TW546295B - Novel carboxylic acid derivatives, their preparation and use as mixed ETA/ETB receptor antagonists - Google Patents

Abstract

The invention relates to carboxylic acid derivatives of formula I, where the radicals have the meanings stated in the description, and to the use thereof as drugs. A carboxylic acid derivative of the formula I, where the substituents have the following meanings: R is COOH; R2 is C1-C4-alkyl or C1-C4-alkoxy; X is nitrogen; Y is nitrogen; W is CH; R3 is C1-C4-alkyl or C1-C4-alkoxy; R4 is phenyl; R5 is phenyl substituted by zero to three C1-C4-alkoxy; R6 is C1-C6-alkyl, C3-C8-alkenyl, phenyl-C1-C4-alkyl (wherein phenyl may be substituted by one to three C1-C4-alkoxy, hydroxy or carboxyl), thiophenyl-C1-C4-alkyl; Z is oxygen; B is C2-C4-alkylene; Het is a heterocyclic radical of the formula Ib and the physiologically tolerated salts.

Description

546295 A7 _________— B7 V. Description of the Invention (,) The present invention relates to novel leptin derivatives, their preparation and uses. (诮 Read the notes on the back of the page before filling in this page) Endothelial test is a peptide composed of 22 kinds of amino acids, which are released by vascular endothelial synthesis. Endothelin has three kinds of isomers, namely Eπ, et_2 and ET-3. The term “endothelin,” or “ET,” as used in this patent specification refers to one of the endothelin constructs or all of the endothelium. Isomers of endothelin. Endothelin has the ability of vasoconstriction, which has a strong effect on vascular tone. It is known that this vasoconstriction ability is caused by endothelin binding to its receptor (Nature, 112_ (1988) 41 1_415; FEBS literature, 211 (1988) 440-444 and biochemical and biophysical research literature, (1988) 868-875). Increasing the release of endothelin or abnormal release of endothelin will cause peripheral blood vessels, Continuous vasoconstriction of renal and cerebral blood vessels. Endothelin has been reported in the literature to be associated with a number of diseases, including hypertension, acute myocardial infarction, pulmonary hypertension, Raynaud's disease, cerebral vasospasm, stroke, benign prostatic hypertrophy, Arteriosclerosis and Asthma (Journal of Biology of Vascular Medicine Z (1990) 207, Journal of the American Medical Association 2M (0990) 2868, Natural Ml (1990) 1 14, N_ eg · Medical Journal HI (1 989) 205, N. eg : Medical Academic Journal 12! (1993) 1732, Nephron Zhao (1994) 373, Stroke

(1994) 904, Nature (1993) 759, Journal of Molecular Cardiomyocytes H (1995) A234; Cancer Research Series (1996) 663). There are at least two subtypes of endothelin receptors found in the literature today, namely ETA and ETB receptors (Nature (1990) 730 and 732). According to this description, substances that can inhibit endothelin binding to these two receptors should be able to antagonize the physiological effects of endothelin, so these substances are valuable drugs. -4- The size of this paper is China National Standard 适 1 CNS) Λ4 gauge plum (210X 297 mm) 546295 A7 B7 V. Description of the invention (^ and 'WO 9 6 / U914 reveals high affinity binding to ETa receptors The bioavailability of slender bismuth to the ETB receptor is quite low (this is called ETf specific insertion resistance).

^ The eTa. Specific-specific antagonist in the patent statement means that its affinity for A-text is at least higher than its affinity for ETB receptor by more than 0 times. The main purpose of the present invention is to provide an endothelin receptor antagonist, which has roughly the same binding affinity for A and EL receptors (referred to as a mixed antagonist). The affinity for the receptor is roughly the same meaning the affinity; for example, greater than 〇ι and less than 10 °. The present invention is about a hydrazone derivative, which is a formula ⑴ or a formula acid derivative: (诮 Please read the attention on the back before filling this page) Spray. R4 R6__ 2 _q—CH. BRI R5 〇 ·

Het The meaning of the substituents is as follows: R is tetrazol [sic] or R1 is OR7 where R7 is hydrogen, metal cation test, earth metal cation test, or biochemically organic ammonium ion; 〇 • C—R1 Order · 丨Alkyl C3-C8-cyclic group, (^ -dagger- 5- Λ4 size (210X 297 mm) This paper size applies to Chinese national standard (rNs) 546295 A7 B7 1. Description of the invention (3) Substituted CH2-phenyl, ---------- (Please read the note on the back before filling this page) Not every substituted or substituted C3-C6 -fluorenyl or c 3-c 6 -Block group, or unsubstituted or substituted phenyl, R2 is hydrogen, # group, NH2, NHCCVCV alkyl), n (Ci-c4_, tigeryl, halogen, CVC4-alkyl, c2-c4 · ene Group, c2_c4_alkynyl, Ci-C4 ^ alkyl, CVC4-alkoxy, cvc4-self-alkoxy, or Cl-c4-alkylsulfur, or CR2 and CR1G (defined below) are combined to form 5 _ Or 6 _member ring, or, if Het is 5 _member ring, CR2 can be combined with CR3 to form an unsubstituted or substituted 5-or 6 -befyl or ring cotton ring; X is nitrogen or methine Γ is nitrogen or methine; w is nitrogen or CR1G, where R1G is Or Cn-alkyl, or CR10 and CR2 or CR3 together to form an unsubstituted or substituted 5- or 6-membered fluorenyl or cycloalkenyl ring in which one or more methylene groups in each case can be replaced by Oxygen, sulfur, -NH or -NCCVCV alkyl) substitution; »丨 R3 is hydrogen, hydroxyl, NH2, NHCCVCf alkyl), alkyl) 2, halogen, (^-(34-alkyl, C2-C4-ene Group, C2-C4-alkynyl, haloalkyl, CVC4-alkoxy, Ci-CV haloalkoxy, CVCV alkylsulfide; or CR3 and CR1G previously defined to form a 5- or 6-membered ring; R4 And R5 (which may be the same or different) are: unsubstituted or substituted phenyl or fluorenyl, or directly linked to methylene, ethylene, or ethenylene, oxygen or sulfur, or S02, NH, or N -Phenyl or fluorenyl group of alkyl group; Unsubstituted or substituted C3-C8-cycloalkyl group; -6- Size of this paper states China National Standard ((, NS) Λ4 size (210 X 297 mm) ） — ° ^ 295 V. Description of the invention (4) —--- -------- Zong Nong— (Read the notes on the back and read the praise page before filling out this page) Μ is hydrogen 'Cl_c8H C3_c ㈣ group or c3_c8_ block group, each group may be Substituted by sulfonium: Southernin, via group, parent group, end group, nitro group, amine group, cyano group, cvc4-fluorenyloxy group, C3-C6-fluorenyloxy group, c3_c6-alkynyloxy group, Ci_C4i group sulfur group, Ci_C4 Ankylosyl alkoxy, cvcv alkoxycarbonyl, Ci_C4- alkoxycarbonyl, CA-alkylbankiyl, NH (Cl々alkyl), n (Ci_c4_alkyl) 2, C3_cs% alkane A 5 or 6 shell aromatic aryloxy or heteroaryl group containing two nitrogen atoms and / or one sulfur atom or oxygen atom, one or more (such as one to three) nans Or hydroxyl, mercapto, carboxyl ', cyano, CA-alkyl, Cl_C4__alkyl, Ci_c4-alkoxy, Cl_c4_valentin alkoxy, amine, NH (C "C4_alkyl" 'Nd-CV alkyl) 2, or Ci_c4-alkylthio substituted phenoxy or phenyl groups; phenyl or fluorenyl groups which may be substituted with one or more of the following groups: halogen' nitro 'cyano, Hydroxyl, amine, Cl_c4_alkyl, Ci_c4 ^ sulfonyl, cvcv alkoxy, Cl_c4_haloalkoxy, phenoxy, CVCVfe sulfide, Cl_c4-alkylamino, Cl_c4_dialkylamino , Dioxymethylene or dioxyethylene; containing one A 5- or 6-membered heteroaromatic system with two nitrogen atoms and / or one sulfur or oxygen atom, which can carry one to four halogen atoms and / or one to two of the following groups: Cl_C4_alkyl, Cl-C4 -valentin alkyl, Ci-CV pitoxy 'CpCU- _sulfinyloxy, CVC4-sulfanylsulfur, phenyl, phenoxy or phenylcarbonyl, phenyl can carry one to five I [素Atoms and / or 1 to 3 of the following groups: CrCV alkyl, d-Cr halogen

耒 The paper size is applicable to China) (21 ox 297 ^ tT 546295 A7 ________B7 V. Description of the invention (5) — radical, CVC4 · unoxy 'C!-(Vhaloalkoxy and / or Ci_C4_ alkyl sulfur; can C3_C8_cycloalkyl substituted one or more times by the following groups: halogen, hydroxy, cyano, carboxy, nitro, cyano, Ci_C4_alkyl, c2_C4-alkenyl, C2-C4-alkynyl, oxygen Group, Ci_Czr alkoxy group, Ci-C4- dry base stone see 'Ci-Czp halooxy group; Z is sulfur or oxygen; B sc2-c4-alkenyl

Het is a heterocyclic group of the formula (la) or (lb), where d = 0, s, nr8 -------- clothing-(read the cautionary matter on the back before filling in this page)

R3 has R 疋 Ci-Ce-fe group # and is pharmacologically tolerant to salts and mirror image isomers. The terms used in this description and the following are defined as follows: Alkali metals are, for example, lithium, sodium, and potassium; Alkaline earth metals are, for example, # 5, thorium, barium;

Cs-Cs-cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl;

Ci Cf halogen radicals may be straight or branched, such as fluorofluorenyl, difluoromethyl'trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, -8- This paper is 14 hearts _ house materials ((TNS) ^^ 7210 X 297 male ΪΊ --- 546295 ΑΊ Β7) 5. Description of the invention (1. Fluoroethyl 'fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, ---------- (Please read the cautions on the back before filling this page) 2. Chloro-2 ± monofluoroethyl, 2,2- Dichloro · 2-fluoromethyl, 2,2,2-trichloroethyl or pentafluoroethyl; dagger functional alkoxy may be straight or branched, such as difluorofluorenyloxy'trifluoro Ethyloxy'chlorodifluoroamyloxy, rfluoromethoxy, 2,2-difluoroethoxy 'U'2'2-tetrafluoroethoxy', 2,2,2_trifluoroethoxy Group, 2_gas_1,1,2-trifluoroethoxy, 2-fluoroethoxy or pentafluoroethoxy; q-C4-alkyl may be straight or branched, such as fluorenyl, Ethyl, __propyl, 2-propyl, 2-fluorenyl_2_propyl, 2-fluorenyl] • propyl, butyl or 2-butyl; c2-c4-diluted may be straight-chain or Branched, such as ethylene, bupropion_3_, 1-propen-2-yl, 1-propene Fluorenyl, 2-methacryl, butyl butynyl or 2-butynyl; G-C4-alkynyl may be straight or branched, such as ethynyl, _propynyl- ^ yl, 1-propynyl- 3-yl, 1-butdecyl_4_yl or 2 • butyne_cardiyl; # -alkoxy may be straight or branched, such as methoxy, ethoxy, propoxy, i- Methylethoxy, butoxy, ^ methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy; C3_C0-alkenyloxy can be straight or branched, such as Allyloxy, 2-buten-1-yloxy or 3-buten-2-yloxy; CVCV block oxygen can be straight or branched, such as 2-propynyl small oxy, 2-butyn-1-yloxy or 3-butynyloxy ;, C〗 -C4-alkylthio may be straight or branched, such as methylsulfide, ethylsulfide, propylsulfide, 1 -Methyl ethyl sulfide, butyl sulfide, 丨 _ methyl propyl sulfide, 2_ 9-This paper size applies to the Chinese national standard bee. (ΓΝ $) Λ4 size (210X 297 mm) 546295 A7 _______B7 V. Description of the invention (7) Methylpropylsulfide or 1,1-dimethylethylsulfide; C! -C4- group may be linear or branched, such as ethylamyl, ethylcarbonyl Or C-C4-lactyl may be straight or branched, such as methoxyisopropyl'ethoxy complex, n-propoxy cleaved, iso- Propoxycarbonyl or n-butoxycarbonyl; the radical may be straight or branched, such as 2-oxo_1-propyl, 3-oxo-1-butyl or 3-oxo-2- Butyl

The Ci-cvfe group may be linear or branched, such as alkyl, pentyl, hexyl, heptyl, or octyl; halogen is, for example, fluorine, chlorine, bromine, or oxo. In addition to this, the present invention also relates to compounds (referred to as prodrugs) that can release compounds of formula VII. Preferred prodrugs are those that are released under certain conditions and are widely stored in certain parts of the body (such as the stomach, intestines, bloodstream, liver). These compounds and intermediates (such as compounds of formulae π, ΙΠ, and IV) have one or more asymmetrically substituted carbon atoms. These types of compounds can be pure mirror isomers or pure non-image isomers or These two mixtures exist. It is preferable to use a pure compound of the image isomer as an active ingredient. In addition, the present invention uses the aforementioned carboxylic acid derivative pharmaceutical agent, particularly to prepare inhibitors of the eta and etb receptors. The compounds according to the invention are particularly suitable as mixed antagonists as originally defined. As disclosed in WO 96/11914, a compound of formula IV can be prepared, which is also a mirror -10- this paper scale ill, _: material (Fns) Λ4 specification (2 丨 0? 297 mm) _ — (read first read Note on the back, please fill in this page) Order 546295 A7 B7 V. Description of the invention (like isomers of pure materials, where z is sulfur or oxygen R4 〇 广 / V / +

, R R4 C- R6- 2 ·

• H R6-2

B

II

III C ~ CH—OH B R IV is or a compound of formula III is known, or the other side is reduced to 玎 玎 I 玎 or its esters, and 化合物 compounds of formula m are synthesized by other generally known methods. The compound of the present invention can be prepared according to the definition of the substituents of Formula 1 by, for example, reacting a carboxylic acid derivative of the formula (whose substituents are as defined in the formula.) ^ IV + R1-Het ^!

V

R1 in formula V is a self-prime or R12_s0_2_, wherein alkyl, q-c: 4-valenyl or phenyl. In addition, at least one of X or Y or Z in the ring structure is nitrogen. When an appropriate base is added, such as a base that has been deprotonated by J v intermediates. The reaction is preferably carried out in an inert solvent or a diluent, and the reaction temperature ranges from room temperature to the boiling point of the solvent. When R is COOH 'in the intermediate negative IV, the protons of two equivalents are appropriately removed and reacted with the compound of formula V to directly prepare the compound of formula I with r = c00h. This reaction is also performed in an inert solvent, and the reaction temperature ranges from room temperature to the boiling point of the solvent. 1-This paper size applies to the Chinese National Standard Bee (rNS) Λ4 specification (210X297 mm) ^ 46295 Five 'invention description (A7 Examples of such solvents and diluents that can be purchased or a) include aliphatic, cycloaliphatic and Aromatic early carbon compounds, each of which can be gasified 'such as hexane, cyclohexyl, sulfide, ether, benzene, toluene, xylene, dichloro: alkane, chloro, and chlorotetrafluorocarbon' Gas ethane and trichloroethylene, ethers such as diisopropyl ether 'dibutyl ether, T-based tertiary butyl ether, propylene oxide, dioxane and tetraoxofuran, nitriles such as acetonitrile and propane Nitriles, amidines, such as dimethylamidoxamine, dimethylacetamide and N-methylpyrrolidone, sulfoxides and amidines such as dimethylsulfinium and tetrahydropyrimidine h dioxide. Compounds of formula V are known or, in some cases, generally known methods. The bases used may be alkali metal or alkaline earth metal hydrides such as sodium hydride, potassium hydride or calcium hydride, Carbonates, such as ^ or potassium carbonate, hydroxides of alkali or alkaline earth metals, such as sodium hydroxide Potassium hydroxide, organometallic compounds, such as butyllithium, or alkali metal amidamine 'such as diisopropylammonium lithium or amido lithium. Compounds can also be prepared starting from the corresponding carboxylic acid, such as Rl C00H The compound of formula I is initially converted into an activated form by conventional methods, such as acid halides, anhydrides or imidazole compounds, and then reacted with the appropriate hydroxy compound HOR7. This reaction can be carried out in traditional solvents, and often An additional test is required, and the appropriate test is described previously. These two steps can also be simplified, for example, by reacting a carboxylic acid with a hydroxy compound in the presence of a dehydrating agent (such as a carbodiimide). Another method consists of an appropriate carboxylic acid. The compound of formula I, such as the compound of formula I in which Rl is a COR group, wherein r * 0m, and M is an alkali metal cation 12- This paper is applicable to Chinese national standard ((, NS) Λ4 specification (210X 297) (Mm) --------— I (Read the first note on the back and fill in this page first), 11 • Ί 546295 A7 B7 V. Description of the invention (—-— 10 ^ • '"' '部 十 ^^^^ member 2 eliminates superfluous bamboo ^ India 1々 ions, or equivalent Alkaline earth metal cations. These salts can react with many compounds of formula RA, where A is a traditional nuclear leaving group, such as halogen, such as chlorine, bromine, broken or unsubstituted or halogen-, alkyl-, or halogen-substituted. Aromatic or alkylsulfonyl groups, such as tosylsulfonyl and methylcontinyl, or other equivalent leaving groups. Compounds of the formula Ra with reactive substituent A are known, or are the basic knowledge of general experts This reaction can be carried out in traditional formulations, and its benefit is that it is redundant and suitable for the conditions described above. In view of biological effects, preferred carboxylic acid derivatives of formula I (including pure mirror image The meanings of the substituents are: R1 COOR7, where R7 is hydrogen, metal cation, earth metal cation, or physiologically tolerable organic ammonium ion. ; C3-C8-cycloalkyl, cvcv alkyl, unsubstituted or substituted CH2-phenyl, unsubstituted or substituted C3-C6-alkenyl or c3-c6-alkynyl, or unsubstituted Or substituted phenyl. R2 hydrogen, hydroxy, halogen, n (cvc4-alkyl) 2, Ci_C4-alkyl, Cl_c4-: fe oxygen 'C ^ -Czr:)% * Cornerstone shortage, CVCV_ sulfenyl, CVC4-fluorene Alkoxy, or CR2 and CR1G (meaning as follows) are combined to form a 5-membered or 6-membered ring, or, if Het is a 5-membered ring, CR2 and CR3 together form an unsubstituted or substituted 5-membered or 6 -Member alkenyl or cyclofluorenyl ring; X nitrogen or methine; -13- This paper size is applicable to Chinese standard __ ((, NS) Λ4 specification (210X 297 mm) ----- --- ----- 衣衣 _ 丨 (Read the cautions on the back before filling this page}, 11 ^ 46295 A7 B7 Λ, invention description (H) Y nitrogen or methine; W nitrogen or CR1G, where R1G Is hydrogen or Ci-CV alkyl, or CR10 and CR2 or CR3 together form a 5- or 6-membered alkylene or alkenylene ring that is unsubstituted or substituted with one or two methyl groups, where in each case Methylene can be replaced by oxygen or sulfur, such as -CH2-CH2-0-, C Η 2-C Η 2-〇-, _ C Η = C Η Ο-, _ C Η two C Η-C Η 2 〇 _, _ C Η (C Η 3) -ch (ch3) -o-, -CH di c (ch3) -o-, -C (CH3) = C (CH3) -〇_, or -C (CH3) C (CH3) -S; At least one ring component X, Y or w is nitrogen. R3 hydrogen, hydroxyl, halogen, N (cvc4-alkyl) 2, CVC4-alkyl, Ci-C4-alkoxy, CVCV alkyl sulfur, Ci-CVi ^ Alkyl, CpCVi ^ alkoxy, or CR3 is linked to the aforementioned CR1G to form a 5-membered or 6-membered ring, or, if Het is a 5-membered ring, CR2 and CR3 can form an unsubstituted or Substituted 5-membered or 6-membered alkenyl or cyclofluorenyl rings; R4 and R5 (which may be the same or different): phenyl or naphthyl which may be substituted by one or more of the following groups: autogen, nitrate Cyl, cyano, mesyl, peptyl, amine, C ^ C: 4-alkyl, Ci-cv haloalkyl, Cl_c4-alkoxy, Cl_Czr haloalkoxy, phenoxy, CrCV alkylsulfur , NHCCVCV alkyl) or N (CVc4-housed) 2 or via hydrogen, nitro, cyano, Cl_C4_alkyl, Ci_C4__sulfanyl'oxy, CVC4 · haloalkyloxy or CVC4-alkyl Phenyl substituted one or more times (such as one to three times); or phenyl or fluorenyl group directly linked to methylene, ethylene or ethylen or oxygen or sulfur atom or S02, NH or N-alkyl in ortho position; _-14- i. Paper size "Zhongguan Household Materials ((ϋ ~ Λ4 size (21GX 297 mm) " _ ^ —__ ------ Order ------ (Please read the notice on the back before filling in this page) 546295 A7 B7 Λ 'Invention Note (12) C3-C8 -Cycloalkyl; R6 CyCp cycloalkyl, which can be passed through halogen, hydroxyl, thiol, carboxyl, nitro's Ci_C4-feoxy, C1-C4-plateyl 'C2-C4-allyl' C2- C4-Block 'C3-C6-alkenyloxy, C3-C6-Blockyloxy' C1-C4-fluorenylsulfur, Ci-CV haloalkoxy, crC4-alkylcarbonyl, CVC4-fluorenyloxy Carbonyl, NH ((VC4 · alkyl), NXCVCV alkyl) 2 substituted ^ many times, or through halogen, nitro, cyano 'C ^ -Czp alkyl, Ci · C4-halo alkyl, cvcv oxygen Phenyl, C1-C4-halohaloxy or CV C 4-fe-based thio substituted phenyl for one or more times (such as one to three times); phenyl or phenyl which may be substituted with one or more of the following groups: halogen , Nitro, thiol, carboxyl, cyano, hydroxy, amine, CVC4-alkyl, C2-C4-diluted, C2-C4-alkynyl, c3-c6-alkenyloxy, crCr haloalkyl, C3 -C6-alkynyloxy, Ci-CV alkylcarbonyl, Ci-Cr haloalkyl, C3-C6-blockyloxy, C1-C4-alkylphenyl, C1-C4-feoxy Group, Ci-Czr alkoxy, CrC4-haloalkoxy, phenoxy, CVC4 · alkylsulfur, NHKCVCV alkyl), NKi-Cr alkyl) 2, dioxomethyl, dioxoethyl [sic] Or substituted one or more times with halogen, nitro, cyano, Cr c4-alkyl, CrC4-haloalkyl, q-CV alkoxy, Ci-CV halooxy or Ci-Cr alkylsulfur (such as 1 to 3) fluorenyl groups; 5-membered or $ -membered heteroaromatic systems containing one to two nitrogen atoms and / or one sulfur or oxygen atom, which may contain one to four self, prime atoms, and / or two The following groups: Ci_C4_alkyl, haloalkyl, Ci_C4-carboxy, CVCV haloalkoxy, cvcv alkylsulfur, phenyl, __ 15- This paper is suitable for A China (, NS specifications (210X 297mm) '------ (Read the first page and read the cautions on the back and fill out this page) 1-· Order # 丨 546295 A7 —_____ B7 V. Description of the invention (13) — Phenoxy 'Or phenyl, phenyl, which may in turn carry one to five atoms; and / or one to three of the following groups: cKc4-alkyl, c. Element A-membered group'oxy 'C1-C4-fluorenin-feoxy and / or c alkylsulfur; ~ 1_cv z sulfur or oxygen; B c2-c4-alkenyl

Het is a heterocyclic group of the formula T or 0, S of la or lb. The meanings of the substituents of particularly preferred compounds of formula (I) (including pure mirror isomers and pure non-mirro isomers and mixtures thereof) are as follows: R 'C00H; X, YN; W CR10; R 2, R 3 hydrogen, light group, ΝΗ2, ΝΗ (< ^ _ ίν alkyl), N (C2C4_ alkyl) 2, price 'C1_C4-Cycyl, C2-C4-Cycyl, C2-C4-Block, C ^ -C4 · halogen Anti-radical 'oxy' Ci-C4 · halogen: 1 complete oxygen or C ^ C: 4-alkyl sulfur, or CR2 linked to CR1G as defined below to form a 5-membered or 6-membered ring 'or' if Het is a 5-membered ring. CR2 and CR3 can jointly form an unsubstituted or substituted 5- or 6-belenyl or cycloalkenyl ring; R4 is a phenyl substituted with one or more of the following groups: Element, nitro group, cyano group, #i group, system group, amine group, cvcv gauge group, c〗 -c4- _ group group, CKC4-alkoxy group, C, C4-haloalkoxy group, phenoxy group Group, Cl-C4- pit-based sulfur 'NH (Ci-C4_'J% * group) or N (Ci_C4_: fe group) 2 or via a halogen' nitro'-daiyl 'Ci-Cf alkyl group' Ci-Cf halogen Burning base, -16- 4 * [paper ^ degrees of Shizhou China C, NS) Λ4 size (210X 297 mm) 546295 A7 B7 V. Description of the invention (14) CV alkoxy, CVCzr is substituted by prime alkoxy or CrCV alkyl sulphur-phenyl that has been substituted to several times (such as ~ to two times); or R5 phenyl or 3,4-dimethoxyphenyl R6 may be substituted by one or more of c5_c7-cycloalkyl with the following groups: cvc4_alkyloxy 'Ci-cv alkyl, cvc ^ -alkylthio, halogen, mesityl, alkyl, cyano, trifluoromethyl Group, ethenyl, or substituted with halogen, cyano, 11 · c4-alkyl, Crcv haloalkyl, cvcv alkoxy, cvcv sulfonyl lactyl, or C 1 -C4-pit sulfur. (Such as one to three times) phenyl; phenyl or naphthyl substituted by one or more of the following groups: halogen, schottyl, fluorenyl, carboxyl, cyano, hydroxyl, amine, Ci_C4_alkyl, Ci-CV haloalkane Group, ethenyl, Ci_c4-alkoxycarbonyl, carboxy, C ^ CV haloalkoxy, phenoxy, Ci_c4-alkylsulfur, NHiCVCV alkyl), N ((ν <: 4-alkyl ) 2, Dioxomethyl, Dioxoethyl or Viadin, Nitro, Cyano, Ci_C4_alkyl, Ci_C4__alkyl, cvc: 4-alkoxy, c ^ -cv haloalkoxy Or Ci_Czr alkyl sulfur substituted one or more times (such as one to three times) Phenyl; a 5- or k-membered heteroaromatic ring system containing one to two nitrogen atoms and / or one sulfur or oxygen atom, which may carry one to four halo atoms and / or — to two of the following groups: Cl_C4_Tigeryl, Ci-C41 sulfenyl, C4_alkoxy, trifluoromethoxy, Ci_c ^ alkylsulfur, phenyl or phenyloxy, phenyl may have one to five _ prime atoms in sequence and / Or to three of the following groups: cvcvfe group, Cl-C4- _environment group, enclosing group, Gc: 4-haloalkoxy and / or Ci_c ^ alkyl sulfur; oxygen read read back 3 '1 page order -17- 546295 A7 * ~~~ ---------- Β7 V. Description of the invention (15) — ~ --- z Sulfur or oxygen; BC ^ -a'kylene

HetR2 and R3 are methyl groups, and T = 0, _Ia. The present invention provides for hypertension, pulmonary hypertension, myocardial infarction, asthma, acute / chronic renal failure, renal insufficiency, cerebral vasospasm, cerebral ischemia, subarachnoid hemorrhage, migraine, asthma, arteriosclerosis, Endotoxin shock, 内 母 素 #fat (organ failure, intravascular coagulation, restenosis after vascular surgery, benign gliosis, metastasis and growth of mesenchymal tumors, renal failure due to contrast agents, pancreatitis, Compounds with gastrointestinal ulcer. In addition, the present invention relates to a combination product containing an endothelin receptor antagonist of formula τ and an inhibitor of the renin-angiotensin system. An inhibitor of the renin-angiotensin system Are renal enzyme inhibitors, angiotensin 11 antagonists' and especially angiotensin-converting enzyme (ACE) inhibitors. These combined products are particularly suitable for the treatment and prevention of hypertension and its secondary symptoms, as well as the treatment of heart failure. These The good effect of the compound can be proved by the following tests: Receptor Bonding Studies Bonding studies are performed using selected human ETA or ETB receptors and expressing CHO cells. Preparation of membranes ETA or ETβ receptor-expressing CHO cells are grown in cells containing 10% fetal bovine serum (PAA Labs GmbH, Linz, No. A1 5-0220, 100 units / ml pancillin and 100 μg / ml streptomyces DMEM NUT MUX F12 Medium (Jibo Ke, Sigma No. P-0781) (Gibo Ke, No. 21331-020) -18- This paper is suitable for China National Standard (rNS) Λ4 Specification (210X 297 (Mm) 546295 A7 B7 ~ ----- 5. In the description of the invention (16). After 48 hours, the cells were washed with PBS and treated with 0.05% trypsin-containing PBS at 37 ° C for 5 minutes. The cells were neutralized with culture medium, and the cells were collected by centrifugation at a speed of 300 g. For the preparation of the membrane, the cells were adjusted to a concentration of 108 cells / liter buffer (50 mM tris · HC1 buffer, pH 7.4), and then disperse the cells with ultrasound (Breshensonifer 250, 40-70 seconds / fixation / output 2 0). Bonding analysis For ETA and ETB receptor bonding analysis, the membrane is suspended in Culture buffer (containing 5 mM MnCl, 40 μg / ml bacitracin and 0.2% BSA in 50 mM tris-HCl, pH 7.4). With 50 micrograms of protein, and with or without the test substance, the membrane preparation was reacted with 25 PM [1251] ^^ (ETA receptor analysis) or 25 pM [1251] -ET3 (ETB receptor (Analyze) incubate at 25 ° C, and bind non-specifically with ΐ0-7 μ ET, j. After 30 minutes, collect with GF / B glass fiber filter paper (Watman, UK) via Scree cells Filter (Skeley, Leine, Norway) to separate the bound ligand from the unbound ligand, using 0.20 / 〇

BSA's ice-cold tris-HCl, pH 7.4 was used to clean the filter. The radioactivity collected on the filter was determined using a Picard 22000 CA Liquid® scintillation counter. Test of in vivo E T antagonists 250-300 g of Sd male rats were anesthetized with ambobidine, artificial ventilation was used to cut off the vagus nerve and remove the pulp, and a catheter was inserted into the carotid artery and jugular vein. In the animals of the control group, 1 microgram / kg of ET1 'was administered intravenously to increase blood pressure for a long period of time. 30 minutes before cast ET1, the test compound was injected by intravenous injection. -19- This paper is ϋι 则, _: 彳 _ (-— ---- --------- 衣衣 —丨 f Please read the back, 5 '> 1, you can fill in this page} D 546295 A7 B7 V. Description of the invention (17 to the test animal body (1 ha g / kg), for the determination of ET_ antagonist The results of blood pressure changes in experimental animals were compared with those of control animals. Oral tests with mixed ETA and ETB antagonists will weigh 250-300 grams of normal blood pressure male rats (Sreek Doyle, Clip) The test substance is administered orally. After 80 minutes, the animal is anesthetized with amine vinegar and the catheter is inserted into the carotid artery (measurement of blood pressure) and jugular vein (administrated with endothelin / endothelin 1). After the period, large endothelin (20 μg / kg, 0.5 ml / kg administered volume) or ET1 (0.3 μg / kg, cast volume 0.5 * liter / kg) was administered intravenously to continuously record blood pressure and heartbeat For 30 minutes, the area under the curve (AUC) was used as a significant change in blood pressure and a long-term change. The AUC obtained from the animals and Auc obtained from the animals in the control group were tested to determine the antagonistic effect of these test substances. The traditional method can be administered orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally). The compound of the invention can also be administered by steam or spray through the nasopharynx. The dosage depends on the age, symptoms and weight of the patient and the way of administration. Usually, when administered orally, the day of the active ingredient The dose is approximately ⑼mg / kg body weight, but not 0. 〇 亳 克 / kg body weight when not administered parenterally. Digestion 11 The novel compounds of the present invention can be used in traditional solid or liquid forms, such as uncoated or (Film) Coated tablets, capsules, powders, granules, formulations, solutions, soft #, emulsions or sprays, all of which can be prepared by conventional methods, and the active ingredients can be processed with traditional pharmaceutical adjuvants according to the purpose This paper is suitable for China National Standards ((, NS) -20- Λ4 Regulations (210X 297 mm) 546295 A7 B7 V. Description of the Invention (18) Principles, such as tablet bonding agent, fill Agents, preservatives, tablet dispersants, rhenium tinctures, plasticizers, humectants, dispersants, emulsifiers, solvents, slow-release agents, antioxidants and / or propellants (see 洒. Sack et al. .: Pharmaceutical technology 'Tai Mi-Fan Le' Steger, 19 9 1). The dosage form obtained by this method contains 0.1 to 90% by weight of the active ingredient. Synthesis example 1: 2,3-¾ Oxy-3,6-phenylhexanoic acid methyl ester 14.3 g (31 1 mole) of 50% hydrogenated steel was added in 8 hours in portions containing 4 g (17.8 mmol) 1. Cardiodiphenyl-1-butanone and 2.7 ml (31 mmol) of methyl chloroacetate in 60 ml of THF. After the ketone had completely reacted, the reaction mixture was added to ice-cold water and extracted with ethyl acetate. The organic layer was dried with magnesium sulfate, and after the solvent was evaporated, 55 g of a further reacted oil was obtained. Example 2: Formyl 2-methoxy-3-methoxy-3,6-diphenylhexanoate 2 g (6.75 ¾ mole) of 2,3-epoxy-3,6-diphenyl After adding 0.5 ml of methanol to ethyl hexanoate, it was added to 20 ml of dichloromethane, and 5 drops of boron trifluoride etherate were added. After 2 hours, the mixture was concentrated, and the residue was purified by MPLC (cyclohexane / ethyl acetate as a solution gradient). Thus, the first non-mirromeric isomer was 53 mg, and the second specular isomer 7 2 was obtained. 0 g and the mixture was separated into 800 mg. Example 3: 2-¾yl-3-methoxy-3,6-diphenylhexanoic acid (a mirror image isomer, stereo-21-the paper standard ί 州-¾ house standard 绛 (('NS) A4 ^ i77T〇x 297 ^ f) ----- ---------- (Read the back t note before filling in this page) Order 丨 · 546295 Α7 Β7 V. Description of the invention ( 19) A chemical unknown) Dissolve the second mirror image isomer (720 mg, 2.2 μmol) in 9 ml of dioxolane, and add 4.5 ml of a 1N sodium hydroxide solution, and stir the mixture for 16 hours. Then water was added and extracted with ether. The aqueous layer was acidified with citric acid and extracted with ether. The organic layer was dried over magnesium sulfate, and the solvent was evaporated, so that 9 3 6 g of oil was separated, and further reaction was performed immediately. Example 4: 2- (4-methoxy-6-methyl-2-pyrimidinyloxy) -3 -methoxy-3,6-diphenyl-hexanoic acid (a mirror image isomer) will be 195 Mg (4.4 mmol) 50% sodium hydride, 465 mg (1.5 mmol) 2-hydroxy-3-methoxy-3,6-diphenylhexanoic acid and 291 mg (1.5 mmol) 3,4-Dimethyl-2-methylsulfone pyrimidine was mixed in 20 ml of DMF and stirred at A for 2 hours. The reaction mixture was added to 1000 ml of ice-cold water, acidified with citric acid, and extracted with ether. The organic phase was dried over magnesium sulfate and the solvent was evaporated. Purification of the residue using MPLC (cyclohexane / ethyl acetate as a concentration gradient) allowed 103 mg of a mirror image isomer to be separated. 1H-NMR (200 MHz? CDC13): 7.1-7.5 ppm (10 H5 m)? 6.2 (1 Η, s), 5.6 (1 H, s), 3 · 8 (3 H, s), 3 · 3 ( 3 H, s), 2.5-2.8 (3 H, m), 2.3 (3 H, s), 2.0 (1 H, m), 1.5-1.8 (2 H, m). ESI MS: M + -436 Example 5: 2,3-Epoxy-3-phenyl-6- (3,4-methoxyphenyl) hexanoic acid, methyl ester (a mixture of mirror isomers) (44 millimolar) 1-phenyl-4- (3,4-dimethoxy) phenyl-1- -22- This paper is applicable to the national-national cockroach (('NS) Λ4ϋ (210X 297 Ϋ '-(Please read the precautions on the back before filling this page) Order 546295 A7 B7 V. Description of the invention (20 Butanone [sic] is dissolved in 50 ml of DMF with 8.3 g of methyl chloroacetate At 1: temperature, 3.7 g of 50% sodium hydride suspension was added to it in batches within the last hour. The reaction of the precursor was completed after 1.5 hours. The reaction solution was added to 3,000 liters of ice water to Citric acid acidified the aqueous layer and extracted several times with diethyl ether. The organic phase was separated, washed, and dried over magnesium sulfate. After evaporation of the solvent, 13 grams of oil could be separated, and it was immediately reacted further. Example 6: 2 -¾yl · 3- (2- (3,4-dimethoxyphenyl) ethoxy) _3-phenyldimethoxyphenyl) hexanoic acid methyl ester stirrer contains 3.6 g (10 mmol) Mol) 2,3-epoxy-3-phenyl-6- (3,4-methoxyphenyl) hexanoate Ester, 1.8 g (10 mmol) of 2- (3,4-dimethoxy) ethanol and 50 ml of methylene chloride mixture of p-toluenesulfonic acid for 1 hour, during which time the part was cooled in ice. The reaction solution was Add to a saturated sodium bicarbonate solution, separate the organic phase and dry over magnesium sulfate. Evaporate off the solvent, and use MPLC to purify 4 · 7 g of the obtained substance (gradient: cyclohexane / ethyl acetate). 750 mg of a mixture of mirror isomers. Example 7: Di-hydroxy ^-^-㈠ ^ -dimethoxyphenyl ^ ethoxyb ^ phenyl ... Quasi-stationary j-combination fi ϋ imprint 2.1 liters of 1N sodium hydroxide solution was added to 750 mg (1.4 millimoles) of 2-acyl-3- (2- (3,4-dimethoxy) Phenyl) ethoxy) -3-phenyl-6- (3,4-dimethoxyphenyl) hexanoate in 4_2 liters of dioxane solution, and the mixture was stirred at room temperature 1 6 hours. Add 100 ml of water to the mixture, and then extract with ether. Then neutralize with hydrochloric acid and extract with ether. 23-Paper scale: (； ((, NS) Λ4 size (fy 546295 A7 B7 21 V. Invention Clear the water phase, dry the ether phase with magnesium sulfate, and evaporate off the solvent. In this way, 62 mg of amidine can be separated and used immediately. Example 8: 2- (4,6-dimethyl-2-pyrimidinyloxy) ) -3- (2- (3, 'dimethoxyphenyl) ethoxy) -3-phenyl-6- (3,4-dimethoxyphenyl) hexanoic acid Ear) hydrogenated steel, 600 mg (1.14 mmol) of 2-hydroxy_3- (2- (3,4-dimethoxyphenyl) ethoxy) _3_phenyl_6_ (3 , 4-dimethoxyphenyl) hexanoic acid and 223 mg (1.2 mmol) of 3,4-dimethyl-2-methylpyrimidine [sic] were mixed in 10 ml of dmF and kept at room temperature After stirring for 6 hours, the reaction mixture was added to 100 liters of ice water, acidified with citric acid, and extracted with ether. The organic phase was dried over magnesium sulfate, and the solvent was evaporated. After purification of the residue by flash chromatography (cyclohexane / ethyl acetate gradient), 115 mg of a crystalline mirror isomer was isolated. Mirror isomer I: Melting point: 93-96 ° C ESI MS: M + = 630 Example 9: 2_ (4,6-dimethyl-2-pyrimidinyloxy) -3- (3,4-dimethoxy Methylfluorenyloxy) -3_phenyl_6_ (3,4-dimethoxyphenyl) hexanoic acid mirror isomer I: Melting point: 130- 133 ° C ESI MS: M + -616 Example 1 0: 2 -(4,6-dimethyl-2-pyrimidinyloxy) -3- (4-methoxyphenoxy) _3_phenyl_ -24- This paper is the China National Monument of Shizhou (rNS) Μ specifications (210X297 mm) 546295 ii Hummel 1V joint printing A7 B7 V. Description of the invention (24) Example 17 7: 2- (4-methoxy-6-methyl-2-pyrimidinyloxy)- 3- (3,4-dimethoxyfluorenyl-oxy) -3,6-diphenylhexanoic acid mirror isomer I: 1H-NMR (200 MHz, CDC13): 7.1-7.5 ppm (10 H , M), 6.9 (3 H, m), 6.25 (1 H, s), 5.75 (1 H, s), 4.45 (1 H, d), 4.35 (1 H, d ), 3.9 (3H, s), 3.85 (6H, s), 2.4-2.7 (3H, m), 2.3 (6H, s), 2.0-2.2 (1 H, m), 1.7-1.9 (2 H, m ). ESI MS: M + = 572 Example 1 8: 2- (4-methoxy-6-methylyloxy) -3- (2- (2-thiotetyl-ethoxylate) -3,6-di Phenylhexanoic acid 3: 1 mirror image isomer mixture

Decomposition: 85 ° C ESI MS: M + = 532 Example 19: 2- (4,6-dimethyl-2-pyrimidinyloxy) -3- (2- (3,4,5-trimethoxybenzene Group) -ethoxy) -3,6-diphenylhexanoic acid isomer I: 1H-NMR (200 MHz? CDC13): 7.0-7.3 ppm (10 H? M)? 6.65 (1 H, m ), 6.4 (2 H, s), 5.75 (1 H, s), 3. 9 (3 H, s), 3.85 (6 H, s), 3.5-3.7 (2 H, m ), 2.8-2.9 (2 H, m), 2.3-2.5 (3 H, m), 2.3 (6 H, s), 2.0-2.3 (1 H, m), 1.5-1.7 (2 H, m ). ESI MS: M + II 600 -27- This paper size applies to the Chinese national standard (ms) Λ4 regulations (210X 297 mm) (read the precautions on the back first and then fill out this page)

1T J ·. 546295 A7 __ V. Description of the Invention (25) Example 20: 2- (4-methoxy-6-methyl-2-pyrimidinyloxy) -3- (2- (3,4, 5-trimethoxy-phenyl) ethoxy) -3,6-diphenylhexanoic acid isomer I · · Melting point: 1 53-1 55 ° C ESI MS: M + = 616 Example 2 1: 2 -(4,6-dimethyl-2-pyrimidinyloxy) -3- (2- (4-hydroxy-3-methoxy-phenyl) ethoxy) -3,6-diphenylhexyl Acid mirror image isomer I: 1H-NMR (200 MHz, CDC13): 7.0-7.4 ppm (10 H, m), 6.9 (1 H, dm), 6.6-6.75 (3 H, m), 5.8 (1 H , S), 5.5 (OH), 3.9 (3 H, s), 3.85 (3 H, s), 3.5-3.7 (2 H, m), 2.8-2.9 (2 H, tr), 2.3-2.5 (3 H, m), 2.3 (6 H, s), 2.0-2.3 (1 H, m), 1.5-1.7 (2 H, m). ESI MS: M + two 556 mirror image isomers II: ESI MS: M + = 556 Example 22: A 屮-贞 准 消 f: Compatible with Vi ϋ (read the back, read the note, and then fill out this page) 2- (4-methoxy-6-methyl-2 -p denselyloxy) -3- (2- (4-¾yl-4 -methyllactylphenyl) ethoxy) -3,6- Diphenylhexanoic acid image isomer I: Melting point: 1 54-157 ° C 'ESI MS: M + two 572 Example 23: -28- This paper is suitable for Sichuan National National Monument (CNS) Λ4 standard orange (210X 297 mm 546295 A7 B7 Five 'invention description (26 yf1, ministry of ten countries j elimination f: total fi printed $) 2- (4,6-dimethyl-2-ylamino) -3- ( 4-Syridyloxy) -3,6-diphenylhexanoic acid image isomer 1 · 1H-NMR (200 MHz, CDC13): 8.0 (2 H, d), 7.1-7.5 ppm (12 H5 m), 6.8 (lH, m), 6.8 (lH, s), 4.6 (lH, d), 4.5 (lH, d), 2.5-2.7 (3 H, m), 2.3 (6 H, s), 2.1-2.25 (1 H, m), 1.5-1.7 (2 H, m). ESI MS: M + = 540 Mirror isomer Π ·· Melting point: 160-167 ° C ESI MS: M + = 540 Example 2 4: 2- (4-methoxy-6-methyl-2-pyrimidinyloxy) -3- (4-carboxybenzyloxy) _ 3.6- diphenylhexanoic acid mirror Isomer 1: 1H-NMR (200 MHz? CDC13): 8.0 (2 H? D)? 7.1-7.5 ppm (12 H5 m), 6.2 (1 H, m), 5.6 (1 H, s), 4.55 (1 H, d), 4.45 (1 H, d), 3.9 (3 H, s), 2.5-2.7 (3 H, m), 2.3 (3 H, s), 2.1-2.25 (1 H, m), 1.6-1.8 (2 H, m). ESI MS: M + di556 isomers II: ESI MS: M + -556 Example 25: 2- (4,6-dimethyl-2-pyrimidinyloxy) Base) -3- (4-methoxyphenoxy) -3,6-diphenyl paper size Shizhou Chinese national standard 磾 ((, NS) Λ4 size (210X297 mm) (谙 Please read the note on the back first Matters refill this page}

、 1T 1 #. 546295 A7 B7 V. Description of the invention (28) 4.2 (1 H, m), 3.85 (3 H? S), 3.8 (3 H? S)? 3.75 (3 H? S)? 3.4 (1 H, m), 2.4 · 2 · 7 (3 H, m), 2.3 (6 H, s), 2.0-2.1 (1 H, m), 1_5_ 1.7 (2 H, m). ESI MS: M + = 612 The compounds listed in Table 1 can be prepared by similar methods or by methods generally described. (Please read the precautions on the back before filling out this page) Φ Today and 11 paper sizes Shizhou China National Standards (rNS) Λ4 size (210X 297 mm) 546295 A7 B7 V. Description of the invention (29) HH 1 Η -* ΗΗ 1 Η- * 〇 hH 1 HH 1 00 HH 1 < 1 HH 1 Os HH i Ux HH 1 HH 1 U) HH 1 to 1-Η Pupil 2: 1 Ο ο ooooonoo Ο ο o O ooo O oo ο ο ο o O ooo O oo ο XXXKK sc KEXX ffi Office > ΐ Lh 1 1 4 ^ 1 1 -a Ch -9 -¾ pp 驷 ο O ooooo 〇in ο ο N ο ooooooo ο ο WX to K to ffi to XN) ffi hj X to ffi K) X to ffi K) κ Ν) X Κ) ο oooooooo ο ο W NJ ffi to ffi hJ ffi K) ffi ro ffi K) ffi to KK) ffi K) κ Κ) κ to ο oooooooo ο κ κ > X to XK) X to K to X to ffi K) EK) KK) X Κ) κ to 1 1 1 1 -¾ o KH -9 -a NJ LO 1 -¾ Zu 1 1 /-" N o -¾ U) o ffi to o K bo K NJ r \ VJX NJ 〇1 o K o K 1 1 1 o ffi to oo ίυ η Ε 1 z 2 1 1 1 z 2 2 X 1 Z 1 1 1 2 2 Z κ > κ ^ 1 1 H- ^ to 1 1 1 II ffi a * * * r * f -32-

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Rto This paper size applies + National Standard Binding (CNS) Λ4 gauge (210X 297 mm) 546295 A7 _______________B7 V. Description of the invention (3〇) HH 1 Ι-Η 1 1— (1 ΗΗ 1 ΗΗ 1 ΚΗ 1 ΗΗ 1 ΗΗ 1 ΗΗ 1 ΗΗ 1 ΗΗ 1 ΗΗ 1 1 tH 1 Η— (1 t— < 1 1 乂 K) 〇〇Κ) <! Κ) Κ) to 仁 Κ) Κ) Κ) to Η—ι to Ο Η— ^ οο 5: 1— * Η—k 払 H— ^ UJ H—1 to a 5 η Ο η ο η η ο Ο η Ο ο Ο η O Ο O o 〇ο ο ο ο ο ο ο ο ο ο ο Ο ο Ο ο ο o ο O 〇〇ο Ο ο ο ο ο ο ο ο ο ο ο ο oo X κ κ κ κ X κ Ε κ κ κ κ κ ffi κ K 舛 舛 τ Lh 1 II 1 1 III 4 ^ I 4 ^ I ί ^ 1 Lk) Lk) L * J Lk) 1 4 ^ 1 On -¾ -a ρ sound t sound τ ρ -ρ ^ 1 -Ρ ^ 1 I 1 -9 -¾ 1 1 1 II 1 kl · 1 l · 1 l · 1 l · 1 p \, \ j,. .Vi, 1 1 pi p 1 1 1 k, 〇〇 Ο Ο Ο ο ο Ο Ο ο ο ο Ο Ο ο o N 〇ο ο η η ο ο ο Ο ο ο Ο Ο η η nn dd K) X Κ) Κ) Κ ΚίΚΚ) κ KJ κ κ) κ to κ to κ κ) κ to ffi κ) ffi κ ) κ to κ Κ) ro K to 〇η η η ο ο η η Ο Ο ο ο ο η Ο nn ffi to κ to X Κ) κ κ) ffi to κ to κ to X to ffi κ) ffi Μ ffi Μ ffi κ) X Κ) κ κ) ffi to a to η ο ο ο ο ο ο ο ο ο ο η ο η Ο oo X to κ Κ) Ε κ Κ) κ κ) κ κ) X NJ κ to κ KJ κ Μ Ε to κ Κ) ffi κ > Ε to ffi NJ Ki K > 1 1 -θ I 1 -Θ 1 K) ρ ρ ρ ρ ρ p 1 ο rN 1 -¾ I 1 ο 1 -a, ^ sn κ Κ) Ο Ε, κ NJ Γ \ ffi Κ) Γ ^ \ Π Ϊ3 X to VJX κ > ο to Ο κ NJ VJ Κ to η \ J Κ to η K) o ffi ho {JK ro o 1 to ο Ο sw ^ 1 η κ η κ κ NJ η I 1 Ο κ ο κ. ffi NJ Ο 1 〇 an ffi o E to o Β Β 2 I 1 ζ 2 2 1 ζ 2 ZX 1 1 Zn 1 1 2 ζ 1 2 2 Z 2 to 1 1 Η- ^ III to Η— ^ III h—kh— ^ * I 1 1 BK a > rt '• clothing II (Read the back page first, 5-note the matter before filling out this page), 11 -33- This paper size applies to the Chinese national standard ((, NS) Λ4 specifications (210X 297 mm) 546295 A7 __ B7 V. Description of the invention (31) Η—1! 〇 \ 1-45 | ΐ-44 I-43 1-42 1-41 ΗΗ 1 ο 1-39 ΗΗ 1 LO οο 1-37 Η-Η 1 LO 〇 \ HH 1 U) 1 -34 1-33 1-30 HH 1 K) \ 〇ζ η Ο Ο Ο Ο η ο Ο ο Ο ο o 〇〇 on Ο n ο Ο Ο ο Ο ο ο ο ο Ο ο oo ο ο ο ο ο ο ο ο ο ο ο ο ο oo ο oo ο o X κ κ κ κ κ Ε X ffi κ X ffi XXK a K 舛 舛 舛 ψτ 1 1 1 1 1 1 LO U) υο U) OJ 1 1 1 1 I 1 σν 〇ο 〇- € -¾ -¾ V 1 VIV 1 V 1 V 1 V 1 -¾ -¾ -a 〇〇ο ο 〇〇l · l · l · l · l · l · ρ pi pi ρ ffi 1 κ 1 E 1 one one | 1 1 ρ pl 1 1 1 II r ο ο ο 〇〇 ο ο ο ο ο Ο oo ο 〇〇〇〇o Ο Ν ο ο ο ο ο ο η Ο η η oo ο η 〇η o Ο dd X Κ) Ε NJ X to X to X (Ο X Ν) X Κ) κ Κ) ffi κ > ffi κ) KK) X to X KK) Κ Κ) K NJ ffi Κ) X (Ό κ to ο η οο ο ο η η ο ο oo ο οo ο n ο κ Κ) κ κ > ffi to κ κ) κ κ) κ κ) κ κ) NJ ffi κ) κ Κ) ffi K) X to κ to X κ > KK) to ffi NJ X to ο Ο ο ο ο ο ο ο ο ο on ο ο o η 〇〇 ffi κ) a Κ) κ to X Κ ) κ to X to X to X Κ) κ ffi κ) ffi NJ ffi K) κ to ffi K) ffi K) X to XK) to -a 1 1 1 1 1 -¾ -¾ hO ρ ρ p -θ I 1 1 η I 1 ffi η κ n ffi η X Κ) ο K Ki η X η κ o Κ) ο ffi KK) ο ffi NJ ο ffi η ο ί ο η 1 1 ο ffi on 1 B n ffi O η NJ 〇 a κ κ X NJ 〇 ffi tr to η ffi X ζ 乂 1 ζ ζ 1 1 2 I 1 Z ζ X ZO 2 1 ζ 1 1 I 1 2 ζ κ; I Β fl 1 b〇! 1 1 B to 1 —K 1 I 8 S Het Complete this page)

、 1T f -34- This paper size is applicable to China National Standards ((, NS) Λ4 Regulations (210X 297 mm) 546295 A7 B7 V. Description of the invention 32 Ψ 4 \ like humble f: A ίΐ 印 HH 1 〇 \ 〇 \) —Η 祖 〇 \ Lh ΗΗ 1 Η—1 1 〇 \ ΗΗ 1 ο \ Κ) ΗΗ 1 Ον ΗΗ 1 ΗΗ 1 U \ Η— (1 LT \ 00) -Η 1 Lh ΗΗ 1 U \ ► —I 1 Lh Lh ΗΗ 1 Lh ΗΗ 1 Lh LO ΗΗ 1 U \ to ΚΗ 1 LT \ ΗΗ 1 Lh 1— (VO »—Η ▲ 1— 1 1 4 ^ ζ ο η ο ο ο ο ο ο η η η η ο η Ο η Π ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο X κ κ κ κ κ X ffi Ε κ κ κ X κ κ X κ X Offices and Offices ^ J \ 1 1 1 I ι U) 1 U) I 1 1 1 1 1 1 1 1 ι I ι 〇 ο η π η ο Ο Ο ο Ο ο iVUf -¾ iSUf 1 1 1 Ο ο η 〇ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ψτ Mr " Η ο ο ο Κ 1 κ κ κ X κ κ 1 κ 1 κ 1 κ 1 κ Cao ffi 1 ffi ι κ 1 UJ 1 υο 1 UJ IU) I UJ IU) 1 LO I LO Ή ~ ^ r Ή: -a -0 4 ρ ρ pi ρ-十 十 r Ο Ο ο Ο ο ο ο Ο ο Ο Ο Ο Ο ο Ο ο Ο Ο Ο Ο Ν 〇η ο ο ο ο ο ο ο ο ο Ο ο 〇η Ο ο η ο ο ο Ο WX Κ) Ε ro X Κ) κ Κ) κ ro ffi to Κ) ffi κ) Ε Κ) X Κ) X Κ) Ε Κ) X to X Κ) to X Κ) ffi κ > X to X Κ) X Κ) 〇η 〇 η ο ο ο ο ο ο ο ο ο ο ο ο ο ο ffi to κ κ) ffi to κ hj κ to κ NJ Ε Μ ίϋ Κ) X NJ ffi to ffi NJ κ to κ κ > a to ffi κ) κ Μ κ ro κ to κ ro ο ο ο ο ο Ο Ο ο η ο η η ο ο ο ο ο ο ο Ε Κ) κ Κ) κ κ) κ κ > X Κ) κ Κί X Κί Ε κ > ffi ro Ε Κ) ffi ho ro X κ > X Κ) XK) κ ro X κ > X Κ) X ro X ΪΌ -a 1 ο Ητ ^ ο 1 -S-€ I -¾ I -a 1 -S- ¾ I ι Κ) ρ u > ρ ρ ρ ρ 1 -9 -9 I -¾ -S 1 -a -a 1 -9 -¾ 1 -9 -¾ 1 I 〇U) ο X Κ) ο κ Ο ο 1 Ο Ο 1 Ο Ο 1 η ο 1 Ο ο Β Ο ο 1! Ο κ Ε κ ffi ffi κ κ κ κ κ κ ζ ζ 1 ζ ZE 1 ζ 1 ζ 1 ζ ζ 1 ζ 1 1 ζ X ZE 2 1 ζ 2 1 ζ ζ 1 乂 ζ 1 乂 ζ 1 ZZ乂 1 1 乂 1 III Κ) IIIIIII 1 to I— ^ 1 κ ο r- ^ -35- ** (Read the precautions on the back before filling in this page)

• Clothing ------ 1T ♦ The size of this paper is 1¾; the kind of thread _ ((, NiS) specifications (210) 097 mm) * —-----1 1 546295 A7 B7 V. Description of the invention (33) HH 1 ΗΗ 1 ΗΗ 1 ΗΗ 1 ΗΗ 1 HH 1 hH 1 1—Η 1 HH 1 HH 1 1 HH 1 HH 1 ΚΗ 1 ΗΗ 1 hH I ΗΗ 1 ΗΗ 1 ZZ 〇0000 U) 00 Κ) 00 00 • ο to Ο 1— ^ -0 ΟΝ Ό σ \ 00 σ \ 〇η Ο ο ο oo 〇 ooooo ο ο ο ο ο ο ο Ο Ο 〇 ο oo oo 〇 ο Ο Ο ο ο Ο ο oo ο ooooo Ο ο Ο ο ο κ Ε XXKK κ KKK a κ κ a ffi κ Office Ul to Κ) Κ) Κ) Κ) 1 K) 1 bO 1 to 1 K) i K) l to 1 b〇1 Κ) 1 1 1 1 1 I ζ ^ \ / ^ s: ψτ Ο ο ο η ο ο ο ο 1 -¾ 1 1 1 -S 1 -¾ 1 1 -s 1 1 1 I 1 ρ p -ρ ^ (> 4 ^ XI κ 1 1 I 1 1 LO ^ r U) 1 Ns «^ 1 1 1 1 1 1 1 1 1 Ο o ο ο ο 唞〇〇 〇 ο Ο o 〇 o 〇〇〇〇〇〇 〇 Ο Ο Ο Ο Ν η Ο η ο η o η noono Ο η η Ο η ω (Nj κ hJ X to ffi κ > κ κ) K to o X to ffi K > ffi hO ffi to to ffi Ki X to κ Κ) κ to ο κ NJ κ to κ to η ο Ο ο ο η o 〇ooo 〇 ο Ο ο Ο X to X to X to κ Κ) Κ Κ ) ffi K) to ffi NJ XK) K to ffi to XK) κ to ffi Κ) Ε to Ε Ν) Ε Κ) X NJ ο ο η ο η n η nnnoo ο ο ο Ο ο Ο ffi κ) κ Κ) X to κ κ > ffi hO ffi K) ffi κ) ffi K > ffi to KK) ffi to KK) ffi NJ Κ Κ) ffi hJ κ κ) X κ) κ κ) -¾ 1 1 -a -a 1 1 -¾ I Κ) ρ ρ ppp ρ ρ 1 1 -a -¾ 1 -¾ 1 η 1 UJ ο κ Κ) ο κ Ν) X NJ Γ \ X Κ) Γ \ o K κ Κ) / -Ν CJ Κ to Ο Κ J to η K) o ffi K) k J ffi Κί η η H2C) Ο κ ο κ 1 1 ffi ΙΌ η, ^ 〆o Pi__ 1 P! __ 1 CH κ Κ) ο 1 Zn ζ 2 1 1 2 1 2 ζ 1 2 1 X ZO ζ 2 1 1 z 1 1 ZO Zn 1 III 1 to 'w " 1- ^ I 1 1 1 1 I to III to Het -------- Φ water-* one (read the precautions on the back before filling this page) -36- This paper is suitable for Sichuan + National Standard Binding (rNS) Λ4 specification (210X 297 mm) 546295 A7 ________j B7 V. Description of the invention (34) 1 HH 1 HH 1 H— (1 HH 1 HH 1 HH 1 HH 1 HH Zu 1 1— (1 HH 1 HH 1 HH 1 1— (1 H— (1 1— (1 lH 1 Z 102 〇h-i 〇Ό Ό Ό 00 Ό ON LT \ Ό UJ 1- ^ o 00 00 oo OO 00 〇 \ 00 〇 nn 〇o 〇nn 〇oo 〇ononoo 〇oo 〇o 〇oo 〇oo 〇ooo O oo oooo 〇〇oooo 〇〇〇o 〇oo KKEEXEEKXXEEKX Office ψτ ψτ to 1 to 1 to 1 1 to 1 to 1 K) 1 to 1 K) 1 o / ^ s / ^ s / ^ NU) ^ -N LO U) NU) U) / 0 ^ U) / ^ s', 4 nn 〇oh 〇oh 〇〇价 ή -P ^ V 1 V 1 1 V 1 1 4 4 oooo 〇ol · l · l · l · l · l · p ρ XXKX ffi X -¾ -9 n λ λ sound t I 1 1 1 1 1 1 1 1 I k 1 1 1 驷 蝌 1 1 1 1 1 1 1 〇 〇〇〇〇〇〇〇oooo 〇〇O 〇〇〇〇〇 〇oooooooooon O ooooood (X to XK) to K NJ KK ) KK) K to K to K to KK) ro rc K) K h〇KK) K K > K NJ X to a (Ό η no 〇onoonn 〇onoonno X NJ X K > X K > E to X NJ K) X K > E to E K > XK) K NJ E NJ EK) X NJ K NJ E N-) a K) E to η noonoooo 〇n 〇O o 〇O o X to ffi k) K) ro ffi K) X Ki ffi NJ ffi to E K > ffi K) K to K) K) KK) K ro K NJ XK) K NJ 1 1 1 -¾ 1 1 -sn hri 1 1 M pi p pi Ή U > 1 1 1 / ^ NN -a 1 1 /-N o -¾ -9 1 1 Lh > n EK) OKK) o KK) o KK) 〇X o ffi K to K > OXK) K) oq ffi K) 〇o E 1 o 〇1 1 w O n 1 1 won 〇1 1 KEEKKX 1 z 1 1 2 z 1 1 2 z fl 1 X 1 1 1 ZZ 2 1 1 2 2 1 I bo 1 K) ^^ / 1— ^ 1 1 1 1 bo t— ^ 1 1 D 1 K) H— ^ X ft) (Please read the precautions on the back before filling out this page) -37- Size of this paper 1¾ State China National Standard ((, NS) Λ4 specification (210X 297mm) 546295 A7 _______B7 V. Description of the invention (35)

HH 1 1—Η 1 ΗΗ 1 HH 1 HH 1 HH 1 ΗΗ 1 HH 1 HH 1 HH 1 HH 1 HH 1 ΗΗ 1 HH 1 Η—1 1 κ— (j 1 1— ^ 1— ^ 〇〇Η- Η — * H— * 1— ^ OS Hh— ^ H— * h- ^ 1—i H— ^ Lk) Η— ^ Η— ^ Κ) 1—-k H— * 1— ^ o H— ^ < 〇00 H— * o Η— ^ H— ^ s Η— ^ 〇 h—1 '〇 U) η η Ο n 〇 n ο 〇onon η n η ο 〇ο 〇 〇o 〇ο o 〇〇o 〇ο 〇ο 〇〇ο Ο ooo ο ooooo ο o ο ο κ ffi m ffi K κ ffi a E ffi K κ K κ Ε 舛 舛 办 ^^^ u > 1 U) 1 U) I to 1 b〇1 K ) I to IK) 1 Κ) I Κ) I Os 1 t〇LO 1 t〇LO 1 ^ to UJ tree w ^ 1 払 w ^ 1 ^ /-VU)? / ^ S wv ψ V wv π price p price ^ ή VVV m berry ^ | n -¾ Review V In ~ S u ^ In -9 aaa _ ο ο κ I LO I _ o 0 ffi 1 U) 1 _ o 0 ffi 1 u > i 丨 声 t 博 声 rk声声 rk sound tk L · ^ 0/1 C 1 I pi -a Ο ρ p Nw ^ 1 1 1 1 O Ο C ^ Ο ο O oo Ο Ο oo oo Ο o Ο Ο ο Ν 〇ο ooo ο Ο oooo ο o Ο Ο ο WX κ > κ Κ) X KJ ffi K) ffi K) ffi bJ Ε Κ) tc KJ ffi K) E to K to κ to ffi to m to ffi Κ) Ε κ > η Ο oo 〇η ο oooo ο o ο ο ο κ Κ) κ ίο K to ro K ro κ Μ DC to KK) K to K to EN) κ κ > E N > κ Ν -> κ to Ν > η ο o O o Ο oon 〇ο 〇〇 ο X to X ίο ffi K) K K > EK) Ε Κ) ffi to ill ffi to ffi to X to κ Μ ffi N) X Ν > κ Κ) Ε 〇〇 1 1 1 1 -¾ 1 -¾ Κ) ppp ρ, 1 1 -¾ 1 -s 1 ^ • N -a 1 u > o ffi to o KK) o 1 ο n 1 o ο 1 on 1 ο O 1 ο η κ XKXK ffi κ ffi ίϋ X 1 2 z 1 1 1 乂 ζ 2 1 X 1 2 z 1 D zi ζ Z 1 弋 I 1 1 layer 1 1 shall I 1 1 I Κ CD (Please read the notes on the back before filling this page)

、 1T -38- This paper size applies to China National Standard Peak ((, NS) Λ4 specification (2I0X297 mm) 546295

A

7 B V. Description of the invention (36) 1-132 1-131 1-130 1-129 1-128 11-127 [1-126 1-125 1-124 1-1231 I 1-122 j _1 1-121 1 -120 1-119 2 COOH COOH COOH COOH COOH COOH COOH COOH COOH] COOH! _ ______1 COOH COOH COOH COOH COOH COOH phenylphenylphenylphenylphenyl 1phenyl 1 1phenyl | | phenylphenylphenyl I 1 phenyl 1 _1 phenyl phenyl phenyl phenyl phenyl phenyl phenyl phenyl 丨 phenyl J motif "phenyl phenyl 1 _______ J phenyl phenyl phenyl phenyl 1! 2- ( 4-hydroxy-3-methoxy-phenyl) -ethyl 2- (4-hydroxy-3-methoxy-phenyl) -ethyl 2- (4-hydroxy-3-methoxy-phenyl) ) -Ethyl 2- (4-hydroxy-3-methoxy-phenyl) -ethyl 2- (4-hydroxy-3-methoxy-phenyl) -ethyl 2- (4-hydroxy-benzene ) -Ethyl 2- (4-hydroxy-phenyl) -ethyl 2- (4-hydroxy-phenyl) -ethyl 2- (4-dimethyl-amino-phenyl) -ethyl 2 -(4-dimethyl-amino-phenyl)-| ethyl | 2- (4-diamidino-amino-phenyl) -ethyl 2- (3,4-methyldioxy -Phenyl) -ethyl 2- (3,4-methylenedioxy-phenylethyl 2- (3,4-methylenedioxy-phenyl | yl;)-ethyl 丨 σ \ 〇 〇〇 〇〇〇〇〇〇〇〇〇〇Ν ch2ch2ch2 η X 〇to ο 〇X 〇κ > ο κ K) ch2ch2ch2 ch2ch2ch2 ch2ch2ch2 ch2ch2ch2 〇K) 〇to ο to 〇to 〇K) η to 〇to 〇K K) 〇X to η to κ ch2ch2ch2 ch2ch2ch2 〇K Μ 〇X to ο κ K) do methoxymethyl1 methoxymethyl1 methoxy1methyl_1 1 methoxymethyl1 methyl Oxymethyl to methyl i! Methyl 1 1 _1 1 methyl methyl 1 methyl methyl 1 methyl methyl 1 methyl methyl OJ CH CH CH CH 1 1CH 1 1CH J 1 CH CH 1 t ' CH CH 2 Layer 2 1 1 1 X 1 2 1 1 1 1 1 1 1 1 1 1 1 K) 1 1 | Het -39- (Please read the precautions on the back before filling this page).家 国 i and ruler paper rule 4 Λ 5 Ν

Centimeter 7 9 2 X 546 295 A7 B7 V. Description of the invention Part 37 ii.

ΗΗ 1 HH 1 H— ^ HH I 1-147 1 1 HH 1 HH 1 HH 1 hH 1 ΗΗ 1) -Η)) — 1 1 ΗΗ 1 ΗΗ 1 ΗΗ 1 Η-Η 1 ΗΗ 1 Κ-Η 1 00 On払 S 4 ^ Η— ^ Ο U) Ό UJ ΟΟ LO Ον UJ LT \ LO 4 ^ UJ LO η nn 〇non 〇ο Ο ο ο η Ο η η η ο square ο ooooooo ο ο ο ο ο ο ο ο ο ο ο ο ooooooo ο ο ο ο ο ο ο ο ο X: EKKE Ε XX κ X κ XXXX 办 办 LO, LO V 1 It LO 1 il U) V 1 | i U) See it U) V 1 | i LO 1 h u > 1 II LO 1 II U) I | ι U) VI | ι UJ I Ιι U) 1 Ιι LO VI h LO V 1 It 1) -¾ 1 1 1 -¾ 1 -¾ 1 -¾ 1 1 -¾ 1 -¾ 1 -S 1 1 1 -ap pi p ρ ρ λ LO 4 ^ 1 1 1 4 ^ 1 1 -¾ -a -a V ^ 1 to 'Κ) 舛 人 _ fv On 1 -a V ^ /-ν LO l · ppp π _; 丨 l · pp 1 1 ρ ρ 1 LO r I 1 1 p 舛 oooo O oo ο Ο Ο ο Ο Ο ο Ο ο Ο 〇N noooonn ο η Ο η Ο ο ο η ο ο 〇tjd XK) KK) KN ·) ffi K) X NJ X h〇XK) X Κ) ffi ΪΌ X KJ κ Κ) κ Κ) κ Κ) κ Κ) X Κ) X to ffi κ) ffi to nooo 〇o O ο Ο ο η Ο Ο Ο η ο ο n X EK) ffi X ffi NJ ffi K) X Κ) X Κ) κ KK) X Κ) ffi to ffi KK) X Κ) ffi to ffi κ) X Κ) ffi K) O oooo 〇n ο η ο η ο η ο ο ο o ffi K) K t ^) KK) X to ffi ro E to ffi to ffi κ) κ) ffi to X Κ) ffi to κ NJ X to Κ) to κ NJ ffi K) 1 -9 1 1 1 ~ 0 ο ΗγΗ 1 1 hO pp ρ U) ρ ρ, 5 n 1 -¾ 1 1 1 / —Ν 5 Ο -θ 1 -a -a 1 U) o K ο κ X Ki o κ to ο n OX 1 〇o 1 I 1 ο Ε ο ο η 1 η η 1 ffi ffi K) OK ffi ffi Κί Ο ffi κ X κ ffi o ffi to η ffi to z 2 1 1 1 1 Z ζ ζ 1 2 1 XZ 1 1 I 1 Zn 2 ζ 1 ZZ 1 & l t; 1 1 1 to to * 1 1 H—1 1— ^ * to * Η— ^ 1 1 1 I I to I I vw ^ K a > r-K (Read the precautions on the back before filling this page)

、 1T -40- This paper is suitable for Sichuan National Standard (rNS) Λ4 specification (210X 297 mm) 546295 A7 _______ B7 V. Description of the invention (38) HH 1 1—Η 1 ΗΗ I Η-Η ΗΗ ΗΗ 1 Η-Η 1 hH 1 h—1 1) —H 1 HH 1 hH 1 HH 1 H- < 1 KH 1 HH 1 hH ΗΗ 1 2 Η— ^-< 1 os Os ι— ^ Ον 1— * 〇 \ 払 〇 \ LO Η— »〇 \ to Η— ^ 〇 \ 1— ^ ON ^ t \ oo (-^ H— * U \ 〇 \ t— ^ H- * ΟΊ (— * LO h— * to Η— »^ Τ \ ι— ^ η Ο Ο η Ο ο onnonnnn O ο Ο 〇〇 〇 ο Ο 〇 〇〇〇〇o 〇O o 〇o ο ο 〇〇 ο ο ο oo ooo O ooo ο ο XXXX ffi K aa XKEE a EXX 舛 U) VI 1, VI \. Lk) IU) V Β \. LO VI 1. U) V 1 1. LO V 1 1. LO 1 1, LO V 1 \. 1 |, LO 1 \. UJ V 1 \. LO 1 1. LO V 1 t. LO V 1 LO V 1 1. LO V 1 1. LT \ Ρ Ρ -¾ Ρ Ρ Ρ Ρ -a P -a P -a PP -¾ PP -9 P -¾ P l · -9 Ρ Ρ -a ρ ρ \ ρ ρ pppppp ρ k η kk 1 I 1 1 1 1 1 1 4 ^ 1 1 1 -P ^ 1 1 1 U) UJ UJ 〇 -¾ -a sound T sound T sound r sound 1 1 -P ^ I, Vj., Vj, ρ, Vj, 1 1 1 1 1 1 l · 1 l · I l · 1 1 ψ- 1 ψ · 1 -a -¾ -9 pp ρ 1 ι ι ο Ο Ο Ο 〇Ο O 〇 O o O ooo Ο Ο Ο Ν ο ο ο Ο η Ο o Ο ooonno η η Ο ω κ κ) Κ to Ε h〇ffi Κ) Κ Κ) Ε Κ) X to KJ ffi K) X to K to K NJ KK) K to X hO Κ) X Κ) Ο η η ο ο ο n η onon O o Ο ο X NJ κ NJ Κ X Κ) κ κ) κ κ > ffi NJ X NJ K to K b〇K ffi K) K NJ KK) κ to Κ Κ) X Κ) ο η η ο η ο n Ο nnnon O η ο η X μ κ to κ ΙΌ Ε E to E Κ ·) NJ K to NJ X to E to E K > Ε Κ) Ε κ > κ NJ -9- 9 -¾ 1 1 1 1 -9 1 to ρ ρ pp ρ ρ 5 Ο 1 5 Ο 1 / ^ N o 1 1 -¾ ^ 2 〇1 UJ X ο κ NJ Ο 〇 an K to κ Κ) 〇 X η ο 1 X ο ffi to ion O ffi K) 1 1 o 〇X 1 ο ο XX ο ffi ffi ffi κ κ t ^ J KK) ο oa KK) ζ ζ 1 2 1 z Z 1 1 2 Z 1 X 乂 ζ ζ 1 ZZ 2 1 XZ 1 1 2 Zn 1 2 弋 III ^ to 1 1 K—k 1 1 1 to 1 1 1 Η— ^ IX ι— ^ * 〇 (Read the precautions on the back before filling in this page) Order -41-This paper uses the Chinese national standard ((, NS) Λ4 specifications (2 丨 OX 297 mm) 546295 A7 B7 V. Description of the invention (39) 1-185 11-184 11-183 1-182 11-181 I | l-180 | l-179 | l-178 | l-177 | l-176 l1-175 1 1-174 1-173 | 1-172 1 I1-171 1 | I-170 | I-169 | ΐ-168 乂 * -5 〇η η ο η o 〇ooonn η no 〇η 〇ο ο ο ο ο ooooo 〇〇ο 〇oo ο ο ο ο ο ο ooooooo ο ooo ο KXXX Ε ffi ffi ffi X ffi a X a κ a X ffi κ ψτ Office V 1 \ {U) VI \ , U) VI \, LO VI \. U) VI 1. LO V 1 l, LO 1 \, LO 1 1. UJ V 1 \. LO 1 \. LO 1 1. LO 1 1, LO V 1 \. Lk) 1 1. LO 1 1. LO V 1 1. LO V 1 \. LO VI 1. P Ρ Ρ Ρ PP PP -Θ I1 -9 PP -¾ PP -¾ P -s Ρ -¾ I1 P -9 P -¾ ρ p ρ ρ ρ ρ pppppppppppp ρ kkkkkk Office 1 1 1 4 ^ I 1 1 4 ^ 1 4 ^ 1 1 U) LO uj LO U) -f ^ 1 1 1 〇ο ο ο ο o -a -s 4 ^ 1 1 1 1 4 ^ 1 V 1 -9 -S 〇〇ο ο ο ο ο ο ool · 1 l · 1 l · 1 l · 1 l · 1 l · 1 p ρ ffi 1 ffi 1 Ε 1 X 1 Ε 1 ffi 1 4 ten -a -s -¾ -a ten rpp pi p 4 ο ο oooooo 〇ο O 〇o Ο ο Ν 〇ο Ο ο ο o 〇O oo 〇o η ooo Ο ο ω K to ffi to X Κ) X Κ) X Μ K to K) K) K to E to X NJ to X to ffi NJ KK) E to κ Κ) to 〇η ο ο ο noooonn ο o 〇o π ο K to Κ) Ε Κ) ffi hJ Ε Κ) ffi K) ffi K) X to ffi K) ffi K) K to ffi K > X Κ) K to XK) KK) κ Κ) X to η η η ο ο ooonono ο ooo ο ο Κ Μ X Κ) X to κ κ > X to KK) XK) KJ KK NJ K to KK) κ Κ) NJ K NJ E to κ Κ) X NJ 1 1 -a -¾ 1 -¾ 1 1 -S -¾ 1 I -¾ Κί ρ pi p pi 1 1 -s 1 -a 1 1 5 η 1 1 u > Ο Ε o X ο X Κ) η X ο X ro 1 1 ο X ο n 1 no 1 1 o ffi on 1 1 Ο κ NJ η ffi ffi X a ffi K) ο ffi tr ffi η X Κ) o κ Κ) ο 1 1 Z ζ 2 1 z 2 1 1 2 2 2 Z 1 1 X 1 ί 2 1 z 1 1 Z 2 1 i Η— ^ 1 I 1 1 1 1 l ~ * 1 1 1 1 K) 1-^ 1 ( (Please read the notes on the back before filling out this page)

、 1T -42- The paper size is suitable for the Chinese national standard ((, NS) Λ4 specification (21 OX 297 mm) 546295 A7 B7 Ministry of Inferiority Bureau 17 ,, / nfr He still printed shirt ^ V. Invention Explanation (4〇) HH 1 to 〇Ι-Η 1 Κ) ο private hH to ο LO ΗΗ 1 Κ) g ΗΗ 1 Μ Η- ^ ►—1 1 Κ) ο ο hH 1 ΗΗ 1 Η—1 00 ΗΗ 1 ) — ^ ΗΗ 1 h—k σ \ ΗΗ 1 Η—1 Lh HH 1 Η—λ Ό RenΗΗ 1 μ— * MD LO tH 1 h— to ΗΗ Η Η— * ΗΗ 1 ο ΗΗ 1 h— ^ 00 ΗΗ 1 Η— ^ 00 00 ΗΗ 1 1— ^ ΟΟ ΗΗ 1 Ον 2 η ο η ο ο ο ο η ο ο ο ο ο η η η ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο Ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο κ X κ X κ XX κ X κ κ κ κ κ ε κ κ X ε κ κ κ ηη DO Lh) U) U) LO Lk > U) V 1 1, U) V 1 1, LO V 1 I. LO LO U) LO U) V 1 \, U) LO LO LO LO u > U \ I 1, V 1 1, 1 1, 1 1, 1 1, 1 \, 1 1. 1 1. 1 1. II 1, I 1, II 1 I. V 1 1. Ρ Ρ Ρ Ρ -a Ρ -S Ρ Ρ Ρ I1 -¾ Ρ Ρ -a Ρ -a I1 -a Ρ Ρ Ρ -¾ I1 -8 Ρ Ρ I1 pi pi ρ ρ ρ ρ ρ ρ ρ ρ ρ ρ k η ο ό ο η ο ό ο ή ο ό ο h ο -Ρ ^ η ο ό ο ο LO 1 ο ο κ 1 LO I η ο ο Ε 1 U) I Ο ο ο Ε 1 4 ^ -a -Ρ ^ I 1 4 ^ 1 sound τ ON ο X UJ ο ffi ΰ) ο κ U) ο XU) ο ffi heart ο X ΰ) ο κ ΰ) ο κ UJ ο ffi L * J ο X ΰ) 1 1 1 4 ^ Avoid ρ ρ ρ ρ ρ ♦ Mr 蝌 蝌 ο Ο Ο ο ο ο ο ο ο ο ο ο ο Ο Ο ο ο ο N ο Ο Ο Ο ο ο ο ο ο ο η η η η ο η η ο ο η dd κ κ X ffi ffi ffi XXXXXXXX ffi XXXX κ ο η η Ο ο ο ο η ο ο η ο ο ο η η ο ο ο ο ο Ε Κ) Κ Κ) X to Κ Κ) X ho κ to κ Κ) κ Κ) Ε NJ ffi to Ε NJ Ε tsJ ffi to Ε to κ NJ Κί X Κ) κ κ) X to X to ο Ο η ο ο η ο ο ο ο η η η ο η η Ο η ο η κ κ) κ NJ κ Κ) Ε Κ) κ κ) κ κ > ffi κ) X Κ) κ κ) X to X ίο κ to X κ) X κ > κ) κ) κ to X to to 1 1 ο ΗτΗ ο 1 -¾ 1 -a 1 ~ a 1 K) ρ ρ U) ρ ρ ρ pi 5 η 1 1 1 -a 1 I -S 1 X ο ο κ 1 Ο ο 1 ο ο 1 ο ο 1 ο ο 1 η η 1 ο n κ ο ffi ffi Μ κ ffi κ κ \ κ κ ffi KX NJ 1 1 1 乂 1 1 2 1 ζ z X 乂 1 ZZ 1 ζ 1 1 1 乂 1 z 弋 1 0 Κ) I 1 h—k 1 1 KK) 1 1 Κ) I 1 II to 1 1 (read the precautions on the back before filling this page) -43- This paper is applicable to the standard + national standard 埤(RNS) Λ4 specification (210X 297 mm) 546295 A7 B7 V. Description of the invention (41) HH 1 ΗΗ HH HH HH 1 Η—1 1 ΗΗ 1 ΗΗ 1 ΗΗ 1 ΗΗ 1 Η-Η 1 ΗΗ 1 HH 1 hH 1 HH 1 HH 1 HH 1 HH 1 2 K) K) LO Κ) Κ) Κ) K) bO 1- ^ bO K) o K) VO to oo Κ) Κ) 〇 \ Κ) h—k Κ) 払 Κ ) LO Κ) to to 1—i to »— * o to s K)% K) o K) 〇η n o 〇 η ο ο η η ο 〇onnon 〇ο oo 〇〇ο ο ο ο ο ο οooo O 〇〇ο oo 〇〇ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο UJ UJ UJ U) U) U) 1 I. U) I \. LO I \, U) LO LO UJ U) 1 Lk) 1 1. U) 1 \. LO LO LO 1 \, 1 1. V 1 t. 1 1. 1 |. 1 1. I 1. I 1. 1 1 1 \. V 1 1. P Ip I1-«I1 I1 P -a P -¾ P P -¾ P P I1 I1 l · -s P -¾ l · PP -9 p ρ pkkk K) to K) K) to to Κ) to y ^ \ Κ) to to to K) to On 4 ^ 1 " ί ^ kk C > VII -¾-€ -¾ ppp ρ 1 See 1 1 1 1 hk vw 1 vw / ΐ C > C > ο oooo ο Ο Ο Ο Ο 〇 〇o O oooo N ο ooon ο ο Ο ο η ο 〇noooonw Ε Κί X rj XK) XN) XK) κ Κ) κ κ) κ Κ) X > ffi Κ) ffi Κ) X bJ X KJ EK) ffi K) EN) ffi r〇XK) ο oon O η ο η ο η ο η ooono OX μ to X to ffi K) X NJ Κ Κ) X Κ ) Κ) κ Κ) PC to X Μ Κ) K to to EK) XK) K NJ KK) ο oono ο ο ο ο ο ο ο onon 〇o κ Κ) ffi K) E to E to X K > ffi NJ ffi to X Κ) κ Κ) X Κ) ffi to ffi to KK) KK) X to X NJ K to X to η μ-Η 1 1 -a 1 1 -a -a 1 -s 1 K) U) p ρ ρ pp -a 1 1 5 o I 1 5 ο 1 -9 1 LO 〇E to EK) n κ Κ) ο 〇 ffi Ν > η 1 1 OK K > ffi K) n Ο η I 1 X η NJ O o 1 〇n 1 n κ Ε ffi ο X 'KKXK n' w ^ XK) Ε to η 1 1 1 1 1 zz 1 z X 1 1 Zn 1 1 1 z 1 z I to H— * 1 1 I 1 Κ ) Η— ^, * 1 I 1 1 to 1 to I ffi CD rf · (Read the precautions on the back before filling this page) -44- This paper is suitable for Sichuan + National Standard Binding (rNS) Λ4 specifications ( 210X297 mm) 546295 A7 B7 V. Description of invention (s if: quasi-offset 1V A bamboo Imprint 42 1—Η 1 to t—1 ΗΗ 1 to 0 ΗΗ 1 Κ) Lk) ^ 0 lH 1 K) OJ 00 I—H 1 K) Lk) * < 1 1-1 1 K) OJ ON Η- Η 1 Κ) U) ^ Τ \ ΗΗ 1 to LO HH 1 K) LO Lk > hH 1 K) U) K) HH 1 K) U) 1- ^ HH 1 b〇LO 〇lH 1 K) to Ό 1 --H 1 to K) 00 lH 1 to to HH 1 K) Κ) Η-Η 1 to Κ)) -I 1 K > K > 2 > -s η η 0 n 0 〇η 0 〇〇〇〇〇 n 〇η ο n ο ο 0 0 0 O ο Ο OOO 0 OOO ο ο 〇ο ο 0 〇0 O ο Ο OOO 0 OOO ο ο 0 ffi X KK KK ffi X ffi KX ffi K ffi ffi KX κ ffi ψτ 1 1. LO I 1, U) 1 1, U) V 1 1. U) 1 \. U) VI 1. U) I 1. U) V 1 1, U) V 1 1. U) 1 U ) V 1 \, LO 1 LO 4 ^ 1 1. LO V 1 Lk) 4 ^ 1 1. LO VI LO VI ι. LO 1 1. I1 Ρ Ρ -0 PP l · I1 P I1 I1 -9 I1 l · I1 -¾ I1 -¾ I1 I1 I1-€ I1 p ρ ρ ppp ρ ppppppp ρ pi kkkkk 唞 K) person to to / ^ s to to bO Κ) 1 to Q 1 to to interest K) 1 K) ^ a ^ A On f " -1 ^ -i ^ 4 ^ sound t -¾ Ο Ο Ο 〇OO n 0 0 〇〇o 〇OO h 0 0 X 1 '4 ^ 1' 丨 • 丨! '' 1 'Ss «^ cooked κ XKXX- ¾ -¾ -¾ -¾ -¾ hhkhhhpp c > 1 wrapped 1 Di 1 (> (S (> 〇0 0 OO ο ο O 0 0 0 〇ό 0 6 ό 6 ό N η η 0 〇〇ο η n 0 0 0 〇o 0 ο ο no ω X Κ) X Κ) KK) XK) ffi to ffi KK) X ro E to XK) K) ffi to to ffi K) to K) Ε to X ro E to η η 0 〇0 ο 〇 〇〇00 〇n 0 0 ο 0 0 〇X Κ) Ε Κί X NJ K Ki ffi K) κ Κ) Κ KK) KK) ffi to ffi K) K to K ffi to E to X to ffi Κ) XK) X t〇η η 0 nn ο ο 0 0 0 0 n 0 n 0 ο 〇〇κ ίΌ κ Κ) E ro EK) K ro κ to κ κ) EK) E to EK) X to XK) X to κ ro Ε NJ K > K ro 1 -¾ -¾ 1 1 1 -a -¾ 1 1-€ -¾ -Q -¾ to ρ ppp 1 -9 -9 1 1 1 5 n I 1 5 〇 u > 〇ffi NJ 〇η X to κ to 〇 I Ο n 8 n η 1 ί n ffi K > K 0 0 1 1 η ffi n 〇ffi XKX na ffi flood 0 XK 0 K bO ο κ κ > 1 z 1 ζ 1 1 z 2 1 1 2 z ZX 1 2 1 2 ζ 1 1 Z z 1 1 2 z Z 弋 to, ^^ 1 1 ^ 0 1 I to) — ^ · 1 1 1 1 ^ 0 H—A 1 1 1 1 K 〇rf -45 (Please read the precautions on the back before filling out this page) 、 1Τ This paper is not used in China National Monument (CNS) Λ4 specification (21 OX 297 mm) 546295 B7 V. Description of the invention (43 sample standard bureau J1 Consumer A India HH 1 Η-Η 1 ΗΗ 1 ΗΗ ΙΙ-Η 1) —1 1 1— Η 1 1—H 1 1—H 1 lH 1 hH 1 HH 1) —1 1 Η-Η 1 ι—ι I 2 b〇 ^ r \ 〇 \ Κ) ΙΜ Κ) Κ) U) Κ) U \ Κ ) Κ) Ln 1— ^ b〇Ln ο to K > oo to Os to K) Ren KK) hJ NJ BU t η Ο Ο Ο Ο Ο Ο Ο o 〇onoo ο n ο ο Ο Ο Ο Ο Ο O 〇oo O 〇oo O o ο O ο ο ο ο Ο ο Ο oooooo ο OX κ Ε XXX ffi XEEXK η η 舛 u > U) U) U) U) υο U) Lk) U) U) LO LO υο U) U) I) «. Private 1 \. 1 t. 払 1 1, V 1 1. V 1 ι. V 1 1. V 1 I. V 1 t. V 1 \. V 1 1. 1 1. V 1 1. V 1 ι. V 1 i. Ρ Ρ Ρ -9 Ρ -¾ Ρ -9 PPP PPP-¾ PP -9 P- ¾ Ρ P -9 ρ ρ ρ ρ ρ ppppp ρ p 1 I 1 1 1 1 1 1 1 1 1 k ¥ r Μ 粑 AV LO U) yj U) ρ UJ h U) h Lk) h V ^ C ^ Price K) p κ > p Κ) ρ to Lk) On > ο > V a 3 > ac ^ ό VVVV -¾ to ψ \ h ί, to ψ Μ Κ) ψ L · ^ Τ \ W ah _ g X _ g X ^ 〇1 i 丨 声 t 1 ί 丨 1 卜 I ί 丨 -9 ~ \ η -a U) 1 ΰ > l · pl · p ψ pp ρ -½ -¾ I hire 1 pp Ψ pkk ο ο Ο Ο ο Ο oooooo 〇Ο ο Ν ο ο Ο Ο ο η n O noo O η ο ο W κ to X to Ε to K Κ) Κ Κ) Ε Κ) K to KK) XK) KK) K K > E to Ε to Ε Κί κ Κ) Ο Ο ο ο ο η onooo O η Ο Ο κ κ > X κ) X κ > Ε) Κ) κ to X NJ KK) K K > to EK) X EK ) Ε Κ) Ε Κ) ο ο η ο ο ο 〇ooooo η ο ο X Κ) κ Νί Κ Κ) Κ Κ ) κ > κ to K to KK) ffi to K Ki K K > K) X to to Ε to -S 1 -a 1 -9 -s 1 -¾ 1 -¾ NJ ρ ρ pp ρ -S 1 -9 1 -Θ 1 1 ^ \ -¾ -¾ UJ Ο κ to ο ο I Ο ο nn 1 no 1 η η Ο ffi κ ffi X ffi KX, ffi X κ) η X ffi ζ I 2 2 1 Z 2 1 2 1 ζ ζ X 1 2 1 z 2 1 2 Z 1 ZZ 1 I 1 I 1 1 1 1 I ι K CD 46 (Please read the precautions on the back before filling this page) 、 11 This paper size applies to Chinese national standards埤 （（、 阳） / \ 4） （210 '乂 297mm） 546295 A7 B7 V. Description of Invention 44

I quasi

Cancel fc joint V

ΗΗ 1 HH 1 lH 1 HH 1 hH 1 Η-Η 1 1—1 1 ΗΗ 1 HH 1 HH 1 lH 1 Η-H 1 ΗΗ 1 Η-Η 1 z to 〇to Ov K > G \ 00 K) 266 Κ ) ΟΝ Lh to Os Κ) 〇 \ UJ 262 K) ON H- K > On 〇to U \ o Κ) U \ 00 to KJ \ 〇Π 〇〇〇η n η 〇o 〇n ο ο OO oooo ο 〇 ο oo 〇〇〇 ο Ο 〇ooo ο o ο ooo 〇ο ο KKKKXKX a XX ffi κ a η 1 U) 1 U) V 1 LO 1 U) 4 ^ 1 LO IV 1 LO I LO V 1 LO 1 LO V 1 U) 1 LO V 1 Lk > V 1 Ul l · l · -¾ l · l · -¾ l · -¾ l · l · l · -¾ l · l · l · l · l · pppp ρ p ρ pppp ρ p 1 I 1 1 1 I kkkk ^ A Al + K) Γ \. + to Γ As Al + K) ^ As 粑 A you A to to K) ^ a ^ A On ^ f " ~ χ -h Q l · l · yah > γ \ x X o L · i i ^ r \ liji m siu ^ siii * ml · i 丨 ~ 9 ^ p \ ΰ > U) ΰ > kk -¾ ψ ψ -9 1 I 4 4 im command skirt ρ p ρ (> (> ψ P p I p 1 p 1 h 1 1 6 〇oo 〇 o ο OOoo 〇 Ο 6 o N nono ο o Ο nono Ο η o dd X K > X to X K > XK) Ε Κί ffi K) X to KK) X NJ ffi K) K to ffi κ) X Κ) X K > no O n η o η O 〇o O ο η o X NJ X to ffi K) ffi K) X ίΌ K to X to K to E NJ KK) KK) ffi to ffi Κ) ffi to nooo ο n Ο nnoo ο η o X ro X K > X ro K ro κ to X NJ κ NJ X ro X ro K K > E NJ κ NJ κ KK) K NJ 1 -9 1 1 1 -a 1 ppp ρ 1 -¾ 1 1 1 -a 1 U) 〇1 o 〇1 n Ο 1 no 1 ο ο 1 X a ffi K a ffi ffi, κ X z 1 z 1 2 乂 1 1 1 X z 1 1 1 1 2 1 κ; 1 H—fc I 1 1 1 1 1 bo 1 I to X CD (Read the precautions on the back before filling this page).

、 1T 47- This paper size applies to the Chinese national standard cockroach ((’NS) Λ4 size (210X29 * 7mm) 546295 A7 B7 V. Description of the invention (45 Ministry of Standards Bureau j Consumer f: Joint printing)

Ι-Η 1 HH 1 HH 1 HH 1 hH 1 hH 1 1—H 1 ΗΗ 1 HH 1 ΗΗ 1 ΗΗ 1 hH 1 ΗΗ 1 ΗΗ 1 HH 1 Z to 00 U \ to 00 Μ 00 OJ κ > 〇〇to K > 00 H— ^ to oo o to Κ) K) Κ) to to LO INJ to to ►—k 〇 〇〇〇〇〇〇〇o ο Ο ο ο ο ο ο o Ο 〇〇〇〇 o ο ο ο ο Ο ο Ο 〇〇; 〇〇Ο o O o ο ο ο ο Ο ο 〇 〇κKX ffi XX a ffi ffi κ a κ a X a SsLA- -ί ^ γ ^ Ύ ι y ^ y ι Office ~ 9 Office ~ 9 -¾ Office ~ 9 ρ p ρ U) U) -P ^ I l · 1 l · ρ p 1 -a -9 -¾ -a -s -3 CSUnON ψτ ^ γι 1 '(丨 〇 〇〇oo ο ο ο Ο ο ο ο ο o N η 〇〇oo 〇η ο ο Ο η ο ο O ω X Κί KK) ro K N-) XK) K to κ ro κ to Ε to X to X to κ to κ NJ X Κί E to ο 〇〇onn ο ο ο Ο ο ο η o X Κ) ΪΌ EK) X to XK) X to ffi Κ) E Κ) X Κ) X to X Κ) Ε Κ) X Κ) X ro X ro ο 〇〇η n ffi to ffi bO K to X to ffi to 1 I -s 1 1 -¾ I NJ pi ρ ρ 1 1 1 1 5 η -9 1 LO η κ ffi κ) η 1 〇〇1 no 1 1 η ο κ ο η 1 n XXXEX Ε to ο 'Κ XX η κ to f 2 Z 1 z 1 1 ζ ζ 2 1 z X Session Z 1 1 Hire 2 1 1- ^ 1 1 1 1 to ι sleep ι ι ι 1 K CD (read first read the back of the (Please fill in this page again)

、 1T 48- This paper size is applicable to China's national standard ((, NS) 规 4 gauge (2) 0X 297 mm) 546295 A7 B7 V. Description of the invention (Ministry of Inferiority and Convergence 46 ΗΗ 1 HH 1 HH 1 Η—H 1 HH 1 h— (1 1— (1 lH 1 HH 1 Ι-Η 1 1— (1 Ι-Η 1 Η— (1 »— (1 2 Κ) Ό K) 00 to K) Ό ON to Ό Lh to K) uo K) K) to i—k Κ) Ό ο Κ > οο to οο οο Κ) οο Κ) 00 η 〇〇no 〇〇〇o η η ο ο η 〇〇O oooo 〇o Ο ο ο Ο ο 〇〇O oooo 〇o ο ο ο ο ο XX ffi EK ffi ffi κ κ X κ a Office Office Office--a Office Office-0 pi L / ϊ 1 LO 1 U) 1 U) 1 LO 1 U) VQ r ^ r QK) 1 Κ) 1 / —Ν Is) 1 2 (3, 'ethylσ \ WW www VC ^ V ^ V 1 4 ^! 1 exclusive respect_ γι γι l · l · l · Ww W -Θ -¾ -9 1 ο 1 1 ο p 1 1 1 1 1 (/) 1 1 (Λ) l " '" Ί ⑺ h- * 1 1 1 Ο ι_ ^ ο 1—J Ο l_J 1 1 1 〇〇ooooo 〇〇 ο Ο Ο 〇〇N 〇〇nooonn Ο ο Ο Ο η 〇dd PC K) X to XK) KK) KK) EC to X K > X NJ κ κ) Ε κ > κ κ ) κ ΙΌ Κ) E to 〇〇O ononn Ο ο ο ο ο 〇XX ffi KX ffi ffi ffi XXXX ffi ffi 〇〇ooooon ο ο ο ο ο η K NJ to ffi K) a K) K) K t 〇KK) κ Κ) κ ί〇NJ κ ίο Κ) ffi to -¾ -¾ -¾ 1 -0 I -a I -s NJ pp ρ -¾ -9 1 I -¾ 1 -¾ u > n ffi K K > o 〇X 〇ffi t ^ T no B o OI η ο 1 η o XK) oo ffi X ffi ffi K κ a κ E NJ o Z zz 1 z 1 ζ ζ 1 ζ XZ 2: 1 z 1 ζ 1 ζ 弋 1 1 1 I 1 1 1 ^ κ > I 1 to I 1 X a rK 49 (Please read the precautions on the back before filling out this page), 1T This paper is suitable for Sichuan China National Standards (CNS) Λ4 specifications (210X 297 mm) 546295 A7 B7 V. Description of the invention (47 ^ Partial quasi-consumption t: The size of the joint paper is applicable to China House Standard Binding (rNS) Λ4 gauge orange (210X 297 mm)

1 * Η2Λ4,5 丨 hf 2 * " 2- (4,5-Buhu ^ None ^; 10 H— (1 U) 〇K) ΗΗ 1 UJ Η— ^ ΗΉ 1 UJ 〇 2 Π 〇〇〇〇 ο ο κ η ο ο ϊ: π ψτ 1 1 丨 ^ | \ ψτ 1 U) WI LO m Os 〇ο ο Ν 〇Κ) 〇ffi hJ η Ε ίΌ η κ ί〇ο ffi κ) η X Ν ·) ο X Κ) η ffi to η κ NJ ω 1 1 hj -a 1 1 u > η κ 1 1 1 1 X 1 1 1I Κ) Ν ^^ K CD (Please read the precautions on the back before filling this page) 546295 A7 B7 V. Explanation of the Invention (48) Example 1 2 The receptor binding data obtained by the above method for the determination of compounds by the above-mentioned method of binding analysis are listed in the following table, and the results are listed in 2. Table 2 Acceptor bonding data (I number 値) Compound ETa Ki [nM] ETb Ki [nM] 1-2 a mirror isomer 43 345 1-224 a mirror isomer 33 6.8 1-171 a mirror isomer 15.7 26.4 1-145 A mirror isomer 1100 13.6 1-137 A mirror isomer 60 11 1-1 A mirror isomer 190 495 1-88 A mirror isomer 50 10 1-89 A mirror isomer 25 17 1-35 one enantiomer 400 250 1-36 one enantiomer 300 250 1-128 one enantiomer 46 9 1-129 one enantiomer 23 10 1-44 one enantiomer 205 365 1-45 an enantiomer 40 255 1-89 an enantiomer 35 93 1_10 an enantiomer 65 190 1-116 an enantiomer 9 43 1-290 an enantiomer 22 700 1-292 A mirror image isomer 1.8 170 1-293 A mirror image isomer 13 15 1-295 A mirror image isomer 215 1400 -51-This paper is applicable to China National Standard ((, NS) Λ4 specifications ( 2] OX 297 mm) (Please read the notes on the back before filling this page)

Claims (1)

546295 No. 87114595 Chinese Patent Application Amendment of Patent Application (January 2009) ABCD lik Application Scope of Patent Application 1. A carboxylic acid derivative of formula I, R6-Z- • C——CH—〇 -Het BR R5 wherein the meanings of the substituents are as follows: R is COOH; R2 is C 丨 -C 4 -fluorenyl or c 丨 -C 4 -alkoxy; X is nitrogen; Y is nitrogen; W is CH; R3 is (^-(: 4-alkyl or Ci-CU-alkyl); R4 is phenyl; R5 is phenyl substituted with 0 to 3 (^-(: 4-alkoxy substituted phenyl: R6 is < ^ -(: 6-alkyl, C3-C8-alkenyl, benzene-CrCr alkyl (wherein the group may be substituted by 1 to 3 C i -C 4 alkoxy, hydroxyl, carboxyl), phenylalkyl; Z is Oxygen; B is (: 2-(: 4-Extended alkyl); Het is a heterocyclic group of formula (lb) R2 X R3 lb This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 546295 A8 B8 C8 D8, patent application scope and pharmacologically tolerable salts. 2. For use in the manufacture of inhibitors of carboxylic acid derivatives ETa and ETB receptors according to item 1 of the scope of patent application. -2- This paper size applies to China National Standard (CNS) A4 (21 0 X 297 mm)