TW542837B - 1,2,4-triazolo[4,3-b]pyrrido[3,2-d]pyridazine derivatives, process for their preparation and their use in medicine - Google Patents
1,2,4-triazolo[4,3-b]pyrrido[3,2-d]pyridazine derivatives, process for their preparation and their use in medicine Download PDFInfo
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- TW542837B TW542837B TW087111560A TW87111560A TW542837B TW 542837 B TW542837 B TW 542837B TW 087111560 A TW087111560 A TW 087111560A TW 87111560 A TW87111560 A TW 87111560A TW 542837 B TW542837 B TW 542837B
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- 229950005741 rolipram Drugs 0.000 description 1
- 230000036303 septic shock Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 1
- 229960002930 sirolimus Drugs 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- NCHGCTIFVCFWGN-UHFFFAOYSA-N tert-butyl 9H-fluorene-1-carboxylate Chemical compound C(C)(C)(C)OC(=O)C=1C=CC=C2C=3C=CC=CC=3CC=12 NCHGCTIFVCFWGN-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- VSAISIQCTGDGPU-UHFFFAOYSA-N tetraphosphorus hexaoxide Chemical compound O1P(O2)OP3OP1OP2O3 VSAISIQCTGDGPU-UHFFFAOYSA-N 0.000 description 1
- 150000004897 thiazines Chemical class 0.000 description 1
- 238000003971 tillage Methods 0.000 description 1
- 230000017423 tissue regeneration Effects 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 108010060757 vasostatin Proteins 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/14—Decongestants or antiallergics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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Description
542837 A7 137 系列化學如下的三峻並 五、發明説明（ 本發明係關於一種新穎、有卷 & 療政用的雜環化合物、其製 備的方法及含該物的醫藥組合物。 ， 已知磷酸二酯酵素4 (PDE 4)的如去丨、， 抑制劑疋用於炎症性及過 敏性症狀，如··氣喘、非固醇~^ +口師4抗炎性藥物引發之腸胃傷 害及遺傳性過敏性皮膚炎的治療。 歐洲專利-A-85,840揭示 (triazolo)-g太嗪衍生物： (請先閲讀背面之注意事項再填寫本頁} 訂
R 經滴部中央標準局员工消费合作社印製 R3-
FT 其用做解焦慮試劑。 現在我們發現在上述結構中吡啶的存在，代替笨並 (benzo)/袤，&供新賴之抑制環狀蹲酸二醋酵素的化合物'， 特定是種類4環狀磷酸二酯酵素，且具有非常低的催吐活 性（在狗類引發嘔吐上，比羅利普蘭活性低1 0-1 00倍）。 1因此’本發明提供一種化學式（I)的雜環化合物： 1 2
N 10 ⑴ N 5 4- 本纸張尺度適用中國國家構率 (CNS ) Λ4規格（2lOX297,:,>^ 542837 五 每濟部中央榡準局貝工消費合作社印製 ΑΊ Β7 發明説明（3 4-氟苯基及3-硝苯基。 < R3的貫例是氫、fe基或氯基，較佳的是在8 _或9 _的位 置。 本發明的最佳化合物是6-(4-氟苯基異丁基υ,ο 二。坐並[4，j - b ]吡咬並[3，2 - d ]嗒畊、3 -環丙甲基_ 6 _ ( 3 _硝 笨基）-1，2,4-三唑並[4,3-b]吡啶並[3,2、4]嗒_、3-環丙 基-6-苯基-1，2,4_三唑並[4,3_b]吡啶並[3,2_d]嗒畊、及 環丁甲基-6-(3 -硝表基）-i，2,4 -三峻並[4,3-b]p比咬並 [3,2-d]嗒畊。 - ' 根據本發明之更進一步特色」化學式（j)雜環化合物可從 化學式（II)足相對應的聯氨衍生物來製備： ^N-NH2
其中 2 3 R及R3如上所定義，與通式（in)之羧酸的有反應性衍 生物反應： HOOC-R1 - (III·) 其中R如上所定義，該幾酸的有反應性衍生物可以是， 例如：卣化物（較佳的是氣化物）、酸酐或混合酸酐。 較佳的是在鈍性有機溶劑，如：二氯甲烷、二噁烷或四 __ _6_ 本錄尺 "—' (請先閱讀背面之注意事項再填寫本頁)
542837 A7 B7 五、發明説明（4 氫咬喃中進行反應，在有機含氮鹼 下，且溫度是在-10 /C及+ 60 r之間 的相對應醯胼首先形成： HN-NHOC-R · % · 5乙基胺的存在 在反應中，通式（IV)
(IV) 其中R1、R2及R3如上所凫義。在有機溶劑，如：二噁 烷、四氫呋喃、異丙醇或正-丁醇中的此醯胼（lv)懸浮物 被加熱，例如：在該溶劑的沸點，以產生相對應之化學式 (I)的雜環化合物。 化學式（II)的聯氨衍生物可如下製備： 1 )將化學式（VJ的醯肼反應： 經濟部中央標準局员工消費合作社印製
COOH N-NHCOOR4 (V) 其中R2及R3如上所定義，且V是帶有函化磷或氧自化磷 (較佳的是氧氣化磷）的烷基，以形成化學式（VI)的中間化 合物： 本纸張尺度適用中國國家標準（CNS ) A4規格（ 210X 297公处
(讀先閱讀背面之注意事項再填寫本1TC
542837 A7 B7 五、發明説明（5
(VI) 其中R2及R3如上所定義，且X是氯或溴原子： 2 )將化學式（VI)化合物與化學式（VII)的肼基曱酸烷酯（較 佳的是肼基甲酸第三-丁酯）：- 、 H2N-NH-COOR5 (VII) 其中R5是烷基，以產生烷氧羰基聯氨衍生物（VIII): HN-NH-COOR 5 (請先閱讀背面之注意事項再填寫本頁 、-口 R3
、N I .N (VIII) 經濟部中央標導局員工消费合作社印製 其中R2、R3及R5如上所定義：且 3 )將化合物（VIII)以在無水溶劑，如··乙醇中，以氯化氫 處理。 化學式（V)的醯肼與函化磷或氧_化磷之濶的反應是在 試劑過量、溫度從80 °c至120'c下進行，然後移除過量的 試劑，並且倒入冷水中。以此方式得到化合物（VI)。 (VI)與化學式（VII)的肼基甲酸烷酯反應，得到相 的 -8- ^•纸張尺度適用中國國家標準（〇^)/\4規格（210'乂 297公处 7 3 8 經濟部中央標準局员工消费合作社印製 kl ^---—____ B7 發明説明（6 ) ^ =氧幾基稱氨衍生物（VIII)，較佳▲的是在有機溶液存在 '、’如.四氫呋喃或二噁烷中，在溫度從6〇至反應介質 的沸點來進行。 、 /列如：、烷氧羰基聯氨衍生物（vm)在室溫下、氯化氫-乙 醇飽和溶液中，可轉化成聯氨衍生物（11) ΰ 化學式（ν)的醯胼衍生物是已知的化合物，其可從相應 的2 -乙醯基菸鹼酸、以敘述於文獻中的已知方法來製備。 從天竺鼠心臟得到之環狀核甘酸磷二酯酵素4的抑制是 使用偉吉斯（Verghese)等人[在-Molecular Pharmac〇l0gy， 第47期，第1164-1171頁（l%5年）中]所述的9卜井微滴定 板來進行。 此測試的結果是顯示表1。 表1 化合物* PDE4 IC50(微米） A’ 10 6 2 7 0.3 12 3 31 0.2 47 0.7 55 _ 0.2 60 '0.1 _ 61 2 109 0.04 112 0.7 113 0.2 — -9- 本纸浪尺度適用中國國家標準（CNS ) Λ4規格（21〇><297公^ (請先閱讀背面之注倉事項界填寫本1];)
542837 五 、發明説明 A7 B7 (* )見表2中的結構。 ▲· 口井一疋j -異丁基·6-苯基β1，2,4_三峻並[3,4-a]g太 ’〜個包括於歐洲專利-A_85,84〇的化合物。 D可從表1中所見的，化學式（1)的化合物是環狀磷二酯 南素抑制劑，特別是種類4環狀AMp磷酸二酯酵素抑制 ^化合物也旎阻止某些前-炎症性細胞漿移動的產生， Y歹丨j 4 口 * Tistt? 、.iNF α。因此，其可用在過敏性的、炎症性及免疫 =疾碼的治療，以及對那些阻礙前·炎症性細胞漿移動或 4選擇性抑制的疾病或狀況能有所助益。 乂些疾病的狀況包括氣喘'風濕性關節炎、骨關節炎、 股質疏鬆症、骨頭形成的失調、腎小球腎炎、多種硬化 钷、突眼性甲狀腺腫、myastheniagravis、依賴跋島素的 水病、私植組織的排斥、腸胃失調，如：潰瘍性結腸炎 或Crohn疾病、敗血性休克、成人的困難（dlstress)呼吸性 症候群、及皮膚疾病十遺傳性的過敏性皮膚炎、接觸 性的皮膚炎、急性皮肌炎、及乾癬。 、其也可以用做腦血管功能的改善物，及其它CNS相關疾 病的治療，如：痠呆症、阿茲海默症（Alzhein^，s disease)、憂鬱症、及改變理智試劑。 當與其它的藥物，如：類固醇及抑制免疫力的試劑，像 是：環抱t A、雷帕黴素或T__-細胞接受㉟阻-礙劑組合施用 時，本發明的化合物也是有益的。在此情況下，該化合物 的施用容許其它藥物劑量減少，因此避免與類固醇及抑制 免疫力試劑相關之不想要副作用的出現。 -10- Μ氏張尺度適用中國國家標準（CNS ) Λ4規枱（2l〇X 297^^ 請 先 間 讀 背 之 注 意- 事 項 再 Η 本 頁 % 訂 經濟部中央標準局負工消费合作社印¾ 542^3 /
t，=月的化口物也顯示其在預防冗及/或治療性的治療之 又·’阻紋腐蝕性的及潰瘍性影響的效力。該 引 目不同的病因試匈，』 t ^ 經濟部中央標準局負工消费合作社印裂 醇的抗炎劑）、壓月力、1炎症性^藥物（類固醇或非類固 、 虱、乙醇及濃酸類。其可在腸胃病理 及/或治療性的治療上，像:藥物引發的潰二肖 '、、、' H.幽門相關的潰瘍、食道炎、胃-食道的逆流 疾病，單獨或與抗酸及/或抗分泌的藥物组合使用。 金二可用万、病理上狀況的治療，其中對細胞或組織的傷 二疋經由像：缺氧症、或過多自由基產生的狀況而產生 祕田本發明的化合物被添♦到意於保存移植器官或流 σ‘如。血液或精子〈儲存溶液中時，冑有益影響的實例 :·在虺狀動脈閉塞或對細胞及組織生存能力的延長之 便’封心臟組織的保護。其也有益於組織的修補及傷口 愈合。 本發明也k供化學式（〗）的雜環化合物，藉著治療、用於 人類或動物體上治.療的方法中，特別是用做㈣4抑制 劑，或阻礙前·炎症性細胞漿移動的產生，如：TNFa。 、本發明另外提供一種醫藥組合物，其包含做爲活性成分 〜土少一種化牵式（I)的雜環化合物、及一種醫藥上可接受 的載體或稀釋劑。 較佳爲該組合物是一種適於口服、吸入_、直腸、皮下 (transdermal)、鼻子、局部或非口服的施用。 醫藥上可接受的載體或稀釋劑，其可與該活性化合物 (compound或compounds)混合，以形成本發明的組合物， 11 - 本紙張尺度適用中國國家標準（〇奶）八4規格（21〇><297公垃） — (請先閱讀背面之注*·事項#.填寫本頁) -? -I I -1 . 542837 A7 五、 發明説明（9 B7 ---〜__ 經濟部中央標準局员工消费合作社印製
:本身已被熟知，且所用的眞正輔A_ 物預期的施用方法。 取决万組含 合物較佳爲適合經口施藥的。°服施用的组 μ : 囊、喉糖鎚或發泡微粒的形式，或製 種液、㈣或料物，所有皆包本一或多 種本發明的化合物。此製備可以此藝中熟知的二^ 广將化學式⑴的雜環化合物與醫藥 的二 稀釋劑混合。 -伐又的載f豆或 可用於製備該組合物的稀釋劑 劑，其可騎 —括·及-或固體的稀釋 香料—/、; ^，-如果想要㈣，可與色料或 士 或膠囊一般可包含從1至⑽毫克的活性 中：,;：：：5至50毫克較佳。該化合物也可摻入鍵劑 生持之適ΐ”然或合成聚合物包覆，以產 〜争巴，或將聚合物摻入錠劑的形式中，$ 生相同的特性。 /八Τ，而產 通合π服使料液態组合物可以是溶液 劑的形式。哕、发访可β Μ， K W務 水m r 與絲或山雜醇相關之 '去/水手溶液，而形成糖漿。該懸浮物可包含本發明之 :性::物：不以爾形式'，與水及其可接= d 及恝'，于劑或香料一起。 :K组合物可以是溶液、懸浮物或微粒化粉末的 /式’衣入適當的吸入器中。 非口服王射组合物的製備可以經過或不經過冷凍虼 故，且其可溶解於水中或適當的非口服注射液中。h
本纸張尺度適财_家_ ( eNS -12- 經消部中央標準局員工消f合作社印製 542837 A7 —___________B7 五、發明説明（1〇 ) ? 〜 在人體治療上，雜環化合物的劑量取決於所要的效果及 治療的期限；成人的劑量通常是從每天i毫克至丨〇〇亳 克。醫生通常考慮所治療之病人的年齡及體重來決定劑 量 0 以下的實例進一步說明本發明。 貫例1 a) 2 -苯醯基菸鹼酸之第三_ 丁氧基羰基聆的混合物（45 克’ 13.2莫耳）在磷醯氯（5〇〇毫升）中回流沸騰一小時，然 後過量的磷醯氯經減壓移除，於冰水處理殘餘物，並以二 氯甲fe萃取兩次。該有機溶液-以4 %的碳酸氫鈉水溶液、 .鹽水洗滌，並乾燥（Na2S〇4)，該溶劑在眞空中移除。所得 的固體以1 : 1的二乙醚-石油醚混合物收集，產生5 _氯 基-8-苯基吡啶並[2,3_d]嗒畊的紅色固體（25 4克：8〇%產 率）。 b) 在上述化合物（18.2克：0.075莫耳）在無水四氫呋喃 (180毫升）的懸浮物·中，加入胼基甲酸第三-丁酯（1〇〇克： 0.0 7 5莫耳），且居此合物回流；弗騰一小時。在冷卻後，該 結晶的固體以過濾收集，而得到第三_ 丁氧基羰肼基_8_ 苯基吡啶並[2,3-d]嗒畊（28.5克）此化合物溶在乙醇（15〇 笔升）中，氯化氫於乙醇的飽和溶液（丨〇〇毫升）被加入，且 所得的混合物在室溫下攪拌iy小時。形成的—固體以過濾收 集，並以二乙醚沖洗，以產生—5-胼基_8_苯基吡啶並[2,3一 d]嗒畊二氫氣化物（2 1.6克：92%產率）。 c) 在5-肼基-8-苯基吡啶並[2,3_d]嗒畊二氫氯化物㈠.％ -13- 本纸張尺度適用中國國家標準（CNS ) Λ4現格（210 X 297公兮） f請先閱讀背面之注t事項#-填寫本頁)
準 標 家 國 國 中 用 適 度 尺 張 纸 -1_I__.本 經濟部中央標本局負工消费合作社印裝 542837 A7 ___________B7 五、發明説明（11 ) 7： 〜 克：〇.004莫耳）在二氯甲烷（3〇毫升▲)的懸笋物中，加入三 乙基胺（1.9毫升：〇.〇13莫耳），然後在室溫下攪拌15分 .鐘，並緩慢地加入三甲基乙醯氯（0.5毫升：〇.⑻44莫 耳）。在1：溫下攪拌兩小時之後，加入水（3 〇毫升），然後 形成黃色的固體，以過濾收集，並以二乙醚沖洗，產生中 間產物醞肼。此化合物被懸浮在正-丁醇（3 〇亳升）中，回 泥滞騰1 5小時，且冷卻結晶成白色固體，其以過濾收集， 並以二乙醚冲洗。所得的固體用矽凝膠及二氯甲烷-乙醇-氫氧化敍1 200 : 8 : 1做沖提液的快、速管柱（flash column) 色層分析純化。得到3 -第三-丁基-6 -苯基-1 , 2，4 -三唑並 [4,3-b]吡啶並[3,2_d]嗒畊（0.83克；69%產率），熔點 18 8.1[以彳政分掃骑卡計測定，帕金*艾爾瑪（？61*]<：丨11-
Elmer)DSC_7](表2中的化合物8)。 表2中之化學式（I)的雜環化合物是根據揭示於此實例中 方法而製備的，但是使用適當的起始物質。 表2 (請先閱讀背面之注念事項再填寫本頁)
542837 A7 B7 五、發明説明（12 經濟部中央標準局员工消费合作社印製 化合物 R1 R2" R3 熔點。c 1 Η C6H5 H 215.8 2 ch3 " ff 215.9 〇 j c2h5 " " 194.1 4 c3h7 " " 168.1 5 異-c3h7 ff ” 176.8 6 正-c4h9 ft " 162.9 7 異-c4h9 ff " 179.7 8 第三-c4h9 M " 188.1 9 正-C5H11 " " 137.4 10 新戊基 " ft 216.3 11 第三·戊基 ff " 153 12 環丙基 ” " 244.3 13 環丁基 ” " 218 14 環戊基 ?r " 202.4 15 環己基 " If 196.3 16 環丙基-CH2 ” " 195 17 環丁基-ch2 " " 183 18 環戊基-ch2 99 193 19 環己基-ch2 " 212.8 20 2-原冰片IS基-CH2 " " 217 21 c6h5. ff ” 304.1 22 c6h5-ch2 ” " 192 23 c6h5-ch2ch2 " " 176 24 c6h5-ch=ch " ff 278 25 cf3 " ff 192.5 26 h3c〇-ch2 " " 159 27 2-ClC6H4 " " 206 28 外匕咬基 333.4 29 ch3 4-FC6H4 276 30 正-C4H9 ft ” 111 31 異-c4h9 " 135 32 第三-c4h9 ?r " 195 (請先閲讀背面之注意事項再填寫本頁)
本纸張尺度適用中國國家標準（CNS ) /\4現格（210X 297公处） 542837 經满部中央標準局負工消费合作社印製 μ B7 五、發明説明（13 ) ' 化合物 R1 R2 R3 溶點。C 勹ο JJ 新戊基 " Μ 216 34 環丙基 ” 245 35 _ 環己基 ” " 177 36 環丙基-ch2 " " 160 37 環丁基-ch2 ff ff 132 38 環戊基-ch2 " " 162 39 2-原冰片醯基-CH2 Μ ” 161 40 c6h5-ch=ch ff " 272 41 c6h5〇〇c-ch2 ” " 185 42 異-c4h9 -3-FC6H4 " 147 43 新戊基 " " 190 44 環丙基 " ” 222 45 環丙基-ch2 ” 174 46 環丁基-ch2 " " 139 47 環戊基-ch2 ff " 145 48 異-c4h9 2-FC6H4 " 202 49 第三-C4H9 " ” 212 50 新戊基 " ” 235 51 環丙基 ” ” 262 52 環丙基-CH2 " fr 224 53 異-c4h9 4-C1C Η " 133 54 環丙基 Ό τ± " Η 208 55 異-c4h9 3-ClC6H4 " 113 56 第三-c4h9 " 160 57 新戊基 rf " 177 58 第三-戊基 ” ff 150 59 環丙基 * " 189 60 環丙基-ch2 — " " 136 61 環丁基-ch2 " " 156 62 環戍基-ch2 " " 147 63 異-c4h9 2-ClC6H4 " 182 請先閱讀背面之注^'事項4-填寫本頁 - . 訂 -16- 本纸張尺度適用中國國家標準（CNS ) Λ4規格（210Χ29·^Μ;,-) 542837 A7 B7 五、發明説明（14 ) 經濟部中央標挲局员工消费合作社印製 化合物 R1 R2 R3 溶點。C 64 新戊基 fl " 216 65 環丙基 ff ” 198 66 異-。4攻 4-BrC6H4 ft 135 67 新戊基 " ff 204 68 環丙基 Μ ” 208 69 環丙基-ch2 " ” 140 70 環戊基-ch2 " 187 71 2-原冰片醯基-CH2 Μ " 174 72 異-c4h9 3-BrC.H^ 6 4 ff 152 73 第三-c4h9 ff If 160 74 新戊基 ff it 177 75 環丙基 " fi 186 76 環戊基-ch2 " ” 143 77 異-c4h9 3,4-:aC6H3 ff 143 78 新戊基 ” ” 215 79 異-c4H9 3-CH3C6H4 ” 119 80 環丙基 " ” 206 81 異-c4h9 2-CH3C6H4 " 147 82 新戊基 " ” 191 83 環丙基 " ff 200 84 異-c4h9 3,4-二 CH3C6H3 ” 165 85 新戊基 If " 184 86 環丙基 M ” 182 87 環己基 " " 211 88 環戊基-ch2 " " 144 89 異-c4h9 3,4-CF3C6H4 ” 139 90 環丙基 - " 172 91 環戊基-ch2 — " " 141 92 異-c4h9 4-CH3OC6H4 " 177 93 環丙基 " 99 164 94 異-C4H9 3-CH3OC6H4 ” 119 -17- 本纸張尺度適用中國國家標準（CNS ) /\4规格（2丨0X297公处） (請先閱讀背面之注倉事項#-填寫本頁)
542837 A7 B7 五、發明説明（15 ) 經濟部中央標準局只工消费合作社印製 化合物 R1 R2 / * R3 溶點。c 95 .,新戊基 ” ” 155 96 環丙基 " " 192 97 _ 異-c4H9 2-CH3oc6H4 ff 181 98 環丙基. 、 ” π 211 99 " 3,4-二〇130(：迟3 " 177 .1QQ- 異-C4H9 158 :0, 101 第三-c4h9 ” " 251 102 新戊基 ?? " 208 103 環丙基 " 208 104 異-c4h9 193 /〆 HjC0-〇T 105 第三-c4h9 ” ff 210 ,106 新戊基 " " 219 107 環丙基 ” " 162 108 異-c3h7 _3-N02C6H4 176 109 異-c4h9 * fr 178 110 新戊基 ，—- ff ” 229 111 環丙基 Η Μ 234 112 環丙基-ch2 " ff 164 113 環丁基-ch2 " ” 150 (請先閱讀背面之注奮事項秦填寫本頁
、1T
AT -18- 本纸張尺度適用中國國家標準（CNS )八4規枱（210 X 297公/;·.-) 542837 A7 B7 五、發明説明（16) 化合物 R1 R2 R3 溶點。C 114 環戊基-ch2 ff " 183 115 116 環丙基 . 異-c4h9 31伊4 ” " 213 140 117 環丙基 ff " 212 118 異-c4h9 2-¾¾戊基 ff 196 119 環丙基 " r? 214 120 異-c4h9 3-硫茂基 M 166 121 環丙基 ff 183 122 異-c4h9 C6H5 8-H3C 170 123 新戊基 ff M 221 124 環丙基 " ” 185 125 環戊基-ch2 If ff 163 126 2-原冰片醯基-CH2 " " 193 127 異-c4h9 ft 9-Q 174 128 環丙基 " ” 149 129 環丙基-ch2 " ” 175 130 環戊基-ch2 " " 175 以下的實例説0J根據本發明之醫藥組合物。 (請先閲讀背面之注意事項再填寫本頁) 中 -火 樣 消 f： A ft 實例2 3,000個吸入瓶的每一個包含40毫克的3 -第三-丁基-6-苯基-1，2，4 -三唑並[4,3 - b ]吡啶並[3 , 2 - d ]嗒畊（活性化合 物），製備如下： .、 活性化合物 120克 三油酸山梨糖醇酐 -.4克 - 推進劑q. s · 6 0升 ' 步驟 以這些成分製備的微結晶懸浮物以填充機被導入每一個 -19- 本纸張尺度適川屮國丨3家標彳（rNS ) Λ4規格（21 OX 297公釐) 542837 300克 330克 195克 165克 495克 A7 Β7 五、發明説明（17) ' 瓶子體積爲2 0毫升的吸入瓶中。該k配有適當的閥門，其 每一次開啓時釋出0.2毫升的懸浮物（0.4毫克的活性化合 物）。 實例3 - 15,000個膠囊，每一個包含20毫克的3 -第三-丁基- 6-苯基-1，2,4 -三唑並[4，3 - b ]吡啶並[3，2 · d ]嗒畊（活性化合 物），從以下的調配物製備： 活性化合物 羧甲基澱粉鈉 滑石 氫化的篦麻油 玉米澱粉 步驟 上面的成分以6 0篩孔的篩子過篩，然後在一個適合的混 合器中混合，並i眞入1 5,0 0 0個膠囊中。 (請先閱讀背面之注意事項再填寫本頁) 樣 車 j] J. 消 ϋ: 合 印 -20 本纸張尺度適力]中國^家標彳（（’奶）八4規掊（210'/ 297公釐）
Claims (1)
- 542837 第087111560號專利申請案 ，文申請專利範圍¥換太防年^， 申請專利範圍 1. 一種式(Ϊ)化合物: N- -N 10 R3. % ,Ν 5 R1 (I) 其中； R代表氫原子或_(CH2)m_Y基團，其中 裝 且Y代表Ci-C6烷基、_CF3、Ci-C4烷氧基、具有至高7個 碳原子的烷氧羰基、CrG環烷基、正莅基、苯乙烯基、 吡啶基、或苯基（其可選擇地以一或多個_素原子取 代）； R代表萘基、4吩基、或苯基（其可選擇地以一或兩個 i素原子、或cvc：4烷基、心-匕烷氧基、C5_C6環烷氧 基、亞甲二氧基、硝基、二甲胺基或三氟曱基所取代）； 且 R3代表氫或鹵素原子或Cl-c4烷基， 及其醫藥上可接受的鹽類。 2·根據申請專利範圍第1項的化合物，其中Rl代表_ γ，其中m是0或1，且γ代表cN6烷基或（：3_7環烷基。m 3·根據申請專利範圍第1或2項的化合物，其中R2代表艾 基、4吩基、或苯基（其可選擇地以一或兩個卣素原子、 甲基、甲氧基、環戊氧基、硝基或二甲胺基取代）。 本紙張尺度適用巾關家鮮(CNS) A4%格(21Q χ 297公羡) '—'—〜 --- 4.根據申請專利範圍第3項的化合物，其中R2代表苯基、 3-氯苯基、4_氯苯基、氟苯基、仁氟苯基或3·硝苯 基0 5·根據申清專利範圍第1或2項的化合物，其中r 3代表在 1，2,4-三嗤並[4,3-1)]吡啶並[3,2-d]嗒畊骨架之8_或9_ 位置處的氫原子、Cl_4烷基或氯原子。 6根據申請專利範圍第1項的化合物，其為ό-(4-氟苯基卜 3-異丁基-1，2,4-三唑ii[4,3-b]吡啶並[3,2-d]嗒畊、3- 環丙甲基-6-(3-硝苯基）-1，2,4-三唑並[4,3_b]吡啶並 [3,2-d]塔畊、3 -環丙基-6 -苯基-1，2,4 -三唑並[4 3-b] p比淀並[3,2-d]嗒畊、及3 -環丁甲基- 6-(3 -硝苯基）_ 1，2,4-二唆並[4,3-1)]1?比咬並[3,2-(1]塔1[1井。 7 一種製備式（I)化合物的方法 2 •N 1 N. 1Ό hR1 ⑴ 其中； R1代表氫原子或-(CH2)nrY基團，其中历是〇、i或2， 且Y代表（：1<6烷基、-CF3、C「C4烷氧基、且右s丄 饲主鬲7個 碳原子的烷氧羰基、C^C：7環烷基、正褚基、笨乙缔其 吡咳：基、或苯基（其可選擇地以一或多個自素原 代）； ^ -2 -本紙張尺度適用中國國家標準(CNS) A4規格(21〇X297公釐) 六、申請專利範圍 R代表莕基、嘧吩基、或笨基（其可選擇地以一或雨個 鹵素原子、或Cl_C4烷基、烷氧基、C5-C6環烷氧基亞甲一氧基、硝基、二甲胺基或三氟甲基所取代）； 且 R3代表氫或齒素原子或Ci_c4烷基， S方法包括以式（〗V)的醯胼之環化，及藉於有機溶劑 中加熱之，而形成存在於式（1)中的i，2，仁三唑環R2 HN-NHOC-R 1 其中R1、R2及R3如上文定義。 8· 一種具有磷酸二酯酶4抑制活性之醫藥組合物，其係用於 治療已知治療是抑制磷酸二酯酶4含過敏性反應及疾病的 狀況、發炎、潰瘍及免疫疾病之症狀，該組合物包含根 據申請專利範圍第丨或2項的化合物或其醫藥上可接受的 鹽類作為活性成分。 9·根據申請專利範圍第丨或2項的化合物或其醫藥上可接受 的鹽類，其係用於治療人體或動物體。 10.根據申請專利範圍第！或2項的化合物或其醫藥上可接受 的鹽類，其係用於製造一種具磷酸二酯酶4抑制活性之 藥組合物。 本紙張尺度適用中國國家標準(CNS) A4規格(21〇X297公釐)
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| ES009701670A ES2137113B1 (es) | 1997-07-29 | 1997-07-29 | Nuevos derivados de triazolo-piridazinas heterociclicos. |
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Families Citing this family (38)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2792938B1 (fr) | 1999-04-28 | 2001-07-06 | Warner Lambert Co | NOUVELLES 1-AMINO TRIAZOLO [4,3-a] QUINAZOLINE-5-ONES INHIBITRICES DE PHOSPHODIESTERASES IV |
| EP1212089B1 (en) | 1999-08-21 | 2006-03-22 | ALTANA Pharma AG | Synergistic combination of roflumilast and salmeterol |
| WO2002080974A1 (en) * | 2001-04-04 | 2002-10-17 | Sankyo Company, Limited | Novel medicinal use of cytokine production inhibitor |
| SI1429807T1 (sl) * | 2001-09-19 | 2007-08-31 | Nycomed Gmbh | Kombinacija NSAID in PDE-4 inhibitorja |
| FR2832711B1 (fr) * | 2001-11-26 | 2004-01-30 | Warner Lambert Co | Derives de triazolo [4,3-a] pyrido [2,3-d] pyrimidin-5-ones, compositions les contenant, procede de preparation et utilisation |
| EP1559716B1 (en) * | 2002-11-06 | 2011-09-14 | ASKA Pharmaceutical Co., Ltd. | Pyrazolonaphthyridine derivative |
| ES2211344B1 (es) | 2002-12-26 | 2005-10-01 | Almirall Prodesfarma, S.A. | Nuevos derivados de piridazin-3(2h)-ona. |
| MXPA05010373A (es) | 2003-04-01 | 2005-12-05 | Applied Research Systems | Inhibidores de fosfodiesterasas en infertilidad. |
| US20050187278A1 (en) * | 2003-08-28 | 2005-08-25 | Pharmacia Corporation | Treatment or prevention of vascular disorders with Cox-2 inhibitors in combination with cyclic AMP-specific phosphodiesterase inhibitors |
| RU2246496C1 (ru) * | 2003-09-12 | 2005-02-20 | Тец Виктор Вениаминович | Вещество с противовирусной и антибактериальной активностью на основе производных 2,8-дитиоксо-1h-пирано[2,3-d, 6,5-d`] дипиримидина и их 10-аза-аналогов |
| ES2251866B1 (es) | 2004-06-18 | 2007-06-16 | Laboratorios Almirall S.A. | Nuevos derivados de piridazin-3(2h)-ona. |
| US8008317B2 (en) * | 2005-06-10 | 2011-08-30 | Merck Sharp & Dohme Corp. | Inhibitors of akt activtiy |
| EP1928437A2 (en) | 2005-08-26 | 2008-06-11 | Braincells, Inc. | Neurogenesis by muscarinic receptor modulation |
| EP2258358A3 (en) | 2005-08-26 | 2011-09-07 | Braincells, Inc. | Neurogenesis with acetylcholinesterase inhibitor |
| CA2622605A1 (en) | 2005-09-15 | 2007-03-22 | Aska Pharmaceutical Co., Ltd. | Heterocycle compound, and production process and application thereof |
| EP1940389A2 (en) | 2005-10-21 | 2008-07-09 | Braincells, Inc. | Modulation of neurogenesis by pde inhibition |
| US20070112017A1 (en) | 2005-10-31 | 2007-05-17 | Braincells, Inc. | Gaba receptor mediated modulation of neurogenesis |
| US20100216734A1 (en) | 2006-03-08 | 2010-08-26 | Braincells, Inc. | Modulation of neurogenesis by nootropic agents |
| AU2007249399A1 (en) | 2006-05-09 | 2007-11-22 | Braincells, Inc. | Neurogenesis by modulating angiotensin |
| WO2007134077A2 (en) | 2006-05-09 | 2007-11-22 | Braincells, Inc. | 5 ht receptor mediated neurogenesis |
| US7683060B2 (en) | 2006-08-07 | 2010-03-23 | Incyte Corporation | Triazolotriazines as kinase inhibitors |
| EP2068872A1 (en) | 2006-09-08 | 2009-06-17 | Braincells, Inc. | Combinations containing a 4-acylaminopyridine derivative |
| US20100184806A1 (en) | 2006-09-19 | 2010-07-22 | Braincells, Inc. | Modulation of neurogenesis by ppar agents |
| ME02372B (me) | 2006-11-22 | 2016-06-20 | Incyte Holdings Corp | Imidazotriazini i imidazopiramidini kao inhibitori kinaze |
| EP2231669A1 (en) * | 2008-01-09 | 2010-09-29 | The U.S.A. As Represented By The Secretary, Department Of Health And Human Services | Phosphodiesterase inhibitors |
| WO2009143211A2 (en) | 2008-05-21 | 2009-11-26 | Incyte Corporation | Salts of 2-fluoro-n-methyl-4-[7-(quinolin-6-yl-methyl)- imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide and processes related to preparing the same |
| EP2196465A1 (en) | 2008-12-15 | 2010-06-16 | Almirall, S.A. | (3-oxo)pyridazin-4-ylurea derivatives as PDE4 inhibitors |
| WO2010099217A1 (en) | 2009-02-25 | 2010-09-02 | Braincells, Inc. | Modulation of neurogenesis using d-cycloserine combinations |
| EP2226323A1 (en) | 2009-02-27 | 2010-09-08 | Almirall, S.A. | New tetrahydropyrazolo[3,4-c]isoquinolin-5-amine derivatives |
| PH12012501361A1 (en) | 2009-12-31 | 2012-10-22 | Centro Nac De Investigaciones Oncologicas Cnio | Tricyclic compounds for use as kinase inhibitors |
| EA025304B1 (ru) | 2010-02-03 | 2016-12-30 | Инсайт Холдингс Корпорейшн | ИМИДАЗО[1,2-b][1,2,4]ТРИАЗИНЫ В КАЧЕСТВЕ c-Met ИНГИБИТОРОВ |
| EP2380890A1 (en) | 2010-04-23 | 2011-10-26 | Almirall, S.A. | New 7,8-dihydro-1,6-naphthyridin-5(6h)-one-derivatives as PDE4 inhibitors |
| EP2394998A1 (en) | 2010-05-31 | 2011-12-14 | Almirall, S.A. | 3-(5-Amino-6-oxo-1,6-dihydropyridazin-3-yl)-biphenyl derivatives as PDE4 inhibitors |
| WO2012098387A1 (en) | 2011-01-18 | 2012-07-26 | Centro Nacional De Investigaciones Oncológicas (Cnio) | 6, 7-ring-fused triazolo [4, 3 - b] pyridazine derivatives as pim inhibitors |
| WO2013005041A1 (en) | 2011-07-07 | 2013-01-10 | Centro Nacional De Investigaciones Oncológicas (Cnio) | Tricyclic heterocyclic compounds as kinase inhibitors |
| WO2013004984A1 (en) | 2011-07-07 | 2013-01-10 | Centro Nacional De Investigaciones Oncologicas (Cnio) | Tricyclic compounds for use as kinase inhibitors |
| WO2013005057A1 (en) | 2011-07-07 | 2013-01-10 | Centro Nacional De Investigaciones Oncológicas (Cnio) | New compounds |
| WO2013106547A1 (en) | 2012-01-10 | 2013-07-18 | President And Fellows Of Harvard College | Beta-cell replication promoting compounds and methods of their use |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3122670A1 (de) | 1981-06-06 | 1982-12-23 | Dr. Karl Thomae Gmbh, 7950 Biberach | "neue 1,4,9,10-tetrahydro-pyrazolo(4,3-e) pyrido(3,2-b)(1,4)diazepin-10-one, verfahren zu ihrer herstellung und ihre verwendung zur herstellung von pharmazeutischen wirkstoffen" |
| FI81350C (fi) * | 1982-01-18 | 1990-10-10 | Lepetit Spa | Analogfoerfarande foer framstaellning av nya, farmakologiskt aktiva 6-substituerade s-triatsolo/3,4-a/ ftalazinderivat. |
| EP0217748B1 (en) * | 1985-09-30 | 1991-02-06 | Ciba-Geigy Ag | 2-Substituted-e-fused-[1,2,4,]triazolo-[1,5-c]pyrimidines pharmaceutical compositions and uses thereof |
| AU7238191A (en) * | 1990-02-19 | 1991-09-03 | Chugai Seiyaku Kabushiki Kaisha | Novel fused heterocyclic compound and antiasthmatic agent prepared therefrom |
| HUT66969A (en) * | 1991-10-09 | 1995-01-30 | Syntex Inc | Benzo- and pyrido-pyridazinone- and pyridazin-thion derivatives, pharmaceutical compositions containing the same and process for the production of thereof |
| GB9514465D0 (en) | 1995-07-14 | 1995-09-13 | Glaxo Lab Sa | Chemical compounds |
| DE19510965A1 (de) * | 1995-03-24 | 1996-09-26 | Asta Medica Ag | Neue Pyrido/3,2-e/pyrazinone mit antiasthmatischer Wirksamkeit und Verfahren zu deren Herstellung |
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