TW200307545A - Nicotinamide derivatives and a tiotropium salt in combination for the treatment of diseases - Google Patents

Abstract

The invention relates to a combination of a nicotinamide derivative and tiotropium or a derivative thereof, compositions containing it and the uses of, such a combination. The combination according to the present invention is useful in numerous diseases, disorders and conditions, in particular inflammatory, allergic and respiratory diseases, disorders and conditions.

Description

200307545 (1) 玖. Description of the invention The present invention relates to nicotinamide derivatives of the general formula

(Where Ri, R2, R3, R4, X, Υ, η, and m have the following

The definitions mentioned above), a composition with a thionine crystal key salt (ie, thionine crystal key bromide), and the use of such a composition. 3 >, 5 / -loop status nucleotide phosphodiesterases (PDEs) contain very

A large variety of enzymes can be classified into at least eleven different families according to their structural, biochemical, and pharmacological differences. These enzymes in each family are commonly known as isozymes or isoenzymes. Gene products with a total of more than 15 are also included in this species, and there are more differences due to the different splicing and post-transfer processing of their gene products. The present invention is mainly concerned with four gene products of four PDEs families, that is, PDE4A, PDE4B, PDE4C, PDE4D. These enzymes are collectively known as isoforms or isoforms of the PDE4 isoenzyme family. PD £ 4S is characterized by a selective, highly hydrolyzable second information cyclic nucleotide, adenine nucleoside 3 /, 5 > -cyclic monophosphate (cAMP), and is a rolipram The selectivity of drug inhibition is characteristic. In recent years, several selective inhibitors of PDE4s have been discovered, and the beneficial pharmacological effects derived from this inhibitor have also been manifested in a variety of disease modes. For example, see Envir of Τ 1 · phy et al. η. H ea 11 h -5- (2) 200307545

Perspect · 1 994, Issue 02 02 Su ρ ρ 1 · 10, pp. 79-84;

J. Med. Chem, Duplantier et al., 1996, 102, pp. 120-125; Schneider et al. Pharmacol · Biochem ·

Behav ·, 1995, Issue 02, pp. 211-217; Banner and Page, Br. J. Pharmacol., 1999, Issue 114, pp. 93-98; Barnette et al., J. Pharmacol. Exp · Ther ·, 1995, Issue 273, pp. 674-679; Wright et al. Can. J. Physiol. Pharmacol., 1997, Issue 75, pp. 1001- 1008; Manabe EU r · J. P harmac ο 1 · et al., 1997, Issue 3, pp. 97-107, and J. Med. Chem., Ukita et al., 19997, 42 Issue, pp. 1 08 8 — 1 099. Accordingly, there is still considerable interest in the industry in discovering more selective inhibitors of PDE4s.

The industry has had successful results in the discovery and development of selective PDE4 inhibitors. In vivo, PDE4 inhibitors can reduce the flow of eosinophils into the lungs of animals challenged with allergens' and also reduce bronchoconstriction and increase the incidence of bronchial responses after the allergen challenge. PDE4 inhibitors can also suppress the activity of immune cells (including CD4 + τ-lymphocytes, monocytes, mast cells, and psychrophils) to reduce pulmonary edema and inhibit neurotransmission of stimulating non-adrenergic and choline-like functions (EN AN C), at the same time strengthen the inhibitory non-adrenergic non-choline-like neurotransmission (iNANC), and reduce the occurrence of mitosis of respiratory smooth muscle, and promote bronchiectasis. PDE4 inhibitors can also suppress the motility of several inflammatory cells (including monocytes / macrophages, CD 4 + T-lymphocytes, eosinophils and neutrophils) related to the pathophysiology of COPD-6 -(3) 200307545 Occurrence and latent neutrophilization: bioreactive 丨 destruction, and some in PDE4 and allergic exhibitions: inflammation and lung qi can be used as: Some effect packages :, chemotaxis, tumor necrosis! Already Synthesized: It is revealed that it is derived from amidine. PDE4 inhibitors can also reduce mitosis of vascular smooth muscle and interfere with respiratory epithelial cells to produce a proinflammatory mediator. Neutral proteases and acid hydrolases are released from sex cell granules, which can produce oxygen substances, which enables them to promote tissues related to chronic inflammation and further correlate with pathological conditions such as emphysema. The inhibitors are particularly useful in the treatment of many inflammatory, respiratory, disease, disorders or conditions, and can be used in trauma. In clinical practice, PDE4 inhibitors are mainly used in the treatment of asthma, COPD, and bronchioma. Effect of PDE4 inhibitors on various inflammatory cell responses The basis for reviewing and selecting inhibitors for further investigation. These include increasing cAMP and inhibiting the production of peroxides, cell degranulation, and the release of factor a (TNFα) in eosinophils, neutrophils and monocytes. Certain nicotinamide derivatives with PDE4 inhibitory activity. For example, patent application N ° W09 8/45268 has a smoke tester that is as active as a selective inhibitor of PDE4D isoenzymes. These selective PDE4D inhibitors have the following chemical formula:

Among them, in particular, m and η are equal to 1 and ρ is equal to 0, A represents oxygen (4) (4) 200307545, B represents NH, r is equal to 0, E represents 0, NH or S, and R5 represents 1 to 4 A heteroatom is a saturated or unsaturated cyclic or bicyclic (c 3-C 7) heterocyclic group, and R1 represents an aryl group which may be optionally substituted with various substituents. At the same time, the patent application N ° WO 01/57036 discloses a nicotinamide derivative of the following formula, which is a P D E 4 inhibitor that can be used to treat a variety of inflammatory allergies and respiratory diseases and conditions:

Among them: η represents 1 or 2, m represents 0 to 2, Y represents = C (Re) —or— [n— (〇)] —, w represents 010, —S (= 〇) t—or -N (r3)-, Q represents a variety of rings in phenyl, z represents -OR12, —C (= 0) R12 or CN, and R12 is selected from the group consisting of alkenyl, alkenyl, cycloalkyl, phenyl, Benzyl and monocyclic heterocyclic moieties. Nuscarinic receptor antagonists prevent effects caused by stimulation of the parasympathetic channels. This effect is due to their ability to inhibit the neurotransmitter acetylcholine by blocking the bond with choline functional receptors such as thymine. There are at least three forms of muscarinic receptor subtypes. The M! Receptor is found in the brain and other central nervous systems, while the M 2 receptor is found in the heart and other cardiovascular tissues, and the Vi3 receptor is found in -8- (5) (5) 200307545 in smooth muscle and Glandular tissue. The muscarinic receptor system is located on the smooth muscle, and the M3 receptor is located in the smooth muscle of the respiratory tract. Therefore, anti-choline-like functional agents can also be called muscarinic receptor antagonists. The parasympathetic nervous system plays a major role in regulating bronchial muscle tone, while bronchoconstriction is mainly the result of increased reflexes in parasympathetic nerve activity (caused in turn by stimulation by the groups). Anticholinergic agents have a long history of treating chronic respiratory diseases, such as COPD and asthma, which are characterized by partial reversible narrowing of the airways, and can be used as bronchodilators before adrenaline appears. Thereafter, it was replaced with a / 3 2 -adrenaline reagent and methylxanthine. However, the recent addition of ipratropium bromid has led to a resurgence of anticholinergic treatment in the treatment of respiratory diseases. Since muscarinic receptors are present in peripheral organ systems such as salivary glands and intestines, systemic active muscarinic receptor antagonists will be limited by dry mouth and constipation. Therefore, bronchodilatory and other effective effects of the phytamine receptor antagonist are ideally produced by inhalants with a high therapeutic index on lung activity (when compared with peripheral intervals). Anticholinergic agents also partially antagonize bronchoconstriction caused by histamine, bradykinin, or prostaglandin F2α. It is believed that in the bronchial reflections elicited by these agents, they also Will reflect the output of the parasympathetic nerve. The anticholinergic thiazole crystal key is structurally a quaternary ammonium compound. The central effect of this agent is usually insufficient because they do not easily cross the blood-brain barrier. When agents with such characteristics are inhaled, their effects are almost entirely confined to the mouth and respiratory tract. Even if the recommended agent -9-(6) 200307545 is inhaled several times, these agents produce little or no change in heart rate, blood pressure, bladder function, intraocular pressure, or pupil diameter. This selectivity results from the very inefficient absorption of these agents in the lung or gastrointestinal tract. The incubation period and clinical review of thiothalium crystal key are based on these characteristics, while the deeper difference between thiothalium crystal key and methamphetamine M3 receptor is that thiothalamine crystal is prolonged due to its slow dissociation Period of action.

The thizone crystal iron and its derivatives disclosed in European Patent EP 0 4 1 8 7 1 6 B 1 are quaternary nitrogen compounds having the structure of the following formula (I): h3cx + / ch3

"(L) (where x- represents a physiologically acceptable anion, especially bromine), and a pharmaceutically acceptable solvate thereof.

Examples of suitable anions X— are fluorine F—, chlorine C1—, bromine Br—, iodine I—, mesylate CH3S (= 〇) 2〇—, ethanesulfonate CH3CH2S (= 0) 2— Sulphate ch3os (= o) 20—, benzene Extender C 6 H 5 S (= 0) 2 0 —, and p-toluenesulfonate 4 — CH3C6H5S (= 0) 2 0—. However, for additional PDE 4 inhibitors' that can exhibit an improved therapeutic index with as few adverse effects as possible (such as D-zone vomiting) and can exhibit enhanced efficacy, and have a better effect on thionine and its derivatives There is still a great demand for tolerance -10- (7) 200307545. [Summary of the Invention] In the present text, the present invention relates to a composition of a tobacco _ PDE4 inhibitor and thiazepine and its derivative (bromide). The novel PDE4 inhibitors of the present invention are, for example, amidine derivatives: The novel 'that is the thiazole crystal pin in the amidine family

Where m represents 0, 1, 2 or 3, ❖ η represents 0, 1, 2 or 3, < ♦ R] and R2 are each independently selected from a hydrogen atom, a halogen group (C 1-C 4) radical And (Cl—C4) alkoxy, ❖ X represents —0—, —S—, or —NH—, and R3 is selected from the group consisting of: (a) phenyl, naphthyl, heteroaryl, and (C3— C8) each is optionally substituted with 1 to 3 substituents, and each is selected from the group consisting of _, cyano, (C〗 -c4 cyano,

Burning base, (C 1-c (Cl— C 4) sulfur base

C naphthene ~ take [) alkyl group, which

NH-substituted group is oxy, -C (= 0) NH (Cl-C4) alkylhydroxy

C -11-(8) 200307545 (Ci— C 4) courtyard foundation, —C (= 0) — O— (Ci— C4) courtyard foundation and Jingji (Cl— C4) courtyard foundation, or (b) meet the following Structures (1. 1) to (1 · 4)

(1.3) (1.4)

The symbol `` * 〃 represents the connection point of each part of the chemical formula (1 · 1) to (1 · 4) connected to the rest of the chemical formula (1), and Υ is selected from the following partial formula (1 · 5) To (1 .1 1) basis:

(1.5) (1.6) (1.7) (1.8)

(1.9) (1.10) (1.11)

Where the symbol `` * 〃 '' represents the connection point of each part of the chemical formula (1 · 5) to (1.1.1) connected to the rest of the chemical formula (1) —NΗ—, and the symbol 〃 represents each part Chemical formulas (1.5) to (1.1.1) are connected to the remaining point of R4-of the remainder of chemical formula (1), ♦ > and R4 represent a group selected from the following:-12- (9) 200307545 ) This group, naphthyl, and heteroaryl, each of which is optionally substituted with 1 to 3 substituents, and each -substituent is selected from carboxylic acid, C (= 〇) (Cl-C0 alkyl ), Halo, cyano, (0) nh2, (c) sC4) alkyl, (Cl-C4) alkoxy, (c "c4) dental, meridian, and meridian (C" C4) College, or (b) optionally via hydroxyl, carboxylic acid,

e (Q) l (C1— ^ 4) (c) C4) substituted with a phenyl group, phenyl group, naphthyl group or heteroaryl group; each of the phenyl group, naphthyl group and heteroaryl group may be L H 1 1 3 substituents are selected, and each-substituent is selected from the group consisting of residual acid, c (= 0) 0 (Cl — c4) fluorenyl, dentyl, cyano, (〇) nh2 (Cl ~ c4) alkane Or (Ci-c4) alkoxy, (C! -C4) haloalkyl, hydroxy, and hydroxy (c) -C4) alkyl, or, if appropriate, their pharmaceutically acceptable salts And / or isomers, tautomers, solvates, polymorphs, isotopic variants, or other metabolites.

It was discovered that 'these nicotinamide derivatives are inhibitors of the PDE4 isoenzymes' are particularly useful for the treatment of inflammatory, respiratory and allergic diseases and conditions, as well as by exhibiting excellent therapeutic effects and therapeutic indices Treatment of trauma. In the above general formula (1), the halogen group represents a halogen atom selected from a fluoro group, a chloro group, a bromo group, and an iodine group, particularly a fluoro group or a chloro group. (CpC4) alkyl means containing;! A linear or branched chain of 2, 3, or 4 carbon atoms. The right one has a substituent or other substituents such as (C! -C4) alkoxy, (c) -c4) sulfanyl, (c) ~ c4) haloalkyl, -13- (10) ( 10) 200307545 Hydroxy (c) —c4) alkyl, c (= 〇) 〇 (Cl—c4), etc.), etc. are also applicable. Examples of suitable (G-C4) alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, fluorene-butyl, second-butyl and third-butyl. Examples of suitable (C1-C4) alkoxy groups include methoxy, ethoxy, n-propoxy, iso-caroxy, n-butoxy, iso-butoxy, table-butoxy And third to butoxy. Examples of suitable (C! -C4) sulfanyl groups include thiomethyl, thioethyl, sulfur-n-propyl, sulfur-iso-propyl, sulfur-n-butyl, sulfur-iso-butyl , Sulfur-second-butyl and sulfur-third-butyl. (Ci ~ c4) haloalkyl refers to a fluorenyl group substituted with a halo group. If not otherwise indicated, they may contain 1, 2, 3, 4, 5, 6, or 7 halogen atoms. If not otherwise indicated, the halo group is preferably a fluoro group, a chloro group, a bromo group or a stilyl group. For example, in a fluoro-substituted alkyl group, a methyl group may be represented as a trifluoromethyl group. The same situation can be applied to the hydroxy (C) -c4) alkyl group, except that their radicals are substituted with a hydroxy (-OΗ) group. According to a preferred embodiment of the invention, such groups may contain a hydroxy substituent. Examples of suitable hydroxy (C) -C4) alkyl include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl. (C3-C8) cycloalkyl means a saturated monocyclic ring having a 3-membered ring to an 8-membered ring. Suitable (C3-C8) cycloalkyl groups are particularly represented as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. These groups may be optionally substituted as described in the definition of R3. Examples of substituted (C3-C8) cycloalkyl include 2-methylcyclohexyl, 3-methylcyclohexyl, 4-methylcyclohexyl, 5-methylcyclohexyl, 6-methylcyclohexyl, 2- Hydroxycyclohexyl, 3-hydroxycyclohexyl, 4-hydroxycyclohexyl, 5-hydroxycyclohexyl, 6 -14- (11) 200307545 monohydroxycyclohexyl, 2 ~ fluorocyclohexyl, 3-fluorocyclohexyl, 4 ~ Fluorocyclohexyl, 5-fluorocyclohexyl, 6-fluorocyclohexyl, 2-methyl-3-hydroxycyclohexyl, 2-methyl 4-hydroxycyclohexyl, 2-methyl 4-methylcyclohexyl ......Wait.

In the above general formula (1), the heteroaryl system represents a monocyclic or polycyclic aromatic system having 5 to 14 member rings, which may contain i, 2, 3, 4 or 5 heteroatoms' ends Depends on the number and quality of all members. Examples of heteroatoms are nitrogen (N), oxygen (0) and sulfur (S). If they contain several heteroatoms, they may be the same or different. Heteroaryl groups may also be unsubstituted, mono- or poly-substituted, as defined by R3 and r4 in the general formula (丨) of the present invention. Preferably, the heteroaryl group is a monocyclic or bicyclic aromatic group containing 1, 2, 3 or 4, especially 1, 2 or 3, the same or different heteroatoms selected from N, 0 and S base. More preferably, the heteroaryl group is a monocyclic or bicyclic aromatic group having 5 to member rings, especially containing (i) 1 to 4 nitrogen heteroatoms or (or 2 nitrogen heteroatoms and 1 oxa) Atom or sulfur heteroatom or

(ill) A 5-membered ring to a 6-membered ring monocyclic square group group of 1 or 2 oxygen or sulfur heteroatoms. Examples of suitable heteroaryl groups include derivatives derived from pyrrole, furan, furazine, thirat, midan, pyrawa, oxazoline, isoxazole, thiazole, isothiazoline, tetrazoline, tri-xiao, hydrazone Dipyridine, pyridazine, pyrimidine indole, indazole, purine, naphthyridine, phthaloline, D quinazoline, carboline, and these such as benzofuran, benzothiophene, phenanthrene, pyridazine, indazine Benzyl hydrazone fused derivatives of Indole, Indazine, Dazine, Df morpholine, Isoquinoline, quinoxa # aryl, 1 oxazole and 1 oxazole. 1,2,3-triazolyl, 1, fluorenyl oxazolyl, thiazolyl, iso is more preferably selected from pyrrolyl, pyrazolyl, 2,4-triazolyl, tetrazolyl, oxazole Radical, -15- (12) (12) 200307545 thienyl radical, 1,2,4-dioxo-D radical, 1,3,4--dioxo-dicyclyl, furanyl, thienyl,卩 DD, 基 晓 基, pyrimidine 定, and 卩 晓 晓. Azaaryl groups can also exist as N-oxides or quaternary salts. In the general formula (1) as in the present invention, when the group is substituted by-or more-, the (etc.) substituent may be positioned at any desired position. Meanwhile, when the groups are multi-substituted, the substituents may be the same or different. Nicotinamide derivatives of the general formula (1) can be prepared using conventional procedures, for example by the following method, wherein unless otherwise indicated, R !, R2, R3, R4, X, fluorene, η and m are as previously defined in relation to the nicotinamide derivative of formula (1). Nicotinamide derivatives of formula (1) can be prepared starting from compounds of formula (2):

-16- (13) 200307545, at room temperature in the presence of organic solvents (such as dimethylformamide) and organic bases (such as N-methylmorpholine), the chemical formula ( 2) The compound is reacted with a corresponding R4-carboxylic acid derivative (R4COOH or R4 S02NH-CH2-COOH or R4C (0) NH-CH2-COOH). The activation of this acid can be achieved by using the following compound examples: a) 1-hydroxybenzotriazole and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, b) Carbonyldiimidazole, or c) chloramphenicol and dimethylformamide (using dichloromethane as the solvent). When Y is expressed as a partial chemical formula (1. The compound of the formula (2) is reacted with carbonyldiimidazole, and the obtained intermediate product is reacted with an amine having a substituent R4. It must be emphasized that when R3 and iU in the nicotinamide derivative of chemical formula (1) represent benzene rings substituted with alkoxy groups, these structures can be protected by using some skilled artisans who know well The compound converted into the hydroxy analogue (chemical formula (2)) can be prepared by removing the protecting group and 'Port' from the compound of the following formula (3) using deprotection conditions known to those skilled in the art: 〇

r3

(3) \ prot where R], r2, X, r3, n, and m are as described in the chemical formula (1) (14) 200307545 Alkalamide derivatives, and Port is a suitable protecting group, which Including but not limited to compounds of formula (3) benzyl, carbamate (such as tertiary-butoxycarbonyl), amidine (such as trifluoroacetamide), or amidine (such as phthalimide) It can be prepared by the following process 1:

(3)

Scheme 1 wherein R !, R2, X, R3, η, m and Port are as described above, and R / represents (C! -C4) alkyl. In a typical step, the smoke of chemical formula (6) can be made at room temperature to 100 ° C in a suitable solvent containing a base such as carbonic acid (such as dimethylformamide or di-Df). The basic acid ester reacts with an alcohol, thiol or amine of the chemical formula RgXH (7) to form a compound of the chemical formula (5.1). This substance can be saponified with alkali-hydroxide to form an acid of the formula (4.1), and then use -18- (15) 200307545 to use one of the activators as mentioned earlier [ie, a] 1-hydroxyl Phenyltriazole and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride or b) carbonyldiimidazole or c) oxadiazine and dimethylformamide (as Dichloromethane as the solvent)] can be converted into the compound of the formula (3) by reacting with the monoprotective diamine of the following formula (8):

(8) Η

Prot According to another scheme, the compound of formula (3) can also be prepared as shown in Scheme 2 = 〇

〇

0H (6)

Prot

-19- 200307545 where R], R2, X, R3, η, ni, R〆 and Port are as described above. In a typical step, a nicotinic acid ester of the formula (6) can be hydrolyzed to a nicotinic acid of the formula (5 · 2) using an alkaline metal hydroxide, and then one of the activators as mentioned above can be borrowed. Let it react with the monoprotected diamine of chemical formula (8). At room temperature to 1⑽ ° C and in a suitable solvent containing a base such as carbonic acid (such as dimethylformamide or dioxane), the chloro group of formula (4 · 2) obtained in the previous step Pyridine is reacted with an alcohol, thiol or amine of the chemical formula R3XH (7). The compounds of the formulae (6) and (7) have been commercialized, or they can be prepared by the usual procedures known to those skilled in the art. The mono-protected diamine of the chemical formula (8) can be obtained by making an excess of the diamine of the following formula (9) at room temperature and in a suitable solvent (such as dichloromethane):

(Wherein m and η are as defined above) are prepared by reacting with a suitable derivatizing agent ' such as a di-third-butyldicarboxylic acid ester which can form a third-butoxycarbonyl derivative. Compounds of formula (9) are commercially available or can be easily prepared by familiar procedures known to those skilled in the art. All the above reactions and the preparation of novel starting materials used in the aforementioned methods are well known, and the appropriate reagents and reaction conditions related to their operation or preparation, as well as the steps required to isolate the desired products, are all skilled in the art So-20- (17) (17) 200307545 It is known that reference can be made to the previous examples and the following examples and preparations. In the above-mentioned method for preparing a nicotinamide derivative of the chemical formula (1), it may be necessary for some steps to protect potentially reactive functions that do not want to react. In this case, any compatible protecting group can be used. For example, as disclosed by Tw GREENE (Protective Groups in Organic Synthesis, A. Wiley—Interscience Publication, 1981) or McOMIE (Protective Groups in Organic Chemistry, Plenum Press, '1933) Special method. Meanwhile, the nicotinamide derivative of the chemical formula (1) and the intermediate product at the time of its preparation can be purified according to various known methods, such as crystallization or chromatography. According to the general form of the present invention, the nicotinamide derivative of the chemical formula (1) as described above is preferably one that excludes the following compounds: 1) m is not 0, and Y represents a part of the chemical formula (1 · 5 ) 'And R4 represents unsubstituted (C! -C4) alkyl, 2) m is equal to 0, while Y represents chemical formula (1.5), and R4 represents phenyl optionally substituted with 1 to 3 substituents , Naphthyl or heteroaryl 'and these substituents may be independently selected from carboxylic acid, halo, cyano, (C! -C4) alkyl, (-C4) alkoxy, (C) -C4) halogen Alkyl, hydroxy, and hydroxy (Cl — C4) alkyl, or R4 represents a (C i-C4) alkyl group optionally substituted with a hydroxy, carboxylic acid, or heteroaryl group, and they are optionally selected from 1 to 3 independently selected from carboxylic acid, halo, cyano, (C) -O) alkyl, (: C! -C4) alkoxy, hydroxyl and hydroxy (C! -C4) alkyl substituted (18 ) 200307545 group substitution, and 3) m is equal to 0, while Y represents a partial chemical formula (1 · 6) 'and R4 represents a phenyl or naphthyl group, each of which is optionally selected from 1 to 3 independently selected from a carboxylic acid , Halo, Group, (C -! C4) hospital group, (C -! C4) oxy hospital, (C]-C4) haloalkyl, hydroxy and hydroxy - substituted group of hospital-yl (Cl C4) group. More preferred is the threonamide derivative of the following chemical formula (1),

Middle: ❖ m and η are equal to 1 ′ ❖ Ri and R2 each represent a group independently selected from a hydrogen atom, a halogen group, a cyano group, a (Cl_C4) alkyl group and a (Ci-C4) alkoxy group, and X represents one. 1, R3 represents a group selected from: (a) phenyl, naphthyl, heteroaryl, and (C3-Cs) cycloalkanes each of which is optionally substituted with 1 to 3 substituents, and each ~ such as The substituent is selected from halo, cyano, (C! —C4) alkyl, (Ci—Cdp

Armoxy, (C! —C4) sulfanyl, —C (= 〇) NH2, —C (= 0) NH ((Ci—Cj alkyl), hydroxyl, —0—C (= 〇) (Ci — C 4) courtyard, C4) alkyl-c (= 0)-o- (C! —C4) alkyl and hydroxy, or (b) one or two of the following structures (K " to ㈧.4) ring

-22- (19) 200307545

(1.1) (1.2) (1.3) (1.4) where the symbols', * 〃 represent the connection points of each part of the chemical formula (1.1.) To (1. 4) connected to the rest of the chemical formula (1),

Y represents one of the partial chemical formula (1.5) C (= 0) -group '♦ and R4 represents a group selected from: (a) phenyl, naphthyl, and heteroaryl, each of which is optionally selected from 1 to 3 substituents are substituted, and each substituent is selected from carboxylic acid, c (-〇) ~ o- (c) -C4) alkyl group, halo group, gas group, c (= 〇) nh2, (〇 Plant (: 4) alkyl, (Ci-C #) alkoxy, (Ci-C4) haloalkyl, hydroxy and hydroxyalkyl, or (b) via hydroxy, carboxylic acid, C (= 0)-0 — (c)-c 4) alkane

(G-C4) alkyl substituted with phenyl, phenyl, naphthyl or heteroaryl, wherein each of the phenyl, naphthyl and heteroaryl is optionally substituted with 1 to 3 substituents, and each ~ The radical is selected from the group consisting of carboxylic acid, C (= 0) 0 (C) -c4), halo, cyano, c (= o) nh2, (c) -c4), and (Cl-C4) Alkoxy, (Cl — C4) haloalkyl, hydroxy and hydroxy (C 1 -C 4) alkyl, or, if appropriate, 'are their pharmaceutically acceptable salts and / or isomers, interconversions Body, solvate, polymorph, isotope variant, or other metabolite. Even more preferred is the nicotinamide derivative of the following chemical formula (1), -23- (20) (20) 200307545 where: m and η are equal to 1, and R! And R2 are each independently selected from a hydrogen atom , Halo and methyl, < ♦ X represents -0-, ♦ > R3 represents phenyl optionally substituted with 1 to 3 substituents, and each substituent is selected from halo, cyano, (C! -C4) alkyl, (C! —C4) alkoxy, (C! —C4) sulfanyl, —C (= 0) NH2, —C (= 0) NH ((Cj-C4) Alkyl), hydroxy, —O—C (= 0) (Ci—C4) courtyard, -C (= 0) — Ο- (C! — C4) alkyl and hydroxy (Ci-C4) alkyl, ❖ Y represents a C (= 0) -group of one of the partial chemical formula (1.5), ♦ > and R4 represent a group selected from: (a) optionally selected from 1 to 3 selected from carboxylic acids, C (= Ο ) — 0— (Ci— C4) courtyard, halo, amino, -C (= 0) nh2, (Ci-c4) alkyl, (c! — C4) alkoxy, (C! — C4) halogen Alkyl, hydroxy and hydroxy (C) -c4) alkyl substituted phenyl, or (b) (c! -C4) alkyl substituted with hydroxy or phenyl, wherein the phenyl is optionally 1 to 3 Substituents are substituted, and each substituent is selected from the group consisting of carboxylic acid, C (= 0) 0 (Ci-C4) alkyl, halo, cyano, —C (= 0) NH2, (G-C4) alkyl Or (Ci—C4) alkoxy, (C] -C4) haloalkyl, hydroxy, and hydroxy (C! —C4) alkyl, or, if appropriate, their pharmaceutically acceptable salts and / or -24- (21) (21) 200307545 Isomers, tautomers, solvates, polymorphs, isotopic variants or other metabolites. Still more preferred is the nicotinamide derivative of the following formula (1), where: m and η are equal to 1, < ♦ R] represents a hydrogen atom or a fluoro group, and R2 represents a hydrogen atom 'X represents -0 -, R3 represents a phenyl group optionally substituted with a substituent selected from a halogen group and a C (= 0) —O— (C! —C4) alkyl group, ♦ > Y represents a part of the chemical formula (1.5) A c (= 0) -group, < ♦ and r4 represent a group selected from: (a) optionally through 1 to 3 substituents selected from halo, (C! -C4) alkyl and hydroxyl Substituted phenyl 'or (b) (C! -C4) alkyl substituted with hydroxyl or phenyl, wherein the phenyl is optionally substituted with 1 to 3 selected from halo, (C) -C4) alkyl And hydroxyl substituents, or, if appropriate, their pharmaceutically acceptable salts and / or isomers, tautomers, solvates, polymorphs, isotopic variants, or their metabolites. A particularly preferred nicotinamide derivative of the chemical formula (1) is illustrated by the following example, that is: 2- (4-fluoro-phenoxy) -N- {4-[(2-hydroxy-3 — Methyl monobenzylamine) monomethyl] monobenzyl} mononicotinyl amine '3 — (3- {4— [(3 —hydroxymonobenzylamino) —methyl] —- 25- (22) (22) 200307545 benzylaminomethyl}}-pyridine-2-yloxy) monobenzoate, 2- (4-fluoromonophenoxy) -N- {4- [ (6-fluoro-2-hydroxy-benzylamine) monomethyl] -benzyl} mononicotinamide, 2- (4-fluoromonophenoxy) -N- {4-[( 5 —Fluoro-2 —Hydroxy-benzylamino] -methyl] -benzyl} mononicotinylamine, 2- (4-fluoro-phenoxy) —N— {4-[(3 —Hydroxy-4—methyl-benzylamido) monomethyl] -benzyl} mononicotinamide, 2- (4-fluorofluoro-phenoxy) —N_ {4-[(3-hydroxy Monobenzylamine) monomethyl] -benzyl} mononicotinylamine, 2- (4-chloromonophenoxy) -N- {4— [(2-meryl-benzylamine Methyl) -methyl]- Benzyl} mononicotinylamine, 2- (4-fluoro-phenoxy) -N- {4 -— [(4-hydroxy-benzylamino) -methyl] -benzyl} -nicotinyl Amido, 2- (4-chloro-phenoxy) -N — {4 -— [(2-—methyl-benzylamino) -methyl] -benzyl} -nicotine Hydrazine, 2- (4-fluoro-phenoxy) -N- {4 -— [(3-hydroxy-2-methyl-benzylamine) -methyl] -benzyl} mononicotine Amine, 2- (4-fluoro-phenoxy) -N- {4 -— [(2-hydroxy-5—methyl-benzylamino) -methyl] -benzyl} mononicotinamide , 5-fluoro-2- (4-fluoro-phenoxy) -N-{4-[[2-hydroxy-benzylamine] -methyl] -benzyl} -nicotinylamine, 5-Fluoro-2— (4-fluoromonophenoxy) -N— {4 — [(2-hydroxy-ethylamido) -methyl] -benzyl} mononicotinamide, 5 — Fluoro-2- (4-fluoro-phenoxy) -N- {4-a [(4 — -26-(23) 200307545 hydroxy-benzylamino) -methyl] -benzyl} —smoke Amidoamine, 3 — (3 — {4— [(3 — -Benzylamino) monomethyl] -benzylaminomethylamidino} -pyridine-2-yloxy) monobenzoate, 3-(3-{4— [(2 -hydroxyl-benzene Ethylamido) -methyl] -benzylaminomethylamidino} -pyridine mono-2-yloxy) monobenzoate, 3- (3 — {4— [(3-hydroxy-phenylethylamidoamine) Group) -methyl] -benzylaminomethylamidino} -pyridine- 2-yloxy) -ethyl benzoate, 3- (3- {4— [(4-hydroxy-phenylethylamidino)) Methyl] -benzylaminomethylamidino} -pyridine-2-yloxy) -ethyl benzoate, the nicotinamide derivatives of formula (1) can also be optionally converted into pharmaceutically acceptable salts . In particular, the pharmaceutically acceptable salts of these nicotinamide derivatives of formula (1) include their acid addition salts and base salts. Suitable acid addition salts are inorganic or organic non-toxic acids ( Can form non-toxic salts). Suitable examples of these acid addition salts include hydrochloride, hydrobromide, hydroiodide, sulfate, hydrogen sulfate, nitrate, phosphate, hydrogen phosphate, acetate, maleate, fumarate , Lactate, tartrate, citrate, gluconate, succinate, gluconate, benzoate, mesylate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate And parabens. Suitable alkali salts are formed from bases which form non-toxic salts, such as alkali metal salts, alkaline earth metal salts, or addition salts with ammonia and physiologically tolerable organic amines. Suitable examples of these alkali salts include sodium, potassium, aluminum, calcium, magnesium, zinc, or ammonium salts, and with triethylamine, ethanolamine, diethanolamine, -27- (24) (24) 200307545 trimethyl Amine, methylamine, propylamine, diisopropylamine, N, N-trimethylethanolamine, benzylamine, dicyclohexylamine, N-benzyl-1 / 3-phenylethylamine, n, N, dibenzylethylenediamine Amine, diphenyldiamine, quinine, choline, arginine, lysine, leucine, dibenzylamine, tris (2-hydroxyethyl) amine, or alpha, alpha, alpha, tris (hydroxy Methyl) methylamine addition salt. Compounds containing acidic and basic groups may also exist in the form of internal salts or betaines, and they are also encompassed by the present invention. For suitable salts, see J. Pharm. Sci., Berge et al., 1997, No. 66, pp. 1-19. In general, it can be prepared from other salts according to customary procedures known to those skilled in the art, such as by combining with organic or inorganic acids or alkaline solvents or dispersants, or additionally by anion exchange or cation exchange Such salts are prepared from nicotinamide derivatives of chemical formula (1). The salt can also be precipitated from the solution and collected by filtration or recovered by evaporation of the solvent. The nicotinamide derivative of the formula (1) may also exist in the form of a stereoisomer. If the nicotinamide derivative of the chemical formula (1) contains one or more asymmetric centers, these may have (S) configuration or (R) configuration independently of each other. The invention includes all possible stereoisomers of nicotinamide derivatives of chemical formula (1), for example, enantiomers and diastereomers, and two or more stereoisomeric forms. Mixtures, such as mixtures of enantiomers and / or diastereomers in all ratios. Accordingly, the present invention relates to purely enantiomeric forms (such as the left and right enantiomers), the racemate form, and the two enantiomeric mixture forms in all ratios-28- (25) (25 ) 200307545 enantiomer. Similarly, the present invention relates to diastereomers in the form of pure diastereomers and mixtures in all ratios. Among the cis / trans isomerisms, the present invention relates to cis and trans morphologies and a mixture of these morphologies in all ratios. If necessary, it can be obtained by using stereochemically homogeneous starting materials in the synthesis, and by stereoselective synthesis or according to conventional methods such as chromatography, crystallization, or chromatography on the palm phase. Separation to obtain individual stereoisomers. If appropriate, a derivatization reaction may be performed before the stereoisomers are separated. Stereoisomers can be separated at the nicotinamide derivative stage of the chemical formula (1), or at the stage of starting materials or intermediate products of the synthetic process. Furthermore, the compound of formula (1) according to the present invention contains a movable hydrogen atom, that is, it exists in various tautomeric forms. The invention also relates to all tautomers of compounds of formula (1). In addition, the present invention may include other forms of derivatives of the nicotinamide derivative of the chemical formula (1), for example, solvates (such as hydrates) and polymorphs, that is, the nicotinamide derivatives of the present invention Of various crystal structures. The present invention also includes all isotopic variations of nicotinamide derivatives of formula (1) or pharmaceutically acceptable salts thereof. An isotope variant of a nicotinamide derivative of the chemical formula (1) or a pharmaceutically acceptable salt thereof is defined in which at least one atom can be replaced with an atom having the same number of atoms but an atomic weight different from that actually found. Examples of isotopes of nicotinamide derivatives and chemically acceptable salts thereof that can be incorporated into chemical formula (1) include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, and chlorine. For example, each is -29. -(26) 200307545 2H, 3H, 13c, 14C, 15N, 170,] 80, 35S, 8F and 36CI. Nicotinamide derivatives of formula (1) and certain isotopic variants of their pharmaceutically acceptable salts, such as those in which a radioisotope such as 3H or 14C is incorporated, can be effectively used for medicines and / or tissues Study of distribution. Since isotopes containing tritium (ie, 3H) and carbon-14 (ie, I4C) isotopes are easier to prepare and detectable, they are better. Furthermore, those who are replaced with deuterium, which is an isotope of 2 tritium, can also provide certain therapeutic advantages derived from greater metabolic stability. For example, it can increase the half-life in vivo or reduce the dose requirement, and in some cases, Is more favorite. The nicotinamide derivative of the chemical formula (1) of the present invention and an isotopic variant of a pharmaceutically acceptable salt thereof can usually be prepared by using appropriate isotopic variant reagents and using conventional procedures, such as the following examples herein And prepared by the illustrative method and preparation method described in the preparation. Where appropriate, the present invention also relates to active metabolites of nicotinamide derivatives of formula (1), that is, derivatives that are formed during cell metabolism and are active on the organism. For example, such a metabolite may be a glucuronide derivative, an N-oxide derivative, or a sulfonate derivative of a compound of formula (1). According to another aspect, the present invention relates to a mixture of nicotinamide derivatives of formula (1), and their pharmaceutically acceptable salts, solvates, polymorphs, isomers, metabolites, and And / or a mixture of isotopic forms. According to the present invention, all the forms of the nicotinamide derivatives of the chemical formula (1) mentioned above, except for pharmaceutically acceptable salts (that is, these solvents -30- (27) (27) 200307545 compounds, and more Crystalline form, isomer form, tautomer, metabolite and / or isotope form) are all defined as the `` derivation '' of threonamine derivative of chemical formula (1) described below (covering the scope of patent application) form〃. The composition of the present invention can be prepared by methods well known to those skilled in the art. When the composition of the present invention is a simple aqueous and / or other solvent solution, the various components of the entire composition can be combined in the order of practical experience, and most of them are for convenience. It is possible to dissolve those components which have lower water solubility but have sufficient solubility in the same subsolvent solution combined with water, and then add this subsolvent solution to the aqueous part of the carrier At this time, the solute inside it will become dissolved in water. To assist this dispersion / dissolution process, a surfactant can be used. The nicotinamide derivatives of the chemical formula (1), their pharmaceutically acceptable salts and / or derivative forms, and the composition of thioxanthene or its derivatives can be applied to the treatment and prevention of a variety of PDE4 involved Disorders of enzymes and betaine receptors, especially inflammatory, allergic and respiratory diseases. The above-mentioned nicotinamide derivatives of chemical formula (1), and their pharmaceutically acceptable salts and derived forms, and thiazepine or their derivatives can be administered to animals as pharmaceuticals according to the present invention, preferably The ground is mammal, especially human, for treatment and prevention. They may be administered by themselves, or may be administered in the form of pharmaceutical preparations which are administered to mammals to be treated and which also contain customary pharmaceutically non-toxic excipients and / or additives. Accordingly, the present invention also relates to nicotinamide derivatives and / or their pharmaceutically acceptable salts and / or derivative forms containing a sufficient amount of at least one chemical formula (1) as defined above, and The composition of a gun or its derivative (28) (28) 200307545, plus a conventionally used pharmaceutical composition with non-toxic excipients and / or additives. Such compositions can be prepared according to known methods compatible with standard pharmaceutical practice. The composition usually contains 0.5% to 60% by weight of the active compound and 40% to 99.5% by weight of excipients and / or additives. According to the present invention, such excipients and / or additives are agents known to those skilled in the art, which can provide advantageous properties in the final pharmaceutical composition. Typical excipients and / or additives include, but are by no means intended to be limited to, acidifying and basifying agents, aerosol propellants, antimicrobial agents (including antibacterial, antisaccharid, and protozoan agents), Oxidants, buffers, chelating agents, dermatologically active agents, dispersants, suspending agents, demulsifiers, emulsifiers, penetration enhancers, preservatives, insulating agents, solvents, stabilizers, viscosity agents, sugars, surfactants , And flavoring agents. Moreover, the compositions can be prepared in a form compatible with the route of administration for the appropriate disease, symptom, or condition of the particular patient and the patient being treated. Appropriate routes of administration that can be addressed include intranasal and pulmonary routes. The nicotinamide derivative of the chemical formula (1), their pharmaceutically acceptable salts and / or derivative forms, and the composition with the thiocarbamate or their derivatives are preferably administered intranasally or by inhalation. It is more convenient to use a dry powder inhaler or aerosol spray from a pressurized container, pump, sprayer, spray bottle or sprayer, and it is delivered with or without the use of a suitable propellant. A suitable propellant is dichloride. Difluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, hydrofluoroalkane, such as 1,1,1,2, tetrafluoroethane (HFA 134A [trade name]) or 1,1,2,3, 3,3-Heptachloropropane (HFA 2 27ΕΑ [brand name]), carbon dioxide or other suitable gas. In the case of pressurized -32- (29) (29) 200307545 aerosol, the dosage unit can be measured by providing a valve to deliver the metered amount. Pressurized containers, pumps, sprayers, spray bottles or sprayers may contain solutions or suspensions of the active compounds, i.e. using a mixture of ethanol and propellant as a solvent, they may additionally contain lubricants such as sorbitol tri-oil Acid ester. Capsules and films for use in inhalers or insufflators (eg, made from gelatin) can be formulated to contain nicotinamide derivatives of formula (1) and suitable powder bases such as lactose or starch. The powder mixture. The aerosol or dry powder preparation is preferably arranged so that each metered dose or `` one puff of tobacco contains 1 microgram g) to 4000 micrograms of the nicotinamide derivative of formula (1) may be Delivered to the patient. The total daily aerosol enzyme dosage is in the range of 1 microgram to 20 milligrams, which can be administered in a single dose or, more often, in multiple doses throughout the day. The various pharmaceutical preparations described above are also detailed in A. Lehir's vv Pharmacie galenique "(Ed. Mason, 1992, Second Edition). A physician in any department will measure the most suitable for any individual patient The actual dosage, which will vary with age, weight, health status, and sex of the patient, as well as the severity of the disease, the condition or condition to be treated, alternative compositions with other therapeutic agents, patient-specific responses, and general It varies depending on the disease, disorder or condition of interest and any rare factors for the patient. Therefore, the daily dosage of enzymes in men usually contains 50 mg to 5 grams of active compound, which can be used once or if appropriate Two or more administrations. Of course, there are also individual examples where higher or lower dosage ranges are beneficial, and this is also within the scope of the present invention. (33) (30) (30) 200307545. According to the present invention, the present invention The composition can also be used in combination with cyclodextrin. Cyclodextrin is known to form inclusion or non-inclusion complexes with drug molecules. The formation of drug-cyclodextrin complexes can modify the dissolution of drug molecules Degree, dissolution rate, biopharmaceutical efficiency and / or stability. In general, drug-cyclodextrin complexes can be used in most dosage forms and routes of administration. In addition to direct drug complexes, cyclodextrin can also be used As auxiliary additives such as carriers, diluents or solubilizers. Α-, / 3-, r-cyclodextrin is the most commonly used 'and suitable examples are disclosed in International Publication Application WO-A-91 / 11172 Case number, case number WO- A-94 / 02518 and case number WO- A-98/5 5 1 4 8. As used herein, the term `` combination '' is intended to mean and covers the following: When nicotine The components of the amine derivative and therapeutic agent composition are formulated together to form a single dosage form, so that these components are released at almost the same time to the patient in need of treatment, and the combination is simultaneously When administered to the patient, when the components of the nicotinamide derivative and the therapeutic agent composition are separately formulated into different dosage forms, the patients in need of treatment can take the drug at almost the same time, and the When the same components are released to the patient almost at the same time, combine this one The drug was administered to the patient at almost the same time. • When the components in the nicotinamide derivative and the therapeutic agent composition are formulated separately from each other into different dosage forms, the patients in need of treatment can The medication is taken continuously within a significant interval between administrations, and these components are released to the patient at substantially different times, in a sequence of several -34- (31) (31) 200307545. When administered to the patient, • When the components of the nicotinamide derivative and the therapeutic agent composition are formulated together to form a single dosage form that can release these components in a controlled manner, Patients in need of treatment can be administered to the patient in sequence when the medicine is taken at the same time and / or at different times, continuously, and / or overlapping. It is important to recognize that all treatment-related in this article includes treatments for healing, alleviation, and prevention. Since the isoenzymes of the PDE4 family play a fundamental role in the physiology of all mammals, and the nicotinamide derivative of formula (1) can inhibit the PDE4 isoenzymes, it exhibits a broad range as further explained below Therapeutic applications. The enzymatic task performed by the PDE4 isoenzyme is to perform intracellular hydrolysis of adenine nucleoside 3 /, 5 /-phosphate (c A MP) in primary inflammatory white blood cells. Sequentially, c A MP is responsible for mediating the effects of most hormones in the body, so PDE4 inhibition plays a significant role in various physiological processes. A wide range of literature in this art reveals the effects of PDE inhibitors on various inflammatory cell responses. In addition to increasing cAMP, it also includes the inhibition of superoxide production, cell degranulation, chemotaxis, and eosinophils, neutrophils. The release of tumor necrosis factor (TNF) in sex cells and monocytes. Therefore, another aspect of the present invention relates to the use of the composition of the present invention to treat diseases, disorders, and conditions involving PDE4 isoenzymes and muscarinic receptors. More specifically, the present invention is also related to the use of the composition of the present invention -35-(32) (32) 200307545 to treat diseases, disorders and conditions selected from the following: • Any form, etiology, or pathogenesis Asthma, particularly selected from the group consisting of hereditary allergic asthma, non-hereditary asthma, asthma, allergic asthma, hereditary allergy, bronchial IgE-mediated asthma, bronchial asthma, essential asthma, True asthma, intrinsic asthma due to pathophysiological interference, extrinsic asthma due to environmental factors, essential asthma due to unknown or insignificant causes, asthmatic asthma asthma, bronchial asthma, emphysema Asthma, exercise-induced asthma, allergen-induced asthma, cold-air-induced asthma, occupational asthma, infectious asthma due to bacteria, fungi, protozoa, or viral infection, non-allergic asthma, initial asthma And infantile syndrome of asthma: chronic or acute bronchoconstriction, chronic bronchitis, small airway obstruction, and emphysema, Obstructive or inflammatory respiratory disease of any morphology, etiology, or pathogenesis, especially selected from the following obstructive or inflammatory respiratory diseases: chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD) COPD that induces chronic bronchitis, emphysema or dyspnea associated therewith, COPD characterized by irreversible and progressive airway obstruction, adult respiratory distress syndrome (ARDS), and hyperrespiratory tract caused by other medications Deteriorating reactivity, • Pneumoconiosis of any morphology, etiology, or pathogenesis, especially selected from the group of pneumoconiosis. • Aluminium pneumoconiosis or bauxite worker lung disease, coal lung disease or miner asthma 'asbestosis or steam assembly Asthma, stone debris into the lung or stone -36- (33) (33) 200307545 Terminal lung disease, eyelash loss caused by inhalation of dust from ostrich feathers, end of pulmonary iron deposit caused by inhalation of iron particles, silicosis Disease or miller pneumonia, cotton fiber aspiration pneumonia or cotton dust asthma and talc pneumoconiosis, bronchitis of any form, etiology, or pathogenesis, Specifically selected from the following: bronchitis: acute bronchitis, acute laryngotracheobronchitis, bronchitis caused by groundnuts, nasal mucositis inflammatory bronchitis, floating membrane bronchitis, dry bronchitis, infectious asthmatic bronchitis, productive Bronchitis caused by bronchitis, staphylococcus or streptococcus, and vesicular bronchitis, bronchiectasis of any morphology, etiology, or pathogenesis, especially selected from the following: bronchiectasis, cylindrical bronchiectasis, Cystic bronchiectasis, spindle bronchiectasis, hairy bronchiectasis, cystic bronchiectasis, dry bronchiectasis, and follicular bronchiectasis, seasonal allergic rhinitis or year-round allergic disease of any morphology, etiology, or pathogenesis Rhinitis or sinusitis, especially sinusitis selected from: purulent or non-purulent sinusitis, acute or chronic sinusitis, and ethmoid bone, frontier, maxilla, or wedge-shaped sinusitis, • any form, Etiology, or pathogenesis-related disorders associated with eosinophils, especially selected from the group consisting of Conditions associated with eosinophilia: increased eosinophilia, increased osmotic eosinophilia in the lungs, Ruffler's syndrome, chronic eosinophilic pneumonia, tropical eosinophilia, bronchopulmonary aspergillosis, aspergillosis , Granuloma with eosinophils, allergic granulomatous lymphangiitis, or Chiirg-Strauss syndrome, nodular polyarteritis (PAN), and systemic necrosis-37- (34) (34 ) 200307545 Fatal vasculitis, • Pulmonary hypertension of any form, etiology, or pathogenesis, including primary pulmonary hypertension / essential hypertension, secondary pulmonary hypertension due to congestive heart failure, causes Chronic obstructive pulmonary disease, secondary pulmonary hypertension, pulmonary disease, venous hypertension, pulmonary artery pressure and hypoxic-induced pulmonary hypertension, and infectious diseases, especially those caused by viral infections, among which Will increase the production of TNF-α in the host, or such viruses are sensitive to the upregulation of TNF-α in the host so that their replication or other vitality is adversely affected, The selected virus included is the HI V - 1, HIV - 2, and HIV - 3, cytomegalovirus, influenza virus, adenovirus, and herpes zoster and herpes simplex cover of herpes virus. Another aspect of the present invention relates to the use of the composition of the present invention for the manufacture of a medicament having PDE4 inhibitory activity and antispinopterin activity. In particular, the present invention relates to the use of the composition of the present invention to produce a medicament for treating inflammatory, respiratory and allergic diseases, disorders, and conditions. More precisely, it treats the diseases, disorders, and conditions listed above. Therefore, the present invention provides a particularly interesting method of treating mammals (including humans) with a combination of a PDE4 inhibitor and thiotoxamine, which includes treating the composition with an effective amount of the composition of the present invention. mammal. More precisely, the present invention provides a particularly interesting method for treating inflammatory, respiratory and allergic diseases, disorders, and conditions in mammals, including humans, which includes an effective amount of a chemical formula ( i) a combination of a threonine derivative, a pharmaceutically acceptable salt thereof, and / or a derivative form of -38- (35) 200307545 and thiazepine or its derivative to treat the mammal. The following example illustrates the preparation of a nicotinamide derivative of the chemical formula (1): [Embodiment] Example 1: 2— (4-fluoromonophenoxy) —N— {4-[(2 — Hydroxy- 3 -methyl-benzylamine) monomethyl] 1-methyl} monoamine

At room temperature and under a nitrogen atmosphere, stir a mixture containing 2-hydroxy-3-methylbenzoic acid (118 mg, 0.7 73 mmol), 1 mile of 3-hydroxybenzidine (157 mg, 1.16 mmol), 1 — (3-dimethylaminopropyl) -3 monoethylcarbodiimide hydrochloride (193 mg, ι · 〇ιmmol), N— (4-aminomethyl monobenzyl) —5 —Fluoro- 2-(4 monofluoro-phenoxy) -nicotinamide hydrochloride (300 mg, 0.773 mmol) (prepared by Daco 3) and N-methylmorpholine (0.17 ml, 1.55 mmol) of N, N-dimethylformamide (6 ml) for u hours. This mixture was then partitioned between ethyl acetate (10 ml) and water (10 ml). The organic layer was separated, washed with a saturated aqueous solution of sodium chloride (10 ml), and dried over anhydrous magnesium sulfate. Then, the solvent was removed in vacuum and the residue was milled with ether (3 times 10 ml) to obtain 2- (4-fluoro-monophenoxy) -N — {4 — [( 2-mono-39- (36) 200307545 hydroxy-3-methyl-benzylamine) -methyl] -benzyl} -nicotinamide (80 mg). ] H NMR (300MHz ^ DMSO-d6): 5 = 13.11 (lH, s), 8.32-8.42 (lH, m), 8.15-8.21 (lH, m), 8.08-8.14 (lH, d) , 7.66— 7.75 (lH, m), 7.10—7.60 (10H, m), 6.73— 6.81 (lH, t), 4.37-4.56 (4H, m),

2.16 (3 H »s) ppni〇LRMS (thermal spray type): m / z [M + H] +486, [M + NH4 广 503 Example 2-1 5 By the similar method of Example 1 and using appropriate Amines and carboxylic acids were used as starting materials to prepare the compounds of the examples of the following general formula (Table 1

-40- (37) 200307545

Table 1 Example No. Preparation of starting amine No. Ri R4 2 3 Η 3 3 Η 〇Η 4 3 Η χχ: 5 3 Η 6 6 3 Η OH 7 3 Η XT 8 3 Η OH 9 3 Η Me 10 3 Η Me OH

-41-(38) (38) 200307545 1 1], 2 6 F 4 ΟΗ 121 6 F / ^ ΟΗ 1 3!, 2 6 F χτ 1 In the processing step, the organic phase is continuously saturated with water and sodium bicarbonate Rinse in aqueous solution. 2 Purify the compound by chromatographic analysis of a flash column on silica gel and eluting with a solvent gradient of (95: 5 to 70:30, volume ratio) pentane: ethyl acetate. Example 2] HNMR (300 MHz, DMSO-d6): δ = 11.28 (lH, s), 8.86-8.92 (1Η, π, 8.73-8.85 (lH, m), 8.10-8.22 (2H, m), 7.16-7.36 (1 OH »m), 6.63-6.76 (2H, m), 4.47-4.56 (2H, d), 4.40-4.46 (2H, d) ppm. LRMS (thermal spray type): ιη / ζ [Μ + ΗΓ49〇, [Μ + ΝΗ4; Γ507 Example 3] U NMR (300MHz ^ DMSO-d6): δ di 12.20 (lH, s), 9.23-9 · 11 (1Η, πm), 8.83 — 8.92 (1Η, η), 8.17-8 · 21 (1Η, η) 8.10— 8.15 (2H, m), 7.67— 7.75 (! H, m) -42- (39) 200307545 7.18— 7.33 (10H, m), 6.86—6.96 (2H, m), 4.42—4.51 (4H, m) ppm. LRMS (thermal spray type): m / z [M + H] 4 4905 [Μ + ΝΗ4; Γ 507 Implementation Example 4] H NMR (300MHz ^ DMSO-d6): 5 2 9 · 46 (1H, s), 8.8 3-8.92 (1 H, t),

8.75— 8.82 (lH, t), 8.16— 8.20 (lH, d), 8.09— 8.14 (lH, d), 7.15—7.32 (llH, m), 7.06— 7.14 (lH, d), 4.43-4.51 (2H, d), 4.34-4.42 (2H, d), 2.13 (3H, s) ppm. LRMS (thermal spray type): m / z [M + H] +486, [M + NH4] +503 Example 5] H NMR (3 00MHz ^ CDC13): (5 =

8.54— 8.61 (lH, d), 8.23— 8.32 (lH, m), 8.17— 8.23 (lH, m), 7.61— 7.80 (lH, m), 7.35— 7.40 (2H, m), 7.02-7.30 (9H, m), 6.90— 7.00 (lH, m), 6.70-6.78 (lH, m), 4.60— 4.70 (2H, d), 4.48—4.59 (2H, d) ppm. LRMS (thermal spray type): m / z [M + H] 4472, [M + NH4] +489 Example 6] H NMR (3 00MHz ^ CDC13) · 5 = -43- (40) (40) 200307545 12.02 — 12.50 (lH, brs), 8.53— 8.70 (lH, brs), 8.10— 8.26 (2H, brs), 6.92— 7.50 (12H, m), 6.63—6.88 (2H, m), 4.56 — 4.77 ( 4H 5 2 xm) ppm. LRMS (thermal spray type): m / z [M + H] 4 472, [M + NH4 Guang 489 Example 7] H NMR (300MHz ^ DMSO-d6): 5 = 9.93 (1H, s), 8.84-8.91 (1H, t), 8.68— 8.76 (lH, t), 8.17— 8.21 (lH, ni), 8.10— 8.15 (lH, d), 7.69— 7.76 (2H, d), 7.18-7.33 (9H, m), 6.74—6.81 (2H, d), 4.44—4.52 (2H, d), 4.37-4.43 (2H, d) ppm LRMS (thermal spray type): m / z [M + H] + 472, [M + NH4] +489 Example 8 1U NMR (300MHz ^ DMSO-d6): 5 = 12.45— 12.60 (lH, brs), 9.17-9.25 (lH, t), 8.84— 8.92 (lH, t) , 8.16— 8.20 (lH, d), 8.09— 8.14 (lH, d), 7.72— 7.78 (lH, d), 7.16— 7.34 (9H, m), 6.67-6.73 (2H, m), 4.40 — 4.58 (4H 5 2 xd), 2.25 (3 H? S) ppm LRMS (thermal spray type): m / z [M + ΗΓ 486JM + NH4] 4 503 -44- (41) (41) 200307545 Examples 9 jNMROOOMHzIMSO- d6): (5 = 9.43 (lH, s), 8.87-8.96 (lH, t), 8.60-8.67 (lH, t), 8.16-8.21 (lH, d), 8.10-8.15 (lH , D), 7.28-7.34 (lH, d), 7.20-7.28 (8H, m), 6.96-7.03 (lH, t), 6.80— 6.86 (lH, d), 6.73—6.77 (lH, d), 4.47—4.54 (2H, d), 4.34—4.40 (2H, d), 2.07 (3H, s) ppm LRMS (thermal spray type ): M / z [M + H] +486, [M + NH4] +503 Example 1 〇] H NMR (300 MHz ^ DMSO-d6): δ = 12.23 (1H, s), 9.18-9 · 26 (1H, t), 8.82-8.92 (lH, t), 8.15— 8.20 (lH, d), 8. 1 0-8 · 1 5 (1 H, d), 7.69 (1H, s) , 7.12— 7.34 (10H, m), 6.77-6.81 (lH, d), 4.42— 4.54 (4H, 2xd), 2.20 (3H, s) ppm. LRMS (thermal spray type): m / z [M + H] + 48 6, [M + NH4] + 503 Example 1 1] H NMR (400MHz ^ DMSO-d6): 5 = 9.24— 9.31 (1H, m ), 8.92— 9.00 (lH, m), 8.18— 8.20 (lH, d), 8.02- 8.07 (lH, dd), -45- (42) 200307545 7.83— 7.87 (lH, d), 7.35— 7.40 (lH, t), 7.18— 7.35 (8H, m), 6.83—6.92 (2H, t), 4.42—4.56 (4H, in) ppm. LRMS (electron spray type): m / z [M + Na] + 5 1 2, [M-H] + 488 Example 1 2 lU NMR (400MHz ^ DMSO-d6): δ =

8.93— 9.00 (lH, m), 8.13— 8.22 (2H, m), 8.02— 8.08 (lH, m), 7.14— 7.27 (8H, m), 5.38— 5.43 (lH, t), 4.43-4.51 (2H, d), 4.21—4.27 (2H, d), 3.79-3.84 (2H, d) ppm. LRMS (electron spray): m / z [M-H] + 426 Example 1 3 JH NMR (400MHz ^ DMSO-d6): 5 =

9.89 (1H, s), 8.90-8.9 8 (1 H, t), 8.64— 8.73 (lH, t), 8.19-8.21 (lH, d), 8.02— 8.06 (lH, dd), 7.70-7.77 (2H , D), 7.24-7.30 (2H, d), 7.17-7.23 (6H, d), 6.73-6.79 (2H, d), 4.42— 4.48 (2H, d), 4.3 6 — 4.40 (2H, d ) ppm. LRMS (electronic spraying): m / z [M + Na] + 512, [MTH] + 488. Example 1 4: 3-(3-{4-[(3 -hydroxy-monobenzylamino) -methyl-46- (43) (43) 200307545 group) -benzylaminomethylamido 丨 -pyridine Mono-2-yloxy) monobenzoate

Add 3-hydroxy-benzoic acid (27 mg, 0.19 mmol), 1-hydroxybenzotriazole (31 mg, 0.23 mmol) and 1- (3-dimethylaminopropyl) _3-ethyl Carbodiimide hydrochloride (45 mg, 0.23 mmol) was added to a solution containing 3- [3- (4-monoaminomethyl-benzylaminomethylamidino) -pyridine-2-yloxy] Ethyl monobenzoate hydrochloride (100 mg, 0.19 mmol) (Reference Preparation 9) and N, N-dimethylformamidine (N-methylmorpholine (0.11 ml, 0.97 mmol)) ( 15 ml) solution. The reaction mixture was stirred under a nitrogen atmosphere at room temperature for 18 hours, concentrated in vacuo, and the residue was partitioned between dichloromethane (20 ml) and water (20 ml). The organic layer was separated, washed with a saturated aqueous solution of sodium chloride (20 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Then, analyze the color of the flash column on the silica gel and elute with dichloromethane: methanol with a solvent gradient (99: 1 to 98: 2, volume ratio) to purify the residue. Obtained as off-white foam of 3-(3-{4-[[3-hydroxy-benzylamino] -methyl] -benzylaminomethylamidino} -pyridine-2-yloxy) -benzoic acid Ethyl ester (45 mg). NMR (400MHz, CDC13): 5 = 8.54— 8.60 (1H, d), -47-(44) 200307545 8.21— 8.38 (2H, t + brs), 8.17— 8.20 (lH, d) , 7.8 6-7.92 (1 H ^ d), 7.78 (lH, s), 7.41-7.48 (lH, t), 7.7.08-7.26 (6H, m), 6 4.6 1-4.67 (2H, d), 4. 4.30-4.37 (2H, quart) 28— 7.37 (2H, m), .8 6 — 6.9 5 (2 H, m), 45-4.53 (2H, d), 1.31— 1.38 (3H, t) ppm LRMS (electronic spray type): m / z [M + H] +526,

[M + Na] + 548, [M-H] + 524 Examples 1 5-1 8 By a similar method to that described in Example 14 and using appropriate starting materials, the compounds of the examples of the following formulae were prepared ( Table 2 ):

-48- (45) (45) 200307545 Table 2 Implementation number N ° Preparation number of the starting amine R4 15 9 χτ 16 9 OH 17 9 18 9 > 0σ0Η Example 1 5] H NMR (400MHz ^ CDC13) · δ = 8.90— 9.10 (lH, brs), 8.49— 8.53 (lH, d), 8.28— 8.34 (lH, m), 8.13— 8.16 (lH, d), 7.87— 7.92 (lH, d), 7.77 (lH , S), 7.53— 7.59 (2H, d), 7.40-7.47 (1Η, 0, 7.2 8 — 7.3 3 (1 H, m), 7. 1 4 — 7 · 2 6 (5 H, m, partially obscured by solvent), 7.08— 7.13 (1Η, 0, 6.75— 6.81 (lH, t), 6.66— 6.73 (2H, d), 4.58— 4.66 (2H, d), 4.46—4.52 (2H , D), 4 · 28-4 · 34 (2Η, quartet), 1.31—1.38 (3H, t) ppm. LRMS (electronic spray type): m / z [M + H; T 526, [M + Na] + 548, [M — H] +524 -49- (46) (46) 200307545 Example 16] ΗΝΜΙΙ (400ΜΗζ, 00 (313): 5 = 9.61 (1Η, s), 8.5 4-8.60 ( 1 H, d), 8.14-8.21 (2 H ^ m), 7.91— 7.96 (lH, d), 7.72— 7.74 (lH, m), 7.43—7.49 (lH, t), 7.29— 7.33 (lH, d ), 7.19— 7.24 (2H, m), 7.08— 7.18 (4H, m), 6.90-7.00 (2H, m), 6.73— 6.80 (2H, m), 4.58—4.63 (2H, d), 4.29— 4.39 (4H, m), 3.56 (2H, s ), 1.35—1.41 (3H, t) ppmo LRMS (electronic spray type): m / z [M + H] + 540, [M + Na] +562, [M-H] + 53 8 Example 1 7 1 H NMR (400MHz, CDC13): δ = 8.52-8.59 (lH, d), 8.19-8.25 (lH, m), 8.16-8.19 (lH, d), 7.90-7.94 (lH, d), 7.78 (lH, s) 7.44 — 7.49 (lH, t), 7.28— 7.32 (lH, d), 7.18-7.23 (2H, d), 7.04— 7.18 (4H, m) 6.64-6.73 (3H, m), 6.28— 6.35 ( lH, m), 4.58—4.66 (2H, d), 4.26— 4.38 (4H, m), 3.42 (2H, s), 1 · 3 3-1 · 3 8 (3 H, t) ppm. LRMS (electron spray type): m / z [M—H] +538 -50- (47) 200307545 Example 1 8 1 H NMR (400MHz, CDC13): 5 2 8.55— 8.61 (lH, d), 8.18— 8.23 (lH, m), 8.15— 8.18 (lH, d), 7.90— 7.94 (lH, d), 7.78 (1 H, s), 7.43 — 7.49 (1 H, t), 7.26— 7.30 (lH , D), 7.18—7.25 (2H, m), 7.04—7 ”7 (3H, m), 6.95—7.01 (2H, d), 6.64— 6.75 (3H, m), 6.17— 6.24 (lH, m) , 4.5 8-4.6 8 (2H ^ d), 4.30-4.40 (4H, m), 3.46 (2H, s), 1.32— 1.40 (3H, t) ppm LRMS (electronic spray type): m / z [M + H] + 5 40, [M + Na] +562, [M—H] + 538 The following preparation examples illustrate the preparation of certain intermediate products used in the above examples. Preparation 1: (4 monoaminomethyl monobenzyl) monocarbamic acid third monobutyl ester

〇Me Under a nitrogen atmosphere and 〇t, a solution of bis-tertiary-butyl dicarboxylate (4.62 g, 21.2 mmol) in methylene chloride (50 ml) was added to 4-amine. Monobenzylamine (14.4 g, 106 mmol) in dichloromethane (50 ml). The reaction mixture was allowed to warm -51-(48) 200307545 to room temperature and stirred for 18 hours. The reaction mixture was then continuously rinsed with water (100 ml) and 10% aqueous citric acid solution (200 ml). The pH of the aqueous layer was increased to greater than 8 by adding 0.88 ammonia water, and then extracted with dichloromethane (3 times 200 ml). Then, the combined organic extract was dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo to obtain (4-monoaminomethyl-benzyl) monoaminocarboxylic acid tri-butyl ester (4.2 9 as a white solid). G). 1U NMR (400MHz ^ CDC13): 5 2.7.2—7.26 (4H, d), 4.80—4.90 (1H, brs), 4.23— 4.30 (2H, m), 3.82 (2H, s), 1.43 (2H , S), 1.38 (2H, s) ppm. LRMS (electron spray type): m / z [M-H] +237 Preparation 2: [4 — ({[2— (4-monofluoro-phenoxy) -pyridine-3 carbonyl] -amino}}-methyl ) Monobenzyl] monocarbamic acid tri-butyl ester

At room temperature, 2- (4-fluorofluoro-phenoxy) -nicotinic acid (see patent application WO 98/45268) (6.20 g, 26 mmol), 1-hydroxyphenylhydrazone Triazole (5.39 g, 40 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride-52- (49) (49) 200307545 (6 · 62 G, 34 mmol) was dissolved in n, N-dimethylformamide (50 ml), followed by addition of n-methylmorpholine (4.4 ml, 40 mmol) and then added (4 Mono-aminomethyl-benzyl) -mono-carbamic acid tri-butyl ester (6.28 g, 26 mmol). The reaction mixture was stirred under a nitrogen atmosphere at room temperature for 18 hours, and then partitioned between ethyl acetate (1000 ml) and water (100 ml), and the organic layer was separated. Then, the organic layer was washed with a saturated aqueous solution of sodium chloride (100 ml), dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo. The residue was triturated with diethyl ether (15 ml) to obtain [4-[[2-((4-fluorofluorophenoxy) -pyridine-3-carbonyl] -amino} -methyl] as an off-white solid.) Monobenzyl] monocarbamic acid tri-butyl ester (9.52 g). H NMR (300 MHz, CDC13): δ = 8.56— 8.76 (1Η, m), 8.06— 8.14 (2Η, m), 6.96 — 7.40 (9 Η, m, partially masked by solvent), 4.58 -4.95 (3H, m), 4.20— 4.40 (2H, brs), 1.56 (9 H 5 s) ppmo LRMS (thermal spray type): m / z [M + NH4] +469 Preparation 3: N— (4- Amine methyl-benzyl)-2- (4-fluoro-phenoxy) nicotinamide amine hydrochloride

-53- (50) 200307545 [4- mono ({[2- — (4-—Gasyl-phenoxy) -pyrene-pyrene-3-mineral] monoamino} monomethyl) monobenzyl] -amine Tert-butyl carbamate (9.51 g, 21 mmol) (Reference Preparation 2) was dissolved in dichloromethane (60 ml), and hydrogen chloride gas was bubbled into the solution at 0 ° C until The solution became saturated (30 minutes). The reaction mixture was then stirred at room temperature under a nitrogen atmosphere for an additional hour before the solvent was removed in vacuo. The obtained white precipitate was milled with diethyl ether (3 times 10 ml) to obtain N— (4-aminomethyl-benzyl) -5—fluoro-2— (4-winyl) as an off-white solid. Monophenoxy) threonamine hydrochloride (7.92 g). 1U NMR (300MΗζ »DMSO-d6): 5 = 8.96— 9.07 (lH, m), 8.40-8.60 (2H, m), 8.17— 8.22 (lH, d), 8.11-8.16 (lH, m), 7.36- 7.44 (4H, m), 7.18-7.33 (5H, m), 4.43-4.5 8 (2H, partially obscured by solvent), 3.86-3.99 (2H, m) ppm. LRMS (thermal spray type): m / z [M + H] +352 Preparation 4: (4-{[(2-chloro- 5 -fluoro-pyridine-3 -carbonyl) monoamine] monomethyl) -Benzyl) monobutylaminocarbamate

〇Me Stir -54- (51) (51) 200307545 in N, N-dimethylformamide (50 ml) at room temperature and mix with 2-chloro-5-fluoro-nicotinic acid (reference Preparation 10) (2.0 grams, 1 1.4 millimoles), 1 monohydroxybenzotriazole (1.85 grams, 13.7 moles), and 1 mono (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.622 g, 13.7 mmol), followed by N-methylmorpholine (2.5 ml, 22.8 mmol) and then (4-monoamine methyl- Benzyl) monocarbamic acid tert-butyl ester (2.69 g, 11.4 mmol) (Reference Preparation 1). The reaction mixture was stirred under a nitrogen atmosphere at room temperature for 18 hours, and then partitioned between dichloromethane (100 ml) and water (100 ml), and the organic layer was separated. Then, the organic layer was washed with a saturated aqueous solution of sodium chloride (100 ml), dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo to obtain (4-a {[(2- 5-Fluoro-pyridine-3-carbonyl) -amino] -methyl} -benzyl) -monocarboxylic acid tert-butyl ester (4.08 g). ] H NMR (400MHz, DMSO-d6): δ = 9.10-9.17 (lH, t), 8.52-8.54 (lH, d), 7.99-8.04 (lH, dd), 7.26-7.35 (3H, m), 7.18 — 7.22 (2H, d), 4.39—4.44 (2H, d), 4.06—4.11 (2H, d), 1.38 (9H, s) ppm. LRMS (electronic spraying): m / z [M + Na] +416, [M — H] + 392 Preparation 5: [4 — ({[5-Fluoro-2— (4 monofluoro-phenoxy ) Monopyridine-3 -carbonyl] monoamino} -methyl) monobenzyl] -aminocarbamic acid third butyl ester -55- (52) 200307545

F. Stir in (N-N-dimethylformamide (10 ml) at 60 ° C under nitrogen atmosphere. —Mineral) monoamino] monomethyl} -benzyl) monobutylaminocarboxylic acid third butyl ester (100 mg, 0.29 mmol) (Reference Preparation 4), 4 monofluorophenol (28 mg, 0.29 mmoles) and carbonic acid (800 mg, 2.5 mmoles) for 18 hours. The reaction mixture was then partitioned between ethyl acetate (20 ml) and water (20 ml), and the organic layer was separated. Next, the organic layer was washed with a saturated aqueous solution of sodium chloride (three times 10 ml), and the solvent was removed in vacuo. The color was analyzed by a flash tower on a silica gel and the solvent gradient was changed to 5.95. Ethyl acetate: pentane at 30:70 (volume ratio) was used to elute to purify the residue ', so as to obtain a white foam of [4 一 ({[5—fluoro 基 一 2— (4- Fluoro-phenoxy) -pyridine-3-carbonyl] -amino} monomethyl) -benzyl] -aminocarboxylic acid tert-butyl ester (57 mg). NMR (400MHz, DMSO-d6): hexane 8.97-9.02 (lH, t), 8.19-8.21 (lH, d), 8.03-8.08 (lH, dd), 7.30-7.36 (1 (, η), 7.11 — 7.16 (2H, d), 4.44—4.50 (2H, d), 4.03—4.08 (2H, d), 1.36 (9H, s) ppm 〇LRMS (electronic spray type): m / z [M + Na] + 492, [M — H] + 468 -56- (53) (53) 200307545 Preparation 6: N-(4-Aminomethyl-benzyl) -5 -Fluoro 2-(4 -Fluoro-phenoxy ) Nicotinamide amine hydrochloride

[4-[([5-Fluoro-2- (4-oxy-phenoxy) batch of pyridine-3-carbonyl] monoamino} monomethyl) monobenzyl] monoaminocarboxylic acid third Butyl ester (1.62 g, 3.44 mmol) (Reference Preparation 5) was dissolved in a solution of 2.25 M hydrochloric acid in methanol (100 ml), and the solvent was stirred at room temperature under a nitrogen atmosphere for 4 hours before removing the solvent in vacuo. . The residue was dissolved in water (50 ml), the pH was raised to more than 8 by the addition of sodium bicarbonate, and extracted with dichloromethane (3 times 50 ml). The combined organic extract was dried over anhydrous magnesium sulfate, and then concentrated in vacuo to obtain rubbery N-(4-monoaminomethyl-yl) -5-fluoro-2-(4-fluoro-1 Phenoxy) nicotinamide hydrochloride (1.25 mg). Preparation 7: (4 — {[((2 -Chloro-l-pyridine-D-Dio-3—fluorenyl) -amino] -methyl] monobenzyl) monocarbamic acid third butyl ester

〇Me at room temperature, 2-chloromononicotinic acid (2.86 grams, 18.2 milli-57- (54) (54) 200307545 mole), 1-hydroxybenzotriazole (3.0 grams, 2 1.8 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (4.18 g, 21.8 mmol) dissolved in N, N-dimethyl Formamidine (50 ml), followed by the addition of N-methylmorpholine (4 ml, 3 6 · 3 mmol) and then (4-monoaminomethyl-benzyl) -carbamic acid third Monobutyl ester (4.29 g, 18.2 mmol) (Reference Preparation 1). The reaction mixture was stirred under a nitrogen atmosphere at room temperature for 18 hours, and then partitioned between ethyl acetate (100 ml) and water (100 ml), and the organic layer was separated. Then, the organic layer was washed with a saturated aqueous solution of sodium chloride (100 ml), dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo. The residue was triturated with diethyl ether (10 ml twice), and thus (4-{[(2-chloro-pyridine-3-carbonyl) -amino] -methyl} -benzyl ) Tertiary butyl monocarbamate (6.71 g). lH NMR (400MHz ^ DMSO- d6): 5 = 9.01— 9.08 (1H, t), 8.43— 8.47 (1H, m), 7.89-7.93 (lH, d), 7.45— 7.50 (lH, m), 7.30— 7.37 (lH, m), 7.26-7.31 (2H, d), 7.17- 7.21 (2H, d), 4.39- 4.43 (2H, d), 4.03--4.10 (2H, d) ,: 1.37 (9H, s) ppm. LRMS (electron spray type): m / z [M—H] +374 Preparation 8: 3— [3— [4—Third-butoxycarbonylaminomethyl] -benzylaminomethylamidino-pyridine Mono-2-yloxy} ethyl monobenzoate (55) (55) 200307545

Stir 4-di [[(2-chloro-pyridine-3-carbonyl) -amino] -methyl} monomethyl) in dioctane (180 ml) at 70 ° C under a nitrogen atmosphere) Tert-butyl monoaminoformate (12.0 g, 32.2 mmol) (Reference Preparation 7), ethyl 3-hydroxymonobenzoate (6.42 g, 38.6 mmol), and carbonic acid (15.7 g, 48.3 mmol) ear). Retain the starting material, and add an additional multiple of 3-hydroxy-benzoic acid ethyl ester (6.42 g, 38.6 mmol) and carbonic acid (15.7 g, 48.3 mmol), together with difane (420 Ml) with N, N-dimethylformamide (40 ml), then the reaction was stirred at 701 ° C for another 22 hours. Then, the solvent was removed under reduced pressure, and the residue was partitioned between ethyl acetate (200 ml) and water (200 ml), and the organic layer was separated. Then, the organic layer was washed with a saturated aqueous solution of sodium chloride (three times 100 ml), and the solvent was removed in vacuo. The color was analyzed by a flash tower on a silica gel and the solvent gradient was 0: 1 0. 0 is changed to 5 0: 50 (by volume) ethyl acetate: hexane to elute to purify the residue, so as to obtain the off-white foamy product 3— {3— [(4 — 三 — Butoxycarbonylaminomethyl) -benzylaminomethylmethyl] -pyridine-2-yloxy} -ethyl benzoate (7.42 ml). ] H NMR (400MHz, DMSO-d6): 5 = 8.92— 8.98 (lH, t), 8.18— 8.21 (lH, d),-59- (56) (56) 200307545 8.14-8.18 (lH, d), 7.81—7.85 (lH, d), 7.77 (1H, s), 7.5 4 — 7.60 (1 H, t), 7.46— 7.50 (1H, m), 7.27— 7.31 (2H 'd)' 7.22— 7.26 (1H, m), 7.14— 7.18 (3H 'd)' 4.47— 4.51 (2H, d), 4.29-4.35 (2H, quart), 4.04-4.08 (2H, d), 1.37 (9H, s) , 1.28 — 1.35 (3H, t) ppmo LRMS (electron spray type): m / z [M + Na] + 528 '[M — H] + 504 Preparation 9: [N — (4 —Aminemethyl— Benzyl)-2- (4-fluoro-phenoxy)] nicotinamide hydrochloride

Add 3- {3-[(4-Third-butoxyamineamino-methyl) monoaminoaminomethyl] -pyridine-2-yloxy} ethyl monobenzoate (7.42 g, I4 · 7 mmol) (Reference Preparation 8) was dissolved in dichloromethane (100 ml), and hydrogen chloride gas was bubbled into the solution at 0 t until the solution became saturated (30 minutes). The solvent was removed in vacuo to obtain [N— (4-aminomethyl-benzyl) —2 ~ (4-fluoro-phenoxy)] nicotinamide hydrochloride (7.16 mg) as a white solid. . ] H NMR (400MHz, DMSO-d6): (5 = 9.48 — 9.54 (1H, in), 8.83— 9.0.3 (3H, brs), -60- (57) 200307545 8.62— 8.66 (1H, m ) 8.3 5 — 8.42 (1 H, d) 8.01-8.08 (1H, t) 7.81-7.91 (4 H ^ m) 4.94— 5.01 (2H, d) 4 · 3 6 — 4.4 2 (2 H, m) LRMS (Electronic spraying type), 8.5 7 — 8.6 3 (1 H, d),, 8.22 (1 H, s),, 7.93 — 7.98 (1H, d),, 7.68 — 7.74 (1 H, d), , 4.7 6 — 4.81 (2H, quart),, 1.75 — 1.80 (3H, t) ppm °: m / z [M + H] ^ 406

Preparation 10: 2-chloro-5-fluoronicotinic acid

Ethyl 2-chloro-5-fluorofluoronicotinate (50.4 g, 0.247 mmol) (see J. Med. Chem., 1993, Issue 36 (18), pp. 2676-88) was dissolved in To tetrahydrofuran (350 ml) was added 2M aqueous lithium hydroxide solution (247 ml, 0.495 mmol). The reaction mixture was stirred at room temperature for 3 days. The pΗ of the solution was reduced to 1 by adding 6N hydrochloric acid, and then extracted with dichloromethane. The combined extract was dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo to obtain 2-chloro-5-fluorofluoronicotinic acid (40.56 g) as a white solid. 1 H NMR (400MHz, DMSO-d6 ): δ 8 · 20 (1Η, s), 8.62 (1H, s) ppm. LRMS (electron spray): m / z [M + H] 4 174 -61-(58) (58) 200307545 The in vitro activity of nicotinamide derivatives by inhibiting the hydrolysis of cAMP by PDE4 to AMP by compounds The ability to measure the PDE4 inhibitory activity of nicotinamide derivatives of chemical formula (1) (see also reference 1). Co-labeled CMMP and PDE4. After co-location, the produced radioisotope-labeled AMP can be bonded to yttrium silicate SPA beads. These SPA beads will then produce light that can be quantified by scintillation counting. The addition of a PDE4 inhibitor prevents c A MP from forming A MP, so the count will decrease. The IC5G of P D E 4 inhibitor can be defined as the concentration at which the count of the compound is reduced to 50% when compared to a single PDE4 (no inhibitor) control well. The anti-inflammatory properties of nicotinamide derivatives of chemical formula (1) can be demonstrated by the ability to inhibit the release of TNF α from human peripheral blood mononuclear cells (see also reference 2). Venous blood can be collected from healthy volunteers, and monocytes can be purified by centrifugal filtration through a Histau p a q u e (F i c ο 11) pad tissue. These cells were stimulated to produce TNFα by adding lipopolysaccharide. After 18 hours of co-existence in the presence of LPS, the upper layer of mash was removed, and the TNFα concentration in the upper layer of mash was measured by ELISA. Adding PDE4 inhibitors will reduce the amount of TNF alpha produced. The IC50 was measured, and IC 5G was equal to the concentration of the compound that inhibited the production of TNF α by 50% when compared with a control well stimulated by LPS. All the examples were tested in the above-mentioned analysis and it was found that their IC5G (TNFα screen) was less than 500 nM. For most of the compounds tested, they were found to have IC so (TNFα screen) even less than 200 Nm. -62-(59) (59) 200307545 Reference

Thompson JW, Teraski WL, Epstein PM, Stad a SJ. Assay of nucleotide phosphordiesterase and resolution of multiple molecular form of the isoenzyme ", Advances in cyclic nucleotides reserch, edited by Brooker G, Greengard P, Robinson GA., Raven Presress , New York, 1979, No. 10, pp. 69-92.

Yoshimura T, Kurit a C? Nagao T, Usami E, Nakao T, Watanabe S, Kobayashi J, Yamazaki F, Tanaka H, N agai H., 'Effect of cAMP — phosphodiesterase isozyme inhibitor on cytokine production by lipopolysaccharide — stimulated human peripheral blood mononuclear cells ", Gen. Pharmacol., 1 997, Issue 29 (4), p. 63. -63-

Claims (1)

200307545 ⑴ Pickup, patent application scope 1 · A compound such as the chemical formula (1) or a pharmaceutically acceptable salt and / or isomer thereof, a tautomer, a solvate, a polymorph, an isotopic variant or another The composition of the metabolite and thiazole crystal key or its derivative: Where m represents 0, 1, 2 or 3, ❖ η represents 0, 1, 2 or 3, ♦ > Ri and R2 are each independently selected from a hydrogen atom, a halogen group, a cyano group, (C!-C4 ) Alkyl and (C) —c4) alkoxy, ♦ > X represents a Q—, —s—, or —NH—, ❖ R3 is selected from the following groups: (a) phenyl, naphthyl, heteroaryl and (C3-Cs) cycloalkyl, each of which is optionally substituted with 1 to 3 substituents, and each substituent is selected from halo, cyano , (C ^ C4) courtyard, (Ci-C4) alkoxy (Cl—C4) sulfur courtyard, —c (= 〇) Nh2, one C (= 0) NH (Ci-C4) alkyl, , -Ο-C (= 〇) (Cl- C4) alkyl,-c (= o)-〇- (Cl-c4) alkyl and hydroxy (Ci-c〇alkyl, or Meet any of the following structures (1,1) to (1.4)-two of them -64-200307545 (1.3) (1.4) where the symbol `` * 〃 represents the connection point of each part of the chemical formula (1 · 1) to (1 · 4) connected to the rest of the chemical formula (1), Υ is selected from the following Bases of chemical formulas (1 · 5) to (1 · 1 1) (1.5) (1.6) (1.7) (1.8) (1.9) (1.10) (1.11) The symbol `` * 〃 '' represents the connection point of each part of the chemical formula (1.5) to (1 · 1 1) connected to the rest of the chemical formula (1) —N 一 —, and the symbol `` * * 〃 represents Each part of the chemical formulas (1 · 5) to (1. 1 1) is connected to the connection point of the remaining part of the chemical formula (1)-R4-, and R4 represents a group selected from: (a) phenyl, Naphthyl and heteroaryl, each of which is optionally substituted with 1 to 3 substituents, and each substituent is selected from carboxylic acid, C (= 0) — 0— (Ci — C4) Base, fluorenyl, —c (= o) nh2, (c! —C4) alkyl, (c, —c4) alkoxy, (C 1 —C 4) haloalkyl, meridian, and meridian ( Cl-C4) courtyard-based or -65- (3) (3) 200307545 (b) optionally via hydroxyl, carboxylic acid, C (= 〇) -10- (Cl ~ c4) alkyl, phenyl, naphthalene Or heteroaryl substituted (G-C4) alkyl, wherein the phenyl, naphthyl, and heteroaryl are each optionally substituted with 1 to 3 substituents, and each substituent is selected from carboxylic acids , C (= 〇) ◦ (G-cd alkyl, halo, cyano, --C (20) NH2, (c! S C4) Or (Cl — c4) alkoxy, (Cr c4) haloalkyl, hydroxy, and hydroxy (Cl — c4) alkyl. 2 • The composition as claimed in item 1 of the patent application, except that the following formula (1) Except for compounds: 1) m is not 0, and γ represents a part of the chemical formula (n. 5), and r4 represents an unsubstituted (C, -C4) compound base, 2) m is at 0 'when γ The chemical formula (ι · 5) is shown, and R4 represents a phenyl, naphthyl or heteroaryl group optionally substituted with 1 to 3 substituents, and these substituents may be independently selected from carboxylic acid, halo, cyano Radical, (Ci-c4), radical, (Cl-C4) alkoxy, (Cl-C4) haloalkyl, hydroxyl and (C) -c4) alkyl, or r4 means optionally via hydroxyl (C) -c4) alkyl substituted with,, residual acid, or heteroaryl, they may also be selected from 1 to 3 independently selected from carboxylic acid, halo, cyano, (CrC4) alkyl, ( C1 ~ C4) substituted by alkoxy, hydroxy, and hydroxy (C) -C4) alkyl substituents, and 3) m is equal to 0, while Y represents part of the chemical formula (1.6), and R4 represents phenyl or naphthyl , Each of which is optional 1 to 3 independently selected from carboxylic acid, halo, cyano, (Ci-C4) alkyl, (C) ~ C4) koxy, (c) -c4) haloalkyl, hydroxyl, and hydroxyl (Cl-C4) alkyl-66-(4) (4) 200307545 is substituted by a substituent. 3. The composition according to item 1 of the scope of patent application, wherein the compound of the chemical formula (1) is: m and η are equal to 1, R! And R2 each represent independently selected from a hydrogen atom, a halogen group, a cyano group, ( Ci—C4) courtyard and (C) —C4) courtyard oxygen, < ♦ X represents —0—, < ♦ r3 represents a group selected from the following: (a) phenyl, naphthyl, heterocyclyl and (C3-Cg) cyclic radicals, each of which is optionally substituted with 1 to 3 substituents, and each substituent is selected from halo, cyano, (Ci-C4) alkyl, (C!- C4) alkoxy, (Ci-c4) sulfanyl, —c (= o) nh2, -C (= 0) NH ((C, — C4) alkyl), hydroxyl, —O— C (= 0 ) (C 1 — C 4) courtyard foundation, one C (= 0) — O— (Ci— C4) courtyard foundation and Jingji (Ci—C4) courtyard foundation, or (b) meet the following structure (1 · 1) Bicyclyl to one of (1.4) -67 (5) (5) 200307545 is the connection point to the remainder of the chemical formula f A β +% (1), ¥ represents the -C (= 0) -group of some chemical formula (1.5), and & Represents a group selected from: (a) phenyl, naphthyl, and heteroaryl, each of which is optionally substituted with 1 to 3 substituents, and each substituent is selected from carboxylic acid, c. ) ~ R —— (c4) alkyl, halo, cyano, NH2, (c) —C4) oxo, (C) —C4) oxo, (Cl ~ C4) haloalkyl, hydroxy And hydroxy (C, —C4) alkyl, or (b) substituted with hydroxy, carboxylic acid, C (= 0) —〇- (C, —c4) alkane S 'benzyl' naphthyl or heteroaryl ( Ci-Ci) alkyl, wherein each of the base, ban and heteroaryl is optionally substituted with 1 to 3 substituents, and each substituent is selected from carboxylic acid, C (= 0) 0 (Cl-c4) fluorenyl, halo, cyano, —C (= 0) Nh2, (c! — C4) alkyl, (Cl ~ C4) alkoxy, (Cl — C4) haloalkyl, hydroxy And hydroxy (Cl-C4) alkyl. 4. The composition according to item 1 of the scope of patent application, wherein the compound of the chemical formula (1) is: + m and η are equal to i, + Ri and R 2 are each independently selected from a hydrogen atom, a halogen group and a methyl group, ♦♦♦ X represents —0—, + R3 represents phenyl optionally substituted with 1 to 3 substituents, and each substituent is selected from halo, cyano, (Cl — C4) alkyl, ( Cl — c4) alkoxy, (C! — C4) sulfanyl, —c (= 0) nh2, —C (= 0) NH ((C) -C4) alkyl), hydroxyl, -68- ( 6) (6) 200307545 —0— C (= 0) (Ci— C4) courtyard, -C (= 0) —10— (C) —c4) alkyl and hydroxy (Ci, alkyl Y represents part One of the chemical formulas (1 · 5) c (= o) ~ #, < ♦ and R4 represent a group selected from the following: (a) optionally selected from 1 to 3 selected from carboxylic acids, C (= 0) — 0— (Ci—C4) courtyard, halo, cyano, —C (= 0) NH2, (C) —C4) alkyl, (Ci—c, 4) alkoxy, (C) —C4) Haloalkyl, hydroxy and hydroxy (C) -C4) phenyl substituted with < substituents, or (b) (C) -C 4) substituted with hydroxy or phenyl > A group in which the phenyl group is optionally substituted with 1 to 3 substituents, and each s substituent is selected from the group consisting of carboxylic acid, c (= o) o (G-c4) alkyl, halo, -C (= 0) NH2, (Ci-C4) alkyl or ((: Guang (: 4) Lu 〆; alkoxy, (C! -C4) haloalkyl, hydroxyl and hydroxyl (G — c4) Alkyl group 5. The composition according to item 1 of the scope of patent application, wherein the compound of the formula (1) is: ♦ > m and η are equal to 1, Ri represents a hydrogen atom or a fluorine group, and r2 represents a hydrogen atom, X Table — 0 —, R3 represents a phenyl group optionally substituted by a substituent selected from a halogen group and a C (= 0) —〇— (C] —C 4) alkyl group, ❖ Y represents a partial chemical formula (1.5) one of the C (= 0) -groups, and ❖ and R4 represent a group selected from the following: -69- (7) 200307545 (a) optionally from 1 to 3 selected from halo, (C! C4) phenyl substituted with alkyl and hydroxy substituents, or (b) (C! -C4) alkyl substituted with hydroxy or phenyl, wherein the phenyl is optionally selected from 1 to 3 selected from halogens With (C! —C4) alkyl and hydroxyl substituents. 6 The composition according to item 1 of the patent application range, wherein the compound of formula (1) is selected from the following: 2-(4 monofluoro-phenoxy) -N-{4— [(2-hydroxy-3_methyl-monobenzylamino) -methyl] -benzyl} mononicotinylamine, 3 — (3- {4 -— [(3-hydroxy-monobenzylamino) -methyl] -benzylaminomethylmethyl}}-pyridine-2-yloxy) ethyl benzoate, 2- (4- Fluoro-phenoxy) —N-{4— [(6-Fluoro-2-hydroxyl-benzylamido) monomethyl] -benzyl} mononicotinamide, 2- (4-fluoro —Phenoxy) —N— {4— [(5-fluorofluoro-2—hydroxy-benzylamine) -methyl] -benzyl} mononicotinylamine, 2— (4—vinyl —Phenoxy) —N— {4-[[3-—Cyclo-4—methyl-benzylamino] -methyl] -benzyl} mononicotinylamine, 2- (4-fluoro Monophenoxy) -N— {4 — [(3-hydroxy-benzylamino) -methyl] -benzyl} mononicotinamide, 2- (4-fluoro-phenoxy)- N — {4— [(2-Cycloyl-benzylamido) -methyl] -benzyl} mononicotinamide, 2- (4-fluoro-phenoxy) —N— {4— [(4-hydroxy-benzyl Amine) monomethyl] monobenzyl} mononicotinamide, 2- (4-monofluoro-phenoxy) -N- {4-[(2-hydroxy-1 4-70- (8) 200307545 Methyl-benzylamino) monomethyl] -benzyl} mononicotinylamine, 2- (4-chloro-phenoxy) -N- {4— [(3 -meryl-2 — Methyl-benzylamino) -methyl] -benzyl) -nicotinylamine, 2- (4-chloro-phenoxy) -N — {4— [(2 — Methyl monobenzylamine) monomethyl] monobenzyl} mononicotinamide, 5-fluoro-2 — (4-monofluoromonophenoxy) —N — {4-[(2 — Hydroxy-benzylamine) monomethyl] -benzyl} mononicotinylamine, 5-Fluoro-2— (4-Fluoro-phenoxy) —N— {4— [(2-hydroxy-ethylamidoamino) -methyl] -benzyl} mononicotinamide, 5 — Fluoro-2- (4-fluoromonophenoxy) —N-{4— [(4-hydroxy-benzylamino) -methyl] -benzyl} mononicotinylamine, 3 — ( 3— {4 — [(3-hydroxy-monobenzylamino) -methyl] —benzylaminomethylamidino} -pyrimidin-2-yloxy) ethyl benzoate, 3— (3— {4 — [(2-Hydroxymonophenethylamino) -methyl] monobenzylaminomethylmethyl} monopyridine mono-2-yloxy) ethyl benzoate, 3— (3 — {4-[[3-Hydroxy-phenylethylamidinoamino] -methyl] -benzylaminomethylamidino} -pyrimidin-2-yloxy) ethylbenzoate, 3— (3- {4-[[4-monohydroxyethylphenylamino] -methyl] -benzylaminomethylmethyl} -pyridine-2-yloxy) -ethyl benzoate. 7. A pharmaceutical composition comprising a compound of the formula (1) defined in item 1 of the scope of the patent application or a pharmaceutically acceptable salt or derivative thereof and a thiazide crystal key as defined in the scope of patent application Or a combination of derivatives thereof, together with customary pharmaceutically non-toxic excipients and / or additives. -71-(9) (9) 200307545 8. The compound of formula (1) or its pharmaceutically acceptable salt or derivative form as described in item 1 of the scope of application for patent The composition can be used as a medicament. 9 · The compound of the formula (1) as defined in item 1 of the scope of the patent application, or a combination of a pharmaceutically acceptable salt or derivative thereof and thiazepine or its derivative, which can be used to treat PDE4 Diseases, disorders and conditions of isoenzymes and muscarinic receptors. 10. The compound of the chemical formula (1) as defined in item 1 of the scope of the patent application, or a combination of a pharmaceutically acceptable salt or derivative thereof and thiazepine tungsten or a derivative thereof, which can be used to treat inflammation, Respiratory and allergic diseases, disorders and conditions. 11. The compound of the chemical formula (1) as defined in item 1 of the scope of the patent application, or a combination of a pharmaceutically acceptable salt or derivative form thereof and thiocyanate or its derivative, which can be used to treat the following diseases , Disorders and conditions: • Asthma of any morphology, etiology, or pathogenesis, especially selected from the following: asthmatic allergy asthma, asthmatic allergy asthma, asthma, allergic asthma, hereditary allergy bronchus Sexual I g E-Intermediate asthma, bronchial asthma, essential asthma, authentic asthma, intrinsic asthma due to pathophysiological interference, external asthma due to environmental factors, unknown or unknown cause Asthma, asthmatic asthma, bronchial asthma, emphysema asthma, exercise-induced asthma, allergen-induced asthma, cold-air-induced asthma, occupational asthma, bacterial, fungal 'protozoa, or Infectivity caused by viral infection -72- (10) 200307545 Qin asthma obstructs the aspiration tract chronically difficult breathing and breathing is selected from the end of work Infants, causes, and cotton nBB are: ¾ ductitis, bronchiolitis and small, non-allergic asthma, initial asthma, and asthmatic infant syndrome • chronic or acute bronchoconstriction, chronic bronchitis, small airways, and emphysema, • Any obstructive or inflammatory respiratory disease of any morphology, etiology, or pathogenesis, especially selected from the following obstructive or inflammatory respiratory diseases: eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD), chronic bronchus COPD of inflammation, emphysema or the breaths associated therewith, COPD characterized by irreversible and progressive airway obstruction, aspiration pain syndrome (ARDS), and exacerbations of overreaction due to other medications, • any Pneumoconiosis of morphology, etiology, or pathogenesis, especially the following: pneumoconiosis of the lungs of pneumoconiosis or alumina workers, coal pneumoconiosis or mineral asthma, asbestosis or asthma of steam assemblers, pneumonia or stone Pulmonary disease, lash loss due to inhalation of dust from ostrich feathers, pulmonary iron deposits caused by inhalation of iron particles, silicosis or miller lung disease Fibrous aspiration pneumonia or cotton dust asthma and talc pneumoconiosis, • Bronchitis of any form, etiology, or pathogenesis, particularly from the following: acute bronchitis, acute laryngotracheal bronchitis, bronchitis caused by groundnuts, Nasal mucosal inflammatory bronchitis, floating membrane inflammation, dry bronchitis, infectious asthmatic bronchitis, bronchitis caused by the production of bronchitis, staphylococcus or streptococcus are vesicular bronchitis, any shape Bronchiectasis due to malignancy, etiology, or pathogenesis, especially -73- (11) (11) 200307545 Specially selected from the group of bronchiectasis: cylindrical bronchiectasis, cystic bronchiectasis, spindle bronchiectasis, hairy bronchiectasis, cystic bronchiectasis, dry bronchodilator and follicle Bronchiectasis, • seasonal allergic rhinitis or year-round allergic rhinitis or sinusitis of any morphology, etiology, or pathogenesis, especially selected from sinusitis: purulent sinusitis or non-purulent sinusitis, acute Or chronic sinusitis and ethmoid, frontal, maxillary, or wedge-shaped sinusitis, • Any morphological, etiological, or pathogenesis-related eosinophil-related disorder, especially selected from the group of Symptoms: increased eosinophilia, increased osmotic eosinophilia in the lungs, Ruffler's syndrome, chronic eosinophilic pneumonia, tropical pulmonary eosinophilia, bronchopulmonary aspergillosis, aspergillosis, containing eosinophilia Erythrocyte granuloma, allergic granulomatous lymphangiitis or Churg-Strauss syndrome, nodular polyarteritis (pan ) And systemic necrotizing vasculitis, • Pulmonary hypertension of any form, etiology, or pathogenesis, including primary pulmonary hypertension / essential hypertension, secondary pulmonary hypertension due to congestive heart failure , Secondary pulmonary hypertension due to chronic obstructive pulmonary disease, venous hypertension of pulmonary disease, pulmonary hypertension, arterial hypertension, and hypoxic-induced pulmonary hypertension, and • infectious diseases, especially infectious diseases due to viral infection, among which Viruses will increase the production of TNF-α in the host, or such viruses are sensitive to the upregulation of TNF-α in the host so that their replication or other vitality is adversely affected. The virus includes a group selected from HIV-1, HIV-2, -74- (12) 200307545 and HIV-3, Cytomegalovirus, Influenza Virus, Adenovirus, and Herpes Virus Covering Herpes Zoster and Herpes Simplex. 1 2. The use of a compound of the formula (1) as defined in item 1 of the scope of patent application, or a pharmaceutically acceptable salt or derivative thereof, and a composition of thiazepine or its derivative, which is provided for Manufacture of a drug that can be used to treat inflammatory, respiratory and allergic diseases, disorders, and conditions. 1 3. The use of a compound of the chemical formula (1) or its pharmaceutically acceptable salt or derivative form as defined in item 1 of the scope of patent application, and a composition of thiazepine or its derivative, which is provided for Manufacture a medicament for the treatment of diseases, disorders, and conditions selected from the group consisting of items 11 in the scope of the patent application. -75- 200307545% Lu, (1), the designated representative figure in this case is ... Figure _ (2), the component representative symbols of this representative figure are simply explained: None 柒 、 The chemical formula that can best show the characteristics of the invention in this case: h3C \ + / Ch3 〇 X -3-