NZ287850A

NZ287850A - Quinoline derivatives; medicaments; used as leukotriene antagonist

Info

Publication number: NZ287850A
Application number: NZ287850A
Authority: NZ
Inventors: Dorte Kirstein; Schneur Rachlin
Original assignee: Leo Pharm Prod Ltd
Priority date: 1994-07-20
Filing date: 1995-06-07
Publication date: 1998-05-27
Also published as: CZ284799B6; FI970143A; HU9603342D0; AU686820B2; AU2669695A; JPH10504026A; WO1996002506A1; GB9414590D0; CA2192478A1; CZ352996A3; PL318106A1; FI970143A0; CN1152915A; KR970704691A; EP0773931A1; HUT76443A

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £87850 New Zealand No. 287850 International No. PCT/DK95/00223 TO BE ENTERED AFTER ACCEPTANCE AND PUBLICATION Priority dates: 20.07.1994; Complete Specification Filed: 07.06.1995 Classificatlon:(6) C07D215/12,18; C07D401/12; A61K31/47 Publication date: 27 May 1998 Journal No.: 1428 Title of Invention: Quinoline derivatives as leukotriene antagonists Name, address and nationality of applicant(s) as in international application form: LEO PHARMACEUTICAL PRODUCTS LTD A/S, Industriparken 55, DK-2750 Ballerup, Denmark NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION WO 96/02506 PCT/DK9.V00223 1 QUINOLINE DERIVATIVES AS LEUKOTRIENE ANTAGONISTS 5 The present invention relates to hitherto unknown compounds useful in the human and veterinary therapy, to pharmaceutical^ acceptable salts thereof, to bioreversible derivatives thereof, to methods for producing said new compounds, to pharmaceutical compositions containing the new compounds, 10 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 arachidcnic acid metabolism, are implicated in a variety of pathophysiologic functions, such as bronchoconstriction, plasma exudation, coronary artery 15 spasm, leucocyte chemotaxis and neutrophil degranulation 1. 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. 20 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-25 alkyl substituted acids with leukotriene antagonistic activity. International patent application No. PCT/DK90/00201 (Publication No. W091/03466) describes a series of quinolyl methoxy substituted N-phenyl substituted isoserine (i.e. 3-amino-2-hydroxypropionic acid) derivatives with good leukotriene antagonistic activity. 30 1 R.A. Lewis, K.F. Austen and R.J. Soberman, New Eng. J. Med. 323 (1990) 645. WO 96/02506 PCI7DK95/00223 287850 International patent application No. PCT/DK93/00254 (Publication No. W094/03431) describes a series of quinolyl ethenyl substituted N-phenyi substituted isoserine derivatives with good leukotriene antagonistic activity. We have now surprisingly found that compounds as defined by gen-5 eral formula I are potent leukotriene antagonists. The new structural features of these compounds, comprising a quinoline ring, optionally substituted by halogen, an £-CH=CH- linkage to a meta-substituted aniline, and further coupled to a substituted benzyl in accordance with formula I, provide compounds with a considerable prolonged dur-10 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; 15 X3 and X4 independently of each other stand for hydrogen, halogen, nitro, cyano, trifluoromethyl, C^-C^ alkyl, C^-C^ alkoxy, carboxy or C^-C^ carbalkoxy; Z is a bond, O, S, S(O), S(0)2, NH or CH2; R1 is hydrogen or a straight or branched, saturated or unsaturated 20 C-pCg hydrocarbon chain; Rg is hydrogen, a straight or branched, saturated or unsaturated C.J-C-J2 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^C^-Rg stands for cycloprop-25 yl; WO 96/02506 PCT/DK9S/00223 > 3 p may be 0 provided that Z is a bond, or p may 1-6 if R1 ■ R3 ■ hydrogen; A is COOR2 or 1H-tetrazoie in which R2 B R1 as defined above or R2 is a pharmaceutically acceptable cation. 5 In particular, 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 0 or S in ortho-position; p is 1; R^ is hydrogen; R3 is hydrogen or a straight or branched, saturated or unsaturated C^Cg hydrocarbon chain, or phenyl; and A is COOR2, where R2 is hydrogen, 10 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-chioroquinolin-2-yl)-ethenyl)phenylaminomethyl)phenoxyJ-2-methyipentanoic acid, E-2-[2-(3-(2-(7-15 chioroquinoiin-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-(7-fluoroquinolin-2-yl)ethenyl)phenylaminomethyl)-phenoxy]hexanoic acid, E-2-[2-(3-(2-(6,7-difluoroquinolin-2-yl)ethenyl)phenyl-aminomethyl)phenoxy]hexanoic acid, and their salts and pure enantiomeric forms. 20 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 comprehend all such possible stereoisomers. Thus, a particularly preferred compound is (S)(+)-E-2-[2-(3-(2-(7-25 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, 30 propionic acid, citric acid, tartaric acid, and maleic acid, without these examples being considered limiting for the invention. Intellectual Property Office of NZ - 2 APR 1998 received WO 96/02506 PCT/DK95/00223 4 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, 5 magnesium, calcium salts, as well as salts with ammonia and suitable non--toxic amines, such as C^-Cg-alkylamines, e.g. triethylamine, C^-Cg alkanolamines, e.g. diethanolamine or triethanolamine, procaine, cycloalkyl-amines, e.g. dicyclohexylamine, benzylamines, e.g. N-methylbenzylamine, N-ethylbenzylamine, N-benzybff-phenethylamine, N.N'-dibenzylethylenediamine 10 or dlbenzylamine, and heterocyclic amines, e.g. morpholine, N-ethylpiperidine and the like. Even if the present compounds are well absorbed after enteral administration, in some cases it can be advantageous to prepare suitable biore-versible derivatives of compounds of the invention, i.e. to prepare so-called 15 prodrugs, preferably derivatives, the physicochemicai 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 derivatives of compounds of the invention, such compounds being prepared by 20 reaction of a secondary amine function of compounds of the invention with formaldehyde 2345 followed by reaction with a suitable acidic compound or activated derivatives of such compounds, for instance with bisulfite ®, N,N-dimethylglycine, N,N-diethyl-£-alanine, or phosphoric acid 2 R.G. Kallen and W.P. Jencks, J. Biol. Chem. 241 (1966) 5864. 25 3 C.J. Martin and M.A. Marini, J. Biol. Chem. 242 (1967) 5736. 4 M. Levy and D.E. Silberman, J. Biol. Chem. 118 (1937) 723. 5 S. Lewin and DA Humphany, J. Chem. Soc. B (1966) 210. 6 B.C. Jain, B.H. Iyer, and P.C. Guha, Science and Culture 11 (1946) 568. 7 S.A. Varia, S. Schuller, K.B. Sloan and V.J. Stella, J. Pharm. Sci., 73 30 (1985) 1068 and following papers. WO 96/02506 PCT/DK95/00223 5 but other suitable acids which form bioreversible derivatives with desirable physicochemicai 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-5 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-10 oxycarbonyloxy)ethyl with from 4 to 6 carbon atoms, and a-aminoalkanoyloxy-methyl with from 2 to 6 carbon atoms. Other preferred esters are lactonyi esters, e.g. 3-phthalidyl, 4-croton-olactonyl or K-butyrolacton-4-yl esters. Also within the scope of the invention are methoxymethyl, cyano-15 methyl, or mono- or dialkyl substituted aminoalkyl esters, e.g. 3-dimethyl-aminoeihyl, 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. 20 These examples are not to be considered as limiting for the inven tion, and other suitable methods to improve the physicochemicai 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-25 arthritis, gout, atherosclerosis, proliferative 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 syndrome, ischemic and reperfusion injury, migraine headache, etc. ®. The 30 8 E.J. Goetzl, D.G. Payan and D.W. Godman, J. Clin. Immunol. 4 (1984) 79. WO 96/02506 PCT/DK95/00223 ► 6 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 5 peritoneal leukocytes labelled with [1-^C]arachidonate and stimulated with the calcium ionophore A23187 9. The compounds of the present invention were observed to inhibit the metabolism at an assay concentration of 10 fiM. Leukotriene antagonists may be identified by observing the contractions elicited in preparations of guinea-pig ileum strips suspended in a physio-10 logical buffer by addition of pure leukotriene D4 (LTD4) 9. When the compounds 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 10~7 M were not 15 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 20 and [3H]LTD4 for binding to the LTD4 receptor9,10. A pICgQ value is determined as the negative logarithm of the molar concentration of antagonist inhibiting [3HJLTD4 binding by 50%. The pICgQ values for the compounds of 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). 25 a I. Ahnfelt-Ronne, D. Kirstein and C. Kaergaard-Nielsen, European J. Pharmacol. 155 (1988) 117. 10 S. Mong, H.-L. Wu, M.O. Scott, M.A. Lewis, MA Clarke, B.M. Weichman, C.M. Kinzig, J.G. Gleason and S.T. Crooke, J. Pharmacol. Exp. Ther. 234 30 (1985) 316. 11 International Appl. No. PCT/DK88/00188 (Publ. No. WO 89/05294), Ex. 9. WO 96/02506 PCT/DK95/00223 IiblSLi Binding of f3H1LTD1 to Quinea-pio luna membranes in the absence or presence of 0.1% human serum albumin folC5Q. mean +SD (n\ or individual values! Compound Absence of albumin Presence of albumin | Example 14 5° • CD • o 9.3 - 9.3 | Example 20 8.9 - 9.1 9.2 - 8.6 Example 12 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 to CO 1 00 00 Example 43 8.7 - 8.3 00 1 CO to Example 44 8.5 - 8.8 8.6 - 8.6 OT 3665 8.2 ± 0.1 (7) 7.3 ± 0.1 (3) 15 The leukotriene antagonistic effect was tested in vivo on LTD^ -induced bronchoconstriction in anaesthetized guinea-pigs9. Intravenously the compounds were administered 10 minutes, orally 4, 8 and 24 hours before the bronchoconstriction. The EDgQ values represent the dose inhibiting the 20 leukotriene induced bronchoconstriction by 50%. The ED5q values were calculated by regression analysis of 2 - 3 doses. The following Table II shows the results. Table II I Compound EDS0 mg/kg i.v 10 min ED50 mg/kg p.o. 4 h ED50 mg/kg p.o. 8 h ED50 mg/kg p.o. 24 h Example 14 0.009 0.17 0.99 10.51 [ Example 20 0.002 0.24 nd. 11.33 I Example 12 0.002 0.24 0.22 3.10 Example 64 0.006 0.15 0.19 7.86 Example 54 0.010 0.60 4.01 19.68 I Example 43 0.0007 0.17 nd. 8.59 I Example 44 0.002 0.04 nd. 2.80 I OT 3665 11 0.42 11.60 > 30 nd. nd. = not done Thus the compounds according to Examples 14, 20, 12, 64, 54, 43, and 44 are more potent and longer lasting as LTD^ antagonists than OT 3665. WO 96/02506 PCT/DK95/00223 9 The present invention also relates to a method for producing the present compounds. In one embodiment, an amine of the formula II, prepared as described 12 or as in Example 2, 5 in which X., and X9 has the above meanings, is reacted with a compound of the formula III, prepared as described 10 or as in Example 25, Y-CH2 in which R1, 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 10 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 15 methanol, ethanol, dimethyl formamide or hexamethyl piosphoric triamide, but EP 0206 751 A Merck Frosst Canada Inc. 13 C.R. Edwards, M.J. Readhead and N.J. Tweedle, J. Heterocyclic Chem. 24 (1987) 495. WO 96/02506 PCT/DK95/00223 10 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 5 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 10 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. 15 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 ^ ^4 ^ IV in which R^, Rg, Xg, X4, A, Z and p have the above meanings, followed by 20 hydrogenation in the presence of a suitable catalyst or by reduction e.g. with 14 J. Bernstein, H.L. Yale, K. Losee, M. Holsing, J. Martins and W.A. Lott, J. Am. Chem. Soc. Z3 (1951) 906. 15 L.A. Flippin, J.M. Muchowski and D.S. Carter, J. Org. Chem. §8 (1993) 2463. 2516 EP 572 712 A Sumitomo Seika Chem. Co. Ltd. WO 96/02506 PCT/DK95/00223 11 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 5 methanol or ethanoi, 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. 10 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 nh-ch2 in which X^, X2, Xg and X4 have the above meanings and Z is O, S or NH, is 15 reacted with a compound of the formula VI which is commercially available or may be prepared by methods as described 17 18 19, 20 17 Y. Ogata, T. Sugimoto and M. Inaishi, in: Organic Synthesis, coll. vol. VI (1988), ed. W.E. Noland (John Wiley, New York) p. 90. 18 D.N. Harpp, L.Q. Bao, in: Organic Syntheses col. vol VIII (1993), ed. J.P. Freemann (John Wiley; New York) p. 190. 2519 B. Koppenhoefer and V. Schurig, in ibid, p. 119. WO 96/02506 PCT/DK95/00223 12 l' Hffc* Vl Ra 5 and in which 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 10 compound II with an appropriate substituted benzaldehyde, followed by reduction with sodium borohydride (NaBH^). The following Scheme I illustrates preparation of compounds of formula V: \ WO 96/02506 PCI7DK95/00223 The present compounds are intended for use in pharmaceutical compositions which are useful in the treatment of the above mentioned diseases. The amount required of a compound of formula (I) (hereinafter 5 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 WO 96/02506 PCT/DK95/00223 14 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 5 of formula (I) is 1 fig to 5 mg of compound per kilogram bodyweight, the most preferred dosage being 1 fjg to 1 mg/kg of mammal bodyweight, for example from 1 A/g to 0.5 mg/kg. While it is possible for an active ingredient to be administered alone as' "< raw chemical, it is preferable to present it as a pharmaceutical formula-10 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. 15 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 20 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 pharmaceutically acceptable carrier therefor and optionally other therapeutic in-25 gredient(s). The carriers) must be "acceptable" in the sense of being compatible 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), 30 transdermal, intra-articular, topical, nasai, or buccal administration. WO 96/02506 PCT/DK95/00223 15 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, 5 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 formulation. Formulations of the present invention suitable for oral administration 10 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 aqueous 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 15 form of a bolus, electuary or paste. Formulations for rectal administration may be in the form of a suppository incorporating the active ingredient and a carrier, or in the form of an enema. Formulations suitable for parenteral administration conveniently 20 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-artisuiar 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 25 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, 30 ointments or pastes; or solutions or suspensions, such as drops. WO 96/02506 PCT/DK9S/00223 16 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 5 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. 10 The compositions may further contain other therapeutically active compounds usually applied in the treatment of the above mentioned pathological conditions, for instance glucocorticoids, anti-histamines, platelet activating factor (PAF) antagonists, anticholinergic agents, methyl xanthines, ^-adrenergic agents, salicylates, indomethacin, flufenamate, naproxen, timegadine, 15 gold salts, penicillamine, serum cholesterol-reducing agents, retinoids, zinc salts, and salicylazosulfapyridin (Salazopyrin). The invention will now be further described in the following Examples: Sxampte 1 20 E-2-f3-(2-Quinolln-2-vhethenvhphenvlaminomethvnphenoxvacatic acid Step 1 E-3-K2-Quinolin-2-v0ethenvn-N-(2-carboxvmethoxvbenzvlideneM-anlline To a solution of E-3-r2-(quinoIin-2-yl)ethenyl]aniline (0.5 g, 2 mmol) (confer EP 0206 751 A Merck Frosst Canada Inc.) in diethyl ether (150 ml), 2-25 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. 30 WO 96/02506 PCT/DK95/00223 17 St?P 2 E-2-f3-(2-Quinolin-2-vhBthenvl}phenvlaminomethvl1phenoxvacatic acid To a suspension of the Schiff base obtained from step 1 (0.41 g, 1 mmol) in ethanoi (10 ml) is added sodium borohydride (0.1 g). This is stirred 5 for 2 hours at room temperature. To this reaction mixture is then added H20 (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, filtered off, washed with methanol and diethyl ether. The title compound is 10 obtained with a melting point of 108-111 °C. Example 2 E-2-[3-(2-(7-Chloroauinolin-2-vl)ethenvlbhenvlaminomethvllphenoxvacetic acid Step 1 E-3-[2-(7-Chloroauinolin-2-vnethenvrinitrobanzane 15 A solution of 7-chloroquinaldine (3.6 g, 20 mmol) and 3-nttrobenz- aldehyde (3.0 g, 20 mmol) in acetic anhydride (20 ml) is sUrred for 4Vi 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. 20 Step 2 E-3-f2-f7-ChlPioouinolin-2-vnethenvnaniline To a solution of SnClg (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. 25 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-f2-f7-Chloroquinolin-2-vl)tethenvn-N-(2-carboxvmethoxvbenzvlid-30 enetaniline To a solution of the aniline (4.23 g, 15 mmol) from step 2 in diethyl ether (500 ml), 2-formylphenoxyacetic acid (2.7 g, 15 mmol) in diethyl ether WO 96/02506 PCT/DK95/00223 18 (300 ml) is added. The mixture is stirred at ambient temperature for 2% 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. 5 Step 4 E-243-(2-/7-ChloroQuinolin-2.vltethenvltohenvlaminomflthvllDhanoxv-acetic acid To a suspension of the SchHf 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 VA hours, while stirring at ambient temperature. The reaction mixture 10 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 temperature 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 15 of 187-189°C. Exampfr 3 E-Ethvl 2-r2-/3-f2-f7-Chloroquinolin-2-vOethenvDphenvlaminomethvnphenoxvT-hexanoate 20 SteP 1 E-2-r3-(2-(7-Ch»oroquinolin-2-vDethenvhphenvlaminomethvnDhenol 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 25 reacted to give the title compound, which is obtained with a melting point of 151-152°C. Step 2 E-Ethvl 2-f2-f3-f2-f7-ChloroauinoHn-2-vi)ethenvnphenvlaminometh-vhohenoxvlhexanoate A mixture of E-2-[3-(2-(7-chloroquinolin-2-yl)ethenyl)phenyiamino-30 methyi]phenol (7.0 g, 18 mmol), ethyl 2-bromohexanoate (4.9 g, 22 mmol), potassium carbonate (10 g, 7? mmol) and acetone (350 ml) is refluxed for 40 hours, whereafter volatile material is removed by evaporation in vacuo. The WO 96/02506 PCT/DK95/00223 19 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 5 (MgS04) and evaporated in vacuo to give the title compound, which after crystallisation from ethanoi is obtained with a melting point of 84-86°C. By following the procedure of Example 3, step 2, but replacing ethyl 10 2-bromohexanoate with the appropriate baromoesters, compounds of Table III are obtained. 15 20 XableJll 25 30 Ex No R1 «2 R3 Melting point °c Remarks 4 h ch2ch3 ch3 - 5 ch3 ch2ch3 ch3 212-213 hydrochloride 6 h ch2ch3 ch2ch3 85-87 7 h ch2ch3 ch(ch3)2 - 8 h ch2ch3 (ch2)7ch3 87-88 9 h ch2ch3 (ch2)9ch3 64-86 10 h CO X o C6H5 143-145 11 h ch2ch3 ch2ch2ch3 138-45 (dec.) WO 96/02506 PCT/DK95/00223 20 Example 12 E-2-r2-(3-(2-(7-Chloroauinolin-2-vhethenvRphenvlaminomethvnDhenoxv1hexan-oic acid A mixture of the ethyl ester from Example 3, step 2 (6.3 g, 12 5 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 recryatallization from ethanoi, it is obtained with a melting point of 181-182°C. 10 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. 25 Table IV 30 Ex. No. R1 R3 Melting point °c 13 h ch3 183-184 14 h ch2ch3 201-202 15 ch3 CO X o 171-172.5 16 h ch(ch3)2 223-224 17 h (ch2)7ch3 130-132 WO 96/02506 PCT/DK95/00223 21 Ex. No. R1 R3 Melting point °c 18 h (ch2)9ch3 115-117 19 h C6H5 198 20 h ch2ch2ch3 193-195 21 ch2ch3 ch2ch3 176-177 g , Example 22 E-Ethvl 2-r3-(2-(7-Chloroauinolin-2-v;!ethenvUohenvlamlnomethvllDhenvhhio acetate 10 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 15 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. 20 Example 23 E-2-f3-(2-f7-Chloroouinolin-2-vhethenvflphenvlaminomethvnphenvlthioacetic The ester from Example 22 (0.5 g, 1 mmol) is hydrolyzed with 2N NaOH (1.0 ml) in ethanoi (10.0 ml). The solution is refluxed for 2 hours and 25 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. ' l WO 96/02506 PCT/DK95/00223 22 Example 24 E-2-f3-(2-fQulnolin-2-vhethenvl)PhenvlaminomethvllPhenvlthioacetic acid Step 1 E-Ethvl 2-r3-f2-fQuinolin-2-vhethenvhphenvlaminomethvllphenvlthio acetate 5 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. 10 Step 2 E-2-r3-(2-(Quinolin-2-vltethenvhphenvlaminomethvltahenvlthioacetic acid By following the procedure from Example 23, but replacing E-ethyl 2-[3-(2-(7-chioroquinoiin-2-yl)ethenyl)phenylaminomethyl]phenylthio acetate with ethyl ester from step 1, the title compound is obtained. 15 The product is triturated with ethyl acetate and gives the title compound with a melting point of 177-179°C. Example 25 E-2-f2-(3-(2-f7-Chloroauinolin-2-vltethenvflphenvlaminomethvnDhenvlthio1hexa-20 noic acid Step 1 E-Ethvl 2-f2-f3-(2-f7-(Chloroauinolin-2-vnethenvhphanvlaminometh-yhphenvlthiolhexanoate By following the procedure of Example 22, but replacing ethyl 2--chloromethylphenylthioacetate with ethyl 2-(2-bromomethylphenylthio)hexano-25 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-r2-f3-f2-r7-Chloroauinolin-2-vnethenvnphenvlaminomethvhphen-vlthiolhexanoic acid By following the procedure of Example 12, but replacing E-ethyl 30 2-[2-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenylaminomethyi)phenoxy]hexanoate with the ester from step 1, the title compound is obtained with a melting point of 169-172°C. WO 96/02506 PCT/DK95/00223 23 Append Preparation of ethvl 2-(2-bromomethvlphenvtthio)hexanoate used in Step 1 (r Vt Stpn A l/\T StefiA^ |( )l CHCOCX^Hs (CH2)3CH3 /CH2OH ^ ^ /\.CH2Br oc ^ oc ^^^S-CHCOOC^Hs \X^S-CHCOOC2H5 (CH2)3CH3 (CH2)3CH3 Step A Ethvl 2-(2-carboxvphenv[thio)hexanoate 5 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 10 three times with diethyl ether. The combined organic extract is dried and evaporated in vacuo to give the title compound, used as such in the next step. Step B Ethvl 2-(2-hvdroxvmethvlphenvtthio)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 15 while stirring at -7°C to -10°C. After stirring for a further 30 minutes, the resulting 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 m!) while stirring at 10°C. After stirring for a further 2 hours, the resulting mixture'is carefully acidified with 4 N hydro-20 chloric acid (100 ml), and is then extracted twice with uie\V>y> v^her. The WO 96/02506 PCT/DK95/00223 24 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 Ethvl 2-(2-Bromomethvlphenvlthio!hexanoate To triphenylphosphine (5.3 g) in acetonitrile (40 ml), bromine (3.2 g) 5 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 10 give 6.0 g of the title compound used as in Example 25, step 1. Example 26 E-2»f2-(3-(2-/7-Chloroguinolln-2-vDethenvnphenvlaminomethvhphenvlaminoT- hexanfflg acid 15 step 1 E-2-T3-(2-(7-(ChloroauinoHn-2-vnethenvl)phenvlamlnomethvnnitro. bgQZfiQS By following the procedure of Example 2, steps 3 and 4, but replacing 2-formylphenoxyacetic acid with 2-nitrobenzaldehyde, the title compound is obtained with a melting point of 150-151 #C. 20 E-2-f3-(2-(7-ChloroQuinolin-2-vltethenvflphenvlaminomethvnaniline 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 25 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 ethanoi, obtained 30 with a melting point of 129-131°C. WO 96/02506 PCT/DK95/00223 25 Step 3 E-Ethvl 2-r2-(3-(2-(7-Chloroauinolin-2-vltethenvnphenvlaminometh-vhphenvlaminolhexanoate 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-5 yl phosphoric triamlde (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 10 evaporated in vacuo to give the title compound as an oil, which is used as such in the following step. Step 4 E-2-r2-(3-(2-(7-Chloroauinolln-2-vltethenvnphenvlaminomethvh-phenvlaminolhexanoic acid By following the procedure of Example 12, but replacing E-ethyl 2-15 [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. 27 20 E-2-r3-(3-(2-f7-Chloroauinolin-2-vDethenvDphenvlaminomethvflphenoxv!hexan- pip acid Step 1 E-3-r3-(2-(7-Chloroquinolin-2-vltethenvnphenvlaminomethvl1phenol By following the procedure of Example 2, steps 3 and 4, but replacing 2-formylphenoxyacetic acid with 3-hydroxybenzaldehyde, the title 25 compound is obtained with a melting point of 179-180°C. Step 2 E-Ethvl 2-r3-(3-(2-<7-Chloroauinolin-2-vnethenvnDhenvlaminomethvn-phenoxvlhexanoate 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 30 substituted phenol of step 1, the title compound is obtained as an oil which is used as such in the following step. WO 96/02506 PCT/DK95/00223 26 step 3 E-2-f3-(3-(2-(7-ChloroauinoHn-2-vltethenvhphenvlaminomethvhphen-oxvlhexanoic acid By following the procedure of Example 12, but replacing E-ethyl 2-[2-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenylaminomethyl)phenoxy]hexanoate 5 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-r4-(3-(2-(7-Chloroauinolin-2-vnethenvnDhenvlaminotohenoxv1hexanoic acid 10 Step 1 E-4-r3-(2-r7-Chloroquinolin.2-vltethenvltahenvlaminomethvllphenol By following the procedure of Example 2, steps 3 and 4, but replacing 2-formylphenoxyacetic acid with 4-hydroxybenzaldehyde, the title compound is obtained with a melting point of 194-195°C. Step 2 E-Ethvl 2.F4-(3-(2-(7-Chloroauinolin-2-vnethenvttohenvlaminometh-15 vltohenoxvlhexanoate 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. 20 Step 3 E-(2-f4-(3-(2-(7-Chloroqulnolin-2-vnethenvnDhenvlaminomethvl}-phenoxvlhexanoic 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 25 point of 173-175°C. Example 29 E-Ethvl 2-f2-(3-f2-f7-Chloroouinolirv»2-vnethenvhphenvlaminomethvlV-6-meth-oxvohenoxvlhexanoate 30 Step 1 E-2-r3-(2-f7-Chloroauinolin-2-vnethenvnDhenvlamlnomethvn-6-meth-pXYPhQOpl PCT/DK95/00223 27 By following the procedure of Example 2, step 3 and 4, but replacing 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-Ethvl 2-f2-(3-f2-f7-chloroquinolin-2-vl>ethenvnphenvtaminometh-vn-6-methoxvphenoxvlhexanoate 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-f2-(3-(2-(7-Chloroouinolin-2-vltethenvflphenv)aminomethvfl-6-methoxvphen-oxvlhexanoic 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. frrcmpiq 31 E-2-r3-(2-(7-ChloroQuinolin-2-vl)ethenvl)phenvlaminomethvnbenzoic acid Step 1 E-3-r2-f7-Chloroquinolin-2-vflethenvn-N-(2-carboxvbenzvlidene)anil-illfi 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 temperature 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 us*id directly in the next step. Step 2 E-2-f3-(2-f7-Chloroquinolin-2-vDethenvftphenvlaminomethvnbenzoic acid To a suspension of the Schiff base (0.82 g, 2 mmol) obtained from step 1 in ethanoi (10.0 ml), sodium borohydride (0.2 g) is added. PCI7DK9S/00223 28 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-Chloroauinolin-2-vhethenvflphenvlaminomethvnbenzoic acid Step 1 E-3-r2-(7-ChloroquinoUn-2-vhethenvl1-N-(4-carboxvbenzvlidene)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 C25H17C,N2°2: %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 ? E-4-f3-(2-(7-Chloroauinolin-2-vhethenvnDhenvlam»nomethvnbenzoic 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-y1)]ethenyt-N-(4-carboxybenzylidene)aniIine, the title compound is obtained with a melting point of 248-250°C. Example 33 E-Ethvl 2-f3-(2-(Quinolin-2-vDethenvnphenvlaminomethvnphenvl acetate A mixture of ethyl 2-bromomethylphenyl acetate (6.0 g, 23 mmol), 3-[2-(quinolin-2-yl)etheny0aniline (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 chromatography (SiC^) to give the title compound with a melting point of 108-109°C. WO 96/02506 PCT/DK95/00223 29 Example 34 E-2.f3-(2-(Quinolin-2-vhethenvDDhenvlaminomethvl1phenvlacatic acid A solution of E-ethyl 2-[3-(2-(quinolin-2-yl)ethenyl)phenylamino-methyl]phenyl acetate (2.7 g, 6.3 mmol) in ethar.ol (25 ml) is at ambient tem-5 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 (Si02) the title compound is obtained with a melting point of 165-166.5°C. 10 Example 35 E-Ethvl 2-f3-(2-(7-Chloroauinolin-2-vltethenvDphenvlaminomethvnphenvl acetate By following the procedure of Example 33, but replacing E-3-[2-15 (quinolin-2-yi)ethenyl]aniline with E-3-[2-(7-chloroquinolin-2-yl)ethenyl]anlline (see Example 2, step 2), the title compound is obtained with a melting point of 94.5-96°C. Example 36 20 E-2-f3-(2-(7-Chloroquinolin-2-vnethenvtiphenvlaminomethvnphenvlacetic 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. 25 Example 37 E-Ethvl 3-r2-(3-(2-f7-Chloroauinolin-2-vl)ethenvnphenvlaminomethvhphenvn-prooionate By following the procedure of Example 33, but replacing ethyl 2-30 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. WO 96/02506 PCT/DK95/00223 30 Sample 39 E-3-f2-(3-2-(7-Chloroguinolln-2-vOethenvnphenvlaminomethvhphenvripropiQniR acid By following the procedure of Example 34, but replacing E-ethyl 5 2-[3-(2-(quinolin-2-yl)ethenyl)phenylaminomethyl]phenyl acetate with E-ethyl 2-[3-(2-(7-chloroquinolin-2-yl)ethenyl)phenylJaminomethylphenyl)propionate, the title compound is obtained with z melting point of 179-181 °C. ftremple 39 10 E-Sodium 2-r2-f3-(2-(7-Chtoroauinolin-2-vnethenvhDhenvlaminomethvnphan-oxvlhexanoate 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) 15 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 20 E-2-f3-(2-(6.7-djfluoroauinolin-2-vnethenvnDhenvlaminomethvHphenoxvacatic acid Step 1 E-3-f2-(6.7-Difluoroquinolin-2-vnethenvnnitrobenzene By following the procedure of Example 2, step 1, but replacing 7-chloroquinaldine with 6,7-difluoroquinaldine, the title compound was obtained 25 with a melting point of 17t>176°C. Step 2 E-3-r2-(6.7-Dtfluoroauinolin-2-vftethenvnaniline The substituted nitrobenzene fror step 1 was reacted with SnC^ following the procedure of Example 2, step 2, to give the title compound with a melting point of 169-171#C. 30 WO 96/02506 PCT/DK95/00223 31 Step 3 E-2-f3-f2-f6.7-dif)uoroqulnolir>-2-vl)ethenvnphenvlaminomethvllDhen-QXYaP9tig agitf By following the procedure) of Example 2, steps 3 and 4, but replacing E-3-[2-(7-(chloroquinolin-2-yl)etheny'] aniline with E-3-[2-(6,7-dlfluoro-5 quinolin-2-yl)ethenyl] aniline, the title compound is obtained with a melting point of 157-159°C. Example 41 E-2-f3-(2-(7-fluorociuinolin-2-vl)ethenvhPhenvlaminomethvllDhenoxvacetic acid 10 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-yi)ethenyl) aniline, the title compound is obtained with a melting point of 199-201 °C. 15 Example 42 E-Ethvl-2-r2-(3-(2-(7-flUQrpquinQlin-2-vl)ethenvl)phenv)aminomethvfiphenoxv-hexanoate §!SEl E-2-f3-(2-(7-fluoroquinolin-2-vhethenvflphenvlaminomethvnphenol By following the procedure of Example 3, step 1, but replacing 20 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. ?teP. 2 E-Ethvl-2-f2-(3-(2-(7-fluoroouinolin-2-vnethenvDphenvlaminomethvlV phenoxvl-hexanoate 25 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) end 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. 30 The title compound is obtained as hydrochloride with a melting point of 174.5-175°C. WO 96/02506 PCT/DK9S/00223 % 32 Example 43 287850 F.9.p./a.f2.{7-fluoraauinolln-2-vnethenvltohenvlamlnomethvltohenoxvl- hexanoic add By following the procedure of Example 12, but replacing the ester 5 from Example 3, step 2, with the ester from Example 42, the title compound is obtained with a melting point of 181-183°C. E-2-f2^3-(2-f6,7-difluoroauinolin«2-vhethenvnphenvlaminomethvl!DhenoxvV 10 hexanoic acid, sodium salt SlfiCJL E-2-r3-(2-(-8.7-dlfluoroQuinolln-2"V0ethenvDphenvlaminomethvn-BhSDfil By following the procedure of Example 3, step 1, but replacing E-2-[3-(2-(7-chloroquinolin-2-yi)ethenyl]aniline with E-2-{3-(2-(6,7-difluoroquin-15 olin-2-yl)ethanyl]aniline, the title compound is obtained with a melting point of 158-160°C. gtW 2 E-Ethvl-2-r2-f3-f2-f6.7-difluoroauinolin.2-vl>ethanvhDhenvlamlno-methvhphflnoxvl-hexanoate By following the procedure of Example 42, step 2, but replacing the 20 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-r2-f3-(2-(6.7-djf)uoroauinolin-2-vnethenvnphenvlaminomethvn-ohenoxvT-hexanoic acid, sodium salt The ester from step 2 (0.85 g, 1.5 mmol) is refluxed for 3% hours in 25 a solution of ethanoi (20 ml) and 2 N aqueous sodium hydroxide (2 ml). Ethanoi is evaporated in vacuo, and the precipitate is filtered off, washed with H20 and diethyl ether. The title compound is obtained as sodium salt with a melting point of 238-240°C. Example 44 30 Intellectual Property Office of NZ - 2 APR 1998 received WO 96/02506 PCT/DK95/00223 33 Examples 45-49 By following the procedure of Example 3, step 1, but replacing saiicylaidehyde with the appropriate aldehydes, compounds of Table V are obtained. 10 TablO V Ex. No. *3 Melting point °C Remarks 45 6-F 183-185 46 4-Br 202-204 47 4-COOH 138- dec. 48 4-N02 193-195 49 4-CH3 176-177 15 20 Examples 50-58 By following the procedu' a of Example 3, step 2, but replacing the phenol with the appropriate phenols from Table V, or following the procedure 25 of Example 12, but replacing the ester with appropriate esters, compounds of Table VI are obtained. \ 30 WO 96/02506 34 PCT/DK95/00223 10 Table VI Ex. No. X3 r2 Melting point °C Remarks 50 6-F C2H5 203-205 Hydrochloride 51 4-Br C2H5 98-100.5 52 4-N02 C2H5 oil 53 6-F H 183-185 54 4-Br H 197-198 55 4-N02 H 221-223 56 4-ch3 H 168-170 57 4-COOH H 173-175 (dec.) 58 4-NH2 H 162-164 (dec.) Example 59 E-2-f3-r2-(7-fluoroaulnolin-2-vnethenvl!phenvlaminomethvnphenoxvacetic acid 30 Step 1 E-3-f2-(7-Fluoroouinolin-2-vflethenvn-N-(2-carboxvmethoxvbenzvHd-enetanillne 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>-ethenyljaniline, the title compound is obtained with a 'netting point of 208-35 210°C. WO 96/02506 PCT/DK95/00223 35 Step 2 E-2-f3-(2-(7-fluoroauinolin-2-vDethenvl)phenvlaminomethvnphanoy\/. arctic 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 5 recrystallization from n-propanol, the title compound is obtained with a melting point of 199-201 °C. Example 90 E-2-r3-(2-(7-chloroauinolin-2-vDethenvl)phenvlaminomethvhohenoxvl heyanoic 10 acid pivalovloxvmethvl 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 dimethylfbrmamide (10.0 ml). 15 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. 20 Example 61 E-2-f3-(2-(7-chloroauinolin-2-vnethenvnphenvlaminomethvnphenoxvl hexanoic acid HN.N-dimethvlaminolcarbonvn methvl 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 25 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. 30 The resulting solid is dissolved in ethyl acetate and filtered. The filtrate is concentrated by colorcn chromatography on silica gel (ethyl acet-ate:hexane, 7:3) and yielded a brown oil. WO 9^/02506 PCT/DK95/00223 36 The resulting solid is dissolved in ethyl acetate and filtered. The filtrate is concentrated by colomn chromatography on silica gel (ethyl acet-ateihexane, 7:3) and yielded a brown oil. The oil is triturated with a solution of HCI/E^O. 5 The title compound is obtained as hydrochloride with a melting point of 99°C dec. Example 62 E-2-f3-(2-(7-chloroauinolln-2-vflethenvflphenvlaminomethvnDhenoxv1 hexanoic 10 acid HN.N-diethvlaminotaarbonvll methvl 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. 15 Example 63 E-2-I3-f2-(7-chloroauinortn-2-vitethenvftphenvlaminomethvftphenoxv1 hexanoic acid HN.N-dialMamlnolcarbonvn methvl ester By following the procedure of Example 61, but replacing 2-chloro-20 -N.N-dimethylacetamide with 2-chloro-N,N-dialtylacetamidel the title compound is obtained and has a melting point of 103-105°C. Example 64 fSV4VE-Ethvl-2-r2-f3-f2-(7-ChloroQuinolin-2-vnethenvnphenvlaminomethvlV 25 Dhenoxvlhexanoic acid Step 1 (+VE-Ethvl-2-f2-(3-(2-f7-Chloroouinotin-2-vr>ethenvnphenvlamino-methvhphenoxvlhexanoate A mixture of E-2-[2-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenylamino- (g> methyl)phenoxy]hexanoate (5.3 g, 10.0 mmol) and Lipozyme (immobilized 30 Mucor miehei lipase) (530 mg, 6.1 Baun/g) in t-butyl ether (100 mi) and phosphate buffer (100 ml, pH 8) was stirred at room temperatur for 120 hours. Filtration through Decaiit followed by washing with ethyl acetate gave two WO 96/02506 PCT/DK9S/00223 37 phases which were separateo. The organic phase was dried (MgS04) and evaporated. The product was then purified by silica gel chromatography (ethyl acetate/diethylether), and crystallized from ethanoi (96%) to give 2.5 g of the title compound used as such in the next step. 5 Melting point: 99-100°C. [a]D20 = 30.3° (c = 1.04, acetone). Step 2 (SW+VE-Ethvl-2-r2-(3-(2-r7-Chloroauinolin-2-vnethenvhDhenvlamino-methvnphenoxvlhexanoic acid To (+)-E-Ethyl-2-[2-(3-(2-(7-Chloroquinolin- 2-yl)ethenyl)phenylamino-10 methyl)phenoxy]hexanoate (10.6 g, 20 mmol) (from step 1) dissolved in methanol (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 15 filtered off, dried, and recrystallized from ethanoi (absolute), yielding a crude product (10.3 g) containing 0.9 eq ethanoi with a melting point of 142/150°C (decomp.), lcr]D20 = 23.4 (c = 0.99, DMSO). Further careful recrystallization from acetonitrile gave the pure product with a melting point of 187-188°C, [o]q2® = 24.5°(c = 1.12, DMSo). 20 Example 65 E-5-2-r2-(3-(2-(7-chloroquinolin-2-v0ethenvflphenvlaminomethvttphenoxvlpent-vMH-tetrazole Step 1 E-2-f2-(3-(2-(7-chloroauinolin-2-vDethenvQphenvlaminomethvhDhen-25 oxvloentvl hvdroxamic acid To E-2-[2-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenylaminomethyf>-phenoxy]hexanoate (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 30 acid (50% aq.) was added until pH 3 - 4 was obtained. The precipitate was filtered and dried in aif yielding 2.1 g of the title compound to be used in the next step. WO 96/02506 PCT/DK95/00223 38 Step 2 E-2-12-(3-(2-(7-chloroquinolln-2-vltethenvnphenvlaminomethvhphan. Qxylpentyl nitrite 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 5 mixture was cooled and then poured into ice water, and made basic with NaHCOg. Extraction with ethyl acetate, drying, and evaporation, followed by chromatography on silica gel yielded 1.8 g of the title compound used in the following step. Step 3 E-5-2-f2-(3-(2-(7-chloroouino)in-2-vflethenvflphenvlaminomethvh.. 10 phenoxvbentvl-1 H-tetrazole To E-2-[2-(3-(2-(7-chloroquinolin-2-yl)ethenyl)pbenylaminomethyl)-phenoxy]pentyl nltrile (1.8 g, 3.3 mmol) (from step 2) in DMF (40 ml, NaNg (1.65 g, 25.4 mmol) and NH^CI (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. 15 The crude product was filtered off and crystallized from ethanoi (absolute) yielding 600 mg of the title compound. Melting point 210-212°C (d^comp.). 20 gxamol&SS Agrqspl (§)(+)-E-2-[2-(3-(2-(7-Chloroquinolin-2-yl)-ethenyl)phenylaminomethyl)phenoxy]hexanoic . acid (the active substance) 1000 mg 25 Sorbitan trioleate 700 mg Monofluorotrichloromethane 595 g Difluorodichloromethane 798 g The active substance is micronized in a jet-mill. The majority of the 30 particles should be less than 5 //m in diameter. A drug concentrate is prepared by dissolving sorbitan trioleate in a small amount of monofluorotrichloromethane and adding the active substance. WO 96/02506 PCT/DK95/00223 39 The concentrate is homogenized carefully. The concentrate is transferred to a sealed tank provided with a refrigeration system. The remaining propellants are added under stirring and cooling to -50°C. Suitable aerosol container are filled with the calculated amount of 5 formulation and sealed immediately with metering valves with suitable actuators. Each puff delivers 50 //g of the active substance. Ewmple 97 Tablet 10 (£)(+)-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-20 ous state in a suitable mixer and moistened with a 5 per cent aqueous solution of methyicellulose 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 25 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. </div>

Claims

<div class="application article clearfix printTableText" id="claims"> WO 96/02506 PCT/DK93/00223 7 Example 99 Formulation for injection (S)(+)-E-2-[2-(3-(2-(7-Chloroquinolin-2-yl)-ethenyl)phenyhminomethyl)phenoxy]hexanoic 5 acid (active substance) 1% Sodium chloride q.s. Water for injection to make 100% 10 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. WO 96/02506 41 WHAT Wf£ CLAIM IS: A compound of the formula I PCT/DK95/00223 287850 10 15 in which 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-C^ alkyl, C-j-C^ alkoxy, carboxy or C^-C^ carbalkoxy; Z is a bond, O, S, S(O), S(0)2, NH or CH2; is hydrogen or a straight or branched, saturated or unsaturated C^-Cg hydrocarbon chain; R3 is hydrogen, a straight or branched, saturated or unsaturated C-pC^ 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 R^C^-Rg stands for cyclopropyi; 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-tetrazoie in which R2 = R1 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 20 independently of each other stand for hydrogen, fluoro or chloro; X3 stands for hydrogen; X^ 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^-Cg hydrocarbon chain, or phenyl; and A is COOR2, where R2 is hydrogen, C^-C3 alkyl, an alkali metal cation, or 25 tetrazol-5-yl. WO 96/02506 PCT/DK95/00223 42
3. A compound according to claim 1 in which the salt Is selected' 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 add, and maleic acid, and lithium, sodium, potassium, magnesium, caldum salts, as well as salts with ammonia, C^Cg-alkylamines, C^-Cg aikanolamines, procaine, cycioalkylamines, benzylamines, and heterocydic 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)ethenyi)phenylaminomethyl)phen-oxy}-2-methylpentanoic add; E-2-[2-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenylaminomethyl)phen-oxy]hexanoic acid; E-2-[2-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenyiaminomethyl)-4- bromophenoxy] hexanoic acid; E-2-[2-(3-(2-(7-fluoroquinolin-2-yl)ethenyl)phenylaminomethyl)-phenoxyjhexanoic acid; and E-2-[2-(3-(2-(6,7-difluoroquinolin-2-yl)ethenyl)phenylaminomethyl)- phenoxy]hexanoic acid; and their salts and pure enantiomeric forms.
5. A compound of daim 1 which is (£)(+)-E-2-[2-(3-(2-(7-Chloroquin-olin-2-yl)-ethenyl)phenylaminomethyl)phenoxy]hexanoic add.
6. A pharmaceutical preparation, containing a compound according to any one of claims 1-5 alone or together with the necessary auxiliary agents. Intellectual Property Office of N2 - 2 APR !S98 received WO 96/02506 % 43 PCT/DK95/00223 287850
7. Method for producing a compound of formula I according to claim 1, in which a) an amine of the formula II II in which and ^ has the above meanings, is reacted with a compound of the formula III Intellectual Property Office of NZ - 2 APR 1298 received WO 96/02506 PCT/DK95/00223 44 y-ch2 ■A III in which R.j, Rg, X3, X4, A, Z and p have the above meanings, and Y is capable of forming a "good leaving group"; or 5 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 10 c) a compound of the formula V b) an amine of the formula II is converted to a compound of the formula I by reaction with a carbonyl compound of the formula IV IV x V xi in which X.jw *3 and X4 have the above meanings and Z is O, S or NH, is reacted with a compound of the formula VI . WO 96/02506 PCT/DK95/00223 45 287850 f—fc]—A VI llJp Ra and in which R^, Rg, A, p and Y have the above meanings, to form the desired compound of formula I.
8. The use of a compound of claim 1 in the manufacture of a medicament for the treatment and prophylaxis of a disease, said disease being asthma, allergy, rhoumatoid arthritis, spondylarthritis, gout, atherosclerosis, proliferative and inflammatory skin disorders, chronic inflammatory bowel disease, and other inflammatory conditions, vasospasm associated with angina pectoris, pulmonary hypertension, cystic fibrosis, the adult respiratory distress syndrome, ischemic and reperfusion injury, or migraine headache.
9. Use according to claim 8, substantially as herein described.
10. A pharmaceutical preparation according to claim 6, substantially as herein described.
11. A compound of formula I, as defined in claim 1, substantially as herein described.
12. A method ?-t producing a compound of formula I, as defined in claim 1, substantially as herein described with reference to the Examples.
13. A compound of formula I whenever produced by a method according to claim 7 or 12. END OF CLAIMS Intellectual Property Office of N2 ■ 2 apr :::s Received </div>