TW201312B - Spiro bridged and unbridged heterocyclic compounds - Google Patents

Abstract

Compounds (I) and (II), including enantiomers, racemates and acid addition and quaternary salts, are for treating diseases of the central and peripheral nervous system, (see claim 1). In which in formula (I) Q is (CH2)m attached to the 1',4' or 1',5' positions of the six-membered ring (m=1, 2 or 3) and in formula (II) Q is two hydrogen atoms, (CH2)m or C(CH3)2 (m=1, 2 or 3) and n and p are each independently 0, 1, 2 or 3, provided that n+p=1-3; Rx is hydrogen, methyl or OH; (see claim 1) R and R' are independently H, NH2, NH-C1-6-alkyl, N(C1-6-alkyl)2, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-7-cycloalkyl, C1-6-alkyl substituted by 1-6 halogen atoms, HO-C1-6-alkyl, C1-6-alkoxy, C1-6-alkylthio, C1-6-alkoxy-C1-6-alkyl, carboxy-C1-6-alkyl, (C1-6-alkoxy)carbonyl-C1-6-alkyl, amino-C1-6-alkyl, mono-(C1-6-alkyl)amino-C1-6-alkyl, di-(C1-6-alkyl)amino-C1-6-alkyl, 2-oxo-pyrrolidin-1-yl-methyl, Ar, di(Ar)methylol, or (Ar)1-2c1-6-alkyl, or R' may be C1-6-alkanoyl or Arcarbonyl; and Ar denotes Ph optionally substituted by 1-3 of halogen, C1-6-alkyl, C1-6-alkoxy and CF3, subject to certain provisos.

Description

201312 The standard issued by the Ministry of Economic Affairs is printed along the S Industry and Consumer Cooperatives A 6 B 6_ V. Description of the invention (j) Invention of sleep and recitation The invention is based on 4-one and 5-spiral ring (1, 3-oxazoline And 1, 3-thiazoline) wherein the ring system saturated heterocyclic ring system connected to the oxazoline or thiazoline via a spiro ring is bridged or unbridged and contains a nitrogen atom, and the pharmaceutical compound containing this spiro compound . These compounds are useful for the treatment of central and peripheral nervous system diseases using such spiro compounds or B drug sister compounds. Novel spiroquinidine compounds in which the spirocyclopentane ring M spiro ring is connected Those who have reached the pyridine ring are described in the following documents: for example, European Patent Application 0205247Α2 (published on December 17, 1986) and US Patent 4,855,290 (published on August 8, 1989), 4,981,858 (January 1991 Announcement on the 1st), +, 900,830 (announcement on February 13, 1990) and 4,876,620 (announcement on October 24, 1989), all of which are incorporated herein for reference. These novel compounds were found to have central nervous system activity. 2-Methyl spiro ring (1,3-Humothicyclopentane-5 ', 3) Ravidin compound system M geometric H and trans. One isomer exists and this depends on the position of 2-methyl group • If the 2-methyl and rapamidine ring nitrogen atoms are on the same side of the mothidine ring as the cis-cyclopentane ring (if the 2-methyl and quinidine ring nitrogen atoms are on the different sides of the thiocyclopentane ring It is called trans (tm), and its biological activity has been specifically studied in detail. Based on the pre-clinical test, it was found that the compound (code AF 1 0 2 Β) is particularly promising to control Alzheimer ’s ( Alzheime "'s) type of Alzheimer's disease (SDAT). It is also of interest to optically resolve each of the cis and [form_ isomers, and to investigate the optical isomers of such optical isomers in several cases. Biological activity. (Please read the “Notes of Vatican” and fill in this page) DP 5 太 R 泞 m Φ Η K A 4 specifications (210 to 297 public goods) 201312 A 6 B 6 V. Description of invention (2) The main purpose of Fa'ming is to provide novel 4- and 5-pyrazol-1,3-oxazoline and 1,3-oxazoline compounds, which are different from the aforementioned spirocyclic oxazoline A pyridation From the following description, you can understand the further purpose of the present invention, in detail, referring to these useful medical products and disease treatment items 0 Invention 槪 Shu The present invention provides novel compounds, equivalent to the structure drawn Formula (I) and (I) Ya-rK) XX (called) 0 (ClDp (II) V> 1. \ IV / (PT.

(I) (Please read the precautions on the back before filling in this page) Outfit * * Can-line Spines and their acid additions 13 and quaternary class a, where in formula (I), Q polyester (c Η 2) „or C (C Η 3) 2 and attached to the six-membered ring 1 ', 4 'Or 1, 5,' position, where m is 1, 2, or 3, and in formula (II), Q is two hydrogen atoms, (CH2) ... or C (CH3) 2, where m (^ l, 2 or 3, and η and p ($; each is 〇, 1, 2 or 3, but n + p = 1 to 3; R3 is a hydrogen atom, methyl or hydroxyl; DP _ 6 too ".i & R Lu Xian Shen Shen entered into a tomb in a group house ((: Milk) A 4 Er grid (210x297 public goods) 201312 A 6 B 6 V. Description of the invention (3)

Y

R stands for Generations Division 0 ix

C——N

R

N 0 — 0

R

S

CIN

N or R

CIS

R Printed by the Ministry of Economic Affairs Standard Αβ 工 消 t Cooperative

R is selected from the group consisting of hydrogen atom, HH2, NH-Ci-s-alkyl, M-Ci-β-alkyl) 2, Cl-β-burned group, 〇2-β-dilute group * Cz-β-block Group, C3-7—ring fused group, Ci-e—alkyl group substituted with 1 to 6 halogen atoms, hydroxy-C 1-β _ burning group, Cl-e — oxy group, Cl-S — burning sulfur Group, Cl-e—homooxy-C 1 -β—homoyl group, Jun-Ci-e—burn group, (Cl-β—homooxy group) bond group—Ci-e—integral group, amine group A Ci-e — burned group, a single (Ci-e — comprehensive group) amine group — a Ci-e — fully synthesized group, a di (―Ci-es — burned group) amino group — a Ci-e — alkyl group, 2 — Keto-tetrahydropyrrole-1-methyl, aryl, diarylhydroxymethyl, and C ^ -e-alkyl substituted with 1 or 2 aryl groups, or R 'is selected from R Group and —alkyl acetyl and aryl carbonyl; and aryl represents unsubstituted phenyl or phenyl and is selected from 1 to 3 by halogen, (: -alkyl, Ci-s-alkoxy and CF3 Substituents are substituted, and subject to the following restrictions (i), (ii), (iii) and (iv), in the case of formula (I), namely: (i) where Q is dihydrogen, n = p = l, R ° A hydrogen atom, R Department N Η 2 and R 'is a methyl-based, then Y --- R! X bh τττν portion parts

P D (please read the back-face • note * -Zhu Xiangzai write this page) Pack-line '

N

CIO

Sub-gene Q is a secondary Q. If R 7 201312 Λ 6 Β 6 V. Description of the invention (4) p = 1 * R ° is a hydrogen atom, and R is a stupid group, then R 'is not the third butyl, (m ) If Q is two hydrogen atoms, n = p = l, R ° is a hydrogen atom, R is p-chlorophenyl, and R 'is a third butyl group, the Y-R part is not 〇- C- R is not N-

N -CI 〇XR, and (iv) If Q is two hydrogen atoms, n = p = 1, R ° is a hydrogen atom, R is 3, 5-dichlorophenyl, and R 'is a third butyl, Then the Y--R part is

X (please ^ read the Vatican face-note! I will write this page again) Not N-

C

R 〇 Contrary to the above, the spiro compound of the present invention has an optical isomerization phenomenon, but only in a few cases has a geometric isomerization phenomenon. In particular, if there is a connection between the spiro ring and R and / or R 'is asymmetric, and / or the spiro ring system contains a single nitrogen atom as a heteroatom, the optical isomerism化 phenomenon. The compounds of formulae (I) and (E) as described above are novel. The compound of formula (1) wherein Q is two hydrogen atoms, n = p = l, R ° is a hydrogen atom, R is NH2 and R 'is methyl and Y-- R is part A of the Ministry of Economics Standards Bureau The X-C — R printed by the consumer cooperative was produced by Harnden and Rasmussen (J. Med. I ο Chera. 1970, 23; 305 to 308) as a series of compounds that were activated by CNS, but not selected. The most active five N- in this series

DP 201312 A 6 B 6 V. Description of the invention (5)

One of several compounds. The compound of formula (H) wherein Q is two hydrogen atoms, n = p = l, R ° is a hydrogen atom, R is a phenyl group, and is known as the third butylbenzene, and among these, Q, η, PR ° and R 'has these values and R is p-chlorophenyl, but Y- -R is 0

C-R

X

N or N-

CR; or R series 3,5-dichlorophenyl, but Ο

Y R is N- C-R | all are known (see

X (Please read the precautions on the back before filling out this page) J ο nes, J · C hem. S 〇c · (1 3) 1 3 0 8 to 1 3 1 5, (1971), but according to reports, These compounds are not biologically active. I am satisfied that the medical sisters according to the present invention do not have the above restrictions (1), (1! 1) and (1 ^ /). '-1 9 8 9 European Patent Application No. 0 3 3 7 5 4 7 A published on October 18, 2009 is said to be useful for the treatment of mental disorders' Aging and Alzheimer's disease, and other physiology The condition is as follows: line. The Ministry of Economic Affairs + Central Standards Bureau Beigong Consumer Cooperative is printed on the table line.

The formula below is based on A Μ. The paper standard uses the National Standard (CNS) A4 specifications (210x297 mm) 201312 Λ 6 Β6 Printed by the Ministry of Economic Affairs, Bureau of Standards, A Gongxiao # Cooperative V. Description of invention ( 6) (where Ri and R2 are hydrogen atoms or specified substituents alone, V is N, -CH or -C-, and W is 0, S or NH and may be substituted by specified substituents), Q series Residues of the aza-heterocyclic system or the azabicyclic system, and two of X, Υ, and Z are independently selected from 0, S, and N, and the other is C, or Υ is C = 0. These documents do not list detailed results of any biological tests, but illustrate that certain specific disclosed compounds (not specified) have an affinity for 5-HT3 receptors. This document does not provide guidance on K biological activity as a benchmark to select any specific type of ear from a wide variety of possible structures (represented by the symbols Q, X, Y, and redundant drawn on the replacement), and is related to the main two Cyclo-A is combined. An example of a bridged ring in formula (I) is: 1 monoazabicyclo [2,2,1] heptane, 7,7-dimethyl-1 monoazabicyclo [2,2,1 〕 Heptane, 1-azabicyclo [2,2,2] octanone quinidine, 1 monoazabicyclo [3,2,2] nonane, 1 monoazabicyclo [3 • 1,1] heptane, 7,7-dimethyl-1-azabicyclo [3,1,1,1] heptane, 1 monoazabi [3,2,1] octane. And 1 monoazabicyclo [3,3,1] nonane. In the formula (I), an example of the M spiro ring connection to the ring of oxazoline or thiazole is if Q is two hydrogen atoms, it is tetrahydropyrrole, hexahydropyridine, and hexamethylene; and if not For two hydrogen atoms, the example is: 5-azabicyclo [2,1,1] hexane, 6,6-dimethyl-5-azabicyclo [2,1,1] Hexane, 7-azabicyclo [2,2,1] heptane, 8-azabicyclo [3,2,1] octane, 6-azabi DP 10 (please read back first ^ (Note * ^ Fill in this page again) 201312 A 6 B6 The Ministry of Economic Affairs Standards were printed along the A Industrial and Consumer Cooperatives. Fifth, the description of the invention (7) Cyclo [3,1,1] heptane, 7, 7, 7-2 Methyl-6-azabicyclowell [3,2,1] heptane, 8-azabicyclo [3,2,1] octane, 9-azabicyclo [3,3,1 〕 Nonane, 7-azabicyclo [4,1,1] octane, 8,8-dimethyl-7-azabicyclo [4,1,1] octane, 9-aza Bicyclo [4,2,1] nonane and 10-nitrocarbacyclo [4,3,1] decane. In addition, as indicated by the symbol R ° in formulas (I) and (I), any of these ring systems are substituted with methyl or 0H. The spiro-linked compounds provided by the present invention have central and peripheral nervous system activity. In the current preferred group of compounds of formula (I), R is a hydrogen atom · NH2, NH-Ci-e-alkyl, Nf-Ci-e-alkyl) 2, Ci-e-alkyl or aryl , At the same time R 'is a hydrogen atom or a methyl group. In the preferred group of compounds of the present-formula (I), R is a hydrogen atom, NH-Ci-e-alkyl, M-Ci-e-alkyl) 2, Cn-alkyl or aryl, and R 'is a hydrogen atom or a methyl group. In terms of the generality of the present invention, examples of the compounds of the present invention are as follows: 2-amino spiro ring connection (1,3-humazoline-5,3 ') quinidine, 2-methyl spiro ring connection (1 , 3-B oxazoline-5,3 ') Ravidin, 2-ethyl spiro linking (1,3-morphazoline-5,3'), 2-phenyl spiro linking (1, 3-pyrazoline-5,3 ') wonton, 1-methylhexahydropyridine-4-spiro-linked 4'-one (2'-methyl-1,3'-oxazoline), 1- Methylhexahydropyridine-4 is a spiro ring connected with a 4'-one (2'-ethyl-1 ', 3'-zazololine), (please read the back first-the precautions before filling out this page) · Line · DP-11-Tailuis with the group 03 pets: 鸪 rn ί CNS) A 4 fold grid f 210 X 297 public funds) 201312 A 6 ___B6_ V. Description of the invention (8) 2-Methyl screw ring connection ( 1, 3—humazoline-5,4 ′) — 1′-methylhexahydropyridine | 2-methylpyridine ring (1,3-siazazoline-5,4 ′) — 1′-methyl Hexahydropyridine * 2-ethyl spiro ring connection (1,3-huizolin-5,4 ')-1'-methylhexahydropyridine , Including its isomers enantiomers, racemates homologs, and acid addition salts four salts. The present invention further provides "medicine composition" for the treatment of central and peripheral nervous system diseases of mammals, including M effective amount of at least one spiro compound of the present invention for the treatment of these diseases. In addition, the present invention provides methods for treating mammalian central and peripheral neurological diseases, including administering an effective amount of at least one spirocyclic compound of the present invention to mammals for treatment of these diseases. As mentioned above, the restrictions of (ii), ___ (Hi) and (iv) are not applied to such sister products and methods. (Please finish reading ¾¾ • Zhuyin *? Please fill in this page again) Printed by β Gongxiaot Cooperative of the Bureau of Standards, Ministry of Economic Affairs

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2 1A Big chromium ruler iA A 4 erbium (210x297 public repair) 201312 A 6 B 6 V. Description of invention (9) Tai 13 detailed description of the war submarine (T) made of the compound of thiazoline compound The reaction of the ring-bonded compound of the above formula (I) to effectively form a morphazoline or oxazoline ring. By way of example, if Q = (CHz) n and: 1 = 2, the suitable starting material for this cyclization reaction is prepared according to the following reaction schemes A 1 and B 1.

(Please read the precautions on the back and then write this page) Pack. Thread · Ministry of Economic Affairs Standard Χ; Α 工 消 f? Cooperative printed flow rate [Si BJL Note in the process _ Β 1, S The reaction of sodium with 3-methylidene hydrochloride in aqueous solution produces a single product, 3-pyridinomethyl-ravidin 3

Jlf. Formation; adding the wet active Nguyen nickel to the latter until the nitrogen evolution ceases to cause the formation of the desired compound. The main advantages of the flow chart method are: a) There is no need to separate any intermediates; and b) The hydrogen content of the catalyst is sufficient, so no argonization device is needed. It has been unexpectedly discovered that any of the 3-amine methyl products in these reaction schemes can easily be condensed with carboxylic acid RCOOH to obtain a ring-linked compound. The formed morpholine can only be carried out smoothly under the following conditions, that is, the carbon atoms on the amino alcohol are fully substituted and the N Η 2 group is connected to it [see "Huizoline, their preparations" , Reactions and Applications "'JA Frunp, Chem.. E_e.V-TJL. 483 to 505 (1971)]. Alternatively, imidic acid R C (= N Η) — 0 —alkyl can be used instead of carboxylic acid R C Ο Ο Η. If it is a cyclodextrin such as raviidine, the reaction to provide the compound of formula I is illustrated as follows

(Please read the precautions on the back and then fill out this page) Installed and set the standard of the Ministry of Economic Affairs and printed by the β-Consumer Cooperative Society D Ρ--14- r / iii + ® a pet: Rose Tungsten C210X297 public bitch) 201312 A 6 B 6 V. Description of the invention (ll) In order to obtain a spiro-linked one-quinone compound, for example, if η = 2 and R = NH2, the preferred method is M cyanogen bromide and 3-aminomethylquinone 3 — Alcohol reacts. I am satisfied that although the previous method is effective in preparing the compounds of the present invention where X is 0 and Υ is Ν. In order to apply a similar formula K to obtain a compound of the present invention, a considerable group of sisters ⑶ where X is Ν and Υ is Ο, A suitable starting material (in the following description, in which the spiro ring is connected to the quinazolidine of the oxazoline ring system) is a 3-amino-3-monomethylquinone pyridine. This starting material is prepared, for example, according to flow diagram D1:

0 WtOJ or KCM, N ♦

Coffee Λ Co〇U reduction For example U A 1 Η

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Flow chart ILL 15 This paper scale uses the Chinese β family standard (CNS) A4 specifications (210x297 g *) 201312 A 6 B 6 V. Description of the invention (12) 靼 备 式 (ff) Xihui postmark The compound of the above formula (I) spiro-linked compound is suitably substituted to be saturated and contains only a nitrogen (hetero) ring system and a reactant that effectively forms a pyrazoline ring reacts. Therefore, for example, a suitable starting material is 4-aminomethyl-1 1-methylhexahydropyridine-4-enzyme, as shown in flowchart A2 from 4-nitromethyl-1 1-methylhexahydropyridine-4 -Made of leaven (for example, its HC1 salt), or as shown in flow chart B2, from 4-azidomethyl-1 1-methylhexahydropyridine-4 monool. 〇 14〇 / CM〇 'μο ciu ^ -ι (R ’= e.g. C Η 3) (please read the precautions on the back before filling out this page)

fi

Printed by the Negative Work Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

DP (R '= for example C Η 流 杆 _ R 2 16 This paper standard is used in the "National Sample Standard (CNS) A 4 specifications (210x297 mm) 201312 A 6 B 6 V. Invention description (13) should be noted in In the flow chart B2, the reaction of sodium nitrate with 4-methylidene-1_methylhexahydropyridine epoxide in aqueous solution results in a single product, namely 4-azidomethyl-1, 1-methylhexahydrogen The formation of pyridine-4-alcohol and the addition of the wet active Raney nickel to the latter until the nitrogen emission ceases resulted in the formation of the desired compound. The main advantages of scheme B 2 have been indicated in the relevant scheme B 1 above. Surprisingly, it was found that any of the three monoamine methyl products in these reaction schemes is easily condensed with carboxylic acid RC00H to obtain spiro-linked products'. However, Xianxin previously used the condensation reaction of amine monoalcohols with carboxylic acids. The formation of the morpholino ring system can only proceed smoothly under the following conditions: if the carbon atom system on the amino-acidase is completely substituted and the HH2 group is attached to it (see "Muzoline" for their production of glucose, Reaction and Application "'JA Frunp, C hem. 1JL, pages 483 to 505 (1971)] .Alternatively use 1 when the imidic acid is RC (: N Η) 0-alkyl to replace the carboxylic acid RC 0 0 Η. I will provide the compound I want to explain as follows (e.g. in the ring ring morphazoline / (In the case of hexaargonemia) ·· The standard of the Ministry of Economic Affairs and the β work consumption " printed by the cooperative (1) RC00H (Shuo Yunkuan) or (2) RC (: N Η) 湧 圆 [2

(Please read the notes on the back before filling this page)

DP 17 201312 A 6 B 6 V. Description of the invention (14) However, in order to obtain spiro-linked compounds, (if R = N Η 2) it is better to use cyanogen bromide and a system such as 4-aminomethyl-1 A methyl hexahydropyridine 4-alcohol reacts. I am satisfied that although the aforementioned method is effective in preparing the compounds of the present invention

In R Ν CIO Y-, its substance is expressed in Dai Ming hair, and it is made Μ γ · 法.

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Class application 7 is R I--

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Explicitly list Μ / IV as the starting material should be suitable, then the RI system is the 4th product I and the final amine is the most I and the 4th quality product is pyridine starting from the hydrogen hexahydrochloride system. Zoliu or Humji D2 to Jiatu connect I Chenghuan 1 stream snail | According to the base of the root as its hydroxy case installed. .Tr line. Printed by the Ministry of Economics # 揮 央 # 准 局 ΚΧ 工 consuming cooperatives

PD 8 1Χ 201312 A 6 B 6 V. Description of the invention (15)

..Rcool ^ _ t or Rc (> h〇〇- 垸 基 ϋ or KCiV >

Mi Pd'C ^ m NaBH.? KCUNH ^ CH.oA, N, (please read the precautions on the back before filling in this page) Ministry of Economic Affairs Standard Λ A 工 消 " Cooperative Society Printed R 苻 車 围 (R · = For example CH.1Z.

Too recognizable; Ψ ssr ^: 揃 人 （CNS) 5 ^ barium 糗 (210x297 public goods) Installation · Order 'line · 201312 A 6 B 6 5 16) / IV Explains the hair compound and the chemical compound berlin beer blind and glance Beer

I Y- if

N for R

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R or

R is similar to oxazolidine and the compounds are combined, or the oxazolidine is connected to the ring 0M; if this is the case, then the pyridine is prepared from quinone G or the pyridine F, the pyridine hydrogen, N, and the K under the six-stream series. Pingruruzo Mingming (Jing first read the precautions on the back and then fill out this page), tT line-Printed by the Ministry of Economic Affairs

P D ο 2 201312 A 6 B 6 V. Description of the invention (17)

◦Or (please read the notes on the back before writing this page).

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66 AB V. Description of the invention (18) Additional methods include preparing equivalent epoxides or thioepoxides as shown in the flow chart H and K reacts with suitable nitriles, in which the spiro ring is connected to mottle or thio The ring system of the Vila ring is, for example, hexahydro-Ovi or pyridine.

(Please read the precautions on the back before writing this page) Outfit · Printed by the Ministry of Economic Affairs + Central Bureau of Standards, male industrial consumer cooperative

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DP 22 This paper scale is selected according to China's "China Family Standard (CNS) A4 specification (210x297 mm) 201312 Λ 6 Β 6 Printed by the Ministry of Economic Affairs, Bureau of Standards, β 工 消 # Cooperative V. Invention description (19) ( The compounds of I) and U), although they themselves form specific examples of the present invention, or are contained in the S drug product of the present invention or used in the method of the present invention, both include addition of these compounds and quaternary salts. By way of example, acid addition salts used for medical purposes include those formed from these acids such as hydrochloric acid, hydrobromic acid, fumaric acid, maleic acid, oxalic acid, malonic acid, malic acid, acetic acid , Citric acid, tartaric acid, dibenzoyl D- and L-tartaric acid, xylyl D- and L-tartaric acid, salicylic acid, carbonic acid, aspartic acid and glutamic acid. In these cases, the spiro compounds of the present invention are optically active, and the racemic compounds are resolved to use optically active acids such as dibenzyl-methyl-tartaric acid and t-toluoyl-L- D-Tartaric acid. At least these cyclic compounds of the present invention (wherein R is methyl) are centrally active pyrotoxin agonists. Due to their pharmacological properties, these compounds can activate central cholinergic stimulation and other sexual functions in cases where the cholinergic system is too low. The spiro-linked compound of the present invention is generally quite useful for the treatment of Alzheimer's disease and Alzheimer's disease (SDAT), atypical Alzheimer's disease (Rerry, advanced neurology- R. J. yurtma η editors, 5 1; 4 1, (1 9 9 0), combined with multiple infarct dementia and Alzheimer's disease, associated with age-related memory impairment (AA Μ I) 'acute confusion Sexual disorders, mood and concentration disorders, mania, delayed movement difficulties, hyperactivity, mixed Alzheimer's disease and beatinson's disease, aphasia, phantom seeking state, post-amnesia syndrome, alcohol withdrawal syndrome , Hurtington's chorea, Pick's disease DP 23 This paper scale uses the Chinese National Standard (CNS) standard 4 (210x297 public splashes) (please read the sound of the back Φ *) Xiangxi then fill out this page) Pack-'νφ _ line. 201312 A 6 B 6 V. Description of the invention (20), Frialr_ick's movement disorders, Gilles de la Tourette disease and Down's disease, because of all these pathological obstacles Hinted central cholinergic stimulation Too low to at least some specific levels. The spiro-linked compounds of the present invention are also potential analgesics and are therefore useful for the treatment of severe pain conditions rheumatism, arthritis, and end-stage diseases. The spiro compounds of the present invention (wherein r is methyl) It has particular potential value in the treatment of SDAT and related abnormalities. The spiro-linked compound of the present invention can use K to bind with acetylcholinesterase inhibitors such as physostigmine or tetrahydroaminoacridine; with acetylcholine precursors Such as the combination of choline or lipase; there are "non-topical" agents such as Piracetam, aniracetam, oxiracetaB / '^ Jpraniiracetara; and compounds that interact with Ca2 + channel agents such as 4-aminopyridine or 3, 4 — Diaminopyridine; or the addition of peptides to acetyl gallbladder to release a regulatory effect such as growth hormone inhibitory factor (somatostatin); and peripheral autologous mycotoxins (such as Pirin Η-aza heptazone, N-A Chiatosine, N Propantheline, propantheline, methantheline glycated pubic acid or tropenzillium to counteract the surrounding SU and is expected to As follows: saliva discharge, diarrhea, excessive gastric juice secretion or vomiting, or in combination with percutaneous ranunculus alkaloids such as S c ο p 〇 d e "m (R > combined with M against vertigo and / or vomiting; and antidepressant

Read the back first, one of the notes, matters, and then write a copy of the book W installed π line, the Ministry of Economic Affairs, the Central Bureau of Standards, the beta industrial consumer cooperatives printed porphyridazine, such as the agent amine Lapumiyi C and e) SD in; ΡΓ 合群 na 混Syndrome RI1, Symptoms ΙΜΙ Curcuma ΑΑ Inhibin tetrimep RH Yueming and the time when there is 0 Reduced for the compound of the system and damage to the knowledge 0 (Zhilin Guanfu covered) West PD such as pharmacological drug poison Sen Chong Jin Kang Bai used a paper standard of Chinese National Standard (CNS) Grade 4 specifications (210x297 public) 201312 Μ Ministry of Economic Affairs Standard i'Jo: Printed by the Industrial Consumers Cooperative Society V. Description of Invention (21) secoverine), The combination of AFDX-116 (refer to Hammers, Life Sci. 1653, 1986) is to counteract the expected side effects of Zhou Jin at high compound doses * to counteract this inhibitory agent in central inhibitory presynaptic and synaptic The inhibitory effect of post-touch M2 type receptors and by inhibiting this M2 type inhibitory autoreceptor at the intact terminal to enhance the release of acetylcholine; in combination with a nicotinic toxin agonist (such as nicotine) In order to Two nicotinic and muscarinic receptors that stimulate the brain; in combination with adrenergic agonists (clonidine or quanfamicine) in order to alleviate the conductivity of mixed cholinergic in SDAT A non-adrenaline-induced lack of consciousness and other impairments; in combination with serotonin and then intercept inhibitors (such as alaproclate, zimelidine) in order to all slow down in SDAT Cognition and other emotional functions in the body; in combination with monoamine oxidase-B inhibitors such as deP "enyl" (deP "enyl) in order to all slow down and mixed states such as SDAT / PD have cognitive and other sports (function) Damage; in combination with nerve growth factor (NGF, administered by nasal smilax or intraventricular administration) 0 Spiral ring compound of the present invention and (or not used) the aforementioned other active substances, such as M, for appropriate release Injection in a drug or carrier | Oral, hydroxyrectal in the form of suppositories, by insufflation or spraying the rice paddles, and radiation in a suitable vehicle, for example, by using this device for the United States 1 6 3 3 4 7 (1 9 8 8 1 January 2 9 announcement) Subject. The spiro compounds of the present invention (in detail, where R = methyl) are also useful for the treatment of bilirubin agonist DP 25 which requires long-acting and mild local activity (please read the notes on the back (This page will be written on the next page). Packed. 201312 A 6 B 6 Ministry of Economic Affairs Standard Λ, Printed by the Industrial and Consumer Investment Cooperative Fifth, the invention description (22) is abnormal. This type of agent is required for abnormalities such as glaucoma, because this compound is not destroyed by enzymes (deactivated acetylcholine, ie acetonitrile-cholinesterase), and can also be used to treat peripheral gallbladder Abnormalities such as prime stress such as myasthenia gravis, bladder dysfunction * Adi's (Adi's) disease and Eton-Lambert (Eaton-Lambert) disease. These compounds can also be used in the following troubles * where the cholinergic stimulatory activity is reduced due to the agent. Obviously, the spiro-linked compound of the present invention (in detail, R is C3-e-alkyl or aryl) is an anticholinergic agonist and is useful for treating abnormalities caused by high cholinergic stimulating function , Regardless of whether it is naturally occurring or caused by a drug. These compounds are useful for treating various diseases such as PD, pseudo-PD, mixed AD / PD, first-degree muscular tonicity disorder, spastic torticollis, insufficient cranial tension, depression and kinetic disorders, and insufficient kinetic energy Syndrome (neurotic symptoms caused by withdrawal), central hypertension, human head trauma, delayed dyskinesia and PD, mania, depression, as an adjuvant in surgery to replace atropine and ranunculus Scopolamine, etc., used for poisoning by acetylcholine (such as inhibiting acetylcholine poisoning). These can also be used in ophthalmology and require long-term or short-term mydriasis. The spiro-linked compounds of the present invention are also potentially useful for the treatment of diseases characterized by peripheral activity of K-pricking such as asthma, chronic obstructive pulmonary disease, and peptic ulcer disease. For these peripheral abnormalities, it is recommended to use the four-level salts of formula (I a), (I b) and (H a): (please read the precautions on the back before filling this page) Installation · Line · DP-26 201312 A 6 B 6 V. Description of the invention (23)

Ah a pR X R. One M

(la)

(lb) ⑽ into ΘΆ R〇 ^ (Gonggong a) where tertiary nitrogen system MR "quaternized, where these are, for example, lower (ci-e) alkyl, aryl such as phenyl, or aryl and Ci -β alkyl substitution, such as benzyl. The following non-limiting examples of the present invention are described below. Cellar Example 1 2 Tian Moushou Fong (1 (a) 3 —Nitrotiana Rollinone. One Kujang Quinone Pyridine 3-Meng (125g, Mohr) was dried by azeotropic distillation (40% by weight (w / w) in Jiaben), placed in a 3-liter flask equipped with a mechanical stirrer, and added After 1 liter of methanolic sodium ethoxylate, the clear solution was mixed at 15 to 20 ° C. 61 g (1.0 mol) of nitromethane (after dissolving in 500 ml of absolute ethanol) was added over 0.5 hours At the same time maintain (please read the precautions on the back before filling in this page). Packing. Order_Line. Printed by the Cargo and Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. The temperature is lower than 20 t. Use HC 1

The solution was acidified to pH 1 with isopropanol, dried after drying to obtain a crude product (although 160 g) and used in the next step. l-NMR (D20, DSS) (HC1 salt): 5 3.79 (d as AB type light

DP 27 The ift scale of this paper is based on the Chinese Standard for the Poor Family (CNS) Grade A (210X297 mm) 201312 A 6 B 6 Printed by the Ministry of Economic Affairs + Central Standards Bureau Beigong Consumer Cooperative V. Invention Instructions (24) Part 1 of the spectrum Part, which is one of CiLzHh Η), 3.38-3.33 (m, 7H), 2.36 (m, 1H), 2.36-1.95 (m, 4H) (b) 3-Amethyst ~ 3 A yeast (i ) Yue "US-Nitromethine 3-hydrogenation of 3-nitrogenquinone pyridine 3-alcohol in methanol using 10% Pd on activated carbon and catalytic hydrogenation to produce 3- The HC1 salt of aminomethyl wonton-3-alcohol is recrystallized from methanol-isoalcohol to obtain a white crystalline product. (ϋ) Hui from the cobweb gas dissolve 3-Methoxyquinone epoxide (25 g, 0.18 mol) and sodium nitrate II (20 g, 0.3 mol) dissolved in 50 ml of water. The mixture was stirred at room temperature overnight. After extraction with M chloroform (2 x 200 mL), the extract was concentrated in a volatile manner. Dissolve the oily residue containing 3-azidomethylquinidine-3-alcohol in water and add it to the wet active active in several portions and stir until the release of nitrogen gas (35 g) ceases. The mixture was filtered and the liquid was concentrated by evaporation, and the residue was recrystallized from isopropanol to produce 9 g of pure 3-aminomethyl hydrazine 3-alcohol. m / z Μ + 156, reference peak m / e 139 (Μ-ΝΗ3), and m / z 96 is a typical quinidine pyridine backbone. UMR (D20, DSS) (free base) · δ1.3-2 · 0ί5Η); 2.3-3 (8 Η Bu (di-HC 1 salt): δ 1.8-2.4 (m, 5H); (Please read back • face ^ note ^ Xianga before filling out this page) Install-* tT 'line- DP 2 8 This paper scale is easy to use Chinese National Standard (CNS) standard 4 (210x297 g; ¢) 201312 A 6 B6 Yinnu, A Gongxiaot Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs V. Description of the invention (25) 3 · 2-3 · 5 (π, 8H). Compared with the free-form inspection and according to the expected structure, its dihydrochloride The HMR of the compound shows a downward magnetic field migration of 6 hydrogen atoms connected to the carbon atom adjacent to the nitrogen atom (eg 52.5 to 2.9 up to 3.3 to 3.5 ppm). (〇2—A certain connection (1, 3 Hui Yixing FS, 3 ') Pyrimidine (AF125) (i) Ethyl Acetate Method 3-Aminomethyl Ravidin-3-ol (9.1 g, 0.058 mol) was dissolved in 500 ml of dichloromethane In methane; after adding ethyl acetamidate-HC1 salt (4 g, 0.11 mol), the mixture was stirred at 510 for 6 hours. The solution was basified with D 〇we X 1 and after filtration, the solvent was volatilized to produce an oil The residue, distilled at 60 to 65t: /〇.5mm Hg to obtain AF125, was Color liquid. M / z (Μ *) 1 8 1 reference peak, 1 3 9 (Μ-C Η 3 CN). ^ -HMR (CDCU-TMS); 5 1.97 (dd, 3H) (J = 1.3Hz) ; 2.8-2.9 (m, lH); 3.14 (d, lH) (J = 12Hz); 3.5 (dd, lH) (J = 13Hz); 3.96 (dd, lH) (J = 13Hz. 1.3Hz). UMR Including the spin decoupling experiment, it can allocate hydrogen atoms adjacent to C2, Cs, and methyl. Each hydrogen atom connected to Ce shows double doublet (J = 13Hz double coupling) and homologous monoene with methyl Propyl coupling (”= 13.). The homo-allyl coupling that occurred at 3.5 and 3.9 at the irradiation of 1.97 (methyl) occurred at 3.5 and 3.9. The signal at 3.96 and the like at 3.5 irradiation must be due to the double Coupling Ηββ and HSb (Table 1). 1 3 C-NMR spectroscopy (in CDC 1 3) can provide sufficient information and can be allocated (please read the back seven face ^^ 篆 順 " again) Page) 装-线 · DP 29 This paper standard uses the Chinese National Standard (CNS) A4 specifications (210X297 g) 201312 Λ 6 Β 6 V. Description of the invention (26) Most resonances are on the appropriate carbon. 13C-NMR (CDCU-TMS) S13.2 (CH3; 20.5 (CH2CH); 21.5 (CH2CH); 30.0 (C_HCH2); 45.3, 45.7 (CH2C_H2H); 62.2, 64.2 (C_H2N); 84.0 (L0 0H2); 165 (LCH3). GC (-peak): Column length 25 meters, diameter 0.2 mm, loaded with 5% phenylmethyl silicon Si; detector type FID; column temperature: 125. C, injection port 220 detector 220 , Carrier gas: N2, 0.7 ml / min; residence time: 6.2 minutes. (Ii) Acetic acid method. ≪ Dissolve 3-aminomethyl wonton-3-ol (10 g) in acetic acid (50 ml ), Azeotropic distillation in Dimethylbenzine for 30 minutes • After cooling the solution, K cold aqueous potassium carbonate is basified. After drying the organic phase, 5.2 g of crude product is obtained and distilled under reduced pressure (60 to 65 = / 0.5 mm) Hg) to obtain a colorless liquid and solidify after freezing. The resulting compound is the same as AF125 obtained by method (c) (i). (Please read the note of ^ φ- before filling in this page) Pack · -V5 * line. The DP 30 printed by the Beigong Consumer Cooperative of the Ministry of Economic Affairs's Central Standards Bureau uses the Chinese National Standard (CNS) A4 specifications (210x297 public) 201312 A 6 B 6 Ministry of Economic Affairs + Central Standards Bureau Printed by Fee Cooperative

3.96dd (J = 13, 1.3HZ) 3.75dd (J = 13, 1.3HZ) Taizi ^ i: / i ii Use Ψ 團 a 甲 4 拗 格 i2i (lx2i) 7 public money) 3.14d (J = 12HZ) 2.8-2,9m 3,50dd (J = 13, r3HZ) 3.10d (J = 12HZ) 2.6d (J = 12HZ). 3.35dd (J = 13, 1.3HZ)

(Please read the precautions on the back before writing this page) DP-31-201312 A 6 B 6 Printed by the Ordnance Consumer Cooperative of the Bureau of Standards, Ministry of Economic Affairs V. Invention Instructions (28) (d) to analyze AF 1 2 5 (Foreword: Since the reliability of measuring polarimetric data using a polarimeter is insufficient, 1H-NMR as described below is used to evaluate optical isomers). In A 1 2 5 (5.5 grams, 0.085 Μ) in acetone (150 ml) after stirring the solution, was added dropwise dibenzoyl-L-tartaric acid (18.8 grams, 0.05Μ ) 'S solution. Immediately separate the crystalline material. After collecting the precipitated salt, M was purified by dissolving in hot isopropanol, cooling and adding ether to the cold solution until it appeared cloudy; repeating this method twice to obtain the product with fixed optical rotation [a] D2〇 = — 28. (MeOH); m.p. 145 X :. Μ in a similar way, starting from AF125 (14.74 g, 0.08M) and the equivalent of tartaric acid dibenzoyl-D-tartaric acid (17.76 g, 0.047M) to obtain the equivalent salt of other enantiomers. · Crystal 3 After this time, the product has [a] D20 = + 26. (MeOH); Di.p. 145 Ό. Individual free bases were obtained and the chloroform was extracted several times after the salt was neutralized with M 10% K 2 C 0 3 solution. The free base is derived from dibenzoyl-D-tartrate with [a] D2 ° =-43 ° (MeOH), and on the other hand from [α]. 2. = + 36 ° (MeOH) dibenzyl-L-tartrate. As mentioned above, the optical purity of the enantiomers is shown by M UMR. Μ AF125 as a racemic material and l-NMR spectrum in the presence of optically pure resolving agent (s) (+) 2,2,2-trifluoro- 1 (9 anthracenyl) -ethanol showed two Kind of optical isomer. The difference in chemical migration (in C e D β) of a rat atom attached to (: 2) can determine the optical purity of AF 1 2 5. Each separated enantiomer is used for these hydrogens on C2 One of the atoms shows the only double peak (half of the AB-type spectrum). (Please read the seven backs, the first note of the face, and then fill in this page again). Pack. Line · DP 32 (CNS) A4 specifications (210x297 public splashes) 201312 A 6 B6 Printed by the Beigong Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs V. Invention description d) Example 2: 2 diethyl strontium 3 Pei TttfS. ·) Drying (af 1?. M Μ is similar to Example 1 (c) to obtain the title product and condensed from 3-aminocydinidine-3-alcohol with propylene • Then azeotropically distilled in dimethylbenzidine. Evacuated under reduced pressure Distillation completes the purification of crude AF123. N / e = Μ195, reference peak. ^ -HMR (CDCU-TMS): δ 4.0 (d, 1H) (J = 13Hz); 3.55 (d.lH) (J = 13Hz); 3.1 (d, lH); 2.7-2.9U); 2.3 (q, 2H) (J = 7.5Hz, CH ^ CHl); ll (t, 3H) (J = 7.5Hz, CH3) 〇GC ( Under the same conditions as used for AF125; a sharp peak): reside Time, 8.86 minutes. Example 3 Prevention of a certain compound (1, 3-Ye favors Z-FS, · ν) A Ρ 1 2 5 (Ν) Amino-huizolin derivative AP125 (N) series electron-rich morphazoline ring For example, because the amine nitrogen is conjugated to a double bond, the negative value on the imine group is strengthened 0 — + N = C- HH2 <--> NC = HH2 < = > NH-CMH Dissolve 3-aminomethylquinolinidine-3-alcohol (6 g) and cyanogen bromide (3.5 g) in methanol (200 mL). · The K reaction mixture was stirred at room temperature for 5 hours and then concentrated in vacuo. Place @ 留 1 物 on the aluminum oxide column (300 g DP 33 paper size, please use the Chinese National Standard (CNS) A4 specifications (210x297 mm) (please read the precautions on the back before filling out this page)-install · order _ 201312 A 6 B6 Printed by the Beigong Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economy V. Invention Instructions (30).) Purified and used multiple solvents as a lotion (i.5: 1.0: 0.2: 0.06 CHCU / ether / Formaldehyde / NH40H) to obtain 450% of most of the pure part, which is finally purified by grinding with acetone and liquid to obtain pure crystalline material. First, the chromatographic separation yielded 2 g of the desired crude product, which was further separated on a silica gel column, and 2% NH3 (in methanol) was used as a washing agent. The pure product has " > .P. 135 to 136 Ό. UMR (CDCU-TMS): 3 3.83, 3.43, 3.2 (3 double peaks, 3Η, Hb and He, J = 0.048Hz); (m, 5H); 1.9 (b, 2H); 1.5 (m, 3). FAB-MS showed molecular ion (M + l) + < 182. Example 4: 2 —Cage a _ 栊 顼 connected (1,3 —brazoline_5 »3 ·) wong Pg AF 1 2 R (P h) will 3-aminomethyl wontidine 3-fermented (2 g , 0.01 mol) and a suspension of ethyl hydrochloride ethyl iminate (2 g, 0.01 mol) in ethanol (200 ml) at room temperature for 24 hours. After filtering and concentrating the filtrate by evaporation, the crude residue MNaHCO3 was alkalized and then extracted with chloroform. The organic extract M is concentrated by volatilization, the crude residue is separated on a silica gel column (30 g, 1.5 cm diameter) and M uses multiple solvents (1.0; 1.0; 0.2; 0.026 CHCU / ether / enzyme / 32% aqueous NaOH) As a lotion. The product was quickly washed out (after 40 ml was washed out). The solvent is obtained as a white solid by evaporation without heating, m.p. 65 to 701.

This paper scale uses the Chinese National Standard (CNS) A4 specifications (210x297 mm) (please read the precautions on the back before filling this page) Binding · Order · 201312 A 6 B6 5. Description of the invention (31)-\ 1H -NMR (CDC13): 6 7.955 (2H). 7.72 (2H), 4.16 (d.lH), 3.73 (d, 1H), 3.26 '(d, 1H), 2.93 (d. 1H) and (t, 2H ), 2.77 (t, 2H), 2.2 (m, 1H), 1.95 (m, 1H), 1.60-1.52 (m, 3H) ppm. IR (CHC13) 292G, 29〇Θ ,, 285〇sh, I640sh, 1630, l'625sh, 1440, 1337. 1265. 1250. 107〇, lQ5〇, l〇35. 1〇〇5, 965 cm_1 m / z: 242 (60%) [M +], 19S (30% .171 (12%), 149 U〇%). 139 (50% 〇, 124 (17Ji), 122 (20%), 121 (2Θ /), 117 (30%), 111 (12%) , 105 (33%), 96 (1GGX), 82 (50 ^), 69 {h2%), 55 (36%). The formula (TU Bu, compound Xihuanju and most of these things are sacred to the gods) The compound is relatively stable. For example, AF125 is thermally stable and is distilled at 130 t without decomposition. Its chemical behavior is similar to the known 2-oxazoline derivatives. The free base lasts a few hours in aqueous solution It decomposes slightly and gradually increases with time. M UMR monitoring Measure the formation of decomposition products and M observe the two regions S 3.3 to 3.5 (presenting two double peaks) and 1.9 to 2.0 ppm (presenting two additional single peaks>. Expected decomposition mode (if, for example, X is Ο and Y System N) includes opening the oxazoline ring M to form amides and esters as shown in Flow Diagram E, which illustrates the compounds derived from Ravidin. The two structures as expected for R: Me are in δ The formation of two new single peaks from 1.9 to 2.Ορριη is consistent with this assumption. (Please read the notes on the back before filling in this page) DP 35 printed by the Staff Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. This paper size is used in BB. Home Standard Bi (CNS) Grade A 4 (210X297mm) 201312 A 6 B6 V. Description of Invention (32)

Rhizoma J is used for the separation of R hydrochloride acid salt and stupid light to overcome this method, or then make = Et (AF123) also in the presence of a faster glycolate also produces a compound (such as AF125 problem and When K is used, the amino alcohol (if the same as the ester shown already shows the same decomposition level. Note that if it is partially decomposed in tetrahydrofuran. Such salts and AF123) become compound. Decomposition and hybridization are added in the opening. Hot wine 1 tendency ί However, the separation of enantiomers AF125 said _ 3-amine methyl pyridine-3-alcohol) solution name. In still other alternative methods, after the cyclization of, for example, 3 or imidate is resolved after the separation of the enantiomeric amine methyl guanidine, the N-acyl derivative of the 3-alcohol described in Figure K, To cyclize the separated enantiomer itself as in the lumen method: (Please read the precautions on the back before filling out this page) Outfit-Printed by Beigong Consumer Cooperative, Central Bureau of Standards, Ministry of Economic Affairs

DP

OUCUxNUGofl

Ux.〇 Flow chart 36 The size of this paper is in the B National Standard (CKS) A 4 specification (210X297 g)

201312 A6 B6 Printed by the Employee Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economy V. Description of the invention (33) For this cyclization, use, for example, p-methanesulfonic acid or boron trifluoride etherate_. Example 5: A certain spiro ring connection (1, ·? A postal sakaichi 5, 41 —; r-methylhexapyridine (π: = Tian Shi-w AF 1 R Ο Μ (£ 〇gasification 〗 1 A certain 4 one magnetic Shen 16 Liu Tongyang; a 4- one slightly prepared this starting material and K uses AD Cale (US Patent 4,746,655, 1998) a slightly improved method. Will N — The mixture of methylhexahydropyridine (142 g, 1.28 mol) and nitromethane (78.1 g, 1.28 mol) is added to the fully stirred 20% sodium ethoxylate (1.28 mol) in the yeast The solution was maintained at an internal temperature of 5 to 8 C. A white solid precipitated and continued to stir for 20 minutes and then at room temperature for another 40 minutes. The resulting solution was acidified with 500 ml of 7.2N HC1 (in isopropanol). After extraction with hydrochloride and inorganic salt MCH30H (3 × 200 ml), the solvent is removed by vacuum to obtain the standard compound, mp 180 C to 182 * C (no deliquescence). M / z: 174 M * of free base, 100% ), 157 (Μ-0Η, 20%), 127 (MH-H02, 25%), 113 (MN〇2-CH3, 40 *) 〇 argon correction radonization 4. Fang Shen Shenyi 1-Tian Mouliu Child snap one one four one palladium (in charcoal (10%, 4g)] Add to the solution of 1-methyl-4-nitromethylhexahydropyridin-4-ol (133.5g) in formazan (1500ml) in several portions. Compound; jfep ^ The pressure of DP 37 at 55psi in the ar device is in accordance with the Chinese National Standard (CNS) A4 specifications (210x297cm) (please read the precautions on the back before filling out this page) Binding-Order_ 201312 A 6 B6 Economy Printed by the Beigong Consumer Cooperative of the Central Bureau of Standards of the Ministry 5. Invention description (34) Hydrogenation at room temperature for 48 hours. The solution was carefully filtered and treated with activated carbon. After removing the solvent, the residue and ethyl yeast ( 200 ml) and liquid research to obtain the title compound, mp 177 to 179 t !. m / z: 144 (M * of free base, 15%), 127 (Μ-0Η, 25%), 114 (M-CH2HH2, 100% .... —Shenmou tg 顼 培 (1, Satoshi — 5, 4 ') a 1 * a field of hexahydropyridine f AF1 KOH (1.43 g, 86%) in formic acid (50 ml) The solution was added to the solution of 4-hydrochloride 4-limbyl methyl-1-shenylhexahydropyridine-4-enzyme (3.61g, 0.02mol) in absolute formazan (50ml). In minutes After adding a solution of ethyl hydrochloride ethylimidate in 20 ml of absolute ethanol, it was stirred at room temperature for 30 minutes. After removing the solvent, the residual solid was dissolved in 2.8 g of Na2C03 He2S04 mp 45T0 (at 40t: /0.05mm Hg sublimation) * washed out on silica TLC with M2% NH3 (in CH30H) to obtain a single point, Rf = 0.4. m / z: 168 (M + of free base, 100 J: at 7.5 ev). UMR (300 MHz, CDCU); S3.56 (2H, q, J = 1.5 Hz), 2.35 (4H, m), 2.34 (3H, s), 1.96 (3H, t, J = 1.5 Hz). 1.82 ( 4H, ra) ° M equivalent of NaOH or Et3N replaces the KOH used in this example with similar results. , (Please read the precautions on the back before filling in this page) Binding · Binding-Line-DP 38 This paper scale is universal Chinese National Standard (CNS) A 4 specifications (210X297 mm) 201312 A 6 B6 V. Description of invention (35 ) (H > 2 — Tian Mouzheng's loss (1, 3 — 絥 邮 蚶 _ R '»A 1, one 1 I — Tian Mouliu Mm airing two cages Shen Shen certain d —Sprinkling stone _ 薷 将 二A solution of benzoyl-D-tartaric acid (5.4 g, 15 mmol) in 500 ml of toluene was added to the sowing and dissolved in AF 150 (5.5 g, 32 mmol) in 200 ml of dried beetle. The solution was allowed to solidify and the supernatant was decanted. The residual solid was washed with 3x100 ml of dry toluene and dried under reduced pressure to obtain 8.4 g (80% yield) of white and slightly deliquescent solid. TLC chloroform / Bauxite (Merck Art 5581) Rf = 0.4. B / z: 168 (ίΤ) ^ HMR (300 MHz, D20 containing 1.5 mg. Na2C03 / 0.5 ml 0 D 2 0): δ 1.95 (s, 6H, CHs- C), 2.35 (s. 6H. CHa-N), 3.5 (s · 4H, CH2) · 5.7 (s, 2H), 7.5-8.2 (b, 10H · aromatic hydrogen atom). Example R: 2—B Giro-spirulina (1,3-Sorazoline-5,4 |) (please first Read the precautions on the back and then fill out this page) Printed by the Employee Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs-1 'Yishen Shili MPH ·. Hang (Tf; R = Yimou Tianmou) This compound is similar to Example 5 Prepared by the preparation method and using M equivalent of ethyl hydrochloride propionimidate to replace the hydrogenated ethyl acetimidate. The resulting product is solid, bp 53t: /0.03min Hg, yield 60.5%. XH- NMR (300 MHz, CDCU: δ3.52 (2H, t, J = 1.5 Hz) 2.47 (4H, m), 2.30 (3H, s minutes 〆'2.26 [2H, quartet DP 39 paper size free China National Standards (CNS) Grade A 4 (210x297 mm) Printed by the Staff Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economy 201312 A 6 _B_6_ V. Description of invention (36)-(J = 7 Hz), triplet (J = 1.5 Hz )], 1.86 (2H, b) 1.72 (2H, m); 1.18 (3H, t). Example 7! 1 A Jiamou Liuqiyang 1 Only 4 — Battle loss connects a 4 'A (2' Yijiamou One 1 ·, · ν —Looking at the beer (I; R = R '= A certain " AF1fn ”(9 ·) 1 One six, one gas Ptf: one 4- one pulling, one 5 1—B meat The vine gland mixes the following three solutions: 1-methylhexahydropyridine-4-one ( 36.44 g, 0.322 mol) in ethanol (150 ml), ammonium carbonate (93.0 g, 0.968 mol) in water (400 ml) and potassium fluoride (25.8 g · 0.396 mol) in water (400 Ml), heated at 60¾ for 2.5 hours, and then left at room temperature. At this time, 1-methyl hexahydropyridine 4-spiro-linked 5'-hydantoin was isolated. After extinguishing each other, a small amount of cold water, ethyl yeast and ether were washed to obtain a crystalline powder (27.0g). The filtrate and lotion were concentrated to obtain the second harvest (£ 0.0g). The product crystallized from ethanol: m.p. 265 to 276 it (decomposed). IR (KBr) 3170 (NH); 1700 (C = 0) cm-1 m / z 183 (M *, 38¾); 71 (100¾) UMR (300 MHz, D2〇); δl.8 (2H), 2.06 (Sixfold, 2H), 2.49 (S, -CH3), 2.58 (t, 2H), 3.14 (t, 1H), 3.20 (t, 1H). (Please read the precautions on the back before filling out this page) Binding · Order _ DP-40-This paper uses the Chinese National Standard (CNS) A 4 specifications (210x297 male dragon) 201312 A 6 B 6 Central Standards of the Ministry of Economic Affairs Printed by the Bureau Cooperative Consumer Cooperative V. Description of the invention (37) (Η) 4 · _ 防 某 1 —Shenmou six g pyridine-4 · -carboxylic acid will 1-methylhexahydropyridine-4-spiro ring A solution of 5'-hydantoin (9.75g, 0.0533mol) and barium hydroxide octahydrate (28.8g · 0.0091 3mol) in water (150ml) was heated in an autoclave (160t :) 3 hours. Four batches of this content were combined and 1 M was filtered to remove the precipitate. The filtrate was shrunk to a small volume to obtain L monoamine methylhexahydropyridine-4 monocarboxylic acid (32.0 g, 95% yield), m.P. 275 to 2 80 t (decomposition). IR (KBr) 33QO, 1655. 1580 cm_1 m / z 15S (M +, 9 acres); 141 (98%, M-OH); 113 (12%. M-C02H); 96 (100%); 71 (52 %) iH-NMR (3G0 MHz, C5D5N + D20): δ 1.2 (m, 2H), 1.48 (s, CH3N-), 1.7 (m, 2H). 1.9 (m. 2H), 2.0 (m, 2H) .-(〇4- one anti-radical one 4 one release a certain one] one one a certain six gas m dark aluminum hydride powder (15.62 g, 0.412 mole) in dry tetrahydrofuran (THF) (600 ml) (of Solution) Heat under reflux for 15 minutes, and then under a nitrogen atmosphere and under full agitation, dry the 4-aminoamine 1-methylhexahydropyridine-4-carboxylic acid (31.0 g, 0.196 M Ear) gradually added. After the addition is complete, the reaction mixture is heated under reflux for 4. hours, cooled to ◦ t under nitrogen: and fully simmered, operate carefully and slowly add human water (20 mL), 15% aqueous Na 0 Η (205 liters) was added with water (10 ml). After the reaction mixture was precipitated, the precipitate was extracted with boiling THF (3 × 150 ml). The THF was quenched and extracted. (Please read the precautions on the back before filling this page) Binding-Strapping. DP 41 For paper scale, use the Chinese National Standard (CNS) Grade 4 (210x297 publication) 201312 A 6 _B6___ V. Description of the invention (38) After extracting the combination, remove the solvent under 25bih Hg to obtain a yellow viscous oil (28. 0 g, 98.9% yield). Engineering R (pure product) 332Θ (NH), 3200 (bi ·. OH), 1587 (NH2>, 1468, 1M8 cm-1 m / z 1 ¥ 4 (M +, 15X); 127 (M-OH); 113 (MC〇2H); 96 (100 ^); 7〇 (4l ^). 1H-NMR (3GQ MHz, CDCl ^): δ lΛΛ (m, 2H), 1.6 〇 (m, 2H), 2.2¾ (s, CH3-N), 2.29 (m, 2H), 2.48 (m, 2H), 2.50 (br., -NH2), 3.29 (s, -CH20H). (Hi 1—A certain six MW: Pyridine 4 · —Hull Pei Pei 4, 1, (2 · — Methyl-1 ', V — Hui Beer 瞅) (AF 1 5 1) 4 4-amino group 4-hydroxyl A mixture of methyl-1-methylhexahydropyridine (1.80 g), acetic acid (20 ml) and xylene (20 l) was azeotropically distilled for 28 hours. The remaining acetic acid and xylene were removed under reduced pressure (25 mm FU) to leave a residual viscous oil. The KK2C03 aqueous solution was alkalized to pH 11 ° W. After chloroform extraction, the extract was evaporated to obtain a small amount of residual brown oil (0.27 g). After the chloroform extraction of the volatile solution of the volatile solution, the volatile water was removed. The residual solid was extracted with chloroform. The extract was dried (Na2S04) and the resulting residue was very deliquescent solid (3.0 g). The result is mainly S5, which is more polar than the starting amino alcohol. Printed by Beigong Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling in this page). Part of the deliquescent solid SI (melted at 1 5 0 t to 1 6 0 t) is heated under vacuum At 45t: /〇.15mm Hg, most of them start to be distilled out and colorless oil. Maintaining this oil in the refrigerator 'forms needle crystals and dissolves at room temperature. The distillate is the acetate salt of the title compound. DP 42 This paper standard uses the Chinese National Standard (CNS) A4 specification (210x297 g *) 201312 A 6 B 6 Printed by the Employee Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs V. Invention Description (39) Worker R (pure product) 1664 (_C = N); 1565 & 1398 (-C02__); 1256 (C-O) cm-1 m / z 168 (μ * of free flamingo); 1; 70.h-NMR. (3〇 〇MHz, CDCI3): < 5 1.77 (rn, 2Η), 1.96 (m. 2Η) 1.98 (s, CH3-), 2.0 (s, CH3-), 2.49 (s, CH3-N-), 2.91 (m, 4H), 3.95 (s, -CH2〇-), 9.3Ο (br. s, -C〇2H). Uc-NMR (3G0 MHz, CDC13): δ 14Θ (gi3C〇2-), 22.9 (gH3C = N-), 35.6 (C3 and C5), 44.4 (CH3N +), 51.1 (¾ and C6), 67.0 (¾). 77.4 (c5,), 164.3 (c- = N), 176.7. (- c〇2-) 1 NMR (3Q0 MHz, CDC13) of yolkine: δ 1.64 (m, 2H). 1.84 (m, 2H), 1.98 (s.CH ^-). 2.26 (m, 2H) , 2-3〇 (s, CH ^-), 2.69 (m. 2H), 3.94 (s, -CH2-). Li A: 1 — A certain six MW ·. Pyridine 4 — Spiral connection 4 ′ One (2'— 乙 某 -1 '», ν — 辉 Beer _) 4 4-amino group 4- 4-hydroxymethyl-1 1-methylhexahydropyridine (30 g) with acid (50 liters) and di Jiaben (90ml The mixture was azeotropically distilled calendar for 5 hours. The residue (7 ml) of MK2C03 aqueous solution was basified to reach pH II to 12. After chloroform extraction, the extract was evaporated to obtain a mixture of non-polar compounds (0.80 g). After extraction with chloroform | The residual aqueous solution is volatilized to remove water, and the residual solid is extracted with chloroform, the extract is dried (N a 2 S (K) Μ after volatilization, the resulting residue is a deliquescent solid (3. 6g). TLC shows that the latter is mainly derived from a little, and is more polar than amino alcohols (silicone, solvent 40: 58: 2 methanol-chloroform-aqueous ammonia). Part of the deliquescent solid (1.5g) in Heat under vacuum and use the Chinese National Standard (CNS) A4 specifications (210x297 mm) at DP 43 paper size (please read the precautions on the back before filling this page) 201312 A 6 B 6 Ministry of Economic Affairs Standard Printed by the Bureau of β-Consumer Cooperative Co., Ltd. V. Description of invention (40) 5 0 t: / 〇. U π H g, most of them immediately start to be distilled out and appear as a diamond colorless oil. Distillate title compound Propionate. M / z 182 (free base, 1 shirt); 167 (5%), Qiao 4 (71%), 125 (9%), 109 (10 Lang), 96 (45 magic , 81 (30%), 74 (57%). 7〇 (89%). 57 (6 states). ^ NMR (3〇〇MHz, CDC13): < 5 1.12 (t, J = 7-5 Hz , CHCH2-), 1.17 (t, J = 7-6 Hz, CH3CH2-), 1.75 (m, 2H), 2.Θ 0 (m, 2H), 2.29 (q, J = 7.5, CH3 £ n2-), 2.3〇 (q, J = 7.6, CH3 ^ 2->, 2.56 (s, CH3N-), 3.G) 2 ( : n, 2--CH2-) (3-95 (s, -CH20-), 7.52 (br. -C02H). Add the aqueous solution of K 2 C 0 3 to the above propionate (700 mg) The stirred solution in hydroform until the release of CO 2 has ceased. The mixture is then stirred for 0.5 hours and the two phases are separated. The aqueous phase is extracted with chloroform, and the separated chloroform phase and extract are combined and dried (N a 2 S (3 4), the volatile compound was obtained as a drift compound, and the free test form, the residual colorless oil (5 50 mg), showed a single point D 1H-Ni-IR (3〇 〇MHz, CDC13): (5 1.17 (t, J = 7.6: Η: ζ · qi3CH2-), 1.61 (a, -CH2-), 1.86 (e, -CH2-), 2.I8 (ai, -CH2 -). 2.29 (q, J = 7-6, Cri3CH2-), 2.3Ο (s, CH ^ N-), 2.7I (επ.-CH2-). 3-94 (s, -CH2〇-). tn / z 182 (M + 25%), 167 (95), 15 ^ (78, ^), i25 (17 "), 109 (100,96 (65%), 81 (5 ^). 7〇 (96% ), 57 (11%) The alternative synthetic routes for compounds such as AF 1 5 0 and AF 1 5 1 depend on the dehydration cyclamate, as shown in the following instructions: (Please Read the precautions on the back and fill out this page) Pack. Line-0 ^ _ 44-too κ 泞 iA ffl Φ due to a ^ iSm (CNS) flat 4 pounds (210 > < 297 public goods) 201312 A 6 B 6 Fifth, the description of the invention (41) Mail c〇C44j, / μ!

----> /} F / i-o CH-3po

Pa 〇r-> IS) For the above reaction, dehydration such as P 2 〇5, sulfuric acid-, B F 3-mystery, Ca C 1 2 and molecular sieve can be used. The use of P 2 S 5 in a similar reaction yields a comparable thiazoline (with which morphazoline is substituted).剐 9: Methyl stacks (1, 3-howl beer Lin 5, 4, 4 '), one, one, one, six, hexapyridine (fi: R = R' = A certain (a) 4 ethylamine Base 4 hydroxymethyl hexahydropyridine (please read the precautions on the back before writing this page) Ministry of Economic Affairs # 揮 央 # quasi-bureau employee consumer cooperatives will print 4-methyl 4-Jingji 1-methyl Hexaoxol (0.83 grams, 5.7 millimoles) was dissolved in 10 ml of acetone, and acetone anhydride (0.58 grams -5.7 millimoles) was added. The reaction mixture was naturally warmed up to 4 〇 to 50 t. After 30 minutes of dredging, after evaporation of the solvent, the ancestral residues are chromatographed on a silica-column column (Merck 7 7 3 4) and K is used (3 3: 6 7) 2% Waterborne Amino One

DP 45 太 .. 珞 尺 / iii »1 Umbrella due to a ^ i * miCNS) ^ 4 phase. Qi (210 ~ 297 public bitch) 201312 A 6 B 6 Printed by Beigong Consumer Cooperative, Central Bureau of Standards, Ministry of Economic Affairs Description (42) Methanol is used as a lotion. m / z 186 (Η *) HMR (300 MHz, CDCU): δ 1.60 (multiple peaks, 4Η, Η3 and Η4), 2.01 (single peak. 3Η, CH3-C), 2.29 (single peak, 3Η, CH3- N), 2.38 (multiple peaks, 2Η, HI), 2_5 5 (multiple peaks, 2Η, Η 2), 2. 9 8 (multiple peaks, 1 Η, Ν Η), 3 · 2 δ (doublet, 2 Η, Η 5) ppm. M-NMR (300 MHz, D20); δ 1.42 (multiple peaks, 4Η, Η3 and Η4), 1.81 (single peak, 3Η, CH3-C), 2.08 (3Η, CH3-N) , 2.27 (multiple peaks, 2H, HI), 2,46 (multiple peaks, 2H., H2), 3.03 (single peak, 2H, H) ppm. Impurities get a sharp peak at 3.4 4 p p m. (h) 2 —Apply for a certain damage training (1,3—Blind beer cocoa 5 ′ 4 ′) — 1 —Tianmou hexahydropyridine will be 4-amidomethyl-4-hydroxy-1-methyl A mixture of hexahydropyridine (6.5 g, 35 mmol) and phosphorus pentasulfide (10 g, 2 mmol) was heated at 220C and transferred to 100 mL of cooled concentrated aqueous sodium hydroxide, and extracted with 2 X 100 mL of chloroform. The combined extract was dried and evaporated to obtain 5 g of black oily residue, which was purified by distillation under 75C / 1 nm Hg to obtain 1.8 g of clear liquid. m / z: 184 (M +) " H-HMR (300 MHz, CDC 1 3): δ 1.8-2.0 (m, 4H). 2.17 (please read the precautions on the back before filling in this page) DP-46 -This paper uses the Chinese National Standard (CNS) Grade 4 (210x297 g *) 201312 A 6 B6 V. Description of the invention (43) (t, 3H, CHa-C), 2.2 (s, 3H. CH3: N), 3.9 (q, 2H, CH2-thiazoline ring). Bovine test compound The compounds according to the present invention are active in the field and are therefore useful, for example, as B-products for therapeutic purposes. In particular, * catalysts are active in the tests detailed below. In the table, the reported results are the results of this test. Some specific compounds are represented by the following references: (1) Carbachol (6) AF 1 5 1 ★ (11) Atorpine ⑵ Oxymetholine _ Μ ⑺ AF 1 5 0 (S) ★ (1 2) Oxotremor ine-H) ⑶Aoximorine • ⑻ AF 1 2 5 ★ (13) AF125 (Η) ★ (Oxotreinorine-M) ( 4) AF 1 0 2 B * (9) Me Η-A3 4 3 (1 4) AF 1 2 3 ★ (5) AF150 * ⑽Pizizepine (Pirenzepine) (15) AF125 (Ph) ★ (Please read first Note on the back and then fill out this page) Printed by the Employee Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs * 'Shun Tie-2 — methyl spiro ring connection (1, 3 — thiocyclopentane_5 ·, 3) roller ( US, 4,855,290) ★ Exemplary compounds of the present invention. D p 4 7 This paper scale uses the Chinese National Standard (CNS) Grade 4 (210x297 g *) 201312 A 6 B 6 V. Description of Invention (44) Test Experience 1: Wang 88 An & Rat 11 Preparation Test The compounds of the present invention are used for their motility and antagonism in guinea pig ileal preparations. Table 2 summarizes qualitatively the results of certain test compounds, of which AF125 is the most effective catalyst. It was found that AF125 was a complete actuation in the ileal preparation of guinea pigs and its EC50 was calculated at a concentration of 1.3 micromolar. The EPMRacr of AF125 is about 14. Compared with that used for AF102B, the latter value ranges from 50 to 100. This compound also has a high affinity for the binding position of the toxin in the brain. In fact, the comparison between AF102B and AF125B shows that AF125 is more active than AF102B and is up to ten times because it has contracted the ileum of the guinea pig. Therefore, AF125 can induce a greater contraction reaction than AF102B at the same concentration. (Please read the precautions on the back before filling in this page) Binding & Ordering-DP 48 printed by the Staff Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. This paper standard uses the Chinese National Standard (CNS) A4 specification (210x297 g *) 201312 A 6 B 6 V. Description of the invention (45) m ρ ,: The concentration of Ke Yan Zi Bao Bao encephalitis spp. Compound against nona & rat si foot stock test minimum concentration * maximum * compound (u μ) concentration __ 林 ____________________ (u Μ) _____ Note 13 0. 133.0 14 66 660.0 15 10 Complete motivator; contraction was interrupted by atorpine. Complete quasi-activator; reversible contraction of Atop-induced contraction-induced contraction antagonist Ι〇5〇 · 0.9〇Μ (wash first read ^ matters needing attention before filling this page) loaded. -B ' The Employee Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs printed the second contraction intensity. The reaction system is qualitatively closed with a positive (+) sign. Explanation, where + represents a small contraction reaction and + + + represents a strong contraction. If there is no shrinkage, Μ negative (one) is marked.

DP 49 The size of this paper is easy to use China National Standards (CNS) A4 specifications (210x297 mm) 201312 A 6 B 6 Printed by the Beigong Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs V. Description of invention (46) AF125 is similar in amine group The substance [AF125 (N)] is also active as a stimulant. If you want to contract the ileum, a higher concentration of this compound is needed. As seen, compared with AF102B, AF125 (H) is only active at a concentration ten times higher than the former K. AF125 (Ph) is an antagonist (IC50 = 0.7w M). Contrary to the amine analogues of AF125, AF125 was found to be an antagonist. A similar experiment showed that the compound of Example 5 (AF150) was a complete muscarinic agonist—with ECsosOJw M (MlOw M Atorpine blockade). Compared with acetylcholine (ACh), AF150 can induce maximum contraction of ileum by 130% (ACh = 100%.). Surprisingly, compared with ACh, the shape of the AF150 curve is different and this curve is analyzed with a one-position or three-position model. This indicates that AF150 has a different affinity for the toxin receptor subtype found in this preparation. In addition, the compound of Example 7 (A F 1 5 1) was also an intact muscarinic agonist with EC50 = 3 (blocked by 10 wM atorpine). Test 2: Conjugation to the # body's body in the brain. The activator binds to the toxic receptor of Ml and has the effect of imiphophosphate (GppNHp). It is known that an agonist is intended to be coupled with a guanidine nucleotide binding protein (G protein). At the same time, quite a lot of studies have been completed on the binding of agonists to M2 zeolite toxic receptors (low affinity ίίΚ 齐 平 (pi 「enzepine）), but the agonist binding to Μ1 簟 toxicity (high affinity good κ flush) The research on receptors is relatively few. The main reason is that most of the mobilizers (except AF 1 0 2 Β, for example, U.S. Patent No. 4,855,290) for M2-subtype ratio for DP 50 are used in this paper standard. National «quasi (CHS) A 4 specifications (210x297 g *) (please read the precautions on the back before writing this page). Binding. Λ 6 Β6 201312 5. Description of the invention (47)

Ml muscarinic receptor has a higher affinity. Non-hydrolyzed guanidine nucleotides such as GppNHp dissolve the G protein from the receptor and reduce the receptor's affinity for agonists (but not for antagonists). Under special conditions, using a low concentration of 3H-〇 to take flush (3H-PZ) and below its KD, you can analyze the affinity K and efficacy of the agonist for Ml muscarinic receptors [Potter, Cell. Molec Neurobiol 8: 181 to 191 (19 8 8); Potter S. Ferrendel 1 i, J. Pharmacol. Exp. Ther. 248: 974 to 978 (1989); Flynn, Eur. J. P harnaco 1. 1 7 2 : 3 6 3 to 3 7 2 (1 9 8 9)]. Under these conditions, a highly potent mobilizer ("fully mobilized") binds directly to the M1 receptor subtype with two affinity positions. The M1 receptor subtype with a higher affinity state is sensitive to guanidine nucleotides and Gpp NHp lines, for example, it is converted from a high-affinity state to a low-affinity state. The low-to-high affinity (fU / KH) ratio of the M1 receptor predicts the relative effectiveness of the motivator on the activation of the M1 receptor-mediated second message system. Table 3 summarizes the use of oxatromethine-M (〇x〇t "eno" ine-M) and Carbacho (Carbacho 1) (two complete but non-selective M 1 and M 2 mobilizers) for selective > < 1 catalyzer eight? 1028 (US Patent 4,85 5,290), six? 150 and AF 1 51 1. The results obtained, as predicted, four-stage complete catalyzer, oximetropine-M and Kaba It can have two kinds of affinity states and predict the relative potency of these compounds by the ratio of k, / Kh. On the other hand, AF1G2B and AF125B have a mass action curve. DP-51 This paper scale uses the Chinese National Standard (CNS) A 4 Specifications (210x297mm) (Please read the precautions on the back before filling in this page) Installation ·-Line · Printed by the Ministry of Economic Affairs Central Standards Bureau Beigong Consumer Cooperatives 201312 A 6 B 6 V. Invention Instructions (48) Ministry of Economic Affairs Printed by the Cooperative Society of Benyang Standards Bureau β 工 消 t Cooperative Society 3: Use Μ 1 in the cortex of the rat brain to replace the shame ψ Crow in the pants% (μιΜ)% (μΜ) Κ: l (um) kl ( um) XL KL-G compound one-one μ -G + G -G + G _G + G--G + G KH-G 1 0.23 flea 36 period 12 20 64 1GQ 52 2 0.11 0.35 53 2.7 6.7 4.2 47 73 61 4 0.7-1 0.7-1 Dance »Θ.7Ί 0.7-1 * Period 1 5 G. Period 11 21 箐 11 21 83 100 10G 6 3-7 Λ.6 39 17 4.8 59 6l 83 13 8 9 9 Spring 12 12 簐 · »1 You _ contention curve is suitable for a position m-type (mass action curve) 〇 Table 3 Xu: K i = K η or Kl-IC50 / 1, C / K where C = K 4.4 n M is the degree of radioactivity coordination (3 Η-Ρ ζ) and Kd = 13.9 η Μ is its dissociation constant Kη-Kl% Η and% L (¾ test m 3d position The body is used for the apparent inhibition constants of the high and low affinity positions, respectively, and is used in the 0.1 him paddle. Replace the 3Η-ΡZ ί 糸 from the cortex '/ shi ^ .TCJ port position at Tr is / Μ η (Ρ Η 7.4) and at 25 t for 1 hour, the pulse contains 1 raH EDTAft 2 Μ Μ η mono ion. This method class iW is described in the DP-52 Taizhiren Riani Ai ill Shen Tuan 03 ¾: 4 m core (210x297 gong) (please first) in the DP-52 Taizhi ren Rian iA ill explained by the Po tte factory and Ferrer η de 1 1 i Read the precautions on the back and then fill out this page) Pack ·. May 'line. 201312 Λ 6 Β6 V. Description of the invention (50) The compound of the present invention has the ability to replace homogenous rat brain, cerebellum or prefrontal cortex (and other cholin (Compared with the conductive compounds), and the following 3H-labeled compounds, namely diphenyl glycolic acid (-) 3H quinidine pyridine ester (3H-QNB;-a non-selective Ml and M2 antagonists) and 3H-feeding c Qiping (3H-PZ; a selective M1 antagonist) investigate it. For comparison, it contains oxymetrine (a third-order catalyzer with M2> Ml), oxymetrine-M and carbachol (mixed M2 and (< 11 /} < 2 fourth-order catalyzer) And 6 卩 1028 (see US Patent No. 4,855,290) and McH-A-343 (a kind of Ml four-stage catalyst). The results are listed in Table 4 and Table 5. (Please read the notes on the back before filling in this Page) Install &Line; DP 5 printed by the Employee Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. The paper size is based on China ’s * 楳 楳 准 (CNS) A 4 specifications (210x297 g; ¢) 201312 Ministry of Economic Affairs + Central Standards Bureau Printed by the industrial and consumer cooperatives A 6 B 6 V. Description of the invention (51) gg 4: Tian Yu M1 (from mouse ancient brainskin Zengmei 3H-P7.) And used for M ~ 2 implantation of pregnancy components (from mouse Cerebellar tube plum 3H-QHB) Apparent affinity state combined dermatophyte% -PZ-binding KH KL substance (a) (b) μΜ Η% L 3h-qnb- KH (c) μΜ cerebellar δπ mouth KL ⑷ Η%- L ratio c: a rate d: bb: a 1 3.4 42 35 55 G. 6〇39 55 45 0.18 0-93 12 2 Θ. 1 6-7 53 0-069 5 · 2 49 51 G. 69 0.78 67 3 0.014 0.58 35 65 k 1 Reed 100 Reed 6 Reed 100 Reed 6. Reed 5 5 Θ.02 18 2U 76 4- 5 79 49 51 225 iiA 9〇〇8 4 篑 1GO period 3-8 prayer 100 * 0-95 springs »9 3.8 static 10〇 普 2k Λ spring 100 6.4 * spring 13 Q.6 3 28 72 5.0 Spring 100 箐 83 14 1.3 * 10Q 3.9 * 100 Spring 3-0 Spring 玐 15 G.G8 * 10G * 1-37 10〇17-1 The spring replacement-PZ and 3H-QNB-combination systems are in 1 〇 and 5 0 ra μ m si in Yanyuan granules. K i = KH or K ^ as shown in Table 3. The KD values for 3H -PZ and 3H -QNB are 13.9 and 0, respectively . 0 9 3 η Η (nemol concentration) (F isher you, J. Pharmacol. Exptl. Τ hera P. DP 5 5 (please read the precautions on the back before filling in this page). Binding. This paper The scales are freely printed in China's National Standards (CNS) Grade 4 (210x297 g *) 201312 Printed by the β-Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs V. Invention Instructions (52) 1991, in publication) Table 5 (Replace 3H -QNR from rat brain L Shao W for 3H-QNR) and hired at M2. L was hired from S. Cerebellum to exchange 3H-QNR) Xi cousin ίπ_ hm W, brain hh m 3r-qnb _ combined% 3h- qnb-bound% KH1 KL1 — KH2 KL2 compound TT H1 L1 H2 L2 (a) (b) (c) ⑷ c: ad: bb: ad: c μιΜ μΜ 1 0.6 235 28 72 0.75 5〇61 39 1.25 0.21 392 67 2 0.11 37 26 74 O.Q69 5.2 49 51 0-6 Θ.14 336 75 3 o.oi6 1.6 13 87 0.014 0-58 35 65 0.9 0.36 1G0 Ul k 1.8 Spring 100 Jing 5-9 Jing 100 * 3-3 Qing Qing * 5 1.4 67 13 87 4.9 83 51 49 3.5 17 49 17 8 lh spring 1GG Qing 3.8 Qing 1G0 * Ο.27 Qing * Jing 9 5-84 * 100 Jing 11 * 10Q * 1.9-»Period Jing 13 112 Lu 10Θ Jing 5〇10Q * 0Λ spring spring 15 0.8 spring 1ΘΘ * 1.37 * 100 * 1.7 Qing ridge Qing * From the competition curve we can see that this is obviously better suited for the-position 1 m type (η 1 action curve). K value and use the non-linear and least square curve suitable for this number and use GA Η PHAD-2 21 and DP 56 as shown in Table 1 (please read the notes on the back before writing this page) too Aunt. Houchimu iA m Φ due to S3 «: 捸 m (CNS) ¥ 4 lead grid (210x297 enthalpy) installation · line · 201312 A 6 B 6 Printed by the Beigong Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention (53) A position analysis and statistics. Displacement 3H-QHB-binding (for 3H-QNB2KD value of 0.093 nM) was performed in 50 mM Phosphate Granules at 37 = for 1 hour (Fisher Fishers, J. Pharmacol. Exptl. Therap., 1991 , Is being published) From Tables 4 and .5, it can be seen that AF150 is highly selective for M1-toxin receptors. To be honest • Among them, AF125 has apparent M2 selectivity and AF150 is unexpectedly highly selective for M1 receptor. Test 4: Box (^ wide + virtual bundle and ftr electrosinus tartaridae ferrets cut on the sequence of the previous meeting. The transition gold ions and guanidine nucleic acid on the agonist for muscarinic receptors Affinity has a strong effect * may be derived from improving the ratio of the binding state of different catalysts (Gurwitz and Sokolovsky, Biochem. Biophys. Res. Commun. Q_Sj 1 2 9 6 to 1 3 0 1 pages, 1980; Aronstaia you , Mol. Pharmacol. IA: pages 575 to 582, 1978). Cu is similar to certain other transition metal ions and is known to form stable coordination complexes with protein argon and sulfur residues. If Cu is added, it will be Shows an increase in the apparent affinity of mycotoxin agonists and K increases the proportion of high-affinity states and eliminates the sensitivity of guanidine nucleotides (Fa "" ar and Hoss. T "ano. Ann. Soc. Neurochem. L2_: 250 , 1982; Gurwitz, Biochea. Biophys. Res. Conmun. 120: pages 271 to 276, 1984) ° As shown in Table 6, treatment with Cu—cannot be improved for the following (please read the back page first (Notes and then fill out this page) Binding · Strapping DP-57 This paper size is used in countries in China Sample Standard (CNS) A4 specifications (210x297 mm) A 6 B 6 201312 V. Description of the invention (M) Affinity, ie traditional non-selective antagonists of atotopine, atorpine and ranunculus, M and M1 Antagonist pirenzepine. On the other hand, the binding parameters of traditional non-selective catalysts (carbabaco and oxymetholine) show that Cu-treatment increases their apparent affinity, which is the competition curve Moved to a lower level of catalyst. The analysis of the competitive binding data based on the horizontal position of the two positions is summarized in Table 6 * and it is pointed out that the MCu—treatment plus high affinity binding position ratio is used for 325 increased to 51%, and used for carboco, increased from 25% to 44% · but did not change their two affinity coefficients KH and Kl.

Cu—also affects the bonding parameters used for AF102B (as shown in the data in Table 6) its interaction with the untreated membrane represents bonding to a single distribution location with Ki = 3.3; uM, but according to Cu—treatment , Also see a high affinity binding state, representing 26% of all positions with Kh = 0.02w Μ. See that there is no change in the low affinity binding constant. Therefore, he showed that AF 102 Β interacts with muscarinic receptors in the preparation of cerebral cortex membranes in a manner typically used as a stimulant, that is, the receptor-ligand complex interacts with G-proteins (reference Discussion by Gurwitz, 1984). In these studies, AF150 also has a combination of catalysers. In the untreated membrane, it showed multiple affinity states (for high and low affinity states of 0.32 uM and 33.5 ϋΗ, respectively). After treatment with Cu. Increase the proportion of high-affinity state from 14% to 37%, and it is proposed that AF150 acts as an agonist for toxic receptors in the cerebral cortex. DP-58 The paper size is in Chinese National Standard (CNS) Grade 4 (210x297mm) (please read the notes on the back before filling this page). Installed-line. Printed by Beigong Consumer Cooperatives, Central Bureau of Standards System 201312 A 6 B 6 V. Description of Invention (55)

Table 6: Earn (-) 3H-QNR m and rat ± cortical cortex and W (and not use) Γ κ, which means that the agitator does not require pretreatment and Cu * —pre-treatment KH_ Kl (viM)% R *% (μΜ) KL (u> l)% H * 1 0.〇93ί〇.〇7 27 ._. 7 25 ± 1 〇.11 ± 〇.〇10 17.5 ± 3.2 3 0.G2 ± 0.0〇5 13.3 ± 1-4 32 ± 3 0.G3 ± 〇 * GQ1 7.2 ± l, 7 51 ± 7 k 3.3 ± 〇 · 6 〇Q.G2 ± 0.001 3 · 〇 ± 〇.〇1 26 ± 5 5 Q.32 ± 0.G6〇33 · 5 ± l · 8 14 ± 1 O.52 ± 0.Q〇3 13.0 ± 2.Q 37 ± 2 9 0.3 ^^ 0.1 8.5 * 〇 · 8 13 ^ 5 q.i8 ± g .〇9 5 · 7 ± 0.2 3〇 ^ 7 KH (nM) KL (aM)% κ * ΚΗ (ηΜ) KL (nM)% E * 10 11 12 19.5 ± 0.5 695 ± 5 0 · 33 ± 0 · 011 0.09 ± 〇 * 0〇4 72 ± 3 0 0 12 ± 2-56〇 ± 6〇64 ± 6 0.2 ± 0.04 G Q.1 ± 0.GG5 G (Please read the precautions on the back before filling this page) · Order 'line-Printed by the β-Consumer Cooperative of the Central Standards Bureau of the Ministry of Economy :::% of high affinity. In the above table, the values are at least 3M cocoon test average (I ± SEM floating standard deviation average); each experiment is carried out on triple samples: the risk of pseudo-modification K reb junction impulse (ρ Η 7. 4) and under 2 5 t) for 2 hours and WC u — (1 0 0 w Μ) pre-conditioning the rat cerebral cortical wedge (or ignore it) 30 minutes S (Fisher Is bit 'J . Pharmacol. Exptt. Therap ·, OP_ 59-Too recognized chromium K ^ m 屮 团 S3 Xuanjia 4 fuge (210 to 297 public goods) A 6 B 6 201312 V. Description of the invention (56) 1991, in publication) . Trial B: Trial credits # Ｍ 臨 表 抻 and other subtypes of 钿 _Beizhong Qiang Kun ’s teaching tendon is based on the number of ridges, and the muscarinic receptors have been divided into three subtypes (Ml, M2 and M3). Molecular homology studies have identified five genetically different muscarinic receptor subtypes (M1 to M5). The functional performance of these genes has been pointed out between the genetically and pharmacologically defined subtypes of Kan, where Ml = Ml, M4 and M5; M2 = m2; and M3 = n3 (Buckloy you, Mol. Pharmacol. 3_5 _ :. 46 9 pages, 1 9 89). Stimulation of the M1 and M3 receptors induces dose-dependent increase in the hydrolysis of inositol phosphate (PI). The agonist activation of the ml receptor also induces increased basal and forskolUs-stimulated cAMP, however, the m3 receptor has no effect on intracellular cAMP concentration (Buck and Fraser, Biochera. Biophys. Res . Comm. 173: 662 to 672 pages, 1990). The muscarinic agonist stimulates the m2 and m4 receptors to preferentially inhibit the activity of adenylate cyclase (AC) (Mei, Life Sciences, pages 1831 to 1851, 1989). Analysis of new compounds AF150, AF151, AF150 (S) and AF125 are used for their ability to stimulate PI (Buck and F "ase", ibid.) In the M M 1 and m 3 receptors to transfer and infect C H 0 cells, respectively The ability of human neuroblastoma cells to stimulate PI in SK-N-S Η is mainly manifested in the m 3 subtype, but not in the ml subtype (Pinkas-Kramarski; you, Neurosci. Lett. 1 88: 335 ^ 3 40. 1 990; Luthiη everyone, Μ ο 1. DP 60 This paper size uses the Chinese editor «quasi (CNS) A 4 specifications (210x297 public *) (please read the ^^ policy item on the back * surface ' " Fill in this page again. Installed. Line · Printed by the Employees ’Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 201312 A 6 B 6 V. Description of Invention (57) Pharmacol. 3 4: pages 327 to 333, 1988). Also under training These compounds were tested on PC12 cells (the main subtype receptors shown) and coupled to the AC activity inhibitory effect (PU kad-Kramarsk; everyone, ibid.) ° test Stimulate PI disintegration and use S te U at (E Μ B 0 J. U 3_〇3 1 to 3 0 3 5 pages, 1 9 8 8), and test to mediate AC activity and KS tei η ibid and Pinkas-Kraraarski ’s method described in (FEBS Lett 239: 1 7 4 to 1 7 8 pages, 1 9 8 8). The results are listed in Table 7 and are combined with carbaco | toxin agonist (mixture) M1 / M2 type) and compared with AF 1 0 2 B. Shou 7: Cun Nongkun m 1. Π 3. And m 4 live special magpie subtype of chrysanthemum and ginger. Test compound hydrolysis of Ρ ί And the effect of AC jobs: (please read the precautions on the back before writing this page). Packed. Printed by the AKX Industrial and Consumer Cooperative Cooperative Standard

1 CHO SK-N-SH PC12 m3 E3 PI ec5〇PI sc5〇pi ec5〇AC ec5〇1 + + + 8 + + + 5 + + + 25 + + + 1.5 4 + 20 ^ a 3〇b — c-d G.lb 5 + + + 13 +38; ia 10b + ^ 0 ^ .3 3 + + + 1 6 + + + 54 + 45f. a 10b NT + + + 1 7 + i7r .a NT NT NT NT 8 + l4 "a NT NT + 2Q% a NT line. 201312 A 6 B6 Printed by the Beigong Consumer Cooperative of the Central Standards Bureau of the Ministry of Economy V. Invention description (58) ECs〇: activation at 50% Effective concentration (WM) + + +: Complete catalyzer compared with carbachol (for all compounds tested at 1 mM for all agonist activity) +: Partial catalyzer compared with carbachol- : Does not stimulate PI or inhibits AC PI: Inosine phosphate hydrolyzes AC: Μ changes c-AMP concentration to express adenylate cyclase activity KT: Not tested a: Carbaco effect% b: Effective concentration to trigger effect ( WM) c: 22WM AF102B inhibits the effect of 1 mM carbachol d: 1 mM AF102B inhibits the effect of 1 mM carbachol. In Table 7, it was confirmed that the catalyzing effect on the ηι receptor and Μ increased PI hydrolysis and AC activity, however ,anti Receptor stimulation Κ inhibiting AC activity; M3 stab lead to increased stimulated PI hydrolysis. From this table, it was unexpectedly confirmed that AF150 and A151 acted as complete agonists on ID i and u-toxin receptor subtypes, but partially on hi 3 subtypes. In addition, although the hydrolysis of M PI confirmed that A 1 5 0 and AF 1 5 1 are completely agonists for the DM receptor system, it was unexpectedly ruled that these compounds are different from carbachol, for example, they strengthen AC activity on the same receptor It has a very weak effect to confirm C: Therefore, carbachol can trigger the activation of ra i M toxin receptor and induce the increase of c-A M P stimulated in the basal and forskolin (2 3 2 to 356% and 546 to 1382%), and AF150 and AF151 are also extremely weak in this test (33% and 76%, respectively). (Please read the precautions on the back before filling out this page) Binding · Threading · DP-62 This paper uses the Chinese National Standard (CNS) A 4 specifications (210x297 mm) 201312 A 6 B 6 Central Standard of the Ministry of Economic Affairs Printed by the Bureau Cooperative Consumer Cooperative V. Description of the invention (59) In a typical experiment with SK-A-SH neuroblastoma cells, it was found that 10mM carbaba stimulates the accumulation of myozyme-1-phosphate (ΙΡα) It is 7.46 times higher than the reference concentration, 5.24 times if ΙπΜ oxymothermine-M. And 1.42 times if MlmM AF125. In contrast, the mi-selective agonist AF102B (U.S. Patent No. 4,855,290) cannot stimulate the hydrolysis of myosin phosphate in these cells, even at 1 mM, and at this concentration, he can completely block The signal is triggered by oximidine-M. This inhibitory effect depends on the concentration of oxymethyleneline-M; for example, lmM AF102B completely blocks the signal from lOuM oxymethyleneline-M up to 34%. In addition, the stimulation effect of carbaco and some specific new compounds on the hydrolysis of inositol phosphate ester was tested; in the same experiment, M combined with 10 mM carbaco and 11 ^ 6 卩 125 stimulation 1 卩 1 push product exceeds the benchmark Value is 6.11 times. Therefore, the new compound AF125 hydrolyzes inositol phosphate in SK-N-SH human neuroblastoma cells up to about 20 to 25% of the stimulatory effect obtained with the non-selective complete catalyzer carbacoate, while being only the lowest (10 To 20%) interferes with the effect of carba.chol. The significance of these results is that AF125 has the only activity as a toxin-like catalyzer in this type of cell rice that exhibits the main m3 toxic receptor subtype. The conclusion is that these compounds have unique activity and selectivity, so it is particularly useful for the treatment of SDAT (B "aam everyone, FEBS Lett. 230: 90 to 94 pages, 1988). (Please read the precautions on the back before filling this page) -Line _ DP-63 This paper scale is free of Chinese National Standard (CNS) A4 specifications (210x297 g *) 201312 Λ 6 Β 6 Printed by the Beigong Consumer Cooperative of the Central Standards Bureau of the Ministry of Economy V. Invention description (eg) Try credit R Test compound releases disaccharides_alkali (Anh) and neodymium_ ○ AF150 on substrate 1 and K * -causing 3H-Ach release effect (and MAF125, MeH-A-343 for comparison purposes) And oximetamine) were studied on the cell process prepared from the mouse cerebral cortex to use the detailed description by Pittel (J. Neurochem., 55: 665 to 672, 1990) Methods. The results are listed in Table 8. Two closely related structures were unexpectedly found, AF125 (IbM) inhibited K * -triggered 3H — Ach release, but AF150 (lmM) unexpectedly strengthened it. These results indicate that The role of presynaptic receptors is like oxytocin (a typical M2 mobilizer). On the one hand, The action of AF150 on precytosolic muscarinic receptors causes an increase in K * -triggered Ach release, which is considered to be an H2 antagonistic or Ml catalyzed effect. Hadhazy and Szerb (Brain Res. 123: 311 to 322, 1977) and Gulya (Neurochem. Int. 15: 153 to 156, 1989) explain that the release of the muscarinic antagonist K * _ triggers Ach. Suzuki (Meu "osci. Lett. 84: 209-212 , 1 988) and Pittel, the same 5, showing that the mycotoxin antagonist also stimulates the release of the basal ACh. The latter study proposes to mediate the stimulatory protonin receptors released by ACh in the CNS and in pharmacology They are scientifically identified as Ml subtypes. In smooth muscle preparations, it has also been confirmed that the autologous toxin-accepting system that increases ACh release exists in PNS (Kilbinger and Nafziger, Haunyn Schmiedebergs Arch. Pharmacol. 328: 304 to 309 pages, 1985). (Please read the precautions on the back before filling out this page) Binding · Order _ Line. DP -64 This paper uses the Chinese "Home # Standard (CNS) A4 specifications (210x297 public *) 201312 A 6 B 6 V. Description of the invention (61) Brother ft: The test compound is obtained from the mouse cerebral cortex and the empty rope body ( Effect of lead acetate dysprosium risk transfer base (Anh) release of - projecting a bottom assembly .1 [(♦. Compound U concentration mM base 3H-ACh release κ +-¥ trigger 3H_ACh ¥ release 3 0.1 NT 56 5 0.1 121 11Q 5 1.0 NT 1154 ⑹ * ρ < 0.〇1 5 G.1 + 10 ΙΟ 87 91 0 1.0 NT 78 ± 9 (2) * 9 0.1 Ikk 172 (please read the notes on the back before writing this page)

, 1T line-Printed by the Ministry of Economic Affairs, Pyongyang Aβ Industrial Consumer Cooperative. Ν Τ: Not tested ★ η Μ is delivered by 1 flush antagonistic effect (a Μ 1 antagonizes 1 to strengthen AF 1 5 0 on K +-triggered 3 Η-A ch release effect (as noted in Table 8) 'And pointed out

Printed by the Ministry of Economy + Central Bureau of Standards and Employee Consumer Cooperative V. 201312 A 6 B 6 V. Description of the invention (62) AF150 is designated as an Ml motivator, thus activating Ml excitatory autoreceptor. However, despite the fact that the action of AF150 has been reversed, is it attributable to, for example: (a) the motility activity of the first and the first after Ml cell junction; or (b) the motility effect and M2 cell junction after Ml cell junction The previous antagonistic effect * This compound system is especially used to control SDAT and have abnormalities. Test credit 7: Yi Cave. Yi Yong tJ) Phytophysiological evaluation of AF150 acetyl 18 base (A C h) in Η has multiple effects in the brain of mammals. The main effects can be found in the Haiyu back slice and include: (1) blocking the continuous potassium outflow activated by depolarization U +) current flow out (Im); (2) after hyperpolarization (ΑΗΡ) , Block the low K + current related to Ca one by one; (3) block the K + current at rest; (4) temporarily flow out the K ~ current; (5) report that ACh engages the cell process Post-potential (naturally increases but decreases after being excited) and effect on Ca-current. (Segal, Brain Res. 452: pages 79 to 98, 1988; Dutta "and Nicoll, J. Neurosci. 8: 4214 to 4224, 1988). Use of gallic amine (an M2 antagonist) and π private flush (pz ,-The result of a kind of M 1 antagonist), it is proposed that the M 2 receptor mediates the suppression of low EPSP and blocks IM. In contrast, the depolarization and blocking of AHP is insensitive to gallic acid and blocked by 0.3 HMPZ. It is similar to being mediated by the Η1 receptor (Duttar and Η ic ο 1 1, fixed). (Please read the precautions on the back before writing this page) Binding · Order · Thread. DP 66 Country # pole (0) A 4 specifications (210x297 mm) A 6 B6 V. Description of the invention (63) In the general name, the recording method in the K cell records the application of A150. ACh and PZ to the rat hippocampus gyrus cells Fine drop effect. Using this method, the exact concentration of the lotion in this body position cannot be known. However, from the electrophysiological point of view, this method is superior to the perfusion method and can obtain more accurate results (Segal, ibid.) The Segal method was used to record the intracellular response of the CAI nerve (in the hippocampal slice) to AF150. Stimulate the Schaffer junction to produce a small hyperpolarized current pulse (without traces of current drawn) after the cell junction. The local application of AF150 in fine droplets (100 // M) causes a powerful depolarization reaction. Hyperpolar Controlling the potential of the cellular M showed a real increase in input resistance at rest. AF150 blocked the slow AHP mediated by Ca + + -Kan * conduction. AF150 caused a small amount of post-conjunct potentials (PSPs) to be flush (100uM), —Ml-toxin antagonist) significantly reduces the polarization effect caused by AF150. Μ 诚 夂 齐 平 also prevents the increase of the input resistance at rest. In I flushed slices significantly reduced due to AF150 blocks the slow ΑΗΡ. AF150 causes PSPs to be reduced and is not affected by pirenzepine. (Please read the precautions on the back before filling this page) Install & Line. Ministry of Economic Affairs Central Standards Bureau Beigong Consumer Cooperative Printing (1) AF 1 50 caused depolarization, increased input of electric bile, and blocked slow AHP, and this effect was antagonized by the M1 receptor antagonist, Qiping; however, it was detected with Compared with AC h, its effect on PSP s It is small and is not affected by α-like flush W. (2) Surprisingly, AF 150 is used in the M1 receptor than in the M2 receiver system. It has a DP 67 and the paper size is easy to use. ) A4 specifications (210x297 g *) 201312 A 6 B6 Printed by the Beigong Consumer Cooperative of the Central Bureau of Economic Affairs of the Ministry of Economic Affairs V. Description of invention (64) More specific catalyst. (3) Compared with AF102B, it is clear that the Af? 150 series is more 'effective and causes depolarization (blocked by Qi Ping), but this is not the case under the condition of A Jie l 2B' Happening. And AF150 & AF102B can block the slow AHP (1 flush-sensitive M1 effect). Test R: Chain reaction power_iL and general toxicity Part A 1. Said: The purpose of this study is to establish preliminary pharmacology * 1 mechanics 11 and ^ 1 (5 AF150 general toxicity, and injection Observe the mice after the dose of AF15〇 concentration. 2. Materials and methods: a. Animals: mice, male CD, 20 to 30 grams. B · Group sister size: η = 5 ° C. Administration route: intraperitoneal ( ί · Ρ.) Injection ° d · Dose concentration: 1, 5, and 10 mg / kg. e. Dose volume: 10 ml / kg. f. Test material preparation: Dissolve AF-150 in saline solution. g .Four doses of AF 1 50 Μ were injected intraperitoneally (i.p.) into mice (η = 5). After the injection, the behavior was recorded to change for up to 2 hours and after the administration, the amount of observation was up to 24 hours for the occurrence of death. The analgesic effect is evaluated and the M tailing method is carried out at 15, 30, 60 and 120 minutes after the injection. In addition to the use of painlessness, observe the following effects of animals: occur (know first Read the precautions on the back and then fill out this page) Binding & Threading · This paper uses the Chinese National Standard (CNS) A4 specifications (210X297 *) 201312 A 6 B6 V. Description of invention (65) tremor, convulsions, respiratory distress, drooling, diarrhea, changes in the diameter of the sleeping hole, rashes, coordination of movement, low mobility-or too high and vocal conditions 0 3. Official removal result 1 gram / grand fr (brand neck injection): After about 30 minutes after injection, minimal salivation (drip) and diarrhea were observed. No pain was observed during any observation period. No other central or autonomous (shenzhen) effects were seen. 5 Jingjing / kg (look at the intra-cervical administration): after 60 minutes of injection, low motor activity (activity) was seen, and then regular activity was obtained. 15 minutes after injection, some painlessness can be seen. Movement coordination is reduced up to 30 minutes after injection. Mydriasis is seen 5 minutes after injection. Slight salivation and diarrhea are seen within 10 to 60 minutes after injection. 10 Kui Jing / Gong fr (Abdomen pelvis): Two of the five animals injected showed complete low activity within 5 to 75 minutes, and the other three received their activity after 120 minutes. . A short period of time is seen after 10 minutes of injection. During the entire 2-hour pro-test period During the interval, exercise coordination is greatly affected. There is no pain at 15 and 30 minutes after injection, and pain is seen after more than 60 minutes. Moderate salivation, diarrhea, tearing and mydriasis are seen after 5 minutes of injection and at 10 It becomes serious after a minute, but after 90 minutes of injection. ® Severe (please read the precautions on the back before filling in this page). Installation and line. Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. Lower middle es, research, Γ1, research, ha, (C, whole mouse, white, white, 3, use, and use, W, and Nei Kung, it, and paper size, and use Chinese National Standards (CNS), Grade 4 (210x297 g *) ) 201312 A 6 B6 V. Description of invention) AF 1 2 5 (N) AF 1 Μ ^^ ancient / kg dose range in the intraperitoneal injection of AF125 to 50 to 200 mg / & _ & reed test. Point out poisoning Consistent amount of dead Xue 1 falls into the mice within the dose ie ® β / / A catty. In addition, it is clear from these preliminary tests that the main symptoms of 100 to 200 mg / Λ, π 6 should be mainly used for the potential establishment of the test material and the treatment of anti- ^ hijacking, such as vibrations, splashes, tears, copper 3. Diseases without pseudo-alkali activity are disturbing. The body temperature is also controlled (iv). Survivors will begin to have signs of recovery about 2 to 3 hours after injection. The results of non-lethal doses of oral and intravenous AF 1 2 5 will be listed in Table 9 in Table 9 below. The main symptoms seen in Table 9 (please read the back The matters needing attention will be written on this page). ·· π, the standard of the Ministry of Economic Affairs and the printed quantity of the Mgongt Cooperative Society Co., Ltd. _____ ____- mg / way T ”2 'fC. Q / c sev sev m〇d 5 / p nod dec nod mod 40 iv 5/5 2/5 〇 / 5 ^-/ 5 sev sev m〇d 5/5 dec mod mod 〇 巧 0/5 mod sli sli 5/5 sli dec sli .sli 0 / 5 0/5 0/5 sli sli 5/5 Sli dec _________ — 0/5 0/5 mod mod sli 5/5 sli dec mod sli dagger ij p.〇s 0/5 0/5 0/5 sli mod sli 3/5 dec sli sli 20 p.os 0/5 0/5 0/5 sli sli 0/5 IQ p.os 0/5 0/5 0/5 _______________________________________ ———————-· " · n Treatment of the whole thing, the shadow of the thing, the value of the data stated is 1

Has Sal Lac Dia Ana Myd Mot Pil Hyp 20 i.v. 10 i.v. 5 i. V. 5〇 p.os

DP 70 Printed by Beigong Consumer Cooperative of Central Bureau of Economic Affairs of Ministry of Economic Affairs 201312 A 6 _ B 6_ V. Description of Invention (67) The other abbreviations used are listed as follows:

Tre = chatter

Con = convulsive convulsions, most of them form a tonic form

Res = Respiratory distress, most of the encounters are degree of breathing and breathing. Copper (sli; mod; sev)

Ana = Painless, indicated by lack of response to tailing

Myd = scattered blind (sli; mod; sev)

Mot = natural change in sport activity, increase (inc) or decrease (dec) P i 1 = Mao Jili (sli; mod; sev) H yp = low body temperature (sli; mod; sev) I. EUo) LD 50 values (95% upper limit of confidence) obtained from the following; I. Intravenous injection 68.9 mg / kg (66.6 to 71.2) Π. Oral administration 1 3 4. 4 mg / kg (1 1 8 · 4 to 1 5 2. 5) Examining the preliminary screening results obtained in mice induced by It, AF 1 25 has the main activity of pseudocholine. It should also be noted that during the activity period, recovery begins approximately 1 to 2 hours after treatment and occurs during administration. In a word, under the condition of oral administration, the comparative recovery time is obviously relatively fast. The ratio between the two individual LD 50 values seems to be narrow. • Intravenous injection or oral DP-71 This paper scale is applicable to China National Standard (CNS) A 4 specifications (210x297 mm) (please read the back (Notes and refill this page) Pack · 201312 A 6 B6 V. Description of the invention (68) Comparison of treatment The "active" dose concentration Fanyuan also pointed out that AF125 is not easy to absorb hydroxyl by the intestine. AF1m'AF123 lists the general effects of these compounds in Table 10. (Please read the precautions on the back before filling in this page) Pack * Line-DP 72 printed by the Staff Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. This paper standard uses the Chinese National Standards (CNS) Grade 4 (210x297) * 201312 A 6 B 6 V. Description of the invention (69) The main diseases seen in the mortality of the dose administration route _ Compound mg / kg Tre Con Res Sal Myd Mod P / H AF125 ⑻ 100 IV 5/5 immediately 50 IV 5/5 immediately 20 Intravenous injection 0/5 3/5 4/5 s 1 is 1 i dec 200 Oral 0/5 s I i inc sl i AF123 200 Intravenous injection 5/5 Immediate 100 Intravenous injection 5/51 minutes 5/5 50 iv Injection 0/5 400 Oral 5/53 minutes 5/5 5/5 5/5 200 Oral 0/53 minutes 4/5 (Please read the precautions on the back before writing this page) Pack · Order-Line. Ministry of Economic Affairs The figures stated in the data printed by the Central Standards Bureau employee consumer cooperatives ¥ refer to the number of animals affected in all animals treated. Used for other abbreviations as detailed above, and additionally: P / H = Mao Jili / low body temperature (sl i; mod; sev) DP-73-This paper standard is used in β- 楳 揳 准 (CNS) A 4 Specifications (210x297 g *) 201312 A 6 B 6 V. Description of the invention (70) Μ 8 # 9: Yi Passive Tao (PA) section trial pilot credits # 鳧 蠪 莪 碱 縲 鼠 夕 測 輔. A three-month-old purebred male cloth was used to connect a squirrel (available from Charles River Breeding Station, England) (weighing 200 to 300 grams). The passive evasion (PA) test is based on the methods of Fishers, Neurosci. Lett. 102: 325 (1989), except that these mice are scopolamine-induced mental disorders. Eight sisters were used and each group had 17 to 20 purebred rats. Each sister was divided into two groups and each had 7 to 10 rats: the second sister was injected with H. angustifolia HBr (0.5 mg / kg in saline, subcutaneously 15 minutes before shock) and the second sister was injected with 2 Saline (1 mg / kg subcutaneously 15 minutes before shock). Seven sisters were treated with one of the following test compounds within 1 minute of shock: 0.1, 0.5, 1, 3, 5, 8, 10 mg / kg (in saline | intraperitoneal injection) and one sister received saline (1 Mg / kg, intraperitoneal injection). A F 1? S Two-way AN0VA was used to analyze the initial latency and retention latency (pre-shock treatment / post-shock AF125 treatment). Table 11 and Table 12 state the average value of the initial and retention latency, respectively, S.E.M. (average standard deviation). (Please read the precautions on the back before writing this page) Packing. Threading · Printed DP-74 by the Beigong Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs-This paper standard is used in "Family Criteria (CNS) A 4 Specifications (210x297 mm) 201312 66 ΑⅤ 5. Description of the invention (71) S11: AF after Tikkyo AF 1 2 ^ Dose (mg / kg) Tucker ’s Precursor Pound 1 AF1 after rest Beijing? The average value of the pre-medicine hydration during the period of S. E. M. mean saline 10 28.7 49.5 42. 0 36.0 51.9 34.7 41.2 46.3 10.9 9.0 14.5 12.9 11.4 6. 8 14.0 23.5 33.6 47.4 23.3 47. 3 51. 3 53.9 45.9 15.8 19.0 4.9 11.8 14.612.2 12.6 (Please read the precautions on the back before filling in this page) Installation-Line-Printed by Beigong Consumer Cooperative of Central Bureau of Standards, Ministry of Economic Affairs

DP 75 This paper is used in β-home standard (CNS) A4 specifications (210X297 mm) 201312 A 6 B 6 V. Description of invention (72) Lane 1 2: Tetragonite alfalfa-Tethou AF1M treatment of the mole of the mole of the rat during the drinking period, the most decimated after eating m 7k before the AF 1 2 5 Μ 鰪 龅 Dose (mg / kg) average S. E. Μ average S. E. Μ. Saline 600.0 0. 0 97.9 42. 5 0.1 572.8 27.2 128.8 69. 4 0.5 6 00.0 0. 0 2 2 2.7 76.5 1.0 5 5 5.8 41.1 261.2 82.7 3.0 5 30.4 49. 5 Z96. 0 84.1 5.0 426.7 53.4 227.3 81.4 8.0 594.1 6.0 294.9 98.0 10.0 498.3 59.0 28 8.3 103.2 (please read the precautions on the back before filling in this page) Printed conclusions of the Employee Consumer Cooperative of the Central Standards Bureau of the Ministry of Economics reversed the screening test and M used scopolamine as a pre-shock treatment and AF 1 25 As a therapeutic agent after shock, a significant dose response curve is produced. Compared with all other doses, K 3, 5, 8 and 10 mg / kg doses have significant advantages. Compared with saline-treated rats, the mice with the above-mentioned doses had the longest incubation period. Because the lower dose has a short incubation period, it is pointed out that it is not DP-76-the Chinese standard (CNS) A4 specification (210x297 g *) on this paper scale. 201312 A6 _ B6_____ V. Invention description (73) Improve cognitive function. There was no significant difference in all the tested sisters during the initial incubation period. It was found that AF125 treatment effect was significant after shock (narrow fee) (F: 104.77, df: l / 126, P <0.001), if 10 mg / kg (P &lt; 0.05), the treatment of ranunculus was significantly increased The incubation period of rats. In addition, AF125 (5 g / kg) significantly shortened (p &lt; 〇.〇5) the incubation period of rats treated with saline water before shock. Finally, it was found that there was a significant difference in the retention latency between rats treated with scopolamine before shock / saline treatment after shock and rats treated with saline before shock / saline treatment after shock (P &lt; 0.001). All rats were treated with saline before shock (the doses of AF125 received after shock: 3, 5, 8 and 10 mg / kg) had side effects. The group sisters who received 3 mg / kg showed slightly diarrhea. The K5 mg / kg treatment group had more severe diarrhea and the groups treated with 8 and 10 mg / kg had severe diarrhea and wept. It is important for them to indicate that if K-shock is treated with scopolamine before treatment with AF125, it really does not have any side effects. With six? Compared with 1028 (US Patent 4,855,290), ^ 125 has a wider dose-response curve; AF102B with 3 and 5 mg / kg doses has a significant strengthening effect on retention behavior, while AF 1 2 5 has a better performance. Wide range (3 to 10 mg / kg) with strengthening effect. Printed by all this, also printed by the Beigong Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs

Yu You are right. He should be effective &quot; movement / U 33 BE .J -mtl @ 催 效 助益 中 强-之 有 7 out of 7 with 7 types of body- 這 受 性 性 在 素 5 毒 2 ί 1 菇 F _ Α 之Knowing the achievements, knowing and recognizing the DP, this paper is used in the "Home Sample Standard (CNS) A 4 specifications (210X297 公 #) 201312 A 6 B 6 V. Invention description (74) AF 1 2 5 (N) Feng The use of 3-month-old purebred male Sprague-Davley rats (available from the Charlie River Breeding House in the UK) (weighing 200 to 300 grams) Behavioral test credit using eight sisters and each sister with 18 to 20 Purebred rats. Each component was divided into 2 sisters and each sister contained 9 to 10 mice: subgroup 1 was injected with scopolamine · HBr (0.5 mg / kg, in saline and 15 minutes before shock g by subcutaneous injection) The second sister 2 was injected with saline (M 1 mg / kg 'injected subcutaneously 15 minutes before shock). Seven sisters were treated with one of the following AF125 (N) doses within one minute after shock: 0.1, 1, 3, 5, 8 or 10 mg / kg (in saline, intraperitoneal injection) and the other sister Receiving saline (1 ml / kg, intraperitoneal injection) ° Two-way AN 0 VA analysis of initial latency and retention latency measurement (pre-shock treatment / post-shock AF 1 25 (N) treatment). Tables 13 and 14 represent the average soil S.E.M. for the initial and retention latency, respectively. (Please read the precautions on the back before writing this page) Binding-Ordered by the Ministry of Economic Affairs, Central Standards Bureau, Beigong Consumer Cooperative Printed DP-78-This paper standard is not used in the CN β A4 (210x297 Mm) 201312 A 6 B6 V. Description of the invention (75) Yi 1 2: AF125 (N) after the treatment of the buttercups after the treatment. AF125 (N) The latent physiotherapy after the initial treatment of the rat 丨 Before shock after shock AF125N Salt water buttercups Alkaline dose (mg / kg) average SEM average SEM saline 0. 1 10. 26.7 4.7 39.1 17.6 21.0 2.7 22.3 5.6 28.1 7.7 62.9 17.4 22.0 4.2 29.1 14.5 44.1 14.1 23.1 4.0 65.1 18.5 24.6 5.3 19.3 5.4 16.3 2.7 1 4.9 2.2 2 1.5 5. 3 (please read the precautions on the back before filling the nest page). Binding. Line. Printed by the Beigong Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. It is found to be treated with AF 1 2 5 (N) There was a significant difference in the initial incubation period between group sisters (F (7/140): 2.37, Ρ &lt; 0.05) (Table 13). It was also found to have an interaction between AF125 (N) treatment and pre-shock treatment (saline solution to scopolamine) (F (7/140): 22.43, P &lt; 0.05). In more detail, the Scheffe test showed that the initial incubation period (6 2 · 9 ± 17.4 seconds) of AF125 (N) (M0.5 mg / kg) treated rats before and after shock was significantly ( ρ &lt; 0.025) is longer than that used to control her sister ’s initial latent her before shock, scopolamine-shock after saline, 39. 1 soil 17.6 seconds). If it is compared with the control sister: DP 79 before the shock, the paper size is based on the Chinese National Standards (CNS) A 4 specifications (210x297 g *) 201312 A 6 B 6 V. Description of the invention (76) Saline-salt water treatment sister after shock In comparison, the pre-shock saline-post-shock AF125 (H) (at 5 μg / kg) treatment group also had a significantly longer initial incubation period (65.1 ± 18.5 vs. 26,7 ± 4.7 seconds, P <0.001). The effect of AF125 (N) treatment after shock was found to be significant (F (7/140): 3.51, P &lt; 0.05 and see Table 14). The Scheffe test specifically showed that the dose of AF125 (H) (0.5 mg / kg) significantly increased the retention latency of rats treated with buttercups (332.7 ± 80.9 vs. 141.1 ± 5.5 seconds) when compared with saline-treated rats. P &lt; 0.0 05). (Please read the precautions on the back before filling in this page) Binding-Order DP 80 printed by the Beigong Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs This paper is used in the Chinese National Standard (CNS) Grade 4 (210x297 g *) 201312 A 6 B 6 V. Description of the invention (77) Cyclops sibiriformis-After the Tick AF12 5 (N) Retained wine of the devoted rats The best friends _ AF125N dose after shock (mg / kg) Average salt water before shock S.E.M. Scopolamine average base S.E.H. saline 483.6 64.9 141.1 55.5 0,1 554.7 22.5 59.79.7 71.7 0.5 600.0 0.0 332.7 * 80.9 1 .0 448.9 56.7 114.8 56.2 3 .0 500.1 44. 0 2 43.4 69.2 5.0 290.3 52.1 1 ^ 1.6 58.2 8.0 552.0 28.3 2 10.2 6 1.5 10.0 417.5 64.9 129.7 42.2 Come to P &lt; 0.005, and compare with fresh water (please read the precautions on the back before filling in this page) Pack. Order 1 Line. Printed by the Employee Consumer Cooperative of the Central Ministry of Economic Affairs of the Ministry of Economy. In addition, AF 1 2 5 (N) (5 mg / kg, intraperitoneal injection) significantly shortens the pre-shock water treatment when compared with their control sisters. Rat incubation period (290.3 ± 52.1 vs 483.6 ± 64.9 seconds, i.e. <0.005): Finally, it was found that there was a significant difference in the retention latency between mice treated with pre-shock methinine / post-shine saline and rats treated with pre-shock saline / post-shock saline (141.1 ± 55.5 vs 483.6 soil 64.9, Ρ &lt; 0.001). Printed on any DP 81 paper scale given by China Jijiazhun (CNS) A4 specifications (210x297 g *) 201312 A6 __B6 printed by the employee consumer cooperative of the Central Bureau of Standards of the Ministry of Economy V. Description of invention (78) Dose of buttercups Obvious side effects. Reversing the screening experiment, using scopolamine as a pre-shock treatment and AF125 (N) as a post-body treatment, only one dose according to the following: 0.5 ng / kg (intraperitoneal injection) can produce a positive and significant response. Comparing with the "water-treated rats", rats treated with this dose have a longer residence time. Except for 10: Exist in the passive Taoban (PA) example. AF15 a. AF64A — 珓 珲 留. 囟 之 ND neodymium. This animal model simulates that S DAT cholinergic stimulatory function is too low to a certain degree (Fisher and Hanin, Ann, Rev, Pharmacol. Toxico1, 26: 161 to 181, p. 1 986). The methods described in Fisher (J. Pharmacol. Exptl. The rap., 1991, in publication) and Fisher (Neurosci. Le’tt. 1.0 2: 325 to 331, 1989) are used here. The results are listed in the table. As can be seen from the table, intraperitoneal injection of all three tested doses of AF150 is beneficial in this animal model. If AF150 (in free form) was administered orally (not entrapped) at 0.2 and 1.0 mg / kg, he significantly improved the incubation latency in A64A-treated rats. It was later discovered that if K is administered orally at a very low dose, this compound will be fully absorbed and effective. Significantly, in the PA test, the effective agent system had no significant side effects. Therefore, as demonstrated in learning and memory tests such as PA, AF150 has a wide margin of safety. Among the different animal groups tested in the initial incubation period, no significant differences were found; the initial incubation period ranged from 20 to 30 seconds. Use all of the AF150 (please read the precautions on the back before filling out this page) Binding · Order · DP-82-This paper is used by the homeless «quasi (CNS) A 4 specifications (210x297 public *) 201312 A 6 B6 V. Description of the invention (79) In order to check the pH, the alkali free travel which is actually used in the combination of the dissolved substances is presented, and the Chinese medicine Chongyuan phosphorus hydrochloride (please read the precautions on the back before filling in this page) Printed by the Staff Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. This paper is used in the national standard (CNS) Grade 4 (210x297 g *) 201312 A 6 B 6 V. Description of the invention (80) Lane 15: AF1M Who carried out the passive Tao study after 72 hours of retention latency (seconds) ΙΟιηΜ phosphate buffer AF150 ng / kg, intraperitoneal injection of saline-treated rats 438.1 ± 57.0 511.8 ± 45.7 479.1 ± 57.2 571.6 ± 28.4 HAF64A * treated rats 174.8 ± 44.2 449.5 ± 52.1 481.1 ± 54_3 600.0 ± 0 m3 nanomolar / 2 μl / each side. Intravenous catheter injection has a significant interaction if F (2.54) = 6.33, P &lt; 0.005. By analyzing the previous data based on Scheffer's main comparison, the following important results were found: (Please read the notes on the back before filling in this page) Installation · Line-Printed by Beigong Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (p &lt; 0.005) AF150 (0.1 mg / kg) for AF64A-yuan granule (P &lt; 0.025) A64A-AF150 (0.2 mg / kg) for AF64A-buffer (P &lt; 0.001) A64A-AF150 (1.0 mg / kg) for AF64A-yuan Agent (P &lt; 0.05) A64A-AF150 (1.0 mg / kg) vs AF64A-AF150 (0.2 mg / kg) (p &lt; 〇.〇5) saline-yuan granule (P &lt; 0.005) saline-yuan granule (P <0.025) saline-yuan granules on AF64A-Cong granules on AF64A-AF150C 1.0 mg / kg) on saline AF150 (1.0 mg / kg)

DP 84 This paper is used in the selection of a home sample standard (CNS) A4 specification (210x297 g *) 201312 A 6 B 6 Printed by the Beigong Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs V. Invention Instructions (81) Credit 1 1 : — The AF125 and AF1 RQ are stored in the AFR4A of the arm roller shooter (RAM) section. This animal model simulates hypocholinergic dysfunction and cognitive dysfunction in S DAT (Fisher and Hamin, ibid; Fishe, "You, Neurosci. Lett. 102: 325 to 331, 1989); in this department Use the method described in the latter publication. Part A—AF125 in RAM MAF64A—Injection of mature mice to evaluate the potential effect of AF125 in memory deficits. Method a) 48 mature mice were used in this study Male (11 to 12 month old) rats. Before August, at the age of 3 months old, their MAF64A (3 nanomolar / 2 microliter / each side) was injected via intravenous catheter. Two weeks before the behavior test, the rats were transferred to individual barns and the food supply was restricted until the weight of the other words was 90% (the rats were free to take water). The room was illuminated for 12 hours (6:00 to 18: 00) and the behavior test period is carried out in the morning. After reaching 90% of the free feeding weight, the rats receive 4 food pellets (A 1 t "〇mi η, 15 grams) per day to further reduce the weight of the rats. In the behavior test The first two days, the rats were fed with nine accurate feeds (produced by Bioserv.), And then used For strengthening in the maze. (Please read the precautions on the back before filling out this page) Binding-Order DP-85 This paper is used in the national standard (CNS) A 4 specifications (210x297 mm) A 6 B 6 201312 V. Description of the invention (82) (Please read the precautions on the back before filling in this page) Μ 奘 置 Behavior Test is carried out in a raised arm (70 cm) made of PVC 8 arm radiation fan array. This arm (75 Cm long and 10 cm wide) extends from the octagonal central event space (40 cm wide). At the end of each arm is placed its own feeder ((45¾ grams of pellets) and the distributor is type 8000) (Lafayette Instrument Company Supply). C) Behavior test 1) Before the start of the actual test, familiarize the rat with RAM. Spread the nine grains in the entire labyrinth area. Place the rat in the central activity place, one episode in a certain place During this period, he is facing the same direction. It is allowed to run from one arm to the other arm until all 8 arms have been visited or until 10 minutes have elapsed. It takes two weeks before training (M 5 days per week). 2) Interview 1 practice due to the size of this batch (48 mice), the experimental department is in the second In each phase, there are 12 AF64A-injected rats and 12 saline-injected rats involved in each phase. The rats in each phase are further divided into two young women-treated with drugs and controlled sisters. Within the training days, place each rat in the central activity place for 30 minutes, and then inject AF125 (0.5 mg / kg dissolved in table salt, and be injected in the abdominal cavity with the printing solution of Beigong Consumer Cooperative of the Ministry of Economic Affairs, Beiyang Standards Bureau) or table salt Water (1¾ g / kg, intraperitoneal injection) was injected. Allow the rat to run from one arm to the other until 8 pellets are collected or until 15 minutes have passed. For each rat, the correct selection, the number of errors, and the five-day trial time are divided into 1 section. Take 2-way AN0VA (2 DP-86-this paper standard uses the Chinese National Standard (CNS) A4 specification (210x297 g *) 201312 A 6 __B_6_ V. Invention description (83) (Please read the precautions on the back first Fill in this page) x2) Analyze the correct choice, the number of errors and the total time integral (injection, AF64A / saline solution and treatment of AF125 0.25 mg / kg / saline solution). if indeed compile: found between the first eight entrances between AF64A—the behavior of rats injected (6.0 ± 0.24) and the behavior of rats injected with saline (6.8 ± 0.15) in the average number of days correctly selected There is a significant difference (F (l / 36): 9.29, P &lt; 0.005). In addition, a significant interaction between injection and treatment was found (F (1/3 6): 6. 3 5, P &lt; 0 2 0 5). The S c h e f f e test showed that AF125 improved the behavior of rats injected with AF64A (6.53 ± 0.36) (P &lt; 0.025) compared with saline-treated rats (5.49 ± 0.26). In addition, it was found that there was no significant difference between the behavior of MAF125 treated mice treated with AF64A-injected rats and M salt treated with 7k saline injected rats. Wrong age: AF64A-injected rats (7.69 ± 1.1) caused significantly more errors than saline-injected rats (3.52 ± 0.5a) (F = (l / 36) = 10.11, P &lt; 0.001). The AF125 process does not have any effect on this parameter. Total time: at the knot! In terms of time measurement, there was no significant difference between any group of sisters. The weight printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs: The average weight of rats was compared before the behavioral test and the t-test showed that it was between AF64A-injected rats (489.5 g) and hydroxysaline-injected rats (579 g) All significant differences (t = (38) = 4.05, P &lt; 0.001). The effect of A F 1 2 5 on body weight was not tested, because the rats were restricted from feeding food. Side effects: In this study, a dose ratio of 0.5 mg / kg was used in the DP-87-This paper standard is used in the Chinese National Standard (CNS) A 4 specifications (210X297 mm) 201312 A 6 B6 Printed by the Bureau Cooperative Consumer Cooperative V. Description of Invention (84) The higher doses (1 and 3 mg / kg) used in the MVMS test caused fewer side effects. Only two KAF125 treated saline-injected mice developed diarrhea. No other side effects were found. Conclusion 1. The AF64A-injected mice showed a significant reduction in behavior and were expressed by the following two parameters: the number correctly selected and the wrong number outside the first eight entrances. AF125 (0.5 mg / kg, intraperitoneal injection) significantly improved The behavior of rats injected with AF64A. As a result, only K is the correct parameter description beyond the first eight entries. 3. Compared with the higher doses (1 and 3 mg / kg) used in the MWM experiment, the dose of test compound AF125 is lower-0.5 mg / kg, so the latter side effects may be the lowest. Part R—AF 1 5 0 In short, in this experiment, after 2.5 months of injury, using saline solution, and AF64A-pretreated rats (3 nanogray ears / 2 microliters / per Side, injected via a vein through a catheter). Conducted this experience for more than 3 weeks. During the first week • Train the rats to find food pellets in all eight-arm maze. After learning this task, use a delay method to train the mole rats. During the pre-delay period, the amount (0.07 mg / kg, intraperitoneal injection) was slightly better than the higher tested dose. The beneficial effect of A F 1 50 in this test is to prevent degradation (memory) in rats treated with A F 6 4 A rather than simply improvement. During the post-delay period, AF150 has no improvement effect on the error in the work, although during this period, the paper size is also 88. The national standard (CNS) A 4 specification (210x297 g *) (please read the back Matters needing attention and then fill out this page) Installation · Line-A 6 B 6 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Invention Instructions (85) will increase these errors. The reasons for this effect may be: (a &gt; the pre-delay period is a simpler job than the post-delay period, because it requires less cognitive ability and is easier to improve; (b &gt; administration of AF1 50 during the pre-delay period, Therefore, the improved memory M was improved to find the first four entrances. It may be that this agent has no effect on the post-delay period | that is, it can be a different recognition process for learning the other four entrances. These results are different from those in the PAL test The results of AF150 together indicate that this compound is a very powerful cognitive activator and unexpectedly stronger and more powerful than AF102B. Therefore, AF150 especially allows SD AT to be controlled with Μ ° TEST 1 2: Cao Lisi 7kj m Array (Morris water maze) (MWH) In the case of tuna, the effect of 铧 -reasonable rat meat. Use such animals as described by Fisher in (J. Pharmacol. Exptl. The "aP. 1991, in publication] Model * This model simulates the cognitive impairment of cholinergic-induced hypofunction in SDAT. Mouse MAF 6 4 A (3 nanomolar / 2 microliters / each side, M catheter via intravenous injection) or table salt Water (2 micro , Injected intravenously through a catheter), in the presence of phosphate Yuan granules, or injected with AF 151. The results of the length of the mouse walking path (cm) are listed in Table Ή. Μ all three dose rates The AF151 showed significant dose-related benefits in the recovery of cognitive dysfunction in rats treated with AF64A. After closing the four arms of the maze, the rats opened the four treasures to collect food pellets. In DP-89-Ben The paper scale uses the Chinese Gull Family Standard (CNS) Grade 4 (210x297 g *) (please read the precautions on the back before filling in this page). Packing and threading. A 6 B 6 5. Description of the invention (86) During this period Record the memory errors during the work. After a delay of 2 hours, return the mouse to the maze. All arms of the maze are opened, but only four of the arms (these were closed during the pre-delay period) are available for M Yu. Although this is before or after the delay, the rat must collect the food pellets without having to enter all the arms that have been visited in advance. After reaching the basal concentration, during the third week of the experiment, the rats ’behaviors were tested, among which After the period before the delay, immediately set 1 0mM phosphate buffer (PH7.3) or AF150 (0.07 or 1.0 mg / kg free base (test) dissolved in 10mM phosphate buffer, pH7.3) is administered via intraperitoneal injection, 5 times per day Days. The results are listed based on the number of weeks (I or JI) and are listed in Table 16. (Please read the notes on the back before filling out this page)-Line-DP printed by the Employee Consumer Cooperative of the Bureau of Standards, Ministry of Economic Affairs 90 This paper is used in the Chinese National Standards (CNS) A4 specifications (210x297 g *) 201312 A 6 B6 V. Description of the invention (87) ms. · Ding Zuozhong's record of miscellaneous Qiang (who travels during τ) AF150 (mg / Kg, intraperitoneal injection) Phosphate powder --------------------------------------- -------- 0.07 1.0 (front) 1 I (front) KI (front) HI Sal. 0.27 ± 0.11 0.27 ± 0.09 0.33 ± 0.12 0.18 ± 0.07 0.Π ± 0.05 0.13 ± 0.07 AF64A 3.51 ± 0.74 9.22 ± 2.59 3.33 ± 1.18 3.75 ± 1.04 3.00 ± 0.94 4.22 ± 1.76 Sa 1. = saline (please read the precautions on the back before filling in this page) Binding-Ordering-Line. Printed by Beigong Consumer Cooperative, Central Bureau of Standards, Ministry of Economic Affairs

DP 91 This paper standard uses the Chinese Lin Ou Jia-like standard (CNS) A4 specification (210X297 mm) 201312 A 6 B 6 5. Description of the invention (88) In the group of rats treated with AF64A + grade granules, there is a delay In the early stage, the error in working memory was increased. As the learning process progressed, it seemed that such rats became more versatile, probably because they were not aware of previous experience, rather than being disturbed by the following- AF150 (0.07 or 1.0 μg / kg, intraperitoneal injection) at the tested dose was significantly beneficial for enhancing the recording of M AF64A-treated rats (in operation) (only during the pre-delay period); Low dose should. Therefore, AF151 is a promising agent in the treatment of SDAT because it is effective at very low doses without significant side effects. The statistical significance of the data recorded in Table 17 is as follows: AF151 (1.0 mg / intraperitoneal injection) for AF64A + Pan Yuan granules: ρ &lt; 0 · 0 1 AF151 (0.3 g / kg, Intraperitoneal injection of AF64A + BJ acid salt granules: ρ &lt; 0.05 AF151 (0.07 mg / kg, intraperitoneal injection) of AF64A + BI acid salt buffer: Ρ &lt; 0.07. (Please read the back of the first (Notes and then fill out this page) Binding 'Line · DP 92 printed by S Industry and Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs This paper standard is used in the Chinese Ogami Standard (CNS) A 4 specifications (210x297 public) 201312 66 ΑΒ The Ministry of Economic Affairs, Ministry of Economic Affairs, XJA Gongxiaot Cooperative printed the five instructions by the guerrilla vortex ^ earned) Rimi) icv ^ treatment .: Block 1 2 3 AFoilA Phosphate: Buffer 331〇 ± lQ〇-8 1Q4Q.2 ± 188.7 3 ^ 0-6 ± 4ι.6 5δ2.6 ± 84.7 AF151 &gt; 0 · 0 01.0 1.0 729.Q ± 98.2 862.3 ± 151.0 656.6 ± 10.7 · 918.1 ± H3 843-5 ^ 197-5 8G2.7 ± H1.1 743.1 ± Qiao 1.1 539 · 9 ± 146.2 795 •. 131 · 3 57 ^ -9 * 101.1 297.9 ± 60.4 33 · 〇Sal. Phosphate buffer * 622.2 ± 71.1 558.7 ^ 69 · β 3l4 · 3 ± 4l · 7 282.i ± klA AF151> 0 · 〇7 0.3 1.0 49〇β ± 7 ^ -0 517.8 ± 45.3 β〇7 · 9Q-6 562.9 ± 92.7 365-1 ± 58Λ 440.2i 9〇.1 429.2 on 76.5 i | 2 ^ .6i 92.3 4〇8. 97-1 278.θ ± 44.0 3 ^ 6.7 * 64Λ 233 · 8 ± 30-6 icv. Treatment reversed. AFo ^ A phosphate n, buffer w 6〇6.6 ± 78.9 AF151> 0.Q7 0.3 1.0 6〇2 · 9ί 97.9 390.5 ^ 77-0 606.0 ± 6Q.0 Sal. O-acid cup buffer net i. 433-2 ^ 93-3 AF151 ^ 0.07 0.3 1.0 ^ 53-9 ^ 7β · 〇306.8 ± 43.3 4'5〇.〇 ± 93-5 ft 13 water 'ί 〇. 2 l / kg, intraperitoneal injection, ★ mg / kg D Ρ 93 Taipan grid ruler 1Λ m Ψ due to its dazzling dimension (CNS) A 4 erbium i2〗 yy297 public loan (please read the precautions on the back before writing this page) Line 201312 A 6 _B6_ V. Description of the invention (90), intraperitoneal injection. 'Table 1 7 Note: In short (refer to Fishers, J. Pharmacol. Exptl. Therap. 1991 · in plate making), continuous training for 5 consecutive days, and each mouse receives four tests per day; the result is blocked Representation (for example, four trials per day). During the test period from 1 to 16 (the training period on days 1 to 4), the platform is placed in the center of the northwest quadrant of the assembly field. During Test No. 17, on Day 5, the platform was completely removed from the assembly field (a transfer test). In this experiment, the rats were placed in water for a limited period (60 seconds) to measure their spatial deflection. During the 18th to 21st test period, on the 5th day, the platform was moved to the center of the southeast quadrant (reversal test). Use the initial position of the four sides around the assembly site: North, South, East or West. Every day, the position sequence is changed by half-bran machine. 30 minutes before the test, AF151 and Phosphate Granules were administered twice a day for 5 days. For this experiment, K uses a trajectory system composed of an image analyzer (cis-2) connected to a microcomputer (8MZHZ-IBM AT, Galai Lab Co., Ltd.). (Please read the precautions on the back before filling out this page) Binding-Order _ Line-Printed by the Consumer Cooperative of the Central Bureau of Economics of the Ministry of Economic Affairs, and has also specified some specific examples of the present invention. Obviously, many improvements and changes can be made. Therefore, the present invention is not limited to such specific examples, and its concept, scope, and essence can be known from the following related patent applications. DP-94-This paper is used in the Chinese national standard «quasi (CNS) A 4 specifications (210x297 g *)

Claims (1)

6 9 A7 B7 C7 D7 L Compounds with structural formulas (I) and (I): k- (I) 〇Y- 1 A- X (CMz) n (C.MO. ^ β · Ί- G? '\ R / IR, (II) (Please read the precautions on the back before filling in this page) Its enantiomers, racemates and their acid addition salts and quaternary salts • Among them in the formula (I), the Q series (CH2) , 5, position, where m is 1, 2, or 3, and in formula (H), Q is a diamine atom or (CH2), where m is 1, 2, or 3, and η and Ρ are each 0, 1, 2, or 3 alone, but η + ρ = 1 to 3; R ° is a hydrogen atom or a methyl group; YR part represents 0 -GRXN Printed by the Central Bureau of Economic Affairs of the Ministry of Economy, R is selected from HH2, "-β alkyl or phenyl; R 'is Ci-β alkyl, and is subject to the following restrictions (i) and (ii) • In formula U) In the case of, (i) where Q is a dioxenogen, n = p = l, R ° is an argon atom, R is} ^ 2 and A 4 (210X297 Gong Feng) 3 1 ο 2 AB c D Six 'Patent application R' is a methyl group, then the Y --- R part is not NXR 1 C——o is the Q. If the central hydrogen bureau of the Ministry of Economic Affairs prints a hydrogen atom, n = p = l, R ° It is a hydrogen atom, R is a stupid group, then R 'is not a third butyl group. 2. According to the compound of the first paragraph of the patent application, each symbol in the formula (I) and U) has the patent The meaning mentioned in Item 1 of Fanyuan has the following exceptions • That is, the Y -pR part only represents X 0-C-R or N-C-R. IIN 0 3. According to the compound of the patent application item 2 • Selected from the following sister groups: 2-Amine spiro ring connection (1 | 3-Pyrazoline 5, 3 ') Roller · 2-Methyl spiro ring connection (1, 3- Pebazoline 5 , 3 ') S quinidine, 2-ethyl spiro ring connection (1, 3-pyridazoline 5 · 3 ') quinonidine · 2-phenyl spiro ring (1,3-pyridazoline 5,3') quinidine, 1-methylhexahydropyridine 4-spiro ring 4'-one (2 ' Monomethyl-1 ', 3'-pyridazoline), 1-Methylhexahydroxyl-4-pyrocyclic-4- (2 · -ethyl-1', 3'-pyridazoline) , 2-methyl cyclic ring connection (1,3-pyrazoline-5,4 ') monomethyl hexahydropyridine, (please read the precautions on the back side before filling in this hundred). Pack · • Order. A 4 (210X297 Public Broadcasting) A7 201312 6. Apply for a patent for a face mask, nail medicine, and diseased body and the first ~ I B type of the structure. I) Except for the treatment of 1'1 '(II I. The usual meaning of the rule))) 1 of 4'4's used it. Its place-, the fourth kind of salt-containing, item 5 5 and a package of grades with a garden 2 1 _ «High range less and tetralinoline formation meets the benefit, and sister-in-law zazolazole plus energy specialty eel medicine range The thief group of meritorious deeds Μ 成 B 利 _ I 、 Shenshen Sister use plus Zhi 3 3 Insult as if it should be. •, the spinner should not allow 4 applications. 1 1 The effect of the digestive effect is as follows (· (, the upper limit of the system is connected with a pyridine, and the body and the combined item should be cyclopyridine Therapeutic treatment includes i) B combined with non-spirohydropyridine treatment package 1) (1 and the specialized system based on six bases for the M, (I Articles please limit the use of A and B and its use and derotation II) Item 1 Base I contains species combination, consumer data ui) 2 2 Base package includes a group of I disease, root formula f 4. -¾ ................................. ........................... *. (Please read the precautions on the back before filling in this page) The Central Bureau of Economic Affairs of the Ministry of Economic Affairs has cracked δ · According to the medical compound of item 4 of the application scope, the compounds of formula (I) and ij formula (I) are as defined in item 3 of patent application. 7. According to the patent application, any one of the items 4 to 6 of the pharmaceutical sister compound. F It is for oral, eye, rectal, non-intestinal or transdermal administration • or for inhalation or nasal mist The way of administration. &amp; According to the application 銂 利范 _Item 7 of the "Sister Medicine Complex", it is available for entanglement ~ in the form of percutaneous injection and includes low molecular weight fatty acids as additional ingredients. 9 · Items of the combination of things and sisters BB 7 7 The first nursery _ 范范利利 专 専 Please apply. Φ According to the formula, according to the root shape, M, the dosage level is as low as 3 of the 4 (210X297 public) 201312 A7 B7 C7 D7 Central Ministry of Economic Affairs prints $ 1 A, the amount of the application of the variety of ingredients The Fanpu is about 0.5 to about 10 grams, M is about 5 to about 100 grams, and more preferably about 10 to about 50 grams, together with a carrier or diluent. lL — a drug compound used to treat sexual function «high abnormalities» with sexual activity, including at least the following components (A) and (A), (A), (B) and (C) B) Two kinds, namely (A) M is the most effective for treating the disease. At least one of the formula (I) and the formula (I) compounds of the formula (I) as defined in item 4 of the patent application park, including its Enantiomers «, convolvers, and B-compatible addition salts and quaternary salts; (B) and at least one compound that complies with the following compounds: poisonous lentil, tetrahydroaminoacridine · Dirty Prophet's egg yolk fat, Piracetam, aniracetan, pramiracetam, oxiracetaa, 4. monoamine% steep, 3, 4-diamine Pyridine, growth hormone release inhibitor (somatostatin), piperazin, N-methyl atorpine, N-butyl ranunculus test, scopolamine, cotinine, guafamisine (quanfanicinez), Pupan Tirin (pr 〇panthe 1 ine), methionin (ethanthe 1 ine), Akiyang: slightly acid vinegar (glycopyrrolate), Toben_Geng (r 〇penzi 1 ium), nortriptyline (η ortripty 1 ine), amitriptyline: (amitriptyline), imipramine, imipramine, minaprine and secoverine, AFDX-116, S? Sickle, Arap S (a 1 apr 〇c 1 ate), zimidine (zie 1 idine), diprenyl (deprenyl) and nerve growth factor; and (C)-erotic load «Or dilute (please read the precautions on the back and then fill out this page). Install .. Play • Line f 4 (210X297 Public Radio) A7 201312-—___ D7 6. Apply for a patent profile (please read the back page first Matters needing attention refill this page) release agent. ^ According to the B-Sister Compound of Item 11 of the application, the compounds of formula (I &gt; and formula (I) are as defined in item 2 of the patent application circle, except for the restriction of item (ii) It does not apply to M. 13. According to the B compound from the eleventh patent application, the compound of formula (I) and the formula (I) are as defined in the third application patent application. K According to the "Sister Medicine Compound" of any one of items 11 to 13 in Shen Fanli's paintings, it is for oral axillary, rectal, non-transcutaneous or transdermal administration, or for insufflation or nasal delivery. The form of injection. 15- According to item 14 of the application patent patent, it is in the form of a universal combination for transdermal administration, and includes low molecular weight * fatty acids as additional ingredients. It should be based on the patent application. Fanpu's 14th compound of paniculata medicine is in the form of unit dosage. 17- According to the 14th item of the application of the patent specification, the sibling compound, in which the amount of at least one component is present 0.5 to about 100 mg, M about 5 to about 100 «g is better, about 10 to about 50« g is better 'with an inert carrier or diluted orchid. Central Ministry of Economic Affairs A printed shut 5 4 (210X297 wide public)