DK170576B1 - New quinolyl methoxy-n-benzyl aniline cpds. - are lipoxygenase inhibitors and leukotriene antagonists useful for treating e.g. inflammatory conditions and asthma - Google Patents

Abstract

Substd. quinolines of formula (I) and its salts and in-vivo hydrolysable esters are new, where R1 = H, opt. unsatd. 1-8C alkyl (opt. substd. by B), Ar or Ar-1-4C alkyl; Ar = phenyl opt. substd. by B; B = halo, pseudohalo such as CF3, CN, NO2, NH2, substd. NH2, COOH, carbalkoxy, carbamyl, OH, alkyl or alkoxy; R2-R7 = H or B; n,m = 0-6; provided n is not zero when A = COOH, and X and Q = a bond; X = a bond, O, S, SO, SO2 or NR8; R8 = as for R1; Q = a bond or 1-6C alkylene; A = an acidic gp., e.g. carboxy, 1H-tetrazolyol or a sulphonic, sulphamyl, sulphinic or hydroxamic acid. gp. X-Q-A = carboxy- 1-6C alkoxy or 1H-tetrazolyl, the salt is formed with HCl, HBr, HI, H3PO4, H2SO4, HNO3, p-toluenesulphonic, methane sulphonic, formic, acetic, propionic, citric, tartaric or maleic acid, or with alkali(ne earth) metals such as Li, Na, K, Mg or Ca, or with ammonia or amines such as 1-6C alkylamines (e.g. NEt3), 1-6C alkanolamine (e.g. diethanolamine or triethanolamine) proccurie, cycloalkylamines (e.g. dicyclohexylamine) benzylamines (e.g. N-methyl benzylamine N-ethylbenzylamine, N-benzyl-B-phenethylamine, N,N'-dibenzylethylenediamine or dibenzylamine) or heterocyclic amines, e.g. morpholine and N-ethyl piperidine.

Description

in DK 170576 B1

The present invention relates to novel compounds which are valuable in human and veterinary treatment, to pharmaceutically acceptable salts thereof, and, after administration in vivo, to hydrolysable esters thereof, to processes for the preparation of said novel compounds, and to pharmaceutical compositions containing the novel compounds. .

It has recently been found that leukotrienes formed by the arachidonic acid metabolization via the 5-lipoxygenase pathway are involved in a variety of pathophysiological functions such as bronchoconstriction, plasma exudation, coronary artery spasm, leukocyte chemotaxis and neutrophil degranulation. develop 10 compounds that inhibit 5-lipoxygenases and thereby the production of leukotrienes, or which counteract the effects of leukotrienes.

German patent application DE 3 607 382 (corresponding to UK patent application No. 8604183 and to Danish patent application 0969/86) discloses a series of quinolyl or pyridylmethoxy or methylthio-substituted N-substituted aniline derivatives having effects as lipoxygenase inhibitors and / or leukotriene antagonists and / or leukotriene : rw5 vf -f-CH2X-- R1 20 Sr R2 wherein X is, for example, O, and R and R, which may be the same or different, represent hydrogen, straight or branched C1 -C6 alkyl, phenyl or phenyl-C1 -C 1-4 alkyl in which a phenyl and / or an alkyl group may be substituted by one or more of the following substituents: halogen, amino, carboxy, hydroxy and alkoxy, while a phenyl group may be further substituted by alkyl, however, R and R are not both hydrogen and, for example, R 2, R 2, R 2 and R 2 can mean hydrogen. The N-substituent of these compounds may be substituted or unsubstituted aryl or aralkyl. The substances have not been found to be particularly well absorbed after oral administration.

EP-A-206751 discloses compounds of the formula: R * 10 In this formula, for example, Y may be CH 2 O, X is O, S, SO, SO 2 or NR where R is, for example, hydrogen, R For example, R ^ is hydrogen, and R ^ may be, for example, a saturated or unsaturated aliphatic group which may be substituted by a carboxyl group. These compounds are stated to counteract the effects of the leukotrienes and to inhibit the leukotrienes. Thus, these compounds are valuable in the prevention and treatment of the diseases caused by the leukotrienes.

EP-A-190722 discloses compounds of the formula

20 ^ I V

Wherein R is, for example, OH, n! is 1 or 2, R 1, R 2, R 2, and R 2 are, for example, hydrogen, A is CH or N, X is for example 0Η20, Z is an alkylene chain containing up to 10 carbon atoms in the main chain which may be attached to the phenyl group through an oxygen atom and R may be ORg where Rg is H, lower alkyl or phenyl. These compounds are lipoxygenase inhibitors which have anti-inflammatory and antiallergic effects.

EP-A-232954 discloses compounds of the general formula: 3 X 170576 B1 R2. X X

5 R'— XX

Kr = wherein X may be, for example, a nitrogen atom and W may be a carbon atom, Y may be CP 2 O, R 1 is, for example, hydrogen, n is 0 or 1, R is hydrogen or lower alkyl, and R is lower alkyl, perfluoro -lower alkyl or perfluorophenyl.

These compounds are useful in the treatment of leukotriene-mediated conditions that prevent the free passage of air through the airways, such as allergic rhinitis, allergic bronchial asthma and the like, as well as in anti-thrombotic therapy.

EP-A-233763 describes compounds of the formula: n1 rL_ j £ V- (CR22) mz * - <CR2RyQ2 20 r2 / xr4 which Y is, for example, CH2O, R1, R2 and R6fe are hydrogen, and X2 and X2 independently of each other may be 0, S, SO or SO and R 1 is H or C 1 -C 4 alkyl.

The residues associated with X and XJ may be saturated or unsaturated aliphatic groups which may be, for example, substituted by a carboxyl group. These compounds are leukotriene antagonists or inhibitors and are useful in the treatment of diseases caused by the leukotriene.

EP-A-271287 has a similar content.

30 Surprisingly, it has now been found that the introduction of one of a number of acidic groups into such N-substituents results in compounds having an even more pronounced effect.

4 DK 170576 B1

In addition, it has been found that in the presence of such acidic groups, compounds which are not anilines, but in which the nitrogen atom is separated from the phenyl group by a carbon chain, become highly active compounds.

Furthermore, these compounds are more specifically active substances, as their leucotrien antagonistic activity is much more pronounced than their lipoxygenase inhibitory activity.

The compounds in question are otherwise well absorbed after enteral administration.

The present compounds have the general formula I

III | - (oys-N-cciyg-- | in which R * means hydrogen, straight or branched C 1 -C 6 alkyl or benzyl; n and 10 m are the same or different and represent an integer from 0-1; provided that n is not 0 when A is a carboxy and X and Q are both a bond; X is a bond or O; Q is a bond or a straight or branched C 1 -C 6 alkylene; A is a carboxy, 1H-tetrazolyl-, a sulfonic acid, a sulfamyl, a sulfinic or hydroxamic acid group, and pharmaceutically acceptable non-toxic salts and after administration in vivo hydrolyzable esters thereof.

Among the preferred compounds of the invention are compounds of formula I wherein -X-Q-A means a carboxy-C 1-6 alkoxy or a 1H-tetrazolyl group.

Particularly preferred compounds are: 3- (2, -quinolylmethoxy) -N- (3 "-carboxymethoxybenzyl) aniline; 3- (2'-quinolylmethoxy) -20 N- (2" -carboxymethoxybenzyl) aniline; 3- (2'-quinolylmethoxy) -N- (4 "-carboxymethoxy-benzyl) aniline; 3- (2, -quinolylmethoxy) -N- (4" - (1-carboxyethoxy) benzyl) aniline; 3- (2'-quinolylmethoxy) -N- (2 "-carboxy- (3-propyloxy) benzyl) -aniline; 3- (2'-quinolylmethoxy) -N- (4" - (1H-tetrazolyl) benzyl) aniline ; 3- (2'-quinolylmethoxy) -N- (3 "- (1H-tetrazolyl) benzyl) aniline; 3- (2, -quinolylmethoxy) -N- (4" - (1H-tetrazolyl) (3-propyloxy) ) benzyl) aniline and 3- (2, -quinolylmethoxy) -N- (3, - (hydrobenzyl) -N- (4,, - hydroxaminocarbonylbenzyl) aniline.

5 DK 170576 B1

The salts of the compounds of formula I may be formed with pharmaceutically acceptable, inorganic or organic acids such as hydrochloric acid, hydrobronic acid, iodine hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, p-toluenesulfonic acid, methanesulfonic acid, formic acid, acetic acid, citric acid, citric acid, without these examples being construed as limiting the invention.

The present salts of the compounds of formula I may also be formed with pharmaceutically acceptable, inorganic or organic bases. Examples of salts formed with pharmaceutically acceptable non-toxic bases include alkali metal and alkaline earth metal salts such as lithium, sodium, potassium, magnesium and calcium salts, as well as salts with ammonia and suitable non-toxic amines such as C alkylamines, e.g. triethylamine, C1-C8 alkanolamines, e.g. diethanolamine or triethanolamine, procaine, cycloalkylamines, e.g. dicyclohexylamine, benzylamines, e.g., N-methylbenzylamine, N-ethylbenzylamine, N-benzyl-P-phenethylamine, Ν , Ν'-dibenzylethylenediamine or dibenzylamine and heterocyclic amines, for example morpholine, N-ethylpiperidine and the like.

Although the compounds of this invention are well absorbed after enteral administration, it may in some cases be advantageous to prepare suitable bioreversible derivatives of compounds of the invention, i.e., to produce so-called prodrugs, preferably derivatives whose physicochemical properties lead to improved solubility at physiological pH and / or absorption of the compound in question.

Such derivatives are, for example, esters of N-hydroxymethyl derivatives of the compounds of the invention prepared by reaction of a secondary amino group in the compounds of the invention with formaldehyde followed by reaction with a suitable acidic compound or activated derivatives of such compounds, e.g. bisulfite Ν, Ν-dimethylglycine, N, N-diethyl-β-alanine or phosphoric acid 2, but also 2 RG Kallen and W.P. Jencks, J. Biol. Vhem. 241 (1966) 5864 ^ C.J. Martin and M.A. Marini, J. Biol. Chem., 242 (1967) 5736.

^ M. Levy and D.E. Silberman, J. Biol. Chem. 118 (1937) 723.

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

^ B.V. Jain, B.H. Iyer, and P.C. Guha, Science and Culture 11 (1946) 568.

Suitable acids which form bioreversible derivatives with desired physicochemical properties may be used.

Further examples include esters formed with the acidic function of the molecule, such as acyloxyalkyl, alkoxycarbonyloxyalkyl or aminoacyloxyalkyl esters, which are readily hydrolyzable in vivo or in vitro.

Among the above esters, the following are preferred: alkanoyloxymethyl having from 3 to 8 carbon atoms, 1- (alkanoyloxy) ethyl having from 4 to 9 carbon atoms, alkoxycarbonylloxymethyl having from 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy) ethyl having from 4 to 7 carbon atoms , and α-aminoalkanoyloxymethyl having from 2 to 6 carbon atoms.

Other preferred esters are lactonyl esters, eg 3-phthalidyl, 4-crotonolactonyl or γ-butyrolacton-4-yl esters.

Also within the scope of the invention are methoxymethyl esters, cyanomethyl esters, or mono- or dialkyl-substituted aminoalkyl esters, for example, 3-dimethylaminoethyl, 2-diethylaminoethyl or 3-dimethylaminopropyl esters.

Especially preferred are esters which are readily absorbable after enteral administration and which are hydrolyzed to the compounds of formula I. during or after absorption.

Arachidonic acid metabolites include prostaglandins and leukotrienes. Both of these metabolite groups are important in the pathophysiology of inflammatory and allergic reactions. Many inhibitors of prostaglandin synthesis are known and used as

ISLAND

Twenty anti-inflammatory drugs, but relatively few leukotriene inhibitors are known to date and are generally clinically unacceptable. The first step in the biochemical synthesis of all leukotrienes is the peroxidation at the 5-carbon atom of the arachidonic acid. This reaction is catalyzed by the enzyme 5-lipoxygenase, which is found mainly in leukocytes. Leukotriene B ^ is one of the strongest chemotaxic agents for polymorphic leukocytes, 25 which at the same time causes aggregation and degranulation of these inflammatory cells. Thus, it is a highly pro-inflammatory hormone. Leukotriene C ^, D og, and together constitute the agent heretofore known as the slow-reacting sub-ana of the anaphylaxis Varia, S. Schuller, KB Sloan, and VJ. Stella, J. Pharm. Sci., 73 (1985) 1068 and following papers.

ISLAND

30 R.J. Flower, S. Moncada and J.R. Vane, in: The Pharmacological Basis of

Therapeutics (1980), eds A.G. Gilman, L.S. Goodmann and A. Gilman), (Macmillan, New York) p.682.

7 DK 170576 B1 stance "(SRS-A), which is on the order of 1000 times as strong initiator of bronchoconstriction as histamine, and which also regulates the contractility and permeability of microvascular smooth muscle cells. It is therefore a mediator of asthmatic, allergic and inflammatory reactions.

Thus, inhibition of 5-lipoxygenase leads to a diminished formation of all these inflammatory and allergy mediators. This is of great clinical importance, with specific 5-lipoxygenase inhibitors and leukotriene antagonists being of potential interest in the treatment of asthma, allergy, rheumatoid arthritis, spondyloarthritis, podagra, atherosclerosis, proliferative and inflammatory skin disorders such as psoriasis and atopic dermatitis, chronic, bladder disease, and other inflammatory conditions, vaso-spasm associated with angina pectoris, pulmonary hypertension, cystic fibrosis, "adult respiratory distress syndrome" (ARDS), ischemia and reperfusion injuries, etc. ^. Thus, the identification of specific 5-lipoxygenase inhibitors and leukotriene antagonists is a new approach with very great potential in the treatment of a variety of diseases.

The following method was used to determine the 5-lipoxygenase activity in vitro: Peritoneal cells from rats were extracted from anesthetized rats by intraperitoneal injection of 10 ml of Hank's balanced saline solution (GIBCO, Cat. No. 4025, USA) containing 12.5 U / ml sodium heparin (Leo, Denmark). The resulting cell suspension, which mainly contained macrophages, was transferred to a test tube and washed twice by centrifugation (200 g, 10 minutes) and resuspended in Hank's balanced saline solution containing 0.5% bovine serum albumin (BSA) (Sigma Chem. Co , USA). Cells from 9 rats were finally resuspended in Hank's balanced saline solution (with BSA) containing 5 µCi [1- C] arachidonic acid (The Radiochemical Center, Amersham, U.K.) and incubated for 90 minutes at 37 ° C. This gave a labeling of the phospholipids of the cell membrane, incorporating radioactive arachidonic acid into the 2-position of the glycerol moiety. Excess arachidonic acid was removed by twice washing the cells as described above. The cells were finally resuspended in the same solution (without BSA) at 10 cells / ml. 475 μΐ of the cell suspension was preincubated at 37 ° C for 5 minutes with either 5 μΐ dimethylsulfoxide (DMSO) (control glass) or 5 µg. Goetzl, D.G. Payan and D.W. Goldman, J. Clin. Immunol. 4 (1984) 79.

8 DK 170576 B1 μΐ of a solution of the subject compound in DMSO. Then, 20 μΐ of -4 was added a mixture of equal parts calcium ionophore A 23187, 10 Mi ethanol (Calbiochem, U.S.A.) and 0.5 M CaCl 2 in water. Thus, the final concentration of A 23187 was 2 x 10 M and of Ca 8 mM. After 5 minutes incubation, the glasses were transferred to an ice bath and centrifuged for 10 minutes at 3,000 g (4 ° C). A sample of the supernatant was counted by liquid scintillation spectrometry to calculate the released radioactivity induced by A 23187 in the presence of the compound of the invention.

A reduction in radioactive release was considered a sign of phospholipase A2 inhibition. The supernatant was then extracted twice with ethyl acetate (2 mL), adjusted to pH 3 with 1 N HCl, and further extracted with 2 mL of ethyl acetate.

The combined extracts were evaporated to dryness in vacuo, the residue was dissolved in a small volume of methanol and applied to a silica gel-coated thin-layer plate with a polar concentration zone (Merck Art. 11798, Darmstadt) using a Desaga Au-ITII ll tospotter 1. The plates were developed in the organic layer by a solvent mixture 15 (ethyl acetic acid / isooctane / water, 55: 10: 25: 50). Radioactive spots were detected by autoradiography (AGFA-GEVAERT, Osray-RPI X-ray film, Belgium), and changes caused by the subject compound in the arachidonic acid metabolite pattern were determined quantitatively with a laser densitometer (LKB, Ultrascan Sweden, Bromma, Sweden), Bromma with an integrating computer (SP 4100, Spectra-Physics, San José, Ca, 20 USA).

These cells produced measurable amounts of radioactive 6-keto-prostaglandin Fja, thromboxane B2, prostaglandin D2, hydroxyheptadecatrienoic acid (HHT) (all cyclooxygenase products), 5-hydroxyyeicosatetraenoic acid (5-HETE) and leukotriene B

When a compound prepared according to one of Examples 2, 8, 9, 11, 12, 13, 14, 16, 20, 21 or 22 at a final concentration of 10 µM was added to the reaction mixture described above, a significant and specific decrease in the production of leukotriene B ^ and 5-HEAT. No simultaneous reduction in the synthesis of the cyclooxygenase products HHT, prostaglandin D2, thromboxane B2 and 6-ketoprostaglandin Fla was observed. This pattern of the compound's activity is indicative of a true specific 5-lipoxygenase inhibition.

9 DK 170576 B1

Leukotriene antagonists can be identified by observing contractions in prepared guinea pig ileum strips which are suspended in a physiological buffer after the addition of pure leukotriene (LTD). Ileum strips are connected to an isotonic transducer and the contractions are continuously recorded on a multi-track printer. Prior to the addition of LTD, atropine and indomethacin are added to the buffer to block the contractile effects that have cholinergic causes or are due to prostaglandin. Test compound schemes to be studied to determine the leukotriene antagonism are dissolved in DMSO and added to the organ bath 2 minutes prior to the addition of LTD 2 at a final n concentration of 10 M such that the final concentration of DMSO which has been shown to be 10 not affecting the ileum's response to LTD ^ is 0.1%. The test compounds may add

C

are tested at different concentrations, often starting at 10 M, the concentration being then reduced in the case of antagonism.

When the compounds of the present invention were added to the ileum preparation prior to the addition of LTD 2, a significant inhibition of the specific LTD 2 -induced contraction occurred. In several cases, this inhibition occurred at concentrations in the submicromolar range, for example, for a compound of one of Examples 1 to 6 or 8 to 19 or 21 to 22 (all Examples except 7 and 20). In contrast, contractions induced by histamine at 10 M were not inhibited by these compounds, even at micromolar concentrations.

Leukotriene antagonists can be further characterized by using guinea pig trachea strips instead of ileum strips 10.1 This relevant in vitro model of human airways is trachea strips suspended in a physiological buffer containing indomethacin. A curve expressing the relationship between the concentration of LTD 2 and the reaction thereof is generated during and without the presence of the leukotriene antagonist. From these curves, the efficiency of the leukotriene antagonist can be expressed as the pKg value, the negative logarithm of the antagonist dissociation constant. The pKg value is determined as -log ([antagonist]) / dose ratio -1)), where the dose ratio is defined as EC ^ q (presence of antagonist) / EC ^ 0 (absence of antagonist), and EC ^ q refers to the ^ I Ahnfelt-Rønne, D. Kirstein and C. Kærgaard-Nielsen, European J. Pharmacol. 155 (1988) 117.

1 R.M. Muccitelli, S.S. Tucker, D.W. P. Hay, T.J. Torphy and M.A. Wasserman, J. Pharmacol. Exp. Ther. 243 (1987) 467.

10 DK 170576 B1 concentration of LTD ^, which provides 50% of the maximum response to LTD ^

This is the generally accepted way of expressing the antagonistic effect of the leukotriene, which is independent of the LTD the pKB values for the compounds.

according to Examples 1, 9 and 10, respectively. 8.3, 9.5 and 8.4.

It is important to investigate the receptor-binding properties of leukotriene antagonists in relation to their pKg values, ie. to correlate the antagonist receptor blockade with the inhibition of the smooth muscle contraction. Investigations of the receptor binding are performed with guinea pig lung membranes by a direct comparison of the competing binding to the LTD 2 receptor for a leukotriene antagonist and for 10 [HJLTD ^ (10.13). A piC ^ value is defined as the negative logarithm of the moderate concentration of the antagonist inhibitory [H] LTD4 found at 50% binding. The pIC values of the compounds prepared according to Examples 1, 9 and 10 were 7.3, 8.1 and 7.5, respectively. These pIC ^ values were found to correlate with the antagonist - pKg values, showing that the inhibition of smooth muscle contraction actually depends mechanically on the binding to the LTD LTD receptor.

The present invention also relates to a method of preparing the subject compounds. In one embodiment, an amine of formula II is reacted

2 ° fj ^ V ^ i * i i J + (C% N-H π

wherein and n have the meanings defined in claim 1 are reacted with a compound of formula III

% ^ R.F. Furchgott, in: Handbook of Experimental Pharmacology, vol 33 (1972), eds O. Eichler, A. Farah, H. Herken and A.D. Welch (Springer Verlag, New York) p.

30 283.

^ S. Mong, H.-L. Wu, M.O. Scott, M.A. Lewis, M.A. Clark, B.M. Weichman, C.M. Kinzig, J.G. Gleason and S.T. Crooke, J. Pharcol. Exp. ther. 234 (1985) 316.

Wherein 170, X, Q, A and m have the meanings defined in claim 1 and Y is capable of forming a good leaving group such as chlorine, bromine or iodine, an alkyl or aryl sulfonyloxy group, alkyl sulfate group, a chlorosulfonyloxy group, an alkyl sulfite group, a mono or dialkyl phosphate group or a nitrate group to form a compound of formula I.

The reaction is carried out in a suitable inert organic solvent such as methanol, ethanol, dimethylformamide or hexamethylphosphorus triamide, but other solvents may also be used; the reaction is carried out at a temperature about or above room temperature, up to the boiling point of the solvent used. In some cases, however, it may be advantageous to cool the reaction mixture to below room temperature, depending on the nature of the compound of formula III used. The reaction may also be conveniently carried out in the presence of an organic base such as pyridine, triethylamine, sodium methanolate or sodium ethanolate or in the presence of a suitable inorganic base such as an alkali metal hydroxide or an alkali metal carbonate or alkali metal hydrogen carbonate, other bases also can be used. The crude reaction products of formula I are filtered off, if desired after dilution with, for example, water, or extracted from the reaction mixture with a suitable solvent such as diethyl ether, ethyl acetate, dichloromethane or chloroform. The products are purified, for example, by recrystallization or by chromatography, if desired after conversion into salts with suitable inorganic or organic acids as defined above.

In another embodiment, an amine of formula II wherein R 1 is hydrogen is converted by reductive alkylation to a compound of formula I wherein r means hydrogen, by reaction with a carbonyl compound of formula IV

f-X-Q-A

IV

OHC - (CH 2) + 9 wherein X, Q, A and m have the meanings set forth above, followed by hydrogenation in the presence of a suitable catalyst or by reduction, for example, with an alkali metal borohydride, the hydrogenation or reduction, if desired, being carried out simultaneously with the reaction with the carbonyl compound, ie without isolation of the intermediate, a so-called 10 Schiff base to give the desired compound of formula I. The reaction is carried out in a suitable inert organic solvent such as methanol or ethanol, but other solvents can also be used. . The reaction is preferably carried out at room temperature, but in some cases it is advantageous to cool the reaction mixture to below room temperature, or to heat it to the boiling point of the solvent used, depending on the nature of the reactants of formula II and IV used. The isolation and purification of the products can be carried out as described above.

In a third embodiment, a compound of formula V is reacted

I - {CHifc-N— (0 «η - I V

S /

wherein R *, X, Q, A, n and m have the above meanings, are reacted with a compound of formula VI

We have n in which Y has the meanings given above to give the desired compound of formula I.

30 13 DK 170576 B1

The solvent used and the reaction conditions may be as described above for the alkylation of amines of formula II, but other solvents and / or reaction conditions may also be used, depending on the nature of the reacted compounds of formulas V and VI. In a fourth embodiment, a compound of formula VII is reacted

II I I - (CH2) rN- (CH2) s - 4χή VII

wherein R, n and m have the above meanings and X 'is O, reacted with a compound of formula VIII

Y-Q-A (VIII) wherein A, Q and Y have the meanings given above to give the desired compound of formula I.

The solvent used and the reaction conditions may be as described above for the alkylation of amines of formula II, but other solvents and / or reaction conditions may also be used, depending on the nature of the reacted compounds of formulas VII and VIII.

In addition, the acidic groups A can be prepared according to the following general reaction schemes: 14 DK 170576 B1 -CN- * - / 1

N

H

<Y

- COOR9-► —CONHOH

* - SO 3 H

diaz. _ © Θ -nh2-► o -n2z-► —so2ci-► - so2h ^ —so2nhr10 in which have the same meanings as R *.

The present compounds are to be used in pharmaceutical compositions useful in the treatment of the above-mentioned diseases.

The amount of a compound of formula I (hereinafter referred to as the active ingredient) required to achieve a therapeutic effect will, of course, vary both by the compound in question, the route of administration, and the subject undergoing treatment. An appropriate dose of a compound of formula I for a patient suffering from, for example, an inflammatory condition, as defined above, is 0.5 to 100 mg per day. The most preferred dose is 0.5 to 50 mg / kg body weight, e.g., 10 to 25 mg / kg, administered once or twice daily.

In the case of treatment or prophylactic treatment of inflammatory respiratory disorders, a suitable anti-asthmatic dose of a compound of formula I is 1 µg to 50 mg of the compound per day. The most preferred dose is 1 µg to 10 mg / kg body weight, for example from 1 µg to 5 mg / kg.

However, while it is possible to administer an active ingredient alone in the form of the completely untreated chemical, it is preferred to give it in the form of a pharmaceutical composition. Thus, the active ingredient is suitably from 0.1% to 100% of the weight of the composition. Dosage units of a preparation should preferably contain between 0.1 mg and 1 g of active ingredient. For topical administration, the active ingredient preferably comprises from 1 to 2% by weight of the composition, however the active ingredient may comprise up to 10% w / w. Nasal or buccal administration compositions (such self-powered powder dispensing preparations are described later) may contain 0.1 to 20% w / w, e.g. 2% w / w of the active ingredient.

By the term "dosage unit" is meant a unit, i.e. a single dose, which can be administered to a patient, which can be easily handled and packaged, remaining a physically and chemically stable unit dose and containing either the active material as such or a mixture thereof with solid or liquid pharmaceutical diluent. or carriers.

The compositions, for both veterinary and human medical use, of the present invention comprise an active ingredient in association with a pharmaceutically acceptable carrier thereof and optionally other therapeutic ingredient (s). The carriers must be "acceptable" in the sense that they are compatible with the other ingredients of the agent and not harmful to the patient.

The preparations include forms for oral, ocular, rectal, parenteral (including subcutaneous, intramuscular or intravenous), intra-articular, topical, nasal or buccal administration.

The compositions may conveniently be given in dosage units and may be prepared by any well-known method in the art of pharmacy. All methods include the step of bringing the active ingredient into contact with the carrier which consists of one or more adjuvants. Generally, the compositions are prepared by bringing the active ingredient into a uniform and close relationship with a liquid and finely divided carrier or both, and then, if necessary, processing the product thereof into the desired composition.

Compositions of the present invention suitable for oral administration may be: in the form of separate units such as capsules, letters, tablets or lozenges, each containing a predetermined amount of the active ingredient; in the form of a powder or granule; in the form of a solution or suspension in an aqueous or non-aqueous liquid; or in the form of an oil-in-water or water-in-oil emulsion. The active ingredient may also be administered in the form of a bolus, latewater or paste.

16 DK 170576 B1

A tablet may be prepared by beating or forming the active ingredient, if desired, with one or more excipients. Stripped tablets may be prepared by compressing in an appropriate machine the active ingredient in a free-flowing form, for example as a powder or granule, if desired mixed with a binder, lubricant, inert solvent or a surfactant or dispersant. Molded tablets are prepared by forming in a suitable machine a mixture of the active substance in powder form and a suitable carrier moistened with an inert liquid solvent.

Rectal administration preparations may be in the form of a suppository containing the active ingredient in a carrier such as cocoa butter, or in the form of an enamel.

Suitable preparations for parenteral administration may conveniently consist of a sterile, oily or aqueous preparation of the active substance which is preferably isotonic with the recipient's blood.

Compositions suitable for intra-articular administration may be in the form of a sterile weaning preparation of the active ingredient which may be in microcrystalline form, for example in the form of an aqueous microcrystalline suspension. Liposomal preparations or biodegradable polymeric systems can also be used to administer the active ingredient both intra-articularly or as an eye preparation.

Suitable topical formulations include liquid or semi-liquid preparations such as liniments, lotions, lubricants, oil-in-water or water-in-oil emulsions, e.g., creams, ointments or pastes; or solutions or suspensions, such as drops. For example, the active ingredient for the treatment of eyes may be in the form of aqueous eye drops, for example a 0.1-1.0% solution.

Suitable compositions for administration to the mouth, nose or sinuses include powders, propellant preparations (hereinafter also called self-propelled preparations) or spray preparations such as aerosols or nebulizers. The compositions, when dispersed, should preferably have a particle size of from 10 to 100 µm.

Such compositions are preferably in the form of a finely divided powder for pulmonary ingestion from a powder inhaler or self-powered powder dispensing preparations, wherein the active ingredient, such as a finely divided powder, may amount to up to 99.9% by weight (wt. In the case of self-propelled solutions and atomizing preparations, the effect can be achieved either by selecting a valve with the desired spray characteristics (e.g., capable of producing a spray). with the desired particle size) or by incorporating the active ingredient as a controlled particle size suspended powder, these self-propelled preparations may be either powder dispensing preparations or dispensing the active ingredient which drops a solution or suspension. .

Preferably, self-propelled powder dispensing compositions contain solid active ingredient particles and a liquid propellant having a boiling point below 18 ° C at atmospheric pressure. The liquid propellant may be any propellant suitable for medical use and may comprise one or more C 1-6 alkyl hydrocarbons or halogenated C 1-6 alkyl hydrocarbons or mixtures thereof; chlorinated and fluorinated C C-C ^ alkyl hydrocarbons are particularly preferred. Generally, the propellant is from 50 to 99.9% by weight of the composition, while the active ingredient is from 0.1 to 15% by weight, e.g. 2% by weight of the composition.

The pharmaceutically acceptable carrier in such self-propelled preparations may contain, in addition to the propellant, other ingredients, in particular a surfactant or solid diluent or both. Surfactants are desirable as they prevent clumping of the active ingredient particles and keep the active ingredient in suspension. Particularly valuable are liquid nonionic and solid anionic surfactants or mixtures thereof. Suitable liquid nonionic surfactants are esters and partial esters of fatty acids with aliphatic polyhydric alcohols, for example sorbitan monooleate and sorbitan trioleate, known commercially as "Span 80" and "Span 85", respectively. The liquid nonionic surfactant may comprise from 0.01 to 25% by weight of the composition, but preferably below 1% by weight of the composition. Suitable solid anionic surfactants include alkali metal, ammonium and amine salts of di-alkyl sulfosuccinates (wherein the alkyl groups have 4 to 12 carbon atoms). The solid anionic surfactants may comprise from 0.01 to 20% by weight of the composition, but preferably below 1% by weight of the composition. Solid diluents may advantageously be included in 30 self-propelled compositions, wherein the density of the active ingredient differs significantly from ^ Added by the translation; the original English text speaks of% w / w 18 DK 170576 B1 density of the propellant. These also help keep the active ingredient in suspension. The solid diluent is in the form of a fine powder and preferably has a particle size of the same order as the particles of the active ingredient. Suitable solid diluents include sodium chloride, sodium sulfate and various sugars.

A composition of the present invention may also be in the form of a self-propelled composition in which the active ingredient is present as such in suspension or solution. Such self-propelled compositions may comprise the active ingredient, propellant and auxiliary solvent, and advantageously an antioxidant stabilizer. The propellant is one or more of the aforementioned. The auxiliary solvents are selected according to their solubility in the propellant, their ability to dissolve the active ingredient, and to which have the lowest boiling point and at the same time have the above properties. Suitable auxiliary solvents are Cj-C og alkyl alcohols and ethers and mixtures thereof. The auxiliary solvent may comprise 5 to 40% by weight of the composition, but preferably less than 20% by weight of the composition. Antioxidant stabilizers can be incorporated into such solutions preparations to inhibit degradation of the active ingredient and are suitably alkali metal ascorbates or bisulfites. They are preferably present in an amount of up to 0.25% by weight of the composition.

Such self-propelled compositions may be prepared by any method known to those skilled in the art. For example, the active ingredient (either as particles, as defined above, as such or in suspension in a suitable liquid or in up to 20% by weight solution in an acceptable auxiliary solvent) is mixed with any other component of a pharmaceutically acceptable carrier. The resulting mixture is cooled, filled into a suitably cooled container, and the propellant is added in liquid form, after which the container is sealed. Alternatively, a self-propelled preparation may be prepared by mixing the active ingredient, either as particles as defined above or in a 2 to 20% by weight alcoholic or aqueous solution, with the other portions of the pharmaceutically acceptable carrier, other than the propellant; then the resulting mixture, optionally together with some propellant, is filled into a suitable container, and the propellant is injected under pressure into the container at room temperature through a valve which is part of the container and used to control the preparation discharge therefrom. If desired, the container may be purified by removing air from it at an appropriate stage during the preparation of the self-propelled preparation.

19 DK 170576 B1

A suitable container for a self-propelled preparation is provided with a manually operated valve and is made of aluminum, stainless steel or reinforced glass. The valve must, of course, have the desired atomization characteristics for a particle size as defined above. Advantageously, the valve is of a type which provides a predetermined amount of composition at each operation of the valve, e.g. 50 to 100 μΐ.

Compositions of the present invention may also be in the form of an aqueous or dilute alcoholic solution, preferably a sterile solution, of the active ingredient for use in a spray or atomizer wherein an accelerated flow of air is used to produce a fine mist consisting of small droplets of the solution. A buffer and a surfactant may also be included in such a composition which should further contain a preservative such as methyl hydroxybenzoate.

Further suitable nasal administration compositions include a fine powder having a particle size of from 10 to 100µ which is administered in the same way as snuff is ingested, i.e. by rapid inhalation through the nose of powder from a container held close to the nose.

In addition to the above ingredients, the compositions of the invention may contain one or more additives, such as diluents, buffers, flavors, binders, surfactants, thickeners, lubricants, preservatives, e.g., methyl hydroxybenzoate (including antioxidants), emulsifiers and the like.

The compositions may further contain other therapeutically active compounds commonly used in the treatment of the above pathological conditions, e.g., glycocorticoids, anti-histamines, platelet activating factor (PAF) antagonists, anti-cholinergic agents, methylxanthines, β-adrenergic agents, salicylates. , indomethacin, flufenamate, naproxen, timegadine, gold salts, penicillamine, serum cholesterol reducing agents, retinoids, zinc salts and salicylazosulfapyridine (Salazopyrin).

According to the invention, the subject compounds are administered to a patient suffering from any of the above pathological conditions in a daily dose (in adults) from 0.1 mg to 7000 mg, preferably from 35 to 3500 mg, and in the veterinary practice of corresponding to the daily doses from 0.5 to 100 mg / kg body weight.

The invention will be described in the following by means of a number of examples.

DK 170576 B1

Example 1 3-f2'-Ouinolylmethoxyvin N-f3 "-carboxymethoxybenzylaniline

To a solution of 2.5 g of 3- (2'-carboxymethoxy) aniline (10 mmol) in 100 ml of methanol is added 2.0 g of 3-formylphenoxyacetic acid and the mixture is stirred for one hour at room temperature. The precipitated 3- (2'-quinolylmethoxy) -N- (3 "-carboxymethoxybenzylidene) aniline is filtered off, washed with a small amount of methanol and with diethyl ether and air dried. It is then suspended in 200 ml of ethanol and 1.5 g of sodium boron. - hydride is added portionwise over stirring at room temperature over one hour, the resulting mixture is filtered using a filter aid and evaporated in vacuo.

The residue is treated with water and the resulting solution neutralized to pH

7.0 using dilute acetic acid. It is then extracted twice with ethyl acetate (about 150 ml) and the organic layer is separated, dried (MgSO4) and evaporated in vacuo to give the title compound which, after recrystallization from ethanol, has a melting point of 122-124 ° C. 1 21 DK 170576 B1

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Example 17 3 - [2'-Omnolylmethoxy] N- (4 "-F1 H-tetrazolylbenzyldaniline

A mixture of 0.75 g of 3- (2, -quinolylmethoxy) -N- (4 "-cyanobenzyl) aniline (2 3 mmol), 0.5 g of sodium azide, 0.2 g of ammonium chloride and 15 ml of dimethylformamide stir 5 The resulting mixture is gently poured, after cooling, into a mixture of ice and water, after which an excess of dilute acetic acid is added, precipitating the title compound, filtering off and dissolving in an equimolar amount of dilute potassium hydroxide. After evaporation in vacuo and re-evaporation several times with ethanol, the residue is treated with isopropanol to give the potassium salt of the title compound as a dihydrate having a melting point above 250 ° C.

Example 18 3 -C2 '-Ouinolylmethoxyvinyl-f31 H-tetrazolylbenzyl Daniline

Following the procedure of Example 17, but replacing 3- (2'-quin-15-olylmethoxy) -N- (4 "-cyanobenzyl) aniline with 3- (2'-quinolylmethoxy) -N- (3" -cyanobenzyl) ) aniline, the title compound is obtained as a hydrate having a melting point of 116-118 ° C.

Example 19 3--2'-Ouinolylmethoxyvin N - ('4' -C 1 H-tetrazolylV 3 -propyloxy) 20 benzyl Daniline

Following the procedure of Example 17, but replacing 3- (2'-quinolylmethoxy) -N- (4 "-cyanobenzyl) aniline with 3- (2'-quinolylmethoxy) -N- (4" -cyano (3- propyloxy (benzyl) aniline, phase the title compound as a dihydrate of the dihydrochloride having a melting point of 115-117 ° C.

25

Example 20 3- ('2'-Ouinolylmethoxy) N-[1,3-fluorobenzyl] N-f4' '- hydroxaminocarbonylbenzylaniline

A mixture of 2.4 g of 3- (2'-quinolylmethoxy) -N- (3 "-fluorobenzyl) -N- (4 '" - carbomethoxybenzyl) aniline (4.7 mmol), 1.4 g of hydroxylamine hydrochloride ( (20 mmol), 5 ml of 6.2 N potassium hydroxide and 25 ml of methanol are stirred at room temperature for about 48 hours.

The resulting solution is then acidified using 4N acetic acid, thereby precipitating the title compound as a hemihydrate having a melting point of 157-160 ° C.

Example 21 3-f 2'-Ouinolylmethoxyvin N-f 2 "hydroxaminocarbonylphenyl D-aniline

Following the procedure of Example 20, but replacing 3- (2'-quinol-ylmethoxy) -N- (3 "-fluorobenzyl) -N- (4-" - carbomethoxybenzyl) aniline with 3- (2'-quinol ylmethoxy) -N- (2 "-carbethoxyphenyl) aniline gives the title compound having a melting point of 184-187 ° C.

10

Example 22 4 - ((2,2-Quinolylmethoxy) -N-f2 "-carboxymethoxybenzyl) aniline

Following the procedure of Example 1, but replacing 3- (2'-quinolylmethoxy) aniline with 4- (2'-quinolylmethoxy) aniline and 3-formylphenoxyacetic acid with 2-formylphenoxyacetic acid, the title compound is obtained as a dihydrochloride, pentahydrate. operated with a melting point of 215-217 ° C.

Claims (5)

26 DK 170576 B1 5 * 1. Quinoline derivatives of the general formula I / V ^, I rX-Q-Λ III I - (OBj-N-tCH2Jg - I in which R * means hydrogen, straight or branched C1 -C6 alkyl or benzyl; n and m is the same or different and represents an integer from 0 to 1, provided that n is not 0 when A 10 is carboxy and X and Q are both a bond; X is a bond or O; Q is a bond or an equal or branched Cj-Cg alkyl; A means a carboxy, 1H-tetrazolyl, a sulfonic acid, a sulfamyl, a sulfamic acid or a hydroxamic acid group, and pharmaceutically acceptable non-toxic salts and, after administration, in vivo hydrolysable esters thereof 15 A compound according to claim 1, characterized in that -X-Q-A means a carboxy-C 1 -C 8 alkoxy or 1 H-tetrazolyl group. A salt according to claim 1, characterized in that the salt is selected from the group 20 consisting of salts formed with hydrochloric acid, hydrobromic acid, iodine hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, p-toluenesulfonic acid, methanesulfonic acid, formic acid, acetic acid, propionic acid and citric acid. maleic acid, and alkali metal salts and alkaline earth metal salts such as lithium, sodium, potassium, magnesium, and calcium salts, as well as salts with ammonia and C 1 -C 8 alkylamines, e.g., triethylamine, C 1 -C 8 alkanolamines, e.g. diethanolamine or triethanolamine, procaine, cycloalkylamines, e.g., dicyclohexylamine, benzylamines, e.g., N-methylbenzylamine, N-ethylbenzylamine, N-benzyl-P-phenethylamine, N, N '-dibenzylethylenediamine or dibenzylamine and heterocycline amine. ethylpiperidin. A compound according to claim 1, characterized by being selected from the group consisting of 3- (2'-quinolylmethoxy) -N- (3 "-carboxymethoxybenzyl) aniline; 3- (2, -quinolylmethoxy) -N- ( 2 "-carboxymethoxybenzyl) aniline; 3- (2'-quinolylmethoxy) -N- (4 "-carboxymethoxybenzyl) aniline; 3- (2'-quinolylmethoxy) -N- (4" - (1-carboxyethoxy) benzyl) aniline; 3- (2, -quinolylmethoxy) -N- (2 "-carboxy- (3-propyloxy) benzyl) -aniline; 3- (2'-quinolylmethoxy) -N- (4" - (1H-tetrazolyl) benzyl) aniline; 3- (2 '-quinolylmethoxy) -N- (3 "- (1H-tetrazolyl) benzyl) aniline; 3- (2, -quinolylmethoxy) -N- (4M- (1H-tetrazolyl) (3-propyloxy) benzyl) ) aniline, and 3- (2'-quinolylmethoxy) -N- (3 "-fluorobenzyl) -N- (4" - hydroxaminocarbonylbenzyl) aniline. A pharmaceutical composition, characterized by containing a compound according to any one of claims 1-4 alone or together with the necessary excipients. 20 Process for the preparation of a compound of formula I, characterized in that a) an amine of formula II 25 in 'V'S τ' IIJJ (CH 2) - N - Η 30 wherein and n have the meanings defined in claim 1 are reacted with a compound of formula III, wherein X, Q, A and m have the meanings defined in claim 1 and Y is capable of forming a compound of formula III. good leaving group such as chlorine, bromine or iodine, an alkyl or aryl sulfonyloxy group, alkyl sulfate group, a chlorosulfonyloxy group, an alkyl sulfite group, a mono or dialkyl phosphate group or a nitrate group to form a compound of formula I; or b) an amine of formula II, wherein R * is hydrogen, by reductive alkylation is converted to a compound of formula I wherein hydrogen means, by reaction 15 with a carbonyl compound of formula IV 4-xqa IV OHC-j 20 wherein X, Q, A and m have the above meanings, followed by hydrogenation in the presence of a suitable catalyst or by reduction, for example, with an alkali metal borohydride, the hydrogenation or reduction, if desired, being carried out simultaneously with the reaction with the carbonyl compound, i.e. without isolation of the intermediate, a so-called Schiff base, to give the desired compound of formula I; or c) a compound of formula V1? (/ \ Rx_Q_A H0'nx5S> ~ (ch 2) j N - (CH 2 m V wherein R, X, Q, A, n and m have the above meanings are reacted with a compound of formula Vj 1 ° IJ 1 VI \ ^^ N CH2Y wherein Y has the above meanings to give the desired compound of formula I; or d) a compound of formula VII p1 I. , Wherein - R 1, n and m have the meanings given above and X 1 is O, is reacted with a compound of formula VIII YQA (VIII) wherein A, Q and Y have the meanings given above to give the desired compound of formula I.