WO1996002506A1

WO1996002506A1 - Quinoline derivatives as leukotriene antagonists

Info

Publication number: WO1996002506A1
Application number: PCT/DK1995/000223
Authority: WO
Inventors: Dorte Kirstein; Schneur Rachlin
Original assignee: Leo Pharmaceutical Products Ltd. A/S (Løvens Kemiske Fabrik Produktionsaktieselskab)
Priority date: 1994-07-20
Filing date: 1995-06-07
Publication date: 1996-02-01
Also published as: CZ352996A3; HUT76443A; NZ287850A; FI970143A0; KR970704691A; JPH10504026A; CN1152915A; FI970143A; PL318106A1; GB9414590D0; AU686820B2; EP0773931A1; CZ284799B6; HU9603342D0; CA2192478A1; AU2669695A

Abstract

The present invention relates to hitherto unknown compounds of formula (I), in which X1 and X2 independently of each other stand for hydrogen or halogen; X3 and X4 independently of each other stand for hydrogen, halogen, nitro, cyano, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy, carboxy or C1-C4 carbalkoxy; Z is a bond, O, S, S(O), S(O)2, NH or CH2; R1 is hydrogen or a straight or branched, saturated or unsaturated C1-C6 hydrocarbon chain; R3 is hydrogen, straight or branched, saturated or unsaturated C1-C12 hydrocarbon chain, unsubstituted or substituted phenyl or unsubstituted or substituted benzyl, the above mentioned substituents being one or more of X3 and X4 as defined above; or the group R1-[C]p-R3 stands for cyclopropyl; p may be 0 provided that Z is a bond, or p may be an integer from 1-6 if R1 = R3 = hydrogen; A is COOR2 or 1H-1,2,3,4-tetrazole in which R2 = R1 as defined above or R2 is a pharmaceutically acceptable cation. The present compounds are of value in the human and veterinary practice as leukotrien antagonists.

Description

QumoLiNE DERIVATIVES AS LEUKOTRIENE ANTAGONISTS

The present invention relates to hitherto unknown compounds useful in the human and veterinary therapy, to pharmaceutically acceptable salts thereof, to bioreversible derivatives thereof, to methods for producing said new compounds, to pharmaceutical compositions containing the new compounds, to dosage units of the compositions, and to methods of treating patients using said compositions and dosage units.

Leukotrienes, which are formed via the 5-lipoxygenase pathway of arachidonic acid metabolism, are implicated in a variety of pathophysiologic functions, such as bronchoconstriction, plasma exudation, coronary artery

•j spasm, leucocyte chemotaxis and neutrophil degranulation . It is therefore of considerable interest to develop compounds which inhibit 5-lipoxygenases and thereby the production of leukotrienes, or antagonize the effects of leukotrienes.

International patent application No. PCT/DK88/00188 (Publication No. WO 89/05294) describes a series of quinolylmethoxyphenyl substituted amino- phenoxyalkyl acids with leukotriene antagonistic and 5-lipoxygenase inhibitory activity.

International patent application No. PCT/US89/02692 (Publication No. WO 89/12629) describes a series of quinolylethenyl-phenoxymethyl phenoxy- alkyl substituted acids with leukotriene antagonistic activity.

International patent application No. PCT/DK90/00201 (Publication No. WO91/03466) describes a series of quinolyl methoxy substituted N-phenyl substituted isoserine (i.e. 3-amino-2-hydroxypropionic acid) derivatives with good leukotriene antagonistic activity.

R.A. Lewis, K.F. Austen and R.J. Soberman, New Eng. J. Med. 323 (1990) 645. International patent application No. PCT/DK93/00254 (Publication No. WO94/03431) describes a series of quinolyl ethenyl substituted N-phenyl substituted isoserine derivatives with good leukotriene antagonistic activity.

We have now surprisingly found that compounds as defined by gen¬ eral formula I are potent leukotriene antagonists.

The new structural features of these compounds, comprising a quinoline ring, optionally substituted by halogen, an E-CH=CH- linkage to a meta-substituted aniline, and further coupled to a substituted benzyl in accord¬ ance with formula I, provide compounds with a considerable prolonged dur¬ ation of action maintaining the potent leukotriene antagonist activity, especially in the presence of human serum albumin.

The present compounds have the general formula I

in which X₁ and X₂ independently of each other stand for hydrogen or halogen; X3 and X₄ independently of each other stand for hydrogen, halogen, nitro, cyano, trifluoromethyl, C- C^ alkyl, C^-C^ alkoxy, carboxy or C..-C_ι carbalkoxy;

Z is a bond, O, S, S(O), S(O)₂, NH or CH₂; R₁ is hydrogen or a straight or branched, saturated or unsaturated C^-Cg hydrocarbon chain;

R_j is hydrogen, a straight or branched, saturated or unsaturated C_|-C._|2 hydrocarbon chain, unsubstituted or substituted phenyl or unsubstitut¬ ed or substituted benzyl, the above mentioned substituents being one or more of X₃ and X₄ as defined above; or the group R-_j-[C]_p-R₃ stands for cycloprop- yl; p may be 0 provided that Z is a bond, or p may be an integer from 1-6 if R._j = R_β = hydrogen;

A is COOR₂ or 1H-tetrazole in which R₂ = R.. as defined above or R₂ is a pharmaceutically acceptable cation. In particular, X^ and X₂ independently of each other stand for hydrogen, fluoro or chloro; X3 stands for hydrogen; X₄ stands for hydrogen, fluoro, chloro or bromo; Z is O or S in ortho-position; p is 1; R₁ is hydrogen; R₃ is hydrogen or a straight or branched, saturated or unsaturated C.-C₆ hydrocarbon chain, or phenyl; and A is COOR₂, where R₂ is hydrogen, C..-C3 alkyl, an alkali metal cation, or tetrazol-5-yl.

More particularly, the compounds are selected from the group consisting of E-2-[2-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenylaminomethyl)- phenoxy]-2-methylpropanoic acid, E-2-[2-(3-(2-(7-chloroquinolin-2-yl)- ethenyl)phenylaminomethyl)phenoxy]-2-methylpentanoic acid, E-2-[2-(3-(2-(7- chloroquinolin-2-yl)ethenyl)phenylaminomethyl)phenoxy]hexanoic acid, E-2- -[2-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenylaminomethyl)-4-bromophenoxy]- hexanoic acid, E-2-[2-(3-2-(2-(7-fluoroquinolin-2-yl)ethenyl)pheπylaminomethyl]- phenoxyhexanoic acid, E-2-[2-(3-(2-(6,7-difluoroquinolin-2-yl)ethenyl)phenyl- aminomethyl)phenoxy]hexanoic acid, sodium salt. Some of the compounds described herein contain one or more centres of asymmetry and may thus give rise to stereoisomers, e.g. enantiomers or diastereoisomers. The present invention is meant to compre¬ hend all such possible stereoisomers.

Thus, a particularly preferred compound is (S)(+)-E-2-[2-(3-(2-(7- chloroquinolin-2-yl)-ethenyl)phenylaminomethyl)phenoxy]hexanoic acid.

The present salts of the compounds of formula I may be formed with pharmaceutically acceptable inorganic or organic acids, such as hydrochloric, hydrobromic and hydroiodic acid, phosphoric acid, sulphuric acid, nitric acid, p-toluenesulphonic acid, methanesulphonic acid, formic acid, acetic acid, propionic acid, citric acid, tartaric acid, and maleic acid, without these examples being considered limiting for the invention. The present salts of the compounds of formula I may also be formed with pharmaceutically acceptable, inorganic or organic bases. Salts formed with pharmaceutically acceptable, non-toxic bases may be alkali metal salts and alkaline earth metal salts, such as lithium, sodium, potassium, magnesium, calcium salts, as well as salts with ammonia and suitable non- -toxic amines, such as C^-Cg-alkylamines, e.g. triethylamine, C_j-Cg alkanolamines, e.g. diethanolamine or triethanolamine, procaine, cycloalkyl- amines, e.g. dicyclohexylamine, benzylamines, e.g. N-methylbenzylamine, N-ethylbenzylamine, N-benzyl-^-phenethylamine, N.N'-dibenzylethylenediamine or dibenzylamine. and heterocyclic amines, e.g. morpholine, N-ethylpiperidine and the like.

Even if the present compounds are well absorbed after enteral ad¬ ministration, in some cases it can be advantageous to prepare suitable biore- versible derivatives of compounds of the invention, i.e. to prepare so-called prodrugs, preferably derivatives, the physicochemical properties of which leads to improved solubility at physiological pH and/or absorption and/or bioavailability of the compound in question.

Such derivatives are for instance esters of N-hydroxymethyl deriva¬ tives of compounds of the invention, such compounds being prepared by reaction of a secondary amine function of compounds of the invention with formaldehyde followed by reaction with a suitable acidic compound or activated derivatives of such compounds, for instance with bi-

R 7 sulfite , N,N-dimethylglycine, N,N-diethyl- ?-alanine, or phosphoric acid ,

R.G. Kallen and W.P. Jencks, J. Biol. Chem. 241 (1966) 5864. C.J. Martin and M.A. Marini, J. Biol. Chem. 242 (1967) 5736. M. Levy and D.E. Silberman, J. Biol. Chem. 118 (1937) 723. S. Lewin and D.A. Humphany, J. Chem. Soc. B (1966) 210. B.C. Jain, B.H. Iyer, and P.C. Guha, Science and Culture 11 (1946) 568. S.A. Varia, S. Schuller, K.B. Sloan and V.J. Stella, J. Pharm. Sci., 73 (1985) 1068 and following papers. but other suitable acids which form bioreversible derivatives with desirable physicochemical properties can be used as well.

Further examples include esters formed with the acidic function in the molecule, such as simple esters, e.g. methyl or ethyl, acyloxyalkyl, alkoxycarb- onyloxyalkyl or aminoacyloxyalkyl esters, which are readily hydrolyzed in vivo or in vitro.

Among the above esters the following are preferred: alkanoyloxy- methyl with from 3 to 6 carbon atoms, 1-(alkanoyloxy)ethyl with from 4 to 6 carbon atoms, alkoxycarbonyloxymethyl with from 3 to 6 carbon atoms, l-(alk- oxycarbonyloxy)ethyl with from 4 to 6 carbon atoms, and σ-aminoalkanoyloxy- methyl with from 2 to 6 carbon atoms.

Other preferred esters are lactonyl esters, e.g. 3-phthalidyl, 4-croton- olactonyl or y-butyrolacton-4-yl esters.

Also within the scope of the invention are methoxymethyl, cyano- methyl, or mono- or dialkyl substituted aminoalkyl esters, e.g. 3-dimethyl- aminoethyl, 2-diethylaminoethyl, or 3-dimethylaminopropyl esters.

In particular, such esters are preferred which are well absorbed upon enteral administration and during or after the absorption are hydrolysed to the compounds of formula I. These examples are not to be considered as limiting for the inven¬ tion, and other suitable methods to improve the physicochemical properties and solubility of the compounds concerned can be used as well.

5-lipoxygenase inhibitors and leukotriene antagonists are of potential interest in the therapy of asthma, allergy, rheumatoid arthritis, spondylo- arthritis, gout, atherosclerosis, prolrferative and inflammatory skin disorders, such as psoriasis and atopic dermatitis, chronic inflammatory bowel disease, and other inflammatory conditions, vasospasm associated with angina pectoris, pulmonary hypertension, cystic fibrosis, the adult respiratory distress syn-

Q drome, ischemic and reperfusion injury, migraine headache, etc. . The

E.J. Goetzl, D.G. Payan and D.W. Godman, J. Clin. Immunol. 4 (1984)

79. identification of specific 5-lipoxygenase inhibitors and leukotriene antagonists is thus a novel approach with very wide implications for the treatment of a diversity of clinical disorders.

Inhibitors of arachidonic acid metabolism may be identified using rat peritoneal leukocytes labelled with [1- C]arachidonate and stimulated with the

Q calcium ionophore A23187 . The compounds of the present invention were observed to inhibit the metabolism at an assay concentration of 10 μM.

Leukotriene antagonists may be identified by observing the contrac¬ tions elicited in preparations of guinea-pig ileum strips suspended in a physio- logical buffer by addition of pure leukotriene D₄ (LTD₄) . When the com¬ pounds of the present invention were added to the ileum preparation before addition of LTD₄ a significant inhibition occurred of the specific LTD₄-induced contraction. This inhibition occurred at concentrations as low as 0.1-1 nM. On the other hand, contractions induced with histamine at 10 M were not inhibited by these compounds even at micromolar concentrations.

It is of importance to investigate the receptor binding properties of leukotriene antagonists in relation to their inhibition of smooth muscle contraction. Receptor binding studies may be performed with guinea-pig lung membranes in a direct competition assay between a leukotriene antagonist and [³H]LTD₄ for binding to the LTD₄ receptor ⁹,¹⁰. A plC₅₀ value is deter¬ mined as the negative logarithm of the molar concentration of antagonist inhibiting [ H]LTD₄ binding by 50%. The plCg₀ values for the compounds o the present invention are unaffected by the presence of 0.1% human serum

11 albumin, contrary to the case for OT 3665 (see Table I).

I. Ahnfelt-Rønne, D. Kirstein and C. Kaergaard-Nielsen, European J. Pharmacol. 155 (1988) 117. S. Mong, H.-L. Wu, M.O. Scott, MA Lewis, M.A. Clarke, B.M. Weichman, CM. Kinzig, J.G. Gleason and S . Crooke, J. Pharmacol. Exp. Ther. 234 (1985) 316. International Appl. No. PCT/DK88/00188 (Publ. No. WO 89/05294), Ex. 9. Table I Binding of f H1LTD₄ to guinea-pig lung membranes in the absence or presence of 0.1% human serum albumin ICCQ. mean +SD (nl or individual values)

The leukotriene antagonistic effect was tested in vivo on LTD₄ - q induced bronchoconstriction in anaesthetized guinea-pigs . Intravenously the compounds were administered 10 minutes, orally 4, 8 and 24 hours before the bronchoconstriction. The EDgQ values represent the dose inhibiting the leukotriene induced bronchoconstriction by 50%. The ED Q values were calcu¬ lated by regression analysis of 2 - 3 doses. The following Table II shows the results.

Table II

CO

nd. = not done

Thus the compounds according to Examples 14, 20, 12, 64, 54, 43, and 44 are more potent and longer lasting as LTD₄- antagonists than OT 3665.

The present invention also relates to a method for producing the present compounds.

In one embodiment, an amine of the formula II, prepared as

12 described or as in Example 2,

in which X₁ and X₂ has the above meanings, is reacted with a compound of the formula III, prepared as described or as in Example 25,

in which R.. , R3, X3, X₄, A, Z and p have the above meanings, and Y is capable of forming a "good leaving group", Y thus standing for e.g. a halogen atom, such as chlorine, bromine or iodine, or an alkyl- or arylsulphonyloxy group, but other leaving groups can be used as well, such as an alkylsulphate group, a chlorosulphonyloxy group, an alkylsulphite group, a mono- or di- alkylphosphate group or a nitrate group, to form a compound of the formula I. The reaction is performed in a suitable inert organic solvent, such as methanol, ethanol, dimethyl formamide or hexamethyl phosphoric triamide, but

EP 0206 751 A Merck Frosst Canada Inc. C.R. Edwards, M.J. Readhead and N.J. Tweedle, J. Heterocyclic Chem. 24 (1987) 495. other solvents can be used as well; the reaction is performed at a temperature about or above room temperature, up to the boiling point of the solvent used. In some cases it can, however, be convenient to cool the reaction mixture below room temperature, depending on the nature of the compound of the formula III used. The reaction is also conveniently performed 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 alkalimetal hydroxide, an alkalimetal carbonate or an alkalimetal hydrogen carbonate, but other bases can be used as well. The crude reaction products of the formula I are collected by filtration, if convenient after dilution with e.g. water, or are extracted from the reaction mixture with a suitable solvent, such as diethyl ether, ethyl acetate, dichloromethane or chloroform. The products are purified e.g. by recrystallization or by chromatography, if convenient after conversion to salts with suitable inorganic or organic acids as defined above. In another embodiment, an amine of the formula II is converted to a compound of the formula I by reductive alkylation, e.g. by reaction with a carbonyl compound of the formula IV, which compounds are commercially available or are prepared as described in ³ ,

in which R^ R3, X3, X₄, A, Z and p have the above meanings, followed by hydrogenation in the presence of a suitable catalyst or by reduction e.g. with

J. Bernstein, H.L. Yale, K. Losee, M. Holsing, J. Martins and W.A. Lott, J. Am. Chem. Soc. 73 (1951) 906. L.A. Flippin, J.M. Muchowski and D.S. Carter, J. Org. Chem. 58 (1993) 2463. EP 572 712 A Sumitomo Seika Chem. Co. Ltd. an alkalimetal borohydride. The hydrogenation or reduction can, if convenient, be performed simultaneously with the reaction with the carbonyl compound, that is, without isolation of the intermediary, so-called Schiff-base.

The reaction is performed in a suitable inert organic solvent, such as methanol or ethanol, but other solvents can be used as well. The reaction is preferably performed at ambient temperature, but in some cases it is convenient to cool the reaction mixture below room temperature, or to heat the reaction mixture above room temperature, up to the boiling point of the solvent used, depending on the nature of the reactants of the formulae II and IV used. The isolation and purification of the products can be performed as described above.

In still another embodiment a compound of the formula V, prepared e.g. as in Example 3

in which X... X₂, X3 and X₄ have the above meanings and Z is O, S or NH, is reacted with a compound of the formula VI which is commercially available or

17 18 1Q may be prepared by methods as described ,

Y. Ogata, T. Sugimoto and M. Inaishi, in: Organic Synthesis, coll. vol. VI (1988), ed. W.E. Noland (John Wiley, New York) p. 90.

D.N. Harpp, L.Q. Bao, in: Organic Syntheses col. vol VIII (1993), ed. J.P. Freemann (John Wiley, New York) p. 190.

B. Koppenhoefer and V. Schurig, in ibid, p. 119.

and in which R- , R3, A, p and Y have the above meanings, to form the desired compound of formula I.

Compounds of formula V are prepared by reacting the appropriate compound II with an appropriate substituted benzaldehyde, followed by reduc¬ tion with sodium borohydride (NaBH₄).

The following Scheme I illustrates preparation of compounds of formula V:

SCHEME I

NaBH, EtOH or MeOH

V

The present compounds are intended for use in pharmaceutical compositions which are useful in the treatment of the above mentioned dis¬ eases.

The amount required of a compound of formula (I) (hereinafter referred to as the active ingredient) for therapeutic effect will, of course, vary both with the particular compound, the route of administration and the mammal under treatment. A suitable dose of a compound of formula (I) for systemic treatment is 0.1 to 20 mg per kilogram bodyweight, the most preferred dosage being 0.1 to 10 mg/kg of mammal bodyweight, for example 0.2 to 10 mg/kg; administered one or more times daily, typically corresponding to a daily dose for an adult human being of from 5 mg to 5 g.

In spray formulations, a suitable anti-asthmatic dose of a compound of formula (I) is 1 μg to 5 mg of compound per kilogram bodyweight, the most preferred dosage being 1 μg to 1 mg/kg of mammal bodyweight, for example from 1 μg to 0.5 mg/kg.

While it is possible for an active ingredient to be administered alone as the raw chemical, it is preferable to present it as a pharmaceutical formula- tion. Conveniently, the active ingredient comprises from 0.1% to 100% by weight of the formulation. Conveniently, dosage units of a formulation contain between 0.07 mg and 1 g of the active ingredient. For topical administration, the active ingredient preferably comprises from 1% to 2% by weight of the formulation but the active ingredient may comprise as much as 10% w/w. Formulations suitable for nasal or buccal administration may comprise 0.1 to 20% w/w, for example about 2% w/w of active ingredient.

By the term "dosage unit" is meant a unitary, i.e. a single dose which is capable of being administered to a patient, and which may be readily handled and packed, remaining as a physically and chemically stable unit dose comprising either the active material as such or a mixture of it with solid or liquid pharmaceutical diluents or carriers.

The formulations, both for veterinary and for human medical use, of the present invention comprise an active ingredient in association with a phar¬ maceutically acceptable carrier therefor and optionally other therapeutic in- gredient(s). The carrier(s) must be "acceptable" in the sense of being compat¬ ible with the other ingredients of the formulations and not deleterious to the recipient thereof.

The formulations include those in a form suitable for oral, ophthalmic, rectal, parenteral (including subcutaneous, intramuscular and intravenous), transdermal, intra-articular, topical, nasal, or buccal administration. The formulations may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formula¬ tion.

Formulations of the present invention suitable for oral administration may be in the form of discrete units as capsules, sachets, tablets or lozenges, each containing a predetermined amount of the active ingredient; in the form of a powder or granules; in the form of a solution or a suspension in an aque¬ ous liquid or non-aqueous liquid; or 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, electuary or paste.

Formulations for rectal administration may be in the form of a sup¬ pository incorporating the active ingredient and a carrier, or in the form of an enema.

Formulations suitable for parenteral administration conveniently comprise a sterile oily or aqueous preparation of the active ingredient which is preferably isotonic with the blood of the recipient.

Formulations suitable for intra-articular or ophthalmic administration may be in the form of a sterile aqueous preparation of the active ingredient which may be in microcrystalline form, for example, in the form of an aqueous microcrystalline suspension. Liposomal formulations or biodegradable polymer systems may also be used to present the active ingredient for both intra-articu¬ lar 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, ointments or pastes; or solutions or suspensions, such as drops. Formulations suitable for administration to the nose or buccal cavity include powder, self-propelling and spray formulations, such as aerosols and atomizers.

Other formulations suitable for nasal administration include a fine powder which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.

In addition to the aforementioned ingredients, the formulations of this invention may include one or more additional ingredients. The compositions may further contain other therapeutically active compounds usually applied in the treatment of the above mentioned pathologi¬ cal conditions, for instance glucocorticoids, anti-histamines, platelet activating factor (PAF) antagonists, anticholinergic agents, methyl xanthines, ?-adre- nergic agents, salicylates, indomethacin, flufenamate, naproxen, timegadine, gold salts, penicillamine, serum cholesterol-reducing agents, retinoids, zinc salts, and salicylazosulfapyridin (Salazopyrin).

The invention will now be further described in the following Examples:

Example 1 E-2-r3-(2-Quinolin-2-yltethenv0phenylaminomethv",phenoxyacetic acid

Step 1 E-3-f⁽2-Quinolin-2-v0ethenyll-N-(2-carboxymethoxybenzylidene - aniline

To a solution of E-3-[2-(quinolin-2-yl)ethenyl]aniline (0.5 g, 2 mmol) (confer EP 0206 751 A Merck Frosst Canada Inc.) in diethyl ether (150 ml), 2- formylphenoxyacetic acid (0.36 g, 2 mmol) in diethyl ether (50 ml) is added, and is stirred at ambient temperature for 4 hours.

The precipitate that forms is filtered off, washed with diethyl ether and dried, the title compound is obtained with a melting point of 201-203°C. This compound is used directly in the next step. Ste^p 2 E-2-r3-⁽2-Quinolin-2-ylιethenvQphenylaminomethvn^phenoxyacetic acid

To a suspension of the Schiff base obtained from step 1 (0.41 g, 1 mmol) in ethanol (10 ml) is added sodium borohydride (0.1 g). This is stirred for 2 hours at room temperature. To this reaction mixture is then added H₂O (5 ml) and evaporated in vacuo. The residue is treated with water (10 ml) and the resulting solution is neutralized to pH 7 with diluted acetic acid (0.5 ml).

The precipitate that forms is filtered off, triturated with MeOH, fil¬ tered off, washed with methanol and diethyl ether. The title compound is obtained with a melting point of 108-111 °C.

Example 2 E-2-r3-(2-(7-Chloroguinolin-2-yl)ethenvπphenylaminomethvnphenoxyacetic acid Step 1 E-3-r2-(7-Chloroguinolin-2-vhethenvnnitrobenzene A solution of 7-chloroquinaldine (3.6 g, 20 mmol) and 3-nitrobenz- aldehyde (3.0 g, 20 mmol) in acetic anhydride (20 ml) is stirred for 414 hours at 130°C. The mixture is cooled to room temperature and the precipitate filtered off, washed with water and diethyl ether. The title compound obtained, with a melting point of 181-183°C, is used directly in the next step. Step 2 E-3-r2-(7-Chloroouinolin-2-vhethenyl1aniline

To a solution of SnCI (15.0 g) in concentrated hydrochloric acid (40 ml), nitrobenzene (5.1 g, 16 mmol) from step 1 in acetic acid (75 ml) is added, and the mixture is stirred at 80°C for 1 hour. The reaction mixture is cooled to room temperature and evaporated to dryness. The residue is treated with water (150 ml) and NaOH solution is added, to an alkaline reaction (pH 9). It is then extracted twice with ethyl acetate (300 ml), dried and evaporated in vacuo to give the title compound, with a melting point of 127-128°C, which is used directly in the next step. Step 3 E-3-r2-f7-Chloroguinolin-2-vπiethenyl1-N-ι2-carboxymethoxybenzylid- ene)aniline

To a solution of the aniline (4.23 g, 15 mmol) from step 2 in diethyl ether (500 ml), 2-formylρhenoxyacetic acid (2.7 g, 15 mmol) in diethyl ether (300 ml) is added. The mixture is stirred at ambient temperature for 2V_ hours. The precipitate that forms is filtered off, washed with diethyl ether and dried. The title compound is obtained with a melting point of 191-192°C. This compound is used directly in the next step. Step 4 E-2-f3-f2-⁽7-Chloroguinolin-2-vhethenyll^phenylaminomethvnphenoxy- acetic acid

To a suspension of the Schiff base (5.5 g, 12.5 mmol) obtained from step 3 in methanol (75 ml), sodium borohydride (1.25 g) is added in portions during 1V_ hours, while stirring at ambient temperature. The reaction mixture is treated with water (60 ml) and is acidified with vigorous stirring to pH 5-6 by the addition of 3N acetic acid (10 ml). The mixture is stirred at room tempera¬ ture for 12 hours, filtered off and washed with water.

The precipitate is dried, then recrystallized from dioxane (75 ml) and the title compound is obtained as a orange crystalline solid with a melting point of 187-189°C.

Example 3 E-Ethyl 2-r2-(3-⁽2-⁽7-Chloro^guinolin-2-vπethenyl⁾phenylaminomethvπphenoxyl- hexanoate Step 1 E-2-f3-⁽2-⁽7-Chloroouinolin-2-vhethenvhphenylaminomethyllphenol By following the procedure of Example 2, step 3, but replacing 2-formylphenoxyacetic acid with salicylaldehyde, E-3-[2-(7-chloroquinolin-2- yl)ethenyl]-N-(2-hydroxybenzylidene)aniline is obtained as an intermediate, which without isolation by following the procedure of Example 2, step 4, is reacted to give the title compound, which is obtained with a melting point of 151-152°C.

Step 2 E-Ethyl 2-f2-(3-(2-(7-Chloroouinolin-2-vnethenvnphenylaminometh- vhphenoxylhexanoate

A mixture of E-2-[3-(2-(7-chloroquinolin-2-yl)ethenyl)phenylamino- methyl]phenol (7.0 g, 18 mmol), ethyl 2-bromohexanoate (4.9 g, 22 mmol), potassium carbonate (10 g, 72 mmol) and acetone (350 ml) is refluxed for 40 hours, whereafter volatile material is removed by evaporation in vacuo. The residue is dissolved in diethylether and the hydrochloride of the title compound is precipitated by acidification with a slight excess of 1 N hydrochloric acid. The obtained hydrochloride is filtrated and treated with 1 N sodium hydrogen- carbonate (200 ml) and diethyl ether. The organic layer is separated, dried (MgSO₄) and evaporated in vacuo to give the title compound, which after crystallisation from ethanol is obtained with a melting point of 84-86°C.

Examples 4-11 By following the procedure of Example 3, step 2, but replacing ethyl 2-bromohexanoate with the appropriate bromoesters, compounds of Table III are obtained.

Table

Example 12 E-2-f2-⁽3- 2-⁽7-Chloroguinolin-2-vπethenyl⁾phenylaminomethv Phenoxylhexan- oic acid

A mixture of the ethyl ester from Example 3, step 2 (6.3 g, 12 mmol), lithium hydroxide hydrate (10 g, 250 mmol), water (100 ml), methanol (200 ml), and tetrahydrofuran (140 ml) is stirred at ambient temperature for 4 hours. After filtration, the mixture is evaporated in vacuo to give the crude title compound. After recrystallization from ethanol, it is obtained with a melting point of 181-182°C.

Examples 13-21 By following the procedure of Example 12, but replacing E-ethyl 2-[2-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenylaminomethyl)phenoxy]hexanoate with the esters of Table III, compounds of Table IV are obtained.

Table IV

Example 22 E-Ethyl 2-r3-t2-(7-Chloroguinolin-2-vπethenvπphenylaminomethvnphenylthio acetate A mixture of the aniline obtained as in Example 2, step 2 (0.85 g, 3 mmol), potassium hydrogencarbonate (2.0 g) and ethyl 2-chloromethylphenyl- thio acetate (1.07 g, 4.4 mmol) in dimethyl sulfoxide (25.0 ml) is stirred at ambient temperature for 96 hours.

The resulting mixture is diluted with water (25.0 ml) and extracted twice with ethylacetate (2 x 25.0 ml).

The extract is dried and evaporated and the resulting product recrystallized from diethyl ether gives the title compound with a melting point of 101-106°C.

Example 23

E-2-f3-f2-(7-Chloroguinolin-2-yllethenvπphenylaminomethvnphenylthioacetic acid

The ester from Example 22 (0.5 g, 1 mmol) is hydrolyzed with 2N NaOH (1.0 ml) in ethanol (10.0 ml). The solution is refluxed for 2 hours and diluted with water (10.0 ml). After acidifying the solution with 3N acetic acid (0.5 ml) the precipitate is filtered off and washed with water and ethyl acetate.

The title compound is obtained after recrystallization from acetic acid and has a melting point of 205-207°C. Example 24 E-2-[3-(2-(Quinolin-2-yl)ethenyl)phenylaminomethvnphenylthioacetic acid Step 1 E-Ethyl 2-r3-f2-fQuinolin-2-vπethenvπ^phenylaminomethvnphenylthio acetate By following the procedure of Example 22, but replacing E-3-[2-(7- chloroquinolin-2-yl)ethenyl]aniline with E-3-[2-(quinolin-2-yl)ethenyl]aniline (see Example 1 , step 1), the title compound is obtained after flash chromatography using ethyl acetate/hexane (3:7) and used as such for the next step.

Step 2 E-2-r3-(2-(Quinolin-2-yl)ethenyl)phenylaminomethvnphenylthioacetic acid

By following the procedure from Example 23, but replacing E-ethyl 2-[3-(2-(7-chloroquinolin-2-yl)ethenyl)phenylaminomethyl]phenylthio acetate with ethyl ester from step 1, the title compound is obtained. The product is triturated with ethyl acetate and gives the title compound with a melting point of 177-179°C.

Example 25 E-2-[2-(3-(2-(7-Chloroguinolin-2-yπethenyl)phenylaminomethyl)phenylthio]hexa- noic acid

Step 1 E-Ethyl 2-f2-(3-(2-(^,7-(Chloroguinolin-2-yl)ethenyl)phefiylaminometh- vDphenylthiolhexanoate

By following the procedure of Example 22, but replacing ethyl 2- -chloromethylphenylthioacetate with ethyl 2-(2-bromomethylphenylthio)hexano- ate (prepared as described in the Appendix below), the title compound is obtained. The ester is without further purification used in the following step. Step 2 E-2-f2-f3-(2-(7-Chloroguinolin-2-vhethenyl)phenylaminomethyl)phen- ylthiolhexanoic acid

By following the procedure of Example 12, but replacing E-ethyl 2-[2-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenylaminomethyl)phenoxy]hexanoate with the ester from step 1 , the title compound is obtained with a melting point of 169-172°C. Appendix Preparation of ethyl 2-(2-bromomethylphenylthio>hexanoate used in Step 1

Step A Ethyl 2-(2-carboχyphenylthio)hexanoate A solution of 2-thiobenzoic acid (7.7 g) and ethyl 2-bromohexanoate

(12 g) in 1 N methanolic potassium hydroxide (100 ml) is stirred at ambient temperature for 16 hours. After evaporation in vacuo, the resulting material is dissolved in water and extracted with diethyl ether. The aqueous solution is then acidified with a slight excess of 4 N hydrochloric acid and is extracted three times with diethyl ether. The combined organic extract is dried and evap¬ orated in vacuo to give the title compound, used as such in the next step. Step B Ethyl 2-(2-hvdroxymethylphenylthio)hexanoate

To a mixture of the carboxyiic acid (6.0 g) from step A, triethylamine (3.0 ml) and tetrahydrofuran (50 ml), ethylchloroformate (1.9 g) is slowly added while stirring at -7°C to -10°C. After stirring for a further 30 minutes, the result¬ ing solution is clarified by filtration whereafter the intermediate mixed anhydride is reduced by addition of sodium borohydride (2.7 g) followed by addition during 1 hour of methanol (15 ml) while stirring at 10°C. After stirring for a further 2 hours, the resulting mixture is carefully acidified with 4 N hydro- chloric acid (100 ml), and is then extracted twice with diethyl ether. The organic extract is washed with brine, dried and evaporated in vacuo to give 6.0 g of the title compound used in the next step.

Step C Ethyl 2-(2-Bromomethylphenylthio)hexanoate

To triphenylphosphine (5.3 g) in acetonitrile (40 ml), bromine (3.2 g) is added while stirring and cooling. After about 10 minutes, a solution of the material from step B (6.0 g) in acetonitrile (30 ml) is slowly added and the mixture is stirred for a further 3 hours. The resulting mixture is evaporated in vacuo and the residue is treated with ice, water and diethyl ether. The organic layer is separated, washed with cold water, dried and evaporated in vacuo to give 6.0 g of the title compound used as in Example 25, step 1.

Example 26 E-2-r2-(3-(2-(7-Chloroguinolin-2-yl)ethenvhphenylaminomethyl)phenylamino1- hexanoic acid Step 1 E-2-r3-(2-(7-(Chloroouinolin-2-vπethenvQphenylaminomethvπnitro- benzene

By following the procedure of Example 2, steps 3 and 4, but replac¬ ing 2-formylphenoxyacetic acid with 2-nitrobenzaldehyde, the title compound is obtained with a melting point of 150-151 °C. Step 2 E-2-r3-(2-f7-Chloroguinolin-2-vπethenvπphenylaminomethvnaniline To a stirred mixture of the nitro compound from step 1 (3.85 g, 9 mmol) and concentrated hydrochloric acid (75 ml), stannous chloride dihydrate (13.7 g, 60 mmol) is added in portions, whereafter the reaction mixture is stirred at ambient temperature overnight. The mixture is then diluted with ice and a concentrated aqueous solution of sodium hydroxide is carefully added until a strong alkaline pH is reached. The mixture is filtered, and the residue is washed with water and then dissolved in acetone. The solution is clarified by filtration, whereafter the title compound is precipitated by dilution with water. It is collected by filtration and is, after recrystallization from ethanol, obtained with a melting point of 129-131 °C. Step 3 E-Ethyl 2-r2-t3-ι2-⁽7-Chloroouinolin-2-yltethenyl)phenylaminometh- vDphenylaminolhexanoate

A mixture of the aniline (1.6 g, 4 mmol) from step 2, ethyl 2-bromo¬ hexanoate (1.8 g, 8 mmol), sodium hydrogen carbonate (1.8 g) and hexameth- yl phosphoric triamide (30 ml) is stirred at 60°C for 48 hours. Further ethyl 2-bromohexanoate (0.9 g, 4 mmol) and sodium hydrogen carbonate (0.9 g) is then added and the mixture is stirred at 60°C for a further 72 hours. The resulting mixture is poured on ice/water and is extracted three times with diethyl ether. The combined organic extract is washed with water, dried and evaporated in vacuo to give the title compound as an oil, which is used as such in the following step. Step 4 E-2-f2-(3-(2-(7-Chloroouinolin-2-ylιethenvhphenylaminomethyl;- phenylaminoϊhexanoic acid

By following the procedure of Example 12, but replacing E-ethyl 2- [2-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenylaminomethyl)phenoxy]hexanoate with the ethyl ester of step 3, the title compound is obtained with a melting point of 169-171 °C.

Example 27 E-2-r3-(3-ι2-(7-Chloroouinolin-2-yltethenvhphenylaminomethylιPhenoxy1hexan- oic acid Step 1 E-3-r3-(2-(7-Chloroouinolin-2-vhethenyl)phenylaminomethyllphenol

By following the procedure of Example 2, steps 3 and 4, but replac¬ ing 2-formylphenoxyacetic acid with 3-hydroxybenzaldehyde, the title compound is obtained with a melting point of 179-180°C.

Step 2 E-Ethyl 2-f3-(3-(2-(7-Chloroouinolin-2-vπethenylιPhenylaminomethylι- phenoxylhexanoate

By following the procedure of Example 3, step 2, but replacing E-2- [3-(2-(7-chloroquinolin-2-yl)ethenyl)phenylaminomethyl]phenol with the meta substituted phenol of step 1 , the title compound is obtained as an oil which is used as such in the following step. Ste^p 3 E-2-r3-⁽3-^('2-⁽7-Chloro^guinolin-2-yl⁾ethenvnDhenylaminomethvnphen- oxylhexanoic acid

By following the procedure of Example 12, but replacing E-ethyl 2-[2-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenylaminomethyl)phenoxy]hexanoate with the ethyl ester of step 2 above, the title compound is obtained with a melting point of 183-185°C.

Example 28 E-2-f4-⁽3-⁽2-⁽7-Chloroouinolin-2-yl)ethenvflphenylamino⁾phenoxy1hexanoic acid Step 1 E-4-,3-⁽2-⁽7-Chloroguinolin-2-yl⁾ethenvhphenylaminomethyllphenol By following the procedure of Example 2, steps 3 and 4, but replac¬ ing 2-formylphenoxyacetic acid with 4-hydroxybenzaldehyde, the title compound is obtained with a melting point of 194-195°C. Step 2 E-Ethyl 2-f4-(3-t2-(7-Chloroouinolin-2-yltethenvnphenylaminometh- yhphenoxylhexanoate

By following the procedure of Example 3, step 2, but replacing E-2-[3-(2-(7-chloroquinolin-2-yl)ethenyl)phenylaminomethyl]phenol with the para substituted phenol of step 1 , the title compound is obtained as an oil, which is used as such in the following step. Step 3 E-ι2-r4-(3-(2-(7-Chloroouinolin-2-v0ethenyltohenylaminomethylι- phenoxylhexanoic acid

By following the procedure of Example 12, but replacing E-ethyl 2-[2-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenylaminomethyl)phenoxy]hexanoate with the ethyl ester of step 2, the title compound is obtained with a melting point of 173-175°C.

Example 29 E-Ethyl 2-r2-f3-(2-(7-Chloroguinolin-2-vhethenvπphenylaminomethvn-6-meth- oxyphenoxylhexanoate Step 1 E-2-f3-f2-f7-Chloroguinolin-2-vπethenvπphenylaminomethvn-6-meth- oxyphenol By following the procedure of Example 2, step 3 and 4, but replac¬ ing 2-formylphenoxyacetic acid with 2-hydroxy-3-methoxybenzaldehyde, the title compound is obtained with a melting point of 139-140.5°C. Step 2 E-Ethyl 2-r2-(3-(2-(7-chloroouinolin-2-vnethenyl,phenylaminometh- vD-6-methoχyphenoxylhexanoate

By following the procedure of Example 3, step 2, but replacing E-2-[3-(2-(7-chloroquinolin-2-yl)ethenyl)phenylaminomethyl]phenol with the phenol from step 1 , the title compound is obtained with a melting point of 101-102.5°C.

Example 30 E-2-r2-(3-(2-(7-Chloroguinolin-2-yl)ethenyl)phenylaminomethyl)-6-methoχyphen- oxylhexanoic acid

By following the procedure of Example 12, but replacing E-ethyl 2-[2-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenylamino)phenoxy]hexanoate with the ethyl ester of Example 26, step 2, the title compound is obtained with a melting point of 173-174°C.

Example 31 E-2-r3-(2-(7-Chloroguinolin-2-vπethenyllphenylaminomethvnbenzoic acid

Step 1 E-3-f2-(7-Chloroguinolin-2-vπethenvπ-N-(2-carboxybenzylidene)anil- ine

To a solution of the aniline (2.8 g, 10 mmol) from Example 2, step 2, in methanol (50.0 ml), 2-carboxybenzaldehyde in methanol (15.0 ml) is added. The precipitate that forms immediately is stirred at ambient tempera¬ ture for 2 hours, filtered off and washed with diethyl ether.

The title compound is obtained with a melting point of 226-228°C. This compound is used directly in the next step.

Step 2 E-2-f3-(2-t7-Chloroouinolin-2-yl)ethenyl)phenylaminomethyllbenzoic acid

To a suspension of the Schiff base (0.82 g, 2 mmol) obtained from step 1 in ethanol (10.0 ml), sodium borohydride (0.2 g) is added. After stirring for 1 hour, the precipitated product is collected by filtration and washed with diethyl ether. This reaction product is treated with water (30.0 ml) and acidified with addition of 3 N acetic acid (1.5 ml).

The resulting precipitate is collected by filtration, washed with water and giving the title compound with a melting point of 223-226°C.

Example 32 E-4-f3-(2-(7-ChloroQuinolin-2-yl)ethenyl)phenylaminomethvπbenzoic acid Step 1 E-3-r2-(7-Chloroguinolin-2-yl)ethenvn-N-(4-carboxybenzylidene)anil- ine

By following the procedure of Example 31 , step 1 , but replacing 2- carboxybenzaldehyde with 4-carboxybenzaldehyde, the title compound is obtained with a melting point over 250°C. Analysis: Calculated for C₂₅H₁₇CIN₂O₂: %C 72.72; %H 4.15; %N 6.79; %CI 8.59;

Found: %C 72.40; %H 4.26; %N 6.79; %CI 8.70. Step 2 E-4-f3-f2-(7-Chloroguinolin-2-yl)ethenyl)phenylaminomethvnbenzoic acid

By following the procedure of Example 31, step 2, but replacing E-3- [2-(7-chloroquinolin-2-yl)ethenyl]-N-(2-carboxybenzylidene)aniline with 3-[2-(7- chloroquinolin-2-yl)]ethenyl-N-(4-carboxybenzylidene)aniline, the title compound is obtained with a melting point of 248-250°C.

Example 33 E-Ethyl 2-r3-(2-fQuinolin-2-vDethenvhphenylaminomethvπphenyl acetate

A mixture of ethyl 2-bromomethylphenyl acetate (6.0 g, 23 mmol), 3- [2-(quinolin-2-yl)ethenyl]aniline (see Example 1 , step 1) (5.0 g, 20 mmol) potassium hydrogen carbonate (10.0 g, 100 mmol) and dimethyl sulfoxide (100 ml) is stirred at ambient temperature for 3 hours. The reaction mixture is poured on water and the resulting precipitate is isolated and purified by chro- matography (SiO₂) to give the title compound with a melting point of 108- 109°C. Example 34 E-2-[3-f2-(Quinolin-2-yl)ethenyl)phenylaminomethyl]phenylacetic acid

A solution of E-ethyl 2-[3-(2-(quinolin-2-yl)ethenyl)phenylamino- methyl]phenyl acetate (2.7 g, 6.3 mmol) in ethanol (25 ml) is at ambient tem- perature slowly added to 2 N sodium hydroxide (25 ml). The mixture is then stirred at 50°C for 5 minutes to give a clear solution, which is diluted with water (100 ml) and acidified with a slight excess of acetic acid to precipitate the title compound. After purification by chromatography (SiO₂) the title compound is obtained with a melting point of 165-166.5°C.

Example 35 E-Ethyl 2-f3-(2-(7-Chloroguinolin-2-vπethenyl)phenylaminomethvnphenyl acet¬ ate

By following the procedure of Example 33, but replacing E-3-[2- (quinolin-2-yl)ethenyl]aniline with E-3-[2-(7-chloroquinolin-2-yl)ethenyl]aniline (see Exampie 2, step 2), the title compound is obtained with a melting point of 94.5-96°C.

Example 36 E-2-r3-f2-f7-Chloroguinolin-2-yl)ethenvπphenylaminomethvnphenylacetic acid By following the procedure of Example 34, but replacing E-ethyl 2-[3-(2-(quinolin-2-yl)ethenyl)phenylaminomethyl]phenyl acetate with E-ethyl 2-[3-(2-(7-chloroquinolin-2-yl)ethenyl)phenylaminomethyl]phenyl acetate, the title compound is obtained with a melting point of 174-176°C.

Example 37 E-Ethyl 3-f2-(3-(2-(7-Chloroαuinolin-2-v0ethenyl)phenylaminomethvhphenvπ- propionate

By following the procedure of Example 33, but replacing ethyl 2- bromomethylphenyl acetate with ethyl 2-bromomethylphenyl-3-propionate, the title compound is obtained as a hydrochloride dihydrate with a melting point of 173°C dec. Example 38 E-3-r2-(3-2-f7-Chloro^guinolin-2-yl⁾ethenyl⁾phenylaminomethvh^phenvnpropionic acid

By following the procedure of Example 34, but replacing E-ethyl 2-[3-(2-(quinolin-2-yl)ethenyl)phenylaminomethyl]phenyl acetate with E-ethyl 2-[3-(2-(7-chloroquinolin-2-yl)ethenyl)phenyl]aminomethylphenyl)propionate, the title compound is obtained with a melting point of 179-181 °C.

Example 39 E-Sodium 2-f2-(3-(2-⁽7-Chloro^guinolin-2-yl⁾ethenvπphenylaminomethvπphen- oxy|hexanoate

E-2-[2-(3-(2-(7-Chloroquinolin-2-yl)ethenyl)phenylaminomethyl)phen- oxy]hexanoic acid (2.5 g, 5 mmol; prepared as described in Example 12) is dissolved in a mixture of 1 N aqueous sodium hydroxide (5.5 ml, 10% excess) and water (50 ml). The resulting solution is clarified by filtration, and left to precipitate the title compound, which is obtained crystallizing with 0.75 mol of water and with a melting point of 120°C.

Example 40 E-2-f3-(2-(6.7-difluoroquinolin-2-yl)ethenyl)phenylaminomethvnphenoxyacetic acid Step 1 E-3-f2-(6.7-Difluoroguinolin-2-yl)ethenyl1nitrobenzene

By following the procedure of Example 2, step 1, but replacing 7-chloroquinaldine with 6,7-difluoroquinaldine, the title compound was obtained with a melting point of 175-176°C.

Step 2 E-3-r2-(6.7-DifluoroQuinolin-2-vDethenvπaniline

The substituted nitrobenzene from step 1 was reacted with SnCI₂ following the procedure of .Example 2, step 2, to give the title compound with a melting point of 169-171 °C. Step 3 E-2-r3-⁽2-⁽6.7-difluoro^guinolin-2-vπethenylιPhenylaminomethvnphen- oxyacetic acid

By following the procedure of Example 2, steps 3 and 4, but re¬ placing E-3-[2-(7-(chloroquinolin-2-yl)ethenyl] aniline with E-3-[2-(6,7-difluoro- quinolin-2-yl)ethenyl] aniline, the title compound is obtained with a melting point of 157-159°C.

Example 41 E-2-r3-(2-(7-fluoroguinolin-2-vπethenvhphenylaminomethyl1phenoxyacetic acid By following the procedure of Example 2, steps 3 and 4, but re¬ placing E-3-[2-(7-(chloroquinolin-2-yl)ethenyl)aniline with E-3-[2-(7-fluoroquinol- in-2-yl)ethenyl) aniline, the title compound is obtained with a melting point of 199-201 °C.

Example 42

E-Ethyl-2-f2-(3-(2-(7-fluoroguinolin-2-yl)ethenyl)phenylaminomethvπphenoxy- hexanoate

Step 1 E-2-f3-(2-(7-fluoroquinolin-2-yl)ethenyl)phenylaminomethvnphenol By following the procedure of Example 3, step 1 , but replacing E-2-[3-(2-(7-fluoroquinolin-2-yl)ethenyl]aniline with E-2-[3-(2-(7-fluoroquinolin-2-

-yl)ethenyl]aniline, the title compound is obtained with a melting point of

174.5-175.0°C.

Step 2 E-Ethyl-2-r2-(3-(2-f7-fluoroouinolin-2-vπethenyl)phenylaminomethvπ- phenoxyl-hexanoate A mixture of ethyl 2-bromohexanoate (0.63 ml, 3.5 mmol), phenol

(from step 1) (0.93 g, 2.5 mmol), potassium hydrogen carbonate (0.75 g) and

N,N-dimethylformamide (25 ml) is stirred at ambient temperatre for 3 hours.

The reaction mixture is poured on water (25 ml) and 4 N hydrochloric acid (3 ml). The precipitate is filtered off and washed with water and ether. The title compound is obtained as hydrochloride with a melting point of 174.5-175°C. Example 43 E-2-f2-(3-2-(2-(7-fluoroquinolin-2-yl⁾ethenyl⁾phenylaminomethvn^phenoxyhexan- oic acid

By following the procedure of Example 12, but replacing the ester from Example 3, step 2, with the ester from Example 42, the title compound is obtained with a melting point of 181-183°C.

Example 44 E-2-r2-(3-(2-(6.7-difluoroouinolin-2-vhethenyl)phenylaminomethvhphenoxyl- hexanoic acid, sodium salt

Step 1 E-2-f3-(2-(-6.7-difluoroouinolin-2-yl)ethenyl)phenylaminomethyl1- phenol

By following the procedure of Example 3, step 1, but replacing E-2-[3-(2-(7-chloroquinolin-2-yl)ethenyl]aniline with E-2-[3-(2-(6,7-difluoroquin- olin-2-yl)ethanyl]aniline, the title compound is obtained with a melting point of 158-160°C.

Step 2 E-Ethyl-2-r2-f3-(2-(6.7-difluoroguinolin-2-vnethenyl)Dhenylamino- methyliPhenoxyl-hexanoate

By following the procedure of Example 42, step 2, but replacing the phenol from Example 42, step 1 , with phenol from step 1 , the title compound is obtained as hydrochloride with a melting point of 182-184°C. Step 3 E-2-f2-(3-(2-(6.7-difluoroguinolin-2-vπethenyl)phenylaminomethylι- phenoxyl-hexanoic acid, sodium salt

The ester from step 2 (0.85 g, 1.5 mmol) is refluxed for 3V_ hours in a solution of ethanol (20 ml) and 2 N aqueous sodium hydroxide (2 ml).

Ethanol is evaporated in vacuo, and the precipitate is filtered off, washed with H₂O and diethyl ether. The title compound is obtained as sodium salt with a melting point of 238-240°C. Examples 45-49 By following the procedure of Example 3, step 1 , but replacing salicylaldehyde with the appropriate aldehydes, compounds of Table V are obtained.

Table V

Examples 50-58 By following the procedure of Example 3, step 2, but replacing the phenol with the appropriate phenols from Table V, or following the procedure of Example 12, but replacing the ester with appropriate esters, compounds of Table VI are obtained.

Table VI

Example 59 E-2-f3-(2-(7-fluoroguinolin-2-yl)ethenyl)phenylaminomethyllphenoxyacetic acid Step 1 E-3-f2-(7-Fluoroguinolin-2-yl)ethenyl1-N-(2-carboxymethoxybenzylid- eneianiline

By following the procedure of Example 2, step 3, but replacing E-3-[2-(7-chloroquinolin-2-yl)ethenyl]aniline with E-3-[2-(7-fluoroquinolin-2-yl)- ethenyl]aniline, the title compound is obtained with a melting point of 208- 210°C. Ste^p 2 E-2-f3-⁽2-⁽7-fluoroQuinolin-2-v ethenvh^phenylaminomethylιPhenoxy- acetic acid

By following the procedure of Example 2, step 4, but replacing the Schiff base from Example 2, step 3, with the Schiff base from step 1 , and after recrystallization from n-propanol, the title compound is obtained with a melting point of 199-201 °C.

Example 60 E-2-r3-(2-f7-chloroguinolin-2-yl)ethenvπphenylaminomethyl)phenoxy1 hexanoic acid pivaloyloxymethyl ester hydrochloride

A mixture of E-2-[2-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenylamino- methyl)-phenylamino]hexanoic acid (0.5 g, 1 mmol), potassium carbonate (0.3 -g, 2.2 mmol) and chloromethyl pivalate (0.18 ml, 1.2 mmol) is stirred for 3 hours at room temperature in dimethylformamide (10.0 ml). The mixture is filtered, and the resulting solution is evaporated in vacuo. The residue is triturated with 4 N hydrochloric acid (5.0 ml).

The resulting precipitate is collected by filtration, washed with water giving the title compound with a melting point of 153-155°C.

Example 61

E-2-f3-(2-(7-chtoroouinolin-2-yl)ethenvhPhenylaminomethvhphenoxyl hexanoic acid [(N.N-dimethylamino)carbonvn methyl ester hydrochloride

To a mixture of the acid obtained from Example 11 (0.5 ml, 1 mmol), triethylamine (0.20 ml, 1.5 mmol) and sodium iodide (0.015 g, 0.1 mmol) in N,N-dimethylformamide (10 ml) is added 2-chloro-N,N-dimethylacet- amide (0.15 ml, 1.5 mmol). This is stirred for 24 hours at room temperature.

The mixture is filtered, and the resulting solution is evaporated in vacuo. The residue is triturated with water and the precipitate is collected by filtration, washed with water. The resulting solid is dissolved in ethyl acetate and filtered. The filtrate is concentrated by colomn chromatography on silica gel (ethyl acet- ate:hexane, 7:3) and yielded a brown oil. The resulting solid is dissolved in ethyl acetate and filtered. The filtrate is concentrated by colomn chromatography on silica gel (ethyl acet- ate:hexane, 7:3) and yielded a brown oil.

The oil is triturated with a solution of HCI/Et₂O. The title compound is obtained as hydrochloride with a melting point of 99°C dec.

Example 62 E-2-f3-(2-f7-chloroguinolin-2-yl)ethenyl)phenylaminomethyl)phenoxy1 hexanoic acid lYN.N-diethylaminoicarbonyll methyl ester hydrochloride

By following the procedure of Example 61, but replacing 2-chloro- -N,N-dimethylacetamide with 2-chloro-N.N-diethylacetamide, the title compound is obtained and has a melting point of 120-122°C.

Example 63 E-2-f3-(2-(7-chloroouinolin-2-vhethenyl)phenylaminomethyl)phenoxy1 hexanoic acid r(N.N-diallylaminotoarbonvπ methyl ester

By following the procedure of Example 61 , but replacing 2-chloro- -N,N-dimethylacetamide with 2-chloro-N,N-diallylacetamide, the title compound is obtained and has a melting point of 103-105°C.

Example 64 ■fS)f+ι-E-Ethyl-2-r2-f3-f2-⁽7-Chloroouinolin-2-yl)ethenyl)phenylaminomethvπ- phenoxy]hexanoic acid

Step 1 m-E-Ethyl-2-r2-ι3-ι2-ι7-Chloroouinolin-2-yljethenyljPhenylamino- methvhphenoxylhexanoate

A mixture of E-2-[2-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenylamino-

(R) methyl)phenoxy]hexanoate (5.3 g, 10.0 mmol) and Lipozyme^ (immobilized Mucor miehei lipase) (530 mg, 6.1 Baun/g) in t-butyl ether (100 ml) and phos¬ phate buffer (100 ml, pH 8) was stirred at room temperatur for 120 hours. Filtration through Decalit followed by washing with ethyl acetate gave two phases which were separated. The organic phase was dried (MgSO₄) and evaporated. The product was then purified by silica gel chromatography (ethyl acetate/diethylether), and crystallized from ethanol (96%) to give 2.5 g of the title compound used as such in the next step. Melting point: 99-100°C.

[σ]_D ²⁰ = 30.3° (c = 1.04, acetone). Step 2 ⁽S -i-j-E-Ethyl-Σ-r∑-O-^-^-Chloroguinolin-Σ-vnethenvnphenylamino- methvDphenoxylhexanoic acid

To (+)-E-Ethyl-2-[2-(3-(2-(7-Chloroquinolin-2-yl)ethenyl)phenylamino- methyl)phenoxy]hexanoate (10.6 g, 20 mmol) (from step 1) dissolved in meth¬ anol (300 ml) and tetrahydrofuran (150 ml), LiOH, monohydrate (4.3 g, 102.5 mmol) in water (45 ml) was added, and the mixture stirred for 4 hours. The mixture was then evaporated and redissolved in water/methanol 3: 1 , followed by acidification with acetic acid (50% aq) to pH = 3 - 4. The precipitate was filtered off, dried, and recrystallized from ethanol (absolute), yielding a crude product (10.3 g) containing 0.9 eq ethanol with a melting point of 142/150°C (decomp.), [σ]_D ²⁰ = 23.4 (c = 0.99, DMSO).

Further careful recrystallization from acetonitrile gave the pure product with a melting point of 187-188°C, [σ]_D ²⁰ = 24.5°(c = 1.12, DMSO).

Example 65

E-5-2-r2-(3-(2-f7-chloroguinolin-2-yl)ethenyl)phenylaminomethvπphenoxy]pent- yl-1H-tetrazole

Step 1 E-2-r2-(3-f2-(7-chloroguinolin-2-yl)ethenyl)Phenylaminomethyl)phen- oxy|pentyl hvdroxamic acid

To E-2-[2-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenylaminomethyl)- phenoxyjhexanoate (2.6 g, 5.3 mmol) (from Example 3, step 2) in methanol

(50 ml) hydroxylamine hydrochloride (1.4 g, 20.15 mmol) and KOH (5 ml, 5 M in methanol) were slowly added. After 72 hous at room temperature, acetic acid (50% aq.) was added until pH 3 - 4 was obtained. The precipitate was filtered and dried in air yielding 2.1 g of the title compound to be used in the next step. Step 2 E-2-r2-(3-(2-(7-chloroouinolin-2-v ethenvQ^phenylaminomethvhphen- oxylpentyl nitrile

To the product from step 1 (2.1 g, 4.1 mmol) in benzene (50 ml) phosphortribromide (0.8 ml, 8.5 mmol) was added. After 5 hours reflux the mixture was cooled and then poured into ice water, and made basic with NaHCO_β. Extraction with ethyl acetate, drying, and evaporation, followed by chromatography on silica gel yielded 1.6 g of the title compound used in the following step.

Step 3 E-5-2-r2-(3-f2-(7-chloroguinolin-2-yl)ethenvhphenylaminomethyl)- phenoxylpentyl-1 H-tetrazole

To E-2-[2-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenylaminomethyl)- phenoxy]pentyl nitrile (1.6 g, 3.3 mmol) (from step 2) in DMF (40 ml, NaN₃ (1.65 g, 25.4 mmol) and NH₄CI (1.4 g, 26.4 mmol) were added. The mixture was heated at 115-120°C for 5 hours, then cooled and poured into ice water. The crude product was filtered off and crystallized from ethanol (absolute) yielding 600 mg of the title compound.

Melting point: 210-212°C (decomp.).

Example 66

Aerosol

(S)(+)-E-2-[2-(3-(2-(7-Chloroquinolin-2-yl)- ethenyl)phenylaminomethyl)phenoxy]hexanoic acid (the active substance) 1000 mg Sorbitan trioleate 700 mg

Monofiuorotrichloromethane 595 g

Difluorodichloromethane 798 g

The active substance is micronized in a jet-mill. The majority of the particles should be less than 5 μm in diameter.

A drug concentrate is prepared by dissolving sorbitan trioleate in a small amount of monofiuorotrichloromethane and adding the active substance. The concentrate is homogenized carefully. The concentrate is transferred to a sealed tank provided with a refrigeration system. The remaining propellents are added under stirring and cooling to -50°C.

Suitable aerosol container are filled with the calculated amount of formulation and sealed immediately with metering valves with suitable actuators. Each puff delivers 50 μg of the active substance.

Example 67 Tablet (S)(+)-E-2-[2-(3-(2-(7-Chloroquinolin-2-yl)- ethenyl)phenylaminomethyl)phenoxy]hexanoic acid (active substance) 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 substance, lactose and starch are mixed to a homogene- ous state in a suitable mixer and moistened with a 5 per cent aqueous solution of methylcellulose 15 cps. The mixing is continued until granules are formed. If necessary, the wet granulation is passed through a suitable screen and dried to a water content of less than 1% in a suitable dryer, e.g. fluid bed or drying oven. The dried granulaton is passed through a 1 mm screen and mixed to a homogeneous state with CMC-Na. Magnesium stearate is added, and the mixing is continued for a short period of time.

Tablets with a weight of 200 mg are produced from the granulation by means of a suitable tabletting machine. Example 68 Formulation for injection

(S)(+)-E-2-[2-(3-(2-(7-Chloroquinolin-2-yl)- ethenyl)phenylaminomethyl)phenoxy]hexanoic acid (active substance) 1%

Sodium chloride q.s.

Water for injection to make 100%

The active substance is dissolved in water for injection. The solution is made isotonic with sodium chloride. The solution is filled into ampoules and sterilized.

Claims

WHAT WE CLAIM IS:

A compound of the formula

in which X₁ and X₂ independently of each other stand for hydrogen or halogen; X3 and X₄ independently of each other stand for hydrogen, halogen, nitro, cyano, trifluoromethyl, C_j-C₄ alkyl, C_j-C₄ alkoxy, carboxy or C_|-C₄ carbalkoxy; Z is a bond, O, S, S(O), S(O)₂, NH or CH₂; R₁ is hydrogen or a straight or branched, saturated or unsaturated C^-Cg hydrocarbon chain; R₃ is hydrogen, a straight or branched, saturated or unsaturated ..-C₁₂ hydro¬ carbon chain, unsubstituted or substituted phenyl or unsubstituted or substi¬ tuted benzyl, the above mentioned substituents being one or more of X and X₄ as defined above; or the group R-_|-[CL-R₃ stands for cyclopropyl; p may be 0 provided that Z is a bond, or p may be an integer from 1-6 if R₁ = R₃ = hydrogen; A is COOR₂ or 1H-tetrazole in which R₂ = R^ as defined above or R₂ is a pharmaceutically acceptable cation; and pharmaceutically acceptable, non-toxic salts and in vivo hydrolysable esters thereof.

2. A compound according to formula I of claim 1, in which X- and X₂ independently of each other stand for hydrogen, fluoro or chloro; X₃ stands for hydrogen; X₄ stands for hydrogen, fluoro, chloro or bromo; Z is O or S in ortho-position; p is 1; R^ is hydrogen; R₃ is hydrogen or a straight or branched, saturated or unsaturated C_j-Cg hydrocarbon chain, or phenyl; and A is COOR₂, where R₂ is hydrogen, C_j-C₃ alkyl, an alkali metal cation, or tetrazol-5-yl.

3. A salt according to claim 1 in which the salt is selected from the group consisting of salts formed with hydrochloric, hydrobromic and hydroiodic acid, phosphoric acid, sulphuric acid, nitric acid, p-toluenesulphonic acid, methanesulphonic acid, formic acid, acetic acid, propionic acid, citric acid, tartaric acid, and maleic acid, and lithium, sodium, potassium, magnesium, calcium salts, as well as salts with ammonia, C_j-Cg-alkylamines, ^-Cg alkanolamines, procaine, cycloalkylamines, benzylamines, and heterocyclic amines.

4. A compound of claim 1 which is selected from the group consisting of:

E-2-[2-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenylaminomethyl)phen- oxy]-2-methylpropanoic acid;

E-2-[2-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenylaminomethyl)phen- oxy]-2-methylpentanoic acid;

E-2-[2-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenylaminomethyl)phen- oxyjhexanoic acid;

E-2-[2-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenylaminomethyl)-4- bromophenoxy] hexanoic acid; E-2-[2-(3-2-(2-(7-fluoroquinolin-2-yl)ethenyl)phenylaminomethyl]- phenoxy hexanoic acid;

E-2-[2-(3-(2-(6,7-difluoroquinolin-2-yl)ethenyl)phenylaminomethyl)- phenoxyjhexanoic acid, sodium salt; and their salts and pure enantiomeric forms.

5. A compound of claim 1 which is (S)(+)-E-2-[2-(3-(2-(7-Chloroquin- olin-2-yl)-ethenyl)phenylaminomethyl)phenoxy]hexanoic acid.

6. A pharmaceutical preparation, containing a compound according to any one of claims 1 - 5 alone or together with the necessary auxiliary agents.

7. A method of treating patients in need of treatment characterized in administering to said patients an effective amount of one or more compounds according to any of claims 1 - 5, if necessary together or concomitantly with one or more other therapeutically active components.

8. A method according to claim 7 for the treatment and prophylaxis of a number of disease states including asthma, allergy, rheumatoid arthritis, spondyloarthritis, gout, atherosclerosis, proliferative and inflammatory skin disorders, chronic inflammatory bowel disease, and other inflammatory condi¬ tions, vasospasm associated with angina pectoris, pulmonary hypertension, cystic fibrosis, the adult respiratory distress syndrome, ischemic and reper- fusion injury, migraine headache.

9. Method for producing a compound of formula I according to claim 1 , in which a) an amine of the formula II

in which X₁ and X-. has the above meanings, is reacted with a compound of the formula III

in which R₁ , R₃, X₃, X₄, A, Z and p have the above meanings, and Y is capable of forming a "good leaving group"; or b) an amine of the formula II is converted to a compound of the for¬ mula I by reaction with a carbonyl compound of the formula IV

in which R^ R₃, X₃, X₄, A, Z and p have the above meanings, followed by hydrogenation in the presence of a suitable catalyst or by reduction with an alkalimetal borohydride, the hydrogenation or reduction, if convenient, being performed simultaneously with the reaction with the carbonyl compound, that is, without isolation of the intermediary, so-called Schiff-base; or c) a compound of the formula V

in which X.. , X₂, X₃ and X₄ have the above meanings and Z is O, S or NH, is reacted with a compound of the formula VI

and in which R^ R₃, A, p and Y have the above meanings, to form the desired compound of formula I.

10. The use of a compound of claim 1 in the manufacture of a medi¬ cament for the treatment and prophylaxis of a number of disease states, including asthma, allergy, rheumatoid arthritis, spondyloarthritis, gout, atherosclerosis, proliferative and inflammatory skin disorders, chronic inflam¬ matory bowel disease, and other inflammatory conditions, vasospasm associ- ated with angina pectoris, pulmonary hypertension, cystic fibrosis, the adult respiratory distress syndrome, ischemic and reperfusion injury, migraine head¬ ache.