AU686820B2 - Quinoline derivatives as leukotriene antagonists - Google Patents

Description

WO 96/02506 PCT/DK95100223 1 QUINOLINE 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 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 aminophenoxyalkyl acids with laukotriene antagonistic and 5-lipoxygenase inhibitory activity.

International patent application No. PCT/US89/02692 (Publication No.

WO 89/12629) describes a series of quinolylethenyl-phenoxymethyl phenoxyalkyl 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 3-amino-2-hydroxypropionic acid) derivatives with good leukotriene antagonistic activity.

1 R.A. Lewis, K.F. Austen and R.J. Soberman, New Eng. J. Med. 323 (1990) 645.

d~ W O 96/02506 PC1I/I)K95100223 2 International patent application No. PCT/DK93/00254 (Publication No.

W094/03431) 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 general 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 accordance with formula I, provide compounds with a considerable prolonged duration of action maintaining the potent leukotriene antagonist activity, especially in the presence of human serum albumin.

The present compounds have the general formula I X3

R

H NC A NH p X2

R

3 in which X 1 and X 2 independently of each other stand for hydrogen or halogen;

X

3 and X 4 independently of each other stand for hydrogen, halogen, nitro, cyano, trifluoromethyl, C 1

-C

4 alkyl, C1-C4 alkoxy, carboxy or C1-C 4 carbalkoxy; Z is a bond, 0, S, S(0) 2 NH or CH 2

R

1 is hydrogen or a straight or branched, saturated or unsaturated C1-C 6 hydrocarbon chain; R3 is hydrogen, a straight or branched, saturated or unsaturated

C

1

-C

12 hydrocarbon chain, unsubstituted or substituted phenyl or unsubstituted or substituted benzyl, the above mentioned substituents being one or more of X 3 and X 4 as defined above; or the group R 1 -[C]p-R 3 stands for cyclopropyl; WO 96/02506 PCTiDK95/00223 3 p may be 0 provided that Z is a bond, or p may be an integer from 1-6 if R 1 R3 hydrogen; A is COOR 2 or 1H-tetrazole in which R2 R1 as defined above or R2 is a pharmaceutically acceptable cation.

In particular, X 1 and X 2 independently of each other stand for hydrogen, fluoro or chloro; X 3 stands for hydrogen; X 4 stands for hydrogen, fluoro, chloro or bromo; Z is 0 or S in ortho-position; p is 1; R 1 is hydrogen;

R

3 is hydrogen or a straight or branched, saturated or unsaturated C1-C6 hydrocarbon chain, or phenyl; and A is COOR 2 where R2 is hydrogen, C1-C3 alkyl, an alkali metal cation, or 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, 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)phenylaminomethyl]phenoxyhexanoic acid, E-2-[2-(3-(2-(6,7-difluoroquinolin-2-yl)ethenyl)phenylaminomethyl)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 comprehend all such possible stereoisomers.

Thus, a particularly preferred compound is 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.

\O 96/102506 PCT/KI)95100223 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, magnesium, calcium salts, as well as salts with ammonia and suitable non- -toxic amines, such as C 1

-C

6 -alkylamines, e.g. triethylamine, C1-C6 alkanolamines, e.g. diethanolamine or triethanolamine, procaine, Gycloalkylamines, 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 administration, in some cases it can be advantageous to prepare suitable bioreversible 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 derivatives of compounds of the invention, such compounds being prepared by reaction of a secondary amine function of compounds of the invention with formaldehyde 2 3 4 5 followed by reaction with a suitable acidic compound or activated derivatives of such compounds, for instance with bi- 6i 7 sulfite 6, N,N-dimethylglycine, N,N-diethyl-p-alanine, or phosphoric acid 2 R.G. Kallen and W.P. Jencks, J. Biol. Chem. 241 (1966) 5864.

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.

S. Lewin and D.A. Humphany, J. Chem. Soc. B (1966) 210.

6 B.C. Jain, B.H. lyer, 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 (1985) 1068 and following papers.

-oL~ L ~L ~C~ WO 9,/0)25)(6 PCT/D (K95/00223 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, alkoxycarbonyloxyalkyl or aminoacyloxyalkyl esters, which are readily hydrolyzed in vivo or in vitro.

Among the above esters the following are preferred: alkanoyloxymethyl 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, I-(alkoxycarbonyloxy)ethyl with from 4 to 6 carbon atoms, and a-aminoalkanoyloxymethyl with from 2 to 6 carbon atoms.

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

Also within the scope of the invention are methoxymethyl, cyanomethyl, or mono- or dialkyl substituted aminoalkyl esters, e.g. 3-dimethylaminoethyl, 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 invention, and other suitable methods to improve the physicochemical properties and solubility of the compounds concerned can be used as well.

inhibitors and leukotriene antagonists are of potential interest in the therapy of asthma, allergy, rheumatoid arthritis, spondyloarthritis, 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. 8. The 8 E.J. Goetzl, D.G. Payan and D.W. Godman, J. Clin. Immunol. 4 (1984) 79.

WO 96/02506 PCT/I) K95/00223 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 peritoneal leukocytes labelled with [1- 1 4 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 pM.

Leukotriene antagonists may be identified by observing the contractions elicited in preparations of guinea-pig ileum strips suspended in a physiological buffer by addition of pure leukotriene D 4

(LTD

4 9. When the compounds of the present invention were added to the ileum preparation before addition of LTD 4 a significant inhibition occurred of the specific LTD 4 -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 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]LTD 4 for binding to the LTD 4 receptor 9,10. A plC 5 0 value is determined as the negative logarithm of the molar concentration of antagonist inhibiting 3

H]LTD

4 binding by 50%. The plC 5 0 values for the compounds of the present invention are unaffected by the presence of 0.1% human serum albumin, contrary to the case for OT 3665 11 (see Table I).

9 1. Ahnfelt-Ronne, D. Kirstein and C. Kaergaard-Nielsen, European J.

Pharmacol. 155 (1988) 117.

S. Mong, Wu, M.O. Scott, M.A. Lewis, M.A. Clarke, B.M. Weichman, C.M. Kinzig, J.G. Gleason and S.T. Crooke, J. Pharmacol. Exp. Ther. 234 (1985) 316.

11 International Appl. No. PCT/DK88/00188 (Publ. No. WO 89/05294), Ex. 9.

0 96/()2506 PCT/DI)K95/00223 Table I Pindinq of [3HILTD4 to guinea-pig lung membranes in the absence or presence of 0.1% human serum albumin (plC 5 0 mean +SD (n) or individual values) Compound Absence of albumin Presence of albumin Example 14 9.1 9.0 9.3 9.3 Example 20 8.9 9.1 9.2 8.6 Example 12 8.5 0.1 8.7 0.2 Example 64 8.7 0.3 9.0 0.3 Example 54 8.4 8.5 8.8 8.6 Example 43 8.7 8.3 8.6 8.4 Example 44 8.5- 8.8 8.6 8.6 OT 3665 8.2 0.1 7.3 0.1 (3) The leukotriene antagonistic effect was tested in vivo on LTD 4 induced bronchoconstriction in anaesthetized guinea-pigs 9 Intravenously the compounds were administered 10 minutes, orally 4, 8 and 24 hours before the bronchoconstriction. The ED 5 0 values represent the dose inhibiting the leukotriene induced bronchoconstriction by 50%. The ED 5 0 values were calculated by regression analysis of 2 3 doses. The following Table II shows the results.

I a r 4, -C_ Table II Compound ED 5 0 mg/kg ED 5 0 mg/kg ED 5 0 mg/kg ED 5 0 mg/kg i.v. 10 min p.o. 4 h p.o. 8 h p.o. 24 h Example 14 0.009 0.17 0.99 10.51 Example 20 0.002 0.24 nd. 11.33 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 Example 43 0.0007 0.17 nd. 8.59 Example 44 0.002 0.04 nd. 2.80 OT 3665 1 1 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 4 antagonists than OT 3665.

1" II WO 96/(125106 PCT/DK 95/00223 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,

X,

H

X2 N O in which X 1 and X 2 has the above meanings, is reacted with a compound of the formula III, prepared as described 13 or as in Example

-A

p

Y-CH

2 in which R 1

R

3

X

3

X

4 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 dialkylphosphate 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 12 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.

I Ir k bdsl*IL~ 0 ~ns WO 96/02506 'PC'T/DK95/00223 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 Ill 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 13141516 available or are prepared as described in R1 OHCZ C A

IV

in which R 1

R

3

X

3

X

4 A, Z and p have the above meanings, followed by 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. 73 (1951) 906.

L.A. Flippin, J.M. Muchowski and D.S. Carter, J. Org. Chem. 58 (1993) 2463.

16 EP 572 712 A Sumitomo Seika Chem. Co. Ltd.

-~I

W\VO 6/0)250(6 PCT/D) C95/10223 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 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 X H

X

3 X4 ZH

SNH-CH

2 V X2H in which X 1

X

2

X

3 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 may be prepared by methods as described 17 18 19 17 Y. Ogata, T. Sugimoto and M. Inaishi, in: Organic Synthesis, coll. vol. VI (1988), ed. W.E. Noland (John Wiley, New York) p. 18 D.N. Harpp, L.Q. Bao, in: Organic Syntheses col. vol VIII (1993), ed. J.P.

Freemann (John Wiley, New York) p. 190.

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

WO< P( /i)(O/002l2 12 R1

I

Y C-A

VI

R3 and in which R 1

R

3 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 reduction with sodium borohydride (NaBH 4 The following Scheme I illustrates preparation of compounds of formula V': WO 9/025106 PC'T/I) 1(5/00223 13 SCHEME I X1, I TT

CHO

MeOH

I-

NaBH 4 EtOH or MeOH

N-CH

2

H

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 (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 for systemic treatment is 0.1 to 20 mg per kilogram bodyweight, the most preferred dosage I I WO( 90,/02506, PCT/D195/00223 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 of formula is 1 ug to 5 mg of compound per kilogram bodyweight, the most preferred dosage being 1 jg to 1 mg/kg of mammal bodyweight, for example from 1 ug 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 formulation. 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 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 pharmaceutically acceptable carrier therefor and optionally other therapeutic ingredient(s). The carrier(s) 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), transdermal, intra-articular, topical, nasal, or buccal administration.

I

96/02500 PC'"171)K95/(00223 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 formulation.

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 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 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 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 ingrediert for both intra-articular and ophthalmic administration.

Formulations suitable for topical or ophthalmic administration include liquid or semi-liquid preparations, such as oil-in-water or water-in-oil emulsions, ointments or pastes; or solutions or suspensions, such as drops.

II I WO %/(025(06 P("ITI) 195/00223 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 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 pathological conditions, for instance glucocorticoids, anti-histamines, platelet activating factor (PAF) antagonists, anticholinergic agents, methyl xanthines, P-adrenergic 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-[3-(2-Quinolin-2-yl)ethenyl)phenylaminomethyl]phenoxyacetic acid Step 1 E-3-[(2-Quinolin-2-yl)ethenvll-N-(2-carboxvmethoxvbenzvlidene)]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), 2formylphenoxyacetic 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 201-203oC.

This compound is used directly in the next step.

\WO 2506 l)95/(00223 17 Step 2 E-2-[3-(2-Quinolin-2-yl)ethenyl)phenylaminomethyllphenoxyacetic 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 This is stirred for 2 hours at room temperature. To this reaction mixture is then added H 2 0 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 obtained with a melting point of 108-111 C.

Example 2 E-2-[3-(2-(7-Chloroquinolin-2-vl)ethenyl)phenylaminomethyllphenoxyacetic acid Step 1 E-3-[2-(7-Chloroquinolin-2-yl)ethenyllnitrobenzene A solution of 7-chloroquinaldine (3.6 g, 20 mmol) and 3-nitrobenzaldehyde (3.0 g, 20 mmol) in acetic anhydride (20 ml) is stirred for 4/2 hours at 1300C. 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 181-1830C, is used directly in the next step.

Step 2 E-3-[2-(7-Chloroquinolin-2-yl)ethenyllaniline To a solution of SnCI 2 (15.0 g) in concentrated hydrochloric acid 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 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 127-1280C, which is used directly in the next step.

Step 3 E-3-[2-(7-Chloroquinolin-2-vl)]ethenyll-N-(2-carboxvmethoxvbenzylidene)aniline 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 a I I I~ /(125(06 PC'r/) )K95/00223 18 (300 ml) is added. The mixture is stirred at ambient temperature for 2/2 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.

Step 4 E-2-[3-(2-(7-Chloroquinolin-2-yl)ethenyl)phenylaminomethyl]phenoxyacetic 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 1/2 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 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 of 187-189 0

C.

Example 3 E-Ethyl 2-[2-(3-(2-(7-Chloroquinolin-2-l)ethenvl)phenvlaminomethvl)phenoxy]hexanoate Step 1 E-2-r3-(2-(7-Chloroquinolin-2-vl)ethenvl)phenylaminomethylphenol By following the procedure of Example 2, step 3, but replacing 2-formylphenoxyacetic acid with salicylaldehyde, E-3-[2-(7-chloroquinolin-2yl)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 151-1520C.

Step 2 E-Ethvl 2-r2-(3-(2-(7-Chloroquinolin-2-yl)ethenvl)phenvlaminomethyl)phenoxylhexanoate A mixture of E-2-[3-(2-(7-chloroquinolin-2-yl)ethenyl)phenylaminomethyl]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 hours, whereafter volatile material is removed by evaporation in vacuo. The WO '9/0250S PCTDK95/(100223 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 hydrogencarbonate (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.

NH R1 15l H oc

COOR,

R

3 Table III Ex R 1

R

2

R

3 Melting Remarks No point °C 4 H CH 2

CH

3

CH

3

CH

3

CH

2

CH

3

CH

3 212-213 hydrochloride 6 H CH 2

CH

3

CH

2

CH

3 85-87 7 H CH 2

CH

3

CH(CH

3 2 8 H CH 2

CH

3

(CH

2 7

CH

3 87-88 9 H CH 2

CH

3

(CH

2 9

CH

3 64-66 H CH 3

C

6

H

5 143-145 11 H CH 2

CH

3

CH

2

CH

2

CH

3 138-45 (dec.) cl I \VO 9/1025016 PC'I/DK95/00223 Example 12 E-2-[2-(3-(2-(7-Chloroauinolin-2-vl)ethenvl)phenylaminomethyl)phenoxy]hexanoic 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 Ex. No. R 1 R3 Melting point °C 13 H CH 3 183-184 14 H CH 2

CH

3 201-202

CH

3

CH

3 171-172.5 16 H CH(CH 3 2 223-224 17 H (CH 2 7

CH

3 130-132

I

VO 96/012506 PCT/I)K95/00223 Ex. No. R 1

R

3 Melting poir °CO 18 H (CH 2 9

CH

3 115-117 19 H C 6

H

5 198 H CH 2

CH

2

CH

3 193-195 21 CH 2

CH

3

CH

2

CH

3 176-177 Example 22 E-Ethyl 2-[3-(2-(7-Chlorocuinolin-2-vl)ethenvl)phenylaminomethyllphenvlthio 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-chloromethylphenylthio 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-[3-(2-(7-Chloroquinolin-2-vl)ethenyl)phenylaminomethyl]phenylthioacetic 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 refiuxed for 2 hours and diluted with water (10.0 ml). After acidifying the solution with 3N acetic acid 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 0

C.

i WO 96/02506 V~ 9/02506PC'I'I)J(95/00223 22 Example 24 E-2-[3-(2-(Quinolin-2-yl)ethenyl)phenylaminomethyllphenylthioacetic acid Step 1 E-Ethyl 2-r3-(2-(Quinolin-2-vl)ethenvl)phenvlaminomethyllphenvlthio acetate By fc~lowing the procedure of Example 22, but replacing chloroquinolin-2-yl) .thenyl]aniline with E-3-[2-(quinolin-2-yl)ethenyl]aniline (see Example 1, step the title compound is obtained after flash chromatography using ethyl acetate/lhexane and used as such for the next step.

Step 2 E-2-[3-(2-(Quinolin-2-yl)ethenvl)phenvlaminomethyllphenvlthioacetic acid By following the procedure from Example 23, but replacing E-ethyi 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 E-2-r2-(3-(2-(7-Chloroquinolin-2-vflethenvl)phenylaminomethyl)phenvlthiolhexanoic acid Step 1 E-Ethyl 2-f2-(3-(2-(7-(Chloroguinolin-2-yl)ethenvl)phenvlaminomethvI) phenylth iol hexanoate By following the procedure of Example 22, but replacing ethyl 2- -chloromethylphenylthioacetate with ethyl 2-(2-bromomethylphenylthio)hexanoate (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-[2 (3-(2-(7-Chloroquinolin-2-yi)ethenvl)phenvlaminomethvl)phenylthiolhexanoic acid By following the procedure of Example 12, but replacing E-ethyl 2-[2-(3-(2-(7-chloroq uinolin-2-yl)ethenyl)phenylaminomethyl)phenoxy]hexanoatLe with the ester from step 1, the title compound is obtained with a melting point of 169-17211C.

WO 6/025116 PCT/I)K'95/00223 23 Appendix Preparation of ethyl 2-(2-bromomethylphenylthio)hexanoate used in Step 1 COOH

COOH

Oa SH SSt AS-CHCOOC 2

H

S(CH

2 3

CH

3 Step CCHBr

S-CHCOOC

2

H

5 C S-CHCOOC 2

H

I I

(CH

2 3

CH

3

(CH

2 3

CH

3 Step A Ethyl 2-(2-carboxvphenvlthio)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 evaporated in vacuo to give the title compound, used as such in the next step.

Step B Ethyl 2-(2-hvdroxvmethvlphenylthio)hexanoate To a mixture of the carboxylic acid (6.0 g) from step A, triethylamine ml) and tetrahydrofuran (50 ml), ethylchloroformate (1.9 g) is slowly added while stirring at -7 0 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 ml) while stirring at 10 0 C. After stirring for a further 2 hours, the resulting mixture is carefully acidified with 4 N hydrochloric acid (100 ml), and is then extracted twice with diethyl ether. The I L I~L \VO 96/02500 ("1I)1)9/0(10223 24 organic extract is washed with brine, dried and evaporated in vacuo to give 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-[2-(3-(2-(7-Chloroauinolin-2-yl)ethenyl)phenylaminomethyl)phenvlaminolhexanoic acid Step 1 E-2-[3-(2-(7-(Chloroquinolin-2-vl)ethenyl)phenylaminomethyl]nitrobenzene 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.

Step 2 E-2-r3-(2-(7-Chloroquinolin-2-vl)ethenvl)phenylaminomethyllaniline 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 mix+ire 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 filtrstion, 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 129-1310C.

WO 96102506 WO 9602506PCT[IDK05/00223 Step~ 3 E-Ethyl hlorog u inolin-2-y)ethe nvl Phe nylamin omethvl)phenylaminolhexanoate A mixture of the aniline (1.6 g, 4 mmol) from step 2, ethyl 2-bromnohexanoate (1.8 g, 8 mmol), sodium hydrogen carbonate (1.8 g) and hexamethyl phosphoric triamide (30 ml) is stirred at 6000 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 6000 for a further 72 hours. The resulting mixture is poured onl ice/water and is extracted three times with diethyl ether. The combined organic extract is washed with water, dried and 3vaporated in vacuo to give the title compound as an oil, which is used as such in the following step.

Step 4 loro u inol in-2-vl)ethe nyl) phenylam inomnethyl)- Dhenvlaminolhexanoic acid By following the procedure of Example 12, but replacing E-ethyl 2- (2-(3-(2-(7-chloroq uinolin-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 g-2-_3-1-(2-(7-Chloropuinolin-2-l)ethenylmphenylarinomethyl)phenoxylhexan oic acid Step 1 E-3-[3-(2-(7-Chlorocauinolin-2-yl)ethenvl)phenvlaminomethvllphenoI By following the procedure of Example 2, steps 3 and 4, but repl acing 2-formylp hen oxya cetic acid with 3-hydroxybenzaldehyde, the title compound is obtained with a melting point of 179-1800C.

Step 2 E-Ethvl 2-f 3-(3-(2-(7-Chlorop uinolin-2-vl)ethenvlhphenylam inomethyllphenoxylhexartoate By following the procedure of Example 3, step 2, but replacing E-2- [3-(2-(7-chloroquinolin-2-yl)ethenyl)phenylaminomethyl]pheno 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.

W0()90/02506 26 Step 3 E-2-[3-(3-(2-(7-Chlorocuinolin-2-vl)ethenl)phenlaminomethl)phenoxylhexanoic acid By following the procedure of Example 12, but replacing E-ethyl 2-[2-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenylaminomethyl)phenoxyjhexanoate with the ethyl ester of step 2 above, the title compound is obtained with a melting point of 183-185 0

C.

Example 28 E-2-[4-(3-(2-(7-Chloropuinolin-2-vl)ethenvl)phenvlamino)phenoxylhexanoic acid Step 1 E-4-13-(2-(7-Chloroguinolin-2-vl)ethenvl)phenylaminomethllphenoI By following the procedure of Example 2, steps 3 and 4, but replacing 2-formylphenoxyacetic acid with 4-hy- roxybenzaldehyde, the title compound is obtained with a melting point of 1 94-1 951C.

Step 2 E-Ethyl 2-f4-(3-(2-(7-Chloropuinolin-2-yI)ethenyl)phenvlaminometh- Alphenoxylhexanoate By following the procedure of Example 3, step 2, but replacing E-2-[3-(2-(7-chloroquinolin-2-yl)ethenyl)phenylaminomethyl]pheno 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-(2-[4-(3-i-(7-Chlorouinolin-2-l)ethenyl)phenylaminomethvl)phenoxvlhexanoic acid By following the procedure of Example 12, but replacing E-ethyl 2-[2-(3-(2-(7-chloroquinolin-2-y)ethenyl)phenylam inomethyf)phenoxyjhexanoate with the ethyl ester of step 2 title compoundi is obtained with a melting point of 173-175*C, Example 29 E-Ethyl 2-r2-(3-(2-(7-Chloroauinolin-2-yvethenl)p henylaminomethvl)-6-methoxyphenoxv hexanoate Step 1 E-2-f3-(2-(7-Chloroquinolin-2-v)ethenvl) phenlaminomethyll-6-methoxvphenol WO 96/02506 XV() 9602506 T/D [95/00223 27 By following the procedure of Example 2, step 3 and 4, but replacing 2-formylphenoxyacetic acid with 2-hydroxy-3-methoxybenzaldehyde, the title compouncd is obtained with a melting point of 139-140.50C.

Step 2 E-Ethyl 2-[.2-(3-(2-(7-chloroguinolin-2-vl)ethenvF)phenylaminomethvl'-6-methoxvphenoxylhexanoate By following the procedure of Example 3, step 2, but replacing E-2-[3-(2-(7-chloroquinolin-2-yl)ethenyl)pnenylaminomethyllpheno with the phenol from step 1, the title compound is obtained with a melting point of 101-102.50C.

Example hlorog uinolin-2-vl) ethenyl) phe nylam inomethyl)-6-meth oxvp henoxy~hexanoic acid By following the procedure of Example 12, but replacing E-ethyl 2-[2-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenylamino)phenoxyjjhexanoate with the ethyl ester of Example 26, step 2, the title compound is obtained with a melting point of 173-174 0

C.

Example 31 E-2-f3-(2-(7-Chloropuinolin-2-vl'iethenvl)phenylaminomethyllbenzoic acid Step 1 E-3-[2-(7-Ch loropquinolin-2-yl)ethenvll-N-(2-carboxybenzylidene)anilmne 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 226-2281C.

This compound is used directly in the next step.

Step 2 E-2-[3-(2-(7-Chlorop Linolin-2-vl)ethenvl)phenvlami,,1omethyllbenzoic acid To a suspension of the Schiff base (0.82 g, 2 mro'ol) obtained from step 1 in ethanol (10.0 ml), sodiumn borohydride (0.2 g) is added.

WO 96/02506 PCT/DI 95/00223 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 223-2260C.

Example 32 E-4-[3-(2-(7-Chloroquinolin-2-vl)ethenvl)phenvlaminomethl]benzoic acid Step 1 E-3-[2-(7-Chloroquinolin-2-yl)ethenyll-N-(4-carboxvbenzylidene)aniline By following the procedure of Example 31, step 1, but replacing 2carboxybenzaldehyde with 4-carboxybenzaldehyde, the title compound is obtained with a melting point over 250 0

C.

Analysis: Calculated for C 2 5

H

1 7

CIN

2 0 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 2 E-4-f3-(2-(7-Chloroquinolin-2-yl)ethenvl)phenylaminomethyl]benzoic 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 chloroquinolin-2-yl)]ethenyl-N-(4-carboxybenzylidene)aniline, the title compound is obtained with a melting point of 248-2500C.

Example 33 E-Ethyl 2-[3-(2-(Quinolin-2-yl)ethenyl)phenylaminomethyllphenyl 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 chromatography (Si02) to give the title compound with a melting point of 108- 1090C.

~s WO 96102506 '6102506PC'rI) 195100223 29 Example 34 E-2-f3-(2-(Quinolin-2-yl)ethenyl)phenylaminomethvllphenylacetic acid A solution of E-ethyl 2-f 3-(2-(quinolin-2-yl)ethenyl)p henylaminomethyl]phenyl acetate (2.7 g, 6.3 mmol) in ethanol (25 ml) is at ambient ternperature slowly added to 2 N sodium hydroxide (25 ml). The mixture is then stirred at 5000 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 (SiC 2 the title compound is obtained with a melting point of 165-166.50C.

Example E-Ethyl 2-[3-(2-(7-Chloroguinolin-2-yl)ethenyl)phenylaminomethyllphenyI acetate 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 E.-ample 2, step the title compound is obtained with a melting point of 94.5-960C.

Example 36 E-2-[3-(2-(7-Chloroqu inolin-2-vl~ethenyl)phenylaminomethvliphenylacetic acid By following the procedure of Example 34, but replacing E-ethyl 2-[3-(2-(quinolin-2-yl)ethenyl)phenylaminomethyl~pheny acetate with E-ethyl 2-[3-(2-(7-chloroquinolin-2-yl)ethenyl)phenylaminomethyljphenyl acetate, the title compound is obtained with a melting point of 174-1760C.

Example 37 E-Ethyl 3-[2-(3-(2-(7-Chlorociuinolin-2-yl)ethenyl)phenylaminomethl)phenyllpropionate By following the procedure of Example 33, but replacing ethyl 2bromomethylphenyl acetaie with ethyl 2-bromomethylphenyl-3-propionate, the title compound is obtained as a hydrochloride dihydrate with a melting point of 1731C dec.

VN/096/02506 P CTI/I)105/00223 Example 38 E-3-f2-(3-2-(7-Chloroquinolin-2-yl)ethenvl)phenlaminometh flohenflpropionic acid By following the procedure of Example 34, but replacing E-ethyl 2-[3-(2-(quinolin-2-yl)ethenyl)phenylaminomethyl]pheny 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 *0.

Example 39 E-Sodium 2-[2-(3-(2-(7-Chloropuinolin-2-vl)ethenvl)iphenylaminomethvl)phenoxyihexanoate hloroq u inoli n-2-yl) ethenyl) phenylam inomethyl) phenoxy]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 12000.

Example E-2-f3-(2-(6,7-difluorocjuinolin-2-yl')ethenyl')phenylaminomethyllphenoxvacetic acid Step 1 E-3-[2-(6,7-Difluoropuinolin-2-vl)ethenvllnitrobenzene 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-[2-(6,7-Difluoropuinolin-2-vlbethenllaniline The substituted nitrobenzene from step 1 was reacted with SnCI 2 fuiowing the procedure of Example 2, step 2, to give the title compound with a melting point of 169-171'C.

NVO 96/62506 96(~25O6PCIIII) 195/00223 31 Step 3 E-2-r3-(2-(6,7-difluoroquinolin-2-vl)ethenl)cphenvlaminomethlphen oxyacetic acid By following the procedure of Example 2, steps 3 and 4, but replacing E-3-[2-(7-(chloroquinolin-2-yl)ethenyl] aniline with E-3-[2-(6,7-difluoroquinolin-2-yl)ethenyl] aniline, the title compound is obtained with a melting point of 157-159'C.

Example 41 E-24[34'247 -fluoroquinolin-2-vl)ethenyl)phenylaminomethyllp~henoxyacetic acid By following the procedure of Example 2, steps 3 and 4, but replacing E-3-[2-(7-(chloroquinolin-2-yl)ethenyl)aniline with E-3-[2-(7-fluoroquinoln-2-yl)ethenyl) aniline, the title compound is obtained with a melting point of 199-201 aC.

Example 42 E- Ethyl-2-r2-( 3-(2-(7-fluoroquinolin-2-yl'jethenyl)p henylaminomethyliphenoxyhexanoate Step 1. E-2-E3-(2-(7-fluoropuinolin-2-l)ethenvl)phenylaminomethyllphenoI 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 1 74.5-175.0 0

C.

Step 2 E-Ethyl-2-[2-(3-(2-(7-fluoroquinolin-2-yl)ethenyl~hhenylaminomethvl)phenoxv]-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.

I

WO 96/02500 PCTI) K2'5/00223 32 Example 43 E-2-f2-(3-2-(2-(7-fluoroquinolin-2-yl)ethenyi)phenylaminomethyllphenoxyhexanoic 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 181-1831C.

Example 44 E-2-[2-(3-(2-(6,7-difluoroquinolin-2-vl)ethenvl)phenylaminomethv!)phenxylhexanoic acid, sodium salt Step 1 E-2-[3 -(-6,7-difluoroquinolin-2-vl)ethenvl)phenylaminomethvllphenol By following the procedure of Example 3, step 1, but replacing E-2-[3-(2-(7-chioroquinolin-2-yl)ethenyljaniline with E-2-[3-(2-(6,7-difluoroquin- 1 5 olin-2-yl)ethanyl]aniline, the title compound is obtained with a melting point of 158-160 0

C.

Step 2 E-Ethvl-2-[2-(3-(2-(6,7-difluoropuinolin-2-vl)ethenyl)phenvlaminomethyl)tphenoxyl-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 0

C.*

Step 3 E-2-12-(3-(2-(6,7-difluorocluinolin-2-Yl)ethenvl)phenvlaminomethyl)phenoxyl-hexanoic acid, sodium salt The ester from step 2 (0.85 g, 1.5 mmol) is refluxed for 31/ 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 H 2 0 and diethyl ether. The title compound is obtained as sodium salt with a melting point of 238-240'C.

I

\WO 9/(0250> CT/IDK95/00223 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 Ex. No. X3 Melting point °C Remarks 6-F 183-185 46 4-Rr 202-204 47 4-COOH 138 dec.

48 4-NO 2 193-195 49 4-CH 3 176-177 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.

I 90102506 96(02506 PCi'I)1C9/00223

H

CH

2

CH

2

CH

2

CH

3 Table VI Ex. Melting point No. X3R 2 OQ Remarks 6-F C 2

H

5 203-205 Hydrochloride 51 4-Br 0 2

H

5 98-100.5 52 4-NO 2

C

2

H

5 oil 53 6-F H 183-185 54 4-Br H 197-198 4-NO 2 H 221-223 56 4-OH 3 H 168-170 57 4-COOH H 173-175 (dec.) 58 4-NH 2 H 162-164 (dec.) Example 59 E-2-[3-(2-(7-fluoroquinolin-2-yl)ethenyl)phenlaminomethy[IlhenoL~yacetic acid Step 1 E-3-f2-7-Fluoi ociuinolin-2-yl)ethenvll-N-t-carboxvmethoxvbenzvlidene)aniline By following the procedure of Example 2, step 3, but replacing E-3-[2-(7-chloroquinolin-2-yI)ethenyl]aniline with E-3-[2-(7-fluoroquinolin-2-yl)ethenyl]aniline, the title compound is obtained with a melting point of 208- 21000C.

96/02506 PC'T/D 195/00223 Step 2 E-2-[3-(2-(7-fluoroquinolin-2-yl)ethenyl)phenylaminomethylphenoxyacetic acid By !ollowing 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 E-2-[3-(2-(7-chloroquinolin-2-vl)ethenyl)phenylaminomethyl)phenoxy] hexanoic acid pivaloyloxymethyl ester hydrochloride A mixture of E-2-[2-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenylaminomethyl)-phenylamino]hexanoic acid (0.5 g, 1 mmol), potassium carbonate (0.3 2.2 mmol) and chloromethyl pivalate (0.18 ml, 1.2 mmol) is stirred for 3 hours ~A 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 0

C.

Example 61 E-2-[3-(2-(7-chloroquinolin-2-yl)ethenyl)phenylaminomethvl)phenoxy] hexanoic acid [(N,N-dimethylamino)carbonyl] 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-dimethylacetamide (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 acetate:hexane, 7:3) and yielded a brown oil.

s WO 90/02506, PC'I'I)K95/00223 36 The resulting solid is dissolved in ethyl acetate and filtered. The filtrate is concentrated by colomn chromatography on silica gel (ethyl acetate:hexane, 7:3) and yielded a brown oil.

The oil is triturated with a solution of The title compound is obtained as hydrochloride with a melting point of 990C dec.

Example 62 E-2-3-(2-(7-chloroauinolin-2-yl)ethen)phenylaminomethyl)phenox hexanoic acid N-diethvlamino)carbonyll 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 120-1220C.

Example 63 E-2-[3(2-(-(7-chloroquinolin-2-l)ethenyl)phenviaminomethyl)phenoxy hexanoic acid [(N,N-diallylamino)carbonyll 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 0

C.

Example 64 (S)(+)--Ethl-2-2-(3-2-(7-Chlorouinolin-2-ylethenyl)phenylaminomethyl)phenoxy]hexanoic acid Step 1 +)-E-Ethyl-2-2-(3-(2-(7-Chloroquinolin-2-yl)ethenyl)phenylamino methyl)phenoxvlhexanoate A mixture of E-2-[2-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenylaminomethyl)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 mi) and phosphate buffer (100 ml, pH 8) was stirred at room temperatur for 120 hours.

Filtration through Decalit followed by washing with ethyl acetate gave two ~B~IIlBI U~I~MDd(UII~ar~ Y~ls~Q~ 9/02506 I(T/I) 195/10223 37 phases which were separated. The organic phase was dried (MgSO 4 and evaporated. The product was then purified by silica gel chromatography (ethyl acetate/diethylether), and crystallized from ethanol to give 2.5 g of the title compound used as such in the next step.

Melting point: 99-1000C.

30.30 (c 1.04, acetone).

Step 2 (S)(+)-E-Ethyl-2-[2-(3-(2-(7-Chloroquinolin-2-yl)ethenyl)phenylaminomethyl)phenoxvlhexanoic acid To (+)-E-Ethyl-2-[2-(3-(2-(7-Chloroquinolin-2-yl)ethenyl)phenylaminomethyl)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 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.), [a]D 2 0 23.4 (c 0.99, DMSO).

Further careful recrystallization from acetonitrile gave the pure product with a melting point of 187-188 0 C, [a]D 2 0 24.5 0 (c 1.12, DMSO).

Example E-5-2-[2-(3-(2-(7-chloroquinolin-2-vl)ethenyl)phenylaminomethvl)phenoxy]pentyl-1 H-tetrazole Ste E-2-[2-(3-(2-(7-chlorouinolin-2-l)ethenl)phenylaminomethl)phenoxylpentvl hydroxamic acid To E-2-[2-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenylaminomethyl)phenoxy]hexanoate (2.6 g, 5.3 mmol) (from Example 3, step 2) in methanol 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.

WO 96102506 PCTII) 1(95/00223 38 Step 2 E-2-[2-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenyl-ninomethyl)phenoxylpentyl 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 3 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-5-2-2-(3-(2-(7-chloroquinolin-2-vl)ethenyl)phenlaminomethyl)phenoxylpentvl-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, NaN 3 (1.65 g, 25.4 mmol) and NH 4 CI (1.4 g, 26.4 mmol) were added. The mixture was heated at 115-120 0 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 0 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 Monofluorotrichloromethane 595 g Difluorodichloromethane 798 g The active substance is micronized in a jet-mill. The majority of the particles should be less than 5 pm in diameter.

A drug concentrate is prepared by dissolving sorbitan trioleate in a small amount of monofluorotrichloromethane and adding the active substance.

,I WVO 96/02506 IPCT/DK(95/00223 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 Suitable aerosol container are filled with the calculated amount of formulation and sealed immediately with metering valves with suitable actuators. Each puff delivers 50 pg 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 homogeneous 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 oroduced from the granulation by means of a suitable tabletting machine.

WO 96/02506 6/0206 VPI7170195/00223 Example 68 Formulation for iniection (Si)(+)-E-2-[2-(3-(2-(7-Chloroquinolin-2-yl)ethenyl)phenylaminomethyl)pheoxy]hexaloic acid (actia substance) 1% Sodium chloride ql.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 (11)

1. A compound of the formula I X X3 X4 R1 X2/ N R 3 in .hich X 1 and X 2 independently of each other stand for hydrogen or halogen; X 3 and X 4 independently of each other stand for hydrogen, halogen, nitro, cyano, trifluoromethyl, C 1 -C 4 alkyl, C1-C 4 alkoxy, carboxy or C1-C4 carbalkoxy; Z is a bond, 0 S, S(0) 2 NH or CH 2 R 1 is hydrogen or a straight or branched, saturated or unsaturated C1-C6 hydrocarbon chain; R 3 is hydrogen, a straight or branched, saturated or unsaturated C1-C12 hydro- carbon chain, unsubstituted or substituted phenyl or unsubstituted or substi- tuted benzyl, the above mentioned substituents being one or more of X 3 and X 4 as defined above; or the group R 1 -[C]p-R 3 stands for cyclopropyl; p may be 0 provided that Z is a bond, or p may be an integer from 1-6 if R 1 R 3 hydrogen; A is COOR 2 or 1H-tetrazole in which R 2 R 1 as defined above or R 2 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 1 and X 2 independently of each other stand for hydrogen, fluoro or chloro; X 3 stands for hydrogen; X 4 stands for hydrogen, fluoro, chloro or bromo; Z is O or S in ortho-position; p is 1; R 1 is hydrogen; R 3 is hydrogen or a straight or branched, saturated or unsaturated C1-C6 hydrocarbon chain, or phenyl; and A is COOR 2 where R 2 is hydrogen, C1-C3 alkyl, an alkali metal cation, or ~-I WO 90/02500 962506PI)1(95/00223 42

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 1 -C 6 -alkylamines, C 1 -0 6 alkanolamines, procaine, cycloalkylamines, benzylamines, and heterocyclic amines.

4. A compound of claim 1 which is selected from the group consisting of: loroq uino li n-2-yl)ethenyl) phenylam inomethyl)p hen- oxy]-2-methylpropanoic acid; E-2-[2-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenylam-inomethyl)phen- oxy]-2-methylpentanoic acid; E-2-[2-(3-(2-(7-chloroquinolin-2-yi)ethenyl)phenylaminomethyl)phen- oxyihexanoic 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]- phenoxyhexanoic acid; E-2-[2-(3-(2-(6,7-difluoroq uinolin-2-yl)ethenyl)phenylaminomethyl)- phenoxy]hexanoic acid, sodium salt; and their salts and pure enantiomeric forms. A compound of claim 1 which is (5)(+)-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. -43-

7. A method for the treatment or prophylaxis of disease states including asthma, allergy, rheumatoid arthritis, spondyloarthritis, 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, migraine heaujache in a patient in need of such treatment or prophylaxis, which method includes administering to said patient an effective amount of one or more compounds according to any one of claims 1 to 5, if necessary together or concomitantly with one or more other therapeutically active components.

8. A method according to claim 7, wherein said proliferative and inflammatory skin disorders include psoriash or atopic dermatitis.

9. Method for producing a compound of formula I according to claim 1, in which an amine of formula II H X2 of the formula III 6/10/97msap9011 .spe.wpd WO 96/(02506 I'("C'T)I95/00223 44 Ri x 3 x4 r1 Y-CH 2 Z- R 3 IA in which R 1 R 3 X 3 X 4 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 R1 OHC Z IV R3 in which R 1 R 3 X 3 X 4 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 Xi H X )ZH X NH-CH2 V in which X 1 X 2 X 3 and X4 have the above meanings and Z is O, S or NH, is reacted with a compound of the formula VI -II I- R1 Y C A VI Ra and in which R 1 R 3 A, p and Y have the above meanings, to form the desired compound of formula I. A compound according to formula I of claim 1, substantially as herein described with reference to any one of the Examples.

11. A pharmaceutical preparation of claim 6, substantially as herein described with reference to any one of the Examples.

12. A method of claim 7 for the treatment and/or prophylaxis of disease states which method is substantially as herein described with reference to any S, one of the Examples.

13. Method for producing a compound of formula I according to claim 1, 1. which method is substantially as herein described with reference to any one of the Examples. DATED this 6' t of November, 1997. Leo Pharmaceutical Products Ltd A/S (Lovens kemiske Fabrik Produktionsaktieselskab) By Their Patent Attorneys: CALLINAN LAWRIE _Ib AAK 6/ 1197msap901 .spewpd ~1 II I II II rNCT/DK 95/00223 A (Ii 1 1 AI~i M) tll l AI ll IPC 6 C6101(5AIIl1*[7D21 112 A61k'31I/ 47 C070215/18 C07D401/12 According u, Internatiional llatent CIaWiication (11'C) or to both national classification and IPC H 11l SI AR( 1ll1A) Minimum dicumrcnitsuon scarched (classification system followed by classification symbols) IPC 6 C07D A61K D~ocumentation searched oither than minimum documentation to the extent that such documents are included in the fields searched Hclctronic data base consulted during the international search (name of data base and, where practical, search terms used) C. DOCtJNIFtNTS (ONSlhiRVi)I) l0 B RI('I.I:VA N1 Categoiry ICitation of document, with indication, whcre appropriate, of thc relevant passages Relevant to claim No. A WO,A,89 05294 (LEO PHARMACEUTICAL PRODUCTS 1,10 LTD.) 15 June 1989 cited in the application *page 20, table 1 A WO,A,89 12629 (RORER INTERNATIONAL, INC.) 1,10 28 December 1989 cited in the application see claims A WO,A,94 03431 (LEO PHARMACEUTICAL PRODUCTS 1,10 LTD.) 17 February 1994 cited in the application see claims I~ r l Iurther documents arc listed in the continuation of bx C. [JA PaetfmIebr aelse nanx Specal ateorie ofcitd doumets T- later document pulihed after the international filing date *M dcumnt efiingthe eneal tat ofthe rt hic isnutor prbonty date and not in conflict with the application but *'dcunside n to h ealsae of partacularirelevance cited to understand the principle or theory underlying the con~dcre tohe o paticuar elevnceInvention *Vearlier document hut published on or after the international document of particular relevance; the claimed invention filing date cannot be consi)dered novel or cannot be considered to document which may throw diiubts on pniority claim(s) or involve an inventive step when the document is taken alone which is ci ted to establish the publication date of another document of particular relevance; the claimsed invention citation or other special reason (as specified) cno ecniee oivlea netv tpwe h .0.docmen reerog t an oral disclosure, use, exhibition or doctument is combined with one or more other such docti- other means ments, such combination being obvious to a person skilled P document published pnior to thr international filing date hut in the arm later than the priority date claimed W document member of the same patent family D~ate of the actual completion of the international -search D~ate of mailing of the intenational search report 24 August 1995 3 1 08 Name and mailing address of the ISA Authorized officer European Patent Office. 1P.11. 5818 Ilatcntlaan 2 NI, 2280 [IV Rijswijk I'c. (i31-70) 3401-20401, l'x. 31 651 Clpo nI, Vn B e F~ar (31.70) 340-3016Va iln H PCT'tSA.210 (Secnd shmt) l holy 1992) page 1 of 2 FPCT/DK 95/00223 it ,nonuaw-nilI)O( UJM IN I, flNS lIl It I 1F RIt.VA", F atego'ry iLlIJon o document, with indication, where appropinate, of the rcicyant pa~sageI 3 RetleVant to claim No. JOURNAL OF MEDICINAL CHEMISTRY, vol. 35, no. 21, 1992 WASHINGTON US, pages 3832-3844, R. ZAMBONI ET AL. 'Development of a novel series of styrylquinoline compounds as high-affinity leukotriene D4 receptor antagonists: page 3832-3834 1,10 I I I Form PCT'IS&1210 (co~ntinuation of secrnd sliett) (July 1992) page 2 of 2 I NTER NATION ALI SEARCH REPORTI jlijl Apphilini Nil PCT/DK 95/00223 Patent document PbcatnPatent famifly -T Publica on cited in search report dlate member(s) date WO-A-8905294 15-06-89 AT-T- 110364 15-09-94 AU-A- 2611888 05-07-89 OE-D- 3851232 29-09-94 DE-T- 3851232 02-02-95 EP-A- 0420844 10-04-91 GR-B- 1000422 30-06-92 JP-T- 3501477 04-04-91 US-A- 5110819 05-05-92 WO-A-8912629 28-12-89 US-A- 4918081 17-04-90 WO-A-9403431 17-02-94 AU-B- 4698293 03-03-94 CA-A- 2134565 17-02-94 EP-A- 0654026 24-05-95 Fl-A- 950515 06-02-95 Form PCT'ISA121O (patent family anneal (July 1992) Il...irnatlona applicauon No. PCT/ DK95/00223 INTERNATIONAL SEARCH REPORT Box I Observations where certajn claims were found unsearchable (Continuation of item 1 of first sheet) This internauonal search report has not been established in respect of certain claims under Article 17(2)(a) for the following reasons: 1. 1 Claims Nos.: because they relate to subject matter not required to be searched by this Authority, namely: Although claims 7 and 8 are directed to a method of treatment of (diagno- stic method practised on) the human/animal body, the search has been carried out and based on the alleged effects of the compound/composition. 2. Claims Nos.: because they relate to parts of the international applicauon that do not comply with the prescribed requirements-to such an extent that no meaningful internauonal search can be carried out, specifically: 3. Claims Nos.: because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6.4(a). Box II Observations where unity of invention is lacking (Continuation of item 2 of first sheet) This Internauonal Searching Authority found multiple invenuons in this international application, as follows: 1. O As all required additional search fees were timely paid by the applicant, this international search report covers all searcnable claims. 2. As all searchable claims could be searches without effort justifying an additional fee, this Authority did not invite payment of any addiuonal fee. 3. O As only some of the required additional search fees were timely paid by the applicant, this international search report covers only those clams for which fees were paid, specifically claims Nos.: 4. D No required additional search fees were timely paid by the applicant. Consequently, this international search report is restricted to the invenuon first mentioned in the claims; it is covered by claims Nos.: Remark on Protest O The additional search fees were accompanied by the applicant's protest. SNo protest accompanied the payment of additional search fees. Form PCT/ISA/210 (conunuation of first sheet (July 1992)