TW200480B - - Google Patents

Description

Λ 6 Π 6 Description (】) The present invention relates to an aminoguanidine with pharmaceutical use, its preparation method, including its medicinal sister compound and its use as a lotion. . ~ More specifically, the present invention provides compounds of formula I:

Where W is S or -HRi-, where IU is argon, "-β alkyl or carboxyl group, R2 is argon, halogen or Ct-β alkyl, IU is hydrogen · halogen or Ci-e alkyl; hydroxyl; Nitro; Amino; Ct- «alkylamino; Methylamino; C2-e alkoxycarbonyl; S02HR * IU where R · and R» are each independently argon or (^ -β alkyl; cyano; or tri Methylsilyl; or, when Α is -CRt =, Re may also be Ci-e alkyl and -SOz-Ci-e alkyl, -SOzNIURb, -C0NRaRb, -NH-SOz-Ci-e em Base, printed by the Central Bureau of Standards, Ministry of Economic Affairs, M Industry and Consumer Cooperatives 31 alkyl) -SOdCi-e alkyl) * -NR-R'b where R, hydrogen, alkyl, C3-7 cycloalkyl, (: 3- «» Alkenyl, phenyl or phenyl Ci-3 alkane (where the phenyl optionally contains substituents), C2-e alkoxycarbonyl, -POtCh * alkyl) 2 or heterocyclic group substitution; carboxyl group; C0NlURb : -POiCi- * alkyl> 2; 〇COHReRd where R. and Rd are each independently Ci-e alkyl; or heterocyclic group, which is krypton • or when rb is 〇imRe is argon or halogen ·

"This paper" is used to the fullest in the "B Family Sample Standard (CNS) 1r4 gauge peak (210X297; it) (please read the ridge first and note the matters to be written by Sun Fang) 81. 4. 10,000 sheets (Η) Λ 6 Π 6 —— V. Description of the invention (2) Z is -CR4 = where R4 is argon, halogen, hydroxy or Ci-β alkyl or, when Rb4 is radon or hydroxy, Z may also be -N =, A Is -N = or -CR7 = where R7 is hydrogen, halogen, Ci-e alkyl or alkoxy, or "^ and 1? 7 together represent-(ςΗ2)»-or -X3 (CH2) P-where m Is 2, 3 or 4, P is 2 or 3 and X3 is 0, S or -NiCi-e * alkyl)-, X3 is attached to the 6-membered ring t · X--Y is -CRe = N- or- CH (Re) -NH- where Re is hydrogen or Ci-e burned group, and B is a group of formula ⑻ or ⑮, (please read the note ^ matters before filling this page)

Binding · Ordering-Line-In the printing system of the Beigong Consumer Cooperation Bureau of the Ministry of Economic Affairs, the η is 1 or 2 * 8 ^ is C = 0 or CH2, and 1 is 5,} < 1? 11 or 〇 { {12 |? 13 · Among them is g or carboxyl, R12 and R13 are each independently hydrogen, alkyl or CB-7 cycloalkyl * R1〇 is radon; Ci-u alkyl; Ci-e alkyl and hydroxyl • Aryl, aryloxy * golden network alkyl * granyl ring * -NR1B-C〇-RleS-HH-S〇2-aryl taken -4-This paper scale is used in the BB standard (CNS) «H Specifications (210 fathers and 2 dragons) 81. 4. 10,000 sheets (H) A 6 Π 6 OqoABO printed by the Beigong Consumer Cooperative of the Bureau of Standards, Ministry of Economic Affairs V. Description of invention (3) Generation; CB-7 ammonium Aryl; gold-net alkyl: carboxyl; or -CONHR14, where CiM. Alkyl · CB-7 cycloalkyl, Ce-T_alkyl-Ci-4 burned S * aryl, aryl Ci-4 aryl or heterocyclic group · R1B is hydrogen or Ci-4 alkyl, and Rie Is Cl-e burned group, Cb-7 ammonium group, Cs-7 cycloalkenyl group Cl-4 group, aryl group or aryl Ci-4 alkyl group, and χ2 is -SR2〇 or -NR3R, 10 where R2 . Is Ci-β alkyl, R3 is argon or Ci-e alkyl, and R'10 has any of the meanings listed in R10 above or R3 and R'10a and the nitrogen atom to which they are connected together form 5- , 6: or 7-Bei Mei and or non-aromatic unsaturated 盁 瑁, which can contain hetero atoms from N, S and 0 and can be further condensed into a stupid ring, the prerequisite is i) When B is the formula ( b) When the base, only one of R10 and 1 ^ 10 may be a non-codile group and only when RlO is oxygen X2 may be -SR20 * and · ii) When B is a base NH NHR, 0 YA. [ Where R'1〇 is 4-methylbenzyl as aryl], Z and -CH =, W is -NH-, R2 & Re # is hydrogen and X--Y is CH = N-, Re is not hydrogen; • When 118 is a hydroxyl group, it is physiologically hydrolyzable and a qualified silver carp or hydra, free type or salt type. Read the back first-and pay attention to _ matters to fill out this page Binding line -5-This paper is used in the beta national beta standard (CNS) A 4 specifications (210X297 mm) 81. 4. 10,000 sheets (Η) Central Ministry of Economic Affairs Bureau of Standards IS: Printed by the Industry and Consumer Cooperatives 2 0048. __6_5. Description of the invention (4) When the compound of formula I | {8 is a hydroxy group used for "physiologically a hydrolyzable and a qualified Vietnamese ester" The term refers to 118% etherified and R β esterified, and it is equivalent to physiologically fermentable enzyme or acid that can be hydrolyzed under physiological conditions. That is, it is non-toxic at the desired cocoon ft concentration Sex. Examples of the chain group of RB include, for example, Cx-e alkoxy; C2-e alkoxy substituted with hydroxy, alkoxy, alkoxy * NRaR'b, CONiUiU or CSNR * Rb, where Re, Rb and R, Both are as defined above; C2-e alkenyloxy. When Re is an ether group, Z may also be = H-. "Examples of the acyl group include, for example, alkoxy and pyridyl-carbonyloxy. When IU is an ester group, pyridyl-carbonyl gas is preferred. When A -CR7 = * ester gas or pyridyl- The carbonyloxy group is preferred. In the compound of formula I, the alkane * portion may be a branched or straight bond. When Re, R1〇 or R, 〇 is a substituted alkyl group, the substituent is preferably located at the end of the alkane bond. Halogen It should preferably refer to fluorine or chlorine. When | {| »is a Ct-β alkoxy group substituted with a hydroxy group, it can also be an alkoxy group substituted with multiple M hydroxyl groups, such as 2,3-dihydroxy-propoxy The aryl group is preferably a stupyl or naphthyl group, more preferably a phenyl group * and it can be substituted. The aryl Ci-4 alkyl group is preferably a stupyl-Ci-4 alkyl group, such as benzyl or stupid ethyl group * and benzene It can be substituted on the ring. The aryloxy group is preferably a phenoxy group and can be substituted. The aryl group (^ -β alkanophilic group is, for example, benzyl group, which can be substituted on the benzene ring. When the aryl group or aryl group is When a part is substituted, it may be substituted with one or more of halogen, alkyl or (^ -β alkyl, for example. An example of a molybdenum or a duo substituted with one or two of Μ 氱 · methyl or methoxy for example The base part. The base part of the base or chelate group should be RC0 * where "is"-: !. Alkyl (please read t and pay attention to the matter before writing this page) -6- This paper is BB standard «1MCNS« 1MCNS) T4 specification (210x297 g) 81. 4. 10,000 sheets (H) 200480 V. Description of the invention (5), (: 2-10-1 alkenyl, CS-7-alkenyl or aryl • Ci-iO alkyl is preferred. When IU and Rii are each independently lanyl, it is preferred to R; C0, where R 'is an alkyl, stupid or stupid alkyl, especially Cz-e alkyl. When R1〇 is a brewing group, it is preferably R " C0, where "is D-:!. Radicals, stupid or stupid Ci-4 alkyl · especially Ci-10 alkyl. When IU is an oxyl group, it is preferably R, -C0-0-. The heterocyclic group as Re is derived from, for example, Pyridazole * thiazole, isopyrazole, beer diazole or _diazole base. When | {6 is or contains a ring group • It should be the base of formula (α)

(Please read the potential and precautions #fill this page first) Employee's Consumer Cooperatives of the Ministry of Economic Affairs, Biyang, Bureau of Economics and Trademark 31 where t is 0, 1, 2 or 3 IT is hydrogen or Ci-e alkyl X 'is N or CH Y · is 0, and Z is N. · As an IU. * RSo or a heteroalkynyl group formed by R3 and R'10 and the nitrogen atoms connected to it, preferably derived from 5- or 6-shell saturated, aromatic or unsaturated complexes, · It can be fused with benzene ring according to the situation, for example, pyridine, imidazole paper, and the paper is used in a B home "Bi (CNS) T4 specification (210X297 public *) 81. 4. 10,000 sheets (H) 200480 A 6 Η 6 five Description of the invention (6), benzimidazole, tetrahydropyrrole, tetrahydropyrrole, hexahydropyridine, pyrrazine or perhydroindole or formula (c >, < d) or (e > group. ~

(c) (d) (please first read the poor and note of the issue # 蜞 write this page) In the printed form of the Industrial and Consumer Cooperative of the Central Standards Bureau of the Ministry of Economy, 'R22 is a crab or Cl-4 yaki, Big-CHzCHz- , -C0CH2- or-(CH2) 3-, in which one or two H can be substituted with MCi-4 alkyl, or 1,2-phenylene * E is -CH2CH2_. -CH2N (R17)-or-(ch2 ) 3-, wherein one or two Η may be substituted with MCi-e alkyl, or 1,2-benzyl, Eig C0 or CH2, R17 is hydrogen or Ci-4 alkyl, 6 is (: 0,-( ： 11 (： 001 {1 «*,-(： {1 (： 01 {18,5,5-Dimethyl-1,3-dipyridin-2-yl or 1,3-dipyridinane -2-yl group, wherein Rie is hydrogen or Ci-e alkyl group and Rie gCi-e alkyl group, and η · is 0 or 1. The heterocyclic group may be further substituted with K such as halogen. * Μheteroyl substituted alkane Examples of radicals are, for example, 2- (2-tetrahydropyrrole «.-1, radical> -ethyl, 3-benzylpyrazolyl-propyl. When B is a radical (b> and wherein R1 is It is gas and X2 is NR3R ': i. Hour, R3 and RS. It is better not to be hydrogen-8 at the same time. This paper standard is not used in the "CNS" T4 specification (210X297 public Λ) 81. 4. 10,000 sheets (H) Pack · Book-Line. 200480 Λ 6 Π 6 Member of the Ministry of Economic Affairs Manufactured by the cooperation of Consumers. 5. Description of the invention (7). In the compound of formula I, the following definitions are preferred whether individually or for any sister or deputy sister: 1. W is S, -NH-, -NCH3- or -NC2HB-. Preferably W is NH. 2. 112 is H, CH3, C1 or Br. Preferably R2 is H. 3. Z is -CR4 =. 4. 1U is hydrogen or alkyl, M Hydrogen or methyl is preferred. 5. Z is -N =, Rs is hydroxy or Ci-4 alkoxy and A is -CR7 =. 6. Rs is hydrogen; hydroxy; or "-β alkoxy; or when When A is -CR7 =, Re can also be K-SOz-Ci-e alkyl, -S〇2HR.Rb, -C0HReRb, -HH-SOz-Ca-e alkyl * alkyl Bu SOz-Ci-e Alkyl or -PtHCa- * alkyl) 2 substituted "-β alkyl; acetoxy; carboxyl; COHR-Rb; alkyl) 2; or 0C0NR mountain 0 7. A is -CR7 =. 8. R7 is Η or CH3. 9. X--Y is -CRe = N-. 10. Re is Η or CH3. 11. B is a group of formula (a), preferably the base of Xig-NH- in formula ⑻. 1 2. B is the type hope base ring. 13. R10 is Μ. 14. Χ2 is NIUR · 10 ° * 15. Rs is [or Ci-4 焼 基. 16. R'10 is hydrogen * Ci-no. Alkyl, R "c., COHHRw •-(CDu-HH-CO-Rw or"-. Burning group, which is substituted by K aryl group at its W position, formula-9- The size of this paper is easy to use. B 8 home samples (CNS) 1M specifications (210X297 male 4) 81. 4. 10,000¾ (H) (please read the precautions before filling in this page) Binding · Threading. 200480 A 6 η 6 V. Description of the invention (8) < d) Base or benzopyrazolyl. Preferred alkyl. 17. R3 and R'10 together with the nitrogen atom to which they are attached form a 5-, 6- or 7-membered saturated or non-aromatic unsaturated heterocyclic group, which may further include a group selected from N, S, and O The molybdenum atom can be further condensed into a benzene ring. Preferably, the nitrogen atom to which {3 and 1 {, 10 are connected, etc. is hexahydropyridyl or perhydroindolyl. 18. The group of formula (d) is

Q

< «·» I un3 ch3 (please read the notes first. Fill in the wooden pages if you have any intentions) •• Installation-C3 of the Central Approval Bureau of the Ministry of Economic Affairs: printed by the industrial and consumer cooperatives according to the present invention. One type of compound is Formula I V, r2, Α, χ--Υ and B are all defined as above * Z is -CR4 = as defined above and Re is hydrogen; Ci-e alkyl; hydroxyl, Ci-β alkoxy; hydrocarbon hydroxy · alkane Oxygen, oxy-, NIUR, b, CORNURb or CSNR «Rb substituted" -β 焼 气 基 'where R · and Rb are each independently hydrogen or Cl_e alkyl and R, b is hydrogen · Ci-e alkane Group, cycloalkyl · C3-e alkenyl, stupyl or phenyl-Ci-3 alkyl, where the stupid group is optionally substituted; C2_e alkenyloxy; pyridyl-carbonyl gas; nitro: amine : Ci-4 alkylamine group; amino amine group; C2-e alkoxycarbonyl group; S02NR «Rb; cyano group; or trimethylsilyl group; or, when A is -CR7 =, 1 ^ may also be S〇2-Cl_e alkyl, -SOzNIUlU * -COHR ^ IU, -NH-SOz-C ^-* detection group, -lUCi- · »alkyl) -SOzMCi-e alkyl), -NReR, b, Cj2_e Alkoxycarbonyl group or -10- 'order · line-the paper ft ruler used in the edge of a Η home 搮 Bi (CNS) A 4 specifications (210 X 297 g) 81. 4. 10,000 sheets (Η) 300480 Λ 6 Π 6 Printed by the Cooperative Society of the Ministry of Economic Affairs of the Ministry of Economic Affairs 92. V. Description of the invention (9) -PtUCi-A alkyl) 2 substituted Ci-e alkyl; sugaroxy; carboxyl; C0NReRb; -PiHCi- * 焼 基) 2; or 〇c〇NReR ^, wherein Re & Rd are independently Ct-β alkyl. Particularly suitable compounds of formula I are where W is NH; R2 is H; Z is -CH = or- CCH3 =; Α is -CH = or -CCH3 =; Re is argon, hydroxy, "-β alkoxy, -SQz-Cx-e alkyl, -S〇2NR * IU, -C0NR, Rb, -NH -SOa-Ci-e alkyl group, -NiCi-e alkyl XOz-Ci-e alkyl group or -POiCi- * alkyl group) 2 substituted Ca-e alkyl group, acetoxy · carboxyl group, C0NR «Rb, P 〇 (Ci-4 alkyl) 2 or OCONRcRd. In formula I, W is Nh; R2 is Η; Z is -N =; A is -CH = or -CCH3 =; RB is also a compound of hydroxyl or Ci-e alkoxy. A more particularly preferred compound of formula I is one in which W, R2, Z, A and Rb have one of the above definitions and B is a / NH- | group or formula (b > group. The compound of formula I may be K free-form, Salt type, medium type or hydrate type exists. Salt type can include acid-salt and scum type available when [^ is a carboxyl group. Qualified acid-salt type available on the basis of the invention can be used as the following The description * includes, for example, "acid sulfonate * sulfonate, oxalate, oxalate, maleate and fumarate. When | {& is a carboxyl group, the salt is, for example, Mt alkaloid salt such as Sodium or potassium * or substituted or unsubstituted ammonium salts. Xianxin Formula I X--Y is -CRe = N- and B is the formula (bM group (b,) shout · 10 -11- (please first M Read the notes on the back- 意 事 #Fill in this page) This paper "uses Zhongming's" Home "standard (CNS) Ή specification (2 丨 0x297 public" :) 81. 4. 10,000 sheets (Η) 200480 • 66 ΛΠ 5. Description of the invention (10)

In the formula, R 2, R β, R β, R 8, A, W, Z and R · α 〇 are as defined above. In Formula I, the compound where Z is -Ν = and RB is hydroxy can also exist as tautomers: (please read the note to the contrary _Important Sun Zang page) Printed by Beigong Consumer Cooperative, Bureau of Standards, Ministry of Economic Affairs 0

Y-NH3 12-this paper "scale edge and middle a Η family" Bi (CNS) specifications (210X297 g; ft) 81. 4. 10,000 sheets (Η) g〇〇48〇A 6 H6 V. Description of the invention (11) In the formula, W, A, R2, B and X --- Y are as defined above. ”Notice when all the tautomeric forms are specified · All the tautomeric forms of the siM of the present invention and their mixtures, that is to say only for the convenience of defining the compounds of formula I-only guanidino type or only 5-oxy type, the only The invention does not intend to be restricted by the special naming or remarks used by K. The same considerations also apply to the starting materials in the presence of guanidine groups __ tautomerism or oxy / hydroxy tautomerism, as described in τ. Another feature of the present invention is a method for preparing a compound of formula I, which includes: a) preparing a compound of formula I where X--Y is -CRe = N-; that is, the compound of formula!

(II) (please read the notes and matters before filling in this page). Binding. Line. Printed by the Ministry of Economic Affairs Central Sample Standard Resident A Industrial Consumer Cooperative [where A, W, Z, R2, Re, And 1 to 8 are as defined above] Reaction with the compound of formula I; H2N-MHB (I) [where B is defined as above] • or b) system #Formula I where X--Y is -CHRe-NH-; That is, the -13- (^ paper) scale in the s-type formula I uses the Chinese national standard (CNS) < P4 gauge (210X297; tt) 81. 4. 10,000 sheets (Η) 200480 Λ 6 Η 6 5. DESCRIPTION OF THE INVENTION (12) Υ--Χ is a compound of -CRe = N-; or c) Preparation of a compound of formula I where B is a group of (b ·); a compound of formula la that is alkylated by amine alkylation '醢 化or

y —ή ΝΚ >-ΝΗ; da) (please read the note on the back? Please write down this page) AWZRss, Re, Re and Χ--Υ are defined as above; d) In the preparation formula Rs in I is a hydroxy compound; the compound of formula I b is subjected to ether cracking reaction equipment · R5a

NH-B (lb) line < A, W, Z, R2, R * ^ X-_Y and B in the Ministry of Economic Affairs + Central Standards Bureau employee consumption cooperation du printing system are defined as above, and U · is a cleavable ether i : Or * e) Preparation of a physiologically hydrolyzable and qualified compound of formula I (where Re is an ether or ester of hydroxy>; ie, etherified or desulfurized compounds of formula I in formula I; -14- this paper size Xiaoyong "National Sample Standard (CNS) Ή Specification (2) 0χ297 Gong;« :) 81. 4. 10,000 sheets (H) A 6 ΙΪ6 200480 V. Description of the invention (1J) (Please read and pay attention to it first Matter #Fill in this page) and recover the compound of formula I or its physiologically hydrolyzable and qualified ether ester M free-type or short-term, medium or hydrate type. The preparation method a) can be similar to known methods For example, it is preferably carried out in the presence of an acid such as an inorganic II such as hydrochloric acid or bromocarboxylic acid * or an organic acid such as p-toluenesulfonic acid or pyridinium p-toluenesulfonate. The reaction can be carried out locally in the presence of a substance and a solvent such as methyl alcohol *, ethyl yeast or isopropyl yeast. The reaction can be carried out locally at a temperature between room temperature and reflux temperature. The production method b) can be carried out according to a known hydrogenation method. When RB is a benzyloxy group, it can be simultaneously cleaved into a hydroxyl group. The manufacturing method c) can be carried out by methods known in the art. The compound of formula la should preferably be reacted with _, such as triethylamine or HunU «[in the presence of *, respectively, with alkyl, cycloalkyl or aryl halide or amide halide or sugar anhydride for proper alkylation Reaction or acidification reaction. Methamidylation reaction is suitable for dissolving B! For example, dimethyl methyl amine reacts with isocyanate such as R14NCO in the presence of dimethylamine to proceed locally. The preparation method d) can be carried out in a similar manner to the ether cracking method known in the technical field. When it is a benzyloxy group, it can be hydrogenated in the presence of a catalyst such as palladium on carbon. This inversion can be carried out in a solution such as yeast and at a temperature from room temperature to 60 * 0. It can be alkoxy, substituted alkoxy, alkenyloxy or benzyloxy. The Ministry of Economic Affairs Central. Bureau of Standards, Beigongxiao Co., Ltd. co-printing production method e) can be completed by reacting a compound with hydroxyl group in formula 18 and glycosyl halide (glycosyl chloride is preferred). The compound of Formula I where Re is pyridyl-carbonyloxy can be prepared by reacting the compound of Formula I where Re is hydroxyl with nicotinic acid halide. The reaction can be carried out locally in the middle class such as trifluoro-acid or trifluoromethanesulfonic acid. -15- This paper is used in a book. A B House squat (CNS) Ή specification (210X297 gonglong) 81.4 . 10,000 sheets (Η) 200480 A 6 B6 V. Description of the invention (1 W The starting materials of the formula I or B are known or can be prepared by similar known methods and applied as shown in the technical field. ._ For example The compound of formula I where V is -NIU- can be prepared according to the following reaction: 1. Bredereck reagent R, — ^ Ά2. M original R2 1. Modified Fissimer (VUsneier) reaction preparation:

T

(Please read the back-end notes first and then write this page) The Ministry of Economic Affairs, Central Bureau of Economic and Trade Cooperation of the Ministry of Economic Affairs and the Ministry of Economic Affairs, Du Printed The above-mentioned compound of formula IV can be prepared locally as follows: Bre dereck) cocoon test • For example (CH3) 2NCH (0CH3> 2, react in the absence of dissolved Η or as dissolved in tetrahydropyrrole _ in the presence of _ afterwards ^ in the presence of palladium catalyst with argon or Raney) Hydrogenation of M hydrazine in the presence of spicy. The compound of formula I where V is -NIU- can be modified by the compound of formula IV Vilsieier. The reaction and subsequent alkylation or brewing also entangles native-16- 本 纸 ft The standard is used in the National B National Standards (CNS) T4 specification (2 丨 0X297 g; St) 81. 4. 10,000 sheets (H) 200480 A 6 η 6 Printed by the Employee Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (15) The Fiesmil reaction modified to 0 can be carried out using dimethylalkanosamine in the presence of pocu according to methods known in the art. The alkylation or infusion reaction can be performed according to known methods, such as ( I, for example, in the presence of K2C〇3 or C2HBMgBr, and carried out in a solvent such as dimethylformamide or tetra-M furan. In the formula of the B is the formula (b> group and its Compounds where Χ2 is not -SR2〇 can be prepared locally as follows: Compound of formula VI * 21 (VI) 11ch3 R, where R1〇 is defined as above and R ai is -NR 3 R ,: 0 or -Ν Η Η H ss reacts with hydrazine at R21 $ -NR3R'10, or when R2i is -ΝΗΝΗ2 with the amine of formula NHR3R'1〇2. The reaction can be carried out under heating at reflux temperature appropriately. It is suitable for solvents such as yeast Such as formazan or ethyl fermentation, water or dimethylmethylamine, with or without Λ compounds such as potassium hydroxide or potassium carbonate. In formula I, B is the group of formula (b) and X2 is -SR2 The compound of 〇 can be prepared as follows. That is, the compound that can produce R2〇 according to the known method M is the alkylation formula W compound-17- the paper ft scale is used in the national «quasi (CNS) T4 specification (210X297 male dragon) 81. 4. 10.000 sheets (H) (please read the notes before Ittl Sun Huang wrote this page). Binding. Thread. 2〇〇48〇Λ 6η 6 V. Description of the invention (16)

(VII) The Ministry of Economic Affairs, Central Bureau of Accreditation and Employee ’s Consumer Cooperatives has not specifically stated the starting material of its preparation method. It is a known compound or can be prepared by a similarly known method and applied as shown in the technical field I or as in the following examples Said. The following examples illustrate the invention. All temperatures are υ. The vines used are written as follows: THF = tetrahydrofuran DHF = dimethylmethylamine EtOH = ethyl yeast MeOH = formic acid AcOEt = ethyl acetoacetate _ (F) = foaming (S) = sintering example 1: 5 ~ 理 某- Sight-3-carboxyl road defense "3-iV-tetrahedron DH: guo nian-v-an-Rui Suihong 1 Xitian contains 0.9g 5-hydroxy- vermido-3-carboxaldehyde diamine sub Methyl hydrazone M. lumol was added to a solution of 10b1 THF (containing 2 · 1 DMF and 0.9b1 Et3N (6.2mm〇U), and 1.3g 3- (2 · -tetrahydropyrrolose was added at room temperature -1'-yl) -bromopropane (6 · 2 ·· ο1) »mixture at 50. Mix -18- the ft scale of this paper with the Chinese National Standard (CHS) Ή specification (210X29 〖Male Dragon) 81. 4. 10,000ft (Η) (please read the back-notes * the matters needing attention before filling out this page) 200480 A 6 Π 6 5. Description of the invention (17) Encounter night. The mixture is cooled to room temperature and the solvent is evaporated ° Residue by Si02 chromatography) Carving agent: toluene / Et0H / NH3 70: 30: 2.5) to obtain crystals of the title compound. MP = 158 ° (foaming). Mass spectrometry b / z (relative intensity): 343.3 (MH *. 100); 217.2 (20); 168.2 (20); 143.2 (23). Example 2: Only-蘼 某-晡 1 »金-戈-絭 浭 某 (》-甲某 -1 < - Heptamine Longi > The Ministry of Economic Affairs, Central Standards Bureau, Beigong Consumer Cooperation Co., Ltd. produced es Tianmouwan containing 0.48g of 5-benzyloxy-indole-3-carboxamide (H-methyl-H-heptylamino > Methylene hydrazone (1.1 ·· 〇1) was added to a solution of EtOH with 0.25g 10X Pd / C. The suspension was argonized at 45 ° C. After that, the suspension was filtered through silica gel and evaporated And the residue was analyzed by silica gel (dissolving agent: Jiaben / EtOH / NH3 85: 15: 1) to obtain the title compound. The pure substance crystallized from CIUCU / hexane 2: 8. Μ.Ρ. = 11〇υ (堍 结). Mass spectrometry · ζζ: 329 (ίΤ, 40); 128 (40); 111 (60); 73 (50). These starting materials can be generated as follows: a) contains 3.2g 5- Benzyloxy-B3 丨 ole-3-carboxaldehyde (12.7ββο1) and 5.0g 1- (H-methyl-N-heptyl) -3-N'-aminoguanidine, hydrosulfonate (16.0mmol) In a solution of 100bI MeOH, at 5 T, MeOH / HCl solution was added to PH = 3. After 2 hours, the solvent was evaporated and the residue was dissolved in AcOEt. The solution was washed with MNa2CO3 solution (2N). The organic layer was dried with oxalate and the solvent was evaporated. Residual & employment analysis (dissolved_: toluene / ^ 11 / «113 85: 15: 0.5) to obtain 椷 囲 compound 〇 Mass spectrum b / z (relative intensity): 420 (MH *, 100); 330 (7 ); 249 (4); 172 (16) 〇-19- This paper is used in a small format a B home standard (CNS) A 4 specifications (210X25) 7 male; ft) 81. 4. 10,000 sheets (Η) ( Please first «] Read the background and note # 塀 write this page) Λ 6 Π 6 200480 V. Description of the invention (1δ) b) l- (N-methyl-Μ-heptyl) -3 · Ν'-amine The guanidine • hydroiodide contains 4.7g of S-methylisoballastamine adenohydroiodide (20 ·· 〇1) and 3.7.1 Ν-methyl Ν-heptylamine (22β · ο1) in The solution of 30 · 1 formazan was refluxed for 6 hours. The solution was then cooled to room temperature and the solvent was distilled off to give 1- (Ν-methyl-Ν-heptyl) -3-N · -aminoguanidine, hydroiodide. The resulting crude product was used in the next step K for further passivation without a box. a_M_2_: only-Xun certain-foot 1¾¾ Ί nouramine certain f N-湮 R certain adenyl) methylene certain containing 0.8g 5-hydroxy-B § | indo-3-carboxaldehyde diamino methylene hydrazone (3.7 «mol) in a solution of 20 ml of DMF, a solution containing 0.5 ml of cyclohexyl isocyanate (4.0 qbo1) in 5 ml of DMF was added during Ο T5 minutes. Then the solvent is vaporized and the residue undergoes precipitation (dissolving agent: toluene / EtOH / NH3 85: 15: 0.5) to obtain crystals of the title compound ». 》 1.?.= 135 < · (Bubbling). En spectrum b / z (relative intensity): 3 "(ΜΗ'100); 244 (50); 218 (85); 159 (33) 〇 Fen Example 4: 5-Yun certain -6-«-阏 Sight- neodymium Lufen (Penfang) Yinshen followed the method of Example 2 to prepare the title compound. M.P. = 125 ° (foaming). 5-Benzyloxy-6-fluoroindole-3-carboxaldehyde Used as a starting material,% prepared as follows · a) One 4 two town monooxy-methyl stupid containing 85.6g 2-nitro-4-fluoro-5-hydroxy-toluene (0.5bo1) in -20- this paper Scale side W China S home standard (CNS) T4 specification (210χ297 & *) (please read «1 to read the notes before filling the nest page). Line < Beigong Consumer Cooperative of the Ministry of Economic Affairs Standards Bureau印 Μ 81. 4. 10,000 sheets (Η) 200480 A 6 Π 6 Ministry of Economics + Central Government Bureau; Industrial and consumer cooperation du printing

V. Description of the invention (19) In a solution of 1300nl propylene glycol, add human I38g K2C03 (1.〇B〇1) at room temperature. Next, 721 »1 benzyl bromide (0.6« 1〇1) was added dropwise within 1 hour and the resulting mixture was stored at 60 ° and stirred overnight. The solvent was evaporated and the residue was dissolved in AcOET. The precipitate was removed by filtration and the solution was washed with water. The organic compound is dried by sodium sulfate, the agent is distilled off, and the residue is crystallized from hexane to obtain 2-nitrohua-4-fluoro-5-benzyl-methylbenzyl. Μ.Ρ. = 95. . Mass spectrometry Β / ζί 261U ·) b) 2- [1 '-(Ν, Ν-dimethylamino) -ethylene-2 · -yl] -4-benzyloxy-5-fluoro-one ··· di Transyl_ben · Containing 126g of 2-nitro-4-fluoro-5-benzyloxy-toluene (0.48 · 〇1) in 200 g of bis-dimethylamino-third butoxy-methane (1.15 · ο1 & gt The solution was stirred overnight at 90 °. Afterwards, the solvent was distilled off. The residue was crystallized from MeOH to obtain b) red crystals of the title compound. Μ.Ρ. = 146 °. Mass spectrum m / z: 316 (Μ *). c) Ϊ 2 6 2% 1 free solution containing 9.5 g of b) compound (30.0 mmol) in 150 ml of methylbenzol and 30 ml of THF (containing lg Ruanlailian) was hydrogenated at room temperature. After 4 hours, the suspension was filtered through hyflo and the solvent was distilled off. Analysis of the residue (solvent: toluene) gave b) the title compound, which crystallized on its own. Μ.P. = 126 °. , Mass spectrum n / z: 241 (M *). d) 5-benzyloxy-6-fluoro-indib! -3-carboxaldehyde 3 · 3 · 1 P0CU (36.0βπιο1) at 0. Add dropwise to 14ml DMF -21- This paper is used in standard size a 揈 家 《華 (CNS) A 4 specifications (210X297 public *) 81. 4. 10,000 sheets (Η) (please read the backing notes first # (Write this page). Binding. Thread · 200480 A 6η 6 5. Description of the invention (20) (180.0ββο1). After 15 minutes, a solution containing 7.30 g of c) compound (30 ·· 1) in 14.1 DMF was added dropwise within 10 minutes. The mixture was stirred at room temperature for 1 hour, then diluted with cold water and then added dropwise with a solution containing 7.2 g of NaOH in 50.1 water. The obtained solid was analyzed by SiO 2 (dissolving agent: CH 2 CU) and crystallized from 銀 銀 to obtain d) the title compound. M.P. = 190. 〇 霣 spectral m / z (relative intensity): 269 (M '72); 178 (20); 150 (15); 91 (100); 65 (38) 〇Window example 5: 5-理 某-雹 Sight- Lulufen (dibutylamine) Yashen contains 0.5g 5-hydroxy-lumbole-3-carboxaldehyde diaminomethylene hydrazone (2.3mmol) in a solution of 5al DMF. .4 · 1 Butyric anhydride (2.5βιπο1) in 5 ml DMF. After 7 hours at room temperature * the solvent was distilled off and the residue was chromatographed on Si02 (dissolving agent: Jiaben / EtOH / NH3 85: 15: 0.3). Then he obtained the title compound and spattered it out of the hexane. Μ.P. = 90 ° (foaming). Mass spectrum a / z (relative intensity): 287 (M'16); 217 (8); 200 (4); 158 (30); 98 (100); 70 (46). Window example 6: 5-Wei Chlorine-Emox-3-carboxyl "Fang Mou (Pen Fang a certain field even neck trifluoro_acetate (please read the back note · intention matters # fill in this page) Pack. Order _ Line-Printed by the Zhenggong Consumption Cooperation of the Central Approval Bureau of the Ministry of Economic Affairs, HP = 138 ° 〇g Li 7: 5_:

R group-鷏 跺 -3-carboxyl Fang Fang (Pen Fang Fang) gg Tian Mou Wan trifluoro _ Yiqu contains 1.0g 5-hydroxy-indole-3-carboxamide (pentylamino) sub Methylhydrazone 22 This paper is used in the standard a B home «Bi (CNS) A 4 specifications (210X297 g; tt) 81. 4. 10,00〇α (Η) a〇〇4® ° Λ 6η 6 V. Description of the invention (21) (3.5 ·· ο1) In a solution of 10 nl CF3C〇2H, 0.72 ml of hexane was added at 〇〇. After 3 hours the quenched M2H JlaiCO3 was quenched and the mixture was stirred for 20 minutes. AcOEt was added and the organic layer was separated * washed with brine and dried Na2S04. The solvent was distilled off and the residue was washed with ether to obtain a crystalline compound. Μ.P. = 205 °.霣 谱 · Zζ: 385 (Μ *, 20); 160 (30): 158 (25); 69 (100). Following the above method, the compound of formula IA can be prepared

In the formula, RB, Re and RS. The definition is shown in Table I below. (Please read the back-to-back notes on W1 # fill this page). Install. Order_-complex. Central Ministry of Economic Affairs Bureau! 3: Printed paper by industrial and consumer cooperatives »• Standard use in beta B home standard (CNS) T4 specification (210X297 mm) 81. 4. 10.000 sheets (H) V. Description of invention (22) Central Bureau of Standards, Ministry of Economic Affairs C3: Industrial and Consumer Cooperative Printed Table I £ χ. R5 | Ra! R, l ° surface Μ.Ρ. 8 och2och3 丨 pentyl group 103 0 9 0CH2CH = C (CH3) 2 •! H 丨 penteryl group: not Crystal form 10 OH | H |-(CH2) 3-NH-CO-CsH5! 179 0 (F) 11 OCO-N (CH3) 2 | H pentyl 90 0 (F) 12 H 1! Pentyl 125 0 13 och3 | H i pentyl 1 group 124 * 14 OH | h 丨 pentyl 1 group 123 0 (F) — 15 OH; H 1 ″ 2M 7. i hydrochloride 16 OH | ch3 1 i is i 130 0 (?) 17 OH 1 ia 1 Ι-(CH-) 2 165 0 1 1 1 1 I II 0 18 OH | H | ca3 I 14〇0 (F ) 19 OH | CH3 丨 pentyl group 200 ° 20 OC2H5 | H 丨 pentyl group. 114 0 21 0-i-C3H7 | H 1 pentyl group 90 0 22 OH 1 1 3,8 1 _ dimethyl-nonyl 150 0 23 OH | H 1 3- (p-F-phenoxy) -propyl 85 0 (F) 24 OH | h |-(CH2) 2-NH-C0-C6H5 110 a (F) 25 benzoyl Oxygenated iH ja base 155 0 (F) 26 —0—CO— Cert.C ^ H9 | H 丨 Pentyl Amorphous-24- This paper scale is used in the middle of the national standard (CHS) 〒4 specifications (210X297 Mm) 81. 4. 10,000 sheets (H) (please read the back-end note ^ matters # 蜞 窝 this page) Binding · Order-line. 2〇〇48〇A 6 n 6 V. Description of invention (2彡 Ministry of Economic Affairs, Central Bureau of Industry and Fisheries Co., Ltd. cooperated with Du Yin to produce Εχ · | Rs 1 | Re R 'i 〇 (MP 1 27 1 1 1 1 1 1 | 0H 1 1 1 1 1 1 1 1 i | H 1 1 I -(ch2) 3-n 1. VNH 0 1 1 1 ί 1 | U0 0 (F) 1 i 1 28 1 | OCH3 j 1 | H-(CH2) 3-NH-CO-CsH5 1 j amorphous 29 | OCH2OCH3 1 | H-(CH2) 3-NH-C0-C6H5 amorphous 1 30 1 | OCH2CH = C (CH3) 2 1 | H-(CH2) 3-NH-C0-C4H5 i amorphous 1 31 1 OH 1 1 1 -S- (CH2) 4-CH3 | 190 0 | M iodate 1 32 1 C00H I 1 I; H 1! Amyl! | 310 3 Hydrochloride 33 1 3-pyridyl-carbonyloxy oxy | H pentyl 1 Bu 5. j * 34 ij〇HI 3-benzylamino-propyl | 179 0 (F) | 35 1 | 0-C0-N (C2H5): l! H pentyl | 75 0 (F &gt; j 36 1 jOH 1 | H-(CH2) 3-〇H | U0 0 (F) j 37 1! 〇-ch2-co-n (ch3) 2 | H pentyl | 160 0 I 38 1 | 0H 1 | H _ 3-benzimidazole-2-yl-propyl · 1 I amorphous. 39 1 | 0H I, | H-(CH2) 3-NH-S〇2-C6H5 1 amorphous Ι 40 1 j〇-CH2-CH2-N (CH3) 2 | H pentyl 1 1 amorphous 41 1 j 0- <CH:> 2 -〇-CH3 j | HI pentyl 1 i amorphous 1 42 | 0- (CH2) 2-0H | H pentyl 1 amorphous 43 1 (OH 1 | H 1 • octyl 1 amorphous [44 1 | Si (CH3) 3 1 | H pentyl 丨 amorphous form 45 1 1 isobutyl Oxygen group: 1 | H pentyl amorphous. 25- This "• Zhang scale Xiaozhong BS Jiayu standard (CN5) Ή specification (2 丨 0X297 public; ¢) 81. 4.〗 M〇〇 Zhang (Η) (Please read the precautions before filling in this page) 2〇0 ^ ° 5. Description of the invention (24) Λ 6 Π 6 Printed by Beigong Consumer Cooperative of Ministry of Economics + Central Standards Bureau

Ex. | Rs 1 1 | R, 10!-| Μ · Ρ · -J- 46 i | 0Ca2C5-N (CH3) 2 ji | HI ii 1pentyl group 1 1 丨 Amorphous I 厶 7 1 jOH 丨 H 1 1 phenethyl '| 130 0 (F) 1 48 1 | 0H., 1 jH i- (CHj) | 3-N (CH3) -benzyl group | 202 0 49 | 2,3-di (OH ) -Propoxy I i | HI 丨 pentyl-1-yl | 105 0 (S) I 50 1 | nh2 1 丨 pentyl 1-yl ilOO 0 (F) | 51 ethoxyl I | H pentyl 丨 225. 1 1 1 1! I | Hydroiodide 52 1 iP〇 (CH3) 2 | 1 l iH j 1 ': pentyl 1 base 1 | 90 0 (?) 53 1 iCG0CH3 1! H 1 ίpentyl-based | 134 . | 54 i | CM i! H 1 丨 pentyl | 138 0 (F) | 55 1 | m〇2 jH j 1pentyl | 153. | 56 i iCH2-S〇2-NaCH3 1! H 1 group | 93 0 (S) | 57 丨 0CH20C0- the third butyl I! H 丨 pentyl 1 group 丨 amorphous J 53 1 | CH2-S02-NHCH3 | H | C0-NHC6H1L ·! | 130 0 (F) 59 1 | 0H | H | 丨 3-phenyl-propyl | 1 amorphous I 60 1 丨 OH 1 | HI 丨. Phosphatoxyphenethyl | 122 0 (F) | 61 1 i〇CH3 1 1 | H | | 62 1 | CH2-CH2-S〇2-CH3 1 | HI | pentyl 1 amorphous 1 63 1 i CONHa 1 1 | HI ja group, | l30 0 (F) | 6 Ji 1 | CON (CH3) 2 1 | H 1penteryl jlOO 0 (F) -26- (please read the back-end notes first # fill in this page) ft scale of this paper in the use of a Β family 楳 quasi (CNS) Τ4 regulations (210X297 public; Jt) 81. 4. 10,000 sheets (Η) ^ 〇〇4B〇A 6 Π6 V. Description of the invention (25)

Ex. | R5] Ra 1 丨 R’10 * 1 jM.P. 1 65 | 〇H I | | 4-chlorobenzyl 1 丨 115. | (F) 66 1 丨 OH 1 I iH! 丨 3-MeO-phenethyl j 1 丨 120. 1 (?) 67 k 1! H I 1 phenethyl | 212 ° (F) 68 iCH2-N (CH3) 2 I iH 1 丨 pentyl 1 丨 amorphous 69 1 ICONH ^ j | CH3 1 1 pentyl j 1 丨 246. I (1) 70 | 0H 1 1! H 1 p, 4-di-Cl-phenethyl 1 丨 274. (1) 71 1; p 1 1 1! S! I 3-MeO-phenethyl 1 | 1135 ° (1) 72!! H 1! IH I icH2CH2CONH2 1 1 amorphous ⑴ 73 icH2-CH2-MH-S0 , CH. J 1 1 «« id | 1 pentyl j 1053 (i: F) 74 iCH: -NH-302CH3 | iH | 丨 pentyl 丨 2Q4a 1 (1; F) 75 I | 3〇2-M: i7 | is »丨 pentyl 1 | 120 ° I (F) 76 | ch (ch3) -oca, | H · I cS * 1 丨: 15. 1 (1; F) 77 | och3! H | 3,4-di-C [phenethyl 丨 209. (1) * m • P · Hydrogen maleate 1 = 190 0 C ** mp hydrochloride »223 0 C ⑴ Hydrochloride (please read back to the precautions # fill out this page) -The Ministry of Economic Affairs, Central Bureau of Precision Industry, Shell Industry Consumer Cooperation Du Yin 9i -27- The original size of the paper BB standard sample (CNS) 4 specifications (210 to 297 male dragons) '.81.4.10,000 sheets (1〇2 〇〇48〇Λ 6 Η 6 V. Description of the invention (26) Following the method disclosed above, the compound of formula IB can be prepared

13 (Please read Poverty first, and note the following items on this page) Printed by Employee Consumer Cooperative of Central Bureau of Standards, Ministry of Economic Affairs R &amp; R a and X are defined in Table I below. Table I-Ex. Rs Ra X M.P. 78 OH * a MH 173 0 (?) 79 OH ch3 MH 240 0 30 OH H ca2 297. Folate S 81 OH H S 165 3 82 och3 K ch2 248. Salt 83 C0N (CH3) 2 H m 225 0 84 ch2so2nhch3 H NH 253 β 85 ca2s〇2NHca3 CH3 NH 249. 86 · OH H NH 140 0 (F) (F) 28-scale side use 8 S home «Bi (CNS) A 4 specifications (210x297 g) 81. 4. 10,000 sheets (H) 2〇〇4B〇A 6 n 6 5. Description of the invention ¢ 7) g Example 87: 5-hydroxyhua-3- [(N methyl) -indole HP = 110 ° (F) Μ · P. = 239. 2 imidazoline-4 keto ) -Hydrazine

Μ—Μ

Following the method disclosed above, the compound of formula IC can be prepared

Ν'Η 'f (IC) (Please read the precautions before filling in this page) Binding-Ordering-Line-R3, IU, Re, R7 and R in the printed form of the β-Consumer Cooperative Society of the Central Standards Bureau of the Ministry of Economic Affairs ,. As defined in the following Table I-29 This paper standard is used in a B family sample standard (CNS) 4 specifications (210x297 g *) 81. 4. 10,000 sheets (Η) 200480 A 6 Π 6 V. Description of invention (28) Εχ · | 1 Ri 1 R4 1_ R7 f R5!: Table IR '10 M.? 1 39 | H 1 H ch3 1 OH jj H pentyl \-| 130 I 9 (F) 90 丨 c2h5 HIH OH 1 1 H Pentyl 1 i 144 1 9 91 | H ch3 HI OH j 1 H pentyl 1; 105 1 0 (F) 92 | H OH H 1 H! E pentyl 1 147 0 93 | j HHH, OH;] VI Pyridinyl 164 0 (F) 94 | 1 HHH 0H 1 1 fully-hydrogenated indolyl 170 0 (S) 95 j 1 KHH OH 1 j ca3 pentyl 100 0 (F) 96 丨 IHHH 0CK3 J ch3 pentyl 139 0 97 丨 j HH ch3 OH! Ch3 pentyl 120 0 (S) 98! J HH ca3! 0CH, jj CH3 pentyl amorphous 99. jf c2h5 HH 1 OH j ch3 pentyl 138 0 (F) I 100 j H ch3 H OH 1 IH 3-benzimidazol-2-yl-propyl amorphous | 1011 HH ch3 H 1 H 3-benzimidazol-2-yl-propyl 120 0 (F) 102; 1 HH 0CH3 1 H j IH 3-benzimidazol-2-yl-propyl '135 0 (F) 103. HH ch3 och3! H 3,4-di- (: 1 phenethyl 220 0 (1) (please read the kidney first And note Matter # fill out this page) Printed by the Staff Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs -30- This paper uses the Chinese 戳 楳 准 (CNS) 4 specifications (210x297 male dragons) 81. 4. 10,000 sheets (H) 2〇 〇48〇A 6 n 6 V. Description of the invention (29) Following the method disclosed above, the compound of formula ID can be prepared

NH one person 1 N 'MHR1 10 (ID) (please read the back-to-back notes on this page)

Where Re and R’10 are as defined in Table IV below Table IV

Ex. | R5 1 R '10 MP 1 1 104 1 〇CH3 j pentyl 107 ° 105 1 OH pentyl 155 0 1 106 1 OH 3-benzimidazol-2-yl-propyl 150 0 (S) 10 &gt; och3 3-benzimidazole-2-Qi-propyl 98 0 (F) By following the method disclosed above, the compound of formula IE can be prepared.

NH 10 (IE :) -31- This paper standard is used in a small format (S) like standard (CNS) A 4 specifications (210X297 g *) 81. 4.] 0,000 sheets (Η) 2〇〇4β〇 Λ 6 η 6

V. Description of the invention In the formula, R: r and R'10 are defined as in the following table ν. Table V

Ex.; R7 ---- R, 10 MP 108 1 1 Η 1 pentyl amorphous 109 ί Η j phenethyl 192 0 110 1 ch3 1 pentyl 195 0 111. 1 a 1 CH2CH2NHCOC6H5 220 0 112 i η benzyl Base 203 0 (Please read Xu Erzhi's precautions to write this page Sun Guo writes this page) Ministry of Economic Affairs Central Bureau of Industry and Commerce hc industrial and consumer cooperation Duin 31 g ga 113 · (7-azinoindole) -3-carboxamide (Pentylamino) methylene hydrazine MP = 78 ° (焼 结) ff Example 114: 覒 什 -fi- 觎 晡 Bg -3-Carboxylic acid HP = 168e (F) 5- (dimethyl Dioxygenate-lumbendo-3-carboxaldehyde, used as a starting material for the production of the compound of Example 52, can be prepared from indole-5-dimethylphosphine oxide according to Example 4d). The indole-5-dimethylphosphine oxide can be prepared as follows: 啻 m 脚-R- 二 田 皤 化 argon a) _n m% m 一 (i 甲 一 基 一 贼 "1〒_) The third- A solution of butyllithium in hexane (10 millimoles h 1.7M) at -78 ° was added with human 5-bromo-N-sulfonyl-hour-dodoline (5 mmol) dissolved in 3〇al ether Of solution. After 10 minutes * A solution of ClP0 (Me) 2 (10 mol) dissolved in 10b1 THF was added thereto. The reaction solution was heated to room temperature for 6 hours. Plus-32- This paper is used for Λ-scale side-by-side B home "Bi (CNS) Τ4 specifications (210X297 · mm) 81. 4. 10,000 sheets (Η) 2〇〇㈣ Λ 6η 6 Ministry of Economic Affairs Central Standards Bureau shellfish consumption Cooperative Duprinting V. Description of the invention (31) Into the water and AcOEt, separated by a layer and extracted by water phase MAcOEt. The combined organic phases are soaked in water, dried, and evaporated to remove dissolved 9Γ. Chromatography of residue K 51〇2 (difficult_: (: 1158 (: 12 / »^ 〇) 195: 5> and obtained the title compound a) ° Η.Ρ. = 180β 〇b) mm 5 (jljp® ) Compound a) (1.5 mmol) was dissolved in a solution of 20 · 1 MeOH (containing 0.2 g pd / c> for 2 hours. The solution was filtered through filter soil and evaporated to obtain the title compound b). c) Indole-5- (dimethylphosphine oxide) _ A solution of compound b) (1.5 mmol) dissolved in 25 ml of xylene (containing 100 Bg Pd / c) was refluxed for 3 hours. The solution was filtered through ground soil and the catalyst was washed with M CH2CU. After distilling off the solvent, hurricane compound c) was obtained. Μ.P. = 195 °. 5-Hydroxy-benzthiophene-3-carboxaldehyde and 5-methoxybenzenephene-3-carboxaldehyde, used as starting materials for the preparation of compounds 104 to 107 of the fu, can be prepared as follows: • Cages are looking forward to Ί 撖 路 a) (4-Methoxy-benzyl) propionylsulfuric acid will be 0.165 mol of hydrogen hydride, and 4-methoxythiophenol (0. 15 mol) dissolved in 300 · 1 THF solution. After 1 hour, add carbamide (0.165 mole). The mixture was stirred at room temperature overnight. Afterwards, the solvent was distilled off and the mixture was dissolved in CHzCU. M2N Na2C〇3 Qingzhu. Dry the organic phase and evaporate the solvent to get the title compound a) · It can be used without further purification. b) 3-Methyl-5-methoxy-benzothiophene «Μ · MB- compound of 0.15 mol a) * Polyphosphoric acid-33 was added under reflux for 1 hour- This paper scale is used in China Η Family Standard (CNS) T4 specification (210 father 297 public goods> 81. 4. 10,000 sheets (H) (please read the back W1 first note t matters # 埸 写 此 页) 2〇〇 ^ 80 Μ Economy Printed by the Ministry of Central Bureau of Standards, S Industry and Consumer Cooperatives 5. Description of the invention (32) (0.17 ear) in 1 liter of gas stupid solution. Save and stir the solution overnight. Filter the mixture and evaporate. The filtrate. Crude product M Si02 Analysis and dissolution agent: hexane) to obtain 抷 《compound b). c) 5-Methoxy-3-bromomethyl-benzthiophene «aw Add 0.01 konil UBS and dibenzoylated oxygen-containing crystals to compound b &gt; (0.01 mol) dissolved in 60 · 1 carbon tetrachloride Of solution. The mixture was soaked and refluxed for 1.5 hours. Pass through the suspension and evaporate the filtrate. The resulting oil crystallizes on cooling and can be used without further purification. d) 5-Methoxy-benzthiophene-3-carboxaldehyde «· MM» 0.09 hexamethylenetetramine was added to compound c) (0.08 qi) in 150 ml of acetone. The mixture was soaked and refluxed for 6 hours. After cooling, the B-boat is added to the suspension and solids emerge from the filter. The residue was dissolved in 100 nl * 50% CH3C00H and the mixture was refluxed for 3 hours. Then add 130b1 water and 25 · 1 MeHCI, and reflux the mixture for 5 minutes. M ice-cooled mixture. The crystallized title compound d) hydrocarbons are separated by filtration and washed with water. M.P. = 50 ° 〇g Example 1 1 7: fi-yun certain cage favors pan-3-carboxyl route BBr3 (0.07 mol) is dissolved in the dissolved knot of 15.1 CH2CU, at 0. A solution of 0.014 mol 5-methoxybenzthiophene-3-carboxaldehyde dissolved in 80al CH2CU was added. After 4 hours, add 2N Ka2C〇3 until pH = 7. Evaporate the organic solvent and suspend the suspension. After washing the solid with water, the crude title compound was recrystallized from CH30H / H20. Μ · Ρ · = 200. ° -34- This paper is used in the national standard (CNS) 1Μ size (210X297 g *) of Λ scale side 81. 4. 10,000 sheets (Η) (please read the information about the warehouse and write down this page first Sun Huang) Xiu, Τ 2〇〇_, 81.9.221 *; for the real blade Α6 Β6 V. Description of the invention (^) Formula I compounds and the preparation of qualified salts (hereinafter referred to as the compounds of the present invention) with K drug activity • Therefore, it can be used as an agent. In particular, the compound of the present invention has an excitatory effect on gigantic gigantea, which can be proved by the horizontal test of the squash. Examples are as follows: The monopolar thunder pole is implanted along the serous surface of the small intestine wall of the beagle. Input the signal into the pre-amplifier and filter the low and high frequencies of the record. This will cause the electrodes to be separated • slow waves and spikes. Measure the following data that appears during 2 minutes: during phase I-II, two consecutive propagation speeds. Record one or two cycles of the tip electrode before subcutaneous injection and then subcutaneous subcutaneous injection for 10-15 minutes. Perform a control test. For dogs that have been fed, additional spikes. In this test, the stimuli of the compounds of the present invention range from about 0.01 to 10 III g / k S s. C. In this test, 10, 13, and 108 compounds stimulated muscle activity of 0.01, 0.03, and 0.1 μg / kg 3. ^ ·. Furthermore, for example, it shows that the compound of the present invention has an excitatory effect on stomach larvae due to its effect on the isolated guinea pig fish intestines. 200-400 g of guinea pigs were stunned and bled. Long-term removal and transmission of Trendelenburg Path Pharnakol., 81. 55-129 (1917) 20m 丨 in organ bath (the initial charge is lg>. The sister suspects M repair solution (HaCl 118.6; CaCU 2.7; KC1 4 . M g S CU 0. 1; N a HC 0 3 2 5. 0; W glucose 5 · 6 37t and W containing 5% CO2 gas bubbling. Increase 4cmH2〇> Induced peristalsis 30S. Use f Tension Reflex® and use the transducer to measure the angulation (AUC) under the ring-shaped muscle activity curve and describe the number of rings and longitudinal peaks in phase II area In this way, the interval of the intercepted segment, I was finally administered with a solvent every 30 minutes when the final concentration of the agent was used to prove that the case of ft was a spontaneous reflex and also showed 0. The final ileum segment 4-5αη in Arch. Exp. The method · Mao Fu Yu Shi Ke K (Krebs) 7; KH2P〇4 1.2; m Μ) without a bath, maintained in the surprise cavity ® from zero 1 to-displacement energy device to determine the longitudinality. Collect the AUC of the activity. {Please first read the notes on the back and then fill out this page.) • Hit the... Line-dip-A 4 (210X297WJ! F) Printed by the Ministry of Economic Affairs, Central Bureau of Economic Development, Beigong Consumer Cooperative, 2004 80 Λ 6 __ η 6_ «V. Description of the invention (34) The area under the curve (AUC) and depict the AUC representing the shape of the ridge and the muscle activity to establish a concentration response curve. Each system is regarded as its own control. The moving ability of the compound to be held before being administered is regarded as 100X. The test compound is added to the serosal surface and brought into contact with the sister for 15 minutes. In this test, the compound of the present invention has an stimulating effect on the motive ability at an irrigation level of about 10-1CM to 10-7M. Therefore, the compound of the present invention can be used to treat the intestinal pancreatic movement disorder with K *, such as the emptying of the body with obstructed pancreatic movement and the normalization of the intestinal transport function or the improvement of the bodhidharma *. The obstruction of pancreatic movement includes examples M-esophageal reflex disease , Esophagus and / or Qi and / or small and / or large intestine motility reduction: or use Μ to treat esophagitis, W light fistula * indigestion * non-ulcer dyspepsia • False obstruction, obstructed colon delivery · intestine Colic * Intestinal sensitivities, constipation, upper abdominal pain, lower back pain after surgery, recurrent nausea and vomiting, anorexia nervosa, or pain when slings control. In addition, the compounds of the present invention have also been shown to be useful for treating bladder pain during movement, adjust cortical enzyme / aldosterone extraction, or promote memory and learning ability. The above-mentioned usage statement • The required cocoon ft of course differs depending on the way of casting * the special condition to be treated and the desired effect. The recommended daily dosage range is about 0.01 to about 3 mg, for example, about 0.01 to about 1 ms for parenteral use, and from about 0.1 to about 3 mg for oral administration, it is advisable to administer it in one dose • divided doses 2 to 4 times / day, or take the release type. Therefore, the unit dosage form for oral administration contains from about 0.0025 to about 1.5 ig of active ingredients (that is, the compound of the present invention or the preparation of the qualified compound), and broadcasted as a solid or liquid, the preparation of the qualified dilute cocoon . According to the foregoing, the present invention also provides: i) a method that can treat the disease of 'momentum movement' (such as irritable bowel movement), painful bladder movement and embedding and release of skin enzymes / aldosterone Or promote (please read the notes before filling out #fill in this page) -36- This paper "Where to Use" Beta B Family «Bi (CN5) T4 Specification (210X297 public *) 81. 4. 10,000 sheets (Η ) ⑼ 〇4β〇Λ 6 Π 6 Printed by the Ordnance Industry Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economy V. Description of Invention (35) The memory and learning ability of individuals in need: The law includes the effective application of the price The compound of the present invention or its pharmaceutically acceptable MΓ. We have further found that the compound of the present invention has a specific antiserotonin effect on 5-HT4, which can be confirmed by the standard test chess. Examples are as follows: Tianzhu »The isolated longitudinal muscle of the gyrus and the intestinal muscular plexus system sticking to it Excellent established chess pattern, which can study the action mechanism of various gods and cocoons. The method kills male guinea pigs (200-400g) to death and bleeds. The small intestine about 2 co long was removed from the cecal flap. The ileal glass rod was stretched and the mesentery was carefully removed. Use a lint of cotton wool to tangentially knock out the mesentery attachment * to detach the suspected muscle and remove the ring-shaped muscle below. The muscle strips, 3-40B long, were placed in 10ml 37t: an organ bath containing Tyrode's solution and bubbled with 5% carbon dioxide in oxygen. The Dairot solution contains the following sister Umol / l): NaCl 137.0; CaCl2 1.8; KC1 2.7; MgCU 1.05; NaHC〇3 11.9; NaHP〇4 0.4; Glucose 5.6: and dimethyl ergoxin Ml 0.1 «M . The muscle strips are maintained at a resting tension of 500 ng. K and other camera records shrink. After an equilibration period of 30 minutes, a specific concentration of aminoformaldehyde gallbladder test was applied at 10-minute intervals until a consistent response was obtained. Production of Niu Sui Ma / Huan Peng Qu Cui Add a synergist of hemp increasing concentration to the organ bath at an interval of at least 15 minutes to establish a non-cumulative concentration-inverse curve of 5-HT. The pre-realization has verified that the interval length is sufficient to avoid rapid response. Contact each sister for 1 minute at each concentration. Each muscle strip is only used to record the second concentration-response curve. • The first time is single »5-HT * The second time is 5-HT in the presence of a certain degree of antagonistic cocoon. Therefore, each -37-k The paper size is in the middle Β home sample standard (CHS) Ή specification (210x 297 g) 81. 4. 10,000ft (Η) (please read the text first and pay attention to the matter # 堉 写 木 页) installed &ordered; --线-〇〇〇4β〇81.9.22 A6-B6 V. Description of the invention (#) Muscle strips are used as their own control group. The antagonist was pre-equilibrated for at least 10 minutes before adding 5-HT. The shrinkage obtained from several formulations * is expressed as a percentage of the maximum response to 5-HT. The mean value of M is used to obtain a concentration-response log curve. The value of the inhibition constant ΜρΑ2 is determined according to the conventional usage (Aru η 1 a k s h a n a) et al. * 1 9 5 9, Mc Hung (M c K a y) 1 9 7 8). This test proves that 5-HT has the contraction effect of concentration concentration. 5-HT causes guinea pigs to release substance P from the nerve endings in the longitudinal muscle strips of the intestine, and induces the main contraction of this texture. Its role is influenced by two different 5-HT media. At low concentrations, 5-HT activated sacred units are released by «•. The released substance P activates the sacred unit receptor P ** and therefore waits for a second article_ 鍮 出 'This substance is then activated at the higher concentration of the beta of the muscle tenant ’s poison army. , 5-HT activates the second unit of the gods, and thus releases the product 霣 Ρ, which can activate the flat muscles. The material on the cell is «• sui. The salivary compounds of the present invention preferentially block the high-affinity 5-HT-4 receptor at a concentration of, for example, about 10-8 to about ^ 10-8 &gt; 11〇1 / 1, thereby inhibiting 5-HT-induced contraction. Its equivalent to low affinity 5-HT3 reliance position is less antagonistic. In this experiment, it has been proved that the ρ of the examples 89, 90 and 97 are 8.1, 8_0 and 8.3 °. Therefore, the compound of the present invention can be used for treatment. Caused by the expense of asking Nao · Mole allergies 'intestinal spasm, intestinal pain spasm, secretion caused by the increase in the degree of hypermagnesia, europium-esophageal reflex disease and biliary system dynamic pain °' _ The present invention The compound can also inhibit the cataract induced by necrosis. As shown in the broadcast test, for example, the use of rats with Yi Biao Faqi disease. The experiment was conducted with male rats (200-250g) (fasted overnight. But not water). -38- 甲 4 (210X297 伂 发) (Please read the precautions on the back before filling in this page) • Install ·. Play. Λ 6 η 6 〇〇4® ° 5. Description of the invention (37) Test object The sc or Μ 金 羼 W tube was administered orally. After the test substance was administered, 30 minutes of shoveling was orally administered to anhydrous ethyl yeast, and the animals were killed 1 hour later. Its M Zhida cut open and flatten the nail. The hemorrhagic disease of Dong is determined in two ways: the area and length of the disease. The compound of the present invention as a test compound M was about 0.1 Bg / kg to 10 »g / kg _Gai sc administration showed that it significantly inhibited the yeast-induced stroke disease, the results can be compared with the control group receiving placebo instead of the test substance . ih first read ih back-and note · items to fill in this page Printed by EX Gongxiaot Cooperative of Central Bureau of Standards of the Ministry of Economic Affairs. Therefore, digestive disorders, such as bladder reaction and vomiting. With regard to the above-mentioned special situation, about 5 mg of the medicinal unit is administered at appropriate times. Based on the symptom, the compound of the present invention has been proved to be useful for the prevention or treatment of waist disease such as lake disease. It was further confirmed that the compound of the present invention can treat diarrhea, and intestinal inflammatory diseases such as inflammatory inflammation and duodenitis, including inflammatory bowel disease, ah heart. In addition, it has been confirmed that they can treat arrhythmia, rapid heartbeat * pain when moving, such as incontinence, reduced stroke, or stress and stress. The required dosage depends on the way of administration, the specific characteristics of the treatment The box varies. The recommended daily dosage is about 5; ug to be used for parenteral use, about 0.1 to about 100ms grade for oral use, suitable for one, divided dose of up to 2 to 4 times / day, or Yuan release type. Therefore, the swelling dosage form contains about 0.025 to about 50 ag of the compound of the present invention and is mixed with a solid or liquid, pharmaceutically acceptable diluent or carbohydrate. In the foregoing, the present invention also provides: a method for treating any of the above-mentioned diseases in an individual in need or the method comprises administering an effective amount of the compound of the present invention to the alligator or its preparation-39 binding line table paper size for use a S home "quasi (CNS) V4 specifications (2 丨 0X297 male dragon) 81. 4. ΙΟ, ΟΟΟίΜΗ) Λ 6η 6 Ministry of Economic Affairs + Central Government Bureau of Industry and Fisheries Consumer Cooperation Du printed five, the description of the invention (38) "Qualified"; We have also found that the compound of the present invention has an antagonistic effect on Zhongli 5HT-Ι (Γ receptor). The compound of the invention has a strong binding affinity to the Zhongtian 5-HT-1C receptor. This is based on, for example, D. Hoyer et al. Eur. J. Pharmacol., I1S_, 13-23 (1985) showed the method. According to GA Kennett (Kennett) and G. Curzon (Br) J. Pharmacol., 137-1 47 (1988) shows that the compounds of the present invention can antagonize the low-activity bluntness induced by the administration of phosphorus-chlorphenyl-hexahydropyrazine (UCPP) in rats. In this test, the compound of the present invention is effective against mCPP-induced retardation after administration of a dose of about 0.1 to 30 ng / kg P.O. Therefore, the compounds of the present invention can be used to prevent headaches or treat mental disorders such as Jiao, obsessive-compulsive disorder and obsessive-compulsive behavior disorder, fear attacks, depression, eating and drinking, schizophrenia, increased intraocular pressure and permanent erection symptoms. Regarding the above uses, the required dosage will of course depend on the particular way of administration * and the special conditions to be treated and the required effects. The recommended daily dose of Dong Fanyuan is about 0.5 to about 300 mg. Tongyi is usually administered in one dose, divided into 2 to 4 times per day, or the first-release type. According to the foregoing, the present invention also provides: iii) a method for treating a sugar headache or mental disorder in need, which method comprises administering the compound of the present invention or a pharmaceutically acceptable salt thereof effective to the stern. % The compounds of the present invention also have a synergistic effect on 5HT-ID. Its -40-this paper is used in the beta country «Bi (MS) V4 specifications (210X297 public 81. 4. 10,000 sheets (Η) (please read the potential note of the first note € 資 事 # 蜞 乔 this page) installed Threading &lt; 2〇〇〇〇〇6 A6 B6 (¢ 1. V. Description of the invention (^) 5HT-ID Waist adhesion affinity has been, for example, according to C. 唏 伯 (Waeber) and others in Haunyn-Schaiedeberg's Arch. Phariacol ., 337. The method shown in 595-601 (1988) was determined. The pKD value of the compound of Example 63 was 8.85. The synergy was further exemplified by the following analytical method: Porcine brain resection obtained from the local slaughterhouse Long veins. The long 3-4 ring-shaped section is placed between two L-shaped gold forks, and placed in a temperature-controlled (37 1C) organ bath filled with Kjeldahl solution and containing 5% Oxygen bubbling of C02. The measurement of "Constrictor-induced vasoconstriction." To confirm that only 5HT-ID is affected by the β-mediated effect • Then add human sericin (Ketanserin, 10-7M, its It can prevent hydrocarbons from being contracted by 5HT2. The compound of the present invention can induce vasoconstriction at 10-1 ° to 10_βΜ (in particular 10-eS10_7M). It has been proved in this test The PD2 value of the compound of Example 63 is 9.0 0 s: Therefore • The present invention can be used for the treatment of a headache with a long-term headache ^ in particular for the treatment of headache • Xuan * headache • Chronic paroxysmal sugar headache and the disease of hematurin- ·-Headache, and can reduce the symptoms of phalanx. For the above purposes • The required dosage will of course vary depending on the way of administration • The special conditions to be treated and the required effects vary. The recommended daily fan rate is about 0.5 to Approx. 300 ms * Tangyi should be fed at one time, divided into 2 to 4 times per day of fR perch • or «release type. According to the above • The present invention also provides: iv &gt;-a method to treat the needy« 有 Μ « Symptoms of headache, such as the above • This method includes the administration of the compound of the present invention or the qualified salt of the protease. The compound of the present invention can be administered by the conventional route, especially the hydrocarbon nose and enteral ( Please read the precautions on the back before filling in this π) • 51.. Order • • Line, 41 A 4 (210X 297 2 Pan) Λ 6 Π 6 2〇〇48 ° Fifth, the invention description (ZfO) (please first (Please read back and pay attention to matters # fill out this page), it is better to use your eyes and eyes • For example, tablets or capsules, or parenteral, Such as injection solution or suspension dosage form or suppository. 'The compound of the present invention can be administered in free form or pharmaceutically acceptable salt form. These H can be prepared by conventional methods and have the same level of activity as the free preparation. The present invention Qualified salts for the preparation of compounds of compounds include, for example, hydrochloride salts. In addition, the present invention also provides: ν) Compounds of the present invention or pharmaceutically acceptable salts thereof, used as, for example, any of the above-mentioned methods; The sister compound contains the above-mentioned compound of the present invention or a pharmaceutically acceptable salt thereof, together with a qualified diluent or carrier. These sister compounds can be manufactured by conventional methods, such as mixing the ingredients. In formula I, 1 ^ is hydrogen, A is -N = or -CH = and Z is -CH =, or wherein A is -CH =, Z is -N = or -CH =, and 1-8 is hydroxyl or Cx -e alkoxy compounds have an irritating effect on the bowel movements. Therefore, they can be used in the method of the present invention to treat osseous diseases, such as stimulating the peristalsis of the guts, as described above, and treating the pain of bladder movements. , Yuan and cortical enzymes / aldehyde retention agents release or promote memory and learning ability. The compounds of Examples 13 and 108 are preferred. The Ministry of Economic Affairs, Ministry of Economic Affairs, Pyongyang Bureau of Industry and Commerce Cooperative Printed 31, “W of Formula I” and / or the compound of which R 7 is not hydrogen * For example, it has a specific antiserotonin effect on 5-HT * receptors and inhibits Pro-necrosis agent induced disease of 霣 * Therefore, it can be used as anti-ulcer or anti-activator of the method of the present invention, for the treatment of intestinal obstruction and the prevention or treatment of ulcer disease. Inflammatory symptoms of the intestine such as inflamed inflammation, duodenitis, including inflamed bowel disease, nausea and vomiting • arrhythmia • rapid heartbeat, sensation of bladder movement such as incontinence, reducing stroke occurrence * or grade and stress response. To 81.4 . 10,000 sheets (H) of this paper are used in the "Sleepy Home Sample Standard (CNS) f 4 specifications (210x297 g * &gt; 2〇〇48 ° A 6 Π6 V. Description of the invention (M) S Example 89, 90 Compound 97 and 97 are preferred. In the formula I, Rb is gas * radical * Ci-e halogen, bromine or "-β alkyl, z is -CR4 = or _ Australia, A is -CRt = where R7 is S Or a compound of formula (B &gt; radical,!?, 〇 is NH-C0-phenyl or Ci-u alkyl or Ci-e alkyl, such as antagonism, and therefore M can be used for preventive diseases such as pyrolysis , Obsessive conception and forced or eating. The compound of Example 38 is preferred. In Formula I, Re is hydrogen, hydroxyl, Ca-e alkyl carbonyl, CONH, SOaNHiCT-e burned group) POiCi- * alkyl) 2 substituted Ci-e alkyl group is -CH = and R2 and R〇 are each Yunnan, especially its group or (b &gt; group wherein 2 is (: 1-12 alkyl group or -CONH-CeHn 5HT-ID Synergistic effect • and can therefore behave like described above. Μ 例 63 合 合

The base or sulfanyl group is argon, chlorine 1? 4 is hydrogen * Cl-β-alkenyl group, gas-β alkyl group, and it is preferred that the benzimidazolyl group is substituted for the Zhonghe 5HT-IC receptor. Headaches and treatment of mental illness, fear attack, depressive group, carboxyoxy group, C2-e alkoxy group, SOsiCi-e alkyl group or W is NH, A is -CH =, Z in B is NH- compounds · For example It is especially good for the treatment of symptoms of kang headache with Μ. (Please read the precautions of "quote" first and then fill out this page) Ministry of Economic Affairs Central Punching Bureau Ordnance Elimination #Cooperative Du Printed-43 This paper is used only in the "National« Bi (CNS) ΤΜ specification (210x297 Public; ¢) 81. 4. 10,000 sheets (Η) 2〇〇4β °-: must 3 :: 1-..... No. 81102161 Patent Supplementary Case Chinese Supplementary Note ί (September 81)抟 g The previous skill of this dish is the English patents GB842323 and GB842325. The former shows the following formula

RiNH-C-KH-N = CH-R2

II

In the NH formula, iU is an optionally substituted aryl group, and R2 is an optionally substituted alkyl group, an optionally substituted arylalkenyl group, or an optionally substituted mono- or bicyclic heteroaluminum. This compound can be used to treat allergies and inflammation. Among them, only one lumbenyl compound is specifically shown as an example in which 2 is an optionally substituted bicyclic heterocycle, namely N1- ^ methylbenzene * -N2_3Vb indolyl-methineaminoguanidine. This compound has been deleted from the scope of the application of Benju, as described in the condition attached to Item 1 of Φ 誰 専 利范 浦 (as stated.-'The compound B requested by GB842325 contains the compound disclosed in GB842323.

HWX0156. G

Claims (1)

A B c D VI. Patent application ffi Formula I compound i? / Y—NH-S (I) where ... W is S or -m-, where Ri is hydrogen or Ci-β alkyl, 1 to 2 is ammonia or Cl-β burned group, and Rs is hydrogen, Halogen or (^ -3 alkyl; hydroxy; nitro; amine; Ci-4 alkylamino; c2-e alkoxycarbonyl; S〇2NRsRb its 1 ^ and 1 ^ are independently hydrogen or Ci-e Alkyl; cyano; or trimethylsilyl .; or, when A is -CR7 =, IU can also be he alkyl and -S 0 2-C 1-β alkyl, -SD 2 NR e R b,-C 0 NR e R b, -NH-SOa-Ci-e alkyl, alkyl) -SOdh-e alkyl), -NReR'b where R'b is hydrogen or Ci-β alkyl, C2-e alkoxycarbonyl or -PfHCi-4 alkyl) 2; carboxy; C0NReRb; -PfHC!-* Alkyl) 2; 0C0NRcRd where Rc and Rd are each gCi-e alkyl; Re is hydrogen, or when Re is hydrogen or halogen when RB is 0H, Z is -CfU = where R4 is hydrogen, hydroxy or Ci-e alkyl or, when Rs is hydrogen or hydroxy, Z can also be -H =, A is -N = Or -CR / = where R 7 is hydrogen, C i-β alkyl or C i-β alkoxy (please read the precautions on the back side before filling this page). Install. • Hit. * 缘 · Ministry of Economic Affairs — The quasi-bureau printed a A4 (210X 297 public) 20048 ° A7 B7 C7 D7 Six 'application Lifan® X--Y is -CRa = N- or -CH (Re) -NH- where Re is hydrogen or Ci-e alkyl, and B is formula ⑻ or base ring,, (CVn, 10 N (a) (b) where n is 1 or 2, eight 1 is C = 0 or CH2, and 1 is 5, "11 or ^ 21? 13 * where 1? 11 is hydrogen, 1? 12 and!? 13 are independently Hydrogen or alkyl ί Rio is gas; Cl-12 burning group; Cl-β burning group and through the group, any substituted stupid group, any substituted phenoxy group, gold net alkyl group, the following groups ... ............................ {................. ¾ .. ............................. tr ...... {................. ... body {please read the precautions on the back before filling. ¾ this page) Ministry of Central Standards Printing, stupid imidazolyl, du 1 {15-(： 0-1? 1 «or -1 ^- 502-stupid; gold steel alkyl; -C0NHR14; or Ci-i. Alkylcarbonyl; where R14 is Ci-no alkyl, C5-7 cycloalkyl, CS-7 o alkyl alkyl 4 (210X297 male; ¥) 2- 200480 A7 BT C7 D7 Sixth, please specialize in Pan® -C3L-4 alkyl, phenyl, Benzyl Cl_4 alkyl, hydrogen or alkyl, and Rie is Ci-e burning group, Cb- t · Cycloinyl group, Cs-7 soil burning group 4 burning group》 Benzy group or Benzyl alkyl group, and Xa is -NR3R i〇where Rs is oxygen or Ci-e alkyl, once 1''10 has any of the meanings listed above Rio or Ra and 1''10 together with the gas atoms to which they are connected form N-hexahydro Base or in the case of a mitochondrial base, with the condition that i) when B is a base of formula ⑸, only one of R10 and R '10-which may be a non-hydrogen group, and ii) when B is the following base ... ........................ {............... install (please first Read the notes on the back and fill in this page) HH, NHR [Where R'10 is 4-methylphenyl], Z and A are each -CH :, W is Ν Η-, R 2 and R β are each hydrogen, and χ--γ is c Η = when , R β is not a sign; when it is hydroxyl, it is physiologically hydrolyzable and qualified ether or distillate, and it is free or salt. 2. The compound according to the first item of the application scope, which is 5-hydroxy-indole-3-carboxamido- (N-cyclohexylureido) methylenehydrazone, 5-hydroxy-indole-3 -Carboxaldehyde amidino (3-benzimidazol-2-yl-propylamino) methylenehydrazone, 5-aminoformyl-indol-3-carboxamido (pentylamino) methylenehydrazone, T 4 (210X297 Gong Feng) line ½. The Central Department of the Central Department of the Kobe Department ¾. The Central Department of the Central Department of the Yaji Department printed the BT C7_D7_ of 2004. VI. Patent application iiffi 5-hydroxy-7-methyl- Indole-3-carboxamido (pentylamino) methylene hydrazone, 1-ethyl-5-hydroxy-worm dol-3-carboxamido (pentylamino) methylene hydrazone, 5- Hydroxy-7-methylindole-3-carboxamide (N-methyl-N-pentylamino •) methylenehydrazone, 5-keto-4-aza-indole-3-carboxy Aldimine (pentylamino) methylene hydrazone, and 5-methoxy-indole-3-carboxamido (pentylamino) methylene hydrazone, in free or salt form. 3. A method for preparing a compound of formula I according to item 1 of the patent application, which includes-a) preparation of a compound of formula I where X--Y is-CRe = N-, consisting of a compound of formula I R5-(II) 4 In the formula, A, W, Z, IU, R5, and Re are as defined in the first item of the application scope and formula Π [compound reaction HzH-NHB (I) In the formula B, as defined in the first item of the application model; Or b) preparing compounds of formula I where X--Y is -CHRe-HH-, by hydrogenating compounds of formula I where Y--X is -CRa = H-; or c) preparing compounds of formula I where B is formula (b ') Group of compounds * by alkylation, acetylation or -4- ................................. { ................ ¾ .............................. ir … A .............. ^ {Please read the notes on the back and then scorpion this page) A 4 (210X 297 Koji) 2〇〇4β 〇6. Applying for nasal vanilla ffl AT BT CT D7 amine formyl compound la NH, (la) (please read the precautions on the back before filling in this page) -A, W, Z, R2, R5, Re, and X--Y are all the same as those in item 1 Definition d) Prepare a compound of formula I in which R5 is a hydroxyl group, and make the compound of formula lb undergo an ether cracking reaction YA〆 N.H-B (lb) Color ·. * £ © Printed by Jifang Central Bureau of Preservation A 4 (210X 297 male dragon) Printed by the Central Bureau of Economic Affairs of the Ministry of Economic Affairs 20048 ^ B7 Cl I_____D7_ VI. Patent Application Paradigm ® A, W, Z, R2, Re and X--Y and B are as defined in item 1 of the patent application scope • And it is a cleavable ether group; or e) preparation of a physiologically hydrolyzable and qualified ether or ester of a compound of formula I (where "is a hydroxy group"), etherification or saccharification of a compound of formula I where R 5 is a hydroxy group; and , The obtained compound of formula I or its physiologically hydrolyzable and qualified ether or ester Μ free type or salt, solvate or hydrate type recovery. 4.-for the treatment of 5HT1C, 5HTlt ^ 5ΗΤ4 betrayed A medicinal composition for disease or symptom, which contains the compound according to item 1 or 2 of the patent application or its qualified salt, together with its pharmaceutically acceptable diluent or carrier. 5. A compound used for the treatment of gastrointestinal diseases Animal diseases, inflammation of the stomach and intestines, stomach-esophageal reflex diseases, and B-drug complexes for the prophylactic treatment of migraine, including the compounds according to item 1 or 2 of the scope of patent application or their qualified salts , Together with its pharmaceutical-qualified diluent or carrier. The "pharmaceutical composition, which includes a compound as defined in item 1 of the patent application scope, wherein RB is H, OH, Cj-e alkoxy, carboxyl, C2-e alkoxycarbonyl, COHH, S〇2HH (Ci -e alkyl) or S〇2 alkyl substituted alkyl, W is NH, A is -CH =, Z is -CH =, R2 &amp; Re are each Η, B is Cl or group where XzgCi — alkane Base or-cONH-CeHu, or its acceptable salt on the 槩 槩 acceptable, and "Pharmaceutically acceptable diluent or carrier. (Please read the precautions on the back before filling this page). · «Ρ 4 (210X297 Public Broadcasting)