TW200400936A - Cyclopentene derivatives - Google Patents

Cyclopentene derivatives Download PDF

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Publication number
TW200400936A
TW200400936A TW092106432A TW92106432A TW200400936A TW 200400936 A TW200400936 A TW 200400936A TW 092106432 A TW092106432 A TW 092106432A TW 92106432 A TW92106432 A TW 92106432A TW 200400936 A TW200400936 A TW 200400936A
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Taiwan
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group
alkyl
formula
hydrogen
independently
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TW092106432A
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Chinese (zh)
Inventor
Walter Hubsch
Matthias Breuning
Gunter Schmidt
Barbara Albrecht
Elisabeth Perzborn
Faeste Christiane
Barfacker Lars
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Bayer Ag
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    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/04—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D309/06—Radicals substituted by oxygen atoms
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
    • C07C45/71—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form being hydroxy groups
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    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/72—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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Abstract

The present invention relates to substituted cyclopentene derivatives, a process for their preparation and their use for producing medicaments, in particular for the treatment and/or prevention of thromboembolic disorders.

Description

B7 五、發明說明（1 ) [發明所屬之技術領域] ,本發明係關於經取代的環戊稀衍生物、其製法及其供 製備藥物之用途，特別是供治療及/或預防血栓性插塞疾 病。 、 5 血栓性插塞疾病與栓塞的併發症為西方人口中死亡及 包a下列疾病之主要原因之一：心肌梗塞、不穩定的狹心 症、穩定的狹心症、瞬時的缺灰侵害(TLA)、中風、周圍 動脈的閉塞性疾病、血管造形術或冠狀主動脈繞道手術之 後的再阻塞與再狹窄、深層靜脈栓塞與血栓性插塞。 10 [先前技術] 經濟部智慧財產局員工消費合作社印製 血栓性插塞疾病與栓塞的併發症之原因是由於介於血 管壁與血液組分間的複雜交互作用，有一大部分要歸因於 血小板，如果血管壁受傷後血小板將粘附至内皮下的細胞 15内的基質並集結著，其可能導致血栓阻塞，ADP為血小板 聚集的重要引發劑與提昇無數的也小板反應[G V R B〇rn， Adenosine diphosphate as a mediator of platelet aggregation in vivo ： An editorial point of view, Circulation 72, 741-742 (1985) » J.P. Maffrand, A. Bernat, D. Delebassee, G. Defreyn, 20 J.P. Cazenave, J.L. Gordon, ADP plays a key role in thrombogenesis in rats, Thromb. Haemost 59, 225-230 (1988)]。 ADP透過專性的ADP受體活化血小板，P2Y1受體對 血小板的基本活化反應有關，即，其引起血小板的形狀改 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 92077A.doc 200400936 A7 B7 五、發明說明（2) 變，並因此引發血小板的聚集[J丄· Daniel, C. Dangelmaier， J. Jin, B. Ashby, J. Bryan Smith, S.P. Kunapuli, Journal of Biological Chemistry 272, 2024-2029 (1998) ； C. Gachet, International Journal of Hematology 74, 375-381 (2001)]，目 前為止，未冒有人揭露藉由選擇地抑制受Ρ2γι受體介導 的血小板活化以作為抗血栓的治療劑而被應用之化合物。 10 15 有必要尋求一種能明確地抑制増加的血小板反應而又 不影響增加流血的危險性’朗此減少祕性併發症的危 險性之醫藥品，其可選擇地抑制受pm受體介導的血小 板聚集之化合物將對標準的療法有相當大的改良。 [發明内容] 、本發月包3的化合物，其會影響ADp結合至ρ2γι受 體=制娜介導的血小板簇集並因此適於治療及/或預 防血栓性插塞疾病。 本發明係關於式(I)的化合物 經濟部智慧財產局員工消費合作社印製 20 其中R1 為(c6-c,B7 V. Description of the invention (1) [Technical field to which the invention belongs] The present invention relates to substituted cyclopentene derivatives, a preparation method thereof, and uses thereof for preparing drugs, especially for treating and / or preventing thrombotic insertion. Stuffed disease. 5 Thromboembolic disease and the complications of embolism are one of the main causes of death and the following diseases in the western population: myocardial infarction, unstable angina, stable angina, transient ash deficiency ( TLA), stroke, occlusive disease of the peripheral arteries, re-occlusion and restenosis after angioplasty or coronary artery bypass surgery, deep vein embolism and thromboembolism. 10 [Prior art] The cause of complications of thromboembolic disease and embolism printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs is due to the complex interaction between the blood vessel wall and blood components, a large part of which is due to platelets If platelets will adhere to the matrix within the endothelium cells 15 after the vascular wall is injured, it may lead to thrombus obstruction. ADP is an important initiator of platelet aggregation and promotes numerous platelet reactions [GVRB〇rn, Adenosine diphosphate as a mediator of platelet aggregation in vivo: An editorial point of view, Circulation 72, 741-742 (1985) »JP Maffrand, A. Bernat, D. Delebassee, G. Defreyn, 20 JP Cazenave, JL Gordon, ADP plays a key role in thrombogenesis in rats, Thromb. Haemost 59, 225-230 (1988)]. ADP activates platelets through specific ADP receptors, and the basic activation response of P2Y1 receptors to platelets is related, that is, it causes changes in the shape of platelets. The paper size applies the Chinese National Standard (CNS) A4 specification (210x297 mm) 92077A.doc 200400936 A7 B7 V. Description of the invention (2) changes, and thus cause platelet aggregation [J 丄 · Daniel, C. Dangelmaier, J. Jin, B. Ashby, J. Bryan Smith, SP Kunapuli, Journal of Biological Chemistry 272, 2024-2029 (1998); C. Gachet, International Journal of Hematology 74, 375-381 (2001)], so far, no one has disclosed that by selectively inhibiting P2γ receptor-mediated platelet activation as an antithrombotic The therapeutic agent is a compound that is applied. 10 15 It is necessary to find a medicine that can clearly inhibit the increased platelet response without increasing the risk of bleeding. 'Lang this to reduce the risk of occult complications, which can selectively inhibit the PM receptor-mediated Platelet aggregation compounds will provide a considerable improvement over standard therapies. [Summary of the Invention] The compound of the present invention monthly package 3, which affects the binding of ADp to the ρ2γι receptor = Na-mediated platelet clustering and is therefore suitable for the treatment and / or prevention of thrombotic plug disease. This invention is about compounds of formula (I) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 20 where R1 is (c6-c,

、R6 (1)， 。)_芳基切有至多達兩個, R6 (1),. ) _Aryl cuts up to two

選自N、〇及/或S 本紙張尺錢时 -4 · 200400936 A7 B7 五、發明說明（3) 的雜原子之5-或6-員雜芳基，其各可分別獨立地經一 至三個選自下列的基取代：鹵素，（C丨-C6)-烷基，三氟 甲基，氰基5經基，（CrCe)-炫氧基，三氟曱氧基，叛 基，（CrC4)-烷氧基羰基，-C(0)-NR9R1G，胺基，單-與 5 二-(Ci_C6)-烧基胺基’其中，上述的烧基與烧氧基也另 可取代下列基：羥基，（Crc4)-烷氧基，羧基，（CrC4)-烧氧基幾基，胺基’單-或二-(C1-C4)-烧基胺基，且 R9與R1G，分別獨立地，為氫或(crc6)-烷基， A 為鍵或(CrC4)-烷二基，（C2-C4)-浠二基或(C2-C4)-炔二 10 基， R2與R5，分別獨立地，為吡啶基，噻吩基，呋喃基，苯 並呋喃基，四氫吡喃基，環己基或苯基，其各可經取 代一或二個，分別獨立地，選自下列基：鹵素，（cr c6)-烷基，三氟曱基，氰基，胺基，（CrCd-烷氧基或 15 三氟曱氧基，其中上述的烷基與烷氧基另可再經下列 基取代：羥基，（CrC4)-烷氧基，羧基，（CVQ)-烷氧基 幾_基，胺基，單-或二-(Ci-C4)-^S胺基， 經濟部智慧財產局員工消費合作社印製 R3與R4，分別獨立地，為氫，（Crc6)-烷基，（C2-C6)-烯 基，（c2-c6)-炔基或(c3-c8)-環烷基，其各可經取代一至 20 三個，分別獨立地，選自下列之基：羥基，（CrC6)-烷 氧基，氰基，氟，氣，-NRUR12，-C(0)-0R13，-C(O)-NRUR12，-S02-OR13 與-S02-NRuR12，其中 R11，R12與R13，分別獨立地，為氳或(Ci-C6)-烷基， 或 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200400936 A7 B7 五、發明說明（4) R3與R4 ’ 一起與其附接的碳形成3_至6_員的，螺_連繫的 環烷基環， R6 為氫，（CVCe)-烷基 ’烷醯基或式-C(0)-C(0)-0R14之基，其中 5 R14為氫或(CrC6)-烷基， R7為氫， R8為經基， 或 R7與R8 —起與其附接的碳形成羰基或式C=N_〇_Ri5之 10 基，其中 R 為氫或為(Ci-C6)-烧基之基，其可經取代下列之基: 經基，（CVC6)-烷氧基，羧基，（Cl_C4)_烷氧基羰基 或式-NR16R17或-c(o)-nr16r17之基，其中 R16與R17，分別獨立地，為氫或(Ci_C6)_烷基， 15為控制疾病’特別是使用這些化合物用於製備醫藥品，供 治療及/或預防血栓性插塞疾病之用途。 經濟部智慧財產局員工消費合作社印製 上述化合物有些是新穎化合物，有些則是可從文獻中 知知者[見 B.H. Freeman et al” 汾加加办⑽ 2P, 4307-4312 (1973), J. Rigaudy et al., Tetrahedron 41, 1345-1353 20 (1986)]，然而對已知的化合物未見有指明其具有治療之用 途，本發明為最先發現其具有治療效果者。 本發明也關於式(I)的化合物， 其中 R1為(C6-C10)-芳基或帶有至多達兩個選自Ν、〇及/或s -6- 本纸張尺度適用宁國國家標準(CNS)A4規格（-2丨〇 x297公釐） 200400936 A7 B7 五、發明說明（5) 的雜原子之5-或6-員雜芳基，其各可分別獨立地經一 至三個選自下列的基取代：鹵素，（CVC6)-烷基，三氟 曱基，氰基，羥基，（CVC6)-烷氧基，三氟甲氧基，羧 基，（crc4)-烷氧基羰基，-C(0)-NR9R1Q，胺基，單-與 5 二-(Ci_C6)-烧基胺基，其中， 上述的烧基與炫氧基也另可取代下列基：經基，（cr c4)-烷氧基，羧基，（crc4)-烷氧基羰基，胺基，單-與 二-(C1-C4)-烧基胺基，且 R9與R1G，分別獨立地，為氳或(crc6)-烷基， 10 A 為鍵或(CrC4)-烷二基，（C2-C4)-烯二基或(C2-C4)-炔二 基’ R2與R5，分別獨立地，為吡啶基，噻吩基，呋喃基，苯 並呋喃基，四氫吡喃基，環己基或苯基，其各可經取 代一或二個，分別獨立地，選自下列基：鹵素，（Cr 15 C6)-烷基，三氟曱基，氰基，胺基，（CrC6)-烷氧基或 三氟甲氧基，其中上述的烷基與烷氧基另可再經下列 基取代：羥基，（CVC4)-烷氧基，羧基，（crc4)-烷氧基 羰基，胺基，單-或二-(Ci-CO-烷基胺基， 經濟部智慧財產局員工消費合作社印製 R3與R4，分別獨立地，為氫，（CrC6)-烷基，（C2-C6)-烯 20 基，（C2-C6)-炔基或(C3-C8)-環烷基，其各可經取代一至 三個，分別獨立地，選自下列之基：羥基，（CrC6)-烷 氧基，氰基，氟，氣，-NRUR12，-C(0)-0R13，-C(O)-NRHR12，-S〇2-OR13 與-SCb-NRUR12，其中 R11，R12與R13，分別獨立地，為氫或(CVC6)-烷基， -7- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200400936 A7 B7 五、發明說明（6) 或 R3與R4，一起與其附接的碳形成3_至6_員的，螺_連繫的 環烷基環， R6 為氫 ’（CrC6)-烷基，（crC6)-烷醢基或式-C(0)-C(0)-5 OR14之基，其中 R14為氫或(CrC6)-烷基， R7為氫， R8為羥基， 或 10 R7與R8 —起與其附接的碳形成羰基或式（^N-O-R15之 基，其中 R15為氫或為（CrC6)-烧基之基，其可經取代下列之 基：羥基，（crc6)-烷氧基，羧基，（crc4)-烷氧基 羰基或式-nr16r17或_C(0)_NR1V7之基，其中 15 Rl6與R17,分別獨立地，為氫或(crc6)-烧基， 附帶條件是’ R3不為氫或甲基，如果在同時間下， -A 為鍵結， -R1 為無取代的苯基， 經濟部智慧財產局員工消費合作社印製 -R2與R5各為苯基’其為無取代的或在對位_ 20 經甲氧基取代者， -R4與R6各為氫且 -R7與R8 —起與其附接的碳形成羰基。 根據本發明的化合物也可能呈其鹽類、溶劑化物或鹽 類的溶劑化物型式存在。 孤 200400936 A7 五、發明說明Selected from N, 〇 and / or S paper rule 4-200400936 A7 B7 V. The 5- or 6-membered heteroaryl group of the heteroatom of the invention description (3), each of which can be independently passed through one to three Substituents selected from the group consisting of: halogen, (C 丨 -C6) -alkyl, trifluoromethyl, cyano-5, (CrCe) -hydroxyl, trifluorofluorenyl, tertyl, (CrC4 ) -Alkoxycarbonyl group, -C (0) -NR9R1G, amine group, mono- and 5-di- (Ci_C6) -alkylamino group 'wherein the above-mentioned alkyl group and alkyloxy group can also replace the following groups: A hydroxyl group, a (Crc4) -alkoxy group, a carboxyl group, a (CrC4) -alkyloxy group, an amine group's mono- or di- (C1-C4) -alkylamino group, and R9 and R1G, each independently, Is hydrogen or (crc6) -alkyl, A is a bond or (CrC4) -alkanediyl, (C2-C4) -fluorenediyl or (C2-C4) -alkyndi10, R2 and R5 are each independently , Is pyridyl, thienyl, furyl, benzofuranyl, tetrahydropyranyl, cyclohexyl or phenyl, each of which may be substituted by one or two, each independently selected from the group consisting of: halogen, ( cr c6) -alkyl, trifluorofluorenyl, cyano, amine, (CrCd-alkoxy or 15 trifluorofluorenyl, which The above-mentioned alkyl group and alkoxy group may be further substituted by the following groups: hydroxyl, (CrC4) -alkoxy, carboxyl, (CVQ) -alkoxyquinyl, amine, mono- or di- (Ci -C4)-^ S amine group, printed by R3 and R4 in the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, which are independently hydrogen, (Crc6) -alkyl, (C2-C6) -alkenyl, (c2-c6 ) -Alkynyl or (c3-c8) -cycloalkyl, each of which may be substituted one to three, each independently selected from the group consisting of: hydroxyl, (CrC6) -alkoxy, cyano, fluorine, Gas, -NRUR12, -C (0) -0R13, -C (O) -NRUR12, -S02-OR13 and -S02-NRuR12, where R11, R12 and R13 are independently 氲 or (Ci-C6) -Alkyl, or this paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) 200400936 A7 B7 V. Description of the invention (4) R3 and R4 together with the carbon to which they are attached form 3_ to 6_ Member, a spiro-linked cycloalkyl ring, R6 is hydrogen, (CVCe) -alkyl'alkylfluorenyl or a group of formula -C (0) -C (0) -0R14, where 5 R14 is hydrogen or (CrC6) -alkyl, R7 is hydrogen, R8 is a radical, or R7 and R8 form a carbonyl group with the carbon to which it is attached or the formula C = N_〇_ 10 groups of Ri5, where R is hydrogen or a (Ci-C6) -alkyl group, which may be substituted by the following groups: mesogen, (CVC6) -alkoxy, carboxyl, (Cl_C4) _alkoxy A carbonyl group or a group of the formula -NR16R17 or -c (o) -nr16r17, wherein R16 and R17 are each independently hydrogen or (Ci_C6) _alkyl, and 15 is used to control diseases. In particular, these compounds are used for the preparation of pharmaceuticals For the treatment and / or prevention of thrombotic plug disease. Some of the above compounds printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs are novel compounds, and some are known from the literature [see BH Freeman et al ”Fenjiajiaban 2P, 4307-4312 (1973), J. Rigaudy et al., Tetrahedron 41, 1345-1353 20 (1986)], however, no known compounds have been shown to have therapeutic use, and the present invention is the first to discover its therapeutic effect. The present invention also relates to formula The compound of (I), wherein R1 is (C6-C10) -aryl or bears up to two selected from N, 〇, and / or s -6- This paper size applies Ningguo National Standard (CNS) A4 specifications (-2 丨 〇x297 mm) 200400936 A7 B7 V. Description of the Invention The 5- or 6-membered heteroaryl group of the hetero atom of (5), each of which may be independently substituted by one to three groups selected from the following: Halogen, (CVC6) -alkyl, trifluorofluorenyl, cyano, hydroxy, (CVC6) -alkoxy, trifluoromethoxy, carboxyl, (crc4) -alkoxycarbonyl, -C (0)- NR9R1Q, amine group, mono- and 5-di- (Ci_C6) -alkylamino group, wherein the above alkyl group and xyloxy group can also replace the following groups: meridian group, (cr c4) -alkane Oxy, carboxyl, (crc4) -alkoxycarbonyl, amine, mono- and di- (C1-C4) -alkylamino, and R9 and R1G are each independently fluorene or (crc6) -alkane 10 A is a bond or (CrC4) -alkanediyl, (C2-C4) -alkenyl or (C2-C4) -alkyndiyl 'R2 and R5, each independently, is pyridyl, thienyl, Furyl, benzofuranyl, tetrahydropyranyl, cyclohexyl or phenyl, each of which may be substituted by one or two, each independently selected from the group consisting of: halogen, (Cr 15 C6) -alkyl, Trifluorofluorenyl, cyano, amine, (CrC6) -alkoxy or trifluoromethoxy, in which the above alkyl and alkoxy groups may be further substituted with the following groups: hydroxyl, (CVC4) -alkoxy Group, carboxyl group, (crc4) -alkoxycarbonyl group, amine group, mono- or di- (Ci-CO-alkylamino group), R3 and R4 are printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, respectively, as Hydrogen, (CrC6) -alkyl, (C2-C6) -alkenyl 20, (C2-C6) -alkynyl or (C3-C8) -cycloalkyl, each of which may be substituted by one to three, each independently , Selected from the group consisting of: hydroxyl, (CrC6) -alkoxy, cyano, fluorine, gas, -NRUR12 -C (0) -0R13, -C (O) -NRHR12, -S〇2-OR13 and -SCb-NRUR12, wherein R11, R12 and R13 are each independently hydrogen or (CVC6) -alkyl,- 7- This paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) 200400936 A7 B7 V. Description of the invention (6) or R3 and R4 together with the carbon attached to form 3_ to 6_ member , A spiro-linked cycloalkyl ring, R6 is hydrogen '(CrC6) -alkyl, (crC6) -alkylfluorenyl or a group of formula -C (0) -C (0) -5 OR14, where R14 is Hydrogen or (CrC6) -alkyl, R7 is hydrogen, R8 is hydroxy, or 10 R7 and R8 together form a carbonyl group with the carbon to which it is attached, or a group of formula (^ NO-R15, where R15 is hydrogen or (CrC6) -A alkynyl radical, which may be substituted by the following radicals: hydroxyl, (crc6) -alkoxy, carboxyl, (crc4) -alkoxycarbonyl or a radical of formula -nr16r17 or _C (0) _NR1V7, of which 15 Rl6 and R17 are each independently hydrogen or (crc6) -alkyl, with the condition that R3 is not hydrogen or methyl. If at the same time, -A is a bond and -R1 is an unsubstituted phenyl group Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs-R2 and R5 are each phenyl ', which is not taken In the para position, or a methoxy group substituted by _ 20 persons, -R4 and R6 -R7 are each hydrogen and and R8 - carbon from attached thereto form a carbonyl group. The compounds according to the invention may also exist in the form of their salts, solvates or solvates of the salts. Solitary 200400936 A7 V. Description of Invention

10 15 經濟部智慧財產局員工消費合作社印製 20 異椹:據Ϊ發明的化合物，視其取代型式，也可能呈立體 此才ί/ί(鏡像物’非對映立體異構物)存在，本發明因 相關於其鏡像物或非對映立^ 物，純態組成分的立體显構：二異構物及其個別的混合 或非對映立體異構物之混合物中分離出來。兄料及/ 異構^明’視化合物的取代型式，也關於化合物的互變 生理;==相關的輕宜為根據本發明的化合物之 根據本發明之生理 鹽類養類、鹽類包括下列酸之酸加成 氫氣酸，氫漠酸，硫酸碟二例如下列酸之鹽類: 酸，笨魏，萘二‘，^’甲_，乙續酸，甲笨續 果夂杯減，反丁烯二酸，順丁烯二酸與苯甲酸。 本發月化α物之生理可接受的鹽類也包括傳統驗類之 ^ ’例如且為較佳地為驗金屬鹽類（例如納與卸之鹽 ’驗土金屬鹽類(例如約與鎂之麵)與衍生自氨或具1 個碳原子之有機胺類者，舉例而言且較佳地為乙基 胺’二乙基胺，三乙基胺，乙基二異丙基胺，單乙醇胺， 二乙醇胺，三乙醇胺，二環己基胺，二甲基胺基乙醇，普 卡因（Pr〇Caine)’二苯甲基胺，Ν-甲基嗎啡，二氣松脂基 胺，精胺酸，離胺酸，乙二胺與甲基六氫吡啶。 與本發明目的相關的签魁也数為那些在固態或液態狀 態中與溶劑分子配接形成錯合物之根據本發明之化合物， -9- 本紙張尺度適用中國國家標準(CNS)A4規格>c 297 ·： i 計 線 200400936 A7 B7 ____ 五、發明說明（8 ) "~ ' - 水合物是種特殊型態的溶劑化物，其中配接者為水。 本發明中，無特別指明下，取代基具有下列的含義： (^1：£企態蘸基.是一種具有1至6個的直鏈或支鏈烷醯 基，舉例而言包括且較佳地為甲醯基，乙醯基，丙酿 5基，丁醯基，異丁醯基，戊醯基，異戊醯基與已醯基， 又以其中具有1至4個碳原子者為較佳，特佳者為^醯 基與丙醯基。 皇迄羞^代表分別具有1至6個與1至4個 碳原子之直鏈型或支鏈型烷基，以具有1至4個碳原子 10之直鍵或支鍵烧基為較佳，特別是具有1至3個碳原子 者，可舉之為例且為較佳者為：甲基，乙基，正丙基， 異丙基，第三丁基，正戊基與正己基。 土 皇瘦基代表分別具有2至6個與2至4個 碳原子之直鏈型或支鏈型烯基，以具有2至4個碳原子 15之直鏈或支鏈烯基為較佳，特別是具有2至3個碳原子 者，可舉之為例且為較佳者為：乙烯基，烯丙基，正丙_ 1-烯-1-基與正丁 _2-烯_丨_基。 經濟部智慧財產局員工消費合作社印製 是一種具有2至ό個碳原子之直鏈型或支鏈 型炔基，以純2至4财原子之直戦支鏈炔基為較 20佳’可舉之為例且為較佳者為：乙块基，正丙_2_快小基 與正丁-2-炔-1-基。 ④β祕减是-種具有i至4個碳原子之直鏈或支鏈 的烧-基’以具有i至2個碳原子之直鏈或支鏈炫二基 為較佳’可舉之為例且為較佳者為：甲烧^•二基，乙 -10- -本紙張尺度適用T國國家標準(CNS)A4規格（2丨〇 χ 297公楚） 200400936 A7 B7 五、發明說明（9) 、元1’2 —基，丙烧”13-二基，丁虎二基，乙烧·ι，卜二 基，丙烷-1，2-二基，丙烷_2,2_二基，丁烷_丨,3_二基與丁 烧-2,4-二基。 趣^是一種具有2至4個碳原子之直鏈型或支 5鏈型稀二基’以具有2或3個碳原子之烯二基為較佳， 可舉之為例且為較佳者為：乙烯_丨，2_二基，乙烯-丨上二 基，丙烯-l，l-二基，丙烯_丨，2_二基，丙烯u-二基，丙 烯-3,3-二基，丙烯-2,3-二基與丁-2-烯-1,4-二基。 (£2_^旌土基是一種具有2至4個碳原子之直鏈型或支 10鏈型炔—基，以具有2或3個碳原子之炔二基為較佳， 可舉之為例且為較佳者為：乙炔-1，2-二基，丙炔二基 與丁-2-炔-i，4-二基。 基代表分別具有1至6個與1至4 個碳原子之直鏈型或支鏈型烷氧基，以具有丨至4個， 15特別疋1至3個碳原子之直鏈型或支鏈型烷氧基為較 佳，可舉之為例且為較佳者為：甲氧基，乙氧基，正丙 氧基，異丙氧基，第三丁氧基，正戊氧基與正己氧基。 經濟部智慧財產局員工消費合作社印製 與卓烧基胺基代表分別具有1至ό個 與1至4個碳原子之直鏈型或支鏈型單烷基胺基，以具 20有1至4個碳原子之直鏈或支鏈烷基胺基為較佳，特別 是具有1至3個碳原子者，可舉之為例且為較佳者為： 甲基胺基，乙基胺基，正丙基胺基，異丙基胺基，第= 丁基胺基，正戊基胺基與正己基胺基。 二烧棊胺基代表其中烧基可為相同或相異且各具 -11- 本紙張尺度適用中國國€^,(CNS)A4規格（210x297公釐） '— ------ 20040093610 15 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. 20 Heterogeneous compounds: According to the compounds invented, depending on the substitution pattern, they may also appear stereoscopically. The present invention is related to the stereoisomerism of its mirror image or diastereomer, pure constituents: the di-isomers and their individual mixed or diastereoisomeric mixtures are separated. Brothers and / isomers ^ Ming 'depending on the substitution pattern of the compound, but also about the physiology of the interconversion of the compound; == related light should be a compound according to the present invention, physiological salts of the species, salts including the following acids Acid addition of hydrogen acid, hydrogen acid, and sulfuric acid, such as the salts of the following acids: acid, Benwei, naphthalene di ', ^' methyl, acetic acid, methyl benzyl peptone cup minus, transbutene Diacids, maleic acid and benzoic acid. The physiologically acceptable salts of the alpha compounds of the present invention also include the traditional tests ^ 'for example and are preferably metal test salts (such as sodium and unloaded salts' soil test metal salts (such as about with magnesium Face) and those derived from ammonia or organic amines having 1 carbon atom, for example and preferably ethylamine'diethylamine, triethylamine, ethyldiisopropylamine, monoamine Ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, Procaine's benzhydrylamine, N-methylmorphine, dipinosylamine, arginine , Lysine, ethylenediamine, and methylhexahydropyridine. The signatures related to the purpose of the present invention are also those compounds according to the present invention that form a complex with a solvent molecule in a solid or liquid state,- 9- This paper size is in accordance with Chinese National Standard (CNS) A4 specifications> c 297 ·: i line 200400936 A7 B7 ____ 5. Description of the invention (8) " ~ '-Hydrate is a special type of solvate, Among them, the adapter is water. In the present invention, unless otherwise specified, the substituents have the following meanings: (^ 1: 企 企Dipyl. Is a linear or branched alkyl alkynyl group having from 1 to 6, including, for example, methyl amidyl, ethyl amidinyl, propyl amidinyl, butanyl, isobutylamyl, pentamidine Group, isopentyl group and hexamyl group, and those having 1 to 4 carbon atoms are more preferred, and the most preferable ones are ^ and propyl, respectively. The emperor so far has 1 to 6 and A linear or branched alkyl group of 1 to 4 carbon atoms is preferred. A straight or branched alkyl group having 1 to 4 carbon atoms is preferred, especially those having 1 to 3 carbon atoms. For example, the following are preferred: methyl, ethyl, n-propyl, isopropyl, third butyl, n-pentyl, and n-hexyl. Tussyl represents 2 to 6 and 2 respectively. A linear or branched alkenyl group of 4 to 4 carbon atoms is preferred, a linear or branched alkenyl group of 2 to 4 carbon atoms of 15 is preferred, especially those having 2 to 3 carbon atoms. As an example and the better ones are: vinyl, allyl, n-prop-1-en-1-yl and n-but_2-ene_ 丨 _. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs A straight chain with 2 to 6 carbon atoms Or branched chain alkynyl, with straight 2 to 4 atom straight branched chain alkynyl being better than 20, for example, and the better are: ethyl block, n-propyl_2_Quick small group and N-but-2-yn-1-yl. ④ β secretion is a kind of straight-chain or branched-chain alkyl group with i to 4 carbon atoms. Two bases are better, for example, and the better ones are: Jia burn ^ • two bases, B-10--This paper size is applicable to National T (CNS) A4 specifications (2 丨 〇χ 297) (Chu) 200400936 A7 B7 V. Description of the invention (9), Yuan 1'2-base, propane "13-diyl, Dinghu diyl, ethene · b, diphenyl, propane-1,2-diyl , Propane_2,2_diyl, butane_ 丨, 3_diyl and butane-2,4-diyl. Qu ^ is a linear or branched 5-chain dilute di 'having 2 to 4 carbon atoms. An alkenyl having 2 or 3 carbon atoms is preferred, and for example, it is preferred. For: ethylene_ 丨, 2_diyl, ethylene- 丨 diyl, propylene-1, l-diyl, propylene_ 丨, 2-diyl, propylene u-diyl, propylene-3,3-diyl , Propylene-2,3-diyl and but-2-ene-1,4-diyl. (£ 2_ ^ celite is a straight-chain or branched 10-chain alkynyl group having 2 to 4 carbon atoms, and an alkynyl group having 2 or 3 carbon atoms is preferred, as an example And preferred ones are: acetylene-1,2-diyl, propynediyl and but-2-yne-i, 4-diyl. The groups represent those having 1 to 6 and 1 to 4 carbon atoms, respectively. A linear or branched alkoxy group is preferably a linear or branched alkoxy group having from 1 to 4, 15 particularly 1 to 3 carbon atoms, for example, and it is The best are: methoxy, ethoxy, n-propoxy, isopropoxy, tertiary butoxy, n-pentoxy and n-hexyloxy. Printed and burned by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. Amino groups represent linear or branched monoalkylamine groups having 1 to 6 and 1 to 4 carbon atoms, respectively, and straight or branched chain alkylamines having 20 to 1 to 4 carbon atoms Is preferred, especially those having 1 to 3 carbon atoms, which may be exemplified and preferred are: methylamino, ethylamino, n-propylamino, isopropylamino, No. = Butylamino, n-pentylamino and n-hexylamino. Group represents a group in which the burn may be the same or different and each scale with -11- This paper applies China State € ^, (CNS) A4 size (210x297 mm) '-------- 200 400 936

五、發明說明（10) 10 15 經 濟 部 智 慧 財 k 局 員 工 消 費 20 • 有1至6個碳原子之直鏈型或支鏈型烷基胺基，以复 的烧基為具有丨至4贿原子，特减丨至3個碳原 之直鏈或支鏈型二烧基胺基為較佳，可舉之為例 佳者為.二甲基胺基，二乙基胺基，二正 \ 異丙基胺基，二·第三丁基胺基，二_正戊基胺基胺基二= :基J基^基甲基胺基’異丙基甲基胺基，正 基第二丁基甲基胺基，正異戊基胺基。 收 域^代表其中烧氧基為具有i至 ::直基’可舉之為例且為:佳 氧基縣料三^:氧基幾氧基基羰基，正丙氧_基，異兩 ^代表具有6至1〇員 基為笨基與魏。至W員之讀基’較佳的芳族 表具有3至8财軒之環絲，以 至ό個碳原子者為較佳者，可 " 環丙基H m $例且為lx佳者為： 又以環己基’環庚基與環辛基， 衣内基，％戊基與環己基為特佳。 是種具5或6_原子與包含1至2個 經由;t及/或硫之雜原子之芳族基，此雜芳基可 ，！由奴原子’或，適當地，經由 士 例且為較佳者為： ， :、：二 嚼嗤基，咪唾A，_A 基料基，噻唾基， _辛… 啶基與吡D井基。 敦與氣為特佳。 I氣與廣為較佳，又以 裝 計 線 -12-W 尺度·中V. Description of the invention (10) 10 15 Employees of the Bureau of Intellectual Property k of the Ministry of Economic Affairs 20 Consumption 20 • Linear or branched chain alkylamine groups with 1 to 6 carbon atoms, with complex radicals as the basis Atoms, especially straight-chain or branched dialkyl radicals with 3 carbon atoms are preferred, and for example, dimethylamino, diethylamino, di-n- \ Isopropylamino, di-tertiary butylamino, di-n-pentylaminoamino di =: yl group, j-methylmethylamino, isopropylmethylamino, n-butylbutylmethyl Amine, n-isoamylamino. The field ^ represents where the alkoxy group has i to :: a straight group, for example, and is: Jiaoxianxian III ^: oxyquinoxycarbonyl group, n-propoxy group, isopropyl group Representatives with 6 to 10 members are Benji and Wei. The best aromatic watch for the member of the W member has a ring yarn of 3 to 8 wealth, and those with 6 carbon atoms are better. For example, cyclopropyl H m : Cyclohexyl 'cycloheptyl and cyclooctyl, capryl,% pentyl and cyclohexyl are particularly preferred. Is an aromatic group with 5 or 6_ atoms and contains 1 to 2 heteroatoms via; t and / or sulfur, this heteroaryl group may be! From the slave atom 'or, suitably, the following examples are preferred and are: ,,,: dimethylpyridyl, imidyl A, _A base, thiothalyl, octyl ... pyridyl and pyridyl wells base. Tun Yu is particularly good. I gas and wide are better, and the packing line is -12-W scale · Medium

I I I I I I I I 1 I I I I I I r I I I ! I I 1 Ϊ I I 200400936 A7 B7 五、發明說明（u) --- 較佳的化合物為式(I)的化合物，其中 R1為(C6-C1G)-芳基，其為經取代一至三個，分別獨立地選 自下列的基.鹵素’（CVC6)-烷基，三氟甲基，氰基， 經基’（crC6)-烧氧基，三氟甲氧基，緩基，（c丨炫 5 氧基羰基，-c(o)-NR9R1G，胺基，單_與二_(Ci_C6)_烷基 胺基， 或 為帶有至多達兩個選自N、〇及/或s的雜原子之5-或 6-員雜芳基，其可經取代一至三個，分別獨立地選自 10 下列的基：鹵素，（CH：6)-烷基’三氟甲基，氰基，羥 基’（CrQ)-烷氧基，三氟甲氧基，羧基 烷氧 基羰基’ -c(o)-nr9r1g，胺基，單_與二_(Ci_C6)_烷基 胺基， 其中，各情況下， 15 上述的烷基與烷氧基另各可經取代下列基：羥基，（Ci- C4)-烷氧基，羧基’（CrC4)-烷氧基羰基，胺基，單-與 二-(Ci-C4)-烧基胺基，且 R9與R1G，分別獨立地，為氫或烷基， 經濟部智慧財產局員工消費合作社印製 A 為鍵或(Cl-C4)-院二基，（C2_c4)_烯二基或(C2_c4)_炔二 20 基， R2與R5 ’分別獨立地，為吡啶基，噻吩基，呋喃基或苯 基，其各可經取代一或二個，分別獨立地，選自下列 基：鹵素，（C丨-C6)-烷基，三氟甲基，氰基，（CrC6)-烷 氧基或三氟甲氧基，其中上述的烷基與烷氧基另可再 -13- 本紙張尺度適用中國國家標準(CNS)A4規袼（210x297公爱） 200400936 A7IIIIIIII 1 IIIIII r III! II 1 Ϊ II 200400936 A7 B7 V. Description of the invention (u) --- The preferred compound is a compound of formula (I), where R1 is (C6-C1G) -aryl, which is Substitute one to three, each independently selected from the following groups. Halogen '(CVC6) -alkyl, trifluoromethyl, cyano, cyclyl' (crC6) -carboxy, trifluoromethoxy, and retarder , (C) 5oxycarbonyl, -c (o) -NR9R1G, amine, mono- and di- (Ci_C6) -alkylamino, or with up to two selected from N, 0 and / Or a 5- or 6-membered heteroaryl group of a hetero atom of s, which may be substituted by one to three, each independently selected from the following groups: halogen, (CH: 6) -alkyl'trifluoromethyl, Cyano, hydroxy '(CrQ) -alkoxy, trifluoromethoxy, carboxyalkoxycarbonyl'-c (o) -nr9r1g, amine, mono- and di_ (Ci_C6) _alkylamino, In each case, the above-mentioned alkyl group and alkoxy group may each be substituted with the following groups: hydroxyl, (Ci-C4) -alkoxy, carboxyl '(CrC4) -alkoxycarbonyl, amino, mono -And di- (Ci-C4) -alkylamino, and R9 and R1G are independent of each other Ground, hydrogen or alkyl, printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs as a bond or (Cl-C4) -Yuan Diji, (C2_c4) _enediyl or (C2_c4) _acetylene 20, R2 And R5 ′ are each independently pyridyl, thienyl, furyl or phenyl, each of which may be substituted by one or two, each independently selected from the group consisting of: halogen, (C 丨 -C6) -alkyl , Trifluoromethyl, cyano, (CrC6) -alkoxy or trifluoromethoxy, in which the above-mentioned alkyl and alkoxy groups may be further -13- This paper size applies to China National Standard (CNS) A4 regulations袼 (210x297 public love) 200400936 A7

經下列基取代：羥基，（CrC4)_烷氧基，羧基，（Ci_C4)_ 烷氧基羰基，胺基，單-或二_(CrC4)_烷基胺基， R3與R4，分別獨立地，為氫，（Ci_C6)_燒基，（C2_C6)_稀 基，（CrQ)-炔基或(C3_C8)_環烷基，其各可經取代一至 5 三個，分別獨立地，選自下列之基：羥基，（CrC6)-烷 氧基，氰基，氟，氣，_NRUR12，-C(0)-〇R13，_c(C〇-NRUR12，-S02-0R13 與-s〇2_NRnRi2，其中 R11 ’ R12與R13，分別獨立地，為氫或(Ci_C6)_烧基， 或 10 R與R，一起與其附接的；6炭形成3-至6-員的，螺-連繫的 ί哀競i基環， R6 為氫 ’（Ci-C6)_烷基，（CrC6)-烷醯基或式-C(0)-C(0)-OR14之基，其中 R14為氫或(CVQ)-烷基， 15 R7為氫， R8為羥基， 或 經濟部智慧財產局員工消費合作社印製 R7與R8 —起與其附接的碳形成羰基或式C=n-0-R15之 基，其中 20 Rl5為氫或為（crc6)-烷基之基，其可經取代下列之 基：羥基，（crc6)-烷氧基，羧基，（crc4)-烷氧基 羰基或式-NR16R17或-c(o)-nr16r17之基，其中 R16與R17，分別獨立地，為氫或(CVC6)-烷基， 特別佳的式(I)化合物為， -14- 本紙張尺度適用中國國豪^(CNS)A4規格（210 X 297公«了 200400936 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（13) 其中 R1為苯基，其為經取代一或二個，分別獨立地選自下列 的基：氟，氯，（Ci-C4)-烷基，三氟甲基，氰基，（Cr C4)-烷氧基，三氟曱氧基，羧基，（CrC4)-烷氧基羰 5 基，-C(0)-NR9R1Q，胺基，單-與二-(CrC6)-烷基胺 基， 或 為吡啶基，噻吩基，噁唑基或噻唑基，其各可經取代 一或二個，分別獨立地選自下列的基：氟，氯，（cr 10 c4)-烷基，三氟甲基，氰基，（crc4)-烷氧基，三氟甲 氧基，羧基，（crc4)-烷氧基羰基，-c(o)-NR9R1Q，胺 基，单-與二-(C1-C4)-烧基胺基’ 其中，各情況下， R9與R1Q，分別獨立地，為氫或(CVC6)-烷基， 15 A 為鍵或為1,2-乙二基， R2與R5，分別獨立地，為吡啶基，噻吩基或苯基，其各 可經取代一或二個，分別獨立地，選自下列基：氟， 氯，（CrQ)-烷基，三氟甲基，氰基，（C丨-c4)-烷氧基 或三氟甲氧基， 2〇 R3為氫或(CrC4)-烷基， R4為(CrC4)-烷基，其可經取代一或二個，分別獨立地， 選自下列之基：羥基，（CrC4)-烷氧基，-NRUR12與-C(0)-0R13，其中 R"，R12與R13，分別獨立地，為氫或(CrC4)-烷基， -15- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐）Substituted by the following groups: hydroxyl, (CrC4) _alkoxy, carboxyl, (Ci_C4) _alkoxycarbonyl, amine, mono- or di_ (CrC4) _alkylamino, R3 and R4, each independently Is hydrogen, (Ci_C6) _alkenyl, (C2_C6) _diluted, (CrQ) -alkynyl or (C3_C8) _cycloalkyl, each of which may be substituted by one to three, each independently selected from the following Base: hydroxyl, (CrC6) -alkoxy, cyano, fluorine, gas, _NRUR12, -C (0) -〇R13, _c (C〇-NRUR12, -S02-0R13 and -s〇2_NRnRi2, where R11 'R12 and R13, independently, are hydrogen or (Ci_C6) _alkyl, or 10 R and R, attached to it together; 6 carbons form 3- to 6-membered, spiro-linked i-based ring, R6 is hydrogen '(Ci-C6) _alkyl, (CrC6) -alkylfluorenyl or a group of formula -C (0) -C (0) -OR14, where R14 is hydrogen or (CVQ)- Alkyl group, 15 R7 is hydrogen, R8 is hydroxyl, or R7 and R8 printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, form a carbonyl group with the carbon attached to it or a group of formula C = n-0-R15, of which 20 Rl5 Is a hydrogen or (crc6) -alkyl group, which may be substituted with the following groups: hydroxyl, (crc6) -alkoxy, carboxyl (Crc4) -alkoxycarbonyl or a group of formula -NR16R17 or -c (o) -nr16r17, wherein R16 and R17 are each independently hydrogen or (CVC6) -alkyl, and particularly preferred compounds of formula (I) For, -14- This paper size is applicable to China Guohao ^ (CNS) A4 specification (210 X 297) «200200936 Printed by A7 B7, Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the invention (13) where R1 is phenyl , Which are substituted one or two, each independently selected from the group consisting of: fluorine, chlorine, (Ci-C4) -alkyl, trifluoromethyl, cyano, (Cr C4) -alkoxy, three Fluorofluorenyloxy, carboxyl, (CrC4) -alkoxycarbonyl5, -C (0) -NR9R1Q, amine, mono- and di- (CrC6) -alkylamino, or pyridyl, thienyl , Oxazolyl or thiazolyl, each of which may be substituted by one or two, each independently selected from the group consisting of: fluorine, chlorine, (cr 10 c4) -alkyl, trifluoromethyl, cyano, (crc4 ) -Alkoxy, trifluoromethoxy, carboxyl, (crc4) -alkoxycarbonyl, -c (o) -NR9R1Q, amine, mono- and di- (C1-C4) -alkylamino In each case, R9 and R1Q are independently hydrogen or (CVC6)- 15 A is a bond or 1,2-ethylenediyl, and R2 and R5 are each independently pyridyl, thienyl, or phenyl, each of which may be substituted by one or two, each independently selected from The following groups: fluorine, chlorine, (CrQ) -alkyl, trifluoromethyl, cyano, (C 丨 -c4) -alkoxy or trifluoromethoxy, 20R3 is hydrogen or (CrC4) -alkane R4 is (CrC4) -alkyl, which may be substituted by one or two, each independently selected from the group consisting of: hydroxyl, (CrC4) -alkoxy, -NRUR12 and -C (0) -0R13 , Where R ", R12 and R13 are independently hydrogen or (CrC4) -alkyl, -15- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)

200400936 A7 B7 五、發明說明（14) 或 R3與R4，一起與其附接的碳形成螺-連繫的環丙基，環丁 基或環戊基環， R6為氫， 5 且 R7與R8 —起與其附接的碳形成羰基或式C=N-0-R15之 基，其中 R15為（CVQ)-烷基，其可經取代下列之基：羥基， (CrC4)-烷氧基，羧基，（CVQ)-烷氧基羰基或式-10 nr16r17 或-c(o)-nr16r17 之基，其中 R16與R17，分別獨立地，為氫或((VQ)-烷基， 極佳的化合物為式(I)的化合物 其中 R1為苯基，其為經取代一或二個，分別獨立地選自下列 15 的基：氟，氣，甲基，三氟甲基與甲氧基， A 為鍵， 經濟部智慧財產局員工消費合作社印製 R2與R5，分別獨立地，為苯基，其可經取代一或二個， 分別獨立地，選自下列基：氟，氯，曱基，三氟甲基 或氰基， 20 R3為氫，甲基或乙基， R4為甲基， 或 R3與R4，一起與其附接的碳形成螺-連繫的環丙基，環丁 基或環戊基環， -16- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200400936 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明（15) R6為氳， 且 R7與R8 —起與其附接的碳形成羰基或式C=N-0-CH3之 基。 5 同樣為極佳的化合物為式(I)的化合物，其中 R3為氫， R4為（CrC4)-烷基或（C2-C4)-烯基，其可經取代一或二 個，分別獨立地，選自下列之基：羥基，（CrC4)-烷氧 基，-NRUR12 與-C(0)-0R13，其中 10 R11，R12與R13，分別獨立地，為氫或(CrQ)-烷基， 且 R1，R2，R5，R6，R7，R8與A具有前面指明的定義。 同樣為極佳的化合物為式(I)的化合物，其中 R3與R4兩者均為甲基， 15 且 R1，R2，R5，R6，R7，R8與A具有前面指明的定義。 同樣為極佳的化合物為式(I)的化合物，其中 R6為氫， 且 20 R1，R2，R3，R4，R5，R7，R8與A具有前面指明的定義。 同樣為極佳的化合物為式(I)的化合物，其中 R3為氫， R4與-O-R6相對彼此為位於順式構型， R6為氫， -17- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐）200400936 A7 B7 V. Description of the invention (14) or R3 and R4 together form a spiro-linked cyclopropyl, cyclobutyl or cyclopentyl ring with the carbon to which they are attached, R6 is hydrogen, 5 and R7 and R8 — From the carbon to which it is attached to form a carbonyl group or a group of the formula C = N-0-R15, where R15 is (CVQ) -alkyl, which can be substituted for the following groups: hydroxyl, (CrC4) -alkoxy, carboxyl, (CVQ) -alkoxycarbonyl or a group of the formula -10 nr16r17 or -c (o) -nr16r17, wherein R16 and R17 are each independently hydrogen or ((VQ) -alkyl, and an excellent compound is of formula The compound of (I) wherein R1 is phenyl, which is one or two substituted, each independently selected from the following 15 groups: fluorine, gas, methyl, trifluoromethyl and methoxy, and A is a bond, The Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs printed R2 and R5, each independently, is a phenyl group, which can be substituted for one or two, each independently selected from the following groups: fluorine, chlorine, fluorenyl, trifluoromethyl 20 R3 is hydrogen, methyl or ethyl, R4 is methyl, or R3 and R4 together form a spiro-linked cyclopropyl, cyclobutyl or cyclopentyl ring with the carbon to which they are attached , -16 -This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200400936 A7 B7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economy V. Invention Description (15) R6 is 氲, and R7 and R8 are attached together The attached carbon forms a carbonyl group or a group of formula C = N-0-CH3. 5 A compound that is also excellent is a compound of formula (I), where R3 is hydrogen and R4 is (CrC4) -alkyl or (C2-C4 ) -Alkenyl, which may be substituted by one or two, each independently selected from the group consisting of: hydroxyl, (CrC4) -alkoxy, -NRUR12 and -C (0) -0R13, of which 10 R11, R12 And R13, independently of each other, are hydrogen or (CrQ) -alkyl, and R1, R2, R5, R6, R7, R8 and A have the previously specified definitions. The same excellent compound is the compound of formula (I) , Where R3 and R4 are both methyl, 15 and R1, R2, R5, R6, R7, R8 and A have the previously specified definitions. The same excellent compound is the compound of formula (I), where R6 is Hydrogen, and 20 R1, R2, R3, R4, R5, R7, R8 and A have the previously specified definitions. Also excellent compounds are compounds of formula (I), where R3 is hydrogen, R 4 and -O-R6 are in the cis configuration relative to each other, R6 is hydrogen, -17- This paper size applies to China National Standard (CNS) A4 (210x297 mm)

200400936 A7 A7 B7 五、發明說明（16) 且 R1，R2，R4，R5，R7，R8與A具有前面指明的定義。 同樣為極佳的化合物為式(I)的化合物，其中 A 為鍵’ 5 且200400936 A7 A7 B7 V. Description of the invention (16) and R1, R2, R4, R5, R7, R8 and A have the previously specified definitions. Also excellent compounds are compounds of formula (I), where A is a bond ' 5 and

Rl，K2，R3 ’ R4，R5，R6，R7與R8具有前面指明的定 義。 同樣為極佳的化合物為式(I)的化合物，其中 R7與R8 —起與其附接的碳形成羰基或式C=N-0-R15之 10 基，其中 R15為（CrC4)-烷基，其可經取代下列之基：羥基， (CrC6)-烷氧基，羧基，（CVQ)-烷氧基羰基或式-NR16R17 或-C(0)-NR16R17 之基，其中 R16與R17，分別獨立地，為氫或(CrC4)·烷基， 15 且 R1，R2，R3，R4，R5，R6與A具有前面指明的定義。 混合兩種或多種上述較佳範圍的化合物也為極佳者。 本發明也關於製備式(I)化合物的方法，特徵為 經濟部智慧財產局員工消費合作社印製 或是 20 [A]式(II)的化合物R1, K2, R3 'R4, R5, R6, R7 and R8 have the definitions previously indicated. Also excellent compounds are compounds of formula (I), in which R7 and R8 together form a carbonyl group with the carbon to which they are attached, or a group of formula C = N-0-R15, where R15 is (CrC4) -alkyl, It can be substituted with the following groups: hydroxy, (CrC6) -alkoxy, carboxyl, (CVQ) -alkoxycarbonyl or a group of formula -NR16R17 or -C (0) -NR16R17, where R16 and R17 are independent of each other Ground is hydrogen or (CrC4) · alkyl, 15 and R1, R2, R3, R4, R5, R6 and A have the definitions specified above. It is also excellent to mix two or more compounds in the above preferable ranges. The present invention also relates to a method for preparing a compound of formula (I), which is characterized by being printed by a consumer cooperative of employees of the Intellectual Property Bureau of the Ministry of Economic Affairs or 20 [A] a compound of formula (II)

本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200400936 Δ7 Α7 Β7 經濟部智慧財產局員工消費合作社印製 五、發明說明（π 其中 A，R1，R3與R4各具有前面指明的定義 被與式(III)的化合物反應 (ΙΠ), 其中 R2與R5各具有前面指明的定義， 是在鹼存在下，惰性溶劑中反應製得式(Ι-A)的化合物 R1—This paper size applies to China National Standard (CNS) A4 specification (210x297 mm) 200400936 Δ7 Α7 Β7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the invention (π where A, R1, R3 and R4 each have the previously specified The definition is reacted with a compound of formula (III) (II), wherein R2 and R5 each have the previously specified definition, and are reacted in an inert solvent in the presence of a base to obtain compound R1-

R (I-A), 15 或 其中 A，R1，R2，R3，R4與R5各具有前面指明的定義 [B]式(IV)的化合物 20R (I-A), 15 or wherein A, R1, R2, R3, R4 and R5 each have the previously specified definitions [B] Compound of formula (IV) 20

R R Ο (IV), 19-R R Ο (IV), 19-

本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200400936 A7 B7 五、發明說明（is 其中 A , R1，R2，R3與R4各具有前面指明的定義 被與式(V)的有機金屬化合物反應 (V),This paper size applies the Chinese National Standard (CNS) A4 specification (210x297 mm) 200400936 A7 B7 V. Description of the invention (is where A, R1, R2, R3 and R4 each have the previously specified definitions and are organic with formula (V) Metal compound reaction (V),

R5-M 其中 R5具有前面指明的定義，且 10 Μ為金屬或金屬衍生物，例如Li，Na或Mg-X，其 中X為氣，溴或碘， 是在惰性溶劑中反應，製得式(Ι-A)的化合物， 或 [C]式(VI)的化合物 15R5-M where R5 has the previously specified definition, and 10 M is a metal or metal derivative, such as Li, Na or Mg-X, where X is gas, bromine or iodine, which is reacted in an inert solvent to obtain the formula ( Compound of I-A), or [C] Compound of formula (VI) 15

R i AR i A

RJ O 0RJ O 0

R 18〆 (VI), 經濟部智慧財產局員工消費合作社印製 20 其中 R1與R3各具有前面指明的定義 A 為鍵， 且 R18 為(CrC4)-烷基， -20- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200400936 Δ7 Α7 Β7 經濟部智慧財產局員工消費合作社印製 五、發明說明（l9 在惰性溶劑内，有機鹼或鹼類混合物的存在下，以式 (III)的化合物反應被轉變成式(I-B)的化合物R 18〆 (VI), printed by the Employees' Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 20 where R 1 and R 3 each have the previously defined A as the bond, and R 18 is (CrC4) -alkyl, -20- This paper size applies to China National Standard (CNS) A4 specification (210x297 mm) 200400936 Δ7 Α7 Β7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the invention (l9 In an inert solvent, in the presence of an organic base or an alkali mixture, the formula ( III) The reaction of the compound is transformed into a compound of formula (IB)

RR

(I-B), 10 15 20 或 其中 R1，R2，R3與R5各具有前面指明的定義，且 A 為鍵’ [D]式(IV)的化合物先藉助錯合金屬氫化物（例如氫棚化鈉 或氫化ISlf)，在惰性溶劑内，轉變成式(IX)的化合物(IB), 10 15 20 or wherein R1, R2, R3 and R5 each have the previously specified definitions, and A is the bond '[D] Compounds of formula (IV) are first aided by a complex metal hydride (such as sodium hydride Or hydrogenated ISlf), in an inert solvent, to a compound of formula (IX)

FT (IX), R Ο 其中 A，R1，R2 , R3與R4各具有前面指明的定義， 務後，再於惰性溶劑内，與式(V)的有機金屬化合物 反應，製得式(Ι-C)的化合物 -21-FT (IX), R 〇 Wherein A, R1, R2, R3 and R4 each have the previously specified definitions, and then reacted with an organometallic compound of formula (V) in an inert solvent to obtain the formula (I- C) Compound-21-

本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200400936 A7 B7 五、發明說明（2〇 )This paper size applies to China National Standard (CNS) A4 specifications (210 X 297 mm) 200400936 A7 B7 V. Description of the invention (2)

RR

(I-C), 5 其中 A ’ κ r5各具有前面指明的定義， 10 然後’適田地’則文獻已知的方法使式(I-A)，（I-B)與(I-C)進灯反應’心，祕之_還原反應，郷成反應及/或 院基化反應或酿化反應，而製得式(I)的化合物。 15 適於進行步驟⑼，卜(I-A)之惰性溶劑為例如醇 類似疋甲SI乙醇，正丙醇，異丙醇，正丁醇或第三丁 醇，函化的烴類’例如二氣甲烷，三氣甲烷，四氣甲：， 三氣乙院，四氣乙烧，u_二氣乙烧或三氣乙稀，賴， 例如二乙醚，甲基第三丁基醚，二。惡烧，四氮咬喃，甘醇 二甲基醚或乙二醇二甲基醚，烴類，例如苯，二甲笨， 經濟部智慧財產局員工消費合作社印製 苯，己烷，環己烷或石油餾分，或其他的溶劑：，：二 酸乙酯，二曱基甲醯胺，二甲基乙醯胺，二甲亞磾 腑’同樣有可能應用水或其他所提及溶劑的混合 ϋ 20劑，以醇類，例如甲醇與乙醇為較佳。 供進行步驟(n)+(Inh(I-A)之驗類為，例如， 或鹼土金屬之氫氧化物類，例如鋰、鈉、鉀戋鈣之Y屬 物，鹼金屬或鹼土金屬之碳酸鹽類，例如鈉、鉀、f二化 之碳酸鹽，驗金屬醇化物類，例如甲醇鈉或甲醇鉀 3舞 -22- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200400936(IC), 5 where A 'κ r5 each has the previously specified definitions, 10 then' Shidadi 'is known in the literature to make formulas (IA), (IB) and (IC) react to the lights. A reduction reaction, a formation reaction, and / or a chemical reaction or a fermentation reaction to prepare a compound of formula (I). 15 Suitable for carrying out step 卜. The inert solvent of Bu (IA) is, for example, an alcohol similar to Methyl SI ethanol, n-propanol, isopropanol, n-butanol or tertiary butanol, a functional hydrocarbon such as digas methane. , Three gas methane, four gas A :, three gas Yiyuan, four gas Bing, u_ two gas Bing or three gas Bing, Lai, such as diethyl ether, methyl third butyl ether, two. Smoldering, tetrazine, dimethyl ether or ethylene glycol dimethyl ether, hydrocarbons such as benzene, dimethylbenzyl, printed by benzene, hexane, cyclohexane Alkane or petroleum distillates, or other solvents:,: Ethyl diacid, dimethylformamide, dimethylacetamide, dimethylformamide 'It is also possible to use water or a mixture of other solvents mentioned剂 20 agents, preferably alcohols, such as methanol and ethanol. The tests for performing step (n) + (Inh (IA) are, for example, or hydroxides of alkaline earth metals, such as the lithium species of lithium, sodium, potassium and calcium, and carbonates of alkali or alkaline earth metals. , Such as sodium, potassium, f dicarbonates, metal alcoholates, such as sodium or potassium methoxide 3 Mai-22- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 200400936

五、發明說明（21) 經濟部智慧財產局員工消費合作社印製 鈉或乙醇鉀或第三丁醇 基三甲美錄气备各n 虱虱化物類，例如苯甲 :基叙虱氧化物(Triton B)，其中以氫氧化鈉或氫氧化 曱醇鈉或乙醇鈉，或Triton B為較佳者。 5行，=Γ1Ιν)+σ〇ϋ)是在自代至15()°c間的溫度間進 壓下^行。…至100。0之溫度範圍間進行，且宜在大氣 ，步驟(Iv)+(v)—(I_A); (VI)+(III)L㈣十⑺ >使狀雜溶劑為，例如，_，例如二乙喊， 二第:丁基醚，二魏，四氫吱喃’甘醇二甲細或乙 :基醚’或烴類’例如苯，二甲苯，曱苯，己烷，環 =或石關分’同财可能制所提及_的混合物作 合劑，各情況下以使用四氫呋喃為較佳。 。步驟(IV)+(V)~>(I-A)與(ΙΧ)+(ν)—(ΐ-c)是在自 _10(rc 至 0C間的溫度間進行，宜在自·贼至_6代之溫度範圍間進 行，且宜在大氣壓下進行。 供進行步驟(νι)+(ΠΙ)~>(I-B)之鹼類為，例如，鹼金 屬或驗土金屬之虱氧化物類，例如链、鈉、卸或約之氫氧 、物驗金屬之醇化物類，例如曱醇納或甲醇卸，乙醇鈉 或乙醇鉀或第三Τ醇鉀’驗金屬氫化物類，例如氮化納， 20醯胺類，例如醯胺化鈉，鋰、鈉或鉀之雙（三甲基矽烷基） 醯胺化物或二異丙基醯胺化鋰，或季銨氫氧化物類，例如 笨曱基二曱基銨氫氧化物(Triton Β)，同樣地可能應用所提 鹼類之混合物，其中以氫化鈉或氫化鈉與Triton B之併用 物為較佳者。 15 -23-V. Description of the invention (21) Sodium or potassium ethoxide or tertiary butanol-based trimethoprim printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, for each n lice compound, such as benzyl: yl oxoxide (Triton B), among which sodium hydroxide or sodium hydroxide or sodium ethoxide, or Triton B is preferred. Five lines, = Γ1Ιν) + σ〇ϋ) are obtained at a temperature between the generation and 15 () ° C. … To a temperature range of 100 to 0, and preferably in the atmosphere, step (Iv) + (v) — (I_A); (VI) + (III) L㈣ 十 ⑺ > Make the heterogeneous solvent, for example, _ , Such as diethyl, dith: butyl ether, diwei, tetrahydrocran 'glyme or ethyl: yl ether' or hydrocarbons' such as benzene, xylene, xylene, hexane, ring = Or Shiguanfen's mixture of the above mentioned materials can be used as a mixture. In each case, tetrahydrofuran is preferred. . Steps (IV) + (V) ~ > (IA) and (Ιχ) + (ν) — (ΐ-c) are performed at a temperature from _10 (rc to 0C, preferably from The temperature range of the 6th generation is performed, and it should be performed under atmospheric pressure. The bases for performing steps (νι) + (ΠΙ) ~ > (IB) are, for example, lice oxides of alkali metals or soil test metals, For example, chain, sodium, sodium hydroxide, or metal alcoholate, such as sodium alcohol or methanol, sodium ethoxide or potassium ethoxide or third potassium alkoxide, metal hydride, such as sodium nitride , 20 ammonium amines, such as ammonium sodium amide, bis (trimethylsilyl) ammonium amide or lithium diisopropyl ammonium amine ammonium hydroxide, or quaternary ammonium hydroxides, such as benzamidine Ditriammonium hydroxide (Triton B), it is also possible to use a mixture of the mentioned bases, of which sodium hydride or a combination of sodium hydride and Triton B is preferred. 15 -23-

甲 二A second

I 言 200400936 A7 B7 五、發明說明（22 步驟(VI)+(III)—(I_B)是在自（TC至120〇C間的溫度間 進行，宜在自10°c至70°c之溫度範圍間進行，且宜在大 氣壓下進行。 有些式(II)的化合物為文獻中已知或可藉由文獻中的 5 方法由適當的刖驅物被合成者[對照，例如，T.C. Myers et al., J.Am. Chem. Soc. 77, 5655 (1955) ； M. Arisawa et al., /. <9尽.毯 4327 (1997)]。 同樣地，有些式(III)的化合物為文獻中已知或可藉由 文獻中的方法由適當的前驅物被合成者[對照，例如，R.E. 10 Koenigkramer, H. Zimmer, Tetrahedron Lett 21, 1017 (1980) ； R.R. Koenigkramer, H. Zimmer, J.Org.Chem. 45, 3994 (1980) ； T. Mueller-Westerhoff, M. Zhou, J.Org.Chem. 59, 4988 (1994) ； G.A. Olah, An-h. Wu, J.Org.Chem. 56, 902 (1991) ； F. Babudri, V. Fiandanese, G. Marchese, A. 15 Punzi, Tetrahedron Lett. 36, 7305 (1995) ； D.Seyferth, R.M. Weinstein, R.C. Hui, W.-L. Wang, C.M. Archer, J.Org.Chem. M，5768 (1991)]。 經濟部智慧財產局員工消費合作社印製 有些式(VI)的化合物為文獻中已知或可藉由文獻中的 方法由適當的前驅物被合成者[對照，例如，P. Coutrot，A. 20 Ghribi，办ώ幼661 (1986)]。I. 200400936 A7 B7 V. Description of the invention (22 Step (VI) + (III) — (I_B) is performed at a temperature from (TC to 120 ° C), preferably at a temperature from 10 ° c to 70 ° c Some compounds of formula (II) are known in the literature or can be synthesized from appropriate permeants by 5 methods in the literature [control, for example, TC Myers et al , J.Am. Chem. Soc. 77, 5655 (1955); M. Arisawa et al., /. &9; blanket 4327 (1997)]. Similarly, some compounds of formula (III) are literature It is known or can be synthesized from appropriate precursors by methods in the literature [control, for example, RE 10 Koenigkramer, H. Zimmer, Tetrahedron Lett 21, 1017 (1980); RR Koenigkramer, H. Zimmer, J. Org. Chem. 45, 3994 (1980); T. Mueller-Westerhoff, M. Zhou, J. Org. Chem. 59, 4988 (1994); GA Olah, An-h. Wu, J. Org. Chem. 56 , 902 (1991); F. Babudri, V. Fiandanese, G. Marchese, A. 15 Punzi, Tetrahedron Lett. 36, 7305 (1995); D. Seyferth, RM Weinstein, RC Hui, W.-L. Wang, CM Archer, J. Org. Chem. M, 5768 (19 91)]. Some compounds of formula (VI) printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs are known in the literature or can be synthesized from appropriate precursors by methods in the literature [control, for example, P. Coutrot , A. 20 Ghribi, Office 661 (1986)].

其中R3及/或R4不為氳之式(IV)的化合物，可由轉變 式(IV-A)的化合物而製得 0 R1—A- (IV-A), 24- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200400936 A7 B7 五、發明說明（23 中A ’ R1與R2各具有前面指明的定義 首先與式(VII)的化合物反應 R'X1 (VII) 10Where R3 and / or R4 are not compounds of formula (IV), they can be obtained by converting compounds of formula (IV-A). 0 R1—A- (IV-A), 24- This paper size applies Chinese national standards (CNS) A4 specification (210 X 297 mm) 200400936 A7 B7 V. Description of the invention (23 A 'R1 and R2 each have the previously specified definitions First react with a compound of formula (VII) R'X1 (VII) 10

R3* 經濟部智慧財產局員工消費合作社印製 其中 R3*具有同於前面的R3但不為氣之含義， X 為適當的釋離基’例如氣，、、鱼 邊’碘，甲磺醯基，甲苯 %醯基或三氟曱笨磺醢基，官i^ 及馬 >昊或破， 是⑽存在下之惰性溶劑内進行’製得式(iv_b)的化合物 15 其中A，R1，R2與R3*具有前面指明的定義， 稍後’適當地與式(篇)的化合物進行第二階段的反應 20 其中 r4*-x2 (VIII) R4·具有同於前面的R4但不為氫之含義，且 X2為適當的釋離基，例如氣，溴，埃，甲確醢基， 磺醯基或三氟甲苯磺醯基，宜為溴或碘， 甲苯 -25- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） A7 B7 24 15 經濟部智慧財產局員工消費合作杜印製 20 二 五、發明說明（ 疋於驗存在下之惰,__進行。 供步驟（iv-a)+(Vii卜（IV叫與（ιν-酬vnmV)使 =之h丨生冷劑為’例如，賴，例如二乙醚，甲基第三丁 基醚，二噁烷，四氫呋喃，甘醇二甲基醚或乙二醇二甲基 例如苯’二甲苯，曱苯，己炫，環己烧或石油 齡’或其他的溶劑類，例如乙酸乙醋，丙酮，二甲基甲 醯胺，二甲基乙酿賊： 联’二甲亞砜或乙腈，同樣有可能應用 所提及冷，的此合物作為溶劑，較佳者為二甲基甲酿胺， 丙嗣或四風咳痛，在步驟CIV-A)+(VII)~>(IV-B)中以使用四 1〇氣吱喃祕佳且在步驟(IVB)+(vm卜㈣中，特佳的溶 劑為二甲基曱醯胺。 供步驟(IV-A)+(Vii) — (IV_B)與(IVB)+(vm 卜(IV)之 驗類為’例如’驗金屬紐土金屬之氫氧化物類，例如 1、鈉、鉀，妈或绝之氫氧化物，驗金屬或驗土金屬之碳 I孤類’例如鈉、鉀、绝或㉝之碳酸鹽類，驗金屬之之醇 化物類，例如甲醇鈉或甲醇鉀，乙醇鈉或乙醇鉀或第三丁 醇卸驗金屬氫化物類，例如氫化納，或醯胺類，例如釀 胺化納’經、鈉或鉀之雙(三甲基石夕炫基）醯胺化物或二里 丙基醯胺化鋰，對於步驟，較佳者為 二異丙基醯胺化鋰且對於步，較佳 者為碳酸铯或礙酸鉀。 步驟（Ιν-Α)+(νπ)〜（IV_B)與（ιν_Β)+(νιπ) — (ιν) (viH(m)—(I-B)是在自（^至5(rc範圍間的溫度下宜在 自〇C至25°c之溫度間進行，且宜在大氣壓下進行。 -26- 本紙張尺度適t g g家標準(CNS)A4規格公爱)-R3 * Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, where R3 * has the same meaning as R3 above but is not qi, and X is an appropriate release group, such as qi, yinbian, iodine, and mesosulfonyl. , Toluene% fluorenyl or trifluoro sulfonium sulfonyl, guan i ^ and Ma & Hao or Po, is performed in an inert solvent in the presence of hydrazone to obtain compound 15 of formula (iv_b) where A, R1, R2 And R3 * have the previously specified definitions, and later 'appropriately perform the second-stage reaction with a compound of formula (section) 20 where r4 * -x2 (VIII) R4 · has the same meaning as R4 but not hydrogen And X2 is an appropriate releasing group, such as gas, bromine, ethene, methylsulfonyl, sulfofluorenyl or trifluorotoluenylsulfonyl, preferably bromine or iodine, toluene-25. This paper size applies to Chinese national standards (CNS) A4 size (210x297 mm) A7 B7 24 15 Duty printing of employee cooperation of Intellectual Property Bureau of the Ministry of Economic Affairs 20 25. Description of invention (Under inertia in the presence of inspection, __ proceed. For steps (iv-a ) + (Viibu (IV is called (ιν--vnmV)) so that the refrigerant is' for example, Lai, such as diethyl ether, methyl tert-butyl Ether, dioxane, tetrahydrofuran, glycol dimethyl ether or ethylene glycol dimethyl such as benzene 'xylene, xylene, hexane, cyclohexane or petroleum age' or other solvents such as ethyl acetate , Acetone, dimethylformamide, dimethylacetate: Dimethyl sulfoxide or acetonitrile, it is also possible to use the mentioned cold, as the solvent, preferably dimethylformamide Fermented amine, propanone, or four wind cough pain, in step CIV-A) + (VII) ~ > (IV-B), it is best to use four 10 air squeaking and in step (IVB) + (vm) In ㈣, a particularly good solvent is dimethylphosphonium. For the steps (IV-A) + (Vii)-(IV_B) and (IVB) + (vm, (IV), the test type is 'for example' metal test New earth metal hydroxides, such as 1, sodium, potassium, ma or absolute hydroxides, metal or earth metal carbon I orphan 'such as sodium, potassium, absolute or tritium carbonate, test Alcohols of metals, such as sodium or potassium methoxide, sodium or potassium ethoxide, or tertiary butanol. Metal hydrides, such as sodium hydride, or ammonium, such as sodium amide, sodium or Potassium bis (trimethyl Xixuanyl) sulfonium amidate or lithium dipropyl sulfonium amination, for the step, preferred is diisopropylfluorenated lithium and for the step, preferred is cesium carbonate or potassium acid inhibitor. Step (Ιν -Α) + (νπ) ~ (IV_B) and (ιν_Β) + (νιπ) — (ιν) (viH (m) — (IB) is at a temperature ranging from (^ to 5 (rc), preferably at The temperature should be between C and 25 ° C, and it should be carried out at atmospheric pressure. -26- The paper size is suitable for tgg home standard (CNS) A4 specifications)-

200400936 A7 B7200400936 A7 B7

五、發明說明（25) 有些式(IV-Α)的化合物為文獻中已知或可藉由文獻中 的方法由適當的前驅物被合成者[對照，例如，M. Giannella et al., Farmaco Ed. Sci. 28 597-610 (1973) ； A.V. Description of the invention (25) Some compounds of formula (IV-A) are known in the literature or can be synthesized from appropriate precursors by methods in the literature [control, for example, M. Giannella et al., Farmaco Ed. Sci. 28 597-610 (1973); A.

Herrera，H. Hoberg，5>价細/5, 831-833 (1981)]。 5 式(V)、（vn)與(vm)的化合物為可購得的、文獻中已 知的或可依類似於文獻中的方法被製備得者。Herrera, H. Hoberg, 5 > Price details / 5, 831-833 (1981)]. 5 Compounds of formulae (V), (vn) and (vm) are commercially available, known in the literature, or can be prepared in a manner similar to that in the literature.

根據本發明的式(I)化合物適於作為醫藥品的用途，供 治療及/或預防人類及/或動物的疾病。 根據本發明的化合物顯現有價值的可被預期的藥學效 10果，匕們以作為Ρ2Υ1受體拮抗劑並抑制血小板受ρ2γι 受體介導被活化而著稱。 15 經 濟 部 智 慧 財 k. 局 員 工 消 費 合 作 杜 印 製 20 根據本發明的化合物之藥學性質，有理由推斷其可被 單獨應贼個他㈣活性成分m療及/或預防血检 性插塞疾病及栓塞併發症，例如心肌梗塞、*敎的狹心 症、穩定的狹心症、瞬時的缺血侵害(TLA)、中風、周圍 動脈的閉塞性赫、血管造形術或職絲職道手 後的再阻塞與窄、深層靜脈栓塞與血栓性插塞症。 本發明也關於一種醫藥品，其係包含至少一種 發明之化合物’宜與-種或多種藥學可接受的賦型劑 劑配製形成，以及關於上述醫藥品之用途。 '栽 活性成分可能具全身的及/或局部的效果，為此可 適當的途徑投與，例如，經由口服，非經消化道，肺^ =。’舌下，舌，，直腸，皮膚，結合膜，耳或作為植 用 -27-The compound of formula (I) according to the present invention is suitable for use as a medicament for the treatment and / or prevention of diseases in humans and / or animals. The compounds according to the present invention can be expected to have expected pharmacological effects. The daggers are known as P2Ρ1 receptor antagonists and inhibit platelets from being activated by ρ2γι receptors. 15 Intellectual property of the Ministry of Economic Affairs k. Consumption cooperation by employees of the Bureau Du printed 20 According to the pharmaceutical properties of the compounds of the present invention, it is reasonable to infer that they can be treated with thirst alone active ingredients and / or prevent blood test plug disease And embolization complications, such as myocardial infarction, severe angina, stable angina, transient ischemic attack (TLA), stroke, occlusive arteries of peripheral arteries, angioplasty, or professional work Re-occlusion and narrow, deep venous embolism and thromboembolism. The present invention also relates to a medicinal product comprising at least one compound of the invention ', preferably formulated with one or more pharmaceutically acceptable excipients, and the use of the aforementioned medicinal product. 'The active ingredient may have systemic and / or local effects, for which reason it can be administered by appropriate routes, for example, orally, parenterally, lung ^ =. ’Sublingual, tongue, rectum, skin, binding membrane, ear or for implantation -27-

言卞Speech

200400936 A7 B7 五 、發明說明（ 26 活性組成分可被作成適當的投與型式供這類投與途徑 投與。供口服投與的適當投與型式為已知的可迅速或呈改 良方式遞送活性成分者，例如錠劑（未包衣或經包衣者， 例如附有腸溶的或薄膜塗覆層者），膠囊劑，糖衣疑，粒 劑’丸劑’粉劑’乳液，懸浮劑，溶液與氣霧劑等。 10 非經胃腸投與型式可為避免吸收步驟者(例如靜脈内， 動脈内，心臟内，椎管内或腰椎内）或包含吸收者（肌肉 内，皮下，皮内，經皮下或經腹膜内），適於非經消化道 投與的型式為，尤其是呈現為注射及灌流型式之溶液類， 懸浮劑類，乳液類，冷凍乾燥劑類與無菌的粉末劑類。 適於其他投與途徑的實例為供吸入的藥劑型式(尤其是 粉末吸入劑，喷霧劑）’鼻滴劑/溶液，喷劑；經舌、舌下 或頰投與之片劑或膠囊劑，栓劑，供耳或眼使用之製劑， ，道膠囊，水性懸浮劑（洗劑，搖動混合物），親月旨性懸浮 i ’油膏，乳劑’乳液，膏劑，粉塵劑或植 steius。 7 w 又 經 濟 部 智 慧 財 產 局 員 X 消 費 合 作 社 印 製 活性組成分可利用習用的方式被配製成所述的投與髮 ^ ’藉由使用惰性的、無毒性的、藥學適當的賦型劑達 如液其是載_(例如微晶纖維素）’溶劑（例 〜聚甘醇類）’孔化劑類(例如月桂酸硫酸_ 類(例如聚乙Μ魏酮），合成的與天㈣生物聚人物 (例如阿㈣膠）’安定_⑽如抗氧化義 或^類色劑類(例如無機色素，例如氧化鐵)或風修/ •28- 未紙張尺度適雨中ϋ家標準(CNS)A4 ^·(210χ297公釐y 200400936 A7 B7 五、發明說明（27) -- 通常’就非經消化道的投與量，建議為對每公斤體重 投與約0·觀至H)毫克，更佳為約〇 〇〇5至3毫克的量即 可達有效的結果，口服時的投與量為對每公斤體重投與約 0.001至100毫克，宜為約〇.〇〇5至3〇毫克之量。 5 無論如何’適當的用量可能會偏離上述的範圍，特別 是要看體重，投與途徑，個體對活性成分之個別反應，製 劑模式與投與時之時間或間隔而定，故，某種情況下，少 於上述範圍的最低劑量可能已足夠療效，但在另種情況 下，卻必須使用高於前述最高劑量之量，建議在需投與大 10量時，最好將一天的劑量分成多數個別劑量投與。 如無另外說明，下面試驗與實例中的百分比數據，是 指重量百分比；份數的重量比例，溶劑比例，稀釋比例與 液體/液體溶液之濃度數據各以體積計算。 15 [實施方式] A.生理活性的評估 1) P2Y1受想括抗物(antagonist)的細胞試驗 經濟部智慧財產局員工消費合作社印製 根據本發明的化合物作為P2Y1受體拮抗物的效果是 於1321N1-Aeq細胞（星狀細胞瘤）中進行，其不僅穩定地 20表現水母發光蛋白（作為Ca2+偵測系統，是一種與鈣結合 時會發光的蛋白），也能穩定地表現人類P2Y1受體基因作 為重组蛋白質之完全打開的讀碼(reading frame)，ADP刺 激導致P2Y1受體的活化其可再導致由細胞内的Ca2+儲存 處釋放Ca2+，釋放的Ca+與水母發光蛋白反應，可得到與 -29- 本纸張尺度適用中國國家標準(CNS)A4規格（210 X297公釐） 200400936 A7 B7 五、發明說明（28) 細胞質的Ca2+濃度成正比之可測量的光訊號。 於ADP刺激之前，細胞與試驗物質一立古 著的測量期間，P2Y1受體拮抗劑防止受體受二二 == 請光訊號，受體_興奮劑本身講發光訊 化支於添加ADP時無進-步的訊號可被測量得到， 表=興奮劑與拮抗劑無法以此測量方式區別，為區別 Ρ2Υ1觉體興奮劑與拮抗劑，在ADp刺激與光測量後，將 細胞與組織胺一起培育，組織胺活化組織胺受體，其為在 細胞内生的表現，此種活化同樣地導致從内部的儲^處釋 放Ca2+’以拮抗劑與Ρ2Υ1細胞一起培育並在其後加入 ADP下，僅在添加組織胺後始能測量得光訊號，是由於内 部的Ca2+儲存物僅能被組織胺打開，反之，若是加入 P2Y1受體興奮劑，則於添加組織胺後也不會產生訊號， 是由於儲存物在先前已被興奮的效果清空。 15 經濟部智慧財產局員工消費合作社印製 20 同樣的測量系統被用來比較其他的P2Y受體副型之 專一性，使用1321N1-Aeq細胞，其能穩定地表現人類 P2Y2或P2Y4受體基因作為重組蛋白質之完全打開的讀 碼，提供研究。 於384-槽之培養板(得自Gibco)上，帶1〇% FCS(得自 Gibco之胎牛血清)之DMEM F12培養基(得自Gibco)中， 對每槽播入1250個細胞，並與5% C02，在37。(：下培育2 天，將培養基替換成含5微克/毫升柯連特井 (coelenterazine)之 Tyrode(130 mM NaCl，5 mM KC1，20 mM HEPES，1 mM MgCl2, 5 mM NaHC03)，並與 5% C02，在 -30- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200400936 A7 B7 五、發明說明（29) ---^ 37 C下將細胞培育4天；將細胞與ρ2γι受體拮抗劑之稀 釋液(一系列稀釋液，典型為1〇-9_1〇-5 M)，KDMs〇中w Mm溶液培育，然後以3xl0·7 M ADP刺激，隨ADP之泰 加同步測量產生的光訊號、然後加入1〇〇"M之組織胺:、 5再次測量光訊號，組織胺訊號的測量指出其為拮抗劑， 冗5〇代表在最大的ADp刺激下有5〇%受到ρ2γι受體·抖 抗劑抑制的值。 ° 2)試管中之灰小板簇集： 測定血小板簇集時，所使用的血液樣品是來自健康的 10對象，其在最近的十天内未曾接受過會影響血小板蔟集之 用藥者，將血液收集至Monovettes(得自 Niimbrecht，Germany)中，其中含有肝素作為抗凝血劑，在 4°C，2,50〇rpm下離心20分鐘取得富含血小板之血漿。 進行簇集測量時，取用一定量富含血小板之血漿，與 15漸增濃度的試驗物質在沉下培育1()分鐘，職在義集 器中添加ADP (0.3-0.5微克/毫升），採用B〇rn的混濁度測 量法在37°C下測定(Bom G.V.R·，Cross M.J.，血小板的簇 經濟部智慧財產局員工消費合作社印製 集，/· PA^/从i^，178_195, 1963)，就各供應者分別測定 其導致最大簇集之ADP濃度。 20 為計算抑制的效果，是對存在或不存在試驗物質者， 經添加興奮劑5分鐘後測定其透光度的增加(簇集圖的幅 度％)，並算出其抑制作用，從抑制圖計算能抑制5〇%簇集 的濃度。 根據本發明的化合物之效果’試管中試驗的數據被舉 -31- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200400936 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（30) 例列於下面表1中： 表1從試驗1)與試驗2)得到的效果數據 實例編號 試驗1): P2Y1受體 IC5〇[/zM1 試驗2): 金小板镇集 ic5〇r//Mi la 0.03 20 實例la的非對映立體 異構物 0.03 10 2a 0.03 40 3a 0.05 20 4a 0.05 50 6a 0.06 50 7a 0.06 50 8a 0.05 30 10 0.05 60 1 la 0.2 100 13 0.05 23 14 0.1 160 18 0.1 100 22 0.08 50 23 0.06 30 29 0.1-0.3 67 32a 0.3 60 46 0.002 2 48 0.025 30 50 0.02 80 52 0.04 50 -32- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐）200400936 A7 B7 V. Description of the invention (26 The active ingredient can be made into an appropriate administration form for administration by this administration route. The appropriate administration form for oral administration is known to deliver the activity quickly or in an improved manner Ingredients, such as lozenges (uncoated or coated, such as those with an enteric or film coating), capsules, dragees, granules, 'pellets', powders, emulsions, suspensions, solutions and Aerosols, etc. 10 Parenteral administration may be for those who avoid absorption steps (eg, intravenous, intra-arterial, intracardiac, spinal canal, or lumbar) or include absorbers (intramuscular, subcutaneous, intradermal, Subcutaneous or intraperitoneal), the types suitable for parenteral administration are, in particular, solutions, suspensions, emulsions, freeze-drying agents and sterile powders that appear as injection and perfusion types. Examples of other routes of administration are formulations for inhalation (especially powder inhalants, sprays) 'nasal drops / solutions, sprays; tablets or capsules for administration by tongue, sublingual or buccal, Suppositories for ear or eye use Agents, capsules, water-based suspensions (lotions, shaking mixtures), pro-monthly suspensions i 'ointments, emulsions' emulsions, ointments, dusts or plant steius. 7 w Member of the Intellectual Property Bureau of the Ministry of Economic Affairs X Consumer Cooperative The printed active ingredients can be formulated into the dosing hair using conventional means ^ 'by using inert, non-toxic, pharmaceutically suitable excipients such as microcrystalline fiber (e.g. microcrystalline fiber Prime) 'solvents (eg ~ polyethylene glycols)' porogens (such as lauric acid sulfuric acid _ type (such as polyethylene weiwei ketone), synthetic and bio-character (such as Ejiao), and stable_ ⑽such as anti-oxidants or ^ -type toners (such as inorganic pigments, such as iron oxide) or wind repair / • 28- not paper-scale suitable for rain in the family standard (CNS) A4 ^ (210 x 297 mm y 200400936 A7 B7 five 2. Description of the invention (27)-In general, the amount of parenteral administration is recommended to be about 0.5 mg to 3 mg per kg of body weight, more preferably about 0.05 to 3 mg An effective result can be achieved. The dosage when taken orally is about 0.0 per kg of body weight. 01 to 100 mg, preferably about 0.0005 to 30 mg. 5 In any case, the appropriate amount may deviate from the above range, especially depending on body weight, route of administration, and individual response to the active ingredient. The response depends on the preparation mode and the time or interval of administration. Therefore, in some cases, the minimum dose less than the above range may be sufficient, but in other cases, it must be used higher than the aforementioned maximum dose. When it is necessary to administer a large amount, it is best to divide the daily dose into most individual doses. Unless otherwise stated, the percentage data in the tests and examples below refer to weight percentages; Solvent ratio, dilution ratio and liquid / liquid solution concentration data are calculated by volume. 15 [Embodiments] A. Evaluation of physiological activity 1) Cell test of P2Y1 receptors (antagonist) Printed by the Consumer Property Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs The effect of the compound according to the present invention as a P2Y1 receptor antagonist is 1321N1-Aeq cells (astrocytoma), which not only stably expresses aequorin (as a Ca2 + detection system, a protein that emits light when bound to calcium), but also stably expresses human P2Y1 receptors. The gene is a fully opened reading frame of the recombinant protein. ADP stimulation results in the activation of the P2Y1 receptor, which can then lead to the release of Ca2 + from the Ca2 + storage in the cell. The released Ca + reacts with the aequorin and can be obtained with- 29- This paper size applies to the Chinese National Standard (CNS) A4 (210 X297 mm) 200400936 A7 B7 V. Description of the invention (28) The measurable optical signal is proportional to the Ca2 + concentration in the cytoplasm. Before the ADP stimulation, the cell and the test substance stand in the ancient period of measurement, the P2Y1 receptor antagonist prevents the receptor from receiving two or two == light signal, the receptor _ stimulant itself emits light when the ADP is added. The further signals can be measured. Table = The stimulants and antagonists cannot be distinguished by this measurement method. In order to distinguish the P2Υ1 sensory stimulants and antagonists, the cells are incubated with histamine after ADp stimulation and light measurement. Histamine activates the histamine receptor, which is an endogenous manifestation of the cell. This activation also results in the release of Ca2 + 'from the internal storage. The antagonist is incubated with P2 细胞 1 cells and subsequently added to ADP, only The optical signal can only be measured after the addition of histamine, because the internal Ca2 + storage can only be opened by histamine. Conversely, if a P2Y1 receptor stimulant is added, no signal will be generated after the addition of histamine, because Stores have been emptied by previously excited effects. 15 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. 20 The same measurement system is used to compare the specificity of other P2Y receptor subtypes. Using 1321N1-Aeq cells, it can stably express human P2Y2 or P2Y4 receptor genes as Fully opened reading frame of recombinant protein for research. On a 384-well culture plate (obtained from Gibco) in DMEM F12 medium (obtained from Gibco) with 10% FCS (Fetal Bovine Serum from Gibco), 1250 cells were seeded into each well, and were mixed with 5% C02 at 37. (: Incubate for 2 days, replace the medium with Tyrode (130 mM NaCl, 5 mM KC1, 20 mM HEPES, 1 mM MgCl2, 5 mM NaHC03) containing 5 μg / ml coelenterazine, and mix with 5 % C02, at -30- This paper size applies the Chinese National Standard (CNS) A4 specification (210x297 mm) 200400936 A7 B7 V. Description of the invention (29) --- ^ 37 C Cultivate the cells for 4 days; Diluents of ρ2γι receptor antagonists (a series of dilutions, typically 1-10-9_1-5 M), incubated with w Mm solution in KDMs〇, and then stimulated with 3x10 · 7 M ADP, measured simultaneously with ADP Tega The generated light signal was then added to 100 " M's histamine:, 5, and the light signal was measured again. The measurement of the histamine signal indicated that it was an antagonist. Redundant 50 represents 50% of the maximum ADp stimulation. ρ2γι receptor and shake inhibitor inhibitor value. ° 2) Gray plate clustering in test tubes: When measuring platelet clustering, the blood samples used were from 10 healthy subjects, which had not been received in the last ten days. Those who can affect platelet aggregation, collect blood to Monovettes (available from Niimbrecht, Ger Many) contain heparin as an anticoagulant, and centrifuge at 20 ° C, 2,50 rpm for 20 minutes to obtain platelet-rich plasma. When performing cluster measurement, take a certain amount of platelet-rich plasma and incubate with 15 increasing concentrations of test substance for 1 () minutes, and add ADP (0.3-0.5 μg / ml) in the sense collector. Measured at 37 ° C using Born's turbidity measurement method (Bom GVR ·, Cross MJ, Platelet Cluster, Printed Collection of Employees' Cooperatives of the Intellectual Property Bureau of the Ministry of Economics, PA ^ / from i ^, 178_195, 1963 ), The ADP concentration that caused the largest clustering was measured for each supplier. 20 In order to calculate the effect of inhibition, for the presence or absence of a test substance, the increase in light transmittance (the width of the cluster map%) is measured after adding a stimulant for 5 minutes, and the inhibition effect is calculated. Can inhibit the concentration of 50% clusters. The effect of the compound according to the present invention 'test data in test tubes is cited -31- This paper size applies Chinese National Standard (CNS) A4 specification (210x297 mm) 200400936 Printed by the Consumers ’Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs A7 B7 5. Description of the invention (30) Examples are listed in Table 1 below: Table 1 Effect data obtained from experiments 1) and 2) Example number Experiment 1): P2Y1 receptor IC50 [/ zM1 Experiment 2): Jin Xiaoban Town Set ic50〇 // Mi la 0.03 20 Diastereomers of Example la 0.03 10 2a 0.03 40 3a 0.05 20 4a 0.05 50 6a 0.06 50 7a 0.06 50 8a 0.05 30 10 0.05 60 1 la 0.2 100 13 0.05 23 14 0.1 160 18 0.1 100 22 0.08 50 23 0.06 30 29 0.1-0.3 67 32a 0.3 60 46 0.002 2 48 0.025 30 50 0.02 80 52 0.04 50 -32- This paper size applies to China National Standard (CNS) A4 (210x297 mm) )

200400936 A7 B7 五、發明說明（31) 實例編號 試驗1): P2Y1受體 ic50["m] 試驗2): 血小板鎮集 IC50 r a Ml 55 0.01 56 0.02 57 0.02 60 0.005 63 0.015 15 65 0.05 50 67 0.03 60 3) 體内之抗血栓的效果： 經濟部智慧財產局員工消費合作社印製 化合物的抗血栓效果是於被麻醉的小鼠之血栓性插塞 5 模式下測定[L· Beviglia，Thrombosis Research 71. 301-315 (1993) C.M, Teng, European Journal of Pharmacology 320, 161-166 (1997) ； C. Leon, Circulation 103. 718-723 (2001)] ’為進行測定，將試驗物質或適當的載劑投與體重 介於18與20克間的小鼠(HSD WIN NMRI)，然後投與膠 10 原的混合物(得自Nycomed，Munich之Horn膠原試劑）與 ADP(得自 Sigma-Aldrich, Deisenhofen)，誘發jk栓性插塞 並導致小鼠的死亡，在各實驗中，測定出會造成未經治療 之小鼠達80%至100%死亡之膠原劑量，溶液（125-300微 克/公斤膠原與1〇〇微克/公斤ADP)是經由動物的尾靜脈注 15 入，觀察動物直至死亡，最長1小時。 -33- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200400936 A7 B7 五、發明說明（32) B.合成實例 經濟部智慧財產局員工消費合作社印製 縮寫字含義： C 濃度 CH 環己烷 5 DCI 直接化學離子化(在MS中） DCM 二氣甲烷 DEA 二乙基胺 DMSO 二甲亞艰 EA 乙酸乙酯 10 EI 電子衝擊離子化(在MS中） ESI 電灑離子化(在MS中） HPLC 高壓，高效能液相層析 cone. 濃縮的 LC/MS 液相層析-偶合的質諸 15 Ref 參考 MS 質譜 NMR 核磁共振光譜 PE 石油醚 Rf 滯留係數(TLC中） 20 RP 反相(HPLC中） RT 室溫 Rt 滯留時間(HPLC中） THF 四氫呋喃 TLC 薄層層析 -34- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200400936 A7 B7 五、發明說明（33 ) HPLC 方 儀器：HP 1100 附 DAD ;柱層：Kromasil RP-18, 60mm X 2 mm，3.5微米；流洗液：A= 5毫升HC104/升 5 H20, B=乙腈；梯度：〇分鐘2% B，0.5分鐘2% B，4.5分 鐘90% B，6.5分鐘90% B ;流速：0_75毫升/分鐘；溫 度·· 30°C ;偵測：UV 210 nm。 HPLC方法2: 10 Daicel Chiralcel OD，10 微米，250 X 4.6 mm ;流速： 1毫升/分鐘；異己烷/異丙醇575:25。 LC/MS 方法 1 : MS 裝置類型：Micromass Platform LCZ 15 離子化：ESI+ HPLC裝置類型 HP 1100 經濟部智慧財產局員工消費合作社印製 柱層: 20 梯度: UV偵測器DAD : 208-400奈米 烘箱溫度：40°C 不對稱的C 18 50 mm X 2.1 mm，3.5 微米 時間(分鐘）A··% B:%流速(毫升/分鐘） 0.00 10.0 90.0 0.50 4.00 90.0 10.0 0.50 6.00 90.0 10.0 0.50 -35- 本紙張尺度適用中國國冢標準(CNS)A4規格（210x297公釐3 200400936 A7 B7 五、發明說明（34 ) 6.10 10.0 90.0 1.00 7.50 10.0 90.0 0.50 A: 乙腈+0.1%甲酸 B: 水+0.1 %曱酸 5 LC/MS 方法 4: MS裝置類型：Micromass ZQ ; HPLC裝置類型： Waters Alliance 2790 ;柱層：Uptisphere C 18, 50 mm X 2.0 mm, 3微米；流洗液B :乙腈+0.05%甲酸，流洗液A :水 10 +0.05%甲酸；梯度：〇·〇 分鐘 5% B—2.0 分鐘 40% B—4.5 分鐘90% B—5.5分鐘90% B ;烘箱溫度：45°C ;流速： 0.0分鐘0.75毫升/分鐘—4.5分鐘0.75毫升/分鐘—5.5分 鐘1.25毫升/分鐘；UV-偵測：210nm。 15 LC/MS 方法 5 ： 經濟部智慧財產局員工消費合作社印製 MS裝置類型：Micromass ZQ ; HPLC裝置類型： Waters Alliance 2790 ;柱層：Grom-Sil 120 ODS-4 HE，50 mm x 2 mm，3微米；流洗液B :乙腈+0.05%甲酸，流洗液 A :水+0.05%甲酸；梯度：0·0分鐘5% B—2.0分鐘40% B 20 —4.5分鐘90% B->5.5分鐘90% B ;烘箱溫度：45°C ;流 速：0.0分鐘0.75毫升/分鐘->4.5分鐘0.75毫升/分鐘— 5.5分鐘1.25毫升/分鐘.；UV-偵測：210nm。 LC/MS 方法 6 ： -36- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200400936 A7 B7 五、發明說明（35 ) 儀器：Micromass Quattro LCZ，附 HPLC Agilent series 1100 ;柱層：Grom-SIL120 ODS-4 HE, 50 mm x 2.0 mm，3 微米；流洗液A : 1升水+1毫升的50%甲酸，流洗液B : 1 升乙腈+1毫升的50%甲酸；梯度：〇.〇分鐘100°/。A—0.2 5 分鐘 100% Α·^2.9 分鐘 30% A—3.1 分鐘 10% A—4.5 分鐘 10% A ;烘箱溫度：55°C ;流速·· 0.8毫升/分鐘；UV-偵 測：208-400 nm。 LC/MS 方法 7 ： 10 儀器：Micromass Platform LCZ，附 HPLC Agilent series 1100 ;柱層：Grom-SIL120 ODS-4 HE，50 mm x 2.0 mm，3微米；流洗液A : 1升水+1毫升的50%甲酸，流洗 液B : 1升乙腈+1毫升的50%甲酸；梯度：0.0分鐘100% Α—·0.2 分鐘 100% A~^2.9 分鐘 30% A-^3.1 分鐘 10% A—> 15 4.5分鐘10% A ;烘箱溫度：55°C ;流速：0.8毫升/分 鐘；UV-偵測：208-400 nm。 LC/MS 方法 8 : 經濟部智慧財產局員工消費合作社印製 MS 裝置類型：Micromass Platform LCZ，HPLC1100 ; 20 柱層：Symmetry C18，50 mm x 2.1 mm，3.5 微米；流洗液 A :乙腈+〇.1〇/0甲酸，流洗液B :水+0.1%甲酸；梯度：0.0 分鐘10% A—4.0分鐘90% A—6.0分鐘90% A ;烘箱溫度： 40°C ;流速：0.5 毫升/分鐘；UV-偵測：208-400 nm。 -37- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200400936 A7 B7 五、發明說明（36) LC/MS 方法 Q : C 夕胺 II ’ 5 微米，250 mm x 4.0 mm + Daicel200400936 A7 B7 V. Description of the invention (31) Example number Test 1): P2Y1 receptor ic50 [" m] Test 2): Platelet ballast IC50 ra Ml 55 0.01 56 0.02 57 0.02 60 0.005 63 0.015 15 65 0.05 50 67 0.03 60 3) Antithrombotic effect in vivo: The antithrombotic effect of compounds printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs was measured under the mode of thrombus plugs in anesthetized mice [L · Beviglia, Thrombosis Research 71. 301-315 (1993) CM, Teng, European Journal of Pharmacology 320, 161-166 (1997); C. Leon, Circulation 103. 718-723 (2001)] 'To perform the measurement, the test substance or appropriate The vehicle was administered to mice weighing between 18 and 20 grams (HSD WIN NMRI), and then a mixture of gum 10 (Horn collagen reagent from Nycomed, Munich) and ADP (from Sigma-Aldrich, Deisenhofen) ), Induced jk plugs and caused mouse death. In each experiment, the collagen dose that caused 80% to 100% death of untreated mice was determined. The solution (125-300 μg / kg collagen With 100 μg / kg ADP) The tail vein was injected 15 times and the animals were observed until death, up to 1 hour. -33- This paper size applies Chinese National Standard (CNS) A4 specification (210x297 mm) 200400936 A7 B7 V. Description of invention (32) B. Synthetic example Printed abbreviations of employees ’cooperatives of the Intellectual Property Bureau of the Ministry of Economy Meaning: C Concentration CH Cyclohexane 5 DCI Direct chemical ionization (in MS) DCM Digas methane DEA Diethylamine DMSO Dimethanine EA Ethyl acetate 10 EI Electron impact ionization (in MS) ESI ionization ionization ( In MS) HPLC high pressure, high performance liquid chromatography cone. Concentrated LC / MS liquid chromatography-coupled masses 15 Ref Reference MS Mass NMR Nuclear magnetic resonance spectrum PE Petroleum ether Rf Retention coefficient (in TLC) 20 RP Reverse phase (in HPLC) RT room temperature Rt retention time (in HPLC) THF tetrahydrofuran TLC thin layer chromatography-34- This paper size applies Chinese National Standard (CNS) A4 (210 X 297 mm) 200400936 A7 B7 V. Description of the invention (33) HPLC square instrument: HP 1100 with DAD; column layer: Kromasil RP-18, 60mm X 2 mm, 3.5 microns; flow washing solution: A = 5 ml HC104 / liter 5 H20, B = acetonitrile; gradient: 〇Min 2% B, 0.5 minutes Clock 2% B, 4.5 minutes 90% B, 6.5 minutes 90% B; flow rate: 0_75 ml / min; temperature · 30 ° C; detection: UV 210 nm. HPLC method 2: 10 Daicel Chiralcel OD, 10 microns, 250 X 4.6 mm; flow rate: 1 ml / min; isohexane / isopropanol 575: 25. LC / MS Method 1: MS Device Type: Micromass Platform LCZ 15 Ionization: ESI + HPLC Device Type HP 1100 Intellectual Property Bureau, Ministry of Economic Affairs, Employee Consumption Cooperative, Printed Column Layer: 20 Gradient: UV Detector DAD: 208-400 nm Oven temperature: 40 ° C Asymmetric C 18 50 mm X 2.1 mm, 3.5 micron time (minutes) A ·% B:% flow rate (ml / minute) 0.00 10.0 90.0 0.50 4.00 90.0 10.0 0.50 6.00 90.0 10.0 0.50 -35 -This paper size is applicable to China National Tomb Standard (CNS) A4 (210x297 mm 3 200400936 A7 B7 V. Description of the invention (34) 6.10 10.0 90.0 1.00 7.50 10.0 90.0 0.50 A: Acetonitrile + 0.1% Formic acid B: Water + 0.1% Osmic acid 5 LC / MS method 4: MS device type: Micromass ZQ; HPLC device type: Waters Alliance 2790; column layer: Uptisphere C 18, 50 mm X 2.0 mm, 3 microns; flow wash solution B: acetonitrile + 0.05% formic acid Flow washing solution A: water 10 + 0.05% formic acid; gradient: 〇minutes 5% B—2.0 minutes 40% B—4.5 minutes 90% B—5.5 minutes 90% B; oven temperature: 45 ° C; flow rate: 0.0 minutes 0.75 ml / minute—4.5 minutes 0.75 ml / minute—5.5 minutes 1.25 ml / minute; UV-detection Measurement: 210nm. 15 LC / MS Method 5: Printed MS device type: Micromass ZQ; HPLC device type: Waters Alliance 2790; Column layer: Grom-Sil 120 ODS-4 HE, 50 mm x 2 mm, 3 microns; flow wash solution B: acetonitrile + 0.05% formic acid, flow wash solution A: water + 0.05% formic acid; gradient: 0 · 0 minutes 5% B—2.0 minutes 40% B 20—4.5 minutes 90% B- > 5.5% 90% B; Oven temperature: 45 ° C; Flow rate: 0.0min 0.75ml / min- > 4.5min 0.75ml / min-5.5min 1.25ml / min .; UV-detection: 210nm. LC / MS Method 6: -36- This paper size applies to Chinese National Standard (CNS) A4 (210x297 mm) 200400936 A7 B7 V. Description of Invention (35) Instrument: Micromass Quattro LCZ with HPLC Agilent series 1100; column layer : Grom-SIL120 ODS-4 HE, 50 mm x 2.0 mm, 3 microns; Flow Wash A: 1 liter of water + 1 ml of 50% formic acid, Flow Wash B: 1 liter of acetonitrile + 1 ml of 50% formic acid; Gradient : 1.00 minute 100 ° /. A—0.2 5 minutes 100% A · ^ 2.9 minutes 30% A—3.1 minutes 10% A—4.5 minutes 10% A; Oven temperature: 55 ° C; Flow rate · 0.8 ml / min; UV-detection: 208- 400 nm. LC / MS Method 7: 10 Apparatus: Micromass Platform LCZ with HPLC Agilent series 1100; Column layer: Grom-SIL120 ODS-4 HE, 50 mm x 2.0 mm, 3 microns; Flow Wash A: 1 liter of water + 1 ml of 50% formic acid, flow washing solution B: 1 liter of acetonitrile + 1 ml of 50% formic acid; gradient: 0.0% 100% Α— · 0.2 minutes 100% A ~ ^ 2.9 minutes 30% A- ^ 3.1 minutes 10% A— & gt 15 4.5 minutes 10% A; oven temperature: 55 ° C; flow rate: 0.8 ml / min; UV-detection: 208-400 nm. LC / MS method 8: MS printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economics Device type: Micromass Platform LCZ, HPLC1100; 20 column layer: Symmetry C18, 50 mm x 2.1 mm, 3.5 microns; Flow wash solution A: Acetonitrile + 〇 .10 / 0 formic acid, flow wash solution B: water + 0.1% formic acid; gradient: 0.0% 10% A—4.0 minutes 90% A—6.0 minutes 90% A; oven temperature: 40 ° C; flow rate: 0.5 ml / Minutes; UV-detection: 208-400 nm. -37- This paper size is in accordance with Chinese National Standard (CNS) A4 (210x297 mm) 200400936 A7 B7 V. Description of the invention (36) LC / MS method Q: C amine II '5 micron, 250 mm x 4.0 mm + Daicel

Chiralcel 〇D^ 微未，250 mm x 4.6 mm ;流速：1宅升/ 分鐘’異己烧/乙醇+1%水。 5 起始化合物： 實 MJ. 1-(4-氟笨基)-2-丁 _ (參考：M_ Adsawa et al，7 你⑽切」"7，钇 μ27 29) 10Chiralcel 〇D ^ Weiwei, 250 mm x 4.6 mm; Flow rate: 1 liter / min. Isotoxime / ethanol + 1% water. 5 Starting compounds: MJ. 1- (4-fluorobenzyl) -2-butyrate (Reference: M_ Adsawa et al, 7 Ni ⑽Chang "" 7, Yttrium μ27 29) 10

經濟部智慧財產局員工消費合作社印製 將1.5克(8.7毫莫耳）的4_氟苯基乙醯基氯溶解在3毫 15升-氣曱烧所成之溶液，於_7(rc下，滴入懸浮於7毫升二 氣甲烧的1.16克(8·7毫莫耳)的三氯化銘懸浮液中將此 混合物擾拌1小時，其間，溫度上升至l〇°C，然後將此黃 色懸浮液冷卻至-3(rc，再以3〇分鐘期間滴入溶解於己烧 的15/。強度之4.29克(5.2毫莫耳)的二乙基鋅之溶液，在 20室温下將混合物授拌7小時並使之靜置過夜，將反應懸浮 液再冷卻至0°C，擾拌下小心地加入5毫升的水，分出有 機層，以乙酸乙酯萃取水溶液層三遍，併合的有機層以 5/〇碳酸氫鈉溶液與水各洗滌一次，經硫酸鈉乾燥後，濃縮 付帶與色的油質物，粗製品不需再精製可供下一步反應。 -38- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200400936 A7 B7 五、發明說明（37) 收量：1.36克(理論值之80%) LC-MS (方法 3) : Rt=4.2 分鐘 MS (ESI+) ： m/z=167 (M+H)+Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, 1.5 g (8.7 mmol) of 4-fluorophenylethylfluorenyl chloride was dissolved in 3 mmol 15 liters of gas-fired solution at _7 (rc , Dropwise into a suspension of 1.16 g (8.7 millimoles) of trichloromethane suspended in 7 ml of dichloromethane, stir this mixture for 1 hour, during which the temperature rose to 10 ° C, and then The yellow suspension was cooled to -3 ° C, and a solution of 15/20 strength diethyl zinc dissolved in hexane was added dropwise over a period of 30 minutes. The mixture was allowed to stir for 7 hours and allowed to stand overnight. The reaction suspension was cooled again to 0 ° C. 5 ml of water was carefully added under stirring, the organic layer was separated, and the aqueous layer was extracted three times with ethyl acetate and combined. The organic layer was washed once with 5/0 sodium bicarbonate solution and water, dried with sodium sulfate, and concentrated with oily matter with color, the crude product does not need to be refined for the next reaction. -38- This paper size Applicable to China National Standard (CNS) A4 specification (210x297 mm) 200400936 A7 B7 V. Description of invention (37) Yield: 1.36 g (80 of theoretical value) %) LC-MS (Method 3): Rt = 4.2 minutes MS (ESI +): m / z = 167 (M + H) +

5 實例II 1-(4-氯苯基)-2-戊酮 (參考：T.C· Myers et al·，/· Z/Z7. 分口. 1955，77, 5655) •i ά 階段a): 10 1-(4-氯苯基)-2-硝基戊烯5 Example II 1- (4-Chlorophenyl) -2-pentanone (Reference: TC · Myers et al ·, / · Z / Z7. Parting. 1955, 77, 5655) • i a Phase a): 10 1- (4-chlorophenyl) -2-nitropentene

計 15 將0.87克（14.5毫莫耳）的乙二胺，於100。(：下，滴入 由17_5克(170毫莫耳）的1-硝基丁烷與11.95克(85毫莫耳） 的4-氣苯甲醛所成混合物中，於此溫度下攪拌過夜，冷卻 後將其置於水與二氣曱烷中分配，水溶液層經二氯甲烷萃 取三遍，併合的有機層以飽和的氣化鈉溶液洗滌，經硫酸 20 鈉乾燥後濃縮之，殘留物置於矽膠60上層析，以環己烷/ 乙酸乙酯20 : 1溶離。 收量：1〇·5克(理論值之49%)之黃色油質物 1H-NMR(200 MHz, DMSO-d6) ： <5=0.95 (t, 3H) ； 1.6 (m, 2H) ； 2.75 (t, 2H) ； 7.6 (s, 5H) ； 8.1 (s, 1H). -39- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 線 經濟部智慧財產局員工消費合作社印製 200400936 A7 B7 發明說明（3〇 階韻1 b): U(4-氣苯基)-2-戊酮 5Total 15 add 0.87 g (14.5 mmol) of ethylenediamine to 100. (: Next, drip into a mixture of 17_5 grams (170 millimoles) of 1-nitrobutane and 11.95 grams (85 millimoles) of 4-air benzaldehyde, stir at this temperature overnight, and cool It was then partitioned into water and dioxane, and the aqueous layer was extracted three times with dichloromethane. The combined organic layer was washed with a saturated sodium gas solution, dried over sodium sulfate 20, and concentrated. The residue was placed in silica gel. Chromatographed on 60 and dissolved with cyclohexane / ethyl acetate 20: 1. Yield: 10.5 g (49% of theory) of a yellow oily substance 1H-NMR (200 MHz, DMSO-d6): < 5 = 0.95 (t, 3H); 1.6 (m, 2H); 2.75 (t, 2H); 7.6 (s, 5H); 8.1 (s, 1H). -39- This paper size applies the Chinese National Standard (CNS ) A4 size (210x297 mm) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 200400936 A7 B7 Invention description (30 ° rhyme 1 b): U (4-Gaphenyl) -2-pentanone 5

ο 1ο 1

5 1A 經濟部智慧財產局員工消費合作社印製 將10.5克(41.5毫莫耳）的實例π，階段a)之化合物溶 解至100毫升的冰酯酸，以4.4克的10%鈀/碳在大氣壓下 進行氫化24小時’經由Celite 545將催化劑濾除後，將滤 液濃縮，殘留物被檀入由1〇〇毫升丙酮、3〇毫升之25°/〇鹽 酸與50毫升水所成混合液中過夜，在真空中汽提除去丙 _，再加入水，經乙酸乙酯萃取三次後，併合的有機層以 飽和的氣化鈉溶液洗滌，經硫酸鈉乾燥後濃縮之，殘留物 置於石夕膠60上層析’以環己烧/乙酸乙酯20:1洛離。 收量：5.27克(理論值之65❶/〇)之無色油質物 'H-NMR(200 MHz, CDC13) ： (5 =0.85 (t, 3H) ； 1.6 2H^ ； 2.45 (t, 2H) ； 3.7 (s, 2H) ； 7.1-7.4 (m, 4H). 下面的起始化合物III-IX為依照類似方法被製備： 20 -40- 本紙張尺度適用申國國家標準(CNS)A4規格（210x297公釐） 200400936 A7 B7 五、發明說明（39) 經濟部智慧財產局員工消費合作社印製 實例編號 結構 收量 (理論值之％) MS (ESI+):, m/z (M+H)+ i ΠΙ C,xxc： 39 MS (El): 182 (NT) IV 70 227 V (prrcH3 ch3 85 163 VI 9h3 47 163 ΥΠ pTTCH3 F 69 MS (El): 166 (NT) vm drr⑶3 83 167 ΓΧ Fj〇T^3 79 MS (El): 180 (M+) -41- 訇- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200400936 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（40 )5 1A Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, dissolving 10.5 g (41.5 mmol) of the compound of Example π, stage a) into 100 ml of glacial acid, and 4.4 g of 10% palladium / carbon at atmospheric pressure Hydrogenation was carried out for 24 hours. After the catalyst was filtered off through Celite 545, the filtrate was concentrated, and the residue was poured into a mixed solution of 100 ml of acetone, 30 ml of 25 ° / 0 hydrochloric acid and 50 ml of water overnight. The acetone was stripped in a vacuum, water was added, and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed with a saturated sodium gas solution, dried over sodium sulfate, and concentrated. The residue was placed in Shixijiao 60 Chromatography was performed on cyclohexane / ethyl acetate 20: 1. Yield: 5.27 g (theoretical value 65❶ / 〇) of a colorless oily substance 'H-NMR (200 MHz, CDC13): (5 = 0.85 (t, 3H); 1.6 2H ^; 2.45 (t, 2H); 3.7 (s, 2H); 7.1-7.4 (m, 4H). The following starting compounds III-IX were prepared according to a similar method: 20 -40- This paper size applies the national standard of China (CNS) A4 (210x297) (%) 200400936 A7 B7 V. Description of the invention (39) Number of printed cases of the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, the structure of the case number (theoretical value) MS (ESI +) :, m / z (M + H) + i C, xxc: 39 MS (El): 182 (NT) IV 70 227 V (prrcH3 ch3 85 163 VI 9h3 47 163 pΠ pTTCH3 F 69 MS (El): 166 (NT) vm drr⑶3 83 167 Γχ Fj〇T ^ 3 79 MS (El): 180 (M +) -41- 訇-This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200400936 Printed by the Consumers ’Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention ( 40)

實例X 2,2-.一甲基-4,5-二苯基-4-¾ 戊稀-1,3-二嗣Example X 2,2-.monomethyl-4,5-diphenyl-4-¾pentane-1,3-difluorene

將10_5克(32.2毫莫耳)的碳酸鉋與10.0毫升(22.9克， 10 161毫莫耳）的碘甲烷，在室溫下，加至溶解在100毫升 二甲基甲醯胺的4.00克（16.1毫莫耳）的4,5-二苯基-4-環戊烯-1,3-二酮溶液中，2小時後，在真空下除去大部分 的溶劑，殘留物置入50毫升的乙酸乙酯與50毫升的水 中，分出有機層，經硫酸鈉乾燥，在真空中除去溶劑，經 15 柱層層析(矽膠，溶離液：環己烷/乙酸乙酯10:1至5:1)， 製得帶黃色的固體。 收量：4.08克(理論值之92%) !Η-ΝΜΚ(200 MHz, CDC13)： δ =1.35 (s, 6Η) ； 7.30-7.45 (m, 10H). 2010_5 g (32.2 mmol) of carbonate shavings and 10.0 ml (22.9 g, 10 161 mmol) of methyl iodide were added at room temperature to 4.00 g (100 ml of dimethylformamide) 16.1 mmol) of 4,5-diphenyl-4-cyclopentene-1,3-dione solution. After 2 hours, most of the solvent was removed under vacuum, and the residue was placed in 50 ml of ethyl acetate. The organic layer was separated from the ester and 50 ml of water, dried over sodium sulfate, the solvent was removed in vacuo, and subjected to 15 column chromatography (silica gel, eluent: cyclohexane / ethyl acetate 10: 1 to 5: 1) , A yellowish solid was obtained. Yield: 4.08 g (92% of theory)! Η-NMK (200 MHz, CDC13): δ = 1.35 (s, 6Η); 7.30-7.45 (m, 10H). 20

實例XI 5,6-二苯基螺[2.4]庚-5-烯-4,7-二酮 -42- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐）Example XI 5,6-Diphenylspiro [2.4] hept-5-ene-4,7-dione -42- This paper size applies to China National Standard (CNS) A4 (210x297 mm)

200400936 A7 B7 五、發明說明（41)200400936 A7 B7 V. Description of Invention (41)

經濟部智慧財產局員工消費合作社印製 5 在室溫下，將0·223克（1.61毫莫耳）的碳酸鉀與〇.〇833 毫升(0.182克，0.967毫莫耳）的i，2-二溴曱烷，加至溶解在 4毫升Λζ#-二甲基甲醯胺的200毫克(0.806毫莫耳)的4,5-二苯基_4_環戊烯-1，3-二酮溶液中，5小時後，在真空下除 去大部分的溶劑，殘留物經製備性HPLC純化(RPC-18相， 10 30 X 250 mm ;溶離液：水/乙腈90:10—1〇:90)，可得無色 的固體。 收量：136毫克(理論值之62%) LC-MS (方法 3) : Rt=4.7 分鐘 MS (ESI+) ： m/z=275 (M+H)+ 15 ^-NMR (200 MHz, CDC13): <5 =1.70 (s, 4H) ； 7.30-7.45 (m, 10H). 下面化合物係依照類似於實例XI之方法製備： 實例編號 結構 收量 MS XII Ο ° 43% MS[DCI(NH3)]: m/z=306(M+NH4)+ -43- 本紙張尺度適用t®國家榡準(CNS)A4規格（210x297公釐） 200400936 Α7 _____Β7 五、發明說明（42 ) 經濟部智慧財產局員工消費合作社印製 15Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 5 At room temperature, 0.223 g (1.61 mmol) of potassium carbonate and 0.0833 ml (0.182 g, 0.967 mmol) of i, 2- Dibromomethane, added to 200 mg (0.806 mmol) of 4,5-diphenyl-4-cyclopentene-1,3-dione dissolved in 4 ml of Λζ # -dimethylformamide After 5 hours in the solution, most of the solvent was removed under vacuum and the residue was purified by preparative HPLC (RPC-18 phase, 10 30 X 250 mm; eluent: water / acetonitrile 90: 10-10: 90) , You can get colorless solid. Yield: 136 mg (62% of theory) LC-MS (Method 3): Rt = 4.7 minutes MS (ESI +): m / z = 275 (M + H) + 15 ^ -NMR (200 MHz, CDC13) : < 5 = 1.70 (s, 4H); 7.30-7.45 (m, 10H). The following compounds were prepared in a similar manner to Example XI: Example Number Structure Yield MS XII 〇 ° 43% MS [DCI (NH3) ]: m / z = 306 (M + NH4) + -43- This paper size is applicable to t® National Standard (CNS) A4 (210x297 mm) 200400936 Α7 _____ Β7 V. Description of Invention (42) Intellectual Property Bureau, Ministry of Economic Affairs Printed by Employee Consumer Cooperatives 15

實例XIV 2-曱基-4,5-二苯基-4-環戊稀-1，3-二酮 (參考：A. Herrera，H· Hoberg，幼仿/s· 1981，831-833)Example XIV 2-fluorenyl-4,5-diphenyl-4-cyclopentane-1,3-dione (Reference: A. Herrera, H. Hoberg, imitation / s · 1981, 831-833)

CH„ 將22.0毫升(44.3毫莫耳)的二丙基醯胺鋰(2.0 Μ,於庚 烷/THF/乙基苯）’在〇。(：下，被加至溶解於250毫升THF 之10.0克(40.3毫莫耳)的4,5-二苯基_4-環庚烯-1，3-二酮溶 液中，30分鐘後’加入2.76毫升(4.75克，44.3毫莫耳）的 甲基碘’於0°C下攪拌1小時並於20。(：下攪拌1小時，混 合入約200毫升的乙酸乙酯與約200毫升的水並以ιΝ鹽 酸將pH調整至6，分出有機層，經硫酸鈉乾燥並於真空下 濃縮，經柱層層析（矽膠，溶離液：環己烷/乙酸乙酯5〇:1 — 10:1)，製得下列流洗液之序列： 溶離份1 : 2,2-二甲基-4,5-二苯基-4-環戊烯-l，3-二酮（見實 -44- 本紙張尺度適用中國國家標準(CNS)A4梘格i X穴7厶铉ΊCH „22.0 ml (44.3 millimoles) of lithium dipropylamidamine (2.0 M in heptane / THF / ethylbenzene) were added at 0. (:, was added to 10.0 dissolved in 250 ml of THF G (40.3 mmol) of 4,5-diphenyl_4-cycloheptene-1,3-dione solution, after 30 minutes' 2.76 ml (4.75 g, 44.3 mmol) of methyl Iodine 'was stirred at 0 ° C for 1 hour and at 20. (: stirred for 1 hour, mixed with about 200 ml of ethyl acetate and about 200 ml of water and adjusted the pH to 6 with 1N hydrochloric acid, and separated the organic layer , Dried over sodium sulfate and concentrated under vacuum, and subjected to column chromatography (silica gel, eluent: cyclohexane / ethyl acetate 50: 1-10: 1), the following sequence of eluent was prepared: 1: 2,2-Dimethyl-4,5-diphenyl-4-cyclopentene-l, 3-dione (see real-44-) This paper size applies to China National Standard (CNS) A4 枧 格 i X hole 7 厶 铉 Ί

200400936 B7 A7200400936 B7 A7

例X) 收量：2.57克(理論值之μ%) 溶離份2 : 2-甲基-4,5-二苯基_4_環戊烯_1，3_二_ 收量：2.23克(理論值之21%) 5 lH_NMR(200 MHz, CDC13) : 5=1.35 (s 6H); 7·30-7·45 (m，l〇fj)· 溶離份3 : 4,5-二苯基-4-環戊烯_i，3_二酮(起始材料） 收量：2.49克(理論值之25%) 10實例货 2-烯芮基-2-曱基-4,5-二苯基-4-環戊烯-1，3-二酿jExample X) Yield: 2.57 g (μ% of theory) Dissolved fraction 2: 2-methyl-4,5-diphenyl_4_cyclopentene_1,3_di_ Yield: 2.23 g ( 21% of theory) 5 lH-NMR (200 MHz, CDC13): 5 = 1.35 (s 6H); 7.30-7 · 45 (m, 10fj) · Dissociation fraction 3: 4,5-diphenyl- 4-cyclopentene_i, 3_dione (starting material) Yield: 2.49 g (25% of theory) 10 Examples of goods 2-enyl-2-fluorenyl-4,5-diphenyl -4-cyclopentene-1,3-secondary

經濟部智慧財產局員工消費合作社印製 將0.373克(1.14毫莫耳)的碳酸鉋與0 523毫升(〇961 克，5.72毫莫耳）的3-碘-1-丙烯，在室溫下〇°c下，被加至 2〇溶解於8宅升—甲基甲酿胺的150毫克(0.582毫莫耳) 的實例XIV的產物(溶離份2)溶液中，1小時後，在真空 下除去大部分的溶劑，殘留物經製備性HPLC純化(Rp 18 相，30 X 250 mm，溶離液：水/乙腈 9〇:l〇—1〇:9〇)，可 得無色油質物。 -45-The Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs printed 0.373 g (1.14 mmol) of carbonic acid planer with 0 523 ml (〇961 g, 5.72 mmol) of 3-iodo-1-propene at room temperature. To a solution of 150 mg (0.582 mmol) of Example XIV dissolved in 8 liters of methylmethylamine at 20 ° C was added to a solution of ° C, and after 1 hour, it was removed under vacuum. Most of the solvents and residues were purified by preparative HPLC (Rp 18 phase, 30 X 250 mm, eluent: water / acetonitrile 90: 10-10: 90), and a colorless oily substance was obtained. -45-

200400936 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（44 ) 收量：1M毫克(理論值之74%) MS[DCI (NH3)] ： m/z=320 (M+NH4)+ !H-NMR (200 MHz, CDC13): (5 =1.30 (s, 3H) ； 2.55 (d, 2H)； 5.10 (m, 2H) ； 5.65 (m, 1H) ； 7.25-7.45 (m, 10H). 下面化合物係依照類似於實例XV之方法製備： 實例編號 結構 收量 MS XVI 0 0 84% MS[DCI(NH3)]： m/z=350(M+NH4)+ XVII 72% MS[DCI(NH3)]: m/z=322(M+NH4)+ XVIII 〇 p-CH3 〇 ° 67% MS[DCI(NH3)]: m/z=3 3 8(M+NH4)+ -46· 11 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200400936 A7 五、發明說明（《 實例XIX (二乙氧基磷醯基)(苯基）乙酸200400936 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 B7 V. Description of Invention (44) Yield: 1M mg (74% of theory) MS [DCI (NH3)]: m / z = 320 (M + NH4) +! H-NMR (200 MHz, CDC13): (5 = 1.30 (s, 3H); 2.55 (d, 2H); 5.10 (m, 2H); 5.65 (m, 1H); 7.25-7.45 (m, 10H ). The following compounds were prepared according to a method similar to Example XV: Example Number Structure Yield MS XVI 0 0 84% MS [DCI (NH3)]: m / z = 350 (M + NH4) + XVII 72% MS [DCI (NH3)]: m / z = 322 (M + NH4) + XVIII 〇p-CH3 〇 ° 67% MS [DCI (NH3)]: m / z = 3 3 8 (M + NH4) + -46 · 11 This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200400936 A7 V. Description of the invention ("Example XIX (diethoxyphosphonium) (phenyl) acetic acid

10 15 經濟部智慧財產局員工消費合作社印製 20 將溶解在己烷的35.05毫升(87.63毫莫耳）的2 5 “正 丁基鋰溶液，於氬氣層中引入40毫升的四氫呋喃，將反 應溶液冷卻至-70°C，滴入溶解在40毫升四氫呋喃中的 18.26毫升(87.63毫莫耳）的苯基甲烷鱗酸二乙基酯，在_7〇 C下將混合物攪拌30分鐘，反應溶液被慢慢倒入至授拌 中的乾冰與120毫升二乙醚所成混合物中，待反應混合物 回溫至室溫後’添入80毫升的水中止反應，並予以授拌 10分鐘，分出此層，有機層再經10%碳酸鈉溶液洗滌二 遍，併合的水溶液層以二乙醚萃取一次，再以濃鹽酸將水 溶液層的pH調至2並以80毫升二氣甲烷萃取三遍，經硫 酸鈉乾燥後，過濾並於真空下濃縮，經高真空乾燥，可得 19.68克(理論值之83%)的產物。 HPLC (方法 I) : Rt=3.77 分鐘 MS (ESI+) : m/z=273 (M+H)+ ^-NMRCSOO MHz, CDC13) ： δ =1.16 (t, 3H) ； 1.27 (t, 3H)； 3.90-4.18 (m, 4H) ； 4.30 (d, 1H) ； 7.25-7.37 (m, 3H) ； 7.48- -47- 本紙張尺度通用肀國國家標準(CNS)A4規格（210 x297公釐）10 15 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 20 A 35.05 ml (87.63 mmol) solution of 2 5 "n-butyllithium dissolved in hexane was introduced into the argon layer with 40 ml of tetrahydrofuran to react The solution was cooled to -70 ° C, and 18.26 ml (87.63 mmol) of diethyl phenylmethanescale acid dissolved in 40 ml of tetrahydrofuran was added dropwise. The mixture was stirred at -70 ° C for 30 minutes. The reaction solution It was slowly poured into a mixture of dry ice and 120 ml of diethyl ether in the mixture. After the reaction mixture was warmed to room temperature, it was added to 80 ml of water to stop the reaction, and the mixture was allowed to mix for 10 minutes. Layer, the organic layer was washed twice with 10% sodium carbonate solution, the combined aqueous layer was extracted once with diethyl ether, and the pH of the aqueous layer was adjusted to 2 with concentrated hydrochloric acid and extracted three times with 80 ml of digas methane. After drying with sodium, it was filtered and concentrated under vacuum and dried under high vacuum to obtain 19.68 g (83% of theory) of the product. HPLC (Method I): Rt = 3.77 min MS (ESI +): m / z = 273 (M + H) + ^ -NMRCSOO MHz, CDC13): δ = 1.16 (t, 3H); 1.27 (t, 3 H); 3.90-4.18 (m, 4H); 4.30 (d, 1H); 7.25-7.37 (m, 3H); 7.48- -47- The paper standards are generally in accordance with the national standard (CNS) A4 specification (210 x297) %)

200400936 A7 B7 五、發明說明（46) 7.52 (m, 2H).200400936 A7 B7 V. Description of the invention (46) 7.52 (m, 2H).

實例XX 2-氣-2-嗣基-1 -苯基乙基填酸二乙基醋Example XX 2-Gas-2-fluorenyl-1 -phenylethyldiacetate

經濟部智慧財產局員工消費合作社印製 10 於氬氣層中，將19.68克(72.29毫莫耳的實例XIX的 化合物溶解在200毫升的二氣甲烷，經冷卻至0°C後，滴 入52.73毫升(722.90毫莫耳）的硫醯氯，反應混合物慢慢 回溫至室溫後，再予以加熱迴流3小時，冷卻後，在真空 15 下將混合物濃縮，殘留物混合二乙醚，再次濃縮，經高真 空乾燥後可得19克(理論值之90%)產物，不需精製而進行 反應。The Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs printed 10 in an argon layer. 19.68 g (72.29 millimoles of the compound of Example XIX was dissolved in 200 ml of digas methane. After cooling to 0 ° C, it was dropped into 52.73 Ml (722.90 mmol) of thionine chloride, the reaction mixture was slowly warmed to room temperature, and then heated to reflux for 3 hours. After cooling, the mixture was concentrated under vacuum 15 and the residue was mixed with diethyl ether and concentrated again. After high vacuum drying, 19 g (90% of theory) of the product can be obtained, and the reaction is carried out without purification.

實例XXI 20 2-酮基-1-苯基己基磷酸二乙基酯Example XXI 20 2-keto-1-phenylhexyl diethyl phosphate

-48- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） A7-48- This paper size applies to China National Standard (CNS) A4 (210x297 mm) A7

發明說明（47 10 15 200400936 在氬氣層下，將27.52毫升(68.80毫莫耳)的正丁基經 (溶在已烧之2.5M溶液)慢慢滴入至懸浮於議毫升四氫 吱喃之6.55克(34.44毫莫耳)的埃化亞銅懸浮液邊在」5 。。下攪拌’可得黑色懸浮液’在，。c下，滴入溶解在6〇 毫升四氫吱口南中的5克（17·2毫莫耳）的實例χχ之化合 物，待溶液回溫至-4(TC ’在此溫度下攪拌9〇分鐘，然後 加入50毫升飽和的氯化銨溶液至此混合物中，令其回溫 至室溫’吸引濾下所得沈㈣以二氣甲院_，將渡液濃 縮’水溶液層經各以30冑升的二氣甲院萃取三遍，併合 的有機層經25%氨水洗蘇直到不顯現藍色，#以飽和的氣 化納溶液_-次，再經硫酸鈉乾燥，過濾、並於真空中濃 縮’經高真空下乾燥’可得5·14克(理論值之95%)的產 物。 HPLC (方法 I) : Rt=4.58 分鐘 MS (ESI+) : m/z=313 (M+H)+ H-NMR(400 MHz，CDC13) : <5=0.84 (t，3H) ; 1.18-1.30 (m， 8H)，1.49-1.57 (m，2H) ; 2.52-2.69 (m，2H) ; 3.94-4.11 (m, 4H) , 4.43 (d, 1H) ； 7.28-7.36 (m, 3H) ； 7.44-7.48 (m, 2H).Description of the invention (47 10 15 200400936 Under an argon layer, 27.52 ml (68.80 mmol) of n-butyl (dissolved in a burned 2.5M solution) was slowly dropped into a suspension of 1 ml of tetrahydrofuran 6.55 grams (34.44 millimoles) of cuprous alfalfa suspension was stirred at "5 ..." to obtain a black suspension. At "c", dripped and dissolved in 60 ml of tetrahydrofuran. 5 grams (17.2 millimoles) of the compound of Example χχ, after the solution was warmed to -4 (TC 'stirred at this temperature for 90 minutes, then 50 ml of saturated ammonium chloride solution was added to this mixture, Allow it to warm to room temperature. Attract the filtrate obtained by the second gas pump, and concentrate the fermented solution. The aqueous layer was extracted three times with each 30 kg gas pump, and the combined organic layer was subjected to 25%. Wash with ammonia until no blue appears. #Saturated vaporized sodium solution _-times, then dried over sodium sulfate, filtered, and concentrated in vacuo 'dried under high vacuum' to obtain 5.14 g (theoretical value) 95%). HPLC (Method I): Rt = 4.58 minutes MS (ESI +): m / z = 313 (M + H) + H-NMR (400 MHz, CDC13): < 5 = 0.84 (t , 3H); 1.18- 1.30 (m, 8H), 1.49-1.57 (m, 2H); 2.52-2.69 (m, 2H); 3.94-4.11 (m, 4H), 4.43 (d, 1H); 7.28-7.36 (m, 3H); 7.44-7.48 (m, 2H).

20 實例XXII 2-(3,5-二氟苯基)-2-羥基-1-苯基乙酮 (參考：R.E· Koenigkmmer，H. Zimmer，/· 〇砂1980, 45, 3994-3998) -49- 玉紙張尺度通用甲國國家標準(CNS)A4規格（210 X 297公釐）20 Example XXII 2- (3,5-difluorophenyl) -2-hydroxy-1-phenylethyl ketone (Reference: RE · Koenigkmmer, H. Zimmer, / · 〇SAR 1980, 45, 3994-3998)- 49- Jade Paper Standard General A National Standard (CNS) A4 Specification (210 X 297 mm)

經濟部智慧財產局員工消費合作社印製 經濟部智慧財產局員工消費合作社印製 200400936 A7 B7 五、發明說明（48Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 200400936 A7 B7 V. Description of the Invention (48

5 在氬氣層下，將33.97毫升(0.242莫耳）的二里雨美胺 加至100毫升分析品級的THF中，將混合物冷卻至"；78 °C，再滴入106.6毫升(0.267莫耳）的正丁基鋰(在己烷中 的2.5 Μ溶液）’在-78。(：下攪拌30分鐘，然後加入溶解在 10 1〇〇毫升’分析品級的THF之76.69克(0.242莫耳）的！_三 曱基矽氧基-1-笨基甲烷磷酸二乙基酯溶液[參考：RE. Koenigkramer, H. Zimmer, /. Org. Chem. 1980, 4S, 3994-3998]，將混合物攪拌30分鐘，再於_6(rc下滴入溶解在 100毫升，分析品級的THF之31.0克(0.218莫耳）的3 5_ 15二氟苯甲醛，加完醛後，令溶液慢慢達室溫，對溶液滴入 150毫升的1N氫氧化鈉溶液，再經攪拌3〇分鐘，從反應 混合物蒸德除去THF後，以二乙越萃取殘留的溶液，併 合乙醚層，經1N鹽酸與飽和氣化鈉溶液洗滌，經硫酸鈉 乾燥後’過濾、並於真空下完全濃縮，粗製品直接被反應製 2〇 得二酮（見實例XXIII)。 收量：13.2克(理論值之21.7%)5 Under argon, add 33.97 ml (0.242 moles) of erylyl melamine to 100 ml of analytical grade THF, cool the mixture to "78 ° C, and drip into 106.6 ml (0.267) Moore) of n-butyllithium (2.5 M solution in hexane) 'at -78. (: Stir for 30 minutes, then add 76.69 g (0.242 mol) of THF in 10 100 ml of analytical grade THF! Trimethylsilyl-1-benzylmethane diethyl phosphate Solution [Reference: RE. Koenigkramer, H. Zimmer, /. Org. Chem. 1980, 4S, 3994-3998], stir the mixture for 30 minutes, and then dissolve in 100 ml at _6 (rc, analytical grade) 31.0 g (0.218 mol) of 3 5-15 difluorobenzaldehyde in THF. After the addition of the aldehyde, the solution was allowed to slowly reach room temperature. 150 ml of a 1N sodium hydroxide solution was dropped into the solution, followed by stirring for 3 hours. After the THF was removed from the reaction mixture by distillation, the residual solution was extracted with diethyl ether, and the ether layer was combined, washed with 1N hydrochloric acid and saturated sodium gas solution, dried over sodium sulfate, filtered, and completely concentrated under vacuum. The crude product was directly reacted to produce 20 to obtain a dione (see Example XXIII). Yield: 13.2 g (21.7% of theory)

Rf=0.51 (甲苯/乙酸乙酯9:1) MS [DCI (NH3)] ： m/z=266 (M+NH4)+ 'H-NMRpOO MHz，CDC13) : (5=4.5 (寬 s，iH) ; 5.91 (s， -50- 本紙張尺度適用中國國家標準(CNS)A4規格（210 x 297公釐）Rf = 0.51 (toluene / ethyl acetate 9: 1) MS [DCI (NH3)]: m / z = 266 (M + NH4) + 'H-NMRpOO MHz, CDC13): (5 = 4.5 (width s, iH ); 5.91 (s, -50- This paper size applies to China National Standard (CNS) A4 (210 x 297 mm)

200400936 A7 B7 五、發明說明（49)200400936 A7 B7 V. Description of Invention (49)

1H) ； 6.64-6.92 (m, 3H) ； 7.4-7.64 (m, 3H) ； 7.9 (m, 2H). 實例XXIII 1-(3,5-二氟苯基)-2-苯基乙烷-1，2-二酮1H); 6.64-6.92 (m, 3H); 7.4-7.64 (m, 3H); 7.9 (m, 2H). Example XXIII 1- (3,5-difluorophenyl) -2-phenylethane- 1,2-dione

經濟部智慧財產局員工消費合作社印製 10 將13.89克(55.98毫莫耳）的2-(3,5-二氟苯基)-2-羥基- 1-苯基乙酮（實例XXII)溶解於700毫升的二氣甲烷，之 後，加入24.13克（111.95毫莫耳）的吡啶鑌氣鉻酸鹽與固 態的11.42克（111.96毫莫耳）的氧化鋁，於室溫下攪拌過 夜，經由矽藻土將反應溶液進行吸引過濾，於真空下濃 15 縮，殘留物置於矽膠60上層析，以甲苯溶離。 收量：6.81克（理論值之49.4%) HPLC (方法 1) : Rt=4.94 分鐘 Rf=0.81 (甲苯/乙酸乙酯9:1) !Η-ΝΜΚ(300 MHz, CDC13) ： (5=7.06-7.14 (m, 1H) ； 7.47-20 7.58 (m, 4H) ； 7.68 (m, 1H) ； 7.97 (m, 2H). 下面的起始化合物為依照類似於實例XXII與XXIII 的方法製備者： -51- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200400936 A7 B7 五、發明說明（50 ) 經濟部智慧財產局員工消費合作社印製 實例編號 結構 收量 (理論值之％) MS XXIV 69.6 MS (El): m/z= 123 (M-105)+ XXV 58.5 MS [DCI _3)]: m/z = 246 (Μ+ΝΗ4Γ XXVI 45.4 MS [DCI (NH3)]: m/z = 246 (M+NH4)+ XXVII F 49.1 MS [DCI (NH3)]: m/z = 264 (M+NH4)+ XXVIII CN 34.8 MS [DCI (NH3)]: m/z = 253 (M+NH4)+ XXIX 34.6 MS [DCI (NH3)]: m/z = 234 (M+NH4)+ -- -52- 本紙張尺度適用中國國家標準(CMS)A4規格（210x297公釐） 200400936 A7B7 五、發明說明（51) 經濟部智慧財產局員工消費合作社印製 貫例編號 結構 收量 (理論值之％) MS XXX o rVCH3 oV7 66.1 MS [DCI (NH3)]： m/z = 248 (Μ+ΝΉ4)+ XXXI o 48.6 MS [DCI (NH3)]： m/z = 236 (M+NH4)+ XXXII 41.6 MS [DCI (NH3)]: m/z = 263 (M+NH4)+ XXXIII 82.2 MS [DCI (NH3)]： m/z = 243 (M+NH4)+ XXXIV 43.7 MS [DCI (冊3)]: m/z = 268 (M+NH4)+ -53- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200400936 A7 B7 t 五、發明說明（52 )Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs10 Dissolved 13.89 g (55.98 mmol) of 2- (3,5-difluorophenyl) -2-hydroxy-1-phenylethyl ketone (Example XXII) in 700 ml of digas methane, after which 24.13 g (111.95 mmol) of pyridinium gas chromate and 11.42 g (111.96 mmol) of alumina solid were added, stirred at room temperature overnight, and passed through diatoms The reaction solution was filtered by suction, concentrated under vacuum in 15 times, and the residue was chromatographed on silica gel 60 and dissolved in toluene. Yield: 6.81 g (49.4% of theory) HPLC (Method 1): Rt = 4.94 minutes Rf = 0.81 (toluene / ethyl acetate 9: 1)! Η-NMK (300 MHz, CDC13): (5 = 7.06 -7.14 (m, 1H); 7.47-20 7.58 (m, 4H); 7.68 (m, 1H); 7.97 (m, 2H). The following starting compounds were prepared according to methods similar to those of Examples XXII and XXIII: -51- This paper size is in accordance with Chinese National Standard (CNS) A4 (210x297 mm) 200400936 A7 B7 V. Description of the invention (50) Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs Employee Cooperative Co., Ltd. Example number structure income (theoretical value%) ) MS XXIV 69.6 MS (El): m / z = 123 (M-105) + XXV 58.5 MS [DCI _3)]: m / z = 246 (Μ + ΝΗ4Γ XXVI 45.4 MS [DCI (NH3)]: m / z = 246 (M + NH4) + XXVII F 49.1 MS [DCI (NH3)]: m / z = 264 (M + NH4) + XXVIII CN 34.8 MS [DCI (NH3)]: m / z = 253 (M + NH4) + XXIX 34.6 MS [DCI (NH3)]: m / z = 234 (M + NH4) +---52- This paper size applies to China National Standard (CMS) A4 (210x297 mm) 200400936 A7B7 V. Description of Invention (51) Number of employees printed by the Intellectual Property Bureau of the Ministry of Economic Affairs, Consumer Cooperatives, and the number structure of the income ( % Of the value) MS XXX o rVCH3 oV7 66.1 MS [DCI (NH3)]: m / z = 248 (Μ + ΝΉ4) + XXXI o 48.6 MS [DCI (NH3)]: m / z = 236 (M + NH4 ) + XXXII 41.6 MS [DCI (NH3)]: m / z = 263 (M + NH4) + XXXIII 82.2 MS [DCI (NH3)]: m / z = 243 (M + NH4) + XXXIV 43.7 MS [DCI (DCI ( Book 3)]: m / z = 268 (M + NH4) + -53- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 200400936 A7 B7 t V. Description of the invention (52)

實例XXXV 消旋-4-羥基-5,5-二甲基-2,3-二苯基-2-環戊烯-1-酮Example XXXV racemic-4-hydroxy-5,5-dimethyl-2,3-diphenyl-2-cyclopenten-1-one

經濟部智慧財產局員工消費合作社印製 將2.00克(7.24毫莫耳)的2,2-二甲基-4,5-二苯基-4-環 10 戊烯-1,3-二酮（實例X)溶解於二氯甲烷(55毫升)/甲醇(20 毫升），加入92.15毫克(2.43毫莫耳）的氫硼化鈉，然後在 室溫下攪拌反應混合物經30分鐘，添加入80毫升的二氯 甲烷與40毫升的水後，接著以1 N鹽酸（約2毫升）中 和，有機層以各20毫升的二氣曱烷萃取二次，以20毫升 15 濃氣化鈉溶液洗滌，併合的有機層經硫酸鈉乾燥，減壓下 蒸餾除去溶劑，粗製品經柱層層析純化（矽膠，溶離液： 環己烷/乙酸乙酯，梯度：10:1—1:1)。 收量：1.56克（理論值之63%) LC-MS (方法 4) : Rt=3.48 分鐘 20 MS (ESI+) ： m/z=279 (M+H)The Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs printed 2.00 g (7.24 mmol) of 2,2-dimethyl-4,5-diphenyl-4-cyclo10pentene-1,3-dione ( Example X) Dissolved in dichloromethane (55 mL) / methanol (20 mL), 92.15 mg (2.43 mmol) of sodium borohydride was added, and the reaction mixture was stirred at room temperature for 30 minutes, and added to 80 mL After dichloromethane and 40 ml of water were neutralized with 1 N hydrochloric acid (approximately 2 ml), the organic layer was extracted twice with 20 ml of dioxane and washed with 20 ml of 15 concentrated sodium gas solution. The combined organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The crude product was purified by column chromatography (silica gel, eluent: cyclohexane / ethyl acetate, gradient: 10: 1 to 1: 1). Yield: 1.56 g (63% of theory) LC-MS (Method 4): Rt = 3.48 minutes 20 MS (ESI +): m / z = 279 (M + H)

實例XXXVI 消旋-4-羥基-5-甲基-2,3-二苯基-2-環戊烯-1-酮 (非對映立體異構物之混合物） -54- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200400936 A7 B7 五、發明說明（53 )Example XXXVI Racemic-4-hydroxy-5-methyl-2,3-diphenyl-2-cyclopenten-1-one (mixture of diastereoisomers) -54- This paper size applies to China National Standard (CNS) A4 specification (210x297 mm) 200400936 A7 B7 V. Description of invention (53)

依類似於實例XXXV之方法，以86.5毫克(2.29毫莫 耳）的氫硼化鈉將2克(7.62毫莫耳）的實例XIV(溶離份2) 的化合物還原，可製得非對映立體異構物之混合物（約 78%的4,5-順式非對映立體異構物，約22%的4,5-反式非 10 對映立體異構物）。 收量：1.67克（理論值之83%) W-NMRPOO MHz, CDC13) : <5=1.35 (d, 3H，優勢異構 物）；1.43 (d，3H，劣勢異構物）；2.63 (m，1H,劣勢異構 物）；2.76 (m，1H，優勢異構物）；4.98 (m，1H，劣勢異構 15 物）；5.4 (m，1H,優勢異構物）；7.2-7.45 (m, 10H,兩種異 構物). 具體實例： 實例1 20 2-(4-氟苯基)-4-羥基-5-曱基-3,4-二苯基-2-環戊烯-1-酮Diastereostereomers were prepared in a similar manner to Example XXXV by reducing 2 g (7.62 mmol) of the compound of Example XIV (Dissolution 2) with 86.5 mg (2.29 mmol) of sodium borohydride. Mixtures of isomers (approximately 78% of 4,5-cis diastereoisomers and approximately 22% of 4,5-trans diastereoisomers). Yield: 1.67 g (83% of theory) W-NMRPOO MHz, CDC13): < 5 = 1.35 (d, 3H, dominant isomer); 1.43 (d, 3H, disadvantaged isomer); 2.63 ( m, 1H, inferior isomer); 2.76 (m, 1H, inferior isomer); 4.98 (m, 1H, inferior isomer); 5.4 (m, 1H, dominant isomer); 7.2-7.45 (m, 10H, two isomers). Specific examples: Example 1 20 2- (4-fluorophenyl) -4-hydroxy-5-fluorenyl-3,4-diphenyl-2-cyclopentene -1-one

本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐）This paper size applies to China National Standard (CNS) A4 (210x297 mm)

T 經濟部智慧財產局員工消費合作杜印製T Printed by the Intellectual Property Bureau of the Ministry of Economy

200400936 A7 B7 五、發明說明（54 ) 將6.5毫克(0.11毫莫耳)的氳氧化鉀與300毫克(1.43 毫莫耳）的苯偶醯(benzil)加至溶解於3毫升曱醇的279毫 克（1.43毫莫耳）的1-(4-氟苯基)-2-丁酮（實例I)溶液中，將 混合物加熱迴流8小時，加入約20毫升的水並以乙酸乙 5 酯萃取三遍，併合有機層，以鹽水洗滌，經硫酸鈉弄乾 後，於真空下濃縮，殘留物於50克的矽膠60上層析，以 環己烷/乙酸乙酯10:1與5:1為溶離液溶離。 製得下面化合物： 10 實例la 消旋-順式-2-(4-氟苯基)-4-羥基-5-曱基-3，4-二苯基-2-環戊 博-\-rni非對映立體異構物I)200400936 A7 B7 5. Description of the invention (54) 6.5 mg (0.11 mmol) of potassium osmium oxide and 300 mg (1.43 mmol) of benzil are added to 279 mg of 3 ml of methanol (1.43 mmol) of 1- (4-fluorophenyl) -2-butanone (Example I), the mixture was heated under reflux for 8 hours, about 20 ml of water was added and extracted three times with ethyl acetate The organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was chromatographed on 50 g of silica gel 60 and dissolved in cyclohexane / ethyl acetate 10: 1 and 5: 1. Liquid dissolves away. The following compound was prepared: 10 Example la Racemic-cis-2- (4-fluorophenyl) -4-hydroxy-5-fluorenyl-3,4-diphenyl-2-cyclopentabol-\-rni Diastereoisomers I)

20 收量：211毫克(理論值之41%)20 Yield: 211 mg (41% of theory)

Rf=0.41 (CH/EA5:1) LC-MS (方法 3) : Rt=5.1 分鐘 MS (ESI+) ： m/z=359 (M+H)+ !Η-ΝΜΚ(200 MHz, DMSO-d6) ： δ =1.1 (d, 3H) ； 2.75 (q, -56- 本紙張尺度適用中國國家標準(CNS)A4規格（210 x 297公釐）Rf = 0.41 (CH / EA5: 1) LC-MS (Method 3): Rt = 5.1 minutes MS (ESI +): m / z = 359 (M + H) +! Η-NMK (200 MHz, DMSO-d6) ： Δ = 1.1 (d, 3H) ； 2.75 (q, -56- The paper size applies to China National Standard (CNS) A4 (210 x 297 mm)

TT

經濟部智慧財產局員工消費合作社印製Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

經濟部智慧財產局員工消費合作杜印製 200400936 A7 B7 五、發明說明（55 ) 1H) ； 6.05 (s, 1H) ； 7.05-7.4 (m, 14H). 與 實例lb 5 消旋··反式-2-(4-氟苯基)-4-羥基-5-甲基-3，4-二苯基-2-環戊 鳴-\-镇{非對映立體異構物2)Consumption Cooperation of Employees of the Intellectual Property Bureau of the Ministry of Economic Affairs 200400936 A7 B7 V. Description of the Invention (55) 1H); 6.05 (s, 1H); 7.05-7.4 (m, 14H). And Example lb 5 Racemic ·· trans -2- (4-fluorophenyl) -4-hydroxy-5-methyl-3,4-diphenyl-2-cyclopentane-\-town {diastereoisomer 2)

收量：203毫克(理論值之4〇%) 15 Rf=0.29 (CH/EA 5:1) LC-MS (方法 3) : Rt=5.1 分鐘 MS (ESI+) ： m/z=359 (M+H)+ 1H-NMR(200 MHz, DMSO-d6) ： 6=0.6 (d, 3H) ； 3.1 (q, 1H) ； 6.3 (s, 1H) ； 6.95-7.45 (m, 14H). 20 實例la對映立體異構物分離 (+)-與(-)-順式-2-(4-氟苯基)-4-羥基-5-甲基-3,4-二苯基-2-環 戊烯-1·•酮 將得自實例la的159毫克之消旋異構物溶解於5毫 -57- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐）Yield: 203 mg (40% of theory) 15 Rf = 0.29 (CH / EA 5: 1) LC-MS (Method 3): Rt = 5.1 min MS (ESI +): m / z = 359 (M + H) + 1H-NMR (200 MHz, DMSO-d6): 6 = 0.6 (d, 3H); 3.1 (q, 1H); 6.3 (s, 1H); 6.95-7.45 (m, 14H). 20 Examples la Enantiomeric separation of (+)-and (-)-cis-2- (4-fluorophenyl) -4-hydroxy-5-methyl-3,4-diphenyl-2-cyclopentane The ene-1 · • one dissolves 159 mg of the racemic isomer from Example la in 5 milli-57- This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

200400936 A7 B7 五、發明說明（56 ) 升的異丙醇/乙腈（9:1)中，經製備性HPLC，於手性相 (Daicel Chiralcel OD 10 微米，20 X 250 mm 柱層）中以異己 烷/異丙醇（85:15)溶離，可製得兩種分開的對映立體異構 物： 5 (+V對映立體異構物1 : 收量：68毫克200400936 A7 B7 V. Description of the invention In 56 liters of isopropanol / acetonitrile (9: 1), preparative HPLC was performed in a chiral phase (Daicel Chiralcel OD 10 micron, 20 X 250 mm column layer). Alkane / isopropanol (85:15) is dissociated to prepare two separate enantiomers: 5 (+ V enantiomer 1: Yield: 68 mg

Rt=4.1 分鐘[Daicel Chiralcel OD 10 微米，20 X 250 mm,異 丙烷/異丙醇(85:15)] 10 <2D20=+199.3° (c=0.51 克/100 毫升，甲醇中） (-V對映立體異構物2: 收量：65毫克Rt = 4.1 minutes [Daicel Chiralcel OD 10 microns, 20 X 250 mm, isopropane / isopropanol (85:15)] 10 < 2D20 = + 199.3 ° (c = 0.51 g / 100 ml in methanol) (- V-enantiomer 2: Yield: 65 mg

Rt=4.6 分鐘[Daicel Chiralcel OD 10 微米，20 X 250 mm,異 15 丙烷/異丙醇(85:15)] aD2()=-217.7° (c=0.51 克/100 毫升，甲醇中） 下面為依類似於實例1的方法製備者： 經濟部智慧財產局員工消費合作社印製 20 -58- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200400936 A7 B7 五、發明說明（57 貫例編號 結構 收量 MS (ESI+) (理論值之％) m/z (M+H)+ 2a 15 375Rt = 4.6 minutes [Daicel Chiralcel OD 10 microns, 20 X 250 mm, iso15 propane / isopropanol (85:15)] aD2 () =-217.7 ° (c = 0.51 g / 100 ml in methanol) The following is Prepared by a method similar to Example 1: Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 20 -58- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 200400936 A7 B7 V. Description of the invention (57 Case Number Structure Yield MS (ESI +) (% of Theory) m / z (M + H) + 2a 15 375

200400936 A7 B7 五、發明說明（58 實例編號 結構 收量 MS (ESI+) (理論值之％) m/z (M+H)+ 4a 39 355200400936 A7 B7 V. Description of the invention (58 Example No. Structure Yield MS (ESI +) (% of theory) m / z (M + H) + 4a 39 355

本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200400936 A7 B7 五、發明說明（59 實例編號 結構 收量 (理論值之％) MS (ESI+) m/z (M+H)+ 6aThis paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 200400936 A7 B7 V. Description of the invention (59 Case number structure yield (% of theoretical value) MS (ESI +) m / z (M + H ) + 6a

36 359 7a36 359 7a

3 3 5 5 IT----------— 經濟部智慧財產局員工消費合作社印製3 3 5 5 IT ------------ Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs

本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200400936 A7 B7 五、發明說明（60) 經濟部智慧財產局員工消費合作社印製 實例編號 結構 收量 (理論值之％) MS (ESI+) m/z (M+H疒 8a 〇〇 23 359 Ob 9a ^-OH + GO 32 347 S^W'CH3 GO 10 GO 12 DCI (NH3)： 406 (M+NH4)+ 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200400936 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（6i) 下面為依類似於實例la的對映立體異構物分離方法 製備者： 實例編號 結構 收量 (理論值之％) Rt (Daicel Chiralcel OD 10 微米，20 x 250 mm) 實例7a的 對映立體 異構物 ΟΧ〇η3 \~U〇H o b 47 4.1分鐘 (異己烷/異 丙醇85:15) 實例5a的 對映立體 異構物 Q p 31 6.6分鐘 (異己烷/乙 醇 90:10) 5 實例11 4-羥基-2,3,4-三苯基-5-丙基-2-環戊烯-1-酮（##/碘_*邀異 構物之混合物、This paper size applies the Chinese National Standard (CNS) A4 specification (210x297 mm) 200400936 A7 B7 V. Description of the invention (60) Number of printed case numbers printed by the employees' cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs (theoretical value) MS ( ESI +) m / z (M + H 疒 8a 〇〇23 359 Ob 9a ^ -OH + GO 32 347 S ^ W'CH3 GO 10 GO 12 DCI (NH3): 406 (M + NH4) + This paper size applies to China National Standard (CNS) A4 Specification (210x297 mm) 200400936 Printed by the Consumers ’Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the Invention (6i) The following is the preparation of an enantiomeric separation method similar to Example la : Example number Structure yield (% of theoretical value) Rt (Daicel Chiralcel OD 10 micron, 20 x 250 mm) Enantiomeric stereoisomer of Example 7a 〇〇〇η3 \ ~ U〇H ob 47 4.1 minutes (isohexane / Isopropanol 85:15) Enantiomer Q p 31 of Example 5a 6.6 min (isohexane / ethanol 90:10) 5 Example 11 4-hydroxy-2,3,4-triphenyl-5-propane 2--2-cyclopenten-1-one (## / IO__Invite a mixture of isomers,

將40毫克的15-冠-5與溶解在4毫升四氫呋喃的743 -63- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐）40 mg of 15-crown-5 and 743-63- dissolved in 4 ml of tetrahydrofuran- This paper is in accordance with China National Standard (CNS) A4 (210x297 mm)

200400936 A7 B7 發明說明（62) 耄克(2.38毫莫耳)的得自實例χχι的化合物，在氬氣層中 於15°C下’加至懸浮在5毫升四氫呋喃中的96毫克(2.62 毫莫耳）的氫化納（6〇%於礦物油中）溶液中’然後在室溫下 將混合物攪拌一小時，再於10。(：下’滴入溶解在4毫升四 5氫呋喃的500毫克(2.38毫莫耳）的苯偶醯(benzil) ’於室溫 下攪拌過夜’再加入一小匙(約4〇毫克）的氫氧化鉀粉末， 將混合物加熱迴流4小時，濃縮反應溶液，殘留物置入乙 酸乙酯，加入氣化鈉溶液，以i M鹽酸將溶液的pH值調 至2.5 ’分出乙酸乙酯層，水溶液層再經乙酸乙酯萃取， 10併合的有機層經硫酸鈉乾燥後，於真空下濃縮，殘留物於 石夕膠60上層析，先以甲苯，再以甲苯/乙酸乙酯2〇: 1單一 溶離相溶離，可得到非對映立體異構物丨(順式）與非對映 立體異構物2(反式）。 收量：168毫克(理論值之19%) 15 MS (ESI+) ： m/z=369 (M+H)+200400936 A7 B7 Description of the invention (62) 耄 grams (2.38 mmol) of the compound from Example χιι was added to 96 mg (2.62 mmol) suspended in 5 ml of tetrahydrofuran in an argon layer at 15 ° C. Ear) in a solution of sodium hydride (60% in mineral oil), and then the mixture was stirred at room temperature for one hour and then at 10 ° C. (: 'Drop in 500 mg (2.38 mmol) of benzil) dissolved in 4 ml of tetra-5hydrofuran' stir at room temperature overnight 'and add a small spoon (about 40 mg) of Potassium hydroxide powder, the mixture was heated under reflux for 4 hours, the reaction solution was concentrated, the residue was put into ethyl acetate, sodium gas solution was added, and the pH of the solution was adjusted to 2.5 'with i M hydrochloric acid, and the ethyl acetate layer was separated. The layers were extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was chromatographed on Shixi Gum 60, first with toluene and then with toluene / ethyl acetate 20: 1. A single dissolving phase dissolves to obtain diastereoisomers 丨 (cis) and diastereoisomers 2 (trans). Yield: 168 mg (19% of theory) 15 MS (ESI +) : M / z = 369 (M + H) +

Rf(非對映立體異構物1)=0.6(甲笨/乙酸乙醋9:1)Rf (diastereoisomer 1) = 0.6 (methylbenzyl / ethyl acetate 9: 1)

Rf(非對映立體異構物2)=0.55(甲笨/乙酸乙醋9:1) 經濟部智慧財產局員工消費合作杜印製 將得自實例11的143毫克的非對映立體異構物的混 合物溶解於2毫升的乙醇與6毫升的異己烷並於YMC_ 2〇 Pack多胺II柱層（5微米，250 X 20 mm)，使用異丙烧/乙醇 (95:5)以單一移動相模式，流速為25毫升/分鐘下溶離，製 得下面化合物： -64- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200400936 Α7 Β7 五、發明說明（63 ) 實例11a 消旋-順式-4-羥基-2,3,4-三苯基-5-丙基-2-環戊烯-1-酮（#势 映立體異構物ί) ηRf (diastereoisomer 2) = 0.55 (methylbenzyl / ethyl acetate 9: 1) Consumer cooperation of Intellectual Property Bureau of the Ministry of Economic Affairs Du printed the 143 mg of diastereomers obtained from Example 11 The material mixture was dissolved in 2 ml of ethanol and 6 ml of isohexane and placed in a YMC_20Pack polyamine II column layer (5 microns, 250 X 20 mm), using isopropane / ethanol (95: 5) in a single movement Phase mode, dissolving at a flow rate of 25 ml / min to prepare the following compounds: -64- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 200400936 Α7 Β7 V. Description of the invention (63) Examples 11a Racemic-cis-4-hydroxy-2,3,4-triphenyl-5-propyl-2-cyclopenten-1-one (# 势 映 STEREO ISOLATE) η

CH. ηCH. Η

收量：66毫克 ^-NMROOO MHz, CDC13) : (5=0.87 (t，3H) ; 1.45-1.59 (m, 2H) ； 1.80-1.88 (m, 2H) ； 2.82 (t, 1H) ； 7.00-7.49 (m, 15H) 與 15 實例lib 消旋-反式-4-羥基-2,3,4-三苯基-5-丙基-2-環戊烯-1-酮（#身 映立體異構物2) 經濟部智慧財產局員工消費合作社印製 20 πYield: 66 mg ^ -NMROOO MHz, CDC13): (5 = 0.87 (t, 3H); 1.45-1.59 (m, 2H); 1.80-1.88 (m, 2H); 2.82 (t, 1H); 7.00- 7.49 (m, 15H) and 15 examples of lib racemic-trans-4-hydroxy-2,3,4-triphenyl-5-propyl-2-cyclopenten-1-one (# 身 映 STEREO Structure 2) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 20 π

CH, ηCH, η

-65- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200400936 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明（64 ) 收量：47毫克 ^-NMRCSOO MHz, CDC13) ： 5=0.75 (t, 3H) ； 1.34-1.63 (m, 4H) ； 3.02 (q, 1H) ； 6.90 (dd, 2H) ； 7.12-7.49 (m, 13H). 5 實例12 3,4-雙(2-氟苯基)-4-羥基-5-甲基-2-苯基-2-環戊烯-1-酮（# 對映立體異構物之混合物、-65- This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200400936 A7 B7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the Invention (64) Yield: 47 mg ^ -NMRCSOO MHz, CDC13): 5 = 0.75 (t, 3H); 1.34-1.63 (m, 4H); 3.02 (q, 1H); 6.90 (dd, 2H); 7.12-7.49 (m, 13H). 5 Example 12 3,4 -Bis (2-fluorophenyl) -4-hydroxy-5-methyl-2-phenyl-2-cyclopenten-1-one (# mixture of enantiomers,

將溶解在5毫升乙醇中的0.39克（1.57毫莫耳）的2,2’-15 二氟苯偶醢與0.28克（1.88毫莫耳）的1-苯基-2-丁酮混合 物，在氬氣層中予以加熱迴流數分鐘直到得到澄清溶液， 然後加入0.2毫升的Triton B(40%溶在甲醇之溶液），使黃 色溶液轉成暗紅色，迴流2小時，將溶液完全濃縮，殘留 物置入乙酸乙醋與飽和氯化鈉溶液内，分出有機層，水溶 20 液層再以乙酸乙酯萃取，併合的乙酸乙酯層經硫酸鈉乾燥 後，在真空下濃縮之。 收量：0.687克（定量地）A mixture of 0.39 g (1.57 mmol) of 2,2'-15 difluorobenzidine and 0.28 g (1.88 mmol) of 1-phenyl-2-butanone dissolved in 5 ml of ethanol, in The argon layer was heated and refluxed for several minutes until a clear solution was obtained. Then 0.2 ml of Triton B (40% solution in methanol) was added to turn the yellow solution into a dark red. The solution was refluxed for 2 hours. The solution was completely concentrated and the residue was placed. Add ethyl acetate and saturated sodium chloride solution, separate the organic layer, and dissolve the aqueous layer in 20 layers and extract with ethyl acetate. The combined ethyl acetate layer is dried over sodium sulfate and concentrated under vacuum. Yield: 0.687 g (quantitatively)

Rf(非對映立體異構物1)=0.53 (甲苯/乙酸乙酯9:1)Rf (diastereoisomer 1) = 0.53 (toluene / ethyl acetate 9: 1)

Rf(非對映立體異構物2)=0.42 (曱苯/乙酸乙酯9:1) -66- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐）Rf (diastereoisomer 2) = 0.42 (toluene / ethyl acetate 9: 1) -66- This paper size applies to China National Standard (CNS) A4 (210x297 mm)

200400936 A7 B7 五、發明說明（65 ) • MS (ESI+) : m/z=377 (M+H)+ 實例12的殘留物被溶解於少量的甲苯(約10-15毫升) 内’置於矽膠60上層析，使用甲苯/乙酸乙酯20:1單一溶 離液溶離，分離得非對映立體異構物1與2 : 5 實例12a 消旋-順式-3,4-雙(2-氟苯基)-4-羥基-5-甲基-2-笨基-2-環戊 烯-1-酮（#势碘立邀姜禕鈐/)200400936 A7 B7 V. Description of the invention (65) • MS (ESI +): m / z = 377 (M + H) + The residue of Example 12 was dissolved in a small amount of toluene (about 10-15 ml) and placed in silicone Chromatography on 60 was performed using toluene / ethyl acetate 20: 1 as a single eluent to separate the diastereoisomers 1 and 2: 5 Example 12a Racemic-cis-3,4-bis (2-fluoro Phenyl) -4-hydroxy-5-methyl-2-benzyl-2-cyclopenten-1-one (## IO 碘 立 立 姜 祎 钤 /)

經濟部智慧財產局員工消費合作社印製 15 收量：61_9毫克(理論值之ιι〇/0) MS (ESI+) : m/z=399 (M+Na)+ !Η-ΝΜΚ(3〇〇 MHz, CDC13) ： δ =1.29 (d, 3H) ； 2.83 (d, 1H) ； 3.12 (q, 1H) ； 6.83-7.88 (m, 13H). 20 HPLC (方法 i) : Rt=5.〇i 分鐘 與 實例12b 消旋-反式-3,4-雙(2-氟苯基)-4-羥基-5-曱基-2-苯基-2-環戊 -67- 本紙張尺度適用中國國豕標準(CNS)A4規格（21〇χ297公釐） 20040093615 printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economics. Yield: 61_9 mg (Theoretical value of 〇〇 / 0) MS (ESI +): m / z = 399 (M + Na) +! Η-ΝΜΚ (300MHz) , CDC13): δ = 1.29 (d, 3H); 2.83 (d, 1H); 3.12 (q, 1H); 6.83-7.88 (m, 13H). 20 HPLC (method i): Rt = 5.〇i minutes And Example 12b Racemic-trans-3,4-bis (2-fluorophenyl) -4-hydroxy-5-fluorenyl-2-phenyl-2-cyclopentyl-67- Standard (CNS) A4 specification (21 × 297 mm) 200400936

經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（66 ) 鳴-\-儀i非對映立體異構物I)Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (66) Naruto-\-Diastereoisomeric I)

收量：48.8毫克(理論值之8%) 10 MS (DCI) ： m/z=394 (M+NH4)+ ^-NMRCSOO MHz, CDC13) ： (5 =1.05 (q, 3H) ； 2.50 (s, 1H) ； 3.10 (d, 1H) ； 6.90-7.34 (m, 13H). HPLC (方法 1) : Rt=4.87 分鐘 15 實例12a對映立體異構物分離 (+)-與(-)-順式-3,4-雙(2-氟苯基)-4-羥基-5-甲基-2-苯基-2-環 戊稀-1-嗣 將130毫克實例12a的消旋異構物溶解於1.5毫升的 異丙醇與1，.5毫升的異己烷，經製備性HPLC，於手性相 20 (Daicel Chiralcel OD 10 微米，20 X 250 mm 柱層）中以異己 烷/異丙醇(75:25)溶離，可製得分開的兩種對映立體異構 物： 對映立體異構物1 : -68- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐）Yield: 48.8 mg (8% of theory) 10 MS (DCI): m / z = 394 (M + NH4) + ^ -NMRCSOO MHz, CDC13): (5 = 1.05 (q, 3H); 2.50 (s , 1H); 3.10 (d, 1H); 6.90-7.34 (m, 13H). HPLC (Method 1): Rt = 4.87 minutes 15 Example 12a Enantiomeric separation of (e)-(-)-cis The formula -3,4-bis (2-fluorophenyl) -4-hydroxy-5-methyl-2-phenyl-2-cyclopentan-1-ene was dissolved in 130 mg of the racemic isomer of Example 12a In preparative HPLC, 1.5 mL of isopropanol and 1.5 mL of isohexane were prepared in chiral phase 20 (Daicel Chiralcel OD 10 micron, 20 X 250 mm column) with isohexane / isopropanol ( 75:25) dissociation, two separate enantiomeric stereoisomers can be prepared: Enantiomeric stereoisomers 1: -68- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)

200400936 A7 B7 五、發明說明（67) * 收量：44毫克 HPLC (方法 2) : Rt=3.9 分鐘 對映立體異構物2 ： 5 收量：40毫克 HPLC (方法 2) : Rt=9.8 分鐘 實例13 消旋-順式-4-羥基-5-甲基-2,3,4-三苯基-2-環戊烯-1-酮（9-甲 10 基肟200400936 A7 B7 V. Description of the invention (67) * Yield: 44 mg HPLC (Method 2): Rt = 3.9 minutes Enantiomer 2: 5 Yield: 40 mg HPLC (Method 2): Rt = 9.8 minutes Example 13 Racemic-cis-4-hydroxy-5-methyl-2,3,4-triphenyl-2-cyclopenten-1-one (9-methyl10 oxime

〒h3 ch3 .〆〇 /〇〒h3 ch3 .〆〇 / 〇

經濟部智慧財產局員工消費合作社印製 將150毫克(0.44毫莫耳)的4-羥基-2,3,4-三苯基-5-甲 20 基-2-環戊烯-1-酮[非對映立體異構物的混合物；依照類似 於 R.S. Atkinson, /.Cfte/n.iSoc. (Q，1971, 3524 的方法，由 苯甲基乙基酮與苯偶醯製備]，與147毫克(1.76毫莫耳）的 〇甲基羥基胺鹽酸鹽，一起在氬氣層下，浴溫為80°C的3 毫升曱醇中攪拌8小時，反應期間，再添入75毫克(0.89 -69- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200400936 A7 _ B7 五、發明說明（68 ) 毫莫耳）的（9-甲基羥基胺鹽酸鹽，迴流8小時後’將混合 物置於室溫下攪拌過夜，在真空下令反應溶液完全濃縮， 殘留物置入二乙醚並以1N鹽酸及飽和的氯化鈉溶液洗 滌’乾燥後蒸發除去溶劑，粗製品以矽膠60層析，使用 5甲苯/乙酸乙酯20:1單一移動相溶離。 收量：100毫克(理論值之57%)The Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs printed 150 mg (0.44 mmol) of 4-hydroxy-2,3,4-triphenyl-5-methyl20-yl-2-cyclopenten-1-one [ A mixture of diastereoisomers; prepared according to a method similar to RS Atkinson, /.Cfte/n.iSoc. (Q, 1971, 3524, benzyl ethyl ketone and benzophenone), with 147 mg (1.76 millimoles) of 0 methylhydroxylamine hydrochloride were stirred in 3 ml of methanol under a argon layer at a bath temperature of 80 ° C for 8 hours. During the reaction, 75 mg (0.89- 69- This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 200400936 A7 _ B7 V. Description of the invention (68) millimolar (9-methylhydroxylamine hydrochloride, reflux 8) After hours, the mixture was stirred at room temperature overnight, and the reaction solution was completely concentrated under vacuum. The residue was put into diethyl ether and washed with 1N hydrochloric acid and saturated sodium chloride solution. After drying, the solvent was removed by evaporation. Chromatography using 5 toluene / ethyl acetate 20: 1 single mobile phase to dissolve. Yield: 100 mg (57% of theory)

Rf=0.62(甲苯/乙酸乙酯9:1) MS (ESI+) ： m/z=370 (M+H)+ *Η-ΝΜΚ(400 MHz, CDC13) ： 5=1.39 (d, 3H) ； 3.40 (q> 10 1H) ; 3.85 (s，3H) ; 6.88 (dd, 2H) ; 7.10 (m，3H) ; 7.22-7.40 (m, 8H) ； 7.51 (dd, 2H). 實例14 消旋-4-羥基-5,5-二曱基-2,3,4-三苯基-2-環戊烯-1-酮Rf = 0.62 (toluene / ethyl acetate 9: 1) MS (ESI +): m / z = 370 (M + H) + * Η-NMK (400 MHz, CDC13): 5 = 1.39 (d, 3H); 3.40 (q > 10 1H); 3.85 (s, 3H); 6.88 (dd, 2H); 7.10 (m, 3H); 7.22-7.40 (m, 8H); 7.51 (dd, 2H). Example 14 Racem-4 -Hydroxy-5,5-difluorenyl-2,3,4-triphenyl-2-cyclopenten-1-one

經濟部智慧財產局員工消费合作社印繁 將0.724毫升(1.30毫莫耳)的笨基經(i 8m溶液，於環 己烧/一乙醚7:3中）’在-78 C下，氬氣層中，加至溶解於 6毫升THF中的300毫克(1·〇9毫莫耳)的實例X之化合物 溶液中，於-78°C下攪拌2小時，混合入約10毫升的乙酸 -70- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公蒼了 200400936 A7 B7 五、發明說明（69 ) • 乙酯與約10毫升的水並以1N鹽酸使之略呈酸性，分出有 機層，在真空下濃縮，殘留物經製備性HPLC純化(RP C-18 相，30 X 250 mm ;溶離液：水/乙腈 90:10—10:90)，可 得無色的晶體。 5 收量：336毫克(理論值之87%) LC-MS (方法 3) : Rt=3.0 分鐘 MS (ESI+) ： m/z=355 (M+H)+ 1H-NMR(200 MHz, CDC13) ： (5 =0.70 (s, 3H) ； 1.40 (s, 3H) ； 2.25 (s, 1H) ； 7.00 (m, 2H) ； 7.10-7.50 (m, 13H). 10 下列化合物為依照類似於實例14的方法製備者： 經濟部智慧財產局員工消費合作社印製 7 本紙張尺度適用t國國家標準(CNS)A4規格（210 X 297公釐） 200400936 A7 B7 五、發明說明（70 ) 經濟部智慧財產局員工消費合作社印製The Intellectual Property Bureau of the Ministry of Economic Affairs, the Consumer Cooperative of the Consumer Council, printed 0.724 ml (1.30 millimoles) of benzine (i 8m solution in cyclohexane / monoethyl ether 7: 3) 'at -78 C, argon layer , To 300 mg (1.09 mmol) of the compound of Example X dissolved in 6 ml of THF, stirred at -78 ° C for 2 hours, and mixed with about 10 ml of acetic acid -70- This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 male Cang 200400936 A7 B7 V. Description of the invention (69) • Ethyl ester and about 10 ml of water and slightly acidic with 1N hydrochloric acid, separated The organic layer was concentrated under vacuum, and the residue was purified by preparative HPLC (RP C-18 phase, 30 X 250 mm; eluent: water / acetonitrile 90: 10-10: 90) to obtain colorless crystals. Amount: 336 mg (87% of theory) LC-MS (Method 3): Rt = 3.0 minutes MS (ESI +): m / z = 355 (M + H) + 1H-NMR (200 MHz, CDC13): ( 5 = 0.70 (s, 3H); 1.40 (s, 3H); 2.25 (s, 1H); 7.00 (m, 2H); 7.10-7.50 (m, 13H). 10 The following compounds follow a method similar to Example 14 Prepared by: Consumer Consumption of Intellectual Property Bureau, Ministry of Economic Affairs Social printing paper 7 t scale applicable National Standards (CNS) A4 size (210 X 297 mm) 200400936 A7 B7 V. description of the invention (70) Ministry of Economic Affairs Intellectual Property Office employees consumer cooperatives printed

-72- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200400936 A7 B7 五、發明說明 實例編號 結構 收量-72- This paper size is in accordance with Chinese National Standard (CNS) A4 (210x297 mm) 200400936 A7 B7 V. Description of the invention Example number Structure Yield

MS 19MS 19

55% MS [ESIpos]: m/z = 411 (M+H)+55% MS [ESIpos]: m / z = 411 (M + H) +

50% MS [ESIpos]: m/z = 383 (M+H)+ 經濟部智慧財產局員工消費合作社印製 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200400936 A7 B7 五、發明說明（72 )50% MS [ESIpos]: m / z = 383 (M + H) + Printed by the Consumers' Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. The paper size is applicable to China National Standard (CNS) A4 (210x297 mm) 200400936 A7 B7 V. Description of the invention (72)

經濟部智慧財產局員工消費合作社印製 實例22 消旋-4-羥基-5,5-二甲基-2,3-二苯基-4-(2-噻吩基)-2-環戊 烯-1-酮Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 22 Racemic-4-hydroxy-5,5-dimethyl-2,3-diphenyl-4- (2-thienyl) -2-cyclopentene- 1-keto

將1.3毫升（1.30毫莫耳）的2-噻吩基鋰(1.0 Μ溶液， 於THF中），在-78°C下，氬氣層中，加至溶解於6毫升 THF中的300毫克(1.09毫莫耳）的實例X之化合物溶液 中，於-78°C下將混合物攪拌2小時，混合入約10毫升的 -74- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200400936 A7 B7 五、發明說明（73 ) • 乙酸乙酯與約10毫升的水並以1N鹽酸使之略呈酸性，分 出有機層，在真空下濃縮，殘留物經製備性HPLC純化 (RP C-18 相，30 X 250 mm ;溶離液··水/乙腈 90:10-> 10:90)，可得無色的晶體。 5 收量：301毫克(理論值之77°/〇) MS [DCI (NH3)] m/z=378 (M+NH4)+ 1H-NMR(200 MHz, CDC13) ： (J =0.90 (s, 3H) ； 1.40 (s, 3H) ； 2.50 (s, 1H) ； 6.90 (m, 1H) ； 7.00 (m, 1H) ； 7.10 (m, 2H) ； 7.15-7.35 (m, 9H). 10 實例23 消旋-4-(3-氣苯基)-4-輕基-5,5-二甲基-2,3-二苯基-2-ί哀戍 烯-1-酮Add 1.3 ml (1.30 mmol) of 2-thienyl lithium (1.0 M solution in THF) at -78 ° C in an argon layer to 300 mg (1.09) dissolved in 6 ml THF In the compound solution of Example X, the mixture was stirred at -78 ° C for 2 hours and mixed into about 10 ml of -74- This paper size is in accordance with China National Standard (CNS) A4 (210x297 mm) 200400936 A7 B7 V. Description of the invention (73) • Ethyl acetate and about 10 ml of water were made slightly acidic with 1N hydrochloric acid. The organic layer was separated and concentrated under vacuum. The residue was purified by preparative HPLC (RP C -18 phase, 30 X 250 mm; eluent · water / acetonitrile 90: 10- > 10:90), colorless crystals can be obtained. 5 Yield: 301 mg (77 ° / 〇 of theory) MS [DCI (NH3)] m / z = 378 (M + NH4) + 1H-NMR (200 MHz, CDC13): (J = 0.90 (s, 3H); 1.40 (s, 3H); 2.50 (s, 1H); 6.90 (m, 1H); 7.00 (m, 1H); 7.10 (m, 2H); 7.15-7.35 (m, 9H). 10 Example 23 Racemic-4- (3-Gaphenyl) -4-lightyl-5,5-dimethyl-2,3-diphenyl-2-fluorene-1-one

經濟部智慧財產局員工消費合作社印製 20 將0.339毫升(0.543毫莫耳）的正丁基鋰（1.6 Μ在正己 烷中溶液），在-78°C下，氬氣層中，加至溶解於2毫升 THF中的82.3毫克(0.470毫莫耳）的1-溴-3-氟苯溶液中， 於-78°C下一小時後加入溶解於0.5毫升的THF中之實例 X之100毫克(0.362毫莫耳)之實例X之化合物溶液，於 -75- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200400936 A7 ___B7 五、發明說明（74 ) 78°c下將混合物攪拌3小時，混合入約5毫升的乙酸乙酯 與約5毫升的水並以in鹽酸使之略呈酸性，分出有機 層，在真空下濃縮，殘留物經製備性HPLC純化(RP C-18 相，30 X 250 mm ;溶離液：水/乙腈90:10—10:90)，可得無 5 色油質物。 收量：75.0毫克(理論值之56%) MS (ESI+) ： m/z=373 (M+H)+ 1H-NMR(200 MHz, CDC13) ： <5 =0.75 (s, 3H) ； 1.40 (s, 3H) ； 2.25 (s, 1H) ； 7.05 (m, 3H) ； 7.10-7.40 (m, 11H). 10 下面的化合物為依照類似實例23的方法製備得者： 經濟部智慧財產局員工消費合作社印製 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200400936 A7 B7 五、發明說明（75 ) -77- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐）Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. 20 0.339 ml (0.543 mmol) of n-butyllithium (1.6 M solution in n-hexane) at -78 ° C in an argon layer. To 82.3 mg (0.470 mmol) of 1-bromo-3-fluorobenzene in 2 ml of THF, 100 mg of Example X dissolved in 0.5 ml of THF was added after one hour at -78 ° C ( 0.362 mmol) of the compound solution of Example X at -75- This paper size applies the Chinese National Standard (CNS) A4 specification (210x297 mm) 200400936 A7 ___B7 V. Description of the invention (74) The mixture is stirred at 78 ° C For 3 hours, mix about 5 ml of ethyl acetate with about 5 ml of water and make it slightly acidic with in hydrochloric acid. Separate the organic layer and concentrate under vacuum. The residue is purified by preparative HPLC (RP C-18 Phase, 30 X 250 mm; eluent: water / acetonitrile 90: 10—10: 90), can be obtained without 5 color oily substance. Yield: 75.0 mg (56% of theory) MS (ESI +): m / z = 373 (M + H) + 1H-NMR (200 MHz, CDC13): < 5 = 0.75 (s, 3H); 1.40 (s, 3H); 2.25 (s, 1H); 7.05 (m, 3H); 7.10-7.40 (m, 11H). 10 The following compounds were prepared according to a method similar to Example 23: Employees of Intellectual Property Office, Ministry of Economic Affairs The paper size printed by the consumer cooperative is applicable to the Chinese National Standard (CNS) A4 specification (210x297 mm) 200400936 A7 B7 V. Description of the invention (75) -77- This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210x297 mm) )

實例編號 結構 收量 MS 24 F 55% MS [ESIpos]: mJz = 373 (M+H)+ 25 O Q CN 44% MS [ESIpos]: m/z = 380 (M+H)+ 26 Br 22% MS [ESIpos]: m/z = 433 (M+H)+ 27 ch3 36% MS [ESIpos]: m/z = 369 (M+H)+ 經濟部智慧財產局員工消費合作社印製 200400936 A7Example Number Structure Yield MS 24 F 55% MS [ESIpos]: mJz = 373 (M + H) + 25 OQ CN 44% MS [ESIpos]: m / z = 380 (M + H) + 26 Br 22% MS [ESIpos]: m / z = 433 (M + H) + 27 ch3 36% MS [ESIpos]: m / z = 369 (M + H) + Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 200400936 A7

营例29 苯基_4_環戊締-1，3-二醇 順式-2,3·反甲 15Example 29 Phenyl-4-cyclopentane-1,3-diol cis-2,3 · transmethyl 15

經 濟 部 智 慧 財 產 局 員 工 消 費 合 作 社 印 20 將0.7〇5毫升(Ο ·毫莫耳⑽氮化铭 中細下，加至溶_6·4毫升ΤΗρ二3 克（〇·588笔莫耳）的順式-4_經基-5-甲基-2,3,4-三笨基_2戸 戊烯-1-酮[具較低滞留時間（7.5分鐘，方法9)之 : 體異構物1，由類似於實例i方法，自4經基甲其 2,3,4-三苯基_2_環⑽_ι__之麵映减異構物之消旋^ -78- 200400936 A7 I-----------B7_____ 五、發明說明（77 ) * 合物（參考前面）取得之非對映立體異構物1，是於YMC多 胺 II，5 微米，250 X 20 mm+Daicel-Chiralcel OD，10 微米， X 20 mm，經異丙烷/乙醇84:16溶離，層析所得]之溶 液中’於-78。(：下攪拌2小時後，混合入約10毫升的乙酸 5乙®旨與約1〇毫升的水並以in鹽酸將其酸鹼度調至6，分 出有機層’在真空下濃縮，殘留物經製備性HPLC純化 (RP C-18 相，30 X 250 mm ;溶離液：水/乙腈 90:10— 10:90) ’可得無色晶體。 收量：139毫克(理論值之69%) 10 1H-NMR(200 MHz, CDC13) ： 6=1.25 (d, 3H) ； 1.85 (d, 1H) ； 1.90 (s, 1H) ； 2.50 (quin, 1H) ； 5.00 (t, 1H) ； 6.85 (m, 2H) ； 7.05 (m, 3H) ； 7.20-7.40 (m, 8H) ； 7.50 (m, 2H). aD2()=+39.0° (c=0.50 克/100 毫升，甲醇内）。 15 實例30 消旋-反式-5-甲基-4-酮基-1，2,3-三苯基環戊-2-烯基草酸乙 醋 經濟部智慧財產局員工消費合作社印製 20The Consumer Cooperatives Association of the Intellectual Property Bureau of the Ministry of Economic Affairs printed 20 and 0.75 ml (0 · millimoles of nitriding inscription, add to the solution of 6.4 milliliters of TΗρ 2 3 grams (0.588 pen moles) Cis-4_Ethyl-5-methyl-2,3,4-tribenzyl-2-penten-1-one [with a lower residence time (7.5 minutes, method 9): isomers 1, by a method similar to that of Example i, the racemization of the isomers from the surface of 2,3,4-triphenyl_2_cyclo⑽_ι__ via the methyl group ^ -78- 200400936 A7 I --- -------- B7_____ V. Description of the invention (77) * The diastereomeric stereoisomer 1 obtained from the compound (refer to the above) is a YMC polyamine II, 5 microns, 250 X 20 mm + Daicel -Chiralcel OD, 10 microns, X 20 mm, dissociated with isopropane / ethanol 84:16, and obtained by chromatography] in -78. (: After stirring for 2 hours, mixed with about 10 ml of acetic acid 5 ethyl ® purpose with about 10 ml of water and adjust its pH to 6 with in hydrochloric acid, the organic layer was separated 'concentrated under vacuum, the residue was purified by preparative HPLC (RP C-18 phase, 30 X 250 mm; dissolution Liquid: water / acetonitrile 90: 10—10: 90) 'Colorless crystals can be obtained. 139 mg (69% of theory) 10 1H-NMR (200 MHz, CDC13): 6 = 1.25 (d, 3H); 1.85 (d, 1H); 1.90 (s, 1H); 2.50 (quin, 1H); 5.00 (t, 1H); 6.85 (m, 2H); 7.05 (m, 3H); 7.20-7.40 (m, 8H); 7.50 (m, 2H). AD2 () = + 39.0 ° (c = 0.50 g / 100 ml in methanol) 15 Example 30 Racemic-trans-5-methyl-4-keto-1,2,3-triphenylcyclopent-2-enylethyl oxalate Ethyl acetate Ministry of Economic Affairs Printed by Employee Consumer Cooperatives 20

紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200400936 A7 B7 五、發明說明（78 將0.03毫升(〇.4宅莫耳）的11比σ定與0.〇5毫升(〇.4毫莫 耳）的乙基草酿氯，於室溫下，氬氣層中，相繼滴入溶解於 5毫升的二氣甲炫中之丨30毫克(0.37毫莫耳)之4羥基_ 2,3,4-三笨基-5-甲基-2-環戊烯-1-¾溶液（非對映立體異構物 5 之混合物，順式/反式3:1) ’在室溫下搜拌過夜後，將反 應溶液混合pH為7之緩衝液並以二氯甲烷萃取，併合的 有機層經1N鹽酸、破酸氫鈉洛液與飽和的鹽水洗滌後， 經硫酸鈉乾燥，過濾並於真空下完全蒸發，粗製品經矽膠 60層析，使用甲笨/乙酸乙酯20:1單一溶離相溶離。 10 收量：27毫克（理論值之14%) 計 HPLC (方法 1) : Rt=5.16 分鐘 MS (DCI) ： m/z=323 (M+H)+ 線 ^-NMRCSOO MHz, CDC13) ： δ =0.82 (d, 3H) ； 1.29 (t, 3H) ； 3.88 (q, 1H) ； 4.25 (q, 2H) ； 6.97 (dd, 2H) ； 7.06-7.51 15 (m, 13H). 列於下面表中的諸實例為依照上述的方法製備得者： 經濟部智慧財產局員工消費合作社印製 適 度 張 紙 本 準 標 祕 釐 公 97 200400936 A7 B7 五、發明說明（79 實例編號 結構 MS (ESF) m/z (M+H)4 HPLC, NMR, Rt或Rf值 31The paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 200400936 A7 B7 V. Description of the invention (78 The 11 ratio σ of 0.03 milliliter (0.4 house mole) is set to 0.05 milliliter ( 0.4 millimolar) of ethyl grass brewed chlorine, and 30 mg (0.37 millimolar) of 4-hydroxy group dissolved in 5 ml of digas methyl chloride were successively dropped into an argon layer at room temperature. _ 2,3,4-Tribenzyl-5-methyl-2-cyclopentene-1-¾ solution (mixture of diastereoisomers 5, cis / trans 3: 1) 'In the chamber After searching overnight at room temperature, the reaction solution was mixed with a buffer solution of pH 7 and extracted with dichloromethane. The combined organic layers were washed with 1N hydrochloric acid, sodium bicarbonate solution and saturated brine, and then dried over sodium sulfate. Filter and evaporate completely under vacuum. The crude product is chromatographed on silica gel 60 using methylbenzyl / ethyl acetate 20: 1 as a single dissolving phase. 10 Yield: 27 mg (14% of theory) Calculated by HPLC (Method 1) : Rt = 5.16 minutes MS (DCI): m / z = 323 (M + H) + line ^ -NMRCSOO MHz, CDC13): δ = 0.82 (d, 3H); 1.29 (t, 3H); 3.88 (q, 1H); 4.25 (q, 2H); 6.97 (dd, 2H); 7.06-7.51 15 ( m, 13H). The examples listed in the table below were prepared in accordance with the methods described above: The Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs printed a moderately printed piece of paper on the standard quasi-centimeter 97 200400936 A7 B7 5. Description of the invention ( 79 Example number Structure MS (ESF) m / z (M + H) 4 HPLC, NMR, Rt or Rf value 31

oror

353353

Rt = 4.22 分鐘 (99.5%) (方法2)Rt = 4.22 minutes (99.5%) (Method 2)

I 計 32aI meter 32a

S 353S 353

Rt=7.86 分鐘 (99.3%) (方法1) 線 經濟部智慧財產局員工消費合作社印製Rt = 7.86 minutes (99.3%) (Method 1) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

SS

本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200400936 A7 B7 五、發明說明（80 ) 經濟部智慧財產局員工消費合作社印製 實例編號 結構 MS (ESI+) m/z (M+H疒 hplc，nmr^ Rt或Rf值 33 + PQ u η \ H3° CH3 0Q h3c ch3 391 (M+Na)+ 11产0.4(甲笨-乙酸乙酯9:1) 34 + CQD 0¾ 'H-NMR (200 MHz, CDC13):5= 1.4 (d, 3H); 1.85 (s, 1H); 3.45 (q, 1H); 6.85 (m, 1H); 7.05 (m, 1H); 7.10-7.30 (m, 9H); 7.4 (m, 1H); 7.8 (m, 1H) -82- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200400936 A7 B7This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 200400936 A7 B7 V. Description of the invention (80) Printed case number structure MS (ESI +) m / z ( M + H 疒 hplc, nmr ^ Rt or Rf value 33 + PQ u η \ H3 ° CH3 0Q h3c ch3 391 (M + Na) + 11 0.4 (methylbenzyl-ethyl acetate 9: 1) 34 + CQD 0¾ ' H-NMR (200 MHz, CDC13): 5 = 1.4 (d, 3H); 1.85 (s, 1H); 3.45 (q, 1H); 6.85 (m, 1H); 7.05 (m, 1H); 7.10-7.30 (m, 9H); 7.4 (m, 1H); 7.8 (m, 1H) -82- This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200400936 A7 B7

五、發明說明（SI 經濟部智慧財產局員工消費合作杜印製 實例編號 結構 MS (ESI+) HPLC, NMR, m/z (M+H)+ Rt或Rf值 35 353 ]^=〇.4(甲苯-乙酸乙酯9:1) ob 36 409V. Description of the invention (SI, Intellectual Property Bureau, Ministry of Economic Affairs, Employee Consumption Cooperation, Du printed example number structure MS (ESI +) HPLC, NMR, m / z (M + H) + Rt or Rf value 35 353] ^ = 0.4.4 ( Toluene-ethyl acetate 9: 1) ob 36 409

αα

αα

I 私=0.32(曱笨-乙酸乙酯9:1) 計 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200400936 A7 B7 五、發明說明（82 ) 經濟部智慧財產局員工消費合作社印製I Private = 0.32 (曱 ben-ethyl acetate 9: 1) The paper size of the paper is applicable to the Chinese National Standard (CNS) A4 (210x297 mm) 200400936 A7 B7 V. Description of the invention (82) Employees of the Intellectual Property Bureau of the Ministry of Economic Affairs Printed by a cooperative

-84- 本紙張尺度適用令國國家標準(CNS)A4規格（210x297公釐） 200400936 A7 B7 五、發明說明（83 實例編號 結構 MS 卿+) m/z (M+H)+ HPLC, NMR, 氏或私值 39-84- The paper size is applicable to the national standard (CNS) A4 specification (210x297 mm) 200400936 A7 B7 V. Description of the invention (83 Example number structure MS Qing +) m / z (M + H) + HPLC, NMR, Family or private value 39

(特定異構物的混合物）(Mixture of specific isomers)

359 428359 428

Rf= 0.36(甲苯-乙酸乙酯9:1) R尸0.35 (甲苯-乙酸乙酯9:1) 計 線Rf = 0.36 (toluene-ethyl acetate 9: 1) Rf 0.35 (toluene-ethyl acetate 9: 1)

200400936 A7 B7 五、發明說明（84 ) 實例編號 結構 MS (ESI+) m/z (M+H)+ HPLC, NMR, 民或！^值 41200400936 A7 B7 V. Description of the invention (84) Example number Structure MS (ESI +) m / z (M + H) + HPLC, NMR, or OR! ^ Value 41

(特定異構物的混合物） 409(Mixture of specific isomers) 409

Rf= 0.38(甲苯-乙酸乙酯9:1) 計 42 〇 …CH,Rf = 0.38 (toluene-ethyl acetate 9: 1) total 42 〇 ... CH,

384384

Rf=0.63 (甲苯-乙酸乙酯9:1) 線Rf = 0.63 (toluene-ethyl acetate 9: 1) line

200400936 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明（85 )200400936 A7 B7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs V. Description of Invention (85)

實例44 15 消旋-4-曱氧基-5,5-二甲基-2,3,4-三苯基-2-環戊烯-1-酮Example 44 15 Racemic-4-fluorenyl-5,5-dimethyl-2,3,4-triphenyl-2-cyclopenten-1-one

於〇°C下，將0.05毫升(0.71毫莫耳）的乙醯基氣慢慢 加至1.5毫升的甲醇内，再加入50.0毫克(0.140毫莫耳) 的實例14之化合物，在室溫下攪拌過夜後，加入5毫升 -87-At 0 ° C, slowly add 0.05 ml (0.71 mmol) of acetamidine to 1.5 ml of methanol, and then add 50.0 mg (0.140 mmol) of the compound of Example 14 at room temperature. After stirring overnight, add 5ml -87-

本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200400936 A7 B7 五、發明說明（86 ) 的乙酸乙酯與5毫升的水，分出有機層，於真空下蒸發除 去大部分的溶劑後，殘留物經製備性HPLC(RP C-18相， 30 X 250 mm ;溶離液：水/乙腈90:10—10:90)，可得無色 固體。 5 收量：21毫克（理論值之41%) LC-MS (方法 3) : Rt=4.7 分鐘 MS (ESI+) ： m/z=368 (M+H)+ 1H-NMR(200 MHz, CDC13) ： δ =0.75 (s, 3H) ； 1.30 (s, 3H) ； 7.05-7.45 (m, 15H). 10 實例45 3-(3,5-二氟苯基)-2-(4-氟苯基)-4-經基-5-甲基-4-苯基環戊-2-烯酮 與 15 4-(3,5-二氟苯基)-2-(4-氟苯基)-4-羥基-5-曱基-3-苯基環戊- 2-浠酮 (非對映立體異構物與特定異構物之混合物) 經濟部智慧財產局員工消費合作社印製 20This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 200400936 A7 B7 V. Description of the invention (86) Ethyl acetate and 5 ml of water, the organic layer is separated and evaporated under vacuum to remove large After part of the solvent, the residue was subjected to preparative HPLC (RP C-18 phase, 30 X 250 mm; eluent: water / acetonitrile 90: 10-10: 90) to obtain a colorless solid. 5 Yield: 21 mg (41% of theory) LC-MS (Method 3): Rt = 4.7 minutes MS (ESI +): m / z = 368 (M + H) + 1H-NMR (200 MHz, CDC13) : Δ = 0.75 (s, 3H); 1.30 (s, 3H); 7.05-7.45 (m, 15H). 10 Example 45 3- (3,5-difluorophenyl) -2- (4-fluorophenyl ) -4-Ethyl-5-methyl-4-phenylcyclopent-2-enone with 15 4- (3,5-difluorophenyl) -2- (4-fluorophenyl) -4- Hydroxy-5-fluorenyl-3-phenylcyclopentan-2-one (mixture of diastereoisomers and specific isomers) Printed by the Consumer Cooperative of Intellectual Property Bureau, Ministry of Economic Affairs 20

與versus

FF

FF

F 8 8 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200400936 A7 B7 五、發明説明 87 10 15 將1.2克(4.87毫莫耳）的1-(3,5-二氟苯基)-2-苯基乙 烧4,2-二酮(實例XXIII)與1.62克(9.75毫莫耳)的1-(4-氟 苯基>2-丁酮（實例I)之混合物’於氬氣層下，溶解於20 毫升的乙醇中，予以加熱迴流直到成為澄清溶液，然後加 入0.8毫升的Trit〇n B (在甲醇中之40%溶液），於75°C的 浴溫下將混合物授拌1小時’以TLC檢測仍有起始材 料，於是再加入0.82克的1-(4-氟苯基)-2-丁蒙|，將混合物 再加熱迴流2小時’反應液冷卻後’蒸餾除去溶劑，令殘 留物溶解於乙酸乙酯’以飽和的鹽水洗滌，乾燥，過濾並 濃縮之，得到呈非對映立體異構物與特定異構物之混合物 的粗製品，將其置於矽膠60上純化及部分分劃，先以甲 苯，再以甲苯/乙酸乙酯(24:1)為移動相溶離（見實例45a與 45b)。 MS (ESI) ： m/z=395 (M+H)+ 實例45a 消旋-順式-3-(3,5-二氟苯基)-2-(4-氟苯基羥基_5_甲基 苯基環戊-2-稀酮 經濟部智慧財產局員工消費合作社印製 20 與 消旋-順式_4_(3,5_二氟笨基)_2_(4_氟苯基X海 本基被戊-2-稀銅 羥基i甲基一3_ (非對映立體異構物i ’特定異構物之混合物F 8 8 This paper size is in accordance with China National Standard (CNS) A4 (210x297 mm) 200400936 A7 B7 V. Description of the invention 87 10 15 1.2 g (4.87 mmol) of 1- (3,5-difluorobenzene) (Methyl) -2-phenylethyl 4,4-dione (Example XXIII) and 1.62 g (9.75 mmol) of 1- (4-fluorophenyl) 2-butanone (Example I) ' Under an argon layer, dissolve in 20 ml of ethanol, heat to reflux until it becomes a clear solution, then add 0.8 ml of Triton B (40% solution in methanol), and remove the solution at a bath temperature of 75 ° C. The mixture was allowed to stir for 1 hour. 'The starting material was still detected by TLC, so 0.82 g of 1- (4-fluorophenyl) -2-butane was added, and the mixture was heated to reflux for another 2 hours.' After the reaction solution was cooled ' The solvent was distilled off, and the residue was dissolved in ethyl acetate ', washed with saturated brine, dried, filtered, and concentrated to obtain a crude product as a mixture of diastereoisomers and specific isomers, which was placed in Purified and partially partitioned on silica gel 60. Toluene was first dissolved in toluene and then toluene / ethyl acetate (24: 1) as mobile phase (see Examples 45a and 45b). MS (ESI): m / z = 395 (M + H) + Example 45a Racemic-cis-3- (3,5-difluorophenyl) -2- (4-fluorophenylhydroxy-5_methylphenylcyclopentane-2-dilute Printed by the Consumers' Cooperative of the Intellectual Property Bureau of the Ministry of Ketone Economics and 20 with racemic-cis_4_ (3,5_difluorobenzyl) _2_ (4_fluorophenyl X Haibenyl by pent-2-dilute copper hydroxy i Methyl- 3_ (diastereoisomer i 'mixture of specific isomers

200400936 kl B7 經濟部智慧財產局員工消費合作社印製 五、發明說明（88 )200400936 kl B7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the invention (88)

15 收量：685毫克(理論值之18%) MS [DCI (NH3)] m/z=412 (M+NH4)+ HPLC (方法 1) : Rt=5.1 分鐘 Rf=0.51 (甲苯/乙酸乙酯9:1) 20 實例45b 消旋-反式-3-(3,5-二氟苯基)-2-(4-氟苯基)-4-羥基-5-甲基-4-苯基環戊-2-烯酮 與 消旋-反式-4-(3,5-二氟苯基)-2-(4-氟苯基)-4-羥基-5-甲基-3- -90-15 Yield: 685 mg (18% of theory) MS [DCI (NH3)] m / z = 412 (M + NH4) + HPLC (Method 1): Rt = 5.1 min Rf = 0.51 (toluene / ethyl acetate 9: 1) 20 Example 45b Racemic-trans-3- (3,5-difluorophenyl) -2- (4-fluorophenyl) -4-hydroxy-5-methyl-4-phenyl ring Pent-2-enone and racemic-trans-4- (3,5-difluorophenyl) -2- (4-fluorophenyl) -4-hydroxy-5-methyl-3- -90-

本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200400936 A7 B7 五、發明說明（89 ) 苯基環戊-2-烯酮 (非對映立體異構物2,特定異構物之混合物)This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 200400936 A7 B7 V. Description of the invention (89) Phenylcyclopent-2-enone (diastereomer 3, specific isomeric Mixture of structures)

經濟部智慧財產局員工消費合作社印製 收量：497毫克(理論值之13%) MS [DCI (NH3)] m/z=412 (M+NH4)+ HPLC (方法 1) : Rt=5.1 分鐘 20 Rf=0.36 (甲苯/乙酸乙酯9:1) 分離實例45a之特定異構物與對映立體異構物 將635毫克實例45a之混合物溶解於15毫升的異丙 醇與35毫升的異己烷中，再以製備性HPLC於手性相 -91- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200400936 A7 B7 五、發明說明（9〇) • (Daicel Chiralpak AD，10 微米，250 X 20 mm)中分離，以異 己烷/異丙醇(90:10)之單一溶離相溶離，分劃並濃縮溶劑 後，得到下面四種同分異構的純化合物： 5 實例46輿實例47 順式-3-(3,5-二氣苯基)-2-(4-氣苯基)-4-每基-5-甲基-4-苯基 環戊-2-烯酮Printed yield of employees' cooperatives in the Intellectual Property Bureau of the Ministry of Economic Affairs: 497 mg (13% of theory) MS [DCI (NH3)] m / z = 412 (M + NH4) + HPLC (Method 1): Rt = 5.1 minutes 20 Rf = 0.36 (toluene / ethyl acetate 9: 1) Separation of specific isomers and enantiomers of Example 45a Dissolve 635 mg of the mixture of Example 45a in 15 ml of isopropanol and 35 ml of isohexane Then, the preparative HPLC was applied to the chiral phase-91- This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 200400936 A7 B7 V. Description of the invention (9〇) • (Daicel Chiralpak AD, 10 micron, 250 X 20 mm), separated with a single dissociation phase of isohexane / isopropanol (90:10), and partitioned and concentrated the solvent to obtain the following four isomeric pure compounds: 5 Examples 46 Example 47 Cis-3- (3,5-Diphenylphenyl) -2- (4-Gaphenyl) -4-Peryl-5-methyl-4-phenylcyclopent-2-ene ketone

15 實例46(鏡像物1) 收量：50毫克 經濟部智慧財產局員工消費合作社印製 HPLC (Daicel Chiralpak AD，異己烷/異丙醇 90:10): Rt=5.43 分鐘 20 ^-NMRCSOO MHz, CDC13) ： 6=1.3 (d, 3H) ； 2.21 (s, 1H)； 2.92 (q, 1H) ； 6.65 (m, 3H) ； 7.0-7.06 (m, 2H) ； 7.22-7.49 (m, 7H). -92- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200400936 A7 B7 五、發明說明（91) 實例47(鏡像物2) 收量：70毫克 HPLC (Daicel Chiralpak AD，異己烷/異丙醇 90:10): Rt=6.48 分鐘 5 !Η-ΝΜΚ(300 MHz, CDC13) ： 5=1.3 (d, 3H) ； 2.22 (s, 1H)； 2.93 (q, 1H) ； 6.6-6.68 (m, 3H) ； 6.97-7.06 (m, 2H) ； 7.21-7.38 (m, 7H). 實例48輿實例49 10 順式-4-(3,5-二敗苯基)-2-(4-氣苯基)-4-輕基-5-甲基-3-苯基 環戊-2-烯酮15 Example 46 (mirror 1) Yield: 50 mg Printed by HPLC (Daicel Chiralpak AD, isohexane / isopropanol 90:10) at the Consumer Cooperatives of Intellectual Property Bureau of the Ministry of Economic Affairs: Rt = 5.43 minutes 20 ^ -NMRCSOO MHz, CDC13): 6 = 1.3 (d, 3H); 2.21 (s, 1H); 2.92 (q, 1H); 6.65 (m, 3H); 7.0-7.06 (m, 2H); 7.22-7.49 (m, 7H) -92- This paper size is in accordance with Chinese National Standard (CNS) A4 (210x297 mm) 200400936 A7 B7 V. Description of the Invention (91) Example 47 (Mirror 2) Yield: 70 mg HPLC (Daicel Chiralpak AD, different) Alkane / isopropanol 90:10): Rt = 6.48 minutes 5! -NMK (300 MHz, CDC13): 5 = 1.3 (d, 3H); 2.22 (s, 1H); 2.93 (q, 1H); 6.6 -6.68 (m, 3H); 6.97-7.06 (m, 2H); 7.21-7.38 (m, 7H). Example 48 and Example 49 10 cis-4- (3,5-diphenylphenyl) -2- (4-Gasphenyl) -4-yl-5-methyl-3-phenylcyclopent-2-enone

經濟部智慧財產局員工消費合作社印製 20 實例48(鏡像物1) 收量：230毫克 HPLC (Daicel Chiralpak AD，異己烷/異丙醇 90:10): Rt=4.81 分鐘 !Η-ΝΜΚ(500 MHz, CDC13) ： 5=1.28 (d, 3H) ； 2.3 (s} 1H)； -93- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200400936 A7 B7 五、發明說明（92) 2.82 (q, 1H) ； 6.68 (t, 1H) ； 6.93-7.04 (m, 4H) ； 7.12-7.3 (m, 7H). 實例49(鏡像物2) 5 收量：210毫克 HPLC (Daicel Chiralpak AD，異己烷/異丙醇 90:10): Rt=6.03 分鐘 !Η-ΝΜΚ(300 MHz, CDC13) ： <5=1.3 (d, 3H) ； 2.23 (s, 1H)； 2.81 (q, 1H) ； 6.68 (m, 1H) ； 6.92-7.02 (m, 4H) ； 7.1-7.3 (m, 10 7H). 列於下面表中的諸實例為依照上述實例45至49的方 法製備得者： 經濟部智慧財產局員工消費合作社印製 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200400936 A7 B7 五、發明說明（93 ) 經濟部智慧財產局員工消費合作社印製 實例編號 結構 HPLC (方法2): 'H- NMR (CDC13): 50 QO CN Rt= 9.82 分鐘 (異己院/異丙醇 90:10; Daicel Chiralpak AD) (200 MHz): δ = 1.3 (d, 3H); 2.25 (s, 1H); 2.95 (q, 1H); 6.96-7.5 (m, 13H) 51 \_AuOH QO CN Rt= 12.48 分鐘 (異己烧/異丙醇 90:10; Daicel Chiralpak AD) (200 MHz): 5 = 1.31 (d, 3H); 2.25 (s, 1H); 2.95 (q, 1H); 6.96-7.5 (m, 13H) 52 op NC Rt= 10.81 分鐘 (異己烧/異丙醇 90:10; Daicel Chiralpak AD) (200 MHz): δ = 1.3 (d, 3H); 2.3 (s, 1H); 2.81 (q, 1H);6.94-7.8 (m, 13H) 53 \_Uon op NC Rt= 13,49 分鐘 (異己燒/異丙醇 90:10； Daicel Chiralpak AD) (500 MHz): δ =1.3 (d, 3H); 2.45 (s, 1H); 2.79 (q, 1H); 6.97-7.8 (m, 13H) -95- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200400936 A7 B7 五、發明說明（94) -96- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐）Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economy 20 Example 48 (Mirror 1) Yield: 230 mg HPLC (Daicel Chiralpak AD, isohexane / isopropanol 90:10): Rt = 4.81 minutes! Η-ΝΜΚ (500 MHz, CDC13): 5 = 1.28 (d, 3H); 2.3 (s) 1H); -93- This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200400936 A7 B7 V. Description of the invention (92 ) 2.82 (q, 1H); 6.68 (t, 1H); 6.93-7.04 (m, 4H); 7.12-7.3 (m, 7H). Example 49 (Mirror 2) 5 Yield: 210 mg HPLC (Daicel Chiralpak) AD, isohexane / isopropanol 90:10): Rt = 6.03 minutes! Η-NMK (300 MHz, CDC13): < 5 = 1.3 (d, 3H); 2.23 (s, 1H); 2.81 (q, 1H); 6.68 (m, 1H); 6.92-7.02 (m, 4H); 7.1-7.3 (m, 10 7H). The examples listed in the table below are prepared according to the methods of Examples 45 to 49 above: Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs of the Consumer Cooperatives. The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210x297 mm) 200400936 A7 B7 V. Description of the invention (93) Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs ’Consumer Cooperatives. HPLC (Method 2): 'H- NMR (CDC13): 50 QO CN Rt = 9.82 minutes (isogenes / isopropanol 90:10; Daicel Chiralpak AD) (200 MHz): δ = 1.3 (d, 3H); 2.25 (s, 1H); 2.95 (q, 1H); 6.96-7.5 (m, 13H) 51 \ _AuOH QO CN Rt = 12.48 minutes (isohexane / isopropanol 90:10; Daicel Chiralpak AD) (200 MHz) : 5 = 1.31 (d, 3H); 2.25 (s, 1H); 2.95 (q, 1H); 6.96-7.5 (m, 13H) 52 op NC Rt = 10.81 minutes (isohexane / isopropanol 90:10; Daicel Chiralpak AD) (200 MHz): δ = 1.3 (d, 3H); 2.3 (s, 1H); 2.81 (q, 1H); 6.94-7.8 (m, 13H) 53 \ _Uon op NC Rt = 13,49 Minutes (isohexane / isopropanol 90:10; Daicel Chiralpak AD) (500 MHz): δ = 1.3 (d, 3H); 2.45 (s, 1H); 2.79 (q, 1H); 6.97-7.8 (m, 13H) -95- This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 200400936 A7 B7 V. Description of the invention (94) -96- This paper size applies the Chinese National Standard (CNS) A4 specification ( 210x297 mm)

實例編號 結構 HPLC (方法2): {U- NMR (CDC13): 54 ot U 非對映立體異構物1(順式), 鏡像物1 Rt =8.69 分鐘 (異己燒/異丙醇 93:7) (300 MHz): δ = 1.31 (d, 3H); 2.48 (d, 1H); 2.98 (q, 1H); 6.82-7.41 (m, 14H) 55 非對映立體異構物1 (順式), 鏡像物1 Rt=6.88 分鐘 (異己烧/異丙醇 93:7) (300 MHz): δ = 1.29 (d, 3H); 2.3 (d, 1H); 3.07 (q, 1H); 6.9 (m, 1H); 7.05-7.28 (m, 12H); 7.69 (m, 1H) 56 0 D F 非對映立體異構物1(順式), 鏡像物1 Rt=6.61 分鐘 (Daicel Chiralpak AD) (400 MHz): δ = 1.31 (d, 3H); 2.2 (s, 1H); 2.91 (q, 1H);6.85 (m, 3H); 7.08 (m, 1H); 7.23-7.45 (m, 10H) 經濟部智慧財產局員工消費合作社印製 200400936 A7 B7 五、發明說明（95 ) 經濟部智慧財產局員工消費合作社印製 實例編號 結構 HPLC (方法2): lH-NMR (CDC13):. 57 α ρ Rt=6.14 分鐘 (Daicel Chiralpak AD) (400 MHz): δ = 1.3 (d, 3H); 2.2 (s, IH); 2.85 (q, 1H); 6.92 (m, 1H); 7.09-7.32 Γ (m, 13H) 非對映立體異構物1(順式 鏡像物1 58 0 〇 Rt=6.12 分鐘 (異己烧/異丙醇 90:10; Daicel Chiralpak AD) (200 MHz): δ = 1.31 (d, 3H); 2.18 (br. s, 1H); 2.88 (q, 1H); 6.8 (m, 2H); 7.08- F 7.45 (m, 12H) 非對映立體異構物1(順式),. 鏡像物1 59 0^rCH3 F Rt= 6.86 分鐘 (異己炫/異丙醇 90:10; Daicel Chiralpak AD) (200 MHz): 5 = 1.31 (d, 3H); 2.18 (s, 1H); 2.85 (q, 1H); 6.98-7.45 (m, 14H) 非對映立體異構物1(順式), 鏡像物1 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） -97- 200400936 A7 B7 五、發明說明（96 ) 經濟部智慧財產局員工消費合作社印製 實例編號 結構 HPLC (方法2)·· 'H- NMR (CDC13): 60 F 非對映立體異構物1(順式)， 鏡像物1 二5.29 分鐘 (異己院/異丙醇 90:10; Daicel Chiralpak AD) (200 MHz): δ = 1.3 (d, 3H); 2.24 (s, 1H); 3.92 (q, 1H); 6.58-6.75 (m, 3H); 7.2-7.43 (m, 10H) 61 F 非對映立體異構物Π順式)， 鏡译物1 Rt =4.57 分鐘 (異己烷/異两醇 90:10; Daicel Chiralpak AD) (300 MHz): 5 = 1.31 (d, 3H); 2.23 (s, 1H); 2.82 (q, 1H); 6.68 (m, 1H); 6.98 (m, 2H); 7.12-7.34 (m, 10H) 62 F 非對映立體異構物1(順式l 鏡像物1 1 Rt=6.25 分鐘 (異己貌/異丙醇 90:10; Daicel j Chiralpak AD) (400 MHz): δ = 1.33 (d, 3H); 2.38 (d, 1H); 3.0 (q, 1H); 6.88 (m, 2H); 7.0 (m, 1H); 7.21-7.4 (m, 10H) -98- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200400936Example NumberStructural HPLC (Method 2): (U-NMR (CDC13): 54 ot U Diastereomer 1 (cis), Mirror 1 Rt = 8.69 min (isohexane / isopropanol 93: 7 ) (300 MHz): δ = 1.31 (d, 3H); 2.48 (d, 1H); 2.98 (q, 1H); 6.82-7.41 (m, 14H) 55 diastereoisomeric 1 (cis) , Mirror 1 Rt = 6.88 minutes (isohexane / isopropanol 93: 7) (300 MHz): δ = 1.29 (d, 3H); 2.3 (d, 1H); 3.07 (q, 1H); 6.9 (m , 1H); 7.05-7.28 (m, 12H); 7.69 (m, 1H) 56 0 DF diastereoisomeric 1 (cis), mirror 1 Rt = 6.61 minutes (Daicel Chiralpak AD) (400 MHz ): δ = 1.31 (d, 3H); 2.2 (s, 1H); 2.91 (q, 1H); 6.85 (m, 3H); 7.08 (m, 1H); 7.23-7.45 (m, 10H) Ministry of Economy Wisdom Printed by the Consumer Cooperative of the Property Bureau 200400936 A7 B7 V. Description of Invention (95) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economics Example number structure HPLC (Method 2): lH-NMR (CDC13):. 57 α ρ Rt = 6.14 Minutes (Daicel Chiralpak AD) (400 MHz): δ = 1.3 (d, 3H); 2.2 (s, IH); 2.85 (q, 1H); 6.92 (m, 1H); 7.09-7.32 Γ (m, 13H) Diastereoisomeric 1 (cis-mirror 1 58 0 〇Rt = 6.12 minutes (isohexane / isopropanol 90:10; Daicel Chiralpak AD) (200 MHz): δ = 1.31 (d, 3H); 2.18 (br.s, 1H); 2.88 (q , 1H); 6.8 (m, 2H); 7.08- F 7.45 (m, 12H) Diastereoisomeric 1 (cis) ,. Mirror 1 59 0 ^ rCH3 F Rt = 6.86 minutes Isopropanol 90:10; Daicel Chiralpak AD) (200 MHz): 5 = 1.31 (d, 3H); 2.18 (s, 1H); 2.85 (q, 1H); 6.98-7.45 (m, 14H) diastereomer Stereoisomers 1 (cis), Mirrors 1 This paper size applies Chinese National Standard (CNS) A4 specifications (210x297 mm) -97- 200400936 A7 B7 V. Description of the invention (96) Employees of Intellectual Property Bureau, Ministry of Economic Affairs Cooperative Society Printed Example Number Structure HPLC (Method 2) ... 'H-NMR (CDC13): 60 F Diastereoisomeric 1 (cis), Mirror 1 25.29 minutes (isopropyl compound / isopropanol 90) : 10; Daicel Chiralpak AD) (200 MHz): δ = 1.3 (d, 3H); 2.24 (s, 1H); 3.92 (q, 1H); 6.58-6.75 (m, 3H); 7.2-7.43 (m, 10H) 61 F diastereoisomeric cis), mirror translation 1 Rt = 4.57 min (isohexane / isodiol 90:10; Daicel Chiralpak AD) (300 M Hz): 5 = 1.31 (d, 3H); 2.23 (s, 1H); 2.82 (q, 1H); 6.68 (m, 1H); 6.98 (m, 2H); 7.12-7.34 (m, 10H) 62 F Diastereoisomeric 1 (cis-l mirror 1 1 Rt = 6.25 minutes (isohexyl / isopropanol 90:10; Daicel j Chiralpak AD) (400 MHz): δ = 1.33 (d, 3H); 2.38 (d, 1H); 3.0 (q, 1H); 6.88 (m, 2H); 7.0 (m, 1H); 7.21-7.4 (m, 10H) -98- This paper size applies to Chinese National Standard (CNS) A4 Specifications (210x297 mm) 200400936

1實例編號 結構1 instance number structure

6464

經濟部智慧財產局員工消費合作社印製Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

非對映立體異構物順式) 鏡像物1 非對映立體異構物1(順式) 鏡像物1 非對映立體異構物1(噸 鏡像物1 ’ HPLC (方法2): 'H- NMR (CDC13)： Rt=4.83 分鐘 (異己炫/異丙醇 90:10； Daicel Chiralpak AD). (400 MHz): 5 = 1.3 (d, 3H); 2.29 (s, 1H); 3.05 (q, 1H); 7.02-7.31 (m, 12H);7.49 (m, 1H) Rt == 7.52 分鐘 (異己烧/異丙醇 35:65) (400 MHz): 6 = 1.3 (d, 3H); 2.22 (br. s, 1H); 2.78 (q, 1H); 3.78 (br. s, 2H); 6.34 (d, 2H); 6.98 (d, 2H); 7.22-7.37 (m, 8H); 7.45 (dd, 2H) Rt = 4·73 分鐘 (異己烧/異丙醇 60:40; 0.2% DEA; Daicel Chiralpak AD) -99-Diastereoisomers cis) Mirror 1 Diastereomers 1 (cis) Mirror 1 Diastereomers 1 (Ton Mirror 1 'HPLC (Method 2):' H -NMR (CDC13): Rt = 4.83 minutes (Isoprene / isopropanol 90:10; Daicel Chiralpak AD). (400 MHz): 5 = 1.3 (d, 3H); 2.29 (s, 1H); 3.05 (q , 1H); 7.02-7.31 (m, 12H); 7.49 (m, 1H) Rt == 7.52 minutes (isohexane / isopropanol 35:65) (400 MHz): 6 = 1.3 (d, 3H); 2.22 (br. s, 1H); 2.78 (q, 1H); 3.78 (br. s, 2H); 6.34 (d, 2H); 6.98 (d, 2H); 7.22-7.37 (m, 8H); 7.45 (dd , 2H) Rt = 4.73 minutes (isohexane / isopropanol 60:40; 0.2% DEA; Daicel Chiralpak AD) -99-

本紙張尺度遇用τ图圈豕孫準(CNS^A規格（21〇 X 297公髮) 200400936 A7 B7 五、發明說明（98 ) 經濟部智慧財產局員工消費合作社印製 實例編號 結構 hplc (方法2): !H- NMR (CDC13): · 66 (?〇 非對映立體異構物1(順式)， 鏡像物1 Rt =5.46 分鐘 (異己院/異丙醇 90:10; Daicel Chiralpak AD) 67 Rt=7.95 分鐘 (異己炫/乙醇 90:10; Daicel Chiralpak AD)) \ ' (400 MHz): δ = 0.87-1.25 (m, 6H); 1.29 (d, 3H); 1.45-1.85 (m, 5H); 2.05 (d, 1H); 2.75 (q, 1H); 6.89 (t, 2H);7.13(m, 2H); 7.35 (m, 5H) 68 ch3 非對映立體異構物U順式h 鏡像物1 Rt= 5.32 分鐘 (方法1) 69 DO h3c Rt=5.29 分鐘 (方法1) -100- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200400936 A7 B7 五、發明說明（99 ) 經濟部智慧財產局員工消費合作社印製 實例編號 結構 ~ HPLC (方法2): 'H- NMR (CDC13): 70 非對映立體異構物Η順式), 鏡像物1 .Rt=5.75 分鐘 (異己烧/異丙醇 80:20) 71 〇13 非對映立體異構物1(順式), 鏡像物1 Rt = 4.45 分鐘 (異己烧/異丙醇 80:20) 72 cr 非對映立體異構物1(順式), 鏡像物1 __ (400 MHz): δ 二 1_3 (d, 3H); 2.3 (d, 1H); 2.94 (q, 1H); 7.05 (d, 1H); 7.2-7.39 (m, 10H); 7.45 (dd, 1H); 8.14 (d, 1H) 73 OQ Cl (400 MHz): 5= 1.3 (d, 3H)； 2.3 (d, 1H); 2.94 (q, 1H); 7.05 (d, 1H); 7.2-7.39 (m, 10H); 7.45 (dd, 1H); 8.14 (d, 1H) -101- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200400936 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明（100) 實例編號 結構 HPLC (方法2): lH- NMR (CDC13)： 74 C^V〇c；3 1^=5.2分鐘 (200 MHz): 5= 137 5 (方法1) (d, 3H); 2.35 (s, 1H); 2.8 (q, 1H); 6.68 (d, 1H); 7.0-7.53 (m, 14H) 非對映立體異構物Η順式)， 消旋異構物 _ 10 75 Rt= 5.04 分鐘 (200 MHz): δ = 1.02 (方法1) (d, 3H); 2.35 (s, 1H); 3.18 (q, 1H);6.85 (d, 1H); 7.0-7.35 (m, 12H); 7.45 (m, 1H); 7.59 (m, 1H) 非對映立體異構物2(反式), 15 消旋異構物 實例76消旋-反式-2,2-二甲基-1，4,5-三苯基-2-環戊烯-1，3-二酮This paper scale meets the τ map circle, Sun Zhun (CNS ^ A specification (21 × X 297)) 200400936 A7 B7 V. Description of the invention (98) Printed by the consumer property cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Example number structure hplc (method 2):! H-NMR (CDC13): · 66 (? 〇 diastereoisomeric 1 (cis), mirror 1 1 Rt = 5.46 minutes (isoquinon / isopropanol 90:10; Daicel Chiralpak AD ) 67 Rt = 7.95 minutes (Dioxin / ethanol 90:10; Daicel Chiralpak AD)) \ '(400 MHz): δ = 0.87-1.25 (m, 6H); 1.29 (d, 3H); 1.45-1.85 (m , 5H); 2.05 (d, 1H); 2.75 (q, 1H); 6.89 (t, 2H); 7.13 (m, 2H); 7.35 (m, 5H) 68 ch3 diastereomeric stereoisomer U-cis h Mirror 1 Rt = 5.32 minutes (method 1) 69 DO h3c Rt = 5.29 minutes (method 1) -100- This paper size applies the Chinese National Standard (CNS) A4 specification (210x297 mm) 200400936 A7 B7 V. Description of the invention (99) Example number structure printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economics ~ HPLC (Method 2): 'H-NMR (CDC13): 70 diastereoisomeric stereoisomer cis), mirror image 1 .Rt = 5.75 minutes (isohexane / isopropanol 80:20) 71 〇1 3 Diastereoisomer 1 (cis), mirror image 1 Rt = 4.45 minutes (isohexane / isopropanol 80:20) 72 cr Diastereomer, 1 (cis), mirror image 1 __ (400 MHz): δ 2 1_3 (d, 3H); 2.3 (d, 1H); 2.94 (q, 1H); 7.05 (d, 1H); 7.2-7.39 (m, 10H); 7.45 (dd, 1H) ); 8.14 (d, 1H) 73 OQ Cl (400 MHz): 5 = 1.3 (d, 3H); 2.3 (d, 1H); 2.94 (q, 1H); 7.05 (d, 1H); 7.2-7.39 ( m, 10H); 7.45 (dd, 1H); 8.14 (d, 1H) -101- This paper size applies to the Chinese National Standard (CNS) A4 specification (210x297 mm) 200400936 A7 B7 Preparation of the invention (100) Example No. Structure HPLC (Method 2): lH-NMR (CDC13): 74 C ^ V〇c; 3 1 ^ = 5.2 minutes (200 MHz): 5 = 137 5 (Method 1) (d, 3H); 2.35 (s, 1H); 2.8 (q, 1H); 6.68 (d, 1H); 7.0-7.53 (m, 14H) diastereoisomeric isomers (cis), racemic isomers Structure_ 10 75 Rt = 5.04 minutes (200 MHz): δ = 1.02 (Method 1) (d, 3H); 2.35 (s, 1H); 3.18 (q, 1H); 6.85 (d, 1H); 7.0- 7.35 (m, 12H); 7.45 (m, 1H); 7.59 (m, 1H) Enantiomer 2 (trans), 15 Examples of racemates 76 Racem-trans-2,2-dimethyl-1,4,5-triphenyl-2-cyclopentene-1 , 3-dione

本紙張尺度適用令國國家標準(CNS)A4規格（210x297公釐） 200400936 A7 B7 五、發明說明（101) 將400毫克（1.44毫莫耳）的消旋-4-羥基-5,5-二甲基-2,3-二苯基-2-環戊烯-1-酮（實例XXXV)溶解於5毫升的 THF中並予以冷卻至-78°C，然後在-78°C下滴入3.59毫莫 耳的苯基鋰(在環己烷/二乙醚中之1.8 Μ溶液），於此溫度 5 下將反應混合物攪拌1.5小時，經2毫升的水水解後，回 溫至室溫，有機層經5毫升的乙酸乙酯萃取並以硫酸鈉乾 燥後，於真空下蒸發除去溶劑，殘留物經製備性HPLC(RP 18柱層，溶離液：乙腈/水，梯度：10:90—90:10)，產物 再自二乙醚/正庚烷中進行再結晶。 10 收量：102毫克（理論值之20%) LC-MS (方法 4) : Rt=4.14 分鐘 MS (ESI+) : m/z=339 (M+H-H20)+ !Η-ΝΜΚ(200 MHz, CDC13) ： <5 =0.79 (s, 3H) ； 1.23 (s, 3H) ； 2.02 (d, 1H) ； 2.87 (s, 1H) ； 4.68 (d, 1H) ； 6.98-7.39 15 (m, 15H). 實例77 漭漩-a/人廣式-2-甲基-1，4,5-三苯基-2-環戊烯-1，3-二酮 經濟部智慧財產局員工消費合作杜印製This paper size applies the national standard (CNS) A4 specification (210x297 mm) 200400936 A7 B7 V. Description of the invention (101) 400 mg (1.44 mmol) of racemic-4-hydroxy-5,5-di Methyl-2,3-diphenyl-2-cyclopenten-1-one (Example XXXV) was dissolved in 5 ml of THF, cooled to -78 ° C, and then dropped to 3.59 at -78 ° C. Millimoles of phenyllithium (1.8 M solution in cyclohexane / diethyl ether). The reaction mixture was stirred at this temperature for 1.5 hours. After hydrolysis with 2 ml of water, the temperature was returned to room temperature. The organic layer After extraction with 5 ml of ethyl acetate and drying over sodium sulfate, the solvent was removed by evaporation under vacuum. The residue was subjected to preparative HPLC (RP 18 column, eluent: acetonitrile / water, gradient: 10: 90-90: 10 ), The product was recrystallized from diethyl ether / n-heptane. 10 Yield: 102 mg (20% of theory) LC-MS (Method 4): Rt = 4.14 minutes MS (ESI +): m / z = 339 (M + H-H20) +! Η-ΝΜΚ (200 MHz , CDC13): < 5 = 0.79 (s, 3H); 1.23 (s, 3H); 2.02 (d, 1H); 2.87 (s, 1H); 4.68 (d, 1H); 6.98-7.39 15 (m, 15H). Example 77 Spiral-a / Human Cantonese-2-methyl-1,4,5-triphenyl-2-cyclopentene-1,3-dione Consumer Cooperative Cooperation of Intellectual Property Bureau, Ministry of Economic Affairs Print

本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200400936 A7 B7 五、發明說明（1G2) ---~ 將400毫克(15毫莫耳）的實例χχχνι化合物，依類 似於/例76的方法，與25毫升(3 78毫莫耳)的苯基鐘 (在環己烧/一乙醚中之1 8 Μ溶液)反應。 收量：218毫克（理論值之42〇/〇) 5 LC-MS (方法 4) : Rt=4.02 分鐘 MS (ESI ) . m/z=365 (M+Na)+ > 325 (Μ+Η-Η20)+ ^-NMROOO MHz, CDC13) ： 5=1.1 (d, 3H) ； 2.0 (d, 1H)； 2.52 (m, 1H) ； 2.64 (s, 1H) ； 5.06 (t, 1H) ； 7.0-7.35 (m, 15H). 10 C.醫藥組成物之具體實例 根據本發明的化合物可依照下述方式被配製成醫藥組 成物： 錠劑： 15 組成： 100毫克實例1的化合物，1·5〇毫克的乳糖(單水合 物）’ 50毫克的玉米殺粉(天然物），1〇毫克的聚乙烯吼略 烧酮(PVP 25)(得自：BASF，Ludwigshafen，Germany)與 2 經濟部智慧財產局員工消費合作社印製 毫克的硬脂酸鎂。 20 錠劑重212毫克，直徑8毫米，曲徑12毫米。 製備： 將活性組成分之混合物、乳糖與澱粉，與溶於水之 5% (m/m)PVP溶液一起作成團粒，乾燥後，將團粒與硬脂 -104- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200400936 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（103) 酸鎂混合5分鐘，使用習用的錠劑壓片機（參照前面的藥 片型式)將混合物塑型，施加的模塑力量為典型的15 kN。 經口服投與之懸浮劑: 5 組成： 1000毫克實例1的化合物，1000毫克的乙醇(96%)， 400毫克的Rhodigel (得自美國賓州FMC之一種三仙膠 (xanthan gum))與 99 克水。 相當於單劑量之10毫升口服懸浮劑中含有100毫克 10 根據本發明的化合物。 製備： 將Rhodigel懸浮於乙醇後，將活性組分加至懸浮液 中，邊授拌邊加水，持續授拌約6小時直到Rhodigel膠膨 15 脹完全。 -105- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐）This paper size applies the Chinese National Standard (CNS) A4 specification (210x297 mm) 200400936 A7 B7 V. Description of the invention (1G2) --- ~ 400 mg (15 millimoles) of the example χχχνι compound, similar to / example The method of 76 was reacted with 25 ml (37 78 mol) of phenyl bell (18 M solution in cyclohexane / monoethyl ether). Yield: 218 mg (42 / theoretical value) 5 LC-MS (Method 4): Rt = 4.02 minutes MS (ESI). M / z = 365 (M + Na) + > 325 (Μ + Η) -Η20) + ^-NMROOO MHz, CDC13): 5 = 1.1 (d, 3H); 2.0 (d, 1H); 2.52 (m, 1H); 2.64 (s, 1H); 5.06 (t, 1H); 7.0 -7.35 (m, 15H). 10 C. Specific examples of pharmaceutical composition The compound according to the present invention can be formulated into a pharmaceutical composition in the following manner: Lozenge: 15 Composition: 100 mg of the compound of Example 1, 1 · 50 mg of lactose (monohydrate) '50 mg of corn bactericidal (natural), 10 mg of polyvinyl valerone (PVP 25) (obtained from BASF, Ludwigshafen, Germany) and 2 Ministry of Economy The Intellectual Property Bureau employee consumer cooperative prints mg of magnesium stearate. The 20 tablets weigh 212 mg, have a diameter of 8 mm, and have a meandering diameter of 12 mm. Preparation: The mixture of active ingredients, lactose and starch, and 5% (m / m) PVP solution in water are used to form granules. After drying, the granules and stearin-104- This paper size applies Chinese national standards ( CNS) A4 size (210 X 297 mm) 200400936 Printed by the Consumers ’Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (103) Magnesium acid is mixed for 5 minutes using a conventional tablet press (refer to the previous tablet) Type) The mixture is shaped with a typical molding force of 15 kN. Suspension by oral administration: 5 Composition: 1000 mg of the compound of Example 1, 1000 mg of ethanol (96%), 400 mg of Rhodigel (xanthan gum from FMC, Pennsylvania, USA) and 99 Grams of water. A single dose of 10 ml of oral suspension contains 100 mg 10 of a compound according to the invention. Preparation: After suspending Rhodigel in ethanol, add the active ingredient to the suspension, add water while stirring, and continue mixing for about 6 hours until Rhodigel gels and swells completely. -105- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)

Claims (1)

經濟部智慧財產局員工消費合作社印製 200400936 A8 B8 C8 D8 六、申請專利範圍 1. 式(I)之化合物Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, 200400936 A8 B8 C8 D8 VI. Patent Application Scope 1. Compound of Formula (I) R6 其中 R1為(C6-C10)-芳基或帶有至多達兩個選自N、0及/ 10 或S的雜原子之5-或6-員雜芳基，其各可分別獨 立地經一至三個選自下列的基取代：鹵素， (CrQ)-烷基，三氟甲基，氰基，羥基，（C丨-c6)-烧氧基’三敗甲氧基，缓基’（C1-C4)-烧氧基幾基， -C(0)-NR9R1()，胺基，單-與二-(CVC6)-烷基胺基， 15 其中 上述的烧基與烧氧基也另可取代下列基：經基’ (C1-C4)-烧氧基’叛基，（C1-C4)*•烧•氧基幾基’胺基， 單-或二-(CrC4)-烷基胺基，且 R9與R1Q，分別獨立地，為氫或(Q-Q)-烷基， 20 A 為鍵或(CrC4)-烷二基，（C2-C4)-烯二基或(C2-C4)- 炔二基， R2與R5，分別獨立地，為吡啶基，噻吩基，呋喃基， 苯並呋喃基，四氫吡喃基，環己基或苯基，其各可 經取代一或二個，分別獨立地，選自下列基：鹵素， -106 - 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 92077B.docR6 wherein R1 is a (C6-C10) -aryl group or a 5- or 6-membered heteroaryl group having up to two heteroatoms selected from N, 0 and / 10 or S, each of which may be independently One to three substituents selected from the group consisting of: halogen, (CrQ) -alkyl, trifluoromethyl, cyano, hydroxy, (C 丨 -c6) -carbyloxy'tridecylmethoxy, tartaryl '( C1-C4) -alkyloxy, -C (0) -NR9R1 (), amine, mono- and di- (CVC6) -alkylamino, 15 The following groups can be substituted: via the group ((C1-C4) -alkyloxy), (C1-C4) * • alkyloxy-amino group, mono- or di- (CrC4) -alkylamine And R9 and R1Q are each independently hydrogen or (QQ) -alkyl, 20 A is a bond or (CrC4) -alkanediyl, (C2-C4) -alkenyl or (C2-C4)- The alkynyl diyl groups, R2 and R5, are each independently pyridyl, thienyl, furyl, benzofuryl, tetrahydropyranyl, cyclohexyl or phenyl, each of which may be substituted by one or two, respectively Independently, selected from the following bases: halogen, -106-This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 92077B.doc 200400936 六、申請專利範圍 經濟部智慧財產局員工消費合作社印製 101520 A8 B8 C8 D8 (CVC6)-烧基’二1曱基’氣基，胺基，（C1_C6)_^ 氧基或三氟甲氧基，其中上述的烷基與烷氧基另可 再經下列基取代：羥基，（CVQ)-烷氧基，^基， (C〗-C4)-烷氧基羰基，胺基，單-或二_(Ci_C4)_烷基胺 基， r3與R4，分別獨立地，為氫，（Cl_C6)_烧基，（C2_C6)_ 烯基’（Q2-C6)-快基或(Cs-Cs)-環烧基，其各可經取 代一至三個，分別獨立地，選自下列之基：羥基， (Ci-C6)-烧氧基，氰基，氟，氯，-νκ11^12， -C(0)-0R13，-C(0)-NRuR12，_S〇2-〇R13 與 -so2-nrur12，其中 R11，R12與R13，分別獨立地，為氫或(Cl_C6)_烧基， 或 R3與R4，一起與其附接的碳形成3-至6-員的，螺-連 繫的環烷基環， R6為氫，（CrC6)-烷基，（CrQ)-烷醯基或式 -C(0)-C(0)-0R14 之基，其中 R14 為氫或(crc6)-烷基， R7為氫， R8為經基， 或 R7與R8 —起與其附接的碳形成羰基或式C=N-0-R15 之基，其中 R15 為氫或為(crc6)-烷基之基，其可經取代下 -107 - 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐）200400936 VI. Scope of Patent Application Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 101520 A8 B8 C8 D8 (CVC6) -Alkyl-based 'di-l-fluorenyl' gas, amine, (C1_C6) _ ^ Oxygen, in which the above-mentioned alkyl and alkoxy groups may be further substituted by the following groups: hydroxy, (CVQ) -alkoxy, alkyl, (C〗 -C4) -alkoxycarbonyl, amino, mono- Or di_ (Ci_C4) _alkylamino, r3 and R4, independently, are hydrogen, (Cl_C6) _alkenyl, (C2_C6) _alkenyl '(Q2-C6) -quick radical or (Cs-Cs ) -Cycloalkyl, each of which may be substituted by one to three, each independently selected from the group consisting of: hydroxyl, (Ci-C6) -alkyloxy, cyano, fluorine, chlorine, -νκ11 ^ 12,- C (0) -0R13, -C (0) -NRuR12, _S〇2-〇R13 and -so2-nrur12, where R11, R12 and R13 are each independently hydrogen or (Cl_C6) _alkyl, or R3 With R4, together with the carbon to which it is attached, forms a 3- to 6-membered, spiro-linked cycloalkyl ring, R6 is hydrogen, (CrC6) -alkyl, (CrQ) -alkylfluorenyl, or formula -C (0) -C (0) -0R14, wherein R14 is hydrogen or (crc6) -alkyl, R7 is hydrogen, and R8 is a warp group, R7 and R8 together form a carbonyl group or a group of the formula C = N-0-R15 from the carbon to which it is attached, where R15 is hydrogen or a (crc6) -alkyl group, which can be replaced by -107-paper size Applicable to China National Standard (CNS) A4 (210 X 297 mm) 200400936 Αδ Β8 C8 ------— D8 ___ 六、申請專利範圍 之基：m基，（Cl_C6)_烷氧基，羧基，（CrC4)_ 烷氧基羰基或式-nr16r17或-c(o)-nr16r17之 基，其中 R16與R17,分別獨立地，為氫或(CrC6)_烷基， 5 以及其鹽類、溶劑化物與鹽類之溶劑化物用於控制疾 病。 2. 式(I)之化合物200400936 Αδ Β8 C8 ------— D8 ___ 6. The scope of patent application: m group, (Cl_C6) _alkoxy, carboxyl group, (CrC4) _ alkoxycarbonyl or formula -nr16r17 or -c ( o) The group of -nr16r17, wherein R16 and R17, independently, are hydrogen or (CrC6) _alkyl, 5 and its salts, solvates and solvates of salts are used to control diseases. 2. Compounds of formula (I) 'R。 其中 R1為(CVCio)-芳基或帶有至多達兩個選自N、0及/ 15 或S的雜原子之5-或6-員雜芳基，其各可分別獨 經濟部智慧財產局員工消費合作社印製 立地經一至三個選自下列的基取代：鹵素， (CH：6)-烷基，三氟甲基，氰基，羥基，（CrQ)-烧氧基，三氟曱氧基，缓基，（C1-C4)-烧氧基幾基， -C(0)-NR9R1Q，胺基，單-與二-(CVC6)-烷基胺基， 20 其中 上述的烷基與烷氧基也另玎取代下列基：羥基’ (CrC4)-烷氧基，羧基，（crC4)-烷氧基羰基，胺基’ 早-或·—_(Ci_C4)-烧基胺基’立 R9與R1Q，分別獨立地’為氫或(Cl-C6)_烷基， -108 - 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200400936 A8 B8 C8 D8 六、申請專利範圍 A 為鍵或(CrC4)-烷二基，（c2-C4)-烯二基或(c2_C4)· 炔二基， R2與R5 ’分別獨立地，為吡啶基，噻吩基，呋喃基， 苯並呋喃基，四氫吡喃基，環己基或苯基，其各 5 可經取代一或二個，分別獨立地，選自下列基： 鹵素，（CrC6)-烷基’三氟甲基，氰基，胺基，(Ci_C6)_ 烷氧基或三氟甲氧基，其中上述的烷基與烷氧基 另可再經下列基取代：羥基’（Cl_c4)_烷氧基，羧 基’（C1-C4)-院氧基数基，胺基，單_或二_(crc4)_ 10 烷基胺基， R3與R4，分別獨立地，為氫’（CrC6)-烷基，（c2_c6)_ 烯基’（CrQ)-快基或(Q-Cs)-環烧基，其各可經取 代一至三個，分別獨立地，選自下列之基：羥基， (Ci_C6)_烧氧基’氰基，氟，氣，-NRUR12， 15 _C(0)-0R13，-C(0)-NRuR12，-SCVOR13 與 -scvnrHr12 ’ 其中 R11，R12與R13，分別獨立地，為氫或(CrC6)·烷基， 或 經 濟 部 智 慧 財 產 局 20 員 消 費 合 作 社 印 製 R3與R4 ’ 一起與其附接的碳形成3-至6-員的，螺-連 繫的環烷基環， R6為氫，（CrC6)-烷基，（CVQ)-烷醯基或式 -C(0)-C(0)-0R14之基，其中 R14 為氫或(CrC6)-烷基， R7為氫， -109 -'R. Where R1 is (CVCio) -aryl or a 5- or 6-membered heteroaryl group with up to two heteroatoms selected from N, 0 and / 15 or S, each of which may be independently owned by the Intellectual Property Office of the Ministry of Economic Affairs Employee Consumer Cooperative printed site is substituted with one to three groups selected from the group consisting of: halogen, (CH: 6) -alkyl, trifluoromethyl, cyano, hydroxyl, (CrQ) -carboxy, trifluorofluorenyl Group, slow group, (C1-C4) -alkoxyoxy group, -C (0) -NR9R1Q, amine group, mono- and di- (CVC6) -alkylamino group, 20 wherein the above-mentioned alkyl group and alkyl group Oxygen is also substituted for the following groups: hydroxy '(CrC4) -alkoxy, carboxyl, (crC4) -alkoxycarbonyl, amine' early-or --- ((Ci_C4) -alkenylamino) R9 And R1Q, respectively, are hydrogen or (Cl-C6) _alkyl, -108-This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 200400936 A8 B8 C8 D8 VI. Patent Application Range A is a bond or (CrC4) -alkanediyl, (c2-C4) -alkenyl or (c2_C4) · alkynediyl, R2 and R5 'are each independently pyridyl, thienyl, furyl, benzene Benzofuranyl, tetrahydropyranyl, cyclohexyl or phenyl, Each 5 may be substituted with one or two, each independently selected from the group consisting of: halogen, (CrC6) -alkyl'trifluoromethyl, cyano, amine, (Ci_C6) _alkoxy or trifluoromethyl Oxygen, in which the above-mentioned alkyl and alkoxy groups may be further substituted by the following groups: hydroxy '(Cl_c4) _alkoxy, carboxy' (C1-C4) -amino group, amine group, mono- or di- _ (crc4) _ 10 Alkylamino groups, R3 and R4, independently, are hydrogen '(CrC6) -alkyl, (c2_c6) _alkenyl' (CrQ) -quick or (Q-Cs) -ring Carbo groups, each of which may be substituted by one to three, are each independently selected from the group consisting of: hydroxyl, (Ci_C6) _alkenoxy 'cyano, fluorine, gas, -NRUR12, 15_C (0) -0R13, -C (0) -NRuR12, -SCVOR13 and -scvnrHr12 'Where R11, R12 and R13 are independently hydrogen or (CrC6) · alkyl, or R3 and R4 printed by the 20-member consumer cooperative of the Intellectual Property Bureau of the Ministry of Economy 'Together with the carbon to which it is attached forms a 3- to 6-membered, spiro-linked cycloalkyl ring, R6 is hydrogen, (CrC6) -alkyl, (CVQ) -alkylfluorenyl or formula -C (0 ) -C (0) -0R14, where R14 is hydrogen or (CrC6)- Group, R7 is hydrogen, -109-- 200400936 A8 B8 C8 D8 六、申請專利範圍 R8為經基， 或 R7與R8 —起與其附接的碳形成羰基或式C=N-0-R15 之基，其中 5 Rl5為氫或為(CVQO-烷基之基，其可經取代下列 之基：羥基，（CrC6)-烷氧基，羧基，（CrC4)-烷氧基羰基或式_nr16r17或-c(o)-nr16r17之 基，其中 R16與R17’分別獨立地，為氫或(CrC6)-烷基， 10 附帶條件是，R3不為氫或甲基，如果在同時間下， -A 為鍵結， 'Rl 為無取代的苯基， -R2與R5各為苯基，其為無取代的或在對位-經甲氧 基取代者， 15 -r4與R6各為氫且 -r7與R8 一起與其附接的碳形成羰基。 以及其鹽類、溶劑化物與鹽類之溶劑化物。 經濟部智慧財產局員工消费合作杜印製 3.根據申請專利範圍第2項之式⑴化合物 其中 20 Rl為(C6-C1())-芳基，其為經取代一至三個，分別獨立 地選自下列的基：鹵素，（CrC6)-烷基，三氟甲基， 氰基，羥基’（CrC6)-烷氧基，三氟曱氧基，羧基， (CVQ)-烷氧基羰基，-C(0)-NR9R1Q，胺基，單-與 一KCi-C6)_院基胺基， -110 - 本紙張尺度適用申國國家標準(CNS)A4規格（210x297公釐） 200400936 A8 B8 C8 D8 六、申請專利範圍 或 為帶有至多達兩個選自N、〇及/或S的雜原子之 5-或6-員雜芳基，其可經取代一至三個，分別獨 立地選自下列的基：鹵素，（CrC6)-烷基，三氟曱 5 基，氰基，羥基，（CVC6)-烷氧基，三氟甲氧基， 羧基，（CrC4)-烷氧基羰基，-C(0)-NR9R1G，胺基， 早·與一-(Ci-C6)-烧基胺基， 其中’各情況下， 上述的烷基與烷氧基另各可經取代下列基：羥 10 基，（Ci-C4)-烷氧基，羧基，（crc4)-烷氧基羰基， 胺基’单-與二烧基胺基’且 R9與R1G，分別獨立地，為氫或(CrC6)-烷基， A 為鍵或(CVQ)-烷二基，（C2-C4)-烯二基或(C2-C4)-炔二基， 15 R與R5，分別獨立地’為吼唆基，β塞吩基，吱喃基或 經濟部智慧財產局員工消費合作社印製 苯基，其各可經取代一或二個，分別獨立地，選 自下列基：鹵素，（crc6)_烷基，三氟甲基，氰基， (CrQ)-烷氧基或三氟甲氧基，其中上述的烷基與 烷氧基另可再經下列基取代：羥基，（CVQ)-烷氧 20 基’羧基，（CrC4)-烷氧基羰基，胺基，單-或二 -((^七士烧基胺基， R3與R4，分別獨立地，為氫，（Ci-CJ-烷基，（C2-C6)-烯基，（C2-C6)-炔基或(C3-C8)-環烷基，其各可經取 代一至三個，分別獨立地，選自下列之基：羥基， -111 - 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200400936 A8 BB C8 D8_ 六、申請專利範圍 . (CrC6)-烷氧基，氰基，氟，氣，-NRUR12， -C(0)-OR13 ，-C(0)-NRuR12 ，-S02-OR13 與 -S02-NRnR12，其中 RU，R12與R13,分別獨立地，為氫或(CVQO-烷基， 5 或 R3與R4，一起與其附接的碳形成3-至6-員的，螺-連 繫的環烷基環， R6為氫，（CrC6)-烷基，（CrC6)-烷醯基或式 -C(0)-C(0)-0R14之基，其中 10 R14為氫或(CrC6)-烷基， R7為氫， R8為羥基， 或 R7與R8 —起與其附接的碳形成羰基或式C=N-0-R15 15 之基，其中 經濟部智慧財產局員工消費合作社印製 R15為氫或為(CrC6)-烷基之基，其可經取代下列 之基：羥基，（Q-C6)-烷氧基，羧基，（CVCO-烷氧基羰基或式-NR16R17或-c(o)-nr16r17之 基，其中 20 R16與R17,分別獨立地，為氫或(CrC6)-烷基， 以及其鹽類、溶劑化物與鹽類之溶劑化物 4. 根據申請專利範圍第2項之式(I)化合物， 其中 -112- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200400936 AB B8 C8 D8 六、申請專利範圍 R為苯基，其為經取代一或二個，分別獨立地選自 下列的基：氟’亂’（C1-C4)-烧基，三氟曱基，氰 基，（crC4)-烧氧基’二氟甲氧基，羧基，（Ci_C4)_ 烷氧基羰基’ -C(0)-NR9R1G，胺基，單-與二_(Ci_c6)_ 5 烷基胺基， 或 為吡啶基’噻吩基’噁唑基或噻唑基，其各可經 取代一或二個，分別獨立地選自下列的基：氟， 氣，（C丨-C4)-炫基’三氟甲基，氰基，（C丨-c4)-烷氧 10 基，三氟甲氧基，羧基，（CVC4)-烷氧基羰基， -C(0)-NR9R1G ’ 胺基，單-與二-(Ci-C4)-烷基胺基， 其中，各情況下， R9與r1q，分別獨立地，為氫或(CrC6)-烷基， A 為鍵或為1，2-乙二基， 15 R2與H5，分別獨立地，為吡啶基，嘍吩基或苯基，其 各可經取代一或二個，分別獨立地，選自下列基： 氟，氣，（C1-C4)-燒基，三氟甲基，氰基，（C!-C4)-燒氧基或三氟甲氧基， 經濟部智慧財產局員工消费合作社印製 R 為氣或(C1-C4)-烧基， 20 r4為(CVC4)-烷基，其可經取代一成二個，分別獨立 地，選自下列之基：羥基，（Cl_C4)-烷氧基，-NRUR12 與-C(0)-0R13，其中 R11 ’ R12與R13 ’分別獨立地，為氫或(CrC4)-烧基’ 或 • 113 - 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200400936 A8 B8 C8 D8 六、申請專利範圍 . R3與R4，一起與其附接的碳形成螺-連繫的環丙基， 環丁基或環戊基環， R6為氫， 且 5 R7與R8 —起與其附接的碳形成羰基或式C=N-0-R15 之基，其中 R15為（CrC4)-烷基，其可經取代下列之基：羥 基，（CrC4)-烷氧基，羧基，（CrC4)-烷氧基羰 基或式-nr16r17或-c(o)-nr16r17之基，其中 10 R16與R17,分別獨立地，為氳或(CrCO-烷基， 以及其鹽類、溶劑化物與鹽類之溶劑化物。 5. 根據申請專利範圍第2項之式(I)化合物， 其中 R1為苯基，其為經取代一或二個，分別獨立地選自 15 下列的基：氟，氯，甲基，三氟甲基與甲氧基， A 為鍵， 經濟部智慧財產局員工消費合作社印製 R2與R5,分別獨立地，為苯基，其可經取代一或二個， 分別獨立地，選自下列基：氟，氯，甲基，三氧 甲基或氰基， 20 R3為氩，甲基或乙基， R4為甲基， 或 -114 - 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200400936 A8 B8 C8 D8 六、申請專利範圍 10 R3與R4，一起與其附接的碳形成螺-連繫的環丙基， 環丁基或環戊基環， R6為氫， 且 R7與R8—起與其附接的碳形成羰基或式C=N-0-CH3 之基， 以及其鹽類、溶劑化物與鹽類之溶劑化物。 6. 一種製備根據申請專利範圍第2項的式(I)化合物之方 法，特徵為 或是 [A]式(II)的化合物 Ο R Λ200400936 A8 B8 C8 D8 VI. The scope of patent application R8 is via a radical, or R7 and R8 together form a carbonyl group with the carbon to which it is attached or a group of formula C = N-0-R15, where 5 Rl5 is hydrogen or (CVQO- Alkyl radicals, which may be substituted with the following radicals: hydroxyl, (CrC6) -alkoxy, carboxyl, (CrC4) -alkoxycarbonyl or a radical of the formula —nr16r17 or —c (o) -nr16r17, where R16 Independently from R17 ', it is hydrogen or (CrC6) -alkyl, 10 with the proviso that R3 is not hydrogen or methyl. If at the same time, -A is a bond and' Rl is an unsubstituted phenyl group -R2 and R5 are each phenyl, which are unsubstituted or substituted at the para-methoxy group, 15-r4 and R6 are each hydrogen, and -r7 and R8 together form a carbonyl group with the carbon to which they are attached; Its salts, solvates and solvates of salts. Produced by the consumer cooperation of the Intellectual Property Bureau of the Ministry of Economic Affairs. 3. The compound of formula ⑴ according to item 2 of the scope of patent application, where 20 Rl is (C6-C1 ())-aromatic Group, which is one to three substituted, each independently selected from the group consisting of: halogen, (CrC6) -alkyl, trifluoromethyl, cyano, hydroxyl '(CrC6)- Oxy group, trifluorofluorenyloxy group, carboxyl group, (CVQ) -alkoxycarbonyl group, -C (0) -NR9R1Q, amine group, mono- and mono-KCi-C6) _yuan amino group, -110-paper Standards apply to the national standard (CNS) A4 specification (210x297 mm) 200400936 A8 B8 C8 D8 6. The scope of patent application may be 5-or with up to two heteroatoms selected from N, 0 and / or S 6-membered heteroaryl, which may be substituted by one to three, each independently selected from the group consisting of: halogen, (CrC6) -alkyl, trifluorofluorenyl-5, cyano, hydroxyl, (CVC6) -alkoxy Group, trifluoromethoxy group, carboxyl group, (CrC4) -alkoxycarbonyl group, -C (0) -NR9R1G, amine group, as early as mono- (Ci-C6) -alkylamino group, where 'in each case In the following, the above-mentioned alkyl group and alkoxy group may each be substituted with the following groups: hydroxy10 group, (Ci-C4) -alkoxy group, carboxyl group, (crc4) -alkoxycarbonyl group, and amino group 'mono- and di Alkylamino 'and R9 and R1G are each independently hydrogen or (CrC6) -alkyl, A is a bond or (CVQ) -alkanediyl, (C2-C4) -alkenyl or (C2-C4 ) -Alkynyl diyl, 15 R and R5, are each independently Or phenyl printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, each of which may be substituted by one or two, each independently selected from the following groups: halogen, (crc6) _alkyl, trifluoromethyl, cyano , (CrQ) -alkoxy or trifluoromethoxy, wherein the above-mentioned alkyl group and alkoxy group may be further substituted with the following groups: hydroxy, (CVQ) -alkoxy 20 group 'carboxyl, (CrC4) -alkane Oxycarbonyl, amine, mono- or di-((Heptastrylamino, R3 and R4, each independently, is hydrogen, (Ci-CJ-alkyl, (C2-C6) -alkenyl, (C2-C6) -alkynyl or (C3-C8) -cycloalkyl, each of which may be substituted by one to three, each independently selected from the group consisting of: hydroxyl, -111-This paper size applies to Chinese national standards (CNS) A4 specification (210x297 mm) 200400936 A8 BB C8 D8_ VI. Patent application scope. (CrC6) -alkoxy, cyano, fluorine, gas, -NRUR12, -C (0) -OR13, -C ( 0) -NRuR12, -S02-OR13 and -S02-NRnR12, where RU, R12 and R13, independently, are hydrogen or (CVQO-alkyl, 5 or R3 and R4, together with the carbon to which they are attached form 3- To 6-membered, spiral-linked ring Base ring, R6 is hydrogen, (CrC6) -alkyl, (CrC6) -alkylfluorenyl or a group of formula -C (0) -C (0) -0R14, where 10 R14 is hydrogen or (CrC6) -alkyl , R7 is hydrogen, R8 is hydroxyl, or R7 and R8 together form a carbonyl group with the carbon to which it is attached, or a base of the formula C = N-0-R15 15 where R15 is printed by hydrogen or Is a (CrC6) -alkyl group, which may be substituted with the following groups: hydroxyl, (Q-C6) -alkoxy, carboxyl, (CVCO-alkoxycarbonyl or formula -NR16R17 or -c (o)- The base of nr16r17, of which 20 R16 and R17 are each independently hydrogen or (CrC6) -alkyl, and salts, solvates and solvates of the salts 4. According to the formula (I ) Compounds, where -112- This paper size applies to Chinese National Standard (CNS) A4 (210x297 mm) 200400936 AB B8 C8 D8 6. The scope of patent application R is phenyl, which is substituted one or two, each independently The ground is selected from the group consisting of: fluorinated (C1-C4) -alkyl, trifluorofluorenyl, cyano, (crC4) -alkyloxy 'difluoromethoxy, carboxyl, (Ci_C4) _alkoxy Carbonyl ' -C (0) -NR9R1G, amine, mono- and di_ (Ci_c6) _ 5 alkylamino, or pyridyl 'thienyl' oxazolyl or thiazolyl, each of which may be substituted by one or two , Each independently selected from the group consisting of: fluorine, gas, (C 丨 -C4) -xyl'trifluoromethyl, cyano, (C 丨 -c4) -alkoxy10, trifluoromethoxy, Carboxyl, (CVC4) -alkoxycarbonyl, -C (0) -NR9R1G 'amine, mono- and di- (Ci-C4) -alkylamino, wherein, in each case, R9 and r1q are independently independent Ground is hydrogen or (CrC6) -alkyl, A is a bond or 1,2-ethylenediyl, 15 R2 and H5 are each independently pyridyl, fluorenyl or phenyl, each of which may be substituted One or two, each independently selected from the group consisting of: fluorine, gas, (C1-C4) -carbyl, trifluoromethyl, cyano, (C! -C4) -carboxy or trifluoromethoxy Base, printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economics, R is gas or (C1-C4) -alkyl, and 20 r4 is (CVC4) -alkyl, which can be substituted into two, each independently selected from The following groups: hydroxyl, (Cl_C4) -alkoxy, -NRUR12 and -C (0) -0R13, where R11 'R12 and R 13 'Respectively, hydrogen or (CrC4) -calcined base' or • 113-This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 200400936 A8 B8 C8 D8 VI. Patent application scope. R3 and R4 together form a spiro-linked cyclopropyl, cyclobutyl or cyclopentyl ring with the carbon to which they are attached, R6 is hydrogen, and 5 R7 and R8 together form a carbonyl or formula C with the carbon to which they are attached = N-0-R15, where R15 is (CrC4) -alkyl, which may be substituted by the following groups: hydroxyl, (CrC4) -alkoxy, carboxyl, (CrC4) -alkoxycarbonyl or formula- The bases of nr16r17 or -c (o) -nr16r17, among which 10 R16 and R17 are each independently fluorene or (CrCO-alkyl, and salts, solvates and solvates of salts thereof). 5. The compound of formula (I) according to item 2 of the scope of patent application, wherein R1 is phenyl, which is one or two substituted, each independently selected from the following 15 groups: fluorine, chlorine, methyl, trifluoro Methyl and methoxy, A is the bond, and R2 and R5 are printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, which are independently phenyl groups, which may be substituted by one or two, each independently selected from the following groups : Fluorine, chlorine, methyl, trioxomethyl or cyano, 20 R3 is argon, methyl or ethyl, R4 is methyl, or -114-This paper size applies to China National Standard (CNS) A4 (210x297) Mm) 200400936 A8 B8 C8 D8 6. Application scope 10 R3 and R4 together form a spiro-linked cyclopropyl, cyclobutyl or cyclopentyl ring with the carbon to which it is attached, R6 is hydrogen, and R7 and R8—from the carbon to which it is attached, forms a carbonyl group or a group of the formula C = N-0-CH3, and its salts, solvates, and solvates of salts. 6. A method for preparing a compound of formula (I) according to item 2 of the patent application, characterized in that [A] a compound of formula (II) Ο R Λ R° (Π), R 15 經濟部智慧財產局員工消費合作社印製 20 其中 A，R1，R3與R4各具有如根據申請專利範圍第2 項中指明的定義， 與式(III)的化合物反應 R2V (m)， 其中 -115 -R ° (Π), R 15 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 20 where A, R1, R3 and R4 each have the definition as specified in item 2 of the scope of the patent application, and react with a compound of formula (III) R2V (m), where -115- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200400936This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200400936 六、申請專利範圍 的定義 製得式(I-A)的化合物 =各具有如根據申請專利範圍第2項令指Definition of the scope of patent application: Compounds of formula (I-A) are prepared. (I-A), 其中 ^ R R ’R，R4與尺5各具有如根據申請專利 範圍第2項中指明的定義， 或 [B]式(IV)的化合物 15(I-A), wherein ^ R R ′ R, R 4 and rule 5 each have the definition as specified in item 2 of the scope of patent application, or [B] Compound of formula (IV) 15 (IV)， 經濟部智慧財產局員工消費合作社印製 20 其中 A ’ R1 ’ R2 ’ R3^ R4各具有如根據巾請專利範圍 第2項中指明的定義， 被與式(V)的化合物反應 r5-m -116 - 本紙張尺度適用中國國家標準(CNS)A4規格（210 X297公爱） (V), 200400936 A8 B8 C8 D8 六、申請專利範圍 其中 R5具有如根據申請專利範圍第2項中指明的定 義，且 Μ 為金屬或金屬衍生物， 製得式(Ι-A)的化合物， 或 [C]式(VI)的化合物 10(IV) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 20 where A 'R1' R2 'R3 ^ R4 each has the definition as specified in item 2 of the patent scope and is reacted with a compound of formula (V) r5-m -116-This paper size applies to Chinese National Standard (CNS) A4 (210 X297 public love) (V), 200400936 A8 B8 C8 D8 VI. Application scope of patents where R5 has The specified definition, and M is a metal or a metal derivative to produce a compound of formula (I-A), or [C] a compound of formula (VI) 10 (VI), 15 經濟部智慧財產局員工消費合作社印製 其中 R1與R3各具有如根據申請專利範圍第2項中指明 的定義， Α 為鍵， 且 R18 為(CrC4)-烷基， 以式(III)的化合物反應被轉變成式(I-B)的化合物 20 R(VI), 15 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, where R1 and R3 each have the definition as specified in item 2 of the scope of the patent application, where A is a bond, and R18 is (CrC4) -alkyl, with the formula The compound (III) is converted into a compound of the formula (IB) 20 R RJ (I-B). 117 - 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200400936 A8 B8 C8 D8 六、申請專利範圍 其中 R1，R2，R3與R5各具有如根據申請專利範圍第2 項中指明的定義，且 A 為鍵’ 或 [D]式(IV)的化合物被轉變成式(IX)的化合物 15RJ (IB). 117-This paper size is applicable to Chinese National Standard (CNS) A4 specification (210x297 mm) 200400936 A8 B8 C8 D8 VI. Application scope of patents where R1, R2, R3 and R5 each have The definition specified in item 2 and A is a bond 'or [D] A compound of formula (IV) is converted to a compound of formula (IX) 15 (IX), 其中 A，R1，R2，R3與R4各具有如根據申請專利範圍 第2項中指明的定義， 稍後，再與式(V)的有機金屬化合物反應，製得式 (Ι-C)的化合物 經濟部智慧財產局員工消費合作社印製 20(IX), wherein A, R1, R2, R3 and R4 each have the definition as specified in item 2 of the scope of the patent application, and later, react with the organometallic compound of formula (V) to obtain formula (I- C) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Compound Economy 20 (I-C), 其中 A，R1，R2，R3，R4與R5各具有如根據申請專利 範圍第2項中指明的定義， -118 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200400936 六 5 ο 1A 經濟部智慧財產局員工消費合作社印製 A8 B8 C8 D8 申請專利範圍 然後，適當地，將式(I-A)，（I-B)與(Ι-C)進行進一 步反應，製得式⑴的化合物。 7. 一種醫藥品，其係包含至少一種根據申請專利範圍第 1項中所定義之式⑴化合物，與至少一種其他的賦型 劑。 8. —種醫藥品，其係包含至少一種根據申請專利範圍第 1項中所定義之式(I)化合物，與至少一種其他的活性 組成分。 9. 根據申請專利範圍第1至4項中任一項的化合物之用 途，係用於供製備一種供治療及/或預防血栓性插塞的 疾病之醫藥品。 -119 - 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200400936 (一） 、本案指定代表圖爲：第_Η (無) (二） 、本代表圖之元件代表符號簡單說明：(IC), where A, R1, R2, R3, R4, and R5 each have the definition as specified in item 2 of the scope of the patent application, -118 This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297) (Centi) 200400936 6 5 ο 1A Printed by A8, B8, C8, D8, Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, the scope of patent application, and then, if appropriate, further reacting formulas (IA), (IB) and (I-C) to obtain Compound of formula VII. 7. A pharmaceutical product comprising at least one compound of formula (I) as defined in item 1 of the scope of the patent application, and at least one other excipient. 8. A pharmaceutical product comprising at least one compound of formula (I) as defined in item 1 of the scope of the patent application, and at least one other active ingredient. 9. The use of a compound according to any one of claims 1 to 4 is for the preparation of a pharmaceutical for treating and / or preventing a thrombotic plug disease. -119-This paper size is in accordance with China National Standard (CNS) A4 (210x297 mm) 200400936 (1). The representative representative of this case is: _Η (none) (二). The component representative symbols of this representative diagram are simply explained. : 本案若有化學式時，請揭示最能顯示發明特徵的If there is a chemical formula in this case, please disclose the one that best shows the characteristics of the invention 第2-1頁Page 2-1
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