TW412533B - PDE IV inhibiting 2-cyanoiminoimidazole derivatives - Google Patents

Description

412533 A7 B7 V. Description of the invention () ROC Patent Appln. No. 86114167 of Patent Application No. 86114167 Supplementary Examples Chinese Version-Annex (III) Supplemaital Examples in Chinese-Enel, (III) (Republic of China 87 > October | Submitted) ~~~ (Submitted on October |, 1999) Compound 27 (Please read the precautions on the back before filling out this page) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

Melting point: 205 ° C -41-1-

86467a The size of this paper is applicable to the Chinese National Standard (CNS) A4 (210 X 297 mm) 412533 at _ B7 V. Description of the invention (i) (Please read the precautions on the back before filling this page) This invention is about having phosphoric acid Diester Xue IV (PDE IV) and cytokine-inhibiting 2-fluoroiminoimidazole derivatives and their preparations; they are further related to compositions containing them, and their use as medicines. WO 95/05386, published by Smithkline Beecham on February 23, 1995, discloses phenethylamine derivatives such as n- [2- (3-cyclopentyloxy-3-methoxyphenyl) ethyl] fluorene Amino diurea and N'-cyano-l- [2- (3-cyclopentyloxy-4 -methoxyphenyl) ethyl] carboximidate, which can be used to treat phosphodiesters IV Related disease states. It also generally discloses phenethylamine derivatives containing a fluguanidine moiety. The compounds of the present invention are structurally different from PDE IV inhibitors known in the art due to the fact that they contain a 2-fluoroiminoimidazole moiety invariably. It has therapeutic utility to treat disease states associated with abnormal enzymes or catalytic activities of PDE IV, and / or disease states associated with physiologically harmful excess cytokines, especially allergies, atopic And inflammatory diseases. The compounds of the present invention also have very few gastrointestinal side effects, which are often accompanied by PDE IV inhibitors. The present invention relates to a 2-fluoroiminoimidazole derivative having the formula

CN

The Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs printed its N-oxide form, pharmaceutically acceptable acid or base addition salt, and stereochemically isomeric forms, where: R1 and R2 are each independently hydrogen; Base; difluoromethyl; trifluoromethyl; This paper size is applicable to Chinese National Standard (CNS) A4 (210X297). Employees' Cooperatives of the Central Government Bureau of the Ministry of Economic Affairs, Printed Poly A7 B7 V. Description of the invention (2) C3-6 cycloalkyl; saturated 5-, 6-, or 7-membered heterocyclic ring containing one or two heteroatoms selected from oxygen, sulfur, or nitrogen; hydroindenyl; 6,7-dihydro-5H- Cyclopentylpyridyl; bicyclofluorene [(2.2.1)]-2-heptanyl; bicyclofluorene [(2.2.1)] heptyl; Ci-6 alkylfluorenyl; arylsulfonyl; or Be one or two

Ci-io alkyl substituted with 1 substituent, each substituent independently selected from aryl, pyridyl, fluorenyl, furanyl, hydroindenyl '6,7-bisfluorene-5H-cyclopentylpyridyl, C3 -7 cycloalkyl and a saturated 5-, 6-, or 7-membered heterocyclic ring containing one or two heteroatoms selected from oxygen, sulfur, or pyrene; R3 is hydrogen, halo, or C! -6 alkoxy; R4 is hydrogen; halo; d-6 alkyl; trifluoromethyl; C3-6 cycloalkyl; carboxy; h-4 alkoxycarbonyl; C3-6 cycloalkylaminocarbonyl; aryl; Het1; or fluorinated , Amine, hydroxy, alkylcarbonylamino, aryl or Het1 substituted alkyl; or K4 is a group of the formula: -0-R7 (a-1); or -NH-R8 (a-2); where R7 is hydrogen; Ci-6 alkyl; h-6 alkyl substituted with hydroxy, carboxyl, behenyl-4-oxocarbonyl, amine, mono- or dialkyl) -amino 'Het1 or aryl; R8 is Hydrogen; alkyl; Ci-4 alkylcarbonyl; Cu alkyl substituted with hydroxyl, carboxyl, alkoxycarbonyl, amine, mono- or di ((: 4-alkyl) amino, Het1 or aryl; R5 Is hydrogen, aryl, aryl, C! -6 alkyl or Ci-6 alkyl; or R4 and R5 can be used together to form a divalent group of the following formula: This paper is applicable to the standard China National Standard (CNS) A4 specification (210X297 mm) (Please read the notes on the back before filling out this page) Order the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs to print 412533 J; 5. Description of the invention (3)-(CH2 ) n- (b-1); -CH2-CH2-0-CH2-CH2- (b-2); -CH2-CH2-N (R9) -CH2-CH2- (b-3); or -CH2- CH = CH-CH2- (b-4); where n is 2, 3, 4 or 5; R9 is hydrogen, Q-6 alkyl, Q-6 alkylsulfonyl or p-toluenesulfonyl; R6 Is argon or alkyl; or R4 and R6 can be used together to form the formula-(CHdn-divalent group; where m is 1, 2, 3, or 4; -AB- is a divalent group of the formula: -CR10 = CRn- (c-1); or -CHR10-, 1 (c-2); wherein each Ri0 and Rii is independently hydrogen or Ci_4 alkyl; and L is hydrogen; Ci-6fluorenyl; Ci-e alkane Carbonyl; C! -6 alkoxycarbonyl; one or two selected from the group consisting of hydroxyl, C! -4 alkoxy, Q-4 alkoxycarbonyl, mono- and di ((^-4 alkyl) amino, (^ -6 alkyl; C3-6 alkenyl; substituted by aryl; C3-6 alkenyl; hexahydropyridyl; substituted by (^ -4 alkyl or aryl (:丨 -4 alkyl substituted hexahydropyridyl; Cn alkylsulfonyl or arylsulfonyl Aryl is phenyl or phenyl substituted by one, two or three substituents, the substituent is selected from the group consisting of self-radical, hydroxyl, Ci-4 alkyl, Ci-4 alkoxy, C3-6 cycloalkane Group, trifluoromethyl group, amino group, nitro group, carboxyl group, alkoxycarbonyl group and Ci-4 alkylcarbonylamino group; This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) II -\ ----------- ir ------ Slope.- (Please read the notes on the back before filling out this page) Printed by the Employees' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 412533 _ ^ __ V. Description of the invention (4)

Het1 is pyridyl; pyridyl substituted with C1-4 alkyl; furanyl; furanyl substituted with alkyl; fluorenyl; fluorenyl substituted with ci-4 alkylamino; pyridyl , Hydroxypyridyl substituted with ci-4 alkyl or Ci_4 alkyloxy_Ci-4 alkyl; imidazolyl; imidazolyl substituted with [1-4 fluorenyl; oxazolyl; substituted with Ci-4 alkyl Mouthyl group; humyl group; humazolyl group substituted with ^ and alkyl; isofluorenyl group; isofluorinyl group substituted with heart-alkyl group; fluorinated transient group, substituted with Ci-4 alkyl group Morphinyl; morphinyl; hexahydropyridyl; hexahydropyridyl substituted with Cl-4 alkyl, Cl-4 alkoxycarbonyl or aryl Q-4 alkyl; hexahydro ; Hexamethylpyridyl substituted with Cl-4 alkyl, Ci_4 alkoxycarbonyl, or aryl Ci-4 alkyl; and

Het2 is morphofluorenyl; hexahydropyridyl; hexahydropyridyl substituted with Ci-4 fluorenyl or aryl Ci-4 alkyl; hexahydropyridyl; Ci-4 alkyl or aryl Ci -4 alkyl substituted hexahydropyridyl; pyridyl; B ratio substituted with Cl-4 alkyl; bitten group; ° furanyl substituted with Cl-4 alkyl; ° sephenyl or It is substituted by Ci-4 alkyl or Ci-4 alkylcarbonylamino. Some compounds of formula (I) may also exist in their tautomeric forms. Although this form is not explicitly shown in the above formula, it is intended to be included in the scope of the present invention. In particular, in the compound of formula (1), in which L is tritium, it may exist in its corresponding tautomeric form. In R1 and R2, it contains one or two saturated 5_ '6- or 7-membered heterocyclic rings selected from oxygen, sulfur, or dopant, and may be appropriately selected from heterocyclics' such as tetrahydrop-furanyl. , Dioxoyl, tetrahydrol, pyrrolyl, morpholin D, hexahydropyridyl, hexahydropyridyl, and tetrahydropiperanyl. The heterocyclic group is based on any carbon paper standard applicable to China National Standard (CNS) A4 (210X297 male thin) ----- ^ -----, 乂 ------ 1T-- ---- ^, (Please read the notes on the back before filling out this page) Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 412533 a7 — ---- B7 V. Description of the invention (5); In the case of the H atomic domain to the submachine, fluorenyl. Also in R1 and P, the term 6,7-dihydroprocyclopentyl, also known as 6,7-dihydro-511-pyridinyl, is intended to represent 6,7_diargon_51 ] [_ Cyclopyrene [b] pyridine or 6,7-bispyrene-5H-cyclopyrene [c] pyridyl, and can be attached to the rest of the molecule by any aliphatic or aromatic carbon atom. As used herein, the term "Southern" refers to the general term for fluoro, fluoro, bromo, and iodo; C1M alkyl refers to straight or branched saturated hydrocarbons having 1 to 4 carbon atoms. , Such as fluorenyl, ethyl, methyl ethyl, phenyl, ethyl, ethyl, propyl, 2-methylpropyl, and butyl; (^ -6 alkyl means to include d-4-alkyl And its higher carbon homologues having 5 or 6 carbon atoms, such as 2-methylbutyl, pentyl, hexyl and the like 圑; (^ _6 alkyl means to include C2-6 alkane Group and its lower carbon homologues having 1 carbon atom, such as methyl; C10 alkyl means to include (^ -6 alkyl and its higher carbon homologues having 7 to 10 carbon atoms, For example, heptyl, octyl, nonyl, decyl, methylhexyl, 2-methylheptyl and similar groups; the term C3-6 alkenyl is defined as a straight chain containing a double bond and having 3 to 6 carbon atoms With branched chain hydrocarbyl groups, such as 2-propenyl, 3-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl and the like ; And the carbon atom of the C3-6 alkenyl group is connected to a nitrogen source , Preferably saturated; the term C3-6 cycloalkyl is a generic term for cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; the term 3-7 cycloalkyl is meant to include C3-6 Cyclofluorenyl and cycloheptyl; The term alkanediyl is meant to include straight-chain and branched saturated divalent hydrocarbon radicals having 1 to 4 carbon atoms, such as methylene, 1,2-ethanediyl , 1,2-ethanediyl, 1,3-propanediyl, 1,2-propanediyl, butanediyl, 2-methyl This paper is sized to the Chinese National Standard (CNS) A4 specification (21〇297 (Mm) (Read the precautions on the back before you fill out this page), π Printed by the Consumer Affairs Cooperation Department of the Central Standards Bureau of the Ministry of Economic Affairs 412533 A7 ____B7 ----- V. Description of the Invention (6) Base-1,3- Propanediyl and its analogous groups. Ci-4 alkyldiyl, as defined in the foregoing definition and used in the following, is defined as a mono- or polysubstituted by a radical, alkyldiyl, especially by a Or more than one fluorine atom substituted by ^ -4 dioxo. The pharmaceutically acceptable acid addition Kang 'indicated above is meant to include acid addition forms, which can be conveniently treated with the appropriate acid formula (I Compound base It is obtained in the form of an acid such as an inorganic acid such as a hydrogen acid such as hydrochloric acid or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or an organic acid such as acetic acid, acetic acid, propionic acid, lactic acid, pyruvate, Oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexane Alkyl sulfamic acid, salicylic acid, p-aminosalicylic acid, paranaphthoic acid, and similar acids. Conversely, the acid addition salt form can be converted to a free state base form by treatment with a suitable base. Contains an acidic proton The compound of formula (I) can also be converted into its non-toxic metal or amine addition salt form by treatment with appropriate organic and inorganic bases. Suitable alkali salt forms include, for example, ammonium, alkali and alkaline earth metal salts, such as lithium, sodium, potassium, magnesium, calcium salts, and the like, and salts with organic hydrazones, such as benzine-thine, N-methyl-D -Salts of glucosamine, hypamine, and salts with amino acids such as arginine and lysine. The term addition salt also includes hydrates and solvent addition forms that the compounds of formula (I) can form. Examples of such forms are, for example, hydrates, alcoholates and the like. The N-oxide form of the compound of formula (丨) is meant to include the compound of formula (I). The paper size is Langzhong, Zhuojia County (㈣), M (210 × 297 mm) {Please read the precautions on the back before filling in this Page)-after! -I n _ 412533 A7 B7 5. Description of the invention (7) One or several nitrogen atoms are oxidized to so-called N-oxides. The term " stereochemically isomeric form " used in the foregoing, defines all possible isomeric forms that a compound of formula (I) can have. Unless otherwise mentioned or indicated, the chemical designation of a compound means a mixture of all possible stereochemically isomeric forms, which mixture contains all diastereomers and paraisomers of the basic molecular structure. More specifically, the stereogenic center may have an R- or S-configuration, and the = N-CN and substituted C3-6 alkenyl moiety may have an E- or Z-configuration. The term compound of formula (I) used at any time in the following is also meant to include its N-oxide form, a pharmaceutically acceptable acid or base addition salt, and all stereoisomeric forms. Printed by the Central Bureau of Standards, Ministry of Economic Affairs, Consumer Cooperatives {Please read the notes on the back before filling this page) Some compounds of formula (I) and some intermediates in the present invention may contain asymmetric carbon atoms. The pure stereochemically isomeric forms of the compound and the intermediate can be obtained by procedures known in the art. For example, diastereomers can be separated by physical methods, such as selective crystallization, or chromatography techniques, such as countercurrent distribution, liquid chromatography, and similar methods. Para-isomers can be obtained from racemic mixtures by first converting the racemic mixture to a mixture of diastereomeric compounds or compounds with an appropriate resolving agent such as para-palmitic acid; then physically Separation of the diastereomeric salt or mixture of compounds, for example by selective crystallization or chromatography techniques such as liquid chromatography and the like; and finally conversion of the separated diastereomers The salt or compound becomes its corresponding para-isomer. Pure stereochemically isomeric forms can also be obtained from the appropriate stereochemically isomeric forms of the appropriate intermediates and starting materials, provided that the reactions involved are in accordance with the Chinese National Standard (CNS) M · (Training) χplus public envy) Printed by the Consumers' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 412 533 A7 B7 V. Description of Invention (8) Occurred in a special way. Pure and mixed stereochemically isomeric forms of the compounds of formula (I) are intended to be included within the scope of this invention. An alternative way to separate isomeric forms of compounds of formula (I) and intermediates involves liquid chromatography, especially liquid chromatography using a stationary phase of the palm. A special group of these compounds includes compounds of formula (I), wherein R1 and R2 are each independently fluorene; Ci-6 alkyl; difluoromethyl; trifluoromethyl; Cs-e cycloalkyl; Saturated 5-, 6-, or 7-membered heterocycles containing one or two heteroatoms selected from oxygen, sulfur, or nitrogen; fluorene indenyl; bicyclic fluorene [(2,2.1)]-2-heptenyl; bicyclic fluorene [(2.2.1)] heptyl; (^ -6 alkylsulfonyl; arylsulfonyl; or alkyl substituted with one or two substituents, each of which is independently selected from aryl and pyridine Group, fluorenyl'furanyl group, C3_7 cycloalkyl group, and saturated 5-, 6-, or 7-membered heterocyclic ring containing one or two heteroatoms selected from oxygen, sulfur, or fluorene. Interesting formula ( I) The compound is wherein ri and R2 are each independently Ci_e alkyl, -6 cycloalkyl, difluoromethyl; containing one or two saturated 5-, 6-, or 7- heteroatoms selected from oxygen, sulfur, or nitrogen heteroatoms Membered heterocyclic ring, which is preferably tetrahydrofuranyl; hydroindenyl; or Ci-ualkane substituted with aryl, fluorenindenyl, 6,7-dihydro-5H-cyclopentylpyridyl, or C3-6 cycloalkyl Also of interest are compounds of formula (I) where RS is hydrogen, hydrogen, More specifically, R4 is methyl. Another interesting group of compounds of formula (I) is where L is hydrogen, Ci4 oxocarbonyl, or Ci 6 alkyl substituted with one or two benzene rings. The specific compound is a compound of the following formula (I), where Ri is cyclopentyl, tetra-10-(Please read the precautions on the back before filling this page), 1T. This paper is suitable for national standards (CNS) of the financial country 4 (2t〇x297 public meal 412533 A7 A7 B7 V. Description of the invention (9) Arfuryl, cyclopropylmethyl, 5-phenylpentyl, 2-hydroindenylethyl, 6, 7-difluorene -5H-cyclopentyl [b] pyridyl or hydroindenyl; and ^ is methyl or difluoromethyl. Preferred compounds are those in which R3 and L are all hydrogen. The most preferred are the following compounds: [1 -[2- [4- (Difluoromethoxy) -3-[(tetrahydro_3-furyl) oxy] phenyl] propyl] -1,3-dihydro-2H-imidazole-2 -Yl] fluorenamine; and [1- [2- [4- (methoxy) -3-[(1,3-dihydro-2H-inden-2-yl) oxy] phenyl] propyl] -], 3-difluorene-2H-imidazol-2-yl] fluorenamine; its N-denoxide, its normal chemically isomeric form, and its pharmaceutically acceptable addition salt. In the following When used, R1 to RU, γ, -AB- and L are as defined under formula (I), unless otherwise mentioned 0 Formula U) compounds, where -AB- is a group of formula (ci) and l is a compound, and the compound is represented by formula (I-al), which can be conveniently prepared by cyclization of the compound of formula (II) or a functional derivative thereof in the presence of a suitable acid such as hydrochloric acid. (Please read the precautions on the back before filling out this page) Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs ^ R3 RlO-

r2o / CN f4? —CM pit (p-CH-NH-c-NI’l-C 丨 H-c-〇-Cm pit

Ks (ΪΙ) R11 H10

CN

R1 RO

Ri (R (, I i. C-CM—N R20 ίο ΓΓ ΐλ

-11-Magnetism in this magnetic scale g | g] Home transfer (⑽) weaving ^ (2 敝 Tear A7 412533 ----- B7 V. Description of the invention (l〇) The cyclization can It is carried out in an inert solvent, such as tetrahydro. Furan or 1,4-dioxoline or a mixture thereof. Stirring and heating can increase the reaction rate. In this and the following preparations, the reaction product can be isolated from the reaction medium. And, if necessary, further purification according to methods generally known in the art, such as extraction, crystallization, development, and chromatography. In particular, compounds of formula (I-al) in which R5 is a hydroxyl group, the compounds are represented by formula ( Ia-1-l) represents that it can be prepared in a similar manner to the compound of formula (I-al) from an intermediate of formula (II), via an intermediate of formula (U-1), wherein P is hydrogen or preferably three The methylsilyl protecting group or its functional derivative is prepared by cyclization. (Please read the notes on the back before filling in this education)

(Γ-aIi)---A compound of formula (丨) printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economy, where -AB- is a group of formula (c-2) and £ is hydrogen, and the compound is based on formula (Ia- 2) indicates that it can be present via an intermediate of formula (UI) or a functional derivative thereof in an appropriate reagent such as a fluorenylcarbodiimide dif-ester or N-fluorocarbiminodiphenyl diphenyl Next, obtained by cyclization. -12 'This paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) --- • 1 ^ 1 1-H- 412533 V. Description of invention (n)

(Id-2) Alternatively, the compound of formula (I) may be obtained by subjecting an organometallic intermediate of formula (IV), where M is a suitable metal ion or metal complex ion, such as Li +, (MgBr) +, B (0H) 2+ Or Sn (CH3) 3+, in a solvent inert to the reaction, with a 2-fluoroiminoimidazole derivative of the formula (V), where ΪΠ is a reactive leaving group such as made by reacting . In the case where R4 and R5 are used together and form a group of the formula (b-1), (b-2), (b-3) or (b-4), W1 can also be a fluoride moiety, and its conditions The intermediate of formula (IV) is a Grignard reagent. (Please read the notes on the back before filling this page)

This reaction can be carried out in a solvent or inert to the reaction, such as dimethoxyethane, tetrahydrofuran or diethyl ether. Stirring and heating can increase the reaction rate. If an intermediate of formula (V) is used in this reaction, in which L is substituted by a suitable protecting group, a compound of formula (I), in which L is hydrogen, is represented by a compound of formula (bu &). A known deprotection reaction is obtained. The compounds of formula (I) can also be converted into each other according to the functional group conversion procedures known in the art. For example, a compound of formula (I) in which L is not hydrogen, the compound is represented by formula (i_b), which can be prepared by reacting a compound of formula (Ia) with L, -f2 (vi)-13-This paper is for China National Building Standard (CNS) A4 Specification (21GX297 Gongchu) --- A7 B7 412533 5. Description of the Invention (12), where L 'is the same as L defined in formula (I) but is not hydrogen, and W2 is a reactive leaving group such as a halogen atom.

N ~ L 'can also use an addition reaction known in the art to convert a compound of formula (I-a) into a compound of formula (丨 -b). The compound of formula (I) can also be converted into its corresponding oxide form according to procedures known in the art to convert trivalent nitrogen into its N-oxide form. This N-oxidation reaction can usually be carried out by reacting a starting material of formula (I) with 3-phenyl-2- (benzenesulfonyl) oxaziridine or with a suitable organic or inorganic peroxide. Suitable inorganic peroxides include, for example, europium peroxide, alkali metal or alkaline earth metal peroxides, such as sodium peroxide, peroxide peroxide; suitable organic peroxides may include peroxyacids, such as benzene carbon peroxyacid or sulfhydryl substitution Benzene peroxyacids, such as 3-gas benzene peroxyacids, peroxyalkanoic acids, such as peroxyacetic acid, alkyl hydroperoxides, such as terbium peroxotri-butane. Suitable solvents are, for example, water, low-carbon burned alcohols such as ethanol, etc., hydrocarbons such as toluene, vehicles such as 2-butane, hydrogenated hydrocarbons such as digas, and mixtures of such solvents. The intermediates mentioned above can be prepared according to techniques known in the art. Specifically, the intermediate of formula (II) can be reacted by first reacting an amine of formula (νπ) with fluorocarbodiimide dithioic acid or fluorocarbimidic acid diphenyl vinegar or its official bioreaction. While made. The reaction may be inert to the reaction i--;-^ ----- > ------ ίτ ------ 1.- (Please read the notes on the back before filling in this Page) Printed by Shellfish Consumer Cooperative, Central Bureau of Standards, Ministry of Economic Affairs-14-

A7 B7 V. Description of the invention (13) In solvents such as dichloromethane, benzene or toluene, they are optionally frozen on ice, and are used in bases such as N, N-diethylethylamine or sodium bicarbonate. Perform in the presence. The intermediate thus obtained may then be reacted with an intermediate of formula (VIII) or a functional derivative thereof to form an intermediate of formula (II). The reaction may conveniently be in an inert reaction such as 1,4-dioxotriol in the presence of a base such as N, N-diethylethylamine, and optionally a catalyst such as N, N- Dimethyl-pyridineamine was carried out. Stirring and increasing the temperature can increase the reaction rate.

Alternatively, the above reaction can be performed in the reverse order, that is, first, the intermediate of formula (VIII) is reacted with dimethylcarbodiimide dithio acid dimethyl or fluorocarbimidic acid diphenyl ester or a functional derivative thereof. , And then the intermediate thus formed is reacted with an amine of formula (VII). Printed by the Employees' Cooperatives of the China Standards Bureau of the Ministry of Economic Affairs ^^^ 1 1 ^^^ 1-I m ^^^ 1 I n ^ in ^ i {Please read the note on the back before filling this page) (1 丨 丨) Intermediate, which is hydrogen. The intermediate is represented by formula (II1-1), which can be prepared in the following manner. First, an amine of formula (VII) and a cyano derivative of formula (IX) are prepared. W3 is a suitable leaving group, such as a pixel, and is reacted in a solvent inert to the reaction, such as dimethylformamide, in the presence of a base such as sodium peroxylate. Then, the fluoride portion in the intermediate formed in this way can be obtained by using a suitable reducing agent, such as aluminum hydride or hydrogen, in the presence of a catalyst such as Raney nickel, and thus obtaining the formula (丨 丨 丨 ^) Intermediate. -15-This paper is a standard car (CNS) Α4 standard} Α7 Β7 alkaline

R3 R'O

R4 R6 I—c—CH-ΝΗί l · — (VII) R20 V. Description of the invention (14 > K)

W ^ -CH-CN (IX) —Some intermediate systems of formula (VII) are described in WO 92/00968, WO 93/15044 and WO 93/15045. In particular, the intermediate of formula (VII) can be obtained by interchanging the intermediate of formula (χ), where W4 is an appropriate radical, such as dentin, and the intermediate of formula (XI), where M is an appropriate metal ion or metal An ion such as Li + or (MgBr) +, and P is a suitable protecting group, such as (1,1-dimethylethyl) oxycarbonyl, is prepared by reaction. The thus-protected intermediate of formula (VII) can then be removed by a technique known in the art such as acid hydrolysis. in · 'n ^ — nf--I I -------- nn m | (Please read the precautions on the back before filling this page) R * 〇-

r2o R4 R6 II, C-CM—W * 1 (X) + M—N. (XI) Intermediate (VI ί) intermediate of the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, where R6 is 氲, the intermediate is It is represented by formula (vin), which can be obtained by biting the unsaturated carbon-nitrogen bond in the intermediate of formula (XII) with a suitable reducing agent such as borane-tetrahydrofuran-complex, lithium hydride, It is produced by reduction in the presence of a medium such as Raney nickel. The halide moiety in the intermediate of the formula (XU) may also be replaced by a functional derivative such as a motif moiety. 16-The paper Λ degree applies to the Chinese National Standard (CNS) A4 specification (2 丨 0X297 mm) 41 ^ 533 A7 B7 V. Description of the invention (15 κ'ο

r2o κΛ reduction — / -_ CN-: l · (XH)

Some intermediates of formula (XΠ) are described in WO 92/00968, wo 93/15044 and WO 93/15045. In particular, an intermediate of formula (XΠ), in which ϋ5 is a protected hydroxyl group and R4 is 氲, the intermediate is represented by formula (XΠ-1), which can conveniently be obtained by combining the aldehyde of formula (XΙΠ) with formula ( XIV) reagents or functional derivatives thereof, in which ρ is a protecting group, such as trimethylsilyl and the like, in a solvent inert to the reaction, such as digas methane, and a catalytic amount of Znl2 or its function It is made by reacting in the presence of sexual derivatives. The intermediate of formula (XI1-1) can be further reacted as described above to form a compound of formula (I) in which R5 is a radical. r'o

〇 II C—Η r2o (XIII)

P—C = N (XIV)

(Xll-1) n ^ i 1 ^^ 1 · nn *-_--t one aJ (Please read the notes on the back before filling out this page) Central Standards Bureau of the Ministry of Economy ) It is expediently made in a reaction procedure similar to that described by Mitsunobu Oyo in Synthetic Journal, 28, 1981. Some compounds of formula (I) and some intermediates in the present invention contain at least one asymmetric carbon atom. The pure stereoisomeric forms of the compound and the intermediate can be obtained using procedures known in the art. For example, diastereoisomers can be separated by physical methods, such as selective crystallization, or extensive analysis techniques, such as countercurrent distribution, liquid chromatography, and similar methods. China National Standard (CNS) A4 Specification {210X297 mm) A7 B7 Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of Invention (16). Para-isomers can be obtained from a racemic mixture by first converting the racemic mixture to a mixture of diastereomeric salts or compounds with a suitable resolving agent such as para-palmitic acid; then physically Separating the mixture of diastereomeric salts or compounds by means of, for example, selective crystallization or chromatography techniques such as liquid chromatography and the like; and finally converting the separated diastereomers The salt or compound becomes the pure stereochemically isomeric form of its corresponding isomeric compound of formula (I), and can also be obtained from the pure stereochemically isomeric form of the appropriate intermediate and starting material, provided that it is involved The reaction occurs in a stereospecific manner. Pure and mixed stereochemically isomeric forms of compounds of formula (I) are intended to be included within the scope of the present invention. Compounds of formula (I), in the form of N-oxides, pharmaceutically acceptable acid or base addition salts and stereochemically isomeric forms, are phosphate diesters (PDE) of group IV (cAMP-specific group) Inhibitors of merits. cAMP (adenosine cyclic 3 ', 5'-monophosphate) is a major secondary messenger whose concentration will affect specific cell activities through the activation of enzymes such as stimulus. PDE IV is known to hydrolyze cAMP to its corresponding inactive 5, -monophosphate metabolite. Therefore, the inhibitory effect of PDE IV will increase the content of cAMP in certain cells, such as respiratory smooth muscle cells, and a variety of inflammatory cells, meaning certain lymphocytes, such as basophils, neutrophils, and Eosinophils, single cells and mast cells. Many allergic, atopic and inflammatory diseases are thought to be caused by higher than normal PDE IV concentrations, which can cause low cAMP levels and the allergic nature of such infected cells to the stimulating stimulus (the Examples of allergies are -18--1--II---: 11-II I- I I- -I ^^ 1 (Please read the precautions on the back before filling this page) This paper size applies to China Standards (CNS) A4 specifications (210X297 mm) 412533 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs B7 V. Description of the invention (17) For example, excessive histamine is released from basophils and mast cells, or excessive Peroxide anion groups are formed by eosinophils. Therefore, the compounds of the present invention having effective phosphodiester and IV inhibitory properties are recognized for reducing and / or treating allergic, atopic and inflammatory diseases. Functional effects of PDE 丨 V inhibitors, such as respiratory smooth muscle loosening, bronchiectasis, platelet aggregation inhibition, and release of leukocyte mediators. Examples of allergic diseases are branches Trachea gas , Cheilitis, combined meningitis, contact dermatitis and eczema, irritating bowel disease, dehydrogenated form of wet therapy, ramie zhen, vasculitis, vulvitis; examples of atopic diseases are dermatitis and wetness Rash, cold feet, asthma, allergic rhinitis; and related disorders are, for example, psoriasis and other hyperproliferative diseases. The present invention therefore also relates to compounds of formula (I) as defined above, for use in medicine, especially as a treatment Medicine for atopic disease or use as anti-asthma medicine. Therefore, the compound of the present invention can be used for the manufacture of a medicament for treating atopic or asthmatic disease, more particularly atopic dermatitis. PDE of the compound of formula (I) IV inhibitory activity can be confirmed in the test of recombinant human mononuclear lymphocyte (MNL) phosphodiesterase [inhibitory effect of VB type] made in insect cells by baculovirus vector. Several kinds of in vivo can be used And in vitro tests to confirm the utility of the compounds of formula (I) in the treatment of allergic, atopic and inflammatory diseases. Such tests are, for example, " German guinea pig trachea in vitro "Small", "Zeropuche trachea shrinkage in vivo", and in vivo test "Inflammation of ears caused by arachidonic acid in mice", "Inflammation of ears caused by TPA in mice And " Delayed allergy in mice ". -19-This paper size applies to National Standard (CNS) A4 (210X297 mm) — I.  1 I HI--I- Hi-I I I.  F / ml n fn-1 I-U3, V5 (please read the notes on the back before filling in this note) 412533 A7 B7 V. Description of the invention (18) Furthermore, the compounds of the present invention are suitable for group III (cGMP- Inhibition group) Phosphodiesters have the same low activity by virtue of the same exercise. In particular, the inhibitory effect of PDE 111 will lead to an increase in cAMP in the heart muscle, which will have an effect on cardiac contractility and on heart relaxation. In the treatment of allergic, atopic and inflammatory diseases, the cardiac and vascular effects are obviously undesirable. Therefore, when the compound of the present invention inhibits PDE IV at extremely low concentrations as it inhibits PDE III, its therapeutic use can be adjusted to avoid cardiac and vascular side effects. PDE IV inhibitors known in the art often cause adverse gastrointestinal side effects. However, most of the compounds of the present invention have very little effect on the gastrointestinal tract, which can be confirmed in the experiment of "hot stomach emptying effect in mice". 0 The names of PDE III and IV used herein are Refers to J.  A.  Beavo and D.  H.  Reifsnyder, TIPS Review, April 1990, pp. 150-155. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs ^^^ 1 1 ^ 1 t ^ i- 1.  An ^ — ^^^ 1 11 '0¾.  ,-= 0 (谙 Please read the precautions on the back before filling this page) The compounds of the present invention also have cytokine inhibitory activity. Cytokines are any secreted polypeptide that affect the function of other cells by modulating the interaction of cells between immune or inflammatory responses. Examples of cytokines are single cytokines and lymphocytokines, and they can be produced by a wide variety of cells. For example, unicellular cytokines are often referred to as being produced and secreted by monocytes such as macrophages and / or single cells, but many other cells produce unicellular cytokines, such as natural killer cells, fibroblasts, Basophils 'neutrophils, endothelial cells' brain stellate cells, bone marrow stromal cells, epidermal keratinocytes and /?-Lymphocytes. Lymphokine is usually printed on this paper by Chinese National Standard (CNS) A4 (2I0X297 mm). It is printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 412533 A7 __________ 一 —___ B7 ______ Description of the invention (W) Examples of cells made of cytokine, including melatonin-1 (IL-1), melatonin_2 (iL_2), melatonin_6 (IL-6), melatonin _8 (丨 L_8), "-Tumor Necrosis Factor (Yu TNF) and Lu-Tumor Necrosis Factor (Ning Dingxie). The cytokine that is particularly wanted to be inhibited is πTNF. Excess or unregulated TNF production It is related to the media or worsening a variety of diseases, including rheumatoid arthritis, rheumatic spondylitis, osteoarthritis, gouty arthritis and other arthritis symptoms; septicemia, septic shock, endotoxin shock, Gram-negative septicemia, toxic shock syndrome, adult dyspnea syndrome, cerebral malaria, chronic pneumonia, siliceous disease, pulmonary sarcoidosis, bone wasting disease, reperfusion injury, graft response to host Homologous transplantation Rejection, fever and myalgia due to infections, such as influenza, infection or malignant secondary cachexia, secondary cachexia of acquired immune deficiency syndrome (AIDS), AIDS, ARC (AIDS recurrence syndrome), keloids Formation, scar tissue formation, Crohn's disease, ulcerative colitis or fever. The cytokine inhibitory activity of the compound of formula (I), such as the inhibitory effect of aTNF production, can be used in " cell viability in human whole blood cultures. It has been tested in vitro in vitro. In addition, it is expected that the compounds of the present invention will not show less or less endocrine side effects. This can be achieved by, for example, " in vivo testnet " The "in vitro inhibition" test and "in vivo inhibition 11 test of aromatic tablet activity" testified. Given the useful PDE IV and cytokine inhibitory properties of the subject compound, it can be formulated into various pharmaceutical compositions for administration purposes , Which contains medicine-21-This paper size applies to Chinese National Standard (CNS) A4 specification (210X29? Mm) Please fill in this page again for the matter. J --- 412533 A7 B7 Yin Fan, Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, 5. Description of invention (20) A scientifically acceptable planting agent, and a therapeutically effective amount as an active ingredient. I) Compounds. In order to prepare the pharmaceutical composition of the present invention, a therapeutically effective amount of a specific compound as an active ingredient is in the form of an alkali or acid addition, and is combined with a pharmaceutically acceptable carrier to form a close intermix. It can take a wide variety of forms, depending on the form of the formulation to be administered. It is generally expected that these pharmaceutical compositions are in a single dosage form, which is preferably suitable for oral, direct, topical, transdermal, inhalation or non-absorption Enteral administration. For example, when preparing the composition in oral dosage form, any commonly used pharmaceutical vehicle can be used, such as water, glycols, oils, in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions, Alcohols, etc .; or in the case of powders, pills, capsules, and tablets, solid cuts such as powder, sugar, kaolin, lubricants, binders, disintegrants, and the like. Since tablets and capsules are easy to administer, they represent the most advantageous oral dosage unit form. In this case, it is clear that Gugu medicine is used. For parenteral compositions, the medicament often contains sterile water, at least in most cases, but other ingredients may be added to it, for example, to aid dissolution. For example, injectable solutions can be prepared in which the vehicle contains saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions can also be prepared, in which case appropriate liquid vehicles, suspensions and the like can be used. . In a composition suitable for transdermal administration, the carrier may optionally include a penetration enhancer and / or a suitable wetting agent, and may be used in combination with a suitable additive having any property in a small proportion as appropriate, which additive does not cause any damage to the skin. Significantly harmful effects. The additive may facilitate administration to the skin and / or may assist in the preparation of the desired composition. These compositions can be administered in a variety of ways, such as transdermal patching, dripping, or -22-This paper size is applicable to China National Standard (CNS) A4 specifications (210X297 cm > ^ 1 ·--· ^^ 1 -I — ^ 1 ----- Is!--II-I--One- (Please read the precautions on the back before filling out this page) Printed by the Consumers' Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs. 4 * 丨 — 412533 A7 _____ B7 V. Invention (21), ~-into ointment. As a suitable composition for topical application, $ list all compositions commonly used for topical administration, such as emulsions , Gel, dressing, shampoo, tincture, paste, ointment, medicinal bone, powder, etc. The application of this group of materials can be by aerosol, such as the use of propellants, such as nitrogen, dioxin, Freon Or without the use of propellants, such as pumped sprays, drops, lotions, or semi-solids, such as thickened compositions, which can be applied by sea block. In particular, it can be suitably used such as medicine , Emulsion, jelly, ointment, etc. In order to improve the solubility and / or stability of the compound of formula (I) in the pharmaceutical composition, α-, or-or r-cyclodextrin can be advantageously used Or its derivatives, especially cyclodextrin substituted with a few alkyl groups, such as 2-lipidyl-5 / 5-cyclodextrin. Co-solvents such as alcohols can also improve the compounds of formula (I) Solubility and / or stability. Additive salts of subject compounds in formulations of aqueous compositions Of course, it is more suitable due to its increased water solubility. It is particularly advantageous to formulate the aforementioned pharmaceutical composition in a dosage unit form that is easy to administer and dose uniformity. A dosage unit form refers to a physical form suitable for a single dose Separate units, each unit containing a predetermined amount of the active ingredient calculated to produce the desired therapeutic effect, along with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (packaged under the (Coated tablets), capsules, pills, powder packs, tablets, injectable solutions or suspensions, etc., and their separated multiple agents. The present invention also relates to a treatment for patients suffering from abnormal enzymes or catalytic activity associated with PDE IV Disease status, and / or excessively physiologically harmful -23-^^^^ Chinese National Standard {〇 阳) 8 4 specifications (210 乂 297 mm > nn 1 · u I] --- I n Bn I— I HI T (Please read the note on the back ^ before filling this page) 412533 A7 ____ B7 Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (22) Diseases related to cytokine Status, special Allergic, ectopic and inflammatory diseases, more particularly asthmatic and ectopic diseases, and most particularly a method of warming animals with atopic dermatitis. The method includes administering a mixture with a pharmaceutical carrier A therapeutically effective amount of a compound of formula (I), or its N-oxide form, a pharmaceutically acceptable acid or base addition salt, or a stereochemically isomeric form. In general, the expected effective daily amount is 0. 0.1 mg / kg to 10 mg / kg ship weight. It is apparent that the effective daily amount can be reduced or increased, depending on the response of the patient to be treated and / or by the physician who prescribes the compound of the present invention It depends on the evaluation. Therefore, the effective daily amount range mentioned above is only a guide, and is not intended to limit the scope or use of the present invention to any extent. The following examples are intended to illustrate rather than limit the scope of the invention. Experimental part The absolute stereochemical configuration of some compounds of formula (I) is not determined experimentally. In these cases, the stereochemically isomeric form that was isolated first is called " A " and the second is called "B ", without further pointing out the actual stereochemical configuration. In the following, " THF " Means tetrahydrofuran, "RT" means room temperature, "DMF," means Ν, Ν-dimethylformamide, and "DIPE" means diisopropylfluorene. Α. Preparation of intermediate compounds 1 a) Under N2 flow, potassium carbonate (0. 0569mol) was added dropwise to the 4-difluoromethoxy_3_ via phenyl hydrazone (0. 053 Mol) and (tetrahydro-3-.furanol) -4-methylbenzenesulfonate (15. 35 g) in DMF (100 ml) 24-1 ^ 1 urn I.  --I 1 n (Please read the precautions on the back before filling in this purchase) This paper size is applicable to China National Standard (CNS) A4 specifications {210X297 mm) 412533 at B7 V. Description of the invention (23) ~~ Inside. The reaction mixture was stirred at 100 ° C for 4 hours. The mixture was allowed to cool, and a solution of (tetrahydrofuran-3-furanol) -4-methylbenzenesulfonate (3 98 g) in DMF (40 ml) was added dropwise, and the reaction mixture was at 1000. Stir for 3 hours and then overnight at RT. The solvent was evaporated and the residue was washed in a saturated Na / O3 aqueous solution and then extracted with DIPE. The separated organic layer was dried, filtered, and the solvent was evaporated to yield 17. 77 g (±) -4- (difluoromethylamino) -3-[(tetrahydro-3-furanyl) oxy] benzaldehyde (intermediate 1) 0 b) Sodium borohydride solution (0. 0177mol) to the intermediate 1 (0. 0532 mole) in a solution of methanol (100 ml), and the reaction mixture was stirred at RT for 1 hour. The solvent was evaporated and the residue was washed with water and extracted with CICI2. The separated organic layer was dried, filtered, and the solvent was evaporated. The residue was purified on silica gel by open column chromatography (eluent: CH2C12 / 2-acetone 96/4 and 90/10; CH / h / CHsOH 96/4). The pure fractions were collected and the solvent was evaporated, yielding 11. 3 g (81%) of (±) -4- (difluoromethoxy) -3-[(tetrahydro-3-furanyl) oxy] benzyl alcohol (Intermediate 2). Central Consumers Bureau, Ministry of Economic Affairs, Consumer Cooperatives, China 0, Intermediate 2 (0. 039 mol) in toluene (45 ml), added dropwise to SOC12 (0. 059 Mol) and DMF (0. 0019 mol) in a mixture of toluene (75 ml) and stirred at 40 ° C. The resulting reaction mixture was stirred at 40 ° C until the release of HC gas was stopped. The solvent was evaporated and the residue was washed with saturated aqueous NaHC03 solution and extracted with CH2C12. The separated organic layer was dried, filtered, and the solvent was evaporated to yield 10. 59 g (96%) (±) -4- (difluorofluorenyloxy) -3-[(tetrahydro ~ 3-furanyl) oxy] benzyl alcohol (Intermediate 3).  d) Set KCN (0. 076 mol) in H20 (4 ml), -25-This paper size is applicable to China National Standards (CNS) A4 (210X297 mm) 412533 Printed by A7 B7, Consumer Cooperatives, Central Bureau of Standards, Ministry of Economic Affairs V. Description of the invention (24) After heating to 80 ° C, it is added dropwise to the intermediate 3 (0. 038 Mol) in DMF (82. 4 mL) of the mixture, stirred at 6 (TC. The resulting reaction mixture was stirred at 60 ° C for 30 minutes. The reaction mixture was cooled, washed with water, and extracted with DIPE. The extract was dried, filtered, And the filtrate was evaporated, yielding 8. 23 g (80%) of (±) -4- (difluoromethoxy) -3-[(tetrahydro-3-furanyl) oxy] phenethyl (Intermediate 4). Prepared in a similar manner: 3- (cyclopropylmethoxy) -4-methoxyphenylacetonitrile (Intermediate 5): 3-[(1,3-dihydro-2H-inden-2-yl) oxy ] -4-Methoxyphenethylfluorene (Intermediate 6); (±) -4-methoxy-3-[(tetramethyl-3-furanyl) oxy] phenylethyl jjcyanine (Intermediate 7) ; Methoxy-3-[(5-phenylpentyl) oxy] phenylethyl cyanide (intermediate 8); 4- (difluoromethoxy) -3-[(5-phenylpentyl) oxy Phenyl] phenylethyl j] cyano (intermediate 23) ° Example A. 2 a) Under Ns flow, n- (1-methylethyl) -2-propylamine lithium salt (0. 0325 Molar; 1M in THF) was added dropwise to Intermediate 4 (0,0309 Molar) and THF (70 ml) cooled to 78 ° C. The mixture was stirred at -78 ° C for 30 minutes. Methyl iodide (0034 moles) was added dropwise, and the reaction mixture was stirred at RT for 2 hours. The mixture was quenched with saturated aqueous NH4C1 and extracted with ethyl acetate. The separated organic layer was dried, filtered, and the residue of the eluent 0 was purified by short open column chromatography on silica gel (eluent: CH2CI2), and then purified by HPLC on silica gel (eluent: -26 _ (210X297 / > F) ~ 'i ϊ-II ^^^ 1-n 1— ^ [I (Please read the precautions on the back before filling out this page) 412533 A7 B7 Employees' Cooperatives, Central Government Bureau of Ministry of Economic Affairs Printed 5. Description of the invention (25) Hexane / ethyl acetate 3/2). The pure fractions were collected and the solvent was evaporated, yielding 4.64 g (53%) of (±) -4- (difluoromethoxyfluorenyl-3 _ [(tetraoxy-3-furanyl) oxy] phenylethyl] (Intermediate 9). B) A mixture of Intermediate 9 (0,0129 mol) in CH3OH / NH3 (100 ml) was subjected to tritiation at RT using Raney nickel (3 g) as a catalyst. After absorption at 112, the catalyst was filtered and the filtrate was evaporated, yielding 3. 66 g (98%) (±) -4- (difluoromethoxy) -lu-methyl-3-[(tetrahydro-3-furanyl) oxy] benzene (Intermediate 10). c) Put intermediate 10 (0. 0158 Mol) and N-fluoro-carbodiimide diphenyl ester (0. 0158 mol) in ethanol (60 ml) and stirred overnight at RT. The solvent was evaporated, and the residue was purified on silica gel by open column chromatography (eluent: hexane / ethyl acetate 3/2, and CH2C12 / CH30, 96/4, 90/10, and 85/5). Collect the pure fractions and evaporate the solvent to yield 5. 11 g (74%) (±)-^ fluoro 4- [2- [4- (difluoromethoxy) -3-[(tetrahydro-3-furyl) oxy] -phenyl] propyl ] Phenylaminocarbamate (Intermediate 11) ° d) 2,2-Dimethoxyethylamine (0. 0129 mole), N, N-diethylethylamine (0. 023 Mol) and N, N-dimethyl-4-pyridylamine (0. 0059 mol) in 1,4-dioxolane, was added to a solution of intermediate 11 (0,0117 mol) in 1,4-dioxolane (10 ml), and stirred at RT. The reaction mixture was stirred and refluxed overnight. The solvent was evaporated and the residue was washed with water and IN NaOH and then extracted with CH2C12. The separated organic layer was dried, filtered, and the solvent was evaporated. The residue was purified by silica gel on open column chromatography (eluent: CH2Cl2 / CH3OH 96/4). Collect pure soluble fractions and steam --------- .  "(Please read the precautions on the back before filling this page) This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) A7 B7 412533 V. Description of the invention (26 solvents, 4'97 grams ( 95%) (±) -ϊγ-fluoro-N- [2- [4- (difluoromethylamino) -3-[(tetrafluorene, 3-furanyl) oxy] phenyl] propyl] _N _ (2,2_dimethoxyethyl) guanidine (Intermediate 12). Prepared in a similar manner: (Earth) -N __- fluoro-N- [2- [3- (cyclofluorenyloxy)- 4-methoxyphenyl] propyl] -N '_ (2,2_dimethoxyethyl) guanidine (intermediate 13); (earthyl-N- [2- [3- (cyclopentyl Oxy) -4- (difluoromethoxy) phenyl] propyl] -N '-(2,2-dimethoxyethyl) guanidine (Intermediate 14); N "-| l-yl-N -[2- [3- (Cyclopentyloxyb 4- (difluoromethoxy) phenyl] ethyl] -N '-(2,2-dimethoxyethyl) guanidine (Intermediate 15 ); (±) -N '_- fluorenyl-N- [2- [3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl] propyl] -N'-( 2,2-dimethoxyethyl) guanidine (Intermediate 16); (±) -N _'- cyano-N- [2- [3- [(1,3-dihydro-2Η-indene-2) -Yl) oxy] _4_methyloxyphenyl] propyl] -N '-(2,2-difluorene Ethyl) guanidine (intermediate ι7)! (±) -N " _fluoro-N- [2- [3- (cyclopropylmethoxy) -4 -methoxyphenyl] propyl] -1 ^ '-(2,2dimethoxyethyl) guanidine (Intermediate 18); (±) 4 " -Fluorofluoro- (2,2-dimethoxyethyl) 1,-[2- [ 4, methoxy_ 3 _ [(5_phenylpentyl) oxy] phenyl] propyl] guanidine (Intermediate 19).  (Ethylfluoro-N- (2,2-dimethoxyethyl) -N,-[2- [4, methoxy_ 3 _ [(tetrahydro-3-ketyl) oxy] phenyl ] Propyl] guanidine (Intermediate 20).  NN-fluorenyl-N,-(2,2-dimethoxyethyl) -N- [2- [4- (difluoromethoxy) _ 3 _ [(5_phenylpentyl) oxy] Phenyl] propyl] guanidine (Intermediate 24).  Ν_ · -nitrogen 4 '-[2- [3-[(2,3-Difluorene-1 !! ^ 而 -2- 基) -4 ~ methoxyphenyl-28 " This paper is applicable to China Standards (CNS > from the grid {21〇X297 mm)! 1 11 11— I-- n I --- II-Order (Please read the precautions on the back before filling this page) Central Bureau of Standards, Ministry of Economic Affairs 舅Printed by the Industrial and Consumer Cooperatives 412533 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the Invention (27)] ethyl] -N- (2,2-dimethoxyethyl) guanidine (Intermediate 25) ; (±) N-fluoro-N- [2- [3- [2- [2,3-difluoren-1H-inden-2-yl) ethoxy] -4_methylphenyl] propyl ] _N, _ (2 2_dimethoxyethyl) guanidine (Intermediate 27); (Earth) -N " -fluorenyl-N- [2- | > [(2,3-dihydro-1H -Ran-2-yl) oxy] -4-methoxyphenyl] -2-[(tetrafluoro-2H-piperan-2-yl) oxy] ethyl] -N,-(2,2 — Methoxyethyl) fox (intermediate 28). Example A. 3 a) (Ethyl) -3- (cyclopentyloxy) _4-methylamino-methylphenethylamine (0. 029 mol), Qiyi holding (〇 0146 mol) and sodium carbonate (0. 0219 mole) in DMF (200 ml), stirred at 6 (rc for 5 hours. The reaction mixture was filtered and the filtrate was evaporated. The residue was washed with water and then 2-methoxy-2-methylpropane Extraction. The separated organic layer was dried, filtered, and the solvent was evaporated. The residue was purified on silica gel by open column chromatography (eluent: CH2C12; CH2C12 / 2-acetone 96/4 and 90/10; then 0ίΚ ^ / ^ ΟΙί 80/20). The pure fractions were collected and the solvent was evaporated to yield 3. 24 g (77%) (±)-[[2- [3- (cyclopentyloxy) -4-methoxyphenyl] propyl] amino] acetonitrile (Intermediate 21). b) Put intermediate 21 (0. 0117 mol) in NH3 / CH30H (60 ml), hydrogenated at RT using Raney nickel (2 g) as catalyst. After H2 absorption, the catalyst was filtered and the filtrate was evaporated. The residue was treated with 10% aqueous HCl, and the mixture was extracted with ethyl acetate. The layers were separated. The aqueous phase was basified and then extracted with ethyl acetate. The separated organic layer was dried, filtered, and the solvent was evaporated to yield 2. 71 g (75%) (±) -N- [2- [3- -29-. -! I-In---1.  I— I (Please read the notes on the back before filling this page) This paper size is applicable to Chinese National Standard (CNS) A4 is now available (210X 297 mm) 412533 A7 B7 Description of the invention (28) (Cyclopentyloxy) 4methoxyphenyl] propyl] ethylenediamine (intermediate 22) 0 Example A. 4a) 6,7-difluorene-5H-cyclopentazone [b] P than pyridin-7-ol (03544 mol), 3-hydroxy-4-foxybenzaldehyde (0. 0322 moles) and triphenylphosphine (00322 moles) in THF (100 ml), stirred at 50 ° C & N2 atmosphere. Bis (1-methylethyl) diazanedicarboxylic acid ester (0 0322 mol) was added dropwise, and the resulting reaction mixture was stirred at RT for 12 hours. Evaporate the solvent. CH / l2 was added to the residue. The mixture was washed with water, dried, filtered and evaporated. The residue was purified on a crusher and carried out on a glass filter. (Eluent: (^ 2 (^ 2 / (卫 3001, from 100 / {) to 98. 5/1. 5). Collect the desired fractions and evaporate the solvent. The residue was dissolved in 2-propanol and converted to the hydrochloride salt (1: 1) with HC1 / 2-propanol. The solvent was evaporated. The residue was stirred in DIPE, filtered and dried to produce 8. 2 grams (83%) of 3-[(5,6_dihydro-7H-pyrazolin-7-yl) oxy] -4-methoxybenzaldehyde hydrochloride (Intermediate 34) Trimethylsilanecarbonitrile (0. 1472 mole) in CH2C12 (60 ml), added dropwise to 3-[(2,3-dihydro-1H-inden-2-yl) oxy]-[methoxy-benzaldehyde (〇 · 1227 Mol) and zinc iodide (0. 0061 mole) in a mixture of CH2C12 (240 ml). The resulting mixture was stirred at RT for one hour. The crude reaction mixture was washed with water and brine, and then extracted with CH2CI2. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was crystallized from DIPE. The precipitate was filtered and dried to yield 37. 39 g (83%) (soil) -3-[(2,3-dihydro-1H-inden-2-yl) oxy] -4-methoxy-30----------- ^-(Please read the notes on the back before filling in this page) The paper size of the book is common Chinese National Standard (CNS) A4 now available {210X297 mm. 4l2533 A7, _______ _ B7___ V. Description of the invention (29) The group [(trimethylsilyl) oxy] phenylethyl cyanide (intermediate 29). 0 makes intermediate 29 (0. 1116 mol) dissolved in methanol. Add HC1 (yes, 25 ml). The mixture was stirred for 5 minutes. Most of the solvent was evaporated and CH2C12 was added. The organic layer was separated, washed with saturated aqueous NaHC03, dried, filtered and the solvent was evaporated. The residue was dissolved in CH2C12 (350 ml), and 3,4-dihydro-2H-pyran (0. 2231 mole) and 4-methylbenzenesulfonic acid (catalytic amount), and the resulting reaction mixture was stirred at RT overnight. The mixture was washed with a saturated aqueous solution of NaHC03, dried, transitioned and evaporated. The residue was purified by short open column chromatography on silica gel (eluent: hexane / ethyl acetate, 9/1, then 8/2). Collect the desired fractions and evaporate the solvent to yield: 28. 01 g (66%) (±) -3-[(2,3-digas, 1 H-inden-2-yl) oxy] -4-methoxy-π-[(tetrafluorene-2H-absorbing Uran-2-yl) oxy] phenylethene (Intermediate 30). ^^ LA, 5 a) A solution of bis (1,1-dimethylethyl) dicarbonate (1.268 mol) in CH2C12 (1800 ml) was added dropwise to (±) -3- [(2,3_ difluoren-1H-inden-2-yl) oxy] -4-fluorenyloxy-/?-Fluorenylphenylethylamine (1. 208 moles) in CH2Cl2 (1800 ml). The mixture was stirred at RT for 2 hours. The solvent was evaporated. The residue was stirred in hexane, filtered and dried, yielding 420 g (soil)-[2- [3-[(2,3_dihydrazine-1 氲 -inden-2-yl) oxy-4-methoxy Phenyl] propyl] aminocarboxylic acid], 1-dimethylethyl ester (Intermediate 31) 〇b) Intermediate 31 (1. 056 mol) Purified and separated on Chiralpack AD by palm column chromatography (eluent: hexane / C2H50H / This paper size is applicable to China National Standard (CNS) A4 specification (2 丨 〇X 297 mm ) ^ N- ^^ 1 in > mm ^^^ 1 n ^ i 1 I- -I-^^ 1 1 ^ 1---{Please read the notes on the back before filling this page) 412533 A7 B7 Five Explanation of the invention (30) ~ CMH 9G / 1G / 1G) 〇 Collect the desired dissolution, and evaporate the solvent to produce 268 g of 8- [2- [3-[(2,3-dihydro_111-indene-2) -Yl) oxy] 4-methoxyphenyl] propyl] aminocarboxylic acid 1,2-diethylethyl (intermediate 32). c) A mixture of intermediate 32 (0,67 moles) in HC1 (670 ml; 6N) and methanol (2700 ml) was stirred and refluxed for 90 minutes. Evaporate the solvent. The residue was dissolved in CHJI2. The organic solution was washed with 1.20 (1000 ml) and a saturated NaHC0 solution. Separating the organic layer, drying, filtering and evaporating the solvent 'yielded 158 g (99%) of (B) -3-[(2,3-dihydro-1H-inden-2-yl) oxy] -4-fluorenyloxy -N-methylphenethylamine (Intermediate 33). According to example A. 2. b to A. 2. The procedure described in cl further reacts intermediate 33 to form fluorenyl-N- [2- [3-[(2,3-difluoren-1H-inden-2-yl) oxy] -4- Methoxyphenyl] propyl] -N, _ (2,2-difoxyethyl) guanidine (Intermediate 26). B, compound of formula (I). 1 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs ^^^ 1 '^ kn HI t.  ^^^ 1 s mu-tm ml (Please read the precautions on the back before filling this page) Insert the intermediate 22 (0. 0068 mole) and fluorocarbodiimide dithio acid dimethyl ester (0. 0068 mole) in ethanol (20 ml), stirred and refluxed for 2 days. The solvent was evaporated and the residue was first purified on silica gel by short open column chromatography (eluents: CH2C12, CH2C12 / CH30H 96/4 and 90/10), and then purified twice by HPLC (1. Eluent: CH2C12 / CH30H 90/10, and 2. Eluent: CH2C12 / CH30H 96/4). The pure fractions were collected and the solvent was evaporated, yielding 0.1 3 g (13%) (±)-[1- [2- [3- (cyclopentyloxy) -4-methoxyphenyl] propyl] -2-tetra-imidazolyl] fluoroamine (compound 1) ° -32-This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm). Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 412533 A7 ___ B7 V. Description of the Invention (31) Example B. 2 Set HC1 0 · 5N (0. 0162 mol) added dropwise to intermediate 12 (0. 0108 mol) in a solution of 1,4-dioxolane (20 ml), stirred and cooled in an ice bath. The reaction mixture was stirred at RT for 2 days. (The alternative is that 1,4-dioxolane can be replaced with THF, and the reaction mixture can be refluxed for 1 hour instead of stirring at RT for 2 days). The reaction mixture was treated with water, basified with a dilute NaOH solution, and then extracted with ethyl acetate. The separated organic layer was dried, filtered, and the solvent was evaporated. The residue was purified on silica gel using open column chromatography (eluent: CH2C12 / 2-acetone 96/4; CH2C12 / CH30H 96/4), and purified twice on silica gel by HPLC (1. Eluent: CH2C12 / CH30H 96/4, and 2. Eluent: CH2C12 / CH30H 97/3). The pure fractions were collected and the solvent was evaporated, yielding 0.1 64 g (15%) (±)-[1- [2- [4- (difluoromethoxy) -3-[(tetrahydro-3-furanyl) oxy] phenyl] propyl] -1 , 3-Difluorene-2H-imidazol-2-yl] fluoroamine (Compound 2; melting point 67. 8. 〇. Example B. 3 a) By palm column chromatography on Chiralpak AD (20 microns, 250 g, 5 cm, flow rate: 60 ml / min; eluent: hexane / ethanol / methanol 80/15/5), Compound 7 (0. 00644 mole) was separated into its palmar isomers. Collect the required dissociated fractions from both groups. Evaporate the solvent of the first group (A). The residue was stirred in DIPE, filtered, washed with DIPE, and then dried. The residue was subjected to column chromatography and further purified on j [romamasi 1 second gel (200 g, 5 microns, eluent: CH2C12 / CH30H 100/0, 90/10 after 30 minutes). The pure fractions were collected and the solvent was evaporated. The residue is stirred in DIPE, filtered, washed with D 丨 PE, and then dried to produce -33-This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) II--I-ί I-I -(H. ^ ϋ n --1------ 1 U3, νβ (Please read the precautions on the back before filling this page) Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 412533 A7 ___-____B7 V. Description of Invention (32 ) 0. 39 g (50%) (±)-(human)-[1- [2- [3-[(2,3-Diargon-111-inden-2-yl) oxy] 4methoxy-phenyl ] • propylimid-2-yl] fluoroamine; [4〇: +95. 46. ((: = 0. 1% in (: 113)} (Compound 16). The second group (B) -solvent was evaporated. The residue was stirred in DIPE, filtered, washed with DIPE, and then dried. The residue was purified by column chromatography on Krmnasil silica (200 g, 5 microns, eluent: CH2C12 / CHsOH 100/0, 90/10 after 30 minutes). The pure fractions were collected and the solvent was evaporated. The residue was stirred in DIPE, filtered, washed with DIPE, and then dried to produce 0. 5 g (90%) (-)-(B)-[l- [2- [3-[(2,3-dihydro-1H-BP-2-yl) oxy] -4-methoxybenzene Propyl] propyl] -1H-imidazole_2_ 20 yl] cyanamide; [from] [| = -109. 04e (c = 0. 1% in CH30H) (Compound 17). b) Compound 17 (0. 0026 mol) in DMF (40 ml) and stirred at 0 ° C. Add sodium hydride (0. 0028 Mol; 60%), and the mixture was stirred at (TC for 30 minutes, and at RT for 30 minutes. Bromomethylbenzene (0. 0028 mole) in DMF (10 ml), and the resulting reaction mixture was stirred at RT for 3 hours. The solvent was evaporated, toluene was added, and the mixture was azeotroped on a rotary evaporator. The residue was dissolved in ch2C ". Water was added. The organic layer was separated, dried, filtered, and the solvent was evaporated. The residue was purified on silica gel by short column chromatography (eluent: cfl2Cl2 / CH3〇H 98/2) The desired fractions were collected and the solvent was evaporated, yielding 0.7 g (63%) (Co-[[[[[[[[2,3-Difluorenyl-111-^-2-yl) oxy]-] 4_methoxy_phenyl] propyl] -3-phenylfluorenyl-in-imidazol-2-yl] fluoroamine (compound 23). Example B. 4 -34-This paper size applies Chinese National Standard (CNS) A4 specification (210X297) 412533 a; B7 V. Description of the invention (33) HC1 (0. 0268 Mol; 0. 5N) was added to intermediate 28 (0. 0179 mol) in THF (250 ml), stir and cool in an ice bath. The reaction mixture was stirred and refluxed 1. After 5 hours, it was chilled in an ice bath. The mixture was partitioned between water and ethyl acetate and basified with solid Na2CO3. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified on silica gel by short open column chromatography (eluent: CH2Cl2 / CH3OH 97/3, then 95/5). Collect the desired pure fractions. The solvent was evaporated to crystallize the residue from CH3CN, filtered and dried to produce (35%) (soil)-[1-a [2- [3-[(2,3-dihydro-1H-benz-2-yl) oxy [] Methyl] -4-methoxyphenyl] -2-ylethyl]. 1,3-bisfluorene-2H-imidazol-2-yl] fluorenamine (Compound 21) — ≫ ^^ 1 1 111--I n 1 ^ 1 ^^ 1 m 1 ^ 1 (Please read the meanings on the back #Fill this tile first) Printed on 35 papers by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs Standards it Cai Guanduo Zhuo (CNS) A4 specifications (A7 B7 412533. Description of the invention (34) Table 1 lists compounds of formula (I) prepared according to one of the examples above,

N N " \ / Α ~ · Β

, CN

V The example of the printed polymer compound of the Consumers' Cooperative of the Central Economic and Technical Bureau of the Ministry of Economic Affairs R1 R2 R4 L -AB- Physical data__ Melting point (° c) 1 B.1 Cyclopentyl ch3 ch3 H -CH2-CH2- ( E + Z) 2 B.2 3-tetrahydrolanyl chf2 ch3 H -CH = CH_ 67.8 ° C 3 B.2 cyclopentyl ch3 ch3 H -CH-CH- 101.3 ° C 4 B.2 cyclopentyl chf2 ch3 H -CI-I = CH- I33 ° C 5 B.2 cyclopentyl ci-if2 HH -CH = CH- ί58.9 ° C 6 B.2 cyclopropylmethyl chf2 CH, H -CH = CH -Liquid 7 B.2 CO ci-i3 ch3 H -CH = CH- 87.5 ° CS B.2 Cyclopropylτyl CH;) CI-I; i H -CH = CH- 66.2 ° C 9 .13.2 Phenylpentyl CH ^ ch3 H -CH = CH--10 B.2 3-tetrahydrofuranyl CH: i CH ;, H -CH = CH- 73.4 ° CU B.2 phenylfluorenyl chf2 CRj H -CH = CH-- 12 B.3 cyclopentyl ch3 ch3 H -CH di-CH- (A) [3 B.3 cyclopentyl ch3 ch3 H -CH = CH- (B) 14 B.3 cyclopropylmethyl 'ch3 ch3 H- CH = CH- (A) 15 IB.3 Cyclopropylmethyl CH, CHi H -CH DiCH- (B) 16 B.3 0〇 ~ ch3 CH, H -CH = CH- (A) 17 B.2 〇 > ch. Ch3 H -CH = CH- (B); 138.7 ° C B.3 18 B.3 Polyylpentyl ch3 ch3 H -CH = CH- (A) 19 B.3 Phenylpentyl CH , ch3 H -CH = CH- (B ) 20 B.2 CO- ci-i3 MH -CH = CH--21 B.4 Γτν cn: i OH H ^ CH = CH- mp. 179.9 ° C -36-(Please read the notes on the back before filling This page). The paper size is in accordance with the Chinese National Standard (CNS) A4 specification (2〗 0X297 mm) A7 B7 V. Description of the invention (35) — Inhibition of human MNL phosphodiester Xue IV type B. Seventy-two hours after infection with the recombinant-like virus, insect cells were collected and pelleted for 5 minutes under 500 g of gravity. Dissolve cells in 10 ml lysis buffer Printed by the Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs

sn 1—, II 1 i, nn!. I · f K ^ (Please read the precautions on the back before filling this page) The agent contains 20mM Tris, 10mM EGTA, 2mM Na2EDTA, 1% Triton-X-100 , IibM Na3V04, 10 mM NaF, 2 μg / ml leukocetin, peptidin and aprotinin each, 0.3 μg / ml benzamidine and 100 μg / ml TPCK, pH 7.5. After scouring for 5 minutes on ice, centrifuge the lysed cells at 4 ° C for 15 minutes at 4000 rpm. Filter the formed supernatant through a 0.45-micron filter (Millipore) and introduce it into a TBS retarder (50mM Tris, 150mM NaCl, pH value 7 · 4 -37-this paper size applies to Chinese national standards (CNS) A4 specification (210X297 mm) Printed by the Central Standards Bureau of the Ministry of Economic Affairs and Consumer Cooperatives 412533 A7 ____B7 V. Description of the Invention (36)) 0 The IV supernatant containing IV β-type phosphate diester (PDE) , And then packed into a 5 liter anti-FLAG-M2 affinity gel column, which was previously activated with 5 ml of 100 mM glycine pH 3.5, and 20 ml of 50 μm 1'1 * 1, , 15〇1115 {skeleton (: 1 卩 11 value of 7.4 reached equilibrium. After washing the column with a balance with a buffer, dissolve? 0 £ 17 in 3ml containing 37.5 microliters)! ^ 5 Dissolve in 1.5 ml of pH 8 The aliquots were dialyzed against 20 mM Tris, 21 ^ such as 2 £ 0? 4 and 40 0 111 11% () 1? 11 value 7.5 dialysis overnight, and tested 卩 0 £ IV activity. SDS PAGE and Western blotting Ink paper (anti-FLAG-M) was identified. Active fractions were pooled, introduced into 10% glycerol, and staggered at -7 ° C. The incubation mixture (pH 8) (200 μl) contained 20 n iM Tris, 10mM magnesium sulfate, 0,8 # M 3H-cAMP (310 mCi / millimolar) and type IV linoleic acid diester, the amount of which depends on the enzyme activity. The protein concentration is selected and it is shown in 37 At ° C, during the incubation period of up to 10 minutes, the linear increase in the phosphodiester activity is increased, and less than 10% of the initial substrate is hydrolyzed. When testing the effect of different compounds on the phosphodiester activity, the The medium without cAMP was incubated with the compound or its vehicle (DMS 〇_ i% final concentration) for 5 minutes. The enzyme reaction was started by adding 3jj-camp and later in a transfer microtiter plate at 100 ° After 5 minutes in a water bath at C, it stopped after 5 minutes. After cooling to room temperature, alkaline phosphonium phosphate (0 25 μg / ml) was added, and the mixture was incubated at 37 ° C. for 20 minutes. 〇μl of the mixture is applied to a GF-B filter-microtiter plate (MilΠpore) filled with 300μl of DEAE-Sephadex-A25 suspension. This plate is 75 μl 20 -38-This paper is in use @ 1 country CNS) A4 size (210 × 297 male ~~ ^ ------ iT (Please read the precautions on the back before filling in this ) 412533 Α7 Β7 V. Description of the Invention (37) mM Tns pH value of 7.5 was washed three times, and the filtrate was collected in the Packard Top Count scintillation counter calculation. The inhibitory effect of the compound of the present invention on the recombinant human MNL phosphodiester siPDE IV B is measured at different concentrations of the compound of the present invention. The IC50 value (expressed as M) is the value of the inhibitory effect thus obtained, which is calculated graphically and is shown in Table 2. Table 2 Consumption Cooperation with Employees of the Central Standards Bureau of the Ministry of Economic Affairs Du printed compound number IC50 (10-8M) 1 33.0 2 10.0 3 3.00 4 1.53 5 2,66 6 2.24 7 1.90 8 5.65 9 3.61 10 19.6 Compound number ICso (l〇 -8M) 11 3.27 12 2.19 13 2.22 14 2.72 15 3.35 16 1.80 17 3.00 18 4.09 19 3.75 20 ------ 7.65 --------- The following formulas are examples of suitable for animals Systematically with human patients or -39-This paper size applies Chinese National Standard {CNS) A4 specification (2 丨 〇297mm) (Please read the precautions on the back before filling out this page) Λ * 1Τ 1.,! Printed by the Central Standard of the Ministry of Economic Affairs 扃 Employee Consumer Cooperatives 412533 A7 _________B7___ V. Description of Invention () 38; Typical pharmaceutical composition according to the present invention for local administration. The " active ingredient " (A.I.) used throughout these examples relates to a compound of formula (I) or a pharmaceutically acceptable addition salt thereof. Example D · 1:% Scale Tablet Tablet Core The preparation of the core was thoroughly mixed with a mixture of 100 g of A.I., 570 g of lactose and 200 g of starch, and then 5 g of sodium dodecyl sulfate and 10 g of polyvinyl tetrahydropyrrolidone in about 200 ml The solution in water was humidified. The wet powder mixture was sieved, dried and sieved again. Then 100 grams of microcrystalline cellulose and 5 grams of hydrogenated vegetable oil were added. The whole hip was thoroughly mixed and compressed into tablets to obtain 1 0.0000 tablets, each containing 10 mg of the active ingredient. To a solution of 10 g of amidoxine in 75 ml of denatured ethanol, add 5 g of ethyl oryzanol in 150 ml of digasmethane. Solution. Then add 75 liters of difluoromethane and 2.5 ml of 1,2,3-propanetriol. Melt and dissolve 10 grams of polyethylene glycol in 75 ml of digas methane. Add the solution described below to the former, Then add 2.5 g of magnesium octadecanoate, 5 g of polyvinyl tetrapyrrolidone and 30 ml of concentrated colored suspension, The whole was homogenized mixture thus obtained to the tablet core coated in the coating apparatus in Example D.2:.. 2% cream session portion

In a solution of 200 mg of hydroxypropylcyclodextrin in pure water, 20 mg of A.I. was added and mixed at the same time. Yu acid was added until it was completely dissolved, and then sodium hydroxide was added until the pH was 6.0. While stirring, add 50 mg of glycerin and 35 mg of polycyanate 60, and heat the mixture to 70 ° C. This paper is sized for China National Standards (CNS) A4 (2 丨 〇X 297 mm) (Please (Please read the notes on the back before filling this page) Order 412533 A7 B7 V. Description of Invention (39). The resulting mixture was added to 100 mg of mineral oil having a temperature of 70 ° C., 20 mg of stearyl alcohol, 20 mg of cetyl alcohol, 20 mg of glyceryl monostearate, and 15 mg of succinate. 60 of the mixture, while slowly mixing. After cooling to below 25 ° C, add the remaining pure water to a sufficient amount to 1 g, and mix the mixture until homogeneous. (Please read the notes on the back before filling out this page} Employees' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, Yinli-41 This paper size is applicable to Chinese National Standard (CMS) A4 (210X297 mm) 412533 A7 B7 V. Description of the invention ( ） Patent Application No. 861 14167 ROC Patent Appln. No. 86114167 Supplemaital Examples in Chinese-Enel, (III) (Republic of China 87 > October | Said to submit) ~~~ (Submitted on October |, 1999) Compound 27 (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives, Intellectual Property Bureau, Ministry of Economic Affairs

Melting point: 205 ° C -41-1-

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Claims (1)

The Intellectual Property Bureau of the Ministry of Economic Affairs printed the immortal co-operative consumer ... 1_VI. Application scope of patents; Patent Application No. 86114167 ROC Patent Appln. No. 86114167 Amendment of the scope of application patent ten texts-Annex (I) Amended Claims in Chinese -End. (I) ^ (Submitted on October |, 1999) 1. A compound of the formula / CN Its pharmaceutically acceptable acid or base addition salt or stereochemically isomeric form, where = R1 and R2 are each independently hydrogen; CV6 alkyl; difluorofluorenyl; trifluoromethyl; C3-6 cyclohexyl; oxygen Atom sign and 5-, 6- or 7-membered heterocyclic ring; Hydroindenyl: 6,7-diargon-5H-cyclopentylpyridyl; or Ci-6 alkyl substituted with one or two substituents, each substituted The radical is independently selected from phenyl, hydroindenyl, or (: 3-7 cycloalkyl; R3 is murine, R4 is hydrogen; Cy alkyl; or hydroxyl; R5 is hydrogen; or R4 and R5 can form a divalent formula of the following formula together Groups: -CH2-CHrO-CH2-CH2- R6 is wind, -AB- is a divalent group of the formula: -CR10 = CRn- (c-1); or -CHR10-CHRn (c-2); -42- (Please read the precautions on the back-please fill in this page) I----1 I- --i-rOJ n I---—] —1 I ^^^ 1 _. Size of this paper Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 86467-claim The imprint of immortality printed by the employee consumer cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs ... 1_ 六 、 Scope of patent application; Patent Application No. 86114167 ROC Patent Appln. No. 86114167 Amended Patent Application Scope-Text . (A) Amended Claims in Chinese - End (I) ^ (Republic of China on October 87, saying I Submission) ^ (Submitted on October |, 1999) 1. A compound having the formula / CN Its pharmaceutically acceptable acid or base addition salt or stereochemically isomeric form, where = R1 and R2 are each independently hydrogen; CV6 alkyl; difluorofluorenyl; trifluoromethyl; C3-6 cyclohexyl; oxygen Atom sign and 5-, 6- or 7-membered heterocyclic ring; Hydroindenyl: 6,7-diargon-5H-cyclopentylpyridyl; or Ci-6 alkyl substituted with one or two substituents, each substituted The radical is independently selected from phenyl, hydroindenyl, or (: 3-7 cycloalkyl; R3 is murine, R4 is hydrogen; Cy alkyl; or hydroxyl; R5 is hydrogen; or R4 and R5 can form a divalent formula of the following formula together Groups: -CH2-CHrO-CH2-CH2- R6 is wind, -AB- is a divalent group of the formula: -CR10 = CRn- (c-1); or -CHR10-CHRn (c-2); -42- (Please read the precautions on the back-please fill in this page) I----1 I- --i-rOJ n I---—] —1 I ^^^ 1 _. Size of this paper Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 86467-claim Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 412533 I C8 D8 Six. The scope of patent application, each of which is independent of the R11 series is nitrogen; and L is Hydrogen; CV6 alkoxycarbonyl; or taken from one or two phenyl groups It is substituted by C | .6 alkyl group. 2. According to the compound in the scope of the patent application, item 1, wherein R1 and R2 are each independently hydrogen; (^ .6 alkyl group; difluoromethyl group; trifluoromethyl group; C3_6 cycloalkane . Groups; saturated 5-, 6- or 7-membered heterocyclic rings containing oxygen atoms; hydroindenyl; or CV6 alkyl substituted with one or two substituents, each substituent is independently selected from phenyl or C3. 7 cycloalkyl. 3. The compound according to item 1 or 2 of the scope of patent application, wherein R1 and R2 are each independently <: μ6 alkyl; C3.6 cycloalkyl; difluoromethyl; saturated with oxygen atom 5-, 6-, or 7-membered heterocyclic ring; hydroindenyl; or CV6 alkyl substituted with phenyl, hydroindenyl or C3_6 cycloalkyl., 4. The compound according to item 1 of the scope of patent application, wherein R4 is alkyl. 5. The compound according to item 1 of the scope of patent application, wherein R1 is cyclopentyl, tetrahydrofuranyl, cyclopropylmethyl, 5-phenylpentyl, 6,7-diargon-5H-ring Penta [b] pyridyl or hydroindenyl; R2 is fluorenyl or difluoromethyl; and R3, R5, R6, R1G, R11, and L are all hydrogen. 6. According to the first item of the scope of patent application, Where the compound is [1- [2- [4- (二(Methoxy) -3-[(tetrahydro-3-furanyl) oxy] phenyl] propyl] -1,3-dihydro-2H-imidazol-2-yl] cyanamide; and [1- [2- [4- (Methoxy) -3-[(1,3-dihydro-2H-benz-2-yl) oxy] phenyl] propyl] -1,3-dihydro-2H- Imidazol-2-yl] cyanamide, or a stereochemically isomeric form or a pharmaceutically acceptable addition salt thereof. -43- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) -------------- " ------- Order ---- ----- Line J (please read the precautions on the back before filling this page) ^ A pharmaceutical composition for the application of patents in the scope of "oral therapy Xing discic acid two g purpose enzyme IV H-related disease state" , Its package 2 or catalytic activity has 8 · =! The compound in the first item of patent scope, which is used for the manufacture of drugs for treating disease states associated with abnormal enzymes or catalytic activity of ~, acetic acid-acetase Ιν . 9. The Radicals Patent _ The compound of item 1 is intended to manufacture medicines for the treatment of atopic or asthmatic diseases. 10. A compound prepared according to item (i) of the scope of the patent application, which is characterized by '3) an intermediate of formula (II) or a functional derivative thereof, wherein r6, r10 and & 1 are all within the scope of the patent application Definition in item 1 R3, CN 1Guangzhou R6 I I C-CIUNH- Ks r2o * 3 (: M pit base c-.CH-i-o—CM alkyl · κ " κ " > αο — printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs R2o Exactly 4 R0 N I —ii ^ M R_o \ || (I ^ a-1) Cyclization in a solvent inert to the reaction and in the presence of a suitable acid; thus forming a compound of formula; -44- Paper size applies to China Solid State Standards (CNS) A4 (21 × 297 mm) 412533 A8B8C8D8 force ', patent application scope b) Formula (II-1) intermediate' where R1 to r4, R6, Rt0 and R11 are all As defined in item 1 of the scope of the patent application, and p is hydrogen or trimethyl crushing group protecting group or a functional derivative thereof (Ia-1-i) cyclization in a solvent inert to the reaction and in the presence of a suitable acid; thus forming a compound of formula (I_a-; c) an intermediate of formula (III) or a functional derivative thereof, Where ri to r6, R10 and R11 are as defined in item i of the scope of patent application da-2) ^-I ----------- Posting '!! 1 Order --- I--II-* (Please read the precautions on the back-before filling this page) Ministry of Economic Affairs Printed by the Intellectual Property Bureau Shellfish Consumer Cooperative in a solvent inert to the reaction, and cyclization in the presence of cyanocarbimidodithiodimethyl or N-fluorenylcarbimidate Action 'therefore forms a compound of formula (Ia-2); -45- This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 MM) ^ 12533 8888 ABCD VI. Application for patent scope d) Make formula (IV) Organometallic intermediates, where R1 to R3 are as defined in the first patent application scope, and M is an appropriate metal ion or metal complex ion CN R3 Ό- M + (IV) W1-C_CH-N 1N Λ Ν—L (I) r2o (V) in a solvent inert to the reaction, and the appropriate formula (V) 2-cyanoimino / miazole derivative Physical reactions, in which R4 to R6, L and -A-B- are as defined in the first patent application scope, and W1 is a reactive leaving group; and if necessary, it is used according to a transformant known in the art, The compounds of formula (I) are converted to each other, and further, if necessary, are treated with an acid to convert the compounds of formula (I) into a therapeutically active non-toxic acid addition salt, or through a test treatment into a therapeutic Non-toxic test addition salt of the activity, or vice versa, to test the acid addition salt to form a free form test, or to treat the addition salt to a free form acid by treatment with an acid; and, if necessary, Then prepare its stereochemically isomeric forms. (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs -46- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)