HUT76443A - Quinoline derivatives as leukotriene antagonists,pharmaceutical compositions containing them and process for producing them - Google Patents

Description

PUBLISHING PAPER r

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Representative:

Danubia Patent and Trademark Office Ltd.

LEUKOTRIEN ANTAGONISTIC QUINOLINE DERIVATIVES AND THEIR PHARMACEUTICAL PREPARATIONS

WHEELS ^ PROCEDURE FOR THEIR PRODUCTION ^ AND APPLICANT

Q TTTZ □ UK

LEÓ PHARMACEUTICAL PRODUCTS LTD. A / S (L0VENS KEMISKE FABRIK PRODUKTIONSAKTIESELSKAB),

Ballerup, DK

inventors:

KIRSTEIN Dorte, Lyngby, DK

RACHLIN Schneuer, Horsholm, DK

Date of filing: 06.06.1995

Priority: 20.07.1994 (9414590.1) GB

International Application Number: PCT / DK95 / 00223 International Publication Number: WO 96/02506

84950-1101

The present invention relates to novel compounds for use in human or veterinary medicine, and to pharmaceutically acceptable salts, biologically reversible derivatives thereof, processes for the preparation of the above new compounds, pharmaceutical compositions containing said new compounds, and unit dosage forms of these compositions.

The leukotrienes produced by the 5-lipoxygenase pathway of arachidonic acid metabolism suggest a number of pathophysiological functions such as bronchoconstriction, plasma exclusion, coronary spasm, leukocyte chemotaxis, and neutrophil degranulation [R. A. Lewis, K. F. Austen and R. J. Soberman, New Eng. J. Med. 323, 645 (1990). Therefore, there is a need to develop compounds that inhibit 5-lipoxygenases and thereby inhibit the formation of leukotrienes or antagonize the action of leukotrienes.

PCT / DK88 / 00188 (WO 89/05294) discloses quinolylmethoxyphenyl substituted aminophenoxyalkyl acids having leukotriene antagonist activity and 5-lipoxygenase inhibitor activity.

PCT / US89 / 02692 (WO 89/12629) discloses quinolyl-ethenyl-phenoxymethyl-phenoxy-alkyl-substituted acids having leukotriene antagonist activity.

PCT / DK90 / 00201 (Publication No. WO 91/03466) describes quinolylmethoxy-substituted N-phenyl-substituted isoserine (i.e., 3-amino-2-hydroxypropionic acid) derivatives which are good for leukotriene. antagonist act • · ·

- Show 3 disputes.

PCT / DK93 / 00254 (Publication No. WO 94/03431) discloses quinolyl ethenyl substituted N-phenyl substituted isoserine derivatives having good leukotriene antagonist activity.

Surprisingly, it has been found that the compounds of formula I exhibit potent leukotriene antagonist activity.

A novel structural feature of the above compounds is that they contain an optionally halogen substituted quinoline ring which is bonded to a meta-substituted aniline by an E-CH 2 CH- bond which in turn is attached to a substituted benzyl group according to formula (I) to give compounds having they have a significantly longer duration of action than known compounds of similar structure, while retaining their potent leukotriene antagonist activity, particularly in the presence of human serum albumin.

In the compounds of formula I, X and X ₂ are each independently hydrogen or halogen;

X ₃ and X ₄ are each independently hydrogen, halogen, nitro, cyano, trifluoromethyl, C 1-4 alkyl, C 1-4 alkoxy, carboxyl or C 1-4 alkoxycarbonyl;

Z is a bond, O, S, S (O), S (O) ₂ , NH or

CH ₂ ;

Rj is hydrogen or straight or branched, saturated or unsaturated C 1 -C 6 · · · ·

- 4 hydrocarbon chains;

R ₃ is hydrogen, a linear or branched, saturated or unsaturated C 1 -C 12 hydrocarbon chain, unsubstituted or substituted phenyl, or unsubstituted or substituted benzyl, wherein the substituent may be one or more of X ₃ and X ₄ as defined above; obsession

R 1 - [C] _p -R _{3 is} cyclopropyl; p may be 0 if Z is a bond or ρ is an integer from 1 to 6 when R 1 and R ₃ are hydrogen;

A is 1 H-tetrazolyl or COOR ₂ in which

R ₂ is a group represented by R 1 or a pharmaceutically acceptable cation.

More specifically,

X ₁ and X ₂ are each independently hydrogen, fluoro, or chloro;

X ₃ is hydrogen;

X ₄ is hydrogen, fluoro, chloro or bromo;

Z is O or S in the ortho position;

p is 1;

Rj is hydrogen;

R ₃ is hydrogen or a linear or branched, saturated or unsaturated C 1 -C 6 hydrocarbon chain or phenyl; and • · ·

- 5A is tetrazol-5-yl or COOR ₂ , wherein

R ₂ is hydrogen, C 1-3 alkyl, or an alkali metal cation.

More specifically, the compound is selected from the group consisting of E-2- [2- {3- [2- (7-chloroquinolin-2-yl) ethenyl] phenylaminomethyl} phenoxy] -2- methyl propionic acid, E-2- [2- {3- [2- (7-chloroquinolin-2-yl) ethenyl] phenylaminomethyl} phenoxy] -2-methylpentanoic acid, E- 2- [2- {3- [2- (7-Chloro-quinolin-2-yl) -ethenyl] -phenylaminomethyl} -phenoxy] -hexanoic acid, E-2- [2- {3- [2 - (7-Chloro-quinolin-2-yl) -ethenyl] -phenylaminomethyl} -4-bromo-phenoxy] -hexanoic acid, E-2- [2- {3- [2- (7-fluoro-) quinolin-2-yl-ethenyl] -phenylaminomethyl} -phenoxy] -hexanoic acid, E-2- [2- {3- [2- (6,7-difluoro-quinolin-2-yl) -ethenyl] ] -phenyl-amino} -phenoxy-methyl-hexanoic acid sodium salt.

The compounds of the present invention may contain one or more centers of asymmetry to form stereoisomers such as enantiomers or diastereoisomers. The invention also relates to all possible stereoisomeric forms.

A particularly preferred compound is (S) - (+) - E-2- [2- {3- [2- (7-chloroquinolin-2-yl) ethenyl] phenylaminomethyl} phenoxy] - acid.

The salts of the compounds of the formula I according to the invention are pharmaceutically acceptable inorganic or organic acids such as hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric, p-toluenesulfonic, methanesulfonic, propionic, acetic, tartaric acid and maleic acid, these examples are included without limitation.

Salts of the compounds of formula I according to the invention with pharmaceutically acceptable inorganic or organic bases

- 6 can be trained. Pharmaceutically acceptable salts formed with non-toxic bases include alkali metal salts and alkaline earth metal salts such as lithium, sodium, potassium, magnesium, calcium, and ammonia and suitable non-toxic amines, e.g.

C 1-6 -alkylamines such as triethylamine, C 1-6 -alkanolamines such as diethanolamine or triethanolamine, procaine, cycloalkylamines such as dicyclohexylamine, benzylamines such as N-methyl- salts with benzylamine, N-ethylbenzylamine, N-benzyl-P-phenethylamine, Ν, Ν'-dibenzylethylenediamine or dibenzylamine and heterocyclic amines such as morpholine, N-ethylpiperidine or the like They are.

Although the compounds of formula (I) are well absorbed after enteral administration, it may in some cases be advantageous to form suitable bioreversible derivatives of the compounds of the present invention, meaning so-called prodrugs, preferably derivatives having physicochemical properties leading to improved physiological pH. -η and / or improved absorption and / or bioavailability of the compound of interest.

Examples of such derivatives are the N-hydroxymethyl derivatives of the compounds of the invention, which are prepared by reacting the secondary amine functional group of the compounds of the invention with formaldehyde [R. G. Kalien and W. P. Jencks, J. Bioi. Chem., 241, 5864 (1966); C. J. Martin et al

M. A. Marini, J. Bioi. Chem. 242, 5736 (1967); M. Levy and D. E. Silberman, J. Bioi. Chem., 18, 723 (1937); S. Lewin and D.A.

Humphany, J. Chem. Soc. B, 210 (1966)] followed by a suitable one

- 7 acidic compounds or their activated derivatives, such as hydrogen sulfite [B. C. Jain, Β. H. Iyer and P. C. Guha, Science and Culture 11, 568 (1946)] with Ν, Ν-dimethylglycine, N, N-diethyl-β-alanine or phosphoric acid [S. A. Varia, S. Schuller, K. B. Sloan, and V. J. Stella, J. Pharm. Sci., 73, 1068 (1968)], but other suitable acids may also be used which form a bioreversible derivative having appropriate physicochemical properties.

Other examples include esters formed with an acidic functional group in the molecule, such as simple esters such as ethyl or methyl esters, acyloxyalkyl esters, alkoxycarbonyloxyalkyl esters or aminoacyloxyalkyl. esters which are readily hydrolyzed in vivo or in vitro.

Among the above esters, the following are preferred: C 3-6 alkanoyloxymethyl esters, C 4-6 1- (alkanoyloxy) ethyl esters, C 3-6 alkoxycarbonyloxymethyl ester, C 1 -C 6 alkoxycarbonyloxyethyl esters and

C2-C6 α-aminoalkanoyloxymethyl esters.

Preferred esters are also lactonyl esters such as 3-phthalidyl ester, 4-crotonolactonyl ester or γ-butyrolacton-4-yl ester.

Also included within the scope of the invention are methoxymethyl, cyanomethyl and mono- or dialkyl-substituted aminoalkyl esters, such as 2- (dimethylamino) ethyl, 2- (diethylamino) ethyl and the like. - (dimethylamino) propyl esters.

Especially preferred are the esters which are well absorbed after enteral administration and during absorption.

- hydrolyzed to a compound of formula (I) after 8 or more.

The above examples are, but are not limited to, any other suitable method for improving the physico-chemical properties and solubility of the compounds of the invention.

5-Lipoxygenase Inhibitors and Leukotriene Antagonists include asthma, allergies, rheumatoid arthritis, vertebral arthritis, gout, atherosclerosis, proliferative and inflammatory skin disorders such as psoriasis and atopic dermatitis, chronic inflammatory bowel disease and other inflammatory conditions, pulmonary hypertension, cystic fibrosis and adult respiratory distress syndrome, ischemic and reperfusion injury, migraine headache, etc. for the treatment of [E. J. Goetzl, D.G. Payan and D.W. Godman, J. Clin. Immunol. 4, 79 (1984)]. The identification of specific 5-lipoxygenase inhibitors and leukotriene antagonists may therefore represent a novel approach to the treatment of a number of clinical disorders.

Inhibitors of arachidonic acid metabolism can be identified using rat peritoneal leukocytes labeled with [l- ^14C ] arachidonate and stimulated with A23187 calcium ionophore [I. Ahnfelt-R <t> nne, D. Kirstein and C. Kaergaard-Nielsen, European J. Pharmacol. 155: 11 (1988). Compounds of the invention have been found to inhibit metabolism at concentrations of 10 pmol / L.

Leukotriene antagonists can be identified by observing contraction induced by guinea-pig ileum strip suspended in physiological buffer in pure leukotriene D ₄ · · ·

- after adding 9 (LTD ₄ ) [I. Ahnfelt-Ronne, D. Kirstein and C. Kaergaard-Nielsen, European J. Pharmacol., 155, 117 (1988). If the ileum preparation was also added to the compound of the invention prior to addition of _LTD4, induced by specific _LTD4 contraction was significantly inhibited. This inhibition is already 0.1-1 nM. observed at η concentrations. On the other hand, histamine-induced contractions at 10 mol / l are not inhibited even in the presence of micromolar concentrations of the compounds of the invention.

It is also important to investigate the ability of leukotriene antagonists to bind to the receptor for their ability to inhibit smooth muscle contraction. Receptor binding assays can be performed on the guinea pig lung membrane by direct competition between the leukotriene antagonist and [ ³ H] -LTD4 for binding to the LTD4 receptor [I. Ahnfelt-Ronne, D. Kirstein, and C. Kaergaard-Nielsen, European J. Pharmacol. 155: 117 (1988); S. Mong, HL Wu, Μ. O. Scott, MA Lewis, MA Clarké, Β. M. Weichman, CM Kinzig, JG Gleason and ST Crooke, J. Pharmacol. Exp. Ther. 234, 316 (1985)]. The pIC50 values were defined as the negative logarithm of the molar concentration of the antagonist that inhibited the binding of [ ³ H] -LTD4 by 50%. The pIC ₅₀ values of the compounds of the invention are unaffected by the presence of 0.1% human serum albumin, contrary to that observed for OT 3665 (PCT / DK88 / OO188, Publication No. WO 89/05294, Example 9) (see Figure 1). table).

- 10 • · · · · · ··· ··· ··· ····

Table 1 Binding of [ ³ H] -LTD ₄ to guinea pig lung membranes in the presence and absence of 0.1% human serum albumin [pIC _S0 , mean ± SD (n) or individual values]

Compound Albumin in absentia Albumin in the presence of Example 14 Compound 9.1 to 9.0 9.3 to 9.3 Example 20 Compound 8.9 to 9.1 9.2 to 8.6 Example 12 Compound 8.5 + 0.1 (5) 8.7 + 0.2 (5) Example 64 8.7 + 0.3 (5) 9.0 + 0.3 (5) Example 54 8.4-8.5 8.8 to 8.6 Example 43 8.7 to 8.3 8.6 to 8.4 Example 44 8.5-8.8 8.6 to 8.6 OT 3665 8.2 + 0.1 (7) 7.3 + 0.1 (3)

The leukotriene antagonist activity was examined in vivo in anesthetized guinea pig for LTD ₄ -induced bronchoconstriction [I. Ahnfelt-Ronne, D. Kirstein, and C. Kaergaard-Nielsen, European J. Pharmacol. 155: 117 (1988)]. The compounds of the invention were administered intravenously 10 minutes, orally, 4, 8 and 24 hours prior to bronchoconstriction. ED ₅₀ values represent doses that inhibit leukotriene-induced bronchoconstriction by 50%. ED ₅₀ values were calculated by 2-3 dose regression analysis. The results are shown in Table 2.

- 11 Ί. spreadsheet

Μ Λ <·! & S ° oh com He. w 10.51 -C C \ r-H 3.10 7.86 19.68 8.59 2.80 nd. 'm <2 ε% s ® uh Ow 0.99 nd. 0.22 · σ \ She r-H She nd. nd. > 30 / -s Ofi Λ 'oh * o s ® com ®- W 0.17 0.24 0.24 0.15 0.60 0.17 0.04 11.60 'ΟΛ y Xí U > 1 s com .u ω 600'0 0,002 0,002 0,006 0,010 0.0007 0,002 0.42 Compound Example 14 Compound Example 20 Compound Example 12 Compound Example 64 Example 54 Example 43 Example 44 OT 3665 *

PCT / DK88 / 00188, Publication No. WO 89/05294, Example 9

12Α Table 2 shows that the compounds of Examples 14, 20, 12, 64, 54, 43 and 44 show a more potent and prolonged LTD ₄ antagonist activity than OT 3665.

The invention also relates to a process for the preparation of compounds of formula (I).

In one embodiment of the invention, an amine of formula II wherein X ₁ and X ₂ are as defined above with a compound of formula III wherein R _{b is} R ₃ , X ₃ , X ₄ , A, Z and p is as defined above and Y is a good leaving group.

Y is, for example, a halogen atom such as chlorine, bromine or iodine, or an alkyl or arylsulfonyloxy group, but other leaving groups such as an alkylsulfate group, a chlorosulfonyloxy group, an alkyl group may be used. a sulfite group, a mono- or dialkyl phosphate group or a nitrate group. The starting compounds of formula II are disclosed in EP-A-0206751 (Merck Frosst Canada Inc.) or in

It can be prepared as described in Example 2. Compounds of formula (III) were prepared according to the method of C. R. Edwards, M. J. Readhead and N. J. Tweedle [J. Heterocyclic Chem., 1987, 24, 495] or as described in Example 25.

The reaction may be carried out in a suitable inert organic solvent, such as methanol, ethanol, dimethylformamide or hexamethylphosphoric triamide, or other solvents may be used; the reaction may be carried out at room temperature or above to the boiling point of the solvents used. In some cases, however, it may be desirable to cool the reaction mixture to room temperature, depending on the nature of the starting compound (III). The reaction may conveniently be carried out in the presence of an organic base such as pyridine, triethylamine, sodium methanolate or sodium ethanolate, or in the presence of a suitable inorganic base such as an alkali metal hydroxide, an alkali metal carbonate or an alkali metal bicarbonate. . The crude reaction products of formula (I) are collected by filtration, for example after dilution with water, or may be extracted from the reaction mixture with a suitable solvent such as diethyl ether, ethyl acetate, dichloromethane or chloroform. The products may be purified, for example, by recrystallization or chromatography, optionally after salt formation with a suitable organic or inorganic acid.

In another embodiment of the invention, the amine of formula (II) may be converted to the compound of formula (I) by reductive alkylation, for example, by reaction with a carbonyl compound of formula (IV)

R _1? R ₃ , X ₃ , X ₄ , A, Z and p are as defined above and then hydrogenated in the presence of a suitable catalyst or reduced with an alkali metal borohydride. Compounds of formula (IV) are commercially available or can be found in CR Edwards, MJ Readhead and

N. J. Tweedle, J. Heterocyclic Chem., 24, 495 (1987); J. Bernstein, H. L. Yale, K. Losee, M. Holsing, J. Martins and W. A. Loott, J. Am. Chem. Soc., 73, 906 (1951); L. A. Flippin, J. M. Muchowski, and D. S. Carter, J. Org. Chem., 58, 2463 (1993); EP-A-572712 to Sumitomo Seika Chem.

- 14Co. Ltd.] by known methods. The hydrogenation or reduction may conveniently be carried out simultaneously with the carbonyl compound, i.e. without isolation of the Schiff base formed as an intermediate.

The reaction is carried out in a suitable inert organic solvent such as methanol or ethanol, but other solvents may be used. The reaction is preferably carried out at room temperature, in some cases the reaction mixture is suitably cooled to room temperature or heated to room temperature to the boiling point of the solvent used, depending on the nature of the reactants (II) and (IV) used. The isolation and purification of the products may be carried out as described above.

In a further embodiment of the invention, the compounds of formula (I) are prepared by reacting a compound of formula (V):

X ₁ , X ₂ , X ₃ and X ₄ are as defined above, and

Z is O, S or NH with a compound of Formula VI: wherein:

R 1, R ₃ , A, p and Y are as defined above. For example, the compound of formula (V) may be prepared as described in Example 3, while the compound of formula (VI) may be commercially available or may be obtained from the literature [Y. Ogata, T. Sugimoto and M. Inaishi, Organic Synthesis, coll. VI. 90, page 90, ed. WE Noland (John Wiley, New York) (1988); DN Harpp, LQ Bao, Organic Syntheses coll. VIII. Volume 190, p. JP Freemann (John Wiley, New York) (1993); B. Koppenhoefer and if ·

- 15V. Schurig, ibid, page 119].

Compounds of formula (V) are prepared by reacting an appropriately substituted compound of formula (II) with an appropriately substituted benzaldehyde, followed by reduction with sodium borohydride (NaBH ₄ ).

Compounds of formula (V ') may be prepared by the procedure outlined in Scheme 1.

The compounds of the present invention are useful as pharmaceutical active ingredients for the treatment of the aforementioned diseases.

The amount of the compound of formula I (hereinafter referred to as "active ingredient") required to produce a therapeutic effect will, of course, vary with the particular compound, the route of administration and the mammal being treated. A suitable dose of a compound of formula I for systemic treatment is 0.1 to 20 mg / kg body weight, most preferably 0.1 to 10 mg / kg body weight, for example 0.2 to 10 mg / kg; administered once or more daily, the daily dose will generally be between 5 mg and 5 g for the treatment of an adult.

In spray formulations, the appropriate anti-asthma dosage of the compound of formula I is from 1 pg to 5 mg compound / kg body weight, most preferably from 1 pg to 1 mg / kg body weight, for example from 1 pg to 0.5 mg / kg body weight.

Although the active ingredient may be used alone as a pure chemical compound, it is preferably used in the form of a pharmaceutical composition. Preferably, the active ingredient will be present in an amount of from 0.1% to 100% of the composition. The unit dosage form of the composition is expedient

It contains 160.07 mg - 1 g of the active ingredient. For topical administration, the active ingredient will preferably comprise from 1 to 2% by weight of the composition, but may be up to 10% by weight. Formulations suitable for nasal or buccal administration may contain from 0.1 to 20% by weight, for example about 2% by weight, of the active ingredient.

Dosage unit means a unit dose, i.e. a single dose that can be administered to a patient and which is easy to handle and package in a physically and chemically stable unit dosage form, or unit dosage form, either as the active ingredient itself or as a solid or liquid pharmaceutical diluent or carrier.

Compositions for veterinary and human use contain the active ingredient in admixture with a pharmaceutically acceptable carrier and optionally other pharmaceutical excipients. The carrier must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The compositions of the invention may be formulated for oral, ophthalmic, rectal, parenteral (e.g., subcutaneous, intramuscular, and intravenous), transdermal, intra-articular, topical, nasal or buccal administration.

The compositions are conveniently formulated in a unit dosage form and may be formulated according to the routine pharmaceutical formulations. Each process comprises the step of mixing the active ingredient with a carrier which may also contain one or more accessory ingredients. In general, the formulations are prepared by:

- Mix thoroughly and uniformly with a liquid carrier or finely divided solid carrier and then, if desired, formulate the product in the desired formulation.

Formulations of the present invention suitable for oral administration may be presented in discrete units such as capsules, cachets, tablets or lozenges, each containing a fixed amount of the active ingredient; or in the form of powder or granules; in the form of a suspension or solution in an aqueous liquid or a non-aqueous liquid; in the form of an oil-in-water emulsion or a water-in-oil emulsion. The active ingredient may also be administered in the form of a bolus, lithium or ointment.

Formulations for rectal administration may be in the form of, for example, a suppository or an enema containing the active ingredient and a carrier.

Formulations suitable for parenteral administration are conveniently sterile oily or aqueous formulations of the active ingredient, which are preferably isotonic with the blood of the treated subject.

Formulations suitable for intra-articular or ophthalmic administration may be in the form of a sterile aqueous preparation containing the active ingredient in microcrystalline form, for example, as an aqueous microcrystalline suspension. Liposomal formulations or biodegradable polymer systems may also be used to formulate the active ingredient, both for intra-articular and ophthalmic administration.

Formulations suitable for topical or ophthalmic administration include liquid or semi-liquid preparations such as oil-in-water or water-in-oil emulsions, balms or

- ointments; or solutions or suspensions such as drops.

Formulations suitable for nasal or oral administration include, for example, powders, non-propellant formulations, and spray formulations, such as aerosol atoms.

Other formulations suitable for nasal administration may, for example, be in the form of a fine powder, which may be administered by the inhalation of a powder in a nasal passage through a nasal passage in a container near the nose.

In addition to the above-mentioned components, the compositions of the invention may contain one or more additional components.

The compositions of the invention may further comprise other pharmaceutically active compounds commonly used in the treatment of the above mentioned conditions, such as glucocorticoids, antihistamines, platelet activating factor antagonists, anticholinergics, methylxanthines, β-adrenergic agents, salomethylate, indomethacin, flufenamate, naproxen, thymegadine, gold salts, penicillamine, serum cholesterol lowering agents, retinoids, zinc salts and salicyl azosulfapyridine (Salazopyrin).

The invention is further illustrated by the following examples.

Example 1

E-2- {3- [2- (quinolin-2-yl) ethenyl] -phenyl-methyl} phenoxyacetic acid

Step 1: E-3- [2- (Quinolin-2-yl) -ethenyl] -N- [2- (carboxymethoxy) -benzylidene] -aniline

0.5 g (2 mmol) of E-3- [2- (quinolin-2-yl) -ethenyl] -aniline (see EP-19-A-0206751, Merck Frosst Canada Inc.) in 150 ml of diethyl To a solution of the ether in ether was added 0.36 g (2 mmol) of 2-formylphenoxyacetic acid in 50 ml of diethyl ether and the mixture was stirred at room temperature for 4 hours.

The precipitate was filtered off, washed with diethyl ether and dried. The title compound is obtained, m.p. 201-203 ° C. This compound was used directly in the next step.

Step 2: E-2- {3- [2- (Quinolin-2-yl) -ethenyl] -phenylaminomethyl} -phenoxy-acetic acid

To a suspension of Schiff's base prepared in Step 1 above (0.41 g, 1 mmol) in ethanol (10 mL) was added sodium borohydride (0.1 g). The reaction mixture was stirred at room temperature for 2 hours. Water (5 mL) was added and the mixture was concentrated in vacuo. The residue was treated with 10 ml of water and the resulting solution was neutralized to pH 7 with 0.5 ml of dilute acetic acid.

The precipitate was filtered off, triturated with methanol, filtered, washed with methanol and diethyl ether. The title compound is obtained, m.p. 108-111 ° C.

Example 2

E-2- {3- [2- (7-Chloro-quinolin-2-yl) ethenyl] -phenyl-methyl} phenoxyacetic acid

Step 1: E-3- [2- (7-Chloro-quinolin-2-yl) -ethenyl] -1-nitrobenzene

A solution of 7-chloroquinaldine (3.6 g, 20 mmol) and 3-nitrobenzaldehyde (3.0 g, 20 mmol) in acetic anhydride (20 mL) was added at 130 ° C.

Stir for 4.5 hours. The reaction mixture was cooled to room temperature and the precipitate was filtered off and washed with water and diethyl ether. The title compound is obtained, m.p.

Mp 20-181-183 ° C. The product is used directly in the next step.

Step 2: E-3- [2- (7-Chloroquinolin-2-yl) -ethenyl] -aniline

To a solution of 15.0 g of SnCl _{2 in} 40 ml of concentrated hydrochloric acid was added 5.1 g (16 mmol) of nitrobenzene prepared in step 1 above in 75 ml of acetic acid, and the reaction mixture was stirred at 80 ° C for 1 hour. The reaction mixture was cooled to room temperature and evaporated to dryness.

The residue was treated with 150 ml of water and basified to pH 9 with sodium hydroxide solution. It was then extracted twice with 300 ml of ethyl acetate, dried and concentrated in vacuo. 127-128 ° C. The product is used directly in the next step.

Step 3: E-3- [2- (7-Chloro-quinolin-2-yl) -ethyl] -N- [2- (carboxymethoxy) -benzylidene] -aniline

To a solution of 4.23 g (15 mmol) of the aniline obtained in Step 2 above in 500 ml of diethyl ether was added 2.7 g (15 mmol) of 2-formylphenoxyacetic acid in 300 ml of diethyl ether. The reaction mixture was stirred at room temperature for 2.5 hours. The precipitate was filtered off, washed with diethyl ether and dried. M.p. 191-192 ° C. The compound was used directly in the next step.

Step 4: E-2- {3- [2- (7-Chloro-quinolin-2-yl) -ethenyl-phenylaminomethyl} -phenoxy-acetic acid

To a suspension of Schiff's base (5.5 g, 12.5 mmol) in methanol (75 ml) was added in portions with sodium borohydride (1.25 g) at room temperature with stirring for 1.5 hours. The reaction mixture is treated with 60 ml of water and ··· ·

It is acidified to pH 5-6 with 10 ml of 3N acetic acid with vigorous stirring. The mixture was stirred at room temperature for 12 hours, filtered and washed with water.

The precipitate is dried and recrystallized from 75 ml of dioxane. The title compound is obtained as an orange crystalline solid, m.p. 187-189 ° C.

Example 3

E-Ethyl 2- [2- {3- [2- (7-chloroquinolin-2-yl) -ethenyl-phenylamino-ethyl] -phenoxy] -hexanoate

Step 1: E-2- {3- [2- (7-Chloro-quinolin-2-yl) -ethenyl] -phenylaminomethyl} -phenol

The procedure of Example 2, Step 3 was followed except that salicylaldehyde was used instead of 2-formylphenoxyacetic acid. Intermediate was obtained E-3- [2- (7-chloroquinolin-2-yl) ethenyl] -N- (2-hydroxybenzylidene) aniline, which was reacted without isolation as described in Example 2, Step 4. . The title compound is obtained, m.p. 151-152 ° C.

Step 2: E-Ethyl-2- [2- {3- (2- (7-chloro-quinolin-2-yl) -ethenyl] -phenylaminomethyl} -phenoxy] -hexanoate

7.0 g (18 mmol) of E-2- {3- [2- (7-chloroquinolin-2-yl) ethenyl] phenylaminomethyl} phenol, 4.9 g (22 mmol) A mixture of ethyl 2-bromohexanoate, 10 g (72 mmol) of potassium carbonate and 350 ml of acetone was refluxed for 40 hours and the volatiles were evaporated in vacuo. The residue was dissolved in diethyl ether and the hydrochloride salt of the title compound was precipitated by acidification with a slight excess of 1N hydrochloric acid. The hydrochloride obtained is filtered and treated with 200 ml of 1N sodium bicarbonate solution and diethyl ether. The organic phase • ·

-22, dried over anhydrous magnesium sulfate and concentrated in vacuo. The title compound is obtained, which is crystallized from ethanol. M.p. 84-86 ° C.

4-11. example

By following the procedure of Example 3, Step 2, but using the appropriate bromo esters instead of ethyl 2-bromohexanoate, the compounds of formula (I-1) described in Table 3 are prepared.

Table 3

Example number ^R 1 r ₂ ^R 3 Melting point (° C) Comment 4th H ch ₂ ch ₃ ch ₃ - 5th ch ₃ ch ₂ ch ₃ ch ₃ 212-213 hydrochloride 6th H ch ₂ ch ₃ ch ₂ ch ₃ 85-87 7th H ch ₂ ch ₃ CH (CH ₃ ) ₂ - 8th H ch ₂ ch ₃ (CH ₂ ) ₇ CH ₃ 87-88 9th H ch ₂ ch ₃ (CH ₂ ) ₉ CH ₃ 64-66 10th H ch ₃ c ₆ h ₅ 143-145 11th H ch ₂ ch ₃ ch ₂ ch ₂ ch ₃ 138-145 (Dec)

Example 12

E-2- | 2- {3- [2- (7-Chloro-quinolin-2-yl) ethenyl] -phenyl-methyl} phenoxy] hexanoic acid

A mixture of 6.3 g (12 mmol) of ethyl ester from Example 3, Step 2, 10 g (250 mmol) of lithium hydroxide hydrate, 100 mL of water, 200 mL of methanol and 140 mL of tetrahydrofuran was added at room temperature.

Stir at -23 for 4 hours. The reaction mixture was filtered and concentrated in vacuo. The crude title compound is recrystallized from ethanol, m.p. 181-182 ° C.

13-21. example

In the same manner as in Example 12, but instead of E-ethyl 2- [2- {3- [2- (7-chloroquinolin-2-yl) ethenyl] phenylaminomethyl} phenoxy] hexanoate. using the esters described in Table 3 to prepare the compounds of Formula 1-2 as described in Table 4.

Table 4

Example number Ri r ₃ Melting point (° C) 13th H ch ₃ 183-184 14th H ch ₂ ch ₃ 201-202 15th ch ₃ ch ₃ 171-172.5 16th H CH (CH ₃ ) ₂ 223-224 17th H (CH ₂ ) ₇ CH ₃ 130-132 18th H (CH ₂ ) ₉ CH ₃ 115-117 19th H C ₆ H ₅ 198 20th H ch ₂ ch ₂ ch ₃ 193-195 21st CH ₂ CH ₃ ch ₂ ch ₃ 176-177

Example 22

E-Ethyl-2- {3- | 2- (7-Chloro-quinolin-2-yl) ethenyl] -phenyl-methyl} phenylthio acetate

0.85 g (3 mmol) of aniline from Example 2, Step 2, 2.0 g of potassium bicarbonate, 1.07 g (4.4 mmol) of ethyl 2- (chloro-24-methyl) - A mixture of phenylthioacetate and 25.0 mL of dimethyl sulfoxide was stirred at room temperature for 96 hours.

The resulting mixture was diluted with water (25.0 mL) and extracted with ethyl acetate (2 x 25.0 mL).

The extract was dried and evaporated. The product was recrystallized from diethyl ether to give the title compound, m.p. 101-106 ° C.

Example 23

E-2- {3- [2- (7-Chloro-quinolin-2-yl) ethenyl] -phenyl-methyl} phenylthio acid

The ester prepared in Example 22 (0.5 g, 1 mmol) was hydrolyzed with 1.0 mL of 2N sodium hydroxide in 10.0 mL of ethanol. The solution was refluxed for 2 hours and diluted with water (10.0 mL). The solution was acidified with 0.5 ml of 3N acetic acid, the precipitate was filtered off and washed with water and ethyl acetate.

Recrystallization from acetic acid gave the title compound, m.p. 205-207 ° C.

Example 24

E-2- {3- [2- (quinolin-2-yl) ethenyl-phenyl-methyl} phenyl-thio-acetic acid

Step 1: E-Ethyl-2- {3- [2- (quinolin-2-yl) -ethenyl] -phenylaminomethyl} -phenyl-thio-acetic acid

In the same manner as in Example 22 but replacing E-3- [2- (7-chloroquinolin-2-yl) -ethenyl] -aniline with E-3- [2- (quinolin-2-yl) -ethenyl] -an Purification by flash chromatography (3/7 ethyl acetate / hexane) using aniline (see Example 1, Step 1) gave the title compound, followed by

We'll use it in the next step.

Step 2: E-2- {3- [2- (Quinolin-2-yl) -ethyl] -phenylaminomethyl} -phenyl-thio-acetic acid

In the same manner as in Example 23, but instead of E-ethyl 2- {3- [2- (7-chloroquinolin-2-yl) ethenyl] phenylaminomethyl} phenylthioacetate, Using the ethyl ester from step 1), the title product is obtained.

Trituration with ethyl acetate gave the title compound, m.p. 177-179 ° C.

Example 25

E-2- [2- {3- [2- (7-Chloro-quinolin-2-yl) -ethenyl] -phenylaminomethyl} -phenyl-thio] -hexanoic acid

Step 1: E-Ethyl 2- [2- {3- [2- (7-chloro-quinolin-2-yl) -ethenyl] -phenylaminomethyl} -phenyl-thio] -hexate

In the same manner as in Example 22, but using ethyl 2- [2- (bromomethyl) phenylthio] hexanoate instead of ethyl 2- (chloromethyl) phenylthioacetate (prepared by ) to give the title compound. The ester was used in the next step without further purification.

Step 2: E-2- [2- {3- [2- (7-Chloro-quinolin-2-yl) -ethenyl] -phenylaminomethyl} -phenyl-thio] -hexanoic acid

In the same manner as in Example 12 but with E-ethyl 2- [2- {3- [2- (7-chloroquinolin-2-yl) ethenyl] phenylaminomethyl} phenoxy] hexanoate. Instead of using the ester from step 1 above, the title compound is obtained, m.p. 169-172 ° C.

Example -26A)

Preparation of ethyl 2- [2- (bromomethyl) phenylthio] hexanoate (Scheme 2)

Step A: Ethyl 2- (2-carboxyphenylthio) hexanoate

A solution of 7.7 g of 2-mercaptobenzoic acid and 12 g of ethyl 2-bromohexanoate in 100 ml of 1N methanolic potassium hydroxide solution was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo, the resulting material was dissolved in water and extracted with diethyl ether. The aqueous solution was acidified with a little excess 4N hydrochloric acid and extracted three times with diethyl ether. The combined organic extracts were dried and evaporated in vacuo. The title compound is obtained which is used in the next step.

Step B: Ethyl 2- [2- (hydroxymethyl) phenylthio] hexanoate

To a mixture of 6.0 g of the carboxylic acid prepared in Step A above, 3.0 ml of triethylamine and 50 ml of tetrahydrofuran, 1.9 g of ethyl chloroformate are added slowly with stirring at -7 to -10 ° C. After stirring for a further 30 minutes, the resulting solution was purified by filtration, the intermediate mixed anhydride was reduced by adding 2.7 g of sodium borohydride, and 15 ml of methanol were added with stirring at 10 ° C for 1 hour. After stirring for a further 2 hours, the mixture was carefully acidified with 100 ml of 4N hydrochloric acid and extracted twice with diethyl ether. The organic extract was washed with brine and dried in vacuo. 6.0 g of the title compound are obtained, which product is used as is in the following stage.

·· · »* · ·

-η Step C: Ethyl 2- [2- (bromomethyl) phenylthiol hexanoate

To a stirred mixture of triphenylphosphine (5.3 g) in acetonitrile (40 mL) was added bromine (3.2 g) with stirring. After 10 minutes, a solution of 6.0 g of the compound obtained in Step B above in 30 ml of acetonitrile is slowly added and the reaction mixture is stirred for 3 hours. The resulting mixture was concentrated in vacuo and the residue treated with ice, water and diethyl ether. The organic layer was separated, washed with cold water, dried and concentrated in vacuo. 6.0 g of the title compound are obtained which are used in Example 25, Step 1.

Example 26

E-2-I2 {3- [2- (7-Chloro-quinolin-2-yl) ethenyl] -phenylamino-methyl-phenyl} -propionic acid

Step 1: E-2- {3- [2- (7-Chloro-quinolin-2-yl) -ethenyl-phenylaminomethyl} -1-nitrobenzene

Following the procedure of Example 2, Steps 3 and 4, but substituting 2-nitrobenzaldehyde for 2-formylphenoxyacetic acid, the title compound is obtained, m.p. 150-151 ° C.

Step 2: E-2- {3- [2- (7-Chloro-quinolin-2-yl) -ethenyl] -phenyl-amino-methyl} -aniline

To a mixture of 3.85 g (9 mmol) of the nitro compound prepared in Step 1 above and 75 mL of concentrated hydrochloric acid was added portionwise 13.7 g (60 mmol) of tin (II) chloride dihydrate and the reaction mixture was stirred at room temperature overnight. stirred. The reaction mixture was diluted with ice and the pH of the reaction was made strongly alkaline by careful addition of concentrated aqueous sodium hydroxide solution. The mixture is filtered and the residue is washed with water.

-28 then dissolved in acetone. The solution was purified by filtration and the title compound precipitated by dilution with water. The precipitate was collected by filtration and recrystallized from ethanol. 129-131 ° C.

Step 3: E-Ethyl-2- [2- {3- [2- (7-chloro-quinolin-2-yl) -ethenyl-phenylaminomethyl} -phenylamino] -hexanoate

A mixture of 1.6 g (4 mmol) of aniline prepared in Step 2 above, 1.8 g (8 mmol) of ethyl 2-bromohexanoate, 1.8 g of sodium bicarbonate and 30 ml of hexamethylphosphoric triamide is added. Stir at 60 ° C for 48 hours. A further 0.9 g (4 mmol) of ethyl 2-bromohexanoate and 0.9 g of sodium bicarbonate are added and the mixture is stirred at 60 ° C for 72 hours. The resulting mixture was poured into ice / water and extracted three times with diethyl ether. The combined organic extracts were washed with water, dried and concentrated in vacuo. The title compound is obtained in the form of an oil which is used in the next step.

Step 4: E-2- [2- {3- [2- (7-Chloro-quinolin-2-yl) -ethenyl] -phenylaminomethyl} -phenylamino] -hexanoic acid

In the same manner as in Example 12, but E-ethyl 2- [2- {3- [2- (7-chloroquinolin-2-yl) -ethenyl] -phenylaminomethyl} -phenoxy] -hexanoate Instead of using the ethyl ester from step 3 above, the title compound is obtained, m.p. 169-171 ° C.

-2 927. example

E-2- [3- {3- | 2- (7-Chloro-quinolin-2-yl) ethenyl] -phenyl-methyl} phenoxy] hexanoic acid

Step 1: E-3- {3- [2- (7-Chloro-quinolin-2-yl) -ethenyl] -phenylaminomethyl} -phenol

Following the procedure of Example 2, Steps 3 and 4, but substituting 3-hydroxybenzaldehyde for 2-formylphenoxyacetic acid, the title compound is obtained, m.p. 179-180 ° C.

Step 2: E-Ethyl 2- [3- {3- [2- (7-chloro-quinolin-2-yl) -ethenyl] -phenyl-aninomethyl} -phenoxy] -hexanoate

In the same manner as in Example 3, Step 2, except for E-2- {3- [2- (7-chloroquinolin-2-yl) -ethenyl] -phenylaminomethyl} -phenol, Step 1) Using the meta-substituted phenol prepared according to the method of (1), the title compound is obtained in the form of an oil which is used in the next step.

Step 3: E-2- [3- {3- [2- (7-Chloro-quinolin-2-yl) -ethenyl] -phenylaminomethyl} -phenoxy] -hexanoic acid

In the same manner as in Example 12 but with E-ethyl 2- [2- {3- [2- (7-chloroquinolin-2-yl) ethenyl] phenylaminomethyl} phenoxy] hexanoate. Instead of using the ethyl ester from step 2 above, the title compound is obtained, m.p. 183-185 ° C.

Example 28

E-2- [4- {3- [2- (7-Chloro-quinolin-2-yl) ethenyl] -phenyl-methyl} phenoxy] hexanoic acid

Step 1: E-3- {3- [2- (7-Chloro-quinolin-2-yl) -ethenyl] -phenylaminomethyl} -phenol

-30Α Example 2 Steps 3 and 4, but using 4-hydroxybenzaldehyde instead of 2-formylphenoxyacetic acid, m.p. 194-195 ° C.

Step 2: E-Ethyl 2- [4- {3- [2- (7-chloroquinolin-2-yl) -ethenyl] -phenylaminomethyl} -phenoxylhexanoate

In the same manner as in Example 3, Step 2, except for E-2- {3- [2- (7-chloroquinolin-2-yl) -ethenyl] -phenylaminomethyl} -phenol, Step 1) Using the para-substituted phenol prepared according to the method of (1), the title compound is obtained in the form of an oil which is used in the next step.

Step 3: E-2- [4- {3- [2- (7-Chloro-quinolin-2-yl) -ethenyl] -phenylaminomethyl} -phenoxy-1-hexanoic acid

In the same manner as in Example 12 but with E-ethyl 2- [2- {3- [2- (7-chloroquinolin-2-yl) ethenyl] phenylaminomethyl} phenoxy] hexanoate. Instead of using the ethyl ester from step 2 above, the title compound is obtained, m.p. 173-175 ° C.

Example 29

E-Ethyl-2- [2- {3- [2- (7-Chloro-quinolin-2-yl) -etenilJ-phenylamino-methyl} -6-methoxyphenoxy] hexanoate

Step 1: E-2- {3- [2- (7-Chloro-quinolin-2-yl) -ethenyl] -phenylaminomethyl} -6-methoxy-phenyl

Example 2, Steps 3 and 4, but substituting 2-hydroxy-3-methoxybenzaldehyde instead of 2-formylphenoxyacetic acid, gave the title compound, m.p. 139-140.5 ° C.

• ·

-31 Step 2: E-Ethyl-2- {2- [3- (2- (7-Chloroquinolin-2-yl) -ethenyl] -phenylaminomethyl} -6-methoxy-phenoxy] -hexanoate

In the same manner as in Example 3, Step 2, but replacing E-2- {3- [2- (7-chloroquinolin-2-yl) -ethenyl] -phenylaminomethyl} -phenol with the above 1) Step 2: Phenol prepared according to Step 1h to give the title compound, m.p. 101-102.5 ° C.

Example 30

E-2- [2- {3- [2- (7-Chloro-quinolin-2-yl) ethenyl] -phenylamino-methyl-phenoxy} -6-methoxy-hexanoic acid

In the same manner as in Example 12, instead of E-ethyl 2- [2- {3- [2- (7-chloroquinolin-2-yl) ethenyl] phenylamino} phenoxy] hexanoate, Using the ethyl ester from Example 26, Step 2, the title compound is obtained, m.p. 173-174 ° C.

Example 31

E-2- {2- {3- (7-Chloro-quinolin-2-yl) -etenilJ-phenylamino-benzoic acid methyl}

Step 1: E-3- [2- (7-Chloro-quinolin-2-yl) -ethenyl] -N- (2-carboxy-benzylidene) -aniline

To a solution of aniline (2.8 g, 10 mmol) prepared in Step 2 (2) in methanol (50.0 mL) was added 2-carboxybenzaldehyde (15.0 mL) in methanol. The precipitate which was immediately precipitated was stirred at room temperature for 2 hours, then filtered and washed with diethyl ether. The title compound is obtained, m.p. 226-228 ° C. This compound was used directly in the next step.

Step-322: E-2- {3- [2- (7-Chloro-quinolin-2-yl) -ethenyl-phenylaminomethyl] -benzoic acid

To a suspension of 0.82 g (2 mmol) of Schiff base prepared in Step 1 above in 10.0 mL of ethanol was added 0.2 g of sodium borohydride. After stirring for 1 hour, the precipitated product was collected by filtration and washed with diethyl ether. The reaction product was treated with 30.0 mL of water and acidified with 1.5 mL of 3N acetic acid. The precipitate was collected by filtration and washed with water. The title compound is obtained, m.p. 223-226 ° C.

Example 32

E-4- {3-L2- (7-Chloro-quinolin-2-yl) -etenilJ-phenylamino-benzoic acid methyl}

Step 1: E-3- [2- (7-Chloro-quinolin-2-yl) -ethenyl-N- (4-carboxybenzylidene) -aniline

Following the procedure of Example 31, Step 1, but substituting 2-carboxybenzaldehyde for 2-carboxybenzaldehyde, the title compound is obtained with a melting point of> 250 ° C.

Elemental Analysis for: C ₂₅ H ₁₇ ClN ₂ O ₂ Calculated: C, 72.72; H, 4.15; N, 6.79; Cl, 8.59; Found: C, 72.40; H, 4.26; N, 6.79; Cl, 8.70.

Step 2: E-4- {3- [2- (7-Chloro-quinolin-2-yl) -ethenyl] -phenylamino-ethyl} -benzoic acid

Following the procedure described in Example 31, Step 2, but replacing E-3- [2- (7-chloroquinolin-2-yl) ethenyl] -N- (2-carboxybenzylidene) aniline with E-3- [2- (7-Chloro-quinolin-2-yl) -ethenyl] -N- (4-carboxybenzylidene) -aniline to give the title compound.

-33 having a melting point of 248-250 ° C.

Example 33

E-Ethyl-2- {3- [2- (quinolin-2-yl) ethenyl] -phenyl-methyl} phenyl acetate

6.0 g (23 mmol) of 2- (bromomethyl) phenylacetate, 5.0 g (20 mmol) of 3- [2- (quinolin-2-yl) -ethenyl] -aniline (shown in Example 1). Prepared as in Example 1, Step 1), a mixture of 10.0 g (100 mmol) of potassium bicarbonate and 100 ml of dimethylsulfoxide was stirred at room temperature for 3 hours. The reaction mixture is poured into water, the precipitate is separated off and purified by chromatography on silica gel. The title compound is obtained, m.p. 108-109 ° C.

Example 34

E-2- {3- [2- (quinolin-2-yl) ethenyl] -phenyl-methyl} -phenyl-acetic acid

A solution of E-ethyl-2- {3- [2- (quinolin-2-yl) -ethenyl] -phenylaminomethyl} -phenyl-acetate (2.7 g, 6.3 mmol) in ethanol (25 mL) at room temperature, is added slowly to 25 ml of 2N sodium hydroxide solution. After stirring at 50 ° C for 5 minutes, the resulting clear solution was diluted with water (100 mL) and acidified with a little excess acetic acid to precipitate the title compound. After purification by silica gel chromatography, the title compound has a melting point of 165-166.5 ° C.

Example 35

E-Ethyl-2- {3- [2- (7-chloro-quinolin-2-yl) ethenyl] -phenylamino--benzoic phenylacetate

Proceeding as in Example 33, but substituting E-3- [2- (7-chloroquinolin-2-yl) ethenyl] for E-3- [2- (quinolin-2-yl) -ethenyl] -aniline]. -ani-

Using -34lin (prepared according to Example 2, Step 2), the title compound is obtained, m.p.

94.5-96 ° C.

Example 36

E-2- {3- [2- (7-chloro-quinolin-2-yl) -eteiiil] phenyl} methyl-amino-phenylacetic acid

In the same manner as in Example 34, but instead of E-ethyl-2- {3- [2- (quinolin-2-yl) -ethenyl] -phenylaminomethyl} -phenyl-acetate, E-ethyl-2- { 3- [2- (7-Chloro-quinolin-2-yl) -ethenyl] -phenylaminomethyl} -phenyl-acetate gives the title compound, m.p. 174-176 ° C.

Example 37

E-Ethyl 3- [2- {3- [2- (7-chloro-quinolin-2-yl) ethenyl] -phenyl-methyl} phenyl] propionate

In the same manner as in Example 33, but using ethyl 3- [2- (bromomethyl) phenyl] propionate in place of ethyl 2- (bromomethyl) phenyl acetate, the title compound is prepared as the hydrochloride dihydrate. m.p. 173 DEG C. (with decomposition).

Example 38

E-3- [2- {3- [2- (7-Chloro-quinolin-2-yl) ethenyl] -phenyl-methyl} phenyl] propionic acid

In the same manner as in Example 34, however, instead of E-ethyl-2- {3- [2- (quinolin-2-yl) -ethenyl] -phenylaminomethyl} -phenyl-acetate, E-ethyl-3- [ 2- {3- [2- (7-Chloro-quinolin-2-yl) -ethenyl] -phenyl} -aminomethyl-phenyl] -propionate, m.p. 179-181 ° C.

«9 • · · · •« • ·· ·

-35 Example 39

Sodium E-2- [2- {3- [2- (7-chloro-quinolin-2-yl) ethenyl] -benzoic -feiiil-amino-phenoxy-hexanoate

E-2- [2- {3- [2- (7-chloro-quinolin-2-yl) -ethenyl] -phenylaminomethyl} -phenoxy] -hexanoic acid (2.5 g, 5 mmol) Prepared as described in Example 12) Dissolved in a mixture of 5.5 ml of 1 N aqueous sodium hydroxide (10% excess) and 50 ml of water. The resulting solution was purified by filtration and allowed to crystallize. The title compound crystallizes with 0.75 mol of water, m.p. 120 ° C.

Example 40

E-2- {3- [2- (6,7-Difluoro-quinolin-2-yl) ethenyl-phenylamino-phenoxy -benzoic acid

Step 1: E-3- [2- (6,7-Difluoro-quinolin-2-yl) -ethenyl-1-nitrobenzene]

Following the procedure of Example 2, Step 1, but substituting 7,7-chloroquinaldine for 6-difluoroquinaldine, the title compound is obtained, m.p. 175-176 ° C.

Step 2: E-3- [2- (6,7-Difluoro-quinolin-2-yl) -ethenyl] -aniline

The nitrobenzene prepared in Step 1 above is reacted with SnCl ₂ as described in Example 2 Step 2. The title compound is obtained, m.p. 169-171 ° C.

Step 3: E-2- {3- [2- (6,7-Difluoro-quinolin-2-yl) -ethenyl] -phenylaminomethyl} -phenoxy-acetic acid

In the same manner as in Example 2, steps 3 and 4, but instead of E-3- [2- (7-chloroquinolin-2-yl) -ethenyl] -aniline, E-3- [2- (6.7) -difluoroquinolin-2-yl) -ethenyl] -aniline to give the title compound, m.p. 157-159 ° C.

-3 641. example

E-2- {3- [2- (7-fluoro-quinolin-2-yl) ethenyl] -phenyl-methyl} phenoxyacetic acid

In the same manner as in Example 2, steps 3 and 4, but instead of E-3- [2- (7-chloroquinolin-2-yl) -ethenyl] -aniline, E-3- [2- (7-fluoro) -quinolin-2-yl) -ethenyl] -aniline to give the title compound, m.p. 199-201 ° C.

Example 42

E-Ethyl-2- [2- {3- [2- (7-fluoro-quinolin-2-yl) ethenyl] -phenyl-methyl} phenoxy] hexanoate

Step 1: E-2- {3- (2- (7-Fluoro-quinolin-2-yl) -ethenyl] -phenylaminomethyl} -phenol

In the same manner as in Example 3, Step 1, but instead of E-2- {3- [2- (7-chloroquinolin-2-yl) -ethenyl] -aniline, E-2- {3- [2- ( Using 7-fluoroquinolin-2-yl) ethenyl] aniline, the title compound is obtained, m.p. 174.5-175.0 ° C.

Step 2: E-Ethyl-2- [2- {3- [2- (7-Fluoro-quinolin-2-yl) -ethenyl] -phenyl-aninomethyl} -phenoxy] -hexanoate

0.63 ml (3.5 mmol) of ethyl 2-bromohexanoate, 0.93 g (2.5 mmol) of phenol prepared in step 1 above, 0.75 g of potassium bicarbonate and 25 ml of Ν, The mixture of Ν-dimethylformamide was stirred at room temperature for 3 hours. The reaction mixture was poured into a mixture of 25 ml of water and 3 ml of 4N hydrochloric acid. The precipitate was filtered off, washed with water and diethyl ether. The title compound is obtained as the hydrochloride, m.p. 174.5-175 ° C.

-3 743. example

E-Ethyl-2- [2- {3- [2- (7-fluoro-quinolin-2-yl) ethenyl] -phenyl-methyl} phenoxy] hexanoic acid

By following the procedure described in Example 12, but using the ester prepared in Example 42 instead of the ester prepared according to Example 3, Step 2, the title compound is obtained, m.p. 181-183 ° C.

Example 44

Sodium E-2- [2- {3- [2- (6,7-difluoro-quinolin-2-yl) ethenyl] -phenyl-methyl} phenoxy] hexanoate

Step 1: E-2- {3- (2- (6,7-Difluoro-quinolin-2-yl) -ethenyl] -phenylaminomethyl} -phenol

In the same manner as in Example 3, Step 1, but instead of E-2- {3- [2- (7-chloroquinolin-2-yl) -ethenyl] -aniline, E-2- {3- [2- ( Using 6,7-difluoroquinolin-2-yl) -ethenyl] -aniline, the title compound is obtained, m.p. 158-162 ° C.

Step 2: E-Ethyl 2- [2- {3- (2- (6,7-difluoroquinolin-2-yl) -ethenyl-phenylaminomethyl} -phenoxy] -hexanoate

Following the procedure of Example 42, Step 2, but using the phenol compound of Example 42, step 1, instead of the phenol compound of Step 1), the title compound is obtained as its hydrochloride salt, m.p. 182-184 ° C. .

Step 3: Sodium E-2- [2- {3- [2- (6,7-Difluoro-quinolin-2-yl) -ethenyl] -phenylaminomethyl} -phenoxy] -hexanoate

The ester prepared in Step 2 above (0.85 g, 1.5 mmol) was heated to reflux in ethanol (20 mL) and 2N aqueous sodium hydroxide (2 mL). The ethanol was evaporated in vacuo and the precipitate was filtered off, washed with water and diethyl ether. The title compound is obtained, m.p. 238-240 ° C.

45-49. example

By following the procedure described in Example 3, Step 1, but employing the appropriate aldehydes instead of salicylaldehyde, the compounds of formula (1-3) described in Table 5 are prepared.

Table 5

Example number X ₃ melting point (° C) Comment 45th 6-F 183-185 46th 4-Br 202-204 47th 4-COOH 138 (decomposition) 48th 4-NO ₂ 193-195 49th 4-CH 176-177

50-58. example

By following the procedure described in Example 3, Step 2, but using the appropriate phenols described in Table 5, instead of the phenol derivative, or using the corresponding esters instead of the ester,

Compounds of general formula 1-4 as described in Table 6.

• ·

Table 6

Example number X ₃ r ₂ Melting point (° C) Comment 50th 6-F c ₂ h ₅ 203-205 hydrochloride 51st 4-Br C ₂ H _s 98-100.5 52nd 4-NO ₂ c ₂ h ₅ oil 53rd 6-F H 183-185 54th 4-Br H 197-198 55th 4-NO ₂ H 221-223 56th 4-CH ₃ H 168-170 57th 4-COOH H 173-175 (Dec) 58th 4-NH ₂ H 162-164 (Dec)

Example 59

E-2- {3- [2- (7-fluoro-quinolin-2-yl) phenyl -etenilJ aminomethyl} phenoxyacetic acid

Step 1: E- {3- [2- (7-Fluoro-quinolin-2-yl) -ethenyl] -N- [2- (carboxymethoxy) -benzylidene] -aniline

Following the procedure of Example 2, Step 3, but replacing E-3- [2- (7-chloroquinolin-2-yl) -ethenyl] -aniline with E-3- [2- (7-fluoro-quinoline). Using 2-yl) -ethenyl] -aniline, the title compound is obtained, m.p. 208-210 ° C.

Step 2: E-2- {3- [2- (7-Fluoro-quinolin-2-yl) -ethenyl] -phenylaminomethyl] -phenoxy-acetic acid

In the same manner as in Example 2, Step 4, but Example 2

Instead of the Schiff base prepared in Step 3), the Schiff base prepared in Step 1 above is used to prepare the title compound, m.p.

After recrystallization from -40, 199-201 ° C.

Example 60

E-2- [2- {3-2- (7-Chloro-quinolin-2-yl) ethenyl] -phenyl-methyl} phenoxy] hexanoic acid (pivaloyloxymethyl) ester hydrochloride

0.5 g (1 mmol) of E-2- [2- {3- [2- (7-chloroquinolin-2-yl) ethenyl] phenylaminomethyl} phenylamino] hexanoic acid, A mixture of potassium carbonate (0.3 g, 2.2 mmol) and chloromethyl pivalate (0.18 mL, 1.2 mmol) was stirred in dimethylformamide (10.0 mL) at room temperature for 3 hours.

The mixture was filtered and the resulting solution was concentrated in vacuo. The residue was triturated with 5 ml of 4N hydrochloric acid. The resulting precipitate was collected by filtration and washed with water.

The title compound is obtained, m.p. 153-155 ° C.

Example 61

E-2- [2- {3- [2- (7-Chloro-quinolin-2-yl) ethenyl] -phenyl-methyl} phenoxy] hexanoic acid - [(N, N-dimethylamino) carbonyl -benzoic ester hydrochloride

0.5 ml (1 mmol) of the acid from Example 11, 0.20 ml (1.5 mmol) of triethylamine and 0.015 g (0.1 mmol) of sodium iodide in 10 ml of Ν, Ν-dimethylformamide To the reaction mixture was added 0.15 mL (1.5 mmol) of 2-chloro-N, N-dimethylacetamide. After stirring at room temperature for 24 hours, the mixture was filtered and the resulting solution concentrated in vacuo. The residue was triturated with water and the precipitate was collected by filtration and washed with water.

The resulting solid was dissolved in ethyl acetate and filtered. THE

• · ·

The filtrate was concentrated on silica gel by column chromatography using 7: 3 ethyl acetate / hexane to give a brown oil.

The oil was triturated with hydrogen chloride in diethyl ether.

The title compound is obtained as the hydrochloride salt, m.p. 99 ° C (with decomposition).

Example 62

E-2- [2- {3-12- (7-Chloro-quinolin-2-yl) -eteniIl-phenylamino-methyl} phenoxy] hexanoic acid - [(N, N-diethylamino) carbonyl methyl methyl ester hydrochloride

In the same manner as in Example 61, but using 2-chloro-N, N-diethylacetamide instead of 2-chloro-N, N-dimethylacetamide, the title compound is obtained, m.p. 120-122 ° C.

Example 63

E2-L2 {3- [2- (7-Chloro-quinolin-2-yl) ethenyl-phenyl-methyl} phenoxy] hexanoic acid - [(N, N-diallylamino) carbonyl methyl ester hydrochloride

In the same manner as in Example 61, but substituting 2-chloro-N, N-diallylacetamide for 2-chloro-N, N-dimethylacetamide, the title compound is obtained, m.p. 103-105 ° C.

Example 64 (S) - (+) - E-Ethyl-2- [2- {3- [2- (7-chloro-quinolin-2-yl) -ethenyl] -phenylaminomethyl} -phenoxy] - acid

Step 1: (+) - E-Ethyl-2- [2- {3- [2- (7-chloroquinolin-2-yl) -ethenyl] -phenylaminomethyl} -phenoxy] -hexanoate

5.3 g (10.0 mmol) of E-ethyl-2- [2- {3- [2- (7-chloroquinolin-2-yl) ····

A mixture of -42-ethenyl] -phenylaminomethyl} -phenoxy] -hexanoate and Lipozyme® (immobilized Mucor miehei lipase) (530 mg, 6.1 Baun / g) in 100 ml of di-tert-butyl ether and ml of phosphate buffer (pH 8) was stirred at room temperature for 120 hours. The mixture was filtered through Decalit and washed with ethyl acetate. The two phases obtained were separated. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The product was purified by column chromatography on silica gel eluting with ethyl acetate / diethyl ether and crystallized from 96% ethanol. 2.5 g of the title compound are obtained, which product is used as is in the following stage.

Melting point: 99-100 ° C.

[α] _D ²⁰ = 30.3 ° (c = 1.04 acetone).

Step 2: (S) - (+) - E-Ethyl-2- [2- {3- {2- (7-chloroquinolin-2-yl) -ethenyl] -phenylaminomethyl} -phenoxy] - acid

10.6 g (20 mmol) of (+) - E-ethyl-2- [2- {3- [2- (7-chloroquinolin-2-yl) -ethenyl] -phenyl] prepared in Step 1 above. Aminomethyl} phenoxy] hexanoate was dissolved in a mixture of methanol (300 ml) and tetrahydrofuran (150 ml), lithium hydroxide monohydrate (4.3 g, 102.5 mmol) in water (45 ml) was added and the mixture was stirred for 4 hours. The reaction mixture was evaporated and redissolved in 3/1 water / methanol, acidified to pH 3-4 with 50% aqueous acetic acid, filtered, dried and recrystallized from absolute ethanol. 10.3 g of crude product are obtained, containing 0.9 equivalents of ethanol, m.p. 142-150 ° C (with decomposition), [α] _D ²⁰ = 23.4 (c = 0.99, DMSO).

The crude product is carefully recrystallized from acetonitrile • ·

Mp 187-188 ° C, [α] _D ²⁰ = 24.5 ° (c = 1.12, DMSO).

Example 65

E-5- {2- [2- {3- [2- (7-Chloro-quinolin-2-yl) ethenyl] -phenyl-methyl} phenoxy] pentyl} -lH-tetrazole

Step 1: E-2- [2- {3- [2- (7-Chloro-quinolin-2-yl) -ethenyl] -phenylaminomethyl} -phenoxy-J-pentyl-hydroxamic acid

2.6 g (5.3 mmol) of E-2- [2- {3- [2- (7-chloroquinolin-2-yl) -ethenyl] -phenyl-amino prepared according to Example 3, Step 2. of methyl methoxyphenoxy) hexanoate and methanol (50 mL) was added slowly

1.4 g (20.15 mmol) of hydroxylamine hydrochloride and 5 ml of a 5 molar solution of potassium hydroxide in methanol. After 72 hours at room temperature, the reaction mixture was adjusted to pH 3-4 with 50% aqueous acetic acid. The precipitate was filtered off and air dried. 2.1 g of the title compound are obtained, which product is used as is in the following stage.

Step 2: E-2- [2- {3- {2- (7-Chloro-quinolin-2-yl) -ethyl] -phenylaminomethyl} -phenoxy] -pentylnitrile

To a mixture of the product of Step 1 above (2.1 g, 4.1 mmol) and benzene (50 mL) was added phosphorus tribromide (0.8 mL, 8.5 mmol). The reaction mixture was refluxed for 5 hours, cooled and poured into ice water, made basic with sodium bicarbonate, extracted with ethyl acetate, dried and evaporated and chromatographed on silica gel. 1.6 g of the expected product are obtained, which product is used as is in the following stage.

Step -443: E-5- {2- [2- {3- [2- (7-Chloro-quinolin-2-yl) -ethenyl] -phenylaminomethyl} -phenoxy} -pentyl} -1 H-tetrazol

E-2- [2- {3- [2- (7-Chloroquinolin-2-yl) -ethenyl] -phenylaminomethyl} (1.6 g, 3.3 mmol) was prepared as described in Step 2 above. To a mixture of phenoxy] pentyl nitrile and 40 ml of dimethylformamide was added 1.65 g (25.4 mmol) of sodium azide and 1.4 g (26.4 mmol) of ammonium chloride. The mixture was heated at 115-120 ° C for 5 hours, then cooled and poured into ice water. The crude product is filtered off and crystallized from absolute ethanol. 600 mg of the title compound are obtained, m.p. 210-212 ° C (with decomposition).

Example 66

Aerosol formulation (S) - (+) - E-2- [2- {3- [2- (7-Chloroquinolin-2-yl) ethenyl] phenylaminomethyl} phenoxy] hexanoic acid (active ingredient) ) 1000 mg

Sorbitan trioleate 700 mg

Monofluorotrichloromethane 595 g

Difluorodichloromethane 798 g

The active ingredient is micronized in a nozzle mill. Most particles should have a diameter of less than 5 µm.

The drug concentrate is prepared by dissolving the sorbitan trioleate in a small amount of monofluorotrichloromethane and adding the active ingredient. The concentrate is thoroughly homogenized. The concentrate was transferred to a sealed container fitted with a cooling system. The remaining amount of fuel is added while stirring and cooling to -50 ° C.

Suitable aerosol containers are filled with a predetermined amount of the formulation and immediately sealed with a convenient container.

-45en can be operated with metering valve. Each blow produces 50 pg of active ingredient.

Example 67

Tablet Preparation (S) - (+) - E-2- [2- {3- [2- (7-Chloro-quinolin-2-yl) -ethenyl] -phenylaminomethyl} -phenoxy] -hexanoic acid ( active ingredient) 100 mg

Lactose 75 mg

Starch 12 mg

Methyl cellulose 2 mg

Sodium Carboxymethyl Cellulose (CMC-Na) 10 mg Magnesium Stearate 1 mg

The active ingredient, lactose and starch are homogenized in a suitable mixer and moistened with 5% aqueous methylcellulose (15 cps). Stirring is continued until a granulate is obtained. If necessary, the wet granulate is screened through a suitable sieve and dried to a moisture content of less than 1% in a suitable drying apparatus, such as a fluid bed or oven. The dry granulate was sieved through a 1 mm sieve and homogenized with CMC-Na. Magnesium stearate was added and stirring continued for a short time.

200 mg tablets are prepared from the granulate using a suitable tabletting machine.

Example 68

Injection Preparation (S) - (+) - E-2- [2- {3- [2- (7-Chloroquinolin-2-yl) -ethenyl] -phenylaminomethyl} -46-phenoxy-hexanoic acid (active ingredient) 1%

Sodium chloride q.s.

Water for injections gives 100%

The active ingredient is dissolved in water for injection.

The solution is made isotonic with sodium chloride. The solution is filled into ampoules and sterilized.

Claims (8)

Compounds of formula (I): wherein X ₁ and X ₂ are each independently hydrogen or halogen; X ₃ and X ₄ are each independently hydrogen, halogen, nitro, cyano, trifluoromethyl, C 1-4 alkyl, C 1-4 alkoxy, carboxyl or C 1-4 alkoxycarbonyl; Z is a bond, O, S, S (O), S (O) ₂ , NH or CH ₂ ; R 1 is hydrogen or a straight or branched, saturated or unsaturated C 1 -C 6 hydrocarbon chain; R ₃ is hydrogen, a linear or branched, saturated or unsaturated C 1 -C 12 hydrocarbon chain, unsubstituted or substituted phenyl, or unsubstituted or substituted benzyl, wherein the substituent may be one or more of X ₃ and X ₄ as defined above; obsession R 1 - [C] _p -R _{3 is} cyclopropyl; p can be 0 when Z is a bond or ρ is an integer from 1 to 6 when R 1 and R ₃ are hydrogen; A is 1 H-tetrazolyl or COOR ₂ in which R ₂ is the group given for R ₂ Or -48 or a pharmaceutically acceptable cation and pharmaceutically acceptable non-toxic salts thereof and in vivo hydrolysable esters thereof. Compounds of formula I according to claim 1, wherein X ₁ and X ₂ are each independently hydrogen, fluoro, or chloro; X ₃ is hydrogen; X ₄ is hydrogen, fluoro, chloro or bromo; Z is O or S in the ortho position; p is 1; R 1 is hydrogen; R ₃ is hydrogen or a linear or branched, saturated or unsaturated C 1 -C 6 hydrocarbon chain or phenyl; and A is tetrazol-5-yl or COOR ₂ where R ₂ is hydrogen, C 1-3 alkyl, or an alkali metal cation. 3. A salt according to claim 1 which is acidified with hydrochloric acid, hydrobromic acid, hydrogen iodide, phosphoric acid, sulfuric acid, nitric acid, p-toluenesulfonic acid, methanesulfonic acid, formic acid, acetic acid, propionic acid, citric acid, tartaric acid and maleic acid, sodium, potassium, magnesium, calcium, and salts with ammonia, C 1-6 alkylamines, C 1-6 alkanolamines, procaine, cycloalkylamines, benzylamines and heterocyclic amines. -494. A compound according to claim 1 selected from the group consisting of: E-2- [2- {3- [2- (7-chloro-quinolin-2-yl) ethenyl] -phenyl-methyl} phenoxy] -2-methyl-propionic acid; E-2- [2- {3- [2- (7-chloro-quinolin-2-yl) ethenyl] -phenyl-methyl} phenoxy] -2-methyl-pentanoic acid; E-2- [2- {3- [2- (7-chloro-quinolin-2-yl) ethenyl] -phenyl-methyl} phenoxy] hexanoic acid; E-2- [2- {3- [2- (7-chloro-quinolin-2-yl) ethenyl] -phenyl-methyl} - 4-bromo-phenoxy] hexanoic acid; E-2- [2- {3- [2- (7-fluoro-quinolin-2-yl) ethenyl] -phenyl-methyl} phenoxy] hexanoic acid; E-2- [2- {3- (2- (6,7-difluoro-quinolin-2-yl) ethenyl] -phenyl-methyl} phenoxy] hexanoic acid, sodium salt; and their salts and pure enantiomeric forms. The compound of claim 1 which is (S) - (+) - E-2- [2- {3- [2- (7-chloroquinolin-2-yl) ethenyl] phenylamino. methyl} phenoxy] hexanoic acid. 6. A pharmaceutical composition comprising a compound according to any one of claims 1-5. A compound according to any one of claims 1 to 6, optionally together with the necessary excipients. 7. A process for the preparation of a compound of the formula I as claimed in claim 1, characterized in that ^a ) ^the amine of the formula II is X and X ₂ are as defined above for a compound of formula III in the formula R _1? R ₃ , X ₃ , X ₄ , A, Z and p are as defined above and Y is a good leaving group. - 50 reactions, or b) an amine of formula II in the formula X ₁ and X ₂ are as defined above with a carbonyl compound of formula IV wherein R ₁₅ R ₃ , X ₃ , X ₄ , A, Z and p are as defined above and then hydrogenated in the presence of a suitable catalyst or alkali metal boron reduced with hydride, optionally in the hydrogenation or reduction can be carried out simultaneously by reacting with the carbonyl compound, that is, without isolating the resulting intermediate Schiff's base, or ^{c) e} w (V) a compound of the formula: - wherein X _B X _2, X ₃ and X _{4 has the} meaning given above, and Z is O, S or NH with a compound of Formula VI: wherein: R 1, R ₃ , A, p and Y are as defined above. Use of compounds according to claim 1 for the manufacture of a medicament for treating a variety of pathological conditions, preferably asthma, allergy, rheumatoid arthritis, vertebral arthritis, gout, atherosclerosis, proliferative and inflammatory skin disorders, chronic bowel inflammation and other inflammatory conditions, angina pectoris, pulmonary hypertension, cystic fibrosis and adult respiratory distress syndrome, ischemic and reperfusion injury, migraine headache.