TW510901B - Angiogenesis inhibiting 5-substituted-1,2,4-thiadiazolyl derivatives - Google Patents

Abstract

This invention concerns compounds of formula the N-oxide forms, the pharmaceutically acceptable acid addition salts and stereochemically isomeric forms thereof, wherein X is CH or N; R1 is hydrogen, C1-6alkyl, C1-6alkyloxy, C1-6alkylthio, amino, mono- or di(C1-6alkyl)amino, Ar1, Ar1NH-, C3-6cycloalkyl, hydroxymethyl or benzyloxymethyl; R2 is hydrogen, C1-6alkyl, amino, aminocarbonyl, mono- or di(C1-6alkyl)amino, C1-6alkyloxycarbonyl, C1-6alkylcarbonylamino, hydroxy or C1-6alkyloxy; R3, R4 and R5 are each independently selected from hydrogen, halo, C1-6alkyl, C1-6alkyloxy, trifluoromethyl, nitro, amino, cyano, azido, C1-6alkyloxyC1-6alkyl, C1-6alkylthio, C1-6alkyloxycarbonyl or Het1; formula is Ar2, Ar2CH2- or Het2; Ar1 and Ar2 optionally substituted phenyl; Het1 and Het2 are optionally substituted monocyclic heterocycles; having angiogenesis inhibiting activity; their preparation, compositions containing them and their use as a medicine.

Description

A7 -一~~Β7 五、發明説明（！）— 一一一一—〜——--—————一一 本發明係有關作為血管生成抑制劑之5_經取代巧24_ ---------裝丨 讀先閱讀背而之注意，?項洱填寫本頁 嗜二唾衍生物，及其製法；其尚有關含其之組合物，及，盆 作為藥物之用途。 ^ 血B生成作用，亦即表皮細胞形成新血管之作用，在 許多生理及病理生理過程中扮演重要角色。血管供應之發 5為正常組織之生長、成熟與維持所必要者。其亦傷口癒 合所必需者。企管生成作用對固體腫瘤生長及轉移报重要 且涉及許多種其他病理症狀，如：新血管青光眼、糖尿病 性視網膜病、牛皮癖及類風濕關節炎。此等病症之特徵為 血管生成作用提高，此期間休眠之内皮細胞活化，分解細 胞外母質障壁，增殖，並移動形成新血管。為了控制此等 依賴血管生成作用之病症，極適合使用具有血管生成抑制 活性之化合物。 .Φ 相關技藝已揭不數種抑制血管生成作用之化合物，亦 稱為血管阻滯劑、血管抑制劑或血管生成拮抗劑。例如： 皮質固酵為一種習知之血管生成抑制劑（福克曼A7-一 ~~ Β7 V. Description of the invention (!) — One by one — — — — — — — — The present invention is related to the 5_ substitutability of angiogenesis inhibitors 24_ --- ------ Installation 丨 Read the first note and read the note, fill in this page, the sialo derivative, and its preparation method; it is still related to the composition containing it, and the use of the basin as a medicine. ^ The formation of blood B, that is, the formation of new blood vessels by epidermal cells, plays an important role in many physiological and pathophysiological processes. The development of vascular supply 5 is necessary for the growth, maturation and maintenance of normal tissues. It is also necessary for wound healing. Enterprise management is important for the growth and metastasis of solid tumors and involves many other pathological symptoms, such as neovascular glaucoma, diabetic retinopathy, psoriasis, and rheumatoid arthritis. These conditions are characterized by increased angiogenesis, during which dormant endothelial cells activate, break down extracellular matrix barriers, proliferate, and move to form new blood vessels. In order to control these conditions that rely on angiogenesis, compounds having angiogenesis-inhibiting activity are very suitable. .Φ Related arts have revealed numerous compounds that inhibit angiogenesis, also known as vascular blockers, angiogenesis inhibitors or angiogenesis antagonists. For example: Corticotrophin is a known inhibitor of angiogenesis (Falkman

Folkman)等人，Science 230 : 1375，1985，“在含有肝 經漭部中央標隼局員工消t合作社印製 素或肝素片斷下抑制血管生成作用之一類新穎類固醇（A new class of steroids inhibits angiogensis in the presence 〇f heparin or a heparin fragment”）；福克曼等人，Science 221 : 719, 1983，”於羥基-脫氫皮質酮存在下，由肝素或 肝素片斷引起之血管生成抑制作用及腫瘤復原作用 (Angiogenesis inhibition and tumor regression caused by 木紙张尺度適用十國國家桴導.；:Γ NS ) Λ 4規,¾ ( 2丨0 X 2 β公/丨） 87164a(9JANSEN) 510901 經滴部中央標準局員工消費合作社印製 A7 B7 五、發明説明（2 ) heparin or a heparin fragment in the presence of cortisone) 〇 EP 0,398,427(1990年11月22日公告)揭示抗鼻病毒 之嗒畊胺類，且EP 0,435,381 ( 1991年7月3日公告）說 明具有抗細小核糖核酸病毒活性之嗒畊胺類。EP 0,429,344(1991年5月29日公告)揭示作為膽鹼激導性促 效劑之胺基嗒畊衍生物。 本發明化合物不同於先前技藝化合物之處在於其一定 經噻二唑基部份取代，且特定言之，此等化合物意外地具 有血管生成抑制性質。 本發明係有關下式化合物Folkman), et al., Science 230: 1375, 1985, "A new class of steroids inhibits angiogensis in the presence of heparin-printed or heparin fragments from employees of the Central Bureau of Standards of the Ministry of Hepatology in the presence 〇f heparin or a heparin fragment "); Falkman et al., Science 221: 719, 1983," in the presence of hydroxy-dehydrocorticosterone, angiogenesis inhibitory effects and tumors caused by heparin or heparin fragments Restoration (Angiogenesis inhibition and tumor regression caused by Wood and paper scales are applicable to the ten countries ’guidance. :: Γ NS) Λ 4-gauge, ¾ (2 丨 0 X 2 βpublic / 丨) 87164a (9JANSEN) 510901 Printed by the Consumer Standards Cooperative of the Central Standards Bureau A7 B7 V. Description of the invention (2) heparin or a heparin fragment in the presence of cortisone 〇EP 0,398,427 (Announcement on November 22, 1990) revealed rhodamine-resistant tamines, And EP 0,435,381 (published on July 3, 1991) describes tamamines with anti-ribonuclease activity. EP 0,429,344 (published on May 29, 1991) is disclosed as choline Derivatives of amino agonists. Compounds of the present invention differ from prior art compounds in that they must be partially substituted with thiadiazolyl and, in particular, these compounds unexpectedly have angiogenesis inhibiting properties The invention relates to compounds of the formula

其N-氧化物型、醫藥上可接受之酸加成鹽、及立體化學 異構型，其中 X為CH或N ; R1為氫、Ck烷基、〇V6烷氧基、Cl_6烷硫基、胺基、單_ 或—(Ck烧基)胺基、Αγ1、Αι^ΝΗ-、C3-6 ^烧基、趣 甲基或苄氧曱基； R2為氫、cv6烷基、胺基、胺羰基、單-或二(c1-6烷基)胺 基、Ck烧乳Ik基、C1<>6燒幾胺基、輕基或C1-6燒氣 基； 本、.，氏张人’又通用中國國家標準（€灿）六4規格（210、乂297公餐 (請先閱讀背面之注意事項再填寫本頁}Its N-oxide type, pharmaceutically acceptable acid addition salt, and stereochemically isomeric type, where X is CH or N; R1 is hydrogen, Ck alkyl, OV6 alkoxy, Cl-6 alkylthio, Amine group, mono- or-(Ck alkyl) amino group, Aγ1, A ^^-, C3-6 ^ alkyl, methyl or benzyloxy; R2 is hydrogen, cv6 alkyl, amine, amine Carbonyl, mono- or di (c1-6 alkyl) amino, Ck roasted milk Ik group, C1 < > 6-kidamine group, light group or C1-6 gas-based group; Also common Chinese national standard (€ can) 6 4 specifications (210, 乂 297 meals (please read the precautions on the back before filling in this page)

510901 A7 B7 五、發明説明（3 ) R3、R4與R5分別選自氫、鹵素、CV6烷基、CV6烷氧基、 三氟甲基、硝基、胺基、氰基、疊氮基、CV6烷氧基 -CV6烷基、CV6烷硫基、CV6烷氧羰基或Het1 ; 為 Ar2、Ar2CH_或 Het2 ;510901 A7 B7 V. Description of the invention (3) R3, R4 and R5 are selected from hydrogen, halogen, CV6 alkyl, CV6 alkoxy, trifluoromethyl, nitro, amine, cyano, azide, CV6 Alkoxy-CV6 alkyl, CV6 alkylthio, CV6 alkoxycarbonyl or Het1; is Ar2, Ar2CH_ or Het2;

Ar1為苯基；經1、2或3個分別選自鹵素、CV6烷基、（^_6 烷氧基、三i甲基、胺基或硝基之取代基取代之苯 基；Ar1 is phenyl; phenyl substituted with 1, 2 or 3 substituents selected from halogen, CV6 alkyl, (^ -6 alkoxy, trimethyl, amine or nitro;

Ar2為苯基；經1、2或3個分別選自鹵素、CV6烷基、CV6 烧氧基、三幽曱基、胺基或石肖基之取代基取代之苯 基；Ar2 is a phenyl group; a phenyl group substituted with 1, 2 or 3 substituents selected from the group consisting of halogen, CV6 alkyl, CV6 alkoxy, tripyridyl, amine or schottyl;

Het1為選自下列之單環狀雜環：呤唑基、異噚唑基、嘮二 a坐基、嗔ϋ坐基、異嗔ϋ坐基、σ塞二唾基、或号。坐σ林基； 且各單.環狀雜環可視需要於碳原子上經CV4烷基取 代；及 經滴部中央標率局員工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁)Het1 is a monocyclic heterocyclic ring selected from the group consisting of a pyrazolyl group, an isoxazolyl group, a fluorenyl group, a fluorenyl group, an isofluorenyl group, a saccharyl group, or an oxo group. Sigma linyl; and each cyclic heterocyclic ring may be substituted with CV4 alkyl on the carbon atom as required; and printed by the staff consumer cooperative of the Central Standards Bureau of Didi (please read the precautions on the back before filling this page) )

Het2為選自下列之單環狀雜環：呋喃基、硫呋喃基、哼二 ϋ坐基、u塞二η坐基、u比ϋ坐基、。密ϋ定基或吼σ井基；且各單 環狀雜環可視需要於碳原子上經1或2個分別選自鹵 素、CV4烷基、CV4烷氧基、硝基或三氟甲基之取代基 取代。 上述定義及下文中採用之“鹵素”一般係指氟、氯、 溴及碘；（^_4烷基之定義為含1至4個碳原子之直鏈及分 支鍵飽和煙基’如’例如·甲基、乙基、丙基、丁基、1 - 甲基乙基、2-甲基丙基，等等；CV6烷基係包括Cm烷 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） A7 五、發明説明（4 =5至6個碳原子之其較高碳數同系物， 如基丁基、己基、2•甲基戊基，等等。 部份之實例為Het2 is a monocyclic heterocyclic ring selected from the group consisting of furanyl, thiofuranyl, humedyl, u-substituted di-n-substituted, u-fluorinated, and. Mesitidine or sigma stilbene; and each monocyclic heterocyclic ring may be substituted on the carbon atom with 1 or 2 selected from halogen, CV4 alkyl, CV4 alkoxy, nitro or trifluoromethyl Radical substitution. The above definition and the "halogen" used hereinafter generally refer to fluorine, chlorine, bromine, and iodine; (^ _4 alkyl is defined as a straight and branched saturated nicotyl group containing 1 to 4 carbon atoms, such as "e.g. · Methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl, etc .; CV6 alkyl series including Cm alkane. Paper size applies to Chinese National Standard (CNS) A4 specifications (210X 297 mm) A7 V. Description of the invention (4 = 5 to 6 carbon atoms with higher carbon number homologs, such as butylbutyl, hexyl, 2 • methylpentyl, etc. Some examples are

• I.....— I · 經濟部中央標隼局員工消費合作社印絮 其中·©為如式的氏自由基，# 乂為ch時該自 由基之CH2 α卩伤隶好連接六氫吼咬基部份之氮原子，或當 X為氮時，則連接六氫㈣基部份之氮原子。 上述醫藥上可接受之酸加成鹽係包括式⑴化合物可形 成之醫藥活性非毒性酸加成鹽。具有驗性性質之式(I)化合 物可經適當酸處理，轉化成其醫藥上可接受之酸加成鹽。適 當酸包括例如··無機酸如：氫錢，例如：鹽酸或氯漠 •酸；硫酸；硝酸；填酸，等等酸類；或有機酸如，例如： 乙酸、丙酸、羥基乙酸、乳酸、丙_酸、草酸、丙二酸、 琥珀8文（即丁二酸）、馬來酸、富馬酸、蘋果酸、酒石酸、 才宁檬酸、甲績酸、乙績酸、苯磺酸、對甲苯確酸、環己胺 〜酸、水楊酸、對胺基水揚酸、二羥萘酸、等等酸類。 酸加成鹽一詞亦包括式⑴化合物可形成之水合物及溶 劑加成型。此等型式實例為例如；水合物、醇鹽，等等。 上文採用之式(I)化合物之立體化學異構型一詞係指式 (I)化合物中，由相同鍵結之相同原子但具有無法交換之不 1,1 本紙張尺度適用中國國家標準（CNS ) Α4規格（ 210X297公釐） -- (請先閱讀背面之注意事項再填寫本頁) w I I —«I ·• I .....— I · Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs, where · © is the formula's free radical, and # 乂 is the CH2 α of the free radical, which is connected to hexahydro. The nitrogen atom of the sulfanyl moiety, or when X is nitrogen, is attached to the nitrogen atom of the hexahydrofluorenyl moiety. The above-mentioned pharmaceutically acceptable acid addition salts include pharmaceutically active non-toxic acid addition salts which can be formed by compounds of the formula (I). Compounds of formula (I) with experimental properties can be converted into their pharmaceutically acceptable acid addition salts by appropriate acid treatment. Suitable acids include, for example, inorganic acids such as: hydrogen, such as: hydrochloric acid or chlorinated acid; sulfuric acid; nitric acid; filling acids, etc .; or organic acids such as: acetic acid, propionic acid, glycolic acid, lactic acid, Malonic acid, oxalic acid, malonic acid, succinic acid (ie succinic acid), maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, formic acid, acetic acid, benzenesulfonic acid, P-toluene acid, cyclohexylamine ~ acid, salicylic acid, p-aminosalicylic acid, dinaphthoic acid, etc. The term acid addition salt also includes hydrates and solvent additions that can be formed by compounds of formula VII. Examples of such types are, for example; hydrates, alkoxides, and the like. The term stereochemically isomeric form of the compound of formula (I) used above refers to the compound of formula (I), which has the same atom bonded by the same bond but has no exchangeable 1,1. CNS) Α4 specification (210X297mm)-(Please read the precautions on the back before filling this page) w II — «I ·

.I- — I 4. A7 B7 、發明説明（ 同立體結構構叙财可能 化合物之化學初除非另外說明，否則 _化合财能具有之所有可能立體化 構之所有非對二:1:Γ 化合物基本分子結.I- — I 4. A7 B7, description of the invention (the chemical chemistry of the possible compounds with the same stereostructure is not stated otherwise, unless otherwise stated, all non-parallel 2: 1: Γ compounds of all possible stereochemical configurations that the chemical compound can possess Basic molecular knot

Mm異構物及/或對映異構物。本發明範圍内 ^物:⑴化合物所有立體化學異構型之純型或其互相之混 有一式(I)化合物亦可呈其互變異構型。雖然上式中並 ♦曰明此等型式’但仍包括在本發明範圍内。 式⑴化合物之N-氧化物型包括彼等式⑴化合物中，一 個或數個氮原子被氧化成所謂之N_氧化物者。 下文中採用之“式⑴化合物，，一詞亦包括醫藥上可接 受之酸加成鹽型及所有立體化學異構型。 一類有利之化合物包括彼等式⑴化合物中，符合下列 一項或多項條件者： a)X 為 N ; ^R1為氫，C1-6烷基，胺基或二(Ci6烷基)胺基； c) R2為氫； d) R3、R4與R5分別選自氫、鹵素、Cl_6烷基、匕6烷氧 基、三氟甲基、硝基或CV6烷氧羰基。 一類特定化合物為彼等式(I)化合物中，X為N ; Ri為 氫，C1-4烷基或二(CV4烷基)胺基；R2為氫；R3、R4與rs 分別選自：氫、鹵素、Cm烷基、（^·4烷氧基或三氟甲 基；且二價自由基為Ar2、Ar2 CH2-或Het2，其中 本紙張尺度適用中國國家標準（CNS ) Α4規格（210Χ 297公釐） (請先閱讀背面之注意事項再填寫本頁) 訂---- 經濟部中央標率局負Η消費合作社印掣 510901 A7 B7 五、發明説明（6 )Mm isomers and / or enantiomers. Within the scope of the present invention: the pure form of all stereochemically isomeric forms of the amidine compound or a mixture of each other. A compound of formula (I) may also be present in its tautomeric form. Although the above formula does not indicate these types', it is still included in the scope of the present invention. The N-oxide type of the compound of the formula (I) includes those compounds of the formula (I) in which one or several nitrogen atoms are oxidized to a so-called N-oxide. The term "compounds of formula (I)" as used below also includes pharmaceutically acceptable acid addition salt forms and all stereochemically isomeric forms. A class of advantageous compounds includes those compounds of formula (I) that meet one or more of the following The conditions are: a) X is N; ^ R1 is hydrogen, C1-6 alkyl, amine or di (Ci6 alkyl) amino; c) R2 is hydrogen; d) R3, R4 and R5 are each selected from hydrogen, Halogen, Cl_6 alkyl, D6 alkoxy, trifluoromethyl, nitro, or CV6 alkoxycarbonyl. A specific class of compounds are their compounds of formula (I) where X is N; Ri is hydrogen and C1-4 alkane Or di (CV4 alkyl) amino; R2 is hydrogen; R3, R4, and rs are selected from: hydrogen, halogen, Cm alkyl, (^ · 4 alkoxy, or trifluoromethyl); and a divalent radical Ar2, Ar2 CH2- or Het2, in which the paper size applies the Chinese National Standard (CNS) A4 specification (210 × 297 mm) (Please read the precautions on the back before filling this page) Order ---- Central Standard of the Ministry of Economic Affairs Led by the Bureau of the Consumer Cooperatives 510901 A7 B7 V. Description of Invention (6)

Ar2為苯基、或經1或2個分別選自：卤素、Cy烷基、 C〗-6烷氧基、三_甲基、胺基或硝基之取代基取代；且 Het2為嗔二嗤基、吼唆基、喷咬基或吼畊基。 較佳一類化合物為彼等式⑴化合物，其中X為N，R1 為甲基，R2為氳、R3與R4為氫且R5為三氟甲基。 更佳一類化合物為彼等較佳化合物中，R5為位於3-位置 之三氟甲基。 最佳者為： 1-[4_(3•甲基-1，2，4-噻二唑-5-基）苯基]-4_[3-(三氟甲基） 苯基]六氫井，及 1-[5-(3·甲基-1，2，4-噻二唑-5-基)-2-吡啶基]·4-[3-(三氟甲 基）苯基]六氫吡畊，及其醫藥上可接受之酸加成鹽、立體 異構型、或Ν-氧化物。 本發明之一般製法為由式（π)中間物與式（m)中間物 反應。Ar2 is phenyl, or substituted with 1 or 2 substituents selected from: halogen, Cyalkyl, C6-6alkoxy, trimethyl, amine or nitro; and Het2 is fluorene. Base, roaring base, spouting base, or roaring base. A preferred class of compounds are their compounds of formula IX, where X is N, R1 is methyl, R2 is fluorene, R3 and R4 are hydrogen, and R5 is trifluoromethyl. A more preferred class of compounds is among their preferred compounds, R5 is a trifluoromethyl group at the 3-position. The best are: 1- [4_ (3 • methyl-1,2,4-thiadiazol-5-yl) phenyl] -4_ [3- (trifluoromethyl) phenyl] hexahydro well, And 1- [5- (3 · methyl-1,2,4-thiadiazol-5-yl) -2-pyridyl] · 4- [3- (trifluoromethyl) phenyl] hexahydropyridine And its pharmaceutically acceptable acid addition salts, stereoisomers, or N-oxides. A general method of the present invention is to react an intermediate of formula (π) with an intermediate of formula (m).

經¾部中央標準局員_τ消費合作社印製 上述及下列反應圖中，w代表合適之反應性脫離基， 如’例如：鹵素·，例如：氟、氯、溴、碘，或有些情況 下’w亦可為磺醯氧基，例如：甲磺醯氧基、苯磺醯氧 _____ _8麵 ^紙張尺度適用中) A4規格（21〇χγ97公釐 經滴部中央標率局負工消費合作社印裂 510901 A7 一… _〜__ _ 五、發明説明（7 ) 基、二氟甲％醯氧基，等等類似之反應性脫離基。該反應 係依相關技藝已知之方法進行，如，例如：由二種反應物 共同於反應惰性溶劑中，例如：N，N_二甲基甲醯胺、乙 腈、甲基異丁基_，等等中，最好於鹼 ，例如· 酸鼠 鈉、碳酸鈉或三乙胺之存在下，共同攪拌。該反應宜在室 溫至反應混合物之回流溫度間進行。 式⑴中’ R1為CH3之化合物(其係由式(I-a)代表)之製 法亦可由式（IV)化合物經羥胺—〇—磺酸，於反應惰性溶劑 中，如，例如：甲醇或乙醇中，於鹼如：吡啶之存在下處 理。The above and the following reaction diagrams have been printed by ¾ Central Standards Bureau _τ Consumer Cooperatives, where w represents a suitable reactive radical, such as 'for example: halogen ·, for example: fluorine, chlorine, bromine, iodine, or in some cases' w can also be sulfonyloxy, for example: methanesulfonyloxy, benzenesulfonyloxy _____ _ 8 faces ^ paper size is applicable) A4 size (21〇χγ97 mm by the Ministry of Standards Bureau of Labor Standards Consumer Cooperative) Printing 510901 A7 I ... _ ~ __ _ V. Description of the invention (7) group, difluoromethyl% fluorenyl group, etc. Reactive radicals similar to this. The reaction is carried out according to methods known in related art, such as, for example, : Two reactants are used together in the reaction inert solvent, for example: N, N_dimethylformamide, acetonitrile, methyl isobutyl_, etc., it is better than alkali, for example Stir together in the presence of sodium carbonate or triethylamine. The reaction is preferably carried out at room temperature to the reflux temperature of the reaction mixture. The compound in formula 'R1 is CH3 (which is represented by formula (Ia)) is also prepared. The compound of formula (IV) can be reacted with hydroxylamine-O-sulfonic acid in a reaction inert solvent. Such as, for example: methanol or ethanol, a base such as: the presence of pyridine handled under.

式(I)化δ物之另種製法為由式⑴化合物根據相關技 藝已知之基團轉化反應互相轉換。 式(I)化合物亦可依相關技藝上已知用於轉化三價氣形 成Ν-氧化物型之方法，轉化成相應之队氧化物型。該Ν_ 氧化反應通常由式⑴起始物與適當有機或無機過氧化物反 應。當之無機過氧化物包括例如：過氧化氫、驗金屬或驗 土金屬過氧化物.，例如··過氧化納、過氧化卸；適當之有 機過氧化物可包括過氧酸類，如，例如：苯甲過氧酸或齒 ___ __ -9- 本紙張纽刺 票準(CNS ) --~~ --- --------0^-------------Φ (請先閱讀背面之注意事項再填寫本頁) 510901 A7 B7 五 、發明说明（ 素取代之苯曱過氧酸，例如：3_氯苯甲過氧酸，過氧烷 酸，例如：過氧乙酸、烷基過氧化物。例如：第三丁基過 氧化物。合適溶劑為例如：水、低碳數烷醇類，例如··乙 酵，等等，烴類，例如：甲苯、酮類，例如：2-丁酮，_ 化烴類，例如：二氯甲烷，及此等溶劑之混合物。 起始物及某些中間物為已知化合物，且可自商品取得 或可根據相關技藝一般已知之反應製得。例如：某些式 (Π)中間物如：5-(4-氟苯基)_3_甲基―丨又各噻二唑已說明於 Y，I ’ 林（Lin)等人之 j 〇rg chem· 45(19)，Ρ·3750_ 3753(1980)，且有些式（m )中間物，如：μ〔3-(三氟 甲基）苯基〕-六氫吡畊可自商品取得。 式（Π)中間物之製法可由式（v)化合物，其中w 為如上述定義之合適脫離基，與式（VI)中間物反應，視 需要呈其酸加成鹽添加。 --------^^衣-- (請先閱讀背面之注意事項再填寫本頁) ^ IV Maw— -'口Another method for preparing the compound of formula (I) is to convert the compounds of formula (I) to each other according to group conversion reactions known in the related art. The compound of formula (I) can also be converted into the corresponding oxide group according to a method known in the related art for converting a trivalent gas into an N-oxide type. The N_ oxidation reaction is usually a reaction of the formula VII starting with an appropriate organic or inorganic peroxide. Inorganic peroxides include, for example: hydrogen peroxide, metal test or soil test metal peroxides, such as sodium peroxide, peroxide discharge; suitable organic peroxides may include peroxy acids, such as, for example, ： Benzylperoxy acid or tooth ___ __ -9- This paper is a Niuziao standard (CNS)-~~ --- -------- 0 ^ ---------- --- Φ (Please read the precautions on the back before filling this page) 510901 A7 B7 V. Description of the invention (Phenylperoxy acid substituted by element, such as 3-chlorobenzoyl peroxy acid, peroxyalkanoic acid, For example: peroxyacetic acid, alkyl peroxide. For example: tertiary butyl peroxide. Suitable solvents are, for example: water, low-carbon alkanols, such as acetic acid, etc., hydrocarbons, such as: Toluene, ketones, such as: 2-butanone, hydrogenated hydrocarbons, such as: dichloromethane, and mixtures of these solvents. The starting materials and certain intermediates are known compounds and can be obtained from commercial products or can be It is prepared according to reactions generally known in related arts. For example: certain intermediates of formula (Π) such as: 5- (4-fluorophenyl) _3_methyl ― and each thiadiazole has been described in Y, I 'Lin (Lin) and others j 〇rg chem · 45 (19), P · 3750_ 3753 (1980), and some intermediates of formula (m), such as: μ [3- (trifluoromethyl) phenyl] -hexahydropyramine The method for preparing the intermediate of formula (Π) can be obtained from the compound of formula (v), where w is a suitable leaving group as defined above, and reacts with the intermediate of formula (VI), and is added as its acid addition salt if necessary. --- ----- ^^ 衣-(Please read the notes on the back before filling this page) ^ IV Maw—-'口

a)-CH3 + SOCU (V)a) -CH3 + SOCU (V)

Rl~C-NH2 (VI) (II) 經漓部中央標率局員工消費合作社印製 式（IV)中間物之製法如圖工圖1 Z-^A^—W1 + (VII)Rl ~ C-NH2 (VI) (II) Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Foreign Affairs (IV) The intermediate method is shown in Figure 1 Z- ^ A ^ —W1 + (VII)

R2 厂K R3 (III) R4 R2 - R3 令 (VIII) R5 R4 -10- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）R2 Factory K R3 (III) R4 R2-R3 Order (VIII) R5 R4 -10- This paper size applies to China National Standard (CNS) A4 specification (210X297 mm)

R2 r3R2 r3

1'發明説明（9 ) 〜--2>^©-( s (IX) 圖I中，由式（w)中間物，其中wl為合適之脫離 基如：齒素或磺醯氧基，且Z為氰基或胺羰基，與式 (ΙΠ )中間物’於上述合成式（I )化合物所述之相關技 藝已知之反應方法下反應，所得式（遞）中間物經勞森試 劑（Lawesson’s reagent)於合適溶劑如，例如：甲苯或口比 啶中處理，或於合適溶劑如，例如：N，N_二甲基甲醯胺 中，可視需要於三乙胺之存在下，以H2S處理。隨後，由 式（IX )中間物，於反應性溶劑中，如，例如：甲苯或二 氣甲烷中，經N，N-二甲基乙醯胺二甲基縮醛處理，產生式 (IV )中間物。 •式（I )化合物及某些中間物之結構可具有一個或多 個立體中心，呈R或S組態。例如：Ri、R2、r3、r4或 R5可為具有一個立體中心之Cy烷基。 依上述方法製備之式（I)化合物<合成對映異構物 之消旋混合物型式，其可依相關技藝上已知之解析法互相 分離。式（I )消旋化合物可經由與合適對掌性酸之反 應，轉化成相應之非對映異構性鹽塑。該非對映異構性鹽 型隨後可例如：經由選擇性結晶法或部份結晶法分離，然 後利用驗釋出對映異構物。另一種分離式(I)化合物之對映 ______ -11 -__________ 本紙張尺ϋ用中國國家標準（CNS ) A4規格（210x297公釐] 一 " --------衣------訂-------AWI (請先M-讀背面之注意事項再填寫本頁) 經滴部中央標準局員Η消費合作社印製 510901 A7 _______________ B7 五、發明説明（1〇 ) ~~ ^ 異構型之方法涉及採用對掌性固定相進行之液相層析法。 合適之對掌性固定相為例如··多醣，特定言之纖維素或直 鏈澱粉衍生物。市售以多醣為主之對掌性固定相商品為1 'Description of the invention (9) ~ --2 > ^ ©-(s (IX) In Figure I, the intermediate of formula (w), where wl is a suitable leaving group such as: dentin or sulfonyloxy, and Z is a cyano group or an amine carbonyl group, and is reacted with an intermediate of the formula (III) under a reaction method known in the related art described in the synthesis of the compound of the formula (I), and the obtained intermediate is passed through Lawesson's reagent ) In a suitable solvent such as, for example, toluene or bipyridine, or in a suitable solvent such as, for example, N, N-dimethylformamide, if necessary, with H2S in the presence of triethylamine. Subsequently, the intermediate of formula (IX) is treated with N, N-dimethylacetamidine dimethyl acetal in a reactive solvent, such as, for example, toluene or methane, to produce formula (IV) Intermediates. • The structure of the compound of formula (I) and some intermediates may have one or more stereocenters in a R or S configuration. For example: Ri, R2, r3, r4 or R5 may be a stereocenter. Cy alkyl. The compound of formula (I) prepared according to the above method < synthetic mixture of enantiomers. The analytical methods known in the art are separated from each other. The racemic compounds of formula (I) can be converted into the corresponding diastereomeric salts by reaction with suitable palmitic acids. The diastereomeric salt forms can then be For example: separation by selective crystallization or partial crystallization, and then the enantiomers are released by inspection. Another separation of the enantiomers of compounds of formula (I) ______ -11 -__________ This paper uses Chinese national standards (CNS) A4 specification (210x297 mm)-"-------- Clothing -------- Order ------- AWI (Please M-read the precautions on the back before filling in this Page) Printed by a member of the Central Bureau of Standards of the Ministry of Standards and Consumer Cooperatives 510901 A7 _______________ B7 V. Description of the invention (1〇) ~~ ^ The isomeric method involves the use of liquid chromatography on a palm stationary phase. Appropriate The palm stationary phase is, for example, a polysaccharide, specifically cellulose or an amylose derivative. The commercially available palm stationary phase is mainly a polysaccharide.

Chiral Cel CA、OA、OB、OC、OD、0F、〇G、〇J 及 OK ’ Chiralpak AD、AS、OP㈩及 〇T(+)。與該多醣對掌 性固定相組合使用之適當溶離液或移動相為己烷，等等， 經醇類如：乙醇、異丙醇，等等修飾。該純立體化學異構 型亦可衍生自適當起始物之相應純立體化學異構型，但其 條件為該反應為立體專一性反應。較佳者，若需要專一性 立體異構物時，該化合物可利用立體專一性製法合成。此 等方法宜採用純對映異構性起始物。 式(I)化合物具有有價值之醫藥性質，其可於活體内及 試管内抑制血管生成。 經满部中央標率局員工消費合作社印繁 就其醫藥活性而言，式(I)化合物、其醫藥上可接受之 酸加成鹽、立體化學異構型或队氧化物型均為血管生成 作用之抑制劑，因此，血管生成性抑制劑適用於控制或治 療依賴血官生成作用之病變，^，例如：眼部新血管疾 病新血官青光眼、糖尿病性視網膜病、晶狀體後纖維組 織增血管瘤、血管纖維瘤、牛皮癖、骨關節炎及類風 Λ、、關節k此外’血管生成性抑制劑亦適用於控制固體膜 瘤生長，如，例如：***、***、黑色素瘤、腎、結 腸、子宮頸等癌症，及轉移。 因此，本發明揭示用為藥物之式⑴化合物及以此等式 ____ -12- 本紙張尺度適用中國準（CNS ) A4規格（210X29^Jy*--—------ Μ满部中央標準局員Η消費合作社印聚 510901 A7 --------——_ _ 五、發明説明（11 ) ~ ⑴化合物於製造藥物用於治療依賴血管形成作用之病變上 之用途。 就該化合物於治療或預防依賴血管形成作用之病變上 之用途而a，本發明提供一種為罹患此等疾病之溫血動物 治療之方法，該方法包括全身投與醫療有效量之式⑴化合 物其氧化物或其醫藥上可接受之酸加成鹽。 就其有用之醫藥性質而言，該等化合物可調配成投藥 用之各種不同醫藥型式。為了製備本發明之醫藥組合物， 由有效量之特定化合物（呈驗型或酸加成鹽型）作為活性成 份，與醫藥上可接受之載體均勻混合，該載體可呈各種不 同型式，端賴投藥所需之製劑型式而定。此等醫藥組合物 需呈適合最好經口、直腸或非經腸式注射投藥之單位劑 型。例如：製備口服劑型組合物時，可採用任何常用之醫 藥介質，如，例如：水、甘醇、油類、醇類，等等，用於 製備口服液製劑如：懸浮液、糖漿、酊劑及溶液；或使用 固體載體如：澱粉、糖類、高嶺土、潤滑劑、結合劑、崩 解劑，等等，用於製備散劑、丸劑、膠囊及錠劑。由於錠 劑與膠囊方便投藥，因此代表最適用之口服單位劑型，其 中當然採用固體醫藥載體。用於非經腸式組合物之載體通 兩包含無菌水，至少大部份為無菌水，但亦可包含其他成 份’例如：協助溶解之成份。可製備注射液，例如··其中 載體包括生理食鹽水溶液、葡萄糖溶液或生理食鹽水與葡 萄糖溶液之混合物。注射用懸浮液亦可使用適當液體載 __ -13- ) Α 21〇χ-^^~~一~~~^ 衣1Τ------- (請先閱讀背面之注意事項再填寫本頁} A7 A7 經滴部中央標率局Μ工消費合作社印製 ---—-~~~——~ 五、發明説明（12) ~ -- 體、懸)于劑，等等製備。在適合經皮膚投藥之組合物中， 載體可視需要包含渗透性加強劑及/或合適之濕化劑，可 視需要與少量任何性質之合適添加物組合，該添加物不應 對皮膚le成顥著不良效果。該添加物可促進投藥給皮膚及 /或有助於製成所需組合物。此等組合物可依各種不同方 式投藥，例如：呈經皮式貼布、定點式投藥、軟膏。⑴之 酸加成鹽由於可提高其相應鹼型在水中之溶解度，因此較 適用於製備水性組合物。 上述醫藥組合物特別適於調配成投藥方便且劑量均一 之單位劑型。本說明書及申請專利範圍所採圍所採用之單 位劑型係指適合單位投藥之物理性分離單位，各單位含有 預定量之活性成份，其用量經計算可與所需之醫藥載體組 合產生所需之·醫療效果。此等單位劑型實例為錠劑（包括 有凹痕或包衣之錠劑）、膠囊、丸劑、散劑藥包、扁片、 注射用溶液或懸浮液、茶匙量、湯匙量，等等，及其分開 之多重組合。 用於經口投藥之醫藥組合物可呈固體劑型，例如：疑 劑（包括僅供呑嚥及可嚼式型）、膠囊或膜衣錠、其係依習 知方式，採用醫藥上可接受之赋形劑製備如：結合劑（例 如：預膠凝化玉米澱粉，聚乙烯吡咯烷酮或羥丙基曱基纖 維素）；填料(例如：乳糖、微晶纖維素或填酸_);潤滑 劑，例如··硬脂酸钱、滑石或石夕石）；崩解劑（例如：馬龄 薯澱粉或澱粉羥乙酸鈉）；或濕化劑（例如：月桂基硫酸酯 -14- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 衣 訂 (讀先閱讀背面之注意事項再填寫本頁) 經濟部中央標率局員工消費合作社印製 Μ 一·， -—— —~Β7 五、發明説明（13 ) 〜-~--- 納），錠劑可依相關技藝已知之方法包覆包衣。 驗難财呈例如：轉、㈣絲浮液等型 呈乾物’臨用前方與水或其他合適載劑組成。此 ί液體製劑可依習知方法製備，可視需要使用醫藥上可接 =:加物製備如：懸浮劑(例如：山梨糖醇糖漿、甲基 :維素、經丙基甲基纖維素或氣化食用油脂）；乳化劑(例 如._脂或金合歡谬）；非水性載劑(例如：杏仁油、油 醋或乙醇）；及防腐劑(例如：對經基苯甲酸甲醋或丙醋或 山酸）。 醫藥上可接受之甜味劑最好包括至少一種強味甜味劑 $ :糖精、糖精鈉或糖精約、阿斯巴甜(aspartame)、亞蘇 芬鉀（aCesulfame potassium)、環己胺磺酸鈉、阿力甜 (aluame)、二氧查取酮甜味劑、蒙納林(_咖）、蛇菊菩 或銨糖(SUCra丨ose)、（q，，。三氣_41，，6，三去氧半乳糖薦 糖）’以糖精、糖精鈉或糖精鈣較佳，且可視需要使用鬆 散之甜味劑如：山梨糖醇、甘露糖醇、果糖、蔗糖、麥芽 糖、異麥芽糖、葡萄糖、氫化葡萄糖糖漿、木糖醇、焦糖 或蜂蜜。 強味甜味劑通常使用低濃度。例如：若使用糖精鈉 時’其濃度範圍為0.04%至〇·ι% (w/v)(以最終調配物 之總體積為基準計），且在低劑量調配物中，為約〇 〇6〇/。 佳’在高劑量調配物中則約0.08%。鬆散之甜味劑可有效 地大量使用，其範圍約10°/。至約35%，最好約1〇%至15% -15_ ^紙張尺度適用中Ϊ國家標準（CNS ) A4規格（21〇X 297公^ - 衣-- (請先閱讀背面之注意事項再填寫本頁) 訂 Φ 510901 A7 B7 五、發明説明（14 ) (w/v) 可在低劑量調配物中遮蔽苦味成份之醫藥上可接受之 香料以水果香料較佳，如：櫻桃、覆盆子、黑醋栗或草莓 香料。組合兩種香料時，可能產生非常好的結果。在高劑 里δ周配物中’可能需要更強的香料，如：焦糖巧克力 (Caramel Chocolate )香料，涼薄荷香料（Mim c〇〇1Chiral Cel CA, OA, OB, OC, OD, 0F, 0G, 0J, and OK 'Chiralpak AD, AS, OP, and 0 (+). A suitable eluent or mobile phase used in combination with the polysaccharide palmitic stationary phase is hexane, etc., and modified with alcohols such as ethanol, isopropanol, and the like. The pure stereochemically isomeric form may also be derived from the corresponding pure stereochemically isomeric form of an appropriate starting material, provided that the reaction is stereospecific. Preferably, if a specific stereoisomer is required, the compound can be synthesized by a stereospecific method. These methods should preferably use pure enantiomeric starting materials. The compound of formula (I) has valuable medicinal properties, which can inhibit angiogenesis in vivo and in a test tube. As far as its pharmaceutical activity is concerned, the compound of formula (I), its pharmaceutically acceptable acid addition salt, stereochemically isomeric or team oxide types are all angiogenic. Inhibitors of action, therefore, angiogenesis inhibitors are suitable for the control or treatment of lesions that depend on the role of hemorrhage, such as: neovascular disease of the eye neoglaucoma glaucoma, diabetic retinopathy, vascularization of the fibrous tissue behind the lens Tumors, angiofibromas, psoriasis, osteoarthritis and wind-like Λ, joint k In addition, 'angiogenesis inhibitors are also suitable for controlling the growth of solid membrane tumors, such as: breast, prostate, melanoma, kidney, colon , Cervical and other cancers, and metastases. Therefore, the present invention discloses a compound of formula (I) used as a drug and the formula ____ -12- This paper size is applicable to China Standard (CNS) A4 specification (210X29 ^ Jy * ----------- M Manbetsu Member of the Central Bureau of Standards, Consumer Cooperative, Yinju 510901 A7 ------------_ _ V. Description of the Invention (11) ~ The use of hydrazone compounds in the manufacture of drugs for the treatment of pathological changes that depend on angiogenesis. The use of a compound for the treatment or prevention of a disease that relies on angiogenesis and a. The present invention provides a method for the treatment of warm-blooded animals suffering from such diseases, which method comprises systemically administering a medically effective amount of a compound of formula IX and its oxide Or a pharmaceutically acceptable acid addition salt thereof. In terms of their useful medicinal properties, these compounds can be formulated into a variety of different pharmaceutical forms for administration. In order to prepare the pharmaceutical composition of the present invention, an effective amount of a specific compound As the active ingredient, it can be uniformly mixed with a pharmaceutically acceptable carrier, which can be in various forms, depending on the type of preparation required for administration. These pharmaceutical combinations It should be in a unit dosage form suitable for oral, rectal or parenteral injection. For example, when preparing oral dosage form compositions, any common pharmaceutical medium can be used, such as, for example, water, glycol, oil, alcohol Class, etc., for the preparation of oral liquid preparations such as: suspensions, syrups, elixirs and solutions; or the use of solid carriers such as: starch, sugars, kaolin, lubricants, binding agents, disintegrating agents, etc., for the preparation of Powders, pills, capsules and lozenges. Because lozenges and capsules are convenient for administration, they represent the most suitable oral unit dosage form, of which solid pharmaceutical carriers are of course used. The carriers used for parenteral compositions contain sterile water, at least Most are sterile water, but can also contain other ingredients' for example: ingredients to assist dissolution. Injectable solutions can be prepared, such as ... where the carrier includes physiological saline solution, glucose solution or a mixture of physiological saline and glucose solution. For injection Suspension can also be filled with a suitable liquid __ -13-) Α 21〇χ-^^ ~~ 一 ~~~ ^ 衣 1Τ ------- (Please read the precautions on the back before filling FABRICATION, suspension) to agents, and the like - p} A7 A7 standard central portion of the dropping Board printed Μ consumer cooperative work ----- ~ - ~ V. invention is described in (12) ~. In a composition suitable for transdermal administration, the carrier may optionally include a penetration enhancer and / or a suitable wetting agent, and may be combined with a small amount of a suitable additive of any nature as required. The additive should not cause skin defects. effect. The additives can facilitate administration to the skin and / or help to make the desired composition. These compositions can be administered in a variety of ways, for example: as a transdermal patch, as a fixed point, or as an ointment. Since the acid addition salt of osmium can increase the solubility of its corresponding basic form in water, it is more suitable for preparing aqueous compositions. The above-mentioned pharmaceutical composition is particularly suitable for formulating into a unit dosage form with convenient administration and uniform dosage. The unit dosage form adopted in this specification and the scope of the patent application refers to a physical separation unit suitable for unit administration. Each unit contains a predetermined amount of active ingredient. The amount can be combined with the required pharmaceutical carrier to produce the required amount. Medical effects. Examples of such unit dosage forms are lozenges (including dents or coated lozenges), capsules, pills, powder packs, tablets, solutions or suspensions for injection, teaspoon amounts, tablespoons, etc., and Separate multiple combinations. Pharmaceutical compositions for oral administration can be in solid dosage forms, such as: suspects (including pharyngeal and chewable types only), capsules or film-coated tablets, which are in a conventional manner and adopt a pharmaceutically acceptable Excipients such as: binding agents (for example: pre-gelatinized corn starch, polyvinylpyrrolidone or hydroxypropyl fluorenyl cellulose); fillers (for example: lactose, microcrystalline cellulose or acid filler); lubricants, For example, stearic acid, talc or stone spar;) disintegrants (for example: aged potato starch or starch sodium glycolate); or wetting agents (for example: lauryl sulfate-14) This paper size applies China National Standard (CNS) A4 specification (210X297 mm) Clothing Binding (Read the precautions on the back before filling out this page) Printed by the Central Consumer Bureau of the Ministry of Economic Affairs Consumer Cooperatives Ⅰ., -——-~ Β7 5 Description of the invention (13) ~-~ --- Na), the tablets can be coated and coated according to methods known in the related art. Difficult financial problems such as: transfer, reeling liquid, and other liquids are dry and are made of water and other suitable carriers. This liquid preparation can be prepared according to conventional methods. If necessary, it can be used medically. =: Additive preparation such as: suspension agent (for example: sorbitol syrup, methyl: vitamins, propyl methyl cellulose or gas Edible fats and oils); emulsifiers (for example, fat or acacia); non-aqueous carriers (for example: almond oil, vinegar or ethanol); and preservatives (for example: parabens or acetic acid) Or mountain acid). The pharmaceutically acceptable sweetener preferably includes at least one strong sweetener: saccharin, sodium saccharin or saccharin, aspartame, aCesulfame potassium, sodium cyclohexylsulfonate , Aluame, dioxin ketone sweetener, monalin (_coffee), snake chrysanthemum or ammonium sugar (SUCra 丨 ose), (q ,,. Sanqi_41,, 6, Trideoxygalactose recommended sugar) 'Saccharin, sodium saccharin or calcium saccharin is preferred, and loose sweeteners such as: sorbitol, mannitol, fructose, sucrose, maltose, isomalt, glucose, Hydrogenated glucose syrup, xylitol, caramel or honey. Strong flavor sweeteners are usually used at low concentrations. For example, if sodium saccharin is used, its concentration ranges from 0.04% to 0.00% (w / v) (based on the total volume of the final formulation), and in a low-dose formulation, it is about 0.06. 〇 /. Good 'is about 0.08% in high dose formulations. Loose sweeteners can be effectively used in large amounts, and their range is about 10 ° /. To about 35%, preferably about 10% to 15% -15_ ^ The paper size is applicable to the China National Standard (CNS) A4 specification (21〇X 297cm ^-clothing-(Please read the precautions on the back before filling This page) Order Φ 510901 A7 B7 V. Description of the invention (14) (w / v) Medically acceptable spices that can mask bitter ingredients in low-dose formulations Fruit flavors are preferred, such as: cherry, raspberry, Black currant or strawberry flavor. When combining two flavors, very good results may be produced. In high doses, δ weekly formulations may require stronger flavors, such as: Caramel Chocolate flavors, cold mint Spice (Mim c〇〇1

Flavour)、奇幻香料（Fantasy Fiav〇urs)等醫藥上可接受 之強味香料。最終組合物中各香料之含量濃度範圍為 0.05%至1%(W/V)。宜採用該強味香料之組合。較佳香 料為在調配物之酸性條件下不產生任何變化或喪失味道與 色澤之香料。 ^ 本發明化合物亦可調配成積貯式製劑。此等長效性調 配物可經由植人（例如：皮下或或肌岐射投藥口。 因此’例如：該等化合物可與合適之聚合性或疏水性材料 調配（例如：於可接受油中配成乳液）或與離子交換樹脂 調配，或配成難溶性衍生物，例如：難溶性鹽。、a曰 經濟部中央標率局员Η消費合作社印製 (請先閱讀背面之注意事項再填寫本頁) 本發明化合物可調配用於非經腸式投藥，經由注射， 宜經靜脈内、舶或皮下注射，例如：姻大丸劑注射或 連續靜脈内灌流。注射用調配物可呈單位劑型，例如·、二 瓶或多劑量容H，其中添加防腐劑。組合物可含於油性= 水性載劑中，呈懸浮液、溶液或乳液，且可包含調配劑 如：等張性劑、懸浮劑、安定劑及/或勻散劑。或者，= 性成份可呈散劑形式，臨用前方使用合適載劑，例如：2 本紙張尺度適财關家標準（CNS ) Μ規格（21Qx 297公襲 五、發明説明（ 經滴部中央標率局员工消費合作社印製 A7 B7 15 菌無熱原水再纽成。 、本&明化合物亦可調配成經直腸用組合物，如：塞劑 或暫留式灌腸劑，例如：含有習用之塞劑基質如：可可奶 油或其他甘油顒。 用於鼻内投藥時，本發明化合物可呈例如：液體喷 霧、散劑或滴_式使用。 才目關技藝專家們报容易由下文出示之試驗結果來決定 有效量。诵舍 . 书’有效篁為0.0001毫克/公斤至10毫克/ 公斤體重，牲〜一 ^特疋5之〇_〇1毫克/公斤至1毫克/公斤體 * :此適合在一天内分二、三、四或多個小劑量間隔投 與所而之#丨量。該小劑量可調配成單位咖，例如 位劑型含〇.〇1 ^ ^ 至5〇0宅克’特疋έ之0 1毫克至 活性成份。 宅兄 下列實例係供說明： 實驗部份 下文中，“DMF% ΝιΝ·二甲基甲醯胺，” DCM “指 二氯甲烷，” DIPE”指二異丙基醚，且”THF，，指四氫= 喃。 A.中間物之 實例A.1 a)取含2-氯-4-甲基射(0.07莫耳)之亞硫酿氯(議毫 升)混合物回流攪拌16小時。溶劑蒸發，產生2_氯 4-[二氯(氯硫）甲基]嘧啶（中間物G。 -17- ^紙張尺度適用中國國家^準^泌^料見格㈠⑴/”了公釐）— (請先閱讀背面之注意事項再填寫本頁)Flavour), Fantasy Fiavours and other medically acceptable strong flavors. The concentration of each fragrance in the final composition ranges from 0.05% to 1% (W / V). The combination of strong flavors should be used. Preferred fragrances are fragrances that do not produce any change or lose taste and color under the acidic conditions of the formulation. ^ The compound of the present invention can also be formulated into a storage preparation. These long-acting formulations can be administered via implantation (for example, subcutaneously or by intramuscular injection). Therefore 'for example: these compounds can be formulated with suitable polymerizable or hydrophobic materials (for example: in an acceptable oil) Into emulsion) or with ion exchange resin, or with insoluble derivatives, such as: insoluble salts. A printed by a member of the Central Standards Bureau of the Ministry of Economic Affairs and a consumer cooperative (please read the precautions on the back before filling in this (Page) The compounds of the present invention can be formulated for parenteral administration, preferably via injection, preferably intravenously, subcutaneously, or subcutaneously, such as: Yin Da Wan injection or continuous intravenous perfusion. Formulations for injection can be in unit dosage form, such as ·, Two bottles or multiple doses of H, with preservative added. The composition can be contained in oily = aqueous carrier, as a suspension, solution or emulsion, and can contain formulation agents such as isotonicity agents, suspension agents, stability Agent and / or dispersing agent. Alternatively, the sexual component can be in the form of a powder, and a suitable carrier is used immediately before use, for example: 2 paper size standards (CNS) M specifications (21Qx 297) Description (A7 B7 15 bacteria-free pyrogen-free water printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Distillation and reconstitution. Ben & Ming compounds can also be formulated into rectal compositions such as: suppositories or temporary enema Agents, for example, containing conventional suppository bases such as cocoa butter or other glycerol tinctures. When used for intranasal administration, the compounds of the present invention can be used in the form of, for example, liquid sprays, powders, or drops. Talented experts It is easy to determine the effective amount from the test results presented below. Recitation. The book 'Effectiveness' is 0.0001 mg / kg to 10 mg / kg body weight. / Kg body *: This is suitable for the administration of two, three, four or more small dose intervals in a day. The amount of # 丨. The small dose can be adjusted into a unit coffee, for example, the dosage form contains 0.001 ^ ^ Up to 500 mg of gramme's special 1 mg to the active ingredient. The following examples of house mate are for illustration: In the experimental part below, "DMF% ΝιΝ · dimethylformamide," "DCM" means dichloride Methane, "DIPE" refers to diisopropyl ether, and "THF," refers to tetrahydro = A. Examples of intermediates A.1 a) Take a mixture of 2-chloro-4-methyl shot (0.07 mole) of sulfurous chlorine (1 ml) and stir at reflux for 16 hours. The solvent evaporates to produce 2-chloro 4- [Dichloro (chlorosulfur) methyl] pyrimidine (Intermediate G. -17- ^ Paper size is applicable to Chinese countries ^ quasi ^ Bi ^ See the standard ㈠⑴ / "mm)-(Please read the note on the back first (Fill in this page again)

經滴部中央標率局員Μ消費合作社印製 510901 A7 — -—-_-___ B7 五、發明説明（16T~ ~~~" -一 b)l-亞胺基-乙胺鹽酸鹽（1:1)(〇 〇8莫耳)於下加至 含中間物1(0.07莫耳)之DCM(3〇〇毫升)攪拌混合物 中。於0°C下滴加氫氧化鈉(5〇%，20毫升）。混合 物於5 C下攪拌1小時。加水（3〇〇毫升）與 DCM(300毫升）。混合物於下攪拌丨小時。加 水(300毫升)與DCM(300毫升）。混合物分層。水層 以DCM洗滌2次。合併之有機相脫水，過濾、及 蒸發溶劑。殘質於玻璃濾器上經矽膠純化(溶離液： DCM)。收集兩份純溶離份，蒸發其溶劑，產生3·5 克2-氣_4_(3-甲基-1，2,4-噻二唑基）务定（中間物 2)。 實例A.2 a) 取含6-氯-3-吼唆缓醯胺(〇·ιι莫耳）、1βι[3_(三氟甲基) 苯基]-六氫吡畊(0·11莫耳）與碳酸鈉(〇·22莫耳）之 DMF(300毫升)混合物於i20°C下擾拌一夜。混合 物倒至冰水(600毫升）中，攪拌1小時。濾除沈澱 物，並乾燥。取一份(4克)溶於DCM及NaHC03水 溶液中。混合物分層。水層以DCM萃取3次。合 併之有機層脫水、過濾及蒸發溶劑至小體積。濾出 沉澱物，乾燥，產生3.2克6_[4-[3-(三氟甲基）苯 基]-1-六氫吡畊基]-3-吼啶羧醯胺（中間物3)。 b) 取含中間物3(0.013莫耳)與勞森試劑(0.007莫耳)之 甲苯(130毫升)混合物回流攪拌2小時。混合物冷 •18- 本紙張尺度適用中關家標準（CNS ) 格（210x297公襲） '~ 衣 i I I ^ 11 I (請先閱讀背面之注意事項再填寫本頁)Printed by a member of the Central Standards Bureau of the Ministry of Consumer Affairs, M Consumer Cooperative, 510901 A7 — -—-_-___ B7 V. Description of the invention (16T ~~~~ " -a b) l-imino-ethylamine hydrochloride ( 1: 1) (0.08 mol) was added below to the stirred mixture containing intermediate 1 (0.07 mol) in DCM (300 ml). Sodium hydroxide (50%, 20 ml) was added dropwise at 0 ° C. The mixture was stirred at 5 C for 1 hour. Water (300 mL) and DCM (300 mL) were added. The mixture was stirred for 1 hour. Water (300 mL) and DCM (300 mL) were added. The mixture was separated. The aqueous layer was washed twice with DCM. The combined organic phases are dehydrated, filtered, and the solvent is evaporated. The residue was purified over silica gel on a glass filter (eluent: DCM). Two pure fractions were collected, and the solvent was evaporated, yielding 3.5 grams of 2-gas_4- (3-methyl-1,2,4-thiadiazolyl) (Intermediate 2). Example A.2 a) Take 6-chloro-3-carboxolamide (〇 · ιmole), 1βι [3_ (trifluoromethyl) phenyl] -hexahydropyr (0.11 mol ) And sodium carbonate (0.22 mol) in DMF (300 ml) and stir overnight at i20 ° C. The mixture was poured into ice water (600 ml) and stirred for 1 hour. The precipitate was filtered off and dried. An aliquot (4 g) was dissolved in DCM and an aqueous solution of NaHC03. The mixture was separated. The aqueous layer was extracted 3 times with DCM. The combined organic layers were dehydrated, filtered, and the solvent was evaporated to a small volume. The precipitate was filtered off and dried, yielding 3.2 g of 6- [4- [3- (trifluoromethyl) phenyl] -1-hexahydropyridyl] -3-carboxamidine (Intermediate 3). b) A toluene (130 ml) mixture containing intermediate 3 (0.013 mole) and Lawson's reagent (0.007 mole) was stirred at reflux for 2 hours. Mixture cold • 18- This paper size applies the Zhongguanjia Standard (CNS) grid (210x297 public attack) '~ clothing i I I ^ 11 I (Please read the precautions on the back before filling this page)

五、發明説明（17) 却。加水(100毫升）。混合物攪拌1小時後，分層。 水層以甲苯萃取三次，以DCM萃取一次。合併之有 機層脫水，過濾及蒸發溶劑，產生：7·3克6-[4·[3-(三氟 甲基)苯基]_1_六氳吡畊基]_3_吼啶羧硫醯胺（中間物4)。 ίΊΗ Α.3 取含中間物4(0.0013莫耳)與1，1-二甲氧基-Ν，Ν-二甲 基-乙胺(0.021莫耳)之混合物靜置一夜，然後未再純化即 使用，產生Ν-[1·(二甲胺基）次乙基]_6-[4-(3-三氟甲基）苯 基]-1_六氫吡畊基]-3-吡啶羧硫醯胺（中間物5)。表1.1列出 根據實例Α.3製備之中間物 表 1.1 : (請先閱讀背面之注意事項再填寫本頁}5. Description of the invention (17) However. Add water (100 ml). After the mixture was stirred for 1 hour, the layers were separated. The aqueous layer was extracted three times with toluene and once with DCM. The combined organic layers were dehydrated, filtered, and the solvent was evaporated to yield: 7.3 g of 6- [4 · [3- (trifluoromethyl) phenyl] _1_hexamethylpyridyl] _3_carbidinecarboxamidine (Intermediate 4). ίΊΗ Α.3 Take a mixture containing intermediate 4 (0.0013 moles) and 1,1-dimethoxy-N, N-dimethyl-ethylamine (0.021 moles) and let stand overnight, then without further purification Used to produce N- [1 · (dimethylamino) ethylidene] _6- [4- (3-trifluoromethyl) phenyl] -1_hexahydropyridyl] -3-pyridinecarboxythione Amine (Intermediate 5). Table 1.1 lists the intermediates prepared according to Example A.3 Table 1.1: (Please read the precautions on the back before filling this page}

、11 N)s H3VH3 Η, 11 N) s H3VH3 Η

)- A)-A

CF3 經滴部中央標率局員,χ消費合作社印f 本紙張尺度適用中國國家標準（CNS ) Α4規格（21〇><297公釐） 510901 Α7 Β7 五、發明説明（CF3 Member of the Central Standards Bureau of the Ministry of Economics, printed by χ Consumer Cooperatives. F This paper size is applicable to the Chinese National Standard (CNS) A4 specification (21〇 > < 297 mm) 510901 Α7 Β7 5. Description of the invention (

No. 麵 No. CH, ch3-n >=Νν_ΛΛ ch3 ~~ s 物理數據 5 6 Α·3 CH, CH^-N ch^N>^V- . · S Α·3 ch3 ch3-n >=N CH3 // S 尸N mp. 156°C 7 Α·3 CH, ch3-n - 8 Α.3 ch3 ch3~n - 9 Α.3 CH, ch3~n -：>f} - 10 Α.3 ch3 CH3~N ch2- - (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局員Μ消費合作社印繁 Β·最終化合物之製法 實例Β.1 取含5-(4-氟苯基)各曱基-1，2,4-噻二唑(0.012莫耳）、 -20- 本紙張尺度適用中國國家標準（CNS ) Α4規格（210Χ 297公釐） 510901 A7 B7 五、發明説明（19 ) 1·[3-(二氟甲基)本基]-六氫吼π井(0.014莫耳)與碳酸納(〇 〇24 莫耳)之DMF(10毫升)混合物於14(TC下攪拌24小時， 然後於150 C下24小時’冷却，倒至冰水(2⑼毫升）中， 並攪拌。濾出沈澱物，溶於DMF中，脫水，過滤，蒸發 >谷劑。殘質自DIPE中結晶。遽出沈殿物，乾燥，產生2 5 克(52%)1-[4·(3-甲基-1，2,4-嗔二嗤-5·基）苯基]_4-[3_(三氣甲 基)苯基]六氫吡畊(化合物2)。 實例B.2 取含羥胺磺酸(0.011莫耳)之甲醇(15毫升)混合物一 次添加全量至含中間物5(0.01莫耳)與吼咬(〇 〇2莫耳)之乙 醇(40毫升)混合物中。混合物於室溫下攪拌9〇分鐘。蒸 發溶劑。殘質溶於DCM中，以水及NaOH水溶液⑴出洗 務’脫水’過丨慮及蒸發溶劑。殘質溶於甲醇中，過淚及乾 燥。殘質溶於乙腈（100毫升）中。混合物攪拌並煮彿至完 全溶解，然後使之結晶析出。濾出沈澱物，乾燥，產生 I·4 克(35%)1-[5_(3_曱基-I，2,4-噻二唑_5_基)_2_吡啶基]_4_ [3-(三氟甲基)苯基]六氫吼畊(化合物8)。 經濟部中央標準局Μ工消費合作社印t (請先閱讀背面之注意事項再填寫本頁} 表F.1列出根據上述實例之一製備之化合物，且表 F.2列出上述實驗部份製得之化合物之碳、氫及氮元素分 析之實驗值（义\?”欄）及理論值（、1^〇1^，攔）。 -21· 本紙張尺度適用中國國家標準（CNS ) A4規格（21 OX 297公釐） 510901 A7 B7 五、發明説明（21 表F.2 化合物 No. 羰 氫No. Surface No. CH, ch3-n > = Nν_ΛΛ ch3 ~~ s Physical data 5 6 Α · 3 CH, CH ^ -N ch ^ N > ^ V-. · S Α · 3 ch3 ch3-n > = N CH3 // S Corpse N mp. 156 ° C 7 Α · 3 CH, ch3-n-8 Α.3 ch3 ch3 ~ n-9 Α.3 CH, ch3 ~ n-: > f}-10 Α .3 ch3 CH3 ~ N ch2--(Please read the notes on the back before filling out this page) Member of the Central Standards Bureau of the Ministry of Economic Affairs, M Consumer Cooperatives, Printing B. Examples of Preparation Methods for Final Compounds B.1 Take 5- (4-fluoro Phenyl) each fluorenyl-1,2,4-thiadiazole (0.012 mole), -20- This paper size applies Chinese National Standard (CNS) A4 specification (210 × 297 mm) 510901 A7 B7 V. Description of the invention (19) A mixture of 1 · [3- (difluoromethyl) benzyl] -hexahydrozine (0.014 mole) and sodium carbonate (0024 mole) in DMF (10 ml) at 14 (TC Stir for 24 hours, then cool at 150 C for 24 hours, pour into ice water (2 ml), and stir. Filter the precipitate, dissolve in DMF, dehydrate, filter, evaporate> cereals. Residue from Crystallized in DIPE. Shen Dianwu was decanted and dried to yield 25 g (52%) of 1- [4 · (3-methyl-1,2,4-fluorenedifluoren-5 · yl) phenyl] _4- [ 3_ ( Gas methyl) phenyl] hexahydropyridine (compound 2). Example B.2 Take a mixture of methanol (15 ml) containing hydroxylamine sulphonic acid (0.011 mole) and add the entire amount at once to 5 (0.01 mole) containing intermediate And roar (0.02 mol) in a mixture of ethanol (40 ml). The mixture was stirred at room temperature for 90 minutes. The solvent was evaporated. The residue was dissolved in DCM and washed with water and aqueous NaOH solution. 'The solvent is taken into consideration. The residue is dissolved in methanol, dried and dried. The residue is dissolved in acetonitrile (100 ml). The mixture is stirred and cooked until completely dissolved, and then the crystals are precipitated. The precipitate is filtered off , Dried to produce 1.4 grams (35%) of 1- [5_ (3_fluorenyl-I, 2,4-thiadiazol_5_yl) _2_pyridyl] _4_ [3- (trifluoromethyl ) Phenyl] Hydrogen (Compound 8). Printed by the Industrial and Commercial Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page) Table F.1 lists those prepared according to one of the above examples Compounds, and Table F.2 lists the experimental values (meaning "?") And theoretical values (, 1 ^ 〇1 ^, block) of carbon, hydrogen, and nitrogen element analysis of the compounds prepared in the above experimental section.- 21 · Paper Zhang scale is applicable to Chinese National Standard (CNS) A4 specification (21 OX 297 mm) 510901 A7 B7 V. Description of the invention (21 Table F.2 Compound No. Carbonyl hydrogen

Exp. 氮Exp. Nitrogen

Theor. 2 3 5 6 7 8 59.39 59.39 55.44 56.29 56.29 53.19Theor. 2 3 5 6 7 8 59.39 59.39 55.44 56.29 56.29 53.19

Exp.Exp.

Theor.Theor.

Exp.Exp.

Theor. 59.31 59.32 55.29 55.30 56.24 52.21 4.73 4.73 4.87 4.47 4.47 4.22 4.68 4.67 4.96 4.33 4.45 4.07 13.85 13.85 12.32 17.27 17.27 20.68 13.88 13.92 12.39 17.06 17.43 2033 (請先閱讀背面之注意事項再填寫本頁) 經滴部中央標準局員Η消費合作社印« C.醫藥實例 實例C.l 依R.F、尼可希亞（Nic〇sia)述於“實驗室研究法”(Laboratory Investigation)，ν〇1·63，ρ·115，1990 之方法，採用 血管生成作用之老鼠主動脈環模式，於試管内測定血管生 成性抑制活性。由化合物抑制微血管形成之能力與載劑處 ;之對照組環比較。培養8天後採用影像分析系統定量 (微血管面積），該系統包括光學顯微鏡、CCD相機及依j· 尼山諾夫（Nissanov)、R.W·吐曼（Tuman)、L.M·克魯弗 (Gruver)及J.M.弗特南多（Fortunato)述於“實驗室研究 法” ，νο1·73(#5)，Ρ·734，1995之自動化定做之影像分析程 式。於數個濃度下測試化合物，以決定抑制效力（1C 50)。 化合物1、2及6之I C 50值低於1〇ηΜ。 23· 本紙張尺度適用中國國家標準（CNS ) Α4規格（210Χ 297公釐） -Α9,Theor. 59.31 59.32 55.29 55.30 56.24 52.21 4.73 4.73 4.87 4.47 4.47 4.22 4.68 4.67 4.96 4.33 4.45 4.07 13.85 13.85 12.32 17.27 17.27 20.68 13.88 13.92 12.39 17.06 17.43 2033 (Please read the notes on the back before filling this page) Bureaux / Consumer Cooperative Seal «C. Examples of pharmaceuticals Cl. Methods described in" Laboratory Investigation ", ν〇 · 63, ρ · 115, 1990 according to RF and Nicosia Using the rat aortic ring model of angiogenesis, the angiogenic inhibitory activity was measured in a test tube. The ability of the compound to inhibit microangiogenesis was compared with that of the control group at the vehicle. After 8 days of incubation, it was quantified (microvascular area) using an image analysis system, which includes an optical microscope, a CCD camera, and J. Nissanov, RW Tuman, and LM Gruver. And JM Fortunato described in "Laboratory Research Method", νο 1.73 (# 5), P.734, 1995, an automated image analysis program. Compounds were tested at several concentrations to determine inhibitory potency (1C 50). Compounds 1, 2 and 6 have IC50 values below 10 nM. 23 · This paper size applies Chinese National Standard (CNS) Α4 specification (210 × 297 mm)-Α9,

Claims (1)

510901 A8 B8 C8 D8 六、申請專利範圍 Π:: 專利申請案第87110129 W ROC Patent Appln. No. 87110129 修正之申請本利範圍中文本一附件（一） Amended Claims in Chinese — Encl.d) (民國91年3月、7日送呈) (Submitted on March η , 2002) 1. 一種式（I)化合物 r,Xhz>-A^ (I) (請先閱讀背面之注意事項再填寫本頁) $ 其醫藥上可接受之酸加成鹽，其中 X為N ; R1為氩或CN6烷基； R2為氩； R3、R4、R5分別選自氫及三氟曱基； 選自噻二唑基、吡啶基及嘧啶基。 2·根據申請專利範圍第1項之化合物，其中X為N ; R1 為甲基，R2為氫，R3與R4為氳且R5為三氟甲基。 3.·根據申請專利範圍第1項之化合物，其中該化合物為 1-[4-(3-甲基-1，2,4-噻二唑-5-基）苯基]-4-[3-(三氟曱基） 苯基]六氫吼σ井；或 1-[5-(3-甲基-1，2,4-噻二唑-5-基）-2-吡啶基]-4-[3-(三氟 甲基）苯基]六氳吡畊；其立體異構型或醫藥上可接受 之酸加成鹽。 -24 -87164-claim 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） IT---------_ 經濟部智慧財產局員工消費合作社印製 90. 11. 2,000 申請專利範圍 4.^用，制血管生成之醫藥組合物，其包含 :專利關第1至3項中任‘r項之化合物作為活性成 ^艮據申請專利範圍第1至3項中任—項之化合物，其 、係用為抑制血管生成之夢物。 、 6.一種製備根射料利範_丨項之化合物之 其中： a)式(Π)中間物與式（m)中間物，於反應惰性溶劑中， 可視需要於合適鹼之存在下反應··510901 A8 B8 C8 D8 VI. Scope of patent application Π :: Patent application No. 87110129 W ROC Patent Appln. No. 87110129 Amended Claims in Chinese — Encl.d) (Republic of China) (Republic of China) (Submitted on March η, 2002) (Submitted on March η, 2002) 1. A compound of formula (I) r, Xhz > -A ^ (I) (Please read the precautions on the back before filling this page) $ its A pharmaceutically acceptable acid addition salt, where X is N; R1 is argon or CN6 alkyl; R2 is argon; R3, R4, and R5 are each selected from hydrogen and trifluorofluorenyl; selected from thiadiazolyl and pyridine And pyrimidinyl. 2. The compound according to item 1 of the scope of patent application, wherein X is N; R1 is methyl, R2 is hydrogen, R3 and R4 are fluorene, and R5 is trifluoromethyl. 3. The compound according to item 1 of the scope of patent application, wherein the compound is 1- [4- (3-methyl-1,2,4-thiadiazol-5-yl) phenyl] -4- [3 -(Trifluorofluorenyl) phenyl] hexahydrozine σ well; or 1- [5- (3-methyl-1,2,4-thiadiazol-5-yl) -2-pyridyl] -4 -[3- (trifluoromethyl) phenyl] hexamethylpyridine; its stereoisomeric or pharmaceutically acceptable acid addition salt. -24 -87164-claim This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) IT ---------_ Printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs 90. 11. 2,000 patent applications 4. Pharmacological composition for the production of angiogenesis, which includes: the compounds of any of the items in item 1 to 3 of the patent as an active ingredient ^ According to any of the items in the range of 1 to 3 of the patent application The compound of the item is used as a dream substance for inhibiting angiogenesis. 6. A compound for the preparation of the root shot of Lifan _ 丨 wherein: a) the intermediate of formula (Π) and the intermediate of formula (m) are reacted in an inert reaction solvent, if necessary, in the presence of a suitable base. + > (Π)+ > (Π) R3 I=vr4 X.R3 I = vr4 X. (I) (請先閱讀背面之注意事項再填寫本頁) (III) b)式（IV)令間物，於反應惰性溶劑中，於合適鹼之存 在下，經羥胺-Ο-磺酸處理，產生式（I_a)化合物，其 定義如式（I)化合物，其中Ri為甲基； ---------tr---------. 經濟部智慧財產局員工消費合作社印製(I) (Please read the precautions on the back before filling in this page) (III) b) Formula (IV) The intermediate is treated with hydroxylamine-O-sulfonic acid in the reaction inert solvent in the presence of a suitable base To produce a compound of formula (I_a), which is defined as a compound of formula (I), where Ri is methyl; --------- tr ---------. Consumption by employees of the Intellectual Property Bureau of the Ministry of Economic Affairs Printed by a cooperative 其中上述反應圖中，X、R1、R2、r3、r4、r5& -25 - ^紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐）_~_ ； 川y〇iAmong the above reaction diagrams, X, R1, R2, r3, r4, r5 & -25-^ The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) _ ~ _; 川 y〇i '申請專利範圍 €)·基團均如申請專利範圍第1項之定義，且w 為適當之脫離基； / 幻或式（I)化合物依相關技藝已知之轉化反應互相轉 化；或若需要時，由式⑴化合物轉化成醫藥上可接 受之酸加成鹽，或反丨之，由式（1)化合物之酸加成鹽 經鹼轉化成游離鹼型；且若需要時，製備其立體化 學異構型。 一種式（IV)化合物'Scope of patent application €) · The groups are as defined in item 1 of the scope of patent application, and w is an appropriate leaving group; / the compounds of formula (I) are converted into each other according to a conversion reaction known in the relevant art; or if necessary From a compound of formula ⑴ into a pharmaceutically acceptable acid addition salt, or vice versa, from an acid addition salt of a compound of formula (1) into a free base form via a base; and, if necessary, preparing its stereochemistry Heterogeneous. A compound of formula (IV) R4 (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員Η消費合作社印製 及其酸加成鹽， 其中X、R2、R3、R4、R5及二價基團均如申請 專利範圍第1項中之定義。 >•一種製備根據申請專利範圍第6項之式（jy)化合物之 方法，其中 a)式（K)中間體’於反應惰性溶劑中，經n，N-二甲 基乙醯胺二曱基縮醛處理，產生式（W)化合物：Λ R：,R4 (Please read the notes on the back before filling out this page) Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs, Consumer Cooperative, and its acid addition salt, where X, R2, R3, R4, R5 and divalent groups are all patented Definition in Scope Item 1. > • A method for preparing a compound of formula (jy) according to item 6 of the scope of patent application, wherein a) the intermediate of formula (K) is reacted with n, N-dimethylacetamidamine in a reaction inert solvent. Acetal treatment to produce a compound of formula (W): Λ R :, (IX) ¢/ (IV) 26 - 本紙張尺度適用中國國家標準（CNS)A4規格(21〇:797公楚）' 90. 11. 2,000 510901 A8 B8 C8 D8 六、申請專利範圍 b)或由式（IV)化合物依相關技藝已知之轉化反應，互 相轉化，或若需要時，由式（IV)化合物轉化成其酸 加成鹽，或反之，由式（IV)化合物之酸加成鹽經驗 處理，轉化成游離鹼型。 —----------amw —-------訂--------- (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 -27 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 90. 11. 2,000(IX) ¢ / (IV) 26-This paper size applies Chinese National Standard (CNS) A4 specification (21〇: 797 Gongchu) '90. 11. 2,000 510901 A8 B8 C8 D8 VI. Patent application scope b) or by Compounds of formula (IV) are converted into each other according to conversion reactions known in the relevant art, or if necessary, from compounds of formula (IV) to their acid addition salts, or vice versa, experience of acid addition salts of compounds of formula (IV) Treated and converted to free base form. —---------- amw —------- Order --------- (Please read the precautions on the back before filling out this page) Employees of the Intellectual Property Bureau of the Ministry of Economy Consumption Printed by the cooperative -27-This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 90. 11. 2,000