TW509676B

TW509676B - Novel unsymmetrically substituted carboxylic acid derivatives, their preparation and use as mixed ETA/ETB receptor antagonists

Info

Publication number: TW509676B
Application number: TW088103317A
Authority: TW
Inventors: Wilhelm Amberg; Rolf Jansen; Dagmar Klinge; Hartmut Riechers; Stefan Hergenroder
Original assignee: Basf Ag
Priority date: 1998-03-04
Filing date: 1999-03-04
Publication date: 2002-11-11
Also published as: HUP0101173A2; ID26183A; BR9908401A; IL137537A0; EP1060167A1; HRP20000650A2; CN1292782A; KR20010041537A; HUP0101173A3; BG104754A; CA2322541A1; JP2002505324A; WO1999044998A1; NO20004351D0; AU2624799A; PL342806A1; ZA991738B; TR200002545T2; AR020317A1; NO20004351L

Abstract

Carboxylic acid derivatives in which R1-R6, Q, W, X, Y and Z have the meanings stated in the description, and their preparation are described. The novel compounds are suitable for controlling diseases.

Description

509676 五、發明說明（1)509676 V. Description of the invention (1)

本發明係關於新穎之羧酸衍生物、其製法及用途。内皮素（Endothelin)係一種由血管内皮合成及釋出之由 21種胺基酸組成之胜肽。内皮素以三種異構物、£τ - 2 及ΕΤ-3存在。此處之"内皮素"或"Ετ"係指内皮素之一種或全部異構物。内皮素為一種強效之血管收縮劑，對血管張力有極大影響。眾所週知，血管收縮係由内皮素與其受體結合所引起（Nature, 332, 41 1 -41 5, 1 988; FEBSThe present invention relates to a novel carboxylic acid derivative, a preparation method and an application thereof. Endothelin is a peptide composed of 21 kinds of amino acids synthesized and released by vascular endothelium. Endothelin exists as three isomers, £ τ-2 and ET-3. "Endothelin" or "Ετ" herein means one or all of the isomers of endothelin. Endothelin is a potent vasoconstrictor that has a significant effect on vascular tension. It is well known that vasoconstriction is caused by the binding of endothelin and its receptor (Nature, 332, 41 1 -41 5, 1 988; FEBS

Letters,拉1， 440-444， 1988及Biochem. Biophys·Letters, Pull 1, 440-444, 1988 and Biochem. Biophys ·

Res· Commun·， 154, 868-875， 1988) 〇Res. Commun., 154, 868-875, 1988)

内皮素增加或不正常釋放將引起周圍、腎臟及腦血管之持續性血管收縮，而導致疾病。如文獻所報導，内皮素與許多疾病有關。此等疾病包括：高血壓、急性心肌梗塞、肺高血壓、雷諾氏症候群、腦血管痙攣、中風、良性前列腺肥大、動脈粥腫樣硬化及氣喘（J. Vascular Med. Biology 2, 207 (1990), J. Am. Med. Association 264，2 868 ( 1 99 0 ), Nature 344，1 1 4 ( 1 990 ), N. Engl. J. Med. 322, 205 (1989), N. Engl. Med. 328, 1732 (1993) , Nephron 66， 373 (1994), Stroke ^5, 904 (1994) , Nature 165, 759 (1993), J. Mol. Cell. Cardiol· 27, A234 ( 1 9 95); Cancer Research 5_6, 6 63 (1996)) 〇至少兩種内皮素受體亞型ETA &ETB已被記載在文獻 (Nature M8, 730 ( 1 99 0 ), Nature Mi，732 ( 1 9 90 )) 中。因此，抑制内皮素與此二受體結合之物質應能拮抗内Increased or abnormal release of endothelin will cause continuous vasoconstriction of surrounding, kidney and cerebral blood vessels, leading to disease. As reported in the literature, endothelin is involved in many diseases. These diseases include: hypertension, acute myocardial infarction, pulmonary hypertension, Raynaud's syndrome, cerebral vasospasm, stroke, benign prostatic hypertrophy, atherosclerosis, and asthma (J. Vascular Med. Biology 2, 207 (1990) , J. Am. Med. Association 264, 2 868 (1 99 0), Nature 344, 1 1 4 (1 990), N. Engl. J. Med. 322, 205 (1989), N. Engl. Med. 328, 1732 (1993), Nephron 66, 373 (1994), Stroke ^ 5, 904 (1994), Nature 165, 759 (1993), J. Mol. Cell. Cardiol 27, A234 (1 9 95); Cancer Research 5-6, 6 63 (1996)). At least two endothelin receptor subtypes ETA & ETB have been documented in the literature (Nature M8, 730 (1 99 0), Nature Mi, 732 (1990)). . Therefore, substances that inhibit the binding of endothelin to this two receptor should be able to antagonize internal

第5頁 509676 五、發明說明（2) 皮素之生理作用，而為有價值之藥物。 W095/2671 6曾記載化合物χχ為内皮素受體拮抗劑：Page 5 509676 V. Description of the invention (2) The physiological effect of cortex is a valuable medicine. W095 / 2671 6 has documented that the compound χχ is an endothelin receptor antagonist:

相對地’本發明目的之一係提供所謂之混合内皮素受體拮抗劑。混合之内皮素受體拮抗劑對ΕΤα受體及ΕΤβ受體以约略相等之親合力結合。當對ΕΤα ·· ΕΤβ親合力之比值大於 0 · 0 5 (而以大於0 · 1為佳）並小於2 〇 (而以小於丨〇為佳）時，‘ 則對受體之親和力約略相等。 ’ DE 196364046.3記載一種與ετα受體及與ετβ受體以高親人力結合之羧酸衍生物。此等化合物之一特性，舉例而古: 係在点中心上用兩個苯環作對稱取代。吾等如今非常地發現，即使点中心上不對稱取代（例如甲基/笨基），“’、異可得到混合受體拮抗劑。 & ’ € 本發明係關於式I之羧酸衍生物：On the contrary, one of the objects of the present invention is to provide a so-called mixed endothelin receptor antagonist. The mixed endothelin receptor antagonists bind to the ETα receptor and ETβ receptor with approximately equal affinity. When the ratio of affinity to ETα · · ETβ is greater than 0 · 0 5 (and more preferably greater than 0 · 1) and less than 2 0 (and more preferably less than 丨 0), ′ has approximately equal affinity for the receptor. DE 196364046.3 describes a carboxylic acid derivative that binds ετα receptor and ετβ receptor with high affinity. One of the characteristics of these compounds is, for example, ancient: it is symmetrically substituted with two benzene rings at the center of the point. We have now discovered very well that even with asymmetric substitutions at the center of the point (such as methyl / benzyl), "', hetero, can give mixed receptor antagonists. &Amp;' € The present invention relates to carboxylic acid derivatives of formula I :

[其中取代基具有下述定義： R1為四唑基或下列基：[Wherein the substituent has the following definition: R1 is a tetrazolyl group or the following group:

509676 五、發明說明509676 V. Description of Invention

R為 a) 0R7基，其中R7為：氫驗金屬之陽離子、驗土金屬之陽離子、生理上可耐受之有1銨離子如匕气4-烷基銨或銨離子， q-C8環-烧基、Ci_Cs_烷基、Ch2_苯基[可被一或多個 :列基取代4素、硝基、氰基、ei_G4mc「鹵炫基、經基、CA-烧氧基、巯基ί烧硫基、胺基、叛基、NHCCi-ϋ基）'NCC^Cr 烧基）2]， Q-C6稀基或Cs-C6快基，此等基可以攜帶丨至5個鹵素原子， R7也可為苯基，其可攜帶丨至5個函素原子及/或個下列基：石肖基、氰基、Cl々烧基、C「C4_函烧基、經基、CrCr烷氧基、威基、（^-〇4-烷硫基、胺基、nh 烷基）、NCC^C4-烷基）2 ; b) 五員雜芳族系統，諸如吡咯基、啦唑基、味唾三嗤基，其經由氮原子鍵結且可攜帶1至2個鹵素原基及 1至2個C广C4 -烧基或1至2個C! _C4 -燒氧基；、或 c) 下列基： —〇-(CH2)p—S-Re 3及4之值其中k為0、1及2之值，P為1 為R is a) 0R7 group, where R7 is: cation of hydrogen test metal, cation of earth test metal, physiologically tolerable 1 ammonium ion such as 4-alkylammonium or ammonium ion, q-C8 ring- Alkyl, Ci_Cs_alkyl, Ch2_phenyl [can be substituted by one or more of: phenyl, 4-nitro, nitro, cyano, ei_G4mc, haloyl, meridyl, CA-alkyloxy, mercapto Thio, amine, ammonium, NHCCi-fluorenyl) 'NCC ^ Cr alkyl) 2], Q-C6 dilute or Cs-C6 fast group, these groups can carry 5 to 5 halogen atoms, R7 also May be phenyl, which can carry 5 to 5 halo atoms and / or the following groups: Shi Xiao Ke, cyano, Cl alkynyl, C "C 4-alkynyl, meridian, CrCr alkoxy, wilyl , (^ -〇4-alkylthio, amine, nh alkyl), NCC ^ C4-alkyl) 2; b) five-membered heteroaromatic system, such as pyrrolyl, azozolyl, triamyl , Which is bonded via a nitrogen atom and can carry 1 to 2 halogen radicals and 1 to 2 C-C4-alkyl groups or 1 to 2 C! _C4-alkyloxy groups; or c) the following groups:- -(CH2) p—S-Re values of 3 and 4, where k is the value of 0, 1 and 2, and P is 1 is

五、發明說明（4) 或苯i[C4可2基：c3一環烧基、Cf c「烯基、C3-C「快基硝基、氰爲或夕個（例如1至3個）下列基取代··鹵素、氧基、c j〜、、Cl〜C4一烷基、CrCr鹵烷基、羥基、C1 一c4一烷基）、n/c 4Γ烷硫基、巯基、胺基、羧基、NHdCr烷 d) %々烷基)2];V. Description of the invention (4) or benzene i [C4co2 group: c3 monocyclic alkyl group, Cf c "alkenyl group, C3-C" fast nitro group, cyano group or (for example, 1 to 3) the following groups Substitutions: halogen, oxy, cj ~,, Cl ~ C4 monoalkyl, CrCr haloalkyl, hydroxyl, C1 ~ c4 monoalkyl), n / c 4Γ alkylthio, mercapto, amine, carboxyl, NHdCr Alkane d)% fluorinated alkyl) 2];

-R 其中R9為： H自4垸3基HC6稀基、c^c6块基、C3-C81烧基、基及/或心中：2;:魏〜烧氧基、 e)可選擇性被取代（特；;如上述者）之苯基； 13-R wherein R9 is: H is a 4 稀 3 group HC6 dilute group, a c ^ c6 block group, a C3-C81 alkyl group, a group, and / or in the heart: 2 ;: Wei ~ alkoxy group, e) can be optionally substituted (Special ;; as above) phenyl; 13

R 14 ，"丨3及P可相同或相異以及具有下列定義： 11、n 烧基、c3-c8-環烧基、c3_c8_ 烯基、c3_c8_ 炔基、苯曱基、苯基[可攜帶丨至5個豳素原子及/或丨至3個下列基：硝严、氣基、Cl-c4_烷基、Ci_c4_ _烷基、羥基、 q-C4-烷氧基、酼基、q-Cr烷硫基、胺基、nh(Ci_C4_烷基）、N(Ci-C4_ 烧基）2]，或者π及R14合表封閉成環之^吒厂伸烷基鏈且可被 q-c：4-烷基取代（其中伸烷基之一可被氧、硫或氮取代），R 14, " 3 and P may be the same or different and have the following definitions: 11, n-alkyl, c3-c8-cycloalkyl, c3_c8_ alkenyl, c3_c8_ alkynyl, phenylfluorenyl, phenyl [portable丨 to 5 halogen atoms and / or 丨 to 3 of the following groups: nitrate, gas group, Cl-c4-alkyl, Ci_c4-alkyl, hydroxyl, q-C4-alkoxy, fluorenyl, q- Cr alkylthio, amine, nh (Ci_C4_alkyl), N (Ci-C4_alkyl) 2], or π and R14 are closed to form a ring. The alkyl chain can be extended by qc: 4 -Alkyl substitution (where one of the alkylene groups may be substituted with oxygen, sulfur or nitrogen),

v^〇/6 五、發明說明（5) 例如-(ch2)4- —（ch2)5（CH2)6— 一（Ch2)2 一〇一（CH2)2 一、〜(CH2V、-CVS-(CH2V、〜CH2〜NH-（CH2)2-、〜（ch2)2 - n-(ch2)2-； R2為氫、羥基、NH2、NHCCrq〜烷基）、N(CrC4-烷基）2、卤素、（VC4-烧基、C2-C4-烯基、c2_Cr炔基、Ci_c4一羥烷基、鹵烷基、1-(：4-烷氧基、Ci一鹵烷氧基、-烷硫基，或者CR2鍵結至下文所述之CR1G，以得到5_或6一員環； Φ X為氮或次甲基； Y為氮或次甲基； Z為氮或CR10 ’其中R10為氫、鹵素、羥基、q-Cr鹵烷基或q-Cf烷基，或者CRIQ與cR2 4CR3合表5或6員之伸烷基環或伸烯基環且此等環可被1或2個^ — ^—烷基取代[其中，在任一情況，一或多個亞曱基可被氧、硫、—NH 4N(Ci_Cr 燒基）取代]; 環成員X、γ或z中至少有一為氮； R3為氫、羥基、NH2、NH(Ci_C4—烷基）、N(C厂C4一烷基）2、鹵素、Ci-C4-烷基、c2-c4-烯基、c2-c4-炔基、一鹵烷基、CrC4-烷氧基、CrC4-鹵烷氧基、CrCr羥烷^、4 C^Cr烧硫基，或者CR3鍵結至上述之CR1〇 ,以形土員環；乂3 一或6〜氧基、笨氧基、羧基、C广C4. R4為(Vc4-烷基、c厂c4—烯基、C2_C4_炔基，彼或多個下列基取代：函素、氰基、經基、疏基寺'破- 鹵烷氧基、（^-(：4〜烷碗^ Ί 4 509676 五、發明說明（6) 基、NIKCr C4-烧基）、^(0「(34-烧基）2或烧幾基； -烧基、- C4-烯基或C2-C4 -炔基藉一鍵、益甲基、伸乙基或伸乙烯基、氧或硫原子或S〇2、NH或N一炫基而鍵結至R5者； R5為苯基或蓄基，其各可被一或多個下列基取代：函素、确基、乱基、經基、疏基、C厂C4 -烧基、稀基v ^ 〇 / 6 V. Description of the invention (5) For example-(ch2) 4- — (ch2) 5 (CH2) 6— One (Ch2) 2 One 〇 (CH2) 2 One, ~ (CH2V, -CVS- (CH2V, ~ CH2 ~ NH- (CH2) 2-, ~ (ch2) 2-n- (ch2) 2-; R2 is hydrogen, hydroxyl, NH2, NHCCrq ~ alkyl), N (CrC4-alkyl) 2 , Halogen, (VC4-alkyl, C2-C4-alkenyl, c2-Cr alkynyl, Ci_c4 monohydroxyalkyl, haloalkyl, 1-(: 4-alkoxy, Ci monohaloalkoxy, -alkylthio Or CR2 is bonded to CR1G described below to obtain a 5- or 6-membered ring; Φ X is nitrogen or methine; Y is nitrogen or methine; Z is nitrogen or CR10 'where R10 is hydrogen, Halogen, hydroxy, q-Cr haloalkyl or q-Cf alkyl, or CRIQ and cR2 4CR3 Table 5 or 6 of the alkylene ring or alkenyl ring and these rings can be 1 or 2 ^ — ^ -Alkyl substitution [wherein, in any case, one or more fluorenylene may be substituted with oxygen, sulfur, -NH 4N (Ci_Cr alkyl)]; at least one of the ring members X, γ or z is nitrogen; R3 For hydrogen, hydroxyl, NH2, NH (Ci_C4-alkyl), N (C plant C4-alkyl) 2, halogen, Ci-C4-alkyl, c2-c4-alkenyl, c2-c4-alkynyl, one Haloalkyl, CrC 4-alkoxy, CrC4-haloalkoxy, CrCr hydroxyalkane ^, 4 C ^ Cr thiothio, or CR3 is bonded to CR10 above to form a ring member; 员 3 one or 6 ~ oxy R4 is (Vc4-alkyl, c4-alkenyl, C2_C4_alkynyl, and one or more of the following groups are substituted: functional group, cyano group, mesyl group, thio group Temple 'Bro-haloalkoxy, (^-(: 4 ~ alkane bowl ^ Ί 4 509676 V. Description of the invention (6) group, NIKCr C4-alkyl group), ^ (0 "(34-alkyl) 2 or Burn a few groups; -Alkyl, -C4-alkenyl or C2-C4 -alkynyl by one bond, methyl, ethyl or vinyl, oxygen or sulfur atom or S02, NH or N And R5 are bonded to R5; R5 is a phenyl group or a radical, each of which may be substituted by one or more of the following groups: functional group, acyl group, random group, meridian group, thiol group, C4 C4-alkyl Dilute

Ci~C4-羥烧基、C2-C4-块基、- C4- _烧基、C!- C〆炫氧基、笨氧基、羧基、c4-鹵烷氧基、q-Cr烷硫基、胺基、 NH%-C4-烷基）'NCq-Cr烷基）2或苯基，其可被下列基一或多次取代（例如1至3次）：齒素、硝基、氰基、CrC4-烷基、1-(：4•"鹵烷基、（：!-(：4-烷氧基、鹵烷氧基或燒硫基，、笨基或著基藉一鍵、亞曱基、伸乙基或伸乙烯基、氧或硫原子或S〇2、NH或N-烷基而鍵結於R4之鄰位者，或者 crC8-環烷基；一烷羰為環烷基，在各情況可被下列基一或多次取基:基、缓基、瑣基、氮基、C1^1氧 c3〜c6〜炔% | 土 Γ 2 4一烯基、c2一C4-炔基、C3-Cr烯氧基基、氧土、Ci一c4一烷硫基、Ci-C4-鹵烷氧基、q-c广怎碳基、C3 —C8燒，炭烧基、NH(Cl—C4〜烧基）、 (例如丨4至2 t ^，或者笨基[其可被下列基一或多次取代烷基、C〜r:人I·/素、硝基、氰基、CrCr烷基、Ci〜C4 笨人心4“元氧基、Cl 一cr鹵烷氧基或Ci — C4一烷硫基， ’ ％或努其，甘方市巷其各可攜帶一或多個下列基··鹵素、Ci ~ C4-Hydroxyalkyl, C2-C4-block, -C4-_alkyl, C! -C-Hexyloxy, benzyloxy, carboxyl, c4-haloalkoxy, q-Cr alkylthio , Amine, NH% -C4-alkyl) 'NCq-Cralkyl) 2 or phenyl, which may be substituted one or more times by the following groups (for example, 1 to 3 times): halo, nitro, cyano , CrC4-alkyl, 1-(: 4 • " haloalkyl, (:!-(: 4-alkoxy, haloalkoxy, or thiosulfanyl), phenyl, or phenylene, by a bond, Fluorenyl, ethylidene or vinylidene, oxygen or sulfur atom or S02, NH or N-alkyl and bonded to the ortho position of R4, or crC8-cycloalkyl; monoalkylcarbonyl is cycloalkyl In each case, it can be taken one or more times by the following groups: base, slow group, Zoyl, nitrogen, C1 ^ 1 oxygen c3 ~ c6 ~ alkyne% | soil Γ 2 4 -alkenyl, c2 -C4-alkyne Group, C3-Cr alkenyloxy group, oxygen clay, Ci-c4-haloalkylthio group, Ci-C4-haloalkoxy group, qc carbon group, C3-C8 group, carbon group, NH (Cl-C4 ~ Alkyl), (for example, 4 to 2 t ^, or benzyl [which may be substituted one or more times by the following alkyl groups, C ~ r: human I · / prime, nitro, cyano, CrCr alkyl , Ci ~ C4 Stupid Heart 4 "Yuan Group, Cl cr haloalkoxy or a Ci - C4 alkylthio group a, '%, or of its efforts, Gan Lane City side which may carry one or more of each of the following groups ·· halo,

第10頁 509676 五、發明說明（7) R15、硝基、巯基、羧基、氰基、羥基、胺基、Ci_C4一烷基、C2-C4-烯基、C2-C4-炔基、c3-C6-烯氧基、（^_(：4-鹵烷基、C3-C6-炔氧基、q-Cf烷羰基、q-Cr烷氧羰基、Ci-C4-烧氧基、_烧氧基、苯氧基、C1-C4-貌硫基、 NH(c「c4-烷基）、N(c「(V烷基）2、亞甲二氧基、伸乙二氧基、或苯基[可被下列基一或多次取代（例如1至3次）：齒素、硝基、氰基、q-Cr烷基、c「c4-鹵烷基、q-Cr烷氧基、G-C4-鹵烧氧基或烧硫基]，附帶條件為如果r6 為未經取代之苯基，則R2與R3不可同時為〇CH3，含有1至3個氮原子及/或1個硫或氧原子之5員或6員雜< 芳族系統，其可攜帶1至4個鹵素原子及/或1至2個下列 ^ : c「c4-烧基:c2-c4-烯基、c「c4-鹵烷基、（:「c4—烧氧土 Cl 一 cr鹵烷氧基、ci — cr烷硫基、苯基或苯氧基，該苯基可攜帶1至5個鹵素原子及/或丨至3個下列基：c -c _烷基”基、C「C4_烷氧基、Ci_C4_J氧基二一c4_烷硫基； ?:=4—烷基、C1_C4_烷硫基、C1々烷氧基，其搞帶個了列基：經基、減、胺基、NH(C1々院基）、 -烷基）2、胺曱醯基或CON(c「cf烷基 W為硫或氧；合0物為中相之;:C2其C4=長度之：隔基’該Q之功能係在式I化鏈之县择〃基間產生一距離，該距離必須相當於c2-c4-又，其可藉由許多化學基[例如Cc伸烧 C〜伸稀基、c3今伸快基，「以^Page 509676 V. Description of the invention (7) R15, nitro, mercapto, carboxyl, cyano, hydroxyl, amine, Ci_C4 monoalkyl, C2-C4-alkenyl, C2-C4-alkynyl, c3-C6 -Alkenyloxy, (^ _ (: 4-haloalkyl, C3-C6-alkynyloxy, q-Cf alkylcarbonyl, q-Cr alkoxycarbonyl, Ci-C4-carboxy, alkoxy, Phenoxy, C1-C4-methylsulfanyl, NH (c "c4-alkyl), N (c" (Valkyl) 2, methylenedioxy, ethylenedioxy, or phenyl [可Substituted one or more times by the following groups (eg 1 to 3 times): halo, nitro, cyano, q-Cr alkyl, c "c4-haloalkyl, q-Cr alkoxy, G-C4- Halooxy or thiothio] with the proviso that if r6 is an unsubstituted phenyl, then R2 and R3 cannot be 0CH3 at the same time, and contain 1 to 3 nitrogen atoms and / or 1 sulfur or oxygen atom. 5- or 6-membered hetero < aromatic system, which can carry 1 to 4 halogen atoms and / or 1 to 2 of the following ^: c "c4-alkenyl: c2-c4-alkenyl, c" c4-halogen Alkyl, (: "c4--oxygenated soil Cl-cr haloalkoxy, ci-cr alkylthio, phenyl or phenoxy, the phenyl can carry 1 to 5 halogen atoms and / or 3 to 3 The following bases: c -c _Alkyl ”group, C” C4_alkoxy group, Ci_C4_Joxydi-c4_alkylthio group;?: = 4-alkyl group, C1_C4_alkylthio group, C1 alkylalkoxy group Benzyl: meridian, amine, amine, NH (C1), alkyl -2, amine, or CON (c "cf alkyl W is sulfur or oxygen; compound 0 is the middle phase ;: C2 its C4 = length: the spacer 'the function of this Q is to create a distance between the selected bases of the chain of formula I, the distance must be equivalent to c2-c4-, which can be used by many chemical groups [For example, Cc, C, C, C, C, C, C, and C3,

509676 五、發明說明（8) -N-C0-CH2-、-C0-N-CH2-CH2-、-C0-N(C「C4-烷基）-CH2-CH2-、-SOfNCCrCr 烷基）-CH2-CH2-、-S02-NH-CH2-CH2-]而達成，在各個情況此等基可被下列基一或多次取代：鹵素、經基、Μ基、-院基、C2-C4-烯基、C2-C4 -炔基、叛基、石肖基、氰基、Cf C4-炫氧基、C3-C6-烯氧基、C3-C6-快氧基、-C4-烧硫基、C〗-C4- ή燒氧基、Ci -C4-燒Μ基、 q -C4-規氧羰基、C3 -C8烧羰炫基、ΝΗ ( q - C4-燒基）、 iUCi-Cr烷基）2、苯基[可被下列基取代一或多次（例如1至 3次）：鹵素、硝基、氰基-炫基、Ci-C4-鹵燒基、 C^-C4-炫氧基、Ci-C4-鹵燒氧基或0厂C4-炫疏基]; 或者間隔基Q為被稠合至R6之5至7員環（雜環或碳環）之一部份。應用於此處及下文之術語之定義如下：驗金屬，例如鋰、納、鉀；驗土金屬，例如約、鎮、鋇； C3-C8環烧基，例如環丙基、環丁基、環戊基、環己基、環庚基、環辛基；509676 V. Description of the invention (8) -N-C0-CH2-, -C0-N-CH2-CH2-, -C0-N (C "C4-alkyl) -CH2-CH2-, -SOfNCCrCr alkyl)- CH2-CH2-, -S02-NH-CH2-CH2-], and in each case these groups may be substituted one or more times by the following groups: halogen, mesogen, M-based, -institutional, C2-C4- Alkenyl, C2-C4-alkynyl, alkyl, schottyl, cyano, Cf C4-xenoyl, C3-C6-alkenyloxy, C3-C6- fastoxy, -C4-sulfanyl, C -C4-alkyloxy group, Ci-C4-alkyl group, q-C4-laneoxycarbonyl group, C3-C8 alkylcarbonyl group, NH (q-C4-alkyl), iUCi-Cr alkyl group 2, Phenyl [can be substituted one or more times by the following groups (eg 1 to 3 times): halogen, nitro, cyano-xyl, Ci-C4-haloalkyl, C ^ -C4-xyloxy, Ci- C4-halohaloxy or 0-C4-hexyl]] or the spacer Q is part of a 5- to 7-membered ring (heterocyclic or carbocyclic ring) fused to R6. Applies here and below The definitions of the terms are as follows: metal test, such as lithium, sodium, potassium; metal test, such as about, town, barium; C3-C8 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Cycloheptyl, cyclooctyl

Ci-Cr鹵烷基可為直鏈或分枝，例如氟甲基、二氟甲基、三氟甲基、氯二氟曱基、二氯氟曱基、三氯甲基、卜氟乙基、2-氣乙基、2，2 -二氣乙基、2，2，2 -三氟i乙基、2-氯-2，2 -二it乙基、2，2-氯-2-氟乙基、2，2，2 -三氯乙基或五氟乙基；燒氧基可為直鍵或分枝，例如二就甲氧基、三氟曱氧基、氯二氟甲氧基、1-氟乙氧基、2, 2 -二氟乙氧Ci-Cr haloalkyl can be linear or branched, such as fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluorofluorenyl, dichlorofluorofluorenyl, trichloromethyl, fluoroethyl , 2-Gasethyl, 2,2-Digasethyl, 2,2,2-Trifluoroiethyl, 2-Chloro-2,2-di-Diethyl, 2,2-chloro-2-fluoro Ethyl, 2,2,2-trichloroethyl or pentafluoroethyl; Carbooxy may be straight or branched, such as dimethoxy, trifluorofluorenyl, chlorodifluoromethoxy, 1-fluoroethoxy, 2, 2-difluoroethoxy

O:\57\57487. PTD 第12頁 509676 五、發明說明（9) 基、1，1，2, 2 -四氟乙氧基、2, 2, 2-三氟乙氧基、2-氯 -1，1,2 -三敦乙氧基、2-氟乙氧基或五說乙氧基；烧基可為直鍵或分枝，例如曱基、乙基、.1-丙基、2-丙基、2-曱基-2-丙基、2-曱基丙基、1 - 丁基或 2- 丁基； _ C2-C4-烯基可為直鏈或分枝，例如乙烯基、1-丙烯-3-基、1-丙稀-2 -基、1-丙稀-1-基、2-曱基-1-丙稀基、1-丁烯基或2- 丁烯基； C2-C4-炔基可為直鏈或分枝，例如乙炔基、1-丙炔-1 -基、1-丙炔-3 -基、1-丁炔-4-基或2 -丁炔-4 -基； -烷氧基可為直鏈或分枝，例如曱氧基、乙氧基、丙氧基、1-曱基-乙氧基、丁氧基、1-甲基-丙氧基、2 -甲基-丙氧基或1,1-二曱基乙氧基； C3-C6-稀氧基可為直鏈或分枝，例如烯丙氧基、2- 丁烯 -卜氧基或3- 丁烯-2-氧基；O: \ 57 \ 57487. PTD Page 12 509676 V. Description of the invention (9) group, 1,1,2,2-tetrafluoroethoxy, 2, 2, 2-trifluoroethoxy, 2-chloro -1,1,2-tridenethoxy, 2-fluoroethoxy or pentaethoxy; the alkyl group may be a straight bond or a branch, such as fluorenyl, ethyl, .1-propyl, 2 -Propyl, 2-fluorenyl-2-propyl, 2-fluorenylpropyl, 1-butyl or 2-butyl; C2-C4-alkenyl can be straight chain or branched, such as vinyl, 1-propen-3-yl, 1-propen-2-yl, 1-propen-1-yl, 2-fluorenyl-1-propenyl, 1-butenyl or 2-butenyl; C2 -C4-alkynyl may be straight-chain or branched, such as ethynyl, 1-propyn-1-yl, 1-propyn-3-yl, 1-butyn-4-yl, or 2-butyn-4 -Radical;-alkoxy may be straight or branched, for example fluorenyl, ethoxy, propoxy, 1-fluorenyl-ethoxy, butoxy, 1-methyl-propoxy, 2-methyl-propoxy or 1,1-difluorenylethoxy; C3-C6-dilutedoxy can be straight-chain or branched, such as allyloxy, 2-butene-butoxy or 3-butene-2-oxy;

Ci-C4-經烧基可為直鏈或分枝，例如經曱基、羥乙基； c3-c6-炔氧基可為直鏈或分枝，例如2-丙炔-1-氧基、2-丁炔-1-氧基或3-丁炔-2-氧基； q - C4 -烧硫基可為直鍵或分枝’例如甲硫基、乙硫基、丙硫基、1_甲基-乙硫基、丁硫基、1-甲基-丙硫基、2-曱基-丙硫基或1，1-二曱基乙硫基；烧黢基可為直鏈或分枝，例如乙醢基、乙羧基或 2-丙羰基； 1-(：4烷氧羰基可為直鏈或分枝，例如曱氧羰基、乙氧羰Ci-C4-cannyl may be straight or branched, such as fluorenyl, hydroxyethyl; c3-c6-alkynyloxy may be straight or branched, such as 2-propyn-1-oxy, 2-butyne-1-oxy or 3-butyne-2-oxy; q-C4-sulfanyl can be straight or branched, such as methylthio, ethylthio, propylthio, 1- Methyl-ethylthio, butylthio, 1-methyl-propylthio, 2-fluorenyl-propylthio, or 1,1-difluorenylethylthio; sulfanyl can be straight chain or branched , Such as ethanoyl, ethylcarboxy, or 2-propoxycarbonyl; 1-(: 4 alkoxycarbonyl may be linear or branched, such as ethoxycarbonyl, ethoxycarbonyl

第13頁 509676 五、發明說明（ίο) 基、正丙氧m基、異丙氧幾基或正丁氧幾基；产q-C8-烷羰烷基可為直鏈或分枝，例如2_氧_卜丙基、3_ 氧-1-丁基或3-氧-2-丁基；基Λ為直鍵或分枝，例如wn戊基、己基、庚基或辛基；鹵素，例如氟、氣、溴、峨。本發明進一步係關於可釋屮Τ儿人仏 A / 原藥）。 9 、』样出式I化合物之化合物（亦稱為較佳之原藥為可在身體之某些部位（例如胃、小腸、血液、肝臟中）之環境下被釋放者。此等化合物及製備其之中間體（如式n, 具有-或多個經不對稱取代之碳原子。此類化合物可對掌異構物或純非對映異構物或其混合物存在。而對掌異構性化合物或純非對映異構性化合物做為活性成分2 佳。此等化合物之製備以下列實例說明。本發明進一步係關於上述羧酸衍生物在製造藥物（特是ET，ETB受體抑制劑)上之用途。根據本發明之化合二別適合做為前文所述之混合拮抗劑。寻通式IV中W為硫或氧之化合物可如趵96/11914或卯 1 9 636046· 3所述而製備，其亦為純對掌異構物形式。具有通式III之化合物為已知，或可藉例如還原相關羧酸或其S旨類或其他一般已知之方法而合成。 509676 五、發明說明（11)Page 13 509676 V. Description of the invention (ίο), n-propoxy m-based, isopropoxy-based or n-butoxy-based; The q-C8-alkylcarbonylalkyl group may be linear or branched, for example 2 _Oxy_bupropyl, 3-oxo-1-butyl or 3-oxo-2-butyl; group Λ is a straight bond or branch, such as wn pentyl, hexyl, heptyl or octyl; halogen, such as fluorine, gas , Bromine, e. The present invention further relates to releasable (Terren A (original)). 9. The compound of the compound of formula I (also known as a better original drug is one that can be released in the environment of some parts of the body (such as the stomach, small intestine, blood, liver). These compounds and their preparation Intermediates (such as formula n, with-or more asymmetrically substituted carbon atoms. Such compounds can exist as isomers or pure diastereomers or mixtures thereof. But the isomers Or pure diastereomeric compounds are preferred as the active ingredient 2. The preparation of these compounds is illustrated by the following examples. The invention further relates to the above carboxylic acid derivatives in the manufacture of drugs (especially ET, ETB receptor inhibitors) The compound II according to the present invention is suitable as a mixed antagonist as described above. The compound in the general formula IV where W is sulfur or oxygen can be as described in 趵 96/11914 or 卯 1 9 636046 · 3. Preparation, which is also in the form of pure palmar isomers. Compounds having the general formula III are known or can be synthesized by, for example, reduction of the relevant carboxylic acid or its S class or other generally known methods. 509676 V. Description of the invention (11)

RR

IIII

R—Q 一 W_ III δ·R—Q-W_ III δ ·

IV 得到式IV純對掌異構性化合物之另—可能方法， ϋ純對掌異構性鹼，將式⑴肖旋或非對映化合物按照二j鉍物解析法而予以解析。適當之該類型鹼，例如有 4-氣笨基乙胺以及W0 96/11914所記載之鹼。本發明之化合物中取代基具有通式I所述之定義者，可藉、，例如，式IV之羧酸衍生物（其中取代基具有上羞與通式V之化合物反應而製備：Another possible method for obtaining pure paraisomeric compounds of formula IV is to obtain pure paraisomeric compounds of formula IV, and the compounds of formula XII or diastereomers can be analyzed according to the bismuth analysis method. Suitable bases of this type include, for example, 4-aminobenzylethylamine and the bases described in WO 96/11914. The substituents of the compounds of the present invention having the definitions described in the general formula I can be prepared by, for example, a carboxylic acid derivative of the formula IV (wherein the substituents have an upper reaction with a compound of the general formula V):

IV 十IV ten

V η，Λ ζ；=<3 [式ν中’ R11為_素或R12_s〇2_(其中R12為C ^基或苯基）；此外，環成員X“少有一 ^ 4 ^ 。此反應較佳在添加適當鹼類（鹼可將式丨v之中間物去 Ϊ惰性溶劑或稀釋劑中，於室溫至溶劑沸點之溫度犯固下進行。廿伽t ^物1 V中…為⑶⑽者以兩當量之適合鹼類去質子，亩式V之化合物反應，則R1=cooh之類型I化合物可被 -声：，。此反應也在惰性溶劑中，&室溫至溶劑沸點之 /皿尻犯圍内進行。此等，谷劑或稀釋劑之例子，如脂肪族、環脂族或芳香族V η, Λ ζ; = < 3 [wherein R11 is a prime or R12_s〇2_ (where R12 is a C ^ group or a phenyl group); In addition, the ring member X "has one less 4 ^. This reaction is more than It is best to add the appropriate bases (the base can remove the intermediate of formula 丨 v into an inert solvent or diluent, and perform at a temperature between room temperature to the boiling point of the solvent. Deprotonate with two equivalents of a suitable base, and react with a compound of formula V, then R1 = cooh of type I compound can be-sounded :. This reaction is also in an inert solvent, & room temperature to the boiling point of the solvent per dish The offense is carried out within this range. Examples of cereals or diluents such as aliphatic, cycloaliphatic or aromatic

第15頁 509676 五、發明說明（12) 煙類（其各個均可選擇性地被氣化），例如己烷、石油醚、石油腦、苯、曱苯、二曱笨、二、^烷、四氣化碳、氣乙烷及三氣乙烯’醚類如二異丙：、：：、 =甲ΐ第三丁醚、氧化丙烯、二氧陸園及四氫夫；，_ 類如乙知及丙睛，醯胺類如二甲基甲醯胺、二月及Ν-曱基Dtt洛酮，亞砚類及砚類如二甲基亞砚及環獅胺式V之化合物為已知，其中一些可以購得，萨/ 之一般方法製備。爷猎已知員者’有可能使用驗金屬或驗土金屬氫化物諸如風化鈉、虱化鉀或氫化鈣，碳酸鹽類諸如鹼金屬碳酸錢，_ 歹”酸納或碳酸鉀’鹼金屬或鹼土金層氫氧化物諸： 2或卸’有機金屬化合物諸如丁基鋰，或鹼金屬胺化物诸如二異丙胺化鋰或胺化鋰。式I之化合物亦可從對應羧酸（亦即…為⑶⑽之式！化合物）開始製備，首先以習用方式將其轉化為活化形式，^列如酸鹵化物、酸酐或咪唑化物，繼而將後者與適當之羥基化合物（H0R7)反應。此反應可在習用溶劑中進行，且通常需要添加驗（可採用上文所述者）。此二步驟也可簡化，例如將該羧酸在脫水劑（如碳化二亞胺）存在下，與輕基化合物反應。式I之化合物也可由對應羧酸之鹽類開始製備，該鹽類亦即式I中R1為C00M基之化合物（其中Μ為驗金屬陽離子或鹼土金屬陽離子）。此等鹽類可與許多式R —Α之化合物反應’其中A為一般離核脫離基，例如鹵素（諸如氯、溴、Page 15 509676 V. Description of the invention (12) Smoke (each of which can be selectively gasified), such as hexane, petroleum ether, petroleum brain, benzene, toluene, dioxin, dioxane, Four gasification carbon, gas ethane and three gas ethylene 'ethers such as diisopropyl:, :: ,, = methane tertiary butyl ether, propylene oxide, dioxin and tetrahydrofuran; And acetonitrile, amines such as dimethylformamide, February and N-fluorenyl Dtt loxone, fluorenes and fluorenes such as dimethylsulfinium and cyclomethamine V are known, Some of them are commercially available and prepared by the usual method. It is possible for the hunter to know that it is possible to use metal or earth metal hydrides such as weathered sodium, potassium hydrate or calcium hydride, carbonates such as alkali metal carbonate, _ 歹 ”sodium or potassium carbonate 'alkali metal or Alkaline earth gold hydroxides: 2 or unorganized metal compounds such as butyl lithium, or alkali metal amine compounds such as lithium diisopropylamide or lithium amine. Compounds of formula I can also be obtained from the corresponding carboxylic acid (ie ... It is the formula of ⑶⑽! Compound), and it is firstly converted into an activated form in a conventional manner, such as an acid halide, an acid anhydride or an imidazolium compound, and then the latter is reacted with an appropriate hydroxyl compound (H0R7). This reaction can be performed at It is performed in a conventional solvent, and usually needs to be added (the above can be used). These two steps can also be simplified, for example, the carboxylic acid is reacted with a light-based compound in the presence of a dehydrating agent such as carbodiimide. The compounds of formula I can also be prepared from the salts of the corresponding carboxylic acids, which are the compounds of formula I in which R1 is a C00M group (where M is a metal test cation or an alkaline earth metal cation). These salts can be used in conjunction with The reaction of compounds of the multi-form R-A 'wherein A is a general ionophore, such as halogen (such as chlorine, bromine,

第16頁 509676 五、發明說明（13) 碘），或被鹵素、烷基或_烷基取代之芳磺醯基或烷磺醯基（例如曱笨績醯基及曱石黃醯基）’或其他相當之脫離基。具有反應性取代基A之式R-A化合物為已知，或者可藉一般專業知識而得到。此反應可在習用溶劑中進行，且最好添加驗（可採用上文所述者）。在某些情況下，製備本發明之化合物I，必須使用一般已知之保護基技術。舉例而言，如果R6為4 _羥苯基，該經基可先做成苯曱基醚而被保護，其接著將在反應系列中之適當階段被打斷。式I中R1為四唑基之化合物可如W〇 96/11914所述之方法φ 製備。. 鑑於生物作用，較佳之通式I羧酸衍生物（純對掌異構物或純非對映異構物或其混合物）為取代基具有下列定義者： R2為氫、羥基、鹵素、烷基）2、（:丨-(：4-烷基、 (VC4-烷氧基、烷硫基、1-(：4-鹵烷基、q-Cr _烷氧基，或者CR2被鍵結於下文所述之crig，以得到5或β員環； X為氮或次曱基； Υ為氮或次曱基； Ζ為氮或CR10 (其中Ri〇為氫、鹵素、C「C4一鹵烷基或CrCf 烷基），或者CR1D與CR2或CR3連結以形成5或6員之伸烷基或伸烯基環且其可被丨或2個曱基取代，其中，在各情況，一個亞曱基可被氧或硫取代，例如—c & 一 c H2 - 0 -、 —ch2-ch「ch2-0- — CH=CH—〜CH=^H一c2Hr〇一、Page 16 509676 V. Description of the invention (13) Iodine), or arylsulfonyl or alkanesulfonyl (such as fluorenyl and ocher fluorenyl) substituted by halogen, alkyl or alkyl Quite off-base. Compounds of the formula R-A having a reactive substituent A are known or can be obtained by general expertise. This reaction can be carried out in customary solvents, and it is best to add tests (the ones described above can be used). In some cases, the preparation of Compound I of the present invention requires the use of generally known protecting group techniques. For example, if R6 is a 4-hydroxyphenyl group, the group may be protected as a phenyl fluorenyl ether, which will then be interrupted at an appropriate stage in the reaction series. Compounds of formula I in which R1 is tetrazolyl can be prepared as described in WO 96/11914. In view of biological effects, the preferred carboxylic acid derivatives of the general formula I (pure paraisomers or pure diastereomers or mixtures thereof) are the substituents having the following definitions: R2 is hydrogen, hydroxyl, halogen, alkane Group) 2, (: 丨-(: 4-alkyl, (VC4-alkoxy, alkylthio, 1-(: 4-haloalkyl, q-Cr_alkoxy, or CR2 is bonded to Crig described below to obtain a 5 or β member ring; X is nitrogen or sulfenyl; 曱 is nitrogen or sulfenyl; Z is nitrogen or CR10 (where Ri0 is hydrogen, halogen, C, C4 monohalane Or CrCf alkyl), or CR1D is bonded to CR2 or CR3 to form a 5- or 6-membered alkylene or alkenyl ring and it may be substituted with one or two fluorenyl groups, where, in each case, one fluorene The group may be substituted by oxygen or sulfur, for example, -c &-c H2-0-, -ch2-ch "ch2-0- — CH = CH— ~ CH = ^ H-c2Hr〇-,

$ 17頁 509676 五、發明說明（14) -CH(CH3)CH(CH3)-0-、-CH = C(CH3)-0-、-c(ch3)=c(ch3)-o-或{(CH3) = C(CH3)-s ; 環成員X、Y或Z中至少有一為氮； R3為氫、羥基、函素、n(Ci_c4-烷基）2、q-Cr烷基、$ 17Page 509676 V. Description of the invention (14) -CH (CH3) CH (CH3) -0-, -CH = C (CH3) -0-, -c (ch3) = c (ch3) -o- or { (CH3) = C (CH3) -s; at least one of the ring members X, Y, or Z is nitrogen; R3 is hydrogen, hydroxyl, functional element, n (Ci_c4-alkyl) 2, q-Cr alkyl,

Ci-Q-烷氧基、-烷硫基、Ci — C4-鹵烷基、Ci-C4- _烷氧基’或者CR3被鍵結於上文所述之CR1G以形成5或6員環； R4為(^-(：4-烷基或〇2_(：4〜烯基，其可被一或多個下列基取代：鹵素、氰基、羥基、巯基、C1-C4_烷氧基、苯氧基、-羧基、CrC4-鹵烷氧基、CrC4-烷硫基、胺基、NH(CrC4-烷基）、Ν((^-C4-烷基）2或(^-C4-烷羰基； _ R5為苯基或著基，其可被一或多個下列基取代：鹵素、硝基、氰基、羥基、酼基、q-Cr烷基、C2-C4-烯基、 q-Cr羥烷基、CrCr豳烷基、（^-(：4-函烷氧基、-烷氧基、苯氧基、羧基、CrC4-烷硫基、胺基、((^-(:厂烷基）C4-烧基）2或本基’其可被下列基^一或多次取代 (例如1至3次）：鹵素、硝基、氰基、Cl-C4-烷基、（：厂(：4-鹵烧基、C「C4-烧氧基、（^-(：4-鹵烧氧基或(^-(：4-烧硫基；或 c3-c8-環烷基； R6為〇3~08壤烧基’此等基可被一或多次取代：鹵素、經儀^ 基、疏基、叛基、硝’基、氰基、（^-C4-烧氧基烧基、c2-c4-烯基、C2-C4-炔基、c3-c6-烯氧基、c3-c6-炔氧基、Q-Cr烷硫基、q-Cr _烷氧基、C^Cr烷羰基、c「C4-燒氧幾基、NIKC^-Cr烧基）、Ν((^-C4-烧基）2，或者苯基，其可被下列基一或多次取代（例如1至3次）：鹵素、硝基、Ci-Q-alkoxy, -alkylthio, Ci-C4-haloalkyl, Ci-C4-_alkoxy 'or CR3 is bonded to CR1G described above to form a 5- or 6-membered ring; R4 is (^-(: 4-alkyl or 〇2 _ (: 4 ~ alkenyl, which may be substituted by one or more of the following groups: halogen, cyano, hydroxyl, mercapto, C1-C4-alkoxy, benzene Oxy, -carboxy, CrC4-haloalkoxy, CrC4-alkylthio, amine, NH (CrC4-alkyl), N ((^-C4-alkyl) 2, or (^ -C4-alkylcarbonyl); _ R5 is phenyl or phenyl, which may be substituted by one or more of the following: halogen, nitro, cyano, hydroxy, fluorenyl, q-Cr alkyl, C2-C4-alkenyl, q-Cr hydroxyl Alkyl group, CrCr alkyl group, (^-(: 4-alkenyloxy group, -alkoxy group, phenoxy group, carboxyl group, CrC4-alkylthio group, amino group, ((^-(: Plant alkyl group)) C4-alkenyl) 2 or this radical may be substituted one or more times by the following groups (for example, 1 to 3 times): halogen, nitro, cyano, Cl-C4-alkyl, (: (4 -Haloalkyl, C "C4-alkyloxy, (^-(: 4-haloalkyl) or (^-(: 4-alkylthio); or c3-c8-cycloalkyl; R6 is 0.3 ~ 08 soil alkynyl 'These groups may be substituted one or more times: halogen, ^ Yl, thiol, thiol, nitryl, cyano, (^ -C4-alkoxyalkynyl, c2-c4-alkenyl, C2-C4-alkynyl, c3-c6-alkenyl, c3 -c6-alkynyloxy, Q-Cr alkylthio, q-Cr alkoxy, C ^ Cr alkylcarbonyl, c "C4-alkyloxy, NIKC ^ -Cr alkyl), N ((^- C4-alkenyl) 2, or phenyl, which may be substituted one or more times by the following groups (eg 1 to 3 times): halogen, nitro,

第18頁五發明說明（15) 氰基、（^-(：4-烷基、（^-(：4-鹵烷基、-烷氧基、Ci-c4_鹵燒氧基或匕·^-烧硫基；苯基或蓄基，其各可被一或多個下列基取代··鹵素、 R15、硝基、魏基、魏基、氰基、經基、胺基、-烧基、c2-c4-烯基、c2-c4-炔基、c3-c6-烯氧基、Ci_c4-鹵烷基、c3-c6-炔氧基、q-Cr烷羰基、-烷氧羰基、q-Cr 燒氧基、q-C4-鹵烷氧基、苯氧基、q-Cr烧硫基、 NHCCrCr烷基）'NCq-Cr烷基）2、亞曱二氧基、伸乙二氧基，或者苯基，其可被下列基一或多次取代（例如丨至3 次）：卣素、硝基、氰基、q-Cr烷基、Ci_C4一齒烷基、 G-Cr烷氧基、Q-Cr鹵烷氧基或Ci_C4_烷硫基，其附帶條件為如果R6為未被取代之苯環，則CR1Q必須與“2或以3共同形成5員環，其中一或二個亞甲基可被〇或3取代； ^含1至3個氮原子及/或丨個硫或氧原子之5員或6員雜方族系統’其可攜帶1至4個函素原子及/或…個下列 $ 烧基、（^-自院基、Ci今院氧基、三說甲氧 Φ 「烧硫基、苯基或苯氧基’該苯基可攜帶1至5個基:、c :及义至3:固下列[々V烷基、CA-齒烧土 R15丄甲4其Λ广^齒烧氧基及/或Cl_C4_烧硫基；某·ί:^ 甲氧基或乙氧基，其攜帶-個下列 L 田叛土、胺基、NH(C「C4—烧基）、N(C「cr 烧基）2、胺甲醯基或con(Ci〜C4一烷基） w為硫或氧； Q為C2 c3-伸烷基、c3〜伸烯基、_s_CH2-CH$P.18 Description of the Invention (15) Cyano, (^-(: 4-alkyl, (^-(: 4-haloalkyl, -alkoxy, Ci-c4-halohaloxy or dagger) -Sulfuryl; phenyl or radical, each of which may be substituted with one or more of the following: halogen, R15, nitro, weyl, weyl, cyano, mesityl, amine, -yl, c2-c4-alkenyl, c2-c4-alkynyl, c3-c6-alkenyloxy, Ci_c4-haloalkyl, c3-c6-alkynyloxy, q-Cr alkylcarbonyl, -alkoxycarbonyl, q-Cr Carbooxy, q-C4-haloalkoxy, phenoxy, q-Cr thio, NHCCrCr alkyl) 'NCq-Cr alkyl) 2, fluorenyldioxy, ethylenedioxy, or Phenyl, which may be substituted one or more times by the following groups (for example, from 1 to 3 times): halogen, nitro, cyano, q-Cr alkyl, Ci_C4 monodentate alkyl, G-Cr alkoxy, Q -Cr haloalkoxy or Ci_C4_ alkylthio, with the proviso that if R6 is an unsubstituted benzene ring, CR1Q must form a 5-membered ring with "2 or 3, of which one or two methylene groups May be replaced by 0 or 3; ^ a 5- or 6-member heterogeneous family system containing 1 to 3 nitrogen atoms and / or 丨 sulfur or oxygen atoms, which may carry 1 to 4 halo atoms and / Or ... one of the following groups: (^ -Self-base, Ci-day-base oxygen, three-speaking methoxy, "thio-thio, phenyl, or phenoxy ', the phenyl group can carry 1 to 5 groups :, c: and meanings to 3: Fix the following [々V alkyl, CA-dentate soil R15 丄甲 4 其 Λ 广 ^ alkoxy group and / or Cl_C4_ thio group; ·: ^ methoxy or Ethoxy, which carries one of the following L-fields, amines, NH (C "C4-alkyl), N (C" cr "), carbamoyl or con (Ci ~ C4 monoalkyl) ) W is sulfur or oxygen; Q is C2 c3-alkylene, c3 ~ alkenyl, _s_CH2-CH $

509676509676

五、發明說明（16) -0-CH^CH2-，此等基在各個情況可被下列基一或多次取代：ή素、羥基、酼基、氰基、C4-烷基、c4-烷氧基、G-04-烧硫基、h-C4-鹵烧氧基、Q-C4-烧氧幾基、 NH (q_C4-烧基）、N ( Q-C4-烧基）2或苯基，其可被下列基一或多次取代（例如1至3次）：齒素、氰基、c广c4-烧基、 _烧基、统氧基、_烧氧基或(^-(^4_烧硫基；或者Q與R6共同形成下列環系統：2-氫茚基、1-氮節基、1，2, 3, 4 -四氫-2 -蓄基、1，2, 3, 4-四氫-卜賓基，其中各個情況中之苯環可被下列基取代：鹵素、羥基、疏基、羧基、硝基、氰基、q-Cr烷氧基、Q-Cr烷基、—烯基、C2-C4-炔基、C3-C6-烯氧基、C3-C6-炔氧基、Ci_C4—烧硫基、-鹵烧氧基、C^-Cr烧叛基、CrCf烧氧幾基、胺基、NHCCrCr烷基）、Ν((^(：4-烷基）2，或苯基。特佳之通式I化合物（純對掌異構物或純非對映異構物或其混合物）為取代基具有下列定義者： 3 R2為三氟甲基、G-Cr烷基、-烷氧基、q —c4-貌硫基，或CR2被鍵結於下文所述之CR1Q以形成5或6員環；爪 X為氮或次曱基； Y為氮或次曱基；5. Description of the invention (16) -0-CH ^ CH2-, these groups can be substituted one or more times by the following groups in each case: valenin, hydroxyl, fluorenyl, cyano, C4-alkyl, c4-alkane Oxy, G-04-sulfanyl, h-C4-haloxanyl, Q-C4-oxanyl, NH (q_C4-alkyl), N (Q-C4-alkyl) 2 or phenyl , Which can be substituted one or more times by the following groups (for example, 1 to 3 times): halo, cyano, c-c4-alkyl, alkynyl, oxy, alkoxy, or (^-(^ 4-sulfanyl; or Q and R6 together form the following ring system: 2-hydroindenyl, 1-azabenzyl, 1,2, 3, 4-tetrahydro-2 -sulfonyl, 1, 2, 3, 4-tetrahydro-bubyl, in which the benzene ring in each case may be substituted by the following groups: halogen, hydroxyl, sulfo, carboxy, nitro, cyano, q-Cr alkoxy, Q-Cr alkyl, --Alkenyl, C2-C4-alkynyl, C3-C6-alkenyloxy, C3-C6-alkynyloxy, Ci_C4--sulfanyl, -halohaloxy, C ^ -Cr alkyl, CrCf oxygen Alkyl, amine, NHCCrCr alkyl), N ((^ (: 4-alkyl) 2, or phenyl. Particularly preferred compounds of general formula I (pure paraisomers or pure diastereomers or Its mixture) is a substituent It has the following definitions: 3 R2 is trifluoromethyl, G-Cr alkyl, -alkoxy, q-c4-mercaptothio, or CR2 is bonded to CR1Q described below to form a 5- or 6-membered ring ; Claw X is nitrogen or sulfenyl; Y is nitrogen or sulfenyl;

Z為氮或CR10(其中R10為氫、氟或曱基），或者CRu)與^2 或CR3鍵結以形成5或6員之伸烷基或伸烯基環，其可被1 2個曱基取代，其中，在各個情況，一個亞甲基可被氧^ 硫所取代，例如-ch2-ch2-o-、-CH2_CH2-CH2-〇-、 SZ is nitrogen or CR10 (where R10 is hydrogen, fluorine, or fluorenyl), or CRu) is bonded to ^ 2 or CR3 to form a 5- or 6-membered alkylene or alkylene ring, which can be bound by 12 Group substitution, where, in each case, a methylene group may be substituted with oxosulfur, such as -ch2-ch2-o-, -CH2-CH2-CH2-〇-, S

第20頁 509676 五、發明說明（17) -CH = CH-0-、-CH = CH-CH20-、-CH(CH3)CH(CH3)-〇-、 -CH = C(CH3)-0-、-C(CH3) = C(CH3)-0-或-CCCiUsCaHs) —S ; 環成員X、Y或z中至少有一為氮； R3為三氟曱基、（：丨-(：4-烷基、Crq-烷氧基、υ4-烷硫基，或者CR3被鍵結於上述之CR1G以形成5或6員環； R4為(^-C4-烷基，其可被一或多個下列基取代：_素、 Ci~C4-烧氧基、Ci_C4- _烧氧基；Page 509676 5. Description of the invention (17) -CH = CH-0-, -CH = CH-CH20-, -CH (CH3) CH (CH3) -〇-, -CH = C (CH3) -0- , -C (CH3) = C (CH3) -0- or -CCCiUsCaHs) —S; at least one of ring members X, Y or z is nitrogen; R3 is trifluorofluorenyl, (: 丨-(: 4-alkane Group, Crq-alkoxy group, υ4-alkylthio group, or CR3 is bonded to CR1G described above to form a 5- or 6-membered ring; R4 is (^ -C4-alkyl group, which may be substituted by one or more of the following groups Substitution: _ prime, Ci ~ C4- alkoxy, Ci_C4- _ alkoxy;

R5為笨基或著基，其可被一或多個下列基取代：鹵素、硝基、氰基、羥基、巯基、胺基、（^-(：4-烷基、q-iv鹵烷基、鹵烧氧基、-烷*氧基、苯氧基、Ci-Cd-烧硫基、NH(CrC4-烷基）、N(CrC4-烷基）2或苯基，其可被下列基一或多次取代（例如1至3次）··鹵素、硝基、氰基、匕-(：4-烷基、Ci-Cf鹵烷基、CrQ-烷氧基、（^-(：4-自烷氧基或Ci-Cf烧硫基，或苯基或蓄基，其可藉一鍵、亞曱基、伸乙基或伸乙烯基、氧或硫原子或S02、NH或N -烷基而被鍵結於R4之鄰位；環己基； R6為環己基，其可被下列基一或多次取代：C! - C4 -烧氧基、q-C4-烷基、函素或笨基[可被下列基取代一或多次 (例如一至三次）：鹵素、-烷基或-烷氧基]; 笨基或荖基，其各可被一或多個下列基取代：齒素、Rls、 Ci~C4_烷基、_烷基、乙醯基、C4-烷氧羰基、 h-Cr烷氧基、苯氧基、q-Cr烷硫基、NHCC^Cr烧基）、 Ν((^-〇4 -烧基）2、亞甲一氧基、伸乙二氧基或笨基[可被下R5 is a benzyl group or an alkyl group, which may be substituted by one or more of the following groups: halogen, nitro, cyano, hydroxyl, mercapto, amino, (^-(: 4-alkyl, q-iv haloalkyl) , Halooxy, -alk * oxy, phenoxy, Ci-Cd-thiothio, NH (CrC4-alkyl), N (CrC4-alkyl) 2, or phenyl, which can be replaced by the following radicals: Or multiple substitutions (for example, 1 to 3 times) ·· halogen, nitro, cyano, d-(: 4-alkyl, Ci-Cf haloalkyl, CrQ-alkoxy, (^-(: 4- From alkoxy or Ci-Cf thio, or phenyl or radical, which can be borrowed by a bond, fluorenylene, ethylidene or vinylidene, oxygen or sulfur atom or S02, NH or N-alkyl And is bonded to the ortho position of R4; cyclohexyl; R6 is cyclohexyl, which may be substituted one or more times by the following groups: C!-C4 -carboxy, q-C4-alkyl, halo or benzyl [Can be substituted one or more times (eg, one to three times) by the following groups: halogen, -alkyl, or -alkoxy]; benzyl or fluorenyl, each of which can be substituted by one or more of the following groups: halo, Rls , Ci ~ C4_alkyl, _alkyl, ethanoyl, C4-alkoxycarbonyl, h-Cr alkoxy, phenoxy, q-Cr alkylthio, NHCC ^ Cr alkyl) , Ν ((^-〇4- -alkynyl) 2, methylene monooxy, ethylene dioxy or benzyl [can be downloaded

第21頁 509676Page 509676

五、發明說明（18) 列基一或多次取代（例如1至3次）：鹵素、氰基、一基、烧氧基或(^-(^4 -烧硫基]’其附帶條件為若卩為一 -CH2-CH2-以及w為0，則苯環必須具有至少一個s认*… 叫吳於虱之取代基； R15為甲氧基或乙氧基，其攜帶一個下列基··經基、幾基、胺基、NH(CrCr烷基）、N(CrC4-烷基）2、胺甲酸基或 COIUCrh-烷基）2 ; 土 3 w為硫或氧； Q 為C2-C3 伸烧基、-S-CH2_CH2-或_0-0112-(^2〜，在各個情况此等基可被下列基一或多次取代：鹵素、（^一(;4-烧基、q-Cr烷氧基、q-Cr烷硫基或苯基，其可被下列基一或多次取代（例如1至3次）：鹵素、C! - C；4 -统基、c i - c4 -烧氧基、或c4-烷硫基；V. Description of the invention (18) One or more substitutions of the phenyl group (for example, 1 to 3 times): halogen, cyano, mono, alkoxy, or (^-(^ 4 -thiothio) 'with an additional condition: If 卩 is mono-CH2-CH2- and w is 0, then the benzene ring must have at least one s * * is called a substituent of Wu Yu Liao; R15 is methoxy or ethoxy, which carries one of the following groups ... Base, alkyl, amine, NH (CrCralkyl), N (CrC4-alkyl) 2, carbamate or COIUCrh-alkyl) 2; soil 3w is sulfur or oxygen; Q is C2-C3 Alkyl, -S-CH2_CH2- or _0-0112-(^ 2 ~, in each case these groups may be substituted one or more times by the following groups: halogen, (^ 一 (; 4-alkyl, q-Cr Alkoxy, q-Cr alkylthio or phenyl, which may be substituted one or more times by the following groups (eg 1 to 3 times): halogen, C!-C; 4-yl, ci-c4-oxygen Or c4-alkylthio;

或者Q與R6共同形成下列環系統：2-氫茚基、1—氫萌基、1，2, 3, 4 -四氫-2-著基、1，2, 3, 4-四氫-1-絮基，在各個情況笨環可被下列基取代：鹵素、經基、魏基、竣基、氰基、烧氧基、烧基、C2-C4-烯基、c2-c4-快基、C3-C6-稀氧基、C3-C6-炔氧基、C「C4-烧硫基、Ci-Cr鹵燒氧基、CrC4-烷氧羰基、NHCCrCr烷基）、N(CrC4-烷基）2或苯基。本發明之化合物提供一種治療下列疾病之新穎治療用途：高血壓、肺高血壓、心肌梗塞、慢性心衰竭、心絞痛、心律不整、急/慢性腎衰竭、腎功能不足、腦血管痙擎、腦缺血、4知蛛膜下腔出血、偏頭痛、氣喘、動脈粥腫Or Q and R6 together form the following ring system: 2-hydroindenyl, 1-hydrogenyl, 1,2, 3, 4-tetrahydro-2-anyl, 1,2, 3, 4-tetrahydro-1 -A fluorinated group, in each case the stupid ring may be substituted by the following groups: halogen, mesityl, weyl, cynyl, cyano, alkoxy, alkynyl, C2-C4-alkenyl, c2-c4-quinyl, C3-C6-dilutedoxy, C3-C6-alkynyloxy, C4-C4-sulfanyl, Ci-Cr halooxy, CrC4-alkoxycarbonyl, NHCCrCr alkyl), N (CrC4-alkyl) 2 or phenyl. The compounds of the present invention provide a novel therapeutic use in the treatment of the following diseases: hypertension, pulmonary hypertension, myocardial infarction, chronic heart failure, angina pectoris, arrhythmia, acute / chronic renal failure, insufficient renal function, cerebral blood vessels Convulsions, cerebral ischemia, subarachnoid hemorrhage, migraine, asthma, atheroma

第22頁 juyu/u 五、發明說明（19) 化、内毒素性休克、内毒素誘生之器官衰肖、血管内血管造型術及旁路手術後之血管再窄縮、良性前列 ^，大、缺血性及中毒誘生之腎衰蝎或高血壓、間葉細胞 ::轉移及生長、顯影劑誘生之腎衰竭、胰臟炎及胃腸返 >貝瘍。 J發明之化合物在某些情況下也令人驚異地顯示對神經激肽受體具拮抗作用。 t式I化合物之R1具有如下定義時特別具有該用途：〇 13 14Page 22 juyu / u V. Description of the invention (19) Chemical, endotoxin-induced shock, endotoxin-induced organ failure, endovascular remodeling and narrowing of blood vessels after bypass surgery, benign forefront ^, large Ischemic and poisoning-induced renal failure scorpion or hypertension, mesenchymal cells :: metastasis and growth, imaging agent-induced renal failure, pancreatitis and gastrointestinal regurgitation > The compounds of the invention J also surprisingly show antagonistic effects on neurokinin receptors in some cases. R1 of the compound of formula I is particularly useful when it has the following definition: 〇 13 14

NR R 本發明尚關於包含式I之内皮素受體拮抗劑及腎素—血管收縮素系統抑制劑之組合產物。腎素—血管抑制劑為腎素抑制劑、血管收縮素][丨拮抗劑/及i特別地）血管收縮素轉化梅（ACE)抑制劑。本發明尚關於包含々_封阻劑及上述内皮素受體拮抗劑之組合產物、及包含混合ACE/中性内肱酶（NEP)抑制劑及上述之内皮素受體拮抗劑之組合產物。NR R The present invention also relates to a combination product comprising an endothelin receptor antagonist of formula I and a renin-angiotensin system inhibitor. Renin-vasoinhibitors are renin inhibitors, angiotensin] [丨 antagonists / and i in particular) angiotensin-converting plum (ACE) inhibitors. The present invention also relates to a combined product comprising a 々-blocker and the above-mentioned endothelin receptor antagonist, and a combined product comprising a mixed ACE / neutral endobrain enzyme (NEP) inhibitor and the above-mentioned endothelin receptor antagonist.

该組合產物可以以單一醫藥劑型投與、或將其隔開為分離之劑型投與。投與可同時或依順序進行。該組合物之劑量可達個別使用時單一劑量之最大量。然而其也可採用比個別治療所用者小之劑量。此組合產物特別適於治療及預防高血壓及其後遺症，以及治療心臟衰竭。The combined product can be administered in a single pharmaceutical dosage form, or divided into separate dosage forms. The administrations can be performed simultaneously or sequentially. The dosage of the composition can reach the maximum amount of a single dose when used individually. However, it can also be used in smaller doses than those used for individual treatments. This combination product is particularly suitable for the treatment and prevention of hypertension and its sequelae, as well as the treatment of heart failure.

第23頁 509676 五、發明說明（20) 本化合物之良好效果以下列試驗證明：受體結合研究：使用被選殖之人類ETA或£1受體-表現CH0細胞以供結合研究。膜製劑：將ETA或ETB受體-表現CH0細胞在添加10%牛胎兒血清（PAA Laboratories GmbH，Linz，A15-02 2 號）、1 mM 榖胺酸（吉柏可公司，2 503 0-024號）、100單位/毫升青黴素及100微克/毫升鏈黴素（西格瑪公司，P-0781號）之DMEM NUT MIX Fia培養基（吉柏可公司，2 1 33 1 -020號）中培養。48小時之❿ 後’將此細胞用PBS清洗，並與包含〇· 〇5%胰蛋白酶之PBS 在37 °C培養5分鐘。隨後以培養基中和，將細胞於3 〇〇 X g 離心而收集。為製備膜，將此細胞之濃度調整為每毫升之緩衝液（5〇 mM Tris : HC1缓衝溶液，ρΗ 7· 4)含1〇8細胞，繼而以超音波（卜蘭生超音波產生器250，4〇一7〇秒/固定輸出2〇)使直崩解。、結合測定：Page 23 509676 V. Description of the invention (20) The good effect of this compound is demonstrated by the following tests: Receptor binding studies: Use of selected human ETA or £ 1 receptor-expressing CH0 cells for binding studies. Membrane preparation: ETA or ETB receptor-expressing CH0 cells were supplemented with 10% bovine fetal serum (PAA Laboratories GmbH, Linz, A15-02 No. 2), 1 mM ammonium acid (Gibco, 2 503 0-024 No.), 100 units / ml penicillin, and 100 μg / ml streptomycin (Sigma, P-0781) in DMEM NUT MIX Fia medium (Gibco, No. 2 1 33 1 -020). After 48 hours, the cells were washed with PBS and cultured with PBS containing 0.05% trypsin at 37 ° C for 5 minutes. The cells were then neutralized with culture medium, and the cells were collected by centrifugation at 3,000 g. In order to prepare a membrane, the concentration of this cell was adjusted to a buffer (50 mM Tris: HC1 buffer solution, ρΗ7.4) containing 108 cells, followed by an ultrasonic wave (Branson Ultrasonic Generator 250, 40-70 seconds / fixed output 20) disintegrated straight. Combined determination:

I 二ETa及ΕΤβ爻體結合分析，將膜懸浮於培養缓衝液緩衝溶液，ρΗ7.4,含有…叫，白ί升枯草桿_素及0.2%BSA)，該分析混合物之蛋白質濃度為5〇微克/亳升，督un25T1 n ^ 定）PM[125I]_ET3dmpM[nET 机受體測不存在下，於25 t培養。B :非'特：吐仕八又1物質存在或口货此非特異性結合以1 ET測I 2 ETa and ETβ carcass binding analysis, the membrane was suspended in a culture buffer buffer solution, ρ 7.4, containing ... called, white liter subtilisin and 0.2% BSA), the protein concentration of the analysis mixture was 50. Μg / L, un25T1 n ^) PM [125I] _ET3dmpM [nET machine receptor test in the absence, culture at 25 t. B: Non-special: Toshiba 1 and 1 substance is present or oral. This non-specific binding is measured by 1 ET

第24頁 509676Page 509676

定。30分鐘之後，經由史卡特蘭（Skatr〇n)細胞收集器（史卡特蘭公司，李耳，挪威）中之GF/B玻璃纖維濾器（/瓦°特曼公司’英格蘭）過濾，’以分離未結合與結合之放射線配體’以及將該濾器用含有〇· 2% BSA之冰冷Tris-HCl緩衝溶液（pH 7· 4)清洗。將濾器上收集到之放射活性用帕卡德办 (Packard)22 00 CA液體閃爍計數器定量。心 ET拮抗劑之活體測試：將重25 0-3 00公克之雄性SD老鼠用戊巴比妥麻醉、人工換氣、切除迷走神經、及除去骨髓。將其頸動脈及頸靜脈 ***導管。在對照組動物中，經靜脈投與！微克/公斤之ET1，此導致血壓明顯上升並維持一段長時間。將文試組動物在投與ET1之前3 0分鐘，靜脈注射受試化合物(1毫升/公斤）。為測定ET拮抗性質，組 AUC與對照.組動物之AUC比較。動物混合ETA或ETB拮抗劑之口服測試： ^250-300公克之雄性、血壓正常之老鼠（斯布拉格-桃 =甲先口服受試物質。80分鐘後，將動物用 Sx乙自日麻醉，並將導管插人頸動脈（供測量血壓）及頭靜脈（供投與大内皮素/内皮素1)。穩定期之後，將大内皮素（20微克/公斤二/=)與m(0.3微克/公斤’投與體積〇5、毫-升積公左靜脈投與。連續紀錄血壓與心跳速率歷3〇分鐘。血之明顯且持續長時間之改變以曲線下面積計算（AM)。set. After 30 minutes, it was filtered through a GF / B glass fiber filter (/ Wattman Company 'England') in a Skatroon cell collector (Skatlan, Lee, Norway) to separate Unbound and bound radioligands' and the filter was washed with ice-cold Tris-HCl buffer solution (pH 7.4) containing 0.2% BSA. The radioactivity collected on the filter was quantified using a Packard 22 00 CA liquid scintillation counter. Cardiac ET antagonist bioassay: Male SD rats weighing 25 0-3 00 g were anesthetized with pentobarbital, artificially ventilated, vagus nerve removed, and bone marrow removed. The carotid artery and jugular vein were inserted into the catheter. In the control animals, it is administered intravenously! Μg / kg of ET1, which caused a significant increase in blood pressure and maintained it for a long time. Animals in the text test group were intravenously injected with the test compound (1 ml / kg) 30 minutes before administration of ET1. To determine the ET antagonistic properties, the AUC of the group AUC was compared with that of the control. Oral test of animals mixed with ETA or ETB antagonists: ^ 250-300 g male, normal blood pressure rats (Sprague-Peach = A first oral test substance. After 80 minutes, the animals were anesthetized with Sx B daily, and The catheter was inserted into the carotid artery (for measuring blood pressure) and the cephalic vein (for administration of macroendothelin / endothelin 1). After the stabilization period, macroendothelin (20 μg / kg 2 / =) and m (0.3 μg / Kg 'administration volume was 05, milli-liter product of left vein administration. Blood pressure and heart rate were continuously recorded for 30 minutes. The obvious and long-term change in blood was calculated as the area under the curve (AM).

第25頁 509676 五、發明說明（22) 為測定受試物質之拮抗效果，將處理組動物之AUC與對照組動物之AUC比較。本發明之化合物可以習用方式進行口服或經非腸道途徑 (皮下、靜脈内、肌内、腹膜腔内）投與。投與也可以蒸氣或噴霧劑經由鼻咽腔進行。劑量視患者之年齡、病況及體重以及投與方式而定。一般而言，活性成分之每日劑量，口服投與時每公斤體重约〇· 5-50毫克，而經非腸道投與時每公斤體重约〇•卜1〇毫克。新賴化合物可以習用固體或液體醫藥劑型使用，例如未❿ 加包衣或加包衣或膜衣之錠劑、膠囊劑、粉劑、顆粒劑、栓劑、溶液劑、軟膏劑、乳膏劑或喷霧劑。此等皆可以習用方法製造。此活性成分可依其目的用一般醫藥助劑加工，該醫藥助劑例如有錠劑用結合劑、填充劑、保存劑、錠劑崩散劑、流動調節劑、可塑劑、潤濕劑、分散劑、乳化劑、溶劑、缓釋劑、抗氧化劑及/或推進氣體（參照ΗPage 25 509676 V. Description of the invention (22) In order to determine the antagonistic effect of the test substance, the AUC of the animals in the treatment group and the AUC of the animals in the control group were compared. The compounds of the present invention can be administered orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally) in a conventional manner. Administration can also be by steam or spray through the nasopharyngeal cavity. The dose depends on the patient's age, condition and weight, and the method of administration. In general, the daily dose of the active ingredient is about 0.5-50 mg per kg of body weight when administered orally and about 10 mg per kg of body weight when administered parenterally. Sin Lai compounds can be used in solid or liquid pharmaceutical formulations, such as uncoated or coated or film-coated tablets, capsules, powders, granules, suppositories, solutions, ointments, creams or sprays. Agent. These can be manufactured by conventional methods. This active ingredient can be processed with general pharmaceutical auxiliaries according to its purpose. The pharmaceutical auxiliaries include, for example, a binding agent for tablets, a filler, a preservative, a tablet disintegrating agent, a flow regulator, a plasticizer, a wetting agent, and a dispersant. , Emulsifiers, solvents, slow release agents, antioxidants and / or propulsion gases (see Η

Sucker et al· :Pharmazeutische Technologie, Thieme-Verlag，Stuttgart, 1991)。經由此等方式所得到之投與劑型一般含有〇· 1至9〇重量％之活性成分。 f 合成實例：則實例1 2-羥基_3-(2_(4-氣苯基）乙氧基）-3-苯基丁酸甲酿 (非對映異構物I，推測為2s, 3r) 將8滴三氟化硼醚合物，在室溫下加至5公克（26赛 $旲耳）Sucker et al .: Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1991). The dosage forms obtained by such means generally contain from 0.1 to 90% by weight of the active ingredient. f Synthesis Example: Then Example 1 2-Hydroxy-3- (2_ (4-Gaphenyl) ethoxy) -3-phenylbutanoic acid methyl ester (diastereomer I, presumed to be 2s, 3r) Add 8 drops of boron trifluoride etherate to 5 grams at room temperature (26 $)

第26頁 509676Page 509676

反式-2, 3 -環氧基苯基丁酸甲酯與4·〇公克（26毫莫耳） 2 -（ 4 -氣笨基）乙醇之混合物中，並將此混合物在3 3 5 攪拌2· 5小時（也可能選擇性地使用氣仿作為溶劑）。為完成本反應，繼而加入另外3滴三氟化硼醚合物，並在3〇一 3 5 C進一步攪拌1小時。最後將此混合物以***溶取，並用2N NaOH萃取二次，將有機相用乾燥並過濾，繼而將溶劑蒸發除去。殘餘物為8· 7公克之黃色油，1立行進一步之反應。 μ 實例2 2-經基-3-(2-(4_氣苯基〕乙氧基）_3—苯基丁酸 ❿ (非對映異構物I，推測為2 s，3 r ) 將8· 7公克之（2s，3r)-2-羥基-3-(2-（4_氣苯基）乙氧基） -3-苯基丁酸甲酯（得自實例i之粗製產物）溶解於5〇毫升之二氧六圜.，並在加入75毫升之1M NaOH後，在室溫攪拌3小時。繼而將水加入此混合物中，並將水相用***萃取。將此水相以鹽酸酸化，以乙酸乙酯萃取，並將有機相用硫酸鎂乾燥。在將溶劑蒸發除去之後，分離得到7· 〇公克油，並立即使用於下一步。非對映異構物之混合物（2s，3r/2s 3s 80 ： 20) 〇 ’ 實例3 〇 2-（4, 6-二曱基-2_嘧啶氧基）一3_(2—(4一氣苯基）乙氧基）-3-苯基丁酸（非對映異構物丨，推測為2s，3r) 將0· 28公克NaH(9毫莫耳，80%白油中）在氮氣下導入l〇毫升之DMF中，並逐滴加公克2-羥基—3_(2 —(4_氣苯基）A mixture of trans-2,3-epoxyphenylbutyric acid methyl ester and 4.0 g (26 mmol) of 2- (4-aminobenzyl) ethanol, and the mixture was stirred at 3 3 5 2.5 hours (optionally using aerosol as solvent). To complete the reaction, another 3 drops of boron trifluoride etherate were added and further stirred at 30-35C for 1 hour. Finally, the mixture was taken up with diethyl ether and extracted twice with 2N NaOH. The organic phase was dried over and filtered, and then the solvent was removed by evaporation. The residue was 8.7 g of yellow oil, and further reaction was carried out. μ Example 2 2-Ethyl-3- (2- (4-Gaphenyl) ethoxy) -3-phenylbutyrate (diastereomer I, presumed to be 2 s, 3 r) will be 8 7 g of (2s, 3r) -2-hydroxy-3- (2- (4-Gaphenyl) ethoxy) -3-phenylbutyric acid methyl ester (crude product from Example i) was dissolved in 50 ml of dioxane, and after adding 75 ml of 1M NaOH, stirred at room temperature for 3 hours. Then water was added to the mixture, and the aqueous phase was extracted with ether. This aqueous phase was acidified with hydrochloric acid , Extracted with ethyl acetate, and the organic phase was dried over magnesium sulfate. After the solvent was removed by evaporation, 7.0 g of oil was isolated and used immediately in the next step. A mixture of diastereomers (2s, 3r / 2s 3s 80: 20) 〇 ′ Example 3 〇 2- (4, 6-Difluorenyl-2_pyrimidinyloxy)-3_ (2- (4-monophenyl) ethoxy) -3-phenylbutyl Acid (diastereomers, presumed to be 2s, 3r) 0.28 g of NaH (9 mmol, in 80% white oil) was introduced into 10 ml of DMF under nitrogen, and gram was added dropwise 2-hydroxy-3_ (2 — (4_gasyl)

第27頁 509676 五、發明說明（24) 乙氧基）-3 -苯基丁酸（得自實例2之粗製產物）溶解於5毫升 DMF之溶液，1〇分鐘後，加入640毫克之2-氣-4, 6 -二甲基 -2-嘴啶。繼而將此混合物在室溫攪拌四天。將水加入此混合物中，並用2N HC1將邱調整至2 ^水相用***萃取。將合併之有機相與2N NaOH —起振搖三次，然後將有機相棄置。將鹼性相以2N HC1調節至PH 2，繼而以***萃取。將合併之有機相用硫酸鎂乾燥及過濾，再將溶劑蒸發除去，殘餘物（1· 1公克之黃色泡沫）藉層析法（二氣甲烷/甲醇9 : 1 )純化。得到兩部分^87毫克兩種 (2s，3r/2s，3s 84: 16)之混人铷.4nn *古工構物物（2S 3rV2S % ^ ^ 克兩種非對映異構初 Us，〇5r/Zs，3s 75:25)之混合物。 ES I -MS : M+ = 4 4 0 實例4 2 -經基-3-（2-（4~氣苯基）乙氯其、 (非對映異構物Η，推測為2^) 土丁酸甲醋將8滴三氟化硼醚合物，順式-2, 3-環氧基_3一笨美，孤下加入5公克（26毫莫耳） 9 Ν , 基丁酸甲_與4· 〇公券古曾甘、 2(4氣本基）乙醇之混人兄莫耳）攪拌2· 5小時（也可能選^中，並，此混合物在30-35 t 成本反應，繼而另外加 ^使^用亂仿作為溶劑）。為完 35 °C進一步攪拌3小時。t^二氟化硼醚合物，並在30 - 用2N NaOH萃取三次，=後將此混合物以***溶取，並將溶劑蒸發。殘餘物為機相’S〇4乾燥並過濾，繼而進一步之反應。 ·公克之黃色油，其被立即進行 ^9676Page 27 509676 V. Description of the invention (24) Ethoxy) -3-phenylbutyric acid (the crude product from Example 2) was dissolved in 5 ml of DMF solution. After 10 minutes, 640 mg of 2- Gas-4, 6-dimethyl-2-propanidine. This mixture was then stirred at room temperature for four days. Water was added to the mixture, and Qiu was adjusted to 2 ^ aqueous phase with 2N HC1 and extracted with ether. The combined organic phases were shaken three times with 2N NaOH, and the organic phases were discarded. The basic phase was adjusted to pH 2 with 2N HC1 and then extracted with ether. The combined organic phases were dried over magnesium sulfate and filtered, and the solvent was removed by evaporation. The residue (1.1 g of yellow foam) was purified by chromatography (methane / methanol 9: 1). Two parts ^ 87 mg of two (2s, 3r / 2s, 3s 84: 16) were mixed 铷. 4nn * ancient structure (2S 3rV2S% ^ ^ two diastereomeric primary Us, 5r / Zs, 3s 75:25). ES I -MS: M + = 4 4 0 Example 4 2 -Ethyl-3- (2- (4- ~ phenylphenyl) ethyl chloride, (diastereomer Η, presumed to be 2 ^) tocoic acid Methyl vinegar added 8 drops of boron trifluoride etherate, cis-2, 3-epoxy_3 to a stupid beauty, and added 5 grams (26 mmol) 9 Ν, methyl butyrate and 4 · 〇 Coupon Gu Zenggan, 2 (4-gas-based) ethanol mixed brother Mo Er) Stir for 2 · 5 hours (may also choose ^, and the mixture reacts at 30-35 t cost, and then add another ^ Make use of chaos as solvent). To complete the stirring at 35 ° C for 3 hours. t ^ boron difluoride etherate, and extracted three times with 2N NaOH at 30-, and then the mixture was taken up with ether, and the solvent was evaporated. The residue was dried over organic phase'S04 and filtered, followed by further reaction. · Grams of yellow oil, which is immediately carried out ^ 9676

實例5 2〜經基-3_( 2-(4-氯苯基）乙氧基）-3-苯基丁酸 (非對映異構物I I，推測為2s，3s) 將8· 1公克之（2s，3s) - 2 -經基-3-(2 -（4-氣苯基）乙氧基）一3一笨基丁酸甲酯（得自實例4之粗製產物）溶解於5〇毫升之二氧六圜，並在加入69毫升之1M NaOH後，在室溫攪拌4小時。繼而將水加入此混合物中，並將水相用***萃取。將此水相以鹽酸酸化，以乙酸乙酯萃取，並將有機相用硫酸鎮乾燥。在將溶劑蒸發除去之後，分離得到5· 8公克油（非子映 ';把&物2 s，3 s / 2 s，3 r 8 7 · 1 3 )。將此粗製產物在少量礓^ 一異丙鱗中攪拌隔夜。將所得到沉澱物濾除，並除去溶劑之後，得到2 · 3公克白色固體（非對映異構性純質，熔點 9 4 9 5 C )。將其進一步使用於實例6之反應。實例6 、，b-二曱基—2-嘧啶氧基）一 3 -（2-(4-氣苯基）乙氧基）—3-笨基丁酸（非對映異構物丨丨，推測為2s，3s)Example 5 2 ~ Ethyl-3- (2- (4-chlorophenyl) ethoxy) -3-phenylbutanoic acid (diastereomer II, presumed to be 2s, 3s) (2s, 3s)-2-Ethyl-3- (2- (4-phenyl) ethoxy) -methyl 3-benzylbutyrate (crude product from Example 4) was dissolved in 50 ml Dioxane, and after adding 69 ml of 1M NaOH, stir at room temperature for 4 hours. Water was then added to the mixture, and the aqueous phase was extracted with ether. This aqueous phase was acidified with hydrochloric acid, extracted with ethyl acetate, and the organic phase was dried over sulfuric acid. After the solvent was removed by evaporation, 5.8 g of oil was isolated (African & 2 s, 3 s / 2 s, 3 r 8 7 · 1 3). This crude product was stirred overnight in a small amount of isopropyl scale. The obtained precipitate was filtered off and the solvent was removed to obtain 2.3 g of a white solid (diastereomeric purity, melting point 9 4 9 5 C). This was further used in the reaction of Example 6. Example 6 ,, b-Difluorenyl-2-pyrimidinyloxy)-3-(2- (4-aminophenyl) ethoxy) -3-benzylbutyric acid (diastereomers), (Estimated as 2s, 3s)

山將〇· 28公克NaH(9毫莫耳，80%白油中）在氮氣下導入1〇毫升之DMF中，逐滴加入1公克之2_羥基-3_(2_(4—氣苯基）乙氧基）-3-苯基丁酸（3毫莫耳，得自實例5)溶解於5毫升 DMF之溶液，10分鐘後，再加入640毫克之2-氣-4, 6 -二甲土 2嘧咬。繼而將此混合物在室溫撥拌隔夜。將水加入此混合物中，並用2N HC1將pH調整至2。水相用***萃取。將合併之有機相與2N NaOH—起振搖三次，然後將有機相棄置。將鹼性相以2N HC1調節至pH2，繼而以***萃28.28 grams of NaH (9 millimoles in 80% white oil) was introduced into 10 ml of DMF under nitrogen, and 1 gram of 2-hydroxy-3_ (2- 4-phenyl) was added dropwise. Ethoxy) -3-phenylbutyric acid (3 mmol, from Example 5) was dissolved in 5 ml of DMF. After 10 minutes, 640 mg of 2-gas-4, 6-dimethylformate was added. 2 pyrimidine bites. The mixture was then stirred overnight at room temperature. Water was added to this mixture and the pH was adjusted to 2 with 2N HC1. The aqueous phase was extracted with ether. The combined organic phases were shaken three times with 2N NaOH, and then the organic phases were discarded. The basic phase was adjusted to pH 2 with 2N HC1 and then extracted with ether

第29頁 509676 五、發明說明（26) '~-一- 取。將合併之有機相用硫酸鎂乾燥及過濾，再將溶劑蒸發除去，將殘餘物（1 · 2 5公克之黃色泡沫）在二異丙醚中攪拌，得到1 · 1公克之產物（純非對映異構物）。 !H NMR (2 70 MHz, DMSO) ： 12.5-13.0 ppm(lH, br); 7.15-7.4(9H, m)； 6.85(1H, s); 5.15(1H, s)； 3.50- 3·65(1Η, m); 3.2 - 3·4(1Η, m); 2.7 - 2·85(2Η, m); 2·25(6H，s); 1 ·65(3H，s)。 ESI-MS : M+ = 440 下列化合物係依照類似上述實例之方法製備。實例7 2-(4-甲氧基-6-甲基一嘧啶氧基）一3一（2一（4一曱苯基）乙氧基）-3-苯基丁酸（非對映異構物I，推測為2s，3r) lH NMR (2 00 MHz, CDC13) :7.0-7.5 ppm(9H, m); 6,25(1H, s); 5.3(1H, s)； 3.9(3H, d); 3.65-3.8(lH, m); 3.4-3.6C1H, m)； 2.8-3.0(2H, in) 2.3(3H, s), 1·8(3H， m) 〇實例8 2-（4-曱氧基-6-甲基一2-嘧啶氧基）一3一（2-(4一曱苯基）乙氧基）-3-苯基丁酸（非對映異構物丨丨，推測為2s，3s) NMR (2 50 MHz, CDC13) ： 7. 0-7. 5 ppm(9H, m); 6·1(1Η，s); 5·5(1Η，s); 3·9(3Η, d); 3.65-3·8(1Η, m); 3.4~3.6(1H, m)； 2.8-3.0(2H, m) 2.3(3H, s), 2·2(6H， s); 1· 8(3H, m)。實例9Page 29 509676 V. Description of Invention (26) '~-一-Take. The combined organic phases were dried over magnesium sulfate and filtered, and the solvent was removed by evaporation. The residue (1.55 g of yellow foam) was stirred in diisopropyl ether to give 1.1 g of the product (pure non-paired Enantiomers). ! H NMR (2 70 MHz, DMSO): 12.5-13.0 ppm (lH, br); 7.15-7.4 (9H, m); 6.85 (1H, s); 5.15 (1H, s); 3.50- 3.65 ( 1Η, m); 3.2-3.4 (1Η, m); 2.7-2.85 (2Η, m); 2.25 (6H, s); 1.65 (3H, s). ESI-MS: M + = 440 The following compounds were prepared according to a method similar to the above example. Example 7 2- (4-methoxy-6-methyl-pyrimidinyloxy) -3 (2- (4- (4-phenyl) ethoxy) -3-phenylbutanoic acid (diastereomer I, speculated to be 2s, 3r) lH NMR (2 00 MHz, CDC13): 7.0-7.5 ppm (9H, m); 6,25 (1H, s); 5.3 (1H, s); 3.9 (3H, d ); 3.65-3.8 (lH, m); 3.4-3.6C1H, m); 2.8-3.0 (2H, in) 2.3 (3H, s), 1.8 (3H, m) 〇Example 8 2- (4- Phenyloxy-6-methyl-2-pyrimidinyloxy) -3- (2- (4-Pyridinyl) ethoxy) -3-phenylbutanoic acid (diastereomers) 丨, speculated 2s, 3s) NMR (2 50 MHz, CDC13): 7. 0-7. 5 ppm (9H, m); 6. · 1 (1Η, s); 5 · 5 (1Η, s); 3 · 9 ( 3Η, d); 3.65-3 · 8 (1Η, m); 3.4 ~ 3.6 (1H, m); 2.8-3.0 (2H, m) 2.3 (3H, s), 2.2 · 6 (6H, s); 1 · 8 (3H, m). Example 9

第30頁 509676 五、發明說明（27) 2-(4,6 -二甲基-2-嘧啶氧基）-3 -（2-(4-甲苯基）乙氧基）-3-苯基丁酸（非對映異構物I，推測為2s，3r) NMR ( 2 00 MHz, DMSO) ： 12-13.5 ppm(lH, br)； 7.0-7.3(9H, m)； 6.8(1H, s); 5.3(1H, s); 3.4-3.7 (2H，m); 2·7 - 2·9(2Η，m); 2·25(6Η, s); 2·2(3Η，s); 1·7(3H, s)。 ’ ESI -MS : M+ = 420 實例1 0 2-（4, 6 -二甲基-2-嘧啶氧基）-3-(3-苯丙氧基）- 3-苯基丁酸（非對映異構物I，推測為2s，3r) NMR (2 00 MHz, DMSO) ： 12-13.5 ppm(lH, br); ?·1-7.4(9Η, m); 6.8(1H, s); 5.3(1H, s); 3. 2-3. 6 (2H, m); 2.5-2·7(2Η, m); 2.25(6H, s); 1·7(3Η，s); -1· 9(2H，m)。 ’ ESI -MS : M+= 420 實例11 2^(4,6-二曱基一2-嘧啶氧基）一3一（2一（2-蓄基）乙氧基）一3一笨基丁酸（非對映異構物I，推測為2s，3r)Page 509676 5. Description of the invention (27) 2- (4,6-dimethyl-2-pyrimidinyloxy) -3-(2- (4-tolyl) ethoxy) -3-phenylbutane Acid (diastereomer I, presumed to be 2s, 3r) NMR (2 00 MHz, DMSO): 12-13.5 ppm (lH, br); 7.0-7.3 (9H, m); 6.8 (1H, s) ; 5.3 (1H, s); 3.4-3.7 (2H, m); 2 · 7-2 · 9 (2Η, m); 2 · 25 (6Η, s); 2 · 2 (3Η, s); 1 · 7 (3H, s). 'ESI -MS: M + = 420 Example 1 0 2- (4, 6-dimethyl-2-pyrimidinyloxy) -3- (3-phenylpropoxy)-3-phenylbutanoic acid (diastereomer Isomer I, presumed to be 2s, 3r) NMR (2 00 MHz, DMSO): 12-13.5 ppm (lH, br);? · 1-7.4 (9Η, m); 6.8 (1H, s); 5.3 ( 1H, s); 3. 2-3. 6 (2H, m); 2.5-2 · 7 (2Η, m); 2.25 (6H, s); 1 · 7 (3Η, s); -1 · 9 ( 2H, m). 'ESI -MS: M + = 420 Example 11 2 ^ (4,6-Difluorenyl-2-pyrimidinyloxy)-3- (2- (2-sodium) ethoxy)-3-benzylbutyric acid (Diastereomer I, presumed to be 2s, 3r)

IfI NMR (2 50 MHz, DMSO) ： 12-13.5 ppm(lH5 br); 7·7 — 7·9(4Η，m); 7」-7·5(8Η，m); 6·9(1Η，s); 5·3 (1H，s); 3·6-3·8(1Η，m); 3·4-3·6(1Η，m); 2·9-3.1 (2Η， m); 2· 3(6H， s); 1·7(3H, s)。 ESI -MS : Μ+ = 4 5 6 實例1 2IfI NMR (2 50 MHz, DMSO): 12-13.5 ppm (lH5 br); 7 · 7 — 7 · 9 (4Η, m); 7 ″ -7 · 5 (8Η, m); 6 · 9 (1Η, s); 5 · 3 (1H, s); 3 · 6-3 · 8 (1Η, m); 3 · 4-3 · 6 (1Η, m); 2 · 9-3.1 (2Η, m); 2 · 3 (6H, s); 1 · 7 (3H, s). ESI -MS: Μ + = 4 5 6 Example 1 2

第31頁 509676 五、發明說明（28) 2-（4,6_二甲基-2-,咬氧基）-3_(3-（4-氯苯基）丙氧基）-3 -苯基丁酸（非對映異構物I，推測為2 s，3 r) !11 NMR (270 MHz, DMS0) : 12.5-13.0 ppm(lH, br); 7.15-7.5C9H, in); 6.9(1H, s)； 5.2(1H, s); 3.3-3.5 (1H, m); 3.1-3.3(1H, m); 2.55-2.7(2H, m); 2.3(6H, s) ; 1· 7(3H，s); 1·65-1·9(2H，m)。 ESI-MS ： M+ = 454 實例1 3 2 -（4,6 -二甲基-2-嘧啶氧基）-3一（2-（4-氟苯基）乙氧基）-3 -苯基丁酸（非對映異構物I，推測為2 s，3 r) ❿ lE NMR ( 2 00 MHz, DMSO) ： 12.0-13,0 ppm(lH, br); 7·0-7·4(9Η，m); 6·8(1Η，s); 5·2(1Η, s); 3.5 - 3.7 (1H, m); 3·3-3·5(1Η, m); 2·7 - 2·85(2Η，m); 2·3(6Η, s); 1· 7(3H, s) 〇 ESI -MS : M+ = 424 實例1 4 2-(4, 6 -二曱基-2-嘧啶氧基）一3一（2-(4-氟苯基）乙氧基）-3-苯基丁酸（非對映異構物丨丨，推測為2s, 3s) lH NMR (2 00 MHz, DMSO) :12.5-13.0 ppm(lH, br); 7.0-7.4(9H, m)； 6.8(1H, s); 5.1(1H, s); 3.5-3.7 (1H, m); 3·2-3·4(1Η，m); 2·7-2·85(2Η，m); 2·3(6Η， s); 1· 65(3H, s)〇 ESI -MS : M+ = 4 24 實例1 5P.31 509676 V. Description of the invention (28) 2- (4,6_dimethyl-2-, tetraoxy) -3_ (3- (4-chlorophenyl) propoxy) -3-phenyl Butyric acid (diastereomer I, presumed to be 2 s, 3 r)! 11 NMR (270 MHz, DMS0): 12.5-13.0 ppm (lH, br); 7.15-7.5C9H, in); 6.9 (1H , s); 5.2 (1H, s); 3.3-3.5 (1H, m); 3.1-3.3 (1H, m); 2.55-2.7 (2H, m); 2.3 (6H, s); 1 · 7 (3H , S); 1.65-1 · 9 (2H, m). ESI-MS: M + = 454 Example 1 3 2-(4,6-dimethyl-2-pyrimidinyloxy) -3- (2- (4-fluorophenyl) ethoxy) -3 -phenylbutane Acid (diastereomer I, presumed to be 2 s, 3 r) ❿ lE NMR (2 00 MHz, DMSO): 12.0-13,0 ppm (lH, br); 7 · 0-7 · 4 (9Η , M); 6 · 8 (1Η, s); 5 · 2 (1Η, s); 3.5-3.7 (1H, m); 3 · 3-3 · 5 (1Η, m); 2 · 7-2 · 85 (2Η, m); 2 · 3 (6Η, s); 1 · 7 (3H, s) oESI-MS: M + = 424 Example 1 4 2- (4, 6-Diamidino-2-pyrimidinoxy Group) -tris (2- (4-fluorophenyl) ethoxy) -3-phenylbutanoic acid (diastereomers, 丨, presumed to be 2s, 3s) lH NMR (2 00 MHz, DMSO ): 12.5-13.0 ppm (lH, br); 7.0-7.4 (9H, m); 6.8 (1H, s); 5.1 (1H, s); 3.5-3.7 (1H, m); 3.2-3 · 4 (1Η, m); 2 · 7-2 · 85 (2Η, m); 2 · 3 (6Η, s); 1 · 65 (3H, s) 〇ESI -MS: M + = 4 24 Example 1 5

第32頁 509676 五、發明說明（29) 2 一（4, 6 -二甲基-2-嘧啶氧基）-3 -（2 -（4-曱氧苯基）乙氧基） - 3 -苯基丁酸（非對映異構物I，推測為2 s，3 r ) NMR ( 2 00 MHz, DMSO) ： 12.0-13-0 ppm(lH, br); 7·2 - 7·4(5Η, m); 7·1(2Η, d); 6·9(1Η, s); 6·75(2Η, d); 5.2(1H, s); 3.7(3H, s); 3.4-3.6(lH, m); 3.2-3.4(1H, m); 2.7-2.85(2H, m); 2.3(6H, s); 1.7(3H, s) 〇 ESI -MS ·· M+ = 436 實例1 6 2〜（4, 6 -二甲基-2-嘧啶氧基）一3-(3_( 4-甲氧苯基）丙氧基） 3 -苯基丁酸（非對映異構物I，推測為2 s，3 r )P.32 509676 V. Description of the invention (29) 2 mono (4, 6-dimethyl-2-pyrimidinyloxy) -3-(2- (4-fluorenyloxy) ethoxy)-3 -benzene Butyric acid (diastereomer I, presumed to be 2 s, 3 r) NMR (2 00 MHz, DMSO): 12.0-13-0 ppm (lH, br); 7 · 2-7 · 4 (5Η , m); 7.1 (2Η, d); 6.9 (1Η, s); 6.75 (2Η, d); 5.2 (1H, s); 3.7 (3H, s); 3.4-3.6 (lH , m); 3.2-3.4 (1H, m); 2.7-2.85 (2H, m); 2.3 (6H, s); 1.7 (3H, s) 〇ESI -MS ·· M + = 436 Example 1 6 2 ~ ( 4, 6-dimethyl-2-pyrimidinyloxy) -3- (3- (4-methoxyphenyl) propoxy) 3-phenylbutanoic acid (diastereomer I, presumed to be 2 s , 3 r)

炫1 點：153-1 56 °CHyun 1 point: 153-1 56 ° C

EsI-MS ： M+ = 450 表1所列之化合物可以用類似之方法或一般章節所述之方法製備。EsI-MS: M + = 450 The compounds listed in Table 1 can be prepared in a similar manner or as described in the general section.

第33頁Page 33

509676 五、發明說明（30) 1丨15509676 V. Description of the invention (30) 1 丨 15

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509676 五、發明說明（31) * δ k δ i ώ δ 1-30 j δ δ 1-27 s mJ 5 i OdLl ON 編號 coon 000Η 000H OOOMe coon OOOBt OOOH OOOH OOOH 1 OOOH ! OOOH ΟΟΟΗ OOOH OOOH OOOH OOOH OOOH OOOH OOOH 四0坐 OOOEt OOOMe OOOH |4Cl·苯基1 |φβγ-笨基| η |丰乙基-苯基1 |丰乙基-苯基i _苯基丨4~0»苯基1 |φο·苯基Π 1苯基 I 丨苯基 I 1苯基 i 1苯基 | |丰乙基-苯基1 1 -€ 丙基i -€ -€ -€ -€ -€ -€ 5 c* -€ ο 1^0^2 細 | -ch2-ch2- ί 1 |-ch2-ch2- I ΌΗ^Όί〗讎 0Η2~^^2· 丨瑪偶-1 J § 1 ί δ i 1 •ΟΗ^ΌΗ〗讎 •CH2 "CH〗誦 ί κ -0^2^013)2- |<ή2<ή2· I •ΌΗ^ΌΗ】** δ δ κ>* 1 -ch2-ch2- 0 丰甲氧基-苯基 3,丰二甲氧基-苯基 3，Φ二甲氧基-苯基 3,4»二甲氧基-苯基 3，Φ二甲氧基-苯基 3«甲氧基-苯基 4~甲疏差本基孓甲氧基-苯基丰甲氧基-苯基 4«曱氧基-苯基苯基苯基丰曱氧基-苯基 Φ甲氧基-苯基丰甲氧基-苯基 3,4~二甲氧基-苯基丰甲氧基-苯基丰甲氧基-苯基丰甲氧基-苯基丰甲氧基-苯基丰曱氧基-苯基 φ甲氧基-苯基丰甲碎L&-笨基 1 3 Ο OMe OMe OMe OMe OMe OMe 1 1 OMe OMe OMe OMe OMe OMe OMe I OMe I 1 CKM2<M2C qch2-ch2-c 1 CH2 -CH2 -CH2 -C 1 1 OMe 1 1 * (XH2-CH2-C ΟΌΗ^ΌΗ^Ό CKM2<H2C 1： Z 9 9 Z 9 Z ζ S Ζ Z s s s s z N Z Ζ z z z z ζ 2： Z Z z Z Z Z z z X Z Z 9 Z 2： z Z z z ζ ζ 3 Z Z z z Z z Z z z 〇〇〇 GO 00 O o 〇 00 0 ο 〇〇 0 0 〇 0 0 0 0 00 0 0 # nlf 第35頁 509676 五、發明說明（32) 5： a 1-60 5 3 δ ώ 5： i s h N-^ S 1-44 S 1-40 編號 _1 coon OOOH OOOH OOOH OOOH OOOH ΟΟΟΗ COOH OOOH ΟΟΟΗ ΟΟΟΗ OOOH OOOH OOOH OOOH OOOBd ΟΟΟΗ ΟΟΟΗ ΟΟΟΗ ΟΟΟΗ ΟΟΟΗ ΟΟΟΗ ΟΟΟΗ t ί； h I3 Ρ Ρ ψ η r n C4 k o k Ρ 舛 5 -€ Μ -¾ -¾ -€ c^ Μ , -€ Ο -€ -€ $ δ ί h Q ί ί ί ο ί t έ 1 ΐ ί ί 1 睡 ί ί β ί 1 1 I S 1 着廿 ίί ± 令 t Ψ Ψ U) u> ψ V U) U) Η U) U) U) Hs -€ ψ ψ -S ψ -€ -€ $: -¾ -€ Ύ > > -s k n h 舛 p( η p( 和 Ο ψ η ψ 械 1“ 淘 p w iv I1 P k n pi n I1 ρ 铲 η μ g η μ -€ Ρ η I1 -€ pi k 1» -€ ζ k ρ k ΓΎ OMe OMe OMe OMe Ο OMe OMe OMe OMe Γ» OMe Ο OMe S SMe ! OMe D* g § 5 1 1 1 Q w g 5 5 1 1 1 I h2-ch2-c h2.ch2-c ΐ 5 * ί έ S ζ S 9 ζ 9 9 s S z ί S s S S S s N * 6 * z Z z ζ ζ ζ ζ ζ z z z Ζ Ζ Ζ ζ ζ Ζ Ζ z X z z z ζ 9 ζ Z ζ ζ z z 9 z z ζ ζ ζ ζ 3 ζ Ζ Z κ： o o o o 00 ο ο 〇 ο ο o o O o o ο GO ο ο ο 00 Ο o <1509676 V. Description of the invention (31) * δ k δ i FREE δ 1-30 j δ δ 1-27 s mJ 5 i OdLl ON number coon 000Η 000H OOOMe coon OOOBt OOOH OOOH OOOH 1 OOOH! OOOH 〇ΟΟΗ OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOEt OOOMe OOOH | 4Cl · phenyl 1 | φβγ-benzyl | η | Phenyl ethyl-phenyl 1 | Phenyl ethyl-phenyl i _phenyl 丨 4 ~ 0 »phenyl 1 | φο · Phenyl Π 1 phenyl I 丨 Phenyl I 1 phenyl i 1 phenyl | | Phenyl ethyl -phenyl 1 1-€ propyl i-€-€-€-€-€-€ 5 c *- € ο 1 ^ 0 ^ 2 Fine | -ch2-ch2- ί 1 | -ch2-ch2- I ΌΗ ^ Όί〗雠 0Η2 ~ ^^ 2 · 丨 Marion-1 J § 1 ί δ i 1 • ΟΗ ^ ΌΗ 〖雠 • CH2 " CH〗 chant ί κ -0 ^ 2 ^ 013) 2- | < ή2 < ή2 · I • ΌΗ ^ ΌΗ】 ** δ δ κ > * 1 -ch2-ch2- 0 Phenyl-phenyl 3, p-dimethoxy-phenyl 3, Φ dimethoxy-phenyl 3,4 »dimethoxy-phenyl 3, Φ dimethoxy-phenyl 3« methoxy -Phenyl 4 ~ methyl stigmabenzyl methoxy-phenyl phenyl methoxy-phenyl 4 «phenyl oxy-phenyl phenyl phenyl pentyl oxy-phenyl Φ methoxy-phenyl Fung methoxy- Phenyl 3,4 ~ dimethoxy-phenyl-p-methoxy-phenyl-p-methoxy-phenyl-p-phenyl-methoxy-phenyl-p-methoxy-phenyl-p-phenyloxy-phenyl Oxy-phenyl phenylmethylbenzene L & -benzyl 1 3 Ο OMe OMe OMe OMe OMe OMe 1 1 OMe OMe OMe OMe OMe OMe I OMe I 1 CKM2 < M2C qch2-ch2-c 1 CH2 -CH2 -CH2- C 1 1 OMe 1 1 * (XH2-CH2-C ΟΌΗ ^ ΌΗ ^ Ό CKM2 < H2C 1: Z 9 9 Z 9 Z ζ S ZZ Z ssssz NZ zz zzzz ζ 2: ZZ z ZZZ zz XZZ 9 Z 2: z Z zz ζ ζ 3 ZZ zz Z z Z zz 〇〇〇GO 00 O o 〇00 0 ο 〇〇0 0 〇0 0 0 0 00 0 0 # nlf Page 35 509676 5. Description of the invention (32) 5: a 1-60 5 3. h I3 Ρ Ρ ψ η rn C4 kok Ρ 舛 5-€ Μ -¾ -¾-€ c ^ Μ,-€ Ο-€- $ δ h Q ί ί ο ί t έ 1 ΐ ί ί 1 sleep ί β ί 1 1 IS 1 着廿 ίί ± let t Ψ Ψ U) u > ψ VU) U) Η U) U) U) Hs-€ ψ ψ -S ψ-€-€ $: -¾-€ Ύ > > -sknh 舛 p (η p (and 〇 ψ η ψ η μ g η μ-€ ρ η I1-€ pi k 1 »-€ ζ k ρ k ΓΎ OMe OMe OMe OMe 〇 OMe OMe OMe OMe Γ» OMe 〇 OMe S SMe! OMe D * g § 5 1 1 1 Q wg 5 5 1 1 1 I h2-ch2-c h2.ch2-c ΐ 5 * ίέ S ζ S 9 ζ 9 9 s S z ί S s SSS s N * 6 * z Z z ζ ζ ζ ζ ζ zzz Ζ ζ ζ Ζ X z z 9 9 9 9 9 ζ zz 9 zz zz 9 ： 3 3 3 ζ Ζ Z 0 ： ο ο ο O oo ο GO ο ο ο 00 〇 o < 1

第36頁 509676 五、發明說明（33) Λ fe & k 5 δ »M* CJ & ►J-* s έί 1-64 S 1-62 編號 § § § § § § § § § § § § § § § § O § § 四嗤 § § § ffi ffi X X X ffi a: X K ffi K a: X K X ffi K K X a η η η 舛 s° 令舛 Ψ ψ η Ρ -€ P 〇〇 Ψ 辦 k n -€ -€ -€ -€ -€ -€ -¾ 〇 -€ -¾ -€ 〇 -¾ | 6 κΓ1 β 8 ί 6 to* Ο ί 1 李 | ί A s hip ί ί έ δ ΐ ί 辛 δ ί ia ΐ ΐ S hSp 1 睡 rP s Β 1 1 隹 1 u> 犬廿令廿廿 t f 令令 V" ΐ f -€ V -€ C4 -€ -€ -€ -¾ -€ -€ FH Ρ FH -¾ -€ -¾ -€ -€ -€ I1 Ρ -€ 萌 £ f 树 >ί 1 Μ pi Μ pi § a P 1 桊 Ψ> 2 ψ 辦 g f r3 -¾ ft •5 k ψ k 铲 k k η • s f> η k n 駟鲥 k OMe Ο OMe OMe 〇 5 OMe OMe OMe ο ί^ OMe OMe OMe i： OMe a g § 1 I 8 5 5 备 1 I , 1 i： * 6 * ί S 9 * 9 2： 9 έ S 9 9 9 9 9 s 9 9 9 9 9 9 9 N 6 6 Ζ Z Z Z Ζ Z z z ζ Z Z ζ 2： Z z z Z z Ζ z 2： X Ζ ζ Z z Z Ζ Z z z z ζ Z 9 ζ z Z z z Z z Ζ z Z *-< Ο ο 〇〇〇〇〇 o 0 0 ο 00 〇 ο 0 〇 0 〇〇 0 〇 0 〇P.36 509676 V. Description of the invention (33) Λ fe & k 5 δ »M * CJ & ►J- * s rud 1-64 S 1-62 number § § § § § § § § § § § § § § § § O § § Four 嗤 § § § ffi ffi XXX ffi a: XK ffi K a: XKX ffi KKX a η η η 舛 s ° Order 舛 Ψ ψ η P-€ P 〇〇Ψ Office kn-€- €-€-€-€-€ -¾ 〇- € -¾-€ 〇-¾ | 6 κΓ1 β 8 ί 6 to * Ο 1 ί | ί A s hip ί δ ΐ ί Xinδ ί ia ΐ ΐ S hSp 1 Sleep rP s Β 1 1 隹 1 u > Dog order 廿廿 tf Order V " ΐ f-€ V-€ C4-€-€-€ -¾-€-€ FH Ρ FH -¾- € -¾-€-€-€ I1 Ρ-€ Meng £ f tree > ί 1 Μ pi Μ pi § a P 1 桊 Ψ > 2 ψ gf r3 -¾ ft • 5 k ψ k shovel kk η • s f > η kn 驷鲥 k OMe Ο OMe OMe 〇5 OMe OMe OMe ο ^ OMe OMe OMe i: OMe ag § 1 I 8 5 5 1 1 I, 1 i: * 6 * ί S 9 * 9 2: 9 S S 9 9 9 9 9 s 9 9 9 9 9 9 9 N 6 6 *-< 〇 ο 〇〇〇〇〇〇o 0 0 ο 00 〇ο 0 〇0 〇〇0 〇0 〇

1BI 第37頁 509676 發明說明（34) 1-107 11-106 I IW05 1 § |M03j 11-102 1 1-101 |ι-ι⑴丨 S i S i vb S i S i ί—* b 編號i OOOH OOOH OOOH OOOH OOOH OOOH 000H ! OOOH OOOH 000Η OOOH OOOH OOOH OOOH OOOMe OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH η |4-F-苯基 | 丨2-甲基-苯基1 丨苯基 | η |2-乙基-苯基I |2-乙基-苯基I 12-甲基-苯基| 苯基 |κ 丨2-甲基-苯基| 苯基 η 苯基 η |孓甲基-苯q 苯基孓甲氧基-苯基 Μ S 丁基 S -€ -¾ -s -¾ -ch2<m2-ch2- -CH2 ·ΟΗ2 "0^2 " la 1 1 CH2*OH2** -CH2*OH2·* 1 -CH2 *0^2 " Q 1 1 g 1 1 -OH] *" -CH2 ~ -CH2 Ό^2 "^^2 " -CH2 ~ oh】· 1 hST1 s κΡ 確 κ β 1 〇 2-甲基-笨基 2-甲基-苯基沿苯基丰甲氧基-苯基 4d«苯基 4<二甲胺基> 苯基 4{二甲胺基)·苯基 3,4-二甲氧基-苯基 3,4·二甲氧基-苯基苯基 4~異丙基-苯基 ‘甲基-笨基 ‘甲基-苯基体苯基车異丙基-苯基丰乙氧基-3·甲氧基-苯基 2-甲基-苯基 2-甲基-苯基 3·甲氧基*4·氯-苯基孓甲氧基斗氯-苯基 3·甲氧基·4«氣-苯基 4·乙氧基-3»甲氧基-苯基 4«乙氧基-3·甲氧基-苯基 OMe 5 OMe OMe Ο 1 % Ο 1 1 OMe OMe 5 OMe 1 1 OMe ! 1 OMe 1 OCH2-CH2*C ch2-ch2-ch2-c 1： % 〇 1： ΟΌΗ2 -^¾ ( 1： ch2-ch2-ch2-o I 1 9 9 9 9 9 9 3 9 9 S Ζ S 9 9 9 9 N Ζ z 2： z Z Z Ζ Z Z Ζ z Ζ Z X Z Ζ z Z z Z Z Z 2： Z Z Z Ζ Z z Ζ Ζ Z κ: 〇〇 0 〇 0 〇〇〇〇〇〇〇 0 0 〇〇〇〇 0 ο 〇〇 01BI Page 37 509676 Description of the invention (34) 1-107 11-106 I IW05 1 § | M03j 11-102 1 1-101 | ι-ι⑴ 丨 S i S i vb S i S i ί— * b number i OOOH OOOH OOOH OOOH OOOH OOOH 000H! OOOH OOOH 000Η OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH η | 4-F-phenyl | 丨 2-methyl-phenyl1 丨 phenyl | η | 2-B -Phenyl I | 2-ethyl-phenyl I 12-methyl-phenyl | phenyl | κ 2-methyl-phenyl | phenyl η phenyl η |孓 methoxy-phenyl M S butyl S-€ -¾ -s -¾ -ch2 < m2-ch2- -CH2 〇 · 2 " 0 ^ 2 " la 1 1 CH2 * OH2 ** -CH2 * OH2 · * 1 -CH2 * 0 ^ 2 " Q 1 1 g 1 1 -OH] * " -CH2 ~ -CH2 Ό ^ 2 " ^^ 2 " -CH2 ~ oh] · 1 hST1 s κΡ Yes κ β 1 〇2-methyl-benzyl 2-methyl-phenyl phenyl phenyl methoxy-phenyl 4d «phenyl 4 < dimethylamino > phenyl 4 (dimethylamino) benzene 3,4-dimethoxy-phenyl 3,4-dimethoxy-phenylphenyl 4 ~ isopropyl-phenyl'methyl-benzyl'methyl-phenyl Phenyl-phenylfungethoxy-3 · Methoxy-phenyl 2-methyl-phenyl 2-methyl-phenyl 3 · methoxy * 4 · chloro-phenyl 孓 methoxymethoxychloro-phenyl 3 · methoxy · 4 «gas -Phenyl-4 · ethoxy-3 »methoxy-phenyl4« ethoxy-3 · methoxy-phenyl OMe 5 OMe OMe 〇 1% 〇 1 1 OMe OMe 5 OMe 1 1 OMe! 1 OMe 1 OCH2-CH2 * C ch2-ch2-ch2-c 1:% 〇1: 〇ΌΗ2-^ ¾ (1: ch2-ch2-ch2-o I 1 9 9 9 9 9 9 3 9 9 S Z S 9 9 9 9 N Z z 2: z ZZ ZZ ZZ z z ZXZ z z z z ZZZ 2: ZZZ z z z z z z κ: 〇〇〇〇0 〇〇〇〇〇〇〇〇〇〇〇〇 0 〇〇〇〇〇〇 0 ο 〇〇 0

AA

第38頁 509676 五、發明說明（35) 1-130 )1-129 1 1-128 1-127 1-126 1-125 1-124 — 11-123 1 Ml Nil 11-120 1 11-118 1 NlJ 11-116 1 mJ mJ 11-110 1 11-109 )1-108 j 1編號 OOOH 000H (ΧΟΗ OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOProp OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOMe OOOH t 苯基丨苯基 I 苯基 η |4»F-苯基 | n t 1丰乙基-苯基1 1丰乙基-苯基1 t n 苯基苯基 ! 苯基 n 5 -¾ -6 -€ 5 丁基 5 -s -a EE -€ -6 •OH〗"^^2_ -οϊ2<ή2- 1 1 1 I <Ή2·〇ν -CH(OH>€H2- 1 δ r〇r* I |-ch2<m2-ch2-| -CH2 "^-^2 "* •CH2OH2 鷄 |<η2<η2· I -CH2OH2*· -CH2-CH2. -ch2-ch2- |-ch2-ch2- I -ch2-ch2- 1 1 |-ch2<h2- I 1 I 1 1 OH] ~ <Ή2<Ή2- I 〇 3>甲氧基4甲基-苯基丰甲基-苯基丰異丙基-苯基丰異丙基-苯基 3>甲氧基4·甲基-苯基丰甲基-苯基 4·甲基-本基 3·甲氧基苯基 3·甲氧基苯基丰甲基-苯基 4{二甲胺基)苯基 4·(立甲胺基)苯基 3,车二甲基-苯基 3,4»亞甲二氧苯基 3,4·二甲氧基-苯基丰甲氧基苯基 3,4·二甲基-苯基 3,本二甲基-苯基丰甲基-苯基 4*異丙基-本基 3,4·亞甲二氧苯基 3,本亞甲二氧苯基 3,Φ亞甲二氧苯基 OMe OMe 1 OMe OMe 5 1 OMe OMe OMe OMe OMe s OMe 1 OMe 1 n, ch2-ch2-ch2-c 1 1 OCH2-CH2-C 1 OCH2-CH2-C ch2-ch2-ch2-c I 0-CH2-CH2-C I 0^13^2 ~OH2 ~C 1 Ζ S S 9 3 9 9 s 9 9 9 s 9 9 s 9 N z Ζ Ζ Z z z Z z z z z z Z z z z Z z z X z 9 Z Z z z z 2： z z z z z 2: z z z z Z z 9 ο 〇〇〇〇〇 ο o 0 〇 0 0 0 0 0 0 0 0 0 0 CO 0 〇P.38 509676 V. Description of the invention (35) 1-130) 1-129 1 1-128 1-127 1-126 1-125 1-124 — 11-123 1 Ml Nil 11-120 1 11-118 1 NlJ 11-116 1 mJ mJ 11-110 1 11-109) 1-108 j 1 number OOOH 000H (ΧΟΗ OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOProp OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOMe OOOH tphenyl I Phenyl η | 4 »F-phenyl | nt 1 Phenyl-phenyl 1 1 Phenyl-phenyl 1 tn Phenylphenyl! Phenyl n 5 -¾ -6-€ 5 Butyl 5- s -a EE-€ -6 • OH〗 " ^^ 2_ -οϊ2 " 2-1 1 1 I < Ή2 · 〇ν -CH (OH > € H2- 1 δ r〇r * I | -ch2 < m2-ch2- | -CH2 " ^-^ 2 " * • CH2OH2 chicken | < η2 < η2 · I -CH2OH2 * · -CH2-CH2. -ch2-ch2- | -ch2-ch2- I -ch2 -ch2- 1 1 | -ch2 < h2- I 1 I 1 1 OH] ~ < Ή2 < Ή2-I 〇3 > methoxy 4methyl-phenylphenylmethyl-phenyl isopropyl-benzene Phenyl isopropyl-phenyl 3 > methoxy 4-methyl-phenyl phenylmethyl-phenyl 4-methyl-benzyl 3. methoxyphenyl 3. methoxyphenyl phenyl -Phenyl 4 (dimethylamino) phenyl 4 · (trimethyl Phenyl) phenyl 3, carbodimethyl-phenyl 3,4 »methylenedioxyphenyl 3,4 · dimethoxy-phenyl p-methoxyphenyl 3,4 · dimethyl-phenyl 3, present dimethyl-phenylfungyl-phenyl 4 * isopropyl-benzyl 3,4 · methylenedioxyphenyl 3, present methylenedioxyphenyl 3, Φmethylenedioxybenzene OMe OMe 1 OMe OMe 5 1 OMe OMe OMe OMe OMe s OMe 1 OMe 1 n, ch2-ch2-ch2-c 1 1 OCH2-CH2-C 1 OCH2-CH2-C ch2-ch2-ch2-c I 0- CH2-CH2-C I 0 ^ 13 ^ 2 ~ OH2 ~ C 1 Z SS 9 3 9 9 s 9 9 9 s 9 9 s 9 N z ZO ZZ Z zz Z zzzzz Z zzz Z zz X z 9 ZZ zzz 2: zzzzz 2: zzzz Z z 9 ο 〇〇〇〇〇ο o 0 〇0 0 0 0 0 0 0 0 0 0 CO 0 〇

509676 五、發明說明（36) δ δ § ►j-fc 1 § § S 1 δ c δ έ ►J-* fe fe a 翁 1 1 1 1 1 1 1 I I I I I 1 1 1 _ I I I 1 I 1 1 η η -€ k η ο k ο ψ η n n i n 廿 ο ψ t> ψ -€ -€ -€ -€ Η 3 -€ -a M 5 -€ -€ M -€ S -€ -ch2-ch2- I 1 ί 1 t ί t 1 1 ί 1 1 B 1 B K ί t β ί 1 ί 1 ί 1 1 β 5 1 1 1 1 β 1 1 β 1 β ί 1 ί 1 〇絲絲 ϊ ρ ί 1 m ϊ pi 1 -€ η t f p -€ ί p( g 5 t 5 裳合 Ο ψ ΐ g 1 ϊ δ Ικ ϊ Ρ k ϊ g k ? Ψ k ? t ί t p( k 廿 -€ pi 駟 η | I 5 1 1 1 i i S Γ* ο 1 1 I i 1 9 1 c^ , Ο I i § τ π I , S 5 s * % ο % Q 1 6 % ο I 5 6 1 I ? 1 * I 9 9 9 ίΰ Ε 9 3 9 9 9 ζ ζ ζ 9 9 9 9 9 ζ Ν Z ζ ζ ζ ζ ζ z z z z z ζ ζ ζ ζ z z z z z ζ z ζ X Z 2： Ζ ζ ζ ζ z z z z z ζ ζ ζ 2： z 2： z z z ζ z ζ 〇〇〇 ο ο ο ο o o o o ο ο ο ο o o o o o 00 o ο 第40頁 509676 五、發明說明（37)509676 V. Description of the invention (36) δ δ § ►j-fc 1 § § S 1 δ c δ ► ►J- * fe fe a Weng 1 1 1 1 1 1 1 IIIII 1 1 1 _ III 1 I 1 1 η η-€ k η ο k ο ψ η nnin 廿 ο ψ t > ψ-€-€-€-€ Η 3-€ -a M 5-€-€ M-€ S-€ -ch2-ch2- I 1 ί 1 t ί t 1 1 ί 1 1 B 1 BK ί t β ί 1 ί 1 1 β 5 1 1 1 1 β 1 1 β 1 β ί 1 〇SiSiϊ ρ ί 1 m ϊ pi 1 -€ η tfp-€ ί p (g 5 t 5 合合〇 ψ ΐ g 1 ϊ δ Ικ ϊ ρ k ϊ gk? Ψ k? T ί tp (k 廿-€ pi 驷 η | I 5 1 1 1 ii S Γ * ο 1 1 I i 1 9 1 c ^, Ο I i § τ π I, S 5 s *% ο% Q 1 6% ο I 5 6 1 I? 1 * I 9 9 9 ίΰ Ε 9 3 9 9 9 ζ ζ ζ 9 9 9 9 9 ζ Ν Ν Z ζ ζ ζ ζ ζ zzzzz ζ ζ ζ ζ zzzzz ζ z ζ XZ 2: ζ ζ ζ ζ zzzzz ζ ζ ζ 2: z 2: zzz ζ z ζ 〇〇〇ο ο ο ο oooo ο ο ο ooooo 00 o ο Page 40 509676 V. Description of the invention (37)

On ργ^ 3 έ S s r δ 1 1 § £ M-A a fe as § k ►j—> k έ 翁溥 1 1 I 1 I I 1 1 1 1 1 1 I 1 I 1 1 I I I 1 1 1 η t V" -€ n 辦 η ? t> Ϊ 5 n 辦 1 n n 5 -€ -€ -€ -€ 5 -€ -€ -a -€ 5 , -€ -€ -¾ M s S § a 1 1 藝 έ 1 5 1 1 έ 1 S 1 ΐ 1 1 1 » i 1 1 5 睡 I 瞧 S 1 B 1 s 1 s ί 1 β 1 5 1 5 5 1 s 1 〇 $ Ik 5 t ί t 卄 ο ψ η ΐ Ρ 卄 ο £ -€ k ί 赶 t 麵 S t -€ p 輙 i t δ 辦 c^ 锑 Ϊ p k ΐ 1 & 1 1 ο 5 5 1 1 1 1 D» K> o $K i： I 5 ? 1：系 S έ * 系 έ 6 έ 6 s 矣 § K»1 β * 系 I I I 1 S 9 z s 9 9 9 9 a * 9 9 z z 9 9 z s 9 9 N z z z z ζ ζ ζ ζ Z ζ z z z z z z z z z z z z z X z z z z 2： ζ ζ ζ Z ζ 2： z z z z 2 z z z 9 9 z z κ: o o o o GO ο ο ο 〇 ο 00 o o o o 〇 o o o o O o oOn ργ ^ 3 S S sr δ 1 1 § £ MA a fe as § k ►j— > k 溥 1 1 I 1 II 1 1 1 1 1 1 1 I 1 I 1 1 III 1 1 1 η t V "-€ n do η? T > Ϊ 5 n do 1 nn 5-€-€-€-€ 5-€-€ -a-€ 5,-€-€ -¾ M s S § a 1 1 1 5 1 1 1 1 S 1 ΐ 1 1 1 »i 1 1 5 Sleep I see S 1 B 1 s 1 s 1 1 1 1 5 1 5 5 1 s 1 〇 $ Ik 5 t ί t 卄 ο ψ η ΐ Ρ 卄 ο £-€ k ί h t face S t-€ p 輙 it δ do c ^ antimony Ϊ pk ΐ 1 & 1 1 ο 5 5 1 1 1 1 D »K > o $ K i: I 5? 1: Department S * * Department 6 6 6 s 矣 § K »1 β * Department III 1 S 9 zs 9 9 9 9 a * 9 9 zz 9 9 zs 9 9 N zzzz ζ ζ ζ ζ Z ζ zzzzzzzzzzzzzzz X zzzz 2: ζ ζ ζ Z ζ 2: zzzz 2 zzz 9 9 zz κ: oooo GO ο ο ο 〇ο 00 oooo 〇oooo O oo

A 第41頁 509676 五、發明說明（38) 1-199 M98 1-197 1-196 W95 11-194 j 1-193 1-192 1-191 1-190 11-189 1 11-188 1 11-187 11-186 | (Μ85 j )1-184 j j 1-183 11-182 11-181 11-180 1 Hin 11-178 j HIU 編號 OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH ； OOOH ! OOOH OOOH OOOH OOOH OOOH OOOH OOOH ΟΟΟΒή ! - j OOOH OOOH OOOH OOOH coon η η 4*CF3-苯基丰¢3¾-苯基 n t n |2-甲基-苯基1 苯基 η η η 本基苯基 a 5 -€ -GHjO^Oy -€ -€ |丙基 1 ia 1 -0312 -ch2-ch2- 1 -ch2-ch2- •ch2-ch2- <1VCH2· <h=ch-ch2- -C3i=CH-CH2- -ch2-ch2- |<ή2<ή2- I ch2-ch2- -ch2-ch2-ch2- 1 <Ή2<Ή2- <Ή(ΟΗ>σν ! -CH2-CH2- ! <ή2<ή2- <ή2<ή2- ! -CH2-CH2. -CH2-CH2. -ch2-ch2- -ch2-ch2- o 1-甲基-奈-2-基 1-甲基-*1-2-基 1-2-基孓甲氧基-苯基 3,4·二甲氧基-苯基 ‘甲硫基-苯基 ‘甲硫基苯基 4«異丙基-苯基 4~氣-苯基菩2-基签2-基 2-甲氧基·苯基 Φ乙氧基-苯基丰乙氧基-苯基 2-甲氧基-苯基簧2-基： 2-甲基斗α·苯基 ! 4"亂-笨基環己基 3·甲氧基-苯基 3·甲氧基-苯基環己基 2-甲基·φ〇·苯基 OMe Ο OMe OMe OMe C4 OMe OMe 1 OMe 5 OMe OMe OMe i： OMe SMe iCH2-CH2-CH2-C 1： qch2-ch2-c ch2-ch2.ch2-c I I OCH2-CH2-C 1 1 och2.ch2c CH2-CH2-CH2-C QCH2-CH2C 1： ch2-ch2-ch2-c 3 Z Ω 0 s 9 s 9 9 S 9 9 9 N z Z z z z z z 2 z z Z z Z z z z z z X z s z z z z z z Z z ζ Z z z z z z z z K： ο 〇 ο o o o o o o GO Ο ο o 〇〇〇 ο ο o ο o o oA Page 41 509676 V. Description of the invention (38) 1-199 M98 1-197 1-196 W95 11-194 j 1-193 1-192 1-190 11-189 1 11-188 1 11-187 11-186 | (Μ85 j) 1-184 jj 1-183 11-182 11-181 11-180 1 Hin 11-178 j HIU number OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH; OOOH! OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH ΟΟΟΒή!-J OOOH OOOH OOOH OOOH coon η η 4 * CF3-phenyl-fon 3¾-phenylntn | 2-methyl-phenyl1 phenylη η η Benzoyl a 5-€ -GHjO ^ Oy-€-€ | propyl 1 ia 1 -0312 -ch2-ch2- 1 -ch2-ch2- • ch2-ch2- < 1VCH2 < h = ch-ch2- -C3i = CH-CH2- -ch2 -ch2- | < ή2 < ή2- I ch2-ch2- -ch2-ch2-ch2- 1 < Ή2 < Ή2- < Ή (ΟΗ > σν! -CH2-CH2-! < ή2 < ή2- < valent2 < valent2-! -CH2-CH2. -CH2-CH2. -ch2-ch2- -ch2-ch2- o 1-methyl-naphthalen-2-yl1-methyl- * 1-2-yl1- 2-ylfluorenylmethoxy-phenyl 3,4 · dimethoxy-phenyl'methylthio-phenyl'methylthiophenyl 4 «isopropyl-phenyl 4 ~ phenyl-phenyl 2 -Radicals 2-yl 2-methoxy-phenylΦethoxy-phenylphenylethoxy-benzene 2-Methoxy-phenylsulfonyl 2-yl: 2-methyl-pitch α · phenyl! 4 " Random-benzylcyclohexyl3 · methoxy-phenyl3 · methoxy-phenylcyclohexyl 2-methyl · φ〇 · phenyl OMe 〇 OMe OMe OMe C4 OMe OMe 1 OMe 5 OMe OMe OMe i: OMe SMe iCH2-CH2-CH2-C 1: qch2-ch2-c ch2-ch2.ch2-c II OCH2-CH2-C 1 1 och2.ch2c CH2-CH2-CH2-C QCH2-CH2C 1: ch2-ch2-ch2-c 3 Z Ω 0 s 9 s 9 9 S 9 9 9 N z Z zzzzz 2 zz Z z Z zzzzz X zszzzzzz Z z ζ Z zzzzzzz K: ο 〇ο oooooo GO Ο ο o 〇〇〇ο ο o ο ooo

第42頁 509676 發明說明（39) ^ 1 I ηPage 42 509676 Description of the invention (39) ^ 1 I η

1-221 1-220 11-219 I 11-218 1 1-217 丨 1-216 I 1-215 1-214 11-213 1-212 Nlj [1-210 1-209 1-208 1-207 1-206 1-205 1-204 1-203 1-202 11-201 1 1-200 丨編號1 OOOH OOOH OOOH OOOH OOOH OOOH OOOH j OOOH OOOH OOOH i OOOH OOOH OOOH OOOH OOOH 四》坐 OOOH OOOH OOOH OOOH OOOEt OOOMe 7t η η t n t 4CF3·苯基 δ W * 1苯基 1 n n η •〇i〇TO -€ 1 丁基 1 丙基 5 -€ -€ -i κΓ^ S I 1 <Ή2^Ή2-ΟΗ2- 偶偶-σν |-ch2-ch2. I -Οβί,ι^ ί 1 1 <ή2<ή2- -ch2-ch2- I -ch2-ch2- -ΟΙ2<Ή2- j -CH2-CH2- I -ch=ch-ch2- j 1 1 -ch2-ch2. ! -CH2-CH2- ! -ch2-ch2- -CH2<H2-CH2- ! <M2-CH2.CH2. i <ή2<ή2- •OH^-(3^- /Ο 丰乙氧基-苯基 4«甲疏差本基 40»苯基 Ιφο·苯基 4-甲•本基丰乙氧基-苯基丰乙氧基-苯基 2·甲氧基^苯基 ! 3«甲氧基-苯基 3,Φ二甲氧基-苯基 3，φ二甲氧基-苯基 40H-苯基 4ΌΗ-苯基 3,丰二甲氧基-苯基 3,4»二甲氧基-苯基 Φ乙氧基-苯基環己基環己基 4»乙氧基-苯基 4»乙氧基-苯基丰乙氧基-苯基奈-2-基 OMe 1 OMe OMe 1 OMe Ο 5 OMe j ο 1 1 OMe D* OMe OMe 5 5 OMe Q€HrCH2-C 1 ；och2-ch2-c ch2<m2-ch2-c 1： ch2-ch2-ch2-c I O-CH^ -Οϊζ 1 5 6 1： I 1 OCH2-CH2C Z 9 9 9 9 Z 9 9 9 9 z 9 9 9 N 2： Z z z z z z ζ 2： z z z z z z z z z Ζ Z X Z Z z z z z z z 2： 2： 9 2： z z z z z z z Ζ z Ο 〇 ο o o o 00 o 0 Ο 〇 0 〇 0 0 0 0 0 0 0 〇 0 第43頁 509676 五、發明說明（40)1-221 1-220 11-219 I 11-218 1 1-217 丨 1-216 I 1-215 1-214 11-213 1-212 Nlj [1-210 1-209 1-208 1-207 1- 206 1-205 1-204 1-203 1-202 11-201 1 1-200 丨 No. 1 OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH j OOOH OOOH OOOH OOOH i OOOH OOOH OOOH OOOH OOOH Four "seats OOOH OOOH OOOH OOOH OOOEt OOOMe 7t η η tnt 4CF3 · phenylδ W * 1phenyl 1 nn η • 〇i〇TO-€ 1 butyl 1 propyl 5-€-€ -i κΓ ^ SI 1 < Ή2 ^ Ή2-〇Η2- even-even- σν | -ch2-ch2. I -Οβί, ι ^ ί 1 1 < ή2 < ή2- -ch2-ch2- I -ch2-ch2- -〇Ι2 < Ή2- j -CH2-CH2- I -ch = ch- ch2- j 1 1 -ch2-ch2.! -CH2-CH2-! -ch2-ch2- -CH2 < H2-CH2-! < M2-CH2.CH2. i < ή2 < ή2- • OH ^-( 3 ^-/ 〇 Phenylethoxy-phenyl 4 «methyl sloppy base 40» Phenyl Ιφο · phenyl 4-methyl Oxy ^ phenyl! 3 «methoxy-phenyl3, Φdimethoxy-phenyl3, φdimethoxy-phenyl 40H-phenyl 4ΌΗ-phenyl3, p-dimethoxy- Phenyl 3,4 »dimethoxy-phenylΦethoxy-phenylcyclohexylcyclohexyl 4 »Ethoxy-phenyl 4» Ethoxy-phenylfungethoxy-phenylnaphthalene-2-yl OMe 1 OMe OMe 1 OMe Ο 5 OMe j ο 1 1 OMe D * OMe OMe 5 5 OMe Q € HrCH2-C 1; och2-ch2-c ch2 < m2-ch2-c 1: ch2-ch2-ch2-c I O-CH ^ -Οϊζ 1 5 6 1: I 1 OCH2-CH2C Z 9 9 9 9 Z 9 9 9 9 z 9 9 9 N 2: Z zzzzz ζ 2: zzzzzzzzz ZZ ZXZZ zzzzzz 2: 2: 9 2: zzzzzzz ZZ z 〇〇o ooo 00 o 0 〇〇0 〇0 0 0 0 0 0 0 〇0 Page 509676 V. Description of the Invention (40)

1-242 1-241 1-240 1-239 1-238 1-237 1-236 11-235 I 1-234 11-233 1 11-232 1 11-231 | 1-230 1-229 1-228 1-227 1-226 1-225 1-224 1-223 1-222 編號 OOOH \COOH OOOH (ΧΟΗ ΟΟΟΗ OOOH OOOMe OOOH ΟΟΟΗ ΟΟΟΗ ΟΟΟΗ OOOH OOOH OOOH OOOH OOOH | OOOH OOOH OOOH OOOH OOOH n B Ψ n Ψ 9 -¾ -€ -€ I 1 s δ δ s 5 s δ o ί s § I δ £ 5 1 ί 5 5 s i 1 ls!r^ i I < < < s 睡 1 < κ 1 1 t 1 1 着 1 s 瞻 1 -€ pi 铲 \i4* -¾ OJ ψ \aL· Ψ -s ψ \l4 u> r、 -€ p 4»α-苯基 4Cl·苯基 U) p( U) Y' ~€ ρ 環己基環己基 U) r' p( U) ρ to p u> r' -€ p( U) r' -*€ p U) ΐ -6 u> 丫' pi U) p t 駟 n 铲 ψ Ψ 輙 ψ ψ η k yr^ n n n n k k Ρ 輙 QMe OMe OMe OMe ο I OMe 1 OMe Γ* OMe OMe 赛 1 ? s 8 s 1 o I 1 i： i： h2-ch2-c Z 3 9 3 s 9 9 Ζ έ S 9 9 z 9 s 3 9 Z 9 z N 6 6 Z z ζ ζ z 2 ζ ζ z z z z 2 Z z z z z z X z z ζ ζ z z z 2： ζ z z z z Z z 9 z z z 9 κ： o o ο ο o o o Ο ο ο o o o o o o 〇 o o o O 1__歷1 第44頁 509676 發明說明（41)1-242 1-241 1-240 1-239 1-238 1-237 1-236 11-235 I 1-234 11-233 1 11-232 1 11-231 | 1-230 1-229 1-228 1 -227 1-226 1-225 1-224 1-223 1-222 No. OOOH \ COOH OOOH (ΧΟΗ ΟΟΟΗ OOOH OOOMe OOOH ΟΟΟΗ ΟΟΟΗ ΟΟΟΗ OOOH OOOH OOOH OOOH OOOH | OOOH OOOH OOOH OOOH OOOH n -€-€ I 1 s δ δ s 5 s δ o ί s § I δ £ 5 1 ί 5 5 si 1 ls! R ^ i I < < < s sleep 1 < κ 1 1 t 1 1 With 1 s look at 1-€ pi shovel \ i4 * -¾ OJ ψ \ aL · Ψ -s ψ \ l4 u > r,-€ p 4 »α-phenyl 4Cl · phenyl U) p (U) Y ' ~ € ρ cyclohexylcyclohexyl U) r 'p (U) ρ to p u > r'-€ p (U) r '-* € p U) ΐ -6 u > ya' pi U) pt 驷 n shovel ψ Ψ 輙 ψ ψ η k yr ^ nnnnkk ρ 輙 QMe OMe OMe OMe ο I OMe 1 OMe Γ * OMe OMe Race 1? s 8 s 1 o I 1 i: i: h2-c h2-c Z 3 9 3 s 9 9 έ S 9 9 z 9 s 3 9 Z 9 z N 6 6 Z z ζ ζ z 2 ζ ζ zzzz 2 Z zzzzz X zz ζ ζ zzz 2: ζ zzzz Z z 9 zzz 9 κ: oo ο ο ooo Ο ο ο oooooo 〇ooo O 1__Calendar 1 p.44 509676 Description of the invention (41)

1-264 1-263 1-262 1-261 1-260 ； 1-259 11-258 | 11-257 | 1-256 Ms! 1-254 11-253 1 1-252 Ml 1-250 )1-249 1 1-248 11-247 1-246 1-245 1-244 11-243 編號 OOOH OOOH OOOH OOOH OOOH OOOH ! _______ _ _ 1 四坐基 OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH αχ)Η 1 _! OOOH OOOH OOOH OOOH j OOOH ! 71 η 1 k ξ w 4 k |苯基 I 丨苯基 i 丨体苯基| 丨苯基 i |苯基 I 苯基 4〇V苯基 -€ 0^0-0^0¾ -€ -a 1 丁基」 -€ 5 -CH2-CH2- 5 1 -ch2-ch2- •CH(2-甲氧基-苯基ΚΉ2- |偶母-1 _2偶-1 |-〇η2<ή2- 1 -ch=ch-ch2- ^h=ch-ch2- -ch2-ch2- -CH2<H(CH3> 丨偶偶-I |-ch2-ch2-ch2- 1 |-ch2-ch2-ch2-| |偶偶· I 丨偶偶-1 |<ή2<ή2- 1 |-ch2-ch2- | ΟΗ2 -CH〗· 偶偶· -ch2-ch2- 1 〇孓甲氧基^苯基 3·甲氧基-苯基 |2-甲氧基4>βγ-苯基 2-甲氧基-苯基丰甲氧基-苯基丰甲氧基-苯基 2-甲氧基-苯基環己基丰甲氧基-苯基丰甲氧基-苯基環己基孓甲氧基-苯基孓甲氧基-苯基得苯基 4Cl·苯基 3«甲氧基-苯基 3«甲氧基-苯基孓甲氧基-苯基 4·甲疏羞》-本基 4-甲硫基-苯基 j Φ甲氧基-苯基丰甲氧基-苯基 1 1 OMe 5 OMe OMe OMe 5 OMe OMe i： OMe Ο OMe OMe j OMe η, 1： 1： I I OMe OCH2-CH2-C ! 1 OCH2-CH2-C CH2-€H2.CH2-C 1 1 OMe ΟΌΗ^ -CH〗 Z 9 9 9 Z S S s -ch2-c s 9 s 9 Ζ S S s S Ν Z Z Ζ Z Z Z Z Z z z z Z z z ζ Z Ζ Z X Z Z Ζ Z Z z z z z z 9 z z z ζ 9 9 z z ζ Z < 〇〇〇〇〇〇〇 o o o o 〇 o o o 00 ο 〇 ο o ο 〇第45頁 509676 五、發明說明（42)1-264 1-263 1-262 1-261 1-260; 1-259 11-258 | 11-257 | 1-256 Ms! 1-254 11-253 1 1-252 Ml 1-250) 1-249 1 1-248 11-247 1-246 1-245 1-244 11-243 Number OOOH OOOH OOOH OOOH OOOH OOOH! _______ _ _ 1 Four-seat base OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH αχ) Η 1 _! OOOH OOOH OOOH OOOH j OOOH! 71 η 1 k ξ w 4 k | Phenyl I 丨 Phenyl 丨 Bodiphenyl | 丨 Phenyl i | Phenyl I Phenyl 40V Phenyl- € 0 ^ 0-0 ^ 0¾-€ -a 1 butyl "-€ 5 -CH2-CH2- 5 1 -ch2-ch2- • CH (2-methoxy-phenyl ΚΉ2- | Even mother-1 _2Even-1 | -〇η2 < ή2- 1 -ch = ch-ch2- ^ h = ch-ch2- -ch2-ch2- -CH2 < H (CH3 > 丨 even-I | -ch2-ch2-ch2- 1 | -ch2-ch2-ch2 -| | Couple · I 丨 Couple-1 | < ή2 < ή2- 1 | -ch2-ch2- | ΟΗ2 -CH〗 · Couple · -ch2-ch2- 1 〇methoxymethoxy ^ phenyl3 · methoxy -Phenyl | 2-methoxy 4 > βγ-phenyl 2-methoxy-phenyl p-methoxy-phenyl p-methoxy-phenyl 2-methoxy-phenyl cyclohexyl p-methyl Oxy-phenylphenylmethoxy-phenylcyclohexylfluorenylmethoxy-phenylfluorenylmethoxy-phenyl Phenyl 4Cl · phenyl 3 «methoxy-phenyl 3« methoxy-phenyl fluorenyl methoxy-phenyl 4 · methyl succinyl "-benzyl 4-methylthio-phenyl j Φmethyl Oxy-phenylfungoxy-phenyl 1 1 OMe 5 OMe OMe OMe 5 OMe OMe i: OMe 〇 OMe OMe j OMe η, 1: 1: II OMe OCH2-CH2-C! 1 OCH2-CH2-C CH2- € H2.CH2-C 1 1 OMe ΟΌΗ ^ -CH〗 Z 9 9 9 ZSS s -ch2-c s 9 s 9 ZZ SS s S Ν ZZ ZZ ZZZZZ zzz Z zz ζ Z ZZ ZXZZ ZZ zzzzz 9 zzz ζ 9 9 zz ζ Z < 〇〇〇〇〇〇〇〇oooo 〇ooo 00 ο 〇ο o ο 〇 page 45 509676 V. Description of the invention (42)

Si 1-284 1-283 1-282 11-281 I 1-280 1-279 1-278 ! 1-277 11-276^ 1-275 1-274 1-273 1-272 MiJ 1-270 1-269 1-268 1-267 1-266 1-265 編號； OOOH OOOH OOOH OOOH OOOH ΟΟΟΗ ΟΟΟΗ ; ΟΟΟΗ OOOH OOOH OOOH ΟΟΟΗ OOOH OOOH I ΟΟΟΗ ΟΟΟΗ OOOH OOOH OOOH OOOH ： OOOH 苯基| |4Cl·苯基1 丨4〇•苯基1 |φα苯基1 40-苯基 1 b |4»乙基-苯基1 |κ 4Br-苯基 η η n -¾ 5 -€ a^aa^· 0¾ 5 -ch2-ch2- -CH2-CH2*· CH2<H2-CH2- "CH2-CH2 · CH2 _ -ch2-ch2- ί 5 1 -ch2-ch2- -ch2-ch2- 谓本甲氧基-苯基>〇V -ch2-ch2- -ch2-ch2- s 1 1 •CH=CH-CH2 讎 ακΉ-σν -ch2-ch2- ΌΗ2ΌΗ2- -ch2-ch2- j -ch2-ch2-ch2- -ch2-ch2-ch2- <ή2<ή2- /Ο 丰乙基-苯基 |车乙基-苯基丰乙基-苯基丰乙基-苯基丰甲氧基-苯基 3,4·亞甲三氧苯基 3，Φ亞甲三氧苯基 3·甲基斗曱氧基-苯基车甲氧基·苯基丰甲氧基-苯基车甲基-苯基 2-甲氧基-苯基 2-甲氧基-苯基 4*甲氧基-苯基 φ曱氧基·苯基丰甲勝苯基 3,4>三甲氧基-苯基 2-曱氧基-苯基 ΦΟ·苯基 4-乙基-苯基 2-甲氧基-苯基 Η, OMe OMe OMe ο ο 1 1 OMe OMe OMe OMe OMe Ο 1 5 OMe 5 OMe 1 OCH2-CH2-C ch2-ch2-ch2-c ch2<h2-ch2-c I 1 och2.ch2c OCH2-CH2-C ch2-ch2-ch2-c CKH2-CH2-C (XH2-CH2-C 3 Ζ 9 9 9 8 9 ζ 9 s 9 Z Ν z z 之 ζ Ζ Z z z ζ 2： z X z z z z ζ ζ Z Z z Z z ζ ζ Z z z z z κ： ο 0 0 〇 ο ο 〇〇〇 0 0 〇 0 ο ο 0 〇 0 00 0 0Si 1-284 1-283 1-282 11-281 I 1-280 1-279 1-278! 1-277 11-276 ^ 1-275 1-274 1-273 1-272 MiJ 1-270 1-269 1-268 1-267 1-266 1-265 number; OOOH OOOH OOOH OOOH OOOH ΟΟΟΗ ΟΟΟΗ; ΟΟΟΗ OOOH OOOH OOOH ΟΟΟΗ OOOH OOOH I ΟΟΟΗ ΟΟΟΗ OOOH OOOH OOOH OOOH: OOOH Phenyl | | 4Cl · phenyl 1 丨 4. • Phenyl 1 | φαphenyl 1 40-phenyl 1 b | 4 »ethyl-phenyl 1 | κ 4Br-phenyl η η n -¾ 5-€ a ^ aa ^ · 0¾ 5 -ch2-ch2- -CH2-CH2 * · CH2 < H2-CH2- " CH2-CH2 · CH2 _ -ch2-ch2- ί 5 1 -ch2-ch2- -ch2-ch2- Presumably methoxy-phenyl > 〇V -ch2-ch2- -ch2-ch2- s 1 1 • CH = CH-CH2 雠 ακΉ-σν -ch2-ch2- ΌΗ2ΌΗ2- -ch2-ch2- j -ch2-ch2-ch2- -ch2-ch2-ch2- < ή2 < ή2- / 〇 Phenylethyl-phenyl | Chetyl-phenylphenylethyl-phenylphenylethyl-phenylphenylmethoxy-phenyl 3,4 · methylenetrioxyphenyl 3, Φmethylenetrioxyphenyl 3 · Methylpyridyloxy-phenylcarpentyloxy · phenyl Phenylmethoxy-phenylcarbomethyl-phenyl 2-methoxy-phenyl 2- Methoxy-phenyl 4 * methoxy-phenyl · Phenyltoluene 3,4 > Trimethoxy-phenyl 2-fluorenyl-phenyl Φ0 · Phenyl 4-ethyl-phenyl 2-methoxy-phenylsulfonium, OMe OMe OMe ο ο 1 1 OMe OMe OMe OMe OMe Ο 1 5 OMe 5 OMe 1 OCH2-CH2-C ch2-ch2-ch2-c ch2 < h2-ch2-c I 1 och2.ch2c OCH2-CH2-C ch2-ch2-ch2 -c CKH2-CH2-C (XH2-CH2-C 3 Z 9 9 9 8 9 ζ 9 s 9 Z Ν zz of ζ Z Z zz ζ 2: z X zzzz ζ ζ ZZ z Z z ζ ζ Z zzzz κ: ο 0 0 〇ο ο 〇〇〇0 0 〇0 ο ο 0 〇0 00 0 0

ill 第46頁 509676 五、發明說明（43)ill Page 46 509676 V. Description of the Invention (43)

1-307 1-306 1-305 urn 11-303 I 1-302 11-301 1 1-300 1-299 1-298 1-297 1-296 1-295 1-294 1-293 1-292 (1-291 1 1-290 1-289 1-288 1-287 1-286 編號 OOOH ,ΟΟΟΗ 000H coon OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH 000H 000H axe OOOH 1_ OOOH 1 axe OOOH OOOH OOOH COOH 丰乙基-苯基 40«苯基 40苯基 η 1苯基丨3,4二氣苯基1 |φο»苯基」 1苯基 |4Cl·苯基| |φα苯基| 1丰乙基-苯基i 1丰乙基-苯基j 丨40«苯基| 3，丰二氣苯基 n 苯基 ΦΟ·苯基 B *€ -€ -€ -€ -€ I -€ -€ -€ 1 1 -ch2-ch2- -CH2-CH2- <h=ch-ch2- <m2-ch2-ch2- 1 ΌΗ2 "CH2 - ΟΗ2 · |偶偶-1 |<x〇U 偶-| |<ή2<ή2- I 偶偶- |-ch2-ch2. I -OH2-CH2- |<ή2偶- | -€H(OH>CH2. -ch2<h2- -CH=CH-CH2. -ch=ch-ch2- -€H2-CH2- 〇牟甲基苯基孓甲基乙基-苯基孓甲基乙基-苯基 4»甲氧基-苯基 3,4>三甲氧基·苯基 3,4«二曱氧基-苯基 3,本二甲氧基-苯基 3,4>三甲氧基-苯基丰乙基-苯基丰乙基·苯基 3,4>三甲氧基-苯基 13，丰二甲氧基-苯基 1_ 3,4»二甲氧基-苯基 3·甲氧基-苯基 3«甲氧基-苯基丰甲基-苯基丰甲基-苯基 i 3,本二甲氧基-苯基| Φ甲氧基-苯基 Φ甲氧基-苯基丰甲氧基-苯基 4»甲氧基-苯基 Hs OMe SMe OMe 5 OMe OMe Ο OMe I· 1 Ο 1 OMe 5 1 OMe OMe I OMe Ο ch2<m2-ch2-c och2.ch2-c CH〗"CH〗 CH】（ 1 OCH2-CH2-C j 9 9 9 9 Z z 9 9 Z 9 S 9 9 Ζ 9 9 3 3 N Z Z z Z Z z Z z ζ X Z Z Z z Z z Z z 2： 2： S Z z Z Z z z ζ 〇〇〇 0 0 0 〇 0 〇〇〇〇〇 Ο 0 〇〇 0 〇 0 0 00 509676 五、發明說明（44) 1 S Ε $ S S K 1 Ε S 1 E s Co s oo ε C3 S Os S D： S ►*· S G S P3 E ►—* S i i 翁 1 1 1 1 1 1 1 1 1 1 I i I i i _ 1 1 1 1 1 _ 7t 1 η 1 1 ? •h ο η η I | i n n 5 I 廿 ψ -¾ -a a -€ -€ -¾ -€ -a Η -€ -€ 謙 1 善雇 h 5 垂 1 5 ί 1 5 ί 睡 5 5 i 1 5 « ί 1 1 hT^ 1 | Ψ t « 1 ί 5 S K I 1 ί I I I ΐ 1 1 o 6 u> 1“ u> 1“ -a η -€ 1 t ΐ I t ί I S ί 1 拿 u> r' js k U) ΐ -€ p ψ t u> W -€ P Ψ U) -€ ί 1 t t 7 Γ* Ψ k ? t Ο h ft 辦 1« l· i a t •h -6 h I 1 1 r* 1 1 | 9 0» 1 I 6 , s 6 s s 6 i： f!»1 s 6 琴 1 s 6 9 9 2 S 9 9 z 9 z 3 9 9 Z 2 S 9 N z Ζ ζ z Z Ζ z ζ z z z z z z z z Z Z Ζ z z z X Ζ z 9 Ζ z ζ z z z z z z z z Z Z Ζ z z z κ：〇〇〇 00 〇〇 ο ο o o o o o o o o 〇〇〇 O o o 0, 第48頁 509676 五、發明說明（45) 1-351 1-350 1-349 1-348 (1-347 1-346 1-345 1-344 1-343 1-342 Νΐϋ 1-340 11-339 1 (1-338 1 11-337 11-336 1 11-335 1 1-334 11-333 1 11-332 11-331 1 1-330 , IOOOH OOOH OOOH OOOMe OOOH ΟΟΟΗ OOOH OOOH OOOH 000H OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH g〇QH_ OOOH 1 t 丨4~0·苯基 1 4<l·苯基 i |4Cl·苯基 1 苯基 |3,丰二氣苯基| 丰甲基^苯基丰甲基-苯基苯基： 4Cl·苯基 I 苯基苯基苯基 4*0·苯基笨基 Pmn -€ -€ 5 a 5 5 -¾ 3\ -ch2-ch2-ch2- 1 睡 -ch2<h2-ch2- 谓本甲基-苯基> ch2- -OH2-OH2- -ch2-ch2- 偶偶· 偶偶讎 I-ch2-ch2- 1 -ch2-ch2- -CH2-CHrCH2- •OH^ ~0^2 · 讎 <Ή(4>甲硫基-苯基ΚΉ2· 1 1 1 -ch2-ch2- ΌΗ2 "^^2 垂^"歸 -CH2-CH2-CH2- I 苯基二曱氧基-苯基二甲氧基-苯基丰甲基-苯基 ‘甲基-苯基丰甲基-苯基丰甲基-苯基车乙氧基3»甲氧基-苯基丰乙基-苯基丰乙基-苯基 4»乙氧基-3·甲氧基-苯基 3,4·二甲氧基-苯基 3,4·二曱氧基-苯基丰異丙基-笨基丰異丙基-笨基 3,4>三甲氧基-苯基 3,4>三甲氧基-苯基丰甲魏-笨基丰乙氧基&甲氧基苯基! 丰甲碎L&-笨基丰曱基-苯基 4>曱基*苯基 OMe 1 1 ο 1 OMe 1 Ο 1 OMe 〇 1 ο 1 1 OMe 〇 OMe OMe OMe 輙 ch2-ch2-ch2-c I I ο 1： 1 〇 ? ¥ 1 QCH=CH-C qch2-ch2*c I 9 Z 9 ζ Q 3 9 9 9 9 9 2： 9 9 9 3 9 z z z ζ Z Z Z Z Z Z Z Z Ζ Z z z z 2 z S ζ Z Z Z Z 2 Z Z Z Z Z Z Z Ζ z z z o 〇 o O ο 〇〇 00 〇〇〇〇〇〇〇〇 0 〇 0 Ο 0 01-307 1-306 1-305 urn 11-303 I 1-302 11-301 1 1-300 1-299 1-298 1-297 1-296 1-295 1-294 1-293 1-292 (1 -291 1 1-290 1-289 1-288 1-287 1-286 No. OOOH, ΟΟΟΗ 000H coon OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH 000H 000H axe OOOH 1_ OOOH 1 axe OOOH OOOH OOOH COOH 40 «phenyl 40 phenyl η 1 phenyl 3,4 dioxophenyl 1 | φο» phenyl "1 phenyl | 4Cl · phenyl | | φα phenyl | Ethyl-phenyl j 丨 40 «Phenyl | 3, Diphenyl phenyl n Phenyl ΦO · phenyl B * €-€-€-€-€ I-€-€-€ 1 1 -ch2-ch2 --CH2-CH2- < h = ch-ch2- < m2-ch2-ch2- 1 ΌΗ2 " CH2-ΟΗ2 · | Even-Even-1 | < x〇U Even- | | < ή2 < ή2- I even----ch2-ch2. I -OH2-CH2- | < price 2 even-|-€ H (OH > CH2. -Ch2 < h2- -CH = CH-CH2. -Ch = ch-ch2-- € H2-CH2- O-Methylphenyl, methylethyl-phenyl, methylethyl-phenyl 4 »methoxy-phenyl 3,4 > trimethoxy · phenyl 3,4« dioxo Phenyl-phenyl 3, bendimethoxy-phenyl 3,4 > trimethoxy-phenylpentylethyl-phenyl Ethyl · phenyl 3,4 > Trimethoxy-phenyl 13, Phenodimethoxy-phenyl 1-3,4 »Dimethoxy-phenyl 3 · methoxy-phenyl 3« methoxy -Phenylphenylmethyl-phenylphenylmethyl-phenyl i 3, bendimethoxy-phenyl | Φmethoxy-phenyl Φmethoxy-phenylfengmethoxy-phenyl 4 » Methoxy-phenyl Hs OMe SMe OMe 5 OMe OMe 〇 OMe I · 1 〇 1 OMe 5 1 OMe OMe I OMe 〇 ch2 < m2-ch2-c och2.ch2-c CH〗 " CH〗 CH】（1 OCH2-CH2-C j 9 9 9 9 Z z 9 9 Z 9 S 9 9 Z 9 9 3 3 NZZ z ZZ z Z z ζ XZZZ z Z z Z z 2: 2: SZ z ZZ zz ζ 〇〇〇0 0 0 〇0 〇〇〇〇〇〇〇〇〇 0 〇〇0 〇 0 00 509676 V. Description of the invention (44) 1 S Ε $ SSK 1 Ε S 1 E s Co s oo ε C3 S Os SD: S ► * · SGS P3 E ►— * S ii 1 1 1 1 1 1 1 1 1 1 1 I i I ii _ 1 1 1 1 1 _ 7t 1 η 1 1? • h ο η η I | inn 5 I 廿 ψ -¾ -aa-€-€ -¾-€ -a Η-€-€ Qian 1 Good hire h 5 hang 1 5 ί 1 5 ί Sleep 5 5 i 1 5 «ί 1 1 hT ^ 1 | Ψ t« 1 ί 5 SKI 1 ί III ΐ 1 1 o 6 u > 1 "u > 1" -a η-€ 1 t ΐ I t ί IS ί 1 take u > r 'js k U) ΐ-€ p ψ t u > W- € P Ψ U)-€ ί 1 tt 7 Γ * Ψ k? T Ο h ft Office 1 «l · iat • h -6 h I 1 1 r * 1 1 | 9 0» 1 I 6, s 6 ss 6 i: f! »1 s 6 harp 1 s 6 9 9 2 S 9 9 z 9 z 3 9 9 Z 2 S 9 N z ζ z z z z z z zzzzzzzzzz ZZ zz zzz X z z 9 zz z zzzzzzzzzz ZZ Z zzz κ: 〇〇〇00 〇〇ο ο oooooooo 〇〇〇O oo 0, p. 48 509676 V. Description of the invention (45) 1-351 1-350 1-349 1-348 (1-347 1-346 1-345 1-344 1-343 1-342 Νΐϋ 1-340 11-339 1 (1-338 1 11-337 11-336 1 11-335 1 1-334 11-333 1 11-332 11-331 1 1-330, IOOOH OOOH OOOH OOOMe OOOH ΟΟΟΗ OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH g〇QH_ OOOH 1 t 丨 4 ~ 0 · phenyl 1 4 < l · phenyl i | 4Cl · phenyl 1 Phenyl | 3, Phenyldiphenyl | Phenylmethyl ^ phenyl Phenylmethyl-phenylphenyl: 4Cl · phenyl I phenylphenylphenyl 4 * 0 · Benzyl Pmn-€-€ 5 a 5 5 -¾ 3 \ -ch2-ch2-ch2- 1 sleep-ch2 < h2-ch2- presupposed methyl-phenyl > -ch2- Even-even Even-even 雠 I-ch2-ch2- 1 -ch2-ch2- -CH2-CHrCH2- • OH ^ ~ 0 ^ 2 -ch2-ch2- ΌΗ2 " ^^ 2 垂 ^ " homing-CH2-CH2-CH2- I phenyldimethoxy-phenyldimethoxy-phenylphenylmethyl-phenyl'methyl- Phenylphenylmethyl-phenylphenylmethyl-phenylcarthoxy 3 »methoxy-phenylphenethyl-phenylphenethyl-phenyl 4» ethoxy-3 · methoxy- Phenyl 3,4 · dimethoxy-phenyl 3,4 · dimethoxy-phenyl isopropyl-benzyl isopropyl-benzyl 3,4 > trimethoxy-phenyl 3, 4 > Trimethoxy-phenyl-fungyl-benzyl-fungethoxy & methoxyphenyl! Phenylmethanyl L & -benzylfungenyl-phenyl 4 > fluorenyl * phenyl OMe 1 1 ο 1 OMe 1 Ο 1 OMe 〇1 ο 1 1 OMe 〇OMe OMe OMe 輙 ch2-ch2-ch2-c II ο 1: 1 〇? ¥ 1 QCH = CH-C qch2-ch2 * c I 9 Z 9 ζ Q 3 9 9 9 9 9 2: 9 9 9 3 9 zzz ζ ZZZZZZZZ Z Z z z z 2 z S ζ Z Z Z Z Z 2 Z Z Z Z Z Z Z Z z z z 〇 o O ο 〇〇 00 〇〇〇〇〇〇〇〇 0 〇 0 〇 0 0

I11B11I1I 第49頁 509676 五、發明說明（46) 1-375 1-374 1-373 1-372 1-371 1-370 1-369 1-368 1-367 1-366 1-365 1-364 1-363 1-362 丨 1-361 1 1-360 11-359 11-358 11-357 1-356 11-355 1 1-354 11-353 1 1-352 OOOH OOOH ΟΟΟΗ 000Η 000Η OOOH OOOH OOOH OOOH CXX)H ! OOOH 1 OOOH OOOH OOOH OOOH 000H OOOH ΟΟΟΗ OOOH OOOH OOOH OOOH 000H 000Η 40·苯基 φο·苯基苯基 |丰甲基-苯基1 |丰甲基-苯基I 丨苯基 I ΦΟ·苯基 n |Φα苯基 1 得苯基 |Φα-笨基 1 η |4〇·苯基 1 丨心苯基 | 似苯基苯基 1丰甲基-苯基1 车甲基-苯基1 4Cl·苯基 |φα苯基 1 苯基 5 ο 5 Μ -€ 5 -οη2<ή2- ί 瞻 <ή2<ή2- •Οί2-CH〗· δ S 1 <h2-ch2-ch2- -QH2 -0¾ ~ CH2 - -ch2-ch2- K -ch2-ch2- ~CH；2 讎 - -CHj** -ch2<h2- -ch2-ch2- 1 1 1 <ή2<ή2· 1 6 S ! 1 <Ή2<Η2-〇ν 4·α-苯基 4·乙基-苯基丰乙基-苯基丰甲氧基-苯基丰甲氧基-苯基丰甲基-苯基丰乙基-苯基 2C1-苯基 2d-苯基 4»異丙基笨基 4»異丙基-苯基车乙基-笨基 4-甲基-苯基丰甲基-苯基丰乙基-苯基丰乙基-苯基丰甲基-苯基 3,4>三曱氧基-苯基 3A5«三曱氧基-苯基 3,4·二甲氧基-苯基 Φ甲氧基-苯基 3,4»二甲基-苯基丰甲基-苯基 3 Α5^甲氧基《苯基 OMe OMe 5 ο 1 OMe SMe 1 1 OMe OMe 5 1 OMe OMe OMe OMe OMe OMe Γ* 1： 5 1 (ΧΉ2-σΐ2-€ 1： ΟΌΗ2 - ΟΙ! C i： I 系 1 CXM2-CH2-C 1 OMe 1 ΟΌΗ2 - ( 9 9 9 2 9 9 z 9 9 Z 9 9 9 3 9 9 S 9 9 z ζ ζ Ζ 2： z z z Z Z Z Z Z ζ z z Z Z Z Ζ Ζ z ζ ζ Ζ Ζ Z z z z Z Z Z 2 9 2 ζ z z Z Z Z Ζ Ζ 00 ο ο 〇〇 Ο 0 0 0 〇 0 〇〇 Ο 〇 m 00 0 0 0 〇〇〇〇I11B11I1I Page 49 509676 V. Description of the invention (46) 1-375 1-374 1-373 1-372 1-371 1-370 1-369 1-368 1-367 1-366 1-365 1-364 1- 363 1-362 丨 1-361 1 1-360 11-359 11-358 11-357 1-356 11-355 1 1-354 11-353 1 1-352 OOOH OOOH ΟΟΟΗ 000Η 000Η OOOH OOOH OOOH OOOH CXX) H ! OOOH 1 OOOH OOOH OOOH OOOH 000H OOOH ΟΟΟΗ OOOH OOOH OOOH OOOH 000H 000Η 40 · phenylφο · phenylphenyl | Phenylmethyl-phenyl 1 | Phenylmethyl-phenyl I 丨 phenyl I ΦΟ · phenyl n | Φα phenyl 1 gives phenyl | Φ α-benzyl 1 η | 4〇 · phenyl 1 丨 cardiophenyl | phenyl-like phenyl 1 p-methyl-phenyl 1 carbo-phenyl 1 4Cl · Phenyl | φαphenyl 1 Phenyl 5 ο 5 Μ-€ 5 -οη2 < ή2- ί & " ή2 < ή2- • 〇2-CH〗 · δ S 1 < h2-ch2-ch2- -QH2 -0¾ ~ CH2--ch2-ch2- K -ch2-ch2- ~ CH; 2 雠--CHj ** -ch2 < h2- -ch2-ch2- 1 1 1 < ή2 < ή2 · 1 6 S! 1 < Ή2 < Η2-〇ν 4 · α-phenyl4 · ethyl-phenylphenylethyl-phenylphenylmethoxy-phenylphenylmethoxy-phenylphenylmethyl-phenylphenethyl-benzene 2C1-phenyl 2d- 4 »Isopropylbenzyl 4» Isopropyl-Phenylethyl-benzyl 4-methyl-phenylphenylmethyl-phenylphenethyl-phenylphenethyl-phenylphenylmethyl -Phenyl 3,4 > trimethoxy-phenyl 3A5 «trimethoxy-phenyl 3,4 · dimethoxy-phenylΦmethoxy-phenyl 3,4» dimethyl-benzene Phenylmethyl-phenyl 3 Α5 ^ methoxy, phenyl OMe OMe 5 ο 1 OMe SMe 1 1 OMe OMe 5 1 OMe OMe OMe OMe OMe OMe Γ * 1: 5 1 (× Ή2-σΐ2- € 1: ΟΌΗ2 -ΟΙ! C i: I series 1 CXM2-CH2-C 1 OMe 1 ΟΌΗ2-(9 9 9 2 9 9 z 9 9 Z 9 9 9 3 9 9 S 9 9 z ζ ζ ZZ 2: zzz ZZZZZ ζ zz ZZZ ZO ZO ZZ ZZ ZZ ZZ ZZZ ZZZ 2 9 2 ζ zz ZZZ ZZ ZOZ 00 00 ο ο 〇〇〇〇 0 0 〇0 〇〇〇〇〇 00 0 0 0 〇〇〇〇〇

第50頁 509676 五、發明說明（47) ε ε S S S s E iS 5 S s ε s ε 8§ ε 23 Ε S Ε 宏 E 83 E gs 1 E S S ε ο^ ε I 1 1 1 1 1 I 1 I I I 1 1 1 1 1 1 1 i 1 1 1 _ 1 η 1 1 η i I I 军 η | 廿 ψ 廿 Ψ η ι^ η 舛 t I 1 树 η t Ϊ -€ -€ -€ -€ B -€ -¾ & -¾ -€ -€ -€ 1 h S 1 1 S I 5 έ 1 5 着喔 5 1 5 睡 s K»4 睡 5 I 1 5 5 1 ί S 1 s 1 s 1 1 1 II pi k 1 έ 1 5 雄麵 δ « 廿 -¾ ψ ρ ψ η ί ca iw -€ 军 Ks 珣 pi n ? U) ΐ -€ pi ψ t ΐ -€ U) ]: pi t 廿 p 輙 η 廿 -δ h 5 Ρ U» W -€ ί 军 t t i p t i pi t u> -€ p h KS -¾ ι* pi 舛 U) -S s Ρ^Λ ml K 1 CD D4 I I 1 Β 1 i 1 1 i i 爹 S * ? i： i： I 1： ? έ * ? έ 6 9 9 z 9 Q z 9 9 ζ s S S 9 9 s s 9 9 9 9 Z ζ ζ z z z z z z ζ 2： ζ ζ ζ z z z z z Ζ z z z Z ζ ζ 9 z 2： s z z s Ζ ζ ζ ζ 2： z z z z ζ z z z 〇 ο ο o o 〇 O o o ο Ο ο ο ο 〇〇 o o o ο 00 o oPage 50 509676 V. Description of the invention (47) ε ε SSS s E iS 5 S s ε s ε 8§ ε 23 Ε S Ε Macro E 83 E gs 1 ESS ε ^ 1 ε 1 1 1 1 1 1 I 1 III 1 1 1 1 1 1 1 i 1 1 1 _ 1 η 1 1 η i II Army η | 廿 ψ 廿 Ψ η ι ^ η 舛 t I 1 tree η t Ϊ-€-€-€-€ B-€- ¾ & -¾-€-€-€ 1 h S 1 1 SI 5 1 1 5 着喔 5 1 5 Sleep s K »4 Sleep 5 I 1 5 5 1 ί S 1 s 1 s 1 1 1 II pi k 1 deg 1 5 male face δ «廿 -¾ ψ ρ ψ ί ca iw-€ Army Ks 珣 pi n? U) ΐ-€ pi ψ t ΐ-€ U)]: pi t 廿 p 輙 η 廿 -δ h 5 Ρ U »W-€ ί Army ttipti pi t u >-€ ph KS -¾ ι * pi 舛 U) -S s Ρ ^ Λ ml K 1 CD D4 II 1 Β 1 i 1 1 ii D S *? i: i: I 1:? * * 6 9 9 z 9 Q z 9 9 ζ s SS 9 9 ss 9 9 9 9 Z ζ ζ zzzzzz ζ 2: ζ ζ ζ zzzzz Zn zzz Z ζ ζ 9 z 2 : Szzs ζ ζ ζ ζ 2: zzzz ζ zzz 〇ο ο oo 〇O oo ο Ο ο ο ο 〇〇ooo ο 00 oo

JL 第51頁 509676 五、發明說明（48) M22 M21 1420 11419 I 11418 I ㈣ |1416 | N5J (1-414 Nil NlJ ο±ιΙ |1410 1-409 1-408 1着 1-406 1-405 ι-m 1观 1402 1401 1400 1-399 OOOH OOOH 000H 000Η —_________ OOOMe 000H 000H 000H 000Η OOOH OOOH OOOH 000H 000Η OOOH 000H OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH |丰乙基-苯基1 |丰乙基-苯基I 叫-苯基 § ω * k 乙基-苯基I |丰乙基-苯基1 |车甲基-苯基I 4*甲基-苯基苯基丰乙基-苯基 η 苯基 ‘乙基-苯基| 1苯基 | Φ乙基-苯基丰乙基-苯基 δ β |φο-苯基 1 n Φ甲基·苯基 -6 -€ -€ 5 -€ |乙基i 5 -€ ch2«ch2· 偶偶· -CH2-€H2- 偶偶· -ch2-ch2- -ch2-ch2-ch2- "CH2 ·€Ή2 CH】脚 |<ή2 偶-| 偶偶· 偶偶- <Ή2·€Η2·(Ή2 觸 -ch2-ch2- |-ch2-ch2. I -ch2-ch2- |-ch2-ch2- I -ch2-ch2- |偶偶-ι •CH〗 OH! · CM】- 偶偶偶-1 3,4-二曱氧基-苯基 3,车二甲氧基-苯基丰甲基-苯基丰甲基-苯基 3,4-二甲氧基-苯基 3，丰二甲氧基-苯基 4«曱基-苯基丰甲基-苯基 3,本二甲氧基-苯基 3,本二甲氧基-苯基丰甲氧基-苯基 3,Φ亞甲二氧苯基 3,4«亞甲二氧苯基 3«甲基斗甲氧基-苯基 3>二甲氧基-苯基 Φ乙氧基-苯基 3*甲基斗甲氧基-苯基丰甲氧基-苯基丰甲基-苯基丰曱基-苯基 3·甲氧基-苯基丰甲基-苯基苯基丰甲基-苯基 1 1 % SMe 1 OMe Ο OMe 5 1 5 OMe 1 OMe OMe ο 1 OMe 5 Ο % ch2-ch2-ch2-c 1 0-C^2 -CH2 1 (XH2-CH2-C I CH2-€H2-CH2-C 3 9 9 9 Z 9 9 9 9 S S S S s 9 9 9 9 2： Z Z z z 8 Z 2： Z Z Z Z Z z z Ζ z z Z 2： 2： 2： Z 2： 9 z Z Z 2： z z Ζ z z 2：〇 00 〇〇〇〇〇〇 Ο Ο 〇 0 〇〇 0 〇〇 00 0 0 〇 0 0 〇第52頁 509676 五、發明說明（49) i 1 1 I I fe 00 5 1 i 1 1 1 6 I 1 I 1 1 i I § 1 1 1 § X i 1 1 1 I I i 1 1 1 I 1 1 1 I 1 1 I I |κ k t 廿 O n t k 5 t § w * h § ca J k ϊ o ί i k 0» Ψ n 辦 Ik ? l 5 n -€ δ "V -€ -¾ -€ -€ 9 駟 -€ -€ -€ £ B I h S 1 5 s 1 5 s 1 1 t 5 5 1 6 3 1 1 5 5 1 蠢 s δ hST"* 1 5 1 P k ί ί 隹 5 5 ί 1 5 1 5 5 1 £ 1 5 έ 1 5 a I β 5 K 1 δ tSr^ 6 tS^ 1 £ ψ -€ i i 1 -€ 1 ti V" ψ η ? 廿 pi k s° g k ft Ϊ t 廿 -€ ψ 1 ΐ Ρ η 5 t 廿 1 t Ψ k ΐ Ϊ 铲 n 轳卄皋 |κ Ϊ 6 t t p P 廿 P W k i I i c^ 1 | I 1 1 1 O 1 i：系 S * s s * , 1： 8 S * ι S * I： p § tH^ 5 6 i: 1 5 6 I： S z s 9 9 z z 9 s 9 s Q z s Ω z 9 Z z z z ζ 2： z z z z Ζ z ζ z z z z z z z z z z z z 2： ζ Z z z z z Ζ z ζ z z z z z z 2： z z z 〇 o o 〇 ο o o o o o 〇 o ο o o o 〇 o o 〇〇 o oJL Page 51 509676 V. Description of the invention (48) M22 M21 1420 11419 I 11418 I ㈣ | 1416 | N5J (1-414 Nil NlJ ο ± ιΙ | 1410 1-409 1-408 1-1-46- 1-405 ι -m 1view 1402 1401 1400 1-399 OOOH OOOH 000H 000Η —_________ OOOMe 000H 000H 000H 000Η OOOH OOOH OOOH OOOH 000H 000H OOOH 000H OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH | Fungethyl-phenyl1 | Fungethyl-benzene The radical I is called -phenyl§ ω * k ethyl-phenyl I | fungyl-phenyl 1 | carbomethyl-phenyl I 4 * methyl-phenylphenylfungyl-phenylη phenyl 'Ethyl-phenyl | 1phenyl | Φethyl-phenylpentylethyl-phenylδ β | φο-phenyl 1 n Φmethyl · phenyl-6-€-€ 5-€ | Ethyl i 5-€ ch2 «ch2 · Even-even · -CH2- € H2- Even-even · -ch2-ch2- -ch2-ch2-ch2- " CH2 · € Ή2 CH】 Foot | < ή2 Even- | Even-even · Even-even- < Ή2 · € Η2 · (Ή2 touch-ch2-ch2- | -ch2-ch2. I -ch2-ch2- | -ch2-ch2- I -ch2-ch2- | Even-Even-CH • OH! · CM 】-偶偶偶 -1 3,4-dimethoxy-phenyl 3, carbodimethoxy-phenylphenylmethyl-phenylphenylmethyl-phenyl 3,4-dimethoxy- Benzyl 3, Phenyldimethoxy-phenyl 4 «Phenyl-phenylphenylmethyl-phenyl 3, Bendimethoxy-phenyl 3, Bendimethoxy-phenyl Phenylmethoxy-benzene 3, Φmethylenedioxyphenyl 3,4 «Methylenedioxyphenyl 3« Methylmethylmethoxy-phenyl3 > Dimethoxy-phenylΦethoxy-phenyl 3 * methyl Benzylmethoxy-phenylphenylmethoxy-phenylphenylmethyl-phenylphenylmethyl-phenyl 1% SMe 1 OMe 〇 OMe 5 1 5 OMe 1 OMe OMe ο 1 OMe 5 〇% ch2-ch2-ch2-c 1 0-C ^ 2 -CH2 1 (XH2-CH2-C I CH2- € H2-CH2- C 3 9 9 9 Z 9 9 9 9 SSSS s 9 9 9 9 2: ZZ zz 8 Z 2: ZZZZZ zz ZZ zz Z 2: 2: 2: Z 2: 9 z ZZ 2: zz ZZ zz 2: 〇00 〇〇〇〇〇〇〇〇〇〇〇〇〇0 〇00 0 0 0 0 0 page 52 509676 V. Description of the invention (49) i 1 1 II fe 00 5 1 i 1 1 1 6 I 1 I 1 1 i I § 1 1 1 § X i 1 1 1 II i 1 1 1 I 1 1 1 I 1 1 II | κ kt 廿 O ntk 5 t § w * h § ca J k ϊ o ί ik 0 »Ψ n Office Ik? L 5 n-€ δ " V-€ -¾-€-€ 9 驷-€-€-€ £ BI h S 1 5 s 1 5 s 1 1 t 5 5 1 6 3 1 1 5 5 1 stupid s δ hST " * 1 5 1 P k ί ί 5 5 ί 1 5 1 5 5 1 £ 1 5 5 1 5 a I β 5 K 1 δ tSr ^ 6 tS ^ 1 £ ψ-€ ii 1-€ 1 ti V " ψ η?廿 pi ks ° gk ft Ϊ t 廿-€ ψ 1 ΐ Ρ η 5 t 廿 1 t Ψ k ΐ Ϊ shovel n 轳卄皋 | κ Ϊ 6 ttp P 廿 PW ki I ic ^ 1 | I 1 1 1 O 1 i: Department S * ss *, 1: 8 S * ι S * I: p § tH ^ 5 6 i: 1 5 6 I: S zs 9 9 zz 9 s 9 s Q zs Ω z 9 Z zzz ζ 2: zzzz z z ζ zzzzzzzzzzzz 2: ζ Z zzzz z z ζ zzzzzz 2: zzz 〇oo 〇ο ooooo 〇 o ο ooo 〇oo

1IBIIII 第53頁 509676 發明說明（50)1IBIIII Page 53 509676 Description of the Invention (50)

k 1 1 fe ►—* i I s 00 I 1 1 § I b 1 I i 1 1 1 1 1 _ 1 1 I 1 1 1 1 _ _ 1 _ 1 I I _ I _ δ W Λ k ξ w J k ί § a Ϊ π t I δ W Λ k ξ k 1 i k •h -€ ψ k Ϊ k -€ -€ -€ ! -€ -€ — -€ 1 1 -€ -€ -€ ~€ -€ -€ 5 -€ 1 1 h Β 1 5 έ 1 £ S 1 I 1 5 5 1 5 1 s 1 5 έ 靡 5 1 1 5 喔睡 5 1 1 5 1 1 1 5 5 1 5 S 着 5 I ί I ϊ 1 廿 -€ pi 辦 η ψ t p( Ψ k p ψ t 廿 ψ η -€ ρ £ -€ t i 6 t ί 1 t Ϊ 皋 t ί 1 隹 ί 6 t pi δ ϊ 皋 ί $ 隹 fi ί 1 k V p 輙 k 轳 Ρ 舛 Ρ η 駟 1 1 1 5 1 i 9 1 I ο 缈 I 1 1 D* ι 1 1 s * 爹 1 S * , 9 S 9 9 9 9 S 9 s 9 z 9 S ζ s z s 9 9 ζ ζ ζ ζ ζ Z ζ ζ s z z z z .z 9 Z ζ ζ z z z z z ζ ζ ζ ζ ζ Z ζ ζ z z z z z z Ζ Z ζ ζ z z z z z ζ ο ο ο ο 〇 ο ο o o o o o o 〇〇 ο ο o o 00 o ο ο 第54頁 509676 五、發明說明（51) i i 1-491 1490 1-489 1-488 1-487 1-486 1-485 1-484 1483 1482 |1481 j 1-480 1479 1478 1-477 11-476 |1475 j 1474 1-473 1472 1-471 \IA70 j 1*469 OOOH ΟΟΟΗ ΟΟΟΗ ΟΟΟΗ OOOH OOOH OOOH OOOH OOOH ΟΟΟΗ OOOH OOOH OOOH OOOH OOOH OOOH OOOH coon OOOH OOOH OOOH COOH OOOH 1 k s k |φο*苯基1 |4d-苯基1 | |·3-苯基1 |^cf3-苯基 j |苯基 | 1丰甲基-苯基I |丰甲基-苯基I |4·〇ν苯基1 4·〇ν苯基苯基苯基 ξ k 4C1-苯基丨40苯基j |φ〇ν苯基1 5 -€ I -¾ -€ -S 55 1 -¾ -Q 丨偶偶-ch2· •CH2 ·€Η2 - CH2 - |-ch2-ch2- 1 -ch2-ch2- |<ή2<ή2- j _2·€Η2- j -CH2"CH2- |-ch2-ch2- j I-CH2-CH2- 1 |-ch2-ch2- j |-CH2-CH2-CH2. j |^h2-ch2-ch2- j |偶偶_ j -ch2-ch2- -CH〗- |<ή2<ή2-οη2- 1 |-ch2-ch2-ch2- 1 丨*ch2偶-1 <ή2<ή2· |-ch2-ch2- j _2偶-1 -ch2-ch2- 3,4-二甲氧基-苯基 3,Φ二甲氧基-苯基车甲基-苯基環己基 2-甲氧基-苯基 3·甲氧基-苯基孓甲基·4»甲碎ti-苯基 3·甲氧基-苯基 |孓甲氧基-苯基 3,丰二甲氧基-苯基 3,4·二甲氧基-苯基 ‘甲氧基-苯基丰甲氧基-苯基 2-甲基>3·甲氧基-苯基孓甲氧基-苯基车乙氧基-苯基 3,4·二甲氧基-苯基 3,4«二甲氧基-苯基丰乙氧基-苯基 3,4·二甲氧基-苯基 1-2-基 40·苯基 3，‘二甲氧基-苯基 1 1 OMe OMe OMe OMe OMe OMe OMe OMe OMe 1 OMe D4 1 OMe OMe OMe Ο I qch2-ch2-c (XB2-CH2-C OMe OCH2-CH2-C qch2-ch2-c I OCH2-CH2-C I OCH2-CH2*C 1： 0€H2-CH2C Ζ 9 9 s S 9 9 9 9 9 z Z 9 9 9 s Ζ Ζ Z Z Z z z Ζ 2： z z z z z z z Z z 8 Ζ Z 2： z z Z 2： z z Z z z z z z z z z z z 〇〇 GO 〇〇 o o o 〇〇 0 0 〇 0 0 0 0 0 0 GO 0 0 0 第55頁 509676 發明說明（52) 1-514 11-513 I 1-512 11-510 I 1-509 1-508 1-507 1-506 1-505 1-5M 1-503 1-502 11-501 1-500 1-499 1498 _ί 1497 1 1-496 1495 1494 1493 1-492 ΟΟΟΗ ΟΟΟΗ ΟΟΟΗ ΟΟΟΗ ΟΟΟΗ ΟΟΟΗ ΟΟΟΗ ΟΟΟΗ ΟΟΟΗ ΟΟΟΗ ΟΟΟΗ ΟΟΟΗ ΟΟΟΗ ΟΟΟΗ ΟΟΟΗ ΟΟΟΗ ΟΟΟΗ ΟΟΟΗ 000H ! ΟΟΟΗ ΟΟΟΗ ΟΟΟΗ \ ΟΟΟΗ |丰甲基-苯基1 4~甲基-苯基 4CF3-苯基 1 k η η |4-甲基-苯基1 η η |4Cl·苯基1 丨俗苯基| |4*甲基-苯基1 |丰甲基-苯基I 辦 1苯基 i 丰甲基-苯基丰甲基-苯基 4CF3-苯基1 |φο·苯基1 4Cl·苯基丰甲基·苯基 β 1 -¾ -6 -S ch2-o- ch2_ch3 -€ -6 1 -ch2-ch2- -ch2-ch2-ch2- -ch2-ch2-ch2- -ch2-ch2- £ κ -ch2-ch2- <Ή2-Ο12-ΟΉ2- -ch2-ch2-ch2- -03^2*0^2*· <ή2<ή2- •CH2 *CH2 - CH2 - -ch2-ch2- -ch2-ch2-ch2- -CH2 ~CH2" -ch2-ch2- 1 <ή2<ή2- 丰甲福苯基 Φ甲痛苯基 4·甲基-苯基 !丰甲基-苯基 4»乙氧基-苯基车乙氧基-苯基環戊基 3,4»二甲氧基-苯基 3,本二甲氧基-苯基得苯基 Φα-苯基 3,4·二甲氧基-苯基 3,4»二甲氧基-苯基 3,Φ亞甲二氧苯基苯基苯基 3,Φ亞甲二氧苯基丰甲氧基-苯基丰甲氧基-苯基丰甲基-苯基丰甲碗^苯基丰甲福1&-苯基環己基 OMe Ο 1 OMe 5 OMe OMe 5 Ο Ο OMe ο OMe OMe 1 1 OMe OMe 〇 1 OMe | 1 1 1 1： I OCH2-CH2-C 1 CH2-€H2-CH2-C OOH^ -CH2 *C 9 9 Z 9 9 3 9 9 9 ζ 9 9 9 9 9 S Ζ 9 Z ζ Z ζ ζ ζ ζ Z ζ 9 Ζ ζ ζ Ζ Z 2 Z Ζ Ζ ζ Z ζ ζ ζ ζ 2： Z ζ ζ 2： ζ ζ ζ Z Z Ζ Z Ζ 〇 00 〇〇 ο ο ο ο Ο 〇 ο 00 〇 Ο ο ο ο 00 〇 ο 〇〇〇 #k 1 1 fe ►— * i I s 00 I 1 1 § I b 1 I i 1 1 1 1 1 _ 1 1 I 1 1 1 1 _ _ 1 _ 1 II _ I _ δ W Λ k ξ w J k ί § a π π t I δ W Λ k ξ k 1 ik • h-€ ψ k Ϊ k-€-€-€!-€-€ —-€ 1 1-€-€-€ ~ €-€- € 5-€ 1 1 h Β 1 5 1 1 £ S 1 I 1 5 5 1 5 1 s 1 5 5 5 1 1 5 Oh sleep 5 1 1 5 1 1 1 5 5 1 5 S with 5 I ί I ϊ 1 廿-€ pi η ψ tp (Ψ kp ψ t 廿 ψ η-€ ρ £-€ ti 6 t ί 1 t Ϊ 皋 t ί 1 隹 ί 6 t pi δ ϊ 皋 $ $ $ 隹 fi ί 1 k V p 輙 k 轳 Ρ 舛 Ρ η 驷 1 1 1 5 1 i 9 1 I ο 缈 I 1 1 D * ι 1 1 s * father 1 S *, 9 S 9 9 9 9 S 9 s 9 z 9 S ζ szs 9 9 ζ ζ ζ ζ ζ Z ζ ζ szzzz .z 9 Z ζ ζ zzzzz ζ ζ ζ ζ ζ Z ζ ζ zzzzzz Z Z ζ ζ zzzzz ζ ο ο ο ο ο OO 00 ο oooooo OO OO 00 ο Page 54 509676 V. Description of the invention (51) ii 1-491 1490 1-489 1-488 1-487 1-486 1-485 1-484 1483 1482 | 1481 j 1-480 1479 1478 1-477 11- 476 | 1475 j 1474 1-473 1472 1-471 \ IA70 j 1 * 469 OOOH ΟΟΟΗ ΟΟΟΗ ΟΟΟΗ OOOH OOOH OOOH OOOH OOOH OOOH ΟΟΟΗ OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH coon OOOH OOOH OOOH COOH OOOH 1 ksk | φο * phenyl 1 | 4d-benzene 1 | | · 3-phenyl 1 | ^ cf3-phenyl j | phenyl | 1 p-methyl-phenyl I | p-methyl-phenyl I | 4 · 〇νphenyl 1 4 · 〇νbenzene Phenylphenylphenyl ξ k 4C1-phenyl 丨 40phenyl j | φ〇νphenyl 1 5-€ I -¾-€ -S 55 1 -¾ -Q 丨 Couple-ch2 · • CH2 · € Η2- CH2-| -ch2-ch2- 1 -ch2-ch2- | < ή2 < ή2- j _2 · € Η2- j -CH2 " CH2- | -ch2-ch2- j I-CH2-CH2- 1 | -ch2 -ch2- j | -CH2-CH2-CH2. j | ^ h2-ch2-ch2- j | Odd and even_ j -ch2-ch2- -CH〗-| < ή2 < ή2-οη2- 1 | -ch2-ch2 -ch2- 1 丨 * ch2 even-1 < ή2 < ή2 · | -ch2-ch2- j _2even-1 -ch2-ch2- 3,4-dimethoxy-phenyl3, Φdimethoxy -Phenylcarbomethyl-phenylcyclohexyl 2-methoxy-phenyl3 · methoxy-phenylfluorenylmethyl · 4 »methyl ti-phenyl3 · methoxy-phenyl | Oxy-phenyl 3, p-dimethoxy-phenyl 3,4-dimethoxy-phenyl'methoxy-phenyl Phenylmethoxy-phenyl 2-methyl > 3 · methoxy-phenylfluorenylmethoxy-phenyl carthoxy-phenyl 3,4 · dimethoxy-phenyl 3,4 « Dimethoxy-phenylfungethoxy-phenyl 3,4 · dimethoxy-phenyl1-2-yl 40 · phenyl 3, 'dimethoxy-phenyl 1 1 OMe OMe OMe OMe OMe OMe OMe OMe OMe 1 OMe D4 1 OMe OMe OMe Ο I qch2-ch2-c (XB2-CH2-C OMe OCH2-CH2-C qch2-ch2-c I OCH2-CH2-C I OCH2-CH2 * C 1: 0 € H2-CH2C Zn 9 9 s S 9 9 9 9 9 z Z 9 9 9 s ZZ ZZ Zzz zz 2: zzzzzzz Z z 8 ZE Z 2: zz Z 2: zz Z zzzzzzzzzz 〇〇GO 〇〇oooo 〇〇0 0 〇0 0 0 0 0 0 GO 0 0 0 Page 55 509676 Description of the invention (52) 1-514 11-513 I 1-512 11-510 I 1-509 1-508 1-507 1-506 1 -505 1-5M 1-503 1-502 11-501 1-500 1-499 1498 _ί 1497 1 1-496 1495 1494 1493 1-492 ΟΟΟΗ ΟΟΟΗ ΟΟΟΗ ΟΟΟΗ ΟΟΟΗ ΟΟΟΗ ΟΟΟΗ ΟΟΗ ΟΟΟΟΟΟΟ〇ΟΟΟΟΟΟΟΟ ΟΟΟΗ 000H! ΟΟΟΗ ΟΟΟΗ ΟΟΟΗ \ ΟΟΟΗ | -Phenyl 1 4 ~ methyl-phenyl 4CF3-phenyl 1 k η η | 4-methyl-phenyl 1 η η | 4Cl · phenyl 1 丨 custom phenyl | | 4 * methyl-phenyl 1 | Phenylmethyl-phenyl I Office 1phenyl i Phenylmethyl-phenyl Phenylmethyl-phenyl 4CF3-phenyl1 | φο · phenyl 1 4Cl · phenylphenylmethyl · phenyl β 1 -¾ -6 -S ch2-o- ch2_ch3-€ -6 1 -ch2-ch2- -ch2-ch2-ch2- -ch2-ch2-ch2- -ch2-ch2- £ κ -ch2-ch2- < Ή2-Ο12 -ΟΉ2- -ch2-ch2-ch2- -03 ^ 2 * 0 ^ 2 * · < ή2 < ή2- • CH2 * CH2-CH2--ch2-ch2- -ch2-ch2-ch2- -CH2 ~ CH2 " -ch2-ch2- 1 < ή2 < ή2- Phenylformyl phenylmethylmethanyl 4-methyl-phenyl! Phenylmethyl-phenyl 4 »ethoxy-phenyl-ethoxy-benzene Cyclopentyl 3,4 »dimethoxy-phenyl 3, Bendimethoxy-phenyl to give phenyl Φα-phenyl 3,4 · dimethoxy-phenyl 3,4» dimethoxy Phenyl-phenyl 3, Φmethylenedioxyphenylphenylphenyl 3, Φmethylenedioxyphenyl Phenyltofyl 1 & -phenylcyclohexyl OMe 〇 1 OMe 5 OMe OMe 5 〇〇 OMe ο OMe OMe 1 1 OMe OMe 〇1 OMe | 1 1 1 1: I OCH2-CH2-C 1 CH2- € H2-CH2-C OOH ^ -CH2 * C 9 9 Z 9 9 3 9 9 9 ζ 9 9 9 9 9 S Zn 9 Z ζ Z ζ ζ ζ ζ Z ζ 9 ζ ζ ζ Z Z 2 Z ZE ζ ζ ζ ζ ζ ζ 2: Z ζ ζ 2: ζ ζ ζ ZZ ZZ Z Z 〇00 〇〇ο ο ο ο ο 〇〇ο 00 ο ο ο ο ο ο ο 00 〇ο 〇〇〇 #

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Me 9 s ,326 9 rs6 z 2： o z z o o z z 2： o 第57頁 z z o z z o z o z o 2： z o o o z z o z z o z z o 509676 五、發明說明（54) 1-558 ! 1-557 ； 1-556 11-555 ! 1-554 11-553 | 1-552 ΜΗ 1-550 1-549 1-548 1-547 1-546 1-545 1-544 1-542 Q^LJ i 11-539 1 1-538 OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOMe OOOH OOOH OOOH OOOH OOOH OOOH OOOH i OOOH OOOH OOOH COOH |φα苯基1 |φο·苯基I t 防t _苯基 | |丰甲基-苯基| |4·甲基-苯基1 1 k ξ w J k 体苯基 40·苯基 ΦΟ·苯基 -€ -€ -€ -€ -€ -€ -€ •CH(苯基>ch2-ch2- -ch2-ch2- -ch2-ch2- "CH!〈3^2 * CH〗~ 1 •CHd&>€H2-CH2^ -ch2-ch2- -CH2-€H2- •CH(苯基>CH2-CH2· •CH(苯基>ch2-ch2· -ch2-ch2- -ch2-ch2- <ή2<ή2- -CH2-CH2. ΌΗ2-0¾ * 讎 •CH2-CH2-CH2. CH2<H2-CH2· I CH2 讎 i OH】 ΌΗ^ ~ 0¾ 觸 ΌΗ^- 0¾ _ 孓甲氧基-苯基孓甲氧基-苯基车甲氧基-苯基丰曱氧基-苯基苯基丰甲氧基-苯基丰甲氧基-苯基苯基 Φ甲基-苯基丰甲基-苯基瞽2-基菩2-基 4»甲苯基 3«甲氧基-苯基 4d-苯基 i 40»苯基 Φ甲氧基-苯基丰甲氧基^苯基 ι OMe OMe 1 OMe 1 OMe D* OMe 1 OMe OMe OMe OMe OMe OMe i： OMe I 〇 1： 1 1 ch2-ch2-ch2-c 1 0€H2-CH2-C CH2 ·ΟΗ2 - CH2 *c 1 OCH2-CH2*C och2-ch2-c 9 Q S 9 9 9 Q 9 9 S 9 9 9 9 z Z Z 9 z Z Z X z z z 2： z z ζ z Z Z Z z Z Z z z z z 2： z z z ζ z 〇〇〇〇〇 ο ο 〇〇〇〇 ο ο o o 〇 o 0 0 ο 0 第58頁 509676 五、發明說明（55) | 5: S 1 1 5: 6： i 1 1 S: fd 1 i i i i 1 1 δ Η— I S νο 1 1 1 1 _ 1 1 1 1 1 1 1 I I I _ 1 1 1 1 1 _ 1 -€ ψ η 5 1 β k t η 1 k k u> * k δ w J η -¾ -¾ -€ -€ 5 -6 δ 5 責 -€ -€ -€ -€ 5 1 5 1 1 S 1 睡 5 I s 1 1 5 ί ia I έ 1 tslP1 ί 5 瞳 k 5 hT^ 6 睡 1 6 s 1 t 5 1 5 ί 雇 5 ί 1 5 5 垂 k 辦 5 t 5 t 1 | -€ ψ η 鰣 Ϊ 1 t -€ pi ft y> pi ψ n UJ p ψ t ? ψ t ί pi -€ k -¾ U) -€ pi t! 军 -€ l· P Ik -€ pi k U) p ψ t U) w -€ ρ ψ ί δ ψ 廿 -€ 1 k p Ψ η η ΐ Ρ t ρ ψ k 轳〇 1 辦 1 1 1 1 1 Ο 1 c^ 5 Γ4 1 § s * i , 赛 § t!»1 s * I * § κ»1 3 1： I s 6 Z Ζ S 9 S 9 9 ζ S 9 9 9 9 9 6 9 9 ζ S Z Ζ z Z z z z ζ ζ ζ ζ z z z z 2： ζ ζ ζ ζ ζ ζ ζ Z Ζ Z z 2； z ζ ζ Q ζ z z 2： Z ζ ζ ζ ζ ζ ζ ζ 〇〇〇〇 o 〇 o ο ο ο ο o o 〇 CO o ο ο ο ο ο ο οMe 9 s, 326 9 rs6 z 2: ozzoozz 2: o p. 57 zzozzozozo 2: zooozzozzo 509676 5. Description of the invention (54) 1-558! 1-557; 1-556 11-555! 1-554 11-553 | 1-552 ΜΗ 1-550 1-549 1-548 1-547 1-546 1-545 1-544 1-542 Q ^ LJ i 11-539 1 1-538 OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOMe OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH COOH | φαphenyl 1 | φο · phenyl I t Anti-t phenyl | | Phenylmethyl-phenyl | | 4 · methyl-phenyl 1 1 k ξ w J k body phenyl 40 · phenyl ΦΟ · phenyl- €-€-€-€-€-€-€ • CH (phenyl > ch2-ch2- -ch2-ch2- -ch2-ch2- " CH! <3 ^ 2 * CH〗 ~ 1 • CHd & > € H2-CH2 ^ -ch2-ch2- -CH2- € H2- • CH (phenyl > CH2-CH2 · • CH (phenyl >; ch2-ch2 · -ch2-ch2- -ch2-ch2- < ή2 < ή2- -CH2-CH2. ΌΗ2-0¾ * 雠 • CH2-CH2-CH2. CH2 < H2-CH2 · I CH2 雠 i OH] ΌΗ ^ ~ 0¾ contact ΌΗ ^-0¾ _ 孓 methoxy-phenyl 孓 methoxy-phenylcarmethoxy-phenylphenyloxy-phenylphenylphenylmethoxy-phenylphenylmethoxy Phenyl-phenylphenylΦmethyl-phenylphenylmethyl-phenylfluorenyl 2-ylphenyl 2-yl 4 »tolyl 3« methoxy-phenyl 4d-phenyl i 40 »phenyl Φmethoxy Phenyl-phenylpentylmethoxy ^ phenyl OMe OMe 1 OMe 1 OMe D * OMe 1 OMe OMe OMe OMe OMe OMe i: OMe I 〇1: 1 1 ch2-ch2-ch2-c 1 0 € H2-CH2 -C CH2 · ΟΗ2-CH2 * c 1 OCH2-CH2 * C och2-ch2-c 9 QS 9 9 9 Q 9 9 S 9 9 9 9 z ZZ 9 z ZZX zzz 2: zz ζ z ZZZ z ZZ zzzz 2: zzz ζ z 〇〇〇〇〇〇ο ο 〇〇〇〇〇ο oo 〇o 0 0 ο 0 Page 58 509676 V. Description of the invention (55) | 5: S 1 1 5: 6: i 1 1 S: fd 1 iiii 1 1 δ Η— IS νο 1 1 1 1 _ 1 1 1 1 1 1 1 1 III _ 1 1 1 1 1 _ 1-€ ψ η 5 1 β kt η 1 kk u > * k δ w J η- ¾ -¾-€-€ 5 -6 δ 5 Responsibility-€-€-€-€ 5 1 5 1 1 S 1 sleep 5 I s 1 1 5 ia I 1 1 tslP1 ί 5 pupil k 5 hT ^ 6 sleep 1 6 s 1 t 5 1 5 ί hire 5 ί 1 5 5 kk do 5 t 5 t 1 |-€ ψ η 鲥 Ϊ 1 t-€ pi ft y > pi ψ n UJ p ψ t? Ψ t ί pi -€ k -¾ U)-€ pi t! Army- € l · P Ik-€ pi k U) p ψ t U) w-€ ρ ψ ί δ ψ 廿-€ 1 kp Ψ η η ΐ ρ t ρ ψ k 轳〇1 Office 1 1 1 1 1 Ο 1 c ^ 5 Γ4 1 § s * i, Sai § t! »1 s * I * § κ» 1 3 1: I s 6 Z ZZ S 9 S 9 9 ζ S 9 9 9 9 9 6 9 9 ζ SZ z z z zzz ζ ζ ζ ζ zzzz 2: ζ ζ ζ ζ ζ ζ ζ Z Z Z z 2; z ζ ζ Q ζ zz 2: Z ζ ζ ζ ζ ζ ζ ζ ζ 〇〇〇〇〇o 〇o ο ο ο ο oo 〇CO o ο ο ο ο ο ο

111BI1 第59頁 509676 五、發明說明（56) 1 I 6： 5： S： ^3 1 1 1 1 5 s 6： 88 6： S3 6： s: 6：玄 S； 83 1 1 1 I 1 1 1 1 1 I I I I 1 I 1 1 1 I 1 1 1 n | | 舛 -€ k ί Ψ g Ϊ δ w J k ? t 1 i ¥i η ΐ Ικ -€ -€ >€ -€ — -€ -€ Μ SS -€ k 1 s 1 5 a δ 1 ί S 瞻 5 S 泰 1 5 5 1 ί δ • s 1 1 β 1 5 s 1 1 5 s 1 ί 1 k ί 1 β 1 β 1 1 k f p( n U) t u> 1“ p ψ n 军 p ψ pi k ί ψ g t 琴 p t U) Y' & 令 -€ g g h -€ i^t t u> -i ? |κ U) 廿 -€ £ η 駟辦 ΐ g ψ η 輙 ϊ p( η ϊ ψ t 1 t 1 I 1 1 1 1 1 5 1 1 D4 I s * * 1 S * έ * 系 I s * S 5 S * , 9 9 Z 9 Ζ 9 S 3 s 9 Ζ 9 s 9 z z z z z 3 2 Z z z z z z Z Ζ 2 z ζ ζ ζ z z z 2 z Ζ Z Z z z z z z z Z Ζ Ζ z ζ ζ ζ z O o 〇 o 〇 00 〇 o o o o o o 〇〇〇 o ο ο ο o 第60頁 509676 五、發明說明（57) 1-623 1-622 11-621 | 1-620 1-619 1-618 1 1-617 i i 1-616 (1-615 ! )1-614 11-613 1 1-612 11-611 1 (1-610 1 1-609 1-608 1-607 1-606 1-605 1-604 1-603 ； OOOH OOOH COOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH t 1_ OOQH OOOH OOOH COOH OOOH OOOH OOOH OOOH OOOH 乙基-苯基 η 苯基 η η Φα苯基丰甲基-苯基丨‘甲基-苯基1 得苯基 4»Br-苯基丰乙基-苯基丰乙基-苯基苯基苯基 t 5 -ch2- CH2-CF3 -€ -¾ -€ -€ ch2-o- ch2-ch3 !-ch2-ch2-ch2- 偶偶· 1 •CH(苯基>CH2-CH2- •ch2<h2-ch2· -CH(OH>CH(OH)- ch2- 1 -CH2-CH2. "CH2 "QH^ - CH〗- -ch2-ch2- <ή2<ή2- -CH2-€H2- -ch2-ch2- 1 CH2 "CH^ - CM]讎 <Ή2<Ή2·ΟΗ2· 1 -OH2 -OH2 ~CH2 ~ -ch2-ch2- j <η2<ή2- i _1 •ch(苯 4·甲1苯基车甲氧基-苯基丰甲氧基-苯基丰甲基-苯基苯基丰甲疏A-苯基签2-基签2-基丰甲硫基-苯基丰乙基-苯基孓甲氧基-苯基 3·甲氧基-苯基丰乙基-苯基丰甲确苯基 S 4»甲基《苯基丰曱碎 1苯基 3,4·二甲氧基-苯基 3+亞甲二氧苯基1 车異丙基-苯基苯基 OMe OMe 1 5 OMe OMe 1 OMe Ο 1 〇 1 1 OMe OMe OMe ； OMe 5 OMe OMe och2-ch2-c (ΧΉ2-Οί2-€ I：〇 1 och2-ch2-c (XH2-CH2-C OCH2-CH2-C 1 9 9 s 9 9 S Z S Z 9 9 9 3 S Ζ z Z Z Z S Z Z Z Z z Z z Z z z Z 9 z Z Z Z 2： Z z z z 〇〇 o 〇〇 o o 〇〇〇〇〇〇〇〇 0 0 GO 0 0 0111BI1 Page 59 509676 V. Description of the invention (56) 1 I 6: 5: S: ^ 3 1 1 1 1 5 s 6: 88 6: S3 6: s: 6: Xuan S; 83 1 1 1 I 1 1 1 1 1 IIII 1 I 1 1 1 I 1 1 1 n | | 舛-€ k ί Ψ g δ δ w J k? T 1 i ¥ i η ΐ Ικ-€-€ > €-€ —-€- € Μ SS-€ k 1 s 1 5 a δ 1 ί S Kan 5 S Thai 1 5 5 1 ί δ • s 1 1 β 1 5 s 1 1 5 s 1 ί 1 k ί 1 β 1 β 1 1 kfp ( n U) t u > 1 "p ψ n army p ψ pi k ί ψ gt pt U) Y '& order-€ ggh-€ i ^ tt u > -i? | κ U) 廿-€ £ η驷 g ψ η 輙 ϊ p (η ϊ ψ t 1 t 1 I 1 1 1 1 1 5 1 1 D4 I s * * 1 S * * * is I s * S 5 S *, 9 9 Z 9 Z 9 S 3 s 9 Zn 9 s 9 zzzzz 3 2 Z zzzzz Z ZZ 2 z ζ ζ ζ zzz 2 z ZZ ZZ zzzzzz Z ZO z z ζ ζ ζ z O o 〇o 〇00 〇oooooo 〇〇〇o ο ο ο ο ο ο ο ο ο o Page 60 509676 V. Description of the invention (57) 1-623 1-622 11-621 | 1-620 1-619 1-618 1 1-617 ii 1-616 (1-615!) 1-614 11- 613 1 1-612 11-611 1 (1-610 1 1-609 1-608 1-607 1-606 1-605 1-604 1-603; OOOH OOOH COOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH t 1_ OOQH OOOH OOOH COOH OOOH OOOH OOOH OOOH OOOH Ethyl-benzene Η phenyl η η Φα Phenylphenylmethyl-phenyl 丨 'methyl-phenyl 1 gives phenyl 4 »Br-phenylphenethyl-phenylphenethyl-phenylphenylphenyl t 5 -ch2- CH2-CF3-€ -¾-€-€ ch2-o- ch2-ch3! -ch2-ch2-ch2- even · 1 • CH (phenyl > CH2-CH2- • ch2 < h2-ch2 · -CH (OH > CH (OH)-ch2- 1 -CH2-CH2. &Quot; CH2 " QH ^-CH〗--ch2-ch2- < ή2 < ή2- -CH2- € H2- -ch2-ch2 -1 CH2 " CH ^-CM] 雠 < Ή2 < Ή2 · ΟΗ2 · 1 -OH2 -OH2 ~ CH2 ~ -ch2-ch2- j < η2 < ή2- i _1 • ch (benzene4 · methyl 1benzene Carbomethoxy-phenyl-p-methoxy-phenyl-p-methyl-phenyl-p-phenyl-p-methyl Stilbene methoxy-phenyl 3 · methoxy-phenylfungethyl-phenylfungrazine Phenyl S 4 »methyl <phenylfungamidine 1 phenyl 3,4 · dimethoxy- Phenyl 3 + methylenedioxyphenyl 1 isopropyl -Phenylphenyl OMe OMe 1 5 OMe OMe 1 OMe 〇 1 〇1 1 OMe OMe OMe; OMe 5 OMe OMe och2-ch2-c (× Ή2-〇ί2- € I: 〇1 och2-ch2-c (XH2-CH2 -C OCH2-CH2-C 1 9 9 s 9 9 SZSZ 9 9 9 3 S Z z ZZZSZZZZ z Z z Z zz Z 9 z ZZZ 2: Z zzz 〇〇〇〇oo 〇〇〇〇〇〇〇〇〇〇 0 GO 0 0 0

第61頁 509676 五、發明說明（58) 1-646 1-645 1-644 1-643 1*642 [1-641 1-640 (1-639 | 11-638 | [1-637 1 1-636 [1-635 1-634 11-633 (1-632 1-631 1-630 1-629 1-628 1-627 1-626 1-625 j 1-624 OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH 000H 000H ； 000H 1丰甲基-苯基1 丰甲基-苯基 4>F-苯基 1苯基 1 |丰乙基-苯基1 |车乙基-苯基1 |体苯基 I |Φα苯基| 丨苯基 | ΦΟ·苯基体苯基 ! 苯基 |4Q-苯基1 n 裕笨基丰甲基-苯基丰甲基-苯基 Φα苯基 1 苯基丰乙基·苯基 5 WHfCF3 B ch2o- CH2-CH3 -ch2-ch2- -ch2-ch2- ί 5 着 t a 1 -CH2-CH2.CH2- Κ -ch2-ch2-ch2- -CH2-CH2- CH2 _ CH2 - -CH2 *GH2 - C3i2 - ch2*〇V -CH2<H2-CH2. -€Η2<Ή2-Οί2- -ch2-ch2-ch2- 1 ! 1 <Ή2<Ή2-ΟΗ2- j -CH2-CH2. ： -ch2-ch2- -CH2-CH2. -ch2-ch2- -CH2<H2-CH2- 1 3,4>二甲氧基-苯基 3，Φ二甲氧基-苯基丰曱基-苯基丰異丙基-苯基 3»甲氧基-苯基 3·甲氧基-苯基丰異丙基-苯基丰甲基-苯基 3,4>三甲氧基-苯基苯基苯基 3,4«二甲氧基-苯基丰甲基-苯基丰乙基-苯基 ‘乙备苯基丰甲基-苯基丰甲基-苯基二甲氧基-苯基 3»甲氧基-苯基 3*曱氧基-苯基 3>二甲氧基-苯基丰甲基-苯基丰曱菊1&-苯基 |〇Me OMe OMe OMe D4 OMe 0» 1 OMe 1 OMe 1 OMe 1 1 OMe _ ! 5 D4 |och2.ch2-c 9 OCH2-CH2-C ch2-ch2-ch2-c OOH2 ( 1 och2-ch2-c 系 OCH2-CH2<： 1 琴 9 S 9 9 9 z z 9 S Z z 9 9 S S 3 2： z z Ζ z z z Z Z Z z Z Ζ z z z z 2： Z 2： z 2 z Z z z z Z Z Z Z Ο 〇 ο o o ο Ο 〇 0 〇 0 〇 0 0 〇 0 0 0 〇〇 6 00 〇P.61 509676 V. Description of the Invention (58) 1-646 1-645 1-644 1-643 1 * 642 [1-641 1-640 (1-639 | 11-638 | [1-637 1 1-636 [1-635 1-634 11-633 (1-632 1-631 1-630 1-629 1-628 1-627 1-626 1-625 j 1-624 OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH 000H 000H; 000H 1 Phenylmethyl-phenyl 1 Phenylmethyl-phenyl 4 > F-phenyl 1phenyl 1 | Phenyl ethyl-phenyl 1 | Cheethyl- Phenyl 1 | Body phenyl I | Φαphenyl | 丨 Phenyl | ΦΟ · phenyl body phenyl! Phenyl | 4Q-phenyl1 n Group 1 Phenylpentylethylphenyl 5 WHfCF3 B ch2o- CH2-CH3 -ch2-ch2- -ch2-ch2- ί 5 ta 1 -CH2-CH2.CH2- K -ch2-ch2-ch2- -CH2 -CH2- CH2 _ CH2--CH2 * GH2-C3i2-ch2 * 〇V -CH2 < H2-CH2.-€ Η2 < Ή2-Οί2- -ch2-ch2-ch2- 1! 1 < Ή2 < Ή2-ΟΗ2 -j -CH2-CH2 .: -ch2-ch2- -CH2-CH2. -ch2-ch2- -CH2 < H2-CH2- 1 3,4 > dimethoxy-phenyl3, Φdimethoxy- Phenylfungyl-phenylphenylisopropyl-phenyl 3 »methoxy-phenyl 3 · methoxy-phenyl isopropyl-phenyl isopropyl-methyl-3,4 > trimethoxy-phenylphenylphenyl 3,4 «dimethoxy-phenyl isopropyl- Phenylfungethyl-phenyl'ethenephenylfungylmethyl-phenylfungmethyl-phenyldimethoxy-phenyl 3 »methoxy-phenyl 3 * methoxy-phenyl 3 > Dimethoxy-phenyl-fungyl-phenyl-fungulose 1 & -phenyl | 〇Me OMe OMe OMe D4 OMe 0 »1 OMe 1 OMe 1 OMe 1 1 OMe _! 5 D4 | och2.ch2-c 9 OCH2-CH2-C ch2-ch2-ch2-c OOH2 (1 och2-ch2-c series OCH2-CH2 <: 1 Qin 9 S 9 9 9 zz 9 SZ z 9 9 SS 3 2: zz zz z zzz zzz z z Z zzzz 2: Z 2: z 2 z Z zzz ZZZZ 〇〇ο oo ο 〇〇0 〇0 〇0 〇0 0 0 〇〇6 00 〇

A 第62頁 509676 五、發明說明（59) 1-669 1-668 1-667 1-666 1-665 1*664 1-663 1-662 11-661 | 1-660 11-659 1 )1-658 ! 1-657 1-656 )1-655 1-654 11-653 11-652 1-651 1-650 1-649 1-648 1-647 丨 OOOH ΟΟΟΗ OOOH OOOH OOOH OOOH ΟΟΟΗ OOOH 1 OOOH OOOH OOOH 1 OOOH OOOH OOOH ί OOOH OOOH OOOH OOOH 000H OOOMe OOOH j OOOH OOOH 得苯基 η φο苯基 |ψα苯基1 4C1-苯基 4Cl·苯基 1丰乙基-苯基1 1丰乙基T苯基! 餘t 体苯基苯基 40·笨基 Φα苯基得苯基 40«笨基 ! ! 体苯基 5 -€ •〇WCF3 ch2o ch2-ch3 偶偶· -ch2-ch2-ch2- -€H2-CH2-CH2. 1 ί έ I -CH2-€H2-CH2- -ch2-ch2- ί 1 -ch2-ch2-ch2- s 1 -CH2 -CH2 · CH2 - 偶偶· -ch2-ch2- ί ΌΗ2 "^^2 讎 " -CH2 ΌΗ^ - CH2 - CH2~CH2· -CH2-CH2.CH2- 1 -ch2-ch2-ch2- j 偶偶_ | CHj *0^2 垂 ¢3¾ 麵 1 <Ή2-€Η2. -ch2-ch2- -CH2 ΌΗ2 - CH2 - 3，Φ二甲氧基-苯基 2>二甲氧基-苯基丰甲基-苯基丰甲基-苯基 3·甲氧基-苯基 3·甲氧基-苯基 3>二甲氧基-苯基丰乙氧基-苯基 4€1-苯基孓甲氧基-苯基 3,4·二甲氧基-苯基丰甲氧基-苯基 4€1-苯基 3,4·二氣-本基寨-2-基丰乙基-苯基丰甲基-苯基 Φα苯基车乙基-苯基丰乙基-苯基丰甲基-苯基车乙基-苯基 1 ；OMe 1 OMe OMe Ο OMe OMe OMe OMe OMe 1 5 OMe 0» 5 OMe OMe OMe OMe OMe 5 OCH2-CH2*C 1 och2-ch2-c CH2 OH^ -CH2 1 o〇Vch2»c qch2-ch2*c 1 och2-ch2>c :琴 OCH2-CH2*C Z 9 Ζ 9 S 9 s Z 9 S 9 s 9 9 Z Z S z z z 2： z z z z Z Z 2： z z z z z 2： Z Z ζ z z z Z 2： Z z z z Z z z z z z 〇 ο 〇〇 o ο o o 00 〇 Ο 〇 0 0 0 〇 0 〇 0 0 0 00 0A Page 62 509676 V. Description of the invention (59) 1-669 1-668 1-667 1-666 1-665 1 * 664 1-663 1-662 11-661 | 1-660 11-659 1) 1- 658! 1-657 1-656) 1-655 1-654 11-653 11-652 1-651 1-650 1-649 1-648 1-647 丨 OOOH ΟΟΟΗ OOOH OOOH OOOH OOOH ΟΟΟΗ OOOH 1 OOOH OOOH OOOH 1 OOOH OOOH OOOH ί OOOH OOOH OOOH OOOH 000H OOOMe OOOH j OOOH OOOH gives phenyl η φο phenyl | ψα phenyl 1 4C1-phenyl 4Cl · phenyl 1 phenethyl-phenyl 1 1 phenethyl Tphenyl! I t phenylphenyl 40 · benzyl Φα phenyl to obtain phenyl 40 «benzyl!! Phenyl 5-€ • 〇WCF3 ch2o ch2-ch3 even--ch2-ch2-ch2--€ H2-CH2 -CH2. 1 ί I I -CH2- € H2-CH2- -ch2-ch2- ί 1 -ch2-ch2-ch2- s 1 -CH2 -CH2 · CH2-Odd and even · -ch2-ch2- ΌΗ ΌΗ2 " ^ ^ 2 雠 " -CH2 ΌΗ ^-CH2-CH2 ~ CH2 · -CH2-CH2.CH2- 1 -ch2-ch2-ch2- j even__ CHj * 0 ^ 2 vertical ¢ 3¾ surface 1 < Ή2- € Η2. -Ch2-ch2- -CH2 ΌΗ2-CH2-3, Φdimethoxy-phenyl 2 > dimethoxy-phenylphenylmethyl-phenylphenylmethyl-phenyl3 · methoxy- Phenyl 3.methoxy-phenyl 3 > Dimethoxy-phenyl-fungethoxy-phenyl 4 € 1-phenylfluorenyl-methoxy-phenyl 3,4 · dimethoxy-phenylfungoxy-phenyl 4 € 1 -Phenyl 3,4 · digas-benzyl-2-ylpentylethyl-phenylphenylmethyl-phenyl Φαphenylcarboethyl-phenylphenethyl-phenylphenylmethyl-phenyl Cheethyl-phenyl 1; OMe 1 OMe OMe Ο OMe OMe OMe OMe OMe 1 5 OMe 0 »5 OMe OMe OMe OMe OMe 5 OCH2-CH2 * C 1 och2-ch2-c CH2 OH ^ -CH2 1 o〇Vch2 »C qch2-ch2 * c 1 och2-ch2 > c: OCH2-CH2 * CZ 9 Zn 9 S 9 s Z 9 S 9 s 9 9 ZZS zzz 2: zzzz ZZ 2: zzzzz 2: ZZ ζ zzz Z 2: Z zzz Z zzzzz 〇ο 〇〇o ο oo 00 〇〇〇0 0 0 〇0 〇0 0 0 00 0

画_驪_11 第63頁 509676 五、發明說明（6Λ) 1-691 1-690 1-689 1-688 1-687 1-686 I 1*685 1-684 1-683 1-682 )1-681 1 1-680 1^679 1-678 1-677 11-676 1 jl-675 j (1-674 j 1-673 1-672 NU 1-670 ΟΟΟΗ ΟΟΟΗ ΟΟΟΗ ΟΟΟΗ OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOQH ΟΟΟΗ OOOH OOOH OOOH OOOH coon ΟΟΟΗ OOOH η |φ乙基-苯基 φ乙基-苯基1 n |3,4-二氣苯基| |4d苯基1 |4Cl·苯基 I |φο苯基1 |φα苯基| |3,丰二氣苯基1 |3，本二氣苯基丨丰乙基苯基1 丰乙基-苯基苯基 |3,4·二氣苯基1 4a苯基 -€ -€ -€ B -s -a^CHrCF3 -€ -€ 1丙基 -6 -€ ch2o ch2-ch3 |-CH2-CH2.CH2- "QH2-CH2- -ch2-ch2- -ch2-ch2-ch2- -QH2 -CH2 ** CH2 * <Ή2·Οί2-〇ν i 1 -ch2-ch2- -CH2-CH2. -CH2 -QH2 -CH2 ~ CH2 "Ο!: - CH2 · •CH2-0¾ - CH2 " -ch2-ch2- j -ch2-ch2- 1 CH2 ~CH2 _ CH2 麵 *ch2 *ΟΗ2 _ CH2 麵 •ch2*ch2_ ΟΗ，ΌΗ! · OH: ** CIH〗. <ή2<η2- ΌΗ2 OH】** ~ -ch2-ch2- 2»0苯基 3,4»二甲基苯基丰甲氧基-苯基 24苯基 2<n-苯基 40苯基 4Cl·苯基丰甲氧基-苯基 3，Φ亞甲二氧苯基 3斗亞甲二氧苯基1 丰甲基^苯基 j Φ甲基-苯基 ! 丰甲氧基-苯基; 丰甲氧基-苯基1 丰異丙基-苯基 1 3，Φ二甲基-苯基 3,4»二甲基-苯基j 丰異丙基-苯基丰甲氧基-苯基 3,车二甲基-苯基 % ο OMe OMe 1 OMe OMe D4 OMe OMe j 1 ο 輙 1 OMe 〇〇 1 (XM2-CH2-C 9 1 CH2<H2-CH2-C ； 9 OCH2-CH2*C CXOH^-CH2*C i 1 9 ζ 9 s S Ζ S 9 9 s 9 9 9 ζ ζ Z 9 z z 2 z Ζ Z z Z z z Z Z z ζ ζ z z z z z Z z 2： z Ζ Ζ Z Z z z Ζ Z DO ο ο o o o o o O 0 〇 0 〇〇〇 0 〇 0 0 〇〇〇Painting_ 骊 _11 Page 63 509676 V. Description of the Invention (6Λ) 1-691 1-690 1-689 1-688 1-687 1-686 I 1 * 685 1-684 1-683 1-682) 1 681 1 1-680 1 ^ 679 1-678 1-677 11-676 1 jl-675 j (1-674 j 1-673 1-672 NU 1-670 ΟΟΟΗ ΟΟΟΗ ΟΟΟΗ ΟΟΟΗ OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOQH ΟΟΟΗ OOOH OOOH OOOH OOOH coon ΟΟΟΗ OOOH η | φethyl-phenylφethyl-phenyl 1 n | 3,4-difluorophenyl | | 4dphenyl1 | 4Cl · phenylI | φοphenyl 1 | φαphenyl | | 3, Isophenyl phenyl 1 | 3, Benzoyl phenyl 丨 Phenethylphenyl 1 Phenethyl-phenylphenyl | 3,4 · Diphenyl phenyl 1 4abenzene Base- €-€-€ B -s -a ^ CHrCF3-€-€ 1propyl-6-€ ch2o ch2-ch3 | -CH2-CH2.CH2- " QH2-CH2- -ch2-ch2- -ch2 -ch2-ch2- -QH2 -CH2 ** CH2 * < Ή2 · Οί2-〇ν i 1 -ch2-ch2- -CH2-CH2. -CH2 -QH2 -CH2 ~ CH2 " 〇 !:-CH2 · • CH2-0¾-CH2 " -ch2-ch2- j -ch2-ch2- 1 CH2 ~ CH2 _ CH2 surface * ch2 * ΟΗ2 _ CH2 surface • ch2 * ch2_ ΟΗ ， ΌΗ! · OH: ** CIH〗. &Lt;价 2 < η2- ΌΗ2 OH】 ** ~ -ch2-ch2- 2 »0phenyl 3,4» Phenyl phenyl methoxy-phenyl 24 phenyl 2 < n-phenyl 40 phenyl 4 Cl · phenyl phenyl methoxy-phenyl 3, Φ methylene dioxyphenyl 3 dimethylene dioxyphenyl 1 Phenylmethyl ^ phenyl j Φmethyl-phenyl! Phenylmethoxy-phenyl; Phenylmethoxy-phenyl 1 Phenylisopropyl-phenyl 1 3, Φdimethyl-phenyl3, 4 »dimethyl-phenyl j p-isopropyl-phenyl p-methoxy-phenyl 3, ch-dimethyl-phenyl% ο OMe OMe 1 OMe OMe D4 OMe OMe j 1 ο O1 OMe 〇〇 1 (XM2-CH2-C 9 1 CH2 <H2-CH2-C; 9 OCH2-CH2 * C CXOH ^ -CH2 * C i 1 9 ζ 9 s S Zn S 9 9 s 9 9 9 ζ ζ Z 9 zz 2 z ZZ Z ZZ ZZ z ζ ζ zzzzz Z z 2: z ZZ ZZ zz ZZ Z DO ο ο ooooo O 0 〇0 〇〇〇〇0 〇0 0 〇〇〇〇

第64頁 509676 五、發明說明（61) 1-714 1-713 1-712 1-711 1-710 1-709 ; 1-708 1-707 1-706 1-705 1-7(H 11-703 1 1-702 11-701 1-700 剛 1-698 1-697 1-696 1-695 1-694 1-693 1-692 | OOOH OOOH 000H coon OOOH OOOH OOOH OOOMe OOOH OOOH OOOH OOOH OOOH OOOH OOOH 000Η OOOH OOOMe OOOH 000Η OOOH OOOH OOOH 1 I苯基 1 Φα苯基 Φα苯基丨4»0·苯基I |φο-苯基I 1苯基 I |车乙基-苯基1 |Φα苯基1 |4>a苯基1 |φο·苯基| 苯基 40-苯基 40«苯基 40·苯基! |4Cl·苯基j 0^00^0¾ -¾ 5 -€ •CHfCHrC^ -€ 0^00^0¾ |-CH2-CH2- -ch=ch-ch2- -ch2-ch2- -ch2-ch2- •OH2 讎^^2 - -CH2 ~ CH2 ~ -ch=ch-ch2- -ch=ch-ch2- -CH2-CH2- -ch2-ch2- CH2 OH】· - |<h2 偶-ch2· I OH! 繼 -ch2-ch2- -ch2-ch2-ch2- -CH2 ~ "* -€H2-CH2-CH2- 1 偶偶- 〇V -OH2 "0^2 ~ 0¾ |偶偶_ | 4C1·苯基 40-苯基丰甲氧基-苯基丰甲基-苯基丰甲基-苯基丰異丙基·苯基丰乙氧基a·甲氧基-苯基 4»曱氧基-苯基丰甲氧基-苯基丰異丙基-苯基丰異丙基-苯基 3>二甲氧基40»苯基丰甲氧基-苯基 3«甲氧基-苯基 3,4»二甲氧基-苯基 3,4»二甲氧基-苯基 3>二甲氧基40·苯基 2·α·苯基 2·α·苯基 ! 3，Φ亞甲二氧苯基 4~異丙基娜苯基丰乙氧基-苯基车乙氧基》苯基 1 1 OMe I OMe 1 OMe OMe 5 1 ο OMe 1 OMe OMe OMe ο OMe Ο Γ4 1 1 1 och2.ch2-c I I QCH2-Oi2-C CH〗"CH】讎( 2： 9 Z 9 S Z s s 9 s s 9 9 9 S S S 9 9 Z Z Z 9 Z Z z Z z z Z z Z Z Z Ζ Z Z Ζ Z Z 2： Z Z Z Z z z z z z z z Ζ z Z Z Ζ 〇 Ο 〇〇〇〇 0 0 00 0 0 〇 0 0 〇 0 〇 0 〇 00 〇〇〇第65頁 509676 五、發明說明（62) 1-737 1-736 11-735 I 1-734 1-733 11-732 1 1-730 1-729 1-728 1-727 1-726 1-725 1-724 1-723 1-722 1-720 11-719 11-718 11-717 1 11-716 1-715 OOOH 000H 000Η OOOH OOOH OOOH OOOH OOOH \CXXM OOOH OOOH OOOMe OOOH OOOH OOOH OOOH OOOH OOOH ΟΟΟΗ OOOH OOOH OOOH i OOOH 40«苯基 ψα苯基 η |κ |4C1-苯基I |4Ό·苯基1 |4<3-笨基| 40·苯基 η n |4Ό·苯基1 丨4-0*苯基| 丨4~0-笨基| 体苯基；苯基苯基 n 40·苯基 4-0·苯基 -€ -¾ 0^00^0¾ -€ 5 -€ •α^α^ -¾ <h2-ch2-ch2- 1 |-ch2-ch2- I «ch=ch-ch2- 丨偶偶-1 -ch2-ch2- -CH2 Ό^2" " |-ch2-ch2-ch2- | -CH=CH-CH2. -CH=CH-CH2. -ch=ch-ch2- |<ή2<ή2- I -ch2-ch2- CH2 參繼 |·σί2<Ή2·σν 1 I s 1 Ι<η2<ή2- I I δ ί Β 1 δ ί 1 ΌΗ^ ΌΗ2 - 0¾ · 丰甲硫基-苯基 4·甲都1&-苯基丰乙氧基各曱氧基-苯基丰乙氧基各甲氧基-苯基環己基丰甲氧基-苯基丰甲氧基-苯基孓甲氧基-苯基孓甲氧基-苯基 3，木二甲氧基-苯基 3,4«二甲氧基-苯基 3,4-二甲氧基-苯基车乙氧基-苯基丰乙氧基-苯基丰乙氧基-3*甲氧基-苯基丰甲福ι&-苯基： 3,4»二甲氧基-苯基 η KPl·甲氧基-苯基 3·〇Φ甲氧基-苯基孓甲氧基-苯基孓甲氧基-苯基 D4 OMe OMe OMe OMe 1 OMe OMe 1 1 1 OMe OMe OMe ! OMe 1 OMe OMe (ΧΉ2-ΟΙ2-0 ch2<h2-ch2-c i： OCH2-CH2*C 1 och2.ch2-c 1： ¥ 1 QCH2-CH2»C I 1 OCH2-CH2-C S Ζ 9 9 9 9 Z s S 3 9 9 9 9 9 9 Ζ Z 2： ζ z z z Z z 9 z z Z Z z z ζ ζ z Z Ζ 2： 2： z z Z z 2: z Z 2： z 2： ζ 2： Ζ 〇〇 Ο O o ο 〇〇〇 GO 〇 o ο 〇 Ο o Ο ο Ο o Ο 〇〇P.64 509676 V. Description of the invention (61) 1-714 1-713 1-712 1-711 1-710 1-709; 1-708 1-707 1-706 1-705 1-7 (H 11-703 1 1-702 11-701 1-700 Gang 1-698 1-697 1-696 1-695 1-694 1-693 1-692 | OOOH OOOH 000H coon OOOH OOOH OOOH OOOMe OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH 000Η OOOH OOOMe OOOH 000Η OOOH OOOH OOOH 1 Iphenyl1 ΦαphenylΦαphenyl 丨 4 »0 · phenyl I | φο-phenyl I 1phenyl I | Cheethyl-phenyl 1 | Φαphenyl 1 | 4 > aphenyl1 | φο · phenyl | phenyl 40-phenyl 40 «phenyl 40 · phenyl! | 4Cl · phenyl j 0 ^ 00 ^ 0¾ -¾ 5-€ • CHfCHrC ^-€ 0 ^ 00 ^ 0¾ | -CH2-CH2- -ch = ch-ch2- -ch2-ch2- -ch2-ch2- • OH2 雠 ^ 2--CH2 ~ CH2 ~ -ch = ch-ch2- -ch = ch-ch2 --CH2-CH2- -ch2-ch2- CH2 OH] ·--< h2 Even-ch2 · I OH! Following -ch2-ch2- -ch2-ch2-ch2- -CH2 ~ " *-€ H2- CH2-CH2- 1 ou even-〇V -OH2 " 0 ^ 2 ~ 0¾ | ou even _ | 4C1 · phenyl 40-phenylfungylmethoxy-phenylfungylmethyl-phenylfungylmethyl-phenylfung Isopropylphenylphenylethoxy a · methoxy-phenyl 4 Phenyl isopropyl-phenyl Phenyl isopropyl-phenyl 3 > Dimethoxy 40 »Phenyl isomethoxy-phenyl 3« methoxy-phenyl 3,4 »dimethoxy-phenyl 3,4 »Dimethoxy-phenyl 3 > Dimethoxy 40 · phenyl 2 · α · phenyl 2 · α · phenyl! 3, Φmethylenedioxyphenyl 4 ~ isopropylnaphthylbenzene Keifeng ethoxy-phenyl carethoxy》 phenyl 1 1 OMe I OMe 1 OMe OMe 5 1 ο OMe 1 OMe OMe OMe ο OMe 〇 Γ4 1 1 1 och2.ch2-c II QCH2-Oi2-C CH 〖&Quot; CH】雠 (2: 9 Z 9 SZ ss 9 ss 9 9 9 SSS 9 9 ZZZ 9 ZZ z Z zz Z z ZZZ ZZ ZZ ZZ ZZ 2: ZZZZ zzzzzzz zz z ZZ ZZ 〇〇〇〇〇〇〇〇 0 00 0 0 〇0 0 〇0 〇00 〇00 〇〇〇 page 65 509676 V. Description of the invention (62) 1-737 1-736 11-735 I 1-734 1-733 11-732 1 1-730 1-729 1-728 1-727 1-726 1-725 1-724 1-723 1-722 1-720 11-719 11-718 11-717 1 11-716 1-715 OOOH 000H 000Η OOOH OOOH OOOH OOOH OOOH \ CXXM OOOH OOOH OOOH OOOMe OOOH OOOH OOOH OOOH OOOH OOOH ΟΟΟΗ OOOH OOOH OOOH i OOOH 40 «phenylψαphenylη | κ | 4C1-benzene I | 4Ό · phenyl1 | 4 < 3-benzyl | 40 · phenylη n | 4Ό · phenyl1 丨 4-0 * phenyl | 丨 4 ~ 0-benzyl | monophenyl; phenylbenzene Group n 40 · phenyl 4-0 · phenyl- € -¾ 0 ^ 00 ^ 0¾-€ 5-€ • α ^ α ^ -¾ < h2-ch2-ch2- 1 | -ch2-ch2- I « ch = ch-ch2- 丨 even-1 -ch2-ch2- -CH2 Ό ^ 2 " " | -ch2-ch2-ch2- | -CH = CH-CH2. -CH = CH-CH2. -ch = ch -ch2- | < ή2 < ή2- I -ch2-ch2- CH2 Participants | · σί2 < Ή2 · σν 1 I s 1 Ι < η2 < price2- II δ ί Β 1 δ ί 1 ΌΗ ^ ΌΗ2-0¾ · Phenylmethylthio-phenyl4.methyl 1 & -phenylpentylethoxy each methoxy-phenylphenylethoxy each methoxy-phenylcyclohexylpentylmethoxy-phenylfungyl Phenyl-phenylfluorenylmethoxy-phenylfluorenylmethoxy-phenyl3, wooddimethoxy-phenyl3,4 «dimethoxy-phenyl3,4-dimethoxy-phenyl Che ethoxy-phenyl-p-ethoxy-phenyl-p-ethoxy-3-3 methoxy-phenyl-p-methane & -phenyl: 3,4 »dimethoxy-phenyl η KPl · Methoxy-phenyl3.〇Φmethoxy-phenyl-methoxy-phenyl-methoxy-phenyl D4 OMe OMe OMe OMe 1 OMe OMe 1 1 1 OMe OMe OMe! OMe 1 OMe OMe (ΧΉ2-ΟΙ2-0 ch2 < h2-ch2-c i: OCH2-CH2 * C 1 och2.ch2-c 1: ¥ 1 QCH2-CH2 »CI 1 OCH2 -CH2-C S Zn 9 9 9 9 Z s S 3 9 9 9 9 9 Zn Z 2: ζ zzz Z z 9 zz ZZ zz ζ ζ z Z Zn 2: 2: zz Z z 2: z Z 2: z 2: ζ 2: Z 〇〇〇〇 O ο 〇〇〇GO 〇o ο 〇〇 o Ο ο Ο o 〇〇〇

A 第66頁 509676 五、發明說明（63) 1-758 1-757 1-756 1-755 1-754 11-753 11-752 | 1-751 1-750 11-749 1 1-748 11-747 1 1-746 丨 1-745 1 1-744 11-743 1 11-742 1 )1-741 1 1-740 11-739 1-738 OOOH coon 000Η 1 OOOH OOOH OOOH ! OOOH 000H 000Η coon 000H OOOH (OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOQH | 40·苯基苯基 |4〇·苯基I |4Cl·苯基I 丨❿苯基丨丨4»0"苯基] η 1体苯基I |4-F-苯基| |4€l·苯基1 |φο*苯基， 40*苯基! |4Cl·苯基| 苯基： η 0^00^0¾ -€ -€ 0^00^-0¾ 0^00^0¾ -CH2 "CH2 * CH2 * 偶偶码· § s 1 XIH2OH2· •o[苯基Κ«»α^ -ch2-ch2- I <Ή2-€Η2-ΟΗ2- •ch2*ch2- δ 1 S 1 -ch=ch-ch2- •ch2-ch2- -CH2^H2-CH2. 〇(苯基ΚΗ·σ^ •^3^2 "OH^· -CH=CH-CH2. -ch=ch-ch2- 丰乙氧基-苯基丰乙氧基-苯基 t 签2-基 Έ-2-基苯基丰乙氧基各甲氧基-苯基 4·甲硫基-本， 4»甲硫差本丰乙氧基各甲氧基-苯基苯基 η ⑽苯基得苯基 3>二甲氧基苯基二甲氧基-苯基 δ 3，Φ亞甲二氧苯基 3,4>亞甲二氧苯基丰甲基-苯基環己基 OMe OMe ο ο 1 OMe 1 1 OMe 5 OMe OMe OMe Ο 1 1 OCH2-CH2<： OCH2-CH2-C I 系 1 1 OCH2-CH2-C 9 S 9 9 9 9 S Z Ζ 9 9 3 9 9 9 9 Z 9 Z 2： z z z Ζ 2 Ζ Z Ζ z z Z z Ζ 2 Ζ z 2： z Ζ Z Ζ Z Ζ z 2： Z Z z 2 2： 2： Z 〇〇 00 〇 0 〇〇〇 0 〇〇〇 0 0 〇〇 0 〇 Ο 00 〇第67頁 509676 五、發明說明（64) 11-765 1-764 (1-763 1 (1-762 11-761 1 1-760 1-759 OOOH ΟΟΟΗ OOOH OOOH ΟΟΟΗ ΟΟΟΗ ΟΟΟΗ P P Ρ Ρ η -¾ -i -€ 5 5 5 蠢 5 1 1 κ t έ 1 s 1 u> u> -€ π D4 Ρ 1 ' 1' Ρ ρ pi ψ ψ η k η η T τ OMe ο OMe § 1 〇 1 S 6 9 ζ S 9 9 Ζ z ζ ζ ζ ζ z Z ζ ζ ζ ζ z 〇〇 ο ο ο ο oA Page 66 509676 V. Description of the Invention (63) 1-758 1-757 1-756 1-755 1-754 11-753 11-752 | 1-751 1-750 11-749 1 1-748 11-747 1 1-746 丨 1-745 1 1-744 11-743 1 11-742 1) 1-741 1 1-740 11-739 1-738 OOOH coon 000Η 1 OOOH OOOH OOOH! OOOH 000H 000Η coon 000H OOOH (OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOOH OOQH | 40 · phenylphenyl | 4〇 · phenyl I | 4Cl · phenyl I 丨 ❿phenyl 丨丨 4 »0 " phenyl] η 1-body phenyl I | 4- F-phenyl | | 4 € l · phenyl1 | φο * phenyl, 40 * phenyl! | 4Cl · phenyl | phenyl: η 0 ^ 00 ^ 0¾-€-€ 0 ^ 00 ^ -0¾ 0 ^ 00 ^ 0¾ -CH2 " CH2 * CH2 * Even and even code · § s 1 XIH2OH2 · • o [phenylΚ «» α ^ -ch2-ch2- I < Ή2- € Η2-ΟΗ2- • ch2 * ch2- δ 1 S 1 -ch = ch-ch2- • ch2-ch2- -CH2 ^ H2-CH2. 〇 (phenyl KΗ · σ ^ • ^ 3 ^ 2 " OH ^ · -CH = CH-CH2. -ch = ch-ch2- Phenylethoxy-phenyl Phenylethoxy-phenyl t signed 2-ylfluoren-2-ylphenylphenethoxy each methoxy-phenyl 4 · methylthio-benzyl, 4 »Methylsulfate, Benthophenoxy, Methoxy-phenylphenyl, ηPhenyl to Phenyl 3 > Dimethoxy Methylphenyldimethoxy-phenylδ 3, Φmethylenedioxyphenyl 3,4 > methylenedioxyphenyl phenylmethyl-phenylcyclohexyl OMe OMe ο ο 1 OMe 1 1 OMe 5 OMe OMe OMe Ο 1 1 OCH2-CH2 <: OCH2-CH2-C I system 1 1 OCH2-CH2-C 9 S 9 9 9 9 SZ ZO 9 9 3 9 9 9 9 Z 9 Z 2: zzz ZZ 2 Z Z ZZ Z z Z 2 Z z 2: Z z Z Z Z Z z z 2: ZZ z 2 2: 2: Z 〇0000 〇0 〇〇〇〇〇〇〇〇0 0 〇〇00 00 〇 page 67 509676 V. Description of the invention (64) 11-765 1-764 (1-763 1 (1-762 11-761 1 1-760 1-759 OOOH ΟΟΟΗ OOOH OOOH ΟΟΟΗ ΟΟΟΗ ΟΟΟΗ) PP Ρ Ρ η -¾ -i-€ 5 5 5 Stupid 5 1 1 κ t deg 1 s 1 u > u >-€ π D4 Ρ 1 '1' ρ ρ pi ψ ψ η k η η T τ OMe ο OMe § 1 〇 1 S 6 9 ζ S 9 9 Z z ζ ζ ζ ζ z Z ζ ζ ζ ζ z 〇〇ο ο ο ο o

IHIRIH 第68頁 509676 五、發明說明（65) 實例17 下列化合物之受體結合數據係使用上述之結合分析法而測定。其結果如表2所述。表2 受體結合數據值）實例 ETA[Nm] ETB[Nm] 3 20 70 6 95 780 7 35 70 8 72 580 9 36 75 10 700 1000 11 95 100 12 90 850 13 350 930 14 100 145 15 45 140 16 40 230 〇 iIHIRIH Page 68 509676 V. Description of the Invention (65) Example 17 The receptor binding data of the following compounds were determined using the above binding analysis method. The results are shown in Table 2. Table 2 Values of receptor binding data) Example ETA [Nm] ETB [Nm] 3 20 70 6 95 780 7 35 70 8 72 580 9 36 75 10 700 1000 11 95 100 12 90 850 13 350 930 14 100 145 15 45 140 16 40 230 〇 i

第69頁Page 69

Claims

509676 _案號88103317_⑴年士月日修正六、申請專利範圍509676 _ Case No. 88103317_ Years, months, months, and days

[其中取代基具有下面定義： R1 為-COOH ； R2烷基、（：厂(：4-烷氧基； X為氣， Y為獻*， Z為CR1Q，其中R113為氫； II R3烷基、C4-烷氧基； ” R4為Ci-C^烧基； R5為苯基； R6為萘基或未經取代或經鹵素、C4-烷基或q-CV-烷氧基取代之苯基； W為氧； Q為（：2-C4伸烷基；及其生理上可耐受之鹽類，及彼等為純對掌異構物形式及純非對映異構物形式。 2. —種供口服、腸道外或腹膜腔内使用之做為内皮素受體拮抗劑之醫藥組合物，其包含至少一種申請專利範圍第<1 1項之羧酸衍生物I，此外尚包含習用醫藥輔助物質。 3. 根據申請專利範圍第1項之羧酸衍生物I，其係做為内[Wherein the substituents have the following definitions: R1 is -COOH; R2 alkyl, (: factory (: 4-alkoxy; X is gas, Y is Xian *, Z is CR1Q, where R113 is hydrogen; II R3 alkyl , C4-alkoxy; "R4 is Ci-C ^ alkyl; R5 is phenyl; R6 is naphthyl or unsubstituted or substituted by halogen, C4-alkyl or q-CV-alkoxy ; W is oxygen; Q is (: 2-C4 alkylene); and physiologically tolerable salts thereof, and they are in pure paraisomeric form and pure diastereoisomeric form. 2. -A pharmaceutical composition for use as an endothelin receptor antagonist for oral, parenteral or intraperitoneal use, comprising at least one carboxylic acid derivative I of the scope of patent application <11, and also contains conventional Auxiliary substances for medicine 3. According to the carboxylic acid derivative I in the scope of patent application No. 1, it is included as

O:\57\57487-910417.ptc 第71頁 509676 案號 88103317 a 修正六、申請專利範圍皮素受體拮抗劑。 4.根據申請專利範圍第1項之羧酸衍生物I，其係作為製造内皮素濃度提高之疾病之藥物。 5 ·根據申請專利範圍第1項之羧酸衍生物I，其係用於治療慢性心衰竭、心肌梗塞、動脈粥腫樣硬化、心律不整、心絞痛、再窄縮、高血壓、肺高血壓、急/慢性腎衰竭、腎功能不足、腦缺血、氣喘、良性***肥大及*** 癌。 6.根據申請專利範圍第1項之羧酸衍生物I，其與腎素-血管收縮素系統之抑制劑、混合ACE/中性内肽酶（NEP)抑制劑或/3 -封阻劑組合使用。O: \ 57 \ 57487-910417.ptc Page 71 509676 Case No. 88103317 a Amendment 6. Scope of patent application Corticosteroid antagonist. 4. The carboxylic acid derivative I according to item 1 of the scope of patent application, which is used as a medicine for producing diseases with an increased endothelin concentration. 5. The carboxylic acid derivative I according to item 1 of the scope of the patent application, which is used to treat chronic heart failure, myocardial infarction, atherosclerosis, arrhythmia, angina pectoris, restenosis, hypertension, pulmonary hypertension, Acute / chronic renal failure, renal insufficiency, cerebral ischemia, asthma, benign prostatic hypertrophy, and prostate cancer. 6. The carboxylic acid derivative I according to item 1 of the scope of patent application, which is combined with an inhibitor of the renin-angiotensin system, a mixed ACE / neutral endopeptidase (NEP) inhibitor, or a / 3-blocker use.

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