effects such as vomiting and vomiting | know. Therefore, it is necessary to develop a method that does not have a small effect or side effect. At present, the research that is very popular is to suppress the side effects of P-music products and the efficacy of efficiency. The material is delivered to the destination tissue or organ. , 』Department of centralized delivery! Gastric drug delivery ". This drug delivery system is a target (targeUng) of the place where the drug is delivered to the target, and it can improve drug absorption in the living body or control the drug in the body; the method is performed. R2 is the carrier, which is low-carbon: In the same way, hydroxyl & digitization is widely used as a drug. In addition to the research of the game, it is released by the release etc. 4 200404540 [Summary of the invention] The inventors have found that the type iv phosphodiesterase represses Compounds, JL try to suppress the side effects of these compounds as much as possible, in order to fully exert the desired effect of the drug delivery system, is to conduct a series of investigations on the drug dynamics of oral administration of type IV phosphodiesterase inhibitor compounds, repeated in various During the discussion, 'finally found that a certain hydroxyl-substituted pyrimidine compound after oral administration' will change into a conjugate during absorption in vivo, and its efficacy will be concentrated and delivered to the desired target tissue, and Greatly exert its pharmacological activity. / Orally administered drugs are absorbed by digestive ridges, and are mainly subjected to chemical changes such as drug metabolism enzymes by the liver. Substances do not confer efficacy, but are thought to be excreted in urine and bile [cf. Mulder, GJ (1990): Conjugation during drug metabolism, London, UK: Taylor and France's]. The research by the present inventors has found that the common compounds of pyridine compounds having specific hydroxyl groups have pharmacological activity, and can be delivered to the desired organ "lung" at the same time, and their pharmacological activity can be exerted. The inside of the device is slowly transformed into the original hydroxypyridine compound, which can further exert its pharmacological action, so that the desired effect can be continuously obtained, and the present invention has been completed. Therefore, the present invention provides a drug delivery system of pyridinated octyl with a substituted hydroxyl group, which comprises ... orally administering the substituted pyridyl compound with a hydroxyl group, and II) the absorption process in vivo The hydroxy-substituted pyridine compound is transformed into a conjugate, and 5 200404540 iii) the common substance is delivered to the target tissue. In the drug delivery system of the present invention, the conjugates of the tissues that further reach the standard can not only achieve the drug effect, but also slowly transform into the original pyrimidine compound with a hydroxy substituent, and then can play the role of type IV phosphodiesterase. Suppresses the activity and makes the pharmacological effect last longer. The pyridyl compounds having a hydroxy group in the drug delivery system of the present invention are compounds represented by the following formula (I) and physiologically acceptable salts thereof:
式中A為氧原子，硫原子，CHR1或NR2，R1及R2為氫原 子或低碳數烷基；X1及X2為相同或相異之氫原子，鹵原 子，硝基，氰基，低碳數烷基，li代低碳數烷基，低級烷 氧基，環低級烷氧基，i代低級烷氧基、低級烷氧基取代 低級燒氧基，低級燒氧羰基取代低級燒氧基，低級燒氧黢 基，單或二低級烷氨基羰基，低級醯基，低級醯氧基，氨 基，低級醯氨基或胺甲醯基， Y1係氫原子或低碳數烷基， z1係氫原子，函原子，氰基，低碳數烷基，iS代低 6 200404540 碳數燒基，低級燒氧基，環低級燒氧基，函代低級燒氧基、 低級烷氧基取代低級烷氧基，低級烷氧基羰基取代低級烷 氧基，低級烷氧基羰基，單或二低級烷氨基羰基，低級醯 氧基，氨基，單或二低碳數烷基氨基，低級醯氨基或胺甲 醯基，低級烷氧基羰氨基，低碳數烷基磺醯胺基或胺甲醯 基，η為2〜4之整數。 本發明藥物傳送系統中較佳之化合物在上式（I )中， Α為氧原子或硫原子，X1及X2為相同或相異之氫原子， 鹵原子，氰基，低碳數烷基，低級烷氧基，低級烷氧基羰 基，單或二低級烷氨基羰基或低級醯基，Y1為氫原子、Z1 為氫原子，i原子，氰基，低碳數烷基，低級烷氧基，低 級烷氧基羰基，單或二低碳數烷基氨基羰基或氨基，η為 2〜4整數之化合物。 更佳之化合物有，Α為氧原子，X1及X2之任一為氫 原子而另一則為鹵原子，Y1為氫原子，Z1為氫原子，η 為3之化合物。In the formula, A is oxygen atom, sulfur atom, CHR1 or NR2, R1 and R2 are hydrogen atom or low carbon number alkyl; X1 and X2 are the same or different hydrogen atom, halogen atom, nitro, cyano, low carbon Number alkyl, li substituted lower carbon number alkyl, lower alkoxy, cyclic lower alkoxy, i substituted lower alkoxy, lower alkoxy substituted lower alkoxy, lower oxycarbonyl substituted lower oxy, Lower oxyhalofluorenyl, mono- or di-lower alkylaminocarbonyl, lower fluorenyl, lower fluorenyloxy, amino, lower fluorenamino or carbamoyl, Y1 hydrogen atom or lower carbon alkyl group, z1 hydrogen atom, Function atom, cyano group, lower carbon number alkyl group, iS lower 6 200404540 carbon number alkyl group, lower alkyl group, cyclo lower alkyl group, lower alkyl group, lower alkyl group substituted lower alkyl group, Lower alkoxycarbonyl replaces lower alkoxy, lower alkoxycarbonyl, mono- or di-lower alkylaminocarbonyl, lower fluorenyloxy, amino, mono- or di-lower alkylamino, lower fluorenylamino or carbamate , Lower alkoxycarbonylamino, low carbon alkylsulfonamido or carbamoyl, η is an integer from 2 to 4. The preferred compounds in the drug delivery system of the present invention are in the above formula (I), A is an oxygen atom or a sulfur atom, X1 and X2 are the same or different hydrogen atoms, a halogen atom, a cyano group, a lower carbon number alkyl group, a lower Alkoxy, lower alkoxycarbonyl, mono- or di-lower alkylaminocarbonyl or lower fluorenyl, Y1 is a hydrogen atom, Z1 is a hydrogen atom, i atom, cyano, lower carbon alkyl, lower alkoxy, lower Alkoxycarbonyl, mono- or di-lower alkylaminocarbonyl or amino compounds, where η is an integer from 2 to 4 More preferred compounds are compounds in which A is an oxygen atom, one of X1 and X2 is a hydrogen atom and the other is a halogen atom, Y1 is a hydrogen atom, Z1 is a hydrogen atom, and η is 3.
特佳之化合物則如下述式（ΙΑ )所示之化合物：A particularly preferred compound is a compound represented by the following formula (IA):
(IA) 7 200404540 在本說明書中，「式（i)所示化合物之共軛物」係在 式（I)所示之化合物使葡酸酸（glucuronic acid)殘基或 硫酸殘基键結之化合物。具體而言，係指式（I )所示化 合物在羥基毗啶環中羥基之氫原子係以葡醛酸殘基所取代 之化合物或以硫酸殘基所取代之化合物，及/或羥基说啶 環中使葡醛酸殘基键結於氮原子之化合物。以式（I )所 示之化合物或其他之化合物為原料，藉化學上變換製造而 得之化合物，不僅含此化合物，亦含式（I )所示化合物 在活體内經藥物代謝酵素所共軛產生之化合物。 在本說明書中所謂「葡醛酸殘基」係指在葡醛酸之1 位碳原子所鍵結之基，而「硫酸殘基」係指以硫酸之硫原 子鍵結之基。 但是在本發明之藥物傳送系統中，活體内吸收過程所 形成之式（I )之共軛物，係指下式（Π ):(IA) 7 200404540 In the present specification, the "conjugate of the compound represented by formula (i)" is a compound in which a compound represented by formula (I) binds a glucuronic acid residue or a sulfuric acid residue. Compounds. Specifically, it refers to a compound of formula (I) in which a hydrogen atom of a hydroxyl group in a hydroxypyridine ring is a compound substituted with a glucuronic acid residue or a compound substituted with a sulfuric acid residue, and / or a hydroxyl group A compound in which a glucuronic acid residue is bonded to a nitrogen atom in a ring. A compound produced by chemical conversion using a compound represented by formula (I) or other compounds as a raw material, not only contains this compound, but also contains a compound represented by formula (I) conjugated in vivo by a drug-metabolizing enzyme. The resulting compound. In the present specification, the "glucuronic acid residue" refers to a group bonded to a carbon atom at the 1-position of glucuronic acid, and the "sulfuric acid residue" refers to a group bonded with a sulfur atom of sulfuric acid. However, in the drug delivery system of the present invention, the conjugate of formula (I) formed in the absorption process in vivo refers to the following formula (Π):
式中八、乂1、乂2、丫1及11與前述相同，尺為 8 200404540 或In the formula, eight, 乂 1, 乂 2, ya1, and 11 are the same as above, and the ruler is 8 200404540 or
z1與前述相同，z指葡醛酸殘基或硫酸 殘基，za則為葡醛酸殘基。 上述式（II)所示之共輛物，可在活體外合成，而本 發明之共軛物亦含該等合成共軛物。 本發明之特佳的共軛物係為下式（IIA )所示之化合 物或其生理上可容許之鹽： 〇、 ,Raz1 is the same as above, z is a glucuronic acid residue or a sulfuric acid residue, and za is a glucuronic acid residue. The conjugates represented by the above formula (II) can be synthesized in vitro, and the conjugates of the present invention also include these synthetic conjugates. A particularly preferred conjugate of the present invention is a compound represented by the following formula (IIA) or a physiologically acceptable salt thereof: 〇,, Ra
、N 〇 (IIA), N 〇 (IIA)
ClCl
z為葡醛酸殘基或硫酸殘基，za表示葡醛酸殘基。 本發明中共軛物之特佳之具體例可有下列之化合物或 其生理上容許之鹽： 4 一 [3 — [2 — ( 3 —氯苯氧基）一 3 —说啶氧基]丙基]—3 —说啶基硫酸氫鹽； 1 — Ο — [4 — [3 — [2 — (3 —氯苯氧基）一 3 —17比淀氧基 9 200404540 ]丙基]一 3 —毗啶基]—β — D —葡萄呋喃糖醛酸酯 (glucopyranuronic acid) ; 1 — [4 — [3 — [2 — （ 3 —氯苯氧基）一 3 —说啶氧]丙基] —3 —氧化（oxido) — 1— p 比淀鹽基（pyridinio) — 1—二 氧一β — D —葡萄略喃糖酸酸。 在本說明書中所謂生理上可容許之鹽係指生理上可容 許之酸加成鹽、鹼金屬鹽、鹼土類金屬鹽或有機鹼之鹽類。 較佳是鹼金屬鹽、鹼土類金屬鹽或有機鹼之鹽類。具 體而言，酸加成鹽有鹽酸鹽，氫溴酸鹽，氫碘酸鹽，硫酸 鹽，磷酸鹽等之無機酸鹽及溴酸鹽，順丁烯二酸鹽，反丁 烯二酸鹽，丙二酸鹽，乳酸鹽，蘋果酸鹽，檸檬酸鹽，酒 石酸鹽，安息香酸鹽，甲磺酸鹽，對甲苯磺酸鹽，葡萄糖 酸鹽等有機酸鹽。鹼金屬鹽有鈉鹽，鉀鹽等之無機鹼鹽， 驗土類金屬鹽有，例如妈鹽，鍰鹽，又有機驗之鹽有例如 氨，甲胺，三乙胺，三丁胺，二異丙基乙胺，Ν —甲基嗎 淋，二環己胺等之鹽。 在本說明書中，式（I )所示之化合物之共軛物即係 本發明所記載之共輛物。 式（I )所示化合物之共軛物或其生理上可容許之鹽 係以水合物及或酶合物之形式存在，該等之水合物，酶合 物亦含於本發明之化合物。 又在式（I )所示化合物之共軛物中具有不對稱碳原 子者，而該等立體異構物及該等混合物亦含於本發明之化 合物中。 10 200404540 所示之化合物例如可由W ο ο 〇 / 2 ο 3 9 1公報所 記載之方法來製造。 如前述，一般 而本發明之藥物傳 具有自體藥理活性 送達至所要之臟器 之共輛物被認為並無藥效並被***掉， 送系統中之共軛物，很剛好的其本身就 ’同時在尿中等並不會加速被***而可 ’為非常特殊之共軛物。 亦即，本發明中式（j ) 之一芡式（ΙΑ )化合物予以 態實驗，並對式（ΙΑ)之化 之分布加以檢討，終於究明 之標的組織之一的肺臟内， 的存在相當量之真理。如上 之性質，而本發明之共軛物 具有持續存在之特徵，就此 殊之共軛物。 之化合物中，將特佳化合物 標記，並用此來進行藥物動 合物及其共軛物於各種組織 為第IV型磷酸二酯酶阻遏藥 式（ΙΙΑ )所示之共軛物持續 述共軛物具有一般為易於*** 則大量分布於標的組織，而且 點可證明本發明之化合物為特 進而依本發明人等之研究，本發明之共軛物難以通過 血腦障’因此可判明其在腦中之分布為極少，藉此可顯著 抑制非所望之副作用。亦即一般而言第IV型蹲酸二醋酶 阻遏劑之多數易於通過血腦障，並作用於嘔吐中心，故被 認為會有嘔吐等之副作用，然而本發明之共軛物就此種嘔 吐謗發之副作用極弱為其特徵。此特徵在將式（〗）所示 之化合物投藥於活體之情形，式（1 )所示之化合物因急 速變換成共軛物，而可以顯著抑制其在腦内之分布，結果 則可說明式（I)所示之化合物，與在一般廣泛被認為係 11 200404540 第1v型磷酸二酯酶阻遏劑之副作用的嘔吐謗發作用為極 弱 < 特徵有關聯。 如上述，依本發明之藥物傳送系統，具有式（I)之 化a物之共輛物存在於標的組織相當量，且在與副作用有 關 < 組織只有極少分布的特徵。因此，本發明之共輛物可 為革巴‘醫藥使用。本發明之共輛物所成之醫藥物，可在 &的組織有特徵地分布而可有效率的表現藥效，且可迴避 ^作用，是一種優異之靶標醫藥物。 本發明人等進而究明在本發明共軛物在為標的組織之 的肺中’使式（Ο所示化合物脫共軛，而成為式（I) 所不化合物（以下亦可記載為母藥parent drug )之供給 來源。然而本發明共軛物係分布於標的組織，具有在標的 、織中知徐的被脫共輛而母藥持續的被供給之特徵，可作 為持續性醫藥使用之本發明共軛物的此種特性，在本發明 哥遗系統則具有可使式（I )化合物藥理活性之持續 時間延長的效果。 4而在本發明之共軛物，與式（I )所示之化合物比 較具有& A ^ /合解度高之特徵，並有例如注射劑，儲存劑（dep〇t ) 」租I劑’吸入劑等經肺投藥製劑，點鼻劑等之經鼻投 樂製劑等劑*製造容易之優點。 【實施方式】z is a glucuronic acid residue or a sulfuric acid residue, and za is a glucuronic acid residue. Particularly preferred specific examples of the conjugates in the present invention may include the following compounds or physiologically acceptable salts thereof: 4-a [3- — [2- — (3-chlorophenoxy) — 3-—pyridyloxy] propyl] —3 — Said pyridyl bisulfate; 1 — 0 — [4 — [3 — [2 — (3-chlorophenoxy) — 3 — 17 than dianoxy 9 200404540] propyl] — 3 —pyridine Group] —β — D —glucopyranuronic acid; 1 — [4 — [3 — [2 — (3-chlorophenoxy) — 3 —said-pyridyloxy] propyl] —3 — Oxidation — 1 — p than pyridinio — 1 —dioxo β — D — grape glutaronic acid. The physiologically tolerable salts in this specification refer to physiologically tolerable acid addition salts, alkali metal salts, alkaline earth metal salts, or organic base salts. Preferred are alkali metal salts, alkaline earth metal salts or organic base salts. Specifically, the acid addition salts include hydrochloride, hydrobromide, hydroiodate, sulfate, phosphate, and other inorganic acid salts and bromates, maleates, and fumarate. Organic salts such as salt, malonate, lactate, malate, citrate, tartrate, benzoate, mesylate, p-toluenesulfonate, gluconate, etc. Alkali metal salts include inorganic alkali salts such as sodium salt and potassium salt, and soil test metal salts such as ma salt, osmium salt, and organic test salts such as ammonia, methylamine, triethylamine, tributylamine, and diamine. Isopropylethylamine, N-methylmorphine, dicyclohexylamine and other salts. In this specification, the conjugate of the compound represented by the formula (I) is the common substance described in the present invention. The conjugate of the compound represented by formula (I) or a physiologically acceptable salt thereof exists in the form of a hydrate and / or an enzyme compound, and such hydrates and enzyme compounds are also included in the compound of the present invention. Those having an asymmetric carbon atom in the conjugate of the compound represented by the formula (I), and these stereoisomers and these mixtures are also included in the compound of the present invention. 10 The compound shown in 200404540 can be produced by the method described in, for example, W ο ο 〇 / 2 ο 3 9 1. As mentioned above, in general, the medicaments of the present invention that have autologous pharmacological activity and are delivered to the desired organs are considered to have no medicinal effect and are excreted. The conjugate in the system is very good in itself 'At the same time in the urine does not accelerate the excretion and can be' is a very special conjugate. That is, in the present invention, a compound of formula (IA), which is one of formula (j), is subjected to a state experiment, and the distribution of formula (IA) is reviewed, and it is finally found that there is a considerable amount of lung in one of the target tissues. truth. The above-mentioned properties, and the conjugate of the present invention have the characteristic of persistence. Among the compounds, the best compound is labeled, and the pharmacokinetics and conjugates thereof are used in various tissues to form a type IV phosphodiesterase repressor conjugate shown in Formula (IIIA). It is generally easy to excrete and is widely distributed in the target tissue, and it can be proved that the compound of the present invention is special and according to the research of the inventors, it is difficult for the conjugate of the present invention to pass the blood-brain barrier. The distribution is extremely small, which can significantly suppress undesired side effects. That is, in general, most of the type IV squatting acid diacetase inhibitors easily pass through the blood-brain barrier and act on the vomiting center, so it is considered to have side effects such as vomiting. It is characterized by extremely weak side effects. This feature is the case when the compound represented by the formula () is administered to a living body. The compound represented by the formula (1) can be rapidly transformed into a conjugate, which can significantly inhibit its distribution in the brain. The result can explain the formula The compound shown in (I) has a very weak < characteristic associated with the vomiting effect of a side effect widely considered to be a side effect of 11 200404540 type 1v phosphodiesterase inhibitor. As described above, according to the drug delivery system of the present invention, a total of the compounds of the formula (I) in the target tissue are present in a considerable amount in the target tissue, and are related to side effects < the tissue has only a very small distribution. Therefore, the total article of the present invention can be used for Gaba'medicine. The medicine formed by the common vehicle of the present invention can be characteristically distributed in the tissue of the & tissue, and can effectively display the efficacy, and can avoid the effect, and is an excellent target medicine. The present inventors have further found that in the lungs of the target tissue of the conjugate of the present invention, the compound represented by formula (0) is deconjugated to become a compound not represented by formula (I) (hereinafter also described as the parent drug parent drug) supply source. However, the conjugate of the present invention is distributed in the target tissue, and has the characteristics of being detached from the target and weaving while the parent drug is continuously supplied, which can be used as a continuous medicine of the present invention. Such properties of the conjugate have the effect of extending the duration of the pharmacological activity of the compound of the formula (I) in the brother system of the present invention. 4 The conjugate of the present invention is similar to the formula (I) The compounds are more characteristic of & A ^ / high resolution, and there are, for example, injections, depots (depot), inhalation agents, inhalants, and other pulmonary preparations, and nasal preparations such as nasal drops. Equal agent * The advantage of easy production. [Embodiment]
j吏用本發明代表性之共軛物化合物[式（II A )之化合 12 200404540 物]，以下就其藥理試驗結果及藥理作用說明之。 例1 :第IV型磷酸二酯酶之阻遏活性實驗 天竺鼠第IV型磷酸二酯酶阻遏活性之試驗係根據由 天竺鼠腹腔所分離出之嗜酸性球的方法（參照Souness,J.E 等人，Biochem. Pharmacol.42 ^，93 7 頁（1991 年）） 所實施者。亦即在5x1 07個細胞添加21 OmL之均化緩衝 液（組成：20mM 鹽酸緩衝液（ρΗ7·5) ，2mM氯化鎂， ImM二硫蘇糖醇（dithiothreitol) ，5mM乙二胺四乙酸 二鈉鹽，250mM蔗糖，20μΜ對甲苯磺醯基一1—離胺酸 —氯甲基酮，1 Opg/mL亮肽素）並離心之。在殘渣上添加 1 0ml可溶解緩衝液（在上述之均化緩衝液添加去氧膽酸 納（sodium deoxycholate)(終濃度 0.5% )，氯化鈉（終 濃度lOOmM))，再離心之。使用Molcutll(日本millipore 有限公司製）將上澄液予以超滤（ultrafiltration )，藉添 加1 0 mL均化緩衝液將膜上之分劃予以回收成為酵素標 本。天竺鼠第IV型磷酸二酯酶阻遏活性係在為基質之含 有cAMP ( nacalai tesque公司製）之溶酶（40mM參鹽酸 緩衝液）上添加上述酵素標本，在30分後測定cAMP之 加水分解率的方法中，在使酵素作用之前添加被驗化合物 時之基質加水分解率，與只添加溶媒之對照群的基質加水 分解率比較來計算求得。又由被驗化合物之濃度及作用曲 線來求得50%阻遏濃度（IC5。） （nM)。 人類第IV型磷酸二酯酶阻遏活性之試驗係由健康者 末梢血液，使用密度梯度離心法及CD16微球（microbead) 13 200404540 之MACS (磁性細胞分離系統）負除去法（ deletion )所分離之嗜酸性球加以使用，並使用上述天竺 鼠嗜酸性球之方法來實施者。其結果示於表1 表1第IV型磷酸二酯酶阻遏作用 被驗化合物 天竺鼠第IV型磷酸二酯酶 50%阻遏濃度（nM) 人第IV型磷酸二酯酶 50%阻遏濃度（nM) 實施例1之化合物 848 775 實施例2之化合物 19,300 10,900 一般共軛物雖沒有藥效但如表1可知，本發明之共輛 物（11A )，相對於由天竺鼠嗜酸性球及人嗜酸性球所分 離精製之第IV型磷酸二醋酶，被認為具有強大的阻遏活A representative conjugate compound of the present invention [combination of formula (II A) 12 200404540] is used, and its pharmacological test results and pharmacological effects are explained below. Example 1: Repression activity test of type IV phosphodiesterase The test of type IV phosphodiesterase suppression activity of guinea pigs was based on the method of eosinophils isolated from the peritoneal cavity of guinea pigs (see Souness, JE et al., Biochem. Pharmacol. 42 ^, p. 93 (1991)). That is, 21 × mL of homogenization buffer (composition: 20mM hydrochloric acid buffer (ρΗ7.5)), 2mM magnesium chloride, 1mM dithiothreitol, 5mM ethylenediamine tetraacetic acid disodium salt are added to 5x107 cells. , 250 mM sucrose, 20 μM p-toluenesulfonyl- 1-lysine-chloromethyl ketone, 1 Opg / mL Leupeptin) and centrifuged. Add 10 ml of dissolvable buffer to the residue (sodium deoxycholate (final concentration 0.5%), sodium chloride (final concentration 100 mM)) were added to the above homogenization buffer, and then centrifuged. The supernatant was subjected to ultrafiltration using Molcutll (manufactured by Japan Millipore Co., Ltd.), and the fractions on the membrane were recovered by adding 10 mL of homogenization buffer to be recovered as enzyme samples. Guinea pig type IV phosphodiesterase repressive activity is obtained by adding the above enzyme sample to a lysozyme (40 mM HCl buffer solution) containing cAMP (manufactured by Nacalai Tesque) as a substrate, and measuring the hydrolysis rate of cAMP after 30 minutes. In the method, the matrix hydrolyzation rate when the test compound is added before the enzyme is allowed to act is compared with the matrix hydrolyzation rate of the control group to which only the solvent is added to calculate and obtain. The 50% inhibitory concentration (IC5) (nM) was obtained from the concentration and action curve of the test compound. The test of human type IV phosphodiesterase repressive activity was isolated from the peripheral blood of healthy people using density gradient centrifugation and CD16 microbead 13 200404540 MACS (magnetic cell separation system) negative removal method. An eosinophil was used, and it was implemented using the method of the above-mentioned guinea pig eosinophil. The results are shown in Table 1. Table 1. Type IV phosphodiesterase repression. Test compound. Guinea pig type IV phosphodiesterase 50% repressive concentration (nM). Human type IV phosphodiesterase 50% repressive concentration (nM). The compound of Example 1 848 775 The compound of Example 2 19,300 10,900 Although the general conjugate has no medicinal effect, as shown in Table 1, the common compound (11A) of the present invention is relatively The isolated and purified type IV phosphodiesterase is considered to have strong repressive activity
性。Sex.
試驗例2 :在試管中之抗原謗發支氣管收縮抑制作用 藉由將卵白白蛋白（席格馬公司製）l〇mg投藥於其 腹腔内及皮下來使哈特立（Hartley )系雄性天竺鼠主動 的致敏化。於數週後摘出其氣管，依常法製作Z型（z i g -zag)標本。在保溫於37 °C之馬格納斯管（Magnus tube) 以1 g之張力負荷之並將標本懸吊，透過F D傳感器 (pickup )及應變壓力放大器，來連接於筆記錄器。標本 14 200404540 在0.5至1小時之安定化後，添加使被驗化合物溶解之溶 液於溶媒（含 DMSO -聚乙二醇之克雷布斯-亨斯雷特緩衝 液Krebs-Henseleit buffer)，處置 15分鐘。進而添加卵 白白蛋白1 X 1 0 - 5 g / L，使引起收縮，藉紀錄於紀錄器之收 縮曲線來計測相對於初期值之收縮高，相對於不含被驗化 合物而僅添加溶媒的對照群，被驗化合物添加群之抑制率 被算出，作為收縮抑制作用。其結果如表2所示。Test Example 2: Antigen deflated bronchoconstriction in a test tube. By injecting 10 mg of ovalbumin (manufactured by Sigma) into the abdominal cavity and under the skin, Hartley male guinea pigs were actively Sensitization. After a few weeks, the trachea was removed, and a Z-shaped (z i g -zag) specimen was prepared according to the usual method. A Magnus tube insulated at 37 ° C was loaded with a tension of 1 g and the specimen was suspended, and connected to a pen recorder through a F D sensor (pickup) and a strain pressure amplifier. Specimen 14 200404540 After 0.5 to 1 hour stabilization, add a solution in which the test compound is dissolved in a solvent (containing Krebs-Henseleit buffer containing DMSO-polyethylene glycol) and dispose of it. 15 minutes. Then add ovalbumin 1 X 1 0-5 g / L to cause contraction. The contraction curve recorded in the recorder is used to measure the high contraction relative to the initial value, compared to the control without the test compound and only the solvent. The inhibitory rate of the test compound-added group was calculated as the contraction-inhibiting effect. The results are shown in Table 2.
表2抗原謗發支氣管收縮抑制作用 被驗化合物 濃度（μΜ) 抑制率（％ ) 實施例1之化合物 1 18.5 實施例1之化合物 10 42.2 實施例1之化合物 30 52.9 實施例2之化合物 10 20.3 實施例2之化合物 30 24.5Table 2 Antibodies against bronchoconstriction inhibition Test compound concentration (μM) Inhibition rate (%) Compound of Example 1 18.5 Compound of Example 1 42.2 Compound of Example 1 30 52.9 Compound of Example 2 10 20.3 Implementation Compound of Example 2 30 24.5
由表2可知，本發明之共軛物（IIA )相對於試管内 天竺鼠抗原謗發氣道收縮，顯示強大之抑制作用。 試驗例3 :炎症細胞内cAMP上升作用 由健康者之末梢血液以試驗例1所記載之方法來分離 嗜酸性球，在 1 06個之細胞浮游液添加被驗化合物，培養 15 200404540 2小時。在此添加異丙基腎上腺素（終濃度1 μιη )，進而 培養5分鐘。藉三氯乙酸（終濃度6% )使反應完成之後，It can be seen from Table 2 that the conjugate (IIA) of the present invention exhibits a strong inhibitory effect on the airway contraction of the guinea pig antigen in the test tube. Test Example 3: Increasing effect of cAMP in inflammatory cells. Eosinophils were isolated from the peripheral blood of healthy subjects by the method described in Test Example 1. Test compounds were added to the cell suspension of 106 cells and cultured for 15 200404540 for 2 hours. Isoproterenol (final concentration: 1 μm) was added here, and the mixture was further cultured for 5 minutes. After the reaction was completed by trichloroacetic acid (final concentration 6%),
以***除去三氯乙酸後，以EIA法來測定反應液中之cAMP 量。 以被驗化合物添加群之cAMP量，在僅添加溶媒之對 照群中自細胞内cAMP量之增加量，來顯示其上升作用。 表3 炎症細胞内cAMP上升作用 被驗化合物 濃度（μΜ) cAMP 增加量（fmol) 實施例1之化合物 1 44.2 實施例1之化合物 3 22.4 實施例1之化合物 10 92.5 實施例1之化合物 30 177 如表 3所示，本發明之共軛物（ΠΑ )，在人嗜酸性 球中顯示自1 μΜ濃度之cAMP量上升作用。 試驗例4 :老_鼠抗原謗發呼吸道恭症抑制作用 將卵白白蛋白8 pg投藥於老鼠腹腔内二次使致敏化。 在最終致敏一週後以卵白白蛋白1 0 0 pg予以點鼻來謗發氣 道炎症。在卵白白蛋白點鼻之3日後進行支氣管之肺泡洗 淨（BAL )，計測洗淨液中之炎症細胞數。被驗化合物在 16 200404540 卵白白蛋白點鼻之3 0分鐘後，1日後，2日後分三次予以 點鼻投藥。 被驗化合物之抑制率（％ )與只投與溶媒之對照群之 BAL中細胞數比較來求得。其結果示於表4。 表4老鼠抗原氣道炎症抑制作用 被驗化合物 投藥量（ng/老鼠） 抑制率（％ ) 實施例1之化合物 100 50.0 實施例1之化合物 1000 78.5 實施例2之化合物 100 12.3 實施例2之化合物 1000 54.0 如表 4所示，本發明之共軛物（ΙΙΑ )，相對於老鼠 抗原謗發呼吸道炎症作用，顯示強大之抑制作用。 由以上之藥理實驗可明瞭，本發明之共軛物（Π A )， 具有強大的第IV型磷酸二酯酶阻遏活性，且顯示優越之 支氣管擴張作用，及炎症細胞内之cAMP量上升作用。 藥物動態試驗 關於為本發明代表性化合物之式（IA )的化合物就 藥物動態試驗結果及其特徵加以說明。 17 200404540 詖驗例 5 :天竺鼠中14 C標記化合物經口投藥後之血漿， 肺，氣管中濃唐。 (1 ) 動物實驗 將被驗動物以卵白白蛋白致敏後，使用經過 4〜5 週之哈特立（H a r 11 e y )系雄性天竺鼠（S L C - S t d， 7〜8週齡）將式（IA )所示化合物之3—氯苯氧基 所鍵結之碳原子以14C標記之化合物（以下記載為 標記化合物）之 0.5%西黃耆膠（Tragacanth)懸 浮液，以 10mg/7.69MBq/kg之用量，經口投藥予 天竺鼠。 在投藥後，於0 · 5，2，4小時之時段在***麻醉下， 由心臟進行全採血後並採取肺、氣管及腦。採例 數在各時段均為3隻。 (2 ) 生物試料之處理 血液在離心分離後，以液體閃爍管（scintillation vial )採取一定量之血漿，添加閃爍混合液 (scintillation cocktail: creazol-I) ( nacalai tesque 公司製），供作放射能測定。組織在濕重量測定 後，添加約4〜5倍量之精製水，使用玻璃均化器 (glass homogenizer)使之均勻化。在液體閃爍管 採取其一定量，添加組織可溶化劑soluene3 50 (主 配方··甲苯）（Packard Instrument 公司製）約 lmL。 在可溶化後添加閃爍混合液：Hionic-Fluor( Packard Instrument公司製），供作放射能測定。剩餘之血 18 200404540 漿及肺，氣管均勻混合物（h 〇 m 〇 g e n a t e )予以陳 結保存，供作代謝物之分析用。 (3 ) 高速液體色層分析法（HPLC )之代謝物分析 (3 -1 )血漿之前處理 相對於一定量之血漿（1〜4mL )添加4倍容積之甲 醇•乙腈（1 : 1 )混合液、以振動機攪拌5分鐘後， 在4°C、3,000rpm下離心分離10分鐘。在回收上 澄液後於沉澱物再次添加同量之甲醇•乙腈（1 : 1 ) 混合液，同樣地振動攪拌後加以離心分離。與此 二回份之除去蛋白的上澄液加在一起，於減壓下 加以乾涸之。使其於少量之0.1 %乙酸再溶解之， 成為HPLC分析之試料。 (3-2 )組織之前處理After trichloroacetic acid was removed with ether, the amount of cAMP in the reaction solution was measured by the EIA method. The increase in the amount of cAMP in cells from the control group with only the vehicle was shown by the amount of cAMP added to the test compound-added group. Table 3 Concentration increase of cAMP in inflammatory cells Test compound concentration (μM) cAMP increase (fmol) Compound of Example 1 44.2 Compound of Example 1 22.4 Compound of Example 1 10 92.5 Compound of Example 30 30 177 As shown in Table 3, the conjugate of the present invention (ΠΑ) shows an effect of increasing the amount of cAMP from a concentration of 1 μM in human eosinophils. Test Example 4: Old_rat antigen suffocates the respiratory tract glaucoma inhibitory effect. Ovalbumin 8 pg was administered to the rat's abdominal cavity twice for sensitization. One week after the final sensitization, a nose was administered with ovalbumin 100 pg to defame airway inflammation. Three days after the ovalbumin was applied to the nose, bronchoalveolar washing (BAL) was performed, and the number of inflammatory cells in the washing solution was measured. The compound to be tested was administered nasally in 30 minutes after 16 200404540 ovalbumin was irrigated into the nose three times a day and two days later. The inhibition rate (%) of the test compound was obtained by comparing with the number of cells in the BAL of the control group to which only the vehicle was administered. The results are shown in Table 4. Table 4 Rat antigen airway inflammation inhibitory effect Dosage of test compound (ng / mouse) Inhibition rate (%) Compound 100 of Example 1 50.0 Compound 1000 of Example 1 78.5 Compound 100 of Example 2 12.3 Compound 1000 of Example 2 54.0 As shown in Table 4, the conjugate of the present invention (IIIA) exhibited a strong inhibitory effect on the airway inflammation induced by mouse antigens. From the above pharmacological experiments, it is clear that the conjugate of the present invention (ΠA) has a powerful type IV phosphodiesterase repressive activity, and shows superior bronchodilatory effect, and an increase in the amount of cAMP in inflammatory cells. Drug dynamic test The compounds of formula (IA), which are representative compounds of the present invention, will be described in terms of the results of the drug dynamic test and their characteristics. 17 200404540 Test Example 5: The 14 C-labeled compounds in guinea pigs are concentrated in the plasma, lungs and trachea after oral administration. (1) Animal experiments: After sensitization of the test animals with ovalbumin, a male guinea pig (SLC-S td, 7-8 weeks old) of Hartle (Har 11 ey) line after 4 ~ 5 weeks will be used. (IA) A 0.5% tragacanth suspension of a compound labeled with 14C (hereinafter referred to as a labeled compound) whose carbon atom is bonded to 3-chlorophenoxy, at 10 mg / 7.69 MBq / The dosage of kg was administered orally to guinea pigs. After administration, the lungs, trachea, and brain were collected after total blood collection from the heart under ether anesthesia for 0.5, 2, 4 hours. The number of cases was 3 in each period. (2) After the blood of the biological sample is centrifuged, a certain amount of plasma is taken by a liquid scintillation vial, and a scintillation cocktail (creazol-I) (manufactured by Nacalai Tesque) is added for radioactivity. Determination. After measuring the wet weight of the tissue, approximately 4 to 5 times the amount of purified water was added and homogenized using a glass homogenizer. Take a certain amount in the liquid scintillation tube, and add approximately 1 mL of tissue solubilizing agent soluene 3 50 (main formula · toluene) (manufactured by Packard Instrument). After solubilization, a scintillation mixture: Hionic-Fluor (manufactured by Packard Instrument) was added for radioactivity measurement. Remaining blood 18 200404540 The homogenous mixture of plasma, lung and trachea (h 0 m 0 g e n a t e) was stored for analysis for metabolites. (3) Metabolite analysis by high-speed liquid chromatography (HPLC) (3 -1) Pre-treatment of plasma Add 4 times the volume of methanol-acetonitrile (1: 1) mixture to a certain amount of plasma (1 to 4 mL) After stirring with a shaker for 5 minutes, the mixture was centrifuged at 4 ° C and 3,000 rpm for 10 minutes. After recovering the supernatant, the same amount of a methanol-acetonitrile (1: 1) mixed solution was added to the precipitate again, and the mixture was shaken and centrifuged in the same manner. The two supernatants of the protein-free supernatant were added together and dried under reduced pressure. It was redissolved in a small amount of 0.1% acetic acid, and became a sample for HPLC analysis. (3-2) Before organization
相對於一定量之肺或氣管均勻混合物（肺：2〜8 mL，氣管：1 .5mL )添加4倍容積之甲醇、以振 動機揽拌5分鐘後，在4 °C、3，0 0 0 r p m下離心分 離1 0分鐘。在回收上澄液後於沉澱物再次添加同 量之甲醇，同樣地振動攪:掉後加以離心分離。與 此二回份之上澄液加在一起，於減壓下加以濃縮。 相對於該濃縮液添加4倍容積之甲醇•乙腈（1 : 1 ) 混合液，振動後加以離心分離，在減壓下濃縮此 上澄液。進而添加相對於此濃縮液之4倍容積之 乙腈，振動後加以離心分離，在減壓下乾涸此上 澄液。使其再溶解於少量之〇. 1%乙酸，成為HPLC 19 200404540 分析之試料。 (3-3 ) HPLC 分析 在40°C使用HPLC泵600E ( Waters公司製），層 柱（column )貝使用 CAPCELLPAKC18UG-120 5pm (資生堂公司製，内徑4.6x250mm)。流動相在 A液係使用5mM七氟丁酸鹽水溶液，B液係使用 乙腈，在流速lmL /min下，在注入後0— 20— 25 分鐘使A液/B液之比率呈73/2 7— 63/37 — 0/100 之梯度（gradient)。 檢查時係使用UV檢測器及流體型放射能檢測器 FLO-ONE βΑ-515 ( Packard Instrument 公司製）， 在放射能檢測器中作為液體閃爍器係使Ultima-floM在2mL /min使用。又將來自放射能檢測器 之洗滌液，使用餾分收集器（fraction collector) —222XL (吉爾森Gilson公司製），自注入時開 始每0.5分鐘作一劃分，因應需要來測定各分劃 之放射能。在試料中放射能所占各放射能成分之 比率，以相對於所檢出之各放射能成分之♦值面 積（或放射能）總和之該成分之峰值面積（或放 射能）之比率計算出。 (4 )放射能之測定 活體試料及HPLC洗滌液係以液體閃爍計數器Tri-Carb 2700TR 或 2200CA ( Packard Instrument 公司製） 來測定。 20 200404540 (5 )數值處理 血漿，組織中放射能濃度係以放射能測定值來除以投 與藥物之比放射能，並換算成式（IA )所示化合物 之當量濃度。在血漿，組織中之母藥及共軛物之濃度， 係在各試料中放射能濃度藉HPLC分析所得之該成分 在試料中放射能所占之比率加以相乘而算出，以式 (IA )所示化合物之當量濃度表示。數值原則上係 以3例之平均值土標準誤差來表示。其結果示於表5。 (6 )結果 表5 組織中之濃度 0.5小時 2小時 4小時 (ng eq./mL 或 ng (ng eq./mL 或 ng (ng eq./mL 或 ng eq./g) eq./g) eq./g) 血 放射能 387.6±52.0 452·8±40·3 346.2±25.9 漿 母藥 1.7±1.7 N.D. N.D. 硫酸共軛物* 43.8±12.7 219.2±38.6 194.4111.9 葡萄糖酸共軛物Θ 130.4±2.0 130·8±11·2 79.3±13.0 肺 放射能 251.2±30.2 232.9±19.4 178.7±16.9 母藥 21.0 土 4.5 12·8±3.5 7.7±1.8 硫酸共軛物* 29.2±5.2 78·9±13·6 79.9+6.6 葡萄糖酸共軛物" 46.5±1.5 59.5±10.8 33.8±7.1 氣 管 放射能 142.1±32.7 85.1±13.3 90.1±2.5 母藥 14.4 N.D. N.D. 21 200404540 硫酸共軛物* 17.2 34.4 葡萄糖酸共軛物** 53.6 33.7 腦 放射能 31.916.7 17.7±2.1Relative to a certain amount of lung or trachea homogeneous mixture (lung: 2 ~ 8 mL, trachea: 1.5 mL), add 4 times the volume of methanol, stir with a shaker for 5 minutes, then at 4 ° C, 3, 0 0 0 Centrifuge at rpm for 10 minutes. After recovering the supernatant, the same amount of methanol was added to the precipitate again, and the mixture was shaken in the same manner: after dropping, it was centrifuged. The two supernatants were added together and concentrated under reduced pressure. A 4-fold volume methanol / acetonitrile (1: 1) mixed solution was added to the concentrated solution, and the mixture was centrifuged after shaking, and the supernatant was concentrated under reduced pressure. Further, acetonitrile having a volume four times that of the concentrated solution was added, and the mixture was centrifuged after shaking, and the supernatant was dried under reduced pressure. It was re-dissolved in a small amount of 0.1% acetic acid and became a sample for HPLC 19 200404540 analysis. (3-3) HPLC analysis An HPLC pump 600E (manufactured by Waters) was used at 40 ° C, and a column was used CAPCELLPAKC18UG-120 5pm (manufactured by Shiseido, inner diameter 4.6x250mm). The mobile phase used 5mM heptafluorobutyrate aqueous solution in liquid A and acetonitrile in liquid B. At a flow rate of 1mL / min, 0-20-20 minutes after injection, the ratio of liquid A / B was 73/2 7 — 63/37 — 0/100 gradient. For the inspection, a UV detector and a fluid-type radiation detector FLO-ONE βΑ-515 (manufactured by Packard Instrument) were used. As a liquid scintillator in the radiation detector, Ultima-floM was used at 2 mL / min. A fraction collector —222XL (made by Gilson Company) was used for the washing liquid from the radioactive energy detector, and it was divided every 0.5 minutes from the time of injection. The radioactive energy of each division was measured as needed. . The ratio of radioactive energy to each radioactive component in the sample is calculated as the ratio of the peak area (or radioactive energy) of the component to the sum of the value area (or radioactive energy) of each radioactive component detected. . (4) Measurement of radioactivity The living sample and HPLC washing liquid were measured using a liquid scintillation counter Tri-Carb 2700TR or 2200CA (manufactured by Packard Instrument). 20 200404540 (5) Numerical processing The radioactive energy concentration in plasma and tissue is calculated by dividing the radioactive energy measurement value by the specific radioactive energy of the administered drug and converting it into the equivalent concentration of the compound represented by formula (IA). The concentration of the parent drug and conjugate in plasma and tissue is calculated by multiplying the ratio of the radioactive energy in the sample obtained by HPLC analysis of the radioactive concentration in each sample by the formula (IA) Equivalent concentrations of the compounds shown are shown. In principle, the values are expressed as the mean ± standard error of the 3 cases. The results are shown in Table 5. (6) Results Table 5 Concentrations in tissues 0.5 hours 2 hours 4 hours (ng eq./mL or ng (ng eq./mL or ng (ng eq./mL or ng eq./g) eq./g) eq./g) blood radioactivity 387.6 ± 52.0 452 · 8 ± 40 · 3 346.2 ± 25.9 plasma parent drug 1.7 ± 1.7 NDND sulfate conjugate * 43.8 ± 12.7 219.2 ± 38.6 194.4111.9 gluconic acid conjugate Θ 130.4 ± 2.0 130 · 8 ± 11 · 2 79.3 ± 13.0 Lung radiation energy 251.2 ± 30.2 232.9 ± 19.4 178.7 ± 16.9 Parent medicine 21.0 Soil 4.5 12 · 8 ± 3.5 7.7 ± 1.8 Sulfate conjugate * 29.2 ± 5.2 78 · 9 ± 13 · 6 79.9 + 6.6 gluconic acid conjugate " 46.5 ± 1.5 59.5 ± 10.8 33.8 ± 7.1 tracheal radioactivity 142.1 ± 32.7 85.1 ± 13.3 90.1 ± 2.5 parent drug 14.4 NDND 21 200404540 sulfuric acid conjugate * 17.2 34.4 gluconic acid conjugate ** 53.6 33.7 Brain radioactivity 31.916.7 17.7 ± 2.1
3—也啶氧基]丙基卜3 N · D ·:無法檢出 *4 一 [3 — [2 —（3— 氯苯氧基） 毗啶基硫酸氫酯。 吼啶氧基 * * : 1 - 〇 - [4 - [3 - [2 - (3— 氯苯氧基） ]丙基]3 —竹b淀基]—β— D —葡萄略喃糖駿酸酉匕 鲁 (glycopyranuronate ) 〇 如表5所明示，以式（I A )所示之化合你 — 物對天竺鼠 經口投藥後，可判明在血漿，肺及氣管中， 卜 野應之硫酸共 輛物及葡駿酸（Glue uronicacid)共輛物比母鏟 、 卜 可^ >辰度為高， 在投藥後4小時仍繼續存在。又在母藥之肺 τ /辰度，使 血漿中濃度大幅超過，而被認為在標的組織 于 T有助於由北 輛物所產生之母藥。再者，可知腦中放射能 ^ 中放撕AH 又#、在血裝 甲艾册此/辰度之1/1 0〜1/20以下，故很難移行至腦部 輛物在肺中之脫共軛反應試^ (1) 試管中反應 將天竺氣之肺以3倍量之均化緩衝液（組成·· 5 二鹽酸緩衝液（ρΗ7·4) 154mM氯化鉀，2mM乙二胺四 乙酸•二4甲臨λ ， ，， τ风）加以均勻化後，於8 0 0 X g離心1 〇分鐘使上 、、登液成玉 … 為肺均勻混合物。將實施例2所得之葡醛酸共軛物 3 -翁 贫3-N-pyridyloxy] propyl 3 N · D ·: Undetectable * 4-[3- —2- (3-chlorophenoxy) pyridinyl hydrogen sulfate. Carminidyloxy * *: 1-〇- [4-[3-[2-(3-chlorophenoxy)] propyl] 3 -bambooyl] -β-D -grape Glycopyranuronate 〇 As shown in Table 5, the compound represented by the formula (IA) can be used to administer guinea pigs through oral administration, and it can be determined that in the plasma, lungs, and trachea, the wild sulphuric acid is a common substance. And Glucuric acid (Glue uronicacid) is higher than the mother shovel, Buco ^ > Chen degree is higher, it still exists 4 hours after administration. In the lung of the parent drug, τ / Chen, the plasma concentration is greatly exceeded, and it is believed that the target tissue at T contributes to the parent drug produced by Beijiawu. In addition, it can be seen that the radioactive energy in the brain is ^ 中 放 裂 AHAH #, in the blood armored album, this is less than 1/1 0 ~ 1/20, so it is difficult to migrate to the brain in the lungs. Conjugation reaction test (1) The reaction in the test tube is to equalize 3 times the amount of homogenization buffer (composition · 5 dihydrochloride buffer (ρΗ7 · 4) 154mM potassium chloride, 2mM ethylenediaminetetraacetic acid • After the 2A, λ, τ, and τ winds are homogenized, centrifuge at 800 × g for 10 minutes to make the upper and lower liquids become jade ... It is a homogeneous mixture of lungs. The glucuronic acid conjugate obtained in Example 2
^ I氣基所鍵結之碳原子以14C所標記之化合物（終 濃度 1 2 S • 3、2.5、5、1 0、20及3 Ομιη )在肺均句混合物（終 22 200404540 濃度lmg/mL)及50mM之乙酸鈉緩衝液（pH5)中於37 。(：反應1 〇分鐘。在反應液中添加乙腈1 · 5 mL使反應停止 後，於3,000rpm離心分離1〇分鐘。使上澄液在減壓下乾 涸後，溶解於HPLC之流動相中成為HPLC分析之試料。 (2 ) HPLC 分析 HPLC 泵係使用 HP 1 090 ( Agilent Technlogies 公司 製），層柱則在 40°C 下使用 CAPCELLPAK C18 UG-120 5μπι(資生堂公司製，内徑4.6x250mm)。流動相則在A 液使用10mM乙酸按’ B液使用乙猜，在流速1 mL/min 下，在注入後0-25-25.5-26-30分鐘使A液/B液之比率成 為7 0/30-45/55-0/100-70/30-70/30之梯度。在檢出時使用 流體型放射能檢測器FLO-ONE β A-515 ( Packard Instrument公司製）。由相對於所檢出之各放射能成分之 峰值面積總和之母藥峰值面積之比，來計算出母藥產生 量 ° (3 ) 數值處理 由母藥生成量來計算出脫共軛速度，相對於作為基質^ Compounds labeled with carbon atoms bound by I group and labeled with 14C (final concentrations 1 2 S • 3, 2.5, 5, 10, 20, and 3 Ομιη) in the lung homogram mixture (final 22 200404540 concentration lmg / mL ) And 50 mM sodium acetate buffer (pH 5) at 37 ° C. (: Reaction for 10 minutes. After adding 1.5 mL of acetonitrile to the reaction solution to stop the reaction, the mixture was centrifuged at 3,000 rpm for 10 minutes. After the supernatant was dried under reduced pressure, it was dissolved in the mobile phase of HPLC to become Samples for HPLC analysis. (2) The HPLC analysis HPLC pump used HP 1 090 (manufactured by Agilent Technlogies), and the column used CAPCELLPAK C18 UG-120 5 μm (made by Shiseido, inner diameter 4.6x250mm) at 40 ° C. The mobile phase uses 10 mM acetic acid in solution A and B guess in solution B. At a flow rate of 1 mL / min, 0-25-25.5-26-30 minutes after injection makes the ratio of solution A / B to 7 0 / Gradient of 30-45 / 55-0 / 100-70 / 30-70 / 30. Use fluid-type radioactive energy detector FLO-ONE β A-515 (manufactured by Packard Instrument) at the time of detection. The ratio of the peak area of the total peak area of each radioactive component to the peak area of the parent drug to calculate the amount of parent drug production ° (3) Numerical processing Calculate the deconjugation speed from the amount of parent drug generated, relative to the matrix
(4 ) 結果 匕加以區劃（p 1 〇 t )。 Michaelis-Menten 擬(4) The result is divided into two parts (p 1 0 t). Michaelis-Menten
/mg蛋白質。 脫共軛反 μ之肺均勻混合物中葡醛酸共軛物被脫共軛月 母$ °此時之脫共軛清除率為〇.〇3 3 2mL /min 23 200404540 如上述之藥物動態實驗所可明獠，本發明之共軛物具 有存在相當量於藥效之標的組織，且在與副作用有關之組 織分布極為少量之特徵，進而具有在標的組織中被脫共軛 而持續的供與母藥之特徵。 本發明之藥物傳送系統所用之式（I)之化合物，係 以錠劑，膠囊劑，顆粒劑，細粒劑，粉劑等之經口投藥用 固體製劑或水溶液劑，糖漿劑，乳劑，懸浮劑等之經口投 藥用液劑之形式予以經口投藥。該等經口投藥用製劑，一 般是經口製劑所用之賦型劑，稀釋劑等之製劑用載體而依 常法製造者。在固形製劑中例如乳糖，白糖，氯化鈉，葡 萄糖，尿素，澱粉，碳酸鈣，高嶺土，結晶纖維素，矽酸 等之賦型劑，***膠，明膠，羧甲基纖維素，蟲膠 (shellac )，甲基纖維素，聚乙晞眺咯淀艱I等之键結劑， 海蕩酸鋼（sodium alginate)，洋菜粉，昆布（laminaran) 粉，聚氧乙烯脫水山梨醇脂肪酸酯類，月桂基硫酸鈉等之 崩解劑，四級銨鹼，月桂基硫酸鈉等之吸收促進劑，精製 滑石，硬脂酸鹽，硼酸粉，聚乙二醇等之潤澤劑。又液劑 有生理食鹽水，單糖漿等。 式（I )中化合物之投藥量，依患者之年齡，性別其 他之條件，患者之症狀等而有不同，通常大人每日為 0.01〜100mg，較佳為 0.1 〜5 0mg。 又使本發明之共軛物作為第IV型磷酸二酯酶阻遏藥 使用之情形，不論經口投藥，非經口投藥或直腸内投藥均 可。亦可經肺投藥，經口腔黏膜投藥，經鼻腔黏膜投藥。 24 200404540 投藥量依投藥方法，患者之症狀，患者之年齡，處置形式 (預防或治療）等均有不同，通常為0.01〜l〇〇mg/曰，較 佳為0.1〜50mg/日。經肺部投藥之情形通常30μ§〜3000pg/ 次，較佳為1 00Kg〜1 00〇pg/次，1日分1〜2次給予。 以本發明之共軛物作為活性成分之PDE IV阻遏 藥，通常係與製藥用載體混合以調整之製劑形式投藥，其 劑型有錠劑，膠囊劑，顆粒劑，散劑，糖漿劑，懸浮劑， 坐劑，膠劑，注射劑，儲存劑（d e p 〇 t )，吸入劑，點鼻 劑等。該等之製劑係在作為製劑用載體而於製劑領域為常 用且與本發明之共軛物不生反應之物質來加以使用，以習 知方法來調製者。此等製劑載體有例如乳糖，葡萄糖，甘 露醇，糊精，澱粉，白糖，間矽酸鋁酸鎂，合成矽酸鎂， 結晶纖維素，羧甲基纖維素鈉鹽，羥丙基澱粉，羧甲基纖 維素舞鹽，離子交換樹脂’甲基纖維素，明膠，***膠， 羥丙基纖維素，低度取代羥丙基纖維素，羥丙基纖維素， 聚乙烯吼咯啶酮，聚乙烯醇，輕質矽酸酐，硬脂酸鎂，滑 石，羧乙烯聚合物，氧化鈥’脫水山梨醇脂肪酸酯，月桂 基硫酸鈉，甘油，脂肪酸甘油酯，精製羊毛脂，甘油明膠， 聚山梨酸酯，聚乙二醇（macr〇g〇i)，植物油，蠟，非離 子界面活性劑，丙二醇’水等。 又在液體製劑方面’使用時可溶解或懸浮於水或其他 適當之溶媒之形式。又叙劑’顆粒劑亦可以周知之方法塗 層。在注射劑之情形，可使本發明之化合物溶解於水來調 製，或因應需要使其溶解於等滲化劑，又可添加pH調節 25 200404540 劑，緩衝劑或保存劑。 又該等製劑可因應需要與抗過敏劑，類固醇劑，β2 刺激藥，抗膽素藥併用。 實施發明之最佳形態 以下舉出實施例，參考例及製劑例就有關本發明共軛 物之合成，含有式（I )之化合物或其共軛物之藥劑之製 造來加以具體說明，但本發明並不限於該等。又本發明之 藥物傳送系統係該共軛物在活體内藉藥物代謝酵素所共軛 而產生。化合物可由元素分析，氫核磁共振吸收光譜（1Η —NMR )等來鑑定。 在1Η — NMR之記載中，為簡略化起見則使用下述之 簡略記號。 J :鍵結常數 s : —重線 d :二重線 dd :二重之二重線 ddd:二重之二重之二重線 t :三重線 dt :二重之三重線 m :多重線 26 200404540 實施例1 :硫酸4 — [3 — [2 — ( 3 —氯苯氧基）一 3 —说啶 氧基]丙基]一 3 —毗啶鈉鹽之製造/ mg protein. The glucuronic acid conjugate was deconjugated in the homogeneous mixture of deconjugated anti-μ lungs. The deconjugation clearance at this time was 0.03 3 2mL / min 23 200404540 as described above by the Drug Dynamics Laboratory It is clear that the conjugate of the present invention has the characteristics that there is a considerable amount of the target tissue with a medicinal effect, and the distribution in the tissue related to the side effect is extremely small, and further has the deconjugation in the target tissue and the continuous supply to the mother. Characteristics of medicine. The compound of formula (I) used in the drug delivery system of the present invention is an orally administered pharmaceutical solid preparation or aqueous solution, syrup, emulsion, suspension, etc. in the form of tablets, capsules, granules, granules, powders, etc. Oral administration in the form of oral medicinal solution. These orally administered pharmaceutical preparations are generally manufactured according to the conventional method by using carriers such as excipients, diluents and the like for oral preparations. In solid preparations such as lactose, sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, etc., excipients, acacia, gelatin, carboxymethyl cellulose, shellac ( shellac), methylcellulose, polyethylene glycol and other bonding agents, sodium alginate, agar powder, laminaran powder, polyoxyethylene sorbitan fatty acid esters , Disintegrating agents such as sodium lauryl sulfate, absorption enhancers such as quaternary ammonium base, sodium lauryl sulfate, etc., and emollients such as refined talc, stearates, boric acid powder, polyethylene glycol and the like. Liquids include physiological saline and single syrup. The dosage of the compound in formula (I) varies depending on the age, sex, other conditions of the patient, the symptoms of the patient, etc., usually 0.01 to 100 mg per adult, preferably 0.1 to 50 mg per day. In the case where the conjugate of the present invention is used as a type IV phosphodiesterase repressor, it can be administered regardless of oral administration, parenteral administration, or intrarectal administration. It can also be administered through the lungs, through the oral mucosa, and through the nasal mucosa. 24 200404540 The dosage depends on the method of administration, the symptoms of the patient, the age of the patient, the type of treatment (prevention or treatment), etc. are different, usually 0.01 ~ 100mg / day, preferably 0.1 ~ 50mg / day. In the case of pulmonary administration, it is usually 30μ§ ~ 3000pg / time, preferably 100Kg ~ 100pg / time, and it is administered once or twice a day. The PDE IV suppressor using the conjugate of the present invention as an active ingredient is usually administered in the form of a formulation mixed with a pharmaceutical carrier, and its dosage forms include lozenges, capsules, granules, powders, syrups, suspensions, Capsules, gels, injections, depots, inhalants, nose drops, etc. These preparations are used as a carrier for preparations, which are commonly used in the preparation field and do not react with the conjugate of the present invention, and are prepared by a conventional method. Such formulation carriers include, for example, lactose, glucose, mannitol, dextrin, starch, white sugar, magnesium aluminosilicate, synthetic magnesium silicate, crystalline cellulose, sodium carboxymethyl cellulose, hydroxypropyl starch, carboxylate Methylcellulose dance salt, ion exchange resin 'methylcellulose, gelatin, acacia, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, poly Vinyl alcohol, light silicic anhydride, magnesium stearate, talc, carboxyvinyl polymer, oxidized sorbitan fatty acid ester, sodium lauryl sulfate, glycerin, fatty acid glyceride, refined lanolin, glycerin gelatin, polysorbate Acid esters, polyethylene glycol (macrogoi), vegetable oils, waxes, non-ionic surfactants, propylene glycol 'water and the like. In the case of liquid preparations, it can be dissolved or suspended in water or other suitable vehicles. The agent 'granules may also be coated by a known method. In the case of injections, the compound of the present invention can be adjusted by dissolving it in water, or it can be dissolved in an isotonicity agent if necessary, and a pH adjusting 25 200404540 agent, a buffering agent or a preservative can be added. These preparations can be used in combination with anti-allergic agents, steroids, β2 stimulants, and anticholinergic drugs as needed. Best Modes for Carrying Out the Invention Examples, Reference Examples and Preparation Examples are specifically described in connection with the synthesis of the conjugate of the present invention and the production of a medicament containing a compound of formula (I) or a conjugate thereof. The invention is not limited to these. In addition, the drug delivery system of the present invention is produced by conjugate of the conjugate in vivo by a drug metabolizing enzyme. Compounds can be identified by elemental analysis, hydrogen nuclear magnetic resonance absorption spectroscopy (1Η-NMR), and the like. In the description of 1Η-NMR, the following abbreviations are used for simplicity. J: Bonding constant s:-Double line d: Double line dd: Double line double ddd: Double line double line t: Triple line dt: Double line triple m: Multiple line 26 200404540 Example 1: Production of 4— [3— [2 -— (3-chlorophenoxy) —3-pyridyloxy] propyl] —3-pyridine sodium salt of sulfuric acid
r^Nr ^ N
Cl 在WO00/2039 1號公報（實施例3 1 )記載之方法所 得之4一 [3 — [2 — （3—氯苯氧基）一 3 —说啶氧基]丙基] —3— ρ比症驗（lO.Og，28.0mmol)及氫氧化鈉（2.24g， 56.0mmol)溶解於水（50mL)後，添加三氧化硫三甲胺錯 合物（7.7 9g、5 6.0mmol )在50°C加熱攪拌3小時。於冰 冷下添加乙醇（5 0 m L )後，慢慢地添加濃鹽酸（4 · 7 m L、 56mmol)，遽取析出之結晶，以水（20mL)、乙醇（20mL) 洗淨後，予以減壓乾燥，得到4 一 [3 — [2 —（ 3 —氯苯氧基） —3 — p比淀氧基]丙基]—3 — ρ比淀硫酸氯鹽（11.8g’ 27.0mmol)之無色結晶。 將此結晶懸浮於水（3 00mL )及甲醇（100mL )，添 加碳酸氫鈉（4 · 5 g，5 4 m m ο 1 )在室溫下攪;拌2 0小時後， 予以減壓濃縮。將殘渣溶解於水（1 5 OmL )，添加乙腈 (3 00mL )，在過濾不溶物後，予以減壓濃縮。進而在添 27 200404540 加乙腈（200mL )予以減壓濃縮後，添加丙酮（300mL )， 在過濾不溶物後予以減壓濃縮。使殘渣溶解於乙醇 (10mL)及二異丙醚（10mL)並過濾後，添加乙醇（10mL) 及二異丙醚（3 OmL )，濾取析出之結晶。使此結晶溶解於 乙醇（17mL )，添加二異丙醚（17mL)再結晶之，得到 標記化合物（8 · 1 Og )為無色結晶。熔點為1 8 5 -1 9 1 °C。 參考例1 2，3，4 —三一0 —乙醯基一D —葡萄哌喃糖醛 酸甲酯之製造 OCOCH3The 4- [3 — [2- — (3-chlorophenoxy) — 3-—pyridyloxy] propyl] —3- obtained by the method described in Cl in WO00 / 2039 1 (Example 31) After the test (10.Og, 28.0mmol) and sodium hydroxide (2.24g, 56.0mmol) were dissolved in water (50mL), sulfur trioxide trimethylamine complex (7.79g, 56.0mmol) was added at 50 ° C was stirred with heating for 3 hours. After adding ethanol (50 ml) under ice cooling, slowly add concentrated hydrochloric acid (4.7 ml, 56mmol), decanting the precipitated crystals, washing with water (20mL), ethanol (20mL), and then Drying under reduced pressure to obtain 4-[[3- —2- (3-chlorophenoxy) —3-p-pyridyloxy] propyl] -3—p-pyridine sulfate (11.8g '27.0mmol) Colorless crystals. This crystal was suspended in water (300 mL) and methanol (100 mL), and sodium bicarbonate (4.5 g, 54 mm 1) was added and stirred at room temperature; after stirring for 20 hours, it was concentrated under reduced pressure. The residue was dissolved in water (150 mL), acetonitrile (300 mL) was added, and insoluble matter was filtered, followed by concentration under reduced pressure. After adding 27 200404540 to acetonitrile (200 mL) and concentrating under reduced pressure, acetone (300 mL) was added, and insoluble matter was filtered and concentrated under reduced pressure. The residue was dissolved in ethanol (10 mL) and diisopropyl ether (10 mL) and filtered, and then ethanol (10 mL) and diisopropyl ether (3 OmL) were added, and the precipitated crystals were collected by filtration. This crystal was dissolved in ethanol (17 mL), and diisopropyl ether (17 mL) was added to recrystallize it to obtain the title compound (8.1 g) as a colorless crystal. Melting point is 1 8 5 -1 9 1 ° C. Reference Example 1 Manufacture of 2,3,4 —trione 0 —acetamido—D — grape piperanuronic acid methyl ester OCOCH3
1—溴一2,3,4 一三一0 —乙酷基一a— D —葡萄略喃糖 酸酸甲酿（20.0g，50.4mmol)溶解於丙酮（125mL)，添 加碳酸銀（15.3g，55.4mmol)及水（0.9mL、50mmol)， 在室溫攪拌16小時，以亞硫酸鈉溶液（sellite )過濾後， 減壓濃縮之。將殘渣進行矽膠柱層析法，以氯仿/乙酸乙 酯洗滌，精製後，藉二異丙基醚再結晶得到標記化合物 (13.8g)之無色結晶。熔點94-98°C。 實施例2 ： 1 — Ο — [4 — [3 — [2 — ( 3 —氯苯氧基）一3 — 口比 28 200404540 淀氧基]丙基]—3 — p比淀基]—β— D—葡萄略喃糖酸酸麵鹽 之製造1-bromo-2,3,4 one-three-zero 0-ethoxy-a-D-grape glucomannanate (20.0g, 50.4mmol) was dissolved in acetone (125mL), and silver carbonate (15.3g) was added (55.4 mmol) and water (0.9 mL, 50 mmol), stirred at room temperature for 16 hours, filtered through a sodium sulfite solution (sellite), and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, washed with chloroform / ethyl acetate, and purified, and then recrystallized from diisopropyl ether to obtain colorless crystals of the title compound (13.8 g). Melting point is 94-98 ° C. Example 2: 1 — Ο — [4 — [3 — [2 — (3-chlorophenoxy) — 3 — port ratio 28 200404540 dianthoxy] propyl] —3 —p than dianyl] — β — D—Manufacturing of acid and salt of grape glucomannan
NN
qnqn
在WO00/2039 1號公報（實施例3 1 )記載之方法所 得之4 — [3 — [2- (3 —氯苯氧基）一3—池啶氧基]丙基] —3 — p比淀ϊ分（12.2g，34.2mmol)及參考例1所得2,3,4 一三一0 —乙醯基一D —葡萄哌喃糖醛酸甲酯（11.4g，34.1 mmol)及三苯基膦（17.9g，68.2mmol)溶解於四氫吹喃 (1 2 0 mL )，在冰冷下於滴定二異丙基偶氮二羧酸酯 (6 · 9 g，3 4.2 m m ο 1 )後，在室溫下揽拌2 4小時。使反應 液減壓濃縮，殘渣進行矽膠柱層析法，以氯仿/乙酸乙酯 洗滌，精製後得到2，3，4 —三一 0 —乙醯基一1 — 0 — [4 一 [3 一 [2 —（3—氯苯氧基）一 3— ^比咬氧基]丙基]一 3—叶t淀基] —β— D —葡萄略喃糖酸酸甲酯（10.3g，15.3mmol)之油 狀物。 29 200404540 使油狀物溶解於丙酮（2 5 5 m L )，添加 1 化納水溶液（9 9 · 5 m L )，在室溫揽拌2小時。 之結晶，以丙酮（1 〇〇 mL )洗淨後，以水/乙醇 得到標記化合物之 1水合物（3 · 1 7 g )之無色結 234-23 8 〇C。 參考例 2 : 1— Ο —二乙氧基騰一a— D —葡萄旅 甲酯之製造 當量氫氧 滤取析出 再結晶， 晶。熔點 喃糖醛酸 qcoch3 h3coco^ ^co2ch3 H3C〇C〇\\、、 〇\ /〇CH2CH3 P I OCH2CH3The ratio of 4 — [3 — [2- (3-chlorophenoxy) -3-isopropylpyridyloxy] propyl] —3 —p is obtained by the method described in WO00 / 2039 1 (Example 31). Yodo (12.2 g, 34.2 mmol) and 2,3,4 obtained in Reference Example 1-one three one 0-ethyl amidino-D-grape piperanuronic acid methyl ester (11.4 g, 34.1 mmol) and triphenyl Phosphine (17.9 g, 68.2 mmol) was dissolved in tetrahydropyran (120 mL), and diisopropylazodicarboxylate (6.9 g, 3 4.2 mm ο 1) was titrated under ice-cooling. Stir at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography, washed with chloroform / ethyl acetate, and purified to obtain 2,3,4 -trione 0 -acetamido 1 1-0-[4 1 [3 1 [2- — (3-chlorophenoxy) — 3 — ^ specific oxy] propyl] — 3-leafyl] — β — D — methyl glucoronanoate (10.3 g, 15.3 mmol ) Of oil. 29 200404540 The oily substance was dissolved in acetone (2.55 m L), and a sodium hydroxide aqueous solution (9.95 m L) was added, followed by stirring at room temperature for 2 hours. The crystals were washed with acetone (100 mL), and water / ethanol was used to obtain the colorless junction of the monohydrate (3.17 g) of the labeled compound, 234-23 ° C. Reference example 2: 1—O—diethoxyl-a—D—Grape brigade Methyl ester production Equivalent hydrogen and oxygen were filtered out, recrystallized, and crystallized. Melting point uronic acid qcoch3 h3coco ^ ^ co2ch3 H3C〇C〇 \\, 〇 \ / 〇CH2CH3 P I OCH2CH3
將參考例1所得之2,3,4 —三一 O —乙醯基-略喃糖酸酸甲酿（2.00g，5.98 mmol)溶解於二氯 mL )於氬氣體氣流，-78°C下，以10分鐘滴定 乙胺（0.93 g，7.2 0 mmol )，接著是氯亞磷酸二乙酯 6.58mmol)之二氯甲燒（3 mL)，進而揽拌 30 添加飽和碳酸氫鈉水溶液（1 〇 mL )使反應完成 溶液減壓濃縮，添加水（1 〇 mL )後，以乙酸乙酯（ -D—葡萄 甲烷（10 二異丙基 (l.〇3g， 分鐘後， 。將反應 3 5 mLx2 ) 30 200404540 萃取，以飽和食鹽水洗淨後，以去水硫酸鈉乾燥，減壓濃 縮之。將殘渣進行矽膠柱層析法，以乙酸乙酯/正己烷洗 滌，精製之以得到無色油狀物之標記化合物（1 · 8 3 g )。 1H-NMR ( 200MHz,CDCl3,3ppm ) ： 1 . 2 7 ( d t, 3 Η , J = 1 Η z , 7 Η z ) ,1.28 (dt,3H, J= 1 Hz,7Hz ) , 2.0 3 ( s , 3 H), 2.0 4 ( s , 3 H), 2.05(s53H), 3.74 (s，3H)，3.8 3 -4.0 3 ( m，4H) ，4.53 ( dd，lH，J=10Hz，lHz) ，4.95 (dd，lH，J=10Hz，4Hz)，5.2 0 ( d d，1 H , J = 1 0 Η z，1 0 H z ) ,5.56 ( t,lH, J=10Hz) ,5.75 ( dd, 1 H, J = 8Hz,4Hz ) 主考例3 ： 1— 〇—(二乙氧基一N —苯基一磷亞胺基）一 a— D —葡萄旅喃糖醛酸甲酯之製造 〇C〇ch3Dissolve 2,3,4-trisyl-O-acetamido-glucuronic acid methyl alcohol (2.00 g, 5.98 mmol) in Dichloromethane obtained in Reference Example 1 in an argon gas stream at -78 ° C Titrate ethylamine (0.93 g, 7.20 mmol) followed by dichloromethane (3 mL) followed by diethyl chlorophosphite (6.58 mmol) over 10 minutes, and then stir for 30 to add a saturated aqueous sodium bicarbonate solution (10%). mL) The reaction completion solution was concentrated under reduced pressure, water (10 mL) was added, and then ethyl acetate (-D- grape methane (10 diisopropyl (1.03 g, minutes) was added. The reaction was 35 mL x 2 ) 30 200404540 extraction, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, washed with ethyl acetate / n-hexane, and purified to obtain a colorless oil. Labeled compound (1.83 g). 1H-NMR (200MHz, CDCl3, 3ppm): 1.27 (dt, 3 3, J = 1 1z, 7Ηz), 1.28 (dt, 3H, J = 1 Hz, 7Hz), 2.0 3 (s, 3 H), 2.0 4 (s, 3 H), 2.05 (s53H), 3.74 (s, 3H), 3.8 3 -4.0 3 (m, 4H), 4.53 (dd, lH, J = 10Hz, lHz), 4.95 (dd, lH, J = 10Hz, 4Hz), 5 .2 0 (dd, 1 H, J = 1 0 Η z, 10 H z), 5.56 (t, lH, J = 10Hz), 5.75 (dd, 1 H, J = 8Hz, 4Hz) Examination Case 3: 1—〇— (diethoxy-N-phenyl-phosphoimino) —a—D—manufacturing of methyl glucosaminoglyoxylate 〇C〇3
將參考例2所得之1 一 〇 一二乙氧基膦基一 α— D —葡 萄略喃糖醛酸甲酯（500mg，1.10mmol)溶解於甲苯（1.2 mL) ’ 依照有機合成刊物 Org.Synth.，Coll.vol.3，p.710-711 記載之方法而合成之苯基疊氮化物（phenylazid )Dissolve 1 10 diethoxyphosphino-α-D-methyl glucomannuronic acid (500 mg, 1.10 mmol) obtained in Reference Example 2 in toluene (1.2 mL) according to the organic synthesis journal Org. Synth ., Phenylazid synthesized by the method described in Coll.vol.3, p.710-711
(I44mg，1.21mm〇l)之甲苯溶液（12niL)，在 45 〜5 0°C 200404540 攪拌2小時。使反應液減壓濃縮得到標記化合物（680mg ) 之為微黃色油狀物。 ^-NMR ( 200MHz,CDCl3,5p pm) ： 1 . 2 6 - 1 . 4 2 ( m , 6 Η ) ,1.97 (s,3H)，2.03(s,6H)，3.74(s，3H)，4.05-4_29(m，4H)，4.51 (d，lH， J= 1 0Hz ) ，4.96-5.06 ( m，lH) ,5.23 ( t,lH,J=10Hz) ,5.56 ( t,lH, J= 1 0Hz ) ,6.04-6. 12 ( m, 1H ) 6.7 2 - 6.8 7 ( m, 3 H ) , 7.0 6 - 7 . 1 7 ( m, 2 H ) 實施例3 : 1 — [4 — [3 — [2 — （ 3 —氯苯氧基）一 3 —说啶氧 基]丙基]—3 —氧化物一 1 —毗啶鹽基]一 1 一二氧一β— D — 葡萄派喃糖酸酸納之製造(I44mg, 1.21mm01) in toluene solution (12niL), stirred at 45 ~ 50 ° C 200404540 for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound (680 mg) as a pale yellow oil. ^ -NMR (200MHz, CDCl3, 5p pm): 1. 2 6-1.4 2 (m, 6 Η), 1.97 (s, 3H), 2.03 (s, 6H), 3.74 (s, 3H), 4.05 -4_29 (m, 4H), 4.51 (d, lH, J = 1 0Hz), 4.96-5.06 (m, lH), 5.23 (t, lH, J = 10Hz), 5.56 (t, lH, J = 1 0Hz ), 6.04-6. 12 (m, 1H) 6.7 2-6.8 7 (m, 3 H), 7.0 6-7. 1 7 (m, 2 H) Example 3: 1 — [4 — [3 — [ 2— (3-chlorophenoxy) —3—saidyloxy] propyl] -3—oxide-1—pyrimidinyl] —1—dioxo—β—D — glucopyranoic acid Made in
在WOO0/2039 1號公報（實施例3 1 )記載之方法所 得之4 — [3 - [2 —（ 3 —氯苯氧基）一3 —批啶氧基]丙基] —3 —毗啶酚（100g，0.28mmol )及參考例3所得之1 — Ο 32 200404540 —(二乙氧基一N—苯基一磷亞氨基）D—葡萄哌喃糖 酸酸甲酯（306mg，0.56mmol)及分子篩 4a ( m〇iecuiar sieve) ( 400mg)添加丙猜（5 mL)、於冰冷下添加三甲基 石夕抗基三敷甲燒續酸酯（249mg，l.lmni〇l)後，在室溫下 揽拌3日。過濾反應液，減壓濃縮後，使殘渣溶解於乙酸 乙醋（2 0 m L )，以飽和碳酸氫鈉水溶液洗淨後以去水硫 酸鎂乾燥，減壓濃縮。 殘渣進行矽膠柱層析法，以氯仿/乙酸乙酯洗滌，精 製後侍到2,3,4 一三一〇 —乙酿基一1— [4 — [3 — [2— (3 — 氯苯氧基）一3 —说淀氧基]丙基]—3 —氧化物—1—说淀鹽 基]—i —二氧一β— D —葡萄哌喃糖醛酸甲酯（26.3mg、 0.039mmol )之淡褐色油狀物。 使油狀物溶解於丙酮（0 · 6 6 m L )，於冰冷下添加1 當量氫氧化鈉水溶液（0.2 5 mL )，攪拌2小時後，添加 丙酮（1 · 3 4 m L )並攪拌3小時。將析出之油狀物加以分 離，添加丙酮使粉末化後，濾取之。使其在Sep-Pak Vac 35ccC18_10g(Waters公司製）反應，以甲醇溶出，精製， 得到標記化合物（1 8.5 mg )之無色粉末。 1H-NMR ( 400MHz，CDCl3,5ppm ) ： 1 .96-2.04 ( m,2H ) , 2.56-2.62 (m,2H) ,3.20-3.44 ( m,5H ) , 4.0 4 - 4.1 0 ( m , 2 H ) ,5.09(d,lH, J = 9Hz ) ，5.20(s，lH)，5.52(s，lH),，7.06(ddd，lH，J = 8Hz，2Hz，lHz)， 7.13-7.16 ( m，2H)，7.21 ( t，lH，J = 2Hz)，7.22-7.25 ( m，2H) ，7.33 (dd,lH, J = 6Hz,2Hz) ,7.412 ( t,lH,J = 8Hz) ,7.54 ( dd,lH, J = 8Hz,2Hz ) ，7.6 9 ( dd，1 H，J = 5 Hz，2Hz )。 33 200404540 製劑例1 :(吸入劑之製法） 依習知之方法，使藥物溶解於溶媒並與喷劑一起充填 來調製MDI (定量喷霧式吸入劑）。 石瓦酸4-[3 — [2 — （ 3 —氯苯氧基）一3 — p比淀氧基]丙 基]一 3 —毗啶鈉鹽（實施例1之化合物（1 OOmg ) 三油酸山梨醋 85 ( sorbitan trioleate)(界面活性劑）4 — [3-[2 — (3-chlorophenoxy) — 3 — batch of pyridyloxy] propyl] — 3 —pyridine obtained by the method described in WOO0 / 2039 1 (Example 31) Phenol (100 g, 0.28 mmol) and 1 — 0 32 200404540 — (diethoxy-N-phenyl-phosphoimino) D-grapepiranoate methyl ester (306 mg, 0.56 mmol) obtained in Reference Example 3 And molecular sieve 4a (molecuiar sieve) (400mg), propidium (5 mL) was added, and trimethylstilbate trimethylsalbumate (249mg, 1.lmniol) was added under ice-cooling, at room temperature Let's stir for 3 days. The reaction solution was filtered and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (20 ml), washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, washed with chloroform / ethyl acetate, and purified, and then served to 2,3,4 130-ethyl ethyl 1- [4 — [3 — [2— (3 — chlorobenzene (Oxy)) 3-said oxy] propyl] -3-oxide-1-said hydrated salt] -i-dioxo-β-D-grape piperanuronic acid methyl ester (26.3mg, 0.039 mmol) as a light brown oil. The oil was dissolved in acetone (0.66 m L), and 1 equivalent of an aqueous sodium hydroxide solution (0.2 5 mL) was added under ice-cooling, and after stirring for 2 hours, acetone (1.3 m 4) was added and stirred for 3 hours. hour. The precipitated oil was separated, and after adding acetone to powder, it was collected by filtration. This was reacted at Sep-Pak Vac 35ccC18_10g (manufactured by Waters), eluted with methanol, and purified to obtain the title compound (18.5 mg) as a colorless powder. 1H-NMR (400MHz, CDCl3,5ppm): 1.96-2.04 (m, 2H), 2.56-2.62 (m, 2H), 3.20-3.44 (m, 5H), 4.0 4-4.1 0 (m, 2 H ), 5.09 (d, lH, J = 9Hz), 5.20 (s, lH), 5.52 (s, lH), 7.06 (ddd, lH, J = 8Hz, 2Hz, lHz), 7.13-7.16 (m, 2H ), 7.21 (t, lH, J = 2Hz), 7.22-7.25 (m, 2H), 7.33 (dd, lH, J = 6Hz, 2Hz), 7.412 (t, lH, J = 8Hz), 7.54 (dd, lH, J = 8Hz, 2Hz), 7.69 (dd, 1 H, J = 5 Hz, 2Hz). 33 200404540 Formulation Example 1: (Manufacturing method of inhalant) According to a conventional method, a drug is dissolved in a solvent and filled with a spray to prepare MDI (quantitative spray inhaler). Lithoic acid 4- [3- —2- (3-chlorophenoxy) -3-p-pyridyloxy] propyl] -3-pyridine sodium salt (the compound of Example 1 (100 mg) tri-oil Acid sorbitan trioleate (surfactant)
(20mg) 1，1，1,2-四氟乙烷（噴劑）（8.58g) 合計（8.70g) 製劑例2 :(注射劑之製法） 依習知方法，溶解下列成分，以〇 . 2 2 μηι之膜過滤器 過濾後，充填於安瓿（ampulla )並調製注射劑。(20mg) 1,1,1,2-tetrafluoroethane (spray) (8.58g) Total (8.70g) Formulation Example 2: (Manufacturing method of injection) According to a known method, the following ingredients were dissolved to 0.2 After filtering with a 2 μm membrane filter, the ampulla was filled and an injection was prepared.
石兔酸4— [3— [2 — (3 —氯苯氧基）一3 —说淀氧基]丙 基]—3 —毗啶鈉鹽（實施例1之化合物）（1 m g )、 葡萄糖（等滲化劑）（1 0 0 m g )， 注射用蒸鶴水（適量） 全量（2ml ) 製劑例3 :(注射劑之製法） 依習知方法，溶解下列成分，以〇 · 2 2 μηι之膜過濾器 過濾後，充填於安瓿並調製注射劑。 石瓦酸4— [3— [2 — (3 —氯苯氧基）一3 —说淀氧基]丙 34 200404540 基]—3 — 4 ρ定納鹽（實施例1之化合物）（1 0 m g )、 氯化鈉（等滲化劑）（250mg ) 注射用蒸傲水（適量） 全量（5ml ) 製劑例4 ：(凍結乾燥注射劑之製法） 依習知方法，溶解下列成分，以〇. 2 2 μηι之膜過滤器過滤 後，充填於安瓿並調製注射劑。 石見酸4 一 [3— [2 — （3 —氯苯氧基）一3 — 0比淀氧基]丙 基]—3 —吡啶鈉鹽（實施例1之化合物）（1 Omg )、 甘露醇（250mg ) 注射用蒸铜水（適量） 全量（5 ml ) 製劑例5 :(儲存劑之製法） 依習知方法，以下列處方在調製徐放性注射劑 (microsphere)時，放進聚乳酸使藥物含量成為2〜20% ， 調製1個月投藥型儲存劑。 石瓦酸4— [3— [2 —（3 —氯苯氧基）一3 —也淀氧基]丙 基]—3 —吡啶鈉鹽（實施例1之化合物）（1 OOmg )、 聚乳酸（5 00mg ) 製劑例6 :(錠劑之製法） 依習知方法將下列成分混合，成為顆粒狀，加以壓縮 35 200404540 成形，調製1錠lOOmg之錠劑1 000錠。 4 — [3 — [2 — （3 —氯苯氧基）一3 —也啶氧基]丙基]— 3 — p比淀酉分(5 g )、 乳糖（59g) 結晶纖維素（30g) 羥丙基纖維素（4 g ) 輕質矽酸酐（1 g )，及 硬脂酸鎂（1 g )。 發明效果 依本發明之藥物傳送系統，將羥基具取代基之毗啶化合物 經口投藥，可在活體内吸收過程變換成共軛物，順次集中 送達標的組織，故可有效率的發揮所要的藥理效果，同時 可抑制一般第IV型磷酸二酯酶阻遏藥所見之嘔吐等副作 用，故可提供極優異之第IV型磷酸二酯酶阻遏劑。 進而本發明之藥物傳送系統所用之共軛物，具有強大 的第IV型磷酸二酯酶阻遏作用，且顯示極優異之支氣管 擴張作用，故作為第IV型磷酸二酯酶阻遏藥對廣泛的過 敏性炎症疾病或組織炎疾病等之治療藥及預防藥極為有 用。尤其是以氣喘為首之氣道閉塞性之肺疾病之治療藥及 預防藥為有效。本發明之共輛物存在於藥效之標的組織有 相當量，且在與副作用有關之組織分布量極為少量為其特 徵，故可作為靶標醫藥使用。本發明之共軛物並分布於標 的組織，在標的組織中被脫共軛而可持續的供給於母藥為 36 200404540 其特徵，故有藥理活性之持續時間延長之效果，可作為持 續性醫藥使用。進而本發明之共輛物，具有溶解度高之特 徵，並有例如注射劑，儲存劑等之液體製劑，吸入劑等之 經肺投藥製劑，點鼻劑等之經鼻投藥製劑等之製造容易之 優點。 37Stone rabbit acid 4- [3-—2- (3-chlorophenoxy) -3—succino] propyl] -3-pyridine sodium salt (the compound of Example 1) (1 mg), glucose (Isotonicity agent) (100 mg), steamed crane water for injection (appropriate amount), full amount (2ml) Formulation Example 3: (Preparation method of injection) According to a known method, the following ingredients are dissolved, and a film of 0.2 2 μηι is used. After filtering through a filter, the ampoule is filled and an injection is prepared. Lithoic acid 4- [3— [2 -— (3-chlorophenoxy) —3-—anhydroxyl] propyl 34 200404540 group] —3—4 ρ sodium (the compound of Example 1) (1 0 mg), sodium chloride (isotonic agent) (250mg), steamed water for injection (appropriate amount), full amount (5ml), preparation example 4: (preparation method of freeze-dried injection) According to a conventional method, the following ingredients are dissolved, and After filtering through a 2 2 μm membrane filter, it was filled in ampoules and prepared for injection. Ishimiic acid 4-[[3-—2- (3-chlorophenoxy) —3-0 than dianoxy] propyl] -3-pyridine sodium salt (the compound of Example 1) (10 mg), mannitol (250mg) Copper water for injection (appropriate amount) Full amount (5 ml) Formulation example 5: (Preparation method of storage agent) According to a conventional method, when preparing a radioactive injection (microsphere) according to the following formula, put polylactic acid into The drug content becomes 2 to 20%, and a one-month dosing storage agent is prepared. Shivaic acid 4- [3- [2- (3-chlorophenoxy) -3-butoxy] propyl] -3-pyridine sodium salt (the compound of Example 1) (100 mg), polylactic acid (500 mg) Preparation Example 6: (Preparation method of lozenges) The following ingredients are mixed into granules according to a conventional method, compressed into a shape of 35,2004,045,040, and 1 lozenge of 100 mg of lozenges is prepared. 4 — [3 — [2 — (3-chlorophenoxy) — 3 — also pyridyloxy] propyl] — 3 — p ratio Yodo (5 g), lactose (59 g), crystalline cellulose (30 g) Hydroxypropyl cellulose (4 g), light silicic anhydride (1 g), and magnesium stearate (1 g). ADVANTAGE OF THE INVENTION According to the drug delivery system of the present invention, a bipyridine compound having a hydroxy group is administered orally, which can be transformed into a conjugate in the absorption process in vivo, and can be sequentially delivered to the target tissue, so the required pharmacology can be effectively exerted. Effect, at the same time can suppress vomiting and other side effects seen in type IV phosphodiesterase inhibitors, so it can provide an excellent type IV phosphodiesterase inhibitor. Furthermore, the conjugate used in the drug delivery system of the present invention has a strong type IV phosphodiesterase repressive effect and shows excellent bronchiectasis, so it is a type IV phosphodiesterase repressor against a wide range of allergies Drugs for the treatment and prevention of sexual inflammatory diseases and tissue inflammation diseases are extremely useful. In particular, therapeutic and preventive drugs for airway occlusive lung diseases, including asthma, are effective. The total amount of the present invention in the target tissue of the medicinal effect is considerable, and its distribution in the tissue related to side effects is very small, so it can be used as a target medicine. The conjugate of the present invention is distributed in the target tissue, and is unconjugated and continuously supplied to the parent drug in the target tissue. It has the characteristics of 36 200404540, so it has the effect of extending the duration of pharmacological activity and can be used as a continuous medicine. use. Furthermore, the common product of the present invention has the characteristics of high solubility, and has the advantages of easy manufacture of liquid preparations such as injections, storage agents, inhaled preparations for pulmonary administration, and nasal preparations such as nasal preparations. . 37
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW092118415A TW200404540A (en) | 2002-07-04 | 2003-07-04 | Drug delivery system of substituted hydropyridine compound, and conjugate of substituted hydroxypyridine compound |
Country Status (4)
| Country | Link |
|---|---|
| JP (1) | JP2006021996A (en) |
| AU (1) | AU2003246252A1 (en) |
| TW (1) | TW200404540A (en) |
| WO (1) | WO2004005259A1 (en) |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9202464D0 (en) * | 1992-02-05 | 1992-03-18 | Danbiosyst Uk | Composition for nasal administration |
| BR9914091A (en) * | 1998-10-06 | 2001-11-27 | Dainippon Pharmaceutical Co | 2,3-di-substituted pyridine derivatives, process for preparing them, drug compositions containing the same and intermediates for the preparation |
-
2002
- 2002-07-04 JP JP2002195341A patent/JP2006021996A/en active Pending
-
2003
- 2003-07-03 WO PCT/JP2003/008462 patent/WO2004005259A1/en active Application Filing
- 2003-07-03 AU AU2003246252A patent/AU2003246252A1/en not_active Abandoned
- 2003-07-04 TW TW092118415A patent/TW200404540A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AU2003246252A1 (en) | 2004-01-23 |
| WO2004005259A1 (en) | 2004-01-15 |
| JP2006021996A (en) | 2006-01-26 |
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