JPH05507698A - Amide-linked pyridyl-benzoic acid derivatives for the treatment of leukotriene-related diseases - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Amide-linked pyridylbenzoic acid derivatives for the treatment of leukotriene-related diseases Field of the invention The present invention provides amide-linked pyridyl rests useful for the treatment of diseases associated with leukotrienes. Concerning aromatic acid derivatives. These compounds include hydroxyleukotrienes, among others , LTB4 and LTB, - particularly useful in the treatment of diseases attributable to agonist active substances. be.

Background of the invention A series of bioactive lipids known as leukotrienes are found in the respiratory system, heart and blood. It exerts pharmacological effects in the tract and gastrointestinal systems. This leukotriene is generally 2 There are two subclasses, namely peptide leukotrienes (leukotriene C4, D 4 and R4) and hydroxyleukotrienes (leukotriene B4). Ru. The present invention relates to hydroxyleukotriene (LTB) as raw material. However, it is not limited to this particular group of leukotrienes.

The peptide leukotriene is classified as “anaphylactic slow-reacting substance J (SR3 - associated with biological responses associated with A). This response in vivo As an extension of bronchoconstriction, cardiovascular effects such as coronary artery constriction and other Expressed as a biological response. The pharmacological action of the peptide leukotrienes is smooth muscle contraction. , including myocardial depression, increased vascular permeability and enhanced mucus production.

By comparison, LTB4 affects the biology of leukocytes and lymphocytes through stimulation of their function. Demonstrate effective results. LTB is associated with chemotaxis and chemotaxis of polymorphonuclear leukocytes (PMNs). Stimulates nesis and aggregation.

They are critically involved in many types of cardiovascular, pulmonary, cutaneous, renal, and allergic diseases. – and inflammatory diseases, such as asthma, adult respiratory distress syndrome, cystic fibrosis, and dryness. associated with habit, and inflammatory bowel disease.

Leukotriene B, (LTB4) was first developed by Borgito and Samuel Singh. (Borgeat and Samuelsson) in 1979. Later, Colley and co-researcher 1: Yo'l 5(S), 12(R)-Sit: Too+C (Z, E, E, Z)-6,8,10,14-Eicosatetra It was revealed that it was enoic acid.

The LTB is derived from the arachidonic acid cascade derived from the enzymatic hydrolysis of LTA. It is a product. It affects mast cells, polymorphonuclear leukocytes, monocytes and macrophages Therefore, it was found that it was generated. LTB, but PMN leukemia in vivo It is a strong irritant of spheres and is involved in chemotactic and chemokinetic migration, adsorption, aggregation, Appears to result in increased degranulation, superoxide production and cytotoxicity was made into The effect of LTB4 is to differentiate distinct molecules on the leukocyte cell surface showing a high degree of stereospecificity. Transmitted via receptor sites. Pharmacological research on PMN leukocytes in human blood is Two different types of LTB, -specific receptors for peptide chemotactic factors It is clear that the existence of Calcium mobilization is involved in both mechanisms .

It has been established that LTB4 is an inflammatory mediator in vitro. Sara In addition, it is associated with airway hyperresponsiveness in dogs, as well as with severe pulmonary dysfunction. It was found at higher levels in lung lavage than in humans.

The compounds and pharmaceutical compositions of the present invention are useful for reducing LTB in end organs, e.g., airway smooth muscle. or by antagonizing the effects of other pharmacologically active transmitters. of value in the treatment of diseases caused by leukotrienes in patients, including patients and animals. It has value. Additionally, some of these compounds inhibit the 5-lipoxygenase enzyme. It can be said to be an inhibitor or LTD, antagonist.

Summary of the invention The compound of the present invention has the formula (I): [In the formula, T is an amide bonding group , where the carbonyl carbon is bonded to the pyridyl ring: R is 01 to CH- Aliphatic group, unsubstituted or substituted phenyl CI-C+. is an aliphatic group and is substituted here Phenyl consists of lower alkoxy, lower alkyl, trihalomethyl and halo has one or more groups selected from the group, or R is 01-C20-aliphatic group- 0-, or R is unsubstituted or substituted phenyl01-Cl0-aliphatic group- 0-, where substituted phenyl is lower alkoxy, lower alkyl, trihalomethane. has one or more groups that are thyl or halo; R, is R4, -(C, -C5 aliphatic group) R4, -(C0-C5 aliphatic group) CH○, -(C1-C7 aliphatic group) CH 20Rs, CH20H or 7': ItCHO; R2 is hydrogen, -COR5 , where R3 is -OH, a pharmaceutically acceptable ester-forming group -OR, or - OX, where X is a pharmaceutically acceptable cation, or R5 is - N (R7)! Here, R7 is H or an aliphatic group having 1 to 10 carbon atoms, carbon cycloalkyl-(CHz) n-group with prime numbers 4 to 10 (where n is 0 to 3) or both R7 groups together form a ring having 4 to 6 carbon atoms, or R2 is NHS○2R9, where Ro is -CF3, C1-C6 alkyl or or phenyl: R1 is hydrogen, lower alkoxy, halo, -CN, CORs or OH.

R4 is -COR5, where R3 is -OH1 pharmaceutically acceptable ester formation the group -OR, or -OX, where X is a pharmaceutically acceptable cation; or R5 is -N(R7)z, where R7 is H or carbon number 1-1o aliphatic group, cycloalkyl-(CHz) n-group having 4 to 10 carbon atoms (where n is 0 to 3), or both R7 groups together form a ring having 4 to 6 carbon atoms R8 means hydrogen, C+-Ca alkyl or 01-c6 acyl] or a pharmaceutically acceptable salt or N-oxide thereof.

In another aspect, the invention provides a method for preparing a compound of the invention and a pharmaceutically acceptable excipient. It includes a pharmaceutical composition.

Leukotrienes, particularly LTB4, or pharmacologically active genes associated with end organs. The treatment of diseases related to or caused by these substances is an aspect of the present invention. within range. This treatment includes the administration of one or more compounds of formula I alone or as pharmaceutically acceptable compounds. This can be done by overdosing in combination with acceptable excipients.

In yet another aspect, the present invention provides The method exemplified in the examples shown in the specification, that is, the conversion of formula This invention relates to a method for producing a compound.

Detailed description of the invention The following definitions are provided by the inventors to describe the invention. Used to describe something that you think exists.

"Aliphatic group" is intended to include saturated and unsaturated groups. This is standard and Branched, with either saturated or mono or both double and triple bonds. polyunsaturated chains which may be present in any combination. "Lower alkyl" The term refers to an alkyl group having 1 to 6 carbon atoms which may be in any isomeric form. , especially of standard or linear form. "Lower alkoxy" , means a lower alkyl-〇- group. "Acyl" has a terminal carbonyl carbon means base. "Halo" means fluoro, chloro, bromo or iodo, and means. The phenyl ring may be substituted with one or more of these groups. many places Substituents include three chloro groups or a combination of chloro and alkyl groups. , and even this latter combination allows for different aptitudes in the case of chloro/alkyl substituents. They may be the same or different so that they have an alkyl group.

The term "pharmaceutically acceptable ester-forming group" in R2 and R3 refers to these All esters that can be prepared from the silicic acid function present in the compounds of include. The resulting esters are acceptable for pharmaceutical use. this This means that the mono- or diester retains the biological activity of the parent compound and is useful for treating diseases. intended to have no undesirable or harmful effects in its application and use in Taste. Such esters are, for example, -0R6, where Ro is: C, -C, . Alkyl, phenylC1-C6 alkyl, cycloalkyl, aryl, aryl alkylarkyl, alkylaryl, alkylarylalkyl, aminoalkyl, Indanyl, pivaloyloxymethyl, acetoxymethyl, propionyloxy Methyl, glycyloxymethyl, phenylglycyloxymethyl or chenyl It is formed by one of the groups which is glynoroxymethyl. Aryl is Fe Nyl and naphthyl or furyl, chenyl, imidazolyl, triazolyl or includes heterocyclic groups such as tetrazolyl. The most preferred ester-forming groups are R6 is alkyl, especially alkyl having 1 to 10 carbon atoms (i.e., CH, -(CH 2) n- (where n is 0 to 9)) or phenyl-(CHz) n (where n is 0 to 4).

This invention is also intended to include pharmaceutically acceptable salts of the compounds of this invention. these Salts are those that are acceptable for pharmaceutical use applications. This means that the chain ring is the parent compound. retains the biological activity of the product and makes the chain unsuitable for application and use in the treatment of diseases. means having no harmful or harmful effect.

Pharmaceutically acceptable salts are prepared by standard methods. parent compound in a suitable solvent , in the case of acid addition salts of basic groups, by reaction with excess organic or inorganic acid, or When R4 is OH, it is reacted with excess organic or inorganic base. Typical acids are Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, maleic acid, succinic acid or methane It is sulfonic acid. Cationic salts include sodium, potassium, calcium, and Easily produced from alkali metal bases such as sium, zinc, copper and ammonia Ru. Organic bases include mono- or di-substituted amines, ethylenediamine, amino acids, cuff Including Ein, tromethamine, tris compounds, triethylamine, piperazine, etc. Contains.

The oxide of the pyridyl ring nitrogen is represented by means known in the art and as examples herein. It can be manufactured by the means shown. These are part of the invention it is conceivable that.

By combining substituents, chiral centers can be obtained in the compounds of the invention, or any other form of isomeric center is obtained, all forms of such isomer are included in the present invention. Compounds with chiral centers are considered racemic mixtures. (or the racemate can be separated and the individual enantiomers isolated) May be used in

As leukotriene antagonists, these compounds can be used as leukotriene antagonists, especially LT Various substances related to B4 or whose origins or effects are attributed to leukotrienes It can be used to treat the following diseases. Thus, these compounds are It can be used to treat allergic diseases including pulmonary diseases. For example, this These compounds are useful in antigen-induced anaphylaxis. The compound is useful for asthma and Useful in treating allergic rhinitis. Uveitis and allergic conjunctivitis Eye diseases can also be treated with these compounds.

In preferred compounds of the present invention, R is alkoxy, particularly alkoxy having 8 to 15 carbon atoms. , or substituted or unsubstituted phenyl-C, -C,. -aliphatic group -0-: R 1 is -((:1~CJ! aliphatic group) R4 or 1t-(C+~Cs aliphatic group) CH 20Rs; and R2 is -COOH or its alkali metal salt or NHSOzR*, where R is -CF, , C, ~C, alkyl or or phenyl. More preferred compounds of the present invention are those in which R is carbon. Alkoxy or alkoxy-substituted phenyl-C3-C, alkenoki having numbers 8 to 15 or 101-C8 alkoxy: R+ is -COR5, CH2CH2CO Rs * f = Ii -CH = CH-CORs Tearari: R2 is -cooH or -NHSO2Rs, in particular R9 is -CF: and R3 is hydrogen or a compound that is chlorine.

The most preferred compounds are shown in Figure II.

Figure 11 *Kimoto trans configuration where the carbonyl carbon is on the pyridyl ring Confusion These compounds can be prepared from the intermediates and reagents in the following reaction equation. Wear. This particular series of intermediates will be used to illustrate the general method. Reaction formula 1 exemplifies methods for making compounds useful for making R groups. Other reaction formulas are also available is R using the substance described in reaction formula (■) or a commercially available intermediate. A method for forming a group and subsequently producing a compound of formula (1) is shown.

The R groups in Formula 1 are available from chemical suppliers or as outlined in Scheme ■. It can be manufactured by one of two methods.

Reaction Scheme 1(a) shows the preparation of an unsaturated phenyl-aliphatic R group.

Reaction formula 1(a) (b) (C) Here, the methoxyphenyl compound will be explained, and this series of steps and reagents are R can be used to prepare other substituted phenyl-ω-aliphatic groups represented by can. The starting material benzaldehyde is commercially available or known It can be easily manufactured by the method.

To produce acid (a), first, an alkyl silacite is inertly heated under an inert atmosphere. Add to solvent. Then add the phosphonium salt. This addition can be done at room temperature or It can be done near. After a short period of mixing, the mixture is usually a suspension. and slowly add benzaldehyde at about room temperature. Add a slight molar excess of phosphorus. Honium salts are used. After another short period of stirring at room temperature, the reaction was quenched with water. do. The solution is acidified and extracted with a suitable organic solvent. Further markings if desired. Standard separation and purification procedures may also be used.

Alcohols are produced by reducing chain acids using reducing agents. Al hydride Minium lithium or a similar reducing agent can be used and is necessary to carry out the reduction. If so, you can change the conditions.

Tosylate is prepared by combining p-toluenesulfonyl chloride and pyridine in an inert solvent. It is produced using a base such as Appropriate conditions are 1 to 5 o'clock at or around room temperature. This includes carrying out intermediate reactions. Other suitable desorbers similar to tosylates in their sensuality A leaving group may be prepared and is useful as a means of adding this R group to the pyridyl ring. .

Reaction formula 1(b) outlines method 1 for producing the R group of alkoxyphenylalkyl. I am explaining. Using this method, phenyl includes a substituted phenyl-containing group, Another R group was prepared which was an ω group on the aliphatic chain.

)(, Co-Ph-1 (CH2)nOSi(Ph)Co-Ph-1(C-(b) Pd [(Ph)i If P12c'zω-yn-1-ol is not commercially available, the compound , by treating the corresponding 3-yn-1-ol with a strong base. It can be manufactured from. Here, an alkali metal amide was used. Then, Protecting the alcohol to add the desired phenyl group at its terminal triple bond position Ru. In this example, to illustrate a general case, silyl ether is formed.

A phenyl group was added at its triple bond position using a halo-substituted phenyl adduct. this At this point, the triple bond is most advantageously removed by catalytic means, for example palladium/ Can be reduced with carbon and hydrogen. Alternatively, retaining the triple bond, It is possible to carry out via said intermediate up to Tornrad. Remove the silyl group and obtain alcohols as tosylates or ethers in the synthesis of these compounds. to other groups that are sufficiently reactive to readily form molecules.

Compounds produced according to Reaction Scheme 1 and other compounds produced by purchasing or known methods Compounds of formula I can be prepared by following the reaction scheme outlined in the following formula using can be done. Furthermore, these reaction equations are illustrated using specific examples. describes the general principles for preparing compounds of Using these reaction formulas, here By varying or modifying the illustrative chemistry, Other compounds can be prepared. Such modifications or modifications may Changes in conditions such as temperature, pressure, length of reaction time, amount of reagents, etc. reagent do not yield the same or equivalent products and may be replaced with their equivalent or similar reagents. It can be replaced. Similarly, starting materials and intermediates can be varied to create a particular compound. It can also be tailored to meet manufacturing requirements.

One method for producing a compound in which the nitrogen of the amide bonding group is on the phenyl ring is shown in the reaction formula. Shown in 2.

(E) The above reaction formula produces a compound of formula 1 in which the carboxyl carbon is on the pyridyl ring. One synthetic route is shown. 3-hydroxy-2-(hydroxymethyl)pyridine is They are commercially available or can be manufactured by known open means.

This diol is converted into an aldehyde and then into a 3-alcoquine compound, but Alternatively, the 3-hydroxy group is first converted to an ether, and then the 2-hydroxymethyl group is converted to an ether. can be converted either by oxidation to an aldehyde. the alcohol Oxidation of the compound is easily accomplished using mild oxidizing agents. Manganese dioxide is preferred However, other oxidizing agents can be used successfully in this step. Ether corresponds α-halo R group, or from compounds such as tosylates under basic conditions. Manufactured in

Then, this 3-substituted-2-carboxaldehyde (C) is subjected to such a reaction. The 2-carbomethyl Convert to toquinethinyl form (d). The resulting ester is then treated with a peroxy acid. Processing to produce N-oxide (e) for producing pyridone. This process is , m-chloroberoxybenzoic acid, but other similar oxidizing agents can also be used in the same way. Then, the rearrangement of the N-oxide is carried out using anhydrous trifluoride. This is done with oroacetic acid or similar reagents to give 2-pyridone (f).

Acylating the 2-pyridone, then in the presence of some catalyst and carbon monoxide, By reacting this ester with the desired aminobenzoate (h), 2- Converts pyridone to amide. The acylation step is performed using trifluoromethanesulfonic acid. Explain in terms of anhydride. The amidation reaction is performed using Pd(○Ac)2.1.1°-bis(di In the presence of phenylphosphino) ferrocene, -carbon oxide is added to a solution of triflate. This is done by bubbling through the medium. Then, the obtained diester (i) is saponified using an inorganic base and its ester group is hydrolyzed. recover free acid The resulting salt may be neutralized in order to Convert the free acid to other esters by known methods. or the corresponding amide.

Saturated 3-position substituents are easily prepared from alkene analogs by catalytic hydrogenation. It will be done. Scheme 3 illustrates this methodology.

The diester is catalytically reduced using a heavy metal catalyst and hydrogen in a traditional catalytic reduction reaction. (3d). After the reduction is complete, if the diacid (3b) is desired, it can be purified using a base. Diesters can be hydrolyzed. Appropriate oxidation, reduction, esterification, amino Any compound can be combined with other compounds of the present invention by hydrogenation reaction or by other means. can be converted to .

Carbon analogs of these compounds, i.e., the group connecting the R group to the 3-position is methylene The compound can be produced by the continuous steps shown in the fourth flowchart ( 4a) 3-Hydroxypicolinic acid is converted into an alkyl compound using the corresponding alkanol and an acid catalyst. Change to luester. This hydroxyl group is converted into trifluoromethanesulfonic anhydride. and converted to trifluoromethanesulfonate (4a) using pyridine. One Then, a suitable alkyl catechol prepared from 1-tridecene and catecholborane using palladium coupling conditions [Pd(○AC)2]. Attach the lipid tail. Then, the alkyl ester is the corresponding alkali using a suitable hydride, e.g. diisobutylaluminum hydride. Transforms into dehyde. This aldehyde is then converted into, for example, methyl (triphenyl Wittig olefin using phosphoranilidene) acetate. Submit to conversion.

The resulting pyridyl acrylate was then subjected to the same procedure outlined in Scheme 2 above. It is transformed into the target compound through a process.

Reverse amide can be produced by a series of steps shown in Reaction Formula 5.

Commercially available 3-hydroxypicolinic acid was synthesized with an acid catalyst and the corresponding alkanoic acid. convert it into an alkyl ester using a tool. For example, 1-iododecane or or similar 1-halo compounds under standard conditions. be exposed. This is done using a weak base such as KtCOs in dimethylformamide. It is best to implement it. This gives a 3-alkoxy derivative. Pili The nitrogen of gin is oxidized and the resulting N-oxide is rearranged to give 2-pyridone.

The oxidation is a peroxy acid such as 3-chloroperoxybensikoic acid or similar oxidation. It is easily done with a drug. N-oxide (5a) rearrangement is possible with dimethylformamide, etc. This can be carried out using trifluoroacetic anhydride in a suitable solvent such as trifluoroacetic anhydride.

Formation of trifluoromethanesulfonate is trifluoromethanesulfonic anhydride and a base such as pyridine. Nuclear displacement using sodium azide A 2-azidopyridine derivative (5b) is obtained. The azide by catalytic hydrogenation is reduced to an amine. using a hydride, e.g. diisobutylaluminum hydride. The alkyl ester is reduced to an aldehyde. Next, the Witsch reaction to produce 2-aminopyridine acrylate (5c). For example, methyl ( Triphenylphosphoranylidene) acetate can be used. the amine (methyl isophthaloyl chloride) and then convert the ester into a base. (LiOH, tetrahydrofuran, methanol) to obtain the desired amide. Ru. These compounds can be prepared by the means described herein or in the art. esters, amides, salts or the like of formula ■ by generally known means. It can be transformed into similar compounds.

prescription The pharmaceutical composition of the present invention comprises a pharmaceutical carrier or diluent and an amount of a compound of formula (1). Consisting of The compound may be present in an amount that produces a physiological response; is such that the user requires two or more units of the composition to achieve the intended therapeutic effect. It may also be present in smaller amounts. These compositions can be used as solids, liquids or may be produced in gaseous form. Alternatively, one of these three forms may be solid If the liquid is prevarnished by aerosol means or if the liquid is sprayed or It may be transformed into other forms at the time of administration, such as when administered as a sol. The characteristics of the composition and pharmaceutical carrier or diluent will, of course, depend on the intended route of administration, e.g. Depending on the route of administration, for example parenteral, topical, oral or by inhalation.

For parenteral administration, the pharmaceutical compositions can be administered in ampoules or as suspensions in aqueous or non-aqueous liquids. It is in the form of a sterile injectable liquid-like solution.

For topical administration, the pharmaceutical composition may be a cream, soft cream, etc. suitable for administration to the eyes, ears or nose. It is in the form of salves, liniments, lotions, pastes and drops.

For oral administration, the pharmaceutical composition may be in the form of tablets, capsules, powders, pellets, troches, It is in the form of a lozenge, lozenge, liquid or emulsion.

When the pharmaceutical composition is used in the form of a solution or suspension, a suitable pharmaceutical carrier or diluent Examples of agents are: water for aqueous systems; ethanol for non-aqueous systems; Serine, propylene glycol, corn oil, cottonseed oil, peanut oil, sesame oil, liquid Raffin and its mixture with water: in solid systems, lactose, kaolin and mannitol, and for aerosols, dichlorodifluoromethane, chloro Includes trifluoroethane and pressurized carbon dioxide. Additionally, a pharmaceutical carrier or In addition to diluents, compositions of the invention may also contain stabilizers, antioxidants, preservatives, lubricants, May contain other ingredients such as suspending agents and viscosity modifiers, provided that the additional ingredients has no detrimental effect on the therapeutic action of the compositions of the invention.

The pharmaceutical preparations so described may be prepared, if appropriate, according to conventional methods in pharmaceutical chemistry. , the desired final product.

Generally, particularly for the prophylactic treatment of asthma, the composition will be in a form suitable for administration by inhalation. be. (The composition, when administered by a conventional nebulizer, contains an aqueous base of the active ingredient.) Consists of a solution or suspension. Alternatively, the composition may be delivered from a pressurized aerosol container. A suspension or solution of the active ingredient in a conventional liquefied propellant or pressurized gas to be administered. Consisting of Additionally, the composition may be used with a solid diluent for administration from a powder inhalation device. Consists of diluted solid active ingredients. In the composition, the amount of carrier or diluent varies, but is preferably the bulk of the active ingredient suspension or solution. dilution If the agent is a solid, it may be present in an amount less than, equal to, or greater than the solid active ingredient. You may.

Typically, compounds of formula I cause suppression of symptoms of diseases in which leukotrienes are the etiology. The composition is administered to the patient in a non-toxic amount sufficient to cause sterilization. using this method the dosage of the composition ranges from 50 mg to 1000 mg of active ingredient for each dose. selected from. For Saili, the daily dosage is selected from about 50mg to about 5000mg. Equal doses are administered from 1 to 5 rgJ per day, depending on the given resin.

A therapeutically effective amount of a compound of formula I is administered to a patient, preferably in the form of a pharmaceutical composition. Included within the scope of this disclosure is a method of treating a disease mediated by LTB, which comprises: be caught. For example, by administering an effective amount of a compound of Formula I, Suppressing symptoms of allergic reactions is within the scope of this disclosure. The administration is Can be carried out in dosage units at appropriate intervals or, if necessary, in a single dose. Ru. Typically, this method is carried out when relief of the symptoms is specifically needed. but, The method is further advantageously carried out as a continuous or prophylactic treatment. Must be treated Administer from the above dosage range, taking into account factors such as severity of symptoms or disease. It is within the skill of the art to determine the effective dose to be administered by routine experimentation.

Additionally, pharmaceutical compositions and methods of use thereof provide a combination of a compound of formula I and H, a blocking agent. The combination includes antigen-induced respiratory anaphylaxis or similar Contains sufficient amounts of both compounds to treat allergic reactions. useful here Typical H1 blockers include cromolyn sodium, ethanolamine species (diphenyl (enhydramine), ethylenediamine (pyrilamine), alkylamine species (chlorpheniramine), piperazine species (chlorcifrizine) and Includes compounds from the enothiazine species (promethacin). 2-C4-(5-but lomo-3-methylpyrid-2-yl)butylamino]-5-[(6-methylpyry H1 blockers such as d-3-yl)methyl]-4-pyrimidone are an aspect of the present invention. It is particularly useful in

biological assay The specificity of the antagonistic activity of many compounds of the invention has been demonstrated by the use of potassium chloride, carbachol, due to its relatively low level of antagonism to agonists such as stamine and PGF2. Measure again.

The receptor binding affinity of the compound used in the method of the present invention was determined by It is measured by the ability to bind to the [”H]-LTB binding site in the cell membrane. The LTB4 antagonist activity of the compounds used in the method was determined in a dose-dependent manner by Fuller 2 ( fura-2), transition state calcium measured with a fluorescent calcium probe It is measured by its ability to antagonize manifested LTB4. The method used is as follows (Pennsylvania Medical College) and Dr. John Lee (Dr. John Lee (SK&F, Department of Immunology) and 10% (v/v) febrile 5% Cot, 95 in RPMI-1640 medium supplemented with activated fetal orchid serum. % air at 37°C in a humidified environment. Transfer the cells to a T-flask and spinner. - grown in both culture media. Differentiate U937 cells into monocyte-like cells with DMSO. The cells were grown at 1X10' cells/ml in the above medium containing 1.3% DMS○. and incubation continued for 4 days. The cells generally have a density of 0 ．． 75-1.25X10' cells/ml and centrifuged at 800xg for 10 minutes. It was collected by attaching it.

Preparation of fraction enriched in U937 cell membrane The collected U937 cells were diluted with 1mM E. Wash with 50mM Tris-HCI (pH 7.4, 25°C) containing DTA (buffer A). Purified. Cells were resuspended in Buffer A at a concentration of 5X10' cells/ml and (P arr) cylinder for 10 minutes at 750 psi and Q°C. pulverized by filtration. Centrifuge the crushed cell preparation at 1.000xg for 10 minutes. The heart was isolated. Boil the supernatant at 50%. Centrifuged at OOOxg for 30 minutes. the The pellet was washed twice with buffer A. The pellet was soaked in 50mM Tris-HCl ( resuspend at approximately 3 mg membrane protein/ml using The samples were immediately frozen and stored at -70°C.

[3H]-LTB4 binding to U397 membrane receptor [3H]-LTB, binding assay 10 m in the presence or absence of various concentrations of LTB4 or SK&F compounds. M CaCl2.10mM MgCl2, [sH Co L T B 4, U937 5QmM Tris-MCI (pH 7,5) containing cell membrane protein in 11 buffer solution, 25 ℃ (standard conditions). Each experimental rating represents the average of three equivalent measurements.

[Total and non-specific binding of 3H3-LTB4 was measured with 2 μM unlabeled, mLTB4, respectively. Measured in the absence or presence of 4. Difference between specific binding, total binding and non-specific binding It was calculated as a difference. Radioligand competition experiments were performed under standard conditions in 0.2 ml reactions. Approximately 2 μM [3H]-LTB in a volume of 4.20 to 40 μg of U937 cell membrane protein. White matter, increasing concentrations of LTB4 (0,1 BM ~ 10 nM) or other competitive lipids Gand (0.1 HM to 30 μM) and incubated at 25°C for 30 minutes. I bet. Unbound radioligand and competitive drugs are membrane-bound by vacuum filtration. separated from the ligand. Liquid scintillation of membrane-bound radioactivity on the filter Measured by spectroscopy.

Saturation binding experiments on U937 cells were performed under standard conditions in a 0.2 ml reaction volume. , about 15-50 μg of U937M protein and increasing concentrations of [lHcoLTB , (0.02-2.0mM) and incubated at 22°C for 30 minutes. became. Ink LTB4 (2 μM) in different sets of incubation tubes. and non-specific binding was measured. Compute data from saturation binding experiments ``subjected to ``ter-assisted nonlinear least squares curve fitting analysis'' and further performed a scutchard ( Analyzed by S catchard method.

Uptake of Fuller 2 by differentiated U937 cells The harvested cells were treated with 0.1% BSA ( RIA grade), 1.1mM Mg5o, 1.0mM CaCl2 and Krebs-Ringer-Hensillet (Krebs R) containing 5mM HEPES 2 x 10 cells in buffer (pH 7.4, buffer B) Resuspend at 6 cells/ml. Diacetomethoxy ester of Fuller 2 (Fuller 2 /AM) to a final concentration of 2BM and the cells were incubated for 30 min at 37°C in the dark. Cubated. The cells were centrifuged at 800Xg for 10 minutes and added with fresh buffer. Resuspend at 2X10' cells/ml in B and incubate for 20 minutes at 37°C. The incorporated ester was completely hydrolyzed. The cells were incubated at 800Xg for 10 minutes. Centrifuge for a while and resuspend at 5xlO' cells/ml in fresh, chilled Buffer B. I set it. Cells were kept on ice in the dark until used for fluorescence measurements.

J ohnson group ndationBiomedical Instrumentation Gr It was measured with a fluorometer designed by Oup).

The fluorometer is equipped with a temperature controller and a magnetic stirrer under the cuvette holder. wave Set the length to 339 nm for excitation and 499 nm for emission. All experiments are , at 37° C. with constant mixing.

U937 cells were diluted with fresh buffer to a concentration of I x 106 cells/ml and kept on ice in the dark. It was maintained strictly. Aliquot (2 ml) of the cell suspension into a 4 ml cuvette. and the temperature was raised to 37°C (maintained in a 37°C water bath for 10 minutes). Q Transfer the bet to a fluorometer and monitor the fluorescence for approximately 1 minute before adding the stimulant or antagonist. The measurements were taken approximately 2 minutes after stimulation. Agonist and antagonist in 2 μm aliquots added.

To detect potential agonist activity, antagonists were first added to the cells in the fluorometer.

Then, after about 1 minute, add 10 nM LTB4 (maximum effective concentration) and Ca” movement [Ca”] i was calculated using the following formula: F is the relative maximum fluorescence of the sample. This is a light measurement value. F @ax is 10 μl of 10% Triton Measurements were made by lysing cells with X-100 (final concentration 0.02%). F After measuring +ax, add 67μ+ 100mM EDTA solution (pH 10). Overall chelate Ca” and quench Fuller 2 signal to obtain F win Ta. [Ca”]i level for 10 nMLTB4 in the absence of antagonist is 100 %, and the basal [Ca”]i was 0%. IC, the concentration was 10 nMLT Concentration of antagonist that blocks 50% of Bn-induced [Ca”]i movement. The EC6° for the increase in [Ca2'']i transfer from the source refers to the concentration at half the maximum increase. . The Ki for calcium transfer was determined using the following formula: In the above experiment, the LTB4 concentration was 10 nM and E Cs. was 2BM.

The results for compounds tested by these methods are shown in Figure III.

U-937PMN U-937PMN Structure, base, tong! Palanquin IC, o, μM Nishisakuri Shidanri Exl 4.0 (1, 4) 2.0 2.4 3.7 0 0Ex2 23 (Fi, 4.7 - 3.0 0 0Ex3 47 (17) 5.8 0,65 0.58 0 0 Ex4 6.5 (2,2) 3.4 2.2 8.5 0 0Ex5 41 (1 4) 1.1 2.2 0.72 0 0Ex6* 6.1 (2,0) 0.6 8 0.14-0.74 0 0* Title compound ! Twisting Next, examples will be given to explain the preparation and use of the compounds of the present invention. these fruits The examples are merely illustrative and are not intended to limit or even limit the scope of the invention. stomach. Acknowledge that this material was owned by the inventors and refer to the claims. It is something.

Example A 8-(4-methoxyphenyl)octane-1-(4-toluenesulfonate) A (1) 7-octyn-1-ol Under an argon atmosphere, 35% KH (27 g, 240 mmol) in mineral oil was dissolved in hexane. and treated dropwise with 1,3-diaminopropane. The mixture until homogeneous was stirred at room temperature. The flask was cooled to 0°C and 3-octyn-1-ol (1 0g179mmol, Lancaster Synthesis (Lancaster 5ynthes) is)) was added slowly. The reaction was then stirred at room temperature for 18 hours.

The reaction was quenched with water (50ml) and the product extracted into ether. organic layer was washed with 10% HCI (3 x 15 m) and brine and dried (with MgSO3). Dry. Evaporation gave the title compound, which was used without further purification: 'HNMR (90MHz, CDCl5) δ 3.65 (t, J=511z, 2H, 0CHt), 2.23 (Otori, 2H, C11z)@, 2,0 (m, LH, acetylene), 1.7-1.2 (11,8H, (C H2) 4): IR (liquid film) vmax 3350.2930.2125cm- '.

A(2) 7-octyne-1-t-butyldiphenylsilyl ether 7-octyne ion-1-ol (3.8 g, 30 mmol) was dissolved in dimethylformamide (10 ml). ) and heated to 0°C with t-butylchlorodiphenylsilane (10.2ml).

33 mmol) and imidazole (3.65 g, 45 mmol).

The reaction was stirred at 0° C. for 10 minutes and at room temperature for 3 hours. Add water and convert the product into acetic acid. Extracted into ethyl. The ethyl acetate extract was washed with H,O and brine, ( dried over Na2SOs). Remove the solvent and flash column chromatography the residue. Purification by chromatography (silica, hexane) gave a yellow oil: 'HNMR ( 250MHz, CDCl5) δ7.7 (d, 411.aryl), 7 ．． 4 (m, 6L aryl), 3.63 (t, 2B, 0clb), 2.23 (m, 2H, cHz), 1.97 (t, IH, acetylene), 1.6-1 ．． 3 (m, 8H, (C112)4), 1.05 (s, 9H, t-butyl ): IR (film) vmax 3321.2940.2125 c m-' .

A(3) 8-(4-methoxyphenyl)-7-octyne-1-t-butyldif phenylsilyl ether Add triethylamine (50 ml) to a flame-dried flask under an argon atmosphere. ) of 4-iodoanisole (5.34 g, 22 mmol) was added, followed by 7 -Octyne-1-t-butyldiphenylsilyl ether C9, 84 g, 27 mi (350 mg, 0.44 mmol), (Pb3P)tPdclz (350 mg, 0.44 mmol) and Cur (200 mg, 0.88 milJ mol) were added. the resulting mixture Heated at 50°C for 4 hours. After cooling to room temperature, filter the reaction mixture and evaporate the solvent. I set it. The residue was partitioned between ethyl acetate and water, the organic layer was collected and washed with brine, Dry (over Na2SO). Evaporate the solvent and subject the residue to flash column chromatography. Purification by chromatography (silica, 1% ethyl acetate/hexanes) gave an oil. :IHNMR (250Melium CDCl,) δ7.7 (d, 411. aryl), 7.4 (i, 6H, aryl), 7.35 (d, 211. aryl) ), 6.8 (d, 2H, aryl), 3.8 (s, 3H, 0CI II3), 3.7 (tA2L OCH2), 2.4 (t, 2H, cHz), 1.7-1.3 (Lotus, 8H, (C1h)4), 1.05 (s, 9H, t-butyl)B A(4) 8-(4-methoxyphenyl)octane-1-t-butyldiphenyl silyl ether 8-(4-methoxy) in ethanol (10ml) and ethyl acetate (10ml) phenyl)-7-octyne-1-t-butyldiphenylsilyl ether (2,2 5% Pd/C (100 mg) was added to the solution. 75% of the mixture B2 at psi for 4 hours. Filter the reaction through Celite and evaporated the solvent to obtain an oil: 'HNMR (250MHz, CDCl5) δ7,7(d, -4H, aryl ), 7.4 (m, 6B, aryl), 7.05 (d, 2H, 7 lizlz) , 6.8 (d, 211.7'J-le), 3.8 (3,311,0C I(3), 3.6 it, 2n.

0CH2), 2.5 (t, 2H, benzyl), 1.75-1.3 (eng, 12 111. (C) + 2) 6), 1.0 (s, 9Fi, @t-bu A(5) 8-(4-methquinphenyl)octan-1-ol tetrahydrof 8-(4-methquinphenyl)octane-1-t-butyl in run (20 ml) Diphenylsilyl ether (2.2 g, 4.6 mmol) was cooled to 0°C and Tetrabutylammonium chloride (14 ml, 14 mmol, IM/Tetrahydro Furan). The cooling bath was removed and the reaction was stirred at room temperature for 24 hours. anti The reaction was diluted with ethyl acetate, washed with B20 and brine, and diluted with (Na2so< ) dried. The solvent was evaporated and the residue was subjected to flash column chromatography ( Purification on silica (0-20% ethyl acetate/hexane) gave a white solid: fused Point 47-49℃: 'HNMR (250MHz, CDCl,) 67, 15 (d, 2H, Ali aryl), 6.86 (d, 2H, aryl), 3.85 (s, 3H, 0 CL), 3.68 (t, 2H, 0CHz), 2.62 (t, 2B, benzyl), 1.75-1.3 (m, 12L (CH2)6).

A(6) 8-(4-methoquinophenyl)octane-1-(4-toluenesulfonate) 6-(4-methoxyphenyl)octan-1-ol (5,9 g, 25 mmol) in dry CH2Cl2 (100 ml) under an argon atmosphere. , cooled to 0°C.

To this solution was added pyridine (2.5 mL, 30 mmol) and 4-toluenesulfonate. Nyl chloride (5.4 g, 28 mmol) was added. The reaction mixture was heated at 0°C for 20 The mixture was stirred for 24 hours at room temperature. Wash the reaction solution with B20 and brine. , (Nasso, ). Evaporate the solvent and transfer the residue to a flash column. Purified by chromatography (silica, 0-10% ethyl acetate/hexane) A white solid was obtained.

'HNMR (250MB2. CDC13) δ7.79 (d, 2H, Ali aryl), 7.35 (d, 211 [, aryl), 7.09 (d, 2H, 7IJ - le), 6.82 (d, 2L7 +) - le), 4.04 ( s, 21f, 0CHJ　, R゜ 8 (s, 3H, 0cH3), 2.55 (t, 2H, benzyl), -2, 46 (s, 3H, cllI,), 1.75-1.15 (Fragrance B 12H, (CHz)s).

Example B 6-(4-methquinphenyl)hexane-1-(4-toluenesulfonate) B (1) 5-hexyne-1-t-butyldiphenylsilyl ether 5-hexyne -1-ol (3 g, 30 mmol, Aldrich) Dissolve t-butylchlorodiphenyl in methylformamide (10 ml) at 0°C. Runlan (10.2 ml, 33 mmol) and imidazole (3.65 g, 4 5 mmol). The reaction was stirred at 0°C for 10 minutes and at room temperature for 3 hours. .

Water was added and the product was extracted into ethyl acetate. The ethyl acetate extract was mixed with B20 and Washed with brine and dried (Na2So4). Evaporate the solvent and remove the residue. Purified by flash column chromatography (silica, hexane) to give a yellow color. Got oil: 'HNMR (250MHz, CDCl5) δ7.7 (d, 4H, Ali ), 7.4 (m, 6H, aryl), 3.65 (t, 2H, 0CHz ), 2.2 (m, 2H, clh), 1.9 (t, LH, acetylene), 1.7 (I++, 4HCCHx -CHz), 1.05 Cs, 911. t-butyl): B(2) 6-( 4-Methoxyphenyl)-7-hexine-1-t-butyldiphenylsilyl ether Tell Add triethylamine (50 ml) to a flame-dried flask under an argon atmosphere. ) was added to 4-iodoanisole (5.34'g, 22 mmol), and then 5-hexyne to 1-t-butyldiphenylsilyl ether (8.83g, 27 mmol), (PhsP)zPdc14 (350 mg, 0.44 mmol) and and CuI (200 mg, 0.88 mmol) were added. The resulting mixture Heated at 0°C for 4 hours. After cooling to room temperature, filter the reaction mixture and evaporate the solvent. Ta. The residue was partitioned between ethyl acetate and water, the organic layer was collected, washed with brine and ( It was dried with Na2S○4). Evaporate the solvent and flash the brutality column chroma Purification by tography (silica, 1% ethyl acetate/hexane) gave an oil: 'HNMR (2501 [z, CDC13) δ7.7 (d, -4H, Ally ), 7.4 (m, 6H, aryl), 7, 35 (d, 2H, aryl) ), 6. g (d, 2a, aryl), 3.8 (s, 311[, OC■s) , 3.7 (t, 2HB 0CR2), 2.4 (t, 2H, CH2), 1.7 (m, 4H, CI '+2-CH2), 1.05 (s, 9H, t-butyl) B B(3) 6-(4-methoxyphenyl)hexane-1-t-butyldiphenyl silyl ether 6-(4-methoxy) in ethanol (10ml) and ethyl acetate (10ml) phenyl)-5-hexyne-1-t-butyldiphenylsilyl ether (2,O 5% Pd/C (100 mg) was added to the solution. 7 of the mixture B2 at 5 psi for 4 hours. Filter the reaction through Celite and evaporate the solvent. I got the oil by: 'HNMR (250MIIZ, CDC13) δ7.7 (d, 411.A reel), 7.4 (m, 6H, aryl), 7,05 (d, 2E1. aryl), 6.8 (d, 2B, aryl), 3.8 (s, 3■, ocB , ), 3.6 (t, 2LOCBz), 2.5 (t, 2H, benzyl) , 1.55 (m, 4H, Cu2 (Hz), 1.3 (m, 4LcB2-C H2), 1,0 (s, 9fl, t-butyl).

B(4) 6-(4-methoxyphenyl)hexane-1-ol tetrahydrof 6-(4-methoxyphenyl)hexane-1-t-butyl in run (20 ml) Diphenylsilyl ether (2.0 g, 4.6 mmol) was cooled to 0°C and filtered. Tetrabutylammonium dichloride (14 ml 14 mmol, LM/tetrahydro Furan). The cooling bath was removed and the reaction was stirred at room temperature for 24 hours. anti The reaction was diluted with ethyl acetate and washed with B20 and brine (Na2So.

) dried. Evaporate the solvent and subject the residue to flash column chromatography. (silica, 0-20% ethyl acetate/hexanes) to give a white solid. HN MR (250MHz, CDC1x) δ7.05 (d, 2L ant aryl), 6.8 (d, 2H, aryl), 3.8 (s, 3H, 0cH3 ), 3.65 (t, 2H, 0cH=), 2.55 (t, 21(, Benji ), 1.6 (m, 4H, b[+2 -CH2), 1.4 (m, 4H, cHz-CH2).

B(5) 6-(4-methquinphenyl)hexane-1-(4-toluenesulfonate) 6-(4-methquinphenyl)hexan-1-ol (5,36 g, 2 5 mmol) was dissolved in dry CH2CH2C12 (ioo) under an argon atmosphere. , cooled to 0°C. To this solution was added pyridine (2.5 ml, 30 mmol) and 4-Toluenesulfonyl chloride (5,4'g, 28 mmol) was added. this The reaction was stirred at 0° C. for 20 minutes and at room temperature for 24 hours. The reaction solution was immersed in H, O or and brine and dried (Na2SO4). Evaporate the solvent and remove the residue flash column chromatography (silica, 0-10% ethyl acetate/hexane) A white solid was obtained: 'HNMR (250MB2. CDC13) δ1.6-1.3 (m, 8B, (CB2) 4), 2.4 (3, 3H, CH3), 2, 5 (t, 2) 1 ．． benzyl), 3.8 (3,3H,0CR3), 4.0 (t, 2H,0 CHJ, 6.80 (d, 211P. Ali ), 7.0 (d, 2H, aryl), 7.3 (d, 2H, aryl) ), 7.8 (d, 2111.aryl).

Lithium hexamethyl in tetrahydrofuran (30 ml) under argon atmosphere. A freshly prepared solution of disilazide (64 mmol) was added with tetrahydrofuran (4 mmol). (4-carboxybutyl)triphenylphosphonium bromide (1 A suspension of 76 g (30 mmol) was added at room temperature. Stir the reaction for 15 minutes, During this time, an orange-red ylide was formed. In tetrahydrofuran (30 ml), 4-a A solution of usaldehyde (4.5 g, 30 mmol) was added dropwise and stirring continued for a further 20 min. It continued for a while. The reaction was quenched with HzO (50ml) and ether (30ml). Diluted. The aqueous layer was acidified with 3N HCI to pH 1.0 and the product was extracted with ethyl acetate ( 3 x 50 ml). The combined organic layers were dried (with MgSO4) to form Chromatography (silica, 1% methanol/CH2C) The E-olefin was purified as a solid by HNMR (200M [IZ, CDC13) δ7.3 (d, 21 (, aryl), 6.8 ( d, 2 ■, aryl), 6, 3 (d, 1) 1. olefin), 6.0 ( m, ltl, olefin), 3.8 (s, 3H, 0cB3), 2.3 (mB 411, allyl CH, and cnzco□), 1.8 (4,2H, C112 ).

C(2) E-6-(4-methoxyphenyl)-5-hexen-1-ol drying E-6-(4-methoxyphenyl)-5-hexene in ether (10ml') Acid (1.1 g, 5.0 mmol) was dissolved in ether (10 ml) under an argon atmosphere. LiAIH<　(240 mg, 6.0 mmol) was added to the vaginal fluid. I got it. The reaction mixture was refluxed for 45 minutes. Cooled to room temperature, the reaction was dissolved in HzO (1 0 ml) followed by quenching with 6N HzSO4 (7 ml). Ethyl acetate (20 ml) and the organic layer was separated, dried (MgSO4) and evaporated. A white crystalline solid was obtained: melting point 65-66°C: 'HNMR (200mg2.CDC13) δ7.2 (d, 2H, aryl ), 6.8 (d, 2■, aryl), 6, 3 (d, ill, olefin ), 6.1 (m, 1B, orefui:/), 3.8 (S, 3H, 0CH 3), 3.6 (tB 21 (, 0CHz), 2.2 (q, 2H, allyl), 1.5 (m, 4 [1, CH2-CD2).

Elemental analysis as HCBH+s○2 Calculated value (%): C, 75, 65; H, 8, 80 Measured value (%): C, 75, 45; H, 8, 95M5 (CI): 207 (M+H).

C(3)E-6~(4-methoxyphenyl)-1-(4-toluenesulfonate )-5-hexE-6-(4-methoxyphenyl)-5-hexen-1-ol ( 1.6 g, 7.0 mmol) in dry ChzCh (50 m 1), 4-toluenesulfonyl chloride (7.0 g, 36 mmol) and and pyridine (3 ml). This reaction solution was stirred at room temperature for 3.5 hours. Ta. Water (,40ml) was added to the reaction and the organic layer was separated and dried (over MgSO). Dry. The product was purified by flash column chromatography (silica, 10% acetic acid). Purification by ethyl/hexane) gave an oil: 'HNMR (200MHz, CDCl5) 67, 8 (d, 2E1.A reel), 7.3 (d, 211. aryl), 7, 2 (d, 2H, aryl) ), 6.8 (d, 2H, aryl), 6.2 (d, LH, olefin ), 6.0 (m, 11 olefin), 4. L (t, 2H, 0cH2) , 3.8 (s, 3111.0cH3), 2.4 (s, 3H, cHR), 2, 1 (q, 2H, allyl), 1.6 (m, 4H, CHl-CJ)-M S (CI): 361 (M+H).

Example I N-(3-carboxyphenyl)-6-(E-2-carboxyethynyl)-5- Decyloxy-2-picolinamide, disodium salt 1(a) 3-decyloxy C-2-(hydroxymethyl)pyridine 3-hydroxy-2-(hydroxymethyl)pyridine ) Pyridine hydrochloride (500 mg, 3.09 mmol, Aldrich, 85% ) was dissolved in dry dimethylformamide (10 ml) and anhydrous KxC (h (1, 30g19.27 mi! J mol) and 1-iododecane (0.80 ml 1.3. 71 mmol). The reactants were heated at 90°C under an argon atmosphere for 1 ．． Stir vigorously for 5 hours. Cooled to room temperature, the reaction mixture was diluted with ethyl acetate (10 (0 ml), washed with HzO (5 x 20 ml) and brine, (MgS dried with O4). This compound was purified by flash column chromatography (silicon column chromatography). 20% ethyl acetate/petroleum ether) to give the title product: ' HNMR (250MHz, CDC13) 68.17 (m, 18.6 -pyridyl), 7.2 (m, 2H, 4-pyridyl, 5-pyridyl), 4. 78 (s, 2H, C11z), 4.48 (broad singlet, IH, O H), 4.05 (t, J=6.6Hz, 2H, 0CR2), 1.9~ 0.90 (m, 19H, aliphatic).

1(b) 3-decyloxo-2-pyridinecarboxaldehyde dry CH2C 14 (7 ml), 3-decyloxy-2-(hydroxymethyl ) Pi’) Zine (560 mg, 2.11 mmol) was added to MnO2 (1,80 g- 20.7 mmol) and stirred at room temperature for 24 hours. This reaction product is Filter through a bed of water and remove the solvent under vacuum to obtain the aldehyde as a light yellow oil. .

The aldehyde was used directly in the next step without further purification.

Hc) 2-(E-2-carboxinemethylethynyl)-3-decyloxypyridi 3-decyloxy-2-pyridinecarboxaldehyde (4 29 mg, 1.63 mmol) was dissolved in dry toluene (3.5 mmol) under an argon atmosphere. Dissolve in methyl (triphenylphosphor-anilidene) acetate ( 820mg.

2.45 mmol). The reaction mixture was heated at 45°C for 30 minutes. , at which point the reaction became homogeneous. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (1 00ml), washed with H2O (2X20ml) and brine, (M g S O4). The product was subjected to flash column chromatography ( Silica, ethyl acetate/CH2Cl□:petroleum ether (10:5:85)) Purification gave the product as a pale yellow solid: 'HNMR (200mg2.CDCl δ8.25 (m, LH,6-pyri Jill), 8.1 (d, J=16.2Hz.

IE [, olefin), 7.25 (m, 2H14-pyridyl, 5-pyridi ), 7.05 (d, J=16.2Hz, LH.

Olefi:/), 4.05 (t, J=6.6Hz, 2H, 0CR2) , 3.85 (s, 3H, C02cHs), 1.95~O. 90 (m, 19L aliphatic).

1(d) 2-(E-2-carboxymethylethynyl)-3-decyloxypyri Gin N-oxide 2-(E-2-carboxymethylethynyl)-3-decyloxypyridine (39 0 mg, 122 mmol) in dry CH2Cl□ (6 ml) under an argon atmosphere. 85% 3-chloroperoxybenzoic acid (278 mg , 1.34 mmol). After the addition, remove the cooling bath and allow the reaction to come to room temperature. The mixture was stirred for 24 hours. This reaction solution was diluted with CHzCh (DOml) and saturated. Poured into aqueous NaHC○3 (50ml). The aqueous phase was heated to CHzClz (3x50m The combined CH2Cl2 extracts were washed with brine and extracted with (MgSO4). ) dried. Furatunyu Rikiram Chromatography (Nori Riki, 10% GHzC 1z/ethyl acetate) to obtain N-oxide as a pale yellow solid: 'HNM R (250M [lZ, CDC13) δ8.18 (d, J=16.2tl z, LH, olefin), 7.97 (d.

J=6.5Hz, LH, 6-pyridyl), 7.58 (d, J=16.2 Hz, LH, 7), 7.11 (dd, J=8, 6.6.5Hz , LH,5-pyridyl), 6.82 (d, J=8.6Hz, IH, 4 -pyridyl), 4.08 (t, l■ 6, 6flz, 2H, 0CB2), 3.82 (s, 3H, C0tCHs ), 1.93-0.88 (m, 19H, aliphatic).

1(e) 6-(E-2-carboxymethylethynyl)-5-decyloxy-2 -pyridone 2-(E-2-carboxymethylethynyl)-3-decyloxypyri Zine N-oxide (180 mg, 0.537 mmol) was added under an argon atmosphere. It was dissolved in dry dimethylformamide (2.2ml) and cooled to 0°C. this Add trifluoroacetic anhydride (0.76ml 1.5.38 mmol) to the solution. and then the cooling bath was removed. The reaction was stirred at room temperature for 18 hours.

The reaction solution was diluted with ethyl acetate (75 ml) and saturated aqueous NaHCOs (30 ml). ml) slowly. The organic layer was diluted with NaHC○x (20ml) and bly and dried (MgSO,). Obtain the product as a yellow solid, which is Used without further purification.

' HNMR (250mg2. CDC13) 67, 75 (d, J=16 ．． 3Hz, LH, olefin), 7.40 (d.

J=9.8Hz, Il, 3-pyridyl), 7.01 (d, J=16. 3Hz, IH, olefin), 6.73 (d, J=X.8 Hz, IH, 4-pyridyl), 3.95 (tJ=6.6Hz, 2H, 0c Hz), 3.82 C5,3H,C0tCHs), 1. W2 ~0.88 (m, 19H, aliphatic) MS (CI): 336 (M H).

1(f) 6-(E-2-carboxymethylethynyl)-5-decyloxy-2 -trifluoromethylsulfonate 6-(E-2-cal) in dry CH2Cl2 (3.0 ml) under argon atmosphere. boxymethylethynyl)-5-decyloxy-2-pyridone (200 mg, 0. Dry pyridine (0.48 ml 1.5.9 6 mmol) and trifluoromethanesulfonic anhydride (0.30 ml, 1.7 Added 8mm thick.

The reaction was stirred at 0°C for 15 minutes. The reaction mixture was diluted with ethyl acetate (50ml). Dilute, B20 (20ml), 2% HCI (10ml), saturated NaHC○ 3 (20 ml) and brine and dried (MgSO4). flash From column chromatography (silica, 5% ethyl acetate/petroleum ether) Purified and obtained the sulfonate as cell-free: 'HNMR (250M11z, CDC13) 67, 97 (d, Im15. 8Hz, IH, olefin), 7.36 (d.

Im8.8Hz, IH, 3-pyridyl), 7.11 (d, Im8.8H z, Il4-pyridyl), 6.96 (d, Im15D8 fiz, 1t [, I7 in), 4.05 (t, Im6.5Hz, 2 H, 0CH2), 3.83 (s, 3H, C0xCHsj, 1.92 ~0.88 (rl, 19L aliphatic). -1(g)N-(3-carboxymethy (ruphenyl)-6-(E-2-carboxymethylethynyl)-5-decyloxy -2-picolinamide 6-(E-2-carboxymethylethynyl)-5-decyl Oxy-2-trifluoromethylsulfonate (160 mg, 0.342 mmol) Dissolve 3-aminobenzoic acid in dry dimethylformamide (1.25ml) and Methyl acid (775 mg, 5.13 mmol, Lancaster) )), Pd(OAc)z (4°5 mg, 0.020 mmol) and 1. 1'-bis(diphenylphosphino)ferrocene (22 mg, 0.040 mmol) It was processed sequentially using - Carbon oxide was bubbled gently through this solution for 5 minutes. . The reaction was then heated at 90° C. for 4 hours under a CO atmosphere (balloon pressure). did. After cooling to room temperature, the reaction was diluted with ethyl acetate (75 ml) and diluted with 2% HCI. (5X10ml), 820 (15ml), saturated NaHC○3 (15ml) and brine and dried (MgS04). flash color Mucochromatography (silica, ethyl acetate: CHzCb: petroleum ether (10 The amide was purified as a colorless solid by HNMR (25 0MHz, CDC13) δ9.85 (s, 11 NH), 8.29 ( s, 11.2-phenyl), 8, 27 (d, Im8.7Hz, 11.3 -pyridyl), 8.14 (d, Im7.9Hz, LH,4-phenyl) , 111. P0 (d, J'15.8Hz, IH, olefin), 7.84 (d, Im7 ．． 9Hz, If [, 6-Fen/S, 7.48 (dd.

J-7,911 [z, IH, 5-phenylene, 7.38 (d, Im8.7 Hz, IH, 4-pyridyl), 7.08 (d, J-1T, 1ll Hz, 1111. I7　I:/)　、4.12　(t、　Im6.6肚、　 211.0CHz), 3.95 (s, 311.C0tCgs), 3.88 (S, 3] 3.C0tCH3), 1.96~0.88 (+a, 19B , aliphatic).

Elemental analysis 'CzsHssO@N, calculated value (%): C, 67, 72: H, 7, 31; N, 5.64 Measured value (%): C, 67, 50; H, 7 , 27: N, 5.57M5 (CI): 497.5 (M10H).

1(h)N-(3-carboxyphenyl)-6-(E-2-carboxyethynyl )-5-decyloxy-2-picolinamide 5 disodium salt N-(3-carbo (oxymethylphenyl)-6: (E-2-carboxymethylethynyl)-5-decy 2-picolinamide (60 mg, 0.121 mmol) in tetrahydrochloride Dissolved in Lofuran (1,25 inl) and MeOH (0,50 ml), IML Treated with iOH (0.50 ml). The reaction was stirred at room temperature for 6 hours. Applicable The reaction mixture was mildly acidified by adding 2% HCI (0.75 ml) and then Dilute with ethyl acetate (50 ml) and add B20 (3X10 ml) and and dried (MgSO4); the solvent was removed under vacuum. this The diacid was dissolved in saturated aqueous Na2CO3 (3-5 ml) and subjected to reverse phase MPLC (RP-1 8 silica, 10-65% MeOH/Hz○) and isolated by lyophilization. and obtained as a white amorphous solid: 'HNMR (250Mllz, CD, OD) 68.22 (s, LH, 2- phenyl), 8.13 (d, Im8.7111z.

1■, 3-pyridyl), 7.90-7.70 (m, 211.4-phenyl, 6-phenyl), 7.73 (d, J-15°8Hz, IH, olefin ), 7.65 (d, J4.7Hz, IH,4-pyridyl), 7.4 8 (dd, Im7.9HzB IH15-phenyl), 7.17 (d, Im15.8Hz, 1H, Ole fin), 4.26 (t, Im6.6Hz, 211K 0CHz), 1.98-0.82 (Im, 19H, aliphatic) FAB-MS : (+v e), 513.1 (M+H); (-v e), 4 89.0 (M-Na).

N-(3-carboxyphenyl)-6-(2-carboxyethyl)-5-zosyl Oxy-2-picolinamide 2(a) N-(3-carboxymethylphenyl)-6-(,2-carboxymethylphenyl) ethyl)-5-decyloxy-2-picolinamide N-(3-carboxymethyl (ruphenyl)-6-(E-2-carboxymethylethynyl)-5-decyloxy -2-picolinamide (70 mg, 0.141 mmol) in ethyl acetate (1 ml) ) and treated with 5% Pd/C (10 mg) under H2 atmosphere (balloon pressure). The mixture was stirred for 4 hours. The reaction could not be followed by TLC and the product was ethyl acetate. It was insoluble in By adding CH, C1□ (5 ml) to the precipitated product, Once dissolved, the solution was filtered through a bed of Celite. Flush the product into a column Purified by chromatography (silica, ethyl acetate/CHZC1□), white The title picolinamide was obtained as a colored solid: 'HNMR (250 MHz, CDC 1g) 610.02 (s, 11. Q), 8.48 (s, IH, 2 -phenyl), 8, 18 (d, Im7.9Hz, 1■, 4-phenyl) , 8.11 (d, J-8,5Hz, Il, 3-pyridyl), 7.8P (d, Im7.9Hz, lH,6-phenyl), 7.46 (dd, I m7.9Hz, IH, 5-phenyl), 7.20 (пB J”8.5Hz, IH,4-pyridyl), 4.05 (t, Im6゜4Hz , 2H, 0CHz), 3.94 (5, 3B, C (hmo g3), 3.68 (s, 3B, C02c]h), 3.24 (t, J-6,9 Hz, 2H, CHz), 2.88 (t, J-6,9gz, 211. CH2), 1.88-0.86 (m, 19L aliphatic).

Elemental analysis: Calculated value (%) as CzsHssOgN2: C, 67, 45; H, 7, 68: N, 5.62 measured value (%'I: C, 67, 26; H, 7,76; N, 5.54M5 (CI): 499 (M10H).

2(b)N-(3-carboxyphenyl')-6-(2-carboxyethyl)- 5-decyloxy-2-picolinamide, dipotassium salt N-(3-carboxyme tylphenyl)-6-(2-carboxymethylethyl)-5-decyloxy-2 - picolinamide (54 mg S0.108 mmol) in tetrahydrofuran (1 , 1 ml) and methanol (0,70 ml), and suspended in IMLiOH (0, 1 ml) and methanol (0,70 ml). 45ml 1.0.45 mmol). The reaction was stirred at room temperature for 30 hours. did. The reaction mixture was diluted with ethyl acetate (50ml) and 2% HCI (15ml). I poured it inside. Wash the ethyl acetate layer with B20 (3X20ml) and brine. , dried (MgSO4). Remove the solvent under vacuum and dissolve the solid diacid in KHCO 3 in an aqueous solution (3-5 ml). Reversed phase MPLC (RP-18 silica, 10~ 65% methanol/B20) and isolated by lyophilization to give a white amorphous solid. Got that salt as a body: 'HNMR (250MHz, CD30D) δ8.49 (s, LH, 2-F phenyl), 8.00 (d, J-8,5Hz.

1■, 3-pyridyl), 7.88 (d, Im7.9Hz, IH, 4-pyridyl) ), 7.72 (d, Im7.9Hz, illA 6- phenyl), 7.36 (m, 211.4-pyridyl, 5-phenyl), 4 ．． 11 (t, Im6.4flz, 2H,0Ctlz)A 3, 19 (t, Im6.9Hz, 2H, CB2), 2.66 (t, Im6. -9tlz, 2H, CBri, 1.92~0.8V (m, 19H , fat ali) FAB-MS: (10v e), 547.4 (M+H); (-we ), 507.3 (M-K).

Example 3 N-(3-carboxyphenyl)-6-(E-2-carboxyethynyl)-5- Tetradecyloxy-2-picolinamide, dilithium salt 3(a) 3-hydro xy-2-pyridinecarboxaldehyde 3-hydroxy-2-(hydroxymethane) pyridine hydrochloride (1.32 g, 6.9 mmol, Aldrich, 85 %) in dry CHzC1t (35 ml) and triethylamine (1.1 m l, 7.89 mmol) and Mn0t (6.0 g, 69 mmol) did. The reaction was stirred at room temperature for 18 hours, filtered through a bed of Celite, and dried under vacuum. Concentrated. This crude aldehyde can be used directly in the next step without further purification. Ta.

3(b) 3-tetradecyloxy-2-pyridinecarboxaldehyde Dry 3-hydroxy-2-pyridinecarboxaldehyde (approximately 6.9 mmol) Dissolved in dry dimethylformamide (10 ml), anhydrous KtCOs (2.86 g .

20.7 mmol) and l-iodotetradecane (2,00 ml, 7.59 mmol) rimol). The reaction was heated at 90°C under an argon atmosphere for 4.5 Stir vigorously for an hour. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (100 ml). Dilute, wash with H2O (5 x 20 ml) and brine, dry (MgSO4). Dry. Flash column chromatography (silica, 30% ethyl acetate/ (petroleum ether) to obtain its carboxaldehyde as light yellow electric oil. .

'HNMR (250MHz, CDC1x) δ10.43 (s, IH, CH, 8.38 (dd, J=4.1.1.5Hz, IdI.

6-pyridyl), 7.42 (m, 2H, 4-pyridyl, 5-pyridyl), 4.10 (t, J=6.5Hz, 2LOCH2), 1.91~0.88 (m, 27H, aliphatic).

Regarding 2-(E-2-carboxymethylethynyl)-3-decyloxypyridine Manufactured according to the method described in 'HNMR (250MHz, CDCh) δ8.22 (dd, J=4.0 ．． 1.8Hz, 18.6-pyridyl), Ill, 10(d, J=15.8 Hz, 1 [1, olefin), 7.21 (m, 2H,4-pyridyl, 5 -pyridyl), 7.02 (d, I=15.8Hz, IH, olefin), 4.02 (t, J=6.5Hz, 2B, 0CH2), 3.81 (s, 3H .

C02CB 1.1.88-0.1118 (m, 27B, aliphatic).

This compound is 2-(E-2-carboxymethylethynyl)-3-decyloxy Prepared according to the method described for pyridine N-oxide: 'HNMR (25 0MHz, CDC13) δ8.18 (d, J=16.2Hz, LH, O Refine), 7.95 (d.

J=6.5Hz, LH, 6-pyridyl), 7.58 (d, J=16.2 Hz, 1B, olefin), 7.10 (dd, J=8, 5.6.5Hz, Il, 5-pyridyl), 6.80 (d, J=8.5Hz, IH, 4 -pyridyl), 4.08 (t, J■ 6, 6Hz, 2H, 0CR2), 3.82 (s, 3H, C0tCHs) , 1.88-0.88 (m, 27H, aliphatic).

This compound is 6-(E-2-carboxymethylethynyl)-5-decyloxy ・’HNMR (250 M°, CD C13) 67, 75 (d, J=16.3+1z, LH, olefin) , 7.40 (d.

J = 9.811z, IH, 3-pyridyl), 7.01 (d, J = 16.3 E[z, lil, olefin), 6.73 (d, l≠X.8 Hz, IH, 4-pyridyl), 3.95 (tJ=6.6Hz, 2B, 0 Hz), 3.82 (s, 3H, cO2cH3), 1D82 ~0.88 (m, 27H1 aliphatic) This compound is 6-(E-2-carboxylic (dimethylethynyl)-5-decyloxy-2-trifluoromethylsulfonate 'HNMR (250MH2, CDC13 ) δ7.96 (d, J=15.7Hz, IH, olefin), 7.3 5 (d.

J=8.8Hz, IH, 3-pyridyl), 7.10 (d, J=8.8- Hz, 1111.4-pyridyl), 6.96 (d, i=15°7 Hz, LH, olefin), 4.04' (t, J=6.5Hz, 2H ,0CHz), 3.82 (S, 3H, C02CH3)@, 1.85 ~0.88 (t2711!, aliphatic).

3(g)N-(3-carboxymethylphenyl)-6-(E-2-carboxymethylphenyl) (Tylethynyl)-5-tetradecyloxy-2-picolinamide Example 1 (g) N-(3-carboxymethylphenyl)-6-(E-2-carboquine) using the method of (oxymethylethynyl)-5-decyloxy-2-picolinamide was produced:' HNMR (250MHz, CDC1,) 69.86 (s, 1111.N H), 8.29 (s, 18.2-phenyl), 8, 27 (d, J=8 ．． 7Hz, IH, 3-pyridyl), 8.13 (d, J=7.9Hz, Il4-phenyl), 8.09 (d, J=15.8Hz, LH, olefin) , 7.84 (d, J=7.9Hz, LH,6-phenyl), 7.48 (ad.

J = 7.9Hz, IH, 5-phenyl), 7.38 (d, J = 8.7H z, lfl, 4-pyridyl), 7.08 (d, I≠P5.8 Hz, LH, r 7 in), 4.12 (t, J=6.6Hz, 21 11. OCH, ), 3.95 (s, 3111.Co, bHs), 3.8 8 (s, 3B, C02clh), 1.94-0.88 (m, 27H, fat Aliphatic) MS (CI): 553.4 (M+H).

3(h)N-(3-carboxyphenyl)-6-(E-2-carboxyethynyl )-5-tetradecyloxo-2-picolinamide, dilithium salt N-(3-ka carboxymethylphenyl)-6-(E-2-carboxymethylethynyl)-5- Tetradecyloxy-2-picolinamide (173 mg, 0313 mmol) Dissolved in tetrahydrofuran (4.0ml) and methanol (1.0ml), ]J4 Treated with LiOH (1.0 ml). The reaction was stirred at room temperature for 48 hours. Stirred. The resulting gel was dissolved in H2O (3 ml), tetrahydrofuran and Methanol was removed under vacuum. This product was purified by reverse phase MPLC (RP-18 silica , 10-65% M e OH/H20) and isolated by lyophilization. , obtained the salt as a colorless amorphous solid: 'HNMR (250M) lz, cD30D) 68.32 (s, IH, 2- phenyl), 8.12 (d, J=8.7111z.

IH13-pyridyl), 7.85 (d, J=15.7Hz, LH, Ole fin), 7.83 (d, J=7.9Hz, 18.S- phenyl), 7.76 (d, J=7.9Hz, IH,6-phenyl) , 7.52 (d, J=8.7Hz, Il4-pyridyl), 7.38 ( dd, J=7.9Hz, LH, 5-)s-le)゛, 7.26 (d, J= 15.7Hz, LH, olefin) A 4, 16 (t, J=6.6Hz, 2■, 0CL), 1.94-0.89 (m, 27H, aliphatic) FAB-MS: (-iv e), 537 (M+H); (-v e), 529 (M-Li).

Example 4 N-(3-carboquinphenyl)-6-(E-2-carboquinethynyl)-5- Dodecyloxy-2-picolinamide, (dilithium salt) N-(3-carboquine) phenyl)-6-(E-carboquinethynyl)-5-dodecyloxy-2-pico Phosphoramide, dilithium salt is a substitute for 1-iodotetradecane (see Example 3). N-(3-carboxyphenyl) -6-(E-carboxyethynyl)-5-tetradecyloxy-2-picolinia Produced according to the method described for the mido, dilithium salt.

4(a) 3-dodecyloxy-2-pyridinecarboxaldehyde: IHNM R (250 Z, CDC13) δ10.43 (s, LH, Clll0), 8.38 (dd, IH, 6-pyridyl), 7, 42 (m, 2H, 4-pyridyl) Lysyl, 5-pyridyl), 4.1 (t, 2H, 0cH2), 1.91~ OJ8 (11,23+(B aliphatic) 4<b) 2-(E-2-carboxymethylethynyl)-3-dodecyloxypi Lysine: 'HNMR (250MHz, CDCh) 68.22 (dd, Il l, 6-pyridyl), 8.1 (d, IH, J=15.8Hz, Olef (in), 7.21 (m, 2H, 4-pyridyl, 5-pyridyl), 7.02 (d, LH, J=15.8Hz.

olefin), 4.02 (t, 2H, 0cHz), 3.81 (s, 3 f(, C0zCH3), 1.88 to 0.88 (m, 2RL aliphatic).

4(c) 2-(E-2-carboxymethylethynyl)-3-dodecyloxypi Lysine IH96-pyridyl), 7.58 (d, IB, J=16.2111 z, olefin), 7.1 (dd, LH, 5-pyridyl), 6, 8 (d, II (, 4-pyridyl), 4.08 (t, 21], 0 cHz), 3.8 2 (S, 3H, C0tCL), 1.88`0 88 (m, 23H, aliphatic).

4(e) 6-(E-2-carboxinemethylethynyl)-5-dodecyloxy- 2- Pirid beggar 'HNMR (250MHz, CDCl3') δ8.0 (s, IH, OH) , 7.75 (d, LH, J=16Hz, olefin), 7.4 (d, Il3-pyridyl), 7.0 (d, IH, J=16Hz, olefin), 6.7 (d, Il4-pyridyl), 4.0 (t, 2H, 0cHi), 3 ．． 82 (s, 3H, C02CHs), 1.85-0.88 (m, 23H ,■ ali).

4(f) 6-(E-2-carboxymethylethynyl)-5-dodecyloxy- 2-trifluoromethylsulfonate: 'HNMR (25014111z, CDC13) 67, 95 (d, IH, J=15.9Hz, olefin), 7.37 (d.

IH13-pyridyl), 7.1 (d, LH,4-pyridyl), 6.96 (d, Ill, J=15.9Hz, olefin), 4, 1 (t, 2H, 0 CH2), 3.8 (S, 3H, C02CB3), 1.89-0.88 (m , 23H, aliphatic).

4'(g)N-(3-carboxymethylphenyl)-6-(E-2-carboxy methylethynyl)-5-dodecyloxydi-2-picolinamide:'HNMR(2 501JHz, CDC13) 69.86 (s, IH, NTI), 8.2 9 (s, IH, aryl), 8゜27 (d, LH, 3-pyridyl), 8.13 (d, IH, aryl), 8.09 (d, IH, J=15. 8Hz, olefin), 7.84 (d, LH, aryl), 7.5 ( t, IH, aryl), 7.38 (d, 111.4-pyridyl), 7,08 (d, IB, J=15.8Hz, olefin), 4.15 (t, 2H ,0cHz), 3.98(s, 3[1,C02b!h), 3, 88 (s, 3H, C (hcHx), 1.94-0.88 (m, 2 3H, aliphatic) elemental analysis: Calculated value (%) as C8゜H4゜N 20g: C, 6111, 6111: H, 769: N, 5.34 measured value (%): C , 68, 43; H, 7, 54: N, 5.21M5 (CI): 525 ( M+H).

'HNMR (250MH2, CD30D) δ8.37 (s, IH, completed - ), 8.12 (d, 1111.3-pyridyl), 7.85 (d, IL J=15.7Hz, olefin), 7.83 (d, LH, ant rule), 7.77 (d.

IH, aryl), 7.55 (d, Ill, 4-pyridyl), 7.3 8 (t, IH, aryl), 7.26 (d.

LH, J-15, 7Hz, I7 I:/), 4.16 (t, 2f1. 0CR2), 1.90-0.88 (m, 231 fat ■j FAB-MS: (+v e), 509 (M+H)-; (-v e) , 501 (M-Li).

N-(3-carboxyphenyl)-6-(E-carboxyethynyl)-5-year-old Tyloxy-2-picolinamide, dilithium salt, is a dilithium salt of 1-iodotetradecane. Using 1-iodooctane instead, N-(3-carboxyphenyl)-6-( E-carpoxylate 5-tetradecyloxy-2-picolinamide 5-di Produced according to the method described for lithium salts (Example 3).

5(a) 3-octyloxy-2-pyridinecarboxaldehyde' HNM R (250MH2, CDC13) 610.43 (s, IH, CHO), & 38 (dd, LH, 6-pyridyl), 7, 42 (m, 2H, 4-pyridyl) Lysyl, 5-pyridi tIi>, 4.1 (t, 2H, 0cH2), 1.91 ~0.88 (m, 15HB aliphatic)'6 5(b) 2-(E-2-carboxymethylethynyl)-3-octyloxypi Lysine' HNMR (250MHz, CDC13) 68.22 (dd, IH, 6-pyridino, 8.1 (d, LH, I=15.1llHz, Olef (in), 7.21 (a2H, 4-pyridyl, 5-pyridyl), 7.02 (d, IH, J=15.8Hz.

I7 I:/), 4.02 (t, 2H, 0cHz), 3.81 (S, 3H, C02CH3), 1.88~0.88 (01, P5L aliphatic).

5(c) 2-(E-2-carboquinomethylethynyl)-3-year-old ctyloxypi Lysine N-oxide 'HNMR' (250MH2, CDC13) δ8.15 (d, Ill , J=16.211z, olefin), 7.9 (d.

IB, 6-pyridyl), 7.58 (d, 11. J = 16.2Hz, olefin ), 7.1 (dd, 1[1,5-pyridyl), 6, 8 (d, III! , 4-pyridyl), 4.08 (t, 2H, 0clh), 3.82 (5 , 3B, C02CH3), 1. W8～0゜ 88 (m, 1511. aliphatic).

5(d) 6-(E-2-carboxymethylethynyl)-5-octyloxo- 2-pyridone ' HNMR (250MHz, CDC13) δ8.0 (s, IH, 01 ? ), 7.75 (d, IH, J=16Dz, olefin), 7.4 ( d, IB, 3-pyridyl), 7, O (cl 1!1. J = 16Hz, olefin ), 6.7 (d, IH, 4-pyridyl), 4.0 (t, 2H, C1 CH2), 3.82 (s, 3H, C01C1h), 1.85 to 0.88 (m, 1TB, fat ali).

5(e) 6-(E-2-carboxymethylethynyl)-5-cutyloxy- 2-trifluoromethylsulfonate 'HNMR (250MH2, CDC13) 67, 95 (d, 111.J =15.9Hz, olefin), 7.37 (d.

IB, 3-pyridyl), 7.1 (d, IH, 4-pyridyl), 6.95 ( d, till, J=15.9 degrees, olefin), 4, 1 (t, 2B, 0c Bx), 3.8 (S, 3H, C0zC1b), 1.89 to 0.88 (m , 15L aliphatic).

5(f) N-(3-carboxymethylphenyl)-6-(E-2-carboxymethylphenyl) (Tylethynyl)-5-octyloxy-2-picolinamide'HNMR (250 MHz, CDC15) 69.86 (s, 111.NU), 8.29 (s, IB, Ori-ru), 8゜27 (d, IH, 3-pyridyl), 8.1 3 (d, IEI, aryl), 8.09 (d, IH, J=15.8 [ 1z, Olef B ), 7.84 (d, lH, aryl), 7.5 (t, 111.a Lille), 7.3111 (d, IL4-pyridyl), 7,08 (d, L H, ]'15.8H2, olefin), 4.15 (t, 2111.0cIh ), 3.98 (S, 3H, C02bH3), 3, 88 (s, 3H, C02CH3), 1.94-0.88 (m, 1 5H, aliphatic).

5(g)N-(3-carboxyphenyl)-6-(E-2-carboxyethynyl )-5-octyloxy-2-picolinamide, dilithium salt' HN MR (250MH2, CD30D) δ8.37 (s, IH, aryl), 8. 12 (d, 11 (, 3-pyridyl), 7.85 (d, LH, 15. 7Hz, olefin), 7.83 (d, 1111.aryl), 7.7 7 (d.

1i+, aryl), 7.55 (d, 1) 1,4-pyridyl), 7.38 (t, [, aryl), 7.26 (d.

IH, J'15.7Hz, olefin), 4.16 (t, 2H, 0cBz) , 1.90-0.88 (m, 15) 1. aliphatic) FAB-MS: (+ ve), 601.3 (M+H); (-ve), 598.9 (M -Li).

Example 6 N-(3-carboxyphenyl)-6-(E-2-carboxyethynyl)-5- C8-(4-methonophenyl)octyloxy]-2-picolinamide, dily thium salt N-(3-carboxyphenyl)-6-(E-2-carboxyethinyl) )-5-[8-(4-methoxyphenyl)octyloxy-2-picolinami The dilithium salt is 8 in place of 1-iodotetradecane (see Example 3). -(4-methquinphenyl)octane-1-(4-1-luenesulfonate) N-(3-carboxyphenyl)-6-(E-2-carboxyethynyl) -5-Tetradecyloxy-2-picolinamide, description of dilithium salt Manufactured according to the method (Example 4).

The following compounds were prepared according to Example 3(d) and the following procedures.

6(a) 2-(E-2-carboxymethylethynyl)-3-18-(4-meth xyphenyl)octyloxycopyridine This compound was prepared using the tosylate of Example A.

'HNMR (250MH2, CDC13) 68.28 (dd, J=4. 0.1.8Hz, IH, 6-pyridyl), 8.17(d, b15.8Hz, LH, olefin), 7.28 (m, 2L4-pyridyl, 5-pyridyl) , 7.12 (d, J=8.6Hz, 2H, aryl), 7.02 (d, J=15. ghHz, II olefin), 6.89 (d, J■ 8, 6Hz, 2H, aryl), 4. , 08 (t, J=6.5Hz, 2 ■, 0CH2), 3.87 (s, 3111.C0QCHs), 3.8 5 (s, 3H, 0CR3), 2.61 (t, J=1.5Hz, 2H, base ), 1.94-1.38 (m, 12H, aliphatic j.

6(b) 2-(E-2-carboxymethylethynyl)-3-r 8-(4-methylethynyl) quinphenyl)octyloxycopyridine N-oxide' HNMR (250 MH2, CDC13) 68.02 (d, J=16.2Hz, LH, I Fin), 7.80 (d.

J-6,5Hz, IB, 6-pyridyl), 7.39 (d, J=16.2 Hz, IH, olefin), 7.00 (m, 2H, 5-s Lysyl, 4-pyrinol), 6.85 (d, J=8.6Hz, 2H, Ali ), 6.6. + (d, J=8.6Hz, 21 aryl), 3.9 1 (t, J=6.5Hz, 2H, OC1]z), 3.68 (S, 3H, C 02CH3), 3.62 (s, 3g.

0CIb), 2.37 (t, J=7.5Hz, 2H, benzyl), 1 ．． 82-1.10 (m, 12H, aliphatic).

6(c) 6-(E-2-carboxymethylethynyl)-5-[8-(4-meth quinphenyl)octyloxy]-2-pyridone 'HNMR (250MEIZ, CDC13) 67, 75 (d, J=, 16 ．． 2Hz, LH, me 7. r:/), 7.40 (dB J=9.8Hz, IH, 3-pyridyl), 7.10 (d, J=l11. 6Hz, 211. Aryl), 7.00 (d, J=P6.2Hz.

II (, olefin), 6.82 (d, I = 8.6Hz, 2H, ary ), 6.70 (d, J=9.8Hz, IL4-pyridyl), 3.9 5 (t, J=6.5Hz, 2H, Of&), 3.85 (s, 3H, c o, CH3), 3.82 (s, 3t 戟A　OC■s), 2, 57 (t, J=7.5Hz, 2H, benzyl), 1.85-1.2 2 (m, 12+1. aliphatic).

6(d) N-(3-carboxymethylphenyl)-er-<E-2-carboxy methylethynyl)-5-[8-(4-methoxyphenyl)octyloxy]-2 -Picolin Ayo Melting point 70-73℃: 'HNMR (2501H2, CDC13) 69.87 (s, Ill, N U), 8.31 (s, IH, 2-phenyl), 8, 28 (d, J=8 ．． 7Hz, IH, 3-pyridyl), 8.15 (d, J=7.9[1z, IH, 4-phenyl), 8.0W (d, J=15.8Hz, IB, olefin), 7.85 (d, J=7. 9Hz, 1B, 6-phenyl), 7.48 (dd.

J = 7.9Hz, IH, 5-phenyl), 7.36 (d, b8.7Hz, If, 4-pyridyl), 7.10 (d, I=8.UHz.

2H, aryl), 7.08 (d, J=15.8Hz, LH, olefin ), 6.85 (d, J=8.6] 11z, 2H, A Ri ), 4.12 (t, J=6.5Hz, 2B, 0CH2), 3.95 (s, 3H, Co, CH3), 3.88 (s, 3g, Co, CH3) , 3.79 (s, 311.0CH3), 2.56Ct, I=7.5F1z, 2H, benzyl), 1.99-1.28 (m, 12H, salt b family).

Elemental analysis: C3xHssNzOt T calculated value (%): C, 68, 97: H,6,67: N,4.88 Measured value (%): C,69,21; H,6, 88; N, 4.46M5 (CI): 575 (M+H).

6(e)N-(3-carboxyethynyl)-6-(E-2-carboxyethynyl )-5-[8-(4-methoxyphenyl)octyloxy]-2-picolinami Do, dilithium pus Melting point 315℃ (decomposition): 'HNMR (250MIIz, CD30D) δ8.31 (s, IH, 2- phenyl), 8.12 (d, J=8.7Hz, 1111.3-pyridyl ), 7.86 (d, J=7.9+1z, IH,4-phenyl), 7. 85 (d, J=15.8Hz, hH, O Lefin), 7.76 (d, J-7°9Hz, LH,6-phenyl) , 7.52 (d, J=8.7Hz, IH,4-bilinol), 7.39 (dd, J=7.9Hz, IH,5-phenyl), 7.26 (d, b 15.8Hz, LH, olefin), 7, 07 (d, J=8.6Hz, 2H, aryl), 6.80 (d, J=8.6Hz, 2H, aryl ), 4.15 (soot A J= 6, 5Hz, 2H, 0CHz), 3.74 (s, 3H, 0CR3), 2.53 (t, J=7.5Hz, 211.benzyl) A1.93 ~1.37 (m, 12H, aliphatic) elemental analysis: C3+Hs□N20. Li 2.5 / 2 Calculated value as H20: C, 61, 69:'H, 6, 1 8; N, 4.64 measurement value (to): C, 61, 69; H, 5, 91: N, 4.60FAB-MS: (+v e), 559.4 (M+H); (-v e), 551.4 (M-Li).

Appropriate chloro-substituted 3-aminobenzoic acid in place of methyl 3-aminobenzoate Following the same method except using methyl acid, the following compounds were prepared: N-( 3-carboxy-6-chlorophenyl)-6-(E-2-carboxyethynyl) -5-[8-(4-methquinphenyl)octyloxy]-2-picolinamide , dilithium salt.

and N-(3-carboxy-4-chlorophenyl)-6-(E-2-carboxyethyl Nyl)-5-[8-(4-methoxyphenyl)octyloxycoke-picoline Amide, dilithium salt Example 7 The salt is prepared by dissolving the ring chain in an aqueous solution to a pH of about neutral (pH 7.0) or close to it. It may be converted to the free acid by adding a sufficient amount of acid to yield the desired result. HCI Any acid can be used, although it is preferred to use any mineral acid. concentrated It is preferred to use diluted acids rather than diluted acids, e.g. Solutions are most useful. Acids can be added at or near room temperature and No conditions are required. When the solution reaches neutral pH or becomes acidic, Acids can be salted out from solution and are useful for crystallization techniques or for a given acid. can be recovered by any known technique.

Example 8 Preparations for pharmaceutical use containing the compounds of the present invention can be prepared in various forms with multiple excipients. It can be prepared as follows.

Inhalation prescription A compound of formula I was dissolved in isotonic saline at 1-1Q mg/ml for each use. Aero more than a nebulizer that operates with a regulated air flow to pre-bar the desired amount of drug. Turn into sol.

The compound of Kusen-2 formula was dissolved in isotonic saline at 1-10 mg/ml for one-time use. The device uses a nebulizer that operates with a regulated air flow to deliver the desired amount of drug. 1. Active ingredient 40mg 400g (Compound of formula I) 2. Corn starch 20mg 200g3, Alginic acid 20mg 200g 4, Sodium alginate 20mg 200g5, Magnesium stearate Mu 1.3mg 13g101.3mg 1013g Tablet manufacturing operations: Step 1 In a suitable mixer/blesseder, put No. 1, No. 2, No. 3, and Blend ingredients No. 4.

Step 2: After adding each ingredient, mix carefully until blended enough to blend in Step 1. Add water little by little. This is done until the mass is soft enough to be transformed into wet granules. Add water and mix as shown.

Step 3 Wet mass is passed through a vibrating type using a N018 mesh (2.38 mm) screen. Pass through granulation equipment to convert into granules.

Step 4: Then, dry the wet granules in an oven (at 60°C) until dry. Ru.

Step 5: Smooth the dry granules with No. 5 ingredient.

Step 6: Compress the smooth granules into tablets using a suitable tablet press.

1. Compound of formula I 40.0mg 40g active ingredient 28 Polyethylene glycol 135 (1, Omg 1.350g3 Polyethylene glycol Tylene glycol 450, Omg 450 g1840, 0mg 1.840 g operation: Step I Melt ingredients No. 2 and No. 3 together and stir until homogeneous. Ru.

Step 2 No. 1, dissolve the ingredients in the melt from step 1 and stir until homogeneous. Ru.

Step 3: Pour the melt from step 2 into a suppository mold, cool it, and remove the suppository from the mold. and rap.

Summary book The present invention is based on the formula (■) [wherein T is an amide bonding group and R group has the same meaning as described in this specification] ]. These compounds are useful as leukotriene antagonists It is.

international search report international search report LIS 9103940 SA 48456

Claims (18)

[Claims] 1. Formula I: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, T is an amide bonding group ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ where the carbonyl carbon is attached to the pyridyl ring; R is C1-C20 - an aliphatic group, an unsubstituted or substituted phenyl C1-C10 aliphatic group, where Substituted phenyl includes lower alkoxy, lower alkyl, trihalomethyl and halo. or R is a C1-C20-aliphatic group. -O-, or R is an unsubstituted or substituted phenyl C1-C10-aliphatic group -O-, where substituted phenyl is lower alkoxy, lower alkyl, trihalo has one or more groups that are methyl or halo; R1 is R4, -(C1-C5 fatty group group) R4, -(C1-C5 aliphatic group) CHO, -(C1-C5 aliphatic group) CH 2OR8, -CH2OH or CHO; R2 is hydrogen, -COR5, Here, R5 is -OH, a pharmaceutically acceptable ester-forming group -OR6 or -OX ( where X is a pharmaceutically acceptable cation) or R5 is -N(R 7) 2, where R7 is H or an aliphatic group having 1 to 10 carbon atoms, or an aliphatic group having 4 to 1 carbon atoms. 0 cycloalkyl-(CH2)n- groups, where n is 0 to 3, or Both R7 groups together form a ring containing 4 to 6 carbon atoms, or R2 is NH SO2R9, where R9 is -CF3, C1-C6 alkyl or phenyl is le; R3 is hydrogen, lower alkoxy, halo, -CN, -COR5 or OH; R 4 is -COR5, where R5 is -OH, a pharmaceutically acceptable ester-forming group -OR6 or -OX (where X is a pharmaceutically acceptable cation) , or R5 is -N(R7)2, where R7 is H or has 1 to 10 carbon atoms. Aliphatic group, cycloalkyl-(CH2) n- group having 4 to 10 carbon atoms (where n is 0 ~3), or both R7 groups together form a ring having 4 to 6 carbon atoms. ; R8 means hydrogen, C1-C6 alkyl or C1-C6 acyl]; or a pharmaceutically acceptable salt or N-oxide thereof. 2. R is a C1-C20 aliphatic group -O- or a C1-C20 aliphatic group, and R1 is -(C1-C5 aliphatic group) R4 or -R4, and R2 is -COOH or a pharmaceutically acceptable salt thereof or -NHSO2R9. thing. 3. R is C8-C15-alkoxy, R1 is -CH=CHR4, 3. The compound according to claim 2, wherein the double bond is cis or trans. 4. R is H17C8-O- and R1 is trans-CH=CHCOOH. , N-(3-carboxyphenyl)-6-( where R2 is meta-substituted -COOH E-2-carboxyethenyl)-5-octyloxy-2-picolinamide compound a dilithium salt or other pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt thereof; 4. The compound according to claim 3, which is an ester. 5. R is H21C10-O- and R1 is trans-CH=CHCOOH Therefore, N-(3-carboxyphenyl)-6- where R2 is meta-substituted -COOH (E-2-carboxyethenyl)-5-decyloxy-2-picolinamide compound compound, its disodium salt or other pharmaceutically acceptable salt or its pharmaceutically acceptable salt 4. The compound according to claim 3, which is an ester of 6. R is H25C12-O- and R1 is trans-CH=CHCOOH Therefore, N-(3-carboxyphenyl)-6- where R2 is meta-substituted -COOH (E-2-carboxyethenyl)-5-dodecyloxy-2-picolinamidation compound, its dilithium salt or other pharmaceutically acceptable salt or its pharmaceutically acceptable salt 4. The compound according to claim 3, which is an ester of 7. R is H29C14-O- and R1 is trans-CH=CHCOOH Therefore, N-(3-carboxyphenyl)-6- where R2 is meta-substituted -COOH (E-2-carboxyethenyl)-5-tetradecyloxy-2-picolinami compound, its dilithium salt or other pharmaceutically acceptable salt or its pharmaceutically acceptable salt 4. A compound according to claim 3 which is an acceptable ester. 8. R is a substituted or unsubstituted phenyl-C1-C10 aliphatic group, and R1 is - The compound according to claim 2, which is (C1-C5 aliphatic group) R4. 9. Claim 8 wherein R is a lower alkoxy-substituted phenyl-C1-C8 alkoxy group. Compounds described. 10. R is P-H3C-O-phenyl-(CH2)8-O-, and R1 is HO N-(3-carboxylic acid) in which 2CCH=CH- and R2 is meta-substituted -COOH xyphenyl)-6-(E-2-carboxyethenyl)-5[8-(4-methoxy Cyphenyl)octyloxy]-2-picolinamide compound, its dilithium salt or other pharmaceutically acceptable salts or pharmaceutically acceptable esters thereof. A compound according to claim 9. 11. 3. A compound according to claim 2, wherein R1 is R4CH2CH2-. 12. R is H21C10-O-, R1 is HO2CCH2CH2-, , N-(3-carboxyphenyl)-6-(2 -carboxyethyl)-5-dodecyloxy-2-picolinamide, N-(3- Carboxy-6-chlorophenyl)-6-(E-2-carboxyethenyl]-5 -[8-(4-methoxyphenyl)octyloxy]-2-picolinamide, N -(3-carboxy-4-chlorophenyl)-6-(E-2-carboxyethenyl )-5-[8-(4-methoxyphenyl)octyloxy]-2-picolinia Mido, its dilithium or dipotassium salts or other pharmaceutically acceptable salts or or a pharmaceutically acceptable ester thereof. 13. It is characterized by consisting of a pharmaceutical carrier or diluent and the compound according to claim 1. A pharmaceutical composition. 14. Claims that are in a form for inhalation, parenteral or oral administration or topical administration The pharmaceutical composition according to item 13. 15. A compound according to claim 1 alone or in combination with a pharmaceutically acceptable excipient. In addition, lung diseases caused by leukotrienes in patients requiring treatment. treatment method. 16. 16. The method according to claim 15, wherein the disease is asthma. 17. comprising administering a compound according to claim 1 and an effective amount of an H1 blocker. 17. The method according to claim 16. 18. An effective amount of a compound according to claim 1 alone or in a pharmaceutically acceptable excipient. Leukotrie, consisting of administration to patients in need of treatment in combination with Methods for treating non-pulmonary diseases in such patients whose etiology is