UA52737C2 - Chinoline antagonists of leuкotriens - Google Patents

Abstract

Compounds of formula are antagonists of the actions of leukotrienes. These compounds are useful as anti-asthmatic, anti-allergic, anti-inflammatory, and cytoprotective agents. They are also useful in treating angina, cerebral spasm, glomerular nephritis, hepatitis, endotoxemia, uveitis, and allograft rejection. (I).

Description

US patent Me5565473 describes a compound of formula (a) "ai on

F te 5 (a) ru : si es fi and is known mainly as montelukast sodium. Montelukast sodium is a leukotriene antagonist and is currently undergoing clinical trials for the treatment of chronic gout.

In published on December 19, 1996. international application PCT MO 96/40638 describes compounds of formulas (B) and (c) and their individual optical isomers, which are metabolites of montelukast sodium and are leukotriene antagonists. soon

He is - I

OO nose

Tk vo Z on (s) pt - x son of Avsya and Hu

And - to - but

Concise presentation of the essence of the invention

This invention relates to quinoline diacid derivatives having leukotriene antagonist activity, methods of their preparation, and methods and pharmaceutical preparations for the use of these compounds in mammals (especially for humans)

Due to their activity as leukotriene antagonists, the compounds of this invention are used as anti-asthmatic, anti-allergic, anti-inflammatory and cytoprotective (cell-protecting) agents. They are also used in the treatment of angina, cerebral spasm, glomerular nephritis, hepatitis, in the presence of endotoxins in the blood, uveitis, and in the case of allograft rejection.

This invention relates to compounds of formula I:

Kai on and Z and : sen and :

Y and Y (A PI and individual optical isomers of these compounds; or their pharmaceutical acceptable derivatives.

In one embodiment, the present invention relates to a compound of formula I that has been isolated and purified, i.e., a compound of formula I that is essentially free of other metabolic products of montelukast sodium.

In another aspect, this invention relates to a method of inhibiting the action of leukotrienes in a mammal, which comprises administering to said mammal a therapeutically effective amount of a compound of formula Y.

In yet another aspect, this invention relates to a method of preventing and treating dysentery, allergy and inflammation in a mammal, which comprises administering to said mammal a therapeutically effective amount of a compound of formula I.

In yet another aspect, the present invention relates to a pharmaceutical composition containing a compound of formula | and a pharmaceutically acceptable carrier.

Another aspect of the present invention relates to methods of obtaining the compound of formula I.

The compounds given in this description contain two asymmetric centers and thus can give diastereomers and optical isomers. This invention contemplates including such possible diastereomers individually or as a mixture of diastereomers, as well as their racemic and split, enantiomerically pure forms and their pharmaceutically acceptable derivatives.

The pharmaceutical compositions of this invention contain a compound of the formula | as an active ingredient or a pharmaceutically acceptable derivative thereof and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The term "composition", as in a pharmaceutical composition, includes a product containing an active ingredient(s) and an inert ingredient(s) that is a carrier, as well as any product that is, directly or indirectly, the result of combining, the complexation or aggregation of any two or more ingredients, or the result of the dissociation of one or more ingredients, or the result of other types of reaction or interaction of one or more ingredients. Thus, the pharmaceutical compositions of the present invention include any composition prepared by mixing a compound of the present invention and a pharmaceutical acceptable carrier.

The term "pharmaceutically acceptable derivative" refers to any pharmaceutically acceptable salt, ester, simple ester, amide, or macromolecular prodrug, or combinations thereof. The invention also includes any other compounds that, when administered to the recipient, contribute to the delivery (directly or indirectly) of the compounds of the present invention.

Pharmaceutically acceptable salts include salts obtained from pharmaceutically acceptable non-toxic inorganic and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper salts, ferric and ferric salts, lithium, magnesium, trivalent and divalent manganese salts, potassium, sodium, zinc salts and the like. Ammonium, calcium, magnesium, potassium and sodium salts are especially acceptable. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted aminones, which include naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as arginine, betaine, caffeine, choline,

M,M'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, M-ethylmorpholine, M-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, dicyclohexylamine , polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

Pharmaceutically acceptable esters include those formed from the hydroxyl groups of a compound of formula I and an organic acid (or its acylation equivalent), such as acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentapropionate, glucoheptanoate , glycerophosphate, gluconate, dodecyl sulfate, ethanesulfonate, fumarate, heptanoate, hexanoate, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalene sulfonate, nicotinate, oxalate, pamoate, pectinate, picrate, pivalate, succinate, tartrate, tosylate, imidazole-1 -carboxylate, phenylpropionate, phenoxyacetate, palmitate, laurate, adamanthoate, stearate, octanoate, cycloalkyl carboxylate, decanoate, meristylate, phthalate, hexanoate, carbamate, adenosine-5'-carboxylate, pivaloyloxymethylate, in substituted or unsubstituted forms, etc.; or those formed from the carboxyl group of the compound of formula I and an alcohol, such as C1-Ca alkanol or other alcohols, generally known to specialists for obtaining ether prodrugs. Pharmaceutically acceptable esters also include those formed from a compound of formula I with inorganic acids such as, but not limited to, sulfates, phosphates, carbonates, or conjugates of a compound of formula I. with glutathione, glucuronic acid, sugars (similar to glucose) and bile acids (similar to taurine), etc.

Pharmaceutically acceptable ethers are those well known to those skilled in the art, and include, for example, methyl to pentyl ethers, cycloalkyl, methoxymethyl, 3'-hydroxypropyl, benzyl, allyl, anisilidene, ethoxyethylidene, tetrahydropyranyl, silyl ethers.

Pharmaceutically acceptable amides are those well known to those skilled in the art, and include, for example, C1i-Ca amides.

Compounds of formula 1 can also be used as macromolecular prodrugs, which include a compound of formula I, bound covalently or reversibly to mono - or polyclonal antibodies, or to other macromolecules, such as polyvinyl, polyacryl, polysaccharide and poly-(o; - amino acid ) and dextran, soluble starch or with ether prodrugs based on hydroxyalkyl starch, and insulin.

It should be understood that in the discussion of methods of treatment that occur, references to compounds of formula I also include pharmaceutically acceptable derivatives.

The ability of the compounds of formula I to antagonize leukotrienes makes them useful for preventing or eliminating leukotriene-induced symptoms in humans. This antagonism to the action of leukotrienes indicates that the compounds and their pharmaceutical compositions are used to treat, prevent or reduce the intensity of disease symptoms in mammals and especially in humans: 1) pulmonary disorders including diseases such as dysentery, chronic bronchitis and similar obstructions respiratory tract, 2) allergy and allergic reactions, such as allergic rhinitis, contact dermatitis, allergic conjunctivitis, etc., 3) inflammation, such as arthritis or inflammatory bowel disease, 4) pain, 5) skin disorders, such as atopic eczema, etc., 6) cardiovascular disorders such as angina pectoris, myocardial ischemia, hypertension, platelet aggregation, etc., 7) renal failure resulting from ischemia, which has an immunological or chemical (cyclosporine) etiology, 8) migraine or "histamine" headache 9) eye conditions such as uveitis 10) hepatitis resulting from chemical, immunological or infectious stimuli 11) trauma or shock conditions such as burns damage, the presence of endotoxins in the blood, etc., 12) rejection of the allograft, 13) prevention of side effects associated with the therapeutic administration of cytokines, such as interleukin II and tumor necrosis factor, 14) chronic lung diseases, such as cystic fibrosis, bronchitis and other diseases upper and lower respiratory tract, and 15) cholecystitis.

Thus, the compounds of this invention may also be used to treat or prevent painful conditions in mammals (especially humans), such as erosive gastritis; erosive esophagitis; diarrhea; brain spasm; premature birth; spontaneous abortion; dysmenorrhea; ischemia, harmful lesions or tissue necrosis of the liver, pancreas, kidneys or myocardium caused by the agent; damage to the liver parenchyma caused by hepatotoxic agents, such as SSRIs and UO-galactosamine; ischemic renal failure; liver damage caused by the disease; damage to the pancreas or stomach caused by bile salts; cellular disruption caused by trauma or stress; and glycerol-induced renal failure.

The compounds also have a cytoprotective effect.

Cytoprotective activity of the compound can be observed both in animals and in humans with the observed increased resistance of the mucous membrane of the gastrointestinal tract to the harmful effects of strong irritants, for example, the ulcer-causing effects of aspirin and indomethacin. In addition to reducing the effects of NSAIDs on the gastrointestinal tract, animal studies show that cytoprotective compounds prevent gastric damage caused by oral administration of strong acids, strong bases, ethanol, hypertonic saline, and the like.

Two assays are used to measure the cytoprotective effect. These analyzes are; (A) the ethanol-induced impairment study and (B) the indomethacin-induced ulcer study and are described in

European patent EP 140684.

The value of the prophylactic or therapeutic dose of the compound of the formula | will, of course, vary depending on the nature and severity of the condition being treated, the individual compound of formula I, and the route of administration. It will also vary depending on the age, weight and response of the individual patient.

As a rule, the daily range of doses when used as anti-asthmatic, anti-allergic and anti-inflammatory agents, other than as cytoprotective agents, lies within the range of from about 0.001 mg to about 100 mg per kg of the body weight of a mammal, more acceptable from 0.0 mg to about 10 mg per kg , and most acceptable from 0.1 to 1 mg per kg, in the form of single or divided doses. On the other hand, in some cases it may be necessary to use dosages that go beyond the limits.

When using a composition for intravenous administration, a suitable dose range for anti-asthmatic, anti-inflammatory or anti-allergic action is from about 0.001 mg to about 25 mg (more preferably from 0.01 mg to about 1 mg) of the compound of formula 1 per kg of body weight per day and for cytoprotective use from about 0.1 mg to about 100 mg (more preferably from about 1 mg to about 100 mg and even more preferably from about 1 mg to about 10 mg) of a compound of formula 1 per kg of body weight per day.

In the case of using an oral composition for anti-asthmatic, anti-inflammatory or anti-allergic action, a suitable dose range is from about 0.01 mg to 100 mg of the compound of formula I! per kg of body weight per day, more preferably from about 0.1 mg to about 10 mg per kg and for cytoprotective action from 0.1 mg to about 100 mg (more preferably from about 1 mg to about 100 mg and even more preferably from about 10 mg to about 100 mg) compounds of formula 1 per kg of body weight per day.

In the treatment of eye diseases, ophthalmic preparations containing 0.001-195% by weight of solutions or suspensions of compounds of formula I in a suitable ophthalmic composition can be used.

The exact amount of a compound of formula I used as a cytoprotective agent will depend, among other things, on whether it is administered to heal damaged cells or to prevent future damage, the nature of the damaged cells (eg, gastrointestinal ulcers versus nephrotic necrosis), and from the nature of the disease-causing agent. An example of the use of a compound of the formula | to prevent future infringement, there should be co-administration of a compound of formula | with MZAIIUO, which can otherwise cause a similar disorder (for example, indomegacin). With this use, the compound of the formula is introduced from 30 minutes before the introduction of M5AIYU up to 30 minutes after the introduction of M5AIYU. It is more acceptable to introduce it earlier or at the same time as M5AIO (for example, in a combined dosage form).

Any suitable method of administration can be used to provide a mammal, especially a human, with an effective dose of a compound of the present invention. For example, you can use oral, rectal, local, parenteral, ocular, pulmonary, nasal methods of administration, etc. Pharmaceutical forms include tablets, lozenges, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, skin patches (bandages), systems that promote secretion, and the like.

Pharmaceutical compositions of the present invention contain a compound of formula I as an active ingredient or a pharmaceutically acceptable derivative thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients.

Compositions include compositions suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular and intravenous) or nasal administration, although the most appropriate route of administration in any given case will depend on the nature and severity of the conditions being treated, and from the nature of the active ingredient. They may be suitably presented in a standard dosage form and may be prepared by any of the methods well known in the art of pharmacy.

For administration by inhalation, the compounds of this invention are conveniently delivered in the form of a spray aerosol from sealed, pressurized packages or inhalers. The compounds can also be delivered as powders that can be administered in a composition, and the powder composition can be inhaled by blowing through a powder inhaler. A more suitable inhalation delivery system is a metered dose inhalation (MI) aerosol, which can be delivered as a suspension or solution of a compound of formula 1 in suitable propellants, such as fluorocarbons and hydrocarbons.

Suitable topical formulations of compounds of formula I include transdermal devices, aerosols, creams, ointments, lotions, dusting powders, and the like.

In practice, the compounds of formula I can be combined as an active ingredient in a homogeneous mixture with a pharmaceutical carrier according to the usual pharmaceutical technique for the preparation of medicinal products.

The carrier can take a wide variety of forms depending on the form of the drug that is required for administration, such as oral or parenteral (including intravenous). In the preparation of oral dosage form compositions, any of the usual pharmaceutical media may be used, such as, for example, water, glycols, oils, alcohols, flavors, preservatives, dyes, and the like in the case of oral liquid preparations, such as, for example, suspensions , elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, capsules and tablets, and solid oral preparations are more acceptable compared to liquid preparations. Due to the ease of their administration, tablets and capsules represent the most favorable oral dosage unit form, in which case solid pharmaceutical carriers are used. If desired, tablets can be coated using standard aqueous and non-aqueous methods.

In addition to the usual, above-mentioned dosage forms, compounds of the formula | can be administered using dose control devices and/or delivery devices such as those described in US Pat

3845770; 3916899; 3536809; 3598123; 3630200 and 4008719, the disclosures of which are incorporated herein by reference.

The pharmaceutical compositions of the present invention suitable for oral administration may be presented in the form of divided units such as capsules, starch wafers or tablets, each containing a predetermined amount of the active ingredient, as a powder or granules, or as a solution or suspension in an aqueous liquid, non-aqueous liquid, oil-in-water emulsion or water-in-oil emulsion. Similar compositions can be obtained in any of the methods of the pharmaceutical industry, but all methods include the stage of introducing the active ingredient into a combination with a carrier that is one or more of the necessary ingredients. As a rule, the compositions are prepared by uniformly and homogeneously mixing the active ingredient with liquid carriers or finely divided solid carriers or with both and then, if necessary, the product is shaped into the desired form. For example, a tablet may be prepared by compression or molding, optionally with one or more additional ingredients. Compressed tablets may be prepared by compression in a suitable apparatus of the active ingredient in a non-dusting form, such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface-active or dispersing agent. Formed tablets can be prepared by molding in a suitable apparatus, the mixture of the powdered compound is moistened with an inert liquid diluent. Preferably, each tablet contains from about 1 mg to about 500 mg of active ingredient and each starch wafer or capsule contains from about 1 to about 500 mg of active ingredient.

Examples of typical pharmaceutical dosage forms for compounds of formula I are given below: (IM) o Benzyl alcohol//-/-: | 90 g of starch tablets and concentrate

Combinations with other drugs

In addition to the compounds of the formula | the pharmaceutical compositions of the present invention may also contain other active ingredients, such as cyclooxygenase inhibitors, non-steroidal anti-inflammatory agents (M5A!Yuv5), peripheral analgesic agents, such as zomepirac, diflunisal and the like. The weight ratio of the compound of formula I to the second active ingredient may vary and depend on the effective dose of each ingredient. As a rule, an effective dose of each ingredient is used. Thus, for example, when a compound of the formula I is combined with M5AI!YUO, the weight ratio of the compound of the formula | to M5AIIII is usually in the range of about 1000:1 to about 1:1000, more preferably about 200:1 to about 1:200. Combinations of compounds of formula I! and other active ingredients: are usually also within the range indicated above, but in each case an effective dose of each active ingredient should be used.

M5AIU" can be divided into five groups: (1) derivatives of propionic acid; (2) acetic acid derivatives; (3) derivatives of fenamic acid; (4) oxicams; and

(5) derivatives of biphenylcarboxylic acid, or pharmaceutically acceptable salts thereof.

Derivatives of propionic acid that can be used include: alminoprofen, benoxaprofen, bucloxic acid (3-chloro-4-cyclohexylso; -oxobenzenebutanoic acid), carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pyrprofen, pranoprofen, suprofen, tiaprofenic acid and thioxaprofen. Structurally related derivatives of propionic acid, having similar analgesic and anti-inflammatory properties, are also expected to be included in this group.

Thus, "propionic acid derivatives" as defined in the description are non-narcotic analgesic/non-steroidal anti-inflammatory agents having free CH(CH3Z)COOH or -

CHCHCOOH group (which may optionally be in the form of a pharmaceutically acceptable salt, for example -CH (CH3)bOO Ma" or -CHNaCHCOO Ma", is typically attached directly or through a carbonyl function to a ring, more preferably to an aromatic ring.

Acetic acid derivatives that can be used include: indomethacin, which is more acceptable M5ZAIIU, acemethacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclosanic acid, fentiazac, furofenac, ibufenac, isoxepac, oxpinac, sulindac, thiopinac, tolmetin, zidomethacin and zomepirac .

Structurally related acetic acid derivatives with similar analgesic and anti-inflammatory properties are also expected to be included in this group.

Thus, "acetic acid derivatives" as defined in the specification are non-narcotic: analgesic/non-steroidal anti-inflammatory agents having a free group (which may optionally be in the form of a pharmaceutically acceptable salt group, e.g. -CH»COO Ma), in a typical method attached directly to the ring, more acceptable to an aromatic or heteroaromatic ring.

Derivatives of fenamic acid that may be used include: flufenamic acid, meclofenamic acid, mefenamic acid, nirlumic acid and tolfenamic acid. Structurally related phenamic acid derivatives, which have similar analgesic and anti-inflammatory properties, are also expected to be included in this group.

Thus, "fenamic acid derivatives", as defined in the description, are non-narcotic analgesic/non-steroidal anti-inflammatory agents containing the basic structure:

A soon which can have multiple substituents and in which the free -COOH group can be in the form of a pharmaceutically acceptable salt, for example -COOH Ma".

Biphenylcarboxylic acid derivatives that can be used include: diflunisal and flufenizal.

Structurally related derivatives of biphenylcarboxylic acid, which have similar analgesic and anti-inflammatory properties, are also expected to be included in this group.

Thus, "biphenylcarboxylic acid derivatives", as defined in the description, are non-narcotic analgesic/non-steroidal anti-inflammatory agents containing the basic structure: o o "cooHn" which may have multiple substituents and in which the free -COOH group may be in the form of a pharmaceutically acceptable salt , for example -SOO Ma".

Oxicams that can be used in the present invention include: isoxicam, piroxicam, sudoxicam and tenoxicam. Structurally related oxicams, which have similar analgesic and anti-inflammatory properties, are also expected to be included in this group.

Thus, "oxicams", as defined in the description, are non-narcotic analgesic/non-steroidal anti-inflammatory drugs having the general formula: ono -M. H 87 "snu (02) where A is an aryl or heteroaryl ring.

The following М5ЗАЙО5 can also be used: sodium amfenac, aminoprofen, anitrazafen, anthrafenin, auranofin, bendazac lysinate, benzidanin, beprozine, broperamol, bufezolac, kinmethacin, cyproquazone, cloximate, dazidamine, deboxamet, delmethacin, detomidine, dexindoprofen, diacerein, diphysalamine, difenpyramide , emorphazone, enfenamov etofenamate, fanetizole mesylate, fenclorac, fendozal, fenflumizole, feprazone, floctafenin, flunixin, flunoxaprofen, fluproquazone, fopirtoline, phosphosal, furcloprofen, glucamethacin, guaimesal, ibuproxam, isofezolac, isonixim, isoprofen, isoxicam, lefetamine hydrochloride, leflunomide lofemizole, lonazolac calcium, lotifazole, loxoprofen, lysine clonixinate, meclofenamate sodium, meseclazone, nabumeton, nictindole, nimesulide, orpanoxine, oxamethacin, oxapadol, perisoxal citrate, pimeprofen, pimethacin, piproxen, pyrazolac, pirfenidone, proglumethacin maleate, proquazone, pyridoxyprofen, sudoxicam , talmetacin, talniflumate, tenoxicam, thiazolinobutazone, tielavin B, t iaramide hydrochloride, tiflamizole, timegadin, tolpadol, tryptamide and ufenamate.

The following M5ZAIIIIUO5, marked with company code numbers (see, for example, Rpaptargoiesiv), can also be used: 4801565, АА861, А01590, АЕРВОг2, АЕРРЗ860, АИ77В, АР504, АО8ВО01, VRRS, VMU540С,

SNIMOIM 127, CM100, EVZ382, EI 508, E1044, 13658, ITE182, KSMTE16090, KME4, GA2851, MA714, MA897,

МУЗ309, ОМО3144, РА823, РМ102, РМ108, АВ830, Н52131, 5СНА152, 5Н440, 5ИВ133, 5РАБ510, 5027239, 5281, 5У6001, ТАбО, ТАЙ-901 (4-benzoyl-1-indanecarboxylic acid), ТУХОВ207206, 6207206, 6 M/u41770.

Finally, MAOIs that may be used include salicylates, especially acetylsalicylic acid and phenylbutazones and their pharmaceutically acceptable salts.

In addition to indomethacin, other more acceptable M5AIO»5 are acetylsalicylic acid, diclofenac, fenbufen, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, naproxen, phenylbutazone, piroxicam, sulindac and tolmetin.

Pharmaceutical compositions comprising compounds of formula I may also contain leukotriene biosynthesis inhibitors such as those described in European Patent EP 138481 (April 24, 1985), EP 115394 (August 8, 1984), EP 136893 (April 10, 1985) and EP 140709 (May 8, 1985), which are referenced in this description.

Compounds of formula I may also be used in combination with leukotriene antagonists such as those described in European Patent EP 106565 (April 25, 1984) and EP 104885 (April 4, 1984) referenced herein and others known in the art. , such as are described in the European patent application No. 56172 (July 21, 1982) and 61800 (June 10, 1982); and in the description of the British patent Me2058785 (April 15, 1981), which are referred to in this description.

Pharmaceutical compositions comprising compounds of formula I also contain, as a second active ingredient, prostaglandin antagonists such as those described in European Patent EP 11067 (May 28, 1980) or thromboxane antagonists such as those described in US Patent 4,237,160. They also may contain inhibitors of histidine decarboxylase, such as o-fluoromethylhistidine, described in US patent 4325961. Compounds of the formula can also be successfully combined with an antagonist of the Ni - or No-receptor, such as, for example, acetamazole, aminothiadiazoles, described in European patent EP 40696 (2 December 1981), benadryl, cimetidine, famotidine, framine, histadyl, phenergan, ranitidine, terfenadine, loratadine and similar compounds described in US patents Me4283408; 4362736 and 4394508. Pharmaceutical compositions may also contain K"/NU inhibitor

ATPases, for example, omeprazole, described in US patent 4,255,431, etc. Compounds of the formula | can also be advantageously combined with mast cell stabilizing agents such as 1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane and related compounds described in UK Patent Specifications 1144905 and 1144906. Another pharmaceutical composition comprises compounds of formula 1 in combination with serotonin antagonists such as methysergin, serotonin antagonists described in Maischge, 316, 126-131 11985), and the like. Each of the references mentioned in this section is incorporated into this description.

Other pharmaceutical compositions include compounds of formula !/ in combination with anticholinergic agents such as ipratropium bromide, bronchodilators such as the beta agonist salbutamol, metagyroterenol, terbutaline fenoterol and the like, and antiasthmatics theophylline, choline theophylline and enprophylline, calcium antagonists nifedipine, diltiazem , nitrendipine, veracamil, nimodipine, felodipine, etc. and corticosteroids hydrocortisone, methylprednisolone, betamethasone, dexamethasone, beclomethasone, etc.

Compounds of the formula | are biliary metabolites of montelukast sodium. Therefore, they can be isolated and purified from the bile of individuals taking montelukast sodium using techniques well known in the art, such as chromatography.

In comparison, the compounds of this invention can be prepared according to the following chemical methods described in Schemes 1 and 2.

Scheme 1 sov

F y Z schi oxalyl chloride si pe (Z i oM5OEvM 1 sov sno (Y r Z OK ves alkyl sote a

SsOooNn

From SsoOon

F y: 5 on u: sostoto

In Scheme 1, the diol ether is oxidized to the corresponding aldehyde 2 using an oxidizing agent such as dimethyl sulfoxide and an electrophile such as oxalyl chloride. The reaction is carried out in an inert organic solvent, such as methylene chloride, and at a temperature below 0"C, for example, at about -60"C. Diol 1 is a known compound and can be prepared according to the method described in .). Ogd. Spet., 1996, 61:8518-8525.

Further oxidation of aldehyde 2 to diacid | performed with silver nitrate and a base such as potassium hydroxide. Oxidation is carried out at room temperature in ethanol.

Scheme of the 2nd M: ORO single Ge | in:

IA EE

From the web

Dioxane

But m V o

FI from RSO NN ro on o

AZMO", 4

CON

І) f y: РОО НО о ту oxalyl 5 chloride 8-phenyl menthol і (о)

For "y si mo Y Another 6 i

Х is phenyl mentholate

RO - protection for the hydroxy group

Scheme 2 (continuation) o 1. memavg SS on "vot LON 2.- RO Ж 65 -li-yu Kha - sha Z

Divided major and minor isomers 1, M5SI: not-- M. YabOzn pvsh i "I on - i eosto to 8

LOoneYUN oson s i on pt- 1 s M | She--------

In Scheme 2, the protected hydroxyketone C is oxidized with selenium dioxide to obtain the corresponding ketoaldehyde 4. The protection for the hydroxyl group can be, for example, a tert-butyldimethylsilyl group.

Hydroxyketone C can be obtained according to the method described in 9. Ogud. Speth., 1993, 58:3731-3735. o-Ketoaldehyde 4 is oxidized to the corresponding o-ketocarboxylic acid 5, from which its derivative 8-phenylmenthol ether 6 is then obtained. Treatment of 6 with bromomethylmagnesium followed by deprotection leads to diol ether 7 as a diastereomeric mixture. Using chromatography, the mixture is divided into individual diastereomers. Each diastereomer is used separately to obtain individual diastereomers of formula I.

Thus, the secondary hydroxyl group of 7 is mesylated to give a derivative, which then reacts with the dianion 1-mercaptomethylcyclopropanoacetic acid, which reacts directly with n-butyllithium to give ester 8. Hydrolysis of 8 with a base such as lithium hydroxide leads to the desired dibasic acid formulas |.

The properties of the compounds of this invention as leukotriene antagonists are evaluated using the following methods: 1. VNITO receptor binding analysis in OM5O-differentiated 0937 cells (human monocytic cell line); 2. INI/TOx receptor binding on guinea pig lung membranes; 3. RNI/TOx receptor binding on human lung membranes; 4. Ip mio trachea of a guinea pig; and 5. IP mimo assay in anesthetized guinea pigs.

The above methods are described by T.V. uopez eyi a!., Sap. 9. Rejections. Rpatasoi 1991, 69, 1847-1854.

Rats are obtained from an inbred line of rats with idiopathic arthritis. Both females (190-250 g) and males (260-400 g) are used.

Egg albumin (EA), degree of purity dgade M, crystalline and lyophilized, obtained from bidta

Spetis! So., 5. And witnesses. Aluminum hydroxide is obtained from Nediz Spetis! Sotrapu, Spisado. Methysergide bimaleate provided bZapadog Tsa., Vaze!.

Provocation and subsequent breath registration are performed in a transparent plastic box with internal dimensions of 10x4 inches. The cover of the box is removable; when in use, it is held firmly in place by four clamps, and the air-tight shutter is supported by a soft-rubber gasket. An atomizer (Mo 40) is inserted through the center of each edge of the Oemiiris5 chamber by means of an airtight seal and each edge of the box also has an outlet. Pneumotachograph RiIeizsp! Me0000 is introduced into one edge of the box and connected to Sgaz5 with a volume pressure sensor (RT5-A), which is then connected to the Vykhso Eiesigopisve amplifier (Vykhso Eiesigopisve Ips., Zpagop, Sopp.). The amplifier is connected to the WeskKtap Toure B dynograph and to the computer

Vikhso consisting of a wave analyzer bag Asdpiviyop I oddeg, with a special weak wave. During antigen injection, the outlet holes are opened, and the pneumotachograph is isolated from the chamber. The outlet holes are closed, and the pneumotachograph and the camera are connected during the recording of the breathing pattern. For provocation, 2 ml of ZFo solution of antigen in saline is placed in each nebulizer and the aerosol is produced with air from a small Royeg diaphragm pump operating at 10 psi and a speed of 8 liters per minute.

Rats are sensitized by injecting (subcutaneously) ml of a suspension containing 1 mg of EA and 200 mg of aluminum hydroxide in a saline solution, they are used between 12 and 24 days after sensitization. In order to exclude the serotonin component of the response, rats are pre-injected intravenously 5 minutes before the aerosol provocation of Zmg/ml of methysergide, the rats are then exposed to an aerosol atmosphere with 395 EA in saline solution for exactly 1 minute, then their breathing profiles are recorded for the next 30 minutes . The duration of persistent shortness of breath is measured using a Vykhso computer.

Compounds are usually administered either orally 2-4 hours before provocation or intravenously 2 minutes before provocation, they are either dissolved in a saline solution or in 1956 methocel or suspended in 195 methocel. The administered volume is ml/kg (intravenous) or 1Oml/kg (oral). Before oral treatment, rats are not fed overnight. The activity of the compounds is determined based on their ability to reduce the duration of antigen-induced dyspnea compared to a vehicle-treated control group. Typically, compounds are evaluated using a series of doses and determined Echo - Activity is expressed as the dose (mg/kg) that inhibits the duration of symptoms by 5095.

The test procedure involves placing trained cynomolgus monkeys on chairs in aerosol-treated chambers. For control tests, assessment of lung function by measuring respiratory parameters is performed over a period of about 30 minutes to establish normal control values for each monkey during that day. For oral administration, the compound is dissolved or suspended in a 1965 solution of methocel (methylcellulose, 65NI, 400 srv) and given in a volume of Tml/kg of body weight. For aerosol introduction of compounds, use an ultrasonic nebulizer ОЯемиризв5. Pretreatment periods vary from 5 minutes to 4 hours before monkeys are challenged with aerosol doses of either leukotriene O4 (TO) or Avsaigi5 zisht antigen, 1:25 dilution.

After provocation, each minute leads to information that is calculated by computer as a percentage of deviation from control values for each respiratory parameter, including airway resistance (Vi) and dynamic relaxation (Saup). Results from each test compound are obtained sequentially for a minimum period of 60 minutes after challenge, which are then compared to previously obtained control values for that monkey. In addition, the total values during 60 minutes after provocations for each monkey (values of the base line and obtained as a result of the tests) are averaged separately and used to calculate the total, percentage inhibition of the response from I TO4 or Avsagi5 antigen with the test compounds. Paired (double) i-test is used for statistics. (References: MeRapape, S.5. ei ai!., Rgoziadiapaipv, 28, 173-182 (1984) apa MeRapape, 0.5. ei. ai., Adepiv Asiiopv, 22, 63-68 (1987).

A. Explanation: A certain allergic sheep with known sensitivity to a specific antigen (Avsagiz vit) reacts to inhalation provocation with an acute and delayed reaction of the bronchi. The time course of both the acute and delayed bronchial responses approximates that observed in asthmatics, and the pharmacological modification of both responses is similar to that found in humans. Antigen action in these sheep is largely observed in the upper tract and is conveniently measured as a change in pulmonary resistance or specific pulmonary resistance.

B. Methods: Animal material: Adult sheep with an average weight of 35 kg (range from 18 to 50 kg) are used. All animals that are used meet 2 criteria: a) they have a natural skin reaction when diluted 1:1000 or 1:10000 of the extract of Avsaigiz zisht (Sugeeg UOiadposiis5, I epoiz, MS); and 5) they previously reacted to inhalation provocation from Asgv cysts with both acute bronchostenosis and delayed bronchial obstruction (MM Abganat ei a!., At. Nem. Nezr. Oiv., 128, 839-44 (1983)) .

Measurement of the functioning of the respiratory tract: Sheep, which are not affected by sedatives, are kept in a flat position with their heads still. After local anesthesia of the nasal passages with a 2965 solution of lysocaine, the balloon catheter is advanced through one nostril into the lower esophagus.

Then an endotracheal tube is inserted into the animals through the other nostril, using a flexible fiber-optic bronchoscope as a probe. The pleural pressure is determined using an esophageal balloon catheter (filled with 1 ml of air), which is positioned so that as a result of inhalation, a wave (displacement) of negative pressure with clearly visible cardiogenic oscillations is observed. Lateral pressure in the trachea is measured using a catheter with a side opening (internal size 2.5 mm), which is advanced and which is located peripherally to the tip (tip) of the nasotracheal tube. Total pulmonary pressure, the difference between tracheal pressure and pleural pressure, is measured using a differential pressure transducer (OR45; Mayidupe Sogr., Moppgpdde, CA). To measure pulmonary resistance (A), the maximum end of the nasotracheal tube is connected to a pneumotachograph (Rieizsy, Oupa 5siepsev, Vischier

VeiI, RA). Signals of flow and total pulmonary pressure are registered on an oscilloscope (Mode! ОВ-12; EIesigopisv TOg

Meaisipe, M/pise Riaip5, MU), which is connected to the computer POR-11 Ridna! (Sida! Edpirtepi Sogr., Maupaga, MA) to calculate on linear section A, based on total pulmonary pressure, tidal volume obtained by integration, and flow. Analysis of 10-15 breaths is used to determine Vi. Chest gas volume (Mo) is measured in a plethysmograph to record changes in whole body volume to obtain specific pulmonary resistance (SPR - Vi : Mo).

Aerosol delivery system: Avsagi zeit extract aerosol (1:20) is prepared using an available medical nebulizer (NaipagorF, Rypyap Veppei) producing an aerosol with a mean aerodynamic diameter greater than 6.2 mm (geometric standard deviation, 2.1) as determined using an analyzer of electrical quantities (Mode! 3030; Tpepta! buvietv, 5. Rush, MM).

The product from the sprayer is directed to a plastic i-section, one end of which is attached to the nasotracheal tube, and the other end of which is connected to the breathing part of the Naguaga respirator. The aerosol is delivered at a tidal volume of 500 ml at a speed of 20 per minute. Thus, each sheep receives an equivalent dose of antigen in both the placebo and drug samples.

Experiment protocol: Before measuring the baseline Z5Ri, after antigenic provocation, the infusion of the test compound is started 1 hour before the provocation, the measurement of ZA is repeated and then the sheep is subjected to inhalation provocation with the antigen Avsagiz 5iit. ZNA measurements are performed after antigen provocation and at 1.2, 3.4, 5.6, 6.5, 7, 7.5, and 8 hours after antigen provocation. Placebo and drug tests are separated by at least 14 days. In a further study, sheep are given a dose of the test compound in the food lump followed by an infusion of the test compound 0.5-1 hour before Avsagis provocation and within 8 hours after Avsagi5, as described above.

Statistical analysis: The KgizKa!-Maiyi one-way AMOMA test was used to compare the acute immediate response to the antigen and the maximum delayed response in control and drug-treated animals.

The invention is now illustrated by the following non-limiting examples in which, unless otherwise noted: (i) all operations are performed at room temperature or at ambient temperature, that is, at a temperature in the region of 18-2520; (ii) evaporation of the solvent is carried out using a rotary evaporator under reduced pressure (600-4000 pascals; 4.5-30 mm Na) with a temperature in the bath up to 60"C; (ii) the course of the reaction is monitored using thin-layer chromatography (TLC) and reaction times are given for illustration purposes only; (m) melting points are uncorrected and 4" means decomposition; melting point data obtained for materials prepared as described; polymorphism can lead to the selection of materials with different melting points in some preparations; (m) the structure and purity of all final products is confirmed by at least one of the following methods: TLC, mass spectrometry, nuclear magnetic resonance spectrometry (NMR) or microanalytical data; (mi) outputs are provided for illustration purposes only; (mi) when indicated, NMR data are in delta form (4) values for the main diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 300 megahertz or 400 megahertz using the specified solvent; the accepted abbreviation used for the waveform is: 5. singlet; and. doublet; Her. triplet; t. multiplet; Mr. wide; etc; on the addition "Ag" means an aromatic signal; (my) chemical symbols have their usual symbols; the following abbreviation is also used: vol. (volume), weight (weight), t.k. (boiling point), m.p. (melting point), l (liter (s)), ml (milliliters), g. (gram (s)), mg. (milligram(s)), mol (moles), mmol (millimoles), equiv. (equivalent to (y) ).

Example 1 (A, A or 3)-1-I(1-I3'(2-(7-chloro-2-quinolinyl)-(E)-ethenyl)phenyl|-3-(2-(2-hydroxy- 2-propionic acid) phenyl)- propyl) thio) methyl| cyclopropanoacetic acid

A diastereomeric mixture

Stage 1 Methyl (A, A or 5)-1 | (1- 3- (2- (7-chloro-2-quinolinyl) - (E) - ethenyl) phenyl) -3 (2- (2-hydroxy-2-propionaldihyd) phenyl) propyl) thio) methyl| cyclopropane acetate

To a mixture of oxalyl chloride (0.45 mmol, 4.3 ml) in SNeSi"; (200 ml) at -60"C add OM5O (0.097 mmol, 7 ml) dropwise and stir for 5 minutes. Then methyl(BA,A or 5)-1 |((1-I3-(2-(7-chloro-2 -quinolinyl)-(E)-ethenyl)phenyl)y-3(2-(1,2-dihydroxy-1-methylethyl)-phenyl)propyl)thio)methyl|cyclopropaneacetate (9. Ogud. Spet., 1996, 61 , 8518-85251 (0.041 mol, 25 mg) in SNeSi»2 (5 bml) is slowly added at -60"C. The reaction mixture is stirred for 15 minutes and the reaction is stopped by adding EM (0.2 mmol, 28ml). The temperature is raised to 25"C and water (2ml) was added, the reaction mixture was extracted with EtOAc (2ml). The organic extracts were dried over Mag25O4 and evaporated to dryness. The residue was brought to constant weight under high vacuum to give 20mg of the title compound, which was used as such in the next step.

IN NMR (СозСОСОО) d 0.38-0.53 (m, 4Н), 1.51 (s, ЗН), 2.05-2.30 (m, 2Н), 2.39 (d, 1Н), 2.46 (d, 1H), 2.55 (s, 2H), 2.60-2.80 (m, 2H), 3.05-3.15 (m, 1H), 3.58 (s, ЗН), 4.05 (t, 1Н), 7.15-7.30 (m, ЗН), 7.39-7.55 (м, 5Н), 7.62 (m, 1Н), 7.75 (s, 1H), 7.85 (d, 1H), 7.9 (m, 2H), 8.0 (s, 1H), 8.95 (d, 1H), 9.62 (s, 1H) .

Stage 2 (A, A or 5)-1-I(1-I3-(2-(7-chloro-2-quinolinyl)-(E)-ethenyl)phenyl|-3-(2-(2-hydroxy- 2-propionic acid (phenyl)-propyl)thio)umethyl| cyclopropanoacetic acid

To the solution of aldehyde from stage 1 (20mg, 0.032mmol) in EUN (500Oml) and AoMOz (1Zmg, 0.76mmol) (previously dissolved in 30ml of water) add KOH solution (0.1bmmol, 0.1bml) dropwise. The reaction mixture was stirred at room temperature overnight. The reaction mixture is acidified with acetic acid (10 ml) and diluted with a saturated solution of MNACI (2 ml) and extracted with EUAs (2 ml). The organic extracts are dried over NaCl5Ox and evaporated. The residue is purified by flash chromatography on silica gel using a solvent mixture of MEON/CHCl3/MH3 x 4:81 and 5 mg of the substance is obtained, which is further purified by HPLC on a Momarak silica gel column using an elution mixture of mM Meon/NaO/AsoOn ( 80-20-0.1905) and controlling the eluted fractions at 350 nm, and obtain 2.8 mg of the title compound.

IN NMR (COzSOS0Oz) d 0.35-0.68 (m, 4H), 1.75 (s, ЗН), 2.10-2.25 (m, 2H), 2.45 (d, 2H), 2.50-2.70 (m, ЗН), 3.0 (m, 1Н), 4.05 (m, 1Н), 7.05-7.20 (m, ЗН), 7.35-7, 55 (m, 5H), 7.6 (s, 1H), 7.8 (s, 1H), 7.85-8.0 (m, ЗН), 8.02 (s, 1H), 8.25 (d, 1H).

VRMS (EAV) t/2 calculated for C3NzaSIMO»5o: 616.192448, found 616.19269.

Example 2 (A, A or 8)-1-((1-(3-(2-(7-chloro-2-quinolinyl)--E)-ethenyl)phenyl3-3-(2-(2-hydroxy- 2-propionic acid)phenyl)-propyl)thio)umethyl|cyclopropanoacetic acid

Stage 1 (8)-2-(3-I3-(2-(7-chloro-2-quinolinyl)-(E)-ethenyl)phenyl|-3-tert-butyldimethylsilyloxypropyl)ethanone

To H (5-(E)-1-(2-I3-I3-(2-(7-chloro-2-quinolinyl)ethenyl|phenyl|-3-hydroxypropylIfenyl| ethanone) (U. Horod. Spet., 1993, 58, 3731-3735) (13.4g, 30.35mmol) in NaCl; (b7ml) add 2.6 lutidine (5.32ml, 45.52mmol). The mixture is cooled to -78"C, then TVOM5O Ti (7 .0ml, 30.35mmol) was added dropwise. The reaction mixture was stirred for 1 hour. The reaction was quenched by adding 2595 MNaOAc solution (50ml) and extracted with EtOAc (100ml). The organic extract was dried over Mag25O4 and evaporated to a residue. The crude product was purified using flash chromatography on silica gel, using a mixture of hexane and EtOAc in the ratio of 95:5 as an eluent and obtain 14.4 33 g of the compound named in the title.

IN NMR (SOZZSOSO) d 0.15 (s, 6H), 0.95 (s, 9H), 2.0 (m, 2H), 2.81-3.02 (m, 2H), 4.95 ( t, 1H), 7.25 (t, 2H), 7.36-7.55 (m, 5H), 7.72 (d, 1H), 7.75 (c, 2H), 7.82 (d , 1H), 7.90 (d, 2H), 8.0 (c, 1H), 8.35 (d, 1H).

Stage 2.

To the previously dissolved 5eOg (2.95g, 26.57mmol) in a mixture of dioxane and water (100ml : 0.48ml) at 607 add the ketone from stage 1 (14.4g, 2bmmol) in a solution with dioxane (7Oml). The reaction mixture is heated at 100"C overnight. The reaction mixture is then cooled to room temperature and filtered through a celite pad and washed with dioxane (20ml). After evaporation to dryness, the title compound is obtained, which is used as such in the next step (Crude weight 14g ).

Stage 3 (5)-2-(3-I3-(2-(7-chloro-2-quinolinyl)-(E)-ethenyl) phenyl| -3-tert-butyldimethylsilyloxypropyl) benzoylformic acid

To the solution of the aldehyde from stage 2 (14g, 24.6mmol) in EUN (118ml) add a solution of AdMOz (10g, 59mmol), previously dissolved in water (23ml), and then add a solution of KOH (118ml, 118mmol 1M) dropwise. The mixture is stirred at room temperature overnight. The volume of EUN is removed by evaporation, the aqueous solution is acidified with 1 M NOSI (118 ml) and extracted with ЕУАСС twice (100 ml). The organic extracts are dried over Mao: and evaporated. The residue is purified by means of flash chromatography, first as an eluent, pure ЕХАСС is used, and then a mixture of ЕХАСС:АСОН - 95:5 and 5.0 g of the compound named in the title are obtained.

IN NMR (SOZZSOSO) d 0.15 (s, 6H), 0.95 (s, 9H), 2.0 (m, 2H), 2.95-3.18 (m, 2H), 4.95 ( t, 1H), 7.35-7.65 (m, 8H), 7.75-7.97 (m, 5H), 8.0 (s, 1H), 8.32 (d, 1H).

Stage 4 8-phenylmenthyl (5)-2-(3-I3-(2-(7-chloro-2-quinolyl)-(E)-ethenyl)phenyl-3-tert-butyldimethylsilyloxypropyl)benzoyl formate

DMR (100 ml) and then oxalyl chloride (1.12 ml, 12.8 mmol) were added dropwise to the keto acid from stage C (5.0 g, 8.5 mmol) in СНоSiO (40 ml) at 0 C. The reaction mixture was stirred for 1 hour. The reaction mixture is then evaporated to dryness and the residue is left under high vacuum for 1 hour and the resulting product is used as such in the next step.

To 8-phenylmenthol (2.0g, 8.bmmol) in toluene (40ml) and pyridine (0.7ml, 8.5mmol) was added the crude chloride from the previous step in toluene (10ml) at room temperature. The mixture is stirred overnight. The reaction is stopped by adding a saturated solution of NiMaCl and HCl 1 M 1:1 (5 Oml) and extracted with EUAsC twice (5 Oml). The organic extracts are dried over NaCl5Ox and evaporated to dryness. The residue is purified by flash chromatography, a mixture of toluene and EAC in the ratio of 99:11 is used as an eluent, and 5.0 g of the compound named in the title is obtained.

IN NMR (COzSOS0O) d 0.18 (s, 6H), 0.8-0.9 (m, 4H), 0.95 (s, 9H), 1.02-1.20 (m, 2H), 1.3 (d, 6H), 1.45-1.60 (m,

ЗН), 1.95-2.15 (m, 4Н), 2.92-3.15 (m, 2Н), 4.95 (t, 1Н), 6.95 (t, 1Н), 7.1 -7.18 (m, 4H), 7.4-7.55 (m, 6H), 7.57-7.75 (m, 4H), 7.8-7.85 (m, 1H), 7 .9-7.98 (d, d, 2H), 8.02 (c, 1H), 8.35 (d, 1H).

Stage 5 (5, A or 5) 8-Phenylmenthyl-2-(3-III- (2-(7-chloro-2-quinolyl)-(E)-ethenyl)-phenyl|-33-tert-butyldimethylsilyloxypropyl)- 2-Hydroxy-2-phenylpropionate

To the ketoester from stage 4 (1.0g, 1.25mmol) in ether (25ml) was added MemoVg ZM (0.83ml, 2.5mmol) at -78°C.

The reaction mixture is stirred for 1.5 hours. The reaction is stopped by adding 04 ml of AcOon directly to the mixture, and then adding a saturated solution of MNACI (10 ml) and extracting with EtOAc (20 ml). Organic extracts are dried over Mag25O4 and evaporated to dryness. The residue was purified by flash chromatography using a 90:10 mixture of hexane and EtOAc to give 0.8 g of the title compound.

IN NMR (COzZSOSO) d 0.2 (s, 6H), 0.62-1.2 (m, 23H), 1.35 (m, 2H), 1.72 (t, 1H), 1.80 ( s, ЗН), 2.70 (t, 1Н), 2.85 (t, 1Н), 4.75 (m, 1Н), 5.0 (m, 1Н), 7.05-7.25 (m , 8H), 7.35-7.55 (m, 5H), 7.65 (s, 1H), 7.75-8.05 (m, 5H), 8.35 (d, 1H).

Stage 6 (5, A or 5) 8-Phenylmenthyl-2-(3- 3- (2-(7-chloro-2-quinolyl)-(E)-ethenyl)phenyl|-3-hydroxy)-2- hydroxide - phenylpropionate

To the ether carbinol from stage 5 (0.8 g, 0.98 mol) in THF was added a solution of TVAE (1 ml, 0.98 mmol) at room temperature overnight. The reaction is stopped by adding a saturated solution of MNACI and extracted with EtOAc (2x1Oml). The organic extracts are dried over Mag5C" and evaporated to dryness. The residue is purified by flash chromatography, eluting with a 95:5 mixture of C2SO4 and acetone, and 0.39g of the major isomer and 0.10g of the minor isomer are obtained.

Main: "H NMR (СОЗСОСО») d 0.65-1.00 (m, 9Н), 1.05 (с, ЗН), 1.18 (m, 1Н), 1.40 (m, 2Н), 1.75 (m, 1H), 1.80 (s, ЗН), 2.00 (m, 2H), 2.28 (m, 1H), 2.7 (m, 1H), 3.02 (m , 1H), 4.70 (m, 1H), 4.80 (m, 1H), 7.08-7.25 (m, 8H), 7.4-7.55 (m, 5H), 7, 62 (m, 1H), 7.82-8.02 (m, 5H), 8.35 (d, 1H).

Minor: -0.060-1.00 (m, 6H), 1.2 (m, 7H), 1.3-1.45 (m, 2H), 1.68 (s, ЗН), 1.8-1 .9 (m, 2H), 2.04 (m, 1H), 2.15-2.25 (m, 1H), 2.65-2.75 (m, 1H), 2.92-3.0 (m, 1H), 4.78-4.90 (m, 2H), 7.09-7.3 (m, 8H), 7.4-7.65 (m, 5H), 7.75-8 .05 (m, 6H), 8.35 (d, 1H).

Stage 7 (5, A or 5) 8-phenylmenthyl-2- (3-|3- (2- (7-chloro-2-quinolyl)-(E)-ethenyl)phenyl|-3-methanesulfonate)-2- hydroxy-2-phenylpropionate

Nipid base (Ubml, 0.433mmol) is added to the main isomer of the alcohol carbinol ether from stage 6 (0.3g, 3.41mmol) in a 1:11 mixture of toluene with CH3ZSM (2.5ml). The reaction mixture is cooled to -40"С and methanesulfonyl chloride (33ml, 0.4Zmmol) is added dropwise. The temperature is gradually raised to -30"С within 1 hour. The reaction is stopped by adding a saturated Mansoz solution (3ml) and extracted with E(OAcS) (3ml).

The organic extracts are dried over Ma»2504 and evaporated to dryness. The obtained title compound is used as such in the next step.

IN NMR (СОЗСОСО») d 0.65-0.98 (m, 9Н), 1.0 (с, ЗН), 1.25-1.45 (m, 2Н), 1.75 (m, 4Н) , 1.9 (m, 1H), 2.28 (m, 1H), 2.42-2.55 (m, 1H), 2.7-2.85 (m, 2H), 2.95-3 .05 (m, 4H), 4.65-4.75 (m, H), 5.80 (t, 1H), 7.05-7.25 (m, 8H), 7.45-7.60 (m, 5H), 7.75-7.82 (d, 1H), 7.83-8.05 (m, 5H), 8.35 (d, 1H)

1-(mercaptomethyl)-1-cyclopropanoacetic acid (Viogdapis) is added to degassed THF (ml) under M

Mea. I ecsegz, 1995, 5(3), 283-288) (bOmg, 0.41 mmol). Butyl lithium (339 ml, 0.82 mmol) is added to this solution, cooled to -157C. The temperature is raised to -8"C for 30 minutes. Then the crude mesylate from the previous stage (0.33g, 0.41mmol), dissolved in degassed THF (ml), is added dropwise to the reaction mixture. The mixture is stirred at 0"C overnight. The reaction is stopped with a saturated solution of MNACI (2 ml) and extracted with EtOAc (2 ml). The organic extracts are dried over Mag50»4 and evaporated to dryness. The residue is purified by flash chromatography using a 1:1 mixture of hexane and EtOAc with the addition of 195

AsOonH and obtain 138 mg of the title compound.

IN NMR (СозСОс0О») d 0.3-0.58 (m, 4Н), 0.6-0.96 (m, 5Н), 1.10-1.25 (m, 7Н), 1.28- 1.45 (m, 1H), 1.62 (s, ЗН), 1.75-1.90 (m, 1H), 2.09-2.20 (m, 1H), 2.25-2, 36 (m, 1H), 2.40-2.52 (m, 2H), 2.60 (s, 2H), 2.65-2.84 (m, 2H), 4.02 (t, 1H) , 4.75 (m, 1H), 7.09 (m, 11), 7.35-7.55 (ZH), 7.62 (M, 1H), 7.75-8.05 (m, 4H ), 8.35 (d, 1H).

Stage 8 (A, A or 5)-1-I(1-I3-(2-(7-chloro-2-quinolinyl)--E)-ethenyl)phenyl)|-3-(2-(2-hydroxy -2-propionic acid)phenyl)-propyl)thio)methyl| cyclopropanoacetic acid

To the carbinol ester from stage 7 (138mg, 01bmmol) in EYN (500ml) add a solution of 1 M PON (480Oml,

Oh, 48 mmol). The reaction mixture is refluxed for 3 days, the reaction is stopped by adding a saturated solution of MNACI (2ml) and acetic acid (30ml) and extracted with EtOAc (2ml). The organic extracts are dried over Ma»25O4 and evaporated to dryness. The residue is purified by flash chromatography, using as an eluent a mixture of CHCl3 and MeOH in a ratio of 2:11, then a mixture of CHCl3/MeOH/MNAaOH - 2/1/0.25 and 6b5mg of the compound named in the title is obtained, which is further purified by HPLC on the column

MomarakK, controlling at 35O0nm, using the eluent MeOH-water-AcSOnH - 80:20:0.195, and 11 mg of the compound named in the title are obtained.

IN NMR (СозСОСОО) d 0.3-0.7 (m, 4Н), 1.78 (d, ЗН), 2.16-2.72 (m, 7Н), 3.05 (t, 1Н), 4.02 (t, 1H), 7.02-7.20 (m,

ZH), 7.25-7.35 (m, 1H), 7.38-7.58 (M, 4H), 7.62 (t, 1H), 7.78 (d, 1H), 7.80 -7.98 (m, ZH), 8.01 (s, 1H), 8.34 (d, 1H). 136 NMR (COzSOS0Oz) d 12.3, 12.3, 17.1, 27.5, 31.8, 39.2, 39.5, 39.6, 50.4, 76.0, 120.7, 125.8, 126.3, 126.2, 126.7, 127.1, 127.5, 128.1, 128.2, 129.0, 129.2, 129.2, 130.0, 131, 2, 135.3, 135.8, 137.0, 137.5, 140.9, 141.7, 144.5, 149.1, 157.7, 173.1, 177 4.

VRMS (EAV; t/2 calculated for C3NzaSIMO»55: 616.192448, found 616.19269.

Example C (A, A or 5)-1-((1-(3-(2-(7-chloro-2-quinolinyl)--E)-ethenyl)phenyl|-3-(2-(2-hydroxy -2-propionic acid)phenyl)-propyl)thio)methyl| cyclopropanoacetic acid

Minor isomer

Stage 1 (5, A or 5) 8-phenylmethyl-2-(3-|3-(2-(7-chloro-2-quinolyl)--E)-ethenyl)phenyl|-3-methanesulfonate)-2- hydroxy-2-phenylpropionate

To the minor isomer of the alcohol carbinol ether from example 2, stage 6 (0.5 g, 0.6 mmol) in a mixture of toluene with

Nipid base (125 ml, 0.6 dmmol) is added to SNZiSM in a ratio of 1:1 (4.0 ml). The reaction mixture is cooled to -40"C. Then methanesulfonyl chloride (55ml, 0.71mmol) is added dropwise. The temperature is gradually raised to -30"C over 71 hours. The reaction is stopped by the addition of a saturated solution of MansSos (3ml) and extracted with EtOAc (3ml). The organic extracts were dried over Mag2504 and evaporated to dryness to give the title compound, which was used as such in the next step.

IN NMR (СОЗСОСО») d 0.65-0.98 (m, 9Н), 1.0 (с, ЗН), 1.25-1.45 (m, 2Н), 1.75 (m, 4Н) , 1.9 (m, 1H), 2.28 (m, 1H), 2.42-2.55 (m, 1H), 2.7-2.85 (m, 2H), 2.95-3 .05 (m, 4H), 4.65-4.75 (m, H), 5.80 (t, 1H), 7.05-7.25 (m, 8H), 7.45-7.60 (m, 5H), 7.75-7.82 (d, 1H), 7.83-8.05 (m, 5H), 8.35 (d, 1H).

1-(Mercaptomethyl)-1-cyclopropanoacetic acid (Viogdapis) is added to degassed THF (ml) under M

May I ecsegz5, 1995, 5 (3), 283-288) (99mg, 0.6v8mmol). Butyllithium (542ml, 1.36bmmol) is added to the atom of the solution cooled to -157С. The temperature is raised to -8"C for 30 minutes. Then the crude mesylate from the previous stage (0.55g, 0.bZmmol), dissolved in degassed TNO (1.6ml), is added dropwise to the reaction mixture. The mixture is stirred at 0"C for at night The reaction is stopped with a saturated solution of MNACI (2 ml) and extracted with EtOAc (2 ml). The organic extracts are dried over NaCl and evaporated to dryness. The residue was purified by flash chromatography using a 1:1 ratio of hexane to EtOAc with the addition of 195% ASON to give 200mg of the title compound.

IN NMR (СозСОСсО:) D 0.3-0.58 (m, AN), 0.6-0.96 (m, 5Н), 1.10-1.25 (m, 7Н), 1.28- 1.45 (m, 1H), 1.62 (s, ЗН), 1.75-1.90 (m, 1H), 2.09-2.20 (m, 1H), 2.25-2, 36 (m, 1H), 2.40-2.52 (m, 2H), 2.60 (s, 2H), 2.65-2.84 (M, 2H), 4.02 (t, 1H) , 4.75 (m, 1H), 7.09 (m, 11), 7.35-7.55 (ZH), 7.62 (m, 1H), 7.75-8.05 (m, AN ), 8.35 (d, 1H).

Stage 2 (B, A or 5)-1-I((1-I3-(2-(7-chloro-2-quinolinyl)--ESU -ethenyl).phenyl| -3- (2- (2-hydroxy -2-propionic acid) phenyl)-propyl)thio)umethyl| cyclopropanoacetic acid

A solution of 1 M PON (70 Oml, 0.70 mmol) is added to the carbinol ester from stage 7 (200 mg, 0.23 mmol) in EYN (500 ml). The reaction mixture is refluxed for 3 days, the reaction is stopped by adding a saturated solution of MNACI (2 ml) and acetic acid (3 ml) and extracted with E(OAc (2 ml). The organic extracts are dried over Mag2504 and evaporated to dryness. The residue is purified by flash chromatography , using as an eluent first a 2:1 CHCl3/Meon mixture and then a 2:1:0.25 CHCl3/UMeEON/MNAOH mixture to give 8mg of the title compound, which was further purified by HPLC on columns

Momarak, controlling at 350 nm, using an elution mixture of MeOH-water-ASON in the ratio of 80:20:0.195 and obtained 1 µg of the title compound.

IN NMR (СозСОСсО:) D 0.3-0.7 (m, 4Н), 1.78, (d, ЗН), 2.16-2.72 (m, 8Н), 3.05 (t, 1Н ), 4.02 (t, 1H), 7.02-7.20 (m.

ЗН), 7.25-7.35 (m, 1Н), 7.38-7.58 (m, 4Н), 7.62 (t, 1Н), 7.78 (d, 1Н), 7.80 -7.98 (m, ZH), 8.01 (s, 1H), 8.34 (d, 1H).

VRMS (EAV) t/2 calculated for Sz5NzaSIMO: 616.192448, found 616.19269.

Example 4

Isolation of -1-(((1-(3-(2-(7-chloro-2-quinolyl)-(E)-ethenyl)phenyl|-3-(2-(2-hydroxy-2-propionic acid)phenyl - propyl)thio)methyl|cyclopropanoacetic acid from human bile

Healthy subjects are administered a single oral dose of 50 mg montelukast sodium after an overnight fast (3 subjects) or 5 hours after a high-fat diet (3 subjects). Bile is collected with the help of a gastroduodenal tube, which is placed through the mouth near the hepatogastric ampulla, from 2 to 8 hours or from 8 to 12 hours after taking the dose. Cholecystokinin C-terminal octapeptide is administered intravenously 2 hours before the end of the collection procedure to stimulate contraction of the gallbladder and thereby increase bile outflow. Subjects are fasted throughout the collection procedure. All samples are stored at -70"C in the dark until analysis, and all analyzes are performed under yellow light conditions.

Bile samples are analyzed immediately after centrifugation using a SIZ5 JuOesctap column (4.6 x 250 mm), eluting at a rate of 1 ml/minute with linear gradients from 3595 to 4595 acetonitrile in 1 mM ammonium acetate, pH 3.5 for 5 minutes, from 4595 to 5595 acetonitrile for 35 minutes, 5595 to 8790 acetonitrile for 20 minutes, 8795 to 9595 acetonitrile for 0.3 minutes. Under these HPLC conditions, the title compound eluted at about 53 minutes as a diastereomeric mixture.

The title compound thus obtained is again purified using a 2700-HOV Esirhse C8 column (4.6 x 250 mm) and eluting for 15 minutes with a linear gradient from 2890 acetonitrile and 2895 methanol in water to 4795 acetonitrile and 4795 methanol in water. The retention time of the title compound under these conditions is 15 minutes. The NMR and mass spectra of the repurified compound correspond to those obtained for an authentic sample of the title compound.

Claims (7)

1. A quinoline derivative of the formula A son : S on Fe : son si M Phi phi and its individual optical isomers or its pharmaceutically acceptable derivatives. 2. The isolated and purified compound according to item I is essentially free from other metabolic products of montelukast sodium. 3. A pharmaceutical composition containing a therapeutically effective amount of compound zap. 11 a pharmaceutically acceptable carrier. 4. A method of preventing leukotriene action in a mammal, which comprises administering to said mammal in need of such treatment a therapeutically effective amount of the compound of claim 1. 5. A method of treating or preventing anger, allergy or inflammation in a mammal, which includes administering to said mammal in need of such treatment a therapeutically effective amount of the compound of claim 1. 6. The method of obtaining the compound according to claim 1, which includes: a) the interaction of the compound of formula 1 sov u on "x Z on - : Y " | FI Another 1, where K means lower alkyl, with dimethylsulfoxide 1 as an electrophile to obtain a compound of formula 2, directly from 7:2 b) interaction of a compound of formula 2 with silver nitrate 1 as a base to obtain a compound according to claim 1. 7. The method of obtaining individual diastereomers of the compound according to item I, which includes: a) separation of the diastereomer mixture of the compound of the formula 7 (o) ХХ, that is ІМ 7 фи " | Хе where "K means 8-phenylmenthyl; b) interaction of an individual diastereomer with methanesulfonyl chloride to obtain the corresponding mesylate; c) interaction of the mesylate from stage B) with the dianion 1-mercaptomethylcyclopropanoacetic acid, with the preparation of the compound of formula 8 and "M o ch" X 5 ko on - H -E ne 4) removal of the 8-phenylmenthyl group to obtain the compound according to claim 1.